OA22157A - Substituted pyridinone compounds as CBL-B inhibitors. - Google Patents

Abstract

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

Description

SUBSTITUTED PYRIDINONE COMPOUNDS AS CBL-B INHIBITORS

RELATED APPLICATIONS

This application daims thc bcncfit of indian Provisional Application No. 202221046493 5 filed on August 16, 2022; which is hereby incorporated by référencé in its entirety.

FILED OF THE INVENTION

The présent patent application is directed to novel heterocyclic compounds which are useful as CBL inhibitors, processes for their préparation, pharmaceutical compositions 10 comprising thc compounds, and thc use of thc compounds or thc compositions in the trcatmcnt or prévention of various diseases, conditions and/or disorders mediated by CBL-b.

BACKGROUND OF INVENTION

CBL (Casitas B-lineage Lymphoma) is a tnammalian gene encoding the protein CBL 15 which is an E3 ubiquitin-protein ligase. CBL proteins are part of a family of ubiquitin ligases involvcd in ccll signaling, protein ubiquitination, and dégradation of protein substrates. The CBL proteins are a highly conserved family of proleins with three isofonns c-Cbl (also termed Cbl2, CbLSL. or RNF55), Cbl-b (also termed RNF56) and Cbl-3 (also called Cbl-3) [Keane et al.. Oncogene, 18: 3365-3375, 1999; Keane et al., Oncogene, 10: 2367-2377, 1995; Kim et al., 20 Gene, 239: 145-154, 1999],

Ail three mammalian Cbl proteins arc RING-type E3 ligases containing an N-terminal tyrosine kinase binding (TKB) domain consisting of a four-helical bundie, a calcium binding EF-hand and a Src homology (SH2) domain, followed by a linker helical région and the RING domain, responsable for their catalytic function. Cbl-b ubiquitinates ail three TAM family 25 members, Tyro-3, Axl. and Mer, which is rcsponsible for immunosuppressive and mctastalic action. The unique feature of the TKB domain is that it recognizes spécifie substrates of Cbl-b. which is achieved by binding lo proleins containing spécifie phosphorylaled tyrosinecontaining motifs, such as Syk and Zap-70, and a range of receptor tyrosine kinases. The interaction of proteins with the TKB domain of Cbl is mediated by 3 distinct subdomains 30 consisting of a 4-helix bundie (4H). a calcium-binding EF hand, and a variant SI 12 domain, ail 3 of which are functionaily required to form a unique PTB (phosphotyrosine-binding) module [Meng et al., Nature. 398(6722): 84-90, 1999], SH2 domain wilhin thc TKB rccognizcs tyrosine-phosphorylated proteins for ubiquitin conjugation [Mohapatra et al„ Biochbn Biopltys Acta., 1833 (1): 122-39, 2013]. A highly conserved a-helix of thc L domain plays an important rôle in maintaining E3 activity [Zeng et al., Cell, 102(4): 533-9,2000; Kassenbrock et aï.. J Biol Chem., 279(27): 28017-27, 2004J. The crystal structure shows that the L région contacts thc TKB, RF, and E2 ubiquitin-conjugating enzymes. The RF domain has intrinsic E3 ubiquitin ligase activity and binds to ubiquitin-E2 for the transfer of ubiquitin to spécifié substrates 5 [Budhidarmo et al., Trends Biochem Sci., 37(2): 58-65,2012; Paolino et al., J Immunol., 186(4):

2138-47, 2011], Recent studies indicates thaï the phosphorylation of Y363, localed in the L région bctwccn TKB and RF domains, régulâtes the E3 activity of Cbl-b by 2 mechanisms: onc is to remove the masking of the RF domain front the TKB domain, and the other is to form a surface to enhance binding affinity to E2s [Ryan et al., J Biol Chem., 285(31): 23687-98.2010;].

Casilas B-lineage lymphoma proto-oncogene-b, a RING finger E3 ubiquilin-protein ligase, has been demonstrated to play a crucial rôle in establishing the threshold for T-cell activation and controlling peripheral T-cell tolérance via multiple mechanisms. In T cells, Cblb is predominantly expressed in peripheral T cells, whereas c-Cbl is mainly expressed in thymus, suggesting a distinct rôle of c-Cbl and Cbl-b in T-cell development and tolérance induction [Liu et al., Trends Immunol., 23(3): 140-3, 2002], The E3 ubiquitin ligase cbl-b has been identified as a key intracellular checkpoint limiting T and NK cell activation. The blockade of cbl-b function by genetic delelion strongly enhances anti-tumor immune responses Cbl-b is expressed in ail leukocyte subsets and régulâtes several signaling pathways in T cells, NK cells, B cells, and different types of myeloid cells. Cbl-b is thoughl to function largeiy by regulaling

T cell activity through dégradation of phospho-inositol-3-kinasc (P1-3-K) downstream of thc CD28 costimulatory receptor. The rôle of Cbl-b in the négative régulation of T cell activation and tolérance induction arc tightly controllcd proccsscs regulating immune responses to pathogens and tumors while preventing autoimmunity. Autoimmunity is mainly averted through central tolérance by négative sélection of thymocytes carrying TCR for self-anligens.

CBL proteins not only regulate adaptive immune cell fonctions but are also critically involved in the régulation of innate lymphocyte populations, such as NK cells. NK cells are among the first cells to arrive at the inflanted tissue where they exert potent cytotoxic effector fonctions and modulate the local immune response [Paolino et al., Nature, 507(7493): 508 12, 2014]. NK colis arc an attractive tool for ccll-bascd immunotherapy bccause of their innate ability to discriminate between healthy and virally infected or naturally transformed cells. NK cell thérapies include adoptive autologous or allogeneic cell therapy, wherein NK cells are used to support hcmatopoietic stem cell transplants.

Adoptive Cell Therapy (ACT) is used in otherwise treatment-resistant cancers, including mctastatic melanomas, gliomas, and rénal carcinomas. In ACT, NK cells or T cells from a patient's own blood or tumor tissue are harvested, then grown mto large numbers in the laboratory, and then the expanded cells arc transfcrrcd back to the patient to enhance the patient’s immune System response to the cancer. In some versions of ACT, the T cells or NK cells are modified using genetic engineering to enable them to targel the patient's cancer cells and kill the cancer cells more efficiently. Types of adoptive cell therapy inciude naturel killer (NK) cell therapy. (umor-mlïltrating lymphocyte (TIL) therapy. engineered T-cell receptor therapy tTCR), and chimeric antigen receptor T-cell (CAR T) therapy. NK ccll therapy uses NK cells, part of the innate immune System, and the first line of defense against infections and diseases, including cancer cells.

As genetic ablation of cbl-b is associated with sponlaneous development of autoimmunity and increased susceptibility to experimental induction of autoimmune diseases [Bachmaicr et al.. Nature. 403(6766): 211 6, 2000] and it is not surprising that several groups laler found links between genetic cbl-b variants and susceptibility to autoimmunity in an animal model for diabètes [Yokoi et al., Nat Genet., 31(4): 391—4. 2002] as well as in varions human autoimmune diseases such as type 1 diabètes |Bcrghokit cl al., J Leukoc Biol., 77(4): 579-85, 2005], lupus erythematodes [Padilla et al., Lupus, 20(6): 628-35, 2011], asthma [Dcwan et al., BMC Med Genet., 13: 95,2012], and multiple sclerosis [Sawceret à\.,Nature, 476(7359): 2149, 2011].

CBL inhibitors inciude small molécules, peptides, nueleic acids, or antibodies thaï inhibit the Cbl enzymes. Cbl enzymes inciude c-C’bl. Cbl-b, and Cbl-c. Cbl inhibitors for use in melhods of trealmenl and compositions of the disclosure, inciude, but are not Limited to, compounds andpharmaceutical compositions forccll-bascd immunotherapy. The Cbl inhibitors can be used in in-vivo treatment methods to modulate the immune System, such as increasing activation of T cells, NK cells, circulating T cells, tumor infillrating lymphocytes and B cells, to increase engraftment of infused ex vivo expanded immune cells, or to increase the durability of response to the infused ex vivo expanded immune cells. In addition, the Cbl inhibitors can be used to help expand such immune cells in vitro or ex vivo to increase their growth and prolifération or to modulate the phenotype of the resulting expanded immune cells.

Several patent applications relate to varions scaffolds and compounds uscful as CBL inhibitors. PCT publication numbers WO/2021/06185 3; WO/2021/061870; WO/2021/021761; WO/2020/264398; WO/2020/236654; WO/2020/210508; WO/2019/148005 discloses compounds as CBL inhibitors in the treatment of T ccll dysfunction and cancer.

Currently, there is a largely unmet need for an effective way of treating disease and disorders associated with CBL-b inhibition includes but not limited to autoimmune diseases.

inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular discascs, allergies and asthma. The improved thcrapcutic compounds, compositions and methods for the treatment for these disease and disorders are urgently required. CBL-b inhibition is an especially attractive larget for cancer immunotherapy.

The major challenge currently faced in the field is the lack of CBL-b spécifie inhibitors. The présent disclosure provides novel, highly effective small-molecule inhibitors of CBL-b.

SUMMARY OF THE INVENTION

In one aspect, the présent invention relates to compound of formula (I)

(I) or a stereoisomer, or a pharmaceutically acceptable sait thereof, wherein.

at each occurrence, R¹ is selected independently from 3-15 membered heterocydylCisalkyl, 5-14 membered heteroarylCi-galkyl and -[CHRJi-NR⁶R⁷; wherein 3-15 membered heterocyclylCi-galkyl and 5-14 membered heteroarylCi salkyl are oplionally substituted with one or more substituents selected from halogcn, oxo, hydroxyl, hydroxyCt-xalkyl, Ci-galkyl, NHC(O)CHî, -NHC(O)CH₃CH3 and-NHC(O)CH=CH₂ ;

Z is CH or N;

XisCHorN;

R is selected from hydrogen and Ci-salkyl;

at each occurrence, R² is selected independently from halogen, -NHC(O)CH₃ and NHC(O)CH=CH₂;

ring A is 5-14 membered heteroaryl;

at each occurrence. R³ is Ci-galkyl;

R⁴ is selected from hydrogen and Ci-galkyl;

R⁵ is selected from Ci-salkyl and C3-i₂cycloalkyl; or

R⁴ and R⁵joined logether with the carbon atom to which they are attached, form a 3-15 membered heterocyclyl, Cîiîcycloalkyl and 3-15 membered spirocyclyl wherein 3-15 membered heterocyclyl, Ca-ncycloalkyl and 3-15 membered spirocyclyl are optionally substitutcd with onc or more substituents selcctcd from halogcn and Ci-salkyl;

‘Y’ is absent or CR⁸R⁹;

R⁶ is selecled from hydrogen and Ci salkyl;

R⁷ is selected from Ci-salkyl. haloCi-salkyl, hydroxyCi-salkyl, Ci-ealkoxyCi-salkyl, CH2CH₂NHC(O)CH=CH₂, C₃ lîcycloalkyl. C₃.i2cydoalkylCi.8alkyl and 3-15 membered hctcrocyclylalkyl; whcrcin C₃-i2cycloalkyl and Cs-ncycloalkylCisalkyl is optionally substituled with Ci-ealkyl and haloCi-salkyl;

R⁸ is hydrogen;

R⁹ is hydrogen;

Rⁱⁿ is selected from hydrogen and Ci-salkyl;

R¹¹ is selected independently from Ci-salkyl, haloCi-salkyl, Ce-uaryl, Ce-uarylCi-galkyl, 3-15 membered heterocyclylCi-salkyl. C₃-i2cycloalkyl and Ca-scycloalkylCi-salkyl; wherein C&. i4aryl, Cô-i4arylCt salkyl are optionally substituled with one or more substituents selected from halogcn;

T is an integer ranging from 0 to 2, both inclusive;

‘m’is an integer ranging from 0 to 4, both inclusive;

‘n’ is an integer ranging from 1 to 3, both inclusive; and ‘r’ is an integer ranging from 0 to 4, both inclusive.

In another aspect, the présent invention provides a pharmaccutical composition comprising at least one of compounds represented by formula (I) as described herein and a pharmaccutical]y acceptable excipient.

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

The compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the présent invention and are not intended to limit the daims to the spécifie embodiments excmplificd. It is also to bc understood that the embodiments defined herein may be used independently or in conjunction with any définition, any other embodiment defined herein. Thus the invention contemplâtes ail possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein ‘Z’ is CH or N (according to an embodiment defined below), ^kn is 1 according to another embodiment dcfincd below) and ‘X’ is CH or N (according to yct another embodiment defined below).

According to one embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH or N.

According to another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH.

According to yet another embodiment, specifically provided arc compounds of formula (I), in which ‘Z’ is N.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is -[CHR]i-NR⁶R⁷, 3-15 membered heterocyclylCi-salkyl and 5-14 membered heteroarylCi-salkyl; whcrcin 3-15 membered hctcrocyclylCi-salkyl and 5-14 membered heteroarylCi salkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyCi-salkyl, Ci-ealkyl, -NHC(O)CH3. -NHC(O)CH=CH; andNHC(O)CH₂CH₃.

According to yct another embodiment, specifically provided arc compounds of formula (1), in which R¹ is -|CHRJi-NR⁶R⁷, wherein R, 1. R⁶ and R⁷ are as defined in formula (1).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R

) and 5-14 membered heteroarylCi-salkyl

J| 'N (e.g. j. whcrcin 3-15 membered hctcrocyclylCi-salkyl and 5-14 membered heteroarylCi-salkyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro), oxo, hydroxyl, hydroxyCi xaikyt (e.g. hydroxyl mcthyl), Ci-saikyl (e.g.

mcthyl or isopropyl), -NHC(O)CH₃, -NHC(O)CH₂CH₃or -NHC(O)CH=CH₂.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹ is a 3-15 membered heterocyclylCi-salkyl (e.g.

or

) or 5-14 membered heteroarylCi-salkyl /-^-n \ 1 _ΖΝ (e.g. ' ' '—); wherein 3-15 membered heterocyclylCisalkyl and 5-14 membered heteroarylCi-galkyl are optionally substituted with one or more substituents selected from fluoro, oxo, hydroxyl, hydroxylmcthyl, mcthyl, isopropyl. -NHC(O)CHs, -NHQOlCHaCHs or -NHC(0)CH=CH₂

According to yet another embodiment, specifïcally provided are compounds of formula

According to yet another embodiment, specifïcally provided arc compounds of formula (I), in which R¹ is -[CHRJi-NR⁶R⁷. In this embodiment, R is hydrogen or Ci-salkyl; R⁶ is hydrogen or Ci-salkyl; R⁷ is Ci-salkyl, haloCi salkyl, hydroxyCi-aalkyl, Ci-galkoxyCi-salkyl, CH₂CH₂NHC(O)CH=CH₂, Cvi2cycloalkyl, Ci |₂cycloalkylCi salkyl and 3-15 membered helerocyclylalkyl; wherein C3-i₂cycloalkyl and C3-i2cycloalkylCi-8alkyl are substituted or unsubstituted with one or more substituents selected from Ci-salkyl and haloCi-salkyl and T is 1.

According to yet another embodiment, specifïcally provided are compounds of formula (I), in which R¹ is -[CHR]i-NR⁶R⁷. In this embodiment, R is hydrogen or Ci-saikyl (e.g. methyl); R⁶ is hydrogen or Ci salkyl (e.g. mcthyl); R⁷ is Ci-salkyl (e.g. cthyl, isobutyl, isopcntyl, neopentyl, tert-pentyl, 2-methylbutyl. 2-ethylbutyl or 3-methylbutan-2-yl), haloCi-salkyl (e.g. difluoroethyl, 2-fluoro-2-methylpropyl, l-fluoro-2,2-dimethylpropyl or 2-fluoro-2mcthylbutyl), hydroxyCi-salkyl (e.g. hydroxycthyl or 2-hydroxy-2-mcthylpropyl), Ci₈alkoxyCi-₈alkyl (e.g. ethoxyethyl), -CH₃CH₃NHC(O)CH=CH2, 3-15 membered helerocyclylalkyl (e.g. melhyloxetane), C3-i₂cycloalkyl (e.g. cyclopropyl or cyclobutyl) or C₃ i2cycloalkylCi-salkyl (e.g. mcthylcycloproyl); wherein the Cs-izcycloalkyl and C3i2cycloalkylCi-salkyl are optionally substituted with one or more substituents selected from Cisalkyl (e.g. methyl) or haloCi-salkyl (e.g. fluoromethyl) and T is 1.

According to yet another embodiment, specifically provided are compounds of formula (1), in which R¹ is -[CHR]i-NR⁶R⁷. In this embodiment, R is hydrogcn or mcthyl; R⁶ is hydrogcn or methyl; R⁷ is ethyl, isobutyl, isopentyl. neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl, 3-methylbutan-2-yl, difluoroethyl, 2-fluoro-2-melhylpropyl, l-fluoro-2,2-dimcthylpropyl. 2- fluoro-2-methylbutyI. hydroxyethyl. 2-hydroxy-metbylpropyl, ethoxyethyl, CH2CH2NHC(O)CH=CH2, methyloxetane, 1-methylcyclopropyl, 1-methylcyclobutyl, cycloproylmcthyl or 1-fluoromcthyl cycloproylmcthyl and T is 1.

According to yet another embodiment, specifically provided are compounds of formula

According to yet another embodiment, speciftcally provided are compounds of formula 5 (I), in which‘n’is 1.

According to yet another embodiment, specifically provided are compounds of formula

According to yet another embodiment. spccifically provided are compounds of formula (I), in which ‘X’ is CH or N.

According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘X’ is CH.

According to yet another embodiment, spccifically provided are compounds of formula (I), in which ‘X’ is N.

According to yct anothcr cmbodimcnt, spccifically providcd arc compounds of formula (I), in which R² is halogen (e.g. chloro or fluoro), -NHC(O)CHa or NHC(O)CH=Clb.

According to yet another embodiment, specifïcally provided are compounds of formula (I). in which R² is chloro, fluoro, NHC(O)CH₃ or -NHC(O)CH=CH₂.

According to yct anothcr cmbodimcnt, spccifically providcd arc compounds of formula (I), in which ‘m’is 0 or 1.

According to yet another embodiment, spccifically provided are compounds of formula (I), in which ‘m’is 0.

According to yct anothcr cmbodimcnt, spccifically providcd arc compounds of formula (1), in which ‘m’is 1.

According to yet another embodiment. specifïcally provided are compounds of formula (I), in which R² is chloro, fluoro, -NHC(O)CH₃ or -NHC(O)CH=CH₂ and ‘m’ is 0 or I.

According to yet another embodiment, specifïcally provided are compounds of formula (I), in which ring A is 5-6 membered heteroaryl (e.g.

or¹¹*

According to yct anothcr cmbodimcnt, spccifically providcd arc compounds of formula (I), in which ring A is

HN or

According to yct anothcr cmbodimcnt, spccifically providcd arc compounds of formula (I), in which ring A is ^H

According to yct anothcr cmbodimcnt. spccifically providcd arc compounds of formula

N'A’ ^{1 l}” (1), in which ring A is

According to yet another embodiment. specifîcally provided are compounds of formula (I), in which ring A is

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R³ is Ci galkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (1), in which R³ is inethyL

According to yet another embodiment. specifîcally provided are compounds of formula (1), in which ‘r’ is 1.

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R³ is methyl and ‘r’ is 1.

According to yet another embodiment, specifîcally provided are compounds of formula (1), in which Y is absent or CR⁸R⁹.

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which Y is absent.

According to yet another embodiment, specifîcally provided are compounds of formula (I). in which Y is CR⁸R⁹. In this embodiment, R⁸ is hydrogen and R⁹ is hydrogen.

According to yet another embodiment, specifîcally provided are compounds of formula (1), in which Y is Cbb.

According to yet another embodiment. specifîcally provided are compounds of formula (I), in which Y is absent or CH2.

According to yet another embodiment, specifîcally provided are compounds of formula (I). in which R⁴ is hydrogen or Ci salkyl (e.g. CH3).

According to yet another embodiment, specifîcally provided are compounds of formula (1), in which R⁴ is hydrogen or CH3.

According to yet another embodiment. specifîcally provided are compounds of formula (I), in which R⁵ is Ci-galkyl (e.g. CH3) or C3-i2cycloalkyl (e.g. cyclobutyl).

According to yet another embodiment, specifîcally provided arc compounds of formula (I), in which R⁵ is CH3 or cyclobutyl.

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R⁴ and R⁵ are CH3.

According to yet another embodiment. specifîcally provided are compounds of formula (I), in which R⁴ is hydrogen and R⁵ is cyclobutyl.

According to yet another embodiment, specifically provided are compounds of formula (1), in which R⁴ and R⁵ joincd togcther with the carbon atom to which thcy arc attachcd, form a

Ca-iïcycloalkyl (e.g.

3-15 membered heterocyclyl (e.g.-----), or 3-15 membered spirocyclyl (e.g.

or--- ), wherein Ca-ncycloalkyl or 3-15 membered spirocyclyl are optionally substituted with one or more subsliluents selected from halogen (e.g. fluoro) or Ci salkyl (e.g. mcthyl or cthyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R⁴ and R⁵joined logether with the carbon atom to which they are attached. form a

O <°>

Ci-ncycloalkyl (e.g. -----), 3-15 membered heterocyclyl (e.g.-----), or 3-15 membered y O spirocyclyl (e.g. --- or--- ), wherein Ca-ijcycloalkyl or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro, methyl or ethyl.

According to yet another embodiment, specifically provided are compounds of formula (Γ), in which R⁴ and R⁵joined together with the carbon atom to which they are attached. form a

Λ à X δ Y δ 8 O

According to yet another embodiment. specifically provided are compounds of formula (I), in which R^l0is hydrogen or Ci-ealkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R^l0is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹⁰is hydrogen.

According to yet another embodiment. specifically provided are compounds of formula (I). in which R¹⁰is methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R¹¹ is Ci-salkyl, haloCi-galkyl, Cf,-i4aryl , Ca-uarylCi-salkyl-, 3-15 membered heterocyclylCi-salkyl, Cî-iicycloalkyl and C3 ecycloalkylCi salkyl; wherein the Cô-uaryl and

Cô-warylCi-salkyl are substituted or unsubstituted with one or more substituents selected from halogcn.

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R¹¹ is Ci-ealkyl (e.g. methyl or ethyl).

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R¹¹ is methyl or ethyl.

According to yet another embodiment, specifîcally provided arc compounds of formula (I), in which R¹¹ is haloC ι-salkyl (e.g. trifluoroethyl, difluoromethyl, difluoroethyl or trifluoropropyl).

According to yet another embodiment, specifîcally provided are compounds of formula (1), in which R is difluoromethyl, difluoroethyl, trifluoroethyl or trifluoropropyl.

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R¹¹ is Cj-ncycloalkyl (e.g. cyclopropyl).

According to yet another embodiment, specifîcally provided are compounds of formula (1), in which R'¹ is cyclopropyl.

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R¹¹ is Ct scycloalkylCt «alkyl (e.g. cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl).

According to yet another embodiment, specifîcally provided are compounds of formula (I), in which R” is cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl.

According to yet another embodiment, specifîcally provided are compounds of formula —0° (T), in which R¹¹ is 3-15 membered hctcrocyclylCi-salkyl (e.g. /'' ^v ).

According to yet another embodiment, specifîcally provided are compounds of formula —0° (I), in which R¹¹ is/'' ^v .

According to yet another embodiment, specifîcally provided arc compounds of formula (I), in which R¹¹ is Cô-14 aryl (e.g. phenyl); wherein the Cû-riaryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro).

According to yet another embodiment, specifîcally provided arc compounds of formula (I), in which R¹¹ is Cô-k aryl (e.g. phenyl); wherein the C^waryl is optionally substituted with one or more substituents selected from fluoro.

According to yet another embodiment, specifically provided are compounds of formula

(I), in which R¹¹ is ^F .

According to yet another embodiment, specifically provided are compounds of formula (1), in which R¹¹ is C6-i4aryICi-8alkyl (e.g.^^); wherein the Cô-uarylCi-aalkyl is optionally substituted with one or more substituents selected front halogen (e.g. fluoro).

According to yet another embodiment, specifically provided are compounds of formula δ (I), in which R¹¹ is C6-i4arylC i salkyl (e.g. ); wherein the Cô-MarylCi-galkyl is optionally substituted with one or more substituents selected front fluoro.

According to yet another embodiment. specifically provided are compounds of formula (I), in which R¹¹ is

According to yet another embodiment, specifically provided are compounds of formula (1), in which R¹¹ is methyl. ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘Z’ is CH or N;

‘X’ is CH or N;

R² is chlore, fluoro, -NHC(O)CH₃ or -NHC(O)CH=CH₂;

R³ is methyl;

Y is absent or CH₂;

R⁴ is hydrogen or CH3;

R⁵ is CHs or cyclobutyl; or

	R4 and R5 joined together with the carbon atom to which they are attached, form a^^- Rl0is hydrogen or methyl; R11 is methyl, cthyl, difluoromcthyl, difluorocthyl, trifluorocthyl, trifluoropropyl
5	cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl, ' ' v , F or F . T is 1; ‘n’ is 1 ; ‘m’is 0 or 1 ; and
10	‘r’ is 1. According to yet another embodiment, spccifîcally providcd are compounds of formula (I), in which ‘Z’ is CH; /\J ___F ><\ -^X/OH x K/—y—Y X N X X N X N L J r1 is a , ।—l, ।—1 , ।—l
15	X/1 X/·1 ^-^F T ï 1 + 1 k^J o k^-θ k^o k^sik 1---1 o 1 5 * » ? X. X-v» r-C !-( ' ? ΊΓ ' 1 l N s/— N ' 1---1 O /x \>k^ ,< /< \

‘X’isCHorN;

R² is chloro, fiuoro, -NHC(0)CH3 or-NHC(O)CH=CH₂;

ring A is

R³ is methyl;

Y is absent or CH₂;

R⁴ is hydrogen or CH3;

R^s is CH3 or cyclobutyl; or

R⁴ and R⁵ joined together with the carbon atom to which they are attached, form a

R¹⁰is hydrogen or methyl;

R¹¹ is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl, ^F or

T is 1;

‘n’ is 1;

‘m’is 0 or 1 ; and ‘r’ is 1.

According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘Z’isCH;

‘X’ is CH;

R² is chloro, fluoro, -NHC(O)CHi or -NHC(O)CH=CH₂;

R³ is melhyl;

Y is absent or CHi;

R⁴ is hydrogen or CH3;

R⁵ is CH3 or cyclobntyl; or

R⁴ and R⁵joined together with the carbon atom to which they are attached. form a----

R¹⁰is hydrogen or methyl;

R¹¹ is melhyl, ethyl, difluoromethyl. diiluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl. cyclopropylethyl or cyclobutylmethyl.

T is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

According to yct anothcr cmbodimcnt, specifically providcd are compounds of formula (I), in which

R² is chloro, fluoro, -NHC(O)CH₃ or-NHC(O)CH=CH₂;

U.H ring A is ;

R³ is methyl;

Y is absent or CH₂;

R⁴ is hydrogen or CHi;

R⁵ is CHj or cyclobutyl; or

R⁴ and R⁵ joined together with the carbon atom to which they are attached, form

R^lüis hydrogen or mcthyl;

R¹¹ is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl. trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,¹ ' , ^F or

T is 1;

‘n’ is 1;

‘m’is 0 or 1; and ‘r’ is 1.

According to an embodiment, specifically provided are compounds of formula (I) with an ICso value of less than 10000 nM, preferably, less than 1000 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity.

Further embodiments relating to groups ring A. X. Y, Z, R¹, R², R³, R⁴, R⁵, R¹⁰, Rⁿ, n, m and r (and groups defined therein) are described hereinafter in relation to the compounds of formula (IA), (IB) or (IC). It is to be understood that these embodiments are not limited to use in conjunction with formula (IA), (LB) or (IC), but apply indcpcndently and individually to the compounds of formula (I).

The invention also provides a compound of formula (IA) which is an embodiment of a compound of formula (I).

Accordingly the invention provides a compound of formula (IA)

(ΙΑ) or a stereoisomer, or a pharmaceutically acceptable sait thereof, wherein, R^1, R², R³, R⁴, R^s, R¹⁰, R¹¹, ring A. Y, X, n, tn and r are as defined in formula (I).

In another aspect, the présent invention provides a pharmaceutical composition 5 comprising at least onc of compounds represented by formula (IA) as dcscribcd hcrcin and a pharmaceutically acceptable excipient.

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

The invention also provides a compound of formula (IB) which is an embodiment of a compound of formula (I).

(IB) or a stereoisomer, or a pharmaceutically acceptable sait thereof, wherein, R^1, R², R³, R⁴, R⁵, R¹⁰, R¹¹, ring A. Y, n, m and r are as deiïned in formula (I).

In another aspect, the présent invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IB) as described herein and a pharmaceutically acceptable excipient.

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

The invention also provides a compound of formula (IC) which is an embodiment of a compound of formula (I).

(IC) or a stereoisomer, or a pharmaceutically acceptable sait thereof, whcrcin, R^1, R², R³, R⁴, R⁵, R^w, R¹¹, Y, n, m and r arc as dcfincd in formula (1).

In another aspect, the présent invention provides a pharmaceutical composition comprising at least one of compounds represented by formula (IC) as described herein and a pharmaceutically acceptable excipient.

In another aspect, the présent invention provides a method for treating a diseasc or disorder mediated by CBL-B comprising administering a compound represented by formula (IC) as described herein.

It should be understood that the formulas (I), (IA), (IB) and (IC) structurally encompass ail gcomctrical isomers, stcrcoisomcrs, enantiomers and diastcrcomcrs, /V-oxidcs, and pharmaceutically acceptable salts that may be contemplated from the Chemical structure of the généra described herein.

DETAILED DESCRIPTION OF THE INVENTION

Définitions:

The terms “halogcn” or “halo” mcans fluorine (fluoro), chlorinc (chloro), brominc (bromo), or iodinc (iodo).

The term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci-salkyl), and which is attached to the rest of the molécule by a single bond, such as, but not limited to, methyl, ethyl. n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term “Ci-6alkyl” refers to an alkyl chain having 1 to 6 carbon atoms. The term “CMalkyl” refers to an alkyl chain having 1 to 4 carbon atoms. Unlcss set forth

or recited to the contrary, ail alkyl groups described or claimed herein may be straight chain or branchcd.

The tenn “haloalkyl” refers to at least one halo group (selected from F, Cl. Br or I), linked to an alkyl group as defined above (i.e. haloCi-salkyl). Examples of such haloalkyl 5 moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term “haloCi-talkyl” refers to al least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unlcss set forth or recited to the contrary, ail haloalkyl groups described herein may be straight chain or branched.

The term “hydroxyalkyl” refers to an alkyl group as defined above wherein one to three 10 hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCisalkyl). Examplcs of hydroxyalkyl moiety includc, but arc not limited to -CH2OH, -C2H4OH and CH(OH)C2H;OH

The term “aikoxy” dénotés an alkyl group atlached via an oxygen linkage to the rest of the molécule (i.e. Ci g aikoxy). The représentative examples of such groups are -OCHs and 15 OC2H5. Unlcss set forth or recited to the contrary, ail aikoxy groups described orclaimed herein may be straight chain or branched.

The term “alkoxyalkyl” or “alkyloxyalkyl” refers to an aikoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci-salkoxyCi-salkyl or Ci-salkyloxyCi-salkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, 20 CH2OCH3 (methoxymethyl) and -CH2OC2H5 (ethoxymethyl). Unlcss set forth or recited to the contrary, ail alkoxyalkyl groups described herein may be straight chain or branched.

The term “hydroxyCi salkyl” refers to a Ci-aalkyl group as defined above wherein onc to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC, 4alkyl). Examples of hydroxyCi aalkyl moieties include. but are not limited to 25 CH2OH and -C2H4OH.

The term “cycloalkyl” dénotés a non-aromatic mono or multicyclic ring System of 3 to about 12 carbon atoms, (i.e.C3-i2cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The examples of multicyclic cycloalkyl groups include, but are not limited to, pcrhydronapthyl, adamantyl and 30 norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4.4)non-2-yl. The term “Cj^cycloalkyl” refers to the cyclic ring having 3 to 6 carbon atoms. Examples of “C3. 6cycloalkyl” includc but arc not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. Cî^cycloalkylQ salkyl). The cycloalkylalkyl group may be attachée! to the main structure at any carbon atom in the alkyl group that rcsults in the création of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The terni “aryl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. Cô-waryl), including monocyclic. bicyclic and tricyclic aromatic Systems, such as phenyl. naphthyl, letrahydronapthyl, indanyl, and biphenyl.

The tcrm “arylalkyl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. Cônaryl) directly attached to an alkyl group (i.e. Cô-HarylCi-ealkyl). The arylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the création of a stable structure.

