Substituted pyridone compounds as CBL-B inhibitors

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof useful as CBL-b inhibitors, processes for their preparation, pharmaceutical compositions comprising said compounds and the use of said compounds or said compositions in the treatment or prevention of various diseases, disorders and / or conditions mediated by CBL-b. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims the benefit of Indian Provisional Patent Application No. 202221046493 filed on August 16, 2022, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present patent application relates to novel heterocyclic compounds useful as CBL inhibitors, methods for preparing the same, pharmaceutical compositions comprising the compounds, and uses of the compounds or compositions in treating or preventing various diseases, disorders and / or conditions mediated by CBL-b. Background Art

[0004] CBL (Casitas B lineage lymphoma) is a mammalian gene encoding protein CBL, which is an E3 ubiquitin-protein ligase. CBL protein is part of a family of ubiquitin ligases involved in cell signaling, protein ubiquitination, and protein substrate degradation. CBL protein is a highly conserved protein family with three isoforms c-Cbl (also known as Cbl2, Cbl-SL or RNF55), Cbl-b (a 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].

[0005] All three mammalian Cbl proteins are RING-type E3 ligases that contain an N-terminal tyrosine kinase binding (TKB) domain consisting of a four-helix bundle, a calcium-binding EF-hand, and a Src homology (SH2) domain, followed by a linker helical region and the RING domain responsible for its catalytic function. Cbl-b ubiquitinates all three TAM family members, Tyro-3, Axl, and Mer, which are responsible for immunosuppression and metastatic effects. The unique feature of the TKB domain is that it recognizes specific substrates of Cbl-b by binding to proteins containing specific phosphorylated tyrosine-containing motifs, such as Syk and Zap-70, and a range of receptor tyrosine kinases. The interaction of proteins with the TKB domain of Cbl is mediated by three different subdomains, consisting of a 4-helix bundle (4H), a calcium-binding EF hand, and a variant SH2 domain, all of which are required for the function of forming 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 ubiquitin conjugation [Mohapatra et al., Biochim Biophys Acta., 1833(1):122-39, 2013]. The highly conserved α-helix of the L domain plays an important role in maintaining E3 activity [Zeng et al., Cell, 102(4):533-9, 2000; Kassenbrock et al., J Biol Chem., 279(27):28017-27, 2004]. The crystal structure shows that the L region contacts TKB, RF, and E2 ubiquitin conjugating enzymes. The RF domain has intrinsic E3 ubiquitin ligase activity and binds to ubiquitin-E2 to transfer 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 in the L region between the TKB domain and the RF domain regulates the E3 activity of Cbl-b by two mechanisms: one is to remove the masking of the RF domain by the TKB domain, and the other is to form a surface to enhance the binding affinity with E2 [Ryan et al., J Biol Chem., 285(31):23687-98, 2010;].

[0006] Casitas B lineage lymphoma proto-oncogene-b is a RING E3 ubiquitin-protein ligase, which has been shown to play a key role in establishing T cell activation thresholds and controlling peripheral T cell tolerance through multiple mechanisms. In T cells, Cbl-b is mainly expressed in peripheral T cells, while c-Cbl is mainly expressed in the thymus, indicating that c-Cbl and Cbl-b have different roles in T cell development and tolerance induction [Liu et al., Trends Immunol., 23 (3): 140-3, 2002]. E3 ubiquitin ligase cbl-b has been identified as a key intracellular checkpoint that limits T and NK cell activation. Blocking cbl-b function by genetic deletion strongly enhances anti-tumor immune response. Cbl-b is expressed in all leukocyte subsets and regulates several signal transduction pathways in T cells, NK cells, B cells, and different types of myeloid cells. Cbl-b is believed to work mainly by regulating T cell activity through the degradation of phosphoinositide-3-kinase (PI-3-K) downstream of the CD28 costimulatory receptor. The role of Cbl-b in the negative regulation of T cell activation and tolerance induction is a tightly controlled process that regulates immune responses to pathogens and tumors while preventing autoimmunity. Autoimmunity is primarily avoided through central tolerance of self-antigens by negative selection of TCR-bearing thymocytes.

[0007] CBL proteins not only regulate adaptive immune cell functions, but also are critically involved in the regulation of innate lymphocyte populations such as NK cells. NK cells are one of the first cells to arrive at inflamed tissues, where they exert effective 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 because they have the innate ability to distinguish healthy cells from virus-infected cells 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.

[0008] Adoptive cell therapy (ACT) is used to treat other treatment-resistant cancers, including metastatic melanoma, glioma and renal cancer. In ACT, NK cells or T cells from the patient's own blood or tumor tissue are harvested, then grown in large quantities in the laboratory, and then the amplified cells are transferred back to the patient to enhance the patient's immune system response to cancer. In some forms of ACT, genetic engineering is used to modify T cells or NK cells so that they can target the patient's cancer cells and kill cancer cells more effectively. The types of adoptive cell therapy include natural killer (NK) cell therapy, tumor infiltrating lymphocytes (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).

[0009] Since genetic ablation of cbl-b is associated with the spontaneous development of autoimmunity and increased susceptibility to experimentally induced autoimmune diseases [Bachmaier et al., Nature, 403(6766):211–6, 2000], several research groups subsequently demonstrated its ability to inhibit cbl-b in animal models of diabetes [Yokoi et al., Nat Genet., 31(4):391-4, 2002] and in various human autoimmune diseases such as type 1 diabetes [Bergholdt 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. It is not surprising that a link between inherited cbl-b variants and susceptibility to autoimmunity has been found in leukemia [Sawcer et al., Nature, 476(7359):214–9, 2011] and multiple sclerosis [Sawcer et al., Nature, 476(7359):214–9, 2011].

[0010] 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 used in the 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 regulate the immune system, such as increasing the activation of T cells, NK cells, circulating T cells, tumor infiltrating lymphocytes and B cells, to increase the implantation of infused ex vivo expanded immune cells or to increase the persistence of the response to infused ex vivo expanded immune cells. In addition, Cbl inhibitors can be used to help expand such immune cells in vitro or ex vivo to increase their growth and proliferation, or to regulate the phenotype of the resulting expanded immune cells.

[0011] There are several patent applications covering various scaffolds and compounds that can be used as CBL inhibitors. PCT Publication Nos. WO / 2021 / 061853; WO / 2021 / 061870; WO / 2021 / 021761; WO / 2020 / 264398; WO / 2020 / 236654; WO / 2020 / 210508; WO / 2019 / 148005 disclose compounds that are CBL inhibitors in the treatment of T cell dysfunction and cancer.

[0012] Currently, there is a great unmet need for effective means to treat diseases and conditions associated with CBL-b inhibition, including but not limited to autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular disease, allergies and asthma. Improved therapeutic compounds, compositions and methods for treating these diseases and conditions are urgently needed. CBL-b inhibition is a particularly attractive target for cancer immunotherapy.

[0013] The major challenge currently faced in this field is the lack of CBL-b specific inhibitors. The present disclosure provides novel, highly effective small molecule inhibitors of CBL-b. Summary of the invention

[0014] In one aspect, the present invention relates to compounds of formula (I)

[0015]

[0016] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0017] in,

[0018] At each occurrence, R 1 Independently selected from 3-15 membered heterocyclyl C 1-8 Alkyl, 5-14 membered heteroaryl C 1-8 Alkyl and -[CHR] l -NR 6 R 7 ; wherein 3-15 membered heterocyclic group C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 The alkyl group is optionally substituted with one or more selected from halogen, oxo, hydroxy, hydroxyl, 1-8 Alkyl, C 1-8 Alkyl, -NHC(O)CH3, -NHC(O)CH2CH3 and -NHC(O)CH=CH 2. Substituents are substituted;

[0019] Z is CH or N;

[0020] X is CH or N;

[0021] R is selected from hydrogen and C 1-8 alkyl;

[0022] At each occurrence, R 2 independently selected from halogen, -NHC(O)CH3 and -NHC(O)CH=CH2;

[0023] Ring A is a 5-14 membered heteroaryl group;

[0024] At each occurrence, R 3 C 1-8 alkyl;

[0025] R 4 Selected from hydrogen and C 1-8 alkyl;

[0026] R 5 Selected from C 1-8 Alkyl and C 3-12 Cycloalkyl; or

[0027] R 4 and R 5 Together with the carbon atoms to which they are attached, they form a 3-15 membered heterocyclic group, a C 3-12 Cycloalkyl and 3-15 membered spirocyclic group, wherein 3-15 membered heterocyclic group, C 3-12 Cycloalkyl and 3-15 membered spirocyclic groups are optionally substituted by one or more selected from halogen and C 1-8 Substitution of alkyl groups;

[0028] 'Y' does not exist or is CR 8 R 9 ;

[0029] R 6 Selected from hydrogen and C 1-8 alkyl;

[0030] R 7 Selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl, hydroxyl C 1-8 Alkyl, C 1-8 Alkoxy C 1-8 Alkyl, -CH2CH2NHC(O)CH=CH2, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-8 alkyl and 3-15 membered heterocyclylalkyl; wherein C 3-12 Cycloalkyl and C 3-12 Cycloalkyl C 1-8 The alkyl group is optionally replaced by C 1-8 Alkyl and halogenated C 1-8 Alkyl substitution;

[0031] R 8 is hydrogen;

[0032] R 9 is hydrogen;

[0033] R 10 Selected from hydrogen and C 1-8 alkyl;

[0034] R 11 Independently selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 6-14 Aryl, C 6-14 Aryl C 1-8 Alkyl, 3-15 membered heterocyclic group C 1-8 Alkyl, C 3-12 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 Alkyl; among which C 6-14 Aryl, C 6-14 Aryl C 1-8 The alkyl group is optionally substituted with one or more substituents selected from halogen;

[0035] 'l' is an integer in the range of 0 to 2, inclusive;

[0036] 'm' is an integer in the range of 0 to 4, inclusive;

[0037] 'n' is an integer in the range of 1 to 3, inclusive; and

[0038] 'r' is an integer in the range of 0 to 4, inclusive.

[0039] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound represented by formula (I) as described herein and a pharmaceutically acceptable excipient.

[0040] In another aspect, the present invention provides a method for treating a disease or condition mediated by CBL-B in a subject, the method comprising administering to a subject in need thereof a compound represented by formula (I), (IA), (IB) or (IC) as described herein, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0041] The compounds of formula (I) may relate to one or more embodiments. It should be understood that the following embodiments are illustrations of the present invention and are not intended to limit the claims to the specific embodiments illustrated. It should also be understood that the embodiments defined herein may be used independently or in combination with any definition defined herein, any other embodiment. Therefore, the present invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the present invention provides compounds of formula (I) as defined above, wherein 'Z' is CH or N (according to an embodiment defined below), 'n' is 1 (according to another embodiment defined below), and 'X' is CH or N (according to another embodiment defined below).

[0042] According to one embodiment, specifically provided are compounds of formula (I), wherein 'Z' is CH or N.

[0043] According to another embodiment, specifically provided are compounds of formula (I), wherein 'Z' is CH.

[0044] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'Z' is N.

[0045] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 for -[CHR] l -NR 6 R 7 、3-15 membered heterocyclic group C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 Alkyl; wherein 3-15 membered heterocyclic group C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 The alkyl group is optionally substituted with one or more selected from halogen, oxo, hydroxy, hydroxyl, 1-8 Alkyl, C 1-8 The substituents are alkyl, -NHC(O)CH3, -NHC(O)CH=CH2 and -NHC(O)CH2CH3.

[0046] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 -[CH R] l -NR 6 R 7 , where R, l, R 6 and R 7 As defined in formula (I).

[0047] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 is a 3-15 membered heterocyclic group C 1-8 Alkyl (e.g. ) and 5-14 membered heteroaryl C 1-8 Alkyl (e.g. ); wherein 3-15 membered heterocyclic group C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 The alkyl group is optionally substituted with one or more selected from halogen (eg fluorine), oxo, hydroxy, hydroxyl, 1-8 Alkyl (e.g. hydroxymethyl), C 1-8 The substituents are alkyl (eg, methyl or isopropyl), -NHC(O)CH3, -NHC(O)CH2CH3, and -NHC(O)CH=CH2.

[0048] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 is a 3-15 membered heterocyclic group C 1-8 Alkyl (e.g. ) or 5-14 membered heteroaryl C 1-8 Alkyl (e.g. ); wherein 3-15 membered heterocyclic group C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 The alkyl group is optionally substituted with one or more substituents selected from fluoro, oxo, hydroxy, hydroxymethyl, methyl, isopropyl, -NHC(O)CH3, -NHC(O)CH2CH3 or -NHC(O)CH=CH2.

