WO2021074279A1 - Inhibiteurs de map4k1 tricycliques spiro fusionnés - Google Patents

Inhibiteurs de map4k1 tricycliques spiro fusionnés Download PDF

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

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

Definitions

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

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Abstract

La présente invention concerne des inhibiteurs de Map4K1 de formule (I), des compositions pharmaceutiques et des combinaisons comprenant les composés selon l'invention, ainsi que l'utilisation prophylactique et thérapeutique des composés selon l'invention, respectivement, l'utilisation desdits composés dans la fabrication de compositions pharmaceutiques pour le traitement ou la prophylaxie de maladies, en particulier de troubles néoplasiques, respectivement, le cancer ou des états pathologiques ayant des réponses immunitaires dérégulées ou d'autres troubles associés à une signalisation aberrante de MAP4K1, en tant qu'agent seul ou en combinaison avec d'autres principes actifs. La présente invention concerne en outre l'utilisation, respectivement, l'utilisation desdits composés pour la fabrication de compositions pharmaceutiques destinées au traitement ou à la prophylaxie d'inhibiteurs de protéines dans des hyperplasies bénignes, des troubles athérosclérotiques, la sepsis, des troubles auto-immuns, des troubles vasculaires, des infections virales, des troubles neurodégénératifs, des troubles inflammatoires, des troubles athérosclérotiques et dans la régulation de la fertilité chez l'homme.
PCT/EP2020/079007 2019-10-16 2020-10-15 Inhibiteurs de map4k1 tricycliques spiro fusionnés WO2021074279A1 (fr)

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WO2021249913A1 (fr) * 2020-06-09 2021-12-16 Bayer Aktiengesellschaft Dérivés de 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azétidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate et des composés apparentés servant d'inhibiteurs de map4k1 (hpk1) pour le traitement du cancer
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
WO2022167627A1 (fr) * 2021-02-05 2022-08-11 Bayer Aktiengesellschaft Inhibiteurs de map4k1
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds

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CN109721620A (zh) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 Hpk1抑制剂及其用途
WO2019164847A1 (fr) * 2018-02-20 2019-08-29 Incyte Corporation Composés d'indazole et leurs utilisations

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CN109721620A (zh) * 2017-10-27 2019-05-07 南京药捷安康生物科技有限公司 Hpk1抑制剂及其用途
WO2019164847A1 (fr) * 2018-02-20 2019-08-29 Incyte Corporation Composés d'indazole et leurs utilisations

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11203591B2 (en) 2018-10-31 2021-12-21 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11453681B2 (en) 2019-05-23 2022-09-27 Gilead Sciences, Inc. Substituted eneoxindoles and uses thereof
WO2021249913A1 (fr) * 2020-06-09 2021-12-16 Bayer Aktiengesellschaft Dérivés de 2'-(quinolin-3-yl)-5',6'-dihydrospiro[azétidine-3,4'-pyrrolo[1,2-b]pyrazole]-1-carboxylate et des composés apparentés servant d'inhibiteurs de map4k1 (hpk1) pour le traitement du cancer
WO2022167627A1 (fr) * 2021-02-05 2022-08-11 Bayer Aktiengesellschaft Inhibiteurs de map4k1

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