The tcrm “hctcrocyclic ring” or “hcterocyclyl” unless otherwise specifïed refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring System, which may includc fuscd, bridged or spiro ring Systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to varions oxidation States. In addition, the nitrogen atom may be optionally quatemized; also, unless otherwise constrained by the définition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such hctcrocyclic ring radicals includc, but arc not limited to azcpinyl, azctidinyl, oxetanyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, dccahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that rcsults in the création of a stable structure.

The term “heterocyclylalkyl” refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. helerocyclylCl-8alkyl). The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the création of a stable structure.

The terni “heteroaryl ’ unless otherwise specified refers to 5 to 14 membered aromatic hcterocyclic ring radical with one or more hcteroatom(s) indcpcndcntly sclcctcd from N, O or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring System. The heteroaryl ring radical may be attached to the main structure al any heteroalom or carbon atom that results in the création of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tctrazoyl, thicnyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl. benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl. quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl. acridinyl, phcnazinyl and phthalazinyl.

The term “heterarylalkyl” refers to a heteraryl ring radical directly bonded to an alkyl group (i.e. heleroarylCl-8alkyl). The heleroaryllalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the création of a stable structure.

The term “pharmaccutically acceptable sait” includcs salts preparcd from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumaratc, gluccptatc. gluconatc, glutamate, glycollylarsanilatc, hcxylrcsorcinatc, hydrabaminc, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, lauratc, malatc, maleate, mandclatc, mesylatc, mcthylbromidc, methylnitratc, mcthylsulfatc, mucate, napsylate, nitrate, Æ-methylglucamine ammonium sait, oleate, oxalate, pamoate (embonale), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stéarate, sulfate, subacetate, succinate. tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferrie, ferrous, lithium, magnésium, manganic, mangamous, potassium, sodium, and zinc.

The term “treating” or “treatment” of a State, disorder or condition includcs: (a) preventing or delaying the appearance of clinical symptoms of the State, disorder or condition developing in a subjecl thaï may be afflicted with or predisposed to the State, disorder or condition but does not yct expérience or display clinical or subclinical symptoms of the State, disorder or condition; (b) inhibiting the State, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing régression of the State, disorder or condition or at least one of its clinical or subclinical symptoms.

The term “subject” includes mammals (especially humans) and other animais, such as domestic animais (e.g., household pets including cats and dogs) and non-domestic animais (such as wildlife).

A “lherapeutically effective amount” means the amount of a compound thaï, when administcrcd to a subjcct for trcating a State, disorder or condition, is sufficicnt to cffcct such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the âge, weight, physical condition and responsiveness of the subject to be treated.

The compounds of formula (I), (IA), (IB ) and (IC) may contain asymmctric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that ail stereoisomeric forms of the compounds of formula (I), (IA), (IB) and (IC) as well as mixtures thereof, including racemic mixtures, form part of the présent invention. In addition, the présent invention embraces ail géométrie and positional isomers. Diastcrcomcric mixtures can bc separated into their individual diastereomers on the basis of their physical Chemical différences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fraclional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Moshcr's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also bc separated by use of chiral HPLC column. The chiral centres of the présent invention can hâve the S or R configuration as defined by the IUPAC 1974.

The ternis sait or solvaté, and the like, is intended to equally apply to the sait, solvaté and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds.

PHARMACEUTICAL COMPOSITIONS

The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients.

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

METHODS OF TREATMENT

The compounds of the présent invention are particularly useful because they inhibil the aelivity of CBL-b, i.c., they prevent, inhibit, or suppress the action of CBL-b, and/or may clicit a CBL-b modulating effect. The compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of CBL-b activity, and particularly CBL-b inhibition, is bénéficiai.

The compounds of the présent application provides a method for treating a disease or disease mediated by CBL-b in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I), compound of formula (IA), compound of formula (IB), compound of formula (IC) or a stereoisomer or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition thereof, to a mammal in need of the treatment, prcfcrably ahuman.

Accordingly to one embodiment, the compounds of the présent patent application are inhibiting CBL-b activity and can be useful in the treatment of diseases or disorder mediated by CBL-b.

Accordingly to another embodiment, the compounds of the invention may be useful in the treatment of cancer mediated by CBL-b.

Accordingly to yet another embodiment, provided herein is a method of treating cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a compounds of the présent invention provided herein to an individu al to treat the cancer responsive to inhibition of Cbl-b activity.

Accordingly to yet another embodiment, the compounds ofthe présent invention for the use of treatment of cancer.

Accordingly to yet another embodiment, the compounds of the présent invention can be used in methods of modulating the immune System, such as increasing activation of T-cells, NK-cclls and B-cells, as well as in the treatment of such cells in vivo, in vitro, or ex vivo.

In one embodiment, the présent inventions provides the use of the compounds described herein in the préparation of a médicament. In another embodiment, the présent inventions provides the use of the compounds described herein in the préparation of a médicament for the treatment of diseases mediated by CBL-b.

Any of the methods of treatment descnbed herein comprise administenng an effective amount of a compound according to Formula (1), (IA), (IB), (IC) or a pharmaccutically acceptable sait thereof, to a subject (particularly a human) in need thereof.

The compounds of the invention are effective bolh in the lherapeulic and/or prophylactic treatment of the above-mentioned conditions.

GENERAL METHODS OF PREPARATION

The compounds, described herein, including those of general formula (IA-1, IA-2, IA3, IA-4. 1A-5, 1A-6, 1A-7, IA-8 and IA-9), intermediates and spécifie examples are prepared through the synthetic methods as depicted in synthetic schemes 1-6. Furthermore. in the following schcmcs, whcrc spécifie acids, bases, rcagcnts, coupling rcagcnts, solvents, etc. arc mentioned, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the présent invention. The modifications to reaction conditions, for example, température, duration of the reaction or combinations thereof, arc envisioned as part of the présent invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromalography using different solvents in suitable ratios. Ail possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.

General Scheme

A general approach for the préparation of compounds of the general formula (1A-1) (wherein X, Y, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 1.

Synthetic scheme-1:

οο

ΠΟ*^*² R'OH R'QA^ZyBr

Ηθ N Estérification O (D(2)

R⁶

ONH ______________(6)R

Oxidative O’^N’’ Reductive clcavagc Amination (5)

N-Alkylation <?F N Rⁿ (3)

R¹¹ (7) ^BF₃K

Suzuki réaction

(8) _______£2)_________

Coupling reagent

N Y ΤΊ (R²)?-X

(IA-1)

The estérification of compound of formula (1) yields ester compound of formula (2) [wherein R’ is Ci^alkylJ. The reaction is carricd out in a suitablc solvent. The suitablc solvent used in the reaction may be methanol.

The sélective N-Alkylation of compound of formula (2) with suitable alkylating agents in the presence of suitable base and solvents yields the compound of formula (3). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from césium carbonate, potassium carbonate, sodium carbonate, sodium hydride, etc. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from DMSO, DMF and THF.

The Suzuki coupling réaction of compound of formula (3) using potassium vinyl trifluoroborate in the presence of suitable base, catalyst and solvent gives the compound of formula (4). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium /eri-butoxide, sodium carbonate or césium carbonate. The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the réaction may be selected from tetrakis(triphenylphosphine)palladium(0), l,l'-bis(diphenylphosphino)ferrocene]dichloropall adium(II) complex with dichloromethane, along with a suitable phosphine ligand, etc. The coupling reaction may be carried out in a suitable solvent or mixture thereof. The suitable solvent used in the réaction may be selected from éthanol, toluène, 1,4-dioxanc. DMSO, water or a combination thereof.

The compound of formula (4) upon oxidative cleavage using osmium tetra oxide and sodium periodatc in a suitable mixture of solvent gives aldéhyde compound of formula (5). The reaction is carried out in presence of suitable mixture of solvents. The suitable mixture of solvent may be selected from mixture of THF / water and t-BuOH.

The reductive amination reaction of compound of formula (5) with appropriate amines of formula (6) using suitable reducing agent in the presence of suitable catalyst gives compound of formula (7). The réaction is carricd out in présence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, dichloroethane, dimethylformamide, methanol, éthanol. The reaction is carried out in presence of suitable 10 reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydridc. The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be acelic acid.

The hydrolysis of compound of formula (7) gives the compound of formula (8). The 15 réaction is carricd out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is carried out in a suitable solvent. The suitable solvent used in the reaction may be selected from methanol, éthanol or telrahydrofuran or combination thereof.

The acid-amine coupling reaction of compound (8) with appropriate aromatic amines 20 compound of formula (9) gives the compound of general formula (IA-1 ). The réaction is carricd out in presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may bc selected from HATU, EDC.HC1, HOBt, DCC or TrP. The réaction is carricd out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane. THF or dimethylformamide. The reaction is carried out in presence of suitable 25 base. The suitable base used in the reaction may be selected from DTPEA or TEA.

A general approach for the préparation of compounds of the general formula (IA-2) (wherein X, Y, Z. R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, ‘m’ and ‘r’ are as defmed in the description) is depicted in synthetic scheme 2.

Synthctic schcmc-2:

R⁴ .N,.

(R³),'R⁵ „R⁶ (6) R⁷ (R³),

NH >·Ν Oxidative 0 'R cleavage

Reductive

Amination <^r3 w r⁵

R*

R⁷ (IA-2) (13)

The hydrolysis reaction of compound of formula (3) [wherein R’ is Ci salkyl] gives the compound of formula (10). The reaction is carried out in presence of suitable base. The suitable base used in thc réaction may bc sclcctcd from lithium hydroxidc, sodium hydroxidc or potassium hydroxide. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol. éthanol or tetrahydrofuran or combination thereof.

The acid-amine coupling reaction of compound (10) with appropriate aromatic amines of compound of formula (9) gives the compound of formula (11). The reaction is carried out in a présence of suitable solvent. The suitable solvent used in thc réaction may bc sclcctcd from dichloromethane, THF or dimethylformamide. The reaction is carried out in a presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. The reaction is carried out in a presence of suitable coupling rcagcnts. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HC1, HOBl. DCC or TjP.

The Suzuki coupling reaction of compound of formula (11) and potassium vinyl trifluoroborate gives the compound of formula (12). The reaction is carried out in a presence of suitable base. The suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium ieri-butoxide, sodium carbonate or césium carbonate. The réaction is carried out in a présence of suitable catalyst. The suitable catalyst used in thc reaction may be selected from tetrakis (triphenylphosphine)palladium(O), 1,1'bis(diphenylphosphino)fenOcene]dichloropalladium (Π) complex with dichloromethane, along with a suitable phosphine ligand, etc. The reaction may bc carried out in a suitable solvent or mixture thereof. The suitable solvent may be selected from éthanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof.

The compound of formula (12) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldéhyde compound of formula (13). The reaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be THF / watcr.

The reductive amination reaction of compound of formula (13) with appropriate amines compound of formula (6) gives compound of general formula (IA-2). The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be acetic acid. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be sclcctcd from TEA and DIPEA. The réaction may be carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, dimethylfonnamide, methanol and éthanol. The reaction is carried out in presence of suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydridc and sodium cyanoborohydridc.

A general approach for the préparation of compounds of the general formula (1A-3 and IA-4) (wherein X, Y, Z. R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 3.

Synthctic schcmc-3:

NH,

Hydmtysis

o ^Br ^BFjK •,, Suzuki reaction R¹¹

Coupling reagent

The Suzuki coupling reaction of compound of formula (3) [wherein R’ is Ci-salkyl] and potassium vinyl trifluoroborate gives the compound of formula (4). The reaction is carried out in presence of suitable base. The suitable base used in the réaction may be sclcctcd from potassium phosphate, potassium acetate, sodium, potassium teri-butoxide, sodium carbonate or césium carbonate. The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the réaction may be selected from tetrakis (triphenylphosphinc)palladium(O), l,T-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane, along with a suitable phosphine ligand, etc. The reaction may be carried ont in presence of suitable solvent or mixture thcrcof. The suitable solvent uscd in the reaction may bc sclcctcd from éthanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof.

The hydrolysis reaction of compound of formula (4) in the presence of a suitable base 5 and solvent gives the compound of formula (14). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The réaction is carried out in présence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, éthanol or tetrahydrofuran or combination thereof.

The acid-amine coupling reaction of compound (14) with appropriale aromalic amines compound of formula (9) gives the compound of formula (15). The réaction is carried out in presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HC1, HOBl, DCC or T3P. The réaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from 15 dichloromcthanc, THFordimcthylformamidc. The réaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from D1PEA or TEA.

The compound of formula (15) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldéhyde compound of formula (16). The réaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may 20 bc THF / water.

The reductive amination reaction of compound of formula (16) with appropriale amines ( 6) yiclds compound of formula (IA-3). The réaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be acetic acid. The reaction is carried out in presence of suitable base. The suitable base used in the réaction may be selected from 25 triethylamine or DIPEA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane, dimethylformamide, methanol and éthanol. The reaction is carried out in presence of a suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacctoxyborohydridc or sodium cyanoborohydridc.

The treatment of compound of formula (IA-3) with suitable inorganic acid in appropriale solvent gives compound of formula (IA-4). The réaction is carried out in presence of suitable inorganic acid. The suitable inorganic acid used in the reaction may be selected from hydrochloric acid or TFA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, dichloroethane or THF.

A general approach for the préparation of compounds of the general formula (IA-5, IA6 and IA-7) (wherein X, Y, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, ‘m’ and Ύ’ are as defined in the description) is depicted in synthetic scheme 4.

Synthetic scheme-4:

Stille coupling ,Ν.,..

,Bu

EtO^Sn Y <

Hydrolysis

O O

HO

N'N RÎ R⁴ (R²) (g)

Coupling reagent

O, (RV^x O 'r (17) (18) (6) V

SFC séparation (IA-5)

Reductive

Amination (19)

(IA-6) (ΙΛ-7)

The Stille coupling reaction of compound of formula (3) and tribulyl(l-ethoxyvinyl)tin givcs the compound of formula (17). The reaction is canied out in présence of suitable catalyst. The suitable catalyst used in the reaction may be selected from tetrakis(triphenyl phosphine) palladium(O), dichlorobis(triphenyl phosphine )palladium(II), palladium acetate, along with a suitable phosphine ligand, etc. The réaction is carricd out in présence of suitable solvent. The suitable solvent used in the reaction may be selected from, 1,4-dioxane, DMSO or DMF.

The hydrolysis reaction of compound of formula (17) gives the compound of formula (18). The reaction is carricd out in présence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, éthanol or tetrahydrofuran or combination thereof.

The acid-amine coupling reaction of compound (18) with appropriate aromatic amines compounds of formula (9) gives the compound of formula (19). The reaction is carried out in presence of suitable coupling rcagcnts. The suitable coupling rcagcnts used in the réaction may be selected from HATU, EDC.HC1, HOBt. DCC or T3P. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromcthanc, THF or dîmcthylformamidc. The réaction is carricd ont in présence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA.

The reductive amination reaction of compound of formula (19) with appropriate amines compound of formula (6) yields compound of formula (IA-5). The reaction is carried out in presence of suitable catalysl. The suitable catalyst used in the reaction may be acetic acid. The réaction is carricd out in présence of suitable base. The suitable base used in the réaction may be selected from triethylamine or DIPEA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane, dichloroethane, dimethylformamide. methanol and éthanol. The réaction is carried oui in presence of a suitable reducing agent. The suitable rcducing agent used in the réaction may bc selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

The Supercritical Fluid Chromatography (SFC) purification of racemic compound of formula (1A-5) yields the compound of general formula (1A-6) and the compound general formula (1A-7).

A general approach for the préparation of compounds of the general formula (IA-8) (wherein X, Y, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R¹¹, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 5.

Synthctic schcmc-5:

o

(20) (21) (22)

(23) (1A-B)

The acid-amine coupling reaction of compound (14) with appropriate aromatic amines compound of formula (20) | wherein Q is C or N] gives the compound of formula (21). The reaction is carried out in presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HC1, HOBt. DCC or T3P. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimcthylformamide. The reaction is carricd out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA orTEA.

The compound of formula (21) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldéhyde compound of formula (22). The reaction is carried out in presence of suitable solvent or mixture thcrcof. The suitable solvent used in the reaction may be THF / water.

The reductive amination reaction of compound of formula (22) with appropriate amines compound of formula (6) yields compound of formula (23). The reaction is carried oui in presence of suitable catalyst. The suitable catalyst used in the réaction id acctic acid. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from triethylamine or DIPEA. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane, dimcthylformamide, mcthanol and cthanol. The réaction is carricd out in présence of a suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride.

The compound of formula (23) on deprotection yields the compound of formula (IA-8). The reaction may be carried in presence of suitable acids. The suitable acids used in the reaction may be selected from hydrochloric acid and trifluoroacctic acid. The réaction is carricd out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from mcthanol, cthanol, dichlorocthanc and 1,4- dioxanc.

A general approach for the préparation of compounds of the general formula (1A-9) (wherein X, Y, Z, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, R^u, ‘m’ and ‘r’ are as deiïned in the description) is depicted in synthetic scheme 6.

Svnthetic scheme-6:

The compound of formula (4) [wherein R’ is Ci-salkyl] upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldéhyde compound of formula (5). The reaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in thc réaction may bc THF / water.

The reductive amination reaction of compound of formula (5) with appropriate amines compound of formula (24) yields compound of formula (26). The reaction is carried out in presence of suitable reducing agent. The suitable reducing agent used in the reaction may be selected from sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloro melhane, dimethylformamide, mcthanol and éthanol.

The amine compound of formula (25) upon N-protection using suitable protecting group (PG) yields the compound of formula (26). The reaction is carried out in presence of suitable protecting group. The suitable protecting group used in the reaction may be selected from ditert-butyl dicarbonate, acetic anhydride and benzylchloroformate.

The hydrolysis reaction of compound of formula (26) yields the compound of formula (27). The reaction is carried out in presence of suitable base. The suitable base used in the réaction may bc selected from lithium hydroxidc, sodium hydroxidc and potassium hydroxidc. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the réaction may be selected from methanol. éthanol and tetrahydrofuran or combination thereof.

The acid-amine coupling reaction of compound of formula (27) with appropriate aromalic amine compound of formula (28) gives the compound of formula (29). The reaction is carried oui in presence of suitable coupling reagents. The suitable coupling reagents used in the réaction may be sclcctcd from HATIJ, EDC.HC1, HOBt, DCC or T3P. The reaction is carried ont in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA.

The acylation réaction of compound of formula (29) yields the compound of formula (30). The réaction is carried out in présence of suitable acylating reagents. The suitable acylating reagents used in the reaction may be acetic anhydride or acryloyl chloride.

The compound of formula (30) on deprotection yields the compound of formula (IA-9). The réaction is carried oui in presence of suitable acid. The suitable acid used in the reaction may bc selected from hydrochloric acid and trifluoroacetic acid. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected form dichloromethane. dichloroethane and 1,4- dioxane.

EXPERIMENTAL SECTION

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parenthèses, séparation of layers and drying the organic layer over sodium sulfate, filtration and évaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographie techniques, generally using ethyl acetate/petrolcum cther mixture of a suitable polarity as the mobile phase. Use of a different eluenl System is indicated within parenthèses.

The abbreviations, symbols and terms used in the examples hâve the following meanings throughout:

Abbreviations	Full Form
HOBt	H ydroxy ben zotri azo le
(Boc)3O	Di-tert-butyl dicarbonate
[Rh(COD)Cl]2	Cyclooctadiene rhodium chloride dimer
AcOH	Acetic Acid
AIBN	Azobisisobutyronitrilc
AICI3	Aluminium chloride
CS2CO3	césium carbonate
Cu(OAc)2	Copper(II) acetate
Cul	Coppcr(l) iodide

Abbreviations	Full Form
DAST	Dicthylaminosulfur trifluoridc
DCC	N, N'-Dicyc lohexy Icarbodiimide
DCM	D ich l oromethane
D1BAL	Diisobutylaluminium hydride
DIPEA	N.N-Diisopropylethylamine
DMF	N,N-Dimethylformamide
DMP	Dcss-Martin periodinanc
DMSO	Dimethyl sulfoxide
EDC	Elhylene dichloride
EDC.HC1	l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EtOAc	Ethyl Acetate
H2O2	Hydrogen Peroxide
HATU	Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium
HCl	Hydrochloric acid
hno3	.Nitric acid
K2CO3	Potassium carbonate
K3PO4	Tripotassium phosphate
KOH	Potassium hydroxide
LiOH	Lithium hydroxide
MeOH	Methanol
Na2SO4	Sodium sulfate
NaH	Sodium hydride
NaHCO3	Sodium bicarbonate
NaHMDS	Sodium bis(lrimelhylsilyl)amide
NaIÛ4	Sodium pcriodatc
NaNOz	Sodium nitrite
NaOH	Sodium hydroxude
NB S	N - Brornos uccinimide
NH4CI	Ammonium Chloride
NMP	N-Methyl-2-pyrrolidone
OsO4	Osmium tctroxide
Pd(dppf)Cl2.DCM	[ l J'-BisfdiphenylphosphinoJfenOcenejpalladiumfri) dichloride.

Abbreviations	Full Form
	DCM Complex
Pd(PPh3)2C12	Bis(triphenylphosphine îpalladium chloride
PTSA	ρ-Toluenesulfonic acid
SFC	Supercritical fluid chromatography
T3P	Propylphosphonic anhydride
t-BuOH	teri-Butyl alcohol
TEA	Tricthy lamine
THF	Telrahydrofuran

INTERMEDIATES Intcrmcdiatc Al 3-(2-Methyl-l-(4-methyl-4H-L2,4-triazoL3-yl)propan-2-yl)aniline

Step-1: 3-(3-Bromophenyl)-3-methylbutanoic acid

To a stirred solution of bromohenzene (10 g, 0.0183 mmol) in DCM (100 mL) was added 3,3 dimethyl acrylic acid (3.19 g, 0.0318 mol). To this reaction mixture AICh was added portion wise al 15-20°C and stirred al room température for 90 min. The reaction mixture was quenched with 1 N HCl and cxtractcd twice with ethyl acétate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by SFC to get 3.1 g of the desired product. 'H NMR (400 MHz, DMSO-î/ô) δ 1.36 (s, 6H), 2.60 (s, 2H), 7.24 - 7.28 (m, 1H), 7.36 - 7.41 (m. 2H), 7.53 (s, 1H), 11.9 (brs, 1H).

Step-2: 2-( 3 -( 3-B romopheny 1)-3-methyIbutanoy l)-N-meth y Ihydrazine carbothioamide

To a stirred solution of 3-(3-bromophenyl)-3-methylbutanoic acid (6.2 g, 0.024 mol) in DMF (60 mL) was added HATU (11g, 0.029 mol) and stirred at room température for 30 min. To this mixture was added DIPEA (12.5 mL. 0.072 mol) and 4-methyllhiosemicarbazide (2.8 g, 0.0265 mmol) and stirred at room température for 18 h. The reaction mixture was diluted with water and stirred for 30 min. The sohd obtained was fïltered and dned under vacuum to yield 4.83 g of the desired product. ‘H NMR (400 MHz, DMSO-rfc) S 1.36 (s, 6H), 2.50 (s, 2H), 2.83 (s, 3H), 7.26-7.30 (m, 1H), 7.39-7.41 (m, 3H), 7.53 (brs, 1H). 9.19 (brs, 1H), 9.60 (brs, 1H). Stcp-3: 3-(2-(3-Bromophcnyl)-2-mcthylpropyl)-4-mcthyl-lH-l,2,4-triazolc-5(4H)-thionc

To a stirred solution of 2-(3-(3-bromophenyl)-3-methylbutanoyl)-N-methylhydrazine carbothioamide (4.8 g, 0.0139 mol) in 1 N NaOH (170 mL) was stirred at room température for 18 h. The reaction mixture was acidified using 3N HCl and stirred for 15 min. The precipitated solid was Fïltered, washed with excess water and dried under vacuum to yield 4.31 g of the desired product. ‘H NMR (400 MHz, DMSO-J₆) δ 1.40 (s, 6H), 3.03 (s, 2H), 3.13 (s, 3H), 7.237.27 (m. 1H), 7.33-7.40 (m,2H), 7.48-7.56 (m. 1H), 13.45 (s, 1H), ESI-MS (m/z) 327 (M+2H)⁺ Step-4: 3-(2-(3-Bromophenyl)-2-melhylpropyl)-4-methyl-4H-l,2,4-triazole

To a stirred solution of 3-(2-(3-bromophenyl)-2-methylpropyl)-4-methyl-lH-l,2,4-triazole5(4H)-thione (4.31 g, 0.013 mol) in DCM / acetic acid (2:1, 130 mL) was added 50 % solution of H2O2 (4.3 mL) and stirred at 0° C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was triturated with diethyl ether, filtered and dried to obtain 4.2 g of the desired product. ‘H NMR (400 MHz, DMSO-Je) δ 1.42 (s, 6H), 3.26 (s, 2H), 3.51 (s, 3H), 7.26-7.30 (m, 1H), 7.38-7.45 (m, 2H), 7.58-7.59 (m, 1H), 9.28 (s. 1H); ESI-MS (m/z) 294 (M+H)⁺

Stcp-5: 3-(2-Methyl-l-(4-mcthyl-4//-1,2,4-triazol-3-yl)piOpan-2-yl)anilinc

In a sealed tube, to a stirred solution of 3-(2-(3-bromophenyl)-2-methylpropyl)-4-melhyl-4H1,2,4-triazole ( 1 g, 0.0034 mol) in NMP ( 10 mL) wcrc added aq. NHs ( 10 mL), Coppcr (I) oxide (194 mg 1.359 mmol) and stirred at 90° C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was triturated with diethyl ether to give 641 mg of the desired product. ^JH NMR (400 MHz, DMSO-dô) δ 1.33 (s, 6H), 2.50 (s, 2H), 3.05 (s, 3H), 4.92 (brs, 2H), 6.37 - 6.42 (m, 2H), 6.49 (s, 1H), 6.88-6.92 (m. 1H), 8.22 (s, 1H); ESI-MS (m/z) 231.2 (M+H)⁺

Intermediatc A2

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

Sten-l : Diethyl 2-(2-(3-bromo-4-fluoropheny])propan-2-yl)malonate

Br

F

EtO₂C

To a stirrcd solution of 2-bromo-4-iodo-l-fluorobcnzcnc (5.86 g, 19.5 mmol) in THF (15 mL) at -10 °C was added dropwise 2M solution of isopropyl magnésium chloride in THF ( 11.25 mL, 22.5 mmol) and stirred at 0°C for 30 min and further stirred at room température for 1 hr. To this mixture at 0°C was added copper (I) iodide (860 mg, 4.5 mmol) and stirred for 10 min and then added diethyl isopropylidcnc malonatc (3 g, 15 mmol). The réaction mixture was hcatcd to 60°C for 2 h. The reaction mixture was quenched with 1 N HCL and diluted with ethyl acetate. The suspension obtained was filtered and washed with ethyl acetale. The fillrate obtained was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphatc and conccntratcd undcr rcduccd pressure. The residue obtained was purifîed by flash chromatography to get 3.5 g of the desired product. ^[H NMR (400 MHz, CDCh): Ô 1.17 (t, J= 7.2 Hz, 6H), 1.57 (s, 6H), 3.73 (s, 1H), 4.10 (q, 7=6.8 Hz, 4H), 7.04-7.09 (m. 1H), 7.30-7.33 (m, 1 H), 7.55-7.57 (m, 1H); ESI-MS (m/z) 375.0 (M+H) ⁺

Stcp-2: Ethyl 3-(3-bromo-4-fluorophcnyl)-3-mcthylbutanoatc

Br

Tj

To a stirred suspension of diethyl 2-(2-(3-bromo-4-fluoro phenyl)propan-2-yl)malonate (2.4 g, 6.39 mmol), lithium chloride (600 mg, 14.04 mmol) and watcr (114 mg, 6.39 mmol) in DMSO (12 mL) was subjected to microwave irradiation for 1 h at 200°C. The reaction mixture was diluted with water and extracted thrice with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purifîed by flash chromatography to get 1.5 g of desired product. *H NMR (400 MHz, CDCh): δ 1.12 (l, J= 7.2 Hz, 3H), 1.45 (s, 6H). 2.60 (s, 2H), 4.01 (q, 7=7.2 Hz, 2H), 7.04-7.09 (m, 1H), 7.27-7.30 (m, 1H), 7.53-7.55 (m, 1H); ESI-MS (m/z) 303.1 (M+H) ⁺

Step-3: 3-(3-Bromo-4-fIuorophenyl)-3-methylbutanehydrazide

To a stirred solution of ethyl 3-(3-bromo-4-fluorophenyl)-3-methylbutanoate (1.5 g, 4.95 mmol) in McOH (7 mL) at 0° C was addcd dropwisc 99% hydrazinc hydrate (7 mL). The reaction mixture was warmed to room température and heated to 90°C for 16 h. The mixture was concenlrated and the obtained residue was dissolved in ethyl acelate. The organic layer was washed with water, brine solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to yield 1.4 g of the desired product. *HNMR (400 MHz, DMSO-d6): δ 133 (s, 6H), 2.33 (s, 2H), 4.10 (brs, 2H), 7.25-7.30 (m, 1H), 7.38-7.42 (m, 1H), 7.60-7.62 (m, 1H), 8.87 (brs, 1H); ESI-MS (m/z) 290.1 (M+2H) ⁺

Step-4: 2-(3-(3-Bromo-4-fluorophenyl)-3-methylbutanoyl)-N-methylhydrazinecarbothioamide

To a stirred solution of 3-(3-bromo-4-fluorophenyl)-3-melhylbu(anehydrazide (1.4 g, 4.62 mmol) in THF (10 mL) at 0°C was added dropwise methylisothiocyanate (1 g, 13.86 mmol). The réaction mixture was stirred at room température for lh and heated to 80° C for 3 h. The mixture was concentrated under reduced pressure and the residue obtained was triturated with pentane. The solid obtained was filtered and dried under vacuum to yield 1.6 g of the desired product. ’HNMR (400 MHz. DMSO dô): δ 1.36 (s, 6H), 2.40 (s, 2H), 2.82 (d, 4.0 Hz, 3H),

7.27 -7.31 (m, 1H), 7.40-7.43 (m, 1H), 7.54 (s, 1H), 7.62-7.64 (m. 1H), 9.18 (s, 1H), 9.59 (s, 1H); ESI-MS (m/z) 363.1 (M+2H)⁺

Step-5: 5-(2-(3-Bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-l,2,4-triazole-3-lhiol HNn . .

' y jl

To a stirred solution of 2-(3-(3-Bromo-4-fluorophcnyl)-3-mcthylbutanoyl)-Nmethylhydrazinecarbothioamide (1.4 g, 3.86 mmol) in 1 N NaOH (30 mL) was stirred at room température for 16 h. The reaction mixture was acidified using 2N HCL and stirred for 15 min. The precipitated solid was filtered, washed with excess water and dried under vacuum to yield 1.3 g of the desired product. 'HNMR (400 MHz, DMSO-d6): δ 1.39 (s, 6H), 3.04 (s, 2H), 3 19 (s, 3H), 7.25-7.30 (m, 1H), 7.38-7.42 (m, 1H). 7.67-7.69 (m. 1H), 13.44 (brs, 1H); ESI-MS (m/z) 345.0 (M+2H) ⁺

Stcp 6: 3-(2-(3-Bromo-4-fluoiOphcnyl)-2-mcthylpropyl)-4-mcthyl-4H-l,2,4-triazolc

To a stirred solution of 5-(2-(3-Bromo-4-fluorophenyl)-2-methylpropyl)-4-methyl-4H-l,2,4triazolc-3-thiol (1.3 g, 3.63 mmol) in DCM (30 mL) and AcOH (3 g, 50.83 mmol) at 0°C was added 30% H2O2 solution (370 mg, 10.89 mmol). The mixture was stirred at room température for 16 h. The reaction mixture was quenched with water and extracted twice with DCM. The 5 solvent was evaporated undcr reduced pressure and the solid obtained was purified by silica gel column chromalography to yield 900 mg of the desired producl. 'HNMR (400 MHz. DMSOd6); δ 1.40 (s, 6H), 2.99 (s. 2H), 3.25 (s,3H), 7.24-7.28 (m. 1H), 7.32-7.36 (m, 1H), 7.58-7.60 (m,lH), 8.25 (s, 1H); ESI MS (m/z) 313.1 (M+2H)⁺

Step-7: 2-Fluoro-5-(2-methyl-L(4-methyL4H-l,2.4triazol-3-yl)propan-2-yl)aniline

In a sealed tube, to a stirred solution of 3-(2-(3-Bromo-4-fluorophenyl)-2-melhylpropyl)-4mcthyl-4H-l,2,4-triazole (400 mg, 1.28 mmol) in NMP(4 mL) was added aqucous NH₃(4mL), copper(I) oxide (73 mg, 0.512 mmol) and stirred at 90° C for 16 h. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under vacuum to give 300 mg of 15 the desired product. 'HNMR (400 MHz, DMSO-d6): δ 1.34 (s, 6H), 2.87 (s, 2H), 3.09 (s, 3H), 4.99 (s, 2H), 6.39-6.43 (m. 1H), 6.68-6.71 (m, 1H), 6.82-6.87 (m, 1H), 8.22 (s, 1H); ESLMS (m/z) 249.2 (M+H) ⁺

The analyticai data of the intermediate prepared by foliowing the procedure described above are given in below Table-1.