[0049] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 for

[0050]

[0051] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 for -[CHR] l -NR 6 R 7 In this embodiment, R is hydrogen or C 1-8 Alkyl; R 6 is hydrogen or C 1-8 Alkyl; R 7 C 1-8 Alkyl, halogenated C 1-8 Alkyl, hydroxyl C 1-8 Alkyl, C 1-8 Alkoxy C 1-8 Alkyl, -CH2CH2NHC(O)CH=CH2, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-8alkyl and 3-15 membered heterocyclylalkyl; wherein C 3-12 Cycloalkyl and C 3-12 Cycloalkyl C 1-8 The alkyl group is one or more selected from C 1-8 Alkyl and halogenated C 1-8 The substituent of the alkyl group may be substituted or unsubstituted, and 'l' is 1.

[0052] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 -[CH R] l -NR 6 R 7 In this embodiment, R is hydrogen or C 1-8 Alkyl (eg methyl); R 6 is hydrogen or C 1-8 Alkyl (eg methyl); R 7 C 1-8 Alkyl (e.g., ethyl, isobutyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl or 3-methylbutan-2-yl), halogenated C 1-8 Alkyl (e.g., difluoroethyl, 2-fluoro-2-methylpropyl, 1-fluoro-2,2-dimethylpropyl or 2-fluoro-2-methylbutyl), hydroxy 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 (eg, methylcyclopropyl); wherein the C 3-12 Cycloalkyl and C 3-12 Cycloalkyl C 1-8 The alkyl group is optionally substituted with one or more selected from C 1-8 Alkyl (such as methyl) or halogenated C 1-8 The alkyl group (eg, fluoromethyl) is substituted with a substituent, and 'l' is 1.

[0053] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 -[CH R] l -NR 6 R 7 In this embodiment, R is hydrogen or methyl; R 6 is hydrogen or methyl; R 7It is ethyl, isobutyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl, 3-methylbut-2-yl, difluoroethyl, 2-fluoro-2-methylpropyl, 1-fluoro-2,2-dimethylpropyl, 2-fluoro-2-methylbutyl, hydroxyethyl, 2-hydroxy-methylpropyl, ethoxyethyl, -CH2CH2NHC(O)CH=CH2, methyloxetane, 1-methylcyclopropyl, 1-methylcyclobutyl, cyclopropylmethyl or 1-fluoromethylcyclopropylmethyl, and 'l' is 1.

[0054] According to yet another embodiment, specifically provided are compounds of formula (I), wherein -[CHR] l -NR

[0055] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 for

[0056] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'n' is 1.

[0057] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 1 for And 'n' is 1.

[0058] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'X' is CH or N.

[0059] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'X' is CH.

[0060] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'X' is N.

[0061] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 2 is halogen (eg, chlorine or fluorine), -NHC(O)CH3 or -NHC(O)CH=CH2.

[0062] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 2 It is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2.

[0063] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'm' is 0 or 1.

[0064] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'm' is 0.

[0065] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'm' is 1.

[0066] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2, and 'm' is 0 or 1.

[0067] According to another embodiment, specifically provided are compounds of formula (I), wherein ring A is a 5-6 membered heteroaryl group (e.g. ).

[0068] According to yet another embodiment, specifically provided are compounds of formula (I), wherein ring A is

[0069] According to yet another embodiment, specifically provided are compounds of formula (I), wherein ring A is

[0070] According to yet another embodiment, specifically provided are compounds of formula (I), wherein ring A is

[0071] According to yet another embodiment, specifically provided are compounds of formula (I), wherein ring A is

[0072] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 3 C 1-8 Alkyl (eg, methyl).

[0073] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 3 It is methyl.

[0074] According to yet another embodiment, specifically provided are compounds of formula (I), wherein 'r' is 1.

[0075] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 3 is a methyl group, and 'r' is 1.

[0076] According to yet another embodiment, specifically provided are compounds of formula (I), wherein Y is absent or is CR 8 R 9 .

[0077] According to yet another embodiment, specifically provided are compounds of formula (I), wherein Y is absent.

[0078] According to yet another embodiment, specifically provided are compounds of formula (I), wherein Y is CR 8 R 9 In this embodiment, R 8 is hydrogen, and R 9 For hydrogen.

[0079] According to yet another embodiment, specifically provided are compounds of formula (I), wherein Y is CH2.

[0080] According to yet another embodiment, specifically provided are compounds of formula (I), wherein Y is absent or is CH2.

[0081] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 4 is hydrogen or C 1-8 Alkyl (eg CH3).

[0082] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 4 It is hydrogen or CH3.

[0083] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 5 C 1-8 Alkyl (such as CH3) or C 3-12 Cycloalkyl (eg, cyclobutyl).

[0084] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 5 It is CH3 or cyclobutyl.

[0085] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 4 and R 5 For CH3.

[0086] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 4 is hydrogen, and R 5 It is cyclobutyl.

[0087] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-12 Cycloalkyl (e.g. ), 3-15 membered heterocyclic group (e.g. ) or a 3-15 membered spirocyclic group (e.g. ), where C 3-12 The cycloalkyl or 3-15 membered spirocyclic group is optionally substituted by one or more selected from halogen (eg fluorine) or C 1-8The alkyl group is substituted with a substituent such as a methyl or ethyl group.

[0088] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-12 Cycloalkyl (e.g. ), 3-15 membered heterocyclic group (e.g. ) or a 3-15 membered spirocyclic group (e.g. ), where C 3-12 The cycloalkyl or 3-15 membered spirocyclyl is optionally substituted with one or more substituents selected from fluoro, methyl or ethyl.

[0089] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 4 and R 5 Together with the carbon atoms to which they are attached, they form

[0090] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 10 is hydrogen or C 1-8 Alkyl (eg, methyl).

[0091] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 10 It is hydrogen or methyl.

[0092] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 10 For hydrogen.

[0093] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 10 It is methyl.

[0094] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 6-14 Aryl, C 6-14 Aryl C 1-8 Alkyl-, 3-15 membered heterocyclic group C 1-8 Alkyl, C 3-12 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 Alkyl; among which C 6-14 Aryl and C 6-14 Aryl C 1-8 The alkyl group may be substituted with one or more substituents selected from halogen or unsubstituted.

[0095] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 1-8 Alkyl (eg, methyl or ethyl).

[0096] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 It is methyl or ethyl.

[0097] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 Halogenated C 1-8 Alkyl (eg, trifluoroethyl, difluoromethyl, difluoroethyl or trifluoropropyl).

[0098] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 is difluoromethyl, difluoroethyl, trifluoroethyl or trifluoropropyl.

[0099] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 3-12 Cycloalkyl (eg cyclopropyl).

[0100] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 It is cyclopropyl.

[0101] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 3-8 Cycloalkyl C 1-8 Alkyl (eg, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl).

[0102] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 It is cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl.

[0103] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 is a 3-15 membered heterocyclic group C 1-8 Alkyl (e.g. ).

[0104] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 for

[0105] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 6-14 Aryl (eg, phenyl); wherein the C 6-14Aryl groups are optionally substituted with one or more substituents selected from halogen (eg fluorine).

[0106] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 6-14 Aryl (eg, phenyl); wherein the C 6-14 The aryl group is optionally substituted with one or more substituents selected from fluorine.

[0107] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 for

[0108] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 6-14 Aryl C 18 Alkyl (e.g. ); wherein said C 614 Aryl C 18 The alkyl group is optionally substituted with one or more substituents selected from halogen (eg fluorine).

[0109] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 C 6-14 Aryl C 1-8 Alkyl (e.g. ); wherein said C 6-14 Aryl C 1-8 The alkyl group is optionally substituted with one or more substituents selected from fluorine.

[0110] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 for

[0111] According to yet another embodiment, specifically provided are compounds of formula (I), wherein R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

[0112] According to yet another embodiment, specifically provided are compounds of formula (I), wherein

[0113] 'Z' is CH or N;

[0114]

[0115] 'X' is CH or N;

[0116] R 2is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2;

[0117] Ring A is

[0118] R 3 is methyl;

[0119] Y does not exist or is CH2;

[0120] R 4 is hydrogen or CH3;

[0121] R 5 is CH3 or cyclobutyl; or

[0122] R 4 and R 5 Together with the carbon atoms to which they are attached, they form

[0123] R 10 is hydrogen or methyl;

[0124] R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

[0125] 'l' is 1;

[0126] 'n' is 1;

[0127] 'm' is 0 or 1; and

[0128] 'r' is 1.

[0129] According to yet another embodiment, specifically provided are compounds of formula (I), wherein

[0130] 'Z' is CH;

[0131] R 1 for

[0132]

[0133] 'X' is CH or N;

[0134] R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2;

[0135] Ring A is

[0136] R 3 is methyl;

[0137] Y does not exist or is CH2;

[0138] R 4 is hydrogen or CH3;

[0139] R 5 is CH3 or cyclobutyl; or

[0140] R 4 and R 5 Together with the carbon atoms to which they are attached, they form

[0141] R 10 is hydrogen or methyl;

[0142] R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

[0143] 'l' is 1;

[0144] 'n' is 1;

[0145] 'm' is 0 or 1; and

[0146] 'r' is 1.

[0147] According to yet another embodiment, specifically provided are compounds of formula (I), wherein

[0148] 'Z' is CH;

[0149]

[0150] 'X' is CH;

[0151] R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2;

[0152] Ring A is

[0153] R 3 is methyl;

[0154] Y does not exist or is CH2;

[0155] R 4 is hydrogen or CH3;

[0156] R 5 is CH3 or cyclobutyl; or

[0157] R 4 and R 5 Together with the carbon atoms to which they are attached, they form

[0158] R 10 is hydrogen or methyl;

[0159] R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

[0160] 'l' is 1;

[0161] 'n' is 1;

[0162] 'm' is 0 or 1; and

[0163] 'r' is 1.

[0164] According to yet another embodiment, specifically provided are compounds of formula (I), wherein

[0165] 'Z' is CH;

[0166] R 1 for

[0167] 'X' is CH;

[0168] R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2;

[0169] Ring A is

[0170] R 3 is methyl;

[0171] Y does not exist or is CH2;

[0172] R 4 is hydrogen or CH3;

[0173] R 5 is CH3 or cyclobutyl; or

[0174] R 4 and R 5 Together with the carbon atoms to which they are attached, they form

[0175] R10 is hydrogen or methyl;

[0176] R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

[0177] 'l' is 1;

[0178] 'n' is 1;

[0179] 'm' is 0 or 1; and

[0180] 'r' is 1.

[0181] According to one embodiment, specifically provided are compounds of formula (I) whose IC values ​​for CBL family inhibitor activity are 50 The value is less than 10000 nM, preferably less than 1000 nM, more preferably less than 100 nM.

[0182] Involving group rings A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 Other embodiments of , n, m and r (and groups defined therein) are described below with respect to compounds of Formula (IA), (IB) or (IC). It should be understood that these embodiments are not limited to use in combination with Formula (IA), (IB) or (IC), but are independently and individually applicable to compounds of Formula (I).

[0183] The present invention also provides a compound of formula (IA), which is an embodiment of the compound of formula (I).

[0184] Therefore, the present invention provides a compound of formula (IA)

[0185]

[0186] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0187] Among them, 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).

[0188] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound represented by formula (IA) as described herein and a pharmaceutically acceptable excipient.

[0189] In another aspect, the present invention provides a method for treating a disease or condition mediated by CBL-B, the method comprising administering a compound represented by formula (IA) as described herein.

[0190] The present invention also provides a compound of formula (IB), which is an embodiment of the compound of formula (I).

[0191]

[0192] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0193] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , Ring A, Y, n, m and r are as defined in formula (I).

[0194] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound represented by formula (IB) as described herein and a pharmaceutically acceptable excipient.

[0195] In another aspect, the present invention provides a method for treating a disease or condition mediated by CBL-B, the method comprising administering a compound represented by formula (IB) as described herein.

[0196] The present invention also provides a compound of formula (IC), which is an embodiment of the compound of formula (I).

[0197]

[0198] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0199] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , Y, n, m and r are as defined in formula (I).

[0200] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound represented by formula (IC) as described herein and a pharmaceutically acceptable excipient.

[0201] In another aspect, the present invention provides a method for treating a disease or condition mediated by CBL-B, the method comprising administering a compound represented by formula (IC) as described herein.

[0202] It is to be understood that Formulas (I), (IA), (IB) and (IC) structurally encompass all geometric isomers, stereoisomers, enantiomers and diastereomers, N-oxides and pharmaceutically acceptable salts that are contemplated from the chemical structures of the compounds described herein. DETAILED DESCRIPTION

[0203] definition :

[0204] The term "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

[0205] The term "alkyl" refers to a group consisting of only carbon and hydrogen atoms in the main chain, containing no unsaturation, having from one to eight carbon atoms (i.e., C 1-8 alkyl) and is 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 (tert-butyl). The term "C 1-6 "Alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "C 1-4 "Alkyl" refers to an alkyl chain having from 1 to 4 carbon atoms. Unless stated or recited to the contrary, all alkyl groups described or claimed herein may be straight or branched.

[0206] The term "haloalkyl" refers to at least one halo group (selected from F, Cl, Br or I) attached to an alkyl group as defined above (i.e., a halo 1-8 Examples of such haloalkyl moieties include, but are not limited to, trifluoromethyl, difluoromethyl, and fluoromethyl. 1-4 "Alkyl" refers to at least one halo group attached to an alkyl chain having 1 to 4 carbon atoms. Unless stated or recited to the contrary, all haloalkyl groups described herein may be straight or branched.

