WO2021074279A1 - Spiro-fused tricyclic map4k1 inhibitors - Google Patents

Spiro-fused tricyclic map4k1 inhibitors Download PDF

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WO2021074279A1
WO2021074279A1 PCT/EP2020/079007 EP2020079007W WO2021074279A1 WO 2021074279 A1 WO2021074279 A1 WO 2021074279A1 EP 2020079007 W EP2020079007 W EP 2020079007W WO 2021074279 A1 WO2021074279 A1 WO 2021074279A1
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Prior art keywords
pyrrolo
rac
pyrrolidine
dihydrospiro
pyrazole
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PCT/EP2020/079007
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French (fr)
Inventor
Ulrich LÜCKING
Lars Wortmann
Jeffrey Stuart MOWAT
Lara Patricia KUHNKE
Judith GÜNTHER
Steffen Müller
Gabriele Leder
Rafael CARRETERO
Anders Roland FRIBERG
Detlef STÖCKIGT
Ulf Bömer
Rienk Offringa
Peng Cheng
Xuewei Wang
Yuanyuan YAN
Julien LEFRANC
Louise EAGLING
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Bayer Aktiengesellschaft
Deutsches Krebsforschungszentrum
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Publication of WO2021074279A1 publication Critical patent/WO2021074279A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • the present invention relates to MAP4K1 inhibitors, to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combination with other active ingredients.
  • the present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.
  • cancer cell commonly can be recognized by the adaptive immune system, the response generated is evidently not capable of eliminating the tumor. A major reason for this is the presence of immunosuppressive mechanisms in the tumor microenvironment.
  • inhibitors of T-cell immune checkpoint such as CTLA-4, PD-1 or PD-L1 were recently shown to result in a remarkable clinical efficacy in subsets of cancer patients.
  • MAP4K1 also known as hematopoietic progenitor kinase 1 (HPK1).
  • HPK1 hematopoietic progenitor kinase 1
  • MAP4K1 (GeneID11184) is a serine/threonine kinase and member of the Germinal Center Kinase family. In the adult organism MAP4K1 expression is restricted to hematopoietic cell types.
  • the MAP4K1 protein consist of a N-terminal kinase domain, followed by a proline-rich domain that can interact with adaptor molecules through SH2 and SH3 domains, and a C-terminal citron homology domain of which the exact function remains to be identified.
  • MAP4K1 is capable of binding to a diversity of adaptors in hematopoietic cells, including those involved in T-cell receptor (TCR), B-cell receptor (BCR) and cytokine signaling (Hu et al., Genes Dev.1996 Sep 15;10(18):2251-64, 2.; Ling et al.,.
  • MAP4K1 has been studied in greatest detail in the context of TCR signaling. Upon TCR stimulation, MAP4K1 is phosphorylated on tyrosine 381 (Y-381; Y-379 in mouse) (Di Bartolo et al., J Exp Med. 2007 Mar 19;204(3):681-91).
  • MAP4K1 is recruited to the TCR-signaling complex where it induces dissociation of this complex through its serine/threonine kinase function.
  • MAP4K1 phosphorylates the SLP-76 adaptor protein at Serine-376, resulting in downregulation of AP-1 and Erk2 pathways.
  • MAPK1 acts as a negative feedback on TCR-signaling (Liou et al., Immunity. 2000 Apr;12(4):399-408; Lasserre et al., J Cell Biol. 2011 Nov 28;195(5):839-53.).
  • MAP4K1 can be triggered to suppress T cell function by prostaglandin E2 (PGE2), and possibly also by transforming growth factor beta (TGF-beta), factors that are commonly found in the tumor microenvironment.
  • PGE2 prostaglandin E2
  • TGF-beta transforming growth factor beta
  • MAP4K1 activation by these mediators involves protein kinase A (PKA)-dependent phosphorylation of Serine 171 (S-171; also in mouse) (Alzabin et al., Cancer Immunol Immunother. 2010 Mar; 59(3) :419-29; Sawasdikosol et al., J Biol Chem. 2007 Nov 30;282(48):34
  • MAP4K1-deficient mice show an apparent normal phenotype, are fertile and exhibit normal lymphocyte development.
  • MAP4K1-/- T-cells are resistant to PGE2-mediated suppression of T cell proliferation, suppression of IL-2 production and induction of apoptosis (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29).
  • MAP4K1-/- mice are much more resistant to tumorigenesis by PGE2-producing Lewis lung carcinoma than wild type mice, which correlated with increased T-lymphocyte infiltration in the tumor areas.
  • the crucial role of T-cells in tumor rejection was supported by experiments in which MAP4K1-/- T-cells adoptively transferred into T-cell-deficient mice were able to eradicate tumors more efficiently than wild-type T-cells (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29).
  • MAP4K1 also regulates the stimulation and activation of dendritic cells.
  • MAP4K1 deficient Bone marrow derived cells express after maturation and stimulation higher level of costimulatory molecules and produce more proinflammatory cytokines.
  • HPK1 inhibitors and methods for their use in treating, preventing or ameliorating diseases or disorders associated with HPK1 such as cancer are described. These compounds differ from the instant compounds in their chemical structure.
  • CN109721620A HPK1 inhibitors and their uses are described. These compounds differ from the instant compounds in their chemical structure.
  • WO2019090198A1 compounds used to modulate or inhibit the activity of HPK1 and methods for their use in treatment of viral infections and proliferative disorders, such as cancer are described. These compounds differ from the instant compounds in their chemical structure.
  • MAP4K1 (HPK1) inhibitors and methods for their use in diseases including hyperproliferative diseases, diseases of immune system dysfunction, intlammatory disorders, neurological diseases, and cardiovascular diseases are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and methods for their use in the treatment of cancer are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and use of such compounds in treating HPK1-dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and use of such compounds in treating HPK1-dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and use of such compounds in treating HPK1-dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 respectively inhibitors and methods of their use in cancer treatment are described.
  • the application concerns thieno-pyridinones that can be used in anti-cancer therapy.
  • thieno-pyridinones that can be used in anti-cancer therapy.
  • WO 2016/195776 inhibitors and methods for leukemia cancer and diabetes treatment dependent on inhibition the interaction of menin with of MLL1, MLL2 and MLL-fusion oncoproteins are described. These compounds differ from the instant compounds in their chemical structure.
  • C-MET modulators and their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • Rho kinase inhibitors and their use in cardiovascular and cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • WO 2015/089479 several inhibitors are described that show inhibition of several kinases (e.g., BTK, HCK, TAK1 and HPK1). These compounds differ from the instant compounds in their chemical structure.
  • BTK inhibitors and methods of their use in cancer treatment are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • WO 2011/090738 Type II RAF kinase inhibitors and their use in various diseases are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • CN102086211 and WO2006116713 protein kinase inhibitors and their use in prophylaxis and treatment of diseases including cancer are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • WO 2010/045095 protein tyrosin kinase modulators and their use in the treatment of hyperproliferative disorders are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • WO 2008/089307 compounds and methods of their use in the treatment of pain, inflammation and cancer are described.
  • NPY receptors compositions and methods of the treatment of physiological disorders associated with an excess of neuropeptide Y are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death are described. It would therefore be desirable to provide novel MAP4K1 inhibitors having prophylactic and therapeutic properties. Accordingly, it is an object of the present invention to provide compounds and pharmaceutical compositions comprising these compounds used for prophylactic and therapeutic applications for hyperproliferative disorders, in particular for cancer, respectively tumour disorders, and conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients.
  • a further object of the present invention is to provide compounds and pharmaceutical compositions comprising these compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.
  • the compounds according to the invention inhibit the MAP4K1 protein and inhibit the growth of cancer cells. Accordingly, they provide novel structures for the therapy of human and animal disorders, in particular of cancers.
  • the compounds of formula (I) are particularly suitable for a large number of prophylactic and therapeutic applications, in particular for hyperproliferative disorders, for tumour disorders and as proteine inhibitors and further for viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for male fertility control. Further, it covers their use in combination with other anti cancer medications such as immunotherapeutics, targeted anti cancer agents, radiation or chemotherapy.
  • DEFINITIONS In case an asterix is used in a formula, like for instance in *-A-B or *-A-, this asterix indicates the bond towards the core of the compound.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or ... atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.
  • the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”.
  • groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified.
  • the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
  • comprising when used in the specification includes “consisting of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.
  • the terms as mentioned in the present text have the following meanings:
  • the term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • C 1 -C 6 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or
  • said group has 1, 2, 3 or 4 carbon atoms (“C 1 -C 4 -alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C 1 -C 4 -alkyl e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C 1 -C 6 -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is defined supra, and in which 1, 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g.
  • C 1 -C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said C 1 -C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.
  • perfluorinated alkyl radicals which are named as “perfluoro-C 1 -C x -alkyl-“ wherein x is the maximum number of carbon atoms such as trifluoromethyl or 2,2,2- trifluoroethyl.
  • C 1 -C 6 -cyanoalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 6 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a cyano group.
  • C 1 -C 6 -alkoxy means a linear or branched, saturated, monovalent group of formula (C 1 -C 6 -alkyl)-O-, in which the term “C 1 -C 6 -alkyl” is as defined supra, e.g.
  • C 1 -C 6 -haloalkoxy means a linear or branched, saturated, monovalent C 1 -C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said C 1 -C 6 -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • perfluorinated alkyl radicals which are named as “perfluoro-C 1 -C x - alkoxy-“ wherein x is the maximum number of carbon atoms such as trifluoromethoxy and 2,2,2-trifluoroethoxy radicals.
  • C 1 -C 6 -cyanoalkoxy means a linear or branched, saturated, monovalent C 1 -C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a cyano group.
  • Mono-(C 1 -C 4 )-alkylamino in the context of the invention means an amino group with one straight-chain or branched alkyl substituent which contains 1, 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino, for example.
  • Di-(C 1 -C 4 )-alkylamino in the context of the invention means an amino group with two identical or different straight-chain or branched alkyl substituents which each contain 1, 2, 3 or 4 carbon atoms, such as: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n- propylamino, N-isopropyl-N-methylamino, N-isopropyl-N-n-propylamino, N,N-diisopropylamino, N-n-butyl-N-methylamino, and N-tert-butyl-N-methylamino, for example.
  • C 3 -C 8 -cycloalkyl means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms (“C 3 -C 8 -cycloalkyl”).
  • Said C 3 -C 8 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl.
  • C 3 -C 8 -cycloalkoxy means a saturated, monovalent, mono- or bicyclic group of formula (C 3 -C 8 -cycloalkyl)-O-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “C 3 -C 8 -cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.
  • heterocycloalkyl and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated or unsaturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-
  • 4- to 6-membered heterocycloalkyl means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S.
  • “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O.
  • Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo- [2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi- cyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicy
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • C 1 -C 6 as used in the present text, e.g. in the context of the definition of “C 1 -C 6 -alkyl”, “C 1 -C 6 -haloalkyl”, “C 1 -C 6 -hydroxyalkyl”, “C 1 -C 6 -alkoxy” or “C 1 -C 6 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 3 -C 8 as used in the present text, e.g.
  • C 3 -C 8 -cycloalkyl in the context of the definition of “C 3 -C 8 -cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompasses each value and sub-range within said range.
  • C 1 -C 6 encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
  • C 2 -C 6 encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C
  • the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropy
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired.
  • one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Preferred isomers are those which produce the more desirable biological activity.
  • These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g.
  • (R)- or (S)- isomers in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio. In the case of stoichiometric solvates, e.g.
  • a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the invention further includes all possible crystallized and polymorphic forms of the inventive compounds, whereby the polymorphs are existing either as a single polymorph form or are existing as a mixture of several polymorphs in all concentrations.
  • the invention further includes all possible cyclodextrin clathrates, i.e alpha-, beta-, or gamma- cyclodextrins, hydroxypropyl-beta-cyclodextrins, methylbetacyclodextrins.
  • H Of selected interest are those compounds defined under A) (page 6) or B (page 32) wherein Y is hydrogen or -Cl.
  • R 1 has the meaning as R 1 as defined under A) (page 6) or B (page 25).
  • a further aspect of this invention is related to compounds of formula (1a) as follows: 1.
  • R 2a is a 9-10 membered bicyclic heteroaryl in which A is selected from the group consisting of a bond, and -C(R 4a )-;
  • D, E and G are independently of each other selected from the group consisting of -C(R 4a )- and -N(R 4a )-;
  • each R 4a is independently of each other selected from the group consisting of a bond, hydrogen, halogen, C 1-4 -alkyl, -CN, -O-CH 3 , and -C(CH 3 ) 2 -phenyl
  • a pharmaceutical composition comprising a compound of general formula (1a) according to any one of claims 1 to 7 and one or more pharmaceutically acceptable excipients. 10.
  • a pharmaceutical combination comprising: ⁇ one or more first active ingredients, in particular compounds of general formula (1a) according to any one of claims 1 to 7, and ⁇ one or more further active ingredients, in particular anti-hyperproliferative agents.
  • R 6b is selected from the group consisting of ⁇ H and ⁇ CH 3 ;
  • R 7b is selected from the group consisting of ⁇ CH 3 , ⁇ CH 2 CH 3 , ⁇ COOCH 2 CH 3 , 1-methyl- 1H-pyrazol-4-yl, and 3,5-dimethyl-1,2-oxazol-4-yl;
  • R 8b is selected from the group consisting of ⁇ CH 3 , cyclopropyl, ⁇ CH(CH 3 ) 2 , ⁇ NHCH 2 CH 3 , and ⁇ N(CH 3 ) 2 ;
  • R 9b is selected from the group consisting of -CO-, -NHCS-, -CH 2 NHCO-, -CO-NH- and -CO-O-;
  • R 10b is selected from the group consisting of ⁇ CH 2 ⁇ and ⁇ CH 2 CH 2 ⁇ ;
  • R 11b is selected from the group consisting of ⁇ N(CH 3 ) 2 , ⁇ NHCH 2 CH
  • R is selected from the group consisting of H and OCH 3 ;
  • R 16b is selected from the group consisting of ⁇ H, ⁇ CH 3 , ⁇ OCH 3 , and cyclopropyl;
  • R 17b is selected from the group consisting of ⁇ CH 2 ⁇ and
  • R 18b is selected from the group consisting of ⁇ CO ⁇ , ⁇ CH 2 NHCO ⁇ , and -CO-CH 2 - and - CO-NH-;
  • R 19b is selected from the group consisting of ⁇ H, ⁇ CH 3 , ⁇ CH 2 CH 3 , ⁇ CN, cyclopropyl, ⁇ CH(CH 3 ) 2 , cyclobutyl, ⁇ CF 2 R 26b , 4-cyano-1,4-dihydropyridazin-4-yl, and
  • R 20b is selected from the group consisting of ⁇ CH 2 CH 2 CH 2 ⁇ and ⁇ CH 2 OCH 2 CH 2 ⁇ ;
  • R 21b is selected from the
  • the compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted.
  • MAP4K1 diseases, preferably cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, in humans and animals.
  • disorders and conditions particularly suitable for treatment with an MAP4K1 inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • ovarian cancer include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
  • cervical cancer examples include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Examples of esophageal cancer include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma.
  • Examples of gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
  • Examples of pancreatic cancer include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • kidney cancer include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
  • kidney cancer include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
  • bladder cancer include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma,
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
  • chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, 4.
  • the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
  • the compounds of general formula (I) of the present invention are used in combination with radiation: i.e.
  • the present invention also provides a method of killing a tumor, wherein conventional radiation therapy is employed previous to administering one or more of the compounds of the present invention.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with one or more compounds of general formula (I) of the present invention
  • the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with: 131 I-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharain, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacit
  • the compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD-1/-L1 axis antagonists.
  • immune checkpoint inhibitors e.g. aPD-1/-L1 axis antagonists.
  • PD-1 along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation.
  • MAP4K1 suppresses immune cell function.
  • PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells. Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev. Immunol.26:677).
  • the present invention covers combinations comprising one or more of the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, and one or more immune checkpoint inhibitors.
  • the immune checkpoint inhibitor is a aPD-1/-L1 axis antagonist.
  • a further use of the compounds of the invention is the combination with chimeric antigen receptor T cells (CAR-T cells) such as Axicabtagen-Ciloleucel or Tisagenlecleucel.
  • the activity of CAR-T cells can be suppressed by the tumor micro environment (TME), which supposedly can be overcome by MAP4K1 inhibition.
  • TAE tumor micro environment
  • the present invention covers compounds of general formula (I), as described herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the expansion of T cells including CAR-T cells, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes ex-vivo.
  • the present invention also relates to the use of the compounds according to the invention for the expansion of T cells, including CAR-T cell, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes, ex-vivo.
  • the present invention also comprises an ex-vivo method for the expansion of T cells, including CAR-T cells, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes, contacting said T cells with compounds according to the invention.
  • the inventive compounds can also be used as a therapeutic in a variety of other disorders wherein MAP4K1 is involved such as, cardiovascular and lung diseases.
  • the compounds according to the invention are suitable for the treatment and/or prophylaxis in particular of cardiovascular, inflammatory and fibrotic disorders and of renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure. Accordingly, the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
  • renal insufficiency comprises both acute and chronic manifestations of renal insufficiency, and also underlying or related renal disorders such as diabetic and non-diabetic nephropathies, hypertensive nephropathies, ischaemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritides; minimal change glomerulonephritis (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membrane-proliferative glomerulonephritis; crescentic glomerulonephritis; mesangioproliferative glomerulonephritis (IgA nephritis, Berger's disease); post-infectious glomerulonephritis; secondary
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
  • the compounds according to the invention are further suitable for the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inappropriate ADH secretion (SIADH). Furthermore, the compounds according to the invention are also suitable for the treatment and/or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, for example atrioventricular blocks degrees I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV-nodal re-entry ta
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left-heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic-obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic-obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • CF
  • the compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer’s disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick ⁇ s syndrome, Parkinson’s disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld- Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff’s psychosis.
  • ALS amy
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of central nervous system disorders such as states of anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances.
  • the compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma.
  • the compounds according to the invention can likewise be used for controlling states of pain and tinnitus.
  • the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for treatment and/or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammations
  • UC chronic intestinal inflammations
  • pancreatitis peritonitis
  • rheumatoid disorders inflammatory skin disorders and inflammatory eye disorders.
  • the compounds according to the invention can also be used for treatment and/or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
  • fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • the compounds according to the invention are also suitable for controlling postoperative scarring, for example as a result of glaucoma operations.
  • the compounds according to the invention can also be used cosmetically for ageing and keratinized skin.
  • the compounds according to the invention are suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.
  • the present invention further provides the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
  • the present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.
  • the present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
  • the present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld- Jakob.
  • inventive compounds can also be used to treat or to prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women.
  • Compounds of the present invention can be utilized to inhibit, block, reduce or decrease MAP4K1 activation by exogenous and/or endogenous ligands for the reduction of tumour growth and the modulation of dysregulated immune responses e.g.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
  • the present invention also provides methods of treating a variety of other disorders wherein MAP4K1 is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination for infection & cancer, viral infections, obesity and diet- induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids.
  • treating or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liquid and solid tumours.
  • the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their activity as MAP4K1 inhibitors.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the use of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • a pharmaceutical composition preferably a medicament
  • the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • a compound of general formula (I) as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a compound of general formula (I) as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at
  • the compounds according to the invention can have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • a suitable manner such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear- rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal administration
  • compositions according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, ⁇ fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )), ⁇ ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), ⁇ bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), ⁇ solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols,
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signalinggeneric name disorders, particularly liquid and solid tumours.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • EXPERIMENTAL SECTION NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1 H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of title compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the title compounds (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the title compounds by known methods can isolate the peaks of title compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H-NMR interpretation.
  • Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. Table 1: Abbreviations ACN acetonitrile aq.
  • Example h hour(s) FCS fetal calf serum HATU N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]- N-methylmethanaminium hexafluorophosphate HMDS Hexamethyldisilazane IFNg Interferon gamma LiHMDS lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide LPS lipopolysaccharide MeOH methanol MCPBA 3-chloroperbenzoic acid mL milliliter ⁇ L microliter min.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil ® or KP-NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate, DCM/methanol, or DCM/ethanol.
  • chromatography particularly flash column chromatography
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g.
  • any of the substituents in particular R 1 , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b , which are as defined in formula (Ia) supra, can be achieved before and/or after the exemplified transformations.
  • modifications can be, for example, the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exemplified by but not limited to e.g. Buchwald, Suzuki, Sonogashira and Ullmann coupling, ester saponifications, amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art.
  • Scheme 1 Route for the preparation of building blocks of general formula 8 and 10, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), PG 2 represents a suitable alcohol protecting group (e.g. TBDMS), X 1 represents a direct bond or –CH 2 -, Z 1 represents a methyl group or a tert-butyl group, R 1 has the meaning as given for general formula (I).
  • Suitable starting materials 1, e.g. 1-tert-butyl 3-methyl pyrrolidine-1,3-dicarboxylate (CAS No: 122684- 33-7) are commercially available.
  • Step 1 ⁇ 3 (Scheme 1) Alkylation
  • pyrrolidine derivative 1 can be alkylated using an alkylbromide or alkyliodide of formula 2 to give the desired product 3.
  • the 1-tert-butyl 3-methyl pyrrolidine-1,3-dicarboxylate 1 can be alkylated using (2- bromoethoxy)(tert-butyl)dimethylsilane 2 in an organic solvent such as THF in the presence of a base such as LiHMDS or LDA.
  • Step 3 ⁇ 4 (Scheme 1) ⁇ -Keto ester formation Methylester 2 is reacted with a methyl acetate or tert-butyl acetate to give ⁇ -keto esters of the general formula 4.
  • the reaction is performed in the presence of a base like LiHMDS or LDA in an organic solvent like THF at a temperature range between -78°C and room temperature.
  • Step 4 ⁇ 5 (Scheme 1) Pyrazol formation ⁇ -Keto esters of formula 4 can be converted with hydrazine to the corresponding pyrazole derivatives of formula 5.
  • the reaction is performed in an organic solvent like ethanol at a temperature between -20°C and the boiling point of the selected solvent.
  • Step 5 ⁇ 6 (Scheme 1) Deprotection of PG 2
  • the protecting group PG 2 of pyrazoles of formula 5 can be cleaved to give an alcohol of formula 6.
  • the cleavage of suitable alcohol protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • PG2 in compounds of formula 5 is TBDMS
  • cleavage can be achieved using e.g. HCl in an organic solvent such as methanol or TBAF in an organic solvent such as THF.
  • Step 6 ⁇ 7 Ring closure
  • Alcohols of formula 6 can be converted to spiro compounds of formula 7 by ring closing reactions.
  • alcohols of formula 6 can be reacted with mesylchloride and DIEA in an organic solvent like DCM to give the corresponding mesylate, which is then reacted to give spiro compounds of formula 7, e.g. in the presence of a base like NaOH using a solvent mixture like methanol / water.
  • ring closure can be achieved using Mitsunobu conditions known to the skilled person.
  • Step 7 ⁇ 8 Spiro compounds of formula 7 can be converted to triflates of formula 7.
  • the reaction is performed using Tf 2 O in the presence of a base like DIEA in an organic solvent like DCM at a temperature range between -78°C and room temperature.
  • Step 8 ⁇ 9 (Scheme 1) Deprotection of P1 2
  • the protecting group PG 1 of spiro compounds of formula 8 can be cleaved to give amines of formula 9.
  • the cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • Step 9 ⁇ 10 Amine decoration Amines of formula 9 can be functionalized with a broad variety of substituents to give compounds of formula 10.
  • secondary amines of formula 9 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 10. All these transformations are known to the skilled person.
  • Step 1 (Scheme 1) C-C cross coupling reaction Compounds of general formula 10 can be reacted with a boronic acid derivative R 2 -B(OR) 2 to give a compound of formula 13.
  • the coupling reaction is catalyzed by palladium catalysts, e.g.
  • Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh 3 ) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (ll) [Pd(PPh 3 ) CI ], palladium (ll) acetate and triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride pre
  • the reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • Step 8 ⁇ 11 (Scheme 1) C-C cross coupling reaction
  • Compounds of general formula 8 can be reacted with a boronic acid derivative R 2 -B(OR) 2 to give a compound of formula 11.
  • the coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh 3 ) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (ll) [Pd(PPh 3 ) CI ], palladium (ll) acetate and triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]pal
  • the reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • Step 11 ⁇ 12 (Scheme 1) Deprotection of P1 2
  • the protecting group PG 1 of spiro compounds of formula 11 can be cleaved to give amines of formula 12.
  • the cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • PG2 in compounds of formula 12 is BOC
  • cleavage can be achieved using e.g. TFA in an organic solvent such as DCM.
  • Step 12 ⁇ 13 Scheme 1
  • Amine decoration Amines of formula 12 can be functionalized with a broad variety of substituents to give compounds of formula 13.
  • secondary amines of formula 13 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 11. All these tranformations are known to the skilled person.
  • Scheme 2 Route for the preparation of compounds of general formula 22, 23 and 24, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), PG 2 represents a suitable pyrazole protecting group (e.g. SEM), R represents a lower alkyl group, R 1 have the meaning as given for general formula (I).
  • Suitable starting materials 14 and 15 are commercially available or described in the literature.
  • Step 14 + 15 ⁇ 16 (Scheme 2)
  • Pyrazole addition to the carbonyl group Ketones of the general formula 15 and pyrazoles of the general formula 14 can be converted to compounds of the general formula 16. The conversion is known to the person skilled in the art.
  • Step 1 Protection with PG 2
  • Compounds of the general formula 16 can be converted to compounds of the general formula 17 using a suitable protecting group to protect the pyrazole NH.
  • protecting groups for pyrazoles are known to the skilled person (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • PG2 in compounds of formula 17 is SEM, then 2-(trimethylsilyl)ethoxymethylchloride, a base such as sodium hydride in an organic solvent such as THF can be used.
  • Step 17 ⁇ 18 Alkylation of the alcohol Alcohols of the general formula 17 can be converted to compounds of the general formula 18 in an alkylation reaction known to the skilled person.
  • an alkylation reaction known to the skilled person.
  • bromo ethyl acetate, a base, such as sodium hydride in an organic solvent such as dioxane at elevated temperature can be used.
  • Step 18 ⁇ 19 Deprotection of PG 2
  • the protecting group PG 2 of pyrazole compounds of general formula 18 can be cleaved to give compounds of formula 19.
  • the cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W.
  • hydride reducing agents known to the skilled person.
  • lithium borohydride in an organic solvent, such as THF can be used.
  • Step 2 (Scheme 2) Mitsunobu reaction Compounds of the general formula 20 can be converted to the corresponding morpholine derivatives of the general formula 21 using Mitsunobu conditions known to the skilled person.
  • Step 21 ⁇ 22 (Scheme 2) Deprotection of PG 1
  • the protecting group PG 1 of spiro compounds of formula 21 can be cleaved to give amines of formula 22.
  • the cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • Step 2 3(Scheme 2) Amine decoration Amines of formula 22 can be functionalized with a broad variety of substituents to give compounds of formula 23.
  • secondary amines of formula 22 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 23. All these transformations are known to the skilled person.
  • Step 2 4(Scheme 2) C-C cross coupling reaction Halogen compounds of general formula 23 can be reacted with a boronic acid derivative R 2 - B(OR) 2 to give a compound of formula 24.
  • the coupling reaction is catalyzed by palladium catalysts, e.g.
  • Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh 3 ) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (ll) [Pd(PPh 3 ) CI ], palladium (ll) acetate and triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride
  • the reaction is preferably carried out in a mixture of a solvent like 1,2- dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • Method 2 Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 ⁇ m, 50x2.1mm; Eluent A: water + 0.05 % formic acid (99%); Eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0-1.7 2-90% B, 1.7-2.0 90% B; flow 1.2 ml/min; temperature: 60°C; DAD scan: 190- 400 nm.
  • Method 3 Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2 vol % aq.
  • Example 1.00 (rac)-tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate
  • a mixture of (rac)-tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate 200 mg, 0.49 mmol, see INT-6
  • quinolin-3-ylboronic acid (252 mg, 1.46 mmol)
  • XPhos Pd G2 (57 mg, 0.07 mmol) in dioxane (16 mL)
  • an aqueous K 3 PO 4 solution 0.5 M, 2.9 mL, 1.46 mmol
  • Example 3.00 (rac)-tert-butyl -2'-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
  • a solution of sodium hydroxide (500 mg, 12.5 mmol) in MeOH (10 mL) was added to a solution of (rac)-tert-butyl -2'-[2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (70 mg, 0.13 mmol, see INT-8) in THF (10 mL) and the mixture was stirred at room temperature overnight.
  • Example 6.00 (rac)-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide N,N-Diisopropylethylamine (0.180 mL; 1.03 mmol) was added to a suspension of crude (rac)- 2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (200 mg; INT-11) in DCM (9.8 mL) at 0°C.
  • Example 6.29 Alternative synthesis approach of Example 6.22 ((rac)-2-(3-chloro-1H-pyrrolo[2,3- b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide), also providing Example 6.31 (rac)-3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide N,N-Diisopropylethylamine (3.66 mL; 21.0 mmol) was added to a suspension of a crude mixture of (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-y
  • Example 6.32 (rac)-3'-chloro-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • the compound was prepared in analogy to example 6.31 using crude (rac)-3'-chloro-2'-(3- methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroactetate (see INT-15) and isocyanatoethane.
  • Example 7.00 (rac)-N-ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • a solution of boron tribromide in DCM (1M, 0.7 mL, 0.7 mmol) was added to a solution of (rac)- N-ethyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (Example 6.21, 50 mg, 0.13 mmol) in DCM (2.6 mL) at 0°C.
  • Example 8.00 (rac)-(Morpholin-4-yl)[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone Morpholine-4-carbonyl chloride (39 mg; 0.26 mmol) was added to a mixture of crude (rac)-2'- (quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11) and N,N-diisopropylethylamine (0.06 mL; 0.34 mmol) in toluene (1.0 mL) at room temperature.
  • Example 9.00 (rac)-2-ethyl-1-[2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]butan-1-one
  • Example 10.00 (rac)-1-(methanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] Under argon, N,N-diisopropylethylamine (0.09 mL; 0.50 mmol) was added to a suspension of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11) in DCM (0.9 mL) at 0°C.
  • Example 11.00 (rac)-1-[(1H-imidazol-2-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]
  • Acetic acid (0.007 ml, 0.12 mmol) and sodium triacetoxyborohydride (36 mg; 0.17 mmol) were added to a mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] trifluoroacetate (100 mg) (see INT-11) and 1H-imidazole-2- carbaldehyde (11 mg, 0.11 mmol) in THF (1.7 mL) at room temperature.
  • Example 12.00 (rac)-1-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]
  • Example 13.00 (rac)-2-methyl-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-2-ol 2,2-Dimethyloxirane (37 mg, 0.52 mmol) was added to a mixture of crude (rac)-2'-(quinolin-3- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT- 11) and N,N-diisopropylethylamine (0.9 mL; 0.52 mmol) in THF (1.0 mL) at room temperature.
  • Example 14.00 (rac)-N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbothioamide 2-isothiocyanato-2-methylpropane (20 mg, 0.17 mmol) was added to a mixture of crude (rac)- 2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11) and N,N-diisopropylethylamine (0.9 mL; 0.52 mmol) in DCM (2.0 mL) at 0 °C.
  • Example 15.00 (rac)-1-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]
  • a solution of lithium bis(trimethylsilyl)amide in THF (1M, 0.59 mL) and 3-bromopyridine (54 mg, 0.34 mmol) were added to a mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11), Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) (13 mg, 0.017
  • Example 17.00 (rac)-3-(ethylamino)-4-[-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]cyclobut-3-ene-1,2-dione
  • a solution of sodium hydroxide (900 mg, 22.5 mmol) in MeOH (18 mL) was added to a solution of (rac)-tert-butyl 2'- ⁇ 1-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (190 mg, 0.31 mmol) (see INT-18) in THF (18 mL) and the mixture was stirred for 2 hours at room temperature.
  • Example 20 was prepared in analogy to Example 19 using (rac)-tert-butyl 2'- ⁇ 3-(3-cyano-4- isopropoxyphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (see INT-21).
  • Intermediate INT-23 was prepared in analogy to Intermediate INT-20 using 5-bromo-3-iodo-1- [(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine and 3-cyano-4-isoprpoxyphenylboronic acid.
  • Examples 21.00 and 21.01 tert-butyl -2'- ⁇ 3-[4-(S-methanesulfonimidoyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (Example 21.00, mixture of 4 stereoisomers) and tert-butyl -2'-(3- ⁇ 4-[N-(methoxycarbonyl)-S- methylsulfonimidoyl]phenyl ⁇ -1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (Example 21.01, mixture of 4 stereoisomers) Examples 21.00 and 21.01 were
  • Example 21.01 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.409 (9.28), 1.448 (7.60), 2.076 (0.64), 2.090 (0.78), 2.119 (0.42), 2.518 (3.79), 2.523 (2.53), 2.581 (0.99), 3.459 (3.30), 3.502 (12.02), 3.512 (16.00), 3.558 (0.61), 3.572 (0.46), 4.219 (0.61), 4.239 (1.06), 4.246 (1.10), 4.264 (0.64), 6.658 (1.01), 6.680 (1.18), 7.984 (2.03), 8.007 (4.26), 8.041 (4.35), 8.063 (1.90), 8.147 (1.82), 8.153 (1.79), 8.609 (2.08), 8.614 (2.24), 8.751 (2.86), 8.755 (2.74), 12.246 (1.04).
  • Intermediate INT-26 was prepared in analogy to Intermediate INT-22 using 5-bromo-3-iodo-1- [(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine and ethyl ⁇ methyl(oxido)[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- ⁇ 6 -sulfanylidene ⁇ carbamate.
  • Example 22.00 (rac)-tert-butyl -2'-[3-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
  • Example 22.00 was prepared in analogy to Example 20.00 using (rac)-tert-butyl 2'- ⁇ 3- (dimethylphosphoryl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'-dihydro- 1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (see INT-27).
  • Intermdiate INT-32 (rac)-tert-butyl 3-(3- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ propyl)-3-(3-hydroxy-1H-pyrazol-5- yl)pyrrolidine-1-carboxylate
  • (rac)-tert-butyl 3-(3- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ propyl)-3-(3-methoxy- 3-oxopropanoyl)pyrrolidine-1-carboxylate 950 mg, 2.14 mmol
  • INT-31 hydrous ethanol (1 mL) was added hydrazine hydrate (0.31 mL).
  • Example 23.00 was prepared in analogy to Example 1.0 using (rac)-tert-butyl 2- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate (see INT-35) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinoline.
  • Example 24.00 (rac)-N-ethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • Example 24.00 was prepared in analogy to Example 6.00 using crude (rac)-2-(3-methyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] trifluoroacetate (see INT-36) and isocyanatoethane.
  • reaction mixture was cooled down to -78 °C and tert-butyl 3-oxopyrrolidine-1-carboxylate (2.00 g, 10.8 mmol) in THF (80 mL) was added at -78 C and stirred for 2 h at -78 C.
  • the reaction mixture was allowed to reach rt overnight.
  • Saturated aqueous sodium hydrogen carbonate solution was added and extracted three times with ethyl acetate.
  • the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to yield 1.35 g (38 % yield) of the title compound.
  • the resultant mixture was stirred at 80°C overnight.
  • the reaction mixture was allowed to cool to rt and then diluted with ethylacetate, water and brine.
  • the organic layer was separated and the aqueous phase extracted with ethylacetate (x2).
  • the combined organics were dried over sodium sulphate, filtered and concentrate.
  • the crude mixture was purified by silica gel chromatography to yield 399 mg (38%) of the title compound.
  • the aqueous phase was extracted with ethyl acetate (x2) and the combined organics were dried over sodium sulfate, filtered and concentrated.
  • the crude mixture was purified by silica gel chromatography to yield 952 mg (80%) of the title compound.
  • the filter was washed twice with ethyl acetate.
  • the filtrate was washed with water, dried through a hydrophobic filter, and concentrated.
  • the residue was purified by silica gel chromatography obtaining 290 mg (64 % yield) of the title compound.
  • reaction was strirred for 16h ate 105°C under nitrogen.
  • the reaction mixture was cooled to rt, diluted with water and extracted with EtOAc.
  • the organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 1.06 g (85 % purity) of the title compound that was used without further purification.
  • reaction mixture was then cooled down, diluted with water and extracted with ethylacetate.
  • Theorganic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 1.17 g (85 % purity, 104 % yield) of the title compound that was used without further purification.
  • the resultant mixture was stirred over night at 100 °C.
  • the reaction mixture was allowed to cool to rt, diluted with dichloromethane, filtered and concentrated.
  • the crude reaction mixture was purified by silica gel chromatography to yield 9.50 g (99%) of the title compound.
  • the resultant mixture was stirred at 100 °C overnight.
  • the reaction mixture was allowed to cool to rt, diluted with dichloromethane, filtered through a hydrophobic membrane and concentrated.
  • the crude reaction mixture was purified by silica gel chromatography to yield 650 mg of the title compound.
  • the reaction mixture was extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution, dried (silicon filter) and concentrated under reduced pressure.
  • the crude mixture was purified by preparative HPLC to give 275 mg (55 % yield) of the title compound.
  • reaction mixture was stirred at 100°C for 6 h and then colled to rt, diluted with water and extratcted with dichloromethane and then with ethyl acetate.
  • the combined organic phases were dried and concentrated under reduced pressure to give 501 mg of the title compound that was used without further purification in the enxt step.
  • N,N-diisopropylethylamine (1.6 mL, 9.4 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (1.4 mL, 7.9 mmol) were added dropwise. It was stirred at 75 °C for 3 h. The reaction mixture was poured into amixture of ice and water and extracted twice with ethyl acetate. The combined organic lyers were dried over sodium sulfate, concentrated and purified by silica gel chromatography affording 2.36 g (67 % yield) of the title compound.
  • Example 25 (rac)-N-cyclobutyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide Under argon (rac)-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]—hydrogen chloride (1/1) (130 mg, 364 ⁇ mol) was dissolved in dichloromethane (4 mL) and then N,N-diisopropylethylamine (320 ⁇ L, 1.8 mmol) and isocyanatocyclobutane (35.4 mg, 364 ⁇ mol) were added at 0° C.
  • Example 27 (rac)-2'-(quinolin-3-yl)-N-[(1S)-2,2,2-trifluoro-1-methoxy-1-phenylethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 28 (rac)-N-[2-(pyrimidin-5-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 29 (rac)-N-[2-(pyrimidin-4-yl)propan-2-yl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 30 2-(5-fluoropyri
  • Example 36 (rac)-N-[1-(4-cyanopyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 37 (rac)-N-(4-phenyloxan-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 38 (rac)-N-cyclobutyl-2'-[6-(cyclohexyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [
  • Example 40 (rac)-2'- ⁇ 3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-cyclobutyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers)
  • Example 41 (rac)-2'- ⁇ 3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers)
  • Example 42 (rac)-2'- ⁇ 3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-(propan-2-y
  • Example 46 (rac)-2'-[3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 0.184 (1.18), 0.195 (4.12), 0.199 (3.86), 0.208 (4.29), 0.211 (3.87), 0.221 (1.36), 0.459 (1.41), 0.469 (3.74), 0.473 (3.61), 0.479 (1.96), 0.483 (1.81), 0.489 (3.86), 0.493 (3.60), 0.504 (1.32), 1.011 (7.09), 1.029 (16.00), 1.047 (7.31), 1.064 (3.80), 1.079 (0.88), 1.082 (0.86), 1.087 (0.86),
  • Example 47 (rac)-N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 48 (rac)-2'-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.010 (2.19), 1.028 (5.06), 1.045 (2.22), 2.116 (0.54), 2.336 (0.72), 2.473 (9.58), 2.518 (11.66), 2.522 (7.46), 2.539 (16.00), 2.546 (1.87), 2.565 (1.00), 2.659 (
  • Example 51 (rac)-N-ethyl-2'-[3-(3-oxomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 52 (rac)-N-ethyl-2'-[3-(2-oxopyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 53 (rac)-N-ethyl-2'-[3-(2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[
  • Example 54 (rac)-2'-[6-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.015 (1.79), 1.033 (4.05), 1.050 (1.81), 2.100 (0.54), 2.118 (0.62), 2.518 (1.14), 2.523 (0.78), 2.540 (16.00), 2.558 (0.67), 2.577 (0.98), 2.594 (0.68), 3.053 (0.71), 3.067 (0.80), 3.071 (0.77), 3.084 (0.70), 3.435 (0.53), 3.455 (2.45), 4.256 (0.65), 4.274 (1.02), 4.291 (0.63), 5.249 (2.72), 6.185 (0.60), 6.691 (2.71), 7.357 (0.72),
  • Example 56 (rac)-2'-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.010 (0.45), 1.028 (1.02), 1.045 (0.47), 1.231 (0.50), 2.326 (0.47), 2.518 (1.76), 2.522 (1.26), 2.539 (16.00), 2.668 (0.47), 3.435 (0.67), 6.524 (0.65).
  • Example 58 (rac)-N-ethyl-2'-[6-(trifluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: -0.004 (1.41), 1.014 (1.94), 1.032 (4.43), 1.050 (2.07), 2.104 (0.74), 2.123 (0.86), 2.522 (0.71), 2.539 (16.00), 2.569 (0.86), 2.586 (1.30), 2.603 (0.88), 3.052 (0.86), 3.066 (0.97), 3.070 (0.96), 3.084 (0.84), 3.444 (0.68), 3.460 (2.46), 3.514 (0.43), 4.271 (0.84), 4.288 (1.32), 4.305 (0.82), 6.189 (0.72), 6.729 (3.00), 7.690 (
  • Example 60 (rac)-N-[1-(3-chloropyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide Cl O N N H N N N N N
  • Example 62 (rac)-N-ethyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • Example 63 (rac)-N-(propan-2-yl)-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • Example 64 (rac)-N-tert-butyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[
  • Example 70 (rac)-N-ethyl-2'- ⁇ 3-[(pyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 72 (rac)-N-[(3-methyloxetan-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 419 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.000 (10.55), 1.212 (16.00), 1.892 (10.93), 2.077 (3.55), 2.117 (0.79), 2.132 (1.62), 2.150 (1.79), 2.168 (0.72), 2.334 (0.54), 2.521 (2.69), 2.525 (1.77), 2.542 (1.72), 2.581 (1.86), 2.599 (2.83), 2.616 (1.98), 2.676 (0.53), 3.168 (0.52), 3.176 (0.61), 3.191 (0.6
  • Example 74 (rac)-N-tert-butyl-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.240 (0.80), 1.256 (1.74), 1.282 (16.00), 1.794 (0.59), 1.806 (0.61), 2.047 (0.54), 2.060 (0.53), 2.074 (0.46), 2.539 (1.98), 3.398 (0.93), 3.407 (1.41), 3.424 (1.34), 3.450 (0.44), 4.120 (0.61), 4.135 (1.25), 4.149 (0.61), 5.337 (1.29), 6.685 (2.21), 7.685 (1.23), 7.691 (1.24), 8.169 (1.16), 8.173 (1.19), 8.
  • Example 78 (rac)-N-ethyl-2'- ⁇ 3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 82 (rac)-N-tert-butyl-2- ⁇ 3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 83 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.009 (7.16), 1.027 (16.00), 1.045 (7.36), 1.879 (0.84), 1.881 (0.80), 1.886 (0.77), 1.900 (0.87), 1.907 (1.31), 1.928 (0.58), 1.984 (0.77), 2.007 (1.60), 2.031 (1.53), 2.057 (2.02), 2.074 (3.43), 2.094 (2.22), 2.112 (1.06), 2.125 (1.15), 2.147 (1.73), 2.152 (1.59), 2.170 (2.04), 2.175 (2.35), 2.197 (1.57), 2.219
  • Example 84 (rac)-N-tert-butyl-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.279 (16.00), 2.012 (0.43), 2.039 (0.57), 2.056 (0.49), 2.070 (0.42), 2.088 (0.48), 2.152 (0.47), 2.158 (0.44), 2.175 (0.57), 2.181 (0.67), 2.203 (0.45), 2.357 (0.45), 2.364 (0.66), 2.385 (0.59), 2.520 (2.43), 2.524 (1.87), 2.542 (3.27), 2.559 (0.73), 3.419 (0.52), 3.435 (1.59), 3.439 (1.72), 3.699 (0.47), 4.201 (0.6
  • Example 85 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.063 (14.70), 1.073 (15.93), 1.079 (16.00), 1.089 (14.81), 1.882 (1.03), 1.885 (1.00), 1.890 (0.94), 1.904 (1.08), 1.911 (1.42), 1.933 (0.69), 1.938 (0.41), 1.988 (0.91), 2.011 (1.97), 2.034 (2.24), 2.054 (1.91), 2.061 (1.74), 2.065 (1.94), 2.070 (2.06), 2.081 (1.64), 2.092 (2.53), 2.110 (1.26), 2.122 (1.04), 2.127
  • Example 88 (rac)-N-ethyl-2'-[6-(methanesulfonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 89 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 90 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 104 (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3-thiazol-2-yl)ethyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers)
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.517 (12.41), 1.528 (13.08), 1.535 (13.59), 1.546 (11.96), 1.579 (0.45), 1.598 (0.39), 2.105 (0.45), 2.121 (0.90), 2.135 (2.36), 2.150 (4.44), 2.167 (4.44), 2.183 (1.85), 2.214 (0.39), 2.318 (1.07), 2.322 (2.30), 2.327 (3.20), 2.332 (2.36), 2.336 (1.01), 2.518 (12.74), 2.523 (8.08), 2.596 (5.11), 2.612
  • Example 108 (rac)-N-[1-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 483 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.931 (1.51), 0.934 (0.51), 0.948 (1.55), 1.629 (1.06), 1.722 (0.68), 1.732 (1.00), 1.739 (0.98), 1.751 (1.34), 1.910 (0.48), 1.923 (0.70), 1.941 (0.87), 1.953 (0.68), 1.971 (0.54), 2.080 (0.67), 2.094 (0.83), 2.107 (0.73), 2.125
  • Example 109 (rac)-N-[(rac)-1-(2-methylpyridin-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers)
  • Example 110 (rac)-N-[(rac)-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereosiomers)
  • MS (ESIpos): m/z 444 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.927 (0.45), 0.930 (1.89), 0.933 (0.55), 0.943 (0.43), 0.946 (1.95), 1.449 (3.81), 1.459 (4.04), 1.466 (4.09), 1.477 (3.85), 2.075 (0.87), 2.087 (0.77), 2.101 (1.50), 2.119 (1.77), 2.137 (0.70), 2.148
  • Example 114 (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers)
  • Example 118 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-phenylpentan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 468 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.773 (0.66), 1.778 (0.69), 1.784 (0.49), 1.789 (0.49), 1.794 (0.70), 1.800 (0.81), 1.817 (0.49), 1.822 (0.41), 1.977 (0.41), 1.992 (0.77), 2.007 (0.56), 2.015 (0.68), 2.019 (0.70), 2.030 (0.56), 2.043 (0.62), 2.061 (0.87), 2.0
  • Example 126 (rac)-N- ⁇ (rac)-1-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]ethyl ⁇ -2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers)
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 0.935 (0.75), 0.951 (0.72), 1.232 (0.51), 1.355 (6.87), 1.367 (8.29), 1.372 (8.25), 1.384 (7.06), 2.074 (0.81), 2.088 (1.55), 2.105 (3.10), 2.124 (3.44), 2.142 (1.58), 2.154 (0.88), 2.172 (0.44), 2.518 (11.65), 2.523 (7.81), 2.565 (4.09), 2.582 (5.94), 2.600 (4.00), 2.729 (1.52
  • Example 128 (rac)-N-[(1R)-1-phenylethyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers)
  • Example 135 (rac)-N-[(pyridin-4-yl)methyl]-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide
  • MS (ESIpos): m/z 439 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.860 (3.66), 1.869 (3.55), 1.903 (0.63), 2.078 (3.10), 2.090 (3.23), 2.195 (0.95), 2.214 (1.93), 2.232 (1.36), 2.245 (1.36), 2.263 (0.75), 2.518 (7.69), 2.523 (5.40), 3.479 (1.94), 3.505 (8.59), 3.513 (9.36), 3.539 (2.68), 3.592 (1.20), 3.605 (1.54
  • Example 138 (rac)-N-(1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 400 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.906 (1.59), 2.167 (2.61), 2.180 (3.08), 2.518 (15.15), 2.523 (10.02), 2.605 (2.66), 2.620 (4.40), 2.626 (4.44), 2.639 (2.65), 3.628 (10.59), 3.671 (1.21), 3.688 (2.00), 4.283 (3.75), 4.299 (7.86), 4.317 (3.76), 6.667 (16.00), 6.763 (15.91), 7.588 (2.00), 7.
  • Example 139 (rac)-N-[(pyridin-4-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 141 (rac)-2'-(quinolin-3-yl)-N-(2H-tetrazol-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.231 (1.56), 1.237 (1.45), 1.907 (0.92), 2.199 (2.46), 2.213 (2.75), 2.326 (1.71), 2.331 (1.26), 2.586 (0.57), 2.603 (1.02), 2.619 (2.30), 2.635 (4.88), 2.651 (5.03), 2.668 (3.85), 2.700 (0.50), 3.680 (8.12), 3.743 (1.79), 4.288 (3.92), 4.304 (7.70), 4.322 (3.99), 6.795 (16.00), 7.589 (1.94), 7.610 (3.96), 7.630 (2.85), 7.705
  • Example 152 (rac)-2'-(quinolin-3-yl)-N-[1-(trifluoromethyl)cyclobutyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 457 [M+H] + H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.822 (0.47), 1.849 (1.11), 1.871 (1.46), 1.893 (1.21), 1.905 (0.68), 1.917 (1.12), 1.929 (1.26), 1.943 (1.18), 1.955 (1.04), 1.969 (0.73), 2.075 (0.53), 2.090 (0.64), 2.104 (1.63), 2.122 (2.54), 2.142 (2.68), 2.160 (1.34), 2.172 (0.85), 2.322 (0.4).
  • Example 156 (rac)-N-(2-cyanopropan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.595 (15.79), 1.602 (16.00), 2.074 (1.03), 2.083 (0.62), 2.107 (0.89), 2.125 (1.58), 2.144 (1.68), 2.162 (0.79), 2.175 (0.47), 2.518 (1.86), 2.522 (1.18), 2.585 (2.28), 2.602 (3.35), 2.620 (2.43), 3.466 (0.43), 3.484 (1.11), 3.491 (0.99), 3.515 (5.44), 3.518 (5.88), 3.544 (0.55), 3.574 (0.62), 3.593 (1.04), 3.601 (0.67), 3.607 (0.78), 3.615
  • Example 158 (rac)-N-[1-(4-chlorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIneg): m/z 496 [M-H]- 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.741 (0.59), 1.758 (1.13), 1.763 (1.19), 1.780 (1.23), 1.785 (1.38), 1.802 (0.85), 1.962 (0.54), 1.968 (0.72), 1.984 (1.29), 1.998 (1.01), 2.007 (1.16), 2.011 (1.16), 2.021 (0.69), 2.026 (0.68), 2.034 (0.61), 2.050 (0.55), 2.074 (3.82),
  • Example 165 (rac)-N-(bicyclo[1.1.1]pentan-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 400 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.952 (16.00), 2.086 (0.57), 2.103 (0.71), 2.354 (2.90), 2.518 (0.40), 2.556 (0.72), 2.573 (1.05), 2.591 (0.76), 3.412 (0.66), 3.420 (0.88), 3.430 (2.91), 4.256 (0.74), 4.274 (1.12), 4.291 (0.71), 6.740 (3.14), 6.830 (1.08), 7.613 (0.51), 7.615 (0.69), 7.
  • Example 166 (rac)-N-(3,3-difluorocyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 424 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.022 (0.57), 1.039 (0.49), 1.147 (1.55), 1.163 (1.64), 1.227 (0.41), 2.074 (0.97), 2.083 (0.85), 2.100 (2.11), 2.114 (4.04), 2.131 (4.60), 2.148 (1.84), 2.162 (0.92), 2.179 (0.44), 2.327 (0.50), 2.522 (1.67), 2.575 (5.21), 2.592 (8.15), 2.609 (6.21), 2.6
  • Example 170 (rac)-2-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 171 (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-phenylethyl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 505 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.966 (2.69), 1.165 (0.63), 1.274 (2.48), 1.291 (2.59), 1.349 (5.70), 1.364 (16.00), 1.376 (14.34), 1.382 (14.60), 1.393 (12.15), 1.408 (5.23), 1.450 (3.46), 2.099 (3.72), 2.114 (6.02), 2.133 (5.62), 2.326 (1.64), 2.576 (7.08), 2.593
  • Example 172 (rac)-N-[2-(3-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • ⁇ [ppm] 1.57 (2s, 6H), 2.06 - 2.21 (m, 2H), 2.56 - 2.63 (m, 2H), 3.43 - 3.56 (m, 3H), 3.57 - 3.65 (m, 1H), 4.29 (t, 2H), 6.15 (s, 1H), 6.72 (s, 1H), 6.93 - 6.99 (m, 1H), 7.15 (dt, 1H), 7.20 (d, 1H), 7.30 (td, 1H), 7.59 - 7.65 (m, 1H), 7.73 (ddd, 1H), 7.99 - 8.04 (m, 2H),
  • Example 176 (rac)-N-[2-(3-fluoropyridin-2-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • ⁇ [ppm] 1.65 (s, 6H), 2.06 - 2.21 (m, 2H), 2.57 - 2.61 (m, 2H), 3.41 - 3.52 (m, 3H), 3.54 - 3.61 (m, 1H), 4.29 (t, 2H), 6.51 (s, 1H), 6.73 (s, 1H), 7.34 (ddd, 1H), 7.55 - 7.64 (m, 2H), 7.73 (ddd, 1H), 8.00 - 8.03 (m, 2H), 8.32 (dt, 1H), 8.65 (d, 1H), 9.35 (d, 1H
  • Example 178 (rac)-N-[2-(2-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIneg): m/z 468 [M-H]- 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.917 (0.59), 0.931 (4.90), 0.934 (1.52), 0.948 (4.79), 0.952 (0.77), 1.648 (16.00), 2.084 (0.46), 2.097 (0.96), 2.111 (1.18), 2.126 (1.09), 2.144 (1.48), 2.161 (0.84), 2.173 (0.58), 2.404 (0.50), 2.422 (0.49), 2.518 (3.44), 2.523 (2.14), 2.572 (1
  • Example 180 (rac)-N-[1-(2-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIneg): m/z 481 [M-H]- 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.932 (3.03), 0.935 (0.98), 0.948 (3.04), 0.953 (0.52), 1.712 (0.56), 1.725 (0.82), 1.733 (1.27), 1.739 (1.22), 1.746 (1.35), 1.753 (1.13), 1.760 (1.44), 1.768 (0.80), 1.774 (0.90), 1.782 (0.64), 2.020 (0.95), 2.043 (1.90), 2.061 (3.11
  • Example 181 (rac)-N-[2-(2-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIneg): m/z 484 [M-H]- 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.932 (1.33), 0.935 (0.44), 0.948 (1.35), 1.701 (16.00), 2.084 (0.84), 2.098 (0.98), 2.112 (0.88), 2.130 (1.29), 2.147 (0.70), 2.160 (0.50), 2.322 (0.48), 2.326 (0.65), 2.332 (0.47), 2.518 (2.51), 2.522 (1.55), 2.548 (1.22), 2.554 (1.18), 2.565 (2.
  • Example 184 (rac)-N-[1-(3-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 483 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.761 (0.53), 1.766 (0.55), 1.782 (1.11), 1.788 (1.17), 1.799 (0.83), 1.805 (1.20), 1.810 (1.38), 1.827 (0.84), 1.970 (0.54), 1.977 (0.72), 1.993 (1.29), 2.008 (0.95), 2.015 (1.15), 2.020 (1.13), 2.031 (0.65), 2.035 (0.64), 2.043 (0.60),
  • Example 186 (rac)-N-(1-phenylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 465 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.747 (0.50), 1.753 (0.61), 1.758 (0.47), 1.769 (1.10), 1.775 (1.17), 1.780 (0.81), 1.786 (0.80), 1.791 (1.18), 1.797 (1.35), 1.813 (0.81), 1.819 (0.68), 1.968 (0.54), 1.975 (0.70), 1.991 (1.28), 2.005 (0.91), 2.014 (1.08), 2.018 (1.12), 2.029 (0.6
  • Example 190 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[1-(pyridin-2-yl)cyclobutyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 198 (rac)-N-ethyl-2-(5-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide
  • the following examples were synthesised analogously via Suzuki coupling
  • Example 199 (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-(1-phenylcyclobutyl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 201 (rac)-N-ethyl-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 202 (rac)-N-ethyl-2'-[3-(1-phenylcyclohexyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 203 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclobutyl)-5',6'- dihydrospiro[pyrrolidine-3,4
  • Example 204 (rac)-N-ethyl-2'- ⁇ 3-[2-(3-methylphenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.003 (4.94), 1.021 (10.97), 1.039 (5.00), 1.065 (1.52), 1.633 (0.99), 1.697 (16.00), 2.010 (0.89), 2.028 (1.35), 2.048 (1.50), 2.066 (0.84), 2.074 (3.77), 2.226 (13.33), 2.472 (2.48), 2.518 (4.32), 2.522 (2.82), 2.539 (2.68), 3.021 (0.65), 3.039 (2.07), 3.053 (2.29), 3.057 (2.25), 3.070 (2.00), 3.
  • Example 205 (rac)-N-ethyl-2-(6-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide
  • Example 206 (rac)-N-ethyl-2-(7-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide
  • Example 207 (rac)-N-ethyl-2'- ⁇ 3-[2-(1,3-thiazol-2-yl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 208 (rac)-2'
  • Example 209 (rac)-N-ethyl-2'- ⁇ 3-[2-(2-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.008 (5.00), 1.026 (10.79), 1.044 (5.05), 1.065 (2.58), 1.156 (1.37), 1.713 (0.42), 1.777 (16.00), 2.014 (0.95), 2.029 (1.66), 2.048 (1.86), 2.067 (0.78), 2.078 (0.48), 2.331 (1.52), 2.522 (6.11), 2.539 (1.64), 2.673 (1.56), 3.028 (0.68), 3.046 (2.12), 3.060 (2.42), 3.063 (2.37), 3.077 (2.03
  • Example 210 (rac)-N-ethyl-2'- ⁇ 3-[2-(4-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • F 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.000 (5.10), 1.018 (11.48), 1.036 (5.33), 1.066 (5.44), 1.156 (1.14), 1.707 (16.00), 2.011 (0.95), 2.030 (1.11), 2.052 (1.47), 2.071 (0.74), 2.083 (0.56), 2.332 (1.44), 2.518 (8.62), 2.523 (5.64), 2.539 (2.25), 2.673 (1.47), 3.017 (0.66), 3.035 (2.16), 3.049 (2.40), 3.052 (2.33), 3.067 (2
  • Example 212 (rac)-2'- ⁇ 3-[2-(3-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 213 (rac)-N-ethyl-2-[6-(methylamino)-1,5-naphthyridin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 214 (rac)-2'-[6-(dimethylamino)-1,5-naphthyridin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 406 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.012 (3.10), 1.029 (7.28), 1.047 (3.24), 2.075 (0.54), 2.088 (0.81), 2.103 (1.17), 2.121 (0.47), 2.518 (0.98), 2.523 (0.65), 2.545 (0.89), 2.562 (1.48), 2.565 (1.50), 2.581 (1.05), 3.048 (1.15), 3.063 (1.32), 3.066 (1.27), 3.081 (1.15),
  • Example 216 (rac)-N-ethyl-2'-(5-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 217 (rac)-N-ethyl-2'- ⁇ 7-fluoro-6-[(propan-2-yl)oxy]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 218 (rac)-2'-(6-methoxyquinolin-3-yl)-N-(1-phenylcyclobutyl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 219 (rac)-N-ethyl-2-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: -0.110 (0.42), 1.010 (4.90), 1.028 (10.75), 1.046 (5.01), 1.232 (0.54), 1.716 (16.00), 1.907 (0.42), 1.954 (1.43), 1.972 (1.61), 1.986 (1.49), 2.084 (0.84), 2.099 (1.07), 2.118 (0.72), 2.130 (0.78), 2.322 (2.63), 2.326 (3.52), 2.331 (2.63), 2.522 (10.51), 2.539 (1.49), 2.664 (2.69), 2.669 (3
  • Example 220 (rac)-N-ethyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • Example 221 (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • Example 222 (rac)-N-ethyl-2-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • Example 239 (rac)-2-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
  • Example 240 (1-benzylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone (Rac)-2'-(Quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) (100 mg, 306 ⁇ mol) was dissolved in DMF (1.3 mL), then N,N- diisopropylethylamine
  • Example 241 (cuban-1-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone
  • Example 242 (1-ethylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone
  • Example 249 (1-methylcyclopropyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone
  • MS (ESIpos): m/z 373 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.509 (4.15), 0.786 (1.33), 0.872 (2.24), 1.154 (0.50), 1.172 (0.79), 1.189 (0.70), 1.234 (5.35), 1.907 (8.08), 1.987 (1.08), 2.084 (1.20), 2.138 (2.57), 2.322 (1.78), 2.327 (2.36), 2.331 (1.74), 2.336 (0.83), 2.518 (7.63), 2.523 (5.06), 2.539 (1.37), 2.560 (0.6
  • Example 250 (3-methyloxetan-3-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone
  • Example 257 [(rac)-2,2-difluoro-1-methylcyclopropyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of diastereomers)
  • Example 258 (rac)-N-ethyl-2- ⁇ 5-[(pyridine-3-carbonyl)amino]quinolin-3-yl ⁇ -5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Rac -2'-(5-Aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 259 (rac)-N-ethyl-2'- ⁇ 5-[(pyridine-4-carbonyl)amino]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 260 (rac)-N-ethyl-2'- ⁇ 5-[(pyridine-2-carbonyl)amino]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 261 1-[(rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]-2
  • Example 266 (rac)-2'-(5-acetamidoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 267 (rac)-2'-[5-(2,2-dimethylpropanamido)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 268 (rac)-N-ethyl-2'-[5-(2-methylpropanamido)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 269 (rac)-2'-(5-benzamidoquinolin-3-
  • Example 271 [(rac)-2,2-difluoro-1-methylcyclopropyl][-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of stereoisomers)
  • Example 272 N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1)
  • LC-MS (Method 1): R t 0.92 min;
  • MS (ESIpos): m/z 494 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.697
  • Example 276 2'-(3- ⁇ 3-cyano-4-[(propan-2-yl)oxy]phenyl ⁇ -1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1)
  • Example 278 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (enantiomer 1)
  • Example 279 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (enantiomer 2)
  • Example 280 N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 1)
  • Example 281 N-benzyl-2'-(quino
  • Example 284 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (isomer 1)
  • Example 285 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (isiomer 2)
  • Example 286 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (isiomer 3)
  • Example 287 1-[1-(1H-imida
  • Example 298 (rac)-2'- ⁇ 3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -1-[(4-chloro-1H-pyrazol-3-yl)methyl]- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers)
  • Example 299 (rac)-1'-[(4-chloro-1H-pyrazol-5-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7- dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]
  • Example 300 (rac)-2'- ⁇ 3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl
  • Example 301 (rac)-1'-[(1H-imidazol-2-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro- 5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]
  • Example 302 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.232 (0.74), 1.716 (16.00), 1.960 (0.69), 1.979 (1.02), 1.987 (0.88), 2.002 (0.92)
  • Example 303 (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1'-[(1H-imidazol-2-yl)methyl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]
  • Example 304 (rac)-2'-(quinolin-3-yl)-1-[(4H-1,2,4-triazol-3-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]
  • Example 305 1-[(rac)-1-(1H-imidazol-2-yl)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of two isomers)
  • Example 306 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'- ⁇ 3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3- b]pyridin-5-yl ⁇ -5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • Example 307 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • Example 308 (rac)-1-[(5-methyl-1H-imidazol-2-yl)methyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • Example 309 (rac)-2'-(quinolin-3-yl)-1-[(rac)-1-(4H-1,2,4-triazol-3-yl)ethyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of diastereomers)
  • Example 316 (rac)-1-[(4-methyl-1H-pyrazol-5-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole] 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.905 (1.73), 2.036 (7.99), 2.047 (0.74), 2.073 (11.14), 2.078 (0.92), 2.084 (0.88), 2.099 (0.58), 2.222 (3.06), 2.224 (3.00), 2.518 (0.79), 2.523 (0.60), 2.529 (0.47), 2.539 (16.00), 2.561 (0.71), 2.578 (0.43), 2.590 (0.41), 2.605 (0.67), 2.623 (1.50), 2.646 (1.58), 2.673 (0.70), 2.689 (0.58), 2.711 (1.68), 2.721 (0.45), 2.735 (1.35), 2.757 (0.48), 3.633 (3.
  • Example 318 (rac)-1-[(4-chloro-1H-pyrazol-3-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: -0.149 (0.45), 0.146 (0.45), 0.853 (0.41), 1.234 (1.96), 1.279 (0.46), 1.889 (1.60), 1.915 (2.14), 1.936 (1.09), 1.969 (0.71), 1.990 (1.93), 2.013 (3.72), 2.036 (3.73), 2.062 (2.86), 2.076 (3.69), 2.135 (1.19), 2.156 (3.25), 2.162 (3.15), 2.179 (4.06), 2.185 (4.55), 2.207 (3.09), 2.231 (0.83),
  • Example 319 (rac)-1-[(4-chloro-3-methyl-1H-pyrazol-5-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: -0.011 (10.97), 1.062 (5.76), 1.581 (0.60), 1.878 (0.44), 1.881 (0.43), 1.886 (0.41), 1.900 (0.45), 1.907 (0.60), 1.980 (1.09), 1.994 (0.56), 2.005 (1.03), 2.008 (1.00), 2.013 (1.00), 2.029 (1.15), 2.050 (0.90), 2.055 (0.92), 2.063 (5.98), 2.071 (0.71), 2.148 (16.00), 2.168 (1.29), 2.174 (1.43), 2.
  • Example 321 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.232 (0.78), 1.868 (0.43), 1.873 (0.44), 1.888 (1.13), 1.890 (1.13), 1.895 (1.09), 1.902 (0.85), 1.909 (1.23), 1.916 (1.59), 1.923 (0.87), 1.937 (0.79), 1.944 (0.47), 1.982 (0.55), 1.991 (1.19), 1.996 (1.06), 2.001 (1.01), 2.014 (3.40), 2.035 (2.89), 2.050 (2.38), 2.058 (1.63), 2.064 (2.62), 2.070 (1
  • Example 322 (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-ethyl-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]
  • Example 325 trifluoroacetic acid—(rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1)
  • Example 326 (rac)-N-ethyl-2'-[6-(4-methyl-2-oxopi
  • Example 328 (rac)-2'-(6- ⁇ [dimethyl(oxo)-lambda 6 -sulfanylidene]amino ⁇ quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 334 (rac)-N-ethyl-2'- ⁇ 6-[(prop-2-en-1-yl)oxy]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • (Rac)-N-Ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (25.0 mg, 66.2 ⁇ mol), 3-bromoprop-1-ene (11.2 mg, 92.7 ⁇ mol), and sodium hydroxide (3.18 mg, 79.5 ⁇ mol) were put into a microwave vial.
  • Example 335 (rac)-2'- ⁇ 6-[3-(dimethylamino)propoxy]quinolin-3-yl ⁇ -N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 336 (rac)-N-ethyl-2'- ⁇ 6-[(oxan-4-yl)oxy]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 337 (rac)-2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Example 338 (rac)-N-ethy
  • Example 349 (rac)-N-ethyl-2'-(5- ⁇ [methyl(1-methylazetidin-3-yl)carbamoyl]amino ⁇ quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 350 (rac)-N-ethyl-2'-(5- ⁇ [(oxetan-3-yl)carbamoyl]amino ⁇ quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.021 (7.67), 1.039 (16.00), 1.058 (7.84), 2.072 (0.43), 2.088 (0.88), 2.103 (1.89), 2.119 (3.57)
  • Example 351 (rac)-N-ethyl-2'-(5- ⁇ [methyl(oxetan-3-yl)carbamoyl]amino ⁇ quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.016 (4.12), 1.034 (8.95), 1.051 (4.22), 2.087 (0.85), 2.101 (0.93), 2.118 (1.08), 2.137 (1.24), 2.155 (0.67), 2.167 (0.53), 2.334 (0.46), 2.542 (0.74), 2.559 (1.67), 2.576 (2.58), 2.595 (1.71), 2.676 (0.48), 2.847 (0.58), 3.036 (0.59), 3.054 (1.88), 3.068 (2.21), 3.071 (2.15), 3.085 (1.84), 3.103 (
  • Example 352 (rac)-N-ethyl-2'-(5- ⁇ [(1-methylazetidin-3-yl)carbamoyl]amino ⁇ quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.001 (0.56), 1.023 (4.56), 1.041 (9.21), 1.059 (4.49), 1.158 (0.42), 1.234 (0.57), 2.087 (0.64), 2.103 (1.19), 2.120 (2.11), 2.138 (2.11), 2.156 (1.04), 2.184 (1.95), 2.195 (2.65), 2.215 (0.57), 2.253 (16.00), 2.276 (3.22), 2.585 (2.80), 2.602 (4.00), 2.619 (2.32), 2.652 (0.42), 2.816 (2.01), 2.835
  • Example 353 (rac)-2'- ⁇ 5-[(cyclopentylcarbamoyl)amino]quinolin-3-yl ⁇ -N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: -0.002 (2.63), 0.999 (0.68), 1.017 (7.15), 1.035 (16.00), 1.052 (7.44), 1.197 (0.81), 1.217 (1.87), 1.232 (3.38), 1.246 (2.81), 1.262 (2.28), 1.278 (1.10), 1.413 (1.22), 1.429 (2.20), 1.444 (2.86), 1.453 (2.49), 1.460 (3.82), 1.466 (2.53), 1.472 (3.63), 1.474 (3.52), 1.489 (2.46), 1.493 (2.13), 1.509 (
  • Example 354 (rac)-N-ethyl-2'- ⁇ 5-[(pyrrolidine-1-carbonyl)amino]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.013 (7.33), 1.031 (16.00), 1.048 (7.45), 1.233 (0.82), 1.907 (3.84), 1.922 (8.40), 1.938 (3.35), 2.073 (0.68), 2.086 (1.44), 2.099 (1.52), 2.118 (1.74), 2.137 (2.06), 2.155 (1.12), 2.167 (0.89), 2.186 (0.40), 2.332 (1.52), 2.522 (5.45), 2.558 (2.69), 2.577 (4.26), 2.594 (2.96), 2.673 (1.58), 3.032 (0.96), 3.050 (3.05), 3.0
  • Example 355 (rac)-2'-(5- ⁇ [cyclobutyl(methyl)carbamoyl]amino ⁇ quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.015 (4.29), 1.033 (9.27), 1.051 (4.43), 1.573 (0.76), 1.579 (0.60), 1.599 (1.02), 1.619 (0.89), 1.645 (1.18), 1.669 (0.80), 2.072 (0.93), 2.086 (1.77), 2.100 (2.22), 2.114 (2.83), 2.134 (2.06), 2.152 (0.79), 2.164 (0.67), 2.174 (0.55), 2.181 (0.55), 2.197 (1.30), 2.223 (1.63), 2.249 (0.94), 2.558 (2.07), 2.576 (3
  • Example 356 (rac)-N-ethyl-2'-(5- ⁇ [(1-methylcyclobutyl)carbamoyl]amino ⁇ quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 357 (rac)-2'-(5- ⁇ [cyclopropyl(methyl)carbamoyl]amino ⁇ quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 358 (rac)-2'-(5- ⁇ [(bicyclo[1.1.1]pentan-1-yl)carbamoyl]amino ⁇ quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'
  • Example 359 (rac)-2'- ⁇ 5-[(cyclobutylcarbamoyl)amino]quinolin-3-yl ⁇ -N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.001 (0.41), 1.022 (6.93), 1.040 (16.00), 1.058 (7.32), 1.597 (0.57), 1.616 (1.07), 1.622 (0.75), 1.635 (0.89), 1.642 (2.02), 1.649 (0.93), 1.662 (1.91), 1.668 (1.63), 1.686 (1.36), 1.861 (0.52), 1.867 (0.47), 1.883 (1.61), 1.889 (1.56), 1.905 (1.84), 1.911 (2.12), 1.937 (1.40), 1.959 (0.42), 2.0
  • Example 360 (rac)-N-ethyl-2'-[5-( ⁇ [2-(trifluoromethyl)cyclopropyl]carbamoyl ⁇ amino)quinolin-3-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: 1.001 (0.42), 1.018 (7.31), 1.036 (16.00), 1.054 (7.25), 1.160 (1.58), 1.170 (2.03), 1.185 (3.18), 1.196 (1.52), 1.205 (2.37), 1.220 (0.49), 2.027 (0.47), 2.034 (0.50), 2.050 (0.95), 2.068 (1.05), 2.084 (0.91), 2.097 (1.35), 2.112 (2.45), 2.129 (2.75), 2.146 (1.09), 2.159 (0.52), 2.325 (1.68), 2.329 (2.29
  • Example 361 (rac)-2'- ⁇ 5-[(cyclopropylcarbamoyl)amino]quinolin-3-yl ⁇ -N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: -0.149 (0.67), 0.146 (0.67), 0.463 (1.04), 0.476 (3.32), 0.484 (3.74), 0.490 (3.63), 0.501 (1.28), 0.661 (1.26), 0.673 (3.16), 0.678 (4.07), 0.690 (4.08), 0.695 (3.02), 0.708 (1.00), 1.018 (6.97), 1.036 (16.00), 1.054 (7.33), 2.096 (1.19), 2.112 (2.25), 2.131 (2.45), 2.149 (1.05), 2.161 (0.59), 2.334 (3.
  • Example 362 (rac)-2'- ⁇ 5-[(cyclohexylcarbamoyl)amino]quinolin-3-yl ⁇ -N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 363 (rac)-N-ethyl-2'-(5- ⁇ [(pyridin-3-yl)carbamoyl]amino ⁇ quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 364 (rac)-N-ethyl-2'- ⁇ 5-[(ethylcarbamoyl)amino]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole
  • Example 368 N-methoxy-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetamide 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.421 (0.76), 0.426 (0.76), 0.430 (0.83), 0.436 (0.83), 0.627 (0.71), 0.633 (0.90), 0.645 (0.90), 0.650 (0.70), 2.038 (0.41), 2.051 (0.83), 2.069 (1.20), 2.079 (0.95), 2.086 (0.99), 2.093 (1.12), 2.098 (1.06), 2.113 (0.91), 2.533 (0.68), 2.552 (0.90), 2.566 (0.90), 2.584 (1.17), 2.601 (0.66), 2.640 (0.43), 2.650 (0.57), 2.655 (0.68), 2.672 (1.32), 2.688 (
  • Example 370 (rac)-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propanamide (mixture of stereoisomers)
  • Example 371 2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]acetamide
  • Example 372 N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetamide
  • Example 373 (rac)-N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyr
  • Example 375 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-3'-methyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (Rac)-3'-Bromo-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (75.0 mg, 162 ⁇ mol) and di- ⁇ -iodobis(tri-t- butylphosphino)dipalladium(I) (14.1 mg, 16.2 ⁇ mol) were stirred in THF (500 ⁇ L) under argon.
  • Example 376 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3'-cyclopropyl-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (Rac)-3'-Bromo-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (75.0 mg, 162 ⁇ mol) and di- ⁇ -iodobis(tri-t- butylphosphino)dipalladium(I) (14.1 mg, 16.2 ⁇ mol) were stirred in toluene (500 ⁇ L) under argon.
  • Example 378 (rac)-2'- ⁇ 3-[1-(cyclopropylmethyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 472 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.135 (0.96), 0.147 (3.64), 0.150 (3.01), 0.158 (3.23), 0.162 (3.45), 0.173 (1.29), 0.353 (1.26), 0.364 (2.98), 0.368 (3.12), 0.373 (1.64), 0.379 (1.50), 0.384 (3.
  • Example 382 (rac)-2'-[3-(2-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 452 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.003 (6.90), 1.021 (16.00), 1.039 (7.16), 2.054 (1.12), 2.072 (1.80), 2.091 (1.97), 2.109 (0.93), 2.121 (0.63), 2.336 (0.45), 2.518 (5.53), 2.522 (4.77), 2.537 (3.38), 2.556 (2.38), 2.659 (0.44), 3.021 (0.86), 3.039 (2.73), 3.053 (2.
  • Tetra-n-butylammonium fluoride (560 ⁇ L, 1.0 M in THF, 560 ⁇ mol) and ethylendiamine (39 ⁇ L, 580 ⁇ mol) were added. It was stirred at 60 °C overnight, the reaction mixture was allowed to reach rt and water was added. It was extracted with dichloromethane/methanol 9:1 and once with ethyl acetate. The combined organic phases were dried, concentrated and purified by HPLC to give 13.0 mg (88 % purity, 17 % yield) of the title compound.
  • Example 390 (rac)-2'-[3-(2,5-dihydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Example 391 (rac)-2'-[3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 1H-NMR 400 MHz, DMSO-d6) ⁇ [ppm]: -0.124 (2.61), -0.101 (0.61), 0.854 (0.53), 0.919 (0.72), 0.934 (5.53),
  • Example 392 (rac)-N-ethyl-2'- ⁇ 6-[2-(methylamino)-2-oxoethoxy]quinolin-3-yl ⁇ -5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ( ⁇ 3-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl ⁇ oxy)acetic acid (30.0 mg, 68.9 ⁇ mol) was dissolved in DMF (0.50 mL).
  • N,N-diisopropylethylamine (45 ⁇ L, 320 ⁇ mol) was added and the reaction mixture was stirred at 70 °C overnight. The raection mixture was allowed to reach rt, water was added and extracted three times with ethyl acetate. The combined organic layers were washed with brine, filtered through a silicone filter and concentrated. The residue was purified by HPLC to give 10.6 mg (90 % purity, 22 % yield) of the title compound.
  • Example 400 (rac)-2'-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • dichloromethane 5.0 mL
  • (rac)-N-ethyl-2'-(1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (50.0 mg, 143 ⁇ mol) was added and stirred for 45 min at rt.
  • Example 401 (rac)-N-ethyl-2'- ⁇ 3-[(rac)-hydroxy(phenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of steroisomers) (3Rac)-N-Ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 143 ⁇ mol) and benzaldehyde (16 ⁇ L, 160 ⁇ mol) were dissolved in methanol (15 mL).
  • Example 402 (rac)-2'- ⁇ 3-[2-(dimethylphosphoryl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Rac -2'- ⁇ 3-[(E)-2-(Dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • 20.0 mg, 44.2 ⁇ mol was dissolved in methanol (1.0 mL) and palladium on charcoal (4.70 mg, 10 % purity, 4.42 ⁇ mol) was added.
  • reaction mixture was stirred for 4 h at rt under an atmosphere of hydrogen.
  • the reaction mixture was filtered through celite and washed with methanol.
  • the filtrate was concentrated and purified by HPLC affording 17.0 mg (95 % purity, 80 % yield) of the title compound.
  • Example 403 ethyl (rac)-2'- ⁇ 3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate Trifluoroacetic acid—(rac)-2'- ⁇ 3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ - 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) (85.0 mg, 90 % purity, 153 ⁇ mol) was suspended in THF (430 ⁇ L) and pyridine (430 ⁇ L, 5.3 mmol) was added.
  • Example 404 (rac)-2'-[3-(ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ⁇ 5-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl]-3- [(piperidin-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-1-yl ⁇ methyl ethylcarbamate (38.0 mg, 69.3 ⁇ mol) was dissolved in ethanol (500 ⁇ L) and sodium ethoxide (5.66 mg, 83.1 ⁇ mol) was added and the reaction mixture was stirred at 60 °C for 4 h.
  • Example 405 (rac)-2'- ⁇ 3-[(dimethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • Acetic acid (1.3 mL, 23 mmol)
  • formaldehyde (12 ⁇ L, 37 % in water, 160 ⁇ mol)
  • water (670 ⁇ L) were dissolved in dioxane (1.3 mL).
  • Formaldehyde (53 ⁇ L, 37 % in water, 710 ⁇ mol) and dimethylamine (90 ⁇ L, 40 % in water, 710 ⁇ mol) were added and stirred overnight at rt. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried through a hydrophobic filter, concentrated and purified by HPLC affording 4.00 mg (95 % purity, 7 % yield) of the title compound.
  • Example 406 (rac)-N-ethyl-2'- ⁇ 3-[1-(trifluoromethyl)cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-5-yl ⁇ -5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ⁇ 5-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl]-3-[1- (trifluoromethyl)cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-1-yl ⁇ methyl ethylcarbamate (5.00 mg, 8.94 ⁇ mol) was dissolved in ethanol (500 ⁇ L) and lithium hydroxide (2.57 mg, 107 ⁇ mol) and water (100 ⁇ L) were added.
  • reaction mixture was stirred for 1 h at 50 °C. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter, concentrated and purified by HPLC yielding 1.00 mg (95 % purity, 23 % yield) of the title compound.
  • Example 407 (rac)-N-ethyl-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide Potassium carbonate (38.2 mg, 378 ⁇ mol) was added to 4-nitrophenyl (rac)-2'-(quinolin-3-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (200 mg, 43 % purity, 189 ⁇ mol) and N-methylethanamine (160 ⁇ L, 1.9 mmol) in DMA (2.0 mL) under nitrogen.
  • Example 408 (rac)-2'-[5-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • (Rac)-N-Ethyl-2'-(5-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (55.0 mg, 146 ⁇ mol), (bromomethyl)benzene (29.9 mg, 175 ⁇ mol), and sodium hydroxide (6.99 mg, 175 ⁇ mol) were put into a microwave vial.
  • Example 409 (rac)-N-(cyclopropanecarbonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
  • Silver(1+) isocyanate 28.4 mg, 189 ⁇ mol was added to cyclopropanecarbonyl chloride (16 ⁇ L, 170 ⁇ mol) in toluene (2.0 mL). It was stirred under exclusion of light for 1 h under reflux. The reaction mixture was allowed to reach rt and filtered.
  • Example 410 (rac)-N-ethyl-2'-(6- ⁇ [(rac)-1-methyl-5-oxopyrrolidin-3-yl]methoxy ⁇ quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (only one group of and/or stereo is supported now.)
  • (Rac)-N-Ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (25.0 mg, 66.2 ⁇ mol), 4-(bromomethyl)-1-methylpyrrolidin-2-one (17.8 mg, 92.7 ⁇ mol), and sodium hydroxide (3.18 mg, 79.5 ⁇ mol) were put into a microwave vial.
  • reaction mixture was allowed to reach rt and ethyl acetate was added. The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous phases were concentrated and purified by silica gel chromatography and HPLC to obtain 3.20 mg (95 % purity, 3 %) of the title compound.
  • Example 417 (rac)-N-ethyl-2'-[6-(2-hydroxy-2-methylpropyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide Methyl ⁇ 3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl ⁇ acetate (30.0 mg, 69.2 ⁇ mol) was dissolved in THF (1.5 mL) under argon and methyl magnesium bromide (210 ⁇ L, 1.0 M in THF, 210 ⁇ mol) was added dropwise.
  • Example 418 (rac)-1-(1-methyl-1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (Rac)-2'-(Quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (100 mg, 344 ⁇ mol) was dissolved in dioxane (5.0 mL) under argon.

Abstract

The present invention relates to Map4K1 inhibitors of formula (I) to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combination with other active ingredients. The present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.

Description

SPIRO-FUSED TRICYCLIC MAP4K1 INHIBITORS The present invention relates to MAP4K1 inhibitors, to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combination with other active ingredients. The present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control. Background Although cancer cell commonly can be recognized by the adaptive immune system, the response generated is evidently not capable of eliminating the tumor. A major reason for this is the presence of immunosuppressive mechanisms in the tumor microenvironment. In this respect, inhibitors of T-cell immune checkpoint such as CTLA-4, PD-1 or PD-L1 were recently shown to result in a remarkable clinical efficacy in subsets of cancer patients. Besides cell surface receptors that act as negative immune regulators, several mediators of intracellular signaling have been identified that also represent potential immunoevasive mechanisms utilized by the tumor. One of these is MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1). MAP4K1 (GeneID11184) is a serine/threonine kinase and member of the Germinal Center Kinase family. In the adult organism MAP4K1 expression is restricted to hematopoietic cell types. The MAP4K1 protein consist of a N-terminal kinase domain, followed by a proline-rich domain that can interact with adaptor molecules through SH2 and SH3 domains, and a C-terminal citron homology domain of which the exact function remains to be identified. Through its proline-rich domain, MAP4K1 is capable of binding to a diversity of adaptors in hematopoietic cells, including those involved in T-cell receptor (TCR), B-cell receptor (BCR) and cytokine signaling (Hu et al., Genes Dev.1996 Sep 15;10(18):2251-64, 2.; Ling et al.,. J Biol Chem.2001 Jun 1;276(22), Sauer et al., J Biol Chem.2001 Nov 30;276(48):45207-16., Tsuji et al., J Exp Med. 2001 Aug 20;194(4):529-39, Boomer et al., J Cell Biochem.2005 May 1;95(1):34-44). The function of MAP4K1 has been studied in greatest detail in the context of TCR signaling. Upon TCR stimulation, MAP4K1 is phosphorylated on tyrosine 381 (Y-381; Y-379 in mouse) (Di Bartolo et al., J Exp Med. 2007 Mar 19;204(3):681-91). Consequently, MAP4K1 is recruited to the TCR-signaling complex where it induces dissociation of this complex through its serine/threonine kinase function. In particular MAP4K1 phosphorylates the SLP-76 adaptor protein at Serine-376, resulting in downregulation of AP-1 and Erk2 pathways. As, such,
MAPK1 acts as a negative feedback on TCR-signaling (Liou et al., Immunity. 2000 Apr;12(4):399-408; Lasserre et al., J Cell Biol. 2011 Nov 28;195(5):839-53.). Alternatively, MAP4K1 can be triggered to suppress T cell function by prostaglandin E2 (PGE2), and possibly also by transforming growth factor beta (TGF-beta), factors that are commonly found in the tumor microenvironment. Notably, MAP4K1 activation by these mediators involves protein kinase A (PKA)-dependent phosphorylation of Serine 171 (S-171; also in mouse) (Alzabin et al., Cancer Immunol Immunother. 2010 Mar; 59(3) :419-29; Sawasdikosol et al., J Biol Chem. 2007 Nov 30;282(48):34693-9.).
Further important insights into the function of MAP4K1 in the regulation of T cell immunity stem from in vivo and in vitro experiments respectively with MAP4K1 deficient mice produced by two laboratories and with immune cells isolated from these mice (Shui et al., Nat Immunol. 2007 Jan;8(1):84-91; Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29). MAP4K1-deficient mice show an apparent normal phenotype, are fertile and exhibit normal lymphocyte development. These animals are prone to develop T-cell dependent autoimmune reactivity as indicated by development of a more severe disease score in the EAE (experimental autoimmune encephalomyelitis) model of multiple sclerosis (Shui et al., Nat Immunol. 2007 Jan;8(1):84-91). In case of the second strain, a dysregulation of immune function was observed when, at the age of approximately 6 months, MAP4K1 -deficient mice develop a spontaneous autoimmune phenotype (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29). In vitro studies showed that MAP4K1-/- T-cells display hyper responsiveness upon TCR-stimulation. These cells proliferate and secrete pro-inflammatory cytokines like IL-2 or IFNg to a significantly greater extent than their wild-type counterparts (Shui et al., Nat Immunol. 2007 Jan;8(1):84-91). Furthermore, MAP4K1-/- T-cells are resistant to PGE2-mediated suppression of T cell proliferation, suppression of IL-2 production and induction of apoptosis (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29).