Table-1: Structure, Name and analyticai data of intermediate (A3)

Intermediate No.	Structure	Name and Analyticai data
A3	N N ' I J	4-Fluoro-3-(2-methyl-l-(4-methy1-4H-l,2,4-triazol3-yl)propan-2-yl)aniline; 'HNMR (400 MHz, DMSO-zfe): δ 1.36 (s, 6H), 2.70 (s, 2H), 3.07 (s,3H), 4.87 (brs,2H), 6.37-6.43 (m, 2H), 6.75-6.81 (m,lH), 8.34 (s, 1H); ESI-MS (m/z) 249.2 (M+H)*

intermediate A4

3-(3-((4-Methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline

Step-1: Ethyl 2-(oxetan-3-ylidene)acelate

To a stirred solution of NaH (611 mg, 15.27 mmol) in THF (25 mL) was added ethyl 2(dicthoxyphosphoryl(acétate ( 3.422 mg, 15.27 mmol) dropwisc for 10-15 min at O C and further stirred at room température for 30 min followed by the addition of oxetan-3-one (1 g, 13.889 mmol). The mixture was stirred for 18 h. The reaction mixture was quenched with aqueous NaHCOa solution and extracted twice with Ethyl acetate. The organic layer was separated, dried over sodium sulphate and concenlrated. The residue obtained was purified by silica gel chromatography to yield 1.2 g of the desired product. 'H NMR (400 MHz, CDCh) δ 1,28 (t, J = 7.2 Hz. 3H), 4.13-4.21 (m, 2H), 5.31 - 5.33 (m. 2H), 5.51-5.54 (m, 2H), 5.64-5.66 (m, 1H).

Stcn-2: Ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acctatc

To a degassed solution of [Rh(COD)Cl]2 (170 mg, 0.352 mmol) in dioxane (15 mL) was added 1.5 aqueous KOH (6 mL) dropwise at room température and stirred for 30 min. To this mixture was added drop wise solution of ethyl 2-(oxetan-3-ylidene (acetate ( 1 g, 7.042 mmol) in dioxane (10 mL) followed by (3-bromo phenyDboronic acid (2 g, 10.56 mmol) in dioxane (10 mL) solution and stirred for 1 hr. The reaction was stirred for 1 h and to this reaction mixture (3bromophenyl)boronic acid (700 mg, 3.521 mmol) was again added and stirred at room température for 48 h. The mixture was quenched with brinc solution and extracted thricc with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography to yield 1.3 g of the desired product. Ή NMR (400 MHz, DMSO-Λ) δ 1.04 (t, J = 7.2 Hz, 3H), 2.50-2.52 (m. 2H), 3.92 (q, J = 6.8 Hz. 2H), 4.75 (d, J = 6.4 Hz. 2H), 4.79 (d, J = 6.4 Hz. 2H), 7.28-7.32 (m. 2H), 7.45-7.46 (m, 2H).

Step-3: 2-(3-(3-Bromophenyl)oxelan-3-yl)acetic acid

To a stirred solution of ethyl 2-(3-(3-bromophenyl)oxetan-3-yl)acetate (150 mg, 0.5 mmol) in THF ( 1.5 mL) was added aqueous solution of LiOH (40 mg , 1 mmol) at 0°C and stirred at room température for 4 h. The solvent was removed and acidified using 1 N HCl. The aqueous layer was extracted twice with ethyl acetate and dried over sodium sulphate. The organic layer was concentrated to yield 140 mg of the desired product. 'H NMR (400 MHz, DMSO) δ 3.09 (s, 2H), 4.74-4,78 (m. 4H), 7.32 (d, J = 4.8 Hz, 2H), 7.44-7.49 (m, 2H). 12.24 (brs, 1H)

Step-4: 2-(2-(3-(3-Bromophenyl)oxetan-3-yl)acetyl)-N-methylhydrazinecarbothioamide

H H

N N_w ï H

To a stirred solution of 2-(3-(3-bromophenyl)oxetan-3-yl)acetic acid (135 mg, 0.498 mmol) in DMF (1.5 mL) was added HATU (227 mg, 0.597 mmol) and stirred for 15 min. To the reaction mixture was added N-methylhydrazinecarbothioamide (57 mg, 0.547 mmol) and DIPEA (192 mg, 1.494 mmol) and stirred at room température for 18 h. The reaction mixture was qucnchcd with water and extracted thrice with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography to yield 145 mg of the desired product. ’H NMR (400 MHz, DMSO) δ 2.51 (d, J = 4.8 Hz, 3H), 3.00 (s, 2H), 4.74-4.81 (m, 4H), 7.29-7.31 (m, 2H), 7.43-7.48 (m, 2H), 7.6 (brs, 1H), 9.14 (s, 1H), 9.70 (s, 1H); ESI-MS (m/z) 359.9 (M+2H)⁺

Step-5: 3-((3-(3-Bromophenyl)oxetan-3-yl)methyl)-4-methyl-lH-l,2,4-triazole-5(4H)-thione hn_n A ¹

To a stirred solution of 2-(2-(3-(3-bromophenyl)oxetan-3-yl)acetyl)-Nmethylhydrazinecarbothioamide (100 mg, 0.28 mmol) in IN NaOH (3.5 mL) was stirred at room température for 18 h. The mixture was cooled and neutralized using IN HCI. The solid obtained was fïltered and dried under vacuum to givc 65 mg of thc desired product. 'H NMR (400 MHz, DMSO-ί/ά) δ 3.01 (s, 3H), 3.53 (s, 2H), 4.78 - 4.82 (m, 4H), 7.17 (d, J = 7.6 Hz, 1H), 7.28(t,J = 7.6 Hz, 1H), 7.44 -7.46 (m, 2H). 13.49 (brs, 1H); ESI-MS (m/z) 340.2 (M+H)⁺ Step-6: 3-((3-(3-Bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-l,2,4-triazole

To a stirred solution of 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-lH-l,2,4-triazole5(4H)-lhione (350 mg, 1.032 mmol) in water (1.5 mL) was added NaNCh (750 mg, 10.32 mmol) followcd by dropwise addition of IN HNO3 (3.5 ml) at 0°C and stirred for 1 h. The réaction mixture was quenched with saturated solution of NaHCOa and extracted thrice with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The residue obtained was purified by silica gel chromatography to yicld 245 mg of thc desired product.

NMR (400 MHz, DMSO-rfô) δ 3.02 (s, 3H), 3.49 (s, 2H), 4.81 (d, J = 6 Hz, 2H), 4.89 (d, J = 6

Hz. 2H), 7.00 (d, J = 7.6 Hz, 1H), 7.24 (m. 2H), 7.41 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H); ESI-MS (tn/z) 309.9 (M+H)⁺

Step-7: 3-(3-((4-Methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline

In a sealed tube, to a stirred solution of 3-((3-(3-bromophenyl)oxelan-3-yl)melhyl)-4-methyl4H-l,2,4-triazole (200 mg, 0.629 mmol) in NMP (2 mL) were added aqueous NHî (2 mL), Copper (I) oxide (35mg, 0.2515 mmol) and stirred al 90° C for 16 h. The reaction mixture was qucnchcd with watcr and cxtracted thrice with cthyl acétate. The organic layer was evaporated under vacuum to give 160 mg of the desired product. *H NMR (400 MHz, DMSO-dô) δ 2.83 (s, 3H), 3.39 (s, 2H), 4.75 (d, J = 6 Hz, 2H), 4.85 (d, J = 6 Hz, 2H), 5.02 (brs. 2H), 5.92 (d, J = 7.2 Hz, l H),6.04 (s, 1 H), 6.39 - 6.41 (m. 1 H), 6.89 (d, J = 8 Hz, 1 H), 8.21 (brs, 1H); ESI-MS (m/z) 245.2 (M+H)⁺

Intermediate A 5

3-(( 1 s,3s)-3-Methyl-l -(4-methyl-4H-1,2,4-triazol-3-yl)cyclobuty!)aniline

Λ O

Step-1 : l,3-Dibromo-2-methylpropane

To a stirred solution of 2-methyl-l,3-propanediol (20 g, 222 mmol) and triphenyl phosphine (128.1 g, 488.3 mmol) in DCM (500 mL) was added N-Bromosuccinimide (86.92 g, 488.35mmol) portion wise at 0°C and stirred at room température for 16 h. The solvent was conccntrated under reduced pressure and the residuc obtaincd was purified by silica gel chromatography to yield 23.4 g of the desired product. ’HNMR (400 MHz, CDCh): δ 1.17 (d, J = 6,4 Hz, 3H), 2.18-2.24 (m, 1H), 3.46-3.56 (m, 4H).

Step-2: l-(3-Bromophenyl)-3-methylcyclobutanecarbonitrile

To a stirred suspension of NaH (60% suspension in minerai oil) (2.58g, 107.65 mmol) in DMF (100 mL) was added dropwise solution of 3-bromophenylacelonilrile (10. 55 g, 53.826 mmol) at 0°C followed by slow addition of l,3-dibromo-2-methylpropane (11.62 g, 53.826 mmol). The reaction mixture was stirred at room température for 2 h and at 80° C for 16 h. The reaction mixture was cooled to 0°C and quenched with aqueous NH4CI solution. The aqueous layer was extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous

Na₂SO4 and concentrated. The residue obtained was purified by silica gel column chromatography to yicld 9.15 g of the dcsircd product. 'HNMR (400 MHz, DMSO-d6): δ 1.22 (d, 7=6 Hz, 3H), 2.18-2.23(m, 1H), 2.45-2.51(m, 2H), 2.77-2.82 (m, 2H), 7.40-7.45 (m, 1H), 7.54-7.71 (m, 2H), 7.72 (d. J = 1.6 Hz. 1 H).

Step-3: l-(3-Bromophenyl)-3-methylcyclobutanecarboxylic acid

To a stirred solution of l-(3-bromophenyl)-3-methylcyclobutanecarbonitrile (17.7 g. 70.76 mmol), in 80 mL of AcOH/H₂O (1:1) was added Conc. H₂SÛ4 (40 mL) dropwise at 0° C and stirred at 0° C for 15 min and heated to 120° C for 16 h. The reaction mixture was cooled to room température 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. ‘HNMR (400 MHz, DMSO-d6): δ 1.06 (d, 7=6.4 Hz, 3H), 2.132.19 (m, 1H), 2.32 (t, 7=5.2 Hz, 2H), 2.51-2.61 (m, 2H),), 7.31-7.39 (m, 2H), 7.42-7.50 (m, 2H), 12.47 (brs, 1H)

Step-4: Methyl 1 -(3-bromophenyl)-3-methylcyclobutanecarboxylate

To a stirred solution of l-(3-bromophenyl)-3-methylcyclobutanecarboxylic acid (18.3 g, 67.99 mmol) in MeOH (180 mL) was added conc. H₂SO4 (18 mL) and stirred al room température for 2 h and heated to 90° C for 16 h. The réaction mixture was concentrated undcr vacuum and diluted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous Na₂SO4. The solvent was evaporated under vacuum to obtain 19.1 g of the desired product. 'HNMR (400 MHz, DMSO-d6): δ 1.15 (d, 7 = 6.8 Hz, 3H), 2.26-2.30 (m, 1H), 2.41-2.46 (m, 2H), 2.66-2.69 (m, 2H), 3.51 (s, 3H), 7.17-7.28 (m, 1H), 7.34-7.41 (m. 2H), 7.56 (d, 7 = 2 Hz, 1H).

Step-5: 1 -(3-Bromophenyl)-3-methylcyclobutanecarbohydrazide

To a stirred solution of Methyl l-(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 température and heated to 90°C for 16 h. The mixture was concentrated and the obtained residue was dissolved with ethyl acetate. The organic layer was washcd with water, brinc solution and dricd ovcr anhydrous sodium sulfate. The solvent was evaporated unde reduced pressure to yield 19.18 g of the desired product. ESI-MS (m/z) 283.1 (M+H)⁺

Step-6: 2-(l-(3-Bromophenyl)-3-methylcyclobutanecarbonyl)-N-methylhydrazinecarbothio amide ^S H A ^{H H} o LJ

To a stirred solution of l-(3-bromophenyl)-3-mcthylcyclobutanccarbohydrazide (19.0 g, 67.09 mmol) in THF (200 mL) was added dropwise methylisothiocyanate (14.71 g, 201.3 mmol) at 0°C. The reaction mixture was stirred at room température for Ih and heated to 80° C for 3 h. The mixture was concentrated under reduced pressure and the residue obtained was triturated with pcntanc. The solid obtained was filtcrcd and dricd under vacuum to yield 23.8 g of the desired product. ESI-MS (m/z) 356.0 (M+H)⁺

Step-7: 5-(l-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-l,2,4-triazole3-thione

To a stirred solution of 2-(l-(3-bromophenyi)-3-methylcyclobutanecarbonyl)-Nmethylhydrazinecarbothioamide (23.4 g, 65.67 mmol) in IN NaOH (500 mL) was stirred at room température for 16 h. The reaction mixture was acidified using 2N HCl and stirred for 15 min. The prccipitatcd solid was filtcrcd, washcd with cxccss water and dricd under vacuum to yield 20.18 g of the desired product. ^JHNMR (400 MHz, DMSO-d6): δ 1.06 (d, J =6.0 Hz, 3H), 2.45-2.51 (m, 3H), 2.76 (d, J =3.6 Hz. 2H), 3.01 (s, 3H), 7.35-7.39 (m, 2H), 7.51-7.54 (m, 2H), 13.7 (brs, 1H); ESI-MS (m/z) 338.0 (M+H)⁺

Step-8: 3-((ls,3s)-l-(3-Bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-l,2,4-triazole 'i-N^

To a stirred solution of 5-(l-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3Hl,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 température for 16 h. The reaction mixture was quenched with water and extracted twice with DCM. The solvent was evaporated undcr rcduced pressure and the solid obtaincd was purified by silica gel column chromatography to yield racemic 4.8 g of the desired product. The racemic product obtained was purified by SFC purification to yield cis isomer 2.65 g of the desired product. 'HNMR (400 5 MHz, CDCb): δ 1.16 (d. J = 5.6 Hz, 3H), 2.64-2.70(m, 3H), 2.82-2.85(m, 2H), 3.23 (s, 3H), 7.23-7.29 (m, 1H), 7.40-7.43 (m, 2H), 7.56 (d, J = 1.6Hz, lH),8.19(s, 1H);ESIMS (m/z) 306.0 (M+H)⁺

Step-9: 3-((ls,3s)-3-Methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)aniline

In a sealed tube, to a stirred solution of 3-((ls,3s)-l-(3-bromophenyl)-3-methylcyclobutyl)-410 methyl-4H-l,2,4-triazole (250 mg, 0. 816 mmol) in NMP (3.5 mL) was added aqueous NHj (3.5 mL), coppcr oxide (47 mg, 0.326 mmol) and stirred at 90° C for 16 h. The réaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphale and the solvent was evaporated under vacuum to give 171 mg of the desired product. 'HNMR (400 MHz. DMSO-d6): δ 1.05 (d, J= 4.8 Hz, 3H), 2.46 - 2.51 (m, 3H), 2.71 (d. J=1.2 Hz, 2H), 3.16 (s, 3H), 5.06 (brs, 2H). 6.41 - 6.46 (m, 3H), 6.78 (t. 7 =

7.6 Hz, 1H), 8.39 (brs, 1H); ES1-MS (m/z)243.2(M+H) ⁺

The analytical data of the intermediate prepared by following the procedure described above are given in below Table-2.

Tahle-2: Structure. Name and analytical data of intermediate (A6-A9)

Intermediate No.	Structure	Name and Analytical data
A6	n *r r r '	2- Fluoro-5 -(( 1 s. 3 s ) - 3 - methy 1-1 -(4-methy 1-4Hl,2,4-triazol-3-yl)cyclobutyl)aniline; 1H NMR (400 MHz, DMSO-76) δ 1.05 (d, J = 5.6 Hz, 3H), 2.432.47 (m, 3H), 2.69-2.71(m, 2H), 3.16 (s, 3H), 5.14 (brs, 2H), 6.49-6.50 (m, 1H), 6.65 (dd. J = 1.6 Hz, 8.4 Hz, 1H), 6.92-6.97 (m, 1H), 8.28 (s, 1H); ESIMS (m/z) 261.2 (M+H)+
A7	N T T T ' t-N LUI	3-Fluoro-5-(( 1 s,3s)-3-methyl-1 -(4-methyl-4Hl,2,4-triazol-3-yl)cyclobutyl)aniline: 'HNMR (400 MHz. DMSO-d6): δ 1.06 (d, 7=8.0 Hz, 3H), 2.142.44 (m, 2H), 2.68-2.72 (m. 2H), 2.95-3.00 (m, 1H), 3.18 (s. 3H), 5.44 (s, 2H), 6.14-6.25 (m, 3H), 8.29 (s, 1H); ES1-MS (m/z) 261.2 (M+H)+

Intermediate No.	Structure	Name and Analytical data
A8	VT Qr	5-(( 1 s,3s)-3-Mcthyl-1 -(4-methyl-4H-1,2,4-triazol3-yl)cyclobutyl)benzene-l,3-diamine: 'HNMR (DMSO-Jî, 400 MHz) δ 1.03 (d, 7 = 4 Hz. 3H), 2.432.35 (m, 3H), 2.66-2.62 (m, 2H), 3.17 (s, 3H), 4.70 (bs, 2H), 5.67 (s, 1H), 5.74 (s, 2H), 8.25 (s, 1H); ESI- MS (m/z) 258 (M+H)+
A9	x1 Z O	4-(3-Mcthyl-1 -(4-mcthyl-4H-1,2,4-triazol-3yl)cyclobutyl)pyridin-2-aminc: ESI-MS (m/z) 244.2 (M+H)+

Intermediate-A10

2-ChIoro-5-((ls.3s)-3-methyl-l-(4-methyl-4H-1.2,4-triazol-3-yl)cyclobutyl)aniline

To a stirred solution of 3-((ls,3s)-l-(3-bromo-4-chlorophenyl)-3-methylcyclobutyl)-4-methyl4H-l,2,4-triazole (50 mg, 0. 147 mmol) in éthanol (l.O mL) and water (0.75mL) was degassed for 10 min. The NaNs (19 mg, 0.294mmol), Cul (28mg, 0.147 mmol), trans N,N-dimethyl-l,2cyclohexanediamine (17 mg,0.147mmol) and sodium ascorbate (58mg, 0.294mmol) were addcd to thc réaction mixture and stirred at 110°C for 18 h in a sealed tube. The réaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphale and the solvent was evaporated. The residue obtained puriiied by column chromatography to givc 21 mg of thc desired product. ^lH NMR (400 MHz. DMSOî/6) δ 1.05 (d, J= 5.6 Hz, 3H), 2.43-2.5 l(m, 3H), 2.68 (m, 2H), 3.16 (s, 3H), 5.35 (s, 2H), 6.50 (dd. 7i= 2.4 Hz, 7:=8.4 Hz, 1H), 6.72 (d, 7=2.4 Hz, 1H), 7.15 (d, 7=8.4Hz, 1H), 8.29 (s,lH); ESI-MS (m/z) 278 (M+2H)⁺

Intermediate-Al 1

3-(3,3-Dimethyl-1-(4-methy!-4H-l ,2,4-triazol-3-yl)cyclobuty l)aniline

Step-1 : 2,2-Dimethylpropane-l,3-diyldimethanesulfonate

MsoVV^OMs

To a stirred solution of 2,2-dimethylpropane-l,3-diol (10 g, 96.1 mmol) in DCM (100 mL) tricthylaminc (33.7 mL, 240 mmol) was addcd. The mcsyl chloridc (18.5 mL, 240 mmol) was added dropwise at 0°C and stirred at room température for 16 h. The reaction mixture was quenched with water and exlracted twice with DCM. The organic layer was washed with brine solution, dried over anhydrous NaaSO* and concentrated to give 11.0 g of the desired product. ’HNMR (400 MHz. DMSO-d6): δ 0.86 (s, 6H). 3.18 (s, 6H), 4.00 (s, 4H).

Stcp-2: 1,3-Diiodo-2,2-dimcthylpropanc

To a stirred solution of 2.2-dimethylpropane-l,3-diyldimethanesulfonate (2.0 g. 7.69 mmol) in DMF (20 mL) was added Kl (5.1 g, 30.7 mmol) portion wise at 0°C and sliiTed at 120°C for 16 h. The reaction mixture was cooled to room température and quenched with water and extracted twice with pctrolcum cthcr. The organic layer was washed with brine solution, dried over anhydrous Na2SÜ4 and concentrated to give 2.1 g of the desired product. 'HNMR (400 MHz, CDCh): δ 1.26 (s, 6H), 3.28 (s, 4H).

Stcn-3: 1 -(3-Bromophcnyl)-3„3-dimcthylcyclobutanc-1 -carbonitrilc

To a stirred suspension of NaH (60% suspension in minerai oil) (734 mg, 15.3 mmol) in DMF (15 mL) was added dropwise solution of 3-bromophenylacetonitrile (1.0 g, 5.10 mmol) and 1.3diiodo-2,2-dimcthylpropanc (2.1 g, 6.63 mmol) in DMF (5 mL) at 0°C and dropwise addition was continued for Ih. The reaction mixture was stirred at RT for 2 h and then at 80°C for 16 h. The reaction mixture was cooled to 0°C and quenched with ice cold water solution. The aqueous layer was extracted twice with pctrolcum cthcr. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The residue obtained was purified by silica gel column chromatography to yield 700 mg of the desired product. *HNMR (400 MHz. CDCh): δ 1.16 (s, 3H), 1.50 (s, 3H), 2.47 (d, J= 13.2 Hz, 2H), 2.74 (d, J=12.4 Hz. 2H), 7.26 - 7.28 (m. 1 H), 7.33 - 7.35 (m, 1H), 7.45-7.47 (m, 1H), 7.54 (s, 1H).

Step-4: l-(3-Bromophenyl)-3.3-dimethylcyclobutane-l-carboxylic acid

To a stirred solution of l-(3-bromophenyI)-3,3-dimethylcyclobutane-l-carbonitrile (700 mg, 2.66 mmol), in 4.2 mL of AcOH/HiO (1:1) was added conc. H2SO4 (2.1 mL) dropwise at 0° C and stirred at 0° C for 15 min and heated to 120 C for 16 h. The reaction mixture was cooled to room température, quenched with water and extractcd twice with cthyl acétate. The organic layer was washed with brine solution, dried over anhydrous Na2SÛ4 and concentrated to give 700 mg of the desired product. ’HNMR (400 MHz, DMSO-d6): 5 0.97 (s, 3H), 1.12 (s, 3H), 2.25 (d, 2=12.8 Hz, 2H), 2.63 (d, 2=12.8 Hz, 2H), 7.26-7.33 (m. 2H), 7.39-7.45 (m, 2H), 12.50 (brs, 1H), ESI-MS (m/z) 281.1(M-H)⁺

Stcp-5: 2-(l-(3-Bromophcnyl)-3,3-dimcthylcyclobutane-l-carbonyl)-N-mcthylhydrazine-lcarbothioamide

To a stirred solution of l-(3-bromophenyl)-3,3-dimethylcyclobulane-l-carboxylic acid (700 mg, 2.47 mmol) in DMF (8.0 mL) was added DIPEA (1.3 mL, 7.42 mmol) and HATU (1.1 g, 2.96 mmol) stirred for 30 min.4 methylthiosemicarbazide (313 mg, 2.96 mmol) was added at 0°C. The reaction mixture was stirred at room température for 16 h. The reaction mixture was quenched with water and extracted twice with EtOAc. The solvent was evaporated under rcduccd pressure and the solid obtained was purified by silica gel column chromatography to yield 820 mg of the desired product. ESI-MS (m/z) 371.1 (M+2H)⁺

Step-6: 5-(l-(3-Bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-2,4-dihydro-3H-l,2,4triazole-3 - thione

To a stirred solution of 2-(l-(3-bromophenyl)-3,3-dimethylcyclobutane-l-carbonyl)-Nmethylhydrazine-1-carbothioamide (820 mg. 2.21 mmol) in IN NaOH (8.0 mL) was stirred al room température for 16 h. The reaction mixture was acidificd using 6N HCl and stirred for 2 h. The prccipitatcd solid was filtercd. washed with exccss water and dried under vacuum to yield 760 mg of the desired product. ESI-MS (m/z) 353.1 (M+2H)⁺

Step-7: 3-(l-(3-Bromophenyl)-3,3-dimethylcyclobutyl)-4-methyl-4H-L2,4-triazole

To a stirred solution of 5-(l-(3-bromophcnyl)-3,3-dimcthylcyclobutyl)-4-methyl-2,4-dihydro3H-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 température for 2

h. The reaction mixture was quenched with water and extracted twice with DCM. The solvent was cvaporatcd undcr reduccd pressure and the solid obtaincd was purificd by silica gel column chromatography to yield 628 mg of the desired product. 'HNMR (400 MHz, CDCh): δ 1.03 (s, 3H), 1,09(s, 3H), 2.57 (d, J = 12.8 Hz, 2H), 2.87(d, J = 10.4 Hz, 2H), 3.22 (s, 3H), 7.32-7.35 (m, 3H), 7.42-7.45 (m. 1H), 8.33 (s, 1H); ESI MS (m/z) 321.1 (M+2H)⁺

Step-7: 3-(3,3-Dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)aniline

In a scalcd tube, to a stirred solution of 3-(l-(3-bromophenyl)-3,3-dimcthylcyclobutyl)-4methyl-4H-l,2,4-triazole (628 mg, 1.96 mmol) in ACN (8.0 mL) was added aqueous NHa(4.0 mL), copper(I)oxide (280 mg, 1.96 mmol) and stirred at 100°C for 16 h. The reaction mixture was quenched with water and elhyl acetate, filtered and filtrate obtained was extracted with cthyl acétate. The organic layer was dried over anhydrous sodium sulphatc and solvent was evaporated under reduced pressure and the solid obtained was purified by silica gel column chromatography to yield 410 mg of the desired product. ‘HNMR (400 MHz, DMSO-d6): δ 1.03 (s, 3H), 1.11 (s, 3H), 2.48 (d, J= 12.8 Hz, 2H), 2.80 (d, J = 12.4 Hz, 2H), 3.19 (s, 3H), 5.07 (brs, 2H), 6.38-6.43 (m, 3H), 6.97 (t. J = 7.6 Hz, 1 H), 8.29 (s, 1 H); ES1-MS (m/z) 257.2 (M+H)⁺ The analytical data of the intermediate prepared by following the procedure described above are given in below Table-3.

Table-3: Structure, Name and analytical data of intermediate (A12-A19)

Intermediate No.	Structure	Name and Analytical data
A12	nh, N T Γ H Μέ	5-(3,3-Dimcthyl-l-(4-mcthyl-4H-l,2,4-triazol-3yl)cyclobutyl)-2-fluoroaniline: 'H NMR (400 MHz, DMSO-Jé) δ 1.02 (s, 3H), 1.10 (s, 3H). 2.46 (d, J = 12.4 Hz, 2H), 2.80 (d, 7=12 Hz, 2H), 3.20 (s, 3H), 5.14 (s, 2H), 6.42-6.44 (m, 1H), 6.58 (d, J = 6.4 Hz, 1H), 6.91 (q, J = 11.2 Hz, 1H), 8.30 (s, 1H)
A13	N NH, n YY ï O	3-(3,3-DÎmethyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyl)-5-fluoroanilinc: 'HNMR (400 MHz, DMSO-dâ): δ 1.02 (s, 3H), 1.1 l(s, 3H), 2.46 (d, 7=12.4 Hz, 2H), 2.79 (d, 7=12.4 Hz, 2H), 3.22 (s, 3H), 5.44 (s, 2H), 6.14-6.20 (m, 3H), 8.33 (s, 1H)
A14	N nht '•ÏU'	2-Chloro-5-(3,3-dimethyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)aniline: 'HNMR (400 MHz, DMSO-i/6): δ 1.03 (S, 3H), 1.10 (S, 3H), 2.47 (d, 7

Inlermediate No.	Structure	Naine and Analytical data
		= 12.4 Hz, 2H), 2.82 (d, J = 12.8 Hz, 2H), 3.21 (s, 3H), 5.35 (s, 2H), 6.45 (d, J = 2Hz, 1H), 6.65 (d, J = 2Hz, 1 H), 7.13 (d, 7 = 8.4Hz, 1 H), 8.32 (s, 1H); ESIMS (m/z) 291(M+H)+
Al5	CI X Z O S?	3-(2-(4-Methy I-4H-1,2,4-triazol-3yl)spiro[3.3Jheptan-2-yl)aniline: 'HNMR (400 MHz, DMSO-J6)ô 1.73-1.77 (m, 2H), 1.88-1.97 (m, 4H), 2.16-2.20 (m, 2H), 2.90-2.93 ( m, 2H), 3.18 (s, 3H), 5.05 (s, 2H), 6.33-6.39 (m. 3H), 6.93-6.97 (m, 1H), 8.30 (s, 1H); ESI-MS (m/z) 269.78 (M+H)+
Al6	N XYï V'F	2-Fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3yl)spiro[3.3]heptan-2-yl)aniline: 'HNMR (400 MHz, DMSO-z/6) 1.72-1.77 (m,2H), 1.86-1.95 (m, 4H), 2.61 (d, 7= 11.8 Hz, 2H),2.95 (d,7= 11.8 Hz, 2H), 3.18 (s, 3H), 5.11 (s,2H), 6.38 (s, 1H), 6.52 (d, 7 = 8.2 Hz, 1H). 6.90 (m. 1H), 8.39 (s, 1 H); ESI-MS (m/z) 287 (M+H)+
Al7	n\ q ' f Y NH-	3-(5-(4-Methyl-4H-l,2,4-triazol-3yl)spiro[2.3]hexan-5-yl)aniline: lHNMR (400 MHz, DMSO-d6): δ 0.41-0.45 (m. 2H), 0.50-0.53 (m, 2H), 2.62-2.65 (m, 2H), 3.04-3.07 (m, 2H), 3.18 (s, 3H). 5.08 (brs, 2H), 6.39-6.45 (m, 3H), 6.99 (t, 7 = 8 Hz, 1H), 8.37 (s, 1H); ESI-MS (m/z) 255.2 (M+H)+
Al8	n\ V3 \ / Vnh2	2-Fluoro-5-(5-(4-mcthyi-4H-l ,2,4-triazol-3yl)spiro[2.3]hexan-5-yl)aniline: ’HNMR (400 MHz, DMSO-dô): δ 0.49-0.52(m, 2H), 0.53-0.59 (m. 2H). 2.68-2.71 (m, 2H), 3.18-3.21 (m, 2H), 3.23 (s, 3H), 3.76 (brs, 2H), 6.59-6.62 (m, 1H), 6.68-6.72 (m, 1H), 6.94-7.28 (m. 1H), 8.05 (s, 1H).
A19	nn^V ch, ' / VNH	3-(3,3-Dimethyl-l-(4-methyl-4H-l,2,4-triazol-3- yl)cyclobulyl)-N-melhylaniline: [HNMR (400 MHz. DMSO-A) δ 1.03 (s, 3H), 1.11 (s, 3H), 2.20-

Intermediate No.	Structure	Name and Analytical data
		2.30 (m, 2H), 2.60 (d, J = 4.9 Hz, 3H), 2.80-2.83 (m, 2H), 3.20 (s, 3H), 5.66 (q, 7 = 4.9 Hz. 1H), 6.32-6.37 (m, 2H), 6.44 (d, 7=8 Hz, 1H), 7.05 (t, 7=8.2 Hz, 1H), 8.30 (s, 1H); ES1-MS (m/z) 271.3 (M+H)+

Intermediate A20

3-(3,3-Difluoro-1 -(4-methyl-4H-1,2,4-triazol-3-y l)cyclobutyl)aniline

Step-l : l -(3-Bromophenyl)-3,3-dimethoxycyclobutane-l-carbonitrile

-O o-

To a stirred suspension of NaH (60% suspension in minerai oil) (2.56g, 63.77 mmol) in DMF (50 mL) was addcd dropwisc solution of 3-bromophcnylacctonitrilc (5.0 g, 25.51 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30min, followed by slow addition of 1,3-dibromo2,2-Dimethox y-propane (5.32 g, 20.40 mmol). The reaction mixture was stirred at room température for 2 h and at 60°C for 48 h. The reaction mixture was cooled to 0°C and quenched with water. The aqueous layer was extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous Na₂SO4 and concentrated. The residue obtained was purified by silica gel column chromatography to yicld 2.4 g of the desired product. 'HNMR (400 MHz, DMSO-d6): δ 2.72 (d. 7=13.6 Hz. 2H), 3.12(d, J= 13.6Hz. 2H), 3.20(s, 3H), 3.30 (s, 3H), 7.297.31 (m. 1H). 7.42-7.44 (m. 1H), 7.48-7.50(m.lH), 7.64(s, 1H)

Step-2: 1 -(3-Bromophcnyl)-3-oxocyclobutanc-1 -carbonitrilc

O

To a stirred solution of l-(3-bromophenyl)-3,3-dimethoxycyclobutane-l-carbonitrile (0.96 g, 3.20 mmol), in 80 mL of acétone was addcd PTSA at room température for 48h. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na₂SO4 and concentrated and purified to give 400mg of the desired product. 'HNMR (400 MHz. DMSO-d6): δ 3.9-3.75 (m, 2H), 4.06-4.11 (m, 2H), 7.36 (t, 7=7.6 Hz. IH), 7.45 (d, J= 8.0Hz. 1H), 7.56 (d, J= 8.0Hz, IH), 7.66 (s, 1H).