[0207] The term "hydroxyalkyl" refers to an alkyl group as defined above in which one to three hydrogen atoms on different carbon atoms are replaced by hydroxy groups (i.e., hydroxy C 1-8 Examples of hydroxyalkyl moieties include, but are not limited to, -CH2OH, -C2H4OH, and -CH(OH)C2H4OH.

[0208] The term "alkoxy" refers to an alkyl group (i.e., C 1-8 Alkoxy). Representative examples of such groups are -OCH3 and -OC2H5. Unless stated or described to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.

[0209] The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group (i.e., C 1-8 Alkoxy C 1-8 Alkyl or C 1-8 Alkyloxy C 1-8 Alkyl). Examples of such alkoxyalkyl moieties include, but are not limited to, -CH2OCH3 (methoxymethyl) and -CH2OC2H5 (ethoxymethyl). Unless stated or described to the contrary, all alkoxyalkyl groups described herein may be straight or branched.

[0210] The term "hydroxy C 1-8 "Alkyl" means a C 1-8 Alkyl groups in which one to three hydrogen atoms on different carbon atoms are replaced by hydroxyl groups (i.e., hydroxyl C 1-4 Alkyl). Hydroxyl C 1-4 Examples of alkyl moieties include, but are not limited to, -CH2OH and -C2H4OH.

[0211] The term "cycloalkyl" refers to a non-aromatic monocyclic or multicyclic ring system of 3 to about 12 carbon atoms (i.e., C 3-12 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, perhydronaphthyl, adamantyl, and norbornyl, bridged ring groups, or spirobicyclic groups, such as spiro(4,4)non-2-yl. The term "C 3-6 "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, and cyclohexyl.

[0212] The term "cycloalkylalkyl" refers to a cyclic ring-containing group having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e., C 3-6 Cycloalkyl C 1-8 The cycloalkylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in a stable structure. Non-limiting examples of such radicals include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

[0213] The term "aryl" refers to an aromatic group having 6 to 14 carbon atoms (i.e., C 6-14aryl), including monocyclic, bicyclic and tricyclic aromatic systems such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.

[0214] The term "arylalkyl" refers to an aromatic group having 6 to 14 carbon atoms (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.

[0215] The term "heterocycle" or "heterocyclyl" refers, unless otherwise indicated, to a substituted or unsubstituted non-aromatic 3 to 15-membered ring group (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 group may be a monocyclic, bicyclic or tricyclic ring system, which may include a fused ring, a bridged ring or a spirocyclic system, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic group may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; similarly, unless otherwise limited by the definition, the heterocycle or heterocyclyl may optionally contain one or more olefinic bonds. Examples of such heterocyclic groups include, but are not limited to, azepinyl, azetidinyl, oxetanyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolinyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyrrolidinyl, 2-oxopyrrolidinyl, 2-oxopyrrolidinyl, 2-oxopyridin ... Oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring group may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0216] The term "heterocyclylalkyl" refers to a heterocyclic group directly bonded to an alkyl group (ie, heterocyclylC1-8alkyl). The heterocyclylalkyl 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.

[0217] The term "heteroaryl" refers, unless otherwise indicated, to a 5- to 14-membered aromatic heterocyclic group (i.e., a 5- to 14-membered heteroaryl) having one or more heteroatoms independently selected from N, O, or S. The heteroaryl group may be a monocyclic, bicyclic, or tricyclic ring system. The heteroaryl ring group may be attached to the main structure at any heteroatom or carbon atom that results in a stable structure. Examples of such heteroaryl ring groups include, without limitation, oxazolyl, isoxazolyl, imidazolyl, furanyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, 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.

[0218] The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group (ie, heteroarylC1-8alkyl). The heteroarylalkyl 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.

[0219] The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids, including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolyl p-aminophenylarsonic acid salt, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide The salts of inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, and zinc.

[0220] The terms "treating" or "treatment" of a condition, disorder, or condition include: (a) preventing or delaying the onset of clinical symptoms of a condition, disorder, or condition that develops in a subject who may have or is susceptible to the condition, disorder, or condition but does not yet experience or express clinical or subclinical symptoms of the condition, disorder, or condition; (b) inhibiting the condition, disorder, or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) ameliorating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0221] The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (eg, domestic pets, including cats and dogs) and non-domestic animals (such as wild animals).

[0222] A "therapeutically effective amount" refers to the amount of a compound that, when administered to a subject to treat a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, physical condition and responsiveness of the subject to be treated.

[0223] Compounds of formula (I), (IA), (IB) and (IC) may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of compounds of formula (I), (IA), (IB) and (IC) and mixtures thereof (including racemic mixtures) form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers based on the physicochemical differences of diastereomers by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated as follows: by reacting with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column. The chiral centers of the present invention can have the S or R configuration as defined by IUPAC 1974.

[0224] The terms "salt" or "solvate" and the like are intended to apply equally to salts, solvates and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers or racemates of the compounds of the invention.

[0225] Pharmaceutical composition

[0226] The compounds of the present invention are generally administered in the form of pharmaceutical compositions. Such compositions can be prepared using formulas well known in the pharmaceutical art and contain at least one compound of the present invention. The pharmaceutical compositions described herein contain one or more compounds described herein and one or more pharmaceutically acceptable excipients.

[0227] In one embodiment, the present invention provides a pharmaceutical composition comprising at least one compound described herein for use in treating a disease or condition mediated by CBL-b.

[0228] Treatment

[0229] The compounds of the invention are particularly useful because they inhibit the activity of CBL-b, i.e. they prevent, inhibit or suppress the action of CBL-b, and / or can induce a CBL-b modulatory effect. Thus, the compounds of the invention are useful in treating those conditions in which inhibition of CBL-b activity, and in particular CBL-b inhibition, is beneficial.

[0230] The compounds of the present application provide a method for treating a disease or disorder mediated by CBL-b in a mammal, the method 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 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of treatment.

[0231] According to one embodiment, the compounds of the present patent application inhibit CBL-b activity and can be used to treat diseases or conditions mediated by CBL-b.

[0232] According to another embodiment, the compounds of the present invention may be used to treat cancers mediated by CBL-b.

[0233] According to yet another embodiment, provided herein is a method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering to a subject an effective amount of a compound of the invention provided herein to treat the cancer responsive to inhibition of Cbl-b activity.

[0234] According to another embodiment, the compounds of the invention are used for the treatment of cancer.

[0235] According to yet another embodiment, the compounds of the invention are useful for modulating the immune system, such as increasing the activation of T cells, NK cells and B cells and for use in methods of treating such cells in vivo, in vitro or ex vivo.

[0236] In one embodiment, the invention provides the use of a compound as described herein in the preparation of a medicament. In another embodiment, the invention provides the use of a compound as described herein in the preparation of a medicament for treating a disease mediated by CBL-b.

[0237] Any of the methods of treatment described herein comprises administering to a subject, particularly a human, in need thereof an effective amount of a compound according to formula (I), (IA), (IB), (IC) or a pharmaceutically acceptable salt thereof.

[0238] The compounds of the present invention are effective in both the therapeutic and / or prophylactic treatment of the above-mentioned disorders.

[0239] General preparation method

[0240] The compounds described herein, including compounds of Formula (IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8 and IA-9), intermediates and specific examples, are prepared by the synthetic methods depicted in Synthetic Schemes 1-6. In addition, in the following schemes, when specific acids, bases, reagents, coupling reagents, solvents, etc. are mentioned, it should be understood that other suitable acids, bases, reagents, coupling reagents, solvents, etc. can be used and are included within the scope of the present invention. Modifications to reaction conditions (e.g., temperature, reaction duration, or a combination thereof) are contemplated as part of the present invention. Compounds obtained using the general reaction sequence may not be sufficiently pure. These compounds can be purified using any method known to those skilled in the art for purifying organic compounds, such as crystallization or silica gel or alumina column chromatography using different solvents in appropriate proportions. All possible geometric isomers and stereoisomers are contemplated within the scope of the present invention.

[0241] General approach

[0242] For preparing a compound of general formula (IA-1) (wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 The general method for preparing the above-mentioned esters (where 'm' and 'r' are as defined in the specification) is depicted in Synthesis Scheme 1.

[0243] Synthesis Scheme-1 :

[0244]

[0245] The esterification of the compound of formula (1) gives an ester compound of formula (2) [wherein R' is C1-8 The reaction is carried out in a suitable solvent. A suitable solvent used in the reaction may be methanol.

[0246] In the presence of a suitable base and solvent, a suitable alkylating agent is used to selectively N-alkylate the compound of formula (2) to obtain a compound of formula (3). The reaction is carried out in the presence of a suitable base. The suitable base 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. The suitable solvent used in the reaction can be selected from DMSO, DMF and THF.

[0247] In the presence of a suitable base, catalyst and solvent, potassium vinyl trifluoroborate is used to carry out the Suzuki coupling reaction of the compound of formula (3) to obtain 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), a complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane and a suitable phosphine ligand, etc. The coupling reaction can be carried out in 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.

[0248] The compound of formula (4) is subjected to oxidative cleavage using osmium tetroxide and sodium periodate in a suitable solvent mixture to obtain an aldehyde compound of formula (5). The reaction is carried out in the presence of a suitable solvent mixture. The suitable solvent mixture can be selected from a mixture of THF / water and t-BuOH.

[0249] In the presence of a suitable catalyst, a suitable reducing agent is used to carry out a reductive amination reaction of a compound of formula (5) with an appropriate amine of formula (6) to obtain a compound of formula (7). 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, dimethylformamide, methanol, ethanol. The reaction is carried out in the presence of a suitable reducing agent. The suitable reducing agent 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. The suitable catalyst used in the reaction can be acetic acid.

[0250] The hydrolysis of the compound of formula (7) yields the 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.

[0251] The acid-amine coupling reaction of compound (8) with a suitable 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.

[0252] For preparing a compound of general formula (IA-2) (wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 The general method for preparing the above-mentioned esters (where 'm' and 'r' are as defined in the specification) is depicted in Scheme 2.

[0253] Synthesis Scheme-2 :

[0254]

[0255] The compound of formula (3) [wherein R' is C 1-8 The hydrolysis reaction of [alkyl] to obtain a compound of formula (10). 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.

[0256] The acid-amine coupling reaction of compound (10) with a suitable aromatic amine of the compound of formula (9) gives a compound of formula (11). The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction may 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 may 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 may be selected from HATU, EDC.HCl, HOBt, DCC or T3P.

[0257] The compound of formula (11) is subjected to a Suzuki coupling reaction with potassium vinyl trifluoroborate to obtain a compound of formula (12). 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), a complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane and a suitable phosphine ligand, etc. The reaction can be carried out in 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.

[0258] The compound of formula (12) is subjected to oxidative cleavage using osmium tetroxide and sodium periodate to obtain an aldehyde compound of formula (13). The reaction is carried out in the presence of a suitable solvent or a mixture thereof. The suitable solvent used in the reaction can be THF / water.

[0259] The reductive amination reaction of the compound of formula (13) with the appropriate amine compound of formula (6) obtains the compound of general formula (IA-2). The reaction is carried out in the presence of a suitable catalyst. The suitable catalyst used in the reaction can be acetic acid. The reaction is carried out in the presence of a suitable base. The suitable base used in the reaction can be selected from TEA and DIPEA. The reaction can be carried out in the presence of a suitable solvent. The 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. The suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.

[0260] For preparing compounds of 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 The general method for preparing the above-mentioned esters (where 'm' and 'r' are as defined in the specification) is depicted in Scheme 3.

[0261] Synthesis Scheme-3 :

[0262]

[0263] The compound of formula (3) [wherein R' is C 1-8The compound of formula (4) is obtained by Suzuki coupling reaction of] alkyl with potassium vinyl trifluoroborate. 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), a complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane and 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.

[0264] In the presence of a suitable base and a solvent, the hydrolysis reaction of the compound of formula (4) obtains the 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.

[0265] The acid-amine coupling reaction of compound (14) with a suitable aromatic amine compound of formula (9) gives 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.

[0266] The compound of formula (15) is subjected to oxidative cleavage using osmium tetroxide and sodium periodate to obtain an aldehyde compound of formula (16). The reaction is carried out in the presence of a suitable solvent or a mixture thereof. The suitable solvent used in the reaction can be THF / water.

[0267] The reductive amination reaction of the compound of formula (16) with the appropriate amine (6) gives the compound of formula (IA-3). The reaction is carried out in the presence of a suitable catalyst. The suitable catalyst used in the reaction can be acetic acid. The reaction is carried out in the presence of a suitable base. The 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. The 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. The suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

[0268] In a suitable solvent, the compound of formula (IA-3) is treated with a suitable mineral acid to obtain a compound of formula (IA-4). The reaction is carried out in the presence of a suitable mineral acid. The suitable mineral 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, ethylene dichloride or THF.

