WO2024062363A1 - Composés hétérocycliques bicycliques en tant qu'inhibiteurs de cbl-b - Google Patents

Composés hétérocycliques bicycliques en tant qu'inhibiteurs de cbl-b Download PDF

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Publication number
WO2024062363A1
WO2024062363A1 PCT/IB2023/059221 IB2023059221W WO2024062363A1 WO 2024062363 A1 WO2024062363 A1 WO 2024062363A1 IB 2023059221 W IB2023059221 W IB 2023059221W WO 2024062363 A1 WO2024062363 A1 WO 2024062363A1
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alkyl
methyl
haloc
alkoxy
trifluoromethyl
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PCT/IB2023/059221
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English (en)
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Murugan CHINNAPATTU
Sachin Chaudhari
Nagaraj GOWDA
Pravin Iyer
Siddeshwar GAIKWAD
Nayan WAGHMARE
Macchindra TAMBE
Akshay KANGANE
Vaibhav Pathak
Jagmohan SAINI
Netra DESHPANDE
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Glenmark Pharmaceuticals Ltd
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Publication of WO2024062363A1 publication Critical patent/WO2024062363A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom

Definitions

  • CBL (Casitas B-lineage Lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase.
  • Cbl proteins are part of a family of ubiquitin ligases involved in cell signaling, protein ubiquitination, and degradation of protein substrates.
  • the Cbl proteins are a highly conserved family of proteins with three isoforms c-Cbl (also termed Cbl2, Cbl-SL, or RNF55), Cbl-b (also termed RNF56) and Cbl-3 (also called Cbl-3) [Keane et al., Oncogene, 18: 3365–3375, 1999; Keane et al., Oncogene, 10: 2367–2377, 1995; Kim et al., Gene, 239: 145–154, 1999].
  • Cbl proteins are RING-type E3 ligases containing an N-terminal tyrosine kinase binding (TKB) domain consisting of a four-helical bundle, a calcium binding EF-hand and a Src homology (SH2) domain, followed by a linker helical region and the RING domain, responsible for their catalytic function.
  • TKB N-terminal tyrosine kinase binding
  • SH2 Src homology
  • the unique feature of the TKB domain is that it recognizes specific substrates of Cbl-b, which is achieved by binding to proteins containing specific phosphorylated tyrosine- containing motifs, such as Syk and Zap-70, and a range of receptor tyrosine kinases.
  • the interaction of proteins with the TKB domain of Cbl is mediated by 3 distinct subdomains consisting of a 4-helix bundle (4H), a calcium-binding EF hand, and a variant SH2 domain, all 3 of which are functionally required to form a unique PTB (phosphotyrosine-binding) module [Meng et al., Nature, 398(6722): 84-90, 1999].
  • SH2 domain within the TKB recognizes tyrosine-phosphorylated proteins for ubiquitin conjugation [Mohapatra et al., Biochim Biophys Acta., 1833(1): 122-39, 2013].
  • a highly conserved ⁇ -helix of the L domain plays an important role in maintaining E3 activity [Zeng et al., Cell, 102(4): 533-9, 2000; Kassenbrock et al., J Biol Chem., 279(27): 28017-27, 2004].
  • the crystal structure shows that the L region contacts the TKB, RF, and E2 ubiquitin-conjugating enzymes.
  • the RF domain has intrinsic E3 ubiquitin ligase activity and binds to ubiquitin-E2 for the transfer of ubiquitin to specific substrates [Budhidarmo et al., Trends Biochem Sci., 37(2): 58-65, 2012; Paolino et al., J Immunol., 186(4): 2138-47, 2011].
  • Cbl- b In T cells, Cbl- b is predominantly expressed in peripheral T cells, whereas c-Cbl is mainly expressed in thymus, suggesting a distinct role of c-Cbl and Cbl-b in T-cell development and tolerance induction [Liu et al., Trends Immunol., 23(3): 140-3, 2002].
  • the E3 ubiquitin ligase cbl-b has been identified as a key intracellular checkpoint limiting T and NK cell activation.
  • Cbl-b function by genetic deletion strongly enhances anti-tumor immune responses
  • Cbl-b is expressed in all leukocyte subsets and regulates several signaling pathways in T cells, NK cells, B cells, and different types of myeloid cells.
  • Cbl-b is thought to function largely by regulating T cell activity through degradation of phospho-inositol-3-kinase (PI-3-K) downstream of the CD28 costimulatory receptor.
  • PI-3-K phospho-inositol-3-kinase
  • NK cells are among the first cells to arrive at the inflamed tissue where they exert potent cytotoxic effector functions and modulate the local immune response [Paolino et al., Nature, 507(7493): 508–12, 2014]. NK cells are an attractive tool for cell-based immunotherapy because of their innate ability to discriminate between healthy and virally infected or naturally transformed cells.
  • NK cell therapies include adoptive autologous or allogeneic cell therapy, wherein NK cells are used to support hematopoietic stem cell transplants.
  • Adoptive Cell Therapy (ACT) is used in otherwise treatment-resistant cancers, including metastatic melanomas, gliomas, and renal carcinomas.
  • ACT adoptive autologous or allogeneic cell therapy
  • NK cells or T cells from a patient's own blood or tumor tissue are harvested, then grown into large numbers in the laboratory, and then the expanded cells are transferred back to the patient to enhance the patient’s immune system response to the cancer.
