Substituted pyridinone compounds as Cbl-b inhibitors

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, which are useful as CBL-b inhibitors, processes for their preparation, pharmaceutical compositions containing the compounds, and the use of the compounds or compositions in the treatment or prevention of various diseases, conditions, and / or disorders mediated by CBL-b. [Formula 1] TIFF2025525947000304.tif49159

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of Indian Provisional Application No. 202221046493, filed on August 16, 2022; which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION This patent application relates to novel heterocyclic compounds that are useful as Cbl-b inhibitors, processes for their preparation, pharmaceutical compositions containing the compounds, and the use of the compounds or compositions in the treatment or prevention of various diseases, conditions and / or disorders mediated by Cbl-b. [Background technology]

[0003] CBL (Casitas B-lineage lymphoma) is a mammalian gene encoding the protein CBL, 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. CBL proteins are a highly conserved family of proteins that includes three isoforms: c-Cbl (also known as Cbl2, Cbl-SL, or RNF55), Cbl-b (also known as RNF56), and Cbl-3 (also known as 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, calcium-binding EF-hands, and an Src homology (SH2) domain, followed by a linker helical region and a RING domain (responsible for catalytic function). Cbl-b ubiquitinates all three TAM family members, Tyro-3, Axl, and Mer, and is responsible for immunosuppression and metastasis. A unique property of the TKB domain is that it recognizes specific substrates of Cbl-b, which is achieved by binding to proteins containing specific phosphotyrosine motifs, such as Syk and Zap-70, as well as a series of receptor tyrosine kinases. The interaction of proteins with the TKB domain of Cbl is mediated by three distinct subdomains: a four-helix bundle (4H), a calcium-binding EF-hand, and a variant SH2 domain, all of which are functionally required to form a unique PTB (phosphotyrosine-binding) module [Meng et al., Nature, 398(6722):84-90, 1999]. The SH2 domain within TKB recognizes tyrosine-phosphorylated proteins for ubiquitination [Mohapatra et al., Biochim Biophys Acta., 1833(1):122-39, 2013]. The highly conserved α-helix in 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 TKB, RF, and E2 ubiquitin-conjugating enzymes. The RF domain possesses intrinsic E3 ubiquitin ligase activity, binding to ubiquitin-E2 and transferring 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 have shown that phosphorylation of Y363, located in the L region between the TKB and RF domains, regulates the E3 activity of Cbl-b through two mechanisms: one is by unmasking the RF domain from the TKB domain, and the other is by forming a surface that enhances the binding affinity for E2s [Ryan et al., J Biol Chem.,285(31):23687-98,2010;].

[0004] Casitas B-lineage lymphoma proto-oncogene-b, a RING finger E3 ubiquitin protein ligase, has been demonstrated to play a critical role in establishing the threshold for T cell activation and controlling peripheral T cell tolerance through multiple mechanisms. In T cells, Cbl-b is primarily expressed in peripheral T cells, whereas c-Cbl is primarily expressed in the thymus, suggesting distinct roles for 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 critical intracellular checkpoint that restricts the activation of T and NK cells. Blocking Cbl-b function by genetic deletion potently enhances antitumor 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 primarily by regulating T cell activity through the degradation of phosphoinositol-3-kinase (PI-3-K), downstream of the CD28 costimulatory receptor. The role of Cbl-b in negatively regulating T cell activation and tolerance induction is a tightly controlled process that regulates immune responses to pathogens and tumors while preventing autoimmunity. Autoimmunity is primarily avoided through central tolerance by the negative selection of thymocytes bearing TCRs against self-antigens.

[0005] CBL proteins not only regulate adaptive immune cell function but also are critically involved in regulating innate lymphoid populations, such as NK cells. NK cells are among the first to arrive at inflamed tissues, where they exert potent cytotoxic effector functions and regulate local immune responses [Paolino et al., Nature, 507(7493):508-12, 2014]. NK cells are attractive tools for cell-based immunotherapy thanks to their unique ability to distinguish between healthy cells and virus-infected or naturally transformed cells. NK cell therapy includes adoptive autologous or allogeneic cell therapy, in which NK cells are used to support hematopoietic stem cell transplantation.

[0006] Adoptive cell therapy (ACT) is used to treat cancers that are resistant to other treatments, including metastatic melanoma, glioma, and renal cancer. In ACT, NK cells or T cells are collected from a patient's own blood or tumor tissue, then grown to large numbers in the laboratory. These expanded cells are then infused back into the patient to enhance the patient's immune system's response to the cancer. In some versions of ACT, T cells or NK cells are modified using genetic engineering so that they can target and more efficiently kill the patient's cancer cells. 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, which are part of the innate immune system and are the first line of defense against infection and disease, including cancer cells. Genetic ablation of Cbl-b has been associated with increased susceptibility to spontaneous autoimmunity and experimental induction of autoimmune diseases [Bachmaier et al., Nature, 403(6766):211-6, 2000], and several groups have subsequently demonstrated its role in animal models of diabetes [Yakoi et al., Nat Genet., 31(4):391-4, 2002], as well as in various human autoimmune diseases such as type 1 diabetes [Bergcholdt et al., J Leukoc Biol., 77(4):579-85, 2005], lupus erythematosus [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. al., Nature, 476(7359):214-9, 2011] found an association between genetic Cbl-b variants and susceptibility to autoimmunity, which is not surprising.

[0007] Cbl inhibitors include small molecules, peptides, nucleic acids, or antibodies that inhibit Cbl enzymes. Cbl enzymes include c-Cbl, Cbl-b, and Cbl-c. Cbl inhibitors for use in the treatment methods and compositions of the present disclosure include, but are not limited to, compounds and pharmaceutical compositions for cell-based immunotherapy. Cbl inhibitors can be used in in vivo treatment methods to modulate the immune system, such as by increasing the activation of T cells, NK cells, circulating T cells, tumor-infiltrating lymphocytes, and B cells, to enhance the engraftment of ex vivo-infused expanded immune cells or to increase the durability of responses to the infused ex vivo-expanded immune cells. Additionally, Cbl inhibitors may be used to support the expansion of such immune cells in vitro or ex vivo, increasing their growth and proliferation, or to modulate the phenotype of the resulting expanded immune cells.

[0008] Several patent applications relate to various scaffolds and compounds useful as CBL inhibitors. PCT Publication Nos. WO / 2021 / 061853; WO / 2021 / 061870; WO / 2021 / 021761; WO / 2020 / 264398; WO / 2020 / 236654; WO / 2020 / 210508; and WO / 2019 / 148005 disclose compounds as CBL inhibitors in the treatment of T cell dysfunction and cancer.

[0009] Currently, there is a great unmet need for effective methods for treating diseases and disorders associated with Cbl-b inhibition, including but not limited to autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma.Improved therapeutic compounds, compositions and methods for treating these diseases and disorders are urgently needed.Cbl-b inhibition is a particularly attractive target for cancer immunotherapy. A major challenge currently faced in the field is the lack of CBL-b specific inhibitors. The present disclosure provides novel and highly effective small molecule inhibitors of CBL-b. Summary of the Invention

[0010] In one aspect, the present invention provides a compound of formula (I) [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, During the ceremony, At each occurrence, R 1 are independently 3- to 15-membered heterocyclyl C 1-8 Alkyl, 5-14 membered heteroarylC 1-8 Alkyl, and -[CHR] l -NR 6 R 7 wherein 3 to 15-membered heterocyclylC 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 Alkyl is halogen, oxo, hydroxyl, hydroxyC 1-8 Alkyl, C 1-8optionally substituted with one or more substituents selected from alkyl, -NHC(O)CH3, -NHC(O)CH2CH3, and -NHC(O)CH=CH2; Z is CH or N; X is CH or N; R is hydrogen and C 1-8 alkyl; At each occurrence, R 2 are independently selected from halogen, —NHC(O)CH3, and —NHC(O)CH═CH2; Ring A is a 5-14 membered heteroaryl; At each occurrence, R 3 is C 1-8 is alkyl; R 4 is hydrogen and C 1-8 alkyl; R 5 is C 1-8 Alkyl and C 3-12 cycloalkyl; or R 4 and R 5 together with the carbon atoms to which they are attached form a 3- to 15-membered heterocyclyl, C 3-12 cycloalkyl and 3- to 15-membered spirocyclyl, where 3- to 15-membered heterocyclyl, C 3-12 Cycloalkyl and 3- to 15-membered spirocyclyl are substituted with halogen and C 1-8 optionally substituted with one or more substituents selected from alkyl; "Y" is not present or CR 8 R 9 and; R 6 is hydrogen and C 1-8 alkyl; R 7 is C 1-8 Alkyl, HaloC 1-8 Alkyl, hydroxy C 1-8 Alkyl, C 1-8 Alkoxy C 1-8 Alkyl, -CH2CH2NHC(O)CH=CH2, C 3-12 Cycloalkyl, C3-12 Cycloalkyl C 1-8 alkyl and 3- to 15-membered heterocyclylalkyl; 3-12 Cycloalkyl and C 3-12 Cycloalkyl C 1-8 Alkyl is C 1-8 Alkyl and HaloC 1-8 alkyl, optionally substituted; R 8 is hydrogen; R 9 is hydrogen; R 10 is hydrogen and C 1-8 alkyl; R 11 independently, C 1-8 Alkyl, HaloC 1-8 Alkyl, C 6-14 Aryl, C 6-14 Aryl C 1-8 Alkyl, 3-15 membered heterocyclylC 1-8 Alkyl, C 3-12 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 alkyl; 6-14 Aryl, C 6-14 Aryl C 1-8 alkyl is 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, inclusive; and "r" is an integer ranging from 0 to 4, inclusive.

[0011] In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound represented by Formula (I) disclosed herein and a pharmaceutically acceptable excipient.

[0012] In another aspect, the present invention provides a method for treating a disease or disorder mediated by CBL-B in a subject, comprising administering to a subject in need thereof a compound represented by Formula (I), (IA), (IB), or (IC), or a stereoisomer or pharmaceutically acceptable salt thereof, as described herein.

[0013] The compound of formula (I) may include one or more embodiments. It should be understood that the following embodiments are illustrative of the present invention and are not intended to limit the scope of the claims to the specific embodiments exemplified. It should also be understood that the embodiments defined herein can be used independently or in combination with any other embodiment defined herein. Thus, the present invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the present invention provides a compound 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).

[0014] According to one embodiment, compounds of formula (I) are specifically provided, wherein "Z" is CH or N.

[0015] According to yet another embodiment, there is specifically provided a compound of formula (I) wherein "Z" is CH.

[0016] According to yet another embodiment, compounds of formula (I) are specifically provided wherein "Z" is N.

[0017] According to yet another embodiment, R 1 But -[CHR] l -NR 6 R 7 , 3- to 15-membered heterocyclyl C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8Specifically provided are compounds of formula (I), wherein: 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 Alkyl is halogen, oxo, hydroxyl, hydroxyC 1-8 Alkyl, C 1-8 Optionally substituted with one or more substituents selected from alkyl, -NHC(O)CH3, -NHC(O)CH=CH2, and -NHC(O)CH2CH3.

[0018] According to yet another embodiment, compounds of formula (I) are specifically provided, wherein R 1 is -[CHR] l -NR 6 R 7 where R, l, R 6 and R 7 is as defined in formula (I).

[0019] According to yet another embodiment, compounds of formula (I) are specifically provided, wherein R 1 wherein 3- to 15-membered heterocyclyl C 1-8 Alkyl (for example, [ka] and 5- to 14-membered heteroaryl C 1-8 Alkyl [ka] 3- to 15-membered heterocyclyl C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 The alkyl may be halogen (e.g., fluoro), oxo, hydroxyl, or C 1-8 Alkyl (e.g., hydroxylmethyl), C 1-8 Optionally substituted with one or more substituents selected from alkyl (e.g., methyl or isopropyl), -NHC(O)CH3 alkyl, -NHC(O)CH2CH3 or -NHC(O)CH=CH2. According to yet another embodiment, there is provided a compound of formula (I) comprising R 1 3-15 membered heterocyclyl C 1-8 Alkyl [ka] or 5- to 14-membered heteroaryl C 1-8 Alkyl [ka] wherein 3- to 15-membered heterocyclyl C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 Specifically provided are compounds wherein the alkyl is optionally substituted with one or more substituents selected from fluoro, oxo, hydroxyl, hydroxymethyl, methyl, isopropyl, —NHC(O)CH3, —NHC(O)CH2CH3, or —NHC(O)CH═CH2.

[0020] According to yet another embodiment, there is provided a compound of formula (I) comprising R 1 but, [ka] Specifically provided is a compound wherein:

[0021] According to yet another embodiment, R 1 But -[CHR] l -NR 6 R 7 Specifically provided are compounds of formula (I) wherein R is hydrogen or C 1-8 alkyl; R 6 is hydrogen or C 1-8 alkyl; R 7 is C 1-8 Alkyl, HaloC 1-8 Alkyl, hydroxy C 1-8 Alkyl, C 1-8 Alkoxy C 1-8 Alkyl, -CH2CH2NHC(O)CH=CH2, C 3-12 Cycloalkyl, C3-12 Cycloalkyl C 1-8 alkyl and 3- to 15-membered heterocyclylalkyl; C 3-12 Cycloalkyl and C 3-12 Cycloalkyl C 1-8 Alkyl is C 1-8 Alkyl and HaloC 1-8 alkyl, or unsubstituted with one or more substituents selected from, and "l" is 1.

[0022] According to yet another embodiment, R 1 But -[CHR] l -NR 6 R 7 Specifically provided are compounds of formula (I) wherein 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., difluoroethyl, 2-fluoro-2-methylpropyl, 1-fluoro-2,2-dimethylpropyl, or 2-fluoro-2-methylbutyl), hydroxy C 1-8 alkyl (e.g., hydroxyethyl or 2-hydroxy-2-methylpropyl), C 1-8 Alkoxy C 1-8 alkyl (e.g., ethoxyethyl), -CH2CH2NHC(O)CH=CH2, 3-15 membered heterocyclylalkyl (e.g., methyloxetane), C 3-12 cycloalkyl (e.g., cyclopropyl or cyclobutyl) or C 3-12 Cycloalkyl C 1-8 alkyl (e.g., methylcyclopropyl); 3-12 Cycloalkyl and C 3-12 Cycloalkyl C 1-8 Alkyl is C 1-8alkyl (e.g., methyl) or haloC 1-8 and "l" is 1; and optionally substituted with one or more substituents selected from alkyl (eg, fluoromethyl).

[0023] According to yet another embodiment, R 1 But -[CHR] l -NR 6 R 7 Specifically provided is a compound of formula (I) wherein: In this embodiment, R is hydrogen or methyl; R 6 is hydrogen or methyl; R 7 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, —CHCHNHC(O)CH═CH, methyloxetane, 1-methylcyclopropyl, 1-methylcyclobutyl, cyclopropylmethyl, or 1-fluoromethylcyclopropylmethyl, and “l” is 1.

[0024] According to yet another embodiment, there is provided a compound of formula (I) comprising -[CHR] l -NR 6 R 7 but, [ka] Specifically provided is a compound wherein:

[0025] According to yet another embodiment, there is provided a compound of formula (I) comprising R 1 but, [ka] Specifically provided is a compound wherein:

[0026] According to yet another embodiment, compounds of formula (I) are specifically provided wherein "n" is 1.

[0027] According to yet another embodiment, there is provided a compound of formula (I) comprising R 1 but, [ka] and "n" is 1.

[0028] According to yet another embodiment, compounds of formula (I) are specifically provided wherein "X" is CH or N.

[0029] According to yet another embodiment, there is specifically provided a compound of formula (I) wherein "X" is CH.

[0030] According to yet another embodiment, there is specifically provided compounds of formula (I) wherein "X" is N.

[0031] According to yet another embodiment, R 2 Specifically provided are compounds of formula (I) wherein is halogen (e.g., chloro or fluoro), -NHC(O)CH3, or -NHC(O)CH=CH2.

[0032] According to yet another embodiment, R 2 Specifically provided are compounds of formula (I) wherein is chloro, fluoro, —NHC(O)CH 3 or —NHC(O)CH═CH 2 .

[0033] According to yet another embodiment, compounds of formula (I) wherein "m" is 0 or 1 are specifically provided.

[0034] According to yet another embodiment, there is specifically provided compounds of formula (I) wherein "m" is 0.