[0269] For preparing compounds of the general formula (IA-5, IA-6 and IA-7) (wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 The general method for preparing the above-mentioned esters (where 'm' and 'r' are as defined in the specification) is depicted in Scheme 4.

[0270] Synthesis Scheme-4 :

[0271]

[0272] The compound of formula (3) is subjected to a Stille coupling reaction with tributyl (1-ethoxyvinyl) tin to obtain a compound of formula (17). 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), dichlorobis (triphenylphosphine) palladium (II), palladium acetate and a suitable phosphine ligand, etc. The reaction is carried out in the presence of a suitable solvent. The suitable solvent used in the reaction can be selected from 1,4-dioxane, DMSO or DMF.

[0273] The hydrolysis reaction of the compound of formula (17) yields the compound of formula (18). 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 or 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 or tetrahydrofuran or a combination thereof.

[0274] The acid-amine coupling reaction of compound (18) with a suitable aromatic amine compound of formula (9) gives 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.

[0275] The reductive amination reaction of the compound of formula (19) with the appropriate amine compound of formula (6) gives the compound of formula (IA-5). The reaction is carried out in the presence of a suitable catalyst. The suitable catalyst used in the reaction can be acetic acid. The reaction is carried out in the presence of a suitable base. The 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. The 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. The suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

[0276] Supercritical fluid chromatography (SFC) purification of the racemic compound of formula (IA-5) affords compounds of formula (IA-6) and (IA-7).

[0277] For preparing a compound of general formula (IA-8) (wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 The general method for preparing the above-mentioned esters (where 'm' and 'r' are as defined in the specification) is depicted in Scheme 5.

[0278] Synthesis Scheme-5 :

[0279]

[0280] Compound (14) is reacted with an appropriate aromatic amine compound of formula (20) [wherein Q is C or N] by acid-amine coupling reaction to obtain 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.

[0281] The compound of formula (21) is subjected to oxidative cleavage using osmium tetroxide and sodium periodate to obtain an aldehyde compound of formula (22). The reaction is carried out in the presence of a suitable solvent or a mixture thereof. The suitable solvent used in the reaction can be THF / water.

[0282] The reductive amination reaction of the compound of formula (22) with the appropriate amine compound of formula (6) gives the compound of formula (23). The reaction is carried out in the presence of a suitable catalyst. The suitable catalyst used in the reaction is acetic acid. The reaction is carried out in the presence of a suitable base. The 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. The 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. The suitable reducing agent used in the reaction can be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

[0283] The compound of formula (23) is deprotected to obtain a compound of formula (IA-8). The reaction can be carried out in the presence of a suitable acid. The suitable acid 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. The suitable solvent used in the reaction can be selected from methanol, ethanol, dichloroethane and 1,4-dioxane.

[0284] For preparing a compound of general formula (IA-9) (wherein X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 The general method for preparing the above-mentioned esters (where 'm' and 'r' are as defined in the specification) is depicted in Scheme 6.

[0285] Synthesis Scheme-6 :

[0286]

[0287] The compound of formula (4) [wherein R' is C 1-8 [alkyl] is oxidatively cleaved using osmium tetroxide and sodium periodate to give an aldehyde compound of formula (5). 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.

[0288] The reductive amination reaction of the compound of formula (5) with the appropriate amine compound of formula (24) gives the 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 can 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 can be selected from dichloromethane, dimethylformamide, methanol and ethanol.

[0289] The amine compound of formula (25) is N-protected using a suitable protecting group (PG) to obtain a compound of formula (26). The reaction is carried out in the presence of a suitable protecting group. The suitable protecting group used in the reaction can be selected from di-tert-butyl dicarbonate, acetic anhydride and benzyl chloroformate.

[0290] The hydrolysis reaction of the compound of formula (26) obtains the compound of formula (27). 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 and 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 and tetrahydrofuran or a combination thereof.

[0291] The acid-amine coupling reaction of the compound of formula (27) with the appropriate aromatic amine compound of formula (28) gives the 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.

[0292] The acylation reaction of the compound of formula (29) gives the compound of formula (30). The reaction is carried out in the presence of a suitable acylating agent. The suitable acylating agent used in the reaction may be acetic anhydride or acryloyl chloride.

[0293] The compound of formula (30) is deprotected to obtain the compound of formula (IA-9). The reaction is carried out in the presence of a suitable acid. The suitable acid 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. The suitable solvent used in the reaction can be selected from dichloromethane, dichloroethane and 1,4-dioxane.

[0294] Experimental Section

[0295] Unless otherwise stated, workup includes partitioning the reaction mixture between the organic phase indicated in brackets and the aqueous phase, separating the layers and drying the organic layer over sodium sulfate, filtering and evaporating the solvent. Unless otherwise stated, purification includes purification by silica gel chromatography techniques, typically using ethyl acetate / petroleum ether mixtures of appropriate polarity as mobile phases. Different eluent systems are indicated in brackets.

[0296] The abbreviations, symbols and terms used in the examples have the following meanings throughout the text:

[0297]

[0298]

[0299]

[0300] Intermediates

[0301] Intermediate A1

[0302] 3-(2-Methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline

[0303]

[0304] Step 1 :3-(3-bromophenyl)-3-methylbutanoic acid

[0305]

[0306] 3,3 dimethyl acrylic acid (3.19 g, 0.0318 mol) was added to a stirred solution of bromobenzene (10 g, 0.0183 mmol) in DCM (100 mL). AlCl was added to the reaction mixture in batches at 15°C-20°C and stirred at room temperature for 90 minutes. The reaction mixture was quenched with 1N 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 obtain 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).

[0307] Step 2 :2-(3-(3-bromophenyl)-3-methylbutyryl)-N-methylhydrazinethiocarboamide

[0308]

[0309] To a stirred solution of 3-(3-bromophenyl)-3-methylbutanoic acid (6.2 g, 0.024 mol) in DMF (60 mL) was added HATU (11 g, 0.029 mol) and stirred at room temperature for 30 minutes. DIPEA (12.5 mL, 0.072 mol) and 4-methylthiosemicarbazide (2.8 g, 0.0265 mmol) were added to the mixture 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. 1H 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).

[0310] Step 3 :3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione

[0311]

[0312] A stirred solution of 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N-methylhydrazinethiocarboamide (4.8 g, 0.0139 mol) in 1N NaOH (170 mL) was stirred at room temperature for 18 hours. The reaction mixture was acidified with 3N 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) +

[0313] Step 4 :3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole

[0314]

[0315] 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% H2O2 solution (4.3 mL) and stirred at 0°C for 1 hour. 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. 1H 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) +

[0316] Step-5 :3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline

[0317] In a sealed tube, to a stirred solution of 3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole (1 g, 0.0034 mol) in NMP (10 mL) was added aqueous NH3 (10 mL), copper (I) oxide (194 mg 1.359 mmol) and stirred at 90 ° C for 16 hours. 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) +

[0318] Intermediate A2

[0319] 2-Fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline

[0320]

[0321] Step 1 :Diethyl 2-(2-(3-bromo-4-fluorophenyl)propan-2-yl)malonate

[0322]

[0323] At -10 ° C, 2-bromo-4-iodo-1-fluorobenzene (5.86g, 19.5mmol) was added dropwise to a stirred solution of THF (15mL) of isopropylmagnesium chloride in THF 2M solution (11.25mL, 22.5mmol), and stirred at 0 ° C for 30 minutes, and further stirred at room temperature for 1 hour. Copper iodide (I) (860mg, 4.5mmol) was added to the mixture at 0 ° C and stirred for 10 minutes, and then diethyl isopropylidene malonate (3g, 15mmol) 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 resulting filtrate was extracted 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 obtain 3.5g 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) +

[0324] Step-2 :3-(3-bromo-4-fluorophenyl)-3-methylbutyric acid ethyl ester

[0325]

[0326] A stirred suspension 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 microwaved 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. 1 H 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) +

[0327] Step-3 :3-(3-bromo-4-fluorophenyl)-3-methylbutyric acid hydrazide

[0328]

[0329] 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 99% hydrazine hydrate (7 mL) dropwise 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) +

[0330] Step-4 :2-(3-(3-bromo-4-fluorophenyl)-3-methylbutyryl)-N-methylhydrazinethiocarbothioamide

[0331]

[0332] Methyl isothiocyanate (1 g, 13.86 mmol) was added dropwise to a stirred solution of 3-(3-bromo-4-fluorophenyl)-3-methylbutanoylhydrazide (1.4 g, 4.62 mmol) in THF (10 mL) at 0 ° C. 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 ground 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) +

[0333] Step-5:5-(2-(3-bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole-3-thiol

[0334]

[0335] A stirred solution of 2-(3-(3-bromo-4-fluorophenyl)-3-methylbutanoyl)-N-methylhydrazinethiocarboamide (1.4 g, 3.86 mmol) in 1N NaOH (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified with 2N 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) +

[0336] Step-6 :3-(2-(3-bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole

[0337]

[0338] 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% H2O2 solution (370 mg, 10.89 mmol) at 0 ° C. The mixture was stirred at room temperature for 16 hours. 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 obtain 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); ESIMS(m / z)313.1(M+2H) +

[0339] Step-7:2-Fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)aniline

[0340] In a sealed tube, to a stirred solution of 3-(2-(3-bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-1,2,4-triazole (400 mg, 1.28 mmol) in NMP (4 mL) was added NH3 aqueous solution (4 mL), copper (I) oxide (73 mg, 0.512 mmol) and stirred at 90 ° C for 16 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 under vacuum to give 300 mg of the desired product. 1 HNMR (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) +

[0341] The analytical data of the intermediates prepared according to the above procedure are given in the following Table-1.

[0342] Table-1: Structure, name and analytical data of intermediate (A3)

[0343]

[0344] Intermediate A4

[0345] 3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline

[0346]

[0347] Step-1 : 2-(oxetane-3-ylidene)ethyl acetate

[0348]

[0349] At 0 ° C, 2- (diethoxyphosphoryl) ethyl acetate (3.422 mg, 15.27 mmol) was added dropwise to a stirred solution of NaH (611 mg, 15.27 mmol) in THF (25 mL) for 10-15 minutes, and further stirred at room temperature for 30 minutes, then oxetanes-3-one (1 g, 13.889 mmol) was added. The mixture was stirred for 18 hours. The reaction mixture was quenched with NaHCO3 aqueous solution 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 obtain 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).

[0350] Step-2 : ethyl 2-(3-(3-bromophenyl)oxetane-3-yl)acetate

[0351]

[0352] At room temperature to [Rh (COD) Cl] 2 (170mg, 0.352mmol) in dioxane (15mL) in degassed solution was added dropwise 1.5KOH aqueous solution (6mL) and stirred for 30 minutes. In the mixture, a solution of 2- (oxetanes -3- subunits) ethyl acetate (1g, 7.042mmol) in dioxane (10mL) was added dropwise, followed by a solution of (3- bromophenyl) boronic acid (2g, 10.56mmol) in dioxane (10mL) and stirred for 1 hour. The reactant was stirred for 1 hour and (3- bromophenyl) boronic acid (700mg, 3.521mmol) was added again to the reaction mixture and stirred at room temperature for 48 hours. The mixture was quenched with saline solution and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain 1.3g 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).

[0353] Step-3: 2-(3-(3-bromophenyl)oxetan-3-yl)acetic acid

[0354]

[0355] To a stirred solution of ethyl 2-(3-(3-bromophenyl)oxetane-3-yl)acetate (150 mg, 0.5 mmol) in THF (1.5 mL) at 0°C was added an aqueous solution of LiOH (40 mg, 1 mmol) and stirred at room temperature for 4 hours. 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. 1 H 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)

[0356] Step-4 :2-(2-(3-(3-bromophenyl)oxetane-3-yl)acetyl)-N-methylhydrazinethiocarboxamide

[0357]

[0358] To a stirred solution of 2-(3-(3-bromophenyl)oxetane-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-methylhydrazinethiocarboxamide (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) δ2.51 (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) +

[0359] Step-5 :3-((3-(3-bromophenyl)oxetane-3-yl)methyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione

[0360]

[0361] A stirred solution of 2-(2-(3-(3-bromophenyl)oxetane-3-yl)acetyl)-N-methylhydrazinecarbothioamide (100 mg, 0.28 mmol) in 1N NaOH (3.5 mL) was stirred at room temperature for 18 hours. The mixture was cooled and neutralized using 1N 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) +

[0362] Step-6 :3-((3-(3-bromophenyl)oxetane-3-yl)methyl)-4-methyl-4H-1,2,4-triazole

[0363]

[0364] To a stirred solution of 3-((3-(3-bromophenyl)oxetane-3-yl)methyl)-4-methyl-1H-1,2,4-triazole-5(4H)-thione (350 mg, 1.032 mmol) in water (1.5 mL) was added NaNO2 (750 mg, 10.32 mmol), then 1N HNO3 (3.5 ml) was added dropwise at 0°C and stirred for 1 hour. The reaction mixture was quenched with saturated NaHCO3 solution 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) +

[0365] Step-7 :3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetane-3-yl)aniline

[0366] In a sealed tube, to a stirred solution of 3-((3-(3-bromophenyl)oxetane-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (200 mg, 0.629 mmol) in NMP (2 mL) was added NH3 aqueous solution (2 mL), copper (I) oxide (35 mg, 0.2515 mmol) and stirred at 90 ° C for 16 hours. 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) +

[0367] Intermediate A5

[0368] 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline

[0369]

[0370] Step-1 :1,3-Dibromo-2-methylpropane

[0371]

[0372] 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) was added N-bromosuccinimide (86.92 g, 488.35 mmol) in portions at 0° C. and stirred at room temperature for 16 hours. 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. 1 HNMR (400MHz, CDCl3): δ1.17 (d, J = 6.4Hz, 3H), 2.18-2.24 (m, 1H), 3.46-3.56 (m, 4H).

