WO2024062363A1 - Bicyclic heterocyclic compounds as cbl-b inhibitors - Google Patents

Bicyclic heterocyclic compounds as cbl-b inhibitors 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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French (fr)
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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/en

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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 System
    • 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 System
    • 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.

Abstract

The present invention is directed to compounds of formula (I) and pharmaceutically acceptable salts thereof, which are useful as CBL-b inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by CBL-b.

Description

BICYCLIC HETEROCYCLIC COMPOUNDS AS CBL-B INHIBITORS RELATED APPLICATIONS This application claims the benefit of Indian Provisional Application No. 202221053973 filed on September 21, 2022; which is hereby incorporated by reference in its entirety. FILED OF THE INVENTION The present patent application is directed to novel heterocyclic compounds which are useful as CBL inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by CBL-b. BACKGROUND OF INVENTION 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]. All three mammalian 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. Cbl-b ubiquitinates all three TAM family members, Tyro-3, Axl, and Mer, which is responsible for immunosuppressive and metastatic action. 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 α-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]. Recent studies indicate that the phosphorylation of Y363, located in the L region between TKB and RF domains, regulates the E3 activity of Cbl-b by 2 mechanisms: one is to remove the masking of the RF domain from the TKB domain, and the other is to form a surface to enhance binding affinity to E2s [Ryan et al., J Biol Chem., 285(31): 23687-98, 2010;]. Casitas B-lineage lymphoma proto-oncogene-b, a RING finger E3 ubiquitin-protein ligase, has been demonstrated to play a crucial role in establishing the threshold for T-cell activation and controlling peripheral T-cell tolerance via multiple mechanisms. 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. The blockade of 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. The role of Cbl-b in the negative regulation of T cell activation and tolerance induction are tightly controlled processes regulating immune responses to pathogens and tumors while preventing autoimmunity. Autoimmunity is mainly averted through central tolerance by negative selection of thymocytes carrying TCR for self-antigens. Cbl proteins not only regulate adaptive immune cell functions but are also critically involved in the regulation of innate lymphocyte populations, such as NK cells. 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. In ACT, 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. In some versions of ACT, 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. As genetic ablation of cbl-b is associated with spontaneous development of autoimmunity and increased susceptibility to experimental induction of autoimmune diseases [Bachmaier et al., Nature, 403(6766): 211–6, 2000] and it is not surprising that several groups later found links between genetic cbl-b variants and susceptibility to autoimmunity in an animal model for diabetes [Yokoi et al., Nat Genet., 31(4): 391–4, 2002] as well as in various human autoimmune diseases such as type 1 diabetes [Bergholdt et al., J Leukoc Biol., 77(4): 579–85, 2005], lupus erythematodes [Padilla et al., Lupus, 20(6): 628–35, 2011], asthma [Dewan et al., BMC Med Genet., 13: 95, 2012], and multiple sclerosis [Sawcer et al., Nature, 476(7359): 214– 9, 2011]. 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. In addition, 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. Currently, there is a largely unmet need for an effective way of treating disease and disorders associated with CBL-b inhibition includes but not limited to autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma. The improved therapeutic compounds, compositions and methods for the treatment for these disease and disorders are urgently required. 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. SUMMARY OF THE INVENTION In one aspect, the present invention relates to compound of formula (I)
Figure imgf000005_0001
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X1’ is CH or N; ‘X2’ is CH or N; ‘X3’ is N, S or O; R1 is –(CHR8)l-NR9R10; at each occurrence, R1a is independently selected from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; at each occurrence, R2 is selected independently from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; R3 is halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R4 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R5 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy; C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl; wherein 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1- 8alkyl; R6 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; or R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6- 14aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; R7 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R8 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R9 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R10 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl, –CH2CH2Si(CH3)3, C3- 8cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; or R9 and R10 joined together with the nitrogen atom to which they are attached, form a C6- 14 aryl, 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and C1-8alkyl; ‘n’ is an integer ranging from 0 to 4, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘p’ is an integer ranging from 0 to 1, both inclusive; and ‘l’ is an integer ranging from 0 to 4, both inclusive. 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. For example, the invention provides compounds of formula (I) as defined above wherein R1a is fluoro, trifluoromethyl or cyclopropyl (according to an embodiment defined below), R3 is CH3 according to another embodiment defined below) and R4 and R5 independently is CH3 (according to yet another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (I), in which R1a is halogen (e.g. fluoro), haloC1-8alkyl (e.g. trifluoromethyl) or C3-12cycloalkyl (e.g. cyclopropyl). According to another embodiment, specifically provided are compounds of formula (I), in which R1a is fluoro, trifluoromethyl or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1a is fluoro. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1a is trifluoromethyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1a is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘n’ is 1. According to another embodiment, specifically provided are compounds of formula (I), in which R1a is fluoro, trifluoromethyl or cyclopropyl and ‘n’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 is hydrogen; R10 is C1-8alkyl (e.g. isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl or neopentyl C), haloC1-8alkyl (e.g. 2-fluoro-2-methylpropyl), C3-8cycloalkyl (e.g. cyclopropyl or cyclobutyl), C3- 8cycloalkylC1-8alkyl (e.g. cyclopropylmethyl) or –CH2CH2Si(CH3)3, wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl optionally substituted with one or more substituents selected from haloC1-8alkyl (e.g. fluoromethyl) or C1-8alkyl (e.g. methyl) and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 is hydrogen; R10 is isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl, neopentyl, 2-fluoro-2-methylpropyl, 1- methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-fluoromethylcyclopropylmethyl or – CH2CH2Si(CH3)3 and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000008_0001
CH2NHCH2CH2Si(CH3)3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 and R10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl
Figure imgf000008_0002
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. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 and R10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl (e.g.
Figure imgf000008_0003
wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from fluoro or methyl and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000009_0001
. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000009_0002
. According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is CH or N. According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is CH. According to yet another embodiment, specifically provided are compounds of formula (I), in which X1 is N. According to yet another embodiment, specifically provided are compounds of formula (I), in which X2 is CH or N. According to yet another embodiment, specifically provided are compounds of formula (I), in which X2 is CH. According to yet another embodiment, specifically provided are compounds of formula (I), in which X2 is N. According to yet another embodiment, specifically provided are compounds of formula (I), in which X3 is N. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is halogen (e.g. fluoro) or C3-12cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is fluoro or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is fluoro. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘m’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘m’ is 0. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘m’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is fluoro or cyclopropyl and ‘m’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen or C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen or CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is C1-8alkyl (e.g. CH3) or C3-12cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is CH3 or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 independently is CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen and R5 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 joined together with the carbon atom to which they are attached, form a C3-12cycloalkyl
Figure imgf000011_0002
Figure imgf000011_0001
3-15 membered heterocyclyl (e.g. ) or 3- 15 membered spirocyclyl
Figure imgf000011_0003
wherein C3-12cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000011_0004
3-15 membered heterocyclyl (e.g.
Figure imgf000011_0005
) or 3- 15 membered spirocyclyl
Figure imgf000011_0006
wherein C3-12cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro or CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000011_0007
According to yet another embodiment, specifically provided are compounds of formula (I), in which R6 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl (e.g. phenyl). In this embodiment, C6-14 aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or cyano. According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 and R6 joined together with the carbon atom to which they are attached, form a phenyl. In this embodiment, C6-14 aryl is optionally substituted with one or more substituents selected from fluoro or cyano. According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 and R6 joined together with the carbon atom to which they are attached, form a 4-fluorophenyl or 4-cyanophenyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R7 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘p’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘p’ is 0. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘p’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1a is fluoro, trifluoromethyl or cyclopropyl;
Figure imgf000012_0001
X1 is CH or N; X2 is CH or N; X3 is N; R2 is fluoro or cyclopropyl; R3 is CH3; R4 is hydrogen or CH3; R5 is CH3 or cyclopropyl; or O R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000013_0001
R6 is hydrogen; or R5 and R6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl; R7 is hydrogen; ‘n’ is 1; ‘m’ is 0 or 1 and ‘p’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1a is fluoro, trifluoromethyl or cyclopropyl;
Figure imgf000013_0002
X1 is CH; X2 is CH or N; X3 is N; R2 is fluoro or cyclopropyl; R3 is CH3; R4 is hydrogen or CH3; R5 is CH3 or cyclopropyl; or R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000014_0001
Figure imgf000014_0002
R6 is hydrogen; or R5 and R6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl; R7 is hydrogen; ‘n’ is 1; ‘m’ is 0 or 1 and ‘p’ is 0 or 1. According to an embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 10000 nM, preferably, less than 500 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity. Further embodiments relating to groups X1, X2, X3, R1, R1a, R2, R3, R4, R5, R6, R7, ‘n’, ‘m’ and ‘p’ (and groups defined therein) are described hereinafter in relation to the compounds of formula (IA) and compounds of formula (IB). It is to be understood that these embodiments are not limited to use in conjunction with formula (IA) and (IB), but apply independently and individually to the compounds of formula (I). The invention also provides a compound of formula (IA) which is an embodiment of a compound of formula (I). Accordingly, the invention provides a compound of formula (IA)