In the context of tumor immunology, in vivo experiments revealed that MAP4K1-/- mice are much more resistant to tumorigenesis by PGE2-producing Lewis lung carcinoma than wild type mice, which correlated with increased T-lymphocyte infiltration in the tumor areas. The crucial role of T-cells in tumor rejection was supported by experiments in which MAP4K1-/- T-cells adoptively transferred into T-cell-deficient mice were able to eradicate tumors more efficiently than wild-type T-cells (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29). The important role of the kinase enzymatic activity was demonstrated by studies were only wild type MAP4K1, but not the MAP4K1 kinase-dead mutant, could mediate serine-phosphorylation of the TCR-signaling complex component SLP-76 and subsequent binding of SLP-76 to the negative regulator of TCR-signaling 14-3-3-t (Shui et al., Nat Immunol. 2007 Jan;8(1):84-91). MAP4K1 also regulates the stimulation and activation of dendritic cells. MAP4K1 deficient Bone marrow derived cells (BMDC) express after maturation and stimulation higher level of costimulatory molecules and produce more proinflammatory cytokines. Also elimination of tumors was observed to be more efficient by MAP4K1 -/- BMDC compared to their wildtype counterparts (Alzabin et al., J Immunol. 2009 May 15;182(10):6187-94). Prior art In WO2019164846A1 HPK1 inhibitors and methods for their use in various forms of cancer are described. These compounds differ from the instant compounds in their chemical structure. In US20190256500A1 HPK1 inhibitors and methods for their use in treating, preventing or ameliorating diseases or disorders associated with HPK1 such as cancer are described. These compounds differ from the instant compounds in their chemical structure. In US20190256520A1 HPK1 inhibitors and methods for their use in treating, preventing or ameliorating diseases or disorders associated with HPK1 such as cancer are described. These compounds differ from the instant compounds in their chemical structure. In CN109721620A HPK1 inhibitors and their uses are described. These compounds differ from the instant compounds in their chemical structure. In WO2019090198A1, compounds used to modulate or inhibit the activity of HPK1 and methods for their use in treatment of viral infections and proliferative disorders, such as cancer are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/215668, MAP4K1 (HPK1) inhibitors and methods for their use in diseases including hyperproliferative diseases, diseases of immune system dysfunction, intlammatory disorders, neurological diseases, and cardiovascular diseases are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/049214, HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/049200, HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/049152, HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/049119, HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/102366, HPK1 inhibitors and methods for their use in the treatment of cancer are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/183956, HPK1 inhibitors and use of such compounds in treating HPK1-dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/183964, HPK1 inhibitors and use of such compounds in treating HPK1-dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure. In WO 2018/167147, HPK1 inhibitors and use of such compounds in treating HPK1-dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.In WO In WO2016/205942 HPK1, respectively inhibitors and methods of their use in cancer treatment are described. Specifically, the application concerns thieno-pyridinones that can be used in anti-cancer therapy. These compounds differ from the instant compounds in their chemical structure. In WO 2016/195776 inhibitors and methods for leukemia, cancer and diabetes treatment dependent on inhibition the interaction of menin with of MLL1, MLL2 and MLL-fusion oncoproteins are described. These compounds differ from the instant compounds in their chemical structure. In WO 2006/014325 C-MET modulators and their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2005/058891 Rho kinase inhibitors and their use in cardiovascular and cancer treatment are described. These compounds differ from the instant compounds in their chemical structure. In WO 2015/089479 several inhibitors are described that show inhibition of several kinases (e.g., BTK, HCK, TAK1 and HPK1). These compounds differ from the instant compounds in their chemical structure. In WO2016/004272 BTK inhibitors and methods of their use in cancer treatment are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2011/090738 Type II RAF kinase inhibitors and their use in various diseases are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In CN102086211 and WO2006116713 protein kinase inhibitors and their use in prophylaxis and treatment of diseases including cancer are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2010/045095 protein tyrosin kinase modulators and their use in the treatment of hyperproliferative disorders are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2008/089307 compounds and methods of their use in the treatment of pain, inflammation and cancer are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2006/114180 kinase inhibitors for treating diseases, particularly tumors are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2006/014325 c-Met modulators and their methods of use to treat kinase-dependent diseases and conditions are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In US 2003/0055049 compounds for treating disorders with abnormal cell growth in mammals are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2001/23389 antagonists of NPY receptors compositions and methods of the treatment of physiological disorders associated with an excess of neuropeptide Y are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention. In WO 2019/149738 protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death are described. It would therefore be desirable to provide novel MAP4K1 inhibitors having prophylactic and therapeutic properties. Accordingly, it is an object of the present invention to provide compounds and pharmaceutical compositions comprising these compounds used for prophylactic and therapeutic applications for hyperproliferative disorders, in particular for cancer, respectively tumour disorders, and conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients. A further object of the present invention is to provide compounds and pharmaceutical compositions comprising these compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control. Surprisingly, the compounds according to the invention inhibit the MAP4K1 protein and inhibit the growth of cancer cells. Accordingly, they provide novel structures for the therapy of human and animal disorders, in particular of cancers. A) The present invention relates to compounds of formula (I)
Figure imgf000008_0001
in which X represents either a direct bond, -CH2- or -O-, Y represents -H, -Cl, -Br, -CN, -CF3, C1-C4-alkyl, C3-C7-cycloalkyl, R1 represents a group *-A-B, in which *-A- represents a direct bond and in which B represents -H or phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, an optionally with an oxo-group (=O) substituted C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) and in which *-A- represents a group *-CRaH-, in which Ra represents -H, C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) and in which B represents -H, -CN, C1-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NHRb, in which Rb represents -H, C1-C4-alkoxy, C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl (optionally - OCH3 substituiert), C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)),
Figure imgf000010_0001
or in which R6 and R7 are hydrogen or bridged by C1-C4-alkyl in which one -CH2-group can be replaced by oxygen, in which A represents a group *-C(=O)- or *-SO2- and in which B represents C1-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, C1-C4- alkoxy, an oxo-group (=O),-S(O)2-CH3, -S(O)(NRz)-CH3, or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=O)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) or 5- to 6-membered heteroaryl, C2-C4-alkenyl, , phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), in which A represents a group *-C(=O)-O-,
Figure imgf000011_0001
, in which Rc represents -H or C1-C4-alkyl, *-C(=O)-NRc-, in which Rc represents -H or C1-C4-alkyl, *-C(=S)-NRc-, in which Rc represents -H or C1-C4-alkyl, *-C(=N-CN)-O- or *-C(=N-CN)-NRg-, in which Rg represents -H or C1-C4-alkyl and in which B represents -H, C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1- C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), -S(O)(NRz)- CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C2-C6-alkenyl, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -SO2-(C1-C4-alkyl), a group –C(=O)-Rd, in which Rd represents -CF3, C1-C4-alkoxy or C3-C7-cycloalkyl, a group -(CH2)n-Re in which n is 1 or 2 and in which Re represents 4 to 7-membered heterocycloalkyl, optionally substituted with an oxo-group (=O), -phenyl or 5- or 6- membered heteroaryl, optionally substituted with C1-C4-alkyl; or N, Rc und B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with C1-C4-alkyl or -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), a group –C(=O)-Rf, in which Rf represents C1-C4-alkyl or C3-C7- cycloalkyl, R2 represents ,
Figure imgf000012_0001
R4 represents -H, -NO2, -CN, -OH, -P(=O)(C1-C4-alkyl)2, -S(=O)2-(C1-C4-alkyl), -N=S(=NH)(C1-C4-alkyl)2, -N=S(=O)(C1-C4-alkyl)2, halogen -C(=O)-O- C1-C4-alkyl, -C(=O)- C1-C4-alkyl, -O-CH3, -C2-C6-alkoxy, optionally substituted with -F, -OH, -O-CH3, -S-CH3, -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=O), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4- alkoxy, an oxo-group (=O), -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NRvRw or -C(=O)-O-Rv, in which Rv represents -H or C1-C4-alkyl, Rw represents -H, C1-C4- alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl - C3-C6-alkenyloxy, C1-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7- membered heterocycloalkenyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), - C(=O)-O-CH3, phenyl or 5- or 6-membered heteroaryl, C2-C4-alkynyl, optionally substituted with 5- to 6-membered heteroaryl, this heteroaryl again optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, - OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), phenyl, optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRiRj, in which Ri represents -H, C1-C4-alkyl and Rj represents -H, C1-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, Ri and Rj together form a 4- to 7-membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=O) or C1-C4-alkyl -NRi-S(=O)2-Rp, in which Ri represents -H, C1-C4-alkyl and Rp represents 5- or 6- membered heteroaryl, -NH-C(=O)-NRkRl, in which Rk represents -H or C1-C4-alkyl and Rl represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -NH-C(=O)-Rm, in which Rm represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -(C=O)-NRnRo, in which Rn represents -H or C1-C4-alkyl, Ro represents C1-C6-
Figure imgf000015_0001
hydroxyalkyl, 5- or 6-membered heteroaryl (N), or
Figure imgf000015_0002
or in which N, Rn and Ro together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN, R5 represents -H, C1-C4-alkyl, -F or -Cl, R15 represents -H, C1-C4-alkyl, -CF3, -F, -Cl,-O-CH3 or -CN or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. A’) The present invention also relates to compounds of formula (I)
Figure imgf000015_0003
in which X represents either a direct bond, -CH2- or -O-, Y represents -H, -Cl, -Br, -CN, -CF3, C1-C4-alkyl, C3-C7-cycloalkyl, R1 represents a group *-A-B, in which *-A- represents • a direct bond and in which B represents • hydrogen or • phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) or in which *-A- represents a group *-CRaH-, in which Ra represents • hydrogen, • C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) and in which B represents • hydrogen, • -CN, • C1-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • -C(=O)-NHRb, in which Rb represents •• hydrogen, •• C1-C4-alkoxy, •• C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or •• phenyl or a 5- or 6- membered heteroaryl or a 9- or 10- membered bicyclic heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl (optionally -OCH3 substituiert), C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, - S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or
Figure imgf000017_0001
• in which R6 and R7 are hydrogen or bridged by C1-C4-alkyl in which one -CH2-group can be replaced by oxygen, or in which A represents a group • *-C(=O)- or *-SO2- and in which B represents • C1-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, C1-C4- alkoxy, an oxo-group (=O),-S(O)2-CH3, -S(O)(NRz)-CH3, or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=O)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) or 5- to 6-membered heteroaryl, • C2-C4-alkenyl, •
Figure imgf000018_0001
, • phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or in which A represents a group • *-C(=O)-O-, •
Figure imgf000018_0002
, in which Rc represents -H or C1-C4-alkyl, • *-C(=O)-NRc-, in which Rc represents -H or C1-C4-alkyl, • *-C(=S)-NRc-, in which Rc represents -H or C1-C4-alkyl, • *-C(=N-CN)-O- or • *-C(=N-CN)-NRc, in which Rc represents -H or C1-C4-alkyl and in which B represents • -H, • C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1- C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), -S(O)(NRz)- CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • C2-C6-alkenyl, • phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • -SO2-(C1-C4-alkyl), • a group –C(=O)-Rd, in which Rd represents •• -CF3, •• C1-C4-alkoxy or •• C3-C7-cycloalkyl, • a group -(CH2)n-Re in which n is 1 or 2 and in which Re represents •• 4 to 7-membered heterocycloalkyl, optionally substituted with an oxo-group (=O), •• -phenyl, optionally substituted with C1-C4-alkyl, or •• 5- or 6- membered heteroaryl, optionally substituted with C1-C4-alkyl, • N, Rc and B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with C1-C4-alkyl or -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or • a group –C(=O)-Rf, in which Rf represents C1-C4-alkyl or C3-C7- cycloalkyl, R2 represents ,
Figure imgf000019_0001
R4 represents • -H, • -NO2, • -CN, • -OH, • -P(=O)(C1-C4-alkyl)2, • -S(=O)2-(C1-C4-alkyl), • -N=S(=NH)(C1-C4-alkyl)2, • -N=S(=O)(C1-C4-alkyl)2, • halogen • -C(=O)-O- C1-C4-alkyl, • -C(=O)- C1-C4-alkyl, • -O-CH3, • -C2-C6-alkoxy, optionally substituted with •• -F, -OH, -O-CH3, -S-CH3, -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=O), •• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), •• C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4- alkoxy, an oxo-group (=O), -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), •• -C(=O)-NRvRw or -C(=O)-O-Rv, in which Rv represents -H or C1-C4-alkyl, Rw represents -H, C1-C4- alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl • C3-C6-alkenyloxy, • C1-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7- membered heterocycloalkenyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), - C(=O)-O-CH3, phenyl or 5- or 6-membered heteroaryl, • C2-C4-alkynyl, optionally substituted with 5- to 6-membered heteroaryl, this heteroaryl again optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, - OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, C1- C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • phenyl, optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • -NRiRj, in which Ri represents -H, C1-C4-alkyl and Rj represents -H, C1-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, Ri and Rj together form a 4- to 7-membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=O) or C1-C4-alkyl • -NRi-S(=O)2-Rp, in which Ri represents -H, C1-C4-alkyl and Rp represents 5- or 6- membered heteroaryl, • -NH-C(=O)-NRkRl, in which Rk represents -H or C1-C4-alkyl and Rl represents •• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or •• C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) • -NH-C(=O)-Rm, in which Rm represents •• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or •• C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), • -(C=O)-NRnRo, in which Rn represents -H or C1-C4-alkyl, Ro represents C1-C6-
Figure imgf000022_0001
hydroxyalkyl, 5- or 6-membered heteroaryl (N), or or in which N, Rn and Ro together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN, R5 represents -H, C1-C4-alkyl, -F or -Cl, R15 represents -H, C1-C4-alkyl, -CF3, -F, -Cl,-O-CH3 or -CN or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. The compounds of formula (I) are particularly suitable for a large number of prophylactic and therapeutic applications, in particular for hyperproliferative disorders, for tumour disorders and as proteine inhibitors and further for viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for male fertility control. Further, it covers their use in combination with other anti cancer medications such as immunotherapeutics, targeted anti cancer agents, radiation or chemotherapy. DEFINITIONS In case an asterix is used in a formula, like for instance in *-A-B or *-A-, this asterix indicates the bond towards the core of the compound. The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible. The term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or … atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3. As used herein, the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”. When groups in the compounds according to the invention are substituted, it is possible for said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent. As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond. The term “ring substituent” means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring. The term “comprising” when used in the specification includes “consisting of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text. The terms as mentioned in the present text have the following meanings: The term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom. The term “C1-C6-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group. The term “C1-C6-hydroxyalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C6-alkyl” is defined supra, and in which 1, 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group. The term “C1-C6-haloalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C6-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C1-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl. Preference is given to perfluorinated alkyl radicals which are named as “perfluoro-C1-Cx-alkyl-“ wherein x is the maximum number of carbon atoms such as trifluoromethyl or 2,2,2- trifluoroethyl. The term “C1-C6-cyanoalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C6-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a cyano group. The term “C1-C6-alkoxy” means a linear or branched, saturated, monovalent group of formula (C1-C6-alkyl)-O-, in which the term “C1-C6-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof. The term “C1-C6-haloalkoxy” means a linear or branched, saturated, monovalent C1-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C1-C6-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy. Preference is given to perfluorinated alkyl radicals which are named as “perfluoro-C1-Cx- alkoxy-“ wherein x is the maximum number of carbon atoms such as trifluoromethoxy and 2,2,2-trifluoroethoxy radicals. The term “C1-C6-cyanoalkoxy” means a linear or branched, saturated, monovalent C1-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a cyano group. Mono-(C1-C4)-alkylamino in the context of the invention means an amino group with one straight-chain or branched alkyl substituent which contains 1, 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino, for example. Di-(C1-C4)-alkylamino in the context of the invention means an amino group with two identical or different straight-chain or branched alkyl substituents which each contain 1, 2, 3 or 4 carbon atoms, such as: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n- propylamino, N-isopropyl-N-methylamino, N-isopropyl-N-n-propylamino, N,N-diisopropylamino, N-n-butyl-N-methylamino, and N-tert-butyl-N-methylamino, for example. (C1-C4)-Alkylcarbonyl in the context of the invention means a straight-chain or branched alkyl group having having 1, 2, 3 or 4 carbon atoms which is bound to the rest of the molecule via a carbonyl group [-C(=O)-], such as: acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, and pivaloyl, for example. (C1-C4)-Alkylcarbonyloxy in the context of the invention means a straight-chain or branched alkyl group having 1, 2, 3 or 4 carbon atoms which is bound to the rest of the molecule via a carboxy group [-C(=O)-O-], such as: acetoxy (=acyloxy), propionyloxy, n-butyryloxy, isobutyryloxy, n-pentanoyloxy, and pivaloyloxy, for example. Mono-(C1-C4)-alkylaminocarbonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a carbonyl group [-C(=O)-] and which has one straight- chain or branched alkyl substituent having 1, 2, 3 or 4 carbon atoms, such as: methylamino- carbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylamino- carbonyl, and tert-butylaminocarbonyl, for example. Di-(C1-C4)-alkylaminocarbonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a carbonyl group [-C(=O)-] and which has two identical or different straight-chain or branched alkyl substituents having in each case 1, 2, 3 or 4 carbon atoms, such as: N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methyl- aminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-methylaminocarbonyl, N,N- diisopropylaminocarbonyl, N-n-butyl-N-methylaminocarbonyl, and N-tert-butyl-N- methylaminocarbonyl, for example. Mono-(C1-C4)-alkylaminosulfonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a sulfonyl group [-S(=O)2-] and which has one straight- chain or branched alkyl substituent having 1, 2, 3 or 4 carbon atoms, such as: methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylamino sulfonyl, and tert-butylaminosulfonyl, for example. Di-(C1-C4)-alkylaminosulfonyl in the context of the invention means an amino group which is bound to the rest of the molecule via a sulfonyl group [-S(=O)2-] and which has two identical or different straight-chain or branched alkyl substituents having in each case 1, 2, 3 or 4 carbon atoms, such as: N,N-dimethylaminosulfonyl, N,N-diethylaminosulfonyl, N-ethyl-N-methyl- aminosulfonyl, N-methyl-N-n-propylaminosulfonyl, N-isopropyl-N-methylaminosulfonyl, N,N- diisopropylaminosulfonyl, N-n-butyl-N-methylaminosulfonyl, and N-tert-butyl-N- methylaminosulfonyl, for example. The term “C3-C8-cycloalkyl” means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms (“C3-C8-cycloalkyl”). Said C3-C8-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl. The term “C3-C8-cycloalkoxy” means a saturated, monovalent, mono- or bicyclic group of formula (C3-C8-cycloalkyl)-O-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “C3-C8-cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group. The terms “4- to 7-membered heterocycloalkyl” and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated or unsaturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. A carbon atom may be substituted with an oxo group or or the sulphur atom with one or two oxo groups to form a –C=O, –S(=O)- or –S(=O)2-group in the ring. Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example, or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl, for example. Particularly, 4- to 6-membered heterocycloalkyl means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O. The term “bridged heterocycloalkyl” means a bicyclic, saturated or unsaturated heterocycle with 7, 8, 9 or 10 ring atoms in total (= “bridged bicyclic 7- to 10-membered heterocycloalkyl”), in which the two rings share two common ring atoms which are not adjacent, which “bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom. A carbon atom may be substituted with an oxo group or or the sulphur atom with one or two oxo groups to form a –C=O, –S(=O)- or –S(=O)2-group in the ring. Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo- [2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi- cyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]- nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiaza- bicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or azabicyclo[4.2.2]decyl. The term “heteroaryl” means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency). Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10- membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl. In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. Particularly, the heteroaryl group is a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group group such as, for example, pyridinyl (=pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl. The term “C1-C6”, as used in the present text, e.g. in the context of the definition of “C1-C6-alkyl”, “C1-C6-haloalkyl”, “C1-C6-hydroxyalkyl”, “C1-C6-alkoxy” or “C1-C6-haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. Further, as used herein, the term “C3-C8”, as used in the present text, e.g. in the context of the definition of “C3-C8-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompasses each value and sub-range within said range. For example: "C1-C6" encompasses C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C2-C6" encompasses C2, C3, C4, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C3-C10" encompasses C3, C4, C5, C6, C7, C8, C9, C10, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9-C10; "C3-C8" encompasses C3, C4, C5, C6, C7, C8, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C3-C6" encompasses C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C4-C8" encompasses C4, C5, C6, C7, C8, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C4-C7" encompasses C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6 and C6-C7; C4-C6 encompasses C4, C5, C6, C4-C6, C4-C5 and C5-C6; "C5-C10" encompasses C5, C6, C7, C8, C9, C10, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6- C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9-C10; "C6-C10" encompasses C6, C7, C8, C9, C10, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9-C10. As used herein, the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butyl- phenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976). The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio. Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides. The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates. The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates. Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention. The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19. A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example. Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3- propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N- trimethylammonium, choline or benzalkonium. Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods. The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio. In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio. Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body. The invention further includes all possible crystallized and polymorphic forms of the inventive compounds, whereby the polymorphs are existing either as a single polymorph form or are existing as a mixture of several polymorphs in all concentrations. The invention further includes all possible cyclodextrin clathrates, i.e alpha-, beta-, or gamma- cyclodextrins, hydroxypropyl-beta-cyclodextrins, methylbetacyclodextrins. B) Of selected interest are those compounds of formula (I) in which X represents either a direct bond, -CH2- or -O-, Y represents -H, -Cl, -Br, -CN, -CF3, C1-C4-alkyl, C3-C7-cycloalkyl, R1 represents a group *-A-B, in which *-A- represents a direct bond and in which B represents -H or in which *-A- represents a group *-CRaH-, in which Ra represents -H, C1-C4-alkyl or C3-C7-cycloalkyl all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1- C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) and in which B represents -H, -CN, C1-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NHRb, in which Rb represents -H, C1-C4-alkoxy, C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl (optionally - OCH3 substituiert), C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or
Figure imgf000035_0001
in which R6 and R7 are hydrogen or bridged by C1-C4-alkyl in which one -CH2-group can be replaced by oxygen, in which A represents a group *-C(=O)- and in which B represents C1-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, C1-C4- alkoxy, an oxo-group (=O),-S(O)2-CH3, -S(O)(NRz)-CH3, or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=O)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) or 5- to 6-membered heteroaryl, C2-C4-alkenyl,
Figure imgf000035_0002
, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), in which A represents a group *-C(=O)-O-, *-C(=O)-NRc-, in which Rc represents -H or C1-C4-alkyl, *-C(=S)-NRc-, in which Rc represents -H or C1-C4-alkyl, in which B represents -H, C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1- C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), -S(O)(NRz)- CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C2-C6-alkenyl, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -SO2-(C1-C4-alkyl), a group –C(=O)-Rd, in which Rd represents -CF3, C1-C4-alkoxy or C3-C7-cycloalkyl, a group -(CH2)n-Re in which n is 1 or 2 and in which Re represents 4 to 7-membered heterocycloalkyl, optionally substituted with an oxo-group (=O), -phenyl or 5- or 6- membered heteroaryl, optionally substituted with C1-C4-alkyl; or N, Rc und B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with C1-C4-alkyl or -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), a group –C(=O)-Rf, in which Rf represents C1-C4-alkyl or C3-C7- cycloalkyl, R2 represents
Figure imgf000037_0001
R4 represents -H, -NO2, -CN, -OH, -P(=O)(C1-C4-alkyl)2, -S(=O)2-(C1-C4-alkyl), halogen -C(=O)- C1-C4-alkyl, -O-CH3, -C2-C6-alkoxy, optionally substituted with -F, -OH, -O-CH3, -S-CH3, -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=O), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4- alkoxy, an oxo-group (=O), -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NRvRw or -C(=O)-O-Rv, in which Rv represents -H or C1-C4-alkyl, Rw represents -H, C1-C4- alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl - C3-C6-alkenyloxy, C1-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7- membered heterocycloalkenyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), - C(=O)-O-CH3, phenyl or 5- or 6-membered heteroaryl, C2-C4-alkynyl, optionally substituted with 5- to 6-membered heteroaryl, this heteroaryl again optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, - OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), phenyl, optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRiRj, in which Ri represents -H, C1-C4-alkyl and Rj represents -H, C1-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, Ri and Rj together form a 4- to 7-membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=O) or C1-C4-alkyl -NRi-S(=O)2-Rp, in which Ri represents -H, C1-C4-alkyl and Rp represents 5- or 6- membered heteroaryl, -NH-C(=O)-NRkRl, in which Rk represents -H or C1-C4-alkyl and Rl represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -NH-C(=O)-Rm, in which Rm represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -(C=O)-NRnRo, in which Rn represents -H or C1-C4-alkyl, Ro represents C1-C6-
Figure imgf000040_0001
hydroxyalkyl, 5- or 6-membered heteroaryl (N), or
Figure imgf000040_0002
or in which N, Rn and Ro together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN, R5 represents -H, -F or -Cl, R15 represents -H, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. C) Of selected interest are those compounds defined under A) (page 6) or B (page 25) in which R2 is selected from
Figure imgf000040_0003
D) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R2 is
Figure imgf000040_0004
E) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R2 is
Figure imgf000040_0005
and wherein R4 is selected from hydrogen, -F, -Cl, methyl, ethyl and isopropyl. F) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R1 is selected from -C(=O)-O-tBu, -C(=O)-NH-Et, -C(=O)-NH-C(=O)-O-Et,
Figure imgf000041_0001
G) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein X is a direct bond. G1) Of selected interest are those compounds defined under A) (page 6), A’ (page 13) or B (page 32) wherein X is oxygen. G2) Of selected interest are those compounds definded under A (page 6), A’ (page 13) or B (page 32) in which R1 represents a group *-A-B, in which A represents a group *-C(=O)-NRc- and in which Rc represents -H or C1-C4-alkyl. H) Of selected interest are those compounds defined under A) (page 6) or B (page 32) wherein Y is hydrogen or -Cl. I) Compounds of most interest are those as follows: ● (rac)-tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(thieno[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6-chloroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(5-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6-fluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(isoquinolin-4-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl (3S)-2'-(2-aminopyrimidin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(1H-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(imidazo[1,2-a]pyrimidin-6-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl (3S)-2'-[6-(methoxycarbonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl (3S)-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6,7-difluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-fluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(5-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(7-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(7-fluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate(rac)-N-ethyl-2'- (quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide ● (rac)-N-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-cyclopropyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-methyl [(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbonyl]carbamate ● (rac)-N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-cyclopentyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-[(furan-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 1) ● (N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 2) ● (rac)-N-(prop-2-en-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-ethyl [2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbonyl]carbamate ● ethyl [(3S)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazole]-1- carbonyl]carbamate (enantiomer 1) ● ethyl [(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbonyl]carbamate (enantiomer 2) ● (rac)-N-(ethanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(2-chloroethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-(6,7-difluoroquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (3S)-N-ethyl-2'-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(1H-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-ethyl [2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carbonyl]carbamate ● (rac)-3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-3'-chloro-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-(Morpholin-4-yl)[(3S)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-N,N-diethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-(pyrrolidin-1-yl)[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(4-methylpiperazin-1-yl)[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2-ethyl-1-[2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]butan-1-one ● (rac)-3-methoxy-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-1-one ● (rac)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbonyl]cyclopropane-1-carbonitrile ● (rac)-2-(morpholin-4-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● (rac)-1-{2-oxo-2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethyl}pyrrolidin-2-one ● (rac)-3-(1H-pyrazol-1-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]propan-1-one ● (rac)-(pyridin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(1-methyl-1H-imidazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-(pyridin-3-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(pyrimidin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(1-methyl-1H-pyrazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-4-oxo-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]- 1-yl]butanenitrile ● (rac)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-one ● (rac)-(3-chlorophenyl)[2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2-(pyrimidin-5-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (rac)-(1H-imidazol-2-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(oxetan-3-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2-methyl-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-1-one9.438 (5.58). ● (rac)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propan-1-one ● (rac)-2-(oxan-4-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (rac)-2-(oxetan-3-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (rac)-(oxan-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2,2-dimethyl-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-1-one ● (rac)-1-(methanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-sulfonamide ● (rac)-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-sulfonamide ● (3R)-1-(cyclopropanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (1-[(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● (1-[(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-1-[(1H-indazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]—hydrogen chloride ● 1-[(1H-indazol-3-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● 1-[(1H-indazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-1-[(2-methylpyrimidin-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-N,N-dimethyl-5-{[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methyl}-1,3-thiazol-2-amine ● (3S)-1-(cyclohexylmethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of 4 stereoisomers) ● (rac)-1-[(4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● 1-[(4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● 1-[(4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-1-[(4-chloro-1H-pyrazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,3-thiazol-5-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-methyl-1H-pyrazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1,2-oxazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(4-methyl-1H-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(2-methyl-1H-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-pyrazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-5-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole] ● (rac)-1-(2-methylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-1-{[1-(2-methoxyethyl)-1H-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-benzimidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,4,5-trimethyl-1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(imidazo[1,5-a]pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-{[4-(trifluoromethyl)-1H-imidazol-2-yl]methyl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-{[1-(propan-2-yl)-1H-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(pyridin-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-{[1-(propan-2-yl)-1H-benzimidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-.2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-ol ● (rac)-3-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propan-1-ol ● (rac)-2-methyl-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]butan-2-ol ● (rac)-N,N-dimethyl-2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-amine ● (rac)-1-[2-(morpholin-4-yl)ethyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole] ● (rac)-N,N-dimethyl-3-[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]propan-1-amine ● (rac)-1-[3-(morpholin-4-yl)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2-methyl-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-2-ol ● (rac)-N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbothioamide ● (rac)-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbothioamide ● (rac)-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carbothioamide ● (rac)-ethyl [2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbothioyl]carbamate ● (rac)-N-(1-methyl-1H-pyrazol-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carbothioamide ● (rac)-N-(3,5-dimethyl-1,2-oxazol-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carbothioamide ● (rac)-1-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-1-(pyridin-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-Phenyl (3S)-N-cyano-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboximidate ● (rac)-N'-cyano-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboximidamide ● (rac)-N'-cyano-N-(2-hydroxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboximidamide ● (rac)-N'-cyano-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboximidamide ● (rac)-3-(ethylamino)-4-[-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]cyclobut-3-ene-1,2-dione ● (rac)-3-(dimethylamino)-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]cyclobut-3-ene-1,2-dione ● (rac)-Ethyl -2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazole]-1- carboxylate ● (rac)-2-methoxyethyl -2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● tert-butyl -2'-{3-[4-(S-methanesulfonimidoyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (21.00, mixture of 4 stereoisomers) and tert-butyl -2'-(3-{4-[N-(methoxycarbonyl)-S- methylsulfonimidoyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (21.01, mixture of 4 stereoisomers) ● (rac)-tert-butyl -2'-[3-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl 2-(quinolin-3-yl)-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate ● (rac)- tert-butyl 2-(6-methoxyquinolin-3-yl)-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxylate ● (rac)-tert-butyl -2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxylate ● (rac)-tert-butyl -2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxylate ● (rac)-N-ethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-cyclobutyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(rac)-2,2-dimethylcyclopropyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(1S)-2,2,2-trifluoro-1-methoxy-1-phenylethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyrimidin-5-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyrimidin-4-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● 2-(5-fluoropyridin-2-yl)-2-methyl-1-[(rac)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]propan-1-one ● (rac)-N-[2-(5-fluoropyridin-2-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3,4-difluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-fluorophenyl)cyclopentyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(6-chloropyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-cyano-1,4-dihydropyridazin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-cyanopyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(4-phenyloxan-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-[6-(cyclohexyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-cyclobutyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-tert-butyl-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-tert-butyl-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(dimethylphosphoryl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[6-(trifluoromethyl)quinolin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(3-oxomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(2-oxopyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(trifluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(3-chloropyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-[6-(difluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(propan-2-yl)-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-tert-butyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(5-amino-4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(cyclopropylmethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(pyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(pyridin-2-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(3-methyloxetan-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-propyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2'-{3-[(pyridin-4-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(propan-2-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● ()-N-(propan-2-yl)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(methanesulfonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(3-fluoropyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(1R)-1-phenylethyl]-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[(rac)-1-(1,2-oxazol-3-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[2-(4-fluorophenyl)propan-2-yl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(quinolin-3-yl)-N-(1H-tetrazol-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine- 4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyridin-4-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-{(rac)-1-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]ethyl}-2-(quinolin-3-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[(rac)-1-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3-thiazol-2-yl)ethyl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-phenyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-ethyl-5-methyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[1-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(rac)-1-(2-methylpyridin-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereosiomers) ● (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-phenylcyclobutyl)-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(4-fluorophenyl)propan-2-yl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-phenylpentan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(rac)-1-(1-methyl-1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-benzimidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3,4-trimethyl-1H-pyrazol-5-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(1R)-1-(1-ethyl-1H-pyrazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-{(rac)-1-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]ethyl}-2'-(quinolin-3-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(1R)-1-phenylethyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[1-(pyridin-4-yl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyridin-2-yl)propan-2-yl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(propan-2-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1H-imidazol-2-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(bicyclo[1.1.1]pentan-1-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(1-methylcyclobutyl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-[(pyridin-4-yl)methyl]-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(pyridin-4-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-[(pyridin-3-yl)methyl]-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(pyridin-4-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(pyridin-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-(quinolin-3-yl)-N-(2H-tetrazol-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-[(pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2,2-dimethylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[[1,1'-bi(cyclopropan)]-1-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(pyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[[1,1-bi(cyclobutan)]-1-yl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-cyclopropylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-methoxyphenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(pyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(pyridin-2-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-benzylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(quinolin-3-yl)-N-[1-(trifluoromethyl)cyclobutyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-methylcyclopentyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-cyanocyclopropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(propan-2-yl)cyclopropyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2-cyanopropan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2-phenylpropan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-chlorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-phenylcyclopropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2,2-dimethylpropyl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(cuban-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(3,3-dimethylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(cis/trans)-3-(dimethylamino)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereoisomers) ● (rac)-N-(1-cyanocyclobutyl)-2-(quinolin-3-yl)-5,6-dihydro-1H-spiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(bicyclo[1.1.1]pentan-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(3,3-difluorocyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(cis/trans)-3-methylcyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereoisomers) ● (rac)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-methylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-phenylethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-N-[2-(pyridin-4-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[2-(pyridin-4-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3-fluoropyridin-2-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(2,6-difluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(2-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(4-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(2-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3-chlorophenyl)propan-2-yl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(3-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-chlorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-phenylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[1-(pyridin-4-yl)cyclobutyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-chlorophenyl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[1-(pyridin-2-yl)cyclobutyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(quinolin-3-yl)-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2'-[7-(morpholin-4-yl)-1,6-naphthyridin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-(5-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-(1-phenylcyclobutyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[6-(morpholin-4-yl)-1,5-naphthyridin-3-yl]-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(1-phenylcyclohexyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclobutyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(3-methylphenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-(6-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(7-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(1,3-thiazol-2-yl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[7-(dimethylamino)-1,6-naphthyridin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(2-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(4-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[2-(4-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[2-(3-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(methylamino)-1,5-naphthyridin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(dimethylamino)-1,5-naphthyridin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-amino-1,5-naphthyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{7-fluoro-6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(6-methoxyquinolin-3-yl)-N-(1-phenylcyclobutyl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3H-imidazo[4,5-b]pyridin-6-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(5-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(6-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-2-(6-chloroquinolin-3-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-2'-(5-chloro-6-methoxyquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)carbamoyl]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-tert-butylquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)methoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-2-yl)methoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● methyl {3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-2'-yl]quinolin-6-yl}acetate ● (rac)-2-[6-(cyclohexyloxy)-7-fluoroquinolin-3-yl]-N-ethyl-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{7-fluoro-6-[(oxan-4-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (1-benzylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (cuban-1-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (1-ethylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● [1-(difluoromethyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● 2-(pyridin-3-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● [1-(4-chlorophenyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (1-methylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● [1-(4-fluorophenyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● 2-cyclobutyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (1-methylcyclopropyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (3-methyloxetan-3-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● cyclobutyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● cyclopentyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● 2-cyclopropyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● 2-phenyl-1-[(rac)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● phenyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone ● 2-methoxy-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● [(rac)-2,2-difluoro-1-methylcyclopropyl][(rac)-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of diastereomers) ● (rac)-N-ethyl-2'-{5-[(pyridine-3-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridine-4-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridine-2-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● 1-[(rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]-2-(1-methyl-1H-imidazol-2-yl)ethan-1-one ● 2-(1H-imidazol-2-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● 2-(1-methyl-1H-imidazol-2-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● (rac)-N-ethyl-2'-{6-[(2-hydroxy-2-methylpropyl)carbamoyl]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(oxane-4-carbonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-acetamidoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-[5-(2,2-dimethylpropanamido)quinolin-3-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[5-(2-methylpropanamido)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-benzamidoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● [(rac)-2,2-difluoro-1-methylcyclopropyl][-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of stereoisomers). ● [(rac)-2,2-difluoro-1-methylcyclopropyl][-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of stereoisomers) ● N-ethyl-2-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) ● N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) ● N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide (enantiomer 1) ● N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide (enantiomer 2) ● 2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) ● 2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) ● 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) ● 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) ● N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 1) ● N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 2) ● 2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide (enantiomer 1) ● 2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide (enantiomer 2) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isomer 1) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isiomer 2) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isiomer 3) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isiomer 4) ● 1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● 1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-2-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(1H- imidazol-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(thiophen-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-chlorothiophen-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1H-1,2,3-triazol-5-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(thiophen-3-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(thiophen-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,3-thiazol-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1,3-oxazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(4-chloro-1H-pyrazol-3- yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1'-[(4-chloro-1H-pyrazol-5-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl]-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(1H-imidazol-2-yl)methyl]- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1'-[(1H-imidazol-2-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7- dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin- 5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1'-[(1H-imidazol-2-yl)methyl]-6,7-dihydro- 5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] ● (rac)-2'-(quinolin-3-yl)-1-[(4H-1,2,4-triazol-3-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● 1-[(rac)-1-(1H-imidazol-2-yl)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of two isomers) ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-methyl-1H-imidazol-2-yl)methyl]-2-[3-(1-methyl-1H-pyrazol-5-yl)-1H- pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(rac)-1-(4H-1,2,4-triazol-3-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(5-ethyl-4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-cyclopropyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(rac)-1-(1H-imidazol-2-yl)ethyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(rac)-cyclopropyl(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-{3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(4-methyl-1H-pyrazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(rac)-(1H-imidazol-2-yl)(phenyl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(4-chloro-1H-pyrazol-3-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(4-chloro-3-methyl-1H-pyrazol-5-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● trifluoroacetic acid—(rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) ● (rac)-N-ethyl-2-[6-(4-methyl-2-oxopiperazin-1-yl)quinolin-3-yl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(2-oxopyrrolidin-1-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-{[dimethyl(oxo)-lambda6-sulfanylidene]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(2,2-dimethyl-2lambda6-diazathia-1,2-dien-1-yl)quinolin-3-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(1-methyl-1H-pyrazol-5-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(1H-pyrazol-5-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(1-methyl-1H-pyrazol-4-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-cyclopropylquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[(prop-2-en-1-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[3-(dimethylamino)propoxy]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[(oxan-4-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(3-methoxypropoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[2-(morpholin-4-yl)ethoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-{[(rac)-butan-2-yl]oxy}quinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2'-(6-{[(rac)-oxolan-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2'-{6-[2-(methylsulfanyl)ethoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{[(rac)-oxolan-3-yl]oxy}quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2-[6-(2-methylpropoxy)quinolin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[2-(dimethylamino)ethoxy]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(2-methoxyethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{[(rac)-1-methylpiperidin-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2'-(5-{[(oxan-4-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[methyl(1-methylazetidin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(oxetan-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[methyl(oxetan-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(1-methylazetidin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{5-[(cyclopentylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyrrolidine-1-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-{[cyclobutyl(methyl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(1-methylcyclobutyl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-{[cyclopropyl(methyl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-{[(bicyclo[1.1.1]pentan-1-yl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{5-[(cyclobutylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[5-({[2-(trifluoromethyl)cyclopropyl]carbamoyl}amino)quinolin-3-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{5-[(cyclopropylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-{5-[(cyclohexylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(pyridin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(ethylcarbamoyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● methyl (1-{[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methyl}cyclopropyl)acetate ● 3-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propanoic acid ● [(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetonitrile ● N-methoxy-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]acetamide ● N-cyclopropyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]acetamide ● (rac)-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propanamide (mixture of stereoisomers) ● 2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetamide ● N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]acetamide ● (rac)-N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl] (mixture of isomers) ● (rac)-3'-bromo-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-3'-methyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3'-cyclopropyl-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[1-(cyclopropylmethyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(1,4-dimethyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-{3-[1-(propan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(2-methylpropyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(2-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(1-ethyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(1-cyclopropyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-3'-cyclopropyl-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-3'-bromo-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(2,5-dihydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[2-(methylamino)-2-oxoethoxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(2-amino-2-oxoethoxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[2-(morpholin-4-yl)-2-oxoethoxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[2-(dimethylamino)-2-oxoethoxy]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-benzyl-N'-cyano-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboximidamide ● (rac)-N-(oxetan-3-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3- pyrrolidine]-1'-carboxamide ● (rac)-1-(propane-2-sulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(rac)-hydroxy(phenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of steroisomers) ● (rac)-2'-{3-[2-(dimethylphosphoryl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● ethyl (rac)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-2'-[3-(ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(dimethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(trifluoromethyl)cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-[5-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(cyclopropanecarbonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{[(rac)-1-methyl-5-oxopyrrolidin-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (only one group of and/or stereo is supported now.) ● cyclopropyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2'-(8-amino-1,7-naphthyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-hydroxy-1,6-naphthyridin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-2-yl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-{5-[(pyridine-2-sulfonyl)amino]quinolin-3-yl}-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridine-3-sulfonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(2-hydroxy-2-methylpropyl)quinolin-3-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-1-(1-methyl-1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● 2-amino-1-[(rac)-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● 2-amino-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one  and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts. J) Also of interest are the intermediates for the synthesis of compounds definded hereunder, especially
Figure imgf000074_0003
wherein R1 has the meaning as R1 as defined under A) (page 6) or B (page 25). A further aspect of this invention is related to compounds of formula (1a) as follows: 1. A compound of general formula (1a): in which
Figure imgf000074_0002
X is selected from the group consisting of -CH2- and -O-; R2a is a 9-10 membered bicyclic heteroaryl
Figure imgf000074_0001
in which A is selected from the group consisting of a bond, and -C(R4a)-; D, E and G are independently of each other selected from the group consisting of -C(R4a)- and -N(R4a)-; and each R4a is independently of each other selected from the group consisting of a bond, hydrogen, halogen, C1-4-alkyl, -CN, -O-CH3, and -C(CH3)2-phenyl R3a is selected from the group consisting of –C(=O)-NH-R8a, −C(=O)-O-C(CH3)3, 5
Figure imgf000075_0005
R a is selected from the group consisting hydrogen and −CH3; R8a is selected from the group consisting of C1-6-alkyl, 5-6 membered heteroaryl, -CH2-5-6 membered heteroaryl, bicyclo[1.1.1]pentan-1-yl,
Figure imgf000075_0001
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2. A compound according to claim 1 of general formula (1a): in which X is selected from the group consisting of -CH2- and -O-; R2a selected from the group consisting of
Figure imgf000075_0002
in which each R4a is independently of each other selected from the group consisting of a bond, hydrogen, -F, -Cl, -CH3, -CH2-CH3, -CH(CH3)2, -CN, -O-CH3, and - C(CH3)2-phenyl R3a is selected from the group consisting of –C(=O)-NH-R8, −C(=O)-O-C(CH3)3,
Figure imgf000075_0003
R5a is selected from the group consisting of hydrogen and −CH3; R8a is selected from the group consisting of −CH2-CH3, −CH(CH3)2, −CH(CH3)3, −CH2-C(CH3)3, 1H-1,2,3,4-tetrazol-5-yl, pyridin- 4-yl, (pyridin-4-yl)methyl, (pyridin-3-yl)methyl, bicyclo[1.1.1]pentan-1-yl,
Figure imgf000075_0004
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2. A compound of general formula (1a) according to claim 1 or 2 in which X is -O- or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 3. A compound of general formula (1a) according to claim 1 or 2 in which X is -CH2- or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 4. A compound of general formula (1a) according to claim 1, 2, 3 or 4 in which R2a is
Figure imgf000076_0001
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 5. A compound of general formula (1a) according to claim 1, 2, 3 or 4 in which R2a is
Figure imgf000076_0002
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 6. A compound of general formula (1a) according to claim 1, 2, 3 or 4 in which R2a is
Figure imgf000076_0003
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 7. A compound of general formula (1a) according to claim 1, 2, 3 or 4 in which R2a is
Figure imgf000076_0004
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 8. A compound of general formula (1a) according to any one of claims 1 to 7 for use in the treatment or prophylaxis of a disease. 9. A pharmaceutical composition comprising a compound of general formula (1a) according to any one of claims 1 to 7 and one or more pharmaceutically acceptable excipients. 10. A pharmaceutical combination comprising: ● one or more first active ingredients, in particular compounds of general formula (1a) according to any one of claims 1 to 7, and ● one or more further active ingredients, in particular anti-hyperproliferative agents. 11. Use of a compound of general formula (1a) according to any one of claims 1 to 7 for the treatment or prophylaxis of a disease. 12. Use of a compound of general formula (1a) according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prophylaxis of a disease. 13. Use according to claim 8, 11 or 12, wherein the disease is a hyperproliferative disease such as cancer, for example. Just another aspect of this invention relates to compounds of formula (1b) as follows: 1. A compound of general formula (1b) in which:
Figure imgf000077_0001
Y is selected from the group consisting of −H, −CH3, −Cl, −Br, and cyclopropyl; R2b is selected from the group consisting of
Figure imgf000077_0002
in which each R4b is independently of each other selected from the group consisting of –H, C1-4-alkyl (−CH3, −CH2CH3, −C(CH3)3,), C3-4-cycloalkyl (cyclopropyl, cyclobutyl), halogen (−F, −Cl, −Br,) −CN, -OH, -O-CH3, −O-CHF2, −NH2, −NHCH3,−N(CH3)2, – NH-C(=O)-R74b, −CH2-OH, −CH2-C(CH3)2-OH, −C(=O)-CH3, −C(=O)-OCH3, −CH2- C(=O)-O-CH3, −CH2-N(CH3)2, −CH2-O-CH2-CH3, −CF3, −P(=O)(CH3)2, −CH2-CH2- P(=O)(CH3)2, −CH=CH-P(=O)(CH3)2, −C≡C-P(=O)(CH3)2, −S(=O)2-CH3, −C(CH3)(R62b)-CH2-R6b, −R67b-CF3, −N=S(CH3)2=R68b, −O-CH(R6b)-CH2R69b, −O- CH2-C(=R71b)R70b, −R73b-CH2-C(CH3)2-R48b,
Figure imgf000078_0002
Figure imgf000078_0001
R5b is selected from the group consisting of −H, −CH3, −F, and −Cl; R3b is selected from the group consisting of −CH2CH3, −CH(CH3)2, −CH2CN, −CH2CH2OR6b, −CSNHR7b, −SO2R8b, −R9bC(CH3)3, −R10bCH2N(CH3)2, −C(R11b)NCN, −COCH(R12b)R13b, −CON(R13b)R14b, pyridin-2-yl, pyridin-3-yl, 1- methyl-1H-imidazol-2-yl, (1H-1,2,3-triazol-5-yl)methyl, (thiophen-3-yl)methyl, −COOCH2CH2R15b, −CH(R6b)CONHR16b, −R17bCH2COOR6b, cyclohexylmethyl, cyclopentanecarbonyl, (3-methyl-1,2-oxazol-5-yl)methyl, pyrrolidine-1-carbonyl, 4- methylpiperazine-1-carbonyl, {imidazo[1,5-a]pyridin-3-yl}methyl, cubane-1- carbonyl,
Figure imgf000078_0003
Figure imgf000079_0001
R6b is selected from the group consisting of −H and −CH3; R7b is selected from the group consisting of −CH3, −CH2CH3, −COOCH2CH3, 1-methyl- 1H-pyrazol-4-yl, and 3,5-dimethyl-1,2-oxazol-4-yl; R8b is selected from the group consisting of −CH3, cyclopropyl, −CH(CH3)2, −NHCH2CH3, and −N(CH3)2; R9b is selected from the group consisting of -CO-, -NHCS-, -CH2NHCO-, -CO-NH- and -CO-O-; R10b is selected from the group consisting of −CH2− and −CH2CH2−; R11b is selected from the group consisting of −N(CH3)2, −NHCH2CH2R48b, and phenoxy; R12b is selected from the group consisting of −H, −CH3, −NH2, −CH2CH3, −OCH3, cyclopropyl, −CH2CN, −CH2OCH3, (1H-pyrazol-1-yl)methyl, and 2-oxopyrrolidin-1- yl; R13b is selected from the group consisting of −H, −CH3, and −CH2CH3; R14b is selected from the group consisting of −CH3, −CH2CH3, −CH2CH2CH3, −CH2CHCH2, −CH2CH2Cl, cyclopropylmethyl, −CH2CH2OCH3, −C(CH3)2R52b, cyclopropanecarbonyl, 2H-1,2,3,4-tetrazol-5-yl, −SO2CH2CH3, −COOCH2R6b, −R53bCF3, pyridin-4-yl, (furan-2-yl)methyl, 1-(1,2-oxazol-3-yl)ethyl, 1-(1,3-thiazol-2- yl)ethyl, cuban-1-yl, 1-(1-methyl-1H-pyrazol-3-yl)ethyl, 1-(1-methyl-1H-1,2,4-triazol- 5-yl)ethyl, 1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl,
Figure imgf000080_0004
R is selected from the group consisting of H and OCH3; R16b is selected from the group consisting of −H, −CH3, −OCH3, and cyclopropyl; R17b is selected from the group consisting of −CH2− and
Figure imgf000080_0001
R18b is selected from the group consisting of −CO−, −CH2NHCO−, and -CO-CH2- and - CO-NH-; R19b is selected from the group consisting of −H, −CH3, −CH2CH3, −CN, cyclopropyl, −CH(CH3)2, cyclobutyl, −CF2R26b, 4-cyano-1,4-dihydropyridazin-4-yl, and
Figure imgf000080_0002
R20b is selected from the group consisting of −CH2CH2CH2− and −CH2OCH2CH2−; R21b is selected from the group consisting of −NHCH2CH3 and −N(CH3)2; R22b is selected from the group consisting of −CH2CH2−, −CO−, −CH2CH2CH2−, and −CH2CO−; R23b is selected from the group consisting of −H, −Cl, and −N(CH3)2; R24b is selected from the group consisting of −H, −CH3, and −Cl; R25b is selected from the group consisting of −H, −CH3, and −CN; R26b is selected from the group consisting of −H and −F; R27b is selected from the group consisting of −CH3 and −OH; R28b is selected from the group consisting of −CH2−, −CO−, −CH2CO−, −C(R6b)2-NH- CO−, and
Figure imgf000080_0003
R29b is selected from the group consisting of −H and −CN; R30b is selected from the group consisting of −H, −CH2CH3, cyclopropyl, and phenyl; R31b is selected from the group consisting of −H, −CH3, and cyclopropyl; R32b s selected from the group consisting of −H and −CH2CH3; R33b is selected from the group consisting of −CH2−, −CHCH3−, −CHCH3−, −CO−, −CHCH3NHCO−, and -CO-CH2- and -CO-NH-; R34b is selected from the group consisting of −H, −CH3, and −CF3; R35b is selected from the group consisting of −H, −CH3, −CH(CH3)2, and −CH2CH2OCH3; R36b is selected from the group consisting of −CO−, −CHCH3NHCO−, and
Figure imgf000081_0001
R37b is selected from the group consisting of −CH3 and −CH2CH3; R38b is selected from the group consisting of −CH2− and −CO−; R39b is selected from the group consisting of −CH2−, −CO−, −C(R6b)2CO−, −C(R34b)(R60b)NHC(=R59b)−,
Figure imgf000081_0002
; R40b is selected from the group consisting of −H, −F, −Cl, and −OCH3; R41b is selected from the group consisting of −H, −F, and −Cl; R42b is selected from the group consisting of −CH2− and −CHCH3NHCO−; R43b is selected from the group consisting of −H, −CH3, and −CH(CH3)2; R48b is selected from the group consisting of −H and −OH; R51b is selected from the group consisting of −H, −CH3, and −F; R52b is selected from the group consisting of −H, −CN,
Figure imgf000081_0003
R53b is selected from the group consisting of −CH2− and
Figure imgf000081_0004
R54b is selected from the group consisting of −H, −CH3, −F, and −N(CH3)2; R55b is selected from the group consisting of −H, −CN, cyclopropyl, and −CH(CH3)2; R56b is selected from the group consisting of −H, −CH3, and −CHF2; R57b is selected from the group consisting of −CH3 and −CH2CH2CH3; R58b is selected from the group consisting of −CO− and −NHCO−; R59b is selected from the group consisting of =O and =NCN; R60b is selected from the group consisting of −H, −CH3, and −OCH3; R61b is selected from the group consisting of −H and −CF3; R62b is selected from the group consisting of −H, 1,3-thiazol-2-yl, and phenyl; R63b is selected from the group consisting of −CH3, −CH2CH3, cyclopropyl, −CH(CH3)2, cyclopropylmethyl, −CH2CH(CH3)2, and oxetan-3-yl; R64b is selected from the group consisting of −H, −CH3, −OCH(CH3)2, and −SCH3ONR77b; R65b is selected from the group consisting of −CC−, −CHOH−, −CO−, −C(CH3)2−,
Figure imgf000082_0001
R66b is selected from the group consisting of −H, −CH3, −NH2, −F, −Cl, and −CN; R67b is selected from the group consisting of −O− and −CH2NHCOCH2O−; R68b is selected from the group consisting of =NH and =O; R69b is selected from the group consisting of −H, −CH3, −OCH3, −SCH3, −N(CH3)2, −CH2OCH3, −CH2N(CH3)2, and morpholin-4-yl; R70b is selected from the group consisting of −H, −NH2, −NHCH3, −N(CH3)2, and morpholin-4-yl; R71b is selected from the group consisting of =CH2 and =O; R72b is selected from the group consisting of −O− and −CH2O−; R73b is selected from the group consisting of −O− and −NHCO−; R74b is selected from the group consisting of −CH3, −NHCH2CH3, −C(CH3)2R6b, pyrrolidin-1-yl, pyridin-4-yl, cyclopentylamino, {bicyclo[1.1.1]pentan-1-yl}amino, oxan-4-yl,
Figure imgf000082_0002
; R75b is selected from the group consisting of −NH−, −CH2O−, −CONH−, and −SO2NH−; R76b is selected from the group consisting of −NH−, −CH2O−, −CONH−, −NHCO−, −NHCONH−, and −SO2NH−; R77b is selected from the group consisting of −H and −COOCH3. or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. The compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art. Similarly, any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art. Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively inhibit MAP4K1 and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, in humans and animals. Disorders and conditions particularly suitable for treatment with an MAP4K1 inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias. Examples of breast cancers include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non- small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour. Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Examples of ovarian cancer include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma. Examples of cervical cancer include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma. Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers. Examples of esophageal cancer include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma. Examples of gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma. Examples of pancreatic cancer include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours. Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers. Examples of kidney cancer include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear-cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour. Examples of bladder cancer include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma. Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head-and-neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. The term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma. The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth. Generally, the use of chemotherapeutic agents and/or anti-cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans, 5. provide for a higher response rate among treated patients, 6. provide for a longer survival time among treated patients compared to standard chemotherapy treatments, 7. provide a longer time for tumour progression, and/or 8. yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects. In addition, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention. In a further embodiment of the present invention, the compounds of general formula (I) of the present invention are used in combination with radiation: i.e. radiation treatment sensitizes cancers to anti-tumor immune responses by induction of tumor cell death and subsequent presentation of tumor neoantigens to tumor-reactive Tcells. As MAP4K1 inhibition is enhancing the antigen specific activation of T cells, the overall effect results in a much stronger cancer cell attack as compared to irradiation treatment alone. Thus, the present invention also provides a method of killing a tumor, wherein conventional radiation therapy is employed previous to administering one or more of the compounds of the present invention. The present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of general formula (I) of the present invention prior to the treatment of the cell to cause or induce cell death. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell. The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with: 131I-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharain, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, cemiplimab, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, darolutamide, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, larotrectinib, Iasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rogaratinib, rolapitant, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc- HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin. The compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD-1/-L1 axis antagonists. PD-1, along with its ligands PD-L1 and PD-L2, function as negative regulators of T cell activation. MAP4K1 suppresses immune cell function. PD-L1 is overexpressed in many cancers and overexpression of PD-1 often occurs concomitantly in tumor infiltrating T cells. Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev. Immunol.26:677). In accordance with a further aspect, the present invention covers combinations comprising one or more of the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, and one or more immune checkpoint inhibitors. In a further embodiment the immune checkpoint inhibitor is a aPD-1/-L1 axis antagonist. A further use of the compounds of the invention is the combination with chimeric antigen receptor T cells (CAR-T cells) such as Axicabtagen-Ciloleucel or Tisagenlecleucel. The activity of CAR-T cells can be suppressed by the tumor micro environment (TME), which supposedly can be overcome by MAP4K1 inhibition. In accordance with a further aspect, the present invention covers compounds of general formula (I), as described herein, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the expansion of T cells including CAR-T cells, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes ex-vivo. Hence, the present invention also relates to the use of the compounds according to the invention for the expansion of T cells, including CAR-T cell, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes, ex-vivo. The present invention also comprises an ex-vivo method for the expansion of T cells, including CAR-T cells, CAR-NKT cells or CAR-NK cells and tumor infiltrated lymphocytes, contacting said T cells with compounds according to the invention. In addition, the inventive compounds can also be used as a therapeutic in a variety of other disorders wherein MAP4K1 is involved such as, cardiovascular and lung diseases. Accordingly, the compounds according to the invention are suitable for the treatment and/or prophylaxis in particular of cardiovascular, inflammatory and fibrotic disorders and of renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure. Accordingly, the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure. For the purpose of the present invention the term renal insufficiency comprises both acute and chronic manifestations of renal insufficiency, and also underlying or related renal disorders such as diabetic and non-diabetic nephropathies, hypertensive nephropathies, ischaemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritides; minimal change glomerulonephritis (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membrane-proliferative glomerulonephritis; crescentic glomerulonephritis; mesangioproliferative glomerulonephritis (IgA nephritis, Berger's disease); post-infectious glomerulonephritis; secondary glomerulonephritides: diabetes mellitus, lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegener granulomatosis, Henoch- Schönlein purpura, microscopic polyangiitis, acute glomerulonephritis, pyelonephritis (for example as a result of: urolithiasis, benign prostate hyperplasia, diabetes, malformations, abuse of analgesics, Crohn's disease), glomerulosclerosis, arteriolonecrose of the kidney, tubulointerstitial diseases, nephropathic disorders such as primary and congenital or aquired renal disorder, Alport syndrome, nephritis, immunological kidney disorders such as kidney transplant rejection and immunocomplex-induced renal disorders, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome which can be characterized diagnostically, for example by abnormally reduced creatinine and/or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and/or creatinine, altered activity of renal enzymes, for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or the need for dialysis. The present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism. The present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism. The compounds according to the invention are further suitable for the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inappropriate ADH secretion (SIADH). Furthermore, the compounds according to the invention are also suitable for the treatment and/or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, for example atrioventricular blocks degrees I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV-nodal re-entry tachycardia, Wolff-Parkinson-White syndrome, of acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathies), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, boxer cardiomyopathy (premature ventricular contraction (PVC)), for treatment and/or prophylaxis of thromboembolic disorders and ischaemias such as myocardial ischaemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischaemic attacks, preeclampsia, inflammatory cardiovascular disorders, spasms of the coronary arteries and peripheral arteries, oedema formation, for example pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral circulatory disturbances, reperfusion damage, arterial and venous thromboses, myocardial insufficiency, endothelial dysfunction, to prevent restenoses, for example after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations, and also micro- and macrovascular damage (vasculitis), increased levels of fibrinogen and of low-density lipoprotein (LDL) and increased concentrations of plasminogen activator inhibitor 1 (PAI-1), and also for treatment and/or prophylaxis of erectile dysfunction and female sexual dysfunction. In addition, the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left-heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic-obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF). The compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer’s disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick´s syndrome, Parkinson’s disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld- Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff’s psychosis. They are also suitable for treatment and/or prophylaxis of central nervous system disorders such as states of anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances. The compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma. The compounds according to the invention can likewise be used for controlling states of pain and tinnitus. In addition, the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for treatment and/or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders. Furthermore, the compounds according to the invention can also be used for treatment and/or prophylaxis of autoimmune diseases. The compounds according to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders. In the context of the present invention, the term fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis). The compounds according to the invention are also suitable for controlling postoperative scarring, for example as a result of glaucoma operations. The compounds according to the invention can also be used cosmetically for ageing and keratinized skin. Moreover, the compounds according to the invention are suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis. The present invention further provides the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above. The present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob. The present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention. The present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld- Jakob. In another embodiment, the inventive compounds can also be used to treat or to prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women. Compounds of the present invention can be utilized to inhibit, block, reduce or decrease MAP4K1 activation by exogenous and/or endogenous ligands for the reduction of tumour growth and the modulation of dysregulated immune responses e.g. to block immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy; This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder. The present invention also provides methods of treating a variety of other disorders wherein MAP4K1 is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination for infection & cancer, viral infections, obesity and diet- induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention. The term “treating” or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liquid and solid tumours. In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling. The pharmaceutical activity of the compounds according to the invention can be explained by their activity as MAP4K1 inhibitors. In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours. In accordance with a further aspect, the present invention covers the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the use of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours. In accordance with a further aspect, the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours. In accordance with a further aspect, the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours. In accordance with a further aspect, the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same. In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized. The present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes. It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms. For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear- rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents. The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, ● fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), ● ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), ● bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), ● solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), ● surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), ● buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), ● isotonicity agents (for example glucose, sodium chloride), ● adsorbents (for example highly-disperse silicas), ● viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine), ● disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)), ● flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)), ● coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl- methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)), ● capsule materials (for example gelatine, hydroxypropylmethylcellulose), ● synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), ● plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), ● penetration enhancers, ● stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), ● preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), ● colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), ● flavourings, sweeteners, flavour- and/or odour-masking agents. The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention. In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signalinggeneric name disorders, particularly liquid and solid tumours. The term “combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts. A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture. A non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight. Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests. EXPERIMENTAL SECTION NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. In some cases not all H atoms are found as a signal in the NMR because the signal could overlays with a solvent signal or it is a very broad signal dependent on the NMR solvent used. The 1H-NMR data of selected examples / intermediates are listed in the form of 1H-NMR peaklists. For each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ1 (intensity1), δ2 (intensity2), ... , δi (intensityi), ... , δn (intensityn). The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1H-NMR peaklist is similar to a classical 1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of title compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the title compounds (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the title compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of title compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching-disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%. Chemical names were generated using the ACD/Name software from ACD/Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD/Name generated names. Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. Table 1: Abbreviations ACN acetonitrile aq. aqueous AUC Area Under Curve d day(s) DCM dichloromethane DIAD dipropan-2-yl (E)-diazene-1,2-dicarboxylate DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethylsulphoxide dppf 1-(diphenylphosphanyl)cyclopentane-1,2,3,4,5-pentayl - iron (2:1) EAE experimental autoimmune encephalomyelitis EDTA Ethylenediaminetetraacetic acid EtOAc ethyl acetate EtOH ethanol Expl. Example h hour(s) FCS fetal calf serum HATU N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]- N-methylmethanaminium hexafluorophosphate HMDS Hexamethyldisilazane IFNg Interferon gamma LiHMDS lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide LPS lipopolysaccharide MeOH methanol MCPBA 3-chloroperbenzoic acid mL milliliter µL microliter min. minute(s) MTBE tert-butyl methyl ether MW microwave NCS 1-chloropyrrolidine-2,5-dione Pd(dppf)2Cl2*DCM [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane PBMCs peripheral blood mononuclear cells Pd2(dba)3 (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one - palladium (3:2) Pd(PPh3)4 tetrakis(triphenyl-lambda5-phosphanyl)palladium PPh3 triphenylphosphine PyBroP bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate RT or rt room temperature sat. saturated SDS Sodium dodecyl sulfate TBAF tetra-n-butylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran TNFa tumour necrosis factor alpha uM micromolar Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) XPhos Pd G2 2'-aminobiphenyl-2-yl)(chloro)palladium - dicyclohexyl[2',4',6'-tri(propan- 2-yl)biphenyl-3-yl]phosphane (1:1) The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. EXPERIMENTAL SECTION – GENERAL PART All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate, DCM/methanol, or DCM/ethanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity. EXPERIMENTAL SECTION – GENERAL SYNTHESIS The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (Ia), and intermediates useful for their synthesis. In addition to the routes described below, also other routes may be used to synthesize the title compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, interconversion of any of the substituents, in particular R1, R2a, R2b, R3a, R3b, R4a and R4b, which are as defined in formula (Ia) supra, can be achieved before and/or after the exemplified transformations. These modifications can be, for example, the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exemplified by but not limited to e.g. Buchwald, Suzuki, Sonogashira and Ullmann coupling, ester saponifications, amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 4th edition, Wiley 2006). Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a “one-pot” reaction, as it is well-known to a person skilled in the art. Syntheses of Compounds (Overview): The compounds of the present invention can be prepared as described in the following section. The schemes and the procedures described below illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in the schemes can be modified in various ways. The order of transformations exemplified in the schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4th edition, Wiley 2006). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a “one-pot” reaction, as is well- known to the person skilled in the art. The syntheses of the xxxe derivatives according to the present invention are preferably carried out according to the general synthetic sequence, shown in schemes xxx.
Figure imgf000104_0001
Scheme 1: Route for the preparation of building blocks of general formula 8 and 10, wherein PG1 represents a suitable amine protecting group (e.g. Boc), PG2 represents a suitable alcohol protecting group (e.g. TBDMS), X1 represents a direct bond or –CH2-, Z1 represents a methyl group or a tert-butyl group, R1 has the meaning as given for general formula (I). Suitable starting materials 1, e.g. 1-tert-butyl 3-methyl pyrrolidine-1,3-dicarboxylate (CAS No: 122684- 33-7) are commercially available. Step 1 ^ 3 (Scheme 1) Alkylation In the first step (scheme 1), pyrrolidine derivative 1 can be alkylated using an alkylbromide or alkyliodide of formula 2 to give the desired product 3. For example the 1-tert-butyl 3-methyl pyrrolidine-1,3-dicarboxylate 1 can be alkylated using (2- bromoethoxy)(tert-butyl)dimethylsilane 2 in an organic solvent such as THF in the presence of a base such as LiHMDS or LDA. Step 3 ^ 4 (Scheme 1) ●-Keto ester formation Methylester 2 is reacted with a methyl acetate or tert-butyl acetate to give ●-keto esters of the general formula 4. Typically the reaction is performed in the presence of a base like LiHMDS or LDA in an organic solvent like THF at a temperature range between -78°C and room temperature. Step 4 ^ 5 (Scheme 1) Pyrazol formation ●-Keto esters of formula 4 can be converted with hydrazine to the corresponding pyrazole derivatives of formula 5. Typically the reaction is performed in an organic solvent like ethanol at a temperature between -20°C and the boiling point of the selected solvent. Step 5 ^ 6 (Scheme 1) Deprotection of PG2 The protecting group PG2 of pyrazoles of formula 5 can be cleaved to give an alcohol of formula 6. The cleavage of suitable alcohol protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4th edition, Wiley 2006). For example, when PG2 in compounds of formula 5 is TBDMS, cleavage can be achieved using e.g. HCl in an organic solvent such as methanol or TBAF in an organic solvent such as THF. Step 6 ^ 7 (Scheme 1) Ring closure Alcohols of formula 6 can be converted to spiro compounds of formula 7 by ring closing reactions. For example, alcohols of formula 6 can be reacted with mesylchloride and DIEA in an organic solvent like DCM to give the corresponding mesylate, which is then reacted to give spiro compounds of formula 7, e.g. in the presence of a base like NaOH using a solvent mixture like methanol / water. Moreover, ring closure can be achieved using Mitsunobu conditions known to the skilled person. For example, DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate), triphenylphosphine in an organic solvent such as for example THF can be used. Step 7 ^ 8 (Scheme 1) Triflate formation Spiro compounds of formula 7 can be converted to triflates of formula 7. Typically the reaction is performed using Tf2O in the presence of a base like DIEA in an organic solvent like DCM at a temperature range between -78°C and room temperature. Alternatively the reaction is performed using N,N-bis-(trifluormethansulfonyl)-aniline in the presence of a base like DIEA in an organic solvent like THF at a temperature range between room temperature and the boiling point of the selected solvent. Step 8 ^ 9 (Scheme 1) Deprotection of P12 The protecting group PG1 of spiro compounds of formula 8 can be cleaved to give amines of formula 9. The cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4th edition, Wiley 2006). For example, when PG2 in compounds of formula 8 is BOC, cleavage can be achieved using e.g. TFA in an organic solvent such as DCM. Step 9 ^ 10 (Scheme 1) Amine decoration Amines of formula 9 can be functionalized with a broad variety of substituents to give compounds of formula 10. For examples, secondary amines of formula 9 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 10. All these transformations are known to the skilled person. Step 1 (Scheme 1) C-C cross coupling reaction Compounds of general formula 10 can be reacted with a boronic acid derivative R2-B(OR)2 to give a compound of formula 13. The boronic acid derivative may be a boronic acid (R = -H) or an ester of the boronic acid, e.g. its isopropyl ester (R = -CH(CH3)2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 4,4,5,5-tetramethyl - l ,3,2- dioxaborolane (R-R = -C(CH3)2-C(CH3)2-). The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (ll) [Pd(PPh3) CI ], palladium (ll) acetate and triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride precatalyst). The reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein). The reaction is performed at temperatures ranging from room temperature to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is preferably completed after 1 to 36 hours. Step 8 ^ 11 (Scheme 1) C-C cross coupling reaction Compounds of general formula 8 can be reacted with a boronic acid derivative R2-B(OR)2 to give a compound of formula 11. The boronic acid derivative may be a boronic acid (R = -H) or an ester of the boronic acid, e.g. its isopropyl ester (R = -CH(CH3)2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 4,4,5,5-tetramethyl - l ,3,2- dioxaborolane (R-R = -C(CH3)2-C(CH3)2-). The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (ll) [Pd(PPh3) CI ], palladium (ll) acetate and triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride precatalyst). The reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein). The reaction is performed at temperatures ranging from room temperature to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is preferably completed after 1 to 36 hours. Step 11 ^ 12 (Scheme 1) Deprotection of P12 The protecting group PG1 of spiro compounds of formula 11 can be cleaved to give amines of formula 12. The cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4th edition, Wiley 2006). For example, when PG2 in compounds of formula 12 is BOC, cleavage can be achieved using e.g. TFA in an organic solvent such as DCM. Step 12 ^ 13 (Scheme 1) Amine decoration Amines of formula 12 can be functionalized with a broad variety of substituents to give compounds of formula 13. For examples, secondary amines of formula 13 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 11. All these tranformations are known to the skilled person.
Figure imgf000108_0001
Scheme 2: Route for the preparation of compounds of general formula 22, 23 and 24, wherein PG1 represents a suitable amine protecting group (e.g. Boc), PG2 represents a suitable pyrazole protecting group (e.g. SEM), R represents a lower alkyl group, R1 have the meaning as given for general formula (I). Suitable starting materials 14 and 15 are commercially available or described in the literature. Step 14 + 15 ^ 16 (Scheme 2) Pyrazole addition to the carbonyl group Ketones of the general formula 15 and pyrazoles of the general formula 14 can be converted to compounds of the general formula 16. The conversion is known to the person skilled in the art. For example, the conversion can be carried out in analogy to a literature procedure described in Tetrahedron, 1983, 39, 2023-2029. Step 1 (Scheme 2) Protection with PG2 Compounds of the general formula 16 can be converted to compounds of the general formula 17 using a suitable protecting group to protect the pyrazole NH. Protecting groups for pyrazoles are known to the skilled person (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4th edition, Wiley 2006). For example, when PG2 in compounds of formula 17 is SEM, then 2-(trimethylsilyl)ethoxymethylchloride, a base such as sodium hydride in an organic solvent such as THF can be used. Step 17 ^ 18 (Scheme 2) Alkylation of the alcohol Alcohols of the general formula 17 can be converted to compounds of the general formula 18 in an alkylation reaction known to the skilled person. For example, bromo ethyl acetate, a base, such as sodium hydride in an organic solvent such as dioxane at elevated temperature can be used. Step 18 ^ 19 (Scheme 2) Deprotection of PG2 The protecting group PG2 of pyrazole compounds of general formula 18 can be cleaved to give compounds of formula 19. The cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4th edition, Wiley 2006). For example, when PG2 in compounds of formula 18 is SEM, cleavage can be achieved using e.g. TFA in an organic solvent such as DCM. Step 1 (Scheme 2) Reduction of the ester Esters of the general formula 19 (R = lower alkyl group) can be converted to the corresponding alcohols of the general formula 20 with hydride reducing agents known to the skilled person. For example lithium borohydride in an organic solvent, such as THF can be used. Step 2 (Scheme 2) Mitsunobu reaction Compounds of the general formula 20 can be converted to the corresponding morpholine derivatives of the general formula 21 using Mitsunobu conditions known to the skilled person. For example, DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate), triphenylphosphine in an organic solvent such as for example THF can be used. Step 21 ^ 22 (Scheme 2) Deprotection of PG1 The protecting group PG1 of spiro compounds of formula 21 can be cleaved to give amines of formula 22. The cleavage of suitable amine protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4th edition, Wiley 2006). For example, when PG2 in compounds of formula 21 is BOC, cleavage can be achieved using e.g. TFA in an organic solvent such as DCM. Step 2 3(Scheme 2) Amine decoration Amines of formula 22 can be functionalized with a broad variety of substituents to give compounds of formula 23. For examples, secondary amines of formula 22 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 23. All these transformations are known to the skilled person. Step 2 4(Scheme 2) C-C cross coupling reaction Halogen compounds of general formula 23 can be reacted with a boronic acid derivative R2- B(OR)2 to give a compound of formula 24. The boronic acid derivative may be a boronic acid (R = -H) or an ester of the boronic acid, e.g. its isopropyl ester (R = -CH(CH3)2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 4,4,5,5-tetramethyl - l ,3,2-dioxaborolane (R-R = -C(CH3)2-C(CH3)2-). The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (ll) [Pd(PPh3) CI ], palladium (ll) acetate and triphenylphosphine, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride precatalyst). The reaction is preferably carried out in a mixture of a solvent like 1,2- dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate. (review: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527- 30991-8 and references cited therein). The reaction is performed at temperatures ranging from room temperature to the boiling point of the solvent. Further on, the reaction can be performed at temperatures above the boiling point under pressure. The reaction is preferably completed after 1 to 36 hours. The steps for the synthesis sequence giving rise to spiro compounds of formula 13 or 24 may be also interchanged using similar reaction conditions for each step as described above EXPERIMENTAL SECTION – METHODS Analytical LC-MS methods: Method 1: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.2 vol % aq. ammonia (32%), eluent B: acetonitrile; gradient: 0- 1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm. Method 2: Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 µm, 50x2.1mm; Eluent A: water + 0.05 % formic acid (99%); Eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0-1.7 2-90% B, 1.7-2.0 90% B; flow 1.2 ml/min; temperature: 60°C; DAD scan: 190- 400 nm. Method 3: Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2 vol % aq. ammonia (32%), eluent B: acetonitrile; gradient: 0- 1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm. Method 4: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60 °C; DAD scan: 210-400 nm. EXPERIMENTAL SECTION – Intermediates and Examples Intermediate INT-1 (rac)-1-tert-butyl 3-methyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrrolidine-1,3- dicarboxylate
Figure imgf000112_0002
To a solution of 1-tert-butyl 3-methyl pyrrolidine-1,3-dicarboxylate (900 g, 3.93 mol) in dry THF (9 L) was added LiHMDS (7.9 L, 7.86 mol) at -78°C under N2 atmosphere, and the reaction mixture was stirred at this temperature for 1 hour. Then a solution of (2-bromoethoxy)(tert- butyl)dimethylsilane (1870 g, 7.86 mol) in dry THF (5 L) was added and the mixture was left to warm to room temperature and stirred overnight (monitored by TLC). A saturated aqueous solution of NH4Cl (15 L) was added in one portion and the mixture was extracted with ethyl acetate (3x10 L). The combined organic phases were washed with brine (3x15 L), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by silica gel column (ethyl acetate/petroleum ether) to give 1-tert-butyl 3-methyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyrrolidine-1,3-dicarboxylate (1330 g, 3.43 mol) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.845 (13.83), 1.375 (16.00), 1.816 (0.48), 1.837 (0.50), 1.847 (0.44), 3.091 (0.41), 3.117 (0.72), 3.143 (0.53), 3.325 (14.22), 3.762 (0.42). Intermediate INT-2 (rac)-tert-butyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(3-methoxy-3- oxopropanoyl)pyrrolidine-1-carboxylate
Figure imgf000112_0001
To a solution of methyl acetate (511 g, 6.9 mol) in dry THF (9 L) was added LiHMDS (6.9 L, 6.90 mol) at -78°C under N2 atmosphere, and the reaction mixture was stirred at this temperature for 1 hour. Then a solution of 1-tert-butyl 3-methyl 3-{2-[(tert- butyldimethylsilyl)oxy]ethyl}pyrrolidine-1,3-dicarboxylate (1330 g, 3.45 mol, see INT-1) in dry THF (2 L) was added and the mixture was left to warm to room temperature and stirred for additional 2 hours (monitored by TLC). A saturated aqueous solution of NH4Cl (10 L) was added and the mixture was extracted with ethyl acetate (3x10 L). The combined organic phases were washed with brine (3x10 L), dried over anhydrous Na2SO4,and concentrated under vacuum to yield a crude product which was directly purified by silica gel column (ethyl acetate/petroleum ether) to give tert-butyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(3-methoxy- 3-oxopropanoyl)pyrrolidine-1-carboxylate (1400 g, 3.28 mol) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.007 (1.55), 0.007 (1.21), 0.843 (16.00), 1.383 (9.00), 1.389 (12.12), 1.817 (4.65), 1.839 (0.43), 1.862 (0.45), 2.176 (3.50), 3.061 (1.35), 3.089 (1.38), 3.479 (7.77), 3.523 (0.71), 3.537 (0.94), 3.551 (0.49), 3.606 (5.09), 3.616 (2.11), 3.628 (4.07), 3.689 (0.41), 3.696 (0.52), 3.736 (1.09), 3.783 (0.46), 3.810 (0.43), 3.827 (2.06), 3.868 (1.20), 4.307 (0.76). Intermediate INT-3 (rac)-tert-butyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(3-hydroxy-1H-pyrazol-5- yl)pyrrolidine-1-carboxylate
Figure imgf000113_0001
To a stirred solution of tert-butyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(3-methoxy-3- oxopropanoyl)pyrrolidine-1-carboxylate (1400 g, 3.28 mol, see INT-2) in anhydrous ethanol (1.4 L) was added N2H4 (314 g, 9.84 mol). This mixture was stirred in an oil bath, and the temperature was warmed to 80oC and stirred for another 1 hour at this temperature (monitored by LCMS). The solvent was removed in vacuum followed by recrystallization from MTBE to afford tert-butyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(3-hydroxy-1H-pyrazol-5-yl)pyrrolidine- 1-carboxylate (1105 g, 2.69 mol) as a white solid. LCMS: (ES, m/z):412 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.038 (14.44), -0.033 (7.30), 0.828 (10.68), 0.840 (16.00), 1.364 (8.42), 1.385 (12.89), 1.855 (0.42), 1.889 (0.57), 1.905 (0.43), 2.080 (4.59), 2.523 (1.05), 3.195 (0.76), 3.222 (0.96), 3.238 (0.42), 3.266 (0.48), 3.285 (0.48), 5.203 (1.17), 5.240 (0.99), 5.262 (0.60). Intermediate INT-4 (rac)-tert-butyl 3-(3-hydroxy-1H-pyrazol-5-yl)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate
Figure imgf000114_0001
To a stirred solution of tert-butyl 3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-(3-hydroxy-1H- pyrazol-5-yl)pyrrolidine-1-carboxylate (1105 g, 2.69 mol, see INT-3) in MeOH (5 L) was added HCl/MeOH (4M, 2 L). This mixture was stirred at room temperature until the TBS group was completely removed (monitored by LCMS), then K2CO3 (2227 g, 16.14 mol) was added followed by Boc2O (871 g, 4.03 mol). This mixture was stirred at room temperature for another 1 hour (monitored by LCMS). The mixture was filterered and the filtrate was concentrated to give tert-butyl 3-(3-hydroxy-1H-pyrazol-5-yl)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (766 g, 2.58 mol) as a white solid. LCMS: (ES, m/z):298 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.915 (4.02), 0.934 (10.54), 0.951 (5.00), 1.172 (0.77), 1.278 (1.17), 1.296 (2.11), 1.315 (2.12), 1.333 (1.22), 1.366 (15.85), 1.386 (16.00), 1.524 (0.49), 1.544 (1.06), 1.564 (1.28), 1.583 (0.90), 1.757 (0.65), 1.777 (1.22), 1.795 (1.18), 1.814 (0.59), 1.888 (0.42), 1.987 (1.51), 2.080 (5.94), 2.149 (0.49), 2.518 (1.58), 2.522 (0.99), 3.036 (0.43), 3.058 (0.61), 3.077 (0.47), 3.139 (1.93), 3.160 (1.83), 3.180 (2.16), 3.193 (0.94), 3.207 (1.02), 3.220 (1.15), 3.240 (0.70), 3.250 (0.63), 3.269 (0.68), 3.288 (0.55), 3.601 (0.90), 3.628 (0.81), 4.360 (0.70), 4.372 (1.36), 4.384 (0.67), 5.203 (1.49), 5.271 (3.36), 5.758 (4.66). Intermediate INT-5 (rac)-tert-butyl 2'-hydroxy-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate
Figure imgf000114_0002
To a stirred solution of tert-butyl 3-(3-hydroxy-1H-pyrazol-5-yl)-3-(2-hydroxyethyl)pyrrolidine-1- carboxylate (766 g, 2.58 mol, see INT-4) in DCM (5 L) was added DIEA (999 g, 7.74 mol) followed by MsCl (650 g, 5.7 mol, 2.20 equiv). This mixture was stirred at room temperature until the starting material disappeared (monitored by LCMS), then the solvent was removed under vacuum and the residue was dissolved in MeOH/H2O (6L, 2/1, v/v), finally NaOH (516 g, 12.9 mol) in water (2 L) was added. The mixture was stirred at room temperature overnight. The pH value was adjust to 7 and extracted with DCM (3x10 L), and the combined organic layer was washed with brine (3x10 L), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by silica gel column (ethyl acetate/petroleum ether) to give tert-butyl 2'-hydroxy-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (388, 1.4 mol) as a yellow oil. LCMS: (ES, m/z):280 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.053 (0.47), 1.388 (16.00), 1.416 (13.47), 1.933 (0.53), 1.947 (0.80), 1.961 (0.81), 1.979 (0.86), 2.005 (0.63), 2.322 (0.47), 2.327 (0.62), 2.332 (0.51), 2.345 (1.05), 2.361 (1.76), 2.379 (1.09), 2.518 (2.19), 2.523 (1.41), 2.669 (0.52), 3.363 (0.80), 3.424 (0.72), 3.431 (0.62), 3.439 (0.64), 3.452 (0.50), 3.911 (1.19), 3.916 (1.41), 3.929 (2.30), 3.933 (2.74), 3.945 (1.17), 3.950 (1.47), 5.205 (11.05), 9.585 (1.91). Intermediate INT-6 (rac)-tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000115_0001
To a solution of tert-butyl 2'-hydroxy-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxylate (380 g, 1.4 mol, see INT-5) in dry DCM (5 L) was added DIEA (903 g, 7.0 mol) at -50°C under N2 atmosphere, then Tf2O (789 g, 2.8 mol) was added dropwise and the mixture was stirred for another 1.5 hours (monitored by TLC) at this temperature. The mixture was washed with brine (2x5 L), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by silica gel column (ethyl acetate/petroleum ether) to give tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (460 g, 1.1 mol) as a yellow solid. LCMS: (ES, m/z):412 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.392 (16.00), 1.419 (12.92), 2.030 (0.60), 2.046 (0.85), 2.059 (0.94), 2.076 (1.11), 2.096 (0.85), 2.107 (0.46), 2.470 (1.69), 2.518 (0.47), 3.332 (1.47), 3.350 (0.80), 3.359 (0.60), 3.369 (0.70), 3.378 (0.90), 3.396 (0.99), 3.454 (0.50), 3.461 (0.80), 3.473 (0.88), 3.480 (1.08), 3.488 (0.78), 3.493 (0.93), 3.500 (0.66), 3.507 (0.64), 3.520 (0.46), 4.190 (0.41), 4.200 (1.18), 4.210 (1.54), 4.215 (1.67), 4.219 (1.67), 4.227 (1.75), 4.231 (1.82), 4.235 (1.33), 4.246 (1.29), 4.256 (0.47), 6.249 (2.94). Example 1.00 (rac)-tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate
Figure imgf000116_0001
A mixture of (rac)-tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (200 mg, 0.49 mmol, see INT-6), quinolin-3-ylboronic acid (252 mg, 1.46 mmol), XPhos Pd G2 (57 mg, 0.07 mmol) in dioxane (16 mL) and an aqueous K3PO4 solution (0.5 M, 2.9 mL, 1.46 mmol) was stirred at 100°C under argon overnight. After cooling the mixture was diluted with ethyl acetate and a saturated, aqueous NaCl solution. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (3x). The combined organic phases were dried using a Whatman filter and concentrated. The residue was purified by flash chromatography (hexane / ethyl acetate) to give the desired product (160 mg, 0.41 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.154 (0.92), 1.171 (1.88), 1.189 (0.92), 1.409 (16.00), 1.450 (12.77), 1.987 (2.86), 2.071 (0.49), 2.087 (1.10), 2.103 (1.38), 2.120 (0.75), 2.132 (0.68), 2.518 (1.90), 2.523 (1.25), 2.590 (1.19), 2.599 (1.53), 2.616 (0.94), 3.468 (5.88), 3.529 (0.63), 3.547 (1.13), 3.556 (0.61), 3.562 (0.72), 3.575 (0.65), 4.017 (0.62), 4.034 (0.62), 4.258 (1.12), 4.267 (1.34), 4.275 (2.03), 4.284 (2.04), 4.293 (1.33), 4.302 (1.14), 6.743 (1.76), 6.760 (2.25), 7.591 (1.01), 7.594 (0.90), 7.609 (1.54), 7.611 (1.95), 7.615 (1.34), 7.629 (1.34), 7.632 (1.48), 7.706 (1.39), 7.709 (1.22), 7.723 (1.21), 7.727 (1.84), 7.731 (1.67), 7.744 (1.15), 7.747 (1.22), 7.996 (3.79), 8.017 (3.45), 8.658 (2.46), 9.347 (4.74), 9.352 (4.66). The following examples were prepared in analogy to example 1.0:
Figure imgf000116_0002
Figure imgf000117_0001
1.02 1.03
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
1.07
Figure imgf000122_0001
1.08 1.09
Figure imgf000123_0001
1.10 1.11
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
1.16 1.17
Figure imgf000128_0001
Figure imgf000129_0002
Example 2.00 (rac)-tert-butyl (3S)-2'-[6-(methoxycarbonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000129_0001
A mixture of (rac)-tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (50 mg, 0.12 mmol, see INT-6), crude methyl 2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-6-carboxylate (320 mg, see INT-7), XPhos Pd G2 (14 mg, 0.018 mmol) in dioxane (7.8 mL) and an aqueous K3PO4 solution (0.5 M, 0.73 mL) was stirred at 100°C under argon for 2 hours. After cooling the mixture was diluted with ethyl acetate and an saturated, aqueous NaCl solution. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (3x). The combined organic phases were dried using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (9 mg, 0.02 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.411 (11.45), 1.452 (9.18), 2.075 (0.40), 2.092 (0.81), 2.109 (0.98), 2.125 (0.55), 2.137 (0.49), 2.518 (1.28), 2.523 (0.86), 2.604 (1.05), 3.469 (3.80), 3.525 (0.46), 3.543 (0.83), 3.552 (0.44), 3.558 (0.54), 3.570 (0.47), 3.940 (16.00), 4.271 (0.79), 4.280 (0.95), 4.288 (1.44), 4.298 (1.39), 4.306 (0.96), 4.315 (0.77), 6.748 (1.26), 6.770 (1.55), 7.147 (0.49), 7.373 (0.49), 7.464 (0.63), 7.484 (0.42), 8.091 (1.71), 8.113 (3.00), 8.163 (2.33), 8.169 (2.38), 8.186 (1.31), 8.191 (1.33), 8.717 (1.97), 8.867 (1.73), 9.462 (3.21), 9.467 (3.07). Intermediate INT-7 Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-6-carboxylate
Figure imgf000130_0001
Potassium acetate (110 mg, 0.38 mmol) and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31 mg, 0.038 mmol) were added to a mixture of methyl 3-bromoquinoline-6-carboxylate (100 mgs, 0.38 mmol) and 4,4,4',4',5,5,5',5'- octamethyl[2,2'-bi-1,3,2-dioxaborolane] (115 mg, 0.45 mmol) in dioxane (1.5 mL) at room temperature. The mixture was stirred at 100 °C for 2 hours. After cooling the mixture was filtered and the filtrate was concentrated to give the crude product (320 mg) which was used without further purification. The following examples were prepared in analogy to example 2.00:
Figure imgf000130_0002
2.01
Figure imgf000131_0001
2.02
Figure imgf000132_0001
2.03
Figure imgf000133_0001
Figure imgf000134_0001
2.05
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0002
Example 3.00 (rac)-tert-butyl -2'-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000138_0001
A solution of sodium hydroxide (500 mg, 12.5 mmol) in MeOH (10 mL) was added to a solution of (rac)-tert-butyl -2'-[2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (70 mg, 0.13 mmol, see INT-8) in THF (10 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate (3x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (18 mg, 0.04 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.259 (0.98), 1.277 (2.30), 1.296 (1.05), 1.403 (2.66), 1.442 (2.18), 1.544 (1.36), 2.055 (0.16), 2.074 (0.60), 2.518 (0.86), 2.523 (0.59), 2.539 (16.00), 2.572 (0.18), 2.706 (0.19), 2.725 (0.53), 2.744 (0.52), 2.763 (0.17), 3.234 (0.19), 3.438 (0.88), 3.532 (0.17), 4.185 (0.16), 4.193 (0.21), 4.203 (0.31), 4.210 (0.36), 4.220 (0.20), 4.228 (0.19), 6.157 (0.46), 6.475 (0.33), 6.484 (0.40), 8.099 (0.56), 8.104 (0.59), 8.512 (0.56), 8.517 (0.56), 11.489 (0.30). Intermediate INT-8 (rac)-tert-butyl -2'-[2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydro- 1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000139_0001
INT-8 was prepared in analogy to Example 2.0 using (rac)-tert-butyl 2'- (trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (see INT-6) and crude [2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5- yl]boronic acid (see INT-9). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.066 (0.81), 1.295 (1.97), 1.331 (4.72), 1.339 (0.98), 1.349 (10.93), 1.368 (4.92), 1.395 (16.00), 1.436 (13.23), 2.047 (1.09), 2.061 (1.48), 2.074 (15.13), 2.518 (2.19), 2.522 (1.54), 2.539 (1.21), 2.543 (1.28), 2.553 (1.79), 2.571 (1.07), 3.114 (0.93), 3.133 (2.78), 3.151 (2.69), 3.169 (0.86), 3.348 (0.49), 3.397 (0.61), 3.427 (6.10), 3.452 (0.52), 3.497 (0.61), 3.515 (1.05), 3.524 (0.66), 3.530 (0.79), 3.539 (0.61), 3.542 (0.64), 4.194 (1.04), 4.202 (1.31), 4.211 (1.86), 4.219 (2.05), 4.228 (1.19), 4.237 (1.13), 6.556 (1.94), 6.569 (2.35), 6.593 (3.84), 7.570 (2.09), 7.573 (0.99), 7.587 (4.92), 7.604 (1.56), 7.608 (3.51), 7.665 (1.21), 7.668 (2.26), 7.672 (1.28), 7.682 (1.01), 7.687 (2.64), 7.692 (0.73), 7.703 (0.61), 7.706 (1.01), 7.709 (0.49), 8.069 (4.02), 8.073 (5.39), 8.078 (1.30), 8.090 (4.39), 8.093 (3.62), 8.098 (0.49), 8.200 (5.00), 8.205 (5.07), 8.666 (2.75). Intermediate INT-9 [2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid
Figure imgf000140_0002
INT-9 was prepared in ana thyl-1-(phenylsulfonyl)-1H- pyrrolo[2,3-b]pyridine. The crude product was used without further purification. Example 4.00 (rac)-tert-butyl -2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000140_0001
A mixture of (rac)-[1-(tert-butoxycarbonyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-2'-yl]boronic acid (25 mg, 0.08 mmol, see INT-10), 5-bromo-3-ethyl-1H-pyrrolo[2,3- b]pyridine (27 mg, 0.12 mmol) and XPhos Pd G2 (10 mg, 0.012 mmol) in dioxane (0.8 mL) and aqueous K3PO4 solution (0.5 M, 0.0.5 mL) was stirred at 100°C under argon overnight. After cooling the mixture was diluted with ethyl acetate washed with an aqueous NaCl solution. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC to give the desired product (9 mg, 0.02 mmol). ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (1.08), 1.247 (6.26), 1.266 (14.92), 1.285 (6.62), 1.404 (16.00), 1.427 (2.17), 1.443 (12.51), 2.044 (0.48), 2.060 (1.08), 2.077 (1.32), 2.083 (0.96), 2.106 (0.72), 2.332 (0.84), 2.518 (4.69), 2.523 (3.13), 2.539 (0.96), 2.564 (1.68), 2.673 (0.84), 2.692 (1.08), 2.709 (3.25), 2.711 (3.37), 2.727 (10.23), 2.748 (0.96), 2.887 (9.26), 3.302 (0.48), 3.308 (0.48), 3.317 (0.96), 3.378 (1.20), 3.389 (0.84), 3.395 (0.84), 3.401 (0.72), 3.413 (0.72), 3.440 (5.17), 3.523 (0.60), 3.541 (0.96), 3.556 (0.60), 3.568 (0.60), 4.192 (1.08), 4.200 (1.20), 4.210 (1.92), 4.217 (2.05), 4.226 (1.20), 4.235 (1.08), 6.190 (0.72), 6.530 (1.68), 6.549 (2.17), 7.216 (2.53), 7.218 (2.29), 7.221 (2.53), 7.949 (1.20), 8.087 (0.48), 8.222 (2.65), 8.226 (2.65), 8.605 (4.45), 8.610 (4.21), 11.296 (1.68). Intermediate INT-10 (rac)-[1-(tert-butoxycarbonyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]boronic acid Potassium acetate (286 mg, 2.92 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.049 mmol) and 1,1'- bis(diphenylphosphino)ferrocene (27 mg, 0.049 mmol) were added to a mixture of (rac)-tert- butyl 2'-{[(trifluoromethyl)sulfonyl]oxy}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate (400 mgs, 0.97 mmol, see INT-6) and 4,4,4',4',5,5,5',5'- octamethyl[2,2'-bi-1,3,2-dioxaborolane] (259 mg, 1.02 mmol) in dioxane (3.8 mL) at room temperature. The mixture was stirred at 100 °C overnight. After cooling the mixture was diluted with DCM, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give the desired product (48 mg, 0.14 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.066 (0.64), 1.243 (6.81), 1.391 (4.81), 1.425 (4.01), 2.002 (0.44), 2.010 (0.42), 2.518 (1.07), 2.523 (0.85), 2.539 (16.00), 2.561 (0.54), 3.349 (0.84), 3.361 (0.96), 3.368 (1.53), 3.394 (0.45), 3.566 (1.49), 4.149 (0.48), 4.159 (0.67), 4.167 (0.74), 4.176 (0.43), 6.242 (0.41), 6.279 (0.53), 6.288 (0.60), 7.890 (1.26). Example 5.00 (rac)-tert-butyl -3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000141_0001
N-Chlorosuccinimide (21 mg, 0.16 mmol) was added to a solution of (rac)-tert-butyl 2'-(1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (40 mg, 0.11 mmol, Example 1.06) in DMF (0.9 mL) at 0°C. The mixture was stirred at 0°C for 1 hour and 2 hours at room temperature. Additional N-chlorosuccinimide (21 mg, 0.16 mmol) was added and the mixture for 1 hour at room temperature. Finally, additional N-chlorosuccinimide (21 mg, 0.16 mmol) was added and the mixture for at room temperature overnight. The mixture was concentrated and the residue was purifiend by preparative HPLC to give the desired product (4 mg, 0.01 mmol). 1H-NMR (600 MHz, DMSO-d6) delta [ppm]: 0.000 (1.67), 1.419 (8.34), 1.435 (7.91), 2.520 (0.75), 2.524 (0.76), 2.527 (0.61), 2.545 (16.00), 2.567 (1.44), 2.574 (0.41), 2.585 (0.53), 2.601 (0.51), 2.614 (0.87), 2.625 (0.54), 2.735 (0.67), 2.894 (0.78), 3.499 (0.40), 3.507 (0.42), 3.518 (0.53), 3.525 (0.53), 3.626 (1.63), 3.644 (1.23), 4.261 (0.46), 4.267 (0.75), 4.273 (0.98), 4.276 (0.96), 4.280 (0.95), 4.285 (0.62), 4.290 (0.75), 5.754 (1.16), 7.745 (1.95), 7.750 (1.98), 8.221 (1.15), 8.702 (1.47), 12.147 (0.89). Example 6.00 (rac)-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
Figure imgf000142_0001
N,N-Diisopropylethylamine (0.180 mL; 1.03 mmol) was added to a suspension of crude (rac)- 2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (200 mg; INT-11) in DCM (9.8 mL) at 0°C. Isocyanatoethane (0.054 mL; 0.69 mmol) was added and the mixture was stirred overnight at room temperature. The batch was concentrated and the mixture was purified by preparative HPLC to give the desired product (100 mg; 0.28 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.015 (6.84), 1.033 (16.00), 1.050 (7.05), 1.137 (0.64), 1.232 (0.52), 2.075 (0.43), 2.087 (1.09), 2.102 (2.14), 2.119 (2.73), 2.137 (1.00), 2.150 (0.52), 2.318 (0.43), 2.518 (6.17), 2.523 (4.13), 2.564 (2.59), 2.582 (3.63), 2.599 (2.71), 2.678 (0.43), 3.034 (0.83), 3.052 (2.64), 3.066 (2.85), 3.070 (2.80), 3.084 (2.56), 3.102 (0.76), 3.399 (0.47), 3.417 (1.16), 3.425 (0.93), 3.436 (0.76), 3.442 (1.90), 3.457 (10.07), 3.503 (0.71), 3.521 (1.16), 3.528 (0.69), 3.536 (0.85), 3.543 (0.69), 3.547 (0.69), 3.562 (0.40), 4.262 (2.64), 4.280 (3.92), 4.297 (2.54), 6.171 (1.00), 6.185 (1.99), 6.198 (0.97), 6.730 (10.85), 7.591 (1.21), 7.594 (1.07), 7.608 (1.73), 7.610 (2.33), 7.614 (1.57), 7.629 (1.54), 7.631 (1.76), 7.705 (1.71), 7.708 (1.35), 7.722 (1.47), 7.727 (2.23), 7.730 (1.99), 7.743 (1.31), 7.747 (1.47), 7.995 (5.74), 8.017 (3.99), 8.019 (4.11), 8.660 (3.44), 8.666 (3.66), 9.350 (5.34), 9.355 (5.41). The enantiomers were seperated by preparative chiral HPLC, using 200 mgs of (rac)-N-ethyl- 2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide.
Figure imgf000142_0002
Figure imgf000143_0002
Intermediate INT-11 (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate
Figure imgf000143_0001
