WO2021249913A9 - 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 - Google Patents

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 Download PDF

Info

Publication number
WO2021249913A9
WO2021249913A9 PCT/EP2021/065122 EP2021065122W WO2021249913A9 WO 2021249913 A9 WO2021249913 A9 WO 2021249913A9 EP 2021065122 W EP2021065122 W EP 2021065122W WO 2021249913 A9 WO2021249913 A9 WO 2021249913A9
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolo
dihydrospiro
azetidine
pyrazole
alkyl
Prior art date
Application number
PCT/EP2021/065122
Other languages
English (en)
Other versions
WO2021249913A1 (fr
Inventor
Ulrich LÜCKING
Lars Wortmann
Jeffrey Stuart MOWAT
Lara Patricia KUHNKE
Judith GÜNTHER
Steffen Müller
Gabriele Leder
Rafael CARRETERO
Anders Roland FRIBERG
Detlef STÖCKIGT
Ulf Bömer
Rienk Offringa
Peng Cheng
Xuewei Wang
Yuanyuan YAN
Original Assignee
Bayer Aktiengesellschaft
Deutsches Krebsforschungszentrum
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft, Deutsches Krebsforschungszentrum filed Critical Bayer Aktiengesellschaft
Publication of WO2021249913A1 publication Critical patent/WO2021249913A1/fr
Publication of WO2021249913A9 publication Critical patent/WO2021249913A9/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems

Definitions

  • the present invention relates to MAP4K1 inhibitors, to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, as a sole agent or in combination with other active ingredients.
  • the present invention further relates to the use, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of protein inhibitors in benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.
  • T-cell immune checkpoint such as CTLA-4, PD-1 or PD-L1 were recently shown to result in a remarkable clinical efficacy in subsets of cancer patients.
  • cell surface receptors that act as negative immune regulators, several mediators of intracellular signaling have been identified that also represent potential immunoevasive mechanisms utilized by the tumor.
  • MAP4K1 also known as hematopoietic progenitor kinase 1 (HPK1).
  • HPK1 hematopoietic progenitor kinase 1
  • MAP4K1 (GenelD11184) is a serine/threonine kinase and member of the Germinal Center Kinase family. In the adult organism MAP4K1 expression is restricted to hematopoietic cell types.
  • the MAP4K1 protein consist of a N-terminal kinase domain, followed by a proline-rich domain that can interact with adaptor molecules through SH2 and SH3 domains, and a C-terminal citron homology domain of which the exact function remains to be identified.
  • MAP4K1 is capable of binding to a diversity of adaptors in hematopoietic cells, including those involved in T-cell receptor (TCR), B-cell receptor (BCR) and cytokine signaling (Hu et al., Genes Dev. 1996 Sep 15;10(18):2251-64, 2.; Ling et al.,.
  • MAP4K1 The function of MAP4K1 has been studied in greatest detail in the context of TCR signaling.
  • MAP4K1 Upon TCR stimulation, MAP4K1 is phosphorylated on tyrosine 381 (Y-381; Y-379 in mouse) (Di Bartolo et al., J Exp Med. 2007 Mar 19;204(3):681-91). Consequently, MAP4K1 is recruited to the TCR-signaling complex MAP4K1 phosphorylates the SLP ⁇ 76 adaptor protein at Serine ⁇ 376, resulting in downregulation of AP ⁇ 1 and Erk2 pathways. As, such, MAPK1 acts as a negative feedback on TCR ⁇ signaling (Liou et al., Immunity.
  • MAP4K1 can be triggered to suppress T cell function by prostaglandin E2 (PGE2), and possibly also by transforming growth factor beta (TGF ⁇ beta), factors that are commonly found in the tumor microenvironment.
  • PGE2 prostaglandin E2
  • TGF ⁇ beta transforming growth factor beta
  • MAP4K1 activation by these mediators involves protein kinase A (PKA) ⁇ dependent phosphorylation of Serine 171 (S ⁇ 171; also in mouse) (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419 ⁇ 29; Sawasdikosol et al., J Biol Chem.
  • MAP4K1 ⁇ deficient mice show an apparent normal phenotype, are fertile and exhibit normal lymphocyte development.
  • MAP4K1 ⁇ / ⁇ T ⁇ cells proliferate and secrete pro ⁇ inflammatory cytokines like IL ⁇ 2 or IFNg to a significantly greater extent than their wild ⁇ type counterparts (Shui et al., Nat Immunol. 2007 Jan;8(1):84 ⁇ 91). Furthermore, MAP4K1 ⁇ / ⁇ T ⁇ cells are resistant to PGE2 ⁇ mediated suppression of T cell proliferation, suppression of IL ⁇ 2 production and induction of apoptosis (Alzabin et al., Cancer Immunol Immunother. 2010 Mar;59(3):419 ⁇ 29).
  • MAP4K1 also regulates the stimulation and activation of dendritic cells.
  • MAP4K1 deficient Bone marrow derived cells express after maturation and stimulation higher level of costimulatory molecules and produce more proinflammatory cytokines. Also elimination of
  • HPK1 inhibitors and their uses are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and their uses are described. These compounds differ from the instant compounds in their chemical structure.
  • WO2019090198A1 compounds used to modulate or inhibit the activity of HPK1 and methods for their use in treatment of viral infections and proliferative disorders, such as cancer are described. These compounds differ from the instant compounds in their chemical structure.
  • MAP4K1 (HPK1) inhibitors and methods for their use in diseases including hyperproliferative diseases, diseases of immune system dysfunction, intlammatory disorders, neurological diseases, and cardiovascular diseases are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 modulators and methods for their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and methods for their use in the treatment of cancer are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and use of such compounds in treating HPK1 ⁇ dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and use of such compounds in treating HPK1 ⁇ dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 inhibitors and use of such compounds in treating HPK1 ⁇ dependent disorders and enhancing immune response are described. These compounds differ from the instant compounds in their chemical structure.
  • HPK1 respectively inhibitors and methods of their use in cancer treatment are described.
  • the application concerns thieno ⁇ pyridinones that can be used in anti ⁇ cancer therapy.
  • thieno ⁇ pyridinones that can be used in anti ⁇ cancer therapy.
  • WO 2016/195776 inhibitors and methods for leukemia cancer and diabetes treatment dependent on inhibition the interaction of menin with of MLL1, MLL2 and MLL ⁇ fusion oncoproteins are described. These compounds differ from the instant compounds in their chemical structure.
  • C ⁇ MET modulators and their use in cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • Rho kinase inhibitors and their use in cardiovascular and cancer treatment are described. These compounds differ from the instant compounds in their chemical structure.
  • WO 2015/089479 several inhibitors are described that show inhibition of several kinases (e.g., BTK, HCK, TAK1 and HPK1). These compounds differ from the instant compounds in their chemical structure.
  • BTK inhibitors and methods of their use in cancer treatment are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • WO 2011/090738 Type II RAF kinase inhibitors and their use in various diseases are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • CN102086211 and WO2006116713 protein kinase inhibitors and their use in prophylaxis and treatment of diseases including cancer are described. No specific example is disclosed which falls in the group of compounds as defined according to the present invention.
  • WO 2010/045095 protein tyrosin kinase modulators and their use in the treatment of hyperproliferative disorders are described.
  • MAP4K1 inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death are described. It would therefore be desirable to provide novel MAP4K1 inhibitors having prophylactic and therapeutic properties. Accordingly, it is an object of the present invention to provide compounds and pharmaceutical compositions comprising these compounds used for prophylactic and therapeutic applications for hyperproliferative disorders, in particular for cancer, respectively tumour disorders, and conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients.
  • a further object of the present invention is to provide compounds and pharmaceutical compositions comprising these compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, in neurodegenerative disorders, in inflammatory disorders, in atherosclerotic disorders and in male fertility control.
  • the compounds according to the invention inhibit the MAP4K1 protein and thereby enhance tumor immunogenicity leading to inhibition of cancer cells growth by the immune response. Accordingly, they provide novel structures for the therapy of human and animal disorders, in particular of cancers.
  • the present invention relates to compounds of formula (I) in which both A represent either ⁇ CH 2 ⁇ or ⁇ CH 2 ⁇ CH 2 ⁇ , R3 represents ⁇ H or ⁇ CH 3 , X represents either a direct bond, ⁇ CH 2 ⁇ or ⁇ O ⁇ ,
  • Y represents ⁇ H, ⁇ Cl, ⁇ F, ⁇ Br, ⁇ CN, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalkyl
  • R v represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R w represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl or ⁇ CH 2 ⁇ CF 3 or in which N
  • R n represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R o represents C 1 ⁇ C 6 ⁇ hydroxyalkyl, 5 ⁇ or 6 ⁇ membered heteroaryl (N), or or in which N, R n and R o together form a 3 ⁇ to 7 ⁇ membered heterocycloalkyl, optionally substituted with ⁇ CN
  • R 5 represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl, ⁇ F or ⁇ Cl
  • R 15 represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl, ⁇ CF 3 , ⁇ F, ⁇ Cl, ⁇ O ⁇ CH 3 or ⁇ CN or a stereoisomer, a tautomer, an N ⁇ oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • A) The present invention also relates to compounds of formula (I) (I) in which both A represent either ⁇ CH 2 ⁇ or ⁇ CH 2 ⁇ CH 2 ⁇ , R 3 represents ⁇ H or ⁇ CH 3 , X represents either a direct bond, ⁇ CH 2 ⁇ or ⁇ O ⁇ , Y represents ⁇ H, ⁇ Cl, ⁇ F, ⁇ Br, ⁇ CN, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalkyl, R 1 represents a group * ⁇ A' ⁇ B, in which * ⁇ A' ⁇ represents • a direct bond and in which B represents • hydrogen or • phenyl or a 5 ⁇ or 6 ⁇ membered heteroaryl, all optionally substituted with ⁇ CN, C 1 ⁇ C 4 ⁇ fluoroalkyl, ⁇ OCF 3 , ⁇ OCF 2 H, halogen, C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalky
  • the compounds of formula (I) are particularly suitable for a large number of prophylactic and therapeutic applications, in particular for hyperproliferative disorders, for tumour disorders and as proteine inhibitors and further for viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for male fertility control. Further, it covers their use in combination with other anti cancer medications such as immunotherapeutics, targeted anti cancer agents, radiation or chemotherapy.
  • DEFINITIONS In case an asterix is used in a formula, like for instance in * ⁇ A ⁇ B or * ⁇ A ⁇ , this asterix indicates the bond towards the core of the compound.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non ⁇ hydrogen substituent on any available carbon or nitrogen or ... atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.
  • the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”.
  • groups in the compounds according to the invention are substituted, it is possible for said groups to be mono ⁇ substituted or poly ⁇ substituted with substituent(s), unless otherwise specified.
  • the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • ring substituent means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.
  • comprising when used in the specification includes “consisting of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.
  • the terms as mentioned in the present text have the following meanings:
  • the term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • C 1 ⁇ C 6 ⁇ alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec ⁇ butyl, isobutyl, tert ⁇ butyl, pentyl, isopentyl, 2 ⁇ methylbutyl, 1 ⁇ methylbutyl, 1 ⁇ ethylpropyl, 1,2 ⁇ dimethylpropyl, neo ⁇ pentyl, 1,1 ⁇ dimethylpropyl, hexyl, 1 ⁇ methylpentyl, 2 ⁇ methylpentyl, 3 ⁇ methylpentyl, 4 ⁇ methylpentyl, 1 ⁇ ethylbutyl, 2 ⁇ ethylbutyl, 1,1 ⁇ dimethylbutyl, 2,2 ⁇ dimethylbutyl, 3,3 ⁇ dimethylbutyl, 2,3 ⁇ dimethylbutyl, 2,
  • said group has 1, 2, 3 or 4 carbon atoms (“C 1 ⁇ C 4 ⁇ alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec ⁇ butyl isobutyl, or tert ⁇ butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 ⁇ C 3 ⁇ alkyl”), e.g. a methyl, ethyl, n ⁇ propyl or isopropyl group.
  • C 1 ⁇ C 4 ⁇ alkyl e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec ⁇ butyl isobutyl, or tert ⁇ butyl group, more particularly 1, 2 or 3 carbon atoms (“C 1 ⁇ C 3 ⁇ alkyl”), e.g. a methyl, ethyl, n ⁇ propyl or isopropyl group.
  • C 1 ⁇ C 6 ⁇ hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 ⁇ C 6 ⁇ alkyl” is defined supra, and in which 1, 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g.
  • a hydroxymethyl 1 ⁇ hydroxyethyl, 2 ⁇ hydroxyethyl, 1,2 ⁇ dihydroxyethyl, 3 ⁇ hydroxypropyl, 2 ⁇ hydroxypropyl, 1 ⁇ hydroxypropyl, 1 ⁇ hydroxypropan ⁇ 2 ⁇ yl, 2 ⁇ hydroxypropan ⁇ 2 ⁇ yl, 2,3 ⁇ dihydroxypropyl, 1,3 ⁇ dihydroxypropan ⁇ 2 ⁇ yl, 3 ⁇ hydroxy ⁇ 2 ⁇ methyl ⁇ propyl, 2 ⁇ hydroxy ⁇ 2 ⁇ methyl ⁇ propyl, 1 ⁇ hydroxy ⁇ 2 ⁇ methyl ⁇ propyl group.
  • C 1 ⁇ C 6 ⁇ haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 ⁇ C 6 ⁇ alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said C 1 ⁇ C 6 ⁇ haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2 ⁇ fluoroethyl, 2,2 ⁇ difluoroethyl, 2,2,2 ⁇ trifluoroethyl, pentafluoroethyl, 3,3,3 ⁇ trifluoropropyl or 1,3 ⁇ difluoropropan ⁇ 2 ⁇ yl.
  • perfluorinated alkyl radicals which are named as “perfluoro ⁇ C 1 ⁇ C x ⁇ alkyl ⁇ “ wherein x is the maximum number of carbon atoms such as trifluoromethyl or 2,2,2 ⁇ trifluoroethyl.
  • C 1 ⁇ C 6 ⁇ cyanoalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 ⁇ C 6 ⁇ alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a cyano group.
  • C 1 ⁇ C 6 ⁇ alkoxy means a linear or branched, saturated, monovalent group of formula (C 1 ⁇ C 6 ⁇ alkyl) ⁇ O ⁇ , in which the term “C 1 ⁇ C 6 ⁇ alkyl” is as defined supra, e.g.