Figure imgf000014_0003
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X2’ is CH or N; ‘X3’ is N, S or O; R1 is –(CHR8)l-NR9R10; at each occurrence, R1a is independently selected from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; at each occurrence, R2 is selected independently from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; R3 is halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R4 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R5 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy; C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl; wherein 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1- 8alkyl; R6 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; or R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6- 14aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; R7 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R8 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R9 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R10 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl, –CH2CH2Si(CH3)3, C3- 8cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; or R9 and R10 joined together with the nitrogen atom to which they are attached, form a C6- 14 aryl, 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and C1-8alkyl; ‘n’ is an integer ranging from 0 to 4, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘p’ is an integer ranging from 0 to 1, both inclusive; and ‘l’ is an integer ranging from 0 to 4, both inclusive. 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. For example, the invention provides compounds of formula (IA) as defined above wherein R1a is fluoro, trifluoromethyl or cyclopropyl (according to an embodiment defined below), R3 is CH3 according to another embodiment defined below) and R4 and R5 independently is CH3 (according to yet another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (IA), in which R1a is halogen (e.g. fluoro), haloC1-8alkyl (e.g. trifluoromethyl) or C3-12cycloalkyl (e.g. cyclopropyl). According to another embodiment, specifically provided are compounds of formula (IA), in which R1a is fluoro, trifluoromethyl or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1a is fluoro. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1a is trifluoromethyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1a is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which ‘n’ is 1. According to another embodiment, specifically provided are compounds of formula (IA), in which R1a is fluoro, trifluoromethyl or cyclopropyl and ‘n’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 is hydrogen; R10 is C1-8alkyl (e.g. isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl or neopentyl), haloC1-8alkyl (e.g. 2-fluoro-2-methylpropyl), C3-8cycloalkyl (e.g. cyclopropyl or cyclobutyl), C3- 8cycloalkylC1-8alkyl (e.g. cyclopropylmethyl) or –CH2CH2Si(CH3)3, wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl optionally substituted with one or more substituents selected from haloC1-8alkyl (e.g. fluoromethyl) or C1-8alkyl (e.g. methyl) and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 is hydrogen; R10 is isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl, neopentyl, 2-fluoro-2-methylpropyl, 1- methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-fluoromethylcyclopropylmethyl or –CH2CH- 2Si(CH3)3 and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000017_0001
CH2NHCH2CH2Si(CH3)3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 and R10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl
Figure imgf000017_0002
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. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 and R10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl
Figure imgf000018_0001
wherein 3-15 membered heterocyclyl is optionally substituted with one or more substituents selected from fluoro or methyl and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000018_0003
. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000018_0002
. According to yet another embodiment, specifically provided are compounds of formula (IA), in which X2 is CH or N. According to yet another embodiment, specifically provided are compounds of formula (IA), in which X2 is CH. According to yet another embodiment, specifically provided are compounds of formula (IA), in which X2 is N. According to yet another embodiment, specifically provided are compounds of formula (IA), in which X3 is N. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R2 is halogen (e.g. fluoro) or C3-12cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (IA), in which R2 is fluoro or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R2 is fluoro. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R2 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which ‘m’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (IA), in which ‘m’ is 0. According to yet another embodiment, specifically provided are compounds of formula (IA), in which ‘m’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R2 is fluoro or cyclopropyl and ‘m’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R3 is C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (IA), in which R3 is CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 is hydrogen or C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 is hydrogen or CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 is CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R5 is C1-8alkyl (e.g. CH3) or C3-12cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (IA), in which R5 is CH3 or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R5 is CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R5 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 and R5 independently is CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 is hydrogen and R5 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000020_0001
3-15 membered heterocyclyl
Figure imgf000020_0002
) or 3- 15 membered spirocyclyl
Figure imgf000020_0003
wherein C3-12cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000020_0004
3-15 membered heterocyclyl
Figure imgf000020_0005
) or 3- 15 membered spirocyclyl
Figure imgf000020_0006
wherein C3-12cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro or CH3. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000020_0007
According to yet another embodiment, specifically provided are compounds of formula (IA), in which R6 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl (e.g. phenyl). In this embodiment, C6-14 aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or cyano. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R5 and R6 joined together with the carbon atom to which they are attached, form a phenyl. In this embodiment, C6-14 aryl is optionally substituted with one or more substituents selected from fluoro or cyano. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R5 and R6 joined together with the carbon atom to which they are attached, form a 4-fluorophenyl or 4-cyanophenyl. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R7 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (IA), in which ‘p’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (IA), in which ‘p’ is 0. According to yet another embodiment, specifically provided are compounds of formula (IA), in which ‘p’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IA), in which R1a is fluoro, trifluoromethyl or cyclopropyl;
Figure imgf000021_0001
X2 is CH or N; X3 is N; R2 is fluoro or cyclopropyl; R3 is CH3; R4 is hydrogen or CH3; R5 is CH3 or cyclopropyl; or R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000022_0001
Figure imgf000022_0002
R6 is hydrogen; or R5 and R6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl; R7 is hydrogen; ‘n’ is 1; ‘m’ is 0 or 1 and ‘p’ is 0 or 1. According to an embodiment, specifically provided are compounds of formula (IA) with an IC50 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). Accordingly the invention provides a compound of formula (IB)
Figure imgf000022_0003
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X2’ is CH or N; R1 is –(CHR8)l-NR9R10; at each occurrence, R1a is independently selected from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; at each occurrence, R2 is selected independently from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; R3 is halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R4 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R5 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy; C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl; wherein 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1- 8alkyl; R6 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; or R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6- 14aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; R7 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R8 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R9 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R10 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl, –CH2CH2Si(CH3)3, C3- 8cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; or R9 and R10 joined together with the nitrogen atom to which they are attached, form a C6- 14 aryl, 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and C1-8alkyl; ‘n’ is an integer ranging from 0 to 4, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘p’ is an integer ranging from 0 to 1, both inclusive; and ‘l’ is an integer ranging from 0 to 4, both inclusive. 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. For example, the invention provides compounds of formula (IB) as defined above wherein R1a is fluoro, trifluoromethyl or cyclopropyl (according to an embodiment defined below), R3 is CH3 according to another embodiment defined below) and R4 and R5 independently is CH3 (according to yet another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (IB), in which R1a is halogen (e.g. fluoro), haloC1-8alkyl (e.g. trifluoromethyl) or C3-12cycloalkyl (e.g. cyclopropyl). According to another embodiment, specifically provided are compounds of formula (IB), in which R1a is fluoro, trifluoromethyl or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1a is fluoro. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1a is trifluoromethyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1a is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which ‘n’ is 1. According to another embodiment, specifically provided are compounds of formula (IB), in which R1a is fluoro, trifluoromethyl or cyclopropyl and ‘n’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 is hydrogen; R10 is C1-8alkyl (e.g. - isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl or neopentyl), haloC1-8alkyl (e.g. 2-fluoro-2-methylpropyl), C3-8cycloalkyl (e.g. cyclopropyl or cyclobutyl), C3- 8cycloalkylC1-8alkyl (e.g. cyclopropylmethyl) or –CH2CH2Si(CH3)3, wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl optionally substituted with one or more substituents selected from haloC1-8alkyl (e.g. fluoromethyl) or C1-8alkyl (e.g. methyl) and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 is hydrogen; R10 is isobutyl, isopentyl, 2-ethylbutyl, 2-methylbutyl, neopentyl , 2-fluoro-2-methylpropyl, 1- methyl-cyclopropyl, 1-methyl-cyclobutyl, 1-fluoromethylcyclopropylmethyl or –CH2CH- 2Si(CH3)3 and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000025_0001
CH2NHCH2CH2Si(CH3)3. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 and R10 joined together with the nitrogen atom to which they are attached, form a 3-15 membered heterocyclyl
Figure imgf000025_0002
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. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1 is –(CHR8)l-NR9R10. In this embodiment, R8 is hydrogen; R9 and R10 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. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000026_0002
. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000026_0001