A mixture of trifluoroacetic acid (12,8 mL) and (rac)-tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (2.00 g; 5,12 mmol) in DCM (40 mL) was stirred at room temperature for 2 h under argon. The batch was concentrated to dryness. Toluene was added and the batch concentrated to dryness (2 x) to give the crude product (4,5 g) that was used without further purification. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 2.218 (0.95), 2.226 (0.93), 2.237 (2.23), 2.258 (1.56), 2.294 (3.42), 2.518 (0.90), 2.522 (0.55), 2.633 (0.49), 2.637 (0.42), 2.650 (0.97), 2.665 (1.34), 2.668 (1.16), 2.684 (0.78), 2.693 (0.75), 2.712 (1.21), 2.729 (0.90), 2.741 (0.42), 2.745 (0.49), 3.374 (0.65), 3.387 (0.94), 3.404 (1.22), 3.418 (1.00), 3.429 (0.56), 3.471 (0.66), 3.482 (0.91), 3.487 (1.04), 3.499 (1.16), 3.516 (0.94), 3.527 (0.61), 4.290 (1.09), 4.298 (1.18), 4.305 (1.69), 4.308 (1.55), 4.313 (1.43), 4.317 (1.51), 4.324 (1.18), 4.332 (1.04), 5.755 (16.00), 6.903 (8.86), 7.157 (0.69), 7.159 (0.78), 7.177 (0.88), 7.227 (0.75), 7.245 (0.78), 7.684 (0.87), 7.687 (0.90), 7.702 (1.25), 7.704 (1.87), 7.707 (1.09), 7.722 (1.20), 7.724 (1.20), 7.807 (1.15), 7.811 (1.19), 7.824 (0.96), 7.828 (1.90), 7.832 (1.39), 7.845 (1.06), 7.849 (0.99), 8.068 (1.91), 8.090 (1.67), 8.101 (1.64), 8.104 (1.71), 8.123 (1.52), 8.125 (1.46), 8.828 (2.35), 8.832 (2.42), 9.262 (0.73), 9.416 (3.81), 9.421 (3.82). The following examples were prepared in analogy to example 6.00:
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
6.11
Figure imgf000151_0001
6.12
Figure imgf000152_0001
6.13
Figure imgf000153_0001
Figure imgf000154_0001
6.15
Figure imgf000155_0001
6.16
Figure imgf000156_0001
6.17
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
6.20
Figure imgf000160_0001
Figure imgf000161_0001
6.22
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
6.29 6.30
Figure imgf000169_0001
Alternative synthesis approach of Example 6.22 ((rac)-2-(3-chloro-1H-pyrrolo[2,3- b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide), also providing Example 6.31 (rac)-3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
Figure imgf000170_0001
N,N-Diisopropylethylamine (3.66 mL; 21.0 mmol) was added to a suspension of a crude mixture of (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] trifluoroacetate and (rac)-3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin- 5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetat (2.20 g) (see INT- 12) in DCM (580 mL) at 0°C. Isocyanatoethane (0.10 mL; 1.26 mmol) was added and the mixture was stirred for 2 hours at room temperature. The batch was diluted with aqueous sodium bicarbonate solution and extracted with DCM (3x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (Example 6.22, 250 mg; 0.65 mmol) and (rac)-3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydro- 1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (Example 6.31, 109 mg, 0.26 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.007 (6.96), 1.025 (16.00), 1.035 (1.32), 1.043 (7.06), 1.052 (2.10), 1.070 (0.88), 2.074 (3.04), 2.094 (0.60), 2.104 (0.60), 2.116 (0.78), 2.125 (0.78), 2.134 (0.72), 2.297 (0.56), 2.318 (1.63), 2.327 (1.66), 2.331 (1.00), 2.340 (0.82), 2.350 (1.07), 2.371 (0.47), 2.518 (3.70), 2.523 (2.54), 2.553 (2.01), 2.570 (3.26), 2.573 (3.39), 2.589 (2.48), 2.665 (0.75), 2.669 (1.04), 2.673 (0.72), 3.027 (0.85), 3.045 (2.64), 3.059 (2.95), 3.063 (2.79), 3.077 (2.60), 3.095 (0.75), 3.364 (1.29), 3.371 (1.10), 3.388 (0.66), 3.422 (0.50), 3.435 (0.60), 3.440 (0.50), 3.452 (0.47), 3.481 (1.85), 3.506 (2.60), 3.537 (0.69), 3.544 (0.82), 3.558 (1.07), 3.564 (1.10), 3.583 (0.66), 3.590 (0.56), 3.616 (3.58), 3.641 (2.64), 4.255 (2.42), 4.273 (4.02), 4.290 (2.42), 4.360 (0.56), 6.203 (1.07), 6.217 (2.16), 6.231 (1.07), 7.755 (4.77), 7.762 (4.80), 8.218 (3.83), 8.224 (4.05), 8.701 (5.49), 8.707 (5.40), 12.154 (1.85). Intermediate INT-12 Mixture of (rac)-2 -(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6 -dihydrospiro[pyrrolidine-
Figure imgf000171_0001
Trifluoroacetic acid (6.2 mL) was added to a mixture of (rac)-tert-butyl 2'-(3-chloro-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate and (rac)- tert-butyl 3'-chloro-2'-(3-chloro-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate(1.34 g) (see INT-13) in DCM (93 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Toluene was added and the batch concentrated to dryness (2x) to give the crude product (2.2 g) that was used without further purification. Intermediate INT-13 Mixture of (rac)-tert-butyl -2'-(3-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxylate and (rac)- tert-butyl -3'-chloro-2'-(3-chloro-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000171_0002
N-Chlorosuccinimide (471 mg, 3.53 mmol) and benzoyl peroxide (941 mg, 3.88 mmol) was added to a solution of (rac)-tert-butyl 2'-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (see INT-14) (1.80 g, 3.5 mmol) in DMF (4.25 mL) at room temperature. The mixture was stirred at 60°C for 1 hour. After cooling, the mixture was diluted with aqeuous sodium bicarbonate solution and extracted with ethyl acetate (3x). The combined organic phases were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography to give a mixture of (rac)-tert-butyl -2'-(3-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate and (rac)- tert-butyl -3'-chloro-2'-(3-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (1.34 g) that was used without further purification. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.109 (0.22), -0.032 (15.31), -0.025 (7.41), 0.000 (0.45), 0.880 (0.62), 0.900 (0.88), 0.920 (0.64), 1.141 (16.00), 1.231 (1.16), 1.248 (2.33), 1.266 (1.16), 1.481 (3.50), 1.490 (2.06), 1.505 (1.73), 1.521 (2.63), 2.063 (4.36), 2.159 (0.30), 2.398 (0.40), 2.403 (0.54), 2.408 (0.39), 2.598 (1.34), 2.638 (9.17), 2.686 (0.21), 2.740 (0.36), 2.745 (0.50), 2.750 (0.36), 3.524 (1.17), 3.587 (0.66), 3.592 (0.50), 3.608 (1.00), 3.627 (0.79), 3.633 (0.52), 3.693 (0.30), 3.720 (0.21), 4.014 (2.78), 4.075 (0.34), 4.093 (0.99), 4.111 (0.97), 4.129 (0.31), 4.292 (0.22), 4.310 (0.40), 4.318 (0.40), 4.336 (0.32), 4.354 (0.27), 5.684 (1.57), 5.711 (0.79), 6.735 (0.31), 6.761 (0.39), 7.982 (1.29), 8.054 (0.59), 8.320 (0.58), 8.833 (0.32), 8.838 (0.33), 8.885 (0.70), 8.890 (0.72). Intermediate INT-14 (rac)-tert-butyl 2'-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000172_0001
The compound was prepared in analogy to example 1.00 using (rac)-tert-butyl 2'- {[(trifluoromethyl)sulfonyl]oxy}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (see INT-6) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.154 (0.58), -0.146 (16.00), -0.138 (0.52), 0.764 (0.53), 0.783 (0.66), 0.804 (0.55), 1.031 (8.13), 1.369 (2.70), 1.408 (2.22), 2.483 (0.49), 3.410 (0.90), 3.464 (0.55), 3.484 (0.75), 3.504 (0.61), 3.905 (1.38), 5.581 (1.47), 6.509 (0.71), 6.517 (0.54), 7.598 (0.66), 7.607 (0.63), 8.257 (0.81), 8.262 (0.83), 8.662 (0.58), 8.666 (0.56). Example 6.32 (rac)-3'-chloro-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
Figure imgf000173_0001
The compound was prepared in analogy to example 6.31 using crude (rac)-3'-chloro-2'-(3- methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroactetate (see INT-15) and isocyanatoethane. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.007 (6.45), 1.025 (15.12), 1.043 (6.83), 1.229 (1.36), 2.081 (0.43), 2.088 (0.53), 2.097 (0.57), 2.110 (0.72), 2.118 (0.74), 2.128 (0.68), 2.135 (0.57), 2.273 (15.25), 2.276 (16.00), 2.294 (0.63), 2.315 (1.26), 2.323 (0.77), 2.331 (0.48), 2.337 (0.82), 2.346 (0.99), 2.368 (0.46), 2.518 (1.28), 2.523 (0.88), 2.546 (1.88), 2.563 (3.09), 2.566 (3.19), 2.582 (2.34), 3.048 (1.41), 3.058 (1.56), 3.065 (1.53), 3.075 (1.40), 3.322 (0.54), 3.340 (0.81), 3.346 (1.14), 3.364 (1.10), 3.371 (0.97), 3.388 (0.63), 3.478 (1.91), 3.504 (2.71), 3.537 (1.40), 3.545 (1.71), 3.566 (2.97), 3.570 (3.07), 3.583 (3.55), 3.591 (3.44), 3.613 (5.03), 3.638 (3.20), 4.238 (2.25), 4.257 (3.76), 4.274 (2.29), 6.218 (0.84), 7.013 (1.81), 7.141 (2.14), 7.268 (1.83), 7.282 (2.24), 7.285 (2.83), 7.287 (2.83), 7.290 (2.25), 8.208 (3.75), 8.212 (3.88), 8.570 (4.54), 8.575 (4.44), 11.450 (1.90). Intermediate INT-15 (rac)-3'-Chloro-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] trifluoroactetate The compound was prepared in analogy to intermediate INT-12 using (rac)-tert-butyl 2'-[1-(tert- butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-3'-chloro-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (see INT-16) and TFA and was used as a crude product. Intermediate INT-16 (rac)-tert-butyl -2'-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-3'- chloro-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000174_0001
Triphenylphosphine sulfide (4 mg, 0.012 mmol) and N-chlorosuccinimide (10 mg, 0.07 mmol) were added to a solution of (rac)-tert-butyl 2'-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (30 mg, 0.06 mmol) (see INT-17) in DCM (0.5 mL) at 0 °C. The mixture was stirred for 2 hours at 0°C and then for 2 hours at room temperature. At 0°C, additional N-chlorosuccinimide (4 mg, 0.03 mmol) was added ant the mixture was stirred for 2 hours at room temperature. Finally additional N-chlorosuccinimide (4 mg, 0.03 mmol) was added and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with water and extracted wit ethyl acetate (3x). The combined organic phases filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (22 mg, 0.04 mmol). 1H-NMR (600 MHz, DMSO-d6) delta [ppm]: 0.000 (0.68), 1.419 (4.31), 1.434 (4.16), 1.614 (16.00), 2.265 (3.70), 2.267 (3.67), 2.620 (0.47), 3.626 (0.75), 3.644 (0.60), 4.280 (0.52), 4.283 (0.49), 4.287 (0.48), 5.755 (1.81), 7.613 (0.95), 7.615 (0.93), 8.270 (0.59), 8.755 (1.03), 8.759 (1.00). Intermediate INT-17 (rac)-tert-butyl 2'-[1-(tert-butoxycarbonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000175_0001
Di-tert-butyl dicarbonate (40 mg, 0.18 mmol), DMAP (2 mg, 0.017 mmol) and triethlamine (47 mg, 0.46 mmol) were added to a solution of (rac)-tert-butyl 2'-(3-methyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (Example 1.08, 65 mg, 0.17 mmol) in DCM (0.6 mL). The mixture was stirred at room temperature for 3 hours and finally concentrated. The residue was purified by preparative HPLC to give the desired product (60 mg, 0.12 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.171 (0.51), 1.404 (5.06), 1.443 (4.13), 1.601 (16.00), 2.075 (2.67), 2.259 (3.62), 2.261 (3.67), 2.539 (1.32), 2.577 (0.56), 3.447 (1.94), 4.225 (0.44), 4.232 (0.62), 4.241 (0.63), 4.249 (0.43), 6.640 (0.53), 6.663 (0.67), 7.558 (1.06), 7.561 (1.06), 8.293 (0.84), 8.787 (1.20), 8.792 (1.18). Example 7.00 (rac)-N-ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide
Figure imgf000175_0002
A solution of boron tribromide in DCM (1M, 0.7 mL, 0.7 mmol) was added to a solution of (rac)- N-ethyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (Example 6.21, 50 mg, 0.13 mmol) in DCM (2.6 mL) at 0°C. The mixture was stirred at room temperature for 18 hours before it was diluted with aqueous sodium bicarbonate solution and aqueous sodium chloride solution and extracted with ethyl acetate / THF (1:1) (3x). The combined organic phases were filtered using a Whatman filter and concentrated to give the desired product (25 mg, 0.08 mmol) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.014 (6.59), 1.031 (16.00), 1.049 (7.19), 1.154 (2.72), 1.172 (5.37), 1.190 (2.54), 1.352 (1.68), 1.741 (0.54), 1.748 (0.47), 1.757 (1.57), 1.767 (0.50), 1.774 (0.50), 1.988 (8.88), 2.078 (1.04), 2.092 (1.83), 2.108 (2.33), 2.125 (0.93), 2.139 (0.43), 2.518 (8.05), 2.523 (5.73), 2.539 (0.57), 2.554 (2.26), 2.572 (3.33), 2.589 (2.40), 3.032 (0.82), 3.050 (2.61), 3.064 (2.94), 3.068 (2.72), 3.082 (2.61), 3.100 (0.79), 3.395 (0.47), 3.413 (1.11), 3.420 (0.93), 3.438 (2.11), 3.447 (8.95), 3.497 (0.64), 3.516 (1.11), 3.530 (0.86), 3.541 (0.72), 3.556 (0.43), 3.582 (0.61), 3.599 (1.32), 3.615 (0.57), 4.000 (0.68), 4.017 (2.00), 4.035 (1.97), 4.053 (0.64), 4.245 (2.29), 4.263 (3.47), 4.280 (2.29), 6.166 (1.04), 6.180 (2.08), 6.194 (1.00), 6.546 (0.93), 6.682 (10.09), 7.164 (3.51), 7.170 (4.04), 7.242 (2.94), 7.248 (2.43), 7.264 (2.97), 7.271 (2.76), 7.820 (3.33), 7.843 (3.04), 8.418 (3.04), 8.424 (3.22), 9.097 (5.19), 9.102 (5.37), 10.022 (1.93). Example 8.00 (rac)-(Morpholin-4-yl)[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone
Figure imgf000176_0001
Morpholine-4-carbonyl chloride (39 mg; 0.26 mmol) was added to a mixture of crude (rac)-2'- (quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11) and N,N-diisopropylethylamine (0.06 mL; 0.34 mmol) in toluene (1.0 mL) at room temperature. The mixture was stirred for 1 h before it was diluted with water and extracted with ethyl acetate (3x). The combined organic phases were washed with saturated, aqueous sodium chloride solution, filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (11 mg; 0.027 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 2.061 (0.54), 2.078 (0.87), 2.102 (1.01), 2.119 (0.52), 2.518 (0.79), 2.523 (0.53), 2.540 (16.00), 2.560 (0.98), 2.575 (1.45), 2.582 (1.48), 2.597 (1.00), 3.067 (0.48), 3.079 (0.60), 3.092 (0.52), 3.188 (2.26), 3.200 (3.27), 3.212 (2.56), 3.509 (5.14), 3.526 (0.64), 3.535 (0.59), 3.544 (0.43), 3.552 (1.01), 3.571 (2.98), 3.584 (3.66), 3.594 (2.55), 3.610 (0.51), 3.618 (0.55), 3.627 (0.42), 3.730 (0.54), 3.743 (0.61), 3.755 (0.52), 4.262 (0.93), 4.265 (0.89), 4.273 (0.53), 4.280 (1.93), 4.297 (0.88), 4.300 (0.90), 6.718 (5.68), 7.592 (0.62), 7.595 (0.61), 7.609 (0.94), 7.612 (1.30), 7.615 (0.79), 7.629 (0.87), 7.632 (0.86), 7.706 (0.82), 7.710 (0.86), 7.724 (0.71), 7.727 (1.36), 7.731 (0.99), 7.744 (0.74), 7.748 (0.69), 7.997 (1.49), 8.005 (1.24), 8.008 (1.26), 8.017 (1.29), 8.026 (1.17), 8.638 (1.82), 8.643 (1.90), 9.343 (2.62), 9.349 (2.70). The following examples were prepared in analogy to example 8.00:
Figure imgf000177_0001
8.02 8.03
Figure imgf000178_0001
Figure imgf000179_0002
Example 9.00
Figure imgf000179_0001
(rac)-2-ethyl-1-[2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]butan-1-one A mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] trifluoroacetate (100 mg) (see INT-11), 2-ethylbutanoic acid (16 mg; 0.14 mmol), HATU (94 mg; 0.25 mmol) and N,N-diisopropylethylamine (0.09 mL; 0.50 mmol) in DCM (0.5 mL) was stirred at room temperature for 4 hours. The batch was concentrated and the residue purified by by preparative HPLC to give the desired product (33 mg; 0.08 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.784 (5.26), 0.803 (13.10), 0.812 (6.11), 0.821 (6.83), 0.831 (13.74), 0.836 (6.07), 0.849 (7.16), 0.855 (11.98), 0.874 (7.43), 0.894 (11.27), 0.912 (5.14), 1.236 (0.69), 1.251 (0.66), 1.266 (0.45), 1.324 (0.69), 1.338 (1.01), 1.343 (1.02), 1.357 (1.96), 1.376 (2.18), 1.392 (2.07), 1.409 (1.99), 1.425 (2.15), 1.443 (1.72), 1.458 (1.62), 1.468 (1.26), 1.479 (1.75), 1.489 (1.72), 1.498 (2.62), 1.508 (2.02), 1.516 (2.64), 1.534 (2.16), 1.549 (1.44), 1.570 (0.85), 1.589 (0.47), 1.907 (0.84), 2.074 (0.45), 2.078 (0.51), 2.093 (1.21), 2.109 (2.76), 2.127 (2.94), 2.144 (1.24), 2.157 (0.71), 2.174 (0.64), 2.185 (1.14), 2.203 (1.28), 2.216 (1.00), 2.228 (1.81), 2.247 (0.92), 2.259 (0.67), 2.318 (0.56), 2.322 (0.51), 2.331 (1.10), 2.339 (1.04), 2.352 (1.55), 2.364 (0.94), 2.374 (0.78), 2.437 (0.44), 2.451 (0.85), 2.459 (1.10), 2.472 (1.70), 2.518 (1.53), 2.522 (1.12), 2.539 (4.20), 2.553 (1.27), 2.569 (2.52), 2.589 (4.37), 2.606 (4.33), 2.625 (3.10), 3.112 (0.48), 3.517 (3.32), 3.539 (2.12), 3.546 (4.77), 3.568 (2.48), 3.586 (1.43), 3.616 (1.54), 3.625 (3.77), 3.634 (2.21), 3.653 (3.17), 3.665 (1.46), 3.671 (1.56), 3.679 (1.40), 3.690 (2.20), 3.697 (1.87), 3.715 (5.28), 3.730 (4.56), 3.755 (1.33), 3.780 (0.74), 3.798 (1.12), 3.805 (0.83), 3.812 (0.93), 3.819 (0.77), 3.824 (0.70), 3.838 (0.48), 4.254 (0.63), 4.258 (0.63), 4.266 (1.47), 4.281 (4.34), 4.286 (3.11), 4.297 (4.45), 4.300 (4.74), 4.307 (3.53), 4.316 (3.04), 4.323 (2.11), 4.332 (0.52), 6.721 (10.44), 6.744 (12.47), 6.975 (2.72), 7.103 (3.11), 7.231 (2.73), 7.594 (1.65), 7.597 (2.41), 7.614 (4.68), 7.617 (4.33), 7.634 (3.55), 7.710 (2.07), 7.713 (3.36), 7.716 (2.03), 7.727 (1.98), 7.731 (4.04), 7.734 (4.67), 7.738 (2.32), 7.747 (1.81), 7.751 (2.86), 7.754 (1.60), 7.999 (7.53), 8.012 (2.88), 8.021 (6.70), 8.136 (16.00), 8.628 (3.38), 8.633 (3.49), 8.668 (3.98), 8.673 (4.11), 9.326 (4.74), 9.331 (4.94), 9.347 (5.59), 9.353 (5.72). The following examples were prepared in analogy to example 9.00:
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
9.05
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
9.11 9.12
Figure imgf000188_0001
Figure imgf000189_0001
9.14
Figure imgf000190_0001
Figure imgf000191_0001
9.16
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0002
Example 10.00 (rac)-1-(methanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]
Figure imgf000198_0001
Under argon, N,N-diisopropylethylamine (0.09 mL; 0.50 mmol) was added to a suspension of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11) in DCM (0.9 mL) at 0°C. Methanesulfonyl chloride (20 mg; 0.17 mmol) was added and the mixture was stirred overnight at room temperature. The batch was concentrated and the residue purified by by preparative HPLC to give the desired product (15 mg; 0.04 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.906 (0.53), 2.158 (1.26), 2.176 (2.46), 2.194 (1.07), 2.322 (0.69), 2.326 (0.96), 2.331 (0.68), 2.518 (4.38), 2.522 (2.83), 2.621 (0.86), 2.637 (1.07), 2.641 (0.88), 2.655 (1.21), 2.664 (0.93), 2.669 (1.60), 2.673 (1.72), 2.690 (0.83), 3.031 (16.00), 3.446 (1.17), 3.471 (3.65), 3.490 (3.77), 3.515 (2.48), 3.533 (0.61), 3.547 (0.63), 3.565 (1.24), 3.572 (0.48), 3.580 (0.68), 3.589 (0.66), 4.268 (0.93), 4.284 (1.45), 4.295 (1.09), 4.300 (1.40), 4.314 (0.88), 6.846 (7.01), 7.596 (0.74), 7.599 (0.66), 7.615 (1.55), 7.634 (0.98), 7.636 (1.06), 7.710 (1.02), 7.713 (0.91), 7.727 (0.88), 7.731 (1.49), 7.734 (1.27), 7.747 (0.83), 7.751 (0.91), 8.000 (3.24), 8.021 (2.60), 8.662 (2.15), 8.667 (2.28), 9.353 (3.34), 9.359 (3.31). The following examples were prepared in analogy to example 10.00:
Figure imgf000199_0001
Figure imgf000200_0001
Example 11.00 (rac)-1-[(1H-imidazol-2-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]
Figure imgf000201_0001
Acetic acid (0.007 ml, 0.12 mmol) and sodium triacetoxyborohydride (36 mg; 0.17 mmol) were added to a mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] trifluoroacetate (100 mg) (see INT-11) and 1H-imidazole-2- carbaldehyde (11 mg, 0.11 mmol) in THF (1.7 mL) at room temperature. The mixture was stirred overnight. Further 1H-imidazole-2-carbaldehyde (11 mg, 0.11 mmol), acetic acid (0.007 ml, 0.12 mmol) and sodium triacetoxyborohydride (36 mg; 0.17 mmol) were added and the mixture was stirred for additional 2 hours at room temperature. The batch was concentrated and the residue purified by by preparative HPLC to give the desired product (37 mg; 0.1 mmol). 1H-NMR (300 MHz, DMSO-d6) delta [ppm]: 1.993 (0.41), 2.018 (0.81), 2.036 (1.76), 2.060 (4.06), 2.083 (4.03), 2.105 (2.05), 2.122 (0.80), 2.148 (0.48), 2.570 (2.83), 2.593 (1.84), 2.603 (1.80), 2.626 (2.86), 2.648 (2.13), 2.668 (1.46), 2.692 (0.92), 2.711 (3.11), 2.742 (7.39), 2.771 (4.67), 2.784 (7.21), 2.816 (4.19), 2.848 (0.69), 3.179 (0.55), 3.716 (16.00), 4.174 (3.44), 4.196 (6.53), 4.219 (3.43), 6.725 (11.37), 6.940 (4.49), 7.587 (1.62), 7.612 (3.64), 7.636 (2.74), 7.700 (2.18), 7.704 (2.18), 7.727 (3.56), 7.751 (2.00), 7.995 (6.93), 8.023 (5.74), 8.642 (5.92), 8.647 (5.98), 9.352 (6.70), 9.359 (6.61). The following examples were prepared in analogy to example 11.00:
Figure imgf000201_0002
Figure imgf000202_0001
Figure imgf000203_0001
11.03
Figure imgf000204_0001
11.04
Figure imgf000205_0001
11.05
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
11.20
Figure imgf000220_0001
Figure imgf000221_0001
11.22
Figure imgf000222_0001
11.23
Figure imgf000223_0001
11.24
Figure imgf000224_0001
11.25
Figure imgf000225_0001
11.26
Figure imgf000226_0001
11.27
Figure imgf000227_0001
11.28
Figure imgf000228_0001
11.29
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0002
Example 12.00 (rac)-1-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]
Figure imgf000234_0001
A mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] trifluoroacetate (60 mg) (see INT-11), 1-bromo-2-methoxyethane (34 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.11 mL; 0.62 mmol) in DMF (1.0 mL) was stirred at room temperature for 3 hours . Additional 1-bromo-2-methoxyethane (29 mg, 0.21 mmol) was added and the mixture was stirred for additional 3 hours at room temperature before it was stirred for 2 hours at 50 °C. The batch was concentrated and the residue purified by by preparative HPLC to give the desired product (7 mg; 0.02 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 2.020 (0.45), 2.039 (0.61), 2.050 (0.50), 2.056 (0.51), 2.064 (0.56), 2.070 (0.55), 2.084 (0.52), 2.518 (0.63), 2.523 (0.41), 2.531 (0.49), 2.545 (0.50), 2.563 (0.73), 2.581 (0.42), 2.601 (0.45), 2.619 (0.80), 2.635 (1.36), 2.641 (0.93), 2.651 (2.27), 2.655 (1.82), 2.666 (2.48), 2.670 (1.73), 2.689 (2.01), 2.808 (1.79), 2.831 (1.51), 3.257 (16.00), 3.446 (1.64), 3.461 (3.64), 3.476 (1.58), 4.186 (0.98), 4.203 (1.92), 4.221 (1.00), 6.707 (4.48), 7.587 (0.50), 7.589 (0.47), 7.604 (0.76), 7.607 (1.06), 7.624 (0.68), 7.627 (0.73), 7.700 (0.68), 7.703 (0.64), 7.717 (0.57), 7.720 (1.10), 7.724 (0.85), 7.738 (0.58), 7.741 (0.57), 7.989 (1.94), 8.010 (1.71), 8.654 (1.43), 8.659 (1.46), 9.347 (2.13), 9.352 (2.06). The following examples were prepared in analogy to example 12.00:
Figure imgf000235_0001
Figure imgf000236_0001
12.02
Figure imgf000237_0001
12.03
Figure imgf000238_0001
12.04
Figure imgf000239_0001
12.05
Figure imgf000240_0001
12.06
Figure imgf000241_0001
Figure imgf000242_0001
Example 13.00 (rac)-2-methyl-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-2-ol 2,2-Dimethyloxirane (37 mg, 0.52 mmol) was added to a mixture of crude (rac)-2'-(quinolin-3- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT- 11) and N,N-diisopropylethylamine (0.9 mL; 0.52 mmol) in THF (1.0 mL) at room temperature. The mixture was stirred at 60 °C overnight. The batch was concentrated and the residue purified by by preparative HPLC to give the desired product (15 mg; 0.04 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.130 (16.00), 1.138 (15.80), 1.983 (0.48), 1.995 (0.86), 2.014 (1.05), 2.031 (1.01), 2.049 (1.03), 2.055 (1.01), 2.069 (0.95), 2.080 (0.50), 2.323 (0.44), 2.327 (0.59), 2.331 (0.46), 2.438 (9.63), 2.522 (2.02), 2.539 (8.86), 2.548 (1.17), 2.567 (1.30), 2.584 (0.79), 2.611 (0.77), 2.626 (1.27), 2.644 (1.14), 2.659 (0.94), 2.669 (0.72), 2.674 (0.66), 2.785 (2.02), 2.808 (3.54), 2.828 (1.14), 2.833 (0.97), 2.849 (0.68), 2.873 (3.12), 2.882 (1.21), 2.888 (1.27), 2.896 (2.15), 4.103 (4.37), 4.189 (1.54), 4.193 (1.47), 4.207 (3.03), 4.227 (1.52), 6.704 (8.55), 7.588 (0.97), 7.591 (0.94), 7.607 (2.06), 7.626 (1.36), 7.627 (1.36), 7.700 (1.28), 7.704 (1.25), 7.717 (1.21), 7.721 (2.07), 7.724 (1.50), 7.738 (1.12), 7.742 (1.06), 7.993 (3.63), 8.014 (3.25), 8.644 (2.97), 8.649 (3.01), 9.343 (4.13), 9.349 (4.07). Example 14.00 (rac)-N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbothioamide
Figure imgf000243_0001
2-isothiocyanato-2-methylpropane (20 mg, 0.17 mmol) was added to a mixture of crude (rac)- 2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11) and N,N-diisopropylethylamine (0.9 mL; 0.52 mmol) in DCM (2.0 mL) at 0 °C. The mixture was stirred for 3 hours, slowly warming to room temperature. The batch was concentrated and the residue purified by by preparative HPLC to give the desired product (9 mg; 0.02 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.239 (0.87), 1.255 (0.74), 1.269 (0.53), 1.501 (16.00), 2.210 (0.47), 2.518 (3.49), 2.523 (2.24), 2.596 (0.73), 2.613 (1.08), 2.632 (0.76), 3.768 (1.54), 4.277 (0.76), 4.295 (1.24), 4.312 (0.74), 6.108 (0.91), 6.763 (3.29), 7.620 (0.74), 7.637 (0.50), 7.640 (0.50), 7.715 (0.45), 7.719 (0.48), 7.736 (0.76), 7.739 (0.57), 7.753 (0.43), 7.757 (0.40), 8.003 (0.83), 8.015 (0.72), 8.022 (0.74), 8.032 (0.67), 8.666 (0.97), 8.670 (1.02), 9.353 (1.50), 9.359 (1.54). The following examples were prepared in analogy to example 14.00:
Figure imgf000244_0001
14.02
Figure imgf000245_0001
14.03
Figure imgf000246_0001
14.04
Figure imgf000247_0001
Figure imgf000248_0002
Example 15.00 (rac)-1-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]
Figure imgf000248_0001
A solution of lithium bis(trimethylsilyl)amide in THF (1M, 0.59 mL) and 3-bromopyridine (54 mg, 0.34 mmol) were added to a mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] trifluoroacetate (50 mg) (see INT-11), Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) (13 mg, 0.017 mmol) in THF at room temperature. The mixture was stirred in a closed microwave tube at 120 °C for 2 h in a microwave oven. After cooling, the mixture was diluted with ethyl acetate and THF, washed with saturated, aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by by preparative HPLC to give the desired product (7 mg; 0.02 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.232 (0.79), 2.074 (1.27), 2.113 (0.48), 2.131 (0.48), 2.260 (1.74), 2.274 (3.33), 2.293 (3.96), 2.310 (1.58), 2.323 (3.01), 2.327 (3.64), 2.332 (2.53), 2.518 (13.78), 2.523 (9.35), 2.540 (0.79), 2.656 (2.85), 2.670 (6.97), 2.674 (6.34), 2.691 (2.85), 3.291 (1.27), 3.299 (1.11), 3.309 (3.01), 3.354 (8.55), 3.378 (1.43), 3.396 (0.79), 3.494 (0.63), 3.515 (1.90), 3.539 (8.24), 3.546 (7.45), 3.570 (2.06), 3.590 (1.74), 3.605 (1.27), 3.628 (0.48), 4.309 (3.80), 4.326 (6.97), 4.343 (3.64), 6.755 (16.00), 6.944 (1.74), 6.948 (1.74), 6.965 (2.06), 6.969 (2.06), 7.173 (2.85), 7.185 (3.01), 7.193 (2.38), 7.205 (2.53), 7.584 (1.74), 7.586 (1.58), 7.601 (2.38), 7.604 (3.64), 7.621 (2.38), 7.624 (2.38), 7.700 (2.22), 7.704 (2.38), 7.717 (2.06), 7.721 (3.80), 7.725 (2.69), 7.739 (1.90), 7.742 (1.90), 7.865 (3.80), 7.868 (3.96), 7.877 (3.80), 7.880 (3.64), 7.992 (7.76), 8.000 (7.29), 8.010 (3.64), 8.542 (0.79), 8.654 (4.75), 8.659 (4.91), 9.353 (7.29), 9.359 (7.29). The following examples were prepared in analogy to example 15.00
Figure imgf000249_0001
Figure imgf000250_0002
Example 16.00 (rac)-Phenyl (3S)-N-cyano-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboximidate
Figure imgf000250_0001
A mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] trifluoroacetate (100 mg) (see INT-11), diphenyl cyanocarbonimidate (90 mg, 0.38 mmol) and triethylamine in DCM was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with DCM (3x). The combined organic phases were filtered using a Whatman filter and concentrated to give the crude product (174 mg), which was used without further purification. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.137 (5.96), 1.155 (11.19), 1.173 (6.09), 1.224 (2.13), 1.734 (0.68), 1.907 (1.28), 2.268 (0.94), 2.287 (1.15), 2.318 (1.19), 2.322 (1.96), 2.326 (2.55), 2.331 (1.83), 2.518 (10.68), 2.522 (6.60), 2.642 (0.55), 2.659 (1.53), 2.664 (2.34), 2.669 (3.15), 2.673 (2.77), 2.716 (0.64), 2.733 (0.43), 2.783 (0.43), 3.065 (2.38), 3.813 (1.36), 3.836 (1.28), 3.865 (0.43), 3.913 (0.72), 3.941 (1.28), 3.973 (1.32), 4.000 (0.68), 4.277 (0.89), 4.295 (1.79), 4.312 (1.19), 4.339 (0.72), 5.758 (11.53), 6.725 (0.85), 6.733 (11.02), 6.750 (4.55), 6.752 (11.28), 6.755 (11.28), 6.771 (2.09), 6.774 (2.51), 6.777 (1.19), 6.884 (1.57), 6.910 (1.91), 6.954 (1.70), 6.957 (1.96), 6.970 (0.64), 6.975 (2.17), 6.978 (1.96), 7.054 (0.64), 7.057 (0.43), 7.072 (1.23), 7.088 (0.51), 7.091 (0.77), 7.133 (5.70), 7.138 (1.96), 7.151 (7.02), 7.154 (5.40), 7.167 (1.79), 7.173 (4.98), 7.179 (0.60), 7.214 (1.40), 7.233 (2.00), 7.251 (1.19), 7.263 (2.72), 7.267 (2.38), 7.281 (2.85), 7.284 (3.23), 7.297 (1.32), 7.302 (2.13), 7.313 (0.81), 7.332 (1.15), 7.353 (2.38), 7.374 (6.13), 7.385 (4.81), 7.391 (4.94), 7.394 (4.43), 7.413 (2.00), 7.433 (2.68), 7.462 (4.00), 7.467 (3.62), 7.484 (9.96), 7.502 (12.81), 7.605 (1.32), 7.623 (2.13), 7.643 (1.53), 7.717 (1.15), 7.738 (1.70), 7.756 (0.98), 8.008 (2.81), 8.029 (2.55), 8.687 (2.60), 9.326 (16.00), 9.373 (5.02), 9.378 (4.89). Example 16.01 (rac)-N'-cyano-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboximidamide
Figure imgf000251_0001
A mixture of crude (rac)-phenyl N-cyano-2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboximidate (50 mg) (see Example 16.00) and ethylamine (52 mg, 1.15 mmol) in isopropanol (1.2 mL) was stirred at 80 °C for 3 hours. The mixture was concentrated and the residue was purified by preparative HPLC to give the desired product (11 mg, 0.03 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.109 (6.88), 1.127 (16.00), 1.145 (7.17), 1.232 (0.66), 2.150 (0.52), 2.163 (1.23), 2.178 (1.47), 2.190 (1.23), 2.208 (1.99), 2.227 (1.04), 2.239 (0.76), 2.518 (10.30), 2.523 (6.98), 2.541 (1.61), 2.585 (0.66), 2.600 (1.42), 2.616 (3.09), 2.632 (3.18), 2.649 (1.47), 3.360 (3.28), 3.376 (1.57), 3.661 (1.23), 3.691 (6.12), 3.718 (1.52), 4.281 (2.28), 4.298 (4.18), 4.317 (2.23), 6.781 (12.53), 6.951 (1.09), 6.964 (2.23), 6.978 (1.14), 7.596 (1.33), 7.599 (1.33), 7.616 (2.94), 7.634 (1.85), 7.636 (1.90), 7.710 (1.95), 7.714 (1.80), 7.727 (1.52), 7.732 (2.90), 7.735 (2.23), 7.749 (1.52), 7.752 (1.57), 8.002 (3.89), 8.023 (3.75), 8.664 (3.89), 8.670 (4.04), 9.352 (6.03), 9.357 (5.98). The following examples were prepared in analogy to example 16.01:
Figure imgf000252_0001
Figure imgf000253_0002
Example 17.00 (rac)-3-(ethylamino)-4-[-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]cyclobut-3-ene-1,2-dione
Figure imgf000253_0001
A mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] trifluoroacetate (50 mg) (see INT-11), 3,4-diethoxycyclobut-3-ene-1,2-dione (59 mg, 0.34 mmol) and triethylamine (35 mg, 0.34 mmol) in ethanol (1.5 mL) was stirred under reflux for 4 hours. Ethylamine (38 mg, 0.86 mmol) was added and the mixture was heated under reflux for 4 hours. The mixture was concentrated and the residue was purified by preparative HPLC to give the desired product (11 mg, 0.03 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.150 (3.39), 1.168 (6.50), 1.185 (3.49), 1.230 (0.97), 2.084 (0.39), 2.191 (1.45), 2.207 (2.42), 2.231 (2.42), 2.248 (1.16), 2.322 (2.81), 2.326 (3.78), 2.332 (2.72), 2.518 (16.00), 2.522 (10.18), 2.539 (7.76), 2.622 (0.68), 2.638 (1.36), 2.664 (4.27), 2.669 (5.04), 2.673 (4.36), 2.679 (3.20), 2.696 (1.45), 3.554 (2.13), 3.901 (4.27), 3.944 (1.84), 4.304 (2.81), 6.842 (8.15), 7.594 (1.84), 7.614 (3.39), 7.631 (2.42), 7.634 (2.52), 7.708 (2.72), 7.712 (2.23), 7.725 (2.42), 7.729 (3.78), 7.732 (3.39), 7.746 (2.52), 7.749 (2.72), 7.995 (7.56), 8.019 (7.27), 8.540 (0.97), 8.666 (5.43), 8.671 (5.53), 9.358 (8.44), 9.364 (7.85). The following examples were prepared in analogy to example 17.00
Figure imgf000254_0001
Example 18.00 (rac)-Ethyl -2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazole]-1- carboxylate
Figure imgf000255_0001
A mixture of crude (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] trifluoroacetate (50 mg) (see INT-11), ethyl carbonochloridate (18 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.9 mL; 0.52 mmol) in DCM (0.9 mL) was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by preparative HPLC to give the desired product (5 mg, 0.01 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.160 (3.72), 1.177 (7.68), 1.195 (4.09), 1.213 (3.78), 1.231 (7.31), 1.248 (3.54), 2.073 (0.50), 2.083 (2.27), 2.103 (2.30), 2.112 (2.56), 2.130 (2.67), 2.147 (2.11), 2.164 (0.90), 2.322 (0.42), 2.326 (0.58), 2.331 (0.42), 2.518 (2.43), 2.522 (1.56), 2.539 (1.03), 2.570 (0.66), 2.586 (1.80), 2.602 (4.12), 2.619 (4.33), 2.636 (1.93), 2.651 (0.69), 2.665 (0.66), 2.669 (0.90), 3.481 (0.82), 3.490 (1.43), 3.514 (11.22), 3.544 (0.95), 3.570 (1.37), 3.587 (2.72), 3.597 (1.32), 3.604 (1.74), 3.613 (1.69), 3.631 (0.84), 4.023 (1.24), 4.040 (3.78), 4.058 (4.54), 4.075 (3.75), 4.091 (2.67), 4.108 (0.90), 4.233 (0.40), 4.250 (0.79), 4.260 (3.17), 4.269 (2.61), 4.277 (5.31), 4.285 (3.99), 4.296 (3.25), 4.302 (2.17), 6.761 (16.00), 7.590 (2.35), 7.593 (2.09), 7.607 (3.72), 7.610 (4.67), 7.627 (3.14), 7.630 (3.38), 7.704 (3.19), 7.708 (2.75), 7.721 (2.80), 7.724 (4.75), 7.729 (3.83), 7.742 (2.53), 7.746 (2.72), 7.994 (9.53), 8.016 (8.84), 8.663 (7.34), 8.668 (7.29), 9.352 (9.32), 9.357 (8.87). The following examples were prepared in analogy to example 18.00
Figure imgf000255_0002
Figure imgf000256_0002
Example 19.00 (rac)-tert-butyl -2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000256_0001
A solution of sodium hydroxide (900 mg, 22.5 mmol) in MeOH (18 mL) was added to a solution of (rac)-tert-butyl 2'-{1-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (190 mg, 0.31 mmol) (see INT-18) in THF (18 mL) and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with aqueous sodium chloride solution and extracted with ethyl acetate (3x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (90 mg, 0.20 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.408 (11.51), 1.447 (9.24), 2.052 (0.40), 2.069 (0.74), 2.074 (0.61), 2.088 (0.74), 2.118 (0.47), 2.331 (0.49), 2.518 (2.83), 2.523 (1.96), 2.540 (16.00), 2.570 (1.28), 2.673 (0.49), 3.428 (0.62), 3.451 (3.49), 3.535 (0.40), 3.554 (0.68), 3.568 (0.51), 3.581 (0.42), 4.213 (0.75), 4.222 (0.89), 4.226 (0.88), 4.231 (1.33), 4.238 (1.38), 4.243 (0.88), 4.248 (0.87), 4.257 (0.77), 6.608 (1.23), 6.631 (1.54), 7.250 (0.75), 7.268 (1.71), 7.286 (1.04), 7.445 (1.96), 7.466 (3.20), 7.484 (1.82), 7.721 (2.67), 7.724 (3.18), 7.742 (2.78), 7.745 (2.24), 7.877 (5.85), 8.528 (3.09), 8.533 (3.21), 8.696 (2.88), 8.701 (2.71). Intermediate INT-18 (rac)-tert-butyl 2'-{1-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000257_0001
Intermediate INT-18 was prepared in analogy to Example 2.0 using (rac)- tert-butyl 2'- (trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (see INT-6) and crude {1-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrolo[2,3- b]pyridin-5-yl}boronic acid (see INT-19). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.352 (0.45), 1.396 (16.00), 1.437 (13.00), 2.059 (1.37), 2.068 (1.38), 2.086 (0.95), 2.340 (14.01), 2.518 (2.93), 2.523 (1.86), 2.561 (2.00), 2.579 (1.16), 2.669 (0.54), 3.433 (5.98), 3.511 (0.62), 3.529 (1.13), 3.538 (0.71), 3.544 (0.80), 3.556 (0.73), 4.208 (1.08), 4.221 (1.44), 4.226 (1.88), 4.234 (1.96), 4.252 (1.08), 5.758 (11.18), 6.683 (1.72), 6.710 (2.10), 7.395 (0.93), 7.413 (2.88), 7.421 (4.43), 7.431 (2.28), 7.442 (4.48), 7.508 (2.84), 7.528 (4.65), 7.546 (2.27), 7.771 (4.43), 7.788 (3.91), 7.792 (3.05), 8.061 (5.70), 8.082 (5.20), 8.203 (7.96), 8.484 (4.26), 8.489 (4.43), 8.835 (3.04). Intermediate INT-19 {1-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl}boronic acid
Intermediate INT-19 was prepared in analogy to Intermediate INT-7 using 5-bromo-1-[(4- methylphenyl)sulfonyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridine (see INT-20). The crude product was used without further purification. Intermediate INT-20 5-Bromo-1-[(4-methylphenyl)sulfonyl]-3-phenyl-1H-pyrrolo[2,3-b]pyridine
Figure imgf000258_0001
A mixture of 5-bromo-3-iodo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.05 mmol), phenylboronic acid (151 mg, 1.24 mmol) and bis(triphenylphosphine)palladium(II) dichloride (38 mg, 0.05 mmol) in acetonitrile (5 mL) and an aqueous solution of sodium carbonate (2M, 5 mL) was stirred at 60°C for 8 hours. After cooling the mixture was diluted with ethyl acetate and THF (1:1) and washed with an aqueous solution of sodium chloride. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography to give the desired product (293 mg, 0.69 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 2.322 (0.46), 2.326 (0.64), 2.331 (0.63), 2.346 (16.00), 2.518 (2.51), 2.522 (1.57), 2.669 (0.51), 5.758 (2.69), 7.377 (0.52), 7.380 (0.93), 7.383 (0.59), 7.393 (0.72), 7.398 (2.64), 7.403 (0.91), 7.417 (2.75), 7.422 (4.46), 7.443 (4.78), 7.474 (3.20), 7.493 (5.32), 7.507 (0.97), 7.512 (2.48), 7.774 (4.79), 7.787 (1.30), 7.792 (4.49), 7.795 (3.33), 8.029 (6.25), 8.050 (5.77), 8.284 (8.79), 8.491 (4.94), 8.496 (6.14), 8.537 (5.16), 8.543 (4.20). Example 20 (rac)-tert-butyl -2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Example 20 was prepared in analogy to Example 19 using (rac)-tert-butyl 2'-{3-(3-cyano-4- isopropoxyphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (see INT-21). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.351 (16.00), 1.366 (15.73), 1.406 (9.73), 1.444 (7.82), 2.070 (0.70), 2.088 (0.76), 2.118 (0.42), 2.518 (3.72), 2.523 (2.45), 2.573 (1.06), 3.452 (3.11), 3.550 (0.59), 3.564 (0.43), 4.216 (0.65), 4.235 (1.12), 4.242 (1.15), 4.259 (0.63), 4.816 (0.77), 4.831 (1.06), 4.846 (0.77), 6.621 (1.05), 6.646 (1.31), 7.367 (1.21), 7.389 (1.32), 7.920 (2.14), 7.927 (2.11), 7.984 (0.95), 7.989 (1.28), 8.005 (0.69), 8.011 (1.56), 8.019 (2.30), 8.024 (1.39), 8.497 (2.07), 8.501 (2.17), 8.703 (2.60), 8.708 (2.41), 11.986 (1.19), 11.991 (1.18). Intermediate 21 (rac) tert-butyl 2'-{3-(3-cyano-4-isopropoxyphenyl)-1-[(4-methylphenyl)sulfonyl]-1H- pyrrolo[2,3-b]pyridin-5-yl}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxylate
Figure imgf000259_0001
Intermediate INT-21 was prepared in analogy to Intermediate INT-18 using (rac)-tert-butyl 2'- {[(trifluoromethyl)sulfonyl]oxy}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (see INT-6) and {3-(3-cyano-4-isopropoxyphenyl)-1-[(4-methylphenyl)sulfonyl]-1H- pyrrolo[2,3-b]pyridin-5-yl}boronic acid (see INT-22). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.230 (0.57), 1.354 (15.91), 1.369 (16.00), 1.395 (10.09), 1.435 (8.14), 2.059 (0.90), 2.075 (4.90), 2.089 (0.57), 2.323 (0.90), 2.327 (1.31), 2.332 (1.31), 2.341 (8.91), 2.518 (4.93), 2.523 (3.30), 2.566 (1.18), 2.665 (0.81), 2.669 (1.10), 2.674 (0.77), 3.434 (3.57), 3.460 (0.53), 3.525 (0.75), 3.535 (0.42), 3.540 (0.50), 3.552 (0.46), 4.213 (0.66), 4.231 (1.16), 4.239 (1.20), 4.256 (0.66), 4.862 (0.81), 4.877 (1.10), 4.892 (0.83), 5.759 (2.04), 6.682 (1.09), 6.710 (1.34), 7.400 (1.49), 7.423 (4.12), 7.442 (2.87), 8.029 (1.38), 8.034 (1.42), 8.048 (4.20), 8.057 (1.60), 8.069 (3.41), 8.179 (1.68), 8.183 (1.68), 8.287 (5.36), 8.465 (2.85), 8.470 (2.93), 8.827 (1.88). Intermediate INT-22 {3-(3-cyano-4-isopropoxyphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin- 5-yl}boronic acid
Figure imgf000260_0001
Intermediate INT-22 was prepared in analogy to Intermediate INT-19 using 5-{5-bromo-1-[(4- methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-2-isopropoxybenzonitrile (see INT-23). The crude product was used without further purification. Intermediate INT-23 5-{5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-2- isopropoxybenzonitrile
Intermediate INT-23 was prepared in analogy to Intermediate INT-20 using 5-bromo-3-iodo-1- [(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine and 3-cyano-4-isoprpoxyphenylboronic acid. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.172 (0.56), 1.344 (15.41), 1.359 (16.00), 1.987 (1.01), 2.331 (0.70), 2.347 (8.93), 2.518 (2.72), 2.523 (1.82), 2.673 (0.54), 3.317 (1.04), 4.857 (0.83), 4.871 (1.13), 4.887 (0.83), 5.758 (0.77), 7.343 (1.80), 7.365 (2.03), 7.424 (2.66), 7.444 (2.70), 8.015 (3.80), 8.019 (1.17), 8.037 (4.68), 8.042 (1.76), 8.059 (1.24), 8.064 (1.33), 8.180 (2.90), 8.186 (2.68), 8.359 (5.45), 8.527 (2.59), 8.533 (3.08), 8.580 (3.65), 8.585 (3.15). Examples 21.00 and 21.01 tert-butyl -2'-{3-[4-(S-methanesulfonimidoyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (Example 21.00, mixture of 4 stereoisomers) and tert-butyl -2'-(3-{4-[N-(methoxycarbonyl)-S- methylsulfonimidoyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (Example 21.01, mixture of 4 stereoisomers)
Figure imgf000261_0001
Examples 21.00 and 21.01 were prepared in analogy to Example 20.00 using tert-butyl -2'-(3- {4-[N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}-1-[(4-methylphenyl)sulfonyl]-1H- pyrrolo[2,3-b]pyridin-5-yl)-5,6-dihydro-1H-spiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazole]-1- carboxylate (mixture of 4 stereoisomers) (see INT-24). Example 21.00: 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.408 (16.00), 1.447 (12.80), 2.075 (1.21), 2.089 (1.43), 2.518 (14.84), 2.522 (9.71), 2.578 (1.82), 3.097 (14.18), 3.098 (13.79), 3.457 (5.52), 3.556 (0.99), 4.175 (3.26), 4.218 (1.10), 4.236 (1.77), 4.244 (1.93), 4.263 (1.10), 6.647 (1.71), 6.669 (2.04), 7.950 (1.43), 7.972 (10.59), 7.980 (11.20), 8.002 (1.38), 8.076 (3.42), 8.083 (3.37), 8.588 (3.42), 8.593 (3.59), 8.736 (4.41), 8.741 (4.25), 12.170 (1.88). Example 21.01: 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.409 (9.28), 1.448 (7.60), 2.076 (0.64), 2.090 (0.78), 2.119 (0.42), 2.518 (3.79), 2.523 (2.53), 2.581 (0.99), 3.459 (3.30), 3.502 (12.02), 3.512 (16.00), 3.558 (0.61), 3.572 (0.46), 4.219 (0.61), 4.239 (1.06), 4.246 (1.10), 4.264 (0.64), 6.658 (1.01), 6.680 (1.18), 7.984 (2.03), 8.007 (4.26), 8.041 (4.35), 8.063 (1.90), 8.147 (1.82), 8.153 (1.79), 8.609 (2.08), 8.614 (2.24), 8.751 (2.86), 8.755 (2.74), 12.246 (1.04). Intermediate INT-24 tert-butyl -2'-(3-{4-[N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}-1-[(4- methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H-spiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (mixture of 4 stereoisomers)
Figure imgf000262_0001
Intermediate INT-24 was prepared in analogy to Intermediate INT-21 using (rac)-tert-butyl 2'- {[(trifluoromethyl)sulfonyl]oxy}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (see INT-6) and (rac)-(3-{4-[N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}-1- [(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (see INT-25). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.098 (5.97), 1.116 (13.24), 1.133 (6.19), 1.230 (0.53), 1.397 (13.68), 1.439 (11.17), 2.045 (0.68), 2.061 (1.43), 2.075 (4.50), 2.348 (12.01), 2.518 (6.45), 2.523 (4.35), 2.540 (0.75), 2.570 (1.60), 3.397 (0.53), 3.424 (1.76), 3.439 (4.64), 3.466 (0.87), 3.522 (16.00), 3.539 (0.77), 3.545 (0.77), 3.557 (0.73), 3.891 (0.65), 3.900 (0.70), 3.908 (0.73), 3.914 (1.11), 3.918 (2.42), 3.932 (2.80), 3.935 (2.78), 3.950 (2.51), 3.958 (0.73), 3.967 (0.70), 3.976 (0.63), 4.213 (0.92), 4.230 (1.57), 4.239 (1.62), 4.257 (0.92), 5.759 (2.71), 6.705 (1.50), 6.730 (1.81), 7.437 (3.70), 7.457 (3.92), 8.052 (3.09), 8.074 (6.67), 8.080 (5.85), 8.101 (4.93), 8.112 (6.04), 8.134 (2.78), 8.461 (7.40), 8.547 (3.82), 8.552 (3.94), 8.862 (2.68), 8.866 (2.71). Intermediate INT-25 (rac)-(3-{4-[N-(ethoxycarbonyl)-S-methylsulfonimidoyl]phenyl}-1-[(4- methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid
Figure imgf000263_0001
Intermediate INT-25 was prepared in analogy to Intermediate INT-22 using (rac)-ethyl [(4-{5- bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}phenyl)(methyl)oxido-^^- sulfanylidene]carbamate (INT-26). The crude product was used without further purification. Intermediate INT-26 (rac)-ethyl [(4-{5-bromo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3- yl}phenyl)(methyl)oxido-λ4-sulfanylidene]carbamate
Intermediate INT-26 was prepared in analogy to Intermediate INT-22 using 5-bromo-3-iodo-1- [(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine and ethyl {methyl(oxido)[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-^6-sulfanylidene}carbamate. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.065 (16.00), 1.094 (1.03), 1.111 (2.26), 1.129 (1.03), 2.353 (2.04), 2.518 (0.44), 3.513 (2.76), 3.913 (0.46), 3.924 (0.50), 3.931 (0.54), 3.938 (2.91), 3.942 (0.51), 7.436 (0.55), 7.438 (0.60), 7.457 (0.65), 8.010 (0.74), 8.032 (1.04), 8.047 (0.88), 8.068 (0.79), 8.125 (0.99), 8.147 (0.67), 8.551 (1.26), 8.571 (0.61), 8.576 (0.74), 8.612 (0.91), 8.618 (0.67). Example 22.00 (rac)-tert-butyl -2'-[3-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
Figure imgf000264_0001
Example 22.00 was prepared in analogy to Example 20.00 using (rac)-tert-butyl 2'-{3- (dimethylphosphoryl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'-dihydro- 1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (see INT-27). 1H-NMR (500 MHz, DMSO-d6) delta [ppm]: 0.000 (2.57), 1.408 (11.61), 1.446 (9.28), 1.711 (15.77), 1.738 (16.00), 2.069 (0.53), 2.080 (0.60), 2.094 (0.57), 2.109 (0.42), 2.518 (0.75), 2.522 (0.72), 2.526 (0.58), 2.566 (0.93), 2.577 (1.17), 3.170 (0.87), 3.312 (0.45), 3.453 (3.03), 3.551 (0.54), 3.561 (0.48), 3.572 (0.40), 4.217 (0.70), 4.227 (1.20), 4.231 (1.29), 4.239 (1.29), 4.243 (1.20), 4.254 (0.73), 6.580 (1.23), 6.605 (1.57), 7.856 (2.29), 7.864 (2.35), 8.316 (3.53), 8.484 (2.40), 8.488 (2.47), 8.734 (3.59), 8.738 (3.33), 12.316 (0.45). Intermediate INT-27 (rac)-tert-butyl 2'-{3-(dimethylphosphoryl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate
Figure imgf000265_0001
Intermediate INT-27 was prepared in analogy to Intermediate INT-24 using (rac)-tert-butyl 2'- {[(trifluoromethyl)sulfonyl]oxy}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate and {3-(dimethylphosphoryl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin- 5-yl}boronic acid (see INT-28). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.395 (13.42), 1.435 (10.89), 1.783 (16.00), 1.817 (15.66), 2.055 (0.97), 2.069 (1.19), 2.095 (0.65), 2.332 (0.53), 2.359 (11.96), 2.518 (3.32), 2.522 (2.06), 2.563 (1.66), 2.580 (0.96), 2.673 (0.48), 3.437 (5.11), 3.463 (0.47), 3.509 (0.49), 3.528 (0.86), 3.542 (0.63), 3.554 (0.56), 4.210 (1.81), 4.214 (1.57), 4.219 (1.51), 4.228 (1.57), 4.237 (1.62), 4.254 (0.92), 4.487 (0.46), 4.492 (0.94), 4.496 (0.92), 5.758 (13.80), 6.647 (1.44), 6.673 (1.78), 7.454 (3.57), 7.474 (3.96), 7.488 (0.78), 7.497 (0.81), 7.506 (0.77), 7.520 (0.68), 7.524 (0.96), 7.542 (0.63), 7.552 (1.33), 7.569 (0.81), 8.079 (4.80), 8.100 (4.42), 8.224 (2.41), 8.236 (2.42), 8.568 (2.53), 8.831 (2.97), 8.836 (2.94). Intermediate INT-28 {3-(dimethylphosphoryl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-5- yl}boronic acid
Intermediate INT-28 was prepared in analogy to Intermediate INT-25 using 5-bromo-3- (dimethylphosphoryl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (see INT-29). The crude product was used without further purification. Intermediate INT-29 5-bromo-3-(dimethylphosphoryl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine
Figure imgf000266_0001
A mixture of 5-bromo-3-iodo-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.05 mmol), dimethylphosphine oxide (98 mg, 1.26 mmol), palladium(II) acetate (5 mg, 0.02 mmol) and 1,1′-ferrocenediyl-bis(diphenylphosphine (13 mg, 0.023 mmol) in DMF (11.5 mL), 1,2-dimethoxyethane (1.3 mL) and N,N-diisopropylethylamine (0.37 mL) was stirred at 110 °C overnight. After cooling the mixture was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography to give the desired product (280 mg, 0.66 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.761 (1.17), 1.769 (15.11), 1.795 (1.23), 1.804 (15.10), 2.331 (0.65), 2.366 (10.24), 2.518 (5.02), 2.523 (3.24), 2.673 (0.61), 2.728 (13.17), 2.888 (16.00), 5.759 (0.44), 7.457 (2.89), 7.476 (3.00), 7.950 (2.06), 8.045 (4.00), 8.050 (1.38), 8.067 (3.83), 8.289 (2.90), 8.301 (2.87), 8.553 (14.21). Synthesis of Intermediates: Intermediate INT-30: (rac)-1-tert-butyl 3-methyl 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)pyrrolidine-1,3- dicarboxylate
To a solution of 1-tert-butyl 3-methyl pyrrolidine-1,3-dicarboxylate (5.0 g, 21.8 mmol) in dry THF (50 mL) at -78°C was added a solution of LiHMDS in THF (1M, 43.6 mL, 43.6 mmol) under argon atmosphere, and the reaction mixture was stirred at this temperature for 1 hour. Then a solution of (3-bromopropoxy)(tert-butyl)dimethylsilane (11.0 g, 43.6 mmol) in dry THF(28 mL) was added and the mixture was left to warm to room temperature and stirred overnight (monitored by TLC). Saturated aqueous solution of NH4Cl (85 mL) was added dropwise and the mixture was stirred for 1 hour before was extracted with ethyl acetate / THF (1:1) (3x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography to give the desired product (5.7 g, 14.1 mmol) 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.008 (0.52), 0.007 (0.52), 0.831 (0.96), 0.838 (16.00), 0.845 (0.96), 1.305 (0.17), 1.321 (0.19), 1.330 (0.16), 1.345 (0.20), 1.372 (4.34), 1.619 (0.24), 1.624 (0.26), 1.634 (0.21), 1.641 (0.42), 1.651 (0.20), 1.659 (0.20), 1.666 (0.18), 3.066 (0.16), 3.093 (0.17), 3.313 (1.44), 3.505 (0.44), 3.521 (0.93), 3.536 (0.43), 3.635 (0.20). Intermediate INT-31: (rac)-tert-butyl 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(3-methoxy-3- oxopropanoyl)pyrrolidine-1-carboxylate
Figure imgf000267_0001
To a solution of methyl acetate (738 mg, 10.0 mmol) in dry THF (13 mL) at -78°C was added a solution of LiHMDS in THF (1M, 10 mL, 10.0 mmol) under argon atmosphere, and the reaction mixture was stirred at this temperature for 1 hour. Then a solution of 1-tert-butyl 3-methyl 3-(3- {[tert-butyl(dimethyl)silyl]oxy}propyl)pyrrolidine-1,3-dicarboxylate (2.0 g, 5.0 mmol) (see INT- 30) in dry THF(2.9 mL) was added under stirring and the mixture was left to warm to room temperature overnight. Saturated aqueous solution of NH4Cl (30 mL) was added and the mixture was extracted ethyl acetate / THF (1:1) (3x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography to give the desired product (950 mg, 2.1 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.016 (0.70), 0.834 (16.00), 1.137 (0.27), 1.154 (0.54), 1.173 (0.31), 1.211 (0.40), 1.225 (0.43), 1.239 (0.37), 1.253 (0.26), 1.359 (4.40), 1.369 (4.79), 1.658 (0.20), 1.683 (0.22), 1.699 (0.25), 1.745 (0.26), 1.763 (0.24), 1.779 (0.26), 1.793 (1.97), 1.969 (1.01), 2.153 (1.38), 2.176 (0.18), 2.190 (0.20), 3.008 (0.27), 3.042 (0.38), 3.070 (0.24), 3.241 (0.22), 3.457 (2.28), 3.491 (0.58), 3.506 (1.16), 3.521 (0.56), 3.592 (5.20), 3.606 (1.79), 3.635 (0.38), 3.663 (0.31), 3.703 (0.35), 3.744 (1.23), 3.774 (0.47), 3.999 (0.23), 4.018 (0.23), 4.285 (0.37). Intermdiate INT-32: (rac)-tert-butyl 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(3-hydroxy-1H-pyrazol-5- yl)pyrrolidine-1-carboxylate
Figure imgf000268_0001
To a stirred solution of (rac)-tert-butyl 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(3-methoxy- 3-oxopropanoyl)pyrrolidine-1-carboxylate (950 mg, 2.14 mmol) (see INT-31) in anhydrous ethanol (1 mL) was added hydrazine hydrate (0.31 mL). The mixture was stirred at 80oC for 1 hour. The solvent was removed in vacuum and the residue was purified by column chromatography to give the desired product (680 mg, 1.60 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.007 (0.45), 0.007 (0.48), 0.842 (0.92), 0.849 (16.00), 0.856 (0.98), 0.866 (0.27), 1.189 (0.23), 1.206 (0.16), 1.383 (3.82), 1.401 (3.90), 1.599 (0.27), 1.619 (0.37), 1.639 (0.21), 2.004 (0.27), 2.535 (0.49), 2.539 (0.33), 3.200 (0.16), 3.226 (0.17), 3.462 (0.39), 3.477 (0.85), 3.493 (0.39), 5.298 (0.33), 5.775 (0.40). Intermediate INT-33: (rac)-tert-butyl 3-(3-hydroxypropyl)-3-(3-hydroxy-1H-pyrazol-5-yl)pyrrolidine-1- carboxylate
A solution of tetrabutylammonium fluoride in THF (1M, 1.8 mL, 1.8 mmol) was added to a suspension of (rac)- tert-butyl 3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(3-hydroxy-1H- pyrazol-5-yl)pyrrolidine-1-carboxylate (650 mg, 1.53 mmol) (see INT-32) in THF (3.3 mL) at 0 °C. The mixture was stirred for 5 hours at 0°C and then overnight at room temperature. The mixture was concentrated and the residue purified by column chromatography to give the desired product (490 mg, 1.57 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 0.915 (0.50), 0.934 (1.28), 0.952 (0.59), 1.035 (3.89), 1.053 (8.82), 1.071 (4.02), 1.137 (0.50), 1.201 (0.55), 1.369 (16.00), 1.387 (15.27), 1.574 (1.05), 1.593 (1.33), 1.848 (0.41), 2.075 (0.41), 2.085 (0.64), 2.137 (0.46), 2.518 (11.15), 2.523 (6.99), 2.552 (0.32), 3.162 (0.73), 3.249 (1.05), 3.264 (2.65), 3.278 (2.70), 3.294 (1.51), 3.405 (0.55), 3.418 (0.59), 3.422 (1.74), 3.435 (1.78), 3.440 (1.69), 3.452 (1.69), 3.457 (0.59), 3.469 (0.55), 3.552 (0.50), 4.342 (1.83), 4.355 (3.52), 4.368 (1.74), 5.286 (0.82), 9.340 (0.27), 11.399 (0.41). Intermediate INT-34 (rac)- tert-butyl 2-hydroxy-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate
Figure imgf000269_0001
Diisopropyl azodicarboxylate (0.4 mL, 2.05 mmol) was added dropwise to a mixture of (rac)- tert-butyl 3-(3-hydroxypropyl)-3-(3-hydroxy-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (490 mg, 1.57 mmol) (see INT-33) and triphenyl phosphine (578 mg, 2.20 mmol) in THF (10.3 mL). The mixture was stirred for 2 hours at room temperature before it was concentrated. The residue was purified by column chromatography to give the desired product (300 mg, 1.02 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.066 (0.29), 1.234 (0.24), 1.331 (0.40), 1.394 (16.00), 1.414 (15.04), 1.696 (1.15), 1.708 (1.09), 1.727 (0.83), 1.907 (1.01), 1.931 (1.49), 1.944 (1.25), 1.993 (0.29), 2.012 (0.51), 2.040 (0.59), 2.337 (0.48), 2.518 (5.97), 2.523 (3.92), 3.262 (0.88), 3.289 (4.19), 3.312 (1.71), 3.364 (1.47), 3.378 (1.09), 3.770 (1.68), 3.785 (2.21), 3.800 (1.07), 3.815 (0.45), 3.830 (0.24), 5.246 (2.53), 5.254 (2.37), 5.759 (3.39), 9.471 (4.45). Intermediate INT-35 (rac)- tert-butyl 2-{[(trifluoromethyl)sulfonyl]oxy}-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxylate
Figure imgf000270_0001
N,N-diisopropylethylamine (0.53 mL, 3.07 mmol) and N-phenyl- bis(trifluoromethanesulfonimide) (427 mg, 1.20 mmol) were added to a solution of tert-butyl 2- hydroxy-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxylate (300 mg, 1.02 mmol) (see INT-34) in THF (6.3 mL) at room temperature. The mixture was stirred at 60°C for 3 hours. After cooling, the mixture was diluted with aqueous sodium chloride solution and extracted with ethyl acetate (3x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (310 mg, 0.73 mmol). 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.066 (1.79), 1.232 (0.25), 1.392 (16.00), 1.415 (14.07), 1.742 (0.26), 1.765 (0.57), 1.778 (0.97), 1.792 (0.97), 1.802 (0.98), 1.817 (0.69), 1.839 (0.25), 1.962 (0.43), 1.975 (0.67), 1.993 (1.13), 2.006 (1.84), 2.021 (1.89), 2.036 (1.08), 2.074 (3.74), 2.097 (0.59), 2.121 (0.62), 2.152 (0.38), 2.518 (2.82), 2.523 (2.00), 2.540 (0.69), 3.292 (0.20), 3.375 (5.67), 3.388 (0.92), 3.403 (0.67), 3.410 (0.67), 3.423 (0.64), 3.432 (0.72), 3.444 (0.67), 3.460 (0.33), 3.471 (0.25), 4.008 (1.39), 4.023 (2.84), 4.038 (1.44), 6.277 (8.70), 7.644 (0.34), 7.660 (0.39), 7.696 (0.64), 7.715 (0.41). Example 23.00 (rac)-tert-butyl 2-(quinolin-3-yl)-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate
Example 23.00 was prepared in analogy to Example 1.0 using (rac)-tert-butyl 2- {[(trifluoromethyl)sulfonyl]oxy}-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate (see INT-35) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)quinoline. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.220 (0.55), 1.409 (16.00), 1.444 (14.09), 1.835 (1.75), 2.053 (2.14), 2.119 (0.40), 2.140 (0.61), 2.156 (0.64), 2.173 (0.76), 2.189 (0.53), 2.536 (0.66), 3.403 (0.90), 3.436 (3.74), 3.452 (2.58), 3.479 (0.81), 3.529 (0.66), 3.542 (0.82), 3.549 (0.98), 3.561 (0.91), 3.575 (0.61), 3.589 (0.41), 4.160 (1.64), 4.174 (3.05), 4.188 (1.65), 6.849 (3.50), 7.589 (0.91), 7.607 (1.87), 7.626 (1.32), 7.705 (1.15), 7.724 (1.79), 7.743 (1.01), 7.997 (3.59), 8.018 (3.34), 8.641 (2.75), 9.327 (3.08). The following examples were prepared in analogy to example 23.00:
Figure imgf000271_0001
23.01 23.02
Figure imgf000272_0001
Figure imgf000273_0002
Example 24.00 (rac)-N-ethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide
Figure imgf000273_0001
Example 24.00 was prepared in analogy to Example 6.00 using crude (rac)-2-(3-methyl-1H- pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] trifluoroacetate (see INT-36) and isocyanatoethane. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.014 (6.67), 1.032 (15.50), 1.050 (6.88), 1.138 (0.50), 1.154 (0.51), 1.777 (0.93), 1.788 (1.79), 1.796 (1.83), 1.806 (1.93), 1.815 (1.16), 1.975 (0.57), 1.988 (0.82), 1.993 (0.92), 2.005 (1.51), 2.018 (1.53), 2.025 (1.66), 2.037 (1.35), 2.043 (1.26), 2.059 (0.95), 2.075 (0.82), 2.139 (0.61), 2.158 (1.26), 2.169 (0.64), 2.177 (0.79), 2.188 (0.91), 2.208 (0.47), 2.269 (15.37), 2.272 (16.00), 2.518 (2.27), 2.523 (1.50), 2.540 (0.96), 3.032 (0.83), 3.050 (2.68), 3.064 (2.94), 3.068 (2.87), 3.082 (2.63), 3.100 (0.77), 3.366 (0.52), 3.385 (1.30), 3.392 (1.02), 3.414 (9.36), 3.429 (0.90), 3.493 (0.65), 3.506 (0.79), 3.514 (0.99), 3.526 (0.87), 3.531 (0.75), 3.539 (0.58), 3.552 (0.44), 4.110 (1.95), 4.125 (4.16), 4.140 (1.91), 6.147 (1.11), 6.161 (2.25), 6.174 (1.08), 6.606 (9.63), 7.218 (3.08), 7.220 (3.07), 7.223 (2.43), 8.184 (4.07), 8.188 (4.17), 8.595 (5.22), 8.600 (5.06), 11.276 (2.21), 11.281 (2.20). Intermediate INT-36 (rac)-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine] trifluoroacetate
Figure imgf000274_0001
Intermediate INT-36 was prepared in analogy to Intermediate INT-11 using (rac)-tert-butyl -2- (3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate (see Example 23.03). The crude product was used without further purification. Intermediate 37 (rac)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate 
Figure imgf000274_0002
To tert-butyl (rac)-2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (5.00 g, 12.2 mmol) in dichloromethane (460 mL) was added trifluoroacetic acid (30 mL, 390 mmol) and stirred overnight at rt.The reaction mixture was concentrated, treated twice with toluene to yield 5.7 g of the title product which was used without further purification in the next step.   Intermediate 38 (rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate  F F O F N N S O O N O N H C H 3 (Rac)-5',6'-Dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate (3.00 g, 9.64 mmol) was suspended in dichloromethane (110 mL) and N,N- diisopropylethylamine (17 mL, 96 mmol) was added. At 0 °C under an atmosphere of argon isocyanatoethane (790 µL, 9.6 mmol) was added. The reaction mixture was allowed to reach rt on the cooling bath and stirred for 2h at rt. The reaction mixture was concentrated and purified by silica gel chromatography to afford 2.80 g (76 % yield) of the title compound. LC-MS (Method 1): Rt = 1.05 min; MS (ESIneg): m/z = 381 [M-H]-  Intermediate 39 (rac)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate- hydrogen chloride (1/1) 
Figure imgf000275_0001
Tert-Butyl (rac)-2'-{[(trifluoromethyl)sulfonyl]oxy}-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (1.00 g, 2.43 mmol) was dissolved in dioxane (21 mL) and hydrochloric acid (3.0 mL, 4.0 M in dioxane, 12.0 mmol) was added at 0 °C. The reaction mixture was stirred overnight at rt and concentrated to obtain 1.11 g of the title compound which was used without further purification in the next step. LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 312 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.391 (1.27), 1.418 (1.03), 2.161 (0.45), 2.164 (0.43), 2.180 (1.26), 2.199 (0.82), 2.518 (0.50), 2.524 (0.64), 2.539 (0.48), 2.652 (0.41), 3.307 (0.49), 3.390 (0.49), 3.400 (1.01), 3.429 (0.61), 3.564 (16.00), 4.210 (0.56), 4.218 (0.61), 4.226 (0.78), 4.228 (0.78), 4.232 (0.67), 4.238 (0.61), 4.245 (0.62), 4.252 (0.47), 6.444 (2.92), 9.626 (0.44).    Intermediate 40 (rac)-1-[(1-phenylcyclobutyl)carbamoyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-2'-yl trifluoromethanesulfonate 
Figure imgf000276_0001
1-Phenylcyclobutan-1-amine (429 mg, 2.92 mmol), carbonyldiimidazole (473 mg, 2.92 mmol), and N,N-diisopropylethylamine (2.1 mL, 12 mmol) were dissolved in DMF (33 mL) and stirred for 1 h at rt. Then (rac)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate—hydrogen chloride (1/1) (845 mg, 2.43 mmol) in DMF (2mL) was added and stirred for 3 h at 60 °C. Half concentrated brine solution was added and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to yield 1.55 g of the title product which was used without further purification in the next step.   LC-MS (Method 1): Rt = 1.31 min; MS (ESIneg): m/z = 483 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.392 (2.75), 1.420 (2.20), 1.739 (0.41), 1.762 (0.63), 1.780 (0.60), 1.785 (0.59), 1.950 (0.50), 1.957 (0.51), 1.972 (0.74), 1.978 (0.60), 1.988 (0.44), 1.995 (0.57), 2.000 (0.58), 2.011 (0.42), 2.023 (0.47), 2.042 (0.73), 2.055 (0.69), 2.060 (0.67), 2.076 (0.66), 2.097 (1.02), 2.117 (0.52), 2.128 (0.47), 2.327 (0.81), 2.332 (0.60), 2.344 (1.28), 2.349 (1.21), 2.353 (1.12), 2.358 (1.13), 2.366 (1.44), 2.380 (1.43), 2.397 (1.02), 2.419 (0.67), 2.438 (0.70), 2.453 (1.77), 2.466 (2.62), 2.472 (2.45), 2.518 (1.05), 2.523 (0.72), 2.728 (13.33), 2.730 (13.09), 2.888 (16.00), 3.382 (0.83), 3.404 (0.54), 3.430 (2.61), 3.436 (2.45), 3.461 (0.46), 3.475 (0.46), 3.480 (0.44), 3.487 (0.56), 3.495 (0.60), 3.501 (0.54), 3.507 (0.60), 3.513 (0.42), 4.207 (1.69), 4.214 (0.70), 4.225 (2.94), 4.235 (0.64), 4.243 (1.59), 6.186 (4.87), 6.253 (0.51), 6.410 (0.71), 6.713 (2.26), 7.012 (1.62), 7.138 (0.73), 7.142 (0.46), 7.147 (0.47), 7.152 (0.57), 7.156 (1.71), 7.164 (1.03), 7.171 (0.78), 7.174 (1.27), 7.178 (0.78), 7.183 (0.81), 7.186 (0.44), 7.254 (1.09), 7.257 (0.73), 7.263 (2.01), 7.267 (0.98), 7.270 (1.03), 7.273 (2.14), 7.282 (3.26), 7.291 (1.47), 7.296 (0.90), 7.300 (1.88), 7.336 (1.74), 7.339 (1.95), 7.352 (0.44), 7.357 (1.32), 7.361 (0.94), 7.406 (2.77), 7.409 (2.96), 7.422 (0.74), 7.427 (2.42), 7.430 (1.93), 7.639 (1.02), 7.951 (1.94).  Intermediate 41 (3-bromo-1H-pyrazol-1-yl)methanol 
Figure imgf000277_0001
3-Bromo-1H-pyrazole (4.04 g, 27.5 mmol) was dissolved in methanol (40 mL). Then formaldehyde (8.2 mL, 37 % in water, 110 mmol) was added at rt. The reaction mixture was stirred overnight at rt and concentrated to dryness to give 4.47 g (92 % yield) of the title compound. LC-MS (Method 2): Rt = 0.40 min; MS (ESIpos): m/z = 177 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (4.57), 2.522 (3.05), 2.673 (0.71), 3.302 (0.60), 4.573 (0.38), 4.591 (0.82), 4.610 (0.44), 5.309 (9.69), 5.326 (9.90), 5.460 (0.49), 5.784 (0.44), 5.803 (0.87), 6.367 (0.65), 6.373 (0.65), 6.401 (15.13), 6.407 (16.00), 6.886 (1.90), 6.904 (4.95), 6.922 (1.80), 7.818 (15.56), 7.824 (16.00).    Intermediate 42 tert-butyl (rac)-3-(3-bromo-1H-pyrazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate 
Figure imgf000277_0002
(3-Bromo-1H-pyrazol-1-yl)methanol (2.10 g, 11.9 mmol) was dissolved in THF (40 mL) and at - 78 °C lithium N-isopropylpropan-2-aminide (12 mL, 2.0 M inTHF/heptane/ethylbenzene, 24 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was allowed to reach -20 °C. The reaction mixture was stirred at -20 °C for 45 min. Then the reaction mixture was cooled down to -78 °C and tert-butyl 3-oxopyrrolidine-1-carboxylate (2.00 g, 10.8 mmol) in THF (80 mL) was added at -78 C and stirred for 2 h at -78 C. The reaction mixture was allowed to reach rt overnight. Saturated aqueous sodium hydrogen carbonate solution was added and extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to yield 1.35 g (38 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 332 [M+H]+    Intermediate 43 tert-butyl (rac)-3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3- hydroxypyrrolidine-1-carboxylate 
Figure imgf000278_0001
To tert-butyl (rac)-3-(3-bromo-1H-pyrazol-5-yl)-3-hydroxypyrrolidine-1-carboxylate (8.90 g, 26.8 mmol) dissolved in THF (150 mL) under an atmosphere of nitrogen was added sodium hydride (1.18 g, 60 % in mineral oil, 29.5 mmol). It was stirred for 10 min. Then [2- (chloromethoxy)ethyl](trimethyl)silane (5.2 mL, 29 mmol) was added and stirred at rt overnight. Saturated aqueous sodium chloride solution was added and then extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated, and purified by silica gel chromatography obtaining 9.67 g (78 % yield) of the title compound.   LC-MS (Method 2): Rt = 1.45 min; MS (ESIpos): m/z = 462 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.069 (0.62), -0.061 (16.00), -0.053 (0.66), 0.792 (0.47), 0.802 (0.46), 0.812 (0.88), 0.832 (0.57), 1.390 (7.72), 1.404 (5.26), 1.991 (0.50), 2.521 (0.93), 2.526 (0.61), 3.397 (0.40), 3.410 (0.56), 3.421 (0.42), 3.534 (0.48), 3.541 (0.46), 3.555 (0.84), 3.559 (0.59), 3.574 (0.52), 3.580 (0.41), 5.382 (1.61), 5.567 (0.69), 6.543 (2.15).    Intermediate 44 tert-butyl (rac)-3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-(2-ethoxy-2- oxoethoxy)pyrrolidine-1-carboxylate 
Figure imgf000279_0001
To tert-butyl (rac)-3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3- hydroxypyrrolidine-1-carboxylate (9.67 g, 20.9 mmol) dissolved in THF (160 mL) was added sodium hydride (1.25 g, 60 % in mineral oil, 31.4 mmol) under an atmosphere of nitrogen. It was stirred for 10 min. at rt and then ethyl bromoacetate (3.5 mL, 31 mmol) was added and stirred at rt overnight. Sodium hydride (627 mg, 60 % in mineral oil, 15.7 mmol) was added and stirred for 10 min. at rt. Then ethyl bromoacetate (1.7 mL, 16 mmol) was added and stirred overnight at rt. Saturated aqueous sodium chloride soltution was added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (hexane/ethyl acetate) to give 6.85 g (60 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.64 min; MS (ESIpos): m/z = 548 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.033 (0.59), 0.042 (11.96), 0.071 (5.53), 0.857 (0.71), 0.878 (1.25), 0.897 (0.80), 1.196 (1.59), 1.200 (2.89), 1.213 (3.50), 1.218 (6.50), 1.231 (1.69), 1.236 (3.10), 1.283 (0.44), 1.468 (16.00), 1.476 (4.10), 2.396 (0.52), 2.400 (0.68), 2.405 (0.51), 2.591 (2.17), 2.596 (1.38), 2.742 (0.50), 3.438 (0.52), 3.453 (0.64), 3.460 (0.52), 3.471 (0.61), 3.501 (0.60), 3.584 (0.41), 3.605 (0.87), 3.628 (1.14), 3.646 (0.68), 3.655 (0.41), 3.715 (0.44), 3.827 (0.41), 3.870 (0.80), 3.910 (1.72), 3.956 (0.56), 3.971 (0.64), 4.085 (0.42), 4.103 (1.14), 4.120 (1.15), 4.141 (0.49), 5.493 (3.13), 5.831 (1.62), 6.678 (0.46), 6.688 (0.61), 6.723 (2.52).    Intermediate 45 ethyl {[(rac)-3-(5-bromo-1H-pyrazol-3-yl)pyrrolidin-3-yl]oxy}acetate trifluoroacetate (1:1) 
Figure imgf000280_0001
To tert-butyl (rac)-3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-(2-ethoxy- 2-oxoethoxy)pyrrolidine-1-carboxylate (3.50 g, 6.38 mmol) in dichloromethane (230 mL) was added trifluoroacetic acid (16 mL, 210 mmol). It was stirred at rt overnight. The reaction mixture was concentrated and treated twice with toluene affording 3.79 g of the title compound.   LC-MS (Method 1): Rt = 0.75 min; MS (ESIpos): m/z = 318 [M+H]+    Intermediate 46 ethyl {[(rac)-3-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)pyrrolidin-3-yl]oxy}acetate 
Figure imgf000280_0002
Isocyanatoethane (510 µL, 6.4 mmol) was added to ethyl {[(rac)-3-(5-bromo-1H-pyrazol-3- yl)pyrrolidin-3-yl]oxy}acetate trifluoroacetate (1:1) (3.79 g, 73 % purity, 6.39 mmol) and N,N- diisopropylethylamine (11 mL, 64 mmol) in dichloromethane (180 mL). It was stirred at rt overnight. The reaction mixture was concentrated and purified by silica gel chromatography to obtain 960 mg (39 % yield) of the title compound. LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 389 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.004 (4.28), 0.945 (0.41), 0.963 (0.94), 0.986 (7.38), 1.003 (14.44), 1.021 (7.28), 1.052 (0.74), 1.077 (11.60), 1.126 (8.49), 1.144 (16.00), 1.161 (7.94), 1.232 (0.50), 1.533 (0.94), 1.552 (1.69), 1.570 (0.98), 1.642 (0.45), 2.176 (0.73), 2.199 (1.62), 2.209 (1.40), 2.232 (2.21), 2.255 (1.12), 2.380 (1.65), 2.413 (1.54), 2.996 (1.44), 3.012 (3.70), 3.029 (4.90), 3.045 (3.57), 3.061 (1.22), 3.406 (5.86), 3.436 (4.37), 3.487 (1.43), 3.504 (1.71), 3.516 (1.75), 3.534 (0.92), 3.575 (0.46), 3.666 (0.45), 3.771 (1.96), 3.792 (4.07), 3.832 (6.12), 3.896 (5.30), 3.936 (2.50), 4.003 (2.13), 4.021 (5.10), 4.039 (4.90), 4.053 (1.96), 4.241 (1.87), 4.315 (0.90), 5.437 (0.66), 6.124 (3.18), 6.448 (8.65), 6.569 (0.52), 13.379 (0.72).    Intermediate 47 (rac)-3-(3-bromo-1H-pyrazol-5-yl)-N-ethyl-3-(2-hydroxyethoxy)pyrrolidine-1-carboxamide 
Figure imgf000281_0001
Ethyl {[(rac)-3-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)pyrrolidin-3-yl]oxy}acetate (958 mg, 2.46 mmol) was dissolved in THF (70 mL) under an atmosphere of nitrogen. Then lithium borohydride (3.0 mL, 4.0 M, 12 mmol) was added dropwise and stirred at rt overnight. The reaction mixture was cooled down to 0 °C and saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to afford 825 mg (97 % yield) of the tilte compound which was used in the next step without further purification. LC-MS (Method 1): Rt = 0.66 min; MS (ESIpos): m/z = 347 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.014 (0.44), -0.002 (0.56), 0.963 (0.88), 0.972 (1.13), 0.982 (7.62), 0.990 (2.60), 1.000 (16.00), 1.007 (2.05), 1.018 (7.42), 1.064 (0.73), 1.070 (0.54), 1.078 (1.13), 1.137 (2.79), 1.154 (1.23), 1.172 (2.00), 1.190 (1.19), 1.208 (11.00), 1.232 (0.79), 1.352 (8.40), 1.643 (0.45), 1.674 (0.91), 1.689 (1.19), 1.703 (0.84), 1.987 (3.18), 2.140 (0.82), 2.161 (1.48), 2.171 (1.20), 2.181 (1.83), 2.194 (1.67), 2.216 (0.85), 2.322 (1.84), 2.327 (2.15), 2.331 (1.78), 2.518 (4.77), 2.522 (3.05), 2.665 (0.95), 2.669 (1.29), 2.673 (0.95), 2.975 (0.43), 2.993 (1.36), 3.008 (2.96), 3.025 (3.92), 3.043 (2.58), 3.058 (0.82), 3.093 (0.98), 3.107 (1.94), 3.119 (1.96), 3.131 (2.53), 3.143 (1.38), 3.165 (1.29), 3.189 (0.53), 3.207 (1.24), 3.221 (2.56), 3.235 (1.89), 3.245 (1.95), 3.259 (1.54), 3.275 (1.54), 3.298 (3.79), 3.388 (4.23), 3.400 (4.87), 3.414 (10.44), 3.428 (3.64), 3.444 (0.86), 3.472 (0.84), 3.487 (0.43), 3.514 (0.47), 3.537 (0.64), 3.564 (0.44), 3.680 (2.01), 3.707 (1.67), 3.886 (0.89), 3.900 (1.18), 3.915 (0.84), 4.017 (0.74), 4.035 (0.72), 5.432 (0.76), 5.758 (4.67), 5.989 (0.99), 6.042 (0.42), 6.063 (1.14), 6.095 (1.36), 6.109 (2.56), 6.122 (1.23), 6.304 (0.52), 6.375 (8.29), 6.573 (0.74), 6.868 (0.73).    Intermediate 48 (rac)-2-bromo-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine-4,3'-pyrrolidine]-1'- carboxamide 
Figure imgf000282_0001
(Rac)-3-(3-Bromo-1H-pyrazol-5-yl)-N-ethyl-3-(2-hydroxyethoxy)pyrrolidine-1-carboxamide (822 mg, 2.37 mmol) was dissolved in THF (30 mL). Triphenylphosphine (869 mg, 3.31 mmol) and diisopropyl azodicarboxylate (610 µL, 3.10 mmol) were added and stirred at rt overnight. The reaction mixture was concentrated and purified by silica gel chromatography obtaining 475 mg (61 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 329 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.990 (6.71), 1.007 (16.00), 1.025 (7.14), 1.078 (3.14), 1.208 (0.44), 2.179 (0.62), 2.184 (0.63), 2.190 (0.87), 2.206 (0.59), 2.212 (1.10), 2.216 (1.14), 2.238 (0.80), 2.264 (1.04), 2.281 (1.15), 2.297 (0.59), 2.313 (0.52), 2.322 (0.44), 2.326 (0.52), 2.518 (1.75), 2.522 (1.16), 2.668 (0.49), 3.003 (0.91), 3.021 (2.92), 3.035 (3.14), 3.039 (3.09), 3.053 (2.82), 3.071 (0.83), 3.275 (0.65), 3.291 (1.03), 3.299 (1.47), 3.316 (1.89), 3.357 (3.33), 3.385 (3.53), 3.466 (1.02), 3.487 (1.67), 3.509 (0.78), 3.711 (1.71), 3.714 (1.72), 3.740 (1.47), 3.743 (1.45), 4.008 (0.56), 4.022 (1.22), 4.039 (1.73), 4.064 (4.45), 4.069 (2.97), 4.074 (6.16), 4.100 (1.22), 4.232 (0.52), 5.758 (0.47), 6.150 (0.97), 6.164 (1.90), 6.178 (0.95), 6.464 (13.61).    Intermediate 49 (rac)-N-ethyl-2'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000282_0002
To (rac)-1-(ethylcarbamoyl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazol]-2-yl trifluoromethanesulfonate (100 mg, 262 µmol) in dioxane (2.0 mL) under an atmosphere of argon was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (69.7 mg, 275 µmol), potassium acetate (77.0 mg, 785 µmol), 1,1'-bis(diphenylphosphino)ferrocene (7.25 mg, 13.1 µmol), and [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex with dichloromethane (10.7 mg, 13.1 µmol). It was stirred for 12 h at 100 °C. The reaction mixture was concentrated and used without further purification in the next step.   Intermediate 50 (rac)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidin]-2-yl trifluoromethanesulfonate 
Figure imgf000283_0001
Tert-Butyl (rac)-2-[(trifluoromethanesulfonyl)oxy]-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine- 4,3'-pyrrolidine]-1'-carboxylate (2.00 g, 4.70 mmol) was dissolved in dichloromethane (80 mL) and then trifluouroacetic acid (12 mL, 150 mmol) was added and stirred for 1 h at rt. The reaction mixture was concentrated and treated twice with toluene and once with dichloromethane yielding 3.20 g of the title compound which was used without further purification in the next step.   LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 326 [M+H]+    Intermediate 51 (rac)-1'-(ethylcarbamoyl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidin]-2-yl trifluoromethanesulfonate 
Under an atmosphere of argon (rac)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidin]-2-yl trifluoromethanesulfonate (4.20 g, 12.9 mmol) was suspended in dichloromethane (310 mL) and N,N-diisopropylethylamine (22 mL, 130 mmol) was added. At 0 °C isocyanatoethane (1.0 mL, 13 mmol) was added and stirred at rt overnight while reaching rt. The reaction mixture was concentrated and purified with silica gel chromatography to give 3.05 g (60 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 397 [M+H]+    Intermediate 52 1-(3-chloropyridin-4-yl)cyclobutane-1-carboxylic acid 
Figure imgf000284_0001
Ethyl 1-(3-chloropyridin-4-yl)cyclobutane-1-carboxylate (224 mg, 934 µmol)was solubilised in a mixture of THF (18 ml) and methanol (6.1 ml). Aqueous lithium hydroxide (3.7 mL, 1M) was added and the rection was stirred at rt for 2 days. The reaction mixture was diluted with water and the organic solvents were removed. The remaining aqueous phase was acidified using 1N HCl and extracted with a mixture of DCM/EtOH. The organic phase was then dired and concentrated under reduced pressure to give 159 mg of the title compound that was used without further purification.   Intermediate 53 3-chloro-4-(1-isocyanatocyclobutyl)pyridine 
Figure imgf000285_0001
1-(3-chloropyridin-4-yl)cyclobutane-1-carboxylic acid (159 mg, 751 µmol) was solubilised in 1,4-dioxane (2.5 ml). diphenyl phosphorazidate (210 µl, 980 µmol) and triethylamine (140 µl) were added and the reaction was stirred at rt for 18 hours. The reaction was then diluted with water and extracted with DCM. The organic phase was dried and concentrated under reduced pressure to give the title compound that was used without purification. The following isocyantes were prepapared similarly.  Intermediate 54 3-fluoro-4-(1-isocyanatocyclobutyl)pyridine 
Figure imgf000285_0002
  Intermediate 55 4-(1-isocyanatocyclobutyl)pyridazine 
Figure imgf000285_0003
  Intermediate 56 4-isocyanato-4-phenyloxane 
Figure imgf000286_0001
  Intermediate 57 1-fluoro-2-(1-isocyanatocyclopentyl)benzene 
Figure imgf000286_0002
  Intermediate 58 2-chloro-5-(1-isocyanatocyclobutyl)pyridine 
Figure imgf000286_0003
  Intermediate 59 1,2-difluoro-4-(2-isocyanatopropan-2-yl)benzene 
Figure imgf000286_0004
  Intermediate 60 4-(2-isocyanatopropan-2-yl)pyrimidine 
Figure imgf000287_0001
  Intermediate 61 5-fluoro-2-(2-isocyanatopropan-2-yl)pyridine 
Figure imgf000287_0002
  Intermediate 62 [(1S)-2,2,2-trifluoro-1-isocyanato-1-methoxyethyl]benzene 
Figure imgf000287_0003
  Intermediate 63 5-(2-isocyanatopropan-2-yl)pyrimidine 
Figure imgf000287_0004
  Intermediate 64 3-bromo-6-methoxyquinoline  To a solution of 3-bromoquinolin-6-ol (1.00 g, 4.46 mmol) in DMF (35 mL), iodomethane (560 µl, 8.9 mmol) and potassium hydroxide (551 mg, 9.82 mmol) were added. The resultant mixture was stirred at 80°C overnight. The reaction mixture was allowed to cool to rt and then diluted with ethylacetate, water and brine. The organic layer was separated and the aqueous phase extracted with ethylacetate (x2). The combined organics were dried over sodium sulphate, filtered and concentrate. The crude mixture was purified by silica gel chromatography to yield 399 mg (38%) of the title compound.  LC-MS (Method 1): Rt = 1.13 min; MS (ESIpos): m/z = 240 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (0.69), 2.522 (0.45), 3.896 (16.00), 7.366 (1.84), 7.373 (2.21), 7.430 (1.64), 7.437 (1.35), 7.452 (1.80), 7.459 (1.54), 7.919 (1.79), 7.941 (1.64), 8.584 (1.72), 8.590 (1.81), 8.766 (2.84), 8.772 (2.63).    Intermediate 65 3-bromo-6-(difluoromethoxy)quinoline 
Figure imgf000288_0001
To a solution of 3-bromoquinolin-6-ol (2.20 g, 9.82 mmol) in DMF (77 mL), sodium chloro(difluoro)acetate (2.99 g, 19.6 mmol) and cesium carbonate (8.00 g, 24.5 mmol) were added. The resultant mixture was stirred at 80°C overnight. The reaction mixture was allowed to cool to rt and then diluted with ethylacetate, water and brine. The organic layer was separated and the aqueous phase extracted with ethylacetate (x2). The combined organics were dried over sodium sulphate, filtered and concentrate. The crude mixture was purified by silica gel chromatography to yield 1.15 g (43%) of the title compound.  LC-MS (Method 1): Rt = 1.24 min; MS (ESIpos): m/z = 276 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (2.75), 2.523 (1.76), 3.565 (0.43), 7.230 (8.56), 7.412 (16.00), 7.596 (8.19), 7.642 (6.00), 7.649 (6.86), 7.665 (6.50), 7.672 (7.77), 7.741 (9.25), 7.748 (7.91), 8.091 (9.60), 8.114 (8.62), 8.748 (8.97), 8.754 (9.29), 8.941 (15.67), 8.946 (14.88).    Intermediate 66 3-bromo-7-fluoro-6-[(oxan-4-yl)oxy]quinoline 
Figure imgf000289_0001
To 3-bromo-7-fluoroquinolin-6-ol (250 mg, 1.03 mmol), 4-bromooxane (205 mg, 1.24 mmol) and sodium hydroxide (49.6 mg, 1.24 mmol), DMF (4.7 mL) was added and the reaction mixture stirred at 100°C overnight. Further 4-bromooxane (205 mg, 1.24 mmol) and sodium hydroxide (49.6 mg, 1.24 mmol) were added and the reaction mixture stirred at 100°C overnight. The resultant mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic phases were dried over a hydrophobic filter and concentrated. The crude mixture was purified by basic HPLC to yield 310 mg (92%) of the title compound.  LC-MS (Method 1): Rt = 1.20 min; MS (ESIpos): m/z = 326 [M+H]+   Intermediate 67 3-bromo-6-tert-butylquinoline 
Figure imgf000289_0002
To a solution of 6-tert-butylquinoline (500 mg, 2.70 mmol) in acetic acid (4.6 ml, 80 mmol), 1- bromopyrrolidine-2,5-dione (432 mg, 2.43 mmol) was added. The resultant mixture was stirred at 100°C for 2 hours. Addition of a equivalent of acetic acid (4.6 ml, 80 mmol) was added and the mixture was stirred at 100°C for a further 2 hours. The resultant mixture was diluted with water and extracted with DCM (3x). The combined organics were dried over a hydrophobic filter and concentrated. The crude mixture was purified by basic HPLC to yield 70.0 mg (10%) of the title compound.  LC-MS (Method 1): Rt = 1.46 min; MS (ESIpos): m/z = 264 [M+H]+   Intermediate 68 3-bromo-6-(cyclohexyloxy)-7-fluoroquinoline 
Figure imgf000290_0001
To 3-bromo-7-fluoroquinolin-6-ol (250 mg, 1.03 mmol), bromocyclohexane (150 µl, 1.2 mmol) and sodium hydroxide (41.3 mg, 1.03 mmol), DMF (4.7 mL) was added and the reaction mixture stirred at 100°C overnight. Further bromocyclohexane (150 µl, 1.2 mmol) and sodium hydroxide (41.3 mg, 1.03 mmol) were added and the reaction mixture stirred at 100°C overnight. The resultant mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic phases were dried over a hydrophobic filter and concentrated. The crude mixture was purified by basic HPLC to yield 32.0 mg (10%) of the title compound.    Intermediate 69 3-bromo-5-[(pyridin-2-yl)methoxy]quinoline 
Figure imgf000290_0002
A solution of 3-bromoquinolin-5-ol (100 mg, 446 µmol), 2-(chloromethyl)pyridine (114 mg, 893 µmol) and potassium carbonate (617 mg, 4.46 mmol) in DMF (2.5 mL) was stirred at 50°C for 3 hours. To this 2-(chloromethyl)pyridine (114 mg, 893 µmol) was added and stirred at 50°C for a further 1 hour. To the resultant mixture saturated NaCl and 1M HCl was added and extracted with ethyl acetate. The combined organics were dried over a hydrophobic filter and concentrated. The crude mixture was purified by basic HPLC to yield 8.10 mg (6%) of the title compound.  LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 315 [M+H]+   Intermediate 70 3-bromo-5-[(pyridin-3-yl)methoxy]quinoline 
Figure imgf000291_0001
A solution of 3-bromoquinolin-5-ol (100 mg, 446 µmol), 3-(chloromethyl)pyridine (114 mg, 893 µmol) and potassium carbonate (617 mg, 4.46 mmol) in DMF (2.5 mL) was stirred at 60°C for 2 hours. The mixture was allowed to cool to room temperature and concentrated. The crude mixture was purified by silica gel chromatography to yield 8.60 mg (6%) of the title compound.  LC-MS (Method 4): Rt = 0.93 min; MS (ESIpos): m/z = 315 [M+H]+    Intermediate 71 3-bromo-N-(pyridin-3-yl)quinoline-5-carboxamide 
Figure imgf000291_0002
To a solution of pyridin-3-amine (100 mg, 1.06 mmol) in dichloromethane (8 mL), 3- bromoquinoline-5-carboxylic acid (402 mg, 1.59 mmol), HATU (808 mg, 2.13 mmol) and N,N- diisopropylethylamine (740 µl, 4.3 mmol) were added and stirred at rt overnight. The resultant mixture was concentrated and purified by silica gel chromatography to yield 380 mg of the title compound.   LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 328 [M+H]+ ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.037 (0.56), 1.055 (1.08), 1.072 (0.54), 1.909 (0.51), 2.688 (2.97), 7.429 (3.97), 7.441 (4.20), 7.449 (4.34), 7.462 (4.32), 7.931 (4.15), 7.949 (6.52), 7.970 (6.40), 8.058 (6.73), 8.075 (4.97), 8.228 (8.52), 8.249 (7.93), 8.355 (6.37), 8.358 (6.31), 8.366 (6.50), 8.370 (5.94), 8.942 (14.93), 8.947 (16.00), 9.064 (11.78), 9.070 (10.92), 10.907 (8.08).    Intermediate 72 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000292_0001
A solution of (3S)-5-bromo-3-ethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.67 g, 11.1 mmol) in phosphorylchloride (30 mL) was stirred overnight at 100 °C. The resultant mixture was added slowly to sodium carbonate solution (100g in 2L), the resultant mixture adjusted to pH 8 and extracted with dichloromethane. The separated organics were dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield 2.73 g (95%) of the title compound. LC-MS (Method 4): Rt = 1.30 min; MS (ESIpos): m/z = 259 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.139 (6.81), 1.158 (16.00), 1.176 (7.03), 2.331 (0.54), 2.335 (0.40), 2.526 (2.43), 2.640 (2.00), 2.658 (6.19), 2.668 (1.06), 2.677 (6.54), 2.696 (1.90), 8.210 (5.10), 8.216 (6.75), 8.249 (7.15), 8.255 (5.47), 12.503 (1.16).    Intermediate 73 7-bromo-2-(morpholin-4-yl)-1,5-naphthyridine 
Figure imgf000292_0002
A solution of 7-bromo-2-chloro-1,5-naphthyridine (100 mg, 411 µmol), morpholine (39 µl, 450 µmol), potassium carbonate (170 mg, 1.23 mmol) in DMF (1 mL) was stirred at 90 °C overnight. The resultant mixture was filtered and the filtrate concentrated. The crude mixture was purified by silica gel chromatography to yield 105 mg (83%) of the title compound. LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 295 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (0.71), 2.522 (0.49), 3.331 (16.00), 7.507 (2.68), 7.531 (2.72), 8.075 (1.90), 8.077 (1.92), 8.099 (1.67), 8.101 (1.73), 8.166 (2.04), 8.168 (1.97), 8.172 (1.95), 8.173 (1.78), 8.625 (3.27), 8.631 (3.15).    Intermediate 74 7-bromo-N-methyl-1,5-naphthyridin-2-amine 
Figure imgf000293_0001
A solution of 7-bromo-2-chloro-1,5-naphthyridine (100 mg, 411 µmol), methylamine (230 µl, 2.0 M) and potassium carbonate (170 mg, 1.23 mmol) in DMF (1 mL) was stirred at 90°C overnight. The resultant mixture was filtered and the filtrate concentrated. The crude mixture was purified by silica gel chromatography to yield 81 mg (83%) of the title compound. LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 239 [M+H]+    Intermediate 75 7-bromo-1,5-naphthyridin-2-amine 
Figure imgf000293_0002
A solution of 7-bromo-2-chloro-1,5-naphthyridine (100 mg, 411 µmol) in ammonia (2.12 g, 33 % in water. 41.1 mmol) was stirred at 120 °C for 8 hours. The resultant mixture was concentrated and purified by silica gel chromatography to yield 49.0 mg (53%) of the title compound. LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 224 [M+H]+    Intermediate 76 3-bromo-7-fluoro-6-[(propan-2-yl)oxy]quinoline 
Figure imgf000293_0003
A solution of 3-bromo-7-fluoroquinolin-6-ol (250 mg, 1.03 mmol), 2-bromopropane (120 µl, 1.2 mmol) and sodium hydroxide (49.6 mg, 1.24 mmol) in DMF (4.7 mL) was heated at 70°C overnight. The resultant mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic phases were dried over a hydrophobic filter and concentrated. The crude mixture was purified by silica gel chromatography to yield 170 mg (58%) of the title compound.  LC-MS (Method 1): Rt = 1.25 min; MS (ESIpos): m/z = 284 [M+H]+    Intermediate 77 5-bromo-3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000294_0001
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.54 mmol) and 2-phenylpropan- 2-ol (346 mg, 2.54 mmol) in nitromethane (5 mL), iron(III) chloride (41.2 mg, 254 µmol) was added and the mixture stirred at rt overnight. Further Iron(III) chloride (41.2 mg, 254 µmol) and 2-phenylpropan-2-ol (346 mg, 2.54 mmol) were added and the mixture stirred at rt overnight. Further Iron(III) chloride (41.2 mg, 254 µmol) and 2-phenylpropan-2-ol (346 mg, 2.54 mmol) were added and the mixture stirred at rt over the weekend. The resultant mixture was concentrated and purified by silica gel chromatography to yield 518 mg (65%) of the title compound.  LC-MS (Method 1): Rt = 1.40 min; MS (ESIpos): m/z = 315 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.410 (1.49), 1.682 (16.00), 2.518 (0.61), 7.154 (0.46), 7.162 (0.43), 7.165 (0.51), 7.169 (0.93), 7.176 (0.61), 7.185 (0.92), 7.191 (0.55), 7.245 (0.69), 7.250 (0.41), 7.260 (0.69), 7.265 (3.13), 7.276 (3.83), 7.281 (9.13), 7.284 (4.35), 7.290 (3.29), 7.294 (0.75), 7.297 (0.75), 7.495 (2.50), 8.152 (2.64), 8.158 (2.60), 11.715 (0.88).    Intermediate 78 5-bromo-3-[2-(3-methylphenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridine  To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.54 mmol) and 2-(3- methylphenyl)propan-2-ol (438 mg, 2.92 mmol) in acetonitrile (5 mL), aluminum trifluoromethanesulfonate (120 mg, 254 µmol) was added and the mixture stirred at 80°C for 3 hours. 2-(3-methylphenyl)propan-2-ol (419 mg, 2.79 mmol) was added and the reaction mixture stirred at 80°C overnight. The resultant mixture was concentrated, purified by silica gel chromatography and basic HPLC to yield 138 mg (16%) of the title compound.  LC-MS (Method 1): Rt = 1.45 min; MS (ESIpos): m/z = 329 [M+H]+    Intermediate 79 5-bromo-3-[2-(3-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000295_0001
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) and 2-(3- chlorophenyl)propan-2-ol (249 mg, 1.46 mmol) in acetonitrile (2.5 mL), aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) was added and the mixture stirred at 80°C for 5 hours. 2-(3-chlorophenyl)propan-2-ol (249 mg, 1.46 mmol) was added and the mixture stirred at 80°C overnight. The resultant mixture was concentrated and purified by silica gel chromatography to yield 261 mg (59%) of the title compound. LC-MS (Method 1): Rt = 1.50 min; MS (ESIpos): m/z = 349 [M+H]+    Intermediate 80 5-bromo-3-[2-(4-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridine  H 3 C Cl H 3C Br N N H To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) and 2-(4- chlorophenyl)propan-2-ol (249 mg, 1.46 mmol) in acetonitrile (2.5 mL), aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) was added and the mixture stirred at 80°C for 5 hours. 2-(3-chlorophenyl)propan-2-ol (249 mg, 1.46 mmol) was added and the mixture stirred at 80°C overnight. The resultant mixture was concentrated and purified by silica gel chromatography to yield 304 mg (69%) of the title compound. LC-MS (Method 1): Rt = 1.50 min; MS (ESIpos): m/z = 349 [M+H]+    Intermediate 81 5-bromo-3-[2-(4-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000296_0001
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) and 2-(4- fluorophenyl)propan-2-ol (225 mg, 1.46 mmol) in acetonitrile (2.5 mL), aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) was added and the mixture stirred at 80°C for 1 hours. Further 2-(3-fluorophenyl)propan-2-ol (249 mg, 1.46 mmol) and aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) were added and the mixture stirred at 80°C overnight. The resultant mixture was concentrated, purified by silica gel chromatography and basic HPLC to yield 200 mg (45%) of the title compound. LC-MS (Method 1): Rt = 1.41 min; MS (ESIpos): m/z = 333 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.677 (16.00), 2.518 (0.74), 2.522 (0.49), 7.055 (1.65), 7.060 (0.56), 7.072 (0.70), 7.077 (3.68), 7.082 (0.69), 7.094 (0.61), 7.100 (2.05), 7.280 (1.94), 7.286 (0.83), 7.294 (2.15), 7.303 (1.84), 7.312 (0.69), 7.317 (1.66), 7.334 (2.79), 7.340 (2.73), 7.493 (1.95), 8.166 (2.78), 8.172 (2.71), 11.738 (0.93).    Intermediate 82 5-bromo-3-[2-(2-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000297_0001
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) and 2-(2- fluorophenyl)propan-2-ol (225 mg, 1.46 mmol) in acetonitrile (2.5 ml), aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) was added and the mixture stirred at 80°C for 1 hours. Further 2-(2-fluorophenyl)propan-2-ol (225 mg, 1.46 mmol) and aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) were added and the mixture stirred at 80°C overnight. The resultant mixture was concentrated, purified by silica gel chromatography and basic HPLC to yield 129 mg (29%) of the title compound. LC-MS (Method 1): Rt = 1.40 min; MS (ESIpos): m/z = 333 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.682 (0.40), 1.739 (16.00), 2.522 (0.51), 6.985 (0.69), 6.988 (0.74), 7.004 (0.84), 7.008 (0.88), 7.016 (0.73), 7.019 (0.76), 7.036 (0.81), 7.039 (0.84), 7.188 (0.63), 7.191 (0.68), 7.207 (1.51), 7.210 (1.50), 7.226 (1.13), 7.229 (1.06), 7.248 (2.97), 7.254 (3.05), 7.268 (0.51), 7.273 (0.59), 7.280 (0.70), 7.288 (0.79), 7.293 (0.75), 7.300 (0.68), 7.305 (0.72), 7.456 (2.71), 7.475 (0.72), 7.479 (0.73), 7.497 (1.20), 7.516 (0.63), 7.521 (0.58), 8.149 (2.96), 8.154 (2.90), 11.712 (1.12).    Intermediate 83 3-bromo-N,N-dimethyl-1,6-naphthyridin-7-amine 
Figure imgf000297_0002
A solution of 3-bromo-7-chloro-1,6-naphthyridine (150 mg, 616 µmol), N-methylmethanamine (620 µL, 2.0 M, 1.2 mmol) and potassium carbonate (170 mg, 1.23 mmol) in DMF (2 mL) was stirred at 90°C overnight. Further N-methylmethanamine (1.55 mL, 2.0 M, 3.1 mmol) was added and the mixture stirred at 90°C overnight. The resultant mixture was filtered and concentrated to yield 155 mg (100%) of the title compound.  LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 253 [M+H]+    Intermediate 84 3-bromo-7-(morpholin-4-yl)-1,6-naphthyridine 
Figure imgf000298_0001
A solution of 3-bromo-7-chloro-1,6-naphthyridine (150 mg, 616 µmol), morpholine (110 µl, 1.2 mmol) and potassium carbonate (170 mg, 1.23 mmol) in DMF (2 mL) was stirred at 90°C overnight. Further morpholine (275 µl, 3.1 mmol) was added and the mixture stirred at 90°C overnight. The resultant mixture was filtered and concentrated to yield 181 mg (100%) of the title compound.  LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 295 [M+H]+    Intermediate 85 5-bromo-3-(1-phenylcyclohexyl)-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000298_0002
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) and 1- phenylcyclohexan-1-ol (257 mg, 1.46 mmol) in acetonitrile (2.5 mL), aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) was added and the mixture stirred at 80°C for 3 hours. Further 1-phenylcyclohexan-1-ol (257 mg, 1.46 mmol)  and aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) were added and the mixture stirred at 80°C overnight. The resultant mixture was concentrated, purified by silica gel chromatography and basic HPLC to yield 99 mg (22%) of the title compound.  LC-MS (Method 1): Rt = 1.55 min; MS (ESIpos): m/z = 355 [M+H]+    Intermediate 86 5-bromo-3-[2-(1,3-thiazol-2-yl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000299_0001
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) and 2-(1,3-thiazol-2- yl)propan-2-ol (209 mg, 1.46 mmol)  in acetonitrile (2.5 mL), aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) was added and the mixture stirred at 80°C for 3 hours. Further 2-(1,3-thiazol-2-yl)propan-2-ol (209 mg, 1.46 mmol)  and aluminum trifluoromethanesulfonate (60.2 mg, 127 µmol) were added and the mixture stirred at 80°C over the weekend. The resultant mixture was concentrated, purified by silica gel chromatography and basic HPLC to yield 220 mg (54%) of the title compound.  LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 322 [M+H]+    Intermediate 87 3-bromo-6-[(propan-2-yl)oxy]quinoline 
Figure imgf000299_0002
3-Bromoquinolin-6-ol (1.00 g, 4.46 mmol), 2-bromopropane (840 µl, 8.9 mmol) and potassium hydroxide (551 mg, 9.82 mmol) in DMF (35 mL) was stirred under argon at 80°C overnight. The resultant mixture was cooled and diluted with ethyl acetate, water and brine. The aqueous phase was extracted with ethyl acetate (x2) and the combined organics were dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield 952 mg (80%) of the title compound.  LC-MS (Method 1): Rt = 1.33 min; MS (ESIpos): m/z = 268 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.341 (15.92), 1.356 (16.00), 2.518 (0.47), 4.741 (0.85), 4.755 (1.15), 4.770 (0.85), 7.365 (1.32), 7.371 (2.25), 7.381 (2.07), 7.388 (0.87), 7.404 (1.76), 7.411 (1.27), 7.898 (1.80), 7.920 (1.62), 8.551 (1.70), 8.556 (1.79), 8.741 (2.94), 8.747 (2.76).  Intermediate 88 5-bromo-3-iodo-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000300_0001
5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.19 mmol) was dissolved in DMF (12 mL) and then sodium hydride (171 mg, 60% in mineral oil, 4.28 mmol) was added at rt and stirred for 1 h at rt. 4-Methylbenzene-1-sulfonyl chloride (1.30 g, 6.81 mmol) was added and stirred overnight at rt. Then sodium hydride (171 mg, 60% in mineral oil, 4.28 mmol) was added at rt and stirred for 1 h at rt and then 4-methylbenzene-1-sulfonyl chloride (1.30 g, 6.81 mmol) was added and stirred for 4 h at rt. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted three times with ethyl acetate. The combine organic layers were dried through a hydrophobic filter, concentrated, and purified by silica gel chromatography to yield 2.34 g (79 % yield) of the title compound.    ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.228 (1.06), 1.347 (0.53), 2.322 (0.71), 2.326 (0.98), 2.332 (0.81), 2.346 (16.00), 2.518 (4.04), 2.522 (2.64), 2.664 (0.65), 2.668 (0.89), 2.673 (0.64), 5.758 (0.42), 7.423 (4.40), 7.444 (4.66), 7.986 (6.18), 8.009 (8.17), 8.015 (6.37), 8.220 (8.87), 8.508 (4.63), 8.513 (4.33).    Intermediate 89 5-bromo-3-(3,6-dihydro-2H-pyran-4-yl)-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3- b]pyridine 
Figure imgf000301_0001
Potassium carbonate (362 mg, 2.62 mmol) was added to a mixture of dioxane/water (5:1, 5.0 mL) under an atmosphere of argon. Then [1,1'- bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex (38.3 mg, 52.4 µmol), 5- bromo-3-iodo-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.05 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (484 mg, 2.31 mmol) were added and stirred at 80 °C overnight. Formic acid solution (5.0 M in water) was added and the reaction mixture was filtered. The filter was washed twice with ethyl acetate. The filtrate was washed with water, dried through a hydrophobic filter, and concentrated. The residue was purified by silica gel chromatography obtaining 290 mg (64 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.160 (1.27), 1.178 (2.58), 1.195 (1.29), 1.204 (0.66), 1.994 (4.41), 2.174 (1.14), 2.178 (1.15), 2.345 (16.00), 3.572 (2.52), 3.704 (1.91), 3.718 (3.92), 3.732 (1.83), 3.821 (2.68), 3.834 (5.74), 3.848 (2.58), 4.024 (0.94), 4.042 (0.93), 4.144 (2.00), 4.149 (2.04), 4.237 (3.99), 4.244 (4.04), 5.760 (0.95), 6.433 (2.34), 7.413 (4.45), 7.433 (4.82), 7.953 (6.33), 7.974 (0.97), 7.979 (6.35), 7.983 (2.18), 7.996 (2.02), 8.000 (5.88), 8.149 (1.49), 8.494 (4.44), 8.500 (5.13), 8.563 (5.55), 8.568 (4.73).    Intermediate 90 5-bromo-3-(2,5-dihydrofuran-3-yl)-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000302_0001
Potassium carbonate (362 mg, 2.62 mmol) was added to a mixture of dioxane/water (5:1, 5.0 mL) under an atmosphere of argon. Then [1,1'- bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex (38.3 mg, 52.4 µmol), 5- bromo-3-iodo-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.05 mmol), and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (247 mg, 1.26 mmol) were added and stirred at 80 °C overnight. Formic acid solution (5.0 M in water) was added and the reaction mixture was filtered. The filter was washed twice with ethyl acetate. The filtrate was washed with water, dried through a hydrophobic filter, and concentrated. The residue was purified by silica gel chromatography obtaining 350 mg (95 % purity, 76 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.159 (1.48), 1.175 (0.93), 1.193 (0.48), 1.233 (0.54), 1.991 (1.40), 2.326 (0.90), 2.330 (1.28), 2.335 (1.23), 2.348 (16.00), 2.526 (2.74), 2.668 (0.72), 2.673 (0.98), 2.677 (0.73), 4.750 (3.03), 4.758 (2.11), 4.917 (1.81), 4.922 (2.26), 4.930 (3.02), 4.934 (3.02), 4.940 (1.82), 6.745 (1.93), 6.749 (2.80), 6.754 (1.91), 7.419 (4.42), 7.439 (4.72), 7.971 (6.88), 7.975 (6.88), 7.997 (5.68), 8.530 (4.33), 8.535 (4.69), 8.633 (5.07), 8.638 (4.65).    Intermediate 91 5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000303_0002
5-bromo-1H-pyrrolo[2,3-b]pyridine (5.00 g, 25.4 mmol) was solubilised in DMF (120 ml) and the reaction was cooled to -40°C. (731 mg, 30.5 mmol) was slowly added and the reaction was stirred for 1h at -40°C. A solution of [2-(chloromethoxy)ethyl](trimethyl)silane (4.5 ml, 25 mmol) in DMF (42 ml) was added dropwise and the reaction was stirred 30 min at -40°C. (2.3 ml, 13 mmol) was added and the reaction was stirred 1h at -20°C and 1h at rt. (365 mg, 15.2 mmol) and (2.3 ml, 13 mmol) were then added and the reaction was stiired at rt for 16h. The reaction mixture was then poured into a ice/water micture and stirred 30 min. The aqueous phase was then extracted with EtOAc, dried and concentrated under reduced pressure. The crude material was purified by flash column chromatography to give 5.90 g (71 % yield) of the title compound.   Intermediate 92 5-bromo-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000303_0001
5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.55 mmol) was solubilised in acetonitrile (7.0 ml) under argon and the reaction mixture was cooled to 0°C. N,N-diisopropylethylamine (400 µl, 2.3 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (300 µl, 1.7 mmol) were added dropwise and the reaction was stirred 16h at rt. The reaction was cooled to 0°C and N,N- diisopropylethylamine (400 µl, 2.3 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (300 µl, 1.7 mmol) were added again dropwise and the reaction was stirred at rt. The reaction mixture was then poured into ice and the aqueous phase was extracted with ethyl acetate. The organic phase was then dried and concentrated iunder reduced pressure. The crude material was purified by flash column chromatography to give 650 mg (93 % yield) of the title compound.  LC-MS (Method 1): Rt = 1.78 min; MS (ESIpos): m/z = 455 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.56), 0.013 (1.78), 0.027 (0.78), 0.106 (13.37), 0.108 (9.79), 0.146 (0.56), 0.890 (4.55), 0.897 (0.89), 0.909 (5.73), 0.922 (0.92), 0.930 (4.72), 0.957 (0.53), 0.968 (0.43), 0.978 (0.53), 0.998 (0.51), 2.632 (1.46), 3.469 (0.45), 3.586 (4.85), 3.593 (0.86), 3.606 (5.96), 3.626 (4.99), 3.653 (0.58), 3.674 (0.52), 3.695 (0.50), 4.662 (0.66), 4.772 (2.33), 5.697 (16.00), 8.035 (7.97), 8.040 (7.40), 8.108 (11.19), 8.511 (6.19), 8.516 (6.10).    Intermediate 93 5-bromo-3-[(4-methylpyridin-3-yl)ethynyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridine 
Figure imgf000304_0001
5-bromo-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (800 mg, 1.77 mmol), 3-ethynyl-4-methylpyridine (248 mg, 2.12 mmol; CAS-RN:[30413-62-8]), (124 mg, 177 µmol; CAS-RN:[13965-03-2]), (16.8 mg, 88.3 µmol; CAS-RN:[7681-65-4]) and triethylamine (740 µl, 5.3 mmol; CAS-RN:[121-44-8]) were solubilised in DMF (12 ml) and the reaction mixture was degassed and stirred for 1h at 80°C in a sealed vial. The reaction mixture was then coiled to rt, diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography to give 360 mg (99 % purity, 46 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.091 (3.09), 0.904 (1.92), 0.912 (0.44), 0.925 (2.66), 0.937 (0.45), 0.944 (2.04), 1.250 (1.06), 1.267 (1.97), 1.285 (0.98), 2.083 (3.28), 3.619 (2.00), 3.640 (2.66), 3.659 (1.95), 4.113 (0.77), 4.130 (0.77), 5.738 (5.93), 5.854 (16.00), 7.463 (1.67), 7.476 (1.70), 8.353 (4.87), 8.473 (3.13), 8.479 (3.26), 8.512 (2.46), 8.524 (2.40), 8.580 (2.93), 8.586 (2.72), 8.822 (3.44).      Intermediate 94 5-bromo-3-(1-methyl-1H-pyrazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridine 
Figure imgf000305_0001
5-Bromo-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.21 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (333 mg, 2.65 mmol; CAS-RN:[720702-41-0]), Bis(triphenylphosphine)palladium(II) Dichloride (77.4 mg, 110 µmol; CAS-RN:[13965-03-2]) and sodium carbonate (3.3 ml, 2.0 M, 6.6 mmol; CAS-RN:[497-19-8]) were solubilised in degassed acetonitrile (9.3 ml). The reaction was strirred for 16h ate 105°C under nitrogen. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 1.06 g (85 % purity) of the title compound that was used without further purification.     Intermediate 95 5-bromo-3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridine 
Figure imgf000305_0002
5-bromo-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.21 mmol), [1-(propan-2-yl)-1H-pyrazol-5-yl]boronic acid (374 mg, 2.43 mmol; CAS-RN:[839714- 33-9]), Bis(triphenylphosphine)palladium(II) Dichloride (77.4 mg, 110 µmol; CAS-RN:[13965- 03-2]) and Cs2CO3 (1.44 g, 4.41 mmol) were solubilised in degassed 1,4-dioxane (15 ml) and the reaction was stirred under nitrogen for 16 hours at 105°C. The reaction mixture was then cooled down, diluted with water and extracted with ethylacetate. Theorganic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 1.17 g (85 % purity, 104 % yield) of the title compound that was used without further purification.   Intermediate 96 5-bromo-3-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000306_0001
5-bromo-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (800 mg, 1.77 mmol) was solubilised in DMF (6.8 ml) and diphenyl(trifluoromethyl)sulfanium trifluoromethanesulfonate (1.43 g, 3.53 mmol) and copper (337 mg, 5.30 mmol; CAS- RN:[7440-50-8]) were added under inert atmosphere. The reaction was stirred for 5h at 60°C. The reaction was cooled down, diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was then purified by flash column chromatography to give 400 mg (80 % purity, 46 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.123 (4.21), -0.110 (16.00), 0.793 (0.76), 0.813 (1.16), 0.833 (0.75), 3.529 (0.76), 3.549 (1.41), 3.569 (1.17), 4.667 (0.66), 5.671 (2.39), 5.756 (0.57), 7.318 (4.20), 8.315 (0.74), 8.512 (0.84), 8.560 (0.91), 8.565 (0.85).  Intermediate 1 3-Brom-6-(trifluormethoxy)chinolin 
Figure imgf000307_0001
To a solution of 6-(Trifluormethoxy)chinolin (500 mg, 2.35 mmol) in acetic acid (3.8 mL),  1- Brompyrrolidin-2,5-dion (376 mg, 2.11 mmol) was added and the reaction mixture stirred at 100 °C for 1 hour. The resultant mixture was diluted with water and extracted with ethyl acetate (x3). The comined organics were filtered through a hydrophobic filter and concentrated. The crude mixture was purified by basic HPLC to give 38 mg (5%) of the title compound.  LC-MS (Method 1): Rt = 1,36 min; MS (293,1): m/z = [M+H]+  1H-NMR (500 MHz, DMSO-d6) delta [ppm]: 1.232 (0.44), 2.520 (4.30), 2.524 (3.66), 2.528 (2.81), 7.786 (4.25), 7.791 (4.44), 7.805 (4.70), 7.809 (4.93), 8.044 (8.00), 8.047 (7.7      Intermediate 97 7-Brom-N,N-dimethyl-1,5-naphthyridin-2-amin 
Figure imgf000307_0002
A solution of 7-Brom-2-chlor-1,5-naphthyridin (100 mg, 411 µmol), N-Methylmethanamin (230 µl, 2.0 M, 450 µmol), Potassium carbonate (170 mg, 1.23 mmol) in DMF (1.0 mL) was stirred overnight at 90 °C. The resultant mixture was filtered, concentrated and purified by silica gel chromatography to give 80 mg (77%) of the title compound.  LC-MS (Method 1): Rt = 1.13min; MS (252.1): m/z = [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (0.59), 3.193 (16.00), 7.343 (1.49), 7.367 (1.50), 8.017 (0.86), 8.019 (0.89), 8.041 (0.80), 8.123 (0.87), 8.125 (0.88), 8.129 (0.88), 8.131 (0.83), 8.558 (1.21), 8.564 (1.26).    Intermediate 98 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine  N H N H3 C O B H3 C O Cl H3 C C H3 To a solution of 5-bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (7.95 g, 34.3 mmol) in 1,4-dioxane (160 mL) under nitrogen, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (9.59 g, 37.8 mmol), potassium acetate (10.1 g, 103 mmol), 1,1’-bis(diphenylphosphino)ferrocene (952 mg, 1.72 mmol) and [1,1'-bis(diphenylphosphin)ferrocen]dichlorpalladium(II) complex with dichloromethane (1.40 g, 1.72 mmol) were added. The resultant mixture was stirred over night at 100 °C. The reaction mixture was allowed to cool to rt, diluted with dichloromethane, filtered and concentrated. The crude reaction mixture was purified by silica gel chromatography to yield 9.50 g (99%) of the title compound.  LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 279 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (7.26), 1.155 (8.93), 1.323 (16.00), 2.518 (0.45), 3.939 (0.82), 7.720 (1.98), 8.129 (1.21), 8.133 (1.29), 8.516 (1.11), 8.520 (1.11).  The following intermediates were prepared analogously Intermediate 99 (5-chloro-6-methoxyquinolin-3-yl)boronic acid 
Figure imgf000308_0001
LC-MS (Method 4): Rt = 0.69 min; MS (ESIpos): m/z = 238 [M+H]+    Intermediate 100 6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline  LC-MS (Method 4): Rt = 0.69 min; MS (ESIpos): m/z = 238 [M+H]+    Intermediate 101 6-(difluoromethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 
Figure imgf000309_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (3.07), 1.153 (5.93), 1.354 (16.00), 1.907 (1.38), 3.563 (7.17), 3.939 (0.40), 7.193 (0.53), 7.378 (1.16), 7.562 (0.63), 7.662 (0.45), 7.669 (0.47), 7.685 (0.46), 7.692 (0.50), 7.873 (0.70), 7.879 (0.66), 8.084 (0.64), 8.107 (0.58), 8.711 (0.74), 8.713 (0.76), 9.002 (1.03), 9.006 (1.02).    Intermediate 102 {7-fluoro-6-[(oxan-4-yl)oxy]quinolin-3-yl}boronic acid 
Figure imgf000309_0002
LC-MS (Method 4): Rt = 0.68 min; MS (ESIpos): m/z = 292 [M+H]+    Intermediate 103 (6-tert-butylquinolin-3-yl)boronic acid 
Figure imgf000310_0001
LC-MS (Method 4): Rt = 0.81 min; MS (ESIpos): m/z = 230 [M+H]+    Intermediate 104 [6-(cyclohexyloxy)-7-fluoroquinolin-3-yl]boronic acid 
Figure imgf000310_0002
LC-MS (Method 4): Rt = 0.96 min; MS (ESIpos): m/z = 290 [M+H]+    Intermediate 105 [6-(2-methoxy-2-oxoethyl)quinolin-3-yl]boronic acid 
Figure imgf000310_0003
LC-MS (Method 4): Rt = 0.52 min; MS (ESIpos): m/z = 246 [M+H]+    Intermediate 106 {5-[(pyridin-2-yl)methoxy]quinolin-3-yl}boronic acid 
Figure imgf000311_0003
LC-MS (Method 4): Rt = 0.53 min; MS (ESIpos): m/z = 281 [M+H]+    Intermediate 107 {5-[(pyridin-3-yl)methoxy]quinolin-3-yl}boronic acid 
Figure imgf000311_0001
LC-MS (Method 4): Rt = 0.47 min; MS (ESIpos): m/z = 281 [M+H]+    Intermediate 108 {5-[(pyridin-3-yl)carbamoyl]quinolin-3-yl}boronic acid 
Figure imgf000311_0002
LC-MS (Method 4): Rt = 0.47 min; MS (ESIpos): m/z = 294 [M+H]+    Intermediate 109 2-chloro-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000312_0001
LC-MS (Method 4): Rt = 1.27 min; MS (ESIpos): m/z = 307 [M+H]+    Intermediate 110 2-(morpholin-4-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-naphthyridine 
Figure imgf000312_0002
  Intermediate 111 N,N-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-naphthyridin-2-amine 
Figure imgf000312_0003
  Intermediate 112 N-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-naphthyridin-2-amine    Intermediate 113 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-naphthyridin-2-amine 
Figure imgf000313_0001
  Intermediate 114 {7-fluoro-6-[(propan-2-yl)oxy]quinolin-3-yl}boronic acid 
Figure imgf000313_0002
LC-MS (Method 4): Rt = 0.73 min; MS (ESIpos): m/z = 250 [M+H]+   Intermediate 115 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline  1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.35 (s, 12H), 4.01 (s, 3H), 7.09 (d, 1H), 7.59 (d, 1H), 7.72 - 7.78 (m, 1H), 7.94 (s, 1H), 8.84 (d, 1H), 9.00 (d, 1H).    Intermediate 116 (5-chloro-1,6-naphthyridin-3-yl)boronic acid 
Figure imgf000314_0001
  Intermediate 117 3-(2-phenylpropan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3- b]pyridine 
Figure imgf000314_0002
  Intermediate 118 3-[2-(3-methylphenyl)propan-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine    Intermediate 119 {3-[2-(3-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}boronic acid 
Figure imgf000315_0001
LC-MS (Method 4): Rt = 1.00 min; MS (ESIpos): m/z = 315 [M+H]+    Intermediate 120 3-[2-(4-chlorophenyl)propan-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine 
Figure imgf000315_0002
  Intermediate 121 3-[2-(4-fluorophenyl)propan-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine    Intermediate 122 3-[2-(2-fluorophenyl)propan-2-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine 
Figure imgf000316_0001
  Intermediate 123 N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-naphthyridin-7-amine 
Figure imgf000316_0002
  Intermediate 124 7-(morpholin-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-naphthyridine  O N N H 3 C O N B H 3 C O H 3 C C H 3   Intermediate 125 [3-(1-phenylcyclohexyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid 
Figure imgf000317_0001
  Intermediate 126 {3-[2-(1,3-thiazol-2-yl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}boronic acid 
Figure imgf000317_0002
  Intermediate 127 3-cyclobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine    Intermediate 128 6-[(propan-2-yl)oxy]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline 
Figure imgf000318_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (16.00), 1.154 (8.16), 1.338 (2.42), 1.347 (2.63), 1.352 (2.57), 1.376 (0.71), 1.391 (0.67), 1.907 (2.12), 3.565 (5.16), 3.939 (1.03).    Intermediate 129 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-6-ol 
Figure imgf000318_0002
LC-MS (Method 1): Rt = 0.51 min; MS (ESIpos): m/z = 272 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.064 (16.00), 1.154 (11.32), 1.163 (1.16), 1.319 (4.45), 1.761 (3.46).    Intermediate 130 [6-(methanesulfonyl)quinolin-3-yl]boronic acid    Intermediate 131 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridine 
Figure imgf000319_0001
  Intermediate 132 [6-(benzyloxy)quinolin-3-yl]boronic acid 
Figure imgf000319_0002
  Intermediate 133 [6-(trifluoromethoxy)quinolin-3-yl]boronic acid    Intermediate 134 3-[(4-methylpyridin-3-yl)ethynyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000320_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.908 (0.60), 0.928 (0.80), 0.948 (0.63), 1.166 (16.00), 1.255 (4.94), 1.271 (0.50), 1.430 (10.12), 2.086 (0.77), 3.625 (0.61), 3.645 (0.80), 3.665 (0.59), 4.040 (1.86), 5.776 (1.58), 5.857 (0.57), 7.474 (0.53), 7.486 (0.55), 8.310 (1.65), 8.413 (1.04), 8.417 (1.07), 8.524 (0.83), 8.536 (0.80), 8.701 (0.96), 8.705 (0.95), 8.805 (1.12).    Intermediate 135 [3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid 
Figure imgf000320_0002
  Intermediate 136 {3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}boronic acid 
Figure imgf000321_0001
  Intermediate 137 3-(1-methyl-1H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000321_0002
LC-MS (Method 1): Rt = 1.51 min; MS (ESIpos): m/z = 455 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.103 (10.17), 0.000 (4.26), 1.068 (16.00), 1.158 (5.45), 1.321 (5.14), 2.521 (0.64), 2.525 (0.42), 3.887 (2.90), 3.942 (1.46), 5.718 (0.80), 6.525 (0.55), 6.530 (0.57), 7.549 (0.58), 7.553 (0.58), 8.097 (0.79), 8.210 (0.48), 8.214 (0.49), 8.589 (0.48), 8.593 (0.47).    Intermediate 138 3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine 
Figure imgf000321_0003
  Intermediate 139 [3-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid 
Figure imgf000322_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.135 (0.43), -0.123 (6.96), -0.114 (16.00), -0.112 (11.60), -0.106 (0.78), -0.077 (0.51), 0.795 (0.50), 0.801 (0.58), 0.815 (0.66), 0.820 (0.71), 0.835 (0.55), 0.841 (0.58), 1.170 (0.73), 1.337 (8.16), 3.534 (0.52), 3.552 (0.85), 3.555 (0.84), 3.574 (0.95), 3.577 (0.46), 3.591 (0.49), 4.669 (1.08), 5.696 (1.08), 5.708 (1.31), 5.751 (0.41), 5.756 (0.74), 5.764 (3.79), 8.260 (0.46), 8.452 (0.48), 8.455 (0.49), 8.653 (0.69), 8.657 (0.69).    Intermediate 140 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-6-yl acetate 
Figure imgf000322_0002
To a solution of 3-bromoquinolin-6-yl acetate (500 mg, 1.88 mmol) in dioxane (8.7 mL) under nitrogen, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (525 mg, 2.07 mmol),  potassium acetate (553 g, 5.64 mmol), and [1,1'- bis(diphenylphosphin)ferrocen]dichlorpalladium(II) complex with dichloromethane (153 mg, 188 µmol), were added. The resultant mixture was stirred at 100 °C overnight. The reaction mixture was allowed to cool to rt, diluted with dichloromethane, filtered through a hydrophobic membrane and concentrated. The crude reaction mixture was purified by silica gel chromatography to yield 650 mg of the title compound.    The following intermediates were prepared similarly Intermediate 141 [3-(3,6-dihydro-2H-pyran-4-yl)-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5- yl]boronic acid 
Figure imgf000323_0001
  Intermediate 142 [3-(2,5-dihydrofuran-3-yl)-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid 
Figure imgf000323_0002
Intermediate 143 (5-nitroquinolin-3-yl)boronic acid 
Figure imgf000324_0001
3-Bromo-5-nitroquinoline (1.00 g, 3.95 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2- dioxaborolane (1.20 g, 4.74 mmol) were put into a microwave vial and dissolved in dioxane (19 mL). Then potassium acetate (1.16 g, 11.9 mmol) and [1,1'- bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex with dichloromethane (322 mg, 395 µmol) were added and stirred at 100 °C for 2 h. The reaction mixture was allowed to reach rt, filtered and concentrated. The residue was purified by silica gel chromatography to obtain 1.87 g of the title compound.     Intermediate 144 (6-methoxyquinolin-3-yl)boronic acid 
Figure imgf000324_0002
To 3-bromo-6-methoxyquinoline (2.07 g, 95 % purity, 8.26 mmol) in dioxane (35 mL) under an atmosphere of argon was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (2.52 g, 9.91 mmol), potassium acetate (2.43 g, 24.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene (229 mg, 413 µmol), and [1,1'-bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex with dichloromethane (337 mg, 413 µmol). It was stirred overnight at 100 °C. The reaction mixture was allowed to reach rt, diluted with dichloromethane, filtered and concentrated to afford 2.07 g of the title compound which was used without further purification in the next step.   LC-MS (Method 4): Rt = 0.50 min; MS (ESIpos): m/z = 204 [M+H]+    Intermediate 145 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine  N H N H3 C O B H3 C O C H 3 H3 C C H3 To 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (474 mg, 2.25 mmol) in dioxane (10 mL) under an atmosphere of argon was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (627 mg, 2.47 mmol), potassium acetate (661 mg, 6.74 mmol), 1,1'- bis(diphenylphosphino)ferrocene (62.3 mg, 112 µmol), and [1,1'- bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex with dichloromethane (91.7 mg, 112 µmol). It was stirred overnight at 100 °C. The reaction mixture was allowed to reach rt, diluted with dichloromethane, filtered, and concentrated, The residue was purified by silica gel chromatography to obtain 337 mg (58 % yield) of the title compound. LC-MS (Method 4): Rt = 1.11 min; MS (ESIpos): m/z = 259 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (1.41), 1.154 (1.25), 1.314 (16.00), 2.261 (3.40), 2.264 (3.48), 7.228 (0.61), 7.231 (0.62), 8.150 (0.83), 8.153 (0.86), 8.420 (1.06), 8.424 (1.07).    Intermediate 146 tert-butyl (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000325_0001
To tert-butyl (rac)-2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (1.18 g, 2.87 mmol) in dioxane (60 mL) under an atmosphere of argon was added 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine (1.00 g, 3.59 mmol), potassium phosphate solution (17 mL, 0.50 M in water, 8.6 mmol), and XPhos Pd G2 (339 mg, 431 µmol). It was stirred overnight at 100 °C. The reaction mixture was allowed to reach rt and concentrated. The residue was treated with water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 1.02 g (86 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 414 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.038 (1.61), 1.055 (3.47), 1.068 (16.00), 1.073 (2.38), 1.408 (1.53), 1.446 (1.20), 3.161 (0.64), 3.175 (0.61), 3.425 (0.80), 3.437 (0.89), 3.442 (0.96), 3.448 (0.55), 3.455 (0.84), 3.941 (2.76), 4.347 (0.47), 4.360 (0.92), 4.372 (0.45).    The following intermediates were prepared via Suzuki coupling. Intermediate 147 tert-butyl (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000326_0001
LC-MS (Method 1): Rt = 1.38 min; MS (ESIpos): m/z = 450 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (0.76), 1.154 (3.90), 1.172 (8.41), 1.190 (4.37), 1.348 (8.26), 1.363 (8.65), 1.388 (2.46), 1.408 (6.44), 1.449 (4.58), 1.987 (16.00), 2.083 (0.41), 2.101 (0.47), 2.518 (1.37), 2.523 (0.87), 2.594 (0.56), 3.463 (1.91), 3.999 (1.17), 4.017 (3.48), 4.034 (3.39), 4.052 (1.08), 4.259 (0.48), 4.267 (0.68), 4.276 (0.70), 4.284 (0.46), 4.760 (0.42), 4.775 (0.56), 4.789 (0.42), 5.206 (0.69), 6.687 (0.68), 6.698 (0.83), 7.300 (0.64), 7.307 (0.72), 7.322 (0.65), 7.329 (0.81), 7.382 (0.93), 7.389 (0.79), 7.868 (0.96), 7.891 (0.87), 8.523 (0.90), 9.148 (1.39), 9.153 (1.33).    Intermediate 148 tert-butyl (rac)-2-[6-(difluoromethoxy)quinolin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000327_0001
Intermediate 149 tert-butyl (rac)-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate 
Figure imgf000327_0002
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 408 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (7.81), 1.053 (16.00), 1.066 (8.99), 1.070 (7.94), 1.342 (1.31), 1.407 (12.20), 1.448 (9.67), 2.078 (0.82), 2.093 (0.98), 2.119 (0.53), 2.518 (0.73), 2.523 (0.54), 2.581 (0.92), 2.590 (1.20), 2.607 (0.71), 3.412 (0.83), 3.429 (2.08), 3.447 (3.10), 3.458 (5.02), 3.523 (0.48), 3.542 (0.86), 3.551 (0.47), 3.557 (0.55), 3.568 (0.50), 4.242 (0.84), 4.251 (1.01), 4.259 (1.50), 4.268 (1.50), 4.277 (0.99), 4.285 (0.83), 4.358 (0.58), 6.694 (1.32), 6.712 (1.68), 7.165 (1.71), 7.171 (1.93), 7.244 (1.78), 7.250 (1.54), 7.266 (1.90), 7.273 (1.68), 7.824 (2.26), 7.847 (2.10), 8.420 (1.95), 9.096 (3.63), 9.101 (3.74), 10.022 (5.31).    Intermediate 150 tert-butyl (3S)-2-[6-(methanesulfonyl)quinolin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000328_0001
  Intermediate 151 tert-butyl (rac)-2'-[6-(benzyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate 
Figure imgf000328_0002
LC-MS (Method 1): Rt = 1.44 min; MS (ESIpos): m/z = 497 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.91), 1.409 (16.00), 1.450 (12.84), 1.601 (0.42), 1.620 (4.00), 2.069 (0.50), 2.085 (1.10), 2.102 (1.26), 2.131 (0.65), 2.336 (0.72), 2.518 (10.10), 2.523 (6.78), 2.539 (0.57), 2.594 (1.52), 2.613 (0.91), 2.678 (0.72), 3.003 (0.42), 3.440 (0.84), 3.464 (5.18), 3.527 (0.61), 3.545 (1.07), 3.554 (0.61), 3.559 (0.72), 3.572 (0.61), 4.253 (1.03), 4.263 (1.26), 4.271 (1.94), 4.280 (1.94), 4.288 (1.26), 4.297 (1.07), 5.252 (8.38), 6.707 (1.87), 6.720 (2.36), 7.306 (0.46), 7.340 (0.72), 7.352 (0.50), 7.358 (2.36), 7.364 (0.72), 7.373 (1.14), 7.376 (2.02), 7.380 (1.10), 7.407 (3.09), 7.411 (1.64), 7.416 (2.32), 7.423 (4.34), 7.426 (5.60), 7.439 (2.93), 7.444 (3.24), 7.446 (4.27), 7.491 (2.51), 7.497 (2.06), 7.525 (4.30), 7.542 (3.35), 7.546 (2.36), 7.904 (3.01), 7.927 (2.70), 8.525 (2.59), 8.529 (2.63), 9.172 (4.50), 9.177 (4.42).  Intermediate 152 tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (enantiomer 1)
Figure imgf000329_0002
The racemic material was separated by chiral HPLC (Instrument: Sepiatec: Prep SFC100; column: Chiralpak IA 5µ 250x30mm; eluent A: CO2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 20% B; flow: 100 mL/min; temperature: 40°C; BPR: 150bar; UV: 254 nm) yielding 710 mg (37%) of the title compound. [α]D 20 = -45.4 ° ( c = 1.00, DMSO) Retension time = 3.14 min (instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5µ 100x4.6mm; eluent A: CO2; eluent B: Methanol + 0.2 vol-% aqueous ammonis (32%); isocratic: 20% B; flow: 4 mL/min; temperature: 37.5°C; BPR: 100bar; UV: 254 nm) Intermediate 153 tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate (enantiomer 2) 
Figure imgf000329_0001
The racemic material was separated by chiral HPLC (Instrument: Sepiatec: Prep SFC100; column: Chiralpak IA 5µ 250x30mm; eluent A: CO2; eluent B: methanol + 0.2 vol % aqueous ammonia (32%); isocratic: 20% B; flow: 100 mL/min; temperature: 40°C; BPR: 150bar; UV: 254 nm) yielding 945 mg (50%) of the title compound. [α]D 20 = +231.9 ° ( c = 1.00, DMSO) Retension time = 6.19 min (instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5µ 100x4.6mm; eluent A: CO2; eluent B: Methanol + 0.2 vol-% aqueous ammonis (32%); isocratic: 20% B; flow: 4 mL/min; temperature: 37.5°C; BPR: 100bar; UV: 254 nm)   Intermediate 154 tert-butyl (rac)-2'-[6-(trifluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000330_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.49), 1.412 (16.00), 1.453 (12.89), 2.079 (0.57), 2.093 (1.17), 2.110 (1.38), 2.128 (0.78), 2.140 (0.69), 2.331 (0.48), 2.522 (2.06), 2.526 (1.32), 2.544 (3.40), 2.600 (1.32), 2.608 (1.54), 2.669 (0.42), 2.673 (0.52), 3.472 (5.36), 3.526 (0.66), 3.544 (1.16), 3.552 (0.65), 3.559 (0.76), 3.569 (0.69), 4.272 (1.12), 4.280 (1.37), 4.289 (1.99), 4.298 (1.94), 4.307 (1.32), 4.316 (1.06), 5.763 (0.95), 6.749 (1.82), 6.765 (2.20), 7.695 (1.20), 7.700 (1.22), 7.718 (1.30), 7.723 (1.34), 8.065 (2.03), 8.128 (2.99), 8.151 (2.66), 8.778 (2.61), 9.408 (4.25), 9.413 (4.08).    Intermediate 155 tert-butyl (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000330_0002
  Intermediate 156 tert-butyl (rac)-2'-(3-[(4-methylpyridin-3-yl)ethynyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate 
Figure imgf000331_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227 (0.44), 1.373 (4.97), 1.391 (4.98), 1.753 (0.64), 1.881 (12.16), 1.942 (0.48), 1.957 (0.74), 1.977 (1.03), 1.995 (1.02), 2.014 (0.75), 2.452 (0.58), 2.468 (0.94), 2.532 (0.84), 2.549 (0.99), 2.563 (1.29), 2.586 (1.49), 2.601 (0.97), 2.613 (1.37), 2.684 (1.04), 2.706 (0.71), 2.753 (0.51), 2.769 (0.46), 2.821 (0.87), 2.844 (0.90), 2.862 (0.52), 2.876 (0.52), 3.707 (1.00), 3.724 (1.27), 3.740 (0.94), 3.905 (16.00), 3.928 (0.74), 4.082 (0.50), 4.099 (1.05), 4.117 (1.20), 4.125 (1.53), 4.144 (0.86), 6.495 (2.34), 6.529 (5.34), 6.533 (3.72), 7.523 (3.19), 7.527 (3.31), 7.833 (3.15), 8.245 (2.85), 8.734 (1.70), 8.738 (2.95), 12.157 (1.01).    Intermediate 157 tert-butyl (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxylate   
Figure imgf000331_0002
Intermediate 158 tert-butyl (rac)-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxylate 
Figure imgf000332_0001
  Intermediate 159 tert-butyl (rac)-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000332_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (0.73), 1.394 (15.03), 1.437 (12.12), 1.712 (16.00), 1.992 (0.51), 2.008 (0.88), 2.023 (0.80), 2.033 (0.86), 2.057 (0.60), 2.332 (0.59), 2.518 (3.82), 2.523 (2.98), 2.539 (2.58), 3.366 (0.69), 3.388 (4.79), 3.473 (0.46), 3.492 (0.79), 3.506 (0.59), 3.516 (0.49), 4.127 (1.02), 4.134 (1.13), 4.145 (1.92), 4.151 (1.96), 4.161 (1.10), 4.168 (1.02), 6.263 (1.66), 6.283 (2.08), 7.116 (0.46), 7.120 (0.82), 7.123 (0.51), 7.133 (0.64), 7.138 (2.05), 7.142 (0.75), 7.152 (0.86), 7.155 (1.54), 7.159 (0.88), 7.225 (2.01), 7.245 (4.04), 7.258 (0.82), 7.263 (3.00), 7.289 (4.35), 7.291 (4.79), 7.309 (2.61), 7.313 (1.85), 7.383 (2.82), 7.389 (2.83), 7.561 (3.20), 7.566 (3.22), 8.503 (2.65), 11.453 (1.70).    Intermediate 160 tert-butyl (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (4 isomers)   
Figure imgf000333_0002
Intermediate 161 tert-butyl (rac)-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate 
Figure imgf000333_0001
  Intermediate 162 tert-butyl (rac)-2'-(3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate 
 
Figure imgf000334_0001
Intermediate 163 tert-butyl (rac)-2'-[3-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate   
Figure imgf000334_0002
Intermediate 164 (rac)-N-ethyl-2'-(5-nitroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide 
Figure imgf000335_0002
(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate (1.02 g, 2.66 mmol), (5-nitroquinolin-3-yl)boronic acid (1.87 g, 8.57 mmol), XPhos Pd G2 (314 mg, 399 µmol), and potassium phosphate solution (16 mL, 0.50 M in water, 8.0 mmol) in dioxane (170 mL) were stirred at 100 °C overnight. The reaction mixture was allowed to reach rt and concentrated. The residue was purified by silica gel chromatography affording 859 mg (79 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 407 [M+H]+    Intermediate 165 (rac)-N-ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000335_0001
(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate (1.75 g, 4.58 mmol), [6-(acetyloxy)quinolin-3-yl]boronic acid (1.59 g, 6.87 mmol), XPhos Pd G2 (540 mg, 687 µmol), and potassium phosphate (27 mL, 0.50 M in water, 13.5 mmol) in dioxane (81 mL) were stirred at 100 °C overnight. The reaction mixture was allowed to reach rt, and concentrated. The resdue was purified by silica gel chromatography to afford 1.60 g (95 % purity, 88 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.62 min; MS (ESIpos): m/z = 378 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (1.97), 1.031 (4.41), 1.050 (2.06), 1.066 (0.47), 1.907 (3.50), 2.090 (0.64), 2.107 (0.80), 2.553 (0.74), 2.570 (1.12), 2.587 (0.78), 3.052 (0.81), 3.066 (0.89), 3.070 (0.87), 3.084 (0.78), 3.160 (15.17), 3.173 (16.00), 3.439 (0.69), 3.449 (2.92), 4.088 (1.14), 4.101 (3.25), 4.114 (3.21), 4.128 (1.06), 4.244 (0.74), 4.262 (1.17), 4.279 (0.74), 6.181 (0.67), 6.682 (3.12), 7.166 (1.17), 7.173 (1.33), 7.243 (0.88), 7.249 (0.72), 7.265 (0.88), 7.272 (0.83), 7.823 (1.06), 7.846 (0.98), 8.420 (1.06), 8.425 (1.09), 9.100 (1.62), 9.105 (1.61), 10.021 (0.42).    Intermediate 166 tert-butyl (rac)-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate 
Figure imgf000336_0001
To tert-butyl (rac)-2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (5.76 g, 14.0 mmol) in dioxane (190 mL) under an atmosphere of argon was added (6-methoxyquinolin-3-yl)boronic acid (4.26 g, 21.0 mmol), potassium phosphate solution (84 mL, 0.50 M in water, 42 mmol), and XPhos Pd G2 (1.65 g, 2.10 mmol). It was stirred overnight at 100 °C. The reaction mixture was allowed to reach rt and diluted with ethyl acetate. The organic layer was washed three times with water and once with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to obtain 4.95 g (95 % purity, 80 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 421 [M+H]+    Intermediate 167 tert-butyl (rac)-2'-(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000337_0002
Tert-Butyl (rac)-2’-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-5-yl)-5’,6’- dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2-b]pyrazole]-1-carboxylate (430 mg, 844 μmol) was solubilised in DMF (19 mLI) and NBS (135 mg, 759 pmol) was added. The reaction mixture was stirred at rt for 2 h and then diluted with water. The reaction mixture was extracted with ethyl acetate and the organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution, dried (silicon filter) and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC to give 275 mg (55 % yield) of the title compound.