[0035] According to yet another embodiment, there is specifically provided compounds of formula (I) wherein "m" is 1.

[0036] According to yet another embodiment, R 2 Specifically provided are compounds of formula (I) wherein is chloro, fluoro, —NHC(O)CH 3 or —NHC(O)CH═CH 2 , and “m” is 0 or 1.

[0037] According to yet another embodiment, ring A is a 5-6 membered heteroaryl [ka] Specifically provided are compounds of formula (I) wherein:

[0038] According to yet another embodiment, ring A is [ka] Specifically provided are compounds of formula (I) wherein:

[0039] According to yet another embodiment, ring A is [ka] Specifically provided are compounds of formula (I) wherein:

[0040] According to yet another embodiment, ring A is [ka] Specifically provided are compounds of formula (I) wherein:

[0041] According to yet another embodiment, ring A is [ka] Specifically provided are compounds of formula (I) wherein:

[0042] According to yet another embodiment, R 3 C 1-8Specifically provided are compounds of formula (I) which are alkyl (eg, methyl).

[0043] According to yet another embodiment, R 3 Specifically provided are compounds of formula (I) wherein is methyl.

[0044] According to yet another embodiment, compounds of formula (I) are specifically provided wherein "r" is 1.

[0045] According to yet another embodiment, R 3 Specifically provided are compounds of formula (I) wherein is methyl and "r" is 1.

[0046] According to yet another embodiment, Y is absent or CR 8 R 9 Specifically provided are compounds of formula (I) wherein:

[0047] According to yet another embodiment, there is specifically provided compounds of formula (I), wherein Y is absent.

[0048] According to yet another embodiment, Y is CR 8 R 9 Specifically provided are compounds of formula (I) wherein R 8 is hydrogen and R 9 is hydrogen.

[0049] According to yet another embodiment, there are specifically provided compounds of formula (I) wherein Y is CH2.

[0050] According to yet another embodiment, there are specifically provided compounds of formula (I) wherein Y is absent or is CH2.

[0051] According to yet another embodiment, R 4 is hydrogen or C 1-8 Specifically provided are compounds of formula (I) which are alkyl (e.g., CH3).

[0052] According to yet another embodiment, R 4 Specifically provided are compounds of formula (I) wherein is hydrogen or CH3.

[0053] According to yet another embodiment, R 5 C 1-8 Alkyl (e.g. CH3) or C 3-12 Specifically provided are compounds of formula (I) that are cycloalkyl (eg, cyclobutyl).

[0054] According to yet another embodiment, R 5 Specifically provided are compounds of formula (I) wherein is CH3 or cyclobutyl.

[0055] According to yet another embodiment, R 4 and R 5 Specifically provided are compounds of formula (I) wherein is CH3.

[0056] According to yet another embodiment, R 4 is hydrogen and R 5 Specifically provided are compounds of formula (I) wherein is cyclobutyl.

[0057] According to yet another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached, C 3-12 cycloalkyl [ka] 3-15 membered heterocyclyl [ka] , or 3- to 15-membered spirocyclyl [ka] where C 3-12 The cycloalkyl or 3- to 15-membered spirocyclyl may be substituted with halogen (e.g., fluoro) or C1-8 Specifically provided are compounds of formula (I) that are optionally substituted with one or more substituents selected from alkyl (eg, methyl or ethyl).

[0058] According to yet another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached, C 3-12 cycloalkyl [ka] , 3- to 15-membered heterocyclyl [ka] , or 3- to 15-membered spirocyclyl [ka] where C 3-12 Specifically provided are compounds of formula (I) wherein the cycloalkyl or 3- to 15-membered spirocyclyl is optionally substituted with one or more substituents selected from fluoro, methyl, or ethyl.

[0059] According to yet another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached, [ka] Specifically provided are compounds of formula (I) which form:

[0060] According to yet another embodiment, R 10 is hydrogen or C 1-8 Specifically provided are compounds of formula (I) which are alkyl (eg, methyl).

[0061] According to yet another embodiment, R 10 Specifically provided are compounds of formula (I) wherein is hydrogen or methyl.

[0062] According to yet another embodiment, R 10 Specifically provided are compounds of formula (I) wherein is hydrogen.

[0063] According to yet another embodiment, R 10 Specifically provided are compounds of formula (I) wherein is methyl.

[0064] According to yet another embodiment, R 11 But C 1-8 Alkyl, HaloC 1-8 Alkyl, C 6-14 Aryl, C 6-14 Aryl C 1-8 Alkyl-, 3- to 15-membered heterocyclylC 1-8 Alkyl, C 3-12 Cycloalkyl, and C 3-8 Cycloalkyl C 1-8 Specifically provided are compounds of formula (I) wherein C is alkyl; 6-14 Aryl and C 6-14 Aryl C 1-8 The alkyl is unsubstituted or substituted with one or more substituents selected from halogen.

[0065] According to yet another embodiment, R 11 C 1-8 Specifically provided are compounds of formula (I) which are alkyl (eg, methyl or ethyl).

[0066] According to yet another embodiment, R 11 Specifically provided are compounds of formula (I) wherein is methyl or ethyl.

[0067] According to yet another embodiment, R 11 Halo C 1-8 Specifically provided are compounds of formula (I) that are alkyl (eg, trifluoroethyl, difluoromethyl, difluoroethyl, or trifluoropropyl).

[0068] According to yet another embodiment, R 11Specifically provided are compounds of formula (I) wherein is difluoromethyl, difluoroethyl, trifluoromethyl, or trifluoropropyl.

[0069] According to yet another embodiment, R 11 C 3-12 Specifically provided are compounds of formula (I) that are cycloalkyl (eg, cyclopropyl).

[0070] According to yet another embodiment, R 11 Specifically provided are compounds of formula (I) wherein is cyclopropyl.

[0071] According to yet another embodiment, R 11 C 3-8 Cycloalkyl C 1-8 Specifically provided are compounds of formula (I) that are alkyl (eg, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl).

[0072] According to yet another embodiment, R 11 Specifically provided are compounds of formula (I) wherein is cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl.

[0073] According to yet another embodiment, R 11 3-15 membered heterocyclylC 1-8 Alkyl [ka] Specifically provided are compounds of formula (I) wherein:

[0074] According to yet another embodiment, R 11 but, [ka] Specifically provided are compounds of formula (I) wherein:

[0075] According to yet another embodiment, wherein R11 But C 6-14 aryl (e.g., phenyl); 6-14 Specifically provided are compounds of formula (I) wherein aryl is optionally substituted with one or more substituents selected from halogen (eg, fluoro).

[0076] According to yet another embodiment, wherein R 11 But C 6-14 aryl (e.g., phenyl); 6-14 Specifically provided are compounds of formula (I) wherein aryl is optionally substituted with one or more substituents selected from fluoro.

[0077] According to yet another embodiment, R 11 but, [ka] Specifically provided are compounds of formula (I) wherein:

[0078] According to yet another embodiment, wherein R 11 But C 6-14 Aryl C 1-8 Alkyl [ka] wherein C 6-14 Aryl C 1-8 Specifically provided are compounds of formula (I) wherein alkyl is optionally substituted with one or more substituents selected from halogen (eg, fluoro).

[0079] According to yet another embodiment, wherein R 11 But C 6-14 Aryl C 1-8 Alkyl [ka] wherein C 6-14 Aryl C 1-8Specifically provided are compounds of formula (I) wherein alkyl is optionally substituted with one or more substituents selected from fluoro.

[0080] According to yet another embodiment, R 11 but, [ka] Specifically provided are compounds of formula (I) wherein:

[0081] According to yet another embodiment, R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropylcyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl; [ka] Specifically provided are compounds of formula (I) wherein:

[0082] According to yet another embodiment, there is provided a compound of formula (I), wherein: "Z" is CH or N; R 1 but, [ka] and; "X" is CH or N; R 2 is chloro, fluoro, -NHC(O)CH3 or -NHC(O)CH=CH2; Ring A is [ka] and; R 3 is methyl; Y is absent or Ch2; R 4 is hydrogen or CH3; R 5is CH3 or cyclobutyl; or R 4 and R 5 together with the carbon atoms to which they are attached, [ka] Forming R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropylcyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl, [ka] and; "l" is 1; "n" is 1; "m" is 0 or 1; and Compounds are specifically provided where "r" is 1.

[0083] According to yet another embodiment, there is provided a compound of formula (I), wherein: "Z" is CH; R 1 but, [ka] and; "X" is CH or N; R 2 is chloro, fluoro, -NHC(O)CH3 or -NHC(O)CH=CH2; Ring A is [ka] and; R 3 is methyl; Y is absent or is CH; R 4 is hydrogen or CH3; R 5 is CH3 or cyclobutyl; or R 4 and R 5 together with the carbon atoms to which they are attached, [ka] Forming R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropylcyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl, [ka] and; "l" is 1; "n" is 1; "m" is 0 or 1; and Compounds are specifically provided where "r" is 1.

[0084] According to yet another embodiment, there is provided a compound of formula (I), wherein: "Z" is CH; R 1 but, [ka] and; "X" is CH; R 2 is chloro, fluoro, -NHC(O)CH3 or -NHC(O)CH=CH2; Ring A is [ka] and; R 3 is methyl; Y is absent or is CH; R4 is hydrogen or CH3; R 5 is CH3 or cyclobutyl; or R 4 and R 5 together with the carbon atoms to which they are attached, [ka] Forming R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropylcyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl, [ka] and; "l" is 1; "n" is 1; "m" is 0 or 1; and Compounds are specifically provided where "r" is 1.

[0085] According to yet another embodiment, there is provided a compound of formula (I), wherein: "Z" is CH; R 1 but, [ka] and; "X" is CH; R 2 is chloro, fluoro, -NHC(O)CH3 or -NHC(O)CH=CH2; Ring A is [ka] and; R 3 is methyl; Y is absent or is CH; R 4 is hydrogen or CH3; R 5 is CH3 or cyclobutyl; or R 4 and R 5 together with the carbon atoms to which they are attached, [ka] Forming R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropylcyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl, [ka] and; "l" is 1; "n" is 1; "m" is 0 or 1; and Compounds are specifically provided where "r" is 1.

[0086] According to certain embodiments, the compound has an IC50 of less than 10,000 nM, preferably less than 1,000 nM, and more preferably less than 100 nM, with respect to CBL family inhibitor activity. 50 Specifically provided are compounds of formula (I) having the values:

[0087] Group rings A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11Further embodiments relating to n, m, and r (and groups defined therein) are described hereinafter in connection with compounds of formula (IA), (IB), or (IC). It is understood that these embodiments are not limited to use in conjunction with formula (IA), (IB), or (IC), but apply independently and individually to compounds of formula (I).

[0088] The present invention also provides compounds of formula (IA), which are embodiments of compounds of formula (I). Thus, the present invention provides a compound of formula (IA) [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, In the formula, 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).

[0089] In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound represented by formula (IA) disclosed herein and a pharmaceutically acceptable excipient.

[0090] In another aspect, the present invention provides a method for treating a disease or disorder mediated by CBL-b, comprising administering a compound of formula (IA) described herein.

[0091] The present invention also relates to an embodiment of the compound of formula (I), the compound of formula (IB): [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 2 , R 3, R 4 , R 5 , R 10 , R 11 Also provided are compounds wherein ring A, Y, n, m and r are as defined in formula (I).

[0092] In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound represented by formula (IB) disclosed herein and a pharmaceutically acceptable excipient.

[0093] In another aspect, the present invention provides a method for treating a disease or disorder mediated by CBL-b, comprising administering a compound of formula (IB) described herein.

[0094] The present invention also relates to an embodiment of the compound of formula (I), the compound of formula (IC): [ka] or a stereoisomer or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 Also provided are compounds wherein Y, n, m and r are as defined in formula (I).

[0095] In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound represented by formula (IC) disclosed herein and a pharmaceutically acceptable excipient.

[0096] 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) described herein.

[0097] Formulas (I), (IA), (IB), and (IC) are understood to structurally encompass all geometric isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the generic chemical structures depicted herein. DETAILED DESCRIPTION OF THE INVENTION

[0098] Definition: The term "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).

[0099] The term "alkyl" refers to a group containing only carbon and hydrogen atoms in its backbone, no unsaturation, and 1 to 8 carbon atoms (i.e., C 1-8 "C" refers to a hydrocarbon chain radical having a substituted or unsubstituted alkyl group (alkyl) and which may be connected 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). 1-6 The term "alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. 1-4 The term "alkyl" refers to an alkyl chain having from 1 to 4 carbon atoms. Unless stated or listed to the contrary, all alkyl groups described or claimed herein can be straight or branched.

[0100] The term "haloalkyl" refers to at least one halo group (selected from F, Cl, Br, or I) (i.e., haloC 1-8 Examples of such haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and fluoromethyl groups. 1-4The term "alkyl" refers to at least one halo group attached to an alkyl chain having from 1 to 4 carbon atoms. Unless stated or listed to the contrary, all alkyl groups described herein can be straight or branched.

[0101] The term "hydroxyalkyl" refers to an alkyl group, as defined above, in which one to three hydrogen atoms on different carbon atoms have been replaced with hydroxyl groups (i.e., hydroxy C 1-8 Examples of hydroxyalkyl moieties include, but are not limited to, —CHOH, —CHOH, and —CH(OH)CHOH.

[0102] The term "alkoxy" means an alkyl group attached to the remainder of the molecule through an oxygen linkage (i.e., C 1-8 alkoxy). Representative examples of such groups are -OCH3 and -OC2H5. Unless stated or listed to the contrary, all alkoxy groups described or claimed herein may be straight or branched.

[0103] 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., C 1-8 Alkoxy C 1-8 Alkyl or C 1-8 Alkyloxy C 1-8 "Alkoxyalkyl" refers to a group consisting of alkoxy groups (alkyl). Examples of such alkoxyalkyl moieties include, but are not limited to, -CHOCH (methoxymethyl) and -CHOCH (ethoxymethyl). Unless stated or listed to the contrary, all alkoxyalkyl groups described herein can be straight-chained or branched.

[0104] "Hydroxy C 1-8 The term "alkyl" refers to a C alkyl group as defined above. 1-8alkyl groups in which one to three hydrogen atoms on different carbon atoms are replaced with hydroxyl groups (i.e., hydroxy C 1-4 (Alkyl) Hydroxy C 1-4 Examples of alkyl moieties include, but are not limited to, -CH2OH and -C2H4OH.

[0105] The term "cycloalkyl" means a non-aromatic monocyclic or multicyclic ring system of 3 to about 12 carbon atoms (i.e., C 3-12 cycloalkyl). Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, perhydronatyl, adamantyl, and norbornyl groups, bridged cyclic groups, or spiro bicyclic groups, such as spiro(4,4)non-2-yl. "C 3-6 The term "cycloalkyl" refers to a cyclic ring having 3 to 6 carbon atoms. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0106] The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e., C 3-6 Cycloalkyl C 1-8 Cycloalkyl groups refer to cycloalkyl groups (alkyl). The cycloalkylalkyl group can 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.

[0107] The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e., C 6-14 Aryl), which includes monocyclic, bicyclic and tricyclic aromatic systems, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0108] The term "arylalkyl" refers to an aromatic radical having 6 to 14 carbon atoms directly attached to an alkyl group (i.e., C 6-14 aryl) (i.e., C 6-14 Aryl C 1-8 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.

[0109] The terms "heterocyclic ring" or "heterocyclyl," unless otherwise specified, refer to a substituted or unsubstituted non-aromatic 3- to 15-membered ring radical (i.e., a 3- to 15-membered heterocyclyl) consisting of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. The heterocyclic ring radical can be a monocyclic, bicyclic, or tricyclic ring system, which can include fused, bridged, or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen, or sulfur atoms in the heterocyclic ring radical can be optionally oxidized to various oxidation states. Furthermore, the nitrogen atom can be optionally quaternized, and, unless otherwise constrained in its definition, the heterocyclic ring or heterocyclyl can 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-oxo Examples include pyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisoquinolyl, 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.

[0110] The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly attached to an alkyl group (i.e., heterocyclylCi_8 alkyl). The heterocyclylalkyl radical can be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

[0111] The term "heteroaryl," unless otherwise specified, refers to a 5- to 14-membered aromatic heterocyclic ring radical having one or more heteroatom(s) independently selected from N, O, or S (i.e., a 5- to 14-membered heteroaryl). A heteroaryl may be a monocyclic, bicyclic, or tricyclic ring system. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that creates 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.

