WO2021249913A9 - 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 - Google Patents

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 Download PDF

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WO2021249913A9
WO2021249913A9 PCT/EP2021/065122 EP2021065122W WO2021249913A9 WO 2021249913 A9 WO2021249913 A9 WO 2021249913A9 EP 2021065122 W EP2021065122 W EP 2021065122W WO 2021249913 A9 WO2021249913 A9 WO 2021249913A9
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pyrrolo
dihydrospiro
azetidine
pyrazole
alkyl
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PCT/EP2021/065122
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French (fr)
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WO2021249913A1 (en
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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
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Bayer Aktiengesellschaft
Deutsches Krebsforschungszentrum
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Publication of WO2021249913A1 publication Critical patent/WO2021249913A1/en
Publication of WO2021249913A9 publication Critical patent/WO2021249913A9/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • 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.
  • 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.
  • 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.
  • MAP4K1 also known as hematopoietic progenitor kinase 1 (HPK1).
  • HPK1 hematopoietic progenitor kinase 1
  • MAP4K1 (GenelD11184) 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 The function of MAP4K1 has been studied in greatest detail in the context of TCR signaling.
  • MAP4K1 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 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.
  • 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.
  • MAP4K1 ⁇ deficient mice show an apparent normal phenotype, are fertile and exhibit normal lymphocyte development.
  • MAP4K1 ⁇ / ⁇ T ⁇ 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).
  • 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. Also elimination of
  • HPK1 inhibitors and their uses are described. These compounds differ from the instant compounds in their chemical structure.
  • 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.
  • 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.
  • MAP4K1 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 thereby enhance tumor immunogenicity leading to inhibition of cancer cells growth by the immune response. Accordingly, they provide novel structures for the therapy of human and animal disorders, in particular of cancers.
  • the present invention relates to compounds of formula (I) in which both A represent either ⁇ CH 2 ⁇ or ⁇ CH 2 ⁇ CH 2 ⁇ , R3 represents ⁇ H or ⁇ CH 3 , X represents either a direct bond, ⁇ CH 2 ⁇ or ⁇ O ⁇ ,
  • Y represents ⁇ H, ⁇ Cl, ⁇ F, ⁇ Br, ⁇ CN, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalkyl
  • R v represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R w represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl or ⁇ CH 2 ⁇ CF 3 or in which N
  • R n represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R o represents C 1 ⁇ C 6 ⁇ hydroxyalkyl, 5 ⁇ or 6 ⁇ membered heteroaryl (N), or or in which N, R n and R o together form a 3 ⁇ to 7 ⁇ membered heterocycloalkyl, optionally substituted with ⁇ CN
  • R 5 represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl, ⁇ F or ⁇ Cl
  • R 15 represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl, ⁇ CF 3 , ⁇ F, ⁇ Cl, ⁇ O ⁇ CH 3 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) (I) in which both A represent either ⁇ CH 2 ⁇ or ⁇ CH 2 ⁇ CH 2 ⁇ , R 3 represents ⁇ H or ⁇ CH 3 , X represents either a direct bond, ⁇ CH 2 ⁇ or ⁇ O ⁇ , Y represents ⁇ H, ⁇ Cl, ⁇ F, ⁇ Br, ⁇ CN, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalkyl, R 1 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, C 1 ⁇ C 4 ⁇ fluoroalkyl, ⁇ OCF 3 , ⁇ OCF 2 H, halogen, C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalky
  • 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, 2,
  • 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.
  • 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.
  • 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.
  • 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 ⁇ methyl ⁇ amino, 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.
  • 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
  • heterocycloalkyl group may 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 ⁇ dioxany
  • “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.
  • 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, azabicyclo[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
  • 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, benzimidazoly
  • 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.
  • a 5 ⁇ membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazoly
  • 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 5 , and C 5 ⁇ C 6 ;
  • C 3 ⁇ C 10 encompasses C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 3 ⁇ C 10 , C 3 ⁇ C 9 , C 3 ⁇ C 8 , C 3 ⁇ C 7 , C 3 ⁇ C 6 , C 3 ⁇ C 5 , C 3 ⁇ C 4 , C 4 ⁇ C 10 , C 4 ⁇ C 9 , C 4 ⁇ C 8 , C 4 ⁇ C 7 , 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 ⁇ triisopropyl
  • 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.
  • 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.
  • 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.
  • polar solvents in particular water
  • 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 may 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. 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 ⁇
  • 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.
  • R 3 represents ⁇ H
  • X represents either a direct bond, ⁇ CH 2 ⁇ or ⁇ O ⁇
  • Y represents ⁇ H, ⁇ Cl, ⁇ Br, ⁇ CN, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalkyl
  • R 1 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 * ⁇ CR a H ⁇ , in which R a represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl or C 3 ⁇ C 7 ⁇ cycloalkyl all optionally substituted with ⁇ OH, halogen, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, ⁇ CN, ⁇ S(O) 2 ⁇ CH 3 , ⁇ S(O)(NR z ) ⁇ CH 3 , C 1 ⁇ C 4 ⁇ alkoxy, an ox
  • R c represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R v represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R w represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl or ⁇ CH 2 ⁇ CF 3 or in which N
  • R n represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R o represents C 1 ⁇ C 6 ⁇ hydroxyalkyl, 5 ⁇ or 6 ⁇ membered heteroaryl (N), or or in which N, R n and R o together form a 3 ⁇ to 7 ⁇ membered heterocycloalkyl, optionally substituted with ⁇ CN
  • R 5 represents ⁇ H, ⁇ F or ⁇ Cl
  • R 15 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 R 2 is selected from or .
  • D) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R 2 is E) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R 2 is and wherein R 4 is selected from hydrogen, ⁇ F, ⁇ Cl, methyl, ethyl and isopropyl.
  • G) Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein X is a direct bond.
  • G 1 ) Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein X is oxygen.
  • 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.
  • 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 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.
  • 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.
  • gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
  • pancreatic cancer examples 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 examples 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, sarcoma and small cell carcinoma.
  • 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. provide for treating a broader spectrum of different cancer types in mammals, especially humans, 5. provide for a higher response rate among treated patients,
  • 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. 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.
  • 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 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
  • 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, flu
  • talimogene laherparepvec tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium ( 99m Tc) nofetumomab merpentan, 99m Tc ⁇ 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, trama
  • 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.
  • 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).
  • PCKD polycystic kidney disease
  • SIADH syndrome of inappropriate ADH secretion
  • 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, a
  • 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
  • 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.
  • 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,
  • 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
  • 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 ⁇
  • 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 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).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • 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.
  • 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
  • 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,
  • ⁇ flow regulators for example magnesium stearate, stearic acid, talc, highly ⁇ disperse silicas (such as, for example, Aerosil ® )
  • ⁇ coating materials for example sugar, shellac
  • 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, hydroxypropylmethylcellulose 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 ® )), ⁇ capsule materials (for example gelatine,
  • 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 and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds
  • 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.
  • 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.
  • a unit dosage contains 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
  • 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.
  • ⁇ n intensity n .
  • 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 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.
  • 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
  • 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.
  • Pd(PPh 3 ) 4 tetrakis(triphenyl ⁇ lambda 5 ⁇ phosphanyl)palladium PPh 3 triphenylphosphine PyBroP bromo(tripyrrolidin ⁇ 1 ⁇ yl)phosphonium hexafluorophosphate RT or rt room temperature sat.
  • 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.
  • 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
  • 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.
  • 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.
  • Analytical LC ⁇ MS methods Method 1: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 ⁇ m, 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 ⁇ 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.
  • interconversion of any of the substituents can be achieved before and/or after the exemplified transformations.
  • 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.
  • 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”, 4 th edition, Wiley 2006). Specific examples are described in the subsequent paragraphs.
  • Scheme 1 Route for the preparation of building blocks of general formula 13 and 15, 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, an ethyl group or a tert ⁇ butyl group, A, R 1 , R 2 , R 3 and Y have the meaning as given for general formula (I). Suitable starting materials 1 are commercially available or described in the literature. Step 1 ⁇ 3 (Scheme 1) Alkylation In the first step (scheme 1), ester derivative 1 can be alkylated using an alkylbromide or alkyliodide of
  • ester 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) beta ⁇ Keto ester formation Methylester 3 is reacted with a methyl acetate or tert ⁇ butyl acetate to give beta ⁇ 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 Pyrazol formation beta ⁇ 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 Deprotection of PG 2
  • the protecting group PG 2 of pyrazoles of formula 5 can be cleaved to give an alcohol of formula 6.
  • 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).
  • 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.
  • 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.
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • triphenylphosphine in an organic solvent such as for example THF
  • THF organic solvent
  • Step 7 ⁇ 8 Scheme 1
  • Triflate formation Spiro compounds of formula 7 can be converted to triflates of formula 8.
  • 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.
  • 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
  • Step 8 ⁇ 9 (Scheme 1) Deprotection of PG 1
  • 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).
  • PG 1 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 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 for example tertiary amines, amides, ureas, carbamates or sulphonamides of formula 10. All these transformations are known to the skilled person.
  • Step 10 ⁇ 13 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.
  • Pd(0) catalysts like tetrakis(triphenyl ⁇ phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di ⁇ palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine) ⁇ palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], 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 amino
  • 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.
  • the coupling reaction is catalyzed by palladium catalysts, e.g.
  • Pd(0) catalysts like tetrakis(triphenyl ⁇ phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di ⁇ palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine) ⁇ palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], 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 amino
  • 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 PG 1
  • 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).
  • PG 1 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.
  • Step 13 ⁇ 14 Bromination Pyrazole compounds of formula 13 can be converted to bromides of formula 14. Typically the reaction is performed using NBS in an organic solvent such as for example DMF.
  • Step 14 ⁇ 15 Scheme 1: Functional group interconversion Bromides 14 can be converted to compounds of the general formula 15 by using functional group interconversion reactions known to the skilled person.
  • Scheme 2 Alternative route for the preparation of building blocks of general formula 7, wherein PG 1 represents a suitable amine protecting group (e.g.
  • Step 1 ⁇ 17 Alkylation Compounds of the general formula 1 can be converted to compounds of the general formula 17 by alkylation. Typically the reaction is performed with an alkylating agent such as for example 16, a base such as LiHMDS or LDA in an organic solvent such as THF.
  • an alkylating agent such as for example 16
  • a base such as LiHMDS or LDA
  • an organic solvent such as THF.
  • Step 17 ⁇ 18 (Scheme 2) beta ⁇ Keto ester formation Methylester 17 is reacted with a methyl acetate or tert ⁇ butyl acetate to give beta ⁇ keto esters of the general formula 18.
  • 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 18 ⁇ 19 (Scheme 2) Pyrazol formation beta ⁇ Keto esters of formula 18 can be converted with hydrazine to the corresponding pyrazole derivatives of formula 19.
  • the reaction is performed in an organic solvent like ethanol at a
  • Step 19 ⁇ 7 (Scheme 2) Cyclization Compounds of the general formula 19 can be converted to compounds of formula 7. Reaction conditions are known to the skilled person. Typically the reaction is performed using Hg(OAc) 2 in an organic solvent such as THF followed by addition of sodium hydroxide in water followed by a reducing agent such as for example sodium borohydride.
  • Scheme 3 Route for the preparation of compounds of general formula 30, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), PG 3 represents a suitable pyrazole protecting group (e.g.
  • R represents a lower alkyl group
  • A, Y, R 1 , R 2 have the meaning as given for general formula (I).
  • Suitable starting materials 20 and 21 are commercially available or described in the literature.
  • Step 20 + 21 ⁇ 22 (Scheme 3) Pyrazole addition to the carbonyl group
  • Ketones of the general formula 21 and pyrazoles of the general formula 20 can be converted to compounds of the general formula 22.
  • 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 22 ⁇ 23 (Scheme 3) Protection with PG 3 Compounds of the general formula 22 can be converted to compounds of the general formula 23 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).
  • PG 3 in compounds of formula 23 is SEM, then 2 ⁇ (trimethylsilyl)ethoxymethylchloride, a base such as sodium hydride in an organic solvent such as THF can be used.
  • Step 23 ⁇ 24 (Scheme 3) Alkylation of the alcohol Alcohols of the general formula 23 can be converted to compounds of the general formula 24 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 24 ⁇ 25 (Scheme 3) Deprotection of PG 3
  • the protecting group PG 3 of pyrazole compounds of general formula 24 can be cleaved to give compounds of formula 25.
  • 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.
  • Mitsunobu reaction Compounds of the general formula 26 can be converted to the corresponding morpholine derivatives of the general formula 27 using Mitsunobu conditions known to the skilled person.
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • triphenylphosphine in an organic solvent such as for example THF
  • Step 27 ⁇ 28 (Scheme 3) Deprotection of PG 1
  • the protecting group PG 1 of spiro compounds of formula 27 can be cleaved to give amines of formula 28.
  • the cleavage of suitable amine protecting groups is well ⁇ known to the person skilled in the art (see for example P.G.M.
  • Halogen compounds of general formula 29 can be reacted with a boronic acid derivative R 2 ⁇ B(OR) 2 to give a compound of formula 30.
  • the coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenyl ⁇ phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di ⁇ palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine) ⁇ palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], 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,
  • 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.
  • Methyl acetate 14 ml, 170 mmol was dissolved in THF (300 ml) with molsieves under nitrogen, cooled to ⁇ 78°C, LiHMDS (170 ml, 1.0 M, 170 mmol; CAS ⁇ RN:[865 ⁇ 47 ⁇ 4]) was added dropwise and the mixture was stirred for 1 h at ⁇ 78°C.
  • LiHMDS 170 ml, 1.0 M, 170 mmol; CAS ⁇ RN:[865 ⁇ 47 ⁇ 4]
  • 1 ⁇ tert ⁇ butyl 4 ⁇ methyl 4 ⁇ (2 ⁇ [tert ⁇ butyl(dimethyl)silyl]oxy ⁇ ethyl)piperidine ⁇ 1,4 ⁇ dicarboxylate 17.4 g, 43.3 mmol, see intermediate 12) in THF (100 ml) was added dropwise at ⁇ 78°C.
  • tert-Butyl 4-(3-tert-butoxy-3-oxopropanoyl)-4-(3- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ propyl)piperidine- 1-carboxylate (6.10 g, 12.2 mmol) was solubilised in ethanol (25 ml), hydrazine—water (1/1) (1.8 ml, 37 mmol; CAS-RN:[7803-57-8]) was added and the mixture was stirred overnight at 80°C. It was evaporated and the residue was purified by flash chromatography to give 4.36 g (81 % yield) of the title compound.
  • Example 19 (pyrimidin ⁇ 4 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 ⁇ mL vial was placed a solution of pyrimidine ⁇ 4 ⁇ carboxylic acid (29 mg, 1.50 equiv, 0.234 mmol) in DMF (3 mL). To this was added DIPEA (201,61 mg, 10.00 equiv, 1.56 mmol).
  • Example 21 4 ⁇ oxo ⁇ 4 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]butanenitrile (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 3 ⁇ cyanopropanoic acid, CAS ⁇ RN: 16051 ⁇ 87 ⁇ 9)
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.234 (0.54), 2.272 (0.52), 2.638 (6.38), 2.659 (8.38), 2.681 (3.09), 2.913 (4.33), 2.935 (7.16), 2.959 (4.83), 3.616 (0.72), 4.123 (1
  • Example 23 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl) ⁇ 1 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]propan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl)propanoic acid, CAS ⁇ RN: [89532 ⁇ 73 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.076 (0.56), 2.273 (0.54), 2.641 (5.32), 2.663 (10.85), 2.685 (5.49), 2.855 (4.86
  • Example 25 2 ⁇ (pyrimidin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]ethan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and pyrimidin ⁇ 5 ⁇ ylacetic acid, CAS ⁇ RN: [5267 ⁇ 07 ⁇ 2]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.837 (1.16), 2.890 (0.54), 2.952 (5.04), 2.963 (3.30), 2.971 (3.00), 2.990 (2.05), 3.625 (10.09), 4.102 (0.44),
  • Example 27 (pyridin ⁇ 4 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and pyridine ⁇ 4 ⁇ carboxylic acid, CAS ⁇ RN [55 ⁇ 22 ⁇ 1]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.234 (0.63), 2.274 (0.84), 2.723 (0.67), 2.951 (5.38), 2.973 (8.79), 2.997 (5.74), 4.238 (6.63), 4.323 (1.85), 4.355 (7.87),
  • Example 29 1 ⁇ 2 ⁇ oxo ⁇ 2 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]ethyl ⁇ pyrrolidin ⁇ 2 ⁇ one (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and (2 ⁇ oxopyrrolidin ⁇ 1 ⁇ yl)acetic acid, CAS ⁇ RN [53934 ⁇ 76 ⁇ 2]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.946 (3.30), 1.971 (5.11), 1.996 (4.08), 2.237 (5.17), 2.264 (7.53), 2.291 (3.64), 2.728
  • Example 31 1 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carbonyl]cyclopropane ⁇ 1 ⁇ carbonitrile (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1 ⁇ cyanocyclopropanecarboxylic acid, CAS ⁇ RN: [6914 ⁇ 79 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.587 (7.78), 1.622 (13.90), 2.078 (2.18), 2.274 (0.52), 2.957 (3.05), 2.980 (3.12), 3.004 (3.01), 4.227 (8.57), 4.244
  • Example 33 (1 ⁇ methyl ⁇ 1H ⁇ imidazol ⁇ 5 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1 ⁇ methyl ⁇ 1H ⁇ imidazole ⁇ 5 ⁇ carboxylic acid, CAS ⁇ RN: [41806 ⁇ 40 ⁇ 0])
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.952 (1.75), 2.975 (3.08), 2.998 (1.93), 3.855 (16.00), 4.230 (1.93), 4.253 (3.18), 4.276 (2
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum.
  • Step 2 A solution of 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (1:1) (61 mg, 0.156 mmol, 1 eq.), 2 ⁇ methoxyethyl carbonochloridoate (32.5 mg, 0.234 mmol, 1.5 eq., CAS ⁇ RN: [628 ⁇ 12 ⁇ 6]) and N ⁇ ethyl ⁇ N,N ⁇ diisopropylamine (201.6 mg, 1.56 mmol, 10 eq.) in tetrahydrofuran (3 mL) was stirred under nitrogen at ambient temperature for two hours.
  • Example 38 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl)propan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl)propanoic acid, CAS ⁇ RN: [89532 ⁇ 73 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.149 (0.90), 1.463 (16.00), 1.484 (15.40), 2.074 (1.95),
  • Example 40 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ (pyrimidin ⁇ 5 ⁇ yl)ethan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and pyrimidin ⁇ 5 ⁇ ylacetic acid, CAS ⁇ RN: [5267 ⁇ 07 ⁇ 2])
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: ⁇ 0.011 (1.28), 0.011 (0.80), 0.748 (1.11), 0.835 (0.86), 0.883 (0.76), 0.943 (
  • Example 41 (3 ⁇ chlorophenyl)[6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 3 ⁇ chlorobenzoic acid, CAS ⁇ RN: [535 ⁇ 80 ⁇ 8]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.489 (8.05), 2.270 (2.80), 2.727 (2.31), 4.346 (2.59), 4.540 (2.94), 4.635 (2.55), 7.041 (16.00), 7.522 (3.62
  • Example 44 1 ⁇ 2 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ oxoethyl ⁇ pyrrolidin ⁇ 2 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 2 ⁇ (2 ⁇ oxopyrrolidin ⁇ 1 ⁇ yl)acetamide, CAS ⁇ RN: [7491 ⁇ 74 ⁇ 9])
  • Example 46 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carbonyl]cyclopropane ⁇ 1 ⁇ carbonitrile (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 1 ⁇ cyanocyclopropanecarboxylic acid, CAS ⁇ RN: [6914 ⁇ 79 ⁇ 0])
  • Example 47 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]ethan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and acetic acid, CAS ⁇ RN: [64 ⁇ 19 ⁇ 7])
  • Example 51 1 ⁇ [(2 ⁇ methylpyrimidin ⁇ 5 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL vial, 2 ⁇ methylpyrimidine ⁇ 5 ⁇ carbaldehyde (29.2 mg, 0.239 mmol, 1.00 equiv) and crude product 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (84 mg, 1.00 equiv, 0.217 mmol,
  • Example 52 N,N ⁇ dimethyl ⁇ 5 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methyl ⁇ 1,3 ⁇ thiazol ⁇ 2 ⁇ amine (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 2 ⁇ (dimethylamino) ⁇ 1,3 ⁇ thiazole ⁇ 5 ⁇ carbaldehyde (CAS ⁇ RN: [1005 ⁇ 28 ⁇ 3]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.813 (0.99), 2.836 (1.73), 2.8
  • Example 53 1 ⁇ [(1H ⁇ imidazol ⁇ 2 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1H ⁇ imidazole ⁇ 2 ⁇ carbaldehyde, CAS ⁇ RN: [10111 ⁇ 08 ⁇ 7])
  • Example 54 1 ⁇ [(pyrazolo[1,5 ⁇ a]pyrimidin ⁇ 3 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and pyrazolo[1,5 ⁇ a]pyrimidine ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [879072 ⁇ 59 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.274 (0.43), 2.796 (2.97), 2.818 (5.11), 2.842 (3.40), 3.449 (16.00), 3.840 (11.18), 4.148
  • Example 55 1 ⁇ [(1H ⁇ indazol ⁇ 3 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1H ⁇ indazole ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [5235 ⁇ 10 ⁇ 9])
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.144 (0.79), 2.271 (1.18), 2.726 (0.96), 2.813 (3.00), 2.835 (5.16), 2.859 (3.15), 3.479 (16.00), 3.994 (10.64), 4.148
  • Example 56 1 ⁇ (cyclohexylmethyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and cyclohexanecarbaldehyde, CAS ⁇ RN: [2043 ⁇ 61 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 0.868 (3.42), 0.907 (4.15), 0.945 (2.06), 1.110 (1.29), 1.183 (5.29), 1.227 (3.13), 1.270 (2.29), 1.649 (6.34), 1.682 (3.47), 1.731 (4.75),
  • Example 58 N,N ⁇ dimethyl ⁇ 5 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methyl ⁇ 1,3 ⁇ thiazol ⁇ 2 ⁇ amine (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 2 ⁇ (dimethylamino) ⁇ 1,3 ⁇ thiazole ⁇ 5 ⁇ carbaldehyde, CAS ⁇ RN: [1005 ⁇ 28 ⁇ 3]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.448 (3.06), 1.470 (3.05), 2.386 (0.53), 2.405
  • Example 59 6' ⁇ methyl ⁇ 1 ⁇ [(pyrazolo[1,5 ⁇ a]pyrimidin ⁇ 3 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and pyrazolo ⁇ [1,5 ⁇ a]pyrimidine ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [879072 ⁇ 59 ⁇ 0])
  • Example 60 1 ⁇ [(1H ⁇ indazol ⁇ 3 ⁇ yl)methyl] ⁇ 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and and 1H ⁇ indazole ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [5235 ⁇ 10 ⁇ 9])
  • Example 62 1 ⁇ (cyclopropanesulfonyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL via, crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (61 mg, 0.156 mmol, 1 eq.) was dissolved in DMF (3 mL) and was cooled in an ice ⁇ bath. DIPEA (201 mg, 1.56 mmol, 10 equiv) was added. Then cyclopropanesulfonyl chloride, (33 mg, 1.50 eq., 0.234 mmol, CAS ⁇ RN: [139631 ⁇ 62 ⁇ 2]) was added slowly to the above solution.
  • DIPEA 201 mg, 1.56 mmol, 10 equiv
  • Example 63 1 ⁇ (cyclopropanesulfonyl) ⁇ 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and and cyclopropanesulfonyl chloride, CAS ⁇ RN: [139631 ⁇ 62 ⁇ 2]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 0.980 (1.49), 0.996 (5.08), 1.003 (5.65), 1.018 (5.
  • Example 64 N ⁇ (pyridin ⁇ 3 ⁇ yl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL via, 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate ((61 mg, 0.156 mmol, 1 eq., 1.00 eq) was dissolved in 3 mL DMF and was cooled in an ice ⁇ bath. DIPEA (201 mg, 1.56 mmol, 10 eq, 1.56 mmol) was added.
  • Example 65 N ⁇ ethyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.009 (5.01), 1.025 (3.86), 1.033 (11.37), 1.047 (5.48), 1.056 (5.25), 1.071 (2.15), 2.870 (1.90),
  • Example 68 1 ⁇ (pyridin ⁇ 3 ⁇ yl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL vial, was placed a solution of crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (61 mg, 0.156 mmol, 1 eq.) in dioxane (3 mL).
  • Example 70 N ⁇ (2 ⁇ chloroethyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (50.0 mg, 181 ⁇ mol) was dissolved in DCM (2.1 ml), DIPEA (95 ⁇ l, 540 ⁇ mol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) was added, cooled to 0°C and 1 ⁇ chloro ⁇ 2 ⁇ isocyanatoethane (19.1 mg, 181 ⁇ mol) was added and the mixture was stirred overnight at ambient temperature. The mixture was evaporated and purified by preparative HPLC to yield the title compound (4.80 mg, 7 % yield).
  • Example 80 1 ⁇ (methanesulfonyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and methanesulfonyl chloride, CAS ⁇ RN: [124 ⁇ 63 ⁇ 0]) 1 H ⁇ NMR (400 MHz, DMSO ⁇ d6) delta [ppm]: 1.239 (0.43), 1.907 (0.68), 2.518 (4.42), 2.522 (2.82), 2.937 (1.55), 2.954 (2.16), 2.972 (1.67
  • Example 82 ethyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (50.0 mg, 181 ⁇ mol) was dissolved in DCM (930 ⁇ l), DIPEA (95 ⁇ l, 540 ⁇ mol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) was added, cooled to 0°C and ethyl carbonochloridate (19.6 mg, 181 ⁇ mol) was added and the mixture was stirred overnight at rt. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.70 mg, 95 % purity, 3 % yield). LC ⁇ MS (Method 3): Rt
  • Example 84 1 ⁇ [(4 ⁇ methyl ⁇ 1H ⁇ imidazol ⁇ 2 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2' ⁇ (quinolin ⁇ 3 ⁇
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (60.0 mg, 217 ⁇ mol) and 5 ⁇ methyl ⁇ 1H ⁇ imidazole ⁇ 2 ⁇ carbaldehyde (26.3 mg, 239 ⁇ mol) were dissolved in THF (2.9 ml).
  • Acetic acid (12 ⁇ l, 220 ⁇ mol; CAS ⁇ RN:[64 ⁇ 19 ⁇ 7]) and sodium triacetoxyborohydride (63.3 mg, 299 ⁇ mol; CAS ⁇ RN:[56553 ⁇ 60 ⁇ 7]) were added and the mixture was stirred overnight at room temperature under argon. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.10 mg, 95 % purity, 1 % yield).
  • Example 93 1 ⁇ [(1H ⁇ pyrazol ⁇ 5 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1H ⁇ pyrazole ⁇ 5 ⁇ carbaldehyde, CAS ⁇ RN: [948552 ⁇ 36 ⁇ 1])
  • Example 99 3 ⁇ (ethylamino) ⁇ 4 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]cyclobut ⁇ 3 ⁇ ene ⁇ 1,2 ⁇ dione
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (50.0 mg, 128 ⁇ mol) was dissolved in EtOH (1.5 ml), triethylamine (36 ⁇ l, 260 ⁇ mol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]) and 3,4 ⁇ diethoxycyclobut ⁇ 3 ⁇ ene ⁇ 1,2 ⁇ dione (43.6 mg,
  • Example 100 3 ⁇ (dimethylamino) ⁇ 4 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]cyclobut ⁇ 3 ⁇ ene ⁇ 1,2 ⁇ dione (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and N ⁇ methylmethanamine, CAS ⁇ RN: [124 ⁇ 40 ⁇ 3])
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum.
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (180 mg, 43 % purity, 198 ⁇ mol) was dissolved in DCM (2.0 ml, 31 mmol; CAS ⁇ RN:[75 ⁇ 09 ⁇ 2]), N,N ⁇ dimethylglycine (24.5 mg, 238 ⁇ mol), DIPEA (170 ⁇ l, 990 ⁇ mol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) and PyBroP (111 mg, 238 ⁇ mol; CAS ⁇ RN:[132705 ⁇ 51 ⁇ 2]) were added and it was stirred overnight at rt.
  • Example 102 3 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carbonyl]pyrrolidin ⁇ 2 ⁇ one (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 2 ⁇ oxopyrrolidine ⁇ 3 ⁇ carboxylic acid, CAS ⁇ RN: [96905 ⁇ 67 ⁇ 8])
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (100 mg, 256 ⁇ mol) was dissolved in DCM (4.5 ml), diphenyl cyanocarbonimidate (67.1 mg, 282 ⁇ mol) and triethylamine (71 ⁇ l, 510 ⁇ mol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]) were added and the mixture was stirred for 2 h at rt. The mixture was diluted with water and extracted 3x with DCM.
  • Step 3 phenyl N ⁇ cyano ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboximidate (60.0 mg, 50 % purity, 71.3 ⁇ mol) was dissolved in 2 ⁇ propanol (740 ⁇ l) and ethanamine (360 ⁇ l, 2.0 M, 710 ⁇ mol; CAS ⁇ RN:[75 ⁇ 04 ⁇ 7]) was added. The mixture was stirred overnight at 80°C. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.60 mg, 100 % purity, 6 % yield).
  • Example 111 N ⁇ [3 ⁇ (dimethylamino)propyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 To a solution of crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro ⁇ [azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (1.40 g, 3.59 mmol) in dichlormethane (59 mL) was added at ambient temperature under argon triethylamine (5.0 ml, 36 mmol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]) and 4 ⁇ nitrophenyl carbonochloridate (867 mg, 4.30 mmol). The reaction was stirred at ambient temperature overnight. DMA (18 mL) was added and the dichlormethane was removed under reduced pressure.
  • Step 3 To a solution of 4 ⁇ nitrophenyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (31.3 mg, 70.9 ⁇ mol) in N,N ⁇ dimethylacetamide (1.0 ml) under nitrogen were added N 1 ,N 1 ⁇ dimethylpropane ⁇ 1,3 ⁇ diamine (72.5 mg, 709 ⁇ mol) and K 2 CO 3 (14.4 mg, 142 ⁇ mol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]). The mixture was stirred overnight at 60°C. The mixture was purified by preparative HPLC to yield title compound (15.1 mg, 95 % purity, 50 % yield).
  • Example 118 (morpholin ⁇ 4 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and morpholine, CAS ⁇ RN: [110 ⁇ 91 ⁇ 8])
  • Example 130 N ⁇ ethyl ⁇ 2' ⁇ (1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide Step 1: To a solution of tert ⁇ butyl 2' ⁇ (1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 3) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (109 mg, 40 % purity, 115 ⁇ mol) was dissolved in DCM (3.0 ml) and DIPEA (200 ⁇ l, 1.1 mmol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) under nitrogen, isocyanatoethane (27 ⁇ l, 340 ⁇ mol) was added and the mixture was stirred overnight at rt. The solution was evaporated and purified by preparative HPLC to yield the title compound (21.8 mg, 95 % purity, 54 % yield).
  • Example 131 2' ⁇ (2 ⁇ aminopyrimidin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Example 132 2' ⁇ (6 ⁇ aminopyridin ⁇ 3 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (6 ⁇ aminopyridin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 168) and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0])
  • Example 144 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide N ⁇ ethyl ⁇ 2' ⁇ (2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (45.0 mg, 128 ⁇ mol, see example 140) was dissolved in DMF (450 ⁇ l), NCS (18.9 mg, 141 ⁇ mol; CAS ⁇ RN:[128 ⁇ 09 ⁇ 6]) and diphenylperoxyanhydride (34.2 mg, 141 ⁇ mol; CAS ⁇ RN:[94 ⁇ 36 ⁇ 0]
  • Example 148 ethyl 2' ⁇ (3 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from ethyl 2' ⁇ [(trifluoromethanesulfonyl)oxy] ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see intermediate 19) and 3 ⁇ methyl ⁇ 5 ⁇ (4,4,5,5 ⁇ tetramethyl ⁇ 1,3,2 ⁇ dioxaborolan ⁇ 2 ⁇ yl) ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridine, CAS ⁇ RN: [1111637 ⁇ 95 ⁇ 6]) LC ⁇ MS (Meth
  • Example 149 ethyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from prepared from ethyl 2' ⁇ [(trifluoromethanesulfonyl)oxy] ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see intermediate 19) and 3 ⁇ chloro ⁇ 5 ⁇ (4,4,5,5 ⁇ tetramethyl ⁇ 1,3,2 ⁇ dioxaborolan ⁇ 2 ⁇
  • Example 150 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ methyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (234 mg, 585 ⁇ mol, see example 170/intermediate 72) in dichloromethane (20 mL) was added under nitrogen at ambient temperature trifluoro acetic acid (1.5 ml, 19 mmol; CAS ⁇ RN:[76 ⁇ 05 ⁇ 1]) and the reaction was stirred at room temperature for four hours.
  • Step 2 To a solution of formaldehyde (20 ⁇ l, 37 % in water, 270 ⁇ mol; CAS ⁇ RN:[50 ⁇ 00 ⁇ 0]) and trifluoroacetic acid—2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (1/1) (127 mg, 59 % purity, 181 ⁇ mol) in THF (2.5 ml) was added under nitrogen at room temperature sodium triacetoxyborohydride (86.4 mg, 407 ⁇ mol; CAS ⁇ RN:[76 ⁇ 05 ⁇ 1]) and acetic acid (10 ⁇ l).
  • Example 153 was prepared in analogy to example 84:
  • Example 153 N N N NH N Cl H N CH 3 N 2' ⁇ (2 ⁇ chloro ⁇ 3 ⁇ ethyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ [(1H ⁇ imidazol ⁇ 2 ⁇ yl)methyl] ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (2 ⁇ chloro ⁇ 3 ⁇ ethyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 169/intermediate 80) and 1H ⁇ imidazole ⁇ 2 ⁇ carbaldehyde, CAS ⁇ RN: [10
  • Example 157 tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate tert ⁇ butyl 2' ⁇ (1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (60.0 mg, 152 ⁇ mol, see example 154) was dissolved in DMF (610 ⁇ l), NCS (22.4 mg, 168 ⁇ mol; CAS ⁇ RN:[128 ⁇ 09 ⁇ 6]) and diphenylperoxyanhydride (40.6 mg, 168 ⁇ mol; CAS ⁇ RN:[94 ⁇ 36 ⁇ 0]) were added and the mixture was stirred overnight at
  • Example 158 tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from tert ⁇ butyl 2' ⁇ (2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example155).
  • Example 160 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0])
  • Example 161 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 158) and and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0])
  • Example 162 N ⁇ ethyl ⁇ 2' ⁇ (3 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 171) and and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0]) 1H ⁇ NMR (400 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.010 (6.52), 1.028 (14.61), 1.046 (6.86), 1.232 (1.78), 1.565 (0.71), 1.574 (
  • Example 164 1 ⁇ [2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ methylpropan ⁇ 1 ⁇ one
  • Example 170/Inermediate 72 tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from intermediate 6 and and 3 ⁇ chloro ⁇ 5 ⁇ (4,4,5,5 ⁇ tetramethyl ⁇ 1,3,2 ⁇ dioxaborolan ⁇ 2 ⁇ yl) ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridine, CAS ⁇ RN: [1111638 ⁇ 73 ⁇ 3])
  • Example 176 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ (2,2,2 ⁇ trifluoroethyl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and 1,1,1 ⁇ trifluoro ⁇ 2 ⁇ isocyanatoethane, CAS ⁇ RN: [371 ⁇ 92 ⁇ 6]) LC ⁇ MS (Method 1): R
  • Example 178 1 ⁇ [2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ hydroxyethan ⁇ 1 ⁇ one
  • Example 180 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ (phenylmethanesulfonyl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and phenylmethanesulfonyl chloride, CAS ⁇ RN: [1939 ⁇ 99 ⁇ 7])
  • Example 181 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ (propane ⁇ 1 ⁇ sulfonyl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and propane ⁇ 1 ⁇ sulfonyl chloride, CAS ⁇ RN: [10147 ⁇ 36 ⁇ 1])
  • Example 185 2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 365 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.042 (0.42), 1.058 (15.83), 1.075 (16.00), 1.136 (0.42), 1.153 (0.42), 2.270
  • Example 201 N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide
  • Example 217 2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • Example 224 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3,3,3-trifluoropropyl)-5',6'-dihydrospiro[piperidine- 4,4'-pyrrolo[1,2-b]pyrazole]
  • Example 228 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(propan-2-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole]
  • Example 231 [2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridin]-1-yl](oxan-4-yl)methanone
  • MS (ESIpos): m/z 454 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.938 (0.83), 0.954 (0.82), 1.519 (0.83), 1.551 (1.95), 1.574 (1.62), 1.604 (3.12), 1.631 (1.80), 1.659 (2.29), 1.692 (2.65), 1.721 (1.88), 1.734 (2.24), 1.748 (2.31), 1.7
  • Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5’,6’-dihydrospiro[piperidine- 4,4’-pyrrolo[1,2-b]pyrazole] (1/1) (100 mg, 69 % purity, 156 ⁇ mol) was solubilised in DMSO (1.0 ml), methanesulfonyl chloride (17.9 mg, 156 ⁇ mol) and triethylamine (65 ⁇ l, 470 ⁇ mol) were added and the mixture was stirred overnight at rt.
  • Example 234 2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine- 4,4'-pyrazolo[1,5-a]pyridine]-1-carboxamide
  • N-Ethyl-2’-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7’-dihydro-5’H-spiro[piperidine-4,4’- pyrazolo[1,5-a]pyridine]-1-carboxamide 39.0 mg, 99.4 ⁇ mol
  • NCS 14.6 mg, 109 ⁇ mol
  • benzoyl peroxide 35.3 mg, 75 % purity, 109 ⁇ mol
  • 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 was used as Alexa647 ⁇ labelled ATP ⁇ competitive kinase inhibitor.
  • test compounds were tested on the same microtiterplate in 11 different concentrations in the range of 20 ⁇ M to 0.07 nM (20 ⁇ M, 5.7 ⁇ M, 1.6 ⁇ M, 0.47 ⁇ M, 0.13 ⁇ M, 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 ScreenerTM software.
  • Table 1 Measured IC 50 values of compounds regarding inhibition of MAP4K1 (HPK1):
  • Phosphorylation assay in human cell line using HTRF Assay 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 transferred to a 384 well format plate at a cell density of 140.000 cells/well and simultaneously treated with 1 ⁇ g/mL a ⁇ CD3 antibody (clone OKT3.
  • the detection of pSer376 ⁇ SLP76 levels in the proprietary Jurkat cell lines was carried out utilizing an adapted protocol of the HTRF pSLP76 Assay (Cisbio # 63ADK076PEG).
  • Cells were lysed using 4 ⁇ l of the supplemented lysis buffer (Cisbio # 63ADK076PEG) for 60 min at room temperature.
  • 4 ⁇ l of the premixed antibody solution (Cisbio # 63ADK076PEG) was added and incubated over night at room temperature. Read ⁇ out and analyses was carried out using a Pherastar and the MARS software (BMG Labtechnologies, Offenburg, Germany).
  • Inhibition constant (IC 50 ) values were calculated by concentration ⁇ response curve fitting applying four ⁇ parameter nonlinear regression analyse.
  • maximal effect maximally possible inhibition of pSer376 ⁇ SLP ⁇ 76 by a test compound
  • cells with no a ⁇ CD3 (clone OKT3. ebioscience #16 ⁇ 0037 ⁇ 85) 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).

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, respectively 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

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
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 (GenelD11184) 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 l;95(l):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 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 thereby enhance  tumor  immunogenicity    leading  to  inhibition  of  cancer  cells  growth  by  the  immune  response.  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)  in which 
Figure imgf000008_0001
both A  represent either ‐CH2‐ or ‐CH2‐CH2‐,  R3  represents ‐H or ‐CH3,  X  represents either a direct bond, ‐CH2‐ or ‐O‐,   
Y  represents ‐H, ‐Cl, ‐F, ‐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  •   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,   •  ,   • 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‐,   •  , 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)),   
• ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted  with ‐F or ‐Cl;  • 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,  • or in which 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  ,  ,  ,   
,   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   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)   (I)  in which  both A  represent either ‐CH2‐ or ‐CH2‐CH2‐,  R3  represents ‐H or ‐CH3,  X  represents either a direct bond, ‐CH2‐ or ‐O‐,  Y  represents ‐H, ‐Cl, ‐F, ‐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)),   • ‐phenyl, C3‐6‐cycloalkyl,   • ‐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  •   in which R6 and R7 are independently of each other hydrogen, ‐CH3  or bridged by C1‐C4‐alkyl in which one ‐CH2‐group can be replaced by oxygen,   •   or  ;  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,   •  ,   • 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‐,   •  , 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)),  • ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted  with ‐F or ‐Cl;  • 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,  • or in which 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  ,  ,  ,  ,   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‐cycloalkoxy,   • 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   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‐methyl‐ amino, 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: methylaminocarbonyl, ethylaminocarbonyl,   
n‐propylaminocarbonyl,  isopropylaminocarbonyl, n‐butylaminocarbonyl, 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‐methylaminocarbonyl,  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‐methylaminosulfonyl,  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,  azabicyclo[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,  thiazabicyclo[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‐butylphenyl)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  both A  represent ‐CH2‐,  R3  represents ‐H,  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   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,   ,   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)),  • ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted  with ‐F or ‐Cl;   
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   or  ,  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‐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, ‐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.  B) Of selected interest are also those compounds of formula (I)  in which  both A  represent ‐CH2‐,   
R3  represents ‐H,  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   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,   ,   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)),  • ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted  with ‐F or ‐Cl;  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   or  ,  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‐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, ‐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   or  .  D) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R2 is     E) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R2 is     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,   ,   or  .  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) or B) (page 25) wherein X is  oxygen.  G2) Of selected interest are those compounds definded under A) (page 6) or B) (page 25) 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 25) wherein Y is  hydrogen or ‐Cl.  I) Compounds of most interest are those as follows:  tert‐butyl 2'‐(2‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(2‐aminopyrimidin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐[5‐(trifluoromethyl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate   
(pyrimidin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (1‐methyl‐1H‐pyrazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanenitrile  3‐methoxy‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]propan‐1‐ one  3‐(1H‐pyrazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  2‐(morpholin‐4‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  2‐(pyrimidin‐5‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  (3‐chlorophenyl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (pyridin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]methanone  2‐ethyl‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butan‐1‐one  1‐{2‐oxo‐2‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethyl}pyrrolidin‐2‐one  (pyridin‐3‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]methanone  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]cyclopropane‐ 1‐carbonitrile  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐one  (1‐methyl‐1H‐imidazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  2‐methoxyethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  2‐methoxyethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyrimidin‐4‐ yl)methanone  (1‐methyl‐1H‐pyrazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐3‐(1H‐ pyrazol‐1‐yl)propan‐1‐one   
1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (morpholin‐4‐yl)ethan‐1‐one  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (pyrimidin‐5‐yl)ethan‐1‐one  (3‐chlorophenyl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐4‐ yl)methanone  2‐ethyl‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]butan‐1‐one  1‐{2‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ oxoethyl}pyrrolidin‐2‐one  [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐3‐ yl)methanone  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐one  (1‐methyl‐1H‐imidazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  3‐methoxy‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  4‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐4‐ oxobutanenitrile  1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  N,N‐dimethyl‐5‐{[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine  1‐[(1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐indazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐(cyclohexylmethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  6'‐methyl‐1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  N,N‐dimethyl‐5‐{[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine   
6'‐methyl‐1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐indazol‐3‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐(cyclohexylmethyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐(cyclopropanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐(cyclopropanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  6'‐methyl‐N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  6'‐methyl‐1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  N‐(2‐chloroethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  2'‐(quinolin‐3‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐cyclopentyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐tert‐butyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  methyl [2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]carbamate  N‐[(furan‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐(2‐methoxyethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐phenyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbothioamide   
1‐(methanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐(methanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  ethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  1‐[(4‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(imidazo[1,5‐a]pyridin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐{[1‐(propan‐2‐yl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(quinolin‐3‐yl)‐1‐{[4‐(trifluoromethyl)‐1H‐imidazol‐2‐yl]methyl}‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐(2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐{[1‐(2‐methoxyethyl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(quinolin‐3‐yl)‐1‐[(1,4,5‐trimethyl‐1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐benzimidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(1H‐pyrazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐[(4‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(2‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐[(5‐methyl‐1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  3‐(ethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione  3‐(dimethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione   
2‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  3‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one  4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one  2‐(1H‐imidazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanamide  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐(4H‐1,2,4‐triazol‐4‐ yl)ethan‐1‐one  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]prop‐2‐en‐1‐one  3‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  N'‐cyano‐N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide  N'‐cyano‐N,N‐dimethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide  N‐[3‐(dimethylamino)propyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐(oxan‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐{[‐oxolan‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (4‐methylpiperazin‐1‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  N‐[2‐oxopyrrolidin‐3‐yl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]azetidine‐3‐ carboxamide  N‐[(1H‐pyrazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  (morpholin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  N‐(3‐hydroxypropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide   
N‐(2‐hydroxyethyl)‐N‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐(2‐oxopiperidin‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐(6‐oxopiperidin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐[2‐(1H‐imidazol‐1‐yl)ethyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐benzyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐(2‐hydroxy‐2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐[(1‐methyl‐1H‐imidazol‐4‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐{[‐5‐oxopyrrolidin‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  [‐3‐(dimethylamino)pyrrolidin‐1‐yl][2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  N‐{2‐[oxolan‐3‐yl]ethyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  2'‐(2‐aminopyrimidin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  2'‐(6‐aminopyridin‐3‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide   
N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  ethyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  ethyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  ethyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate   
tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]ethan‐1‐one  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐methylpropan‐1‐one  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carbonyl]cyclopropane‐1‐carbonitrile  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](phenyl)methanone  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](oxan‐4‐yl)methanone  tert‐butyl 2'‐(6‐aminopyridin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide   
2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (rac)‐6'‐methyl‐N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (rac)‐N‐tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  N‐ethyl‐2'‐(6‐methoxyquinolin‐3‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]‐1‐ carboxamide  N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐yl}‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐phenyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(quinolin‐3‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]‐1‐ carboxamide  N‐ethyl‐2'‐[6‐(trifluoromethyl)quinolin‐3‐yl]‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐[3‐(propan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl]‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide   
N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide  N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐yl}‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  2'‐[6‐(cyclohexyloxy)quinolin‐3‐yl]‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  cyclopentyl (rac)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(5‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐ dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐c][1,4]oxazine]  2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  (rac)‐1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydrospiro[azetidine‐ 3,4'‐pyrazolo[5,1‐c][1,4]oxazine]  (rac)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydro‐5'H‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydro‐5'H‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(3,3,3‐trifluoropropyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]   
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]  1‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(cyclohexylmethyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1‐methyl‐1H‐pyrazol‐4‐yl)methyl]‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridin]‐1‐yl](4‐fluorophenyl)methanone  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridin]‐1‐yl](oxan‐4‐yl)methanone  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(methanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐sulfonamide  2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](morpholin‐4‐yl)methanone  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2‐hydroxy‐2‐methylpropyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐methyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐hydroxyethan‐1‐one   
1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐(pyridin‐3‐yl)ethan‐1‐one  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(phenylmethanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propane‐1‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐sulfonamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(pyridine‐3‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(morpholine‐4‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  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 under A) (page 6) or  B) (page 25), especially  , , or .  wherein R1, R3, A and Y have the same meaning as defined under A) (page 6) or B) (page 25).    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 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,  hydroxypropylcellulose,  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,  hydroxypropylmethylcellulose  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. The multiplicities are stated according to the signal form which appears  in the spectrum,  NMR‐spectroscopic effects of a higher order were not taken into consideration. Multiplicity of the NMR  signals: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br = broad signal, m = multiplet.  NMR signals: shift in [ppm]. Combinations of multiplicity could be e.g. dd = doublet from doublet.    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 braod 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.    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.    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 derivatives according to the present invention are preferably carried out according  to the general synthetic sequence, shown in schemes 1‐3.    
Figure imgf000082_0001
Scheme 1: Route  for  the preparation of building blocks of general  formula 13 and 15, 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, an ethyl group  or a tert‐butyl group, A, R1, R2, R3and Y have the meaning as given for general formula (I). Suitable starting  materials 1 are commercially available or described in the literature.   Step 1  ^ 3 (Scheme 1)  Alkylation  In the first step (scheme 1), ester derivative 1 can be alkylated using an alkylbromide or alkyliodide of   
formula 2 to give the desired product 3.   For example ester 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)  beta‐Keto ester formation   Methylester 3  is  reacted with a methyl acetate or  tert‐butyl acetate  to give beta‐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  beta‐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  8.  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 PG1  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 PG1 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 for example tertiary  amines,  amides,  ureas,  carbamates  or  sulphonamides  of  formula  10.  All  these  transformations  are  known to the skilled person.  Step 10  ^ 13 (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(triphenyl‐ phosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di‐palladium(0) [Pd2(dba)3], or by Pd(ll)  catalysts  like  dichlorobis(triphenylphosphine)‐palladium  (ll)  [Pd(PPh3)2CI2],  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(triphenyl‐ phosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di‐palladium(0) [Pd2(dba)3], or by Pd(ll)  catalysts  like  dichlorobis(triphenylphosphine)‐palladium  (ll)  [Pd(PPh3)2CI2],  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 PG1  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 PG1 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 13. All these tranformations are known to the  skilled person.    Step 13  ^ 14 (Scheme 1)  Bromination  Pyrazole compounds of formula 13 can be converted to bromides of formula 14. Typically the reaction  is performed using NBS in an organic solvent such as for example DMF.    Step 14  ^ 15 (Scheme 1)    Functional group interconversion  Bromides  14  can  be  converted  to  compounds  of  the  general  formula  15  by  using  functional  group  interconversion reactions known to the skilled person. 
Figure imgf000086_0001
Scheme 2: Alternative route for the preparation of building blocks of general formula 7, wherein PG1  represents  a  suitable  amine  protecting  group  (e.g.  Boc),  X1  represents  a  direct  bond  or  –CH2‐,  Z1  represents a methyl group or a tert‐butyl group and R3 represents a methyl group (In this method R3 can  only be a methyl group) and A has the meaning as given for general formula (I).    Step 1  ^ 17 (Scheme 2)  Alkylation  Compounds of the general formula 1 can be converted to compounds of the general formula 17 by  alkylation. Typically the reaction is performed with an alkylating agent such as for example 16, a base  such as LiHMDS or LDA in an organic solvent such as THF.    Step 17  ^ 18 (Scheme 2)  beta‐Keto ester formation   Methylester 17  is reacted with a methyl acetate or  tert‐butyl acetate to give beta‐keto esters of the  general formula 18. 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 18  ^ 19 (Scheme 2)  Pyrazol formation  beta‐Keto  esters  of  formula  18  can  be  converted  with  hydrazine  to  the  corresponding  pyrazole  derivatives of  formula 19. 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 19  ^ 7 (Scheme 2)  Cyclization  Compounds of the general formula 19 can be converted to compounds of formula 7. Reaction  conditions are known to the skilled person. Typically the reaction is performed using Hg(OAc)2 in an  organic solvent such as THF followed by addition of sodium hydroxide in water followed by a reducing  agent such as for example sodium borohydride.     
Figure imgf000088_0001
Scheme 3: Route for the preparation of compounds of general formula 30, wherein PG1 represents a  suitable amine protecting group  (e.g. Boc), PG3  represents a suitable pyrazole protecting group  (e.g.   