[0373] Step-2 :1-(3-bromophenyl)-3-methylcyclobutanenitrile

[0374]

[0375] To a suspension of NaH (60% suspension in mineral oil) (2.58 g, 107.65 mmol) in DMF (100 mL) at 0 ° C, a solution of 3-bromobenzeneacetonitrile (10.55 g, 53.826 mmol) was added dropwise, and then 1,3-dibromo-2-methylpropane (11.62 g, 53.826 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and at 80 ° C for 16 hours. The reaction mixture was cooled to 0 ° C and quenched with NH4Cl aqueous solution. The aqueous layer was extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 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).

[0376] Step-3 :1-(3-bromophenyl)-3-methylcyclobutanecarboxylic acid

[0377]

[0378] To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanenitrile (17.7 g, 70.76 mmol) in 80 mL of AcOH / H2O (1:1) was added concentrated H2SO4 (40 mL) dropwise at 0°C and stirred for 15 minutes at 0°C and heated to 120°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated to give 18 g of the desired product. 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)

[0379] Step-4: Methyl 1-(3-bromophenyl)-3-methylcyclobutanecarboxylate

[0380]

[0381] To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarboxylic acid (18.3 g, 67.99 mmol) in MeOH (180 mL) was added concentrated H2SO4 (18 mL) and stirred at room temperature for 2 hours and heated to 90 ° C for 16 hours. The reaction mixture was concentrated under vacuum and diluted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum to 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).

[0382] Step-5 :1-(3-bromophenyl)-3-methylcyclobutanecarbohydrazide

[0383]

[0384] 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 hours. The mixture was concentrated and the resulting residue was dissolved with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 19.18 g of the desired product. ESI-MS (m / z) 283.1 (M+H) +

[0385] Step-6 :2-(1-(3-bromophenyl)-3-methylcyclobutanecarbonyl)-N-methylhydrazinethiocarbothioamide

[0386]

[0387] To a stirred solution of 1-(3-bromophenyl)-3-methylcyclobutanecarbohydrazide (19.0 g, 67.09 mmol) in THF (200 mL) at 0°C was added methyl isothiocyanate (14.71 g, 201.3 mmol) dropwise. 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 23.8 g of the desired product. ESI-MS (m / z) 356.0 (M+H) +

[0388] Step-7 :5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

[0389]

[0390] A stirred solution of 2-(1-(3-bromophenyl)-3-methylcyclobutanecarbonyl)-N-methylhydrazinethiocarboamide (23.4 g, 65.67 mmol) in 1N NaOH (500 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified with 2N 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) +

[0391] Step-8 :3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole

[0392]

[0393] To a stirred solution of 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (10 g, 19.56 mmol) in DCM (240 mL) and AcOH (40 mL) was added 30% H2O2 solution at 0°C. The mixture was stirred at room temperature for 16 hours. 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 desired product of racemic. The resulting racemic product was purified by SFC to give 2.65 g of the desired product of the cis isomer. 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); ESIMS(m / z)306.0(M+H) +

[0394] Step-9 :3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline

[0395] In a sealed tube, to a stirred solution of 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (250 mg, 0.816 mmol) in NMP (3.5 mL) was added NH3 aqueous solution (3.5 mL), copper oxide (47 mg, 0.326 mmol) and stirred at 90 ° C for 16 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 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) +

[0396] The analytical data of the intermediates prepared according to the above procedure are given in Table-2 below.

[0397] Table-2: Structure, name and analytical data of intermediates (A6-A9)

[0398]

[0399] Intermediate-A10

[0400] 2-Chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline

[0401]

[0402] 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. NaN3 (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 and stirred at 110 ° C for 18 hours in a sealed tube. 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) +

[0403] Intermediate-A11

[0404] 3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline

[0405]

[0406] Step-1 :2,2-Dimethylpropane-1,3-diyl dimethanesulfonate

[0407]

[0408] 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). Methanesulfonyl 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 Na2SO4 and concentrated to give 11.0 g of the desired product. 1HNMR (400MHz, DMSO-d6): δ0.86 (s, 6H), 3.18 (s, 6H), 4.00 (s, 4H).

[0409] Step-2 :1,3-Diiodo-2,2-dimethylpropane

[0410]

[0411] To a stirred solution of 2,2-dimethylpropane-1,3-diyl dimethanesulfonate (2.0 g, 7.69 mmol) in DMF (20 mL) was added KI (5.1 g, 30.7 mmol) in portions at 0 ° C and stirred at 120 ° C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water and extracted twice with petroleum ether. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated to give 2.1 g of the desired product. 1 HNMR (400MHz, CDCl3): δ1.26 (s, 6H), 3.28 (s, 4H).

[0412] Step-3 :1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonitrile

[0413]

[0414] To a stirred suspension of NaH (60% suspension in mineral oil) (734 mg, 15.3 mmol) in DMF (15 mL) was added dropwise 3-bromobenzeneacetonitrile (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 continued to be added dropwise for 1 hour. The reaction mixture was stirred at room temperature for 2 hours and then stirred at 80 ° C for 16 hours. The reaction mixture was cooled to 0 ° C and quenched with an ice-cold aqueous solution. The water layer was extracted twice with petroleum ether. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 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).

[0415] Step-4 :1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carboxylic acid

[0416]

[0417] To a stirred solution of 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonitrile (700 mg, 2.66 mmol) in 4.2 mL of AcOH / H2O (1:1) was added concentrated H2SO4 (2.1 mL) dropwise at 0°C and stirred for 15 minutes at 0°C and heated to 120°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted twice with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated to give 700 mg of the desired product. 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) +

[0418] Step-5 :2-(1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonyl)-N-methylhydrazine-1-thiocarboxamide

[0419]

[0420] To a stirred solution of 1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carboxylic acid (700 mg, 2.47 mmol) in DMF (8.0 mL) was added DIPEA (1.3 mL, 7.42 mmol) and HATU (1.1 g, 2.96 mmol) and stirred for 30 minutes. 4-Methylthiosemicarbazide (313 mg, 2.96 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. 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) +

[0421] Step-6 :5-(1-(3-bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

[0422]

[0423] A stirred solution of 2-(1-(3-bromophenyl)-3,3-dimethylcyclobutane-1-carbonyl)-N-methylhydrazine-1-thiocarboxamide (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) +

[0424] Step-7 :3-(1-(3-bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-4H-1,2,4-triazole

[0425]

[0426] To a stirred solution of 5-(1-(3-bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (760 mg, 2.16 mmol) in DCM (10.0 mL) and AcOH (2.2 mL) was added 30% H2O2 solution (0.9 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. 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); ESIMS(m / z)321.1(M+2H) +

[0427] Step-7 :3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline

[0428] In a sealed tube, NH3 aqueous solution (4.0 mL), copper (I) oxide (280 mg, 1.96 mmol) were added 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), and stirred at 100 ° C for 16 hours. 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 and the solvent was evaporated under reduced pressure, and the resulting solid was purified by silica gel column chromatography to obtain 410 mg of the desired product. 1 HNMR (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) +

[0429] The analytical data of the intermediates prepared according to the above procedure are given in Table-3 below.

[0430] Table-3: Structure, name and analytical data of intermediates (A12-A19)

[0431]

[0432]

[0433]

[0434] Intermediate A20

[0435] 3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline

[0436]

[0437] Step-1 :1-(3-bromophenyl)-3,3-dimethoxycyclobutane-1-carbonitrile

[0438]

[0439] To a stirred suspension of NaH (60% suspension in mineral oil) (2.56 g, 63.77 mmol) in DMF (50 mL) at 0 ° C, a solution of 3-bromobenzeneacetonitrile (5.0 g, 25.51 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 30 minutes, and then 1,3-dibromo-2,2-dimethoxy-propane (5.32 g, 20.40 mmol) was slowly added. 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 water layer was extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 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)

[0440] Step-2 :1-(3-bromophenyl)-3-oxocyclobutane-1-carbonitrile

[0441]

[0442] 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 for 48 hours at room temperature. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated, and purified to give 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).

[0443] Step-3 :1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonitrile

[0444]

[0445] 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 hours. The reactant 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 obtain 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).

[0446] Step-4 :1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carboxylic acid

[0447]

[0448] 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 H2SO4 (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 filtered and dried thoroughly 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) +

[0449] Step-5 :2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-thiocarboxamide

[0450]

[0451] 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-methylhydrazinethiocarboxamide (48 mg, 0.453 mmol). EDCI.HCl (118 mg, 0.618 mmol), triethylamine (54 mg, 0.536 mmol) and HOBt (72 mg, 0.536 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched by adding water and the aqueous layer was 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) +

[0452] Step-6 :5-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

[0453]

[0454] A stirred solution of 2-(1-(3-bromophenyl)-3,3-difluorocyclobutane-1-carbonyl)-N-methylhydrazine-1-thiocarboxamide (2.9 g, 7.67 mmol) in 1N NaOH (100 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified with 2N 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) +

[0455] Step-7 :3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole

[0456]

[0457] 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 (0.144 ml) was added 30% H2O2 (0.045 ml) solution at 0 ° C. The mixture was stirred at room temperature for 16 hours. 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); ESIMS(m / z)328(M+H) +

[0458] Step-8 :3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline

[0459] In a sealed tube, to a stirred solution of 3-(1-(3-bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-4H-1,2,4-triazole (300 mg, 0.914 mmol) in ACN (3.0 mL) was added NH3 aqueous solution (3.0 mL), copper oxide (52 mg, 0.365 mmol) and stirred at 90 ° C for 16 hours. 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. 1 HNMR (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) +

[0460] Intermediate A21

[0461] 3-(Cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)aniline

[0462]

[0463] Step-1 :Methyl 2-(3-bromophenyl)acetate

[0464]

[0465] 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 hours. 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 and separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography to obtain 9.3 g of the desired product as a light 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) +

[0466] Step-2 :Methyl 2-(3-bromophenyl)-2-cyclobutylacetate

[0467]

[0468] To a stirred solution of 2-(3-bromophenyl)methyl acetate (2g, 8.77mmol) in DMF (15mL) was added dropwise potassium tert-butoxide solution (11.34ml, 11.34mmol) at 0°C. A solution of bromocyclobutane (1.41g, 10.48mmol) in DMF (5ml) was added dropwise and stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated NH4Cl 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 obtain 1.21g of the desired product as a light 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) +

[0469] Step-3:2-(3-bromophenyl)-2-cyclobutylacetohydrazide

[0470]

[0471] To a stirred solution of methyl 2-(3-bromophenyl)-2-cyclobutaneacetate (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 completely evaporated 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) +

[0472] Step-4 :2-(2-(3-bromophenyl)-2-cyclobutylacetyl)-N-methylhydrazine-1-thiocarboamide

[0473]

[0474] 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 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 1.1 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) +

[0475] Step-5:5-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

[0476]

[0477] A stirred solution of 2-(2-(3-bromophenyl)-2-cyclobutylacetyl)-N-methylhydrazine-1-thiocarboxamide (1.1 g) in 1 N NaOH (40 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified with 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. 1 H 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) +

[0478] Step-6 :3-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole

[0479]

[0480] 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. 30% H2O2 solution (1.2 ml, 11.84 mmol) was added to the reaction mixture and stirred at 0°C for 2 hours. The reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 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. 1HNMR(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) +

[0481] Step-7 :3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)aniline

[0482]

[0483] In a sealed tube, to a stirred solution of 3-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole (500 mg, 1.63 mmol) in NMP (5 mL) was added NH3 aqueous solution (5 mL), copper (I) oxide (70 mg 0.49 mmol) and stirred at 100 ° C for 16 hours. The reaction mixture was diluted with ethyl acetate and filtered. The organic layer was separated and 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) +

[0484] The analytical data of the intermediates prepared according to the above procedure are given in Table-4 below.

[0485] Table-4: Structure, name and analytical data of intermediate (A22)

[0486]

[0487] Intermediate A23

[0488] 3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)aniline

[0489]

[0490] Step-1 :(1s,3s)-1-(3-bromophenyl)-N-methoxy-N,3-dimethylcyclobutane-1-carboxamide

[0491]

[0492] To a stirred solution of (1s, 3s)-1-(3-bromophenyl)-3-methylcyclobutane-1-carboxylic acid (4.0g, 14.86mmol) in DCM (40ml) was added CDI (4.81g, 29.72mmol) in batches, followed by AIBN (2.0g, 12.33mmol). 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 (50ml) and extracted with DCM (3x 100ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the product. The resulting product was purified by combiflash chromatography to obtain 3.1g 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).