Step-3: 1 -(3-Bromophenyl)- 3,3 -difluorocyclobu tane-1 -carbonitrile

F F

To a stirred solution of l-(3-broinophenyl)-3-oxocyclobutane-l-carbonitrile (0.95g. 3.8 mmol) in DCM (20 mL) was added DAST (2.45g, L5.2mmo1) at 0°C and stirred at room température for 18 h. The reaction was quenched with saturated NaHCCh and extracted with ethyl acetate. The organic layer was washed with water, brine solution and dried over anhydrous Na2SO4. The solvent was evaporated and purified to obtain 760mg of the desired product. 'HNMR (400 MHz, DMSO-d6): δ 3.17-3.27 (m, 2H), 3.49-3.57 (m, 2H), 7.35 (t, 7=7.6 Hz, IH), 7.42 (d. 7= 7.6 Hz, IH), 7.55 (d, 7= 7.6 Hz, IH), 7.62 (s, IH).

Step-4: l-(3-Bromophenyl)-3,3-difluorocyclobutane-l-carboxylic acid

F F

HOBr O XJ

To a stirred solution of l-(3-bromophenyl)-3,3-difluorocyclobutane-l-carbonitrile (2.0 g, 7.35 mmol) in acetic acid (4.0 ml) and water (4.0ml) was added conc H2SO4 (4.0 mL) at 0°C. The reaction mixture was warmed to room température and heated to 120°C for 16 h. The mixture was cooled to room température and diluted with water. Precipitated solid was filtered dried well to yield 1.9 g of the desired product. 'HNMR (400 MHz, DMSO-d6): δ 3.08-3.18 (m, 2H), 3.30-3.40 (m, 2H), 7.36 (t, 7=4.4 Hz. 2H), 7.52 (d, J= 6.4 Hz. IH), 7.54(s, IH), 13.01-13.16 (brs, IH). ESI-MS (m/z) 291 (M)⁺

Step-5: 2-(l-(3-Bromophenyl)-3.3-difluorocyclobutane-l-carbonyl)-N-methylhydrazine-lcarbothioamide

F F

S H X 'N^'-X/sX H H J) OJ

To a stirred solution of l-(3-bromophenyl)-3,3-difluorocyclobutane-l-carboxylic acid (120 mg, 0.412 mmol) in DMF (3.0 mL) was added N-methylhydrazinecarbothioamide (48mg. 0.453 mmol). To this réaction mixture EDCI.HC1 (118mg, 0.618mmol), triethylaminc (54mg, 0.536mmol) and HOBt (72mg, 0.536mmol) was added. The reaction mixture was stirred at room température for 18h. The mixture was quenched by adding water, aq. Layer was extracted with ethyl acetate. Organic layer was separated, concentrated to yield l40mg desired product. ES1-MS (m/z) 378.0 (M+H)⁺

Stepô: 5-(l-(3-Bromophenyl)-3,3-difluorocyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4triazole-3-lhione

JL F ' O“^Br

To a stirred solution of 2-(l-(3-bromophenyl)-3.3-difluorocyclobutane-l-carbonyl)-Nmethylhydrazine-l-carbolhioamide (2.9 g. 7.67 mmol) in IN NaOH (100 mL) was stirred al room température for 16 h. The réaction mixture was acidified using 2N HCl and stirred for 15 min. The precipitated solid was filtered, washed with excess water and dried under vacuum to yield 2.1 g of the desired product. ^NMR (400 MHz, DMSO-d6): δ 3.04 (s, 3H), 3,38-3.47 (m, 2H), 3.58-3.68 (m, 2H), 7.33-7.40 (m, 2H), 7.55-7.59 (m, 2H), 13.86 (brs, 1H); ESI-MS (m/z) 360 (M+H)⁺

Step-7: 3-(l-(3-Bromophenyl)-3,3-difhiorocyclobutyl)-4-methyl-4H-l,2,4-triazole

To a stirred solution of 5-(l-(3-bromophenyl)-3,3-difluorocyclobulyl)-4-melhyl-2,4-dihydro3H-1,2,4-triazole-3-thione (65mg, 0.18 mmol) in DCM (1.0 mL) and AcOH (0.144ml) was added 30% H₃O₂ (0.045ml) solution at 0°C. The mixture was stirred at room température for 16 h. The reaction mixture was quenched with water and extracted twice with DCM. The solvent was evaporated under reduced pressure and the solid obtained was purified by silica gel column chromatography to yield 43 mg of the desired product. ’HNMR (400 MHz, CDCh): δ 3.27 (s, 3H), 3.29-3.36(m, 2H), 3.68-3.78(m. 2H). 7.20(d, J= 7.6Hz, 1H), 7.26(d, J= 8.0Hz. 1H), 7.43 (s, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 8.09 (s, 1 H); ESI MS (m/z) 328 (M+H)⁺

Sten-8: 3-(3,3-Difluoro-l-(4-methyl-4H-L2,4-triazol-3-yl)cyclobutyl)aniline

In a sealed tube, to a stirred solution of 3-(l-(3-bromophenyl)-3,3-difluorocyclobutyl)-4methyl-4H-l,2,4-triazole (300 mg, 0. 914 mmol) in ACN (3.0mL) was added aqueous NH₃(3.O mL), coppcr oxide (52 mg, 0.365 mmol) and stirred at 90°C for 16 h. The réaction mixture was extracted thrice with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated under vacuum to give 280 mg of the desired product. *HNMR (400 MHz, DMSO-d6): δ 3.24 (s, 3H), 3.24-3.27 (m, 2H), 3.58-3.68 (m, 2H),5.16 (s, 2H), 6.37 (s, 1H), 6.56(d, J=7.6Hz,2H), 7.01 (t, J = 8.0 Hz, 1H), 8.40 (brs. 1H); ESI-MS (m/z) 265 (M+H)

Intermediate A21

3-(Cyclobutyl(4-methyl-4H-l,2,4-triazol-3-yl)methyl)aniline

Step-1: Methyl 2-(3-bromophenyl)acetate

To a stirred solution of 3-bromophenyl acelic acid (17 g) in methanol (300 niL) was dropwise added conc. H2SO4 (10 mL) and heated to 110°C for 18 h. The reaction mixture was concentratcd undcr rcduccd pressure. The rcsiduc obtaincd was diluted with water and cxtractcd thrice with ethyl acetate. The organic layer was washed with sat, NaHCCh solution and separated. dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purified with chromatography to get 9.3 g of the desired product as pale yellow oil. ‘HNMR (400 MHz. CDC13) δ 3.62 (s, 2H), 3.72 (s, 3H), 7.19-7.28 (m. 2H), 7.417.44 (m, 1H), 7.43 (s, 1H); ESI-MS (m/z) 229.07 (M+H)⁺

Step-2: Methyl 2-(3-bromophenyl)-2-cyclobutylacelate

To a stirred solution of methyl 2-(3-bromophenyl)acetate (2 g, 8.77 mmol) in DMF (15 mL) was dropwise added potassium tert-buloxide solution (11.34 ml, 11.34 mmol) at 0°C. A solution of bromocyclobutane (1.41 g, 10.48 mmol) in DMF (5 ml) was dropwise added and stirred at room température for 18 h. The reaction mixture was quenched with sat NH4CI solution and extracted twice with ethyl acetate. Then organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purified with chromatography to get 1.21 g of the desired product as pale yellow oil. ^]HNMR (400 MHz, CDCh)ô 1.611-1.63(m, 1H), 1.82-1.88(m, 4 H), 2.18-2.21( m, 1H), 2.93-2.95( m. lH).3.52(d, J=11.2 Hz, 1 H), 3.95 (s, 3H), 7.17(m, 2H), 7.38-7.41 (m, 1 H), 7.45 (s, 1 H); ESI-MS (m/z) 283.03 (M+H)⁺

Step-3: 2-(3-Bromophenyl)-2-cyclobutylacelohydrazide

To a stirred solution of mcthyl 2-(3-bromophcnyl)-2-cyclobutylacctatc (1.1 g) in éthanol (10 mL) was added hydrazine hydrate (3 mL) and heated to 90°C for 18 h. The reaction mixture was evaporated completely and diluted with water. The mixture was extracted twice with ethyl acétate. The organic layer was dried over anhydrous sodium sulphatc and conccntrated under reduced pressure to yield 1.05 g of the desired product. ’HNMR (400 MHz, DMSO-dô) δ 1.481.50 (m, 1H), 1.72-1.79 (m, 4H), 1.98-2.00 ( m, 1H), 2.92-2.94 ( m, 1H), 3.18 (d. J=9.6 Hz, 1H),4.22( brs, 2H), 7.23-7.29 (m. 2H).7.39-7.42 (m, 1H), 7.50(s,lH), 9.22(s, 1H); ESI-MS (m/z) 283.1 (M+H)⁺

Step-4: 2-(2-(3-Bromophcnyl)-2-cyclobutylacctyl)-N-mcthylhydrazinc-1 -carbothioamidc

S H Y ^{H H} o LJI

To a stirred solution of 2-(3-Bromophenyl)-2-cyclobutylacetohydrazidc (1.0 g, 3.53 mmol) in THF (10 mL) was added dropwise methyl isothiocyanate (776 mg. 10.65 mmol) and heated to 90°C for 4 h. The mixture was concentrated under reduced pressure and the residue obtained was triturated with pentane. The solid obtained was filtered and dried under vacuum to yield 1.1 g of the desired product.¹ H NMR (400 MHz, DMSO-Æ) δ 1.53-1.57(m, 1H), 1.76-1.80 (m, 3H), 1.91-1.98( m, 2H), 2.78-2.81(m, 1H), 2.85 ( s, 3H), 3.47( d. 7=9.6 Hz, 1 H),7.25-7.32 (m, 2H), 7.43( d, 7=7.6 Hz. 1H), 7.52(s,lH), 7.60(bs,lH), 9.26(s, 1H), 9.90(s, 1H), ESI-MS (m/z) 356.1 (M+H)⁺

Step-5: 5-((3-Bromophenyl)(cyclobulyl)methyl)-4-melhyl-2,4-dihydro-3H-1.2,4-triazole-3thione

To a stirred solution of 2-(2-(3-Bromophenyl)-2-cyclobutylacetyl)-N-methylhydrazine-lcarbothioamide (1.1 g) in IN NaOH (40 mL) was stirred at room température for 16 h. The reaction mixture was acidified using 2N HCL and stirred for 15 min. The precipitated solid was filtered. washed with excess water and dried under vacuum to yield 1.05 g of the desired product. Ή NMR (400 MHz, DMSO-Jô) δ 1.68-75 (m, 5H), 2.07-2.09 ( m, 1H), 2.94-2.96 (m.

IH), 3.20 (s, 3H), 4.25 (d, 7=10.8 Hz. 1H), 7.23 (d, J=7.6 Hz. 1H), 7.31 (t, 7=8 Hz, 1H), 7.457.49 (m,2H), 13.71 (s, 1H); ESI-MS (m/z) 338.0 (M+H)⁺

Step-6: 3-((3-Bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-l,2,4-triazole \ M-Br

To a stirred solution of 25-((3-bromophcnyl)(cyclobutyl)mcthyl)-4-mcthyl-2,4-dihydro-3Hl,2,4-trîazole-3-thione (1.6 g, 4.74 mmol) in DCM (30 ml) was added acetic acid (3.8 ml, 66.26 mmol) at 0°C and stirred the reaction mixture for 10 min, to thaï réaction mixture, 30% solution of H2O2 (1.2 ml, 11.84 mmol) was added and stirred at 0°C for 2 h. The reaction mixture was diluted with DCM and washed with water, and sat NaHCOs solution. Then organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The obtained product was stirred in diethyl ether, filtered and dried to obtain 607 mg of the desired product. ‘HNMR (400 MHz, DMSO-î/₆) δ 1.63-78 (m, 5H), 2.03-2.05( m, 1H), 3.06-3.10 ( m. 1H), 3.39 (s, 3H), 4.22 (d. 7=10.4 Hz, 1H),7.27-7.28 (m, 2H), 7.41-7.44 (m, 2H), 8.34 (s. 1 H); ESI-MS (m/z) 306.0 (M+H)⁺

Step-7: 3-(Cyclobutyl(4-me(hyl-4H-l,2,4-triazol-3-yl)methyI)aniline

N N lt J

In a scalcd tube, to a stirred solution of 3-((3-Bromophcnyl)(cyclobutyl)mcthyl)-4-mcthyl-4H1,2.4-triazole (500 mg, 1.63 mmol) in NMP (5 mL) were added aq. NHs (5 mL), Copper (I) oxide (70 mg 0.49 mmol) and stirred at 100°C for 16 h. The réaction mixture was diluted with ethyl acetate and filtered. The organic layer was separated out and dried over anhydrous sodium sulphate and concentrated under reduced pressure up to dryness. The residue obtained was triturated with diethyl ether to give 373 mg of the desired product. ^]H NMR (400 MHz, DMSOd₆) δ 1.61-65 (m, 1H), 1.75-1.77 ( m, 4 H), 2.07-2.15( m, 1H), 3.08-3.10 ( m, lH),3.35(s, 3H), 3.92( d, J=10.4 Hz, 1H), 5.01( bs,2H), 6.32-3.39(m , 3H), 6.91(t. J=8 Hz, 1H), 8.32 (s, 1H); ESI-MS (m/z) 243.3 (M+H)⁺

The analytical data of the intermediate prepared by following the procedure described above are given in below Table-4.

Table-4: Structure. Name and analytical data of intermediate (A22)

Intennediate No.	Structure	Name and Analytical data
A22	\ / Vnh2	5-(Cyclobutyl(4-mcthyl-4H-l,2,4-triazol-3yl)methyl)-2-fluoroaniline: 'HNMR (400 MHz, DMSO-dâ) δ 1.63-65 (m, 1H), 1.75-1.82 (m, 4H), 2.05-2.06 (m, 1H), 3.05-3.08 (m, 1H), 3.36 (s, 3H), 3.97 (d, 7=10.4 Hz, 1H), 5,09 (brs, 2H), 6.38 (s, 1H), 6.53 (d, 7=8.4 Hz, 1H), 6.86-6.90 (m. 1H), 8.32 (s, IH); ESI-MS (m/z) 261.2 (M+H)+

Intennediate A23

3-((ls,3s)-3-Methyl-l-(5-methyl-l-trityl-lH-imidazol-4-yl)cyclobutyl)aniline

Step-1: ( 1 s,3s)-1 -(3-Bromophenyl)-N-methoxy-N,3-dimethylcyclobutane-1 -carboxamide

To a stirred solution of (ls,3s)-l-(3-bromophenyl)-3-methylcyclobutane-l-carboxylic acid (4.0 g, 14.86 mmol) in DCM (40 ml) was added CDI (4.81 g, 29.72 mmol) portion wise followed by ΑΓΒΝ (2.0 g, 12.33 mmol). The reaction mixture was stirred at room température for Ih. The N,O-Dimethylhydroxylamine / was added and stirred at room température for 16 h. The reaction mixture was quenched with water (50 ml) and extracted with DCM (3 x 100 ml). The organic layer dried over anhydrous NasSCh and evaporated under rcduccd pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 3.1 g of the tille compound. 'HNMR (DMSO-rfc, 400 MHz) δ 1.09 (d. J = 5.2 Hz, 3H), 2.36-2.34 (m. 3H), 2.54-2.52 (m, 2H), 3.11 (s, 6H), 7.23 (t, 7 = 7.6 Hz, 1H), 7.35 (d, 7 = 8.0 Hz, 1H), 7.39 (d, 7= 7.6 Hz, lH),7.58(s, 1H).

Sten-2: 1 -((1 s,3s)-1 -(3-Bromophenyl)-3-methylcyclobutyl)propan-1 -one

To a stirred solution of (15,3î)-l-(3-bromophcnyl)-N-mcthoxy-N,3-dimcthyl cyclobutanc-1carboxamide (3.0 g, 9.61 mmol) in dry THF (30 ml) at 0°C was added ethyl magnésium bromide (6.4 g, 48.05 mmol). The reaction mixture was stirred at room température for 16 h. The reaction mixture was qucnchcd with NH4CI solution (50 ml) and extractcd with DCM (3 x 100 ml). The organic layer dried over anhydrous Na₂SO4, evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromalography to afford 2.0 gm of the title compound. ‘HNMR ( DMSO-Je. 400 MHz) δ 1.09 (d. J = 5.2 Hz, 3H), 2.24-2.19 (q, J = 7.2 Hz, 2H), 2.21 (t, J = 7.2 Hz, 3H), 2.40-2.36 (m, 3H), 2.58-2.54 (m, 2H), 7.27-7.23 (m, 2H), 7.50-7.39 (m, 1H), 7.51 (s, 1H); ESI-MS (m/z) 280 [M-H]⁺.

Step-3: l-((ls.3s)-l-(3-Bromophenyî)-3-methylcyclobulyl)-2-hydroxypropan-l-one

To a stirred solution of 1-((15,3.s)-l-(3-bromophenyl)-3-methylcyclobulyl)propan-l-one (2.0 g, 7.09 mmol) in dry THF (30 ml) at -78°C was added NaHMDS (1.95 g, 10.64 mmol, 1.0 M in THF). Aftcr 15 min, a solution of (R)-3-mcthyl-3-phcnyl-2-(phcnylsulfonyl)-l,2-oxaziridinc (2.78 g, 10.64 mmol) was added al -78°C and the reaction mixture was stirred at room température for 3 h. The reaction mixture was quenched with NH4CI solution (50 ml) and extractcd with EtOAc (3 x 100 ml). The organic layer dried over anhydrous Na₂SO₂, evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 1.4 g of the titie compound. 'HNMR (DMSO-dû, 400 MHz) δ 1.051.09 (m. 6H), 2.29-2.24 (m, 1 H), 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, lH),7.52(s, 1H).

Step-4: l-((ls,3s)-l-(3-Bromophenyl)-3-methylcyclobutyl)propane-l,2-dione

To a stirred solution of l-(( ls,3s)-l-(3-bromophcnyl)-3-mcthylcyclobutyl)-2-hydroxypropan1-one (1.4 g, 4.71 mmol) in dry DCM (30 ml) at 0 °C was added DMP (3.99 g, 9.42mmol) portion wise. The reaction mixture was stirred at room température for 16 h. The reaction mixture was quenched with sat. NaHCOs solution and extractcd thricc with DCM. The organic layer dried over anhydrous Na₂SO4, evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 1.1 g of the tille compound. 'HNMR (DMSO-Jô, 400 MHz) δ 1.07 (d, J = 6 Hz, 3H), 2.18 (s, 3H), 2.39-2.42 (m, 3H), 2.70-2.71 (m. 2H), 7.23 (1,7 = 7.6 Hz, 1H), 7.29 (d. 7=8.0 Hz. 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.52(s, 1H).

Step-5: 4-((ls,3s)-l-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-lH-imidazole

To a stirred solution of l-((ls,3s)-l-(3-bromophenyl)-3-methylcyclobulyl)propane-l,2-dione (l.l g, 3.72 mmol) in MeOH was added paraformaldéhyde (0.12 g, 4.09 rnmol) followed by ammonium acetate (2.87 g, 37.26 mmol). The reaction mixture was heated at 80 °C in a sealed tube for 16 h. The reaction mixture was concentrated and the product obtained was purified by combiflash chromatography to afford 1.0 g of the title compound. ^]HNMR (DMSO-dô, 400 MHz) δ 7.56 (s, 1H), 7.30-7.36 (m. 2H), 7.28 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 5.01 (brs. 1H). 2.81-2.83 (m, 2H). 2.38-2.44 (m, 3H), 2.04 (s, 3H), 1.11 (d. J = 5.6 Hz, 3H); ESI-MS (m/z) 305.1 [M+H] ⁺

Stcp-6: 4-((ls,3s)-l-(3-Bromophcnyl)-3-mcthylcyclobutyl)-5-mcthyl-l-trityl-lH-imidazole

To a stirred solution of 4-((ls,3s)-l-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-lHimidazolc (1.0 g, 3.27 mmol) in dry DCM (30 ml) at 0°C was added triethylaminc (0.31 g, 3.06 mmol) followed by trityl chloride (0.4 g, 1.46 mmol) portion wise. The reaction mixture was stirred al room température for 16 h. The réaction mixture was concentrated and the obtained product was purified by combiflash chromatography to afford 1.3 g of the title compound. ESIMS (m/z) 547.3 [M+H]⁺

Step-7: N-(3-((ls,3s)-3-melhyl-l-(5-methyM-trilyl-lH-imidazol-4-yl)cyclobutyl)phenyl)-

1,1 -diphcnylmcthaniminc

To a stirred solution of 4-((ls,3s)-l-(3-bromophenyl)-3-methylcyclobutyl)-5-methyl-l-tritylIH-imidazole (1.2 g. 2.19 mmol) in dry dioxane (30 ml) was added benzophenoneimine (1.58 g. 8.76 mmol), Xantphos (0.25 g, 0.438 mmol) and ccsium carbonate (1.78 g, 5.47 mmol). The réaction mixture was degassed for 15 min using nitrogen gas. Palladium acétate (0.049 g,

0.2Immol) was added and réaction mixture was heated at 80 °C in a sealed tube for I6h. The reaction mixture was dilutcd with EtOAc and filtcrcd. The filtrate was concentrated and the crude compound was purified by combiflash chromatography to afford 1.1 g of the title compound. ESI-MS (m/z) 648.4 [M+HJ⁺

Step-8: 3-((ls,3s)-3-Methyl-l-(5-methyl-1-trityl- lH-imidazol-4-yl)cyclobutyl)aniline

To a stirred solution of N-(3-(( ls.3s)-3-methyl-l-(5-melhyl-1-trilyl-l H-imidazol-4yl)cyclobutyl)phenyl)-l,l-diphenylmethanimine (1.1 g, 1.69 mmol) in MeOH (30 ml) was added hydroxylamine hydrochloride (0.35 g. 5.09 mmol). The réaction mixture was stirred at room température for 16 h. The réaction mixture was concentrated and the crude compound was partitioned between EtOAc (3 x 100 ml) and sat. NaHCOs (50 ml). The EtOAc layer was separated, dried over anhydrous Na₂SO4 and evaporated under reduced pressure to obtain product. The obtained product was purified by combiflash chromatography to afford 0.6 g of the title compound. ESI-MS (m/z) 484.3 [M+H]⁺

The analytical data of the intermediate prepared by following the procedure described above are given in below Table-5.

Table-5: Structure, Name and analytical data of intermediate (A24)

Intermediate No.	Structure	Name and Analytical data
A24	Ph «/O	3-(3,3-Dimethyl-l-(5-methyl-l-trityl-lH-imidazol- 4-yl)cyclobutyl)anilinc: ESI-MS (m/z) 498 (M+H) +

Intermediate A25

3-(3-Methyl-1 -(5-methyl-1 -(tetrahydro-2H-pyran-2-yl)- 1H-1,2,3-triazol-4yl)cyclobulyl)aniline

NH,

Step-1: 1 -( 3 -Bromophe ny 1 )-3 - methylcyclobutane-1 -carbaldeh yde

OHC

Br

To a stirred solution of l-(3-bromophenyl)-3-methylcyclobulane-l-carbonilrile (5.0 g, 0.02 mol) in DCM (50 ml) was added DIBAL (47 ml, 0.04 mol) at -78°C. The réaction mixture was stirred at -78°C for 4 h. The reaction mixture was quenched with saturated solution of ammonium chloride, filtered and washed with ethyl acetate. The filtrate obtained was cvaporatcd under reduced pressure togive 3.8 gof desired product. ESI-MS (m/z) 254 (M+2H)⁺ Step-2: 4-(l-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-lH-l,2,3-triazole

To a stirred solution of l-(3-bromophenyl)-3-methylcyclobutane-l-carbaldehyde (3.8 g, 0.0150 mol) in dry DMSO (10 mL) was added nitrœthanc (1.61 ml, 0.0225 mol), sodium azidc (1.17 g, 0.018 mol) and stirred at room température for 5 min, and then aluminium chloride (0.2 g, 5 0.0015 mol) was added. The réaction mixture was stirred for 10 min and hcated at 70°C for 18

h. The réaction mixture was cooled to room température, quenched with icc water and extracted thrice with DCM. The organic layer was dried over anhydrous Na^SCL. evaporated under reduced pressure to obtain desired product which was purilïed by flash chromatography to give 2.3 g of desired product. ESI-MS (m/z) 306 [M+HJ⁺

Step-3: 4-(l-(3-Bromophenyl)-3-methylcyclobutyl)-5-methyl-l-(tetrahydro-2H-pyran-2-yl)lH-l,2,3-triazole

To a stirred solution of 5-(l-(3-bromophcnyl)-3-mcthylcyclobutyl)-4-mcthyl-l H-l,2,3-triazolc (2.3 g. 7.516 mmol) in THF (30 ml) were added 2,3 dihydropyran (1.36 ml, 15.03 mmol) and 15 trifluoroacetic acid (0.172 ml. 2.25 mmol). The reaction was stirred at room température for ovemight. The reaction mass was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, evapoprated under reduced pressure. The obtained product was purified with flash chromatography to obtain 2.5 g of desired product as ycllow oil. ESI-MS (m/z) 390 |M+HJ⁺

Step-5: 3-(3-Methyl-1 -(5-methyl-1 (tetrahydro-2H-pyran-2-yl)-1 H-1,2.3-triazol-4yl)cyclobulyl)aniline

To a stirred solution of 4-(l-(3-bromophcnyl)-3-methylcyclohutyl)-5-mcthyl-L(tctrahydro2H-pyran-2-yl)-lH-1.2,3-triazole (2.0 g, 5.12 mmol) in acetonitrile (15 mL) was added aq. ammonia (15 mL), copper oxide (1.46 g. 10.24 mmol) and stirred at 110°C for ovemight in a 25 sealed tube. The reaction mixture was cooled to room température and extracted with ethyl acétate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to obtain 0.8 g of desired product as yellow oil. ESI-MS (m/z) 327 [M+l]⁺

The analytical data of the intermediate prepared by following the procedure described above are given in below Table-6.

Table-6: Structure, Name and analytical data of intermediate (A26)

Intermediate No.	Structure	Name and Analytical data
A26	Ph Ph-j-N \ H Ύ vif N '	3-(3,3-Dimcthyl-l -(5-mcthyl-1 -trityl-1 H-l .2,3triazol-4-yl)cyclobutyl) aniline: ESI-MS (m/z) 499 (M+H) +

The mentioned below intermediates were synthesized by following the procedure described above for intermediate Al 1 and the analytical data are given in below Table-7. Table-7: Structure, Name and analytical data of intermediate (A27-A3O)

Intermediate No.	Structure	Name and Analytical data
A27	i ZVnh,	5-(3,3-Dicthyl-1 -(4-mcthyl-4H-1,2,4-triazol-3yl)cyclobutyl)-2-fIuoroaniline: *HNMR (400 MHz, DMSO-Æ) δ 0.65-0.72 (m, 6H), 1.30-1.44 (m, 4H), 2.36 (d, J = 12.9 Hz, 2H), 2.73 (d, J = 12.9 Hz, 2H), 3.19 (s, 3H), 5.12 (s, 2H), 6.41-6.45 (m. 1H), 6.566.59 (m, 1H), 6.88-6.93 (m, 1H), 8.29 (s, 1H)
A28	' ΖΆ-νη2	5-(6,6-Dimethyl-2-(4-methyl-4H-l,2,4-triazol-3yl)spiro[3.3]heptan-2-yl)-2-fluoroaniline: ’HNMR (400 MHz. DMSO-é?6) δ 1.02 (s, 6H), 1.75 (s, 2H), 1.82 (s, 2H), 2.62-2.64 (m, 2H), 2.95-2.98 (m. 2H). 3,18 (s, 3H), 5.10(brs, 2H), 6.35-6.37 (Μ, 1H), 6.516.53 (m, 1 H), 6.87-6.92 (m, 1 H), 8.50 (brs, 1H); ESIMS (m/z) 315.3 (M+H)+
A29	Nn rP ILî/~V_ » ΛΛ-νη,	3-(6-Methyl-2-(4-methyl-4H-1,2,4-triazol-3yl)spiro[3.3]heptan-2-yl)aniline: *HNMR (400 MHz, DMSO-dé): δ 0.97 (d. J= 6.32 Hz. 3H), 1.481.60 (m, 2H), 1.88-2.01 (m, 1H), 2.11-2.19 (m, 2H), 2.55-2.69 (m, 2H), 2.87-2.89 (m, 1H), 2.97-3.00 (m, 1H), 3.17 (s, 3H), 5.04 (brs, 2H), 6.33-6.38 (m, 3H), 6.93-6.96(m, 1H). 8.30 (s, 1H); ESI-MS (m/z) 283.3 (M+H)+

Intermediate No.	Structure	Name and Analyticai data
A30	N * Q ' ΖΆ_νη2	2-F1uoro-5-(6-mcthyl-2-(4-mcthyl-4H-l,2,4-triazol3-yl)spiro[3.3]heptan-2-yl)aniline: ESI-MS (m/z) 301.23 (M+H)+

Intermediate B1

Melhyl 5-bromo-1 -(cyclopropylmelhyl)-2-oxo-1,2-dihydropyridine-3-carboxylate o ^oAn^Br (F N

Step-1: Methyl 5-bromo-2-oxo-l,2-dihydropyridine-3-carboxylate

O

To a stirred solution of 5-Bromo-2-hydroxy nicotinic acid (5.0 g, 35.94 mmol) in dry methanol (100 mL) was added conc. H2SO4 (1 mL) and relluxed for 18 h. The reaction mixture was cooicd to room température and concentratcd under rcduccd pressure. The obtaincd rcsiduc was basified with saturated sodium bicarbonate solution and stirred for 30 min. The solid obtained was filtered and dried under vacuum to give 4.2 g of the desired product. 'HNMR (400 MHz, DMSO-dû) δ 3.75 (s, 3H), 7.99 (d, J= 2.8 Hz), 8.08 (d, J = 2.8 Hz, 1H). 12.41 (brs, 1H); ES1MS (m/z) 233 (M+2H)⁺.

Stcp-2: Methyl 5-bromo-1 -(cyclopropylmethyl)-2-oxo-1,2-dihydropyridinc-3-carboxylate

To a stirred solution of methyl 5-bromo-2-oxo-l,2-dihydropyridine-3-carboxylate (250 mg, 1.077 mmol) in DMF (5 mL) was added potassium carbonate (223 mg, 1.616 mmol) and stirred at room température for 30 min. To this mixture was added cyclopropyl methyl bromidc (157 pL, 1.616 mmol) and heated to 70°C for ovemight. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentratcd. The obtained residue was purified by silica gel chromatography to yield 126 mg of the desired compound. 'H NMR (400 MHz, DMSO-ife) δ 0.35- 0.45 (m, 2H), 0.45- 0.55 (m, 2H), 1.18-1.35 (m, 1 H), 3.75 (s, 3H), 3.77 (d, J = 9.6 Hz. 2H), 8.058 (d, J = 2.8 Hz, 1 H), 8.38 (d, J = 2.8 Hz. 1 H); ESI-MS (m/z) 287 (M+2H)*

The analyticai data of the intermediate prepared by following the procedure described above arc given in below Tablc-8.