  • the T cells or NK cells are modified using genetic engineering to enable them to target the patient's cancer cells and kill the cancer cells more efficiently.
  • Types of adoptive cell therapy include natural killer (NK) cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, engineered T-cell receptor therapy (TCR), and chimeric antigen receptor T-cell (CAR T) therapy.
  • NK cell therapy uses NK cells, part of the innate immune system, and the first line of defense against infections and diseases, including cancer cells.
  • Cbl inhibitors include small molecules, peptides, nucleic acids, or antibodies that inhibit the Cbl enzymes.
  • Cbl enzymes include c-Cbl, Cbl-b, and Cbl-c.
  • Cbl inhibitors for use in methods of treatment and compositions of the disclosure include, but are not limited to, compounds and pharmaceutical compositions for cell-based immunotherapy.
  • the Cbl inhibitors can be used in in-vivo treatment methods to modulate the immune system, such as increasing activation of T cells, NK cells, circulating T cells, tumor infiltrating lymphocytes and B cells, to increase engraftment of infused ex vivo expanded immune cells, or to increase the durability of response to the infused ex vivo expanded immune cells.
  • the Cbl inhibitors can be used to help expand such immune cells in vitro or ex vivo to increase their growth and proliferation or to modulate the phenotype of the resulting expanded immune cells.
  • Several patent applications relate to various scaffolds and compounds useful as CBL inhibitors.
  • PCT publication numbers WO/2021/061853; WO/2021/061870; WO/2021/021761; WO/2020/264398; WO/2020/236654; WO/2020/210508; WO/2019/148005 discloses compounds as CBL inhibitors in the treatment of T cell dysfunction and cancer.
  • CBL-b inhibition is an especially attractive target for cancer immunotherapy.
  • the major challenge currently faced in the field is the lack of CBL-b specific inhibitors.
  • the present disclosure provides novel, highly effective small-molecule inhibitors of CBL-b.
  • the present invention relates to compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X 1 ’ is CH or N; ‘X 2 ’ is CH or N; ‘X 3 ’ is N, S or O; R 1 is –(CHR 8 ) l -NR 9 R 10 ; at each occurrence, R 1a is independently selected from halogen, cyano, hydroxyl, C 1- 8 alkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl and C 3-12 cycloalkyl; at each occurrence, R 2 is selected independently from halogen, cyano, hydroxyl, C 1- 8 alkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxy, C 1
  • the compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein R 1a is fluoro, trifluoromethyl or cyclopropyl (according to an embodiment defined below), R 3 is CH 3 according to another embodiment defined below) and R 4 and R 5 independently is CH 3 (according to yet another embodiment defined below).
  • R 1a is halogen (e.g. fluoro), haloC 1-8 alkyl (e.g. trifluoromethyl) or C 3-12 cycloalkyl (e.g. cyclopropyl).
  • R 1a is fluoro, trifluoromethyl or cyclopropyl.
  • compounds of formula (I) in which R 1a is fluoro.
  • compounds of formula (I), in which R 1a is trifluoromethyl are compounds of formula (I), in which R 1a is cyclopropyl.
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 10 is C 1-8 alkyl (e.g. isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl or neopentyl C), haloC 1-8 alkyl (e.g.
  • C 3-8 cycloalkyl e.g. cyclopropyl or cyclobutyl
  • C 3- 8 cycloalkylC 1-8 alkyl e.g. cyclopropylmethyl
  • –CH 2 CH 2 Si(CH 3 ) 3 wherein C 3-8 cycloalkyl and C 3-8 cycloalkylC 1-8 alkyl optionally substituted with one or more substituents selected from haloC 1-8 alkyl (e.g. fluoromethyl) or C 1-8 alkyl (e.g. methyl) and ‘l’ is 1.
  • R 1 is –(CHR 8 )l-NR 9 R 10 .
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 10 is isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl, neopentyl, 2-fluoro-2-methylpropyl, 1- methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-fluoromethylcyclopropylmethyl or – CH 2 CH 2 Si(CH 3 ) 3 and ‘l’ is 1.
  • specifically provided are compounds of formula CH 2 NHCH 2 CH 2 Si(CH 3 ) 3 .
  • R 1 is –(CHR 8 ) l -NR 9 R 10 .
  • R 8 is hydrogen;
  • R 9 and R 10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C 1-8 alkyl (e.g. methyl) and ‘l’ is 1.
  • R 1 is –(CHR 8 ) l -NR 9 R 10 .
  • R 8 is hydrogen; R 9 and R 10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl (e.g. wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from fluoro or methyl and ‘l’ is 1.
  • specifically provided are compounds of formula .
  • specifically provided are compounds of formula (I), in which X 1 is CH or N.
  • specifically provided are compounds of formula (I), in which X 1 is CH.
  • R 2 is fluoro or cyclopropyl.
  • R 4 and R 5 joined together with the carbon atom to which they are attached, form a C 3-12 cycloalkyl 3-15 membered heterocyclyl (e.g. ) or 3- 15 membered spirocyclyl wherein C 3-12 cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C 1-8 alkyl (e.g. CH 3 ).
  • halogen e.g. fluoro
  • C 1-8 alkyl e.g. CH 3
  • compounds of formula (I) in which R 4 and R 5 joined together with the carbon atom to which they are attached, form a
  • C 6-14 aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or cyano.
