WO2021249913A1 - 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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WO2021249913A1
WO2021249913A1 PCT/EP2021/065122 EP2021065122W WO2021249913A1 WO 2021249913 A1 WO2021249913 A1 WO 2021249913A1 EP 2021065122 W EP2021065122 W EP 2021065122W WO 2021249913 A1 WO2021249913 A1 WO 2021249913A1
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pyrrolo
dihydrospiro
azetidine
alkyl
pyrazole
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PCT/EP2021/065122
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French (fr)
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WO2021249913A9 (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 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 where it induces dissociation of this complex through its serine/threonine kinase function.
  • MAP4K1 phosphorylates the SLP-76 adaptor protein at Serine-376, resulting in downregulation of AP-1 and Erk2 pathways.
  • MAPK1 acts as a negative feedback on TCR-signaling (Liou et al., Immunity. 2000 Apr;12(4):399-408; Lasserre et al., J Cell Biol. 2011 Nov 28;195(5):839-53.).
  • MAP4K1 can be triggered to suppress T cell function by prostaglandin E2 (PGE2), and possibly also by transforming growth factor beta (TGF-beta), factors that are commonly found in the tumor microenvironment.
  • PGE2 prostaglandin E2
  • TGF-beta transforming growth factor beta
  • MAP4K1 activation by these mediators involves protein kinase A (PKA)-dependent phosphorylation of Serine 171 (S-171; also in mouse) (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29; Sawasdikosol et al., J Biol Chem. 2007 Nov 30;282(48):34693-9.).
  • PKA protein kinase A
  • MAP4K1 deficient mice produced by two laboratories and with immune cells isolated from these mice (Shui et al., Nat Immunol. 2007 Jan;8(l):84-91; Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29).
  • MAP4Kl-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(l):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-/- mice are much more resistant to tumorigenesis by PGE2-producing Lewis lung carcinoma than wild type mice, which correlated with increased T-lymphocyte infiltration in the tumor areas.
  • the crucial role of T-cells in tumor rejection was supported by experiments in which MAP4K1-/- T-cells adoptively transferred into T-cell- deficient mice were able to eradicate tumors more efficiently than wild-type T-cells (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29).
  • MAP4K1 also regulates the stimulation and activation of dendritic cells.
  • MAP4K1 deficient Bone marrow derived cells express after maturation and stimulation higher level of costimulatory molecules and produce more proinflammatory cytokines. 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).
  • 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.
  • 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.
  • 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.
  • MAP4K1 (HPK1) inhibitors and methods for their use in diseases including hyperproliferative diseases, diseases of immune system dysfunction, intlammatory disorders, neurological diseases, and cardiovascular diseases are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 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 HPKl-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 HPKl-dependent disorders and enhancing immune response 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.
  • NPY receptors compositions and methods of the treatment of physiological disorders associated with an excess of neuropeptide Y are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • protein kinase MKK4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death are described.
  • 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 M AP4K1 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 -CH2- or -CH2-CH2-,
  • R3 represents -H or -CH3,
  • X represents either a direct bond -CH2- or -0-
  • Y represents -H, -Cl, -F, -Br, -CN, -CF3, Ci-C4-alkyl, C3-C7-cycloalkyl,
  • Ri represents a group in which *-A'- represents
  • R c represents -H or Ci-C4-alkyl
  • R c represents -H or Ci-C4-alkyl
  • R f represents Ci-C4-alkyl or C3-C7-cycloalkyl
  • R2 represents R 4 represents
  • R v represents -H or Ci-C 4 -alkyl
  • R w represents -H, Ci-C 4 -alkyl or -CH 2 -CF 3 or in which N, R v and R w together form a 4- to 7-membered heterocycloalkyl
  • N 6-membered heteroaryl (N), . o or — or in which N, R n and R 0 together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN,
  • R 5 represents -H, Ci-C 4 -alkyl, -F or -Cl,
  • Ri 5 represents -H, Ci-C4-alkyl, -CF3, -F, -CI,-0-CFl3 or -CN or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention also relates to compounds of formula (I) in which both A represent either -CH2- or -CH2-CH2-,
  • R3 represents -FI or -CH3
  • X represents either a direct bond, -CH2- or -0-
  • Y represents -FI, -Cl, -F, -Br, -CN, -CF 3 , Ci-C 4 -alkyl, C 3 -C 7 -cycloalkyl,
  • Ri represents a group *-A'-B, in which *-A'- represents
  • R c represents -H or Ci-C 4 -alkyl
  • R c represents -H or Ci-C 4 -alkyl
  • R f represents Ci-C4-alkyl or C3-C7-cycloalkyl
  • R 2 represents
  • R 4 represents
  • R v represents -H or Ci-C 4 -alkyl
  • R w represents -H, Ci-C 4 -alkyl or -CH2-CF3 or in which N, R v and R w together form a 4- to 7-membered heterocycloalkyl
  • R n represents -H or Ci-C 4 -alkyl
  • R 0 represents Ci-C 6 -hydroxyalkyl, 5- or 6- membered heteroaryl (N), or or in which N, R n and R 0 together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN,
  • R 5 represents -H, Ci-C 4 -alkyl, -F or -Cl,
  • Ri5 represents -H, Ci-C 4 -alkyl, -CF 3 , -F, -CI,-0-CFl 3 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.
  • 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".
  • 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.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • Ci-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, ferf-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl,
  • 1.2-dimethylbutyl or 1,3-dimethylbutyl group or an isomer thereof.
  • said group has 1, 2, 3 or 4 carbon atoms ("Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or ferf- butyl group, more particularly 1, 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • Ci-C 6 -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-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, l-hydroxypropan-2-yl, 2-hydroxypropan-2-yl,
  • Ci-C 6 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-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 Ci-C 6 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl,
  • perfluorinated alkyl radicals which are named as "perfluoro-Ci-C x -alkyl-" wherein x is the maximum number of carbon atoms such as trifluoromethyl or 2,2,2-trifluoroethyl.
  • Ci-C 6 -cyanoalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “Ci-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.
  • Ci-C 6 -alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-Cs-alkyl)-O-, in which the term "Ci-C 6 -alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
  • Ci-C 6 -haloalkoxy means a linear or branched, saturated, monovalent Ci-C 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said Ci-C 6 -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • perfluorinated alkyl radicals which are named as "perfluoro-Ci-C x -alkoxy-" wherein x is the maximum number of carbon atoms such as trifluoromethoxy and 2,2,2-trifluoroethoxy radicals.
  • Ci-C 6 -cyanoalkoxy means a linear or branched, saturated, monovalent Ci-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-(Ci-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 ferf-butylamino, for example.
  • Di-(Ci-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: A/,A/-dimethylamino, A/,A/-diethylamino, A/-ethyl-A/-methylamino, A/-methyl-A/-n-propylamino, N- isopropyl-A/-methylamino, A/-isopropyl-A/-n-propylamino, A/,A/-diisopropylamino, A/-n-butyl-A/-methyl- amino, and A/-ferf-butyl-A/-methylamino, for example.
  • C3-Cs-cycloalkyl means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-Cs-cycloalkyl").
  • Said C3-Cs-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)-0-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “C 3 -C 8 -cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.
  • heterocycloalkyl and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated or unsaturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl,
  • 1.4-dioxanyl or 1,2-oxazinanyl for example, or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or
  • 4- to 6-membered heterocycloalkyl means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S.
  • 5- or 6-membered heterocycloalkyl means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O.
  • Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, 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, benzimidazolyl,
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • Ci-Ce as used in the present text, e.g. in the context of the definition of "Ci-C 6 -alkyl”, “Ci-C 6 -haloalkyl", “Ci-C 6 -hydroxyalkyl”, “Ci-C 6 -alkoxy” or “Ci-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. 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.
  • C 6 M encompasses Ci, C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , Ci-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 2 -C 6 , C 2 -Cs, C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 ,
  • C 3 -C 10 encompasses C 3 , C 4 , C 5 , Ce, C 7 , Cs, Cg, C 10 , C 3 -C 10 , C 3 -C 9 , C 3 -C 8 , C 3 -C 7 ,
  • C 3 -C 8 encompasses C 3 , C 4 , C 5 , C 6 , C 7 , Cs, C 3 -C 8 , C 3 -C 7 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 8 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , Cs-Cs, C 5 -C 7 , C 5 -C 6 , Cs-Cs, C 6 -C 7 and C 7 -C 8 ;
  • C3-C6 encompasses C3, C 4 , C5, C6, C3-C6, C3-C5, C3-C 4 , C 4 -C6, C 4 -C5, and C5-C6;
  • C 4 -C 8 encompasses C 4 , C 5 , C 6 , C 7 , Cs, C 4 -C 8 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , Cs-Cs, C 5 -C 7 ,
  • C 4 -C 7 encompasses C 4 , C 5 , C 6 , C 7 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C 5 -C 7 , C 5 -C 6 and C 6 -C 7 ;
  • C 4 -C 6 encompasses C 4 , C 5 , C 6 , C 4 -C 6 , C 4 -C 5 and C 5 -C 6 ;
  • C 5 -C 10 encompasses C 5 , C 6 , C 7 , Cs,C g , C 10 , C 5 -C 10 , C 5 -C 9 , Cs-Cs, C 5 -C 7 , C 5 -C 6 , C 6 -C 10 , C 6 -C 9 , C 6 -Cs, C 6 -C 7 , C 7 - C 10 , C 7 -C 9 , C 7 -C 8 , Cs-Cio, Cs-Cg and C 9 -C 10 ;
  • C 6 -C 10 encompasses C 6 , C 7 , Cs,C g , C 10 , C 6 -C 10 , C 6 -C 9 , C 6 -Cs, C 6 -C 7 , C 7 -C 10 , C 7 -C 9 , C 7 -C 8 , Cs-Cio,Cs-Cg and Cg- Cio-
  • 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-triisopropylphen
  • 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.
  • 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.
  • 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.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • 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
  • D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid for example.
  • 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.
  • R3 represents -H
  • X represents either a direct bond, -CH2- or -0-
  • Y represents -H, -Cl, -Br, -CN, -CF 3 , Ci-C4-alkyl, Cs-Grcycloalkyl,
  • Ri represents a group *-A'-B, in which *-A'- represents a direct bond and in which B represents -FI or in which *-A'- represents a group
  • R 6 and R 7 are hydrogen or bridged by Ci-C 4 -alkyl in which one -CH 2 -group can be replaced by oxygen
  • R c represents -FI or Ci-C 4 -alkyl
  • R c represents -FI or Ci-C 4 -alkyl
  • B represents -H
  • R 2 o is -CH 3
  • Ci-C4-alkoxy or C 3 -C 7 -cycloalkyl a group -(CH 2 ) n -R e in which n is 1 or 2 and in which R e represents
  • R 2 represents or
  • R 4 represents
  • R n represents -FI or Ci-C4-alkyl
  • R 0 represents Ci-C 6 -hydroxyalkyl
  • N 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 -FI, -F or -Cl
  • Ri5 represents -FI, 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 -CFI2-, R3 represents -H,
  • X represents either a direct bond, -CH 2 - or -0-
  • Y represents -H, -Cl, -Br, -CN, -CF 3 , Ci-C 4 -alkyl, C 3 -C 7 -cycloalkyl,
  • Ri represents a group in which *-A'- represents a direct bond and in which B represents -H or in which *-A'- represents a group
  • R6 or R7 in which R 6 and R 7 are hydrogen or bridged by Ci-C 4 -alkyl in which one -Chh-group can be replaced by oxygen, in which A' represents a group *-C( 0)- and in which B represents
  • Ci-C4-alkoxy or C 3 -C 7 -cycloalkyl a group -(CH 2 )n-Re in which n is 1 or 2 and in which R e represents
  • R 2 represents
  • R 4 represents -H
  • R n represents -H or Ci-C4-alkyl
  • R 0 represents Ci-C 6 -hydroxyalkyl
  • N 6-membered heteroaryl (N), ⁇ o ' or or in which N, R n and R 0 together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN,
  • R 5 represents -H, -F or -Cl
  • Ri 5 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
  • Gi Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein X is oxygen.
  • H Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein Y is hydrogen or -Cl.
  • the compounds of general formula (I) of the present invention can be converted to any salt, preferably pharmaceutically acceptable salts, as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of general formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted.
  • 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 examples include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli-Leydig cell tumour and arrhenoblastoma.
  • cervical cancer examples include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • esophageal cancer examples 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 examples 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 examples 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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: m l-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
  • the compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD-l/-Ll axis antagonists.
  • immune checkpoint inhibitors e.g. aPD-l/-Ll 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-l/-Ll 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.
  • CAR-T cells chimeric antigen receptor T cells
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 l-lll (AB block l-lll), 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, valvo
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left-heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic-obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1- antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic-obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • AATD alpha-1- antitrypsin deficiency
  • CF
  • the compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post- traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick ' s syndrome, Parkinson's disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They
  • the compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma.
  • the compounds according to the invention can likewise be used for controlling states of pain and tinnitus.
  • the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for treatment and/or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammations
  • Crohn's disease UC
  • pancreatitis peritonitis
  • rheumatoid disorders inflammatory skin disorders and inflammatory eye disorders.
  • the compounds according to the invention can also be used for treatment and/or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
  • fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • the compounds according to the invention are also suitable for controlling postoperative scarring, for example as a result of glaucoma operations.
  • the compounds according to the invention can also be used cosmetically for ageing and keratinized skin.
  • the compounds according to the invention are suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.
  • the present invention further provides the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
  • the present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.
  • the present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
  • the present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld-Jakob.
  • 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.
  • treating or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liquid and solid tumours.
  • the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their activity as MAP4K1 inhibitors.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the use of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • a pharmaceutical composition preferably a medicament
  • the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N- oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • a compound of general formula (I) as described supra, or stereoisomers, tautomers, N- oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a 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 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.
  • 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
  • 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, Avicef ), 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
  • 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 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 for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • 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 for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopof ); 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 AcDiSof )
  • flow regulators for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosif)
  • 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
  • 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),
  • 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
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • antioxidants 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 • 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.
  • 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 of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • 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.
  • a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • 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.
  • NMR signals: shift in [ppm]. Combinations of multiplicity could be e.g. dd doublet from doublet.
  • ⁇ -NMR peaklists The ⁇ -NMR data of selected examples / intermediates are listed in the form of ⁇ -NMR peaklists. For each signal peak the d value in ppm is given, followed by the signal intensity, reported in round brackets. The d value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: di (intensityi), d 2 (intensity2), ... , d, (intensity,), ... , d h (intensity,,).
  • 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 ⁇ -NMR peaklist is similar to a classical ⁇ -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 intensity compared to the peaks of the title compounds (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the title compounds by known methods can isolate the peaks of title compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical ⁇ -NMR interpretation.
  • LiHMDS lithium l,l,l,3,3,3-hexamethyldisilazan-2-ide
  • peripheral blood mononuclear cells (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one - palladium (3:2)
  • 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.
  • 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.
  • 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.
  • 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, 4 th edition, Wiley 2006).
  • 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.
  • 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.
  • 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. 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.
  • 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 ora 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.
  • 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 ora tert-butyl group
  • A, R 1 , R 2 , R 3 and Y have the meaning as given for general formula (I).
  • ester derivative 1 can be alkylated using an alkylbromide or alkyliodide of formula 2 to give the desired product 3.
  • 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 LiFIMDS or LDA.
  • 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 LiFIMDS or LDA in an organic solvent like THF at a temperature range between -78°C and room temperature.
  • the protecting group PG 2 of pyrazoles of formula 5 can be cleaved to give an alcohol of formula 6.
  • the cleavage of suitable alcohol protecting groups is well-known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in "Protective Groups in Organic Synthesis", 4 th edition, Wiley 2006).
  • PG2 in compounds of formula 5 is TBDMS
  • cleavage can be achieved using e.g. HCI in an organic solvent such as methanol or TBAF in an organic solvent such as THF.
  • 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 can be used.
  • Spiro compounds of formula 7 can be converted to triflates of formula 8.
  • the reaction is performed using Tf 2 0 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 temperature range between room temperature and the boiling point of the selected solvent.
  • 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.
  • 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.
  • the coupling reaction is catalyzed by palladium catalysts, e.g.
  • Pd(0) catalysts like tetrakis(triphenyl- phosphine)palladium(O) [Pd(PPhs) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba) ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (II) [PdfPPhs C ], palladium (II) acetate and triphenylphosphine, [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(ll), X-Phos aminobiphenyl
  • the reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, TFIF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate (review: D.G. Flail, Boronic Acids, 2005 WILEY-VCFI Verlag GmbFI & 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.
  • boronic acid derivative R 2 -B(OR) 2
  • the coupling reaction is catalyzed by palladium catalysts, e.g.
  • Pd(0) catalysts like tetrakis(triphenyl- phosphine)palladium(O) [Pd(PPh 3 )4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (II) [Pd(PPh 3 )2Cl2], palladium (II) acetate and triphenylphosphine, [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(ll), X-P
  • 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. Flail, Boronic Acids, 2005 WILEY-VCFI Verlag GmbFI & 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 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.
  • Amines of formula 12 can be functionalized with a broad variety of substituents to give compounds of formula 13.
  • secondary amines of formula 13 can be reacted to give tertiary amines, amides, ureas, carbamates or sulphonamides of formula 13. All these tranformations are known to the skilled person.
  • Pyrazole compounds of formula 13 can be converted to bromides of formula 14.
  • the reaction is performed using NBS in an organic solvent such as for example DMF.
  • 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. Boc), X 1 represents a direct bond or -CH2-, Z 1 represents a methyl group or a tert-butyl group and R 3 represents a methyl group (In this method R 3 can only be a methyl group) and A has the meaning as given for general formula (I).
  • PG 1 represents a suitable amine protecting group (e.g. Boc)
  • X 1 represents a direct bond or -CH2-
  • Z 1 represents a methyl group or a tert-butyl group
  • R 3 represents a methyl group
  • A has the meaning as given for general formula (I).
  • Compounds of the general formula 1 can be converted to compounds of the general formula 17 by alkylation.
  • 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.
  • 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.
  • 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 temperature between -20°C and the boiling point of the selected solvent.
  • 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. SEM), 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.
  • 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.
  • the conversion can be carried out in analogy to a literature procedure described in Tetrahedron, 1983, 39, 2023-2029.
  • 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
  • 2- (trimethylsilyl)ethoxymethylchloride a base such as sodium hydride in an organic solvent such as THF can be used.
  • 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.
  • 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. Greene in "Protective Groups in Organic Synthesis", 4 th edition, Wiley 2006).