SEM), R represents a lower alkyl group, A, Y, R1, R2 have the meaning as given for general formula (I).  Suitable starting materials 20 and 21 are commercially available or described in the literature.     Step 20 + 21  ^ 22 (Scheme 3)  Pyrazole addition to the carbonyl group  Ketones  of  the  general  formula  21  and  pyrazoles  of  the  general  formula  20  can  be  converted  to  compounds of  the general  formula 22. 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 22  ^ 23 (Scheme 3)  Protection with PG3  Compounds of the general formula 22 can be converted to compounds of the general formula 23 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 PG3 in compounds of formula 23 is SEM, then 2‐ (trimethylsilyl)ethoxymethylchloride, a base such as sodium hydride in an organic solvent such as THF  can be used.  Step 23  ^ 24 (Scheme 3)  Alkylation of the alcohol  Alcohols of  the general  formula 23 can be converted  to compounds of  the general  formula 24  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 24  ^ 25 (Scheme 3)  Deprotection of PG3  The  protecting  group  PG3  of  pyrazole  compounds  of  general  formula  24  can  be  cleaved  to  give  compounds of formula 25. 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 PG3 in compounds of formula 24 is SEM, cleavage  can be achieved using e.g. TFA in an organic solvent such as DCM.   Step 25  ^ 26 (Scheme 3)  Reduction of the ester   Esters of the general formula 25 (R = lower alkyl group) can be converted to the corresponding alcohols  of the general formula 26 with hydride reducing agents known to the skilled person. For example lithium  borohydride in an organic solvent, such as THF can be used.  Step 26  ^ 27 (Scheme 3)   
Mitsunobu reaction  Compounds of the general formula 26 can be converted to the corresponding morpholine derivatives of  the general  formula 27 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 27  ^ 28 (Scheme 3)  Deprotection of PG1  The protecting group PG1 of spiro compounds of formula 27 can be cleaved to give amines of formula  28. 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 PG1 in compounds of formula 27 is BOC, cleavage can be achieved using e.g.  TFA in an organic solvent such as DCM.   Step 28  ^ 29(Scheme 3)  Amine decoration  Amines of formula 28 can be functionalized with a broad variety of substituents to give compounds of  formula 23.  For  examples,  secondary  amines of  formula 29  can be  reacted  to  give  tertiary  amines,  amides, ureas, carbamates or sulphonamides of formula 29. All these transformations are known to the  skilled person.  Step 29  ^ 30(Scheme 3)  C‐C cross coupling reaction  Halogen compounds of general formula 29 can be reacted with a boronic acid derivative R2‐B(OR)2 to  give a compound of formula 30. 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(triphenyl‐ phosphine)palladium(0) [Pd(PPh3)4], tris(dibenzylideneacetone)di‐palladium(0) [Pd2(dba)3], or by Pd(ll)  catalysts  like  dichlorobis(triphenylphosphine)‐palladium  (ll)  [Pd(PPh3)2CI2],  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 7, 15 or 30 may be also  interchanged using similar reaction conditions for each step as described above.    EXPERIMENTAL SECTION ‐ INTERMEDIATES    Intermediate 1  1‐tert‐butyl 3‐methyl 3‐(prop‐2‐en‐1‐yl)azetidine‐1,3‐dicarboxylate      To a solution of 1‐tert‐butyl 3‐methyl azetidine‐1,3‐dicarboxylate (940 g, 4.37 mol, 1.00 equiv, CAS‐RN  [610791‐05‐4]) in dry THF(9 L) was added LiHMDS (8.8 L, 8.74 mol, 2.00 equiv) at ‐78°C under nitrogen  atmosphere, and the reaction mixture was stirred at this temperature for 30 min. Then a solution of 3‐ bromoprop‐1‐ene (1058 g, 8.74 mol, 2.00 equiv) in dry THF (5 L) was added and the mixture was left to  warm to ambient temperature and stirred overnight (monitored by TLC). Sat. aq. solution of NH4Cl (15  L) was added and the mixture was extracted with 3 x 10 L of EtOAc, and the combined organic layer was  washed with 3x15 L of brine, dried over anhydrous Na2SO4, and concentrated under vacuum to yield a  crude product which was directly purified by silica gel column (EtOAc / petroleum ether) to give 832 g  (75%) of the title compound as yellow oil.     Intermediate 2  tert‐butyl 3‐(3‐methoxy‐3‐oxopropanoyl)‐3‐(prop‐2‐en‐1‐yl)azetidine‐1‐carboxylate     To a solution of methyl acetate (482 g, 6.52 mol, 2.00 equiv) in dry THF(9 L) was added LiHMDS (6.6 L,  6.52 mol, 2.00 equiv) at ‐78°C under nitrogen atmosphere, and the reaction mixture was stirred at this  temperature  for  1  h.  Then  a  solution  of  1‐tert‐butyl  3‐methyl  3‐(prop‐2‐en‐1‐yl)azetidine‐1,3‐  
dicarboxylate  (832 g, 3.26 mol, 1.00 equiv,  see  intermediate 1)  in dry THF( 2 L) was added and  the  mixture was left to warm to rt and stirred for another 2 h (monitored by TLC). Sat. aq. NH4Cl (10 L) was  added and the mixture was extracted with 3x10 L of EtOAc, and the combined organic layer was washed  with 3x10 L of brine, dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude  product which was directly purified by silica gel column (EtOAc/petroleum ether) to give 810 g (84%) of  the title compound as yellow oil.     Intermediate 3  tert‐butyl 3‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)‐3‐(prop‐2‐en‐1‐yl)azetidine‐1‐carboxylate     To  a  stirred  solution  of  tert‐butyl  3‐(3‐methoxy‐3‐oxopropanoyl)‐3‐(prop‐2‐en‐1‐yl)azetidine‐1‐ carboxylate  (810  g,  2.73 mol,  1.00  equiv,  see  intermediate  2)  in  anhydrous  EtOH  (3  L) was  added  hydrazine—water  (1:1)  (280  g,  8.75 mol,  3.00  equiv).  This mixture was  stirred  at  an  oil  bath.  The  temperature was warmed to 80°C and stirred for another 1 h (monitored by LCMS). The solvent was  removed in vacuum and the residue was dissolved in 2 L EtOAc and washed with 2x2 L of aq. HCl (1 M),  1x2 L of brine, dried over anhydrous Na2SO4 to afford 779 g (96%) of the title compound as white solid.  LCMS: (ES, m/z):280 [M+H]+    Intermediate 4  tert‐butyl 3‐(prop‐2‐en‐1‐yl)‐3‐[3‐(trifluoromethanesulfonyloxy)‐1H‐pyrazol‐5‐yl]azetidine‐1‐ carboxylate    To  a  stirred  solution  of  tert‐butyl  3‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)‐3‐(prop‐2‐en‐1‐yl)azetidine‐1‐ carboxylate (779 g, 2.79 mol, 1.00 equiv, see intermediate 3) in anhydrous THF (10 L) was added DIPEA   
(1079  g,  8.37  mol,  3.00  equiv)  followed  by  1,1,1‐trifluoro‐N‐phenyl‐N‐ trifluoromethanesulfonylmethanesulfonamide (1095 g, 3.07 mol, 1.10 equiv). This mixture was stirred  at 60 °C in an oil bath for 2 h, the solvent was removed under vacuum and the residue was dissolved in  2 L EtOAc and washed with 3x2 L of aq. HCl (1 M) and 3x2 L of water, dried over anhydrous Na2SO4,  concentrated under vacuum and recrystallization from MTBE to afford 810 g (71%) of the title compound  as white solid. LCMS: (ES, m/z):412 [M+H]+    Intermediate 5  tert‐butyl 3‐(2‐hydroxyethyl)‐3‐[3‐(trifluoromethanesulfonyloxy)‐1H‐pyrazol‐5‐yl]azetidine‐1‐ carboxylate    To  a  stirred  solution of  tert‐butyl 3‐(prop‐2‐en‐1‐yl)‐3‐[3‐(trifluoromethanesulfonyloxy)‐1H‐pyrazol‐5‐ yl]azetidine‐1‐carboxylate (400 g, 0.97 mol, 1.00 equiv, see intermediate 4) in dioxane/H2O (2L, 3/2, v/v)  was added 2,6‐Lutidine (207 g, 1.94 mol, 2.00 equiv) followed by K2OsO4*2H2O (7.87 g, 0.02 mol, 0.02  equiv). This mixture was stirred at rt for 40 min before NaIO4 (888 g, 4.15 mol, 4.00 equiv) was added in  batches. The final mixture was stirred for another 2 h at rt. The reaction mixture was filtrated and the  filtrate cake was washed with EtOAc (4 L), the filtrate was separated. The organic layer was concentrated  under vacuum. The residue was dissolved  in 2 L MeOH and stirred at 0 °C  in an  ice‐water bath, then  NaBH4 (19.0 g, 0.51 mol, 0.50 equiv) was added in small portions. The pH value of the reaction mixture  was adjusted to 7 by 0.1 mol/L HCl aq. solution when the addition was completed. The resulting mixture  was extracted with 3x5 L of DCM. The organic phase was combined, washed with 3x5 L of brine, dried  over anhydrous Na2SO4, concentrated under vacuum yield a crude product which was directly purified  by silica gel column (EtOAc/petroleum ether) to give 360 g (89.4%) of the title compound as yellow oil.  LCMS: (ES, m/z):416 [M+H]+    Intermediate 6  tert‐butyl 2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate   
  To  a  solution  of  tert‐butyl  3‐(2‐hydroxyethyl)‐3‐[3‐(trifluoromethanesulfonyloxy)‐1H‐pyrazol‐5‐ yl]azetidine‐1‐carboxylate (360 g, 0.87 mol, 1.00 equiv, see intermediate 5) and PPh3 (320 g, 1.22 mol,  1.40 equiv) in dry THF (4 L) was added DIAD (246 g, 1.4 mol, 1.30 equiv) dropwise at rt under nitrogen  atmosphere. The reaction mixture was stirred at this temperature for 16 h. The solvent was removed  under vacuum and the residue was dissolved in MTBE (2 L) and stirred overnight until white solid was  precipitated. The solid was removed by filtration. The filtrate was concentrated under vacuum and the  crude product was re‐crystallized from MeOH to give 240 g (69.5%) of the title compound as white solid.  LCMS: (ES, m/z):398 [M+H]+, 1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.399 (16.00), 2.787 (0.67), 2.805  (1.02), 2.822 (0.71), 4.044 (1.70), 4.129 (0.72), 4.148 (1.05), 4.165 (0.67), 6.536 (2.35).    Intermediate 7  [1‐(tert‐butoxycarbonyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl]boronic acid    tert‐butyl  2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (1.00  g,  2.52  mmol,  see  intermediate  6)  was  dissolved  in  1,4‐dioxane  (10  ml),  4,4,4',4',5,5,5',5'‐octamethyl‐2,2'‐bi‐1,3,2‐dioxaborolane  (671  mg,  2.64  mmol),  KOAc  (741  mg,  7.55  mmol; CAS‐RN:[127‐08‐2]), Pd(dppf)2Cl2 complex with DCM (103 mg, 126 µmol; CAS‐RN:[14221‐01‐3])  and dppf (69.8 mg, 126 µmol; CAS‐RN:[12150‐46‐8]) were added and the mixture was stirred overnight  at 100°C.  The mixture was diluted with DCM,  filtered  and  evaporated.  The  residue was purified by  preparative HPLC to yield the title compound (657 mg, 89 % yield). LC‐MS (Method 1): Rt = 0.62 min; MS  (ESIpos): m/z = 294  [M+H]+.  ¹H‐NMR  (400 MHz, DMSO‐d6) δ  [ppm]: 1.249  (5.06), 1.399  (7.17), 1.403  (2.56), 2.539 (16.00), 2.862 (0.41), 4.091 (0.41), 6.466 (0.82).   
  Intermediate 8/Intermediate 18  trifluoroacetic acid—5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl  trifluoromethanesulfonate (1/1)    tert‐butyl  2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (1.00 g, 2.52 mmol, see intermediate 6) was dissolved in DCM (60 ml), under argon, TFA (6.3  ml, 82 mmol; CAS‐RN:[76‐05‐1]) was added and the mixture was stirred for 2 h at rt. The mixture was  evaporated  to  yield  the  title  compound  (1,23  g), which was  used  in  the  next  step without  further  purification. LC‐MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 298 [M+H]+     Intermediate 9  1‐(ethylcarbamoyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl  trifluoromethanesulfonate    Trifluoroacetic  acid—5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl  trifluoro‐ methanesulfonate (1/1) (126 mg, 41 % purity, 126 µmol, see intermediate 8) was dissolved in DCM (3.0  ml) and DIPEA  (220 µl, 1.3 mmol; CAS‐RN:[7087‐68‐5]) under nitrogen,  isocyanatoethane  (50 µl, 630  µmol) was added and the mixture was stirred overnight at rt. The solution was evaporated and purified  by preparative HPLC to yield the title compound (37.8 mg, 82 % yield). LC‐MS (Method 1): Rt = 1.01 min;  MS (ESIpos): m/z = 369 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.983 (7.36), 0.996 (5.33), 1.000  (16.00), 1.014  (2.88), 1.018  (7.47), 1.232  (1.71), 1.906  (0.64), 2.322  (1.07), 2.327  (1.49), 2.331  (1.07),  2.522 (5.23), 2.539 (1.71), 2.649 (0.75), 2.668 (2.45), 2.673 (1.39), 2.684 (0.85), 2.770 (2.99), 2.788 (4.80),  2.806 (3.20), 2.977 (0.53), 2.986 (1.28), 3.003 (3.63), 3.010 (1.81), 3.017 (4.05), 3.021 (3.84), 3.027 (1.60),  3.035  (3.41), 3.053  (1.07), 3.861  (0.85), 3.879  (1.49), 3.899  (6.40), 3.934  (2.35), 3.955  (12.05), 3.962  (12.69), 3.982  (2.35), 4.139  (3.41), 4.157  (5.01), 4.174  (3.20), 5.412  (2.88), 6.401  (0.53), 6.445  (1.28),  6.459 (2.45), 6.472 (1.28), 6.495 (10.88), 9.644 (0.53).   
  Intermediate 10  tert‐butyl 2'‐hydroxy‐6'‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate    tert‐butyl 3‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)‐3‐(prop‐2‐en‐1‐yl)azetidine‐1‐carboxylate (50 g,0.12 mol, 1.00  equiv, see intermediate 3) was gradually added to a stirred solution of Hg(OAc)2 (77 g, 0.24 mol, 2.00  equiv) in THF (0.3 L)/H2O (0.2 L). After stirring for 24 h at rt, the yellow color disappeared. The reaction  mixture was alkalinized with 3 mol/L NaOH aq. Solution (0.2 L), then a solution of NaBH4 (2.4 g, 0.06 mol,  0.50 equiv) in NaOH aq. solution (100 mL, 3 mol/L) was added dropwise. 6 bathes were run at the same  time. After 24 h the 6 reactions were mixed and added with sat. aq. NaCl solution. The organic layer was  separated  and  the  aq.  layer was  further  extracted with  4x500 mL  of  EtOAc.  The  combined  organic  extracts were then washed with 3x250 mL of water, dried over anhydrous Na2SO4. The aq. phase was  treated with sulfur powder. The organic phase was evaporated under vacuum to give 160 g (79.6%) of  the title compound as yellow oil in total. LCMS: (ES, m/z):280 [M+H]+.    Intermediate 11  tert‐butyl 6'‐methyl‐2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate     To  a  stirred  solution  of  tert‐butyl  2'‐hydroxy‐6'‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (160 g, 0.57 mol, 1.00 equiv, see intermediate 10) in anhydrous THF (2 L) was   
added  DIPEA  (222  g,  1.72  mol,  3.00  equiv)  followed  by  1,1,1‐trifluoro‐N‐phenyl‐N‐ trifluoromethanesulfonylmethanesulfonamide (239 g, 0.67 mol, 1.17 equiv). This mixture was stirred at  60 °C in an oil bath for 2 h, the solvent was removed under vacuum and the residue was dissolved in 2 L  EtOAc and washed with 2 x 2  L of aq. HCl  (1 M) and 3x2  L of water, dried over anhydrous Na2SO4,  concentrated under vacuum and recrystallization from MTBE to afford 200 g (81%) of the title compound  as white solid. LCMS: (ES, m/z):412 [M+H]+    Intermediate 12  1‐tert‐butyl 4‐methyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)piperidine‐1,4‐dicarboxylate    1‐tert‐butyl  4‐methyl  piperidine‐1,4‐dicarboxylate  (15.0  g,  61.7  mmol,  CAS‐RN  [124443‐68‐1])  was  dissolved in THF (150 ml) under nitrogen, cooled to ‐78°C, LiHMDS (120 ml, 1.0 M in THF, 120 mmol; CAS‐ RN:[865‐47‐4]) was added dropwise and the mixture was stirred for 1 h at ‐78°C. (2‐bromoethoxy)(tert‐ butyl)dimethylsilane (29.5 g, 123 mmol) in THF (75 ml) was added dropwise at ‐78°C. The mixture was  warmed up to rt overnight. Sat. NH4Cl solution was added to the mixture, diluted with EtOAc and the  phases were separated. The organic phase was washed with sat. NaCl solution, dried with Na2SO4 and  concentrated under reduced pressure. The residue was purified by flash chromatography (Hex/EtOAc)  to yield the title compound (23.1 g, 93 % yield). LC‐MS (Method 2): Rt = 1.71 min; MS (ESIpos): m/z = 302  [M+H]‐BOC+.  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  ‐0.007  (0.53), 0.007  (0.52), 0.067  (4.71), 0.831  (1.01), 0.838 (16.00), 0.845 (0.96), 0.869 (0.42), 0.876 (6.49), 1.376 (13.87), 1.716 (0.41), 1.732 (0.88),  1.749 (0.42), 2.519 (0.60), 3.526 (0.70), 3.532 (0.54), 3.541 (0.52), 3.548 (1.10), 3.566 (0.48), 3.622 (5.65),  3.877 (0.60).    Intermediate 13  tert‐butyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)‐4‐(3‐methoxy‐3‐oxopropanoyl)piperidine‐1‐ carboxylate   
  Methyl acetate (14 ml, 170 mmol) was dissolved in THF (300 ml) with molsieves under nitrogen, cooled  to ‐78°C, LiHMDS (170 ml, 1.0 M, 170 mmol; CAS‐RN:[865‐47‐4]) was added dropwise and the mixture  was stirred  for 1 h at  ‐78°C. 1‐tert‐butyl 4‐methyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)piperidine‐ 1,4‐dicarboxylate (17.4 g, 43.3 mmol, see intermediate 12) in THF (100 ml) was added dropwise at ‐78°C.  The mixture was warmed up to rt in 2 h and stirred overnight at rt. Sat. NH4Cl solution was added to the  mixture, diluted with EtOAc and the phases were separated. The organic phase was washed with sat.  NaCl solution, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by  flash chromatography (Hex/EtOAc) to yield the title compound (10.8 g, 56 % yield). LC‐MS (Method 2):  Rt = 1.60 min; MS (ESIpos): m/z = 344 [M+H]‐BOC+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: ‐0.008 (0.62),  0.007 (0.57), 0.828 (1.30), 0.835 (16.00), 0.842 (1.00), 1.382 (13.72), 1.816 (0.85), 1.849 (0.88), 1.865  (0.56), 2.176 (5.75), 2.523 (0.96), 2.528 (0.63), 3.479 (1.44), 3.500 (0.66), 3.516 (0.96), 3.533 (0.41), 3.606  (6.20), 3.616 (3.35), 3.628 (7.06), 3.728 (2.24).    Intermediate 14  tert‐butyl 4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)‐4‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)piperidine‐1‐ carboxylate    Tert‐butyl  4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)‐4‐(3‐methoxy‐3‐oxopropanoyl)piperidine‐1‐ carboxylate  (10.8 g, 24.2 mmol, see  intermediate 13) was dissolved  in EtOH  (25 ml) under nitrogen,  hydrazine—water (1:1) (3.5 ml, 73 mmol; CAS‐RN:[7803‐57‐8]) was added and the mixture was stirred  for 3 h at 80°C. The mixture was evaporated, diluted with DCM/MeOH (9:1), filtered and the filtrate was  evaporated. The residue was purified by flash chromatography (DCM/EtOH) to yield the title compound   
(7.57 g, 73 % yield). LC‐MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 426 [M+H]+. ¹H‐NMR (400 MHz,  DMSO‐d6) δ [ppm]: ‐0.064 (0.51), ‐0.056 (13.74), ‐0.051 (0.41), ‐0.049 (0.47), ‐0.011 (2.02), 0.000 (2.05),  0.798 (0.95), 0.805 (16.00), 0.813 (0.89), 0.818 (0.41), 0.825 (2.78), 0.830 (2.84), 1.367 (13.30), 1.760  (1.10), 1.809 (0.55), 1.819 (0.56), 1.921 (1.31), 2.512 (1.14), 2.517 (0.75), 3.342 (0.56), 3.361 (0.61), 3.595  (0.97).    Intermediate 15  tert‐butyl 4‐(2‐hydroxyethyl)‐4‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)piperidine‐1‐carboxylate    Tert‐butyl  4‐(2‐{[tert‐butyl(dimethyl)silyl]oxy}ethyl)‐4‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)piperidine‐1‐ carboxylate (7.56 g, 17.8 mmol, see intermediate 14) was dissolved in THF (140 ml), TBAF (21 ml, 1.0 M  in THF, 21.3 mmol) was added and  the mixture was  stirred overnight at ambient  temperature. The  mixture was evaporated. The residue was purified by flash chromatography (DCM/MeOH) to yield the  title compound (3.53 g, 64% yield). LC‐MS (Method 1): Rt = 0.51 min; MS (ESIpos): m/z = 312 [M+H]+. ¹H‐ NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.375 (16.00), 1.472 (0.41), 1.609 (0.43), 1.628 (0.66), 1.647 (0.45),  1.914 (0.44), 2.518 (0.78), 2.523 (0.51), 3.159 (1.23), 3.172 (1.50), 3.186 (0.48), 3.563 (0.44), 3.596 (0.41),  4.252 (0.44), 5.278 (0.78).    Intermediate 16  tert‐butyl 2'‐hydroxy‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate    Tert‐butyl 4‐(2‐hydroxyethyl)‐4‐(3‐hydroxy‐1H‐pyrazol‐5‐yl)piperidine‐1‐carboxylate (2.48 g, 7.98 mmol,  see  intermediate 15) was dissolved  in THF (40 ml), PPh3 (2.93 g, 11.2 mmol; CAS‐RN:[603‐35‐0]) was  added and DIAD (2.0 ml, 10.4 mmol) was added dropwise. The mixture was stirred overnight at ambient   
temperature. The mixture was evaporated and purified by flash chromatography (DCM/EtOH) to yield  the title compound (2.43 g, 73% yield). LC‐MS (Method 1): Rt = 0.64 min; MS (ESIpos): m/z = 294 [M+H]+.  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.406  (16.00), 1.519  (0.41), 1.576  (0.41), 2.235  (0.62), 2.252  (1.00), 2.269 (0.65), 3.876 (0.69), 3.894 (1.05), 3.910 (0.65), 5.369 (2.76), 9.531 (0.46).    Intermediate 17  tert‐butyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate    Tert‐butyl  2'‐hydroxy‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (2.42  g,  8.25 mmol, see intermediate 16) was dissolved in THF (65 ml), DIPEA (4.3 ml, 25 mmol; CAS‐RN: [7087‐ 68‐5])  and  1,1,1‐trifluoro‐N‐phenyl‐N‐[(trifluoromethyl)sulfonyl]methanesulfonamide  (3.24  g,  9.07  mmol) were added and stirred overnight at 60°C. The mixture was evaporated and purified by  flash  chromatography (DCM/EtOH) to yield the title compound (2.98 g, 85 % yield). LC‐MS (Method 1): Rt =  1.36 min; MS (ESIpos): m/z = 326 [M+H]+. 1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.411 (16.00), 1.597  (0.41), 1.612 (0.65), 1.670 (0.68), 2.366 (0.64), 2.384 (0.96), 2.402 (0.67), 2.518 (0.99), 2.523 (0.64), 3.408  (0.69), 3.421 (1.14), 3.434 (0.68), 3.566 (6.84), 4.165 (0.69), 4.183 (1.05), 4.200 (0.66), 6.476 (2.24).    Intermediate 18/Intermediate 8  trifluoroacetic acid—5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl  trifluoromethanesulfonate (1/1)    To  a  solution  of  tert‐butyl  2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (1.00 g, 2.52 mmol, see intermediate 6) in dichloromethane (60  mL) was added under nitrogen at ambient  temperature  trifluoroacetic acid  (6.3 mL, 82 mmol; CAS‐ RN:[76‐05‐1])  and  the  reaction was  stirred  at  ambient  temperature  for  two hours. The  solvent was   
evaporated, toluene was added and the reaction was evaporated again (2x). Toluene was added, the  organic  layer was dried over sodium sulfate and the solvent was removed under reduced pressure to  yield the crude title compound (1.23 g). The material was used withour further purification in the next  step.   Intermediate 19  ethyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate    To  a  suspension  of  trifluoroacetic  acid—5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl  trifluoromethanesulfonate  (1/1)  (1.13  g,  84  %  purity,  2.31  mmol,  see  intermediate  18)  in  dichloromethane (11 mL) was added at ambient temperature under argon N,N‐diisopropylethylamine  (1.2 ml, 6.9 mmol; CAS‐RN:[7087‐68‐5]). The reaction was cooled to 0°C and ethyl carbonochloridate  (220 µl, 2.3 mmol) was added. The reaction was warmed to ambient temperature and stirred at this  temperature for three hours. The solvent was removed under reduced pressure and the crude product  was purified by flash column chromatography to yield 92 % (784 mg) of the title compound. 1H‐NMR  (400 MHz, DMSO‐d6) delta [ppm]: 1.157 (7.26), 1.175 (16.00), 1.192 (7.45), 1.232 (0.21), 2.065 (0.17),  2.518 (3.52), 2.522 (2.24), 2.803 (2.69), 2.820 (4.09), 2.838 (2.87), 4.004 (1.69), 4.022 (5.11), 4.040 (5.07),  4.058 (1.80), 4.104 (4.39), 4.134 (3.60), 4.143 (1.16), 4.152 (4.46), 4.169 (2.91), 5.759 (0.22), 6.548 (9.54).  Intermediate 20 3-bromo-6-[(propan-2-yl)oxy]quinoline  3-Bromoquinolin-6-ol (500 mg, 2.23 mmol) was solubilised in DMF (8.6 ml), sodium hydride (179 mg, 60 % purity, 4.46 mmol) was added and the mixture was stirred for 30 min at rt. 2- bromopropane (420 µl, 4.5 mmol) was added and the mixture was stirred overnight at 50°C. The mixture was diluted with sat. NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried with Na2SO4 and concentrated under reduced pressure to give 680 mg of the title compound, which was used without further purification.  
LC-MS (Method 1): Rt = 1.37 min; MS (ESIpos): m/z = 266 [M+H]+  Intermediate 21 3-bromo-6-methoxyquinoline  3-Bromoquinolin-6-ol (25.0 g, 112 mmol) was solubilised in DMF (500 ml), sodium hydride (13.4 g, 60 % purity, 335 mmol) was added and the mixture was stirred for 30 min at rt. iodomethane (14 ml, 220 mmol; CAS-RN:[74-88-4]) was added and the mixture was stirred overnight at 50°C. The mixture was diluted with sat. NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were washed with sat. NaCl solution, dried with Na2SO4 and concentrated under reduced pressure to give 25.1 g (94 % yield) of the title compound.  LC-MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 237 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.106 (0.86), 1.224 (0.57), 2.518 (0.92), 2.522 (0.59), 3.333 (16.00), 7.363 (5.43), 7.370 (6.53), 7.427 (5.18), 7.434 (3.91), 7.450 (5.24), 7.458 (4.44), 7.917 (5.29), 7.940 (4.89), 8.581 (5.00), 8.587 (5.31), 8.764 (8.08), 8.770 (7.41).  Intermediate 22 quinolin-6-yl acetate  Quinolin-6-ol (10.0 g, 68.9 mmol) was solubilised in dichloromethane (100 ml) and pyridine (6.7 ml, 83 mmol) was added. Under argon, the mixture was cooled to 0°C and acetyl chloride (5.9 ml, 83 mmol; CAS-RN:[75-36-5]) was added. The mixture was stirred overnight at rt. Sat. NaHCO3 solution was added and the mixture was extracted with DCM. The organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 12.1 g (93 % yield) of the title compound. LC-MS (Method 3): Rt = 0.64 min; MS (ESIpos): m/z = 188 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.345 (16.00), 2.518 (0.42), 3.360 (0.49), 7.550 (1.11), 7.557 (1.24), 7.560 (1.27), 7.563 (1.35), 7.570 (1.13), 7.580 (1.75), 7.586 (1.34), 7.755 (1.79), 7.762 (1.61), 8.048 (1.43), 8.071 (1.32), 8.359 (0.77), 8.362 (0.77), 8.380 (0.73), 8.383 (0.74), 8.900 (1.16), 8.904 (1.15), 8.910 (1.16), 8.914 (1.09).   
Intermediate 23 3-bromoquinolin-6-yl acetate  N O Br O C H 3 Quinolin-6-yl acetate (1.00 g, 5.34 mmol) was solubilised in 1,1,2,2-tetrachloroethane (20 ml) and pyridine (1.3 ml, 16 mmol) was added. Under argon, the mixture was cooled to 0°C and bromine (823 µL, 16.03 mmol) was added. The mixture was stirred for 3 h at 90°C. The mixture was diluted with DCM and washed with water, Na2S2O3 solution, water and brine. It was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 1.18 g (83 % yield) of the title compound. LC-MS (Method 3): Rt = 1.06 min; MS (ESIpos): m/z = 266 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.349 (16.00), 2.518 (0.90), 2.522 (0.56), 7.611 (1.32), 7.618 (1.54), 7.634 (1.34), 7.641 (1.66), 7.742 (2.03), 7.749 (1.77), 8.067 (1.60), 8.090 (1.42), 8.737 (1.49), 8.743 (1.56), 8.952 (2.53), 8.957 (2.36).  Intermediate 24 3-bromoquinolin-6-ol  3-Bromoquinolin-6-yl acetate (1.18 g, 4.43 mmol) was solubilised in methanol (50 ml), under argon, lithium hydroxide (636 mg, 26.6 mmol) was added and the mixture was stirred overnight at rt. The mixture was evaporated to give 1.90 g of the title compound, which was used without further purification. LC-MS (Method 3): Rt = 0.85 min; MS (ESIpos): m/z = 224 [M+H]+  Intermediate 25 5-bromo-2-[(2E)-2-butylidenehydrazinyl]pyridine   
5-Bromo-2-hydrazinylpyridine (25.0 g, 133 mmol) was solubilised in methanol (250 ml), butanal (24 ml, 270 mmol; CAS-RN:[123-72-8]) was added and the mixture was stirred for 4 h at 70°C. The mixture was evaporated to give 34.3 g of the title compound, which was used without further purification. LC-MS (Method 1): Rt = 1.27 min; MS (ESIpos): m/z = 242 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.899 (6.43), 0.917 (16.00), 0.935 (7.64), 1.450 (0.55), 1.468 (2.25), 1.486 (4.08), 1.505 (4.17), 1.523 (2.27), 1.541 (0.48), 2.166 (2.10), 2.180 (2.56), 2.185 (3.41), 2.199 (3.43), 2.203 (2.22), 2.216 (1.94), 2.521 (1.52), 2.526 (1.02), 6.951 (3.32), 6.974 (3.52), 7.328 (1.55), 7.341 (3.18), 7.355 (1.50), 7.694 (2.01), 7.700 (2.04), 7.716 (1.87), 7.722 (1.94), 8.106 (3.57), 8.112 (3.64), 10.491 (3.12).  Intermediate 26 5-bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine  5-Bromo-2-[(2E)-2-butylidenehydrazinyl]pyridine (34.3 g, 94 % purity, 133 mmol) and polyphosphoric acid (130.0 g, 3.2 mol) were stirred under nitrogen for 15 min at 160°C. The mixture was allowed to cool down to rt and diluted with water. The mixture was cooled to 0°, conc. NH3 solution was added (pH 9-10) and extracted 3x with DCM. The combined organic layers were dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 5.24 g (17 % yield) of the title compound. LC-MS (Method 1): Rt = 1.13 min; MS (ESIpos): m/z = 225 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.215 (6.38), 1.234 (16.00), 1.253 (7.19), 2.521 (1.13), 2.526 (0.82), 2.646 (1.17), 2.649 (1.21), 2.665 (3.69), 2.668 (3.79), 2.676 (0.44), 2.685 (3.31), 2.686 (3.43), 2.703 (1.06), 2.705 (1.08), 7.309 (2.38), 8.164 (3.89), 8.170 (4.68), 8.221 (4.22), 8.227 (3.37), 11.556 (0.81).  Intermediate 27 (rac)-5-bromo-3-ethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one  N H N O Br C H 3  
5-Bromo-3-ethyl-1H-pyrrolo[2,3-b]pyridine (4.00 g, 17.8 mmol) was solubilised in acetonitrile (800 ml), under argon, N-Chlorosuccinimide (2.61 g, 19.55 mmol) was added and the mixture was stirred overnight at rt. Half sat. Na2S2O3 solution was added and the organic solvent was evaporated. The mixture was extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.68 g (62 % yield) of the title compound. LC-MS (Method 3): Rt = 0.89 min; MS (ESIpos): m/z = 241 [M+H]+  Intermediate 28 5-bromo-2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridine  (rac)-5-Bromo-3-ethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.67 g, 11.1 mmol) was solubilised in POCl3 (30 ml), and the mixture was stirred overnight at 100°C. The mixture was added dropwise into Na2CO3 solution (2 L, pH 8) and extracted with DCM. The organic layer was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.73 g (95 % yield) of the title compound. LC-MS (Method 3): 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 29 5-bromo-2-[(2E)-2-propylidenehydrazinyl]pyridine  5-Bromo-2-hydrazinylpyridine (10.0 g, 53.2 mmol) was solubilised in methanol (100 ml), propanal (7.7 ml, 110 mmol) was added and the mixture was stirred overnight at 50°C. The mixture was evaporated to give 13.1 g of the title compound, which was used without further purification. LC-MS (Method 1): Rt = 1.16 min; MS (ESIpos): m/z = 228 [M+H]+   
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.771 (0.44), 0.828 (0.56), 0.843 (0.73), 0.862 (0.62), 0.879 (0.70), 0.893 (0.47), 1.023 (7.67), 1.038 (16.00), 1.053 (7.66), 2.202 (1.21), 2.213 (1.34), 2.218 (3.73), 2.228 (3.75), 2.233 (3.50), 2.242 (3.41), 2.247 (1.20), 2.257 (1.11), 2.514 (1.13), 2.518 (1.01), 2.522 (0.81), 6.958 (3.66), 6.976 (3.86), 7.352 (1.79), 7.363 (3.64), 7.373 (1.74), 7.695 (2.12), 7.701 (2.15), 7.713 (2.02), 7.718 (2.07), 8.103 (3.53), 8.104 (3.62), 8.108 (3.60), 10.494 (3.30).  Intermediate 30 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine  5-Bromo-2-[(2E)-2-propylidenehydrazinyl]pyridine (13.1 g, 57.3 mmol) and polyphosphoric acid (55.5 g, 1.4 mol) were stirred under nitrogen for 10 min at 160°C. The mixture was allowed to cool down to rt and diluted with water. The mixture was cooled to 0°, conc. NH3 solution was added (pH 9-10) and extracted 3x with DCM. The combined organic layers were dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 956 mg (8 % yield) of the title compound. LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 211 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.129 (0.47), 2.228 (16.00), 2.230 (15.77), 2.327 (0.54), 2.518 (2.17), 2.523 (1.46), 7.300 (2.35), 7.302 (2.38), 8.141 (3.07), 8.145 (3.49), 8.218 (4.31), 8.224 (3.72), 11.530 (0.88).  Intermediate 31 5-bromo-3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine  5-Bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.37 mmol) was solubilised in acetonitrile (20 ml), N,N-diisopropylethylamine (1.0 ml, 5.9 mmol) and [2-  
(chloromethoxy)ethyl](trimethyl)silane (460 µl, 2.6 mmol) were added. The mixture was stirred overnight at rt. The mixture was diluted with water and extracted 2x with EtOAc. The combined organic layers were dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 601 mg (74 % yield) of the title compound. LC-MS (Method 1): Rt = 1.66 min; MS (ESIpos): m/z = 341 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.120 (0.42), -0.116 (0.49), -0.108 (16.00), -0.100 (0.47), -0.002 (1.37), 0.000 (1.78), 0.777 (0.49), 0.797 (0.55), 0.817 (0.50), 2.240 (2.05), 2.243 (2.10), 3.440 (0.54), 3.460 (0.58), 3.480 (0.54), 5.534 (1.82), 7.463 (0.47), 7.465 (0.47), 8.213 (0.79), 8.218 (0.80), 8.306 (0.61), 8.312 (0.56).  Intermediate 32 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine  5-Bromo-3-chloro-1H-pyrrolo[2,3-b]pyridine (7.95 g, 34.3 mmol) was solubilised in 1,4-dioxane (160 ml), 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), dppf (952 mg, 1.72 mmol) and Pd(dppf)2Cl2*DCM were added. The mixture was stirred overnight at 100°C. The mixture was diluted with DCM, filtered and evaporated. The residue was purified by flash chromatography to give 9.50 g (99 % yield) 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 compounds (intermediate 33 to 41) were prepared in analogy to intermediate 32: Intermediate 33 3-cyclobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine   
LC-MS (Method 3): Rt = 0.69 min; MS (ESIpos)  Intermediate 34 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine  LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 259 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.066 (2.88), 1.156 (3.04), 1.314 (16.00), 2.261 (3.42), 2.264 (3.44), 2.518 (0.67), 2.522 (0.42), 3.940 (0.49), 7.228 (0.64), 7.231 (0.64), 8.150 (0.86), 8.152 (0.87), 8.419 (1.11), 8.423 (1.06).  Intermediate 35 {6-[(propan-2-yl)oxy]quinolin-3-yl}boronic acid  LC-MS (Method 3): Rt = 0.51 min; MS (ESIpos): m/z = 232 [M+H]+  Intermediate 36 [6-(trifluoromethyl)quinolin-3-yl]boronic acid  LC-MS (Method 1): Rt = 0.52 min; MS (ESIpos): m/z = 242 [M+H]+  Intermediate 37  
[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid  LC-MS (Method 1): Rt = 0.65 min; MS (ESIpos): m/z = 205 [M+H]+  Intermediate 38 3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine  LC-MS (Method 1): Rt = 1.18 min; MS (ESIpos): m/z = 273 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (16.00), 1.155 (13.89), 1.227 (1.02), 1.246 (2.38), 1.265 (1.04), 1.314 (9.94), 2.518 (0.48), 2.703 (0.55), 2.706 (0.55), 2.722 (0.53), 2.725 (0.53), 3.318 (0.41), 3.943 (2.68), 7.946 (0.78), 8.161 (0.53), 8.163 (0.53), 8.418 (0.72), 8.422 (0.70).  Intermediate 39 [6-(acetyloxy)quinolin-3-yl]boronic acid  LC-MS (Method 3): Rt = 0.55 min; MS (ESIpos): m/z = 232 [M+H]+  Intermediate 40 (6-methoxyquinolin-3-yl)boronic acid  LC-MS (Method 1): Rt = 0.38 min; MS (ESIpos): m/z = 203 [M+H]+    Intermediate 41 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrrolo[2,3-b]pyridine 
Figure imgf000110_0001
LC-MS (Method 3): Rt = 1.71 min; MS (ESIpos): m/z = 389 [M+H]+  Intermediate 42 (3-bromo-1H-pyrazol-1-yl)methanol 
Figure imgf000110_0002
3-Bromo-1H-pyrazole (30.0 g, 204 mmol) was solubilised in methanol (300 ml), formaldehyde (61 ml, 37 % purity, 820 mmol; CAS-RN:[50-00-0]) was added and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure to give 36.1 g (100 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.334 (0.53), 2.520 (2.82), 2.525 (1.79), 5.311 (9.24), 5.329 (9.42), 5.463 (0.73), 6.369 (0.46), 6.375 (0.47), 6.404 (14.66), 6.410 (15.83), 6.883 (1.80), 6.902 (4.87), 6.920 (1.68), 7.821 (16.00), 7.827 (15.86), 9.567 (0.45).  Intermediate 43 tert-butyl 3-(3-bromo-1H-pyrazol-5-yl)-3-hydroxyazetidine-1-carboxylate   
(3-Bromo-1H-pyrazol-1-yl)methanol (3.10 g, 17.5 mmol) was solubilised in THF (90 ml), cooled to -78°C and LDA (18 ml, 2.0 M in THF/heptane/ethylbenzene, 35 mmol) was added dropwise. The mixture was allowed to warm up to -20°C and was stirred for 45 min at -20°C. The mixture was cooled to -78°C and tert-butyl 3-oxoazetidine-1-carboxylate (2.50 g, 14.6 mmol), solubilised in THF (25 ml), was added dropwise. It was stirred for 2 h at -78°C and was allowed to warm up to rt overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 3.69 g (79 % yield) of the title compound. LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 318 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.392 (16.00), 2.519 (0.90), 2.524 (0.58), 3.960 (0.47), 4.063 (0.48), 6.419 (0.94).  Intermediate 44 tert-butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-hydroxyazetidine-1- carboxylate  Tert-butyl 3-(3-bromo-1H-pyrazol-5-yl)-3-hydroxyazetidine-1-carboxylate (3.68 g, 11.57 mmmol) was dissolved in THF (65 mL) under nitrogen. Sodium hydride (509 mg, 801 mmol) was added and the mixture was stirred for 10 min at rt. [2-(chloromethoxy)ethyl](trimethyl)silane (2.3 mLl, 13 mmol) was added and the mixture was stirred overnight at rt. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.31 g (45 % yield) of the title compound.  
LC-MS (Method 1): Rt = 1.49 min; MS (ESIpos): m/z = 448 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.061 (2.74), 0.860 (0.76), 0.880 (0.97), 0.900 (0.80), 1.235 (0.51), 1.440 (16.00), 2.050 (0.93), 2.581 (0.52), 3.617 (0.90), 3.638 (1.08), 3.657 (0.87), 5.479 (2.73), 6.453 (2.57), 6.571 (2.91).  Intermediate 45 tert-butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-(2-ethoxy-2- oxoethoxy)azetidine-1-carboxylate  tert-Butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-hydroxyazetidine-1- carboxylate (4.20 g, 9.37 mmol) was solubilised in THF (60 ml) under nitrogen, NaH (562 mg, 60 % purity, 14.0 mmol) was added and the mixture was stirred for 10 min at rt. ethyl bromoacetate (1.6 ml, 14 mmol) was added and the mixture was stirred overnight at 60°C. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 4.41 g (88 % yield) of the title compound. LC-MS (Method 1): Rt = 1.61 min; MS (ESIpos): m/z = 534 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.046 (10.31), 0.077 (1.27), 0.862 (0.81), 0.870 (0.44), 0.882 (1.14), 0.890 (0.44), 0.902 (0.90), 1.183 (0.78), 1.201 (1.75), 1.213 (2.08), 1.219 (0.89), 1.231 (4.70), 1.249 (2.23), 1.451 (16.00), 1.457 (6.77), 2.597 (0.96), 2.601 (0.60), 3.627 (0.94), 3.647 (1.41), 3.667 (0.88), 3.995 (3.45), 4.006 (0.75), 4.086 (0.66), 4.104 (0.68), 4.116 (0.65), 4.134 (2.02), 4.151 (2.12), 4.169 (0.96), 4.201 (0.46), 5.434 (0.61), 5.520 (2.73), 6.736 (3.20), 6.930 (1.02).  Intermediate 46 ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate   
tert-Butyl 3-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-3-(2-ethoxy-2- oxoethoxy)azetidine-1-carboxylate (1.00 g, 1.87 mmol) was solubilised in dichloromethane (20 ml) and TFA (2.2 ml, 28 mmol) was added. The mixture was stirred overnight at rt. The mixture was diluted with toluene and concentrated under reduced pressure to give 1.30 g (43 % purity, 98 % yield) of the title compound, which was used without further purification. Intermediate 47 ethyl {[3-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)azetidin-3-yl]oxy}acetate  Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate (1.30 g, 43 % purity, 1.84 mmol), isocyanatoethane (157 mg, 2.21 mmol) and N,N-diisopropylethylamine (1.6 ml, 9.2 mmol) were solubilised in dichloromethane (1.1 ml) and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 680 mg (99 % yield) of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.50), 0.951 (0.41), 0.957 (0.92), 0.969 (1.43), 0.975 (4.61), 0.985 (2.46), 0.993 (6.84), 1.003 (1.54), 1.011 (2.90), 1.021 (0.51), 1.031 (0.46), 1.082 (2.21), 1.093 (2.16), 1.100 (9.99), 1.111 (4.02), 1.118 (2.92), 1.125 (2.48), 1.138 (3.48), 1.143 (6.45), 1.162 (7.12), 1.180 (2.80), 1.240 (0.57), 1.363 (0.54), 1.586 (0.95), 1.624 (0.46), 1.642 (0.75), 1.666 (7.61), 2.090 (2.53), 2.524 (0.72), 2.529 (0.49), 2.965 (1.02), 2.980 (1.18), 2.983 (1.62), 2.997 (1.44), 3.000 (1.34), 3.009 (0.74), 3.013 (0.89), 3.027 (0.57), 3.031 (0.41), 3.215 (0.67), 3.231 (1.01), 3.242 (0.98), 3.248 (1.29), 3.260 (0.88), 3.264 (1.03), 3.275 (0.62), 3.281 (0.69), 3.336 (16.00), 3.507 (1.26), 3.622 (0.72), 3.626 (0.85), 3.908 (1.51), 3.934 (1.65), 3.948 (1.75), 3.951 (1.82), 3.966 (1.66), 3.969 (1.20), 3.978 (3.24), 3.986 (0.68), 3.992 (1.39), 4.000 (1.64), 4.018 (1.06), 4.031 (1.74), 4.035 (1.43), 4.043 (0.64), 4.047 (0.87), 4.052 (1.99), 4.057 (1.07), 4.064 (2.59), 4.070 (3.14), 4.082 (1.90), 4.087 (1.92), 4.101 (0.69), 4.105 (0.73),  
4.135 (0.63), 4.165 (0.98), 4.189 (0.71), 4.304 (1.44), 4.336 (0.79), 4.363 (0.49), 4.501 (0.41), 4.583 (0.47), 4.610 (0.45), 4.699 (0.45), 4.851 (0.59), 5.764 (9.95), 6.436 (0.51), 6.451 (0.52), 6.576 (0.95), 6.778 (0.42), 6.782 (1.97), 6.847 (0.51), 6.849 (2.48), 6.975 (1.08), 7.075 (2.30), 8.538 (0.44).  Intermediate 48 3-(5-bromo-1H-pyrazol-3-yl)-N-ethyl-3-(2-hydroxyethoxy)azetidine-1-carboxamide  Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)azetidin-3-yl]oxy}acetate (680 mg, 1.81 mmol) was solubilised in THF (14 ml) under nitrogen, lithium borohydride (2.2 ml, 4.0 M in THF, 11 mmol) was added dropwise and the mixture was stirred overnight at rt. It was cooled to 0°C, diluted with sat. NH4Cl solution and extracted with EtOAc. The organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated to give 330 mg (55 % yield) of the title compound, which was used without further purification. Intermediate 491 2'-bromo-N-ethyl-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxamide  3-(5-Bromo-1H-pyrazol-3-yl)-N-ethyl-3-(2-hydroxyethoxy)azetidine-1-carboxamide (330 mg, 990 µmol) was solubilised in THF (5.0 ml), PPh3 (364 mg, 1.39 mmol) was added and DIAD (250 µl, 1.29 mmol) was added dropwise. The mixture was stirred overnight at rt. DIAD (250 µl, 1.29 mmol) were added dropwise and the mixture was stirred for 3 h at rt. It was evaporated and purified by flash chromatography to give 90.0 mg (29 % yield) of the title compound.  
Intermediate 50 tert-butyl 3-(5-bromo-1H-pyrazol-3-yl)-3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate  Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate (569 mg, 1.87 mmol) was solubilised in dichloromethane (30 ml), di-tert-butyl dicarbonate (210 µl, 940 µmol) and triethylamine (1.6 ml, 11 mmol) were added and the mixture was stirred overnight at rt. It was diluted with water and extracted 3x with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to give 530 mg (70 % yield) of the title compound, which was used without further purification.  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.53), 1.077 (0.59), 1.092 (0.59), 1.095 (1.17), 1.109 (0.47), 1.112 (0.73), 1.116 (0.45), 1.134 (0.62), 1.137 (0.45), 1.144 (2.09), 1.148 (1.17), 1.153 (1.34), 1.162 (4.29), 1.166 (2.41), 1.171 (2.33), 1.180 (2.06), 1.183 (1.05), 1.189 (1.11), 1.244 (0.68), 1.393 (16.00), 1.572 (1.38), 1.580 (3.39), 1.606 (7.17), 1.671 (0.58), 2.530 (0.55), 3.937 (0.75), 3.951 (1.39), 3.962 (0.61), 3.968 (0.58), 3.992 (0.92), 4.019 (0.45), 4.024 (0.52), 4.035 (0.84), 4.042 (0.47), 4.046 (0.57), 4.052 (1.89), 4.064 (1.06), 4.070 (1.92), 4.075 (1.70), 4.081 (1.51), 4.088 (1.00), 4.093 (1.07), 4.099 (1.26), 4.111 (0.99), 4.116 (1.14), 4.140 (0.47), 5.770 (4.51), 6.852 (0.71), 6.923 (0.94), 7.149 (0.58).  Intermediate 51 2-{[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}ethan-1-ol  Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate (containing tert-butyl 3-(5-bromo- 1H-pyrazol-3-yl)-3-(2-ethoxy-2-oxoethoxy)azetidine-1-carboxylate) (530 mg, 1.74 mmol) was solubilised in THF (200 ml), and lithium borohydride (2.6 ml, 4.0 M in THF, 10 mmol) were added and the mixture was stirred overnight at rt. It was poured into water and NH4Cl was added. The aq. layer was extracted 3x with DCM and the combined organic layers were dried with Na2SO4  
and evaporated. The residue was purified by flash chromatography to give 156 mg (34 % yield) of the title compound. Intermediate 52 tert-butyl 2'-bromo-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate  tert-Butyl 3-(5-bromo-1H-pyrazol-3-yl)-3-(2-hydroxyethoxy)azetidine-1-carboxylate (153 mg, 422 µmol) was solubilised in THF (2.0 ml), PPh3 (155 mg, 591 µmol) was added and DIAD (110 µl, 0.55 mmol) was added dropwise. The mixture was stirred overnight at rt. It was evaporated to give 200 mg of the title compound, which was used without further purification.  Intermediate 53 1-tert-butyl 4-methyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)piperidine-1,4-dicarboxylate  1-tert-Butyl 4-methyl piperidine-1,4-dicarboxylate (10.4 g, 42.7 mmol) was solubilised in THF (100 ml), cooled to -78°C and LiHMDS (73 ml, 1.0 M, 73 mmol) was added dropwise. The mixture was stirred at -78°C for 1 h and (3-bromopropoxy)(tert-butyl)dimethylsilane (17 ml, 73 mmol), solubilised in THF (50 ml), was added dropwise. It was allowed to warm up to rt overnight. The mixture was diluted with sat. NH4Cl solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 11.5 g (65 % yield) of the title compound. LC-MS (Method 1): Rt = 1.74 min; MS (ESIpos): m/z = 316 [M+H]-BOC+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (2.38), 0.005 (12.87), 0.012 (0.50), 0.838 (0.94), 0.845 (16.00), 0.852 (0.90), 1.275 (0.47), 1.280 (0.43), 1.285 (0.46), 1.304 (0.46), 1.314 (0.45), 1.376 (12.17), 1.480 (0.42), 2.518 (0.45), 3.495 (0.45), 3.511 (0.96), 3.526 (0.43), 3.628 (5.17).   