Intermediate 168 tert-butyl (rac)-2'-(3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1 ,2-b]pyrazole]-1-carboxylate
Figure imgf000337_0001
Tert-Butyl (rac)-2’-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-5-yl)-5’,6’- dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2-b]pyrazole]-1-carboxylate (500 mg, 981 pmol) was solubilised in dichloromethane (2.5 ml_) and the reaction mixture was cooled to 0°C. 1- iodopyrrolidine-2,5-dione (331 mg, 1.47 mmol) was added and the reaction was stirred at rt for 2.5 h. The reaction mixture was quenched with saturated aqueous sodium thiosulfate and and saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried (silicon filter), concentrated under reduced pressure and purified by flash column chromatography to give 400 mg (64 % yield) of the title compound.   Intermediate 169 tert-butyl (rac)-2'-[3-(3-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000338_0001
Tert-Butyl (rac)-2’-(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5’,6’-dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2-b]pyrazole]-1-carboxylate (90.0 mg, 153 µmol) was solubilised in acetonitrile (730 µL). (3-Methylphenyl)boronic acid (24.9 mg, 183 µmol), bis(triphenylphosphine)palladium(II) dichloride (5.58 mg, 7.95 µmol) and sodium carbonate (730 µL, 2.0 M in water, 1.5 mmol) were added. The reaction mixture was stirred for 16 h at 60°C. The reaction mixture was cooled to rt and extracted with a mixture of ethyl acetate and THF. The organic phase was washed with saturated aqueous sodim chloride solution, dried (silicon filiter), concentrated under reduced pressure and purified by preparative HPLC to give 33.0 mg (36 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.155 (0.53), -0.146 (16.00), -0.138 (0.51), 0.780 (0.48), 0.800 (0.58), 0.821 (0.48), 1.351 (2.39), 1.390 (1.94), 2.347 (2.13), 2.464 (1.12), 2.469 (0.76), 3.399 (0.74), 3.512 (0.55), 3.531 (0.61), 3.552 (0.47), 5.618 (1.11), 7.477 (0.43), 7.971 (1.19), 8.468 (0.67), 8.473 (0.72), 8.706 (0.46), 8.710 (0.45).    The following example were prepared similarly via Suzuki coupling Intermediate 170 tert-butyl (rac)-2'-[3-(4-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000339_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.154 (0.47), -0.146 (16.00), -0.138 (0.56), 0.779 (0.42), 0.800 (0.52), 0.820 (0.45), 1.354 (2.15), 1.394 (1.69), 2.304 (1.75), 2.466 (1.23), 2.471 (0.80), 3.400 (0.66), 3.510 (0.50), 3.530 (0.59), 3.550 (0.44), 5.614 (0.98), 7.241 (0.48), 7.261 (0.55), 7.558 (0.75), 7.578 (0.64), 7.945 (1.06), 8.466 (0.64), 8.471 (0.70), 8.701 (0.63), 8.706 (0.61).  Intermediate 171 tert-butyl (rac)-2'-[3-(pyridin-3-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5- yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000339_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.049 (0.57), -0.030 (1.85), -0.016 (0.57), -0.008 (16.00), 0.000 (0.47), 0.923 (0.47), 0.943 (0.54), 0.963 (0.44), 1.486 (2.42), 1.525 (1.88), 2.407 (2.02), 2.412 (1.41), 2.417 (0.61), 2.598 (7.97), 2.603 (5.34), 2.749 (2.02), 2.754 (1.38), 2.759 (0.64), 3.535 (0.71), 3.660 (0.54), 3.680 (0.54), 3.700 (0.44), 5.771 (1.04), 5.839 (0.44), 8.301 (1.08), 8.644 (0.54), 8.649 (0.54), 8.885 (0.67), 8.890 (0.64), 9.062 (0.40), 9.066 (0.44).    Intermediate 172 tert-butyl (rac)-2'-[3-(2-oxopyrrolidin-1-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000340_0001
Tert-Butyl (rac)-2’-(3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5’,6’-dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2-b]pyrazole]-1-carboxylate (75.0 mg, 118 µmol), pyrrolidin-2-one (22.1 mg, 260 µmol), N,N'-dimethylethane-1,2-diamine (5.1 µL 47 µmol), copper(I) iodide (4.49 mg, 23.6 µmol) and potassium carbonate (48.9 mg, 354 µmol) were solubilised in dioxane (500 µL). The reaction mixture was stirred for 3 h at 100°C in a sealed tube. The reaction mixture was then cooled to rt, filtered and concentrated under reduced pressure. The crude mixture was then purified by preparative HPLC to give 30.0 mg (95 % purity, 41 % yield) of the title compound   Intermediate 173 tert-butyl (rac)-2'-[3-(3-oxomorpholin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000341_0001
This intermediate was synthesised analogously to the precendent compound   Intermediate 174 tert-butyl (rac)-2'-(3-cyclopropyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000341_0002
Tert-Butyl (rac)-2’-(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5’,6’-dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2-b]pyrazole]-1-carboxylate (50.0 mg, 84.9 µmol), potassium cyclopropyl(trifluorido)borate (13.8 mg, 93.4 µmol), palladium(II)-acetate (1.91 mg, 8.49 µmol), potassium carbonate (23.5 mg, 170 µmol) and tricyclohexylphosphine (4.76 mg, 17.0 µmol) were solubilised in toluene (1000 µL)/water (50 µL) mixture under an inert atmosphere. The reaction mixture was stirred overnight at 90°C. Palladium(II)-acetate (1.91 mg, 8.49 µmol), potassium cyclopropyl(trifluorido)borate (12.6 mg, 84.9 µmol) and tricyclohexylphosphine (4.76 mg, 17.0 µmol) were again added and the reaction was stirred for 24 h at 90°C. The reaction mixture was allowed to cool down then filtrered through Celite ®, concentrated and purified by flash column chromatography to give 19.0 mg (41 % yield) of the title comoound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.078 (0.62), -0.070 (16.00), -0.067 (5.03), -0.062 (1.23), -0.056 (1.54), 0.672 (0.51), 0.677 (0.51), 0.685 (0.58), 0.690 (0.51), 0.826 (0.54), 0.846 (0.74), 0.866 (0.68), 0.928 (0.51), 0.933 (0.47), 0.949 (0.51), 0.954 (0.48), 1.450 (3.57), 1.489 (2.88), 2.376 (0.54), 2.562 (3.47), 2.567 (2.27), 2.615 (0.42), 2.717 (0.56), 3.491 (1.18), 3.507 (0.74), 3.527 (0.73), 3.546 (0.58), 4.270 (0.41), 4.277 (0.41), 5.568 (1.36), 7.374 (0.85), 8.362 (0.51), 8.367 (0.51), 8.715 (0.73), 8.721 (0.70).    Intermediate 175 tert-butyl (rac)-2'-(3-[(pyridin-4-yl)ethynyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000342_0001
Tert-Butyl (rac)-2’-(3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5’,6’-dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2-b]pyrazole]-1-carboxylate (125 mg, 197 µmol), 4- ethynylpyridine (24.3 mg, 236 µmol), bis(triphenylphosphine)palladium(II) dichloride (6.90 mg, 9.83 µmol), copper(I) iodide (3.75 mg, 19.7 µmol) and triethylamine (82 µL, 590 µmol) were solubilised in DMF (5.0 mL) under an inert atmostphere and the reaction mixture was stirred at 80°C for 2.5h. The reaction mixture was then cooled to rt, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give 169 mg of the title compound that was used without further purification in the next step. LC-MS (Method 1): Rt = 1.59 min; MS (ESIpos): m/z = 612 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.111 (0.43), -0.082 (16.00), -0.073 (0.81), 0.842 (0.61), 0.862 (0.81), 0.883 (0.59), 1.085 (5.19), 1.426 (3.31), 1.466 (2.63), 2.347 (0.41), 2.542 (1.39), 2.608 (0.46), 2.689 (0.44), 2.748 (7.37), 2.908 (8.74), 3.480 (1.17), 3.574 (0.70), 3.594 (0.94), 3.614 (0.59), 3.961 (0.87), 5.682 (1.37), 6.748 (0.41), 7.970 (1.24), 8.257 (1.39), 8.447 (0.85), 8.452 (0.85), 8.864 (0.69), 8.869 (0.67).  The following intermediates were synthesised similarlly via sonogashira coupling  Intermediate 176 tert-butyl (rac)-2'-(3-[(pyridin-2-yl)ethynyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000343_0001
LC-MS (Method 1): Rt = 1.59 min; MS (ESIpos): m/z = 612 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.171 (0.52), -0.101 (2.68), -0.083 (0.92), -0.077 (11.37), -0.069 (16.00), -0.061 (0.85), -0.056 (1.14), 0.830 (0.45), 0.852 (0.69), 0.855 (0.72), 0.875 (0.83), 0.895 (0.58), 1.093 (5.73), 1.184 (0.42), 1.411 (0.78), 1.434 (4.90), 1.473 (3.62), 2.360 (0.71), 2.547 (3.98), 2.551 (2.62), 2.591 (0.56), 2.609 (0.65), 2.702 (0.76), 2.758 (8.23), 2.917 (9.96), 3.484 (1.27), 3.536 (0.42), 3.557 (0.52), 3.577 (0.54), 3.588 (0.72), 3.608 (0.92), 3.628 (0.61), 3.973 (0.92), 4.267 (0.45), 4.276 (0.49), 4.284 (0.47), 5.634 (0.92), 5.694 (1.27), 7.743 (0.47), 7.816 (0.80), 7.835 (0.49), 7.847 (0.74), 7.950 (1.01), 7.979 (1.36), 8.257 (1.45), 8.426 (0.63), 8.431 (0.60), 8.771 (0.45), 8.775 (0.45), 8.863 (0.58), 8.867 (0.56).    Intermediate 177 tert-butyl (rac)-2'-[3-(phenylethynyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000344_0001
LC-MS (Method 1): Rt = 1.71 min; MS (ESIpos): m/z = 611 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.041 (0.40), -0.029 (0.52), -0.022 (0.81), -0.016 (1.79), 0.000 (1.50), 0.913 (1.33), 0.933 (1.68), 0.954 (1.33), 1.154 (9.42), 1.320 (0.40), 1.493 (7.05), 1.532 (5.72), 2.165 (0.52), 2.180 (0.64), 2.421 (1.16), 2.607 (4.97), 2.611 (3.18), 2.669 (0.81), 2.763 (1.16), 2.816 (13.23), 2.977 (16.00), 3.440 (1.04), 3.512 (0.40), 3.546 (2.14), 3.636 (1.39), 3.656 (1.91), 3.676 (1.33), 4.030 (1.56), 4.313 (0.46), 4.332 (0.75), 4.339 (0.75), 4.356 (0.40), 5.738 (3.00), 6.779 (0.75), 6.806 (0.92), 7.318 (0.52), 7.327 (0.40), 7.458 (1.21), 7.474 (0.58), 7.498 (0.92), 7.504 (0.98), 7.508 (1.39), 7.513 (2.71), 7.515 (2.71), 7.535 (3.06), 7.541 (1.56), 7.552 (1.21), 7.555 (2.37), 7.568 (0.87), 7.572 (1.44), 7.576 (0.98), 7.583 (0.64), 7.589 (1.21), 7.608 (0.46), 7.638 (0.46), 7.644 (0.46), 7.654 (0.40), 7.696 (3.29), 7.700 (3.29), 7.712 (2.37), 7.717 (3.00), 8.040 (2.08), 8.211 (3.47), 8.465 (1.85), 8.469 (1.85), 8.911 (1.21), 8.915 (1.21).    Intermediate 178 tert-butyl (rac)-2'-(3-[(5-amino-4-methylpyridin-3-yl)ethynyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}- 1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate 
Figure imgf000345_0002
LC-MS (Method 1): Rt = 1.49 min; MS (ESIpos): m/z = 641 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.201 (0.70), -0.159 (0.47), -0.152 (0.47), -0.136 (1.29), -0.113 (1.70), -0.108 (0.76), -0.102 (0.64), -0.093 (16.00), -0.085 (0.59), -0.083 (0.53), 0.826 (0.53), 0.845 (0.70), 0.866 (0.53), 1.063 (3.63), 1.173 (0.41), 1.191 (0.82), 1.210 (0.41), 1.401 (3.28), 1.436 (2.40), 2.125 (0.64), 2.149 (0.53), 2.202 (2.93), 2.246 (0.76), 2.301 (3.05), 2.331 (1.00), 2.518 (4.57), 2.523 (2.93), 2.727 (9.49), 2.888 (11.78), 3.455 (0.88), 3.547 (0.64), 3.567 (0.70), 3.588 (0.47), 3.958 (0.59), 5.324 (0.82), 5.430 (0.70), 5.652 (1.05), 7.909 (0.88), 7.949 (2.34), 7.968 (0.76), 8.150 (1.23), 8.343 (0.47), 8.814 (0.59), 8.818 (0.53).    Intermediate 179 tert-butyl (rac)-2'-[3-(cyclopropylethynyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000345_0001
LC-MS (Method 1): Rt = 1.69 min; MS (ESIpos): m/z = 575 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.094 (0.56), -0.086 (16.00), -0.080 (0.60), -0.078 (0.52), -0.054 (0.41), 0.789 (0.44), 0.796 (0.50), 0.801 (0.44), 0.808 (0.51), 0.822 (0.46), 0.842 (0.55), 0.862 (0.47), 0.917 (0.51), 0.923 (0.41), 0.938 (0.56), 1.433 (2.34), 1.474 (1.86), 2.543 (0.90), 2.549 (0.61), 3.476 (0.73), 3.520 (0.45), 3.541 (0.55), 3.560 (0.51), 5.607 (1.05), 7.897 (1.06), 8.235 (0.50), 8.240 (0.52), 8.778 (0.48), 8.783 (0.48).    Intermediate 180 tert-butyl (rac)-2'-(3-[(dimethylphosphoryl)ethynyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate 
Figure imgf000346_0001
LC-MS (Method 1): Rt = 1.41 min; MS (ESIpos): m/z = 611 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.154 (0.52), -0.146 (16.00), -0.138 (0.58), -0.115 (0.44), 0.772 (0.44), 0.792 (0.58), 0.812 (0.47), 1.367 (2.36), 1.407 (1.92), 1.719 (3.95), 1.755 (4.03), 2.481 (1.23), 2.486 (0.79), 3.418 (0.71), 3.498 (0.49), 3.519 (0.63), 3.538 (0.49), 5.608 (1.04), 8.268 (1.07), 8.281 (0.68), 8.286 (0.68), 8.801 (0.44).    Intermediate 181 tert-butyl (rac)-2'-(3-[(E)-2-(dimethylphosphoryl)ethenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate 
Tert-Butyl (rac)-2’-(3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5’,6’-dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2-b]pyrazole]-1-carboxylate (356 mg, 560 µmol), ethenyl(dimethyl)oxo-lambda5-phosphane (70.0 mg, 672 µmol), palladium(II) acetate (2.52 mg, 11.2 µmol), sodium hydrogen carbonate (56.5 mg, 672 µmol) and tetra-n-butylammonium chloride (187 mg, 672 µmol) were solublised in degassed DMF (10 mL) under an inert atmosphere. The reaction mixture was stirred at 100°C for 6 h and then colled to rt, diluted with water and extratcted with dichloromethane and then with ethyl acetate. The combined organic phases were dried and concentrated under reduced pressure to give 501 mg of the title compound that was used without further purification in the enxt step. LC-MS (Method 1): Rt = 1.37 min; MS (ESIpos): m/z = 613 [M+H]+    Intermediate 182 tert-butyl (rac)-2'-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000347_0001
tert-butyl (3S)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazole]-1-carboxylate (4.00 g, 10.5 mmol) was solubilised in DMF (130 ml) and NBS (1.69 g, 9.49 mmol; CAS-RN:[128-08-5]) was added. The reaction was stirred at rt for 2h. the reaction was then diluted with water and extracted with EtOAc. The organic phase was dried and concentrated under reduced pressure to give 3.7g of the title compound that was used without further purification. LC-MS (Method 1): Rt = 1.20 min; MS (ESIneg): m/z = 456 [M-H]-    Intermediate 183 tert-butyl (rac)-2'-[6-(cyclohexyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate 
Figure imgf000348_0001
Tert-Butyl (rac)-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro[pyrrolidine-3,4’-pyrrolo[1,2- b]pyrazole]-1-carboxylate (150 mg, 369 µmol), bromocyclohexane (120 mg, 738 µmol), potassium hydroxide (45.5 mg, 812 µmol) were solubilized in degassed DMF (5.0 mL) and the reaction was stirred 16 h at 100 °C unter argon. Bromocyclohexane (45.5 mg, 812 µmol) was added and the reaction was stirred for 72 h at 100 °C. The reaction mixture was cooled to rt, ethyl acetate, water and brine were added. The layers were separated and the aqueous phasewas extracted twice with ethyl acetate.. The organic phase was dried and concentrated under reduced pressure to give 203 mg of the title compound that was used without further purification in the enxt step. LC-MS (Method 1): Rt = 1.56 min; MS (ESIpos): m/z = 489 [M+H]+    Intermediate 184 (rac)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3-pyrrolidine]—hydrogen chloride (1/1) 
Figure imgf000349_0001
To a solution of tert-butyl (rac)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine- 4,3'-pyrrolidine]-1'-carboxylate (2.38 g, 5.88 mmol) dissolved in dioxane (50 mL), HCl (7.4 mL, 4M in Dioxane) was added and the reaction mixture was stirred for overnight at 55°C. The resultant mixture was concentrated, redissolved MTBE and concentrated twice to yield 2.83 g of the title compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.84 - 1.93 (m, 1H), 1.98 - 2.14 (m, 3H), 2.15 - 2.30 (m, 2H), 3.25 - 3.33 (m, 1H), 3.34 - 3.55 (m, 3H), 4.15 - 4.25 (m, 2H), 7.25 (s, 1H), 7.78 - 7.84 (m, 1H), 7.95 (ddd, 1H), 8.23 (dd, 2H), 9.10 (s, 1H), 9.49 (d, 1H), 9.73 - 9.84 (m, 1H), 9.92 (br s, 1H).   LC-MS (Method 1): Rt = 0.93 min; MS (ESIpos): m/z = 305 [M+H]+    The following intermediates were prepared similarly by deprotection using HCl Intermediate 185 (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]—hydrogen chloride (1/1)
Figure imgf000349_0002
LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 349 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.47), 1.351 (0.66), 1.373 (15.80), 1.388 (16.00), 1.410 (1.43), 1.450 (0.87), 2.067 (1.07), 2.085 (2.09), 2.104 (1.23), 2.210 (0.87), 2.216 (0.93), 2.230 (2.33), 2.249 (1.63), 2.327 (0.77), 2.403 (0.66), 2.417 (0.66), 2.435 (0.54), 2.522 (3.21), 2.542 (0.71), 2.556 (0.40), 2.608 (0.41), 2.623 (0.64), 2.640 (0.91), 2.659 (0.96), 2.673 (1.07), 2.751 (0.49), 2.770 (0.89), 2.785 (0.79), 2.803 (0.53), 3.218 (0.50), 3.233 (0.63), 3.250 (0.44), 3.315 (1.04), 3.327 (1.33), 3.344 (1.50), 3.357 (1.54), 3.374 (1.33), 3.384 (1.44), 3.468 (1.56), 3.478 (1.50), 3.597 (0.63), 3.930 (1.26), 3.937 (1.34), 3.949 (1.76), 3.964 (1.47), 3.971 (1.40), 4.100 (1.01), 4.292 (1.50), 4.308 (2.10), 4.317 (1.93), 4.336 (1.31), 4.801 (0.47), 4.816 (1.10), 4.831 (1.44), 4.847 (1.09), 4.862 (0.49), 5.437 (3.56), 6.972 (4.94), 7.555 (0.99), 7.561 (1.07), 7.578 (1.07), 7.583 (1.20), 7.666 (1.81), 7.672 (1.71), 8.120 (1.54), 8.143 (1.57), 9.005 (1.37), 9.321 (2.36), 9.325 (2.33), 9.744 (0.63).    Intermediate 186 (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) 
Figure imgf000350_0001
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 291 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.151 (0.51), 1.169 (0.93), 1.187 (0.48), 1.349 (0.53), 1.409 (7.52), 1.450 (6.09), 1.591 (5.41), 1.985 (1.86), 2.101 (0.75), 2.180 (0.55), 2.211 (4.70), 2.219 (4.65), 2.232 (12.41), 2.251 (8.94), 2.322 (1.87), 2.326 (2.64), 2.331 (1.88), 2.518 (16.00), 2.522 (10.50), 2.608 (2.57), 2.624 (3.81), 2.627 (3.39), 2.641 (5.19), 2.656 (5.31), 2.659 (4.98), 2.668 (3.57), 2.673 (4.28), 2.725 (0.55), 2.761 (2.49), 2.780 (4.38), 2.795 (3.99), 2.812 (2.70), 2.829 (1.88), 2.887 (0.58), 3.305 (1.81), 3.322 (4.01), 3.336 (4.08), 3.352 (6.03), 3.368 (4.50), 3.383 (3.22), 3.389 (3.24), 3.406 (2.12), 3.467 (8.26), 3.481 (7.32), 3.497 (5.75), 3.509 (3.44), 3.540 (1.24), 4.168 (10.72), 4.271 (8.74), 4.286 (9.20), 4.298 (12.32), 4.307 (12.67), 4.313 (14.70), 4.317 (13.92), 4.322 (13.22), 4.327 (13.23), 4.332 (11.47), 4.342 (10.04), 4.354 (6.09), 6.890 (0.61), 6.911 (0.74), 7.021 (15.01), 7.811 (2.62), 7.829 (5.73), 7.847 (4.18), 7.948 (3.02), 7.968 (5.18), 7.987 (3.48), 8.011 (1.53), 8.029 (0.75), 8.138 (1.33), 8.232 (5.11), 8.249 (10.79), 8.268 (7.12), 8.296 (1.07), 9.145 (4.83), 9.261 (0.69), 9.351 (1.19), 9.519 (11.86), 9.579 (1.35), 9.707 (1.89), 9.819 (4.43).  Intermediate 187 (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]—hydrogen chloride (1/1) 
Figure imgf000351_0001
ClH LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 357 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.007 (0.43), 1.170 (0.74), 1.231 (2.28), 1.248 (1.85), 1.351 (1.05), 1.407 (0.68), 1.449 (0.62), 1.756 (1.42), 1.906 (0.92), 1.986 (0.43), 2.068 (4.92), 2.086 (9.35), 2.105 (5.66), 2.125 (1.05), 2.149 (0.68), 2.211 (3.51), 2.229 (6.83), 2.247 (4.18), 2.322 (2.65), 2.326 (3.51), 2.331 (2.58), 2.371 (1.17), 2.386 (1.66), 2.404 (3.02), 2.419 (2.77), 2.437 (2.09), 2.522 (12.31), 2.537 (3.26), 2.555 (1.85), 2.570 (1.35), 2.600 (1.11), 2.615 (1.35), 2.633 (2.09), 2.648 (2.28), 2.668 (4.37), 2.673 (2.65), 2.732 (1.42), 2.751 (2.34), 2.767 (1.91), 2.784 (1.35), 2.800 (0.86), 3.192 (0.92), 3.209 (1.48), 3.221 (2.09), 3.236 (2.77), 3.253 (1.78), 3.267 (1.05), 3.308 (4.06), 3.317 (4.55), 3.334 (4.98), 3.347 (5.72), 3.364 (6.28), 3.383 (5.54), 3.393 (3.20), 3.454 (3.51), 3.467 (3.82), 3.483 (3.20), 3.496 (2.28), 3.597 (1.60), 3.931 (5.60), 3.939 (6.15), 3.949 (8.25), 3.958 (7.88), 3.965 (7.94), 3.972 (8.31), 4.044 (16.00), 4.284 (3.14), 4.292 (3.45), 4.303 (4.55), 4.318 (3.63), 4.326 (3.14), 5.435 (15.69), 6.167 (1.05), 6.924 (13.66), 7.248 (3.45), 7.292 (0.43), 7.431 (7.32), 7.450 (1.17), 7.476 (0.98), 7.615 (4.92), 7.624 (2.83), 7.640 (2.89), 7.647 (3.08), 7.844 (5.05), 7.851 (4.86), 7.871 (0.68), 8.113 (4.49), 8.135 (5.85), 8.203 (0.55), 8.225 (0.49), 8.763 (4.74), 9.025 (0.62), 9.355 (6.52), 9.360 (6.52), 9.478 (2.40), 9.621 (2.77).    Intermediate 188 (rac)-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]— hydrogen chloride (1/1) 
Figure imgf000352_0002
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 321 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.593 (1.33), 2.230 (0.47), 2.332 (0.53), 2.518 (2.22), 2.523 (1.54), 2.669 (0.83), 2.673 (0.62), 2.727 (0.84), 2.729 (0.81), 2.888 (0.80), 3.375 (0.47), 3.385 (0.98), 3.565 (16.00), 3.922 (2.75), 4.008 (0.51), 6.877 (1.00).    Intermediate 189 (rac)-2'-[6-(cyclohexyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]—hydrogen chloride (1/1) 
Figure imgf000352_0001
LC-MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 389 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.593 (1.32), 2.518 (1.84), 2.522 (1.14), 2.729 (0.61), 2.888 (0.67), 3.384 (1.04), 3.488 (4.94), 3.565 (16.00), 3.677 (0.44), 6.925 (0.45).    Intermediate 190 (rac)-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]—hydrogen chloride (1/1) 
Figure imgf000353_0003
  Intermediate 191 (rac)-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) 
Figure imgf000353_0001
  Intermediate 192 (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) (As a mixture of diastereomers) 
Figure imgf000353_0002
  Intermediate 193 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]—hydrogen chloride (1/1) 
Figure imgf000354_0001
LC-MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 294 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.45), 1.350 (0.69), 1.412 (0.77), 2.073 (0.89), 2.082 (0.40), 2.091 (1.52), 2.110 (0.71), 2.182 (1.33), 2.188 (1.27), 2.202 (3.36), 2.221 (2.32), 2.320 (15.27), 2.323 (16.00), 2.374 (0.43), 2.388 (0.43), 2.406 (0.52), 2.421 (0.47), 2.518 (2.41), 2.523 (1.73), 2.544 (0.55), 2.560 (0.44), 2.575 (0.75), 2.590 (0.92), 2.594 (0.87), 2.608 (1.23), 2.623 (1.32), 2.627 (1.01), 2.642 (0.79), 2.664 (0.52), 2.669 (0.71), 2.673 (0.50), 2.729 (0.78), 2.748 (1.36), 2.763 (1.14), 2.777 (0.73), 2.781 (0.80), 2.796 (0.55), 3.237 (0.48), 3.273 (0.64), 3.290 (1.35), 3.304 (1.50), 3.319 (1.79), 3.335 (1.17), 3.344 (1.00), 3.362 (1.05), 3.384 (2.54), 3.393 (0.62), 3.423 (0.84), 3.438 (1.47), 3.450 (1.55), 3.456 (1.58), 3.466 (1.73), 3.468 (1.85), 3.485 (1.18), 3.487 (1.08), 3.495 (0.58), 3.497 (0.70), 3.587 (0.87), 3.595 (0.47), 3.597 (0.55), 3.603 (0.55), 3.605 (0.47), 3.613 (0.43), 3.661 (0.47), 3.665 (0.51), 3.673 (0.49), 3.675 (0.62), 3.697 (0.48), 3.700 (0.60), 3.708 (0.46), 3.712 (0.50), 3.839 (0.91), 3.859 (1.13), 3.943 (0.54), 3.949 (0.53), 3.958 (0.77), 3.960 (0.80), 3.969 (0.65), 3.977 (0.52), 3.983 (0.52), 4.181 (1.34), 4.202 (1.22), 4.221 (0.42), 4.233 (1.47), 4.241 (1.52), 4.249 (2.05), 4.252 (1.98), 4.257 (1.89), 4.261 (1.92), 4.268 (1.53), 4.275 (1.92), 4.288 (0.42), 4.327 (0.44), 5.363 (0.70), 5.484 (4.78), 6.352 (2.20), 6.829 (10.61), 7.416 (2.75), 8.139 (1.75), 8.575 (2.68), 8.578 (2.76), 8.678 (4.74), 8.683 (4.36), 9.797 (1.25), 12.074 (1.24).    Intermediate 194 trifluoroacetic acid-(rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000355_0002
tert-Butyl (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (1.02 g, 2.47 mmol) was dissolved in dichloromethane (40 mL). Trifluoroacetic acid (5.0 mL, 65 mmol mmol) was added and stirred for 2 h at rt. The reaction mixture was concentrated to afford 1.28 g of the title compound which was used without further purification in the next step.   LC-MS (Method 1): Rt = 0.88 min; MS (ESIpos): m/z = 314 [M+H]+  1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.06 (s, 12H), 2.15 - 2.26 (m, 2H), 2.57 - 2.74 (m, 2H), 3.29 - 3.58 (m, 4H), 4.19 - 4.32 (m, 2H), 6.75 (s, 1H), 7.71 (d, 1H), 8.18 (d, 1H), 8.74 (d, 1H), 9.11 (br s, 2H), 12.04 (br d, 1H).   The following intermediates were prepared similarly by deprotection using TFA  Intermediate 195 (rac)-2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] 
Figure imgf000355_0001
LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 356 [M+H]+    Intermediate 196 (rac)-2'-[6-(methanesulfonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]   
Figure imgf000356_0003
Intermediate 197 trifluoroacetic acid—(rac)-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000356_0001
  Intermediate 198 trifluoroacetic acid—(rac)-2'-[6-(benzyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000356_0002
  Intermediate 199 1-{5-[(rac)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazol]-2-yl]-1H-pyrrolo[2,3- b]pyridin-3-yl}pyrrolidin-2-one 
Figure imgf000357_0001
  Intermediate 200 trifluoroacetic acid—(rac)-2'-[6-(trifluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000357_0002
  Intermediate 201 trifluoroacetic acid—(rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000357_0003
  Intermediate 202 trifluoroacetic acid—(rac)-2'-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000358_0002
LC-MS (Method 1): Rt = 0.88 min; MS (ESIpos): m/z = 358 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.113 (1.91), 1.177 (0.79), 1.194 (0.42), 1.536 (10.47), 1.991 (1.52), 2.197 (2.07), 2.201 (2.03), 2.216 (5.62), 2.235 (3.36), 2.334 (0.54), 2.525 (1.80), 2.530 (1.21), 2.568 (0.51), 2.596 (0.56), 2.611 (0.88), 2.615 (0.76), 2.629 (1.74), 2.644 (2.17), 2.662 (1.40), 2.671 (1.69), 2.676 (0.96), 2.681 (0.75), 2.690 (2.29), 2.706 (1.60), 2.719 (0.78), 2.723 (0.89), 2.733 (5.19), 2.893 (6.07), 3.338 (0.57), 3.354 (1.31), 3.368 (1.44), 3.384 (2.50), 3.399 (1.46), 3.410 (1.17), 3.426 (1.28), 3.439 (1.48), 3.452 (2.18), 3.466 (1.39), 3.482 (1.38), 3.503 (1.32), 3.518 (1.17), 3.534 (0.88), 3.550 (0.45), 4.228 (0.48), 4.239 (1.99), 4.246 (1.98), 4.255 (3.18), 4.261 (2.80), 4.265 (2.79), 4.274 (1.97), 4.280 (1.93), 4.292 (0.47), 5.761 (0.51), 6.757 (16.00), 7.746 (6.09), 7.753 (6.12), 7.956 (0.79), 8.103 (5.11), 8.106 (5.20), 8.668 (0.52), 8.673 (0.54), 8.727 (7.01), 8.733 (7.09), 9.167 (2.19), 12.153 (2.39).    Intermediate 203 trifluoroacetic acid—(rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] (1/1) 
Figure imgf000358_0001
  Intermediate 204 trifluoroacetic acid—(rac)-2'-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5- yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000359_0001
To a solution of tert-butyl (3S)-2'-(3-[(E)-2-(dimethylphosphoryl)ethenyl]-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate (340 mg, 556 µmol) in dichloromethane (9 mL), trifluoroacetic acid (4.0 ml, 52 mmol) was added and the reaction mixture was stirred for 3 hours at rt. The resultant mixture was concentrated to yield 332 mg of the title compound  LC-MS (Method 1): Rt = 0.68 min; MS (ESIneg): m/z = 379 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.044 (1.95), -0.012 (2.80), 0.000 (0.85), 1.129 (2.22), 1.188 (0.48), 1.296 (0.44), 1.556 (3.42), 1.573 (2.12), 1.589 (3.59), 1.606 (2.15), 1.679 (0.44), 1.712 (0.58), 1.748 (0.58), 1.803 (15.93), 1.817 (11.35), 1.839 (16.00), 1.853 (11.45), 2.147 (0.55), 2.263 (2.15), 2.279 (4.07), 2.297 (2.32), 2.381 (0.68), 2.386 (1.44), 2.390 (1.91), 2.395 (1.44), 2.400 (0.65), 2.582 (6.91), 2.586 (4.41), 2.603 (0.51), 2.657 (0.48), 2.673 (0.85), 2.689 (1.33), 2.706 (1.74), 2.728 (2.63), 2.733 (2.67), 2.737 (2.09), 2.742 (1.78), 2.745 (1.78), 2.762 (1.20), 2.777 (0.72), 2.791 (2.39), 2.951 (2.63), 3.229 (5.95), 3.414 (0.96), 3.420 (0.89), 3.434 (1.30), 3.445 (1.85), 3.462 (1.74), 3.477 (1.40), 3.497 (1.71), 3.510 (2.02), 3.524 (1.54), 3.540 (1.78), 3.555 (1.64), 3.571 (1.26), 3.586 (0.92), 3.601 (0.62), 3.644 (0.92), 3.653 (0.65), 3.683 (0.89), 3.691 (0.65), 4.024 (3.79), 4.304 (4.00), 4.311 (4.58), 4.321 (5.13), 4.330 (5.50), 4.338 (4.85), 4.346 (4.65), 4.655 (1.09), 5.701 (3.38), 5.742 (0.96), 6.795 (1.71), 6.821 (5.85), 6.847 (4.14), 7.033 (0.55), 7.161 (0.62), 7.289 (0.51), 8.192 (2.09), 8.199 (2.12), 8.264 (3.18), 8.326 (2.19), 8.331 (2.22), 8.350 (2.12), 8.355 (2.15), 8.677 (0.72), 8.685 (0.65), 8.810 (0.99), 8.819 (0.96), 8.824 (1.06), 8.832 (2.70), 8.838 (2.70), 8.879 (0.85), 8.884 (1.09), 8.889 (0.92), 8.897 (2.91), 8.902 (2.46), 9.156 (1.61), 12.559 (1.03), 12.565 (1.06).  The following intermediates were prepared similarly by deprotection using TFA  Intermediate 205 trifluoroacetic acid—(rac)-2'-[3-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000360_0001
  Intermediate 206 trifluoroacetic acid—(rac)-2'-[3-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000360_0002
  Intermediate 207 trifluoroacetic acid—(rac)-2'-[3-(2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000361_0003
  Intermediate 208 4-{5-[(rac)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl]-1H-pyrrolo[2,3- b]pyridin-3-yl}morpholin-3-one 
Figure imgf000361_0001
  Intermediate 209 trifluoroacetic acid—(rac)-2'-[3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000361_0002
  Intermediate 210 trifluoroacetic acid—(rac)-2-[3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000362_0001
  Intermediate 211 trifluoroacetic acid—(rac)-2'-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000362_0002
  Intermediate 212 trifluoroacetic acid—(rac)-2'-{3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000363_0001
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 395 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.864 (0.61), 0.890 (0.56), 0.909 (0.48), 1.128 (1.08), 1.157 (0.95), 1.175 (1.00), 1.193 (0.60), 1.234 (1.81), 1.280 (0.63), 1.990 (1.00), 2.076 (0.54), 2.095 (1.25), 2.115 (0.84), 2.208 (1.29), 2.226 (2.72), 2.245 (1.51), 2.301 (16.00), 2.332 (0.91), 2.419 (0.48), 2.434 (0.45), 2.452 (0.43), 2.464 (0.46), 2.544 (0.71), 2.597 (0.51), 2.613 (2.19), 2.628 (9.17), 2.633 (6.78), 2.645 (1.53), 2.669 (1.46), 2.687 (1.28), 2.704 (0.91), 2.719 (0.54), 3.274 (0.61), 3.361 (1.17), 3.375 (1.36), 3.389 (1.48), 3.406 (1.22), 3.420 (0.82), 3.447 (0.80), 3.463 (1.01), 3.475 (1.08), 3.496 (1.16), 3.511 (0.92), 3.528 (0.61), 3.935 (0.59), 3.944 (0.64), 3.951 (0.85), 3.964 (0.72), 3.969 (0.65), 3.977 (0.58), 4.252 (1.51), 4.268 (2.12), 4.286 (1.49), 4.598 (2.66), 4.794 (5.07), 5.327 (0.46), 5.390 (3.34), 5.670 (3.70), 6.622 (0.55), 6.757 (2.47), 6.783 (3.56), 6.814 (0.58), 7.127 (0.56), 7.146 (1.64), 7.166 (3.45), 7.184 (4.11), 7.234 (3.36), 7.252 (3.76), 7.270 (1.45), 7.646 (1.06), 7.659 (1.74), 7.673 (0.80), 8.073 (1.08), 8.080 (1.11), 8.155 (3.45), 8.273 (0.56), 8.371 (1.12), 8.375 (1.20), 8.391 (1.98), 8.396 (2.06), 8.563 (2.47), 8.576 (2.42), 8.767 (1.45), 8.772 (1.33), 8.831 (1.90), 8.836 (2.00), 8.889 (1.83), 8.901 (2.51), 9.181 (0.98), 12.401 (0.63).    Intermediate 213 (rac)-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000364_0002
LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 360 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.185 (0.90), 2.202 (2.19), 2.221 (1.24), 2.523 (1.45), 2.540 (0.57), 2.612 (0.67), 2.627 (0.82), 2.646 (0.52), 2.654 (0.50), 2.673 (1.09), 2.690 (0.62), 3.341 (0.77), 3.356 (1.08), 3.371 (1.71), 3.499 (0.83), 3.892 (1.06), 3.905 (16.00), 3.934 (0.88), 4.221 (0.78), 4.228 (0.85), 4.238 (1.31), 4.247 (1.18), 4.256 (0.84), 4.262 (0.80), 6.509 (3.19), 6.514 (3.29), 6.729 (5.15), 6.998 (0.91), 7.126 (1.05), 7.254 (0.91), 7.527 (3.53), 7.532 (3.45), 7.858 (2.22), 7.865 (2.32), 8.239 (2.01), 8.243 (2.14), 8.742 (2.43), 8.747 (2.53), 9.174 (0.78), 12.196 (1.14).    Intermediate 214 (rac)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000364_0001
LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 388 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.103 (0.57), -0.066 (0.48), 0.012 (2.71), 0.060 (0.47), 0.172 (0.60), 0.205 (0.94), 0.223 (0.78), 1.110 (0.98), 1.127 (2.64), 1.159 (1.96), 1.175 (1.49), 1.193 (0.84), 1.234 (1.40), 1.375 (15.02), 1.391 (16.00), 1.398 (8.66), 1.413 (7.79), 1.428 (1.04), 1.535 (2.59), 1.909 (2.23), 2.180 (1.51), 2.196 (2.88), 2.214 (1.78), 2.325 (2.07), 2.330 (2.69), 2.335 (2.04), 2.339 (1.03), 2.521 (8.52), 2.526 (5.57), 2.595 (0.55), 2.608 (0.93), 2.627 (1.23), 2.647 (0.92), 2.667 (3.24), 2.672 (3.32), 2.677 (2.25), 2.681 (1.56), 2.700 (0.69), 3.363 (1.45), 3.388 (1.13), 3.412 (1.25), 3.426 (1.65), 3.440 (1.17), 3.457 (0.95), 3.478 (0.92), 3.492 (0.86), 4.220 (1.56), 4.238 (2.34), 4.595 (2.21), 4.607 (0.96), 4.624 (1.44), 4.642 (1.30), 4.662 (1.04), 4.678 (0.90), 5.702 (3.86), 6.140 (1.15), 6.384 (5.37), 6.389 (5.40), 6.420 (2.90), 6.424 (2.91), 6.695 (6.87), 6.724 (3.77), 7.593 (3.58), 7.596 (3.55), 7.613 (1.77), 7.617 (1.85), 7.724 (2.85), 7.731 (2.86), 7.853 (2.86), 8.125 (2.48), 8.129 (2.51), 8.137 (0.96), 8.156 (1.88), 8.161 (1.95), 8.745 (3.58), 8.750 (3.60), 8.806 (1.86), 8.811 (1.83), 9.070 (1.18), 12.191 (1.57).    Intermediate 215 (rac)-2'-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] 
Figure imgf000365_0001
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 348 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.082 (0.55), 0.700 (1.65), 0.854 (1.07), 0.905 (1.05), 0.961 (0.98), 0.998 (1.00), 1.055 (0.90), 1.068 (16.00), 1.140 (1.06), 1.234 (4.80), 1.296 (1.10), 1.355 (0.51), 1.809 (0.44), 1.851 (0.56), 1.906 (1.92), 1.937 (0.65), 2.036 (0.80), 2.048 (1.01), 2.087 (12.93), 2.099 (1.52), 2.128 (2.69), 2.179 (0.82), 2.335 (2.49), 2.521 (10.37), 2.526 (7.37), 2.559 (1.06), 2.578 (1.16), 2.600 (0.89), 2.677 (2.69), 2.785 (0.49), 2.889 (0.78), 2.912 (0.77), 3.029 (0.58), 3.463 (1.29), 3.506 (0.40), 3.944 (1.14), 4.186 (1.33), 4.237 (0.86), 5.761 (1.47), 6.585 (0.67), 6.615 (0.70), 6.622 (0.74), 6.643 (1.09), 6.681 (1.02), 8.161 (2.74), 8.242 (0.59), 8.275 (2.72), 8.374 (0.52), 8.447 (0.66), 8.469 (2.86), 8.697 (2.52), 8.716 (0.43), 8.735 (0.62), 8.740 (0.58), 8.768 (0.56), 8.803 (2.06), 8.808 (2.36), 8.824 (0.88), 8.829 (0.81).    Intermediate 216 trifluoroacetic acid—(rac)-2'-{3-[(pyridin-4-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000366_0002
LC-MS (Method 1): Rt = 0.82 min; MS (ESIpos): m/z = 381 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.101 (2.90), 1.065 (4.09), 1.155 (0.44), 2.226 (0.50), 2.323 (0.59), 2.327 (0.81), 2.332 (0.57), 2.518 (2.92), 2.523 (1.86), 2.665 (0.75), 2.669 (1.03), 2.673 (0.72), 2.727 (12.74), 2.888 (16.00), 4.256 (0.48), 4.271 (0.60), 4.290 (0.47), 4.592 (0.84), 4.730 (0.92), 5.672 (0.53), 6.786 (1.10), 6.811 (0.63), 7.951 (2.14), 8.165 (0.40), 8.231 (0.45), 8.440 (0.43).    Intermediate 217 trifluoroacetic acid—(rac)-2'-{3-[(pyridin-2-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000366_0001
LC-MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 381 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.48), 0.000 (1.24), 1.162 (1.17), 1.252 (0.60), 1.328 (0.60), 2.294 (0.57), 2.312 (1.04), 2.327 (0.57), 2.419 (1.41), 2.423 (1.97), 2.427 (1.41), 2.432 (0.67), 2.614 (7.87), 2.619 (4.89), 2.720 (0.44), 2.736 (0.50), 2.756 (0.84), 2.761 (1.54), 2.765 (2.08), 2.769 (1.51), 2.774 (0.80), 2.796 (0.47), 2.825 (12.72), 2.984 (16.00), 3.470 (0.77), 3.487 (0.67), 3.526 (0.60), 3.541 (0.60), 3.554 (0.50), 3.572 (0.54), 3.584 (0.50), 3.602 (0.47), 4.202 (3.92), 4.340 (2.14), 4.354 (2.24), 5.698 (1.00), 6.878 (1.27), 6.890 (1.41), 6.916 (0.44), 7.873 (0.87), 7.884 (0.67), 7.905 (0.84), 7.934 (1.04), 7.976 (0.57), 8.046 (2.28), 8.055 (0.90), 8.158 (0.64), 8.165 (0.64), 8.451 (0.54), 8.456 (0.57), 8.835 (0.57), 8.840 (0.54), 9.346 (0.44).    Intermediate 218 trifluoroacetic acid—(rac)-2'-[3-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000367_0001
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 381 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.029 (0.80), -0.016 (0.73), -0.008 (16.00), 0.000 (0.46), 0.912 (0.46), 0.932 (0.53), 0.952 (0.44), 1.153 (1.56), 1.243 (3.03), 1.318 (0.44), 2.289 (0.60), 2.306 (1.15), 2.325 (0.62), 2.410 (0.92), 2.414 (1.31), 2.419 (0.92), 2.605 (4.01), 2.610 (2.80), 2.731 (0.46), 2.752 (1.26), 2.756 (1.44), 2.761 (0.99), 2.766 (0.60), 2.814 (9.17), 2.975 (10.82), 3.438 (0.44), 3.453 (0.53), 3.468 (0.73), 3.484 (0.62), 3.503 (0.53), 3.522 (0.57), 3.536 (0.71), 3.550 (0.64), 3.565 (0.73), 3.582 (0.71), 3.597 (0.69), 3.612 (0.69), 3.636 (1.01), 3.657 (1.24), 3.677 (1.38), 4.333 (0.53), 4.340 (0.57), 4.349 (0.76), 4.367 (0.48), 5.729 (1.17), 5.740 (0.96), 6.889 (2.38), 7.496 (0.48), 7.500 (0.48), 7.503 (0.57), 7.507 (0.73), 7.513 (1.54), 7.517 (2.13), 7.521 (1.10), 7.523 (1.10), 7.529 (1.01), 7.534 (2.64), 7.539 (1.72), 7.550 (1.03), 7.553 (2.20), 7.555 (1.67), 7.558 (0.66), 7.565 (0.76), 7.569 (1.35), 7.573 (0.89), 7.581 (0.60), 7.587 (1.19), 7.602 (0.46), 7.606 (0.48), 7.636 (0.41), 7.641 (0.41), 7.661 (0.41), 7.683 (0.94), 7.686 (1.38), 7.690 (1.12), 7.693 (2.22), 7.697 (2.41), 7.703 (1.21), 7.706 (1.17), 7.710 (1.44), 7.714 (1.88), 7.718 (1.44), 8.038 (1.42), 8.121 (1.40), 8.231 (1.08), 8.433 (0.80), 8.438 (0.85), 8.445 (0.73), 8.450 (0.76), 8.905 (0.87), 8.909 (0.89), 9.164 (0.46).    Intermediate 219 trifluoroacetic acid—5-({5-[(rac)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazol]-2-yl]- 1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)-4-methylpyridin-3-amine (2/1) 
Figure imgf000368_0001
LC-MS (Method 1): Rt = 0.84 min; MS (ESIpos): m/z = 411 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.034 (0.55), -0.015 (0.83), 0.000 (4.38), 1.160 (5.03), 1.251 (0.83), 1.275 (2.79), 1.293 (5.76), 1.311 (2.76), 1.326 (0.91), 2.287 (0.55), 2.304 (0.81), 2.324 (0.44), 2.421 (2.08), 2.425 (1.80), 2.430 (1.30), 2.434 (0.76), 2.449 (5.50), 2.541 (1.85), 2.616 (5.50), 2.621 (3.75), 2.659 (0.42), 2.758 (0.55), 2.763 (1.15), 2.767 (1.62), 2.771 (1.15), 2.776 (0.52), 2.823 (13.06), 2.985 (16.00), 3.120 (0.39), 3.127 (1.28), 3.139 (1.28), 3.145 (1.25), 3.157 (1.25), 3.521 (0.42), 3.535 (0.44), 3.550 (0.47), 4.337 (1.04), 4.355 (1.22), 4.612 (1.36), 4.964 (0.83), 5.761 (0.73), 6.943 (0.63), 6.966 (0.81), 7.592 (0.65), 7.597 (0.70), 7.734 (0.47), 7.753 (0.42), 8.047 (1.95), 8.126 (0.50), 8.150 (0.57), 8.175 (0.52), 8.188 (0.50), 8.195 (0.63), 8.311 (0.81), 8.363 (0.73), 8.485 (0.44), 8.514 (0.47), 8.519 (0.47), 8.924 (0.65), 8.929 (0.57).    Intermediate 220 trifluoroacetic acid—(rac)-2'-[3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000369_0002
LC-MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 345 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.028 (1.97), 0.000 (1.89), 0.274 (1.26), 0.284 (1.73), 0.296 (1.10), 0.531 (0.55), 0.541 (1.18), 0.545 (1.34), 0.555 (1.18), 0.561 (1.42), 0.565 (1.34), 0.575 (1.02), 1.136 (4.33), 1.169 (0.55), 1.303 (0.55), 2.155 (1.73), 2.269 (1.26), 2.287 (2.29), 2.306 (1.18), 2.388 (1.50), 2.393 (3.23), 2.398 (4.49), 2.402 (3.23), 2.407 (1.50), 2.589 (14.19), 2.594 (9.62), 2.604 (1.58), 2.618 (1.97), 2.632 (1.10), 2.698 (0.79), 2.716 (1.02), 2.730 (2.21), 2.735 (3.94), 2.740 (5.28), 2.744 (3.78), 2.749 (1.97), 2.758 (1.02), 2.773 (0.79), 2.799 (13.16), 2.820 (3.00), 2.837 (2.84), 2.959 (16.00), 3.220 (0.39), 3.236 (6.86), 3.286 (0.47), 3.391 (0.79), 3.468 (1.73), 3.491 (1.89), 3.505 (2.13), 3.519 (1.89), 4.031 (1.89), 4.339 (1.58), 5.644 (0.47), 5.734 (1.34), 6.783 (3.15), 6.811 (1.97), 6.830 (0.71), 7.026 (0.47), 7.153 (0.47), 7.281 (0.47), 7.861 (0.55), 8.021 (1.97), 8.536 (1.26), 8.544 (1.26), 8.652 (1.42), 8.808 (1.50), 8.813 (1.66), 8.822 (0.39), 8.875 (0.95), 8.880 (1.10), 8.897 (1.42), 8.902 (1.34), 8.907 (1.26), 8.912 (0.95), 9.107 (0.87), 12.577 (0.55).    Intermediate 221 trifluoroacetic acid—(rac)-2'-{3-[(dimethylphosphoryl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000369_0001
H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.033 (0.89), 0.982 (0.60), 1.000 (1.58), 1.017 (0.73), 1.606 (0.54), 1.639 (0.55), 2.585 (0.58), 2.794 (13.24), 2.955 (16.00), 8.017 (1.94).  Intermediate 222 tert-butyl (rac)-2'-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000370_0001
Tert-Butyl (rac)-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate (4.00 g, 10.5 mmol) was dissolved in DMF (130mL) and then treated with N-bromosuccinimide (1.69 g, 9.49 mmol). It was stirred for 2 h at rt. Water was added to the reaction mixture extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 3.70 g (77 % yield) of the title compound which was used without further purification in the next step. LC-MS (Method 1): Rt = 1.20 min; MS (ESIneg): m/z = 456 [M-H]-    Intermediate 223 (rac)-2'-(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000371_0002
(Rac)-2'-(3-Bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (2.70 g, 6.29 mmol) was dissolved in acetonitrile (75 mL) under an atmosphere of argon. At 0 °C N,N-diisopropylethylamine (1.6 mL, 9.4 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (1.4 mL, 7.9 mmol) were added dropwise. It was stirred at 75 °C for 3 h. The reaction mixture was poured into amixture of ice and water and extracted twice with ethyl acetate. The combined organic lyers were dried over sodium sulfate, concentrated and purified by silica gel chromatography affording 2.36 g (67 % yield) of the title compound. LC-MS (Method 1): Rt = 1.41 min; MS (ESIpos): m/z = 561 [M+H]+    Intermediate 224 (rac)-2'-(5-aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide 
Figure imgf000371_0001
(Rac)-N-Ethyl-2'-(5-nitroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide (859 mg, 2.11 mmol) was dissolved in ethanol (10 mL) and stirred under an atmosphere of hydrogen with palladium on charcoal (15%, 22.5 mg, 211 µmol). The catalyst was filtered off, washed with dichloromethane, and concentrated to obtain 847 mg of the title compound which was used in the next step without further purification. LC-MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 377 [M+H]+    Intermediate 225 phenyl {3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-5-yl}carbamate 
Figure imgf000372_0001
(Rac)-2'-(5-Aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (400 mg, 1.06 mmol) was dissolved in THF (8.0 mL). Then pyridine (520 µL, 6.4 mmol) was added and at 0 °C phenyl carbonochloridate (270 µL, 2.1 mmol) was added and stirred for 1 h at 0 °C. Water was added and extracted three times with dichlomethane. The combined organic layers were filtered through a hydrophobic filter and concentrated giving 758 mg of the title compound which was used without further purification in the next step. LC-MS (Method 4): Rt = 1.01 min; MS (ESIpos): m/z = 497 [M+H]+  Intermediate 226 3-[(rac1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl]quinolin- 6-yl trifluoromethanesulfonate 
Figure imgf000372_0002
(Rac)-N-Ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (1.05 g, 2.78 mmol), 1,1,1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl]methanesulfonamide (1.09 g, 3.06 mmol), and N,N- diisopropylethylamine (1.5 mL, 8.3 mmol) were stirred at 60 C overnight in THF (230 mL). 1,1,1-Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (1.09 g, 3.06 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.3 mmol) were added and stirred at 60 °C for 4 h. The reaction mixture was allowed to reach rt , concentrated and purified by silica gel chromatography to obtain 2.20 g (60 % purity, 93 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 510 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.01), 1.036 (0.76), 1.224 (0.62), 1.242 (3.44), 1.256 (2.74), 1.258 (2.97), 1.272 (2.14), 2.544 (16.00), 6.752 (0.50).    Intermediate 227 methyl 3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinoline-6-carboxylate 
Figure imgf000373_0001
3-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl trifluoromethanesulfonate (1.10 g, 60 % purity, 1.30 mmol) was dissolved in a mixture of THF/methanol 1 : 10 (33 mL). Then [1,1'- bis(diphenylphosphin)ferrocene]dichloropalladium(II) complex with dichloromethane (106 mg, 130 µmol) and triethylamine (360 µL, 2.6 mmol) were added. Then the reaction mixture was stirred under 14.5 bar of carbon monoxide for 23 h at 100 °C. The reaction mixture was allowed to reach rt, concentrated and purified by silica gel chromatography to yield 770 mg of the title compound. LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 420 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.021 (0.59), 1.039 (1.66), 1.056 (1.34), 1.157 (2.66), 1.175 (5.82), 1.194 (2.63), 1.242 (0.62), 1.255 (0.47), 1.258 (0.53), 2.544 (16.00), 3.082 (0.41), 3.088 (1.09), 3.100 (1.03), 3.106 (1.07), 3.118 (0.96), 3.467 (0.64), 3.943 (2.51), 6.745 (0.90), 9.469 (0.45), 9.475 (0.45).    Intermediate 228 3-[(rac)-1-(ethylcarbamoyl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazol]-2- yl]quinoline-6-carboxylic acid 
Figure imgf000374_0001
Methyl 3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinoline-6-carboxylate (770 mg, 1.84 mmol) was dissolved in THF (5 mL) and ethanol (5 mL). Then lithium hydroxide (7.3 mL, 1.0 M in water, 7.3 mmol) was added and stirred at rt overnight. The reaction mixture was diluted with water and the pH was adjusted to 1 with hydrochloric acid. The volatile was removed under vacuum and the aqueous residue was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to give 330 mg (44 % yield) of the title compound which was used without further purification in the next step.   LC-MS (Method 4): Rt = 0.74 min; MS (ESIpos): m/z = 406 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.021 (6.70), 1.039 (15.17), 1.057 (7.51), 1.158 (0.55), 1.170 (2.16), 1.176 (1.17), 1.194 (0.56), 1.231 (0.62), 1.236 (0.67), 1.242 (0.47), 1.272 (0.52), 1.913 (16.00), 2.082 (0.48), 2.096 (1.27), 2.112 (2.58), 2.129 (2.84), 2.147 (1.13), 2.160 (0.63), 2.528 (1.30), 2.545 (4.14), 2.575 (2.73), 2.592 (4.31), 2.610 (2.86), 3.001 (0.41), 3.042 (0.85), 3.060 (2.65), 3.074 (3.11), 3.077 (3.09), 3.092 (2.67), 3.109 (0.89), 3.171 (0.55), 3.410 (0.93), 3.428 (1.51), 3.436 (1.43), 3.454 (2.41), 3.468 (9.23), 3.494 (0.68), 3.507 (1.05), 3.525 (1.50), 3.532 (0.98), 3.539 (1.12), 3.547 (0.92), 3.565 (0.53), 4.279 (2.71), 4.296 (4.39), 4.313 (2.68), 6.184 (1.14), 6.197 (2.18), 6.211 (1.13), 6.752 (9.83), 8.071 (2.95), 8.093 (4.65), 8.160 (3.81), 8.164 (3.66), 8.182 (2.28), 8.187 (2.46), 8.679 (4.71), 8.683 (4.75), 8.847 (3.92), 8.852 (4.07), 9.456 (5.42), 9.461 (5.47).  Intermediate 229 4-nitrophenyl (rac)-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate 
Figure imgf000375_0002
(Rac)-2'-(6-Methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]— hydrogen chloride (1/1) (500 mg, 1.40 mmol) was dissolved in dichloromethane (23 mL) and triethylamine (980 µL, 7.0 mmol) under an atmosphere of nitrogen. 4-Nitrophenyl carbonochloridate (339 mg, 1.68 mmol) was added and stirred at rt overnight. N,N- Dimethylacetamide (3 mL) was added and evaporated on a rotary evaporator to give 840 mg of the title compound which was used without further purification in the next step.   LC-MS (Method 4): Rt = 1.15 min; MS (ESIpos): m/z = 486 [M+H]+  Intermediate 230 4-nitrophenyl (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate 
Figure imgf000375_0001
Trifluoroacetic acid—(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (1/1) (150 mg, 51 % purity, 189 µmol) was dissolved in dichloromethane (3.0 mL) and triethylamine (260 µL, 1.9 mmol) under an atmosphere of nitrogen. 4-Nitrophenyl carbonochloridate (45.8 mg, 227 mmol) was added and stirred at rt overnight. N,N- Dimethylacetamide (2.0 mL) was added and concentrated to give 200 mg of the title compound which was used without further purification in the next step.   LC-MS (Method 1): Rt = 1.20 min; MS (ESIpos): m/z = 456 [M+H]+  Intermediate 231 4-nitrophenyl (rac)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3- pyrrolidine]-1'-carboxylate 
Figure imgf000376_0001
(Rac)-2-(Quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]— hydrogen chloride (1/1) (1.80 g, 90 % purity, 4.75 mmol) was dissolved in dichloromethane (41 mL) and then triethylamine (4.0 mL, 29 mmol) and 4-nitrophenyl carbonochloridate (1.34 g, 6.65 mmol) were added. It was stirred for 1 h at rt. N,N-Dimethylacetamide was added and the reaction mixture was concentrated. The residue was dissolved in ethyl actetate and washed three times with half saturated aqeous sodium hydrogen carbonate solution and once with saturated aqueous sodium chloride solutuion, filtered through a hydrophobic filter, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate) and crystallized from dichloromethane/MTBE to give 1.64 g (96 % purity, 71 % yield) of the title 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.86 - 2.03 (m, 2H), 2.08 - 2.21 (m, 3H), 2.23 - 2.33 (m, 1H), 3.58 - 3.79 (m, 3H), 3.79 - 3.94 (m, 1H), 4.14 - 4.27 (m, 2H), 6.99 (d, 1H), 7.45 - 7.55 (m, 2H), 7.60 - 7.65 (m, 1H), 7.73 (t, 1H), 8.02 (dd, 2H), 8.30 (t, 2H), 8.69 (d, 1H), 9.37 (d, 1H).   LC-MS (Method 4): Rt = 1.20 min; MS (ESIpos): m/z = 470 [M+H]+  Intermediate 232 ethyl ({3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl}oxy)acetate 
Figure imgf000376_0002
(Rac)-N-Ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (540 mg, 1.43 mmol) was dssolved in THF (12 mL) under an atmosphere of nitrogen. Sodium hydride (68.7 mg, 60 % in mineral oil, 1.72 mmol) was added at rt and stirred for 10 minutes. Then ethyl bromoacetate (190 µL, 1.7 mmol) was added and stirred overnight at rt. Then sodium hydride (68.7 mg, 60 % in mineral oil, 1.72 mmol) was added at rt and stirred for 10 minutes. Then ethyl bromoacetate (190 µL, 1.7 mmol) was added and stirred overnight at rt. Saturated aqueous sodium chloride solution was added, the layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated and purified by silical gel chromatography to obtain 221 mg (32%) of the title compound.   LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 464 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.41), 0.862 (0.59), 0.878 (0.62), 0.885 (0.62), 0.968 (0.62), 1.078 (6.39), 1.096 (14.01), 1.113 (6.74), 1.283 (7.56), 1.301 (16.00), 1.318 (7.82), 2.133 (0.53), 2.147 (1.35), 2.163 (2.55), 2.180 (2.81), 2.199 (1.20), 2.211 (0.70), 2.386 (1.35), 2.391 (1.79), 2.395 (1.38), 2.622 (3.05), 2.640 (4.60), 2.657 (2.99), 2.729 (1.38), 2.733 (1.82), 2.737 (1.38), 3.097 (0.97), 3.115 (2.96), 3.130 (3.46), 3.147 (2.90), 3.165 (0.88), 3.456 (0.67), 3.475 (1.41), 3.482 (1.26), 3.500 (2.29), 3.517 (9.90), 3.543 (0.59), 3.563 (0.91), 3.581 (1.49), 3.595 (1.14), 3.603 (0.97), 3.621 (0.56), 3.802 (0.50), 4.243 (2.40), 4.261 (7.12), 4.279 (7.03), 4.296 (2.37), 4.319 (2.81), 4.337 (4.57), 4.354 (2.78), 4.994 (12.54), 5.016 (0.41), 5.823 (3.28), 6.232 (1.32), 6.246 (2.58), 6.260 (1.32), 6.755 (8.97), 7.410 (3.58), 7.417 (4.40), 7.460 (2.73), 7.467 (2.08), 7.483 (2.78), 7.490 (2.37), 7.975 (3.87), 7.998 (3.58), 8.592 (3.99), 8.596 (4.13), 9.255 (4.98), 9.260 (5.10).    Intermediate 233 ({3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl}oxy)acetic acid 
Figure imgf000377_0001
Ethyl ({3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl}oxy)acetate (216 mg, 466 µmol) was dissolved in THF (12 mL) and ethanol (4.0 mL). Then lithium hydroxide (2.8 mL, 1.0 M in water, 2.8 mmol) was added and stirred overnight at rt. The reaction mixture was diluted with water and the pH was adjusted to 4. The organic solvents were evaporated and the precipitate was filtered off and dried at 80 °C under vacuum to afford 169 mg (83%) of the title compound. The filtrate was purified by HPLC obtaining 12.4 mg (6%) of the title compound. LC-MS (Method 1): Rt = 0.54 min; MS (ESIpos): m/z = 436 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.065 (0.83), 1.014 (7.15), 1.031 (16.00), 1.049 (7.47), 1.166 (0.86), 1.232 (0.45), 1.386 (0.46), 2.068 (0.46), 2.082 (1.33), 2.097 (2.54), 2.114 (3.07), 2.132 (1.19), 2.145 (0.65), 2.522 (3.50), 2.557 (2.78), 2.575 (4.37), 2.592 (2.91), 3.034 (0.96), 3.052 (2.97), 3.065 (3.45), 3.069 (3.39), 3.083 (2.98), 3.101 (0.92), 3.392 (1.47), 3.410 (1.87), 3.418 (1.57), 3.428 (1.46), 3.436 (2.50), 3.452 (10.74), 3.478 (0.58), 3.499 (0.99), 3.518 (1.51), 3.525 (1.05), 3.532 (1.16), 3.539 (0.99), 3.558 (0.60), 4.254 (2.75), 4.271 (4.47), 4.288 (2.69), 4.823 (12.02), 6.168 (1.31), 6.182 (2.64), 6.196 (1.32), 6.695 (10.64), 7.331 (3.72), 7.338 (4.63), 7.380 (3.06), 7.387 (2.32), 7.402 (3.04), 7.410 (2.63), 7.905 (4.20), 7.927 (3.80), 8.536 (4.11), 8.541 (4.26), 9.185 (5.86), 9.190 (5.75).  Intermediate 234 (rac)-N-ethyl-2'-(5-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000378_0001
(Rac)-N-Ethyl-2'-(5-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (155 mg, 396 µmol) was dissolved in dichloromethane (8.1 mL). At 0 °C tribromoborane (2.2 mL, 1.0 M in dichloromethane, 2.2 mmol) was added dropwise and stirred for 5 h at rt. Saturated aqueous sodium hydrogen carbonate and sodium chloride solution (1 :1) were added and stirred for 15 min. The reaction mixture was extracted with a mixture of ethyl acetate/THF. The combined organic layers were dried through a hydrophobic filter and concentrated yielding 55.0 mg (37 % yield) of the title compound.   Intermediate 235 (rac)-N-ethyl-2'-[3-methyl-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000379_0001
(Rac)-N-Ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (664 mg, 1.82 mmol) was dissolved in DMF (25 mL) under an atmosphere of argon and cooled to 0 °C. Sodium hydride (83.8 mg, 60 % in mineral oil, 2.10 mmol) was added and stirred for 30 min. At 0 °C 4-methylbenzene-1-sulfonyl chloride (382 mg, 2.00 mmol) was added and stirred for 2 h at rt. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 1.29 g of the title compound which was used without further purification in the next step.     Intermediate 236 (rac)-3'-bromo-N-ethyl-2'-[3-methyl-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5- yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000380_0002
(Rac)-N-Ethyl-2'-[3-methyl-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (940 mg, 1.81 mmol) was dissolved in DMF (30 mL) and treated with N-bromosuccinimide (645 mg, 3.62 mmol). It was stirred for 1 h at rt. Water was added and the pricipitate was filtered, washed with water, dried and purified by silica gel chromatography.   Intermediate 237 tert-butyl {2-oxo-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethyl}carbamate 
Figure imgf000380_0001
To a solution of N-(tert-butoxycarbonyl)glycine (193 mg, 1.10 mmol) in DMF (5 mL), HATU (419 mg, 1.10 mmol) and N,N-diisopropylethylamine (800 µl, 4.6 mmol) were added. The mixture was stirred at rt under Argon for 30min. 2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] hydrogen chloride (1/1) (300 mg, 918 µmol) was added and the mixture stirred at RT overnight. The resultant mixture was diluted with ethyl acetate and 0.5 N HCl. The aqueous phase was extracted with ethyl acetate (x2) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by basic HPLC to give 86.5mg (21%) of the title compound.   LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 449 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.380 (16.00), 1.401 (15.75), 2.099 (0.53), 2.118 (0.62), 2.180 (0.62), 2.197 (1.34), 2.214 (0.66), 2.327 (0.51), 2.522 (1.24), 2.596 (0.70), 2.610 (1.40), 2.627 (1.31), 2.639 (0.61), 2.664 (0.45), 2.669 (0.60), 2.673 (0.48), 3.512 (0.70), 3.540 (1.15), 3.573 (1.26), 3.602 (0.60), 3.623 (0.74), 3.631 (0.69), 3.648 (1.45), 3.674 (1.18), 3.683 (1.19), 3.708 (0.87), 3.723 (0.72), 3.739 (0.55), 3.756 (0.57), 3.765 (0.57), 3.798 (0.53), 3.813 (0.50), 3.838 (0.48), 3.853 (0.49), 4.269 (0.53), 4.286 (1.27), 4.299 (2.02), 4.317 (0.90), 6.763 (1.90), 6.808 (2.01), 6.830 (0.55), 6.846 (1.08), 6.859 (0.54), 7.595 (0.71), 7.614 (1.39), 7.632 (1.05), 7.707 (0.95), 7.710 (0.95), 7.728 (1.47), 7.731 (1.21), 7.745 (0.80), 7.749 (0.84), 7.997 (2.43), 8.019 (2.26), 8.630 (1.07), 8.636 (1.04), 8.661 (1.03), 8.666 (1.00), 9.351 (2.09).  Example 25 (rac)-N-cyclobutyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000381_0001
Under argon (rac)-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]—hydrogen chloride (1/1) (130 mg, 364 µmol) was dissolved in dichloromethane (4 mL) and then N,N-diisopropylethylamine (320 µL, 1.8 mmol) and isocyanatocyclobutane (35.4 mg, 364 µmol) were added at 0° C. It was stirred overnight at rt. The solvent was removed and the residue was purified by HPLC yielding 38.0 mg (95 % purity, 24 % yield) of the title compound.  LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 419 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (1.36), 0.948 (1.37), 1.515 (0.57), 1.521 (0.46), 1.541 (1.08), 1.560 (0.93), 1.585 (0.66), 1.902 (0.54), 1.930 (0.98), 1.953 (0.96), 1.979 (0.53), 2.076 (0.96), 2.094 (1.92), 2.100 (1.48), 2.112 (1.99), 2.119 (1.22), 2.129 (1.15), 2.143 (0.61), 2.331 (1.05), 2.336 (0.49), 2.518 (4.80), 2.523 (3.17), 2.557 (1.42), 2.575 (2.07), 2.593 (1.46), 2.673 (1.06), 2.678 (0.48), 3.414 (0.68), 3.421 (0.56), 3.440 (1.10), 3.455 (4.22), 3.503 (0.41), 3.522 (0.68), 3.529 (0.42), 3.536 (0.49), 3.544 (0.40), 3.899 (16.00), 4.120 (0.68), 4.140 (0.65), 4.255 (1.45), 4.273 (2.19), 4.290 (1.38), 6.335 (1.22), 6.355 (1.19), 6.686 (6.30), 7.340 (1.43), 7.348 (1.83), 7.363 (1.34), 7.370 (2.35), 7.387 (2.64), 7.394 (1.76), 7.885 (2.22), 7.907 (1.99), 8.550 (2.08), 8.555 (2.10), 9.168 (3.47), 9.173 (3.26).  The following examples were synthesised analogously reaction an amine with an isocyanate.  Example 26 (rac)-N-[(rac)-2,2-dimethylcyclopropyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000382_0001
LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 403 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.356 (0.75), 0.360 (0.84), 0.367 (1.52), 0.379 (0.94), 0.383 (0.86), 0.495 (0.75), 0.501 (0.84), 0.507 (0.86), 0.514 (1.46), 0.521 (0.95), 0.526 (0.77), 0.533 (0.69), 0.968 (9.84), 0.985 (0.71), 0.999 (11.16), 1.005 (16.00), 2.088 (0.87), 2.105 (1.60), 2.123 (1.60), 2.142 (0.73), 2.155 (0.42), 2.269 (0.68), 2.278 (0.99), 2.287 (1.16), 2.297 (0.97), 2.305 (0.61), 2.322 (0.43), 2.326 (0.57), 2.331 (0.42), 2.518 (1.99), 2.522 (1.31), 2.557 (1.48), 2.568 (1.79), 2.576 (2.54), 2.592 (1.67), 2.664 (0.43), 2.669 (0.59), 2.673 (0.42), 3.379 (0.43), 3.397 (0.61), 3.405 (0.47), 3.422 (1.46), 3.431 (0.80), 3.447 (1.93), 3.456 (2.16), 3.471 (2.02), 3.488 (1.96), 3.496 (0.80), 3.514 (1.18), 3.525 (0.44), 3.537 (0.54), 3.556 (0.55), 4.261 (2.17), 4.279 (4.06), 4.296 (2.06), 6.143 (1.20), 6.150 (1.99), 6.157 (1.17), 6.698 (3.85), 6.709 (4.71), 7.593 (0.93), 7.612 (1.91), 7.633 (1.33), 7.708 (1.19), 7.710 (1.06), 7.725 (1.10), 7.728 (1.85), 7.732 (1.46), 7.746 (0.96), 7.749 (1.02), 7.996 (4.50), 8.019 (3.64), 8.635 (1.56), 8.640 (1.61), 8.648 (1.60), 8.653 (1.56), 9.331 (2.29), 9.338 (2.92), 9.345 (2.26).    Example 27 (rac)-2'-(quinolin-3-yl)-N-[(1S)-2,2,2-trifluoro-1-methoxy-1-phenylethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000383_0001
  Example 28 (rac)-N-[2-(pyrimidin-5-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000383_0002
  Example 29 (rac)-N-[2-(pyrimidin-4-yl)propan-2-yl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000384_0001
  Example 30 2-(5-fluoropyridin-2-yl)-2-methyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]propan-1-one
Figure imgf000384_0002
  Example 31 (rac)-N-[2-(5-fluoropyridin-2-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000385_0002
  Example 32 (rac)-N-[2-(3,4-difluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000385_0001
  Example 33 (rac)-N-[1-(2-fluorophenyl)cyclopentyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide   
Figure imgf000386_0002
Example 34 (rac)-N-[1-(6-chloropyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000386_0001
  Example 35 (rac)-N-[1-(4-cyano-1,4-dihydropyridazin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
 
Figure imgf000387_0001
Example 36 (rac)-N-[1-(4-cyanopyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide   
Figure imgf000387_0002
Example 37 (rac)-N-(4-phenyloxan-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide   
Figure imgf000388_0002
Example 38 (rac)-N-cyclobutyl-2'-[6-(cyclohexyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000388_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.218 (0.59), 1.234 (0.48), 1.243 (1.29), 1.253 (1.03), 1.259 (1.50), 1.265 (1.67), 1.271 (1.44), 1.282 (1.98), 1.303 (1.40), 1.328 (0.88), 1.380 (1.19), 1.389 (0.88), 1.407 (2.75), 1.413 (2.32), 1.439 (3.35), 1.463 (4.37), 1.484 (3.94), 1.492 (3.13), 1.512 (4.49), 1.518 (3.30), 1.538 (4.77), 1.559 (4.68), 1.583 (3.58), 1.741 (2.67), 1.750 (2.86), 1.764 (2.67), 1.774 (2.53), 1.881 (0.53), 1.904 (1.91), 1.908 (1.75), 1.931 (3.52), 1.954 (3.49), 1.980 (2.02), 2.021 (3.07), 2.032 (2.92), 2.045 (2.78), 2.056 (2.82), 2.074 (7.17), 2.091 (5.97), 2.105 (6.92), 2.119 (4.67), 2.137 (2.22), 2.155 (0.70), 2.518 (1.19), 2.522 (0.78), 2.556 (4.48), 2.574 (7.11), 2.591 (4.67), 2.744 (0.68), 3.401 (8.52), 3.418 (9.15), 3.426 (8.24), 3.436 (6.15), 3.479 (2.13), 3.501 (2.19), 3.519 (3.00), 3.526 (2.01), 3.534 (2.20), 3.542 (1.84), 3.560 (1.14), 4.102 (1.24), 4.123 (2.26), 4.143 (2.23), 4.164 (1.17), 4.250 (4.57), 4.267 (7.28), 4.285 (4.38), 4.462 (0.66), 4.471 (1.13), 4.483 (1.74), 4.492 (2.24), 4.502 (1.46), 4.514 (1.20), 6.343 (3.73), 6.364 (3.62), 6.675 (16.00), 7.030 (1.19), 7.158 (1.36), 7.286 (1.19), 7.332 (3.19), 7.339 (3.52), 7.355 (3.33), 7.362 (3.86), 7.433 (6.26), 7.440 (5.44), 7.879 (6.68), 7.902 (6.05), 8.574 (6.06), 9.165 (8.28), 9.170 (8.07).    Example 39 (rac)-N-cyclobutyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000389_0001
LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 447 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.347 (15.68), 1.356 (1.51), 1.363 (16.00), 1.514 (0.54), 1.521 (0.46), 1.540 (0.99), 1.560 (0.87), 1.584 (0.62), 1.902 (0.48), 1.930 (0.89), 1.953 (0.88), 1.978 (0.52), 2.074 (1.02), 2.092 (1.70), 2.110 (1.90), 2.119 (1.13), 2.128 (1.14), 2.140 (0.55), 2.518 (3.64), 2.523 (2.36), 2.557 (1.32), 2.574 (1.95), 2.592 (1.35), 3.414 (0.62), 3.423 (0.59), 3.440 (1.10), 3.452 (3.92), 3.520 (0.63), 3.534 (0.50), 4.120 (0.63), 4.141 (0.62), 4.252 (1.32), 4.270 (2.01), 4.287 (1.29), 4.755 (0.89), 4.771 (1.20), 4.786 (0.88), 6.334 (1.16), 6.354 (1.11), 6.672 (5.67), 7.299 (1.30), 7.306 (1.50), 7.322 (1.31), 7.329 (1.68), 7.383 (2.12), 7.390 (1.80), 7.867 (2.03), 7.890 (1.85), 8.525 (1.85), 8.530 (1.95), 9.151 (3.04), 9.156 (3.15).    Example 40 (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-cyclobutyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers)   
Figure imgf000390_0003
Example 41 (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000390_0001
  Example 42 (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000390_0002
  Example 43 (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-tert-butyl-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers)   
Figure imgf000391_0002
Example 44 (rac)-N-tert-butyl-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000391_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.85), 1.269 (16.00), 1.712 (4.28), 2.036 (0.44), 2.465 (1.22), 2.518 (4.97), 2.523 (3.17), 2.539 (0.76), 3.349 (1.04), 3.375 (1.53), 3.387 (1.26), 4.129 (0.62), 4.147 (1.02), 4.164 (0.60), 5.309 (1.20), 6.267 (2.53), 7.140 (0.65), 7.157 (0.48), 7.226 (0.65), 7.246 (1.34), 7.264 (1.02), 7.290 (1.54), 7.309 (0.84), 7.312 (0.58), 7.384 (1.07), 7.390 (1.06), 7.559 (1.04), 7.564 (1.04), 8.494 (1.29), 8.499 (1.25), 11.457 (0.61).    Example 45 (rac)-2'-{3-[(dimethylphosphoryl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000392_0002
LC-MS (Method 1): Rt = 0.68 min; MS (ESIpos): m/z = 451 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (3.35), 1.026 (7.84), 1.044 (3.51), 1.740 (16.00), 1.776 (16.00), 2.067 (0.56), 2.086 (0.83), 2.105 (0.92), 2.125 (0.44), 2.518 (0.86), 2.523 (0.61), 2.534 (0.97), 2.539 (1.28), 2.550 (1.53), 2.553 (1.51), 2.570 (1.06), 3.027 (0.42), 3.045 (1.30), 3.059 (1.43), 3.063 (1.40), 3.077 (1.28), 3.389 (0.92), 3.396 (0.66), 3.407 (0.55), 3.415 (0.92), 3.442 (4.47), 3.517 (0.41), 3.522 (0.53), 3.535 (0.44), 4.219 (1.11), 4.237 (1.88), 4.254 (1.05), 6.163 (0.54), 6.177 (1.08), 6.190 (0.52), 6.638 (5.08), 8.112 (4.43), 8.284 (3.19), 8.289 (3.26), 8.771 (2.73), 8.776 (2.69).    Example 46 (rac)-2'-[3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000392_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.184 (1.18), 0.195 (4.12), 0.199 (3.86), 0.208 (4.29), 0.211 (3.87), 0.221 (1.36), 0.459 (1.41), 0.469 (3.74), 0.473 (3.61), 0.479 (1.96), 0.483 (1.81), 0.489 (3.86), 0.493 (3.60), 0.504 (1.32), 1.011 (7.09), 1.029 (16.00), 1.047 (7.31), 1.064 (3.80), 1.079 (0.88), 1.082 (0.86), 1.087 (0.86), 1.091 (0.64), 1.099 (1.41), 1.107 (0.64), 1.111 (0.79), 1.116 (0.81), 1.119 (0.79), 1.131 (0.41), 2.049 (0.50), 2.054 (0.54), 2.066 (1.25), 2.080 (1.26), 2.083 (1.18), 2.098 (1.44), 2.118 (1.85), 2.130 (0.62), 2.137 (0.96), 2.149 (0.83), 2.518 (1.32), 2.522 (1.01), 2.532 (2.32), 2.539 (3.16), 2.549 (3.59), 2.551 (3.59), 2.568 (2.53), 2.748 (7.02), 2.765 (6.90), 3.031 (0.91), 3.048 (2.80), 3.063 (3.19), 3.066 (3.07), 3.081 (2.77), 3.098 (0.83), 3.383 (1.62), 3.390 (1.22), 3.402 (1.01), 3.409 (1.86), 3.417 (0.72), 3.428 (1.02), 3.443 (8.67), 3.469 (0.45), 3.509 (0.72), 3.521 (0.90), 3.528 (1.15), 3.533 (0.90), 3.540 (0.98), 3.546 (0.81), 3.553 (0.72), 3.566 (0.50), 3.944 (0.41), 4.222 (2.58), 4.240 (4.39), 4.257 (2.47), 6.161 (1.22), 6.174 (2.44), 6.188 (1.20), 6.542 (10.47), 8.445 (8.50), 8.732 (5.54), 8.737 (6.34), 8.816 (6.95), 8.821 (6.04).    Example 47 (rac)-N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000393_0001
  Example 48 (rac)-2'-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000393_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.010 (2.19), 1.028 (5.06), 1.045 (2.22), 2.116 (0.54), 2.336 (0.72), 2.473 (9.58), 2.518 (11.66), 2.522 (7.46), 2.539 (16.00), 2.546 (1.87), 2.565 (1.00), 2.659 (0.79), 3.046 (0.86), 3.060 (0.93), 3.063 (0.93), 3.077 (0.83), 3.381 (0.50), 3.406 (0.57), 3.440 (2.48), 4.220 (0.75), 4.238 (1.33), 4.255 (0.75), 6.170 (0.68), 6.542 (3.30), 8.469 (3.09), 8.726 (1.72), 8.731 (1.90), 8.784 (2.33), 8.790 (1.83).    Example 49 (rac)-N-ethyl-2'-[3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000394_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.010 (7.19), 1.028 (16.00), 1.045 (7.31), 1.137 (0.46), 1.154 (0.50), 1.232 (0.75), 2.067 (1.21), 2.084 (3.74), 2.102 (2.45), 2.120 (1.04), 2.132 (0.62), 2.243 (1.25), 2.336 (0.79), 2.518 (11.76), 2.523 (7.77), 2.534 (3.16), 2.539 (7.36), 2.551 (3.86), 2.570 (2.49), 2.623 (0.75), 3.028 (0.91), 3.046 (2.87), 3.060 (3.24), 3.064 (3.16), 3.077 (2.83), 3.095 (0.87), 3.382 (0.66), 3.400 (1.41), 3.407 (1.16), 3.426 (1.99), 3.442 (10.31), 3.507 (0.83), 3.525 (1.25), 3.532 (0.91), 3.539 (1.00), 3.546 (0.79), 3.565 (0.50), 4.216 (2.58), 4.233 (4.24), 4.251 (2.37), 4.552 (2.83), 6.155 (1.16), 6.169 (2.41), 6.183 (1.21), 6.499 (0.42), 6.658 (9.93), 7.468 (1.70), 7.469 (1.70), 7.482 (1.75), 7.489 (1.79), 7.501 (1.91), 8.032 (3.82), 8.135 (1.50), 8.139 (2.04), 8.145 (1.62), 8.154 (1.45), 8.160 (1.91), 8.164 (1.50), 8.465 (2.78), 8.469 (2.74), 8.477 (2.74), 8.481 (2.62), 8.544 (4.61), 8.549 (5.07), 8.739 (5.11), 8.744 (5.03), 8.986 (3.37), 8.990 (3.45), 12.108 (1.95).    Example 50 (rac)-N-ethyl-2'-[3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000394_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.014 (7.03), 1.031 (16.00), 1.049 (7.03), 1.232 (0.90), 2.075 (1.23), 2.090 (2.00), 2.108 (2.52), 2.126 (0.97), 2.139 (0.58), 2.336 (1.23), 2.518 (15.03), 2.523 (10.45), 2.543 (2.65), 2.559 (3.48), 2.578 (2.32), 2.679 (1.23), 3.032 (0.84), 3.050 (2.71), 3.064 (3.03), 3.068 (2.84), 3.082 (2.65), 3.100 (0.77), 3.392 (0.52), 3.411 (1.29), 3.418 (0.97), 3.436 (2.06), 3.450 (9.68), 3.513 (0.71), 3.532 (1.10), 3.539 (0.77), 3.546 (0.84), 3.552 (0.71), 3.572 (0.45), 4.228 (2.39), 4.245 (3.94), 4.263 (2.26), 6.164 (1.10), 6.178 (2.19), 6.191 (1.03), 6.499 (0.45), 6.682 (10.19), 7.776 (7.03), 7.780 (3.94), 7.787 (4.13), 7.791 (6.97), 8.226 (8.13), 8.553 (0.65), 8.568 (7.61), 8.572 (4.00), 8.580 (4.06), 8.583 (6.84), 8.645 (5.10), 8.650 (5.61), 8.751 (5.42), 8.756 (5.23), 12.265 (2.00).    Example 51 (rac)-N-ethyl-2'-[3-(3-oxomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000395_0001
  Example 52 (rac)-N-ethyl-2'-[3-(2-oxopyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000395_0002
  Example 53 (rac)-N-ethyl-2'-[3-(2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000396_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.998 (5.40), 1.016 (12.38), 1.034 (5.67), 1.137 (1.01), 1.233 (0.81), 2.040 (0.97), 2.059 (1.49), 2.080 (1.67), 2.084 (0.99), 2.098 (0.81), 2.110 (0.56), 2.116 (0.56), 2.311 (16.00), 2.322 (1.37), 2.327 (1.53), 2.332 (1.10), 2.518 (8.66), 2.523 (7.43), 2.540 (2.75), 2.665 (0.99), 2.669 (1.37), 2.673 (0.99), 3.017 (0.68), 3.034 (2.25), 3.048 (2.50), 3.052 (2.48), 3.066 (2.21), 3.084 (0.65), 3.368 (1.24), 3.375 (0.95), 3.394 (1.55), 3.415 (8.21), 3.484 (0.56), 3.497 (0.72), 3.503 (0.95), 3.509 (0.72), 3.516 (0.77), 3.522 (0.63), 3.528 (0.59), 4.176 (2.03), 4.194 (3.58), 4.211 (1.96), 6.135 (0.95), 6.149 (1.89), 6.162 (0.95), 6.530 (8.06), 7.235 (0.45), 7.239 (0.54), 7.253 (1.51), 7.257 (1.76), 7.270 (3.04), 7.275 (3.53), 7.288 (1.60), 7.292 (1.82), 7.306 (0.72), 7.337 (1.87), 7.341 (1.80), 7.355 (1.26), 7.359 (1.26), 7.374 (2.16), 7.378 (1.82), 7.392 (1.73), 7.397 (1.40), 7.579 (3.74), 7.585 (3.76), 8.082 (3.44), 8.086 (3.53), 8.688 (4.05), 8.692 (4.05), 11.882 (1.94), 11.887 (1.98).    Example 54 (rac)-2'-[6-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000396_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (1.79), 1.033 (4.05), 1.050 (1.81), 2.100 (0.54), 2.118 (0.62), 2.518 (1.14), 2.523 (0.78), 2.540 (16.00), 2.558 (0.67), 2.577 (0.98), 2.594 (0.68), 3.053 (0.71), 3.067 (0.80), 3.071 (0.77), 3.084 (0.70), 3.435 (0.53), 3.455 (2.45), 4.256 (0.65), 4.274 (1.02), 4.291 (0.63), 5.249 (2.72), 6.185 (0.60), 6.691 (2.71), 7.357 (0.72), 7.376 (0.63), 7.407 (0.94), 7.410 (0.49), 7.416 (0.72), 7.422 (1.41), 7.425 (1.70), 7.438 (0.89), 7.445 (1.28), 7.494 (1.07), 7.500 (0.89), 7.525 (1.38), 7.542 (1.06), 7.546 (0.76), 7.903 (1.00), 7.925 (0.91), 8.527 (0.95), 8.532 (0.98), 9.174 (1.43), 9.180 (1.49).    Example 55 (rac)-N-ethyl-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000397_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.008 (4.07), 1.026 (9.02), 1.043 (4.15), 1.064 (2.12), 1.163 (0.88), 1.228 (0.44), 1.300 (15.73), 1.317 (16.00), 2.056 (0.80), 2.069 (2.03), 2.075 (1.24), 2.095 (1.33), 2.113 (0.62), 2.125 (0.44), 2.518 (2.92), 2.523 (2.74), 2.540 (2.48), 2.559 (1.59), 3.027 (0.53), 3.045 (1.77), 3.059 (1.94), 3.062 (1.94), 3.077 (1.68), 3.095 (0.53), 3.134 (0.88), 3.151 (1.15), 3.168 (0.80), 3.419 (2.48), 3.431 (7.07), 3.498 (0.53), 3.517 (0.80), 3.523 (0.53), 3.530 (0.62), 3.537 (0.53), 3.542 (0.53), 4.195 (1.59), 4.213 (2.83), 4.230 (1.59), 6.164 (0.71), 6.177 (1.41), 6.191 (0.71), 6.532 (6.10), 6.561 (1.24), 7.183 (2.21), 7.188 (2.30), 7.627 (0.44), 8.254 (2.56), 8.259 (2.74), 8.598 (3.09), 8.603 (3.09), 11.293 (1.50), 11.297 (1.50).    Example 56 (rac)-2'-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000397_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.010 (0.45), 1.028 (1.02), 1.045 (0.47), 1.231 (0.50), 2.326 (0.47), 2.518 (1.76), 2.522 (1.26), 2.539 (16.00), 2.668 (0.47), 3.435 (0.67), 6.524 (0.65).    Example 57 (rac)-N-ethyl-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000398_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.983 (0.72), 1.005 (3.76), 1.022 (7.98), 1.040 (3.87), 1.134 (2.39), 1.151 (2.38), 2.055 (0.82), 2.071 (1.61), 2.081 (1.12), 2.090 (1.53), 2.109 (0.71), 2.121 (0.46), 2.522 (2.28), 2.541 (2.56), 2.557 (1.67), 3.024 (0.69), 3.042 (1.77), 3.057 (2.03), 3.059 (2.06), 3.074 (1.71), 3.091 (0.53), 3.412 (2.04), 3.430 (6.78), 3.498 (0.55), 3.516 (0.85), 3.523 (0.67), 3.530 (0.71), 3.537 (0.61), 3.542 (0.57), 3.902 (16.00), 4.199 (1.59), 4.216 (2.84), 4.233 (1.59), 5.752 (5.35), 6.156 (0.80), 6.169 (1.55), 6.183 (0.80), 6.523 (3.33), 6.528 (3.46), 6.605 (5.23), 7.517 (3.46), 7.521 (3.51), 7.834 (2.40), 7.839 (2.47), 8.260 (2.73), 8.264 (2.84), 8.744 (2.75), 8.749 (2.81), 12.160 (1.48).    Example 58 (rac)-N-ethyl-2'-[6-(trifluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000398_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.004 (1.41), 1.014 (1.94), 1.032 (4.43), 1.050 (2.07), 2.104 (0.74), 2.123 (0.86), 2.522 (0.71), 2.539 (16.00), 2.569 (0.86), 2.586 (1.30), 2.603 (0.88), 3.052 (0.86), 3.066 (0.97), 3.070 (0.96), 3.084 (0.84), 3.444 (0.68), 3.460 (2.46), 3.514 (0.43), 4.271 (0.84), 4.288 (1.32), 4.305 (0.82), 6.189 (0.72), 6.729 (3.00), 7.690 (0.47), 7.695 (0.49), 7.713 (0.52), 7.718 (0.55), 8.056 (0.93), 8.059 (0.91), 8.123 (1.21), 8.146 (1.08), 8.775 (1.18), 8.779 (1.22), 9.406 (1.64), 9.412 (1.65).    Example 59 (rac)-N-ethyl-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000399_0001
LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 460 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.854 (0.68), 1.005 (7.08), 1.023 (15.89), 1.040 (7.43), 1.234 (3.66), 1.259 (1.77), 1.298 (0.48), 1.336 (0.54), 1.366 (4.97), 1.374 (16.00), 1.382 (6.60), 1.389 (15.95), 1.453 (0.46), 2.039 (0.49), 2.051 (1.36), 2.069 (2.22), 2.088 (2.41), 2.107 (1.14), 2.119 (0.77), 2.526 (3.84), 2.534 (4.41), 2.553 (2.77), 3.023 (0.93), 3.041 (2.98), 3.055 (3.36), 3.059 (3.33), 3.073 (2.91), 3.090 (0.86), 3.379 (1.59), 3.386 (1.27), 3.404 (2.12), 3.426 (11.00), 3.493 (1.02), 3.512 (1.38), 3.526 (1.12), 3.551 (0.62), 3.599 (0.98), 3.834 (6.98), 3.849 (1.36), 4.011 (0.93), 4.191 (2.67), 4.209 (4.72), 4.226 (2.66), 4.595 (0.78), 4.611 (1.79), 4.628 (2.38), 4.644 (1.72), 4.660 (0.58), 5.346 (0.59), 5.761 (2.17), 6.146 (1.28), 6.159 (2.51), 6.173 (1.30), 6.355 (0.72), 6.358 (0.75), 6.389 (6.62), 6.394 (6.80), 6.563 (10.25), 6.962 (0.46), 7.090 (0.52), 7.218 (0.47), 7.557 (0.63), 7.560 (0.62), 7.580 (5.50), 7.584 (5.45), 7.684 (0.65), 7.697 (4.86), 7.704 (4.85), 7.985 (0.67), 8.143 (4.67), 8.148 (4.76), 8.741 (5.60), 8.746 (5.60), 12.145 (2.66), 12.150 (2.70).    Example 60 (rac)-N-[1-(3-chloropyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  Cl O N N H N N N N   Example 61 (rac)-N-cyclobutyl-2'-[6-(difluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000400_0001
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 455 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.309 (0.98), 1.326 (2.20), 1.344 (1.04), 1.495 (0.84), 1.515 (1.53), 1.522 (1.40), 1.541 (3.13), 1.560 (2.64), 1.586 (1.83), 1.902 (1.49), 1.930 (2.69), 1.953 (2.61), 1.979 (1.52), 2.002 (0.44), 2.079 (2.71), 2.094 (5.49), 2.113 (5.94), 2.129 (3.21), 2.142 (1.61), 2.336 (0.96), 2.518 (9.97), 2.522 (6.36), 2.563 (3.72), 2.580 (5.51), 2.598 (3.93), 3.402 (0.76), 3.420 (1.83), 3.428 (1.88), 3.446 (3.83), 3.457 (11.21), 3.483 (0.82), 3.501 (1.14), 3.520 (1.91), 3.533 (1.38), 3.540 (1.11), 3.559 (0.65), 4.100 (1.05), 4.121 (1.88), 4.142 (1.85), 4.162 (0.94), 4.264 (3.94), 4.282 (5.80), 4.299 (3.72), 4.312 (1.09), 6.336 (3.26), 6.356 (3.19), 6.686 (0.67), 6.729 (16.00), 6.736 (1.40), 7.216 (4.58), 7.400 (9.19), 7.549 (3.37), 7.556 (3.46), 7.572 (3.47), 7.578 (3.96), 7.584 (4.22), 7.755 (4.96), 7.761 (4.59), 7.865 (0.43), 7.871 (0.48), 8.052 (5.41), 8.074 (4.87), 8.679 (5.08), 8.684 (5.15), 9.331 (8.84), 9.337 (8.25), 9.354 (0.58), 9.359 (0.55).    Example 62 (rac)-N-ethyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000401_0001
  Example 63 (rac)-N-(propan-2-yl)-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000401_0002
  Example 64 (rac)-N-tert-butyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000401_0003
  Example 65 (rac)-2'-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000402_0001
LC-MS (Method 1): Rt = 0.70 min; MS (ESIpos): m/z = 454 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (4.81), 1.027 (10.78), 1.045 (4.97), 1.510 (15.93), 1.544 (16.00), 2.073 (1.00), 2.087 (1.39), 2.106 (1.68), 2.125 (0.66), 2.518 (0.79), 2.522 (0.60), 2.537 (1.46), 2.553 (2.29), 2.556 (2.32), 2.572 (1.61), 3.029 (0.49), 3.046 (1.56), 3.060 (1.76), 3.064 (1.74), 3.078 (1.52), 3.096 (0.47), 3.399 (2.42), 3.418 (1.18), 3.425 (1.72), 3.449 (5.42), 3.475 (0.43), 3.507 (0.57), 3.520 (0.67), 3.525 (0.84), 3.532 (0.61), 3.539 (0.67), 3.546 (0.54), 3.551 (0.52), 4.218 (1.67), 4.235 (2.79), 4.252 (1.59), 6.169 (0.63), 6.183 (1.18), 6.197 (0.61), 6.513 (1.14), 6.556 (1.31), 6.570 (1.24), 6.614 (1.31), 6.642 (7.17), 7.350 (1.38), 7.395 (1.30), 7.402 (1.48), 7.446 (1.22), 7.905 (2.47), 7.912 (2.46), 8.573 (2.50), 8.578 (2.68), 8.729 (3.78), 8.734 (3.49), 12.117 (1.48), 12.123 (1.51).    Example 66 (rac)-2'-{3-[(5-amino-4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000402_0002
LC-MS (Method 1): Rt = 0.82 min; MS (ESIpos): m/z = 481 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.006 (5.03), 1.024 (11.70), 1.041 (5.32), 1.765 (0.62), 2.069 (0.95), 2.087 (1.33), 2.106 (1.43), 2.125 (0.68), 2.137 (0.58), 2.142 (0.96), 2.145 (1.57), 2.153 (0.55), 2.183 (0.90), 2.230 (1.24), 2.327 (0.43), 2.332 (0.41), 2.345 (16.00), 2.435 (0.49), 2.518 (1.25), 2.522 (0.87), 2.533 (1.37), 2.550 (2.21), 2.553 (2.24), 2.569 (1.53), 3.027 (0.65), 3.045 (1.90), 3.058 (2.14), 3.062 (2.09), 3.076 (1.93), 3.094 (0.68), 3.373 (2.23), 3.391 (2.72), 3.397 (2.47), 3.409 (2.28), 3.417 (2.80), 3.506 (1.03), 3.519 (1.07), 3.525 (1.22), 3.532 (1.01), 3.538 (1.04), 3.545 (0.89), 3.551 (0.84), 3.563 (0.63), 4.220 (1.61), 4.237 (2.81), 4.255 (1.54), 6.160 (0.79), 6.174 (1.57), 6.188 (0.78), 6.632 (7.12), 7.830 (0.44), 7.834 (0.55), 7.894 (0.70), 7.904 (7.24), 7.912 (0.63), 7.953 (0.60), 7.980 (3.08), 7.987 (3.14), 8.034 (5.55), 8.330 (2.93), 8.335 (2.98), 8.756 (3.71), 8.761 (3.72), 12.251 (1.50), 12.257 (1.50).    Example 67 (rac)-N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide 
Figure imgf000403_0001
LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 389 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.495 (0.73), 1.514 (1.50), 1.521 (1.23), 1.533 (1.34), 1.541 (2.82), 1.547 (1.28), 1.560 (2.53), 1.585 (1.80), 1.907 (5.79), 1.931 (2.68), 1.954 (2.62), 1.980 (1.47), 2.003 (0.40), 2.074 (5.24), 2.079 (2.75), 2.093 (5.63), 2.100 (4.27), 2.111 (6.32), 2.119 (3.35), 2.129 (3.37), 2.142 (1.61), 2.160 (0.46), 2.331 (0.75), 2.518 (3.92), 2.522 (2.51), 2.539 (1.15), 2.562 (3.96), 2.580 (5.86), 2.597 (4.12), 2.673 (0.75), 3.403 (0.79), 3.421 (1.85), 3.429 (1.67), 3.439 (1.39), 3.447 (3.46), 3.457 (14.55), 3.483 (0.49), 3.506 (1.14), 3.525 (1.92), 3.532 (1.15), 3.539 (1.37), 3.547 (1.14), 3.551 (1.12), 3.565 (0.66), 4.101 (0.99), 4.122 (1.81), 4.143 (1.78), 4.163 (0.92), 4.260 (4.07), 4.278 (6.18), 4.295 (3.87), 5.770 (0.55), 6.337 (3.23), 6.357 (3.13), 6.733 (16.00), 7.590 (1.81), 7.593 (1.61), 7.610 (3.43), 7.627 (2.44), 7.630 (2.60), 7.704 (2.51), 7.708 (2.09), 7.722 (2.16), 7.726 (3.32), 7.729 (2.95), 7.743 (1.96), 7.746 (2.09), 7.993 (8.94), 8.014 (6.45), 8.017 (6.98), 8.662 (5.72), 8.667 (5.86), 9.350 (8.16), 9.356 (7.92).    Example 68 (rac)-N-(cyclopropylmethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000404_0001
LC-MS (Method 1): Rt = 1.01 min; MS (ESIneg): m/z = 387 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (1.10), 0.008 (1.07), 0.150 (1.56), 0.161 (5.94), 0.165 (5.33), 0.173 (6.01), 0.177 (5.58), 0.187 (2.10), 0.354 (2.10), 0.364 (5.08), 0.368 (5.48), 0.374 (2.74), 0.379 (2.45), 0.384 (5.58), 0.389 (5.19), 0.399 (1.81), 0.914 (0.50), 0.919 (0.64), 0.932 (1.17), 0.935 (1.17), 0.939 (1.17), 0.943 (1.00), 0.951 (1.96), 0.959 (1.00), 0.964 (1.21), 0.968 (1.32), 0.980 (0.57), 0.983 (0.64), 0.988 (0.85), 1.162 (0.50), 1.234 (0.75), 1.906 (4.23), 2.077 (1.53), 2.086 (0.60), 2.098 (1.71), 2.112 (3.31), 2.130 (4.02), 2.148 (1.49), 2.161 (0.78), 2.334 (1.10), 2.339 (0.50), 2.521 (5.55), 2.525 (3.56), 2.542 (0.78), 2.575 (3.91), 2.592 (5.72), 2.609 (4.16), 2.676 (1.14), 2.681 (0.50), 2.909 (2.99), 2.911 (2.95), 2.925 (5.83), 2.940 (2.88), 2.943 (2.88), 3.418 (0.82), 3.436 (1.85), 3.443 (1.53), 3.453 (1.35), 3.461 (2.92), 3.477 (13.76), 3.503 (0.64), 3.524 (1.10), 3.542 (1.88), 3.549 (1.14), 3.557 (1.35), 3.564 (1.10), 3.567 (1.10), 3.582 (0.68), 4.268 (4.05), 4.287 (6.19), 4.304 (3.91), 5.775 (0.71), 6.266 (1.60), 6.279 (3.20), 6.294 (1.53), 6.737 (16.00), 7.594 (1.88), 7.596 (1.64), 7.611 (2.88), 7.613 (3.38), 7.631 (2.45), 7.634 (2.63), 7.708 (2.52), 7.712 (2.17), 7.726 (2.24), 7.729 (3.34), 7.733 (2.99), 7.746 (2.06), 7.750 (2.10), 7.997 (9.03), 7.999 (6.76), 8.017 (6.40), 8.021 (7.25), 8.661 (5.72), 8.667 (5.97), 9.352 (8.68), 9.357 (8.32).    Example 69 (rac)-N-ethyl-2-[3-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000405_0001
LC-MS (Method 1): Rt = 1.11 min; MS (ESIpos): m/z = 452 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (6.90), 1.026 (16.00), 1.044 (7.16), 2.070 (1.15), 2.074 (1.27), 2.086 (1.86), 2.105 (2.13), 2.124 (0.93), 2.136 (0.58), 2.518 (2.29), 2.522 (1.56), 2.536 (1.93), 2.552 (3.13), 2.556 (3.09), 2.572 (2.17), 3.028 (0.83), 3.046 (2.66), 3.060 (2.91), 3.063 (2.82), 3.077 (2.62), 3.095 (0.76), 3.374 (0.52), 3.393 (1.23), 3.400 (0.93), 3.412 (0.78), 3.418 (1.65), 3.445 (9.23), 3.511 (0.65), 3.524 (0.82), 3.529 (1.08), 3.536 (0.76), 3.542 (0.85), 3.549 (0.71), 3.554 (0.68), 3.568 (0.44), 4.218 (2.26), 4.236 (3.96), 4.253 (2.20), 6.157 (1.11), 6.171 (2.24), 6.185 (1.09), 6.659 (10.05), 7.368 (0.66), 7.372 (0.45), 7.377 (0.44), 7.386 (2.20), 7.394 (1.02), 7.400 (1.85), 7.404 (3.54), 7.408 (2.36), 7.412 (4.31), 7.416 (2.13), 7.427 (2.18), 7.431 (5.56), 7.443 (0.90), 7.447 (1.78), 7.453 (1.50), 7.547 (0.80), 7.549 (0.74), 7.555 (0.69), 7.564 (0.92), 7.574 (1.30), 7.580 (4.76), 7.583 (5.59), 7.587 (2.54), 7.595 (2.51), 7.600 (4.56), 7.603 (3.85), 7.612 (1.05), 7.621 (1.12), 7.624 (1.11), 7.641 (0.66), 7.645 (0.67), 7.931 (4.91), 7.938 (4.78), 8.345 (4.16), 8.350 (4.28), 8.758 (5.46), 8.763 (5.30), 12.188 (2.20), 12.194 (2.18).    Example 70 (rac)-N-ethyl-2'-{3-[(pyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000406_0002
LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 452 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.007 (7.24), 1.025 (16.00), 1.043 (7.35), 1.160 (0.58), 1.230 (1.45), 2.073 (1.40), 2.086 (2.45), 2.104 (2.86), 2.123 (1.13), 2.135 (0.64), 2.518 (3.83), 2.522 (2.56), 2.539 (2.61), 2.555 (3.99), 2.574 (2.63), 3.028 (0.92), 3.045 (2.98), 3.059 (3.44), 3.063 (3.41), 3.077 (2.91), 3.095 (0.88), 3.379 (0.64), 3.397 (1.41), 3.423 (1.87), 3.445 (10.61), 3.509 (0.78), 3.528 (1.31), 3.541 (1.06), 3.567 (0.51), 4.219 (2.63), 4.236 (4.64), 4.253 (2.53), 6.160 (1.24), 6.173 (2.38), 6.187 (1.22), 6.616 (0.41), 6.667 (9.52), 7.445 (1.64), 7.457 (1.77), 7.464 (1.82), 7.476 (1.75), 7.999 (3.37), 8.019 (2.35), 8.381 (4.98), 8.386 (5.23), 8.553 (1.89), 8.563 (1.87), 8.774 (4.29), 8.778 (4.29), 8.798 (2.70), 12.271 (1.29).    Example 71 (rac)-N-ethyl-2'-{3-[(pyridin-2-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000406_0001
LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 452 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (4.96), 1.027 (11.48), 1.045 (5.35), 1.230 (0.57), 2.072 (0.83), 2.083 (1.17), 2.090 (1.26), 2.110 (1.41), 2.129 (0.69), 2.140 (0.47), 2.518 (1.71), 2.522 (1.21), 2.539 (16.00), 2.555 (2.28), 2.558 (2.26), 2.574 (1.57), 3.028 (0.61), 3.046 (1.95), 3.060 (2.14), 3.063 (2.11), 3.078 (1.93), 3.096 (0.57), 3.374 (0.42), 3.393 (0.93), 3.400 (0.69), 3.411 (0.59), 3.418 (1.23), 3.447 (6.58), 3.510 (0.56), 3.523 (0.62), 3.530 (0.80), 3.536 (0.61), 3.542 (0.66), 3.549 (0.56), 3.555 (0.50), 4.224 (1.66), 4.242 (2.86), 4.259 (1.58), 6.157 (0.81), 6.170 (1.65), 6.184 (0.81), 6.657 (7.55), 7.357 (1.27), 7.360 (1.26), 7.369 (1.34), 7.372 (1.34), 7.376 (1.40), 7.379 (1.39), 7.388 (1.40), 7.391 (1.32), 7.655 (1.29), 7.658 (2.26), 7.660 (1.29), 7.675 (1.65), 7.678 (2.74), 7.680 (1.53), 7.819 (1.51), 7.824 (1.47), 7.839 (2.09), 7.844 (2.23), 7.858 (1.11), 7.863 (1.10), 8.033 (3.10), 8.040 (3.05), 8.368 (3.13), 8.373 (3.24), 8.588 (1.42), 8.591 (1.56), 8.592 (1.60), 8.595 (1.42), 8.600 (1.45), 8.603 (1.62), 8.604 (1.48), 8.607 (1.34), 8.771 (3.97), 8.776 (3.84), 12.310 (1.46), 12.316 (1.46).    Example 72 (rac)-N-[(3-methyloxetan-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000407_0001
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 419 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (10.55), 1.212 (16.00), 1.892 (10.93), 2.077 (3.55), 2.117 (0.79), 2.132 (1.62), 2.150 (1.79), 2.168 (0.72), 2.334 (0.54), 2.521 (2.69), 2.525 (1.77), 2.542 (1.72), 2.581 (1.86), 2.599 (2.83), 2.616 (1.98), 2.676 (0.53), 3.168 (0.52), 3.176 (0.61), 3.191 (0.66), 3.210 (1.97), 3.225 (2.17), 3.230 (2.23), 3.246 (2.15), 3.265 (1.14), 3.281 (1.49), 3.449 (0.67), 3.470 (1.92), 3.495 (3.62), 3.510 (0.79), 3.522 (3.20), 3.547 (1.40), 3.556 (0.66), 3.575 (1.02), 3.582 (0.63), 3.590 (0.72), 3.597 (0.63), 4.143 (3.20), 4.151 (3.25), 4.157 (3.52), 4.165 (3.30), 4.272 (2.03), 4.290 (3.20), 4.307 (1.93), 4.440 (2.86), 4.454 (5.22), 4.468 (2.51), 6.414 (0.69), 6.429 (1.36), 6.444 (0.67), 6.720 (7.30), 7.595 (0.94), 7.597 (0.85), 7.612 (1.44), 7.615 (1.90), 7.632 (1.23), 7.635 (1.28), 7.709 (1.26), 7.712 (1.14), 7.726 (1.05), 7.729 (1.86), 7.733 (1.51), 7.747 (0.98), 7.750 (1.06), 7.996 (3.79), 8.018 (3.44), 8.646 (2.80), 8.651 (2.83), 9.341 (4.04), 9.346 (4.00).    Example 73 (rac)-N-propyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide 
Figure imgf000408_0001
LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 377 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (3.67), 0.827 (1.65), 0.846 (3.97), 0.864 (1.86), 1.193 (0.43), 1.212 (2.46), 1.408 (0.53), 1.426 (0.90), 1.444 (0.89), 1.462 (0.49), 1.882 (16.00), 2.106 (0.66), 2.124 (0.81), 2.526 (0.77), 2.543 (4.23), 2.567 (0.74), 2.583 (1.28), 2.601 (1.15), 2.972 (0.49), 2.987 (0.82), 3.006 (0.83), 3.022 (0.51), 3.211 (0.45), 3.227 (0.48), 3.231 (0.49), 3.246 (0.47), 3.389 (0.48), 3.405 (0.53), 3.424 (0.74), 3.431 (0.70), 3.449 (1.00), 3.465 (3.30), 3.496 (0.97), 3.511 (0.72), 3.523 (1.03), 3.548 (0.74), 3.571 (0.57), 3.591 (0.44), 4.144 (0.54), 4.151 (0.55), 4.158 (0.60), 4.166 (0.54), 4.265 (0.82), 4.272 (0.53), 4.283 (1.36), 4.289 (0.85), 4.300 (0.88), 4.441 (0.45), 4.455 (0.81), 4.469 (0.41), 6.192 (0.59), 6.721 (1.14), 6.728 (2.91), 7.597 (0.40), 7.614 (0.83), 7.634 (0.67), 7.709 (0.57), 7.712 (0.52), 7.729 (0.90), 7.732 (0.76), 7.746 (0.48), 7.750 (0.52), 7.997 (2.16), 8.018 (1.74), 8.646 (0.41), 8.651 (0.47), 8.659 (1.05), 8.664 (1.12), 9.341 (0.61), 9.350 (1.52), 9.355 (1.52).    Example 74 (rac)-N-tert-butyl-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000408_0002
  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.240 (0.80), 1.256 (1.74), 1.282 (16.00), 1.794 (0.59), 1.806 (0.61), 2.047 (0.54), 2.060 (0.53), 2.074 (0.46), 2.539 (1.98), 3.398 (0.93), 3.407 (1.41), 3.424 (1.34), 3.450 (0.44), 4.120 (0.61), 4.135 (1.25), 4.149 (0.61), 5.337 (1.29), 6.685 (2.21), 7.685 (1.23), 7.691 (1.24), 8.169 (1.16), 8.173 (1.19), 8.720 (1.32), 8.725 (1.30), 12.007 (0.69).    Example 75 (rac)-N-ethyl-2'-{3-[(pyridin-4-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000409_0001
LC-MS (Method 1): Rt = 0.84 min; MS (ESIpos): m/z = 452 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.012 (6.61), 1.030 (16.00), 1.048 (7.20), 1.065 (2.47), 1.156 (0.47), 1.232 (0.94), 2.077 (1.08), 2.090 (1.91), 2.108 (2.54), 2.126 (0.92), 2.139 (0.49), 2.336 (0.42), 2.460 (0.47), 2.518 (5.06), 2.522 (3.41), 2.533 (0.59), 2.543 (1.74), 2.560 (3.04), 2.563 (2.96), 2.579 (2.07), 2.678 (0.45), 3.031 (0.75), 3.049 (2.31), 3.063 (2.54), 3.067 (2.52), 3.081 (2.28), 3.098 (0.75), 3.385 (6.54), 3.404 (5.25), 3.423 (3.11), 3.430 (3.58), 3.449 (10.42), 3.512 (0.99), 3.530 (1.34), 3.537 (0.96), 3.544 (1.04), 3.551 (0.87), 3.556 (0.89), 3.570 (0.59), 4.225 (2.16), 4.243 (3.76), 4.260 (2.12), 6.162 (0.92), 6.176 (1.74), 6.190 (0.85), 6.672 (10.33), 7.590 (5.84), 7.594 (3.51), 7.601 (3.51), 7.605 (6.00), 8.060 (4.68), 8.067 (4.71), 8.404 (3.98), 8.409 (4.12), 8.618 (6.68), 8.622 (3.98), 8.630 (3.62), 8.633 (6.45), 8.785 (5.55), 8.790 (5.44), 12.380 (2.00), 12.386 (1.98).    Example 76 (rac)-N-tert-butyl-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000410_0001
LC-MS (Method 1): Rt = 0.95 min; MS (ESIneg): m/z = 457 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.034 (1.22), 1.051 (2.31), 1.069 (1.28), 1.271 (16.00), 2.081 (0.48), 2.517 (0.70), 2.534 (0.98), 2.551 (0.64), 3.383 (0.58), 3.390 (0.53), 3.408 (0.80), 3.412 (0.90), 3.430 (2.72), 3.432 (2.24), 3.447 (1.53), 3.461 (0.49), 3.464 (0.77), 3.518 (0.57), 3.531 (0.63), 3.537 (0.70), 3.543 (0.64), 3.549 (0.67), 3.556 (0.63), 3.562 (0.61), 3.575 (0.55), 3.601 (0.43), 3.905 (8.31), 4.197 (0.68), 4.215 (1.08), 4.232 (0.65), 5.332 (1.32), 6.515 (1.67), 6.519 (1.77), 6.597 (2.69), 7.516 (1.84), 7.521 (1.81), 7.839 (2.55), 8.255 (1.52), 8.260 (1.55), 8.739 (1.42), 8.744 (1.39).    Example 77 (rac)-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000410_0002
LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 446 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.033 (2.46), 1.050 (6.18), 1.055 (5.64), 1.065 (6.26), 1.068 (5.31), 1.071 (6.15), 1.081 (5.69), 2.045 (0.56), 2.064 (0.77), 2.076 (0.53), 2.085 (0.94), 2.104 (0.46), 2.522 (1.06), 2.539 (1.71), 2.556 (1.09), 3.428 (10.76), 3.433 (10.46), 3.445 (5.31), 3.463 (2.30), 3.510 (0.82), 3.523 (0.79), 3.529 (0.89), 3.535 (0.71), 3.542 (0.72), 3.549 (0.62), 3.554 (0.58), 3.568 (0.43), 3.738 (0.49), 3.755 (0.70), 3.774 (0.71), 3.790 (0.48), 3.893 (0.79), 3.902 (16.00), 3.927 (0.59), 4.198 (1.16), 4.216 (2.06), 4.233 (1.13), 5.841 (1.13), 5.860 (1.11), 6.521 (3.26), 6.526 (3.25), 6.600 (4.80), 7.516 (3.40), 7.521 (3.34), 7.837 (4.78), 8.259 (2.75), 8.264 (2.87), 8.742 (2.63), 8.747 (2.58).    Example 78 (rac)-N-ethyl-2'-{3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000411_0001
LC-MS (Method 1): Rt = 0.94 min; MS (ESIneg): m/z = 464 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.944 (1.92), 0.960 (1.90), 1.012 (4.19), 1.030 (8.74), 1.047 (4.28), 1.058 (0.86), 1.876 (4.99), 2.079 (2.05), 2.093 (1.50), 2.113 (1.55), 2.132 (0.80), 2.144 (0.55), 2.531 (16.00), 2.555 (2.98), 2.574 (1.86), 3.033 (0.84), 3.050 (2.19), 3.065 (2.67), 3.082 (2.19), 3.100 (0.84), 3.377 (5.98), 3.395 (6.27), 3.420 (5.43), 3.512 (1.77), 3.531 (1.88), 3.544 (1.64), 3.569 (1.03), 4.224 (1.86), 4.242 (3.28), 4.259 (1.79), 6.168 (0.94), 6.182 (1.84), 6.196 (0.95), 6.643 (5.46), 7.373 (2.19), 7.385 (2.24), 8.001 (5.53), 8.348 (3.58), 8.353 (3.69), 8.410 (2.71), 8.422 (2.63), 8.700 (4.48), 8.771 (3.42), 8.775 (3.38).    Example 79 (rac)-2'-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000412_0002
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 431 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (6.63), 1.031 (16.00), 1.049 (7.00), 2.067 (1.08), 2.082 (1.80), 2.101 (2.25), 2.120 (0.91), 2.132 (0.58), 2.334 (0.59), 2.521 (3.25), 2.525 (2.19), 2.535 (2.15), 2.552 (3.17), 2.555 (3.17), 2.571 (2.27), 2.676 (0.62), 3.032 (0.79), 3.049 (2.55), 3.063 (2.81), 3.067 (2.68), 3.081 (2.51), 3.099 (0.73), 3.377 (0.50), 3.395 (1.17), 3.403 (0.86), 3.414 (0.73), 3.421 (1.71), 3.439 (9.96), 3.507 (0.65), 3.521 (0.79), 3.526 (1.05), 3.532 (0.71), 3.539 (0.80), 3.546 (0.66), 3.552 (0.66), 3.565 (0.42), 4.214 (2.35), 4.232 (3.95), 4.250 (2.27), 6.156 (1.00), 6.169 (2.03), 6.183 (0.99), 6.618 (10.80), 7.721 (4.28), 7.727 (4.40), 8.113 (3.80), 8.118 (3.92), 8.727 (5.03), 8.733 (5.05), 12.097 (1.77), 12.102 (1.80).    Example 80 ()-N-(propan-2-yl)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000412_0001
LC-MS (Method 1): Rt = 0.93 min; MS (ESIneg): m/z = 471 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.009 (0.47), 1.050 (11.29), 1.059 (13.06), 1.066 (12.20), 1.074 (11.87), 1.149 (4.30), 1.166 (8.72), 1.184 (4.57), 1.224 (1.15), 1.318 (1.43), 1.328 (1.52), 1.363 (10.86), 1.367 (11.74), 1.379 (11.36), 1.383 (11.66), 1.627 (8.20), 1.982 (16.00), 2.036 (1.23), 2.054 (1.93), 2.074 (11.52), 2.080 (2.67), 2.092 (1.10), 2.104 (0.72), 2.523 (5.59), 2.539 (3.37), 2.544 (2.54), 3.397 (3.77), 3.424 (9.61), 3.501 (0.89), 3.520 (1.23), 3.532 (1.06), 3.559 (0.58), 3.727 (0.93), 3.743 (1.44), 3.762 (1.40), 3.778 (0.90), 3.993 (1.24), 4.011 (3.66), 4.029 (3.58), 4.047 (1.12), 4.184 (2.30), 4.202 (4.35), 4.219 (2.19), 4.588 (0.46), 4.605 (1.24), 4.621 (1.73), 4.637 (1.31), 4.653 (0.57), 5.858 (2.24), 5.878 (2.19), 6.378 (5.68), 6.382 (5.77), 6.528 (1.25), 6.549 (8.38), 7.570 (4.86), 7.575 (4.64), 7.686 (7.96), 7.729 (1.38), 7.752 (0.49), 7.766 (1.24), 7.991 (0.78), 7.996 (0.77), 8.128 (4.93), 8.133 (5.08), 8.727 (4.70), 8.732 (4.76), 8.739 (0.99), 8.744 (0.84).    Example 81 (rac)-N-ethyl-2'-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide
Figure imgf000413_0001
LC-MS (Method 1): Rt = 0.94 min; MS (ESIneg): m/z = 417 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.948 (0.47), 1.009 (6.94), 1.026 (16.00), 1.044 (7.24), 1.128 (0.88), 2.050 (0.49), 2.062 (1.26), 2.079 (2.15), 2.097 (2.45), 2.116 (1.08), 2.128 (0.72), 2.518 (2.12), 2.523 (1.52), 2.534 (2.41), 2.550 (3.53), 2.553 (3.56), 2.569 (2.55), 3.027 (1.02), 3.045 (2.91), 3.059 (3.22), 3.063 (3.18), 3.077 (2.89), 3.095 (1.02), 3.394 (11.81), 3.420 (7.55), 3.436 (14.23), 3.503 (1.82), 3.517 (1.80), 3.521 (1.98), 3.528 (1.55), 3.535 (1.58), 3.542 (1.37), 3.547 (1.33), 3.561 (0.98), 4.215 (2.60), 4.233 (4.37), 4.250 (2.54), 6.159 (1.12), 6.172 (2.24), 6.186 (1.11), 6.638 (10.13), 8.157 (3.62), 8.160 (3.61), 8.302 (3.63), 8.304 (3.62), 8.812 (5.23), 8.817 (5.15).    Example 82 (rac)-N-tert-butyl-2-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000414_0001