  • compounds of formula (I) in which R 5 and R 6 joined together with the carbon atom to which they are attached, form a phenyl.
  • C 6-14 aryl is optionally substituted with one or more substituents selected from fluoro or cyano.
  • R 1a is fluoro, trifluoromethyl or cyclopropyl
  • X 1 is CH or N
  • X 2 is CH or N
  • X 3 is N
  • R 2 is fluoro or cyclopropyl
  • R 3 is CH 3
  • R 4 is hydrogen or CH 3
  • R 5 is CH3 or cyclopropyl
  • O R 4 and R 5 joined together with the carbon atom to which they are attached, form a
  • R 6 is hydrogen
  • R 7 is hydrogen
  • ‘n’ is 1
  • ‘m’ is 0 or 1
  • ‘p’ is 0 or 1.
  • R 1a is fluoro, trifluoromethyl or cyclopropyl
  • X 1 is CH
  • X 2 is CH or N
  • X 3 is N
  • R 2 is fluoro or cyclopropyl
  • R 3 is CH 3
  • R 4 is hydrogen or CH 3
  • R 5 is CH 3 or cyclopropyl
  • R 6 is hydrogen; or R 5 and R 6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl
  • R 7 is hydrogen
  • ‘n’ is 1
  • ‘m’ is 0 or 1
  • ‘p’ is 0 or 1.
  • compounds of formula (I) with an IC 50 value of less than 10000 nM, preferably, less than 500 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity.
  • IC 50 value of less than 10000 nM, preferably, less than 500 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity.
  • groups X 1 , X 2 , X 3 , R 1 , R 1a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ‘n’, ‘m’ and ‘p’ (and groups defined therein) are described hereinafter in relation to the compounds of formula (IA) and compounds of formula (IB).
  • the invention provides a compound of formula (IA) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X 2 ’ is CH or N; ‘X 3 ’ is N, S or O; R 1 is –(CHR 8 ) l -NR 9 R 10 ; at each occurrence, R 1a is independently selected from halogen, cyano, hydroxyl, C 1- 8 alkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl and C3-12cycloalkyl; at each occurrence, R 2 is selected independently from halogen, cyano, hydroxyl, C 1- 8 alkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl and C 3-12 cycloalkyl;
  • the compounds of formula (IA) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (IA) as defined above wherein R 1a is fluoro, trifluoromethyl or cyclopropyl (according to an embodiment defined below), R 3 is CH 3 according to another embodiment defined below) and R 4 and R 5 independently is CH3 (according to yet another embodiment defined below).
  • R 1a is halogen (e.g. fluoro), haloC 1-8 alkyl (e.g. trifluoromethyl) or C 3-12 cycloalkyl (e.g. cyclopropyl).
  • R 1a is fluoro, trifluoromethyl or cyclopropyl.
  • R 1a is fluoro
  • R 1a is trifluoromethyl.
  • haloC 1-8 alkyl e.g. 2-fluoro-2-methylpropyl
  • C 3-8 cycloalkyl e.g. cyclopropyl or cyclobutyl
  • C 3- 8 cycloalkylC 1-8 alkyl e.g. cyclopropylmethyl
  • C 3-8 cycloalkyl and C 3-8 cycloalkylC 1-8 alkyl optionally substituted with one or more substituents selected from haloC 1-8 alkyl (e.g.
  • R 1 is –(CHR 8 ) l -NR 9 R 10 .
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 10 is isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl, neopentyl, 2-fluoro-2-methylpropyl, 1- methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-fluoromethylcyclopropylmethyl or —CH 2 CH- 2 Si(CH 3 ) 3 and ‘l’ is 1.
  • R 8 is hydrogen; R 9 and R 10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C1-8alkyl (e.g. methyl) and ‘l’ is 1.
  • R 1 is –(CHR 8 ) l -NR 9 R 10 .
  • R 8 is hydrogen;
  • R 9 and R 10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from fluoro or methyl and ‘l’ is 1.
  • compounds of formula specifically provided are compounds of formula .
  • compounds of formula (IA) in which X 2 is CH or N.
  • cyclopropyl According to yet another embodiment, specifically provided are compounds of formula (IA), in which R 5 is CH 3 or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R 5 is CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R 5 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R 4 and R 5 independently is CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R 4 is hydrogen and R 5 is cyclopropyl.
  • R 4 and R 5 joined together with the carbon atom to which they are attached, form 3-15 membered heterocyclyl ) or 3- 15 membered spirocyclyl wherein C 3-12 cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C 1-8 alkyl (e.g. CH 3 ).
  • halogen e.g. fluoro
  • C 1-8 alkyl e.g. CH 3
  • compounds of formula (IA) in which R 4 and R 5 joined together with the carbon atom to which they are attached, form
  • R 6 is hydrogen.
  • C 6-14 aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or cyano.
  • compounds of formula (IA) in which R 5 and R 6 joined together with the carbon atom to which they are attached, form a phenyl.
  • C 6-14 aryl is optionally substituted with one or more substituents selected from fluoro or cyano.