[0493] Step-2 :1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propan-1-one

[0494]

[0495] 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 (3x100 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the product. The resulting product was purified by combiflash chromatography to obtain 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] + .

[0496] Step-3 :-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-2-hydroxypropan-1-one

[0497]

[0498] 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 minutes, a solution of (R)-3-methyl-3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (2.78 g, 10.64 mmol) was added at -78 °C, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with NH4Cl solution (50 ml) and extracted with EtOAc (3 x 100 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the product. The resulting product was purified by combiflash chromatography to obtain 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).

[0499] Step-4 :1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propane-1,2-dione

[0500]

[0501] 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) was added DMP (3.99 g, 9.42 mmol) in portions at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted three times with DCM. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the product. The resulting 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).

[0502] Step-5 :4-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-imidazole

[0503]

[0504] To a stirred solution of 1-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)propane-1,2-dione (1.1 g, 3.72 mmol) in MeOH was added paraformaldehyde (0.12 g, 4.09 mmol) followed by ammonium acetate (2.87 g, 37.26 mmol). The reaction mixture was heated at 80 °C in a sealed tube for 16 h. The reaction mixture was concentrated and the resulting product was purified by combiflash chromatography to give 1.0 g of the title compound. 1 HNMR(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] +

[0505] Step-6 :4-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1-trityl-1H-imidazole

[0506]

[0507] 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 was added triethylamine (0.31 g, 3.06 mmol) followed by trityl chloride (0.4 g, 1.46 mmol) in portions. 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] +

[0508] Step-7 :N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)phenyl)-1,1-benzophenone imine

[0509]

[0510] 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 anhydrous 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 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] +

[0511] Step-8 :3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)aniline

[0512] To a stirred solution of N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)phenyl)-1,1-benzophenone imine (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 hours. 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 obtain 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] +

[0513] The analytical data of the intermediates prepared according to the above procedure are given in the following Table-5.

[0514] Table-5: Structure, name and analytical data of intermediate (A24)

[0515]

[0516] Intermediate A25

[0517] 3-(3-methyl-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)cyclobutyl)aniline

[0518]

[0519] Step-1 :1-(3-bromophenyl)-3-methylcyclobutane-1-carbaldehyde

[0520]

[0521] 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 ammonium chloride solution, filtered and washed with ethyl acetate. The resulting filtrate was evaporated under reduced pressure to give 3.8 g of the desired product. ESI-MS (m / z) 254 (M+2H) +

[0522] Step-2 :4-(1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1H-1,2,3-triazole

[0523]

[0524] 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, followed by the addition of aluminum chloride (0.2 g, 0.0015 mol). 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 Na2SO4 and evaporated under reduced pressure to obtain 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] +

[0525] Step-3 :4-(1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazole

[0526]

[0527] 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 mixture 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 product as a yellow oil. ESI-MS (m / z) 390 [M+H] +

[0528] Step-5 :3-(3-methyl-1-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)cyclobutyl)aniline

[0529] To a stirred solution of 4-(1-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazole (2.0 g, 5.12 mmol) in acetonitrile (15 mL) was added aqueous ammonia (15 mL), copper oxide (1.46 g, 10.24 mmol) and stirred overnight at 110 ° C 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 obtain 0.8 g of the desired product as a yellow oil. ESI-MS (m / z) 327 [M+1] +

[0530] The analytical data of the intermediates prepared according to the above procedure are given in Table-6 below.

[0531] Table-6: Structure, name and analytical data of intermediate (A26)

[0532]

[0533] The following intermediates were synthesized following the procedure described above for intermediate A11 and the analytical data are given in Table-7 below.

[0534] Table-7: Structure, name and analytical data of intermediates (A27-A30)

[0535]

[0536] Intermediate B1

[0537] 5-Bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0538]

[0539] Step-1 :5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0540]

[0541] To a stirred solution of 5-bromo-2-hydroxynicotinic acid (5.0 g, 35.94 mmol) in anhydrous methanol (100 mL) was added concentrated H2SO4 (1 mL) and refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was alkalized with saturated sodium bicarbonate solution and stirred for 30 minutes. The obtained solid was filtered and dried under vacuum to obtain 4.2 g of the desired product. 1HNMR(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) + .

[0542] Step-2 :5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0543] To a stirred solution of 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (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. Cyclopropylmethyl bromide (157 μL, 1.616 mmol) was added to the mixture 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) +

[0544] The analytical data of the intermediates prepared according to the above procedure are given in Table-8 below.

[0545] Table-8: Structure, name and analytical data of intermediates (B2-B4)

[0546]

[0547] Intermediate B5

[0548] 5-Bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0549]

[0550] To a stirred solution of 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (5.2 gm, 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 the 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) +

[0551] The analytical data of the intermediates prepared according to the above procedure are given in Table-9 below.

[0552] Table-9: Structure, name and analytical data of intermediate (B6)

[0553]

[0554] Intermediate B7

[0555] 5-Bromo-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0556]

[0557] Step-1 :1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0558]

[0559] To a solution of 2-oxo-1,2-dihydropyridine-3-formic acid methyl ester (4.8g, 31.16mmol) in dichloroethane (150mL) was added cyclopropylboronic acid (5.30g, 62.33mmol), Cs2CO3 (5.06g, 15.58mmol), pyridine (12.32g, 155.8mmol), and stirred at room temperature for 30 minutes under an oxygen atmosphere. Cu(OAc)2 (5.65g, 31.16mmol) was added to the mixture and stirred for 4 days. The reaction mixture was diluted with DCM and filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 230mg of the desired product. 1HNMR(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) +

[0560] Step-2 :5-bromo-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0561] To a stirred solution of 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (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 hours. 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) +

[0562] Intermediate B8

[0563] 2-Oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0564]

[0565] Step-1 :2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0566]

[0567] A stirred solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate (Intermediate B5) (1.5 g, 4.76 mmol) and potassium vinyl trifluoroborate (1.91 gm., 14.28 mmol) in a solvent mixture of toluene (50 mL) / water (15 mL) was degassed for 15 minutes. To the reaction mixture were added K3PO4 (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 under vacuum. The resulting residue was purified by silica gel column chromatography to obtain 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) +

[0568] Step-2 :2-Oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0569] To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester (1 g, 3.831 mmol) in THF / MeOH (40 mL, 1: 1) was added LiOH aqueous solution (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 1N 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) +

[0570] The analytical data of the intermediates prepared according to the above procedure are given in the following Table-10.

[0571] Table-10: Structure, name and analytical data of intermediates (B9-B12)

[0572]

[0573] Intermediate B13

[0574] 1-(Difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0575]

[0576] Step-1 :5-bromo-1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0577]

[0578] To a stirred solution of 5-bromo-2-oxo-1,2-dihydropyridine-3-formic acid methyl ester (300 mg, 1.293 mmol) in DMF (2 mL) was added K2CO3 (356 mg, 2.586 mmol), 2-chloro-2,2-difluoroacetic acid sodium (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 obtain 201 mg of the desired product. 1 HNMR (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) +

[0579] Step-2 :1-(Difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0580]

[0581] A stirred solution of methyl 5-bromo-1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (150 mg, 0.5319 mmol) and potassium vinyl trifluoroborate (212 mg, 1.595 mmol) in a solvent mixture of toluene (5 mL) / water (1 mL) was degassed for 15 minutes. K3PO4 (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 under vacuum. The resulting residue was purified by silica gel column chromatography to obtain 120 mg of the desired product. 1 H 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) +

[0582] Step-3 :1-(Difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0583] To a stirred solution of 1-(difluoromethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester (27 mg, 0.0118 mmol) in THF / methanol (2 mL) was added aqueous lithium hydroxide solution (14.85 mg, 0.3537 mmol) at 0°C 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) +

[0584] Intermediate B14

[0585] 2-Oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0586]

[0587] Step-1 :5-bromo-2-oxo-1-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0588]

[0589] Cesium carbonate (4.2g, 12.99mmol) is added to the stirring solution of 5-bromo-2-hydroxynicotinate (2g, 8.66mmol) in anhydrous DMF (20mL), and the resulting mixture is stirred at room temperature for 30 minutes. (3-bromoprop-1-yn-1-yl) trimethylsilane (1.65mL, 10.39mmol) is added and stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted three times with ethyl acetate, and the combined organic layer is washed with water and concentrated. The resulting residue is purified by column chromatography to obtain 1.8g 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) +

[0590] Step-2 :2-oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0591]

[0592] To a stirred solution of 5-bromo-2-oxo-1-(3-(trimethylsilyl)prop-2-yn-1-yl)-1,2-dihydropyridine-3-carboxylic acid methyl ester (1.8 g, 5.232 mmol) in toluene (25 mL) and water (5 mL) under a nitrogen atmosphere was added K3PO4 (4.4 g, 20.93 mmol) and trifluoro(vinyl)-l4-borane potassium salt (2.0 g, 15.69 mmol), 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, and the resulting residue was purified by silica gel column chromatography to obtain 190 mg of the product as an off-white solid; 1 HNMR (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).

[0593] Step-3:2-Oxo-1-(prop-2-yn-1-yl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0594] 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) +

[0595] Intermediate B15

[0596] 1-(4-Fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0597]

[0598] Step-1: 5-Bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0599]

[0600] To a stirred solution of 5-bromo-2-oxo-1,2-dihydropyridine-3-formic acid methyl ester (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), then diacetoxycopper (3.4 g, 17.24 mmol) and activated molecular sieves were added, and stirred at room temperature overnight. The reaction mixture was filtered and 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 obtain 650 mg of the desired compound. 1HNMR (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) +

[0601] Step-2 :1-(4-fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0602]

[0603] A stirred solution of 5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (650 mg, 1.99 mmol) and potassium vinyl trifluoroborate (800 mg, 5.98 mmol) in a mixture of toluene (5 mL) and water (2 mL) was degassed for 15 minutes. K3PO4 (1.7 g, 7.96 mmol), Pd(dppf)Cl2.DCM (163 mg, 199 mmol) were added to the reaction mixture 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 under vacuum. The resulting residue was purified by silica gel column chromatography to obtain 550 mg of the desired product. 1 H 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) +

[0604] Step-3 :1-(4-fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0605] To a stirred solution of 1-(4-fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester (550 mg, 2.01 mmol) in THF / methanol / water (25 mL) at 0°C was added aqueous lithium hydroxide solution (423 mg, 10.07 mmol) and stirred at the same temperature overnight. 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) + .

[0606] The following intermediates were synthesized following the procedure described above for Intermediate B8 and the analytical data are given in Table-11 below.

[0607] Table-11: Structure, name and analytical data of intermediates (B16-B19)

[0608]

[0609]

[0610] Example

[0611] Method A :

[0612] Example-1

[0613] 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

[0614]

[0615] Step-1 :5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0616]

[0617] To a stirred solution of 5-bromo-2-hydroxynicotinic acid (5.0 g, 35.94 mmol) in anhydrous methanol (100 mL) was added concentrated H2SO4 (1 mL) and refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was alkalized with saturated sodium bicarbonate solution and stirred for 30 minutes. The obtained solid was filtered and dried under vacuum to obtain 4.2 g of the desired product. 1HNMR(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) + .