  • PG 3 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)
  • hydride reducing agents known to the skilled person.
  • lithium borohydride in an organic solvent, such as THF can be used.
  • Step 27 28 (Scheme 3)
  • 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. Wuts and T.W. Greene in "Protective Groups in Organic Synthesis", 4 th edition, Wiley 2006).
  • PG1 in compounds of formula 27 is BOC
  • cleavage can be achieved using e.g. TFA in an organic solvent such as DCM.
  • Amines of formula 28 can be functionalized with a broad variety of substituents to give compounds of formula 23.
  • 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.
  • Flalogen 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.
  • Pd(0) catalysts like tetrakis(triphenyl- phosphine)palladium(O) [Pd(PPhs)4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (II) [Pd PPhs C ], palladium (II) acetate and triphenylphosphine, [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(ll), X-Phos aminobipheny
  • the reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, TFIF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate, (review: D.G. Flail, Boronic Acids, 2005 WILEY-VCFI Verlag GmbFI & 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.
  • 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.

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

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 where it induces dissociation of this complex through its serine/threonine kinase function. In particular MAP4K1 phosphorylates the SLP-76 adaptor protein at Serine-376, resulting in downregulation of AP-1 and Erk2 pathways. As, such, MAPK1 acts as a negative feedback on TCR-signaling (Liou et al., Immunity. 2000 Apr;12(4):399-408; Lasserre et al., J Cell Biol. 2011 Nov 28;195(5):839-53.). Alternatively, MAP4K1 can be triggered to suppress T cell function by prostaglandin E2 (PGE2), and possibly also by transforming growth factor beta (TGF-beta), factors that are commonly found in the tumor microenvironment. Notably, MAP4K1 activation by these mediators involves protein kinase A (PKA)-dependent phosphorylation of Serine 171 (S-171; also in mouse) (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29; Sawasdikosol et al., J Biol Chem. 2007 Nov 30;282(48):34693-9.).
Further important insights into the function of MAP4K1 in the regulation of T cell immunity stem from in vivo and in vitro experiments respectively with MAP4K1 deficient mice produced by two laboratories and with immune cells isolated from these mice (Shui et al., Nat Immunol. 2007 Jan;8(l):84-91; Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419-29). MAP4Kl-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(l):84-91). In case of the second strain, a dysregulation of immune function was observed when, at the age of approximately 6 months, MAP4Kl-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(l):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(l):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 W02019090198A1, 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 HPKl-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 HPKl-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 HPKl-dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.ln 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 W02016/004272 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 W02006116713 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 M AP4K1 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 both A represent either -CH2- or -CH2-CH2-,
R3 represents -H or -CH3,
X represents either a direct bond -CH2- or -0- Y represents -H, -Cl, -F, -Br, -CN, -CF3, Ci-C4-alkyl, C3-C7-cycloalkyl,
Ri represents a group 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, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)) or in which *-A'- represents a group
*-CRaFI-, in which Ra represents
• hydrogen,
• Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CFI3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0)),
• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -FI 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 (=0)) and in which B represents
• hydrogen,
• -CN, • Ci-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, - S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -C(=0)-NHRb, in which Rb represents ·· hydrogen,
·· Ci-C4-alkoxy,
·· Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CH3, -S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or ·· phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl (optionally -OCH3 substituiert), C3- Cycycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or
R6
• R7 in which R6 and R7 are hydrogen or bridged by Ci-C4-alkyl in which one -CH2-group can be replaced by oxygen, in which A' represents a group
• *-C(=0)- or *-S02- and in which B represents
• Ci-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, Ci-C4-alkoxy, an oxo-group (=0),-S(0)2-CH3, -S(0)(NRZ)-CH3, or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=0)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) or 5- to 6- membered heteroaryl,
• C2-C4-alkenyl,
• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
• -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 (=0)), or in which A' represents a group
*-C(=0)-0-,
N(Rc)-
, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=0)-NRc-, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=S)-NRc-, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=N-CN)-0- or
• *-C(=N-CN)-NRc, in which Rc represents -H or Ci-C4-alkyl and in which B represents
• -H,
• Ci-C6-alkyl, Ci-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)), • -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, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)),
• -SC>2-(Ci-C4-alkyl),
• a group -C(=0)-Rd, in which Rd represents
·· -CF3,
·· Ci-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 (=0),
·· -phenyl, optionally substituted with Ci-C4-alkyl, or
·· 5- or 6- membered heteroaryl, optionally substituted with
Ci-C4-alkyl,
• or in which N, Rc and B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci-C4-alkyl or -NRxRy, in which Rx and Ry represent independently of each other -FI 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 (=0)), or
• a group -C(=0)-Rf, in which Rf represents Ci-C4-alkyl or C3-C7-cycloalkyl,
R2 represents R4 represents
• -H,
• -NO2,
• -CN,
• -OH,
• -P(=0)(Ci-C4-alkyl)2,
• -S(=0)2-(Ci-C4-alkyl),
. -N=S(=NH)(Ci-C4-alkyl)2,
• -N=S(=0)(Ci-C4-alkyl)2,
• halogen
• -C(=0)-0- Ci-C4-alkyl,
• -C(=0)- Ci-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 Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=0),
·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)),
·· C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)),
·· -C(=0)-NRvRw or -C(=0)-0-Rv, in which Rv represents -H or Ci-C4-alkyl, Rw represents -H, Ci-C4-alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl
• C3-C6-alkenyloxy,
• Ci-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7-membered heterocycloalkenyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, - S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)), -C(=0)-0-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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
• 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
• phenyl, optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci- C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), C1-C4- alkoxy, -S(0)2-CH3, -S(0)(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 (=0)),
• -NRiRj, in which R, represents -H, Ci-C4-alkyl and Rj represents -H, Ci-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, R, and Rj together form a 4- to 7- membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=0) or Ci-C4-alkyl
• -NRrS(=0)2-Rp, in which R, represents -H, Ci-C4-alkyl and Rp represents 5- or 6-membered heteroaryl,
• -NH-C(=0)-NRkR|, in which Rk represents -H or Ci-C4-alkyl and Ri represents
·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -FI 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 (=0)), or ·· Ci-C4-alkyl, C3-Grcycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CFI3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0))
• -NFI-C(=0)-Rm, in which Rm represents
·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with - CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)), or
·· Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CFl3, - S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0)),
• -(C=0)-NRnRo, in which Rn represents -H or Ci-C4-alkyl, R0 represents Ci-C6-hydroxyalkyl, 5- or
6-membered heteroaryl (N), . o or — or in which N, Rn and R0 together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN,
R5 represents -H, Ci-C4-alkyl, -F or -Cl,
Ri5 represents -H, Ci-C4-alkyl, -CF3, -F, -CI,-0-CFl3 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) in which both A represent either -CH2- or -CH2-CH2-,
R3 represents -FI or -CH3,
X represents either a direct bond, -CH2- or -0-,
Y represents -FI, -Cl, -F, -Br, -CN, -CF3, Ci-C4-alkyl, C3-C7-cycloalkyl,
Ri 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, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)) or in which *-A'- represents a group
*-CRaH-, in which Ra represents
• hydrogen,
• Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CH3, -S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -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 (=0)),
• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), C C4-alkoxy, -S(0)2-CH3, -S(0)(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 (=0)) and in which B represents
• hydrogen,
• -CN,
• Ci-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, - S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -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 (=0)),
• -phenyl, C3.6-cycloalkyl,
• -C(=0)-NHRb, in which Rb represents
·· hydrogen,
·· Ci-C4-alkoxy,
·· Ci-C4-alkyl, C3-Grcydoalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-
CH3, -S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -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 (=0)), or ·· phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, - OCF3, -OCF2H, halogen, Ci-C4-alkyl (optionally -OCFI3 substituiert), C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -FI 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 (=0)), or
• R7 in which R6 and R7 are independently of each other hydrogen, -CFI3 or bridged by Ci-C4-alkyl in which one -CFh-group can be replaced by oxygen, in which A' represents a group
• *-C(=0)- or *-S02- and in which B represents
• Ci-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, Ci-C4-alkoxy, an oxo-group (=0),-S(0)2-CFl3, -S(0)(NRz)-CFl3, or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or C1-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=0)-NFI2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) or 5- to 6- membered heteroaryl,
• C2-C4-alkenyl,
• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo group ( 0)) C C alkoxy S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)),
• -NRxRy, in which Rx and Ry represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or in which A' represents a group
*-C(=0)-0-,
N(Rc)-
, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=0)-NRc-, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=S)-NRc-, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=N-CN)-0- or
• *-C(=N-CN)-NRc, in which Rc represents -H or Ci-C4-alkyl and in which B represents
• -H,
• Ci-C6-alkyl, Ci-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -CR20R21-R22 in which R2o is -CH3, R2I is -H, -CH3 or R2o and R2I 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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)),
• -S02-(Ci-C4-alkyl),
• a group -C(=0)-Rd, in which Rd represents
·· -CF¾
·· Ci-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 (=0),
·· -phenyl, optionally substituted with Ci-C4-alkyl, or
·· 5- or 6- membered heteroaryl, optionally substituted with Ci-C4-alkyl,
• or in which N, Rc and B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci-C4-alkyl or -NRxRy, in which Rx and Ry represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)), or
• a group -C(=0)-Rf, in which Rf represents Ci-C4-alkyl or C3-C7-cycloalkyl,
R2 represents
R4 represents
• -H,
• -N02,
• -CN,
• -OH,
• -P(=0)(Ci-C4-alkyl)2,
• -S(=0 )2-(Ci-C4-al kyl ),
. -N=S(=NH)(Ci-C4-alkyl)2, • -N=S(=0)(Ci-C4-alkyl)2,
• halogen
• -C(=0)-0- Ci-C4-alkyl,
• -C(=0)- C C4-alkyl,
• -O-CHs,
• -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 Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=0),
·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, Cs-Grcycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
·· C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with - OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), - S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
·· -C(=0)-NRvRw or -C(=0)-0-Rv, in which Rv represents -H or Ci-C4-alkyl, Rw represents -H, Ci-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,
• Ci-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7-membered heterocycloalkenyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or C C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), -C(=0)-0-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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl, 4- to 7 membered heterocycloalkyl, Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRZ)-CH3 or - NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, Ci-C4-fluoroalkyl, - OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci- C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• phenyl, optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFI3, - S(0)(NRZ)-CFI3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI or Ci- C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -N RjRj, in which R, represents -FI, Ci-C4-alkyl and Rj represents -FI, Ci-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, R, and Rj together form a 4- to 7-membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=0) or Ci-C4-alkyl
• -NRi-S(=0)2-Rp, in which R, represents -FI, Ci-C4-alkyl and Rp represents 5- or 6-membered heteroaryl,
• -NH-C(=0)-NRkRi, in which Rk represents -FI or Ci-C4-alkyl and Ri represents
·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4- fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or
·· Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, -S(0)(NRz)-CH3, Ci-C4- alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0))
• -NH-C(=0)-Rm, in which Rm represents ·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4- fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or
·· Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, -S(0)(NRz)-CH3, Ci-C4- alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -(C=0)-NRnRo, in which Rn represents -H or Ci-C4-alkyl, R0 represents Ci-C6-hydroxyalkyl, 5- or 6- membered heteroaryl (N), or or in which N, Rn and R0 together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN,
R5 represents -H, Ci-C4-alkyl, -F or -Cl,
Ri5 represents -H, Ci-C4-alkyl, -CF3, -F, -CI,-0-CFl3 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 "Ci-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, ferf-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 ("Ci-C4-alkyl"), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or ferf- butyl group, more particularly 1, 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group.
The term "Ci-C6-hydroxyalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-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, l-hydroxypropan-2-yl, 2-hydroxypropan-2-yl,
2.3-dihydroxypropyl, l,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl,
1-hydroxy-2-methyl-propyl group.
The term "Ci-C6-haloalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-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 Ci-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-Ci-Cx-alkyl-" wherein x is the maximum number of carbon atoms such as trifluoromethyl or 2,2,2-trifluoroethyl.
The term "Ci-C6-cyanoalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-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 "Ci-C6-alkoxy" means a linear or branched, saturated, monovalent group of formula (Ci-Cs-alkyl)-O-, in which the term "Ci-C6-alkyl" is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ferf-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof. The term "Ci-C6-haloalkoxy" means a linear or branched, saturated, monovalent Ci-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 Ci-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-Ci-Cx-alkoxy-" wherein x is the maximum number of carbon atoms such as trifluoromethoxy and 2,2,2-trifluoroethoxy radicals.
The term "Ci-C6-cyanoalkoxy" means a linear or branched, saturated, monovalent Ci-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-(Ci-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 ferf-butylamino, for example.
Di-(Ci-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: A/,A/-dimethylamino, A/,A/-diethylamino, A/-ethyl-A/-methylamino, A/-methyl-A/-n-propylamino, N- isopropyl-A/-methylamino, A/-isopropyl-A/-n-propylamino, A/,A/-diisopropylamino, A/-n-butyl-A/-methyl- amino, and A/-ferf-butyl-A/-methylamino, for example.
(Ci-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(=0)-L such as: acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl, and pivaloyl, for example.
(Ci-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(=0)- 0-], such as: acetoxy (=acyloxy), propionyloxy, n-butyryloxy, isobutyryloxy, n-pentanoyloxy, and pivaloyloxy, for example.
Mono-(Ci-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(=0)-] 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 ferf-butylaminocarbonyl, for example.
Di-(Ci-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(=0)-] 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, A/,A/-diethylaminocarbonyl, A/-ethyl-A/-methylaminocarbonyl, A/-methyl-A/-n- propylaminocarbonyl, A/-isopropyl-A/-methylaminocarbonyl, A/,A/-diisopropylaminocarbonyl, A/-n-butyl- /V-methylaminocarbonyl, and A/-ferf-butyl-A/-methylaminocarbonyl, for example.
Mono-(Ci-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(=0)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 ferf-butylaminosulfonyl, for example.
Di-(Ci-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(=0)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, A/,A/-diethylaminosulfonyl, A/-ethyl-A/-methylaminosulfonyl, A/-methyl-A/-n- propylaminosulfonyl, A/-isopropyl-A/-methylaminosulfonyl, A/,A/-diisopropylaminosulfonyl, A/-n-butyl- /V-methylaminosulfonyl, and A/-ferf-butyl-A/-methylaminosulfonyl, for example.