. According to yet another embodiment, specifically provided are compounds of formula (IB), in which X2 is CH or N. According to yet another embodiment, specifically provided are compounds of formula (IB), in which X2 is CH. According to yet another embodiment, specifically provided are compounds of formula (IB), in which X2 is N. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R2 is halogen (e.g. fluoro) or C3-12cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (IB), in which R2 is fluoro or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R2 is fluoro. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R2 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which ‘m’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (IB), in which ‘m’ is 0. According to yet another embodiment, specifically provided are compounds of formula (IB), in which ‘m’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R2 is fluoro or cyclopropyl and ‘m’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R3 is C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (IB), in which R3 is CH3. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 is hydrogen or C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 is hydrogen or CH3. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 is CH3. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R5 is C1-8alkyl (e.g. CH3) or C3-12cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (IB), in which R5 is CH3 or cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R5 is CH3. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R5 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 and R5 independently is CH3. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 is hydrogen and R5 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 and R5 joined together with the carbon atom to which they are attached, form a C3-12cycloalkyl
Figure imgf000028_0001
3-15 membered heterocyclyl
Figure imgf000028_0002
) or 3- 15 membered spirocyclyl
Figure imgf000028_0003
wherein C3-12cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C1-8alkyl (e.g. CH3). According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000028_0004
3-15 membered heterocyclyl
Figure imgf000028_0005
) or 3- 15 membered spirocyclyl
Figure imgf000028_0006
wherein C3-12cycloalkyl, or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro or CH3. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000028_0007
According to yet another embodiment, specifically provided are compounds of formula (IB), in which R6 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl (e.g. phenyl). In this embodiment, C6-14 aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or cyano. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R5 and R6 joined together with the carbon atom to which they are attached, form a phenyl. In this embodiment, C6-14 aryl is optionally substituted with one or more substituents selected from fluoro or cyano. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R5 and R6 joined together with the carbon atom to which they are attached, form a 4-fluorophenyl or 4-cyanophenyl. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R7 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (IB), in which ‘p’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (IB), in which ‘p’ is 0. According to yet another embodiment, specifically provided are compounds of formula (IB), in which ‘p’ is 1. According to yet another embodiment, specifically provided are compounds of formula (IB), in which R1a is fluoro, trifluoromethyl or cyclopropyl;
Figure imgf000029_0001
X2 is CH or N; R2 is fluoro or cyclopropyl; R3 is CH3; R4 is hydrogen or CH3; R5 is CH3 or cyclopropyl; or O R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000030_0001
R6 is hydrogen; or R5 and R6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl; R7 is hydrogen; ‘n’ is 1; ‘m’ is 0 or 1 and ‘p’ is 0 or 1. According to an embodiment, specifically provided are compounds of formula (IB) with an IC50 value of less than 10000 nM, preferably, less than 500 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity. It should be understood that the 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. DETAILED DESCRIPTION OF THE INVENTION Definitions: The terms “halogen” or “halo” means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo). The term “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. C1-8alkyl), and 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). The term “C1-6alkyl” refers to an alkyl chain having 1 to 6 carbon atoms. The term “C1-4alkyl” refers to an alkyl chain having 1 to 4 carbon atoms. The term “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. The term “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. The term “cyanoalkyl” refers to cyano group, linked to an alkyl group as defined above (i.e. cyanoC1-8alkyl). Examples of such haloalkyl moiety include, but are not limited to, cyanomethyl, cyanoethyl and cyanopropyl groups. The term “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. haloC1-8alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term “haloC1-8alkyl” refers to at least one halo group linked an alkyl chain having 1 to 8 carbon atoms. The term “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- 8alkyl). Examples of hydroxyalkyl moiety include, but are not limited to –CH2OH, -C2H4OH and –CH(OH)C2H4OH. The term “alkoxy” denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C1-8 alkoxy). Representative examples of such groups are –OCH3 and – OC2H5. The term “haloalkoxy” refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloC1-8alkoxy). Examples of “haloalkoxy” include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy. The term “alkoxyalkyl” or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. C1-8alkoxyC1-8alkyl or C1-8alkyloxyC1-8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, - CH2OCH3 (methoxymethyl) and –CH2OC2H5 (ethoxymethyl). The term “hydroxyC1-8alkyl” refers to a C1-8alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC1-4alkyl). Examples of hydroxyC1-4alkyl moieties include, but are not limited to – CH2OH and –C2H4OH. The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-12cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of 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. The term “C3-6cycloalkyl” refers to the cyclic ring having 3 to 6 carbon atoms. Examples of “C3- 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. C3-6cycloalkylC1-8alkyl). 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. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl The term “aryl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6-14aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. The term “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. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such 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, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The 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. The term “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. The term “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. Examples of such 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, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl. The term “pharmaceutically acceptable salt” includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts 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, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of 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. The term “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. The term “subject” includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). 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. It is intended that all stereoisomeric forms of the compounds of formula (I), (IA) and (IB) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. 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. 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. The terms “salt” or “solvate”, and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds. PHARMACEUTICAL COMPOSITIONS The compounds 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. In one embodiment, 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. METHODS OF TREATMENT 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. Accordingly to one embodiment, 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. Accordingly to another embodiment, the compounds of the invention may be useful in the treatment of cancer mediated by CBL-b. Accordingly, to yet another embodiment, provided herein is a method of treating cancer responsive to inhibition of Cbl-b activity, the method 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. Accordingly to yet another embodiment, the compounds of the present invention for the use of treatment of cancer. Accordingly to yet another embodiment, 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. In one embodiment, the present inventions provides the use of the compounds described herein in the preparation of a medicament. In another embodiment, 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. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling reagents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the present invention. The modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography or Supercritical fluid chromatography (SFC) using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention. Following are the list of reagents or terms used in the method of preparation. HOBt: Hydroxybenzotriazole (Boc)2O: Di-tert-butyl dicarbonate [Rh(COD)Cl]2: Cyclooctadiene rhodium chloride dimer AcOH: Acetic Acid AIBN: Azobisisobutyronitrile AlCl3: Aluminium chloride Cs2CO3: 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-Dimethylformamide DMP: Dess–Martin periodinane DMSO: Dimethyl sulfoxide EDC: Ethylene dichloride EDC.HCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc: Ethyl Acetate H2O2: Hydrogen Peroxide HATU: Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium HCl: Hydrochloric acid H2SO4: Sulfuric acid HNO3: Nitric acid K2CO3: Potassium carbonate K3PO4: Tripotassium phosphate KOH: Potassium hydroxide LiOH: Lithium hydroxide MeOH: Methanol Na2SO4: Sodium sulphate NaH: Sodium hydride NaHCO3: Sodium bicarbonate NaHMDS: Sodium bis(trimethylsilyl)amide NaIO4: Sodium periodate NaNO2: Sodium nitrite NaOH: Sodium hydroxude NBS: N-Bromosuccinimide NH4Cl: Ammonium Chloride NMP: N-Methyl-2-pyrrolidone OsO4: Osmium tetroxide Pd(dppf)Cl2.DCM: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II)dichloride Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium chloride Pd(OAc)2: Palladium(II) acetate PTSA: p-Toluenesulfonic acid SFC: Supercritical fluid chromatography T3P: Propylphosphonic anhydride t-BuOH: tert-Butyl alcohol TEA: Triethylamine THF: Tetrahydrofuran General Scheme: A general approach for the preparation of compounds of the general formula (I) (wherein X1, X2, X3, R1, R1a, R2, R3, R4, R5, R6, R7, ‘n’, ‘m’ and ‘p’ are as defined in the description) is depicted in synthetic scheme 1. Synthetic scheme 1
Figure imgf000038_0001
The substitution reaction of compound of formula (1) [wherein X = Cl, Br, I] with aqueous ammonia yields the compound of formula (2). 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 T3P. 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. Alternatively, 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. A general approach for the preparation of compounds of the formula (9) (wherein R1a, R8, R9 and ‘n’ are as defined in the general description) is depicted in synthetic scheme 2. Synthetic scheme 2 Suzuki reaction
Figure imgf000040_0002
Figure imgf000040_0001
Oxidative Cleavage
Figure imgf000040_0003
Figure imgf000040_0005
Figure imgf000040_0004
The bromination reaction of compound of formula (10) using N-bromosuccinimide in a suitable solvent yields the compound of formula (11). The reaction may be carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dimethylformamide or dimethylacetamide. The compound of formula (11) upon cyclization using formamide yields the compound of formula (12). The Suzuki coupling reaction of compound of formula (12) with potassium vinyl trifluoroborate or vinyl boronic acid gives the compound of formula (13). 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. INTERMEDIATES Intermediate-A1 3-(2-(3-Bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000041_0001
Step-1: 3-(3-Bromophenyl)-3-methylbutanoic acid
Figure imgf000041_0002
To a stirred solution of bromobenzene (10 g, 0.0183 mmol) in DCM (100 mL) was added 3,3 dimethyl acrylic acid (3.19 g, 0.0318 mol). To this reaction mixture AlCl3 was added portion wise at 15-20oC and stirred at room temperature for 90 min. The reaction mixture was quenched with 1 N HCl and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained product was purified by SFC to get 3.1 g of the desired
Figure imgf000041_0003
(400 MHz, DMSO- d6) δ 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
Figure imgf000041_0004
To a stirred solution of 3-(3-bromophenyl)-3-methylbutanoic acid (6.2 g, 0.024 mol) in DMF (60 mL) was added HATU (11 g, 0.029 mol) and stirred at room temperature for 30 min. To this mixture was added DIPEA (12.5 mL, 0.072 mol) and 4-methyl thiosemicarbazide (2.8 g, 0.0265 mmol) and stirred at room temperature for 18 h. The reaction mixture was diluted with water and stirred for 30 min. The solid obtained was filtered and dried under vacuum to yield 4.83 g of the desired product.1H NMR (400 MHz, DMSO-d6) δ 1.36 (s, 6H), 2.50 (s, 2H), 2.83 (s, 3H), 7.26-7.30 (m, 1H), 7.39-7.41 (m, 3H), 7.53 (brs, 1H), 9.19 (brs, 1H), 9.60 (brs, 1H). Step-3: 3-(2-(3-Bromophenyl)-2-methylpropyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione
Figure imgf000042_0001
