WO2024038378A1 - Substituted pyridinone compounds as cbl-b inhibitors - Google Patents

Substituted pyridinone compounds as cbl-b inhibitors Download PDF

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WO2024038378A1
WO2024038378A1 PCT/IB2023/058197 IB2023058197W WO2024038378A1 WO 2024038378 A1 WO2024038378 A1 WO 2024038378A1 IB 2023058197 W IB2023058197 W IB 2023058197W WO 2024038378 A1 WO2024038378 A1 WO 2024038378A1
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methyl
oxo
dihydropyridine
triazol
carboxamide
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PCT/IB2023/058197
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French (fr)
Inventor
Murugan CHINNAPATTU
Sachin Chaudhari
Nagaraj GOWDA
Sanjib Das
Pravin Iyer
Nayan WAGHMARE
Sandeep Shelke
Balasaheb GAVHANE
Jagmohan SAINI
Sheetal Kadam
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Glenmark Pharmaceuticals Ltd
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Publication of WO2024038378A1 publication Critical patent/WO2024038378A1/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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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.
  • Z is CH or N;
  • X is CH or N;
  • ring A is 5-14 membered heteroaryl; at each occurrence, R 3 is C 1-8 alkyl;
  • R 4 is selected from hydrogen and C 1-8 alkyl;
  • R 5 is selected from C 1-8 alkyl and C 3-12 cycloalkyl; or R 4 and R 5 joined together with the carbon atom to which they are attached, form a 3-15 membered heterocyclyl, C 3-12 cycloalkyl and 3-15 membered spirocyclyl wherein 3-15 membered heterocyclyl, C 3-12 cycloalkyl and 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen and C 1-8 alkyl; ‘Y’
  • the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (I) as described herein and a pharmaceutically acceptable excipient.
  • the present invention provides a method for treating a disease or disorder mediated by CBL-B in a subject comprising administering the subject in need thereof a compound represented by formula (I), (IA), (IB) or (IC) or a stereoisomer or a pharmaceutically acceptable salt thereof as described herein.
  • 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.
  • the invention provides compounds of formula (I) as defined above wherein ‘Z’ is CH or N (according to an embodiment defined below), ‘n’ is 1 according to another embodiment defined below) and ‘X’ is CH or N (according to yet another embodiment defined below).
  • compounds of formula (I) in which ‘Z’ is CH or N.
  • compounds of formula (I), in which ‘Z’ is CH in which ‘Z’ is CH.
  • compounds of formula (I), in which ‘Z’ is N.
  • R 1 is -[CHR] l -NR 6 R 7 , wherein R, l, R 6 and R 7 are as defined in formula (I).
  • R 1 is 3-15 membered heterocyclylC1-8alkyl (e.g. , and 5-14 membered heteroarylC 1-8 alkyl (e.g. ); wherein 3-15 membered heterocyclylC 1-8 alkyl and 5-14 membered heteroarylC 1-8 alkyl are optionally substituted with one or more substituents selected from halogen (e.g.
  • R 1 is a 3-15 membered heterocyclylC 1-8 alkyl (e.g. , ) or 5-14 membered heteroarylC 1-8 alkyl (e.g.
  • R is hydrogen or C 1-8 alkyl
  • R 6 is hydrogen or C 1-8 alkyl
  • C 3-12 cycloalkyl and C 3-12 cycloalkylC 1-8 alkyl are substituted or unsubstituted with one or more substituents selected from C 1-8 alkyl and haloC 1-8 alkyl and ‘l’ is 1.
  • R 1 is -[CHR] l -NR 6 R 7 .
  • R is hydrogen or C 1-8 alkyl (e.g. methyl);
  • R 6 is hydrogen or C 1-8 alkyl (e.g. methyl);
  • R 7 is C 1-8 alkyl (e.g. ethyl, isobutyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl or 3-methylbutan-2-yl), haloC 1-8 alkyl (e.g.
  • cyclopropyl or cyclobutyl or C 3- 12 cycloalkylC 1-8 alkyl (e.g. methylcycloproyl); wherein the C 3-12 cycloalkyl and C 3- 12 cycloalkylC 1-8 alkyl are optionally substituted with one or more substituents selected from C 1- 8 alkyl (e.g. methyl) or haloC 1-8 alkyl (e.g. fluoromethyl) and ‘l’ is 1.
  • R 1 is -[CHR] l -NR 6 R 7 .
  • R is hydrogen or methyl
  • R 6 is hydrogen or methyl
  • specifically provided are compounds of formula , According to yet another embodiment, specifically provided are compounds of formula According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘n’ is 1. According to yet another embodiment, specifically provided are compounds of formula According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘X’ is CH or N. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘X’ is CH. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘X’ is N. According to yet another embodiment, specifically provided are compounds of formula (I), in which R 2 is halogen (e.g. chloro or fluoro), –NHC(O)CH 3 or –NHC(O)CH CH 2 .
  • R 2 is halogen (e.g. chloro or fluoro)
  • specifically provided are compounds of formula (I), in which R 2 is chloro, fluoro, –NHC(O)CH 3 or –NHC(O)CH CH 2 .
  • compounds of formula (I), in which R 2 is chloro, fluoro, –NHC(O)CH 3 or –NHC(O)CH CH 2 and ‘m’ is 0 or 1.
  • R 4 and R 5 joined together with the carbon atom to which they are attached, form a O C 3-12 cycloalkyl (e.g. ), 3-15 membered heterocyclyl (e.g. ), or 3-15 membered spirocyclyl (e.g. ), wherein C 3-12 cycloalkyl or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro, methyl or ethyl.
  • R 4 and R 5 joined together with the carbon atom to which they are attached, form a O C 3-12 cycloalkyl (e.g. ), 3-15 membered heterocyclyl (e.g. ), or 3-15 membered spirocyclyl (e.g. ), wherein C 3-12 cycloalkyl or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro, methyl or ethyl.
  • R 11 is C 1-8 alkyl, haloC 1-8 alkyl, C 6-14 aryl , C 6-14 arylC 1-8 alkyl-, 3-15 membered heterocyclylC 1-8 alkyl, C 3-12 cycloalkyl and C 3-8 cycloalkylC 1-8 alkyl; wherein the C 6-14 aryl and C 6-14 arylC 1-8 alkyl are substituted or unsubstituted with one or more substituents selected from halogen.
  • R 11 is C 1-8 alkyl (e.g. methyl or ethyl).
  • R 11 is C 3-8 cycloalkylC 1-8 alkyl (e.g. cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl).
  • compounds of formula (I) in which R 11 is cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl.
  • compounds of formula O (I) in which R 11 is 3-15 membered heterocyclylC 1-8 alkyl (e.g. ).
  • R 11 is C 6-14 aryl (e.g. phenyl); wherein the C 6-14 aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro).
  • R 11 is C 6-14 aryl (e.g. phenyl); wherein the C 6-14 aryl is optionally substituted with one or more substituents selected from fluoro.
  • halogen e.g. fluoro
  • R 3 is methyl
  • Y is absent or CH 2
  • R 4 is hydrogen or CH 3
  • R 5 is CH 3 or cyclobutyl
  • R 4 and R 5 joined together with the carbon atom to which they are attached, form a R 10 is hydrogen or methyl
  • R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl
  • ‘l’ is 1
  • ‘n’ is 1
  • ‘m’ is 0 or 1
  • ‘r’ is 1.
  • R 10 is hydrogen or methyl
  • R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl
  • ‘l’ is 1
  • ‘n’ is 1
  • ‘m’ is 0 or 1
  • ‘r’ is 1.
  • R 10 is hydrogen or methyl
  • R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl
  • ‘l’ is 1
  • ‘n’ is 1
  • ‘m’ is 0 or 1
  • ‘r’ is 1.
  • R 10 is hydrogen or methyl
  • R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or ‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1.
  • compounds of formula (I) with an IC 50 value of less than 10000 nM, preferably, less than 1000 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 1000 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity.
  • Further embodiments relating to groups ring A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , n, m and r (and groups defined therein) are described hereinafter in relation to the compounds of formula (IA), (IB) or (IC). It is to be understood that these embodiments are not limited to use in conjunction with formula (IA), (IB) or (IC), 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) or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 1, R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , ring A, Y, X, n, m and r are as defined in formula (I).
  • the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IA) as described herein and a pharmaceutically acceptable excipient.
  • the present invention provides a method for treating a disease or disorder mediated by CBL-B comprising administering a compound represented by formula (IA) as described herein.
  • the invention also provides a compound of formula (IB) which is an embodiment of a compound of formula (I). or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 1, R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , ring A, Y, n, m and r are as defined in formula (I).
  • the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IB) as described herein and a pharmaceutically acceptable excipient.
  • the present invention provides a method for treating a disease or disorder mediated by CBL-B comprising administering a compound represented by formula (IB) as described herein.
  • the invention also provides a compound of formula (IC) which is an embodiment of a compound of formula (I). or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 1, R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , Y, n, m and r are as defined in formula (I).
  • the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IC) as described herein and a pharmaceutically acceptable excipient.
  • the present invention provides a method for treating a disease or disorder mediated by CBL-B comprising administering a compound represented by formula (IC) as described herein.
  • IC formula
  • the formulas (I), (IA), (IB) and (IC) 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), 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).
  • 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. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
  • 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 1-4 alkyl refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms.
  • haloalkyl groups described herein may be straight chain or branched.
  • 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. hydroxyC 1- 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).
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. C 1-8 alkoxyC 1-8 alkyl or C 1-8 alkyloxyC 1-8 alkyl).
  • alkoxyalkyl moiety includes, but are not limited to, - CH 2 OCH 3 (methoxymethyl) and -CH 2 OC 2 H 5 (ethoxymethyl).
  • alkoxyalkyl groups described herein may be straight chain or branched.
  • 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).
  • 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).
  • Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • the term “C 3-6 cycloalkyl” refers to the cyclic ring having 3 to 6 carbon atoms.
  • C 3- 6 cycloalkyl examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • 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.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • 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.
  • arylalkyl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6- 14 aryl) directly attached to an alkyl group (i.e. C 6-14 arylC 1-8 alkyl). The arylalkyl 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.
  • 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
  • heteroarylalkyl refers to a heteraryl ring radical directly bonded to an alkyl group (i.e. heteroarylC1-8alkyl).
  • the heteroaryllalkyl 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.
  • pharmaceutically acceptable salt includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids.
  • 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, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,
  • salts derived from inorganic bases include, but are not limited to, aluminum, 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.
  • 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), (IB) and (IC) 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), compound of formula (IC) 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), (IB), (IC) 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.
  • the esterification of compound of formula (1) yields ester compound of formula (2) [wherein R’ is C 1-8 alkyl].
  • the reaction is carried out in a suitable solvent.
  • the suitable solvent used in the reaction may be methanol.
  • the selective N-Alkylation of compound of formula (2) with suitable alkylating agents in the presence of suitable base and solvents yields the compound of formula (3).
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from cesium carbonate, potassium carbonate, sodium carbonate, sodium hydride, etc.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from DMSO, DMF and THF.
  • the Suzuki coupling reaction of compound of formula (3) using potassium vinyl trifluoroborate in the presence of suitable base, catalyst and solvent gives the compound of formula (4).
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate or cesium carbonate.
  • the reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be selected from tetrakis(triphenylphosphine)palladium(0), 1,1′-bis(diphenylphosphino)ferrocene]dichloropall adium(II) complex with dichloromethane, along with a suitable phosphine ligand, etc.
  • the coupling 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 (4) upon oxidative cleavage using osmium tetra oxide and sodium periodate in a suitable mixture of solvent gives aldehyde compound of formula (5).
  • the reaction is carried out in presence of suitable mixture of solvents.
  • the suitable mixture of solvent may be selected from mixture of THF / water and t-BuOH.
  • the reductive amination reaction of compound of formula (5) with appropriate amines of formula (6) using suitable reducing agent in the presence of suitable catalyst gives compound of formula (7).
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, dichloroethane, dimethylformamide, methanol, ethanol.
  • the reaction is carried out in presence of suitable reducing agent.
  • the suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.
  • the reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be acetic acid.
  • the hydrolysis of compound of formula (7) gives the compound of formula (8).
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the reaction is carried out in a suitable solvent.
  • the suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof.
  • the acid-amine coupling reaction of compound (8) with appropriate aromatic amines compound of formula (9) gives the compound of general formula (IA-1).
  • the reaction is 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 is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from DIPEA or TEA.
  • the suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof.
  • the acid-amine coupling reaction of compound (10) with appropriate aromatic amines of compound of formula (9) gives the compound of formula (11).
  • the reaction is carried out in a presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide.
  • the reaction is carried out in a presence of suitable base.
  • the suitable base used in the reaction may be selected from DIPEA or TEA.
  • the reaction is carried out in a 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 Suzuki coupling reaction of compound of formula (11) and potassium vinyl trifluoroborate gives the compound of formula (12).
  • the reaction is carried out in a presence of suitable base.
  • the suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate or cesium carbonate.
  • the reaction is carried out in a presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be selected from 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 may be selected from ethanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof.
  • the reaction is carried out in presence of suitable solvent or mixture thereof.
  • the suitable solvent used in the reaction may be THF / water.
  • the reductive amination reaction of compound of formula (13) with appropriate amines compound of formula (6) gives compound of general formula (IA-2).
  • the reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be acetic acid.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from TEA and DIPEA.
  • the reaction may be carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, dimethylformamide, methanol and ethanol.
  • the reaction is carried out in presence of suitable reducing agent.
  • the suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.
  • the reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be selected from 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 presence of 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 hydrolysis reaction of compound of formula (4) in the presence of a suitable base and solvent gives the compound of formula (14).
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof.
  • the acid-amine coupling reaction of compound (14) with appropriate aromatic amines compound of formula (9) gives the compound of formula (15).
  • the reaction is 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 is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from DIPEA or TEA.
  • the compound of formula (15) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (16).
  • the reaction is carried out in presence of suitable solvent or mixture thereof.
  • the suitable solvent used in the reaction may be THF / water.
  • the reductive amination reaction of compound of formula (16) with appropriate amines (6) yields compound of formula (IA-3).
  • the reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be acetic acid.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from triethylamine or DIPEA.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane, dimethylformamide, methanol and ethanol.
  • the reaction is carried out in presence of a suitable reducing agent.
  • the suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the treatment of compound of formula (IA-3) with suitable inorganic acid in appropriate solvent gives compound of formula (IA-4).
  • the reaction is carried out in presence of suitable inorganic acid.
  • the suitable inorganic acid used in the reaction may be selected from hydrochloric acid or TFA.
  • the reaction is carried out in presence of suitable solvent.
  • suitable solvent used in the reaction may be selected from dichloromethane, dichloroethane or THF.
  • a general approach for the preparation of compounds of the general formula (IA-5, IA- 6 and IA-7) (wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 4.
  • Synthetic scheme-4 The Stille coupling reaction of compound of formula (3) and tributyl(1-ethoxyvinyl)tin gives the compound of formula (17). The reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be selected from tetrakis(triphenyl phosphine) palladium(0), dichlorobis(triphenyl phosphine)palladium(II), palladium acetate, along with a suitable phosphine ligand, etc.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from, 1,4-dioxane, DMSO or DMF.
  • the hydrolysis reaction of compound of formula (17) gives the compound of formula (18).
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof.
  • the acid-amine coupling reaction of compound (18) with appropriate aromatic amines compounds of formula (9) gives the compound of formula (19).
  • the reaction is 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 is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from DIPEA or TEA.
  • the reductive amination reaction of compound of formula (19) with appropriate amines compound of formula (6) yields compound of formula (IA-5).
  • the reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction may be acetic acid.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from triethylamine or DIPEA.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane, dimethylformamide, methanol and ethanol.
  • the reaction is carried out in presence of a suitable reducing agent.
  • the suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the suitable coupling reagents used in the reaction may be selected from HATU, EDC.HCl, HOBt, DCC or T 3 P.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from DIPEA or TEA.
  • the compound of formula (21) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (22).
  • the reaction is carried out in presence of suitable solvent or mixture thereof.
  • the suitable solvent used in the reaction may be THF / water.
  • the reductive amination reaction of compound of formula (22) with appropriate amines compound of formula (6) yields compound of formula (23).
  • the reaction is carried out in presence of suitable catalyst.
  • the suitable catalyst used in the reaction id acetic acid.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from triethylamine or DIPEA.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected form dichloromethane, dimethylformamide, methanol and ethanol.
  • the reaction is carried out in presence of a suitable reducing agent.
  • the suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.
  • the compound of formula (23) on deprotection yields the compound of formula (IA-8).
  • the reaction may be carried in presence of suitable acids.
  • the suitable acids used in the reaction may be selected from hydrochloric acid and trifluoroacetic acid.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from methanol, ethanol, dichloroethane and 1,4- dioxane.
  • a general approach for the preparation of compounds of the general formula (IA-9) (wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 6. Synthetic scheme-6:
  • the compound of formula (4) [wherein R’ is C 1-8 alkyl] upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (5).
  • the reaction is carried out in presence of suitable solvent or mixture thereof.
  • the suitable solvent used in the reaction may be THF / water.
  • the reductive amination reaction of compound of formula (5) with appropriate amines compound of formula (24) yields compound of formula (26).
  • the reaction is carried out in 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 reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloro methane, dimethylformamide, methanol and ethanol.
  • the amine compound of formula (25) upon N-protection using suitable protecting group (PG) yields the compound of formula (26).