[0112] The term "heteroarylalkyl" refers to a heteroaryl ring radical directly attached to an alkyl group (i.e., heterocyclylCi_8 alkyl). The heteroarylalkyl radical can be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

[0113] 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, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, hydrochloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactate, and the like. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc.

[0114] The terms "treating" or "treatment" of a condition, disorder, or condition include (a) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition in a subject who may be affected by or is susceptible to the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (b) inhibiting the condition, disorder, or condition, i.e., arresting or alleviating the development of the disease or at least one clinical or subclinical symptom thereof; or (c) alleviating the disease, i.e., regressing the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms.

[0115] The term "subject" includes mammals (especially humans), as well as other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

[0116] "Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, 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 being treated.

[0117] The compounds of Formulas (I), (IA), (IB), and (IC) may contain asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of Formulas (I), (IA), (IB), and (IC), and mixtures thereof, including racemic mixtures, are intended to form part of this disclosure. Furthermore, the present invention encompasses all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, 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., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column. The chiral centers of the present invention can have the S or R configuration as defined by IUPAC 1974.

[0118] Terms such as "salt" or "solvate" are intended to apply equally to salts, solvates, and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, regioisomers, or racemates of the compounds of the invention.

[0119] Pharmaceutical Compositions The compound of the present invention is usually administered in the form of pharmaceutical composition.This composition can be prepared by the procedure well known in the pharmaceutical field, and comprises at least one compound of the present invention.The pharmaceutical composition described herein comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.

[0120] In one embodiment, the present invention provides a pharmaceutical composition comprising at least a compound described herein for use in the treatment of a disease or disorder mediated by CBL-b.

[0121] Treatment method The compounds of the present invention are particularly useful because they can inhibit the activity of CBL-b, i.e., prevent, inhibit, or suppress the action of CBL-b, and / or induce a CBL-b modulating effect. Thus, the compounds of the present invention are useful for treating conditions in which inhibition of CBL-b activity, particularly CBL-b inhibition, is beneficial.

[0122] The present application provides a method for the treatment of a disease or disorder mediated by CBL-b in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I), a compound of formula (IA), a compound of formula (IB), a compound of formula (IC), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a mammal, preferably a human, in need of treatment.

[0123] Thus, according to one embodiment, the compounds of the present patent application inhibit CBL-b activity and may be useful in the treatment of diseases or disorders mediated by CBL-b.

[0124] Thus, according to another embodiment, the compounds of the present invention may be useful in the treatment of cancers mediated by CBL-b.

[0125] According to yet another embodiment, provided herein is a method for treating cancer that responds to inhibition of Cbl-b activity, the method comprising administering to an individual an effective amount of a compound of the invention provided herein to treat the cancer that is responsive to inhibition of Cbl-b activity.

[0126] According to yet another embodiment, the compounds of the present invention for use in the treatment of cancer.

[0127] According to yet another embodiment, the compounds of the present invention can be used in methods of modulating the immune system, such as increasing the activation of T cells, NK cells, and B cells, and for the treatment of such cells in vivo, in vitro, or ex vivo.

[0128] In one embodiment, the present invention provides the use of a compound described herein in the preparation of a medicament. In another embodiment, the present invention provides the use of a compound described herein in the preparation of a medicament for the treatment of a disease mediated by CBL-b.

[0129] Any of the methods of treatment described herein involve 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.

[0130] The compounds of the present invention are effective in both the therapeutic and / or prophylactic treatment of the above conditions.

[0131] General method of preparation The compounds, intermediates, and specific examples described herein, including those of general formulae (IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, and IA-9), are prepared via the synthetic methods depicted in Synthetic Schemes 1-6. Furthermore, in the following schemes, when a particular acid, base, reagent, coupling reagent, solvent, or the like is referred to, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents, or the like may be used and are within the scope of the present invention. Modifications to reaction conditions, e.g., temperature, reaction duration, or combinations thereof, are contemplated as part of the present invention. Compounds obtained using the general reaction procedures may be of insufficient purity. These compounds can be purified using any method for purifying organic compounds known to those skilled in the art, such as crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometric and stereoisomers are contemplated within the scope of the present invention.

[0132] General Scheme General formula (IA-1) (wherein, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 A general approach for the preparation of compounds of formula (where "m" and "r" are as defined in the Description) is shown in Synthetic Scheme 1.

[0133] [ka]

[0134] Esterification of the compound of formula (1) gives an ester compound of formula (2) [wherein R' is C 1-8 The reaction is carried out in a suitable solvent. A suitable solvent used in the reaction can be methanol.

[0135] The compound of formula (3) can be obtained by selective N-alkylation of the compound of formula (2) with a suitable alkylating agent in the presence of a suitable base and solvent. The reaction is carried out in the presence of a suitable base. Suitable bases used in the reaction can be selected from cesium carbonate, potassium carbonate, sodium carbonate, sodium hydride, etc. The reaction is carried out in the presence of a suitable solvent. Suitable solvents used in the reaction can be selected from DMSO, DMF, and THF.

[0136] Suzuki coupling of compound (3) with potassium vinyltrifluoroborate in the presence of a suitable base, catalyst, and solvent provides compound (4). The reaction is carried out in the presence of a suitable base. A suitable base used in the reaction can be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate, or cesium carbonate. The reaction is carried out in the presence of a suitable catalyst. A suitable catalyst used in the reaction can 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 coupling reaction can be carried out in a suitable solvent or a mixture thereof. A suitable solvent used in the reaction can be selected from ethanol, toluene, 1,4-dioxane, DMSO, water, or a combination thereof. The compound of formula (4) is oxidatively cleaved using osmium tetroxide and sodium periodate in a suitable mixture of solvents to give the aldehyde compound of formula (5). The reaction is carried out in the presence of a suitable mixture of solvents. The suitable mixture of solvents can be selected from a mixture of THF / water and t-BuOH.

[0137] The reductive amination reaction of a compound of formula (5) with an appropriate amine of formula (6) using a suitable reducing agent in the presence of a suitable catalyst provides a compound of formula (7). The reaction is carried out in the presence of a suitable solvent. Suitable solvents used in the reaction can be selected from dichloromethane, dichloroethane, dimethylformamide, methanol, and ethanol. The reaction is carried out in the presence of a suitable reducing agent. Suitable reducing agents used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride. The reaction is carried out in the presence of a suitable catalyst. A suitable catalyst used in the reaction can be acetic acid.

[0138] Hydrolysis of the compound of formula (7) gives a compound of formula (8). The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can 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 can be selected from methanol, ethanol, or tetrahydrofuran, or a combination thereof.

[0139] The acid-amine coupling reaction of compound (8) with an appropriate aromatic amine compound of formula (9) gives a compound of general formula (IA-1). The reaction is carried out in the presence of a suitable coupling reagent. The suitable coupling reagent used in the reaction can be selected from HATU, EDC.HCl, HOBt, DCC, or T3P. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from dichloromethane, THF, or dimethylformamide. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from DIPEA or TEA.

[0140] General formula (IA-2) (wherein, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10, R 11 A general approach for the preparation of compounds of formula (where "m" and "r" are as defined in the Description) is shown in Synthetic Scheme 2.

[0141] [ka]

[0142] A compound of formula (3) [wherein R' is C 1-8

[0039] The compound of formula (10) is obtained by hydrolysis of the aryl group of the aryl group, which is an alkyl group. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from methanol, ethanol, or tetrahydrofuran, or a combination thereof.

[0143] An acid-amine coupling reaction of compound (10) with an appropriate aromatic amine compound of formula (9) provides a compound of formula (11). The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from dichloromethane, THF, or dimethylformamide. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from DIPEA or TEA. The reaction is carried out in the presence of a suitable coupling reagent. The suitable coupling reagent used in the reaction can be selected from HATU, EDC.HCl, HOBt, DCC, or T3P.

[0144] Suzuki coupling of a compound of formula (11) with potassium vinyltrifluoroborate provides a compound of formula (12). The reaction is carried out in the presence of a suitable base. Suitable bases used in the reaction can be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate, or cesium carbonate. The reaction is carried out in the presence of a suitable catalyst. Suitable catalysts used in the reaction can be selected from tetrakis(triphenylphosphine)palladium(0), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane, and the like, along with suitable phosphine ligands. The reaction can be carried out in the presence of a suitable solvent or a mixture thereof. The suitable solvent can be selected from ethanol, toluene, 1,4-dioxane, DMSO, water, or a combination thereof.

[0145] Upon oxidative cleavage using osmium tetroxide and sodium periodate, the compound of formula (12) yields an aldehyde compound of formula (13). The reaction is carried out in the presence of a suitable solvent or a mixture thereof. A suitable solvent used in the reaction may be THF / water.

[0146] The compound of formula (13) is subjected to a reductive amination reaction with an appropriate amine compound of formula (6) to obtain a compound of general formula (IA-2). The reaction is carried out in the presence of a suitable catalyst. A suitable catalyst used in the reaction can be acetic acid. The reaction is carried out in the presence of a suitable base. A suitable base used in the reaction can be selected from TEA or DIPEA. The reaction can be carried out in the presence of a suitable solvent. A suitable solvent used in the reaction can be selected from dichloromethane, dimethylformamide, methanol, and ethanol. The reaction is carried out in the presence of a suitable reducing agent. A suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride. General formula (IA-3 and IA-4) (wherein X, Y, Z, R 2 , R 3 , R 4, R 5 , R 6 , R 7 , R 10 , R 11 A general approach for the preparation of compounds of formula (where "m" and "r" are as defined in the Description) is shown in Synthetic Scheme 3.

[0147] [ka]

[0148] A compound of formula (3) [wherein R' is C 1-8 Suzuki coupling reaction of the alkyl group with potassium vinyltrifluoroborate provides a compound of formula (4). The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate, or cesium carbonate. The reaction is carried out in the presence of a suitable catalyst. The suitable catalyst used in the reaction can 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 can be carried out in the presence of a suitable solvent or a mixture thereof. The suitable solvent used in the reaction can be selected from ethanol, toluene, 1,4-dioxane, DMSO, water, or a combination thereof.

[0149] Hydrolysis of the compound of formula (4) in the presence of a suitable base and solvent provides a compound of formula (14). The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from methanol, ethanol, or tetrahydrofuran, or a combination thereof.

[0150] An acid-amine coupling reaction of compound (14) with an appropriate aromatic amine compound of formula (9) provides a compound of formula (15). The reaction is carried out in the presence of a suitable coupling reagent. The suitable coupling reagent used in the reaction can be selected from HATU, EDC.HCl, HOBt, DCC, or T3P. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from dichloromethane, THF, or dimethylformamide. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from DIPEA or TEA.

[0151] Upon oxidative cleavage using osmium tetroxide and sodium periodate, the compound of formula (15) yields the aldehyde compound of formula (16). The reaction is carried out in the presence of a suitable solvent or a mixture thereof. A suitable solvent used in the reaction may be THF / water.

[0152] The reductive amination reaction of the compound of formula (16) with an appropriate amine (6) provides a compound of formula (IA-3). The reaction is carried out in the presence of a suitable catalyst. A suitable catalyst used in the reaction can be acetic acid. The reaction is carried out in the presence of a suitable base. A suitable base used in the reaction can be selected from triethylamine or DIPEA. The reaction is carried out in the presence of a suitable solvent. A suitable solvent used in the reaction can be selected from dichloromethane, dichloroethane, dimethylformamide, methanol, and ethanol. The reaction is carried out in the presence of a suitable reducing agent. A suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride.

[0153] Compound of formula (IA-4) can be obtained by treating compound of formula (IA-3) with a suitable inorganic acid in a suitable solvent. The reaction is carried out in the presence of a suitable inorganic acid. The suitable inorganic acid used in the reaction can be selected from hydrochloric acid or TFA. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from dichloromethane, dichloroethane or THF.

[0154] 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 A general approach for the preparation of compounds of formula (where "m" and "r" are as defined in the Description) is shown in Synthetic Scheme 4.

[0155] [ka] Stille coupling reaction of the compound of formula (3) with tributyl(1-ethoxyvinyl)tin gives the compound of formula (17). The reaction is carried out in the presence of a suitable catalyst. Suitable catalysts used in the reaction can be selected from tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium acetate, and the like, along with suitable phosphine ligands. The reaction is carried out in the presence of a suitable solvent. Suitable solvents used in the reaction can be selected from 1,4-dioxane, DMSO, or DMF.

[0156] Hydrolysis of the compound of formula (17) gives a compound of formula (18). The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from methanol, ethanol, or tetrahydrofuran, or a combination thereof.

[0157] An acid-amine coupling reaction of compound (18) with an appropriate aromatic amine compound of formula (9) provides a compound of formula (19). The reaction is carried out in the presence of a suitable coupling reagent. The suitable coupling reagent used in the reaction can be selected from HATU, EDC.HCl, HOBt, DCC, or T3P. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from dichloromethane, THF, or dimethylformamide. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from DIPEA or TEA.

[0158] The compound of formula (19) is subjected to a reductive amination reaction with an appropriate amine compound of formula (6) to obtain a compound of formula (IA-5). The reaction is carried out in the presence of a suitable catalyst. A suitable catalyst used in the reaction can be acetic acid. The reaction is carried out in the presence of a suitable base. A suitable base used in the reaction can be selected from triethylamine or DIPEA. The reaction is carried out in the presence of a suitable solvent. A suitable solvent used in the reaction can be selected from dichloromethane, dichloroethane, dimethylformamide, methanol, and ethanol. The reaction is carried out in the presence of a suitable reducing agent. A suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride.

[0159] Supercritical fluid chromatography (SFC) purification of the racemic compound of formula (IA-5) gives compounds of general formula (IA-6) and compounds of general formula (IA-7).

[0160] General formula (IA-8) (wherein, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 A general approach for the preparation of compounds of formula (where "m" and "r" are as defined in the Description) is shown in Synthetic Scheme 5.

[0161] [ka] An acid-amine coupling reaction of compound (14) with a suitable aromatic amine compound of formula (20) (wherein Q is C or N) provides a compound of formula (21). The reaction is carried out in the presence of a suitable coupling reagent. The suitable coupling reagent used in the reaction can be selected from HATU, EDC.HCl, HOBt, DCC, or T3P. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from dichloromethane, THF, or dimethylformamide. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from DIPEA or TEA.

[0162] Upon oxidative cleavage using osmium tetroxide and sodium periodate, the compound of formula (21) yields an aldehyde compound of formula (22). The reaction is carried out in the presence of a suitable solvent or a mixture thereof. A suitable solvent used in the reaction may be THF / water.

[0163] The reductive amination reaction of a compound of formula (22) with an appropriate amine compound of formula (6) provides a compound of general formula (23). The reaction is carried out in the presence of a suitable catalyst. A suitable catalyst used in the reaction is acetic acid. The reaction is carried out in the presence of a suitable base. A suitable base used in the reaction can be selected from triethylamine or DIPEA. The reaction is carried out in the presence of a suitable solvent. A suitable solvent used in the reaction can be selected from dichloromethane, dimethylformamide, methanol, and ethanol. The reaction is carried out in the presence of a suitable reducing agent. A suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride. Deprotection of the compound of formula (23) gives a compound of formula (IA-8). The reaction may be carried out in the presence of a suitable acid. Suitable acids used in the reaction may be selected from hydrochloric acid and trifluoroacetic acid. The reaction is carried out in the presence of a suitable solvent. Suitable solvents used in the reaction may be selected from methanol, ethanol, dichloroethane, and 1,4-dioxane.

[0164] General formula (IA-9) (wherein, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 A general approach for the preparation of compounds of formula (where "m" and "r" are as defined in the Description) is shown in Synthetic Scheme 6.

[0165] [ka] Upon oxidative cleavage using osmium tetroxide and sodium periodate, compounds of formula (4) [wherein R' is C 1-8 The reaction of the alkyl group with the aldehyde compound of formula (5) is carried out in the presence of a suitable solvent or a mixture thereof. A suitable solvent used in the reaction may be THF / water.

[0166] The compound of formula (5) is subjected to a reductive amination reaction with an appropriate amine compound of formula (24) to obtain a compound of formula (26). The reaction is carried out in the 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 reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, dimethylformamide, methanol, and ethanol.