  • C 1 ⁇ C 6 ⁇ haloalkoxy means a linear or branched, saturated, monovalent C 1 ⁇ C 6 ⁇ alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said C 1 ⁇ C 6 ⁇ haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2 ⁇ trifluoroethoxy or pentafluoroethoxy.
  • perfluorinated alkyl radicals which are named as “perfluoro ⁇ C 1 ⁇ C x ⁇ alkoxy ⁇ “ wherein x is the maximum number of carbon atoms such as trifluoromethoxy and 2,2,2 ⁇ trifluoroethoxy radicals.
  • C 1 ⁇ C 6 ⁇ cyanoalkoxy means a linear or branched, saturated, monovalent C 1 ⁇ C 6 ⁇ alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a cyano group.
  • Mono ⁇ (C 1 ⁇ C 4 ) ⁇ alkylamino in the context of the invention means an amino group with one straight ⁇ chain or branched alkyl substituent which contains 1, 2, 3 or 4 carbon atoms, such as: methylamino, ethylamino, n ⁇ propylamino, isopropylamino, n ⁇ butylamino, and tert ⁇ butylamino, for example.
  • Di ⁇ (C 1 ⁇ C 4 ) ⁇ alkylamino in the context of the invention means an amino group with two identical or different straight ⁇ chain or branched alkyl substituents which each contain 1, 2, 3 or 4 carbon atoms, such as: N,N ⁇ dimethylamino, N,N ⁇ diethylamino, N ⁇ ethyl ⁇ N ⁇ methylamino, N ⁇ methyl ⁇ N ⁇ n ⁇ propylamino, N ⁇ isopropyl ⁇ N ⁇ methylamino, N ⁇ isopropyl ⁇ N ⁇ n ⁇ propylamino, N,N ⁇ diisopropylamino, N ⁇ n ⁇ butyl ⁇ N ⁇ methyl ⁇ amino, and N ⁇ tert ⁇ butyl ⁇ N ⁇ methylamino, for example.
  • C 3 ⁇ C 8 ⁇ cycloalkyl means a saturated, monovalent, mono ⁇ or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms (“C 3 ⁇ C 8 ⁇ cycloalkyl”).
  • Said C 3 ⁇ C 8 ⁇ cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl.
  • C 3 ⁇ C 8 ⁇ cycloalkoxy means a saturated, monovalent, mono ⁇ or bicyclic group of formula (C 3 ⁇ C 8 ⁇ cycloalkyl) ⁇ O ⁇ , which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term “C 3 ⁇ C 8 ⁇ cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.
  • 4 ⁇ to 7 ⁇ membered heterocycloalkyl and “4 ⁇ to 6 ⁇ membered heterocycloalkyl” mean a monocyclic, saturated or unsaturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it
  • heterocycloalkyl group may be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4 ⁇ membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5 ⁇ membered ring, such as tetrahydrofuranyl, 1,3 ⁇ dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1 ⁇ dioxidothiolanyl, 1,2 ⁇ oxazolidinyl, 1,3 ⁇ oxazolidinyl or 1,3 ⁇ thiazolidinyl, for example; or a 6 ⁇ membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3 ⁇ dioxanyl, 1,4 ⁇ dioxany
  • “4 ⁇ to 6 ⁇ membered heterocycloalkyl” means a 4 ⁇ to 6 ⁇ membered heterocycloalkyl as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5 ⁇ or 6 ⁇ membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O.
  • Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5 ⁇ to 14 ⁇ membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5 ⁇ membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6 ⁇ membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9 ⁇ membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazoly
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin ⁇ 2 ⁇ yl, pyridin ⁇ 3 ⁇ yl and pyridin ⁇ 4 ⁇ yl; or the term thienyl includes thien ⁇ 2 ⁇ yl and thien ⁇ 3 ⁇ yl.
  • a 5 ⁇ membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazoly
  • C 1 ⁇ C 6 as used in the present text, e.g. in the context of the definition of “C 1 ⁇ C 6 ⁇ alkyl”, “C 1 ⁇ C 6 ⁇ haloalkyl”, “C 1 ⁇ C 6 ⁇ hydroxyalkyl”, “C 1 ⁇ C 6 ⁇ alkoxy” or “C 1 ⁇ C 6 ⁇ haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 3 ⁇ C 8 as used in the present text, e.g.
  • C 3 ⁇ C 8 ⁇ cycloalkyl in the context of the definition of “C 3 ⁇ C 8 ⁇ cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompasses each value and sub ⁇ range within said range.
  • C 1 ⁇ C 6 encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 ⁇ C 6 , C 1 ⁇ C 5 , C 1 ⁇ C 4 , C 1 ⁇ C 3 , C 1 ⁇ C 2 , C 2 ⁇ C 6 , C 2 ⁇ C 5 , C 2 ⁇ C 4 , C 2 ⁇ C 3 , C 3 ⁇ C 6 , C 3 ⁇ C 5 , C 3 ⁇ C 4 , C 4 ⁇ C 6 , C 4 ⁇ C 5 , and C 5 ⁇ C 6 ;
  • C 2 ⁇ C 6 encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 ⁇ C 6 , C 2 ⁇ C 5 , C 2 ⁇ C 4 , C 2 ⁇ C 3 , C 3 ⁇ C 6 , C 3 ⁇ C 5 , C 3 ⁇ C 4 , C 4 ⁇ C 6 , C 4 ⁇ C 5 , and C 5 ⁇ C 6 ;
  • C 3 ⁇ C 10 encompasses C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 3 ⁇ C 10 , C 3 ⁇ C 9 , C 3 ⁇ C 8 , C 3 ⁇ C 7 , C 3 ⁇ C 6 , C 3 ⁇ C 5 , C 3 ⁇ C 4 , C 4 ⁇ C 10 , C 4 ⁇ C 9 , C 4 ⁇ C 8 , C 4 ⁇ C 7 , C 4 ⁇ C 6 , C 4 ⁇ C
  • the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4 ⁇ methylphenyl)sulfonyl]oxy, [(4 ⁇ bromophenyl)sulfonyl]oxy, [(4 ⁇ nitrophenyl)sulfonyl]oxy, [(2 ⁇ nitrophenyl)sulfonyl]oxy, [(4 ⁇ isopropylphenyl)sulfonyl]oxy, [(2,4,6 ⁇ triisopropyl
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more
  • asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Preferred isomers are those which produce the more desirable biological activity.
  • These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11 ⁇ 30, 1976).
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R) ⁇ or (S) ⁇ isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of
  • the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N ⁇ oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N ⁇ oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co ⁇ precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non ⁇ stoichiometric ratio.
  • polar solvents in particular water
  • stoichiometric solvates e.g. a hydrate, hemi ⁇ , (semi ⁇ ), mono ⁇ , sesqui ⁇ , di ⁇ , tri ⁇ , tetra ⁇ , penta ⁇ etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 ⁇ 19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid ⁇ addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid ⁇ addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2 ⁇
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the invention further includes all possible crystallized and polymorphic forms of the inventive compounds, whereby the polymorphs are existing either as a single polymorph form or are existing as a mixture of several polymorphs in all concentrations.
  • the invention further includes all possible cyclodextrin clathrates, i.e alpha ⁇ , beta ⁇ , or gamma ⁇ cyclodextrins, hydroxypropyl ⁇ beta ⁇ cyclodextrins, methylbetacyclodextrins.
  • R 3 represents ⁇ H
  • X represents either a direct bond, ⁇ CH 2 ⁇ or ⁇ O ⁇
  • Y represents ⁇ H, ⁇ Cl, ⁇ Br, ⁇ CN, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, C 3 ⁇ C 7 ⁇ cycloalkyl
  • R 1 represents a group * ⁇ A' ⁇ B, in which * ⁇ A' ⁇ represents a direct bond and in which B represents ⁇ H or in which * ⁇ A' ⁇ represents a group * ⁇ CR a H ⁇ , in which R a represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl or C 3 ⁇ C 7 ⁇ cycloalkyl all optionally substituted with ⁇ OH, halogen, ⁇ CF 3 , C 1 ⁇ C 4 ⁇ alkyl, ⁇ CN, ⁇ S(O) 2 ⁇ CH 3 , ⁇ S(O)(NR z ) ⁇ CH 3 , C 1 ⁇ C 4 ⁇ alkoxy, an ox
  • R c represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R v represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R w represents ⁇ H, C 1 ⁇ C 4 ⁇ alkyl or ⁇ CH 2 ⁇ CF 3 or in which N
  • R n represents ⁇ H or C 1 ⁇ C 4 ⁇ alkyl
  • R o represents C 1 ⁇ C 6 ⁇ hydroxyalkyl, 5 ⁇ or 6 ⁇ membered heteroaryl (N), or or in which N, R n and R o together form a 3 ⁇ to 7 ⁇ membered heterocycloalkyl, optionally substituted with ⁇ CN
  • R 5 represents ⁇ H, ⁇ F or ⁇ Cl
  • R 15 represents ⁇ H, or a stereoisomer, a tautomer, an N ⁇ oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • C) Of selected interest are those compounds defined under A) (page 6) or B (page 25) in which R 2 is selected from or .
  • D) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R 2 is E) Of selected interest are those compounds defined under A) (page 6) or B (page 25) wherein R 2 is and wherein R 4 is selected from hydrogen, ⁇ F, ⁇ Cl, methyl, ethyl and isopropyl.
  • G) Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein X is a direct bond.
  • G 1 ) Of selected interest are those compounds defined under A) (page 6) or B) (page 25) wherein X is oxygen.
  • Compounds of general formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted.
  • Compounds of the present invention have surprisingly been found to effectively inhibit MAP4K1 and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, preferably cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, in humans and animals.
  • disorders and conditions particularly suitable for treatment with an MAP4K1 inhibitor of the present invention are liquid and solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, triple negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small ⁇ cell and non ⁇ small ⁇ cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • ovarian cancer include, but are not limited to serous tumour, endometrioid tumour, mucinous cystadenocarcinoma, granulosa cell tumour, Sertoli ⁇ Leydig cell tumour and arrhenoblastoma.
  • cervical cancer include, but are not limited to squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumour, glassy cell carcinoma and villoglandular adenocarcinoma.
  • Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small ⁇ intestine, and salivary gland cancers.
  • esophageal cancer include, but are not limited to esophageal cell carcinomas and adenocarcinomas, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma.
  • gastric cancer include, but are not limited to intestinal type and diffuse type gastric adenocarcinoma.
  • pancreatic cancer examples include, but are not limited to ductal adenocarcinoma, adenosquamous carcinomas and pancreatic endocrine tumours.
  • Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • kidney cancer examples include, but are not limited to renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumour (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, clear ⁇ cell sarcoma of the kidney, mesoblastic nephroma and Wilms' tumour.
  • bladder cancer include, but are not limited to transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma and small cell carcinoma.
  • Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi’s sarcoma, malignant melanoma, Merkel cell skin cancer, and non ⁇ melanoma skin cancer.
  • Head ⁇ and ⁇ neck cancers include, but are not limited to, squamous cell cancer of the head and neck, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to, AIDS ⁇ related lymphoma, non ⁇ Hodgkin’s lymphoma, cutaneous T ⁇ cell lymphoma, Burkitt lymphoma, Hodgkin’s disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the term “treating” or “treatment” as stated throughout this document is used conventionally, for example the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a carcinoma.
  • the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre ⁇ treatment of the tumour growth.
  • chemotherapeutic agents and/or anti ⁇ cancer agents in combination with a compound or pharmaceutical composition of the present invention will serve to: 1. yield better efficacy in reducing the growth of a tumour or even eliminate the tumour as compared to administration of either agent alone, 2. provide for the administration of lesser amounts of the administered chemotherapeutic agents, 3. provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, 4. provide for treating a broader spectrum of different cancer types in mammals, especially humans, 5. provide for a higher response rate among treated patients,
  • the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and/or surgical intervention.
  • the compounds of general formula (I) of the present invention are used in combination with radiation: i.e. radiation treatment sensitizes cancers to anti ⁇ tumor immune responses by induction of tumor cell death and subsequent presentation of tumor neoantigens to tumor ⁇ reactive Tcells.
  • the present invention also provides a method of killing a tumor, wherein conventional radiation therapy is employed previous to administering one or more of the compounds of the present invention.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with: 131 I ⁇ chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado ⁇ trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, alpharain, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacit
  • dianhydrogalactitol diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, flu
  • talimogene laherparepvec tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium ( 99m Tc) nofetumomab merpentan, 99m Tc ⁇ HYNIC ⁇ [Tyr3] ⁇ octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tisagenlecleucel, tislelizumab, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, trama
  • the compounds of the invention can further be combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, e.g. aPD ⁇ 1/ ⁇ L1 axis antagonists.
  • immune checkpoint inhibitors e.g. aPD ⁇ 1/ ⁇ L1 axis antagonists.
  • PD ⁇ 1 along with its ligands PD ⁇ L1 and PD ⁇ L2, function as negative regulators of T cell activation.
  • MAP4K1 suppresses immune cell function.