  • the reaction is carried out in presence of suitable protecting group.
  • the suitable protecting group used in the reaction may be selected from di- tert-butyl dicarbonate, acetic anhydride and benzylchloroformate.
  • the hydrolysis reaction of compound of formula (26) yields the compound of formula (27).
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from methanol, ethanol and tetrahydrofuran or combination thereof.
  • the acid-amine coupling reaction of compound of formula (27) with appropriate aromatic amine compound of formula (28) gives the compound of formula (29).
  • the reaction is 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 is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide.
  • the reaction is carried out in presence of suitable base.
  • the suitable base used in the reaction may be selected from DIPEA or TEA.
  • the acylation reaction of compound of formula (29) yields the compound of formula (30).
  • the reaction is carried out in presence of suitable acylating reagents.
  • the suitable acylating reagents used in the reaction may be acetic anhydride or acryloyl chloride.
  • the compound of formula (30) on deprotection yields the compound of formula (IA-9).
  • the reaction is carried out in presence of suitable acid.
  • the suitable acid used in the reaction may be selected from hydrochloric acid and trifluoroacetic acid.
  • the reaction is carried out in presence of suitable solvent.
  • the suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane and 1,4- dioxane.
  • EXPERIMENTAL SECTION includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulfate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • Step-2 2-(3-(3-Bromophenyl)-3-methylbutanoyl)-N-methylhydrazine carbothioamide H H O Br
  • 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-methylhydrazine carbothioamide 4.8 g, 0.0139 mol
  • 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.
  • reaction mixture was diluted with water and extracted thrice with ethyl acetate.
  • the organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the residue obtained was purified by flash chromatography to get 1.5 g of 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 residue was dissolved in ethyl acetate.
  • the organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate.
  • the solvent was evaporated under reduced pressure to yield 1.4 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 1.5 aqueous KOH (6 mL) dropwise 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 twice with ethyl acetate and dried over sodium sulphate.
  • the organic layer was concentrated to yield 140 mg of the desired product.
  • reaction mixture was quenched with saturated solution of NaHCO 3 and extracted thrice with ethyl acetate.
  • the organic layer was dried over sodium sulphate and concentrated.
  • the residue obtained 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, 53.826 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-5 1-(3-Bromophenyl)-3-methylcyclobutanecarbohydrazide
  • 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 residue was dissolved with ethyl acetate.
  • the organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate.
  • 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 and quenched with water and extracted twice 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 RT 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 twice with petroleum ether.
  • the organic layer was separated, dried over anhydrous Na 2 SO4 and concentrated.
  • the residue obtained was purified by silica gel column chromatography to yield 700 mg of the desired product.
  • Step-4 1-(3-Bromophenyl)-3,3-dimethylcyclobutane-1-carboxylic acid H OOC Br
  • 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonitrile 700 mg, 2.66 mmol
  • conc. H 2 SO 4 2.1 mL
  • the reaction mixture was cooled to room temperature, quenched with water and extracted twice with ethyl acetate.
  • reaction mixture was stirred at room temperature for 16 h.
  • the reaction mixture was quenched with water and extracted twice 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.
  • reaction mixture was quenched with water and ethyl acetate, filtered and filtrate obtained was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulphate and solvent was evaporated under reduced pressure and the solid obtained was purified by silica gel column chromatography to yield 410 mg of the desired product.
  • the reaction mixture was stirred at 0°C for 30min, followed by slow 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 twice with ethyl acetate.
  • the organic layer was separated, dried over anhydrous Na 2 SO4 and concentrated.
  • the residue obtained was purified by silica gel column chromatography to yield 2.4 g of the desired product.
  • Step-4 1-(3-Bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid
  • acetic acid 4.0 ml
  • water 4.0ml
  • conc H 2 SO 4 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.
  • the reaction mixture was stirred at room temperature for 1h.
  • the N,O-Dimethylhydroxylamine / was added and stirred at room temperature for 16 h.
  • the reaction mixture was quenched with water (50 ml) and extracted with DCM (3 x 100 ml).
  • the organic layer dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to obtain product.
  • the obtained product was purified by combiflash chromatography to afford 3.1 g of the title compound.
  • Step-2 1-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)propan-1-one
  • ethyl magnesium bromide 6.4 g, 48.05 mmol
  • Step-3 1-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)-2-hydroxypropan-1-one
  • 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propan-1-one 2.0 g, 7.09 mmol
  • NaHMDS 1.95 g, 10.64 mmol, 1.0 M in THF
  • Step-5 4-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-imidazole
  • 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propane-1,2-dione 1.1 g, 3.72 mmol
  • paraformaldehyde 0.12 g, 4.09 mmol
  • ammonium acetate 2.87 g, 37.26 mmol
  • reaction mixture was degassed for 15 min using nitrogen gas. Palladium acetate (0.049 g, 0.21mmol) was added and reaction mixture was heated at 80 °C in a sealed tube for 16h. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated and the crude compound was purified by combiflash chromatography to afford 1.1 g of the title compound.
  • reaction mixture was stirred at -78 o C for 4 h.
  • the reaction mixture was quenched with saturated solution of ammonium chloride, filtered and washed with ethyl acetate.
  • the filtrate obtained was evaporated under reduced pressure to give 3.8 g of desired product.
  • reaction mixture was stirred for 10 min and heated at 70°C for 18 h.
  • the reaction mixture was cooled to room temperature, quenched with ice water and extracted thrice with DCM.
  • the organic layer was dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain desired product which was purified by flash chromatography to give 2.3 g of desired product.
  • the reaction was stirred at room temperature for overnight.
  • the reaction mass was quenched with sodium bicarbonate solution and extracted with ethyl acetate.
  • the organic layer was dried over sodium sulphate, evapoprated under reduced pressure.
  • the obtained product was purified with flash chromatography to obtain 2.5 g of desired product as yellow oil.
  • Step-2 Methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate
  • DMF dimethyl sulfoxide
  • potassium carbonate 223 mg, 1.616 mmol
  • cyclopropyl methyl bromide 157 ⁇ L, 1.616 mmol
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the (3-bromoprop-1-yn-1-yl)trimethylsilane (1.65 mL, 10.39 mmol) was added and stirred at room temperature for 2h.
  • the reaction mixture was diluted with water and extracted thrice with ethyl acetate and the combined organic layers were washed with water and concentrated.
  • the obtained residue was purified by column chromatography to yield 1.8 g of the desired product.
  • the reaction mixture was filtered and diluted with water and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulphate and concentrated.
  • the obtained residue was purified by silica gel chromatography to yield 650 mg of the desired compound.
  • Step-2 Methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate
  • DMF dimethyl sulfoxide
  • potassium carbonate 223 mg, 1.616 mmol
  • cyclopropyl methyl bromide 157 ⁇ L, 1.616 mmol
  • the reaction mixture was diluted with water and extracted with ethyl acetate.
  • the reaction mixture was concentrated and the residue obtained was diluted with water and acidified with 1N citric acid.
  • the aqueous layer was extracted with 20 % MeOH / DCM.
  • the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield 74 mg of the desired product.
  • Step-4 5-Formyl-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2- oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
  • N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (215 mg, 0.468 mmol) in THF / H 2 O (4:1, 25 mL) were added NaIO 4 (200 mg, 0.936 mmol) followed by 2.5% OsO 4 in t-BuOH (10 ⁇ L, 0.0009 mmol).
  • Example 60 – 69 The racemic compounds were prepared from the above mentioned methods and separated using SFC purification to obtain respective chiral isomers (Example 60 – 69).
  • Table-14 Structure, chemical name, method, intermediate used and analytical data of Examples (48-94)
  • Example 95 N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
  • Step-1 N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1- (2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide
  • reaction mixture was brought to room temperature and then added sodium triacetoxy borohydride (130 mg, 0.61 mmol) portion wise and stirred at room temperature for overnight.
  • the reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 24 mg of the desired product.
  • Tributyl(1-ethoxyvinyl)tin (943 ⁇ L, 2.793 mmol) and Pd(PPh 3 ) 2 Cl 2 (89 mg, 0.126 mmol) were added to reaction mixture at room temperature under nitrogen atmosphere.
  • the reaction mixture was heated to 120 o C for overnight in a sealed tube.
  • the reaction mixture was cooled to room temperature and then 2 M HCl (40 ml) was added to reaction mixture and stirred for 1 hr at room temperature.
  • the reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate.
  • the organic layer was concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 450 mg of the desired compound.
  • Step-3 5-Acetyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
  • HATU 388 mg, 1.022 mmol
  • the reaction mixture was heated to 50 o C for 4 h.
  • the reaction mixture was brought to room temperature and then added sodium cyanoborohydride (39 mg, 0.616 mmol) and stirred at room temperature for overnight.
  • the reaction mixture was quenched with saturated NH 4 Cl solution and diluted with ethyl acetate.
  • the reaction mixture was filtered.
  • the organic layer was separated, concentrated and purified by flash chromatography to obtain 54 mg of the desired racemic product.
  • the racemic product was purified by using SFC 0.1 % NH 3 in Methanol to yield 21 mg of the desired Isomer-1 and 23 mg of desired Isomer-2.
  • the reaction mixture was stirred at room temperature for 16 h.
  • the reaction mixture was quenched with 10 % of sodium thiosulfate solution (25 mL) and extracted thrice with EtOAc.
  • the organic layer was separated, dried over anhydrous Na 2 SO 4 , evaporated under reduced pressure to give crude compound.
  • the crude compound was purified by combiflash chromatography to afford 0.550 g of the title compound.
  • the reaction mixture was cooled to 0 °C, sodium triacetoxyborohydride (0.26 g, 1.25 mmol) was added and stirred at room temperature for 16 h.
  • the reaction mixture was basified with sat. NaHCO 3 and extracted thrice with DCM.
  • the organic layer was separated, dried over anhydrous Na 2 SO 4 , evaporated under reduced pressure to give crude compound.
  • the crude compound was purified by combiflash chromatography to afford 0.17 g of the title compound.
  • reaction mixture was stirred at room temperature for 3 h.
  • the reaction mixture was quenched with 10 % of sodium thiosulfate solution (25 ml) and partitioned between EtOAc (3 x 50 ml) and water (25 ml).
  • EtOAc 3 x 50 ml
  • water 25 ml
  • the organic layer was separated, dried over anhydrous Na 2 SO 4 , evaporated under reduced pressure to afford 0.5 g of the title compound.
  • reaction mixture was cooled to 0 °C, sodium triacetoxy borohydride (1.2 g, 5.7 mmol) was added and stirred at room temperature for 16 h.
  • the reaction mixture was basified with sat. NaHCO3 and extracted thrice with DCM.
  • the organic layer was separated, dried over anhydrous Na 2 SO 4 , evaporated under reduced pressure to afford 0.52 g of the title compound.
  • reaction mass was stirred at RT for 18 h.
  • the reaction mass was diluted with brine solution (3 mL) and extracted with ethyl acetate (3 x 20 mL).
  • the organic layer separated and dried over anhydrous Na 2 SO 4 , evaporated under reduced pressure to afford crude compound which was purified by column to obtain 57 mg of required product as yellow solid.
  • reaction mass was stirred at room temperature for 18 hrs.
  • the reaction mass was diluted with brine solution (3 ml) and extracted with DCM (3 x 10 ml).
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , evaporated under reduced pressure to result crude compound which was purified by column to afford 60 mg of the desired product.
  • Table-18 Structure, chemical name, method, intermediate used and analytical data of Example- 162 The details of synthesis and analytical data of the examples synthesized from the above- mentioned methods are given below in Table-19.
  • Table-19 Structure, method, intermediates used, chemical name and analytical data of Examples (163-205)
  • 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 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-20 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 1000.1 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

SUBSTITUTED PRYIDINONE COMPOUNDS AS CBL-B INHIBITORS RELATED APPLICATIONS This application claims the benefit of Indian Provisional Application No.202221046493 filed on August 16, 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 indicates 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, at each occurrence, R1 is selected independently from 3-15 membered heterocyclylC1- 8alkyl, 5-14 membered heteroarylC1-8alkyl and -[CHR]l-NR6R7; wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyC1-8alkyl, C1-8alkyl, – NHC(O)CH3, –NHC(O)CH2CH3 and –NHC(O)CH=CH2.; Z is CH or N; X is CH or N; R is selected from hydrogen and C1-8alkyl; at each occurrence, R2 is selected independently from halogen, -NHC(O)CH3 and – NHC(O)CH=CH2; ring A is 5-14 membered heteroaryl; at each occurrence, R3 is C1-8alkyl; R4 is selected from hydrogen and C1-8alkyl; R5 is selected from C1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a 3-15 membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl wherein 3-15 membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen and C1-8alkyl; ‘Y’ is absent or CR8R9; R6 is selected from hydrogen and C1-8alkyl; R7 is selected from C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxyC1-8alkyl, – CH2CH2NHC(O)CH=CH2, C3-12cycloalkyl, C3-12cycloalkylC1-8alkyl and 3-15 membered heterocyclylalkyl; wherein C3-12cycloalkyl and C3-12cycloalkylC1-8alkyl is optionally substituted with C1-8alkyl and haloC1-8alkyl; R8 is hydrogen; R9 is hydrogen; R10 is selected from hydrogen and C1-8alkyl; R11 is selected independently from C1-8alkyl, haloC1-8alkyl, C6-14aryl, C6-14arylC1-8alkyl, 3-15 membered heterocyclylC1-8alkyl, C3-12cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C6- 14aryl, C6-14arylC1-8alkyl are optionally substituted with one or more substituents selected from halogen; ‘l’ is an integer ranging from 0 to 2, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘n’ is an integer ranging from 1 to 3, both inclusive; and ‘r’ is an integer ranging from 0 to 4, both inclusive. In another aspect, the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (I) as described herein and a pharmaceutically acceptable excipient. In another aspect, the present invention provides a method for treating a disease or disorder mediated by CBL-B in a subject comprising administering the subject in need thereof a compound represented by formula (I), (IA), (IB) or (IC) or a stereoisomer or a pharmaceutically acceptable salt thereof as described herein. 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 ‘Z’ is CH or N (according to an embodiment defined below), ‘n’ is 1 according to another embodiment defined below) and ‘X’ is CH or N (according to yet another embodiment defined below). According to one embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH or N. According to another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is N. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7, 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl; wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyC1-8alkyl, C1-8alkyl, -NHC(O)CH3, –NHC(O)CH=CH2 and- NHC(O)CH2CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7, wherein R, l, R6 and R7 are as defined in formula (I). According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is 3-15 membered heterocyclylC1-8alkyl (e.g.
Figure imgf000007_0001
,
Figure imgf000007_0002
and 5-14 membered heteroarylC1-8alkyl (e.g.
Figure imgf000007_0003
); wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro), oxo, hydroxyl, hydroxyC1-8alkyl (e.g. hydroxyl methyl), C1-8alkyl (e.g. methyl or isopropyl), -NHC(O)CH3, -NHC(O)CH2CH3 or –NHC(O)CH=CH2. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is a 3-15 membered heterocyclylC1-8alkyl (e.g.
Figure imgf000007_0004
,
Figure imgf000007_0005
) or 5-14 membered heteroarylC1-8alkyl (e.g. ); wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from fluoro, oxo, hydroxyl, hydroxylmethyl, methyl, isopropyl, -NHC(O)CH3, -NHC(O)CH2CH3 or –NHC(O)CH=CH2. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000008_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7. In this embodiment, R is hydrogen or C1-8alkyl; R6 is hydrogen or C1-8alkyl; R7 is C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxyC1-8alkyl, - CH2CH2NHC(O)CH=CH2, C3-12cycloalkyl, C3-12cycloalkylC1-8alkyl and 3-15 membered heterocyclylalkyl; wherein C3-12cycloalkyl and C3-12cycloalkylC1-8alkyl are substituted or unsubstituted with one or more substituents selected from C1-8alkyl and haloC1-8alkyl and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7. In this embodiment, R is hydrogen or C1-8alkyl (e.g. methyl); R6 is hydrogen or C1-8alkyl (e.g. methyl); R7 is C1-8alkyl (e.g. ethyl, isobutyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl or 3-methylbutan-2-yl), haloC1-8alkyl (e.g. difluoroethyl, 2-fluoro-2-methylpropyl, 1-fluoro-2,2-dimethylpropyl or 2-fluoro-2- methylbutyl), hydroxyC1-8alkyl (e.g. hydroxyethyl or 2-hydroxy-2-methylpropyl), C1- 8alkoxyC1-8alkyl (e.g. ethoxyethyl), -CH2CH2NHC(O)CH=CH2, 3-15 membered heterocyclylalkyl (e.g. methyloxetane), C3-12cycloalkyl (e.g. cyclopropyl or cyclobutyl) or C3- 12cycloalkylC1-8alkyl (e.g. methylcycloproyl); wherein the C3-12cycloalkyl and C3- 12cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from C1- 8alkyl (e.g. methyl) or haloC1-8alkyl (e.g. fluoromethyl) and ‘l’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7. In this embodiment, R is hydrogen or methyl; R6 is hydrogen or methyl; R7 is ethyl, isobutyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl, 3-methylbutan-2-yl, difluoroethyl, 2-fluoro-2-methylpropyl, 1-fluoro-2,2-dimethylpropyl, 2- fluoro-2-methylbutyl, hydroxyethyl, 2-hydroxy-methylpropyl, ethoxyethyl, - CH2CH2NHC(O)CH=CH2, methyloxetane, 1-methylcyclopropyl, 1-methylcyclobutyl, cycloproylmethyl or 1-fluoromethyl cycloproylmethyl and ‘l’ is 1. 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
Figure imgf000009_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘n’ is 1. According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000010_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘X’ is CH or N. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘X’ is CH. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘X’ is N. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is halogen (e.g. chloro or fluoro), –NHC(O)CH3 or –NHC(O)CH=CH2. According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is chloro, fluoro, –NHC(O)CH3 or –NHC(O)CH=CH2. 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 chloro, fluoro, –NHC(O)CH3 or –NHC(O)CH=CH2 and ‘m’ is 0 or 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which ring A is 5-6 membered heteroaryl
Figure imgf000011_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which ring
Figure imgf000011_0002
According to yet another embodiment, specifically provided are compounds of formula (I), in which ring
Figure imgf000011_0003
According to yet another embodiment, specifically provided are compounds of formula (I), in which ring
Figure imgf000011_0004
According to yet another embodiment, specifically provided are compounds of formula (I), in which ring
Figure imgf000012_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is C1-8alkyl (e.g. methyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is methyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘r’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is methyl and ‘r’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which Y is absent or CR8R9. According to yet another embodiment, specifically provided are compounds of formula (I), in which Y is absent. According to yet another embodiment, specifically provided are compounds of formula (I), in which Y is CR8R9. In this embodiment, R8 is hydrogen and R9 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (I), in which Y is CH2. According to yet another embodiment, specifically provided are compounds of formula (I), in which Y is absent or CH2. 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 R5 is C1-8alkyl (e.g. CH3) or C3-12cycloalkyl (e.g. cyclobutyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is CH3 or cyclobutyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 are CH3. According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen and R5 is cyclobutyl. 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 O C3-12cycloalkyl (e.g.