LC-MS (Method 1): Rt = 1.02 min; MS (ESIneg): m/z = 485 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.224 (0.93), 1.264 (16.00), 1.364 (3.48), 1.369 (3.75), 1.380 (3.75), 1.385 (3.57), 2.024 (0.42), 2.039 (0.51), 2.054 (0.55), 2.079 (0.93), 2.525 (1.71), 2.544 (0.91), 3.523 (0.50), 4.184 (0.80), 4.201 (1.41), 4.218 (0.78), 4.601 (0.44), 4.618 (0.59), 4.634 (0.43), 5.323 (1.65), 6.382 (1.70), 6.548 (2.05), 7.577 (1.65), 7.691 (1.29), 8.132 (1.48), 8.731 (1.46), 12.145 (0.89).    Example 83 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000414_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (7.16), 1.027 (16.00), 1.045 (7.36), 1.879 (0.84), 1.881 (0.80), 1.886 (0.77), 1.900 (0.87), 1.907 (1.31), 1.928 (0.58), 1.984 (0.77), 2.007 (1.60), 2.031 (1.53), 2.057 (2.02), 2.074 (3.43), 2.094 (2.22), 2.112 (1.06), 2.125 (1.15), 2.147 (1.73), 2.152 (1.59), 2.170 (2.04), 2.175 (2.35), 2.197 (1.57), 2.219 (0.42), 2.223 (0.46), 2.331 (1.09), 2.335 (1.18), 2.342 (1.08), 2.348 (0.82), 2.355 (1.80), 2.362 (2.66), 2.369 (1.44), 2.376 (1.49), 2.383 (2.44), 2.390 (1.42), 2.397 (0.62), 2.404 (0.77), 2.411 (0.58), 2.518 (4.46), 2.523 (4.72), 2.539 (11.50), 2.559 (2.70), 2.673 (0.78), 3.028 (0.89), 3.046 (2.84), 3.060 (3.13), 3.063 (3.10), 3.077 (2.77), 3.095 (0.82), 3.374 (0.91), 3.393 (1.51), 3.400 (1.17), 3.419 (2.26), 3.432 (10.90), 3.499 (0.77), 3.513 (0.95), 3.517 (1.20), 3.524 (0.84), 3.531 (0.97), 3.537 (0.78), 3.543 (0.75), 3.556 (0.49), 3.678 (1.28), 3.698 (1.95), 3.719 (1.20), 4.198 (2.68), 4.215 (4.56), 4.232 (2.57), 6.158 (1.15), 6.172 (2.28), 6.186 (1.11), 6.521 (11.41), 7.274 (3.57), 7.278 (3.54), 8.201 (4.43), 8.206 (4.52), 8.600 (5.61), 8.605 (5.39), 11.346 (2.46), 11.351 (2.44).    Example 84 (rac)-N-tert-butyl-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000415_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.279 (16.00), 2.012 (0.43), 2.039 (0.57), 2.056 (0.49), 2.070 (0.42), 2.088 (0.48), 2.152 (0.47), 2.158 (0.44), 2.175 (0.57), 2.181 (0.67), 2.203 (0.45), 2.357 (0.45), 2.364 (0.66), 2.385 (0.59), 2.520 (2.43), 2.524 (1.87), 2.542 (3.27), 2.559 (0.73), 3.419 (0.52), 3.435 (1.59), 3.439 (1.72), 3.699 (0.47), 4.201 (0.64), 4.219 (1.09), 4.236 (0.63), 5.331 (1.21), 6.520 (2.52), 7.275 (0.88), 7.280 (0.89), 8.194 (1.06), 8.198 (1.09), 8.596 (1.21), 8.601 (1.20), 11.351 (0.62).    Example 85 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000415_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.063 (14.70), 1.073 (15.93), 1.079 (16.00), 1.089 (14.81), 1.882 (1.03), 1.885 (1.00), 1.890 (0.94), 1.904 (1.08), 1.911 (1.42), 1.933 (0.69), 1.938 (0.41), 1.988 (0.91), 2.011 (1.97), 2.034 (2.24), 2.054 (1.91), 2.061 (1.74), 2.065 (1.94), 2.070 (2.06), 2.081 (1.64), 2.092 (2.53), 2.110 (1.26), 2.122 (1.04), 2.127 (0.84), 2.131 (0.78), 2.151 (2.07), 2.156 (1.97), 2.173 (2.56), 2.179 (2.95), 2.201 (2.00), 2.227 (0.54), 2.325 (1.08), 2.329 (1.57), 2.334 (1.37), 2.338 (1.43), 2.344 (1.29), 2.350 (0.95), 2.357 (2.17), 2.365 (3.20), 2.371 (1.74), 2.379 (1.81), 2.385 (2.94), 2.393 (1.70), 2.399 (0.72), 2.406 (0.92), 2.414 (0.68), 2.520 (5.75), 2.525 (5.63), 2.543 (4.47), 2.547 (4.46), 2.562 (3.10), 2.667 (1.07), 2.671 (1.46), 2.676 (1.05), 3.377 (1.27), 3.395 (1.94), 3.403 (1.49), 3.411 (1.50), 3.421 (2.60), 3.439 (9.64), 3.465 (0.82), 3.512 (0.93), 3.526 (1.15), 3.531 (1.48), 3.538 (1.07), 3.545 (1.18), 3.551 (0.99), 3.557 (0.95), 3.571 (0.64), 3.657 (0.47), 3.680 (1.54), 3.700 (2.40), 3.720 (1.51), 3.744 (1.46), 3.761 (1.75), 3.780 (1.73), 3.796 (1.13), 3.813 (0.41), 4.201 (3.24), 4.219 (5.84), 4.236 (3.11), 5.827 (2.93), 5.847 (2.83), 6.520 (13.19), 7.278 (7.15), 8.199 (7.44), 8.204 (7.61), 8.600 (6.92), 8.605 (6.70), 11.350 (1.34).    Example 86 (rac)-N-ethyl-2'-[3-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000416_0001
LC-MS (Method 1): Rt = 1.07 min; MS (ESIneg): m/z = 439 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (7.04), 1.029 (16.00), 1.047 (7.37), 1.231 (0.60), 2.052 (0.42), 2.064 (1.17), 2.075 (1.44), 2.084 (1.56), 2.095 (1.04), 2.104 (1.89), 2.123 (0.94), 2.135 (0.67), 2.332 (1.34), 2.345 (15.13), 2.518 (5.95), 2.523 (3.97), 2.530 (2.33), 2.546 (3.32), 2.550 (3.37), 2.565 (2.28), 2.673 (1.04), 2.678 (0.47), 3.030 (0.84), 3.047 (2.75), 3.061 (3.03), 3.065 (2.98), 3.079 (2.70), 3.097 (0.79), 3.375 (0.52), 3.394 (1.19), 3.401 (0.97), 3.419 (1.76), 3.442 (9.55), 3.506 (0.69), 3.520 (0.84), 3.525 (1.12), 3.531 (0.79), 3.538 (0.89), 3.544 (0.74), 3.550 (0.67), 3.563 (0.45), 4.214 (2.28), 4.232 (3.99), 4.249 (2.23), 4.551 (0.64), 6.155 (1.14), 6.169 (2.31), 6.183 (1.14), 6.597 (10.47), 6.628 (0.72), 7.266 (4.37), 7.286 (4.96), 7.608 (6.33), 7.628 (5.46), 7.810 (3.40), 7.815 (3.40), 7.914 (0.60), 8.503 (4.47), 8.508 (4.81), 8.516 (0.52), 8.685 (5.31), 8.690 (5.18), 11.887 (2.11).    Example 87 (rac)-N-ethyl-2'-[3-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000417_0001
LC-MS (Method 1): Rt = 1.06 min; MS (ESIneg): m/z = 439 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (6.78), 1.027 (16.00), 1.045 (7.16), 1.232 (1.36), 1.251 (0.56), 2.052 (0.42), 2.065 (1.08), 2.075 (1.50), 2.084 (1.50), 2.090 (1.08), 2.109 (1.68), 2.127 (0.80), 2.139 (0.65), 2.332 (2.01), 2.336 (0.94), 2.392 (14.55), 2.400 (2.67), 2.518 (12.63), 2.522 (8.33), 2.539 (1.73), 2.545 (3.13), 2.549 (3.37), 2.565 (2.06), 2.673 (2.06), 2.678 (0.94), 3.028 (0.80), 3.046 (2.57), 3.059 (2.85), 3.063 (2.81), 3.077 (2.57), 3.095 (0.75), 3.372 (0.56), 3.390 (1.12), 3.396 (0.98), 3.415 (1.64), 3.444 (8.09), 3.507 (0.65), 3.519 (0.80), 3.526 (1.03), 3.532 (0.75), 3.538 (0.84), 3.545 (0.70), 3.551 (0.65), 3.564 (0.47), 4.216 (2.06), 4.234 (3.70), 4.251 (2.06), 4.551 (2.34), 5.657 (0.42), 5.673 (0.42), 6.157 (1.03), 6.170 (2.15), 6.184 (1.03), 6.602 (8.94), 6.634 (1.26), 7.079 (1.54), 7.098 (1.78), 7.336 (1.78), 7.356 (2.85), 7.376 (1.96), 7.513 (2.48), 7.526 (3.65), 7.528 (3.70), 7.834 (2.99), 7.839 (3.04), 7.940 (1.12), 8.508 (3.93), 8.513 (4.12), 8.522 (0.80), 8.550 (0.65), 8.690 (4.68), 8.695 (4.49), 8.763 (0.65), 8.768 (0.65), 11.920 (1.78).    Example 88 (rac)-N-ethyl-2'-[6-(methanesulfonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000417_0002
  Example 89 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000418_0001
  Example 90 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000418_0002
  Example 91 (rac)-N-ethyl-2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000418_0003
  Example 92 (rac)-N-tert-butyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  H
Figure imgf000419_0001
  Example 93 (rac)-N-[1-(3-fluoropyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000419_0002
Example 94 (rac)-N-[(1R)-1-phenylethyl]-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) 
Figure imgf000420_0001
(1R)-1-Phenylethan-1-amine (26.4 mg, 218 µmol) was dissolved in DMF (3.0 mL) and 1,1'- carbonyldiimidazole (35.4 mg, 218 µmol) and N,N-diisopropylethylamine (190 µL, 1.1 mmol) were added. It was stirred 1 h at rt then (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) (70.0 mg, 182 µmol) was added and stirred for 2 h at 60 °C. Water was added and the reaction mixture was purified by HPLC to yield 22.0 mg (98 % purity, 24 % yield) of the title compound.  LC-MS (Method 1): Rt = 1.24 min; MS (ESIneg): m/z = 494 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.351 (13.97), 1.366 (16.00), 1.375 (3.28), 1.383 (3.08), 1.392 (2.81), 2.094 (0.56), 2.110 (0.93), 2.128 (0.85), 2.137 (0.64), 2.148 (0.42), 2.518 (0.97), 2.523 (0.64), 2.570 (1.19), 2.588 (2.02), 2.604 (1.29), 3.461 (0.44), 3.473 (0.79), 3.487 (0.74), 3.499 (1.40), 3.508 (1.87), 3.513 (1.83), 3.519 (1.35), 3.545 (0.47), 3.572 (0.52), 3.586 (0.49), 3.592 (0.52), 3.597 (0.42), 4.259 (1.26), 4.277 (2.23), 4.294 (1.22), 4.757 (0.58), 4.761 (0.63), 4.772 (0.81), 4.777 (0.83), 4.787 (0.61), 4.791 (0.61), 4.843 (0.61), 4.861 (0.90), 4.879 (0.59), 6.490 (0.82), 6.495 (0.85), 6.511 (0.81), 6.516 (0.79), 6.651 (2.42), 6.656 (3.60), 7.166 (0.85), 7.177 (0.44), 7.181 (0.54), 7.185 (0.63), 7.188 (0.42), 7.195 (0.85), 7.213 (0.63), 7.256 (0.86), 7.275 (1.75), 7.293 (1.80), 7.303 (1.69), 7.310 (3.05), 7.326 (2.59), 7.329 (3.41), 7.332 (3.41), 7.347 (1.08), 7.352 (1.01), 7.356 (1.73), 7.358 (1.82), 7.376 (1.14), 7.381 (2.06), 7.383 (1.82), 7.387 (1.51), 7.873 (2.33), 7.896 (2.13), 8.509 (2.07), 9.141 (1.85), 9.147 (2.15), 9.154 (1.91).    The following examples were synthesised analogously Example 95 (rac)-N-[(rac)-1-(1,2-oxazol-3-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000421_0002
LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 429 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.425 (7.52), 1.435 (8.09), 1.442 (8.05), 1.452 (7.61), 2.092 (0.57), 2.106 (1.44), 2.121 (2.90), 2.139 (3.20), 2.157 (1.28), 2.169 (0.68), 2.322 (0.73), 2.327 (1.00), 2.332 (0.73), 2.518 (4.00), 2.523 (2.58), 2.579 (3.80), 2.597 (5.64), 2.615 (4.00), 2.665 (0.71), 2.669 (1.01), 2.673 (0.73), 3.447 (0.44), 3.453 (0.48), 3.464 (1.08), 3.473 (2.51), 3.479 (1.23), 3.490 (2.10), 3.498 (4.44), 3.508 (8.25), 3.523 (3.38), 3.549 (1.42), 3.559 (1.07), 3.578 (1.87), 3.585 (1.12), 3.593 (1.33), 3.601 (1.12), 3.619 (0.66), 4.269 (3.66), 4.287 (5.92), 4.304 (3.52), 5.016 (1.49), 5.033 (2.22), 5.050 (1.48), 6.523 (5.12), 6.528 (5.21), 6.563 (4.60), 6.567 (4.84), 6.616 (2.65), 6.637 (2.54), 6.739 (16.00), 7.596 (1.80), 7.613 (3.43), 7.615 (3.20), 7.633 (2.61), 7.708 (2.12), 7.712 (1.90), 7.726 (1.99), 7.729 (3.09), 7.732 (2.61), 7.746 (1.74), 7.749 (1.80), 7.999 (7.36), 8.021 (6.49), 8.651 (2.97), 8.656 (5.65), 8.661 (3.24), 8.765 (4.02), 8.769 (4.04), 8.801 (4.32), 8.805 (4.20), 9.349 (8.82), 9.355 (8.92).    Example 96 (rac)-N-[2-(4-fluorophenyl)propan-2-yl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000421_0001
LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 460 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.238 (0.81), 1.253 (1.02), 1.269 (0.58), 1.564 (16.00), 2.050 (0.43), 2.062 (0.89), 2.076 (1.01), 2.094 (1.09), 2.114 (1.30), 2.131 (0.75), 2.144 (0.58), 2.518 (1.46), 2.523 (1.03), 2.535 (1.92), 2.551 (2.85), 2.554 (2.87), 2.570 (1.93), 3.387 (0.41), 3.404 (0.41), 3.422 (0.84), 3.446 (1.59), 3.470 (2.77), 3.485 (2.53), 3.511 (0.73), 3.556 (0.47), 3.574 (0.83), 3.587 (0.72), 4.212 (2.16), 4.229 (3.92), 4.246 (2.12), 6.090 (4.19), 6.457 (2.48), 6.462 (2.82), 6.466 (2.84), 6.470 (2.53), 6.490 (9.16), 7.034 (2.73), 7.039 (0.95), 7.056 (5.89), 7.073 (1.03), 7.078 (3.19), 7.367 (2.88), 7.372 (1.34), 7.381 (3.17), 7.389 (3.02), 7.397 (1.17), 7.403 (2.59), 7.465 (2.32), 7.472 (2.81), 7.479 (2.26), 8.247 (3.61), 8.252 (3.63), 8.641 (4.71), 8.646 (4.60), 11.659 (1.98).    Example 97 (rac)-2-(quinolin-3-yl)-N-(1H-tetrazol-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000422_0001
LC-MS (Method 1): Rt = 0.62 min; MS (ESIpos): m/z = 415 [M]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.751 (0.93), 1.832 (0.58), 1.857 (1.30), 1.885 (2.17), 1.907 (2.19), 1.911 (1.68), 1.936 (0.73), 1.945 (0.52), 2.084 (2.05), 2.092 (2.46), 2.102 (2.69), 2.122 (2.15), 2.137 (1.62), 2.240 (0.62), 2.259 (1.31), 2.278 (0.96), 2.290 (0.97), 2.308 (0.47), 2.518 (4.74), 2.523 (3.01), 2.540 (0.41), 3.659 (6.13), 3.686 (2.13), 3.705 (0.86), 3.732 (0.83), 3.753 (1.27), 3.765 (1.12), 3.793 (0.46), 4.192 (2.59), 4.207 (5.50), 4.223 (2.74), 6.777 (0.62), 6.909 (16.00), 7.589 (1.96), 7.592 (2.00), 7.606 (2.88), 7.609 (4.16), 7.612 (2.41), 7.627 (2.67), 7.629 (2.75), 7.706 (2.70), 7.710 (2.72), 7.723 (2.19), 7.727 (4.21), 7.730 (3.14), 7.744 (2.33), 7.747 (2.20), 7.998 (4.57), 8.007 (3.80), 8.010 (3.92), 8.018 (4.07), 8.027 (3.58), 8.030 (3.47), 8.658 (5.57), 8.663 (5.77), 9.336 (0.43), 9.347 (8.98), 9.353 (8.52).    Example 98 (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000423_0002
LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 512 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.350 (12.40), 1.365 (12.32), 1.601 (16.00), 2.112 (0.49), 2.126 (0.54), 2.143 (0.60), 2.162 (0.71), 2.179 (0.41), 2.518 (1.01), 2.523 (0.67), 2.590 (1.10), 2.608 (1.66), 2.625 (1.18), 3.481 (0.45), 3.506 (0.68), 3.527 (3.30), 3.609 (0.48), 4.274 (1.07), 4.291 (1.83), 4.309 (1.04), 4.763 (0.85), 4.779 (1.18), 4.794 (0.88), 6.464 (2.17), 6.701 (5.30), 7.171 (0.83), 7.174 (0.88), 7.183 (0.86), 7.186 (0.96), 7.190 (0.96), 7.192 (0.89), 7.202 (0.93), 7.204 (0.91), 7.305 (1.35), 7.312 (1.52), 7.328 (1.35), 7.335 (1.68), 7.391 (2.07), 7.398 (1.70), 7.471 (1.45), 7.491 (1.63), 7.693 (0.88), 7.698 (0.92), 7.712 (1.07), 7.717 (1.04), 7.732 (0.68), 7.736 (0.67), 7.876 (1.92), 7.900 (1.76), 8.454 (0.97), 8.457 (1.06), 8.459 (1.12), 8.461 (0.97), 8.466 (0.99), 8.469 (1.11), 8.471 (1.02), 8.473 (0.88), 8.522 (1.80), 8.527 (1.84), 9.156 (2.91), 9.161 (3.00).    Example 99 (rac)-N-[2-(pyridin-4-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000423_0001
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.55 (d, 6H), 2.06 - 2.21 (m, 2H), 2.56 - 2.64 (m, 2H), 3.44 - 3.56 (m, 3H), 3.57 - 3.65 (m, 1H), 4.30 (t, 2H), 6.26 (s, 1H), 6.74 (s, 1H), 7.32 - 7.36 (m, 2H), 7.62 (ddd, 1H), 7.74 (ddd, 1H), 8.00 - 8.04 (m, 2H), 8.41 - 8.45 (m, 2H), 8.65 (d, 1H), 9.36 (d, 1H).     Example 100 (rac)-N-{(rac)-1-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]ethyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000424_0001
LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 510 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.010 (0.73), 1.027 (0.58), 1.032 (0.42), 1.232 (0.58), 1.310 (0.42), 1.340 (7.50), 1.350 (8.50), 1.357 (8.50), 1.367 (7.71), 2.074 (1.15), 2.092 (1.73), 2.110 (3.46), 2.128 (3.72), 2.146 (1.73), 2.159 (1.00), 2.177 (0.47), 2.323 (0.84), 2.327 (1.21), 2.332 (0.89), 2.518 (6.61), 2.523 (4.04), 2.564 (3.57), 2.581 (6.03), 2.599 (3.67), 2.665 (0.94), 2.669 (1.26), 2.673 (0.94), 3.406 (0.63), 3.427 (2.62), 3.443 (2.89), 3.452 (3.99), 3.468 (4.88), 3.487 (1.84), 3.501 (3.72), 3.520 (3.72), 3.527 (2.99), 3.545 (3.10), 3.568 (1.42), 3.583 (0.89), 3.591 (0.79), 3.608 (0.47), 3.854 (15.16), 3.872 (1.15), 3.886 (16.00), 4.266 (4.35), 4.285 (8.13), 4.302 (4.20), 4.917 (0.42), 4.934 (1.68), 4.952 (2.52), 4.970 (1.68), 4.987 (0.47), 6.398 (3.20), 6.418 (3.10), 6.713 (15.16), 7.596 (1.99), 7.614 (3.72), 7.617 (3.67), 7.634 (2.99), 7.710 (2.36), 7.730 (3.88), 7.748 (2.20), 7.817 (4.09), 7.867 (4.04), 7.998 (6.98), 8.019 (6.66), 8.634 (3.20), 8.639 (3.41), 8.649 (3.72), 8.654 (3.62), 9.340 (4.98), 9.345 (9.65), 9.351 (5.04).    Example 101 (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers)  
Figure imgf000425_0002
LC-MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 516 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (2.91), 0.934 (0.93), 0.947 (3.03), 0.952 (0.50), 1.352 (15.90), 1.367 (16.00), 1.406 (3.18), 1.414 (3.33), 1.423 (3.40), 1.432 (3.18), 2.084 (0.41), 2.102 (0.58), 2.118 (1.05), 2.136 (0.99), 2.154 (0.49), 2.322 (0.50), 2.327 (0.72), 2.332 (0.52), 2.518 (3.50), 2.523 (2.22), 2.576 (1.60), 2.594 (2.51), 2.611 (1.70), 2.664 (0.52), 2.669 (0.75), 2.673 (0.54), 3.456 (0.46), 3.465 (1.06), 3.483 (0.93), 3.490 (1.55), 3.513 (3.09), 3.538 (1.06), 3.563 (0.92), 3.612 (0.40), 4.261 (1.46), 4.279 (2.52), 4.296 (1.43), 4.761 (0.99), 4.775 (1.32), 4.791 (0.98), 4.919 (0.71), 4.938 (1.10), 4.955 (0.74), 6.620 (0.85), 6.633 (0.96), 6.639 (0.99), 6.654 (3.07), 6.660 (4.43), 7.303 (1.47), 7.309 (1.72), 7.326 (1.50), 7.332 (1.91), 7.381 (1.59), 7.387 (2.63), 7.393 (1.36), 7.657 (0.41), 7.663 (0.54), 7.668 (0.45), 7.683 (0.41), 7.687 (0.56), 7.694 (0.52), 7.703 (0.57), 7.708 (0.45), 7.722 (0.41), 7.727 (0.56), 7.733 (0.43), 7.872 (2.60), 7.894 (2.38), 8.397 (1.69), 8.404 (1.69), 8.421 (1.83), 8.428 (1.79), 8.445 (0.87), 8.451 (1.61), 8.455 (0.92), 8.471 (0.88), 8.475 (1.60), 8.480 (0.89), 8.508 (2.43), 8.513 (2.48), 9.145 (4.20), 9.150 (4.39).    Example 102 (rac)-N-[(rac)-1-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000425_0001
LC-MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 456 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.118 (2.28), 1.134 (2.62), 1.138 (2.59), 1.155 (2.31), 1.289 (1.12), 1.307 (1.15), 1.330 (4.50), 1.343 (5.33), 1.347 (5.39), 1.361 (4.50), 2.058 (0.40), 2.074 (1.24), 2.088 (1.85), 2.106 (1.90), 2.124 (0.81), 2.137 (0.46), 2.160 (3.17), 2.186 (14.13), 2.202 (14.07), 2.322 (0.75), 2.327 (1.07), 2.332 (0.78), 2.518 (4.35), 2.523 (2.83), 2.539 (0.40), 2.550 (1.82), 2.567 (3.11), 2.570 (2.94), 2.585 (2.13), 2.665 (0.75), 2.669 (1.10), 2.673 (0.78), 3.401 (0.63), 3.409 (0.52), 3.419 (1.30), 3.426 (1.01), 3.433 (1.01), 3.444 (2.28), 3.459 (3.52), 3.464 (2.91), 3.479 (2.19), 3.489 (0.46), 3.504 (1.21), 3.521 (0.75), 3.542 (0.92), 3.557 (0.55), 3.649 (14.96), 3.655 (4.58), 3.671 (16.00), 4.256 (2.59), 4.273 (4.73), 4.290 (2.54), 4.751 (1.27), 4.770 (1.61), 4.789 (1.30), 6.172 (1.44), 6.177 (1.50), 6.193 (1.41), 6.197 (1.41), 6.687 (4.04), 6.704 (6.54), 7.244 (0.78), 7.290 (4.18), 7.319 (3.98), 7.591 (0.72), 7.594 (1.24), 7.597 (0.78), 7.611 (2.28), 7.615 (2.13), 7.632 (1.67), 7.706 (1.44), 7.710 (1.33), 7.723 (1.30), 7.727 (2.36), 7.730 (1.79), 7.744 (1.21), 7.747 (1.24), 7.996 (3.98), 8.014 (3.00), 8.017 (3.43), 8.029 (1.15), 8.033 (1.10), 8.547 (0.52), 8.645 (3.60), 8.650 (2.22), 9.338 (4.50), 9.343 (4.50).    Example 103 (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000426_0001
LC-MS (Method 4): Rt = 0.84 min; MS (ESIpos): m/z = 443 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.959 (0.40), 1.357 (4.27), 1.370 (5.64), 1.375 (5.16), 1.387 (5.00), 2.093 (0.99), 2.107 (1.81), 2.126 (1.96), 2.143 (0.75), 2.322 (0.44), 2.327 (0.63), 2.332 (0.46), 2.518 (2.88), 2.523 (1.81), 2.571 (2.28), 2.589 (3.43), 2.606 (2.47), 2.665 (0.46), 2.669 (0.65), 2.673 (0.48), 3.441 (0.67), 3.449 (0.63), 3.467 (1.88), 3.477 (0.69), 3.492 (3.47), 3.504 (2.58), 3.511 (2.38), 3.530 (0.75), 3.536 (1.09), 3.554 (0.62), 3.565 (0.61), 3.579 (0.83), 3.590 (0.49), 3.597 (0.60), 3.608 (0.43), 3.755 (16.00), 3.774 (15.04), 4.264 (2.36), 4.282 (3.76), 4.300 (2.31), 4.864 (0.94), 4.883 (1.39), 4.901 (0.97), 6.114 (2.75), 6.119 (2.79), 6.150 (2.36), 6.155 (2.39), 6.244 (1.29), 6.252 (1.19), 6.265 (1.28), 6.273 (1.12), 6.728 (9.67), 7.517 (2.43), 7.522 (2.47), 7.546 (2.25), 7.551 (2.26), 7.592 (1.07), 7.594 (0.98), 7.611 (2.04), 7.632 (1.53), 7.706 (1.54), 7.710 (1.29), 7.723 (1.35), 7.727 (2.25), 7.730 (1.83), 7.744 (1.25), 7.748 (1.33), 7.996 (5.27), 8.017 (3.98), 8.019 (4.47), 8.649 (1.88), 8.654 (3.56), 8.659 (2.17), 9.342 (2.73), 9.347 (5.17), 9.352 (3.17).    Example 104 (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3-thiazol-2-yl)ethyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000427_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.517 (12.41), 1.528 (13.08), 1.535 (13.59), 1.546 (11.96), 1.579 (0.45), 1.598 (0.39), 2.105 (0.45), 2.121 (0.90), 2.135 (2.36), 2.150 (4.44), 2.167 (4.44), 2.183 (1.85), 2.214 (0.39), 2.318 (1.07), 2.322 (2.30), 2.327 (3.20), 2.332 (2.36), 2.336 (1.01), 2.518 (12.74), 2.523 (8.08), 2.596 (5.11), 2.612 (8.20), 2.631 (5.84), 2.660 (1.07), 2.665 (2.36), 2.669 (3.31), 2.673 (2.41), 2.678 (1.07), 3.473 (0.90), 3.491 (1.74), 3.504 (3.31), 3.517 (3.65), 3.530 (5.89), 3.539 (6.40), 3.552 (5.73), 3.562 (1.63), 3.572 (5.05), 3.578 (2.47), 3.597 (3.82), 3.607 (1.85), 3.615 (1.57), 3.625 (2.36), 3.632 (1.24), 3.640 (1.57), 3.648 (1.12), 3.666 (0.62), 4.282 (4.88), 4.298 (8.98), 4.315 (4.72), 5.099 (0.51), 5.104 (0.56), 5.116 (2.19), 5.122 (2.41), 5.136 (2.98), 5.140 (3.09), 5.153 (2.36), 5.158 (2.25), 5.171 (0.62), 5.176 (0.56), 6.741 (10.61), 6.745 (16.00), 6.939 (3.54), 6.958 (3.54), 7.538 (6.12), 7.546 (6.68), 7.580 (8.42), 7.589 (9.94), 7.598 (3.03), 7.615 (5.73), 7.618 (5.16), 7.636 (4.38), 7.691 (9.32), 7.700 (8.31), 7.712 (12.69), 7.720 (9.49), 7.728 (3.65), 7.731 (5.39), 7.734 (4.49), 7.749 (2.92), 7.751 (3.03), 8.001 (13.64), 8.022 (10.72), 8.381 (0.79), 8.642 (4.27), 8.647 (4.55), 8.656 (4.77), 8.662 (4.88), 9.344 (7.07), 9.350 (7.97), 9.352 (8.76), 9.357 (7.64).    Example 105 (rac)-N-[(rac)-1-(1-phenyl-1H-pyrazol-4-yl)ethyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000428_0001
1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 - 1.47 (m, 3 H) 2.06 - 2.19 (m, 2 H) 2.60 (t, 2 H) 3.45 - 3.64 (m, 4 H) 4.29 (t, 2 H) 4.89 - 4.98 (m, 1 H) 6.37 and 6.39 (2s, 1 H) 6.74 (s, 1 H) 7.23 - 7.30 (m, 1 H) 7.42 - 7.51 (m, 2 H) 7.58 - 7.64 (m, 1 H) 7.67 - 7.75 (m, 2 H) 7.76 - 7.83 (m, 2 H) 7.97 - 8.03 (m, 2 H) 8.33 and 8.36 (2s, 1 H) 8.63 - 8.67 (m, 1 H) 9.34 - 9.37 (m, 1 H)   LC-MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 504 [M+H]+    Example 106 (rac)-N-[(rac)-1-(1-ethyl-5-methyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000428_0002
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 470 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.222 (3.90), 1.240 (9.98), 1.245 (4.93), 1.259 (4.55), 1.263 (10.38), 1.281 (4.36), 1.332 (4.69), 1.347 (6.27), 1.349 (6.30), 1.364 (4.82), 2.059 (0.44), 2.074 (1.12), 2.090 (2.06), 2.109 (2.13), 2.127 (0.93), 2.140 (0.53), 2.199 (16.00), 2.214 (15.62), 2.322 (0.72), 2.327 (1.03), 2.332 (0.74), 2.518 (4.38), 2.523 (2.76), 2.553 (2.15), 2.569 (3.43), 2.572 (3.37), 2.588 (2.44), 2.664 (0.70), 2.669 (1.03), 2.673 (0.72), 3.406 (0.67), 3.413 (0.61), 3.425 (1.28), 3.431 (1.20), 3.437 (1.10), 3.450 (2.51), 3.463 (3.73), 3.468 (3.16), 3.481 (2.51), 3.494 (0.53), 3.507 (1.41), 3.526 (0.88), 3.547 (1.01), 3.561 (0.61), 3.948 (1.12), 3.966 (3.73), 3.971 (1.54), 3.984 (3.85), 3.989 (4.08), 4.002 (1.39), 4.007 (3.75), 4.026 (1.10), 4.256 (2.84), 4.274 (5.14), 4.291 (2.76), 4.766 (1.26), 4.785 (1.70), 4.803 (1.26), 6.190 (1.73), 6.211 (1.64), 6.694 (4.72), 6.707 (6.76), 7.321 (4.67), 7.350 (4.44), 7.591 (0.82), 7.594 (1.35), 7.596 (0.88), 7.611 (2.53), 7.613 (2.36), 7.631 (1.98), 7.706 (1.62), 7.710 (1.52), 7.723 (1.47), 7.727 (2.65), 7.730 (1.96), 7.744 (1.41), 7.747 (1.41), 7.995 (4.61), 8.007 (1.52), 8.016 (3.85), 8.027 (1.31), 8.550 (0.46), 8.647 (3.79), 9.338 (6.21), 9.344 (6.15).    Example 107 (rac)-N-[(rac)-1-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000429_0001
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 484 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.192 (3.71), 1.206 (5.02), 1.210 (9.45), 1.224 (9.51), 1.228 (5.01), 1.242 (3.99), 1.338 (5.52), 1.349 (6.01), 1.357 (5.95), 1.366 (5.56), 2.057 (0.55), 2.070 (1.24), 2.087 (2.15), 2.106 (2.12), 2.136 (15.78), 2.162 (14.71), 2.201 (15.51), 2.219 (16.00), 2.323 (0.61), 2.327 (0.87), 2.332 (0.61), 2.518 (3.75), 2.523 (2.38), 2.555 (2.20), 2.572 (3.81), 2.589 (2.20), 2.665 (0.64), 2.669 (0.88), 2.673 (0.63), 3.410 (0.79), 3.422 (1.64), 3.433 (1.79), 3.447 (2.78), 3.457 (2.99), 3.464 (1.44), 3.479 (2.53), 3.494 (2.17), 3.504 (1.38), 3.519 (1.72), 3.538 (0.93), 3.557 (0.81), 3.564 (0.70), 3.571 (0.57), 3.579 (0.49), 3.855 (1.00), 3.874 (4.10), 3.891 (6.27), 3.910 (4.10), 3.927 (0.97), 4.256 (2.87), 4.273 (5.32), 4.291 (2.77), 4.715 (1.75), 4.732 (2.59), 4.749 (1.75), 6.100 (2.56), 6.117 (2.50), 6.684 (3.93), 6.703 (6.56), 7.591 (0.87), 7.594 (1.38), 7.597 (0.91), 7.611 (2.41), 7.614 (2.50), 7.631 (2.02), 7.706 (1.64), 7.709 (1.44), 7.727 (2.60), 7.744 (1.39), 7.747 (1.38), 7.994 (5.17), 8.016 (5.94), 8.034 (1.33), 8.635 (2.18), 8.644 (2.74), 8.650 (2.44), 9.336 (3.56), 9.340 (4.80), 9.345 (3.60).    Example 108 (rac)-N-[1-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000430_0001
LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 483 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (1.51), 0.934 (0.51), 0.948 (1.55), 1.629 (1.06), 1.722 (0.68), 1.732 (1.00), 1.739 (0.98), 1.751 (1.34), 1.910 (0.48), 1.923 (0.70), 1.941 (0.87), 1.953 (0.68), 1.971 (0.54), 2.080 (0.67), 2.094 (0.83), 2.107 (0.73), 2.125 (1.03), 2.142 (0.57), 2.322 (0.58), 2.327 (0.83), 2.332 (0.61), 2.387 (0.96), 2.402 (1.01), 2.422 (0.86), 2.518 (4.32), 2.523 (2.72), 2.539 (0.61), 2.557 (1.06), 2.562 (1.06), 2.573 (1.84), 2.580 (1.81), 2.592 (1.08), 2.596 (1.10), 2.664 (0.60), 2.669 (0.87), 2.673 (0.63), 3.423 (0.66), 3.430 (0.57), 3.449 (1.33), 3.476 (2.94), 3.482 (2.78), 3.508 (0.48), 3.519 (0.46), 3.538 (0.73), 3.545 (0.51), 3.552 (0.57), 3.560 (0.47), 3.839 (16.00), 4.264 (1.57), 4.282 (3.32), 4.300 (1.54), 6.067 (4.15), 6.072 (4.12), 6.220 (2.77), 6.685 (6.76), 7.178 (4.45), 7.183 (4.51), 7.598 (0.80), 7.601 (0.83), 7.615 (1.23), 7.618 (1.75), 7.621 (1.03), 7.636 (1.14), 7.638 (1.16), 7.711 (1.10), 7.714 (1.17), 7.728 (0.96), 7.732 (1.84), 7.735 (1.30), 7.749 (1.01), 7.752 (0.96), 8.000 (1.95), 8.007 (1.63), 8.011 (1.71), 8.020 (1.67), 8.028 (1.51), 8.031 (1.44), 8.636 (2.31), 8.642 (2.38), 9.336 (3.72), 9.342 (3.66).    Example 109 (rac)-N-[(rac)-1-(2-methylpyridin-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000431_0001
LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 454 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.916 (0.60), 0.931 (5.14), 0.934 (1.52), 0.947 (5.23), 0.952 (0.79), 1.348 (6.06), 1.356 (6.27), 1.366 (6.39), 1.373 (6.06), 2.095 (0.48), 2.111 (1.13), 2.126 (2.14), 2.142 (2.12), 2.159 (0.92), 2.167 (0.74), 2.179 (0.41), 2.322 (0.72), 2.327 (1.02), 2.332 (0.74), 2.406 (13.88), 2.422 (0.78), 2.444 (16.00), 2.518 (4.40), 2.523 (2.86), 2.586 (2.53), 2.603 (4.52), 2.620 (2.72), 2.664 (0.76), 2.669 (1.08), 2.673 (0.76), 3.473 (1.09), 3.479 (1.84), 3.490 (1.13), 3.499 (1.91), 3.504 (2.86), 3.524 (6.02), 3.544 (1.98), 3.559 (0.64), 3.570 (1.20), 3.577 (1.02), 3.585 (0.55), 3.593 (0.88), 3.614 (0.85), 3.620 (0.69), 3.628 (0.58), 3.636 (0.49), 4.275 (2.95), 4.291 (5.07), 4.309 (2.86), 4.775 (1.08), 4.793 (1.55), 4.808 (1.06), 6.577 (1.66), 6.583 (1.71), 6.597 (1.70), 6.603 (1.59), 6.716 (5.00), 6.726 (9.09), 7.123 (1.41), 7.136 (1.47), 7.162 (1.47), 7.172 (3.89), 7.207 (2.67), 7.596 (1.04), 7.598 (1.61), 7.601 (1.01), 7.616 (2.70), 7.618 (2.84), 7.636 (2.35), 7.710 (2.35), 7.713 (2.17), 7.727 (1.91), 7.730 (3.07), 7.734 (2.74), 7.747 (1.87), 7.751 (2.00), 7.998 (4.64), 8.001 (5.17), 8.009 (1.89), 8.022 (5.19), 8.312 (2.30), 8.324 (2.23), 8.350 (2.40), 8.363 (2.31), 8.636 (2.19), 8.641 (2.28), 8.651 (2.68), 8.656 (2.61), 9.347 (3.97), 9.352 (6.99), 9.357 (4.31).    Example 110 (rac)-N-[(rac)-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereosiomers) 
Figure imgf000432_0001
LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 444 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.927 (0.45), 0.930 (1.89), 0.933 (0.55), 0.943 (0.43), 0.946 (1.95), 1.449 (3.81), 1.459 (4.04), 1.466 (4.09), 1.477 (3.85), 2.075 (0.87), 2.087 (0.77), 2.101 (1.50), 2.119 (1.77), 2.137 (0.70), 2.148 (0.40), 2.327 (0.45), 2.518 (1.82), 2.523 (1.21), 2.558 (1.26), 2.575 (2.41), 2.594 (1.30), 2.669 (0.47), 3.441 (0.51), 3.449 (0.79), 3.459 (1.07), 3.467 (0.99), 3.476 (1.03), 3.488 (4.70), 3.499 (2.00), 3.525 (0.56), 3.541 (0.41), 3.554 (0.77), 3.559 (0.76), 3.567 (0.61), 3.574 (0.58), 3.580 (0.53), 3.843 (14.56), 3.856 (16.00), 4.257 (1.57), 4.273 (2.94), 4.290 (1.53), 5.075 (0.66), 5.079 (0.74), 5.094 (1.02), 5.112 (0.73), 5.116 (0.66), 6.668 (0.82), 6.681 (1.06), 6.687 (1.01), 6.700 (3.51), 6.717 (5.42), 6.724 (0.50), 7.594 (0.89), 7.612 (1.72), 7.614 (1.70), 7.632 (1.33), 7.707 (1.19), 7.710 (1.10), 7.725 (1.12), 7.728 (1.77), 7.731 (1.43), 7.745 (1.01), 7.749 (1.02), 7.784 (3.77), 7.803 (3.98), 7.996 (3.51), 7.998 (3.76), 8.020 (3.52), 8.639 (1.38), 8.645 (2.34), 8.652 (1.69), 9.340 (2.73), 9.342 (2.97), 9.345 (2.90), 9.347 (2.86).    Example 111 (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000433_0001
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 472 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (1.48), 1.251 (1.78), 1.267 (1.04), 1.727 (0.53), 1.731 (0.58), 1.737 (0.52), 1.748 (1.17), 1.753 (1.28), 1.771 (1.26), 1.776 (1.40), 1.793 (0.86), 1.956 (0.57), 1.963 (0.73), 1.978 (1.32), 1.993 (1.02), 2.001 (1.20), 2.005 (1.20), 2.021 (0.95), 2.028 (0.87), 2.043 (0.93), 2.054 (1.47), 2.069 (1.75), 2.083 (1.75), 2.100 (2.18), 2.119 (1.24), 2.131 (0.92), 2.149 (0.42), 2.349 (1.01), 2.376 (2.39), 2.387 (2.24), 2.393 (2.74), 2.414 (1.55), 2.455 (1.49), 2.472 (2.76), 2.478 (2.46), 2.522 (3.94), 2.537 (4.69), 2.542 (4.62), 2.558 (2.89), 2.575 (0.46), 3.383 (0.64), 3.388 (0.63), 3.401 (1.47), 3.408 (1.37), 3.420 (2.49), 3.426 (2.24), 3.445 (5.14), 3.461 (4.22), 3.487 (1.38), 3.526 (0.96), 3.545 (1.59), 3.557 (1.39), 3.564 (1.24), 3.584 (0.82), 3.618 (0.41), 3.624 (0.41), 3.633 (0.42), 3.738 (0.87), 4.201 (3.70), 4.219 (7.19), 4.236 (3.63), 6.465 (16.00), 6.471 (5.89), 6.475 (4.83), 6.736 (5.98), 7.063 (0.54), 7.071 (5.08), 7.076 (1.77), 7.088 (2.27), 7.093 (10.93), 7.099 (2.21), 7.110 (1.88), 7.115 (5.63), 7.124 (0.66), 7.432 (0.67), 7.440 (5.21), 7.445 (2.36), 7.453 (5.91), 7.462 (5.66), 7.469 (5.83), 7.476 (9.57), 7.484 (4.42), 8.248 (6.21), 8.252 (6.23), 8.634 (7.80), 8.639 (7.64), 11.682 (3.47).    Example 112 (rac)-N-(1-phenylcyclobutyl)-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000434_0001
LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 454 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.224 (0.49), 1.239 (1.94), 1.242 (1.43), 1.256 (3.44), 1.272 (1.66), 1.746 (0.52), 1.752 (0.64), 1.757 (0.49), 1.768 (1.13), 1.774 (1.18), 1.779 (0.83), 1.786 (0.83), 1.791 (1.22), 1.796 (1.39), 1.813 (0.84), 1.818 (0.69), 1.966 (0.56), 1.973 (0.73), 1.989 (1.31), 2.004 (0.96), 2.012 (1.16), 2.016 (1.20), 2.027 (0.96), 2.039 (1.02), 2.059 (1.48), 2.074 (1.85), 2.087 (1.63), 2.105 (2.14), 2.123 (1.19), 2.135 (0.88), 2.153 (0.40), 2.327 (0.57), 2.332 (0.41), 2.390 (2.01), 2.408 (2.29), 2.423 (1.47), 2.461 (1.38), 2.466 (1.47), 2.518 (3.06), 2.523 (3.57), 2.525 (3.65), 2.542 (4.66), 2.546 (4.54), 2.562 (3.04), 2.669 (0.57), 2.673 (0.41), 3.387 (0.87), 3.408 (1.40), 3.424 (2.39), 3.433 (2.01), 3.449 (4.54), 3.473 (3.80), 3.498 (1.50), 3.533 (0.81), 3.552 (1.37), 3.566 (1.18), 3.573 (1.05), 3.591 (0.67), 4.202 (3.67), 4.219 (7.05), 4.237 (3.59), 6.452 (16.00), 6.455 (7.75), 6.460 (5.95), 6.464 (5.74), 6.468 (5.19), 6.717 (6.32), 7.133 (1.11), 7.136 (1.93), 7.139 (1.13), 7.150 (1.48), 7.154 (4.81), 7.159 (1.65), 7.169 (1.92), 7.173 (3.44), 7.176 (1.82), 7.268 (5.50), 7.273 (2.09), 7.289 (8.55), 7.302 (1.75), 7.307 (5.11), 7.430 (7.45), 7.433 (8.24), 7.446 (2.12), 7.451 (6.96), 7.454 (5.41), 7.462 (4.58), 7.469 (4.92), 7.476 (4.12), 8.228 (6.08), 8.233 (6.39), 8.623 (8.86), 8.628 (8.65), 11.652 (3.28).    Example 113 (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) 
Figure imgf000435_0001
LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 446 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.959 (1.03), 1.403 (13.53), 1.410 (13.80), 1.420 (14.22), 1.428 (13.03), 2.082 (2.36), 2.095 (3.89), 2.115 (3.82), 2.124 (3.10), 2.133 (2.04), 2.142 (1.84), 2.154 (1.10), 2.323 (0.88), 2.327 (1.26), 2.331 (0.90), 2.518 (5.75), 2.523 (4.04), 2.542 (7.24), 2.560 (11.06), 2.577 (7.01), 2.665 (0.94), 2.669 (1.30), 2.673 (0.94), 3.416 (0.85), 3.435 (2.29), 3.449 (3.55), 3.460 (3.62), 3.474 (6.29), 3.492 (12.90), 3.517 (4.09), 3.543 (2.79), 3.553 (2.07), 3.567 (1.51), 3.592 (1.42), 3.609 (1.66), 3.622 (1.35), 3.648 (0.76), 4.207 (6.97), 4.224 (11.42), 4.241 (6.72), 4.910 (1.91), 4.918 (2.25), 4.928 (2.99), 4.936 (3.12), 4.946 (2.09), 4.954 (1.98), 6.446 (4.99), 6.450 (9.08), 6.455 (10.07), 6.459 (9.33), 6.463 (5.91), 6.470 (8.09), 6.492 (16.00), 6.550 (0.43), 6.607 (3.48), 6.619 (3.96), 6.626 (3.91), 6.639 (3.21), 7.457 (6.45), 7.465 (9.28), 7.472 (6.16), 7.657 (1.73), 7.663 (2.31), 7.668 (1.75), 7.683 (1.87), 7.688 (2.47), 7.693 (3.48), 7.699 (2.61), 7.704 (1.91), 7.719 (1.82), 7.724 (2.31), 7.730 (1.75), 8.236 (6.38), 8.241 (11.03), 8.246 (6.34), 8.407 (6.85), 8.413 (6.76), 8.424 (7.46), 8.430 (7.21), 8.443 (3.87), 8.448 (6.65), 8.452 (3.80), 8.464 (3.80), 8.469 (6.61), 8.473 (3.69), 8.629 (14.45), 8.634 (14.04), 11.643 (6.25).    Example 114 (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) 
Figure imgf000436_0001
LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 461 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.952 (1.12), 0.968 (1.03), 1.402 (5.13), 1.410 (4.85), 1.420 (5.30), 1.428 (4.53), 2.081 (0.87), 2.095 (1.52), 2.112 (1.55), 2.119 (1.26), 2.129 (0.74), 2.138 (0.65), 2.273 (9.94), 2.275 (16.00), 2.278 (11.20), 2.326 (0.45), 2.518 (1.32), 2.522 (0.91), 2.547 (2.45), 2.565 (3.94), 2.582 (2.53), 2.668 (0.43), 3.444 (0.88), 3.450 (1.54), 3.468 (1.58), 3.475 (2.31), 3.493 (4.72), 3.518 (1.50), 3.542 (0.95), 3.556 (0.71), 3.563 (0.45), 3.571 (0.51), 3.582 (0.42), 3.593 (0.46), 3.611 (0.62), 3.617 (0.45), 3.625 (0.47), 3.632 (0.45), 4.204 (2.47), 4.221 (4.00), 4.239 (2.31), 4.915 (0.93), 4.933 (1.37), 4.950 (0.88), 6.498 (3.30), 6.506 (6.48), 6.602 (1.33), 6.617 (1.49), 6.622 (1.56), 6.636 (1.10), 7.219 (3.37), 7.654 (0.59), 7.660 (0.77), 7.665 (0.62), 7.680 (0.63), 7.690 (1.24), 7.696 (0.96), 7.701 (0.71), 7.715 (0.74), 7.720 (0.88), 7.726 (0.66), 8.194 (2.66), 8.198 (4.43), 8.202 (2.56), 8.401 (2.52), 8.408 (2.46), 8.416 (3.05), 8.423 (2.93), 8.442 (1.27), 8.447 (2.31), 8.452 (1.28), 8.464 (1.42), 8.468 (2.53), 8.473 (1.38), 8.608 (4.29), 8.613 (4.06), 11.282 (2.56).    Example 115 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000437_0002
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 457 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.242 (0.71), 1.246 (0.49), 1.258 (1.06), 1.276 (0.64), 1.598 (16.00), 2.089 (0.47), 2.104 (0.55), 2.119 (0.62), 2.137 (0.73), 2.155 (0.41), 2.276 (8.40), 2.279 (8.58), 2.518 (0.95), 2.523 (0.63), 2.563 (1.12), 2.580 (1.74), 2.597 (1.20), 3.463 (0.49), 3.479 (0.56), 3.488 (0.72), 3.504 (2.30), 3.609 (0.51), 3.615 (0.45), 3.623 (0.43), 4.217 (1.17), 4.235 (1.91), 4.252 (1.12), 6.449 (1.96), 6.542 (6.03), 7.183 (0.51), 7.200 (0.64), 7.213 (0.60), 7.223 (1.29), 7.225 (1.60), 7.228 (1.58), 7.231 (1.23), 7.478 (0.90), 7.498 (1.04), 7.705 (0.41), 7.721 (0.66), 8.206 (2.08), 8.210 (2.07), 8.457 (0.90), 8.459 (1.04), 8.461 (1.05), 8.463 (0.93), 8.469 (0.92), 8.471 (1.05), 8.473 (0.96), 8.475 (0.82), 8.621 (2.78), 8.625 (2.68), 11.291 (1.14), 11.296 (1.13).    Example 116 (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000437_0001
LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 486 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.946 (2.17), 0.963 (2.04), 1.753 (0.67), 1.758 (0.68), 1.775 (0.71), 1.780 (0.81), 1.797 (0.48), 1.966 (0.42), 1.982 (0.74), 1.997 (0.55), 2.004 (0.67), 2.009 (0.68), 2.025 (0.55), 2.032 (0.47), 2.047 (0.48), 2.057 (0.82), 2.075 (1.09), 2.088 (0.84), 2.099 (1.29), 2.117 (0.77), 2.130 (0.49), 2.274 (15.37), 2.277 (16.00), 2.327 (0.47), 2.347 (0.53), 2.371 (1.21), 2.379 (1.37), 2.386 (1.19), 2.394 (1.60), 2.401 (1.31), 2.416 (0.94), 2.447 (0.92), 2.472 (1.75), 2.518 (2.04), 2.523 (1.60), 2.527 (1.56), 2.544 (2.56), 2.550 (2.60), 2.565 (1.53), 2.669 (0.42), 3.409 (0.86), 3.422 (1.26), 3.434 (1.27), 3.447 (2.81), 3.464 (2.35), 3.489 (0.75), 3.532 (0.47), 3.551 (0.83), 3.565 (0.68), 3.572 (0.60), 4.200 (2.14), 4.217 (4.27), 4.235 (2.07), 6.486 (9.02), 6.731 (3.70), 7.067 (3.35), 7.072 (1.05), 7.084 (1.24), 7.090 (6.68), 7.095 (1.24), 7.106 (1.06), 7.112 (3.71), 7.223 (2.86), 7.226 (2.84), 7.228 (2.24), 7.438 (3.32), 7.444 (1.36), 7.452 (3.66), 7.460 (3.38), 7.468 (1.21), 7.474 (2.96), 8.188 (3.76), 8.192 (3.83), 8.607 (5.06), 8.612 (4.91), 11.290 (2.12), 11.294 (2.12).    Example 117 (rac)-N-[2-(4-fluorophenyl)propan-2-yl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000438_0001
LC-MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 474 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.028 (0.51), 1.043 (0.45), 1.556 (12.80), 1.568 (13.58), 2.050 (0.45), 2.064 (0.93), 2.079 (1.16), 2.093 (1.04), 2.110 (1.42), 2.127 (0.82), 2.140 (0.57), 2.279 (15.82), 2.281 (16.00), 2.327 (0.45), 2.518 (1.57), 2.523 (1.11), 2.541 (1.98), 2.558 (3.01), 2.561 (3.04), 2.577 (2.10), 2.669 (0.44), 3.428 (0.87), 3.435 (0.82), 3.446 (1.51), 3.452 (1.30), 3.471 (3.07), 3.489 (2.54), 3.515 (0.84), 3.561 (0.51), 3.579 (0.91), 3.594 (0.73), 3.601 (0.68), 4.209 (2.32), 4.227 (4.21), 4.245 (2.24), 6.088 (4.65), 6.507 (12.02), 7.029 (3.31), 7.034 (1.08), 7.046 (1.28), 7.052 (6.78), 7.057 (1.32), 7.068 (1.10), 7.074 (3.74), 7.225 (2.40), 7.227 (3.07), 7.230 (3.09), 7.233 (2.43), 7.366 (3.23), 7.371 (1.46), 7.379 (3.67), 7.388 (3.42), 7.396 (1.27), 7.401 (2.99), 8.199 (4.00), 8.203 (4.19), 8.620 (5.41), 8.625 (5.28), 11.296 (2.24), 11.300 (2.26).    Example 118 (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-phenylpentan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000439_0001
LC-MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 468 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.773 (0.66), 1.778 (0.69), 1.784 (0.49), 1.789 (0.49), 1.794 (0.70), 1.800 (0.81), 1.817 (0.49), 1.822 (0.41), 1.977 (0.41), 1.992 (0.77), 2.007 (0.56), 2.015 (0.68), 2.019 (0.70), 2.030 (0.56), 2.043 (0.62), 2.061 (0.87), 2.078 (1.13), 2.093 (0.86), 2.102 (1.31), 2.120 (0.78), 2.133 (0.47), 2.277 (15.36), 2.280 (16.00), 2.327 (0.41), 2.364 (0.66), 2.379 (0.80), 2.386 (1.19), 2.394 (1.50), 2.401 (1.10), 2.410 (1.80), 2.416 (1.42), 2.432 (1.09), 2.461 (0.86), 2.518 (1.83), 2.523 (1.36), 2.533 (1.98), 2.550 (2.71), 2.553 (2.73), 2.569 (1.90), 3.425 (1.60), 3.450 (2.58), 3.477 (2.16), 3.503 (0.92), 3.540 (0.47), 3.558 (0.84), 3.572 (0.67), 3.579 (0.61), 4.201 (2.13), 4.219 (4.02), 4.236 (2.08), 6.474 (9.06), 6.715 (3.78), 7.129 (0.62), 7.131 (1.15), 7.135 (0.69), 7.145 (0.84), 7.150 (2.87), 7.154 (1.01), 7.165 (1.11), 7.168 (1.98), 7.171 (1.07), 7.223 (2.21), 7.226 (2.87), 7.228 (2.86), 7.231 (2.27), 7.267 (3.21), 7.271 (1.29), 7.287 (5.10), 7.300 (1.03), 7.305 (2.97), 7.430 (4.40), 7.433 (4.82), 7.446 (1.20), 7.451 (3.91), 7.454 (3.06), 8.185 (3.75), 8.189 (3.82), 8.604 (5.01), 8.609 (4.94), 11.291 (2.08), 11.296 (2.11).    Example 119 (rac)-N-[(rac)-1-(1-methyl-1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000440_0001
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 441 [M]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.427 (4.34), 1.439 (5.27), 1.443 (5.18), 1.456 (4.48), 1.907 (0.41), 2.074 (0.58), 2.083 (0.85), 2.099 (1.68), 2.115 (1.98), 2.132 (0.80), 2.327 (0.51), 2.518 (1.91), 2.523 (1.20), 2.559 (1.38), 2.567 (1.71), 2.575 (2.10), 2.587 (1.25), 2.594 (1.31), 2.669 (0.55), 2.673 (0.41), 3.401 (1.48), 3.419 (1.78), 3.427 (1.66), 3.445 (2.69), 3.450 (2.37), 3.471 (3.10), 3.476 (3.60), 3.497 (2.94), 3.511 (3.06), 3.523 (1.76), 3.537 (2.17), 3.550 (1.19), 3.561 (1.30), 3.566 (1.27), 3.581 (1.35), 3.617 (15.61), 4.255 (2.02), 4.272 (3.57), 4.290 (1.96), 5.010 (1.30), 5.028 (1.45), 5.030 (1.48), 5.047 (1.26), 6.447 (0.98), 6.458 (1.10), 6.467 (1.04), 6.478 (0.99), 6.704 (3.91), 6.709 (5.66), 6.758 (2.73), 6.761 (2.92), 6.782 (2.94), 6.786 (2.81), 7.019 (2.76), 7.022 (2.82), 7.044 (2.87), 7.047 (2.71), 7.592 (0.92), 7.611 (1.92), 7.631 (1.39), 7.706 (1.35), 7.710 (1.12), 7.723 (1.17), 7.727 (2.01), 7.730 (1.66), 7.744 (1.09), 7.747 (1.18), 7.996 (5.06), 8.017 (3.72), 8.019 (4.06), 8.152 (16.00), 8.640 (1.70), 8.645 (3.19), 8.651 (1.85), 9.338 (3.01), 9.340 (3.34), 9.344 (3.18), 9.345 (3.14).    Example 120 (rac)-N-[(rac)-1-(1-methyl-1H-benzimidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000441_0001
LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 492 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.553 (4.80), 1.565 (5.32), 1.570 (5.45), 1.581 (4.78), 2.092 (1.03), 2.108 (2.02), 2.126 (2.29), 2.143 (0.92), 2.156 (0.49), 2.322 (0.72), 2.327 (1.01), 2.332 (0.74), 2.518 (4.26), 2.523 (2.69), 2.564 (1.68), 2.580 (2.63), 2.592 (1.48), 2.599 (1.57), 2.665 (0.72), 2.669 (1.05), 2.673 (0.76), 3.455 (0.67), 3.484 (1.48), 3.510 (5.59), 3.518 (3.46), 3.544 (0.67), 3.568 (0.96), 3.586 (0.92), 3.593 (0.76), 3.601 (0.58), 3.608 (0.63), 3.784 (16.00), 3.801 (15.73), 4.258 (1.88), 4.271 (3.43), 4.288 (1.84), 5.241 (0.85), 5.246 (0.96), 5.263 (1.24), 5.278 (0.96), 5.283 (0.83), 6.701 (1.19), 6.718 (11.04), 6.737 (1.14), 7.129 (0.54), 7.131 (0.58), 7.147 (1.84), 7.150 (1.95), 7.166 (2.33), 7.185 (2.20), 7.188 (2.16), 7.208 (2.02), 7.212 (1.37), 7.223 (0.78), 7.226 (1.28), 7.229 (1.50), 7.231 (1.37), 7.247 (0.78), 7.250 (0.65), 7.476 (1.46), 7.496 (1.28), 7.507 (1.64), 7.526 (1.35), 7.563 (1.43), 7.582 (1.46), 7.585 (1.61), 7.588 (1.71), 7.594 (1.37), 7.610 (2.51), 7.613 (2.42), 7.632 (1.70), 7.707 (1.84), 7.712 (1.75), 7.725 (1.53), 7.728 (2.92), 7.732 (2.11), 7.746 (1.57), 7.749 (1.53), 7.996 (4.11), 8.017 (3.61), 8.636 (1.98), 8.640 (3.72), 8.645 (2.20), 9.338 (4.71), 9.344 (4.58).    Example 121 (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3,4-trimethyl-1H-pyrazol-5-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000442_0002
LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 470 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.396 (5.58), 1.405 (6.05), 1.414 (6.00), 1.423 (5.77), 1.932 (13.91), 1.954 (13.93), 1.970 (14.95), 1.980 (14.37), 2.000 (0.47), 2.085 (1.26), 2.100 (2.23), 2.117 (2.21), 2.134 (1.00), 2.190 (0.44), 2.322 (0.81), 2.327 (1.16), 2.332 (0.84), 2.518 (5.07), 2.523 (3.14), 2.539 (0.70), 2.553 (1.12), 2.562 (2.33), 2.569 (2.12), 2.579 (3.72), 2.596 (2.28), 2.665 (0.88), 2.669 (1.23), 2.673 (0.93), 3.414 (0.81), 3.428 (1.56), 3.438 (2.02), 3.454 (2.30), 3.463 (2.88), 3.487 (1.16), 3.500 (2.44), 3.520 (2.51), 3.525 (2.28), 3.545 (1.44), 3.578 (0.77), 3.592 (0.56), 3.603 (0.56), 3.709 (16.00), 3.726 (15.16), 4.261 (2.67), 4.278 (5.07), 4.295 (2.56), 4.906 (0.98), 4.914 (1.05), 4.924 (1.35), 4.931 (1.30), 4.940 (1.05), 4.948 (1.00), 6.471 (2.02), 6.486 (2.00), 6.691 (3.56), 6.696 (7.70), 7.595 (1.37), 7.615 (2.67), 7.633 (2.12), 7.707 (1.70), 7.711 (1.67), 7.728 (2.67), 7.746 (1.51), 7.748 (1.44), 7.995 (4.93), 8.018 (4.79), 8.028 (1.44), 8.641 (4.49), 8.647 (2.67), 9.333 (3.33), 9.339 (6.35), 9.345 (3.56).    Example 122 (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000442_0001
LC-MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 470 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.109 (2.62), 1.125 (2.73), 1.137 (2.67), 1.154 (2.65), 1.285 (1.31), 1.303 (1.38), 1.336 (5.76), 1.345 (6.26), 1.354 (6.18), 1.363 (5.93), 2.055 (0.55), 2.069 (1.35), 2.075 (1.12), 2.086 (2.46), 2.095 (4.34), 2.105 (2.71), 2.118 (15.60), 2.146 (14.33), 2.168 (3.85), 2.190 (16.00), 2.207 (15.45), 2.323 (0.83), 2.327 (1.16), 2.332 (0.83), 2.518 (5.40), 2.522 (3.24), 2.552 (2.41), 2.562 (2.33), 2.570 (3.92), 2.587 (2.33), 2.665 (0.83), 2.669 (1.12), 2.673 (0.83), 3.382 (0.42), 3.401 (0.85), 3.415 (1.61), 3.425 (2.16), 3.439 (2.69), 3.450 (2.88), 3.461 (1.27), 3.476 (2.58), 3.491 (2.29), 3.501 (1.38), 3.516 (1.97), 3.535 (1.02), 3.553 (15.98), 3.561 (4.95), 3.571 (15.41), 3.594 (0.42), 4.256 (2.98), 4.273 (5.48), 4.290 (2.81), 4.679 (0.40), 4.696 (1.48), 4.714 (2.24), 4.732 (1.48), 6.109 (2.81), 6.126 (2.73), 6.679 (3.81), 6.698 (6.84), 7.595 (1.42), 7.612 (2.65), 7.615 (2.54), 7.632 (2.05), 7.707 (1.69), 7.727 (2.84), 7.745 (1.46), 7.747 (1.44), 7.995 (5.16), 8.017 (6.01), 8.035 (1.38), 8.634 (2.24), 8.642 (2.88), 8.648 (2.50), 9.334 (3.39), 9.339 (6.16), 9.344 (3.56).    Example 123 (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000443_0001
LC-MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 442 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.401 (4.42), 1.413 (5.13), 1.419 (5.17), 1.431 (4.60), 2.074 (0.44), 2.088 (1.06), 2.104 (1.99), 2.123 (2.03), 2.140 (0.88), 2.154 (0.49), 2.323 (0.44), 2.327 (0.57), 2.331 (0.44), 2.523 (2.74), 2.562 (2.08), 2.580 (3.45), 2.597 (2.21), 2.665 (0.44), 2.669 (0.62), 2.673 (0.44), 3.380 (1.19), 3.385 (1.15), 3.395 (0.71), 3.409 (0.44), 3.425 (0.75), 3.434 (0.62), 3.446 (1.28), 3.460 (0.97), 3.471 (2.43), 3.486 (5.17), 3.506 (2.39), 3.532 (1.19), 3.556 (0.80), 3.569 (0.80), 3.581 (0.62), 3.588 (0.66), 3.596 (0.49), 3.765 (16.00), 3.782 (16.00), 4.258 (2.52), 4.276 (4.64), 4.293 (2.48), 5.005 (1.10), 5.023 (1.55), 5.042 (1.10), 6.171 (2.34), 6.175 (2.34), 6.202 (2.30), 6.206 (2.30), 6.495 (1.15), 6.506 (1.33), 6.516 (1.24), 6.527 (1.19), 6.699 (3.62), 6.706 (5.70), 7.255 (2.39), 7.260 (2.39), 7.286 (2.52), 7.290 (2.48), 7.595 (1.10), 7.613 (2.25), 7.633 (1.77), 7.708 (1.55), 7.711 (1.50), 7.725 (1.41), 7.729 (2.52), 7.732 (1.94), 7.746 (1.33), 7.750 (1.37), 7.997 (4.46), 8.021 (3.93), 8.636 (1.94), 8.642 (3.54), 8.648 (2.17), 9.338 (4.24), 9.344 (4.20).    Example 124 (rac)-N-[(rac)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000444_0001
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 444 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.925 (2.77), 0.931 (2.35), 0.934 (1.02), 0.940 (3.01), 0.948 (2.39), 1.154 (0.82), 1.171 (0.84), 1.483 (5.54), 1.489 (5.70), 1.501 (5.79), 1.507 (5.66), 1.752 (0.53), 2.128 (1.85), 2.142 (2.03), 2.158 (0.95), 2.458 (16.00), 2.518 (7.32), 2.523 (5.20), 2.582 (2.64), 2.600 (4.03), 2.618 (2.76), 3.445 (0.46), 3.462 (1.99), 3.473 (1.30), 3.488 (3.41), 3.500 (2.62), 3.510 (2.89), 3.530 (2.13), 3.556 (1.37), 3.566 (1.04), 3.578 (1.04), 3.594 (0.90), 4.269 (2.65), 4.287 (4.31), 4.304 (2.61), 5.048 (0.88), 5.058 (0.97), 5.067 (1.24), 5.077 (1.23), 5.085 (0.98), 5.095 (0.89), 6.745 (5.27), 6.753 (5.93), 6.856 (1.48), 6.874 (1.47), 7.597 (1.32), 7.600 (0.80), 7.614 (2.42), 7.617 (2.24), 7.634 (1.91), 7.708 (1.75), 7.711 (1.66), 7.725 (1.51), 7.729 (2.90), 7.733 (2.04), 7.746 (1.57), 7.750 (1.50), 7.997 (3.15), 8.019 (4.05), 8.039 (1.20), 8.665 (2.02), 8.670 (2.23), 8.674 (2.24), 8.680 (2.08), 9.352 (3.38), 9.357 (4.12), 9.361 (3.27).    Example 125 (rac)-N-[(1R)-1-(1-ethyl-1H-pyrazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) 
Figure imgf000445_0001
LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 456 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.916 (0.63), 0.931 (5.58), 0.934 (1.81), 0.948 (5.54), 0.952 (0.96), 1.265 (6.46), 1.282 (15.34), 1.291 (7.26), 1.300 (7.25), 1.309 (16.00), 1.327 (6.90), 1.406 (8.70), 1.418 (10.14), 1.424 (10.21), 1.435 (8.92), 2.074 (1.28), 2.090 (2.10), 2.105 (4.23), 2.123 (4.87), 2.140 (1.97), 2.153 (1.09), 2.171 (0.48), 2.404 (0.62), 2.421 (0.62), 2.439 (0.42), 2.518 (10.66), 2.523 (7.64), 2.553 (3.28), 2.571 (5.26), 2.579 (4.12), 2.590 (3.37), 3.393 (0.58), 3.411 (1.23), 3.433 (2.57), 3.446 (2.28), 3.459 (4.03), 3.472 (4.93), 3.493 (4.04), 3.512 (4.80), 3.531 (1.64), 3.538 (2.99), 3.556 (1.35), 3.575 (1.45), 3.597 (0.88), 3.616 (0.49), 4.039 (0.83), 4.056 (1.37), 4.063 (0.77), 4.073 (2.67), 4.080 (1.56), 4.092 (2.70), 4.098 (3.85), 4.103 (2.93), 4.115 (5.01), 4.120 (3.16), 4.132 (3.44), 4.150 (1.34), 4.155 (1.03), 4.167 (0.71), 4.258 (5.32), 4.276 (10.86), 4.293 (5.24), 5.018 (0.61), 5.036 (2.21), 5.055 (2.86), 5.074 (2.24), 5.091 (0.62), 6.166 (4.67), 6.169 (4.66), 6.196 (4.65), 6.200 (4.61), 6.528 (2.40), 6.539 (2.60), 6.549 (2.50), 6.560 (2.32), 6.684 (6.15), 6.702 (12.34), 7.291 (5.05), 7.295 (5.00), 7.320 (5.32), 7.324 (5.29), 7.596 (2.30), 7.613 (4.62), 7.615 (4.38), 7.634 (3.66), 7.708 (3.03), 7.712 (2.85), 7.726 (2.80), 7.730 (4.89), 7.733 (3.68), 7.746 (2.61), 7.750 (2.63), 7.997 (8.91), 8.021 (7.95), 8.548 (0.80), 8.627 (3.52), 8.632 (3.65), 8.643 (3.98), 8.648 (4.10), 9.332 (5.77), 9.338 (10.77), 9.343 (6.01).    Example 126 (rac)-N-{(rac)-1-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]ethyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000446_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.935 (0.75), 0.951 (0.72), 1.232 (0.51), 1.355 (6.87), 1.367 (8.29), 1.372 (8.25), 1.384 (7.06), 2.074 (0.81), 2.088 (1.55), 2.105 (3.10), 2.124 (3.44), 2.142 (1.58), 2.154 (0.88), 2.172 (0.44), 2.518 (11.65), 2.523 (7.81), 2.565 (4.09), 2.582 (5.94), 2.600 (4.00), 2.729 (1.52), 2.888 (1.93), 3.410 (0.52), 3.435 (2.60), 3.454 (2.65), 3.461 (3.73), 3.474 (4.39), 3.490 (3.61), 3.509 (3.31), 3.516 (1.94), 3.534 (2.73), 3.561 (1.58), 3.575 (1.07), 3.601 (0.44), 3.808 (12.49), 3.839 (13.00), 4.264 (4.03), 4.283 (7.01), 4.299 (4.00), 4.942 (1.76), 4.960 (2.48), 4.979 (1.77), 4.996 (0.49), 6.307 (3.55), 6.328 (3.48), 6.712 (16.00), 6.852 (1.71), 6.867 (1.67), 6.987 (3.49), 7.002 (3.32), 7.122 (1.46), 7.137 (1.41), 7.595 (1.99), 7.612 (3.52), 7.633 (2.89), 7.696 (4.44), 7.708 (2.47), 7.728 (3.56), 7.741 (4.84), 7.995 (9.15), 8.019 (7.68), 8.637 (3.12), 8.643 (3.43), 8.648 (3.59), 8.654 (3.48), 9.339 (4.83), 9.344 (8.09), 9.349 (5.10).    Example 127 (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000446_0001
LC-MS (Method 1): Rt = 0.94 min; MS (ESIneg): m/z = 440 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.935 (0.55), 0.951 (0.53), 1.232 (0.80), 1.342 (5.21), 1.355 (6.76), 1.358 (6.67), 1.371 (5.21), 2.072 (0.56), 2.085 (1.34), 2.101 (2.52), 2.119 (2.63), 2.138 (1.11), 2.150 (0.65), 2.331 (1.48), 2.522 (7.19), 2.539 (2.25), 2.567 (3.09), 2.585 (4.72), 2.602 (3.16), 2.673 (1.50), 3.436 (1.47), 3.453 (2.20), 3.461 (1.92), 3.479 (4.61), 3.485 (6.64), 3.497 (3.38), 3.523 (1.09), 3.547 (1.15), 3.565 (1.69), 3.591 (0.80), 3.753 (15.45), 3.778 (16.00), 4.263 (2.96), 4.280 (4.96), 4.297 (2.91), 4.797 (1.17), 4.815 (1.72), 4.833 (1.17), 6.229 (2.70), 6.250 (2.60), 6.718 (5.09), 6.724 (6.03), 7.309 (4.00), 7.336 (3.88), 7.517 (3.84), 7.543 (3.84), 7.594 (1.40), 7.611 (2.72), 7.632 (2.08), 7.706 (1.76), 7.710 (1.72), 7.727 (2.88), 7.744 (1.54), 7.747 (1.52), 7.996 (4.74), 8.017 (4.21), 8.461 (0.58), 8.656 (4.28), 8.661 (2.61), 9.345 (5.85), 9.351 (5.73).    Example 128 (rac)-N-[(1R)-1-phenylethyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) 
Figure imgf000447_0001
LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 427 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.241 (1.00), 1.246 (0.64), 1.258 (1.47), 1.276 (0.92), 1.363 (10.50), 1.369 (10.85), 1.381 (10.82), 1.387 (10.49), 2.056 (0.85), 2.074 (16.00), 2.088 (2.91), 2.099 (2.18), 2.107 (2.77), 2.116 (2.27), 2.126 (1.47), 2.135 (1.27), 2.146 (0.77), 2.332 (0.76), 2.518 (4.27), 2.522 (2.76), 2.536 (4.53), 2.554 (7.23), 2.570 (5.01), 2.673 (0.76), 3.386 (7.00), 3.420 (1.64), 3.438 (2.78), 3.446 (2.29), 3.456 (3.91), 3.464 (3.64), 3.481 (8.77), 3.495 (6.21), 3.521 (1.86), 3.523 (1.84), 3.544 (0.81), 3.563 (1.39), 3.570 (1.56), 3.577 (1.31), 3.584 (1.70), 3.589 (2.02), 3.596 (1.13), 3.603 (1.45), 3.609 (0.95), 3.615 (0.92), 3.629 (0.56), 3.905 (1.09), 4.204 (5.23), 4.222 (9.09), 4.239 (5.03), 4.820 (0.44), 4.832 (1.44), 4.838 (1.61), 4.851 (2.16), 4.856 (2.21), 4.869 (1.57), 4.875 (1.45), 4.887 (0.42), 6.449 (3.70), 6.454 (6.13), 6.457 (6.25), 6.462 (12.39), 6.468 (4.53), 6.482 (5.12), 6.487 (14.88), 6.502 (4.41), 6.982 (1.56), 7.110 (1.73), 7.152 (0.63), 7.155 (1.18), 7.159 (0.72), 7.168 (0.92), 7.173 (3.01), 7.179 (2.03), 7.183 (0.95), 7.188 (1.41), 7.192 (2.93), 7.197 (3.25), 7.202 (1.16), 7.212 (1.25), 7.215 (2.19), 7.219 (1.24), 7.238 (1.62), 7.257 (3.02), 7.277 (6.40), 7.289 (3.74), 7.295 (4.58), 7.308 (6.57), 7.327 (10.76), 7.345 (3.78), 7.349 (3.66), 7.353 (6.18), 7.355 (6.41), 7.373 (3.37), 7.376 (2.33), 7.461 (4.43), 7.468 (6.67), 7.475 (4.32), 7.702 (0.69), 7.705 (0.67), 8.234 (4.20), 8.239 (4.36), 8.248 (4.43), 8.252 (4.47), 8.626 (5.81), 8.633 (7.14), 8.639 (5.72), 11.657 (4.19).    Example 129 (rac)-N-[1-(pyridin-4-yl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000448_0001
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 454 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (1.36), 0.950 (1.27), 1.806 (0.61), 1.825 (1.22), 1.831 (1.25), 1.848 (1.27), 1.853 (1.54), 1.870 (0.96), 1.985 (0.61), 1.993 (0.80), 2.007 (1.42), 2.022 (1.16), 2.031 (1.27), 2.036 (1.28), 2.045 (1.10), 2.059 (1.28), 2.075 (1.74), 2.088 (1.73), 2.104 (1.77), 2.122 (2.13), 2.140 (1.20), 2.152 (0.88), 2.336 (0.83), 2.349 (0.63), 2.364 (1.07), 2.378 (2.09), 2.394 (2.47), 2.406 (2.12), 2.423 (2.06), 2.441 (2.30), 2.455 (2.69), 2.518 (7.53), 2.522 (5.17), 2.539 (3.06), 2.555 (4.73), 2.560 (4.76), 2.575 (3.00), 2.660 (0.76), 3.442 (2.10), 3.452 (2.05), 3.468 (4.32), 3.484 (3.34), 3.509 (1.09), 3.573 (1.35), 4.209 (4.00), 4.226 (7.65), 4.244 (3.84), 6.458 (5.41), 6.462 (6.18), 6.466 (6.20), 6.471 (5.34), 6.485 (16.00), 6.889 (6.55), 7.402 (11.39), 7.407 (7.04), 7.414 (7.14), 7.418 (11.01), 7.463 (4.75), 7.469 (5.30), 7.477 (4.60), 8.239 (6.72), 8.243 (6.99), 8.466 (12.10), 8.470 (7.37), 8.477 (7.20), 8.481 (11.53), 8.633 (9.42), 8.638 (9.19), 11.650 (3.57).    Example 130 (rac)-N-[2-(pyridin-2-yl)propan-2-yl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000449_0002
LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 442 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.85), 0.949 (0.80), 1.595 (16.00), 2.074 (0.62), 2.088 (0.60), 2.101 (0.62), 2.121 (0.62), 2.141 (0.88), 2.159 (0.49), 2.171 (0.40), 2.518 (1.73), 2.522 (1.08), 2.557 (1.43), 2.574 (2.13), 2.592 (1.47), 3.455 (0.57), 3.480 (0.84), 3.504 (3.07), 3.604 (0.56), 3.616 (0.48), 3.623 (0.41), 4.219 (1.39), 4.237 (2.28), 4.254 (1.35), 6.442 (2.74), 6.454 (2.04), 6.459 (2.15), 6.463 (2.17), 6.468 (1.97), 6.525 (7.37), 7.170 (1.13), 7.173 (1.15), 7.182 (1.12), 7.185 (1.22), 7.188 (1.25), 7.191 (1.11), 7.200 (1.20), 7.203 (1.12), 7.461 (1.87), 7.466 (3.46), 7.475 (1.73), 7.486 (2.07), 7.687 (1.11), 7.693 (1.16), 7.706 (1.36), 7.711 (1.35), 7.726 (0.86), 7.731 (0.87), 8.253 (2.41), 8.257 (2.51), 8.451 (1.19), 8.454 (1.38), 8.456 (1.37), 8.458 (1.24), 8.463 (1.21), 8.466 (1.42), 8.468 (1.26), 8.470 (1.12), 8.641 (3.46), 8.646 (3.40), 11.649 (1.27).    Example 131 (rac)-N-[1-(propan-2-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000449_0001
LC-MS (Method 1): Rt = 1.18 min; MS (ESIpos): m/z = 430 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.845 (13.52), 0.855 (14.59), 0.862 (14.82), 0.872 (14.05), 1.239 (0.50), 1.254 (0.52), 1.553 (0.48), 1.571 (0.99), 1.576 (1.06), 1.594 (1.10), 1.599 (1.21), 1.618 (0.73), 1.782 (0.43), 1.796 (0.66), 1.807 (1.10), 1.820 (1.00), 1.834 (1.02), 1.846 (0.78), 1.859 (0.49), 2.026 (0.99), 2.038 (1.10), 2.057 (2.51), 2.071 (3.01), 2.075 (2.92), 2.080 (2.64), 2.083 (2.73), 2.097 (2.37), 2.119 (2.82), 2.129 (3.10), 2.138 (3.13), 2.144 (3.91), 2.150 (4.26), 2.162 (2.88), 2.167 (4.47), 2.185 (2.19), 2.193 (1.06), 2.202 (0.78), 2.518 (2.71), 2.522 (1.70), 2.565 (2.68), 2.581 (4.39), 2.585 (4.32), 2.601 (3.10), 3.406 (0.68), 3.425 (1.65), 3.432 (1.29), 3.442 (1.05), 3.450 (2.44), 3.473 (13.12), 3.527 (0.96), 3.541 (1.19), 3.546 (1.59), 3.553 (1.05), 3.560 (1.22), 3.567 (1.01), 3.572 (0.96), 3.586 (0.63), 4.266 (3.60), 4.284 (6.39), 4.301 (3.45), 5.768 (5.59), 6.722 (16.00), 7.593 (1.75), 7.596 (1.49), 7.610 (2.60), 7.613 (3.13), 7.616 (2.28), 7.630 (2.25), 7.633 (2.40), 7.707 (2.56), 7.711 (2.04), 7.724 (2.09), 7.728 (3.02), 7.732 (2.92), 7.745 (1.83), 7.749 (2.13), 7.996 (8.66), 7.999 (6.11), 8.017 (5.71), 8.021 (6.66), 8.641 (5.07), 8.646 (5.36), 9.338 (7.84), 9.344 (7.80).    Example 132 (rac)-N-(1H-imidazol-2-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000450_0001
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 413 [M]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.751 (0.68), 1.816 (0.64), 1.839 (1.64), 1.857 (3.05), 1.867 (3.13), 1.885 (2.04), 1.911 (0.75), 1.973 (0.80), 2.043 (1.52), 2.074 (4.06), 2.090 (3.48), 2.209 (0.80), 2.229 (1.72), 2.247 (1.22), 2.259 (1.26), 2.278 (0.65), 2.518 (7.94), 2.523 (5.54), 2.539 (1.77), 3.571 (1.69), 3.597 (6.46), 3.613 (6.14), 3.640 (2.62), 3.678 (1.04), 3.699 (1.57), 3.713 (1.45), 4.188 (3.40), 4.203 (6.91), 4.219 (3.29), 6.666 (4.88), 6.877 (16.00), 7.587 (2.09), 7.589 (2.09), 7.607 (4.35), 7.624 (2.89), 7.627 (2.98), 7.705 (2.83), 7.709 (2.79), 7.723 (2.50), 7.726 (4.42), 7.730 (3.59), 7.743 (2.48), 7.747 (2.46), 7.997 (5.07), 8.013 (4.90), 8.017 (4.85), 8.030 (3.99), 8.549 (0.51), 8.653 (6.16), 8.658 (6.27), 9.343 (9.36), 9.349 (9.31).    Example 133 (rac)-N-(bicyclo[1.1.1]pentan-1-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000451_0001
LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 414 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.810 (0.57), 1.817 (0.64), 1.826 (0.62), 1.952 (16.00), 2.017 (0.47), 2.031 (0.52), 2.048 (0.48), 2.354 (2.80), 2.522 (0.98), 3.388 (0.43), 3.407 (2.62), 4.170 (0.60), 4.186 (1.24), 4.201 (0.61), 6.813 (1.35), 6.839 (2.77), 7.610 (0.77), 7.631 (0.51), 7.707 (0.48), 7.710 (0.46), 7.724 (0.43), 7.728 (0.76), 7.731 (0.57), 7.745 (0.41), 7.749 (0.40), 7.998 (0.88), 8.011 (0.77), 8.018 (0.78), 8.028 (0.70), 8.643 (1.10), 8.648 (1.11), 9.330 (1.54), 9.335 (1.53).    Example 134 (rac)-N-(1-methylcyclobutyl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000451_0002
LC-MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 414 [M-H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.297 (2.01), 1.396 (16.00), 1.715 (1.27), 1.736 (1.85), 1.753 (2.26), 1.763 (1.23), 1.775 (1.24), 1.807 (1.04), 1.818 (1.97), 1.835 (2.95), 1.843 (2.27), 1.851 (2.14), 1.862 (2.10), 1.874 (1.91), 1.880 (1.50), 1.892 (0.89), 1.988 (0.46), 2.006 (0.80), 2.019 (1.32), 2.031 (1.33), 2.038 (1.24), 2.050 (1.37), 2.073 (1.26), 2.084 (1.12), 2.102 (0.78), 2.146 (0.67), 2.166 (1.28), 2.178 (0.68), 2.185 (0.85), 2.197 (0.97), 2.216 (1.34), 2.237 (2.35), 2.267 (1.98), 2.291 (0.80), 2.518 (4.48), 2.523 (3.14), 3.381 (0.59), 3.401 (1.34), 3.431 (6.22), 3.435 (6.36), 3.461 (0.64), 3.521 (0.66), 3.534 (0.80), 3.542 (1.01), 3.555 (0.91), 3.568 (0.62), 3.581 (0.48), 4.174 (1.95), 4.189 (4.12), 4.205 (1.97), 6.002 (4.36), 6.836 (9.31), 7.593 (1.21), 7.596 (1.12), 7.613 (2.48), 7.631 (1.61), 7.633 (1.74), 7.709 (1.64), 7.712 (1.49), 7.726 (1.44), 7.730 (2.42), 7.733 (1.98), 7.747 (1.38), 7.750 (1.44), 8.000 (5.02), 8.022 (4.26), 8.634 (3.59), 8.638 (3.70), 9.324 (5.35), 9.330 (5.13).    Example 135 (rac)-N-[(pyridin-4-yl)methyl]-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000452_0001
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 439 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.860 (3.66), 1.869 (3.55), 1.903 (0.63), 2.078 (3.10), 2.090 (3.23), 2.195 (0.95), 2.214 (1.93), 2.232 (1.36), 2.245 (1.36), 2.263 (0.75), 2.518 (7.69), 2.523 (5.40), 3.479 (1.94), 3.505 (8.59), 3.513 (9.36), 3.539 (2.68), 3.592 (1.20), 3.605 (1.54), 3.612 (1.92), 3.625 (1.63), 3.638 (1.22), 3.650 (0.81), 4.186 (3.49), 4.201 (7.43), 4.216 (3.56), 4.279 (7.23), 4.293 (7.42), 6.843 (16.00), 6.921 (1.83), 6.935 (3.83), 6.951 (1.84), 7.280 (8.87), 7.295 (9.23), 7.599 (2.12), 7.602 (2.07), 7.619 (4.55), 7.636 (2.98), 7.639 (3.06), 7.714 (2.84), 7.717 (2.80), 7.731 (2.48), 7.735 (4.58), 7.738 (3.49), 7.752 (2.49), 7.755 (2.44), 8.008 (5.56), 8.011 (5.44), 8.032 (5.46), 8.462 (11.85), 8.465 (7.16), 8.473 (7.14), 8.477 (11.56), 8.640 (6.41), 8.644 (6.56), 9.339 (9.31), 9.345 (9.25).    Example 136 (rac)-N-(pyridin-4-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000453_0002
LC-MS (Method 1): Rt = 0.94 min; MS (ESIneg): m/z = 423 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.238 (0.55), 1.848 (0.99), 1.871 (2.17), 1.881 (2.46), 1.900 (3.49), 1.916 (2.62), 1.924 (2.66), 1.950 (1.39), 1.958 (1.17), 2.075 (3.99), 2.102 (5.95), 2.113 (6.15), 2.233 (0.97), 2.252 (2.44), 2.269 (2.68), 2.283 (2.30), 2.299 (1.56), 2.323 (1.76), 2.327 (2.26), 2.332 (1.60), 2.518 (8.59), 2.523 (5.50), 2.540 (0.54), 2.665 (1.55), 2.669 (2.10), 2.673 (1.51), 3.616 (1.32), 3.641 (9.61), 3.661 (2.81), 3.679 (1.31), 3.736 (3.10), 3.750 (3.36), 3.775 (1.20), 3.867 (1.44), 4.197 (4.93), 4.213 (8.27), 4.228 (4.03), 6.921 (16.00), 6.984 (0.59), 7.047 (2.90), 7.562 (10.73), 7.566 (7.24), 7.574 (7.38), 7.578 (10.87), 7.587 (2.78), 7.590 (2.65), 7.597 (2.27), 7.601 (2.54), 7.604 (3.85), 7.607 (5.27), 7.610 (3.30), 7.615 (3.38), 7.618 (4.44), 7.621 (2.97), 7.625 (3.82), 7.627 (3.69), 7.636 (2.91), 7.638 (2.94), 7.680 (1.38), 7.705 (3.52), 7.708 (3.62), 7.713 (3.01), 7.717 (3.16), 7.722 (3.07), 7.726 (5.43), 7.730 (5.47), 7.734 (4.43), 7.737 (3.32), 7.743 (3.08), 7.747 (2.83), 7.751 (2.40), 7.755 (2.15), 7.997 (5.81), 8.007 (8.84), 8.017 (8.02), 8.026 (8.20), 8.038 (3.12), 8.250 (1.08), 8.307 (11.53), 8.311 (7.41), 8.319 (7.08), 8.323 (10.52), 8.556 (0.58), 8.662 (8.56), 8.667 (10.75), 8.674 (7.96), 9.350 (10.57), 9.355 (11.20), 9.364 (3.03).    Example 137 (rac)-N-[(pyridin-3-yl)methyl]-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000453_0001
LC-MS (Method 1): Rt = 0.92 min; MS (ESIneg): m/z = 437 [M-H]-  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.803 (0.42), 1.826 (1.68), 1.838 (3.06), 1.844 (3.36), 1.853 (3.25), 1.863 (2.12), 1.888 (0.54), 2.029 (1.20), 2.047 (2.33), 2.060 (3.35), 2.077 (3.25), 2.092 (2.58), 2.107 (1.25), 2.123 (0.70), 2.176 (0.91), 2.196 (1.88), 2.214 (1.27), 2.226 (1.29), 2.245 (0.67), 2.336 (0.41), 2.518 (4.57), 2.523 (3.04), 2.539 (0.40), 2.679 (0.43), 3.452 (0.88), 3.461 (1.39), 3.471 (2.06), 3.487 (9.07), 3.492 (10.04), 3.517 (1.76), 3.561 (1.13), 3.573 (1.40), 3.581 (1.76), 3.594 (1.48), 3.599 (1.24), 3.606 (1.00), 3.620 (0.71), 4.178 (3.17), 4.194 (6.75), 4.209 (3.25), 4.278 (7.03), 4.293 (7.05), 6.819 (16.00), 6.884 (1.76), 6.898 (3.66), 6.913 (1.72), 7.312 (2.61), 7.314 (2.66), 7.326 (2.79), 7.333 (2.97), 7.343 (2.91), 7.345 (2.99), 7.599 (2.10), 7.602 (2.09), 7.616 (3.20), 7.619 (4.32), 7.622 (2.71), 7.636 (2.55), 7.639 (2.94), 7.687 (2.08), 7.692 (3.26), 7.696 (2.21), 7.706 (2.14), 7.712 (5.93), 7.715 (4.28), 7.728 (2.47), 7.732 (4.37), 7.736 (3.47), 7.749 (2.47), 7.753 (2.42), 8.003 (4.71), 8.024 (9.92), 8.042 (3.61), 8.044 (3.50), 8.421 (3.83), 8.425 (3.88), 8.433 (3.87), 8.437 (3.65), 8.519 (5.30), 8.523 (5.26), 8.553 (0.41), 8.628 (6.05), 8.633 (6.31), 9.328 (8.97), 9.333 (9.25).    Example 138 (rac)-N-(1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000454_0001
LC-MS (Method 4): Rt = 0.68 min; MS (ESIpos): m/z = 400 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.906 (1.59), 2.167 (2.61), 2.180 (3.08), 2.518 (15.15), 2.523 (10.02), 2.605 (2.66), 2.620 (4.40), 2.626 (4.44), 2.639 (2.65), 3.628 (10.59), 3.671 (1.21), 3.688 (2.00), 4.283 (3.75), 4.299 (7.86), 4.317 (3.76), 6.667 (16.00), 6.763 (15.91), 7.588 (2.00), 7.608 (3.72), 7.626 (2.72), 7.629 (2.82), 7.704 (2.70), 7.708 (2.30), 7.725 (3.68), 7.729 (3.25), 7.743 (2.11), 7.746 (2.25), 7.993 (9.47), 8.016 (8.21), 8.172 (10.64), 8.668 (6.31), 8.674 (6.24), 9.357 (8.49), 9.362 (8.48).    Example 139 (rac)-N-[(pyridin-4-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000455_0001
  Example 140 (rac)-N-(pyridin-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide 
Figure imgf000455_0002
LC-MS (Method 4): Rt = 0.68 min; MS (ESIpos): m/z = 411 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.327 (1.37), 1.906 (1.05), 2.074 (0.76), 2.176 (1.40), 2.192 (2.76), 2.211 (3.02), 2.229 (1.42), 2.323 (1.48), 2.327 (2.07), 2.331 (1.51), 2.518 (11.36), 2.523 (7.52), 2.540 (1.63), 2.597 (0.48), 2.615 (0.93), 2.630 (2.18), 2.646 (4.70), 2.661 (5.59), 2.669 (3.14), 2.674 (2.75), 2.678 (2.95), 2.692 (1.01), 2.710 (0.42), 3.639 (2.19), 3.664 (7.70), 3.709 (1.32), 3.728 (1.99), 3.770 (0.75), 4.294 (4.25), 4.312 (8.88), 4.330 (4.19), 6.805 (16.00), 7.043 (0.62), 7.564 (8.34), 7.568 (6.03), 7.576 (6.09), 7.580 (8.63), 7.589 (2.44), 7.610 (3.94), 7.627 (2.88), 7.630 (3.21), 7.638 (0.99), 7.705 (2.64), 7.709 (2.35), 7.723 (2.48), 7.726 (3.96), 7.730 (3.37), 7.743 (2.35), 7.747 (2.51), 7.993 (8.93), 8.017 (9.01), 8.170 (6.63), 8.201 (0.69), 8.308 (8.89), 8.312 (6.21), 8.321 (5.81), 8.324 (8.37), 8.668 (6.86), 8.674 (6.79), 8.690 (5.36), 9.360 (8.78), 9.365 (9.02).    Example 141 (rac)-2'-(quinolin-3-yl)-N-(2H-tetrazol-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000456_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (1.56), 1.237 (1.45), 1.907 (0.92), 2.199 (2.46), 2.213 (2.75), 2.326 (1.71), 2.331 (1.26), 2.586 (0.57), 2.603 (1.02), 2.619 (2.30), 2.635 (4.88), 2.651 (5.03), 2.668 (3.85), 2.700 (0.50), 3.680 (8.12), 3.743 (1.79), 4.288 (3.92), 4.304 (7.70), 4.322 (3.99), 6.795 (16.00), 7.589 (1.94), 7.610 (3.96), 7.630 (2.85), 7.705 (2.50), 7.709 (2.28), 7.726 (3.91), 7.730 (3.24), 7.743 (2.13), 7.747 (2.21), 7.994 (8.60), 8.016 (8.02), 8.141 (0.50), 8.667 (6.16), 8.672 (6.25), 9.357 (8.33), 9.362 (8.13), 10.400 (0.44).    Example 142 (rac)-N-[(pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000457_0002
LC-MS (Method 4): Rt = 0.66 min; MS (ESIpos): m/z = 425 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.906 (0.94), 2.116 (1.60), 2.131 (3.29), 2.149 (3.78), 2.166 (1.54), 2.179 (0.82), 2.518 (7.21), 2.523 (5.01), 2.582 (4.06), 2.600 (6.19), 2.617 (4.32), 3.455 (1.40), 3.474 (2.37), 3.483 (2.78), 3.499 (3.65), 3.509 (9.00), 3.515 (9.93), 3.540 (1.59), 3.561 (1.32), 3.579 (2.24), 3.587 (1.39), 3.594 (1.60), 3.601 (1.39), 3.620 (0.83), 4.272 (8.69), 4.287 (13.46), 4.303 (4.44), 6.722 (16.00), 6.898 (1.58), 6.913 (3.24), 6.927 (1.59), 7.321 (2.64), 7.323 (2.67), 7.334 (2.86), 7.342 (3.00), 7.354 (3.07), 7.596 (1.97), 7.600 (1.86), 7.616 (4.24), 7.634 (2.74), 7.636 (2.80), 7.688 (2.05), 7.693 (3.27), 7.698 (2.24), 7.709 (4.53), 7.712 (5.54), 7.726 (2.48), 7.730 (4.25), 7.733 (3.29), 7.747 (2.36), 7.750 (2.31), 8.001 (6.44), 8.022 (5.99), 8.192 (4.28), 8.425 (3.79), 8.429 (3.92), 8.437 (3.89), 8.441 (3.68), 8.517 (5.20), 8.521 (5.17), 8.655 (5.91), 8.660 (6.04), 9.348 (8.81), 9.353 (8.82).    Example 143 (rac)-N-(2,2-dimethylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000457_0001
LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 402 [M-H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.837 (16.00), 2.119 (0.45), 2.138 (0.50), 2.518 (1.40), 2.523 (0.98), 2.567 (0.53), 2.584 (0.84), 2.587 (0.84), 2.603 (0.60), 2.889 (1.13), 2.905 (1.19), 3.481 (0.45), 3.503 (2.65), 4.270 (0.65), 4.288 (1.14), 4.304 (0.65), 6.023 (0.50), 6.715 (2.54), 7.612 (0.55), 7.630 (0.40), 7.633 (0.44), 7.707 (0.40), 7.728 (0.54), 7.731 (0.50), 7.995 (1.42), 8.016 (1.04), 8.019 (1.22), 8.641 (0.94), 8.646 (0.97), 9.337 (1.32), 9.342 (1.30).    Example 144 (rac)-N-[[1,1'-bi(cyclopropan)]-1-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000458_0001
LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 415 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.013 (5.00), 0.154 (4.86), 0.159 (4.76), 0.165 (2.65), 0.170 (2.31), 0.175 (5.02), 0.179 (4.57), 0.300 (6.32), 0.305 (6.90), 0.316 (2.66), 0.407 (2.84), 0.417 (6.84), 1.231 (2.99), 1.953 (2.70), 1.973 (2.91), 2.385 (2.76), 2.417 (2.76), 2.433 (4.86), 2.438 (4.90), 2.453 (3.30), 3.281 (2.48), 3.303 (12.31), 4.123 (3.90), 4.141 (6.83), 4.158 (3.79), 6.378 (5.80), 6.588 (16.00), 7.475 (2.86), 7.477 (3.31), 7.481 (2.50), 7.495 (2.47), 7.498 (2.77), 7.572 (2.78), 7.576 (2.25), 7.590 (2.32), 7.593 (3.35), 7.597 (3.24), 7.614 (2.41), 7.861 (9.29), 7.864 (7.02), 7.882 (6.24), 7.885 (7.66), 8.513 (5.75), 8.519 (6.00), 9.208 (8.95), 9.213 (8.67).    Example 145 (rac)-N-[1-(pyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000459_0002
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 466 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.779 (0.84), 1.797 (1.63), 1.803 (1.56), 1.825 (1.92), 1.842 (1.23), 1.863 (0.47), 1.983 (0.41), 2.005 (1.02), 2.021 (1.76), 2.035 (1.39), 2.043 (1.73), 2.074 (2.19), 2.088 (2.17), 2.106 (2.85), 2.129 (2.99), 2.147 (1.70), 2.159 (1.11), 2.420 (1.17), 2.447 (3.56), 2.469 (5.62), 2.565 (4.43), 2.582 (6.79), 2.601 (4.79), 2.728 (3.12), 2.887 (3.82), 3.355 (2.94), 3.386 (2.89), 3.424 (2.22), 3.455 (3.63), 3.468 (3.75), 3.481 (6.88), 3.495 (5.57), 3.547 (1.45), 3.566 (2.17), 4.265 (5.01), 4.283 (8.68), 4.299 (4.92), 6.690 (16.00), 6.905 (7.69), 7.044 (0.84), 7.172 (0.92), 7.299 (0.86), 7.388 (3.18), 7.400 (3.51), 7.408 (3.55), 7.420 (3.54), 7.602 (2.42), 7.604 (2.50), 7.621 (5.34), 7.639 (3.55), 7.641 (3.55), 7.687 (3.34), 7.690 (3.29), 7.712 (3.30), 7.716 (3.40), 7.730 (2.92), 7.734 (5.34), 7.737 (3.94), 7.751 (2.96), 7.755 (2.67), 7.901 (3.66), 7.921 (3.45), 7.950 (0.61), 8.004 (6.11), 8.016 (5.18), 8.024 (5.41), 8.033 (4.79), 8.420 (5.07), 8.424 (5.18), 8.432 (5.21), 8.436 (4.88), 8.649 (7.46), 8.655 (7.57), 8.693 (6.75), 8.698 (6.61), 9.080 (1.37), 9.342 (10.62), 9.347 (10.12).    Example 146 (rac)-N-[[1,1'-bi(cyclobutan)]-1-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000459_0001
LC-MS (Method 1): Rt = 1.24 min; MS (ESIpos): m/z = 443 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.549 (0.54), 1.569 (1.10), 1.574 (1.19), 1.597 (1.79), 1.610 (1.34), 1.620 (1.70), 1.686 (0.57), 1.705 (1.12), 1.730 (1.27), 1.748 (1.06), 1.756 (1.33), 1.774 (3.07), 1.783 (3.84), 1.796 (4.99), 1.804 (4.76), 1.820 (4.20), 1.846 (1.61), 1.872 (0.43), 1.987 (1.16), 2.000 (1.28), 2.019 (2.43), 2.031 (2.39), 2.042 (2.14), 2.055 (1.78), 2.075 (9.17), 2.083 (1.24), 2.089 (1.97), 2.099 (1.66), 2.106 (1.58), 2.118 (3.64), 2.147 (3.38), 2.167 (2.60), 2.195 (0.94), 2.518 (2.07), 2.522 (1.37), 2.558 (2.77), 2.573 (4.64), 2.578 (4.66), 2.594 (3.20), 2.892 (0.45), 2.914 (1.57), 2.935 (2.12), 2.957 (1.39), 3.386 (0.76), 3.404 (1.73), 3.412 (1.39), 3.425 (1.72), 3.430 (2.60), 3.450 (9.22), 3.454 (9.35), 3.480 (0.91), 3.508 (1.01), 3.527 (1.70), 3.533 (1.15), 3.540 (1.28), 3.548 (1.09), 3.552 (1.03), 3.566 (0.65), 4.263 (3.79), 4.280 (6.97), 4.297 (3.72), 5.805 (6.15), 6.713 (16.00), 7.592 (1.83), 7.595 (1.63), 7.610 (2.83), 7.613 (3.26), 7.630 (2.37), 7.632 (2.57), 7.706 (2.46), 7.710 (2.13), 7.723 (2.10), 7.727 (3.29), 7.730 (2.93), 7.744 (1.95), 7.748 (2.09), 7.995 (8.04), 7.998 (7.02), 8.019 (7.77), 8.640 (5.64), 8.645 (5.70), 9.338 (8.02), 9.344 (8.23).    Example 147 (rac)-N-(1-cyclopropylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000460_0001
LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 429 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.271 (0.90), 0.286 (3.67), 0.296 (3.76), 0.299 (4.15), 0.309 (1.82), 0.317 (0.81), 0.330 (1.55), 0.339 (3.49), 0.351 (1.98), 0.360 (3.66), 0.370 (0.80), 0.377 (0.72), 1.411 (0.60), 1.424 (1.18), 1.432 (1.25), 1.445 (2.11), 1.452 (0.83), 1.458 (1.16), 1.466 (1.13), 1.479 (0.48), 1.556 (0.43), 1.580 (0.96), 1.600 (1.22), 1.617 (0.43), 1.626 (0.68), 1.742 (0.67), 1.759 (1.42), 1.770 (2.18), 1.786 (3.62), 1.791 (2.91), 1.804 (1.61), 1.814 (1.53), 1.826 (0.87), 2.075 (16.00), 2.083 (1.71), 2.097 (1.72), 2.101 (1.79), 2.107 (1.92), 2.114 (1.90), 2.125 (3.01), 2.139 (2.52), 2.143 (2.63), 2.155 (2.05), 2.166 (1.37), 2.188 (0.66), 2.518 (1.71), 2.522 (1.04), 2.569 (2.75), 2.585 (4.17), 2.589 (4.16), 2.604 (3.14), 3.402 (0.60), 3.420 (1.51), 3.428 (1.13), 3.445 (2.26), 3.469 (10.24), 3.495 (0.51), 3.524 (0.83), 3.537 (1.05), 3.543 (1.40), 3.550 (0.94), 3.556 (1.09), 3.563 (0.89), 3.569 (0.85), 3.582 (0.55), 4.267 (3.26), 4.285 (5.36), 4.302 (3.20), 5.950 (5.23), 6.737 (14.71), 7.592 (1.66), 7.596 (1.38), 7.610 (2.39), 7.612 (2.84), 7.615 (2.06), 7.630 (2.07), 7.633 (2.28), 7.706 (2.37), 7.710 (1.91), 7.724 (1.84), 7.728 (2.80), 7.731 (2.65), 7.745 (1.77), 7.748 (1.88), 7.996 (7.99), 7.999 (5.64), 8.017 (5.22), 8.021 (6.14), 8.647 (4.67), 8.653 (4.98), 9.344 (7.38), 9.349 (7.31).    Example 148 (rac)-N-[1-(4-methoxyphenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000461_0001
LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 495 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.097 (0.56), 2.118 (0.63), 2.356 (0.50), 2.365 (0.64), 2.381 (0.73), 2.387 (0.59), 2.402 (0.44), 2.455 (0.49), 2.462 (0.55), 2.518 (0.94), 2.522 (0.60), 2.558 (0.61), 2.563 (0.62), 2.575 (1.14), 2.581 (1.15), 2.597 (0.67), 3.438 (0.63), 3.448 (0.59), 3.463 (1.45), 3.480 (1.15), 3.551 (0.42), 3.685 (16.00), 4.263 (1.03), 4.281 (2.06), 4.298 (0.98), 6.640 (1.70), 6.693 (4.54), 6.822 (2.97), 6.827 (0.84), 6.839 (0.91), 6.844 (3.23), 7.341 (3.00), 7.347 (0.89), 7.358 (0.85), 7.363 (2.71), 7.596 (0.55), 7.599 (0.48), 7.613 (0.78), 7.617 (1.07), 7.620 (0.67), 7.634 (0.68), 7.637 (0.75), 7.710 (0.78), 7.713 (0.64), 7.727 (0.61), 7.731 (1.10), 7.734 (0.86), 7.747 (0.59), 7.751 (0.63), 8.001 (2.19), 8.022 (1.81), 8.633 (1.49), 8.639 (1.56), 9.339 (2.36), 9.345 (2.45).    Example 149 (rac)-N-[1-(pyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000462_0001
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 466 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (1.04), 0.948 (1.03), 1.808 (0.59), 1.814 (0.49), 1.826 (1.21), 1.831 (1.24), 1.849 (1.27), 1.854 (1.53), 1.872 (0.95), 1.987 (0.58), 1.995 (0.77), 2.010 (1.39), 2.024 (1.14), 2.033 (1.20), 2.038 (1.19), 2.048 (0.80), 2.054 (0.69), 2.061 (0.68), 2.076 (0.56), 2.083 (1.22), 2.101 (1.43), 2.117 (1.99), 2.143 (2.25), 2.160 (1.24), 2.173 (0.80), 2.358 (1.02), 2.388 (2.64), 2.403 (3.02), 2.409 (2.68), 2.425 (2.65), 2.444 (2.04), 2.449 (2.16), 2.467 (2.66), 2.518 (3.05), 2.522 (1.83), 2.577 (3.03), 2.592 (4.91), 2.596 (4.99), 2.612 (3.40), 3.316 (0.50), 3.437 (0.61), 3.469 (2.07), 3.482 (2.18), 3.495 (4.82), 3.509 (3.67), 3.535 (1.06), 3.563 (0.87), 3.582 (1.47), 3.596 (1.19), 3.622 (0.57), 4.272 (4.17), 4.290 (7.50), 4.307 (4.01), 6.710 (16.00), 6.907 (6.50), 7.409 (11.25), 7.412 (7.15), 7.419 (7.05), 7.424 (11.65), 7.601 (2.22), 7.604 (2.23), 7.618 (3.22), 7.622 (4.65), 7.625 (2.61), 7.639 (2.94), 7.642 (3.08), 7.713 (2.98), 7.717 (3.17), 7.730 (2.46), 7.734 (4.91), 7.738 (3.48), 7.751 (2.73), 7.755 (2.62), 8.005 (4.93), 8.012 (4.07), 8.016 (4.15), 8.025 (4.20), 8.033 (3.88), 8.036 (3.73), 8.471 (13.55), 8.476 (7.25), 8.483 (7.40), 8.487 (12.59), 8.635 (5.85), 8.640 (6.09), 9.348 (9.81), 9.353 (9.65).    Example 150 (rac)-N-[1-(pyridin-2-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000463_0001
LC-MS (Method 1): Rt = 1.04 min; MS (ESIneg): m/z = 463 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (1.11), 0.949 (1.13), 1.871 (0.49), 1.887 (0.93), 1.891 (0.99), 1.897 (0.84), 1.914 (1.37), 1.930 (0.80), 1.936 (0.72), 1.952 (0.49), 1.967 (0.59), 1.973 (0.70), 1.990 (1.29), 2.005 (0.89), 2.012 (1.05), 2.029 (0.58), 2.039 (0.46), 2.083 (0.66), 2.107 (0.62), 2.121 (1.32), 2.135 (1.65), 2.147 (1.47), 2.165 (2.02), 2.183 (1.12), 2.195 (0.80), 2.389 (1.80), 2.394 (1.98), 2.405 (1.86), 2.411 (2.08), 2.416 (1.93), 2.518 (1.89), 2.522 (1.18), 2.569 (1.47), 2.585 (2.40), 2.596 (4.65), 2.611 (5.79), 2.615 (5.71), 2.631 (3.85), 3.474 (0.51), 3.492 (1.20), 3.499 (1.10), 3.517 (1.90), 3.539 (6.66), 3.567 (0.56), 3.603 (0.77), 3.622 (1.30), 3.636 (1.05), 3.662 (0.51), 4.283 (3.62), 4.301 (6.01), 4.318 (3.50), 6.746 (16.00), 6.824 (5.91), 7.161 (2.53), 7.164 (2.70), 7.173 (2.57), 7.176 (2.84), 7.180 (2.87), 7.183 (2.76), 7.192 (2.71), 7.195 (2.82), 7.384 (4.20), 7.404 (4.66), 7.600 (1.88), 7.603 (1.63), 7.618 (2.75), 7.620 (3.35), 7.623 (2.42), 7.638 (2.38), 7.641 (2.65), 7.661 (2.55), 7.667 (2.65), 7.681 (3.35), 7.685 (3.28), 7.700 (2.12), 7.705 (2.00), 7.713 (2.63), 7.717 (2.11), 7.730 (2.22), 7.734 (3.33), 7.738 (2.95), 7.751 (2.01), 7.755 (2.23), 8.006 (8.90), 8.008 (6.40), 8.026 (6.26), 8.029 (6.86), 8.525 (2.91), 8.527 (3.11), 8.530 (3.43), 8.532 (2.84), 8.537 (2.93), 8.539 (3.27), 8.542 (3.14), 8.544 (2.60), 8.651 (5.38), 8.656 (5.70), 9.352 (8.48), 9.358 (8.43).    Example 151 (rac)-N-(1-benzylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000464_0002
LC-MS (Method 1): Rt = 1.24 min; MS (ESIpos): m/z = 479 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.721 (0.60), 1.742 (1.83), 1.764 (3.32), 1.785 (3.65), 1.807 (2.23), 2.042 (4.78), 2.062 (8.15), 2.080 (6.18), 2.106 (6.00), 2.130 (5.48), 2.148 (2.40), 2.160 (1.56), 2.178 (0.64), 2.552 (1.16), 2.568 (2.37), 2.583 (4.99), 2.601 (5.28), 2.616 (2.79), 2.632 (0.97), 2.648 (0.51), 3.040 (2.80), 3.073 (5.85), 3.118 (5.95), 3.150 (2.87), 3.391 (3.11), 3.399 (2.99), 3.416 (7.67), 3.427 (5.79), 3.453 (1.38), 3.487 (1.11), 3.505 (2.03), 4.269 (2.59), 4.276 (3.34), 4.287 (4.92), 4.293 (5.83), 4.303 (3.48), 4.310 (3.34), 4.338 (0.40), 5.798 (8.35), 6.751 (16.00), 7.121 (7.25), 7.138 (10.50), 7.141 (10.84), 7.155 (4.96), 7.174 (3.50), 7.218 (6.69), 7.237 (8.54), 7.254 (3.23), 7.596 (2.17), 7.614 (4.68), 7.634 (3.48), 7.708 (2.66), 7.712 (2.92), 7.729 (4.47), 7.733 (4.28), 7.747 (2.35), 7.750 (2.82), 8.000 (9.59), 8.021 (9.16), 8.665 (6.52), 8.670 (7.88), 9.359 (8.79), 9.365 (10.13).    Example 152 (rac)-2'-(quinolin-3-yl)-N-[1-(trifluoromethyl)cyclobutyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000464_0001
LC-MS (Method 1): Rt = 1.11 min; MS (ESIpos): m/z = 457 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.822 (0.47), 1.849 (1.11), 1.871 (1.46), 1.893 (1.21), 1.905 (0.68), 1.917 (1.12), 1.929 (1.26), 1.943 (1.18), 1.955 (1.04), 1.969 (0.73), 2.075 (0.53), 2.090 (0.64), 2.104 (1.63), 2.122 (2.54), 2.142 (2.68), 2.160 (1.34), 2.172 (0.85), 2.322 (0.49), 2.327 (0.70), 2.332 (0.67), 2.337 (1.08), 2.352 (1.18), 2.373 (2.88), 2.387 (2.75), 2.396 (2.21), 2.409 (1.77), 2.439 (1.52), 2.462 (2.84), 2.518 (3.11), 2.522 (1.93), 2.578 (3.51), 2.595 (5.48), 2.597 (5.42), 2.614 (4.01), 2.664 (0.48), 2.669 (0.63), 2.673 (0.47), 3.431 (0.79), 3.449 (1.93), 3.457 (1.49), 3.469 (1.55), 3.475 (2.99), 3.497 (12.90), 3.523 (0.73), 3.547 (1.15), 3.561 (1.47), 3.566 (1.92), 3.573 (1.28), 3.580 (1.47), 3.587 (1.20), 3.592 (1.15), 3.606 (0.74), 4.270 (4.26), 4.287 (7.04), 4.305 (4.13), 6.640 (5.49), 6.743 (16.00), 7.594 (2.12), 7.597 (1.82), 7.611 (3.09), 7.613 (3.94), 7.617 (2.65), 7.631 (2.66), 7.634 (2.91), 7.708 (2.97), 7.712 (2.34), 7.725 (2.55), 7.729 (3.87), 7.732 (3.30), 7.746 (2.23), 7.749 (2.32), 7.998 (9.78), 8.019 (7.04), 8.022 (7.19), 8.650 (5.93), 8.655 (6.29), 9.344 (9.20), 9.349 (9.32), 9.467 (0.41), 9.473 (0.40).    Example 153 (rac)-N-(1-methylcyclopentyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000465_0001
LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 417 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.330 (16.00), 1.466 (0.43), 1.482 (0.92), 1.497 (1.18), 1.515 (1.91), 1.525 (2.59), 1.545 (1.04), 1.549 (1.02), 1.556 (0.80), 1.563 (0.88), 1.593 (0.56), 1.625 (1.16), 1.638 (1.09), 1.653 (0.88), 1.660 (0.78), 1.965 (0.93), 1.974 (0.93), 1.995 (1.44), 2.009 (1.03), 2.068 (0.88), 2.081 (0.97), 2.085 (0.90), 2.095 (0.88), 2.113 (1.41), 2.125 (0.41), 2.132 (0.73), 2.144 (0.55), 2.518 (0.97), 2.522 (0.63), 2.557 (1.82), 2.575 (2.65), 2.592 (2.01), 3.417 (0.96), 3.424 (0.72), 3.434 (0.68), 3.442 (1.44), 3.459 (8.18), 3.518 (0.53), 3.532 (0.66), 3.537 (0.88), 3.544 (0.58), 3.551 (0.68), 3.558 (0.56), 3.563 (0.53), 4.261 (2.04), 4.279 (3.26), 4.296 (1.96), 5.494 (3.28), 6.727 (9.26), 7.591 (0.97), 7.594 (0.85), 7.609 (1.38), 7.611 (1.84), 7.615 (1.25), 7.629 (1.23), 7.632 (1.39), 7.706 (1.42), 7.709 (1.11), 7.723 (1.19), 7.727 (1.79), 7.730 (1.60), 7.744 (1.04), 7.747 (1.19), 7.996 (4.61), 8.018 (3.23), 8.020 (3.34), 8.644 (2.76), 8.649 (2.94), 9.340 (4.48), 9.346 (4.48).    Example 154 (rac)-N-(1-cyanocyclopropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000466_0001
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 399 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.123 (2.83), 1.137 (7.37), 1.143 (7.36), 1.156 (3.47), 1.404 (4.34), 1.416 (9.44), 1.423 (8.85), 1.436 (3.71), 2.074 (3.62), 2.083 (1.89), 2.099 (1.95), 2.113 (3.66), 2.130 (4.07), 2.148 (1.66), 2.160 (0.89), 2.179 (0.43), 2.518 (2.26), 2.522 (1.47), 2.571 (5.26), 2.589 (7.64), 2.606 (5.51), 3.438 (1.90), 3.468 (10.24), 3.532 (1.62), 4.261 (5.49), 4.278 (9.35), 4.296 (5.38), 5.772 (0.48), 6.738 (16.00), 7.348 (5.47), 7.591 (2.93), 7.594 (2.46), 7.608 (4.33), 7.611 (5.22), 7.628 (3.62), 7.631 (4.02), 7.705 (3.98), 7.709 (3.29), 7.723 (3.21), 7.726 (5.38), 7.730 (4.68), 7.744 (2.96), 7.747 (3.21), 7.993 (11.96), 7.995 (11.04), 8.017 (11.98), 8.652 (8.52), 8.657 (8.57), 9.345 (12.82), 9.350 (12.93).    Example 155 (rac)-N-[1-(propan-2-yl)cyclopropyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000467_0002
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 417 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.536 (0.95), 0.557 (4.58), 0.565 (3.45), 0.587 (3.27), 0.594 (4.70), 0.615 (0.87), 0.816 (1.45), 0.838 (14.73), 0.855 (15.20), 1.596 (0.51), 1.613 (1.36), 1.630 (1.80), 1.647 (1.26), 1.664 (0.45), 2.056 (0.42), 2.074 (16.00), 2.083 (2.00), 2.100 (1.03), 2.109 (1.78), 2.126 (0.89), 2.139 (0.59), 2.518 (1.63), 2.522 (1.08), 2.543 (1.52), 2.548 (1.48), 2.560 (2.99), 2.566 (2.96), 2.578 (1.64), 2.582 (1.66), 3.320 (0.45), 3.371 (0.51), 3.389 (1.16), 3.397 (0.89), 3.408 (0.73), 3.415 (1.78), 3.440 (9.37), 3.488 (0.67), 3.507 (1.12), 3.514 (0.76), 3.520 (0.86), 3.528 (0.70), 3.533 (0.67), 3.547 (0.42), 4.256 (2.57), 4.273 (4.99), 4.291 (2.52), 6.311 (3.94), 6.703 (10.85), 7.592 (1.25), 7.594 (1.06), 7.609 (1.89), 7.611 (2.15), 7.629 (1.61), 7.632 (1.70), 7.706 (1.71), 7.710 (1.46), 7.723 (1.39), 7.727 (2.18), 7.730 (1.99), 7.744 (1.32), 7.747 (1.40), 7.995 (5.82), 7.997 (4.59), 8.015 (4.07), 8.018 (4.94), 8.637 (3.75), 8.642 (3.87), 9.335 (5.50), 9.340 (5.46).    Example 156 (rac)-N-(2-cyanopropan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000467_0001
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.595 (15.79), 1.602 (16.00), 2.074 (1.03), 2.083 (0.62), 2.107 (0.89), 2.125 (1.58), 2.144 (1.68), 2.162 (0.79), 2.175 (0.47), 2.518 (1.86), 2.522 (1.18), 2.585 (2.28), 2.602 (3.35), 2.620 (2.43), 3.466 (0.43), 3.484 (1.11), 3.491 (0.99), 3.515 (5.44), 3.518 (5.88), 3.544 (0.55), 3.574 (0.62), 3.593 (1.04), 3.601 (0.67), 3.607 (0.78), 3.615 (0.62), 3.619 (0.62), 4.273 (2.42), 4.290 (3.74), 4.307 (2.33), 6.458 (3.45), 6.752 (8.52), 7.592 (1.17), 7.595 (1.04), 7.610 (1.75), 7.612 (2.36), 7.615 (1.53), 7.630 (1.54), 7.632 (1.66), 7.707 (1.58), 7.710 (1.37), 7.724 (1.43), 7.728 (2.30), 7.732 (1.86), 7.745 (1.29), 7.749 (1.41), 7.996 (5.43), 8.017 (3.92), 8.020 (3.75), 8.653 (3.29), 8.659 (3.41), 9.347 (5.25), 9.352 (5.21).    Example 157 (rac)-N-(2-phenylpropan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000468_0001
LC-MS (Method 1): Rt = 1.17 min; MS (ESIpos): m/z = 453 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.572 (15.49), 1.580 (16.00), 2.074 (14.55), 2.083 (1.06), 2.094 (1.04), 2.109 (1.28), 2.123 (1.16), 2.140 (1.60), 2.157 (0.91), 2.169 (0.62), 2.518 (1.10), 2.522 (0.72), 2.578 (2.28), 2.596 (3.46), 2.613 (2.49), 3.440 (0.41), 3.458 (0.94), 3.466 (0.82), 3.483 (1.99), 3.508 (3.70), 3.519 (3.36), 3.544 (0.76), 3.574 (0.59), 3.592 (1.02), 3.599 (0.75), 3.607 (0.79), 3.615 (0.72), 4.277 (2.68), 4.294 (4.44), 4.311 (2.60), 6.075 (4.91), 6.724 (12.39), 7.107 (0.66), 7.109 (1.20), 7.112 (0.74), 7.128 (3.12), 7.143 (1.22), 7.146 (2.04), 7.148 (1.18), 7.235 (3.39), 7.255 (5.64), 7.269 (1.12), 7.274 (3.44), 7.363 (5.15), 7.365 (5.52), 7.383 (4.37), 7.386 (3.31), 7.602 (1.32), 7.604 (1.13), 7.619 (1.98), 7.622 (2.38), 7.625 (1.76), 7.639 (1.70), 7.642 (1.85), 7.714 (1.85), 7.718 (1.53), 7.731 (1.51), 7.735 (2.30), 7.739 (2.17), 7.752 (1.35), 7.756 (1.56), 8.007 (6.45), 8.010 (4.80), 8.028 (4.46), 8.031 (5.12), 8.644 (3.99), 8.649 (4.16), 9.351 (6.01), 9.357 (5.90).    Example 158 (rac)-N-[1-(4-chlorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000469_0001
LC-MS (Method 1): Rt = 1.26 min; MS (ESIneg): m/z = 496 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.741 (0.59), 1.758 (1.13), 1.763 (1.19), 1.780 (1.23), 1.785 (1.38), 1.802 (0.85), 1.962 (0.54), 1.968 (0.72), 1.984 (1.29), 1.998 (1.01), 2.007 (1.16), 2.011 (1.16), 2.021 (0.69), 2.026 (0.68), 2.034 (0.61), 2.050 (0.55), 2.074 (3.82), 2.083 (2.34), 2.100 (2.04), 2.125 (2.30), 2.142 (1.24), 2.155 (0.83), 2.343 (0.96), 2.366 (2.10), 2.375 (2.47), 2.390 (2.82), 2.397 (2.35), 2.412 (1.62), 2.439 (1.16), 2.456 (2.02), 2.461 (2.65), 2.467 (2.43), 2.518 (3.13), 2.522 (2.01), 2.545 (0.56), 2.560 (2.35), 2.565 (2.39), 2.577 (4.36), 2.583 (4.41), 2.595 (2.47), 2.599 (2.53), 2.615 (0.45), 3.411 (0.64), 3.429 (1.43), 3.436 (1.32), 3.448 (2.08), 3.454 (2.25), 3.474 (6.25), 3.482 (4.92), 3.508 (0.92), 3.539 (0.90), 3.556 (1.52), 3.570 (1.22), 3.578 (1.07), 3.597 (0.59), 4.265 (3.91), 4.282 (7.80), 4.300 (3.81), 6.706 (16.00), 6.788 (6.27), 7.315 (0.99), 7.321 (10.00), 7.326 (3.27), 7.338 (3.83), 7.343 (14.26), 7.350 (1.70), 7.431 (1.73), 7.438 (13.52), 7.443 (3.78), 7.454 (3.17), 7.459 (9.05), 7.466 (1.02), 7.596 (2.04), 7.599 (1.86), 7.613 (2.96), 7.616 (4.05), 7.619 (2.61), 7.634 (2.62), 7.637 (2.86), 7.710 (2.71), 7.713 (2.53), 7.727 (2.37), 7.730 (4.15), 7.734 (3.16), 7.747 (2.26), 7.751 (2.36), 8.002 (8.36), 8.023 (6.96), 8.636 (5.73), 8.641 (5.95), 9.344 (8.96), 9.349 (8.84).    Example 159 (rac)-N-(1-phenylcyclopropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000470_0002
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 451 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.117 (1.16), 1.134 (3.48), 1.140 (4.44), 1.148 (3.85), 1.175 (3.60), 1.183 (4.58), 1.204 (1.08), 2.074 (16.00), 2.083 (0.76), 2.095 (0.45), 2.109 (1.04), 2.128 (1.50), 2.149 (1.65), 2.167 (0.86), 2.179 (0.54), 2.518 (1.16), 2.522 (0.82), 2.582 (2.23), 2.599 (3.52), 2.602 (3.54), 2.618 (2.55), 3.441 (0.51), 3.459 (1.23), 3.466 (1.00), 3.476 (1.39), 3.485 (1.87), 3.502 (6.42), 3.506 (6.06), 3.532 (0.69), 3.565 (0.72), 3.583 (1.26), 3.590 (0.84), 3.597 (0.94), 3.604 (0.80), 3.609 (0.77), 3.623 (0.47), 4.273 (2.77), 4.291 (4.63), 4.308 (2.67), 6.736 (11.07), 7.091 (4.22), 7.098 (2.47), 7.101 (1.38), 7.111 (1.01), 7.116 (3.39), 7.120 (1.34), 7.130 (1.16), 7.133 (2.07), 7.136 (1.33), 7.168 (3.02), 7.171 (3.96), 7.184 (1.64), 7.189 (6.99), 7.193 (5.37), 7.232 (5.11), 7.237 (1.61), 7.250 (5.20), 7.266 (0.94), 7.270 (2.21), 7.599 (1.43), 7.602 (1.23), 7.617 (2.14), 7.620 (2.57), 7.637 (1.77), 7.639 (1.97), 7.712 (2.04), 7.716 (1.58), 7.729 (1.65), 7.732 (2.58), 7.737 (2.33), 7.750 (1.46), 7.754 (1.69), 8.003 (5.79), 8.006 (5.26), 8.026 (5.82), 8.651 (4.17), 8.656 (4.15), 9.352 (6.43), 9.357 (6.40).    Example 160 (rac)-N-(2,2-dimethylpropyl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000470_0001
LC-MS (Method 1): Rt = 1.15 min; MS (ESIneg): m/z = 416 [M-H]-  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.810 (0.55), 0.841 (16.00), 1.824 (0.50), 1.839 (0.52), 2.056 (0.43), 2.069 (0.44), 2.522 (0.65), 2.897 (1.26), 2.912 (1.29), 3.450 (0.42), 3.476 (1.41), 3.485 (1.26), 4.178 (0.51), 4.193 (1.08), 4.208 (0.51), 6.039 (0.56), 6.789 (2.35), 7.611 (0.46), 7.614 (0.65), 7.631 (0.42), 7.634 (0.43), 7.708 (0.41), 7.729 (0.66), 7.733 (0.50), 7.998 (1.08), 8.019 (0.92), 8.606 (0.92), 8.611 (0.96), 9.312 (1.29), 9.317 (1.33).    Example 161 (rac)-N-(cuban-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide 
Figure imgf000471_0001
LC-MS (Method 1): Rt = 1.15 min; MS (ESIneg): m/z = 434 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.074 (8.21), 2.095 (1.42), 2.114 (2.33), 2.133 (2.54), 2.151 (1.23), 2.164 (0.77), 2.518 (1.44), 2.522 (0.95), 2.570 (3.55), 2.587 (5.30), 2.605 (3.77), 3.320 (0.59), 3.423 (0.68), 3.442 (1.72), 3.449 (1.37), 3.460 (1.21), 3.468 (2.98), 3.480 (14.38), 3.533 (0.96), 3.551 (1.68), 3.558 (1.09), 3.565 (1.26), 3.572 (1.00), 3.577 (0.97), 3.591 (0.61), 3.788 (0.50), 3.794 (2.80), 3.806 (6.92), 3.819 (8.26), 3.825 (2.39), 3.831 (4.96), 3.885 (1.18), 3.891 (1.77), 3.897 (2.36), 3.903 (2.62), 3.909 (2.19), 3.914 (1.85), 3.921 (0.93), 3.927 (0.62), 4.024 (4.83), 4.029 (5.97), 4.036 (6.56), 4.040 (6.95), 4.049 (5.04), 4.055 (3.52), 4.264 (3.75), 4.282 (5.68), 4.299 (3.59), 6.746 (16.00), 6.920 (5.87), 7.591 (1.87), 7.594 (1.62), 7.608 (2.73), 7.610 (3.38), 7.614 (2.37), 7.629 (2.36), 7.631 (2.60), 7.705 (2.66), 7.709 (2.04), 7.722 (2.18), 7.727 (3.28), 7.730 (3.01), 7.743 (1.92), 7.747 (2.23), 7.995 (8.87), 7.998 (6.22), 8.016 (6.22), 8.019 (6.68), 8.658 (5.42), 8.663 (5.75), 9.350 (8.65), 9.356 (8.16).    Example 162 (rac)-N-(3,3-dimethylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000472_0001
LC-MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 417 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.074 (16.00), 1.101 (12.34), 1.730 (0.52), 1.754 (1.28), 1.758 (1.21), 1.782 (1.49), 1.805 (0.67), 1.953 (1.50), 1.962 (0.77), 1.972 (2.03), 1.977 (1.41), 1.981 (1.78), 1.993 (0.65), 2.001 (1.11), 2.075 (2.77), 2.092 (1.48), 2.110 (1.76), 2.128 (0.69), 2.518 (1.23), 2.522 (0.79), 2.563 (1.80), 2.580 (2.65), 2.597 (1.88), 3.422 (0.83), 3.429 (0.98), 3.447 (1.60), 3.457 (5.02), 3.508 (0.49), 3.526 (0.88), 3.533 (0.53), 3.540 (0.63), 3.547 (0.51), 3.551 (0.51), 4.098 (0.57), 4.119 (1.09), 4.139 (1.08), 4.160 (0.53), 4.260 (1.88), 4.278 (2.82), 4.295 (1.80), 6.258 (1.56), 6.278 (1.52), 6.732 (8.29), 7.590 (0.91), 7.592 (0.77), 7.607 (1.36), 7.610 (1.54), 7.627 (1.16), 7.630 (1.24), 7.704 (1.26), 7.708 (1.08), 7.721 (1.00), 7.725 (1.58), 7.728 (1.47), 7.742 (0.97), 7.746 (1.03), 7.993 (4.20), 7.996 (3.30), 8.014 (2.91), 8.017 (3.68), 8.660 (2.75), 8.665 (2.82), 9.349 (4.09), 9.355 (4.18).    Example 163 (rac)-N-[(cis/trans)-3-(dimethylamino)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereoisomers) 
Figure imgf000473_0001
LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 432 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.737 (0.66), 1.742 (0.56), 1.760 (0.55), 1.977 (0.45), 1.991 (0.58), 2.010 (16.00), 2.032 (14.45), 2.058 (0.55), 2.069 (0.71), 2.078 (1.00), 2.090 (1.50), 2.099 (1.18), 2.107 (1.32), 2.116 (0.93), 2.236 (0.55), 2.249 (0.97), 2.266 (0.68), 2.270 (0.65), 2.281 (0.41), 2.287 (0.57), 2.518 (0.65), 2.522 (0.42), 2.558 (0.92), 2.567 (0.91), 2.576 (1.46), 2.582 (1.30), 2.592 (1.10), 2.601 (0.81), 3.419 (0.49), 3.431 (0.55), 3.444 (0.90), 3.457 (3.38), 3.470 (2.26), 3.522 (0.60), 3.537 (0.56), 3.547 (0.44), 4.258 (1.04), 4.262 (0.99), 4.276 (1.78), 4.292 (1.08), 4.297 (0.88), 6.295 (0.74), 6.315 (0.76), 6.326 (0.65), 6.343 (0.60), 6.727 (4.24), 6.735 (3.34), 7.589 (0.77), 7.592 (0.66), 7.606 (1.16), 7.609 (1.35), 7.627 (1.00), 7.629 (1.07), 7.703 (1.05), 7.707 (0.92), 7.721 (0.88), 7.725 (1.35), 7.728 (1.25), 7.742 (0.86), 7.746 (0.90), 7.993 (3.60), 7.996 (2.85), 8.014 (2.54), 8.017 (3.14), 8.660 (2.32), 8.665 (2.35), 9.350 (3.70), 9.356 (3.70).      Example 164 (rac)-N-(1-cyanocyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000474_0002
LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 414 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.943 (0.92), 1.958 (1.63), 1.967 (3.80), 1.981 (3.29), 1.987 (5.28), 1.995 (2.25), 2.007 (3.53), 2.016 (1.13), 2.027 (0.94), 2.036 (0.52), 2.074 (1.60), 2.118 (1.82), 2.135 (3.28), 2.154 (3.36), 2.172 (1.60), 2.185 (0.95), 2.204 (0.45), 2.322 (1.77), 2.327 (2.29), 2.332 (2.49), 2.343 (2.85), 2.353 (2.49), 2.364 (2.85), 2.518 (5.29), 2.522 (3.61), 2.537 (4.29), 2.544 (2.99), 2.551 (3.94), 2.558 (2.54), 2.564 (3.25), 2.570 (2.50), 2.579 (1.46), 2.591 (5.42), 2.609 (7.65), 2.626 (5.38), 2.664 (0.67), 2.669 (0.91), 2.673 (0.67), 3.455 (1.01), 3.473 (2.49), 3.482 (2.32), 3.491 (1.76), 3.499 (4.23), 3.513 (14.59), 3.539 (1.16), 3.565 (1.36), 3.584 (2.35), 3.592 (1.53), 3.598 (1.77), 3.610 (1.42), 3.625 (0.82), 4.275 (5.57), 4.292 (8.96), 4.309 (5.36), 6.753 (16.00), 7.088 (5.97), 7.592 (2.91), 7.595 (2.43), 7.610 (4.32), 7.613 (4.83), 7.630 (3.65), 7.633 (3.84), 7.707 (4.08), 7.711 (3.22), 7.724 (3.26), 7.728 (4.95), 7.732 (4.66), 7.745 (3.03), 7.749 (3.39), 7.995 (12.83), 7.998 (10.50), 8.017 (8.90), 8.019 (11.56), 8.654 (8.39), 8.659 (8.32), 9.348 (13.11), 9.354 (12.66).    Example 165 (rac)-N-(bicyclo[1.1.1]pentan-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000474_0001
LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 400 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.952 (16.00), 2.086 (0.57), 2.103 (0.71), 2.354 (2.90), 2.518 (0.40), 2.556 (0.72), 2.573 (1.05), 2.591 (0.76), 3.412 (0.66), 3.420 (0.88), 3.430 (2.91), 4.256 (0.74), 4.274 (1.12), 4.291 (0.71), 6.740 (3.14), 6.830 (1.08), 7.613 (0.51), 7.615 (0.69), 7.618 (0.44), 7.633 (0.44), 7.636 (0.49), 7.710 (0.47), 7.732 (0.68), 7.735 (0.55), 7.998 (1.51), 8.020 (1.18), 8.022 (1.09), 8.676 (0.96), 8.681 (1.00), 9.356 (1.56), 9.362 (1.49).  Example 166 (rac)-N-(3,3-difluorocyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000475_0001
LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 424 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.022 (0.57), 1.039 (0.49), 1.147 (1.55), 1.163 (1.64), 1.227 (0.41), 2.074 (0.97), 2.083 (0.85), 2.100 (2.11), 2.114 (4.04), 2.131 (4.60), 2.148 (1.84), 2.162 (0.92), 2.179 (0.44), 2.327 (0.50), 2.522 (1.67), 2.575 (5.21), 2.592 (8.15), 2.609 (6.21), 2.635 (2.10), 2.651 (1.79), 2.665 (2.07), 2.680 (1.23), 2.693 (0.86), 2.712 (0.48), 2.772 (1.16), 2.783 (1.60), 2.793 (1.77), 2.807 (2.79), 2.817 (2.75), 2.827 (2.64), 2.838 (2.51), 2.848 (1.26), 2.862 (1.05), 2.872 (0.71), 3.424 (1.07), 3.441 (2.42), 3.449 (2.74), 3.476 (13.99), 3.502 (1.02), 3.524 (1.38), 3.542 (2.41), 3.549 (1.52), 3.557 (1.73), 3.565 (1.46), 3.582 (0.78), 3.972 (0.69), 3.992 (1.50), 4.010 (1.85), 4.029 (1.37), 4.043 (0.56), 4.264 (4.88), 4.282 (7.71), 4.299 (4.58), 6.611 (3.93), 6.628 (3.80), 6.741 (16.00), 7.591 (2.20), 7.594 (2.00), 7.611 (4.11), 7.629 (2.92), 7.631 (3.05), 7.705 (2.93), 7.708 (2.55), 7.722 (2.76), 7.726 (4.03), 7.729 (3.44), 7.743 (2.32), 7.747 (2.38), 7.994 (10.27), 8.017 (8.88), 8.660 (7.11), 8.665 (6.97), 9.351 (9.21), 9.357 (8.79).    Example 167 (rac)-N-[(cis/trans)-3-methylcyclobutyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereoisomers) 
Figure imgf000476_0001
LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 403 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (1.22), 1.029 (1.23), 1.099 (0.59), 1.115 (0.60), 2.074 (0.43), 2.109 (0.48), 2.518 (1.16), 2.523 (0.81), 2.562 (0.41), 2.578 (0.62), 2.596 (0.42), 3.159 (3.62), 3.171 (3.48), 3.451 (1.12), 3.459 (0.60), 4.098 (0.76), 4.111 (0.80), 4.260 (0.51), 4.278 (0.71), 4.295 (0.44), 5.758 (16.00), 6.731 (1.80), 7.993 (1.06), 7.996 (0.76), 8.014 (0.72), 8.017 (0.81), 8.661 (0.63), 8.666 (0.64), 9.349 (0.90), 9.354 (0.86).    Example 168 (rac)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000476_0002
LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 418 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.085 (0.55), 2.099 (1.04), 2.116 (1.24), 2.134 (0.47), 2.268 (16.00), 2.274 (15.69), 2.518 (0.70), 2.523 (0.49), 2.561 (1.35), 2.578 (1.96), 2.596 (1.40), 3.421 (0.61), 3.429 (0.53), 3.455 (5.02), 3.520 (0.63), 3.535 (0.45), 4.257 (1.39), 4.275 (2.10), 4.291 (1.34), 6.740 (6.05), 6.971 (2.07), 7.591 (0.72), 7.594 (0.59), 7.608 (1.04), 7.611 (1.15), 7.613 (0.85), 7.628 (0.88), 7.631 (0.97), 7.705 (0.99), 7.708 (0.82), 7.722 (0.80), 7.725 (1.17), 7.729 (1.09), 7.743 (0.77), 7.747 (0.78), 7.993 (3.22), 7.996 (2.43), 8.014 (2.18), 8.017 (2.66), 8.661 (2.07), 8.666 (2.05), 9.349 (3.03), 9.354 (3.04).    Example 169 (rac)-N-(1-methylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000477_0001
LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 402 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.391 (16.00), 1.713 (1.22), 1.727 (1.54), 1.732 (1.72), 1.736 (1.76), 1.749 (2.08), 1.760 (1.00), 1.772 (0.84), 1.829 (1.03), 1.838 (1.28), 1.847 (1.53), 1.857 (1.79), 1.869 (1.65), 1.875 (1.21), 1.888 (0.79), 2.056 (0.43), 2.061 (0.45), 2.073 (1.16), 2.087 (1.33), 2.091 (1.35), 2.104 (1.01), 2.114 (1.86), 2.133 (0.93), 2.145 (0.65), 2.220 (0.66), 2.243 (1.73), 2.266 (1.53), 2.287 (0.50), 2.518 (1.37), 2.523 (0.94), 2.561 (2.41), 2.578 (3.47), 2.596 (2.60), 3.392 (0.51), 3.411 (1.27), 3.418 (0.94), 3.429 (0.86), 3.437 (1.90), 3.455 (10.87), 3.511 (0.72), 3.525 (0.89), 3.530 (1.15), 3.537 (0.77), 3.544 (0.88), 3.551 (0.72), 3.556 (0.68), 3.570 (0.44), 4.263 (2.65), 4.280 (4.11), 4.297 (2.55), 6.005 (4.07), 6.737 (11.74), 7.592 (1.31), 7.595 (1.14), 7.609 (1.88), 7.611 (2.51), 7.615 (1.60), 7.629 (1.60), 7.632 (1.80), 7.706 (1.77), 7.710 (1.53), 7.723 (1.55), 7.727 (2.61), 7.731 (1.99), 7.744 (1.40), 7.748 (1.52), 7.997 (5.47), 8.018 (4.14), 8.021 (3.72), 8.652 (3.52), 8.657 (3.65), 9.346 (5.75), 9.352 (5.69).    Example 170 (rac)-2-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000478_0001
LC-MS (Method 1): Rt = 1.19 min; MS (ESIpos): m/z = 523 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.958 (2.09), 1.126 (0.41), 1.176 (0.41), 1.263 (4.62), 1.281 (4.66), 1.354 (9.76), 1.365 (10.74), 1.371 (11.27), 1.382 (9.02), 2.095 (2.37), 2.112 (4.09), 2.130 (3.87), 2.148 (1.88), 2.327 (1.21), 2.573 (4.79), 2.590 (7.84), 2.608 (5.12), 2.668 (1.27), 3.456 (1.74), 3.466 (3.25), 3.492 (6.20), 3.507 (11.40), 3.540 (2.01), 3.561 (1.80), 3.585 (2.25), 3.600 (1.47), 3.625 (0.59), 4.271 (4.64), 4.288 (8.35), 4.305 (4.48), 4.668 (0.59), 4.686 (0.84), 4.703 (0.59), 4.838 (2.17), 4.856 (3.23), 4.875 (2.13), 6.261 (1.08), 6.281 (1.04), 6.507 (2.91), 6.516 (2.91), 6.527 (3.05), 6.535 (2.60), 6.715 (16.00), 7.072 (2.91), 7.095 (6.16), 7.105 (4.91), 7.117 (4.21), 7.128 (9.04), 7.150 (4.99), 7.218 (4.07), 7.273 (1.55), 7.287 (1.80), 7.294 (1.58), 7.309 (1.29), 7.352 (3.27), 7.366 (4.11), 7.375 (5.03), 7.381 (3.46), 7.390 (5.40), 7.401 (9.72), 7.412 (3.40), 7.552 (4.60), 7.558 (4.71), 7.575 (4.87), 7.582 (5.85), 7.585 (4.95), 7.761 (7.20), 8.056 (7.80), 8.079 (7.08), 8.663 (7.96), 9.324 (6.42), 9.328 (8.80), 9.332 (6.12).    Example 171 (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-phenylethyl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000479_0002
LC-MS (Method 1): Rt = 1.18 min; MS (ESIpos): m/z = 505 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.966 (2.69), 1.165 (0.63), 1.274 (2.48), 1.291 (2.59), 1.349 (5.70), 1.364 (16.00), 1.376 (14.34), 1.382 (14.60), 1.393 (12.15), 1.408 (5.23), 1.450 (3.46), 2.099 (3.72), 2.114 (6.02), 2.133 (5.62), 2.326 (1.64), 2.576 (7.08), 2.593 (11.62), 2.611 (7.29), 2.669 (1.74), 3.477 (4.65), 3.503 (8.37), 3.516 (12.67), 3.547 (2.83), 3.572 (3.14), 3.590 (3.22), 4.273 (6.76), 4.290 (11.06), 4.306 (6.23), 4.696 (0.50), 4.844 (2.96), 4.862 (4.41), 4.881 (2.96), 6.250 (0.58), 6.270 (0.58), 6.499 (4.15), 6.513 (4.12), 6.708 (8.90), 6.715 (10.53), 7.152 (1.29), 7.170 (3.35), 7.197 (3.91), 7.219 (5.49), 7.257 (4.04), 7.276 (8.11), 7.294 (8.37), 7.311 (9.21), 7.330 (13.68), 7.357 (9.98), 7.376 (4.94), 7.405 (8.05), 7.553 (5.41), 7.559 (5.62), 7.575 (5.86), 7.582 (6.63), 7.760 (9.21), 7.868 (0.82), 7.893 (0.63), 8.057 (8.69), 8.080 (7.92), 8.527 (0.84), 8.661 (9.50), 9.154 (0.90), 9.326 (10.19).    Example 172 (rac)-N-[2-(3-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000479_0001
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.57 (2s, 6H), 2.06 - 2.21 (m, 2H), 2.56 - 2.63 (m, 2H), 3.43 - 3.56 (m, 3H), 3.57 - 3.65 (m, 1H), 4.29 (t, 2H), 6.15 (s, 1H), 6.72 (s, 1H), 6.93 - 6.99 (m, 1H), 7.15 (dt, 1H), 7.20 (d, 1H), 7.30 (td, 1H), 7.59 - 7.65 (m, 1H), 7.73 (ddd, 1H), 7.99 - 8.04 (m, 2H), 8.64 (d, 1H), 9.35 (d, 1H).     Example 173 (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-N-[2-(pyridin-4-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000480_0001
LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 511 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (3.03), 0.935 (0.99), 0.948 (3.14), 0.952 (0.51), 1.341 (0.51), 1.354 (15.70), 1.356 (15.83), 1.368 (16.00), 1.370 (15.85), 1.546 (14.63), 1.553 (15.45), 2.080 (0.48), 2.096 (0.91), 2.111 (1.13), 2.127 (1.17), 2.144 (1.36), 2.163 (0.81), 2.175 (0.58), 2.323 (0.71), 2.327 (0.99), 2.331 (0.71), 2.404 (0.43), 2.518 (5.82), 2.523 (4.14), 2.577 (2.05), 2.593 (3.06), 2.612 (2.10), 2.665 (0.69), 2.669 (1.01), 2.673 (0.68), 3.474 (1.39), 3.484 (1.26), 3.500 (2.80), 3.519 (2.25), 3.544 (0.78), 3.571 (0.51), 3.590 (0.89), 4.270 (2.27), 4.288 (4.02), 4.304 (2.32), 4.756 (0.61), 4.771 (1.62), 4.786 (2.23), 4.802 (1.65), 4.816 (0.65), 6.257 (4.58), 6.674 (11.43), 7.310 (2.80), 7.317 (3.21), 7.327 (6.85), 7.332 (5.39), 7.339 (6.54), 7.343 (6.95), 7.402 (4.05), 7.408 (3.41), 7.881 (3.82), 7.904 (3.51), 8.425 (7.69), 8.429 (4.32), 8.437 (4.27), 8.441 (7.23), 8.515 (3.57), 8.519 (3.64), 9.156 (6.20), 9.161 (5.76).    Example 174 (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000481_0001
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 519 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (0.78), 0.948 (0.79), 1.601 (16.00), 2.117 (0.54), 2.131 (0.63), 2.147 (0.67), 2.165 (0.81), 2.183 (0.46), 2.327 (0.49), 2.518 (1.84), 2.523 (1.15), 2.596 (1.25), 2.614 (1.83), 2.632 (1.33), 2.669 (0.50), 3.487 (0.50), 3.494 (0.45), 3.512 (0.79), 3.530 (3.98), 3.609 (0.55), 3.622 (0.43), 4.286 (1.19), 4.304 (2.04), 4.322 (1.15), 6.469 (2.37), 6.758 (6.26), 7.174 (0.91), 7.177 (1.00), 7.186 (0.95), 7.189 (1.09), 7.193 (1.09), 7.195 (1.00), 7.205 (1.06), 7.207 (1.04), 7.223 (1.77), 7.407 (3.64), 7.471 (1.64), 7.492 (1.87), 7.554 (1.36), 7.561 (1.40), 7.577 (1.40), 7.584 (1.53), 7.592 (1.66), 7.696 (1.02), 7.700 (1.01), 7.715 (1.16), 7.719 (1.21), 7.734 (0.79), 7.739 (0.75), 7.767 (1.97), 7.774 (1.86), 8.060 (2.14), 8.083 (1.92), 8.454 (1.10), 8.457 (1.19), 8.459 (1.28), 8.461 (1.10), 8.466 (1.13), 8.469 (1.25), 8.471 (1.17), 8.473 (1.00), 8.672 (2.00), 8.677 (2.06), 9.334 (3.41), 9.340 (3.30).    Example 175 (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[2-(pyridin-4-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000482_0001
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 519 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (0.75), 0.949 (0.75), 1.552 (16.00), 2.084 (0.46), 2.101 (0.82), 2.115 (1.02), 2.130 (1.02), 2.148 (1.23), 2.166 (0.77), 2.178 (0.54), 2.322 (0.81), 2.327 (1.11), 2.331 (0.84), 2.518 (8.58), 2.522 (6.08), 2.582 (1.98), 2.598 (2.84), 2.601 (2.86), 2.617 (1.94), 2.665 (0.86), 2.669 (1.19), 2.673 (0.90), 3.483 (1.15), 3.490 (1.15), 3.509 (2.88), 3.518 (2.46), 3.544 (0.59), 3.571 (0.48), 3.590 (0.81), 4.282 (2.03), 4.299 (3.65), 4.317 (2.03), 6.256 (3.95), 6.724 (0.84), 6.739 (9.32), 7.227 (2.63), 7.326 (5.76), 7.331 (3.66), 7.338 (3.72), 7.342 (5.77), 7.404 (0.56), 7.411 (5.33), 7.559 (2.00), 7.566 (2.21), 7.581 (2.15), 7.588 (2.63), 7.595 (2.51), 7.776 (3.01), 7.783 (2.90), 8.064 (3.30), 8.087 (3.01), 8.425 (6.66), 8.429 (3.82), 8.437 (3.68), 8.441 (6.31), 8.669 (3.07), 8.674 (3.20), 9.312 (0.42), 9.318 (0.46), 9.334 (5.16), 9.340 (5.05).    Example 176 (rac)-N-[2-(3-fluoropyridin-2-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000483_0002
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.65 (s, 6H), 2.06 - 2.21 (m, 2H), 2.57 - 2.61 (m, 2H), 3.41 - 3.52 (m, 3H), 3.54 - 3.61 (m, 1H), 4.29 (t, 2H), 6.51 (s, 1H), 6.73 (s, 1H), 7.34 (ddd, 1H), 7.55 - 7.64 (m, 2H), 7.73 (ddd, 1H), 8.00 - 8.03 (m, 2H), 8.32 (dt, 1H), 8.65 (d, 1H), 9.35 (d, 1H).   LC-MS (Method 1): Rt = 1.12 min; MS (ESIneg): m/z = 469 [M-H]-    Example 177 (rac)-N-[2-(2,6-difluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000483_0001
LC-MS (Method 1): Rt = 1.23 min; MS (ESIneg): m/z = 487 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.956 (0.90), 0.970 (0.84), 1.707 (16.00), 2.074 (1.32), 2.091 (1.47), 2.105 (1.28), 2.121 (1.92), 2.138 (1.09), 2.150 (0.75), 2.518 (4.76), 2.523 (3.68), 2.536 (2.10), 2.553 (3.57), 2.568 (3.45), 2.584 (1.67), 2.600 (0.65), 2.617 (0.47), 3.314 (0.80), 3.383 (1.08), 3.402 (1.57), 3.426 (2.23), 3.453 (8.43), 3.480 (0.55), 3.502 (0.81), 3.521 (1.28), 3.535 (1.12), 3.561 (0.57), 4.261 (2.89), 4.279 (5.77), 4.296 (2.88), 6.296 (5.41), 6.680 (11.27), 6.891 (0.40), 6.905 (2.66), 6.928 (3.64), 6.952 (3.11), 6.965 (0.46), 7.185 (0.54), 7.200 (1.35), 7.206 (1.09), 7.221 (2.15), 7.236 (1.11), 7.241 (1.19), 7.256 (0.58), 7.600 (1.45), 7.603 (1.39), 7.619 (3.02), 7.640 (2.07), 7.713 (1.97), 7.716 (1.92), 7.730 (1.77), 7.734 (3.17), 7.738 (2.34), 7.751 (1.71), 7.755 (1.69), 8.006 (5.00), 8.028 (4.55), 8.628 (4.21), 8.632 (4.36), 9.332 (6.17), 9.338 (6.34).    Example 178 (rac)-N-[2-(2-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000484_0001
LC-MS (Method 1): Rt = 1.17 min; MS (ESIneg): m/z = 468 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.917 (0.59), 0.931 (4.90), 0.934 (1.52), 0.948 (4.79), 0.952 (0.77), 1.648 (16.00), 2.084 (0.46), 2.097 (0.96), 2.111 (1.18), 2.126 (1.09), 2.144 (1.48), 2.161 (0.84), 2.173 (0.58), 2.404 (0.50), 2.422 (0.49), 2.518 (3.44), 2.523 (2.14), 2.572 (1.61), 2.575 (1.59), 2.588 (2.83), 2.594 (2.78), 2.609 (1.66), 3.435 (0.41), 3.452 (0.95), 3.460 (0.83), 3.472 (1.27), 3.478 (1.47), 3.498 (4.32), 3.506 (3.86), 3.532 (0.64), 3.559 (0.59), 3.578 (1.00), 3.585 (0.72), 3.592 (0.77), 3.599 (0.67), 4.274 (2.45), 4.291 (4.86), 4.309 (2.34), 6.115 (4.46), 6.720 (10.76), 7.028 (1.03), 7.031 (1.15), 7.048 (1.37), 7.051 (1.50), 7.060 (1.06), 7.063 (1.28), 7.070 (1.41), 7.074 (1.23), 7.083 (1.76), 7.089 (2.99), 7.092 (2.16), 7.108 (2.02), 7.111 (1.59), 7.183 (0.70), 7.187 (0.83), 7.195 (0.83), 7.200 (1.13), 7.207 (1.03), 7.214 (1.08), 7.219 (1.04), 7.226 (0.55), 7.233 (0.50), 7.238 (0.46), 7.321 (1.13), 7.326 (1.11), 7.343 (1.76), 7.362 (1.01), 7.366 (0.85), 7.601 (1.22), 7.604 (1.10), 7.618 (1.85), 7.621 (2.54), 7.624 (1.57), 7.639 (1.62), 7.641 (1.67), 7.714 (1.73), 7.717 (1.55), 7.731 (1.48), 7.735 (2.44), 7.739 (1.98), 7.752 (1.39), 7.756 (1.46), 8.007 (4.92), 8.028 (4.13), 8.642 (3.45), 8.647 (3.56), 9.345 (5.44), 9.351 (5.43).    Example 179 (rac)-N-[2-(4-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000485_0002
LC-MS (Method 1): Rt = 1.23 min; MS (ESIneg): m/z = 484 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.82), 0.948 (0.80), 1.549 (15.30), 1.561 (16.00), 2.074 (0.88), 2.090 (1.12), 2.105 (1.40), 2.118 (1.23), 2.135 (1.73), 2.153 (0.99), 2.166 (0.67), 2.332 (0.60), 2.518 (3.28), 2.522 (2.01), 2.574 (1.98), 2.588 (3.40), 2.593 (3.44), 2.609 (2.09), 2.673 (0.62), 3.429 (0.44), 3.447 (1.00), 3.454 (0.90), 3.471 (2.02), 3.497 (3.89), 3.507 (3.38), 3.533 (0.75), 3.563 (0.62), 3.582 (1.09), 3.596 (0.86), 3.603 (0.79), 3.622 (0.42), 4.275 (2.89), 4.292 (5.48), 4.310 (2.84), 6.148 (5.40), 6.724 (13.93), 7.274 (0.65), 7.281 (6.55), 7.286 (2.15), 7.297 (2.77), 7.302 (11.35), 7.309 (1.37), 7.359 (1.42), 7.365 (10.52), 7.370 (2.69), 7.381 (2.11), 7.387 (5.78), 7.393 (0.65), 7.600 (1.48), 7.603 (1.45), 7.618 (2.21), 7.620 (3.17), 7.623 (1.80), 7.638 (2.03), 7.641 (2.09), 7.713 (2.14), 7.717 (1.99), 7.730 (1.70), 7.734 (3.13), 7.737 (2.42), 7.751 (1.72), 7.754 (1.74), 8.007 (3.74), 8.009 (3.92), 8.014 (2.93), 8.030 (3.79), 8.645 (4.16), 8.651 (4.28), 9.353 (6.47), 9.359 (6.62).    Example 180 (rac)-N-[1-(2-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000485_0001
LC-MS (Method 1): Rt = 1.24 min; MS (ESIneg): m/z = 481 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (3.03), 0.935 (0.98), 0.948 (3.04), 0.953 (0.52), 1.712 (0.56), 1.725 (0.82), 1.733 (1.27), 1.739 (1.22), 1.746 (1.35), 1.753 (1.13), 1.760 (1.44), 1.768 (0.80), 1.774 (0.90), 1.782 (0.64), 2.020 (0.95), 2.043 (1.90), 2.061 (3.11), 2.079 (2.82), 2.103 (2.75), 2.121 (1.43), 2.133 (0.96), 2.152 (0.44), 2.332 (1.52), 2.336 (0.68), 2.518 (12.68), 2.522 (8.69), 2.540 (6.92), 2.557 (7.19), 2.563 (7.27), 2.576 (3.96), 2.669 (2.17), 2.673 (1.58), 2.678 (0.72), 3.386 (0.74), 3.404 (1.74), 3.411 (1.52), 3.425 (2.54), 3.430 (2.77), 3.450 (6.87), 3.461 (5.68), 3.487 (1.39), 3.505 (1.12), 3.523 (1.84), 3.531 (1.31), 3.537 (1.41), 3.545 (1.19), 3.563 (0.68), 4.251 (4.32), 4.268 (8.89), 4.286 (4.17), 6.612 (6.95), 6.661 (16.00), 7.040 (1.81), 7.043 (2.00), 7.060 (2.43), 7.063 (2.77), 7.069 (1.95), 7.072 (2.30), 7.077 (2.91), 7.080 (2.45), 7.092 (3.47), 7.096 (6.73), 7.099 (4.57), 7.114 (3.66), 7.117 (2.83), 7.186 (1.35), 7.191 (1.52), 7.199 (1.55), 7.204 (2.28), 7.211 (1.91), 7.218 (1.97), 7.224 (2.01), 7.230 (0.99), 7.238 (0.92), 7.242 (0.86), 7.423 (2.04), 7.428 (2.06), 7.444 (3.17), 7.463 (1.87), 7.468 (1.57), 7.596 (2.33), 7.599 (1.96), 7.613 (3.38), 7.616 (3.85), 7.634 (2.85), 7.636 (3.18), 7.709 (3.32), 7.713 (2.68), 7.726 (2.67), 7.730 (3.98), 7.733 (3.78), 7.747 (2.42), 7.751 (2.73), 7.998 (10.32), 8.001 (8.29), 8.019 (7.34), 8.022 (9.34), 8.618 (6.72), 8.623 (6.77), 9.321 (10.10), 9.327 (9.47).    Example 181 (rac)-N-[2-(2-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000486_0001
LC-MS (Method 1): Rt = 1.25 min; MS (ESIneg): m/z = 484 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (1.33), 0.935 (0.44), 0.948 (1.35), 1.701 (16.00), 2.084 (0.84), 2.098 (0.98), 2.112 (0.88), 2.130 (1.29), 2.147 (0.70), 2.160 (0.50), 2.322 (0.48), 2.326 (0.65), 2.332 (0.47), 2.518 (2.51), 2.522 (1.55), 2.548 (1.22), 2.554 (1.18), 2.565 (2.23), 2.572 (2.19), 2.583 (1.19), 2.589 (1.22), 2.664 (0.48), 2.669 (0.66), 2.673 (0.48), 3.434 (0.76), 3.442 (0.68), 3.460 (1.31), 3.475 (6.21), 3.527 (0.47), 3.546 (0.81), 3.559 (0.64), 3.566 (0.53), 4.263 (1.96), 4.280 (4.24), 4.298 (1.91), 6.152 (3.93), 6.711 (9.68), 7.164 (0.82), 7.168 (0.92), 7.183 (1.89), 7.186 (1.89), 7.202 (1.81), 7.206 (1.65), 7.236 (1.35), 7.240 (1.58), 7.256 (1.78), 7.259 (2.08), 7.274 (1.10), 7.278 (1.01), 7.302 (3.20), 7.305 (2.92), 7.321 (2.31), 7.325 (2.05), 7.469 (2.03), 7.473 (2.00), 7.489 (1.74), 7.493 (1.63), 7.602 (1.08), 7.605 (0.93), 7.619 (1.60), 7.622 (2.16), 7.625 (1.34), 7.639 (1.37), 7.642 (1.45), 7.714 (1.57), 7.717 (1.25), 7.731 (1.27), 7.735 (2.09), 7.739 (1.77), 7.752 (1.17), 7.756 (1.29), 8.006 (4.60), 8.028 (3.51), 8.030 (3.23), 8.632 (2.95), 8.637 (3.10), 9.336 (4.85), 9.342 (4.77).    Example 182 (rac)-N-[2-(3-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000487_0001
LC-MS (Method 1): Rt = 1.26 min; MS (ESIneg): m/z = 484 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.73), 0.948 (0.76), 1.558 (14.80), 1.568 (16.00), 2.086 (0.50), 2.099 (1.00), 2.115 (1.41), 2.125 (1.12), 2.142 (1.62), 2.160 (0.93), 2.172 (0.58), 2.518 (3.57), 2.522 (2.21), 2.579 (2.08), 2.595 (3.38), 2.599 (3.42), 2.615 (2.27), 3.444 (0.42), 3.461 (0.95), 3.476 (1.65), 3.487 (1.43), 3.502 (3.38), 3.522 (2.65), 3.547 (0.92), 3.573 (0.57), 3.592 (1.04), 3.607 (0.78), 3.615 (0.74), 4.278 (2.79), 4.295 (4.91), 4.313 (2.71), 6.179 (5.23), 6.717 (12.67), 7.182 (1.50), 7.185 (1.83), 7.187 (1.92), 7.190 (1.62), 7.201 (2.16), 7.204 (2.60), 7.206 (2.91), 7.209 (2.27), 7.271 (2.26), 7.290 (5.08), 7.309 (3.31), 7.321 (2.35), 7.324 (4.02), 7.328 (2.65), 7.340 (0.95), 7.344 (1.63), 7.348 (1.08), 7.370 (3.16), 7.374 (4.77), 7.379 (2.53), 7.601 (1.46), 7.603 (1.29), 7.618 (2.16), 7.621 (2.91), 7.638 (1.90), 7.641 (2.02), 7.713 (2.08), 7.717 (1.88), 7.730 (1.61), 7.733 (3.15), 7.737 (2.40), 7.751 (1.65), 7.754 (1.69), 8.003 (5.24), 8.024 (4.68), 8.637 (4.03), 8.642 (4.14), 9.347 (6.56), 9.352 (6.25).    Example 183 (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000488_0001
LC-MS (Method 1): Rt = 1.20 min; MS (ESIpos): m/z = 483 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.728 (0.53), 1.732 (0.58), 1.749 (1.12), 1.755 (1.18), 1.772 (1.18), 1.777 (1.35), 1.794 (0.84), 1.959 (0.54), 1.966 (0.69), 1.981 (1.30), 1.996 (0.93), 2.004 (1.12), 2.008 (1.12), 2.019 (0.65), 2.024 (0.64), 2.031 (0.58), 2.047 (0.47), 2.068 (0.64), 2.074 (2.59), 2.081 (1.44), 2.098 (1.88), 2.112 (1.43), 2.123 (2.24), 2.141 (1.22), 2.153 (0.81), 2.352 (1.18), 2.367 (1.46), 2.374 (2.07), 2.383 (2.58), 2.389 (1.93), 2.398 (3.04), 2.404 (2.41), 2.420 (1.76), 2.456 (1.33), 2.473 (2.72), 2.518 (3.05), 2.522 (2.28), 2.544 (0.50), 2.559 (2.35), 2.562 (2.39), 2.575 (4.39), 2.581 (4.44), 2.597 (2.68), 3.410 (0.60), 3.428 (1.40), 3.435 (1.23), 3.453 (2.23), 3.474 (6.36), 3.481 (5.29), 3.507 (0.87), 3.535 (0.88), 3.554 (1.49), 3.568 (1.19), 3.575 (1.01), 3.594 (0.58), 4.264 (3.88), 4.282 (7.42), 4.298 (3.72), 6.699 (16.00), 6.746 (6.16), 7.065 (0.50), 7.073 (5.58), 7.079 (1.77), 7.090 (2.05), 7.095 (11.11), 7.101 (2.10), 7.112 (1.81), 7.118 (6.18), 7.126 (0.62), 7.434 (0.62), 7.442 (5.48), 7.447 (2.30), 7.456 (5.97), 7.464 (5.52), 7.473 (2.03), 7.478 (4.88), 7.486 (0.49), 7.596 (2.03), 7.599 (1.74), 7.614 (2.95), 7.617 (3.43), 7.634 (2.54), 7.637 (2.84), 7.710 (2.92), 7.713 (2.34), 7.727 (2.36), 7.730 (3.47), 7.734 (3.26), 7.747 (2.12), 7.751 (2.40), 8.000 (9.38), 8.003 (7.21), 8.021 (6.47), 8.024 (7.92), 8.631 (5.95), 8.637 (6.07), 9.341 (8.91), 9.346 (8.82).    Example 184 (rac)-N-[1-(3-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000489_0001
LC-MS (Method 1): Rt = 1.20 min; MS (ESIpos): m/z = 483 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.761 (0.53), 1.766 (0.55), 1.782 (1.11), 1.788 (1.17), 1.799 (0.83), 1.805 (1.20), 1.810 (1.38), 1.827 (0.84), 1.970 (0.54), 1.977 (0.72), 1.993 (1.29), 2.008 (0.95), 2.015 (1.15), 2.020 (1.13), 2.031 (0.65), 2.035 (0.64), 2.043 (0.60), 2.059 (0.52), 2.074 (2.05), 2.092 (1.36), 2.109 (1.96), 2.133 (2.18), 2.151 (1.19), 2.163 (0.77), 2.362 (1.14), 2.383 (1.75), 2.392 (2.58), 2.399 (1.78), 2.408 (2.99), 2.415 (2.50), 2.430 (1.95), 2.450 (1.45), 2.466 (2.54), 2.472 (2.55), 2.518 (3.03), 2.522 (1.99), 2.539 (0.51), 2.569 (2.83), 2.585 (4.68), 2.589 (4.74), 2.605 (3.26), 2.887 (0.43), 3.425 (0.55), 3.443 (1.34), 3.459 (2.17), 3.469 (2.05), 3.485 (5.15), 3.499 (3.88), 3.525 (1.14), 3.551 (0.83), 3.570 (1.44), 3.583 (1.12), 3.591 (1.00), 3.610 (0.54), 4.268 (3.87), 4.286 (6.80), 4.303 (3.82), 6.695 (16.00), 6.794 (6.22), 6.958 (1.08), 6.962 (1.24), 6.965 (1.31), 6.969 (1.31), 6.981 (2.30), 6.984 (2.26), 6.988 (2.56), 7.001 (1.27), 7.003 (1.35), 7.007 (1.49), 7.010 (1.41), 7.185 (1.87), 7.190 (2.34), 7.195 (2.05), 7.212 (1.88), 7.216 (2.44), 7.223 (1.96), 7.275 (2.32), 7.295 (4.84), 7.312 (2.79), 7.326 (2.84), 7.331 (3.49), 7.347 (3.40), 7.350 (1.45), 7.366 (1.25), 7.599 (2.03), 7.601 (1.85), 7.616 (3.09), 7.619 (4.19), 7.622 (2.50), 7.636 (2.69), 7.639 (2.82), 7.711 (3.06), 7.715 (2.69), 7.728 (2.35), 7.732 (4.40), 7.735 (3.44), 7.749 (2.29), 7.752 (2.44), 8.002 (7.60), 8.022 (6.86), 8.626 (5.62), 8.631 (5.73), 9.336 (9.44), 9.342 (9.10).    Example 185 (rac)-N-[1-(2-chlorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000490_0001
LC-MS (Method 1): Rt = 1.28 min; MS (ESIpos): m/z = 499 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.658 (0.78), 1.669 (1.27), 1.680 (1.81), 1.695 (1.84), 1.706 (2.00), 1.717 (1.56), 1.728 (0.87), 2.040 (2.46), 2.061 (3.78), 2.067 (4.27), 2.086 (4.54), 2.097 (3.98), 2.108 (2.83), 2.127 (1.60), 2.145 (0.64), 2.322 (1.05), 2.327 (1.44), 2.332 (1.08), 2.518 (8.00), 2.522 (8.25), 2.532 (5.40), 2.539 (8.74), 2.550 (7.83), 2.558 (5.53), 2.565 (3.93), 2.581 (1.63), 2.617 (1.78), 2.628 (2.33), 2.639 (3.88), 2.650 (3.57), 2.661 (3.67), 2.669 (3.66), 2.673 (3.86), 2.695 (1.08), 3.381 (0.91), 3.399 (2.19), 3.412 (3.09), 3.425 (3.59), 3.437 (6.90), 3.454 (6.83), 3.479 (2.28), 3.489 (1.57), 3.508 (2.42), 3.523 (1.88), 3.530 (1.60), 3.549 (0.88), 4.244 (5.65), 4.262 (11.37), 4.279 (5.34), 6.551 (10.12), 6.623 (16.00), 7.159 (2.43), 7.163 (2.84), 7.178 (6.01), 7.182 (5.99), 7.197 (5.61), 7.201 (5.19), 7.235 (4.11), 7.238 (4.78), 7.254 (5.98), 7.257 (6.94), 7.272 (3.30), 7.276 (3.04), 7.293 (8.21), 7.297 (7.35), 7.312 (6.01), 7.316 (5.30), 7.541 (6.10), 7.546 (6.28), 7.561 (5.57), 7.565 (5.22), 7.597 (3.30), 7.601 (2.72), 7.615 (4.84), 7.618 (5.58), 7.635 (4.11), 7.638 (4.45), 7.710 (4.54), 7.714 (3.60), 7.727 (3.73), 7.731 (5.67), 7.735 (5.25), 7.748 (3.35), 7.752 (3.79), 8.000 (13.34), 8.003 (11.85), 8.024 (13.19), 8.605 (9.10), 8.610 (9.15), 9.310 (13.19), 9.316 (13.39).    Example 186 (rac)-N-(1-phenylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000491_0001
LC-MS (Method 1): Rt = 1.20 min; MS (ESIpos): m/z = 465 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.747 (0.50), 1.753 (0.61), 1.758 (0.47), 1.769 (1.10), 1.775 (1.17), 1.780 (0.81), 1.786 (0.80), 1.791 (1.18), 1.797 (1.35), 1.813 (0.81), 1.819 (0.68), 1.968 (0.54), 1.975 (0.70), 1.991 (1.28), 2.005 (0.91), 2.014 (1.08), 2.018 (1.12), 2.029 (0.62), 2.034 (0.63), 2.041 (0.60), 2.056 (0.55), 2.074 (8.11), 2.085 (1.42), 2.101 (1.88), 2.117 (1.41), 2.126 (2.24), 2.144 (1.20), 2.157 (0.78), 2.367 (1.10), 2.382 (1.33), 2.389 (1.87), 2.398 (2.53), 2.404 (1.77), 2.414 (3.01), 2.420 (2.36), 2.435 (1.73), 2.468 (1.43), 2.518 (2.88), 2.522 (2.12), 2.548 (0.53), 2.566 (2.65), 2.580 (4.49), 2.585 (4.55), 2.600 (2.98), 3.418 (0.59), 3.437 (1.38), 3.444 (1.24), 3.454 (2.21), 3.462 (2.10), 3.480 (5.61), 3.493 (4.32), 3.519 (1.15), 3.544 (0.87), 3.562 (1.48), 3.577 (1.16), 3.584 (1.02), 3.603 (0.60), 4.265 (3.79), 4.283 (7.07), 4.300 (3.71), 6.692 (16.00), 6.729 (6.15), 7.130 (1.01), 7.133 (1.93), 7.136 (1.13), 7.147 (1.39), 7.151 (4.76), 7.155 (1.62), 7.166 (1.82), 7.169 (3.24), 7.173 (1.71), 7.270 (5.23), 7.273 (2.11), 7.289 (8.58), 7.303 (1.67), 7.307 (5.01), 7.433 (7.38), 7.436 (7.92), 7.449 (1.95), 7.454 (6.58), 7.457 (5.10), 7.599 (2.00), 7.602 (1.68), 7.617 (2.93), 7.620 (3.64), 7.636 (2.47), 7.639 (2.78), 7.712 (2.83), 7.715 (2.23), 7.728 (2.25), 7.732 (3.69), 7.736 (3.25), 7.749 (2.03), 7.753 (2.37), 8.002 (8.04), 8.003 (7.47), 8.026 (8.13), 8.630 (5.73), 8.635 (5.76), 9.337 (9.01), 9.343 (8.73).  Example 187 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[1-(pyridin-4-yl)cyclobutyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000492_0002
LC-MS (Method 1): Rt = 1.28 min; MS (ESIpos): m/z = 489 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.810 (0.68), 1.815 (0.57), 1.827 (1.31), 1.833 (1.38), 1.850 (1.40), 1.855 (1.67), 1.867 (0.64), 1.873 (1.04), 1.988 (0.65), 1.996 (0.88), 2.011 (1.53), 2.025 (1.26), 2.034 (1.39), 2.038 (1.34), 2.049 (1.17), 2.062 (1.19), 2.074 (2.20), 2.081 (1.70), 2.099 (2.46), 2.120 (2.61), 2.138 (1.39), 2.150 (0.88), 2.336 (0.60), 2.376 (2.22), 2.381 (2.51), 2.391 (2.53), 2.397 (3.01), 2.413 (1.97), 2.419 (2.48), 2.437 (2.28), 2.442 (2.40), 2.455 (2.93), 2.518 (6.03), 2.522 (3.83), 2.533 (0.80), 2.549 (2.93), 2.565 (5.04), 2.570 (5.10), 2.586 (3.07), 2.602 (0.46), 2.660 (0.59), 3.420 (0.70), 3.444 (2.54), 3.469 (4.82), 3.487 (3.96), 3.513 (1.25), 3.570 (0.84), 3.587 (1.52), 3.627 (0.60), 4.222 (4.24), 4.240 (8.39), 4.258 (4.12), 6.599 (16.00), 6.887 (7.34), 7.404 (12.71), 7.407 (7.55), 7.415 (7.74), 7.419 (12.55), 7.693 (7.35), 7.699 (7.21), 8.186 (9.12), 8.191 (9.24), 8.454 (0.54), 8.464 (14.61), 8.469 (8.60), 8.476 (8.37), 8.480 (13.16), 8.741 (10.23), 8.746 (9.96), 12.015 (3.42).    Example 188 (rac)-N-[1-(2-chlorophenyl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000492_0001
LC-MS (Method 1): Rt = 1.17 min; MS (ESIpos): m/z = 488 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.948 (0.43), 1.657 (0.79), 1.667 (1.32), 1.678 (1.90), 1.693 (1.97), 1.705 (2.17), 1.716 (1.57), 1.727 (0.94), 1.738 (0.52), 2.017 (1.51), 2.030 (2.67), 2.043 (3.66), 2.059 (5.59), 2.076 (4.92), 2.084 (4.03), 2.093 (2.60), 2.106 (3.13), 2.125 (0.99), 2.318 (0.96), 2.322 (2.12), 2.326 (2.92), 2.332 (2.13), 2.336 (0.93), 2.453 (1.80), 2.518 (16.00), 2.522 (11.43), 2.543 (3.32), 2.565 (3.43), 2.586 (1.69), 2.596 (1.33), 2.606 (2.18), 2.617 (2.47), 2.637 (3.19), 2.644 (2.84), 2.660 (3.25), 2.664 (4.99), 2.668 (5.44), 2.673 (4.34), 2.684 (1.63), 2.695 (1.25), 2.727 (7.38), 2.729 (7.14), 2.888 (8.67), 3.373 (3.73), 3.398 (6.72), 3.433 (6.93), 3.459 (3.49), 3.473 (1.67), 3.492 (2.63), 3.506 (2.10), 3.531 (0.94), 4.178 (5.47), 4.197 (10.76), 4.214 (5.17), 6.366 (13.17), 6.457 (8.45), 6.462 (9.44), 6.466 (9.60), 6.470 (8.64), 6.545 (11.32), 7.162 (2.73), 7.167 (3.12), 7.181 (6.58), 7.186 (6.48), 7.200 (6.19), 7.205 (5.77), 7.231 (4.76), 7.235 (5.81), 7.250 (6.77), 7.254 (7.79), 7.269 (3.47), 7.273 (3.25), 7.298 (8.71), 7.302 (8.27), 7.318 (6.51), 7.322 (5.72), 7.461 (7.55), 7.467 (8.50), 7.475 (7.30), 7.537 (6.58), 7.540 (6.85), 7.556 (6.21), 7.560 (5.71), 7.951 (1.07), 8.197 (10.68), 8.201 (10.92), 8.545 (0.45), 8.592 (14.22), 8.597 (13.88), 11.649 (5.84).    Example 189 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000493_0001
LC-MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 477 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.605 (16.00), 2.074 (0.54), 2.094 (0.60), 2.109 (0.75), 2.137 (0.94), 2.155 (0.52), 2.332 (0.55), 2.518 (2.66), 2.522 (1.68), 2.567 (1.39), 2.584 (2.21), 2.602 (1.48), 2.673 (0.55), 3.385 (0.99), 3.488 (0.97), 3.505 (2.73), 3.613 (0.58), 4.232 (1.51), 4.249 (2.41), 4.266 (1.46), 6.471 (1.10), 6.631 (6.97), 7.100 (0.41), 7.228 (0.53), 7.693 (3.31), 7.699 (3.59), 8.192 (2.63), 8.196 (2.62), 8.482 (0.91), 8.492 (0.87), 8.749 (3.51), 8.754 (3.40), 12.013 (1.38), 12.020 (1.39).    Example 190 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[1-(pyridin-2-yl)cyclobutyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000494_0001
LC-MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 489 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.868 (0.61), 1.889 (1.11), 1.895 (0.97), 1.912 (1.47), 1.928 (0.86), 1.934 (0.77), 1.951 (0.42), 1.982 (0.77), 1.998 (1.38), 2.014 (1.02), 2.021 (1.16), 2.038 (0.69), 2.048 (0.55), 2.066 (0.51), 2.074 (1.02), 2.084 (0.76), 2.099 (1.49), 2.118 (2.16), 2.139 (2.34), 2.157 (1.25), 2.170 (0.83), 2.188 (0.42), 2.332 (1.08), 2.336 (0.52), 2.400 (2.14), 2.410 (2.20), 2.417 (2.30), 2.423 (2.11), 2.518 (6.31), 2.522 (3.92), 2.569 (4.45), 2.584 (6.98), 2.603 (5.17), 2.622 (1.63), 2.637 (0.62), 2.673 (1.05), 2.678 (0.47), 3.385 (4.52), 3.452 (1.08), 3.480 (2.43), 3.506 (4.43), 3.521 (3.87), 3.547 (1.18), 3.602 (1.09), 3.623 (1.44), 3.636 (1.53), 3.904 (0.80), 4.232 (3.80), 4.250 (6.50), 4.268 (3.61), 6.611 (16.00), 6.854 (3.04), 6.975 (0.78), 7.103 (0.90), 7.231 (1.80), 7.468 (1.22), 7.680 (0.42), 7.695 (8.22), 7.701 (8.90), 7.719 (0.44), 7.759 (1.04), 8.186 (6.28), 8.189 (6.55), 8.547 (3.06), 8.557 (2.92), 8.747 (8.66), 8.751 (8.70), 12.017 (3.47), 12.023 (3.50).    Example 191 (rac)-N-ethyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine-4,3'- pyrrolidine]-1'-carboxamide  Under nitrogen
Figure imgf000495_0001
(rac)-2-bromo-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine-4,3'- pyrrolidine]-1'-carboxamide (54.0 mg, 164 µmol) was dissolved in dioxane (3.0 mL) and 1H- pyrrolo[2,3-b]pyridin-5-ylboronic acid (39.8 mg, 246 µmol), aqueous potassium phosphate solution (980 µL, 0.50 M, 490 µmol), and XPhos Pd G2 (19.4 mg, 24.6 µmol) were added. It was stirred at 100 °C overnight. The reaction mixture was allowed to reach rt and diluted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solutuion, dried over sodium sulfate and concentrated. The residue was purified by HPLC affording 22.7 mg (95 % purity, 36 % yield) of the title compound.  LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 367 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.008 (6.75), 1.026 (16.00), 1.044 (7.25), 2.251 (0.79), 2.277 (1.06), 2.300 (0.64), 2.323 (0.75), 2.327 (1.13), 2.332 (1.17), 2.337 (1.21), 2.354 (1.09), 2.370 (0.57), 2.387 (0.49), 2.518 (3.81), 2.523 (2.64), 2.540 (1.06), 2.665 (0.68), 2.669 (0.98), 2.673 (0.68), 3.026 (0.83), 3.043 (2.72), 3.057 (3.02), 3.061 (2.91), 3.075 (2.68), 3.093 (0.79), 3.159 (0.75), 3.172 (0.83), 3.354 (1.85), 3.372 (1.43), 3.381 (0.87), 3.397 (0.64), 3.449 (2.68), 3.477 (3.09), 3.533 (0.94), 3.554 (1.58), 3.577 (0.72), 3.776 (1.74), 3.802 (1.47), 4.066 (0.57), 4.082 (0.91), 4.097 (1.66), 4.105 (0.94), 4.117 (1.13), 4.130 (1.66), 4.138 (1.70), 4.162 (4.94), 4.171 (2.87), 5.758 (0.87), 6.177 (1.17), 6.190 (2.34), 6.204 (1.13), 6.464 (2.91), 6.468 (3.21), 6.472 (3.17), 6.476 (2.83), 6.776 (10.79), 7.469 (2.60), 7.476 (3.09), 7.484 (2.45), 8.257 (4.34), 8.261 (4.42), 8.633 (5.70), 8.639 (5.55), 11.671 (2.15).  The following examples were synthesised analogously via Suzuki coupling  Example 192 (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000496_0002
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 401 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (7.26), 1.026 (16.00), 1.044 (7.53), 2.222 (0.42), 2.254 (1.05), 2.281 (1.37), 2.304 (0.84), 2.322 (1.11), 2.326 (1.47), 2.332 (1.26), 2.342 (1.32), 2.358 (1.47), 2.375 (0.84), 2.391 (0.74), 2.664 (1.05), 2.669 (1.37), 2.673 (1.00), 3.026 (1.00), 3.043 (3.21), 3.058 (3.79), 3.075 (3.16), 3.093 (0.95), 3.373 (2.68), 3.399 (1.11), 3.453 (3.16), 3.482 (3.68), 3.537 (1.21), 3.559 (2.11), 3.581 (0.95), 3.780 (2.32), 3.808 (2.00), 4.072 (0.79), 4.088 (1.21), 4.102 (2.26), 4.113 (1.47), 4.135 (2.16), 4.145 (2.05), 4.173 (5.68), 4.185 (3.79), 5.757 (0.47), 6.177 (1.47), 6.191 (2.95), 6.205 (1.47), 6.891 (10.47), 7.705 (10.79), 8.200 (6.32), 8.205 (6.53), 8.737 (6.05), 8.741 (5.84), 12.039 (0.79).    Example 193 (rac)-N-ethyl-2-(quinolin-3-yl)-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine-4,3'-pyrrolidine]-1'- carboxamide 
Figure imgf000496_0001
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 378 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (6.69), 1.031 (16.00), 1.048 (6.91), 2.267 (0.58), 2.271 (0.58), 2.277 (0.71), 2.294 (0.53), 2.303 (0.98), 2.318 (0.44), 2.323 (1.02), 2.327 (1.51), 2.332 (0.89), 2.365 (0.80), 2.382 (0.98), 2.398 (0.53), 2.415 (0.44), 2.518 (4.03), 2.523 (2.75), 2.665 (0.71), 2.669 (1.02), 2.673 (0.71), 3.031 (0.75), 3.049 (2.53), 3.063 (2.75), 3.067 (2.66), 3.081 (2.48), 3.098 (0.71), 3.365 (1.06), 3.373 (1.29), 3.391 (1.20), 3.399 (0.84), 3.416 (0.58), 3.476 (2.53), 3.504 (2.93), 3.552 (0.84), 3.573 (1.37), 3.594 (0.62), 3.802 (1.60), 3.829 (1.33), 4.098 (0.71), 4.115 (0.84), 4.129 (1.82), 4.142 (1.06), 4.161 (1.60), 4.171 (1.29), 4.192 (0.66), 4.202 (0.71), 4.223 (2.44), 4.237 (3.19), 4.250 (1.20), 5.758 (1.68), 6.193 (1.02), 6.207 (2.04), 6.220 (0.98), 7.010 (10.73), 7.606 (1.15), 7.609 (1.20), 7.623 (1.73), 7.626 (2.48), 7.629 (1.42), 7.644 (1.64), 7.646 (1.60), 7.725 (1.68), 7.729 (1.68), 7.743 (1.29), 7.747 (2.61), 7.750 (1.91), 7.764 (1.46), 7.767 (1.33), 8.012 (2.66), 8.020 (2.22), 8.024 (2.26), 8.032 (2.30), 8.040 (2.08), 8.043 (1.99), 8.656 (3.28), 8.661 (3.41), 9.333 (5.58), 9.338 (5.32).    Example 194 (rac)-N-ethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000497_0001
LC-MS (Method 1): Rt = 0.82 min; MS (ESIpos): m/z = 381 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.662 (0.89), 0.679 (0.89), 1.010 (5.99), 1.028 (13.77), 1.045 (6.30), 1.232 (0.62), 1.329 (0.97), 1.371 (8.06), 2.075 (0.52), 2.085 (0.52), 2.248 (0.89), 2.250 (0.91), 2.255 (0.87), 2.274 (15.19), 2.277 (16.00), 2.323 (0.89), 2.327 (1.24), 2.332 (1.10), 2.337 (1.05), 2.356 (1.01), 2.372 (0.54), 2.389 (0.45), 2.518 (4.44), 2.523 (2.91), 2.673 (0.81), 3.027 (0.76), 3.044 (2.40), 3.058 (2.73), 3.062 (2.65), 3.076 (2.34), 3.094 (0.70), 3.349 (1.49), 3.357 (1.39), 3.374 (1.22), 3.384 (0.83), 3.400 (0.56), 3.453 (2.38), 3.482 (2.77), 3.536 (0.85), 3.557 (1.45), 3.580 (0.66), 3.777 (1.63), 3.805 (1.39), 4.068 (0.56), 4.084 (0.87), 4.098 (1.45), 4.106 (0.89), 4.119 (1.18), 4.133 (1.67), 4.142 (1.67), 4.163 (4.71), 6.174 (1.07), 6.188 (2.11), 6.201 (1.01), 6.798 (9.10), 7.235 (3.00), 7.237 (2.94), 8.210 (3.91), 8.215 (3.95), 8.608 (4.80), 8.613 (4.65), 11.313 (2.19).    Example 195 (rac)-N-ethyl-2-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000497_0002
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 395 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (6.50), 1.029 (14.34), 1.047 (6.63), 1.134 (0.55), 1.159 (0.70), 1.234 (1.20), 1.255 (7.34), 1.274 (16.00), 1.292 (7.59), 2.258 (0.84), 2.284 (1.14), 2.307 (0.68), 2.325 (0.69), 2.329 (0.99), 2.334 (1.08), 2.339 (1.20), 2.356 (1.18), 2.373 (0.66), 2.389 (0.56), 2.525 (2.56), 2.542 (0.96), 2.667 (0.62), 2.671 (0.83), 2.676 (0.63), 2.698 (1.49), 2.717 (4.33), 2.736 (4.18), 2.754 (1.37), 3.028 (0.87), 3.046 (2.68), 3.061 (3.08), 3.064 (3.01), 3.078 (2.60), 3.096 (0.78), 3.350 (1.44), 3.358 (1.49), 3.376 (1.35), 3.384 (0.94), 3.401 (0.64), 3.458 (2.63), 3.487 (3.03), 3.539 (0.97), 3.560 (1.69), 3.583 (0.75), 3.778 (1.87), 3.806 (1.58), 4.068 (0.68), 4.085 (1.00), 4.099 (1.75), 4.108 (1.06), 4.121 (1.19), 4.133 (1.80), 4.142 (1.79), 4.166 (5.01), 4.175 (3.08), 5.761 (7.34), 6.175 (1.20), 6.189 (2.39), 6.203 (1.17), 6.810 (9.10), 7.237 (3.38), 7.243 (3.38), 8.234 (4.33), 8.239 (4.46), 8.608 (4.76), 8.613 (4.69), 11.340 (2.46).    Example 196 (rac)-N-ethyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine- 4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000498_0001
LC-MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 368 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.004 (2.41), 0.850 (0.56), 1.007 (7.55), 1.025 (16.00), 1.043 (7.89), 1.230 (5.08), 2.216 (0.60), 2.249 (1.38), 2.274 (1.87), 2.298 (1.08), 2.346 (1.72), 2.361 (1.98), 2.378 (1.25), 2.395 (1.11), 2.539 (7.64), 3.025 (1.23), 3.043 (3.79), 3.059 (4.74), 3.075 (3.76), 3.092 (1.21), 3.376 (2.37), 3.385 (1.72), 3.401 (1.11), 3.451 (3.55), 3.480 (4.12), 3.538 (1.59), 3.560 (2.74), 3.583 (1.27), 3.783 (2.92), 3.811 (2.50), 4.075 (1.04), 4.091 (1.57), 4.104 (2.76), 4.117 (2.00), 4.137 (2.87), 4.147 (2.59), 4.177 (6.48), 4.191 (5.24), 6.188 (1.80), 6.200 (3.46), 6.214 (1.84), 6.861 (10.25), 8.175 (7.54), 8.227 (0.75), 8.506 (6.28), 8.510 (6.56), 8.572 (0.58), 8.577 (0.62), 8.902 (0.60), 8.907 (0.60), 8.949 (6.29), 8.953 (6.41), 13.700 (2.41).    Example 197 (rac)-N-ethyl-2-[7-(morpholin-4-yl)-1,6-naphthyridin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000499_0001
Under argon (rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]- 2'-yl trifluoromethanesulfonate (50.0 mg, 131 µmol), [7-(morpholin-4-yl)-1,6-naphthyridin-3- yl]boronic acid (50.8 mg, 196 µmol), XPhos Pd G2 (15.4 mg, 19.6 µmol) and aqueous potassium phosphate solution (780 µL, 0.50 M, 390 µmol) were combined in dioxane (1.0 mL) and stirred at 100 °C overnight. The reaction mixture was allowed to reach rt, the solid particles were filtered off and the filtrate was purified by HPLC to give 12.0 mg (98 % purity, 20 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 448 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (7.02), 1.030 (16.00), 1.047 (7.37), 1.230 (0.43), 2.074 (1.48), 2.089 (2.06), 2.102 (2.60), 2.119 (1.14), 2.133 (0.50), 2.331 (0.74), 2.518 (3.55), 2.522 (2.30), 2.551 (2.75), 2.569 (4.09), 2.586 (2.87), 2.673 (0.75), 3.031 (0.96), 3.049 (2.90), 3.063 (3.30), 3.066 (3.12), 3.081 (2.88), 3.098 (0.89), 3.148 (0.59), 3.390 (0.73), 3.408 (1.41), 3.415 (1.22), 3.433 (2.70), 3.443 (10.42), 3.492 (0.85), 3.509 (1.46), 3.517 (0.94), 3.525 (1.08), 3.535 (1.02), 3.557 (4.74), 3.568 (7.00), 3.581 (6.13), 3.748 (6.42), 3.761 (7.38), 3.772 (5.02), 4.236 (2.64), 4.254 (4.18), 4.271 (2.63), 6.167 (1.22), 6.181 (2.40), 6.194 (1.18), 6.647 (10.22), 7.031 (5.61), 8.592 (3.74), 8.598 (3.85), 9.076 (7.51), 9.316 (5.96), 9.322 (5.79).    Example 198 (rac)-N-ethyl-2-(5-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000499_0002
The following examples were synthesised analogously via Suzuki coupling  Example 199 (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-(1-phenylcyclobutyl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000500_0001
LC-MS (Method 1): Rt = 1.27 min; MS (ESIpos): m/z = 531 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.408 (0.60), 1.450 (0.44), 1.752 (0.74), 1.768 (1.40), 1.773 (1.48), 1.796 (1.72), 1.813 (1.06), 1.835 (0.41), 1.973 (0.94), 1.988 (1.64), 2.003 (1.26), 2.010 (1.46), 2.031 (0.90), 2.054 (0.81), 2.074 (1.16), 2.085 (1.87), 2.102 (2.52), 2.128 (2.81), 2.146 (1.58), 2.157 (1.08), 2.178 (0.53), 2.366 (1.49), 2.388 (2.56), 2.397 (3.30), 2.413 (3.83), 2.419 (3.17), 2.435 (2.42), 2.466 (2.24), 2.539 (5.09), 2.565 (3.39), 2.580 (5.67), 2.585 (5.61), 2.600 (3.78), 3.417 (0.85), 3.435 (1.80), 3.455 (2.78), 3.461 (2.88), 3.480 (7.37), 3.490 (5.85), 3.516 (1.34), 3.540 (1.18), 3.558 (1.98), 3.596 (0.70), 4.088 (0.47), 4.269 (4.43), 4.287 (8.27), 4.304 (4.35), 4.750 (0.45), 6.695 (16.00), 6.731 (7.58), 6.760 (0.47), 7.132 (2.13), 7.150 (5.38), 7.169 (3.54), 7.225 (4.78), 7.268 (6.11), 7.288 (10.15), 7.307 (5.84), 7.328 (0.43), 7.409 (9.85), 7.434 (9.70), 7.452 (8.03), 7.455 (6.13), 7.555 (4.23), 7.562 (4.30), 7.578 (4.46), 7.585 (4.77), 7.593 (4.54), 7.763 (6.73), 7.770 (6.12), 8.061 (6.93), 8.083 (6.29), 8.649 (6.87), 8.655 (6.83), 9.316 (9.47), 9.321 (9.41).    Example 200 (rac)-N-ethyl-2'-[6-(morpholin-4-yl)-1,5-naphthyridin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000501_0002
LC-MS (Method 4): Rt = 0.74 min; MS (ESIpos): m/z = 449 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (6.79), 1.029 (16.00), 1.047 (7.14), 2.075 (1.30), 2.088 (1.75), 2.103 (2.44), 2.121 (0.99), 2.133 (0.48), 2.518 (1.32), 2.523 (0.87), 2.539 (0.91), 2.546 (1.87), 2.562 (3.14), 2.565 (3.19), 2.581 (2.25), 3.031 (0.86), 3.048 (2.62), 3.062 (2.90), 3.066 (2.80), 3.080 (2.53), 3.098 (0.78), 3.377 (1.33), 3.396 (1.78), 3.403 (1.36), 3.414 (1.14), 3.421 (1.99), 3.446 (9.50), 3.510 (0.75), 3.524 (0.93), 3.528 (1.19), 3.535 (0.84), 3.542 (0.93), 3.549 (0.79), 3.554 (0.80), 3.568 (0.53), 3.696 (4.45), 3.700 (4.60), 3.708 (7.32), 3.727 (7.45), 3.734 (4.76), 3.739 (4.83), 4.249 (2.34), 4.266 (4.01), 4.283 (2.31), 6.159 (1.10), 6.172 (2.20), 6.181 (0.89), 6.186 (1.09), 6.767 (10.37), 7.418 (3.79), 7.442 (4.05), 8.052 (3.29), 8.054 (3.30), 8.076 (2.99), 8.173 (5.34), 8.176 (3.95), 8.178 (3.67), 9.047 (6.19), 9.052 (6.20).    Example 201 (rac)-N-ethyl-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000501_0001
  Example 202 (rac)-N-ethyl-2'-[3-(1-phenylcyclohexyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide   
Figure imgf000502_0002
Example 203 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclobutyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000502_0001
LC-MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 508 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.756 (0.78), 1.778 (1.54), 1.795 (1.61), 1.800 (1.77), 1.817 (1.11), 1.839 (0.46), 1.861 (0.54), 1.883 (1.57), 1.912 (2.21), 1.933 (1.14), 1.952 (0.41), 1.968 (1.14), 1.976 (0.99), 1.991 (2.84), 2.012 (4.11), 2.035 (3.75), 2.060 (3.24), 2.074 (8.81), 2.084 (4.86), 2.102 (2.82), 2.120 (1.69), 2.133 (2.07), 2.153 (3.48), 2.176 (3.90), 2.181 (4.33), 2.198 (2.34), 2.204 (3.00), 2.229 (0.95), 2.323 (0.90), 2.327 (1.19), 2.331 (1.20), 2.337 (1.92), 2.345 (2.17), 2.357 (3.90), 2.364 (6.32), 2.373 (3.65), 2.378 (4.69), 2.385 (7.38), 2.393 (6.02), 2.409 (4.88), 2.414 (4.15), 2.432 (2.57), 2.457 (2.02), 2.523 (5.91), 2.529 (6.16), 2.539 (3.84), 2.546 (6.28), 2.566 (4.04), 2.665 (0.77), 2.669 (1.09), 2.673 (0.78), 3.397 (1.16), 3.423 (3.74), 3.449 (5.47), 3.480 (4.55), 3.505 (2.15), 3.542 (1.08), 3.560 (1.86), 3.601 (0.78), 3.657 (0.74), 3.680 (2.36), 3.700 (3.58), 3.720 (2.24), 3.743 (0.65), 4.204 (4.42), 4.221 (8.49), 4.238 (4.35), 4.495 (0.41), 6.478 (16.00), 6.714 (7.93), 7.131 (2.29), 7.150 (5.62), 7.167 (3.81), 7.265 (6.40), 7.285 (15.95), 7.303 (6.43), 7.431 (10.12), 7.449 (8.43), 7.452 (6.59), 7.479 (0.46), 7.498 (0.43), 7.507 (0.40), 7.525 (0.52), 7.551 (0.68), 7.569 (0.45), 8.186 (8.12), 8.191 (8.38), 8.590 (9.72), 8.595 (9.48), 11.363 (4.78).    Example 204 (rac)-N-ethyl-2'-{3-[2-(3-methylphenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000503_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.003 (4.94), 1.021 (10.97), 1.039 (5.00), 1.065 (1.52), 1.633 (0.99), 1.697 (16.00), 2.010 (0.89), 2.028 (1.35), 2.048 (1.50), 2.066 (0.84), 2.074 (3.77), 2.226 (13.33), 2.472 (2.48), 2.518 (4.32), 2.522 (2.82), 2.539 (2.68), 3.021 (0.65), 3.039 (2.07), 3.053 (2.29), 3.057 (2.25), 3.070 (2.00), 3.088 (0.60), 3.359 (1.54), 3.365 (1.11), 3.385 (7.84), 3.402 (0.73), 3.453 (0.56), 3.471 (0.87), 3.478 (0.63), 3.485 (0.71), 3.492 (0.58), 3.497 (0.53), 4.132 (1.83), 4.150 (3.09), 4.167 (1.76), 6.137 (0.86), 6.151 (1.71), 6.165 (0.84), 6.278 (7.10), 6.944 (1.44), 6.961 (1.75), 7.063 (0.98), 7.084 (2.03), 7.110 (2.34), 7.129 (4.24), 7.147 (1.05), 7.363 (3.12), 7.369 (3.06), 7.597 (3.10), 7.602 (3.15), 8.500 (3.92), 8.505 (3.88), 11.433 (1.85), 11.438 (1.85).    Example 205 (rac)-N-ethyl-2-(6-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000504_0003
  Example 206 (rac)-N-ethyl-2-(7-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000504_0001
  Example 207 (rac)-N-ethyl-2'-{3-[2-(1,3-thiazol-2-yl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000504_0002
  Example 208 (rac)-2'-[7-(dimethylamino)-1,6-naphthyridin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000505_0002
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 406 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (2.06), 1.030 (4.66), 1.047 (2.14), 2.085 (0.57), 2.099 (0.76), 2.518 (0.62), 2.522 (0.42), 2.546 (0.78), 2.564 (1.15), 2.582 (0.84), 3.049 (0.82), 3.063 (0.93), 3.066 (0.89), 3.081 (0.82), 3.147 (16.00), 3.431 (0.73), 3.440 (3.07), 4.228 (0.77), 4.246 (1.20), 4.263 (0.78), 6.179 (0.66), 6.619 (3.37), 6.794 (1.83), 8.530 (1.04), 8.534 (1.05), 8.536 (1.02), 9.019 (2.12), 9.259 (1.83), 9.265 (1.80).    Example 209 (rac)-N-ethyl-2'-{3-[2-(2-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000505_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.008 (5.00), 1.026 (10.79), 1.044 (5.05), 1.065 (2.58), 1.156 (1.37), 1.713 (0.42), 1.777 (16.00), 2.014 (0.95), 2.029 (1.66), 2.048 (1.86), 2.067 (0.78), 2.078 (0.48), 2.331 (1.52), 2.522 (6.11), 2.539 (1.64), 2.673 (1.56), 3.028 (0.68), 3.046 (2.12), 3.060 (2.42), 3.063 (2.37), 3.077 (2.03), 3.095 (0.61), 3.359 (1.71), 3.386 (8.13), 3.455 (0.59), 3.474 (0.93), 3.487 (0.78), 4.136 (1.94), 4.153 (3.26), 4.170 (1.84), 6.146 (0.92), 6.161 (1.76), 6.174 (0.89), 6.235 (6.95), 6.989 (0.90), 7.010 (1.09), 7.021 (0.94), 7.039 (1.02), 7.141 (0.82), 7.144 (0.88), 7.160 (1.96), 7.164 (1.86), 7.179 (1.36), 7.183 (1.23), 7.242 (0.68), 7.256 (0.96), 7.270 (0.89), 7.293 (0.45), 7.341 (3.20), 7.347 (3.19), 7.402 (0.85), 7.406 (0.88), 7.424 (1.45), 7.443 (0.78), 7.533 (3.16), 7.538 (3.14), 8.507 (3.73), 8.512 (3.65), 11.449 (1.96), 11.453 (1.96).    Example 210 (rac)-N-ethyl-2'-{3-[2-(4-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide  F
Figure imgf000506_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.000 (5.10), 1.018 (11.48), 1.036 (5.33), 1.066 (5.44), 1.156 (1.14), 1.707 (16.00), 2.011 (0.95), 2.030 (1.11), 2.052 (1.47), 2.071 (0.74), 2.083 (0.56), 2.332 (1.44), 2.518 (8.62), 2.523 (5.64), 2.539 (2.25), 2.673 (1.47), 3.017 (0.66), 3.035 (2.16), 3.049 (2.40), 3.052 (2.33), 3.067 (2.09), 3.084 (0.60), 3.353 (1.60), 3.359 (1.27), 3.387 (7.71), 3.459 (0.57), 3.478 (0.88), 3.490 (0.74), 3.938 (0.90), 4.136 (1.90), 4.154 (3.36), 4.171 (1.85), 6.131 (0.91), 6.145 (1.79), 6.159 (0.86), 6.319 (7.79), 7.036 (2.36), 7.058 (5.12), 7.081 (2.80), 7.294 (2.65), 7.300 (1.25), 7.308 (2.96), 7.316 (2.64), 7.325 (1.03), 7.330 (2.28), 7.385 (3.31), 7.391 (3.28), 7.591 (3.21), 7.596 (3.21), 8.512 (3.90), 8.516 (3.91), 11.473 (1.91).    Example 211 (rac)-2'-{3-[2-(4-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000507_0002
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.039 (1.58), 1.053 (3.49), 1.067 (1.65), 1.737 (3.88), 1.748 (3.23), 2.513 (2.34), 2.517 (1.83), 2.522 (1.88), 2.538 (1.96), 3.076 (16.00), 3.104 (1.31), 3.118 (0.49), 3.401 (0.47), 3.422 (1.60), 3.427 (1.58), 4.151 (0.82), 4.165 (1.19), 4.179 (0.78), 6.239 (1.21), 6.242 (1.69), 7.275 (0.64), 7.288 (1.22), 7.292 (1.97), 7.298 (1.42), 7.319 (1.50), 7.330 (1.41), 7.336 (0.66), 7.348 (0.89), 7.630 (0.83), 7.634 (0.82), 7.642 (0.52), 7.647 (0.54), 8.523 (0.75), 8.526 (0.75), 8.531 (0.49), 8.535 (0.48).    Example 212 (rac)-2'-{3-[2-(3-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000507_0001
  Example 213 (rac)-N-ethyl-2-[6-(methylamino)-1,5-naphthyridin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000508_0002
LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 393 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.012 (6.74), 1.029 (16.00), 1.047 (7.21), 2.073 (1.21), 2.086 (1.85), 2.102 (2.67), 2.120 (1.03), 2.132 (0.52), 2.518 (1.67), 2.523 (1.22), 2.539 (15.13), 2.558 (3.22), 2.562 (3.29), 2.577 (2.23), 2.911 (10.91), 2.923 (11.22), 3.031 (0.83), 3.048 (2.60), 3.063 (2.91), 3.066 (2.82), 3.080 (2.58), 3.098 (0.76), 3.185 (0.54), 3.373 (0.57), 3.392 (1.27), 3.399 (0.95), 3.410 (0.79), 3.417 (1.72), 3.444 (9.85), 3.513 (0.67), 3.527 (0.84), 3.532 (1.12), 3.538 (0.79), 3.544 (0.88), 3.552 (0.73), 3.556 (0.74), 3.570 (0.47), 4.242 (2.49), 4.260 (4.35), 4.278 (2.44), 6.156 (1.11), 6.170 (2.24), 6.183 (1.12), 6.748 (10.62), 6.918 (4.93), 6.941 (5.07), 7.300 (1.04), 7.311 (1.04), 7.842 (2.98), 7.865 (2.84), 8.111 (3.39), 8.113 (3.63), 8.116 (3.75), 8.134 (1.00), 8.929 (5.52), 8.934 (5.57).    Example 214 (rac)-2'-[6-(dimethylamino)-1,5-naphthyridin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000508_0001
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 406 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.012 (3.10), 1.029 (7.28), 1.047 (3.24), 2.075 (0.54), 2.088 (0.81), 2.103 (1.17), 2.121 (0.47), 2.518 (0.98), 2.523 (0.65), 2.545 (0.89), 2.562 (1.48), 2.565 (1.50), 2.581 (1.05), 3.048 (1.15), 3.063 (1.32), 3.066 (1.27), 3.081 (1.15), 3.197 (16.00), 3.395 (0.62), 3.402 (0.45), 3.420 (0.82), 3.445 (4.55), 3.531 (0.52), 3.544 (0.40), 4.246 (1.13), 4.264 (1.93), 4.282 (1.11), 6.157 (0.48), 6.171 (0.98), 6.185 (0.48), 6.763 (4.71), 7.261 (1.16), 7.285 (1.22), 8.000 (1.02), 8.023 (0.95), 8.146 (1.02), 8.988 (1.84), 8.993 (1.83).    Example 215 (rac)-2'-(6-amino-1,5-naphthyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000509_0001
LC-MS (Method 1): Rt = 0.67 min; MS (ESIpos): m/z = 378 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.998 (0.94), 1.009 (6.93), 1.016 (2.48), 1.027 (16.00), 1.033 (1.56), 1.045 (7.09), 2.052 (0.49), 2.057 (0.45), 2.070 (1.27), 2.088 (1.88), 2.107 (2.04), 2.119 (0.51), 2.126 (0.94), 2.138 (0.64), 2.518 (1.52), 2.523 (1.23), 2.539 (1.93), 2.555 (3.18), 2.559 (3.17), 2.574 (2.21), 3.028 (0.96), 3.046 (2.98), 3.060 (3.00), 3.064 (3.12), 3.077 (2.66), 3.095 (0.78), 3.364 (0.55), 3.372 (0.69), 3.390 (2.00), 3.397 (1.02), 3.410 (0.79), 3.417 (1.74), 3.446 (9.76), 3.505 (0.72), 3.518 (0.82), 3.523 (1.07), 3.530 (0.78), 3.536 (0.88), 3.543 (0.71), 3.549 (0.67), 3.562 (0.45), 4.150 (0.49), 4.245 (2.43), 4.263 (4.26), 4.280 (2.38), 6.159 (1.20), 6.173 (2.26), 6.181 (2.05), 6.186 (1.12), 6.703 (11.71), 6.712 (5.37), 6.918 (5.60), 6.941 (5.95), 7.891 (3.43), 7.913 (3.29), 8.026 (3.67), 8.028 (3.73), 8.031 (3.93), 8.926 (6.11), 8.931 (6.07).    Example 216 (rac)-N-ethyl-2'-(5-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000509_0002
  Example 217 (rac)-N-ethyl-2'-{7-fluoro-6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000510_0001
  Example 218 (rac)-2'-(6-methoxyquinolin-3-yl)-N-(1-phenylcyclobutyl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000510_0002
LC-MS (Method 1): Rt = 1.22 min; MS (ESIpos): m/z = 495 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.230 (0.46), 1.769 (0.48), 1.775 (0.49), 1.791 (0.51), 1.797 (0.56), 1.990 (0.54), 2.005 (0.42), 2.012 (0.48), 2.017 (0.47), 2.083 (0.60), 2.097 (0.74), 2.111 (0.71), 2.128 (0.87), 2.146 (0.51), 2.366 (0.48), 2.388 (0.81), 2.397 (1.09), 2.404 (0.84), 2.413 (1.28), 2.419 (1.04), 2.435 (0.80), 2.466 (0.69), 2.518 (2.38), 2.522 (1.62), 2.539 (5.56), 2.559 (1.10), 2.575 (1.83), 2.580 (1.84), 2.595 (1.21), 3.430 (0.58), 3.437 (0.53), 3.453 (1.05), 3.477 (2.12), 3.490 (1.75), 3.516 (0.49), 3.559 (0.61), 3.573 (0.51), 3.906 (16.00), 4.260 (1.45), 4.278 (2.72), 4.295 (1.42), 6.651 (5.84), 6.730 (2.47), 7.134 (0.74), 7.137 (0.46), 7.152 (1.82), 7.167 (0.75), 7.170 (1.22), 7.270 (2.03), 7.289 (3.35), 7.303 (0.76), 7.308 (1.91), 7.346 (1.44), 7.354 (1.92), 7.369 (1.32), 7.376 (2.50), 7.390 (2.90), 7.396 (1.87), 7.433 (2.93), 7.435 (3.24), 7.453 (2.65), 7.456 (2.05), 7.894 (2.33), 7.917 (2.13), 8.522 (2.24), 8.527 (2.27), 9.156 (3.30), 9.161 (3.41).    Example 219 (rac)-N-ethyl-2-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000511_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.110 (0.42), 1.010 (4.90), 1.028 (10.75), 1.046 (5.01), 1.232 (0.54), 1.716 (16.00), 1.907 (0.42), 1.954 (1.43), 1.972 (1.61), 1.986 (1.49), 2.084 (0.84), 2.099 (1.07), 2.118 (0.72), 2.130 (0.78), 2.322 (2.63), 2.326 (3.52), 2.331 (2.63), 2.522 (10.51), 2.539 (1.49), 2.664 (2.69), 2.669 (3.58), 2.673 (2.69), 3.032 (0.66), 3.050 (2.15), 3.064 (2.45), 3.081 (2.09), 3.099 (0.66), 3.357 (8.36), 3.376 (1.79), 3.395 (0.78), 3.450 (0.96), 3.463 (0.84), 4.031 (1.55), 4.047 (3.22), 4.062 (1.55), 5.759 (0.90), 6.135 (0.96), 6.148 (1.91), 6.162 (0.96), 6.358 (6.57), 7.124 (0.84), 7.142 (2.03), 7.160 (1.49), 7.228 (2.03), 7.247 (4.30), 7.265 (3.22), 7.289 (5.01), 7.307 (2.51), 7.376 (3.34), 7.381 (3.34), 7.541 (3.34), 7.545 (3.34), 8.484 (3.64), 8.489 (3.64), 11.454 (2.09).    Example 220 (rac)-N-ethyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000511_0002
  Example 221 (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000512_0001
  Example 222 (rac)-N-ethyl-2-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000512_0002
  Example 223 (rac)-N-ethyl-2-(3H-imidazo[4,5-b]pyridin-6-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine- 4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000512_0003
  Example 224 (rac)-2-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000513_0003
  Example 225 (rac)-N-ethyl-2-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000513_0001
  Example 226 (rac)-N-ethyl-2-(5-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000513_0002
  Example 227 (rac)-N-ethyl-2-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000514_0003
  Example 228 (rac)-N-ethyl-2-(6-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000514_0001
  Example 229 (rac)-2-(6-chloroquinolin-3-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000514_0002
  Example 230 (rac)-2'-(5-chloro-6-methoxyquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide   
Figure imgf000515_0003
Example 231 (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)carbamoyl]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000515_0001
  Example 232 (rac)-2'-(6-tert-butylquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000515_0002
  Example 233 (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)methoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000516_0001
LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 469 [M+H]+    Example 234 (rac)-N-ethyl-2'-{5-[(pyridin-2-yl)methoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000516_0002
LC-MS (Method 1): Rt = 0.95 min; MS (ESIneg): m/z = 467 [M-H]-    Example 235 methyl {3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl}acetate 
Figure imgf000517_0003
  Example 236 (rac)-2'-[6-(cyclohexyloxy)-7-fluoroquinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000517_0001
  Example 237 (rac)-N-ethyl-2'-{7-fluoro-6-[(oxan-4-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000517_0002
  Example 238 (rac)-2'-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000518_0002
LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 413 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.13), 1.103 (6.73), 1.121 (16.00), 1.139 (7.07), 1.268 (5.20), 1.287 (12.47), 1.305 (5.47), 1.326 (4.67), 1.345 (8.33), 1.363 (4.27), 1.373 (0.47), 1.391 (0.73), 1.410 (0.40), 2.152 (1.07), 2.168 (2.40), 2.182 (2.53), 2.199 (1.00), 2.212 (0.47), 2.412 (0.73), 2.417 (1.53), 2.421 (2.13), 2.426 (1.53), 2.431 (0.67), 2.612 (8.93), 2.617 (6.07), 2.623 (3.00), 2.634 (2.47), 2.640 (3.60), 2.659 (2.47), 2.754 (0.80), 2.759 (2.20), 2.763 (2.53), 2.768 (2.00), 2.773 (1.93), 2.778 (2.47), 2.781 (2.40), 2.791 (3.60), 2.797 (2.73), 2.799 (2.60), 2.810 (3.47), 2.829 (1.20), 3.121 (0.80), 3.139 (2.60), 3.153 (2.87), 3.157 (2.80), 3.171 (2.53), 3.189 (0.73), 3.465 (0.67), 3.475 (0.67), 3.494 (1.20), 3.502 (1.07), 3.524 (9.93), 3.538 (1.07), 3.588 (0.67), 3.605 (1.13), 3.613 (0.73), 3.620 (0.87), 3.631 (0.73), 3.646 (0.47), 4.292 (2.33), 4.310 (3.80), 4.327 (2.33), 6.249 (1.00), 6.263 (2.07), 6.277 (1.07), 6.649 (10.40), 7.086 (1.47), 7.098 (1.53), 7.106 (1.60), 7.118 (1.53), 7.301 (1.27), 7.304 (1.13), 7.306 (1.27), 8.004 (0.93), 8.007 (0.93), 8.024 (0.87), 8.027 (0.87), 8.253 (1.07), 8.257 (1.07), 8.265 (1.07), 8.268 (1.00), 8.318 (5.47), 8.323 (5.60), 8.716 (6.33), 8.721 (6.20), 12.306 (0.87).    Example 239 (rac)-2-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide 
Figure imgf000518_0001
  Example 240 (1-benzylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone 
Figure imgf000519_0001
(Rac)-2'-(Quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) (100 mg, 306 µmol) was dissolved in DMF (1.3 mL), then N,N- diisopropylethylamine (320 µL, 1.8 mmol), 1-benzylcyclobutane-1-carboxylic acid (69.9 mg, 367 µmol), and HATU (140 mg, 367 µmol) were added. The reaction mixture was stirred overnight at rt and purified by HPLC to obtain 17.8 mg (95 % purity, 12 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 464 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.946 (0.88), 0.961 (0.85), 1.561 (1.04), 1.586 (1.30), 1.609 (0.65), 1.647 (1.07), 1.670 (1.29), 1.686 (1.16), 1.708 (1.50), 1.731 (1.37), 1.757 (0.84), 1.829 (2.18), 1.846 (4.83), 1.863 (2.58), 1.889 (1.17), 1.905 (1.68), 1.914 (1.99), 1.936 (3.26), 1.957 (4.32), 1.968 (2.59), 1.978 (2.65), 2.030 (0.60), 2.042 (1.58), 2.057 (3.03), 2.076 (3.84), 2.094 (1.46), 2.107 (0.77), 2.278 (0.72), 2.302 (1.99), 2.318 (1.71), 2.323 (3.57), 2.327 (5.46), 2.332 (5.72), 2.361 (2.12), 2.370 (1.57), 2.385 (0.96), 2.395 (1.21), 2.422 (0.80), 2.435 (1.47), 2.447 (1.45), 2.464 (3.14), 2.518 (14.54), 2.523 (10.89), 2.537 (2.92), 2.550 (2.23), 2.556 (2.47), 2.570 (1.56), 2.578 (1.61), 2.595 (1.60), 2.599 (1.84), 2.615 (1.46), 2.632 (0.76), 2.647 (0.55), 2.660 (1.15), 2.665 (2.56), 2.669 (3.58), 2.673 (2.51), 2.679 (1.14), 2.943 (1.37), 2.976 (5.38), 2.994 (5.28), 3.027 (1.37), 3.074 (9.88), 3.147 (0.90), 3.155 (1.05), 3.173 (1.84), 3.190 (1.47), 3.204 (1.68), 3.221 (1.00), 3.230 (0.88), 3.417 (2.21), 3.443 (4.15), 3.465 (0.85), 3.484 (5.97), 3.494 (2.02), 3.513 (4.03), 3.525 (9.59), 3.556 (0.42), 3.605 (0.95), 3.624 (1.69), 3.639 (1.44), 3.655 (1.01), 3.669 (0.65), 4.202 (0.50), 4.230 (1.88), 4.238 (3.07), 4.245 (3.96), 4.257 (5.35), 4.263 (4.56), 4.272 (3.62), 4.278 (4.10), 4.291 (1.86), 4.305 (0.89), 4.318 (0.49), 6.725 (16.00), 6.792 (13.16), 7.181 (5.46), 7.199 (8.75), 7.202 (10.91), 7.221 (6.67), 7.224 (6.26), 7.232 (4.96), 7.249 (6.20), 7.265 (9.21), 7.278 (4.06), 7.283 (6.56), 7.299 (2.18), 7.303 (1.44), 7.316 (5.12), 7.334 (6.44), 7.352 (2.30), 7.592 (2.00), 7.595 (3.20), 7.612 (5.80), 7.615 (5.20), 7.632 (4.48), 7.705 (2.72), 7.708 (4.59), 7.712 (2.41), 7.721 (2.42), 7.725 (5.64), 7.728 (6.20), 7.732 (2.90), 7.742 (2.44), 7.746 (3.90), 7.749 (1.96), 7.995 (9.75), 8.015 (8.64), 8.652 (10.09), 9.340 (7.91), 9.345 (8.18), 9.357 (6.67), 9.363 (6.51).  The following examples were synthesised analogously via amide bond formation  Example 241 (cuban-1-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone 
Figure imgf000520_0001
  Example 242 (1-ethylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone 
Figure imgf000520_0002
LC-MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 402 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.764 (6.14), 0.783 (14.63), 0.801 (7.07), 0.810 (3.96), 0.828 (7.67), 0.847 (3.49), 1.239 (1.31), 1.254 (1.10), 1.268 (0.76), 1.608 (1.14), 1.616 (1.26), 1.631 (1.51), 1.638 (1.29), 1.660 (2.02), 1.679 (2.20), 1.695 (3.03), 1.714 (2.77), 1.723 (2.67), 1.742 (2.84), 1.759 (2.19), 1.777 (2.66), 1.799 (5.64), 1.816 (4.05), 1.827 (4.02), 1.846 (4.69), 1.865 (4.44), 1.883 (1.61), 1.907 (0.81), 1.936 (0.41), 2.035 (0.76), 2.047 (1.66), 2.066 (3.67), 2.084 (3.65), 2.102 (1.80), 2.116 (0.84), 2.146 (1.26), 2.157 (2.12), 2.164 (2.27), 2.285 (0.93), 2.311 (1.47), 2.322 (2.44), 2.326 (3.39), 2.332 (2.80), 2.336 (2.58), 2.363 (1.55), 2.380 (2.18), 2.408 (1.17), 2.424 (1.19), 2.450 (1.20), 2.518 (8.93), 2.522 (5.73), 2.559 (4.39), 2.577 (7.95), 2.594 (6.12), 2.610 (3.58), 2.626 (1.79), 2.664 (1.52), 2.668 (1.99), 2.673 (1.47), 3.508 (11.98), 3.533 (3.95), 3.544 (4.02), 3.566 (6.04), 3.573 (5.53), 3.587 (2.23), 3.607 (3.95), 3.623 (2.61), 3.636 (2.41), 3.653 (1.29), 4.243 (0.45), 4.250 (0.60), 4.260 (1.96), 4.270 (3.01), 4.278 (4.77), 4.287 (5.03), 4.297 (5.57), 4.305 (3.23), 4.314 (2.61), 4.324 (0.99), 4.342 (0.43), 6.695 (16.00), 6.762 (7.40), 7.603 (2.89), 7.620 (5.69), 7.641 (4.16), 7.719 (3.72), 7.737 (5.42), 7.739 (4.99), 7.754 (2.79), 7.757 (3.18), 8.000 (5.74), 8.011 (6.56), 8.022 (5.19), 8.029 (6.06), 8.677 (6.74), 8.682 (5.77), 9.349 (8.04), 9.354 (8.79), 9.363 (3.95).    Example 243 [1-(difluoromethyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone 
Figure imgf000521_0001
LC-MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 424 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.221 (1.37), 1.239 (7.81), 1.255 (7.76), 1.270 (5.02), 1.693 (1.21), 1.709 (1.11), 1.718 (1.66), 1.729 (1.15), 1.744 (1.33), 1.770 (0.87), 1.838 (0.83), 1.860 (1.56), 1.885 (1.59), 1.907 (1.49), 1.932 (1.14), 1.954 (0.95), 1.963 (1.02), 1.983 (0.94), 2.048 (0.46), 2.064 (0.76), 2.080 (1.66), 2.095 (2.33), 2.114 (1.85), 2.124 (2.93), 2.141 (3.09), 2.155 (4.62), 2.172 (2.53), 2.209 (2.45), 2.219 (2.46), 2.233 (2.97), 2.242 (3.29), 2.258 (2.25), 2.266 (2.42), 2.273 (2.06), 2.318 (1.14), 2.322 (2.22), 2.326 (2.92), 2.332 (2.10), 2.336 (0.99), 2.421 (0.72), 2.447 (1.65), 2.518 (10.37), 2.522 (7.28), 2.539 (1.46), 2.555 (4.35), 2.572 (6.38), 2.590 (5.29), 2.606 (2.16), 2.620 (2.58), 2.639 (1.98), 2.647 (2.36), 2.664 (3.41), 2.668 (3.59), 2.673 (2.52), 2.678 (1.42), 3.126 (0.71), 3.136 (0.72), 3.144 (0.75), 3.155 (0.72), 3.533 (0.95), 3.558 (2.28), 3.564 (2.07), 3.584 (8.45), 3.597 (7.80), 3.608 (7.39), 3.622 (4.25), 3.642 (3.19), 3.666 (2.05), 3.680 (1.93), 3.688 (1.31), 3.706 (0.83), 3.723 (0.41), 3.904 (0.44), 4.263 (1.67), 4.272 (5.05), 4.280 (3.94), 4.290 (9.58), 4.307 (4.93), 6.188 (2.11), 6.328 (5.20), 6.468 (4.10), 6.609 (1.03), 6.707 (16.00), 6.825 (8.35), 7.603 (3.04), 7.620 (6.22), 7.640 (4.45), 7.715 (3.63), 7.718 (3.90), 7.735 (5.95), 7.739 (4.82), 7.752 (3.24), 7.756 (3.28), 8.002 (6.24), 8.008 (7.78), 8.023 (5.50), 8.029 (7.52), 8.656 (3.29), 8.661 (3.66), 8.670 (5.77), 8.675 (5.58), 9.350 (8.09), 9.356 (11.43), 9.362 (4.72).    Example 244 2-(pyridin-3-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one 
Figure imgf000522_0001
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 411 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.918 (0.91), 0.932 (6.87), 0.949 (6.83), 1.044 (5.38), 1.060 (5.47), 1.140 (1.36), 1.156 (1.38), 1.276 (5.89), 1.292 (6.02), 1.751 (0.51), 1.879 (0.44), 1.961 (0.68), 2.043 (0.73), 2.074 (1.02), 2.106 (1.83), 2.123 (2.55), 2.150 (3.06), 2.168 (1.80), 2.182 (1.39), 2.209 (2.85), 2.227 (5.40), 2.244 (3.00), 2.327 (3.25), 2.406 (1.06), 2.424 (1.35), 2.584 (1.43), 2.600 (3.09), 2.615 (6.50), 2.631 (7.59), 2.645 (5.64), 2.665 (4.10), 2.669 (3.90), 2.942 (0.41), 2.959 (0.57), 3.513 (0.81), 3.537 (2.33), 3.566 (7.43), 3.580 (7.78), 3.609 (1.92), 3.619 (1.36), 3.637 (2.16), 3.652 (1.71), 3.666 (1.48), 3.691 (6.51), 3.700 (16.00), 3.751 (3.05), 3.777 (6.97), 3.797 (9.33), 3.808 (11.56), 3.836 (3.63), 3.856 (2.83), 3.873 (1.55), 3.881 (1.58), 3.898 (0.77), 4.272 (2.80), 4.277 (2.99), 4.290 (8.61), 4.308 (10.18), 4.325 (4.14), 6.728 (13.75), 6.763 (13.52), 7.312 (3.18), 7.324 (3.40), 7.332 (3.69), 7.343 (3.68), 7.355 (2.85), 7.367 (2.93), 7.374 (3.16), 7.385 (2.95), 7.602 (3.72), 7.622 (6.37), 7.640 (5.00), 7.643 (4.84), 7.648 (3.72), 7.668 (2.96), 7.695 (3.50), 7.714 (7.16), 7.734 (6.54), 7.752 (3.66), 8.006 (13.44), 8.026 (12.21), 8.413 (5.95), 8.417 (5.34), 8.425 (5.04), 8.429 (4.81), 8.441 (5.54), 8.445 (5.49), 8.462 (4.01), 8.465 (4.12), 8.474 (4.04), 8.477 (3.84), 8.495 (5.63), 8.500 (5.59), 8.622 (5.83), 8.627 (5.98), 8.668 (5.82), 8.674 (5.90), 9.340 (7.29), 9.346 (7.46), 9.357 (7.47), 9.363 (7.28).    Example 245 [1-(4-chlorophenyl)cyclobutyl][(rac)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazol]-1-yl]methanone 
Figure imgf000523_0001
LC-MS (Method 1): Rt = 1.32 min; MS (ESIpos): m/z = 483 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.945 (0.53), 1.153 (3.61), 1.171 (7.63), 1.189 (3.85), 1.760 (0.86), 1.772 (1.17), 1.784 (1.39), 1.795 (1.34), 1.807 (1.09), 1.821 (1.58), 1.843 (1.73), 1.864 (1.38), 1.870 (1.12), 1.886 (0.97), 1.892 (0.88), 1.906 (1.18), 1.929 (0.79), 1.935 (0.79), 1.964 (2.01), 1.986 (16.00), 1.993 (3.55), 2.016 (2.52), 2.032 (1.35), 2.047 (0.69), 2.186 (1.06), 2.207 (1.68), 2.218 (2.18), 2.233 (2.02), 2.254 (1.33), 2.274 (0.50), 2.304 (0.73), 2.327 (1.54), 2.332 (1.26), 2.357 (1.44), 2.366 (1.56), 2.382 (2.14), 2.396 (2.04), 2.403 (1.93), 2.416 (2.24), 2.428 (1.50), 2.435 (1.47), 2.448 (1.85), 2.461 (1.19), 2.467 (1.05), 2.518 (3.38), 2.523 (2.64), 2.539 (1.10), 2.543 (1.16), 2.559 (0.86), 2.575 (0.58), 2.591 (0.41), 2.665 (0.57), 2.669 (0.76), 2.673 (0.62), 2.685 (0.79), 2.708 (2.15), 2.733 (2.70), 2.758 (2.12), 2.774 (1.04), 2.825 (0.45), 2.848 (0.92), 2.876 (0.86), 3.081 (1.71), 3.107 (4.90), 3.119 (3.04), 3.132 (4.91), 3.158 (1.69), 3.304 (0.55), 3.378 (0.63), 3.545 (2.07), 3.553 (1.77), 3.573 (5.78), 3.584 (4.52), 3.602 (0.65), 3.614 (0.81), 3.998 (1.04), 4.016 (3.10), 4.034 (3.28), 4.052 (1.83), 4.059 (1.05), 4.065 (1.37), 4.072 (1.05), 4.078 (1.51), 4.086 (1.26), 4.099 (1.05), 4.143 (1.08), 4.157 (1.36), 4.163 (1.63), 4.170 (1.26), 4.178 (1.38), 4.185 (1.28), 4.190 (1.37), 4.198 (1.07), 4.206 (1.10), 4.214 (1.33), 4.225 (0.96), 4.239 (1.15), 4.246 (1.10), 4.259 (0.90), 4.273 (0.40), 6.344 (6.73), 6.392 (11.02), 7.369 (4.65), 7.375 (1.96), 7.392 (12.37), 7.418 (11.86), 7.435 (1.92), 7.440 (4.40), 7.461 (3.06), 7.483 (6.30), 7.521 (6.80), 7.544 (3.13), 7.593 (1.50), 7.596 (1.63), 7.604 (1.15), 7.611 (2.55), 7.613 (3.41), 7.624 (2.17), 7.630 (2.36), 7.634 (2.40), 7.641 (1.40), 7.644 (1.31), 7.702 (2.03), 7.706 (2.14), 7.711 (1.43), 7.715 (1.50), 7.719 (1.91), 7.723 (3.43), 7.727 (3.06), 7.732 (2.26), 7.735 (1.67), 7.740 (1.98), 7.744 (1.88), 7.749 (1.17), 7.752 (1.04), 7.991 (3.65), 8.001 (2.48), 8.012 (6.58), 8.023 (3.86), 8.030 (3.25), 8.045 (1.77), 8.532 (2.68), 8.537 (2.75), 8.573 (4.54), 8.578 (4.71), 9.293 (9.38), 9.298 (9.48).    Example 246 (1-methylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone 
Figure imgf000524_0001
LC-MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 388 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.323 (16.00), 1.418 (9.10), 1.582 (0.90), 1.608 (1.13), 1.633 (0.90), 1.661 (0.62), 1.690 (0.76), 1.716 (1.61), 1.740 (2.19), 1.768 (1.74), 1.779 (1.37), 1.863 (0.72), 1.886 (1.07), 1.911 (1.06), 1.933 (0.94), 1.956 (0.77), 1.979 (0.59), 2.036 (0.56), 2.048 (1.05), 2.068 (2.18), 2.073 (3.35), 2.085 (2.15), 2.104 (1.11), 2.119 (0.60), 2.147 (1.05), 2.165 (1.81), 2.179 (0.98), 2.311 (0.56), 2.335 (1.56), 2.361 (1.46), 2.374 (1.56), 2.399 (1.45), 2.413 (0.95), 2.442 (0.89), 2.545 (0.58), 2.562 (1.56), 2.577 (2.44), 2.591 (3.07), 2.606 (2.91), 2.623 (2.01), 2.640 (0.95), 2.669 (0.50), 3.482 (0.92), 3.511 (7.58), 3.528 (2.44), 3.538 (1.80), 3.552 (6.15), 3.582 (2.07), 3.599 (1.93), 3.613 (1.27), 3.625 (0.73), 4.259 (1.13), 4.275 (2.45), 4.288 (3.62), 4.300 (3.02), 4.316 (1.48), 4.328 (0.54), 6.694 (7.81), 6.778 (4.31), 7.592 (1.73), 7.609 (3.42), 7.629 (2.44), 7.706 (2.25), 7.725 (3.23), 7.727 (3.12), 7.744 (1.86), 7.998 (6.09), 8.019 (5.44), 8.663 (4.46), 8.668 (3.81), 9.348 (4.36), 9.353 (4.91), 9.363 (2.61).    Example 247 [1-(4-fluorophenyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone 
Figure imgf000525_0001
LC-MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 468 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.001 (1.00), 1.154 (0.61), 1.172 (1.13), 1.190 (0.57), 1.756 (1.13), 1.767 (1.62), 1.780 (1.86), 1.791 (1.76), 1.803 (1.54), 1.820 (1.76), 1.843 (2.26), 1.864 (1.65), 1.870 (1.55), 1.892 (1.14), 1.898 (1.40), 1.907 (2.75), 1.921 (1.03), 1.926 (0.95), 1.948 (0.90), 1.966 (2.44), 1.983 (4.64), 1.988 (4.98), 2.000 (3.49), 2.021 (2.65), 2.038 (1.60), 2.052 (0.92), 2.069 (0.48), 2.136 (0.89), 2.151 (1.16), 2.157 (1.24), 2.169 (1.58), 2.183 (1.60), 2.189 (1.39), 2.204 (1.18), 2.230 (0.82), 2.260 (1.77), 2.283 (1.64), 2.318 (1.84), 2.323 (3.17), 2.327 (3.90), 2.332 (3.45), 2.352 (1.08), 2.369 (1.73), 2.382 (1.81), 2.389 (2.24), 2.402 (2.60), 2.415 (2.19), 2.422 (2.27), 2.435 (1.98), 2.451 (2.12), 2.464 (2.03), 2.518 (11.86), 2.523 (8.14), 2.541 (1.71), 2.546 (1.71), 2.562 (1.17), 2.573 (0.73), 2.578 (0.74), 2.594 (0.52), 2.660 (0.99), 2.665 (2.20), 2.669 (3.11), 2.673 (2.19), 2.679 (1.10), 2.696 (1.13), 2.718 (3.34), 2.739 (3.77), 2.767 (1.89), 2.789 (0.48), 2.826 (0.56), 2.848 (1.24), 2.876 (1.16), 2.899 (0.48), 3.097 (1.66), 3.124 (6.15), 3.137 (7.72), 3.154 (4.05), 3.164 (2.52), 3.171 (2.03), 3.525 (2.29), 3.538 (1.83), 3.554 (7.07), 3.570 (3.59), 3.587 (5.25), 3.617 (1.96), 4.017 (0.49), 4.027 (0.90), 4.035 (0.69), 4.040 (1.12), 4.048 (1.29), 4.054 (1.75), 4.062 (1.30), 4.067 (1.90), 4.075 (1.60), 4.089 (1.30), 4.141 (1.36), 4.155 (1.66), 4.161 (2.00), 4.168 (1.63), 4.176 (1.69), 4.183 (1.68), 4.188 (1.75), 4.196 (1.37), 4.204 (1.46), 4.212 (1.73), 4.223 (1.29), 4.235 (1.57), 4.244 (1.42), 4.250 (0.76), 4.257 (1.19), 4.270 (0.56), 6.221 (9.64), 6.404 (16.00), 7.131 (4.68), 7.154 (10.06), 7.176 (5.39), 7.281 (2.80), 7.303 (6.16), 7.325 (3.41), 7.426 (5.00), 7.431 (2.44), 7.439 (5.65), 7.447 (5.30), 7.456 (2.08), 7.461 (4.57), 7.482 (3.24), 7.495 (3.58), 7.504 (3.15), 7.518 (2.66), 7.596 (1.95), 7.599 (2.00), 7.613 (4.12), 7.616 (4.29), 7.630 (3.17), 7.633 (3.94), 7.636 (3.21), 7.648 (1.76), 7.650 (1.69), 7.706 (2.78), 7.709 (2.64), 7.715 (1.95), 7.719 (1.96), 7.723 (2.52), 7.727 (4.35), 7.730 (3.92), 7.736 (2.87), 7.739 (2.19), 7.744 (2.57), 7.747 (2.45), 7.753 (1.56), 7.757 (1.35), 7.992 (4.65), 8.005 (6.24), 8.010 (8.62), 8.025 (5.73), 8.029 (5.12), 8.491 (3.52), 8.496 (3.60), 8.572 (5.77), 8.577 (5.91), 9.280 (5.34), 9.288 (9.90), 9.293 (8.69).    Example 248 2-cyclobutyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-one 
Figure imgf000526_0001
LC-MS (Method 1): Rt = 1.11 min; MS (ESIpos): m/z = 387 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.101 (0.45), 1.117 (0.45), 1.604 (1.21), 1.625 (2.30), 1.649 (2.78), 1.655 (2.59), 1.678 (2.52), 1.686 (2.01), 1.706 (2.59), 1.725 (1.79), 1.733 (1.47), 1.744 (0.67), 1.751 (1.56), 1.757 (1.44), 1.762 (1.53), 1.772 (1.85), 1.777 (2.04), 1.781 (3.07), 1.793 (1.88), 1.800 (3.70), 1.803 (3.07), 1.809 (1.85), 1.819 (3.58), 1.827 (2.62), 1.842 (2.84), 1.845 (2.59), 1.865 (1.69), 1.869 (1.41), 1.887 (0.61), 1.892 (0.61), 1.907 (1.69), 2.001 (0.96), 2.019 (2.01), 2.030 (2.75), 2.039 (3.54), 2.050 (4.15), 2.059 (3.96), 2.068 (4.06), 2.078 (4.73), 2.083 (3.96), 2.088 (4.31), 2.097 (3.32), 2.107 (3.70), 2.116 (1.41), 2.125 (1.66), 2.137 (1.09), 2.156 (2.24), 2.163 (1.85), 2.173 (3.45), 2.181 (3.83), 2.190 (2.33), 2.198 (2.36), 2.212 (1.21), 2.228 (1.79), 2.247 (1.05), 2.282 (0.48), 2.297 (0.64), 2.318 (0.77), 2.322 (1.37), 2.326 (1.98), 2.331 (1.25), 2.336 (0.67), 2.345 (0.45), 2.366 (4.12), 2.371 (4.22), 2.385 (5.30), 2.388 (5.01), 2.409 (0.42), 2.426 (0.89), 2.445 (0.83), 2.465 (4.02), 2.477 (5.59), 2.518 (5.78), 2.523 (3.67), 2.534 (0.86), 2.539 (1.05), 2.550 (0.51), 2.576 (3.51), 2.582 (3.16), 2.593 (6.32), 2.600 (8.14), 2.611 (4.44), 2.618 (7.57), 2.642 (3.19), 2.663 (3.51), 2.668 (2.52), 2.673 (2.11), 2.680 (2.40), 2.699 (1.56), 2.715 (0.86), 2.730 (0.42), 3.300 (0.48), 3.310 (0.86), 3.349 (1.66), 3.355 (1.44), 3.365 (0.48), 3.373 (0.51), 3.384 (1.56), 3.412 (0.70), 3.447 (0.70), 3.459 (1.44), 3.464 (1.63), 3.476 (1.37), 3.487 (1.72), 3.494 (2.52), 3.512 (13.89), 3.536 (0.64), 3.561 (1.02), 3.580 (1.66), 3.595 (1.31), 3.611 (1.47), 3.628 (3.32), 3.637 (1.47), 3.653 (7.50), 3.670 (6.26), 3.696 (2.36), 3.716 (2.24), 3.725 (1.21), 3.733 (1.50), 3.741 (2.04), 3.759 (0.83), 3.782 (0.51), 3.858 (1.63), 4.248 (0.64), 4.258 (2.33), 4.265 (2.65), 4.277 (7.19), 4.286 (3.80), 4.296 (8.62), 4.313 (4.28), 4.321 (1.72), 4.336 (0.54), 6.745 (15.65), 6.754 (0.73), 6.772 (15.62), 6.784 (0.54), 6.810 (2.78), 6.823 (2.24), 6.862 (3.74), 7.592 (3.74), 7.595 (3.45), 7.612 (7.15), 7.629 (5.52), 7.632 (5.62), 7.645 (0.70), 7.648 (0.70), 7.706 (5.27), 7.709 (4.66), 7.723 (5.17), 7.727 (7.86), 7.731 (6.45), 7.744 (4.95), 7.748 (5.21), 7.762 (0.57), 7.765 (0.54), 7.995 (16.00), 8.007 (2.52), 8.018 (14.85), 8.038 (0.89), 8.634 (1.66), 8.640 (6.20), 8.645 (5.40), 8.655 (1.09), 8.664 (5.43), 8.670 (6.13), 9.334 (2.14), 9.340 (2.36), 9.347 (8.05), 9.352 (13.83), 9.357 (9.13), 9.467 (0.48), 9.473 (0.45).    Example 249 (1-methylcyclopropyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone 
Figure imgf000527_0001
LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 373 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.509 (4.15), 0.786 (1.33), 0.872 (2.24), 1.154 (0.50), 1.172 (0.79), 1.189 (0.70), 1.234 (5.35), 1.907 (8.08), 1.987 (1.08), 2.084 (1.20), 2.138 (2.57), 2.322 (1.78), 2.327 (2.36), 2.331 (1.74), 2.336 (0.83), 2.518 (7.63), 2.523 (5.06), 2.539 (1.37), 2.560 (0.62), 2.576 (1.12), 2.593 (3.03), 2.610 (7.13), 2.627 (7.46), 2.645 (3.69), 2.664 (2.36), 2.669 (2.61), 2.673 (1.99), 2.678 (1.49), 3.521 (1.87), 3.820 (2.86), 4.298 (5.76), 6.703 (2.20), 6.949 (0.83), 7.077 (0.83), 7.204 (0.79), 7.592 (3.77), 7.595 (3.65), 7.612 (8.04), 7.630 (5.35), 7.633 (5.39), 7.706 (4.93), 7.710 (4.68), 7.724 (4.31), 7.728 (7.96), 7.731 (5.97), 7.745 (4.23), 7.748 (4.23), 7.999 (13.06), 8.019 (11.90), 8.665 (8.79), 8.669 (8.75), 9.355 (15.96), 9.360 (16.00).    Example 250 (3-methyloxetan-3-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone 
Figure imgf000528_0002
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 389 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (3.43), 1.528 (1.47), 1.637 (0.84), 1.890 (5.72), 2.521 (0.89), 2.525 (0.61), 2.542 (16.00), 2.890 (0.48), 3.427 (0.59), 3.452 (0.43), 3.587 (0.56), 6.713 (0.85), 6.830 (0.46), 8.002 (0.44), 9.352 (0.42), 9.358 (0.42).    Example 251 cyclobutyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone 
Figure imgf000528_0001
LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 373 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.919 (0.49), 0.933 (3.81), 0.950 (3.81), 1.055 (0.45), 1.072 (0.90), 1.088 (0.67), 1.723 (0.54), 1.733 (0.99), 1.743 (0.94), 1.750 (1.17), 1.757 (1.39), 1.766 (1.21), 1.773 (1.17), 1.780 (1.21), 1.789 (1.08), 1.800 (1.03), 1.812 (0.90), 1.824 (0.58), 1.835 (1.43), 1.857 (1.97), 1.879 (1.88), 1.884 (1.43), 1.902 (0.85), 1.907 (1.57), 1.931 (1.79), 1.954 (1.61), 1.959 (1.17), 1.981 (0.99), 2.003 (0.45), 2.025 (0.49), 2.035 (0.72), 2.047 (1.93), 2.057 (1.75), 2.068 (3.14), 2.074 (3.50), 2.079 (3.85), 2.090 (3.14), 2.100 (3.85), 2.107 (3.45), 2.124 (4.35), 2.130 (2.82), 2.145 (5.15), 2.151 (5.15), 2.165 (6.59), 2.169 (6.36), 2.183 (3.99), 2.189 (4.97), 2.202 (1.43), 2.206 (1.39), 2.211 (1.84), 2.226 (1.57), 2.247 (1.43), 2.253 (1.12), 2.269 (0.63), 2.276 (0.99), 2.336 (0.76), 2.518 (8.69), 2.522 (5.83), 2.539 (2.51), 2.551 (0.76), 2.557 (0.85), 2.567 (2.33), 2.573 (3.72), 2.583 (5.69), 2.592 (6.05), 2.602 (4.84), 2.608 (3.85), 2.619 (1.93), 2.635 (0.58), 2.673 (1.66), 2.678 (0.76), 2.686 (0.85), 2.727 (1.61), 2.888 (1.97), 3.187 (0.45), 3.208 (1.66), 3.230 (2.46), 3.250 (1.61), 3.272 (0.49), 3.357 (2.82), 3.378 (1.61), 3.399 (0.45), 3.468 (0.58), 3.486 (1.21), 3.498 (1.34), 3.504 (1.21), 3.512 (2.73), 3.533 (13.58), 3.556 (6.23), 3.564 (3.50), 3.582 (4.17), 3.598 (1.34), 3.609 (1.70), 3.626 (2.24), 3.642 (1.08), 3.652 (1.08), 3.668 (0.54), 4.247 (0.54), 4.258 (2.02), 4.270 (4.53), 4.275 (4.35), 4.287 (8.83), 4.305 (3.85), 6.731 (16.00), 6.741 (13.67), 7.591 (2.60), 7.609 (5.06), 7.630 (3.90), 7.705 (3.36), 7.708 (3.05), 7.725 (5.11), 7.728 (4.35), 7.742 (2.73), 7.746 (3.00), 7.992 (9.37), 7.995 (12.19), 8.015 (10.89), 8.644 (4.44), 8.649 (4.66), 8.665 (4.84), 8.670 (5.06), 9.349 (9.59), 9.353 (9.28).    Example 252 cyclopentyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone 
Figure imgf000529_0001
LC-MS (Method 1): Rt = 1.11 min; MS (ESIpos): m/z = 387 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.35), 0.008 (2.24), 1.007 (0.53), 1.046 (0.80), 1.063 (0.80), 1.118 (1.39), 1.135 (1.12), 1.241 (2.08), 1.257 (1.65), 1.271 (1.12), 1.484 (2.35), 1.495 (2.93), 1.502 (3.04), 1.512 (2.24), 1.524 (1.87), 1.543 (2.24), 1.557 (2.88), 1.564 (2.72), 1.582 (2.19), 1.591 (2.29), 1.611 (3.20), 1.622 (4.48), 1.633 (4.91), 1.647 (4.64), 1.650 (4.69), 1.661 (5.92), 1.680 (4.69), 1.695 (3.68), 1.711 (2.67), 1.726 (2.35), 1.747 (2.40), 1.767 (2.24), 1.785 (1.92), 1.805 (1.49), 1.815 (1.28), 1.836 (1.71), 1.855 (1.76), 1.875 (1.71), 1.895 (1.12), 1.909 (1.12), 2.052 (0.43), 2.070 (0.80), 2.083 (1.60), 2.099 (2.51), 2.117 (1.76), 2.126 (2.88), 2.144 (1.71), 2.156 (1.07), 2.179 (1.81), 2.195 (2.88), 2.206 (3.36), 2.223 (1.55), 2.237 (0.59), 2.334 (2.19), 2.520 (13.39), 2.525 (8.48), 2.542 (1.65), 2.577 (1.01), 2.590 (4.21), 2.608 (8.37), 2.623 (7.04), 2.639 (2.45), 2.655 (0.80), 2.676 (2.29), 2.764 (0.69), 2.784 (1.65), 2.804 (2.19), 2.822 (1.44), 2.887 (0.53), 2.905 (1.28), 2.925 (1.76), 2.944 (1.17), 3.129 (0.43), 3.147 (0.43), 3.254 (0.48), 3.481 (0.96), 3.498 (1.65), 3.512 (2.56), 3.528 (2.93), 3.541 (7.63), 3.548 (7.63), 3.578 (2.24), 3.598 (2.24), 3.613 (1.65), 3.625 (1.28), 3.643 (0.75), 3.683 (2.61), 3.709 (7.47), 3.727 (7.47), 3.742 (1.17), 3.753 (2.13), 3.773 (1.01), 3.791 (1.97), 3.807 (1.28), 3.816 (1.17), 3.833 (0.59), 4.257 (0.69), 4.267 (2.24), 4.274 (2.77), 4.286 (6.56), 4.303 (7.79), 4.320 (3.36), 4.334 (0.59), 6.751 (16.00), 6.760 (14.45), 6.950 (1.07), 7.078 (1.17), 7.206 (1.07), 7.598 (3.04), 7.617 (6.51), 7.637 (4.64), 7.712 (3.89), 7.716 (3.73), 7.733 (6.40), 7.750 (3.41), 7.753 (3.36), 8.001 (10.99), 8.022 (9.65), 8.655 (4.75), 8.660 (4.80), 8.679 (5.44), 8.684 (5.49), 9.353 (6.88), 9.359 (13.60), 9.365 (7.73).    Example 253 2-cyclopropyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]- 1-yl]ethan-1-one 
Figure imgf000530_0001
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 373 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (2.55), 0.012 (4.91), 0.020 (2.18), 0.025 (2.55), 0.058 (2.73), 0.063 (2.00), 0.071 (4.36), 0.081 (2.00), 0.085 (2.73), 0.110 (0.55), 0.325 (0.91), 0.336 (4.91), 0.341 (4.91), 0.357 (5.09), 0.361 (4.73), 0.373 (1.27), 0.380 (5.64), 0.385 (5.64), 0.400 (5.82), 0.405 (5.27), 0.417 (0.73), 0.680 (0.36), 0.760 (0.55), 0.864 (0.73), 0.876 (1.27), 0.880 (1.09), 0.884 (1.09), 0.896 (2.00), 0.904 (1.27), 0.908 (1.64), 0.912 (1.45), 0.916 (1.45), 0.921 (1.45), 0.925 (1.45), 0.928 (1.64), 0.933 (1.45), 0.941 (2.00), 0.953 (1.09), 0.957 (1.27), 0.961 (1.09), 0.978 (0.73), 1.014 (0.55), 1.030 (0.55), 1.069 (1.09), 1.141 (2.00), 1.808 (0.73), 1.957 (0.55), 1.975 (0.73), 1.988 (1.64), 2.003 (2.18), 2.021 (1.64), 2.030 (2.73), 2.048 (1.82), 2.071 (2.55), 2.084 (4.18), 2.094 (6.18), 2.099 (6.55), 2.111 (5.09), 2.116 (4.73), 2.139 (1.82), 2.156 (1.64), 2.178 (3.27), 2.196 (3.27), 2.219 (3.27), 2.237 (6.36), 2.241 (3.09), 2.259 (1.27), 2.275 (1.27), 2.428 (13.09), 2.433 (8.36), 2.450 (1.09), 2.462 (0.55), 2.480 (1.09), 2.495 (3.82), 2.512 (6.91), 2.524 (6.73), 2.540 (3.45), 2.556 (1.09), 2.574 (2.91), 2.579 (3.64), 2.584 (2.55), 3.289 (2.18), 3.390 (0.73), 3.407 (1.45), 3.421 (1.82), 3.437 (2.36), 3.451 (7.27), 3.457 (7.64), 3.486 (1.09), 3.503 (1.64), 3.522 (4.73), 3.538 (2.55), 3.547 (8.73), 3.563 (6.55), 3.589 (2.55), 3.607 (2.36), 3.615 (1.09), 3.624 (1.27), 3.632 (1.27), 3.649 (0.55), 4.172 (2.36), 4.182 (5.82), 4.190 (4.91), 4.200 (11.09), 4.208 (3.64), 4.217 (4.91), 6.641 (0.55), 6.650 (0.73), 6.660 (15.45), 6.686 (16.00), 6.697 (0.91), 7.504 (3.09), 7.521 (6.18), 7.524 (5.82), 7.541 (4.73), 7.617 (4.18), 7.619 (3.45), 7.637 (6.73), 7.640 (4.91), 7.655 (3.09), 7.658 (3.45), 7.905 (13.64), 7.926 (10.91), 7.929 (11.45), 8.016 (0.36), 8.551 (5.27), 8.556 (5.27), 8.572 (5.09), 8.577 (5.27), 9.258 (14.91), 9.264 (15.45), 9.377 (0.55), 9.382 (0.55).    Example 254 2-phenyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-one 
Figure imgf000531_0001
LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 409 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.942 (0.70), 0.958 (0.75), 0.985 (2.15), 1.001 (2.15), 1.014 (0.61), 1.032 (1.22), 1.049 (0.61), 1.072 (1.73), 1.089 (1.73), 1.113 (1.08), 1.131 (0.89), 1.162 (0.65), 1.231 (1.12), 1.287 (0.94), 1.303 (0.89), 1.906 (0.56), 2.055 (0.42), 2.074 (0.75), 2.086 (1.59), 2.102 (2.15), 2.112 (1.68), 2.120 (1.59), 2.131 (2.71), 2.149 (1.59), 2.169 (3.04), 2.187 (6.41), 2.204 (3.13), 2.331 (2.01), 2.518 (10.95), 2.522 (6.78), 2.539 (3.65), 2.555 (1.17), 2.569 (4.82), 2.587 (8.98), 2.604 (5.89), 2.627 (2.06), 2.642 (0.84), 2.673 (2.01), 3.145 (0.47), 3.162 (0.47), 3.249 (0.42), 3.267 (0.47), 3.503 (0.89), 3.518 (2.99), 3.533 (1.59), 3.547 (6.78), 3.575 (6.36), 3.604 (3.23), 3.621 (1.96), 3.636 (2.95), 3.648 (16.00), 3.666 (0.94), 3.678 (3.09), 3.695 (2.57), 3.704 (5.52), 3.716 (1.78), 3.733 (9.12), 3.741 (10.67), 3.754 (5.66), 3.768 (1.59), 3.780 (4.02), 3.785 (3.09), 3.804 (1.40), 3.812 (1.45), 3.829 (0.61), 4.228 (0.56), 4.246 (1.12), 4.255 (4.16), 4.264 (4.87), 4.272 (7.11), 4.283 (6.64), 4.291 (4.73), 4.298 (4.26), 4.325 (0.51), 6.585 (15.95), 6.721 (15.77), 7.183 (1.26), 7.187 (0.84), 7.193 (1.12), 7.200 (3.93), 7.212 (2.06), 7.217 (2.67), 7.221 (2.29), 7.227 (1.64), 7.244 (3.84), 7.260 (11.51), 7.264 (7.95), 7.276 (11.13), 7.294 (9.26), 7.299 (5.66), 7.304 (5.29), 7.312 (3.51), 7.315 (3.60), 7.321 (10.62), 7.343 (8.19), 7.348 (2.25), 7.360 (6.88), 7.379 (2.39), 7.596 (1.87), 7.600 (1.82), 7.604 (2.01), 7.607 (2.01), 7.617 (3.93), 7.621 (3.93), 7.624 (4.21), 7.634 (2.71), 7.637 (2.85), 7.642 (2.71), 7.645 (2.71), 7.710 (2.71), 7.714 (4.49), 7.717 (2.71), 7.728 (2.62), 7.731 (5.75), 7.735 (6.27), 7.738 (3.27), 7.749 (2.25), 7.752 (3.88), 7.755 (2.15), 8.001 (8.56), 8.006 (9.45), 8.025 (8.23), 8.106 (0.47), 8.127 (0.42), 8.579 (5.47), 8.584 (5.57), 8.655 (5.29), 8.660 (5.43), 9.309 (7.81), 9.314 (7.72), 9.345 (7.49), 9.350 (7.49), 9.468 (0.51), 9.473 (0.51).    Example 255 phenyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone 
Figure imgf000532_0001
LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 395 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.162 (0.77), 1.230 (1.04), 1.553 (16.00), 2.138 (2.42), 2.145 (2.36), 2.160 (1.65), 2.177 (0.99), 2.191 (1.37), 2.208 (2.03), 2.235 (1.98), 2.253 (1.26), 2.266 (0.71), 2.284 (0.38), 2.322 (2.31), 2.327 (3.13), 2.331 (2.31), 2.518 (10.17), 2.522 (6.43), 2.539 (0.66), 2.565 (2.47), 2.583 (4.78), 2.601 (2.53), 2.622 (0.55), 2.636 (0.71), 2.655 (1.37), 2.659 (1.54), 2.664 (2.69), 2.669 (4.18), 2.673 (3.24), 2.686 (1.98), 2.726 (0.82), 2.746 (1.26), 2.762 (0.99), 2.774 (0.66), 2.794 (0.44), 3.617 (0.88), 3.647 (7.92), 3.674 (1.48), 3.698 (1.59), 3.711 (2.86), 3.730 (10.06), 3.801 (0.88), 3.820 (1.65), 3.837 (1.10), 3.851 (0.99), 3.868 (0.55), 4.200 (0.55), 4.210 (1.54), 4.228 (2.42), 4.238 (2.42), 4.255 (1.59), 4.265 (0.82), 4.283 (0.77), 4.291 (1.15), 4.310 (2.36), 4.326 (1.92), 4.345 (1.10), 6.720 (9.84), 6.917 (7.04), 7.404 (1.15), 7.417 (4.51), 7.434 (8.30), 7.445 (1.92), 7.466 (0.77), 7.490 (3.46), 7.504 (6.10), 7.507 (6.27), 7.532 (5.17), 7.538 (4.18), 7.552 (4.07), 7.556 (3.13), 7.595 (1.54), 7.612 (3.13), 7.622 (2.58), 7.632 (2.42), 7.642 (1.92), 7.651 (3.63), 7.658 (2.97), 7.671 (3.13), 7.674 (2.42), 7.708 (2.14), 7.714 (1.70), 7.726 (3.24), 7.730 (3.02), 7.735 (2.42), 7.743 (1.76), 7.747 (1.70), 7.752 (1.26), 7.834 (0.44), 7.992 (3.41), 8.009 (8.14), 8.028 (5.33), 8.106 (0.55), 8.127 (0.55), 8.539 (1.70), 8.659 (4.18), 8.664 (4.34), 8.680 (3.41), 8.684 (3.24), 8.938 (0.55), 8.945 (0.55), 9.333 (5.11), 9.338 (5.00), 9.386 (3.85), 9.391 (3.79), 9.467 (0.82), 9.473 (0.77).    Example 256 2-methoxy-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-one 
Figure imgf000533_0002
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 363 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.211 (5.12), 2.166 (8.19), 3.612 (16.00), 4.012 (7.40), 4.131 (6.84), 4.287 (11.49), 6.770 (5.03), 7.615 (6.30), 7.723 (6.51), 8.007 (11.63), 8.656 (5.73), 9.359 (5.97).  Example 257 [(rac)-2,2-difluoro-1-methylcyclopropyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of diastereomers)   
Figure imgf000533_0001
Example 258 (rac)-N-ethyl-2-{5-[(pyridine-3-carbonyl)amino]quinolin-3-yl}-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000534_0001
(Rac)-2'-(5-Aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 133 µmol) was suspended in dichloromethane (1.0 mL). At rt pyridine-3-carboxylic acid (24.5 mg, 199 µmol), N,N-diisopropylethylamine (93 µL, 530 µmol), and HATU (101 mg, 266 µmol) were added and stirred overnight at rt. The reaction mixture was concentrated and the residue was purified by HPLC to obtain 2.50 mg (98 % purity, 4 % yield) of the title product. The following examples were synthesised analogously via amide bond formation    Example 259 (rac)-N-ethyl-2'-{5-[(pyridine-4-carbonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000534_0002
  Example 260 (rac)-N-ethyl-2'-{5-[(pyridine-2-carbonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000535_0001
  Example 261 1-[(rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]-2-(1-methyl-1H-imidazol-2-yl)ethan-1-one 
Figure imgf000535_0002
(Rac)-2'-(3-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]—hydrogen chloride (1/1) (204 mg, 79 % purity, 458 µmol) was dissolved in DMF (3.6mL). (1-Methyl-1H-imidazol-2-yl)acetic acid (64.2 mg, 458 µmol), N,N- diisopropylethylamine (478 µL, 2.7 mmol), and T3P (400 µL, 50 % in DMF, 690 µmol) were added. It was stirred at rt for 20 h. The reaction mixture was purified by HPLC to afford 28.0 mg (98 % purity, 14 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.984 (1.34), 0.999 (1.31), 1.218 (0.47), 2.081 (0.42), 2.094 (0.43), 2.114 (0.47), 2.121 (0.51), 2.135 (0.66), 2.163 (0.96), 2.180 (1.69), 2.197 (0.90), 2.336 (0.46), 2.518 (12.40), 2.522 (8.89), 2.539 (3.86), 2.561 (1.43), 2.578 (1.44), 2.594 (1.75), 2.612 (1.67), 2.625 (0.85), 2.638 (0.44), 3.417 (0.86), 3.462 (1.70), 3.491 (2.46), 3.518 (1.68), 3.537 (1.37), 3.558 (11.51), 3.577 (1.71), 3.615 (1.70), 3.622 (1.72), 3.634 (1.68), 3.645 (1.52), 3.665 (1.44), 3.716 (1.94), 3.742 (2.19), 3.776 (3.05), 3.785 (3.25), 3.801 (2.49), 3.809 (1.57), 3.827 (1.87), 3.841 (3.06), 3.872 (1.61), 3.911 (2.76), 3.927 (1.44), 3.951 (2.00), 3.971 (0.91), 4.190 (0.46), 4.217 (1.05), 4.221 (1.11), 4.234 (2.08), 4.250 (2.01), 4.267 (1.09), 6.657 (4.78), 6.661 (4.20), 6.734 (2.18), 6.737 (2.21), 6.815 (2.74), 6.818 (2.83), 7.042 (1.98), 7.046 (2.08), 7.086 (2.49), 7.089 (2.55), 7.690 (3.50), 7.695 (4.51), 8.163 (2.48), 8.168 (2.67), 8.205 (2.10), 8.210 (2.22), 8.316 (16.00), 8.744 (2.13), 8.749 (3.76), 8.754 (1.95).  The following examples were synthesised analogously via amide bond formation  Example 262 2-(1H-imidazol-2-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one 
Figure imgf000536_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.870 (0.66), 0.970 (2.38), 1.230 (0.67), 2.084 (0.76), 2.101 (1.51), 2.115 (1.60), 2.133 (1.91), 2.152 (2.45), 2.171 (1.47), 2.184 (3.72), 2.202 (6.71), 2.219 (3.10), 2.322 (3.88), 2.326 (5.34), 2.331 (3.93), 2.522 (15.35), 2.568 (1.82), 2.584 (2.44), 2.601 (4.79), 2.618 (6.57), 2.638 (5.59), 2.655 (3.14), 2.659 (2.95), 2.665 (4.55), 2.669 (6.55), 2.673 (4.81), 3.492 (3.69), 3.507 (1.75), 3.521 (6.19), 3.538 (2.35), 3.556 (1.06), 3.565 (1.74), 3.588 (5.52), 3.599 (1.41), 3.617 (4.46), 3.631 (1.53), 3.649 (1.04), 3.657 (1.44), 3.696 (7.33), 3.707 (7.28), 3.726 (3.62), 3.733 (3.25), 3.747 (1.51), 3.759 (4.94), 3.764 (7.57), 3.820 (8.00), 3.843 (2.49), 3.860 (5.58), 3.889 (2.77), 3.910 (1.10), 3.928 (2.38), 3.946 (1.33), 3.954 (1.67), 3.971 (0.68), 4.268 (3.52), 4.276 (3.56), 4.286 (7.11), 4.302 (4.86), 5.758 (0.91), 6.757 (13.76), 6.794 (16.00), 6.867 (0.96), 6.991 (0.96), 7.600 (2.72), 7.619 (5.24), 7.637 (3.49), 7.713 (4.11), 7.734 (5.64), 7.751 (3.35), 8.004 (13.04), 8.025 (10.85), 8.610 (5.81), 8.616 (6.04), 8.663 (4.96), 8.668 (5.05), 9.337 (8.19), 9.342 (8.13), 9.353 (7.10), 9.359 (6.60), 11.864 (0.98).    Example 263 2-(1-methyl-1H-imidazol-2-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one 
Figure imgf000537_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.950 (0.50), 0.964 (0.45), 2.102 (0.62), 2.116 (0.66), 2.136 (0.70), 2.157 (0.97), 2.176 (0.64), 2.190 (1.36), 2.208 (2.47), 2.225 (1.19), 2.322 (0.86), 2.326 (1.17), 2.332 (0.88), 2.522 (4.24), 2.560 (0.43), 2.578 (0.62), 2.592 (0.90), 2.603 (1.15), 2.611 (1.46), 2.618 (2.18), 2.637 (2.62), 2.653 (1.28), 2.665 (1.20), 2.669 (1.74), 3.503 (1.18), 3.532 (2.36), 3.561 (14.67), 3.574 (2.45), 3.594 (16.00), 3.625 (0.66), 3.638 (0.61), 3.753 (1.14), 3.783 (3.65), 3.790 (3.28), 3.822 (1.51), 3.831 (0.80), 3.840 (0.97), 3.861 (3.25), 3.882 (1.09), 3.901 (2.72), 3.926 (0.94), 3.941 (1.36), 3.952 (0.68), 4.269 (1.18), 4.274 (1.26), 4.286 (2.78), 4.301 (2.60), 4.319 (1.14), 6.734 (3.14), 6.737 (3.26), 6.772 (4.91), 6.792 (5.71), 6.810 (3.57), 6.814 (3.62), 7.044 (3.01), 7.046 (2.98), 7.090 (3.41), 7.092 (3.36), 7.600 (1.09), 7.620 (2.13), 7.637 (1.45), 7.713 (1.66), 7.731 (2.18), 7.733 (2.36), 7.751 (1.37), 8.005 (4.50), 8.026 (3.91), 8.613 (2.19), 8.618 (2.26), 8.668 (1.96), 8.673 (2.00), 9.336 (3.15), 9.341 (2.98), 9.356 (2.64), 9.362 (2.60).  Example 264 (rac)-N-ethyl-2'-{6-[(2-hydroxy-2-methylpropyl)carbamoyl]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000537_0002
LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 477 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.020 (2.72), 1.037 (6.46), 1.055 (2.89), 1.154 (16.00), 2.095 (0.42), 2.110 (0.78), 2.128 (0.95), 2.522 (0.50), 2.571 (0.86), 2.588 (1.32), 2.606 (0.93), 3.057 (0.97), 3.072 (1.08), 3.075 (1.04), 3.090 (0.95), 3.317 (2.06), 3.332 (2.08), 3.422 (0.70), 3.429 (0.65), 3.441 (0.71), 3.448 (1.06), 3.467 (3.80), 3.493 (0.67), 3.510 (0.76), 3.536 (0.67), 3.543 (0.68), 3.550 (0.59), 3.569 (0.40), 4.276 (0.89), 4.293 (1.41), 4.310 (0.87), 6.194 (0.79), 6.764 (4.17), 8.049 (0.97), 8.071 (1.69), 8.120 (1.34), 8.124 (1.32), 8.141 (0.73), 8.146 (0.79), 8.471 (0.82), 8.521 (1.48), 8.526 (1.50), 8.745 (1.32), 8.750 (1.36), 9.419 (2.21), 9.424 (2.29).  The following examples were synthesised analogously via amide bond formation    Example 265 (rac)-N-ethyl-2'-{5-[(oxane-4-carbonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000538_0001
(Rac)-2'-(5-Aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 133 µmol) was dissolved in THF (2.5 mL) and triethylamine (100 µL, 720 µmol) was added. At 0 °C tetrahydro-2H-pyran-4-carbonyl chloride (29.6 mg, 199 µmol) was added. The reaction mixture was stirred for 2 h at rt, water was added and extracted three times with ethyl acetate. The combined organic phase were filtered through a hydrophobic filter, concentrated, and purified by HPLC to obtain 2.00 mg (95 % purity, 3 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.018 (6.75), 1.036 (16.00), 1.054 (7.08), 1.733 (1.05), 1.743 (1.04), 1.763 (1.56), 1.774 (1.39), 1.792 (0.90), 1.816 (1.96), 1.847 (0.90), 2.082 (0.45), 2.095 (1.03), 2.109 (1.19), 2.126 (1.31), 2.144 (1.51), 2.162 (0.83), 2.174 (0.63), 2.334 (0.83), 2.520 (3.89), 2.524 (2.51), 2.542 (0.51), 2.571 (2.17), 2.588 (3.36), 2.605 (2.28), 2.676 (0.83), 2.871 (0.54), 2.889 (0.56), 2.899 (0.98), 2.910 (0.57), 2.927 (0.44), 3.038 (0.82), 3.056 (2.65), 3.070 (2.86), 3.074 (2.83), 3.088 (2.59), 3.106 (0.75), 3.405 (1.48), 3.421 (1.52), 3.428 (3.00), 3.434 (2.61), 3.446 (2.10), 3.456 (2.04), 3.468 (4.68), 3.476 (4.63), 3.501 (1.23), 3.519 (0.84), 3.524 (1.08), 3.530 (0.71), 3.537 (0.81), 3.544 (0.65), 3.550 (0.60), 3.950 (1.69), 3.978 (1.49), 3.983 (1.40), 4.277 (2.19), 4.295 (3.38), 4.312 (2.11), 6.184 (1.04), 6.198 (2.06), 6.211 (0.99), 6.671 (0.59), 6.705 (10.54), 7.664 (2.25), 7.685 (4.01), 7.704 (3.47), 7.812 (3.78), 7.815 (3.48), 7.831 (2.12), 7.837 (2.23), 8.561 (0.44), 8.717 (3.14), 8.721 (3.11), 9.346 (5.22), 9.351 (5.07), 10.084 (2.62).  The following examples were synthesised analogously.    Example 266 (rac)-2'-(5-acetamidoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000539_0001
  Example 267 (rac)-2'-[5-(2,2-dimethylpropanamido)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000539_0002
  Example 268 (rac)-N-ethyl-2'-[5-(2-methylpropanamido)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide   
Figure imgf000540_0003
Example 269 (rac)-2'-(5-benzamidoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000540_0001
The following examples were prepared by chiral separation by preparative HPLC of compounds described before. Example 270 [(rac)-2,2-difluoro-1-methylcyclopropyl][-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of stereoisomers). 