The term "C3-Cs-cycloalkyl" means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("C3-Cs-cycloalkyl"). Said C3-Cs-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)-0-, 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=0, -S(=0)- or -S(=0)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=0, -S(=0)- or -S(=0)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 "Ci-Ce", as used in the present text, e.g. in the context of the definition of "Ci-C6-alkyl", "Ci-C6-haloalkyl", "Ci-C6-hydroxyalkyl", "Ci-C6-alkoxy" or "Ci-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:
"CI-C6 M encompasses Ci, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, Ci-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, , C2-C6, C2-Cs, C2-C4, C2-C3, C3-C6, C3-C5,
C3-C4, C4-C6, C4-C5, and C5-C6;
"C3-C10" encompasses C3, C4, C5, Ce, C7, Cs, Cg, 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, Ce-Cio, Cs-Cg and
C9-C10;
"C3-C8" encompasses C3, C4, C5, C6, C7, Cs, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Cs, C5-C7, C5-C6, Cs-Cs, 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, Cs, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Cs, C5-C7,
C5-C6, Cs-Cs, 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, Cs,Cg, C10, C5-C10, C5-C9, Cs-Cs, C5-C7, C5-C6, C6-C10, C6-C9, C6-Cs, C6-C7, C7- C10, C7-C9, C7-C8, Cs-Cio, Cs-Cg and C9-C10;
"C6-C10" encompasses C6, C7, Cs,Cg, C10, C6-C10, C6-C9, C6-Cs, C6-C7, C7-C10, C7-C9, C7-C8, Cs-Cio,Cs-Cg and Cg- Cio-
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-ferf-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 lUPAC 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, seeS. M. Berge, etal. "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, A/-methylpiperidine, /V-methyl-glucamine, A/,A/-dimethyl-glucamine, /V-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2- amino-1, 3-propanediol, 3-amino-l, 2-propanediol, 4-amino-l,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, A/-benzyl-A/,A/,A/- 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 HCI", "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 -0-,
Y represents -H, -Cl, -Br, -CN, -CF3, Ci-C4-alkyl, Cs-Grcycloalkyl,
Ri represents a group *-A'-B, in which *-A'- represents a direct bond and in which B represents -FI or in which *-A'- represents a group
*-CRaFI-, in which Ra represents -H,
Ci-C4-alkyl or Cs-Grcycloalkyl all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, -S(0)(NRz)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -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 (=0)) and in which B represents -H,
-CN,
Ci-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, - S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -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 (=0)),
-C(=0)-NHRb, in which Rb represents
-H,
Ci-C -alkoxy,
Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CH3, -S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -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 (=0)), or phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl (optionally -OCH3 substituiert), C3- Cycycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(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 (=0)),
H or R7 in which R6 and R7 are hydrogen or bridged by Ci-C4-alkyl in which one -CH2-group can be replaced by oxygen, in which A' represents a group *-C(=0)- and in which B represents Ci-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, Ci-C4-alkoxy, an oxo-group (=0),-S(0)2-CFI3, -S(0)(NRZ)-CFI3, or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=0)-NFI2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) or 5- to 6- membered heteroaryl,
C2-C4-alkenyl, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-Chl3, -S(0)(NRZ)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)),
-NRxRy, in which Rx and Ry represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), in which A' represents a group *-C(=0)-0-,
*-C(=0)-NRc-, in which Rc represents -FI or Ci-C4-alkyl,
*-C(=S)-NRc-, in which Rc represents -FI or Ci-C4-alkyl, in which B represents -H,
Ci-C6-alkyl, Ci-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CFI3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -CR2OR2I-R22 in which R2o is -CH3, R is -FI, -CFH3 or R2o and Rn together are - CH2-CH2-CF-I2- 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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-Chl3, -S(0)(NRZ)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)),
-S02-(Ci-C4-alkyl), a group -C(=0)-Rd, in which Rd represents
-CF3,
Ci-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 (=0),
-phenyl or
5- or 6- membered heteroaryl, optionally substituted with Ci- C4-alkyl; or
N, Rc und B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci-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 (=0)), a group -C(=0)-Rf, in which Rf represents Ci-C4-alkyl or C3-C7-cycloalkyl,
R2 represents or
R4 represents
-H,
-N02, -CN,
-OH,
-P(=0)(C1-C4-alkyl)2,
-S(=0)2-(Ci-C4-alkyl), halogen
-C(=0)- Ci-C4-alkyl,
-O-CHs,
-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 Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl optionally substituted with an oxo-group (=0), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)),
C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), -C(=0)-NRvRw or -C(=0)-0-Rv, in which Rv represents -H or Ci-C4-alkyl, Rw represents -H, Ci-C4-alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl - C3-C6-alkenyloxy,
Ci-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7-membered heterocycloalkenyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, - S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)), -C(=0)-0-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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4- alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, Ci-C4-alkoxy, -S(0)2-CFI3, - S(0)(NRZ)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, Ci-C4- fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), phenyl, optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci- C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4- alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
-NRiRj, in which R, represents -FI, Ci-C4-alkyl and Rj represents -FI, Ci-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, R, and Rj together form a 4- to 7- membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=0) or Ci-C4-alkyl -NRrS(=0)2-Rp, in which R, represents -FI, Ci-C4-alkyl and Rp represents 5- or 6-membered heteroaryl,
-NH-C(=0)-NRkR|, in which Rk represents -FI or Ci-C4-alkyl and Ri represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CFI3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0))
-NH-C(=0)-Rm, in which Rm represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)), or
Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CFl3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0))
-(C=0)-NRnRo, in which Rn represents -FI or Ci-C4-alkyl, R0 represents Ci-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 -FI, -F or -Cl,
Ri5 represents -FI, 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 -CFI2-, R3 represents -H,
X represents either a direct bond, -CH2- or -0-,
Y represents -H, -Cl, -Br, -CN, -CF3, Ci-C4-alkyl, C3-C7-cycloalkyl,
Ri represents a group 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,
Ci-C4-alkyl or C3-C7-cycloalkyl all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, -S(0)(NRz)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) and in which B represents -H,
-CN,
Ci-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, - S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
-C(=0)-NHRb, in which Rb represents -H,
Ci-C4-alkoxy,
Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CH3, -S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl (optionally -OCH3 substituiert), C3- Cycycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
R6 or R7 in which R6 and R7 are hydrogen or bridged by Ci-C4-alkyl in which one -Chh-group can be replaced by oxygen, in which A' represents a group *-C(=0)- and in which B represents
Ci-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, Ci-C4-alkoxy, an oxo-group (=0),-S(0)2-CH3, -S(0)(NRZ)-CH3, or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=0)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) or 5- to 6- membered heteroaryl,
C2-C4-alkenyl, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)),
-NRxRy, in which Rx and Ry represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), in which A' represents a group *-C(=0)-0-,
*-C(=0)-NRc-, in which Rc represents -H or Ci-C4-alkyl, *-C(=S)-NRc-, in which Rc represents -H or Ci-C4-alkyl, in which B represents -H,
Ci-C6-alkyl, Ci-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
• -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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
-S02-(Ci-C4-alkyl), a group -C(=0)-Rd, in which Rd represents -CF3,
Ci-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 (=0),
-phenyl or
5- or 6- membered heteroaryl, optionally substituted with Ci- C4-alkyl; or
N, Rc und B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci-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 (=0)), a group -C(=0)-Rf, in which Rf represents Ci-C4-alkyl or C3-C7-cycloalkyl,
R2 represents
R4 represents -H,
-N02,
-CN,
-OH,
-P(=0)(Ci-C4-alkyl)2,
-S(=0)2-(Ci-C4-alkyl), halogen
-C(=0)- Ci-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 (=0), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)), -C(=0)-NRvRw or -C(=0)-0-Rv, in which Rv represents -H or Ci-C4-alkyl, Rw represents -H, Ci-C4-alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl - C3-C6-alkenyloxy,
Ci-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7-membered heterocycloalkenyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, - S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)), -C(=0)-0-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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4- alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, Ci-C4-alkoxy, -S(0)2-CH3, - S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, Ci-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), phenyl, optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci- C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4- alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
-NRiRj, in which R, represents -H, Ci-C4-alkyl and Rj represents -H, Ci-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, R, and Rj together form a 4- to 7- membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=0) or Ci-C4-alkyl -NRrS(=0)2-Rp, in which R, represents -H, Ci-C4-alkyl and Rp represents 5- or 6-membered heteroaryl,
-NH-C(=0)-NRkR|, in which Rk represents -H or Ci-C4-alkyl and Ri represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -FI 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 (=0)), or Ci-Czi-alkyl, C3-Grcycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CFI3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0)) -NFI-C(=0)-Rm, in which Rm represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)), or
Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CFl3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0))
-(C=0)-NRnRo, in which Rn represents -H or Ci-C4-alkyl, R0 represents Ci-C6-hydroxyalkyl, 5- or
N
6-membered heteroaryl (N), ^o ' or or in which N, Rn and R0 together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN,
R5 represents -H, -F or -Cl,
Ri5 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
NH
R15 \= R15
R4 R4
R2 is selected from or
D) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R2 is
/=N
E) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R2 is
R4 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 Ri is selected from
-C(=0)-0-tBu, -C(=0)-NH-Et, -C(=0)-NH-C(=0)-0-Et,
H H
G) Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein X is a direct bond.
Gi) 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 Ri represents a group *-A'-B, in which A' represents a group *-C(=0)-NRc- and in which Rc represents -FI or Ci-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[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-aminopyrimidin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(lH-pyrrolo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-[5-(pyrrolidin-l-yl)pyridin-3-yl]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-[5-(trifluoromethyl)pyridin-3-yl]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate tert-butyl 2'-(lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate tert-butyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(pyrido[2,3-b]pyrazin-7-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(furo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(3-methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(6-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl -6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (pyrimidin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
(l-methyl-lH-pyrazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
4-oxo-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]butanenitrile
3-methoxy-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]propan-l- one
3-(lH-pyrazol-l-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]propan-l-one
2-(morpholin-4-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
2-(pyrimidin-5-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
(3-chlorophenyl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
(pyridin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]methanone
2-ethyl-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]butan-l-one l-{2-oxo-2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethyl}pyrrolidin-2-one
(pyridin-3-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]methanone l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]cyclopropane-
1-carbonitrile
1-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]ethan-l-one (l-methyl-lH-imidazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
2-methoxyethyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate
2-methoxyethyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate
[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl](pyrimidin-4- yl)methanone
(l-methyl-lH-pyrazol-5-yl)[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazol]-l-yl]methanone l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-3-(lH- pyrazol-l-yl)propan-l-one l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2-
(morpholin-4-yl)ethan-l-one
1-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2- (pyrimidin-5-yl)ethan-l-one
(3-chlorophenyl)[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl](pyridin-4- yl)methanone
2-ethyl-l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]butan-l-one l-{2-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2- oxoethyl}pyrrolidin-2-one
[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl](pyridin-3- yl)methanone l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carbonyl]cyclopropane-l-carbonitrile l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]ethan-l-one
(l-methyl-lH-imidazol-5-yl)[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazol]-l-yl]methanone
3-methoxy-l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]propan-l-one
4-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-4- oxobutanenitrile l-[(2-methylpyrimidin-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
N,N-dimethyl-5-{[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]methyl}-l,3-thiazol-2-amine l-[(lH-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-[(pyrazolo[l,5-a]pyrimidin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(lH-indazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-(cyclohexylmethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
6'-methyl-l-[(2-methylpyrimidin-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
N,N-dimethyl-5-{[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]methyl}-l,3-thiazol-2-amine 6'-methyl-l-[(pyrazolo[l,5-a]pyrimidin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(lH-indazol-3-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-(cyclohexylmethyl)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-(cyclopropanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-(cyclopropanesulfonyl)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
N-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
6'-methyl-N-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N -ethyl -6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide l-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
6'-methyl-l-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
N-(2-chloroethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
2'-(quinolin-3-yl)-N-(2,2,2-trifluoroethyl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-cyclopentyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide methyl [2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carbonyl]carbamate
N-[(furan-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ethyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carbothioamide l-(methanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-(methanesulfonyl)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole] ethyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate ethyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate l-[(4-methyl-lH-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(imidazo[l,5-a]pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-{[l-(propan-2-yl)-lH-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(quinolin-3-yl)-l-{[4-(trifluoromethyl)-lH-imidazol-2-yl]methyl}-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-(2-methylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-{[l-(2-methoxyethyl)-lH-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(quinolin-3-yl)-l-[(l,4,5-trimethyl-lH-imidazol-2-yl)methyl]-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(lH-benzimidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(l-methyl-lH-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(lH-pyrazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-[(4-methyl-lH-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(2-methyl-lH-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(lH-pyrrol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-[(lH-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-[(5-methyl-lH-pyrrol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
3-(ethylamino)-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]cyclobut-3-ene-l,2-dione
3-(dimethylamino)-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]cyclobut-3-ene-l,2-dione 2-(dimethylamino)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
3-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]pyrrolidin-2- one
4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]pyrrolidin-2- one
2-(lH-imidazol-l-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
4-oxo-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]butanamide l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2-(4H-l,2,4-triazol-4- yl)ethan-l-one l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]prop-2-en-l-one
3-(dimethylamino)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]propan-l-one
N'-cyano-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboximidamide
N'-cyano-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboximidamide
N-[3-(dimethylamino)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-(oxan-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-{[-oxolan-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
(4-methylpiperazin-l-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
N-[2-oxopyrrolidin-3-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]azetidine-3- carboxamide
N-[(lH-pyrazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-
1-carboxamide
(morpholin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
N-(3-hydroxypropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide N-(2-hydroxyethyl)-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-(2-oxopiperidin-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-(6-oxopiperidin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-[2-(lH-imidazol-l-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-(2-hydroxy-2-methylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-[(l-methyl-lH-imidazol-4-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-{[-5-oxopyrrolidin-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
[-3-(dimethylamino)pyrrolidin-l-yl][2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazol]-l-yl]methanone
N-{2-[oxolan-3-yl]ethyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
2'-(2-aminopyrimidin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
2'-(6-aminopyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(pyrido[2,3-b]pyrazin-7-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(furo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(6-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-[5-(pyrrolidin-l-yl)pyridin-3-yl]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide N-ethyl-2'-(lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(3-methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(lH-pyrrolo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide ethyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate ethyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate ethyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-methyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] tert-butyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate tert-butyl 2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate
N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]ethan-l-one l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]-2-methylpropan-l-one l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]- l-carbonyl]cyclopropane-l-carbonitrile
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]-l- yl](phenyl)methanone
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]-l- yl](oxan-4-yl)methanone tert-butyl 2'-(6-aminopyridin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate
2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-cyclobutyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-cyclobutyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide 2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
(rac)-6'-methyl-N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
(rac)-N-ferf-butyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-
1-carboxamide
N-ethyl-2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]-l- carboxamide
N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
N-ferf-butyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
N-ethyl-2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]-l- carboxamide
N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-[3-(propan-2-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
N-ethyl-2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(lH-pyrazolo[3,4-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide
N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-
1-carboxamide
2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide cyclopentyl (rac)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(5-methyl-lH-imidazol-2-yl)methyl]-6',7'- dihydrospiro[azetidine-3,4'-pyrazolo[5,l-c][l,4]oxazine]
2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(4-chloro-lH-pyrazol-5-yl)methyl]-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
(rac)-l-[(4-chloro-lH-pyrazol-5-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-6',7'-dihydrospiro[azetidine-
3,4'-pyrazolo[5,l-c][l,4]oxazine]
(rac)-l-[(lH-imidazol-2-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(l-methyl-lH-imidazol-2-yl)methyl]-6',7'-dihydro-5'H- spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-6',7'-dihydro-5'H- spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(3,3,3-trifluoropropyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole] 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-5',6'-dihydrospiro[piperidine-
4,4'-pyrrolo[l,2-b]pyrazole] l-benzyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- bjpyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(cyclohexylmethyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(propan-2-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(l-methyl-lH-pyrazol-4-yl)methyl]-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridin]-l-yl](4-fluorophenyl)methanone
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridin]-l-yl](oxan-4-yl)methanone
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(methanesulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-sulfonamide
2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide tert-butyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]-l- yl](morpholin-4-yl)methanone
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-hydroxy-2-methylpropyl)-5',6'-dihydrospiro[piperidine-
4,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-benzyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]-2-hydroxyethan-l-one l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]-2-(pyridin-3-yl)ethan-l-one
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(phenylmethanesulfonyl)-5',6'-dihydrospiro[piperidine-
4,4'-pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(propane-l-sulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-sulfonamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(pyridine-3-sulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(morpholine-4-sulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,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
R or wherein Ri, 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: ml-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 (123l), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, larotrectinib, lasocholine, 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, "mTc-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-l/-Ll 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-l/-Ll 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-Schonlein 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 l-lll (AB block l-lll), 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, Avicef ), 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, Carbopof ); 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 AcDiSof )) • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosif)),
• 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 ^-NMR data of selected examples / intermediates are listed in the form of ^-NMR peaklists. For each signal peak the d value in ppm is given, followed by the signal intensity, reported in round brackets. The d value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: di (intensityi), d2 (intensity2), ... , d, (intensity,), ... , dh (intensity,,).
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 ^-NMR peaklist is similar to a classical ^-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical ^-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 ^-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 perse 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-l,2-dicarboxylate
DIPEA N,N-diisopropylethylamine
DMA N,N-dimethylacetamide
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide dppf l-(diphenylphosphanyl)cyclopentane-l,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-[l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N- methylmethanaminium hexafluorophosphate
HMDS Hexamethyldisilazane
IFNg Interferon gamma
LiHMDS lithium l,l,l,3,3,3-hexamethyldisilazan-2-ide
LPS lipopolysaccharide
MeOH methanol
MCPBA 3-chloroperbenzoic acid mL milliliter
PL microliter min. minute(s)
MTBE tert-butyl methyl ether
MW microwave
NCS l-chloropyrrolidine-2,5-dione
Pd(dppf)2CI2*DCM [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane
PBMCs peripheral blood mononuclear cells (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one - palladium (3:2)
Pd(PPh3)4 tetrakis(triphenyl-lambda5-phosphanyl)palladium
PPh3 triphenylphosphine
PyBroP bromo(tripyrrolidin-l-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 (la), 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 (la) 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 miti, 50x2. lmm; 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 pm, 50x2. lmm; 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- 2.090% 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. lmm; 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.
15 14
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 ora 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 LiFIMDS 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 LiFIMDS 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. HCI 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 Tf20 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 = -FI) or an ester of the boronic acid, e.g. its isopropyl ester (R = -CFliCF ), 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(CFl ) -C(CFl ) -). The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenyl- phosphine)palladium(O) [Pd(PPhs) ], tris(dibenzylideneacetone)di-palladium(0) [Pd (dba) ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (II) [PdfPPhs C ], palladium (II) acetate and triphenylphosphine, [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(ll), 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, TFIF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate (review: D.G. Flail, Boronic Acids, 2005 WILEY-VCFI Verlag GmbFI & 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(O) [Pd(PPh3)4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (II) [Pd(PPh3)2Cl2], palladium (II) acetate and triphenylphosphine, [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(ll), 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. Flail, Boronic Acids, 2005 WILEY-VCFI Verlag GmbFI & 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.
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.