Figure imgf000013_0001
), 3-15 membered heterocyclyl (e.g. ), or 3-15 membered spirocyclyl (e.g.
Figure imgf000013_0002
), 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. methyl or ethyl). 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 O C3-12cycloalkyl (e.g.
Figure imgf000013_0003
), 3-15 membered heterocyclyl (e.g. ), or 3-15 membered spirocyclyl (e.g.
Figure imgf000013_0004
), wherein C3-12cycloalkyl or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro, methyl or ethyl. 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 imgf000013_0005
According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is hydrogen or C1-8alkyl (e.g. methyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is hydrogen or methyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is hydrogen. According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is methyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C1-8alkyl, haloC1-8alkyl, C6-14aryl , C6-14arylC1-8alkyl-, 3-15 membered heterocyclylC1-8alkyl, C3-12cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein the C6-14aryl and C6-14arylC1-8alkyl are substituted or unsubstituted with one or more substituents selected from halogen. According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C1-8alkyl (e.g. methyl or ethyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is methyl or ethyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is haloC1-8alkyl (e.g. trifluoroethyl, difluoromethyl, difluoroethyl or trifluoropropyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is difluoromethyl, difluoroethyl, trifluoroethyl or trifluoropropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C3-12cycloalkyl (e.g. cyclopropyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is cyclopropyl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C3-8cycloalkylC1-8alkyl (e.g. cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl). According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl. According to yet another embodiment, specifically provided are compounds of formula O (I), in which R11 is 3-15 membered heterocyclylC1-8alkyl (e.g. ). According to yet another embodiment, specifically provided are compounds of formula O (I), in which R11 is . According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C6-14 aryl (e.g. phenyl); wherein the C6-14aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro). According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C6-14 aryl (e.g. phenyl); wherein the C6-14aryl is optionally substituted with one or more substituents selected from fluoro. According to yet another embodiment, specifically provided are compounds of formula (I), in which
Figure imgf000015_0001
According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C6-14arylC1-8alkyl
Figure imgf000015_0002
wherein the C6-14arylC1-8alkyl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro). According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C6-14arylC1-8alkyl
Figure imgf000015_0003
wherein the C6-14arylC1-8alkyl is optionally substituted with one or more substituents selected from fluoro. According to yet another embodiment, specifically provided are compounds of formula (I), in which
Figure imgf000015_0004
According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,
Figure imgf000015_0005
Figure imgf000015_0006
. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH or N; R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000017_0001
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,
Figure imgf000017_0002
Figure imgf000017_0003
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH;
Figure imgf000017_0004
R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000018_0001
Figure imgf000018_0002
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,
Figure imgf000019_0001
Figure imgf000019_0002
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH;
Figure imgf000019_0003
R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000020_0001
Figure imgf000020_0002
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,
Figure imgf000020_0003
Figure imgf000020_0004
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH;
Figure imgf000021_0001
R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000022_0001
Figure imgf000022_0002
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or
Figure imgf000022_0003
Figure imgf000022_0004
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. According to an embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 10000 nM, preferably, less than 1000 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity. Further embodiments relating to groups ring A, X, Y, Z, R1, R2, R3, R4, R5, R10, R11, n, m and r (and groups defined therein) are described hereinafter in relation to the compounds of formula (IA), (IB) or (IC). It is to be understood that these embodiments are not limited to use in conjunction with formula (IA), (IB) or (IC), 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) or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, X, n, m and r are as defined in formula (I). In another aspect, the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IA) as described herein and a pharmaceutically acceptable excipient. In another aspect, the present invention provides a method for treating a disease or disorder mediated by CBL-B comprising administering a compound represented by formula (IA) as described herein. The invention also provides a compound of formula (IB) which is an embodiment of a compound of formula (I).
Figure imgf000023_0001
or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, n, m and r are as defined in formula (I). In another aspect, the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IB) as described herein and a pharmaceutically acceptable excipient. In another aspect, the present invention provides a method for treating a disease or disorder mediated by CBL-B comprising administering a compound represented by formula (IB) as described herein. The invention also provides a compound of formula (IC) which is an embodiment of a compound of formula (I).
Figure imgf000024_0001
or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R10, R11, Y, n, m and r are as defined in formula (I). In another aspect, the present invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IC) as described herein and a pharmaceutically acceptable excipient. In another aspect, the present invention provides a method for treating a disease or disorder mediated by CBL-B comprising administering a compound represented by formula (IC) as described herein. It should be understood that the formulas (I), (IA), (IB) and (IC) 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. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched. 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 “haloC1-4alkyl” refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched. 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). The representative examples of such groups are -OCH3 and - OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched. 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). Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched. 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. The examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl 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 “arylalkyl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6- 14aryl) directly attached to an alkyl group (i.e. C6-14arylC1-8alkyl). The arylalkyl 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. 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 “heterarylalkyl” refers to a heteraryl ring radical directly bonded to an alkyl group (i.e. heteroarylC1-8alkyl). The heteroaryllalkyl 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 “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, isothionate, 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, aluminum, 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), (IB) and (IC) 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), (IB) and (IC) 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), compound of formula (IC) 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), (IB), (IC) 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 (IA-1, IA-2, IA- 3, IA-4, IA-5, IA-6, IA-7, IA-8 and IA-9), intermediates and specific examples are prepared through the synthetic methods as depicted in synthetic schemes 1-6. 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 using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention. General Scheme A general approach for the preparation of compounds of the general formula (IA-1) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 1. Synthetic scheme-1:
The esterification of compound of formula (1) yields ester compound of formula (2) [wherein R’ is C1-8alkyl]. The reaction is carried out in a suitable solvent. The suitable solvent used in the reaction may be methanol. The selective N-Alkylation of compound of formula (2) with suitable alkylating agents in the presence of suitable base and solvents yields the compound of formula (3). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from cesium carbonate, potassium carbonate, sodium carbonate, sodium hydride, etc. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from DMSO, DMF and THF. The Suzuki coupling reaction of compound of formula (3) using potassium vinyl trifluoroborate in the presence of suitable base, catalyst and solvent gives the compound of formula (4). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate or cesium carbonate. The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be selected from tetrakis(triphenylphosphine)palladium(0), 1,1′-bis(diphenylphosphino)ferrocene]dichloropall adium(II) complex with dichloromethane, along with a suitable phosphine ligand, etc. The coupling 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 (4) upon oxidative cleavage using osmium tetra oxide and sodium periodate in a suitable mixture of solvent gives aldehyde compound of formula (5). The reaction is carried out in presence of suitable mixture of solvents. The suitable mixture of solvent may be selected from mixture of THF / water and t-BuOH. The reductive amination reaction of compound of formula (5) with appropriate amines of formula (6) using suitable reducing agent in the presence of suitable catalyst gives compound of formula (7). The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, dichloroethane, dimethylformamide, methanol, ethanol. The reaction is carried out in presence of suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride. The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be acetic acid. The hydrolysis of compound of formula (7) gives the compound of formula (8). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is carried out in a suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof. The acid-amine coupling reaction of compound (8) with appropriate aromatic amines compound of formula (9) gives the compound of general formula (IA-1). The reaction is 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 is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. A general approach for the preparation of compounds of the general formula (IA-2) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 2. Synthetic scheme-2: The hydrolysis reaction of compound of formula (3) [wherein R’ is C1-8alkyl] gives the compound of formula (10). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof. The acid-amine coupling reaction of compound (10) with appropriate aromatic amines of compound of formula (9) gives the compound of formula (11). The reaction is carried out in a presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in a presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. The reaction is carried out in a 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 Suzuki coupling reaction of compound of formula (11) and potassium vinyl trifluoroborate gives the compound of formula (12). The reaction is carried out in a presence of suitable base. The suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate or cesium carbonate. The reaction is carried out in a presence of suitable catalyst. The suitable catalyst used in the reaction may be selected from 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 may be selected from ethanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof. The compound of formula (12) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (13). The reaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be THF / water. The reductive amination reaction of compound of formula (13) with appropriate amines compound of formula (6) gives compound of general formula (IA-2). The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be acetic acid. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from TEA and DIPEA. The reaction may be carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, dimethylformamide, methanol and ethanol. The reaction is carried out in presence of suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride. A general approach for the preparation of compounds of the general formula (IA-3 and IA-4) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 3. Synthetic scheme-3:
Figure imgf000034_0002
Figure imgf000034_0001
The Suzuki coupling reaction of compound of formula (3) [wherein R’ is C1-8alkyl] and potassium vinyl trifluoroborate gives the compound of formula (4). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate or cesium carbonate. The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be selected from 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 presence of 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 hydrolysis reaction of compound of formula (4) in the presence of a suitable base and solvent gives the compound of formula (14). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof. The acid-amine coupling reaction of compound (14) with appropriate aromatic amines compound of formula (9) gives the compound of formula (15). The reaction is 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 is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. The compound of formula (15) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (16). The reaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be THF / water. The reductive amination reaction of compound of formula (16) with appropriate amines (6) yields compound of formula (IA-3). The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be acetic acid. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from triethylamine or DIPEA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane, dimethylformamide, methanol and ethanol. The reaction is carried out in presence of a suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. The treatment of compound of formula (IA-3) with suitable inorganic acid in appropriate solvent gives compound of formula (IA-4). The reaction is carried out in presence of suitable inorganic acid. The suitable inorganic acid used in the reaction may be selected from hydrochloric acid or TFA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, dichloroethane or THF. A general approach for the preparation of compounds of the general formula (IA-5, IA- 6 and IA-7) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 4. Synthetic scheme-4:
Figure imgf000036_0001
The Stille coupling reaction of compound of formula (3) and tributyl(1-ethoxyvinyl)tin gives the compound of formula (17). The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be selected from tetrakis(triphenyl phosphine) palladium(0), dichlorobis(triphenyl phosphine)palladium(II), palladium acetate, along with a suitable phosphine ligand, etc. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from, 1,4-dioxane, DMSO or DMF. The hydrolysis reaction of compound of formula (17) gives the compound of formula (18). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof. The acid-amine coupling reaction of compound (18) with appropriate aromatic amines compounds of formula (9) gives the compound of formula (19). The reaction is 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 is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. The reductive amination reaction of compound of formula (19) with appropriate amines compound of formula (6) yields compound of formula (IA-5). The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be acetic acid. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from triethylamine or DIPEA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane, dimethylformamide, methanol and ethanol. The reaction is carried out in presence of a suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. The Supercritical Fluid Chromatography (SFC) purification of racemic compound of formula (IA-5) yields the compound of general formula (IA-6) and the compound general formula (IA-7). A general approach for the preparation of compounds of the general formula (IA-8) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 5. Synthetic scheme-5:
Figure imgf000037_0001
The acid-amine coupling reaction of compound (14) with appropriate aromatic amines compound of formula (20) [wherein Q is C or N] gives the compound of formula (21). The reaction is 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 is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. The compound of formula (21) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (22). The reaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be THF / water. The reductive amination reaction of compound of formula (22) with appropriate amines compound of formula (6) yields compound of formula (23). The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction id acetic acid. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from triethylamine or DIPEA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane, dimethylformamide, methanol and ethanol. The reaction is carried out in presence of a suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. The compound of formula (23) on deprotection yields the compound of formula (IA-8). The reaction may be carried in presence of suitable acids. The suitable acids used in the reaction may be selected from hydrochloric acid and trifluoroacetic acid. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol, dichloroethane and 1,4- dioxane. A general approach for the preparation of compounds of the general formula (IA-9) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 6. Synthetic scheme-6:
The compound of formula (4) [wherein R’ is C1-8alkyl] upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (5). The reaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be THF / water. The reductive amination reaction of compound of formula (5) with appropriate amines compound of formula (24) yields compound of formula (26). The reaction is carried out in 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 reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloro methane, dimethylformamide, methanol and ethanol. The amine compound of formula (25) upon N-protection using suitable protecting group (PG) yields the compound of formula (26). The reaction is carried out in presence of suitable protecting group. The suitable protecting group used in the reaction may be selected from di- tert-butyl dicarbonate, acetic anhydride and benzylchloroformate. The hydrolysis reaction of compound of formula (26) yields the compound of formula (27). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide and potassium hydroxide. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol and tetrahydrofuran or combination thereof. The acid-amine coupling reaction of compound of formula (27) with appropriate aromatic amine compound of formula (28) gives the compound of formula (29). The reaction is 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 is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. The acylation reaction of compound of formula (29) yields the compound of formula (30). The reaction is carried out in presence of suitable acylating reagents. The suitable acylating reagents used in the reaction may be acetic anhydride or acryloyl chloride. The compound of formula (30) on deprotection yields the compound of formula (IA-9). The reaction is carried out in presence of suitable acid. The suitable acid used in the reaction may be selected from hydrochloric acid and trifluoroacetic acid. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane and 1,4- dioxane. EXPERIMENTAL SECTION Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulfate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses. The abbreviations, symbols and terms used in the examples have the following meanings throughout:
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0005
INTERMEDIATES Intermediate A1 3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline
Figure imgf000042_0001
Step-1: 3-(3-Bromophenyl)-3-methylbutanoic acid
Figure imgf000042_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 twice with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by SFC to get 3.1 g of the desired
Figure imgf000042_0003
NMR (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-methylhydrazine carbothioamide H H O
Figure imgf000042_0004
Br 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-methylthiosemicarbazide (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 imgf000043_0001
To a stirred solution of 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N-methylhydrazine carbothioamide (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 imgf000043_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 residue obtained 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)+ Step-5: 3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline In a sealed tube, to a stirred solution of 3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-4H- 1,2,4-triazole (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 residue obtained was triturated with diethyl ether to give 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 2-Fluoro-5-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline Step-1: Diethyl 2-(2-(3-bromo-4-fluorophenyl)propan-2-yl)malonate
Figure imgf000044_0001
To a stirred solution of 2-bromo-4-iodo-1-fluorobenzene (5.86 g, 19.5 mmol) in THF (15 mL) at -10 oC was added dropwise 2M solution of isopropyl magnesium chloride in THF (11.25 mL, 22.5 mmol) and stirred at 0oC for 30 min and further stirred at room temperature for 1 hr. To this mixture at 0oC was added copper (I) iodide (860 mg, 4.5 mmol) and stirred for 10 min and then added diethyl isopropylidene malonate (3 g, 15 mmol). The reaction mixture was heated to 60oC for 2 h. The reaction mixture was quenched with 1 N HCL and diluted with ethyl acetate. The suspension obtained was filtered and washed with ethyl acetate. The filtrate obtained was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by flash chromatography to get 3.5 g of the desired product. 1H NMR (400 MHz, CDCl3): δ 1.17 (t, J= 7.2 Hz, 6H), 1.57 (s, 6H), 3.73 (s, 1H), 4.10 (q, J=6.8 Hz, 4H), 7.04-7.09 (m, 1H), 7.30 - 7.33 (m, 1H), 7.55-7.57 (m, 1H); ESI-MS (m/z) 375.0 (M+H) + Step-2: Ethyl 3-(3-bromo-4-fluorophenyl)-3-methylbutanoate
Figure imgf000044_0002
To a stirred suspension of diethyl 2-(2-(3-bromo-4-fluoro phenyl)propan-2-yl)malonate (2.4 g, 6.39 mmol), lithium chloride (600 mg, 14.04 mmol) and water (114 mg, 6.39 mmol) in DMSO (12 mL) was subjected to microwave irradiation for 1 h at 200oC. The reaction mixture was diluted with water and extracted thrice with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by flash chromatography to get 1.5 g of desired product. 1H NMR (400 MHz, CDCl3): δ 1.12 (t, J= 7.2 Hz, 3H), 1.45 (s, 6H), 2.60 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 7.04-7.09 (m, 1H), 7.27-7.30 (m, 1H), 7.53-7.55 (m, 1H); ESI-MS (m/z) 303.1 (M+H) + 3-(3-Bromo-4-fluorophenyl)-3-methylbutanehydrazide
Figure imgf000044_0003
To a stirred solution of ethyl 3-(3-bromo-4-fluorophenyl)-3-methylbutanoate (1.5 g, 4.95 mmol) in MeOH (7 mL) at 0° C was added dropwise 99% hydrazine hydrate (7 mL). The reaction mixture was warmed to room temperature and heated to 90°C for 16 h. The mixture was concentrated and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to yield 1.4 g of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 1.33 (s, 6H), 2.33 (s, 2H), 4.10 (brs, 2H), 7.25-7.30 (m, 1H), 7.38-7.42 (m, 1H), 7.60-7.62 (m, 1H), 8.87 (brs, 1H); ESI-MS (m/z) 290.1 (M+2H) + Step-4: 2-(3-(3-Bromo-4-fluorophenyl)-3-methylbutanoyl)-N-methylhydrazinecarbothioamide
Figure imgf000045_0001
. To a stirred solution of 3-(3-bromo-4-fluorophenyl)-3-methylbutanehydrazide (1.4 g, 4.62 mmol) in THF (10 mL) at 0°C was added dropwise methylisothiocyanate (1 g, 13.86 mmol). 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 residue obtained was triturated with pentane. The solid obtained was filtered and dried under vacuum to yield 1.6 g of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.36 (s, 6H), 2.40 (s, 2H), 2.82 (d, J= 4.0 Hz, 3H), 7.27-7.31 (m, 1H), 7.40-7.43 (m, 1H), 7.54 (s, 1H), 7.62-7.64 (m, 1H), 9.18 (s, 1H), 9.59 (s, 1H); ESI-MS (m/z) 363.1 (M+2H)+ Step-5: 5-(2-(3-Bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole-3-thiol
Figure imgf000045_0002
To a stirred solution of 2-(3-(3-Bromo-4-fluorophenyl)-3-methylbutanoyl)-N- methylhydrazinecarbothioamide (1.4 g, 3.86 mmol) in 1 N NaOH (30 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 1.3 g of the desired product. 1HNMR (400 MHz, DMSO-d6): δ 1.39 (s, 6H), 3.04 (s, 2H), 3.19 (s, 3H), 7.25-7.30 (m, 1H), 7.38-7.42 (m, 1H), 7.67-7.69 (m, 1H), 13.44 (brs, 1H); ESI-MS (m/z) 345.0 (M+2H) + 3-(2-(3-Bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole
Figure imgf000045_0003
To a stirred solution of 5-(2-(3-Bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4- triazole-3-thiol (1.3 g, 3.63 mmol) in DCM (30 mL) and AcOH (3 g, 50.83 mmol) at 0°C was added 30% H2O2 solution (370 mg, 10.89 mmol). 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 900 mg of the desired product.1HNMR (400 MHz, DMSO- d6): δ 1.40 (s, 6H), 2.99 (s, 2H), 3.25 (s,3H), 7.24-7.28 (m, 1H), 7.32-7.36 (m, 1H), 7.58-7.60 (m,1H), 8.25 (s, 1H); ESI MS (m/z) 313.1 (M+2H)+ Step-7: 2-Fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline In a sealed tube, to a stirred solution of 3-(2-(3-Bromo-4-fluorophenyl)-2-methylpropyl)-4- methyl-4H-1,2,4-triazole (400 mg, 1.28 mmol) in NMP (4 mL) was added aqueous NH3 (4 mL), copper(I) oxide (73 mg, 0.512 mmol) and stirred at 90° C for 16 h. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under vacuum to give 300 mg of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.34 (s, 6H), 2.87 (s, 2H), 3.09 (s, 3H), 4.99 (s, 2H), 6.39-6.43 (m, 1H), 6.68-6.71 (m, 1H), 6.82-6.87 (m, 1H), 8.22 (s, 1H); ESI-MS (m/z) 249.2 (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 (A3)
Figure imgf000046_0003
Intermediate A4 3-(3-((4-Methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline
Figure imgf000046_0001
Step-1: Ethyl 2-(oxetan-3-ylidene)acetate
Figure imgf000046_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) dropwise 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 twice with Ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated. The residue obtained 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 imgf000047_0001
To a degassed solution of [Rh(COD)Cl]2 (170 mg, 0.352 mmol) in dioxane (15 mL) was added 1.5 aqueous KOH (6 mL) dropwise at room temperature and stirred for 30 min. To this mixture was added drop wise solution of ethyl 2-(oxetan-3-ylidene)acetate (1g, 7.042 mmol) in dioxane (10 mL) followed by (3-bromo phenyl)boronic acid (2 g, 10.56 mmol) in dioxane (10 mL) solution and stirred for 1 hr. The reaction was stirred for 1 h and to this reaction mixture (3- bromophenyl)boronic acid (700 mg, 3.521 mmol) was again 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 residue obtained 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 imgf000047_0002
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 twice 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 imgf000048_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. To the reaction mixture was added N-methylhydrazinecarbothioamide (57 mg, 0.547 mmol) and DIPEA (192 mg, 1.494 mmol) and stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained 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 imgf000048_0002
To a stirred solution of 2-(2-(3-(3-bromophenyl)oxetan-3-yl)acetyl)-N- methylhydrazinecarbothioamide (100 mg, 0.28 mmol) in 1N NaOH (3.5 mL) was stirred at room temperature for 18 h. The mixture was cooled and neutralized using 1N 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 imgf000048_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 dropwise addition of 1N HNO3 (3.5 ml) at 0oC and stirred for 1 h. The reaction mixture was quenched with saturated solution of NaHCO3 and extracted thrice with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The residue obtained 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)+ Step-7: 3-(3-((4-Methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline In a sealed tube, to a stirred solution of 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl- 4H-1,2,4-triazole (200 mg, 0.629 mmol) in NMP (2 mL) were added aqueous NH3 (2 mL), Copper (I) oxide (35mg, 0.2515 mmol) and stirred at 90° C for 16 h. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was evaporated under vacuum to give 160 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 2.83 (s, 3H), 3.39 (s, 2H), 4.75 (d, J = 6 Hz, 2H), 4.85 (d, J = 6 Hz, 2H), 5.02 (brs.2H), 5.92 (d, J = 7.2 Hz, 1H),6.04 (s, 1H), 6.39 - 6.41 (m, 1H), 6.89 (d, J = 8 Hz, 1H), 8.21 (brs, 1H); ESI-MS (m/z) 245.2 (M+H)+ Intermediate A5 3-((1s,3s)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline
Figure imgf000049_0001
Step-1: 1,3-Dibromo-2-methylpropane Br Br 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 temperature for 16 h. The solvent was concentrated under reduced pressure and the residue obtained 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 imgf000049_0002
To a stirred suspension of NaH (60% suspension in mineral oil) (2.58g, 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 slow addition of 1,3-dibromo-2-methylpropane (11.62 g, 53.826 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 twice with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The residue obtained 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). 1-(3-Bromophenyl)-3-methylcyclobutanecarboxylic acid
Figure imgf000050_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 twice with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated to give 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 imgf000050_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 imgf000050_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 residue 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-methylhydrazinecarbothio amide
Figure imgf000051_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 residue obtained 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)+ 5-(1-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole- 3-thione
Figure imgf000051_0002
To a stirred solution of 2-(1-(3-bromophenyl)-3-methylcyclobutanecarbonyl)-N- methylhydrazinecarbothioamide (23.4 g, 65.67 mmol) in 1N 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
Figure imgf000051_0003
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)+ Step-9: 3-((1s,3s)-3-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline 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 oxide (47 mg, 0.326 mmol) and stirred at 90° C for 16 h. The reaction mixture was quenched with water and extracted thrice 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 (A6-A9)
Figure imgf000052_0001
Figure imgf000053_0003
Intermediate-A10 2-Chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline
Figure imgf000053_0001
To a stirred solution of 3-((1s,3s)-1-(3-bromo-4-chlorophenyl)-3-methylcyclobutyl)-4-methyl- 4H-1,2,4-triazole (50 mg, 0.147 mmol) in ethanol (1.0 mL) and water (0.75mL) was degassed for 10 min. The NaN3 (19 mg, 0.294mmol), CuI (28mg, 0.147 mmol), trans N,N-dimethyl-1,2- cyclohexanediamine (17 mg,0.147mmol) and sodium ascorbate (58mg, 0.294mmol) were added to the reaction mixture and stirred at 110°C for 18 h in a sealed tube. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated. The residue obtained purified by column chromatography to give 21 mg of the desired product.1H NMR (400 MHz, DMSO- d6) δ 1.05 (d, J = 5.6 Hz, 3H), 2.43-2.51(m, 3H), 2.68 (m, 2H), 3.16 (s, 3H), 5.35 (s, 2H), 6.50 (dd, J1= 2.4 Hz, J2=8.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.4Hz, 1H), 8.29 (s,1H); ESI-MS (m/z) 278 (M+2H)+ Intermediate-A11 3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline
Figure imgf000053_0002
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 dropwise at 0°C and stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted twice 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 imgf000054_0001
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 and quenched with water and extracted twice 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 imgf000054_0002
To a stirred suspension of NaH (60% suspension in mineral oil) (734 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 and dropwise addition was continued for 1h. The reaction mixture was stirred at RT 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 twice with petroleum ether. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The residue obtained 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 HOOC Br 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 twice 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 (brs, 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 imgf000055_0001
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.4 methylthiosemicarbazide (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 twice 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)+ 5-(1-(3-Bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4- triazole-3-thione
Figure imgf000055_0002
To a stirred solution of 2-(1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonyl)-N- methylhydrazine-1-carbothioamide (820 mg, 2.21 mmol) in 1N 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
Figure imgf000055_0003
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)+ Step-7: 3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline In a sealed tube, to a stirred solution of 3-(1-(3-bromophenyl)-3,3-dimethylcyclobutyl)-4- methyl-4H-1,2,4-triazole (628 mg, 1.96 mmol) in ACN (8.0 mL) was added aqueous NH3 (4.0 mL), copper(I)oxide (280 mg, 1.96 mmol) and stirred at 100°C for 16 h. The reaction mixture was quenched with water and ethyl acetate, filtered and filtrate obtained was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and solvent was evaporated under reduced pressure and the solid obtained was purified by silica gel column chromatography to yield 410 mg of the desired product.1HNMR (400 MHz, DMSO-d6): δ 1.03 (s, 3H), 1.11 (s, 3H), 2.48 (d, J = 12.8 Hz, 2H), 2.80 (d, J = 12.4 Hz, 2H), 3.19 (s, 3H), 5.07 (brs, 2H), 6.38-6.43 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H), 8.29 (s, 1H); ESI-MS (m/z) 257.2 (M+H)+ 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 (A12-A19)
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0004
Intermediate A20 3-(3,3-Difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline
Figure imgf000058_0001
Step-1: 1-(3-Bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile
Figure imgf000058_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 0°C for 30min, followed by slow 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 twice with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The residue obtained 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 imgf000058_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 twice 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). 1-(3-Bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile
Figure imgf000059_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 temperature for 18 h. The reaction was quenched with saturated 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
Figure imgf000059_0002
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 room temperature and heated to 120°C for 16 h. The mixture was cooled to room temperature and diluted with water. 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 imgf000059_0003
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 reaction mixture 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. 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 imgf000060_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 1N 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
Figure imgf000060_0002
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)+ 3-(3,3-Difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline In a sealed tube, to a stirred solution of 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4- methyl-4H-1,2,4-triazole (300 mg, 0.914 mmol) in ACN (3.0 mL) was added aqueous NH3 (3.0 mL), copper oxide (52 mg, 0.365 mmol) and stirred at 90°C for 16 h. The reaction mixture was extracted thrice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under vacuum to give 280 mg of the desired product.1HNMR (400 MHz, DMSO-d6): δ 3.24 (s, 3H), 3.24-3.27 (m, 2H), 3.58-3.68 (m, 2H),5.16 (s, 2H), 6.37 (s, 1H), 6.56(d, J=7.6Hz,2H), 7.01 (t, J = 8.0 Hz, 1H), 8.40 (brs, 1H); ESI-MS (m/z) 265 (M+H) + Intermediate A21 3-(Cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)aniline
Figure imgf000061_0001
Methyl 2-(3-bromophenyl)acetate
Figure imgf000061_0002
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 residue obtained was diluted with water and extracted thrice 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 residue obtained was purified with chromatography to get 9.3 g of the desired product as pale yellow oil.1HNMR (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)+ Methyl 2-(3-bromophenyl)-2-cyclobutylacetate
Figure imgf000061_0003
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. A solution of bromocyclobutane (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 residue obtained was purified with chromatography to get 1.21 g of the desired product as pale yellow oil.1HNMR (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)+ 2-(3-Bromophenyl)-2-cyclobutylacetohydrazide 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.1HNMR (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( brs, 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
Figure imgf000062_0001
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 residue obtained 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 imgf000062_0002
To a stirred solution of 2-(2-(3-Bromophenyl)-2-cyclobutylacetyl)-N-methylhydrazine-1- carbothioamide (1.1 g) in 1N 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- 7.49 (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
Figure imgf000063_0001
To a stirred solution of 25-((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 the reaction mixture for 10 min, to that reaction mixture, 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. 1HNMR (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)+ Step-7: 3-(Cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)aniline
Figure imgf000063_0002