To a stirred solution of 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N- methylhydrazinecarbothioamide (4.8 g, 0.0139 mol) in 1 N NaOH (170 mL) was stirred at room temperature for 18 h. 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.1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 6H), 3.03 (s, 2H), 3.13 (s, 3H), 7.23-7.27 (m, 1H), 7.33-7.40 (m, 2H), 7.48-7.56 (m, 1H), 13.45 (s, 1H), ESI-MS (m/z) 327 (M+2H)+. Step-4: 3-(2-(3-Bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000042_0002
To a stirred solution of 3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-1H-1,2,4-triazole- 5(4H)-thione (4.31 g, 0.013 mol) in DCM/Acetic acid (2:1, 130 mL) was added 50 % solution of H2O2 (4.3 mL) and stirred at 0°C for 1 h. 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.1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 6H), 3.26 (s, 2H), 3.51 (s, 3H), 7.26-7.30 (m, 1H), 7.38-7.45 (m, 2H), 7.58-7.59 (m, 1H), 9.28 (s, 1H); ESI-MS (m/z) 294 (M+H)+ Intermediate-B1 3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline
Figure imgf000042_0003
In a sealed tube, to a stirred solution of 3-(2-(3-bromophenyl)-2-methylpropyl)-4- methyl-4H-1,2,4-triazole (Intermediate-A1) (1 g, 0.0034 mol) in NMP (10 mL) were added aq. NH3 (10 mL), copper (I) oxide (194 mg 1.359 mmol) and stirred at 90°C for 16 h. The reaction mixture was concentrated under reduced pressure. The obtained product was triturated with diethyl ether to yield 641 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 6H), 2.50 (s, 2H), 3.05 (s, 3H), 4.92 (brs, 2H), 6.37 - 6.42 (m, 2H), 6.49 (s, 1H), 6.88-6.92 (m, 1H), 8.22 (s, 1H); ESI-MS (m/z) 231.2 (M+H)+ Intermediate-A2 3-((3-(3-Bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000043_0001
Step-1: Ethyl 2-(oxetan-3-ylidene)acetate
Figure imgf000043_0002
To a stirred solution of NaH (611 mg, 15.27 mmol) in THF (25 mL) was added ethyl 2- (diethoxyphosphoryl)acetate (3.422 mg, 15.27 mmol) drop wise for 10-15 min at 0oC and further stirred at room temperature for 30 min followed by the addition of oxetan-3-one (1 g, 13.889 mmol). The mixture was stirred for 18 h. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated. The obtained product was purified by silica gel chromatography to yield 1.2 g of the desired product.1H NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz, 3H), 4.13-4.21 (m, 2H), 5.31 - 5.33 (m, 2H), 5.51-5.54 (m, 2H), 5.64-5.66 (m, 1H). Step-2: Ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate
Figure imgf000043_0003
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. To this mixture was added drop wise solution of ethyl 2-(oxetan-3-ylidene)acetate (1 g, 7.042 mmol) in dioxane (10 mL) followed by (3-bromophenyl)boronic acid (2 g, 10.56 mmol) in dioxane (10 mL) solution and stirred for 1 hr. The (3-bromophenyl)boronic acid (700 mg, 3.521 mmol) was added and stirred at room temperature for 48 h. The mixture was quenched with brine solution and extracted thrice 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 1.3 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 1.04 (t, J = 7.2 Hz, 3H), 2.50-2.52 (m, 2H), 3.92 (q, J = 6.8 Hz, 2H), 4.75 (d, J = 6.4 Hz, 2H), 4.79 (d, J = 6.4 Hz, 2H), 7.28-7.32 (m, 2H), 7.45-7.46 (m, 2H). Step-3: 2-(3-(3-Bromophenyl)oxetan-3-yl)acetic acid
Figure imgf000043_0004
To 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 0oC 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. 1H NMR (400 MHz, DMSO) δ 3.09 (s, 2H), 4.74-4.78 (m, 4H), 7.32 (d, J = 4.8 Hz, 2H), 7.44-7.49 (m, 2H), 12.24 (brs, 1H) Step-4: 2-(2-(3-(3-Bromophenyl)oxetan-3-yl)acetyl)-N-methylhydrazinecarbothioamide
Figure imgf000044_0001
To a stirred solution of 2-(3-(3-bromophenyl)oxetan-3-yl)acetic acid (135 mg, 0.498 mmol) in DMF (1.5 mL) was added HATU (227 mg, 0.597 mmol) and stirred for 15 min. 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.1H NMR (400 MHz, DMSO) δ 2.51 (d, J = 4.8 Hz, 3H), 3.00 (s, 2H), 4.74-4.81 (m, 4H), 7.29-7.31 (m, 2H), 7.43-7.48 (m, 2H), 7.6 (brs, 1H), 9.14 (s, 1H), 9.70 (s, 1H); ESI-MS (m/z) 359.9 (M+2H)+ Step-5: 3-((3-(3-Bromophenyl)oxetan-3-yl)methyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione
Figure imgf000044_0002
To a stirred solution of 2-(2-(3-(3-bromophenyl)oxetan-3-yl)acetyl)-N- methylhydrazinecarbothioamide (100 mg, 0.28 mmol) in 1 N NaOH (3.5 mL) was stirred at room temperature for 18 h. The mixture was cooled and neutralized using 1 N HCl. The solid obtained was filtered and dried under vacuum to give 65 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 3.01 (s, 3H), 3.53 (s, 2H), 4.78 - 4.82 (m, 4H), 7.17 (d, J = 7.6 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.44 -7.46 (m, 2H), 13.49 (brs, 1H); ESI-MS (m/z) 340.2 (M+H)+ Step-6: 3-((3-(3-Bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000044_0003
To a stirred solution of 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-1H-1,2,4- triazole-5(4H)-thione (350 mg, 1.032 mmol) in water (1.5 mL) was added NaNO2 (750 mg, 10.32 mmol) followed by drop wise addition of 1 N HNO3 (3.5 ml) at 0oC and stirred for 1 h. The reaction mixture was quenched with saturated solution of NaHCO3 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.1H NMR (400 MHz, DMSO-d6) δ 3.02 (s, 3H), 3.49 (s, 2H), 4.81 (d, J = 6 Hz, 2H), 4.89 (d, J = 6 Hz, 2H), 7.00 (d, J = 7.6 Hz, 1H), 7.24 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H); ESI- MS (m/z) 309.9 (M+H)+ Intermediate-A3a 3-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000045_0001
Intermediate-A3b 3-((1r,3r)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000045_0002
Step-1: 1,3-Dibromo-2-methylpropane
Figure imgf000045_0003
To a stirred solution of 2-Methyl-1,3-propanediol (20 g, 222 mmol) and triphenyl phosphine (128.1 g, 488.3 mmol) in DCM (500 mL) was added N-Bromosuccinimide (86.92 g, 488.35mmol) portion wise at 0°C and stirred at room tempearature for 16 h. The solvent was concentrated under reduced pressure and the obtained product was purified by silica gel chromatography to yield 23.4 g of the desired product.1HNMR (400 MHz, CDCl3) δ 1.17 (d, J = 6.4 Hz, 3H), 2.18 – 2.24 (m, 1H), 3.46 – 3.56 (m, 4H). Step-2: 1-(3-Bromophenyl)-3-methylcyclobutanecarbonitrile
Figure imgf000045_0004
To a stirred suspension of NaH (60% suspension in mineral oil) (4.31 g, 107.65 mmol) in DMF (100 mL) was added dropwise solution of 3-bromophenylacetonitrile (10.55 g, 53.826 mmol) at 0°C followed by addition of 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 NH4Cl solution. The aqueous layer was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The obtained product was purified by silica gel column chromatography to yield 9.15 g of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 1.22 (d, J=6 Hz, 3H), 2.18 – 2.23(m, 1H), 2.45 – 2.51(m, 2H), 2.77 – 2.82 (m, 2H), 7.40 – 7.45 (m, 1H), 7.54 – 7.71 (m, 2H), 7.72 (d, J = 1.6 Hz, 1H). Step-3: 1-(3-Bromophenyl)-3-methylcyclobutanecarboxylic acid
Figure imgf000046_0001
To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarbonitrile (17.7 g, 70.76 mmol), in 80 mL of AcOH/H2O (1:1) was added Conc. H2SO4 (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 Na2SO4 and concentrated to yeild 18 g of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.06 (d, J=6.4 Hz, 3H), 2.13 – 2.19 (m, 1H), 2.32 (t, J=5.2 Hz, 2H), 2.51 – 2.61 (m, 2H),), 7.31 – 7.39 (m, 2H), 7.42 – 7.50 (m, 2H), 12.47 (brs, 1H) Step-4: Methyl 1-(3-bromophenyl)-3-methylcyclobutanecarboxylate
Figure imgf000046_0002
To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarboxylic acid (18.3 g, 67.99 mmol) in MeOH (180 mL) was added Conc. H2SO4 (18 mL) and stirred at room temperature for 2 h and heated to 90° C for 16 h. The reaction mixture was concentrated under vacuum and diluted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum to obtain 19.1 g of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.15 (d, J = 6.8 Hz, 3H), 2.26 – 2.30 (m, 1H), 2.41 – 2.46 (m, 2H), 2.66 – 2.69 (m, 2H), 3.51 (s, 3H), 7.17 – 7.28 (m, 1H), 7.34 – 7.41 (m, 2H), 7.56 (d, J = 2 Hz, 1H) Step-5: 1-(3-Bromophenyl)-3-methylcyclobutanecarbohydrazide
Figure imgf000046_0003
To a stirred solution of Methyl 1-(3-bromophenyl)-3-methylcyclobutanecarboxylate (19.1 g, 67.45 mmol) in MeOH (95 mL) was added 99% hydrazine hydrate (95 mL) at 0° C. 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. ESI-MS (m/z) 283.1 (M+H)+ Step-6: 2-(1-(3-Bromophenyl)-3-methylcyclobutanecarbonyl)-N- methylhydrazinecarbothioamide
Figure imgf000047_0001
To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarbohydrazide (19.0 g, 67.09 mmol) in THF (200 mL) was added dropwise methylisothiocyanate (14.71 g, 201.3 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1h and heated to 80° C for 3 h. The mixture was concentrated under reduced pressure and the obtained product was triturated with pentane. The solid obtained was filtered and dried under vacuum to yield 23.8 g of the desired product. ESI-MS (m/z) 356.0 (M+H)+ Step-7: 5-(1-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole- 3-thione
Figure imgf000047_0002
To a stirred solution of 2-(1-(3-bromophenyl)-3-methylcyclobutanecarbonyl)-N- methylhydrazinecarbothioamide (23.4 g, 65.67 mmol) in 1 N NaOH (500 mL) was stirred at room temperature for 16 h. The reaction mixture was acidified using 2N HCl and stirred for 15 min. The precipitated solid was filtered, washed with excess water and dried under vacuum to yield 20.18 g of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.06 (d, J =6.0 Hz, 3H), 2.45-2.51 (m, 3H), 2.76 (d, J =3.6 Hz, 2H), 3.01 (s ,3H), 7.35 – 7.39 (m, 2H), 7.51-7.54 (m, 2H), 13.7 (brs, 1H); ESI-MS (m/z) 338.0 (M+H)+ Step-8: 3-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (Intermediate-A3a) & 3-((1r,3r)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4- triazole (Intermediate-A3b) To a stirred solution of 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H- 1,2,4-triazole-3-thione (10 g, 19.56 mmol) in DCM (240 mL) and AcOH (40 mL) was added 30% H2O2 solution at 0°C. 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.1HNMR (400 MHz, CDCl3): δ 1.16 (d, J = 5.6 Hz, 3H), 2.64-2.70 (m, 3H), 2.82-2.85(m, 2H), 3.23 (s, 3H), 7.23-7.29 (m, 1H), 7.40-7.43 (m, 2H), 7.56 (d, J = 1.6Hz, 1H), 8.19 (s, 1H); ESI MS (m/z) 306.0 (M+H)+. The trans isomer obtained as mixture was further purified by SFC purification (using 0.1%NH3 in methanol as co solvent) to yield trans isomer 416 mg of the desired product. 1H NMR (400 MHz, CDCl3) δ 1.15 (d, J = 6.8 Hz, 3H), 2.26-2.32 (m, 2H), 2.55-2.59 (m, 1H), 3.12-3.17 (m, 2H), 3.28 (s, 3H), 7.11 (d, J = 8Hz, 1H), 7.19-7.23 (m, 1H), 7.38-7.40 (m, 2H), 8.31 (s, 1H); ESI MS (m/z) 306.0 (M+H)+. The analytical data of the intermediate prepared by following the procedure described above are given in below Table-1. Table-1: Structure, Name and analytical data of intermediate (A4-A7)
Figure imgf000048_0001
Figure imgf000049_0002
Intermediate B2 3-((1s,3s)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline
Figure imgf000049_0001
In a sealed tube, to a stirred solution of 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4- methyl-4H-1,2,4-triazole (250 mg, 0. 816 mmol) in NMP (3.5 mL) was added aqueous NH3 (3.5 mL), copper (I) oxide (47 mg, 0.326 mmol) and stirred at 90°C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under vacuum to give 171 mg of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.05 (d, J= 4.8 Hz, 3H), 2.46 – 2.51 (m, 3H), 2.71 (d, J=7.2 Hz, 2H), 3.16 (s, 3H), 5.06 (brs, 2H), 6.41 – 6.46 (m, 3H), 6.78 (t, J = 7.6 Hz, 1H), 8.39 (brs, 1H); ESI-MS (m/z) 243.2 (M+H) + The analytical data of the intermediate prepared by following the procedure described above are given in below Table-2. Table-2: Structure, Name and analytical data of intermediate (B3)
Figure imgf000049_0003
Figure imgf000050_0004
Intermediate-A8 3-(1-(3-Bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000050_0001
Step-1: 2,2-Dimethylpropane-1,3-diyldimethanesulfonate MsO OMs To a stirred solution of 2,2-dimethylpropane-1,3-diol (10 g, 96.1 mmol) in DCM (100 mL) triethylamine (33.7 mL, 240 mmol) was added. The mesyl chloride (18.5 mL, 240 mmol) was added drop wise at 0°C and stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated to give 11.0 g of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 3.18 (s, 6H), 4.00 (s, 4H). Step-2: 1,3-Diiodo-2,2-dimethylpropane
Figure imgf000050_0002
To a stirred solution of 2,2-dimethylpropane-1,3-diyldimethanesulfonate (2.0 g, 7.69 mmol) in DMF (20 mL) was added KI (5.1 g, 30.7 mmol) portion wise at 0°C and stirred at 120°C for 16 h. 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 Na2SO4 and concentrated to give 2.1 g of the desired product.1HNMR (400 MHz, CDCl3): δ 1.26 (s, 6H), 3.28 (s, 4H). Step-3: 1-(3-Bromophenyl)-3,3-dimethylcyclobutane-1-carbonitrile
Figure imgf000050_0003