  • R 1a is fluoro, trifluoromethyl or cyclopropyl
  • X 2 is CH or N
  • X 3 is N
  • R 2 is fluoro or cyclopropyl
  • R 3 is CH 3
  • R 4 is hydrogen or CH 3
  • R 5 is CH 3 or cyclopropyl
  • R 6 is hydrogen; or R 5 and R 6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl
  • R 7 is hydrogen
  • ‘n’ is 1
  • ‘m’ is 0 or 1
  • ‘p’ is 0 or 1.
  • compounds of formula (IA) with an IC 50 value of less than 10000 nM, preferably, less than 500 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity.
  • the invention also provides a compound of formula (IB) which is an embodiment of a compound of formula (I).
  • the invention provides a compound of formula (IB) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X 2 ’ is CH or N; R 1 is –(CHR 8 ) l -NR 9 R 10 ; at each occurrence, R 1a is independently selected from halogen, cyano, hydroxyl, C 1- 8 alkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl and C 3-12 cycloalkyl; at each occurrence, R 2 is selected independently from halogen, cyano, hydroxyl, C 1- 8 alkyl, haloC 1-8 alkyl, hydroxyC 1-8 alkyl, C 1-8 alkoxy, haloC 1-8 alkoxy, C 1-8 alkoxyC 1-8 alkyl and C 3-12 cycloalkyl; R 3 is halogen, cyano, cyan
  • the compounds of formula (IB) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (IB) as defined above wherein R 1a is fluoro, trifluoromethyl or cyclopropyl (according to an embodiment defined below), R 3 is CH 3 according to another embodiment defined below) and R 4 and R 5 independently is CH 3 (according to yet another embodiment defined below).
  • R 1a is halogen (e.g. fluoro), haloC 1-8 alkyl (e.g. trifluoromethyl) or C 3-12 cycloalkyl (e.g. cyclopropyl).
  • R 1a is fluoro, trifluoromethyl or cyclopropyl.
  • R 1a is fluoro
  • R 1a is trifluoromethyl.
  • R 1 is –(CHR 8 ) l -NR 9 R 10 .
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 10 is isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl, neopentyl , 2-fluoro-2-methylpropyl, 1- methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-fluoromethylcyclopropylmethyl or —CH 2 CH- 2Si(CH3)3 and ‘l’ is 1.
  • R 8 is hydrogen; R 9 and R 10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C 1-8 alkyl (e.g. methyl) and ‘l’ is 1.
  • R 1 is –(CHR 8 ) l -NR 9 R 10 .
  • R 8 is hydrogen;
  • R 9 and R 10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl N N N (e.g. , O or Si ), wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from fluoro or methyl and ‘l’ is 1.
  • specifically provided are compounds of formula .
  • specifically provided are compounds of formula .
  • compounds of formula (IB) in which X 2 is CH or N.
  • R 4 and R 5 joined together with the carbon atom to which they are attached, form a C 3-12 cycloalkyl 3-15 membered heterocyclyl ) or 3- 15 membered spirocyclyl wherein C 3-12 cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C 1-8 alkyl (e.g. CH 3 ).
  • halogen e.g. fluoro
  • C 1-8 alkyl e.g. CH 3
  • compounds of formula (IB) in which R 4 and R 5 joined together with the carbon atom to which they are attached, form
  • R 6 is hydrogen.
  • C 6-14 aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or cyano.
  • compounds of formula (IB) in which R 5 and R 6 joined together with the carbon atom to which they are attached, form a phenyl.
  • C 6-14 aryl is optionally substituted with one or more substituents selected from fluoro or cyano.
  • R 1a is fluoro, trifluoromethyl or cyclopropyl
  • X 2 is CH or N
  • R 2 is fluoro or cyclopropyl
  • R 3 is CH 3
  • R 4 is hydrogen or CH 3
  • R 5 is CH 3 or cyclopropyl
  • O R 4 and R 5 joined together with the carbon atom to which they are attached, form a
  • R 6 is hydrogen
  • R 7 is hydrogen
  • ‘n’ is 1
  • ‘m’ is 0 or 1
  • ‘p’ is 0 or 1.
  • IC 50 value of less than 10000 nM, preferably, less than 500 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity.
  • formulas (I), (IA) and (IB) are structurally encompass all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
  • halogen or “halo” means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e.
  • C 1-8 alkyl which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • C 1-6 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl chain having 1 to 4 carbon atoms.
  • alkynyl refers to a straight or branched hydrocarbon chain radical that having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are –OCH3 and –OC2H5.
  • cyanoalkyl refers to cyano group, linked to an alkyl group as defined above (i.e. cyanoC 1-8 alkyl).
  • haloalkyl examples include, but are not limited to, cyanomethyl, cyanoethyl and cyanopropyl groups.
  • haloalkyl refers to at least one halo group (selected from F, Cl, Br or I), linked to an alkyl group as defined above (i.e. haloC 1-8 alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups.
  • haloC 1-8 alkyl refers to at least one halo group linked an alkyl chain having 1 to 8 carbon atoms.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC1- 8 alkyl).
  • hydroxyalkyl moiety include, but are not limited to –CH 2 OH, -C 2 H 4 OH and –CH(OH)C 2 H 4 OH.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C 1-8 alkoxy). Representative examples of such groups are –OCH 3 and – OC 2 H 5 .
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloC 1-8 alkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e.
  • Example of such alkoxyalkyl moiety includes, but are not limited to, - CH 2 OCH 3 (methoxymethyl) and –CH 2 OC 2 H 5 (ethoxymethyl).