[0167] The amine compound of formula (25) is N-protected using a suitable protecting group (PG) to give a compound of formula (26). The reaction is carried out in the presence of a suitable protecting group. Suitable protecting groups used in the reaction can be selected from di-tert-butyl dicarbonate, acetic anhydride, and benzyl chloroformate.

[0168] The compound of formula (26) is hydrolyzed to give the compound of formula (27). The reaction is carried out in the presence of a 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 the presence of a suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol, and tetrahydrofuran, or a combination thereof.

[0169] An acid-amine coupling reaction between a compound of formula (27) and an appropriate aromatic amine compound of formula (28) provides a compound of formula (29). The reaction is carried out in the presence of a suitable coupling reagent. The suitable coupling reagent used in the reaction can be selected from HATU, EDC.HCl, HOBt, DCC, or T3P. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from dichloromethane, THF, or dimethylformamide. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from DIPEA or TEA.

[0170] Acylation of the compound of formula (29) gives the compound of formula (30). The reaction is carried out in the presence of a suitable acylating reagent. The suitable acylating reagent used in the reaction can be acetic anhydride or acryloyl chloride.

[0171] Deprotection of the compound of formula (30) gives a compound of formula (IA-9). The reaction is carried out in the presence of a suitable acid. Suitable acids used in the reaction can be selected from hydrochloric acid and trifluoroacetic acid. The reaction is carried out in the presence of a suitable solvent. Suitable solvents used in the reaction can be selected from dichloromethane, dichloroethane, and 1,4-dioxane.

[0172] Experimental Section Unless otherwise specified, workup includes partitioning the reaction mixture between organic and aqueous phases, as indicated in parentheses, separating the layers and drying the organic layer with sodium sulfate, filtering, and evaporating the solvent. Unless otherwise noted, purification includes purification by silica gel chromatographic techniques, typically using a polar ethyl acetate / petroleum ether mixture as the mobile phase. The use of different eluent systems is indicated in parentheses.

[0173] The abbreviations, symbols and terms used throughout the examples have the following meanings: [Table 1] TIFF2025525947000056.tif80159

[0174] Intermediates Intermediate A1 3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline [ka] Step 1: 3-(3-bromophenyl)-3-methylbutyric acid [ka] To a stirred solution of bromobenzene (10 g, 0.0183 mmol) in DCM (100 mL) was added 3,3-dimethylacrylic acid (3.19 g, 0.0318 mol). AlCl was added portionwise to the reaction mixture at 15-20 °C 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 sulfate, and concentrated under reduced pressure. The resulting residue was purified by SFC to give 3.1 g of the desired product. 1 H NMR (400MHz, DMSO-d6) δ1.36 (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).

[0175] Step-2: 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N-methylhydrazinecarbothioamide [ka] To a stirred solution of 3-(3-bromophenyl)-3-methylbutyric 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 minutes. 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 hours. The reaction mixture was diluted with water and stirred for 30 minutes. The resulting solid was filtered and dried under vacuum to give 4.83 g of the desired product. 1 H NMR (400MHz, DMSO-d6) δ1.36(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).

[0176] Step-3: 3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione [ka]

[0177] A stirred solution of 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N-methylhydrazinecarbothioamide (4.8 g, 0.0139 mol) in 1 N NaOH (170 mL) was stirred at room temperature for 18 hours. The reaction mixture was acidified using 3 N HCl and stirred for 15 minutes. The precipitated solid was filtered, washed with excess water, and dried under vacuum to give 4.31 g of the desired product. 1 H NMR(400MHz,DMSO-d6)δ1.40(s,6H),3.03(s,2H),3.13(s,3H),7.23-7.27(m,1 H),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 [ka] 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% HO solution (4.3 mL) and stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether, filtered, and dried to give 4.2 g of the desired product. 1 H NMR(400MHz,DMSO-d6)δ1.42(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) +

[0178] Step-5: 3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline 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) in a sealed tube was added aqueous NH (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 resulting residue was triturated with diethyl ether to give 641 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ1.33(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) +

[0179] Intermediate A2 2-Fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline [ka]

[0180] Step-1: Diethyl 2-(2-(3-bromo-4-fluorophenyl)propan-2-yl)malonate [ka] To a stirred solution of 2-bromo-4-iodo-1-fluorobenzene (5.86 g, 19.5 mmol) in THF (15 mL) was added dropwise a 2 M solution of isopropylmagnesium chloride in THF (11.25 mL, 22.5 mmol) at −10° C., stirred for 30 minutes at 0° C., and then stirred at room temperature for 1 hour. To this mixture was added copper(I) iodide (860 mg, 4.5 mmol) at 0° C., stirred for 10 minutes, and then diethyl isopropylidenemalonate (3 g, 15 mmol) was added. The reaction mixture was heated to 60° C. for 2 hours. The reaction mixture was quenched with 1N HCl and diluted with ethyl acetate. The resulting suspension was filtered and washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to give 3.5 g of the desired product. 1 H NMR (400MHz, CDCl3): δ1.17(t,J=7.2Hz,6H),1.57(s,6H),3.73(s,1H),4.10(q,J=6.8Hz ,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) +

[0181] Step 2: Ethyl 3-(3-bromo-4-fluorophenyl)-3-methylbutanoate [ka] A stirred solution of diethyl 2-(2-(3-bromo-4-fluorophenyl)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 at 200° C. for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to give 1.5 g of the desired product. 1H NMR (400MHz, CDCl3): δ1.12(t,J=7.2Hz,3H),1.45(s,6H),2.60(s,2H),4.01(q,J=7.2Hz ,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) +

[0182] Step-3: 3-(3-bromo-4-fluorophenyl)-3-methylbutanehydrazide [ka] To a stirred solution of ethyl 3-(3-bromo-4-fluorophenyl)-3-methylbutanoate (1.5 g, 4.95 mmol) in MeOH (7 mL) was added dropwise 99% hydrazine hydrate (7 mL) at 0° C. The reaction mixture was warmed to room temperature and heated to 90° C. for 16 hours. The mixture was concentrated, and the resulting 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 give 1.4 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.33(s,6H),2.33(s,2H),4.10(brs,2H),7.25-7.30(m,1 H),7.38-7.42(m,1H),7.60-7.62(m,1H),8.87(brs,1H);ESI-MS(m / z)290.1(M+2H) +

[0183] Step-4: 2-(3-(3-bromo-4-fluorophenyl)-3-methylbutanoyl)-N-methylhydrazinecarbothioamide [ka] 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 methyl isothiocyanate (1 g, 13.86 mmol). The reaction mixture was stirred at room temperature for 1 hour and heated to 80° C. for 3 hours. The mixture was concentrated under reduced pressure, and the resulting residue was triturated with pentane. The resulting solid was filtered and dried under vacuum to give 1.6 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.36(s,6H),2.40(s,2H),2.82(d,J=4.0Hz,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) +

[0184] Step-5: 5-(2-(3-bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole-3-thiol [ka] 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 hours. The reaction mixture was acidified using 2 N HCl and stirred for 15 minutes. The precipitated solid was filtered, washed with excess water, and dried under vacuum to give 1.3 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.39(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) +

[0185] Step 6: 3-(2-(3-bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole [ka] 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) was added 30% HO 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 resulting solid was purified by silica gel column chromatography to give 900 mg of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.40(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) +

[0186] Step-7: 2-fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline 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 NH (4 mL), copper(I) oxide (73 mg, 0.512 mmol) in a sealed tube and stirred at 90° C. for 16 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under vacuum to give 300 mg of the desired product. 1HNMR (400MHz, DMSO-d6): δ1.34(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) +

[0187] The analytical data of the intermediates prepared according to the above procedures are shown in Table 1 below. [Table 2]

[0188] Intermediate A4 3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline [ka] Step 1: Ethyl 2-(oxetan-3-ylidene)acetate [ka] To a stirred solution of NaH (611 mg, 15.27 mmol) in THF (25 mL), ethyl 2-(diethoxyphosphoryl)acetate (3.422 mg, 15.27 mmol) was added dropwise over 10-15 min at 0 °C 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 and extracted twice with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel chromatography to give 1.2 g of the desired product. 1 H NMR (400MHz, CDCl3) δ1.28(t,J=7.2Hz,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).

[0189] Step-2: Ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate [ka] To a degassed solution of [Rh(COD)Cl] (170 mg, 0.352 mmol) in dioxane (15 mL), 1.5% aqueous KOH (6 mL) was added dropwise at room temperature and stirred for 30 minutes. To this mixture, a solution of ethyl 2-(oxetan-3-ylidene)acetate (1 g, 7.042 mmol) in dioxane (10 mL) followed by a solution of (3-bromophenyl)boronic acid (2 g, 10.56 mmol) in dioxane (10 mL) was added dropwise and stirred for 1 hour. The reaction was stirred for 1 hour, and (3-bromophenyl)boronic acid (700 mg, 3.521 mmol) was added again to the reaction mixture and stirred for 48 hours at room temperature. The mixture was quenched with brine solution and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give 1.3 g of the desired product. 1 H NMR(400MHz,DMSO-d6)δ1.04(t,J=7.2Hz,3H),2.50-2.52(m,2H),3.92(q,J=6.8Hz,2H ),4.75(d,J=6.4Hz,2H),4.79(d,J=6.4Hz,2H),7.28-7.32(m,2H),7.45-7.46(m,2H).

[0190] Step-3: 2-(3-(3-bromophenyl)oxetan-3-yl)acetic acid [ka] 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 LiOH (40 mg, 1 mmol) at 0° C. and stirred at room temperature for 4 h. The solvent was removed and acidified using 1N HCl. The aqueous layer was extracted twice with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated to give 140 mg of the desired product. 1H NMR(400MHz,DMSO)δ3.09(s,2H),4.74-4.78(m,4H),7.32(d,J=4.8Hz,2H),7.44-7.49(m,2H),12.24(brs,1H)

[0191] Step 4: 2-(2-(3-(3-bromophenyl)oxetan-3-yl)acetyl)-N-methylhydrazinecarbothioamide [ka] 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 minutes. N-methylhydrazinecarbothioamide (57 mg, 0.547 mmol) and DIPEA (192 mg, 1.494 mmol) were added to the reaction mixture and stirred at room temperature for 18 hours. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to give 145 mg of the desired product. 1 H NMR(400MHz,DMSO)δ 2.51(d,J=4.8Hz,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) +

[0192] Step-5: 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione [ka] A stirred solution of 2-(2-(3-(3-bromophenyl)oxetan-3-yl)acetyl)-N-methylhydrazinecarbothioamide (100 mg, 0.28 mmol) in 1 N NaOH (3.5 mL) was stirred at room temperature for 18 hours. The mixture was cooled and neutralized using 1 N HCl. The resulting solid was filtered and dried under vacuum to give 65 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ3.01(s,3H),3.53(s,2H),4.78-4.82(m,4H),7.17(d,J=7.6Hz, 1H),7.28(t,J=7.6Hz,1H),7.44-7.46(m,2H),13.49(brs,1H);ESI-MS(m / z)340.2(M+H) +

[0193] Step-6: 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole [ka] 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 mol) in water (1.5 mL) was added NaNO (750 mg, 10.32 mmol), followed by dropwise addition of 1N HNO (3.5 mL) at 0 °C and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography to give 245 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ3.02(s,3H),3.49(s,2H),4.81(d,J=6Hz,2H),4.89(d,J=6Hz,2H),7. 00(d,J=7.6Hz,1H),7.24(m,2H),7.41(d,J=7.6Hz,1H),8.23(s,1H);ESI-MS(m / z)309.9(M+H) +

[0194] Step-7: 3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline 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) was added aqueous NH (2 mL), copper(I) oxide (35 mg, 0.2515 mmol) in a sealed tube and stirred at 90 °C for 16 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic layer was evaporated under vacuum to give 160 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ2.83(s,3H),3.39(s,2H),4.75(d,J=6Hz,2H),4.85(d,J=6Hz,2H),5.02(brs.2H),5.92 (d,J=7.2Hz,1H),6.04(s,1H),6.39-6.41(m,1H),6.89(d,J=8Hz,1H),8.21(brs,1H);ESI-MS(m / z)245.2(M+H) +

[0195] Intermediate A5 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka] Step 1: 1,3-Dibromo-2-methylpropane [ka] To a stirred solution of 2-methyl-1,3-propanediol (20 g, 222 mmol) and triphenylphosphine (128.1 g, 488.3 mmol) in DCM (500 mL), N-bromosuccinimide (86.92 g, 488.35 mmol) was added portionwise at 0° C. and stirred at room temperature for 16 h. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography to give 23.4 g of the desired product. 1HNMR (400MHz, CDCl3): δ1.17 (d, J=6.4Hz, 3H), 2.18-2.24 (m, 1H), 3.46-3.56 (m, 4H).

[0196] Step-2: 1-(3-bromophenyl)-3-methylcyclobutanecarbonitrile [ka] To a stirred suspension of NaH (60% suspension in mineral oil) (2.58 g, 107.65 mmol) in DMF (100 mL) was added dropwise a 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 NH Cl solution. The aqueous layer was extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous Na SO and concentrated. The resulting residue was purified by silica gel column chromatography to give 9.15 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.22(d,J=6Hz,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=1.6Hz,1H).

[0197] Step-3: 1-(3-bromophenyl)-3-methylcyclobutanecarboxylic acid [ka] To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarbonitrile (17.7 g, 70.76 mmol) in 80 mL of AcOH / HO (1:1) was added concentrated HSO (40 mL) dropwise at 0 °C, 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 NaSO, and concentrated to give 18 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.06(d,J=6.4Hz,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)

[0198] Step 4: Methyl 1-(3-bromophenyl)-3-methylcyclobutanecarboxylate [ka] To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarboxylic acid (18.3 g, 67.99 mmol) in MeOH (180 mL) was added concentrated HSO (18 mL), stirred at room temperature for 2 h, and heated to 90 °C for 16 h. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate. The organic layer was washed with water, brine solution, and dried over anhydrous NaSO. The solvent was evaporated in vacuo to give 19.1 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.15(d,J=6.8Hz,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=2Hz,1H).

[0199] Step 5: 1-(3-bromophenyl)-3-methylcyclobutanecarbohydrazide [ka] 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 resulting 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 give 19.18 g of the desired product. ESI-MS (m / z) 283.1 (M+H). +

[0200] Step-6: 2-(1-(3-bromophenyl)-3-methylcyclobutanecarbonyl)-N-methylhydrazinecarbothioamide [ka] To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarbohydrazide (19.0 g, 67.09 mmol) in THF (200 mL) was added methyl isothiocyanate (14.71 g, 201.3 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h and heated to 80° C. for 3 h. The mixture was concentrated under reduced pressure, and the resulting residue was triturated with pentane. The resulting solid was filtered and dried under vacuum to give 23.8 g of the desired product. ESI-MS (m / z) 356.0 (M+H). +

[0201] Step-7: 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ka] A stirred solution of 2-(1-(3-bromophenyl)-3-methylcyclobutanecarbonyl)-N-methylhydrazinecarbothioamide (23.4 g, 65.67 mmol) in 1 N NaOH (500 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified using 2 N HCl and stirred for 15 minutes. The precipitated solid was filtered, washed with excess water, and dried under vacuum to give 20.18 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.06(d,J=6.0Hz,3H),2.45-2.51(m,3H),2.76(d,J=3.6Hz,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) +

[0202] Step-8: 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole [ka] 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% HO 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 resulting solid was purified by silica gel column chromatography to give 4.8 g of the racemic desired product. The resulting racemic product was purified by SFC purification to give 2.65 g of the cis isomer of the desired product. 1HNMR (400MHz, CDCl3): δ1.16(d,J=5.6Hz,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) +

[0203] Step-9: 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline 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) in a sealed tube, and copper oxide (47 mg, 0.326 mmol) was added and stirred at 90 °C for 16 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under vacuum to give 171 mg of the desired product. 1 HNMR(400MHz,DMSO-d6):δ1.05(d,J=4.8Hz,3H),2.46-2.51(m,3H),2.71(d,J=7.2Hz,2H),3.16(s,3 H),5.06(brs,2H),6.41-6.46(m,3H),6.78(t,J=7.6Hz,1H),8.39(brs,1H);ESI-MS(m / z)243.2(M+H) +

[0204] The analytical data of the intermediates prepared according to the above procedures are shown in Table 2 below. [Table 3]

[0205] Intermediate A10 2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka] 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 (0.75 mL) was degassed for 10 minutes. NaN (19 mg, 0.294 mmol), CuI (28 mg, 0.147 mmol), trans N,N-dimethyl-1,2-cyclohexanediamine (17 mg, 0.147 mmol), and sodium ascorbate (58 mg, 0.294 mmol) were added to the reaction mixture, which was stirred in a sealed tube at 110 °C for 18 hours. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residue was purified by column chromatography to give 21 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ1.05(d,J=5.6Hz,3H),2.43-2.51(m,3H),2.68(m,2H),3.16(s,3H),5.35(s,2H),6.50( dd,J1=2.4Hz,J2=8.4Hz,1H),6.72(d,J=2.4Hz,1H),7.15(d,J=8.4Hz,1H),8.29(s,1H);ESI-MS(m / z)278(M+2H) +

[0206] Intermediate A11 3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka]

[0207] Step 1: 2,2-dimethylpropane-1,3-diyl dimethanesulfonate [ka] To a stirred solution of 2,2-dimethylpropane-1,3-diol (10 g, 96.1 mmol) in DCM (100 mL) was added triethylamine (33.7 mL, 240 mmol). Mesyl chloride (18.5 mL, 240 mmol) was added dropwise at 0° C. and stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted twice with DCM. The organic layer was washed with brine solution, dried over anhydrous NaSO, and concentrated to give 11.0 g of the desired product. 1 HNMR (400MHz, DMSO-d6): δ0.86 (s, 6H), 3.18 (s, 6H), 4.00 (s, 4H).