In a sealed tube, to a stirred solution of 3-((3-Bromophenyl)(cyclobutyl)methyl)-4-methyl-4H- 1,2,4-triazole (500 mg, 1.63 mmol) in NMP (5 mL) were added aq. NH3 (5 mL), Copper (I) oxide (70 mg 0.49 mmol) and stirred at 100°C for 16 h. The reaction mixture was diluted with ethyl acetate and filtered. The organic layer was separated out and dried over anhydrous sodium sulphate and concentrated under reduced pressure up to dryness. The residue obtained was triturated with diethyl ether to give 373 mg of the desired product.1H NMR (400 MHz, DMSO- d6) δ 1.61-65 (m, 1H), 1.75-1.77 ( m, 4 H), 2.07-2.15( m, 1H), 3.08-3.10 ( m, 1H), 3.35 ( s, 3H), 3.92( d, J=10.4 Hz, 1H), 5.01( bs,2H), 6.32-3.39(m , 3H), 6.91(t, J=8 Hz, 1H), 8.32 (s, 1H); ESI-MS (m/z) 243.3 (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 (A22)
Figure imgf000064_0004
Intermediate A23 3-((1s,3s)-3-Methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)aniline
Figure imgf000064_0001
Step-1: (1s,3s)-1-(3-Bromophenyl)-N-methoxy-N,3-dimethylcyclobutane-1-carboxamide
Figure imgf000064_0002
To a stirred solution of (1s,3s)-1-(3-bromophenyl)-3-methylcyclobutane-1-carboxylic acid (4.0 g, 14.86 mmol) in DCM (40 ml) was added CDI (4.81 g, 29.72 mmol) portion wise followed by AIBN (2.0 g, 12.33 mmol). The reaction mixture was stirred at room temperature for 1h. The N,O-Dimethylhydroxylamine / was added and stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 ml) and extracted with DCM (3 x 100 ml). The organic layer dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 3.1 g of the title compound.1HNMR (DMSO-d6, 400 MHz) δ 1.09 (d, J = 5.2 Hz, 3H), 2.36-2.34 (m, 3H), 2.54-2.52 (m, 2H), 3.11 (s, 6H), 7.23 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H). Step-2: 1-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)propan-1-one
Figure imgf000064_0003
To a stirred solution of (1s,3s)-1-(3-bromophenyl)-N-methoxy-N,3-dimethyl cyclobutane-1- carboxamide (3.0 g, 9.61 mmol) in dry THF (30 ml) at 0°C was added ethyl magnesium bromide (6.4 g, 48.05 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with NH4Cl solution (50 ml) and extracted with DCM (3 x 100 ml). The organic layer dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 2.0 gm of the title compound.1HNMR ( DMSO-d6, 400 MHz) δ 1.09 (d, J = 5.2 Hz, 3H), 2.24-2.19 (q, J = 7.2 Hz, 2H), 2.21 (t, J = 7.2 Hz, 3H), 2.40-2.36 (m, 3H), 2.58-2.54 (m, 2H), 7.27-7.23 (m, 2H), 7.50-7.39 (m, 1H), 7.51 (s, 1H); ESI-MS (m/z) 280 [M-H] +. Step-3: 1-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)-2-hydroxypropan-1-one
Figure imgf000065_0001
To a stirred solution of 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propan-1-one (2.0 g, 7.09 mmol) in dry THF (30 ml) at -78°C was added NaHMDS (1.95 g, 10.64 mmol, 1.0 M in THF). After 15 min, a solution of (R)-3-methyl-3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (2.78 g, 10.64 mmol) was added at -78°C and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with NH4Cl solution (50 ml) and extracted with EtOAc (3 x 100 ml). The organic layer dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 1.4 g of the title compound.1HNMR (DMSO-d6, 400 MHz) δ 1.05- 1.09 (m, 6H), 2.29-2.24 (m, 1H), 2.45-2.30 (m, 1H), 2.52-2.49 (m, 2H), 2.69-2.64 (m, 2H), 4.22 (q, J = 6.8 Hz, 1H), 7.26-7.28 (m, 2H), 7.45-7.42 (m, 1H), 7.52 (s, 1H). 1-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)propane-1,2-dione
Figure imgf000065_0002
To a stirred solution of 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-2-hydroxypropan- 1-one (1.4 g, 4.71 mmol) in dry DCM (30 ml) at 0 °C was added DMP (3.99 g, 9.42mmol) portion wise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with sat. NaHCO3 solution and extracted thrice with DCM. The organic layer dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 1.1 g of the title compound.1HNMR (DMSO-d6, 400 MHz) δ 1.07 (d, J = 6 Hz, 3H), 2.18 (s, 3H), 2.39-2.42 (m, 3H), 2.70-2.71 (m, 2H), 7.23 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H). Step-5: 4-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-imidazole
Figure imgf000066_0001
To a stirred solution of 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propane-1,2-dione (1.1 g, 3.72 mmol) in MeOH was added paraformaldehyde (0.12 g, 4.09 mmol) followed by ammonium acetate (2.87 g, 37.26 mmol). The reaction mixture was heated at 80 °C in a sealed tube for 16 h. The reaction mixture was concentrated and the product obtained was purified by combiflash chromatography to afford 1.0 g of the title compound. 1HNMR (DMSO-d6, 400 MHz) δ 7.56 (s, 1H), 7.30-7.36 (m, 2H), 7.28 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 5.01 (brs, 1H), 2.81-2.83 (m, 2H), 2.38-2.44 (m, 3H), 2.04 (s, 3H), 1.11 (d, J = 5.6 Hz, 3H); ESI-MS (m/z) 305.1 [M+H] + 4-((1s,3s)-1-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-1-trityl-1H-imidazole
Figure imgf000066_0002
To a stirred solution of 4-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1H- imidazole (1.0 g, 3.27 mmol) in dry DCM (30 ml) at 0°C was added triethylamine (0.31 g, 3.06 mmol) followed by trityl chloride (0.4 g, 1.46 mmol) portion wise. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the obtained product was purified by combiflash chromatography to afford 1.3 g of the title compound. ESI- MS (m/z) 547.3 [M+H] + N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)phenyl)- 1,1-diphenylmethanimine
Figure imgf000066_0003
To a stirred solution of 4-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1-trityl- 1H-imidazole (1.2 g, 2.19 mmol) in dry dioxane (30 ml) was added benzophenoneimine (1.58 g, 8.76 mmol), Xantphos (0.25 g, 0.438 mmol) and cesium carbonate (1.78 g, 5.47 mmol). The reaction mixture was degassed for 15 min using nitrogen gas. Palladium acetate (0.049 g, 0.21mmol) was added and reaction mixture was heated at 80 °C in a sealed tube for 16h. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated and the crude compound was purified by combiflash chromatography to afford 1.1 g of the title compound. ESI-MS (m/z) 648.4 [M+H] + Step-8: 3-((1s,3s)-3-Methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)aniline To a stirred solution of N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4- yl)cyclobutyl)phenyl)-1,1-diphenylmethanimine (1.1 g, 1.69 mmol) in MeOH (30 ml) was added hydroxylamine hydrochloride (0.35 g, 5.09 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and the crude compound was partitioned between EtOAc (3 x 100 ml) and sat. NaHCO3 (50 ml). The EtOAc layer was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 0.6 g of the title compound. ESI-MS (m/z) 484.3 [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 (A24)
Figure imgf000067_0003
Intermediate A25 3-(3-Methyl-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4- yl)cyclobutyl)aniline
Figure imgf000067_0001
Step-1: 1-(3-Bromophenyl)-3-methylcyclobutane-1-carbaldehyde
Figure imgf000067_0002
To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutane-1-carbonitrile (5.0 g, 0.02 mol) in DCM (50 ml) was added DIBAL (47 ml, 0.04 mol) at -78°C. The reaction mixture was stirred at -78oC for 4 h. The reaction mixture was quenched with saturated solution of ammonium chloride, filtered and washed with ethyl acetate. The filtrate obtained was evaporated under reduced pressure to give 3.8 g of desired product. ESI-MS (m/z) 254 (M+2H)+ Step-2: 4-(1-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-1,2,3-triazole To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutane-1-carbaldehyde (3.8 g, 0.0150 mol) in dry DMSO (10 mL) was added nitroethane (1.61 ml, 0.0225 mol), sodium azide (1.17 g, 0.018 mol) and stirred at room temperature for 5 min, and then aluminium chloride (0.2 g, 0.0015 mol) was added. The reaction mixture was stirred for 10 min and heated at 70°C for 18 h. The reaction mixture was cooled to room temperature, quenched with ice water and extracted thrice with DCM. The organic layer was dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain desired product which was purified by flash chromatography to give 2.3 g of desired product. ESI-MS (m/z) 306 [M+H]+ Step-3: 4-(1-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-1,2,3-triazole
Figure imgf000068_0001
To a stirred solution of 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-1H-1,2,3-triazole (2.3 g, 7.516 mmol) in THF (30 ml) were added 2,3 dihydropyran (1.36 ml, 15.03 mmol) and trifluoroacetic acid (0.172 ml, 2.25 mmol). The reaction was stirred at room temperature for overnight. The reaction mass was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, evapoprated under reduced pressure. The obtained product was purified with flash chromatography to obtain 2.5 g of desired product as yellow oil. ESI-MS (m/z) 390 [M+H]+ Step-5: 3-(3-Methyl-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4- yl)cyclobutyl)aniline To a stirred solution of 4-(1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-1,2,3-triazole (2.0 g, 5.12 mmol) in acetonitrile (15 mL) was added aq. ammonia (15 mL), copper oxide (1.46 g, 10.24 mmol) and stirred at 110°C for overnight in a sealed tube. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to obtain 0.8 g of desired product as yellow oil. ESI-MS (m/z) 327 [M+1]+ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-6. Table-6: Structure, Name and analytical data of intermediate (A26)
Figure imgf000069_0001
The mentioned below intermediates were synthesized by following the procedure described above for intermediate A11 and the analytical data are given in below Table-7. Table-7: Structure, Name and analytical data of intermediate (A27-A30)
Figure imgf000069_0002
Figure imgf000070_0003
Intermediate B1 Methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate
Figure imgf000070_0001
Step-1: Methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate
Figure imgf000070_0002
To a stirred solution of 5-Bromo-2-hydroxy nicotinic acid (5.0 g, 35.94 mmol) in dry methanol (100 mL) was added conc. H2SO4 (1 mL) and refluxed for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was basified with saturated sodium bicarbonate solution and stirred for 30 min. The solid obtained was filtered and dried under vacuum to give 4.2 g of the desired product. 1HNMR (400 MHz, DMSO-d6) δ 3.75 (s, 3H), 7.99 (d, J = 2.8 Hz), 8.08 (d, J = 2.8 Hz, 1H), 12.41 (brs, 1H); ESI- MS (m/z) 233 (M+2H) +. Step-2: Methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (250 mg, 1.077 mmol) in DMF (5 mL) was added potassium carbonate (223 mg, 1.616 mmol) and stirred at room temperature for 30 min. To this mixture was added cyclopropyl methyl bromide (157 μL, 1.616 mmol) and heated to 70°C for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by silica gel chromatography to yield 126 mg of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 0.35- 0.45 (m, 2H), 0.45- 0.55 (m, 2H), 1.18- 1.35 (m, 1H), 3.75 (s, 3H), 3.77 (d, J = 9.6 Hz, 2H), 8.058 (d, J = 2.8 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H); ESI-MS (m/z) 287 (M+2H)+ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-8. Table-8: Structure, Name and analytical data of intermediates (B2-B4)
Figure imgf000071_0002
Intermediate B5 Methyl 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate
Figure imgf000071_0001
To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (5.2 gm, 22.413 mmol) in DMF (80 mL) was added cesium carbonate (10.9 g, 33.620 mmol) and stirred for 30 min at room temperature. To this mixture was added 2,2,2-Trifluoro ethyltrifluoromethane sulfate (7.8 g, 33.62 mmol) and heated to 70 °C for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was over anhydrous sodium sulphate and concentrated. The obtained residue was purified by silica gel chromatography to yield 2.9 g of the desired compound.1HNMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 4.875 (q, J= 9.2 Hz, 2H), 8.14 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H); ESI- MS (m/z) 315 (M+2H)+ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-9. Table-9: Structure, Name and analytical data of intermediate (B6)
Figure imgf000072_0002
Intermediate B7 Methyl 5-bromo-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate O Br O N O Step-1: Methyl 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate
Figure imgf000072_0001
To a stirred solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (4.8 g, 31.16 mmol) in ethylene dichloride (150 mL) were added cyclopropyl boronic acid (5.30 g, 62.33 mmol), Cs2CO3 (5.06 g, 15.58 mmol), pyridine (12.32 g, 155.8 mmol) and stirred under oxygen atmosphere for 30 min at room temperature. To this mixture was added Cu(OAc)2 (5.65 g, 31.16 mmol) and stirred for 4 days. The reaction mixture was diluted with DCM and filtered. The filtrate obtained was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 230 mg of the desired product. 1HNMR (400 MHz, DMSO-d6) δ 0.83-0.87 (m, 2H), 0.99-1.04 (m, 2H), 3.32-3.38 (m, 1H), 3.73 (s, 3H), 6.26 (t, J = 7.2 Hz, 1H), 7.87 (d, J = 6.8 Hz, 1H), 8.0 (d, J = 7.2 Hz, 1H) ESI-MS (m/z) 194.1 (M+H)+ Step-2: Methyl 5-bromo-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate To a stirred solution of methyl 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (230 mg, 1.18 mmol) in DCM (10 mL) was added NBS (274 mg, 1.54 mmol) and the mixture was heated at 60°C for 18 h. The mixture was diluted with DCM and washed thrice with water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield 260 mg of the desired product.1HNMR (400 MHz, DMSO-d6) δ1.12- 1.15 (m, 4H), 3.30-3.35 (m, 1H), 3.37 (s, 3H), 6.02 (s, 1H), 8.09 (s,1H); ESI-MS (m/z) 274.2 (M+ 2H)+ Intermediate B8 2-Oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid
Figure imgf000073_0001
Step-1: Methyl 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylate
Figure imgf000073_0002
To a stirred solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxylate (Intermediate B5) (1.5 g, 4.76 mmol) and potassium vinyl trifluoroborate (1.91 gm., 14.28 mmol) in a solvent mixture of toluene (50 mL)/water (15 mL) was degassed for 15 min. To this reaction mixture were added K3PO4 (4 g, 19.04 mmol), Pd(dppf)Cl2.DCM (390 mg, 0.476 mmol) and heated to 100°C for 5 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 residue was purified by silica gel column chromatography to yield 1.09 g of the desired compound.1H NMR (400 MHz, DMSO- d6) δ 3.78 (s, 3H), 4.90 (q, J = 9.2 Hz, 2H), 5.22 (d, J= 11.2 Hz, 1H), 5.68 (d, J = 17.6 Hz, 1H), 6.45- 6.6 (m, 1H), 8.103 (d, J = 2Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H); ESI-MS (m/z) 262.3 (M+H) + 2-Oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid To a stirred solution of methyl 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxylate (1 g, 3.831 mmol) in THF/MeOH (40 mL, 1:1) was added aqueous LiOH (481 mg, 11.49 mmol) and stirred at room temperature for overnight. The reaction mixture was concentrated and the residue obtained was diluted with water and acidified using 1N HCl. The solid precipitated was filtered and dried to yield 809 mg desired product.1H NMR (400 MHz, DMSO-d6) δ 5.01 (q, J = 9.2 Hz, 2H), 5.28 (d, J = 11.2 Hz, 1H), 5.76 (d, J = 17.6 Hz, 1H), 6.50- 6.70 (m, 1H), 8.19 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 13.86 (brs, 1H); ESI-MS (m/z) 248.2 (M+H)+ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-10. Table-10: Structure, Name and analytical data of intermediates (B9-B12)
Figure imgf000074_0002
Intermediate B13 1-(Difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid
Figure imgf000074_0001
Step-1: Methyl 5-bromo-1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate O O Br O N F F To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 1.293 mmol) in DMF (2 mL) were added K2CO3 (356 mg, 2.586 mmol), sodium 2-chloro-2,2- difluoroacetate (393 mg, 2.586 mmol) at room temperature and heated to 80oC for 18 h. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The residue obtained was purified by silica gel chromatography to yield 201 mg of the desired product.1H NMR (400 MHz, DMSO) δ 3.78 (s, 3H), 7.79 (t, J = 59.2 Hz, 1H), 8.18 (s, 1H), 8.42 (s, 1H); ESI-MS (m/z) 283.6 (M+H)+ Step-2: Methyl 1-(difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylate
Figure imgf000075_0001
To a stirred solution of methyl 5-bromo-1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3- carboxylate (150 mg, 0.5319 mmol) and potassium vinyl trifluoroborate (212 mg, 1.595 mmol) in a solvent mixture of toluene (5 mL)/water (1mL) was degassed for 15 min. To this reaction mixture were added K3PO4 (451 mg, 2.127 mmol), Pd(dppf)Cl2.DCM (43 mg,0.05319 mmol) and heated to 120°C for 2 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography to yield 120 mg of the desired product.1H NMR (400 MHz, DMSO) δ 3.80 (s, 3H), 5.27 (d, J = 11.2 Hz, 1H), 5.76 (m, 1H), 6.65 (m, 1H), 7.87 (t, J = 59.2 Hz, 1H), 8.18 (s, 1H), 8.41 (s, 1H); ESI-MS (m/z) 230.1 (M+H)+ Step-3: 1-(Difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid To a stirred solution of methyl 1-(difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3- carboxylate (27 mg, 0.0118 mmol) in THF/Methanol (2 mL) at 0oC was added aqueous lithium hydroxide (14.85 mg, 0.3537 mmol) and stirred at 0oC for 30 min. The solvent was evaporated and acidified with 1N citric acid solution. The aqueous layer was extracted twice with 10% MeOH / DCM and dried over sodium sulphate. The organic layer was concentrated under reduced pressure to yield 19 mg of the desired product. ESI-MS (m/z) 216.20 (M+H)+ Intermediate B14 2-Oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid Methyl 5-bromo-2-oxo-1-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2-dihydropyridine-3- carboxylate
Figure imgf000076_0001
To a stirred solution of methyl 5-bromo-2-hydroxynicotinate (2 g, 8.66 mmol) in dry DMF (20 mL) was added cesium carbonate (4.2 g, 12.99 mmol) and resulting mixture was stirred at room temperature for 30 min. The (3-bromoprop-1-yn-1-yl)trimethylsilane (1.65 mL, 10.39 mmol) was added and stirred at room temperature for 2h. The reaction mixture was diluted with water and extracted thrice with ethyl acetate and the combined organic layers were washed with water and concentrated. The obtained residue was purified by column chromatography to yield 1.8 g of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.24 (s, 9H), 3.92 (s, 3H), 4.78 (s, 2H), 8.13 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H); ESI-MS (m/z) 344.0 (M+2H)+ Methyl 2-oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylate
Figure imgf000076_0002
To a stirred solution of methyl 5-bromo-2-oxo-1-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2- dihydropyridine-3-carboxylate (1.8 g, 5.232 mmol) in toluene (25 mL) and water (5 mL) was added K3PO4 (4.4 g, 20.93 mmol) and trifluoro(vinyl)-l4-borane, potassium salt (2.0 g, 15.69 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. The [1,1′- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (426 mg, 0.523 mmol) was added and the mixture was stirred at 100°C for overnight under nitrogen atmosphere. The mixture was diluted with water and extracted thrice with ethyl acetate. The organic layer was separated and concentrated under vacuum, The obtained residue was purified by silica gel column chromatography to give 190 mg of the product as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H), 4.81 (s, 2H), 5.24 (d, J = 10.8 Hz, 1H), 5.59 (d, J = 17.6 Hz, 1H), 6.43- 6.51 (m, 1H), 7.97 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H). 2-Oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid To a stirred solution of methyl 2-oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3- carboxylate (500 mg, 2.304 mmol) in THF (15 mL), methanol (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (193 mg, 4.608 mmol) and resulting mixture was stirred at room temperature for overnight. The solvent was evaporated completely under reduced pressure, acidified with HCl, solid obtained was collected by filtration to yield 170 mg of desired product as off white solid.1H NMR 400 MHz, DMSO-d6) δ 5.30 (d, J = 11.2 Hz, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.93 (d, J = 6.4 Hz, 2H), 7.58 (d, J =6.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H).8.52-8.59 (m, 1H), 14.00 (s, 1H); ESI-MS (m/z) 204.1 (M+H)+ Intermediate B15 1-(4-Fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid
Figure imgf000077_0001