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
Flalogen 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 = -FI) or an ester of the boronic acid, e.g. its isopropyl ester (R = -CFH(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(CFl3)2-C(CFl3)2-). The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenyl- phosphine)palladium(O) [Pd(PPhs)4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)-palladium (II) [Pd PPhs C ], palladium (II) acetate and triphenylphosphine, [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- l,l'-biphenyl)]palladium(ll), 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, TFIF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate, (review: D.G. Flail, Boronic Acids, 2005 WILEY-VCFI Verlag GmbFI & 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-l-yl)azetidine-l,3-dicarboxylate
To a solution of 1-tert-butyl 3-methyl azetidine-l,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-l-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 N H4CI (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 I ^SC , 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-l-yl)azetidine-l-carboxylate
To a solution of methyl acetate (482 g, 6.52 mol, 2.00 equiv) in dry TH F(9 L) was added LiFIMDS (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-l-yl)azetidine-l 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. NH4CI (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 Na2S04, 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-lH-pyrazol-5-yl)-3-(prop-2-en-l-yl)azetidine-l-carboxylate
To a stirred solution of tert-butyl 3-(3-methoxy-3-oxopropanoyl)-3-(prop-2-en-l-yl)azetidine-l- 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. HCI (1 M), 1x2 L of brine, dried over anhydrous Na2S04 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-l-yl)-3-[3-(trifluoromethanesulfonyloxy)-lH-pyrazol-5-yl]azetidine-l- carboxylate
To a stirred solution of tert-butyl 3-(3-hydroxy-lH-pyrazol-5-yl)-3-(prop-2-en-l-yl)azetidine-l- 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. HCI (1 M) and 3x2 L of water, dried over anhydrous Na2S04, 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)-lH-pyrazol-5-yl]azetidine-l- carboxylate
To a stirred solution of tert-butyl 3-(prop-2-en-l-yl)-3-[3-(trifluoromethanesulfonyloxy)-lH-pyrazol-5- yl]azetidine-l-carboxylate (400 g, 0.97 mol, 1.00 equiv, see intermediate 4) in dioxane/H20 (2L, 3/2, v/v) was added 2,6-Lutidine (207 g, 1.94 mol, 2.00 equiv) followed by K20s04*2H20 (7.87 g, 0.02 mol, 0.02 equiv). This mixture was stirred at rt for 40 min before Nal04 (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 HCI 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 Na2S04, 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[l,2-b]pyrazole]-l- carboxylate To a solution of tert-butyl 3-(2-hydroxyethyl)-3-[3-(trifluoromethanesulfonyloxy)-lH-pyrazol-5- yl]azetidine-l-carboxylate (360 g, 0.87 mol, 1.00 equiv, see intermediate 5) and PPfi3 (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]+, ^-NMR (400 MHz, DMSO-d6) d [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
[l-(tert-butoxycarbonyl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-2'-yl]boronic acid
O tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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-l,3,2-dioxaborolane (671 mg, 2.64 mmol), KOAc (741 mg, 7.55 mmol; CAS-RN:[127-08-2]), Pd(dppf)2CI2 complex with DCM (103 mg, 126 pmol; CAS-RN:[14221-01-3]) and dppf (69.8 mg, 126 pmol; 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): R = 0.62 min; MS (ESIpos): m/z = 294 [M+H]+. ’H-NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazol]-2'-yl trifluoromethanesulfonate (1/1) tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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-l]) 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 l-(ethylcarbamoyl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-2'-yl trifluoromethanesulfonate
F
Trifluoroacetic acid— 5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-2'-yl trifluoro methanesulfonate (1/1) (126 mg, 41 % purity, 126 pmol, see intermediate 8) was dissolved in DCM (3.0 ml) and DIPEA (220 pi, 1.3 mmol; CAS-RN:[7087-68-5]) under nitrogen, isocyanatoethane (50 mI, 630 mitioI) 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): R = 1.01 min; MS (ESIpos): m/z = 369 [M+H]+. ’H-NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazole]-l-carboxylate tert-butyl 3-(3-hydroxy-lH-pyrazol-5-yl)-3-(prop-2-en-l-yl)azetidine-l-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 Lj/h O (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 NaBhU (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. NaCI 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 Na2S04. 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[l,2- b]pyrazole]-l-carboxylate To a stirred solution of tert-butyl 2'-hydroxy-6'-methyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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. HCI (1 M) and 3x2 L of water, dried over anhydrous Na2S04, 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-l,4-dicarboxylate
? H3
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. NFUCI solution was added to the mixture, diluted with EtOAc and the phases were separated. The organic phase was washed with sat. NaCI solution, dried with Na2S04 and concentrated under reduced pressure. The residue was purified by flash chromatography (Flex/EtOAc) to yield the title compound (23.1 g, 93 % yield). LC-MS (Method 2): R = 1.71 min; MS (ESIpos): m/z = 302 [M+H]-BOC+. ^-NMR (400 MHz, DMSO-d6) d [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-l- carboxylate C H
I 3 n n
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. NH4CI solution was added to the mixture, diluted with EtOAc and the phases were separated. The organic phase was washed with sat. NaCI solution, dried with Na2S04 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+. ^-NMR (400 MHz, DMSO-d6) d [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-lH-pyrazol-5-yl)piperidine-l- carboxylate
HO
Tert-butyl 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(3-methoxy-3-oxopropanoyl)piperidine-l- 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]+. ’H-NMR (400 MHz, DMSO-d6) d [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-lH-pyrazol-5-yl)piperidine-l-carboxylate
HO Tert-butyl 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(3-hydroxy-lH-pyrazol-5-yl)piperidine-l- carboxylate (7.56 g, 17.8 mmol, see intermediate 14) was dissolved in THF (140 ml), TBAF (21 ml, 1.0 M in TH F, 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/MeOFI) to yield the title compound (3.53 g, 64% yield). LC-MS (Method 1): Rt = 0.51 min; MS (ESIpos): m/z = 312 [M+FI]+. ’H- NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazole]-l-carboxylate
Tert-butyl 4-(2-hydroxyethyl)-4-(3-hydroxy-lH-pyrazol-5-yl)piperidine-l-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]+. ^-NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazole]- 1-carboxylate Tert-butyl 2'-hydroxy-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l-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 l,l,l-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]+. ^-NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazol]-2'-yl trifluoromethanesulfonate (1/1)
To a solution of tert-butyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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-l]) 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[l,2-b]pyrazole]-l- carboxylate n u
3
To a suspension of trifluoroacetic acid— 5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,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 pi, 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 pi, 4.5 mmol) was added and the mixture was stirred overnight at 50°C. The mixture was diluted with sat. NaHC03 solution and extracted three times with EtOAc. The combined organic layers were washed with sat. NaCI solution, dried with Na2S04 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
O Br
H3C
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. NaHC03 solution and extracted three times with EtOAc. The combined organic layers were washed with sat. NaCI solution, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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. NaHC03 solution was added and the mixture was extracted with DCM. The organic layer was washed with sat. NaCI solution, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
Br C H3
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 pl_, 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, Na2S203 solution, water and brine. It was dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
C H 3 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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°, cone. NH3 solution was added (pH 9-10) and extracted 3x with DCM. The combined organic layers were dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
H 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. Na2S203 solution was added and the organic solvent was evaporated. The mixture was extracted with EtOAc and the organic layer was washed with sat. NaCI solution, dried with Na2S04 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 POCI3 (30 ml), and the mixture was stirred overnight at 100°C. The mixture was added dropwise into Na2C03 solution (2 L, pH 8) and extracted with DCM. The organic layer was dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
Br
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]+ Ή-NMR (500 MHz, DMSO-d6) d [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
C H 3 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°, cone. NH3 solution was added (pH 9-10) and extracted 3x with DCM. The combined organic layers were dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
C H3
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 pi, 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 Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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)-1 H-pyrrolo[2,3-b]pyridine
5-Bromo-3-chloro-1 H-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)2CI2*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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
N
C H 3
HO
B o c H 3
I
O H
LC-MS (Method 3): Rt = 0.51 min; MS (ESIpos): m/z = 232 [M+H]+
Intermediate 36 [6-(trifluoro ethyl)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)-1 H-pyrrolo[2,3-b]pyridin-5-yl]boronic acid
3
LC-MS (Method 1): Rt = 0.65 min; MS (ESIpos): m/z = 205 [M+H]+
Intermediate 38 3-ethyl-5-(4,4,5,5-tetra ethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine
C H 3
LC-MS (Method 1): Rt = 1.18 min; MS (ESIpos): m/z = 273 [M+H]+
1H-NMR (400 MHz, DMSO-d6) d [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
I
O H
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}-1 H- pyrrolo[2,3-b]pyridine LC-MS (Method 3): Rt = 1.71 min; MS (ESIpos): m/z = 389 [M+H]
Intermediate 42
(3-bromo-1 H-pyrazol-1-yl)methanol
Br
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.
Ή-NMR (400 MHz, DMSO-d6) d [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 — Br
HC
(3-Bromo-1 H-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/ethyl benzene, 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. NaHC03 solution, extracted with EtOAc and the organic layer was washed with sat. NaCI solution, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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}-1 H-pyrazol-3-yl)-3-hydroxyazetidine-1- carboxylate r O
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 mLI, 13 mmol) was added and the mixture was stirred overnight at rt. Sat. NaCI solution was added and the mixture was extracted with EtOAc, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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. NaCI solution was added and the mixture was extracted with EtOAc, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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-1 H-pyrazol-3-yl)-1-(ethylcarbamoyl)azetidin-3-yl]oxy}acetate
H
H 3C^
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.
Ή-NMR (400 MHz, DMSO-d6) d [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 (069) 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
H
Ethyl {[3-(5-bromo-1H-pyrazol-3-yl)-1-(ethylcarbamoyl)azetidin-3-yl]oxy}acetate (680 g, 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. NH4CI solution and extracted with EtOAc. The organic layer was washed with sat. NaCI solution, dried with Na2S04 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 pmol) was solubilised in THF (5.0 ml), PPh3 (364 mg, 1.39 mmol) was added and DIAD (250 pi, 1.29 mmol) was added dropwise. The mixture was stirred overnight at rt. DIAD (250 pi, 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-te/f-butyl dicarbonate (210 pi, 940 pmol) 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 Na2S04 and concentrated under reduced pressure to give 530 mg (70 % yield) of the title compound, which was used without further purification.
Ή-NMR (400 MHz, DMSO-d6) d [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
N
H
Ethyl {[3-(5-bromo-1 H-pyrazol-3-yl)azetidin-3-yl]oxy}acetate (containing terf-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 NH4CI was added. The aq. layer was extracted 3x with DCM and the combined organic layers were dried with Na2S04 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 pmol) was solubilised in THF (2.0 ml), PPh3 (155 mg, 591 pmol) was added and DIAD (110 mI, 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-te/f-butyl 4-methyl 4-(3-{[te/f-butyl(dimethyl)silyl]oxy}propyl)piperidine-1 ,4-dicarboxylate
C H
1-te/f-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)(ferf-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. NH4CI solution, extracted with EtOAc and the organic layer was washed with sat. NaCI solution, dried with Na2S04 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+
Ή-NMR (400 MHz, DMSO-d6) d [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-te/f-butoxy-3-oxopropanoyl)-4-(3-{[te/f-butyl(dimethyl)silyl]oxy}propyl)piperidine- 1 -carboxyl ate 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-te/f-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. NH4CI solution, extracted with EtOAc and the organic layer was washed with sat. NaCI solution, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-{[te/f-butyl(dimethyl)silyl]oxy}propyl)-4-(3-hydroxy-1H-pyrazol-5-yl)piperidine-1- carboxylate
HO tert- Butyl 4-(3-te/f-butoxy-3-oxopropanoyl)-4-(3-{[te/f-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
HO tert- Butyl 4-(3-{[te/f-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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
— N
,1 j — Br
HO
(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/ethyl benzene, 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 terf-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. NaHC03 solution, extracted with EtOAc and the organic layer was washed with sat. NaCI solution, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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 -carboxyl ate r O tert- Butyl 4-(3-bromo-1 H-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. NaCI solution was added and the mixture was extracted with EtOAc, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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 r O tert- Butyl 4-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-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. NaCI solution was added and the mixture was extracted with EtOAc, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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-1 H-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 pi, 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.
Ή-NMR (400 MHz, DMS0-d6) d [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-1 H-pyrazol-3-yl)-N-ethyl-4-(2-hydroxyethoxy)piperidine-1-carboxamide
H
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. NH4CI solution and extracted with EtOAc. The organic layer was washed with sat. NaCI solution, dried with Na2S04 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 C H 3
4-(5-Bromo-1 H-pyrazol-3-yl)-N-ethyl-4-(2-hydroxyethoxy)piperidine-1-carboxamide (350 mg, 969 pmol) was solubilised in THF (5.0 ml), PPh3 (356 mg, 1.36 mmol) was added and DIAD (250 mI, 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 pi, 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+ Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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-1 H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1,2- b]pyrazole]-1-carboxylate o
C H 3
LC-MS (Method 1): Rt = 1.17 min; MS (ESIpos): m/z = 400 [M+H]+
Intermediate 73 tert- butyl 2'-(3-methyl-1-{[2-(tri ethylsilyl)ethoxy] ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate
H3C p H 3
Si-C H3
O
LC-MS (Method 1): Rt = 1.66 min; MS (ESIpos): m/z = 539 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [ppm]: -0.003 (0.57), 1.066 (12.77), 1.404 (2.96), 1.432 (16.00),
I.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),
I I .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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[azetidine-3,4'- pyrazolo[5, 1 -c][1 ,4]oxazi ne]- 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-1 H-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] Ή-NMR (400 MHz, DMSO-d6) d [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)
N
H 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]+
Ή-NMR (500 MHz, DMSO-d6) d [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)
HO
F 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)
HO
O
H 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]oxazi ne] (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 trifluoro ethanesulfonate trifluoroacetate (1:1) F 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[l,2-b]pyrazole]-l- carboxylate
F
O
To a solution of tert-butyl 2'-(trifluoromethanesulfonyloxy)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (intermediate 6) (100 mg, 252 pmol) in 1,4-dioxane (4.0 ml) were added (2-fluoroquinolin-3-yl)boronic acid (96.1 mg, 503 pmol, CAS-RN [745784-10-5]), K3PO4 (1.5 ml, 0.50 M, 750 pmol) and XPhos Pd G2 (29.7 mg, 37.7 pmol; CAS-RN:[14221-01-3]). The mixture was stirred overnight at 100°C. The mixture was diluted with EtOAc, washed with sat. NaCI 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]+. ’H-NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazole]-l-carboxylate
(prepared from intermediate 6 and quinolin-3-ylboronic acid, CAS-RN: [191162-39-7]) *H-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 '-ilH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -blpyrazole]-
1-carboxylate
(prepared from intermediate 6 and lH-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-i -aminopyrimidin-S-ylJ-S' S'-dihydrospirotazetidine-S^'-pyrrolotl -b pyrazole]-!- 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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-ilH-pyrroloIB -blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]- 1-carboxylate
(prepared from intermediate 6 and 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
O tert-butyl '-lS-ipyrrolidin-l-ylJpyridin-B-yll-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]- 1-carboxylate
(prepared from intermediate 6 and [5-(pyrrolidin-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-i -oxo- B-dihydro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]-l-carboxylate
(prepared from intermediate 6 and (2-oxo-2,3-dihydro-lH-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-lS-itrifluoromethylJpyridin-B-yll-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-ilH-pyrazoloIB^-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- b]pyrazole]-l-carboxylate
(prepared from intermediate 6 and lH-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-iB-methyl-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]-l-carboxylate
(prepared from intermediate 6 and 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- 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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-ipyrido^B-b pyrazin- -ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -blpyrazole]-!- carboxylate
(prepared from intermediate 6 and 7-(4,4,5,5-tetramethyl-l,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]+
’H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.427 (16.00), 2.327 (0.42), 2.518 (2.00), 2.522 (1.21), 2.669 (043) 2 899 (062) 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 [l-(tert-butoxycarbonyl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-2'- yl]boronic acid (50.0 mg, 171 pmol, see intermediate 7) and 5-bromo-3-ethyl-lH-pyrrolo[2,3-b]pyridine (57.6 mg, 256 pmol, preparation described in WO2018/167147) in DMSO (1.5 ml) were added Pd(PPfi3)4 (19.7 mg, 17.1 pmol; CAS-RN:[865-47-4]) and Na2C03 (2.0 M, 340 pi). The mixture was stirred overnight at 110°C. The mixture was diluted with EtOAc, washed with sat. NaCI 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]+. ^-NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazole]-l- carboxylate
To a stirred solution of tert-butyl 6'-methyl-2'-(trifluoromethanesulfonyloxy)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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)CI2 (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]+. ^-NMR: (300 MHz, CDCI3, ppm):5 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^-ylH '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -blpyrazol]-!- yl]methanone
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,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. ^-NMR (300 MHz, DMSO-d6) d [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 0
H3
(l-methyl-lH-pyrazol-S-ylH '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -blpyrazol]- l-yl]methanone
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l-methyl-lH-pyrazole-5-carboxylic acid, CAS-RN: [16034-46-1])
LC-MS: (ES, m/z): 385, [M+H]+, H-NMR: (300 MHz,DMSO-d6, ppm): d 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[l,2-b]pyrazol]-l-yl]butanenitrile
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 3-cyanopropanoic acid, CAS-RN: 16051-87-9)
^-NMR (300 MHz, DMSO-d6) d [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 O
H 3C
B-methoxy-l-I '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazoll-l-yllpropan-
1-one
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 3-methoxypropanoic acid, CAS-RN: [2544-06-1])
!H-NMR (300 MHz, DMSO-d6) d [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
N-N
S-ilH-pyrazol-l-ylJ-l-t '-iquinolin-S-ylJ-S' S'-dihydrospirotazetidine-S^'-pyrrolotl -b pyrazol]-!- yl]propan-l-one (prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 3-(lH-pyrazol-l-yl)propanoic acid, CAS-RN: [89532-73-0])
^-NMR (300 MHz, DMSO-d6) d [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 -imorpholin-^ylJ-l-^'-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazol]-!- yl]ethan-l-one
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and morpholin-4-ylacetic acid, CAS-RN: [3235-69-6])
^-NMR (300 MHz, DMSO-d6) d [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 -ipyrimidin-S-ylJ-l-t '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -b pyrazol]-!- yl]ethan-l-one (prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and pyrimidin-5-ylacetic acid, CAS-RN: [5267-07-2])
^-NMR (300 MHz, DMSO-d6) d [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 O
Cl
(B-chlorophenylJ^'-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazol]-!- yl]methanone
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 3-chlorobenzoic acid, CAS-RN: [535-80-8])
^-NMR (300 MHz, DMSO-d6) d [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^-ylJ^'-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazol]-!- yl]methanone (prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and pyridine-4-carboxylic acid, CAS-RN [55-22-1])