Table-8: Structure, Name and analytical data of intermediates (B2-B4)

Intermediate No.	Structure	Name and Analytical data
B2	O O^N ^chf2	Methyl 5-bromo-1-(2,2-difluoroethyl)-2-oxo-1,2dihydropyridine-3-carboxyiate; 1HNMR (400 MHz, DMSO-z/6) δ 3.75 (s, 3H), 4.37 - 4.45 (m, 2H), 6.19 -6.49 (m, 1H), 8.13 (d, J = 2.8 Hz, 1H), 8.32-8.38 (m. 1H); ES1-MS (m/z) 297 (M+2H)+
B3	O ΟΛ FF 1	Methyl 5-bromo- l-(2-cyclopropylcthyl)-2-oxo-1,2dihydropyridinc-3-carboxylatc; 1HNMR (400 MHz, DMSO-d6) δ -0.02-0.003 (m, 2H), 0.35-0.55 (m, 2H), 0.77-0.81 (m, 1H), 1.50-1.56 (m, 2H), 3.74 (s, 3H), 3.99 (t, J = 7.2 Hz, 2H), 8.03 (d, J = 3.2 Hz, 1H), 8.37 (s. 1H); ESI-MS (m/z) 301.6 (M+H)+
B4	O CFN	Methyl 5-bromo-1 -(cyclobutylmethyl)-2-oxo-1,2dihydropyridine-3-carboxylate; 'HNMR (400 MHz, DMSO-î/6) Ô 1.72-1.86 (m, 6H), 2.67-2.71 (m, 1H), 3.74 (s, 3H), 3.95, (d, J = 7.6 Hz, 2H), 8.03 (d, J = 2.8 Hz. 1H), 8.35 (d, J = 3.2 Hz, 1H), ESI-MS (m/z) 300.0 (M+H)+

Intermediate B5

Methyl 5-bromo-2-oxo-l-(2,2,2-trinuorocthyl)-L2-dihydropyridinc-3-carboxylatc

O ^CFj

To a stirred solution of methyl 5-bromo-2-oxo-l,2-dihydropyridinc-3-carboxylatc (5.2 gm, 22.413 mmol) in DMF (80 mL) was added césium carbonate (10.9 g. 33.620 mmol) and stirred for 30 min at room température. To this mixture was addcd 2,2,2-Trifluoro ethyltrifluoromethane sulfate (7.8 g. 33.62 mmol) and heated to 70 ^DC for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was over anhydrous sodium sulphate and concentrated. The obtained residue was purified by silica gel chromatography to yield 2.9 g of the desired compound 'HNMR (400 MHz. DMSOdô) δ

3,77 (s, 3H), 4.875 (q. J= 9.2 Hz, 2H), 8.14 (d,/= 2.4 Hz, 1H), 8.36 (d, / = 2.4 Hz, 1H); ESIMS (m/z) 315 (M+2H)⁺

The analytical data of the intermediate prepared by following the procedure described above are given in below Table-9.

Table-9: Structure. Name and analytical data of intermediate (B6)

Intermediate No.	Structure	Namc and Analytical data
B6	O ^οΛχγΒΓ o^n cf3	Methyl 5-hromo-2-oxo-1 -(3,3,3-trifluoropropyl)l,2-dihydropyridinc-3-carboxylatc; 'HNMR (400 MHz. DMSO-d6) δ 2.72-2.76 (m, 2H), 3.75 (s, 3H), 4.17 (t, J = 14 Hz, 2H), 8.09 (s, 1H), 8.41 (s, 1H), ESI-MS (m/z) 327.9 (M+H)+

Intermediate B7

Methyl 5-bromo-1 -cyclopropyl-2-oxo- l,2-dihydropyridine-3-carboxylate o

A

Step-l: Methyl l-cyclopropy]-2-oxo-l,2-dihydropyridinc-3-carboxylatc

O

N O A

To a stirred solution of methyl 2-oxo-l,2-dihydropyridine-3-carboxylate (4.8 g. 31.16 mmol) in ethylene dichloride (150 mL) were added cyclopropyl boronic acid (5.30 g, 62.33 mmol), CS2CO3 (5.06 g. 15.58 mmol), pyridine (12.32 g, 155.8 mmol) and stirred under oxygen atmosphère for 30 min at room température. To this mixture was added Cu(OAc)î (5.65 g. 31.16 mmol) and stirred for 4 days. The reaction mixture was diluted with DCM and filtered. The filtrate obtained was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 230 mg of the desired product. *HNMR (400 MHz, DMSO-dé) δ 0.83-0.87 (m, 2H), 0.99-1.04 (m, 2H), 3.32-3.38 (m. 1H), 3.73 (s, 3H), 6.26 (t. / = 7.2 Hz. 1H), 7.87 (d, / = 6.8 Hz. 1H), 8.0 (d,/=7.2 Hz. 1H) ESI-MS (m/z) 194.1 (M+H)⁺ Step-2: Methyl 5-bromo-l-cyclopropyl-2-oxo-l ,2-dihydropyridine-3-carboxylate

To a stirred solution of methyl l-cyclopropyl-2-oxo-l,2-dihydropyridinc-3-carboxylate (230 mg, 1.18 mmol) in DCM (10 mL) was added NBS (274 mg, 1.54 mmol) and the mixture was heated at 60°C for 18 h. The mixture was diluted with DCM and washed thnce with water. The organic laycr was scparatcd, dried over anhydrous sodium sulphatc and conccntratcd under reduced pressure to yield 260 mg of the desired product. ’HNMR (400 MHz, DMSO-r/ό) ôl .121.15 (m, 4H), 3.30-3.35 (m, 1H), 3.37 (s, 3H), 6.02 (s, 1H), 8.09 (s,lH); ESI-MS (m/z) 274.2 (M+ 2H)⁺

Intermediate B8

2-Oxo-l-(2,2,2-trifluoroethyl)-5-vinyl·l,2-dihydroρyridine-3-carboxylic acid O πθΛΠΓ* ‘x'Fj

Step-1 : Methyl 2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3-carboxylate O

To a stirred solution of 5-bromo-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxylate (Intermediate B5) (1.5 g, 4.76 mmol) and potassium vinyl trifluoroborate ( 1.91 gm., 14.28 mmol) in a solvent mixture of toluene (50 mL)/water (15 mL) was degassed for 15 min. To this reaction mixture wcrc added K3PO4 (4 g, 19.04 mmol), Pd(dppf)Ch.DCM (390 mg, 0.476 mmol) and heated to 100°C for 5 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separaled, dried over anhydrous sodium sulfate and conccntratcd under vacuum. The obtaincd residuc was purified by silica gel cohimn chromatography to yield 1.09 g of the desired compound 'H NMR (400 MHz, DMSOd₆) δ 3.78 (s,3H),4.90 (q,2 = 9.2 Hz, 2H), 5.22 (d, J= 11.2 Hz, 1H), 5.68 (d, 2= 17.6 Hz, 1H), 6.45- 6.6 (m, 1H), 8.103 (d, J = 2Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H); ESI-MS (m/z) 262.3 (M+H) h

Step-2: 2-Oxo-l-(2,2.2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3-carboxylic acid

To a stirred solution of methyl 2-oxo-l-(2,2,2-trifluorocthyl)-5-vinyl-l ,2-dihydropyridinc-3carboxylate (1 g, 3.831 mmol) in THF/MeOH (40 mL, 1:1) was added aqueous LiOH (481 mg, 11.49 mmol) and stirred at room température for ovemight. The reaction mixture was conccntratcd and the rcsidue obtaincd was diluted with water and acidified using IN HCl. The solid precipitated was filtered and dried to yield 809 mg desired product. ’H NMR (400 MHz, DMSO-dô) δ 5.01 (q, 2 = 9.2 Hz, 2H), 5.28 (d. 2 = 11.2 Hz, 1H), 5.76 (d, 2 = 17.6 Hz, 1 H), 6.5022157

6.70 (m. IH), 8.19 (s, 1H), 8.53 (d. J = 2.4 Hz, 1H), 13.86 (brs, 1H); ESI-MS (m/z) 248.2 (M+H)⁺

The analytical data of the intermediate prepared by following the procedure described above are given in below Table-10.

Table-10: Structure, Name and analytical data of intermediates (B9-B12)

Intermediate No.	Structure	Name and Analytical data
B9	0	1 -(Cyclopropylmcthyl)-2-oxo-5-vinyl-1,2dihydropyridinc-3-carboxylic acid: 'HNMR (400 MHz, DMSO-dû) δ 0.40-0.6 (m. 4H), 1.2-1.4 (m, 2H), 3.96 (d, J = 7.6 Hz, 2H), 5.30 (d, J = 14.8 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H), 6.59-6.70 (m, 1H), 8.44 ((d, J = 2.4 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H); ESI-MS (m/z) 220.1 (M+H)+
B10	0 H0Yif^ ^f3	2-Oxo-1-(3,3,3-trifluoropropyl)-5-vinyl-1.2dihydropyridine-3-carboxylic acid: 'HNMR (400 MHz. DMSO-76) δ 2.83-2.92 (m. 2H). 4.34 (t. J = 7.2 Hz. 2H), 5.31 (d, J = 10.8 Hz, 1H), 5.82 (d. J = 17.6 Hz, 1H), 6.56-6.64 (m, 1H), 8.44 (d. J = 2.4 Hz.lH), 8.57 (d,7 = 2.4 Hz.lH), 14.28 (brs, 1H)
Bll	O HoVr	l-(2-Cyclopropylethyl)-2-oxo-5-vinyl-l,2dihydropyridinc-3-carboxylic acid: ESI-MS (m/z) 234.1 (M+H)+
B12	O	l-(Oxetan-3-ylmethyl)-2-oxo-5-vinyl-l,2dihydropyridine-3-carboxylic acid: ESI-MS (/n/z) 236.1 (M+H)+

Intermediate B13

-(Difluoromcthyl)-2-oxo-5-vinyl-l ,2-dihydropyridinc-3-carboxylic acid

O

Step-1 : Methyl 5-bromo-l-(difluoromethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate

To a stirred solution of methyl 5-bromo-2-oxo-l,2-dihydropyridinc-3-carboxylatc (300 mg, 1.293 mmol) in DMF (2 mL) were added K2CO3 (356 mg, 2.586 mmol), sodium 2-chloro-2,2difluoroacctatc (393 mg, 2.586 mmol) at room température and heated to 80°C for 18 h. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The residue obtained was purified by silica gel chromatography to yield 201 mg of the desired product. 'H NMR (400 MHz, DMSO) δ 3.78 (s, 3H), 7.79 (t, J = 59.2 Hz, 1H), 8.18 (s, 1H), 8.42 (s, 1H); ESLMS (m/z) 283.6 (M+H)⁺ Step-2: Methyl l-(difluoromelhyl)-2-oxo-5-vinyl-l,2-dihydropyridine-3-carboxylate

To a stirred solution of methyl 5-bromo-1-(difluoromcthyl)-2-oxo-1,2-dihydropyridinc-3carboxylate (150 mg, 0.5319 mmol) and potassium vinyl trifluoroborate (212 mg. 1.595 mmol) in a solvent mixture of toluene (5 mL)/water (ImL) was degassed for 15 min. To this reaction mixture were added K3PO4 (451 mg, 2.127 mmol), Pd(dppf)Cl₂ DCM (43 mg.0.05319 mmol) and heated to 120°C for 2 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were separated. dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by silica gel column chromatography to yield 120 mg of the desired product. ’H NMR (400 MHz, DMSO) δ 3.80 (s, 3H), 5.27 (d, J = 11.2 Hz, 1H), 5.76 (m, 1H), 6.65 (m, 1H), 7.87 (t, J = 59.2 Hz. 1H), 8.18 (s, IH), 8.41 (s, 1H); ESLMS (m/z) 230.1 (M+H)⁺

Step-3: l-(Difluoromethyl)-2-oxo-5-vinyl-l,2-dihydropyridine-3-carboxylic acid

To a stirred solution of methyl l-(difluoromethyl)-2-oxo-5-vinyl-l,2-dihydropyridine-3carboxylate (27 mg. 0.0118 mmol) in THF/Melhanol (2 mL) at 0°C was added aqueous lithium hydroxidc (14.85 mg, 0.3537 mmol) and stirred at 0°C for 30 min. The solvent was evaporated and acidified with IN citric acid solution. The aqueous layer was extracted twice with 10% MeOH / DCM and dried over sodium sulphate. The organic layer was concentrated under reduced pressure to yield 19 mg of the desired product. ESI-MS (m/z) 216.20 (M+H)⁺

Intermediate B14

2-Oxo-l-(prop-2-yn-l-yl)-5-vinyl-l,2-dihydropyridine-3-carboxylic acid

Step-l : Methyl 5-bromo-2-oxo-1-(3-( trimethylsilyl )prop-2-yn-l -yl)-L 2-dihydropyridine-3carboxylate

Br σ'

I

To a stirred solution of methyl 5-bromo-2-hydroxynicotinate (2 g, 8.66 mmol) in dry DMF (20 mL) was added césium carbonate (4.2 g, 12.99 mmol) and resulting mixture was stirred at room température for 30 min. The (3-bromoprop-l-yn-l-yl)trimethylsilane (1.65 mL, 10.39 mmol) was added and stirred at room température for 2h. The reaction mixture was diluted with water and extractcd thricc with ethyl acétate and the combincd organic layers wcrc washed with water and concentrated. The obtained residue was purified by column chromatography to yield 1.8 g of the desired product. Ή NMR (400 MHz, DMSO-A) δ 0.24 (s, 9H), 3.92 (s, 3H), 4.78 (s, 2H). 8.13 (d, 7 = 2.8 Hz, 1H), 8.23 (d,7= 2.8 Hz, 1H); ESI-MS (m/z) 344.0 (M+2H)⁺

Stcp-2: Methyl 2-oxo-1 -(prop-2-yn-1 -yl)-5-vinyl-1,2-dihydropyridinc-3-carboxylatc

To a stirred solution of methyl 5-bromo-2-oxo-l-(3-(trimethylsilyl)prop-2-yn-l-yl)-l,2dihydropyridine-3-carboxylate (1.8 g, 5.232 mmol) in toluene (25 mL) and water (5 mL) was added KxPCL (4.4 g, 20.93 mmol) and trifluoro(vinyl)-14-boranc, potassium sait (2.0 g, 15.69 mmol) under nitrogen atmosphère and the mixture was degassed for 10 min. The [Ι,Γbis(diphenylphosphino)ferrocene] dichloropalladium(II) (426 mg. 0.523 mmol) was added and the mixture was stirred at 100°C for ovemight under nitrogen atmosphère. The mixture was diluted with water and extracted thrice with ethyl acelate. The organic layer was separated and concentrated under vacuum, The obtained residue was purified by siiica gel column chromatography to give 190 mg of the product as an off-white solid; 'H NMR (400 MHz, CDCh) δ 3.94 (s, 3H), 4.81 (s, 2H), 5.24 (d, 7 = 10.8 Hz, 1H), 5.59 (d, 7 = 17.6 Hz, 1H), 6.436.51 (m, 1H), 7.97 (d,7=2.4 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H).

Step-3: 2-Oxo-l-(prop-2-yn-l-yl)-5-vinyl-l,2-dihydropyridine-3-carboxylic acid

To a stirred solution of methyl 2-oxo-l-(prop-2-yn-l-yl)-5-vinyl-l,2-dihydropyridine-3carboxylatc (500 mg. 2.304 mmol) in THF (15 mL), mcthanol (5 mL) and water (5 mL) was added lithium hydroxide monohydrate ( 193 mg, 4.608 mmol) and resulting mixture was stirred at room température for ovemight. The solvent was evaporated completel y under reduced pressure, acidified with HCl, solid obtained was collected by filtration to yield 170 mg of desired product as off white solid. ’H NMR 400 MHz, DMSO-Js) δ 5.30 (d. J = 11.2 Hz, 1H), 5.82 (d. J= 17.6 Hz, 1H), 5.93 (d, J = 6.4 Hz. 2H), 7.58 (d. J =6.4 Hz, 1H), 8.12 (d, 7 = 2.4 Hz, 1H). 8.52-8.59 (m, 1H), 14.00 (s, 1 H); ESI-MS (m/z) 204.1 (M+H)⁺

Intermediate B15

-(4-Fluorophenyl)-2-oxo-5-vinyl-1.2-dihydropyridine-3-carboxylic acid

M HO \-N q

Step-1: Methyl 5-bromo-l-(4-fluorophenyl)-2-oxo-l,2-dihydropyridine-3-carboxylate Br

Γ

To a stirred solution of methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (2.0 g, 1.077 mmol) in DCM (50 mL) were added (4-fluorophenyl)boronic acid (3.2 g, 23.27 mmol), pyridine (3.4 mL, 34.48 mmol) followcd by diacctoxycoppcr (3.4 g, 17.24 mmol) and activatcd molecular sieves and stirred at room température for overnight. The reaction mixture was filtered and diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphatc and concentratcd. The obtained residue was purified by silica gel chromatography to yield 650 mg of the desired compound. *H NMR (400 MHz, DMSO-de) δ 3.76 (s, 3H), 7.34-7.39 (m. 2H), 7.50-7.54 (m, 2H), 8.15 (d, 7 = 3.0 Hz, 1H), 8.30 (d, 7 = 3.0 Hz. 1H); ESI-MS (m/z) 327.8 (M+H)⁺

Step-2: Methyl l-(4-fluorophenyl)-2-oxo-5-vinyl-l,2-dihydropyridine-3-carboxylate

To a stirred solution of methyl 5-bromo-l-(4-fluorophenyl)-2-oxo-l,2-dihydropyridine-3carboxylate (650 mg, 1.99 mmol) and potassium vinyl trifluoroborate (800 mg. 5.98 mmol) in a mixture of toluène (5 mL) and water (2 mL) was degassed for 15 min. To this réaction mixture were added K3PO4 (1.7 g, 7.96 mmol), Pd(dppf)Ch DCM (163 mg. 199 mmol) and heated to 100°C for 3 h. The réaction mixture was diluted with water and extracted twicc with ethyl acetate. The organic layers were separated, dried over anhydrous sodium sulfate and concenlrated under vacuum. The obtained residue was purified by silica gel column 5 chromatography to yield 550 mg of the desired product. 'H NMR (400 MHz, DMSO-dô) δ 3.78 (s, 3H), 5.17 (d, J= 11.3 Hz, 1 H), 5.69 (d, J = 17.6 Hz, IH), 6.56 (d, J = 17.7 Hz. 1 H), 7.357.40 (m, 2H), 7.50-7.54 (m, 2H), 8.07 (s, IH), 8.35 (s, IH); ESI-MS (»i/z) 274.1 (M+H)⁺ Step-3: l-(4-Fluorophenyl)-2-oxo-5-vinyl-1.2-dihydropyridine-3-carboxylic acid

To a stirred solution of methyl l-(4-fluorophenyl)-2-oxo-5-vinyl-1,2-dihydropyridine-310 carboxylatc (550 mg. 2.01 mmol) in THF / Mcthanol / Water (25 mL) at 0°C was added aqucous lithium hydroxide (423 mg. 10.07 mmol) and stirred at same température for ovemight. The solvent was evaporated and acidified with 1 N hydrochloric acid solution. The aqueous layer was extracted twice with 10% MeOH/DCM and dried over sodium sulphate. The organic layer was concenlrated under rcduccd pressure to yield 400 mg of the desired product. ESI-MS (m/z) 15 260.1 (M+H)⁺.

The menlioned below inlermediates were synthesized by following the procedure described above for intermediate B8 and the analytical data are given in below Table-11. Table-11: Structure, Name and analvtical data of inlermediates (B 16-B19)

Intermediate No.	Structure	Name and Analytical data
B16	«Xf Cf ^cf3	3-Oxo-4-(2,2,2-trifluoroethyI)-6-vinyl-3,4dihydropyrazine-2-carboxylic acid: 'H NMR (400 MHz. DMSO-ώ) Ô 5.06-5.15 (m, 2H), 5.55 (d, J = 9.6 Hz, IH); 6.23 (d.7 = 16.4 Hz, IH), 6.82-6.91 (m. IH), 8.53 (s, IH), 13.81 (brs, IH)
B17	0 HO Λ-Ν	1 -Mcthyl-2-oxo-5-vinyl-1,2-dihydropyridinc-3carboxylic acid: ESI-MS (m/z) 180.15 (M+H)+
B18	0	l-Ethyl-2-oxo-5-vinyl-l,2-dihydropyridinc-3carboxylic acid: ‘H NMR (400 MHz. DMSO-d6): δ 1.33(t, 7=7.14 Hz. 3H), 4.10-4.13(m. 2H). 5.29(d. 7=10.99 Hz, IH), 5.82(d, 7=17.58 Hz. IH). 6.61(dd. 7/=17.72 Hz,7z=l 1.13 Hz. 1 H), 8.43(d, 7=2.47, IH), 8.55(d,7=2.48 Hz. IH), 14.63(s, IH); ESI-MS (m/z) 194.3 (M+H)+

Intermediate No.	Structure	Name and Analytical data
B19	0 Hoiy	1 -(4-Fluorobenzyl)-2-oxo-5-vinyl'l,2dihydropyridine-3-carboxylic acid: ’H NMR (400 MHz, DMSO-dô) δ 5.28 (s, 2H), 5.31 (d, 7=1.6 Hz.lH), 5.82 (d, 7 = 17.58 Hz, 1H), 6.60-6.65 (m, 1H), 7.18-7.23 (m. 2H). 7.44-7.47 (m. 2H), 8.558.56 (m. 2H), 14.33 (brs, 1H); ESI-MS (m/z) 274.1 (M+H)+

EXAMPLES

Method A:

Ex ample-1 l-(Cyclopropylmethyl)-N-(3-(2-methyl-l-(4-methyl-4H-1.2,4-triazol-3-yl)propan-2yl)phenyI)-2-oxo-5-(piperidin-l-ylmethyl)-l,2-dihydropyridine-3-carboxamide

Step-1: Methyl 5-bromo-2-oxo-l,2-dihydropyridine-3-carboxyIate

To a stirred solution of 5-bromo-2-hydroxy nicotinic acid (5.0 g, 35.94 mmol) in dry Methanol (100 mL) was added conc. H2SO4 (1 mL) and refluxed for 18 h. The réaction mixture was cooled to room température and concentrated under reduced pressure. The obtained residue was basified with saturated sodium bicarbonate solution and stirred for 30 min. The solid obtained was filtered and dried under vacuum to give 4.2 g of the desired product. 'HNMR (400 MHz,

DMSO-dâ) δ 3.75 (s, 3H), 7.99 (d, J = 2.8 Hz), 8.08 (d, J = 2.8 Hz, 1H), 12.41 (brs. 1H); ESIMS (m/z) 233 (M+2H)⁺.

Step-2: Methyl 5-bromo- l-(cyclopropylmethyl)-2-oxo-l,2-dihydropyridine-3-carboxylate O

To a stirred solution of methyl 5-bromo-2-oxo-l ,2-dihydropyndme-3-carboxylate (250 mg, I.077 mmol) in DMF(5 mL) was addcd potassium carbonate (223 mg, 1.616 mmol) and stirred at room température for 30 min. To this mixture was added cyclopropyl methyl bromide (157 pL, 1.616 mmol) and heated to 70°C for ovemight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by silica gel chromatography to yield 126 mg of the desired compound. Ή NMR (400 MHz, DMSO-7₆) δ 0.35- 0.45 (m, 2H), 0.45- 0.55 (m, 2H), 1.18- 1.35 (m, 1H), 3.75 (s, 3H), 3.77 (d, 7 = 9.6 Hz. 2H), 8.058 (d, 7 = 2.8 Hz, 1H), 8.38 (d, 7 = 2.8 Hz, 1H); ESLMS (m/z) 287 (M+2H)⁺

Stcp-3: Methyl l-(cyclopropylmcthyl)-2-oxo-5-vinyM ,2-dihydropyridinc-3-carboxylatc O

To a stirred solution of methyl 5-bromo-l-(cyclopropylmethyi)-2-oxo-l,2-dihydropyridine-3carboxylatc (500 mg, 1.74 mmol) and potassium vinyl trifluoroborate (700 mg, 5.2 mmol) in a solvent mixture of toluene and water (30 mL) and degassed for 15 min. To this reaction mixture were added K3PO4 (1.5 gm, 6.9 mmol), Pd(dppf)C12 DCM ( 140 mg, 0.17 mmol) and heated to 100°C for 5 h. The reaction mixture was diluted with water and extracted twice with ethyl acétate. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained residue was purified by silica gel column chromatography to yield 350 mg of the desired compound. ‘HNMR (400 MHz, DMSO-r/è) δ 0.30 - 0.45 (m, 2H), 0.45- 0.55 (m, 2H), 1.15- 1.35 (m, 1H), 3.77 (s, 3H), 3.78 (d, 7 = 8.8 Hz, 2H), 5.14 (d,7= 11.2 Hz, 1H), 5.64 (d, 7 = 17.6 Hz, 1H),6.48- 6.57 (m, 1H), 8.16 (d, 7 = 2.8 Hz. 1 H), 8.23 (d, 7 = 2.8 Hz, 1 H); ESLMS (m/z) 234.2 (M+H)⁺

Step-4: Methyl l-(cyclopropylmethyl)-5-formyl-2-oxo-l,2-dihydropyridine-3-carboxylate

To a stirred solution of methyl l-(cyclopropylmethyl)-2-oxo-5-vinyl-l,2-dihydropyridine-3carboxylate (375 mg. 1.712 mmol) inTHF/HiO (4:1,25 mL) were added NaIO4(768 mg, 3.59 mmol) followed by 2.5% OsO4int-BuOH (36 μΐ, 0034 mmol). The reaction mixture was stirred at RT for ovemight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield 303 mg of the desired product. *HNMR (400 MHz, DMSO-de) δ 0.41- 0.55 (m, 4H), 1.26- 1.31 (m, 1H), 3.79 (s, 3H), 3.88 (d, J = 7.6 Hz, 2H), 8.355 (d, J = 2.8 Hz. 1H), 8.9 (d, J = 2.8 Hz. 1H), 9.66 (s. 1H); ESI-MS (m/z) 236 (M+H) ⁺

Stcp-5: Mcthyl l-(cyclopropylmclhyl)-2-oxo-5-(pipcridin-l-ylmcthyl)-l,2-dihydro pyridine-3carboxylate

To a stirred solution of melhyl l-(cyclopropylmethyl)-5-formyl-2-oxo-l,2-dihydropyridine-3carboxylate (180 mg, 0.765 mmol) and piperidine (152 μΐ, 1 53 mmol) in DCM (5 mL) was added catalytic amount of acetic acid and stirred for 2 h. To this réaction mixture was added sodium cyano borohydride (144 mg, 2.295 mmol) and stirred at zoom température for overnight. The réaction mixture was quenched with Methanol and concentrated. The obtained residue was purified hy flash chromatography to yield 172 mg of the desired product. *HNMR (400 MHz, DMSO-î/6) δ 0.40- 0.60 (m. 4H), 1.30- 1.40 (m, 1H), 1.50- 1.60 (m, 2H), 1.60 - 1.75 (m. 4H), 2.90-3.10 (m. 4H), 3.77 (s, 3H), 3.78 (d. 7 = 9.2 Hz. 2H), 4.12 (brs, 2H), 8.10- 8.30 (m. 2H); ESI-MS (m/z) 305.3 (M+H) ⁺

Step-6: 1 -(Cyclopropylmethyl )-2-oxo-5-(piperidin-1 -ylmethyl)-1,2-dihydropyridine-3carboxylic acid ^ho5to

To a stirred solution of methyl l-(cyclopropylmethyl)-2-oxo-5-(piperidin-l-ylmethyl)-l,2dihydropyridine-3-carboxylate (100 mg. 0.328 mmol) in THF ! McOH (2 mL) was added aqueous LiOH (69 mg. 1.644 mmol) and stirred at room température for overnight. The reaction mixture was concentrated and the residue obtained was diluted with water and acidified with

IN citric acid. The aqueous layer was extracted with 20 % MeOH / DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield 74 mg of the desired product. Ή NMR (400 MHz. DMSO-Jôlô 0.43- 0.55 (m, 4H), 1.20- 1.30 (m, 1H), 1.30- 1.40 (m. 2H). 1.40- 1.60 (m. 4H), 2.30- 2.50 (m. 4H), 3.35 (s, 2H), 3.96 (d. J = 7.2 Hz. 2H), 8.23 (s, 1H), 8.37 (s, 1H), 14.8 (brs. 1H); ESI-MS (m/z) 291.4 (M+H) ⁺

Step-7: l-(Cyclopropylmethyl)-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phcnyl)-2-oxo-5-(pipcridin-l-ylmethyl)-l,2-dihydropyridinc-3-carboxamidc

To a stirred solution of l-(cyclopropylmethyl)-2-oxo-5-(piperidin-l-ylmethyl)-l,2dihydropyridine-3-carboxylic acid (70 mg, 0.241 mmol) in DMF was added HATU (110 mg, 0.289 mmol) and stirred at RT for 30 min. To this mixture were added DIPEA (129 μΐ, 0.723 mmol) and 3-(2-methyl-l-(4-methyl-4H-l,2,4-lriazol-3-yl)propan-2-yl)aniline (66 mg, 0.289 mmol) and stirred for ovemight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The residuc obtaincd was purificd by flash column chromatography to yicld 9 mg of the desired product. Ή NMR (400 MHz, DMSO-A) δ 0.40- 0.60 (m, 4H), 1.20- 1.30 (m, 2H), 1.30- 1.40 (m, IH), 1.43 (s, 6H), 1.60- 1.80 (m, 4H), 2.30-2.40 (m, 4H). 2.94 (s, 2H), 3.12 (s, 3H), 3.31 (s, 2H), 3.95 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 8 Hz, 1 H), 7.26 (t, J = 8 Hz. 1 H), 7.55 (s, 1 H), 7.64 (d, J = 8.4 Hz, IH). 8.07 (s, IH), 8.21 (s, IH), 8.42 (d, J = 2.4 Hz, IH), 12.2 (brs. IH); ESI-MS (m/z) 503.4 (M+H) ⁺

Method B:

Example-2

N-(3-(2-methyl-l-(4-melhyl-4H-l,2.4-lriazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-lylmethyl)-1 -(2,2.2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide

Step-1: 5-Bromo-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxylic acid

To a stirred solution of methyl 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxylate (1 g, 3.174 mmol) in THF / MeOH (20, mL) was added aqueous LiOH (666 mg, 15.873 mmol) at room température for ovemight. The reaction mixture was concentrated and the obtaincd residuc diluted with water and acidificd with IN HCl. The solid obtaincd was fïltered and dried under vacuum to yield 630 mg of the desired product. 'H NMR (400 MHz, DMSO-dô) δ 4.97 (q. J = 8.8 Hz. 2H), 8.3 (s, IH), 8.47 (s, IH), 13.53 (brs, IH); ESI-MS (m/z) 301.9 (M+2H)⁺

Step-2: 5-Bromo-N-(3-(2-methyl-l-(4-melhyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-2oxo-l-(2,2,2-trifluorocthyl)-l,2-dihydropyridinc-3-carboxamidc

To a stirred solution of 5-bromo-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxylic acid (250 mg, 0.833 mmol) in DMF (10 mL) was added HATU (380 mg. 0.999 mmol) and stirred at room température for 30 min. To this mixture were added DIPEA (430 pL, 2.499 mmol) and 3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)aniline (191 mg, 0.833 mmol) and stirred for ovemight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by flash column chromatography to yield 330 mg of the desired compound *H NMR (400 MHz, DMSO-dù) δ 1.42 (s, 6H), 2.98 (s, 2H), 3.16 (s, 3H), 5.04 (q, 7 = 9.2 Hz, 2H), 7.07 (d, J =8 Hz, 1H), 7.28 (t, J = 8 Hz. 1H). 7.55 (s, 1H). 7.62 (d. 7=8 Hz, 1H), 8.23 (s, 1H). 8.45-8.55 (m, 2H), 11.50 (s, 1H); ESLMS (m/z) 512.2 (M+H) ⁺ Stcp-3: N-(3-(2-mcthyl-1 -(4-mcthyl-4H-1,2,4-triazol-3-yl)propan-2-y l)phcnyl)-2-oxo-1 (2,2,2-trifluoiOcthyl)-5-vinyl-l,2-dihydropyridinc-3-carboxamidc

0¾

To a stirred solution of 5-bromo-N-(3-(2-mcthyl-l-(4-methyl-4H-1.2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide (250 mg, 0.488 mmol) and potassium vinyl trifluoroborate (196 mg, 1.464 mmol) in toluene (5 mL) / water (1 mL) was degassed for 10 min. To this réaction mixture wcrc added K3PO4 (414 mg. 1.954 mmol), Pd(dppf)Cl₂.DCM (40 mg, 0.0488 mmol) and heated to 100°C for 3 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained residue was purified by silica gel column chromatography to yield 230 mg of the desired product. ‘HNMR (400 MHz, DMSO-J₆) δ 1.42 (s, 6H), 2.98 (s. 2H), 3.33 (s, 3H), 5.07 (q. J = 9.2 Hz, 2H), 5.31 (d,7 = 10.8 Hz, 1H), 5.79 (d. J= 17.6 Hz, 1H), 6.60 - 6.75 (m, 1H). 7.0-7.15 (m. 1H), 7.15-7.25 (m. 1H), 7.25-7.40 (m, 1H), 7.6-7.75 (m. 1H), 8.15-8.30 (m, 2H). 8.73 (s, 1 H), 11.64 (s, 1 H); ESI-MS (m/z) 460.2 (M+H)⁺.