To a stirred suspension of NaH (60% suspension in mineral oil) (612 mg, 15.3 mmol) in DMF (15 mL) was added dropwise solution of 3-bromophenylacetonitrile (1.0 g, 5.10 mmol) and 1,3- diiodo-2,2-dimethylpropane (2.1 g, 6.63 mmol) in DMF (5 mL) at 0°C for the period of 1h. 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 Na2SO4 and concentrated. The obtained product was purified by silica gel column chromatography to yield 700 mg of the desired product.1HNMR (400 MHz, CDCl3) δ 1.16 (s, 3H), 1.50 (s, 3H), 2.47 (d, J=13.2 Hz, 2H), 2.74 (d, J=12.4 Hz, 2H), 7.26 – 7.28 (m, 1H), 7.33 – 7.35 (m, 1H), 7.45-7.47 (m, 1H), 7.54 (s, 1H) Step-4: 1-(3-Bromophenyl)-3,3-dimethylcyclobutane-1-carboxylic acid
Figure imgf000051_0001
To a stirred solution of 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonitrile (700 mg, 2.66 mmol), in 4.2 mL of AcOH/H2O (1:1) was added conc. H2SO4 (2.1 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, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated to give 700 mg of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 0.97 (s, 3H), 1.12 (s, 3H), 2.25 (d, J=12.8 Hz, 2H), 2.63 (d, J=12.8 Hz, 2H), 7.26 – 7.33 (m, 2H), 7.39 – 7.45 (m, 2H), 12.50 (bs, 1H), ESI-MS (m/z) 281.1(M-H)+ Step-5: 2-(1-(3-Bromophenyl)-3,3-dimethylcyclobutane-1-carbonyl)-N-methylhydrazine-1- carbothioamide
Figure imgf000051_0002
To a stirred solution of 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carboxylic acid (700 mg, 2.47 mmol) in DMF (8.0 mL) was added DIPEA (1.3 mL, 7.42 mmol) and HATU (1.1 g, 2.96 mmol) stirred for 30 min. 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. ESI-MS (m/z) 371.1 (M+2H)+ Step-6: 5-(1-(3-Bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triaz ole-3-thione
Figure imgf000051_0003
To a stirred solution of 2-(1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonyl)-N- methylhydrazine-1-carbothioamide (820 mg, 2.21 mmol) in 1 N NaOH (8.0 mL) was stirred at room temperature for 16 h. The reaction mixture was acidified using 6N HCl and stirred for 2 h. The precipitated solid was filtered, washed with excess water and dried under vacuum to yield 760 mg of the desired product. ESI-MS (m/z) 353.1 (M+2H)+ Step-7: 3-(1-(3-Bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-4H-1,2,4-triazole To a stirred solution of 5-(1-(3-bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-2,4-dihydro- 3H-1,2,4-triazole-3-thione (760 mg, 2.16 mmol) in DCM (10.0 mL) and AcOH (2.2 mL) was added 30% H2O2 solution (0.9 mL) at 0°C. The mixture was stirred at room temperature for 2 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 628 mg of the desired product.1HNMR (400 MHz, CDCl3): δ 1.03 (s, 3H), 1.09(s, 3H), 2.57 (d, J = 12.8 Hz, 2H), 2.87(d, J = 10.4 Hz, 2H), 3.22 (s, 3H), 7.32-7.35 (m, 3H), 7.42-7.45 (m, 1H), 8.33 (s, 1H); ESI MS (m/z) 321.1 (M+2H)+ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-3. Table-3: Structure, Name and analytical data of intermediate (A9-A14)
Figure imgf000052_0001
Figure imgf000053_0002
Intermediate-B4 2-Fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)aniline
Figure imgf000053_0001
In a sealed tube, to a stirred solution of 3-(2-(3-bromo-4-fluorophenyl)spiro[3.3]heptan-2-yl)- 4-methyl-4H-1,2,4-triazole (1.0 g, 2.85 mmol) in NMP (20 mL) was added aqueous NH3 (20 mL), copper (I) oxide (408 mg, 2.85 mmol) and stirred at 100°C for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under vacuum to give 171 mg of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.7.2-1.76 (m, 2H), 1.85-1.88 (m, 2H), 1.93-1.97 (m, 2H), 2.61 (d, J = 11.6Hz, 2H), 2.96 (d, J = 11.6Hz, 2H), 3.19 (s,3H), 5.11 (s, 2H), 6.38 (s, 1H), 6.52 (d, J = 8.4Hz, 1H), 6.91 (dd, J1 = 8.0Hz, J2 = 3.2 Hz, 1H), 8.36 (s, 1H); ESI- MS (m/z) 287.2 (M+H) + Intermediate-A15 3-(1-(3-Bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000054_0001
Step-1: 1-(3-Bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile
Figure imgf000054_0002
To a stirred suspension of NaH (60% suspension in mineral oil) (2.56g, 63.77 mmol) in DMF (50 mL) was added dropwise solution of 3-bromophenylacetonitrile (5.0 g, 25.51 mmol) at 0°C. 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 Na2SO4 and concentrated. The obtained product was purified by silica gel column chromatography to yield 2.4 g of the desired product.1HNMR (400 MHz, DMSO-d6): δ 2.72(d, J=13.6 Hz, 2H), 3.12(d, J= 13.6Hz, 2H), 3.20(s, 3H), 3.30 (s, 3H), 7.29- 7.31 (m, 1H), 7.42 – 7.44 (m, 1H), 7.48-7.50(m,1H), 7.64(s, 1H) Step-2: 1-(3-Bromophenyl)-3-oxocyclobutane-1-carbonitrile
Figure imgf000054_0003
To a stirred solution of 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile (0.96 g, 3.20 mmol), in 80 mL of acetone, was added pTSA at room temperature for 48h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated and purified to give 400mg of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 3.9-3.75 (m, 2H), 4.06-4.11 (m, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.45 (d, J= 8.0Hz,1H), 7.56 (d, J= 8.0Hz, 1H), 7.66 (s, 1H). Step-3: 1-(3-Bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile
Figure imgf000055_0001
To a stirred solution of 1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile (0.95g, 3.8 mmol) in DCM (20 mL) was added DAST (2.45g, 15.2mmol) at 0oC and stirred at room teperature for 18 h, The reaction was quenched with sat. NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous Na2SO4. The solvent was evaporated and purified to obtain 760mg of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 3.17-3.27 (m, 2H), 3.49-3.57 (m, 2H), 7.35 (t, J=7.6 Hz, 1H), 7.42 (d, J= 7.6 Hz,1H), 7.55 (d, J= 7.6 Hz, 1H), 7.62 (s, 1H). Step-4: 1-(3-Bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid F F HO Br O To a stirred solution of 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile (2.0 g, 7.35 mmol) in acetic acid (4.0 ml) and water (4.0ml) was added Conc H2SO4 (4.0 mL) at 0° C. The reaction mixture was warmed to RT and heated to 120°C for 16 h. The mixture was cooled to room temperature and diluted with water. The precipitated solid was filtered dried well to yield 1.9 g of the desired product.1HNMR (400 MHz, DMSO-d6): δ 3.08-3.18 (m, 2H), 3.30-3.40 (m, 2H), 7.36 (t, J=4.4 Hz, 2H), 7.52 (d, J= 6.4 Hz,1H), 7.54(s, 1H), 13.01-13.16 (brs, 1H). ESI-MS (m/z) 291 (M)+ Step-5: 2-(1-(3-Bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1- carbothioamide
Figure imgf000055_0002
To a stirred solution of 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid (120 mg, 0.412 mmol) in DMF (3.0 mL) was added N-methylhydrazinecarbothioamide (48mg, 0.453 mmol). To this EDCI.HCl (118mg, 0.618mmol), triethylamine (54mg,0.536mmol) and HOBt (72mg,0.536mmol) was added. The reaction mixture was stirred at room temperature for 18h. The mixture was quenched by adding water, aq. Layer was extracted with ethyl acetate. The organic layer was separated, concentrated to yield 140mg desired product. ESI-MS (m/z) 378.0 (M+H)+ Step-6: 5-(1-(3-Bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4- triazole-3-thione
Figure imgf000056_0001
To a stirred solution of 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N- methylhydrazine-1-carbothioamide (2.9 g, 7.67 mmol) in 1 N NaOH (100 mL) was stirred at room temperature for 16 h. The reaction mixture was acidified using 2N HCl and stirred for 15 min. The precipitated solid was filtered, washed with excess water and dried under vacuum to yield 2.1 g of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 3.04 (s, 3H), 3.38-3.47 (m, 2H), 3.58-3.68 (m, 2H), 7.33-7.40 (m ,2H), 7.55 – 7.59 (m, 2H), 13.86 (brs, 1H); ESI-MS (m/z) 360 (M+H)+ Step-7: 3-(1-(3-Bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole To a stirred solution of 5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-2,4-dihydro- 3H-1,2,4-triazole-3-thione (65mg, 0.18 mmol) in DCM (1.0 mL) and AcOH (0.144ml) was added 30% H2O2 (0.045ml) solution at 0°C. 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 43 mg of the desired product. 1HNMR (400 MHz, CDCl3): δ 3.27 (s, 3H), 3.29-3.36(m, 2H), 3.68-3.78(m, 2H), 7.20(d, J= 7.6Hz, 1H), 7.26(d, J= 8.0Hz, 1H),), 7.43 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H); ESI MS (m/z) 328 (M+H)+ Intermediate-A16 3-((3-Bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000056_0002
Step-1: Methyl 2-(3-bromophenyl)acetate
Figure imgf000056_0003
To a stirred solution of 3-bromophenyl acetic acid (17 g) in methanol (300 mL) was dropwise added conc. H2SO4 (10 mL) and heated to 110oC for 18 h. The reaction mixture was concentrated under reduced pressure. The obtained product was diluted with water and extracted with ethyl acetate. The organic layer was washed with sat. NaHCO3 solution and separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained product was purified with chromatography to get 9.3 g of the desired product as pale yellow oil.1H NMR (400 MHz, CDCl3) δ 3.62 (s, 2H), 3.72 (s, 3H), 7.19 - 7.28 (m, 2H), 7.41 - 7.44 (m, 1H), 7.43 (s, 1H); ESI-MS (m/z) 229.07 (M+H)+ Step-2: Methyl 2-(3-bromophenyl)-2-cyclobutylacetate
Figure imgf000057_0001
To a stirred solution of methyl 2-(3-bromophenyl)acetate (2 g, 8.77 mmol) in DMF (15 mL) was dropwise added potassium tert-butoxide solution (11.34 ml, 11.34 mmol) at 0°C. The solution of bromo cyclobutane (1.41 g, 10.48 mmol) in DMF (5 ml) was dropwise added and stirred at room temperature for 18 h. The reaction mixture was quenched with sat NH4Cl solution and extracted twice with ethyl acetate. Then organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained product was purified with chromatography to get 1.21 g of the desired product as pale yellow oil.1H NMR (400 MHz, CDCl3) δ 1.611-1.63(m, 1H), 1.82-1.88(m, 4 H), 2.18-2.21( m, 1H), 2.93-2.95 ( m, 1H), 3.52(d, J=11.2 Hz, 1H), 3.95 (s, 3H), 7.17(m, 2H), 7.38-7.41(m, 1H), 7.45 (s,1H); ESI-MS (m/z) 283.03 (M+H)+ Step-3: 2-(3-Bromophenyl)-2-cyclobutylacetohydrazide
Figure imgf000057_0002
To a stirred solution of methyl 2-(3-bromophenyl)-2-cyclobutylacetate (1.1 g) in ethanol (10 mL) was added hydrazine hydrate (3 mL) and heated to 90°C for 18 h. The reaction mixture was evaporated completely and diluted with water. The mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield 1.05 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 1.48- 1.50 (m, 1H), 1.72-1.79 (m, 4H), 1.98-2.00 ( m, 1H), 2.92-2.94 ( m, 1H), 3.18 ( d, J=9.6 Hz, 1H),4.22( bs, 2H), 7.23-7.29 (m, 2H),7.39-7.42 (m, 1H), 7.50(s,1H), 9.22(s, 1H); ESI-MS (m/z) 283.1 (M+H)+ Step-4: 2-(2-(3-Bromophenyl)-2-cyclobutylacetyl)-N-methylhydrazine-1-carbothioamide S H N N N Br H H O To a stirred solution of 2-(3-Bromophenyl)-2-cyclobutylacetohydrazide (1.0 g, 3.53 mmol) in THF (10 mL) was added dropwise methyl isothiocyanate (776 mg, 10.65 mmol) and heated to 90° C for 4 h. The mixture was concentrated under reduced pressure and the obtained product was triturated with pentane. The solid obtained was filtered and dried under vacuum to yield 1.1 g of the desired product.1H NMR (400 MHz, DMSO-d6) δ 1.53-1.57(m, 1H), 1.76-1.80 (m, 3H), 1.91-1.98 (m, 2H), 2.78-2.81 (m, 1H), 2.85 (s, 3H), 3.47 (d, J=9.6 Hz, 1H),7.25-7.32 (m, 2H), 7.43(d, J=7.6 Hz, 1H), 7.52(s,1H), 7.60(bs,1H), 9.26 (s, 1H), 9.90 (s, 1H), ESI-MS (m/z) 356.1 (M+H)+ Step-5: 5-((3-Bromophenyl)(cyclobutyl)methyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3- thione
Figure imgf000058_0001
To a stirred solution of 2-(2-(3-Bromophenyl)-2-cyclobutylacetyl)-N-methylhydrazine-1- carbothioamide (1.1 g) in 1 N NaOH (40 mL) was stirred at room temperature for 16 h. The reaction mixture was acidified using 2N HCL and stirred for 15 min. The precipitated solid was filtered, washed with excess water and dried under vacuum to yield 1.05 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 1.68-75 (m, 5H), 2.07-2.09 (m, 1H), 2.94-2.96 (m, 1H), 3.20 (s, 3H), 4.25 (d, J=10.8 Hz, 1H),7.23 (d, J=7.6 Hz, 1H), 7.31 (t, J=8 Hz, 1H), 7.45- 749 (m, 2H), 13.71 (s, 1H); ESI-MS (m/z) 338.0 (M+H)+ Step-6: 3-((3-Bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole To a stirred solution of 5-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-2,4-dihydro-3H- 1,2,4-triazole-3-thione (1.6 g, 4.74 mmol) in DCM (30 ml) was added acetic acid (3.8 ml, 66.26 mmol) at 0°C and stirred for 10 min and to that 30 % solution of H2O2 (1.2 mL, 11.84 mmol) was added and stirred at 0°C for 2 h. The reaction mixture was diluted with DCM and washed with water, and sat NaHCO3 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. 1H NMR (400 MHz, DMSO- d6) δ 1.63-78 (m, 5H), 2.03-2.05( m, 1H), 3.06-3.10 ( m, 1H), 3.39 ( s, 3H), 4.22( d, J=10.4 Hz, 1H),7.27-7.28 (m, 2H), 7.41-7.44 (m, 2H), 8.34 (s, 1H); ESI-MS (m/z) 306.0 (M+H)+ Intermediate-A17 3-(4-Fluoro-3'-iodo-[1,1'-biphenyl]-2-yl)-4-methyl-4H-1,2,4-triazole
Figure imgf000059_0001
Step-1: 3-(3-Bromophenyl)-3-methylbutanoic acid
Figure imgf000059_0002
To a stirred solution of methyl 2-bromo-5-fluorobenzoate (5 g, 22.83 mmol) in methanol (50 mL) was added conc. H2SO4 (5 mL) dropwise and stirred at 90°C for 16 h. The reaction mixture was concentrated under reduced pressure and neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get 4.2 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 1H), 7.38 - 7.43 (m, 1H), 7.64 (dd, J = 3.2 Hz, J =8.8 Hz, 1H), 7.80 (dd, J = 4.8 Hz, J =8.8 Hz, 1H). Step-2: 2-Bromo-5-fluorobenzohydrazide
Figure imgf000059_0003