[0208] Step 2: 1,3-Diiodo-2,2-dimethylpropane [ka] 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) portionwise at 0° C. and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted twice with petroleum ether. The organic layer was washed with brine solution, dried over anhydrous NaSO, and concentrated to give 2.1 g of the desired product. 1 HNMR (400MHz, CDCl3): δ1.26 (s, 6H), 3.28 (s, 4H).

[0209] Step-3: 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonitrile [ka] To a stirred suspension of NaH (60% suspension in mineral oil) (734 mg, 15.3 mmol) in DMF (15 mL) was added dropwise a 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 the addition was continued for 1 h. 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 NaSO, and concentrated. The resulting residue was purified by silica gel column chromatography to give 700 mg of the desired product. 1 HNMR (400MHz, CDCl3): δ1.16(s,3H),1.50(s,3H),2.47(d,J=13.2Hz,2H),2.74(d,J =12.4Hz,2H),7.26-7.28(m,1H),7.33-7.35(m,1H),7.45-7.47(m,1H),7.54(s,1H).

[0210] Step 4: 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carboxylic acid [ka] To a stirred solution of 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonitrile (700 mg, 2.66 mmol) in 4.2 mL of AcOH / HO (1:1) was added concentrated HSO (2.1 mL) dropwise at 0 °C, 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 NaSO, and concentrated to give 700 mg of the desired product. 1 HNMR(400MHz,DMSO-d6):δ0.97(s,3H),1.12(s,3H),2.25(d,J=12.8Hz,2H),2.63(d,J=12 .8Hz,2H),7.26-7.33(m,2H),7.39-7.45(m,2H),12.50(brs,1H),ESI-MS(m / z)281.1(MH) +

[0211] Step-5: 2-(1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonyl)-N-methylhydrazine-1-carbothioamide [ka] To a stirred solution of 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carboxylic acid (700 mg, 2.47 mmol) in DMF (8.0 mL), DIPEA (1.3 mL, 7.42 mmol) and HATU (1.1 g, 2.96 mmol) were added and 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 resulting solid was purified by silica gel column chromatography to give 820 mg of the desired product. ESI-MS (m / z) 371.1 (M+2H). +

[0212] Step-6: 5-(1-(3-bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ka] A stirred solution of 2-(1-(3-bromophenyl)-3,3-dimethylchlorobutane-1-carbonyl)-N-methylhydrazine-1-carbothioamide (820 mg, 2.21 mmol) in 1N NaOH (8.0 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified using 6N HCl and stirred for 2 hours. The precipitated solid was filtered, washed with excess water, and dried under vacuum to give 760 mg of the desired product. ESI-MS (m / z) 353.1 (M+2H). +

[0213] Step-7: 3-(1-(3-bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-4H-1,2,4-triazole [ka] 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% HO 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 resulting solid was purified by silica gel column chromatography to give 628 mg of the desired product. 1 HNMR(400MHz,CDCl3):δ1.03(s,3H),1.09(s,3H),2.57(d,J=12.8Hz,2H),2.87(d, J=10.4Hz,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) +

[0214] Step 7: 3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline 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) in a sealed tube, aqueous NH3 (4.0 mL) and copper(I) oxide (280 mg, 1.96 mmol) were added and stirred at 100 °C for 16 h. The reaction mixture was quenched with water and ethyl acetate, filtered, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting solid was purified by silica gel column chromatography to give 410 mg of the desired product. 1HNMR(400MHz,DMSO-d6):δ1.03(s,3H),1.11(s,3H),2.48(d,J=12.8Hz,2H),2.80(d,J=12.4Hz,2H),3.1 9(s,3H),5.07(brs,2H),6.38-6.43(m,3H),6.97(t,J=7.6Hz,1H),8.29(s,1H);ESI-MS(m / z)257.2(M+H) +

[0215] The analytical data of the intermediates prepared according to the above procedures are shown in Table 3 below. [Table 4] TIFF2025525947000097.tif109159

[0216] Intermediate A20 3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka]

[0217] Step 1: 1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile [ka]

[0218] To a stirred suspension of NaH (60% suspension in mineral oil) (2.56 g, 63.77 mmol) in DMF (50 mL) was added dropwise a solution of 3-bromophenylacetonitrile (5.0 g, 25.51 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, followed by the 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 hours and at 60° C. for 48 hours. 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 NaSO, and concentrated. The resulting residue was purified by silica gel column chromatography to give 2.4 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ2.72(d,J=13.6Hz,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)

[0219] Step-2: 1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile [ka] 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 48 hours. 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 to give 400 mg of the desired product. 1 HNMR (400MHz, DMSO-d6): δ3.9-3.75(m,2H),4.06-4.11(m,2H),7.36(t,J=7.6Hz,1H),7.45(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.66(s,1H).

[0220] Step-3: 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile [ka] To a stirred solution of 1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile (0.95 g, 3.8 mmol) in DCM (20 mL) was added DAST (2.45 g, 15.2 mmol) at 0 °C and stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO and extracted with ethyl acetate. The organic layer was washed with water, brine solution, and dried over anhydrous NaSO. The solvent was evaporated and purified to give 760 mg of the desired product. 1 HNMR (400MHz, DMSO-d6): δ3.17-3.27(m,2H),3.49-3.57(m,2H),7.35(t,J=7.6Hz,1H),7.42(d,J=7.6Hz),1H),7.55(d,J=7.6Hz,1H),7.62(s,1H).

[0221] Step-4: 1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid [ka] 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 (4.0 mL) was added concentrated HSO (4.0 mL) at 0° C. The reaction mixture was warmed to room temperature and heated to 120° C. for 16 hours. The mixture was cooled to room temperature and diluted with water. The precipitated solid was thoroughly filtered and dried to give 1.9 g of the desired product. 1 HNMR (400MHz, DMSO-d6): δ3.08-3.18(m,2H),3.30-3.40(m,2H),7.36(t,J=4.4Hz,2H),7.52(d,J=6.4Hz,1H),7.54(s,1H),13.01-13.16(brs,1H). ESI-MS(m / z)291(M) +

[0222] Step-5: 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-carbothioamide [ka] 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 (48 mg, 0.453 mmol). To this reaction mixture were added EDCI.HCl (118 mg, 0.618 mmol), triethylamine (54 mg, 0.536 mmol), and HOBt (72 mg, 0.536 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched by the addition of aqueous HCl. The layers were extracted with ethyl acetate. The organic layer was separated and concentrated to give 140 mg of the desired product. ESI-MS (m / z) 378.0 (M+H). +

[0223] Step-6: 5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ka] A stirred solution of 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-carbothioamide (2.9 g, 7.67 mmol) in 1 N NaOH (100 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified using 2 N HCl and stirred for 15 minutes. The precipitated solid was filtered, washed with excess water, and dried under vacuum to give 2.1 g of the desired product. 1 HNMR(400MHz,DMSO-d6):δ3.04(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) +

[0224] Step-7: 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole [ka] To a stirred solution of 5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (65 mg, 0.18 mmol) in DCM (1.0 mL) and AcOH (0.14 mL) was added a 30% solution of HO (0.045 mL) 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 resulting solid was purified by silica gel column chromatography to give 43 mg of the desired product. 1 HNMR(400MHz,CDCl3):δ3.27(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=8.0Hz,1H),8.09(s,1H);ESI MS(m / z)328(M+H) +

[0225] Step 8: 3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline 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) in a sealed tube was added aqueous NH (3.0 mL), copper oxide (52 mg, 0.365 mmol), and stirred at 90 °C for 16 h. The reaction mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under vacuum to give 280 mg of the desired product. 1HNMR(400MHz,DMSO-d6):δ3.24(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=8.0Hz,1H),8.40(brs,1H);ESI-MS(m / z)265(M+H) +

[0226] Intermediate A21 3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)aniline [ka]

[0227] Step 1: 2-(3-bromophenyl)methyl acetate [ka] To a stirred solution of 3-bromophenylacetic acid (17 g) in methanol (300 mL) was added concentrated H2SO4 (10 mL) dropwise and heated to 110 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by chromatography to give 9.3 g of the desired product as a pale yellow oil. 1 HNMR(400MHz,CDCl3)δ3.62(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) +

[0228] Step 2: 2-(3-bromophenyl)-2-cyclobutyl methyl acetate [ka] To a stirred solution of methyl 2-(3-bromophenyl)acetate (2 g, 8.77 mmol) in DMF (15 mL) was added potassium tert-butoxide solution (11.34 mL, 11.34 mmol) dropwise at 0 °C. A solution of bromocyclobutane (1.41 g, 10.48 mmol) in DMF (5 mL) was added dropwise and stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated NH solution and extracted twice with ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography to give 1.21 g of the desired product as a pale yellow oil. 1 HNMR(400MHz,CDCl3)δ1.611-1.63(m,1H),1.82-1.88(m,4H),2.18-2.21(m,1H),2.93-2.95(m,1H),3.5 2(d,J=11.2Hz,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) +

[0229] Step-3: 2-(3-bromophenyl)-2-cyclobutylacetohydrazide [ka] 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 hours. 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 sulfate and concentrated under reduced pressure to give 1.05 g of the desired product. 1 HNMR(400MHz,DMSO-d6)δ1.48-1.50(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. 6Hz,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) +

[0230] Step 4: 2-(2-(3-bromophenyl)-2-cyclobutylacetyl)-N-methylhydrazine-1-carbothioamide [ka] To a stirred solution of 2-(3-bromophenyl)-2-cyclobutylacetohydrazide (1.0 g, 3.53 mmol) in THF (10 mL) was added methyl isothiocyanate (776 mg, 10.65 mmol) dropwise and heated to 90° C. for 4 h. The mixture was concentrated under reduced pressure, and the resulting residue was triturated with pentane. The resulting solid was filtered and dried under vacuum to give 1.1 g of the desired product. 1 H NMR(400MHz,DMSO-d6)δ1.53-1.57(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=7.6Hz,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) +

[0231] Step-5: 5-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione [ka] 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 hours. The reaction mixture was acidified using 2N HCl and stirred for 15 minutes. The precipitated solid was filtered, washed with excess water, and dried under vacuum to give 1.05 g of the desired product. 1H NMR(400MHz,DMSO-d6)δ1.68-75(m,5H),2.07-2.09(m,1H),2.94-2.96(m,1H),3.20(s,3H),4.25(d,J=10.8H z,1H),7.23(d,J=7.6Hz,1H),7.31(t,J=8Hz,1H),7.45-7.49(m,2H),13.71(s,1H);ESI-MS(m / z)338.0(M+H) +

[0232] Step-6: 3-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole [ka] 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 the reaction mixture was stirred for 10 minutes. To the reaction mixture was added 30% HO solution (1.2 mL, 11.84 mmol) and stirred at 0 °C for 2 hours. The reaction mixture was diluted with DCM and washed with water and saturated NaHCO solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting product was stirred in diethyl ether, filtered, and dried to give 607 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ1.63-78(m,5H),2.03-2.05(m,1H),3.06-3.10(m,1H),3.39(s,3H),4.2 2(d,J=10.4Hz,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) +

[0233] Step 7: 3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)aniline [ka] 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) was added NH (5 mL), copper(I) oxide (70 mg, 0.49 mmol) in a sealed tube and stirred at 100° C. for 16 h. The reaction mixture was diluted with ethyl acetate and filtered. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The resulting residue was triturated with diethyl ether to give 373 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ1.61-65(m,1H),1.75-1.77(m,4H),2.07-2.15(m,1H),3.08-3.10(m,1H),3.35(s,3H),3. 92(d,J=10.4Hz,1H),5.01(bs,2H),6.32-3.39(m,3H),6.91(t,J=8Hz,1H),8.32(s,1H);ESI-MS(m / z)243.3(M+H) +

[0234] The analytical data of the intermediates prepared according to the above procedures are shown in Table 4 below. [Table 5]

[0235] Intermediate A23 3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)aniline [ka]

[0236] Step-1: (1s,3s)-1-(3-bromophenyl)-N-methoxy-N,3-dimethylcyclobutane-1-carboxamide [ka] 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), CDI (4.81 g, 29.72 mmol) was added portionwise, followed by AIBN (2.0 g, 12.33 mmol). The reaction mixture was stirred at room temperature for 1 hour. N,O-dimethylhydroxylamine was added and stirred at room temperature for 16 hours. The reaction mixture was quenched with water (50 ml) and extracted with DCM (3 × 100 ml). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give the product. The product was purified by Combiflash chromatography to give 3.1 g of the title compound. 1 HNMR(DMSO-d6,400MHz)δ1.09(d,J=5.2Hz,3H),2.36-2.34(m,3H),2.54-2.52(m,2H),3.1 1(s,6H),7.23(t,J=7.6Hz,1H),7.35(d,J=8.0Hz,1H),7.39(d,J=7.6Hz,1H),7.58(s,1H).

[0237] Step-2: 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propan-1-one [ka] To a stirred solution of (1s,3s)-1-(3-bromophenyl)-N-methoxy-N,3-dimethylcyclobutane-1-carboxamide (3.0 g, 9.61 mmol) in anhydrous THF (30 ml) was added ethylmagnesium bromide (6.4 g, 48.05 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with NH4Cl solution (50 ml) and extracted with DCM (3 x 100 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the product. The product was purified by Combiflash chromatography to give 2.0 gm of the title compound. 1HNMR(DMSO-d6,400MHz)δ1.09(d,J=5.2Hz,3H),2.24-2.19(q,J=7.2Hz,2H),2.21(t,J=7.2Hz,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[MH] + .

[0238] Step-3: 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-2-hydroxypropan-1-one [ka] To a stirred solution of 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propan-1-one (2.0 g, 7.09 mmol) in anhydrous THF (30 ml) was added NaHMDS (1.95 g, 10.64 mmol, 1.0 M in THF) at −78° C. After 15 min, a solution of (R)-3-methyl-3-phenyl-2-(phenylsulfonyl)-1,2-oxazine (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 (3×100 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the product. The product was purified by Combiflash chromatography to give 1.4 g of the title compound. 1 HNMR(DMSO-d6,400MHz)δ1.05-1.09(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=6.8Hz, 1H), 7.26-7.28 (m, 2H), 7.45-7.42 (m, 1H), 7.52 (s, 1H).

[0239] Step 4: 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propane-1,2-dione [ka] To a stirred solution of 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-2-hydroxypropan-1-one (1.4 g, 4.71 mmol) in anhydrous DCM (30 ml) at 0° C. was added DMP (3.99 g, 9.42 mmol) in portions. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO solution and extracted three times with DCM. The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give the product. The product was purified by Combiflash chromatography to give 1.1 g of the title compound. 1 HNMR(DMSO-d6,400MHz)δ1.07(d,J=6Hz,3H),2.18(s,3H),2.39-2.42(m,3H),2.70-2.71 (m,2H),7.23(t,J=7.6Hz,1H),7.29(d,J=8.0Hz,1H),7.38(d,J=7.6Hz,1H),7.52(s,1H).