^-NMR (300 MHz, DMSO-d6) d [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 -ethyl-l-I '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazoll-l-yllbutan-l-one
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 2-ethylbutanoic acid, CAS-RN: [88-09-5]) ^-NMR (300 MHz, DMSO-d6) d [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 l-i -oxo- -t '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -b pyrazol]-!- yl]ethyl}pyrrolidin-2-one
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and (2-oxopyrrolidin-l-yl)acetic acid, CAS-RN [53934-76-2])
^-NMR (300 MHz, DMSO-d6) d [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 0
(pyridin-3-yl)[2,-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]methanone
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and pyridine-3-carboxylic acid, CAS-RN: [59-67-6])
^-NMR (300 MHz, DMSO-d6) d [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 l-I '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carbonyl]cyclopropane-l-carbonitrile
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 1-cyanocyclopropanecarboxylic acid, CAS-RN: [6914-79-0])
^-NMR (300 MHz, DMSO-d6) d [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 l-[2'-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4,-pyrrolo[l,2-b]pyrazol]-l-yl]ethan-l-one
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and acetic acid, CAS-RN: [64-19-7] ^-NMR (300 MHz, DMSO-d6) d [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
(l-methyl-lH-imidazol-S-ylJ^'-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- b]pyrazol]-l-yl]methanone
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l-methyl-lH-imidazole-5-carboxylic acid, CAS-RN: [41806-40-0]) ^-NMR (300 MHz, DMSO-d6) d [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[l,2-b]pyrazole]-l- carboxylate Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,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. ^-NMR (300 MHz, DMSO-d6) d [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
H3C
N
2-methoxyethyl S'-methyl^'-iquinolin-S-ylJ-S' S'-dihydrospiroIazetidine-S^'-pyrroloIl^-bJpyrazole]- 1-carboxylate (prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 2-methoxyethyl carbonochloridoate (CAS-RN: [628-12- 6])
!H-NMR (300 MHz, DMSO-d6) d [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
H 3C
N
[S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazoll-l-ylKpyrimidin-
4-yl)methanone (prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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): d 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
(l-methyl-lH-pyrazol-S-ylJIS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazol]-l-yl]methanone
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and l-methyl-lH-pyrazole-5-carboxylic acid, CAS-RN: [16034-46-1])
^-NMR (300 MHz, DMSO-d6) d [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 l-IS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazoll-l-yll-B-ilH- pyrazol-l-yl)propan-l-one
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 3-(lH-pyrazol-l-yl)propanoic acid, CAS-RN: [89532-73-
0])
^-NMR (300 MHz, DMS0-d6) d [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 H3C
N l-IS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazoll-l-yl]^-
(morpholin-4-yl)ethan-l-one
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and morpholin-4-ylacetic acid, CAS-RN: [3235-69-6])
!H-NMR (300 MHz, DMSO-d6) d [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 l-IS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazoll-l-yll- - (pyrimidin-5-yl)ethan-l-one
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and pyrimidin-5-ylacetic acid, CAS-RN: [5267-07-2])
^-NMR (300 MHz, DMSO-d6) d [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
H 3C o
Cl
(B-chlorophenylJIS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazol]- l-yl]methanone
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 3-chlorobenzoic acid, CAS-RN: [535-80-8])
!H-NMR (300 MHz, DMSO-d6) d [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
H 3C
O
[S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -b pyrazolj-l-ylHpyridin^- yl)methanone (prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and pyridine-4-carboxylic acid, CAS-RN: [55-22-1]) ^-NMR (300 MHz, DMSO-d6) d [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
H 3C -ethyl-l-IS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazol]-!- yl]butan-l-one
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 2-ethylbutanoic acid, CAS-RN: [88-09-5])
*H-NMR (300MHZ, DMSO-ds): d [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 l-i -IS'-methyl- '-iquinolin-S-ylJ-S' S'-dihydrospiroIazetidine-S^'-pyrroloIl -blpyrazoll-l-yl]^- oxoethyl}pyrrolidin-2-one
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 2-(2-oxopyrrolidin-l-yl)acetamide, CAS-RN: [7491-74- 9]) ^-NMR (300 MHz, DMSO-d6) d [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
H [S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazoll-l-ylKpyridin-B- yl)methanone
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and pyridine-3-carboxylic acid, CAS-RN: [59-67-6])
^-NMR (300 MHz, DMSO-ds): d [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
H3C
N l-IS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carbonyl]cyclopropane-l-carbonitrile
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 1-cyanocyclopropanecarboxylic acid, CAS-RN: [6914-79- 0]) ^-NMR (300 MHz, DMSO-d6) d [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 l-IS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazoll-l-yllethan-l- one (prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and acetic acid, CAS-RN: [64-19-7])
!H-NMR (300 MHz, DMSO-d6) d [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
O
N
C H 3
(l-methyl-lH-imidazol-S-ylJIS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazol]-l-yl]methanone (prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and l-methyl-lH-imidazole-5-carboxylic acid, CAS-RN: [41806-40-0])
!H-NMR (300 MHz, DMSO-d6) d [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
C H
B-methoxy-l-IS'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazol]-!- yl]propan-l-one
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 3-methoxypropanoic acid, CAS-RN: [2544-06-1]) ^-NMR (300 MHz, DMSO-d6) d [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 H3C
N
4-[6'-methyl-2,-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4,-pyrrolo[l,2-b]pyrazol]-l-yl]-4- oxobutanenitrile
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 3-cyanopropanoic acid, CAS-RN: [16051-87-9])
!H-NMR (300 MHz, DMSO-d6) d [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 l-K -methylpyrimidin-S-ylJmethylj- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,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. ^-NMR (300 MHz, DMSO- d6) d [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-S-il '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazol]-!- yl]methyl}-l,3-thiazol-2-amine
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 2-(dimethylamino)-l,3-thiazole-5-carbaldehyde (CAS-RN: [1005-28-3]) !H-NMR (300 MHz, DMSO-d6) d [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 l-KlH-imidazol^-ylJmethyl^'-iquinolin-S-ylJ-S' S'-dihydrospiroIazetidine-S^'-pyrroloIl^- bjpyrazole]
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and lH-imidazole-2-carbaldehyde, CAS-RN: [10111-08-7]) ^-NMR (300 MHz, DMSO-d6) d [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 l-Kpyrazolotl S-alpyrimidin-B-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B,^- pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and pyrazolo[l,5-a]pyrimidine-3-carbaldehyde, CAS-RN: [879072-59-0])
^-NMR (300 MHz, DMSO-d6) d [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 l-KlH-indazol-B-ylJmethylj- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole] (prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and lH-indazole-3-carbaldehyde, CAS-RN: [5235-10-9])
^-NMR (300 MHz, DMSO-d6) d [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 l-icyclohexylmethylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and cyclohexanecarbaldehyde, CAS-RN: [2043-61-0])
^-NMR (300 MHz, DMSO-d6) d [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
S'-methyl-l-Ii -methylpyrimidin-S-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 2-methylpyrimidine-5-carbaldehyde, CAS-RN: [90905- 33-2])
^-NMR (300 MHz, DMSO-d6) d [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-S-ilS'-methyl- '-iquinolin-S-ylJ-S' S'-dihydrospiroIazetidine-S^'-pyrroloIl^-blpyrazol]- l-yl]methyl}-l,3-thiazol-2-amine
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 2-(dimethylamino)-l,3-thiazole-5-carbaldehyde, CAS- RN: [1005-28-3]) ^-NMR (300 MHz, DMSO-d6) d [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
H3C
S'-methyl-l-IipyrazoloIl S-alpyrimidin-B-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-
3,4'-pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and pyrazolo-[l,5-a]pyrimidine-3-carbaldehyde, CAS-RN: [879072-59-0]) ^-NMR (300 MHz, DMSO-d6) d [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 l-IilH-indazol-B-ylJmethyll-S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- bjpyrazole]
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and and lH-indazole-3-carbaldehyde, CAS-RN: [5235-10-9]) ^-NMR (300 MHz, DMSO-d6) d [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 l-icyclohexylmethylJ-S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and and cyclohexanecarbaldehyde, CAS-RN: [2043-61-0]) ^-NMR (300 MHz, DMSO-d6) d [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 l-tcyclopropanesulfony - '-tquinolin-B-y^-S^e'-dihydrospirotazetidine-B^'-pyrrolotl^-bJpyrazole]
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,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. ^-NMR (300 MHz, DMSO-d6) d [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
H3C
IN l-icyclopropanesulfonylJ-S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- b]pyrazole]
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and and cyclopropanesulfonyl chloride, CAS-RN: [139631- 62-2])
^-NMR (300 MHz, DMSO-d6) d [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-ipyridin-B-ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carboxamide
0=(
NH
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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-34'-pyrrolo[l 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[l,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^H-NMR (300 MHz, DMSO- d6) d [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
J
O
NH
( C H3
N-ethyl- '-tquinolin-B-y -S'^'-dihydrospirotazetidine-B^'-pyrrolotl^-bJpyrazoleJ-l-carboxamide (prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and isocyanatoethane, CAS-RN: [109-90-0])
^-NMR (300 MHz, DMSO-d6) d [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
S'-methyl-N-ipyridin-B-ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]-
1-carboxamide
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and 3-isocyanatopyridine, CAS-RN: [15268-31-2])
^-NMR (300 MHz, DMSO-d6) d [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-S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and and isocyanatoethane, CAS-RN: [109-90-0])
^-NMR (300 MHz, DMSO-d6) d [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 l-ipyridin-B-ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,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 Cs2C03 (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. ^-NMR (300 MHz, DMSO-d6) d [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
H3C
IN S'-methyl-l-ipyridin-B-ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see example 18) and and 3-bromopyridine, CAS-RN: [626-55-1])
!H-NMR (300 MHz, DMSO-d6) d [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[l,2-b]pyrazole]-l- carboxamide
Cl
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,2-b]pyrazole] trifluoroacetate (50.0 mg, 181 pmol) was dissolved in DCM (2.1 ml), DIPEA (95 pi, 540 pmol; CAS-RN:[7087-68-5]) was added, cooled to 0°C and l-chloro-2-isocyanatoethane (19.1 mg, 181 pmol) 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]+ ^-NMR (400 MHz, DMSO-d6) d [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-ipropan- -ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -b pyrazole]-!- carboxamide
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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
F '-iquinolin-B-ylJ-N-i -trifluoroethylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide (prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l,l,l-trifluoro-2-isocyanatoethane, CAS-RN: [371-92-6])
LC-MS (Method 1): Rt = 0.97 min; MS (ESIpos): m/z = 402 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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 ϋ O N-cyclopentyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+ ^-NMR (400MHZ, DMSO-ds): d [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- '-iquinolin-S-ylJ-S' S'-dihydrospirotazetidine-S^'-pyrrolotl -blpyrazolel-l- carboxamide
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+ ^-NMR (400 MHz, DMSO-d6) d [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 ° HrN^
Y° o
C H3 methyl [ '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carbonyl]carbamate
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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-Iifuran- -ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400MHz, DMSO-ds): d [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 H3C"°
N-i -methoxyethylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carboxamide
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l-isocyanato-2-methoxyethane, CAS-RN: [42170-95-6])
LC-MS (Method 1): Rt = 0.86 min; MS (ESIpos): m/z = 378 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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- '-tquinolin-B-y^-S^e'-dihydrospirotazetidine-B^'-pyrrolotl^-blpyrazoleJ-l-carboxamide
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
!H-NMR (400 MHz, DMSO-d6) d [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
H,C
>
N-ethyl-S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carbothioamide
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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]+
!H-NMR (400 MHz, DMSO-d6) d [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 l-fmethanesulfonylJ-Z'-fquinolin-B-ylJ-S^e'-dihydrospirotazetidine-B^'-pyrrolotl^-blpyrazole]
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and methanesulfonyl chloride, CAS-RN: [124-63-0])
^-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 H C l-imethanesulfonylJ-S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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[l,2-b]pyrazole]-l-carboxylate
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,2-b]pyrazole] trifluoroacetate (50.0 mg, 181 pmol) was dissolved in DCM (930 pi), DIPEA (95 mI, 540 mitioI; CAS-RN:[7087-68-5]) was added, cooled to 0°C and ethyl carbonochloridate (19.6 mg, 181 mitioI) 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]+ ^-NMR (400 MHz, DMSO-d6) d [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 S'-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxylate
(prepared from tert-butyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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): d [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 l-[(4-methyl-lH-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,2-b]pyrazole] trifluoroacetate (60.0 mg, 217 pmol) and 5-methyl-lH-imidazole-2- carbaldehyde (26.3 mg, 239 pmol) were dissolved in THF (2.9 ml). Acetic acid (12 pi, 220 pmol; CAS- RN:[64-19-7]) and sodium triacetoxyborohydride (63.3 mg, 299 pmol; 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]+ ^-NMR (400 MHz, DMSO-d6) d [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 l-IiimidazoIl S-alpyridin-B-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and imidazo[l,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]+
^-NMR (400 MHz, DMSO-d6) d [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 l-ill-ipropan- -ylJ-lH-imidazol- -yllmethylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and l-(propan-2-yl)-lH-imidazole-2-carbaldehyde, CAS-RN: [53332-64-2])
LC-MS (Method 1): Rt = 1.05 min; MS (ESIpos): m/z = 399 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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 '-iquinolin-B-ylJ-l-i^-itrifluoromethylJ-lH-imidazol- -yllmethylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and 4-(trifluoromethyl)-lH-imidazole-2-carbaldehyde, CAS-RN: [102808-02-6])
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 425 [M+H]+
!H-NMR (400 MHz, DMSO-d6) d [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
H,C X C H l-i -methylpropylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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 l-ill-i -methoxyethylJ-lH-imidazol- -yllmethylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and l-(2-methoxyethyl)-lH-imidazole-2-carbaldehyde, CAS-RN: [558446-64-3])
LC-MS (Method 1): Rt = 0.96 min; MS (ESIpos): m/z = 415 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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)-l-[(l,4,5-trimethyl-lH-imidazol-2-yl)methyl]-5,,6,-dihydrospiro[azetidine-3,4,- pyrrolo[l,2-b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and l,4,5-trimethyl-lH-imidazole-2-carbaldehyde, CAS-RN: [185910-12-7])
LC-MS (Method 1): Rt = 1.01 min; MS (ESIpos): m/z = 399 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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 l-IilH-benzimidazol- -ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and lH-benzimidazole-2-carbaldehyde, CAS-RN: [3314-30-5])
LC-MS (Method 1): Rt = 0.98 min; MS (ESIpos): m/z = 407 [M+H]+ ^-NMR (400MHz, DMSO-ds): d [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 H 3C l-Kl-methyl-lH-imidazol- -ylJmethylj- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and l-methyl-lH-imidazole-2-carbaldehyde, CAS-RN: [13750-81-7])
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 371 [M+H]+
!H-NMR (400 MHz, DMSO-d6) d [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 l-IilH-pyrazol-S-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and lH-pyrazole-5-carbaldehyde, CAS-RN: [948552-36-1])
LC-MS (Method 1): Rt = 0.89 min; MS (ESIpos): m/z = 357 [M+H]+
!H-NMR (400 MHz, DMSO-d6) d [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 l-[(4-methyl-lH-imidazol-5-yl)methyl]-2,-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4,-pyrrolo[l,2- b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and 4-methyl-lH-imidazole-5-carbaldehyde, CAS-RN: [68282-53-1])
LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 371 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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
C H l-Ii -methyl-lH-imidazol-S-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and 2-methyl-lH-imidazole-5-carbaldehyde, CAS-RN: [35034-22-1])
LC-MS (Method 1): Rt = 0.85 min; MS (ESIpos): m/z = 371 [M+H]+
!H-NMR (400 MHz, DMSO-d6) d [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 l-IilH-pyrrol- -ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and lH-pyrrole-2-carbaldehyde, CAS-RN: [1003-29-8])
LC-MS (Method 3): Rt = 1.00 min; MS (ESIpos): m/z = 356 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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 l-KlH-imidazol-S-ylJmethylj- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and lH-imidazole-5-carbaldehyde, CAS-RN: [3034-50-2])
LC-MS (Method 3): Rt = 0.79 min; MS (ESIpos): m/z = 357 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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
C H 3 l-IiS-methyl-lH-pyrrol- -ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- bjpyrazole]
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and 5-methyl-lH-pyrrole-2-carbaldehyde, CAS-RN: [1192-79-6])
LC-MS (Method 3): Rt = 1.06 min; MS (ESIpos): m/z = 370 [M+H]+ ^-NMR (400MHz, DMSO-d6): d [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[l,2-b]pyrazol]-l- yl]cyclobut-3-ene-l,2-dione
O
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,2-b]pyrazole] trifluoroacetate (50.0 mg, 128 pmol) was dissolved in EtOH (1.5 ml), triethylamine (36 pi, 260 pmol; CAS-RN:[121-44-8]) and 3,4-diethoxycyclobut-3-ene-l,2-dione (43.6 mg, 256 pmol) were added. The mixture was stirred for 4 h at reflux. Ethanamine (320 pi, 2.0 M in THF, 640 pmol; CAS-RN:[75-04-7]) was added dropwise and the mixture was stirred for 4 h at reflux. Ethanamine (320 mI, 2.0 M in THF, 640 mitioI; 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]+ ^-NMR (400 MHz, DMSO-d6) d [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
B-idimethylaminoJ-^ '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -blpyrazol]-!- yl]cyclobut-3-ene-l,2-dione
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400MHz, DMSO-d6): d [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)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
H 3C-N ^ί o
C H3 Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,2-b]pyrazole] trifluoroacetate (180 mg, 43 % purity, 198 pmol) was dissolved in DCM (2.0 ml, 31 mmol; CAS-RN:[75-09-2]), N,N-dimethylglycine (24.5 mg, 238 pmol), DIPEA (170 pi, 990 pmol; CAS- RN:[7087-68-5]) and PyBroP (111 mg, 238 pmol; 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]+. ^-NMR (400 MHz, DMSO-d6) d [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
B-I '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l-carbonyllpyrrolidin- - one
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
!H-NMR (400MHZ, DMSO-ds): d [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[l,2-b]pyrazole]-l-carbonyl]pyrrolidin-2- one
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400MHz, DMSO-ds): d [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 ^C O
2-(lH-imidazol-l-yl)-l-[2,-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4,-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and lH-imidazol-l-ylacetic acid, CAS-RN: [22884-10-2])
LC-MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 385 [M+H]+
’H-NMR (400 MHz, DMSO-d6) d [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 C
H2N
4-oxo-4-[2'-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4,-pyrrolo[l,2-b]pyrazol]-l-yl]butanamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
O l-[2,-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4,-pyrrolo[l,2-b]pyrazol]-l-yl]-2-(4H-l,2,4-triazol-
4-yl)ethan-l-one
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 2) and 4H-l,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]+
’H-NMR (400 MHz, DMSO-d6) d [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 H 2 l-I '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazoll-l-yllprop- -en-l-one
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
H 3C
B-idimethylaminoJ-l-I '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazol]-!- yl]propan-l-one
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboximidamide
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,2-b]pyrazole] trifluoroacetate (100 mg, 256 pmol) was dissolved in DCM (4.5 ml), diphenyl cyanocarbonimidate (67.1 mg, 282 pmol) and triethylamine (71 pi, 510 pmol; 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[l,2-b]pyrazole]-l- 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[l,2-b]pyrazole]-l-carboximidate (60.0 mg, 50 % purity, 71.3 pmol) was dissolved in 2- propanol (740 pi) and ethanamine (360 pi, 2.0 M, 710 pmol; 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]+. ^-NMR (400MHz, DMSO-ds): d [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
H 3C N'-cyano-N N-dimethyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carboximidamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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-tB-idimethylaminoJpropylj- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]-l-carboxamide