Methyl 5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate
Figure imgf000077_0002
To a stirred solution of methyl 5-bromo-2-oxo-1, 2-dihydropyridine-3-carboxylate (2.0 g, 1.077 mmol) in DCM (50 mL) were added (4-fluorophenyl)boronic acid (3.2 g, 23.27 mmol), pyridine (3.4 mL, 34.48 mmol) followed by diacetoxycopper (3.4 g, 17.24 mmol) and activated molecular sieves and stirred at room temperature for overnight. The reaction mixture was filtered and diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by silica gel chromatography to yield 650 mg of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 3.76 (s, 3H), 7.34-7.39 (m, 2H), 7.50-7.54 (m, 2H), 8.15 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 3.0 Hz, 1H); ESI-MS (m/z) 327.8 (M+H)+ Methyl 1-(4-fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylate
Figure imgf000077_0003
To a stirred solution of methyl 5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxylate (650 mg, 1.99 mmol) and potassium vinyl trifluoroborate (800 mg, 5.98 mmol) in a mixture of toluene (5 mL) and water (2 mL) was degassed for 15 min. To this reaction mixture were added K3PO4 (1.7 g, 7.96 mmol), Pd(dppf)Cl2.DCM (163 mg, 199 mmol) and heated to 100°C for 3 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained residue was purified by silica gel column chromatography to yield 550 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 3.78 (s, 3H), 5.17 (d, J = 11.3 Hz, 1H), 5.69 (d, J = 17.6 Hz, 1H), 6.56 (d, J = 17.7 Hz, 1H), 7.35- 7.40 (m, 2H), 7.50-7.54 (m, 2H), 8.07 (s, 1H), 8.35 (s, 1H); ESI-MS (m/z) 274.1 (M+H)+ Step-3: 1-(4-Fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid To a stirred solution of methyl 1-(4-fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3- carboxylate (550 mg, 2.01 mmol) in THF / Methanol / Water (25 mL) at 0oC was added aqueous lithium hydroxide (423 mg, 10.07 mmol) and stirred at same temperature for overnight. The solvent was evaporated and acidified with 1 N hydrochloric acid solution. The aqueous layer was extracted twice with 10% MeOH/DCM and dried over sodium sulphate. The organic layer was concentrated under reduced pressure to yield 400 mg of the desired product. ESI-MS (m/z) 260.1 (M+H)+. The mentioned below intermediates were synthesized by following the procedure described above for intermediate B8 and the analytical data are given in below Table-11. Table-11: Structure, Name and analytical data of intermediates (B16-B19)
Figure imgf000078_0001
Figure imgf000079_0004
EXAMPLES Method A: Example-1 1-(Cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000079_0001
Step-1: Methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate
Figure imgf000079_0002
To a stirred solution of 5-bromo-2-hydroxy nicotinic acid (5.0 g, 35.94 mmol) in dry Methanol (100 mL) was added conc. H2SO4 (1 mL) and refluxed for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was basified with saturated sodium bicarbonate solution and stirred for 30 min. The solid obtained was filtered and dried under vacuum to give 4.2 g of the desired product. 1HNMR (400 MHz, DMSO-d6) δ 3.75 (s, 3H), 7.99 (d, J = 2.8 Hz), 8.08 (d, J = 2.8 Hz, 1H), 12.41 (brs, 1H); ESI- MS (m/z) 233 (M+2H) +. Step-2: Methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate
Figure imgf000079_0003
To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (250 mg, 1.077 mmol) in DMF (5 mL) was added potassium carbonate (223 mg, 1.616 mmol) and stirred at room temperature for 30 min. To this mixture was added cyclopropyl methyl bromide (157 μL, 1.616 mmol) and heated to 70°C for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by silica gel chromatography to yield 126 mg of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 0.35- 0.45 (m, 2H), 0.45- 0.55 (m, 2H), 1.18- 1.35 (m, 1H), 3.75 (s, 3H), 3.77 (d, J = 9.6 Hz, 2H), 8.058 (d, J = 2.8 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H); ESI-MS (m/z) 287 (M+2H)+ Step-3: Methyl 1-(cyclopropylmethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylate
Figure imgf000080_0001
To a stirred solution of methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3- carboxylate (500 mg, 1.74 mmol) and potassium vinyl trifluoroborate (700 mg, 5.2 mmol) in a solvent mixture of toluene and water (30 mL) and degassed for 15 min. To this reaction mixture were added K3PO4 (1.5 gm, 6.9 mmol), Pd(dppf)Cl2.DCM (140 mg, 0.17 mmol) and heated to 100°C for 5 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained residue was purified by silica gel column chromatography to yield 350 mg of the desired compound.1HNMR (400 MHz, DMSO-d6) δ 0.30 - 0.45 (m, 2H), 0.45- 0.55 (m, 2H), 1.15- 1.35 (m, 1H), 3.77 (s, 3H), 3.78 (d, J = 8.8 Hz, 2H), 5.14 (d, J = 11.2 Hz, 1H), 5.64 (d, J = 17.6 Hz, 1H), 6.48 - 6.57 (m, 1H), 8.16 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H); ESI-MS (m/z) 234.2 (M+H)+ Methyl 1-(cyclopropylmethyl)-5-formyl-2-oxo-1,2-dihydropyridine-3-carboxylate
Figure imgf000080_0002
To a stirred solution of methyl 1-(cyclopropylmethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3- carboxylate (375 mg, 1.712 mmol) in THF / H2O (4:1, 25 mL) were added NaIO4 (768 mg, 3.59 mmol) followed by 2.5% OsO4 in t-BuOH (36 μl, 0034 mmol). The reaction mixture was stirred at RT for overnight. 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 to yield 303 mg of the desired product.1HNMR (400 MHz, DMSO-d6) δ 0.41- 0.55 (m, 4H), 1.26- 1.31 (m, 1H), 3.79 (s, 3H), 3.88 (d, J = 7.6 Hz, 2H), 8.355 (d, J = 2.8 Hz, 1H), 8.9 (d, J = 2.8 Hz, 1H), 9.66 (s, 1H); ESI-MS (m/z) 236 (M+H) + Step-5: Methyl 1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydro pyridine-3- carboxylate
Figure imgf000081_0001
To a stirred solution of methyl 1-(cyclopropylmethyl)-5-formyl-2-oxo-1,2-dihydropyridine-3- carboxylate (180 mg, 0.765 mmol) and piperidine (152 μl, 1.53 mmol) in DCM (5 mL) was added catalytic amount of acetic acid and stirred for 2 h. To this reaction mixture was added sodium cyano borohydride (144 mg, 2.295 mmol) and stirred at room temperature for overnight. The reaction mixture was quenched with Methanol and concentrated. The obtained residue was purified by flash chromatography to yield 172 mg of the desired product.1HNMR (400 MHz, DMSO-d6) δ 0.40- 0.60 (m, 4H), 1.30- 1.40 (m, 1H), 1.50- 1.60 (m, 2H), 1.60 - 1.75 (m, 4H), 2.90-3.10 (m, 4H), 3.77 (s, 3H), 3.78 (d, J = 9.2 Hz, 2H), 4.12 (brs, 2H), 8.10- 8.30 (m, 2H); ESI-MS (m/z) 305.3 (M+H) + 1-(Cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3- carboxylic acid
Figure imgf000081_0002
To a stirred solution of methyl 1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2- dihydropyridine-3-carboxylate (100 mg, 0.328 mmol) in THF / MeOH (2 mL) was added aqueous LiOH (69 mg, 1.644 mmol) and stirred at room temperature for overnight. The reaction mixture was concentrated and the residue obtained was diluted with water and acidified with 1N citric acid. The aqueous layer was extracted with 20 % MeOH / DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield 74 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.43- 0.55 (m, 4H), 1.20- 1.30 (m, 1H), 1.30- 1.40 (m, 2H), 1.40- 1.60 (m, 4H), 2.30- 2.50 (m, 4H), 3.35 (s, 2H), 3.96 (d, J = 7.2 Hz, 2H), 8.23 (s, 1H), 8.37 (s, 1H), 14.8 (brs, 1H); ESI-MS (m/z) 291.4 (M+H) + 1-(Cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide To a stirred solution of 1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2- dihydropyridine-3-carboxylic acid (70 mg, 0.241 mmol) in DMF was added HATU (110 mg, 0.289 mmol) and stirred at RT for 30 min. To this mixture were added DIPEA (129 μl, 0.723 mmol) and 3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline (66 mg, 0.289 mmol) and stirred for overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The residue obtained was purified by flash column chromatography to yield 9 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 0.40- 0.60 (m, 4H), 1.20- 1.30 (m, 2H), 1.30- 1.40 (m, 1H), 1.43 (s, 6H), 1.60 - 1.80 (m, 4H), 2.30- 2.40 (m, 4H), 2.94 (s, 2H), 3.12 (s, 3H), 3.31 (s, 2H), 3.95 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 8 Hz, 1H), 7.26 (t, J = 8 Hz, 1H), 7.55 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 8.21 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 12.2 (brs, 1H); ESI-MS (m/z) 503.4 (M+H) + Method B: Example-2 N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1- ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000082_0001
Step-1: 5-Bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid
Figure imgf000082_0002
To a stirred solution of methyl 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxylate (1 g, 3.174 mmol) in THF / MeOH (20, mL) was added aqueous LiOH (666 mg, 15.873 mmol) at room temperature for overnight. The reaction mixture was concentrated and the obtained residue diluted with water and acidified with 1N HCl. The solid obtained was filtered and dried under vacuum to yield 630 mg of the desired product.1H NMR (400 MHz, DMSO-d6) δ 4.97 (q, J = 8.8 Hz, 2H), 8.3 (s, 1H), 8.47 (s, 1H), 13.53 (brs, 1H); ESI-MS (m/z) 301.9 (M+2H)+ Step-2: 5-Bromo-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2- oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide To a stirred solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxylic acid (250 mg, 0.833 mmol) in DMF (10 mL) was added HATU (380 mg, 0.999 mmol) and stirred at room temperature for 30 min. To this mixture were added DIPEA (430 μL, 2.499 mmol) and 3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline (191 mg, 0.833 mmol) and stirred for overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by flash column chromatography to yield 330 mg of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 6H), 2.98 (s, 2H), 3.16 (s, 3H), 5.04 (q, J = 9.2 Hz, 2H), 7.07 (d, J =8 Hz, 1H), 7.28 (t, J = 8 Hz, 1H), 7.55 (s, 1H), 7.62 (d, J =8 Hz, 1H), 8.23 (s, 1H), 8.45- 8.55 (m, 2H), 11.50 (s, 1H); ESI-MS (m/z) 512.2 (M+H) + Step-3: N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1- (2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide
Figure imgf000083_0001
To a stirred solution of 5-bromo-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (250 mg, 0.488 mmol) and potassium vinyl trifluoroborate (196 mg, 1.464 mmol) in toluene (5 mL) / water (1 mL) was degassed for 10 min. To this reaction mixture were added K3PO4 (414 mg, 1.954 mmol), Pd(dppf)Cl2.DCM (40 mg, 0.0488 mmol) and heated to 100°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 residue was purified by silica gel column chromatography to yield 230 mg of the desired product.1HNMR (400 MHz, DMSO-d6) δ 1.42 (s, 6H), 2.98 (s.2H), 3.33 (s, 3H), 5.07 (q, J = 9.2 Hz, 2H), 5.31 (d, J = 10.8 Hz, 1H), 5.79 (d, J = 17.6 Hz, 1H), 6.60 - 6.75 (m, 1H), 7.0-7.15 (m, 1H), 7.15-7.25 (m, 1H), 7.25-7.40 (m, 1H), 7.6-7.75 (m, 1H), 8.15-8.30 (m, 2H), 8.73 (s, 1H), 11.64 (s, 1H); ESI-MS (m/z) 460.2 (M+H) +. Step-4: 5-Formyl-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2- oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide To a stirred solution of N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (215 mg, 0.468 mmol) in THF / H2O (4:1, 25 mL) were added NaIO4 (200 mg, 0.936 mmol) followed by 2.5% OsO4 in t-BuOH (10 μL, 0.0009 mmol). The reaction mixture was stirred at room temperature for overnight. 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 to yield 89 mg of the desired product.1HNMR (400 MHz, DMSO-d6) δ 1.43 (s, 6H), 2.99 (s, 2H), 3.13 (s, 3H), 5.10-5.25 (m, 2H), 7. 7.15 (m, 1H), 7.20-7.35 (m, 1H), 7.50- 7.75 (m, 2H), 8.21 (brs, 1H), 8.70-8.85 (m, 1H), 8.94 (s, 1H), 9.81 (s, 1H), 11.21 (s, 1H); ESI- MS (m/z) 461.9 (M+H) + Step-5: N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5- (piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide To a stirred solution of 5-formyl-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (70 mg, 0.151 mmol) and piperidine (45 μl, 0.555 mmol) in DCM (4 mL) was added drop of acetic acid and stirred for 2 h. To this reaction mixture was added sodium triacetoxy borohydride (96 mg, 0.455 mmol) and stirred at room temperature for overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 12 mg of the desired product.1HNMR (400 MHz, DMSO-d6) δ 1.25- 1.40 (m, 2H), 1.43 (s, 6H), 1.40-1.70 (m, 4H), 2.15-2.45 (m, 4H), 2.98 (s, 2H), 3.12 (s, 3H), 3.42 (brs, 2H), 5.0-5.20 (m, 2H), 7.05 (brs, 1H), 7.27 (brs, 1H), 7.5-7.7 (m, 2H), 8.02 (brs, 1H), 8.21 (s, 1H), 8.48 (brs, 1H), 11.75 (brs, 1H); ESI-MS (m/z) 531.2 (M+H)+ The details of synthesis and analytical data of the examples synthesized from the above- mentioned methods are given below in Table-12. Table-12: Structure, method, intermediates used, chemical name and analytical data of Examples (3-8)
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0003
Method C: Example-9 (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide
Figure imgf000087_0001
Step-1: Methyl 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylate
Figure imgf000087_0002
To a stirred solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxylate (1.5 g, 4.76 mmol) and potassium vinyl trifluoroborate (1.91 gm., 14.28 mmol) in a solvent mixture of toluene (50 mL)/water (15 mL) was degassed for 15 min. To this reaction mixture were added K3PO4 (4 g, 19.04 mmol), Pd(dppf)Cl2.DCM (390 mg, 0.476 mmol) and heated to 100°C for 5 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 residue was purified by silica gel column chromatography to yield 1.09 g of the desired compound. 1HNMR (400 MHz, DMSO-d6) δ 3.78 (s, 3H), 4.90 (q, J = 9.2 Hz, 2H), 5.22 (d, J= 11.2 Hz, 1H), 5.68 (d, J = 17.6 Hz, 1H), 6.45- 6.6 (m, 1H), 8.103 (d, J = 2Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H); ESI-MS (m/z) 262.3 (M+H) + Step-2: 2-Oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid
Figure imgf000088_0001
To a stirred solution of methyl 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxylate (1 g, 3.831 mmol) in THF / MeOH (40 mL, 1:1) was added aqueous LiOH (481 mg, 11.49 mmol) and stirred at room temperature for overnight. The reaction mixture was concentrated and the residue obtained was diluted with water and acidified using 1N HCl. The solid precipitated was filtered and dried to yield 809 mg desired product.1HNMR (400 MHz, DMSO-d6) δ 5.01 (q, J = 9.2 Hz, 2H), 5.28 (d, J = 11.2 Hz, 1H), 5.76 (d, J = 17.6 Hz, 1H), 6.50- 6.70 (m, 1H), 8.19 (s, 1H), 8.53 (d, J = 2.4 Hz, 1H), 13.86 (brs, 1H); ESI-MS (m/z) 248.2 (M+H)+ Step-3: N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1- (2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide
Figure imgf000088_0002
To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxylic acid (800 mg, 3.238 mmol) in DMF (15 mL) was added HATU (1.5 g, 3.885 mmol) and stirred at room temperature for 30 min. To this mixture were added DIPEA (1.7 ml, 9.714 mmol) and 3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline (744 mg, 3.238 mmol) and stirred for overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by flash column chromatography to yield 1.41 g of the desired compound.1HNMR (400 MHz, DMSO-d6) δ 1.43 (s, 6H), 3.02 (s, 2H), 3.17 (s, 3H), 5.07 (q, J = 9.2 Hz, 2H), 5.32 (d, J = 10.8 Hz, 1H), 5.79 (d, J = 17.6 Hz, 1H), 6.55- 6.75 (m, 1H), 7.06 (d, J = 8Hz, 1H), 7.28 (d, J = 8 Hz, 1H), 7.55- 7.70 (m, 2H), 8.26 (d, J = 2 Hz, 1H), 8.33 (brs, 1H), 8.73 (d, J = 2.4 Hz, 1H), 11.65 (s, 1H); ESI-MS (m/z) 460.3 (M+H) + Step-4: 5-Formyl-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2- oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000089_0001
To a stirred solution of N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (1.5 g, 3.267 mmol) in THF / H2O (50 mL) were added NaIO4 (2 g, 6.534 mmol) followed by 2.5% OsO4 in t-BuOH (320 μl , 0.032 mmol). The reaction mixture was stirred at room temperature for overnight. 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 to yield 1.12 g of the desired compound. 1HNMR (400 MHz, DMSO-d6) δ 1.47 (s, 6H), 2.99 (s, 2H), 3.13 (s, 3H), 5.19 (q, J = 9.2 Hz, 2H), 7.07 (d, J = 8 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 7.55 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 8.22 (d, J = 3.2 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.95 (d, J = 2.4 Hz, 1H), 9.81 (s, 1H), 11.22 (s, 1H); ESI-MS (m/z) 462.1 (M+H) + Step-5: (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide To a stirred solution of 5-formyl-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (80 mg, 0.173 mmol) and (3S)-3-Methylpiperidine HCl (47 mg, 0.347 mmol) in DCM (3 mL) was added DIPEA (89 μL, 0.519 mmol) and stirred for 2 h. To this reaction mixture was added sodium triacetoxyborohydride (110 mg, 0.519 mmol) and stirred at room temperature for overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by supercritical fluid chromatography (SFC) to yield 29 mg of the desired compound.1HNMR (400 MHz, DMSO-d6) δ 0.82 (d, J = 5.2 Hz, 3H), 1.43 (s, 6H), 1.45-1.70 (m, 5 H), 1.80-1.92 (m, 1H), 2.45-2.50 (m, 1H), 2.70-2.80 (m, 2H), 2.85-2.95 (m, 1H), 3.00 (s, 2H), 3.12 (s, 3H), 3.33 (s, 2H), 5.072 (q, J = 9.2 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 7.27 (t, J =8 Hz, 1H), 7.55 (s, 1H), 7.63 (d, J = 8 Hz, 1H), 8.0 (d, J = 2 Hz, 1H), 8.21 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 11.70 (s, 1H); ESI-MS (m/z) 545.2 (M+H)+ The details of synthesis and analytical data of the examples synthesized from the above- mentioned methods are given below in Table-13. Table-13: Structure, method, intermediates used, chemical name and analytical data of Example (10-46)
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0003
Example 47 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000107_0001
Step-1: N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo- 1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide
Figure imgf000107_0002
To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxylic acid (1.15g, 4.653 mmol) in DMF (15 mL) was added HATU (2.12 g, 5.58 mmol) and stirred at room temperature for 30 min. To this mixture were added DIPEA (2.4 mL, 13.96 mmol) and 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (1.13 g, 4.653 mmol) and stirred for overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by flash column chromatography to yield 1.32 g of the desired compound. 1HNMR (400 MHz, DMSO-d6) δ 1.08 (d, J = 4.8 Hz, 3H), 2.50- 2.53 (m, 3H), 2.79-2.82(m, 2H), 3.16 (s, 3H), 5.08 (q, J = 8.8 Hz, 2H), 5.31 (d, J = 10.8 Hz, 1H), 5.76 (d, J = 3.6 Hz, 1H), 6.60-6.67 (m, 1H), 7.10 (d, J = 7.6Hz, 1H), 7.36-7.39 (m, 1H), 7.62-7.64 (m, 2H), 8.25 (s, 1H), 8.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 11.69 (s, 1H); ESI-MS (m/z) 472.4 (M+H) + Step-2: 5-Formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide To a stirred solution of N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxamide (5.8 g, 12.30 mmol) in THF/H2O (250 mL) were added NaIO4 (5.53 g, 25.83 mmol) followed by 2.5% OsO4 in t-BuOH (800 μl , 0.025 mmol). The reaction mixture was stirred at room temperature for overnight. 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 to yield 4.72 g of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 1.08 (d, J = 4.8 Hz, 3H), 2.50-2.52(m, 3H), 2.81-2.83(m, 2H), 3.18 (s, 3H), 5.19 (q, J = 8.8 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.94 (s, 1H), 9.81 (s, 1H), 11.25 (s, 1H); ESI-MS (m/z) 474.3 (M+H)+ Step-3: 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl) phenyl)-2-oxo-1-(2,2,2-trifluoro ethyl)-1,2-dihydropyrid ine-3-carboxamide: To a stirred solution of 5-Formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide( (3.6 g, 7.603 mmol) and isobutyl amine (2.78 g, 38.02 mmol) in 1,2, Dichloroethane (120 mL) was added acetic acid (1.37 gm, 22.81 mmol) and reflux for 4 h. Cooled the reaction mixture. To this reaction mixture was added sodium triacetoxy borohydride (4.83 gm, 22.81 mmol) portion wise and stirred at room temperature for overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 2.1 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (400 MHz, DMSO-d6): δ 0.87 (d, J = 6.8Hz, 6H), 1.09 (d, J = 4.4 Hz, 3H), 1.66 -1.69 (m, 1H), 2.29 -2.30 (m, 2H), 2.50 - 2.52 (m, 3H), 2.80-2.82 (m, 2H), 3.18 (s, 3H), 3.58 (s, 2H), 5.11 (q, J = 8.4 Hz, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 8.02 (s, 1H), 8.30 (s, 1H), 8.57 (s, 1H), 11.84 (s, 1H); ESI-MS (m/z) 531.4 (M+H)+ The details of synthesis and analytical data of the examples prepared from the above mentioned methods are given below in Table-14. The racemic compounds were prepared from the above mentioned methods and separated using SFC purification to obtain respective chiral isomers (Example 60 – 69). Table-14: Structure, chemical name, method, intermediate used and analytical data of Examples (48-94)