Intermediate 54 tert-butyl 4-(3-tert-butoxy-3-oxopropanoyl)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)piperidine- 1-carboxylate  LDA (69 ml, 2.0 M in THF/heptane/ethylbenzene, 140 mmol) was solubilised in THF (150 ml), at -78°C under argon and tert-butyl acetate (19 ml, 140 mmol), solubilized in THF (30 ml) was added dropwise. The mixture was stirred at -78°C for 1 h and 1-tert-butyl 4-methyl 4-(3-{[tert- butyl(dimethyl)silyl]oxy}propyl)piperidine-1,4-dicarboxylate (11.5 g, 27.7 mmol), solubilised in THF (40 ml), was added dropwise. It was allowed to warm up to rt overnight. The mixture was diluted with sat. NH4Cl solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 6.10 g (44 % yield) of the title compound. LC-MS (Method 1): Rt = 1.75 min; MS (ESIpos): m/z = 500 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.015 (0.91), -0.013 (1.38), 0.828 (1.42), 0.830 (1.44), 0.838 (16.00), 1.321 (0.47), 1.363 (13.37), 1.373 (15.28), 1.447 (0.60), 1.530 (0.44), 3.477 (0.70), 3.493 (1.26), 3.509 (0.72), 3.528 (2.60).  Intermediate 55 tert-butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-(3-hydroxy-1H-pyrazol-5-yl)piperidine-1- carboxylate   
tert-Butyl 4-(3-tert-butoxy-3-oxopropanoyl)-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)piperidine- 1-carboxylate (6.10 g, 12.2 mmol) was solubilised in ethanol (25 ml), hydrazine—water (1/1) (1.8 ml, 37 mmol; CAS-RN:[7803-57-8]) was added and the mixture was stirred overnight at 80°C. It was evaporated and the residue was purified by flash chromatography to give 4.36 g (81 % yield) of the title compound. LC-MS (Method 1): Rt = 1.08 min; MS (ESIpos): m/z = 440 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.026 (2.10), 0.846 (0.78), 0.853 (16.00), 0.859 (0.81), 0.878 (0.41), 1.401 (10.39), 2.547 (0.40), 3.453 (0.75).  Intermediate 56 tert-butyl 4-(3-hydroxypropyl)-4-(3-hydroxy-1H-pyrazol-5-yl)piperidine-1-carboxylate  tert-Butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-(3-hydroxy-1H-pyrazol-5-yl)piperidine-1- carboxylate (4.36 g, 9.92 mmol) was solubilised in THF (80 ml) under nitrogen, TBAF (14 ml, 1.0 M in THF, 13.9 mmol) was added and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 2.74 g (85 % yield) of the title compound. LC-MS (Method 1): Rt = 0.56 min; MS (ESIpos): m/z = 326 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (0.91), 0.865 (0.45), 1.140 (0.44), 1.154 (0.62), 1.160 (0.42), 1.172 (0.72), 1.375 (16.00), 1.399 (1.07), 1.421 (0.81), 1.441 (0.48), 1.933 (0.53), 1.968 (0.48), 1.987 (1.12), 3.231 (0.88), 3.244 (0.88), 3.584 (0.51), 3.618 (0.47), 4.310 (0.42), 4.323 (0.88), 4.336 (0.41), 5.276 (1.10), 5.757 (0.63).  Intermediate 57 tert-butyl 2'-hydroxy-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine]-1- carboxylate   
tert-Butyl 4-(3-hydroxypropyl)-4-(3-hydroxy-1H-pyrazol-5-yl)piperidine-1-carboxylate (2.73 g, 8.39 mmol) was solubilised in THF (45 ml), PPh3 (3.08 g, 11.7 mmol) was added and DIAD (2.1 ml, 10.9 mmol) was added dropwise. It was evaporated and purified by flash chromatography to give 1.97 g (76 % yield) of the title compound. LC-MS (Method 1): Rt = 0.75 min; MS (ESIpos): m/z = 308 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.404 (16.00), 1.591 (0.67), 1.604 (0.50), 1.616 (0.43), 1.643 (0.41), 1.760 (0.40), 1.765 (0.42), 1.781 (0.56), 1.895 (0.42), 2.518 (0.57), 3.735 (0.56), 3.751 (1.05), 3.766 (0.51), 5.338 (2.55), 9.407 (0.75).  Intermediate 58 tert-butyl 2'-[(trifluoromethanesulfonyl)oxy]-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxylate  tert-Butyl 2’-hydroxy-6’,7’-dihydro-5’H-spiro[piperidine-4,4’-pyrazolo[1,5-a]pyridine]-1- carboxylate (1.97 g, 6.41 mmol), 1,1,1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl]methanesulfonamide (2.52 g, 7.05 mmol) and N,N- diisopropylethylamine (3.3 ml, 19 mmol) were solubilised in THF (50 ml) and the mixture was stirred overnight at 60°C. It was evaporated and the residue was purified by flash chromatography to give 2.78 g (99 % yield) of the title compound. LC-MS (Method 1): Rt = 1.45 min; MS (ESIpos): m/z = 440 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.408 (16.00), 1.660 (0.67), 1.690 (0.44), 1.708 (0.41), 1.718 (0.44), 1.866 (0.44), 1.884 (0.56), 1.966 (0.42), 1.977 (0.44), 2.518 (0.87), 2.523 (0.53), 3.977 (0.54), 3.992 (1.04), 4.007 (0.48), 6.442 (2.20).  Intermediate 59  
tert-butyl 4-(3-bromo-1H-pyrazol-5-yl)-4-hydroxypiperidine-1-carboxylate  (3-Bromo-1H-pyrazol-1-yl)methanol (2.66 g, 15.1 mmol) was solubilised in THF (75 ml), cooled to -78°C and LDA (15 ml, 2.0 M in THF/heptane/ethylbenzene, 30 mmol) was added dropwise. The mixture was allowed to warm up to -20°C and was stirred for 45 min at -20°C. The mixture was cooled to -78°C and tert-butyl 4-oxopiperidine-1-carboxylate (2.50 g, 12.5 mmol), solubilised in THF (25 ml), was added dropwise. It was stirred for 2 h at -78°C and was allowed to warm up to rt overnight. The mixture was diluted with sat. NaHCO3 solution, extracted with EtOAc and the organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated. The residue was stirred in DCM, filtered and dried under reduced pressure. The filtrate was purified by flash chromatography. The combined fractions and the solid were combined to give 3.16 g (72 % yield) of the title compound. LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 346 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (1.99), 1.035 (0.46), 1.053 (0.86), 1.070 (0.46), 1.382 (0.58), 1.398 (16.00), 1.712 (0.81), 2.518 (0.72), 2.523 (0.47), 5.460 (0.76), 6.244 (0.63), 6.249 (0.67).  Intermediate 60 tert-butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-4-hydroxypiperidine- 1-carboxylate   
tert-Butyl 4-(3-bromo-1H-pyrazol-5-yl)-4-hydroxypiperidine-1-carboxylate (3.15 g, 9.10 mmol) was solubilised in THF (50 ml) under nitrogen, NaH (400 mg, 60 % purity, 10.0 mmol) was added and the mixture was stirred for 10 min at rt. [2-(chloromethoxy)ethyl](trimethyl)silane (1.8 ml, 10 mmol) was added and the mixture was stirred overnight at rt. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 2.57 g (59 % yield) of the title compound. LC-MS (Method 1): Rt = 1.55 min; MS (ESIpos): m/z = 476 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.007 (1.24), 0.071 (2.95), 0.853 (0.85), 0.873 (1.24), 0.893 (0.89), 1.246 (0.44), 1.460 (16.00), 1.709 (0.46), 1.742 (0.66), 1.887 (0.53), 2.061 (0.82), 3.598 (0.92), 3.619 (1.47), 3.638 (1.25), 3.666 (0.42), 5.269 (1.53), 5.445 (2.99), 6.565 (2.48).  Intermediate 61 tert-butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-4-(2-ethoxy-2- oxoethoxy)piperidine-1-carboxylate  tert-Butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-4-hydroxypiperidine- 1-carboxylate (3.48 g, 7.30 mmol) was solubilised in THF (50 ml) under nitrogen, NaH (438 mg, 60 % purity, 11.0 mmol) was added and the mixture was stirred for 10 min at rt. ethyl bromoacetate (1.2 ml, 11 mmol) was added and the mixture was stirred overnight at 60°C. It was stirred for 3 d at 80°C and overnight at 90°C. The mixture was diluted with dioxane (50 ml), THF was evaporated. The mixture was stirred for 6 d at 120°C. Sat. NaCl solution was added and the mixture was extracted with EtOAc, dried with Na2SO4 and evaporated. The residue was purified by flash chromatography to give 1.80 g (44 % yield) of the title compound. LC-MS (Method 1): Rt = 1.67 min; MS (ESIpos): m/z = 562 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.039 (0.42), 0.047 (12.00), 0.056 (0.46), 0.862 (0.86), 0.868 (0.52), 0.881 (1.26), 0.901 (0.94), 0.908 (0.47), 1.208 (2.04), 1.226 (4.79), 1.242 (3.16), 1.260 (1.45), 1.471 (16.00), 1.482 (7.27), 1.989 (0.76), 2.002 (1.31), 2.016 (0.88), 2.075 (0.97),  
2.605 (1.62), 2.610 (1.00), 3.454 (1.07), 3.462 (0.75), 3.466 (0.76), 3.606 (0.86), 3.626 (1.21), 3.645 (0.82), 3.653 (0.63), 3.721 (0.46), 3.872 (1.28), 3.880 (3.49), 4.096 (0.58), 4.113 (1.83), 4.127 (0.41), 4.131 (1.85), 4.144 (0.82), 4.149 (0.64), 4.162 (0.75), 5.503 (2.75), 5.634 (0.89), 5.845 (0.64), 6.622 (1.06), 6.699 (2.66).  Intermediate 62 ethyl {[4-(5-bromo-1H-pyrazol-3-yl)piperidin-4-yl]oxy}acetate  tert-Butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-4-(2-ethoxy-2- oxoethoxy)piperidine-1-carboxylate (1.00 g, 1.78 mmol) was solubilised in dichloromethane (20 ml) and TFA (4.5 ml, 58 mmol) was added. The mixture was stirred overnight at rt. The mixture was diluted with toluene and concentrated under reduced pressure to give 1.20 g (49 % purity, 100 % yield) of the title compound, which was used without further purification. Intermediate 63 ethyl {[4-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)piperidin-4-yl]oxy}acetate  Ethyl {[4-(5-bromo-1H-pyrazol-3-yl)piperidin-4-yl]oxy}acetate (1.20 g, 49 % purity, 1.77 mmol), isocyanatoethane (170 µl, 2.1 mmol) and N,N-diisopropylethylamine (1.5 ml, 8.9 mmol) were solubilised in dichloromethane (1.2 ml) and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 780 mg of the title compound. ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.000 (0.58), 0.975 (4.92), 0.984 (1.69), 0.992 (12.18), 1.001 (1.38), 1.010 (8.13), 1.016 (2.74), 1.027 (2.05), 1.034 (1.37), 1.052 (0.49), 1.069 (0.40),  
1.073 (0.69), 1.085 (0.55), 1.092 (1.44), 1.110 (4.67), 1.123 (6.83), 1.128 (14.87), 1.136 (3.01), 1.146 (16.00), 1.153 (3.08), 1.159 (1.11), 1.164 (5.73), 1.170 (2.19), 1.176 (0.46), 1.180 (0.45), 1.187 (3.82), 1.197 (0.50), 1.205 (1.92), 1.215 (0.44), 1.230 (0.72), 1.250 (0.47), 1.392 (0.45), 1.549 (0.41), 1.641 (0.80), 1.651 (8.05), 1.693 (0.83), 1.755 (0.66), 1.795 (0.70), 1.813 (0.42), 1.906 (2.09), 1.917 (3.42), 1.934 (1.84), 2.064 (0.51), 2.083 (0.68), 2.517 (1.33), 2.521 (0.88), 2.970 (0.40), 2.975 (0.41), 2.988 (0.82), 2.996 (0.94), 3.002 (1.23), 3.006 (1.25), 3.014 (1.97), 3.020 (1.25), 3.027 (2.24), 3.032 (2.19), 3.041 (1.21), 3.045 (2.14), 3.058 (0.97), 3.063 (1.05), 3.072 (0.61), 3.077 (0.47), 3.210 (0.75), 3.229 (2.36), 3.244 (2.95), 3.246 (2.95), 3.262 (2.90), 3.279 (1.52), 3.293 (0.73), 3.425 (1.78), 3.438 (1.77), 3.452 (1.05), 3.458 (1.26), 3.472 (0.70), 3.592 (2.29), 3.651 (0.52), 3.876 (7.91), 3.894 (1.57), 3.904 (0.87), 3.933 (0.44), 4.016 (1.48), 4.034 (4.33), 4.052 (4.31), 4.069 (1.54), 4.087 (0.75), 4.105 (1.71), 4.123 (1.63), 4.140 (0.54), 4.475 (1.04), 4.480 (0.72), 4.498 (0.42), 4.507 (2.42), 6.462 (0.49), 6.475 (0.94), 6.488 (1.41), 6.502 (0.75), 6.517 (1.14), 6.639 (0.51), 6.672 (1.16), 6.736 (7.22), 6.968 (0.58), 8.432 (0.61), 8.447 (1.22), 8.462 (0.61).  Intermediate 64 4-(5-bromo-1H-pyrazol-3-yl)-N-ethyl-4-(2-hydroxyethoxy)piperidine-1-carboxamide  Ethyl {[4-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)piperidin-4-yl]oxy}acetate (730 mg, 1.81 mmol) was solubilised in THF (17 ml) under nitrogen, lithium borohydride (2.2 ml, 4.0 M in THF, 11 mmol) was added dropwise and the mixture was stirred overnight at rt. It was cooled to 0°C, diluted with sat. NH4Cl solution and extracted with EtOAc. The organic layer was washed with sat. NaCl solution, dried with Na2SO4 and evaporated to give 350 mg (54 % yield) of the title compound, which was used without further purification. Intermediate 65 2'-bromo-N-ethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,1-c][1,4]oxazine]-1-carboxamide   
4-(5-Bromo-1H-pyrazol-3-yl)-N-ethyl-4-(2-hydroxyethoxy)piperidine-1-carboxamide (350 mg, 969 µmol) was solubilised in THF (5.0 ml), PPh3 (356 mg, 1.36 mmol) was added and DIAD (250 µl, 1.29 mmol) was added dropwise. The mixture was stirred overnight at rt. It was evaporated and purified by flash chromatography to give 170 mg (55 % purity, 28 % yield) of the title compound. Intermediate 66 1-(ethylcarbamoyl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridin]-2'-yl trifluoromethanesulfonate  Trifluoroacetic acid—6’,7’-dihydro-5’H-spiro[piperidine-4,4’-pyrazolo[1,5-a]pyridin]-2’-yl trifluoromethanesulfonate (1/1) (1.11 g, 74 % purity, 1.82 mmol), isocyanatoethane (220 µl, 2.7 mmol; CAS-RN:[109-90-0]) and N,N-diisopropylethylamine (1.6 ml, 9.1 mmol) were solubilised in dichloromethane (25 ml) and the mixture was stirred overnight at rt. It was evaporated and the residue was purified by flash chromatography to give 729 mg (98 % yield) of the title compound.  LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 411 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (4.81), 0.989 (7.05), 1.007 (16.00), 1.025 (6.99), 1.137 (0.68), 1.154 (0.66), 1.603 (1.11), 1.636 (2.58), 1.660 (1.24), 1.670 (1.46), 1.688 (1.40), 1.698 (1.53), 1.722 (0.69), 1.732 (0.57), 1.854 (1.33), 1.862 (1.61), 1.867 (1.69), 1.883 (2.27), 1.974 (1.57), 1.985 (1.69), 1.998 (1.07), 2.332 (0.78), 2.518 (3.66), 2.522 (2.39), 2.673 (0.80), 2.911 (0.92), 2.918 (1.04), 2.945 (1.91), 2.973 (1.16), 2.981 (0.89), 3.014 (0.85), 3.032 (2.68), 3.045 (2.81), 3.050 (2.78), 3.063 (2.55), 3.081 (0.78), 3.350 (1.12), 3.728 (1.84), 3.753 (0.97),  
3.762 (1.71), 3.975 (2.05), 3.990 (4.08), 4.005 (1.92), 6.403 (9.85), 6.440 (0.96), 6.454 (1.90), 6.467 (0.93).  The following compounds (intermediate 67 to intermediate 80) were prepared in analogy to example 1: Intermediate 67 tert-butyl 2'-(isoquinolin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate  LC-MS (Method 1): Rt = 1.20 min; MS (ESIpos): m/z = 377 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.420 (16.00), 2.518 (0.61), 2.523 (0.40), 2.919 (0.60), 2.936 (0.92), 2.954 (0.65), 4.130 (0.90), 4.245 (0.67), 4.263 (0.98), 4.280 (0.63), 6.843 (3.12), 7.723 (0.41), 7.726 (0.60), 7.743 (0.41), 7.815 (0.43), 7.832 (0.60), 7.836 (0.45), 8.167 (0.55), 8.187 (0.51), 8.727 (2.58), 8.777 (0.57), 8.779 (0.56), 8.798 (0.54), 8.800 (0.52), 9.274 (1.49).  Intermediate 68 tert-butyl 2'-(8-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate  LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 395 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.426 (16.00), 2.518 (1.22), 2.522 (0.76), 2.889 (0.57), 2.907 (0.87), 2.924 (0.61), 4.098 (0.73), 4.115 (0.74), 4.202 (0.62), 4.220 (0.94), 4.237 (0.59), 7.055 (2.80), 7.545 (0.41), 7.572 (0.46), 7.576 (0.65), 7.596 (0.42), 7.609 (0.43), 7.830 (0.52), 7.833 (0.56), 7.854 (0.43), 8.756 (0.55), 8.760 (0.90), 8.765 (0.55), 9.402 (1.16), 9.407 (1.12).   
Intermediate 69/Example 11 tert-butyl 2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate  LC-MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 380 [M+H]+  Intermediate 70/Example 17 tert-butyl 2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate  LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 394 [M+H]+  Intermediate 71 tert-butyl 2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate  LC-MS (Method 1): Rt = 1.31 min; MS (ESIpos): m/z = 420 [M+H]+  Intermediate 72/Example 170 tert-butyl 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate   
LC-MS (Method 1): Rt = 1.17 min; MS (ESIpos): m/z = 400 [M+H]+  Intermediate 73 tert-butyl 2'-(3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate  LC-MS (Method 1): Rt = 1.66 min; MS (ESIpos): m/z = 539 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.111 (0.41), -0.075 (0.61), -0.067 (16.00), -0.059 (0.54), 0.836 (0.49), 0.855 (0.59), 0.876 (0.50), 1.071 (1.53), 1.088 (3.40), 1.106 (1.46), 1.446 (0.45), 1.466 (8.49), 2.319 (1.88), 2.322 (1.90), 2.474 (0.50), 2.554 (0.41), 3.458 (0.83), 3.471 (0.82), 3.476 (0.73), 3.488 (0.73), 3.509 (0.52), 3.529 (0.59), 3.549 (0.49), 4.221 (0.49), 4.381 (0.42), 4.394 (0.83), 4.406 (0.41), 5.584 (1.26), 6.872 (1.12), 7.410 (0.56), 7.412 (0.56), 8.319 (0.73), 8.324 (0.72), 8.742 (0.66), 8.747 (0.64).  Intermediate 74 tert-butyl 2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxylate   
LC-MS (Method 2): Rt = 1.31 min; MS (ESIpos): m/z = 449 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.439 (16.00), 1.700 (0.51), 1.801 (0.41), 1.887 (0.43), 1.907 (0.49), 2.030 (0.41), 2.518 (0.68), 2.523 (0.46), 3.899 (6.90), 4.127 (0.47), 4.142 (0.92), 4.157 (0.45), 6.970 (2.34), 7.336 (0.59), 7.343 (0.93), 7.366 (2.23), 7.373 (0.53), 7.886 (0.83), 7.907 (0.77), 8.575 (0.87), 8.580 (0.89), 9.173 (1.53), 9.178 (1.41).  Intermediate 75 tert-butyl 2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxylate  LC-MS (Method 2): Rt = 1.61 min; MS (ESIpos): m/z = 477 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.351 (7.09), 1.367 (7.28), 1.381 (0.63), 1.396 (0.55), 1.441 (16.00), 1.700 (0.51), 1.802 (0.42), 1.888 (0.44), 1.907 (0.50), 2.031 (0.42), 2.521 (0.46), 4.127 (0.47), 4.142 (0.92), 4.156 (0.46), 4.757 (0.40), 4.772 (0.55), 4.787 (0.41), 6.961 (2.21), 7.297 (0.59), 7.304 (0.69), 7.320 (0.57), 7.327 (0.80), 7.363 (1.01), 7.370 (0.81), 7.871 (0.94), 7.893 (0.85), 8.552 (0.88), 8.557 (0.91), 9.159 (1.47), 9.164 (1.38).  Intermediate 76 tert-butyl 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxylate   
LC-MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 442 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (0.57), 1.066 (12.77), 1.404 (2.96), 1.432 (16.00), 1.642 (0.46), 1.676 (0.60), 1.772 (0.45), 1.797 (0.49), 1.865 (0.56), 1.884 (0.66), 2.009 (0.50), 2.523 (0.72), 3.750 (0.55), 3.941 (2.11), 4.083 (0.52), 4.098 (1.01), 4.112 (0.51), 5.757 (1.99), 6.893 (2.13), 7.670 (1.07), 7.677 (1.08), 8.234 (1.11), 8.238 (1.13), 8.761 (1.27), 8.765 (1.27), 11.972 (0.56).  Intermediate 77 tert-butyl 2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole]-1- carboxylate  LC-MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 435 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.434 (16.00), 1.645 (0.49), 1.709 (0.47), 2.450 (0.60), 2.468 (0.96), 2.518 (0.67), 2.522 (0.44), 3.585 (0.41), 3.902 (6.49), 4.219 (0.60), 4.236 (0.95), 4.254 (0.57), 6.972 (2.26), 7.345 (0.93), 7.355 (0.87), 7.363 (1.60), 7.885 (0.71), 7.910 (0.65), 8.562 (0.84), 8.567 (0.85), 9.182 (1.28), 9.187 (1.31).  Intermediate 78 tert-butyl 2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine]-1- carboxylate   
LC-MS (Method 1): Rt = 1.29 min; MS (ESIpos): m/z = 419 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (7.11), 1.438 (16.00), 1.703 (0.48), 1.910 (0.47), 2.518 (1.20), 2.523 (0.79), 4.134 (0.45), 4.149 (0.90), 4.164 (0.44), 7.014 (2.31), 7.605 (0.41), 7.608 (0.61), 7.625 (0.40), 7.629 (0.40), 7.701 (0.40), 7.705 (0.41), 7.721 (0.62), 7.725 (0.46), 7.981 (0.54), 7.984 (0.55), 7.993 (0.63), 7.995 (0.63), 8.001 (0.53), 8.005 (0.47), 8.015 (0.54), 8.670 (0.80), 8.675 (0.82), 9.354 (1.36), 9.359 (1.29).  Intermediate 79 tert-butyl 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[azetidine-3,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxylate  LC-MS (Method 1): Rt = 1.17 min; MS (ESIpos): m/z = 416 [M+H]+  Intermediate 80/Example 169 tert-butyl 2'-(2-chloro-3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxylate  LC-MS (Method 1): Rt = 1.27 min; MS (ESIpos): m/z = 428 [M+H]+   
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.011 (0.58), -0.002 (14.76), 0.005 (0.52), 1.066 (1.56), 1.118 (0.44), 1.180 (1.32), 1.199 (3.00), 1.209 (0.44), 1.218 (1.41), 1.228 (0.75), 1.246 (0.41), 1.371 (0.86), 1.384 (12.94), 1.408 (4.20), 1.419 (16.00), 2.518 (4.19), 2.523 (2.60), 2.678 (0.63), 2.697 (0.93), 2.716 (0.90), 2.855 (0.71), 2.872 (1.09), 2.881 (0.74), 2.890 (0.79), 2.899 (0.86), 2.917 (0.50), 4.026 (0.80), 4.049 (1.22), 4.073 (1.06), 4.092 (0.99), 4.133 (0.72), 4.150 (1.07), 4.167 (0.66), 4.178 (0.55), 4.196 (0.79), 4.213 (0.47), 5.758 (0.86), 6.432 (0.61), 6.667 (1.08), 6.670 (1.11), 6.844 (2.47), 7.496 (0.43), 7.500 (0.41), 7.503 (0.44), 7.513 (1.10), 7.517 (0.97), 7.521 (1.13), 7.532 (0.96), 7.539 (0.98), 7.562 (0.85), 7.566 (0.85), 7.580 (0.82), 7.584 (0.71), 7.693 (1.00), 7.696 (1.20), 7.713 (0.95), 7.722 (0.96), 7.727 (1.08), 7.743 (0.89), 8.254 (1.28), 8.259 (1.33), 8.640 (1.38), 8.645 (1.36), 12.226 (0.82).  Intermediate 81 trifluoroacetic acid—2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1)  tert-Butyl 2’-(quinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’-pyrrolo[1,2-b]pyrazole]-1- carboxylate (750 mg, 1.99 mmol) was solubilised in dichloromethane (15 ml) and TFA (5.0 ml, 65 mmol) was added. The mixture was stirred for 2 h at rt. The mixture was diluted with toluene and concentrated under reduced pressure to give 1.80 g of the title compound, which was used without further purification. LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 277 [M+H]+  ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.532 (2.40), 1.907 (0.51), 2.298 (5.83), 2.515 (4.04), 2.518 (3.99), 2.522 (3.06), 2.987 (2.50), 3.001 (3.50), 3.015 (2.67), 4.215 (3.11), 4.230 (4.63), 4.244 (4.24), 4.255 (2.28), 4.269 (2.38), 4.281 (1.57), 4.290 (0.96), 4.304 (0.51), 5.758 (16.00), 7.044 (10.81), 7.143 (0.64), 7.165 (0.96), 7.179 (1.35), 7.233 (1.20), 7.248 (1.42), 7.263 (0.56), 7.658 (1.08), 7.660 (1.20), 7.674 (2.33), 7.688 (1.42), 7.690 (1.42), 7.777 (1.37), 7.780 (1.40), 7.791 (1.18), 7.794 (2.30), 7.797 (1.59), 7.808 (1.27), 7.811 (1.25), 8.043 (2.25), 8.060 (1.98), 8.091 (1.96), 8.106 (1.81), 8.752 (2.70), 8.757 (2.70), 8.949 (0.69), 9.386 (4.68), 9.391 (4.58).  The following compounds (intermediate 82 to intermediate 98) were prepared in analogy to intermediate 81:  
Intermediate 82 trifluoroacetic acid—2'-(isoquinolin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 277 [M+H]+  Intermediate 83 trifluoroacetic acid—2'-(8-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 295 [M+H]+  Intermediate 84 trifluoroacetic acid—2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 0.73 min; MS (ESIpos): m/z = 266 [M+H]+  Intermediate 85 trifluoroacetic acid—2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)   
LC-MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 280 [M+H]+  Intermediate 86 trifluoroacetic acid—2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 294 [M+H]+  Intermediate 87 trifluoroacetic acid—2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine- 3,4'-pyrrolo[1,2-b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 320 [M+H]+  Intermediate 88/Intermediate 91 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)   
LC-MS (Method 1): Rt = 0.82 min; MS (ESIpos): m/z = 300 [M+H]+  Intermediate 89 trifluoroacetic acid—2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 342 [M+H]+  Intermediate 90 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 328 [M+H]+  Intermediate 91/Intermediate 88 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole] (1/1)   
LC-MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 300 [M+H]+  Intermediate 92 trifluoroacetic acid—2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine] (1/1)  LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 349 [M+H]+  Intermediate 93 trifluoroacetic acid—2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine] (1/1)  LC-MS (Method 1): Rt =1.15 min; MS (ESIpos): m/z = 377 [M+H]+  Intermediate 94 trifluoroacetic acid—6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridin]-2'-yl trifluoromethanesulfonate (1/1)   
LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 340 [M+H]+  Intermediate 95 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H- spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine] (1/1)  LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 342 [M+H]+  Intermediate 96 trifluoroacetic acid—2'-(6-methoxyquinolin-3-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[1,2- b]pyrazole] (1/1)  LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 336 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (0.96), 1.876 (0.61), 1.896 (0.88), 1.911 (1.44), 1.926 (0.76), 1.943 (0.75), 1.956 (1.48), 1.969 (0.85), 1.991 (0.59), 2.327 (1.02), 2.332 (0.72), 2.518 (3.40), 2.523 (2.38), 2.537 (1.62), 2.555 (2.25), 2.573 (1.49), 2.673 (0.70), 3.252 (2.41), 3.915 (16.00), 4.254 (1.50), 4.272 (2.26), 4.289 (1.43), 6.984 (3.21), 7.393 (1.02), 7.400 (1.96), 7.414 (1.88), 7.419 (5.84), 7.924 (1.50), 7.944 (0.65), 7.950 (1.35), 8.573 (0.62), 8.641 (1.87), 8.645 (1.87), 9.222 (3.09), 9.228 (3.00).  Intermediate 97  
trifluoroacetic acid—2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine] (1/1)  LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 319 [M+H]+  Intermediate 98 trifluoroacetic acid—2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[azetidine-3,4'- pyrazolo[5,1-c][1,4]oxazine] (1/1)  LC-MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 316 [M+H]+ The following compound (intermediate 99) was prepared in analogy to example 1: Intermediate 99 N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’-pyrrolo[1,2-b]pyrazole]-1- carboxamide LC-MS (Method 1): Rt = 0.57 min; MS (ESIpos): m/z = 364 [M+H]+ Intermediate 100 6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridin]-2'-yl trifluoromethanesulfonate trifluoroacetate (1:1)  
Figure imgf000138_0002
tert-Butyl (800 mg, 1.82 mmol) was solubilised in dichloromethane (20 mL) and TFA (4.6 mL, 59 mmol) was added. The mixture was stirred overnight at rt. The mixture was concentrated, the residue was treated twice with toluene and concentrated under reduced pressure to give 1.11 g of the title compound, which was used without further purification. LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 340 [M+H]+ EXPERIMENTAL SECTION – EXAMPLES  Example 1  tert‐butyl 2'‐(2‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate 
Figure imgf000138_0001
To  a  solution  of  tert‐butyl  2'‐(trifluoromethanesulfonyloxy)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (intermediate 6) (100 mg, 252 µmol) in 1,4‐dioxane (4.0 ml) were  added  (2‐fluoroquinolin‐3‐yl)boronic acid  (96.1 mg, 503 µmol, CAS‐RN  [745784‐10‐5]), K3PO4  (1.5 ml,  0.50 M, 750 µmol) and XPhos Pd G2 (29.7 mg, 37.7 µmol; CAS‐RN:[14221‐01‐3]). The mixture was stirred  overnight at 100°C. The mixture was diluted with EtOAc, washed with sat. NaCl solution and the organic  phase was dried and concentrated under reduced pressure. The mixture was purified by preparative  HPLC to yield the title compound (5.00 mg, 95 % purity, 5 % yield). LC‐MS (Method 1): Rt = 1.20 min; MS  (ESIpos): m/z = 395 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.421 (16.00), 2.518 (0.75), 2.523  (0.48), 2.896 (0.60), 2.913 (0.89), 2.931 (0.64), 4.099 (0.86), 4.112 (0.72), 4.211 (0.64), 4.229 (0.99), 4.246  (0.65), 6.823 (0.97), 6.833 (0.95), 7.630 (0.57), 7.790 (0.55), 7.793 (0.43), 7.872 (0.68), 7.893 (0.43), 8.123  (0.52), 8.142 (0.48), 8.967 (0.63), 8.992 (0.64).  The following compounds (example 2 to example 16) were synthesized in analogy to example 1:   
Example 2  tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate     (prepared from intermediate 6 and quinolin‐3‐ylboronic acid, CAS‐RN: [191162‐39‐7])  1H‐NMR (400 MHz, DMSO‐d6) delta [ppm]: 1.426 (16.00), 2.884 (0.72), 2.901 (1.22), 2.919 (0.76), 4.100  (1.32), 4.111 (1.35), 4.191 (0.78), 4.208 (1.32), 4.226 (0.73), 7.016 (2.33), 7.617 (0.68), 7.634 (0.47), 7.731  (0.66), 7.999 (0.97), 8.016 (0.77), 8.021 (0.82), 8.675 (1.07), 8.679 (1.07), 9.358 (1.25), 9.363 (1.23).  Example 3    tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  (prepared from intermediate 6 and 1H‐pyrrolo[2,3‐b]pyridin‐5‐ylboronic acid, CAS‐RN: [944059‐24‐9])  LC‐MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 366 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.420  (16.00), 2.518  (1.57), 2.523  (0.96), 2.539  (1.41), 2.853  (0.58), 2.871 (0.93), 2.888 (0.62), 3.566 (0.53), 4.085 (1.15), 4.131 (0.66), 4.149 (0.99), 4.166 (0.60), 6.450  (0.68), 6.454 (0.73), 6.459 (0.71), 6.463 (0.67), 6.770 (2.92), 7.458 (0.59), 7.465 (0.71), 7.472 (0.57), 8.269  (0.93), 8.273 (0.95), 8.652 (1.25), 8.657 (1.21), 11.643 (0.45).  Example 4    tert‐butyl 2'‐(2‐aminopyrimidin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (prepared from intermediate 6 and (2‐aminopyrimidin‐5‐yl)boronic acid, CAS‐RN: [936250‐22‐5])   
LC‐MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 343 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.407  (16.00), 2.827  (0.83), 2.844  (1.44), 2.861  (0.87), 4.032  (1.12), 4.066 (1.22), 4.088 (1.52), 4.105 (1.61), 4.123 (0.88), 6.654 (2.21), 6.720 (2.35), 8.591 (4.30).  Example 5    tert‐butyl 2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  (prepared from intermediate 6 and 6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[3,2‐ b]pyridine, CAS‐RN: [1045855‐91‐1])  LC‐MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 366 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.399  (0.62), 1.422  (16.00), 2.518  (1.19), 2.522  (0.74), 2.858  (0.61), 2.876 (0.97), 2.893 (0.65), 4.089 (1.56), 4.141 (0.68), 4.159 (1.04), 4.176 (0.62), 6.530 (0.55), 6.533  (0.55), 6.537 (0.56), 6.822 (2.64), 7.624 (0.52), 7.631 (0.73), 7.638 (0.51), 8.047 (0.87), 8.050 (0.98), 8.052  (0.95), 8.054 (0.87), 8.770 (1.51), 8.774 (1.42), 11.349 (0.52).  Example 7    tert‐butyl 2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  (prepared from intermediate 6 and [5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]boronic acid, CAS‐RN: [1218790‐56‐ 7])  LC‐MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 396 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.413  (16.00), 1.955  (0.76), 1.964  (0.95), 1.971  (2.19), 1.979  (1.02), 1.988 (0.83), 2.518 (1.14), 2.523 (0.73), 2.845 (0.62), 2.862 (1.00), 2.879 (0.66), 3.275 (0.79), 3.290  (2.02), 3.307 (0.83), 4.062 (0.78), 4.077 (0.86), 4.133 (0.69), 4.150 (1.05), 4.168 (0.63), 6.828 (2.72), 7.185  (0.55), 7.190 (0.73), 7.197 (0.56), 7.845 (1.01), 7.852 (0.98), 8.241 (1.15), 8.246 (1.14).  Example 8   
  tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (prepared from intermediate 6 and (2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)boronic acid, CAS‐ RN: [1111637‐70‐7])  LC‐MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 382 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.401  (0.68), 1.413  (16.00), 2.518  (1.32), 2.523  (0.91), 2.840  (0.58), 2.858 (0.94), 2.875 (0.63), 3.584 (1.94), 4.051 (0.66), 4.074 (0.74), 4.111 (0.71), 4.128 (0.99), 4.145  (0.61), 6.736 (2.76), 7.893 (0.80), 7.898 (0.79), 8.463 (0.93), 8.468 (0.91), 11.033 (0.76).  Example 9    tert‐butyl 2'‐[5‐(trifluoromethyl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from intermediate 6 and [5‐(trifluoromethyl)pyridin‐3‐yl]boronic acid, CAS‐RN: [947533‐51‐ 9])  LC‐MS (Method 1): Rt = 1.28 min; MS (ESIpos): m/z = 395 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.415  (16.00), 2.870  (0.58), 2.888  (0.88), 2.905  (0.62), 4.058  (0.59), 4.101 (0.59), 4.176 (0.64), 4.194 (0.94), 4.211 (0.60), 7.089 (2.74), 8.448 (0.44), 8.451 (0.72), 8.456  (0.46), 8.458 (0.40), 8.879 (0.68), 8.882 (0.69), 8.885 (0.60), 9.284 (0.77), 9.288 (0.76).  Example 10     
tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from intermediate 6 and 1H‐pyrazolo[3,4‐b]pyridin‐5‐ylboronic acid, CAS‐RN: [1417985‐25‐ 1])  LC‐MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 367 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.399  (0.50), 1.420  (16.00), 2.522  (1.10), 2.539  (0.78), 2.863  (0.64), 2.880 (1.02), 2.898 (0.67), 4.080 (0.85), 4.095 (0.90), 4.151 (0.69), 4.168 (1.08), 4.186 (0.64), 6.865  (2.50), 8.160 (1.66), 8.519 (1.36), 8.524 (1.39), 8.972 (1.28), 8.977 (1.25).  Example 11/Intermediate 69    tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from intermediate 6 and 3‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐ pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111637‐95‐6])  LC‐MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 380 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.421  (16.00), 2.272  (3.92), 2.273  (3.80), 2.518  (2.17), 2.523  (1.36), 2.856 (0.61), 2.874 (0.99), 2.891 (0.65), 4.089 (1.02), 4.130 (0.71), 4.148 (1.06), 4.165 (0.63), 6.801  (2.81), 7.221 (0.77), 7.223 (0.77), 8.236 (1.00), 8.240 (1.02), 8.629 (1.27), 8.634 (1.24), 11.285 (0.54).  Example 12    tert‐butyl  2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (prepared  from  intermediate  6  and  7‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyrido[2,3‐ b]pyrazine, CAS‐RN: [1210047‐44‐1])  LC‐MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 379 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.427  (16.00), 2.327  (0.42), 2.518  (2.00), 2.522  (1.21), 2.669  (0.43), 2.899 (0.62), 2.917 (0.97), 2.934 (0.66), 4.101 (0.74), 4.122 (0.79), 4.227 (0.67), 4.245 (1.04), 4.262   
(0.63), 7.211 (2.65), 8.772 (1.30), 8.777 (1.30), 9.066 (1.08), 9.070 (1.54), 9.088 (1.82), 9.093 (1.31), 9.648  (1.34), 9.654 (1.27).  Example 13    tert‐butyl 2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (prepared from intermediate 6 and 6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)furo[3,2‐b]pyridine,  CAS‐RN: [1188539‐34‐5])  LC‐MS (Method 1): Rt = 1.13 min; MS (ESIpos): m/z = 367 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.420  (16.00), 2.518  (0.94), 2.523  (0.61), 2.864  (0.61), 2.882  (0.95), 2.899 (0.66), 4.073 (0.66), 4.098 (0.71), 4.161 (0.69), 4.178 (1.03), 4.195 (0.64), 6.940 (2.76), 7.135  (0.90), 7.138 (0.94), 7.141 (0.93), 7.143 (0.90), 8.310 (1.91), 8.312 (1.15), 8.316 (2.63), 8.319 (0.97), 8.992  (1.53), 8.997 (1.52).  Example 14    tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from intermediate 6 and 2‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐ pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111638‐03‐9])  LC‐MS (Method 1): Rt = 1.14 min; MS (ESIpos): m/z = 380 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.418  (16.00), 2.387  (3.61), 2.518  (2.14), 2.522  (1.31), 2.539  (0.91), 2.847 (0.62), 2.864 (1.01), 2.882 (0.66), 4.080 (1.16), 4.119 (0.73), 4.137 (1.09), 4.154 (0.64), 6.141  (0.92), 6.143 (0.92), 6.732 (2.76), 8.101 (0.99), 8.105 (1.01), 8.520 (1.22), 8.526 (1.22), 11.454 (0.60).  Example 15      tert‐butyl 2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from intermediate 6 and 3‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐ pyrazolo[3,4‐b]pyridine, CAS‐RN: [1111637‐76‐3])  LC‐MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 381 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.399  (0.43), 1.421  (16.00), 2.331  (0.42), 2.517  (8.12), 2.522  (1.89), 2.539 (0.60), 2.673 (0.43), 2.864 (0.57), 2.881 (0.89), 2.898 (0.60), 4.074 (0.66), 4.101 (0.66), 4.146  (0.63), 4.164 (0.95), 4.181 (0.58), 6.879 (2.87), 8.510 (1.46), 8.515 (1.50), 8.932 (1.43), 8.937 (1.40).  Example 16  N N N N F O O H 3 C H 3 C C H 3   tert‐butyl  2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (prepared from intermediate 6 and (6‐fluoroquinolin‐3‐yl)boronic acid, CAS‐RN: [1264511‐20‐7])  LC‐MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 395 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.425  (16.00), 2.518  (0.73), 2.523  (0.45), 2.886  (0.62), 2.904  (0.97), 2.921 (0.66), 4.099 (0.95), 4.109 (0.98), 4.195 (0.66), 4.213 (1.03), 4.230 (0.62), 7.019 (2.56), 7.634  (0.43), 7.641 (0.49), 7.786 (0.48), 7.793 (0.47), 7.810 (0.49), 7.816 (0.44), 8.055 (0.42), 8.069 (0.43), 8.679  (0.88), 8.683 (0.89), 9.333 (1.07), 9.338 (1.05).  Example 17/Intermediate 70  tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate   
  To  a  solution  of  [1‐(tert‐butoxycarbonyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐ yl]boronic acid (50.0 mg, 171 µmol, see intermediate 7) and 5‐bromo‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridine  (57.6 mg, 256 µmol, preparation described in WO2018/167147) in DMSO (1.5 ml) were added Pd(PPh3)4  (19.7 mg, 17.1 µmol; CAS‐RN:[865‐47‐4]) and Na2CO3 (2.0 M, 340 µl). The mixture was stirred overnight  at 110°C. The mixture was diluted with EtOAc, washed with sat. NaCl solution and the organic layer was  dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to yield  the title compound (24.9 mg, 95 % purity, 35 % yield). LC‐MS (Method 1): Rt = 1.21 min; MS (ESIpos):  m/z = 394 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.247 (1.83), 1.266 (4.03), 1.284 (1.83), 1.402  (2.27), 1.415  (16.00), 1.428  (0.61), 2.513  (1.23), 2.518  (0.84), 2.705  (0.92), 2.707  (0.92), 2.724  (0.91),  2.726 (0.91), 2.849 (0.61), 2.866 (0.92), 2.884 (0.62), 4.078 (1.05), 4.125 (0.66), 4.142 (0.98), 4.159 (0.59),  6.805 (2.86), 7.215 (0.72), 7.218 (0.68), 7.221 (0.71), 8.250 (0.92), 8.255 (0.95), 8.623 (0.79), 8.627 (0.78),  11.298 (0.48).  Example 18  tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate    To  a  stirred  solution  of  tert‐butyl  6'‐methyl‐2'‐(trifluoromethanesulfonyloxy)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (intermediate 11) (15 g , 36.4 mmol,  1.00 equiv)  in dioxane (300 mL) was added quinolin‐3‐ylboronic acid (19.0 g, 109.2 mmol, 3.00 equiv,  CAS‐RN:  [191162‐39‐7]),  this was  followed  by  addition  of  Cs2CO3  (35.6  g,  109.2 mmol,  3.00  equiv),  Pd(dppf)Cl2  (3.64 g, 3.65 mmol, 0.10 equiv). The mixture was  stirred at 110  °C  in an oil bath under  nitrogen atmosphere for 4 h. The resulting mixture was filtrated. The filtrate was then purified by flash    chromatography  directly.The  collected  fractions were  evaporated  to  give  9.5  g  (65 %)  of  the  title  compound. LC‐MS: (ES, m/z): 391 [M+H]+. 1H‐NMR: (300 MHz, CDCl3, ppm):δ 9.52‐9.50 (m, 1H), 8.73‐ 8.70 (m, 1H), 8.33‐8.27 (m, 1H), 7.99‐7.93 (m, 1H), 7.85‐7.77 (m, 1H), 7.71‐7.63 (m, 1H), 6.70 (s, 1H),  4.62‐4.50 (m, 1H), 4.35‐4.31 (m, 1H), 4.27 ‐4.10 (m, 3H), 3.18‐3.06 (m, 1H), 2.58‐2.48 (m, 1H), 1.63 (d, J  = 6.4 Hz, 3H), 1.52 (s, 9H).  Example 19  (pyrimidin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone 
Figure imgf000146_0001
Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of  toluene  (2x) and dried  in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (1:1) was used  in the next step without further purification. Step 2: Into a 40‐mL vial was placed a solution of pyrimidine‐ 4‐carboxylic acid (29 mg, 1.50 equiv, 0.234 mmol) in DMF (3 mL). To this was added DIPEA (201,61 mg,  10.00 equiv, 1.56 mmol). This was followed by the addition of HATU (119 mg, 2.00 equiv, 0.312 mmol).  The resulting mixture was stirred for 5 h at ambient temperature. To this was added 2'‐(quinolin‐3‐yl)‐ 5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) (61 mg, 1.00 equiv, 0.156  mmol). The resulting mixture stirred for 2 h at rt. The crude mixture was purified by HPLC to provide the  title compound. 1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.236 (0.82), 2.271 (1.10), 2.727 (1.53), 2.969  (3.83), 2.991 (6.34), 3.015 (4.77), 4.230 (4.26), 4.253 (6.89), 4.276 (4.30), 4.356 (2.03), 4.392 (6.22), 4.413  (6.26), 4.449  (2.07), 4.925  (7.90), 7.053 (16.00), 7.587  (1.76), 7.614  (3.87), 7.641  (3.01), 7.709  (2.66),  7.731 (3.72), 7.759 (2.43), 7.992 (5.83), 8.015 (8.88), 8.027 (9.11), 8.032 (7.12), 8.660 (5.36), 8.667 (5.99),  9.066 (8.33), 9.084 (8.37), 9.310 (8.45), 9.315 (9.19), 9.350 (7.63), 9.357 (8.18).  The following compounds (example 20 to example 33) were synthesized in analogy to example 19:  Example 20   
  (1‐methyl‐1H‐pyrazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]methanone  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐methyl‐1H‐pyrazole‐5‐carboxylic acid, CAS‐RN: [16034‐46‐1])  LC‐MS: (ES, m/z): 385, [M+H]+, H‐NMR: (300 MHz,DMSO‐d6, ppm): δ 9.36 (d, J = 2.2 Hz, 1H), 8.67 (d, J =  2.2 Hz, 1H), 8.05‐7.96 (m, 2H), 7.83‐7.56 (m, 2H), 7.52 (d, J = 2.1 Hz, 1H), 7.05 (s, 1H), 6.70 (d, J = 2.1 Hz,  1H), 4.64 (s, 2H), 4.53‐4.15 (m, 4H), 4.07 (s, 3H), 3.03‐2.91 (m, 2H).  Example 21    4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanenitrile  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐cyanopropanoic acid, CAS‐RN: 16051‐87‐9)  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.234 (0.54), 2.272 (0.52), 2.638 (6.38), 2.659 (8.38), 2.681 (3.09),  2.913 (4.33), 2.935 (7.16), 2.959 (4.83), 3.616 (0.72), 4.123 (1.26), 4.162 (9.03), 4.195 (1.47), 4.218 (4.87),  4.241 (7.85), 4.264 (4.56), 4.415 (14.27), 6.992 (16.00), 7.594 (1.80), 7.620 (3.83), 7.647 (3.24), 7.709  (2.61), 7.714 (2.66), 7.738 (3.88), 7.742 (3.89), 7.760 (2.43), 7.765 (2.61), 8.000 (9.48), 8.031 (8.42), 8.667  (6.25), 8.673 (7.07), 9.353 (8.16), 9.360 (8.70).  Example 22   
  3‐methoxy‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]propan‐ 1‐one  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐methoxypropanoic acid, CAS‐RN: [2544‐06‐1])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.341 (3.30), 2.362 (7.04), 2.383 (3.55), 2.900 (2.54), 2.923 (4.13),  2.946  (2.88), 3.317  (16.00), 3.549  (3.93), 3.570  (8.35), 3.592  (3.69), 4.083  (0.54), 4.120  (5.63), 4.153  (0.71), 4.212  (2.85), 4.235  (4.54), 4.258 (2.73), 4.406 (8.45), 6.983 (10.63), 7.591  (1.06), 7.614  (1.83),  7.618 (2.40), 7.641 (1.72), 7.645 (1.84), 7.707 (1.52), 7.712 (1.48), 7.735 (2.37), 7.740 (2.16), 7.758 (1.35),  7.763 (1.40), 7.999 (5.06), 8.028 (4.58), 8.672 (3.67), 8.678 (3.81), 9.358 (5.07), 9.365 (5.17).  Example 23    3‐(1H‐pyrazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐(1H‐pyrazol‐1‐yl)propanoic acid, CAS‐RN: [89532‐73‐0])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 2.076  (0.56), 2.273  (0.54), 2.641  (5.32), 2.663  (10.85), 2.685  (5.49), 2.855  (4.86), 2.878  (8.32), 2.902 (5.25), 4.058 (1.41), 4.092 (10.99), 4.131  (1.55), 4.194  (5.47),  4.217 (9.19), 4.240 (5.97), 4.264 (16.00), 4.337 (5.96), 4.359 (11.88), 4.382 (5.64), 6.257 (5.61), 6.263  (8.89), 6.269  (5.58), 6.926  (15.13), 7.479  (8.37), 7.594  (2.24), 7.620  (4.78), 7.645  (3.66), 7.720  (8.78),  7.727 (9.16), 7.737 (5.71), 7.760 (2.78), 8.003 (9.27), 8.031 (8.30), 8.664 (7.50), 8.670 (7.70), 9.350 (8.52),  9.357 (8.66).  Example 24   