Stcp-4: 5-Formyl-N-(3-(2-mcthyl-l-(4-mcthyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phcnyl)-2oxo-l-(2,2,2-triiluoroelhyl)-l,2-dihydropyridine-3-carboxamide

To a stirred solution of N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phcnyl)-2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridinc-3-carboxamidc (215 mg, 0.468 mmol) in THF ! H₂O (4:1,25 mL) were added NaIÛ4 (200 mg, 0.936 mmol) followed 5 by 2.5% OsCL in t-BuOH (10 pL, 0.0009 mmol). The reaction mixture was stirred at room température for ovemight. The réaction mixture was diluted with water and extracted twicc with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield 89 mg of the desired product. 'HNMR (400 MHz, DMSO-dû) Ô 1.43 (s, 6H), 2.99 (s, 2H), 3.13 (s, 3H), 5.10-5.25 (m, 2H), 7. 7.15 (m. 1H), 7.20-7.35 (m, 1H), 7.5010 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); ESIMS (m/z) 461.9 (M+H) ⁺

Stcp-5: N-(3-(2-mcthyl-l-(4-mcthyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phcnyl)-2-oxo-5(pipcridin-l-ylmcthyl)-l-(2,2,2-trifluorocthyl)-l,2-dihydropyridinc-3-carboxamidc

To a stirred solution of 5-formyl-N-(3-(2-methyl-l-(4-methyl-4H-1.2,4-triazol-3-yl)propan-215 yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide (70 mg, 0.151 mmol) and piperidine (45 pi, 0.555 mmol) in DCM (4 mL) was added drop of acetic acid and stirred for 2 h. To this réaction mixture was added sodium triacctoxy borohydride (96 mg, 0.455 mmol) and stirred at room température for overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was 20 concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 12 mg of the desired product. 'HNMR (400 MHz, DMSO-ds) δ 1.251.40 (m, 2H), 1.43 (s, 6H), 1.40-1.70 (m, 4H), 2.15-2.45 (m, 4H), 2.98 (s, 2H), 3.12 (s, 3H), 3.42 (brs, 2H), 5.0-5.20 (m, 2H), 7.05 (brs, 1H), 7.27 (brs, 1H), 7.5-7.7 (m, 2H), 8.02 (brs, 1H), 8.21 (s, 1H), 8.48 (brs, 1H), 11.75 (brs. 1H); ESI-MS (m/z) 531.2 (M+H)⁺

The details of synthesis and analyticai data of the examples synthesized from the abovementioned methods are given below in Table-12.

Table-12: Structure, method, intermediates used, Chemical name and analyticai data of

Examples (3-8)

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
3	w	Method B; Al / B7	l-Cyclopropyl-N-(3-(2-methyl-l-(4-methyl4H-1,2,4-triazol-3-y1)propan-2-yl)phenyl)-2oxo-5-(pipcridin- 1-ylmcthyl)-1,2dihydropyridine-3-carboxamide; ’HNMR (400 MHz, DMSO-J6) δ 0.99-1.10 (m. 4H), 1.4-1.5 (m, 12 H). 2.34 (m. 4H), 2.98 (s, 2H), 3.11 (s, 3H), 3.42-3.44 (m, 2H). 3.48-3.49 (m, 1H), 7.03 (d, J = 8 Hz. 1H), 7.24-7.28 (m, 1 H), 7.56 (s, 1 H), 7.67 (d, J = 8 Hz. 1H), 7.86 (S,1H), 8.21 (s. 1H), 8.40 (s, 1H) 12.18 (s, 1H); ESI-MS (m/z) 489.2 (M+H)+
4	s f N „ 'WJ?	Method B; Al / B2	1 -(2,2-Difluoroethyl)-N-(3-(2-methyl-1 -(4methyl-4H-1.2,4-lriazol-3-yl)propan-2yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)- 1,2 -dihy dropyridine- 3 -carboxamide ; 1H NMR (400 MHz, DMSO-î/6) δ 1.39-1.43 (m, 2H), 1.45 (s, 6H), 1.41-1.50 (m, 4H), 2.302.33 (m, 4H), 2.98 (s, 2H), 3.11 (s, 3H), 3.34 (s, 2H), 4.57-4.63 (m. 2H), 6.30-6.57 (m, 1H), 7.05 (d, J =7.6 Hz, 1H), 7.25-7.29 (m, 1H), 7.53 (s, 1H), 7.65 (d. 7=8.4 Hz. lH),8.00(s, 1H), 8.21 (s, 1H), 8.46 (d, 7 = 2 Hz. 1H), 11.88 (brs. 1H); ESI-MS (m/z) 513 (M+H)+
5	LT .X ' w σ λ-CHFj	Method B; Al /B2	(S)-l-(2,2-Difluoroethyl)-N-(3-(2-methyl-l(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phcnyl)-5-((3-mcthyIpipcridin-1 yl)melhyl)-2-oxo-1,2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz. DMSO-J6) δ 0.81-0.85 (m, 3H), 1.11-1.23 (m, 2H), 1.43 (s, 6H), 1.58-1.63 (m. 4H), 1.84-1.91 (m, 1 H), 2.67-2.75 (m, 2H), 2.98 (s, 2H), 3.11 (s, 3H),

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			3.31 (s, 2H), 4.56-4.64 (m, 2H), 6.30-6.57 (m, 1H), 7.05 (d. J = 7.6 Hz, 1H), 7.25-7.29 (m, 1H), 7.53 (s, 1H), 7.64 {d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 8.21 (s, 1H), 8.46 (d. J = 2.0 Hz, 1H), 11.88 (brs, 1H); ESI-MS (m/z) 527 (M+H)+
6		Method B; A4/B7	l-Cyclopropyl-N-(3-(3-((4-methyl-4H-l ,2,4triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2oxo-5-(piperidin- 1-ylmethyl)-1,2dihydropyridine-3-carboxamide; ‘H NMR (400 MHz. DMSO-76) δ 0.95-0.99 (m, 2H), 1.09-1.11 (m, 2H), 1.23-1.42 (m. 3H), 1.531.82 (m,4H), 2.68-2.74 (m. 4H), 2.91 (s, 3H), 3.48-3.5 (m. 4H), 4.86 (d, J= 8 Hz. 2H), 4.93 (d. J = 8Hz, 2H), 6.62 (d, J = 8 Hz. 1 H). 7.237.28 (m, 2H), 7.74 (d, J = 8 Hz, 1H), 7.91 (s, 1H). 8.20 (s,lH). 8.42 (s,lH) 12.16 (s.lH); ESI-MS (m/z) 503.3 (M+H)+
7		Method B; A5/B5	N-(3-(( 1 s,3s)-3-methyl-l -(4-methy!-4Hl,2,4-triazoI-3-yl)cyclobutyl)phenyl)-2-oxo5-(piperidin-1 -ylmethyl)-1 -(2,2,2trifluoroethyl )-1,2-dihydropyridine-3carboxamidc; 'HNMR (400 MHz, DMSOd6): S 1.07 (d, 7 = 4.4 Hz, 3H), 1.60-1.64 (m, 6H), 2.45 (s, 2H), 2.78 (brs, 3H), 3.16 (s, 3H), 3.43-3.52 (m, 4H), 4.24 (t, 7 = 9.4 Hz, 2H), 4.7 (s, 2H), 6.95 (d, 7 = 6.4 Hz, 1H), 7.26 (d, 7 = 8 Hz, 1H), 7.29 (s, 1H), 7.41 (s, 1H), 7.58 (d, J = 7.2 Hz, 1 H), 7.87 (s, 1 H), 8.28 (s, 1 H), 11.57 (s, 1H). ESI-MS (m/z) 543.2 (M+H)+

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
8		Method B; Al /B4	(S)-l-(Cyclobutylmethyl)-N-(3-(2-methyl-l(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phcnyl)-5-((3-mcthylpipcridin-lyl)methyl)-2-oxo-l,2-dihydropyridine-3carboxamidc; 1H NMR (400 MHz. DMSOJ6) 5 0.82-0.88 (m, 5H), 1.23-1.29 (m, 2H), 1.27-1.31 (m,4H), 1.43 (s,6H), 1.57-1.94 (m, 6H), 2.77 (m, 4H), 2.98 (s, 2H), 3.11 (s, 3H), 4.12 (d. J = 7.2 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1H). 7.26 (t, J = 7.6 Hz, 1H). 7.53 (s, 1H), 7.64, (d, J = 7.6 Hz. 1 H), 8.03 (s, 1H),8.21, (s, 1H), 8.39 (s, 1H), 12.16 (s, 1H). ESI-MS (m/z) 531.4 (M+H)+

Method C:

Example-9 (S)-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((35 methylpiperidin-l-yl)methyl)-2-oxo-l-(2,2,2-trifluoroethyI)-l,2-dihydropyridine-3carboxamide

Step-1: Methyl 2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3-carboxylate

O

^kCF₃

To a stirred solution of 5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxylatc (1.5 g, 4.76 mmol) and potassium vinyl trifluoroboratc (1.91 gm., 14.28 mmol) in a solvent mixture of toluene (50 mL)/water (15 mL) was degassed for 15 min. To this reaction mixture wcrc added K3PO4 (4 g, 19.04 mmol), Pd(dppf)Ch.DCM (390 mg, 0.476 mmol) and heated to 100°C for 5 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separated. dried over anhydrous sodium sulfate and conccntratcd under vacuum. The obtaincd rcsiduc was purified by silica gel column chromatography to yield 1.09 g of the desired compound. 'HNMR (400 MHz. DMSO-î/ô) δ 3.78 (s, 3H). 4.90 (q,/ = 9.2 Hz. 2H), 5.22 (d,/= 11.2 Hz. 1H),5.68 (d,/= 17.6 Hz, 1H),6.456.6 (m, 1H), 8.103 (d,/ = 2Hz, 1H). 8.33 (d./ = 2.8 Hz, 1H); ESI-MS (m/z) 262.3 (M+H) ⁺ Step-2: 2-Oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-1.2-dihydropyridine-3-carboxylic acid

O

To a stirred solution of methyl 2-oxo-l-(2,2,2-trifluorocthyl)-5-vinyl-l,2-dihydropyridinc-3carboxylate (1 g. 3.831 mmol) in THF / MeOH (40 mL. 1:1) was added aqueous LiOH (481 mg. 11.49 mmol) and stirred at room température for ovemight. The reaction mixture was conccntratcd and the rcsiduc obtaincd was diluted with water and acidificd using IN HCl. The solid precipitated was fïltered and dried to yield 809 mg desired product 'HNMR (400 MHz, DMSO-d₆) δ 5.01 (q,/ = 9.2 Hz, 2H), 5.28 (d,/ = 11.2 Hz, IH), 5.76 (d,/ = 17.6 Hz, 1H), 6.506.70 (m. 1H). 8.19 (s, 1H). 8.53 (d, / = 2.4 Hz, 1H), 13.86 (brs, 1H); ESI-MS (m/z) 248.2 (M+H)⁺

Stcp-3: N-(3-(2-mcthyI-l-(4-mcthyl-4H-L2,4-triazol-3-yl)propan-2-yl)phcnyl)-2-oxo-l(2.2,2-trinuoroethyl)-5-vinyl-l,2-dihydropyridine-3-carboxamide

To a stirred solution of 2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3carboxylic acid (800 mg, 3.238 mmol) in DMF (15 mL) was added HATU (1.5 g, 3.885 mmol) and stirred at room température for 30 min. To this mixture were added DIPEA (1.7 ml. 9.714 mmol) and 3-(2-methyl-l-(4-melhyl-4H-l,2,4-triazol-3-yi)propan-2-yl)aniline (744 mg. 3.238 mmol) and stirred for ovemight. The réaction mixture was diiutcd with water and cxtractcd with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by flash column chromatography to yield 1.41 g of the desired compound. 'HNMR (400 MHz. DMSO-d₆) δ 1.43 (s. 6H), 3.02 (s, 2H). 3.17 (s, 3H). 5.07 (q, / = 9.2 Hz. 2H). 5.32 (d, / = 10.8 Hz, 1H). 5.79 (d,/= 17.6 Hz. 1H). 6.55-6.75 (m. 1H).7.O6 (d, / = 8Hz, 1H),7.28 (d,/=8Hz, 1H), 7.55-7.70 (m, 2H), 8.26 (d./ = 2 Hz, 1H), 8.33 (brs, 1H), 8.73 (d, J = 2.4 Hz. 1 H), 11.65 (s, 1 H); ESI-MS (m/z) 460.3 (M+H)⁺

Step-4: 5-Formyl-N-(3-(2-methyl-l-(4-methyL4H-l,2,4-tnazol-3-yl)propan-2-yl)phenyl)-2oxo-l-(2,2,2-trifluorocthyl)-l,2-dihydropyridinc-3-carboxamide

To a stirred solution of N-(3-(2-methyLl-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3-carboxamide (l.5 g, 3.267 mmol) in THF / HiO (50 mL) were added NaICh (2 g, 6.534 mmol) followcd by 2.5% OsCUint-BuOH (320 μΐ , 0.032 mmol). The reaction mixture was stirred at room température for overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield 1.12 g of the desired compound. 'HNMR (400 MHz, DMSO-Æ) δ 1.47 (s, 6H), 2.99 (s, 2H), 3.13 (s, 3H), 5.19 (q, J = 9.2 Hz. 2H), 7.07 (d, J = 8 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 7.55 (s, IH), 7.66 (d, 7= 8 Hz, 1H), 8.22 (d, J = 3.2 Hz, 1H), 8.78 (d,7=2.4 Hz, 1H). 8.95 (d. 7=2.4 Hz, 1H), 9.81 (s, 1H), 11.22 (s, 1H); ESLMS (m/z) 462.1 (M+H) ⁺

Step-5: (S)-N-(3-(2-methyl- l-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3methylpiperidin-l-yl)methyl)-2-oxo-l-(2,2.2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide

To a stitred solution of 5-formyl-N-(3-(2-mcthyl-l-(4-methyL4H-l,2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,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 pL, 0.519 mmol) and stirred for 2 h. To this reaction mixture was added sodium triacetoxyborohydride (110 mg, 0.519 mmol) and stitred at room température for overnight. The réaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by supcrcritical fluid chromatography (SFC) to yield 29 mg of the desired compound. 'HNMR (400 MHz, DMSO-7₆) δ 0.82 (d, 7 = 5.2 Hz, 3H), 1.43 (s, 6H), 1.45-1.70 (m. 5 H), 1.80-1.92 (m. 1 H), 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, 7 = 9.2 Hz, 2H), 7.04 (d. 7 = 8.4 Hz, 1 H), 7.27 (t, 7 =8 Hz, 1 H), 7.55 (s, 1 H), 7.63 (d, 7 = 8 Hz, 1H), 8.0 (d, 7 = 2 Hz, 1 H), 8.21 (s, 1 H), 8.48 (d, 7 = 2.4 Hz, 1H), 11.70 (s, 1H); ESLMS (m/z) 545.2 (M+H)⁺

The details of synthesis and analylical data of the examples synthesized from the abovementioned methods are given below in Table-13.

Table-13: Structure, method. intermediates used, Chemical name and analytical data of Example (10-46)

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
10		Method C; A4/B1	l-(Cyclopropylmcthyl)-N-(3-(3-((4-mcthyl4H-l,2,4-triazol-3-yl)methyl)oxetan-3yl)phcnyl)-2-oxo-5-(pipcridin-l-ylmethyl)1,2-dihydropyridinc-3-carboxamidc;1HN M R (400 MHz. DMSO-î/6) δ 0.47-0.57 (m. 4H), 0.90-1.00 (m, 1H), 1.23-1.91 (m. 6H), 2.392.40 (m, 2H), 2.45-2.53 (m, 2H), 2.88 (s, 3H), 3.50 (s, 2H), 3.93 ( d, J = 6.8 Hz. 2H), 4.83 (d. J = 6 Hz, 2H), 4.93 (d. J = 6 Hz. 2H), 5.40 (bs, 2H), 6.68 (d, J = 5.6 Hz. 1H), 7.20 (s, 1H). 7.28 (d. J = 8.4 Hz. 1H), 7.72 (d. J = 8 Hz, 1H), 8.20 (s, 1H), 8.39 (s, 1H), 8.62 (s, 1H), 11.98 (s, 1H); ESI-MS (m/z) 517,3 (M+H)+
11		Method C; A4/B8	N-(3-(3-((4-melhyl-4H-1,2,4-triazol-3yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5(pipcridin-l-ylmcthyl)-l-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide; ’HNMR (400 MHz. DMSO-J6) δ 1.09-1.91 (m 6H), 2.33-2.45 (m, 2H). 2.502.67 (m. 2H), 2.92 (s, 3H), 3.50 (s, 2H), 4.23 (s, 2H), 4.85 (d, J = 6 Hz. 2H),4.92 (d, J = 6 Hz, 2H), 5.10 (m, 2H), 6.69 (s, 1H), 7.20 (s, 1H), 7.26-7.30 (m. 1H), 7.7 l(d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.70 (s, 1H), 9.49 (s, 1H), 11.59 (s, 1H); ESI-MS (m/z) 545.3 (Μ+ΗΓ

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
12		Method C; Al / B8	N-(3-(2-methyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5(pyrrolidin-1 -ylmcthyl)-1-(2,2,2trifluoroethy 1 )-1,2-dih ydro pyrid ine-3 carboxamidc; lHNMR (400 MHz. DMSO-76) ô 1.43 (s, 6H), 1.60-1.75 (m, 4H), 2.30-2.50 (m, 4H), 2.98 (s, 2H), 3.12 (s, 3H), 3.48 (s, 2H), 5.1 (q, J = 9.2 Hz, 2H), 7.05 (d, J = 8 Hz, 1H), 7.27 (t. 7 = 8 Hz. 1H), 7.45-7.55 (m. 1H), 7.60-7.75 (m, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 11.75 (s, 1H); ESI-MS (m/z) 517.2(M+H)+
13	Λ „ 'W?	Method C; Al /B8	N-(3-(2-methyl-1 -(4-methyl-4H-1.2.4triazol-3-yl)propan-2-yl)phenyl)-5(morpholinomethyl)-2-oxo-1-(2,2,2tri fl uoroethy 1 )-1,2-dihydropyridine-3 carboxamide; *HNMR (400 MHz, DMSO-76) δ 1.66 (s, 6H), 2.38-2.41 (m, 4H), 2.98 (s, 2H), 3.11 (s, 3H), 3.37-3.33 (m, 2H), 3.583.60 (m, 4H), 5.05-5.12 (m. 2H),7.04 (d, J = 7.6 Hz, 1H),7.27 (t, 7 = 8.0 Hz. 1H), 7.55 (s, 1H),7.63 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.50 (d. 7 = 2.4 Hz, 1H), 11.74 (s, 1H); ESI-MS (m/z) 533.3 (M+H)+

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
14	w*	Method C; AI/B8	5-((4,4-Difluoropiperidin-l-yl)methyl)-N-( 3(2-methyl-1 -(4-methyi-4H-1,2.4-triazol-3yl)propan-2-yl)phcnyl)-2-oxo-1-(2,2,2trifluoroethyl)-l,2-dihydropyridine-3carboxamide; 'HNMR (400 MHz, DMSO76) δ 1.23 (s, 6H), 1.35-1.40 (m, 2H), 2.012.13 (m, 2H), 2.98 (s, 2H), 3.14 (s, 3H), 3.583.62 (m. 4H). 4.26 (d, J = 8.8 Hz, 2H), 4.73 (s, 2H), 6.91 (d, 7 = 8.0 Hz, 1H), 6.17 (d, 7 = 7.6 Hz, 1H). 7.24 (s, lH),7.41(s, lH).7.57(d, 7 = 7.2 Hz. 1H), 7.90 (s, 1H), 8.26 (s, 1H), 11.50 (s, 1 H); ESI-MS (m/z) 567.2 (M+H) +
15	VA	Method C; Al /B13	1 -(Difluoromethyl)-N-(3-(2-melhyl-1 -(4methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phenyI)-2-oxo-5-(piperidin-1 -ylmethyl)l,2-dihydropyridine-3-carboxamide; 'HNMR (400 MHz. DMSO) δ 1.23-1.51 (m. 6H), 1.42 (s, 6H), 2.33-2.50 (m, 2H), 2.67-2.73 (m, 2H), 3.12 (s. 3H), 3.97 (s. 2H), 6.90 (s, 1H), 7.08 (s, 1H), 7.28 (m, 1 H), 7.54 (brs, 1H), 7.63 (d, J = 8 Hz. 1H), 8.02 (t, 7 = 59.6 Hz. 1H), 8.21 (s, 1H), 8.52 (brs, 1H), 11.32 (brs. 1H); ESIMS (m/z) 497.3 (M-H)+
16	-t° A UH w ' ' 0 '-CF,	Method C; Al /B8	5-((3-Acetamidopiperidin-1 -yl)methyl)-N(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)propan-2-y 1 )phcnyl)-2-oxo-1 -(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide (Isomer-1); 'HNMR (400 MHz, DMSO-76)ô 1.13-1.15 (m,2H), 1.42 (s, 6H), 1.68-1.71 (m,2H), 1.81 (s, 3H), 1.83-1.85 (m, 1H), 1.96-1.98 (m, IH), 2.67-274 (m, 1H),

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			2.76-2.81 (m, 1H), 2.98 (s, 2H). 3.16 (s, 3H), 3.37 (s, 2H), 3.38-3.68 (m, 1H), 5.05-5.11 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 7.6, 8.0 Hz, 1H). 7.55 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H). 8.03 (s, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 11.78 (s, 1H); ESI-MS (m/z) 588.30 (M+H)+
17	A ( >ΝΗ >N 0 ^CFj	Method C; Al /B8	5-((3-Acetamidopiperidin-l-yl)methyl)-N(3-(2-methyl-l-(4-methyI-4H-l,2,4-triazol-3yl) propan-2-yl)phenyl)-2-oxo-1 -(2,2,2- trifluoroethyl)-1,2-dihydropyridine-3carboxamide (Isomer-2); 1H NMR (400 MHz, DMSO-J6) δ 1.23-1.26 (m, 2H), 1.43 (s, 6H), 1.61-1.65 (m, 2H), 1.81-1.84 (s, 3H), 1.93-1.96 (m. 1H), 1.97-1.99 (m, 1H), 2.632.65 (m, 1H), 2.67-2.71 (m, 1H), 2.98 (s, 2H), 3.11 (s, 3H), 3.42 (s, 2H), 3.70-3.74 (m, 1H), 5.09-5.16 (m, 2H), 7.05 (d, J = 8.0 Hz. 1H), 7.29 (dd, J = 7.6, 8.0 Hz, 1H), 7.55 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 11.75 (s, 1H); ESI-MS (m/z) 588.50 (M+H)+
18	‘WJ’	Method C; Al/B11	l-(2-Cyclopropylcthyl)-N-(3-(2-mcthyl-l-(4methyl-4H-1,2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)- 1,2-dihydropyridine-3-carhoxamide; *H NMR (400 MHz, DMSO-d6) δ 0.00-0.01 (m, 2H), 0.37-0.39 (m, 2H), 0.68-0.69 (m. 1H), 1.23-1.43 (m, 14H), 2.91 (s, 2H), 2.31-2.37 (m,4H), 2.95 (s, 2H), 3.12 (s, 3H), 4.16 (t, J = 6.8 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H),

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			7.26 (t, J = 8.0 Hz, IH), 7.55 (s, IH), 7.63 (d, J = 8.4 Hz, IH), 8.06 (s, IH), 8.21 (s, IH), 8.41 (s, IH), 12.16 (s, IH); ESI-MS (m/z) 517.3(M+H)+
19	λ w σ '-cf3	Method C; A1/B8	(R)-5-((3-Fluoropyrrolidin-l-yl)methyl)-N(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-1 -(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamidc; ‘HNMR (400 MHz. DMSO-76) δ 1.40 (s, 6H). 1.93-1.95 (m, IH), 2.03-2.12 (m, IH), 2.33-2.36 (m, 2H), 2.67-2.71 (m, 2H), 2.98 (s, 2H), 3.12 (s, 3H), 3.52 (d, 7=8.0 Hz 2H), 5.06-5.30 (m,3H), 7.04 (d, 7=8.0 Ηζ,ΙΗ), 7.27 (t. 7 =8.0 Hz, IH), 7.54 (s, IH), 7.65 (d. 7 =8.0 Hz, IH), 8.30 (s, IH), 8.21 (s, IH), 8.50 (s, IH), 11.75 (s, IH); ESI-MS (m/z) 535.2 (M+H)+
20	fNN ^OH	Method C; A1/B8	(S)-5-((3-Hydroxypyrrolidin-l-yl)methyl)-N(3-(2-methyl-1 -(4-methyl-4H-1,2,4-lriazol-3yl)propan-2-yl)phenyl)-2-oxo-l -(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz, DMSO-76) Ô 1.43 (s, 6H), 1.50-1.65 (m. 2H), 1.90-2.10 (m, IH), 2.20-2.50 (m, 2H), 2.50-2.70 (m, 2H), 2.98 (s. 2H), 3.12 (s, 3H), 3.4 (s, 2H), 4.21 (brs, IH), 5.09 (q, 7 = 9.2 Hz,, 2H), 7.04

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(d, J = 7.6 Hz, 1 H), 7.27 (t, 7 = 8 Hz, 1 H), 7.54 (s, 1H), 7.64 (d, 7 = 8 Hz, 1H), 8.09 (s, 1H), 8.21 (s, 1H), 8.48 (d, 7 = 2.4 Hz, 1H), 11.75 (s, 1H); ESI-MS (m/z) 533.2 (M+H)+
21	A ,OH	Method C; A1/B8	(R)-5-((3-Hydroxypyrrolidin-l-y])methyl)N-(3-(2-methyl-1 -(4-methyl-4H-l ,2,4triazol-3-yI)propan-2-yl)phenyl)-2-oxo-l(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamidc; ’HNMR (400 MHz, DMSO-rf6) δ 1.43 (s, 6H). 1.50- 1.65 (m. 2H), 1.90-2.10 (m, 1H), 2.20- 2.5 (m, 2H), 2.5- 2.7 (m. 2H), 2.98 (s, 2H), 3.12 (s, 3H), 3.35 (s, 2H), 4.28 (brs, 1H), 5.1 (q,7 = 9.2 Hz, 2H), 7.06 (d, 7 = 8 Hz, 1H), 7.27 (t, 7 = 7.6 Hz, 1H), 7.53 (s, 1H), 7.65 (d, 7 = 7.6 Hz, 1H), 8.13 (s, 1H), 8.21 (s, 1H), 8.57 (brs, 1H), 11.69 (s, 1H); ESI-MS (m/z) 533.2 (M+H)+
22	A h	Method C; A1/B8	(S)-5-((3-Fluoropyrrolidin-l-yl)methyl)-N(3-(2-methyl-1 -(4-methyl-4H-1,2,4-lriazol-3yl)propan-2-yl)phenyl)-2-oxo-1 -(2,2,2tri flu oroethyl )-1,2-dih ydropy ridine-3 carboxamide; *HNMR (400 MHz, DMSO-d6) δ 1.43 (s, 6H), 1.80-2.0 (m, 1H), 2.1-2.3 (m, 1H), 2.6-2.75 (m, 2H), 2.7-2,95 (m, 2H), 2.98 (s, 2H), 3.11 (s, 3H), 3.52 (d, 7 = 7.6 Hz, 2H), 5.05-5.20 (m, 2H), 5.26-5.30 (m, 1H), 7.045

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(d,7=8.4 Hz. IH), 7.27 (t,7 = 8 Hz, 1H),7.54 (s, IH), 7.64 (d, 7=7.6 Hz. IH), 8.06 (s, 1H), 8.21 (s, IH), 8.5 (d, 7 = 2.4 Hz, IH), 11.75 (s, IH); ESI-MS (m/z) 535.7 (M+H)+
23		Method C; A4/B11	l-(2-Cyclopropylethyl)-N-(3-(3-((4-methyl4H-1,2,4-triazol- 3 -y 1 )methy 1 )o xetan -3 yl)phenyl)-2-oxo-5-(piperidin-1 -yimethyl)l,2-dihydropyridine-3-carboxamide; ’HNMR (400 MHz. DMSO-d6) δ 0.02 (d, 7 = 7.2 Hz, 2H), 0.39 (d, 7 = 7.2 Hz, 2H), 0.69-0.71 (m, IH), 0.84-0.88 (m. 2H), 1.17-1.27 (m. 6H), 1.39-1.63 (m, 6H), 2.90 (s, 3H), 3.49 (s, 2H), 4.15 (l, J = 6.4 Hz, 2H), 4.83 (d, 7 = 6.0 Hz. 2H), 4.93 (d, 7 = 6.0 Hz, 2H), 6.00 (d. J = 7.2 Hz, 1H),7.21-7.27 (m. 2H), 7.71 (d, J = 8.4 Hz, IH), 8.18 (brs, IH), 8.20 (s, IH), 8.45 (brs, IH), 12.15 (s. IH). ESI-MS (m/z) 531.4 (M+H)+
24	cf4	Method C; Al/BlO	(S)-N-(3-(2-methyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)propan-2-yI)phenyl)-5-((3methylpiperidin-l-yl)methyl)-2-oxo-l(3,3,3-trifluoropropyl)-l,2-dihydropyridine3-carboxamidc; ’HNMR (400 MHz, DMSOJ6) Ô 0.77 (d. 7= 5.2 Hz, 3H), 1.43 (s, 6 H), 1.45-1.63 (m, 4H). 1.80-1.92 (m, IH), 2.682.70 (m, 2H), 2.85-2.93 (m, 2H), 2.98 (s, 2H), 3.12 (s, 3H), 3.3-3.4(m, 4H), 4.34 (t, 7 = 7.8 Hz, 2H), 7.02 (d, J = 8.0 Hz, IH), 7.26 (t, J =8.0 Hz, IH), 7.56 (s, IH), 7.64 (d, 7 = 8 Hz, IH), 8.06 (s, IH), 8.22 (s, IH), 8.43 (s, IH), 11.99 (s, IH); ESI-MS (m/z) 559.3 (M+H)+

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
25		Method C; A4/B9	(S)-l-(Cyclopropylmethyl)-N-(3-(3-((4methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan3-yl)phenyl)-5-((3-mcthylpipcridin-lyl)methyl)-2-oxo-1,2-dihydropyridine-3carboxamide; ’HNMR (400 MHz. DMSO) δ 0.52-0.54 (m. 4H), 0.83-0.86 (m, 3H), 1.191.35 (m. 5H), 1.67-1.69 (m, 1H). 2.46-2.50 (m, 2H), 2.53 (s, 2H), 2.91 (s, 3H), 3.36-3.37 (m. 2H), 3.49 (s. 2H), 3.95 (d, J = 7.2 Hz, 2H), 4.85 (d, J = 6 Hz, 2H), 4.93 (d, J = 6 Hz, 2H). 6.63-6.65 (m, 2H), 7.20 (s, 1H), 7.27 (t, J = 8 Hz, 1H), 7,71 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.40 (s, 1H), 12.13 (brs. 1H); ESI-MS (m/z) 531.3 (M+H)+
26		Method C; Al / B9	(S ) -1 -(C yclopropy Ime thyl)-N-(3-(2-methyll-(4-methyl-4H-1.2,4-triazol-3-yl)propan-2yl)phenyl)-5-((3-melhylpiperidin-lyl)methyl)-2-oxo-1,2-dihydropyridine-3carboxamidc; 1H NMR (400 MHz, DMSO) δ ô 0.50 -0.52 (m, 4H), 0.82-0.85 (m, 3H), 1.231.38 (m. 2H). 1.46 (s, 6H), 1.58-1.66, (m, 2H),1.86 (m, 1H), 2.33 (s, 2H), 2.50 (m. 2H), 2.53 (s, 2H), 2.67 (brs, 2H), 2.98 (s, 2H), 3.16 (s, 3H), 3.96 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 7.26 (l, J = 8 Hz. 1H). 7.55 (s, 1 H), 7.63 (d, J = 9.2 Hz, 1 H), 8.6 (s, 1 H), 8.21 (s, 1H), 8.41 (s, 1H). 12.91 (s.lH); ESI-MS (m/z) 517.4 (M+H)+