Step 1: To a solution of tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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[l,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[l,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[l,2-b]pyrazole]-l-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[l,2-b]pyrazole]-l-carboxylate (31.3 mg, 70.9 pmol) in N,N- dimethylacetamide (1.0 ml) under nitrogen were added N^N^dimethylpropane-l, 3-diamine (72.5 mg, 709 pmol) and K2CO3 (14.4 mg, 142 pmol; 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]+. ’H-NMR (400 MHz, DMSO-d6) d [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-ioxan^-ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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-iloxolan- -yllmethylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l-(tetrahydrofuran-2-yl)methanamine, CAS-RN: [4795-29-3])
LC-MS (Method 1): Rt = 0.92 min; MS (ESIpos): m/z = 405 [M+H]+
’H-NMR (400 MHz, DMSO-d6) d [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-l-yl)[2,-(quinolin-3-yl)-5,,6,-dihydrospiro[azetidine-3,4,-pyrrolo[l,2-b]pyrazol]-l- yl]methanone
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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 H N
C
N-I -oxopyrrolidin-B-yll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]-!- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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
O l-I '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l-carbonyllazetidine-B- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400MHz, DMSO-ds): d [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-IilH-pyrazol-B-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]-l-carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l-(lH-pyrazol-3-yl)methanamine, CAS-RN: [37599-58-9])
LC-MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 400 [M+H]+
’H-NMR (400 MHz, DMSO-d6) d [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^-ylH '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -b pyrazol]-!- yl]methanone
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
’H-NMR (400 MHz, DMSO-d6) d [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-iB-hydroxypropylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 3-aminopropan-l-ol, CAS-RN: [156-87-6])
LC-MS (Method 1): Rt = 0.81 min; MS (ESIpos): m/z = 379 [M+H]+
’H-NMR (400 MHz, DMSO-d6) d [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-i -hydroxyethylJ-N-methyl- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]-l-carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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-i -oxopiperidin^-ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
’H-NMR (400 MHz, DMSO-d6) d [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-iS-oxopiperidin-B-ylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]-!- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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-I -ilH-imidazol-l-ylJethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- b]pyrazole]-l-carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and 2-(lH-imidazol-l-yl)ethanamine, CAS-RN: [5739-10-6])
LC-MS (Method 1): Rt = 0.82 min; MS (ESIpos): m/z = 415 [M+H]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-tquinolin-B-y -S^e'-dihydrospirotazetidine-B^'-pyrrolotl^-bJpyrazoleJ-l-carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+ ’H-NMR (400 MHz, DMSO-d6) d [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-^-hydroxy^-methylpropylJ^'-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- b]pyrazole]-l-carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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-Iil-methyl-lH-imidazol^-ylJmethyll- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (see example 2) and l-(l-methyl-lH-imidazol-4-yl)methanamine, CAS-RN: [486414-83-9]) LC-MS (Method 1): Rt = 0.83 min; MS (ESIpos): m/z = 415 [M+H]+ ’H-NMR (400 MHz, DMSO-d6) d [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-ilS-oxopyrrolidin- -yllmethylJ- '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^- b]pyrazole]-l-carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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 [B-idimethylaminoJpyrrolidin-l-ylll '-iquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazol]-l-yl]methanone
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
’H-NMR (400 MHz, DMSO-d6) d [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-^-toxolan-B-yljethylJ- '-iquinolin-B-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -blpyrazole]-!- carboxamide
(prepared from 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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- '-ilH-pyrrolo^S-blpyridin-S-ylJ-S' S'-dihydrospirotazetidine-S^'-pyrrolotl -blpyrazole]-!- carboxamide
Step 1: To a solution of tert-butyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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[l,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[l,2-b]pyrazole] trifluoroacetate (109 mg, 40 % purity, 115 pmol) was dissolved in DCM (3.0 ml) and DIPEA (200 pi, 1.1 mmol; CAS-RN:[7087-68-5]) under nitrogen, isocyanatoethane (27 mI, 340 mitioI) 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]+. ^-NMR (400 MHz, DMSO-d6) d [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 '-i -aminopyrimidin-S-ylJ-N-ethyl-S' S'-dihydrospiroIazetidine-S^'-pyrroloIl -blpyrazolel-l- carboxamide (prepared from tert-butyl 2'-(2-aminopyrimidin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-iS-aminopyridin-B-ylJ-N-ethyl-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -b pyrazole]-!- carboxamide
(prepared from tert-butyl 2'-(6-aminopyridin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-iS-methyl-lH-pyrrolo^S-b pyridin-S-ylJ-S' S'-dihydrospirotazetidine-S^'-pyrrolotl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+ ’H-NMR (400 MHz, DMSO-d6) d [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- '-ipyrido^B-blpyrazin- -ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl -blpyrazole]-!- carboxamide
(prepared from tert-butyl 2'-(pyrido[2,3-b]pyrazin-7-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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- '-ifurotS -b pyridin-S-ylJ-S' S'-dihydrospirotazetidine-S^'-pyrrolotl -b pyrazole]-!- carboxamide
(prepared from tert-butyl 2'-(furo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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- '-iS-fluoroquinolin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide
(prepared from tert-butyl 2'-(6-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-tS-ipyrrolidin-l-ylJpyridin-S-ylj-S' S'-dihydrospirotazetidine-S^'-pyrrolotl -b pyrazole]-!- carboxamide
(prepared from tert-butyl 2'-[5-(pyrrolidin-l-yl)pyridin-3-yl]-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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- '-ilH-pyrazoloIB^-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazole]-
1-carboxamide
(prepared from tert-butyl 2'-(lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-iS-methyl-lH-pyrazoloIS^-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-S^'-pyrroloIl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-i -methyl-lH-pyrroloI B-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-iB-ethyl-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 Cl o '-i -chloro-B-ethyl-lH-pyrrolo^B-blpyridin-S-ylJ-N-ethyl-S' S'-dihydrospirotazetidine-B,^- pyrrolo[l,2-b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-i -oxo- S-dihydro-lH-pyrroloI S-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-S^'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-iB-chloro- -methyl-lH-pyrroloI B-blpyridin-S-ylJ-N-ethyl-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
O
N-ethyl-2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide (45.0 mg, 128 mitioI, see example 140) was dissolved in DMF (450 mI), NCS (18.9 mg, 141 mitioI; CAS-RN:[128-09-6]) and diphenylperoxyanhydride (34.2 mg, 141 mitioI; CAS-RN:[94- 36-0]) were added and the mixture was stirred overnight at rt. The mixture was quenched with an aq. Na2S203 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]+. ’H-NMR (400 MHz, DMSO-d6) d [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
O
H C H3 '-iB-chloro-lH-pyrrolo^B-b pyridin-S-ylJ-N-ethyl-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]-l-carboxamide
(prepared from N-ethyl-2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide (see example 130)
LC-MS (Method 1): Rt = 0.87 min; MS (ESIpos): m/z = 371 [M+H]+ ’H-NMR (400 MHz, DMSO-d6) d [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- '-ilH-pyrroloIB -blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- carboxamide
To a solution of l-(ethylcarbamoyl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-2'-yl trifluoromethanesulfonate (100 mg, 271 mitioI, intermediate 9) in 1,4-dioxane (4.3 ml) were added 6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[3,2-b]pyridine (133 mg, 543 pmol), K3PO4 (1.6 ml, 0.50 M, 810 pmol; CAS-RN:[7778-53-2]) and XPhos Pd G2 (32.0 mg, 40.7 pmol; CAS-RN:[14221-01- 3]). The mixture was stirred overnight at 100°C. The mixture was diluted with EtOAc, washed with sat. NaCI 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]+. ^-NMR (400 MHz, DMSO-d6) d [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 '-ilH-pyrrolo^ B-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl^-blpyrazole]-!- carboxylate H
O o — \nu 3
To a solution of ethyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (66.0 mg, 179 pmol, see intermediate 19) in 1,4-dioxane (2.8 ml) was added under nitrogen at ambient temperature 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3- bjpyridine (87.2 mg, 357 pmol), potassium phosphate solution (1.1 ml, 0.50 M, 540 pmol; CAS-RN:[7778- 53-2]) and 2nd generation XPhos Pd (21.1 mg, 26.8 pmol; 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) d [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 u
3 ethyl '-iB-methyl-lH-pyrrolo^B-b pyridin-S-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]-l-carboxylate
(prepared from ethyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate (see intermediate 19) and 3-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-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]
^-NMR (400 MHz, DMSO-d6) d [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 '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]-l-carboxylate
(prepared from prepared from ethyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[azetidine- 3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (see intermediate 19) and 3-chloro-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-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]
^-NMR (400 MHz, DMSO-d6) d [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 '-iB-chloro-lH-pyrrolo^B-b pyridin-S-ylJ-l-methyl-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]
C H3
Step 1: To a solution of tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate (234 mg, 585 pmol, 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-l]) 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-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] (1/1) (412mg > 100%). This material was used in the following step without further purification. LC-MS (Method 1): R = 0.83 min; MS (ESIpos): m/z = 300 [M+H]+. Step 2: To a solution of formaldehyde (20 mI, 37 % in water, 270 pmol; CAS-RN:[50-00-0]) and trifluoroacetic acid— 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] (1/1) (127 mg, 59 % purity, 181 pmol) in THF (2.5 ml) was added under nitrogen at room temperature sodium triacetoxyborohydride (86.4 mg, 407 pmol; CAS-RN:[76-05-l]) and acetic acid (10 mI). 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%). ^-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
H 3C '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-l-ethyl-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - bjpyrazole]
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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 N
X C H '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-l-ipropan- -ylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 '-i -chloro-S-ethyl-lH-pyrroloI S-blpyridin-S-ylJ-l-IilH-imidazol- -ylJmethyll-S' S'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate
(see example 169/intermediate 80) and lH-imidazole-2-carbaldehyde, CAS-RN: [10111-08-7)]
LC-MS (Method 1): Rt = 0.91 min; MS (ESIpos): m/z = 408 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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 '-ilH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl - b]pyrazole]-l-carboxylate
(prepared from tert-butyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see intermediate 17) and lH-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]+
^-NMR (500 MHz, DMSO-d6) d [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 '-i -methyl-lH-pyrrolo^B-b pyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl - b]pyrazole]-l-carboxylate
(prepared from tert-butyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see intermediate 17) and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-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]+ ^-NMR (500 MHz, DMSO-d6) d [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 '-tquinolin-B-y -S'^'-dihydrospirotpiperidine^^'-pyrrolotl^-blpyrazolel-l-carboxylate
(prepared from tert-butyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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 '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospiroIpiperidine^^'-pyrroloIl - b]pyrazole]-l-carboxylate tert-butyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate (60.0 mg, 152 mitioI, see example 154) was dissolved in DMF (610 mI), NCS (22.4 mg, 168 mitioI; CAS-RN:[128-09-6]) and diphenylperoxyanhydride (40.6 mg, 168 mitioI; CAS-RN:[94-36-0]) were added and the mixture was stirred overnight at rt. The mixture was quenched with an aq. Na2S203 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]+. ’H-NMR (400 MHz, DMSO-d6) d [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 '-iB-chloro- -methyl-lH-pyrroloI B-blpyridin-S-ylJ-S' S'-dihydrospiroIpiperidine^^'- pyrrolo[l,2-b]pyrazole]-l-carboxylate
(prepared from tert-butyl 2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see examplel55).
LC-MS (Method 1): Rt = 1.33 min; MS (ESIpos): m/z = 443 [M+H]+
^-NMR (400 MHz, DMSO-d6) d [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- '-tquinolin-B-y -S^e'-dihydrospirotpiperidine^^'-pyrrolotl^-bJpyrazoleJ-l-carboxamide
(prepared from tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l- 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]+ ’H-NMR (400 MHz, DMSO-d6) d [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 '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-N-ethyl-S' S'-dihydrospirotpiperidine^^'-pyrrolotl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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 3
H '-iB-chloro- -methyl-lH-pyrroloI B-blpyridin-S-ylJ-N-ethyl-S' S'-dihydrospiroIpiperidine^^'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
N H
3
H
N-ethyl- '-iB-methyl-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine-^'-pyrrolotl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 171) and and isocyanatoethane, CAS-RN: [109-90- 0])
’H-NMR (400 MHz, DMSO-d6) d [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 l-I '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-S' S'-dihydrospiroIpiperidine^^'-pyrroloIl - b]pyrazol]-l-yl]ethan-l-one
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-lH-spiro[piperidine- 4,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 l-t '-iS-chloro-lH-pyrrolo^S-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl - b]pyrazol]-l-yl]-2-methylpropan-l-one (prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-lH-spiro[piperidine- 4,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
N l-I '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-S' S'-dihydrospiroIpiperidine^^'-pyrroloIl - b]pyrazole]-l-carbonyl]cyclopropane-l-carbonitrile
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-lH-spiro[piperidine- 4,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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 [ '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl -b pyrazol]- l-yl](phenyl)methanone
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-lH-spiro[piperidine- 4,4'-pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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
M H
[ '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine-^'-pyrrolotl -blpyrazol]- l-yl](oxan-4-yl)methanone
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydro-lH-spiro[piperidine- 4,4'-pyrrolo[l,2-b]pyrazole]-l-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]+ ’H-NMR (600 MHz, DMSO-d6) d [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 '-iS-aminopyridin-B-ylJ-S' S'-dihydrospiroIazetidine-B^'-pyrroloIl -blpyrazolel-l- 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]+
^-NMR (400 MHz, DMSO-d6) d [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 tert-butyl '-i -chloro-B-ethyl-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospiroIazetidine-B^'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (prepared from intermediate 6 and 2-chloro-3-ethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-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]+
’H-NMR (400 MHz, DMSO-d6) d [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/lnermediate 72 tert-butyl '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotazetidine-B^'-pyrrolotl - b]pyrazole]-l-carboxylate
(prepared from intermediate 6 and and 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- 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]+ ’H-NMR (400 MHz, DMSO-d6) d [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 '-iS-methyl-lH-pyrrolo^S-b pyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl - b]pyrazole]-l-carboxylate (prepared from tert-butyl 2'-[(trifluoromethanesulfonyl)oxy]-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see intermediate 17) and and 3-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-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]+ ’H-NMR (400 MHz, DMSO-d6) d [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
[ '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl -b pyrazol]- l-yl](morpholin-4-yl)methanone
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
I
C H3 '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-N N-dimethyl-S' S'-dihydrospiroIpiperidine^^'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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 '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-N-i -hydroxy- -methylpropylJ-S' S'- dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 157) and and l-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]+
^-NMR (400 MHz, DMSO-d6) d [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 H '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-N-methyl-S' S'-dihydrospiroIpiperidine^^'-pyrroloIl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
N H '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-N-i -trifluoroethylJ-S' S'-dihydrospiroIpiperidine^^'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 157) and and l,l,l-trifluoro-2-isocyanatoethane, CAS-RN: [371-92-6])
LC-MS (Method 1): Rt = 1.00 min; MS (ESIpos): m/z = 453 [M+H]+
’H-NMR (400 MHz, DMSO-d6) d [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- '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-S' S'-dihydrospiroIpiperidine^^'-pyrroloIl - b]pyrazole]-l-carboxamide
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
C l-t '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl - b]pyrazol]-l-yl]-2-hydroxyethan-l-one (prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-fc>]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [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 l-t '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-S' S'-dihydrospirotpiperidine^^'-pyrrolotl - b]pyrazol]-l-yl]-2-(pyridin-3-yl)ethan-l-one
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
^-NMR (400 MHz, DMSO-d6) d [ppm]: 1.230 (0.62), 1.588 (0.62), 1.598 (0.82), 1.621 (1.64), 1.631 (1.44),
I.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),
II.992 (1.64).
The following compounds (example 180 to example 184) were prepared in analogy to example 62: Example 180
IN
I
0=S=0 '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-l-iphenylmethanesulfonylJ-S' S'-dihydrospiroIpiperidine-
4,4'-pyrrolo[l,2-b]pyrazole] (prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
M H
I o=s=o
CHj '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-l-ipropane-l-sulfonylJ-S' S'-dihydrospiroIpiperidine^^'- pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate (see example 157) and and propane-l-sulfonyl chloride, CAS-RN: [10147-36-1])
LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 435 [M+H]+ ’H-NMR (400 MHz, DMSO-d6) d [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
I
,N.
H 3C" "C H3 '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-N N-dimethyl-S' S'-dihydrospiroIpiperidine^^'- pyrrolo[l,2-b]pyrazole]-l-sulfonamide
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
N '-iB-chloro-lH-pyrroloI B-blpyridin-S-ylJ-l-ipyridine-B-sulfonylJ-S' S'-dihydrospiroIpiperidine^^'- pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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
INI
0=S=0 '-iB-chloro-lH-pyrrolo^B-blpyridin-S-ylJ-l-imorpholine^-sulfonylJ-S' S'-dihydrospirotpiperidine-
4,4'-pyrrolo[l,2-b]pyrazole]
(prepared from tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-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]+
’H-NMR (400 MHz, DMSO-d6) d [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) d [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-terf-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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) d [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-terf-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) d [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) d [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-te/f-butyl-2'-(3-ethyl-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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) d [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-terf-butyl-2'-(3-chloro-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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 H,C
LC-MS (Method 1): Rt = 1.02 min; MS (ESIpos): m/z = 376 [M+H]+
Example 194
(rac)-N-te/f-butyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[1 ,2- b]pyrazole]-1 -carboxamide
H,C
H C H S
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
C H3
LC-MS (Method 2): Rt = 1.00 min; MS (ESIpos): m/z = 420 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) d [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
C H 3
LC-MS (Method 2): Rt = 1.13 min; MS (ESIpos): m/z = 448 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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
H
LC-MS (Method 2): Rt = 1.11 min; MS (ESIpos): m/z = 427 [M+H] 1H-NMR (400 MHz, DMSO-d6) d [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-terf-butyl-2'-(3-chloro-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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] Ή-NMR (400 MHz, DMSO-d6) d [ppm]: 1.707 (2.33), 1.741 (3.30), 1.849 (1.56), 1.859 (2.02),
I.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),
I I .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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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)-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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),
I.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),
I I .272 (1.30), 11.277 (1.32).