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.1H NMR (400 MHz, DMSO-d6) δ 4.50 (s, 2H), 7.24 – 7.28 (m, 2H), 7.69 - 7.70 (m, 1H), 9.62 (s, 1H); ESI-MS (m/z) 235 (M+2H)+. Step-3: 5-(2-Bromo-5-fluorophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol
Figure imgf000059_0004
To a stirred solution of 2-bromo-5-fluorobenzohydrazide (530 mg, 2.27 mol) in methanol (10 mL) was added methylisothiocyanate (211 mg, 2.72 mol) and stirred at room temperature for 16 h. The 2N NaOH solution (384 mg, 9.6 mol) was added and stirred at 90°C for 2 h. The reaction mixture was cooled to room temperature and acidified with 1N HCL (pH ~ 2). The solid precipitated was filtered and dried under pressure to get 550 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 3.26 (s, 3H), 7.48 - 7.57 (m, 1H), 7.65 – 7.68 (m, 1H), 7.87 - 7.93 (m, 1H), 14.08 (s, 1H); ESI-MS (m/z) 290 (M+2H)+. Step-4: 3-(2-Bromo-5-fluorophenyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000060_0001
To a stirred solution of 5-(2-bromo-5-fluorophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol (550 mg, 1.90 mol) and acetic acid (3.42 g, 3 mL, 57 mol) in DCM (10 mL) was cooled to 0°C and added dropwise H2O2 (30% in water) (646 mg, 0.19 mL, 19.0 mol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water and separated the organic layer. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The obtained product was purified using silica gel column chromatography to get 190 mg of the desired product as white solid.1H NMR (400 MHz, DMSO-d6) δ 3.50 (s, 3H), 7.42 – 7.48 (m, 1H), 7.50 - 7.53 (m, 1H), 7.87-7.90 (m,1H), 8.66 (s, 1H), ESI-MS (m/z) 258 (M+2H)+ Step-5: 4'-Fluoro-2'-(4-methyl-4H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-3-aminetriazole
Figure imgf000060_0002
To a stirred solution of 3-(2-bromo-5-fluorophenyl)-4-methyl-4H-1,2,4-triazole (200 mg, 0.78 mol), 3-aminophenylboronic acid (128 mg, 0.93 mol) and K2CO3 (323 mg, 2.34 mol) in 1,4- dioxane (5 mL) and water (1 mL) was degassed using nitrogen for 10 min. To this reaction mixture was added Pd(PPh3)4 (360 mg, 0.31 mol) and degassed for 5 min and heated to 120°C for 3 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained product was triturated with diethyl ether to get 150 mg of the desired product as pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ 3.00 (s, 3H), 5.12 (s, 2H), 6.13 (d, J = 7.6 Hz, 1H), 6.37 (s, 1H), 6.47 (d, J = 8 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 7.38 – 7.35 (m, 1H), 7.63 - 7.47 (m, 2H), 8.41 (s, 1H); ESI-MS (m/z) 269 (M+H)+ Step-6: 3-(4-Fluoro-3'-iodo-[1,1'-biphenyl]-2-yl)-4-methyl-4H-1,2,4-triazole To a stirred solution of 4'-fluoro-2'-(4-methyl-4H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-3- aminetriazole (50 mg, 0.18 mol) and CuI (71 mg, 0.37 mol) in acetonitrile (1 mL) was added t- butyl nitrite (38 mg, 0.37 mol) and stirred at room temperature for 16 h. 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.1H NMR (400 MHz, DMSO-d6) δ 3.13 (s, 3H), 7.13 – 7.09 (m, 2H), 7.53 (s, 1H), 7.57 – 7.54 (m, 2H), 7.68 - 7.62 (m, 2H), 8.52 (s, 1H); ESI-MS (m/z) 380 (M+H)+ Intermediate-A18 4-(2-Chloro-6-cyclopropylpyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile
Figure imgf000061_0001
Step-1: Methyl 5-cyano-2-(2,6-dichloropyridin-4-yl)benzoate
Figure imgf000061_0002
To a stirred solution of methyl 2-bromo-5-cyanobenzoate (2.0g, 8.33 mmol) in dioxane (40 mL) and water (4.0mL) in a sealed tube was degassed for 15 min. To this 2,6-dichloropyridinyl boronic acid (1.6g, 8.33mmol), potassium carbonate (3.5g, 24.99 mmol) and Pd(dppf)Cl2 (340 mg, 0.41 mmol) was added. The reaction mixture was stirred at 100oC for 18h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained product was purified by column chromatography to get 2.11 g of the desired product.1H NMR (400 MHz, DMSO-d6) δ 3.72 (s, 3H), 7.65 (s, 2H), 7.19 (d, J=8.0 Hz, 1H), 8.22 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H); ESI-MS (m/z) 308 (M+H)+. Step-2: 5-Cyano-2-(2,6-dichloropyridin-4-yl)benzoic acid
Figure imgf000061_0003
To a stirred solution of methyl 5-cyano-2-(2,6-dichloropyridin-4-yl)benzoate (2.0 g, 6.51 m mol) in THF (30 mL) and water (10 mL) was added LiOH.H2O (1.36 g, 32.56 mmol) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and diluted with water and acidified with 1N HCl (pH = 4). The precipitated solid was filtered and dried under vacuum to yield 1.9 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.61-7.69 (m, 3H), 8.17 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H) 8.36 (d, J = 1.6 Hz, 1H),13.16 (bs,1H); ESI-MS (m/z) 293 (M+H)+ Step-3: 2-(5-Cyano-2-(2,6-dichloropyridin-4-yl)benzoyl)-N-methylhydrazine-1- carbothioamide
Figure imgf000062_0001
To a stirred solution of 5-cyano-2-(2,6-dichloropyridin-4-yl)benzoic acid (1.6 g, 5.46 mmol) in DMF (25 mL) was added 4-methyl-3-thiosemicarbazide (574 mg, 5.46 mmol), DIPEA (5.88 ml 32.76 mmol). The resulting reaction mixture was cooled to 0oC and added dropwise T3P (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.1H NMR (400 MHz, DMSO-d6) δ 2.93 (d, J = 3.6 Hz, 3H), 7.64 (s, 1H), 7.72 (d, J =8.4 Hz, 1H), 8.06 (d, J = 6 Hz, 1H), 8.16 (dd, J = 1.2 Hz, J = 8.0 Hz, 1H), 8.36 (s, 1H), 9.50 (s, 1H), 10.54 (s,1H); ESI-MS (m/z) 380 (M+H)+ Step-4: 4-(2,6-Dichloropyridin-4-yl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol-3- yl)benzonitrile
Figure imgf000062_0002
To a stirred solution of 2-(5-cyano-2-(2,6-dichloropyridin-4-yl)benzoyl)-N-methylhydrazine- 1-carbothioamide (1.2 g, 3.31 mmol) in saturated aqueous NaHCO3 (10 mL). The reaction mixture was refluxed for 2h and reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain 980 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 2.88 (s, 3H), 7.52 (s, 2H), 7.92 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 8.28 (s,1H), 8.38 (s, 1H); ESI-MS (m/z) 362 (M+H)+ Step-5: 4-(2,6-Dichloropyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile
Figure imgf000062_0003
To a stirred solution of 4-(2,6-dichloropyridin-4-yl)-3-(5-mercapto-4-methyl-4H-1,2,4-triazol- 3-yl)benzonitrile (600 mg, 1.65 mmol) in DCM (15 mL) was added acetic acid (199 mg, 3.31 mmol) and cooled to 0oC and H2O2 (281 mg, 8.28 mmol) added dropwise. The 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. 1H NMR (400 MHz, DMSO-d6) δ 3.51 (s, 3H), 7.37 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 8.23 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.60 (s, 1H); ESI-MS (m/z) 330 (M+H)+ Step-6: 4-(2-chloro-6-cyclopropylpyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile In a sealed tube, stirred solution of 4-(2,6-dichloropyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol- 3-yl)benzonitrile (500 mg, 1.38 mmol) in toluene (30 mL) was degassed for 15 min. To this mixture was added cyclopropyl boronic acid (166 mg,1.93mmol), K3PO4 (880 mg, 4.14 mmol), tricyclohexylphosphine(36 mg, 0.138mmol) and Pd(OAc)2 (31 mg, 0.138 mmol). The reaction mixture was stirred at 130oC for 18 h. The reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate obtained was concentrated and purified by column chromatography to get 267 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.82 – 0.85 (m, 2H), 0.98 – 1.00 (m, 2H), 2.05 – 2.10 (m, 1H), 3.38 (s, 3H), 6.98 (d, J = 1.2 Hz, 1H), 7.02 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 8.19-8.21 (m, 2H), 8.57 (s, 1H); ESI-MS (m/z) 336 (M+H)+ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-4. Table-4: Structure, Name and analytical data of intermediate (A-19)
Figure imgf000063_0001
Intermediate-C1 (S)-6-((3-Methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one N O HN N CF3 Step-1: 2-Amino-5-bromo-3-(trifluoromethyl)benzoic acid
Figure imgf000064_0001
To stirred suspension of 2-amino-3-(trifluoromethyl)benzoic acid (10 g, 48.78 mmol) in DMF (50 mL) was added NBS (9.5 g, 53.65 mmol) and stirred at room temperature for 16 h. The reaction mixture was diluted with water and the solid precipitated was filtered and dried under vacuum to yield 12.53 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (brs, 2H), 7.77 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 13.55 (brs, 1H); ESI-MS (m/z) 283.9 (M+H) + Step-2: 6-Bromo-8-(trifluoromethyl)quinazolin-4(3H)-one
Figure imgf000064_0002
To a stirred suspension of 2-amino-5-bromo-3-(trifluoromethyl)benzoic acid (2 g, 7.04 mmol) in formamide (30 mL) was heated to 165o C in a sealed tube for overnight. The reaction mixture was cooled to room temperature and diluted with ice cold water and stirred for 1 hr. The solid obtained was filtered and dried under vacuum to yield 1.41 g of the desired product.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.32 (s, 1H), 8.46 (d, J = 2 Hz, 1H), 12.8 (brs, 1H); ESI- MS (m/z) 294 (M+2H) + Step-3: 8-(Trifluoromethyl)-6-vinylquinazolin-4(3H)-one
Figure imgf000064_0003
To a stirred solution of 6-bromo-8-(trifluoromethyl)quinazolin-4(3H)-one (360 mg, 1.228 mmol) and potassium vinyl trifluoro borate (493 mg, 3.686 mmol) in a solvent mixture of ethanol, toluene and water (12 mL) was degassed for 15 min. To this reaction mixture K3PO4 (1.04g, 4.912mmol) and Pd(dppf)Cl2.DCM (100 mg, 0.122 mmol) were added and heated to 110°C for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained product was purified by silica gel column chromatography to yield 178 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 5.40 – 5.55 (m, 1H), 6.05 – 6.15 (m, 1H), 6.90 – 7.10 (m, 1H), 8.25 (s, 1H), 8.31 (s, 1H), 8.41 (s, 1H), 12.64 (brs, 1H); ESI- MS (m/z) 241.1 (M+H) + Step-4: 4-Oxo-8-(trifluoromethyl)-3,4-dihydroquinazoline-6-carbaldehyde
Figure imgf000065_0001
To a stirred solution of 8-(trifluoromethyl)-6-vinylquinazolin-4(3H)-one (300 mg, 1.25 mmol) in THF/Water (12 mL/3 mL) was added NaIO4 (534 mg, 2.5 mmol) followed by drop wise addition of OsO4 (2.5 % solution in tBuOH) (65 μL, 0.0062 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with 20% MeOH/DCM. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield 228 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.54 (s, 1H), 8.91 (s, 1H), 10.18 (s, 1H), 12.94 (brs, 1H); ESI-MS (m/z) 243.2 (M+H)+ Step-5: (S)-6-((3-Methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one To a stirred solution of 4-oxo-8-(trifluoromethyl)-3,4-dihydroquinazoline-6-carbaldehyde (220 mg, 0.909 mmol) and (3S)-3-Methylpiperidine HCl (246 mg, 1.818 mmol) in DCM/MeOH (5 mL/1 mL) was added DIPEA (470 μl, 2.727 mmol) and stirred at room temperature for 2 h. 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.1H NMR (400 MHz, DMSO-d6) δ 0.82 (d, J = 6 Hz, 3H), 1.35- 1.50 (m, 1H), 1.50- 1.70 (m, 3H), 1.80- 1.95 (m, 1H), 2.50 – 2.55 (m, 2H), 2.60- 2.75 (m, 2H), 3.63 (s, 2H), 8.09 (s, 1H), 8.24 (s, 1H), 8.28 (s, 1H), 12.6 (brs, 1H); ESI-MS (m/z) 326.2 (M+H)+ Intermediate-C2 6-((Isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one
Figure imgf000065_0002
To a stirred mixture 4-oxo-8-(trifluoromethyl)-3,4-dihydroquinazoline-6-carbaldehyde (step-4 intermediate of C1) (1 g, 4.13 mmol) and isobutylamine HCl (1.11 g, 10.33 mmol) in dichloroethane (80 mL) was heated to reflux for 4 h. 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.1H NMR (400 MHz, DMSO-d6) δ 0.87 (d, J = 6 Hz, 6H), 1.50- 1.75 (m, 1H), 2.30 (d, J = 6.4 Hz, 2 H), 3.87 (s, 2H), 8.16 (s, 1H), 8.22 (s, 1H), 8.33 (s, 1H), 12.6 (bs, 1H); ESI-MS (m/z) 300.2 (M+H)+ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-5. Table-5: Structure, Name and analytical data of intermediate (C3-C17)
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0004
Intermediate-C18 (S)-8-Cyclopropyl-6-((3-methylpiperidin-1-yl)methyl)quinazolin-4(3H)-one
Figure imgf000069_0001
Step-1: Methyl 2-amino-3-cyclopropylbenzoate
Figure imgf000069_0002
To a stirred solution of methyl 2-amino-3-bromobenzoate (5.0 g, 21.70 mmol) and cyclopropylboronic acid (5.2 g, 60.00 mmol) in a solvent mixture of (2:1) toluene and water (50 mL) was degassed for 15 min. To this reaction mixture were added K3PO4 (12.79 g, 60.00 mmol), tricyclohexylphosphine (0.60 g, 2.1 mmol) and Pd(OAc)2 (1.46 g, 2.1 mmol) and heated to 110°C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained product was purified by silica gel column chromatography to yield 3.0 g of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 0.48-0.52 (m, 2H), 0.88-0.93 (m, 2H), 1.64-1.68 (m, 1H), 3.79 (s, 3H), 6.48 (t, J = 7.6 Hz, 1H), 6.62 (bs, 2H), 7.10 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H); ESI-MS (m/z) 192.45 (M+H)+ Step-2: 2-Amino-3-cyclopropylbenzoic acid
Figure imgf000069_0003
To a stirred solution of methyl 2-amino-3-cyclopropylbenzoate (3.0 g, 15.60 mmol) in THF/MeOH (30 mL) was added aqueous solution of LiOH (2.6 g, 62.50 mmol) at 0oC 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 2.8 g of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.47-0.51 (m, 2H), 0.87-0.92 (m, 2H), 1.63-1.67 (m, 1H), 6.45 (t, J = 7.6 Hz, 1H), 6.62 (br s, 2H), 7.08 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), 12.02 (bs, 1H); ESI-MS (m/z) 178.38 (M+H)+ Step-3: 2-Amino-5-bromo-3-cyclopropylbenzoic acid
Figure imgf000070_0001