  • hydroxyC 1-8 alkyl refers to a C 1-8 alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC 1-4 alkyl).
  • Examples of hydroxyC 1-4 alkyl moieties include, but are not limited to – CH 2 OH and –C 2 H 4 OH.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C 3-12 cycloalkyl).
  • monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, 31yridine31 and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • C 3-6 cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms.
  • Examples of “C 3- 6cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the term “cycloalkylalkyl” refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C 3-6 cycloalkylC 1-8 alkyl).
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6-14 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e.3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, oxetanyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl,
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclylC1-8alkyl).
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heteroaryl unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl).
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinol
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, pyridinee, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate
  • salts derived from inorganic bases include, but are not limited to, pyridine, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • the compounds of formula (I), (IA) and (IB) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • Enantiomers can also be separated by use of chiral HPLC column.
  • the chiral centres of the present invention can have the S or R configuration as defined by the IUPAC 1974.
  • compositions of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition comprision at least a compound described herein for use in the treatment of disease or disorder mediated by CBL-b.
  • the compounds of the present invention are particularly useful because they inhibit the activity of CBL-b, i.e., they prevent, inhibit, or suppress the action of CBL-b, and/or may elicit a CBL-b modulating effect.
  • the compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of CBL-b activity, and particularly CBL-b inhibition, is beneficial.
  • the compounds of the present application provides a method for treating a disease or disease mediated by CBL-b in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I), compound of formula (IA), compound of formula (IB) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammal in need of the treatment, preferably a human.
  • the compounds of the present patent application are inhibiting CBL-b activity and can be useful in the treatment of diseases or disorder mediated by CBL-b.
  • the compounds of the invention may be useful in the treatment of cancer mediated by CBL-b.
  • a method of treating cancer responsive to inhibition of Cbl-b activity comprising administering an effective amount of a compounds of the present invention provided herein to an individual to treat the cancer responsive to inhibition of Cbl-b activity.
  • the compounds of the present invention for the use of treatment of cancer.
  • the compounds of the present invention can be used in methods of modulating the immune system, such as increasing activation of T-cells, NK-cells and B-cells, as well as in the treatment of such cells in vivo, in vitro, or ex vivo.
  • the present inventions provides the use of the compounds described herein in the preparation of a medicament.
  • the present inventions provides the use of the compounds described herein in the preparation of a medicament for the treatment of diseases mediated by CBL-b.
  • Any of the methods of treatment described herein comprise administering an effective amount of a compound according to Formula (I), (IA) and (IB) or a pharmaceutically acceptable salt thereof, to a subject (particularly a human) in need thereof.
  • the compounds of the invention are effective both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • GENERAL METHODS OF PREPARATION The compounds, described herein, including those of general formula (I), intermediates and specific examples are prepared through the synthetic methods as depicted in synthetic schemes 1-2.
  • HOBt Hydroxybenzotriazole (Boc) 2 O: Di-tert-butyl dicarbonate [Rh(COD)Cl] 2 : Cyclooctadiene rhodium chloride dimer AcOH: Acetic Acid AIBN: Azobisisobutyronitrile AlCl 3 : Aluminium chloride Cs 2 CO 3 : Cesium carbonate Cu(OAc) 2 : Copper(II) acetate CuI: Copper(I) iodide DAST: Diethylaminosulfur trifluoride DCC: N,N′-Dicyclohexylcarbodiimide DCM: Dichloromethane DIBAL: Diisobutylaluminium hydride DIPEA: N,N-Diisopropylethylamine DMF: N,N-Di
  • the reaction may be carried out in presence of a suitable catalyst.
  • the suitable catalyst may be Copper (I) oxide.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be NMP.
  • the acid-amine coupling reaction of compound of formula (2) with compound of formula (3) gives the compound of formula (4).
  • the reaction may be carried out in presence of a suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide.
  • the reaction may be carried out in presence of suitable coupling reagents.
  • the suitable coupling reagents used in the reaction may be selected from HATU, EDC.HCl, HOBt, DCC or T 3 P.
  • the reaction may be carried out in presence of a suitable base.
  • the suitable base used in the reaction may be selected from DIPEA or TEA.
  • the cyclization reaction of compound of formula (4) yields the compound of formula (5).
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be triethyl orthoformate.
  • the Suzuki coupling reaction of compound of formula (5) with potassium vinyl trifluoroborate or vinyl boronic acid gives the compound of formula (6).
  • the reaction is carried out in presence of suitable reagent.
  • the suitable reagent used in the reaction may be potassium vinyl trifluoroborate or vinyl boronic acid.
  • the reaction may be carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium or potassium tert-butoxide, sodium carbonate or cesium carbonate.
  • the reaction is carried out in presence of suitable palladium catalyst.
  • the suitable palladium catalyst used in the reaction may be tetrakis(triphenylphos phi ne)palladium(0), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) com plex with dichloromethane, along with a suitable phosphine ligand, etc.
  • the reaction is carried out in presence of a suitable polar solvent or mixture thereof.
  • the suitable polar solvent used in the reaction may be selected from ethanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof.
  • the compound of formula (6) upon oxidative cleavage gives aldehyde compound of formula (7).
  • the reaction is carried out in presence of suitable solvent and mixture thereof.
  • the suitable solvent used in the reaction may be selected from dioxane or THF and water and mixture thereof.