  • PD ⁇ L1 is overexpressed in many cancers and overexpression of PD ⁇ 1 often occurs concomitantly in tumor infiltrating T cells. Thus results in attenuation of T cell activation and evasion of immune surveillance, which contributes to impaired antitumor immune responses. (Keir M E et al. (2008) Annu. Rev. Immunol. 26:677).
  • the present invention covers combinations comprising one or more of the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N ⁇ oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, and one or more immune checkpoint inhibitors.
  • the immune checkpoint inhibitor is a aPD ⁇ 1/ ⁇ L1 axis antagonist.
  • a further use of the compounds of the invention is the combination with chimeric antigen receptor T cells (CAR ⁇ T cells) such as Axicabtagen ⁇ Ciloleucel or Tisagenlecleucel.
  • the activity of CAR ⁇ T cells can be suppressed by the tumor micro environment (TME), which supposedly can be overcome by MAP4K1 inhibition.
  • TAE tumor micro environment
  • the present invention covers compounds of general formula (I), as described herein, or stereoisomers, tautomers, N ⁇ oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the expansion of T cells including CAR ⁇ T cells, CAR ⁇ NKT cells or CAR ⁇ NK cells and tumor infiltrated lymphocytes ex ⁇ vivo.
  • the present invention also relates to the use of the compounds according to the invention for the expansion of T cells, including CAR ⁇ T cell, CAR ⁇ NKT cells or CAR ⁇ NK cells and tumor infiltrated lymphocytes, ex ⁇ vivo.
  • the present invention also comprises an ex ⁇ vivo method for the expansion of T cells, including CAR ⁇ T cells, CAR ⁇ NKT cells or CAR ⁇ NK cells and tumor infiltrated lymphocytes, contacting said T cells with compounds according to the invention.
  • the inventive compounds can also be used as a therapeutic in a variety of other disorders wherein MAP4K1 is involved such as, cardiovascular and lung diseases.
  • the compounds according to the invention are suitable for the treatment and/or prophylaxis in particular of cardiovascular, inflammatory and fibrotic disorders and of renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure. Accordingly, the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular of acute and chronic renal insufficiency, and also of acute and chronic renal failure.
  • renal insufficiency comprises both acute and chronic manifestations of renal insufficiency, and also underlying or related renal disorders such as diabetic and non ⁇ diabetic nephropathies, hypertensive nephropathies, ischaemic renal disorders, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenoses, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritides; minimal change glomerulonephritis (lipoidnephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membrane ⁇ proliferative glomerulonephritis; crescentic glomerulonephritis; mesangioproliferative glomerulonephritis (IgA nephritis, Berger's disease); post ⁇ infectious glomerulonephritis; secondary
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
  • renal enzymes for example glutamyl synthetase, altered urine osmolarity or urine volume, elevated microalbuminuria, macroalbuminuria, lesions on glomerulae and arterioles, tubular dilatation, hyperphosphataemia and/or the need for dialysis.
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uremia, anemia, electrolyte disturbances (for example hypercalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.
  • the present invention also comprises the use of the compounds according to the invention for the treatment and/or prevention of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
  • the compounds according to the invention are further suitable for the treatment and/or prevention of polycystic kidney disease (PCKD) and of the syndrome of inappropriate ADH secretion (SIADH).
  • PCKD polycystic kidney disease
  • SIADH syndrome of inappropriate ADH secretion
  • the compounds according to the invention are also suitable for the treatment and/or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, for example atrioventricular blocks degrees I ⁇ III (AB block I ⁇ III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV ⁇ junctional extrasystoles, sick sinus syndrome, syncopes, AV ⁇ nodal re ⁇ entry tachycardia, Wolff ⁇ Parkinson ⁇ White syndrome, of acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvolitis, a
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left ⁇ heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis ⁇ associated pulmonary hypertension, chronic ⁇ obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha ⁇ 1 ⁇ antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic ⁇ obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • AATD alpha ⁇ 1 ⁇ antitrypsin deficiency
  • the compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age ⁇ associated learning and memory impairments, age ⁇ associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post ⁇ traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer’s disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick ⁇ s syndrome, Parkinson’s disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld ⁇ Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff’s psychosis.
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of central nervous system disorders such as states of anxiety, tension and depression, CNS ⁇ related sexual dysfunctions and sleep disturbances, and for controlling pathological disturbances of the intake of food, stimulants and addictive substances.
  • the compounds according to the invention are furthermore also suitable for controlling cerebral blood flow and thus represent effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma.
  • the compounds according to the invention can likewise be used for controlling states of pain and tinnitus.
  • the compounds according to the invention have anti ⁇ inflammatory action and can therefore be used as anti ⁇ inflammatory agents for treatment and/or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD,
  • the compounds according to the invention can also be used for treatment and/or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are also suitable for treatment and/or prophylaxis of fibrotic disorders of the internal organs, for example the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
  • fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • the compounds according to the invention are also suitable for controlling postoperative scarring, for example as a result of glaucoma operations.
  • the compounds according to the invention can also be used cosmetically for ageing and keratinized skin.
  • the compounds according to the invention are suitable for treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.
  • the present invention further provides the use of the compounds according to the invention for treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
  • the present invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropaties, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld ⁇ Jakob.
  • the present invention further provides a method for treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
  • the present invention further provides a method for the treatment and/or prophylaxis of chronic renal disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathies, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostate hyperplasia, dysuria associated with benign prostate hyperplasia, Huntington, dementia, Alzheimer and Creutzfeld ⁇ Jakob.
  • inventive compounds can also be used to treat or to prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women.
  • Compounds of the present invention can be utilized to inhibit, block, reduce or decrease MAP4K1 activation by exogenous and/or endogenous ligands for the reduction of tumour growth and the modulation of dysregulated immune responses e.g.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
  • the present invention also provides methods of treating a variety of other disorders wherein MAP4K1 is involved such as, but not limited to, disorders with dysregulated immune responses, inflammation, vaccination for infection & cancer, viral infections, obesity and diet ⁇ induced obesity, adiposity, metabolic disorders, hepatic steatosis and uterine fibroids.
  • treating or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as liquid and solid tumours.
  • the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N ⁇ oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N ⁇ oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers the compounds of general formula (I), as described supra, or stereoisomers, tautomers, N ⁇ oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the use of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers the use of compounds of general formula (I), as described supra, or stereoisomers, tautomers, N ⁇ oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, in a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • the present invention covers use of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N ⁇ oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prophylaxis or treatment of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours.
  • a pharmaceutical composition preferably a medicament
  • the present invention covers a method of treatment or prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, particularly liquid and solid tumours, using an effective amount of a compound of general formula (I), as described supra, or stereoisomers, tautomers, N ⁇
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N ⁇ oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a medicament comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N ⁇ oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.
  • the compounds according to the invention can have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • a suitable manner such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally ⁇ disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar ⁇ coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear ⁇ rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • compositions according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, ⁇ fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di ⁇ Cafos ® )), ⁇ ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), ⁇ bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), ⁇ solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain ⁇ length triglycerides fatty oils, liquid polyethylene glycols,
  • ⁇ flow regulators for example magnesium stearate, stearic acid, talc, highly ⁇ disperse silicas (such as, for example, Aerosil ® )
  • ⁇ coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ® )), ⁇ capsule materials (for example gelatine, hydroxypropylmethylcellulose), ⁇ synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® )), ⁇ capsule materials (for example gelatine,
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signalinggeneric name disorders, particularly liquid and solid tumours.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non ⁇ fixed combination or “kit ⁇ of ⁇ parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • non ⁇ fixed combination or kit ⁇ of ⁇ parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non ⁇ fixed combination or kit ⁇ of ⁇ parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant MAP4K1 signaling, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • a unit dosage contains from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • ⁇ n intensity n .
  • the intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown.
  • a 1 H ⁇ NMR peaklist is similar to a classical 1 H ⁇ NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation.
  • peaklists can show solvent signals, signals derived from stereoisomers of title compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower
  • Example h hour(s) FCS fetal calf serum HATU N ⁇ [(dimethylamino)(3H ⁇ [1,2,3]triazolo[4,5 ⁇ b]pyridin ⁇ 3 ⁇ yloxy)methylidene] ⁇ N ⁇ methylmethanaminium hexafluorophosphate HMDS Hexamethyldisilazane IFNg Interferon gamma LiHMDS lithium 1,1,1,3,3,3 ⁇ hexamethyldisilazan ⁇ 2 ⁇ ide LPS lipopolysaccharide MeOH methanol MCPBA 3 ⁇ chloroperbenzoic acid mL milliliter ⁇ L microliter min.
  • Pd(PPh 3 ) 4 tetrakis(triphenyl ⁇ lambda 5 ⁇ phosphanyl)palladium PPh 3 triphenylphosphine PyBroP bromo(tripyrrolidin ⁇ 1 ⁇ yl)phosphonium hexafluorophosphate RT or rt room temperature sat.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP ⁇ Sil ® or KP ⁇ NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate, DCM/methanol, or DCM/ethanol.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on ⁇ line electrospray ionization mass spectrometer in
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • EXPERIMENTAL SECTION – GENERAL SYNTHESIS The following paragraphs outline a variety of synthetic approaches suitable to prepare compounds of the general formula (Ia), and intermediates useful for their synthesis.