[0240] Step 5: 4-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-imidazole [ka] 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 in a sealed tube at 80° C. for 16 h. The reaction mixture was concentrated and the resulting product was purified by Combiflash chromatography to give 1.0 g of the title compound. 1HNMR(DMSO-d6,400MHz)δ7.56(s,1H),7.30-7.36(m,2H),7.28(s,1H),7.17(t,J=8.0Hz,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=5.6Hz,3H);ESI-MS(m / z)305.1[M+H] +

[0241] Step-6: 4-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1-trityl-1H-imidazole [ka] To a stirred solution of 4-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-imidazole (1.0 g, 3.27 mmol) in anhydrous DCM (30 ml) at 0° C., triethylamine (0.31 g, 3.06 mmol) was added portionwise, followed by trityl chloride (0.4 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the resulting product was purified by Combiflash chromatography to give 1.3 g of the title compound. ESI-MS (m / z) 547.3 [M+H] +

[0242] Step-7: N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)phenyl)-1,1-diphenylmethanimine [ka] 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 benzophenone imine (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 using nitrogen gas for 15 minutes. Palladium acetate (0.049 g, 0.21 mmol) was added, and the reaction mixture was heated in a sealed tube at 80° C. for 16 hours. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated, and the crude compound was purified by Combiflash chromatography to give 1.1 g of the title compound. ESI-MS (m / z) 648.4 [M+H] +

[0243] 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 saturated NaHCO3 (50 ml). The EtOAc layer was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the product. The resulting product was purified by Combiflash chromatography to give 0.6 g of the title compound. ESI-MS (m / z) 484.3 [M+H] + The analytical data of the intermediates prepared according to the above procedures are shown in Table 5 below. [Table 6]

[0244] Intermediate A25 3-(3-methyl-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)cyclobutyl)aniline [ka]

[0245] Step 1: 1-(3-bromophenyl)-3-methylcyclobutane-1-carbaldehyde [ka] 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 −78° C. for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, filtered, and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give 3.8 g of the desired product. ESI-MS (m / z) 254 (M+2H). +

[0246] Step-2: 4-(1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-1,2,3-triazole [ka] To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutane-1-carbaldehyde (3.8 g, 0.0150 mol) in anhydrous 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 minutes. Aluminum chloride (0.2 g, 0.0015 mol) was then added. The reaction mixture was stirred for 10 minutes and heated at 70°C for 18 hours. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted three times with DCM. The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give the desired product, which was purified by flash chromatography to give 2.3 g of the desired product. ESI-MS (m / z) 306 [M+H] +

[0247] Step-3: 4-(1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazole [ka] 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) was 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 overnight. The reaction mass was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting product was purified by flash chromatography to give 2.5 g of the desired product as a yellow oil. ESI-MS (m / z) 390 [M+H] +

[0248] 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), ammonia (15 mL), copper oxide (1.46 g, 10.24 mmol) were added and stirred at 110° C. 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 sulfate and evaporated under reduced pressure to give 0.8 g of the desired product as a yellow oil. ESI-MS (m / z) 327 [M+1] +

[0249] The analytical data of the intermediates prepared according to the above procedures are shown in Table 6 below. [Table 7]

[0250] The following intermediates mentioned were synthesized according to the procedure described above for Intermediate A11 and the analytical data are shown in Table-7 below. [Table 8]

[0251] Intermediate B1 5-Bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka]

[0252] Step-1: 5-Bromo-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of 5-bromo-2-hydroxynicotinic acid (5.0 g, 35.94 mmol) in anhydrous methanol (100 mL) was added concentrated HSO (1 mL) and refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was made basic with saturated sodium bicarbonate solution and stirred for 30 minutes. The resulting solid was filtered and dried under vacuum to give 4.2 g of the desired product. 1 HNMR(400MHz,DMSO-d6)δ3.75(s,3H),7.99(d,J=2.8Hz),8.08(d,J=2.8Hz,1H),12.41(brs,1H);ESI-MS(m / z)233(M+2H) + .

[0253] Step-2: 5-Bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester 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 minutes. To this mixture was added cyclopropylmethyl bromide (157 μL, 1.616 mmol) and heated to 70° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography to give 126 mg of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ0.35-0.45(m,2H),0.45-0.55(m,2H),1.18-1.35(m,1H),3.75(s,3H) ,3.77(d,J=9.6Hz,2H),8.058(d,J=2.8Hz,1H),8.38(d,J=2.8Hz,1H);ESI-MS(m / z)287(M+2H) +

[0254] Analytical data for the intermediates prepared according to the above procedures are shown in Table 8 below. [Table 9]

[0255] Intermediate B5 5-Bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (5.2 g, 22.413 mmol) in DMF (80 mL) was added cesium carbonate (10.9 g, 33.620 mmol) and stirred at room temperature for 30 minutes. To this mixture was added 2,2,2-trifluoroethyl trifluoromethane sulfate (7.8 g, 33.62 mmol) and heated to 70° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography to give 2.9 g of the desired compound. 1 HNMR(400MHz,DMSO-d6)δ3.77(s,3H),4.875(q,J=9.2Hz,2H),8.14(d,J=2.4Hz,1H),8.36(d,J=2.4Hz,1H);ESI-MS(m / z)315(M+2H) +

[0256] Analytical data for the intermediates prepared according to the above procedures are shown in Table 9 below. [Table 10]

[0257] Intermediate B7 5-Bromo-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka]

[0258] Step-1: 1-Cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (4.8 g, 31.16 mmol) in ethylene dichloride (150 mL) was added cyclopropylboronic acid (5.30 g, 62.33 mmol), CsCO 3( The mixture was added with 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 was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 230 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ0.83-0.87(m,2H),0.99-1.04(m,2H),3.32-3.38(m,1H),3.73(s,3H) ),6.26(t,J=7.2Hz,1H),7.87(d,J=6.8Hz,1H),8.0(d,J=7.2Hz,1H)ESI-MS(m / z)194.1(M+H) +

[0259] Step-2: 5-Bromo-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester 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 three times with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 260 mg of the desired product. 1 HNMR(400MHz,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) +

[0260] Intermediate B8 2-Oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid [ka]

[0261] Step-1: 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylate methyl ester [ka] 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 vinyltrifluoroborate (1.91 gm, 14.28 mmol) in a solvent mixture of toluene (50 mL) and water (15 mL) was degassed for 15 minutes. To this reaction mixture was added KPO (4 g, 19.04 mmol), Pd(dppf)Cl 2. DCM (390 mg, 0.476 mmol) was added and heated to 100° C. for 5 hours. 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 in vacuo. The residue was purified by silica gel column chromatography to give 1.09 g of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ3.78(s,3H),4.90(q,J=9.2Hz,2H),5.22(d,J=11.2Hz,1H),5.68(d,J=17 .6Hz,1H),6.45-6.6(m,1H),8.103(d,J=2Hz,1H),8.33(d,J=2.8Hz,1H);ESI-MS(m / z)262.3(M+H) +

[0262] Step-2: 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 overnight. The reaction mixture was concentrated, and the resulting residue was diluted with water and acidified with 1 N HCl. The precipitated solid was filtered and dried to give 809 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ5.01(q,J=9.2Hz,2H),5.28(d,J=11.2Hz,1H),5.76(d,J=17.6Hz,1H),6 .50-6.70(m,1H),8.19(s,1H),8.53(d,J=2.4Hz,1H),13.86(brs,1H);ESI-MS(m / z)248.2(M+H) +

[0263] The analytical data of the intermediates prepared according to the above procedures are shown in Table 10 below. [Table 11]

[0264] Intermediate B13 1-(Difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid [ka]

[0265] Step-1: 5-bromo-1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 1.293 mmol) in DMF (2 mL) was added KCO (356 mg, 2.586 mmol), sodium 2-chloro-2,2-difluoroacetate (393 mg, 2.586 mmol) at room temperature and heated to 80° C. for 18 hours. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography to give 201 mg of the desired product. 1 H NMR(400MHz,DMSO)δ3.78(s,3H),7.79(t,J=59.2Hz,1H),8.18(s,1H),8.42(s,1H);ESI-MS(m / z)283.6(M+H) +

[0266] Step-2: 1-(Difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylate methyl ester [ka] A stirred solution of methyl 5-bromo-1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (150 mg, 0.5319 mmol) and potassium vinyltrifluoroborate (212 mg, 1.595 mmol) in a solvent mixture of toluene (5 mL) and water (1 mL) was degassed for 15 minutes. The reaction mixture was added with KPO (451 mg, 2.127 mmol), Pd(dppf)Cl 2. DCM (43 mg, 0.05319 mmol) was added and heated to 120° C. for 2 hours. 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 in vacuo. The resulting residue was purified by silica gel chromatography to give 120 mg of the desired product. 1H NMR(400MHz,DMSO)δ3.80(s,3H),5.27(d,J=11.2Hz,1H),5.76(m,1H),6.65(m, 1H),7.87(t,J=59.2Hz,1H),8.18(s,1H),8.41(s,1H);ESI-MS(m / z)230.1(M+H) +

[0267] 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 0° C., aqueous lithium hydroxide (14.85 mg, 0.3537 mmol) was added and stirred at 0° C. for 30 minutes. 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 sulfate. The organic layer was concentrated under reduced pressure to give 19 mg of the desired product. ESI-MS (m / z) 216.20 (M+H). +

[0268] Intermediate B14 2-Oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid [ka]

[0269] Step-1: 5-bromo-2-oxo-1-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of methyl 5-bromo-2-hydroxynicotinate (2 g, 8.66 mmol) in anhydrous DMF (20 mL) was added cesium carbonate (4.2 g, 12.99 mmol), and the resulting mixture was stirred at room temperature for 30 minutes. (3-Bromoprop-1-yn-1-yl)trimethylsilane (1.65 mL, 10.39 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and concentrated. The resulting residue was purified by column chromatography to give 1.8 g of the desired product. 1 H NMR(400MHz,DMSO-d6)δ0.24(s,9H),3.92(s,3H),4.78(s,2H),8.13(d,J=2.8Hz,1H),8.23(d,J=2.8Hz,1H);ESI-MS(m / z)344.0(M+2H) +

[0270] Step-2: 2-oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylate methyl [ka] 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), KPO (4.4 g, 20.93 mmol) and trifluoro(vinyl)-14-borane, potassium salt (2.0 g, 15.69 mmol) were added under a nitrogen atmosphere, and the mixture was degassed for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (426 mg, 0.523 mmol) was added, and the mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was separated and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give 190 mg of the product as an off-white solid. 1H NMR(400MHz,CDCl3)δ3.94(s,3H),4.81(s,2H),5.24(d,J=10.8Hz,1H),5.59(d, J=17.6Hz,1H),6.43-6.51(m,1H),7.97(d,J=2.4Hz,1H),8.39(d,J=2.8Hz,1H).

[0271] Step-3: 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 the resulting mixture was stirred at room temperature overnight. The solvent was completely evaporated under reduced pressure, acidified with HCl, and the resulting solid was collected by filtration to give 170 mg of the desired product as an off-white solid. 1 H-NMR 400MHz,DMSO-d6)δ5.30(d,J=11.2Hz,1H),5.82(d,J=17.6Hz,1H),5.93(d,J=6.4Hz,2H),7.58(d ,J=6.4Hz,1H),8.12(d,J=2.4Hz,1H).8.52-8.59(m,1H),14.00(s,1H);ESI-MS(m / z)204.1(M+H) +

[0272] Intermediate B15 1-(4-Fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid [ka]

[0273] Step-1: 5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka] 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) was added (4-fluorophenyl)boronic acid (3.2 g, 23.27 mmol), pyridine (3.4 mL, 34.48 mmol), followed by copper diacetoxy (3.4 g, 17.24 mmol), and activated molecular sieves and stirred overnight at room temperature. The reaction mixture was filtered, diluted with water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography to give 650 mg of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ3.76(s,3H),7.34-7.39(m,2H),7.50-7.54(m,2H),8.15(d,J=3.0Hz,1H),8.30(d,J=3.0Hz,1H);ESI-MS(m / z)327.8(M+H) +

[0274] Step-2: 1-(4-fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylate methyl ester [ka] A stirred solution of methyl 5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (650 mg, 1.99 mmol) and potassium vinyltrifluoroborate (800 mg, 5.98 mmol) in a mixture of toluene (5 mL) and water (2 mL) was degassed for 15 minutes. To this reaction mixture was added KPO (1.7 g, 7.96 mmol), Pd(dppf)Cl 2. DCM (163 mg, 199 mmol) was added and heated to 100° C. for 3 hours. 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 in vacuo. The resulting residue was purified by silica gel chromatography to give 550 mg of the desired product. 1H NMR(400MHz,DMSO-d6)δ3.78(s,3H),5.17(d,J=11.3Hz,1H),5.69(d,J=17.6Hz,1H),6.56(d,J=17. 7Hz,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) +

[0275] 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) was added aqueous lithium hydroxide (423 mg, 10.07 mmol) at 0° C. and stirred overnight at the same temperature. The solvent was evaporated and acidified with 1N hydrochloric acid solution. The aqueous layer was extracted twice with 10% MeOH / DCM and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give 400 mg of the desired product. ESI-MS (m / z) 260.1 (M+H). + . The following intermediates mentioned were synthesized according to the procedure described above for Intermediate B8 and the analytical data are shown in Table-11 below. [Table 12] [Example]

[0276] 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 [ka]

[0277] Step-1: 5-Bromo-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of 5-bromo-2-hydroxynicotinic acid (5.0 g, 35.94 mmol) in anhydrous methanol (100 mL) was added concentrated HSO (1 mL) and refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was made basic with saturated sodium bicarbonate solution and stirred for 30 minutes. The resulting solid was filtered and dried under vacuum to give 4.2 g of the desired product. 1 HNMR(400MHz,DMSO-d6)δ3.75(s,3H),7.99(d,J=2.8Hz),8.08(d,J=2.8Hz,1H),12.41(brs,1H);ESI-MS(m / z)233(M+2H) + .