Figure imgf000540_0002
  Example 271 [(rac)-2,2-difluoro-1-methylcyclopropyl][-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of stereoisomers) 
Figure imgf000541_0001
  Example 272 N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) 
Figure imgf000541_0002
LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 494 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.697 (1.34), 0.744 (1.12), 0.833 (0.80), 0.851 (0.89), 1.029 (5.43), 1.047 (11.47), 1.065 (5.77), 1.137 (2.52), 1.152 (3.55), 1.232 (3.79), 1.293 (1.16), 2.057 (1.29), 2.069 (2.02), 2.075 (2.23), 2.084 (1.57), 2.536 (4.13), 2.553 (2.48), 3.058 (0.72), 3.076 (2.21), 3.090 (2.60), 3.093 (2.55), 3.108 (2.19), 3.126 (0.66), 3.388 (1.26), 3.414 (4.29), 3.425 (4.28), 3.435 (1.82), 3.450 (1.40), 3.493 (0.65), 3.509 (1.25), 3.526 (0.81), 3.535 (0.80), 3.551 (0.40), 4.173 (2.02), 4.190 (3.32), 4.208 (1.98), 6.194 (1.00), 6.207 (1.94), 6.221 (1.00), 6.248 (7.30), 6.700 (4.77), 6.704 (4.76), 7.301 (0.44), 7.307 (0.85), 7.327 (4.45), 7.334 (3.83), 7.343 (1.23), 7.377 (1.38), 7.392 (16.00), 7.399 (5.48), 7.407 (4.30), 7.427 (0.63), 7.695 (3.62), 7.699 (3.65), 7.787 (4.95), 7.792 (4.87), 8.656 (3.89), 8.660 (3.89), 12.001 (1.81).    Example 273 N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) 
Figure imgf000542_0001
LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 494 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.697 (0.89), 0.744 (0.85), 0.762 (0.85), 0.831 (0.52), 0.851 (0.58), 1.030 (5.42), 1.048 (12.11), 1.066 (5.75), 1.151 (2.76), 1.232 (2.74), 1.293 (0.69), 2.058 (1.13), 2.069 (1.76), 2.076 (1.97), 2.084 (1.39), 2.518 (5.37), 2.522 (3.12), 2.536 (3.35), 2.553 (2.07), 3.058 (0.65), 3.076 (2.12), 3.090 (2.38), 3.094 (2.34), 3.108 (2.06), 3.126 (0.60), 3.389 (1.10), 3.414 (3.90), 3.425 (3.95), 3.435 (1.59), 3.451 (1.26), 3.492 (0.56), 3.510 (1.12), 3.526 (0.71), 3.535 (0.70), 4.173 (1.87), 4.191 (3.02), 4.207 (1.81), 6.193 (0.91), 6.207 (1.78), 6.220 (0.89), 6.249 (7.38), 6.700 (5.12), 6.705 (5.08), 7.307 (0.78), 7.316 (0.86), 7.322 (1.70), 7.328 (4.14), 7.333 (3.63), 7.344 (1.12), 7.377 (1.29), 7.392 (16.00), 7.400 (5.22), 7.407 (4.05), 7.428 (0.59), 7.696 (3.47), 7.701 (3.45), 7.787 (5.39), 7.792 (5.36), 8.656 (3.76), 8.661 (3.75), 12.005 (1.66).    Example 274 N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 1) 
Figure imgf000543_0002
LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 389 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.698 (1.39), 0.834 (0.81), 0.852 (1.22), 1.060 (0.58), 1.233 (5.91), 1.294 (1.09), 1.348 (0.51), 1.496 (0.52), 1.515 (0.85), 1.522 (0.73), 1.541 (1.51), 1.560 (1.28), 1.586 (0.95), 1.903 (1.00), 1.931 (1.29), 1.953 (1.32), 1.980 (0.77), 2.080 (1.29), 2.094 (2.65), 2.112 (3.03), 2.120 (1.57), 2.130 (1.59), 2.142 (0.77), 2.336 (1.56), 2.518 (16.00), 2.522 (10.54), 2.563 (1.92), 2.580 (2.77), 2.597 (1.92), 2.673 (3.58), 2.678 (1.61), 3.420 (0.90), 3.429 (0.82), 3.447 (1.60), 3.457 (6.98), 3.506 (0.62), 3.525 (0.96), 3.539 (0.65), 3.546 (0.54), 4.101 (0.48), 4.121 (0.87), 4.142 (0.84), 4.163 (0.48), 4.261 (1.99), 4.279 (2.92), 4.295 (1.86), 6.335 (1.52), 6.354 (1.48), 6.733 (8.18), 7.148 (0.58), 7.591 (0.93), 7.610 (1.70), 7.628 (1.20), 7.630 (1.29), 7.705 (1.32), 7.708 (1.12), 7.722 (1.08), 7.726 (1.69), 7.729 (1.52), 7.743 (1.01), 7.747 (1.07), 7.993 (4.54), 8.017 (3.41), 8.151 (0.76), 8.157 (0.86), 8.272 (0.90), 8.279 (0.80), 8.661 (2.68), 8.667 (2.82), 9.350 (4.01), 9.355 (4.04).    Example 275 N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 2) 
Figure imgf000543_0001
LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 389 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.698 (1.86), 0.822 (1.10), 0.833 (1.17), 0.841 (1.12), 0.852 (1.72), 0.905 (0.56), 1.082 (0.74), 1.100 (1.19), 1.118 (0.81), 1.137 (0.71), 1.233 (8.45), 1.293 (1.52), 1.348 (0.74), 1.495 (0.90), 1.515 (1.51), 1.522 (1.33), 1.541 (2.64), 1.561 (2.21), 1.586 (1.62), 1.880 (0.42), 1.903 (1.36), 1.931 (2.31), 1.954 (2.30), 1.980 (1.36), 2.004 (0.44), 2.080 (2.25), 2.094 (4.71), 2.112 (5.30), 2.120 (2.77), 2.130 (2.84), 2.143 (1.38), 2.159 (0.52), 2.336 (1.53), 2.518 (16.00), 2.522 (10.30), 2.534 (0.77), 2.539 (0.51), 2.563 (3.38), 2.580 (4.82), 2.597 (3.45), 2.660 (1.58), 3.291 (0.45), 3.364 (0.42), 3.403 (0.72), 3.421 (1.60), 3.429 (1.43), 3.446 (2.89), 3.457 (12.36), 3.483 (0.46), 3.506 (1.06), 3.525 (1.60), 3.532 (0.98), 3.539 (1.18), 3.546 (0.97), 3.565 (0.59), 4.101 (0.81), 4.121 (1.55), 4.142 (1.48), 4.162 (0.78), 4.261 (3.48), 4.279 (5.20), 4.296 (3.35), 6.335 (2.74), 6.354 (2.65), 6.733 (14.23), 7.591 (1.62), 7.593 (1.36), 7.608 (2.40), 7.610 (3.00), 7.628 (2.12), 7.630 (2.23), 7.705 (2.35), 7.708 (1.94), 7.722 (1.92), 7.726 (2.94), 7.729 (2.66), 7.743 (1.72), 7.746 (1.88), 7.993 (7.95), 8.017 (6.03), 8.661 (4.75), 8.667 (4.94), 9.350 (7.01), 9.355 (6.88).    Example 276 2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) 
Figure imgf000544_0001
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 510 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.837 (0.48), 0.850 (0.56), 1.008 (3.81), 1.026 (8.44), 1.044 (3.99), 1.124 (0.46), 1.142 (0.77), 1.160 (0.85), 1.190 (0.45), 1.206 (0.42), 1.231 (1.84), 1.350 (16.00), 1.365 (15.83), 2.066 (0.63), 2.084 (1.05), 2.103 (1.10), 2.121 (0.52), 2.331 (0.58), 2.518 (2.65), 2.522 (1.73), 2.534 (1.18), 2.553 (1.78), 2.570 (1.23), 2.673 (0.57), 3.027 (0.45), 3.046 (1.44), 3.060 (1.59), 3.063 (1.55), 3.077 (1.42), 3.095 (0.42), 3.403 (0.66), 3.410 (0.53), 3.428 (1.05), 3.443 (5.03), 3.502 (0.41), 3.521 (0.60), 3.527 (0.42), 3.534 (0.47), 4.218 (1.25), 4.236 (2.08), 4.253 (1.17), 4.816 (0.84), 4.831 (1.16), 4.847 (0.86), 6.159 (0.62), 6.173 (1.24), 6.186 (0.60), 6.625 (5.23), 7.369 (1.65), 7.391 (1.87), 7.920 (2.29), 7.927 (2.26), 7.987 (1.12), 7.993 (1.53), 8.009 (0.77), 8.014 (1.83), 8.022 (3.11), 8.027 (1.82), 8.502 (2.08), 8.507 (2.19), 8.706 (2.68), 8.711 (2.58), 11.984 (1.19), 11.990 (1.19).    Example 277 2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) 
Figure imgf000545_0001
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 510 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.008 (3.78), 1.026 (8.40), 1.044 (3.94), 1.232 (1.34), 1.350 (15.87), 1.365 (16.00), 2.066 (0.63), 2.084 (1.08), 2.103 (1.11), 2.121 (0.53), 2.327 (1.04), 2.331 (0.75), 2.518 (3.64), 2.523 (2.41), 2.534 (1.29), 2.551 (1.89), 2.570 (1.30), 2.669 (1.07), 2.673 (0.78), 3.027 (0.46), 3.045 (1.48), 3.060 (1.63), 3.063 (1.60), 3.077 (1.44), 3.095 (0.43), 3.403 (0.67), 3.410 (0.56), 3.428 (1.08), 3.443 (5.14), 3.521 (0.62), 3.528 (0.43), 3.535 (0.49), 4.218 (1.24), 4.236 (2.14), 4.253 (1.20), 4.552 (1.44), 4.816 (0.86), 4.831 (1.18), 4.847 (0.88), 6.159 (0.63), 6.173 (1.27), 6.186 (0.62), 6.625 (5.32), 7.369 (1.71), 7.391 (1.88), 7.920 (2.27), 7.927 (2.21), 7.987 (1.16), 7.993 (1.54), 8.009 (0.80), 8.014 (1.87), 8.022 (3.19), 8.027 (1.85), 8.502 (2.20), 8.507 (2.24), 8.706 (2.87), 8.711 (2.67), 11.984 (1.20), 11.990 (1.19).    Example 278 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (enantiomer 1) 
Figure imgf000546_0003
  Example 279 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (enantiomer 2) 
Figure imgf000546_0001
  Example 280 N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 1) 
Figure imgf000546_0002
  Example 281 N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 2) 
Figure imgf000547_0002
  Example 282 2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine- 4,3'-pyrrolidine]-1'-carboxamide (enantiomer 1) 
Figure imgf000547_0001
LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 401 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (7.15), 1.026 (16.00), 1.044 (7.44), 1.231 (0.81), 2.222 (0.41), 2.254 (0.96), 2.280 (1.33), 2.304 (0.81), 2.322 (1.34), 2.327 (1.80), 2.331 (1.46), 2.337 (1.19), 2.343 (1.24), 2.359 (1.39), 2.375 (0.83), 2.390 (0.72), 2.522 (5.05), 2.665 (1.29), 2.669 (1.73), 2.673 (1.27), 3.025 (0.98), 3.043 (3.09), 3.057 (3.56), 3.060 (3.46), 3.075 (3.01), 3.093 (0.89), 3.373 (2.48), 3.382 (1.64), 3.399 (1.04), 3.453 (3.10), 3.482 (3.56), 3.538 (1.19), 3.559 (2.02), 3.582 (0.91), 3.779 (2.20), 3.808 (1.84), 4.072 (0.79), 4.088 (1.12), 4.102 (2.13), 4.113 (1.35), 4.136 (2.04), 4.145 (1.97), 4.173 (5.36), 4.185 (3.56), 6.178 (1.40), 6.192 (2.77), 6.206 (1.35), 6.892 (10.34), 7.706 (9.69), 8.200 (6.42), 8.205 (6.60), 8.737 (5.92), 8.742 (5.80), 12.042 (1.73).    Example 283 2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine- 4,3'-pyrrolidine]-1'-carboxamide (enantiomer 2) 
Figure imgf000548_0002
LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 401 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (7.05), 1.026 (16.00), 1.044 (7.38), 1.231 (0.96), 2.255 (0.92), 2.281 (1.25), 2.304 (0.76), 2.322 (1.34), 2.327 (1.84), 2.331 (1.49), 2.337 (1.15), 2.342 (1.17), 2.358 (1.29), 2.374 (0.73), 2.391 (0.65), 2.518 (8.00), 2.522 (5.00), 2.665 (1.32), 2.669 (1.78), 2.673 (1.32), 3.025 (0.93), 3.043 (2.95), 3.057 (3.36), 3.060 (3.28), 3.075 (2.90), 3.093 (0.85), 3.158 (0.75), 3.171 (0.82), 3.295 (0.72), 3.374 (2.26), 3.383 (1.48), 3.399 (1.00), 3.453 (2.97), 3.482 (3.42), 3.537 (1.11), 3.559 (1.88), 3.582 (0.85), 3.780 (2.05), 3.808 (1.73), 4.072 (0.74), 4.088 (1.11), 4.102 (2.14), 4.113 (1.42), 4.136 (1.93), 4.145 (1.85), 4.173 (5.06), 4.185 (3.32), 6.178 (1.31), 6.192 (2.63), 6.206 (1.28), 6.892 (10.34), 7.706 (9.24), 8.200 (6.45), 8.205 (6.61), 8.737 (5.82), 8.742 (5.68), 12.042 (1.73).    Example 284 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (isomer 1) 
Figure imgf000548_0001
  Example 285 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (isiomer 2) 
Figure imgf000549_0003
  Example 286 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (isiomer 3) 
Figure imgf000549_0001
  Example 287 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] (isiomer 4) 
Figure imgf000549_0002
  Example 288 1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 1)   
Figure imgf000550_0003
Example 289 1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 2) 
Figure imgf000550_0001
  Example 290 (rac)-2'-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(1H-imidazol-2- yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000550_0002
The trifluoroacetic acid salt of (rac)-2'-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (135 mg, 272 µmol) and 1H-imidazole-2-carbaldehyde (28.8 mg, 300 µmol) were dissolved in THF (4 mL) under argon. Acetic acid (16 µL, 270 µmol) and sodium triacetoxyborohydride (127 mg, 599 µmol) were added and the reaction mixture was stirred overnight at rt. Two equivalents of 1H-imidazole-2- carbaldehyde and 2 equivalents of sodium triacetoxyborohydride were added and the reaction mixture was stirred overnight. Three drops of methanol and water were added until the solids were dissolved. The reaction mixture was purified by HPLC to give 6.00 mg (95 % purity, 5 % yield) of the title compound. LC-MS (Method 1): Rt = 0.64 min; MS (ESIpos): m/z = 462 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.516 (16.00), 1.549 (15.94), 2.016 (0.40), 2.029 (0.72), 2.047 (0.94), 2.062 (0.97), 2.076 (0.84), 2.081 (0.84), 2.096 (0.77), 2.518 (1.37), 2.523 (1.51), 2.540 (1.35), 2.559 (0.61), 2.588 (0.62), 2.603 (1.02), 2.621 (0.95), 2.635 (0.66), 2.669 (0.41), 2.701 (1.44), 2.724 (2.42), 2.754 (0.63), 2.771 (2.50), 2.793 (1.71), 2.804 (0.88), 3.503 (0.78), 4.131 (1.22), 4.136 (1.22), 4.149 (2.05), 4.165 (1.18), 4.171 (1.16), 6.523 (1.15), 6.567 (1.38), 6.580 (1.18), 6.625 (1.40), 6.637 (7.32), 6.934 (6.91), 7.348 (1.37), 7.392 (1.35), 7.400 (1.48), 7.444 (1.25), 7.899 (2.23), 7.905 (2.23), 8.157 (2.98), 8.562 (2.90), 8.567 (3.05), 8.737 (4.00), 8.742 (3.89), 12.109 (1.36).  The following examples were prepared analogously via reductive amination  Example 291 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(thiophen-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000551_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.012 (0.71), 2.031 (1.18), 2.045 (2.10), 2.063 (2.85), 2.080 (2.80), 2.092 (2.44), 2.097 (2.40), 2.111 (2.24), 2.123 (0.98), 2.144 (0.71), 2.327 (2.49), 2.540 (3.89), 2.558 (3.62), 2.576 (2.33), 2.585 (2.25), 2.601 (3.05), 2.619 (2.67), 2.633 (1.63), 2.651 (1.25), 2.672 (6.14), 2.694 (6.20), 2.710 (1.49), 2.732 (2.87), 2.749 (2.76), 2.770 (1.93), 2.781 (6.11), 2.803 (4.36), 2.833 (2.55), 2.848 (2.28), 2.869 (0.92), 3.565 (1.15), 3.847 (0.78), 3.882 (16.00), 3.917 (0.52), 4.098 (0.47), 4.126 (2.81), 4.133 (3.22), 4.143 (5.04), 4.160 (3.20), 4.168 (2.69), 6.169 (0.64), 6.580 (15.36), 6.952 (3.50), 6.961 (5.99), 6.964 (4.17), 6.973 (6.35), 6.988 (6.31), 7.416 (5.46), 7.419 (5.38), 7.428 (5.11), 7.431 (4.89), 7.681 (12.28), 8.188 (8.63), 8.193 (8.59), 8.732 (8.24), 8.737 (8.10), 11.984 (1.49).    Example 292 (rac)-1-[(5-chlorothiophen-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] 
Figure imgf000552_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.040 (0.49), 2.059 (0.88), 2.073 (4.25), 2.092 (2.74), 2.111 (2.80), 2.117 (2.35), 2.131 (2.05), 2.144 (0.78), 2.149 (0.70), 2.164 (0.57), 2.322 (0.93), 2.326 (1.22), 2.331 (0.92), 2.522 (4.11), 2.539 (1.39), 2.558 (1.73), 2.572 (2.08), 2.589 (3.09), 2.607 (1.90), 2.615 (1.90), 2.631 (3.06), 2.647 (2.33), 2.664 (2.30), 2.668 (1.57), 2.673 (1.15), 2.679 (1.04), 2.713 (3.78), 2.736 (6.16), 2.750 (0.99), 2.772 (2.24), 2.793 (8.15), 2.815 (5.17), 2.829 (2.24), 2.834 (2.35), 2.849 (1.94), 2.871 (0.70), 3.838 (15.94), 4.187 (3.88), 4.203 (7.56), 4.222 (3.85), 6.716 (16.00), 6.866 (5.08), 6.875 (6.11), 6.951 (9.72), 6.960 (7.66), 7.591 (1.87), 7.593 (1.82), 7.610 (4.08), 7.629 (2.71), 7.631 (2.71), 7.703 (2.40), 7.707 (2.42), 7.721 (2.28), 7.724 (4.01), 7.728 (3.04), 7.742 (2.11), 7.745 (2.04), 7.996 (6.19), 8.017 (5.84), 8.655 (5.94), 8.660 (6.05), 9.345 (7.91), 9.350 (7.63).    Example 293 (rac)-2'-(quinolin-3-yl)-1-[(1H-1,2,3-triazol-5-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] 
Figure imgf000553_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.012 (0.47), 2.031 (0.85), 2.044 (1.81), 2.063 (2.90), 2.082 (3.06), 2.087 (2.43), 2.102 (2.04), 2.114 (0.81), 2.119 (0.67), 2.134 (0.54), 2.322 (0.99), 2.326 (1.34), 2.331 (0.99), 2.522 (3.71), 2.533 (2.00), 2.547 (2.13), 2.565 (2.87), 2.582 (1.72), 2.598 (1.66), 2.614 (2.77), 2.632 (2.24), 2.646 (1.54), 2.664 (1.81), 2.668 (1.57), 2.673 (1.12), 2.692 (3.65), 2.715 (6.66), 2.737 (2.16), 2.758 (2.78), 2.767 (7.20), 2.789 (5.61), 2.803 (1.93), 2.826 (0.64), 3.789 (16.00), 4.175 (3.32), 4.193 (6.61), 4.212 (3.30), 6.710 (13.54), 7.588 (2.00), 7.590 (1.87), 7.605 (3.22), 7.608 (4.21), 7.626 (2.76), 7.628 (2.90), 7.700 (2.76), 7.704 (2.64), 7.717 (2.47), 7.721 (4.23), 7.725 (3.41), 7.739 (2.40), 7.742 (2.51), 7.785 (0.89), 7.989 (8.25), 8.010 (7.33), 8.654 (6.16), 8.659 (6.29), 9.345 (8.63), 9.351 (8.72).    Example 294 (rac)-2'-(quinolin-3-yl)-1-[(thiophen-3-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] 
Figure imgf000553_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.103 (1.46), 1.156 (0.74), 1.227 (0.74), 1.324 (1.92), 2.074 (6.11), 2.095 (6.30), 2.326 (1.78), 2.577 (7.40), 2.625 (6.04), 2.642 (5.23), 2.673 (7.14), 2.696 (10.57), 2.719 (13.57), 2.741 (12.68), 3.072 (0.65), 3.681 (16.00), 4.192 (10.05), 6.725 (11.77), 7.114 (6.85), 7.124 (7.29), 7.363 (8.73), 7.491 (7.05), 7.591 (3.27), 7.610 (6.00), 7.627 (4.37), 7.704 (3.86), 7.723 (6.02), 7.740 (3.64), 7.992 (12.59), 8.013 (11.52), 8.665 (9.88), 9.355 (9.83).    Example 295 (rac)-2'-(quinolin-3-yl)-1-[(thiophen-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] 
Figure imgf000554_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.036 (0.41), 2.055 (0.68), 2.068 (1.52), 2.088 (2.19), 2.092 (1.83), 2.107 (2.28), 2.112 (1.96), 2.128 (1.74), 2.140 (0.67), 2.145 (0.58), 2.160 (0.50), 2.322 (0.69), 2.326 (0.96), 2.331 (0.71), 2.518 (3.90), 2.522 (2.43), 2.536 (0.88), 2.555 (1.20), 2.568 (1.73), 2.587 (2.27), 2.604 (1.57), 2.612 (1.58), 2.627 (2.27), 2.630 (2.01), 2.645 (1.97), 2.659 (1.37), 2.669 (1.13), 2.673 (0.94), 2.677 (1.00), 2.706 (3.20), 2.729 (5.63), 2.743 (0.77), 2.765 (2.01), 2.775 (6.08), 2.798 (4.04), 2.817 (1.79), 2.822 (1.91), 2.837 (1.58), 2.859 (0.56), 3.853 (0.54), 3.890 (9.06), 3.892 (9.13), 3.929 (0.53), 4.166 (0.49), 4.177 (2.27), 4.183 (2.35), 4.195 (3.82), 4.198 (3.46), 4.202 (2.79), 4.212 (2.34), 4.218 (2.17), 4.230 (0.44), 6.711 (16.00), 6.956 (3.37), 6.965 (5.22), 6.969 (3.25), 6.977 (6.24), 6.991 (4.24), 6.993 (4.64), 6.999 (2.71), 7.421 (5.11), 7.424 (5.01), 7.434 (4.97), 7.437 (4.79), 7.589 (1.65), 7.593 (1.64), 7.607 (2.50), 7.610 (3.57), 7.612 (2.08), 7.627 (2.30), 7.630 (2.40), 7.702 (2.23), 7.705 (2.26), 7.719 (1.97), 7.723 (3.65), 7.727 (2.68), 7.740 (1.98), 7.744 (1.93), 7.995 (5.11), 8.016 (4.81), 8.653 (4.95), 8.658 (5.10), 9.342 (7.44), 9.347 (7.18).    Example 296 (rac)-2'-(quinolin-3-yl)-1-[(1,3-thiazol-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] 
Figure imgf000555_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.073 (0.43), 2.092 (0.73), 2.105 (1.72), 2.125 (3.41), 2.142 (3.56), 2.161 (1.86), 2.174 (0.72), 2.193 (0.49), 2.322 (0.72), 2.326 (0.99), 2.331 (0.69), 2.518 (3.44), 2.522 (2.28), 2.567 (0.72), 2.585 (1.27), 2.598 (1.79), 2.617 (2.39), 2.634 (1.55), 2.646 (1.54), 2.662 (2.81), 2.664 (2.85), 2.673 (1.13), 2.680 (2.16), 2.694 (1.24), 2.712 (0.74), 2.838 (2.82), 2.860 (7.01), 2.883 (6.97), 2.900 (2.41), 2.906 (3.56), 2.911 (2.72), 2.917 (2.93), 2.920 (3.06), 2.927 (2.99), 2.930 (2.77), 2.947 (1.87), 4.029 (1.01), 4.066 (11.76), 4.072 (11.76), 4.110 (1.00), 4.188 (0.50), 4.199 (2.70), 4.204 (2.59), 4.218 (4.96), 4.234 (2.60), 4.239 (2.59), 6.747 (16.00), 7.591 (1.73), 7.594 (1.77), 7.609 (2.73), 7.611 (3.82), 7.629 (2.53), 7.632 (2.52), 7.667 (8.83), 7.675 (11.58), 7.704 (2.50), 7.708 (2.46), 7.721 (12.58), 7.725 (4.75), 7.730 (9.41), 7.742 (2.08), 7.746 (2.03), 7.995 (4.33), 8.002 (3.59), 8.005 (3.61), 8.015 (3.70), 8.022 (3.37), 8.659 (5.26), 8.663 (5.30), 9.348 (7.76), 9.354 (7.33).    Example 297 (rac)-1-[(1,3-oxazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] 
Figure imgf000555_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.751 (0.41), 2.055 (3.20), 2.073 (7.00), 2.090 (6.53), 2.108 (3.38), 2.139 (0.79), 2.326 (1.39), 2.540 (5.22), 2.556 (4.44), 2.573 (5.48), 2.591 (3.40), 2.601 (3.32), 2.618 (5.18), 2.635 (3.80), 2.650 (2.72), 2.668 (2.65), 2.792 (6.78), 2.815 (12.23), 2.841 (3.66), 2.863 (12.43), 2.885 (6.81), 3.821 (1.89), 3.857 (13.70), 3.867 (13.58), 3.903 (1.81), 4.186 (6.72), 4.203 (12.41), 4.221 (6.37), 6.695 (16.00), 7.190 (13.92), 7.587 (3.02), 7.606 (5.95), 7.625 (4.14), 7.701 (3.64), 7.720 (5.63), 7.740 (3.10), 7.988 (13.50), 8.009 (11.57), 8.090 (14.12), 8.654 (9.57), 9.340 (9.94), 9.345 (9.60).    Example 298 (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(4-chloro-1H-pyrazol-3-yl)methyl]- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) 
Figure imgf000556_0001
  Example 299 (rac)-1'-[(4-chloro-1H-pyrazol-5-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7- dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]   
Figure imgf000556_0002
Example 300 (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) 
Figure imgf000557_0001
  Example 301 (rac)-1'-[(1H-imidazol-2-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro- 5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]   
Figure imgf000557_0002
Example 302 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000557_0003
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.74), 1.716 (16.00), 1.960 (0.69), 1.979 (1.02), 1.987 (0.88), 2.002 (0.92), 2.007 (0.86), 2.022 (0.76), 2.318 (0.86), 2.322 (1.90), 2.327 (2.65), 2.332 (1.91), 2.336 (0.84), 2.439 (0.77), 2.453 (1.11), 2.518 (9.75), 2.523 (6.32), 2.534 (1.38), 2.539 (1.72), 2.551 (1.00), 2.565 (0.62), 2.622 (1.54), 2.646 (2.57), 2.665 (2.41), 2.669 (3.55), 2.673 (2.22), 2.678 (1.06), 2.686 (0.87), 2.712 (2.30), 2.735 (1.93), 2.755 (0.81), 2.772 (0.69), 3.286 (0.46), 3.379 (0.67), 3.664 (7.56), 4.040 (1.00), 4.046 (1.01), 4.059 (1.69), 4.074 (1.00), 4.080 (1.00), 5.758 (6.38), 6.280 (8.03), 6.788 (3.24), 7.023 (2.49), 7.118 (0.73), 7.136 (1.84), 7.150 (0.79), 7.154 (1.36), 7.157 (0.76), 7.226 (1.82), 7.245 (3.67), 7.264 (2.81), 7.290 (3.87), 7.292 (4.22), 7.310 (2.26), 7.314 (1.63), 7.372 (2.59), 7.378 (2.60), 7.601 (3.07), 7.606 (3.06), 8.506 (3.73), 8.510 (3.60), 8.547 (1.26), 11.440 (1.44), 11.846 (0.89).    Example 303 (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1'-[(1H-imidazol-2-yl)methyl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] 
Figure imgf000558_0001
  Example 304 (rac)-2'-(quinolin-3-yl)-1-[(4H-1,2,4-triazol-3-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] 
Figure imgf000558_0002
LC-MS (Method 1): Rt = 0.74 min; MS (ESIpos): m/z = 373 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (8.73), 1.071 (2.64), 2.016 (0.69), 2.029 (1.46), 2.048 (2.21), 2.053 (1.76), 2.068 (2.28), 2.074 (1.90), 2.088 (1.69), 2.100 (0.64), 2.105 (0.59), 2.120 (0.46), 2.332 (0.47), 2.523 (2.86), 2.539 (1.66), 2.557 (2.23), 2.574 (1.30), 2.601 (1.26), 2.617 (2.20), 2.635 (1.82), 2.650 (1.39), 2.667 (0.89), 2.674 (0.55), 2.757 (3.73), 2.780 (6.32), 2.794 (1.97), 2.798 (1.84), 2.814 (1.32), 2.821 (1.43), 2.836 (6.55), 2.859 (4.18), 2.878 (0.59), 4.164 (0.45), 4.175 (2.89), 4.193 (5.61), 4.212 (2.85), 6.706 (16.00), 7.589 (1.69), 7.592 (1.50), 7.607 (2.61), 7.610 (3.37), 7.627 (2.21), 7.629 (2.46), 7.702 (2.35), 7.705 (1.99), 7.719 (1.91), 7.722 (3.41), 7.726 (2.88), 7.740 (1.80), 7.743 (1.96), 7.991 (6.73), 7.993 (6.82), 8.015 (6.94), 8.066 (11.96), 8.552 (4.38), 8.648 (5.10), 8.653 (5.22), 9.346 (7.56), 9.351 (7.61).    Example 305 1-[(rac)-1-(1H-imidazol-2-yl)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of two isomers) 
Figure imgf000559_0001
  Example 306 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000559_0002
LC-MS (Method 1): Rt = 0.84 min; MS (ESIneg): m/z = 466 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.004 (0.42), 0.847 (0.49), 1.170 (0.40), 1.226 (2.24), 1.362 (3.36), 1.372 (16.00), 1.389 (15.66), 1.556 (0.45), 1.986 (0.94), 2.000 (1.11), 2.017 (1.56), 2.034 (1.66), 2.048 (1.32), 2.053 (1.32), 2.067 (1.24), 2.083 (0.82), 2.099 (0.43), 2.322 (0.74), 2.326 (0.97), 2.331 (0.74), 2.535 (1.54), 2.566 (1.03), 2.582 (1.55), 2.600 (1.44), 2.613 (0.99), 2.632 (0.62), 2.659 (2.64), 2.669 (1.46), 2.682 (3.67), 2.697 (1.54), 2.715 (1.56), 2.727 (1.10), 2.735 (1.07), 2.748 (3.93), 2.770 (3.52), 2.785 (1.30), 2.807 (0.51), 2.887 (0.73), 3.214 (0.62), 3.564 (0.68), 3.680 (10.48), 4.098 (1.63), 4.104 (1.71), 4.116 (2.84), 4.132 (1.68), 4.138 (1.58), 4.596 (0.59), 4.612 (1.43), 4.629 (1.91), 4.645 (1.36), 4.662 (0.53), 6.350 (0.47), 6.354 (0.48), 6.393 (5.70), 6.397 (5.76), 6.540 (9.59), 7.552 (0.41), 7.557 (0.42), 7.580 (4.88), 7.585 (4.93), 7.681 (1.15), 7.690 (8.62), 8.137 (5.23), 8.142 (5.39), 8.538 (0.48), 8.732 (4.94), 8.737 (4.98).    Example 307 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000560_0001
LC-MS (Method 1): Rt = 0.75 min; MS (ESIneg): m/z = 438 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.169 (0.66), 1.184 (0.55), 2.007 (0.52), 2.024 (0.68), 2.043 (0.78), 2.057 (0.59), 2.063 (0.59), 2.077 (0.57), 2.082 (0.43), 2.518 (0.73), 2.523 (0.95), 2.542 (0.42), 2.572 (0.44), 2.587 (0.69), 2.606 (0.65), 2.620 (0.45), 2.668 (1.31), 2.681 (0.44), 2.691 (1.77), 2.702 (0.72), 2.720 (0.69), 2.741 (0.44), 2.756 (1.91), 2.779 (1.65), 2.793 (0.58), 3.563 (0.51), 3.687 (5.38), 3.906 (16.00), 3.929 (0.40), 4.110 (0.79), 4.117 (0.81), 4.129 (1.29), 4.132 (1.20), 4.144 (0.77), 4.151 (0.72), 6.530 (3.43), 6.534 (3.31), 6.586 (5.38), 6.915 (0.83), 7.520 (3.31), 7.525 (3.46), 7.833 (4.77), 8.252 (3.00), 8.257 (2.99), 8.741 (2.72), 8.746 (2.62).    Example 308 (rac)-1-[(5-methyl-1H-imidazol-2-yl)methyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000561_0001
  Example 309 (rac)-2'-(quinolin-3-yl)-1-[(rac)-1-(4H-1,2,4-triazol-3-yl)ethyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) 
Figure imgf000561_0002
LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 386 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.426 (15.79), 1.443 (16.00), 1.942 (0.68), 1.959 (1.48), 1.973 (2.33), 1.991 (3.26), 2.005 (2.84), 2.009 (2.78), 2.020 (1.83), 2.036 (0.77), 2.041 (0.64), 2.056 (0.45), 2.327 (0.40), 2.332 (0.56), 2.463 (0.74), 2.467 (0.75), 2.481 (1.88), 2.486 (1.82), 2.523 (2.64), 2.528 (2.20), 2.545 (1.02), 2.560 (2.17), 2.576 (2.77), 2.593 (2.07), 2.608 (1.42), 2.625 (0.57), 2.678 (3.36), 2.688 (0.84), 2.701 (3.97), 2.711 (2.06), 2.716 (2.65), 2.739 (5.04), 2.753 (4.86), 2.776 (1.30), 2.797 (0.86), 2.812 (1.04), 2.818 (1.58), 2.833 (1.30), 2.840 (0.86), 2.855 (0.75), 2.864 (3.49), 2.887 (3.48), 2.908 (1.10), 2.927 (0.53), 3.899 (1.01), 3.912 (3.26), 3.916 (2.98), 3.929 (3.28), 3.933 (2.89), 3.946 (1.05), 4.148 (0.44), 4.160 (1.79), 4.163 (1.85), 4.175 (4.50), 4.191 (6.47), 4.208 (3.08), 6.627 (10.17), 6.650 (13.11), 7.591 (2.48), 7.593 (2.16), 7.608 (3.77), 7.610 (4.26), 7.614 (3.23), 7.628 (3.20), 7.631 (3.47), 7.703 (3.44), 7.706 (2.87), 7.720 (2.92), 7.724 (4.32), 7.727 (4.03), 7.741 (2.77), 7.745 (2.97), 7.994 (10.81), 7.996 (9.15), 8.014 (7.87), 8.016 (9.50), 8.115 (12.58), 8.634 (3.68), 8.640 (7.60), 8.645 (4.45), 9.338 (5.78), 9.341 (7.39), 9.343 (6.77), 9.346 (6.94).    Example 310 (rac)-1-[(5-ethyl-4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000562_0001
LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 413 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.061 (6.54), 1.080 (16.00), 1.099 (6.99), 1.998 (0.43), 2.026 (12.63), 2.047 (1.79), 2.059 (1.28), 2.065 (1.30), 2.074 (1.52), 2.079 (1.38), 2.094 (1.27), 2.106 (0.55), 2.111 (0.48), 2.327 (0.41), 2.371 (0.90), 2.390 (2.46), 2.409 (2.40), 2.427 (0.87), 2.518 (2.29), 2.523 (1.56), 2.531 (1.40), 2.545 (1.30), 2.563 (1.65), 2.580 (1.01), 2.608 (0.98), 2.624 (1.60), 2.642 (1.36), 2.656 (1.06), 2.665 (0.46), 2.669 (0.58), 2.674 (0.89), 2.691 (2.60), 2.715 (4.65), 2.734 (1.40), 2.754 (0.79), 2.772 (0.99), 2.782 (3.83), 2.791 (1.55), 2.806 (3.23), 2.829 (0.48), 3.542 (0.71), 3.576 (6.03), 3.582 (6.30), 3.615 (0.80), 4.176 (1.94), 4.195 (3.80), 4.214 (1.96), 6.705 (12.99), 7.590 (1.33), 7.592 (1.34), 7.607 (1.93), 7.610 (2.88), 7.613 (1.70), 7.627 (1.90), 7.630 (1.89), 7.702 (1.81), 7.706 (1.90), 7.719 (1.53), 7.723 (2.96), 7.727 (2.17), 7.740 (1.62), 7.744 (1.62), 7.984 (2.56), 7.987 (2.71), 7.993 (3.06), 7.995 (3.04), 8.003 (2.41), 8.007 (2.26), 8.014 (2.72), 8.637 (3.71), 8.642 (3.84), 9.340 (6.19), 9.345 (5.98).    Example 311 (rac)-2-(quinolin-3-yl)-1-[(1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000563_0001
LC-MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 412 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.997 (0.40), 2.017 (0.74), 2.030 (1.37), 2.048 (1.95), 2.060 (1.55), 2.065 (1.59), 2.074 (3.16), 2.080 (1.72), 2.094 (1.62), 2.106 (0.70), 2.112 (0.60), 2.126 (0.49), 2.318 (0.56), 2.332 (1.68), 2.351 (3.17), 2.358 (1.81), 2.367 (2.48), 2.385 (1.13), 2.518 (4.51), 2.525 (10.01), 2.543 (5.99), 2.562 (2.38), 2.578 (1.34), 2.611 (1.31), 2.627 (2.21), 2.645 (1.86), 2.660 (1.57), 2.668 (0.46), 2.677 (0.88), 2.710 (3.35), 2.733 (6.35), 2.753 (1.95), 2.772 (2.25), 2.786 (6.43), 2.809 (4.18), 2.829 (0.60), 3.364 (1.19), 4.175 (2.91), 4.193 (5.78), 4.211 (2.94), 6.709 (16.00), 7.587 (1.75), 7.590 (1.71), 7.604 (2.52), 7.608 (3.71), 7.610 (2.18), 7.625 (2.43), 7.628 (2.41), 7.700 (2.40), 7.703 (2.41), 7.717 (1.89), 7.720 (3.87), 7.724 (2.79), 7.738 (2.05), 7.741 (2.01), 7.989 (4.69), 7.992 (4.31), 8.005 (3.14), 8.010 (3.61), 8.014 (3.76), 8.636 (5.02), 8.641 (5.13), 9.342 (7.95), 9.347 (7.95).    Example 312 (rac)-1-[(5-cyclopropyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] 
N N H N N N N LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 411 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.562 (1.65), 0.572 (4.60), 0.575 (3.00), 0.578 (5.56), 0.585 (5.23), 0.591 (5.75), 0.600 (2.38), 0.721 (1.82), 0.737 (1.88), 1.714 (0.42), 1.726 (0.83), 1.734 (0.97), 1.747 (1.53), 1.759 (0.92), 1.768 (0.79), 2.017 (0.64), 2.030 (1.25), 2.049 (1.93), 2.055 (1.47), 2.070 (1.94), 2.075 (1.70), 2.089 (1.50), 2.102 (0.59), 2.107 (0.51), 2.122 (0.42), 2.325 (0.78), 2.329 (1.11), 2.334 (0.77), 2.521 (5.00), 2.525 (3.55), 2.543 (1.60), 2.562 (1.90), 2.578 (1.16), 2.607 (1.11), 2.623 (1.89), 2.641 (1.57), 2.655 (1.22), 2.662 (0.53), 2.667 (0.95), 2.672 (1.52), 2.676 (1.10), 2.681 (0.49), 2.694 (2.93), 2.702 (0.75), 2.717 (5.06), 2.745 (1.69), 2.764 (1.73), 2.774 (4.83), 2.784 (1.75), 2.797 (3.70), 2.821 (0.49), 3.614 (13.40), 4.177 (2.31), 4.180 (2.19), 4.196 (4.41), 4.212 (2.18), 4.215 (2.28), 6.707 (16.00), 7.593 (1.62), 7.595 (1.59), 7.610 (2.33), 7.613 (3.47), 7.616 (2.02), 7.630 (2.22), 7.633 (2.26), 7.705 (2.23), 7.709 (2.28), 7.722 (1.84), 7.725 (3.50), 7.729 (2.68), 7.743 (1.97), 7.746 (1.97), 7.992 (5.00), 7.997 (3.67), 8.009 (2.83), 8.014 (4.04), 8.640 (4.44), 8.646 (4.62), 9.344 (7.54), 9.350 (7.33).    Example 313 (rac)-1-[(rac)-1-(1H-imidazol-2-yl)ethyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) 
N N H C H 3 N N N N N H3 C N N H LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 454 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (0.46), 1.171 (0.71), 1.229 (0.48), 1.374 (4.42), 1.391 (4.45), 1.762 (0.64), 1.958 (0.60), 1.977 (0.83), 1.986 (1.39), 1.995 (0.85), 2.014 (0.62), 2.451 (0.49), 2.468 (0.81), 2.518 (1.53), 2.522 (0.99), 2.539 (8.31), 2.549 (0.84), 2.564 (1.08), 2.587 (1.05), 2.593 (0.92), 2.603 (0.70), 2.616 (1.15), 2.684 (0.89), 2.706 (0.60), 2.822 (0.68), 2.844 (0.70), 3.702 (0.68), 3.719 (1.02), 3.737 (0.66), 3.906 (16.00), 3.929 (0.60), 4.100 (0.82), 4.114 (0.86), 4.119 (0.93), 4.127 (1.21), 4.145 (0.65), 6.497 (2.65), 6.529 (5.47), 6.534 (3.31), 6.780 (0.63), 7.022 (0.58), 7.523 (3.52), 7.527 (3.40), 7.835 (3.08), 8.241 (1.71), 8.245 (2.47), 8.249 (1.63), 8.734 (1.57), 8.739 (2.78), 8.743 (1.45), 12.160 (1.02).    Example 314 (rac)-1-[(rac)-cyclopropyl(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) 
Figure imgf000565_0001
LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 411 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.834 (1.52), 0.852 (2.23), 0.935 (0.42), 1.231 (11.71), 1.258 (2.81), 1.281 (1.59), 1.299 (1.36), 1.336 (0.94), 1.356 (0.71), 1.370 (0.75), 1.389 (0.84), 1.413 (1.60), 1.422 (1.99), 1.453 (1.32), 1.493 (0.66), 1.549 (0.46), 1.826 (2.08), 1.840 (2.10), 1.868 (1.65), 1.909 (2.71), 1.925 (2.11), 1.937 (2.10), 1.964 (1.40), 1.996 (3.78), 2.010 (5.00), 2.027 (4.49), 2.040 (3.84), 2.055 (3.73), 2.075 (3.29), 2.090 (2.62), 2.107 (1.78), 2.122 (1.25), 2.150 (1.06), 2.204 (2.35), 2.220 (2.24), 2.282 (0.76), 2.554 (4.06), 2.571 (2.54), 2.588 (2.08), 2.614 (3.40), 2.631 (2.86), 2.646 (2.03), 2.755 (0.51), 2.774 (0.52), 2.883 (1.01), 2.905 (2.47), 2.925 (3.78), 2.954 (16.00), 2.996 (1.15), 3.016 (2.39), 3.033 (2.87), 3.051 (2.06), 3.071 (0.85), 3.472 (0.81), 3.507 (0.91), 3.671 (2.69), 3.683 (4.58), 3.693 (2.78), 3.874 (1.10), 3.893 (1.65), 3.905 (2.78), 3.923 (2.73), 3.937 (1.95), 3.981 (2.92), 3.994 (2.86), 4.011 (2.03), 4.024 (1.56), 4.190 (5.85), 4.206 (7.49), 4.224 (3.82), 4.280 (0.93), 4.296 (0.93), 6.706 (11.37), 6.752 (0.82), 6.821 (0.47), 6.871 (9.68), 7.032 (6.58), 7.042 (5.19), 7.545 (0.64), 7.591 (3.23), 7.610 (6.11), 7.629 (4.46), 7.705 (3.80), 7.724 (5.73), 7.741 (3.29), 7.993 (13.31), 8.014 (11.81), 8.659 (9.17), 8.663 (9.30), 9.351 (10.36), 9.355 (10.13).    Example 315 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-{3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin- 5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000566_0001
LC-MS (Method 1): Rt = 0.91 min; MS (ESIneg): m/z = 473 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.022 (0.49), 2.038 (0.66), 2.056 (0.68), 2.075 (1.28), 2.088 (0.55), 2.530 (7.73), 2.588 (0.40), 2.603 (0.68), 2.617 (0.57), 2.634 (0.41), 2.689 (1.07), 2.712 (1.94), 2.735 (0.84), 2.767 (1.65), 2.788 (1.22), 3.346 (16.00), 3.698 (4.61), 4.151 (1.50), 6.628 (2.33), 6.806 (0.53), 7.044 (0.52), 7.379 (1.11), 7.993 (3.08), 8.351 (2.22), 8.410 (1.16), 8.420 (1.12), 8.711 (2.79), 8.769 (2.13), 8.774 (2.21).    Example 316 (rac)-1-[(4-methyl-1H-pyrazol-5-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole] 
Figure imgf000567_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.905 (1.73), 2.036 (7.99), 2.047 (0.74), 2.073 (11.14), 2.078 (0.92), 2.084 (0.88), 2.099 (0.58), 2.222 (3.06), 2.224 (3.00), 2.518 (0.79), 2.523 (0.60), 2.529 (0.47), 2.539 (16.00), 2.561 (0.71), 2.578 (0.43), 2.590 (0.41), 2.605 (0.67), 2.623 (1.50), 2.646 (1.58), 2.673 (0.70), 2.689 (0.58), 2.711 (1.68), 2.721 (0.45), 2.735 (1.35), 2.757 (0.48), 3.633 (3.92), 4.165 (0.75), 4.169 (0.72), 4.183 (1.51), 4.200 (0.73), 4.204 (0.74), 6.690 (3.27), 7.322 (0.86), 7.587 (0.56), 7.590 (0.47), 7.605 (0.84), 7.608 (0.95), 7.625 (0.69), 7.628 (0.75), 7.700 (0.72), 7.704 (0.62), 7.718 (0.61), 7.721 (0.96), 7.725 (0.84), 7.739 (0.56), 7.742 (0.57), 7.989 (2.38), 8.012 (2.18), 8.635 (1.65), 8.641 (1.63), 9.333 (2.36), 9.339 (2.20), 9.946 (0.94).    Example 317 (rac)-1-[(rac)-(1H-imidazol-2-yl)(phenyl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) 
Figure imgf000567_0002
LC-MS (Method 1): Rt = 1.10 min; MS (ESIneg): m/z = 445 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.63), 1.412 (0.75), 1.422 (0.63), 1.453 (0.60), 2.119 (0.74), 2.136 (1.30), 2.150 (1.25), 2.161 (1.06), 2.178 (0.57), 2.328 (0.51), 2.332 (0.69), 2.337 (0.50), 2.524 (2.36), 2.528 (1.57), 2.545 (16.00), 2.572 (0.51), 2.586 (0.71), 2.604 (1.01), 2.619 (0.86), 2.639 (0.42), 2.670 (1.02), 2.674 (1.11), 2.679 (1.01), 2.690 (1.09), 2.706 (1.46), 2.728 (1.54), 2.746 (1.45), 2.760 (1.28), 2.780 (1.31), 3.470 (1.00), 4.167 (0.95), 4.187 (1.92), 4.203 (1.93), 4.222 (0.99), 4.229 (0.49), 5.058 (0.42), 6.922 (4.35), 7.031 (3.41), 7.170 (2.70), 7.296 (3.27), 7.314 (2.21), 7.333 (1.54), 7.339 (1.65), 7.358 (1.26), 7.377 (1.96), 7.399 (4.49), 7.418 (5.70), 7.428 (4.95), 7.538 (0.43), 7.602 (0.63), 7.607 (0.82), 7.611 (0.72), 7.625 (1.61), 7.644 (3.24), 7.648 (2.84), 7.662 (2.03), 7.666 (1.94), 7.670 (2.03), 7.713 (0.96), 7.718 (1.26), 7.721 (0.88), 7.731 (0.87), 7.734 (1.81), 7.738 (1.80), 7.743 (1.01), 7.751 (0.80), 7.755 (1.11), 7.760 (0.68), 8.006 (1.66), 8.012 (2.47), 8.023 (2.13), 8.032 (2.29), 8.684 (1.60), 8.689 (1.68), 8.697 (1.63), 8.702 (1.60), 9.365 (2.48), 9.370 (2.37), 9.386 (2.28), 9.392 (2.29).    Example 318 (rac)-1-[(4-chloro-1H-pyrazol-3-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000568_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.45), 0.146 (0.45), 0.853 (0.41), 1.234 (1.96), 1.279 (0.46), 1.889 (1.60), 1.915 (2.14), 1.936 (1.09), 1.969 (0.71), 1.990 (1.93), 2.013 (3.72), 2.036 (3.73), 2.062 (2.86), 2.076 (3.69), 2.135 (1.19), 2.156 (3.25), 2.162 (3.15), 2.179 (4.06), 2.185 (4.55), 2.207 (3.09), 2.231 (0.83), 2.324 (3.40), 2.329 (4.56), 2.333 (3.80), 2.338 (3.15), 2.346 (2.36), 2.359 (3.56), 2.366 (4.82), 2.374 (3.03), 2.380 (3.01), 2.387 (4.34), 2.394 (2.76), 2.408 (1.70), 2.415 (1.44), 2.525 (16.00), 2.584 (1.69), 2.643 (4.08), 2.666 (8.01), 2.671 (6.43), 2.693 (2.74), 2.710 (2.54), 2.732 (1.33), 2.787 (2.57), 3.657 (2.94), 3.676 (3.53), 3.698 (4.39), 3.719 (3.98), 4.112 (2.89), 4.128 (5.35), 4.146 (2.86), 6.474 (1.41), 6.521 (1.42), 7.266 (5.89), 7.270 (5.76), 7.527 (1.20), 7.926 (1.20), 8.159 (0.40), 8.195 (7.27), 8.200 (7.28), 8.594 (5.09), 9.915 (0.85), 11.328 (4.12), 12.970 (0.97), 13.163 (0.96).    Example 319 (rac)-1-[(4-chloro-3-methyl-1H-pyrazol-5-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000569_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.011 (10.97), 1.062 (5.76), 1.581 (0.60), 1.878 (0.44), 1.881 (0.43), 1.886 (0.41), 1.900 (0.45), 1.907 (0.60), 1.980 (1.09), 1.994 (0.56), 2.005 (1.03), 2.008 (1.00), 2.013 (1.00), 2.029 (1.15), 2.050 (0.90), 2.055 (0.92), 2.063 (5.98), 2.071 (0.71), 2.148 (16.00), 2.168 (1.29), 2.174 (1.43), 2.190 (0.71), 2.197 (0.96), 2.331 (0.62), 2.338 (0.64), 2.344 (0.41), 2.351 (0.95), 2.358 (1.44), 2.366 (0.77), 2.371 (0.77), 2.379 (1.29), 2.386 (0.74), 2.399 (0.42), 2.479 (0.81), 2.518 (0.93), 2.522 (0.66), 2.528 (0.53), 2.552 (0.48), 2.567 (0.77), 2.585 (0.74), 2.599 (0.48), 2.629 (1.31), 2.652 (1.74), 2.680 (0.77), 2.698 (0.71), 2.744 (1.68), 2.757 (0.52), 2.767 (1.39), 2.777 (0.73), 2.792 (0.62), 3.162 (6.90), 3.559 (0.78), 3.632 (5.71), 3.667 (0.76), 3.668 (0.77), 3.689 (1.12), 3.709 (0.68), 3.711 (0.66), 4.096 (0.92), 4.100 (0.87), 4.114 (1.77), 4.131 (0.91), 4.134 (0.94), 6.473 (6.28), 7.259 (2.98), 8.189 (3.12), 8.194 (3.17), 8.581 (2.97), 8.587 (2.88).    Example 320 (rac)-2'-(quinolin-3-yl)-1-[(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000569_0001
LC-MS (Method 1): Rt = 0.88 min; MS (ESIneg): m/z = 425 [M-H]-  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.010 (0.45), 2.029 (0.82), 2.042 (1.51), 2.061 (2.18), 2.079 (1.87), 2.087 (1.96), 2.093 (1.83), 2.107 (1.75), 2.119 (0.74), 2.125 (0.66), 2.139 (0.52), 2.523 (3.14), 2.528 (2.03), 2.542 (2.04), 2.555 (1.93), 2.574 (2.63), 2.591 (1.88), 2.617 (2.86), 2.626 (3.06), 2.643 (2.75), 2.660 (2.03), 2.675 (1.92), 2.693 (0.87), 2.714 (3.74), 2.738 (5.80), 2.749 (2.27), 2.769 (1.22), 2.783 (1.29), 2.804 (6.65), 2.820 (2.02), 2.826 (3.92), 2.840 (0.78), 3.651 (11.65), 3.804 (2.91), 3.818 (5.73), 3.831 (2.95), 4.186 (3.41), 4.203 (6.58), 4.222 (3.42), 4.457 (4.69), 4.562 (1.11), 6.721 (16.00), 7.593 (1.86), 7.596 (1.76), 7.611 (2.85), 7.614 (3.88), 7.631 (2.53), 7.634 (2.69), 7.705 (2.48), 7.710 (2.39), 7.723 (2.17), 7.726 (4.01), 7.730 (3.08), 7.744 (2.15), 7.748 (2.10), 7.996 (7.11), 8.018 (6.24), 8.644 (5.56), 8.650 (5.67), 9.350 (8.26), 9.355 (8.03), 11.730 (0.72).    Example 321 (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000570_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.78), 1.868 (0.43), 1.873 (0.44), 1.888 (1.13), 1.890 (1.13), 1.895 (1.09), 1.902 (0.85), 1.909 (1.23), 1.916 (1.59), 1.923 (0.87), 1.937 (0.79), 1.944 (0.47), 1.982 (0.55), 1.991 (1.19), 1.996 (1.06), 2.001 (1.01), 2.014 (3.40), 2.035 (2.89), 2.050 (2.38), 2.058 (1.63), 2.064 (2.62), 2.070 (1.78), 2.078 (1.18), 2.084 (2.08), 2.096 (0.78), 2.102 (0.69), 2.117 (0.58), 2.137 (0.79), 2.141 (0.72), 2.157 (2.43), 2.163 (2.27), 2.180 (3.04), 2.185 (3.40), 2.202 (1.75), 2.208 (2.34), 2.230 (0.60), 2.232 (0.64), 2.331 (0.54), 2.336 (0.62), 2.341 (1.26), 2.348 (1.51), 2.362 (2.50), 2.369 (3.62), 2.376 (2.06), 2.382 (2.10), 2.389 (3.27), 2.397 (1.93), 2.403 (0.87), 2.410 (1.07), 2.417 (0.75), 2.481 (1.17), 2.527 (2.72), 2.547 (1.27), 2.577 (1.18), 2.593 (1.93), 2.611 (1.82), 2.625 (1.21), 2.643 (0.73), 2.668 (0.49), 2.673 (0.74), 2.681 (3.10), 2.691 (1.00), 2.705 (5.05), 2.730 (1.86), 2.750 (1.09), 2.767 (5.01), 2.790 (4.41), 2.804 (1.58), 2.826 (0.60), 3.658 (0.60), 3.680 (2.01), 3.698 (16.00), 3.721 (1.78), 3.743 (0.50), 4.103 (0.52), 4.113 (2.10), 4.119 (2.18), 4.131 (3.73), 4.147 (2.17), 4.153 (2.06), 4.165 (0.48), 6.515 (13.68), 6.929 (4.47), 7.270 (4.83), 7.274 (4.85), 8.203 (5.75), 8.208 (5.85), 8.606 (7.12), 8.612 (7.01), 9.650 (1.21), 11.337 (3.34), 11.341 (3.37).    Example 322 (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-ethyl-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole] 
Figure imgf000571_0001
LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 342 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.845 (1.00), 0.862 (2.15), 0.881 (1.94), 0.900 (3.16), 0.918 (1.51), 1.033 (7.39), 1.051 (16.00), 1.070 (7.61), 1.227 (2.65), 1.274 (0.93), 1.293 (1.22), 1.332 (0.57), 1.347 (0.79), 1.387 (0.72), 1.405 (0.79), 1.425 (0.50), 1.975 (0.57), 1.994 (0.93), 2.007 (1.58), 2.026 (2.22), 2.043 (2.65), 2.057 (1.79), 2.064 (1.94), 2.078 (1.87), 2.089 (0.79), 2.096 (0.79), 2.109 (0.65), 2.303 (0.79), 2.452 (2.73), 2.465 (6.31), 2.470 (7.75), 2.518 (10.40), 2.536 (3.87), 2.553 (2.51), 2.563 (5.52), 2.586 (7.25), 2.596 (3.37), 2.613 (2.44), 2.629 (1.72), 2.646 (0.93), 2.767 (4.88), 2.778 (2.30), 2.789 (4.81), 2.813 (0.86), 4.134 (3.66), 4.150 (6.96), 4.168 (3.59), 4.223 (0.86), 4.229 (1.00), 4.237 (1.00), 4.243 (0.93), 6.579 (13.49), 7.670 (5.24), 7.676 (5.24), 8.083 (5.02), 8.191 (6.24), 8.195 (6.39), 8.733 (6.67), 8.738 (6.60), 11.980 (2.80).    Example 323 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(propan-2-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000571_0002
LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 356 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.041 (15.84), 1.057 (16.00), 1.978 (0.43), 1.990 (0.75), 2.006 (0.94), 2.029 (0.87), 2.043 (0.85), 2.050 (0.90), 2.064 (0.85), 2.075 (0.43), 2.323 (0.46), 2.327 (0.69), 2.332 (0.49), 2.413 (0.41), 2.428 (1.13), 2.444 (1.54), 2.460 (1.18), 2.518 (2.82), 2.523 (1.94), 2.530 (1.61), 2.548 (0.74), 2.572 (0.69), 2.589 (1.56), 2.606 (1.05), 2.621 (1.58), 2.627 (2.23), 2.637 (1.05), 2.643 (1.36), 2.649 (2.61), 2.660 (1.26), 2.665 (1.23), 2.669 (0.90), 2.673 (0.61), 2.680 (0.57), 2.810 (0.59), 2.827 (2.79), 2.850 (2.23), 2.867 (0.43), 4.140 (2.05), 4.157 (4.07), 4.175 (2.02), 6.583 (9.42), 7.675 (2.48), 7.680 (2.54), 8.194 (3.76), 8.199 (3.82), 8.738 (3.81), 8.743 (3.82), 11.984 (1.21).    Example 324 (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000572_0001
LC-MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 436 [M+H]+    Example 325 trifluoroacetic acid—(rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) 
Figure imgf000572_0002
  Example 326 (rac)-N-ethyl-2'-[6-(4-methyl-2-oxopiperazin-1-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000573_0002
3-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl trifluoromethanesulfonate (100 mg, 60 % purity, 118 µmol), 4-methylpiperazin- 2-one (20.2 mg, 177 µmol), 4,5-bis-(diphenylphosphino)-9,9-dimethyl xanthene (10.2 mg, 17.7 µmol), cesium carbonate (57.6 mg, 177 µmol), and tris(dibenzylideneacetone)dipalladium (5.39 mg, 5.89 µmol) were stirred in dioxane (1 mL) at 100 °C overnight. The insoluble material was filtered off and the filtrate was purified by HPLC to obtain 6.00 mg (97 % purity, 10 % yield) of the title compound.  LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 474 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (0.64), 1.017 (6.14), 1.035 (13.72), 1.053 (6.29), 2.088 (0.96), 2.106 (1.55), 2.126 (1.70), 2.144 (0.83), 2.156 (0.54), 2.319 (16.00), 2.521 (0.96), 2.526 (0.61), 2.564 (2.03), 2.582 (3.11), 2.600 (2.15), 2.775 (2.13), 2.789 (2.97), 2.802 (2.26), 3.038 (0.85), 3.056 (2.44), 3.070 (2.65), 3.073 (2.56), 3.087 (2.35), 3.105 (0.70), 3.180 (10.26), 3.398 (0.43), 3.417 (0.99), 3.424 (0.83), 3.435 (1.02), 3.442 (1.55), 3.463 (6.12), 3.489 (0.49), 3.504 (0.61), 3.523 (1.02), 3.530 (0.66), 3.537 (0.76), 3.544 (0.62), 3.548 (0.59), 3.781 (2.33), 3.795 (3.02), 3.808 (2.23), 4.267 (2.06), 4.284 (3.25), 4.301 (2.01), 6.175 (0.98), 6.189 (1.97), 6.203 (0.95), 6.723 (8.81), 7.701 (2.24), 7.707 (2.34), 7.724 (2.50), 7.729 (2.74), 7.946 (3.56), 7.952 (3.44), 7.983 (3.29), 8.005 (2.78), 8.628 (2.93), 8.633 (3.02), 9.331 (4.86), 9.336 (4.87).  The following examples were prepared analogously via cross-couling  Example 327 (rac)-N-ethyl-2'-[6-(2-oxopyrrolidin-1-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000573_0001
LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 445 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.017 (6.98), 1.035 (16.00), 1.053 (7.07), 2.057 (0.46), 2.074 (0.57), 2.087 (1.27), 2.094 (1.41), 2.101 (2.34), 2.113 (3.24), 2.117 (3.33), 2.131 (4.06), 2.150 (2.60), 2.168 (1.02), 2.471 (0.75), 2.521 (2.48), 2.525 (1.60), 2.542 (0.43), 2.555 (4.36), 2.564 (3.07), 2.576 (7.60), 2.596 (4.39), 3.038 (0.87), 3.056 (2.68), 3.070 (3.03), 3.073 (2.87), 3.087 (2.66), 3.105 (0.79), 3.400 (0.51), 3.418 (1.20), 3.426 (1.02), 3.431 (0.72), 3.436 (0.89), 3.444 (2.01), 3.457 (9.07), 3.504 (0.72), 3.522 (1.24), 3.529 (0.77), 3.537 (0.89), 3.545 (0.75), 3.548 (0.75), 3.562 (0.43), 3.829 (0.51), 3.961 (2.90), 3.979 (4.89), 3.997 (2.84), 4.261 (2.48), 4.279 (3.86), 4.296 (2.41), 6.176 (1.10), 6.189 (2.19), 6.203 (1.07), 6.731 (10.87), 7.980 (3.29), 8.003 (3.82), 8.049 (3.90), 8.055 (4.06), 8.252 (3.25), 8.258 (2.96), 8.274 (2.52), 8.281 (2.52), 8.616 (3.50), 8.621 (3.58), 9.267 (5.78), 9.272 (5.80).    Example 328 (rac)-2'-(6-{[dimethyl(oxo)-lambda6-sulfanylidene]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000574_0001
LC-MS (Method 1): Rt = 0.75 min; MS (ESIpos): m/z = 453 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.017 (1.51), 1.035 (3.60), 1.053 (1.61), 2.095 (0.42), 2.110 (0.54), 2.543 (0.48), 2.557 (0.53), 2.574 (0.80), 2.592 (0.56), 3.054 (0.58), 3.069 (0.65), 3.072 (0.63), 3.087 (0.57), 3.322 (13.11), 3.343 (16.00), 3.443 (0.52), 3.460 (0.41), 4.248 (0.53), 4.267 (0.84), 4.284 (0.52), 6.182 (0.51), 6.687 (2.46), 7.292 (0.65), 7.298 (0.73), 7.315 (0.64), 7.320 (0.78), 7.405 (1.02), 7.411 (0.95), 7.803 (0.87), 7.826 (0.78), 8.449 (0.78), 8.454 (0.80), 9.118 (1.35), 9.123 (1.26).    Example 329 (rac)-2'-[6-(2,2-dimethyl-2lambda6-diazathia-1,2-dien-1-yl)quinolin-3-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000575_0002
LC-MS (Method 1): Rt = 0.64 min; MS (ESIpos): m/z = 452 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (2.02), 1.033 (4.82), 1.051 (2.17), 2.092 (0.58), 2.108 (0.75), 2.520 (0.99), 2.525 (0.63), 2.553 (0.68), 2.570 (1.06), 2.588 (0.76), 2.927 (0.65), 3.052 (0.80), 3.066 (0.89), 3.070 (0.85), 3.083 (0.78), 3.217 (0.51), 3.300 (16.00), 3.436 (0.65), 3.447 (2.77), 4.242 (0.71), 4.260 (1.13), 4.277 (0.71), 6.177 (0.67), 6.668 (3.18), 7.296 (0.85), 7.301 (0.88), 7.318 (0.90), 7.324 (1.00), 7.507 (1.34), 7.513 (1.26), 7.726 (1.22), 7.748 (1.08), 8.364 (1.06), 8.369 (1.06), 9.038 (1.73), 9.043 (1.75).    Example 330 (rac)-N-ethyl-2'-[6-(1-methyl-1H-pyrazol-5-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000575_0001
LC-MS (Method 1): Rt = 0.74 min; MS (ESIpos): m/z = 442 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.020 (3.11), 1.037 (7.10), 1.055 (3.15), 2.097 (0.48), 2.113 (0.92), 2.131 (1.04), 2.149 (0.45), 2.523 (0.46), 2.575 (1.10), 2.593 (1.67), 2.610 (1.17), 3.058 (1.19), 3.073 (1.34), 3.076 (1.29), 3.090 (1.18), 3.424 (0.51), 3.432 (0.43), 3.442 (0.48), 3.449 (0.81), 3.468 (3.64), 3.528 (0.55), 3.971 (16.00), 4.275 (1.11), 4.292 (1.73), 4.310 (1.08), 6.180 (0.50), 6.194 (1.01), 6.208 (0.49), 6.576 (3.24), 6.581 (3.38), 6.737 (4.89), 7.544 (3.35), 7.548 (3.37), 7.867 (1.24), 7.872 (1.23), 7.888 (1.46), 7.893 (1.53), 8.088 (1.82), 8.110 (1.47), 8.206 (1.89), 8.211 (1.88), 8.752 (1.58), 8.757 (1.63), 9.391 (2.62), 9.397 (2.62).    Example 331 (rac)-N-ethyl-2-[6-(1H-pyrazol-5-yl)quinolin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000576_0001
LC-MS (Method 1): Rt = 0.71 min; MS (ESIpos): m/z = 428 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.023 (6.69), 1.040 (16.00), 1.058 (7.23), 2.082 (0.40), 2.096 (1.06), 2.114 (1.74), 2.134 (1.92), 2.152 (0.92), 2.164 (0.58), 2.522 (1.44), 2.527 (0.87), 2.571 (2.32), 2.589 (3.51), 2.606 (2.48), 3.044 (0.85), 3.061 (2.64), 3.075 (2.97), 3.079 (2.77), 3.093 (2.61), 3.111 (0.75), 3.405 (0.47), 3.423 (1.13), 3.431 (0.91), 3.443 (1.09), 3.448 (1.74), 3.471 (6.58), 3.497 (0.56), 3.515 (0.68), 3.534 (1.11), 3.540 (0.73), 3.548 (0.84), 3.555 (0.69), 3.559 (0.67), 3.573 (0.42), 4.274 (2.34), 4.292 (3.68), 4.310 (2.26), 6.182 (1.10), 6.196 (2.23), 6.209 (1.08), 6.735 (2.65), 6.881 (2.66), 6.886 (2.61), 7.870 (0.95), 8.013 (0.94), 8.034 (1.22), 8.220 (0.73), 8.240 (0.58), 8.398 (1.63), 8.664 (1.54), 9.308 (2.01), 13.054 (0.86).    Example 332 (rac)-N-ethyl-2'-[6-(1-methyl-1H-pyrazol-4-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000576_0002
LC-MS (Method 1): Rt = 0.77 min; MS (ESIpos): m/z = 442 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.022 (4.31), 1.040 (10.17), 1.058 (4.63), 2.093 (0.70), 2.112 (1.02), 2.125 (0.70), 2.132 (1.22), 2.150 (0.61), 2.163 (0.40), 2.523 (0.72), 2.527 (0.46), 2.568 (1.49), 2.585 (2.28), 2.602 (1.65), 3.044 (0.54), 3.061 (1.71), 3.075 (1.90), 3.079 (1.82), 3.093 (1.69), 3.111 (0.49), 3.418 (0.75), 3.426 (0.57), 3.443 (1.20), 3.469 (4.20), 3.515 (0.46), 3.529 (0.55), 3.533 (0.72), 3.539 (0.51), 3.547 (0.55), 3.553 (0.45), 3.558 (0.43), 3.917 (16.00), 4.269 (1.55), 4.288 (2.46), 4.304 (1.54), 6.181 (0.70), 6.195 (1.43), 6.209 (0.69), 6.718 (7.12), 7.937 (0.70), 7.941 (0.62), 7.959 (2.88), 7.963 (3.27), 7.971 (3.99), 7.992 (0.76), 8.021 (5.01), 8.023 (5.06), 8.146 (2.43), 8.149 (2.45), 8.296 (4.39), 8.565 (2.49), 8.570 (2.51), 9.258 (3.91), 9.263 (3.76).    Example 333 (rac)-2'-(6-cyclopropylquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000577_0001
LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 402 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.804 (1.09), 0.815 (3.80), 0.821 (3.28), 0.828 (3.65), 0.833 (3.58), 0.844 (1.42), 1.018 (6.58), 1.037 (16.00), 1.046 (3.70), 1.054 (7.91), 1.063 (1.80), 1.067 (3.44), 1.073 (3.28), 1.084 (1.19), 1.141 (0.53), 2.085 (1.11), 2.091 (0.92), 2.103 (2.69), 2.112 (1.68), 2.120 (2.76), 2.124 (2.55), 2.138 (1.76), 2.145 (1.12), 2.151 (0.67), 2.158 (0.51), 2.522 (1.14), 2.527 (0.75), 2.561 (2.40), 2.578 (3.58), 2.595 (2.61), 3.039 (0.83), 3.057 (2.60), 3.071 (2.90), 3.074 (2.75), 3.089 (2.57), 3.106 (0.76), 3.397 (0.48), 3.416 (1.13), 3.422 (0.93), 3.432 (0.92), 3.441 (1.81), 3.458 (8.56), 3.484 (0.41), 3.504 (0.70), 3.523 (1.15), 3.530 (0.73), 3.537 (0.85), 3.544 (0.69), 3.548 (0.68), 3.563 (0.42), 4.257 (2.48), 4.275 (3.81), 4.292 (2.43), 6.174 (1.04), 6.188 (2.08), 6.201 (1.02), 6.691 (10.20), 7.415 (2.35), 7.420 (2.36), 7.437 (2.48), 7.442 (2.58), 7.683 (3.79), 7.688 (3.65), 7.871 (3.38), 7.892 (3.06), 8.526 (3.35), 8.531 (3.40), 9.239 (5.44), 9.244 (5.45).    Example 334 (rac)-N-ethyl-2'-{6-[(prop-2-en-1-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000578_0002
(Rac)-N-Ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (25.0 mg, 66.2 µmol), 3-bromoprop-1-ene (11.2 mg, 92.7 µmol), and sodium hydroxide (3.18 mg, 79.5 µmol) were put into a microwave vial. DMF (300 µL) was added and the reaction mixture was stirred at 100 °C for 2 h. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried through a hydrophobic filter and purified by preparative tlc to yield 800 µg (97 % purity, 3 % yield) of the title compound.  The following examples were prepared analogously  Example 335 (rac)-2'-{6-[3-(dimethylamino)propoxy]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000578_0001
  Example 336 (rac)-N-ethyl-2'-{6-[(oxan-4-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide   
Figure imgf000579_0003
Example 337 (rac)-2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000579_0001
  Example 338 (rac)-N-ethyl-2'-[6-(3-methoxypropoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000579_0002
  Example 339 (rac)-N-ethyl-2-{6-[2-(morpholin-4-yl)ethoxy]quinolin-3-yl}-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000580_0001
  Example 340 (rac)-2'-(6-{[(rac)-butan-2-yl]oxy}quinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000580_0002
  Example 341 (rac)-N-ethyl-2'-(6-{[(rac)-oxolan-3-yl]methoxy}quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000580_0003
  Example 342 (rac)-N-ethyl-2'-{6-[2-(methylsulfanyl)ethoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000581_0001
  Example 343 (rac)-N-ethyl-2'-(6-{[(rac)-oxolan-3-yl]oxy}quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000581_0002
  Example 344 (rac)-N-ethyl-2'-[6-(2-methylpropoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000581_0003
  Example 345 (rac)-2'-{6-[2-(dimethylamino)ethoxy]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000582_0001
  Example 346 (rac)-N-ethyl-2'-[6-(2-methoxyethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000582_0003
  Example 347 (rac)-N-ethyl-2'-(6-{[(rac)-1-methylpiperidin-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) 
Figure imgf000582_0002
  Example 348 (rac)-N-ethyl-2'-(5-{[(oxan-4-yl)carbamoyl]amino}quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000583_0001
Phenyl {3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-5-yl}carbamate (50.0 mg, 101 µmol) and tetrahydro-2H-pyran-4-amine (15.3 mg, 151 µmol) were dissolved in DMSO (1 mL). Triethylamine (21 µL, 150 µmol) was added and stirred for 2 h at rt. The reaction mixture was purified by HPLC to afford 2.00 mg (95 % purity, 4 % yield) of the title compound.  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.004 (3.44), 1.017 (7.81), 1.035 (16.00), 1.052 (7.95), 1.202 (0.44), 1.229 (0.73), 1.255 (0.41), 1.397 (0.92), 1.408 (1.14), 1.434 (2.77), 1.456 (3.02), 1.482 (1.38), 1.493 (1.14), 1.857 (3.58), 1.883 (3.08), 2.073 (0.76), 2.082 (0.98), 2.097 (1.94), 2.114 (3.28), 2.133 (3.27), 2.152 (1.66), 2.164 (0.98), 2.182 (0.47), 2.579 (4.00), 2.596 (6.28), 2.613 (3.81), 3.038 (1.42), 3.055 (4.03), 3.070 (5.00), 3.088 (3.88), 3.105 (1.25), 3.249 (0.68), 3.386 (6.06), 3.415 (7.10), 3.443 (5.22), 3.448 (5.25), 3.455 (5.42), 3.467 (14.05), 3.503 (1.74), 3.521 (2.51), 3.535 (1.89), 3.561 (0.93), 3.712 (0.72), 3.729 (1.26), 3.738 (1.57), 3.748 (1.48), 3.756 (1.72), 3.766 (1.49), 3.782 (1.00), 3.844 (4.29), 3.865 (2.82), 3.873 (3.72), 4.276 (3.72), 4.292 (6.00), 4.310 (3.48), 6.184 (1.92), 6.197 (3.48), 6.211 (1.81), 6.709 (10.75), 6.719 (3.96), 6.738 (3.27), 7.587 (0.81), 7.608 (5.19), 7.615 (5.89), 7.622 (10.38), 8.106 (2.89), 8.114 (2.91), 8.121 (2.75), 8.128 (2.58), 8.694 (5.68), 8.781 (5.45), 8.784 (5.44), 9.298 (6.30), 9.303 (6.20).  The following examples were prepared similarly.  Example 349 (rac)-N-ethyl-2'-(5-{[methyl(1-methylazetidin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide   
Figure imgf000584_0002
Example 350 (rac)-N-ethyl-2'-(5-{[(oxetan-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000584_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.021 (7.67), 1.039 (16.00), 1.058 (7.84), 2.072 (0.43), 2.088 (0.88), 2.103 (1.89), 2.119 (3.57), 2.138 (3.68), 2.155 (1.68), 2.168 (0.95), 2.186 (0.45), 2.584 (3.79), 2.601 (6.06), 2.619 (3.72), 3.032 (2.19), 3.043 (1.36), 3.061 (3.93), 3.075 (4.77), 3.092 (3.79), 3.110 (1.18), 3.419 (0.97), 3.437 (1.95), 3.444 (1.95), 3.472 (14.10), 3.510 (1.36), 3.528 (2.20), 3.543 (1.63), 3.569 (0.72), 4.282 (3.70), 4.299 (6.04), 4.316 (3.49), 4.480 (4.45), 4.495 (9.00), 4.510 (4.85), 4.765 (3.68), 4.783 (7.91), 4.798 (6.23), 4.810 (1.10), 4.824 (1.85), 4.841 (2.52), 4.859 (2.00), 4.876 (0.88), 6.186 (1.84), 6.199 (3.39), 6.213 (1.78), 6.724 (10.34), 7.387 (2.95), 7.404 (2.94), 7.600 (1.66), 7.621 (4.16), 7.640 (4.51), 7.655 (5.55), 7.674 (2.12), 8.019 (3.65), 8.035 (3.38), 8.794 (5.44), 8.845 (5.32), 9.313 (6.40), 9.318 (6.34).    Example 351 (rac)-N-ethyl-2'-(5-{[methyl(oxetan-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000585_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.016 (4.12), 1.034 (8.95), 1.051 (4.22), 2.087 (0.85), 2.101 (0.93), 2.118 (1.08), 2.137 (1.24), 2.155 (0.67), 2.167 (0.53), 2.334 (0.46), 2.542 (0.74), 2.559 (1.67), 2.576 (2.58), 2.595 (1.71), 2.676 (0.48), 2.847 (0.58), 3.036 (0.59), 3.054 (1.88), 3.068 (2.21), 3.071 (2.15), 3.085 (1.84), 3.103 (0.55), 3.195 (16.00), 3.225 (0.56), 3.389 (0.54), 3.407 (0.96), 3.414 (0.78), 3.432 (1.31), 3.465 (3.98), 3.468 (4.24), 3.494 (0.54), 3.508 (0.55), 3.528 (0.84), 3.541 (0.71), 3.553 (0.52), 4.267 (1.71), 4.284 (2.91), 4.301 (1.64), 4.704 (9.99), 4.722 (10.69), 5.224 (1.33), 5.242 (1.88), 5.260 (1.21), 6.177 (0.85), 6.190 (1.65), 6.204 (0.82), 6.711 (5.80), 6.736 (1.30), 6.755 (1.45), 6.757 (1.49), 7.135 (0.73), 7.153 (0.97), 7.175 (0.60), 7.482 (1.69), 7.499 (2.13), 7.636 (1.59), 7.657 (2.23), 7.676 (1.54), 7.806 (2.19), 7.827 (1.68), 8.552 (2.57), 8.555 (2.55), 8.727 (2.88), 9.313 (3.29), 9.319 (3.26).    Example 352 (rac)-N-ethyl-2'-(5-{[(1-methylazetidin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000585_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.001 (0.56), 1.023 (4.56), 1.041 (9.21), 1.059 (4.49), 1.158 (0.42), 1.234 (0.57), 2.087 (0.64), 2.103 (1.19), 2.120 (2.11), 2.138 (2.11), 2.156 (1.04), 2.184 (1.95), 2.195 (2.65), 2.215 (0.57), 2.253 (16.00), 2.276 (3.22), 2.585 (2.80), 2.602 (4.00), 2.619 (2.32), 2.652 (0.42), 2.816 (2.01), 2.835 (3.59), 2.851 (2.10), 3.044 (0.92), 3.062 (2.33), 3.076 (2.78), 3.094 (2.18), 3.111 (0.88), 3.420 (1.43), 3.437 (1.94), 3.445 (1.98), 3.473 (8.61), 3.511 (1.18), 3.529 (1.65), 3.541 (2.98), 3.558 (4.22), 3.577 (2.21), 4.232 (0.79), 4.249 (1.35), 4.267 (1.57), 4.282 (2.76), 4.299 (3.78), 4.316 (2.04), 6.187 (1.20), 6.201 (1.95), 6.214 (0.97), 6.722 (5.83), 7.151 (1.81), 7.171 (1.70), 7.588 (0.80), 7.609 (2.44), 7.628 (4.81), 7.650 (0.98), 8.061 (1.73), 8.066 (1.72), 8.079 (1.60), 8.083 (1.52), 8.738 (3.05), 8.788 (2.88), 9.308 (3.62), 9.312 (3.46).    Example 353 (rac)-2'-{5-[(cyclopentylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000586_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (2.63), 0.999 (0.68), 1.017 (7.15), 1.035 (16.00), 1.052 (7.44), 1.197 (0.81), 1.217 (1.87), 1.232 (3.38), 1.246 (2.81), 1.262 (2.28), 1.278 (1.10), 1.413 (1.22), 1.429 (2.20), 1.444 (2.86), 1.453 (2.49), 1.460 (3.82), 1.466 (2.53), 1.472 (3.63), 1.474 (3.52), 1.489 (2.46), 1.493 (2.13), 1.509 (0.92), 1.515 (1.56), 1.522 (0.92), 1.531 (1.42), 1.557 (3.42), 1.567 (3.67), 1.576 (4.28), 1.586 (3.60), 1.595 (3.09), 1.615 (0.92), 1.622 (1.05), 1.642 (0.82), 1.669 (1.78), 1.686 (2.19), 1.697 (1.76), 1.707 (2.26), 1.724 (2.47), 1.736 (2.84), 1.753 (2.61), 1.765 (1.95), 1.783 (1.08), 1.862 (0.87), 1.879 (1.61), 1.892 (1.96), 1.904 (1.81), 1.909 (1.82), 1.925 (1.22), 2.083 (0.56), 2.095 (1.23), 2.114 (1.97), 2.135 (2.11), 2.152 (1.09), 2.166 (0.66), 2.331 (1.82), 2.518 (9.92), 2.522 (6.23), 2.578 (2.72), 2.596 (4.09), 2.613 (2.71), 2.673 (1.87), 3.023 (0.61), 3.037 (1.33), 3.055 (3.08), 3.069 (3.27), 3.072 (3.23), 3.086 (2.86), 3.105 (0.88), 3.410 (0.68), 3.428 (1.37), 3.435 (1.37), 3.454 (2.37), 3.467 (10.16), 3.503 (0.87), 3.522 (1.45), 3.537 (0.98), 3.544 (0.84), 3.563 (0.47), 3.790 (1.49), 3.807 (2.86), 3.824 (2.81), 3.841 (1.48), 3.984 (0.95), 4.001 (1.81), 4.018 (1.79), 4.034 (0.91), 4.276 (2.55), 4.293 (4.09), 4.310 (2.55), 5.607 (2.38), 5.624 (2.28), 6.180 (1.33), 6.193 (2.45), 6.207 (1.16), 6.697 (2.56), 6.710 (11.49), 7.578 (0.47), 7.600 (5.46), 7.602 (5.01), 7.612 (8.98), 8.121 (2.43), 8.132 (2.95), 8.144 (2.19), 8.622 (4.14), 8.770 (3.84), 8.775 (3.85), 9.295 (5.43), 9.300 (5.24).    Example 354 (rac)-N-ethyl-2'-{5-[(pyrrolidine-1-carbonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000587_0002
Figure imgf000587_0003
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (7.33), 1.031 (16.00), 1.048 (7.45), 1.233 (0.82), 1.907 (3.84), 1.922 (8.40), 1.938 (3.35), 2.073 (0.68), 2.086 (1.44), 2.099 (1.52), 2.118 (1.74), 2.137 (2.06), 2.155 (1.12), 2.167 (0.89), 2.186 (0.40), 2.332 (1.52), 2.522 (5.45), 2.558 (2.69), 2.577 (4.26), 2.594 (2.96), 2.673 (1.58), 3.032 (0.96), 3.050 (3.05), 3.065 (3.47), 3.068 (3.52), 3.082 (3.01), 3.100 (0.94), 3.403 (2.24), 3.410 (1.79), 3.428 (2.64), 3.436 (1.86), 3.462 (8.24), 3.470 (9.61), 3.481 (7.61), 3.495 (4.50), 3.521 (1.45), 3.528 (1.59), 3.540 (1.30), 3.566 (0.61), 4.267 (2.85), 4.285 (4.74), 4.302 (2.72), 6.173 (1.29), 6.186 (2.49), 6.200 (1.28), 6.724 (10.06), 7.559 (2.46), 7.577 (3.70), 7.636 (2.86), 7.657 (4.00), 7.676 (2.46), 7.779 (3.66), 7.800 (2.68), 8.404 (5.36), 8.619 (4.05), 8.623 (4.07), 9.314 (5.43), 9.319 (5.31).    Example 355 (rac)-2'-(5-{[cyclobutyl(methyl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000587_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (4.29), 1.033 (9.27), 1.051 (4.43), 1.573 (0.76), 1.579 (0.60), 1.599 (1.02), 1.619 (0.89), 1.645 (1.18), 1.669 (0.80), 2.072 (0.93), 2.086 (1.77), 2.100 (2.22), 2.114 (2.83), 2.134 (2.06), 2.152 (0.79), 2.164 (0.67), 2.174 (0.55), 2.181 (0.55), 2.197 (1.30), 2.223 (1.63), 2.249 (0.94), 2.558 (2.07), 2.576 (3.12), 2.593 (2.01), 3.024 (16.00), 3.052 (2.10), 3.069 (2.45), 3.083 (1.99), 3.101 (0.60), 3.389 (0.70), 3.406 (1.10), 3.413 (0.95), 3.432 (1.99), 3.458 (3.72), 3.467 (3.75), 3.493 (0.86), 3.501 (0.70), 3.520 (0.99), 3.534 (0.80), 4.264 (1.87), 4.282 (3.16), 4.299 (1.84), 4.716 (0.70), 4.738 (1.13), 4.760 (0.68), 6.172 (0.91), 6.185 (1.78), 6.199 (0.91), 6.674 (5.86), 7.464 (1.90), 7.482 (2.28), 7.629 (1.57), 7.650 (2.39), 7.669 (1.60), 7.791 (2.36), 7.812 (1.81), 8.524 (4.33), 9.301 (3.33), 9.307 (3.34).    Example 356 (rac)-N-ethyl-2'-(5-{[(1-methylcyclobutyl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000588_0001
  Example 357 (rac)-2'-(5-{[cyclopropyl(methyl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000588_0002
  Example 358 (rac)-2'-(5-{[(bicyclo[1.1.1]pentan-1-yl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000588_0003
H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.020 (1.98), 1.038 (4.27), 1.056 (2.03), 2.041 (16.00), 2.114 (0.78), 2.132 (0.86), 2.441 (2.83), 2.525 (1.65), 2.542 (0.62), 2.582 (0.83), 2.599 (1.27), 2.617 (0.80), 3.058 (0.89), 3.072 (1.01), 3.075 (0.99), 3.090 (0.84), 3.435 (0.43), 3.443 (0.42), 3.467 (3.15), 3.522 (0.48), 4.276 (0.79), 4.293 (1.27), 4.310 (0.77), 6.180 (0.41), 6.194 (0.74), 6.707 (2.85), 7.298 (1.40), 7.603 (1.02), 7.621 (2.04), 7.627 (1.28), 8.079 (0.79), 8.084 (0.80), 8.097 (0.72), 8.101 (0.70), 8.617 (1.20), 8.768 (1.11), 8.772 (1.12), 9.305 (1.52), 9.310 (1.47).    Example 359 (rac)-2'-{5-[(cyclobutylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000589_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.001 (0.41), 1.022 (6.93), 1.040 (16.00), 1.058 (7.32), 1.597 (0.57), 1.616 (1.07), 1.622 (0.75), 1.635 (0.89), 1.642 (2.02), 1.649 (0.93), 1.662 (1.91), 1.668 (1.63), 1.686 (1.36), 1.861 (0.52), 1.867 (0.47), 1.883 (1.61), 1.889 (1.56), 1.905 (1.84), 1.911 (2.12), 1.937 (1.40), 1.959 (0.42), 2.087 (0.59), 2.101 (1.27), 2.119 (2.26), 2.137 (2.30), 2.155 (1.06), 2.167 (0.61), 2.217 (0.75), 2.223 (0.98), 2.230 (0.94), 2.235 (1.57), 2.242 (2.20), 2.249 (1.48), 2.258 (1.47), 2.263 (2.01), 2.271 (1.34), 2.276 (0.73), 2.282 (0.85), 2.289 (0.55), 2.334 (1.33), 2.339 (0.61), 2.521 (6.77), 2.525 (4.35), 2.542 (1.09), 2.583 (2.62), 2.601 (3.90), 2.618 (2.56), 2.672 (1.81), 2.676 (1.32), 3.042 (0.99), 3.060 (2.95), 3.074 (3.26), 3.078 (3.12), 3.092 (2.81), 3.109 (0.82), 3.297 (0.50), 3.417 (0.59), 3.435 (1.25), 3.443 (1.17), 3.460 (2.72), 3.471 (10.16), 3.508 (0.83), 3.527 (1.38), 3.533 (0.81), 3.541 (0.97), 3.550 (0.79), 3.567 (0.43), 4.172 (0.72), 4.191 (1.36), 4.213 (1.33), 4.233 (0.72), 4.280 (2.63), 4.297 (4.01), 4.315 (2.42), 6.183 (1.27), 6.197 (2.40), 6.211 (1.15), 6.715 (10.64), 6.733 (0.45), 6.925 (2.15), 6.945 (2.11), 7.583 (1.11), 7.604 (4.05), 7.617 (4.04), 7.621 (7.15), 7.638 (0.83), 8.066 (2.25), 8.072 (2.13), 8.082 (1.96), 8.088 (1.94), 8.661 (3.84), 8.778 (3.58), 8.783 (3.58), 9.301 (5.33), 9.306 (5.29).    Example 360 (rac)-N-ethyl-2'-[5-({[2-(trifluoromethyl)cyclopropyl]carbamoyl}amino)quinolin-3-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000590_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.001 (0.42), 1.018 (7.31), 1.036 (16.00), 1.054 (7.25), 1.160 (1.58), 1.170 (2.03), 1.185 (3.18), 1.196 (1.52), 1.205 (2.37), 1.220 (0.49), 2.027 (0.47), 2.034 (0.50), 2.050 (0.95), 2.068 (1.05), 2.084 (0.91), 2.097 (1.35), 2.112 (2.45), 2.129 (2.75), 2.146 (1.09), 2.159 (0.52), 2.325 (1.68), 2.329 (2.29), 2.334 (1.66), 2.339 (0.73), 2.521 (8.54), 2.525 (5.51), 2.542 (1.56), 2.579 (2.58), 2.597 (3.95), 2.614 (2.64), 2.667 (1.69), 2.672 (2.32), 2.676 (1.68), 3.005 (0.56), 3.014 (1.04), 3.026 (1.46), 3.038 (1.87), 3.046 (1.30), 3.056 (3.23), 3.070 (3.19), 3.074 (3.19), 3.088 (2.82), 3.106 (0.83), 3.377 (0.41), 3.416 (0.58), 3.433 (1.23), 3.441 (1.18), 3.465 (10.25), 3.501 (0.83), 3.519 (1.44), 3.526 (0.83), 3.534 (0.96), 3.544 (0.81), 3.560 (0.42), 4.273 (2.51), 4.290 (4.00), 4.308 (2.48), 6.179 (1.26), 6.193 (2.44), 6.206 (1.20), 6.707 (10.09), 7.056 (2.06), 7.063 (2.01), 7.612 (1.56), 7.633 (3.51), 7.652 (4.37), 7.664 (3.71), 7.683 (1.23), 8.040 (2.68), 8.044 (2.63), 8.059 (2.41), 8.063 (2.26), 8.762 (3.55), 8.767 (3.51), 8.801 (3.51), 9.310 (5.39), 9.315 (5.29).    Example 361 (rac)-2'-{5-[(cyclopropylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000590_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.67), 0.146 (0.67), 0.463 (1.04), 0.476 (3.32), 0.484 (3.74), 0.490 (3.63), 0.501 (1.28), 0.661 (1.26), 0.673 (3.16), 0.678 (4.07), 0.690 (4.08), 0.695 (3.02), 0.708 (1.00), 1.018 (6.97), 1.036 (16.00), 1.054 (7.33), 2.096 (1.19), 2.112 (2.25), 2.131 (2.45), 2.149 (1.05), 2.161 (0.59), 2.334 (3.06), 2.520 (15.57), 2.524 (10.02), 2.542 (1.65), 2.577 (2.54), 2.595 (4.08), 2.612 (3.48), 2.622 (1.71), 2.631 (1.63), 2.640 (1.18), 2.648 (0.68), 2.676 (3.11), 3.038 (0.89), 3.056 (2.91), 3.070 (3.22), 3.073 (3.19), 3.088 (2.84), 3.106 (0.82), 3.293 (0.78), 3.372 (0.77), 3.410 (0.56), 3.428 (1.28), 3.436 (1.09), 3.455 (2.38), 3.465 (10.47), 3.502 (0.82), 3.521 (1.32), 3.536 (0.97), 4.272 (2.52), 4.290 (4.04), 4.308 (2.49), 6.178 (1.26), 6.192 (2.42), 6.206 (1.21), 6.703 (10.53), 6.853 (2.41), 6.859 (2.43), 7.599 (1.10), 7.620 (3.89), 7.636 (6.79), 7.655 (0.81), 8.057 (1.82), 8.063 (1.76), 8.073 (1.68), 8.078 (1.57), 8.646 (3.75), 8.750 (3.67), 8.755 (3.67), 9.301 (5.49), 9.306 (5.30).    Example 362 (rac)-2'-{5-[(cyclohexylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000591_0001
  Example 363 (rac)-N-ethyl-2'-(5-{[(pyridin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000591_0002
  Example 364 (rac)-N-ethyl-2'-{5-[(ethylcarbamoyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide   
Figure imgf000592_0002
Example 365 methyl (1-{[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methyl}cyclopropyl)acetate 
Figure imgf000592_0001
(Rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) (47.0 mg, 144 µmol), methyl [1-(bromomethyl)cyclopropyl]acetate (35.7 mg, 173 µmol), and N,N-diisopropylethylamine (75 µL, 430 µmol) were dissolved in DMF (1.4 mL). It was stirred for 50 h at rt and 2 h at 100 °C. The reaction mixture was allowed to reach rt and purified by HPLC obtaining 14.4 mg (95 % purity, 23 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.34 min; MS (ESIpos): m/z = 417 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.368 (1.04), 0.420 (1.79), 0.446 (1.94), 0.460 (2.48), 1.987 (0.44), 2.041 (0.45), 2.076 (0.60), 2.092 (0.79), 2.103 (0.76), 2.119 (0.65), 2.139 (0.46), 2.322 (0.47), 2.326 (0.64), 2.332 (0.51), 2.356 (3.92), 2.403 (3.88), 2.518 (2.71), 2.522 (1.70), 2.535 (0.75), 2.541 (0.64), 2.550 (0.72), 2.560 (0.97), 2.567 (1.03), 2.573 (0.89), 2.591 (1.65), 2.609 (1.07), 2.621 (0.86), 2.637 (1.15), 2.654 (1.23), 2.665 (1.11), 2.669 (1.77), 2.687 (0.90), 2.703 (0.64), 2.805 (0.74), 2.830 (0.70), 2.947 (0.68), 2.970 (0.49), 3.587 (0.67), 3.606 (16.00), 4.198 (1.19), 4.214 (3.08), 4.231 (2.83), 4.248 (1.08), 6.698 (2.78), 6.743 (4.03), 7.590 (0.97), 7.610 (2.05), 7.630 (1.44), 7.703 (1.04), 7.706 (1.10), 7.723 (1.64), 7.727 (1.68), 7.744 (1.07), 7.994 (4.72), 8.015 (4.27), 8.627 (3.07), 8.632 (3.11), 9.333 (4.76), 9.338 (4.88).  The following examples were prepared similarly  Example 366 3-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]propanoic acid 
Figure imgf000593_0001
LC-MS (Method 1): Rt = 0.64 min; MS (ESIpos): m/z = 364 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.155 (0.46), 1.228 (0.83), 2.035 (1.34), 2.048 (2.39), 2.067 (3.74), 2.087 (3.76), 2.107 (2.60), 2.119 (1.16), 2.140 (0.84), 2.322 (2.13), 2.326 (2.70), 2.331 (2.12), 2.404 (3.82), 2.421 (6.83), 2.439 (4.68), 2.522 (6.58), 2.538 (2.34), 2.552 (2.83), 2.570 (3.92), 2.587 (2.44), 2.600 (2.22), 2.617 (3.69), 2.634 (3.03), 2.649 (2.61), 2.668 (3.68), 2.673 (2.87), 2.686 (4.46), 2.709 (7.15), 2.734 (6.48), 2.752 (8.01), 2.770 (3.84), 2.801 (2.26), 2.823 (6.94), 2.846 (4.83), 2.887 (0.85), 4.193 (5.12), 4.209 (9.63), 4.227 (5.04), 6.692 (1.56), 6.704 (16.00), 7.589 (2.86), 7.609 (5.55), 7.626 (3.93), 7.629 (3.97), 7.702 (3.58), 7.705 (3.28), 7.723 (5.45), 7.726 (4.62), 7.740 (3.06), 7.743 (3.16), 7.990 (12.14), 8.013 (11.52), 8.643 (8.53), 8.648 (8.31), 9.339 (10.18), 9.344 (10.25).    Example 367 [(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]acetonitrile 
Figure imgf000594_0002
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 330 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.852 (0.48), 1.228 (1.90), 1.258 (0.52), 2.105 (0.44), 2.119 (1.74), 2.128 (1.84), 2.137 (2.83), 2.145 (3.05), 2.154 (1.85), 2.164 (1.91), 2.177 (0.45), 2.523 (0.65), 2.528 (0.47), 2.564 (0.67), 2.582 (1.54), 2.597 (1.63), 2.615 (2.69), 2.632 (1.47), 2.643 (1.43), 2.661 (2.85), 2.670 (0.48), 2.678 (1.93), 2.693 (1.59), 2.710 (0.69), 2.815 (1.58), 2.822 (0.51), 2.837 (7.92), 2.845 (9.37), 2.865 (3.66), 2.867 (4.54), 2.880 (1.88), 2.886 (1.88), 3.930 (15.91), 4.216 (3.82), 4.234 (7.26), 4.251 (3.62), 5.765 (2.60), 6.757 (16.00), 7.594 (1.56), 7.597 (1.53), 7.611 (2.29), 7.615 (3.29), 7.617 (1.94), 7.632 (2.15), 7.634 (2.19), 7.708 (2.24), 7.712 (2.24), 7.726 (1.90), 7.729 (3.51), 7.733 (2.63), 7.746 (1.85), 7.750 (1.88), 7.993 (3.32), 7.996 (4.78), 8.012 (2.82), 8.017 (3.79), 8.678 (4.40), 8.684 (4.40), 9.361 (5.58), 9.367 (5.34).    Example 368 N-methoxy-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetamide 
Figure imgf000594_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.421 (0.76), 0.426 (0.76), 0.430 (0.83), 0.436 (0.83), 0.627 (0.71), 0.633 (0.90), 0.645 (0.90), 0.650 (0.70), 2.038 (0.41), 2.051 (0.83), 2.069 (1.20), 2.079 (0.95), 2.086 (0.99), 2.093 (1.12), 2.098 (1.06), 2.113 (0.91), 2.533 (0.68), 2.552 (0.90), 2.566 (0.90), 2.584 (1.17), 2.601 (0.66), 2.640 (0.43), 2.650 (0.57), 2.655 (0.68), 2.672 (1.32), 2.688 (0.89), 2.704 (0.72), 2.764 (1.35), 2.774 (1.11), 2.787 (2.23), 2.811 (0.52), 2.856 (2.08), 2.878 (1.67), 2.888 (0.92), 3.121 (4.93), 3.430 (0.42), 3.613 (16.00), 3.973 (4.07), 4.199 (1.74), 4.216 (3.22), 4.234 (1.69), 5.761 (1.84), 6.778 (3.54), 7.594 (0.85), 7.614 (1.66), 7.634 (1.20), 7.707 (1.07), 7.710 (0.98), 7.727 (1.61), 7.731 (1.37), 7.745 (0.87), 7.748 (0.90), 7.997 (3.80), 8.019 (3.46), 8.648 (2.64), 8.652 (2.64), 9.350 (3.33), 9.355 (3.24).    Example 369 N-cyclopropyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]- 1-yl]acetamide 
Figure imgf000595_0001
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.006 (4.48), 0.411 (0.61), 0.417 (0.43), 0.423 (1.19), 0.434 (2.87), 0.437 (3.02), 0.444 (5.81), 0.454 (4.62), 0.463 (1.42), 0.470 (0.56), 0.475 (0.76), 0.480 (0.52), 0.485 (0.55), 0.558 (0.53), 0.573 (1.24), 0.591 (6.29), 0.608 (5.89), 0.625 (0.56), 0.628 (0.82), 2.016 (0.48), 2.032 (0.70), 2.036 (0.80), 2.048 (1.68), 2.067 (2.22), 2.077 (1.84), 2.083 (1.91), 2.092 (2.20), 2.097 (2.11), 2.112 (1.83), 2.124 (0.82), 2.128 (0.73), 2.144 (0.57), 2.518 (1.59), 2.523 (0.98), 2.537 (0.86), 2.556 (1.59), 2.570 (1.85), 2.588 (2.58), 2.605 (1.55), 2.613 (0.67), 2.623 (1.40), 2.630 (2.67), 2.641 (3.01), 2.645 (3.29), 2.649 (3.51), 2.662 (3.12), 2.669 (1.87), 2.679 (1.93), 2.696 (0.82), 2.741 (2.72), 2.763 (6.70), 2.787 (7.52), 2.810 (4.62), 2.820 (1.94), 2.828 (1.80), 2.836 (2.30), 2.839 (2.26), 2.855 (1.83), 2.878 (0.58), 3.041 (3.58), 3.078 (7.28), 3.135 (7.45), 3.172 (3.42), 4.181 (0.44), 4.192 (3.09), 4.209 (6.29), 4.228 (3.17), 5.757 (1.62), 6.773 (16.00), 7.591 (1.81), 7.593 (1.75), 7.608 (2.80), 7.611 (3.87), 7.628 (2.54), 7.630 (2.60), 7.703 (2.46), 7.707 (2.47), 7.720 (2.91), 7.724 (5.37), 7.727 (5.49), 7.741 (3.96), 7.744 (3.01), 7.993 (6.51), 8.014 (5.50), 8.652 (5.56), 8.657 (5.71), 9.350 (7.83), 9.356 (7.71).    Example 370 (rac)-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propanamide (mixture of stereoisomers)   
Figure imgf000596_0003
Example 371 2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]acetamide 
Figure imgf000596_0001
  Example 372 N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetamide 
Figure imgf000596_0002
  Example 373 (rac)-N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl] (mixture of isomers) 
Figure imgf000597_0002
  Example 374 (rac)-3'-bromo-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000597_0001
(Rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (900 mg, 2.34 mmol) was dissolved in DMF (50 mL) and treated with N-bromosuccinimide (458 mg, 2.57 mmol). It was stirred for 30 min. at rt. At 0°C ethyl acetate, water, and saturated aqueous sodium chloride solution were added. The layers were separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic phasese were concentrated and purified by silica gel chromatography to give 312 mg (26%) of the title compound. LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 465 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (4.94), 1.027 (11.41), 1.045 (5.23), 1.065 (9.35), 2.073 (0.47), 2.084 (0.55), 2.103 (0.61), 2.116 (0.58), 2.322 (0.94), 2.326 (1.08), 2.331 (0.72), 2.345 (0.83), 2.354 (0.56), 2.369 (0.62), 2.378 (0.69), 2.518 (3.48), 2.522 (2.15), 2.532 (0.57), 2.546 (1.15), 2.555 (1.33), 2.562 (16.00), 2.572 (2.13), 2.582 (1.12), 2.589 (1.16), 2.664 (0.60), 2.668 (0.82), 2.673 (0.61), 2.727 (5.34), 2.888 (6.63), 3.027 (0.65), 3.046 (2.05), 3.060 (2.26), 3.063 (2.20), 3.077 (1.99), 3.095 (0.59), 3.159 (11.52), 3.171 (11.81), 3.306 (0.53), 3.347 (1.42), 3.355 (0.85), 3.372 (0.51), 3.480 (1.32), 3.505 (1.82), 3.549 (0.66), 3.570 (1.05), 3.590 (0.52), 3.617 (2.52), 3.642 (1.89), 3.939 (1.57), 4.083 (1.01), 4.096 (3.21), 4.110 (3.16), 4.123 (0.97), 4.260 (1.56), 4.277 (3.16), 4.296 (1.62), 6.206 (0.83), 6.220 (1.66), 6.233 (0.81), 7.756 (2.74), 7.762 (2.82), 7.950 (0.83), 8.152 (0.41), 8.157 (0.42), 8.225 (2.79), 8.230 (2.91), 8.672 (0.54), 8.680 (3.45), 8.685 (3.40), 12.152 (1.19).  Example 375 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-3'-methyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000598_0001
(Rac)-3'-Bromo-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (75.0 mg, 162 µmol) and di-µ-iodobis(tri-t- butylphosphino)dipalladium(I) (14.1 mg, 16.2 µmol) were stirred in THF (500 µL) under argon. Then methyl zinc chloride (400 µL, 2.0 M in THF, 810 µmol) was added and stirrrred for 2 h at rt. Water, ethyl acetate and brine were added and stirred for 5 min. The reaction mixture was filtered, the layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were concentrated and purified by HPLC yielding 5.00 mg (95 % purity, 7 % yield) of the title compound. LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 400 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.008 (4.28), 1.026 (10.28), 1.043 (4.47), 1.331 (0.40), 2.043 (0.48), 2.054 (0.46), 2.063 (0.43), 2.152 (16.00), 2.272 (0.83), 2.294 (0.47), 2.303 (0.68), 2.323 (0.61), 2.327 (0.74), 2.332 (0.46), 2.518 (2.41), 2.523 (2.66), 2.539 (15.77), 2.665 (0.41), 2.669 (0.58), 2.673 (0.41), 3.029 (0.50), 3.047 (1.60), 3.061 (1.78), 3.065 (1.71), 3.079 (1.57), 3.097 (0.46), 3.365 (1.08), 3.370 (0.98), 3.387 (0.52), 3.433 (1.09), 3.459 (1.67), 3.477 (0.46), 3.485 (0.52), 3.499 (0.66), 3.506 (0.69), 3.529 (2.39), 3.554 (1.43), 4.155 (1.57), 4.173 (2.40), 4.190 (1.51), 6.179 (0.64), 6.193 (1.28), 6.207 (0.62), 7.710 (5.13), 7.981 (4.19), 7.986 (4.31), 8.525 (3.21), 8.530 (3.22).    Example 376 (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3'-cyclopropyl-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000599_0001
(Rac)-3'-Bromo-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (75.0 mg, 162 µmol) and di-µ-iodobis(tri-t- butylphosphino)dipalladium(I) (14.1 mg, 16.2 µmol) were stirred in toluene (500 µL) under argon. Then cycloproply zinc bromide (1.6 mL, 0.5 M in THF, 810 µmol) was added and stirrrred overnight at rt. Water, ethyl acetate and brine were added and stirred for 5 min. The reaction mixture was filtered, the layers were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were concentrated and purified by HPLC yielding 5.00 mg (95 % purity, 7 % yield) of the title compound. LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 426 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.173 (1.12), 0.186 (3.11), 0.195 (3.22), 0.209 (1.15), 0.696 (1.04), 0.742 (1.05), 0.762 (1.09), 0.781 (1.62), 0.790 (3.15), 0.795 (2.90), 0.804 (2.23), 0.811 (3.14), 0.816 (2.90), 0.825 (1.40), 0.850 (0.77), 1.013 (7.34), 1.031 (16.00), 1.049 (7.51), 1.137 (2.04), 1.151 (3.02), 1.205 (1.23), 1.231 (3.60), 1.265 (3.95), 1.296 (4.01), 1.797 (0.51), 1.809 (0.99), 1.816 (1.06), 1.829 (1.75), 1.843 (0.98), 1.850 (0.92), 1.863 (0.45), 2.035 (0.76), 2.052 (0.85), 2.067 (0.93), 2.083 (0.98), 2.386 (0.63), 2.409 (1.30), 2.440 (1.62), 2.454 (1.81), 2.463 (2.35), 2.472 (3.73), 2.518 (3.14), 2.522 (2.00), 3.032 (0.88), 3.050 (2.81), 3.064 (3.28), 3.068 (3.12), 3.082 (2.79), 3.100 (0.83), 3.378 (1.02), 3.464 (1.94), 3.490 (2.52), 3.561 (0.93), 3.581 (1.49), 3.616 (3.59), 3.642 (2.70), 4.155 (2.55), 4.172 (5.08), 4.189 (2.41), 6.170 (1.20), 6.184 (2.39), 6.198 (1.20), 7.697 (3.88), 8.126 (5.29), 8.130 (5.43), 8.651 (5.38), 8.656 (5.34), 12.009 (1.65).  Example 377 (rac)-2-{3-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000600_0001
Trifluoroacetic acid (1.5 mL, 19 mmol) was added to (rac)-2'-(3-[1-(4-cyanophenyl)-1H-pyrazol- 5-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (90.0 mg, 139 µmol) in dichloromethane (4.0 mL). It was stirred at rt overnight and the reaction mixture was made basic with aqueous sodium hydroxide solution (2.0 M) and concentrated. The residue was purified by HPLC to afford 15.0 mg (95 % purity, 20 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 519 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.016 (7.23), 1.035 (16.00), 1.052 (7.46), 1.237 (0.51), 1.254 (0.42), 2.038 (0.41), 2.051 (1.27), 2.065 (2.29), 2.083 (3.26), 2.101 (1.10), 2.113 (0.56), 2.332 (0.52), 2.518 (3.48), 2.522 (2.87), 2.530 (3.92), 2.547 (2.79), 2.673 (0.52), 3.040 (0.82), 3.057 (2.59), 3.071 (2.91), 3.075 (2.91), 3.089 (2.55), 3.107 (0.74), 3.419 (10.98), 3.494 (0.78), 3.513 (1.29), 3.520 (0.88), 3.527 (1.00), 3.533 (0.84), 3.552 (0.49), 4.177 (2.55), 4.195 (4.29), 4.212 (2.46), 6.159 (1.09), 6.172 (2.06), 6.186 (1.02), 6.306 (10.66), 6.744 (6.71), 6.749 (6.69), 6.951 (0.90), 7.079 (0.92), 7.207 (0.87), 7.518 (5.07), 7.524 (5.11), 7.566 (1.06), 7.572 (7.80), 7.577 (2.47), 7.589 (2.75), 7.594 (8.61), 7.599 (1.20), 7.696 (4.49), 7.701 (4.56), 7.841 (1.36), 7.846 (9.13), 7.851 (2.68), 7.863 (2.53), 7.868 (7.46), 7.874 (1.01), 7.896 (7.72), 7.900 (7.48), 8.685 (5.76), 8.690 (5.73), 12.121 (2.55), 12.127 (2.53).  The following examples were prepared similarly by deprotection using TFA.  Example 378 (rac)-2'-{3-[1-(cyclopropylmethyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000601_0001
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 472 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.135 (0.96), 0.147 (3.64), 0.150 (3.01), 0.158 (3.23), 0.162 (3.45), 0.173 (1.29), 0.353 (1.26), 0.364 (2.98), 0.368 (3.12), 0.373 (1.64), 0.379 (1.50), 0.384 (3.15), 0.389 (2.98), 0.399 (1.09), 0.833 (0.41), 0.850 (0.90), 1.003 (6.73), 1.010 (1.26), 1.021 (16.00), 1.028 (2.46), 1.039 (7.03), 1.046 (1.09), 1.112 (0.71), 1.115 (0.68), 1.119 (0.74), 1.124 (0.60), 1.132 (1.23), 1.140 (0.63), 1.144 (0.74), 1.149 (0.71), 1.152 (0.74), 1.164 (0.46), 1.169 (0.52), 1.231 (3.45), 2.050 (1.09), 2.066 (1.83), 2.073 (0.98), 2.083 (3.47), 2.103 (0.93), 2.115 (0.63), 2.518 (3.83), 2.522 (2.30), 2.534 (3.15), 2.537 (3.01), 2.553 (2.38), 2.568 (0.41), 2.729 (0.44), 2.887 (0.52), 3.022 (0.77), 3.039 (2.54), 3.053 (2.79), 3.057 (2.76), 3.071 (2.49), 3.089 (0.74), 3.363 (0.66), 3.380 (1.18), 3.388 (0.93), 3.399 (0.90), 3.406 (1.72), 3.424 (9.22), 3.437 (1.56), 3.492 (0.60), 3.506 (0.90), 3.511 (1.04), 3.518 (0.79), 3.525 (0.88), 3.532 (0.71), 3.537 (0.71), 3.551 (0.44), 4.055 (5.01), 4.072 (4.95), 4.191 (2.11), 4.209 (3.80), 4.226 (2.35), 4.653 (0.96), 5.758 (13.95), 6.144 (1.04), 6.157 (2.16), 6.171 (1.12), 6.457 (6.76), 6.462 (7.08), 6.579 (9.90), 6.615 (1.20), 7.551 (7.25), 7.555 (7.47), 7.717 (0.57), 7.724 (0.55), 7.760 (4.16), 7.767 (4.32), 8.066 (2.68), 8.111 (0.44), 8.115 (0.44), 8.182 (3.69), 8.186 (3.83), 8.725 (0.63), 8.730 (0.68), 8.738 (5.17), 8.743 (5.11), 12.124 (2.00), 12.129 (2.00).    Example 379 (rac)-2'-[3-(1,4-dimethyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000602_0002
LC-MS (Method 1): Rt = 0.84 min; MS (ESIpos): m/z = 445 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.000 (3.68), 1.018 (8.79), 1.036 (3.85), 1.943 (11.52), 2.044 (0.59), 2.057 (1.03), 2.076 (1.38), 2.094 (0.50), 2.518 (1.42), 2.523 (1.31), 2.526 (1.73), 2.530 (1.67), 2.539 (0.56), 2.546 (1.14), 2.727 (0.45), 2.888 (0.54), 3.019 (0.43), 3.036 (1.38), 3.050 (1.52), 3.054 (1.47), 3.068 (1.37), 3.086 (0.40), 3.373 (1.08), 3.380 (0.80), 3.392 (0.65), 3.399 (1.08), 3.418 (5.20), 3.508 (0.58), 3.515 (0.49), 3.521 (0.47), 3.544 (0.49), 3.691 (16.00), 4.182 (1.20), 4.200 (2.12), 4.217 (1.17), 6.138 (0.56), 6.152 (1.16), 6.165 (0.56), 6.585 (5.71), 7.371 (3.78), 7.715 (5.48), 8.003 (3.22), 8.008 (3.31), 8.739 (2.83), 8.744 (2.86).    Example 380 (rac)-N-ethyl-2'-{3-[1-(propan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin- 5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000602_0001
LC-MS (Method 1): Rt = 1.13 min; MS (ESIpos): m/z = 527 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.999 (7.10), 1.016 (16.00), 1.035 (7.21), 1.399 (15.03), 1.415 (15.08), 2.048 (1.17), 2.066 (1.87), 2.085 (2.11), 2.104 (0.93), 2.115 (0.63), 2.331 (1.97), 2.336 (0.86), 2.518 (10.28), 2.522 (6.38), 2.531 (3.68), 2.535 (3.54), 2.551 (2.32), 2.673 (1.93), 2.678 (0.84), 3.018 (0.87), 3.036 (2.79), 3.050 (3.06), 3.053 (3.03), 3.068 (2.71), 3.086 (0.86), 3.376 (3.70), 3.402 (2.77), 3.423 (10.08), 3.488 (0.86), 3.507 (1.24), 3.520 (1.01), 3.545 (0.55), 4.190 (2.37), 4.208 (4.08), 4.225 (2.28), 4.691 (0.48), 4.707 (1.31), 4.723 (1.81), 4.740 (1.30), 4.755 (0.48), 6.145 (1.15), 6.159 (2.34), 6.173 (1.10), 6.579 (9.11), 6.849 (5.94), 7.813 (9.49), 8.137 (5.59), 8.142 (5.69), 8.743 (4.38), 8.747 (4.29).    Example 381 (rac)-N-ethyl-2'-{3-[1-(2-methylpropyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000603_0001
LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 473 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.686 (15.84), 0.703 (16.00), 1.003 (4.99), 1.021 (11.71), 1.039 (5.23), 2.020 (0.53), 2.037 (1.04), 2.054 (1.35), 2.068 (1.61), 2.086 (1.68), 2.105 (0.74), 2.116 (0.45), 2.331 (1.44), 2.336 (0.64), 2.518 (7.74), 2.523 (4.59), 2.533 (2.45), 2.536 (2.42), 2.552 (1.65), 2.673 (1.45), 3.022 (0.58), 3.039 (1.87), 3.053 (2.09), 3.057 (2.01), 3.071 (1.85), 3.089 (0.56), 3.379 (1.01), 3.386 (0.74), 3.405 (1.34), 3.424 (7.23), 3.492 (0.48), 3.511 (0.78), 3.524 (0.61), 3.531 (0.52), 3.983 (3.78), 4.002 (3.72), 4.191 (1.65), 4.208 (2.90), 4.226 (1.60), 6.146 (0.79), 6.160 (1.58), 6.173 (0.77), 6.435 (4.98), 6.439 (5.05), 6.570 (7.51), 7.562 (5.40), 7.567 (5.19), 7.739 (3.18), 7.746 (3.29), 8.163 (2.90), 8.168 (2.99), 8.729 (3.92), 8.734 (3.76), 12.102 (1.55), 12.108 (1.60).    Example 382 (rac)-2'-[3-(2-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000604_0002
LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 452 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.003 (6.90), 1.021 (16.00), 1.039 (7.16), 2.054 (1.12), 2.072 (1.80), 2.091 (1.97), 2.109 (0.93), 2.121 (0.63), 2.336 (0.45), 2.518 (5.53), 2.522 (4.77), 2.537 (3.38), 2.556 (2.38), 2.659 (0.44), 3.021 (0.86), 3.039 (2.73), 3.053 (2.96), 3.057 (2.92), 3.070 (2.66), 3.088 (0.80), 3.385 (2.28), 3.392 (1.71), 3.404 (1.38), 3.410 (2.27), 3.429 (10.34), 3.489 (0.78), 3.508 (1.19), 3.514 (0.85), 3.521 (0.96), 3.528 (0.79), 3.533 (0.74), 3.547 (0.49), 4.198 (2.33), 4.215 (3.98), 4.232 (2.26), 6.148 (1.09), 6.162 (2.24), 6.175 (1.10), 6.568 (9.30), 7.469 (1.03), 7.474 (1.12), 7.491 (1.71), 7.506 (1.17), 7.511 (1.24), 7.767 (1.08), 7.783 (3.63), 7.787 (5.52), 7.804 (2.03), 7.807 (2.17), 7.824 (0.67), 7.827 (0.67), 7.932 (11.26), 7.947 (2.41), 8.315 (5.65), 8.320 (5.83), 8.731 (4.46), 8.736 (4.44).    Example 383 (rac)-2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000604_0001
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 510 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (3.88), 1.026 (9.17), 1.044 (4.04), 1.305 (0.61), 1.319 (0.59), 1.350 (15.86), 1.365 (16.00), 2.066 (0.58), 2.084 (0.99), 2.103 (1.04), 2.121 (0.49), 2.518 (4.57), 2.522 (3.00), 2.534 (1.25), 2.554 (1.72), 2.570 (1.17), 2.673 (0.98), 2.678 (0.43), 3.027 (0.44), 3.045 (1.42), 3.060 (1.56), 3.063 (1.52), 3.077 (1.39), 3.095 (0.40), 3.403 (0.63), 3.410 (0.52), 3.429 (1.00), 3.442 (4.95), 3.521 (0.58), 3.534 (0.45), 4.218 (1.19), 4.236 (2.01), 4.253 (1.15), 4.551 (0.67), 4.816 (0.83), 4.831 (1.14), 4.846 (0.87), 6.157 (0.60), 6.171 (1.21), 6.185 (0.59), 6.624 (5.43), 7.369 (1.67), 7.390 (1.82), 7.923 (4.24), 7.986 (1.14), 7.993 (1.56), 8.009 (0.75), 8.014 (1.94), 8.021 (3.13), 8.026 (1.82), 8.501 (2.84), 8.506 (2.93), 8.705 (2.96), 8.710 (2.73), 11.986 (0.77).    Example 384 (rac)-N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000605_0001
LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 494 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (4.72), 1.048 (10.69), 1.066 (4.92), 2.052 (0.77), 2.068 (1.32), 2.074 (4.97), 2.094 (0.72), 2.332 (1.10), 2.336 (0.48), 2.518 (6.55), 2.522 (3.84), 2.534 (2.61), 2.552 (1.71), 2.673 (1.15), 2.678 (0.51), 3.058 (0.60), 3.076 (1.83), 3.090 (2.04), 3.093 (1.96), 3.108 (1.82), 3.126 (0.55), 3.388 (1.48), 3.413 (3.45), 3.425 (3.54), 3.434 (1.51), 3.450 (1.29), 3.492 (0.52), 3.511 (0.95), 3.518 (0.54), 3.526 (0.60), 3.535 (0.60), 4.171 (1.60), 4.188 (2.52), 4.206 (1.54), 6.192 (0.73), 6.206 (1.51), 6.220 (0.77), 6.237 (6.70), 6.679 (3.55), 6.683 (3.59), 7.307 (0.89), 7.317 (7.20), 7.324 (0.95), 7.328 (0.85), 7.329 (0.86), 7.336 (0.97), 7.342 (0.94), 7.378 (1.08), 7.383 (0.71), 7.392 (16.00), 7.400 (4.93), 7.405 (3.88), 7.686 (3.95), 7.691 (4.01), 7.774 (4.62), 7.778 (4.43), 8.633 (3.01), 8.638 (2.94).    Example 385 (rac)-N-ethyl-2'-[3-(1-ethyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000606_0002
LC-MS (Method 1): Rt = 0.84 min; MS (ESIpos): m/z = 446 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.006 (6.69), 1.024 (16.00), 1.042 (7.10), 1.294 (6.26), 1.312 (15.68), 1.330 (6.57), 2.054 (1.08), 2.070 (1.81), 2.089 (2.16), 2.107 (0.91), 2.119 (0.61), 2.338 (0.49), 2.520 (10.41), 2.524 (6.50), 2.536 (3.67), 2.540 (3.58), 2.556 (2.24), 2.680 (0.49), 3.024 (0.79), 3.042 (2.56), 3.056 (2.77), 3.059 (2.83), 3.074 (2.50), 3.092 (0.76), 3.365 (1.17), 3.383 (1.36), 3.391 (1.05), 3.409 (1.83), 3.428 (9.68), 3.496 (0.64), 3.515 (1.09), 3.521 (0.77), 3.528 (0.86), 3.535 (0.70), 3.540 (0.70), 3.554 (0.44), 4.163 (1.59), 4.180 (5.27), 4.198 (6.52), 4.214 (4.51), 4.231 (2.29), 6.146 (1.04), 6.160 (2.16), 6.174 (1.08), 6.454 (7.03), 6.459 (6.88), 6.584 (10.43), 7.557 (7.29), 7.562 (6.88), 7.753 (9.91), 8.193 (5.78), 8.198 (6.00), 8.739 (5.21), 8.744 (5.30).    Example 386 (rac)-2'-[3-(1-cyclopropyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000606_0001
LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 457 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.005 (0.78), 0.957 (0.79), 0.965 (0.80), 0.977 (3.39), 0.989 (3.18), 0.995 (3.31), 1.006 (8.20), 1.025 (16.00), 1.036 (2.59), 1.043 (10.05), 1.052 (3.88), 1.065 (1.21), 1.075 (0.83), 1.224 (0.42), 1.753 (0.84), 2.044 (0.49), 2.057 (1.38), 2.074 (2.30), 2.082 (1.27), 2.093 (2.44), 2.112 (1.14), 2.125 (0.76), 2.523 (2.82), 2.541 (4.27), 2.559 (2.79), 3.026 (1.02), 3.044 (3.18), 3.058 (3.64), 3.062 (3.55), 3.076 (3.14), 3.093 (1.01), 3.166 (2.94), 3.369 (2.95), 3.388 (3.30), 3.395 (2.79), 3.407 (2.35), 3.414 (3.28), 3.435 (12.36), 3.502 (1.14), 3.516 (1.33), 3.521 (1.60), 3.528 (1.25), 3.534 (1.33), 3.540 (1.13), 3.546 (1.06), 3.559 (0.74), 3.742 (0.67), 3.751 (1.31), 3.759 (1.77), 3.769 (2.27), 3.778 (1.43), 3.787 (1.25), 3.796 (0.62), 4.203 (2.78), 4.220 (4.93), 4.238 (2.76), 6.157 (1.39), 6.171 (2.84), 6.185 (1.43), 6.563 (5.95), 6.567 (6.12), 6.606 (10.07), 7.471 (6.21), 7.476 (6.09), 7.947 (10.51), 8.322 (5.77), 8.327 (6.00), 8.746 (5.73), 8.751 (5.56).  Example 387 (rac)-N-ethyl-2'-{3-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000607_0001
(Rac)-N-Ethyl-2'-(3-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (85.0 mg, 141 µmol) was dissolved in DMF (2.0 mL). Tetra-n-butylammonium fluoride (560 µL, 1.0 M in THF, 560 µmol) and ethylendiamine (39 µL, 580 µmol) were added. It was stirred at 60 °C overnight, the reaction mixture was allowed to reach rt and water was added. It was extracted with dichloromethane/methanol 9:1 and once with ethyl acetate. The combined organic phases were dried, concentrated and purified by HPLC to give 13.0 mg (88 % purity, 17 % yield) of the title compound. LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 474 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.003 (7.07), 1.008 (1.71), 1.021 (16.00), 1.026 (3.19), 1.039 (7.24), 1.044 (1.46), 1.751 (1.44), 2.038 (0.44), 2.051 (1.26), 2.067 (2.09), 2.084 (2.50), 2.097 (0.86), 2.104 (1.05), 2.116 (0.77), 2.331 (0.52), 2.518 (4.55), 2.522 (3.08), 2.534 (3.64), 2.538 (3.88), 2.554 (2.54), 2.673 (0.52), 3.021 (0.88), 3.039 (2.84), 3.053 (3.16), 3.057 (3.19), 3.071 (2.75), 3.088 (0.83), 3.362 (0.80), 3.381 (1.38), 3.387 (1.18), 3.406 (2.03), 3.425 (10.41), 3.492 (0.75), 3.510 (1.26), 3.523 (1.00), 3.530 (0.83), 3.535 (0.80), 3.549 (0.49), 4.194 (2.56), 4.212 (4.47), 4.229 (2.50), 4.858 (3.06), 4.875 (4.73), 4.877 (4.37), 4.894 (3.83), 4.990 (3.94), 5.005 (7.18), 5.021 (3.27), 5.667 (0.49), 5.683 (1.22), 5.702 (1.99), 5.720 (1.13), 6.147 (1.21), 6.160 (2.45), 6.174 (1.27), 6.447 (0.41), 6.451 (0.41), 6.500 (1.59), 6.533 (6.58), 6.538 (6.58), 6.577 (10.27), 7.459 (0.41), 7.715 (8.54), 7.739 (5.67), 7.743 (5.53), 8.139 (5.75), 8.144 (5.89), 8.251 (0.61), 8.256 (0.63), 8.635 (0.77), 8.640 (0.77), 8.748 (5.56), 8.753 (5.54).    Example 388 (rac)-3'-cyclopropyl-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000608_0001
(Rac)-3'-Cyclopropyl-N-ethyl-2'-[3-methyl-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (4.00 mg, 7.16 µmol) was dissolved in methanol (500 µL). Sodium hydroxide (1.43 mg, 35.8 µmol) was added and stirred at rt overnight. The reaction mixture was concentrated. Water was added and extracted twice with ethyl acetate. The combined organic layers were dried and concentrated giving 2.00 mg (90 % purity, 62 % yield) of the title compound.  LC-MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 406 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.156 (0.90), 0.169 (2.39), 0.178 (2.45), 0.191 (0.99), 0.765 (0.82), 0.774 (2.28), 0.779 (2.07), 0.787 (1.49), 0.794 (2.27), 0.799 (2.10), 0.808 (0.82), 0.851 (0.52), 1.014 (6.75), 1.031 (16.00), 1.049 (6.96), 1.232 (1.68), 1.256 (0.65), 1.266 (0.84), 1.297 (0.86), 1.587 (5.87), 1.775 (0.40), 1.789 (0.80), 1.796 (0.85), 1.802 (0.57), 1.810 (1.49), 1.817 (0.60), 1.822 (0.78), 1.830 (0.77), 2.030 (0.59), 2.042 (0.66), 2.061 (0.73), 2.073 (0.73), 2.265 (15.20), 2.268 (15.69), 2.285 (0.45), 2.383 (0.45), 2.406 (1.01), 2.414 (0.73), 2.429 (0.85), 2.435 (1.14), 2.448 (1.37), 2.459 (1.70), 2.465 (2.81), 2.475 (3.08), 2.518 (7.69), 2.523 (6.68), 2.537 (8.28), 2.539 (7.79), 3.032 (0.81), 3.050 (2.51), 3.064 (2.89), 3.068 (2.70), 3.083 (2.46), 3.100 (0.73), 3.436 (0.85), 3.459 (1.76), 3.485 (2.18), 3.561 (0.79), 3.581 (1.22), 3.602 (0.71), 3.614 (2.96), 3.639 (2.24), 4.138 (2.20), 4.155 (4.39), 4.173 (2.12), 6.172 (1.14), 6.186 (2.08), 6.200 (0.99), 6.614 (0.43), 7.226 (2.79), 7.228 (2.81), 8.109 (3.88), 8.113 (3.99), 8.511 (5.05), 8.516 (4.93), 11.305 (1.90).    Example 389 (rac)-3'-bromo-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000609_0001
(Ras)-3'-Bromo-N-ethyl-2'-[3-methyl-1-(4-methylbenzene-1-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5- yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (65.0 mg, 109 µmol) was dissolved in methanol (2.0 mL). Sodium hydroxide (21.8 mg, 544 µmol) was added and stirred at rt overnight. The reaction mixture was purified by HPLC obtaining 10.0 mg (93 % purity, 19 % yield) of the title compound. LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 443 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.004 (4.32), 1.009 (6.54), 1.026 (15.16), 1.044 (6.75), 1.592 (0.64), 1.752 (2.70), 2.012 (0.41), 2.066 (0.58), 2.081 (0.65), 2.096 (0.76), 2.110 (0.74), 2.271 (15.43), 2.273 (16.00), 2.322 (0.77), 2.326 (0.56), 2.344 (1.07), 2.351 (0.70), 2.368 (0.79), 2.376 (0.87), 2.398 (0.47), 2.518 (1.24), 2.523 (0.98), 2.539 (1.33), 2.548 (1.30), 2.556 (2.52), 2.565 (2.49), 2.572 (2.25), 2.581 (1.43), 2.728 (2.56), 2.887 (3.21), 3.028 (0.82), 3.046 (2.62), 3.060 (2.82), 3.063 (2.80), 3.077 (2.53), 3.095 (0.76), 3.305 (0.70), 3.322 (1.39), 3.331 (2.73), 3.371 (1.10), 3.476 (1.68), 3.501 (2.31), 3.544 (0.70), 3.549 (0.79), 3.570 (1.32), 3.590 (0.69), 3.614 (3.28), 3.640 (2.47), 4.243 (2.05), 4.261 (4.06), 4.279 (2.06), 6.211 (1.05), 6.225 (2.07), 6.238 (1.00), 7.280 (4.23), 7.283 (4.25), 8.187 (6.12), 8.192 (6.33), 8.531 (1.62), 8.544 (5.12), 8.549 (5.00).  The following examples were prepared similarly.  Example 390 (rac)-2'-[3-(2,5-dihydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000610_0001
  Example 391 (rac)-2'-[3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000610_0002
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.124 (2.61), -0.101 (0.61), 0.854 (0.53), 0.919 (0.72), 0.934 (5.53), 0.937 (1.80), 0.951 (5.71), 0.955 (0.93), 1.011 (3.24), 1.029 (7.72), 1.047 (3.74), 1.055 (0.49), 1.234 (2.70), 1.250 (1.02), 1.258 (0.61), 1.268 (0.64), 1.281 (0.67), 1.351 (0.68), 1.387 (0.56), 1.719 (4.52), 2.065 (0.57), 2.079 (0.96), 2.087 (0.73), 2.098 (1.16), 2.117 (0.45), 2.339 (0.60), 2.407 (0.62), 2.425 (0.64), 2.521 (6.68), 2.526 (4.87), 2.543 (6.12), 2.546 (1.75), 2.566 (1.10), 2.681 (0.59), 2.960 (0.51), 3.030 (0.44), 3.047 (1.32), 3.061 (1.44), 3.065 (1.41), 3.079 (1.31), 3.097 (0.43), 3.167 (16.00), 3.399 (1.92), 3.424 (1.57), 3.440 (4.87), 3.506 (0.53), 3.524 (0.68), 3.538 (0.54), 3.568 (1.16), 3.842 (1.19), 3.856 (2.49), 3.869 (1.12), 4.112 (0.46), 4.207 (1.13), 4.225 (1.92), 4.242 (1.07), 4.287 (1.83), 4.293 (1.83), 6.163 (0.51), 6.177 (1.03), 6.191 (0.49), 6.263 (1.08), 6.605 (4.90), 7.550 (1.55), 7.556 (1.52), 8.480 (1.68), 8.484 (1.76), 8.664 (2.47), 8.669 (2.32), 11.738 (0.92), 11.743 (0.91).  Example 392 (rac)-N-ethyl-2'-{6-[2-(methylamino)-2-oxoethoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000611_0001