  • modifications can be, for example, the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalysed coupling reactions, exemplified by but not limited to e.g. Buchwald, Suzuki, Sonogashira and Ullmann coupling, ester saponifications, amide coupling reactions, and/or substitution or other reactions known to a person skilled in the art.
  • These transformations include those which introduce a functionality allowing for further interconversion of substituents.
  • Appropriate protective groups and their introduction and cleavage are well ⁇ known to a person skilled in the art (see for example T.W. Greene and P.G.M.
  • Analytical LC ⁇ MS methods Method 1: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 ⁇ m, 50x2.1mm; eluent A: water + 0.2 vol % aq. ammonia (32%), eluent B: acetonitrile; gradient: 0 ⁇ 1.6 min 1 ⁇ 99% B, 1.6 ⁇ 2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210 ⁇ 400 nm.
  • Method 2 Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 ⁇ m, 50x2.1mm; Eluent A: water + 0.05 % formic acid (99%); Eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0 ⁇ 1.7 2 ⁇ 90% B, 1.7 ⁇ 2.0 90% B; flow 1.2 ml/min; temperature: 60°C; DAD scan: 190 ⁇ 400 nm.
  • Method 3 Instrument: Waters Acquity UPLCMS SingleQuad; Colum: Acquity UPLC BEH C18 1.7 50x2.1mm; eluent A: water + 0.2 vol % aq.
  • interconversion of any of the substituents can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, exchange, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well ⁇ known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006). Specific examples are described in the subsequent paragraphs.
  • Scheme 1 Route for the preparation of building blocks of general formula 13 and 15, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), PG 2 represents a suitable alcohol protecting group (e.g. TBDMS), X 1 represents a direct bond or –CH 2 ⁇ , Z 1 represents a methyl group, an ethyl group or a tert ⁇ butyl group, A, R 1 , R 2 , R 3 and Y have the meaning as given for general formula (I). Suitable starting materials 1 are commercially available or described in the literature. Step 1 ⁇ 3 (Scheme 1) Alkylation In the first step (scheme 1), ester derivative 1 can be alkylated using an alkylbromide or alkyliodide of
  • ester 1 can be alkylated using (2 ⁇ bromoethoxy)(tert ⁇ butyl)dimethylsilane 2 in an organic solvent such as THF in the presence of a base such as LiHMDS or LDA.
  • Step 3 ⁇ 4 (Scheme 1) beta ⁇ Keto ester formation Methylester 3 is reacted with a methyl acetate or tert ⁇ butyl acetate to give beta ⁇ keto esters of the general formula 4.
  • the reaction is performed in the presence of a base like LiHMDS or LDA in an organic solvent like THF at a temperature range between ⁇ 78°C and room temperature.
  • Step 4 ⁇ 5 Pyrazol formation beta ⁇ Keto esters of formula 4 can be converted with hydrazine to the corresponding pyrazole derivatives of formula 5. Typically the reaction is performed in an organic solvent like ethanol at a temperature between ⁇ 20°C and the boiling point of the selected solvent.
  • Step 5 ⁇ 6 Deprotection of PG 2
  • the protecting group PG 2 of pyrazoles of formula 5 can be cleaved to give an alcohol of formula 6.
  • suitable alcohol protecting groups is well ⁇ known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • cleavage can be achieved using e.g. HCl in an organic solvent such as methanol or TBAF in an organic solvent such as THF.
  • Step 6 ⁇ 7 (Scheme 1) Ring closure Alcohols of formula 6 can be converted to spiro compounds of formula 7 by ring closing reactions.
  • alcohols of formula 6 can be reacted with mesylchloride and DIEA in an organic solvent like DCM to give the corresponding mesylate, which is then reacted to give spiro compounds of formula 7, e.g. in the presence of a base like NaOH using a solvent mixture like methanol / water.
  • ring closure can be achieved using Mitsunobu conditions known to the skilled person.
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • triphenylphosphine in an organic solvent such as for example THF
  • THF organic solvent
  • Step 7 ⁇ 8 Scheme 1
  • Triflate formation Spiro compounds of formula 7 can be converted to triflates of formula 8.
  • the reaction is performed using Tf 2 O in the presence of a base like DIEA in an organic solvent like DCM at a temperature range between ⁇ 78°C and room temperature.
  • the reaction is performed using N,N ⁇ bis ⁇ (trifluormethansulfonyl) ⁇ aniline in the presence of a base like DIEA in an organic solvent like THF at a
  • Step 8 ⁇ 9 (Scheme 1) Deprotection of PG 1
  • the protecting group PG 1 of spiro compounds of formula 8 can be cleaved to give amines of formula 9.
  • the cleavage of suitable amine protecting groups is well ⁇ known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • PG 1 in compounds of formula 8 is BOC
  • cleavage can be achieved using e.g. TFA in an organic solvent such as DCM.
  • Step 9 ⁇ 10 Amine decoration
  • Amines of formula 9 can be functionalized with a broad variety of substituents to give compounds of formula 10.
  • secondary amines of formula 9 can be reacted to give for example tertiary amines, amides, ureas, carbamates or sulphonamides of formula 10. All these transformations are known to the skilled person.
  • Step 10 ⁇ 13 Scheme 1
  • C ⁇ C cross coupling reaction Compounds of general formula 10 can be reacted with a boronic acid derivative R 2 ⁇ B(OR) 2 to give a compound of formula 13.
  • Pd(0) catalysts like tetrakis(triphenyl ⁇ phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di ⁇ palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine) ⁇ palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], palladium (ll) acetate and triphenylphosphine, [1,1' ⁇ bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2 ⁇ dicyclohexylphosphino ⁇ 2′,4′,6′ ⁇ triisopropyl ⁇ 1,1′ ⁇ biphenyl)[2 ⁇ (2′ ⁇ amino ⁇ 1,1′ ⁇ biphenyl)]palladium(II), X ⁇ Phos amino
  • the reaction is preferably carried out in a mixture of a solvent like 1,2 ⁇ dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • the coupling reaction is catalyzed by palladium catalysts, e.g.
  • Pd(0) catalysts like tetrakis(triphenyl ⁇ phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di ⁇ palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine) ⁇ palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], palladium (ll) acetate and triphenylphosphine, [1,1' ⁇ bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2 ⁇ dicyclohexylphosphino ⁇ 2′,4′,6′ ⁇ triisopropyl ⁇ 1,1′ ⁇ biphenyl)[2 ⁇ (2′ ⁇ amino ⁇ 1,1′ ⁇ biphenyl)]palladium(II), X ⁇ Phos amino
  • the reaction is preferably carried out in a mixture of a solvent like 1,2 ⁇ dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • Step 11 ⁇ 12 (Scheme 1) Deprotection of PG 1
  • the protecting group PG 1 of spiro compounds of formula 11 can be cleaved to give amines of formula 12.
  • the cleavage of suitable amine protecting groups is well ⁇ known to the person skilled in the art (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • PG 1 in compounds of formula 12 is BOC
  • cleavage can be achieved using e.g. TFA in an organic solvent such as DCM.
  • Step 12 ⁇ 13 (Scheme 1) Amine decoration
  • Amines of formula 12 can be functionalized with a broad variety of substituents to give compounds of formula 13.
  • Step 13 ⁇ 14 Bromination Pyrazole compounds of formula 13 can be converted to bromides of formula 14. Typically the reaction is performed using NBS in an organic solvent such as for example DMF.
  • Step 14 ⁇ 15 Scheme 1: Functional group interconversion Bromides 14 can be converted to compounds of the general formula 15 by using functional group interconversion reactions known to the skilled person.
  • Scheme 2 Alternative route for the preparation of building blocks of general formula 7, wherein PG 1 represents a suitable amine protecting group (e.g.
  • Step 1 ⁇ 17 Alkylation Compounds of the general formula 1 can be converted to compounds of the general formula 17 by alkylation. Typically the reaction is performed with an alkylating agent such as for example 16, a base such as LiHMDS or LDA in an organic solvent such as THF.
  • an alkylating agent such as for example 16
  • a base such as LiHMDS or LDA
  • an organic solvent such as THF.
  • Step 17 ⁇ 18 (Scheme 2) beta ⁇ Keto ester formation Methylester 17 is reacted with a methyl acetate or tert ⁇ butyl acetate to give beta ⁇ keto esters of the general formula 18.
  • the reaction is performed in the presence of a base like LiHMDS or LDA in an organic solvent like THF at a temperature range between ⁇ 78°C and room temperature.
  • Step 18 ⁇ 19 (Scheme 2) Pyrazol formation beta ⁇ Keto esters of formula 18 can be converted with hydrazine to the corresponding pyrazole derivatives of formula 19.
  • the reaction is performed in an organic solvent like ethanol at a
  • Step 19 ⁇ 7 (Scheme 2) Cyclization Compounds of the general formula 19 can be converted to compounds of formula 7. Reaction conditions are known to the skilled person. Typically the reaction is performed using Hg(OAc) 2 in an organic solvent such as THF followed by addition of sodium hydroxide in water followed by a reducing agent such as for example sodium borohydride.
  • Scheme 3 Route for the preparation of compounds of general formula 30, wherein PG 1 represents a suitable amine protecting group (e.g. Boc), PG 3 represents a suitable pyrazole protecting group (e.g.
  • R represents a lower alkyl group
  • A, Y, R 1 , R 2 have the meaning as given for general formula (I).
  • Suitable starting materials 20 and 21 are commercially available or described in the literature.
  • Step 20 + 21 ⁇ 22 (Scheme 3) Pyrazole addition to the carbonyl group
  • Ketones of the general formula 21 and pyrazoles of the general formula 20 can be converted to compounds of the general formula 22.
  • the conversion is known to the person skilled in the art. For example, the conversion can be carried out in analogy to a literature procedure described in Tetrahedron, 1983, 39, 2023 ⁇ 2029.
  • Step 22 ⁇ 23 (Scheme 3) Protection with PG 3 Compounds of the general formula 22 can be converted to compounds of the general formula 23 using a suitable protecting group to protect the pyrazole NH.
  • Protecting groups for pyrazoles are known to the skilled person (see for example P.G.M. Wuts and T.W. Greene in “Protective Groups in Organic Synthesis”, 4 th edition, Wiley 2006).
  • PG 3 in compounds of formula 23 is SEM, then 2 ⁇ (trimethylsilyl)ethoxymethylchloride, a base such as sodium hydride in an organic solvent such as THF can be used.
  • Step 23 ⁇ 24 (Scheme 3) Alkylation of the alcohol Alcohols of the general formula 23 can be converted to compounds of the general formula 24 in an alkylation reaction known to the skilled person.
  • an alkylation reaction known to the skilled person.
  • bromo ethyl acetate, a base, such as sodium hydride in an organic solvent such as dioxane at elevated temperature can be used.
  • Step 24 ⁇ 25 (Scheme 3) Deprotection of PG 3
  • the protecting group PG 3 of pyrazole compounds of general formula 24 can be cleaved to give compounds of formula 25.
  • the cleavage of suitable amine protecting groups is well ⁇ known to the person skilled in the art (see for example P.G.M. Wuts and T.W.
  • Mitsunobu reaction Compounds of the general formula 26 can be converted to the corresponding morpholine derivatives of the general formula 27 using Mitsunobu conditions known to the skilled person.
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • triphenylphosphine in an organic solvent such as for example THF
  • Step 27 ⁇ 28 (Scheme 3) Deprotection of PG 1
  • the protecting group PG 1 of spiro compounds of formula 27 can be cleaved to give amines of formula 28.
  • the cleavage of suitable amine protecting groups is well ⁇ known to the person skilled in the art (see for example P.G.M.
  • Halogen compounds of general formula 29 can be reacted with a boronic acid derivative R 2 ⁇ B(OR) 2 to give a compound of formula 30.
  • the coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenyl ⁇ phosphine)palladium(0) [Pd(PPh 3 ) 4 ], tris(dibenzylideneacetone)di ⁇ palladium(0) [Pd 2 (dba) 3 ], or by Pd(ll) catalysts like dichlorobis(triphenylphosphine) ⁇ palladium (ll) [Pd(PPh 3 ) 2 CI 2 ], palladium (ll) acetate and triphenylphosphine, [1,1' ⁇ bis(diphenylphosphino)ferrocene] palladium dichloride or by second generation XPhos Pd (Chloro(2 ⁇ dicyclohexylphosphino ⁇ 2′,4′,6′ ⁇ triisopropyl ⁇ 1,1′ ⁇ biphenyl)[2 ⁇ (2′ ⁇ amino ⁇ 1,
  • the reaction is preferably carried out in a mixture of a solvent like 1,2 ⁇ dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • a base like potassium carbonate, sodium bicarbonate or potassium phosphate.
  • Methyl acetate 14 ml, 170 mmol was dissolved in THF (300 ml) with molsieves under nitrogen, cooled to ⁇ 78°C, LiHMDS (170 ml, 1.0 M, 170 mmol; CAS ⁇ RN:[865 ⁇ 47 ⁇ 4]) was added dropwise and the mixture was stirred for 1 h at ⁇ 78°C.
  • LiHMDS 170 ml, 1.0 M, 170 mmol; CAS ⁇ RN:[865 ⁇ 47 ⁇ 4]