[0618] Step-2 :5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0619]

[0620] To a stirred solution of 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (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. Cyclopropylmethyl bromide (157 μL, 1.616 mmol) was added to the mixture 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 obtain 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) +

[0621] Step-3 :1-(Cyclopropylmethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0622]

[0623] A stirred solution of methyl 5-bromo-1-(cyclopropylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.74 mmol) and potassium vinyl trifluoroborate (700 mg, 5.2 mmol) in a solvent mixture of toluene and water (30 mL) was degassed for 15 minutes. To the reaction mixture were added K3PO4 (1.5 gm, 6.9 mmol), Pd(dppf)Cl 2.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 and dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain 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),3.77(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) +

[0624] Step-4 :1-(Cyclopropylmethyl)-5-formyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0625]

[0626] To a stirred solution of 1-(cyclopropylmethyl)-2-oxo-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester (375 mg, 1.712 mmol) in THF / H2O (4:1, 25 mL) was added NaIO4 (768 mg, 3.59 mmol) followed by 2.5% OsO4 in t-BuOH (36 μl, 0034 mmol). The reaction mixture was stirred at 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) +

[0627] Step-5 :1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0628]

[0629] To a stirred solution of 1-(cyclopropylmethyl)-5-formyl-2-oxo-1,2-dihydropyridine-3-formic acid methyl ester (180mg, 0.765mmol) and piperidine (152 μl, 1.53mmol) in DCM (5mL) was added a catalytic amount of acetic acid and stirred for 2 hours. Sodium cyanoborohydride (144mg, 2.295mmol) 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 obtain 172mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ0.40-0.60(m,4H),1.30-1.40(m,1H),1.50-1.60(m,2H),1.60-1.75(m,4H),2.90- 3.10(m,4H),3.77(s,3H),3.78(d,J=9.2Hz,2H),4.12(brs,2H),8.10-8.30(m,2H); ESI-MS(m / z)305.3(M+H) +

[0630] Step-6: 1-(Cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxylic acid

[0631]

[0632] To a stirred solution of 1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester (100 mg, 0.328 mmol) in THF / MeOH (2 mL) was added LiOH aqueous solution (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) +

[0633] 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

[0634] To a stirred solution of 1-(cyclopropylmethyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxylic acid (70 mg, 0.241 mmol) in DMF was added HATU (110 mg, 0.289 mmol) and stirred at room temperature for 30 minutes. 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 to the mixture 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 HNMR(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) +

[0635] Method B :

[0636] Example-2

[0637] N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo

[0638] -5-(piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide

[0639]

[0640] Step-1 :5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid

[0641]

[0642] To a stirred solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester (1 g, 3.174 mmol) in THF / MeOH (20 mL) was added LiOH aqueous solution (666 mg, 15.873 mmol) overnight at room temperature. 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) +

[0643] 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

[0644]

[0645] 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. 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) were added to the mixture 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. 1HNMR (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) +

[0646] 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

[0647]

[0648] A stirred solution of 5-bromo-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (250 mg, 0.488 mmol) and potassium vinyl trifluoroborate (196 mg, 1.464 mmol) in toluene (5 mL) / water (1 mL) was degassed for 10 minutes. To the reaction mixture were added K3PO4 (414 mg, 1.954 mmol), Pd(dppf)Cl 2. DCM (40 mg, 0.0488 mmol) 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 under vacuum. The resulting residue was purified by silica gel column chromatography to obtain 230 mg of the desired product. 1 HNMR(400MHz,DMSO-d6)δ1.42(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),7.0-7.15(m,1H),7.15-7.25(m,1H),7.25-7.40(m,1H),7.6-7.75(m,1 H),8.15-8.30(m,2H),8.73(s,1H),11.64(s,1H); ESI-MS(m / z)460.2(M+H) + .

[0649] 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

[0650]

[0651] To a stirred solution of N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (215 mg, 0.468 mmol) in THF / H2O (4:1, 25 mL) was added NaIO4 (200 mg, 0.936 mmol) followed by 2.5% OsO4 in t-BuOH (10 μL, 0.0009 mmol). The reaction mixture was stirred at room temperature 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) +

[0652] 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

[0653] 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 a drop of acetic acid and stirred for 2 hours. Sodium triacetoxyborohydride (96 mg, 0.455 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the 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) +

[0654] The synthesis details and analytical data of the examples synthesized by the above method are given in the following Table-12.

[0655] Table-12: Structure, method, intermediates used, chemical names and analytical data of Examples (3-8)

[0656]

[0657]

[0658]

[0659] Method C :

[0660] Example-9

[0661] (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

[0662]

[0663] Step-1 :2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0664]

[0665] A stirred solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate (1.5 g, 4.76 mmol) and potassium vinyl trifluoroborate (1.91 gm., 14.28 mmol) in a solvent mixture of toluene (50 mL) / water (15 mL) was degassed for 15 minutes. To the reaction mixture were added K3PO4 (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 under vacuum. The resulting residue was purified by silica gel column chromatography to obtain 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) +

[0666] Step-2 :2-Oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid

[0667]

[0668] To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid methyl ester (1 g, 3.831 mmol) in THF / MeOH (40 mL, 1: 1) was added LiOH aqueous solution (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 1N HCl. The precipitated solid was filtered and dried to give 809 mg of the desired product. 1HNMR(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) +

[0669] 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

[0670]

[0671] 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. 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) were added to the mixture 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) +

[0672] 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

[0673]

[0674] To a stirred solution of N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (1.5 g, 3.267 mmol) in THF / H2O (50 mL) was added NaIO4 (2 g, 6.534 mmol) followed by 2.5% OsO4 in t-BuOH (320 μl, 0.032 mmol). The reaction mixture was stirred at room temperature 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) +

[0675] 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

[0676] 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 hours. Sodium triacetoxyborohydride (110 mg, 0.519 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the 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) +

[0677] The synthesis details and analytical data of the examples synthesized by the above method are given in the following Table-13.

[0678] Table-13: Structures, methods, intermediates used, chemical names and analytical data of Examples (10-46)

[0679]

[0680]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695] Embodiment 47

[0696] 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

[0697]

[0698] 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

[0699]

[0700] 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. 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) were added to the mixture 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) +

[0701] 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

[0702]

[0703] To a stirred solution of N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (5.8 g, 12.30 mmol) in THF / H2O (250 mL) was added NaIO4 (5.53 g, 25.83 mmol) followed by 2.5% OsO4 in t-BuOH (800 μl, 0.025 mmol). The reaction mixture was stirred at room temperature 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) +

[0704] 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:

[0705] To a stirred solution of 5-formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (3.6 g, 7.603 mmol) and isobutylamine (2.78 g, 38.02 mmol) in 1,2, dichloroethane (120 mL) was added acetic acid (1.37 gm, 22.81 mmol) and refluxed for 4 hours. The reaction mixture was cooled. To the reaction mixture was added sodium triacetoxyborohydride (4.83 gm, 22.81 mmol) portionwise and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue obtained was purified by flash chromatography to obtain 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),5.11(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) +

[0706] The synthetic details and analytical data of the examples prepared by the above method are given in the following Table- 14. The racemic compounds were prepared by the above method and separated using SFC purification to give the corresponding chiral isomers (Examples 60-69).

[0707] Table-14: Structures, chemical names, methods, intermediates used and analytical data of Examples (48-94)

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724] Embodiment 95

[0725] 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

[0726]

[0727] 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

[0728]

[0729] 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. DIPEA (1.04 mL, 6.07 mmol) and 3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (518 mg, 2.02 mmol) were added to the mixture 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)+

[0730] 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

[0731]

[0732] To a stirred solution of N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (830 mg, 1.71 mmol) in THF (10.0 mL) and H2O (5.0 mL) was added NaIO4 (733 mg, 3.42 mmol) followed by 1.0% OsO4 in t-BuOH (0.017 mL, 0.007 mmol). The reaction mixture was stirred at room temperature 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) +

[0733] 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

[0734] 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 a drop of acetic acid and refluxed for 4 hours. The reaction mixture was returned to room temperature, and then sodium triacetoxyborohydride (130 mg, 0.61 mmol) was added in batches and stirred at room temperature overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the 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) +

[0735] The synthetic details and analytical data of the examples prepared by the above mentioned method are given in the following Table-15.

[0736] Table-15: Structures, chemical names, methods, intermediates used and analytical data of Examples (96-151)

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0755]

[0756]

[0757]

[0758] Method D :

[0759] Example-152

[0760] 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)

[0761]

[0762] Example-153

[0763] 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)

[0764]

[0765] Step-1:5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0766]

[0767] The stirring solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-formic acid methyl ester (800mg, 2.539mmol) in 1,4-dioxane was degassed for 15 minutes using N2. Tributyl (1-ethoxyvinyl) tin (943μL, 2.793mmol) and Pd (PPh3) 2Cl2 (89mg, 0.126mmol) 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 2M HCl (40ml) was then added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography to obtain 450mg 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)

[0768] Step-2 :5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid

[0769]

[0770] To a stirred solution of 5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylate (440mg, 1.582mmol) in THF / MeOH (10mL), 2mL of LiOH aqueous solution (199mg, 4.748mmol) was added, and stirred at room temperature overnight. The reaction mixture was concentrated, and the resulting residue was diluted with water and acidified with 1N HCl solution, and extracted twice with ethyl acetate. The organic layer was concentrated and dried under reduced pressure to obtain 270mg 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).

[0771] 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

[0772]

[0773] 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. 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) were added to the mixture 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. 1 H 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).

[0774] 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)

[0775] 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) at room temperature. The reaction mixture was heated to 50 ° C for 4 hours. The reaction mixture was returned to room temperature, 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. The racemic product was purified by using SFC 0.1% NH3 in methanol to give 21 mg of desired isomer-1 and 23 mg of desired isomer-2.

[0776] 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) +

[0777] 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) +

[0778] The synthetic details and analytical data of the examples prepared by the above mentioned method are given in the following Table-16.

[0779] Table-16: Structures, chemical names, methods, intermediates used and analytical data of Examples (154-155)

[0780]

[0781]

[0782] Method E :

[0783] Example-156

[0784] 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

[0785]

[0786] 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

[0787]

[0788] To a stirred solution of 2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxylic acid (0.3 g, 1.21 mmol) in DMF (5 ml) at 0°C was added HATU (0.69 g, 1.82 mmol). After 30 minutes, 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 hours. The reaction mixture was poured into ice-cold water, 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) +

[0789] 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

[0790]

[0791] To a stirred solution of N-(3-((1s,3s)-3-methyl-1-(5-methyl-1-trityl-1H-imidazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-5-vinyl-1,2-dihydropyridine-3-carboxamide (0.8 g, 1.21 mmol) in THF (20 ml) and water (4 ml) was added NaIO4 (0.85 g, 3.36 mmol) followed by OsO4 (1% in t-BuOH, 0.0048 g, 0.0224 mmol, 0.5 ml). The reaction mixture was stirred at room temperature for 16 hours. 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 Na2SO4 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) +

[0792] Step-3 :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

[0793]

[0794] 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 hours. The reaction mixture was cooled to 0° C., sodium triacetoxyborohydride (0.26 g, 1.25 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was basified with saturated NaHCO3 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. The crude compound was purified by combiflash chromatography to give 0.17 g of the title compound. ESI-MS (m / z) 772 (M+H) +

[0795] 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

[0796] 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 4M HCl in dioxane (3 ml) at 0°C and heated at 80°C for 3 hours. The reaction mixture was concentrated, basified with saturated NaHCO3 and extracted with EtOAc (3 x 25 ml). The organic layer was separated, dried over anhydrous Na2SO4 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. 1H 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) +

[0797] The synthetic details and analytical data of the examples prepared by the above mentioned method are given in the following Table-17.

[0798] Table-17: Structures, chemical names, methods, intermediates used and analytical data of Examples (157-160)

[0799]

[0800]

[0801] Method F :

[0802] Example-161

[0803] 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

[0804]

[0805] Step-1 :5-Formyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0806]

[0807] 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 NaIO4 (0.82 g, 3.83 mmol) followed by OsO4 (1% in t-BuOH, 0.97 mL, 0.038 mmol). The reaction mixture was stirred at room temperature for 3 hours. 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 Na2SO4 and evaporated under reduced pressure to give 0.5 g of the title compound. ESI-MS (m / z) 264 (M+H) +

[0808] Step-2 :5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0809]

[0810] 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 hours. The reaction mixture was cooled to 0 ° C, sodium triacetoxyborohydride (1.2 g, 5.7 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was basified with saturated NaHCO3 and extracted three times with DCM. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 0.52 g of the title compound. ESI-MS (m / z) 321 (M+H) +

[0811] Step-3 :5-(((tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester

[0812]

[0813] 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) were 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 obtain the compound. The obtained compound was purified by combiflash chromatography to give 0.16 g of the title compound. ESI-MS (m / z) 421 (M+H) +

[0814] Step-4 :5-(((tert-Butyloxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid

[0815]

[0816] To a stirred solution of 5-(((tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxylic acid methyl ester (0.162g, 0.38mmol) in THF:MeOH:water (1:1:0.5,5ml), lithium hydroxide (46mg, 1.14mmol) was added and stirred at room temperature for 16 hours. The organic solvent was evaporated under reduced pressure. The obtained residue was acidified with 1NHCl solution and extracted with ethyl acetate (3x 10ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a compound. The obtained compound was triturated with hexane solvent to obtain 135mg 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) +

[0817] Step-5 : ((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)carbamic acid tert-butyl ester

[0818]

[0819] 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 50% solution of T3P in DMF (0.371 ml, 0.583 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 ethyl acetate (3 x 20 mL). The organic layer was separated and dried over anhydrous Na2SO4, evaporated under reduced pressure to give the crude compound, which was purified by column to afford 57 mg of desired product as a yellow solid. ESI-MS (m / z) 646 (M+H) +

[0820] Step-6 : ((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)carbamic acid tert-butyl ester

[0821]

[0822] 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 (0.055g, 0.085mmol) in DCM was added triethylamine (0.022ml, 0.170mmol) followed by acetic anhydride (0.012ml, 0.127mmol). The reaction mass was stirred at room temperature for 18 hours. The reaction mass was diluted with saline solution (3ml) and extracted with DCM (3x 10mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a crude compound which was purified by column to give 60mg of the desired product. ESI-MS (m / z) 688 (M+H) +

[0823] 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

[0824] 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 4M hydrochloric acid in dioxane (1 ml) and stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and the resulting solid was washed with diethyl ether and dried to give 31 mg of the desired product as a yellow solid. 1 H 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) +

[0825] The synthetic details and analytical data of the examples prepared by the above method are given in the following Table-18.