  2‐(morpholin‐4‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and morpholin‐4‐ylacetic acid, CAS‐RN: [3235‐69‐6])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.438 (8.23), 2.468 (9.36), 2.902 (3.91), 2.925 (6.61), 2.949 (4.68),  3.011 (0.69), 3.063 (16.00), 3.114 (0.94), 3.281 (0.95), 3.585 (9.83), 3.600 (12.72), 3.615 (9.89), 4.109  (0.85), 4.144 (9.62), 4.179 (1.14), 4.210 (4.52), 4.234 (7.62), 4.256 (4.34), 4.489 (12.88), 6.992 (14.64),  7.593 (1.73), 7.620 (3.88), 7.643 (2.81), 7.646 (2.88), 7.708 (2.39), 7.713 (2.36), 7.736 (3.79), 7.741 (3.35),  7.760 (2.10), 7.764 (2.08), 8.002 (8.37), 8.030 (7.25), 8.673 (6.14), 8.679 (6.27), 9.363 (7.76), 9.370 (7.65).  Example 25    2‐(pyrimidin‐5‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyrimidin‐5‐ylacetic acid, CAS‐RN: [5267‐07‐2])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.837 (1.16), 2.890 (0.54), 2.952 (5.04), 2.963 (3.30), 2.971 (3.00),  2.990  (2.05), 3.625  (10.09), 4.102  (0.44), 4.105  (0.44), 4.142  (0.79), 4.175  (5.03), 4.214  (0.98), 4.234  (2.93), 4.257  (5.24), 4.280  (2.30), 4.387 (0.49), 4.553 (8.14), 6.999 (0.75), 7.020 (10.23), 7.094  (0.58),  7.597 (1.22), 7.623 (2.46), 7.647 (1.75), 7.651 (1.76), 7.712 (1.65), 7.717 (1.47), 7.741 (2.30), 7.745 (2.09),  7.763  (1.30), 7.768  (1.30), 8.005  (5.85), 8.034  (4.22), 8.675  (3.96), 8.682  (3.88), 8.717  (16.00), 9.085  (7.84), 9.364 (5.48), 9.372 (4.90).  Example 26   
  (3‐chlorophenyl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐chlorobenzoic acid, CAS‐RN: [535‐80‐8])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.233 (0.48), 2.728 (0.48), 2.948 (3.54), 2.973 (6.08), 2.994 (4.35),  4.216  (2.95), 4.236  (5.37), 4.256  (3.14), 4.343  (5.71), 4.617  (4.25), 7.052  (16.00), 7.499  (2.27), 7.525  (6.19), 7.551 (5.49), 7.595 (1.97), 7.614 (7.11), 7.629 (2.99), 7.641 (5.10), 7.660 (5.87), 7.686 (4.22), 7.707  (2.86), 7.712  (2.83), 7.730  (7.27), 7.735 (11.19), 7.758  (2.88), 7.763  (2.94), 8.000  (8.90), 8.028  (8.48),  8.664 (6.08), 8.670 (6.90), 9.353 (7.76), 9.361 (8.48).  Example 27    (pyridin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyridine‐4‐carboxylic acid, CAS‐RN [55‐22‐1])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.234 (0.63), 2.274 (0.84), 2.723 (0.67), 2.951 (5.38), 2.973 (8.79),  2.997  (5.74), 4.238  (6.63), 4.323  (1.85), 4.355  (7.87), 4.368  (8.04), 4.403  (1.95), 4.620  (12.11), 7.060  (16.00), 7.594 (2.59), 7.620 (5.23), 7.641 (15.24), 7.660 (13.05), 7.709 (3.40), 7.736 (4.89), 7.761 (2.97),  7.999 (11.92), 8.028 (10.10), 8.671 (8.42), 8.730 (12.75), 8.749 (12.06), 9.353 (9.17), 9.359 (9.01).  Example 28   
  2‐ethyl‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butan‐1‐one  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐ethylbutanoic acid, CAS‐RN: [88‐09‐5])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 0.807  (0.79), 0.835  (5.62), 0.860  (13.68), 0.878  (7.89), 0.884  (8.76), 0.902  (13.77), 0.927  (6.82), 1.401  (2.27), 1.425  (2.70), 1.451  (2.76), 1.478  (2.69), 1.496  (2.88),  1.522 (2.36), 1.543 (1.30), 2.109 (0.68), 2.127 (1.33), 2.138 (1.51), 2.156 (2.30), 2.173 (1.38), 2.184 (1.27),  2.202 (0.66), 2.908 (3.98), 2.931 (6.55), 2.954 (4.33), 4.105 (0.84), 4.139 (8.41), 4.177 (1.02), 4.218 (4.37),  4.242  (6.66), 4.264  (4.18), 4.376  (1.30), 4.406  (6.40), 4.415  (6.38), 4.444  (1.37), 6.956  (16.00), 7.590  (1.75), 7.617 (3.36), 7.640 (2.69), 7.644 (2.75), 7.705 (2.46), 7.710 (2.27), 7.733 (3.35), 7.738 (3.21), 7.756  (2.08), 7.761 (2.07), 7.997 (8.42), 8.029 (7.45), 8.690 (5.85), 8.697 (5.94), 9.368 (7.86), 9.375 (7.73).  Example 29    1‐{2‐oxo‐2‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethyl}pyrrolidin‐2‐one  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and (2‐oxopyrrolidin‐1‐yl)acetic acid, CAS‐RN [53934‐76‐2])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.946 (3.30), 1.971 (5.11), 1.996 (4.08), 2.237 (5.17), 2.264 (7.53),  2.291 (3.64), 2.728 (0.68), 2.920 (3.72), 2.943 (6.26), 2.966 (4.18), 3.381 (4.78), 3.405 (7.71), 3.428 (4.48),  3.928 (16.00), 4.167 (8.70), 4.212 (4.69), 4.235 (7.96), 4.258 (4.33), 4.441 (11.59), 7.027 (11.92), 7.594  (1.77), 7.620 (3.86), 7.645 (2.94), 7.710 (2.44), 7.738 (3.69), 7.762 (2.29), 8.000 (8.87), 8.029 (7.79), 8.679  (6.52), 9.357 (6.87), 9.363 (7.21).  Example 30   
  (pyridin‐3‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyridine‐3‐carboxylic acid, CAS‐RN: [59‐67‐6])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.235 (0.46), 2.074 (0.55), 2.271 (0.45), 2.727 (0.45), 2.957 (3.67),  2.980  (5.54),  3.003  (4.06),  4.223  (2.34),  4.241  (3.74),  4.261  (2.23),  4.363  (4.21),  4.640  (3.43),  7.057  (16.00), 7.508  (2.63), 7.511  (2.64), 7.527  (2.80), 7.534  (2.93), 7.537  (2.85), 7.550  (3.01), 7.553  (2.92),  7.591 (1.73), 7.619 (3.22), 7.645 (2.62), 7.707 (2.36), 7.712 (2.10), 7.735 (3.27), 7.740 (3.14), 7.758 (1.94),  7.763 (1.95), 7.997 (7.89), 8.028 (7.13), 8.087 (2.54), 8.093 (3.60), 8.100 (2.62), 8.113 (2.38), 8.120 (3.31),  8.127 (2.34), 8.663 (5.62), 8.670 (5.69), 8.713 (4.42), 8.718 (4.47), 8.729 (4.54), 8.734 (4.09), 8.899 (5.59),  8.904 (5.55), 9.352 (7.76), 9.359 (7.59).  Example 31    1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐cyanocyclopropanecarboxylic acid, CAS‐RN: [6914‐79‐0])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 1.587  (7.78), 1.622  (13.90), 2.078  (2.18), 2.274  (0.52), 2.957  (3.05), 2.980  (3.12), 3.004  (3.01), 4.227 (8.57), 4.244 (9.86), 4.764 (3.00), 4.818 (2.98), 7.078 (16.00),  7.598  (2.42), 7.625  (4.99), 7.650  (3.86), 7.713  (3.08), 7.740  (4.84), 7.765  (2.75), 8.005  (11.53), 8.033  (9.95), 8.694 (8.47), 9.369 (9.07), 9.376 (9.26).  Example 32   
  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐one  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and acetic acid, CAS‐RN: [64‐19‐7]  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 1.837  (16.00), 2.901  (1.70), 2.922  (2.81), 2.947  (1.97), 4.068  (0.40), 4.102 (4.51), 4.137 (0.43), 4.212 (2.19), 4.235 (3.67), 4.258 (2.02), 4.388 (6.48), 6.999 (6.76), 7.592  (0.76), 7.619 (1.71), 7.642 (1.23), 7.646 (1.26), 7.708 (1.05), 7.713 (1.03), 7.735 (1.65), 7.741 (1.49), 7.759  (0.91), 7.763 (0.93), 8.000 (3.70), 8.028 (3.30), 8.669 (2.64), 8.675 (2.77), 9.357 (3.37), 9.364 (3.45).  Example 33    (1‐methyl‐1H‐imidazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐methyl‐1H‐imidazole‐5‐carboxylic acid, CAS‐RN: [41806‐40‐0])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 2.952  (1.75), 2.975  (3.08), 2.998  (1.93), 3.855  (16.00), 4.230  (1.93), 4.253 (3.18), 4.276 (2.27), 4.642 (0.81), 7.045 (6.90), 7.425 (4.36), 7.428 (4.27), 7.591 (0.78), 7.618  (1.83), 7.641 (1.36), 7.707 (1.14), 7.712 (1.20), 7.735 (1.83), 7.740 (1.66), 7.758 (1.08), 7.763 (1.08), 7.831  (4.17), 7.998 (3.63), 8.025 (3.22), 8.671 (2.65), 8.677 (2.94), 9.358 (3.52), 9.365 (3.72).  Example 34  2‐methoxyethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate   
  Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of  toluene  (2x) and dried  in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (1:1) was used  in  the  next  step  without  further  purification.  Step  2:  A  solution  of  2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1:1) (61 mg, 0.156 mmol, 1 eq.), 2‐ methoxyethyl carbonochloridoate (32.5 mg, 0.234 mmol, 1.5 eq., CAS‐RN: [628‐12‐6]) and N‐ethyl‐N,N‐ diisopropylamine (201.6 mg, 1.56 mmol, 10 eq.) in tetrahydrofuran (3 mL) was stirred under nitrogen at  ambient temperature for two hours. After addition of water and phase separation, the organic phase  was washed with water and with saturated aqueous sodium chloride solution, dried over sodium sulfate,  filtered and concentrated under reduced pressure. The crude product was then purified by preparative  HPLC  to yield  the  title compound.  1H‐NMR  (300 MHz, DMSO‐d6) δ  [ppm]: 2.903  (2.72), 2.926  (4.66),  2.949  (3.02), 3.329  (16.00), 3.515  (4.11), 3.530  (5.02), 3.546  (4.52), 4.132  (4.49), 4.148  (5.97), 4.152  (5.47), 4.163  (5.64), 4.195  (8.80), 4.221 (6.39), 4.243 (3.37), 7.025 (10.19), 7.593  (1.19), 7.596  (1.17),  7.616 (2.16), 7.620 (2.74), 7.642 (1.96), 7.646 (2.00), 7.708 (1.70), 7.713 (1.73), 7.736 (2.77), 7.741 (2.42),  7.759 (1.54), 7.764 (1.52), 8.000 (5.39), 8.028 (4.63), 8.671 (4.05), 8.676 (4.40), 9.357 (5.29), 9.365 (5.43).  The following example was prepared in analogy to example34:  Example 35    2‐methoxyethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate   
(prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐methoxyethyl carbonochloridoate (CAS‐RN: [628‐12‐ 6])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.470 (4.28), 1.491 (4.25), 3.090 (0.68), 3.114 (0.81), 3.135 (0.67),  3.159  (0.60), 3.281  (16.00), 3.511  (1.60), 3.526  (1.81), 3.542  (1.81), 4.086  (0.48), 4.113  (0.79), 4.126  (1.86), 4.142 (1.85), 4.158 (1.77), 4.193 (1.27), 4.241 (0.89), 4.269 (0.50), 4.492 (0.42), 4.514 (0.72), 4.537  (0.71), 4.558 (0.42), 7.012 (4.56), 7.589 (0.43), 7.616 (1.06), 7.643 (0.80), 7.705 (0.63), 7.710 (0.66), 7.734  (1.04), 7.739 (0.88), 7.756 (0.56), 7.762 (0.58), 8.002 (1.21), 8.036 (1.10), 8.673 (1.40), 8.680 (1.63), 9.353  (2.12), 9.360 (2.26).  The following examples (36 to 50) were prepared in analogy to the procedure described for example 19:  Example 36    [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyrimidin‐ 4‐yl)methanone  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyrimidine‐4‐carboxylic acid, CAS‐RN: [31462‐59‐6])  LC‐MS: (ES, m/z): 397 [M+H]+, H‐NMR: (300 MHz, DMSO‐d6, ppm): δ 9.43‐9.23 (m, 2H), 9.09‐9.06 (m,  1H), 8.67 (d, J = 2.6 Hz, 1H), 8.04‐8.00 (m, 3H), 7.76‐7.58 (m, 2H), 7.04 (s, 1H), 5.08‐4.75 (m, 2H), 4.63‐ 4.22 (m, 3H), 3.26‐3.06 (m, 1H), 2.62‐2.50 (m, 1H), 1.51‐1.48 (m, 3H).  Example 37     
(1‐methyl‐1H‐pyrazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 1‐methyl‐1H‐pyrazole‐5‐carboxylic acid, CAS‐RN:  [16034‐46‐1])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.500 (2.14), 2.558 (0.75), 2.583 (0.76), 2.603 (0.82), 3.142 (0.42),  3.166  (0.47), 4.078  (16.00), 4.264  (0.46), 4.336  (0.66), 4.380  (0.52), 4.554  (0.72), 4.580  (0.79), 4.639  (0.56), 4.659 (0.59), 4.697 (0.48), 6.690 (0.68), 6.717 (0.69), 7.042 (5.17), 7.524 (1.46), 7.590 (0.54), 7.594  (0.56), 7.616 (1.26), 7.640 (0.89), 7.643 (0.92), 7.707 (0.76), 7.711 (0.82), 7.730 (0.63), 7.735 (1.25), 7.739  (1.04), 7.757 (0.71), 7.762 (0.70), 8.005 (1.56), 8.012 (1.37), 8.017 (1.33), 8.033 (1.34), 8.039 (1.35), 8.673  (1.76), 8.680 (1.88), 9.357 (2.37), 9.364 (2.45).  Example 38    1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐3‐(1H‐ pyrazol‐1‐yl)propan‐1‐one  (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐(1H‐pyrazol‐1‐yl)propanoic acid, CAS‐RN: [89532‐73‐ 0])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.149 (0.90), 1.463 (16.00), 1.484 (15.40), 2.074 (1.95), 2.273  (1.85), 2.628 (4.10), 2.650 (8.98), 2.669 (8.76), 2.690 (3.49), 3.037 (3.33), 3.062 (3.74), 3.083 (3.28), 3.107  (3.02), 3.999 (2.45), 4.030 (4.12), 4.069 (2.76), 4.099 (6.96), 4.127 (2.99), 4.155 (4.75), 4.172 (3.41), 4.200  (4.55), 4.238  (3.08), 4.264  (6.17), 4.287 (3.19), 4.333 (8.97), 4.358 (13.64), 4.379  (6.18), 4.492  (2.50),  4.513  (4.36), 4.534  (4.25), 4.556  (2.36), 6.266  (7.21), 6.917  (11.21), 7.475  (5.57), 7.488  (5.99), 7.593  (2.94), 7.619 (6.02), 7.645 (4.89), 7.723 (10.87), 7.761 (4.09), 8.004 (7.37), 8.028 (10.19), 8.051 (6.99),  8.675 (9.77), 9.355 (10.32).  Example 39   
  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (morpholin‐4‐yl)ethan‐1‐one  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and morpholin‐4‐ylacetic acid, CAS‐RN: [3235‐69‐6])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.145 (0.91), 1.476 (15.78), 1.497 (16.00), 2.073 (3.74), 2.271  (1.20), 2.456 (11.74), 2.726 (1.40), 3.050 (9.45), 3.060 (8.59), 3.090 (2.28), 3.114 (2.44), 3.587 (11.97),  3.603  (12.03), 4.039  (1.83), 4.072  (3.01), 4.112  (1.73), 4.142  (4.79), 4.174  (1.96), 4.197  (3.23), 4.228  (1.79), 4.397 (1.83), 4.428 (3.04), 4.456 (1.86), 4.485 (4.35), 4.508 (3.30), 4.529 (3.55), 4.550 (5.84), 4.572  (2.28), 6.981  (11.48), 7.591  (1.96), 7.616  (4.30), 7.642  (3.43), 7.710  (2.76), 7.734  (4.23), 7.761  (2.59),  8.001 (5.40), 8.017 (5.07), 8.030 (5.21), 8.041 (4.99), 8.685 (7.17), 9.357 (7.68), 9.364 (8.34).  Example 40    1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (pyrimidin‐5‐yl)ethan‐1‐one  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyrimidin‐5‐ylacetic acid, CAS‐RN: [5267‐07‐2])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]:  ‐0.011  (1.28), 0.011  (0.80), 0.748  (1.11), 0.835  (0.86), 0.883  (0.76), 0.943 (0.77), 1.014 (0.81), 1.034 (2.59), 1.132 (2.74), 1.492 (11.97), 1.498 (12.10), 1.514 (12.07),  1.519  (11.38), 2.076  (0.65), 2.272  (0.58), 2.563  (3.06), 2.585  (2.43), 2.607  (1.51), 2.729  (0.46), 3.117  (1.94), 3.141 (3.73), 3.162 (3.28), 3.184 (3.27), 3.208 (1.92), 3.269 (1.11), 3.372 (1.76), 3.536 (1.09), 3.615   
(11.21), 3.628 (10.93), 3.997 (0.59), 4.083 (1.92), 4.115 (3.25), 4.155 (1.82), 4.185 (4.35), 4.213 (1.96),  4.238 (3.34), 4.270 (1.73), 4.466 (1.95), 4.495 (3.38), 4.547 (4.76), 4.564 (5.05), 4.605 (1.22), 4.621 (3.32),  4.650  (1.83), 7.012  (13.31), 7.597  (2.17), 7.600  (2.33), 7.623  (5.00), 7.650  (3.71), 7.712  (3.16), 7.717  (3.25), 7.736 (2.76), 7.741 (5.02), 7.745 (4.19), 7.763 (2.91), 7.768 (2.72), 8.009 (6.03), 8.029 (5.57), 8.036  (5.53), 8.052 (4.74), 8.191 (2.04), 8.249 (0.72), 8.684 (7.17), 8.691 (7.56), 8.713 (15.88), 8.721 (16.00),  9.088 (10.69), 9.365 (8.72), 9.372 (8.81).  Example 41    (3‐chlorophenyl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]methanone  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐chlorobenzoic acid, CAS‐RN: [535‐80‐8])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.489 (8.05), 2.270 (2.80), 2.727 (2.31), 4.346 (2.59), 4.540 (2.94),  4.635  (2.55), 7.041  (16.00), 7.522  (3.62), 7.549  (3.05), 7.612  (5.96), 7.640  (4.61), 7.734  (8.90), 7.762  (2.77), 8.002 (4.97), 8.014 (4.54), 8.029 (4.36), 8.677 (6.17), 9.350 (7.73), 9.357 (7.95).  Example 42    [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐4‐ yl)methanone  (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyridine‐4‐carboxylic acid, CAS‐RN: [55‐22‐1])   
1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.827 (0.77), 0.835 (0.77), 1.235 (1.70), 1.314 (1.30), 1.338 (2.23),  1.361  (1.29), 1.464  (8.06), 1.487  (11.39), 1.512  (7.51), 2.273  (1.09), 2.581  (3.74), 2.600  (3.42), 2.727  (1.08), 3.140 (2.90), 3.163 (3.19), 3.184 (2.86), 3.208 (2.61), 4.268 (1.79), 4.301 (3.01), 4.376 (4.79), 4.400  (2.47), 4.416 (3.40), 4.452 (1.68), 4.530 (3.18), 4.557 (4.94), 4.623 (3.61), 4.645 (3.87), 4.675 (3.43), 4.703  (1.66), 7.049 (16.00), 7.595 (2.36), 7.618 (5.32), 7.646 (11.96), 7.712 (3.64), 7.736 (5.19), 7.758 (3.13),  7.823 (1.19), 7.844 (1.22), 8.004 (6.56), 8.018 (6.34), 8.030 (6.21), 8.044 (5.83), 8.679 (7.74), 8.738 (8.57),  8.794 (1.66), 9.351 (8.38), 9.357 (8.96).  Example 43    2‐ethyl‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]butan‐1‐one  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐ethylbutanoic acid, CAS‐RN: [88‐09‐5])  1H‐NMR (300MHz, DMSO‐d6): δ [ppm]= 0.74 ‐ 0.96 (m, 7H), 1.30 ‐ 1.59 (m, 7H), 2.03 ‐ 2.22 (m, 1H), 3.11  (dd, 1H), 4.00 ‐ 4.25 (m, 2H), 4.28 ‐ 4.61 (m, 3H), 6.94 (d, 1H), 7.56 ‐ 7.66 (m, 1H), 7.73 (t, 1H), 8.02 (dd,  2H), 8.69 (s, 1H), 9.37 (d, 1H).  Example 44    1‐{2‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ oxoethyl}pyrrolidin‐2‐one  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (see example 18) and 2‐(2‐oxopyrrolidin‐1‐yl)acetamide, CAS‐RN: [7491‐74‐ 9])   
1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.479 (15.76), 1.500 (16.00), 1.919 (1.10), 1.945 (3.51), 1.970  (5.51), 1.995 (4.38), 2.019 (1.67), 2.238 (4.89), 2.264 (7.62), 2.291 (3.60), 2.558 (2.87), 2.576 (1.86), 2.729  (0.48), 3.101 (1.48), 3.124 (1.95), 3.140 (2.22), 3.160 (1.77), 3.182 (1.44), 3.380 (4.97), 3.404 (8.16), 3.426  (4.54), 3.919 (9.60), 3.934 (9.51), 4.067 (1.63), 4.099 (2.77), 4.142 (1.64), 4.172 (4.88), 4.201 (1.89), 4.224  (3.07), 4.257 (1.63), 4.350 (1.72), 4.379 (2.87), 4.438 (3.32), 4.452 (3.30), 4.509 (4.22), 4.534 (4.31), 4.554  (3.37), 4.576  (1.72), 7.017  (13.27), 7.594  (2.02), 7.619  (4.62), 7.643  (3.51), 7.710  (2.84), 7.738  (4.62),  7.761 (2.62), 8.005 (5.94), 8.018 (5.75), 8.032 (5.67), 8.044 (5.25), 8.686 (7.54), 9.358 (8.02), 9.364 (7.95).  Example 45    [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐3‐ yl)methanone  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and pyridine‐3‐carboxylic acid, CAS‐RN: [59‐67‐6])  1H‐NMR (300 MHz, DMSO‐d6): δ [ppm]= 1.48 (br t, 3H), 2.59 (br d, 1H), 3.11 ‐ 3.23 (m, 1H), 4.23 ‐ 4.47  (m, 2H), 4.50 ‐ 4.74 (m, 3H), 7.04 (s, 1H), 7.48 ‐ 7.56 (m, 1H), 7.57 ‐ 7.65 (m, 1H), 7.73 (t, 1H), 8.02 (dd,  2H), 8.10 (br d, 1H), 8.64 ‐ 8.75 (m, 2H), 8.90 (br s, 1H), 9.35 (d, 1H).  Example 46    1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 1‐cyanocyclopropanecarboxylic acid, CAS‐RN: [6914‐79‐ 0])   
1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.487 (15.64), 1.509 (16.00), 1.584 (5.97), 1.619 (10.99), 2.075  (1.38), 2.272 (0.52), 2.730 (0.60), 3.182 (1.32), 4.151 (1.14), 4.245 (2.20), 4.276 (2.04), 4.558 (1.92), 4.693  (1.26), 4.824  (2.82), 7.064  (14.76), 7.598  (2.16), 7.621  (4.83), 7.648  (3.62), 7.711  (2.94), 7.715  (3.10),  7.738 (4.81), 7.761 (2.66), 7.766 (2.70), 8.008 (6.01), 8.021 (5.37), 8.036 (5.33), 8.045 (5.27), 8.690 (7.11),  8.697 (7.61), 9.366 (9.17), 9.373 (9.65).  Example 47    1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐ one  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and acetic acid, CAS‐RN: [64‐19‐7])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.478 (12.08), 1.499 (12.52), 1.828 (15.71), 1.842 (16.00), 2.077  (3.35), 2.557 (1.85), 3.077 (1.22), 3.100 (1.75), 3.119 (2.19), 3.139 (1.51), 3.144 (1.52), 3.162 (1.19), 4.010  (1.30), 4.042 (2.43), 4.076 (1.34), 4.106 (3.81), 4.135 (1.49), 4.164 (2.57), 4.196 (1.39), 4.299 (1.43), 4.327  (2.61), 4.367 (1.58), 4.382 (2.82), 4.395 (2.86), 4.410 (1.75), 4.453 (2.60), 4.481 (1.58), 4.509 (1.50), 4.530  (2.69), 4.553  (2.69), 4.574  (1.47), 6.990 (13.40), 7.595  (1.65), 7.618  (3.75), 7.645  (2.77), 7.708  (2.16),  7.713 (2.35), 7.736 (3.67), 7.741 (3.22), 7.759 (2.05), 7.764 (2.02), 8.006 (4.77), 8.018 (4.34), 8.033 (4.28),  8.042 (4.12), 8.678 (5.45), 8.684 (5.85), 9.357 (6.37), 9.365 (6.62).  Example 48    (1‐methyl‐1H‐imidazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone   
(prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (see  example  18)  and  1‐methyl‐1H‐imidazole‐5‐carboxylic  acid,  CAS‐RN:  [41806‐40‐0])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.494 (5.11), 1.516 (5.17), 2.561 (1.02), 2.585 (1.06), 2.606 (1.01),  3.142  (1.14), 3.167  (1.32), 3.187  (1.17), 3.211  (1.11), 3.884  (1.94), 3.911  (16.00), 4.376  (0.51), 4.555  (1.04), 4.578 (1.06), 6.636 (0.45), 6.643 (0.47), 7.027 (6.67), 7.145 (0.48), 7.309 (0.50), 7.602 (0.76), 7.625  (1.78), 7.651 (1.38), 7.682 (1.74), 7.716 (1.12), 7.720 (1.17), 7.744 (1.67), 7.749 (1.41), 7.767 (1.00), 7.771  (1.26), 8.009 (1.93), 8.025 (1.73), 8.036 (1.75), 8.048 (1.58), 8.261 (0.42), 8.270 (0.48), 8.305 (2.17), 8.389  (0.50), 8.398 (0.44), 8.690 (2.35), 8.697 (2.51), 9.361 (3.36), 9.368 (3.41).  Example 49    3‐methoxy‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐methoxypropanoic acid, CAS‐RN: [2544‐06‐1])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.475 (9.10), 1.496 (9.32), 2.326 (1.75), 2.347 (4.30), 2.364 (4.40),  2.384 (1.92), 3.084 (1.11), 3.101 (1.23), 3.107 (1.26), 3.121 (1.10), 3.127 (1.11), 3.145 (1.04), 3.151 (1.01),  3.248 (16.00), 3.255 (15.94), 3.541 (2.43), 3.546 (2.59), 3.562 (4.90), 3.568 (4.90), 3.583 (2.52), 3.589  (2.36), 4.020 (0.99), 4.052 (1.79), 4.090 (0.99), 4.118 (2.64), 4.148 (1.10), 4.174 (1.89), 4.207 (0.99), 4.315  (1.03), 4.344 (1.85), 4.379 (1.18), 4.395 (2.06), 4.408 (2.02), 4.423 (1.20), 4.469 (1.80), 4.498 (1.31), 4.505  (1.30), 4.528 (1.97), 4.549 (1.93), 4.570 (1.02), 6.971 (7.00), 7.591 (1.21), 7.614 (2.77), 7.641 (2.04), 7.704  (1.61), 7.708 (1.73), 7.732 (2.73), 7.736 (2.33), 7.755 (1.51), 7.759 (1.45), 8.001 (3.59), 8.010 (3.24), 8.029  (3.22), 8.037 (3.09), 8.677 (4.15), 8.683 (4.38), 9.355 (4.99), 9.362 (5.09).  Example 50   
  4‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐4‐ oxobutanenitrile  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐cyanopropanoic acid, CAS‐RN: [16051‐87‐9])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.148 (0.41), 1.481 (15.52), 1.503 (16.00), 2.076 (5.37), 2.272  (0.71), 2.561 (6.31), 2.637 (5.03), 2.659 (6.98), 2.680 (2.99), 2.728 (0.90), 3.099 (1.92), 3.117 (2.11), 3.123  (2.17), 3.137 (1.91), 3.144 (1.88), 3.161 (1.76), 3.167 (1.74), 4.061 (1.59), 4.093 (2.68), 4.135 (1.58), 4.165  (4.42), 4.193 (1.80), 4.218 (2.98), 4.250 (1.60), 4.329 (1.61), 4.358 (2.96), 4.391 (2.03), 4.404 (3.28), 4.419  (3.15), 4.432  (2.03), 4.483  (2.83), 4.514 (2.73), 4.538 (3.03), 4.560 (2.97), 4.581 (1.58), 6.979 (10.30),  6.982  (10.48), 7.592  (2.01), 7.596  (2.09), 7.618  (4.51), 7.642  (3.30), 7.645  (3.27), 7.708  (2.85), 7.713  (3.00), 7.732 (2.82), 7.737 (4.66), 7.741 (3.98), 7.759 (2.69), 7.764 (2.57), 8.003 (5.28), 8.022 (5.28), 8.030  (5.21), 8.044 (4.49), 8.674 (6.36), 8.680 (6.69), 9.351 (7.17), 9.357 (7.41).  Example 51  1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of  toluene  (2x) and dried  in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (1:1) was used  in  the  next  step  without  further  purification.  Step  2:  Into  a  40  mL  vial,  2‐methylpyrimidine‐5‐ carbaldehyde  (29.2  mg,  0.239  mmol,  1.00  equiv)  and  crude  product  2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (84 mg,  1.00  equiv,  0.217 mmol,   
1.00 equiv) were dissolved in MeOH (3 mL) followed by 2 drops of DIEA. The mixture was stirred for 1 h  at  room  temperature. NaBH3CN  (1.50 equiv) was added. The mixture was  stirred  for one h at  room  temperature. The residue was purified by HPLC to afford the title compound. 1H‐NMR (300 MHz, DMSO‐ d6)  δ  [ppm]: 2.611  (16.00), 2.827  (1.89), 2.850  (3.02), 2.874  (2.03), 3.342  (0.55), 3.441  (1.71), 3.464  (5.63), 3.475 (5.69), 3.498 (1.69), 4.165 (2.01), 4.189 (3.09), 4.211 (1.96), 6.951 (7.62), 7.593 (0.80), 7.619  (1.64), 7.643 (1.31), 7.646 (1.37), 7.706 (1.19), 7.711 (1.09), 7.734 (1.64), 7.739 (1.65), 7.757 (1.03), 7.762  (1.04), 7.998  (4.19), 8.029  (3.64), 8.140 (4.04), 8.665 (11.83), 8.689  (3.15), 8.697  (3.28), 9.366  (3.91),  9.374 (4.01).  The following compounds (example 52 to example 61) were synthesized in analogy to example 51:  Example 52    N,N‐dimethyl‐5‐{[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(dimethylamino)‐1,3‐thiazole‐5‐carbaldehyde (CAS‐RN: [1005‐28‐3])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 2.813  (0.99), 2.836  (1.73), 2.859  (1.13), 3.000  (16.00), 3.352  (1.59), 3.376 (2.54), 3.413 (2.49), 3.436 (1.32), 3.653 (3.34), 4.161 (1.09), 4.184 (1.72), 4.208 (1.01), 6.906  (2.87), 6.996 (2.36), 7.591 (0.46), 7.617 (0.94), 7.640 (0.79), 7.704 (0.60), 7.731 (0.96), 7.755 (0.55), 7.995  (2.19), 8.023 (1.98), 8.693 (1.58), 9.359 (1.66), 9.366 (1.79).  Example 53    1‐[(1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1H‐imidazole‐2‐carbaldehyde, CAS‐RN: [10111‐08‐7])   
1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 2.075 (1.90), 2.272 (1.84), 2.727 (1.73), 2.816 (4.32), 2.839 (6.93),  2.862 (4.69), 3.432 (4.49), 3.456 (12.06), 3.473 (11.80), 3.495 (4.36), 3.654 (16.00), 4.161 (4.71), 4.185  (7.19), 4.209  (4.45), 6.901  (14.58), 7.591  (2.15), 7.616  (3.83), 7.643  (3.19), 7.702  (2.59), 7.731  (3.72),  7.753 (2.17), 7.995 (9.12), 8.025 (7.97), 8.674 (6.77), 9.351 (7.66), 9.358 (7.77), 11.877 (1.97).  Example 54    1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and pyrazolo[1,5‐a]pyrimidine‐3‐carbaldehyde, CAS‐RN: [879072‐59‐0])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]:  2.274  (0.43),  2.796  (2.97),  2.818  (5.11),  2.842  (3.40),  3.449  (16.00), 3.840 (11.18), 4.148 (3.20), 4.171 (5.26), 4.194 (3.27), 6.898 (9.69), 7.015 (2.54), 7.028 (2.78),  7.038 (2.91), 7.052 (2.88), 7.590 (1.29), 7.614 (2.92), 7.640 (2.21), 7.705 (1.87), 7.728 (2.89), 7.751 (1.74),  7.990 (5.28), 8.018 (4.68), 8.232 (8.66), 8.550 (3.13), 8.556 (3.69), 8.564 (3.73), 8.569 (3.62), 8.691 (4.85),  9.078 (3.09), 9.083 (3.44), 9.101 (3.45), 9.107 (3.50), 9.359 (5.18), 9.366 (5.80).  Example 55    1‐[(1H‐indazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1H‐indazole‐3‐carbaldehyde, CAS‐RN: [5235‐10‐9])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.144 (0.79), 2.271 (1.18), 2.726 (0.96), 2.813 (3.00), 2.835 (5.16),  2.859 (3.15), 3.479 (16.00), 3.994 (10.64), 4.148 (3.17), 4.172 (5.31), 4.195 (3.09), 6.897 (8.03), 7.109  (1.72), 7.132 (3.16), 7.156 (2.27), 7.318 (1.72), 7.346 (3.11), 7.369 (2.15), 7.482 (4.04), 7.510 (3.15), 7.590   
(1.32), 7.612 (3.06), 7.638 (2.39), 7.702 (1.95), 7.729 (2.99), 7.755 (1.90), 7.901 (3.33), 7.928 (3.28), 7.992  (6.57), 8.021 (5.92), 8.679 (4.97), 9.356 (5.17), 12.839 (4.52).  Example 56    1‐(cyclohexylmethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and cyclohexanecarbaldehyde, CAS‐RN: [2043‐61‐0])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.868 (3.42), 0.907 (4.15), 0.945 (2.06), 1.110 (1.29), 1.183 (5.29),  1.227 (3.13), 1.270 (2.29), 1.649 (6.34), 1.682 (3.47), 1.731 (4.75), 1.775 (4.40), 2.284 (5.56), 2.305 (5.39),  2.806  (5.24),  2.829  (8.67),  2.853  (5.77),  3.380  (6.53),  4.155  (6.65),  4.179  (9.84),  4.202  (6.30),  6.894  (16.00), 7.586  (2.39), 7.613  (5.54), 7.639  (4.33), 7.699  (3.48), 7.704  (3.40), 7.726  (5.35), 7.732  (5.05),  7.750 (3.08), 7.755 (3.26), 7.994 (11.73), 8.022 (10.97), 8.687 (8.31), 8.694 (8.92), 9.363 (11.38), 9.371  (11.85).  Example 57    6'‐methyl‐1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 2‐methylpyrimidine‐5‐carbaldehyde, CAS‐RN: [90905‐ 33‐2])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.236 (0.47), 1.448 (7.45), 1.469 (7.62), 2.272 (0.49), 2.396 (1.37),  2.416  (1.37), 2.441  (1.58), 2.460  (1.77), 2.607  (16.00), 2.694  (0.43), 2.728  (0.41), 3.016  (1.21), 3.042  (1.39), 3.061 (1.25), 3.086 (1.08), 3.372 (1.47), 3.395 (2.30), 3.435 (1.29), 3.455 (3.82), 3.475 (1.39), 3.495  (2.41), 3.519 (1.24), 3.664 (6.26), 4.453 (0.72), 4.473 (1.26), 4.495 (1.20), 4.518 (0.75), 6.928 (7.69), 7.592   
(0.92), 7.615 (1.92), 7.642 (1.51), 7.707 (1.26), 7.730 (1.94), 7.735 (1.69), 7.758 (1.12), 8.000 (2.30), 8.015  (2.06), 8.028 (2.15), 8.039 (1.93), 8.656 (12.10), 8.689 (2.77), 8.696 (3.09), 9.364 (3.86), 9.371 (3.84).  Example 58    N,N‐dimethyl‐5‐{[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]methyl}‐1,3‐thiazol‐2‐amine  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (see example 18) and 2‐(dimethylamino)‐1,3‐thiazole‐5‐carbaldehyde, CAS‐ RN: [1005‐28‐3])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.448 (3.06), 1.470 (3.05), 2.386 (0.53), 2.405 (0.56), 2.430 (0.63),  2.449  (0.67), 2.999  (16.00), 3.027  (0.72), 3.047  (0.55), 3.072  (0.47), 3.302  (0.95), 3.387  (0.50), 3.410  (2.06), 3.431 (1.84), 3.454 (0.52), 3.652 (2.74), 4.473 (0.52), 4.495 (0.53), 6.888 (2.87), 6.995 (2.10), 7.613  (0.78), 7.640 (0.60), 7.705 (0.51), 7.729 (0.77), 7.752 (0.44), 7.757 (0.45), 8.000 (0.99), 8.013 (0.94), 8.027  (0.93), 8.037 (0.92), 8.690 (1.17), 8.696 (1.31), 9.360 (1.45), 9.367 (1.60).  Example 59    6'‐methyl‐1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (see  example 18)  and pyrazolo¬[1,5‐a]pyrimidine‐3‐carbaldehyde, CAS‐RN:  [879072‐59‐0])   
1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 0.931  (1.57), 0.952  (1.46), 1.231  (0.52), 1.436  (15.93), 1.457  (15.66), 2.273  (0.67), 2.368  (2.72), 2.388  (2.84), 2.412  (3.12), 2.432  (3.22), 2.729  (0.51), 2.987  (2.68),  3.012 (3.03), 3.031 (2.72), 3.056 (2.46), 3.375 (3.59), 3.398 (5.44), 3.427 (3.27), 3.446 (8.24), 3.465 (3.03),  3.502  (5.18), 3.525  (3.17), 3.594  (0.94), 3.837  (14.95), 4.436  (1.50), 4.457  (2.83), 4.481  (2.53), 4.501  (1.50), 6.880  (16.00), 7.014  (4.30), 7.028  (4.31), 7.038  (4.44), 7.051  (4.54), 7.588  (1.78), 7.611  (4.03),  7.638 (3.04), 7.699 (2.48), 7.703 (2.66), 7.727 (3.94), 7.731 (3.52), 7.749 (2.18), 7.754 (2.29), 7.999 (7.03),  8.027  (6.41), 8.138  (0.59), 8.231  (14.03), 8.550  (4.84), 8.555  (5.35), 8.563  (5.18), 8.569  (4.95), 8.688  (5.76), 8.695 (6.32), 9.077 (4.93), 9.083 (5.16), 9.101 (5.34), 9.107 (5.06), 9.359 (8.07), 9.366 (8.33).  Example 60    1‐[(1H‐indazol‐3‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and 1H‐indazole‐3‐carbaldehyde, CAS‐RN: [5235‐10‐9])  1H‐NMR  (300 MHz, DMSO‐d6) δ  [ppm]:  ‐0.007  (0.95), 0.946  (0.71), 1.230  (1.04), 1.429  (15.69), 1.451  (15.78), 2.270  (0.91), 2.377  (2.67), 2.397  (2.82), 2.421  (3.10), 2.441  (3.19), 2.720  (0.90), 3.001  (2.70),  3.025  (3.01), 3.044  (2.65), 3.069  (2.54), 3.397  (3.74), 3.419  (5.63), 3.450  (3.66), 3.471  (10.25), 3.492  (3.64), 3.526  (5.53), 3.549 (3.60), 3.985 (16.00), 4.430  (1.77), 4.451  (2.98), 4.475  (3.07), 4.496  (1.74),  6.871  (15.27), 7.101  (2.57), 7.124  (4.95), 7.150  (3.40), 7.313  (2.90), 7.337  (4.70), 7.364  (3.26), 7.475  (6.57), 7.503 (4.81), 7.581 (2.12), 7.604 (4.59), 7.627 (3.35), 7.696 (3.13), 7.720 (4.56), 7.724 (4.23), 7.748  (2.70), 7.895  (5.46), 7.921  (5.26), 7.991  (5.95), 8.019  (5.71), 8.677  (7.29), 9.348  (8.02), 9.355  (8.64),  12.833 (2.47).  Example 61     
1‐(cyclohexylmethyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and cyclohexanecarbaldehyde, CAS‐RN: [2043‐61‐0])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]:  ‐0.022  (0.70), 0.833  (1.32), 0.863  (2.97), 0.903  (3.66), 0.941  (1.73), 1.151 (4.29), 1.181 (4.60), 1.232 (5.96), 1.254 (2.74), 1.447 (15.70), 1.469 (16.00), 1.647 (5.27),  1.730 (3.89), 1.774 (3.51), 2.075 (4.63), 2.277 (8.94), 2.300 (8.32), 2.377 (2.72), 2.396 (2.92), 2.421 (3.15),  2.440 (3.32), 2.728 (0.60), 2.996 (2.72), 3.020 (3.07), 3.040 (2.71), 3.064 (2.59), 3.247 (4.10), 3.269 (5.39),  3.374 (14.84), 3.389 (5.46), 4.444 (1.48), 4.465 (2.61), 4.488 (2.66), 4.508 (1.59), 6.876 (14.45), 7.588  (1.78), 7.610 (4.07), 7.637 (3.12), 7.702 (2.62), 7.726 (3.98), 7.749 (2.29), 7.753 (2.30), 7.998 (5.31), 8.030  (5.15), 8.693 (5.95), 8.699 (6.45), 9.363 (7.38), 9.370 (7.83).  Example 62  1‐(cyclopropanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of  toluene  (2x) and dried  in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (1:1) was used  in  the next  step without  further purification.  Step 2:  Into  a 40 mL  via,  crude 2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (61 mg,  0.156 mmol,  1  eq.) was  dissolved in DMF (3 mL) and was cooled in an ice‐bath. DIPEA (201 mg, 1.56 mmol, 10 equiv) was added.  Then cyclopropanesulfonyl chloride, (33 mg, 1.50 eq., 0.234 mmol, CAS‐RN: [139631‐62‐2]) was added  slowly to the above solution. The reaction mixture was allowed to ambient temperature and stirred for  3 h. The mixture was diluted with 1 mL of water. The mixture was purified by HPLC to afford the title  compound. 1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.982 (1.30), 0.998 (4.59), 1.006 (4.87), 1.014 (4.58),  1.021 (5.40), 1.034 (1.96), 1.072 (0.69), 1.086 (0.54), 1.098 (0.54), 1.122 (2.51), 1.135 (4.43), 1.144 (4.90),  1.162 (5.15), 1.169 (3.60), 1.185 (1.10), 2.073 (0.54), 2.866 (0.89), 2.883 (1.75), 2.893 (1.96), 2.909 (3.36),  2.925  (1.98), 2.935  (2.37), 2.945  (4.41), 2.968  (6.68), 2.991  (4.48), 4.155  (5.36), 4.182  (13.18), 4.212  (16.00), 4.239 (12.41), 4.263 (4.52), 7.024 (15.56), 7.595 (1.63), 7.622 (3.54), 7.645 (2.65), 7.649 (2.80),  7.710 (2.35), 7.715 (2.18), 7.737 (3.48), 7.742 (3.29), 7.761 (1.99), 7.765 (2.07), 8.004 (7.77), 8.032 (7.46),  8.702 (5.75), 8.709 (5.88), 9.381 (7.64), 9.388 (7.72).   
The following compound (example 63) was synthesized in analogy to example 62:  Example 63    1‐(cyclopropanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and cyclopropanesulfonyl chloride, CAS‐RN: [139631‐ 62‐2])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 0.980 (1.49), 0.996 (5.08), 1.003 (5.65), 1.018 (5.85), 1.032 (2.34),  1.070 (0.70), 1.137 (4.82), 1.147 (4.37), 1.163 (5.24), 1.483 (15.76), 1.504 (16.00), 2.272 (0.55), 2.573  (3.08), 2.594 (3.06), 2.728 (0.60), 2.872 (0.84), 2.889 (1.72), 2.899 (2.00), 2.915 (3.32), 2.931 (1.94), 2.941  (1.77), 2.957 (0.88), 3.137  (2.69), 3.161 (3.04), 3.181 (2.62), 3.205 (2.48), 4.148 (4.70), 4.170 (13.04),  4.198  (1.70),  4.295  (6.14),  4.322  (4.57),  4.512  (1.55),  4.535  (2.90),  4.557  (2.94),  4.579  (1.57),  7.016  (14.69), 7.598  (1.77), 7.621  (4.08), 7.648  (3.13), 7.714  (2.63), 7.738  (3.91), 7.742  (3.63), 7.761  (2.27),  7.765 (2.32), 8.008 (5.04), 8.023 (4.71), 8.036 (4.72), 8.047 (4.50), 8.709 (5.99), 8.715 (6.68), 9.383 (7.38),  9.390 (8.11).  Example 64  N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next   
step without further purification. Step 2: Into a 40 mL via, 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate ((61 mg, 0.156 mmol, 1 eq., 1.00 eq) was dissolved in 3 mL  DMF and was cooled in an ice‐bath. DIPEA (201 mg, 1.56 mmol, 10 eq, 1.56 mmol) was added. Then 3‐ isocyanatopyridine, (28 mg, 0.234 mmol, 1.5 eq., CAS‐RN: [15268‐31‐2]) was added slowly to the above  solution. The reaction mixture was stirred at ambient temperature for 3 h. The mixture was diluted with  1 mL of water. The mixture was purified by HPLC to afford the title compound.1H‐NMR (300 MHz, DMSO‐ d6)  δ  [ppm]: 2.940  (1.78), 2.963  (3.11), 2.986  (2.06), 4.234  (2.41), 4.259  (16.00), 7.047  (6.32), 7.276  (1.20), 7.292 (1.38), 7.304 (1.50), 7.320 (1.56), 7.594 (0.73), 7.619 (1.78), 7.646 (1.45), 7.712 (1.12), 7.735  (1.76), 7.763 (0.99), 7.955 (1.34), 7.999 (3.79), 8.027 (3.27), 8.169 (2.11), 8.181 (2.13), 8.691 (3.01), 8.704  (2.98), 8.712 (3.07), 8.846 (3.60), 9.370 (3.25), 9.377 (3.66).  The following compounds (example 65 to example 67) were synthesized in analogy to example 64:  Example 65    N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and isocyanatoethane, CAS‐RN: [109‐90‐0])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 1.009  (5.01), 1.025  (3.86), 1.033  (11.37), 1.047  (5.48), 1.056  (5.25), 1.071 (2.15), 2.870 (1.90), 2.894 (3.14), 2.917 (2.10), 3.011 (0.71), 3.035 (2.19), 3.054 (2.49), 3.059  (2.46), 3.078 (2.18), 3.103 (0.93), 3.109 (1.07), 3.127 (1.06), 3.133 (1.03), 3.151 (0.94), 3.649 (0.71), 3.672  (0.70), 4.030  (16.00), 4.200  (2.05), 4.224  (3.16), 4.246  (1.96), 6.462  (0.92), 6.481  (1.85), 6.499  (0.94),  6.984 (7.93), 7.590 (0.82), 7.594 (0.86), 7.617 (1.92), 7.640 (1.35), 7.644 (1.40), 7.705 (1.13), 7.710 (1.26),  7.733 (1.91), 7.738 (1.59), 7.756 (1.04), 7.761 (1.04), 7.991 (2.17), 7.998 (2.42), 8.018 (1.81), 8.026 (2.10),  8.680 (2.78), 8.686 (2.87), 9.364 (3.88), 9.372 (3.86).  Example 66   
  6'‐methyl‐N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and 3‐isocyanatopyridine, CAS‐RN: [15268‐31‐2])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]:  1.166  (5.94),  1.188  (5.94),  1.242  (1.69),  1.264  (1.74),  1.496  (15.02), 1.517 (15.19), 2.272 (0.51), 2.569 (2.70), 2.589 (2.56), 2.729 (0.51), 3.123 (2.35), 3.146 (2.81),  3.167 (2.40), 3.191 (2.20), 3.681 (0.40), 4.171 (3.24), 4.199 (5.41), 4.236 (3.13), 4.256 (6.01), 4.264 (6.16),  4.284 (3.33), 4.318 (5.44), 4.346 (3.21), 4.533 (1.47), 4.555 (2.61), 4.578 (2.80), 4.599 (1.42), 4.898 (0.65),  4.941  (0.66), 7.035  (16.00), 7.275  (2.85), 7.291  (2.99), 7.303  (3.11), 7.318  (3.23), 7.404  (0.73), 7.447  (0.66), 7.594 (1.72), 7.617 (3.87), 7.644 (2.93), 7.707 (2.32), 7.711 (2.51), 7.735 (3.77), 7.739 (3.26), 7.758  (2.18), 7.762 (2.15), 7.947 (2.12), 7.952 (2.76), 7.960 (2.60), 7.974 (2.15), 7.983 (2.71), 7.988 (2.37), 8.005  (5.10), 8.037 (4.80), 8.098 (0.65), 8.164 (4.15), 8.169 (4.35), 8.180 (4.32), 8.184 (4.22), 8.689 (5.54), 8.696  (6.40), 8.702 (7.08), 8.711 (6.63), 8.842 (7.81), 9.369 (7.86), 9.377 (8.11).  Example 67    N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and isocyanatoethane, CAS‐RN: [109‐90‐0])  1H‐NMR  (300 MHz, DMSO‐d6)  δ  [ppm]: 0.922  (0.48), 0.943  (0.55), 1.006  (7.54), 1.030  (16.00), 1.054  (7.68), 1.471 (12.15), 1.492 (12.33), 2.455 (2.84), 2.475 (4.20), 2.728 (0.46), 3.008 (1.33), 3.032 (3.85),  3.055 (6.48), 3.075 (5.11), 3.098 (3.18), 3.122 (2.01), 3.947 (2.82), 3.974 (5.23), 3.997 (3.40), 4.022 (7.28),   
4.046 (3.04), 4.097 (4.88), 4.123 (3.19), 4.496 (1.32), 4.517 (2.34), 4.539 (2.36), 4.560 (1.33), 6.455 (1.68),  6.473  (3.36), 6.492  (1.83), 6.970  (11.03), 7.591  (1.39), 7.614  (3.14), 7.641  (2.46), 7.708  (2.01), 7.732  (3.05), 7.759 (1.84), 8.002 (6.55), 8.031 (5.93), 8.684 (4.78), 8.690 (5.35), 9.363 (5.66), 9.370 (6.18).  Example 68  1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next  step without further purification. Step 2: Into a 40 mL vial, was placed a solution of crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (61 mg, 0.156 mmol, 1 eq.)  in dioxane (3 mL). Then 3‐bromopyridine, (37 mg, 0.234 mmol, 1.5 eq., CAS‐RN: [626‐55‐1]) and Cs2CO3  (153 mg, 0.468 mmol, 3 equiv) were added, Xantphos (18.1 mg, 0.0312 mmol, 0.20 equiv), Pd2(dba)3  (14.3 mg, 0.0156 mmol, 0.10 equiv) was added, protected by nitrogen. The mixture was stirred overnight  at 100 °C. The residue was purified by HPLC to afford the title compound. 1H‐NMR (300 MHz, DMSO‐d6)  δ [ppm]: 2.266 (0.99), 2.734 (1.48), 2.984 (5.25), 3.007 (8.80), 3.030 (5.71), 4.120 (6.11), 4.145 (16.00),  4.170  (15.81), 4.195  (7.09), 4.252  (5.72), 4.275  (9.11), 4.298  (6.01), 6.940  (2.85), 6.966  (3.76), 6.998  (15.36), 7.208  (3.71), 7.224  (4.23), 7.235  (3.72), 7.251  (3.71), 7.585  (2.04), 7.610  (4.60), 7.636  (3.80),  7.705  (3.03), 7.729  (4.47), 7.756  (3.04), 7.936  (5.77), 7.944  (6.56), 7.979  (5.12), 7.994  (11.27), 8.006  (10.68), 8.021 (7.27), 8.678 (8.07), 9.357 (7.71), 9.364 (9.11).  The following compound (example 69) was synthesized in analogy to example 68:  Example 69     
6'‐methyl‐1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared from tert‐butyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and and 3‐bromopyridine, CAS‐RN: [626‐55‐1])  1H‐NMR (300 MHz, DMSO‐d6) δ [ppm]: 1.234 (0.61), 1.509 (15.79), 1.530 (16.00), 2.075 (2.53), 2.561  (2.72), 2.581 (2.69), 2.605 (2.83), 2.625 (2.85), 3.169 (2.62), 3.194 (2.99), 3.214 (2.60), 3.238 (2.46), 4.064  (3.91), 4.088 (5.89), 4.151 (3.00), 4.165 (6.39), 4.175 (7.32), 4.190 (4.66), 4.203 (7.23), 4.228 (3.15), 4.547  (1.51), 4.568 (2.67), 4.591 (2.70), 4.612 (1.52), 6.927 (2.28), 6.932 (2.29), 6.954 (2.78), 6.959 (3.03), 6.981  (15.22), 7.206  (3.17), 7.221  (3.47), 7.233  (2.87), 7.249  (2.94), 7.581  (1.65), 7.608  (3.61), 7.635  (2.91),  7.699  (2.36),  7.704  (2.25),  7.727  (3.53),  7.732  (3.44),  7.754  (2.20),  7.930  (5.38),  7.939  (5.64),  7.994  (12.83), 8.006 (5.83), 8.024 (8.47), 8.677 (5.99), 8.684 (6.49), 9.357 (7.47), 9.364 (7.89).  Example 70  N‐(2‐chloroethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of  toluene  (2x) and dried  in vacuum. The crude product 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (1:1) was used  in the next step without further purification. Step 2: 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (50.0 mg, 181 µmol) was dissolved in DCM (2.1 ml), DIPEA (95  µl, 540 µmol; CAS‐RN:[7087‐68‐5]) was added, cooled to 0°C and 1‐chloro‐2‐isocyanatoethane (19.1 mg,  181 µmol) was added and the mixture was stirred overnight at ambient temperature. The mixture was  evaporated and purified by preparative HPLC to yield the title compound (4.80 mg, 7 % yield). LC‐MS  (Method 1): Rt = 0.93 min; MS (ESIpos): m/z = 382 [M+H]+ 1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.073  (1.94), 2.517 (3.68), 2.522 (2.31), 2.884 (1.84), 2.901 (2.95), 2.919 (2.01), 3.299 (0.47), 3.310 (1.37), 3.585  (2.78), 3.601  (5.42), 3.618  (2.14), 4.061 (16.00), 4.103  (0.40), 4.206  (2.04), 4.223  (3.15), 4.240  (1.94),  6.834 (0.94), 6.848 (1.91), 6.862 (0.87), 6.992 (8.10), 7.596 (0.87), 7.599 (0.87), 7.617 (1.91), 7.634 (1.27),  7.636 (1.27), 7.710 (1.14), 7.714 (1.21), 7.727 (1.00), 7.731 (1.94), 7.735 (1.41), 7.749 (1.00), 7.752 (1.00),  7.991 (2.01), 7.998 (2.31), 8.009 (1.71), 8.019 (2.01), 8.682 (2.74), 8.687 (2.74), 9.362 (3.88), 9.367 (3.85).   