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0002
Example 95 N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000129_0001
Step-1: N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1- (2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide
Figure imgf000130_0001
To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxylic acid (500 mg, 2.02 mmol) in DMF (10 mL) was added HATU (923 mg., 2.42 mmol) and stirred at room temperature for 30 min. To this mixture were added DIPEA (1.04 mL, 6.07 mmol), 3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (518 mg, 2.02 mmol) and stirred for overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The residue obtained was purified by flash column chromatography to yield 830 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 1.06 (s, 3H), 1.12 (s, 3H), 2.58 (d, J = 12.4Hz, 2H), 2.90 (d, J = 12.8Hz, 2H), 3.22 (s, 3H), 5.03 (q, J = 8.8 Hz, 2H), 5.30 (d, J = 10.8 Hz, 1H), 5.78 (d, J = 22.4 Hz, 1H), 6.60- 6.67 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.54-7.62 (m, 2H), 8.24 (d, J = 1.6 Hz, 1H), 8.32(s, 1H), 8.71 (s, 1H), 11.67 (s, 1H); ESI-MS (m/z) 486.3 (M+H) + Step-2: N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-formyl-2- oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000130_0002
To a stirred solution of N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (830 mg, 1.71 mmol) in THF (10.0 mL and H2O (5.0 mL) were added NaIO4 (733 mg, 3.42 mmol) followed by 1.0% OsO4 in t-BuOH (0.017 mL , 0.007 mmol). The reaction mixture was stirred at room temperature for overnight. 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 to yield 710 mg of the desired compound.1H NMR (400 MHz, DMSO-d6) δ 1.05 (s, 3H), 1.13 (s, 3H), 2.58 (d, J = 12.4Hz, 2H), 2.90 (d, J = 12.4Hz, 2H), 3.23 (s, 3H), 5.18 (q, J = 8.8 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 8.33 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.95 (d, J = 2.0 Hz, 1H), 9.81 (s, 1H), 11.23 (s, 1H); ESI-MS (m/z) 488.2 (M+H)+ Step-3: N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide To a stirred solution of N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-formyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (100 mg, 0.20 mmol) and isobutylamine (72 mg, 0.61 mmol) in 1,2, dichloroethane (5.0 mL) was added drop of acetic acid and reflux for 4 h. The reaction mixture was brought to room temperature and then added sodium triacetoxy borohydride (130 mg, 0.61 mmol) portion wise and stirred at room temperature for overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 24 mg of the desired product.1HNMR (400 MHz, DMSO-d6) δ 0.86 (d, J =8.0 Hz, 6H), 1.05 (s, 3H), 1.12 (s, 3H), 1.61-1.71 (m, 1H), 2.27 (d, J =8.0 Hz, 2H), 2.57 (d, J =12.0 Hz, 2H), 2.89 (d, J =12.0 Hz, 2H), 3.22 (s, 3H), 3.56 (s, 2H), 5.08 (q, J =9.2 Hz, 2H), 7.04 (d, J =7.6 Hz, 1H), 7.35 (t, J =7.6 Hz, 1H), 7.56-7.58 (m, 2H), 7.99 (s, 1H), 8.32 (s, 1H), 8.56 (s, 1H), 11.82 (s,1H); ESI-MS (m/z) 545.3 (M+H)+ The details of synthesis and analytical data of the examples prepared from the above mentioned methods are given below in Table-15. Table-15: Structure, chemical name, method, intermediate used and analytical data of Examples (96-151)
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0004
Method D: Example-152 5-(1-(Isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1)
Figure imgf000156_0001
Example-153 5-(1-(isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2)
Figure imgf000156_0002
Step-1: Methyl 5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate
Figure imgf000156_0003
To a stirred solution of methyl 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxylate (800 mg, 2.539 mmol) in 1,4-Dioxane was degassed using N2 for 15 min. Tributyl(1-ethoxyvinyl)tin (943 μL, 2.793 mmol) and Pd(PPh3)2Cl2 (89 mg, 0.126 mmol) were added to reaction mixture at room temperature under nitrogen atmosphere. The reaction mixture was heated to 120oC for overnight in a sealed tube. The reaction mixture was cooled to room temperature and then 2 M HCl (40 ml) was added to reaction mixture and stirred for 1 hr at room temperature. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 450 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 3.8 (s, 3H), 4.9-5.1 (m, 2H), 8.47 (d, J = 2.4 Hz, 1H), 8.92 (d, J = 2.4 Hz, 1H) Step-2: 5-Acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid
Figure imgf000157_0001
To a stirred solution of 5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxylate (440 mg, 1.582 mmol) in THF/MeOH (10 mL) was added 2 mL of aqueous LiOH (199 mg, 4.748 mmol) and stirred at room temperature for overnight. The reaction mixture was concentrated and the residue obtained was diluted with water and acidified using 1N HCl solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and dried to yield 270 mg desired product.1H NMR (400 MHz, DMSO-d6) δ 2.45 (s, 3H), 4.9- 5.2 (m, 2H), 8.57 (d, J = 2.4 Hz, 1H), 8.96 (d, J = 2.4 Hz, 1H), 13.03 (brs, 1H). Step-3: 5-Acetyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000157_0002
To a stirred solution of 5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxylic acid (225 mg, 0.852 mmol) in DMF (4 mL) was added HATU (388 mg, 1.022 mmol) and stirred at room temperature for 30 min. To this mixture were added DIPEA (440 μl, 2.556 mmol) and 3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl)aniline (206 mg, 0.852 mmol) and stirred for overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by flash column chromatography to yield 191 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 1.08(d, J = 5.2 Hz, 3H), 2.4- 2.55 (m, 3H), 2.53 (s, 3H), 3.1- 3.25 (m, 2H), 3.17 (s, 3H), 5.17 (q, J = 8.8 Hz, 2H), 7.12 (d, J = 8 Hz, 1H), 7.38 (t, J = 8 Hz, 1H), 7.59 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 8.3 (s, 1H), 8.84 (d, J = 2.4 Hz, 1H), 8.99 (d, J = 2.4 Hz, 1H), 11.35 (s, 1H). 5-(1-(Isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1) & 5-(1-(isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-2) To a stirred mixture of 5-acetyl-N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl) cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (100 mg, 0.205 mmol) and isobutyl amine hydrochloride (67 mg, 0.616 mmol) in THF were added triethylamine (288 μL, 2.05 mmol) and titanium isopropoxide (174 mg, 0.616 mmol) at room temperature. The reaction mixture was heated to 50oC for 4 h. The reaction mixture was brought to room temperature and then added sodium cyanoborohydride (39 mg, 0.616 mmol) and stirred at room temperature for overnight. The reaction mixture was quenched with saturated NH4Cl solution and diluted with ethyl acetate. The reaction mixture was filtered. The organic layer was separated, concentrated and purified by flash chromatography to obtain 54 mg of the desired racemic product. The racemic product was purified by using SFC 0.1 % NH3 in Methanol to yield 21 mg of the desired Isomer-1 and 23 mg of desired Isomer-2. Isomer-1: 1HNMR (400 MHz, DMSO-d6) δ 0.83 (d, J = 6.4 Hz, 6H), 1.08 (d, J = 5.2 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.4- 1.55 (m, 1H), 1.9- 2.1 (m, 1H), 2.1- 2.3 (m, 1H), 2.40- 2.55 (m, 3H), 2.65- 2.8 (m, 2H), 3.17 (s, 3H), 3.5- 3.65 (m, 1H), 5.02- 5.20 (m, 2H), 7.1 (d, J = 8 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.60- 7.80 (m, 2H), 8.02 (s, 1H), 8.3 (s, 1H), 8.61 (s, 1H), 11.83 (s, 1H); ESI-MS (m/z) 545.31(M+H) + Isomer-2: 1HNMR (400 MHz, DMSO-d6) δ 0.6- 0.8 (m, 6H), 1.08 (d, J = 4.8 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.5- 1.65 (m, 1H), 2- 2.15 (m, 1H), 2.2- 2.3 (m, 1H), 2.40 - 2.60 (m, 3H), 2.70- 2.85 (m, 2H), 3.17 (s, 3H), 3.60- 3.75 (m, 1H), 4.9- 5.2 (m, 2H), 7.1 (d, J = 8 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.60- 7.80 (m, 2H), 8.04 (s, 1H), 8.3 (s, 1H), 8.62 (s, 1H), 11.81 (s, 1H); ESI- MS (m/z) 545.3 (M+H) + The details of synthesis and analytical data of the examples prepared from the above mentioned methods are given below in Table-16. Table-16: Structure, chemical name, method, intermediate used and analytical data of Examples (154-155)
Figure imgf000158_0001
Figure imgf000159_0001
Method E: Example-156 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1H-imidazol-4-yl) cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)phenyl)-2- oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide
Figure imgf000160_0001
To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxylic acid (0.3 g, 1.21 mmol) in DMF (5 ml) at 0 °C was added HATU (0.69 g, 1.82 mmol). After 30 min, 3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl) cyclobutyl)aniline (Intermediate A23) (0.587 g, 1.21 mmol) was added followed by DIPEA (0.47 g, 3.64 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured onto ice-cold water, precipitated solid was filtered and dried under vacuum to afford 0.8 g of the desired compound. ESI-MS (m/z) 713.3 (M+H) + 5-Formyl-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide
Figure imgf000160_0002
To a stirred solution of N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3- carboxamide (0.8 g, 1.21 mmol) in THF (20 ml) and water (4 ml) was added NaIO4 (0.85 g, 3.36 mmol) followed by OsO4 (1 % in t-BuOH, 0.0048 g, 0.0224 mmol, 0.5 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with 10 % of sodium thiosulfate solution (25 mL) and extracted thrice with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, evaporated under reduced pressure to give crude compound. The crude compound was purified by combiflash chromatography to afford 0.550 g of the title compound. ESI-MS (m/z) 715.4 (M+H) + 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol- 4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro pyridine-3-carboxamide To a stirred solution of 5-formyl-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (0.3 g, 0.41 mmol) in EDC (10 ml) was added isobutylamine (0.153 g, 2.09 mmol) and AcOH (0.125 g, 2.09 mmol) and heated at 80 °C for 3h. The reaction mixture was cooled to 0 °C, sodium triacetoxyborohydride (0.26 g, 1.25 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was basified with sat. NaHCO3 and extracted thrice with DCM. The organic layer was separated, dried over anhydrous Na2SO4, evaporated under reduced pressure to give crude compound. The crude compound was purified by combiflash chromatography to afford 0.17 g of the title compound. ESI-MS (m/z) 772 (M+H)+ Step-4: 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1H-imidazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide To a stirred solution of 5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl- 1H-imidazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (0.15 g, 0.1943 mmol) in MeOH (2 ml) at 0 °C was added 4M HCl in dioxane (3 ml) and heated at 80 °C for 3h. The reaction mixture was concentrated, basified with sat NaHCO3 and extracted with EtOAc (3 x 25 ml). The organic layer was separated, dried over anhydrous Na2SO4, evaporated under reduced pressure to give crude compound. The obtained compound was purified by combiflash chromatography to afford 0.05 g of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 0.89 (d, J = 4 Hz, 6H), 1.04 (d, J = 5.2 Hz, 3H), 1.75-1.85 (m, 1H), 1.91 (s, 3H), 2.32-2.34 (m, 3H), 2.46-2.50 (m, 2H), 2.74-2.79 (m, 2H), 3.77 (s, 2H), 5.09 (q, J = 9.0 Hz, 2H), 7.18 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 8.12 (s, 1H), 8.65 (s, 1H), 11.72 (s, 1H); ESI-MS M/Z 530.4 (M+H)+ The details of synthesis and analytical data of the examples prepared from the above mentioned methods are given below in Table-17. Table-17: Structure, chemical name, method, intermediate used and analytical data of Examples (157-160)
Figure imgf000162_0001
Figure imgf000163_0002
Method F: Example-161 N-(3-acetamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide hydrochloride
Figure imgf000163_0001
Step-1: Methyl 5-formyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate To a stirred solution of methyl 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydro pyridine-3- carboxylate (0.5 g, 1.92 mmol) in THF (8 ml) and water (2 ml) was added NaIO4 (0.82 g, 3.83 mmol) followed by OsO4 (1 % in t-BuOH, 0.97 ml, 0.038 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with 10 % of sodium thiosulfate solution (25 ml) and partitioned between EtOAc (3 x 50 ml) and water (25 ml). The organic layer was separated, dried over anhydrous Na2SO4, evaporated under reduced pressure to afford 0.5 g of the title compound. ESI-MS (m/z) 264 (M+H)+ Step-2: Methyl 5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine- 3-carboxylate
Figure imgf000164_0001
To a stirred solution of Methyl 5-formyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihy dropyridine-3- carboxylate (0.5 g, 1.9 mmol) in DCE (10 ml) was added isobutylamine (0.94 ml, 9.5 mmol) and AcOH (0.53 ml, 9.5 mmol) and heated at 80 °C for 3h. The reaction mixture was cooled to 0 °C, sodium triacetoxy borohydride (1.2 g, 5.7 mmol) was added and stirred at room temperature for 16 h. The reaction mixture was basified with sat. NaHCO3 and extracted thrice with DCM. The organic layer was separated, dried over anhydrous Na2SO4, evaporated under reduced pressure to afford 0.52 g of the title compound. ESI-MS (m/z) 321 (M+H)+ Methyl 5-(((tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2- trifluoroethyl)-1,2-dihydropyridine-3-carboxylate
Figure imgf000164_0002
To a stirred solution of methyl 5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxylate (0.52 g, 1.62 mmol) in DCM (5 ml) was added trimethylamine (0.33 ml, 2.43 mmol) and (Boc)2O (0.55 ml, 2.43 mmol) and stirred at room temperature for 16 h. The organic solvent was evaporated under reduced pressure to obtain compound. The obtained compound was purified by combiflash chromatography to afford 0.16 g of the title compound. ESI-MS (m/z) 421 (M+H)+ Step-4: 5-(((Tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxylic acid
Figure imgf000165_0001
To a stirred solution of methyl 5-(((tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1- (2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate (0.162 g, 0.38 mmol) in THF:MeOH:Water (1:1:0.5, 5 ml) was added lithium hydroxide (46 mg, 1.14 mmol) and stirred at room temperature for 16 h. The organic solvent was evaporated under reduced pressure. The obtained residue was acidified by 1N HCl solution and extracted with ethyl acetate (3 x 10 ml). The organic layer dried over anhydrous Na2SO4, evaporated under reduced pressure to obtain compound. The obtained compound was triturated with hexane solvent to afford 135 mg of the title compound.1H NMR (DMSO-d6, 400 MHz) δ 0.81 (d, J = 4 Hz, 6H), 1.40 (s, 9H), 1.86- 1.90 (m, 1H), 2.98-3.0 (m, 2H), 4.25 (s, 2H), 5.07 (q, J = 8 Hz, 2H), 8.09 (s, 1H), 8.39 (s, 1H), 13.8 (bs, 1H); ESI-MS (m/z) 407 (M+H)+ Step-5: Tert-butyl ((5-((3-amino-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)carbamoyl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3- yl)methyl)(isobutyl)carbamate
Figure imgf000165_0002
To a stirred solution of 5-((1r,3r)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cy clobutyl)benzene-1,3-diamine (Intermediate A8) (0.1 g, 0.389 mmol), 5-(((tert- butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxylic acid (0.0631 g, 0.155 mmol) in DMF (5 ml) was added 4- methylmorpholine (0.428ml, 3.89 mmol) and then 50% solution of T3P in DMF (0.371 ml, 0.583 mmol). The reaction mass was stirred at RT for 18 h. The reaction mass was diluted with brine solution (3 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer separated and dried over anhydrous Na2SO4, evaporated under reduced pressure to afford crude compound which was purified by column to obtain 57 mg of required product as yellow solid. ESI-MS (m/z) 646 (M+H)+ Step-6: Tert-butyl ((5-((3-acetamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)carbamoyl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3- yl)methyl)(isobutyl)carbamate
Figure imgf000166_0001
To a stirred solution tert-butyl ((5-((3-amino-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)cyclobutyl)phenyl)carbamoyl)-6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3- yl)methyl)(isobutyl)carbamate (0.055g, 0.085 mmol) in DCM were added triethylamine (0.022 ml, 0.170 mmol) and then acetic anhydride (0.012 ml, 0.127 mmol). The reaction mass was stirred at room temperature for 18 hrs. The reaction mass was diluted with brine solution (3 ml) and extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous Na2SO4, evaporated under reduced pressure to result crude compound which was purified by column to afford 60 mg of the desired product. ESI-MS (m/z) 688 (M+H)+ Step-7: N-(3-acetamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide hydrochloride To a stirred solution N-(3-acrylamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (0.04 g) in DCM was added 4M hydrochloric acid in dioxane (1 ml) and was stirred at room temperature for 2 h. The solvent was evaporated under vacuum and the resulted solid was washed with diethyl ether and dried it to obtain 31 mg of required product as yellow solid.1H NMR (DMSO-d6, 400 MHz) δ 0.96 (d, J = 4 Hz, 6H), 1.10-1.09 (m, 3H), 2.08 (s, 3H), 2.59- 2.58 (m, 3H), 2.79-2.73 (m, 4H), 3.56 (s, 3H), 4.06-4.02 (m, 2H), 5.11 (q, J = 8 Hz, 2H), 7.35 (s, 1H), 7.41 (s, 1H), 8.04 (s, 1H), 8.32 (s, 1H), 8.78 (d, J = 4 Hz, 1H), 9.09 (bs, 2H), 9.18 (s, 1H), 10.17 (s, 1H), 11.66 (s, 1H); ESI-MS (m/z) 588 (M+H)+ The details of synthesis and analytical data of the example prepared from the above mentioned methods are given below in Table-18. Table-18: Structure, chemical name, method, intermediate used and analytical data of Example- 162
Figure imgf000167_0001
The details of synthesis and analytical data of the examples synthesized from the above- mentioned methods are given below in Table-19. Table-19: Structure, method, intermediates used, chemical name and analytical data of Examples (163-205)
Figure imgf000167_0002
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_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-20 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 1000.1 nM. Table-20:
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
(-): Not determined Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WHAT IS CLAIMED IS: 1. A compound of formula (I)
Figure imgf000192_0001
or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, at each occurrence, R1 is selected independently from 3-15 membered heterocyclylC1- 8alkyl, 5-14 membered heteroarylC1-8alkyl and –[CHR]l-NR6R7; wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyC1-8alkyl, C1-8alkyl, – NHC(O)CH3, –NHC(O)CH2CH3 and –NHC(O)CH=CH2.; Z is CH or N; X is CH or N; R is selected from hydrogen and C1-8alkyl; at each occurrence, R2 is selected independently from halogen, –NHC(O)CH3 and – NHC(O)CH=CH2; ring A is 5-14 membered heteroaryl; at each occurrence, R3 is C1-8alkyl; R4 is selected from hydrogen and C1-8alkyl; R5 is selected from C1-8alkyl and C3-12cycloalkyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a 3-15 membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl wherein 3-15 membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen and C1-8alkyl; ‘Y’ is absent or CR8R9; R6 is selected from hydrogen and C1-8alkyl; R7 is selected from C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxyC1-8alkyl, – CH2CH2NHC(O)CH=CH2, C3-12cycloalkyl, C3-12cycloalkylC1-8alkyl and 3-15 membered heterocyclylalkyl; wherein C3-12cycloalkyl and C3-12cycloalkylC1-8alkyl is optionally substituted with C1-8alkyl and haloC1-8alkyl; R8 is hydrogen; R9 is hydrogen; R10 is selected from hydrogen and C1-8alkyl; R11 is selected independently from C1-8alkyl, haloC1-8alkyl, C6-14aryl, C6-14arylC1-8alkyl, 3-15 membered heterocyclylC1-8alkyl, C3-12cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C6- 14aryl, C6-14arylC1-8alkyl are optionally substituted with one or more substituents selected from halogen; ‘l’ is an integer ranging from 0 to 2, both inclusive; ‘m’ is an integer ranging from 0 to 4, both inclusive; ‘n’ is an integer ranging from 1 to 3, both inclusive; and ‘r’ is an integer ranging from 0 to 4, both inclusive. 2. The compound of claim 1, having represented by formula (IA)