  • the reaction is carried out in presence of suitable reagent.
  • the suitable reagent used in the reaction may be selected from osmium tetraoxide and sodium periodate.
  • the reductive amination reaction of compound of formula (7) with appropriate amines of formula (8) yields the compound of general formula (I).
  • the reductive amination reaction is carried out in the presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be acetic acid.
  • the reductive amination reaction is carried out in the presence of suitable base.
  • the suitable base used in the reaction may be selected from triethylamine or DIPEA.
  • the reductive amination reaction is carried out in the presence of suitable reducing agent.
  • the suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the reductive amination reaction is carried out in suitable solvent.
  • the suitable solvent used in the reaction may be selected form dichloromethane, dimethyl formamide, methanol or ethanol.
  • the substitution reaction of compound of formula (9) with halogen derivative of formula (1) gives the compound of general formula (I).
  • the reaction may be carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be selected from copper iodide, copper bromide or copper oxide.
  • the reaction may be carried out in presence of suitable ligand.
  • the suitable ligand used in the reaction may be N-N-dimethyl ethylene diamine.
  • the reaction may be carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from potassium phosphate, cesium carbonate, sodium or potassium tert-butoxide.
  • the reaction may be carried out in a presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dioxane, dimethylformamide or dimethylacetamide.
  • the reaction may be carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium or potassium tert-butoxide, sodium carbonate or cesium carbonate.
  • the reaction may be carried out in presence of suitable palladium catalyst.
  • the suitable palladium catalyst used in the reaction may be tetrakis (triphenylphosphine)palladium(0), 1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane, along with a suitable phosphine ligand, etc.
  • the reaction may be carried out in a suitable solvent or mixture thereof.
  • the suitable solvent used in the reaction may be selected from ethanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof.
  • the compound of formula (13) upon oxidative cleavage gives aldehyde compound of formula (14).
  • the reaction is carried out in presence of suitable reagent.
  • the suitable reagent used in the reaction may be selected from osmium tetraoxide and sodium periodate.
  • the reaction is carried out in presence of suitable solvent and mixture thereof.
  • the suitable solvent may be selected from dioxane or THF or water and mixture thereof.
  • the reductive amination reaction of compound of formula (14) with appropriate amines of formula (8) yields the compound of formula (9).
  • the reductive amination reaction is carried out in the presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be acetic acid.
  • the reductive amination reaction is carried out in the presence of suitable base.
  • the suitable base used in the reaction may be selected from triethylamine or DIPEA.
  • the reductive amination reaction is carried out in the presence of suitable reducing agent.
  • the suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the reductive amination reaction is carried out in suitable solvent.
  • the suitable solvent used in the reaction may be selected form dichloromethane, dimethylformamide, methanol or ethanol.
  • the obtained product was purified by SFC to get 3.1 g of the desired (400 MHz, DMSO- d 6 ) ⁇ 1.36 (s, 6H), 2.60 (s, 2H), 7.24 - 7.28 (m, 1H), 7.36 - 7.41 (m, 2H), 7.53 (s, 1H), 11.9 (brs, 1H).
  • Step-2 2-(3-(3-Bromophenyl)-3-methylbutanoyl)-N-methylhydrazinecarbothioamide
  • HATU 11 g, 0.029 mol
  • Step-3 3-(2-(3-Bromophenyl)-2-methylpropyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione
  • 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N- methylhydrazinecarbothioamide 4.8 g, 0.0139 mol
  • 1 N NaOH 170 mL
  • the reaction mixture was acidified using 3N HCl and stirred for 15 min.
  • the precipitated solid was filtered, washed with excess water and dried under vacuum to yield 4.31 g of the desired product.
  • Step-4 3-(2-(3-Bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole
  • DCM/Acetic acid 2:1, 130 mL
  • 50 % solution of H2O2 4 mL
  • the reaction mixture was concentrated under reduced pressure.
  • the obtained product was triturated with diethyl ether, filtered and dried to obtain 4.2 g of the desired product.
  • Step-2 Ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate To a degassed solution of [Rh(COD)Cl] 2 (170 mg, 0.352 mmol) in dioxane (15 mL) was added KOH (1.5 eq) (6 mL) drop wise at room temperature and stirred for 30 min.
  • Step-3 2-(3-(3-Bromophenyl)oxetan-3-yl)acetic acid
  • a stirred solution of ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate (150 mg, 0.5 mmol) in THF (1.5 mL) was added aqueous solution of LiOH (40 mg , 1 mmol) at 0 o C and stirred at room temperature for 4 h.
  • the solvent was removed and acidified using 1 N HCl.
  • the aqueous layer was extracted with ethyl acetate and dried over sodium sulphate.
  • the organic layer was concentrated to yield 140 mg of the desired product.
  • the 4-Methyl- 3-thiosemicarbazide (57 mg, 0.547 mmol) and DIPEA (192 mg, 1.494 mmol) was added to the reaction mixture and stirred at room temperature for 18 h.
  • the reaction mixture was quenched with water and extracted with ethyl acetate.
  • the organic layer was dried over sodium sulphate and concentrated under reduced pressure.
  • the obtained product was purified by silica gel chromatography to yield 145 mg of the desired product.
  • the reaction mixture was quenched with saturated solution of NaHCO 3 and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The obtained product was purified by silica gel chromatography to yield 245 mg of the desired product.