The following compounds (example 71 to example 79) were synthesized in analogy to example 70:  Example 71    N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐isocyanatopropane, CAS‐RN: [1795‐48‐8])  LC‐MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 362 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.995 (1.07), 1.012 (1.08), 1.064 (15.84), 1.081 (16.00), 1.243  (0.45), 1.260 (0.47), 2.518 (2.04), 2.523 (1.29), 2.540 (0.54), 2.869 (1.56), 2.886 (2.36), 2.904 (1.68), 3.715  (0.54), 3.731  (0.79), 3.751  (0.80), 3.767 (0.55), 4.017 (13.64), 4.202  (1.73), 4.221  (2.54), 4.237  (1.60),  5.759 (0.63), 6.254 (1.53), 6.273 (1.49), 6.990 (7.79), 7.596 (0.72), 7.599 (0.76), 7.613 (1.09), 7.617 (1.57),  7.634 (1.06), 7.636 (1.07), 7.710 (1.00), 7.713 (1.05), 7.727 (0.85), 7.731 (1.62), 7.734 (1.20), 7.748 (0.91),  7.752 (0.87), 7.991 (1.54), 8.000 (1.75), 8.007 (1.40), 8.011 (1.31), 8.019 (1.54), 8.683 (2.15), 8.688 (2.24),  9.364 (3.41), 9.370 (3.45).  Example 72    2'‐(quinolin‐3‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1,1,1‐trifluoro‐2‐isocyanatoethane, CAS‐RN: [371‐92‐6])  LC‐MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 402 [M+H]+   1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 2.518  (0.82), 2.522  (0.56), 2.539  (16.00), 2.897  (0.54), 2.914  (0.83), 2.932 (0.57), 3.821 (0.43), 3.829 (0.40), 3.845 (0.40), 4.111 (3.46), 4.209 (0.58), 4.227 (0.89), 4.244   
(0.57), 5.758 (0.57), 7.006 (2.78), 7.233 (0.56), 7.617 (0.56), 7.732 (0.61), 7.736 (0.45), 7.992 (0.54), 7.998  (0.61), 8.008 (0.49), 8.012 (0.46), 8.020 (0.55), 8.683 (0.77), 8.689 (0.80), 9.363 (1.22), 9.368 (1.21).  Example 73    N‐cyclopentyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and isocyanatocyclopentane, CAS‐RN: [4747‐71‐1])  LC‐MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 388 [M+H]+   1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 1.34 ‐ 1.43 (m, 2H), 1.44 ‐ 1.52 (m, 2H), 1.59 ‐ 1.67 (m, 2H), 1.74  ‐ 1.85 (m, 2H), 2.89 (t, 2H), 3.84 ‐ 3.96 (m, 1H), 4.02 (s, 4H), 4.22 (t, 2H), 6.34 (d, 1H), 6.99 (s, 1H), 7.62  (ddd, 1H), 7.73 (ddd, 1H), 8.00 (td, 2H), 8.68 (d, 1H), 9.36 (d, 1H).  Example 74    N‐tert‐butyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐isocyanato‐2‐methylpropane, CAS‐RN: [1609‐86‐5])  LC‐MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 376 [M+H]+   1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.200  (1.06), 1.272  (16.00), 2.518  (1.48), 2.522  (0.98), 2.857  (0.58), 2.874 (0.86), 2.892 (0.61), 4.010 (5.01), 4.200 (0.62), 4.218 (0.92), 4.235 (0.59), 5.853 (1.17), 6.977  (2.94), 7.617 (0.60), 7.637 (0.40), 7.731 (0.62), 7.735 (0.45), 7.991 (0.56), 7.997 (0.63), 8.008 (0.50), 8.012  (0.48), 8.019 (0.56), 8.685 (0.79), 8.690 (0.82), 9.364 (1.29), 9.370 (1.22).  Example 75   
  methyl [2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]carbamate  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and methyl carbonisocyanatidoate, CAS‐RN: [5843‐42‐5])  LC‐MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 378 [M+H]+   1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  2.518  (0.60),  2.886  (1.41),  2.904  (2.22),  2.921  (1.54),  3.636  (16.00), 3.688  (0.80), 4.038  (0.62), 4.201  (2.31), 4.219  (4.30), 4.236  (2.64), 6.984  (0.48), 6.997  (6.53),  7.595 (0.74), 7.598 (0.71), 7.612 (1.09), 7.615 (1.56), 7.633 (1.02), 7.636 (1.02), 7.710 (0.93), 7.714 (0.92),  7.728 (0.86), 7.731 (1.53), 7.735 (1.13), 7.749 (0.84), 7.752 (0.80), 7.997 (2.33), 8.014 (1.39), 8.018 (1.89),  8.678 (2.05), 8.682 (2.16), 9.358 (3.16), 9.364 (3.07), 9.772 (0.95).  Example 76    N‐[(furan‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(isocyanatomethyl)furan, CAS‐RN: [71189‐15‐6])  LC‐MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 400 [M+H]+   1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 2.89 (t, 2H), 4.07 (s, 4H), 4.18 ‐ 4.25 (m, 4H), 6.22 ‐ 6.24 (m, 1H),  6.40 (dd, 1H), 6.99 (s, 1H), 7.05 (t, 1H), 7.58 (dd, 1H), 7.61 (td, 1H), 7.73 (ddd, 1H), 8.00 (dd, 2H), 8.68 (d,  1H), 9.36 (d, 1H).  Example 77   
  N‐(2‐methoxyethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐isocyanato‐2‐methoxyethane, CAS‐RN: [42170‐95‐6])  LC‐MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 378 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.133 (0.64), 1.150 (0.67), 2.872 (1.43), 2.889 (2.25), 2.907 (1.53),  3.159 (0.67), 3.174 (2.23), 3.189 (2.55), 3.204 (1.01), 3.231 (0.58), 3.237 (0.49), 3.327 (2.63), 3.340 (4.91),  3.358 (16.00), 4.040 (12.29), 4.200 (1.54), 4.218 (2.41), 4.235 (1.50), 5.758 (0.42), 6.565 (0.70), 6.579  (1.47), 6.593 (0.69), 6.984 (6.42), 7.594 (0.68), 7.597 (0.68), 7.612 (1.03), 7.615 (1.47), 7.632 (0.97), 7.635  (0.99), 7.709 (0.89), 7.713 (0.95), 7.727 (0.79), 7.730 (1.48), 7.734 (1.11), 7.747 (0.80), 7.751 (0.79), 7.990  (1.46), 8.000 (1.70), 8.007 (1.35), 8.011 (1.27), 8.020 (1.49), 8.680 (2.08), 8.685 (2.16), 9.363 (2.93), 9.368  (3.00).  Example 78    N‐phenyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and isocyanatobenzene, CAS‐RN: [103‐71‐9])  LC‐MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 396 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.326 (0.54), 2.522 (1.53), 2.539 (0.40), 2.668 (0.53), 2.933 (2.07),  2.950  (3.33), 2.967  (2.20), 4.207  (0.55), 4.226  (16.00), 4.251  (3.77), 4.269  (2.18), 6.933  (1.21), 6.951  (2.63), 6.970 (1.51), 7.039 (8.81), 7.236 (2.75), 7.257 (4.14), 7.275 (2.87), 7.524 (3.86), 7.526 (4.32), 7.545  (3.83), 7.548 (3.11), 7.596 (1.03), 7.599 (0.99), 7.616 (2.12), 7.634 (1.37), 7.636 (1.41), 7.711 (1.30), 7.715  (1.32), 7.728 (1.15), 7.732 (2.12), 7.736 (1.57), 7.750 (1.13), 7.753 (1.13), 7.997 (2.99), 8.018 (2.37), 8.021  (2.36), 8.629 (4.18), 8.685 (3.08), 8.690 (3.13), 9.369 (4.29), 9.375 (4.11).   
Example 79  H3 C N N N N HN S H3 C   N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbothioamide  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and isothiocyanatoethane, CAR‐RN: [542‐85‐8])  LC‐MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 378 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.085 (6.97), 1.103 (16.00), 1.121 (7.14), 1.481 (10.98), 1.498  (11.08), 2.074  (1.50), 2.518  (1.76), 2.523  (2.46), 2.539  (2.90), 2.556  (1.86), 3.090  (1.68), 3.108  (1.93),  3.124 (1.71), 3.141 (1.58), 3.427 (0.94), 3.445 (2.93), 3.459 (3.23), 3.462 (3.22), 3.476 (2.83), 3.494 (0.84),  4.123 (2.32), 4.146 (3.29), 4.210 (2.00), 4.231 (5.24), 4.253 (2.30), 4.277 (3.59), 4.301 (2.03), 4.528 (1.00),  4.544  (1.87), 4.561  (1.87), 4.577  (0.96), 6.993  (12.65), 7.593  (1.33), 7.595  (1.26), 7.610  (2.12), 7.612  (2.72), 7.630 (1.81), 7.633 (1.95), 7.696 (1.38), 7.709 (4.24), 7.726 (2.53), 7.730 (2.90), 7.733 (2.30), 7.747  (1.50), 7.750 (1.58), 8.001 (6.28), 8.023 (4.89), 8.683 (4.11), 8.688 (4.29), 9.361 (5.80), 9.366 (5.70).  The following compounds (example 80 and example 81) were synthesized in analogy to example 62:  Example 80    1‐(methanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and methanesulfonyl chloride, CAS‐RN: [124‐63‐0])  1H‐NMR (400 MHz, DMSO‐d6) delta [ppm]: 1.239 (0.43), 1.907 (0.68), 2.518 (4.42), 2.522 (2.82), 2.937  (1.55), 2.954 (2.16), 2.972 (1.67), 3.145 (16.00), 4.149 (12.94), 4.218 (1.62), 4.236 (2.32), 4.253 (1.53),  7.043 (6.87), 7.606 (0.67), 7.609 (0.67), 7.626 (1.46), 7.644 (0.93), 7.646 (0.95), 7.720 (0.92), 7.724 (0.93),  7.738 (0.76), 7.742 (1.51), 7.745 (1.04), 7.759 (0.84), 7.763 (0.77), 8.011 (1.80), 8.032 (1.74), 8.705 (1.83),  8.710 (1.85), 9.374 (3.06), 9.379 (2.91).  Example 81   
  1‐(methanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and methanesulfonyl chloride, CAS‐RN: [124‐63‐0])  LC‐MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 369 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.479 (6.19), 1.496 (6.19), 2.518 (4.00), 2.523 (2.81), 2.540 (1.08),  2.558  (1.09), 2.574  (1.03), 3.129  (1.12), 3.145  (16.00), 3.162  (1.06), 3.181  (0.97), 4.074  (1.45), 4.095  (2.36), 4.127 (1.42), 4.142 (2.33), 4.148 (2.20), 4.162 (1.28), 4.224 (2.23), 4.245 (1.58), 4.517 (0.55), 4.533  (0.97), 4.550 (0.95), 4.566 (0.50), 7.029 (7.52), 7.601 (0.72), 7.604 (0.72), 7.618 (1.08), 7.621 (1.48), 7.641  (1.02), 7.716 (1.03), 7.720 (0.84), 7.733 (0.86), 7.737 (1.50), 7.741 (1.22), 7.754 (0.86), 7.758 (0.88), 8.009  (1.56), 8.029 (3.33), 8.046 (1.25), 8.700 (2.08), 8.705 (2.19), 9.370 (3.31), 9.376 (3.19).  Example 82  ethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next  step  without  further  purification.  Step  2:  Crude  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (50.0 mg, 181 µmol) was dissolved in DCM (930 µl), DIPEA (95  µl, 540 µmol; CAS‐RN:[7087‐68‐5]) was added, cooled to 0°C and ethyl carbonochloridate (19.6 mg, 181  µmol) was added and the mixture was stirred overnight at rt. The mixture was evaporated and purified  by preparative HPLC to yield the title compound (1.70 mg, 95 % purity, 3 % yield). LC‐MS (Method 3): Rt   
= 1.01 min; MS (ESIpos): m/z = 349 [M+H]+ 1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.183 (7.43), 1.201  (16.00), 1.218  (7.57), 2.326  (0.58), 2.522  (1.74), 2.664  (0.42), 2.668  (0.58), 2.902  (2.69), 2.919  (4.31),  2.936 (2.84), 4.037 (2.28), 4.055 (7.00), 4.073 (6.89), 4.091 (2.21), 4.166 (4.21), 4.198 (3.99), 4.216 (4.81),  4.233  (2.84), 7.025  (10.46), 7.598  (1.19), 7.618  (2.47), 7.635  (1.63), 7.638  (1.68), 7.712  (1.56), 7.716  (1.44), 7.733 (2.44), 7.736 (1.93), 7.750 (1.30), 7.754 (1.30), 7.999 (5.00), 8.020 (4.52), 8.670 (3.77), 8.675  (3.77), 9.354 (4.97), 9.359 (4.92).  The following compound (example 83) was synthesized in analogy to example 82:  Example 83    Ethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (prepared  from  tert‐butyl  6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 18) and ethyl carbonochloridoate, CAS‐RN: [79‐22‐1])  LC‐MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 363 [M+H]+   1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 1.20 (t, 3H), 1.28 (s, 2H), 1.48 (d, 3H), 4.06 (q, 2H), 4.14 ‐ 4.31  (m, 4H), 4.52 (sxt, 1H), 7.01 (s, 1H), 7.62 (ddd, 1H), 7.73 (ddd, 1H), 7.98 ‐ 8.05 (m, 2H), 8.68 (d, 1H), 9.36  (d, 1H).   Example 84  1‐[(4‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]      Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐  
yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next  step  without  further  purification.  Step  2:  Crude  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (60.0  mg,  217  µmol)  and  5‐methyl‐1H‐imidazole‐2‐ carbaldehyde  (26.3 mg, 239 µmol) were dissolved  in THF (2.9 ml). Acetic acid (12 µl, 220 µmol; CAS‐ RN:[64‐19‐7]) and sodium triacetoxyborohydride (63.3 mg, 299 µmol; CAS‐RN:[56553‐60‐7]) were added  and the mixture was stirred overnight at room temperature under argon. The mixture was evaporated  and purified by preparative HPLC to yield the title compound (1.10 mg, 95 % purity, 1 % yield). LC‐MS  (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 371 [M+H]+ 1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.905  (1.33), 2.099  (4.22), 2.135  (1.22), 2.197 (1.07), 2.518 (10.00), 2.522  (6.67), 2.819  (3.37), 2.836  (5.11),  2.853  (3.56), 3.414  (4.44), 3.432  (8.33), 3.460  (8.63), 3.478  (4.33), 3.575  (13.96), 4.164  (3.93), 4.182  (5.85), 4.199  (3.74), 4.251  (0.48), 6.900 (16.00), 6.951  (0.52), 7.037  (1.15), 7.596  (1.89), 7.615  (3.41),  7.633 (2.52), 7.636 (2.52), 7.708 (2.56), 7.712 (2.19), 7.725 (2.30), 7.729 (3.41), 7.733 (3.07), 7.746 (2.00),  7.750 (2.19), 7.996 (8.59), 8.020 (7.11), 8.668 (5.52), 8.673 (5.85), 9.350 (7.70), 9.356 (7.81).  The following compounds (example 85 to example 98) were synthesized in analogy to example 84:  Example 85      1‐[(imidazo[1,5‐a]pyridin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and imidazo[1,5‐a]pyridine‐3‐carbaldehyde, CAS‐RN: [56671‐66‐0])  LC‐MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 407 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.907 (1.28), 2.518 (8.29), 2.522 (5.53), 2.810 (3.39), 2.827 (5.25),  2.845 (3.73), 3.469 (7.60), 4.100 (5.11), 4.149 (4.08), 4.166 (5.91), 4.183 (3.90), 6.711 (1.66), 6.713 (1.76),  6.729 (3.42), 6.744 (2.63), 6.748 (2.45), 6.780 (2.66), 6.782 (2.73), 6.796 (1.83), 6.798 (1.73), 6.803 (2.73),  6.805  (2.90), 6.819  (1.94), 6.917  (16.00), 7.304  (8.09), 7.540  (4.39), 7.563  (3.97), 7.594  (1.94), 7.597  (1.66), 7.611 (2.83), 7.614 (3.63), 7.632 (2.38), 7.635 (2.70), 7.707 (2.66), 7.711 (2.07), 7.724 (2.21), 7.729  (3.42), 7.732 (3.08), 7.746 (2.00), 7.749 (2.21), 7.996 (8.74), 8.016 (6.19), 8.019 (6.36), 8.356 (3.46), 8.359  (3.49), 8.374 (3.32), 8.376 (3.25), 8.676 (5.29), 8.682 (5.56), 9.353 (8.33), 9.358 (8.02).  Example 86   
  1‐{[1‐(propan‐2‐yl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1‐(propan‐2‐yl)‐1H‐imidazole‐2‐carbaldehyde, CAS‐RN: [53332‐64‐2])  LC‐MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 399 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.404 (16.00), 1.421 (15.86), 2.518 (3.21), 2.522 (2.13), 2.804  (1.91), 2.822 (2.81), 2.839 (2.04), 3.378 (1.78), 3.395 (6.31), 3.406 (5.95), 3.423 (1.68), 3.725 (7.91), 4.155  (2.07), 4.173 (3.01), 4.190 (1.98), 4.659 (0.94), 4.675 (1.26), 4.692 (0.90), 6.791 (4.23), 6.793 (4.22), 6.874  (9.37), 7.254 (4.77), 7.257 (4.76), 7.595 (0.95), 7.598 (0.95), 7.613 (1.41), 7.615 (2.05), 7.618 (1.14), 7.633  (1.33), 7.636 (1.33), 7.708 (1.35), 7.712 (1.32), 7.725 (1.12), 7.729 (2.14), 7.733 (1.55), 7.746 (1.21), 7.750  (1.15), 7.997 (2.14), 8.005 (1.77), 8.008 (1.80), 8.017 (1.82), 8.025 (1.66), 8.663 (2.61), 8.668 (2.70), 9.347  (4.40), 9.352 (4.13).  Example 87    2'‐(quinolin‐3‐yl)‐1‐{[4‐(trifluoromethyl)‐1H‐imidazol‐2‐yl]methyl}‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 4‐(trifluoromethyl)‐1H‐imidazole‐2‐carbaldehyde, CAS‐RN: [102808‐02‐6])  LC‐MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 425 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (3.97), 2.522 (2.75), 2.834 (3.29), 2.852 (4.90), 2.869 (3.55),  3.469  (4.07), 3.487  (9.43), 3.508  (8.87), 3.527  (3.81), 3.706  (14.92), 4.169  (3.62), 4.187  (5.27), 4.204  (3.43), 6.913  (16.00), 7.597  (1.65), 7.599  (1.46), 7.614  (2.57), 7.617  (3.23), 7.620  (2.09), 7.634  (2.19),  7.637 (2.31), 7.710 (6.50), 7.727 (2.07), 7.730 (3.20), 7.734 (2.90), 7.748 (1.74), 7.751 (2.05), 7.996 (6.59),  7.998 (6.37), 8.020 (6.89), 8.660 (4.90), 8.665 (4.90), 9.345 (7.79), 9.351 (7.69), 12.621 (0.90).   
Example 88    1‐(2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 2‐methylpropanal, CAS‐RN: [78‐84‐2])  LC‐MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 333 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.882 (15.27), 0.899 (16.00), 1.534 (0.64), 1.550 (1.15), 1.567  (1.39), 1.584 (1.13), 1.600 (0.60), 2.256 (4.30), 2.273 (4.20), 2.326 (0.76), 2.668 (0.73), 2.819 (2.56), 2.835  (4.31), 2.853 (2.70), 3.399 (5.30), 3.415 (4.02), 4.163 (2.66), 4.181 (4.36), 4.198 (2.64), 6.901 (5.20), 7.552  (0.44), 7.594 (1.28), 7.612 (2.39), 7.631 (1.72), 7.707 (1.40), 7.726 (2.20), 7.743 (1.29), 7.994 (4.98), 8.015  (4.47), 8.693 (3.83), 9.365 (3.74).  Example 89    1‐{[1‐(2‐methoxyethyl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1‐(2‐methoxyethyl)‐1H‐imidazole‐2‐carbaldehyde, CAS‐RN: [558446‐64‐3])  LC‐MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 415 [M+H]+   1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 2.803  (1.03), 2.820  (1.56), 2.838  (1.10), 3.271  (16.00), 3.392  (1.19), 3.410 (3.40), 3.419 (3.26), 3.437 (0.92), 3.649 (1.31), 3.663 (2.76), 3.677 (1.46), 3.725 (3.96), 4.154  (1.12), 4.164 (0.44), 4.172 (1.68), 4.189 (1.09), 4.210 (1.24), 4.223 (2.26), 4.237 (1.12), 6.765 (2.61), 6.769  (2.69), 6.901 (4.82), 7.119 (2.60), 7.122 (2.53), 7.594 (0.53), 7.596 (0.45), 7.611 (0.81), 7.613 (0.92), 7.631  (0.69), 7.634 (0.73), 7.706 (0.72), 7.710 (0.62), 7.724 (0.60), 7.727 (0.93), 7.731 (0.85), 7.745 (0.57), 7.748  (0.60), 7.998 (2.45), 8.000 (1.97), 8.019 (1.75), 8.021 (2.16), 8.666 (1.64), 8.671 (1.64), 9.354 (2.42), 9.359  (2.34).  Example 90   
  2'‐(quinolin‐3‐yl)‐1‐[(1,4,5‐trimethyl‐1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1,4,5‐trimethyl‐1H‐imidazole‐2‐carbaldehyde, CAS‐RN: [185910‐12‐7])  LC‐MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 399 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.977 (8.88), 2.061 (8.45), 2.518 (0.86), 2.522 (0.58), 2.539 (7.17),  2.795  (1.29), 2.813  (1.89), 2.831  (1.37), 3.397  (4.68), 3.408  (4.36), 3.425  (1.22), 3.502  (16.00), 3.616  (5.39), 4.149 (1.37), 4.159 (0.54), 4.168 (2.05), 4.185 (1.33), 6.903 (6.12), 7.594 (0.70), 7.597 (0.57), 7.611  (1.04), 7.615 (1.14), 7.632 (0.88), 7.635 (0.95), 7.706 (0.93), 7.710 (0.80), 7.724 (0.79), 7.727 (1.18), 7.731  (1.08), 7.745 (0.76), 7.749 (0.79), 7.995 (3.01), 7.998 (2.45), 8.017 (2.13), 8.019 (2.79), 8.678 (2.07), 8.683  (2.00), 9.359 (2.84), 9.364 (2.91).  Example 91    1‐[(1H‐benzimidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1H‐benzimidazole‐2‐carbaldehyde, CAS‐RN: [3314‐30‐5])  LC‐MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 407 [M+H]+   1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 2.89 (t, 2H), 3.51 ‐ 3.57 (m, 2H), 3.57 ‐ 3.63 (m, 2H), 3.90 (s, 2H),  4.20 (t, 2H), 6.93 (s, 1H), 7.10 ‐ 7.20 (m, 2H), 7.43 ‐ 7.49 (m, 1H), 7.57 (d, 1H), 7.59 ‐ 7.66 (m, 1H), 7.73  (ddd, 1H), 8.01 (d, 2H), 8.66 (d, 1H), 9.35 (d, 1H), 12.31 (br s, 1H).  Example 92   
  1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1‐methyl‐1H‐imidazole‐2‐carbaldehyde, CAS‐RN: [13750‐81‐7])  LC‐MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 371 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.799 (1.38), 2.817 (2.13), 2.834 (1.48), 3.402 (1.44), 3.419 (5.22),  3.426  (5.01), 3.443  (1.12), 3.693  (16.00), 3.697  (7.77), 4.150  (1.48), 4.168  (2.25), 4.185  (1.44), 6.759  (3.40), 6.763 (3.28), 6.912 (5.60), 7.087 (3.06), 7.090 (3.07), 7.592 (0.65), 7.595 (0.58), 7.609 (1.04), 7.612  (1.31), 7.629 (0.88), 7.632 (0.92), 7.704 (0.83), 7.708 (0.75), 7.722 (0.76), 7.725 (1.29), 7.729 (1.06), 7.743  (0.69), 7.746 (0.71), 7.997 (2.71), 8.018 (2.59), 8.682 (2.02), 8.687 (2.02), 9.364 (2.85), 9.369 (2.76).  Example 93    1‐[(1H‐pyrazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1H‐pyrazole‐5‐carbaldehyde, CAS‐RN: [948552‐36‐1])  LC‐MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 357 [M+H]+   1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 2.522  (0.50), 2.539  (16.00), 2.822  (0.54), 2.839  (0.89), 2.857  (0.58), 3.698 (0.41), 4.163 (0.64), 4.181 (1.01), 4.199 (0.64), 6.911 (2.13), 7.615 (0.60), 7.633 (0.44), 7.636  (0.47), 7.729 (0.56), 7.732 (0.51), 7.996 (1.32), 8.019 (1.20), 8.677 (0.90), 8.682 (0.93), 9.354 (1.19), 9.359  (1.17).  Example 94   
N N N N C H 3 H N N   1‐[(4‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 4‐methyl‐1H‐imidazole‐5‐carbaldehyde, CAS‐RN: [68282‐53‐1])  LC‐MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 371 [M+H]+   1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.907  (0.51), 2.163  (16.00), 2.518  (1.13), 2.523  (0.78), 2.539  (0.68), 2.792 (2.13), 2.810 (3.21), 2.827 (2.27), 3.361 (7.38), 3.378 (8.68), 3.395 (7.42), 3.413 (3.22), 4.152  (2.36), 4.161  (0.90), 4.170  (3.49), 4.187 (2.25), 6.872 (9.54), 7.421 (11.41), 7.592  (1.11), 7.596  (0.97),  7.610 (1.69), 7.613 (2.10), 7.616 (1.42), 7.630 (1.43), 7.633 (1.59), 7.705 (1.61), 7.709 (1.28), 7.722 (1.22),  7.726 (2.13), 7.730 (1.87), 7.744 (1.16), 7.747 (1.29), 7.993 (4.52), 7.995 (4.29), 8.017 (4.70), 8.676 (3.34),  8.682 (3.32), 9.354 (5.21), 9.359 (5.14).  Example 95    1‐[(2‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 2‐methyl‐1H‐imidazole‐5‐carbaldehyde, CAS‐RN: [35034‐22‐1])  LC‐MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 371 [M+H]+   1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 2.259  (16.00), 2.518  (0.44), 2.822  (1.28), 2.839  (1.95), 2.857  (1.37), 3.500 (1.57), 3.519 (2.98), 3.544 (2.96), 3.563 (1.56), 4.161 (1.47), 4.171 (0.62), 4.180 (2.15), 4.196  (1.40), 6.845 (3.61), 6.887 (5.98), 7.596 (0.68), 7.599 (0.58), 7.613 (0.97), 7.615 (1.26), 7.618 (0.85), 7.633  (0.85), 7.636 (0.94), 7.709 (0.95), 7.713 (0.74), 7.726 (0.77), 7.731 (1.23), 7.734 (1.08), 7.747 (0.69), 7.751  (0.79), 7.998 (3.11), 8.019 (2.24), 8.022 (2.31), 8.664 (1.93), 8.670 (2.04), 9.347 (3.03), 9.353 (3.09).  Example 96   
  1‐[(1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1H‐pyrrole‐2‐carbaldehyde, CAS‐RN: [1003‐29‐8])  LC‐MS (Method 3): Rt = 1.00 min; MS (ESIpos): m/z = 356 [M+H]+  1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.898 (1.36), 0.913 (1.36), 2.518 (4.68), 2.523 (3.30), 2.539 (0.81),  2.544 (1.16), 2.548 (1.06), 2.807 (3.40), 2.824 (4.96), 2.842 (3.48), 3.296 (1.06), 3.339 (6.21), 3.358 (8.73),  3.372  (1.36), 3.389  (8.14), 3.408  (4.04), 3.551  (12.50), 4.162  (3.62), 4.171  (1.55), 4.180  (5.20), 4.187  (1.50), 4.197 (3.45), 5.898 (1.18), 5.906 (2.98), 5.910 (3.28), 5.916 (2.39), 5.919 (2.93), 5.925 (4.83), 5.932  (3.13), 5.940 (1.28), 6.641 (2.19), 6.645 (2.88), 6.647 (4.22), 6.651 (4.27), 6.654 (2.64), 6.658 (2.05), 6.882  (16.00), 6.896  (0.94), 7.595  (1.73), 7.598  (1.45), 7.613  (2.69), 7.615  (2.88), 7.633  (2.19), 7.636  (2.29),  7.708 (2.42), 7.712 (1.95), 7.725 (2.02), 7.729 (2.91), 7.732 (2.69), 7.746 (1.75), 7.749 (1.90), 7.995 (7.67),  7.998 (5.89), 8.016 (5.33), 8.019 (6.51), 8.673 (5.03), 8.679 (4.91), 9.352 (7.42), 9.357 (7.27), 9.367 (0.49),  10.699 (1.58).  Example 97    1‐[(1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1H‐imidazole‐5‐carbaldehyde, CAS‐RN: [3034‐50‐2])  LC‐MS (Method 3): Rt = 0.79 min; MS (ESIpos): m/z = 357 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (1.48), 2.523 (1.06), 2.805 (3.03), 2.822 (4.60), 2.840 (3.22),  3.377 (3.41), 3.394 (6.17), 3.420 (7.38), 3.438 (3.62), 3.551 (4.16), 4.159 (3.50), 4.169 (1.30), 4.178 (5.10),  4.195  (3.33), 6.885  (16.00), 7.560  (7.83), 7.563  (8.10), 7.592  (1.62), 7.596  (1.41), 7.610  (2.43), 7.613  (3.24), 7.616 (2.02), 7.630 (2.07), 7.633 (2.27), 7.705 (2.23), 7.710 (1.95), 7.723 (1.79), 7.726 (3.40), 7.730   
(2.63), 7.744 (1.80), 7.747 (1.81), 7.995 (6.24), 8.016 (5.77), 8.678 (4.50), 8.683 (4.56), 9.356 (7.29), 9.361  (7.17).  Example 98    1‐[(5‐methyl‐1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 5‐methyl‐1H‐pyrrole‐2‐carbaldehyde, CAS‐RN: [1192‐79‐6])  LC‐MS (Method 3): Rt = 1.06 min; MS (ESIpos): m/z = 370 [M+H]+   1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 2.14 (s, 3H), 2.83 (t, 2H), 3.32 (br s, 2H), 3.37 ‐ 3.42 (m, 2H), 3.48  (s, 2H), 4.18 (t, 2H), 5.58 (t, 1H), 5.74 (t, 1H), 6.87 (s, 1H), 7.58 ‐ 7.65 (m, 1H), 7.73 (ddd, 1H), 7.97 ‐ 8.04  (m, 2H), 8.68 (d, 1H), 9.35 (d, 1H), 10.42 (br s, 1H).  Example 99  3‐(ethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next  step  without  further  purification.  Step  2:  Crude  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (50.0  mg,  128  µmol)  was  dissolved  in  EtOH  (1.5  ml),  triethylamine (36 µl, 260 µmol; CAS‐RN:[121‐44‐8]) and 3,4‐diethoxycyclobut‐3‐ene‐1,2‐dione (43.6 mg,   
256 µmol) were added. The mixture was stirred for 4 h at reflux. Ethanamine (320 µl, 2.0 M in THF, 640  µmol; CAS‐RN:[75‐04‐7]) was added dropwise and the mixture was stirred for 4 h at reflux. Ethanamine  (320 µl, 2.0 M  in THF, 640 µmol; CAS‐RN:[75‐04‐7]) was added dropwise and the mixture was stirred  overnight  at  70°C.  The mixture was  evaporated  and  purified  by  preparative HPLC  to  yield  the  title  compound (1.40 mg, 95 % purity, 3 % yield). LC‐MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 400  [M+H]+  1H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.094  (0.86), 1.112  (1.76), 1.121  (0.60), 1.130  (1.03),  1.140  (1.03), 1.150  (7.19), 1.168  (16.00), 1.185  (7.45), 1.206  (0.93), 1.223  (0.93), 1.747  (0.70), 2.518  (4.24), 2.535 (1.09), 2.986 (2.98), 3.004 (5.10), 3.020 (3.21), 3.171 (1.95), 4.216 (3.38), 4.233 (5.50), 4.250  (3.21), 4.603  (2.88), 4.625  (9.41), 4.643 (8.68), 4.665 (2.68), 7.099 (11.63), 7.597  (1.52), 7.599  (1.42),  7.617 (3.15), 7.637 (2.22), 7.712 (1.92), 7.715 (1.79), 7.733 (2.98), 7.736 (2.48), 7.750 (1.66), 7.753 (1.69),  7.999 (7.69), 8.021 (6.19), 8.666 (4.84), 8.671 (5.07), 9.352 (6.29), 9.357 (6.33).  The following compound (example 100) was synthesized in analogy to example 99:  Example 100    3‐(dimethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and N‐methylmethanamine, CAS‐RN: [124‐40‐3])  LC‐MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 400 [M+H]+   1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 3.01 (t, 2H), 3.14 (br s, 6H), 4.24 (t, 2H), 4.61 ‐ 4.72 (m, 4H), 7.07  (s, 1H), 7.58 ‐ 7.65 (m, 1H), 7.70 ‐ 7.77 (m, 1H), 8.02 (d, 2H), 8.67 (d, 1H), 9.36 (d, 1H).   Example 101  2‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one     
Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next  step  without  further  purification.  Step  2:  Crude  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] trifluoroacetate (180 mg, 43 % purity, 198 µmol) was dissolved in DCM (2.0 ml,  31 mmol; CAS‐RN:[75‐09‐2]), N,N‐dimethylglycine (24.5 mg, 238 µmol), DIPEA (170 µl, 990 µmol; CAS‐ RN:[7087‐68‐5]) and PyBroP (111 mg, 238 µmol; CAS‐RN:[132705‐51‐2]) were added and it was stirred  overnight at rt. The mixture was evaporated and purified by preparative HPLC (ACN/H2O+0,2% NH3) and  preparative TLC  (DCM/MeOH)  to yield  the  title  compound  (6.90 mg, 95 % purity, 9 % yield).  LC‐MS  (Method 1): Rt = 0.88 min; MS (ESIpos): m/z = 362 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.213  (16.00), 2.518  (1.86), 2.522  (1.15), 2.902  (0.78), 2.919  (1.16), 2.936  (0.86), 2.982  (3.82), 4.129  (1.15),  4.140 (1.14), 4.210 (0.90), 4.228 (1.36), 4.245 (0.84), 4.443 (1.96Luck), 6.998 (3.73), 7.615 (0.59), 7.619  (0.73), 7.621 (0.49), 7.636 (0.50), 7.638 (0.52), 7.712 (0.55), 7.716 (0.45), 7.730 (0.45), 7.733 (0.73), 7.737  (0.65), 7.754 (0.45), 7.998 (1.47), 8.000 (1.46), 8.021 (1.53), 8.679 (1.13), 8.684 (1.11), 9.359 (1.73), 9.364  (1.67).  The following compounds (example 102 to example 108) were synthesized in analogy to example 101:  Example 102    3‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 2‐oxopyrrolidine‐3‐carboxylic acid, CAS‐RN: [96905‐67‐8])  LC‐MS (Method 1): Rt = 0.81 min; MS (ESIpos): m/z = 388 [M+H]⁺  1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 2.12 (dtt, 1H), 2.34 ‐ 2.41 (m, 1H), 2.94 (dd, 2H), 3.16 ‐ 3.25 (m,  1H), 3.25 ‐ 3.31 (m, 1H), 3.37 ‐ 3.46 (m, 1H), 4.10 ‐ 4.21 (m, 2H), 4.24 (t, 2H), 4.48 (dd, 1H), 4.68 (dd, 1H),  6.94 ‐ 7.03 (m, 1H), 7.59 ‐ 7.66 (m, 1H), 7.73 (ddt, 1H), 7.88 (d, 1H), 8.01 (d, 2H), 8.69 (dd, 1H), 9.36 (dd,  1H).  Example 103   
  4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 5‐oxopyrrolidine‐3‐carboxylic acid, CAS‐RN: [7268‐43‐1])  LC‐MS (Method 1): Rt = 0.79 min; MS (ESIpos): m/z = 388 [M+H]⁺  1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 2.30 ‐ 2.35 (m, 2H), 2.89 ‐ 2.98 (m, 2H), 3.26 ‐ 3.31 (m, 1H), 3.39  ‐ 3.50 (m, 1H), 4.11 ‐ 4.19 (m, 2H), 4.21 ‐ 4.28 (m, 2H), 4.38 ‐ 4.49 (m, 2H), 7.02 (d, 1H), 7.59 ‐ 7.68 (m,  2H), 7.74 (ddd, 1H), 7.97 ‐ 8.05 (m, 2H), 8.68 (s, 1H), 9.36 (dd, 1H).  Example 104    2‐(1H‐imidazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 1H‐imidazol‐1‐ylacetic acid, CAS‐RN: [22884‐10‐2])  LC‐MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 385 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.983 (0.51), 1.833 (0.93), 2.326 (2.58), 2.669 (2.53), 2.935 (5.07),  2.952 (8.06), 2.969 (5.36), 4.166 (1.90), 4.190 (8.23), 4.200 (7.98), 4.228 (5.74), 4.247 (8.23), 4.264 (4.43),  4.387 (0.72), 4.445 (14.86), 4.787 (0.59), 4.830 (13.00), 4.834 (12.96), 4.876 (0.55), 6.786 (0.68), 6.901  (10.60), 6.967 (0.51), 7.004 (16.00), 7.124 (10.43), 7.485 (0.55), 7.590 (10.64), 7.606 (3.04), 7.625 (5.23),  7.643 (3.50), 7.722 (3.12), 7.741 (4.90), 7.758 (2.62), 8.007 (7.35), 8.028 (6.33), 8.678 (7.77), 8.682 (7.56),  9.361 (9.25), 9.366 (8.53).  Example 105   
  4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 4‐amino‐4‐oxobutanoic acid, CAS‐RN: [638‐32‐4])  LC‐MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 376 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.188 (0.58), 1.204 (0.64), 1.231 (1.68), 1.751 (2.25), 1.907 (0.69),  1.955  (1.44), 2.287  (2.37), 2.303  (7.45), 2.316  (9.59), 2.326  (10.86), 2.337  (9.07), 2.352  (2.48), 2.362  (1.33), 2.387  (0.64), 2.408  (0.64), 2.540 (14.21), 2.563  (4.79), 2.669  (1.96), 2.781  (1.44), 2.905  (3.00),  2.910 (3.12), 2.922 (5.55), 2.928 (5.72), 2.941 (5.03), 4.071 (1.44), 4.096 (8.20), 4.103 (8.26), 4.128 (1.50),  4.218 (5.08), 4.236 (10.05), 4.253 (4.97), 4.419 (15.48), 5.758 (1.04), 6.795 (3.29), 6.993 (16.00), 7.010  (0.52), 7.333 (3.23), 7.599 (2.31), 7.619 (4.62), 7.639 (3.29), 7.714 (2.89), 7.717 (2.83), 7.735 (4.33), 7.752  (2.43), 7.755 (2.48), 8.000 (10.92), 8.023 (9.47), 8.672 (7.28), 8.677 (7.51), 9.354 (8.78), 9.360 (8.84).  Example 106    1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐(4H‐1,2,4‐triazol‐ 4‐yl)ethan‐1‐one  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and 4H‐1,2,4‐triazol‐4‐ylacetic acid, CAS‐RN: [110822‐97‐4])  LC‐MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 386 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.322 (0.79), 2.326 (1.10), 2.331 (0.86), 2.664 (0.79), 2.669 (1.10),  2.673 (0.90), 2.952 (1.76), 2.969 (2.76), 2.986 (2.03), 4.184 (0.66), 4.208 (2.97), 4.219 (3.07), 4.243 (2.00),  4.257 (2.79), 4.272 (1.38), 4.277 (1.45), 4.502 (6.10), 4.945 (4.62), 4.949 (5.03), 7.003 (7.59), 7.607 (0.83),  7.610 (0.97), 7.627 (2.00), 7.647 (1.38), 7.721 (1.10), 7.724 (1.28), 7.738 (1.00), 7.742 (1.93), 7.745 (1.66),  7.759  (1.03), 7.762  (1.07), 8.008  (2.34), 8.019  (2.17), 8.029  (2.14), 8.037  (1.97), 8.439  (16.00), 8.678  (2.83), 8.682 (3.07), 9.362 (3.76), 9.368 (4.03).  Example 107   
  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]prop‐2‐en‐1‐one  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and prop‐2‐enoic acid, CAS‐RN: [79‐10‐7])  LC‐MS (Method 2): Rt =  0.69 min; MS (ESIpos): m/z = 331 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.000 (0.60), 0.838 (0.90), 1.231 (1.33), 1.376 (0.73), 2.333 (0.97),  2.519 (6.77), 2.523 (4.20), 2.540 (2.07), 2.670 (1.40), 2.674 (1.03), 2.931 (3.33), 2.947 (5.27), 2.950 (5.27),  2.965 (3.77), 4.175 (1.20), 4.201 (5.13), 4.213 (5.27), 4.223 (4.70), 4.240 (7.47), 4.258 (3.97), 4.476 (1.10),  4.498 (5.43), 4.506 (5.33), 4.529 (1.07), 5.714 (3.47), 5.720 (3.27), 5.739 (3.33), 5.745 (3.80), 6.143 (2.80),  6.149  (2.93),  6.186  (4.37),  6.191  (4.27),  6.341  (4.10),  6.367  (4.17),  6.384  (2.97),  6.410  (2.50),  7.028  (16.00), 7.598  (1.70), 7.600  (1.57), 7.615  (2.67), 7.618  (3.53), 7.635  (2.30), 7.638  (2.47), 7.714  (2.23),  7.717 (2.17), 7.731 (2.03), 7.734 (3.60), 7.738 (2.77), 7.752 (1.93), 7.755 (1.93), 7.999 (6.70), 8.021 (6.10),  8.673 (5.10), 8.677 (5.23), 9.355 (7.23), 9.360 (7.40).  Example 108    3‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and N,N‐dimethyl‐beta‐alanine hydrochloride, CAS‐RN: [14788‐12‐6])  LC‐MS (Method 1): Rt =  0.88 min; MS (ESIpos): m/z = 376 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 2.145  (16.00), 2.230  (0.65), 2.248  (1.30), 2.267  (0.90), 2.463  (1.15), 2.482 (2.07), 2.518 (1.04), 2.523 (0.73), 2.905 (0.49), 2.921 (0.85), 2.926 (0.85), 2.941 (0.59), 4.100  (1.05), 4.109 (1.04), 4.216 (0.76), 4.234 (1.31), 4.251 (0.70), 4.409 (1.83), 6.996 (3.10), 7.617 (0.52), 7.619  (0.58), 7.636 (0.42), 7.639 (0.45), 7.713 (0.45), 7.734 (0.60), 7.738 (0.54), 7.999 (1.49), 8.021 (1.08), 8.023  (1.32), 8.675 (1.03), 8.680 (0.98), 9.357 (1.45), 9.363 (1.34).  Example 109   
N'‐cyano‐N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next  step  without  further  purification.  Step  2:  Crude  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (100 mg, 256 µmol) was dissolved  in DCM  (4.5 ml), diphenyl  cyanocarbonimidate (67.1 mg, 282 µmol) and triethylamine (71 µl, 510 µmol; CAS‐RN:[121‐44‐8]) were  added and the mixture was stirred for 2 h at rt. The mixture was diluted with water and extracted 3x  with DCM. The combined organic phases were dried and concentrated under reduced pressure to yield  phenyl  N‐cyano‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidate (120 mg), which was used without further purification. LC‐MS (Method 1): Rt = 1.14 min;  MS (ESIpos): m/z = 421 [M+H]+. Step 3: phenyl N‐cyano‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboximidate  (60.0 mg,  50 %  purity,  71.3  µmol) was  dissolved  in  2‐ propanol (740 µl) and ethanamine (360 µl, 2.0 M, 710 µmol; CAS‐RN:[75‐04‐7]) was added. The mixture  was stirred overnight at 80°C. The mixture was evaporated and purified by preparative HPLC to yield the  title compound (1.60 mg, 100 % purity, 6 % yield). LC‐MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z =  372 [M+H]+. 1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 1.08 (t, 3H), 2.96 (t, 2H), 3.12 ‐ 3.22 (m, 2H), 4.23 (t,  2H), 4.35 ‐ 4.49 (m, 4H), 7.05 ‐ 7.12 (m, 2H), 7.59 ‐ 7.65 (m, 1H), 7.74 (ddd, 1H), 8.01 (d, 2H), 8.68 (d, 1H),  9.36 (d, 1H).  The following compound (example 110) was synthesized in analogy to example 109:  Example 110     
N'‐cyano‐N,N‐dimethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 2) and N‐methylmethanamine, CAS‐RN: [124‐40‐3])  LC‐MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 372 [M+H]+   1H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.077 (0.58), 2.074 (0.60), 2.905 (0.78), 2.923 (0.68), 2.940 (1.10),  2.958  (0.85), 2.988  (16.00), 4.208  (0.76), 4.226  (1.15), 4.243  (0.72), 4.456  (3.37), 4.458  (3.32), 7.038  (3.09), 7.075 (0.48), 7.617 (0.56), 7.619 (0.68), 7.622 (0.49), 7.637 (0.48), 7.640 (0.52), 7.714 (0.52), 7.717  (0.45), 7.731 (0.46), 7.735 (0.67), 7.738 (0.62), 7.755 (0.44), 8.002 (1.71), 8.004 (1.34), 8.023 (1.20), 8.026  (1.35), 8.676 (1.08), 8.682 (1.14), 9.357 (1.47), 9.363 (1.49).  Example 111  N‐[3‐(dimethylamino)propyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide    Step  1:  To  a  solution  of  tert‐butyl  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (750 mg,  1.992 mmol,  see  example  2)  in DCM  (15 mL) was  added  under  nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature  for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐(quinolin‐3‐ yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate  (1:1) was used  in the next  step without  further purification.  Step  2:  To  a  solution of  crude  2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro‐ [azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (1.40 g, 3.59 mmol)  in dichlormethane (59 mL)  was added at ambient temperature under argon triethylamine (5.0 ml, 36 mmol; CAS‐RN:[121‐44‐8])  and  4‐nitrophenyl  carbonochloridate  (867  mg,  4.30  mmol).  The  reaction  was  stirred  at  ambient  temperature overnight. DMA (18 mL) was added and the dichlormethane was removed under reduced  pressure.  The  DMA  solution  containing  crude  4‐nitrophenyl  2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  was  directly  used  in  the  next  step.  Step  3:  To  a  solution  of  4‐nitrophenyl  2'‐(quinolin‐3‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (31.3  mg,  70.9  µmol)  in  N,N‐ dimethylacetamide (1.0 ml) under nitrogen were added N1,N1‐dimethylpropane‐1,3‐diamine (72.5 mg,  709 µmol) and K2CO3 (14.4 mg, 142 µmol; CAS‐RN:[121‐44‐8]). The mixture was stirred overnight at 60°C.  The mixture was purified by preparative HPLC to yield title compound (15.1 mg, 95 % purity, 50 % yield).   