Example 203 N-ethyl-2'-(2-methyl-1 H-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]+ Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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]+ Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5, 1 -c][1 ,4]oxazi ne]- 1 -carboxamide LC-MS (Method 1): Rt = 0.88 min; MS (ESIpos): m/z = 395 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) d [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- ethyl-1 H-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]+ Ή-NMR (400 MHz, DMSO-d6) d [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'-(1 H-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]
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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),
I.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),
I I .265 (2.11), 11.269 (2.12). Example 210
N-ethyl-2'-(1 H-pyrazolo[3,4-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1 ,5- a]pyridine]-1-carboxa ide
LC-MS (Method 1): Rt = 0.88 min; MS (ESIpos): m/z = 380 [M+H]+ Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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]+ Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydrospiro[piperidine-4,4'- pyrazolo[5, 1 -c][1 ,4]oxazi ne]- 1 -carboxa ide
LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 415 [M+H] Ή-NMR (400 MHz, DMSO-d6) d [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
H C H3
N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’-pyrrolo[1 ,2-b]pyrazole]-1- carboxamide (75.0 mg, 206 pmol), 2-bromopropane (30.5 mg, 248 pmol) and NaOH (9.91 mg, 248 pmol) were solubilised in DMF (300 pi) 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
H C H3
N-Ethyl-2’-(6-hydroxyquinolin-3-yl)-5’,6’-dihydrospiro[azetidine-3,4’-pyrrolo[1 ,2-b]pyrazole]-1- carboxamide (75.0 mg, 206 pmol), bromocyclohexane (40.4 mg, 248 pmol) and NaOH (9.91 mg, 248 pmol) were solubilised in DMF (300 pi) 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
°*CO
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 pmol), cyclopentyl carbonochloridate (55.1 g, 371 pmol) and N,N-diisopropylethylamine (97 pi, 560 pmol) 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 pmol) and 5-methyl-1H-imidazole-2- carbaldehyde (11.5 mg, 105 pmol) were solubilized in THF (1.0 ml), sodium triacetoxyborohydride (33.4 mg, 158 pmol) and acetic acid (4.0 pi, 70 pmol) were added and the mixture was stirred overnight at rt. 5-methyl-1H-imidazole-2-carbaldehyde (11.5 mg, 105 pmol) and sodium triacetoxyborohydride (33.4 mg, 158 pmol) were added an dthe mixture was stirred for 4 h at rt. It was poured into sat. NaHC03 soultion and extracted 3x with EtOAc. The combined organic layers were dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-pyrazol-5-yl)methyl]-2'-(3-ethyl-1 H-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]
IN
LC-MS (Method 1): Rt = 1.03 min; MS (ESIpos): m/z = 408 [M+H] Example 219
(rac)-1-[(4-chloro-1 H-pyrazol-5-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole] LC-MS (Method 1): Rt = 1.10 min; MS (ESIpos): m/z = 405 [M+H]+
Example 220
2'-(3-chloro-1 H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1 H-imidazol-2-yl)methyl]-6',7'- dihydrospiro[azetidine-3,4'-pyrazolo[5,1-c][1 ,4]oxazine] LC-MS (Method 2): Rt = 0.82 min; MS (ESIpos): m/z = 396 [M+H]+
Ή-NMR (400 MHz, DMSO-d6) d [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-[(1 H-imidazol-2-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1 ,2-b]pyrazole] HSC
LC-MS (Method 1): Rt = 0.90 min; MS (ESIpos): m/z = 371 [M+H]+
Example 222
2'-(3-chloro-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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) d [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-1 H-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]+ Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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 pmol) was solubilised in DMF (2.0 ml), 4-fluorobenzoic acid (29.5 mg, 211 pmol), N,N-diisopropylethylamine (92 pi, 530 pmol) and T3P (120 pi, 50 % purity in DMF, 210 pmol) 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-pyrrolo[2,3-b]pyridin-5-yl)-1-(methanesulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1 ,2-b]pyrazole] C H 3
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 pmol) was solubilised in DMSO (1.0 ml), methanesulfonyl chloride (17.9 mg, 156 pmol) and triethylamine (65 pi, 470 pmol) 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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 pmol) was solubilised in DMSO (2.0 ml), dimethylsulfamyl chloride (27.7 mg, 193 pmol) and N,N-diisopropylethylamine (92 pi,
530 pmol) 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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-1 H-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 pmol) was solubilised in DMF (500 pi), NCS (14.6 g, 109 pmol) and benzoyl peroxide (35.3 mg, 75 % purity, 109 pmol) were added and the mixture was stirred for 3 h at rt. It was diluted with half cone. Na2S203 solution, extracted with EtOAc. The organic layer was washed with brine, dried with Na2S04 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]+
Ή-NMR (400 MHz, DMSO-d6) d [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),
I.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),
I I .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 lOOfold 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 pL solution of Tracer 222 (25 nM => final concentration in 5 pL assay volume is 15 nM) in aqueous assay buffer [25 mM T ris/HCI pH 7.5, 10 mM MgC , 5 mM b-glycerolphosphate, 2.5 mM dithiothreitol, 0.5 mM ethylene glycol-bis(2-aminoethylether)-A/,A/,A/,,A/'- 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 pL of a solution of the GST- fusion protein (2.5 nM => final cone in the 5 pL assay volume is 1 nM) and of Anti-GST-Tb (1.25 nM => final cone in the 5 pL 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 mM to 0.07 nM (20 pM, 5.7 pM, 1.6 pM, 0.47 pM, 0.13 pM, 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 lOOfold 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):
Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
1 7040 11 38 21 1620
2 12 10500 22 1820
3 306 13 4170 23 871
4 3350 14 1140 24 1870
5 3430 15 1010 25 796
16 975 26 346
7 6250 17 46 27 1680
8 2410 18 28 1770
9 17000 19 1700 29 1120
10 1880 20 1370 30 867
Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
31 1870 41 457 51 1600
32 1560 42 6420 52 1300
33 1740 43 3620 53 468
34 1310 44 2090 54 2090
35 3200 45 1660 55 682
36 3750 46 3030 56 706
37 2060 47 3230 57 3100
38 1570 48 3790 58 3270
39 2860 49 3970 59 5400
40 1700 50 2270 60 2250 Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
61 5220 71 1020 81 5630
62 2950 72 816 82 1720
63 5950 73 486 83 696
64 781 74 914 84 675
65 934 75 2260 85 990
66 741 76 505 86 1200
67 1940 77 4090 87 782
68 1330 78 393 88 2730
69 4230 79 1670 89 7430
70 650 80 9600 90 1460
Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
91 419 101 2660 111 661
92 1780 102 3430 112 713
93 1790 103 1340 113 445
94 2120 104 789 114 1050
95 2360 105 2630 115 1050
96 392 106 654 116 2410
97 2030 107 1350 117 349
98 695 108 1230 118 1060
99 336 109 542 119 741
100 874 110 1140 120 1650
Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
121 900 131 3010 141 21
122 1080 132 16100 142 17
123 750 133 38 143 2390
124 173 134 15000 144 267
125 1030 135 3340 145 27
126 433 136 288 146 3540
127 666 137 6600 147 279
128 1040 138 1200 148 43
129 410 139 899 149 30 Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
130 162 140 716 150 42
Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
151 42 161 97 171
152 37 162 19 172 19
153 12 163 30 173 30
154 227 164 24 174 24
155 1910 165 24 175 24
156 1240 166 22 176 22
157 100 167 24 177 24
158 793 168 178 25
159 546 169 179 6
160 19 170 180
Example IC50 [nM]
181
182
183
184
Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
185 32 202 10 219 718
186 39 203 434 220 20
187 7 204 124 221 297
188 10 205 80 222 52
189 10 206 80 223 54
190 11 207 67 224 67
191 26 208 499 225 48
192 24 209 35 226 45
193 469 210 6660 227 100
194 877 211 34 228 45
195 261 212 56 229 53
196 214 213 337 230 25
197 24 214 437 231 43 Example ICso [nM] Example IC50 [nM] Example IC50 [nM]
198 29 215 702 232 66
199 16 216 29 233 67
200 771 217 7 234 95
201 89 218 15
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 pg/mL a-CD3 antibody (clone OKT3. ebioscience #16-0037-85) and 4 pg/mL anti-lgG crosslinking antibody (Invitrogen goat anti-mouse IgG (Fl+L) 2 #31160) together with the test compound for 30 min at 37 °C. Applied compounds were tested at either fixed concentration of 10 pmol/L and 20 pmol/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 pmol/L. 5 pmol/L. 10 pmol/L and 20 pmol/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 pi of the supplemented lysis buffer (Cisbio # 63ADK076PEG) for 60 min at room temperature. Subsequently 4 pi 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

1. Compounds of formula (I) in which both A represent either -CH2- or -CH2-CH2-,
R3 represents -H or -CH3,
X represents either a direct bond, -CH2- or -0-,
Y represents -H, -Cl, -F, -Br, -CN, -CF3, Ci-C4-alkyl, C3-C7-cycloalkyl,
Ri represents a group 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, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-Chl3, -S(0)(NRZ)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo- group (=0)) or in which *-A'- represents a group
*-CRaFI-, in which Ra represents
• hydrogen,
• Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CH3, -S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -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 (=0)),
• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -FI 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 (=0)) and in which B represents
• hydrogen,
• -CN,
• Ci-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-Chl3, - S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0)),
• -phenyl, C3-6-cycloalkyl,
• -C(=0)-NFIRb, in which Rb represents
·· hydrogen,
·· Ci-C4-alkoxy,
·· Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CFI3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0)), or ·· phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, - OCF3, -OCF2FI, halogen, Ci-C4-alkyl (optionally -OCFI3 substituiert), C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(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 (=0)), or in which R6 and R7 are independently of each other hydrogen, -CH3 or bridged by Ci-C4-alkyl in which one -CH2-group can be replaced by oxygen, or in which A' represents a group
• *-C(=0)- or *-S02- and in which B represents
• Ci-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, Ci-C4-alkoxy, an oxo-group (=0),-S(0)2-CH3, -S(0)(NRZ)-CH3, or -NRxRy, in which Rx,Ryand 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(=0)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) or 5- to 6- membered heteroaryl,
• C2-C4-alkenyl,
• phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
• -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 (=0)), or in which A' represents a group
• *-C(=0)-0-,
N(Rc)-
• , in which Rc represents -H or Ci-C4-alkyl,
• *-C(=0)-NRc-, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=S)-NRc-, in which Rc represents -H or Ci-C4-alkyl,
• *-C(=N-CN)-0- or
• *-C(=N-CN)-NRc, in which Rc represents -H or Ci-C4-alkyl and in which B represents
• -H,
• Ci-C6-alkyl, Ci-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
• -S02-(Ci-C4-alkyl),
• a group -C(=0)-Rd, in which Rd represents
·· -CF3,
·· Ci-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 (=0),
·· -phenyl, optionally substituted with Ci-C4-alkyl, or
·· 5- or 6- membered heteroaryl, optionally substituted with Ci-C4-alkyl,
• or in which N, Rc and B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci-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 (=0)), or
• a group -C(=0)-Rf, in which Rf represents Ci-C4-alkyl or C3-C7-cycloalkyl,
R2 represents
R4 represents
• -H,
• -NO2,
• -CN,
• -OH,
• -P(=0)(Ci-C4-alkyl)2,
• -S(=0)2-(Ci-C4-alkyl),
. -N=S(=NH)(Ci-C4-alkyl)2,
• -N=S(=0)(Ci-C4-alkyl)2,
• halogen
• -C(=0)-0- Ci-C4-alkyl,
• -C(=0)- Ci-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 (=0), ·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
·· C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with - OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CFI3, Ci-C4-alkoxy, an oxo-group (=0), - S(0)(NRZ)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
·· -C(=0)-NRvRw or -C(=0)-0-Rv, in which Rv represents -FI or Ci-C4-alkyl, Rw represents -FI, Ci-C4-alkyl or -CFI2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl
• C3-C6-cycloalkoxy,
• C3-C6-alkenyloxy,
• Ci-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7-membered heterocycloalkenyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CFH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), -C(=0)-0-CFI3, 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, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl, 4- to 7 membered heterocycloalkyl, Ci-C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or - NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, Ci-C4-fluoroalkyl, - OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci- C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), • phenyl, optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFl3, - S(0)(NRz)-CFl3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI or C C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -NRiRj, in which R, represents -FI, Ci-C4-alkyl and Rj represents -FI, Ci-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, R, and Rj together form a 4- to 7-membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=0) or Ci-C4-alkyl
• -NRi-S(=0)2-RP, in which R, represents -FI, Ci-C4-alkyl and Rp represents 5- or 6-membered heteroaryl,
• -NH-C(=0)-NRkRi, in which Rk represents -FI or Ci-C4-alkyl and Ri represents
·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)), or
·· Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, -S(0)(NRz)-CH3, C1-C4- alkoxy, an oxo-group (=0), -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 (=0))
• -NH-C(=0)-Rm, in which Rm represents
·· phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, C1-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)), or ·· Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, C C4-alkyl, -CN, -S(0)2-CH3, -S(0)(NRz)-CH3, Ci-C4- alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
• -(C=0)-NRnRo, in which Rn represents -H or Ci-C4-alkyl, R0 represents Ci-C6-hydroxyalkyl, 5- or 6- membered heteroaryl (N), or —9 or in which N, Rn and R0 together form a 3- to 7-membered heterocycloalkyl, optionally substituted with -CN,
R5 represents -H, Ci-C4-alkyl, -F or -Cl,
Ri5 represents -H, Ci-C4-alkyl, -CF3, -F, -CI,-0-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 -0-,
Y represents -H, -Cl, -Br, -CN, -CF3, Ci-C4-alkyl, C3-C7-cycloalkyl,
Ri 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,
Ci-C4-alkyl or C3-C7-cycloalkyl all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, -S(0)(NRz)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) and in which B represents -H,
-CN, Ci-C6-alkyl, C3-C7-cycloalkyl or a 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, - S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or C C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
-C(=0)-NHRb, in which Rb represents -H,
Ci-C4-alkoxy,
Ci-C4-alkyl, C3-C7-cycloalkyl or 4- to 7 membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CH3, -S(0)(NRZ)-CH3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or phenyl or a 5- or 6- membered heteroaryl or a 9- or 10-membered bicyclic heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl (optionally -OCH3 substituiert), C3- Cycycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)),
H
R6 or R7 in which R6 and R7 are hydrogen or bridged by Ci-C4-alkyl in which one -CH2-group can be replaced by oxygen, in which A' represents a group *-C(=0)- and in which B represents
Ci-C6-alkyl, C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, Ci-C4-alkoxy, an oxo-group (=0),-S(0)2-CH3, -S(0)(NRZ)-CH3, or -NRxRy, in which Rx,Ryand Rz represent independently of each other -H or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl, -C(=0)-NH2, 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)) or 5- to 6- membered heteroaryl,
C2-C4-alkenyl, phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)),
-NRxRy, in which Rx and Ry represent independently of each other -FI 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 (=0)), in which A' represents a group *-C(=0)-0-,
*-C(=0)-NRc-, in which Rc represents -FI or Ci-C4-alkyl,
*-C(=S)-NRc-, in which Rc represents -FI or Ci-C4-alkyl, in which B represents -H,
Ci-C6-alkyl, Ci-C4-alkoxy, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)),
• -CR2OR2I-R22 in which R2o is -CFI3, R2I is -FI, -CFI3 or R2o and R together are - CH2-CH2-CF-I2- 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, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
-S02-(Ci-C4-alkyl), a group -C(=0)-Rd, in which Rd represents -CF¾
Ci-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 (=0),
-phenyl or
5- or 6- membered heteroaryl, optionally substituted with Ci- C4-alkyl; or
N, Rc und B together form a 4- to 7-membered heterocycloalkyl, optionally substituted with Ci-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 (=0)), a group -C(=0)-Rf, in which Rf represents Ci-C4-alkyl or C3-C7-cycloalkyl,
R2 represents
R4 represents -H,
-N02,
-CN,
-OH,
-P(=0)(Ci-C4-alkyl)2,
-S(=0)2-(Ci-C4-alkyl), halogen -C(=0)- Ci-C4-alkyl,
-O-CHs,
-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 (=0), phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CH3, -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)),
C3-C7-cycloalkyl, 4 to 7-membered heterocycloalkyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)), -C(=0)-NRvRw or -C(=0)-0-Rv, in which Rv represents -H or Ci-C4-alkyl, Rw represents -H, Ci-C4-alkyl or -CH2-CF3 or in which N, Rv and Rw together form a 4- to 7-membered heterocycloalkyl - C3-C6-alkenyloxy,
Ci-C6-alkyl, C3-C7-cycloalkyl, 4- to 7-membered heterocycloalkyl or 4 to 7-membered heterocycloalkenyl, all optionally substituted with -OH, halogen, -CF3, Ci-C4-alkyl, -CN, - S(0)2-CH3, Ci-C4-alkoxy, an oxo-group (=0), -S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)), -C(=0)-0-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, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, C1-C4- alkyl, C3-C7-cycloalkyl, 4- to 7 membered heterocycloalkyl, Ci-C4-alkoxy, -S(0)2-CH3, - S(0)(NRZ)-CH3 or -NRxRy, in which Rx,Ryand 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 (=0)), 5- or 6- membered heteroaryl, all optionally substituted with -phenyl, -CN, Ci-C4- fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), phenyl, optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci- C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4- alkoxy, -S(0)2-CFI3, -S(0)(NRz)-CFI3 or -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), -NRiRj, in which R, represents -FI, Ci-C4-alkyl and Rj represents -FI, Ci-C4-alkyl, a 5- to 6 membered heteroaryl or in which N, R, and Rj together form a 4- to 7- membered heterocycloalkyl, optionally substituted (1 or more times) with an oxo-group (=0) or Ci-C4-alkyl -NRrS(=0)2-Rp, in which R, represents -FI, Ci-C4-alkyl and Rp represents 5- or 6-membered heteroaryl,
-NH-C(=0)-NRkRi, in which Rk represents -FI or Ci-C4-alkyl and Ri represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2FI, halogen, Ci-C4-alkyl, C3-C7- cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), C C4-alkoxy, -S(0)2-CH3, -S(0)(NRz)-CH3 or -NRxRy, in which Rx,Ry and Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), or Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2- CFH3, -S(0)(NRZ)-CFI3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI or Ci-C4 alkyl or in which N, Rx and Ry together form a 4 to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0))
-NH-C(=0)-Rm, in which Rm represents phenyl or a 5- or 6- membered heteroaryl, all optionally substituted with -CN, Ci-C4-fluoroalkyl, -OCF3, -OCF2H, halogen, Ci-C4-alkyl, C3-C7-cycloalkyl (optionally substituted with an oxo-group (=0)), 4- to 7 membered heterocycloalkyl (optionally substituted with an oxo-group (=0)), Ci-C4-alkoxy, - S(0)2-CFl3, -S(0)(NRz)-CFl3 or -NRxRy, in which Rx,Ryand Rz represent independently of each other -FI 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 (=0)), or
Ci-C4-alkyl, C3-C7-cycloalkyl or 4 to 7-membered heterocycloalkyl, all optionally substituted with -OFI, halogen, -CF3, Ci-C4-alkyl, -CN, -S(0)2-CFl3, -S(0)(NRz)-CFl3, Ci-C4-alkoxy, an oxo-group (=0), -NRxRy, in which Rx, Ry and Rz represent independently of each other -FI 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 (=0))
-(C=0)-NRnRo, in which Rn represents -FI or Ci-C4-alkyl, R0 represents Ci-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,
Rs represents -FI, -F or -Cl,
Ri5 represents -FI, 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 rw
R R4 2 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 /=N *~ H
R4 and wherein F is selected from hydrogen, -F, -Cl, methyl, ethyl and isopropyl.