  • 1 ⁇ tert ⁇ butyl 4 ⁇ methyl 4 ⁇ (2 ⁇ [tert ⁇ butyl(dimethyl)silyl]oxy ⁇ ethyl)piperidine ⁇ 1,4 ⁇ dicarboxylate 17.4 g, 43.3 mmol, see intermediate 12) in THF (100 ml) was added dropwise at ⁇ 78°C.
  • tert-Butyl 4-(3-tert-butoxy-3-oxopropanoyl)-4-(3- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ propyl)piperidine- 1-carboxylate (6.10 g, 12.2 mmol) was solubilised in ethanol (25 ml), hydrazine—water (1/1) (1.8 ml, 37 mmol; CAS-RN:[7803-57-8]) was added and the mixture was stirred overnight at 80°C. It was evaporated and the residue was purified by flash chromatography to give 4.36 g (81 % yield) of the title compound.
  • Example 19 (pyrimidin ⁇ 4 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 ⁇ mL vial was placed a solution of pyrimidine ⁇ 4 ⁇ carboxylic acid (29 mg, 1.50 equiv, 0.234 mmol) in DMF (3 mL). To this was added DIPEA (201,61 mg, 10.00 equiv, 1.56 mmol).
  • Example 21 4 ⁇ oxo ⁇ 4 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]butanenitrile (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 3 ⁇ cyanopropanoic acid, CAS ⁇ RN: 16051 ⁇ 87 ⁇ 9)
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.234 (0.54), 2.272 (0.52), 2.638 (6.38), 2.659 (8.38), 2.681 (3.09), 2.913 (4.33), 2.935 (7.16), 2.959 (4.83), 3.616 (0.72), 4.123 (1
  • Example 23 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl) ⁇ 1 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]propan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl)propanoic acid, CAS ⁇ RN: [89532 ⁇ 73 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.076 (0.56), 2.273 (0.54), 2.641 (5.32), 2.663 (10.85), 2.685 (5.49), 2.855 (4.86
  • Example 25 2 ⁇ (pyrimidin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]ethan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and pyrimidin ⁇ 5 ⁇ ylacetic acid, CAS ⁇ RN: [5267 ⁇ 07 ⁇ 2]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.837 (1.16), 2.890 (0.54), 2.952 (5.04), 2.963 (3.30), 2.971 (3.00), 2.990 (2.05), 3.625 (10.09), 4.102 (0.44),
  • Example 27 (pyridin ⁇ 4 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and pyridine ⁇ 4 ⁇ carboxylic acid, CAS ⁇ RN [55 ⁇ 22 ⁇ 1]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.234 (0.63), 2.274 (0.84), 2.723 (0.67), 2.951 (5.38), 2.973 (8.79), 2.997 (5.74), 4.238 (6.63), 4.323 (1.85), 4.355 (7.87),
  • Example 29 1 ⁇ 2 ⁇ oxo ⁇ 2 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]ethyl ⁇ pyrrolidin ⁇ 2 ⁇ one (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and (2 ⁇ oxopyrrolidin ⁇ 1 ⁇ yl)acetic acid, CAS ⁇ RN [53934 ⁇ 76 ⁇ 2]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.946 (3.30), 1.971 (5.11), 1.996 (4.08), 2.237 (5.17), 2.264 (7.53), 2.291 (3.64), 2.728
  • Example 31 1 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carbonyl]cyclopropane ⁇ 1 ⁇ carbonitrile (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1 ⁇ cyanocyclopropanecarboxylic acid, CAS ⁇ RN: [6914 ⁇ 79 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.587 (7.78), 1.622 (13.90), 2.078 (2.18), 2.274 (0.52), 2.957 (3.05), 2.980 (3.12), 3.004 (3.01), 4.227 (8.57), 4.244
  • Example 33 (1 ⁇ methyl ⁇ 1H ⁇ imidazol ⁇ 5 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1 ⁇ methyl ⁇ 1H ⁇ imidazole ⁇ 5 ⁇ carboxylic acid, CAS ⁇ RN: [41806 ⁇ 40 ⁇ 0])
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.952 (1.75), 2.975 (3.08), 2.998 (1.93), 3.855 (16.00), 4.230 (1.93), 4.253 (3.18), 4.276 (2
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum.
  • Step 2 A solution of 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (1:1) (61 mg, 0.156 mmol, 1 eq.), 2 ⁇ methoxyethyl carbonochloridoate (32.5 mg, 0.234 mmol, 1.5 eq., CAS ⁇ RN: [628 ⁇ 12 ⁇ 6]) and N ⁇ ethyl ⁇ N,N ⁇ diisopropylamine (201.6 mg, 1.56 mmol, 10 eq.) in tetrahydrofuran (3 mL) was stirred under nitrogen at ambient temperature for two hours.
  • Example 38 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl)propan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 3 ⁇ (1H ⁇ pyrazol ⁇ 1 ⁇ yl)propanoic acid, CAS ⁇ RN: [89532 ⁇ 73 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.149 (0.90), 1.463 (16.00), 1.484 (15.40), 2.074 (1.95),
  • Example 40 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ (pyrimidin ⁇ 5 ⁇ yl)ethan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and pyrimidin ⁇ 5 ⁇ ylacetic acid, CAS ⁇ RN: [5267 ⁇ 07 ⁇ 2])
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: ⁇ 0.011 (1.28), 0.011 (0.80), 0.748 (1.11), 0.835 (0.86), 0.883 (0.76), 0.943 (
  • Example 41 (3 ⁇ chlorophenyl)[6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 3 ⁇ chlorobenzoic acid, CAS ⁇ RN: [535 ⁇ 80 ⁇ 8]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.489 (8.05), 2.270 (2.80), 2.727 (2.31), 4.346 (2.59), 4.540 (2.94), 4.635 (2.55), 7.041 (16.00), 7.522 (3.62
  • Example 44 1 ⁇ 2 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ oxoethyl ⁇ pyrrolidin ⁇ 2 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 2 ⁇ (2 ⁇ oxopyrrolidin ⁇ 1 ⁇ yl)acetamide, CAS ⁇ RN: [7491 ⁇ 74 ⁇ 9])
  • Example 46 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carbonyl]cyclopropane ⁇ 1 ⁇ carbonitrile (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 1 ⁇ cyanocyclopropanecarboxylic acid, CAS ⁇ RN: [6914 ⁇ 79 ⁇ 0])
  • Example 47 1 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]ethan ⁇ 1 ⁇ one (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and acetic acid, CAS ⁇ RN: [64 ⁇ 19 ⁇ 7])
  • Example 51 1 ⁇ [(2 ⁇ methylpyrimidin ⁇ 5 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL vial, 2 ⁇ methylpyrimidine ⁇ 5 ⁇ carbaldehyde (29.2 mg, 0.239 mmol, 1.00 equiv) and crude product 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (84 mg, 1.00 equiv, 0.217 mmol,
  • Example 52 N,N ⁇ dimethyl ⁇ 5 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methyl ⁇ 1,3 ⁇ thiazol ⁇ 2 ⁇ amine (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 2 ⁇ (dimethylamino) ⁇ 1,3 ⁇ thiazole ⁇ 5 ⁇ carbaldehyde (CAS ⁇ RN: [1005 ⁇ 28 ⁇ 3]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.813 (0.99), 2.836 (1.73), 2.8
  • Example 53 1 ⁇ [(1H ⁇ imidazol ⁇ 2 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1H ⁇ imidazole ⁇ 2 ⁇ carbaldehyde, CAS ⁇ RN: [10111 ⁇ 08 ⁇ 7])
  • Example 54 1 ⁇ [(pyrazolo[1,5 ⁇ a]pyrimidin ⁇ 3 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and pyrazolo[1,5 ⁇ a]pyrimidine ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [879072 ⁇ 59 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 2.274 (0.43), 2.796 (2.97), 2.818 (5.11), 2.842 (3.40), 3.449 (16.00), 3.840 (11.18), 4.148
  • Example 55 1 ⁇ [(1H ⁇ indazol ⁇ 3 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1H ⁇ indazole ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [5235 ⁇ 10 ⁇ 9])
  • 1 H ⁇ NMR 300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.144 (0.79), 2.271 (1.18), 2.726 (0.96), 2.813 (3.00), 2.835 (5.16), 2.859 (3.15), 3.479 (16.00), 3.994 (10.64), 4.148
  • Example 56 1 ⁇ (cyclohexylmethyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and cyclohexanecarbaldehyde, CAS ⁇ RN: [2043 ⁇ 61 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 0.868 (3.42), 0.907 (4.15), 0.945 (2.06), 1.110 (1.29), 1.183 (5.29), 1.227 (3.13), 1.270 (2.29), 1.649 (6.34), 1.682 (3.47), 1.731 (4.75),
  • Example 58 N,N ⁇ dimethyl ⁇ 5 ⁇ [6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methyl ⁇ 1,3 ⁇ thiazol ⁇ 2 ⁇ amine (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and 2 ⁇ (dimethylamino) ⁇ 1,3 ⁇ thiazole ⁇ 5 ⁇ carbaldehyde, CAS ⁇ RN: [1005 ⁇ 28 ⁇ 3]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.448 (3.06), 1.470 (3.05), 2.386 (0.53), 2.405
  • Example 59 6' ⁇ methyl ⁇ 1 ⁇ [(pyrazolo[1,5 ⁇ a]pyrimidin ⁇ 3 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and pyrazolo ⁇ [1,5 ⁇ a]pyrimidine ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [879072 ⁇ 59 ⁇ 0])
  • Example 60 1 ⁇ [(1H ⁇ indazol ⁇ 3 ⁇ yl)methyl] ⁇ 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and and 1H ⁇ indazole ⁇ 3 ⁇ carbaldehyde, CAS ⁇ RN: [5235 ⁇ 10 ⁇ 9])
  • Example 62 1 ⁇ (cyclopropanesulfonyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL via, crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (61 mg, 0.156 mmol, 1 eq.) was dissolved in DMF (3 mL) and was cooled in an ice ⁇ bath. DIPEA (201 mg, 1.56 mmol, 10 equiv) was added. Then cyclopropanesulfonyl chloride, (33 mg, 1.50 eq., 0.234 mmol, CAS ⁇ RN: [139631 ⁇ 62 ⁇ 2]) was added slowly to the above solution.
  • DIPEA 201 mg, 1.56 mmol, 10 equiv
  • Example 63 1 ⁇ (cyclopropanesulfonyl) ⁇ 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 6' ⁇ methyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 18) and and cyclopropanesulfonyl chloride, CAS ⁇ RN: [139631 ⁇ 62 ⁇ 2]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 0.980 (1.49), 0.996 (5.08), 1.003 (5.65), 1.018 (5.
  • Example 64 N ⁇ (pyridin ⁇ 3 ⁇ yl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL via, 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate ((61 mg, 0.156 mmol, 1 eq., 1.00 eq) was dissolved in 3 mL DMF and was cooled in an ice ⁇ bath. DIPEA (201 mg, 1.56 mmol, 10 eq, 1.56 mmol) was added.
  • Example 65 N ⁇ ethyl ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0]) 1 H ⁇ NMR (300 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.009 (5.01), 1.025 (3.86), 1.033 (11.37), 1.047 (5.48), 1.056 (5.25), 1.071 (2.15), 2.870 (1.90),
  • Example 68 1 ⁇ (pyridin ⁇ 3 ⁇ yl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Into a 40 mL vial, was placed a solution of crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (61 mg, 0.156 mmol, 1 eq.) in dioxane (3 mL).
  • Example 70 N ⁇ (2 ⁇ chloroethyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (50.0 mg, 181 ⁇ mol) was dissolved in DCM (2.1 ml), DIPEA (95 ⁇ l, 540 ⁇ mol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) was added, cooled to 0°C and 1 ⁇ chloro ⁇ 2 ⁇ isocyanatoethane (19.1 mg, 181 ⁇ mol) was added and the mixture was stirred overnight at ambient temperature. The mixture was evaporated and purified by preparative HPLC to yield the title compound (4.80 mg, 7 % yield).
  • Example 80 1 ⁇ (methanesulfonyl) ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and methanesulfonyl chloride, CAS ⁇ RN: [124 ⁇ 63 ⁇ 0]) 1 H ⁇ NMR (400 MHz, DMSO ⁇ d6) delta [ppm]: 1.239 (0.43), 1.907 (0.68), 2.518 (4.42), 2.522 (2.82), 2.937 (1.55), 2.954 (2.16), 2.972 (1.67
  • Example 82 ethyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (50.0 mg, 181 ⁇ mol) was dissolved in DCM (930 ⁇ l), DIPEA (95 ⁇ l, 540 ⁇ mol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) was added, cooled to 0°C and ethyl carbonochloridate (19.6 mg, 181 ⁇ mol) was added and the mixture was stirred overnight at rt. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.70 mg, 95 % purity, 3 % yield). LC ⁇ MS (Method 3): Rt
  • Example 84 1 ⁇ [(4 ⁇ methyl ⁇ 1H ⁇ imidazol ⁇ 2 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum. The crude 2' ⁇ (quinolin ⁇ 3 ⁇
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (60.0 mg, 217 ⁇ mol) and 5 ⁇ methyl ⁇ 1H ⁇ imidazole ⁇ 2 ⁇ carbaldehyde (26.3 mg, 239 ⁇ mol) were dissolved in THF (2.9 ml).
  • Acetic acid (12 ⁇ l, 220 ⁇ mol; CAS ⁇ RN:[64 ⁇ 19 ⁇ 7]) and sodium triacetoxyborohydride (63.3 mg, 299 ⁇ mol; CAS ⁇ RN:[56553 ⁇ 60 ⁇ 7]) were added and the mixture was stirred overnight at room temperature under argon. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.10 mg, 95 % purity, 1 % yield).
  • Example 93 1 ⁇ [(1H ⁇ pyrazol ⁇ 5 ⁇ yl)methyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 1H ⁇ pyrazole ⁇ 5 ⁇ carbaldehyde, CAS ⁇ RN: [948552 ⁇ 36 ⁇ 1])
  • Example 99 3 ⁇ (ethylamino) ⁇ 4 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]cyclobut ⁇ 3 ⁇ ene ⁇ 1,2 ⁇ dione
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (50.0 mg, 128 ⁇ mol) was dissolved in EtOH (1.5 ml), triethylamine (36 ⁇ l, 260 ⁇ mol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]) and 3,4 ⁇ diethoxycyclobut ⁇ 3 ⁇ ene ⁇ 1,2 ⁇ dione (43.6 mg,
  • Example 100 3 ⁇ (dimethylamino) ⁇ 4 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]cyclobut ⁇ 3 ⁇ ene ⁇ 1,2 ⁇ dione (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and N ⁇ methylmethanamine, CAS ⁇ RN: [124 ⁇ 40 ⁇ 3])
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol). The reaction was stirred at ambient temperature for two hours, evaporated after addition of toluene (2x) and dried in vacuum.
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (180 mg, 43 % purity, 198 ⁇ mol) was dissolved in DCM (2.0 ml, 31 mmol; CAS ⁇ RN:[75 ⁇ 09 ⁇ 2]), N,N ⁇ dimethylglycine (24.5 mg, 238 ⁇ mol), DIPEA (170 ⁇ l, 990 ⁇ mol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) and PyBroP (111 mg, 238 ⁇ mol; CAS ⁇ RN:[132705 ⁇ 51 ⁇ 2]) were added and it was stirred overnight at rt.
  • Example 102 3 ⁇ [2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carbonyl]pyrrolidin ⁇ 2 ⁇ one (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and 2 ⁇ oxopyrrolidine ⁇ 3 ⁇ carboxylic acid, CAS ⁇ RN: [96905 ⁇ 67 ⁇ 8])