LC‐MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 405 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]:  1.551 (0.56), 1.588 (0.45), 1.605 (1.17), 1.623 (1.62), 1.641 (1.17), 1.815 (0.43), 1.834 (0.53), 1.856 (0.43),  1.906 (0.77), 2.156 (0.91), 2.173 (3.94), 2.322 (2.29), 2.326 (2.98), 2.332 (3.06), 2.349 (3.94), 2.518 (8.60),  2.522 (5.91), 2.539 (1.65), 2.554 (1.36), 2.664 (1.17), 2.668 (1.60), 2.673 (1.17), 2.877 (2.34), 2.895 (4.15),  2.912  (3.22), 2.930  (0.83), 3.031  (1.14), 3.060  (15.28), 3.079  (1.68), 3.093  (1.49), 3.109  (1.41), 3.125  (0.75), 3.793  (1.36), 4.036  (16.00), 4.057  (5.75), 4.163  (4.34), 4.206  (2.34), 4.216  (2.61), 4.224  (3.86),  4.233 (2.58), 4.240 (2.48), 4.250 (1.04), 4.287 (0.72), 6.603 (0.72), 6.618 (1.41), 6.632 (0.72), 6.698 (0.69),  6.953 (3.14), 6.977 (8.97), 6.989 (2.42), 7.597 (1.22), 7.600 (1.28), 7.618 (2.80), 7.635 (1.76), 7.637 (1.81),  7.712 (1.49), 7.715 (1.70), 7.720 (0.75), 7.732 (2.61), 7.736 (2.29), 7.750 (1.38), 7.753 (1.41), 7.998 (4.45),  8.015 (3.17), 8.020 (3.81), 8.678 (4.18), 8.682 (3.33), 8.694 (0.85), 9.360 (6.12), 9.365 (6.15).  The following compounds (example 112 to example 129) were synthesized in analogy to example 111:  Example 112    N‐(oxan‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and tetrahydro‐2H‐pyran‐4‐amine, CAS‐RN: [38041‐19‐9])  LC‐MS (Method 1): Rt =  0.88 min; MS (ESIpos): m/z = 404 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.395 (0.47), 1.415 (1.09), 1.425 (1.14), 1.445 (1.29), 1.456 (1.14),  1.474 (0.57), 1.485 (0.52), 1.669 (1.50), 1.675 (1.50), 1.700 (1.19), 1.705 (1.19), 2.332 (0.67), 2.518 (4.14),  2.522 (2.69), 2.669 (0.98), 2.673 (0.72), 2.874 (1.86), 2.891 (2.90), 2.909 (2.02), 3.296 (1.55), 3.321 (3.83),  3.598 (0.47), 3.608 (0.62), 3.617 (0.52), 3.627 (0.62), 3.636 (0.47), 3.823 (1.45), 3.829 (1.45), 3.852 (1.29),  3.858  (1.29), 4.036  (16.00), 4.204  (2.02), 4.221  (3.16), 4.239  (1.97), 5.757  (0.67), 6.384  (1.97), 6.404  (1.92), 6.994 (9.53), 7.596 (0.93), 7.599 (0.98), 7.613 (1.40), 7.617 (2.02), 7.634 (1.35), 7.636 (1.35), 7.710  (1.29), 7.714 (1.35), 7.727 (1.09), 7.731 (2.07), 7.735 (1.50), 7.748 (1.09), 7.752 (1.09), 7.990 (1.97), 7.997  (2.23), 8.007 (1.71), 8.010 (1.66), 8.019 (1.97), 8.682 (2.80), 8.687 (2.80), 9.363 (4.40), 9.368 (4.14).  Example 113     
N‐{[oxolan‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐(tetrahydrofuran‐2‐yl)methanamine, CAS‐RN: [4795‐29‐3])  LC‐MS (Method 1): Rt =  0.92 min; MS (ESIpos): m/z = 405 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.521 (0.76), 1.531 (0.52), 1.538 (0.99), 1.546 (0.64), 1.555 (0.64),  1.562 (0.52), 1.567 (0.76), 1.584 (0.47), 1.764 (0.47), 1.779 (0.87), 1.784 (0.81), 1.793 (1.16), 1.800 (1.45),  1.807 (1.51), 1.818 (1.45), 1.826 (1.22), 1.834 (1.34), 1.843 (1.05), 1.850 (0.93), 1.855 (0.64), 1.861 (1.11),  1.874 (0.76), 1.877 (0.76), 1.881 (0.58), 1.892 (0.52), 1.898 (0.47), 2.331 (0.81), 2.518 (4.95), 2.522 (3.08),  2.673 (0.81), 2.874 (2.09), 2.891 (3.20), 2.908 (2.27), 3.052 (2.44), 3.067 (4.71), 3.082 (2.56), 3.585 (0.64),  3.601 (1.34), 3.604 (1.40), 3.621 (1.80), 3.639 (0.93), 3.728 (0.93), 3.745 (1.57), 3.761 (1.40), 3.764 (1.34),  3.782  (0.87), 3.811  (0.41), 3.827  (1.11), 3.843  (1.92), 3.858  (1.28), 4.020  (0.52), 4.040  (16.00), 4.063  (0.47), 4.203  (2.27), 4.220  (3.43), 4.238 (2.15), 6.568 (0.99), 6.583 (2.09), 6.598 (0.99), 6.985 (10.12),  7.595 (1.05), 7.599 (1.05), 7.613 (1.51), 7.615 (2.15), 7.633 (1.45), 7.636 (1.45), 7.710 (1.45), 7.714 (1.45),  7.727 (1.22), 7.731 (2.33), 7.735 (1.69), 7.749 (1.16), 7.752 (1.22), 7.990 (2.15), 7.997 (2.39), 8.007 (1.86),  8.011 (1.80), 8.018 (2.09), 8.682 (2.97), 8.687 (3.08), 9.362 (4.60), 9.367 (4.71).  Example 114    (4‐methylpiperazin‐1‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐methylpiperazine, CAS‐RN: [109‐01‐3])  LC‐MS (Method 1): Rt =  0.91 min; MS (ESIpos): m/z = 404 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 2.175  (16.00), 2.254  (3.29), 2.266  (4.59), 2.278  (3.44), 2.327  (1.00), 2.331 (0.75), 2.518 (3.94), 2.523 (2.39), 2.669 (1.00), 2.673 (0.70), 2.886 (1.84), 2.903 (2.74), 2.921  (1.94), 3.262  (3.49), 3.274  (4.29), 3.287 (3.39), 4.142 (14.95), 4.197  (1.94), 4.215  (2.94), 4.232  (1.84),  6.987 (9.37), 7.596 (0.90), 7.599 (0.85), 7.613 (1.30), 7.616 (1.89), 7.619 (1.10), 7.633 (1.25), 7.636 (1.25),  7.710 (1.30), 7.714 (1.30), 7.727 (1.05), 7.731 (2.04), 7.735 (1.50), 7.749 (1.10), 7.752 (1.05), 7.993 (2.24),  7.997 (2.14), 7.999 (1.99), 8.009 (1.60), 8.014 (1.74), 8.018 (1.89), 8.686 (2.49), 8.692 (2.59), 9.361 (4.09),  9.367 (4.09).  Example 115   
  N‐[2‐oxopyrrolidin‐3‐yl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐aminopyrrolidin‐2‐one, CAS‐RN: [2483‐65‐0])  LC‐MS (Method 1): Rt =  0.78 min; MS (ESIpos): m/z = 403 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.825 (1.06), 1.855 (1.36), 1.882 (1.13), 1.907 (0.98), 2.232 (0.45),  2.240 (0.68), 2.252 (0.83), 2.261 (1.13), 2.269 (0.91), 2.274 (0.98), 2.283 (0.75), 2.291 (0.60), 2.303 (0.38),  2.331 (1.21), 2.336 (0.60), 2.518 (7.25), 2.522 (4.53), 2.539 (1.89), 2.673 (1.13), 2.678 (0.53), 2.891 (2.87),  2.909 (4.30), 2.926 (2.94), 3.145 (1.89), 3.157 (3.02), 3.168 (2.11), 3.181 (2.64), 4.036 (1.06), 4.043 (1.21),  4.063  (16.00), 4.083  (0.83), 4.088  (0.91), 4.182  (0.98), 4.204  (2.42), 4.212  (3.55), 4.230  (6.87), 4.247  (3.17), 5.757  (3.92), 6.760  (3.25), 6.781 (3.09), 6.986 (0.53), 7.021 (13.21), 7.595  (1.51), 7.597  (1.51),  7.612 (2.19), 7.615 (3.17), 7.632 (2.11), 7.636 (2.11), 7.710 (2.04), 7.713 (2.11), 7.727 (1.74), 7.731 (3.32),  7.734 (2.49), 7.748 (2.19), 7.751 (2.79), 7.758 (4.08), 7.988 (3.02), 7.999 (3.62), 8.005 (2.87), 8.008 (2.64),  8.019 (3.17), 8.689 (4.45), 8.694 (4.38), 9.366 (6.49), 9.371 (6.34).  Example 116    1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]azetidine‐3‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and azetidine‐3‐carboxamide, CAS‐RN: [740768‐99‐4])  LC‐MS (Method 1): Rt = 0.78 min; MS (ESIpos): m/z = 403 [M+H]⁺  1H‐NMR (400MHz, DMSO‐d6): δ [ppm]= 2.90 (t, 2H), 3.24 ‐ 3.31 (m, 1H), 3.86 ‐ 4.00 (m, 4H), 4.06 ‐ 4.13  (m, 4H), 4.21 (t, 2H), 6.99 ‐ 7.02 (m, 1H), 7.02 ‐ 7.08 (m, 1H), 7.42 ‐ 7.50 (m, 1H), 7.59 ‐ 7.65 (m, 1H), 7.73  (ddd, 1H), 8.01 (d, 2H), 8.68 (d, 1H), 9.36 (d, 1H).  Example 117   
  N‐[(1H‐pyrazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐(1H‐pyrazol‐3‐yl)methanamine, CAS‐RN: [37599‐58‐9])  LC‐MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 400 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.907 (0.44), 2.336 (0.62), 2.518 (8.62), 2.522 (5.63), 2.539 (0.88),  2.673  (1.32),  2.678  (0.62),  2.881  (3.16),  2.898  (5.10),  2.916  (3.43),  3.356  (2.37),  3.377  (1.14),  4.069  (16.00), 4.205 (4.48), 4.223 (7.91), 4.240 (5.36), 6.145 (2.11), 6.944 (0.70), 6.985 (15.38), 7.003 (0.44),  7.596 (1.93), 7.599 (2.02), 7.613 (2.99), 7.617 (4.13), 7.634 (2.99), 7.636 (2.99), 7.710 (2.37), 7.714 (2.46),  7.727 (2.02), 7.731 (3.87), 7.735 (2.81), 7.748 (2.02), 7.752 (2.11), 7.991 (3.60), 7.997 (4.22), 8.008 (3.16),  8.012 (2.99), 8.019 (3.69), 8.681 (5.10), 8.686 (5.27), 9.361 (8.09), 9.367 (7.65), 12.538 (0.79).  Example 118    (morpholin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and morpholine, CAS‐RN: [110‐91‐8])  LC‐MS (Method 1): Rt =  0.92 min; MS (ESIpos): m/z = 391 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.518 (3.90), 2.885 (2.01), 2.903 (3.22), 2.920 (2.09), 3.261 (4.38),  3.272  (6.43), 3.285  (5.27), 3.544  (5.11), 3.557  (6.23), 3.568  (4.34), 4.160  (16.00), 4.196  (2.21), 4.214  (3.42), 4.231 (2.05), 6.983 (7.32), 7.593 (0.88), 7.613 (1.89), 7.630 (1.25), 7.633 (1.25), 7.706 (1.13), 7.710  (1.13), 7.727 (1.85), 7.731 (1.45), 7.745 (1.01), 7.748 (0.96), 7.991 (3.22), 8.012 (2.65), 8.682 (2.85), 8.687  (2.85), 9.357 (3.66), 9.363 (3.66).  Example 119   
  N‐(3‐hydroxypropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 3‐aminopropan‐1‐ol, CAS‐RN: [156‐87‐6])  LC‐MS (Method 1): Rt =  0.81 min; MS (ESIpos): m/z = 379 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.530 (0.62), 1.546 (2.03), 1.563 (2.95), 1.580 (2.09), 1.596 (0.62),  2.517 (6.09), 2.522 (3.82), 2.673 (0.86), 2.874 (1.91), 2.892 (2.95), 2.909 (2.03), 3.054 (1.11), 3.071 (2.34),  3.087 (2.34), 3.103 (0.98), 3.297 (0.62), 3.306 (0.80), 3.375 (0.62), 3.406 (1.35), 3.422 (3.14), 3.436 (3.14),  3.450  (1.23), 4.029  (16.00), 4.202  (2.03), 4.221  (3.14), 4.237  (1.91), 4.433  (1.35), 4.446  (2.89), 4.459  (1.29), 5.757 (8.74), 6.477 (0.92), 6.491 (1.91), 6.506 (0.92), 6.986 (8.25), 7.596 (0.86), 7.599 (0.92), 7.613  (1.35), 7.616 (1.91), 7.634 (1.29), 7.636 (1.29), 7.710 (1.17), 7.713 (1.23), 7.727 (1.05), 7.731 (1.91), 7.734  (1.42), 7.748 (1.05), 7.752 (0.98), 7.991 (2.03), 7.997 (2.28), 8.008 (1.72), 8.019 (1.97), 8.681 (2.77), 8.686  (2.83), 9.361 (4.00), 9.367 (4.00).  Example 120    N‐(2‐hydroxyethyl)‐N‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(methylamino)ethanol, CAS‐RN: [109‐83‐1])  LC‐MS (Method 1): Rt =  0.86 min; MS (ESIpos): m/z = 378 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.331 (0.58), 2.518 (3.26), 2.522 (1.99), 2.669 (0.78), 2.673 (0.58),  2.854  (16.00), 2.884  (1.51), 2.902  (2.24), 2.919  (1.56), 3.229  (1.31), 3.245  (3.16), 3.260  (1.70), 3.497  (0.78), 3.512  (1.90), 3.526  (1.80), 3.541 (0.63), 4.128 (11.28), 4.204  (1.60), 4.222  (2.38), 4.239  (1.51),  4.690 (0.63), 4.703 (1.31), 4.717 (0.63), 6.976 (7.10), 7.597 (0.73), 7.599 (0.68), 7.614 (1.07), 7.617 (1.51),  7.619 (0.92), 7.634 (0.97), 7.636 (0.97), 7.710 (0.97), 7.714 (0.97), 7.728 (0.88), 7.731 (1.51), 7.735 (1.17),  7.749 (0.83), 7.752 (0.83), 7.997 (2.43), 8.018 (2.14), 8.687 (2.04), 8.692 (2.04), 9.364 (3.11), 9.369 (3.16).   
Example 121    N‐(2‐oxopiperidin‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 4‐aminopiperidin‐2‐one, CAS‐RN: [5513‐66‐6])  LC‐MS (Method 1): Rt =  0.79 min; MS (ESIpos): m/z = 417 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.228 (0.54), 1.564 (0.53), 1.571 (0.51), 1.577 (0.68), 1.584 (0.54),  1.589 (0.51), 1.595 (0.89), 1.602 (0.59), 1.609 (0.69), 1.845 (0.73), 1.854 (0.77), 1.864 (0.54), 1.875 (0.61),  1.885 (0.59), 2.092 (1.11), 2.115 (1.11), 2.135 (1.46), 2.157 (1.53), 2.331 (0.51), 2.349 (1.05), 2.361 (1.07),  2.388 (0.76), 2.392 (0.78), 2.403 (0.78), 2.518 (3.58), 2.522 (2.21), 2.669 (0.67), 2.673 (0.50), 2.879 (2.01),  2.897 (3.23), 2.914 (2.15), 3.108 (0.83), 3.116 (0.75), 3.133 (0.76), 3.145 (0.94), 3.157 (1.01), 3.166 (1.03),  3.176 (0.75), 3.187 (0.45), 3.195 (0.41), 3.820 (0.56), 3.829 (0.58), 3.838 (0.74), 3.846 (0.70), 3.854 (0.58),  3.863  (0.60), 4.051  (16.00), 4.205  (2.19), 4.223  (3.45), 4.240  (2.11), 6.525  (2.18), 6.544  (2.11), 6.999  (8.87), 7.521 (1.82), 7.597 (1.05), 7.599 (1.03), 7.614 (1.54), 7.617 (2.20), 7.634 (1.44), 7.637 (1.43), 7.710  (1.38), 7.714 (1.39), 7.728 (1.22), 7.731 (2.20), 7.735 (1.62), 7.749 (1.15), 7.752 (1.16), 7.993 (2.36), 7.998  (2.61), 8.009 (1.99), 8.013 (1.96), 8.019 (2.26), 8.683 (3.10), 8.688 (3.16), 9.364 (4.45), 9.369 (4.43).  Example 122    N‐(6‐oxopiperidin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 5‐aminopiperidin‐2‐one, CAS‐RN: [154148‐70‐6])  LC‐MS (Method 1): Rt =  0.79 min; MS (ESIpos): m/z = 417 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.913 (0.71), 0.932 (0.58), 0.945 (4.11), 0.951 (0.53), 0.962 (8.26),  0.981 (4.03), 1.230 (2.63), 1.374 (2.75), 1.399 (0.61), 1.702 (0.41), 1.711 (0.45), 1.721 (0.53), 1.728 (0.65),  1.735 (0.74), 1.744 (0.42), 1.753 (0.78), 1.758 (0.55), 1.776 (0.43), 1.820 (0.69), 1.831 (0.78), 1.845 (0.53),   
1.862 (0.42), 2.217 (1.17), 2.233 (1.99), 2.244 (1.81), 2.249 (1.57), 2.256 (1.19), 2.262 (1.23), 2.332 (0.41),  2.518 (2.56), 2.522 (1.64), 2.876 (1.95), 2.893 (3.11), 2.910 (2.09), 2.943 (1.33), 2.962 (2.83), 2.968 (1.21),  2.976 (2.42), 2.980 (2.23), 2.993 (2.84), 3.011 (0.63), 3.226 (0.56), 3.235 (0.91), 3.244 (0.66), 3.252 (0.56),  3.256  (0.55), 3.264  (0.79), 3.273  (0.50), 3.791  (0.48), 3.800  (0.59), 3.810  (0.64), 4.057  (16.00), 4.204  (2.11), 4.221 (3.31), 4.239 (2.08), 5.715 (0.48), 6.523 (2.11), 6.542 (2.03), 6.992 (8.85), 7.388 (1.64), 7.392  (1.65), 7.597 (0.97), 7.599 (0.96), 7.614 (1.48), 7.617 (2.07), 7.634 (1.37), 7.637 (1.39), 7.710 (1.33), 7.714  (1.39), 7.728 (1.12), 7.731 (2.12), 7.735 (1.54), 7.749 (1.14), 7.752 (1.11), 7.992 (2.16), 7.998 (2.43), 8.009  (1.85), 8.013 (1.80), 8.019 (2.14), 8.680 (2.95), 8.685 (3.02), 9.362 (4.31), 9.368 (4.32).  Example 123    N‐[2‐(1H‐imidazol‐1‐yl)ethyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(1H‐imidazol‐1‐yl)ethanamine, CAS‐RN: [5739‐10‐6])  LC‐MS (Method 1): Rt = 0.82 min; MS (ESIpos): m/z = 415 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.229 (0.86), 2.323 (0.75), 2.327 (1.01), 2.331 (0.75), 2.665 (0.78),  2.669  (1.01), 2.673  (0.78), 2.874  (1.72), 2.892  (2.86), 2.909  (1.82), 4.023  (16.00), 4.039  (4.08), 4.053  (1.90), 4.202 (1.87), 4.219 (2.99), 4.236 (1.77), 6.687 (0.83), 6.701 (1.74), 6.715 (0.83), 6.910 (3.98), 6.984  (6.37), 7.171 (3.98), 7.600 (0.88), 7.615 (5.00), 7.638 (1.22), 7.712 (1.01), 7.715 (0.99), 7.732 (1.64), 7.736  (1.35), 7.751 (0.88), 7.753 (0.91), 8.000 (3.54), 8.021 (3.15), 8.689 (2.63), 8.693 (2.73), 9.368 (3.30), 9.373  (3.28).  Example 124    N‐benzyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and benzylamine, CAS‐RN: [100‐46‐9])  LC‐MS (Method 1): Rt =  1.05 min; MS (ESIpos): m/z = 411 [M+H]⁺   
¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.323 (0.62), 2.327 (0.85), 2.332 (0.62), 2.522 (2.69), 2.665 (0.62),  2.669  (0.87), 2.673  (0.64), 2.894  (1.90), 2.911  (3.07), 2.929  (2.03), 4.088  (16.00), 4.210  (2.09), 4.228  (3.48), 4.240 (4.39), 4.255 (3.84), 5.758 (0.47), 7.000 (7.83), 7.096 (0.96), 7.111 (2.03), 7.126 (0.94), 7.221  (0.66), 7.238 (1.83), 7.250 (0.70), 7.255 (1.19), 7.259 (0.85), 7.287 (1.98), 7.304 (5.25), 7.319 (4.35), 7.324  (1.11), 7.337 (3.65), 7.355 (1.15), 7.599 (0.90), 7.601 (0.90), 7.618 (1.94), 7.636 (1.28), 7.639 (1.26), 7.712  (1.15), 7.715 (1.17), 7.733 (1.90), 7.736 (1.41), 7.750 (1.00), 7.753 (0.98), 7.993 (2.07), 8.000 (2.33), 8.010  (1.79), 8.021 (2.03), 8.685 (2.84), 8.689 (2.88), 9.365 (3.88), 9.371 (3.75).  Example 125    N‐(2‐hydroxy‐2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐amino‐2‐methylpropan‐2‐ol, CAS‐RN: [2854‐16‐2])  LC‐MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 393 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.061  (16.00), 1.339  (0.44), 2.518  (1.66), 2.522  (1.07), 2.886  (0.91), 2.903 (1.39), 2.921 (0.99), 2.997 (1.86), 3.012 (1.90), 4.075 (7.68), 4.208 (0.95), 4.226 (1.47), 4.244  (0.91), 4.515 (3.17), 6.346 (0.40), 6.361 (0.91), 6.377 (0.40), 6.983 (4.51), 7.596 (0.48), 7.599 (0.48), 7.613  (0.67), 7.617 (0.99), 7.619 (0.59), 7.634 (0.63), 7.637 (0.63), 7.710 (0.63), 7.714 (0.63), 7.728 (0.51), 7.731  (0.99), 7.735 (0.71), 7.749 (0.55), 7.752 (0.51), 7.995 (1.07), 7.998 (1.11), 8.000 (1.07), 8.010 (0.83), 8.015  (0.87), 8.019 (0.99), 8.685 (1.31), 8.690 (1.35), 9.364 (2.14), 9.370 (2.06).  Example 126    N‐[(1‐methyl‐1H‐imidazol‐4‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 1‐(1‐methyl‐1H‐imidazol‐4‐yl)methanamine, CAS‐RN: [486414‐83‐9])  LC‐MS (Method 1): Rt =  0.83 min; MS (ESIpos): m/z = 415 [M+H]⁺   
¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 2.332 (0.71), 2.518 (5.52), 2.522 (3.86), 2.576 (0.55), 2.587 (0.47),  2.673  (0.71), 2.872  (1.42), 2.890  (2.21), 2.907  (1.58), 3.383  (0.95), 3.608  (16.00), 4.028  (1.02), 4.050  (11.19), 4.072  (3.07), 4.086  (2.84), 4.202  (1.58), 4.220  (2.36), 4.237  (1.50), 6.798  (0.71), 6.813  (1.50),  6.827 (0.71), 6.909 (2.52), 6.912 (2.52), 6.979 (0.71), 6.983 (6.94), 7.467 (2.52), 7.469 (2.52), 7.596 (0.79),  7.598 (0.79), 7.613 (1.10), 7.616 (1.58), 7.618 (0.95), 7.633 (1.10), 7.636 (1.02), 7.710 (1.02), 7.713 (1.10),  7.727 (0.87), 7.731 (1.66), 7.734 (1.18), 7.748 (0.95), 7.752 (0.87), 7.990 (1.50), 7.997 (1.73), 7.999 (1.73),  8.007 (1.26), 8.010 (1.26), 8.018 (1.50), 8.680 (2.05), 8.685 (2.13), 9.360 (3.23), 9.365 (3.39).  Example 127    N‐{[5‐oxopyrrolidin‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 5‐(aminomethyl)pyrrolidin‐2‐one, CAS‐RN: [154148‐69‐3])  LC‐MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 418 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.689 (0.72), 1.703 (1.15), 1.719 (0.86), 1.729 (1.15), 1.740 (0.58),  2.028 (0.72), 2.033 (0.72), 2.051 (1.15), 2.067 (2.02), 2.078 (0.72), 2.083 (0.86), 2.088 (0.58), 2.097 (2.02),  2.103 (1.15), 2.112 (3.46), 2.118 (1.73), 2.135 (1.73), 2.143 (1.59), 2.159 (1.59), 2.183 (0.58), 2.331 (1.15),  2.336 (0.58), 2.518 (7.06), 2.522 (4.32), 2.539 (0.72), 2.678 (0.43), 2.883 (2.59), 2.900 (4.18), 2.917 (2.74),  3.029 (1.73), 3.034 (1.73), 3.044 (3.17), 3.048 (3.32), 3.060 (1.87), 3.063 (1.87), 3.386 (0.86), 3.397 (0.43),  3.552  (1.15), 3.567  (1.59), 3.582  (1.15), 4.042  (1.30), 4.062  (16.00), 4.087  (1.01), 4.208  (2.88), 4.226  (4.47), 4.243  (2.74), 6.579  (1.30), 6.594 (2.74), 6.609 (1.15), 6.980 (12.54), 7.597  (1.44), 7.600  (1.30),  7.614 (2.16), 7.617 (2.88), 7.634 (1.87), 7.637 (1.87), 7.681 (3.89), 7.711 (2.02), 7.715 (1.87), 7.728 (1.59),  7.732 (3.03), 7.736 (2.31), 7.750 (1.59), 7.753 (1.59), 7.997 (4.76), 8.018 (4.04), 8.681 (4.04), 8.686 (4.18),  9.362 (6.05), 9.368 (6.05).  Example 128     
[3‐(dimethylamino)pyrrolidin‐1‐yl][2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and N,N‐dimethylpyrrolidin‐3‐amine, CAS‐RN: [69478‐75‐7])  LC‐MS (Method 1): Rt =  0.94 min; MS (ESIpos): m/z = 418 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.627 (0.74), 1.654 (1.05), 1.679 (0.84), 1.907 (0.84), 1.987 (0.53),  2.001  (1.05), 2.017  (0.95), 2.028  (0.84), 2.042  (0.53), 2.169  (16.00), 2.318  (0.63), 2.322  (1.37), 2.326  (1.79), 2.332 (1.37), 2.336 (0.63), 2.518 (7.47), 2.522 (4.74), 2.539 (0.53), 2.620 (0.63), 2.660 (0.84), 2.664  (1.47), 2.669 (2.00), 2.673 (1.47), 2.678 (0.63), 2.888 (2.53), 2.904 (4.21), 2.907 (4.11), 2.923 (2.95), 2.997  (1.26), 3.020 (1.79), 3.043 (1.16), 3.223 (0.84), 3.240 (1.16), 3.248 (2.00), 3.266 (2.11), 3.274 (1.47), 3.291  (1.47), 3.299 (1.05), 3.395 (1.89), 3.401 (1.89), 3.422 (2.21), 3.442 (1.05), 3.448 (0.95), 3.483 (1.58), 3.501  (1.79), 3.508 (1.68), 3.526 (1.37), 4.067 (3.16), 4.074 (3.37), 4.088 (4.32), 4.094 (4.74), 4.173 (7.26), 4.194  (5.37), 4.202  (3.79), 4.210  (1.16), 4.219 (5.89), 4.237 (3.26), 6.988 (15.37), 7.596  (1.58), 7.599  (1.47),  7.614 (2.32), 7.617 (3.26), 7.620 (2.00), 7.634 (2.11), 7.637 (2.21), 7.711 (2.21), 7.715 (2.11), 7.728 (1.79),  7.732 (3.26), 7.736 (2.63), 7.749 (1.79), 7.752 (1.89), 7.996 (5.47), 8.017 (4.84), 8.678 (4.53), 8.683 (4.63),  9.359 (7.26), 9.364 (7.05).  Example 129    N‐{2‐[oxolan‐3‐yl]ethyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 2) and 2‐(tetrahydrofuran‐3‐yl)ethanamine, CAS‐RN: [770709‐01‐8])  LC‐MS (Method 1): Rt =  0.91 min; MS (ESIpos): m/z = 419 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.415 (1.05), 1.425 (0.53), 1.434 (1.16), 1.444 (1.26), 1.453 (1.37),  1.464 (1.58), 1.472 (2.84), 1.489 (2.95), 1.507 (1.16), 1.972 (0.42), 1.984 (0.53), 1.991 (0.74), 2.002 (1.05),  2.010 (0.63), 2.013 (0.53), 2.021 (1.16), 2.033 (0.74), 2.039 (0.53), 2.051 (0.53), 2.099 (0.53), 2.117 (1.16),  2.135 (1.37), 2.154 (1.05), 2.172 (0.42), 2.331 (0.84), 2.518 (5.37), 2.522 (3.37), 2.673 (0.84), 2.874 (1.89),  2.891 (2.95), 2.909 (2.00), 3.003 (0.63), 3.020 (1.47), 3.032 (1.58), 3.045 (1.37), 3.063 (0.63), 3.197 (1.79),  3.216 (2.53), 3.235 (1.89), 3.589 (0.84), 3.608 (1.89), 3.628 (2.42), 3.646 (1.16), 3.688 (1.05), 3.700 (1.16),  3.709  (1.79),  3.721  (1.79),  3.730  (0.74),  3.741  (0.74),  3.793  (1.68),  3.811  (2.32),  3.831  (1.58),  4.029  (16.00), 4.202  (2.00), 4.220  (3.16), 4.237  (1.89), 6.520  (0.95), 6.535  (1.89), 6.549  (0.95), 6.978  (8.63),  7.596 (0.95), 7.599 (0.95), 7.614 (1.37), 7.616 (2.00), 7.633 (1.26), 7.636 (1.26), 7.710 (1.16), 7.714 (1.16),   
7.728 (1.05), 7.731 (1.89), 7.735 (1.47), 7.749 (1.05), 7.752 (1.05), 7.992 (2.00), 7.997 (2.32), 8.008 (1.79),  8.012 (1.68), 8.018 (2.00), 8.679 (2.74), 8.684 (2.84), 9.360 (4.00), 9.365 (4.00).  Example 130  N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide    Step  1:  To  a  solution  of  tert‐butyl  2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (750 mg, 1.992 mmol, see example 3) in DCM (15 mL) was added  under  nitrogen  trifluoroacetic  acid  (4.988  mL,  64,75  mmol).  The  reaction  was  stirred  at  ambient  temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2'‐ (quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  trifluoroacetate  (1:1) was used  in the next step without further purification. Step 2: Crude 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole] trifluoroacetate (109 mg, 40 % purity, 115 µmol) was dissolved in DCM (3.0  ml) and DIPEA  (200 µl, 1.1 mmol; CAS‐RN:[7087‐68‐5]) under nitrogen,  isocyanatoethane  (27 µl, 340  µmol) was added and the mixture was stirred overnight at rt. The solution was evaporated and purified  by preparative HPLC to yield the title compound (21.8 mg, 95 % purity, 54 % yield). LC‐MS (Method 1):  Rt = 0.73 min; MS (ESIpos): m/z = 337 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.002 (7.18), 1.020  (16.00), 1.038  (7.23), 2.332  (0.66), 2.518  (3.89), 2.523  (2.52), 2.539  (1.75), 2.840  (2.47), 2.858  (3.89),  2.875 (2.68), 3.008 (0.93), 3.026 (3.01), 3.039 (3.18), 3.043 (3.18), 3.057 (2.85), 3.076 (0.82), 3.980 (1.15),  4.003  (14.14), 4.023  (1.15), 4.141  (2.63), 4.150  (0.99), 4.159  (4.11), 4.176  (2.58), 6.447  (2.85), 6.452  (3.34), 6.456  (4.16), 6.460  (3.23), 6.470 (2.68), 6.484 (1.26), 6.734 (12.71), 7.456  (2.41), 7.463  (2.90),  7.470 (2.36), 8.272 (4.16), 8.278 (4.33), 8.656 (5.37), 8.661 (5.32), 11.642 (1.97).  The following compounds (example 131 to example 143) were synthesized in analogy to example 130:  Example 131    2'‐(2‐aminopyrimidin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide   
(prepared from tert‐butyl 2'‐(2‐aminopyrimidin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 4) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.58 min; MS (ESIpos): m/z = 314 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.991 (4.08), 1.009 (9.51), 1.026 (4.12), 2.331 (0.44), 2.518 (3.17),  2.522 (1.86), 2.673 (0.44), 2.813 (1.46), 2.831 (2.30), 2.848 (1.53), 2.995 (0.55), 3.013 (1.75), 3.027 (1.86),  3.031 (1.86), 3.044 (1.68), 3.062 (0.47), 3.327 (2.51), 3.371 (0.44), 3.376 (0.40), 3.945 (0.95), 3.965 (6.63),  3.970 (6.38), 3.990 (0.95), 4.098 (1.57), 4.107 (0.58), 4.116 (2.37), 4.132 (1.49), 6.444 (0.73), 6.458 (1.46),  6.473 (0.69), 6.621 (7.40), 6.716 (4.05), 8.595 (16.00).  Example 132    2'‐(6‐aminopyridin‐3‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from tert‐butyl 2'‐(6‐aminopyridin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 168) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.64 min; MS (ESIpos): m/z = 313 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 0.991  (5.82), 1.010  (13.28), 1.028  (6.20), 1.221  (0.42), 1.239  (1.99), 1.255 (1.91), 1.270 (1.15), 1.907 (0.88), 2.332 (1.22), 2.518 (7.96), 2.522 (5.01), 2.673 (1.26), 2.808  (2.33), 2.826 (3.83), 2.843 (2.49), 2.996 (0.84), 3.013 (2.68), 3.027 (2.99), 3.031 (2.95), 3.045 (2.60), 3.063  (0.77), 3.946  (0.88), 3.967  (16.00), 3.988  (0.96), 4.086  (2.49), 4.104  (3.90), 4.121  (2.37), 6.354  (0.80),  6.440 (1.26), 6.454 (2.45), 6.468 (1.22), 6.539 (1.84), 6.566 (8.57), 7.816 (1.26), 7.821 (1.26), 7.838 (1.22),  8.305 (3.37), 8.310 (3.33).  Example 133    N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 11) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.81 min; MS (ESIpos): m/z = 351 [M+H]⁺   
¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  0.932  (1.81),  0.935  (0.56),  0.948  (1.81),  1.004  (6.50),  1.021  (15.69), 1.039 (6.99), 2.270 (15.27), 2.273 (15.34), 2.331 (0.91), 2.336 (0.42), 2.518 (4.90), 2.523 (3.11),  2.678 (0.39), 2.844 (2.26), 2.861 (3.57), 2.879 (2.41), 3.010 (0.85), 3.027 (2.76), 3.041 (3.03), 3.045 (2.93),  3.059  (2.72), 3.077  (0.79), 3.983  (0.81), 4.004  (16.00), 4.025  (0.79), 4.139  (2.41), 4.158  (3.74), 4.174  (2.30), 5.759  (1.29), 6.456  (1.18), 6.470 (2.43), 6.484 (1.14), 6.765 (11.64), 7.218  (2.84), 7.221  (2.86),  8.241 (3.82), 8.245 (3.86), 8.632 (5.11), 8.637 (4.94), 11.279 (2.03).  Example 134    N‐ethyl‐2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from tert‐butyl 2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 12) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt = 0.65 min; MS (ESIpos): m/z = 350 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.009  (5.21), 1.026  (11.77), 1.045  (5.25), 2.518  (4.19), 2.522  (2.63), 2.673 (0.80), 2.886 (1.84), 2.903 (2.71), 2.921 (1.97), 3.016 (0.67), 3.034 (2.13), 3.048 (2.30), 3.051  (2.24), 3.066  (2.13), 3.084  (0.61), 4.030 (16.00), 4.237  (1.97), 4.255  (2.87), 4.272  (1.85), 5.758  (1.54),  6.490 (0.85), 6.504 (1.74), 6.518 (0.83), 7.181 (8.95), 8.780 (4.08), 8.786 (4.30), 9.063 (3.54), 9.067 (5.12),  9.086 (6.60), 9.090 (4.39), 9.654 (4.36), 9.660 (4.34).  Example 135    N‐ethyl‐2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared  from  tert‐butyl  2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 13) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt = 0.77 min; MS (ESIpos): m/z = 338 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  0.931  (1.78),  0.934  (0.60),  0.948  (1.82),  1.002  (5.26),  1.019  (12.08), 1.037  (5.23), 2.331  (0.61), 2.518  (3.26), 2.523  (2.08), 2.673  (0.63), 2.851  (1.89), 2.868  (2.84),  2.886  (2.01),  3.008  (0.67),  3.025  (2.19),  3.039  (2.38),  3.043  (2.32),  3.057  (2.14),  3.075  (0.61),  4.003   
(16.00), 4.170  (2.01), 4.188  (3.06), 4.205  (1.92), 5.759  (2.65), 6.468  (0.85), 6.482  (1.72), 6.496  (0.85),  6.908 (9.05), 7.134 (2.87), 7.137 (2.97), 7.140 (3.02), 7.143 (2.90), 8.308 (5.61), 8.313 (5.71), 8.318 (2.94),  8.320 (3.26), 8.322 (3.22), 8.325 (2.74), 8.997 (5.04), 9.002 (4.88).  Example 136    N‐ethyl‐2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from tert‐butyl 2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see example 16) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 366 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 0.932  (1.13), 0.948  (1.13), 1.007  (5.05), 1.025  (11.49), 1.043  (5.08), 2.327 (1.49), 2.331 (1.08), 2.336 (0.49), 2.518 (5.80), 2.522 (3.63), 2.669 (1.52), 2.673 (1.11), 2.678  (0.49), 2.873 (1.88), 2.891 (2.86), 2.908 (1.98), 3.014 (0.67), 3.032 (2.14), 3.046 (2.40), 3.050 (2.27), 3.064  (2.14), 3.082  (0.62), 4.021  (16.00), 4.205  (2.06), 4.223  (3.01), 4.240  (1.86), 5.758  (6.54), 6.476  (0.90),  6.490 (1.86), 6.504 (0.88), 6.985 (8.35), 7.610 (0.80), 7.617 (0.98), 7.633 (1.29), 7.640 (1.52), 7.655 (0.90),  7.662 (1.03), 7.780 (1.47), 7.787 (1.44), 7.804 (1.52), 7.811 (1.39), 8.054 (1.26), 8.068 (1.29), 8.077 (1.21),  8.090 (1.16), 8.685 (2.71), 8.690 (2.73), 9.338 (3.38), 9.343 (3.27).  Example 137    N‐ethyl‐2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  (prepared from tert‐butyl 2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 7) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.91 min; MS (ESIpos): m/z = 367 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 0.995  (5.14), 1.013  (11.74), 1.031  (5.06), 1.953  (2.20), 1.962  (2.65), 1.969 (6.37), 1.977 (2.64), 1.986 (2.33), 2.331 (0.42), 2.518 (2.39), 2.522 (1.51), 2.673 (0.42), 2.832  (1.84), 2.849 (2.82), 2.867 (1.95), 3.001 (0.65), 3.018 (2.17), 3.032 (2.33), 3.036 (2.29), 3.050 (2.08), 3.069  (0.61), 3.274  (2.28), 3.290  (5.92), 3.306 (2.35), 3.987 (16.00), 4.142  (1.95), 4.160  (2.93), 4.177  (1.85),   
5.758 (2.74), 6.450 (0.89), 6.464 (1.82), 6.478 (0.87), 6.795 (8.92), 7.189 (1.67), 7.194 (2.14), 7.196 (2.11),  7.201 (1.66), 7.843 (3.13), 7.850 (3.05), 8.246 (3.64), 8.250 (3.49).  Example 138    N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  (prepared from tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 10) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.65 min; MS (ESIpos): m/z = 338 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.002  (5.49), 1.020  (12.74), 1.038  (5.52), 2.331  (0.70), 2.518  (3.73), 2.522 (2.38), 2.673 (0.72), 2.850 (1.93), 2.867 (2.94), 2.884 (2.05), 3.008 (0.70), 3.026 (2.28), 3.040  (2.46), 3.044  (2.43), 3.058  (2.23), 3.076 (0.63), 4.005 (16.00), 4.161  (2.03), 4.179  (3.09), 4.196  (1.93),  5.758 (1.46), 6.464 (0.95), 6.478 (1.98), 6.492 (0.93), 6.832 (9.46), 8.156 (4.82), 8.524 (4.47), 8.529 (4.61),  8.977 (4.61), 8.982 (4.51), 13.669 (1.08).  Example 139    N‐ethyl‐2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 11) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt = 0.72 min; MS (ESIpos): m/z = 352 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.003 (3.84), 1.021 (9.00), 1.039 (4.05), 2.326 (0.74), 2.332 (0.54),  2.516  (16.00), 2.522  (2.96), 2.669  (0.77), 2.673  (0.61), 2.851  (1.37), 2.869  (2.19), 2.886  (1.47), 3.010  (0.51), 3.027  (1.66), 3.041  (1.78), 3.045 (1.78), 3.060 (1.60), 3.077 (0.47), 4.006 (11.39), 4.155  (1.46),  4.173 (2.29), 4.190 (1.43), 6.466 (0.73), 6.480 (1.52), 6.494 (0.71), 6.846 (6.56), 8.515 (2.92), 8.520 (2.95),  8.936 (2.84), 8.941 (2.84), 13.212 (1.28).  Example 140   
  N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 14) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.82 min; MS (ESIpos): m/z = 351 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.001  (6.46), 1.019  (15.34), 1.036  (6.93), 2.332  (0.75), 2.387  (13.81), 2.518  (4.79), 2.522  (3.03), 2.539  (0.78), 2.673  (0.75), 2.834  (2.33), 2.851  (3.74), 2.869  (2.51),  3.006  (0.85),  3.024  (2.80),  3.038  (3.03),  3.041  (3.01),  3.055  (2.73),  3.073  (0.80),  3.974  (0.85),  3.995  (16.00), 4.016  (0.87), 4.129  (2.49), 4.147  (3.90), 4.164  (2.37), 6.136  (2.56), 6.138  (3.41), 6.140  (3.45),  6.143  (2.68), 6.451  (1.22), 6.464  (2.54), 6.478  (1.20), 6.696  (10.69), 8.104  (3.81), 8.109  (3.92), 8.525  (4.93), 8.530 (4.93), 11.452 (2.28).  Example 141    N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 17) and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 365 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.003  (6.12), 1.021  (14.47), 1.039  (6.43), 1.251  (6.78), 1.265  (1.25), 1.270  (16.00), 1.289  (6.89), 2.332  (0.87), 2.518  (4.83), 2.523  (3.27), 2.673  (0.87), 2.679  (0.42),  2.692 (1.25), 2.710 (3.58), 2.711 (3.65), 2.729 (3.48), 2.730 (3.51), 2.749 (1.11), 2.842 (2.12), 2.860 (3.34),  2.877 (2.23), 3.009 (0.77), 3.027 (2.54), 3.041 (2.75), 3.045 (2.71), 3.059 (2.47), 3.077 (0.73), 3.159 (0.70),  3.172  (0.77), 3.983  (0.94), 4.005  (12.83), 4.026  (0.94), 4.140  (2.30), 4.149  (0.94), 4.158  (3.51), 4.175  (2.12), 6.456  (1.11), 6.470  (2.33), 6.484 (1.08), 6.775 (10.78), 7.218  (2.96), 7.221  (2.71), 7.224  (2.89),  8.260 (3.55), 8.265 (3.62), 8.630 (4.73), 8.635 (4.42), 11.297 (1.98).  Example 142   
  2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 169/intermediate 80)  and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  1.01 min; MS (ESIpos): m/z = 400 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.001  (5.48), 1.019  (12.29), 1.037  (5.57), 1.178  (4.33), 1.197  (10.08), 1.216  (4.51), 1.232  (0.53), 1.252  (0.53), 2.331  (0.97), 2.518  (6.81), 2.522  (4.42), 2.539  (0.80),  2.673 (1.59), 2.677 (1.41), 2.695 (3.09), 2.714 (3.01), 2.733 (0.97), 2.842 (1.94), 2.859 (3.18), 2.877 (2.12),  3.007 (0.71), 3.025 (2.39), 3.039 (2.65), 3.043 (2.56), 3.057 (2.30), 3.074 (0.71), 3.290 (0.44), 3.294 (0.44),  3.300  (0.44), 3.382  (0.80), 3.385  (0.62), 4.001  (16.00), 4.142  (2.03), 4.159  (3.27), 4.176  (2.03), 5.756  (4.86), 6.459 (1.06), 6.473 (2.21), 6.487 (1.06), 6.810 (8.84), 8.258 (3.80), 8.263 (3.89), 8.642 (4.51), 8.647  (4.33), 12.222 (2.92).  Example 143    N‐ethyl‐2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 8) and  isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.61 min; MS (ESIpos): m/z = 353 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 0.995  (5.26), 1.013  (12.28), 1.030  (5.68), 1.230  (0.78), 2.331  (0.68), 2.518 (4.96), 2.522 (3.09), 2.673 (0.70), 2.827 (2.02), 2.844 (3.28), 2.862 (2.16), 2.999 (0.75), 3.017  (2.39), 3.031  (2.64), 3.034  (2.66), 3.049 (2.33), 3.067 (0.70), 3.582 (6.73), 3.960 (0.54), 3.980 (16.00),   
4.120 (2.13), 4.138 (3.33), 4.155 (2.05), 6.450 (1.09), 6.464 (2.21), 6.478 (1.09), 6.702 (8.80), 7.898 (2.86),  7.900 (2.72), 7.902 (2.94), 8.467 (3.13), 8.472 (3.09), 11.030 (2.24).  Example 144  2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide    N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (45.0 mg, 128 µmol, see example 140) was dissolved in DMF (450 µl), NCS  (18.9 mg, 141 µmol; CAS‐RN:[128‐09‐6]) and diphenylperoxyanhydride (34.2 mg, 141 µmol; CAS‐RN:[94‐ 36‐0]) were added and the mixture was stirred overnight at rt. The mixture was quenched with an aq.  Na2S2O3 solution and extracted 3x with EtOAc. The combined organic layers were dried and evaporated.  The residue was purified by preparative HPLC to yield the title compound (15.0 mg, 95 % purity, 29 %  yield). LC‐MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 385 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ  [ppm]: 1.002 (3.80), 1.020 (9.10), 1.035 (8.56), 1.038 (4.47), 1.052 (16.00), 1.070 (8.72), 2.336 (0.43),  2.388  (10.99), 2.518  (5.71), 2.523  (3.91), 2.678  (0.43), 2.844  (1.24), 2.862  (1.93), 2.879  (1.33), 3.008  (0.47), 3.025 (1.57), 3.039 (1.66), 3.043 (1.66), 3.057 (1.51), 3.076 (0.45), 3.405 (1.17), 3.417 (1.21), 3.422  (3.62), 3.435 (3.64), 3.440 (3.64), 3.452 (3.75), 3.457 (1.10), 3.469 (1.03), 3.979 (0.63), 4.000 (6.52), 4.002  (6.90), 4.023 (0.63), 4.146 (1.33), 4.164 (2.04), 4.181 (1.28), 4.344 (2.27), 4.356 (4.45), 4.369 (2.18), 6.457  (0.67), 6.471  (1.42), 6.485  (0.65), 6.818  (6.49), 8.089  (2.61), 8.094  (2.52), 8.648  (2.90), 8.653  (2.88),  11.900 (1.39).  The following example was prepared in analogy to example 144:   Example 145    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide (see example 130)  LC‐MS (Method 1): Rt =  0.87 min; MS (ESIpos): m/z = 371 [M+H]⁺   
¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.003  (7.01), 1.021  (16.00), 1.035  (7.62), 1.039  (7.68), 1.052  (12.22), 1.070  (6.30), 2.322  (0.52), 2.326  (0.72), 2.331  (0.51), 2.522  (2.46), 2.664  (0.57), 2.668  (0.76),  2.673 (0.55), 2.850 (2.62), 2.867 (4.33), 2.884 (2.80), 3.009 (0.96), 3.027 (3.11), 3.041 (3.49), 3.044 (3.38),  3.059 (3.02), 3.077 (0.89), 3.404 (0.93), 3.417 (1.07), 3.422 (2.73), 3.435 (2.89), 3.439 (2.66), 3.452 (2.63),  3.457 (1.00), 3.469 (0.90), 3.983 (1.40), 4.004 (14.06), 4.006 (14.18), 4.027 (1.46), 4.155 (2.77), 4.172  (4.41), 4.189 (2.72), 4.344 (1.61), 4.356 (3.10), 4.369 (1.51), 6.461 (1.35), 6.475 (2.74), 6.489 (1.33), 6.855  (10.96), 7.687 (7.08), 8.223 (5.87), 8.228 (5.85), 8.760 (5.40), 8.765 (5.30), 12.002 (0.91).  Example 146  N‐ethyl‐2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide    To  a  solution  of  1‐(ethylcarbamoyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐2'‐yl  trifluoromethanesulfonate (100 mg, 271 µmol, intermediate 9)  in 1,4‐dioxane (4.3 ml) were added 6‐ (4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[3,2‐b]pyridine (133 mg, 543 µmol), K3PO4 (1.6  ml, 0.50 M, 810 µmol; CAS‐RN:[7778‐53‐2]) and XPhos Pd G2 (32.0 mg, 40.7 µmol; CAS‐RN:[14221‐01‐ 3]). The mixture was stirred overnight at 100°C. The mixture was diluted with EtOAc, washed with sat.  NaCl solution and the organic phase was dried and concentrated under reduced pressure. The mixture  was purified by preparative HPLC to yield the title compound (41.0 mg, 95 % purity, 43 % yield). LC‐MS  (Method 1): Rt = 0.69 min; MS (ESIpos): m/z = 337 [M+H]+. ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.904  (0.41), 1.004 (4.79), 1.021 (11.41), 1.039 (4.97), 1.751 (0.64), 2.518 (4.18), 2.523 (2.72), 2.540 (16.00),  2.728 (0.74), 2.846 (1.61), 2.863 (2.52), 2.881 (1.76), 2.888 (1.12), 3.009 (0.61), 3.027 (1.96), 3.041 (2.09),  3.044 (2.06), 3.059 (1.94), 3.077 (0.58), 3.981 (1.51), 4.002 (6.14), 4.011 (6.75), 4.032 (1.65), 4.151 (1.74),  4.161 (0.66), 4.170 (2.68), 4.186 (1.71), 6.457 (0.81), 6.471 (1.66), 6.485 (0.79), 6.530 (1.47), 6.533 (1.55),  6.536 (1.55), 6.593 (0.43), 6.596 (0.43), 6.599 (0.44), 6.786 (8.07), 7.621 (1.50), 7.629 (2.14), 7.636 (1.53),  7.673 (0.44), 7.680 (0.61), 7.687 (0.43), 8.018 (0.74), 8.021 (0.76), 8.023 (0.81), 8.026 (0.72), 8.052 (2.44),  8.054  (2.67), 8.057  (2.83), 8.059  (2.52), 8.661  (1.32), 8.666  (1.28), 8.774  (4.46), 8.779  (4.46), 11.347  (1.35).  Example 147  ethyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate   