[0278] Step-2: 5-Bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka] 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 minutes. To this mixture was added cyclopropylmethyl bromide (157 μL, 1.616 mmol) and heated to 70° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography to give 126 mg of the desired compound. 1H NMR(400MHz,DMSO-d6)δ0.35-0.45(m,2H),0.45-0.55(m,2H),1.18-1.35(m,1H),3.75(s,3H) ,3.77(d,J=9.6Hz,2H),8.058(d,J=2.8Hz,1H),8.38(d,J=2.8Hz,1H);ESI-MS(m / z)287(M+2H) +

[0279] Step-3: 1-(cyclopropylmethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylate methyl ester [ka] A stirred solution of methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.74 mmol) and potassium vinyltrifluoroborate (700 mg, 5.2 mmol) in a solvent mixture of toluene and water (30 mL) was degassed for 15 minutes. To the reaction mixture was added KPO (1.5 gm, 6.9 mmol), Pd(dppf)Cl.DCM (140 mg, 0.17 mmol), and heated to 100°C for 5 hours. 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 resulting residue was purified by silica gel chromatography to give 350 mg of the desired compound. 1 HNMR(400MHz,DMSO-d6)δ0.30-0.45(m,2H),0.45-0.55(m,2H),1.15-1.35(m,1H),3.7 7(s,3H),3.78(d,J=8.8Hz,2H),5.14(d,J=11.2Hz,1H),5.64(d,J=17.6Hz,1H),6.48- 6.57(m,1H),8.16(d,J=2.8Hz,1H),8.23(d,J=2.8Hz,1H);ESI-MS(m / z)234.2(M+H) +

[0280] Step-4: 1-(cyclopropylmethyl)-5-formyl-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of methyl 1-(cyclopropylmethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylate (375 mg, 1.712 mmol) in THF / HO (4:1, 25 mL) was added NaIO (768 mg, 3.59 mmol), followed by t-BuOH (36 μL, 0.034 mmol) containing 2.5% OsO. The reaction mixture was stirred at room temperature 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 give 303 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ0.41-0.55(m,4H),1.26-1.31(m,1H),3.79(s,3H),3.88(d,J=7. 6Hz,2H),8.355(d,J=2.8Hz,1H),8.9(d,J=2.8Hz,1H),9.66(s,1H);ESI-MS(m / z)236(M+H) +

[0281] Step-5: 1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxylate methyl ester [ka] 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 a catalytic amount of acetic acid and stirred for 2 hours. Sodium cyanoborohydride (144 mg, 2.295 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with methanol and concentrated. The resulting residue was purified by flash chromatography to give 172 mg of the desired product. 1HNMR(400MHz,DMSO-d6)δ0.40-0.60(m,4H),1.30-1.40(m,1H),1.50-1.60(m,2H),1.6 0-1.75(m,4H),2.90-3.10(m,4H),3.77(s,3H),3.78(d,J=9.2Hz,2H),4.12(brs,2H), 8.10-8.30(m,2H);ESI-MS(m / z)305.3(M+H) +

[0282] Step-6: 1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxylic acid [ka] 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 overnight. The reaction mixture was concentrated, and the resulting residue 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 sulfate and concentrated under reduced pressure to give 74 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ0.43-0.55(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=7.2Hz,2H),8.23(s,1H),8.37(s,1H),14.8(brs,1H);ESI-MS(m / z)291.4(M+H) +

[0283] Step-7: 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, HATU (110 mg, 0.289 mmol) was added and stirred at room temperature for 30 minutes. To this mixture, 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) were added and stirred overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography to give 9 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ0.40-0.60(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=7.2Hz,2H),7.03(d,J=8Hz,1H),7.26(t,J=8Hz,1H),7.55(s,1H),7.64(d,J=8.4Hz,1H) ,8.07(s,1H),8.21(s,1H),8.42(d,J=2.4Hz,1H),12.2(brs,1H);ESI-MS(m / z)503.4(M+H) +

[0284] 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 [ka]

[0285] Step-1: 5-Bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid [ka] 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 overnight. The reaction mixture was concentrated, and the resulting residue was diluted with water and acidified with 1N HCl. The resulting solid was filtered and dried under vacuum to give 630 mg of the desired product. 1 H NMR(400MHz,DMSO-d6)δ4.97(q,J=8.8Hz,2H),8.3(s,1H),8.47(s,1H),13.53(brs,1H);ESI-MS(m / z)301.9(M+2H) +

[0286] 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 [ka] 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 minutes. 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 overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography to give 330 mg of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ1.42(s,6H),2.98(s,2H),3.16(s,3H),5.04(q,J=9.2Hz,2H),7.07(d,J=8Hz,1H),7.28(t,J =8Hz,1H),7.55(s,1H),7.62(d,J=8Hz,1H),8.23(s,1H),8.45-8.55(m,2H),11.50(s,1H);ESI-MS(m / z)512.2(M+H) +

[0287] 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 [ka] 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 vinyltrifluoroborate (196 mg, 1.464 mmol) in toluene (5 mL) / water (1 mL) was degassed for 10 min. To this reaction mixture was added KPO (414 mg, 1.954 mmol), Pd(dppf)Cl 2. DCM (40 mg, 0.0488 mmol) was added and heated to 100° C. for 3 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give 230 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ 1.42(s,6H),2.98(s.2H),3.33(s,3H),5.07(q,J=9.2Hz,2H),5.31(d,J=10.8Hz,1H),5.79(d,J=17.6Hz,1H),6.60-6.75(m,1H),7.0-7.1 5(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) + .

[0288] 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 [ka] 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 / HO (4:1, 25 mL) was added NaIO 4( To the reaction mixture was added 2.5% OsO in t-BuOH (10 μL, 0.0009 mmol) followed by 2.5% OsO in t-BuOH (10 μL, 0.0009 mmol). The reaction mixture was stirred at room temperature 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 give 89 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ1.43(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) +

[0289] 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 acetic acid dropwise and stirred for 2 h. To the reaction mixture was added sodium triacetoxyborohydride (96 mg, 0.455 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography to give 12 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ1.25-1.40(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) +

[0290] The details of the synthesis and analytical data of the examples synthesized by the above-mentioned methods are shown in Table 12 below. [Table 13] TIFF2025525947000163.tif240159TIFF2025525947000164.tif50159

[0291] 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 [ka]

[0292] Step-1: 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylate methyl ester [ka] 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 vinyltrifluoroborate (1.91 g, 14.28 mmol) in a solvent mixture of toluene (50 mL) and water (15 mL) was degassed for 15 minutes. The reaction mixture was added with KPO (4 g, 19.04 mmol), Pd(dppf)Cl 2. DCM (390 mg, 0.476 mmol) was added and heated to 100° C. for 5 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give 1.09 g of the desired compound. 1 HNMR(400MHz,DMSO-d6)δ3.78(s,3H),4.90(q,J=9.2Hz,2H),5.22(d,J=11.2Hz,1H),5.68(d,J=17 .6Hz,1H),6.45-6.6(m,1H),8.103(d,J=2Hz,1H),8.33(d,J=2.8Hz,1H);ESI-MS(m / z)262.3(M+H) +

[0293] Step-2: 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid [ka] 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 overnight. The reaction mixture was concentrated, and the resulting residue was diluted with water and acidified with 1 N HCl. The precipitated solid was filtered and dried to give 809 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ 5.01(q,J=9.2Hz,2H),5.28(d,J=11.2Hz,1H),5.76(d,J=17.6Hz,1H),6.50-6.70(m ,1H),8.19(s,1H),8.53(d,J=2.4Hz,1H),13.86(brs,1H);ESI-MS(m / z)248.2(M+H) +

[0294] 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 [ka] 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 minutes. 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 overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography to give 1.41 g of the desired compound. 1 HNMR(400MHz,DMSO-d6)δ1.43(s,6H),3.02(s,2H),3.17(s,3H),5.07(q,J=9. 2Hz,2H),5.32(d,J=10.8Hz,1H),5.79(d,J=17.6Hz,1H),6.55-6.75(m,1H),7 .06(d,J=8Hz,1H),7.28(d,J=8Hz,1H),7.55-7.70(m,2H),8.26(d,J=2Hz,1H) ,8.33(brs,1H),8.73(d,J=2.4Hz,1H),11.65(s,1H);ESI-MS(m / z)460.3(M+H) +

[0295] 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 [ka] 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 / HO (50 mL) was added NaIO (2 g, 6.534 mmol), followed by 2.5% OsO in t-BuOH (320 μL, 0.032 mmol). The reaction mixture was stirred at room temperature 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 give 1.12 g of the desired compound. 1 HNMR(400MHz,DMSO-d6)δ1.47(s,6H),2.99(s,2H),3.13(s,3H),5.19(q,J=9.2Hz,2H),7.07(d,J=8Hz,1H),7.23(t,J=8Hz,1H),7.55(s,1H), 7.66(d,J=8Hz,1H),8.22(d,J=3.2Hz,1H),8.78(d,J=2.4Hz,1H),8.95(d,J=2.4Hz,1H),9.81(s,1H),11.22(s,1H);ESI-MS(m / z)462.1(M+H) +

[0296] 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. Sodium triacetoxyborohydride (96 mg, 0.519 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by supercritical fluid chromatography (SFC) to give 29 mg of the desired compound. 1 HNMR(400MHz,DMSO-d6)δ0.82(d,J=5.2Hz,3H),1.43(s,6H),1.45-1.70(m,5H),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=9.2Hz,2H),7.04(d,J=8.4Hz,1H),7.27(t,J=8Hz,1H),7.55(s,1H),7.63(d,J=8Hz,1 H),8.0(d,J=2Hz,1H),8.21(s,1H),8.48(d,J=2.4Hz,1H),11.70(s,1H);ESI-MS(m / z)545.2(M+H) +

[0297] The details of the synthesis and analytical data of the examples synthesized by the above-mentioned methods are shown in Table 13 below. [Table 14] TIFF2025525947000171.tif240159TIFF2025525947000172.tif186159JPEG2025525947000173.jpg198159JPEG202 5525947000174.jpg237159JPEG2025525947000175.jpg188159TIFF2025525947000176.tif186159TIFF20255259470 00177.tif236159JPEG2025525947000178.jpg226159TIFF2025525947000179.tif198159TIFF2025525947000180.t if241159TIFF2025525947000181.tif192159TIFF2025525947000182.tif234159TIFF2025525947000183.tif239159 TIFF2025525947000184.tif233159TIFF2025525947000185.tif108159

[0298] 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 [ka]

[0299] 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 [ka] To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid (1.15 g, 4.653 mmol) in DMF (15 mL) was added HATU (2.12 g, 5.58 mmol) and stirred at room temperature for 30 minutes. 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 overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography to give 1.32 g of the desired compound. 1 HNMR(400MHz,DMSO-d6)δ1.08(d,J=4.8Hz,3H),2.50-2.53(m,3H),2.79-2.82(m,2H ),3.16(s,3H),5.08(q,J=8.8Hz,2H),5.31(d,J=10.8Hz,1H),5.76(d,J=3.6Hz,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),8.2 5(s,1H),8.31(s,1H),8.72(d,J=2.4Hz,1H),11.69(s,1H);ESI-MS(m / z)472.4(M+H) +

[0300] 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 [ka] 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 / HO (250 mL) was added NaIO (5.53 g, 25.83 mmol), followed by 2.5% OsO in t-BuOH (800 μL, 0.025 mmol). The reaction mixture was stirred at room temperature 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 give 4.72 g of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ1.08(d,J=4.8Hz,3H),2.50-2.52(m,3H),2.81-2.8 3(m,2H),3.18(s,3H),5.19(q,J=8.8Hz,2H),7.13(d,J=7.6Hz,1H),7.39(t, J=7.6Hz,1H),7.86(s,1H),7.69(d,J=8.4Hz,1H),8.30(s,1H),8.75(d,J=2 .0Hz,1H),8.94(s,1H),9.81(s,1H),11.25(s,1H);ESI-MS(m / z)474.3(M+H) +

[0301] 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-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide: 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 To a stirred solution of (2.78 g, 38.02 mmol) and isobutylamine (2.78 g, 38.02 mmol) in 1,2-dichloroethane (120 mL) was added acetic acid (1.37 g, 22.81 mmol) and refluxed for 4 hours. The reaction mixture was cooled. Sodium triacetoxyborohydride (4.83 g, 22.81 mmol) was added in portions to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography to give 2.1 g of the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR(400MHz,DMSO-d6):δ0.87(d,J=6.8Hz,6H),1.09(d,J=4.4Hz,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),5.1 1(q,J=8.4Hz,2H),7.10(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.56(s,1H),7.66(d,J= 8Hz,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) +

[0302] The details of the synthesis and analytical data of the examples prepared from the above methods are shown below in Table 14. The racemates prepared from the above methods were separated using SFC purification to give the respective chiral isomers (Examples 60-69). [Table 15] TIFF2025525947000190.tif223159TIFF2025525947000191.tif241159TIFF2025525947000192.tif240159JPEG20255259470 00193.jpg242159TIFF2025525947000194.tif241159JPEG2025525947000195.jpg240159JPEG2025525947000196.jpg239159 TIFF2025525947000197.tif235159TIFF2025525947000198.tif240159TIFF20255259470 00199.tif241159JPEG2025525947000200.jpg235159TIFF2025525947000201.tif238159 TIFF2025525947000202.tif239159TIFF2025525947000203.tif241159TIFF20255259470 00204.tif239159JPEG2025525947000205.jpg239159TIFF2025525947000206.tif154159

[0303] 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 [ka] 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 [ka] 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 minutes. 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 overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography to give 830 mg of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ1.06(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=8.8Hz,2H),5.30(d,J=10.8Hz,1H),5.78(d,J=22.4Hz, 1H),6.60-6.67(m,1H),7.06(d,J=7.6Hz,1H),7.35(t,J=8.0Hz,1H),7.54-7.62(m,2H), 8.24(d,J=1.6Hz,1H),8.32(s,1H),8.71(s,1H),11.67(s,1H);ESI-MS(m / z)486.3(M+H) +

[0304] 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 [ka] 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 HO (5.0 mL) was added NaIO (733 mg, 3.42 mmol), followed by 1.0% OsO in t-BuOH (0.017 mL, 0.007 mmol). The reaction mixture was stirred at room temperature 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 give 710 mg of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ1.05(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=8.8Hz,2H),7.07(d,J=8.0Hz,1H),7.36( t,J=8.1Hz,1H),7.55(s,1H),7.61(d,J=8.4Hz,1H),8.33(s,1H),8.75(d,J=2.4H) z,1H),8.95(d,J=2.0Hz,1H),9.81(s,1H),11.23(s,1H);ESI-MS(m / z)488.2(M+H) +

[0305] 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 acetic acid dropwise and refluxed for 4 hours. The reaction mixture was allowed to reach room temperature, then sodium triacetoxyborohydride (130 mg, 0.61 mmol) was added in small portions and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography to give 24 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ0.86(d,J=8.0Hz,6H),1.05(s,3H),1.12(s,3H),1.61-1.71(m, 1H),2.27(d,J=8.0Hz,2H),2.57(d,J=12.0Hz,2H),2.89(d,J=12.0Hz,2H),3.22(s,3H),3 .56(s,2H),5.08(q,J=9.2Hz,2H),7.04(d,J=7.6Hz,1H),7.35(t,J=7.6Hz,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) +

[0306] The details of the synthesis and analytical data of the examples prepared by the above methods are shown in Table 15 below. [Table 16] TIFF2025525947000211.tif228159TIFF2025525947000212.tif240159TIFF20255259470 00213.tif239159TIFF2025525947000214.tif236159TIFF2025525947000215.tif241159 TIFF2025525947000216.tif240159TIFF2025525947000217.tif240159TIFF20255259470 00218.tif235159TIFF2025525947000219.tif240159TIFF2025525947000220.tif240159 TIFF2025525947000221.tif233159TIFF2025525947000222.tif240159TIFF20255259470 00223.tif241159TIFF2025525947000224.tif241159TIFF2025525947000225.tif241159 TIFF2025525947000226.tif240159TIFF2025525947000227.tif239159TIFF20255259470 00228.tif240159TIFF2025525947000229.tif230159TIFF2025525947000230.tif239159 TIFF2025525947000231.tif82159

[0307] 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) [ka]

[0308] 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) [ka]

[0309] Step-1: 5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate methyl ester [ka] 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 with N for 15 minutes. Tributyl(1-ethoxyvinyl)tin (943 μL, 2.793 mmol) and Pd(PPh)Cl (89 mg, 0.126 mmol) were added to the reaction mixture at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 120° C. overnight in a sealed tube. The reaction mixture was cooled to room temperature, and then 2 M HCl (40 mL) was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous bicarbonate and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography to give 450 mg of the desired compound. 1 H NMR(400MHz,DMSO-d6)δ2.46(s,3H),3.8(s,3H),4.9-5.1(m,2H),8.47(d,J=2.4Hz,1H),8.92(d,J=2.4Hz,1H)

[0310] Step-2: 5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid [ka] 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 overnight. The reaction mixture was concentrated, and the resulting residue was diluted with water, acidified with 1 N HCl solution, and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and dried to give 270 mg of the desired product. 1 H NMR (400MHz, DMSO-d6) δ2.45 (s, 3H), 4.9-5.2 (m, 2H), 8.57 (d, J = 2.4Hz, 1H), 8.96 (d, J = 2.4Hz, 1H), 13.03 (brs, 1H).

[0311] 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 [ka] 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 minutes. To this mixture was 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 overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography to give 191 mg of the desired compound. 1H NMR(400MHz,DMSO-d6)δ1.08(d,J=5.2Hz,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=8.8Hz,2H),7.12(d ,J=8Hz,1H),7.38(t,J=8Hz,1H),7.59(s,1H),7.66(d,J=8Hz,1H),8.3(s,1H),8.84(d,J=2.4Hz,1H),8.99(d,J=2.4Hz,1H),11.35(s,1H).

[0312] Step-4: 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) and 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 isobutylamine hydrochloride (67 mg, 0.616 mmol) in THF was added triethylamine (288 μL, 2.05 mmol), and titanium isopropoxide (174 mg, 0.616 mmol) was added at room temperature. The reaction mixture was heated to 50° C. for 4 hours. The reaction mixture was allowed to reach room temperature, and then sodium cyanoborohydride (39 mg, 0.616 mmol) was added and stirred at room temperature 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 give 54 mg of the desired racemic product, which was purified using 0.1% NH3 in SFC in methanol to give 21 mg of desired isomer-1 and 23 mg of desired isomer-2.