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
27		Method C; Al / B8	(R)-N-(3-(2-methyl- l-(4-methyl-4H-1,2,4triazol-3-yl)propan-2-yl)phenyl)-5-((3mcthylpipcridin-1 -yl)mcthyl)-2-oxo-1(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamidc; ‘HNMR (400 MHz. DMSO-76) δ 0.82 (d. J= 5.2Hz, 3H), 1.20-1.35 (m, 3H), 1.43 (s, 6H), 1.50-1.65 (m,4H), 1.8- 1.95 (m, 1H), 2.6-2.8 (m, 3H), 2.98 (s, 2H), 3.11 (s, 3H), 5.09 (q, J = 9.2 Hz, 2H), 7.04 (d. J = 7.6 Hz, 1H), 7.27 (t, 7=8 Hz, 1H), 7.55 (s, 1H), 7.63 (d, 7 = 8 Hz, 1H), 8.02 (s, 1H), 8.21 (s, 1 H), 8.48 (d, 7 = 2.4 Hz, 1 H), 11.76 (s, 1 H); ESI-MS (m/z) 545.2 (M+H)+
28	N i ' ° J-y. λ (T^CFj	Method C; A1/B8	(S)-N-(3-(2-methyl-1 -(4-methyl-4H-1.2,4triazol-3-yl)propan-2-yl)phenyl)-5-((2methylmorpholino)methyl)-2-oxo-1 -(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide; 1H NMR (400 MHz, DMSOr/6) δ 1.03 (d. J = 6.8 Hz, 3H), 1.34 (s, 6H), 1.35-1.42 (m, 2H), 0.71-1.77 (m, 2H), 2.632.70 (m. 2H), 2.97 (d, 7 = 13.6 Hz. 2H), 3.11 (s, 3H), 3.44-3.51 (m, 2H), 3.75 (d, J = 9.6 Hz, 1H), 5.05 - 5.12 (m, 2H), 7.04 (d, J = 8.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.54 (s, 1 H), 7.63 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.50 (d, J = 2.4 Hz, 1H), 12.75 (s, 1H); ESI-MS (m/z) 547.3 (M+H)*

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
29	f NN F	Method C; Al / B11	(S)-1 -(2-C yclopropylethyl )-5-((3fluoropyrrolidin-1 -yl)methyl)-N-(3-(2mcthy l-1 -(4-mcthyl-4H-1,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-1,2dihydropyridinc-3-carboxamidc; *HNMR (400 MHz. DMS0-J6) δ 0.02 (d. J = 7.2 Hz, 2H), 0.39 (d, J = 7.2 Hz, 2H), 0.69-0.71 (m, 1H), 1.61 (s, 6H), 1.64-1.66 (m, 2H), 1.821.84 (m, 2H), 2.09-2.12 (m, 1H), 2.21-2.37 (m, 1H), 2.51-2.59 (m. 1H), 2.61-2.64 (m, 1H), 2.74-2.76 (m, 2H), 2.94 (s, 2H), 3.11 (s, 3H), 3.49-3.53 (m, 2H), 5.14-5.28 (m, 1H), 7.02 (d. J = 7.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.54 (s, 1H),7.65 (d, J = 7.6 Hz. 1H), 8.10 (s, 1H), 8.21 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 12.16 (s, 1 H),ESI-MS (m/z) 521.4 (M+H)+
30	Λ ~	Method C; A1/B8	5-((4-Fluoropiperidin-l-yl)methyl)-N-(3-(2mcthyl-1 -(4-mcthyl-4H-1,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide; *HNMR (400 MHz. DMSO-r/6) Ô 1.20-1.35 (m, 2H), 1.43 (s, 6H), 1.60-2.0 (m, 4 H), 2.25-2.40 (m, 2H), 2.98 (s, 2H), 3.11 (s, 3H), 3.38 (s, 2H), 4.50-4.80 (m. 1H), 5.09 (q, J = 8.8 Hz, 2H), 7.05 (d. J = 8 Hz, 1H), 7.27 (t. J =8 Hz, 1H), 7.55 (s, 1H), 7.63 (d, J = 8.8 Hz. 1H), 8.03 (s, 1H). 8.21 (s, 1H). 8.49 (d, J= 2.4 Hz, 1H), 11.75 (s, 1H); ESI-MS (m/z) 549.3 (M+H)+

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
31		Method C; AI/B8	(R)-N-(3-(2-methyl-l-(4-methyl-4H-1,2,4triazol-3-yl)propan-2-yl)phenyl)-5-((2mclhylrnorpholino)mclhyl)-2-oxo-1-(2,2,2trifluoroethyl)- l,2-dihydropyridine-3carhoxamide; ‘HNMR (400 MHz, DMSO-J6) δ 1.05 (d, J = 4.5 Hz, 3H), 1.20-1.35 (m, 2H), 1.43 (s, 6H), 1.70- 1.85 (m, 1 H), 2.00- 2.15 (m, IH), 2.60 - 2.75 (m, 2H), 3 (s, 2H), 3.11 (s, 3H), 3.40 - 3.55 (m, 2H), 3.70 - 3.80 (m, IH), 5.09 (q, J = 8.8 Hz, 2H), 7.05 (d, J = 8 Hz, IH), 7.27 (t, J =8 Hz, IH), 7.55 (s, IH), 7.63 (d, J = 8.4 Hz, 1 H), 8.21 (s, 1 H), 8.32 (s, IH), 8.5 (d, J = 2.4 Hz, IH), 11.75 (s, IH); ESI-MS (m/z) 547.3 (M+H)+
32		Method C; Al / B11	(S)-l-(2-Cyclopropylethyl)-N-(3-(2-me(hyll-(4-methyl-4H-l,2.4-triazol-3-yl)propan-2yl)phenyl)-5-((3-methylpiperidin- 1-yl) methyl)-2-oxo-1,2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz. DMSO-J6) δ 0.00 (d, J = 7.2 Hz, 2H), 0.37 (d, J = 7.2 Hz. 2H), 0.68-0.70 (m, IH). 0.82-0.88 (m, 5H), 1.23-1.29 (m, 4H), 1.23 (s, 6H), 1.601.66 (m, 4H), 1.85 (s, IH), 2.73 (s, 2H), 2.98 (s, 2H), 3.11 (s, 3H), 4.14-4.18 (m, 2H), 7.02 (d, J = 7.6 Hz, IH), 7.25 (t, J = 8.0 Hz, IH), 7.55 (s, IH), 7.63 (d, J = 7.2 Hz. IH), 8.05 (s, IH), 8.21 (s, IH), 8.40 (d, J = 2.0 Hz, IH), 12.17 (s, IH); ESI-MS (m/z) 531.1 (M+H)+

100

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
33	N F	Method C; A1/B10	(S )-5-((3 -Fluoropyrrolidin-1 - yl)methyl )-N(3-(2-methyl-1 -(4-methyl-4H-l ,2,4-triazol-3yl)propan-2-yl)phcnyl)-2-oxo-1-(3,3,3trifluoropropyl)-1,2-dihydropyridine-3carboxamidc; ’HNMR (400 MHz. DMSO-76) 1.43 (s,6H), 1.80-1.91 (m, 2H), 2.07-2.19 (m, 2H), 2.75-2.90 (m, 4H), 2.97 (s, 2H), 3.13 (s, 3H), 3.49-3.53 (m, 2H), 4.34 (t, J =6.8 Hz 2H), 5.22(d, J =55.2 Hz , 1 H), 7.03 (d, J = 8.0 Hz, 1H), 7.26 (t, J =8.0 Hz, 1H), 7.55 (s, 1H), 7.65 (d, J= 8.0 Hz. 1H), 8.12 (s, 1H), 8.21 (s, 1H), 8.45 (d, J = 2 Hz, 1H), 11.97 (s, 1H); ESI-MS (m/z) 549.3 (M+H)+
34	L,N NiX	Method C; A1/B8	5-((Isobutylamino)methyl)-N-(3-(2-methyll-(4-methyl-4H-1.2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)l,2-dihydropyridine-3-carboxamide; lHNMR (400 MHz, DMSO-d6) δ 0.87 (d, J = 6.8 Hz, 6H), 1,42 (s, 6H), 1.65-1.68 (m, 1H). 2.28 (d, J =6.4 Hz, 2H), 2.98 (s, 2H), 3.12 (s, 3H), 3.57 (s, 2H), 5.09 (q, J = 8.8 Hz, 2H), 7.04 (d, J =7.6 Hz, 1H). 7.27 (t, J =7.6 Hz, 1H), 7.54 (brs, 1H), 7.64 (d, J = 9,2 Hz, 1H). 8.01 (brs. 1H), 8.21 (s, 1H), 8.57 (d, J = 2.8 Hz. 1H), 11.79 (s, 1 H); ESI-MS (m/z) 519.6 (M+H)+

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
35		Method C; Example 35 / Formaldéhyde	5-((Isobutyl(methyl)amino)methyl)-N-(3-(2methyl-1 -(4-methyl-4H-1,2,4-triazo!-3yl)propan-2-yl )phenyl)-2-oxo-1 -(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide; 'HNMR (400 MHz. DMSO-d6) δ 0.86 (d, J = 6.4 Hz, 6H).1.43 (s. 6H), 1.651.68 (m. IH). 2.09 (d, J = 7.2Hz, 2H), 2.13 (s, 3H), 2.98 (s, 2H), 3.12 (s, 3H), 3.18 (d, J = 5.2Hz. 2H), 5.09 (q, J = 8 Hz. 2H), 7.04 (d, J = 8 Hz IH). 7.26 (t, J =8 Hz. IH), 7.55 (s, IH), 7.63 (d, J =8.4 Hz, IH), 8.01 (s, IH), 8.21 (s, 1 H), 8.51 (d, J = 2.4 Hz, IH), 11.77 (s, IH); ESI-MS (m/z) 533.3 (M+H)+
36	L·	Method C; A1/B8	N-(3-(2-methyl-l-(4-methyl-4H-l,2,4lriazol-3-yl)propan-2-yl)phenyl)-5-(((oxetan3-ylmethyl)amino)methyl)-2-oxo-1-(2.2,2tri Π uoroethy 1 )-1,2 -dih ydropy ridine- 3 carboxamide; 'HNMR (400 MHz, DMSO-d6) δ 1.42 (s, 6H), 2.76 (d, J = 7.2 Hz. 2H), 2.98 (s, 2H), 3.00-3.15 (m, IH), 3.12 (s, 3H), 3.58 (s, 2H), 4.2-4.30 (m, 2H), 4.55-4.70 (m. 2H), 5.09 (q. J = 9.2 Hz. 2H), 7.05 (d, J = 7.6 Hz, 1 H), 7.27 (t, J =8 Hz. 1 H), 7.54 (s, 1 H), 7.64 (d, J = 8 Hz, IH), 8.02 (s, IH), 8.21 (s, IH), 8.57 (d, J = 2.4 Hz. IH), 11.78 (s, IH); ESIMS (m/z) 533.3 (M+H)+

102

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
37		Method C; A2 / B8	N-(2-fluoro-5-(2-methyl-l-(4-methyl-4H1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5((isobutyIamino)mcthyl)-2-oxo-1 -(2,2,2trifluoroethyl)-1.2-dihydropyridine-3carboxamidc; 'HNMR (400 MHz, DMSOd6): δ 0.79 (d, J = 6.8 Hz, 6H), 1.36 (s, 6H), 1.63-1.69 (m, 1H), 2.95-2.97 (m, 2H), 3.17 (s, 3H), 3.63 (brs, 2H). 5.11 (q, J = 8.8 Hz, 2H), 7.04-7.05 (m, 1 H), 7.15-7.22 (m, 1 H), 8.07 (s, 1H), 8.22 (s, 1H), 8.47 - 8.58 (m,lH), 8.63 (s, 1H), 12.06 (s, 1H); ESI-MS (tn/z) 537.4 (M+H)+
38	N *	Method C; A2/B8	(S)-N-(2-fluoro-5-(2-methyl-l-(4-methyl4H-l,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-3carboxamide; 'HNMR (400 MHz, DMSO76) δ 0.82 (d, 7=5.2 Hz, 3H), 1.39 (s, 6H), 1.58-1.67 (m, 4H). 1.88-1.91 (m, 1H), 2.482.50 (m, 2H), 2.67-2.75 (m, 2H), 2.96 (s, 2H), 3.18 (s, 3H), 3.33 (s, 2H), 5.10 (q, J =9.2 Hz, 2H), 7.04-7.05 (m, 1H), 7.19-7.23 (m, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.47-8.51 (m. 2H), 12.05 (s, 1H); ESI-MS (m/z) 563.2 (M+H)+
39	«y .Λ	Method C; Al /B8	5-((3-Isopropylpiperidin-l-yl)methyl)-N-(3(2-methyl-1 -(4-methyl-4H-l ,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-1 -(2,2,2trifluoroethyl)- 1,2-dihydropyridine-3carboxamide (Isomer-1); 'HNMR (400 MHz, DMSO-76) δ 0.87 (d, 7 = 4.0 Hz, 6H), 1.201.23 (m, 2H), 1.45 (s, 6H), 1.72-1.84 (m. 4H),

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analyticai data
			3.24 (s, 2H), 3.35-3.39 (m, 4H), 3.57 (s, 3H), 4.22-4.28 (m, 2H), 5.08-5.12 ( m. 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz. 1H), 7.58 (s, 1H), 7.70 (d, J = 6.8 Hz. 1H), 8. 39 (s, 1H),8.75(S, 1H) 9.17 (s, 1H), 10.63 (brs, 1H), 11.58 (s, 1H); ESI-MS (m/z) 573.4 (M+H)+
40	G G 'W	Method C; Al /B8	5-((3-Isopropylpiperidin-l-yl)methyl)-N-(3(2-methyl-1-(4-methyl-4H-l,2,4-tri azol-3yI)propan-2-yl)phenyl)-2-oxo-1-(2.2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide (lsomer-2); 'HNMR (400 MHz. DMSO-d6) δ 0.87 (d, J = 4.0 Hz. 6H), 1.201.23 (m, 2H), 1.45 (s, 6H), 1.72-1.84 (m. 4H), 3.23 (s, 2H), 3.35-3.39 (m, 4H), 3.57 (s, 3H), 4.21-4.26 (m, 2H), 5.08-5.15 (m, 2H),7.14 (d, J = 7.6Hz, 1H). 7.33 (t, J = 7.6 Hz, 1H). 7.58 (s, 1 H), 7.70 (d, J = 6.8 Hz, 1 H), 8.38 (s. 1 H), 8.75 (s, 1H), 9.11 (s, 1H), 10.47 (brs. 1H), 11.59 (s, 1H); ESI-MS (m/z) 573.4 (M+H)+
41	N ^0H ‘W?	Method C; A1/B8	(S)-5-((3-(hydroxymethyl)piperidin-lyl)methyl)-N-(3-(2-methyl-l-(4-methyl-4Hl,2,4-triazol-3-yl)propan-2-yl)phcnyl)-2oxo-l-(2,2,2-trifluoroethyl)-l,2dihydropyridine-3-carboxamide; ' HNMR (400 MHz. DMSO-r/6) δ 1.12 (s, 6H), 1.671.70 (m, 2H).1.76-1.79 (m, 2H), 1.95-1.99 (m, 1H), 2.63-2.79 (m, 2H), 3.24 (s, 2H), 3.36-3.53 (m, 7H), 3.57 (s, 2H), 4.21-4.25 (m, 2H), 5.12-5.14 (m. 2H), 7.14 (d, J = 7.6 Hz. 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.58 (s, 1H),

104

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			7.70 (d. J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.75 (s, 1H), 9.15 (s, 1H), 10.52 (brs, 1H), 11.58 (s, 1H); ESI-MS (m/z) 561.4 (M+H)+
42	N CH 'W	Method C; Al / B8	5-(((2-Hydroxyethyl)amino)methyl)-N-(3-(2methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2trifluoroethyl)-l,2-dihydropyridine-3- carboxamide; 1HNMR (400 MHz, DMSOd6) 1.45 (s, 6H), 2.98-3.05 (m. 2H), 3.23 (s, 2H), 3.36 (s, 3H), 3.55-3.70 (m, 4H), 4.11 (s, 2H), 5.08- 5.14 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.8 Hz , 1H), 7.55 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 8.30 (brs, 1H), 8.79 (d, 7 = 2.4 Hz, 1H), 9.12-9 .17 (m, 3H), 11.61 (s, 1H); ESI-MS (m/z) 507.3 (M+H)+
43	w	Method C; Al /B8	5-(((2-Hydroxy-2- melhylpropyl)amino)methyl)-N-(3-(2methyl-l-(4-methyl-4H-1,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2tri fl uoroethy l )-1,2 - di h ydropyridi ne-3 carboxamidc: 1HNMR (400 MHz. DMSO76) 51.24 (d. 7 = 13.2 Hz, 6H), 1.45 (s, 6H), 2.86 (s, 2H), 3.17 (s, 2H), 3.21 (s, 3H), 4.10 (s, 2H), 5.08-5.15 (m, 2H), 7.15 (d, 7= 8.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.55 (s, 1H), 7.72 (d, 7 = 9.2 Hz, 1 H), 8.33 (s, 1 H), 8.83 (d, 7= 2.4 Hz, 1H), 8.85-8.91 (m, 2H), 9.02 (brs, 1H), 11.62 (brs, IH); ESI-MS (m/z) 535.5 (M+H)+
44	N F 1 _ν1Υη	Method C; Al /B8	5-(((2,2-Difluoroethyl)ainmo)methyl)-N-(3(2-melhyl-l-(4-methyl-4H-1.2,4-triazol-3-yl) propan-2-yl)phcnyl)-2-oxo-1-(2,2,2-

105

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			trifluoroethyl)-1,2-dihydropyridine-3carhoxamide; 1HNMR (400 MHz, DMSOdG) δ 1.4l(s, 6H), 3.21 (s, 2H), 3.45-3.72 (m, 5H), 4.17 (s, 2H), 5.11 (q, J=8.4Hz, 2H), 6.33-6.62 (m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.32 (t, J =7.6 Hz, 1H), 7.53 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 8.24 (s, 1H), 8.77 (s, 1H), 9.62 (brs, 2H), 11.61 (s, 1H); ESI-MS (m/z) 527.3 (M+H)*
45		Method C; A3/B8	(S)-N-(4-fluoro-3-(2-mcthyl-1 -(4-mcthyl4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-5((3-methylpiperidin- l-yl)methyl)-2-oxo-l(2,2,2-trilluoroethyl)-1,2-dihydropyridine-3carboxamide; 1HNMR (400 MHz, DMSOJ6) δ 0.88 (d, J = 6.4 Hz, 3H), 1.47 (s. 6H), 1.72-1.93 (m, 4H), 2.75-2.77 (m. 1H), 3.293.42 (m, 4H), 3.57 (s, 3H), 4.21 (s, 2H), 5.11 (q, 7=8.8 Hz. 2H), 7.18-7.23 (m, 1H), 7.50-7. 51(m, 1H), 7.75-7.78 (m, 1H), 8.35 (s, 1H), 8.72 (s, 1H), 9.20 (s, 1H), 10.53 (brs, 1H), 11.56 (s, 1H); ESI-MS (m/z) 563.5 (M+H)+
46		Method C; Al / B8	5-((4,4-Dimethy 1-1,4-azasilinan-1 - yl)mcthyl)-N-(3-(2-methyl-l-(4-methyl-4Hl,2,4-triazol-3-yl)propan-2-yl)phenyl)-2oxo-1 -(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide; 1 HNMR (400 MHz, DMSO-ûf6) δ 0.13 (s, 3H), 0.91 (s, 3H), 0.90-1.10 (m, 2H), 1.10-1.15 (m, 2H), 1.45 (s, 6H), 3.00- 3.15 (m, 4H), 3.22 (s, 2H), 3.34 (s, 3H), 4.22 (brs, 2H), 5.11 (q, J = 9.2 Hz, 2H), 7.14 (d, J = 8 Hz, 1H), 7.33 (t. J =8

106

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			Hz, 1H), 7.58 (s, 1H), 7.69 (d, J = 8 Hz, 1H), 8.35 (s, 1 H), 8.76 (d, J = 2.4 Hz, 1 H), 9.08 (s, 1H), 10.28 (brs. 1H), 11.59 (s, 1H); ESI-MS (m/z) 575.4 (M+H)+

Example 47

5-((Isobuty lamino)methyl)-N-(3-(( 1 s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-l-(2.2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide _n.n rZ \=/ σ s-cpj

Step-1: N-(3-(( 1 s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxol-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3-carboxamide

To a stirred solution of 2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3carboxylic acid (1.15g, 4.653 mmol) in DMF (15 mL) was added HATU (2.12 g, 5.58 mmol) and stirred at room température for 30 min. To this mixture were added DIPEA (2.4 mL, 13.96 mmol) and 3-((ls,3s)-3-methyl-l-(4-methyl-4H-1.2,4-triazol-3-yl)cyclobulyl)aniline (1.13 g, 4.653 mmol) and stirred for ovcmight. The réaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained residue was purified by flash column chromatography to yield 1.32 g of the desired compound. ’HNMR (400 MHz, DMSO-ί/ό) δ 1.08 (d. J = 4.8 Hz. 3H), 2.502.53 (m, 3H), 2.79-2.82(m, 2H), 3.16 (s, 3H), 5.08 (q, J = 8.8 Hz. 2H), 5.31 (d, J = 10.8 Hz. 1H), 5.76 (d, J = 3.6 Hz, 1H), 6.60-6.67 (m. 1H), 7.10 (d. J = 7.6Hz, 1H), 7.36-7.39 (m, 1H), 7.62-7.64 (m, 2H), 8.25 (s, 1H), 8.31 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 11.69 (s, 1H); ESI-MS (m/z) 472.4 (M+H)⁺

Step-2: 5-Formyl-N-(3-(( 1 s,3s)-3-methyl-1 -(4-melhyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxamide

107

To a stirred solution of N-(3-((1s,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trinuoroethyl)-5-vinyl-l,2-dihydropyridine-3carboxamide (5.8 g, 12.30 mmol) in THF/H2O (250 mL) were added NalCL (5.53 g, 25.83 mmol) followcd by 2.5% OsCU in t-BuOH (800 μΐ , 0.025 mmol). The réaction mixture was stirred at room température for ovemight. The reaction mixture was diluted with water and exlracted twice with elhyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield 4.72 g of the desired compound. 'H NMR (400 MHz, DMSO-dù) δ 1.08 (d, J = 4.8 Hz, 3H), 2.50-2.52(m, 3H), 2.81-2.83(m, 2H), 3.18 (s, 3H). 5.19 (q,/ = 8.8 Hz, 2H),7.13 (d,/ = 7.6 Hz. 1H),7.39 (1,/ = 7.6 Hz, 1H),7.86 (s, 1H).7.69 (d,/ = 8.4 Hz, 1H), 8.30 (s, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.94 (s, 1H), 9.81 (s, 1H), 11.25 (s, 1H); ESI-MS (m/z) 474.3 (M+H)⁺

Step-3: 5-((Isobutylamino)methyl)-N-(3-((ls,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyl) phenyl)-2-oxo-l-(2,2,2-trifluoro ethyl)-l,2-dihydropyrid ine-3-carboxamide: To a stirred solution of 5-Formyl-N-(3-((ls,3s)-3-methyl-l-(4-methyl-4H-1.2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide( (3.6 g, 7.603 mmol) and isobutyl amine (2.78 g, 38.02 mmol) in 1.2, Dichloroethane ( 120 mL) was added acelic acid (1.37 gm, 22.81 mmol) and reflux for 4 h. Cooled the reaction mixture. To this réaction mixture was added sodium triacetoxy borohydridc (4.83 gm, 22.81 mmol) portion wise and stirred at room température for ovemight. The reaction mixture was quenched with aqueous bicarbonate solution and exlracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtaincd residue was purified by flash chromatography to yield 2.1 g of the desired product. 'H NMR (400 MHz, DMSO-<76) δ ’H NMR (400 MHz. DMSO-J6): δ 0.87 (d. J = 6.8Hz, 6H), 1.09 (d, / = 4.4 Hz. 3H), 1.66 -1.69 (m, 1H), 2.29 -2.30 (m, 2H), 2.50 - 2.52 (m, 3H), 2.80-2.82 (m, 2H), 3.18 (s, 3H), 3.58 (s, 2H), 5.11 (q,/ = 8.4 Hz, 2H), 7.10 (d,/= 8.0 Hz. 1H), 7.38 (t, / = 8.0 Hz, 1H), 7.56 (s, 1H), 7.66 (d,/ = 8 Hz, 1H), 8.02 (s, 1H), 8.30 (s, 1H), 8.57 (s, 1H), 11.84 (s, 1H); ESI-MS (m/z) 531.4 (M+H)⁺

The details of synlhesis and analytical data of the examples prepared from the above mentioned methods arc given below in Tablc-14. The raccmic compounds were prepared from

the above mentioned methods and separated using SFC purification to obtain respective chiral isomers (Examplc 60-69).

Table-14: Structure, Chemical name, method, intermediate used and analytical data of Examples (48-94)

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
48		Method C; A5 / B8	N-(3-((ls,3R)-3-mcthyl-l-(4-mcthyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phcnyl)-5-(((S)3-piperidin- l-yl)methyl)-2-oxo-1 -(2,2,2trifluoroethy 1)-1,2-dihydropy ridi ne-3 carboxamidc; 1HNMR (400 MHz, DMSOd6): Ô 0.82 (d, 7=5.6 Hz, 3H), 1.08 (d, 7= 4.8 Hz, 3H), 1.44-1.47 (m. 1H), 1.58-1.67 (m, 3H), 1.85-1.87 (m, 1H), 2.50 - 2.5l(m, 5H), 2.68-2.82 (m, 4H). 3.17 (s, 3H), 3.34 (s, 2H), 5.06-5.13 (m, 2H),7.10 (d, 7 = 8.0 Hz, 1H), 7.37 (t, 7= 8.0 Hz, 1H), 7.58 (s, 1H), 7.64 (d. 7 = 8.4 Hz, 1H), 8.00 (s, 1H), 8.30 (s, 1H), 8.47 (d, J = 3.2 Hz, 1H), 11.81 (s, 1H); ESIMS (zm/z) 557.4 (M+H)+
49	V/ σ v-cf,	Method C; A6/B8	N-(2-fluoro-5-((ls,3s)-3-mcthyl-l-(4methyl-4H-l,2,4-lriazol-3yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-1-(2,2,2lrifluoroethyl)-l,2-dihydropyridine-3carboxamide; 1HNMR (400 MHz, DMSO¢/6): δ 0.87 (d, 7 = 6.4 Hz, 6H), 1.08 (d, J = 4.8 Hz, 3H), 1.63-1.71 (m, 1 H), 2.26-2.28 (m, 2H), 2.49-2.52 (m. 3H), 2.68-2.78 (m, 2H), 3.19(s, 3H), 3.54-3.57 (m, 2H), 5.06-5.13 (m, 2H), 7.07-7.08 (m, 1H), 7.29-7.34 (m, 1H), 8.04 (s, 1H), 8.31 (s, 1H), 8.50-8.52 (m, 1H),

109

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			8.59 (d, J = 2.4 Hz, 1H), 12.16 (brs. 1H); ESI- MS (m/z) 549.3 (M+H)+
50		Method C; A6/B8	N-(2-nuoro-5-(( 1 s,3R)-3-methyl-1 -(4methyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)-5-(((S)-3methylpiperidin-l-yl)melhyl)-2-oxo-l(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide; 1HNMR (400 MHz. DMSOJ6): δ 0.82 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 5.2 Hz, 3H), 1.44-1.47 (m, 1 H), 1.53-1.58 (m, 3H), 1.85-1.88 (m, 1H), 2.34-2.51(m, 5H), 2.68-2.78 (m, 4H), 3.19 (s, 3H), 3.34 (s, 2H), 5.09-5.1 l(m. 2H), 7.07-7.08 (m. 1H), 7.297.34 (m. 1 H), 8.04 (s, 1H), 8.31 (s, 1H), 8.478.49 (m. 2H),8.3O(s, 1H), 12.13 (s, 1H); ESIMS (m/z) 575.4 (M+H)+
51		Method C; A5/B8	5-(((2-Hydroxy-2- methylpropyl)amino)methyl)-N-(3-((ls,3s)3-methyl-1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phcnyl)-2-oxo-1-(2,2,2trifluoroethyl)-1.2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz. DMSO-d6) δ 1.07-1.10 (m, 9H), 2.41-2.50 (m, 5H), 2.81 (s, 2H), 3.17 (s, 3H), 3.68 (s, 2H), 4.34 (brs, 1H), 5.05-5.12 (m, 2H), 7.11 (d, 7 = 7.6 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.66 (d. J = 8.8 Hz. 1H), 8.05 (s, 1H), 8.29 (s, 1H), 8.60 (s, 1H), 11.81 (s, 1H); ESI-MS (m/z) 547.3 (M+H)+
52		Method C; A10/B8	N-(2-chloro-5-(( 1 s,3R)-3-mcthyl-1 -(4methyl-4H-1,2,4-triazol-3-

110

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			yl)cyclobutyl)phenyl)-5-(((S)-3methylpiperidin-1 -yl)methy l)-2-oxo-l (2,2,2-trifluorocthyl)-I,2-dihydropyridinc-3carboxamide; 'HNMR (400 MHz. DMSO-J6) δ 0.80-0.83 (m. 3H), 1.45-1.10 (m, 4H), 1.80 (m, 1H), 2.50-2.56 (m, 5H), 2.73-2.78 (m. 4H), 3.19 (s, 3H), 5.09-5.11 (m, 2H), 7.056 (d, J = 8.4 Hz. 1H), 7.52 (d, J=8.4Hz. 1H), 8.03 (s, 1H), 8.31 (s, 1H), 8.52 (s, 1H), 8.61 (s, 1H), 12.22 (s, 1H); ESI-MS (m/z) 592 (M+H)+
53		Method C; A10/B8	N-(2-chloro-5-((ls,3s)-3-methyl-l-(4methyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-1 -(2,2,2trifluoroethyl )-1,2-dihydropyridine-3carboxamide; *H NMR (400 MHz, DMSOd6) δ 0.870 (d, J= 6.8 Hz, 6H), 1.86 (d, J = 4.8 Hz,3H), 1.67-1.69 (m,lH), 2.33-2.65 (m, 5H), 2.79 (s, 2H), 3.19 (s, 3H), 3.62 (s, 2H), 5.075.13 (m. 2H), 7.07 (d. J= 8.4 Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 8.06 (s, 1H), 8.31 (s, 1H), 8.60(s, 1H), 8.64 (s, 1H), 12.23 (s, 1H); ESIMS (m/z) 566.55 (M+2H)+
54		Method C; A5/B8	N-(3-((ls,3s)-3-methyl-l-(4-methyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phcnyl)-5-(((lmethylcyclopropyl)amino)melhyl)-2-oxo-l(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide; 'HNMR (400 MHz, DMSO</6): δ 0.34-0.51(m, 4H), 1.07-1.11 (m, 3H), 1.25 (s, 3H), 2.49-2.52 (m, 3H), 2.81 (s, 2H),

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			3.17 (s, 3H), 3.66 (s, 2H), 5.04-5.11 (m. 2H), 7.10 (d, J=7.6Hz, 1 H), 7.37 (t, J=8.0Hz, 1H), 7.56 (s, IH), 7.65 (d, J=7.2Hz, IH), 8.03 (s, IH), 8.29 (s, IH), 8.53 (s, IH), 11.82 (s, IH); ESI-MS (m/z) 529.4 (M+H)+
55	v-CFj	Method C; A5 ! B8	N-(3-(( ls.3S)-3-methyl-l -(4-melhyl-4Hl,2,4-triazo]-3-yl)cyclobutyl)phenyl)-5(((R)-3-methylpiperidin-1 -yl)methyl)-2-oxol-(2,2,2-trifluoroethyl)-l,2-dihydropyridine3-carboxamide; 'HNMR (400 MHz, DMSO76): δ 0.82 (d. J=5.2Hz, 3H), 1.08 (d, J=4.8Hz, 3H), 1.23 (s, IH), 1.47-1.67 (m, 4H), 1.87 (m, IH), 2.48-2.55 (m, 5H), 2.722.8l(m, 4H), 3.17(s,3H), 3.32-3.35(m,2H), 5.06-5.12 (m, 2H), 7.10(d, J = 7.6 Hz, IH), 7.34 (t. J=8.0Hz, IH), 7.57 (s, IH), 7.64 (d, J=8.4Hz, IH), 8.00 (s, IH), 8.29 (s, IH), 8.47(s, IH), 11.80 (s, IH); ESI-MS (m/z) 557.6 (M+H)+
56		Method C; A5/B8	N-(3-(( 1 s,3s)-3-mcthyl-1 -(4-mcthy 1-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyI)-5-(((lmethylcyclobutyl)amino)methyl)-2-oxo-l-(2, 2,2-trifluorocthyl)-1,2-dihydropyridinc-3carboxamide; 'HNMR (400 MHz, DMSO76): δ 1.09 (t, J=8.8Hz. 3H), 1.22(s, 3H), 1.65-1.69 (m, 4H), 1.91-1.96 (m, 2H), 2.492.52 (m, 3H). 3.17 (s, 2H), 3.33 (s, 3H), 3.52 (s,2H), 5.07-5.11 (m, 2H), 7.10 (d, J=6.8Hz, IH), 7.37 (t, J = 8.0 Hz, IH), 7.57 (s, IH), 7.65 (d, 7=8.0 Hz, IH), 8.04(s, IH), 8.30 (s,