  To  a  solution  of  ethyl  2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (66.0 mg, 179 µmol, see intermediate 19) in 1,4‐dioxane (2.8 ml) was added  under nitrogen at ambient temperature 5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐ b]pyridine (87.2 mg, 357 µmol), potassium phosphate solution  (1.1 ml, 0.50 M, 540 µmol; CAS‐RN:[7778‐ 53‐2]) and 2nd generation XPhos Pd (21.1 mg, 26.8 µmol; CAS‐RN:[14221‐01‐3]). The reaction mixture  was  stirred at 100°C overnight,  cooled  to ambient  temperature  and diluted with ethyl acetate. The  organic  layer was washed with brine, dried over sodium sulfate and  the solvent was removed under  reduced pressure. The crude product was purified via HPLC chromatography to yield the title compound  15.0 mg (95 % purity, 24 % yield). LC‐MS (Method 1): Rt = 0.93 min; MS (ESIpos): m/z = 338 [M+H]+. ¹H‐ NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.177 (7.10), 1.195 (16.00), 1.213 (7.36), 2.074 (0.69), 2.518 (4.35),  2.523 (2.84), 2.674 (0.69), 2.870 (2.23), 2.888 (3.45), 2.905 (2.35), 4.029 (1.99), 4.047 (6.21), 4.065 (6.08),  4.082 (1.92), 4.138 (4.62), 4.147 (4.71), 4.155 (6.19), 4.172 (2.96), 6.452 (2.02), 6.455 (2.12), 6.460 (2.14),  6.464  (1.99), 6.780  (10.22), 7.460  (1.71), 7.466  (2.00), 7.474  (1.71), 8.264  (3.99), 8.269  (4.09), 8.649  (4.55), 8.654 (4.45), 11.650 (1.45).  The following compounds (example 148 and example 149) were prepared in analogy to example 147:  Example 148    ethyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from ethyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate (see intermediate 19) and 3‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐ dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111637‐95‐6])  LC‐MS (Method 1): Rt =  1.00 min; MS (ESIneg): m/z = 350 [M‐H]⁻  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  1.036  (1.01),  1.053  (2.24),  1.071  (1.05),  1.178  (7.14),  1.195  (16.00), 1.213 (7.53), 2.271 (14.25), 2.274 (14.68), 2.518 (2.13), 2.523 (1.39), 2.872 (2.22), 2.889 (3.53),  2.906 (2.36), 4.031 (2.10), 4.048 (6.68), 4.066 (6.55), 4.084 (2.04), 4.136 (4.01), 4.154 (6.95), 4.170 (3.27),   
4.358  (0.44), 6.809  (11.10), 7.222  (2.71), 7.225  (2.72), 8.230  (3.61), 8.235  (3.73), 8.626  (4.62), 8.631  (4.60), 11.290 (1.86).  Example 149    ethyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared  from  prepared  from  ethyl  2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[azetidine‐ 3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see  intermediate  19)  and  3‐chloro‐5‐(4,4,5,5‐tetramethyl‐ 1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111638‐73‐3])  LC‐MS (Method 1): Rt =  1.05 min; MS (ESIneg): m/z = 370 [M‐H]⁻  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 0.905  (0.40), 1.178  (7.28), 1.196  (16.00), 1.213  (7.52), 1.232  (0.48), 2.337 (0.50), 2.518 (6.04), 2.523 (4.00), 2.540 (0.79), 2.678 (0.50), 2.878 (2.25), 2.895 (3.63), 2.912  (2.44), 4.030 (2.07), 4.048 (6.54), 4.066 (6.46), 4.084 (2.01), 4.151 (6.09), 4.168 (5.03), 4.186 (2.75), 5.759  (1.30), 6.897  (10.25), 7.692  (8.08), 8.089  (0.66), 8.211  (5.09), 8.216  (5.30), 8.752  (4.58), 8.756  (4.53),  12.015 (1.43).  Example 150  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]    Step  1:  To  a  solution  of  tert‐butyl  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (234  mg,  585  µmol,  see  example  170/intermediate 72) in dichloromethane (20 mL) was added under nitrogen at ambient temperature  trifluoro  acetic  acid  (1.5  ml,  19  mmol;  CAS‐RN:[76‐05‐1])  and  the  reaction  was  stirred  at  room  temperature  for  four hours. The  reaction was evaporated,  toluene was added and evaporated again  (repeated twice). The residue was dissolved  in toluene, dried over sodium sulfate and evaporated to  obtain  crude  trifluoroacetic  acid—2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole] (1/1) (412mg > 100%). This material was used in the  following step without further purification. LC‐MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 300   
[M+H]+. Step 2: To a solution of formaldehyde (20 µl, 37 % in water, 270 µmol; CAS‐RN:[50‐00‐0]) and  trifluoroacetic  acid—2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole] (1/1) (127 mg, 59 % purity, 181 µmol) in THF (2.5 ml) was added under nitrogen  at room temperature sodium triacetoxyborohydride (86.4 mg, 407 µmol; CAS‐RN:[76‐05‐1]) and acetic  acid (10 µl). The reaction was stirred at ambient temperature overnight, the solvent was removed under  reduced  pressure  and  the  crude  product  was  purified  by  HPLC  chromatography  to  yield  the  title  compound (6,0mg, 10,03%). 1H‐NMR (400 MHz, DMSO‐d6) delta [ppm]: 1.229 (0.48), 1.750 (0.99), 1.907  (0.45), 2.315  (16.00), 2.326  (3.19), 2.331  (1.92), 2.336  (0.96), 2.518  (6.64), 2.522  (4.44), 2.539  (1.41),  2.659 (0.67), 2.664 (1.44), 2.668 (1.92), 2.673 (1.41), 2.678 (0.67), 2.795 (3.86), 2.812 (5.65), 2.831 (4.02),  3.436 (3.93), 3.453 (2.87), 4.113 (4.31), 4.122 (1.44), 4.131 (6.04), 4.139 (1.44), 4.148 (4.12), 4.552 (2.01),  5.758  (1.12), 6.792  (15.55), 7.682  (6.74), 7.689  (6.87), 8.212  (5.68), 8.216  (5.94), 8.742  (0.42), 8.752  (7.57), 8.757 (7.50), 11.995 (2.52).  The following compounds (example 151 and example 152) were prepared in analogy to example 150:  Example 151    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 170/intermediate 72) and acetaldehyde, CAS‐RN:  [75‐07‐0])  LC‐MS (Method 1): Rt =  1.02 min; MS (ESIpos): m/z = 328 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 0.896  (6.24), 0.915  (15.16), 0.932  (6.50), 2.422  (1.67), 2.439  (5.66), 2.458 (5.82), 2.475 (2.28), 2.518 (4.15), 2.523 (2.78), 2.795 (3.29), 2.813 (4.82), 2.831 (3.59), 3.254  (5.32), 3.273 (7.08), 3.368 (6.95), 3.386 (5.15), 4.121 (3.59), 4.130 (1.15), 4.138 (5.10), 4.146 (1.15), 4.155  (3.46), 6.770  (16.00), 7.681  (4.95), 7.687  (4.97), 8.216  (5.73), 8.221  (5.88), 8.754  (6.59), 8.760  (6.52),  11.993 (2.13).  Example 152   
  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 170/intermediate 72) and aceton, CAS‐RN: [67‐64‐ 1])  LC‐MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 342 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.889 (15.82), 0.904 (16.00), 2.295 (0.42), 2.310 (1.11), 2.318  (0.60), 2.326 (2.36), 2.331 (1.16), 2.337 (0.69), 2.341 (1.11), 2.518 (4.62), 2.523 (3.10), 2.660 (0.42), 2.665  (0.92), 2.669 (1.29), 2.673 (0.88), 2.678 (0.42), 2.790 (2.22), 2.807 (3.24), 2.825 (2.40), 3.257 (3.42), 3.276  (4.49), 3.371 (4.62), 3.389 (3.33), 4.124 (2.36), 4.133 (0.88), 4.141 (3.42), 4.148 (0.92), 4.158 (2.31), 6.759  (10.08), 7.683 (3.93), 8.217 (4.67), 8.222 (4.76), 8.754 (4.39), 8.759 (4.30), 11.992 (1.39).  The following compound (example 153) was prepared in analogy to example 84:  Example 153  N N N NH N Cl H N CH3 N   2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared from tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 169/intermediate 80) and 1H‐imidazole‐2‐carbaldehyde, CAS‐RN: [10111‐08‐7)]  LC‐MS (Method 1): Rt =  0.91 min; MS (ESIpos): m/z = 408 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 0.832 (0.41), 0.851 (0.82), 0.867 (0.70), 0.886 (0.45), 0.905 (0.78),  1.182  (6.93), 1.201  (16.00), 1.219  (7.59), 1.232  (4.84), 1.256  (0.78), 1.278  (0.66), 1.296  (0.53), 1.352  (0.49), 1.395  (15.18), 1.420  (5.05), 2.318  (0.78), 2.323  (1.76), 2.327  (2.54), 2.332  (1.76), 2.337  (0.78),  2.518  (10.63), 2.523  (7.18), 2.660  (0.94), 2.665  (2.46), 2.669  (2.79), 2.674  (2.13), 2.683  (2.30), 2.702  (4.39), 2.721 (4.10), 2.740 (1.27), 2.796 (2.54), 2.813 (3.98), 2.831 (2.67), 3.436 (2.71), 3.454 (4.84), 3.482  (4.80), 3.499 (2.67), 3.672 (7.38), 3.853 (0.66), 3.870 (0.98), 3.887 (0.62), 3.977 (0.62), 3.992 (0.66), 4.106   
(2.87), 4.124  (4.27), 4.141  (2.75), 5.453 (2.71), 6.731 (13.42), 6.845  (0.90), 6.954  (4.02), 8.088  (1.35),  8.237 (5.95), 8.242 (6.15), 8.255 (0.45), 8.260 (0.45), 8.629 (7.79), 8.634 (7.59), 8.640 (0.70), 8.645 (0.62),  12.221 (3.45).  The following compounds (example 154 to example 156) were synthesized in analogy to example 1:  Example 154    tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from tert‐butyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see intermediate 17) and 1H‐pyrrolo[2,3‐b]pyridin‐5‐ylboronic  acid, CAS‐RN: [944059‐24‐9])  LC‐MS (Method 1): Rt =  1.16 min; MS (ESIpos): m/z = 394 [M+H]⁺  ¹H‐NMR  (500 MHz, DMSO‐d6)  δ  [ppm]: 1.430  (16.00), 1.622  (0.47), 2.422  (0.57), 2.436  (0.84), 2.450  (0.62), 2.514 (0.99), 2.518 (0.97), 2.522 (0.79), 4.164 (0.58), 4.179 (0.95), 4.192 (0.57), 5.758 (1.71), 6.440  (0.65), 6.443 (0.69), 6.447 (0.71), 6.450 (0.66), 6.766 (2.36), 7.451 (0.56), 7.456 (0.66), 7.462 (0.56), 8.273  (0.84), 8.276 (0.86), 8.661 (1.19), 8.665 (1.16), 11.622 (0.41).  Example 155    tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared from tert‐butyl 2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see intermediate 17) and 2‐methyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐ dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111638‐03‐9])  LC‐MS (Method 1): Rt =  1.21 min; MS (ESIpos): m/z = 408 [M+H]⁺   
1H‐NMR  (500 MHz, DMSO‐d6)  δ  [ppm]: 1.039  (0.97), 1.053  (2.06), 1.067  (1.04), 1.428  (16.00), 1.615  (0.56), 1.680 (0.48), 1.691 (0.40), 2.384 (3.68), 2.414 (0.64), 2.428 (1.01), 2.442 (0.70), 2.518 (1.33), 2.522  (1.01), 3.411 (0.42), 3.421 (0.40), 3.425 (0.64), 3.435 (0.59), 3.439 (0.54), 3.449 (0.50), 3.561 (0.46), 4.151  (0.63), 4.165 (1.07), 4.179 (0.62), 4.358 (0.61), 6.132 (0.88), 6.728 (2.20), 8.104 (0.93), 8.108 (0.97), 8.530  (1.14), 8.535 (1.18), 11.432 (0.61).  Example 156    tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (prepared  from  tert‐butyl  2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see  intermediate  17)  and  quinolin‐3‐ylboronic  acid,  CAS‐RN:  [191162‐39‐7])  LC‐MS (Method 1): Rt = 1.29 min; MS (ESIpos): m/z = 405 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.035  (1.19), 1.052  (2.20), 1.070  (1.28), 1.436  (16.00), 1.648  (0.46), 1.712 (0.45), 1.987 (0.52), 2.454 (0.63), 2.472 (0.99), 2.518 (0.75), 2.523 (0.51), 3.423 (0.62), 3.435  (0.61), 3.440 (0.60), 3.452 (0.53), 4.226 (0.58), 4.244 (0.93), 4.261 (0.57), 4.357 (0.46), 7.019 (2.26), 7.609  (0.40), 7.612 (0.56), 7.707 (0.41), 7.724 (0.59), 7.728 (0.46), 7.975 (0.51), 7.978 (0.53), 7.996 (1.29), 8.017  (0.52), 8.664 (0.79), 8.668 (0.79), 9.364 (1.25), 9.369 (1.23).  Example 157  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate    tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (60.0 mg, 152 µmol, see example 154) was dissolved  in DMF (610 µl), NCS (22.4 mg, 168  µmol; CAS‐RN:[128‐09‐6]) and diphenylperoxyanhydride (40.6 mg, 168 µmol; CAS‐RN:[94‐36‐0]) were  added and  the mixture was  stirred overnight at  rt. The mixture was quenched with an  aq. Na2S2O3  solution and extracted 3x with EtOAc. The combined organic  layers were dried and evaporated. The   
residue was purified by preparative HPLC and preparative TLC to yield the title compound (12.0 mg, 95  % purity, 17 % yield). LC‐MS (Method 1): Rt = 1.27 min; MS (ESIpos): m/z = 429 [M+H]+.  ¹H‐NMR (400  MHz, DMSO‐d6)  δ  [ppm]: 1.431  (16.00), 1.623  (0.48), 1.688  (0.50), 2.421  (0.60), 2.439  (0.96), 2.456  (0.78), 2.518 (3.08), 2.523 (2.05), 3.603 (0.43), 4.172 (0.57), 4.190 (0.95), 4.208 (0.57), 6.915 (2.17), 7.678  (2.17), 8.234 (1.48), 8.239 (1.52), 8.771 (1.21), 8.776 (1.19).  The following compound (example 158) was synthesized in analogy to example 157:   Example 158    tert‐butyl 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (prepared from tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example155).  LC‐MS (Method 1): Rt = 1.33 min; MS (ESIpos): m/z = 443 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.430  (16.00), 1.619  (0.45), 1.682  (0.52), 1.906  (1.19), 2.336  (0.61), 2.387 (5.02), 2.416 (0.58), 2.434 (0.87), 2.451 (0.74), 2.518 (8.27), 2.523 (5.70), 2.678 (0.61), 3.594  (0.42), 4.164 (0.55), 4.181 (0.90), 4.199 (0.55), 6.876 (2.35), 8.088 (0.42), 8.101 (1.26), 8.106 (1.26), 8.659  (1.22), 8.664 (1.26).  The following compounds (example 159 to example 162) were prepared in analogy to example 64:  Example 159    N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate (see example 156) and and isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt =  0.96 min; MS (ESIpos): m/z = 376 [M+H]⁺   
¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  0.916  (0.82),  0.930  (5.87),  0.947  (5.85),  1.015  (7.47),  1.033  (16.00), 1.051  (7.64), 1.591  (0.93), 1.601  (1.24), 1.624  (2.72), 1.634  (2.24), 1.646  (2.33), 1.655  (1.93),  1.688 (2.77), 1.701 (2.28), 1.726 (1.35), 2.323 (0.86), 2.326 (1.15), 2.331 (0.89), 2.385 (0.42), 2.403 (0.97),  2.421 (1.18), 2.451 (4.50), 2.469 (8.22), 2.665 (0.84), 2.668 (1.13), 2.673 (0.87), 2.940 (0.40), 2.956 (0.53),  3.045 (1.11), 3.063 (3.39), 3.076 (3.74), 3.080 (3.81), 3.094 (3.28), 3.112 (1.00), 3.355 (1.68), 3.364 (1.80),  3.378 (1.60), 3.388 (2.53), 3.398 (2.10), 3.411 (1.97), 3.419 (1.66), 3.535 (2.46), 3.548 (1.95), 3.557 (1.53),  3.573 (1.69), 4.225 (3.41), 4.243 (5.54), 4.260 (3.26), 5.758 (0.73), 6.527 (1.49), 6.541 (2.86), 6.554 (1.48),  6.982  (10.19), 7.592  (1.42), 7.610  (3.04), 7.629  (2.15), 7.701  (1.71), 7.704  (1.95), 7.722  (2.92), 7.725  (2.42), 7.739 (1.40), 7.742 (1.62), 7.976 (3.32), 7.994 (6.85), 8.015 (3.17), 8.672 (4.67), 8.677 (4.79), 9.368  (5.70), 9.374 (5.72).  Example 160    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and isocyanatoethane, CAS‐RN: [109‐90‐ 0])  LC‐MS (Method 1): Rt =  0.93 min; MS (ESIpos): m/z = 399 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.010  (7.20), 1.028  (16.00), 1.046  (7.53), 1.565  (0.73), 1.574  (0.93), 1.597 (2.13), 1.607 (1.67), 1.621 (1.73), 1.629 (1.47), 1.662 (2.13), 1.700 (1.07), 2.084 (0.60), 2.418  (2.73), 2.436  (4.40), 2.453  (3.20), 2.518 (10.27), 2.523  (6.67), 2.540  (1.00), 3.039  (0.93), 3.057  (2.93),  3.070 (3.20), 3.074 (3.13), 3.088 (2.87), 3.105 (0.87), 3.375 (2.73), 3.385 (1.87), 3.398 (1.67), 3.531 (1.87),  3.544 (1.47), 3.552 (1.13), 3.568 (1.33), 4.171 (2.67), 4.189 (4.33), 4.206 (2.60), 6.509 (1.27), 6.523 (2.47),  6.537  (1.20), 6.877  (9.67), 7.676  (9.53), 8.237  (6.40), 8.242  (6.47), 8.773  (5.53), 8.778  (5.47), 11.985  (1.00).  Example 161      2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 158) and and  isocyanatoethane, CAS‐RN: [109‐90‐0])  LC‐MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 413 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.009  (5.25), 1.027  (11.79), 1.045  (5.50), 1.570  (0.76), 1.592  (1.76), 1.603 (1.37), 1.615 (1.44), 1.658 (1.80), 1.694 (0.90), 2.084 (0.43), 2.323 (1.44), 2.327 (1.94), 2.331  (1.44), 2.386  (16.00), 2.413  (2.27), 2.431  (3.67), 2.449  (2.59), 2.522  (6.51), 2.539  (1.62), 2.665  (1.40),  2.669 (1.94), 2.673 (1.40), 3.038 (0.72), 3.055 (2.27), 3.069 (2.52), 3.073 (2.44), 3.086 (2.19), 3.104 (0.68),  3.374 (1.91), 3.384 (1.47), 3.398 (1.33), 3.524 (1.58), 3.561 (1.11), 4.162 (2.09), 4.180 (3.42), 4.197 (2.01),  6.506 (1.01), 6.519 (1.98), 6.532 (0.97), 6.837 (6.87), 8.103 (3.88), 8.108 (3.88), 8.661 (4.10), 8.666 (3.92),  11.877 (2.23).  Example 162 
Figure imgf000224_0001
  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared from tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 171) and and isocyanatoethane, CAS‐RN: [109‐90‐ 0])  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.010  (6.52), 1.028  (14.61), 1.046  (6.86), 1.232  (1.78), 1.565  (0.71), 1.574 (0.94), 1.597 (2.12), 1.607 (1.69), 1.620 (1.78), 1.629 (1.48), 1.662 (2.17), 1.676 (1.82), 1.700  (1.07), 2.084 (0.45), 2.271 (15.68), 2.273 (16.00), 2.322 (0.97), 2.326 (1.33), 2.331 (0.99), 2.415 (2.53),   
2.432 (4.35), 2.449 (2.96), 2.522 (5.02), 2.539 (1.31), 2.664 (0.97), 2.668 (1.31), 2.673 (0.99), 3.039 (0.86),  3.057 (2.75), 3.070 (3.05), 3.074 (3.00), 3.088 (2.70), 3.105 (0.82), 3.366 (1.42), 3.377 (2.08), 3.386 (1.67),  3.400 (1.57), 3.527 (1.91), 3.539 (1.52), 3.547 (1.20), 3.563 (1.37), 4.157 (2.60), 4.175 (4.27), 4.192 (2.53),  6.509 (1.22), 6.522 (2.38), 6.535 (1.20), 6.764 (8.77), 7.211 (3.35), 8.240 (4.10), 8.245 (4.29), 8.644 (4.20),  8.649 (4.12), 11.258 (2.42).  The following compounds (example 163 to example 167) were prepared in analogy to example 101:  Example 163    1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]ethan‐1‐one  (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and acetic acid, CAS‐RN: [64‐19‐7])  LC‐MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 370 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.595 (0.74), 1.605 (0.51), 1.618 (0.56), 1.628 (0.47), 1.682 (0.88),  1.693  (0.79),  1.704  (0.98),  1.716  (0.98),  1.726  (0.88),  1.738  (0.84),  1.753  (0.88),  1.764  (0.60),  2.053  (16.00), 2.323  (0.60), 2.327  (0.88), 2.331  (0.65), 2.439  (1.72), 2.457  (2.79), 2.475  (2.74), 2.523  (3.67),  2.665 (0.65), 2.669 (0.88), 2.673 (0.65), 3.394 (0.56), 3.402 (0.56), 3.426 (0.79), 3.436 (0.51), 3.450 (0.47),  3.552 (0.65), 3.561 (0.60), 3.574 (0.65), 3.585 (0.60), 3.591 (0.56), 3.604 (0.84), 3.616 (0.56), 3.801 (0.56),  3.813 (0.47), 3.821 (0.42), 3.835 (0.51), 4.186 (1.77), 4.203 (3.02), 4.220 (1.72), 6.903 (5.91), 7.678 (2.51),  7.685 (2.56), 8.227 (2.93), 8.231 (3.02), 8.768 (3.21), 8.773 (3.30), 11.990 (1.26).  Example 164    1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]‐2‐methylpropan‐1‐one   
(prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and 2‐methylpropanoic acid, CAS‐RN:  [79‐31‐2])  LC‐MS (Method 1): Rt =  1.05 min; MS (ESIpos): m/z = 398 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 0.971  (0.77), 0.988  (0.88), 0.993  (0.77), 1.025  (16.00), 1.041  (15.89), 1.230  (0.44), 1.572  (0.55), 1.595  (1.21), 1.620  (0.99), 1.690  (2.19), 1.714  (1.64), 1.752  (1.42),  1.789 (0.77), 2.322 (1.32), 2.327 (1.86), 2.332 (1.32), 2.443 (2.96), 2.462 (5.15), 2.522 (6.79), 2.539 (1.10),  2.665 (1.42), 2.669 (1.86), 2.673 (1.42), 2.899 (0.77), 2.916 (1.86), 2.933 (2.52), 2.949 (1.86), 2.966 (0.66),  3.292 (0.55), 3.385 (1.21), 3.423 (1.32), 3.449 (0.88), 3.568 (0.66), 3.594 (1.10), 3.618 (0.88), 3.703 (1.21),  3.738  (0.77),  3.852  (0.99),  3.887  (0.88),  4.185  (3.51),  4.202  (6.36),  4.220  (3.40),  5.757  (3.84),  6.937  (11.40), 7.675 (5.59), 7.682 (5.70), 8.232 (5.37), 8.236 (5.48), 8.773 (6.36), 8.778 (6.36), 11.983 (2.63).  Example 165    1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carbonyl]cyclopropane‐1‐carbonitrile  (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and 1‐cyanocyclopropanecarboxylic acid,  CAS‐RN: [6914‐79‐0])  LC‐MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 421 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.170 (0.73), 1.186 (0.73), 1.405 (0.88), 1.524 (4.40), 1.630 (8.51),  1.637  (6.17), 1.817  (2.20), 1.907  (0.73), 2.323  (2.06), 2.327  (2.79), 2.331  (2.06), 2.522  (10.42), 2.665  (2.20), 2.669 (2.94), 2.673 (2.20), 3.466 (0.88), 3.858 (1.17), 3.989 (0.88), 4.201 (5.14), 4.219 (8.95), 4.236  (4.84), 5.758  (0.59), 6.987  (16.00), 7.681  (8.81), 7.688  (8.95), 8.234  (8.37), 8.238  (8.51), 8.779  (9.69),  8.784 (9.69), 9.430 (0.44), 11.997 (4.55).  Example 166   
  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl](phenyl)methanone  (prepared from tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and benzoic acid, CAS‐RN: [65‐85‐0])  LC‐MS (Method 1): Rt =  1.10 min; MS (ESIpos): m/z = 432 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  1.711  (2.09),  2.326  (2.20),  2.331  (1.62),  2.336  (0.81),  2.518  (14.14), 2.522  (9.28), 2.668  (2.20), 2.673  (1.62), 2.678  (0.81), 3.493  (1.86), 3.580  (0.81), 4.037  (0.70),  4.207  (2.67), 5.758  (0.58), 6.978  (12.75), 7.423  (1.97), 7.430  (2.90), 7.440  (4.52), 7.445  (4.75), 7.448  (7.77), 7.455  (4.64), 7.457  (5.22), 7.463 (16.00), 7.470  (8.23), 7.475  (3.83), 7.480  (4.29), 7.488  (1.04),  7.685 (7.07), 8.226 (7.77), 8.231 (8.12), 8.771 (7.19), 8.776 (7.30), 11.993 (2.43).  Example 167    [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl](oxan‐4‐yl)methanone  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydro‐1H‐spiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see  example  157)  and  tetrahydro‐2H‐pyran‐4‐carboxylic  acid, CAS‐RN: [5337‐03‐1])  LC‐MS (Method 1): Rt =  0.95 min; MS (ESIpos): m/z = 440 [M+H]⁺  ¹H‐NMR (600 MHz, DMSO‐d6) δ [ppm]: 0.850 (0.55), 1.230 (2.22), 1.531 (1.06), 1.552 (2.48), 1.575 (2.06),  1.593 (1.35), 1.599 (2.38), 1.620 (2.87), 1.628 (1.74), 1.640 (1.74), 1.647 (1.13), 1.662 (0.71), 1.670 (0.90),  1.677 (0.80), 1.692 (2.61), 1.699 (2.03), 1.708 (1.77), 1.714 (1.67), 1.759 (1.29), 1.782 (0.74), 2.378 (0.58),  2.381 (1.38), 2.384 (1.96), 2.387 (1.42), 2.390 (0.61), 2.447 (2.90), 2.449 (2.74), 2.458 (4.89), 2.462 (4.96),    2.472 (3.35), 2.515 (5.51), 2.518 (5.76), 2.521 (4.57), 2.606 (0.61), 2.609 (1.38), 2.612 (1.90), 2.615 (1.32),  2.618 (0.58), 2.919 (0.58), 2.925 (1.13), 2.932 (0.68), 2.938 (1.26), 2.944 (2.22), 2.950 (1.13), 2.956 (0.71),  2.963 (1.09), 2.969 (0.52), 3.387 (2.58), 3.390 (2.61), 3.406 (5.76), 3.410 (5.54), 3.425 (4.02), 3.429 (3.64),  3.445 (0.84), 3.590 (0.74), 3.607 (1.26), 3.614 (0.93), 3.624 (0.90), 3.736 (1.16), 3.744 (0.93), 3.752 (0.74),  3.761 (0.87), 3.845 (3.61), 3.849 (4.06), 3.852 (3.80), 3.861 (3.38), 3.865 (3.41), 3.868 (3.54), 4.192 (4.22),  4.198 (1.09), 4.204 (8.82), 4.210 (1.13), 4.216 (4.25), 6.934 (16.00), 7.683 (14.45), 8.088 (0.68), 8.229  (9.95), 8.232 (10.78), 8.772 (9.21), 8.775 (8.92), 11.999 (2.51).  The following compounds (intermediate 168 to intermediate 171) were prepared in analogy to example 1: Example 168    tert‐butyl 2'‐(6‐aminopyridin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (prepared from intermediate 6 and (6‐aminopyridin‐3‐yl)boronic acid, CAS‐RN: [851524‐96‐4])  LC‐MS (Method 1): Rt =  0.98 min; MS (ESIpos): m/z = 342 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.383  (4.76), 1.394  (16.00), 2.518  (0.86), 2.522  (0.58), 2.807  (0.58), 2.824 (0.86), 2.833 (0.43), 2.841 (0.58), 4.031 (0.86), 4.041 (1.01), 4.045 (1.01), 4.055 (1.15), 4.072  (1.15), 4.089 (0.58), 5.712 (9.80), 5.962 (1.44), 6.220 (0.43), 6.451 (0.72), 6.453 (0.72), 6.473 (0.72), 6.474  (0.72), 6.545 (3.03), 7.706 (0.58), 7.712 (0.58), 7.727 (0.58), 7.733 (0.58), 8.290 (0.72), 8.296 (0.72).  Example 169/Intermediate 80 
Figure imgf000228_0001
tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate   
(prepared from intermediate 6 and 2‐chloro‐3‐ethyl‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐ 1H‐pyrrolo[2,3‐b]pyridine, (preparation described in WO 2018/167147))  LC‐MS (Method 1): Rt = 1.31 min; MS (ESIpos): m/z = 428 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.180  (0.69), 1.199  (1.60), 1.218  (0.70), 1.394  (16.00), 1.419  (7.84), 2.518 (1.28), 2.523 (0.84), 2.665 (0.83), 2.669 (0.49), 2.673 (0.41), 2.681 (1.03), 2.698 (0.96), 2.716  (0.42), 2.872 (0.45), 3.853 (0.69), 3.870 (1.00), 3.887 (0.65), 3.976 (0.62), 3.991 (0.71), 4.150 (0.46), 5.452  (3.21), 6.845 (1.45), 8.255 (0.62), 8.260 (0.64), 8.640 (0.77), 8.645 (0.77), 9.651 (0.41).  Example 170/Inermediate 72    tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  (prepared  from  intermediate  6  and  and  3‐chloro‐5‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1H‐ pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111638‐73‐3])  LC‐MS (Method 1): Rt = 1.21 min; MS (ESIpos): m/z = 400 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.065  (2.29), 1.172  (0.54), 1.394  (2.93), 1.420  (16.00), 1.987  (0.87), 2.518 (1.35), 2.522 (0.89), 2.862 (0.56), 2.879 (0.87), 2.896 (0.59), 4.089 (0.97), 4.144 (0.62), 4.162  (0.95), 4.179 (0.57), 5.451 (0.52), 6.890 (3.02), 7.689 (0.79), 7.692 (0.80), 8.217 (1.21), 8.222 (1.26), 8.756  (1.24), 8.760 (1.22), 12.010 (0.41).  Example 171    tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate   
(prepared  from  tert‐butyl  2'‐[(trifluoromethanesulfonyl)oxy]‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see  intermediate 17) and and 3‐methyl‐5‐(4,4,5,5‐tetramethyl‐ 1,3,2‐dioxaborolan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridine, CAS‐RN: [1111637‐95‐6])  LC‐MS (Method 1): Rt =  1.19 min; MS (ESIpos): m/z = 408 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.431  (16.00), 1.622  (0.51), 1.645  (0.42), 1.685  (0.54), 1.697  (0.42), 2.272 (3.89), 2.275 (3.87), 2.416 (0.62), 2.434 (1.01), 2.451 (0.74), 2.518 (2.23), 2.522 (1.61), 2.539  (0.55), 3.594 (0.47), 4.157 (0.60), 4.175 (0.99), 4.193 (0.60), 5.758 (0.40), 6.804 (2.09), 7.211 (0.77), 7.214  (0.76), 8.237 (0.97), 8.242 (1.00), 8.642 (1.25), 8.647 (1.22), 11.259 (0.54).  The following compounds (example 172 to example 175) were prepared in analogy to example 111:  Example 172    [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl](morpholin‐4‐yl)methanone  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and morpholine, CAS‐RN: [110‐91‐8])  LC‐MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 441 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.644 (1.02), 1.654 (1.40), 1.676 (3.48), 1.688 (2.95), 1.698 (3.14),  1.710 (3.96), 1.724 (4.21), 1.735 (3.00), 1.758 (1.60), 1.906 (0.77), 2.336 (0.92), 2.428 (4.59), 2.446 (7.44),  2.463 (6.04), 2.518 (10.39), 2.522 (7.15), 2.539 (3.77), 2.678 (0.97), 3.146 (7.35), 3.158 (10.49), 3.169  (8.02), 3.295  (1.89), 3.379  (3.96), 3.391 (2.66), 3.414 (1.84), 3.577 (8.41), 3.589 (10.54), 3.599  (7.44),  4.175  (4.50), 4.193  (7.01), 4.210  (4.30), 5.758  (2.95), 6.898  (16.00), 7.676  (6.53), 7.681  (6.57), 8.233  (8.99), 8.238 (9.18), 8.771 (9.52), 8.775 (9.38), 11.984 (3.00).  Example 173     
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and N‐methylmethanamine, CAS‐RN: [124‐ 40‐3])  LC‐MS (Method 1): Rt =  1.00 min; MS (ESIpos): m/z = 399 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.681 (0.59), 1.692 (0.49), 1.701 (0.56), 1.713 (0.79), 1.725 (0.75),  1.737  (0.52), 2.430  (0.81), 2.447  (1.28), 2.465  (1.06), 2.518  (1.18), 2.522  (0.79), 2.765  (16.00), 3.266  (0.56), 3.276 (0.50), 3.288 (0.62), 3.297 (0.83), 3.309 (0.90), 4.174 (0.81), 4.192 (1.22), 4.209 (0.76), 6.891  (2.92), 7.678 (1.91), 8.241 (1.98), 8.246 (1.99), 8.776 (1.65), 8.781 (1.63), 11.982 (0.58).  Example 174    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2‐hydroxy‐2‐methylpropyl)‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 157) and and 1‐amino‐2‐methylpropan‐2‐ol, CAS‐ RN: [2854‐16‐2])  LC‐MS (Method 1): Rt =  0.89 min; MS (ESIpos): m/z = 443 [M+H]⁺  ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]: 1.054  (16.00), 1.616  (0.75), 1.626  (0.60), 1.639  (0.60), 1.648  (0.50), 1.683 (0.75), 1.695 (0.65), 2.426 (0.89), 2.444 (1.49), 2.461 (1.09), 2.518 (2.68), 2.523 (1.74), 3.041  (1.84), 3.055 (1.84), 3.159 (1.59), 3.171 (1.59), 3.314 (0.70), 3.393 (0.75), 3.406 (0.60), 3.417 (0.84), 3.427  (0.60), 3.440 (0.55), 3.582 (0.65), 3.594 (0.50), 3.603 (0.40), 3.618 (0.50), 4.176 (0.94), 4.194 (1.54), 4.211  (0.89), 4.687 (2.34), 6.452 (0.40), 6.467 (0.84), 6.889 (3.38), 7.675 (3.58), 8.240 (2.34), 8.245 (2.43), 8.776  (1.99), 8.781 (1.99).  Example 175   
Figure imgf000232_0001
  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐methyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and methanamine, CAS‐RN: [74‐89‐5])  LC‐MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 385 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.229 (0.40), 1.564 (1.00), 1.574 (1.20), 1.596 (2.80), 1.606 (2.20),  1.619 (2.40), 1.628 (1.80), 1.660 (2.80), 1.673 (2.20), 1.697 (1.40), 2.331 (1.40), 2.336 (0.60), 2.416 (3.60),  2.434 (6.00), 2.452 (4.60), 2.518 (8.40), 2.522 (5.60), 2.539 (1.20), 2.586 (16.00), 2.596 (15.80), 2.673  (1.60), 2.678 (0.60), 3.400 (3.00), 3.519 (2.60), 3.532 (2.00), 3.541 (1.60), 3.556 (1.80), 4.168 (3.60), 4.187  (5.60), 4.204  (3.40), 5.755  (6.40), 6.470 (1.00), 6.480 (2.60), 6.491 (2.60), 6.501 (0.80), 6.872 (13.40),  7.673 (12.80), 8.233 (8.80), 8.238 (9.00), 8.770 (7.40), 8.775 (7.20), 11.983 (1.00).  The following compounds (example 176 and example 177) were prepared in analogy to example 70:   Example 176    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see  example  157)  and  and  1,1,1‐trifluoro‐2‐isocyanatoethane,  CAS‐RN: [371‐92‐6])  LC‐MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 453 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.588 (1.10), 1.597 (1.66), 1.619 (3.59), 1.629 (2.76), 1.643 (2.76),  1.651  (2.48), 1.688  (3.59), 1.725  (1.93), 2.428  (4.69), 2.446  (8.00), 2.464  (7.45), 2.518  (12.14), 2.522  (8.00), 3.394 (3.03), 3.397 (3.31), 3.407 (3.03), 3.433 (3.86), 3.442 (3.03), 3.457 (2.76), 3.612 (3.31), 3.624   
(2.48), 3.633 (1.93), 3.647 (2.48), 3.811 (1.10), 3.835 (3.03), 3.851 (3.31), 3.860 (3.03), 3.875 (3.03), 3.899  (0.83), 4.175  (4.41), 4.193  (7.17), 4.210 (4.14), 6.907 (15.45), 7.192  (1.93), 7.207  (4.14), 7.222  (1.93),  7.674 (16.00), 8.237 (9.93), 8.242 (10.21), 8.773 (9.10), 8.778 (8.83), 11.983 (1.10).  Example 177    N‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and (isocyanatomethyl)benzene, CAS‐RN:  [3173‐56‐6])  LC‐MS (Method 1): Rt =  1.07 min; MS (ESIpos): m/z = 461 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.594 (1.08), 1.604 (1.36), 1.627 (2.98), 1.636 (2.17), 1.650 (2.44),  1.658 (1.90), 1.691 (2.98), 1.703 (2.44), 1.729 (1.36), 2.337 (0.81), 2.432 (3.80), 2.450 (5.97), 2.467 (5.15),  2.518  (10.85), 2.523  (7.32), 2.679  (0.81), 3.299  (1.08), 3.391  (1.36), 3.399  (1.90), 3.410  (2.17), 3.425  (1.90), 3.434 (2.71), 3.444 (2.17), 3.457 (1.90), 3.602 (2.44), 3.614 (1.90), 3.623 (1.63), 3.638 (1.90), 4.177  (3.80), 4.195  (5.97), 4.213  (3.80), 4.266 (6.78), 4.281 (6.78), 6.895 (15.46), 7.136  (1.63), 7.151  (3.53),  7.166 (1.63), 7.196 (0.81), 7.200 (1.63), 7.204 (0.81), 7.211 (1.08), 7.218 (4.07), 7.230 (1.63), 7.235 (2.71),  7.238  (1.63), 7.268  (4.07), 7.285  (10.31), 7.289  (7.59), 7.303  (9.49), 7.309  (2.44), 7.321  (7.86), 7.336  (1.08), 7.340 (2.71), 7.676 (16.00), 8.240 (10.85), 8.245 (11.12), 8.777 (8.68), 8.782 (8.41), 11.985 (0.81).  The following compounds (example 178 and example 179) were prepared in analogy to example 101:   Example 178    1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]‐2‐hydroxyethan‐1‐one   
(prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and hydroxyacetic acid, CAS‐RN: [79‐14‐ 1])  LC‐MS (Method 1): Rt =  386.00 min; MS (ESIpos): m/z = 1 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.052 (0.71), 1.230 (0.57), 1.608 (0.57), 1.631 (1.29), 1.641 (1.00),  1.655 (1.14), 1.665 (1.14), 1.720 (2.43), 1.731 (2.71), 1.744 (2.29), 2.443 (3.86), 2.461 (6.14), 2.479 (5.71),  2.518 (7.57), 2.523 (5.29), 2.539 (5.86), 2.679 (0.57), 3.159 (4.57), 3.171 (4.71), 3.305 (1.14), 3.310 (1.29),  3.393 (1.29), 3.401 (0.71), 3.446 (1.29), 3.471 (2.57), 3.481 (2.43), 3.495 (2.57), 3.537 (0.57), 3.833 (1.14),  3.844 (0.86), 3.867 (0.86), 4.094 (0.57), 4.107 (1.00), 4.130 (3.00), 4.140 (5.00), 4.151 (3.00), 4.186 (4.29),  4.204 (6.29), 4.221 (3.86), 4.554 (1.29), 4.567 (2.43), 4.580 (1.14), 6.911 (16.00), 7.679 (15.29), 8.224  (10.29), 8.229 (10.43), 8.767 (8.14), 8.772 (8.14), 11.995 (0.71).  Example 179    1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]‐2‐(pyridin‐3‐yl)ethan‐1‐one  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and pyridin‐3‐ylacetic acid, CAS‐RN: [501‐ 81‐5])  LC‐MS (Method 1): Rt =  0.93 min; MS (ESIpos): m/z = 447 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.230 (0.62), 1.588 (0.62), 1.598 (0.82), 1.621 (1.64), 1.631 (1.44),  1.644 (1.85), 1.655 (1.44), 1.667 (1.64), 1.677 (1.23), 1.700 (1.85), 1.740 (2.26), 1.774 (0.82), 2.318 (0.62),  2.439 (3.90), 2.456 (6.15), 2.474 (5.13), 2.518 (9.23), 2.523 (6.36), 2.539 (0.62), 2.679 (0.62), 3.159 (1.23),  3.171 (1.23), 3.290 (0.41), 3.309 (1.23), 3.324 (3.08), 3.391 (1.44), 3.396 (0.82), 3.404 (0.82), 3.418 (0.41),  3.444 (1.03), 3.468 (1.64), 3.478 (1.03), 3.492 (1.03), 3.501 (0.82), 3.618 (0.82), 3.643 (1.23), 3.653 (1.03),  3.667  (1.03), 3.758  (1.44), 3.783  (0.82), 3.795  (1.03), 3.825  (14.77), 3.848  (1.44), 3.861  (1.03), 3.883  (1.03), 4.185  (4.10), 4.202  (6.77), 4.219 (3.90), 5.756 (5.13), 6.915 (16.00), 7.340  (2.87), 7.342  (2.87),  7.352 (3.08), 7.354 (3.08), 7.359 (3.28), 7.361 (3.28), 7.371 (3.49), 7.373 (3.49), 7.646 (2.26), 7.651 (3.49),  7.656 (2.46), 7.665 (2.05), 7.671 (3.28), 7.675 (2.87), 7.681 (14.56), 8.229 (10.87), 8.234 (10.87), 8.440  (4.51), 8.445  (4.92), 8.452  (4.92), 8.457  (5.54), 8.461  (5.95), 8.466  (5.54), 8.770  (9.03), 8.775  (9.03),  11.992 (1.64).  The following compounds (example 180 to example 184) were prepared in analogy to example 62:    
Example 180    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(phenylmethanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and phenylmethanesulfonyl chloride, CAS‐ RN: [1939‐99‐7])  LC‐MS (Method 1): Rt =  1.19 min; MS (ESIpos): m/z = 482 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.231 (0.60), 1.659 (1.13), 1.669 (1.49), 1.691 (3.66), 1.702 (2.96),  1.715 (3.16), 1.724 (2.78), 1.749 (4.35), 1.784 (1.91), 2.075 (0.85), 2.327 (1.21), 2.399 (4.05), 2.416 (7.00),  2.434 (4.43), 2.669 (1.23), 3.186 (1.99), 3.209 (3.80), 3.233 (2.52), 3.349 (4.23), 3.361 (2.96), 3.382 (2.64),  4.172 (4.15), 4.189 (6.92), 4.207 (4.03), 4.526 (16.00), 6.763 (12.02), 7.369 (1.07), 7.386 (3.52), 7.394  (1.69), 7.404 (4.67), 7.408 (3.70), 7.415 (6.14), 7.433 (8.47), 7.450 (3.42), 7.508 (8.75), 7.525 (5.88), 7.694  (6.92), 7.701 (7.02), 8.218 (6.66), 8.222 (6.82), 8.789 (7.37), 8.794 (7.31), 12.021 (3.94).  Example 181    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propane‐1‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and propane‐1‐sulfonyl chloride, CAS‐RN:  [10147‐36‐1])  LC‐MS (Method 1): Rt =  1.10 min; MS (ESIpos): m/z = 435 [M+H]⁺    ¹H‐NMR  (400 MHz, DMSO‐d6)  δ  [ppm]:  1.009  (0.79),  1.014  (0.65),  1.021  (6.96),  1.033  (1.42),  1.040  (16.00), 1.051  (0.91), 1.058  (7.39), 1.705  (0.74), 1.723  (2.27), 1.729  (1.34), 1.742  (3.98), 1.747  (2.04),  1.761 (4.91), 1.774 (2.39), 1.780 (3.14), 1.784 (2.48), 1.796 (1.94), 1.805 (1.74), 1.816 (2.39), 1.829 (1.90),  1.838  (1.02), 1.853  (1.02), 1.861  (0.79), 2.075  (10.67), 2.444  (2.74), 2.461  (4.41), 2.479  (3.43), 2.518  (2.28), 2.523 (1.47), 3.091 (3.65), 3.105 (2.65), 3.111 (3.72), 3.116 (2.76), 3.130 (3.45), 3.269 (0.93), 3.277  (1.13), 3.299 (2.26), 3.309 (1.77), 3.361 (1.35), 3.373 (2.22), 3.385 (1.65), 3.406 (1.18), 3.417 (0.68), 4.186  (2.77), 4.204  (4.40), 4.221  (2.72), 6.230 (0.52), 6.875 (10.12), 7.684  (5.11), 7.691  (5.09), 8.225  (4.36),  8.229 (4.48), 8.788 (5.48), 8.792 (5.39), 12.003 (2.16), 12.008 (2.16).  Example 182 
Figure imgf000236_0001
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐sulfonamide  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  (see example 157) and and dimethylsulfamyl chloride, CAS‐RN:  [13360‐57‐1])  LC‐MS (Method 1): Rt =  1.07 min; MS (ESIpos): m/z = 435 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.766 (0.43), 1.784 (0.44), 1.799 (0.56), 2.448 (0.52), 2.466 (0.82),  2.484  (0.75), 2.518  (0.44), 2.796  (16.00), 3.340  (0.54), 3.351  (0.70), 3.360  (1.01), 3.371  (0.58), 4.180  (0.52), 4.198 (0.81), 4.215 (0.50), 6.859 (1.94), 7.680 (0.84), 7.686 (0.84), 8.238 (0.86), 8.243 (0.89), 8.787  (1.05), 8.792 (1.03).  Example 183     
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(pyridine‐3‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and pyridine‐3‐sulfonyl chloride, CAS‐RN:  [16133‐25‐8])  LC‐MS (Method 1): Rt =  1.04 min; MS (ESIpos): m/z = 469 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.230 (0.43), 1.723 (1.35), 1.737 (2.67), 1.755 (3.67), 1.772 (4.62),  1.786 (2.74), 1.813 (2.63), 1.825 (4.97), 1.839 (3.50), 1.859 (2.76), 1.872 (1.39), 2.075 (4.41), 2.323 (1.22),  2.327 (1.95), 2.335 (5.47), 2.352 (8.29), 2.370 (5.36), 2.522 (4.86), 2.665 (0.96), 2.669 (1.32), 2.673 (1.00),  2.796  (0.76), 3.195  (6.60), 3.208  (10.85), 3.222  (6.47), 4.124  (5.19), 4.142  (8.34), 4.159  (5.06), 6.347  (16.00), 7.690  (7.47), 7.696  (7.69), 7.745  (3.69), 7.757  (3.84), 7.763  (3.82), 7.765  (3.93), 7.777  (3.95),  8.078 (9.20), 8.083 (9.62), 8.248 (3.19), 8.253 (4.19), 8.258 (3.36), 8.268 (3.00), 8.274 (3.93), 8.278 (3.06),  8.662 (9.99), 8.667 (9.99), 8.952 (5.69), 8.956 (5.97), 8.964 (5.84), 8.968 (5.67), 9.008 (7.55), 9.012 (7.51),  12.007 (3.91).  Example 184    2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(morpholine‐4‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]  (prepared  from  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate (see example 157) and and morpholine‐4‐sulfonyl chloride, CAS‐ RN: [1828‐66‐6])  LC‐MS (Method 1): Rt =  1.05 min; MS (ESIpos): m/z = 477 [M+H]⁺  ¹H‐NMR (400 MHz, DMSO‐d6) δ [ppm]: 1.231 (0.60), 1.722 (1.26), 1.734 (1.91), 1.755 (4.37), 1.768 (4.84),  1.786 (6.17), 1.799 (6.25), 1.810 (4.28), 1.834 (2.23), 2.075 (2.57), 2.323 (1.03), 2.327 (1.35), 2.332 (1.07),  2.454 (5.55), 2.472 (10.17), 2.540 (12.51), 2.665 (1.01), 2.669 (1.35), 2.673 (1.01), 3.140 (10.92), 3.151  (14.65), 3.162 (11.91), 3.209 (0.62), 3.351 (1.80), 3.374 (4.90), 3.386 (8.10), 3.399 (9.98), 3.433 (1.46),  3.648 (12.10), 3.660 (14.37), 3.671 (11.05), 4.142 (0.41), 4.182 (5.23), 4.200 (8.65), 4.217 (5.08), 6.348   
(0.56), 6.879  (16.00), 7.682  (7.75), 7.688  (8.14), 8.235  (8.63), 8.240  (8.97), 8.785  (9.47), 8.789  (9.40),  11.999 (4.31).  The following compounds (example 185 to example 200) were prepared in analogy to example 64: Example 185 2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 365 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.042 (0.42), 1.058 (15.83), 1.075 (16.00), 1.136 (0.42), 1.153 (0.42), 2.270 (10.99), 2.273 (11.14), 2.322 (0.45), 2.326 (0.61), 2.331 (0.46), 2.522 (1.59), 2.665 (0.45), 2.669 (0.63), 2.673 (0.47), 2.839 (1.68), 2.857 (2.74), 2.874 (1.80), 3.707 (0.63), 3.724 (0.91), 3.744 (0.92), 3.760 (0.64), 3.976 (0.45), 3.997 (13.49), 4.017 (0.46), 4.139 (1.78), 4.157 (2.85), 4.174 (1.72), 6.232 (1.80), 6.252 (1.78), 6.769 (7.74), 7.219 (2.24), 7.221 (2.23), 8.243 (2.86), 8.247 (3.01), 8.634 (3.52), 8.639 (3.52), 11.284 (1.59).  Example 186 N-tert-butyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 379 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.198 (0.54), 1.241 (0.48), 1.268 (16.00), 2.271 (3.86), 2.274 (4.07), 2.539 (0.59), 2.827 (0.61), 2.845 (1.00), 2.862 (0.65), 3.993 (4.19), 4.137 (0.65), 4.155 (1.04), 4.172 (0.64), 5.830 (1.36), 6.756 (2.73), 7.219 (0.81), 7.221 (0.81), 8.247 (1.02), 8.251 (1.06), 8.637 (1.26), 8.642 (1.25), 11.285 (0.59).   