To stirred suspension of 2-amino-3-cyclopropylbenzoic acid (2.8 g, 15.81 mmol) in DMF (30 mL) was added NBS (4.2 g, 23.72 mmol) and stirred at room temperature for 16 h. The reaction mixture was diluted with water and the solid precipitated was filtered and dried under vacuum to yield 1.8 g of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.52-0.56 (m,2H), 0.89- 0.92 (m, 2H), 1.63-1.67 (m, 1H), 6.97 (bs, 2H), 7.15 (s, 1H), 7.68 (s, 1H), 13.55 (bs, 1H); ESI- MS (m/z) 257.36 (M+H)+ Step-4: 6-Bromo-8-cyclopropylquinazolin-4(3H)-one
Figure imgf000070_0002
To a stirred suspension of 2-amino-5-bromo-3-cyclopropylbenzoic acid (1 g, 3.90 mmol) in formamide (10 mL) was added formamidine acetate (1.22 g, 11.71 mmol) and heated to 165oC for 1 hr. The reaction mixture was cooled to room temperature and diluted with ice cold water and stirred for 1 hr. The solid obtained was filtered and dried under vacuum to yield 400 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.84-0.87 (m,2H), 1.02-1.08 (m, 2H), 1.63-1.67 (m, 1H),7.37 (s, 1H), 7.90 (s, 1H), 8.13 (s, 1H), 12.43 (bs, 1H); ESI-MS (m/z) 266.96 (M+H) + Step-5: 8-cyclopropyl-6-vinylquinazolin-4(3H)-one
Figure imgf000070_0003
To a stirred solution of 6-bromo-8-cyclopropylquinazolin-4(3H)-one (200 mg, 0.75 mmol) and potassium vinyl trifluoro borate (303 mg, 2.26 mmol) in a solvent mixture of ethanol, toluene and water (10 mL) was degassed for 15 min. To this reaction mixture were added K3PO4 (640 mg, 3.01 mmol) and Pd(dppf)2Cl2: DCM complex (61 mg, 0.075 mmol) and heated to 110°C for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained product was purified by silica gel column chromatography to yield 100 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 0.77-0.85 (m,2H), 1.02-1.08 (m, 2H), 1.63-1.67 (m, 1H), 5.38 – 5.51 (m, 1H), 6.02 – 6.10 (m, 1H), 6.90 – 7.10 (m, 1H), 7.45 (s, 1H), 7.92 (s, 1H), 8.21 (s, 1H), 12.34 (brs, 1H); ESI-MS (m/z) 213.56 (M+H) + Step-6: 8-Cyclopropyl-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde
Figure imgf000071_0001
To a stirred solution of 8-cyclopropyl-6-vinylquinazolin-4(3H)-one (100 mg, 0.471 mmol) in THF/Water (12 mL/3 mL) was added NaIO4 (211 mg, 0.99 mmol) followed by drop wise addition of OsO4 (2.5 % solution in tBuOH) (23 μL, 0.0062 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with 20% MeOH/DCM. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield 228 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 0.77-0.85 (m, 2H), 1.02-1.08 (m, 2H), 1.63-1.67 (m, 1H), 7.43 (s, 1H), 7.54 (s, 1H), 8.91 (s, 1H), 10.10 (s, 1H), 12.78 (bs, 1H); ESI-MS (m/z) 215.89 (M+H)+ Step-7: (S)-8-cyclopropyl-6-((3-methylpiperidin-1-yl)methyl)quinazolin-4(3H)-one To a stirred solution of 8-cyclopropyl-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde (100 mg, 0.467 mmol) and (3S)-3-methylpiperidine HCl (127 mg, 0.934 mmol) in DCM/MeOH (6 mL, 5:1) was added DIPEA (181 μL, 1.40 mmol) and stirred at room temperature for 2 h. 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.1H NMR (400 MHz, DMSO-d6) δ 0.77- 0.85 (m,2H), 0.82 (d, J = 6.0 Hz, 3H), 1.02-1.08 (m, 2H), 1.51- 1.70 (m, 4H), 1.80- 1.93 (m, 1H), 2.51 – 2.56 (m, 2H), 2.62- 2.75 (m, 2H), 3.64 (s, 2H), 7.62 (s, 1H), 8.24 (s, 1H), 8.28 (s, 1H), 12.6 (brs, 1H); ESI-MS (m/z) 298.33 (M+H)+ EXAMPLES Method-A: Example-1 (S)-3-(3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one
Figure imgf000072_0001
Step-1: 2-Amino-5-bromo-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-3-(trifluoromethyl)benzamide
Figure imgf000072_0002
To a stirred solution of 2-amino-5-bromo-3-(trifluoromethyl)benzoic acid (250 mg, 0.88 mmol) in DMF(5 mL) was added HATU (671 mg, 1.76 mmol) followed by DIPEA (0.35 mL, 2.55 mmol). To this mixture was added 3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)aniline (245 mg, 1.05 mmol) and stirred at room temperature for overnight. The reaction mixture was diluted with water, the solid precipitated was filtered, washed with water and dried under vacuum to yield 230 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 6H), 2.98 (s, 2H), 3.13 (s, 3H), 6.66 (s, 2H), 7.07 (d, J = 8 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.61 (t, J=8.0 Hz, 2H), 7.71 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 8.24 (s, 1H), 10.33 (s, 1H); ESI-MS (m/z) 496.1 (M+H) + Step-2: 6-Bromo-3-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-8- (trifluoromethyl)quinazolin-4(3H)-one
Figure imgf000072_0003
To a stirred solution of 2-amino-5-bromo-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-3-(trifluoromethyl)benzamide (230 mg, 0.46 mmol) in triethylorthoformate (5 mL) was stirred overnight at 120°C. The reaction mixture was concentrated under vacuum. The obtained product was purified by flash column chromatography to yield 130 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 1.45 (s, 6H), 3.00 (s, 2H), 3.10 (s, 3H), 7.42 (m, 3H), 7.54 (s, 1H), 8.27 (s, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.56 (s, 1H); ESI-MS (m/z) 508.1 (M+2H) + Step-3: 3-(3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-8- (trifluoromethyl)-6-vinylquinazolin-4(3H)-one
Figure imgf000073_0001
To a stirred solution of 6-bromo-3-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (130 mg, 0.26 mmol) and potassium vinyl trifluoroborate (105 mg, 0.78 mmol) in a solvent mixture of toluene and water (5 mL, 4:1) and degassed for 15 min. To this reaction mixture K3PO4 (220 mg, 1.04 mmol), Pd(dppf)Cl2.DCM (21 mg, 0.026 mmol) were added and heated to 100°C for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained product was purified by silica gel column chromatography to yield 80 mg of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 1.46 (s, 6H), 2.99 (s, 2H), 3.10 (s, 3H), 5.50 (d, J = 11.0 Hz, 1H), 6.15 (d, J=17 Hz, 1H), 7.02 (t, J = 6 Hz, 1H),7.49 – 7.37 (m, 2H), 7.56 (s, 1H), 8.23 (s, 1H), 8.32 (s, 1H), 8.39 (s, 1H), 8.43 (s, 1H), 8.49 (s, 1H); ESI-MS (m/z) 454.2 (M+H) + Step-4: 3-(3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-4-oxo-8- (trifluoromethyl)-3,4-dihydroquinazoline-6-carbaldehyde
Figure imgf000073_0002
To a stirred solution of 3-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)- 8-(trifluoromethyl)-6-vinylquinazolin-4(3H)-one (80 mg, 0.1762 mmol) in THF/H2O (4:1, 5 mL) were added NaIO4 (76 mg,0.352 mmol) followed by 2.5% OsO4 in t-BuOH (5 μL , 0.0035 mmol). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield 80 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 1.46 (s, 6H), 3.00 (s, 2H), 3.11 (s, 3H), 7.49-7.40 (m, 3H), 7.59 (s, 1H), 8.26 (s, 1H), 8.58 – 8.61 (m, 2H), 8.99 (s, 1H), 10.22 (s, 1H); ESI-MS (m/z) 456.1 (M+H) + Step-5: (S)-3-(3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one To a stirred solution of 3-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)- 4-oxo-8-(trifluoromethyl)-3,4-dihydroquinazoline-6-carbaldehyde (80 mg, 0.17 mmol) and (3S)-3-methylpiperidine HCl (71 mg, 0.52 mmol) in DCM (4 mL) was added DIPEA (89 μL, 0.35mmol) and stirred at room temperature for 2 h. To this reaction mixture was added sodium triacetoxyborohydride (112 mg, 0.528 mmol) and stirred at room temperature for overnight. The reaction mixture was quenched with water and extracted with DCM. The organic layer was concentrated under reduced pressure and the obtained product was purified by flash chromatography to yield 35 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.77 (d, J= 5.2 Hz, 3H), 1.43 (s, 6H), 1.49 – 1.69 (m, 4 H), 1.91 – 1.95 (m, 1H), 2.52- 2.60 (m, 2H), 2.65 – 2.70 (m, 2H), 2.99 (s, 2H), 3.10 (s, 3H), 3.66 (s, 2H), 7.37 – 7.49 (m, 3H), 7.55 (s, 1H), 8.15 (s, 1H), 8.23 (s, 1H), 8.36 (s, 1H), 8.41 (s, 1H); ESI-MS (m/z) 539.3 (M+H)+ The details of synthesis and analytical data of the examples synthesized from the above- mentioned method are given below in Table-6. Table-6: Structure, method, intermediates used, chemical name and analytical data of Examples (2-7)
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0002
Method-B: Example-8 6-((Isobutylamino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one
Figure imgf000077_0001
In a sealed tube, to a stirred solution of 6-((isobutylamino)methyl)-8- (trifluoromethyl)quinazolin-4(3H)-one (intermediate-C2) (800 mg, 2.67 mmol) and 3-((1s,3s)- 1-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (intermediate A3-a) (820 mg, 2.67 mmol) in Dioxane (60 mL) was added K3PO4 (850 mg, 4.005 mmol) and degassed for 15 min. To this mixture CuI (254 mg, 1.335 mmol) and N-N-dimethyl ethylene diamine (118 mg, 1.335 mmol) were added under nitrogen atmosphere and heated to 140o C for 16 h. The reaction mixture was diluted with water and extracted twice with 20% DCM/MeOH. The organic layer was washed with aqueous ammonium chloride and ammonia solution and separated and then dried over anhydrous sodium sulphate. The organic layer was filtered, concentrated and the obtained product was purified by flash-column chromatography to yield 402 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.87 (d, J = 6.8 Hz, 6H), 1.08 (d, J =4.8Hz, 3H), 1.55- 1.75 (m, 1H), 2.29 ( d, J = 6.8 Hz, 2H), 2.40 - 2.65 (m, 3H), 2.75- 2.95 (m, 2H), 3.23 (s, 3H), 3.90 (s, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H), 7.68 (s, 1H), 8.23 (s, 1H), 8.31 (s, 1H), 8.41 (s, 1H), 8.51 (s, 1H); ESI-MS (m/z) 525.2 (M+H)+ The details of synthesis and analytical data of the examples synthesized from the above- mentioned methods are given below in Table-7. The racemic compounds were synthesized by above methods and purified by SFC using co-solvent 0.1% NH3 in MeOH to yield corresponding chiral isomers (Example 15 & 16, 36 & 37 and 39 & 40). Table-7: Structure, method, intermediates used, chemical name and analytical data of Examples (9-54)
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
PHARMACOLOGICAL ACTIVITY Cbl-b phosphorylation inhibition assay: The assay measures ability of test compounds to inhibit SRC kinase-mediated phosphorylation of a truncated version of His-tagged Cbl-b protein containing residues 36-427. This TR-FRET assay is performed in a 384 well plate at room temperature in a 10µl reaction volume with buffer containing 50mM HEPES pH 7.5, 5mM mgCl2, 1mM DTT, 0.1mg/ml BSA. Candidate compounds (1% DMSO final) were preincubated with 30nM Cbl-b (Accession number NP_733762.2) for one hour followed by an additional one hour in the presence of 30nM of GST-tagged SRC kinase (Accession number NP_005408.1) with 100µM ATP (final concentrations). Following, incubation, 10ul of a mixture containing 3.75nM Anti-His XL665 antibody (CisBio) and 1:200 TK-Cryptate Antibody (CisBio HTRF TK kit) prepared in detection buffer, was added to the reaction. The plate was incubated for one hour at room temperature followed by overnight in cold and fluorescence signal was measured with excitation of 337nm and dual emission of 665 and 620nm on Artemis HRTF reader. Signal was expressed as HTRF ratio (fluorescence intensity @665nm/fluorescence intensity @620nm x 10000). The resulting data were analysed and IC50 values were determined using nonlinear regression analysis, variable slope fitting (GraphPad Prism version 8.4.3). The IC50 (nM) values of some of the compounds are set forth in Table-8 wherein “A” refers to an IC50 value of less than 100 nM, “B” refers to IC50 value in range of 100.01 to 500.0 nM, “C” refers to IC50 value in range of 500.01 to 1000.0 nM and “D” refers to IC50 values more than 1000 nM. Table-8:
Figure imgf000098_0001
Figure imgf000099_0001
ND: not determined

Claims

WHAT IS CLAIMED IS: 1. A compound of formula (I)
Figure imgf000100_0001
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X1’ is CH or N; ‘X2’ is CH or N; ‘X3’ is N, S or O; R1 is –(CHR8)l-NR9R10; at each occurrence, R1a is independently selected from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; at each occurrence, R2 is selected independently from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; R3 is halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R4 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R5 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy; C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl; wherein 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1- 8alkyl; R6 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; or R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6- 14aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; R7 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R8 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R9 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R10 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl, –CH2CH2Si(CH3)3, C3- 8cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; or R9 and R10 joined together with the nitrogen atom to which they are attached, form a C6- 14 aryl, 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and C1-8alkyl; ‘n’ is an integer ranging from 0 to 4, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘p’ is an integer ranging from 0 to 1, both inclusive; and ‘l’ is an integer ranging from 0 to 4, both inclusive.