[0826] Table-18: Structure, chemical name, method, intermediates used and analytical data of Example-162

[0827]

[0828]

[0829] The synthesis details and analytical data of the examples synthesized by the above method are given in the following Table-19.

[0830] Table-19: Structures, methods, intermediates used, chemical names and analytical data of Examples (163-205)

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845] Pharmacological activity

[0846] Cbl-b phosphorylation inhibition assay ：

[0847] The assay measures the ability of a test compound to inhibit SRC kinase-mediated phosphorylation of a truncated version of a His-tagged Cbl-b protein containing residues 36-427. The TR-FRET assay was performed in a 384-well plate at room temperature in a 10 μl reaction volume with a buffer containing 50 mM HEPES pH 7.5, 5 mM mgCl2, 1 mM DTT, 0.1 mg / ml BSA. Candidate compounds (final 1% DMSO) were pre-incubated with 30 nM Cbl-b (Accession No. NP_733762.2) for one hour and then incubated in the presence of 30 nM GST-tagged SRC kinase (Accession No. NP_005408.1) with 100 μM ATP (final concentration) for another hour. After incubation, 10 ul of a mixture containing 3.75 nM anti-His XL665 antibody (CisBio) and 1:200 TK-cryptate antibody (CisBio HTRF TK kit) prepared in detection buffer was added to the reaction. The plate was incubated at room temperature for one hour, then overnight in the cold, and the fluorescence signal was measured on an Artemis HRTF reader with excitation at 337 nm and dual emission at 665 and 620 nm. The signal is expressed as the HTRF ratio (fluorescence intensity at 665 nm / fluorescence intensity at 620 nm x 10000). The resulting data were analyzed and IC50 values ​​were determined using nonlinear regression analysis, variable slope fitting (GraphPad Prism version 8.4.3).

[0848] IC of some compounds 50 The (nM) values ​​are listed in Table-20, where “A” refers to IC 50 Values ​​less than 100 nM, "B" refers to IC 50 Values ​​range from 100.01 to 500.0 nM, and “C” refers to IC 50 The values ​​range from 500.01 to 1000.0 nM, and “D” refers to IC 50 The value is greater than 1000.1nM.

[0849] Table-20 :

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857] (-): Not determined

[0858] Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are only illustrative of the principles and applications of the present invention. Therefore, it should be understood that various modifications can be made to the illustrative embodiments, and other arrangements can be designed without departing from the spirit and scope of the present invention as described above.

[0859] 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 a stereoisomer or a pharmaceutically acceptable salt thereof, in, At each occurrence, R 1 Independently selected from 3-15 membered heterocyclyl C 1-8 Alkyl, 5-14 membered heteroaryl C 1-8 Alkyl and -[CHR] l -NR 6 R 7 ; wherein 3-15 membered heterocyclic group C 1-8 Alkyl and 5-14 membered heteroaryl C 1-8 The alkyl group is optionally substituted with one or more selected from halogen, oxo, hydroxy, hydroxyl, 1-8 Alkyl, C 1-8 Alkyl, -NHC(O)CH3, -NHC(O)CH2CH3 and -NHC(O)CH=CH 2. Substituents are substituted; Z is CH or N; X is CH or N; R is selected from hydrogen and C 1-8 alkyl; At each occurrence, R 2 independently selected from halogen, -NHC(O)CH3 and -NHC(O)CH=CH2; Ring A is a 5-14 membered heteroaryl group; At each occurrence, R 3 C 1-8 alkyl; R 4 Selected from hydrogen and C 1-8 alkyl; R 5 Selected from 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, they form a 3-15 membered heterocyclic group, a C 3-12 Cycloalkyl and 3-15 membered spirocyclic group, wherein 3-15 membered heterocyclic group, C 3-12 Cycloalkyl and 3-15 membered spirocyclic groups are optionally substituted by one or more selected from halogen and C 1-8 Substitution of alkyl groups; 'Y' does not exist or is CR 8 R 9 ; R 6 Selected from hydrogen and C 1-8 alkyl; R 7 Selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl, hydroxyl C 1-8 Alkyl, C 1-8 Alkoxy C 1-8 Alkyl, -CH2CH2NHC(O)CH=CH2, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-8 alkyl and 3-15 membered heterocyclylalkyl; wherein C 3-12 Cycloalkyl and C 3-12 Cycloalkyl C 1-8 The alkyl group is optionally replaced by C 1-8 Alkyl and halogenated C 1-8 Alkyl substitution; R 8 is hydrogen; R 9 is hydrogen; R 10 Selected from hydrogen and C 1-8 alkyl; R 11 Independently selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 6-14 Aryl, C 6-14 Aryl C 1-8 Alkyl, 3-15 membered heterocyclic group C 1-8 Alkyl, C 3-12 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 Alkyl; among which C 6-14 Aryl, C 6-14 Aryl C 1-8 The alkyl group is optionally substituted with one or more substituents selected from halogen; 'l' is an integer in the range of 0 to 2, inclusive; 'm' is an integer in the range of 0 to 4, inclusive; 'n' is an integer in the range of 1 to 3, inclusive; and 'r' is an integer in the range of 0 to 4, inclusive.

2. The compound according to claim 1, which is represented by formula (IA) or a stereoisomer or a pharmaceutically acceptable salt thereof, in, 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 claim 1.

3. The compound according to claim 1, which is represented by formula (IB) or a stereoisomer or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , Ring A, Y, n, m and r are as defined in claim 1.

4. The compound according to claim 1, which is represented by formula (IC) or a stereoisomer or a pharmaceutically acceptable salt thereof, in, R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , Y, n, m and r are as defined in claim 1.

5. A compound according to any one of claims 1 to 4, wherein R 1 for And 'n' is 1.

6. A compound according to any one of claims 1 to 5, wherein R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2, and 'm' is 0 or 1.

7. A compound according to any one of claims 1 to 6, wherein R 3 is a methyl group, and 'r' is 1.

8. A compound according to any one of claims 1 to 7, wherein Y is absent or is CH2.

9. A compound according to any one of claims 1 to 8, wherein R 4 It is hydrogen or CH3.

10. A compound according to any one of claims 1 to 9, wherein R 5 It is CH3 or cyclobutyl.

11. A compound according to any one of claims 1 to 10, wherein R 4 and R 5 For CH3.

12. A compound according to any one of claims 1 to 8, wherein R 4 and R 5 Together with the carbon atoms to which they are attached, they form 13. A compound according to any one of claims 1 to 12, wherein R 10 It is hydrogen or methyl.

14. A compound according to any one of claims 1 to 4, wherein R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl, 15. The compound according to any one of claims 1 to 3, wherein ring A is 16. The compound according to any one of claims 1 to 3, wherein ring A is 17. The compound according to any one of claims 1, wherein 'Z' is C or N.

18. The compound according to any one of claims 1, wherein 'Z' is C.

19. The compound according to any one of claims 1-2, wherein 'X' is C or N.

20. The compound according to claim 1, wherein 'Z' is CH or N; R 1 for 'X' is CH or N; R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2; Ring A is R 3 is methyl; Y does not exist or is CH2; 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, they form R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl, 'l' is 1; 'n' is 1; 'm' is 0 or 1; and 'r' is 1.

21. The compound according to claim 2, wherein R 1 for 'X' is CH or N; R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2; Ring A is R 3 is methyl; Y does not exist or is CH2; 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, they form R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl, 'l' is 1; 'n' is 1; 'm' is 0 or 1; and 'r' is 1.

22. The compound according to claim 3, wherein R 1 for R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2; Ring A is R 3 is methyl; Y does not exist or is CH2; 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, they form R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl, 'l' is 1; 'n' is 1; 'm' is 0 or 1; and 'r' is 1.

23. The compound according to claim 4, wherein R 1 for R 2 is chlorine, fluorine, -NHC(O)CH3 or -NHC(O)CH=CH2; R 3 is methyl; Y does not exist or is CH2; 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, they form R 10 is hydrogen or methyl; R 11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl, 'l' is 1; 'n' is 1; 'm' is 0 or 1; and 'r' is 1.

24. A compound selected from: 1-(Cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-cyclopropyl-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2,2-difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(2,2-difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-cyclopropyl-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(cyclobutylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(pyrrolidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-(morpholinomethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((4,4-difluoropiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(difluoromethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; 5-((3-acetamidopiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); 5-((3-acetamidopiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2); 1-(2-cyclopropylethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (R)-5-((3-fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-hydroxypyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-hydroxypyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2-cyclopropylethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(cyclopropylmethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-1-(cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (R)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((2-methylmorpholino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(2-cyclopropylethyl)-5-((3-fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((4-fluoropiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (R)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((2-methylmorpholino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-1-(2-cyclopropylethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-5-((3-fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutyl(methyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-(((oxetan-3-ylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(2-fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((3-isopropylpiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); 5-((3-isopropylpiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2); (S)-5-((3-(hydroxymethyl)piperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-hydroxyethyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-hydroxy-2-methylpropyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2,2-difluoroethyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(4-fluoro-3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((4,4-dimethyl-1,4-azasilan-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-piperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-hydroxy-2-methylpropyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1-methylcyclopropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((R)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1-methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-ethylbutyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3-methylbutyl-2-yl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1): N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3-methylbutyl-2-yl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2): N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2); N-(5-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); N-(5-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-1); N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (isomer-2); N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-ethoxyethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-hydroxy-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1-methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-5-((tert-pentylamino)methyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-5-((isobutylamino)methyl)-N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-N-(2-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((ethylamino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-fluoro-2-methylpropyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(cyclopropylmethyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-5-(((Cyclopropylmethyl)amino)methyl)-N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((S)-3-acrylamidopyrrolidin-1-yl)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 1-(2-cyclopropylethyl)-5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-5-(((S)-3-propionamidopyrrolidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-fluoro-2-methylpropyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(4-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; ((S)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; (S)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((2-ethylbutyl)amino)methyl)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-ethylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-ethylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-5-(((2-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1); N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-5-(((2-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2); 5-(((Cyclopropylmethyl)amino)methyl)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-chloro-5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((neopentylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 1-(2,2-difluoroethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((4-methyl-3-oxopiperazin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2-cyclopropylethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hex-5-yl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-fluoro-3-methylazetidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 1-(2,2-difluoroethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(2,2-difluoroethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((neopentylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1-methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(Cyclopropylmethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2-cyclopropylethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-(2-cyclopropylethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutyl(methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(4-fluorophenyl)-5-(isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; (S)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-N-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-1-(2,2-difluoroethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(1-(Isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1); 5-(1-(Isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2); ( + )N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(1-(isobutylamino)ethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; ( + )N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(1-(isobutylamino)ethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1H-imidazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-(3,3-dimethyl-1-(5-methyl-1H-imidazol-4-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-(3-methyl-1-(5-methyl-1H-1,2,3-triazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide hydrochloride; 5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1H-1,2,3-triazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-((1r,3r)-3-methyl-1-(5-methyl-1H-1,2,3-triazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(3-acetamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide hydrochloride; N-(3-Acrylamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide 2,2,2-trifluoroacetate; N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1-ethyl-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-ethyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-1-ethyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((3-fluoro-3-methylbutyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide: N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1-(4-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1-(4-fluorobenzyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-1-methyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-1-(2,2-difluoroethyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((3-fluoro-2,2-dimethylpropyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(2,2-difluoroethyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((3-fluoro-2,2-dimethylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-Cyclopropyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-6-((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)-2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)-2-fluorophenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)-2-fluorophenyl)-5-(((3-fluoro-3-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide: N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)-2-fluorophenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)-2-fluorophenyl)-5-(((3-fluoro-2,2-dimethylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((isobutylamino)methyl)-N-(3-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((3-fluoro-3-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((3-fluoro-3-methylbutyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)phenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-(((cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoro-methyl)cyclopropyl)methyl)amino)methyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 1-Cyclopropyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((3-Fluoro-2,2-dimethylpropyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]hept-2-yl)-phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; N-(2-Fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; or 6-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; and pharmaceutically acceptable salts thereof.

25. A compound of the formula or a pharmaceutically acceptable salt thereof.

26. A compound of the formula or a pharmaceutically acceptable salt thereof.

27. A compound of the formula or a pharmaceutically acceptable salt thereof.

28. A compound of the formula or a pharmaceutically acceptable salt thereof.

29. A compound of the formula or a pharmaceutically acceptable salt thereof.

30. A compound of the formula or a pharmaceutically acceptable salt thereof.

31. A compound of the formula or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31 and a pharmaceutically acceptable excipient.

33. The pharmaceutical composition of claim 32, wherein the pharmaceutically acceptable excipient is a carrier or a diluent.

34. A method of treating or preventing a CBL-b mediated disease, disorder or condition in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 32.

35. The method of claim 34, wherein the disease, disorder or condition is cancer.

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