  • Step-2 1-(3-Bromophenyl)-3-methylcyclobutanecarbonitrile
  • NaH 60% suspension in mineral oil
  • DMF 100 mL
  • 3-bromophenylacetonitrile 10.55 g, 53.826 mmol
  • 1,3-dibromo-2-methylpropane 11.62 g, 53.82 mmol
  • the reaction mixture was stirred at room temperature for 2 h and at 80° C for 16 h.
  • the reaction mixture was cooled to 0°C and quenched with aqueous NH 4 Cl solution.
  • Step-3 1-(3-Bromophenyl)-3-methylcyclobutanecarboxylic acid
  • 1-(3-bromophenyl)-3-methylcyclobutanecarbonitrile 17.7 g, 70.76 mmol
  • 80 mL of AcOH/H 2 O (1:1) was added Conc. H 2 SO 4 (40 mL) dropwise at 0°C and stirred at 0°C for 15 min and heated to 120°C for 16 h.
  • the reaction mixture was cooled to room temperature and quenched with water and extracted with ethyl acetate.
  • the organic layer was washed with brine solution and dried over anhydrous Na 2 SO4 and concentrated to yeild 18 g of the desired product.
  • the reaction mixture was warmed to room temperature and heated to 90°C for 16 h.
  • the mixture was concentrated and the obtained product was dissolved with ethyl acetate.
  • the organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate.
  • the solvent was evaporated unde reduced pressure to yield 19.18 g of the desired product.
  • the mixture was stirred at room temperature for 16 h.
  • the reaction mixture was quenched with water and extracted twice with DCM.
  • the solvent was evaporated under reduced pressure and the solid obtained was purified by silica gel column chromatography to yield racemic 4.8 g of the desired product.
  • the racemic product obtained was purified by SFC purification to yield cis isomer 2.65 g of the desired product.
  • Step-2 1,3-Diiodo-2,2-dimethylpropane
  • 2,2-dimethylpropane-1,3-diyldimethanesulfonate 2.0 g, 7.69 mmol
  • DMF 20 mL
  • KI 5.1 g, 30.7 mmol
  • the reaction mixture was cooled to room temperature, quenched with water and extracted with petroleum ether. The organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated to give 2.1 g of the desired product.
  • the reaction mixture was stirred at room temperature for 2 h and then at 80°C for 16 h.
  • the reaction mixture was cooled to 0°C and quenched with ice cold water solution.
  • the aqueous layer was extracted with petroleum ether.
  • the organic layer was separated, dried over anhydrous Na 2 SO4 and concentrated.
  • the obtained product was purified by silica gel column chromatography to yield 700 mg of the desired product.
  • the 4-methyl thiosemicarbazide (313 mg, 2.96 mmol) was added at 0°C.
  • the reaction mixture was stirred at room temperature for 16 h.
  • the reaction mixture was quenched with water and extracted with EtOAc.
  • the solvent was evaporated under reduced pressure and the solid obtained was purified by silica gel column chromatography to yield 820 mg of the desired product.
  • the reaction mixture was stirred at same temp for 30min, followed by addition of 1,3-dibromo- 2,2-Dimethoxy-propane (5.32 g, 20.40 mmol).
  • the reaction mixture was stirred at room temperature for 2 h and at 60°C for 48 h.
  • the reaction mixture was cooled to 0°C and quenched with water.
  • the aqueous layer was extracted with ethyl acetate.
  • the organic layer was separated, dried over anhydrous Na 2 SO4 and concentrated.
  • the obtained product was purified by silica gel column chromatography to yield 2.4 g of the desired product.
  • Step-3 1-(3-Bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile
  • DCM dimethyl methyl
  • DAST 2-(3-Bromophenyl)-3-oxocyclobutane-1-carbonitrile
  • DAST 2.45g, 15.2mmol
  • the reaction was quenched with sat. NaHCO 3 and extracted with ethyl acetate.
  • the organic layer was washed with water, brine solution and dried over anhydrous Na 2 SO4. The solvent was evaporated and purified to obtain 760mg of the desired product.
  • Step-4 1-(3-Bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid F F HO Br O
  • acetic acid 4.0 ml
  • water 4.0ml
  • Conc H2SO4 4.0 mL
  • reaction mixture was diluted with DCM and washed with water, and sat NaHCO 3 solution. Then organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained product was stirred in diethyl ether, filtered and dried to obtain 607 mg of the desired product.
  • Step-2 2-Bromo-5-fluorobenzohydrazide To a stirred solution of 3-(3-bromophenyl)-3-methylbutanoic acid (600 mg, 2.57 mol) in methanol (1 mL) was added hydrazine hydrate (412 mg, 12.87 mol) dropwise at 0°C and stirred for 5 min. The reaction mixture was stirred at 90°C for 2 h. The reaction mixture was cooled to room temperature. The precipitated solid was washed with water and dried under vacuum to get 530 mg of the desired product.
  • Step-4 3-(2-Bromo-5-fluorophenyl)-4-methyl-4H-1,2,4-triazole
  • acetic acid 3.42 g, 3 mL, 57 mol
  • DCM DCM
  • H 2 O 2 30% in water
  • the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were separated, dried over anhydrous sodium sulfate and concentrated under vacuum The obtained product was purified using silica gel column chromatography to get 20 mg of the desired product as brown solid.