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (100 mg, 256 ⁇ mol) was dissolved in DCM (4.5 ml), diphenyl cyanocarbonimidate (67.1 mg, 282 ⁇ mol) and triethylamine (71 ⁇ l, 510 ⁇ mol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]) were added and the mixture was stirred for 2 h at rt. The mixture was diluted with water and extracted 3x with DCM.
  • Step 3 phenyl N ⁇ cyano ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboximidate (60.0 mg, 50 % purity, 71.3 ⁇ mol) was dissolved in 2 ⁇ propanol (740 ⁇ l) and ethanamine (360 ⁇ l, 2.0 M, 710 ⁇ mol; CAS ⁇ RN:[75 ⁇ 04 ⁇ 7]) was added. The mixture was stirred overnight at 80°C. The mixture was evaporated and purified by preparative HPLC to yield the title compound (1.60 mg, 100 % purity, 6 % yield).
  • Example 111 N ⁇ [3 ⁇ (dimethylamino)propyl] ⁇ 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 2) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 To a solution of crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro ⁇ [azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (1.40 g, 3.59 mmol) in dichlormethane (59 mL) was added at ambient temperature under argon triethylamine (5.0 ml, 36 mmol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]) and 4 ⁇ nitrophenyl carbonochloridate (867 mg, 4.30 mmol). The reaction was stirred at ambient temperature overnight. DMA (18 mL) was added and the dichlormethane was removed under reduced pressure.
  • Step 3 To a solution of 4 ⁇ nitrophenyl 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (31.3 mg, 70.9 ⁇ mol) in N,N ⁇ dimethylacetamide (1.0 ml) under nitrogen were added N 1 ,N 1 ⁇ dimethylpropane ⁇ 1,3 ⁇ diamine (72.5 mg, 709 ⁇ mol) and K 2 CO 3 (14.4 mg, 142 ⁇ mol; CAS ⁇ RN:[121 ⁇ 44 ⁇ 8]). The mixture was stirred overnight at 60°C. The mixture was purified by preparative HPLC to yield title compound (15.1 mg, 95 % purity, 50 % yield).
  • Example 118 (morpholin ⁇ 4 ⁇ yl)[2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl]methanone (prepared from 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 2) and morpholine, CAS ⁇ RN: [110 ⁇ 91 ⁇ 8])
  • Example 130 N ⁇ ethyl ⁇ 2' ⁇ (1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide Step 1: To a solution of tert ⁇ butyl 2' ⁇ (1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (750 mg, 1.992 mmol, see example 3) in DCM (15 mL) was added under nitrogen trifluoroacetic acid (4.988 mL, 64,75 mmol).
  • Step 2 Crude 2' ⁇ (quinolin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] trifluoroacetate (109 mg, 40 % purity, 115 ⁇ mol) was dissolved in DCM (3.0 ml) and DIPEA (200 ⁇ l, 1.1 mmol; CAS ⁇ RN:[7087 ⁇ 68 ⁇ 5]) under nitrogen, isocyanatoethane (27 ⁇ l, 340 ⁇ mol) was added and the mixture was stirred overnight at rt. The solution was evaporated and purified by preparative HPLC to yield the title compound (21.8 mg, 95 % purity, 54 % yield).
  • Example 131 2' ⁇ (2 ⁇ aminopyrimidin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide
  • Example 132 2' ⁇ (6 ⁇ aminopyridin ⁇ 3 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (6 ⁇ aminopyridin ⁇ 3 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 168) and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0])
  • Example 144 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide N ⁇ ethyl ⁇ 2' ⁇ (2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (45.0 mg, 128 ⁇ mol, see example 140) was dissolved in DMF (450 ⁇ l), NCS (18.9 mg, 141 ⁇ mol; CAS ⁇ RN:[128 ⁇ 09 ⁇ 6]) and diphenylperoxyanhydride (34.2 mg, 141 ⁇ mol; CAS ⁇ RN:[94 ⁇ 36 ⁇ 0]
  • Example 148 ethyl 2' ⁇ (3 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from ethyl 2' ⁇ [(trifluoromethanesulfonyl)oxy] ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see intermediate 19) and 3 ⁇ methyl ⁇ 5 ⁇ (4,4,5,5 ⁇ tetramethyl ⁇ 1,3,2 ⁇ dioxaborolan ⁇ 2 ⁇ yl) ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridine, CAS ⁇ RN: [1111637 ⁇ 95 ⁇ 6]) LC ⁇ MS (Meth
  • Example 149 ethyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from prepared from ethyl 2' ⁇ [(trifluoromethanesulfonyl)oxy] ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see intermediate 19) and 3 ⁇ chloro ⁇ 5 ⁇ (4,4,5,5 ⁇ tetramethyl ⁇ 1,3,2 ⁇ dioxaborolan ⁇ 2 ⁇
  • Example 150 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ methyl ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole]
  • Step 1 To a solution of tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (234 mg, 585 ⁇ mol, see example 170/intermediate 72) in dichloromethane (20 mL) was added under nitrogen at ambient temperature trifluoro acetic acid (1.5 ml, 19 mmol; CAS ⁇ RN:[76 ⁇ 05 ⁇ 1]) and the reaction was stirred at room temperature for four hours.
  • Step 2 To a solution of formaldehyde (20 ⁇ l, 37 % in water, 270 ⁇ mol; CAS ⁇ RN:[50 ⁇ 00 ⁇ 0]) and trifluoroacetic acid—2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (1/1) (127 mg, 59 % purity, 181 ⁇ mol) in THF (2.5 ml) was added under nitrogen at room temperature sodium triacetoxyborohydride (86.4 mg, 407 ⁇ mol; CAS ⁇ RN:[76 ⁇ 05 ⁇ 1]) and acetic acid (10 ⁇ l).
  • Example 153 was prepared in analogy to example 84:
  • Example 153 N N N NH N Cl H N CH 3 N 2' ⁇ (2 ⁇ chloro ⁇ 3 ⁇ ethyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ [(1H ⁇ imidazol ⁇ 2 ⁇ yl)methyl] ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (2 ⁇ chloro ⁇ 3 ⁇ ethyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 169/intermediate 80) and 1H ⁇ imidazole ⁇ 2 ⁇ carbaldehyde, CAS ⁇ RN: [10
  • Example 157 tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate tert ⁇ butyl 2' ⁇ (1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (60.0 mg, 152 ⁇ mol, see example 154) was dissolved in DMF (610 ⁇ l), NCS (22.4 mg, 168 ⁇ mol; CAS ⁇ RN:[128 ⁇ 09 ⁇ 6]) and diphenylperoxyanhydride (40.6 mg, 168 ⁇ mol; CAS ⁇ RN:[94 ⁇ 36 ⁇ 0]) were added and the mixture was stirred overnight at
  • Example 158 tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from tert ⁇ butyl 2' ⁇ (2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example155).
  • Example 160 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0])
  • Example 161 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ ethyl ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 2 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 158) and and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0])
  • Example 162 N ⁇ ethyl ⁇ 2' ⁇ (3 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ methyl ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 171) and and isocyanatoethane, CAS ⁇ RN: [109 ⁇ 90 ⁇ 0]) 1H ⁇ NMR (400 MHz, DMSO ⁇ d6) ⁇ [ppm]: 1.010 (6.52), 1.028 (14.61), 1.046 (6.86), 1.232 (1.78), 1.565 (0.71), 1.574 (
  • Example 164 1 ⁇ [2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ methylpropan ⁇ 1 ⁇ one
  • Example 170/Inermediate 72 tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[azetidine ⁇ 3,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (prepared from intermediate 6 and and 3 ⁇ chloro ⁇ 5 ⁇ (4,4,5,5 ⁇ tetramethyl ⁇ 1,3,2 ⁇ dioxaborolan ⁇ 2 ⁇ yl) ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridine, CAS ⁇ RN: [1111638 ⁇ 73 ⁇ 3])
  • Example 176 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ N ⁇ (2,2,2 ⁇ trifluoroethyl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxamide (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and 1,1,1 ⁇ trifluoro ⁇ 2 ⁇ isocyanatoethane, CAS ⁇ RN: [371 ⁇ 92 ⁇ 6]) LC ⁇ MS (Method 1): R
  • Example 178 1 ⁇ [2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazol] ⁇ 1 ⁇ yl] ⁇ 2 ⁇ hydroxyethan ⁇ 1 ⁇ one
  • Example 180 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ (phenylmethanesulfonyl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and phenylmethanesulfonyl chloride, CAS ⁇ RN: [1939 ⁇ 99 ⁇ 7])
  • Example 181 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 1 ⁇ (propane ⁇ 1 ⁇ sulfonyl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] (prepared from tert ⁇ butyl 2' ⁇ (3 ⁇ chloro ⁇ 1H ⁇ pyrrolo[2,3 ⁇ b]pyridin ⁇ 5 ⁇ yl) ⁇ 5',6' ⁇ dihydrospiro[piperidine ⁇ 4,4' ⁇ pyrrolo[1,2 ⁇ b]pyrazole] ⁇ 1 ⁇ carboxylate (see example 157) and and propane ⁇ 1 ⁇ sulfonyl chloride, CAS ⁇ RN: [10147 ⁇ 36 ⁇ 1])
  • Example 185 2'-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-(propan-2-yl)-5',6'-dihydrospiro[azetidine-3,4'- pyrrolo[1,2-b]pyrazole]-1-carboxamide
  • MS (ESIpos): m/z 365 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 1.042 (0.42), 1.058 (15.83), 1.075 (16.00), 1.136 (0.42), 1.153 (0.42), 2.270
  • Example 201 N-ethyl-2'-[6-(trifluoromethyl)quinolin-3-yl]-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridine]-1-carboxamide
  • Example 217 2'-(3-ethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-[(1H-imidazol-2-yl)methyl]-5',6'- dihydrospiro[azetidine-3,4'-pyrrolo[1,2-b]pyrazole]
  • Example 224 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3,3,3-trifluoropropyl)-5',6'-dihydrospiro[piperidine- 4,4'-pyrrolo[1,2-b]pyrazole]
  • Example 228 2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(propan-2-yl)-5',6'-dihydrospiro[piperidine-4,4'- pyrrolo[1,2-b]pyrazole]
  • Example 231 [2'-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-6',7'-dihydro-5'H-spiro[piperidine-4,4'-pyrazolo[1,5- a]pyridin]-1-yl](oxan-4-yl)methanone
  • MS (ESIpos): m/z 454 [M+H] + 1H-NMR (400 MHz, DMSO-d6) ⁇ [ppm]: 0.938 (0.83), 0.954 (0.82), 1.519 (0.83), 1.551 (1.95), 1.574 (1.62), 1.604 (3.12), 1.631 (1.80), 1.659 (2.29), 1.692 (2.65), 1.721 (1.88), 1.734 (2.24), 1.748 (2.31), 1.7
  • Trifluoroacetic acid—2’-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5’,6’-dihydrospiro[piperidine- 4,4’-pyrrolo[1,2-b]pyrazole] (1/1) (100 mg, 69 % purity, 156 ⁇ mol) was solubilised in DMSO (1.0 ml), methanesulfonyl chloride (17.9 mg, 156 ⁇ mol) and triethylamine (65 ⁇ l, 470 ⁇ mol) were added and the mixture was stirred overnight at rt.
  • Example 234 2'-(3-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-ethyl-6',7'-dihydro-5'H-spiro[piperidine- 4,4'-pyrazolo[1,5-a]pyridine]-1-carboxamide
  • N-Ethyl-2’-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6’,7’-dihydro-5’H-spiro[piperidine-4,4’- pyrazolo[1,5-a]pyridine]-1-carboxamide 39.0 mg, 99.4 ⁇ mol
  • NCS 14.6 mg, 109 ⁇ mol
  • benzoyl peroxide 35.3 mg, 75 % purity, 109 ⁇ mol
  • Binding competition assay The ability of the compounds of the present invention to inhibit the binding of an Alexa647 ⁇ labelled ATP ⁇ competitive kinase inhibitor to a Glutathione ⁇ S ⁇ transferase ⁇ (GST ⁇ ) fusion protein was quantified employing the TR ⁇ FRET ⁇ based binding competition assay as described in the following paragraphs.
  • a recombinant fusion protein of N ⁇ terminal GST and full ⁇ length human expressed by baculovirus infected SF9 insect cells and purified by Glutathione Sepharose affinity chromatography, was used as GST ⁇ fusion protein.
  • Tracer 222 from Invitrogen was used as Alexa647 ⁇ labelled ATP ⁇ competitive kinase inhibitor.
  • test compounds were tested on the same microtiterplate in 11 different concentrations in the range of 20 ⁇ M to 0.07 nM (20 ⁇ M, 5.7 ⁇ M, 1.6 ⁇ M, 0.47 ⁇ M, 0.13 ⁇ M, 38 nM, 11 nM, 3.1 nM, 0.9 nM, 0.25 nM and 0.07 nM, the dilution series prepared separately before the assay on the level of the 100fold concentrated solutions in DMSO by serial dilutions, exact concentrations may vary depending pipettors used) in duplicate values for each concentration and IC50 values were calculated using Genedata ScreenerTM software.
  • Table 1 Measured IC 50 values of compounds regarding inhibition of MAP4K1 (HPK1):
  • Phosphorylation assay in human cell line using HTRF Assay Phosphorylation assays were carried out in Jurkat E6.1 cells from American Type Culture Collection (ATCC) stably overexpressing human FLAG ⁇ tagged SLP ⁇ 76 (proprietary). Cultured cells were kept in RPMI 1640 medium supplemented with 1% FCS at a cell density of 2x 10e6/mL 24h prior compound testing. Starved cells were transferred to a 384 well format plate at a cell density of 140.000 cells/well and simultaneously treated with 1 ⁇ g/mL a ⁇ CD3 antibody (clone OKT3.
  • the detection of pSer376 ⁇ SLP76 levels in the proprietary Jurkat cell lines was carried out utilizing an adapted protocol of the HTRF pSLP76 Assay (Cisbio # 63ADK076PEG).
  • Cells were lysed using 4 ⁇ l of the supplemented lysis buffer (Cisbio # 63ADK076PEG) for 60 min at room temperature.
  • 4 ⁇ l of the premixed antibody solution (Cisbio # 63ADK076PEG) was added and incubated over night at room temperature. Read ⁇ out and analyses was carried out using a Pherastar and the MARS software (BMG Labtechnologies, Offenburg, Germany).
  • Inhibition constant (IC 50 ) values were calculated by concentration ⁇ response curve fitting applying four ⁇ parameter nonlinear regression analyse.
  • maximal effect maximally possible inhibition of pSer376 ⁇ SLP ⁇ 76 by a test compound
  • cells with no a ⁇ CD3 (clone OKT3. ebioscience #16 ⁇ 0037 ⁇ 85) and no test compound treatment were used.
  • Cells with a ⁇ CD3 treatment only were used as negative control (min control. which represent the minimally possible inhibition of pSer376 ⁇ SLP ⁇ 76 by a test compound).