({3-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl}oxy)acetic acid (30.0 mg, 68.9 µmol) was dissolved in DMF (0.50 mL). Methylamine (69 µL, 2.0 M in THF, 140 µmol), N,N-diisopropylethylamine (24 µL, 140 µmol) and T3P (87.7 mg, 50 % purity in DMF, 138 µmol) were added and stirred at rt overnight. Two equivalents of methylamine and T3P were added and stirred for 4 h at rt. Two equivalents of methylamine, N,N-diisopropylethylamine, and T3P were added and stirred for 4 h at rt. The reaction mixture was filtered and purified by HPLC affording 15.0 mg (95 % purity, 46 % yield) of the title compound.  LC-MS (Method 1): Rt = 0.77 min; MS (ESIpos): m/z = 449 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.017 (6.97), 1.035 (16.00), 1.053 (7.07), 2.086 (1.08), 2.100 (2.08), 2.119 (2.48), 2.137 (0.94), 2.149 (0.52), 2.325 (0.61), 2.330 (0.84), 2.334 (0.64), 2.521 (3.07), 2.526 (1.98), 2.561 (2.32), 2.578 (3.56), 2.596 (2.52), 2.667 (0.72), 2.672 (1.09), 2.682 (11.16), 2.693 (10.76), 2.878 (0.89), 3.037 (0.81), 3.055 (3.20), 3.069 (2.92), 3.072 (2.79), 3.087 (2.56), 3.104 (0.74), 3.396 (0.55), 3.414 (1.19), 3.421 (0.98), 3.431 (0.93), 3.439 (1.85), 3.456 (8.99), 3.503 (0.70), 3.522 (1.16), 3.529 (0.76), 3.536 (0.88), 3.543 (0.71), 3.561 (0.57), 4.258 (2.32), 4.276 (3.65), 4.293 (2.26), 4.614 (10.49), 6.171 (1.06), 6.185 (2.16), 6.199 (1.05), 6.705 (10.09), 7.354 (3.40), 7.361 (3.94), 7.434 (2.82), 7.442 (2.37), 7.458 (2.88), 7.465 (2.67), 7.930 (3.66), 7.952 (3.29), 8.154 (1.16), 8.164 (1.16), 8.534 (3.34), 8.540 (3.45), 9.194 (5.85), 9.199 (5.59). The following examples were prepared similalrly.    Example 393 (rac)-2-[6-(2-amino-2-oxoethoxy)quinolin-3-yl]-N-ethyl-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000612_0001
LC-MS (Method 1): Rt = 0.69 min; MS (ESIpos): m/z = 435 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.842 (0.44), 0.896 (0.81), 0.913 (1.26), 0.932 (0.64), 1.017 (7.14), 1.035 (16.00), 1.053 (7.21), 1.269 (0.74), 1.455 (0.58), 1.465 (0.71), 2.086 (1.13), 2.099 (2.12), 2.118 (2.56), 2.136 (0.95), 2.148 (0.53), 2.521 (1.52), 2.526 (1.07), 2.560 (2.36), 2.577 (3.55), 2.595 (2.49), 3.037 (0.75), 3.056 (2.57), 3.069 (2.54), 3.073 (2.43), 3.087 (2.17), 3.104 (0.67), 3.395 (0.92), 3.413 (1.71), 3.421 (1.53), 3.431 (1.61), 3.438 (2.52), 3.456 (10.15), 3.482 (1.22), 3.504 (1.60), 3.523 (1.98), 3.529 (1.55), 3.536 (1.58), 3.544 (1.41), 3.562 (1.00), 4.258 (2.40), 4.276 (3.79), 4.292 (2.34), 4.576 (12.11), 6.174 (0.88), 6.188 (1.68), 6.201 (0.87), 6.709 (10.38), 7.337 (3.51), 7.344 (3.96), 7.432 (3.03), 7.439 (2.55), 7.455 (3.12), 7.462 (3.04), 7.478 (1.78), 7.667 (1.75), 7.921 (3.73), 7.944 (3.36), 8.532 (3.40), 8.537 (3.51), 9.192 (5.86), 9.197 (5.64).    Example 394 (rac)-N-ethyl-2'-(6-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000612_0002
LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 517 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.018 (6.90), 1.035 (16.00), 1.053 (7.17), 2.086 (1.10), 2.103 (1.97), 2.122 (2.16), 2.140 (0.96), 2.152 (0.59), 2.521 (1.73), 2.526 (1.11), 2.561 (2.34), 2.579 (3.63), 2.596 (2.50), 3.038 (0.82), 3.056 (2.61), 3.070 (2.92), 3.073 (2.85), 3.087 (2.57), 3.105 (0.77), 3.395 (0.63), 3.414 (1.24), 3.421 (1.00), 3.432 (1.14), 3.439 (1.84), 3.458 (8.25), 3.485 (0.47), 3.505 (0.71), 3.524 (1.19), 3.531 (0.79), 3.538 (0.90), 3.545 (0.74), 3.549 (0.72), 3.564 (0.44), 3.949 (0.67), 3.965 (0.83), 3.973 (1.97), 3.989 (2.15), 3.997 (2.01), 4.013 (1.94), 4.038 (0.59), 4.260 (2.38), 4.278 (3.80), 4.295 (2.32), 4.757 (11.16), 6.173 (1.10), 6.187 (2.22), 6.201 (1.10), 6.705 (10.20), 7.346 (3.56), 7.353 (4.00), 7.448 (2.91), 7.455 (2.42), 7.470 (2.90), 7.477 (2.67), 7.937 (3.77), 7.960 (3.40), 8.508 (3.58), 8.514 (3.65), 8.883 (1.04), 8.899 (2.15), 8.915 (1.01), 9.199 (5.63), 9.204 (5.73).    Example 395 (rac)-N-ethyl-2'-{6-[2-(morpholin-4-yl)-2-oxoethoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000613_0001
LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 505 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.017 (6.70), 1.035 (16.00), 1.052 (7.11), 2.086 (1.01), 2.100 (1.92), 2.119 (2.32), 2.137 (0.88), 2.149 (0.50), 2.521 (1.32), 2.526 (0.88), 2.561 (2.16), 2.578 (3.25), 2.596 (2.29), 3.037 (0.79), 3.054 (2.47), 3.069 (2.72), 3.072 (2.61), 3.087 (2.40), 3.105 (0.70), 3.395 (0.50), 3.413 (1.14), 3.420 (0.92), 3.431 (0.96), 3.439 (1.76), 3.457 (8.85), 3.479 (2.47), 3.490 (2.19), 3.504 (1.60), 3.522 (3.24), 3.536 (2.53), 3.562 (0.56), 3.586 (1.82), 3.597 (2.28), 3.652 (1.94), 3.662 (2.22), 4.256 (2.20), 4.274 (3.41), 4.290 (2.11), 4.996 (9.23), 6.172 (1.04), 6.186 (2.09), 6.200 (1.00), 6.702 (10.77), 7.337 (3.14), 7.344 (3.86), 7.387 (3.01), 7.395 (2.15), 7.410 (2.89), 7.418 (2.44), 7.902 (3.56), 7.925 (3.21), 8.517 (3.32), 8.522 (3.36), 9.182 (5.94), 9.187 (5.60).    Example 396 (rac)-2'-{6-[2-(dimethylamino)-2-oxoethoxy]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide  N N N C H O 3 H N N N CH H C O 3 3 O LC-MS (Method 1): Rt = 0.76 min; MS (ESIpos): m/z = 463 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.016 (4.21), 1.034 (9.99), 1.052 (4.36), 2.084 (0.63), 2.098 (1.19), 2.116 (1.50), 2.134 (0.56), 2.521 (0.88), 2.525 (0.57), 2.560 (1.37), 2.568 (0.56), 2.578 (2.09), 2.595 (1.58), 2.878 (12.55), 3.037 (0.60), 3.056 (16.00), 3.068 (1.89), 3.072 (1.71), 3.086 (1.51), 3.104 (0.44), 3.413 (0.69), 3.421 (0.56), 3.432 (0.49), 3.439 (1.09), 3.455 (5.37), 3.503 (0.40), 3.521 (0.69), 3.528 (0.43), 3.536 (0.49), 3.543 (0.41), 3.547 (0.41), 4.254 (1.40), 4.272 (2.15), 4.289 (1.34), 4.965 (5.77), 6.171 (0.64), 6.184 (1.28), 6.198 (0.62), 6.700 (6.69), 7.318 (2.04), 7.325 (2.42), 7.381 (1.83), 7.388 (1.49), 7.404 (1.85), 7.411 (1.68), 7.894 (2.25), 7.917 (2.03), 8.518 (2.03), 8.523 (2.08), 9.178 (3.69), 9.183 (3.52).    Example 397 (rac)-N-benzyl-N'-cyano-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboximidamide 
Figure imgf000614_0001
Phenyl (rac)-N-cyano-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboximidate (100 mg, 230 µmol) was dissolved in 2-propanol (2.4 mL). 1- Phenylmethanamine (250 µL, 2.3 mmol) was added and stirred at 80 °C for 3 h. The reaction mixture was allowed to reach rt and concentrated. The residue was purified by HPLC to obtain 10.3 mg (99 % purity, 10 % yield) of the title compound.   Example 398 (rac)-N-(oxetan-3-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide 
Figure imgf000615_0001
4-Nitrophenyl (rac)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate (50.0 mg, 106 µmol) and oxetan-3-amine (37 µL, 530 µmol) were dissolved in DMSO. N,N-diisopropylethylamine (45 µL, 320 µmol) was added and the reaction mixture was stirred at 70 °C overnight. The raection mixture was allowed to reach rt, water was added and extracted three times with ethyl acetate. The combined organic layers were washed with brine, filtered through a silicone filter and concentrated. The residue was purified by HPLC to give 10.6 mg (90 % purity, 22 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 404 [M+H]+ 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.77 - 1.90 (m, 2H), 1.98 - 2.15 (m, 3H), 2.20 (dt, 1H), 3.42 - 3.51 (m, 3H), 3.55 - 3.60 (m, 1H), 4.19 (t, 2H), 4.50 (q, 2H), 4.64 - 4.79 (m, 3H), 6.83 - 6.89 (m, 2H), 7.61 (ddd, 1H), 7.73 (ddd, 1H), 7.98 - 8.04 (m, 2H), 8.65 (d, 1H), 9.34 (d, 1H).    Example 399 (rac)-1-(propane-2-sulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] 
Figure imgf000615_0002
Under argon at 0 C N,N-diisopropylethylamine (96 µL, 550 µmol) was added to a suspension of (rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]—hydrogen chloride (1/1) (50.0 mg, 153 µmol) in dichloromethane (3.0 mL). Then propane-2-sulfonyl chloride (26.2 mg, 184 µmol) was added and the reaction mixture was stirred overnight at rt. Water was added and extracted twice with ethyl acetate. The combined organic phases were concentrated and purified by HPLC to afford 2.90 mg (95 % purity, 5 % yield) of the title compound. LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 397 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.697 (0.49), 1.232 (1.17), 1.277 (2.66), 1.278 (2.71), 1.293 (2.88), 1.295 (2.83), 2.073 (3.90), 2.212 (0.45), 2.322 (0.80), 2.327 (1.14), 2.332 (0.82), 2.518 (4.25), 2.523 (2.84), 2.665 (0.93), 2.669 (1.22), 2.673 (0.86), 2.678 (0.42), 3.158 (16.00), 3.171 (14.54), 3.291 (0.49), 3.373 (0.69), 3.387 (0.54), 3.460 (0.46), 3.518 (0.96), 3.530 (0.89), 4.090 (1.29), 4.104 (3.75), 4.117 (3.35), 4.130 (1.08), 4.288 (0.42), 4.297 (0.42), 5.756 (1.25), 6.805 (1.93), 7.615 (0.44), 7.731 (0.46), 7.999 (0.48), 8.016 (0.54), 8.647 (0.57), 8.652 (0.57), 9.344 (0.90), 9.350 (0.85).    Example 400 (rac)-2'-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000616_0001
To aluminum trichloride (95.1 mg, 713 µmol) in dichloromethane (5.0 mL) (rac)-N-ethyl-2'-(1H- pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (50.0 mg, 143 µmol) was added and stirred for 45 min at rt. Then benzoyl chloride (83 µL, 710 µmol) was added dropwise and the reaction mixture was stirred 3 h at rt. The temperature was raised to 50 °C and benzoyl chloride (83 µL, 710 µmol) was added. It was stirred for 3 h at 50 °C, Then benzoyl chloride (83 µL, 710 µmol) was added and it was stirred for 3 h at 50 °C. The reaction mixture was cooled down and at 0°C methanol was added. The pH was adjusted to 4 with sodium hydroxide (1.0 M in water) and extracted with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by HPLC to obtain 11.8 mg (95 % purity, 17 % yield) of the title compound.    Example 401 (rac)-N-ethyl-2'-{3-[(rac)-hydroxy(phenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of steroisomers) 
Figure imgf000617_0001
(3Rac)-N-Ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 143 µmol) and benzaldehyde (16 µL, 160 µmol) were dissolved in methanol (15 mL). Under argon potassium hydroxide (160 mg, 2.85 mmol) was added and stirred for 4 h at rt. Benzaldehyde (29 µl, 290 µmol) was added and stirred for 2 h at rt. The reaction mixture was concentrated and purified by HPLC obtaining 3.30 mg (95 % purity, 5 % yield) of the title compound.   Example 402 (rac)-2'-{3-[2-(dimethylphosphoryl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000617_0002
(Rac)-2'-{3-[(E)-2-(Dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (20.0 mg, 44.2 µmol) was dissolved in methanol (1.0 mL) and palladium on charcoal (4.70 mg, 10 % purity, 4.42 µmol) was added. The reaction mixture was stirred for 4 h at rt under an atmosphere of hydrogen. The reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated and purified by HPLC affording 17.0 mg (95 % purity, 80 % yield) of the title compound. LC-MS (Method 1): Rt = 0.65 min; MS (ESIpos): m/z = 455 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (4.76), 1.026 (11.01), 1.044 (4.89), 1.231 (0.43), 1.255 (0.48), 1.331 (0.72), 1.387 (16.00), 1.403 (0.56), 1.420 (15.98), 1.435 (0.41), 1.508 (0.60), 1.541 (0.61), 2.033 (0.90), 2.047 (0.91), 2.055 (1.13), 2.062 (1.95), 2.076 (2.72), 2.094 (2.02), 2.105 (1.24), 2.112 (0.73), 2.125 (0.43), 2.518 (1.87), 2.523 (1.47), 2.527 (1.58), 2.546 (2.32), 2.563 (1.62), 2.900 (0.73), 2.913 (0.60), 2.921 (1.33), 2.942 (1.25), 2.964 (0.67), 3.027 (0.53), 3.044 (1.59), 3.058 (1.80), 3.062 (1.75), 3.076 (1.53), 3.095 (0.53), 3.395 (1.41), 3.402 (1.13), 3.414 (0.95), 3.421 (1.58), 3.434 (6.32), 3.496 (0.52), 3.515 (0.80), 3.521 (0.58), 3.528 (0.64), 3.535 (0.54), 3.540 (0.52), 4.198 (1.54), 4.216 (2.57), 4.233 (1.52), 6.165 (0.65), 6.178 (1.20), 6.192 (0.62), 6.534 (6.60), 7.310 (1.98), 7.316 (1.96), 8.280 (2.48), 8.285 (2.53), 8.627 (3.25), 8.632 (3.22), 11.390 (1.45), 11.395 (1.45).    Example 403 ethyl (rac)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate 
Figure imgf000618_0001
Trifluoroacetic acid—(rac)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) (85.0 mg, 90 % purity, 153 µmol) was suspended in THF (430 µL) and pyridine (430 µL, 5.3 mmol) was added. Then at 0 °C ethyl carbonochloridate (15 µL, 160 µmol) was added slowly and stirred for 1 h at 0 °C. The reaction mixture was concentrated and purified by HPLC and preparative TLC to yield 12.0 mg (95 % purity, 16 % yield) of the title compound.  LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 460 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.47), 1.149 (1.56), 1.167 (3.15), 1.185 (1.84), 1.198 (1.73), 1.216 (3.28), 1.233 (3.19), 1.370 (16.00), 1.387 (15.99), 1.410 (0.40), 1.907 (0.74), 2.066 (0.84), 2.077 (1.05), 2.094 (1.06), 2.112 (0.82), 2.518 (2.48), 2.522 (1.70), 2.539 (3.08), 2.560 (1.41), 2.570 (1.41), 3.369 (0.43), 3.450 (0.49), 3.484 (3.71), 3.559 (0.47), 3.575 (0.88), 3.585 (0.54), 3.592 (0.64), 3.601 (0.60), 4.027 (1.06), 4.042 (1.26), 4.058 (1.59), 4.075 (1.35), 4.093 (0.43), 4.188 (1.05), 4.196 (1.02), 4.206 (1.90), 4.213 (1.51), 4.223 (1.19), 4.231 (0.81), 4.608 (1.02), 4.624 (1.37), 4.640 (1.00), 4.656 (0.50), 5.758 (5.37), 6.388 (4.76), 6.392 (4.76), 6.595 (2.57), 6.599 (2.69), 7.577 (3.64), 7.581 (3.64), 7.692 (3.24), 7.699 (3.28), 8.066 (0.66), 8.146 (3.04), 8.150 (3.10), 8.746 (2.47), 12.140 (1.56), 12.145 (1.59).    Example 404 (rac)-2'-[3-(ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000619_0001
{5-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl]-3- [(piperidin-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-1-yl}methyl ethylcarbamate (38.0 mg, 69.3 µmol) was dissolved in ethanol (500 µL) and sodium ethoxide (5.66 mg, 83.1 µmol) was added and the reaction mixture was stirred at 60 °C for 4 h. Then sodium ethoxide (7.07 mg, 104 µmol) was added and stirred for 2 h at 80 °C and over the weekend at 100 °C. The reaction mixture was allowed to reach rt and saturated aqueous ammonium chloride solution was added. It was extracted with ethyl acetate and the combined organic layers were filtered through a hydrophobic filter, concentrated and purified by HPLC obtaining 500 µg (95 % purity, 2 % yield) of the title compound. ¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 2.544 (16.00).    Example 405 (rac)-2'-{3-[(dimethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000620_0002
Acetic acid (1.3 mL, 23 mmol), formaldehyde (12 µL, 37 % in water, 160 µmol), and water (670 µL) were dissolved in dioxane (1.3 mL). At 0 °C dimethylamine (20 µL, 40 % in water, 160 µmol) was added and (rac)-N-ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (50.0 mg, 143 µmol) in dioxane (1.3 mL) was added dropwise. It was stirred for 2 h at 0 °C and at rt overnight. Formaldehyde (53 µL, 37 % in water, 710 µmol) and dimethylamine (90 µL, 40 % in water, 710 µmol) were added and stirred overnight at rt. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried through a hydrophobic filter, concentrated and purified by HPLC affording 4.00 mg (95 % purity, 7 % yield) of the title compound.  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (5.56), 1.013 (2.00), 1.031 (4.63), 1.048 (2.08), 2.105 (0.57), 2.135 (0.41), 2.153 (10.80), 2.521 (0.90), 2.526 (1.05), 2.542 (16.00), 2.563 (0.76), 3.049 (0.83), 3.063 (0.91), 3.066 (0.89), 3.080 (0.80), 3.391 (0.41), 3.416 (0.57), 3.436 (2.93), 3.519 (0.43), 3.535 (2.64), 4.201 (0.76), 4.219 (1.27), 4.236 (0.72), 6.173 (0.68), 6.496 (3.09), 7.335 (1.07), 7.341 (1.05), 8.301 (1.24), 8.305 (1.27), 8.611 (1.58), 8.616 (1.51), 11.459 (0.68), 11.463 (0.68).    Example 406 (rac)-N-ethyl-2'-{3-[1-(trifluoromethyl)cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000620_0001
{5-[(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl]-3-[1- (trifluoromethyl)cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-1-yl}methyl ethylcarbamate (5.00 mg, 8.94 µmol) was dissolved in ethanol (500 µL) and lithium hydroxide (2.57 mg, 107 µmol) and water (100 µL) were added. The reaction mixture was stirred for 1 h at 50 °C. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter, concentrated and purified by HPLC yielding 1.00 mg (95 % purity, 23 % yield) of the title compound.   ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.42), 0.000 (15.53), 0.008 (0.47), 0.835 (1.61), 0.853 (3.01), 0.867 (1.40), 1.013 (6.13), 1.031 (13.71), 1.049 (6.39), 1.115 (3.64), 1.229 (15.95), 1.336 (0.99), 1.350 (16.00), 1.370 (4.31), 1.375 (4.00), 1.387 (1.71), 1.512 (0.42), 1.580 (15.12), 2.049 (0.47), 2.061 (1.04), 2.075 (1.09), 2.092 (1.25), 2.110 (1.56), 2.127 (0.83), 2.139 (0.68), 2.339 (0.99), 2.521 (12.10), 2.525 (8.31), 2.542 (2.70), 2.547 (3.64), 2.566 (2.23), 2.681 (0.99), 2.731 (1.56), 2.890 (1.56), 3.031 (0.78), 3.049 (2.49), 3.063 (2.70), 3.066 (2.65), 3.080 (2.44), 3.098 (0.78), 3.393 (2.86), 3.418 (2.34), 3.440 (7.17), 3.467 (0.68), 3.508 (1.77), 3.522 (1.19), 3.536 (0.99), 3.561 (0.47), 3.973 (0.78), 4.215 (2.23), 4.232 (3.69), 4.250 (2.08), 6.165 (0.99), 6.178 (1.92), 6.192 (0.94), 6.532 (9.35), 6.895 (1.77), 7.595 (3.22), 8.288 (3.06), 8.292 (3.06), 8.656 (4.78), 8.661 (4.68), 11.817 (1.66).    Example 407 (rac)-N-ethyl-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000621_0001
Potassium carbonate (38.2 mg, 378 µmol) was added to 4-nitrophenyl (rac)-2'-(quinolin-3-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (200 mg, 43 % purity, 189 µmol) and N-methylethanamine (160 µL, 1.9 mmol) in DMA (2.0 mL) under nitrogen. Then it was stirred at 60 °C overnight. Dichloromethan was added and the reaction mixture was filtered, concentrated and purified by HPLC to give 35.7 mg (95 % purity, 48 % yield) of the title compound. LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 376 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.061 (3.49), 1.079 (7.74), 1.096 (3.42), 2.043 (0.46), 2.056 (0.83), 2.072 (1.30), 2.090 (0.88), 2.097 (1.44), 2.114 (0.76), 2.127 (0.48), 2.322 (0.72), 2.326 (0.92), 2.331 (0.72), 2.517 (3.30), 2.522 (2.18), 2.545 (0.50), 2.560 (1.34), 2.566 (1.31), 2.577 (2.07), 2.585 (2.08), 2.596 (1.24), 2.601 (1.20), 2.665 (0.66), 2.668 (0.88), 2.673 (0.65), 2.767 (16.00), 3.139 (1.05), 3.157 (3.02), 3.174 (2.93), 3.192 (0.94), 3.464 (7.55), 3.485 (0.88), 3.493 (0.79), 3.502 (0.59), 3.511 (1.28), 3.529 (0.58), 3.550 (0.61), 3.568 (1.09), 3.576 (0.57), 3.583 (0.70), 3.592 (0.59), 4.261 (1.52), 4.279 (3.00), 4.298 (1.44), 5.759 (0.90), 6.724 (6.61), 7.592 (0.81), 7.595 (0.86), 7.612 (1.78), 7.632 (1.20), 7.706 (1.08), 7.709 (1.09), 7.723 (0.94), 7.727 (1.73), 7.730 (1.33), 7.744 (0.91), 7.748 (0.88), 7.997 (2.19), 8.008 (1.88), 8.018 (1.86), 8.026 (1.63), 8.644 (2.60), 8.649 (2.61), 9.346 (3.45), 9.351 (3.34).    Example 408 (rac)-2'-[5-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000622_0001
(Rac)-N-Ethyl-2'-(5-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (55.0 mg, 146 µmol), (bromomethyl)benzene (29.9 mg, 175 µmol), and sodium hydroxide (6.99 mg, 175 µmol) were put into a microwave vial. DMF (660 µL) was added and the reaction mixture was stirred at 70 °C overnight. Water was added and the reaction mixture was three times with ethyl acetate. The combined organic layers were dried through a hydrophobic filter and purified by HPLC to afford 1.60 mg (96 % purity, 2 % yield) of the title compound.    Example 409 (rac)-N-(cyclopropanecarbonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000623_0001
Silver(1+) isocyanate (28.4 mg, 189 µmol) was added to cyclopropanecarbonyl chloride (16 µL, 170 µmol) in toluene (2.0 mL). It was stirred under exclusion of light for 1 h under reflux. The reaction mixture was allowed to reach rt and filtered. (Rac)-2'-(Quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (50.0 mg, 172 µmol) in toluene (1.0 mL) was added to the filtrate and stirred for 3 h at 110 °C. The reaction mixture was allowed to reach rt, concentrated and purified by HPLC to obtain 9.00 mg (99 % purity, 13 % yield) of the title compound.  LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 403 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.805 (11.72), 1.232 (0.79), 1.964 (1.12), 2.046 (1.28), 2.141 (6.53), 2.150 (6.57), 2.167 (8.24), 2.185 (4.54), 2.334 (2.41), 2.521 (7.50), 2.526 (5.55), 2.542 (0.59), 2.592 (5.28), 2.609 (9.27), 2.627 (6.52), 2.672 (3.30), 2.676 (2.34), 4.277 (7.31), 4.294 (13.22), 4.311 (6.74), 5.377 (0.42), 6.777 (16.00), 6.810 (0.73), 7.613 (5.49), 7.616 (5.55), 7.630 (8.25), 7.633 (11.48), 7.636 (6.51), 7.651 (7.52), 7.653 (7.37), 7.729 (7.61), 7.733 (7.26), 7.746 (6.54), 7.750 (11.68), 7.754 (8.43), 7.767 (6.49), 7.771 (6.13), 8.013 (12.85), 8.022 (10.23), 8.026 (10.12), 8.033 (11.01), 8.042 (9.21), 8.137 (0.44), 8.697 (7.85), 9.365 (13.45), 9.371 (12.66), 9.815 (4.89).    Example 410 (rac)-N-ethyl-2'-(6-{[(rac)-1-methyl-5-oxopyrrolidin-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (only one group of and/or stereo is supported now.) 
Figure imgf000624_0002
(Rac)-N-Ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (25.0 mg, 66.2 µmol),  4-(bromomethyl)-1-methylpyrrolidin-2-one (17.8 mg, 92.7 µmol), and sodium hydroxide (3.18 mg, 79.5 µmol) were put into a microwave vial. DMF (300 µL) was added and the reaction mixture was stirred at 100 °C overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried through a hydrophobic filter and purified by HPLC obtaining 1.00 mg (100 % purity, 3 % yield) of the title compound.    Example 411 cyclopropyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone 
Figure imgf000624_0001
Potassium thiocyanate (27.6 mg, 284 µmol) and cyclopropanecarbonyl chloride (24 µL, 260 µmol) were dissolved in acetone (2.0 mL) and stirred for 1 h at 60 °C. (Rac)-2'-(Quinolin-3-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (100 mg, 344 µmol) in acetone (1.0 mL) was added and stirred for 2 h at 60 °C. The reaction mixture was allowed to reacht rt and was directly purified by HPLC affording 20.0 mg (95 % purity, 15 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 359 [M+H]+  H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.75), -0.008 (9.73), 0.008 (6.27), 0.146 (0.84), 0.695 (0.65), 0.707 (1.87), 0.714 (3.37), 0.721 (1.50), 0.727 (2.15), 0.733 (4.02), 0.741 (1.59), 0.760 (4.30), 0.767 (4.40), 0.772 (7.58), 0.776 (6.36), 0.784 (4.68), 0.795 (5.71), 0.821 (0.56), 0.854 (0.65), 1.235 (1.59), 1.713 (0.47), 1.725 (1.03), 1.732 (1.03), 1.744 (1.59), 1.756 (0.94), 1.763 (0.84), 1.827 (0.47), 1.844 (0.94), 1.858 (1.96), 1.873 (0.84), 2.083 (0.47), 2.097 (1.12), 2.115 (2.25), 2.134 (2.25), 2.152 (1.03), 2.165 (0.56), 2.183 (0.47), 2.216 (1.22), 2.231 (1.96), 2.242 (2.43), 2.259 (1.12), 2.320 (1.87), 2.324 (3.93), 2.329 (5.52), 2.334 (3.93), 2.338 (1.68), 2.520 (16.00), 2.525 (11.98), 2.603 (2.90), 2.621 (4.02), 2.638 (3.84), 2.642 (3.84), 2.661 (4.12), 2.667 (4.40), 2.671 (6.08), 2.676 (5.15), 2.692 (0.56), 3.491 (0.56), 3.509 (1.12), 3.519 (1.78), 3.538 (1.96), 3.547 (4.96), 3.562 (4.68), 3.590 (1.12), 3.612 (0.75), 3.630 (1.31), 3.646 (0.94), 3.657 (0.75), 3.675 (0.47), 3.816 (0.47), 3.833 (1.22), 3.839 (1.50), 3.864 (5.43), 3.871 (5.05), 3.897 (0.84), 3.913 (0.75), 3.930 (1.31), 3.946 (0.94), 3.955 (0.84), 3.971 (0.47), 4.274 (1.87), 4.279 (1.78), 4.296 (4.68), 4.314 (5.71), 4.332 (2.25), 6.780 (13.29), 6.784 (13.10), 7.595 (2.71), 7.598 (2.25), 7.613 (3.74), 7.615 (5.15), 7.618 (3.18), 7.633 (3.27), 7.636 (3.56), 7.709 (3.65), 7.713 (3.09), 7.727 (3.09), 7.731 (5.33), 7.734 (4.02), 7.748 (2.71), 7.752 (2.90), 8.000 (9.26), 8.021 (7.95), 8.554 (2.99), 8.661 (3.65), 8.666 (3.74), 8.675 (3.56), 8.680 (3.56), 9.357 (6.36), 9.360 (7.11), 9.362 (7.11), 9.365 (5.80).    Example 412 (rac)-2'-(8-amino-1,7-naphthyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000625_0001
(Rac)-N-Ethyl-2'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (80.4 mg, 223 µmol) was dissolved in dioxane (1.5 mL) under argon. Then 3-bromo-1,7-naphthyridin-8-amine (50.0 mg, 223 µmol), potassium phosphate (1.3 mL, 0.50 M in water, 670 µmol), and XPhos Pd G2 (26.3 mg, 33.5 µmol) were added and stirred at 100 °C overnight. The reaction mixture was allowed to reach rt and purified by HPLC to give 5.00 mg (98 % purity, 6 % yield) of the title compound.   LC-MS (Method 1): Rt = 0.75 min; MS (ESIpos): m/z = 378 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.016 (7.10), 1.033 (16.00), 1.052 (7.19), 2.086 (1.23), 2.100 (2.06), 2.114 (2.66), 2.132 (1.11), 2.145 (0.51), 2.522 (1.02), 2.526 (0.68), 2.564 (2.68), 2.582 (4.03), 2.599 (2.86), 3.036 (0.94), 3.054 (2.86), 3.068 (3.21), 3.071 (3.06), 3.086 (2.83), 3.103 (0.83), 3.401 (0.55), 3.419 (1.26), 3.426 (1.05), 3.437 (0.91), 3.444 (2.24), 3.457 (10.87), 3.500 (0.79), 3.518 (1.37), 3.525 (0.79), 3.533 (0.96), 3.543 (0.80), 3.558 (0.46), 4.268 (2.73), 4.286 (4.21), 4.302 (2.65), 6.174 (1.18), 6.188 (2.39), 6.202 (1.16), 6.757 (11.40), 6.909 (5.52), 6.922 (6.08), 6.936 (5.62), 7.843 (5.93), 7.858 (5.48), 8.440 (5.43), 8.446 (5.37), 9.200 (6.11), 9.205 (5.87).    Example 413 (rac)-N-ethyl-2'-(5-hydroxy-1,6-naphthyridin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000626_0001
(Rac)-1-(Ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'-yl trifluoromethanesulfonate (100 mg, 262 µmol), (5-chloro-1,6-naphthyridin-3-yl)boronic acid (712 mg, 3.42 mmol), XPhos Pd G2 (30.9 mg, 39.2 µmol), and potassium phosphate (1.6 mL, 0.50 M in water, 780 µmol) were stirred in dioxane (7.7 mL) at 100 °C overnight. The reaction mixture was allowed to reach rt and ethyl acetate was added. The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous phases were concentrated and purified by silica gel chromatography and HPLC to obtain 3.20 mg (95 % purity, 3 %) of the title compound.  ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.006 (1.11), 1.018 (7.66), 1.032 (16.00), 1.047 (7.56), 2.063 (0.48), 2.067 (0.49), 2.077 (1.26), 2.088 (1.34), 2.091 (1.24), 2.097 (1.22), 2.113 (1.95), 2.122 (0.53), 2.127 (0.96), 2.137 (0.72), 2.369 (0.44), 2.518 (1.98), 2.522 (1.77), 2.526 (1.47), 2.544 (0.53), 2.554 (2.12), 2.567 (3.36), 2.570 (3.36), 2.583 (2.42), 2.643 (0.45), 3.041 (1.20), 3.055 (2.98), 3.066 (3.24), 3.068 (2.99), 3.080 (2.65), 3.094 (0.77), 3.386 (1.13), 3.393 (1.55), 3.401 (1.67), 3.407 (1.18), 3.416 (0.98), 3.421 (1.92), 3.436 (1.01), 3.447 (10.46), 3.517 (0.71), 3.528 (0.85), 3.533 (1.09), 3.538 (0.81), 3.543 (0.91), 3.548 (0.77), 3.553 (0.72), 3.563 (0.51), 4.154 (0.60), 4.252 (2.69), 4.266 (4.40), 4.280 (2.60), 6.159 (1.20), 6.171 (2.22), 6.183 (2.55), 6.621 (3.24), 6.635 (3.25), 6.736 (10.20), 7.406 (1.06), 7.416 (1.22), 7.419 (1.17), 7.430 (1.03), 8.316 (4.37), 8.522 (1.26), 8.726 (3.68), 8.728 (3.73), 8.731 (3.84), 8.733 (3.72), 9.312 (6.44), 9.317 (6.77), 11.570 (1.08), 11.576 (1.08).    Example 414 (rac)-N-ethyl-2'-{5-[(pyridin-2-yl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000627_0001
(Rac)-2'-(5-Aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 133 µmol) was dissolved in dioxane/water 4:1 (3.0 mL). 2-Chloropyridine (15.1 mg, 133 µmol), cesium carbonate (64.9 mg, 199 µmol), and XantPhos (15.4 mg, 26.6 µmol) were added and degassed for 5 min. Then tris(dibenzylideneacetone)dipalladium (12.2 mg, 13.3 µmol) was added and stirred for 1 h at 100 °C. 2-Chloropyridine (15.1 mg, 133 µmol) was added and stirred for 3 h at 110 °C. The reaction mixture was allowed to reach rt, filtered through celite, which was washed with dioxane, and concentrated. The residue was purified by HPLC obtaining 2.20 mg (97 % purity, 4 % yield) of the title compound.     Example 415 (rac)-N-ethyl-2'-{5-[(pyridine-2-sulfonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000627_0002
(Rac)-2'-(5-Aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 133 µmol) and pyridine-2-sulfonyl chloride (23.6 mg, 133 µmol) were dissolved in pyridine (500 µL, 6.2 mmol). It was stirred at rt overnight. Water was added and the pH was adjusted to 5 with acetic acid and it was extracted three times with ethyl acetate. The combined organic layers were filtered through a hydrophobic filter, concentrated and purified by HPLC to afford 13.3 mg (95 % purity, 18 % yield) of the title compound.     Example 416 (rac)-N-ethyl-2'-{5-[(pyridine-3-sulfonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000628_0001
(Rac)-2'-(5-Aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 133 µmol) and pyridine-3-sulfonyl chloride (23.6 mg, 133 µmol) were dissolved in pyridine (500 µL, 6.2 mmol). It was stirred at rt overnight. Water was added and the pH was adjusted to 5 with acetic acid and it was extracted three times with ethyl acetate. The combined organic layers were filtered through a hydrophobic filter, concentrated and purified by HPLC giving 3.70 mg (98 % purity, 5 % yield) of the title compound.     Example 417 (rac)-N-ethyl-2'-[6-(2-hydroxy-2-methylpropyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000628_0002
Methyl {3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-2'- yl]quinolin-6-yl}acetate (30.0 mg, 69.2 µmol) was dissolved in THF (1.5 mL) under argon and methyl magnesium bromide (210 µL, 1.0 M in THF, 210 µmol) was added dropwise. It was stirred at 60 °C overnight. The reaction mixture was allowed to reach rt and saturated aqueous ammonium chloride solution was added and extracted three times with dichloromethane. The combined organic phases were filtered through a hydrophobic filter, concentrated and purified by HPLC and preparatice TLC to give 800 µg (99 % purity, 3 % yield) of the title compound.     Example 418 (rac)-1-(1-methyl-1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] 
Figure imgf000629_0001
(Rac)-2'-(Quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (100 mg, 344 µmol) was dissolved in dioxane (5.0 mL) under argon. Then 2-bromo-1-methyl-1H-imidazole (111 mg, 689 µmol), palladium(π-cinnamyl) chloride dimer (8.92 mg, 17.2 µmol), di-tert- butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (12.1 mg, 34.4 µmol), and cesium carbonate (337 mg, 1.03 mmol) were added. The reaction mixture was stirred at 95 °C overnight. The reaction mixture was allowed to reach rt then water was added. It was extraceted twice with ethyl acetate. The combined organic layers were dried, concentrated and purified by HPLC to yield 22.0 mg (99 % purity, 17 % yield) of the title compound.   LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 371 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.170 (0.49), 2.184 (0.62), 2.189 (0.63), 2.192 (0.57), 2.203 (0.50), 2.211 (0.82), 2.229 (0.48), 2.325 (0.76), 2.329 (1.10), 2.334 (0.79), 2.521 (3.62), 2.525 (2.58), 2.612 (0.46), 2.626 (0.51), 2.644 (0.92), 2.662 (0.75), 2.667 (1.00), 2.671 (1.36), 2.676 (0.84), 2.681 (0.42), 2.686 (0.96), 2.705 (0.50), 2.719 (0.44), 3.507 (2.94), 3.515 (16.00), 3.548 (0.44), 3.555 (0.53), 3.572 (0.88), 3.591 (0.85), 3.605 (0.53), 3.610 (0.67), 3.624 (0.50), 4.275 (1.19), 4.292 (2.44), 4.310 (1.16), 6.531 (3.53), 6.535 (3.62), 6.785 (3.07), 6.788 (2.79), 6.807 (5.10), 7.595 (0.53), 7.598 (0.47), 7.612 (0.80), 7.614 (1.14), 7.617 (0.69), 7.632 (0.71), 7.635 (0.76), 7.707 (0.73), 7.711 (0.68), 7.725 (0.63), 7.729 (1.15), 7.732 (0.86), 7.746 (0.60), 7.750 (0.65), 8.000 (2.17), 8.021 (1.76), 8.656 (1.45), 8.662 (1.53), 9.358 (2.42), 9.363 (2.33).    Example 419 (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000630_0001
3-Bromopyridine (21.0 mg, 133 µmol) was placed into a microwave vial. Then (rac)-2'-(5- aminoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (50.0 mg, 133 µmol) dissolved in tert-butanol (800 µL), (2'-amino[biphenyl]-2- yl)(methanesulfonato-kappaO)palladium - di-tert-butyl(2',4',6'-triisopropyl-3,6- dimethoxy[biphenyl]-2-yl)phosphine (1:1) (11.3 mg, 13.3 µmol), di-tert-butyl(2',4',6'-triisopropyl- 3,6-dimethoxy[biphenyl]-2-yl)phosphine (12.9 mg, 26.6 µmol), and potassium phosphate (63.7 mg, 300 µmol) were added. It was stirred for 4 h at 105 °C in the microwave oven. The reaction mixture was allowed to reach rt, concentrated and purified by HPLC affording 9.90 mg (96 % purity, 16 % yield) of the title compound.     Example 420 (rac)-N-ethyl-2'-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000630_0002
(Rac)-N-Ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (50.0 mg, 143 µmol), paraformaldehyde (4.0 µL, 140 µmol) and sodium hydroxide (11.4 mg, 285 µmol) were dissolved in methanol (730 µL) and stirred at rt overnight. Paraformaldehyde (4.0 µL, 140 µmol) was added and stirred at rt overnight. Saturated aqueous sodium hydrogen carbonate solution was added and filtered through celite. The filtrate was concentrated and purified by HPLC to obtain 1.00 mg (95 % purity, 2 % yield) of the title compound.   ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (1.11), 0.850 (1.36), 1.018 (7.17), 1.035 (16.00), 1.053 (7.27), 1.241 (1.51), 1.371 (0.61), 1.384 (0.96), 2.070 (1.26), 2.088 (1.67), 2.110 (2.07), 2.128 (1.01), 2.140 (0.71), 2.526 (14.94), 2.531 (9.99), 2.537 (4.49), 2.548 (3.28), 2.555 (4.39), 2.573 (2.88), 2.682 (2.22), 3.037 (0.91), 3.054 (2.93), 3.068 (3.38), 3.072 (3.23), 3.086 (2.93), 3.104 (0.86), 3.400 (2.02), 3.407 (1.72), 3.426 (2.42), 3.442 (11.05), 3.503 (0.91), 3.522 (1.41), 3.536 (1.16), 3.562 (0.61), 4.206 (2.52), 4.224 (4.29), 4.241 (2.52), 4.560 (2.07), 4.643 (8.18), 5.575 (0.81), 6.163 (1.21), 6.177 (2.42), 6.191 (1.21), 6.497 (9.79), 6.518 (0.91), 7.356 (5.00), 7.471 (0.56), 8.341 (5.40), 8.346 (5.65), 8.357 (0.61), 8.362 (0.56), 8.634 (5.20), 8.639 (5.15), 8.700 (0.45), 8.705 (0.45), 11.427 (1.31).    Example 421 (rac)-N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000631_0001
(Rac)-N-Ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide (25.0 mg, 66.2 µmol),  2-bromopropane (7.5 µL, 79 µmol), and sodium hydroxide (3.18 mg, 79.5 µmol) were put into a microwave vial. DMF (300 µL) was added and the reaction mixture was stirred at 70 °C overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried through a hydrophobic filter and purified by HPLC obtaining 15.8 mg (98 % purity, 56 % yield) of the title compound.    Example 422 (rac)-2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide 
Figure imgf000632_0002
(Rac)-N-Ethyl-2'-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (30.0 mg, 82.3 µmol) was dissolved in DMF (100 µL). 1- Chloropyrrolidine-2,5-dione (12.1 mg, 90.5 µmol) and benzoyl peroxide (21.9 mg, 90.5 µmol) were added. It was stirred 2 h at rt. Water was added and extracted three times with ethyl acetate. The combined organic layers were dried through a hydrophobic filter, concentrated and purified by HPLC to afford 5.00 mg (100 % purity, 15 % yield) of the title compound.   Example 423 (rac)-N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide 
Figure imgf000632_0001
LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 425 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.138 (0.80), 2.116 (0.86), 2.133 (1.27), 2.150 (1.49), 2.168 (0.57), 2.518 (1.10), 2.523 (0.71), 2.584 (1.57), 2.601 (2.29), 2.619 (1.68), 3.478 (0.73), 3.487 (0.65), 3.490 (0.67), 3.496 (0.53), 3.504 (1.20), 3.516 (3.58), 3.521 (3.98), 3.547 (0.46), 3.568 (0.44), 3.587 (0.78), 3.594 (0.45), 3.601 (0.55), 3.609 (0.45), 3.613 (0.46), 4.262 (3.14), 4.270 (2.40), 4.277 (3.38), 4.288 (2.58), 4.305 (1.60), 6.728 (7.14), 6.819 (0.62), 6.834 (1.27), 6.849 (0.59), 7.192 (0.53), 7.195 (0.46), 7.199 (0.59), 7.205 (0.95), 7.208 (0.78), 7.214 (0.61), 7.218 (0.84), 7.226 (0.62), 7.283 (0.70), 7.295 (16.00), 7.304 (4.33), 7.308 (4.99), 7.314 (0.45), 7.595 (0.83), 7.598 (0.70), 7.613 (1.24), 7.616 (1.44), 7.633 (1.01), 7.636 (1.13), 7.708 (1.21), 7.712 (0.94), 7.725 (0.93), 7.729 (1.50), 7.733 (1.35), 7.746 (0.81), 7.750 (0.95), 7.997 (3.32), 7.999 (3.02), 8.001 (2.96), 8.021 (3.32), 8.652 (2.42), 8.658 (2.37), 9.349 (3.46), 9.354 (3.47).    Example 424 2-amino-1-[(rac)-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one 
Figure imgf000633_0001
To a solution of glycine (28.5 mg, 380 µmol) in DMF (2 mL), HATU (144 mg, 380 µmol) and N,N-diisopropylethylamine (280 µl) were added and stirred for 30 minutes under argon. (3S)- 2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]— hydrogen chloride (1/1) (100 mg, 317 µmol) was added and the reaction mixture stirred for 2 hours at rt. The resultant mixture was diluted with water and extracted with ethyl acetate (x3). The combined organic phases were dried through a hydrophobic filter and concentrated. The crude mixture was purified by silica gel chromatography to give 28.1 mg (26%) of the title compound.   LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 337 [M+H]+    Example 425 2-amino-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-one 
Figure imgf000633_0002
To a solution of tert-butyl {2-oxo-2-[(3S)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazol]-1-yl]ethyl}carbamate (86.5 mg, 193 µmol) in dioxane (1 mL), HCl in dioxane (970 µl, 4.0 M, 3.9 mmol) was added and the reaction mixture stirred for 5 hours at rt. The resultant mixture was concentrated and purified by basic HPLC to give 15.0 mg (22%) of the title compound.  LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 348 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.026 (0.46), 2.044 (0.80), 2.057 (1.93), 2.075 (2.76), 2.090 (2.02), 2.097 (3.43), 2.116 (1.89), 2.128 (1.36), 2.147 (3.50), 2.165 (6.34), 2.182 (3.43), 2.518 (0.97), 2.523 (0.66), 2.535 (0.71), 2.544 (0.72), 2.552 (1.49), 2.559 (1.31), 2.567 (2.56), 2.576 (3.31), 2.584 (5.80), 2.591 (6.94), 2.606 (8.34), 2.624 (4.20), 2.639 (1.92), 2.656 (1.04), 2.669 (0.42), 3.031 (4.95), 3.195 (1.82), 3.238 (4.51), 3.264 (4.40), 3.312 (1.97), 3.355 (4.22), 3.391 (4.23), 3.434 (1.53), 3.490 (0.87), 3.516 (3.54), 3.575 (9.35), 3.596 (6.71), 3.603 (4.79), 3.623 (3.34), 3.629 (3.47), 3.646 (3.40), 3.655 (2.66), 3.673 (2.25), 3.690 (0.86), 4.228 (0.44), 4.245 (0.94), 4.255 (3.23), 4.265 (7.17), 4.272 (6.22), 4.283 (13.39), 4.291 (4.35), 4.299 (6.34), 4.310 (1.16), 4.325 (0.46), 6.739 (15.80), 6.786 (16.00), 7.586 (4.06), 7.588 (3.84), 7.603 (6.42), 7.606 (8.44), 7.623 (5.64), 7.626 (5.66), 7.700 (5.26), 7.704 (5.12), 7.717 (4.82), 7.721 (8.64), 7.724 (6.51), 7.738 (4.47), 7.742 (4.48), 7.997 (12.24), 8.013 (7.41), 8.018 (11.15), 8.642 (6.48), 8.646 (6.64), 8.660 (6.31), 8.664 (6.22), 9.356 (13.24), 9.361 (13.10). 
EXPERIMENTAL SECTION – BIOLOGICAL ASSAYS Biological in vitro assays The in vitro activity of the compounds of the present invention can be demonstrated in the following assays: The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. Biological Evaluation In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety. Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent to inhibit and be selective against something the following assays may be used. Binding competition assay The ability of the compounds of the present invention to inhibit the binding of an Alexa647- labelled ATP-competitive kinase inhibitor to a Glutathione-S-transferase- (GST-) fusion protein was quantified employing the TR-FRET-based binding competition assay as described in the following paragraphs. A recombinant fusion protein of N-terminal GST and full-length human , expressed by baculovirus infected SF9 insect cells and purified by Glutathione Sepharose affinity chromatography, was used as GST- fusion protein. Tracer 222 from Invitrogen (catalogue no. PR9198A) was used as Alexa647-labelled ATP-competitive kinase inhibitor. For the assay 50 nl of a 100fold concentrated solution of the test compound in DMSO was pipetted into either a black low volume 384well microtiter plate or a black 1536well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), 3 µL solution of Tracer 222 (25 nM => final concentration in 5 µL assay volume is 15 nM) in aqueous assay buffer [25 mM Tris/HCl pH 7.5, 10 mM MgCl2, 5 mM β-glycerolphosphate, 2.5 mM dithiothreitol, 0.5 mM ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid [EGTA], 0.5 mM sodium ortho- vanadate, 0.01 % (w/v) bovine serum albumin [BSA], 0.005% (w/v) Pluronic F-127 (Sigma)] were added. Then the binding competition was started by the addition of 2 µL of a solution of the GST- fusion protein (2.5 nM => final conc. in the 5 µL assay volume is 1 nM) and of Anti- GST-Tb (1.25 nM => final conc. in the 5 µL assay volume is 0.5 nM), a Lumi4®-Tb Cryptate- conjugated anti-GST-antibody from Cisbio Bioassays (France), in assay buffer. The resulting mixture was incubated 30 min at 22°C to allow the formation of a complex between the Tracer 222, the fusion protein and Anti-GST-Tb. Subsequently the amount of this complex was evaluated by measurement of the resonance energy transfer from the Tb- cryptate to the Tracer 222. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a TR-FRET reader, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of the complex. The data were normalised (assay reaction without inhibitor = 0 % inhibition, all other assay components but GST- fusion protein = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in 11 different concentrations in the range of 20 µM to 0.07 nM (20 µM, 5.7 µM, 1.6 µM, 0.47 µM, 0.13 µM, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the 100fold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC50 values were calculated using Genedata Screener™ software.
Table 1: Measured IC50 values of compounds regarding inhibition
Figure imgf000637_0001
Figure imgf000638_0001
 
Figure imgf000638_0002
Figure imgf000638_0003
Figure imgf000639_0001
Figure imgf000640_0001
Phosphorylation assay in human cell line Phosphorylation assays were carried out in Jurkat E6.1 cells from American Type Culture Collection (ATCC) stably overexpressing human FLAG-tagged SLP-76 (proprietary). Cultured cells were kept in RPMI 1640 medium supplemented with 1% FCS at a cell density of 2x 10e6/mL 24h prior compound testing. Starved cells were simultaneously treated with 350 ng/mL a-CD3 antibody (clone OKT3. ebioscience #16-0037-85. plate-bound) and test compound for 30 min at 37 ⁰C. Applied compounds were tested at either fixed concentration of 10 µmol/L and 20 µmol/L or in a 8 point dose response titration of increase compound concentration with 10 nmol/L.50 nmol/L. 100 nmol/L. 500 nmol/L.1 μmol/L.5 μmol/L. 10 μmol/L and 20 μmol/L in triplicates. The cells were washed once in phosphate-buffered saline (pH 7.4). Cells were lysed using a lysis buffer containing 50 mmol/L Tris-Cl (pH 7.5).150 mM NaCl.2 mM EDTA. 1% Triton-X 100.0.5 % Na-DOC. 0.1% SDS.1/10 complete mini protease inhibitor cocktail (Roche #11836170001) and 1/10 PhosSTOP phosphatase inhibitor cocktail (Roche #04906837001). A total of 1.25 µg cell lysate was analyzed by capillary electrophoresis using the Peggy Sue™ System (proteinsimple® San Jose. CA USA) with a 12-230kDa size- based master kit with split buffer / a-rabbit-HRP #PS-MK18 / a-mouse-HRP #PS-MK19 according to manufacture´s protocol. Probe antibodies used were a rabbit monoclonal antibody supernatant raised against human phospho-Ser376-SLP-76 peptide (proprietary) and for mormalization an anti-alpha-Tubulin mouse monoclonal antibody (Sigma #T9026). As control for maximal effect (max control. which represent the maximally possible inhibition of pSer376- SLP-76 by a test compound) cells with no a-CD3 (clone OKT3. ebioscience #16-0037-85. plate-bound) and no test compound treatment were used. Cells with a-CD3 treatment only were used as negative control (min control. which represent the minimally possible inhibition of pSer376-SLP-76 by a test compound) AUC values of each respective test sample were normalized using the AUC of housekeeping gene alpha-Tubulin and AUC of pSer376-SLP-76 of the min control. The percentage of the amount of pSer-SLP-76 in the treatment samples was calculated using the max control and min control values of the respective Peggy Sue™ run. Stimulation of IFNg production from human primary peripheral blood mononuclear cells (PBMCs) The effect of the compound in the activation of human T cells was tested by measuring the production of the proinflammatory cytokine IFNg in vitro. Fresh human PBMCs were isolated and activated in vitro with coated a-CD3 (clone OKT3. ebioscience #16-0037-85. plate-bound). Concentration of a-CD3 was titrated in order to obtain a sub-optimal activation of PBMCs (1x106 PBMCs/mL). Cells were activated with a-CD3 and 1 μmol/L PGE2 for 22 hours in the presence of the compounds and the supernatant of the culture was isolated and tested for IFNg concentration. Applied compounds were tested at either fixed concentration of 200 nmol/L or in a 6 point dose response titration of increase compound concentration from 12 nmol/L to 3 μmol/L in triplicates. IFNg concentration was determined by ELISA (Opt EIA human IFNg ELISA BD #555142). Plate was coated with a-IFNg overnight. The plates were washed 3 times and the supernatant from the PBMCs culture was added to the wells and incubated for 2 hours. Plates were washed and detection antibody and the SAv-HRP was added for 1h. Plates were washed and the substrate was added until the standard turns blue. The reaction is stopped by adding 50 µL 2N H2SO4. Absorbance was measured with a TECAN Reader at 450 to 570 nm. Concentration of IFNg was calculated from the absorbance using standards of known concentration.

Claims

CLAIMS 1. Compounds of formula (I)
Figure imgf000643_0001
in which X represents either a direct bond, -CH2- or -O-, Y represents -H, -Cl, -Br, -CN, -CF3, C1-C4-alkyl, C3-C7-cycloalkyl, R1 represents a group *-A-B, in which *-A- represents a direct bond and in which B represents -H or phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, an optionally with an oxo-group (=O) substituted C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) and in which *-A- represents a group *-CRaH-, in which Ra represents -H, C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) and in which B represents -H, -CN, C1-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NHRb, in which Rb represents -H, C1-C4-alkoxy, C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl (optionally - OCH3 substituiert), C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)),
Figure imgf000644_0001
or in which R6 and R7 are hydrogen or bridged by C1-C4-alkyl in which one -CH2-group can be replaced by oxygen, in which A represents a group *-C(=O)- or *-SO2- and in which B represents C1-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, C1-C4- alkoxy, an oxo-group (=O),-S(O)2-CH3, -S(O)(NRz)-CH3, or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=O)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) or 5- to 6-membered heteroaryl, C2-C4-alkenyl,
Figure imgf000645_0001
, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), in which A represents a group *-C(=O)-O-,
Figure imgf000645_0002
, in which Rc represents -H or C1-C4-alkyl, *-C(=O)-NRc-, in which Rc represents -H or C1-C4-alkyl, *-C(=S)-NRc-, in which Rc represents -H or C1-C4-alkyl, *-C(=N-CN)-O- or *-C(=N-CN)-NRg-, in which Rg represents -H or C1-C4-alkyl and in which B represents -
Figure imgf000645_0003
C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1- C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), -S(O)(NRz)- CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C2-C6-alkenyl, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -SO2-(C1-C4-alkyl), a group –C(=O)-Rd, in which Rd represents -CF3, C1-C4-alkoxy or C3-C7-cycloalkyl, a group -(CH2)n-Re in which n is 1 or 2 and in which Re represents 4 to 7-membered heterocycloalkyl, optionally substituted with an oxo-group (=O), -phenyl or 5- or 6- membered heteroaryl, optionally substituted with C1-C4-alkyl; or N, Rc und B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with C1-C4-alkyl or -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), a group –C(=O)-Rf, in which Rf represents C1-C4-alkyl or C3-C7- cycloalkyl, R2 represents
Figure imgf000646_0001
, or , R4 represents -H, -NO2, -CN, -OH, -P(=O)(C1-C4-alkyl)2, -S(=O)2-(C1-C4-alkyl), -N=S(=NH)(C1-C4-alkyl)2, -N=S(=O)(C1-C4-alkyl)2, halogen -C(=O)-O- C1-C4-alkyl, -C(=O)- C1-C4-alkyl, -O-CH3, -C2-C6-alkoxy, optionally substituted with -F, -OH, -O-CH3, -S-CH3, -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=O), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4- alkoxy, an oxo-group (=O), -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NRvRw or -C(=O)-O-Rv, in which Rv represents -H or C1-C4-alkyl, Rw represents -H, C1-C4- alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl - C3-C6-alkenyloxy, C1-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7- membered heterocycloalkenyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), - C(=O)-O-CH3, phenyl or 5- or 6-membered heteroaryl, C2-C4-alkynyl, optionally substituted with 5- to 6-membered heteroaryl, this heteroaryl again optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, - OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), phenyl, optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRiRj, in which Ri represents -H, C1-C4-alkyl and Rj represents -H, C1-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, Ri and Rj together form a 4- to 7-membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=O) or C1-C4-alkyl -NRi-S(=O)2-Rp, in which Ri represents -H, C1-C4-alkyl and Rp represents 5- or 6- membered heteroaryl, -NH-C(=O)-NRkRl, in which Rk represents -H or C1-C4-alkyl and Rl represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -NH-C(=O)-Rm, in which Rm represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -(C=O)-NRnRo, in which Rn represents -H or C1-C4-alkyl, Ro represents C1-C6- hydroxyalkyl, 5- or 6-membered heteroaryl (N), or
Figure imgf000650_0001
or in which N, Rn and Ro together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN, R5 represents -H, C1-C4-alkyl, -F or -Cl, R15 represents -H, C1-C4-alkyl, -CF3, -F, -Cl,-O-CH3 or -CN or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 2. Compounds of formula (I) in which X represents either a direct bond, -CH2- or -O-, Y represents -H, -Cl, -Br, -CN, -CF3, C1-C4-alkyl, C3-C7-cycloalkyl, R1 represents a group *-A-B, in which *-A- represents a direct bond and in which B represents -H or in which *-A- represents a group *-CRaH-, in which Ra represents -H, C1-C4-alkyl or C3-C7-cycloalkyl all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1- C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) and in which B represents -H, -CN, C1-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NHRb, in which Rb represents -H, C1-C4-alkoxy, C1-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl (optionally - OCH3 substituiert), C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)),
Figure imgf000651_0001
or in which R6 and R7 are hydrogen or bridged by C1-C4-alkyl in which one -CH2-group can be replaced by oxygen, in which A represents a group *-C(=O)- and in which B represents C1-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, C1-C4- alkoxy, an oxo-group (=O),-S(O)2-CH3, -S(O)(NRz)-CH3, or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=O)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) or 5- to 6-membered heteroaryl, C2-C4-alkenyl,
Figure imgf000651_0002
, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), in which A represents a group *-C(=O)-O-, *-C(=O)-NRc-, in which Rc represents -H or C1-C4-alkyl, *-C(=S)-NRc-, in which Rc represents -H or C1-C4-alkyl, in which B represents -H, C1-C6-alkyl, C1-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1- C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), -S(O)(NRz)- CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C2-C6-alkenyl, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -SO2-(C1-C4-alkyl), a group –C(=O)-Rd, in which Rd represents -CF3, C1-C4-alkoxy or C3-C7-cycloalkyl, a group -(CH2)n-Re in which n is 1 or 2 and in which Re represents 4 to 7-membered heterocycloalkyl, optionally substituted with an oxo-group (=O), -phenyl or 5- or 6- membered heteroaryl, optionally substituted with C1-C4-alkyl; or N, Rc und B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with C1-C4-alkyl or -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), a group –C(=O)-Rf, in which Rf represents C1-C4-alkyl or C3-C7- cycloalkyl, R2 represents
Figure imgf000653_0001
R4 represents -H, -NO2, -CN, -OH, -P(=O)(C1-C4-alkyl)2, -S(=O)2-(C1-C4-alkyl), halogen -C(=O)- C1-C4-alkyl, -O-CH3, -C2-C6-alkoxy, optionally substituted with -F, -OH, -O-CH3, -S-CH3, -NRxRy, in which Rx and Ry represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=O), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4- alkoxy, an oxo-group (=O), -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -C(=O)-NRvRw or -C(=O)-O-Rv, in which Rv represents -H or C1-C4-alkyl, Rw represents -H, C1-C4- alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl - C3-C6-alkenyloxy, C1-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7- membered heterocycloalkenyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, C1-C4-alkoxy, an oxo-group (=O), - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), - C(=O)-O-CH3, phenyl or 5- or 6-membered heteroaryl, C2-C4-alkynyl, optionally substituted with 5- to 6-membered heteroaryl, this heteroaryl again optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, - OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), phenyl, optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), -NRiRj, in which Ri represents -H, C1-C4-alkyl and Rj represents -H, C1-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, Ri and Rj together form a 4- to 7-membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=O) or C1-C4-alkyl -NRi-S(=O)2-Rp, in which Ri represents -H, C1-C4-alkyl and Rp represents 5- or 6- membered heteroaryl, -NH-C(=O)-NRkRl, in which Rk represents -H or C1-C4-alkyl and Rl represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo- group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, - S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, - CF3, C1-C4-alkyl, -CN, -S(O)2-CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -NH-C(=O)-Rm, in which Rm represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, C1-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=O)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), C1-C4-alkoxy, -S(O)2-CH3, -S(O)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)), or C1-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C1-C4-alkyl, -CN, -S(O)2- CH3, -S(O)(NRz)-CH3, C1-C4-alkoxy, an oxo-group (=O), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=O)) -(C=O)-NRnRo, in which Rn represents -H or C1-C4-alkyl, Ro represents C1-C6-
Figure imgf000656_0001
hydroxyalkyl, 5- or 6-membered heteroaryl (N), or
Figure imgf000656_0002
or in which N, Rn and Ro together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN, R5 represents -H, -F or -Cl, R15 represents -H, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 3. Compounds according to claim 1 or 2 in which R2 is selected from
Figure imgf000656_0003
4. Compounds according to claim 1 or 2 wherein R2 is
Figure imgf000656_0004
5. Compounds according to claim 1 or 2 wherein R2 is
Figure imgf000656_0005
and wherein R4 is selected from hydrogen, -F, -Cl, methyl, ethyl and isopropyl. 6. Compounds according to claim 1 or 2 wherein R1 is selected from -C(=O)-O-tBu, -C(=O)-NH-Et, -C(=O)-NH-C(=O)-O-Et, , or . 7. Compounds according to claim 1 or 2 wherein X is a direct bond. 8. Compounds according to claim 1 or 2 wherein Y is hydrogen or -Cl. 9. Compound according to claim 1, which is selected from ● (rac)-tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(thieno[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6-chloroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(5-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6-fluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(isoquinolin-4-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl (3S)-2'-(2-aminopyrimidin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(1H-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(imidazo[1,2-a]pyrimidin-6-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl (3S)-2'-[6-(methoxycarbonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl (3S)-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(6,7-difluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-fluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(5-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(7-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(7-fluoroquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(4-methylquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -3-chloro-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate(rac)-N-ethyl-2'- (quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide ● (rac)-N-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-cyclopropyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-methyl [(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbonyl]carbamate ● (rac)-N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-cyclopentyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-[(furan-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 1) ● (N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 2) ● (rac)-N-(prop-2-en-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-ethyl [2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbonyl]carbamate ● ethyl [(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbonyl]carbamate (enantiomer 1) ● ethyl [(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbonyl]carbamate (enantiomer 2) ● (rac)-N-(ethanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(2-chloroethyl)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-(6,7-difluoroquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (3S)-N-ethyl-2'-(2-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(1H-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-ethyl [2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carbonyl]carbamate ● (rac)-3'-chloro-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-3'-chloro-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-hydroxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-(Morpholin-4-yl)[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-N,N-diethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-(pyrrolidin-1-yl)[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(4-methylpiperazin-1-yl)[(3S)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2-ethyl-1-[2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]butan-1-one ● (rac)-3-methoxy-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-1-one ● (rac)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbonyl]cyclopropane-1-carbonitrile ● (rac)-2-(morpholin-4-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● (rac)-1-{2-oxo-2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethyl}pyrrolidin-2-one ● (rac)-3-(1H-pyrazol-1-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]propan-1-one ● (rac)-(pyridin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(1-methyl-1H-imidazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-(pyridin-3-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(pyrimidin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(1-methyl-1H-pyrazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (rac)-4-oxo-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]- 1-yl]butanenitrile ● (rac)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-one ● (rac)-(3-chlorophenyl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2-(pyrimidin-5-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (rac)-(1H-imidazol-2-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-(oxetan-3-yl)[2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2-methyl-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-1-one9.438 (5.58). ● (rac)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propan-1-one ● (rac)-2-(oxan-4-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (rac)-2-(oxetan-3-yl)-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (rac)-(oxan-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2,2-dimethyl-1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]propan-1-one ● (rac)-1-(methanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-sulfonamide ● (rac)-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-sulfonamide ● (3R)-1-(cyclopropanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (1-[(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● (1-[(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-1-[(1H-indazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]—hydrogen chloride ● 1-[(1H-indazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● 1-[(1H-indazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-1-[(2-methylpyrimidin-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-N,N-dimethyl-5-{[2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazol]-1-yl]methyl}-1,3-thiazol-2-amine ● (3S)-1-(cyclohexylmethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of 4 stereoisomers) ● (rac)-1-[(4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● 1-[(4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● 1-[(4-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-1-[(4-chloro-1H-pyrazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,3-thiazol-5-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(3-methyl-1,2-oxazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-methyl-1H-pyrazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1,2-oxazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(4-methyl-1H-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(2-methyl-1H-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-pyrazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-(2-methylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-1-{[1-(2-methoxyethyl)-1H-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-benzimidazol-2-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,4,5-trimethyl-1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(imidazo[1,5-a]pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-{[4-(trifluoromethyl)-1H-imidazol-2-yl]methyl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-{[1-(propan-2-yl)-1H-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(pyridin-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-{[1-(propan-2-yl)-1H-benzimidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1-methyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-.2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]ethan-1-ol ● (rac)-3-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propan-1-ol ● (rac)-2-methyl-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]butan-2-ol ● (rac)-N,N-dimethyl-2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-amine ● (rac)-1-[2-(morpholin-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-N,N-dimethyl-3-[(3S)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]propan-1-amine ● (rac)-1-[3-(morpholin-4-yl)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2-methyl-1-[2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazol]-1-yl]propan-2-ol ● (rac)-N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbothioamide ● (rac)-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carbothioamide ● (rac)-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carbothioamide ● (rac)-ethyl [2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carbothioyl]carbamate ● (rac)-N-(1-methyl-1H-pyrazol-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carbothioamide ● (rac)-N-(3,5-dimethyl-1,2-oxazol-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carbothioamide ● (rac)-1-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-1-(pyridin-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole] ● (rac)-Phenyl (3S)-N-cyano-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboximidate ● (rac)-N'-cyano-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboximidamide ● (rac)-N'-cyano-N-(2-hydroxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboximidamide ● (rac)-N'-cyano-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboximidamide ● (rac)-3-(ethylamino)-4-[-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]cyclobut-3-ene-1,2-dione ● (rac)-3-(dimethylamino)-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]cyclobut-3-ene-1,2-dione ● (rac)-Ethyl -2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate ● (rac)-2-methoxyethyl -2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl -2-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5- yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● tert-butyl -2'-{3-[4-(S-methanesulfonimidoyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (21.00, mixture of 4 stereoisomers) and tert-butyl -2'-(3-{4-[N-(methoxycarbonyl)-S- methylsulfonimidoyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate (21.01, mixture of 4 stereoisomers) ● (rac)-tert-butyl -2'-[3-(dimethylphosphoryl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-tert-butyl 2-(quinolin-3-yl)-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxylate ● (rac)- tert-butyl 2-(6-methoxyquinolin-3-yl)-6,7-dihydro-1'H,5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxylate ● (rac)-tert-butyl -2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxylate ● (rac)-tert-butyl -2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxylate ● (rac)-N-ethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-cyclobutyl-2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(rac)-2,2-dimethylcyclopropyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(1S)-2,2,2-trifluoro-1-methoxy-1-phenylethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyrimidin-5-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyrimidin-4-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● 2-(5-fluoropyridin-2-yl)-2-methyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]propan-1-one ● (rac)-N-[2-(5-fluoropyridin-2-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3,4-difluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-fluorophenyl)cyclopentyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(6-chloropyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-cyano-1,4-dihydropyridazin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-cyanopyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(4-phenyloxan-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-[6-(cyclohexyloxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-cyclobutyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-tert-butyl-5',6'-dihydro-1H- spiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-tert-butyl-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(dimethylphosphoryl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(cyclopropylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[3-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(3-oxomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(2-oxopyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(trifluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(3-chloropyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-[6-(difluoromethoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(propan-2-yl)-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-tert-butyl-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2'-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(5-amino-4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(cyclopropylmethyl)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(pyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(pyridin-2-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(3-methyloxetan-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-propyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2'-{3-[(pyridin-4-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-(propan-2-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● ()-N-(propan-2-yl)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[3-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(3-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(methanesulfonyl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-tert-butyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(3-fluoropyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(1R)-1-phenylethyl]-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[(rac)-1-(1,2-oxazol-3-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[2-(4-fluorophenyl)propan-2-yl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(quinolin-3-yl)-N-(1H-tetrazol-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine- 4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyridin-4-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-{(rac)-1-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]ethyl}-2'-(quinolin-3-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[(rac)-1-(1,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(quinolin-3-yl)-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3-thiazol-2-yl)ethyl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-phenyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-ethyl-5-methyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[1-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(rac)-1-(2-methylpyridin-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereosiomers) ● (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-phenylcyclobutyl)-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[(1R)-1-(5-fluoropyridin-3-yl)ethyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(4-fluorophenyl)propan-2-yl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-phenylpentan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(rac)-1-(1-methyl-1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-benzimidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3,4-trimethyl-1H-pyrazol-5-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-2'-(quinolin-3-yl)-N-[(rac)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(1R)-1-(1-ethyl-1H-pyrazol-5-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-{(rac)-1-[3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl]ethyl}-2'-(quinolin-3-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(rac)-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-[(1R)-1-phenylethyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of 2 diastereomers) ● (rac)-N-[1-(pyridin-4-yl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(pyridin-2-yl)propan-2-yl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(propan-2-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1H-imidazol-2-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(bicyclo[1.1.1]pentan-1-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(1-methylcyclobutyl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-[(pyridin-4-yl)methyl]-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(pyridin-4-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-[(pyridin-3-yl)methyl]-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(pyridin-4-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(pyridin-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-(quinolin-3-yl)-N-(2H-tetrazol-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-[(pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2,2-dimethylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[[1,1'-bi(cyclopropan)]-1-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(pyridin-3-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[[1,1'-bi(cyclobutan)]-1-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-cyclopropylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-methoxyphenyl)cyclobutyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(pyridin-4-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(pyridin-2-yl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-benzylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(quinolin-3-yl)-N-[1-(trifluoromethyl)cyclobutyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-methylcyclopentyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-cyanocyclopropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(propan-2-yl)cyclopropyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2-cyanopropan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2-phenylpropan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-chlorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-phenylcyclopropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(2,2-dimethylpropyl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-(cuban-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-(3,3-dimethylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(cis/trans)-3-(dimethylamino)cyclobutyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereoisomers) ● (rac)-N-(1-cyanocyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydro-1H-spiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(bicyclo[1.1.1]pentan-1-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(3,3-difluorocyclobutyl)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[(cis/trans)-3-methylcyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of stereoisomers) ● (rac)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-methylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[(1R)-1-phenylethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-N-[2-(pyridin-4-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-[2-(pyridin-4-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3-fluoropyridin-2-yl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(2,6-difluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(2-fluorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(4-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(2-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[2-(3-chlorophenyl)propan-2-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(4-fluorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(3-fluorophenyl)cyclobutyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-chlorophenyl)cyclobutyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(1-phenylcyclobutyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[1-(pyridin-4-yl)cyclobutyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-[1-(2-chlorophenyl)cyclobutyl]-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[2-(pyridin-2-yl)propan-2-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-[1-(pyridin-2-yl)cyclobutyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(quinolin-3-yl)-6,7-dihydrospiro[pyrazolo[5,1-c][1,4]oxazine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2'-[7-(morpholin-4-yl)-1,6-naphthyridin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-(5-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-2'-[6-(difluoromethoxy)quinolin-3-yl]-N-(1-phenylcyclobutyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(morpholin-4-yl)-1,5-naphthyridin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[3-(1-phenylcyclohexyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(1-phenylcyclobutyl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(3-methylphenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-(6-methylquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(7-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(1,3-thiazol-2-yl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[7-(dimethylamino)-1,6-naphthyridin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(2-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[2-(4-fluorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[2-(4-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[2-(3-chlorophenyl)propan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(methylamino)-1,5-naphthyridin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(dimethylamino)-1,5-naphthyridin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-amino-1,5-naphthyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-methoxyquinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{7-fluoro-6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-methoxyquinolin-3-yl)-N-(1-phenylcyclobutyl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3H-imidazo[4,5-b]pyridin-6-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-2-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5- a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(5-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (rac)-N-ethyl-2-(6-fluoroquinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-2-(6-chloroquinolin-3-yl)-N-ethyl-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-2'-(5-chloro-6-methoxyquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)carbamoyl]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-tert-butylquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)methoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-2-yl)methoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● methyl {3-[(rac)-1-(ethylcarbamoyl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-2'-yl]quinolin-6-yl}acetate ● (rac)-2'-[6-(cyclohexyloxy)-7-fluoroquinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{7-fluoro-6-[(oxan-4-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(3-cyano-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydro-5H- spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine]-1'-carboxamide ● (1-benzylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (cuban-1-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (1-ethylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● [1-(difluoromethyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● 2-(pyridin-3-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● [1-(4-chlorophenyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (1-methylcyclobutyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● [1-(4-fluorophenyl)cyclobutyl][(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● 2-cyclobutyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● (1-methylcyclopropyl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● (3-methyloxetan-3-yl)[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]methanone ● cyclobutyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● cyclopentyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● 2-cyclopropyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● 2-phenyl-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● phenyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]methanone ● 2-methoxy-1-[(rac)-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one ● [(rac)-2,2-difluoro-1-methylcyclopropyl][(rac)-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of diastereomers) ● (rac)-N-ethyl-2'-{5-[(pyridine-3-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridine-4-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridine-2-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● 1-[(rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]-2-(1-methyl-1H-imidazol-2-yl)ethan-1-one ● 2-(1H-imidazol-2-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● 2-(1-methyl-1H-imidazol-2-yl)-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● (rac)-N-ethyl-2'-{6-[(2-hydroxy-2-methylpropyl)carbamoyl]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(oxane-4-carbonyl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-acetamidoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-[5-(2,2-dimethylpropanamido)quinolin-3-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[5-(2-methylpropanamido)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-benzamidoquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● [(rac)-2,2-difluoro-1-methylcyclopropyl][-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of stereoisomers). ● [(rac)-2,2-difluoro-1-methylcyclopropyl][-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazol]-1-yl]methanone (mixture of stereoisomers) ● N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) ● N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) ● N-cyclobutyl-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine-3,4-pyrrolo[1,2-b]pyrazole]- 1-carboxamide (enantiomer 1) ● N-cyclobutyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]- 1-carboxamide (enantiomer 2) ● 2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) ● 2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) ● 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 1) ● 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (enantiomer 2) ● N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 1) ● N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxamide (enantiomer 2) ● 2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide (enantiomer 1) ● 2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6,7-dihydrospiro[pyrazolo[5,1- c][1,4]oxazine-4,3'-pyrrolidine]-1'-carboxamide (enantiomer 2) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isomer 1) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isiomer 2) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isiomer 3) ● 1-[1-(1H-imidazol-2-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (isiomer 4) ● 1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 1) ● 1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (enantiomer 2) ● (rac)-2'-{3-[(E)-2-(dimethylphosphoryl)ethenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(1H- imidazol-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(thiophen-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-chlorothiophen-2-yl)methyl]-2-(quinolin-3-yl)-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1H-1,2,3-triazol-5-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(thiophen-3-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(thiophen-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,3-thiazol-2-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1,3-oxazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(4-chloro-1H-pyrazol-3- yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1'-[(4-chloro-1H-pyrazol-5-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5- yl]-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] ● (rac)-2'-{3-[(rac)-butan-2-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-[(1H-imidazol-2-yl)methyl]- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1'-[(1H-imidazol-2-yl)methyl]-2-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6,7- dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(2-phenylpropan-2-yl)-1H-pyrrolo[2,3-b]pyridin- 5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1'-[(1H-imidazol-2-yl)methyl]-6,7-dihydro- 5H-spiro[pyrazolo[1,5-a]pyridine-4,3'-pyrrolidine] ● (rac)-2'-(quinolin-3-yl)-1-[(4H-1,2,4-triazol-3-yl)methyl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● 1-[(rac)-1-(1H-imidazol-2-yl)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] (mixture of two isomers) ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-methyl-1H-imidazol-2-yl)methyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H- pyrrolo[2,3-b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(rac)-1-(4H-1,2,4-triazol-3-yl)ethyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(5-ethyl-4-methyl-1H-imidazol-2-yl)methyl]-2-(quinolin-3-yl)-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(5-cyclopropyl-1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(rac)-1-(1H-imidazol-2-yl)ethyl]-2'-[3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3- b]pyridin-5-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(rac)-cyclopropyl(1H-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-{3-[(4-methylpyridin-3-yl)ethynyl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(4-methyl-1H-pyrazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(rac)-(1H-imidazol-2-yl)(phenyl)methyl]-2'-(quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (mixture of diastereomers) ● (rac)-1-[(4-chloro-1H-pyrazol-3-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(4-chloro-3-methyl-1H-pyrazol-5-yl)methyl]-2'-(3-cyclobutyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(quinolin-3-yl)-1-[(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(propan-2-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● (rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] ● trifluoroacetic acid—(rac)-1-[(1H-imidazol-2-yl)methyl]-2'-(3-methyl-1H-pyrrolo[2,3- b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1) ● (rac)-N-ethyl-2'-[6-(4-methyl-2-oxopiperazin-1-yl)quinolin-3-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(2-oxopyrrolidin-1-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-(6-{[dimethyl(oxo)-lambda6-sulfanylidene]amino}quinolin-3-yl)-N-ethyl-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(2,2-dimethyl-2lambda6-diazathia-1,2-dien-1-yl)quinolin-3-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(1-methyl-1H-pyrazol-5-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(1H-pyrazol-5-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(1-methyl-1H-pyrazol-4-yl)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-cyclopropylquinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[(prop-2-en-1-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[3-(dimethylamino)propoxy]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[(oxan-4-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[6-(3-methoxypropoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[2-(morpholin-4-yl)ethoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(6-{[(rac)-butan-2-yl]oxy}quinolin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2'-(6-{[(rac)-oxolan-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2'-{6-[2-(methylsulfanyl)ethoxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{[(rac)-oxolan-3-yl]oxy}quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2'-[6-(2-methylpropoxy)quinolin-3-yl]-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[2-(dimethylamino)ethoxy]quinolin-3-yl}-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[6-(2-methoxyethoxy)quinolin-3-yl]-5,6-dihydrospiro[pyrrolidine-3,4- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{[(rac)-1-methylpiperidin-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of diastereomers) ● (rac)-N-ethyl-2'-(5-{[(oxan-4-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[methyl(1-methylazetidin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(oxetan-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[methyl(oxetan-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(1-methylazetidin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{5-[(cyclopentylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyrrolidine-1-carbonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-{[cyclobutyl(methyl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(1-methylcyclobutyl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-{[cyclopropyl(methyl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(5-{[(bicyclo[1.1.1]pentan-1-yl)carbamoyl]amino}quinolin-3-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{5-[(cyclobutylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[5-({[2-(trifluoromethyl)cyclopropyl]carbamoyl}amino)quinolin-3-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{5-[(cyclopropylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{5-[(cyclohexylcarbamoyl)amino]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-{[(pyridin-3-yl)carbamoyl]amino}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-{5-[(ethylcarbamoyl)amino]quinolin-3-yl}-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● methyl (1-{[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methyl}cyclopropyl)acetate ● 3-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propanoic acid ● [(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetonitrile ● N-methoxy-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]acetamide ● N-cyclopropyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]acetamide ● (rac)-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]propanamide (mixture of stereoisomers) ● 2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazol]-1- yl]acetamide ● N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]acetamide ● (rac)-N-methyl-2-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl] (mixture of isomers) ● (rac)-3'-bromo-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-3'-methyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3'-cyclopropyl-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[1-(cyclopropylmethyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(1,4-dimethyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(propan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3- b]pyridin-5-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(2-methylpropyl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2-[3-(2-cyanophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-{3-cyano-4-[(propan-2-yl)oxy]phenyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl- 5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(1-phenyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(1-ethyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(1-cyclopropyl-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-3'-cyclopropyl-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-3'-bromo-N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(2,5-dihydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[2-(methylamino)-2-oxoethoxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-[6-(2-amino-2-oxoethoxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[2-(morpholin-4-yl)-2-oxoethoxy]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{6-[2-(dimethylamino)-2-oxoethoxy]quinolin-3-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-benzyl-N'-cyano-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboximidamide ● (rac)-N-(oxetan-3-yl)-2-(quinolin-3-yl)-6,7-dihydro-5H-spiro[pyrazolo[1,5-a]pyridine-4,3'- pyrrolidine]-1'-carboxamide ● (rac)-1-(propane-2-sulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-2-(3-benzoyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5,6-dihydrospiro[pyrrolidine- 3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[(rac)-hydroxy(phenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (mixture of steroisomers) ● (rac)-2'-{3-[2-(dimethylphosphoryl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● ethyl (rac)-2'-{3-[1-(propan-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate ● (rac)-2'-[3-(ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-{3-[(dimethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{3-[1-(trifluoromethyl)cyclopropyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● (rac)-2'-[5-(benzyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-(cyclopropanecarbonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(6-{[(rac)-1-methyl-5-oxopyrrolidin-3-yl]methoxy}quinolin-3-yl)-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide (only one group of and/or stereo is supported now.) ● cyclopropyl[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]methanone ● (rac)-2'-(8-amino-1,7-naphthyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-(5-hydroxy-1,6-naphthyridin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridin-2-yl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridine-2-sulfonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{5-[(pyridine-3-sulfonyl)amino]quinolin-3-yl}-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2-[6-(2-hydroxy-2-methylpropyl)quinolin-3-yl]-5,6- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-1-(1-methyl-1H-imidazol-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole] ● (rac)-N-ethyl-2'-{5-[(pyridin-3-yl)amino]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'- dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxamide ● (rac)-N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide ● 2-amino-1-[(rac)-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'- pyrrolo[1,2-b]pyrazol]-1-yl]ethan-1-one ● 2-amino-1-[(rac)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[pyrrolidine-3,4'-pyrrolo[1,2- b]pyrazol]-1-yl]ethan-1-one and their polymorphs, enantiomers, diastereomers, racemates, tautomers, solvates, physiologically acceptable salts and solvates of these salts. 10. A compound of general formula (I) according to any one of claims 1 to 9 for the use as a medicament. 11. A compound of general formula (I) according to any one of claims 1 to 9 for use in the treatment or prophylaxis of a disease. 12. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients. 13. A pharmaceutical combination comprising: one or more first active ingredients, in particular compounds of general formula (I) according to any one of claims 1 to 9, and one or more pharmaceutical active anti cancer compounds or one or more pharmaceutical active immune checkpoint inhibitors. 14. A pharmaceutical combination according to claim 13, characterized in that the pharmaceutical active immune checkpoint inhibitor is an antibody. 15. Use of a compound of general formula (I) according to any one of claims 1 to 9 for the treatment or prophylaxis of a disease. 16. Use of a compound of general formula (I) according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a disease. 17. Use according to claim 15 or 16, wherein the disease is cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, such as liquid and solid tumours. 18. Use according to claim 15 or 16, wherein the diseases, respectively the disorders are benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, neurodegenerative disorders, in inflammatory disorders, and male fertility control. 19. The intermediates for the synthesis of compounds of claim 1 or 2 wherein R1 has the meaning as R1 in claim 1 or 2.
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WO2021249913A1 (en) * 2020-06-09 2021-12-16 Bayer Aktiengesellschaft 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate derivatives and related compounds as map4k1 (hpk1) inhibitors for the treatment of cancer
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
WO2022167627A1 (en) * 2021-02-05 2022-08-11 Bayer Aktiengesellschaft Map4k1 inhibitors
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WO2019164847A1 (en) * 2018-02-20 2019-08-29 Incyte Corporation Indazole compounds and uses thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
WO2021249913A1 (en) * 2020-06-09 2021-12-16 Bayer Aktiengesellschaft 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate derivatives and related compounds as map4k1 (hpk1) inhibitors for the treatment of cancer
WO2022167627A1 (en) * 2021-02-05 2022-08-11 Bayer Aktiengesellschaft Map4k1 inhibitors

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