Example 187 2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  LC-MS (Method 1): Rt = 1.06 min; MS (ESIpos): m/z = 403 [M-H]- ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.058 (15.94), 1.075 (16.00), 1.885 (0.56), 1.914 (0.75), 1.984 (0.54), 2.007 (1.00), 2.031 (0.94), 2.052 (0.48), 2.057 (0.54), 2.084 (1.71), 2.157 (1.29), 2.164 (1.21), 2.180 (1.60), 2.186 (1.85), 2.202 (0.88), 2.209 (1.25), 2.331 (0.94), 2.337 (0.85), 2.344 (0.75), 2.357 (1.17), 2.364 (1.75), 2.372 (0.96), 2.378 (0.98), 2.385 (1.60), 2.392 (0.92), 2.399 (0.42), 2.406 (0.52), 2.518 (3.83), 2.522 (2.46), 2.837 (1.65), 2.855 (2.71), 2.872 (1.73), 3.674 (0.87), 3.695 (1.37), 3.707 (0.71), 3.715 (0.92), 3.723 (1.00), 3.743 (0.92), 3.759 (0.60), 3.975 (0.79), 3.997 (10.25), 4.018 (0.77), 4.141 (1.73), 4.159 (2.79), 4.176 (1.67), 6.230 (1.87), 6.250 (1.83), 6.783 (7.56), 7.270 (2.37), 7.274 (2.33), 8.240 (2.90), 8.245 (2.94), 8.628 (3.56), 8.633 (3.46), 11.342 (1.65).  Example 188 N-tert-butyl-2'-(3-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  LC-MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 837 [2M+H]+¹H-NMR (400 MHz, DMSO- d6) δ [ppm]: 1.239 (0.65), 1.267 (16.00), 2.159 (0.52), 2.164 (0.51), 2.181 (0.66), 2.187 (0.73), 2.209 (0.50), 2.359 (0.57), 2.365 (0.77), 2.373 (0.51), 2.379 (0.52), 2.386 (0.72), 2.394 (0.50), 2.539 (0.95), 2.825 (0.68), 2.843 (1.10), 2.860 (0.68), 3.697 (0.51), 3.969 (0.45), 3.991 (3.61), 4.140 (0.71), 4.157 (1.12), 4.175 (0.66), 5.825 (1.26), 6.772 (2.36), 7.274 (0.95), 7.278 (0.94), 8.249 (1.08), 8.253 (1.09), 8.630 (1.25), 8.635 (1.20), 11.356 (0.68).  Example 189  
2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  LC-MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 379 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.058 (15.92), 1.075 (16.00), 1.251 (4.86), 1.260 (0.60), 1.270 (10.93), 1.289 (4.97), 2.522 (1.24), 2.692 (1.05), 2.711 (3.04), 2.730 (2.94), 2.748 (0.96), 2.838 (1.75), 2.855 (2.93), 2.872 (1.87), 3.707 (0.64), 3.724 (0.94), 3.743 (0.96), 3.759 (0.65), 3.976 (0.63), 3.997 (13.06), 4.017 (0.62), 4.139 (1.86), 4.157 (3.01), 4.174 (1.79), 6.231 (1.91), 6.251 (1.88), 6.779 (7.21), 7.218 (2.36), 7.221 (2.31), 7.224 (2.40), 8.263 (3.00), 8.267 (3.10), 8.632 (3.56), 8.637 (3.48), 11.302 (1.77).  Example 190 N-tert-butyl-2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 393 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.239 (1.07), 1.252 (2.90), 1.267 (16.00), 1.289 (1.77), 2.539 (0.48), 2.693 (0.44), 2.711 (1.18), 2.730 (1.14), 2.826 (0.71), 2.843 (1.22), 2.860 (0.73), 3.990 (4.57), 4.137 (0.74), 4.155 (1.22), 4.172 (0.70), 5.829 (1.31), 6.768 (1.96), 6.961 (0.73), 7.089 (0.77), 7.219 (1.33), 8.270 (1.15), 8.273 (1.15), 8.634 (1.19), 8.638 (1.15), 11.308 (0.78). Example 191 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide   
LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 385 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.058 (15.81), 1.074 (16.00), 1.228 (0.52), 1.266 (0.46), 2.522 (0.84), 2.846 (1.72), 2.863 (2.80), 2.881 (1.81), 3.708 (0.63), 3.724 (0.91), 3.744 (0.95), 3.760 (0.64), 3.978 (0.76), 4.000 (11.19), 4.021 (0.79), 4.154 (1.82), 4.172 (2.92), 4.188 (1.77), 6.238 (1.83), 6.257 (1.81), 6.858 (7.39), 7.684 (2.55), 7.689 (2.69), 8.226 (3.19), 8.231 (3.43), 8.763 (3.32), 8.767 (3.41), 12.005 (1.32). Example 192 N-tert-butyl-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide  LC-MS (Method 1): Rt = 1.04 min; MS (ESIpos): m/z = 399 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.253 (2.17), 1.267 (16.00), 2.518 (0.46), 2.834 (0.65), 2.851 (0.97), 2.868 (0.63), 3.955 (0.57), 3.994 (3.31), 4.151 (0.63), 4.170 (1.01), 4.186 (0.61), 5.836 (1.37), 6.844 (2.56), 7.687 (2.35), 8.226 (1.44), 8.231 (1.48), 8.762 (1.26), 8.767 (1.24). Example 193 (rac)-6'-methyl-N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide   
Figure imgf000242_0001
LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 376 [M+H]+ Example 194 (rac)-N-tert-butyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide 
Figure imgf000242_0002
LC-MS (Method 1): Rt = 1.12 min; MS (ESIpos): m/z = 390 [M+H]+ Example 195 N-ethyl-2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide 
Figure imgf000242_0003
LC-MS (Method 2): Rt = 1.00 min; MS (ESIpos): m/z = 420 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.929 (0.44), 0.946 (0.45), 1.018 (4.22), 1.036 (10.22), 1.054 (4.54), 1.638 (0.86), 1.672 (1.30), 1.753 (0.68), 1.763 (0.79), 1.790 (1.02), 1.814 (0.53), 1.824 (0.43), 1.877 (0.90), 1.885 (1.08), 1.891 (1.12), 1.905 (1.31), 2.024 (0.99), 2.034 (1.05), 2.518 (0.60), 3.048 (0.74), 3.062 (1.38), 3.065 (1.97), 3.079 (2.43), 3.083 (2.58), 3.097 (2.20),  
3.115 (1.19), 3.744 (1.18), 3.754 (0.68), 3.768 (0.62), 3.779 (1.07), 3.897 (16.00), 4.124 (1.16), 4.140 (2.28), 4.155 (1.12), 6.481 (0.70), 6.495 (1.41), 6.509 (0.68), 6.929 (5.65), 7.334 (1.45), 7.341 (2.10), 7.356 (0.84), 7.363 (3.82), 7.367 (3.15), 7.373 (1.39), 7.883 (2.20), 7.905 (1.97), 8.577 (2.14), 8.581 (2.20), 9.176 (3.64), 9.181 (3.49). Example 196 N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 448 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.931 (0.70), 0.947 (0.70), 1.017 (3.93), 1.035 (9.01), 1.053 (3.97), 1.348 (16.00), 1.363 (15.49), 1.636 (0.77), 1.670 (1.17), 1.751 (0.63), 1.761 (0.71), 1.787 (0.93), 1.812 (0.48), 1.884 (0.97), 1.891 (1.00), 1.905 (1.19), 2.024 (0.90), 2.034 (0.95), 2.518 (0.79), 2.523 (0.53), 3.048 (0.59), 3.065 (1.89), 3.079 (2.00), 3.083 (2.27), 3.089 (1.46), 3.097 (2.14), 3.115 (0.96), 3.741 (1.06), 3.765 (0.56), 3.776 (0.96), 4.122 (1.03), 4.137 (2.04), 4.152 (1.00), 4.750 (0.88), 4.765 (1.22), 4.780 (0.90), 6.480 (0.64), 6.494 (1.30), 6.507 (0.63), 6.917 (4.70), 7.293 (1.39), 7.300 (1.63), 7.316 (1.35), 7.322 (1.83), 7.361 (2.23), 7.368 (1.76), 7.865 (2.07), 7.888 (1.89), 8.553 (1.94), 8.558 (1.99), 9.158 (3.12), 9.163 (3.18). Example 197 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-6',7'-dihydro-5'H-spiro[piperidine- 4,4'-pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 2): Rt = 1.11 min; MS (ESIpos): m/z = 427 [M+H]+   
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.069 (15.80), 1.085 (16.00), 1.618 (0.91), 1.652 (1.30), 1.754 (0.61), 1.763 (0.78), 1.789 (1.05), 1.814 (0.57), 1.824 (0.47), 1.866 (1.11), 1.871 (1.14), 1.886 (1.35), 2.008 (1.02), 2.018 (1.08), 2.521 (0.69), 2.526 (0.49), 3.034 (0.69), 3.061 (1.31), 3.089 (0.72), 3.751 (0.76), 3.763 (1.30), 3.767 (1.30), 3.784 (1.46), 3.801 (1.44), 3.819 (0.62), 4.085 (1.17), 4.101 (2.32), 4.115 (1.15), 6.156 (1.45), 6.175 (1.41), 6.861 (5.82), 7.673 (2.35), 7.679 (2.37), 8.239 (3.17), 8.244 (3.25), 8.766 (3.41), 8.770 (3.37), 11.975 (1.19). Example 198 N-tert-butyl-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 2): Rt = 1.23 min; MS (ESIpos): m/z = 441 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.188 (0.95), 1.255 (0.83), 1.281 (16.00), 1.654 (0.52), 1.799 (0.42), 1.857 (0.44), 1.863 (0.46), 1.877 (0.54), 2.005 (0.40), 2.015 (0.43), 3.033 (0.51), 3.738 (0.49), 3.773 (0.44), 4.085 (0.46), 4.101 (0.92), 4.116 (0.45), 5.758 (1.16), 6.845 (2.22), 7.678 (0.90), 8.237 (1.36), 8.242 (1.42), 8.764 (1.31), 8.769 (1.32), 11.978 (0.40). Example 199 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 1): Rt = 1.11 min; MS (ESIpos): m/z = 461 [M+H]+   
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.707 (2.33), 1.741 (3.30), 1.849 (1.56), 1.859 (2.02), 1.885 (2.88), 1.921 (3.84), 1.942 (3.66), 2.037 (2.72), 2.048 (2.75), 2.329 (2.48), 2.334 (1.78), 2.338 (0.78), 2.520 (10.16), 2.525 (6.54), 2.676 (1.78), 2.680 (0.81), 3.224 (1.78), 3.251 (3.34), 3.279 (2.07), 3.375 (0.48), 3.936 (3.06), 3.970 (2.75), 4.105 (2.93), 4.120 (5.74), 4.135 (2.85), 5.760 (1.49), 6.916 (16.00), 6.934 (5.04), 6.950 (1.77), 6.952 (2.92), 6.955 (1.59), 7.218 (5.63), 7.223 (2.09), 7.239 (7.77), 7.253 (1.95), 7.258 (5.61), 7.484 (7.46), 7.486 (8.41), 7.505 (7.37), 7.508 (5.68), 7.674 (11.07), 8.244 (9.68), 8.249 (9.68), 8.522 (7.16), 8.770 (8.27), 8.774 (8.08), 11.976 (3.27). Example 200 N-ethyl-2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine]-1- carboxamide  LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 390 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (5.49), 1.017 (7.15), 1.036 (16.00), 1.054 (7.42), 1.641 (1.63), 1.675 (2.51), 1.758 (1.18), 1.768 (1.49), 1.794 (1.95), 1.819 (1.00), 1.829 (0.83), 1.890 (2.05), 1.896 (2.14), 1.910 (2.54), 2.029 (1.88), 2.038 (2.02), 2.518 (4.56), 2.523 (2.87), 3.048 (1.52), 3.061 (2.34), 3.065 (3.40), 3.079 (4.67), 3.083 (5.11), 3.097 (3.79), 3.114 (2.19), 3.159 (0.85), 3.172 (0.92), 3.751 (2.25), 3.776 (1.19), 3.786 (2.04), 4.132 (2.20), 4.147 (4.34), 4.162 (2.14), 6.480 (1.27), 6.494 (2.54), 6.507 (1.24), 6.974 (9.70), 7.585 (1.30), 7.588 (1.26), 7.603 (1.93), 7.606 (2.74), 7.623 (1.81), 7.626 (1.79), 7.699 (1.73), 7.703 (1.77), 7.716 (1.48), 7.720 (2.78), 7.723 (2.04), 7.737 (1.48), 7.740 (1.44), 7.983 (2.71), 7.991 (3.11), 8.000 (2.50), 8.012 (2.70), 8.676 (3.91), 8.681 (3.96), 9.356 (5.69), 9.361 (5.65). The following compounds (examples 201 to example 212) were prepared in analogy to example 146: Example 201  N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide   
LC-MS (Method 2): Rt = 1.17 min; MS (ESIpos): m/z = 458 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.022 (6.72), 1.040 (16.00), 1.058 (6.92), 1.650 (1.24), 1.684 (1.93), 1.760 (0.92), 1.769 (1.17), 1.796 (1.51), 1.820 (0.77), 1.830 (0.62), 1.892 (1.30), 1.900 (1.57), 1.906 (1.62), 1.920 (1.95), 2.039 (1.44), 2.048 (1.53), 2.522 (1.46), 2.526 (0.95), 3.052 (0.88), 3.070 (3.42), 3.084 (3.01), 3.089 (3.36), 3.102 (3.66), 3.120 (1.16), 3.125 (1.14), 3.752 (1.75), 3.762 (0.99), 3.776 (0.91), 3.787 (1.57), 4.151 (1.71), 4.167 (3.40), 4.181 (1.67), 6.491 (1.04), 6.505 (2.11), 6.518 (1.01), 7.004 (8.44), 7.949 (1.73), 7.954 (1.69), 7.971 (2.02), 7.976 (2.03), 8.200 (2.31), 8.222 (2.06), 8.505 (2.74), 8.903 (3.03), 8.907 (3.07), 9.510 (4.54), 9.515 (4.53).  Example 202  N-ethyl-2'-[3-(propan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 2): Rt = 1.04 min; MS (ESIpos): m/z = 421 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (4.24), 1.030 (9.60), 1.049 (4.28), 1.307 (15.88), 1.324 (16.00), 1.621 (0.88), 1.654 (1.26), 1.756 (0.57), 1.766 (0.73), 1.793 (0.98), 1.818 (0.55), 1.828 (0.45), 1.865 (1.04), 1.871 (1.08), 1.885 (1.29), 2.002 (0.96), 2.011 (1.01), 2.521 (1.33), 2.525 (0.93), 3.027 (0.67), 3.042 (0.81), 3.055 (1.87), 3.059 (2.38), 3.073 (1.93), 3.078 (2.04), 3.091 (2.03), 3.109 (0.54), 3.138 (0.76), 3.155 (0.99), 3.171 (0.71), 3.759 (1.13), 3.783 (0.62), 3.793 (1.04), 4.074 (1.08), 4.089 (2.16), 4.104 (1.09), 6.460 (0.69), 6.474 (1.41), 6.487 (0.69), 6.772 (5.29), 7.176 (1.96), 7.181 (1.97), 8.279 (2.33), 8.284 (2.45), 8.624 (3.20), 8.629 (3.14), 11.272 (1.30), 11.277 (1.32).  Example 203   
N-ethyl-2'-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 393 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.011 (6.52), 1.029 (14.77), 1.047 (6.80), 1.614 (1.65), 1.648 (2.42), 1.736 (1.12), 1.745 (1.45), 1.772 (1.97), 1.797 (1.14), 1.807 (0.88), 1.863 (2.32), 1.878 (2.48), 1.996 (2.00), 2.006 (2.04), 2.333 (1.35), 2.384 (16.00), 2.524 (6.00), 2.542 (1.12), 2.675 (1.30), 3.025 (1.28), 3.039 (1.41), 3.056 (4.45), 3.070 (3.45), 3.074 (3.57), 3.088 (3.63), 3.106 (0.87), 3.736 (2.14), 3.770 (1.95), 4.057 (2.47), 4.072 (4.25), 4.087 (2.05), 5.760 (4.78), 6.127 (3.88), 6.460 (1.26), 6.474 (2.52), 6.487 (1.21), 6.615 (0.77), 6.679 (8.30), 8.107 (4.12), 8.111 (4.19), 8.510 (0.63), 8.519 (5.13), 8.524 (4.96), 11.423 (2.90).  Example 204  N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxamide  LC-MS (Method 1): Rt = 0.80 min; MS (ESIpos): m/z = 367 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.017 (6.87), 1.035 (16.00), 1.052 (7.07), 1.176 (0.61), 1.231 (0.83), 2.118 (0.42), 2.278 (15.24), 2.281 (15.64), 2.518 (1.85), 2.522 (1.21), 2.539 (1.61), 2.673 (0.46), 3.027 (0.91), 3.045 (2.86), 3.059 (3.10), 3.063 (3.05), 3.077 (2.74), 3.095 (0.83), 4.021 (2.64), 4.045 (7.40), 4.064 (7.55), 4.086 (2.77), 4.113 (2.94), 4.117 (2.76), 4.125 (3.10), 4.152 (3.31), 4.159 (2.59), 4.164 (2.88), 6.543 (1.25), 6.557 (2.59), 6.571 (1.22), 6.946 (10.35), 7.230 (3.07), 7.231 (3.06), 8.295 (4.19), 8.300 (4.56), 8.673 (5.20), 8.678 (5.05), 11.306 (2.14).  Example 205   
2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,1- c][1,4]oxazine]-1-carboxamide  LC-MS (Method 1): Rt = 1.26 min; MS (ESIpos): m/z = 387 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.54), 1.016 (7.23), 1.034 (16.00), 1.052 (7.34), 1.065 (0.40), 1.137 (1.45), 1.232 (2.73), 1.295 (0.49), 2.084 (0.49), 2.115 (0.58), 2.451 (0.45), 2.456 (0.60), 2.518 (4.70), 2.522 (2.86), 2.539 (3.38), 3.027 (0.92), 3.045 (3.00), 3.058 (3.11), 3.062 (3.09), 3.077 (2.82), 3.095 (0.81), 4.020 (3.02), 4.043 (7.12), 4.068 (7.18), 4.091 (3.16), 4.118 (3.13), 4.130 (3.00), 4.164 (3.09), 4.178 (3.04), 6.542 (1.25), 6.556 (2.60), 6.570 (1.23), 7.056 (11.30), 7.701 (5.12), 8.285 (5.84), 8.290 (6.13), 8.798 (5.10), 8.803 (5.08), 12.028 (1.07).  Example 206  N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxamide  LC-MS (Method 1): Rt = 0.88 min; MS (ESIpos): m/z = 395 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (5.72), 1.033 (12.82), 1.051 (5.91), 1.232 (0.57), 1.753 (0.68), 1.764 (0.82), 1.786 (1.59), 1.795 (1.51), 1.819 (1.19), 1.829 (0.98), 1.925 (2.54), 1.958 (1.64), 2.273 (14.43), 2.523 (0.88), 2.985 (1.19), 3.014 (2.18), 3.044 (1.94), 3.062 (2.53), 3.076 (2.63), 3.079 (2.62), 3.093 (2.34), 3.111 (0.71), 3.846 (1.75), 3.879 (1.59), 4.125 (16.00), 6.516 (1.12), 6.530 (2.20), 6.543 (1.07), 6.742 (8.02), 7.23 (2.91), 8.231 (3.76), 8.236 (3.82), 8.626 (4.47), 8.631 (4.34), 11.290 (2.15).  Example 207   
N-ethyl-2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 393 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.003 (3.52), 1.011 (6.34), 1.028 (14.52), 1.046 (6.78), 1.231 (1.29), 1.618 (1.69), 1.651 (2.48), 1.745 (1.14), 1.754 (1.46), 1.781 (1.98), 1.805 (1.04), 1.816 (0.87), 1.869 (2.19), 1.883 (2.52), 2.002 (1.94), 2.012 (2.06), 2.270 (15.56), 2.272 (16.00), 2.331 (1.32), 3.039 (2.03), 3.057 (4.16), 3.070 (4.67), 3.074 (4.20), 3.089 (3.56), 3.106 (1.29), 3.159 (0.44), 3.171 (0.46), 3.742 (2.18), 3.777 (2.00), 4.068 (2.06), 4.083 (4.07), 4.098 (2.08), 6.463 (1.25), 6.476 (2.50), 6.490 (1.26), 6.746 (8.40), 7.206 (3.39), 8.232 (4.23), 8.236 (4.33), 8.629 (5.01), 8.633 (4.99), 11.251 (2.52).  Example 208  N-ethyl-2'-(1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide  LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 379 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.010 (0.45), -0.002 (16.00), 0.006 (0.51), 1.011 (4.30), 1.017 (0.64), 1.029 (10.12), 1.047 (4.45), 1.620 (0.91), 1.654 (1.32), 1.742 (0.62), 1.751 (0.96), 1.779 (1.02), 1.803 (0.56), 1.812 (0.46), 1.868 (1.15), 1.883 (1.33), 2.001 (1.02), 2.011 (1.06), 2.518 (3.61), 2.523 (2.37), 2.540 (0.49), 3.027 (0.73), 3.039 (0.75), 3.057 (2.80), 3.070 (2.00), 3.074 (2.00), 3.088 (2.15), 3.105 (0.51), 3.159 (1.72), 3.172 (1.81), 3.739 (1.18), 3.764 (0.62), 3.774 (1.06), 4.067 (1.22), 4.083 (2.36), 4.098 (1.50), 4.111 (0.45), 6.432 (1.56), 6.436 (1.72), 6.440 (1.80), 6.444 (1.66), 6.462 (0.75), 6.476 (1.44), 6.489 (0.68), 6.717 (5.59), 7.442 (1.40), 7.449 (1.68), 7.457 (1.40), 8.273 (2.59), 8.278 (2.66), 8.650 (3.32), 8.655 (3.23), 11.611 (1.26).   
Example 209  N-ethyl-2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 407 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (3.84), 1.010 (6.79), 1.028 (15.79), 1.046 (6.96), 1.249 (7.22), 1.268 (16.00), 1.286 (7.52), 1.617 (1.40), 1.651 (2.04), 1.748 (0.94), 1.757 (1.21), 1.784 (1.59), 1.808 (0.87), 1.819 (0.70), 1.869 (1.75), 1.883 (2.08), 2.001 (1.56), 2.011 (1.64), 2.336 (0.44), 2.518 (5.31), 2.523 (3.60), 2.679 (0.48), 2.692 (1.27), 2.709 (3.69), 2.711 (3.79), 2.728 (3.65), 2.730 (3.70), 2.748 (1.16), 3.033 (1.14), 3.039 (1.19), 3.057 (4.15), 3.071 (3.53), 3.075 (3.09), 3.088 (3.61), 3.106 (0.85), 3.159 (0.55), 3.172 (0.58), 3.747 (1.85), 3.781 (1.67), 4.069 (1.78), 4.085 (3.56), 4.099 (1.86), 6.460 (1.11), 6.473 (2.26), 6.487 (1.09), 6.754 (8.52), 7.204 (2.95), 7.207 (2.82), 7.210 (2.96), 8.249 (3.99), 8.254 (4.08), 8.626 (5.16), 8.631 (5.02), 11.265 (2.11), 11.269 (2.12).  Example 210  N-ethyl-2'-(1H-pyrazolo[3,4-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide  LC-MS (Method 1): Rt = 0.88 min; MS (ESIpos): m/z = 380 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.002 (1.70), 1.012 (6.67), 1.029 (16.00), 1.047 (7.24), 1.623 (1.44), 1.657 (2.17), 1.738 (1.01), 1.749 (1.33), 1.775 (1.73), 1.799 (0.98), 1.810 (0.74), 1.875 (2.04), 1.889 (2.20), 2.007 (1.75), 2.017 (1.78), 2.332 (0.87), 2.518 (5.02), 2.523 (3.19), 2.540 (2.94), 2.673 (0.88), 3.039 (1.62), 3.057 (3.95), 3.064 (2.68), 3.071 (4.12), 3.075 (3.53),  
3.089 (3.45), 3.106 (1.00), 3.159 (6.78), 3.172 (7.41), 3.739 (1.96), 3.764 (1.03), 3.774 (1.77), 4.086 (2.84), 4.099 (4.68), 4.112 (2.78), 4.125 (0.79), 6.468 (1.16), 6.481 (2.35), 6.495 (1.13), 6.751 (0.80), 6.820 (8.72), 8.140 (9.79), 8.515 (0.64), 8.524 (5.81), 8.529 (5.90), 8.964 (0.73), 8.971 (6.47), 8.976 (6.11), 13.644 (1.44).  Example 211  2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-carboxamide  LC-MS (Method 1): Rt = 1.07 min; MS (ESIpos): m/z = 413 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.013 (7.10), 1.032 (16.00), 1.049 (7.34), 1.234 (0.44), 1.619 (1.55), 1.653 (2.23), 1.752 (0.99), 1.762 (1.31), 1.788 (1.76), 1.812 (0.96), 1.823 (0.81), 1.873 (1.97), 1.888 (2.35), 2.008 (1.74), 2.018 (1.85), 2.520 (5.24), 2.525 (3.40), 3.042 (2.05), 3.060 (3.81), 3.073 (4.52), 3.078 (4.00), 3.091 (3.27), 3.096 (2.35), 3.109 (1.15), 3.161 (1.37), 3.174 (1.44), 3.747 (2.00), 3.756 (1.29), 3.770 (1.08), 3.781 (1.83), 4.084 (1.94), 4.099 (4.14), 4.113 (2.13), 6.463 (1.21), 6.477 (2.42), 6.490 (1.16), 6.844 (0.79), 6.856 (8.97), 7.674 (8.19), 7.719 (0.65), 8.108 (0.45), 8.113 (0.49), 8.235 (6.34), 8.240 (6.59), 8.684 (0.41), 8.689 (0.41), 8.736 (0.46), 8.741 (0.43), 8.762 (5.30), 8.766 (5.26), 11.967 (0.57).  Example 212  2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5,1-c][1,4]oxazine]-1-carboxamide  LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 415 [M+H]+   
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.015 (7.08), 1.033 (16.00), 1.050 (7.17), 1.230 (0.47), 1.757 (0.73), 1.768 (0.91), 1.791 (1.77), 1.800 (1.68), 1.822 (1.34), 1.833 (1.11), 1.923 (2.85), 1.957 (1.81), 2.074 (1.19), 2.518 (1.72), 2.522 (1.15), 2.986 (1.36), 3.014 (2.41), 3.044 (2.14), 3.061 (2.94), 3.075 (3.05), 3.079 (3.01), 3.093 (2.72), 3.110 (0.82), 3.847 (1.94), 3.879 (1.78), 4.133 (11.41), 6.516 (1.24), 6.530 (2.47), 6.543 (1.21), 6.848 (9.89), 7.688 (3.58), 7.693 (3.60), 8.224 (4.98), 8.229 (5.22), 8.754 (5.30), 8.759 (5.33), 12.010 (1.89).  Example 213 N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide  N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’-pyrrolo[1,2-b]pyrazole]-1- carboxamide (75.0 mg, 206 µmol), 2-bromopropane (30.5 mg, 248 µmol) and NaOH (9.91 mg, 248 µmol) were solubilised in DMF (300 µl) and the mixture was stirred overnight at 70°C. Water was added and the mixture was extracted 3x with EtOAc, dried with a silicone filter and evaporated. The residue was purified by preparative HPLC to give 2.30 mg (96 % purity, 3 % yield) of the title compound. LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 446 [M+H]+  Example 214 2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxamide  N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’-pyrrolo[1,2-b]pyrazole]-1- carboxamide (75.0 mg, 206 µmol), bromocyclohexane (40.4 mg, 248 µmol) and NaOH (9.91 mg, 248 µmol) were solubilised in DMF (300 µl) and the mixture was stirred overnight at 70°C. Water   was added and the mixture was extracted 3x with EtOAc, dried with a silicone filter and evaporated. The residue was purified by preparative HPLC to give 1.10 mg (98 % purity, 1 % yield) of the title compound. LC-MS (Method 1): Rt = 1.23 min; MS (ESIpos): m/z = 446 [M+H]+  Example 215 cyclopentyl (rac)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate 
Figure imgf000253_0001
Trifluoroacetic acid—(rac)-6’-methyl-2’-(quinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’- pyrrolo[1,2-b]pyrazole] (1/1) (75.0 mg, 185 µmol), cyclopentyl carbonochloridate (55.1 mg, 371 µmol) and N,N-diisopropylethylamine (97 µl, 560 µmol) were solubilised in dichloromethane (1.3 ml) and the mixture was stirred for 1 h at rt. It was evaporated and the residue was purified by preparative HPLC to give 6.70 mg (100 % purity, 9 % yield) of the title compound. LC-MS (Method 1): Rt = 1.27 min; MS (ESIpos): m/z = 403 [M+H]+  Example 216 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(5-methyl-1H-imidazol-2-yl)methyl]-6',7'- dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1,4]oxazine]  Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7’-dihydrospiro[azetidine-3,4’- pyrazolo[5,1-c][1,4]oxazine] (1/1) (30.0 mg, 69.8 µmol) and 5-methyl-1H-imidazole-2- carbaldehyde (11.5 mg, 105 µmol) were solubilized in THF (1.0 ml), sodium triacetoxyborohydride (33.4 mg, 158 µmol) and acetic acid (4.0 µl, 70 µmol) were added and the mixture was stirred overnight at rt.5-methyl-1H-imidazole-2-carbaldehyde (11.5 mg, 105 µmol)  
and sodium triacetoxyborohydride (33.4 mg, 158 µmol) were added an dthe mixture was stirred for 4 h at rt. It was poured into sat. NaHCO3 soultion and extracted 3x with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3.00 mg (97 % purity, 10 % yield) of the title compound. LC-MS (Method 2): Rt = 0.86 min; MS (ESIpos): m/z = 410 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.170 (0.56), 1.186 (0.61), 1.231 (1.22), 2.106 (3.76), 2.327 (2.68), 2.331 (1.98), 2.518 (8.94), 2.523 (5.69), 2.539 (0.56), 2.669 (2.73), 2.673 (1.93), 3.493 (3.62), 3.513 (8.28), 3.538 (6.49), 3.558 (3.01), 3.577 (0.99), 3.670 (16.00), 4.037 (3.06), 4.049 (6.96), 4.061 (5.65), 4.120 (5.88), 4.133 (6.92), 4.144 (3.15), 6.489 (0.42), 6.547 (0.61), 6.753 (0.66), 6.919 (15.44), 7.708 (7.76), 7.714 (7.62), 8.238 (9.04), 8.243 (8.99), 8.783 (10.07), 8.788 (9.84), 11.560 (0.71), 11.677 (0.56), 12.034 (3.86).  The following compounds (example 217 to example 229) were prepared in analogy to example 216: Example 217 2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]  LC-MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 374 [M+H]+  Example 218 1-[(4-chloro-1H-pyrazol-5-yl)methyl]-2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]  LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 408 [M+H]+    Example 219 (rac)-1-[(4-chloro-1H-pyrazol-5-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole] 
Figure imgf000255_0001
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 405 [M+H]+  Example 220 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-6',7'- dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1,4]oxazine] 
Figure imgf000255_0002
LC-MS (Method 2): Rt = 0.82 min; MS (ESIpos): m/z = 396 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.170 (0.68), 1.186 (0.78), 1.231 (1.14), 2.327 (3.01), 2.331 (2.13), 2.518 (10.29), 2.523 (6.49), 2.669 (3.06), 2.673 (2.18), 3.499 (4.26), 3.519 (10.03), 3.542 (10.13), 3.562 (4.21), 3.578 (1.71), 3.747 (16.00), 4.038 (2.34), 4.050 (5.56), 4.063 (4.42), 4.123 (4.68), 4.136 (5.45), 4.148 (2.44), 6.834 (3.32), 6.983 (15.01), 7.074 (3.12), 7.707 (6.34), 7.713 (6.29), 8.249 (7.01), 8.254 (7.17), 8.787 (8.16), 8.792 (7.95), 11.902 (2.18), 12.032 (3.12).  Example 221 (rac)-1-[(1H-imidazol-2-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]   
Figure imgf000256_0001
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 371 [M+H]+  Example 222 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1-methyl-1H-imidazol-2-yl)methyl]-6',7'-dihydro- 5'H-spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine]  LC-MS (Method 2): Rt = 1.08 min; MS (ESIpos): m/z = 436 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.650 (0.92), 1.684 (1.14), 1.812 (0.85), 1.826 (1.06), 1.840 (1.23), 1.871 (0.51), 1.881 (0.64), 1.909 (0.98), 1.933 (0.57), 1.942 (0.48), 1.979 (0.94), 1.989 (1.02), 2.285 (0.61), 2.309 (1.16), 2.325 (0.41), 2.330 (0.51), 2.338 (0.70), 2.521 (0.93), 2.526 (0.65), 2.626 (1.19), 2.646 (0.64), 2.656 (1.00), 2.667 (0.59), 2.672 (0.44), 3.593 (5.07), 3.697 (16.00), 4.066 (1.10), 4.081 (2.20), 4.096 (1.09), 6.761 (4.44), 6.764 (4.67), 6.818 (5.25), 7.089 (3.75), 7.092 (3.70), 7.674 (2.59), 7.681 (2.66), 8.213 (2.42), 8.218 (2.46), 8.753 (3.08), 8.757 (3.00), 11.976 (1.16), 11.982 (1.15).  Example 223 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-6',7'-dihydro-5'H- spiro[piperidine-4,4'-pyrazolo[1,5-a]pyridine]   
LC-MS (Method 2): Rt = 0.98 min; MS (ESIpos): m/z = 422 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.654 (2.73), 1.687 (3.28), 1.784 (2.60), 1.791 (2.99), 1.797 (3.15), 1.812 (3.60), 1.897 (1.52), 1.907 (2.18), 1.933 (2.96), 1.958 (2.69), 1.969 (3.53), 1.985 (3.11), 2.308 (1.85), 2.331 (3.88), 2.335 (3.74), 2.360 (1.88), 2.521 (2.13), 2.526 (1.50), 2.543 (1.92), 2.662 (3.52), 2.668 (2.56), 2.672 (2.62), 2.678 (2.12), 2.691 (2.96), 3.576 (16.00), 4.067 (3.27), 4.082 (6.54), 4.097 (3.26), 6.730 (15.88), 6.828 (0.91), 7.042 (0.91), 7.684 (7.34), 8.195 (9.94), 8.200 (10.35), 8.741 (9.31), 8.747 (9.15), 11.886 (1.48), 11.997 (2.77).  Example 224 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3,3,3-trifluoropropyl)-5',6'-dihydrospiro[piperidine- 4,4'-pyrrolo[1,2-b]pyrazole]  LC-MS (Method 1): Rt = 1.21 min; MS (ESIpos): m/z = 424 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.55), 1.230 (4.75), 1.696 (5.85), 1.714 (5.66), 1.757 (7.02), 1.769 (5.82), 1.791 (3.87), 2.040 (3.67), 2.054 (3.19), 2.302 (0.46), 2.322 (1.40), 2.327 (1.89), 2.331 (1.43), 2.391 (7.80), 2.409 (12.88), 2.427 (8.39), 2.522 (12.81), 2.539 (8.62), 2.557 (7.74), 2.585 (6.60), 2.644 (6.24), 2.664 (6.96), 2.668 (6.73), 3.582 (0.65), 3.761 (0.42), 4.156 (8.52), 4.174 (13.69), 4.191 (8.72), 4.213 (1.85), 4.231 (1.14), 6.794 (8.78), 6.939 (1.17), 7.026 (2.76), 7.555 (0.46), 7.678 (14.86), 7.685 (16.00), 7.693 (2.15), 8.156 (1.14), 8.225 (13.01), 8.230 (12.98), 8.280 (0.94), 8.285 (0.91), 8.767 (1.89), 8.772 (2.08), 8.782 (15.67), 8.787 (15.54), 8.850 (0.68), 8.855 (0.68), 11.995 (7.22).   
Example 225 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole]  LC-MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 409 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.664 (1.47), 1.686 (3.53), 1.696 (2.90), 1.707 (3.21), 1.746 (3.55), 1.778 (1.73), 2.323 (0.75), 2.327 (1.03), 2.331 (0.77), 2.379 (4.35), 2.397 (7.28), 2.414 (4.83), 2.578 (2.91), 2.598 (3.45), 2.665 (0.98), 2.669 (1.22), 2.673 (0.95), 3.602 (16.00), 4.148 (4.66), 4.166 (7.59), 4.183 (4.73), 6.672 (9.44), 6.835 (0.88), 7.036 (0.87), 7.683 (7.18), 7.689 (7.06), 8.206 (8.36), 8.211 (8.24), 8.764 (9.31), 8.769 (9.09), 11.889 (2.08), 11.998 (3.85).  Example 226 1-benzyl-2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[1,2- b]pyrazole]  LC-MS (Method 1): Rt = 1.30 min; MS (ESIpos): m/z = 418 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.227 (3.58), 1.696 (3.00), 1.716 (2.99), 1.755 (3.28), 2.074 (4.45), 2.327 (0.57), 2.390 (3.39), 2.408 (5.88), 2.425 (4.10), 2.668 (0.65), 3.574 (10.60), 4.148 (3.36), 4.165 (5.60), 4.182 (3.21), 6.710 (5.94), 7.250 (1.62), 7.260 (2.36), 7.270 (2.36), 7.280 (1.48), 7.339 (16.00), 7.350 (14.82), 7.685 (5.71), 8.209 (5.25), 8.213 (5.27), 8.767 (5.25), 8.771 (5.19), 11.995 (3.08).   
Example 227 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(cyclohexylmethyl)-5',6'-dihydrospiro[piperidine- 4,4'-pyrrolo[1,2-b]pyrazole]  LC-MS (Method 1): Rt = 1.57 min; MS (ESIpos): m/z = 424 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.807 (1.65), 0.832 (4.78), 0.861 (5.28), 0.890 (2.27), 1.123 (1.86), 1.174 (6.58), 1.201 (5.49), 1.231 (4.22), 1.262 (1.45), 1.487 (1.86), 1.496 (2.07), 1.505 (2.30), 1.514 (2.66), 1.523 (2.21), 1.533 (1.95), 1.541 (1.77), 1.653 (11.39), 1.676 (9.68), 1.687 (9.27), 1.743 (11.13), 1.760 (7.85), 1.771 (7.97), 2.163 (12.96), 2.181 (12.01), 2.323 (1.74), 2.327 (2.24), 2.331 (1.80), 2.379 (10.39), 2.397 (15.88), 2.414 (11.28), 2.459 (3.19), 2.464 (4.07), 2.468 (5.08), 2.518 (8.71), 2.523 (6.23), 2.530 (3.19), 2.535 (2.45), 2.539 (1.77), 2.544 (1.24), 2.548 (0.92), 2.665 (1.33), 2.669 (1.80), 2.673 (1.27), 4.146 (8.44), 4.164 (13.02), 4.181 (7.97), 6.729 (15.91), 7.678 (14.61), 8.220 (15.26), 8.225 (16.00), 8.768 (15.97), 8.773 (15.50), 11.984 (4.99).  Example 228 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(propan-2-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole]  LC-MS (Method 1): Rt = 1.15 min; MS (ESIpos): m/z = 370 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.018 (15.67), 1.035 (16.00), 1.635 (0.60), 1.643 (0.74), 1.653 (0.77), 1.665 (1.38), 1.675 (1.18), 1.684 (1.32), 1.693 (1.04), 1.750 (1.32), 1.760 (1.21),  
1.768 (1.31), 1.782 (0.74), 1.791 (0.73), 2.074 (1.48), 2.378 (2.10), 2.395 (3.27), 2.413 (2.26), 2.518 (2.07), 2.523 (1.45), 2.593 (1.12), 2.612 (1.42), 2.632 (0.73), 2.703 (0.41), 2.719 (1.04), 2.735 (1.38), 2.752 (1.00), 4.148 (2.22), 4.165 (3.36), 4.182 (2.16), 6.668 (5.98), 7.678 (2.90), 7.681 (2.90), 8.210 (3.98), 8.215 (4.04), 8.768 (4.08), 8.773 (4.01), 11.993 (1.46).  Example 229 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole]  LC-MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 422 [M+H]+   ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.665 (1.04), 1.684 (0.91), 1.694 (0.75), 1.733 (0.99), 1.746 (0.85), 1.765 (0.51), 2.368 (1.50), 2.385 (2.41), 2.403 (1.74), 2.518 (1.61), 2.523 (1.37), 3.410 (4.66), 3.809 (16.00), 4.142 (1.51), 4.160 (2.36), 4.177 (1.46), 6.649 (3.91), 7.322 (4.22), 7.587 (3.94), 7.684 (4.23), 8.200 (3.27), 8.205 (3.26), 8.757 (2.99), 8.762 (2.94), 11.995 (1.07).  Example 230 [2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridin]-1-yl](4-fluorophenyl)methanone  Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7’-dihydro-5’H- spiro[piperidine-4,4’-pyrazolo[1,5-a]pyridine] (1/1) (80.0 mg, 175 µmol) was solubilised in DMF (2.0 ml), 4-fluorobenzoic acid (29.5 mg, 211 µmol), N,N-diisopropylethylamine (92 µl, 530 µmol) and T3P (120 µl, 50 % purity in DMF, 210 µmol) were added and the mixture was stirred  
overnight at rt. It was evaporated and purified by preparative HPLC to give 27.0 mg (99 % purity, 33 % yield) of the title compound.  LC-MS (Method 2): Rt = 1.24 min; MS (ESIpos): m/z = 464 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.942 (0.95), 0.956 (0.90), 1.673 (0.90), 1.801 (0.91), 1.909 (3.51), 2.024 (2.96), 2.078 (0.72), 2.521 (2.65), 2.526 (1.67), 3.503 (0.79), 4.111 (4.59), 4.205 (0.76), 6.993 (16.00), 7.278 (0.68), 7.285 (6.03), 7.290 (2.05), 7.302 (2.69), 7.307 (12.32), 7.313 (2.61), 7.324 (2.20), 7.329 (6.90), 7.519 (0.88), 7.526 (6.84), 7.532 (2.71), 7.540 (7.50), 7.548 (6.46), 7.557 (2.33), 7.562 (5.68), 7.686 (7.91), 7.693 (7.89), 8.227 (8.48), 8.231 (8.47), 8.774 (9.94), 8.779 (9.61), 11.991 (3.94).  The following compound (example 231) was prepared in analogy to example 230: Example 231 [2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridin]-1-yl](oxan-4-yl)methanone  LC-MS (Method 2): Rt = 1.07 min; MS (ESIpos): m/z = 454 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.938 (0.83), 0.954 (0.82), 1.519 (0.83), 1.551 (1.95), 1.574 (1.62), 1.604 (3.12), 1.631 (1.80), 1.659 (2.29), 1.692 (2.65), 1.721 (1.88), 1.734 (2.24), 1.748 (2.31), 1.782 (0.64), 1.833 (1.09), 1.861 (1.51), 1.907 (3.20), 1.921 (3.55), 2.018 (2.77), 2.029 (2.91), 2.521 (3.24), 2.526 (2.25), 2.889 (0.62), 2.898 (1.04), 2.916 (1.28), 2.926 (2.08), 2.936 (1.10), 2.943 (0.83), 2.953 (1.06), 2.964 (0.50), 3.056 (0.79), 3.084 (1.44), 3.111 (0.84), 3.379 (2.28), 3.409 (4.58), 3.438 (2.55), 3.849 (3.06), 3.863 (3.45), 4.096 (4.25), 4.110 (7.11), 4.125 (3.94), 6.777 (0.41), 6.903 (16.00), 7.679 (6.78), 8.229 (10.03), 8.234 (10.15), 8.766 (9.37), 8.771 (9.28), 11.980 (2.75).  Example 232 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(methanesulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole]   
Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5’,6’-dihydrospiro[piperidine- 4,4’-pyrrolo[1,2-b]pyrazole] (1/1) (100 mg, 69 % purity, 156 µmol) was solubilised in DMSO (1.0 ml), methanesulfonyl chloride (17.9 mg, 156 µmol) and triethylamine (65 µl, 470 µmol) were added and the mixture was stirred overnight at rt. It was filtered and purified by preparative HPLC to give 33.0 mg (99 % purity, 52 % yield) of the title compound.  LC-MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 406 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.770 (0.48), 1.782 (0.43), 1.793 (1.27), 1.803 (1.04), 1.816 (1.16), 1.827 (1.39), 1.840 (1.49), 1.853 (1.09), 1.862 (0.50), 1.877 (0.54), 2.075 (0.85), 2.443 (1.69), 2.461 (2.68), 2.478 (1.96), 2.518 (0.76), 2.523 (0.51), 2.539 (0.76), 2.999 (16.00), 3.195 (0.50), 3.204 (0.67), 3.225 (1.34), 3.234 (0.94), 3.248 (0.86), 3.256 (0.73), 3.344 (1.40), 3.356 (0.93), 3.377 (0.82), 3.387 (0.46), 4.191 (1.72), 4.209 (2.65), 4.226 (1.66), 6.879 (6.37), 7.686 (2.29), 7.691 (2.31), 8.222 (3.35), 8.228 (3.43), 8.792 (3.44), 8.797 (3.44), 12.010 (1.13).  Example 233 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[1,5-a]pyridine]-1-sulfonamide  Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7’-dihydro-5’H- spiro[piperidine-4,4’-pyrazolo[1,5-a]pyridine] (1/1) (80.0 mg, 175 µmol) was solubilised in DMSO (2.0 ml), dimethylsulfamyl chloride (27.7 mg, 193 µmol) and N,N-diisopropylethylamine (92 µl, 530 µmol) were added and the mixture was stirred overnight at rt. It was filtered and purified by preparative HPLC to give 30.0 mg (99 % purity, 38 % yield) of the title compound.   
LC-MS (Method 2): Rt = 1.21 min; MS (ESIpos): m/z = 449 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.789 (0.47), 1.900 (0.63), 1.906 (0.66), 2.806 (16.00), 3.140 (0.45), 3.459 (0.44), 4.089 (0.41), 4.105 (0.82), 4.120 (0.40), 6.888 (1.94), 7.680 (0.83), 7.686 (0.85), 8.230 (0.95), 8.235 (0.97), 8.768 (1.09), 8.772 (1.10).  Example 234 2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine- 4,4'-pyrazolo[1,5-a]pyridine]-1-carboxamide  N-Ethyl-2’-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7’-dihydro-5’H-spiro[piperidine-4,4’- pyrazolo[1,5-a]pyridine]-1-carboxamide (39.0 mg, 99.4 µmol) was solubilised in DMF (500 µl), NCS (14.6 mg, 109 µmol) and benzoyl peroxide (35.3 mg, 75 % purity, 109 µmol) were added and the mixture was stirred for 3 h at rt. It was diluted with half conc. Na2S2O3 solution, extracted with EtOAc. The organic layer was washed with brine, dried with Na2SO4 and evaporated. The residue was purified by preparative HPLC to give 21.2 mg (95 % purity, 47 % yield) of the title compound.  LC-MS (Method 1): Rt = 0.99 min; MS (ESIpos): m/z = 427 [M+H]+  ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.009 (5.42), 1.027 (12.33), 1.045 (5.60), 1.612 (1.28), 1.645 (1.85), 1.745 (0.86), 1.754 (1.09), 1.781 (1.47), 1.805 (0.80), 1.816 (0.64), 1.867 (1.64), 1.881 (1.89), 2.000 (1.46), 2.010 (1.53), 2.331 (0.91), 2.383 (16.00), 2.518 (4.99), 2.522 (3.14), 2.673 (0.91), 3.032 (1.08), 3.038 (1.14), 3.056 (3.63), 3.069 (3.20), 3.073 (2.81), 3.087 (3.15), 3.105 (0.77), 3.742 (1.68), 3.776 (1.54), 4.072 (1.61), 4.087 (3.15), 4.102 (1.59), 6.460 (1.01), 6.473 (1.99), 6.487 (0.97), 6.813 (6.77), 8.099 (3.36), 8.104 (3.39), 8.644 (4.08), 8.649 (4.02), 11.868 (2.79).      
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 complExample  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 of MAP4K1 (HPK1): 
Figure imgf000265_0001
 
Figure imgf000266_0001
 
Figure imgf000267_0001
 
Figure imgf000268_0001
Phosphorylation assay in human cell line using HTRF Assay  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  transferred  to a 384 well  format plate at a  cell density of 140.000 cells/well and  simultaneously  treated with  1 µg/mL  a‐CD3  antibody  (clone OKT3.  ebioscience  #16‐0037‐85)  and  4  µg/mL anti‐IgG crosslinking antibody (Invitrogen goat anti‐mouse IgG (H+L) 2  #31160) together with the  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). The detection of pSer376‐ SLP76 levels in the proprietary Jurkat cell lines was carried out utilizing an adapted protocol of the HTRF  pSLP76 Assay  (Cisbio # 63ADK076PEG). Cells were  lysed using 4 µl of  the  supplemented  lysis buffer  (Cisbio # 63ADK076PEG) for 60 min at room temperature. Subsequently 4 µl of the premixed antibody  solution (Cisbio # 63ADK076PEG) was added and incubated over night at room temperature. Read‐out  and  analyses  was  carried  out  using  a  Pherastar  and  the  MARS  software  (BMG  Labtechnologies,  Offenburg, Germany). Inhibition constant (IC50) values were calculated by concentration‐response curve  fitting applying four‐parameter nonlinear regression analyse.  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) 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).   

Claims

CLAIMS  1. Compounds of formula (I)  in which 
Figure imgf000269_0001
both A  represent either ‐CH2‐ or ‐CH2‐CH2‐,  R3  represents ‐H or ‐CH3,  X  represents either a direct bond, ‐CH2‐ or ‐O‐,  Y  represents ‐H, ‐Cl, ‐F, ‐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)),   • ‐phenyl, C3‐6‐cycloalkyl,   • ‐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  •   in which R6 and R7 are independently of each other hydrogen, ‐CH3  or bridged by C1‐C4‐alkyl in which one ‐CH2‐group can be replaced by oxygen,   •   or  ;  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,   •  ,   • 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‐,   •  , 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)),  • ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted  with ‐F or ‐Cl;  • 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,  • or in which 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  ,  ,  ,  ,   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‐cycloalkoxy,   • 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   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) according to claim 1  in which  both A  represent ‐CH2‐,  R3  represents ‐H,  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   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,   ,   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)),  • ‐CR20R21‐R22 in which R20 is ‐CH3, R21 is ‐H, ‐CH3 or R20 and R21 together are ‐ CH2‐CH2‐CH2‐ and in which R22 is phenyl or pyridyl, both optionally substituted  with ‐F or ‐Cl;  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   or  ,  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‐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, ‐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   or  .  4.  Compounds according to claim 1 or 2 wherein R2 is     5.  Compounds according to claim 1 or 2 wherein R2 is    
  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  tert‐butyl 2'‐(2‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(2‐aminopyrimidin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐[5‐(trifluoromethyl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  tert‐butyl 2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate   
tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  tert‐butyl 2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  (pyrimidin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (1‐methyl‐1H‐pyrazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanenitrile  3‐methoxy‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]propan‐1‐ one  3‐(1H‐pyrazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  2‐(morpholin‐4‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  2‐(pyrimidin‐5‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  (3‐chlorophenyl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  (pyridin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]methanone  2‐ethyl‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butan‐1‐one  1‐{2‐oxo‐2‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethyl}pyrrolidin‐2‐one  (pyridin‐3‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]methanone  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]cyclopropane‐ 1‐carbonitrile  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐one  (1‐methyl‐1H‐imidazol‐5‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone   
2‐methoxyethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  2‐methoxyethyl 6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyrimidin‐4‐ yl)methanone  (1‐methyl‐1H‐pyrazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐3‐(1H‐ pyrazol‐1‐yl)propan‐1‐one  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (morpholin‐4‐yl)ethan‐1‐one  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ (pyrimidin‐5‐yl)ethan‐1‐one  (3‐chlorophenyl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐4‐ yl)methanone  2‐ethyl‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]butan‐1‐one  1‐{2‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐ oxoethyl}pyrrolidin‐2‐one  [6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl](pyridin‐3‐ yl)methanone  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]cyclopropane‐1‐carbonitrile  1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]ethan‐1‐one  (1‐methyl‐1H‐imidazol‐5‐yl)[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  3‐methoxy‐1‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  4‐[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐4‐ oxobutanenitrile  1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]   
N,N‐dimethyl‐5‐{[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine  1‐[(1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐indazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐(cyclohexylmethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  6'‐methyl‐1‐[(2‐methylpyrimidin‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  N,N‐dimethyl‐5‐{[6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methyl}‐1,3‐thiazol‐2‐amine  6'‐methyl‐1‐[(pyrazolo[1,5‐a]pyrimidin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐indazol‐3‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐(cyclohexylmethyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐(cyclopropanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐(cyclopropanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  6'‐methyl‐N‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  6'‐methyl‐1‐(pyridin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  N‐(2‐chloroethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  2'‐(quinolin‐3‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide   
N‐cyclopentyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐tert‐butyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  methyl [2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbonyl]carbamate  N‐[(furan‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐(2‐methoxyethyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐phenyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carbothioamide  1‐(methanesulfonyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐(methanesulfonyl)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  ethyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  ethyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  1‐[(4‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(imidazo[1,5‐a]pyridin‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐{[1‐(propan‐2‐yl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(quinolin‐3‐yl)‐1‐{[4‐(trifluoromethyl)‐1H‐imidazol‐2‐yl]methyl}‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐(2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐{[1‐(2‐methoxyethyl)‐1H‐imidazol‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(quinolin‐3‐yl)‐1‐[(1,4,5‐trimethyl‐1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐benzimidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(1H‐pyrazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]   
1‐[(4‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(2‐methyl‐1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  1‐[(1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐[(1H‐imidazol‐5‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  1‐[(5‐methyl‐1H‐pyrrol‐2‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  3‐(ethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione  3‐(dimethylamino)‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]cyclobut‐3‐ene‐1,2‐dione  2‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  3‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one  4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]pyrrolidin‐2‐ one  2‐(1H‐imidazol‐1‐yl)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]ethan‐1‐one  4‐oxo‐4‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]butanamide  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]‐2‐(4H‐1,2,4‐triazol‐4‐ yl)ethan‐1‐one  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐yl]prop‐2‐en‐1‐one  3‐(dimethylamino)‐1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]propan‐1‐one  N'‐cyano‐N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide  N'‐cyano‐N,N‐dimethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboximidamide  N‐[3‐(dimethylamino)propyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐(oxan‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐{[‐oxolan‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide   
(4‐methylpiperazin‐1‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  N‐[2‐oxopyrrolidin‐3‐yl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  1‐[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carbonyl]azetidine‐3‐ carboxamide  N‐[(1H‐pyrazol‐3‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  (morpholin‐4‐yl)[2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl]methanone  N‐(3‐hydroxypropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐(2‐hydroxyethyl)‐N‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐(2‐oxopiperidin‐4‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐(6‐oxopiperidin‐3‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐[2‐(1H‐imidazol‐1‐yl)ethyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐benzyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐(2‐hydroxy‐2‐methylpropyl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐[(1‐methyl‐1H‐imidazol‐4‐yl)methyl]‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐{[‐5‐oxopyrrolidin‐2‐yl]methyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  [‐3‐(dimethylamino)pyrrolidin‐1‐yl][2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazol]‐1‐yl]methanone  N‐{2‐[oxolan‐3‐yl]ethyl}‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  2'‐(2‐aminopyrimidin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide   
2'‐(6‐aminopyridin‐3‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(pyrido[2,3‐b]pyrazin‐7‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(furo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(6‐fluoroquinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐[5‐(pyrrolidin‐1‐yl)pyridin‐3‐yl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(2‐oxo‐2,3‐dihydro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(1H‐pyrrolo[3,2‐b]pyridin‐6‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  ethyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate  ethyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  ethyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate   
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐methyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]  tert‐butyl 2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  tert‐butyl 2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  N‐ethyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]ethan‐1‐one  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐methylpropan‐1‐one  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carbonyl]cyclopropane‐1‐carbonitrile  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](phenyl)methanone  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](oxan‐4‐yl)methanone  tert‐butyl 2'‐(6‐aminopyridin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxylate   
tert‐butyl 2'‐(2‐chloro‐3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxylate  tert‐butyl 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐cyclobutyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (rac)‐6'‐methyl‐N‐(propan‐2‐yl)‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  (rac)‐N‐tert‐butyl‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  N‐ethyl‐2'‐(6‐methoxyquinolin‐3‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]‐1‐ carboxamide  N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐yl}‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(propan‐2‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  N‐tert‐butyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐phenyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(quinolin‐3‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]‐1‐ carboxamide   
N‐ethyl‐2'‐[6‐(trifluoromethyl)quinolin‐3‐yl]‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐[3‐(propan‐2‐yl)‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl]‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide  N‐ethyl‐2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  N‐ethyl‐2'‐(1H‐pyrazolo[3,4‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridine]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydrospiro[piperidine‐4,4'‐pyrazolo[5,1‐ c][1,4]oxazine]‐1‐carboxamide  N‐ethyl‐2'‐{6‐[(propan‐2‐yl)oxy]quinolin‐3‐yl}‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxamide  2'‐[6‐(cyclohexyloxy)quinolin‐3‐yl]‐N‐ethyl‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐ carboxamide  cyclopentyl (rac)‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]‐ 1‐carboxylate  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(5‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐ dihydrospiro[azetidine‐3,4'‐pyrazolo[5,1‐c][1,4]oxazine]  2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐2'‐(3‐ethyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐ dihydrospiro[azetidine‐3,4'‐pyrrolo[1,2‐b]pyrazole]   
(rac)‐1‐[(4‐chloro‐1H‐pyrazol‐5‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydrospiro[azetidine‐ 3,4'‐pyrazolo[5,1‐c][1,4]oxazine]  (rac)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6'‐methyl‐2'‐(quinolin‐3‐yl)‐5',6'‐dihydrospiro[azetidine‐3,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydro‐5'H‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐6',7'‐dihydro‐5'H‐ spiro[piperidine‐4,4'‐pyrazolo[1,5‐a]pyridine]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(3,3,3‐trifluoropropyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1H‐imidazol‐2‐yl)methyl]‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]  1‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(cyclohexylmethyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propan‐2‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐[(1‐methyl‐1H‐pyrazol‐4‐yl)methyl]‐5',6'‐ dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazole]  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridin]‐1‐yl](4‐fluorophenyl)methanone  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐pyrazolo[1,5‐ a]pyridin]‐1‐yl](oxan‐4‐yl)methanone  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(methanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐sulfonamide  2'‐(3‐chloro‐2‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐ethyl‐6',7'‐dihydro‐5'H‐spiro[piperidine‐4,4'‐ pyrazolo[1,5‐a]pyridine]‐1‐carboxamide  tert‐butyl 2'‐(3‐methyl‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxylate  [2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐1‐ yl](morpholin‐4‐yl)methanone   
2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide 2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2‐hydroxy‐2‐methylpropyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐methyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N‐(2,2,2‐trifluoroethyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]‐1‐carboxamide  N‐benzyl‐2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐carboxamide  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐hydroxyethan‐1‐one  1‐[2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐b]pyrazol]‐ 1‐yl]‐2‐(pyridin‐3‐yl)ethan‐1‐one  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(phenylmethanesulfonyl)‐5',6'‐dihydrospiro[piperidine‐ 4,4'‐pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(propane‐1‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐N,N‐dimethyl‐5',6'‐dihydrospiro[piperidine‐4,4'‐pyrrolo[1,2‐ b]pyrazole]‐1‐sulfonamide  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(pyridine‐3‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  2'‐(3‐chloro‐1H‐pyrrolo[2,3‐b]pyridin‐5‐yl)‐1‐(morpholine‐4‐sulfonyl)‐5',6'‐dihydrospiro[piperidine‐4,4'‐ pyrrolo[1,2‐b]pyrazole]  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  , , or   wherein R1, R3, A, X and Y have the same meaning in claim 1 or 2.   
PCT/EP2021/065122 2020-06-09 2021-06-07 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 WO2021249913A1 (en)

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