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Oncology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Virology (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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/EP2021/065122 2020-06-09 2021-06-07 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 WO2021249913A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2020095073 2020-06-09
CNPCT/CN2020/095073 2020-06-09

Publications (2)

Publication Number Publication Date
WO2021249913A1 WO2021249913A1 (fr) 2021-12-16
WO2021249913A9 true WO2021249913A9 (fr) 2022-02-03

Family

ID=76421961

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/065122 WO2021249913A1 (fr) 2020-06-09 2021-06-07 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

Country Status (1)

Country Link
WO (1) WO2021249913A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102650496B1 (ko) 2018-10-31 2024-03-26 길리애드 사이언시즈, 인코포레이티드 Hpk1 억제제로서의 치환된 6-아자벤즈이미다졸 화합물
CN117105933A (zh) 2018-10-31 2023-11-24 吉利德科学公司 具有hpk1抑制活性的取代的6-氮杂苯并咪唑化合物
WO2020237025A1 (fr) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Exo-méthylène-oxindoles substitués qui sont des inhibiteurs de hpk1/map4k1
EP4288437A1 (fr) * 2021-02-05 2023-12-13 Bayer Aktiengesellschaft Inhibiteurs de map4k1

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3270834B2 (ja) 1999-01-27 2002-04-02 ファイザー・プロダクツ・インク 抗がん剤として有用なヘテロ芳香族二環式誘導体
JP2003510327A (ja) 1999-09-30 2003-03-18 ニューロジェン・コーポレーション 特定のアルキレンジアミンで置換された複素環
DE10357510A1 (de) 2003-12-09 2005-07-07 Bayer Healthcare Ag Heteroarylsubstituierte Benzole
JP5368701B2 (ja) 2004-07-02 2013-12-18 エクセリクシス、インコーポレイテッド ｃ−Ｍｅｔモジュレーター及び使用方法
WO2006114180A1 (fr) 2005-04-25 2006-11-02 Merck Patent Gmbh Nouveaux aza-heterocycles constituant des inhibiteurs de kinases
JO2787B1 (en) 2005-04-27 2014-03-15 امجين إنك, Alternative amide derivatives and methods of use
WO2008089307A2 (fr) 2007-01-18 2008-07-24 Lexicon Pharmaceuticals, Inc. Méthodes et compositions utilisés dans le traitement de la douleur, de l'inflammation et du cancer
KR20110075016A (ko) 2008-10-14 2011-07-05 닝 시 화합물 및 사용 방법
CN102086211B (zh) 2009-12-08 2013-09-11 广东东阳光药业有限公司 作为蛋白激酶抑制剂的芳杂环化合物
EP2519517B1 (fr) 2009-12-29 2015-03-25 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinase raf de type ii
WO2015089479A1 (fr) 2013-12-13 2015-06-18 Dana-Farber Cancer Institute, Inc. Procédé pour traiter un lymphome lymphoplasmocytaire
WO2016004272A1 (fr) 2014-07-02 2016-01-07 Pharmacyclics Llc Inhibiteurs de la tyrosine kinase de bruton
TWI703150B (zh) 2015-06-04 2020-09-01 美商庫拉腫瘤技術股份有限公司 用於抑制ｍｅｎｉｎ及ｍｌｌ蛋白之交互作用的方法及組合物
SG10202105964RA (en) 2015-06-25 2021-07-29 Univ Health Network Hpk1 inhibitors and methods of using same
US20180072741A1 (en) 2016-09-09 2018-03-15 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
EP3510457A1 (fr) 2016-09-09 2019-07-17 The Procter and Gamble Company Procédés de production simultanée de produits différents sur une seule ligne de production
CN115819417A (zh) 2016-09-09 2023-03-21 因赛特公司 作为hpk1调节剂的吡唑并吡啶衍生物及其用于治疗癌症的用途
WO2018049214A1 (fr) 2016-09-09 2018-03-15 Incyte Corporation Dérivés de pyrazolopyridine comme modulateurs de hpk1 et leurs utilisations pour le traitement du cancer
US11180482B2 (en) 2016-11-30 2021-11-23 Ariad Pharmaceuticals, Inc. Anilinopyrimidines as haematopoietic progenitor kinase 1 (HPK1) inhibitors
CN110402248B (zh) 2017-03-15 2023-01-06 豪夫迈·罗氏有限公司 作为hpk1抑制剂的氮杂吲哚类
US10407424B2 (en) 2017-03-30 2019-09-10 Genentech, Inc. Naphthyridines as inhibitors of HPK1
AU2018243770A1 (en) 2017-03-30 2019-09-19 F. Hoffmann-La Roche Ag Isoquinolines as inhibitors of HPK1
EP3630778A1 (fr) 2017-05-26 2020-04-08 Ichnos Sciences SA Nouveaux inhibiteurs de map4k1
CN109721620B (zh) 2017-10-27 2022-05-13 药捷安康(南京)科技股份有限公司 Hpk1抑制剂及其用途
US11166959B2 (en) 2017-11-06 2021-11-09 Bristol-Myers Squibb Company Isofuranone compounds useful as HPK1 inhibitors
KR20200138166A (ko) 2018-01-31 2020-12-09 헤파레게닉스 게엠베하 간 재생을 촉진하거나 또는 간세포 사멸을 감소 또는 예방하기 위한 단백질 키나제 mkk4 저해제
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
PL3755703T3 (pl) 2018-02-20 2022-11-07 Incyte Corporation Pochodne n-(fenylo)-2-(fenylo)pirymidyno-4-karboksyamidu i związki pokrewne jako inhibitory hpk1 do leczenia nowotworu
WO2019164847A1 (fr) * 2018-02-20 2019-08-29 Incyte Corporation Composés d'indazole et leurs utilisations
WO2020061377A1 (fr) * 2018-09-19 2020-03-26 Genentech, Inc. Composés 2,3-dihydro-7-azaindole spirocycliques et leurs utilisations
WO2021074279A1 (fr) * 2019-10-16 2021-04-22 Bayer Aktiengesellschaft Inhibiteurs de map4k1 tricycliques spiro fusionnés

Also Published As

Publication number Publication date
WO2021249913A1 (fr) 2021-12-16

Similar Documents

Publication Publication Date Title
TWI498325B (zh) ３－取代吡唑及其用途
US11427578B1 (en) Substituted pyrrolopyridine-derivatives
WO2021249913A9 (fr) 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
WO2017207387A1 (fr) Dérivés d'azétidine spiro condensés en tant qu'inhibiteurs de l'interaction ménine-mml1
EP3638670B1 (fr) Dérivés de pyrrolopyridine substitués utilisés en tant que modulateurs de map4k1 pour le traitement de maladies cancéreuses
EP3638669A1 (fr) Dérivés de pyrrolopyridine substitués
WO2018228925A1 (fr) Dérivés de pyrrolopyridine substitués
WO2021074279A1 (fr) Inhibiteurs de map4k1 tricycliques spiro fusionnés
CA3082857A1 (fr) 3-oxo-6-heteroaryl-2-phenyl-2,3-dihydropyridazine-4-carboxamides
CA3082858A1 (fr) 2-phenylpyrimidine-4-carboxamides a utiliser en tant qu'inhibiteurs d'ahr
CA3093189A1 (fr) Identification et utilisation d'inhibiteurs d'erk5
US20220047603A1 (en) Substituted pyrrolopyridine-derivatives
US20230113037A1 (en) [1,2,4]triazolo[1,5-c]quinazolin-5-amines
KR20200078567A (ko) P2x3 억제제로서의 신규 피라졸로-피롤로-피리미딘-디온 유도체
EP4288437A1 (fr) Inhibiteurs de map4k1
WO2022029063A1 (fr) Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines
US20240174683A1 (en) Map4k1 inhibitors
WO2023118092A1 (fr) Pyrazolo [1,5-a] pyrido [3,2-e] pyrimidines et pyrazolo [1,5-a] [1,3] thiazolo [5,4-e] pyrimidines en tant qu'inhibiteurs de p2x3 pour le traitement de troubles neurogènes

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21731956

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21731956

Country of ref document: EP

Kind code of ref document: A1