Figure imgf000193_0001
or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, X, n, m and r are as defined in claim 1. 3. The compound of claim 1, having represented by formula (IB)
Figure imgf000193_0002
or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, n, m and r are as defined in claim 1. 4. The compound of claim 1, having represented by formula (IC)
Figure imgf000194_0001
or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R1, R2, R3, R4, R5, R10, R11, Y, n, m and r are as defined in claim 1.
Figure imgf000194_0002
6. The compound according to any one of claims 1 to 5, wherein R2 is chloro, fluoro, – NHC(O)CH3 or –NHC(O)CH=CH2 and ‘m’ is 0 or 1. 7. The compound according to any one of claims 1 to 6, wherein R3 is methyl and ‘r’ is 1. 8. The compound according to any one of claims 1 to 7, wherein Y is absent or CH2. 9. The compound according to any one of claims 1 to 8, wherein R4 is hydrogen or CH3. 10. The compound according to any one of claims 1 to 9, wherein R5 is CH3 or cyclobutyl. 11. The compound according to any one of claims 1 to 10, wherein R4 and R5 are CH3. 12. The compound according to any one of claims 1 to 8, wherein R4 and R5 joined together
Figure imgf000195_0001
13. The compound according to any one of claims 1 to 12, wherein R10 is hydrogen or methyl.
14. The compound according to any one of claims 1 to 4, wherein R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,
Figure imgf000196_0001
15. The compound according to any one of claims 1 to 3, wherein ring A
Figure imgf000196_0002
,
Figure imgf000196_0003
16. The compound according to any one of claims 1 to 3, wherein ring A is
Figure imgf000196_0004
. 17. The compound according to any one of claims 1, wherein ‘Z’ is C or N. 18. The compound according to any one of claims 1, wherein ‘Z’ is C. 19. The compound according to any one of claims 1-2, wherein ‘X’ is C or N. 20. The compound according to claim 1, wherein ‘Z’ is CH or N;
Figure imgf000196_0005
R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000197_0001
Figure imgf000197_0002
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,
Figure imgf000198_0001
Figure imgf000198_0002
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. 21. The compound according to claim 2, wherein
Figure imgf000198_0003
R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000199_0001
Figure imgf000199_0002
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or
Figure imgf000199_0003
Figure imgf000199_0004
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. 22. The compound according to claim 3, wherein
Figure imgf000200_0001
R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000201_0001
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or
Figure imgf000201_0002
Figure imgf000201_0003
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. 23. The compound according to claim 4, wherein
Figure imgf000201_0004
R2 is chloro, fluoro, –NHC(O)CH3 or –NHC(O)CH=CH2; R3 is methyl; Y is absent or CH2; R4 is hydrogen or CH3; R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a
Figure imgf000202_0001
Figure imgf000202_0002
R10 is hydrogen or methyl; R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or
Figure imgf000202_0003
Figure imgf000202_0004
‘l’ is 1; ‘n’ is 1; ‘m’ is 0 or 1; and ‘r’ is 1. 24. A compound selected from: 1-(Cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5- (piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-Cyclopropyl-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2,2-Difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(2,2-Difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-Cyclopropyl-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)- 2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-5- (piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(Cyclobutylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan- 2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 1-(Cyclopropylmethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5- (piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5- (pyrrolidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5- (morpholinomethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((4,4-Difluoropiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(Difluoromethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1, 2-dihydropyridine-3-carboxamide; 5-((3-Acetamidopiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1); 5-((3-Acetamidopiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2); 1-(2-Cyclopropylethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (R)-5-((3-Fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-Hydroxypyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; (S)-5-((3-Hydroxypyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; (S)-5-((3-Fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2-Cyclopropylethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3- yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carbox amide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3- carboxamide; (S)-1-(Cyclopropylmethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3- yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-1-(Cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan- 2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((2- methylmorpholino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; (S)-1-(2-Cyclopropylethyl)-5-((3-fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((4-Fluoropiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (R)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((2- methylmorpholino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; (S)-1-(2-Cyclopropylethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan- 2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-Fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol- 3-yl)propan-2-yl)phenyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan- 2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutyl(methyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-(((oxetan-3- ylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(2-fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5- ((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-((3-Isopropylpiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1); 5-((3-Isopropylpiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2); (S)-5-((3-(hydroxymethyl)piperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((2-Hydroxyethyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-Hydroxy-2-methylpropyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((2,2-Difluoroethyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-fluoro-3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5- ((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-((4,4-Dimethyl-1,4-azasilinan-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)- 3-piperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-dihydropyridine-3-carboxamide; 5-(((2-Hydroxy-2-methylpropyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine- 3-carboxamide; N-(2-chloro-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1- methylcyclopropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((R)- 3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1- methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((2-Ethylbutyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3- methylbutan-2-yl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-1); N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3- methylbutan-2-yl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-2); N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2- methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-1); N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2- methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-2); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2); N-(5-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-fluorophenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1); N-(5-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-fluorophenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5- (((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-1); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5- (((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-2); N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 5-(((2-Ethoxyethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2- trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-(((1-methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-5-((tert-pentylamino)methyl)-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-5-((isobutylamino)methyl)-N-(3-(3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl) phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine- 3-carboxamide; 1-(Cyclopropylmethyl)-N-(2-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((Ethylamino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((2-Fluoro-2-methylpropyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1- (cyclopropylmethyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-5-(((cyclopropylmethyl)amino)methyl)-N-(3-(3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-5-(((cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)- 3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; N-(2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; 5-(((S)-3-Acrylamidopyrrolidin-1-yl)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 1-(2-Cyclopropylethyl)-5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo- 5-(((S)-3-propionamidopyrrolidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine- 3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2- dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2- dihydropyridine-3-carboxamide; 5-(((2-Fluoro-2-methylpropyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-1-(4-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2- dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)pyridin-2-yl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; ((S)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-((Isobutylamino)methyl)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan- 5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; (S)-N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan- 2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5-((3- methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((2-Ethylbutyl)amino)methyl)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3- yl)Spiro[2.3]hexan-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2- ethylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2- ethylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5-(((2- methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-1); N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5-(((2- methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide (Isomer-2); 5-(((Cyclopropylmethyl)amino)methyl)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3- yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol- 3-yl)spiro[2.3]hexan-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((neopentylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3- carboxamide; 1-(2,2-Difluoroethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((4- methyl-3-oxopiperazin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro pyridine-3- carboxamide; 1-(2-Cyclopropylethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5- ((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((1- methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-fluorophenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3- fluoro-3-methylazetidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-fluorophenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 1-(2,2-Difluoroethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; 1-(2,2-Difluoroethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)-2-fluorophenyl)-5-((neopentylamino)methyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1- methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 1-(Cyclopropylmethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2- fluoro-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- (((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 1-(2-Cyclopropylethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; 1-(2-Cyclopropylethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)-2-fluorophenyl)-5-(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1,2- dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutyl(methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1- (fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(4- fluorophenyl)-5-(isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2- fluorophenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine- 3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-N-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol- 3-yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-1-(2,2-difluoroethyl)-N-(5-(3,3-dimethyl-1- (4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(1-(isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1); 5-(1-(isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2); (+)N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(1- (isobutylamino)ethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (+)N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)- 5-(1-(isobutylamino)ethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1H-imidazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(5-methyl-1H-imidazol-4-yl)cyclobutyl)phenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(3-(3-methyl-1-(5-methyl-1H-1,2,3-triazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide hydrochloride; 5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1H-1,2,3-triazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(3-((1r,3r)-3-methyl-1-(5-methyl-1H-1,2,3-triazol-4- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-acetamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide hydrochloride; N-(3-acrylamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide 2,2,2-trifluoroacetate; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6- ((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1- ethyl-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-Ethyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2- dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-1-ethyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((3-Fluoro-3-methylbutyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4- methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1- (4-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1- (4-fluorobenzyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-1-methyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-1-(2,2-difluoroethyl)-N-(2-fluoro-5-((1s,3s)- 3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; 5-(((3-Fluoro-2,2-dimethylpropyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1- (4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 1-(2,2-Difluoroethyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2- dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- (((3-fluoro-2,2-dimethylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5- ((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5- ((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((((1-(Fluoromethyl)cyclopropyl)methyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1- (4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1- (3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-1-(4-fluorophenyl)-2-oxo-1,2- dihydropyridine-3-carboxamide; 1-Cyclopropyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-6- ((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2- fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine- 3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4- triazol-3-yl)spiro[3.3]heptan-2-yl)-2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2- fluorophenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2- trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2- fluorophenyl)-5-(((3-fluoro-3-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2- fluorophenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine- 3-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2- fluorophenyl)-5-(((3-fluoro-2,2-dimethylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1- (2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(3-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3- yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2- yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H- 1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- (((3-fluoro-3-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine- 3-carboxamide; N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2- yl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2- trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((3-Fluoro-3-methylbutyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H- 1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5- ((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2- yl)phenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3- carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl- 4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((((1-(fluoro-methyl)cyclopropyl)methyl)amino)methyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-Cyclopropyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2- dihydropyridine-3-carboxamide; 5-(((3-Fluoro-2,2-dimethylpropyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4- methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)- 1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-6-((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4- dihydropyrazine-2-carboxamide; or 6-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3- yl)cyclobutyl)phenyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; and pharmaceutically acceptable salt thereof. 25. A compound of formula
Figure imgf000219_0001
or a pharmaceutically acceptable salt thereof. 26. A compound of formula
Figure imgf000219_0002
or a pharmaceutically acceptable salt thereof. 27. A compound of formula
Figure imgf000219_0003
or a pharmaceutically acceptable salt thereof. 28. A compound of formula or a pharmaceutically acceptable salt thereof. 29. A compound of formula
Figure imgf000220_0001
or a pharmaceutically acceptable salt thereof. 30. A compound of formula
Figure imgf000220_0002
or a pharmaceutically acceptable salt thereof. 31. A compound of formula
Figure imgf000220_0003
or a pharmaceutically acceptable salt thereof. 32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31 and a pharmaceutically acceptable excipient. 33. The pharmaceutical composition according to claim 32, wherein the pharmaceutically acceptable excipient is a carrier or diluent. 34. 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 32.
35. The method according to claim 34, wherein the disease, disorder, or condition is cancer.
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