2. The compound of claim 1, having represented by formula (IA) R6 R5 R7 R4 R1 p O (R2 N )m (R1a)n N N N R3 X2 X3 (IA) or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X2’ is CH or N; ‘X3’ is N, S or O; R1 is –(CHR8)l-NR9R10; at each occurrence, R1a is independently selected from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; at each occurrence, R2 is selected independently from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; R3 is halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R4 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R5 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy; C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl; wherein 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1- 8alkyl; R6 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; or R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6- 14aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; R7 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R8 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R9 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R10 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl, –CH2CH2Si(CH3)3, C3- 8cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; or R9 and R10 joined together with the nitrogen atom to which they are attached, form a C6- 14 aryl, 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and C1-8alkyl; ‘n’ is an integer ranging from 0 to 4, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘p’ is an integer ranging from 0 to 1, both inclusive; and ‘l’ is an integer ranging from 0 to 4, both inclusive. 3. The compound of claim 1, having represented by formula (IB)
Figure imgf000103_0001
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, ‘X2’ is CH or N; R1 is –(CHR8)l-NR9R10; at each occurrence, R1a is independently selected from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; at each occurrence, R2 is selected independently from halogen, cyano, hydroxyl, C1- 8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; R3 is halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R4 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R5 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy; C1-8alkoxyC1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl; wherein 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1- 8alkyl; R6 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; or R5 and R6 joined together with the carbon atom to which they are attached, form a C6-14 aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6- 14aryl, 3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; R7 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R8 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R9 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1-8alkoxyC1-8alkyl; R10 is selected from hydrogen, halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy, C1-8alkoxyC1-8alkyl, –CH2CH2Si(CH3)3, C3- 8cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C3-8cycloalkyl and C3-8cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, C1-8alkyl, cyanoC1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkoxy and C1- 8alkoxyC1-8alkyl; or R9 and R10 joined together with the nitrogen atom to which they are attached, form a C6- 14 aryl, 3-15 membered heterocyclyl, 3-15 membered spirocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl; wherein C6-14 aryl,
3-15 membered heterocyclyl, 5-14 membered heteroaryl and C3-12cycloalkyl are optionally substituted with one or more substituents selected from halogen, hydroxyl and C1-8alkyl; ‘n’ is an integer ranging from 0 to 4, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘p’ is an integer ranging from 0 to 1, both inclusive; and ‘l’ is an integer ranging from 0 to 4, both inclusive.
4. The compound according to any one of claims 1 to 3, wherein R1a is fluoro, trifluoromethyl or cyclopropyl and ‘n’ is 1.
5. The compound according to any one of claims 1 to 4, wherein R1 is
Figure imgf000105_0001
, , ,
Figure imgf000105_0002
6. The compound according to any one of claims 1 to 5, wherein X1 is CH or N.
7. The compound according to any one of claims 1 to 6, wherein X2 is CH or N.
8. The compound according to any one of claims 1 to 7, wherein X3 is N.
9. The compound according to any one of claims 1 to 8, wherein R2 is fluoro or cyclopropyl and ‘m’ is 1.
10. The compound according to any one of claims 1 to 9, wherein R3 is CH3.
11. The compound according to any one of claims 1 to 10, wherein R4 is hydrogen or CH3.
12. The compound according to any one of claims 1 to 11, wherein R5 is CH3 or cyclopropyl.
13. The compound according to any one of claims 1 to 12, wherein R4 and R5 independently is CH3.
14. The compound according to any one of claims 1 to 13, wherein R4 is hydrogen and R5 is cyclopropyl.
15. The compound according to any one of claims 1 to 14, wherein R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000106_0001
Figure imgf000106_0002
16. The compound according to any one of claims 1 to 15, wherein R6 is hydrogen.
17. The compound according to any one of claims 1 to 16, wherein R5 and R6 joined together with the carbon atom to which they are attached, form a 4-fluorophenyl or 4-cyanophenyl.
18. The compound according to any one of claims 1 to 17, wherein R7 is hydrogen.
19. The compound according to any one of claims 1 to 18, wherein ‘p’ is 0 or 1.
20. The compound according to claim 1, wherein R1a is fluoro, trifluoromethyl or cyclopropyl;
Figure imgf000107_0001
X1 is CH or N; X2 is CH or N; X3 is N; R2 is fluoro or cyclopropyl; R3 is CH3; R4 is hydrogen or CH3; R5 is CH3 or cyclopropyl; or R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000107_0002
Figure imgf000107_0003
R6 is hydrogen; or R5 and R6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl; R7 is hydrogen; ‘n’ is 1; ‘m’ is 0 or 1 and ‘p’ is 0 or 1.
21. The compound according to any one of claims 1 to 3, wherein R1a is fluoro, trifluoromethyl or cyclopropyl;
Figure imgf000108_0001
X1 is CH; X2 is CH or N; X3 is N; R2 is fluoro or cyclopropyl; R3 is CH3; R4 is hydrogen or CH3; R5 is CH3 or cyclopropyl; or R4 and R5 joined together with the carbon atom to which they are attached, form
Figure imgf000108_0002
Figure imgf000108_0003
R6 is hydrogen; or R5 and R6 joined together with the carbon atom to which they are attached, form a 4- fluorophenyl or 4-cyanophenyl; R7 is hydrogen; ‘n’ is 1; ‘m’ is 0 or 1 and ‘p’ is 0 or 1.
22. A compound selected from: (S)-3-(3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-1); 3-(3-((1s,3R)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)- 3-methyl piperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-2); 3-(3-((1s,3S)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((R)- 2-methylmorpholino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-3); 6-((4,4-Dimethyl-1,4-azasilinan-1-yl)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-4); 3-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-5); 6-(((Cyclopropylmethyl)amino)methyl)-3-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol- 3-yl)spiro[3.3]heptan-2-yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-6); 6-(((Cyclopropylmethyl)amino)methyl)-3-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example- 7); 6-((Isobutylamino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-8); (S)-3-(3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-9); (S)-3-(3-(1-(4-Methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-10); (S)-3-(3-(5-(4-Methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-11); (S)-3-(3-(2-(4-Methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-12); 6-(((2-Ethylbutyl)amino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-13); 3-(3-((1s,3s)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-8- (trifluoromethyl)-6-(((2-(trimethylsilyl)ethyl)amino)methyl)quinazolin-4(3H)-one (Example- 14); 6-((4,4-Difluoro-3-methylpiperidin-1-yl)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Isomer-1) (Example-15); 6-((4,4-Difluoro-3-methylpiperidin-1-yl)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Isomer-2) (Example-16); (S)-3-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-17); (((S)-3-methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-18); 6-((Isopentylamino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-19); 6-((Isobutylamino)methyl)-3-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5- yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-20); 6-((4,4-Difluoropiperidin-1-yl)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-21); 3-(3-(3,3-Difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- ((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-22); 3-(3-((1s,3S)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((R)- 3-methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-23); 3-(3-((1s,3s)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1- methylcyclobutyl)amino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-24); 6-((Isobutylamino)methyl)-3-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan- 2-yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-25); (S)-3-(3-(3,3-Difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3- methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-26); 3-(3-((1s,3s)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1- methylcyclopropyl)amino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-27); 3-(3-Fluoro-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin- 4(3H)-one (Example-28); 6-((Isobutylamino)methyl)-3-(3-((1r,3r)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-29); 3-(3-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-30); 3-(3-(3,3-Difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((2- ethylbutyl)amino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-31); 6-(((2-Ethylbutyl)amino)methyl)-3-(3-(5-(4-methyl-4H-1,2,4-triazol-3- yl)spiro[2.3]hexan-5-yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-32); 6-((Isobutylamino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)quinazolin-4(3H)-one (Example-33); 8-Fluoro-6-((isobutylamino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)quinazolin-4(3H)-one (Example-34); 3-(3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- ((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-35); 3-(3-((1s,3R)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- ((((S)-2-methylbutyl)amino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Isomer-1) (Example-36); 3-(3-((1s,3S)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- ((((R)-2-methylbutyl)amino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Isomer-2) (Example-37); 8-Cyclopropyl-3-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)quinazolin-4(3H)-one (Example-38); 3-(3-(Cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6- ((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Isomer-1) (Example-39); 3-(3-(Cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-6- ((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Isomer-2) (Example-40); 3-(4-Fluoro-3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-41); 3-(3-((1s,3s)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- ((neopentylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-42); 6-(((2-Fluoro-2-methylpropyl)amino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-43); 6-((Cyclopropylmethyl)amino)methyl)-3-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example44-); 6-(((Cyclopropylmethyl)amino)methyl)-3-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-45); 6-((((1-(Fluoromethyl)cyclopropyl)methyl)amino)methyl)-3-(3-((1s,3s)-3-methyl-1- (4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-46); 6-(((Cyclopropylmethyl)amino)methyl)-3-(3-(6,6-dimethyl-2-(4-methyl-4H-1,2,4- triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-47); 3-(4'-Fluoro-2'-(4-methyl-4H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-3-yl)-6- ((isobutylamino)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-48); (S)-4-(2-Cyclopropyl-6-(6-((3-methylpiperidin-1-yl)methyl)-4-oxo-8- (trifluoromethyl)quinazolin-3(4H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3- yl)benzonitrile (Example-49); 4-(2-Cyclopropyl-6-(6-((isobutylamino)methyl)-4-oxo-8-(trifluoromethyl)quinazolin- (4H)-yl)pyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile (Example-50); (S)-3-(6-Cyclopropyl-4-(4-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2- yl)-6-((3-methylpiperidin-1-yl)methyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example- 51); 6-(((Cyclopropylmethyl)amino)methyl)-3-(3-(2-(4-methyl-4H-1,2,4-triazol-3- yl)spiro[3.3]heptan-2-yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-52); 6-(((Cyclopropylmethyl)amino)methyl)-3-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-53) or 6-(((Cyclopropylmethyl)amino)methyl)-3-(3-(6-methyl-2-(4-methyl-4H-1,2,4-triazol- 3-yl)spiro[3.3]heptan-2-yl)phenyl)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example-54) and pharmaceutically acceptable salt thereof.
23. A compound of formula
Figure imgf000112_0001
or a pharmaceutically acceptable salt thereof.
24. A compound of formula N N NH O N N N CF3 or a pharmaceutically acceptable salt thereof.
25. A compound of formula
Figure imgf000113_0001
or a pharmaceutically acceptable salt thereof.
26. A compound of formula
Figure imgf000113_0002
or a pharmaceutically acceptable salt thereof.
27. A compound of formula
Figure imgf000113_0003
or a pharmaceutically acceptable salt thereof.
28. A compound of formula
Figure imgf000113_0004
or a pharmaceutically acceptable salt thereof.
29. A compound of formula F N O N N N N N N CF3 or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 and a pharmaceutically acceptable excipient.
31. The pharmaceutical composition according to claim 30, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
32. A method of treating or preventing from a CBL-b mediated disease, disorder, or condition in a subject comprising administering the subject in need thereof an effective amount of a compound according to any one of claims 1 to 29.
33. The method according to claim 32, wherein the disease, disorder, or condition is cancer.
PCT/IB2023/059221 2022-09-21 2023-09-18 Bicyclic heterocyclic compounds as cbl-b inhibitors WO2024062363A1 (en)

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WO2020264398A1 (en) * 2019-06-26 2020-12-30 Nurix Therapeutics, Inc. Substituted benzyl-triazole compounds for cbl-b inhibition, and further uses thereof
WO2021021761A1 (en) * 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Urea, amide, and substituted heteroaryl compounds for cbl-b inhibition
WO2021061853A1 (en) * 2019-09-24 2021-04-01 Nurix Therapeutics, Inc. Cbl inhibitors and compositions for use in adoptive cell therapy
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WO2020236654A1 (en) * 2019-05-17 2020-11-26 Nurix Therapeutics, Inc. Cyano cyclobutyl compounds for cbl-b inhibition and uses thereof
WO2020264398A1 (en) * 2019-06-26 2020-12-30 Nurix Therapeutics, Inc. Substituted benzyl-triazole compounds for cbl-b inhibition, and further uses thereof
WO2021021761A1 (en) * 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Urea, amide, and substituted heteroaryl compounds for cbl-b inhibition
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