6. Compounds according to claim 1 or 2 wherein Ri is selected from -C(=0)-0-tBu, -C(=0)-NH-Et, -C(=0)-NH-C(=0)-0-Et,
H H
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[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-aminopyrimidin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(lH-pyrrolo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-[5-(pyrrolidin-l-yl)pyridin-3-yl]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-[5-(trifluoromethyl)pyridin-3-yl]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate tert-butyl 2'-(lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate tert-butyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(pyrido[2,3-b]pyrazin-7-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(furo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(3-methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(6-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl -6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate
(pyrimidin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]methanone
(l-methyl-lH-pyrazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
4-oxo-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]butanenitrile
3-methoxy-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]propan-l- one
3-(lH-pyrazol-l-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]propan-l-one
2-(morpholin-4-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
2-(pyrimidin-5-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
(3-chlorophenyl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]methanone
(pyridin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]methanone
2-ethyl-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]butan-l-one l-{2-oxo-2-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethyl}pyrrolidin-2-one
(pyridin-3-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]methanone l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]cyclopropane-
1-carbonitrile l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]ethan-l-one
(l-methyl-lH-imidazol-5-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone 2-methoxyethyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate
2-methoxyethyl 6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate
[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl](pyrimidin-4- yl)methanone
(l-methyl-lH-pyrazol-5-yl)[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazol]-l-yl]methanone l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-3-(lH- pyrazol-l-yl)propan-l-one l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2-
(morpholin-4-yl)ethan-l-one
1-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2- (pyrimidin-5-yl)ethan-l-one
(3-chlorophenyl)[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl](pyridin-4- yl)methanone
2-ethyl-l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]butan-l-one l-{2-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2- oxoethyl}pyrrolidin-2-one
[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl](pyridin-3- yl)methanone l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carbonyl]cyclopropane-l-carbonitrile l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]ethan-l-one
(l-methyl-lH-imidazol-5-yl)[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazol]-l-yl]methanone
3-methoxy-l-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]propan-l-one
4-[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-4- oxobutanenitrile l-[(2-methylpyrimidin-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] N,N-dimethyl-5-{[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]methyl}-l,3-thiazol-2-amine l-[(lH-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-[(pyrazolo[l,5-a]pyrimidin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(lH-indazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-(cyclohexylmethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
6'-methyl-l-[(2-methylpyrimidin-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
N,N-dimethyl-5-{[6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]methyl}-l,3-thiazol-2-amine
6'-methyl-l-[(pyrazolo[l,5-a]pyrimidin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(lH-indazol-3-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-(cyclohexylmethyl)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-(cyclopropanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-(cyclopropanesulfonyl)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
N-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
6'-methyl-N-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide l-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
6'-methyl-l-(pyridin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
N-(2-chloroethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
2'-(quinolin-3-yl)-N-(2,2,2-trifluoroethyl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide N-cyclopentyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-tert-butyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide methyl [2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carbonyl]carbamate
N-[(furan-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-(2-methoxyethyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-phenyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ethyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carbothioamide l-(methanesulfonyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-(methanesulfonyl)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] ethyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate ethyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate l-[(4-methyl-lH-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(imidazo[l,5-a]pyridin-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-{[l-(propan-2-yl)-lH-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(quinolin-3-yl)-l-{[4-(trifluoromethyl)-lH-imidazol-2-yl]methyl}-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-(2-methylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-{[l-(2-methoxyethyl)-lH-imidazol-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(quinolin-3-yl)-l-[(l,4,5-trimethyl-lH-imidazol-2-yl)methyl]-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(lH-benzimidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(l-methyl-lH-imidazol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(lH-pyrazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-[(4-methyl-lH-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(2-methyl-lH-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole] l-[(lH-pyrrol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] l-[(lH-imidazol-5-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]
1-[(5-methyl-lH-pyrrol-2-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
3-(ethylamino)-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]cyclobut-3-ene-l,2-dione
3-(dimethylamino)-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]cyclobut-3-ene-l,2-dione
2-(dimethylamino)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
3-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]pyrrolidin-2- one
4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]pyrrolidin-2- one
2-(lH-imidazol-l-yl)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]ethan-l-one
4-oxo-4-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]butanamide l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]-2-(4H-l,2,4-triazol-4- yl)ethan-l-one l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l-yl]prop-2-en-l-one
3-(dimethylamino)-l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yl]propan-l-one
N'-cyano-N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboximidamide
N'-cyano-N,N-dimethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboximidamide
N-[3-(dimethylamino)propyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-(oxan-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-{[-oxolan-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide (4-methylpiperazin-l-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
N-[2-oxopyrrolidin-3-yl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide l-[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carbonyl]azetidine-3- carboxamide
N-[(lH-pyrazol-3-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-
1-carboxamide
(morpholin-4-yl)[2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazol]-l- yljmethanone
N-(3-hydroxypropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-(2-hydroxyethyl)-N-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-(2-oxopiperidin-4-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-(6-oxopiperidin-3-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-[2-(lH-imidazol-l-yl)ethyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-benzyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-(2-hydroxy-2-methylpropyl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-[(l-methyl-lH-imidazol-4-yl)methyl]-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-{[-5-oxopyrrolidin-2-yl]methyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
[-3-(dimethylamino)pyrrolidin-l-yl][2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazol]-l-yl]methanone
N-{2-[oxolan-3-yl]ethyl}-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
2'-(2-aminopyrimidin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide 2'-(6-aminopyridin-3-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(pyrido[2,3-b]pyrazin-7-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(furo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(6-fluoroquinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-[5-(pyrrolidin-l-yl)pyridin-3-yl]-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide
N-ethyl-2'-(3-methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ethyl-2'-(lH-pyrrolo[3,2-b]pyridin-6-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide ethyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate ethyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate ethyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-methyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- bjpyrazole]
2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] tert-butyl 2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate tert-butyl 2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(quinolin-3-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate tert-butyl 2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate
N-ethyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]ethan-l-one l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]-2-methylpropan-l-one l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]- l-carbonyl]cyclopropane-l-carbonitrile
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]-l- yl](phenyl)methanone
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]-l- yl](oxan-4-yl)methanone tert-butyl 2'-(6-aminopyridin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxylate tert-butyl 2'-(2-chloro-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxylate tert-butyl 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate
2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-cyclobutyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-cyclobutyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-ferf-butyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
(rac)-6'-methyl-N-(propan-2-yl)-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
(rac)-N-ferf-butyl-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-
1-carboxamide
N-ethyl-2'-(6-methoxyquinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]-l- carboxamide
N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
N-ferf-butyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-phenyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
N-ethyl-2'-(quinolin-3-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]-l- carboxamide N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-[3-(propan-2-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide
N-ethyl-2'-(2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydrospiro[azetidine-3,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide
N-ethyl-2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
N-ethyl-2'-(lH-pyrazolo[3,4-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridine]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydrospiro[piperidine-4,4'-pyrazolo[5,l- c][l,4]oxazine]-l-carboxamide
N-ethyl-2'-{6-[(propan-2-yl)oxy]quinolin-3-yl}-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-
1-carboxamide
2'-[6-(cyclohexyloxy)quinolin-3-yl]-N-ethyl-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]-l- carboxamide cyclopentyl (rac)-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole]- 1-carboxylate
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(5-methyl-lH-imidazol-2-yl)methyl]-6',7'- dihydrospiro[azetidine-3,4'-pyrazolo[5,l-c][l,4]oxazine]
2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole] l-[(4-chloro-lH-pyrazol-5-yl)methyl]-2'-(3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[l,2-b]pyrazole] (rac)-l-[(4-chloro-lH-pyrazol-5-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-6',7'-dihydrospiro[azetidine-
3,4'-pyrazolo[5,l-c][l,4]oxazine]
(rac)-l-[(lH-imidazol-2-yl)methyl]-6'-methyl-2'-(quinolin-3-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(l-methyl-lH-imidazol-2-yl)methyl]-6',7'-dihydro-5'H- spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-6',7'-dihydro-5'H- spiro[piperidine-4,4'-pyrazolo[l,5-a]pyridine]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(3,3,3-trifluoropropyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(lH-imidazol-2-yl)methyl]-5',6'-dihydrospiro[piperidine-
4,4'-pyrrolo[l,2-b]pyrazole] l-benzyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- bjpyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(cyclohexylmethyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(propan-2-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-[(l-methyl-lH-pyrazol-4-yl)methyl]-5',6'- dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazole]
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridin]-l-yl](4-fluorophenyl)methanone
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[l,5- a]pyridin]-l-yl](oxan-4-yl)methanone
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(methanesulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-sulfonamide
2'-(3-chloro-2-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine-4,4'- pyrazolo[l,5-a]pyridine]-l-carboxamide tert-butyl 2'-(3-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxylate
[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]-l- yl](morpholin-4-yl)methanone 2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(2-hydroxy-2-methylpropyl)-5',6'-dihydrospiro[piperidine-
4,4'-pyrrolo[l,2-b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]-l-carboxamide
N-benzyl-2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-carboxamide l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]-2-hydroxyethan-l-one l-[2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2-b]pyrazol]- l-yl]-2-(pyridin-3-yl)ethan-l-one
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(phenylmethanesulfonyl)-5',6'-dihydrospiro[piperidine-
4,4'-pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(propane-l-sulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-N,N-dimethyl-5',6'-dihydrospiro[piperidine-4,4'-pyrrolo[l,2- b]pyrazole]-l-sulfonamide
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(pyridine-3-sulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,2-b]pyrazole]
2'-(3-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-l-(morpholine-4-sulfonyl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[l,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
R or wherein Ri, 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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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022167627A1 (en) * 2021-02-05 2022-08-11 Bayer Aktiengesellschaft Map4k1 inhibitors
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds

Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001023389A2 (en) 1999-09-30 2001-04-05 Neurogen Corporation Certain alkylene diamine-substituted heterocycles
US20030055049A1 (en) 1999-01-27 2003-03-20 Pfizer Inc. Heteroaromatic bicyclic derivatives useful as anticancer agents
WO2005058891A1 (en) 2003-12-09 2005-06-30 Bayer Healthcare Ag Pyrrolopyridine-substituted benzol derivatives for treating cardiovascular diseases
WO2006014325A2 (en) 2004-07-02 2006-02-09 Exelixis, Inc. C-met modulators and method of use
WO2006114180A1 (en) 2005-04-25 2006-11-02 Merck Patent Gmbh Novel aza- heterocycles serving as kinase inhibitors
WO2006116713A1 (en) 2005-04-27 2006-11-02 Amgen Inc. Substituted amide derivatives as protein kinase inhibitors
WO2008089307A2 (en) 2007-01-18 2008-07-24 Lexicon Pharmaceuticals, Inc. Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer
WO2010045095A1 (en) 2008-10-14 2010-04-22 Ning Xi Compounds and methods of use
CN102086211A (en) 2009-12-08 2011-06-08 深圳市东阳光实业发展有限公司 Aromatic heterocyclic compounds serving as protein kinase inhibitor
WO2011090738A2 (en) 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Type ii raf kinase inhibitors
WO2015089479A1 (en) 2013-12-13 2015-06-18 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
WO2016004272A1 (en) 2014-07-02 2016-01-07 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
WO2016195776A1 (en) 2015-06-04 2016-12-08 Kura Oncology, Inc. Methods and compositions for inhibiting the interaction of menin with mll proteins
WO2016205942A1 (en) 2015-06-25 2016-12-29 University Health Network Hpk1 inhibitors and methods of using same
WO2018049119A1 (en) 2016-09-09 2018-03-15 The Procter & Gamble Company Methods for simultaneously producing different products on a single production line
WO2018049152A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyrimidine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049214A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049200A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018102366A1 (en) 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors
WO2018167147A1 (en) 2017-03-15 2018-09-20 F. Hoffmann-La Roche Ag Azaindoles as inhibitors of hpk1
WO2018183956A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Naphthyridines as inhibitors of hpk1
WO2018183964A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Isoquinolines as inhibitors of hpk1
WO2018215668A1 (en) 2017-05-26 2018-11-29 Glenmark Pharmaceuticals S.A. Novel inhibitors of map4k1
CN109721620A (en) 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 HPK1 inhibitors and uses thereof
WO2019090198A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Isofuranone compounds useful as hpk1 inhibitors
WO2019149738A1 (en) 2018-01-31 2019-08-08 Heparegenix Gmbh Protein kinase mkk4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US20190256500A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
US20190256520A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
WO2019164846A1 (en) 2018-02-20 2019-08-29 Incyte Corporation N-(phenyl)-2-(phenyl)pyrimidine-4-carboxamide derivatives and related compounds as hpk1 inhibitors for treating cancer
WO2020061377A1 (en) * 2018-09-19 2020-03-26 Genentech, Inc. Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
WO2021074279A1 (en) * 2019-10-16 2021-04-22 Bayer Aktiengesellschaft Spiro-fused tricyclic map4k1 inhibitors

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030055049A1 (en) 1999-01-27 2003-03-20 Pfizer Inc. Heteroaromatic bicyclic derivatives useful as anticancer agents
WO2001023389A2 (en) 1999-09-30 2001-04-05 Neurogen Corporation Certain alkylene diamine-substituted heterocycles
WO2005058891A1 (en) 2003-12-09 2005-06-30 Bayer Healthcare Ag Pyrrolopyridine-substituted benzol derivatives for treating cardiovascular diseases
WO2006014325A2 (en) 2004-07-02 2006-02-09 Exelixis, Inc. C-met modulators and method of use
WO2006114180A1 (en) 2005-04-25 2006-11-02 Merck Patent Gmbh Novel aza- heterocycles serving as kinase inhibitors
WO2006116713A1 (en) 2005-04-27 2006-11-02 Amgen Inc. Substituted amide derivatives as protein kinase inhibitors
WO2008089307A2 (en) 2007-01-18 2008-07-24 Lexicon Pharmaceuticals, Inc. Delta 5 desaturase inhibitors for the treatment of pain, inflammation and cancer
WO2010045095A1 (en) 2008-10-14 2010-04-22 Ning Xi Compounds and methods of use
CN102086211A (en) 2009-12-08 2011-06-08 深圳市东阳光实业发展有限公司 Aromatic heterocyclic compounds serving as protein kinase inhibitor
WO2011090738A2 (en) 2009-12-29 2011-07-28 Dana-Farber Cancer Institute, Inc. Type ii raf kinase inhibitors
WO2015089479A1 (en) 2013-12-13 2015-06-18 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
WO2016004272A1 (en) 2014-07-02 2016-01-07 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
WO2016195776A1 (en) 2015-06-04 2016-12-08 Kura Oncology, Inc. Methods and compositions for inhibiting the interaction of menin with mll proteins
WO2016205942A1 (en) 2015-06-25 2016-12-29 University Health Network Hpk1 inhibitors and methods of using same
WO2018049214A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049152A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyrimidine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018049119A1 (en) 2016-09-09 2018-03-15 The Procter & Gamble Company Methods for simultaneously producing different products on a single production line
WO2018049200A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer
WO2018102366A1 (en) 2016-11-30 2018-06-07 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (hpk1) inhibitors
WO2018167147A1 (en) 2017-03-15 2018-09-20 F. Hoffmann-La Roche Ag Azaindoles as inhibitors of hpk1
WO2018183956A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Naphthyridines as inhibitors of hpk1
WO2018183964A1 (en) 2017-03-30 2018-10-04 Genentech, Inc. Isoquinolines as inhibitors of hpk1
WO2018215668A1 (en) 2017-05-26 2018-11-29 Glenmark Pharmaceuticals S.A. Novel inhibitors of map4k1
CN109721620A (en) 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 HPK1 inhibitors and uses thereof
WO2019090198A1 (en) 2017-11-06 2019-05-09 Bristol-Myers Squibb Company Isofuranone compounds useful as hpk1 inhibitors
WO2019149738A1 (en) 2018-01-31 2019-08-08 Heparegenix Gmbh Protein kinase mkk4 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US20190256500A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
US20190256520A1 (en) 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
WO2019164846A1 (en) 2018-02-20 2019-08-29 Incyte Corporation N-(phenyl)-2-(phenyl)pyrimidine-4-carboxamide derivatives and related compounds as hpk1 inhibitors for treating cancer
WO2019164847A1 (en) * 2018-02-20 2019-08-29 Incyte Corporation Indazole compounds and uses thereof
WO2020061377A1 (en) * 2018-09-19 2020-03-26 Genentech, Inc. Spirocyclic 2,3-dihydro-7-azaindole compounds and uses thereof
WO2021074279A1 (en) * 2019-10-16 2021-04-22 Bayer Aktiengesellschaft Spiro-fused tricyclic map4k1 inhibitors

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
"CAS", Database accession no. 1045855-91-1
"Citation of NMR Peaklist Data within Patent Applications", CITATION OF NMR PEAKLIST DATA WITHIN PATENT APPLICATIONS, vol. 605005, 1 August 2014 (2014-08-01), Retrieved from the Internet <URL:http://www.researchdisclosure.com/searching-disclosures>
ALZABIN ET AL., CANCER IMMUNOL IMMUNOTHER, vol. 59, no. 3, March 2010 (2010-03-01), pages 419 - 29
ALZABIN ET AL., J IMMUNOL, vol. 182, no. 10, 15 May 2009 (2009-05-15), pages 6187 - 94
BOOMER ET AL., J CELL BIOCHEM, vol. 95, no. 1, 1 May 2005 (2005-05-01), pages 34 - 44
CAS, no. 1111638-73-3
CAS, no. 1417985-25-1
D.G. HALL: "Boronic Acids", 2005, WILEY-VCH VERLAG GMBH & CO. KGAA
DI BARTOLO ET AL., J EXP MED., vol. 204, no. 3, 19 March 2007 (2007-03-19), pages 681 - 91
HU ET AL., GENES DEV, vol. 10, no. 18, 15 September 1996 (1996-09-15), pages 2251 - 64
KEIR M E ET AL., ANNU. REV. IMMUNOL., vol. 26, 2008, pages 677
LASSERRE ET AL., J CELL BIOL, vol. 195, no. 5, 28 November 2011 (2011-11-28), pages 839 - 53
LING ET AL., J BIOL CHEM, vol. 276, no. 22, 1 June 2001 (2001-06-01)
LIOU ET AL., IMMUNITY., vol. 12, no. 4, April 2000 (2000-04-01), pages 399 - 408
P.G.M. WUTST.W. GREENE: "Protective Groups in Organic Synthesis", 2006, WILLEY
PURE APPL CHEM, vol. 45, 1976, pages 11 - 30
S. M. BERGE: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
SAUER ET AL., J BIOL CHEM, vol. 276, no. 48, 30 November 2001 (2001-11-30), pages 45207 - 16
SAWASDIKOSOL ET AL., J BIOL CHEM, vol. 282, no. 48, 30 November 2007 (2007-11-30), pages 34693 - 9
SHUI ET AL., NAT IMMUNOL, vol. 8, no. 1, January 2007 (2007-01-01), pages 84 - 91
SHUI ET AL., NAT IMMUNOL., vol. 8, no. 1, January 2007 (2007-01-01), pages 84 - 91
TETRAHEDRON, vol. 39, 1983, pages 2023 - 2029
TSUJI ET AL., J EXP MED., vol. 194, no. 4, 20 August 2001 (2001-08-20), pages 529 - 39

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
WO2022167627A1 (en) * 2021-02-05 2022-08-11 Bayer Aktiengesellschaft Map4k1 inhibitors

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