  • Step-2 5-Cyano-2-(2,6-dichloropyridin-4-yl)benzoic acid
  • methyl 5-cyano-2-(2,6-dichloropyridin-4-yl)benzoate 2.0 g, 6.51 m mol
  • water 10 mL
  • LiOH.H 2 O 1.36 g, 32.56 mmol
  • reaction mixture was cooled to 0 o C and added dropwise T 3 P (6.95 g,21.84mmole) and the reaction was stirred at room teperature for 18h.
  • the reaction mixture was quenched with water.
  • the precipitated solid was filtered, washed with excess water and dried under vacuum to yield 1.2 g of the desired product.
  • reaction mixture was stirred at room temperature for 18 h.
  • the reaction mixture was quenched with sat. NaHCO3 and extracted with ethyl acetate.
  • the organic layer was separated, concentrated and purified with column chromatography to give 332 mg of the desired product.
  • the sodium triacetoxy borohydride (580 mg, 2.727 mmol) was added to the reaction mixture and stirred at room temperature for overnight.
  • the reaction mixture was diluted with water and extracted with 20% DCM/MeOH. The organic layer was separated and dried over anhydrous sodium sulphate. The solution was filtered, concentrated and the obtained product was purified by flash column chromatography to yield 104 mg of the desired product.
  • the reaction mixture was cooled to roon temperature and added sodium triacetoxyborohydride (2.2 g, 10.33 mmol) and stirred for overnight at room temperature.
  • the reaction mixture was quenched with water and extracted with 10% DCM/ MeOH.
  • the organic layer was separated and dried over anhydrous sodium sulphate.
  • the organic layer was filtered, concentrated and the obtained product was purified by flash chromatography to yield 900 mg of the desired product.
  • the sodium triacetoxy borohydride (297 mg, 1.40 mmol) was added to the reaction mixture and stirred at room temperature for overnight.
  • the reaction mixture was diluted with water and extracted with 20% DCM/MeOH.
  • the organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated.
  • the obtained product was purified by flash-column chromatography to yield 50 mg of the desired product.
  • This TR-FRET assay is performed in a 384 well plate at room temperature in a 10 ⁇ l reaction volume with buffer containing 50mM HEPES pH 7.5, 5mM mgCl2, 1mM DTT, 0.1mg/ml BSA.
  • Candidate compounds 1% DMSO final
  • 30nM Cbl-b accesion number NP_733762.2
  • 30nM of GST-tagged SRC kinase accesion number NP_005408.1
  • IC 50 (nM) values of some of the compounds are set forth in Table-8 wherein “A” refers to an IC 50 value of less than 100 nM, “B” refers to IC 50 value in range of 100.01 to 500.0 nM, “C” refers to IC 50 value in range of 500.01 to 1000.0 nM and “D” refers to IC 50 values more than 1000 nM.

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Abstract

La présente invention concerne des composés de formule (I) et des sels pharmaceutiquement acceptables de ceux-ci, qui sont utiles en tant qu'inhibiteurs de CBL-b, des procédés pour leur préparation, des compositions pharmaceutiques comprenant les composés, et l'utilisation des composés ou des compositions dans le traitement ou la prévention de diverses maladies, affections et/ou troubles médiés par CBL-b.
PCT/IB2023/059221 2022-09-21 2023-09-18 Composés hétérocycliques bicycliques en tant qu'inhibiteurs de cbl-b WO2024062363A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020236654A1 (fr) * 2019-05-17 2020-11-26 Nurix Therapeutics, Inc. Composés cyano-cyclobutyle pour l'inhibition de cbl-b et leurs utilisations
WO2020264398A1 (fr) * 2019-06-26 2020-12-30 Nurix Therapeutics, Inc. Composés benzyl-triazoles substitués pour l'inhibition de cbl-b et autres utilisations de ces composés
WO2021021761A1 (fr) * 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Composés d'urée, d'amide et d'hétéroaryle substitué pour l'inhibition de cbl-b
WO2021061853A1 (fr) * 2019-09-24 2021-04-01 Nurix Therapeutics, Inc. Inhibiteurs de cbl et compositions destinés à être utilisés dans une thérapie cellulaire adoptive
WO2022169998A1 (fr) * 2021-02-03 2022-08-11 Genentech, Inc. Amides utilisés comme inhibiteurs de cbl-b

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020236654A1 (fr) * 2019-05-17 2020-11-26 Nurix Therapeutics, Inc. Composés cyano-cyclobutyle pour l'inhibition de cbl-b et leurs utilisations
WO2020264398A1 (fr) * 2019-06-26 2020-12-30 Nurix Therapeutics, Inc. Composés benzyl-triazoles substitués pour l'inhibition de cbl-b et autres utilisations de ces composés
WO2021021761A1 (fr) * 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Composés d'urée, d'amide et d'hétéroaryle substitué pour l'inhibition de cbl-b
WO2021061853A1 (fr) * 2019-09-24 2021-04-01 Nurix Therapeutics, Inc. Inhibiteurs de cbl et compositions destinés à être utilisés dans une thérapie cellulaire adoptive
WO2022169998A1 (fr) * 2021-02-03 2022-08-11 Genentech, Inc. Amides utilisés comme inhibiteurs de cbl-b

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