[0313] Isomer-1: 1 HNMR(400MHz,DMSO-d6)δ0.83(d,J=6.4Hz,6H),1.08(d,J=5.2Hz,3H),1.26(d,J=6.4Hz,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=8Hz,1H),7.37(t,J=8Hz,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(400MHz,DMSO-d6)δ0.6-0.8(m,6H),1.08(d,J=4.8Hz,3H),1.28(d,J=6.4Hz,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=8Hz,1H),7.37(t,J=8Hz,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) +

[0314] The details of the synthesis and analytical data of the examples prepared by the above methods are shown in Table 16 below. [Table 17]

[0315] 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 [ka]

[0316] Step-1: 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 [ka] 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) was added HATU (0.69 g, 1.82 mmol) at 0 °C. 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 into ice-cold water, and the precipitated solid was filtered and dried under vacuum to give 0.8 g of the desired compound. ESI-MS (m / z) 713.3 (M+H). +

[0317] Step-2: 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 [ka] 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 NaIO (0.85 g, 3.36 mmol) followed by OsO (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% sodium thiosulfate solution (25 mL) and extracted three times with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by Combiflash chromatography to give 0.550 g of the title compound. ESI-MS (m / z) 715.4 (M+H) +

[0318] Step-3: 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 [ka] 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 3 h. The reaction mixture was cooled to 0° C., sodium triacetoxyborohydride (0.26 g, 1.25 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was basified with saturated NaHCO and extracted three times with DCM. The organic layer was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by Combiflash chromatography to give 0.17 g of the title compound. ESI-MS (m / z) 772 (M+H) +

[0319] 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) was added 4 M HCl in dioxane (3 ml) and heated at 80° C. for 3 h. The reaction mixture was concentrated, basified with saturated NaHCO and extracted with EtOAc (3×25 ml). The organic layer was separated, dried over anhydrous NaSO and evaporated under reduced pressure to give the crude compound. The resulting compound was purified by Combiflash chromatography to give 0.05 g of the title compound. 1 H NMR(DMSO-d6,400MHz)δ0.89(d,J=4Hz,6H),1.04(d,J=5.2Hz,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=9.0Hz,2H),7.18(d,J=7.7Hz,1H),7.29(t,J=8.0Hz,1H),7.40(s,1H), 7.57(d,J=8.0Hz,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) +

[0320] The details of the synthesis and analytical data of the examples prepared by the above methods are shown in Table 17 below. [Table 18] JPEG2025525947000243.jpg131159

[0321] 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 [ka]

[0322] Step-1: 5-Formyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of methyl 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylate (0.5 g, 1.92 mmol) in THF (8 mL) and water (2 mL) was added NaIO (0.82 g, 3.83 mmol) followed by OsO (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% 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 NaSO, and evaporated under reduced pressure to give 0.5 g of the title compound. ESI-MS (m / z) 264 (M+H). +

[0323] Step-2: 5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate methyl ester [ka] To a stirred solution of methyl 5-formyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-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 3 h. The reaction mixture was cooled to 0° C., sodium triacetoxyborohydride (1.2 g, 5.7 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was made basic with saturated NaHCO and extracted three times with DCM. The organic layer was separated, dried over anhydrous NaSO, and evaporated under reduced pressure to give 0.52 g of the title compound. ESI-MS (m / z) 321 (M+H). +

[0324] Step-3: 5-(((tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate methyl ester [ka] 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 hours. The organic solvent was evaporated under reduced pressure to give the compound. The compound was purified by Combiflash chromatography to give 0.16 g of the title compound. ESI-MS (m / z) 421 (M+H). +

[0325] Step-4: 5-(((tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid [ka] 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 hours. The organic solvent was evaporated under reduced pressure. The resulting residue was acidified with 1 N HCl solution and extracted with ethyl acetate (3 × 10 ml). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give the compound. The resulting compound was triturated with hexane solvent to give 135 mg of the title compound. 1 H NMR(DMSO-d6,400MHz)δ0.81(d,J=4Hz,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=8Hz,2H),8.09(s,1H),8.39(s,1H),13.8(bs,1H);ESI-MS(m / z)407(M+H) +

[0326] 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 [ka] To a stirred solution of 5-((1r,3r)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)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 (0.428 ml, 3.89 mmol) followed by a 50% solution of T3P in DMF (0.371 ml, 0.583 mmol). The reaction mass was stirred at RT for 18 hours. The reaction mass was diluted with brine solution (3 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography to give 57 mg of the required product as a yellow solid. ESI-MS (m / z) 646 (M+H) +

[0327] 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 [ka] To a stirred solution of 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 (0.055 g, 0.085 mmol) in DCM was added triethylamine (0.022 ml, 0.170 mmol) followed by acetic anhydride (0.012 ml, 0.127 mmol). The reaction mass was stirred at room temperature for 18 hours. The reaction mass was diluted with brine solution (3 ml) and extracted with DCM (3×10 ml). The combined organic layers were dried over anhydrous NaSO and evaporated under reduced pressure to give the crude compound, which was purified by column to give 60 mg of the desired product. ESI-MS (m / z) 688 (M+H) +

[0328] 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 of 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 4 M hydrochloric acid in dioxane (1 ml) and stirred at room temperature for 2 hours. The solvent was evaporated in vacuo and the resulting solid washed with diethyl ether and dried to give 31 mg of the required product as a yellow solid. 1H NMR(DMSO-d6,400MHz)δ0.96(d,J=4Hz,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=4Hz,1H) ,9.09(bs,2H),9.18(s,1H),10.17(s,1H),11.66(s,1H);ESI-MS(m / z)588(M+H) +

[0329] The details of the synthesis and analytical data of the examples prepared by the above methods are shown in Table 18 below. [Table 19]

[0330] The details of the synthesis and analytical data of the examples synthesized by the above-mentioned methods are shown in Table 19 below. [Table 20] TIFF2025525947000253.tif241159TIFF2025525947000254.tif241159TIFF2025525947000255.tif231159TIFF20255259470 00256.tif235159TIFF2025525947000257.tif240159TIFF2025525947000258.tif240159TIFF2025525947000259.tif238159 TIFF2025525947000260.tif230159TIFF2025525947000261.tif238159TIFF2025525947000262.tif242159TIFF20255259470 00263.tif234159JPEG2025525947000264.jpg233159TIFF2025525947000265.tif240159TIFF2025525947000266.tif204159

[0331] Pharmacological activity Cbl-b phosphorylation inhibition assay: This assay measures the ability of test compounds to inhibit SRC kinase-mediated phosphorylation of a truncated form of His-tagged Cbl-b protein containing residues 36-427. The TR-FRET assay is performed in a 10 μl reaction volume at room temperature in a 384-well plate using a buffer containing 50 mM HEPES pH 7.5, 5 mM MgCl2, 1 mM DTT, and 0.1 mg / ml BSA. Candidate compounds (final 1% DMSO) were preincubated with 30 nM Cbl-b (accession number NP_733762.2) for 1 hour, followed by an additional 1 hour in the presence of 30 nM GST-tagged SRC kinase (accession number NP_005408.1) containing 100 μM ATP (final concentration). After incubation, 10 μl of a mixture containing 3.75 nM anti-His XL665 antibody (CisBio) and 1:200 TK-Crypto antibody (CisBio HTRF TK kit) prepared in detection buffer was added to the reaction. The plate was incubated at room temperature for 1 hour, followed by overnight incubation in the cold. Fluorescence signals were measured in an Artemis HRTF reader with excitation at 337 nm and dual emission at 665 and 620 nm. Signals were expressed as HTRF ratios (fluorescence intensity at 665 nm / fluorescence intensity at 620 nm × 10,000). The resulting data were analyzed and IC50 values determined using nonlinear regression analysis with variable slope fitting (GraphPad Prism version 8.4.3). IC of some compounds 50 The (nM) values are shown in Table 20, where "A" indicates an IC of less than 100 nM. 50 "B" refers to IC values in the range of 100.01-500.0 nM 50 "C" refers to IC values in the range of 500.01-1000.0 nM 50 "D" refers to an IC value greater than 1000.1 nM 50 Points to a value. [Table 21] TIFF2025525947000268.tif240159TIFF2025525947000269.tif236159JPEG20255259470 00270.jpg235159JPEG2025525947000271.jpg240159TIFF2025525947000272.tif118159

[0332] 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 many modifications may be made to the exemplary embodiments and that other arrangements may be devised without departing from the spirit and scope of the invention as set forth above.

[0333] 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 by reference.

Claims

1. A compound of formula (I), or its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 In the formula, R １ teeth, 【Chemistry 2】 Selected from the group consisting of; Z is either CH or N; X is either CH or N; R is hydrogen or C １－８ Selected from alkyl groups; At each location where it appears, R ２ Chlorine, fluorine, -NHC(O)CH 3 and -NHC(O)CH=CH 2 Selected from the group consisting of; Ring A is 【Transformation 3】 Selected from the group consisting of; At each location where it appears, R ３ It is methyl; R ４ is selected from hydrogen or methyl; R ５ is selected from methyl or cyclobutyl; or R ４ and R ５ together with the carbon atoms to which they are attached 【Chemistry 4】 Forming; Y does not exist, or CR ８ R ９ And; R ６ is hydrogen or C １－８ Selected from alkyl groups; R ７ 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-hydroxymethylpropyl, ethoxyethyl, -CH 2 CH 2 NHC(O)CH=CH 2 Selected from methyloxetane, 1-methylcyclopropyl, 1-methylcyclobutyl, cyclopropylmethyl, or 1-fluoromethylcyclopropylmethyl; R ８ is hydrogen; R ９ is hydrogen; R １０ is selected from hydrogen or methyl; R １１ This includes methyl, ethyl, propynyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl. 【Transformation 5】 And; "l" is 1; "m" is either 0 or 1; "n" is 1; and "r" is 1. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (IA), or its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Transformation 6】 In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R １０ , R １１ The compound according to claim 1, wherein rings A, Y, X, n, m, and r are as defined in claim 1.

3. A compound of formula (IB), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Transformation 7】 In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R １０ , R １１ The compound according to claim 1, wherein rings A, Y, n, m, and r are as defined in claim 1.

4. A compound of formula (IC), or its stereoisomer, or a pharmaceutically acceptable salt thereof, 【Transformation 8】 In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R １０ , R １１ The compound according to claim 1, wherein Y, n, m, and r are as defined in claim 1.

5. "Z" is either CH or N; R １ The following can be selected: 【Chemistry 9】 "X" is either CH or N; R ２ Chlorine, fluorine, -NHC(O)CH 3 and -NHC(O)CH=CH 2 Selected from the group consisting of; Ring A is 【Chemistry 10】 Selected from the group consisting of; R ３ It is methyl; Y does not exist, or CH ２ And; R ４ is selected from hydrogen or methyl; R ５ is selected from methyl or cyclobutyl; or R ４ and R ５ However, together with the carbon atoms to which they are bonded, 【Chemistry 11】 Forming; R １０ is selected from hydrogen or methyl; R １１ This includes methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl. 【Chemistry 12】 And; "l" is 1; "n" is 1; "m" is 0 or 1; and "r" is 1. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof.

6. R １ The following can be selected: 【Chemistry 13】 X is either CH or N; R ２ Chlorine, fluorine, -NHC(O)CH 3 and -NHC(O)CH=CH 2 Selected from the group consisting of; Ring A is 【Chemistry 14】 Selected from the group consisting of; R ３ It is methyl; Y does not exist, or CH ２ And; R ４ is selected from hydrogen or methyl; R ５ is selected from methyl or cyclobutyl; or R ４ and R ５ However, together with the carbon atoms to which they are bonded, 【Chemistry 15】 Forming; R １０ is selected from hydrogen or methyl; R １１ This includes methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl. 【Chemistry 16】 And; "l" is 1; "n" is 1; "m" is 0 or 1; and "r" is 1. The compound according to claim 2.

7. R １ The following can be selected: 【Chemistry 17】 R ２ Chlorine, fluorine, -NHC(O)CH 3 and -NHC(O)CH=CH 2 Selected from the group consisting of; Ring A is [Chemistry 18] Selected from the group consisting of; R ３ It is methyl; Y does not exist, or CH ２ And; R ４ is selected from hydrogen or methyl; R ５ is selected from methyl or cyclobutyl; or R ４ and R ５ However, together with the carbon atoms to which they are bonded, 【Chemistry 19】 Forming; R １０ is selected from hydrogen or methyl; R １１ This includes methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl. 【Chemistry 20】 And; "l" is 1; "n" is 1; "m" is 0 or 1; and "r" is 1. The compound according to claim 3.

8. R １ The following can be selected: 【Chemistry 21】 R ２ Chlorine, fluorine, -NHC(O)CH 3 and -NHC(O)CH=CH 2 Selected from the group consisting of; R ３ It is methyl; Y does not exist, or CH ２ And; R ４ is selected from hydrogen or methyl; R ５ is selected from methyl or cyclobutyl; or R ４ and R ５ However, together with the carbon atoms to which they are bonded, 【Chemistry 22】 Forming; R １０ is selected from hydrogen or methyl; R １１ This includes methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, or cyclobutylmethyl. 【Chemistry 23】 And; "l" is 1; "n" is 1; "m" is 0 or 1; and "r" is 1. The compound according to claim 4.

9. Compounds, including the following: 1-(cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidine-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-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2,2-difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(2,2-difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-Cyclopropyl-N-(3-(3-((4-methyl-4H-1,2,4-triazole-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)cyclobutyl)phenyl)-2-oxo-5-(piperidine-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-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-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-triazole-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3-((4-methyl-4H-1,2,4-triazole-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-5-(pyrrolidine-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-5-(morpholinomethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((4,4-difluoropiperidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; 5-((3-acetamidopiperidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); 5-((3-acetamidopiperidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (R)-5-((3-fluoropyrrolidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-hydroxypyrrolidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-hydroxypyrrolidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-fluoropyrrolidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-3-yl)methyl)oxetane-3-yl)phenyl)-2-oxo-5-(piperidine-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-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-triazole-3-yl)methyl)oxetane-3-yl)phenyl)-5-((3-methylpiperidine-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-1-(cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-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-triazole-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-fluoropyrrolidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((4-fluoropiperidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-fluoropyrrolidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-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-triazole-3-yl)propan-2-yl)phenyl)-5-(((oxetane-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-triazole-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-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((3-isopropylpiperidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); 5-((3-isopropylpiperidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2); (S)-5-((3-(hydroxymethyl)piperidine-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidine-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((4,4-dimethyl-1,4-azacilinan-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-(((S)-3-piperidine-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidine-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidine-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-(((R)-3-methylpiperidine-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((S)-3-acrylamidopyrrolidine-1-yl)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazole-3-yl)cyclobutyl)phenyl)-2-oxo-5-(((S)-3-propionamidepyrrolidine-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)pyridine-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidine)-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-triazole-3-yl)spiro[2,3]hexane-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-triazole-3-yl)spiro[2.3]hexane-5-yl)phenyl)-5-((3-methylpiperidine-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-triazole-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidine-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-triazole-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-triazole-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-triazole-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5-((3-methylpiperidine-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-triazole-3-yl)spiro[2.3]hexane-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-triazole-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-triazole-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-triazole-3-yl)spiro[2.3]hexane-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-triazole-3-yl)spiro[2.3]hexane-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-triazole-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-triazole-3-yl)spiro[2.3]hexane-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)spiro[2,3]hexane-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-((4-methyl-3-oxopiperazine-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2-cyclopropylethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-3-yl)spiro[2,3]hexane-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-triazole-3-yl)cyclobutyl)phenyl)-5-((1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-5-((3-fluoro-3-methylazetidine-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-triazole-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(propa-2-in-1-yl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)-2-fluorophenyl)-5-((3-methylpiperidine-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole)-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-imidazole-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-imidazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-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-triazole-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-triazole-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-triazole-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-triazole-3-yl)cyclobutyl)phenyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; A compound selected from, and a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and a pharmaceutically acceptable excipient thereof.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutically acceptable excipient is a carrier or a diluent.

12. A compound according to any one of claims 1 to 9, used for the treatment of a CBL-b-mediated disease, disorder, or condition in a subject.

13. The compound according to claim 12, wherein the disease, disorder, or condition mediated by CBL-b is cancer.

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