112

Example No.	Structure	Method and Intennediate	Chemical Name and Analytical data
			1H), 8.57 (s, 1H), 11.84 (s, 1H); ESI-MS (m/z) 543.4 (M+H)+
57	x-/ σ v. cf j	Method C; A5/B8	5-(((2-Ethylbutyl)amino)methyl)-N-(3- (( 1 s,3s)-3-methyl-l -(4-methyl-4H-l ,2,4triazol-3-yI)cyclobutyl)phenyl)-2-oxo-l(2,2,2-tri fl uoroelhy 1 )-1,2 -dih ydropyridine-3 carboxamide; 1HNMR (400 MHz, DMSOî/6): 6 0.80 (t, 7=6.8Hz, 6H), 1.08(d, 7=3.2Hz, 3H), 1.23-1.35 (m, 5H), 2.40-2.53 (m, 5H), 2.75-2.81 (m. 2H), 3.17 (s, 3H), 3.58 (s. 2H), 5.05-5.12 (m. 2H), 7.10 (d, 7 = 7.2 Hz, 1H), 7.37 (t, 7=8.0Hz, 1H), 7.55 (s, 1H), 7.66 (d, 7 = 8.8 Hz, 1H), 8.01 (s, 1H), 8.29 (s, 1H), 8.57 (d, 7 = 2.4 Hz, 1H), 11.83 (s, 1H); ESI-MS (m/z) 559.6 (M+H)+
58	' ( VNH En 0 '-CF,	Method C; A5 / B8	N-(3-((ls,3s)-3-methyl-l-(4-methyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3methylbutan-2-yl)amino)methyl)-2-oxo-l(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamidc (lsomer-1): 'HNMR (400 MHz, DMSO-di): δ 0.83-0.9 (m, 9H), 1.08 (d, J = 2.8 Hz, 3H), l.63-1.65(m, 1H), 1.98-2.01 (m, 1H), 2.36-2.37 (m. 3H), 2.80-2.81 (m, 2H), 3.25 (s, 3H), 3.52-3.64 (m, 2H), 5.10 (q, 7 = 8.8 Hz, 2H), 7.09(d, 7 = 8 Hz, 1 H), 7.37(t, 7 = 8 Hz, 1H), 7.57(s, 1H), 7.65 (d, 7 = 5.6 Hz, 1H), 8.02(s, 1H), 8.3 (s, 1H), 8.58(s, 1H), 11 _85(s, 1H); ESI-MS (m/z) 545.4 (M+H)+

113

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
59	n-vÏ n il N 7 ' f Vnh >n Ü ^CI-3	Method C; A5/B8	N-(3-((ls,3s)-3-methyl-l-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3mcthylbutan-2-yl)amino)mcthyl)-2-oxo-l(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamidc (Isomer-2): ‘HNMR (400 MHz, DMSO-dô): δ 0.81-0.92(m. 9H), 1.08(d, J = 2.8 Hz, 3H), 1.66-1.68(m, 1H), 2.37-2.39 (m, 3H), 2.79-2.81 (m, 2H), 3.17 (s, 3H), 3.573.63 (m, 2H), 5.10 (q, J = 7.6 Hz, 2H), 7.09(d, 7= 7.6 Hz, 1H), 7.37 (t. 7 = 8 Hz, IH), 7.57(s, 1H), 7.66 (d, J = 5.6 Hz, 1H), 8.03(s, 1H), 8.3 (s, 1H), 8.59(s, 1H), 11 _84(s, 1H). ESI-MS (m/z) 545.4 (M+H)+
60	' C ΓΝΗ >b 0 '-ΓΗ,	Method C; A5/B8	N-(3-(( 1 s,3s)-3-methyl-1 -(4-methy I-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2methylbutyl)amino)methyl)-2-oxo-1-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide (Isomer-1): ‘H NMR (400 MHz, DMS0-d6): δ 0.81-0.86 (m, 6H), 1.04-1.08 (m, 3H), 1.38-1.47 (m, 2H), 2.26 - 2.28 (m, 3H), 2.33-2.50 (m. 2H), 2.80 (s, 2H). 3.17 (s,3H), 3.57 (s, 2H), 5.05-5.12 (m. 2H), 7.10 (d, 7= 8 Hz. 1 H),7.38 (t. 7= 7.6 Hz, 1H),7.55 (s, 1H), 7.66 (d, 7= 8 Hz, 1H), 8.01 (s, 1H), 8.29 (s. 1 H), 8.56 (s, 1 H), 11.83 (s, 1 H); ESIMS (m/z) 545.5 (M+H) +
61	VN ri /-Nli^—	Method C; A5/B8	N-(3-(( 1 s,3s)-3-methyl-1 -(4-methyl-4Hl,2,4-triazol-3-yl)cyclobulyl)phenyl)-5-(((2methylbutyl)amino)methyl)-2-oxo-1 -(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide (Isomer-2): ‘H NMR (400 MHz,

114

Example No.	Structure	Method and Intennediate	Chemical Name and Analytical data
			DMSO-d6): δ 0.81-0.86 (m, 6H), 1.05-1.08 (m, 3H), 1.38-1.45 (m, 2H), 2.27 - 2.28 (m, 3H), 2.33-2.50 (m, 2H), 2.80-2.81 (m, 2H), 3.17 (s, 3H), 3.57 (s, 2H), 5.07-5.09 (m. 2H), 7.10 (d, J= 8 Hz,IH),7.37 (t, J= 7.6 Hz, 1H),7.55 (s, IH), 7.66 (d, J= 8 Hz, 1H),8.O1 (s, IH), 8.29 (s. IH), 8.56 (s, IH), 11.83 (s, IH); ESI-MS (m/z) 545.5 (M+H) +
62		Method C; A21/B8	N-(3-(cyclobutyl(4-methyl-4H-l,2,4-triazol3-yl)methyl)phenyl)-5((isobutylamino)methyl)-2-oxo-l -(2,2,2trifluoroethyl)-l,2-dihydropyridine-3carboxamide (Isomer-1): 'HNMR (400 MHz, DMSO-dâ) δ 0.87(d, J = 6.4 Hz. 6H), 1.651.78 (m, 6H), 2.08-2.09 (m, lH),2.40-2.49(m, 2H), 3.11-3.15(m, IH), 3.39( s, 3H), 3.693.7l(m, 2H), 4.19 (d. J =10.4 Hz, IH). 5.10 (q, J = 9.2 Hz, 2H), 7.01(d, 7=4.4 Hz, IH), 7.31(t, 7=7.6 Hz, IH), 7,42 (s, IH), 7.71(d, 7= 8.4 Hz, IH), 8.07 (s, IH), 8,32 (s, IH), 8.61(s, IH), 11.80(s, IH); ESI-MS (m/z) 531.3 (M+H)+
63		Method C; A21 /B8	N-(3-(cyclobutyl(4-mcthyl-4H-l,2,4-triazol3-yl)methyl)phenyl)-5((isobutylamino)methyl)-2-oxo-1 -(2,2,2tri fluoroethy 1 )-1,2-di h ydropyridine-3carboxamide (Isomer-2): 'HNMR (400 MHz, DMSO-de) δ 0.87 (d, 7 = 6.4 Hz, 6H),1.651.78 (m, 6H),2.08-2.09 (m, lH),2.40-2.49(m, 2H), 3.1 l-3.15(m, IH), 3.39( s, 3H), 3.693.71(m.2H), 4.19 (d, 7=10.4Hz, IH), 5.10 (q,

115

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			J = 9.2 Hz. 2H). 7.01 (d, 7=4.4 Hz. 1H), 7.31 (t, 7=7.6 Hz. 1 H), 7.42(s, 1 H), 7.71 (d, J= 8.4 Hz, 1H), 8.07 (s, 1H), 8.32 (s, 1H), 8.61(s, 1H), 11.80 (s, 1H); ESI-MS (m/z) 531.3 (M+Hf
64	' \ /-KH /S '-C 0^ ^ίΤ. F	Method C; A22 / B8	N-(5-(cyclobutyl(4-melhyl-4H-l,2,4-triazol3-yi)methyl)-2-fluorophenyl)-5((isobutylamino)methyl)-2-oxo-1-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide (Isomer-1): ]HNMR (400 MHz, DMSO-dô) δ 0.88 (d, 7 = 6.8 Hz, 6H),1.701.83 (m. 6H), 2.07-2.09 (m, 1H), 2.36-2.40 (m. 2H), 3.13-3.16 (m, 1H), 3.40 (s, 3H), 3.66 (s,2H), 4.21 (d. J= 10.8Hz. 1H), 5.10 (q, 7 = 9.2 Hz. 2H). 6.99-7.02(m. 1 H), 7.24-7.29 (m. 1H), 8.07 (s, 1H), 8.33 (s, 1H), 8.34-8.36 (m, 1H), 8.62 (s, 1H), 12.07 (s. 1H); ESI-MS (m/z) 549.3 (M+H)+
65	F	Method C; A22 ! B8	N-(5-(cyclobutyl(4-methyl-4H-l,2,4-triazol3-yl)mcthyl)-2-fluorophenyl)-5((isobutylamino)methyl)-2-oxo-1 -(2,2.2t ri fluoroethy 1 )-1,2-dihydropyridi ne- 3 carboxamidc (Isotncr-2): 'H NMR (400 MHz, DMSO-dô) δ 0.88(d, 7 = 6.8 Hz. 6H),1.701.83 (m. 6H). 2.07-2.09 (m. 1H). 2.36-2.40 (m, 2H), 3.13-3.16(m, 1H), 3.40 ( s, 3H), 3.66(s,2H). 4.21(d, 7=10.8Hz, 1H). 5.10 (q, 7 = 9.2 Hz. 2H), 6.99-7.02(m. IH), 7.247.29(m. 1H). 8.07(s, 1H), 8.33(s, 1H), 8.348.36(m. 1H). 8.62(s, 1H). 12.07(s, 1H); ESIMS (m/z) 549.3 (M+H)+

116

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
66	0* '-CF,	Method C; A21 /B8	N-(3-(cyclobutyl(4-methyl-4H-l,2,4-triazol3-yl)methyl)phenyl)-5- (((cyclopropylmcthyl)amino)mcthyl)-2-oxol-(2,2,2-trifluoroethyl)- 1,2-dihydropyridine3-carboxamidc (ïsomcr-1): *HNMR (400 MHz, DMSO-dft): δ 0.11 (d, J =4.4 Hz, 2H), 0.39-0.43 (m, 2H), 0.89 (m, 1H), 1.65-1.83 (m, 6H), 2.10 (m, 7=5.2Hz, 1H), 2.39-2.43 (m, 2H), 3.14 (d, 7=7.2Hz, 1H), 3.37 (s, 3H), 3.64 (s, 2H), 4.19(d, 7=10.8Hz, 1H), 5.065.12 (m. 2H), 6.91(d, J =7.6 Hz, 1H), 7.32 (t, 7=7.6 Hz, 1H), 7.42 (s, 1H), 7.71 (d, 7= 7.6 Hz, 1H), 8.03 (s, 1H), 8.32(s, 1H), 8.56 (d, J=2.4Hz. 1H), 11.83 (s, 1H); ESI-MS (m/z) 529.52 (M+H)+
67	0 '-CF,	Method C; A21 /B8	N-(3-(cyclobutyl(4-methyl-4H-l,2,4-triazol3-yl)methyl)phenyl)-5- (((cyclopropylmethyl)amino)methyl)-2-oxol-(2,2,2-trifluorocthyl)-1,2-dihydropyridine3-carboxamide (Isomer-2): 'HNMR (400 MHz, DMSO-dâ): δ 0.14 (d. J =4.8 Hz, 2H), 0.44 (d, 7=7.2Hz. 2H), 0.85 (m. 1H), 1.671.78 (m, 6H), 2.08 (m, 1H), 2.45-2.54 (m, 2H), 3.14 (m, 1H), 3.37 (s, 3H), 3.70 (s, 2H), 4.19 (d, 7= 10.4Hz, 1H), 5.06-5.13 (m. 2H), 6.70(d. 7=5.2 Hz, 1H), 7.3 l(t, J=7.6 Hz, 1H), 7.42(s, 1H), 7.71(d, 7= 8.4 Hz, 1H), 8.32 (s, 1H), 8.59 (d. 7=2.4Hz, 1H), 11.81 (s, 1H); ESI-MS (m/z) 529.55 (M+Hf
68	V»/ σ \-cf.	Method C; A6/B8	N-(2-fluoro-5-(( 1 s.3s)-3-methyl-1 -(4methyl-4H-l,2,4-triazol-3-

117

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			yl)cyclobutyl )phenyl)-5 ((neopentylamino)methyl)-2-oxo-1 -(2,2,2trifluorocthy 1 )-1,2-di h ydropyridinc-3 carboxamide: ‘HNMR (400 MHz. DMSOd^: δ 0.86 (s, 9H). 1.08 (d. J = 4.4 Hz. 3H), 2.20-2.22 (m, 2H), 2.51-2.55 (m. 3H), 2.772.79 (m. 2H), 3.19 (s, 3H), 3.59-3.61 (m. 2H), 5.10 (q, J = 8.8 Hz, 2H), 7.08 (d, J = 2.8 Hz, IH), 7.32 (t, 7 = 9.2 Hz, IH), 8.04 (s, IH), 8.3 (s, IH), 8.50 (d, J = 6.4 Hz, IH), 8.62 (s. IH), 12.15 (s, IH); ESI-MS (m/z) 563.3 (M+H)+
69	OFi	Method C; A6/B8	5-(((2-Ethoxyethyl)amino)methyl)-N-(2fluoro-5-((ls.3s)-3-methyl-l-(4-melhyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxol-(2,2,2-lrinuoroelhyl)-l,2-dihydropyridine3-carboxamide: 'HNMR (400 MHz. DMSOd6): δ 1.08-1.13 (m, 6H), 2.54-2.55 (m, 3H), 2.65-2.68 (m, 2H), 2.77-2.79 (m. 2H), 3.19 (s, 3H), 3.39-3.46 (m, 4H), 3.4 (d, 7 = 6.8 Hz, 2H), 5.10 (q, 7 = 8.8 Hz, 2H), 7.08 (d, 7 = 4.8 Hz, IH), 7.29-7.34 (m, IH), 8.05(s, IH), 8.31 (s, IH), 8.50 (d, 7 = 6.4 Hz, IH), 8.61 (s, IH), 12.12 (s, IH); ESI-MS (m/z) 565.3 (M+H)+
70	/ ,—^OEL	Method C; A6/B8	N-(2-fluoro-5-((ls,3s)-3-methyl-l-(4methyl-4H-1,2,4-triazol-3-yl)cyclobutyl) phcnyI)-5-(((2-hydroxy-2methylpropyl)amino)methyl)-2-oxo-l-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide: ’HNMR (400 MHz, DMSOd6): 51.06-1.07 (m, 3H), 1.08 (s, 3H), 1.09 (s, 3H), 2.40 -2.50 (m, 2H), 2.53 - 2.60 (m, 3H),

118

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			2.67-2.70(m. 2H), 3.18(s, 3H), 3.63 (brs, IH), 4.23 (s, IH), 5.06-5.13(m, 2H), 7.0-7.08 (m, IH), 7.29-7.34(m. IH), 8.05 (s, IH), 8.30 (s, IH), 8.50 (d. 7=7.2 Hz, IH), 8.60 (s, IH), 12.14 (brs, IH); ESI MS (m/z) 565 (M+H)+
71		Method C; A6/B8	N-(2-0uoro-5-(( 1 s,3s)-3-melhyl-1 -(4methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((( 1methylcyclobutyl)amino)methyl)-2-oxo-l(2,2,2-trifIuoroethyl)-l,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DMSOί/6): δ 1.08 (s, 3H), 1.23(s, 3H), 1.69-1.71 (m, 4H), 1.95 (m, 2H). 2.50 - 2.52 (m, 3H), 2.78 (m, 2H), 3.19 (s, 3H), 3.53 (s,2H), 5.08-5.10 (m, 2H), 7.07 (s, IH), 7.31 (t, 7=9.6Hz, IH), 8.07 (s, IH), 8.31 (s, IH), 8.50 (s, IH), 8.61 (s, IH), 12.15 (s, IH); ESI-MS (m/z) 561.3 (M+H)+
72		Method C; A6/B8	N-(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4mcthyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-5-((tertpentylamino)methyl)-1-(2,2,2trifluoroethyl)-1,2-dihydropyridinc-3 carboxamide: 'HNMR (400 MHz. DMSO76): Ô 0.85 (t, 7=7.2Hz, 3H), 1.05-1.19 (m, 9H), 1.43 (m, 2H), 2.51 (m, 3H), 2.67-2.79 (m, 2H), 3.19 (s, 3H), 3.43-3.57 (m, 2H), 5.06-5.13 (m, 2H), 7.08 (s, IH), 7.29-7.34 (m, IH), 8.08 (s, IH), 8.30 (s, IH), 8.50 (d, 7=6.8Hz, IH), 8.61 (s, IH), 12.13 (s, IH); ESI-MS (m/z) = 563.8 (M+H)+

119

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
73		Method C; A5 ! B9	1 -(Cyclopropy 1 methy l)-5 - ((isobutylamino)methyl)-N-(3-(3-methyl-l(4-mcthyl-4H-l,2,4-triazol-3-yl)cycIobutyl) phenyl)-2-oxo-1,2-dihydropyridine-3carboxamidc: 'HNMR (400 MHz, DMSO-dj δ 0.45 - 0.62 (m, 4H), 0.88 (d, J = 6.4 Hz, 6H), 1.08 (d. J = 6.4 Hz. 3H).1.23- 1.41 (m. 1H), 1.60- 1.80 (m, 1H), 2.20- 2.40 (m, 2H), 2.42- 2.59 (m, 3H), 2.70- 2.85 (m, 2H), 3.18 (s, 3H). 3.6 (bs, 2H), 3.94 (d, J = 7.2 Hz. 2H), 7.09 (d, J = 7.2 Hz, 1H), 7.37 (t. J = 8.4 Hz, 1 H), 7.56 (s. 1 H), 7.66 (d. J = 8.4 Hz, 1 H), 8.1 (s, 1H), 8.3 (s, 1H), 8.52 (s, 1H) 12.26 (s, 1H); ESI-MS (m/z) 503.4 (M+H) +
74		Method C; A5/B8	N-(3-(( ls.3s)-3-methyl-1 -(4-melhyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((neopentylamino)melhyl)-2-oxo-1-(2.2.2trifluoroethyl )-1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DMSOd6): δ 0.87( s, 9H), 1.09 (d. J = 2.4 Hz. 3H), 2.22 (m. 2H), 2.50-2.54 (m. 3H), 2.81 (d, J = 3.6Hz, 2H), 3.17(s, 3H), 3.60 (s, 2H), 5.055.12 (m. 2H). 7.11 (d, J=7.2Hz. 1 H), 7.37 (t, J = 8.0 Ηζ,ΙΗ), 7.55 (s, 1H), 7.61 (d, J = 8.0 Hz.lH), 8.01 (s,lH), 8.29 (s,lH), 8.60 (s, 1H), 11.82 (s, 1 H); ESI-MS (m/z) 545 (M+H)+
75		Method C; A6/B8	5-(((Cyclopropylmelhyl)amino)methyl)-N(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4-methyl4H-1,2,4-triazol-3-yl)cyclobuty l)phenyl )-2oxo-1 -(2,2.2-triiluoroethy 1)-1,2- dihydropyridine-3-carboxamide: ‘HNMR

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(400 MHz. DMSO-de): δ 0.14(d. 7=4.4 Hz. 2H), 0.44(d, 7=7.6 Hz, 2H), 0.90-0.92(m. 1H), 1.08(d, 7 = 4.8 Hz, 3H), 2.45-2.47 (m, 2H), 2.51-2.55 (m, 3H), 2.77-2.79 (m, 2H), 3.19 (s, 3H), 3.7O(s, 2H), 5.12(q, 7 = 8.8 Hz. 2H), 7.08-7.10(m. 1H), 7.3O-7.35(m. 1H), 8.09(s, 1H), 8.31 (s, 1H). 8.48(d. 7 = 6 Hz, 1H), 8.63(s, 1H), 12.10 (brs, 1H). ESI-MS (m/z) 547.3 (M+H)+
76		Method C; A6/B9	l-(Cyclopropylmcthyl)-N-(2-fluoro-5-(3methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyI)phenyl)-5((isobutylamino)methyl)-2-oxo-l,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-Jô) δ 0.40- 0.60 (m, 4H). 0.89 (d, 7 = 6.8 Hz. 6H), 1.08 (d, 7 = 4.8 Hz, 3H),1.3O- 1.45 (m. 1H), 1.60- 1.80 (m, 1H), 2.20- 2.40 (m, 2H), 2.40- 2.60 (m, 3H), 2.702.85 (m, 2H). 3.19 (s, 3H). 3.65 (s. 2H). 3.94 (d, 7 = 7.2 Hz, 2H). 7.00- 7.10 (m. 1 H), 7.30 (t, J = 8.8 Hz. 1H), 8.14 (s, 1H), 8.3 (s. 1H), 8.51 (d, 7 = 6.8 Hz. 1H), 8.55 (s, 1H), 12.52 (s, 1H); ESI-MS (m/z) 521.5 (M+H)+
77		Method C; A6/B8	5-((Ethylamino)melhyl)-N-(2-fluoro-5- (( 1 s,3s)-3-methy 1-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phcnyl)-2-oxo-l(2,2,2-trinuoroethyl)-l,2-dihydropyridine-3carboxamide: *HNMR (400 MHz, DMSOdb): δ 1.02-1.09(m, 6H), 2.32-2.33 (m, 2H), 2.50-2.51 (m. 3H), 2.77-2.79 (m, 2H), 3.18 (s, 3H), 3.59-3.61 (m, 2H), 5.10(q, 7 = 8.6 Hz,

121

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			2H), 7.07-7.10(m, 1H), 7.29-7.34(m. 1H), 8.05(s, 1H), 8.31 (s, 1 H), 8.48-8.50 (m, 1H), 8.59(d. 7=2.4 Hz, 1H), 12.13(brs, 1H); ESIMS (m/z) 521.44 (M+H)+
78		Method C; A5/B8	5-(((2-Fluoro-2methylpropyl)amino)methyl)-N-(3-(( 1 s,3s)3-methy i-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2tri fluoroethy 1 )-1,2 -dih ydropyridine-3 carboxamide: ’HNMR (400 MHz, DMSO76): δ 1.09 (t. 7=8.8Hz, 3H), 1.28 (s, 3H), 1.33 (s, 3H), 2.50-2.67 (m, 5H), 2.81 (d, 7 = 3.2 Hz, 2H), 3.17 (s. 3H), 3.38 (d, 7 = 7.2Hz, 3H), 3.62 (s, 2H), 5.05-5.12 (m, 2H ), 7.10 (d, 7=7.2Hz,lH), 7.37 (l, 7=8.0Hz, 1H), 7.56 (s, 1H), 7.65 (d. 7=6.8Hz, 1H), 8.01 (s, 1H), 8.29 (s,lH), 8.58 (d. 7=2.4Hz, 1H), 11.83 (s.lH); ESI-MS (m/z) 549.49 (M+H)+
79		Method C; A7/B8	N-(3-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4mcthyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-1 -(2,2,2trifluorocthyl)-l,2-dihydropyridinc-3carboxamide; 1HNMR (400 MHz, DMSO76) δ 0.98 (d, 7 =8.0 Hz, 6H), 1.08 (d, 7 =7.2 Hz, 3H), 1.63-1.70 (m, 1H), 2.28 (d, 7 =6.4 Hz, 2H ), 2.52-2.55 (m, 3H), 2.82-2.89 (m, 2H), 3.23 (s, 3H), 3.57 (s, 2H), 5.07 (q, 7 =8.8 Hz, 2H),6.95-7.00 (m,lH), 7.14 (s, 1H), 7.23 (d,7 = 10.8 Hz, lH),8.02(s, 1H), 8.31 (s, 1H),

Example No.	Structure	Method and Intennediate	Chemical Name and Analytical data
			8.55 (s, 1H), 11.93 (s, 1H); ESI-MS (m/z) = 549.1 (M+H)*
80		Method C; A10/B9	N-(2-chloro-5-(3-methyl-l-(4-methyl-4H1,2,4-triazol-3-yl)cyclobutyl)pheny 1)-1 (cyclopropylmethyl)-5((isobutylamino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide; 'HNMR (400 MHz, DMSO-dô) 5 0.3- 0.7 (m, 4H), 0.89 (d, J = 6 Hz, 6H), 1.09 (d, J = 4.8 Hz, 3H),1.2-1.35 (m, 1H), 1.50-1.75 (m, 1H), 2.20- 2.40 (m, 2H), 2.4- 2.6 (m, 3H), 2.6- 2.8 (m, 2H), 3.2 (s, 3H), 3.64 (s, 2H), 3.94 (d, J = 6.8 Hz. 2H). 7.05 (d, J = 8 Hz. 1H), 7.52 (d, J = 8.8 Hz, 1 H), 8.15 (s, 1H), 8.31 (s, 1H), 8.57 (s, 1H), 8.62 (s. 1H), 12.62 (s, 1H); ESI-MS (m/z) 537.3 (M+H) +
81		Method C; A5/B9	1 -(Cyclopropylmcthyl)-5- (((cyclopropylmethyl)amino)methyl)-N-(3(3-methyI-1 -(4-methyl-4H-l ,2,4-triazol-3yl)cyclobutyl)phcnyl)-2-oxo-l,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-dâ) δ 0.1- 0.2 (m. 2H). 0.20.7 (m, 6H), 0.8- 1.2 (m, 5H), 2.42 (m, 2H), 2.5- 2.65 (m. 3H), 2.70- 2.85 (m, 2H), 3.33 (s, 3H), 3.67 (bs, 2H), 3.94 (d, J = 6 Hz, 2H), 7.09 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.66 (d, 7 = 7.2 Hz, 1H), 8.12 (s, 1H), 8.3 (s, 1H), 8.53 (s, 1H) 12.23 (s, 1H); ESI-MS (m/z) 501.5 (M+H)+

123

Example No.	Structure	Method and Intermediate	Chemical Name and Analyticai data
82		Method C; A6/B9	l-(Cyclopropylmethyl)-5- (((cyclopropylmethyl)amino)methyl)-N-(2fluoro-5-((ls,3s)-3-mcthyl-l-(4-methyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo1,2-dÎhydropyridinc-3-carboxamidc; ’HNMR (400 MHz, DMSO-dô): δ 0.I7(d, J =4.4 Hz, 2H), 0.45-0.53(m, 6H), 0.92-1.32 (m, 5H), 2,47-2.49 (m, 2H), 2.51-2.55 (m, 3H), 2.762.78 (m, 2H), 3.19 (s, 3H), 3.72 (s, 2H), 3.94(d. J =7.2 Hz, 2H), 7.07-7.09 (m, 1H). 7.29-7.33(m. 1H), 8.18 (s, 1H), 8.31 (s, 1H), 8.52 (t, J =2 Hz. 1 H), 8.57 (d, J =2.4 Hz, 1 H), 12.49 (brs. 1H); ESI-MS (m/z) 519.5 (M+H)+
83	r/ ^-ΝίτΦ λ—( σ Λ-cf, r ι	Method C; A10/B8	N-(2-chloro-5-(( 1 s,3s)-3-methyl-l -(4melhyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyI)-5((neopenlylamino)methyl)-2-oxo-1-(2,2,2trifluoroethy] )-1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DMSOd6): Ô 0.87 (s. 9H), 1.08 (d. 7=3.6Hz. 3H), 2.22 (s, 2H), 2.50-2.54 (m, 3H), 2.78 (s,2H), 3.19 (s,3H), 3.60 (s,2H), 5.06-5.11 (m, 2H ), 7.06 (d, 7= 9.2 Hz, 1H), 7.53 (d. J = 8.42 Hz, 1H), 8.04 (s,lH).8.31 (s,lH),8.60 (s,lH), 8.64 (s,lH), 12.24 (s.lH); ESI-MS (m/z) 579.4 (M+H)+
84	\=/ σ ^γρ.	Method C; A10/B8	N-(2-chloro-5-((ls,3s)-3-methyl-l-(4methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5- (((cyclopropylmelhyl)amino)methyl)-2-oxo1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-

124

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			3-carboxamide: 'HNMR (400 MHz. DMSOJ6): δ 0.13 (m. 2H). 0.43 (m. 2H). 0.86-0.89 (m,lH), 1.23 (s, 3H), 2.49-2.50 (m, 5H), 2.78 (s,2H),3.19 (s,3H), 3.67 (s, 2H). 5.9-5.11 (m, 2H ), 7.07 (d. J = 7.2Hz,lH), 7.53 (d. 7=7.6 Hz, 1H), 8.07 (s,lH), 8.32 (s.lH), 8.59 (s,lH), 8.64 (s,lH), 12.21 (s, 1H); ES-MS (m/z) 563.35 (M+H)+
85		Method C; A5 / B9	l-(Cyclopropylmethyl)-N-(3-(3-methyl-l-(4mcthyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5((neopentylamino)methyl)-2Oxo-1,2dihydropyridine-3-carboxamide; 'HNMR (400 MHz, DMSO-dé) δ 0.30- 0.60 (m, 4H). 0.86 (s. 9H), 1.08 (d, J = 6.4 Hz, 3H),1.21.35 (m, 1H), 2.22 (s, 2H), 2.40-2.60 (m. 3H), 2.60-2.75 (m. 2H), 3.17 (s, 3H), 3.58 (s, 2H), 3.93 (d, J = 6.4 Hz, 2H), 7.08 (d. J = 8 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.65 (d, J = 8.4 Hz, 1 H), 8.07 (s, 1 H), 8.30 (s, 1H), 8.52 (d, J = 2.8 Hz. 1H), 12.28 (s, 1H); ESI-MS (m/z) 517.57 (M+H)+
86	’î K.irp W Q '-CE	Method C; A5/B8	5-(((S)-3-Acrylamidopyrrolidin-lyl)methyl)-N-(3-((ls,3R)-3-methyl-l-(4methyl-4H-l ,2,4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2trifluoroethyl )-1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, CDC13) Ô 1.15 (d, J=5.6Hz, 3H), 1.73 (m, 2H), 2.352.40 (m. 2H), 2.63-2.72 (m. 6H), 2.88-2.95 (m, 2H), 3.21(s, 3H), 4.54 (m, 1H), 4.71-4.82

125

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(m, 2H), 5.64-5.67 (m, 1H), 6.08-6.15 (m,lH), 6.30 (d, J = 16.8 Hz. 1H), 7.04 (d, 7=8.0 Hz, 1H), 7.33 (t, 7 =8.0 Hz. 1H). 7.54 (s, 1H), 7.59 (d,7=7.6 Hz, 1H), 7.91(s, 1H), 7.98 (s,1H), 8.7 l(d, 7= 2.4 Hz, 1H), 11.71(s,IH); ESI-MS (m/z) 598.55 (M+H)+
87	CT}	Method C; A5/B10	5-((Isobutylamino)methyl)-N-(3-(( 1 s,3s)-3methyl-1 -(4-methyl-4H- l,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-1-(3,3,3lrifluoropropyl)-l,2-dihydropyridine-3carboxamide: ’HNMR (400 MHz. DMSO-J6) δ 0.87 (d, 7 = 6.4 Hz, 6H), 1.08 (d, 7 = 5.2 Hz, 4H), 1.69-1.71 (m, 1H), 2.31-2.33 (m, 3H), 2.81-2.88 (m, 5H), 3.17 (s, 3H),3.59(s, 2H), 4.32 (q, 7 = 9.2 Hz, 2H), 7.10 (d. J = 7.6 Hz, 1H), 7.37 (t. J = 7.6, 1H), 7.56 (s, 1H). 7.67 (d, 7 = 8 Hz, 1H), 8.09 (s, 1H), 8.30 (s, 1H), 8.56 (s, 1H), 12.04 (s, 1H); EST-MS (m/z) 545.62 (M+H)+
88		Method C; A5/B11	1 -(2-CycIopropylcthyl)-5((isobutylamino)methyl)-N-(3-((ls,3s)-3methyl- l-(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-1,2dihydropyridine-3-carboxamide: 'HNMR (DMSO-Jô, 400 MHz) δ 0.09-0.1 (m, 2H), 0.37-0.4 (m. 2H), 0.80-0. 69 (m. 2H), 0.860.87 (m, 7H), 1.08 (d, 7 = 4 Hz, 3H), 1.681.62 (m, 3H), 2.32 (d. 7 = 6 Hz, 2H), 1.621.70 (m, 4H), 2.32-2.33 (m, 2H), 3.21 (s, 3H), 3.60 (s, 2H), 4.13-4.16, (m, 2H), 7.08 (d,7 = 7.52 Hz, 1 H), 7.36 (t, 7 = 8 Hz, 1 H), 7.56 (s,

126

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			1H), 7.66 (d, J = 7.40 Hz, 1H), 8.08 (s, 1H), 8.29 (s, 1 H), 8.59 (s, 1H), 12.24 (s, 1 H); ESIMS (m/z) = 517.4 [M+Hf
89	U w σ \-CFj	Method C; A5/B8	N-(3-((l s,3R)-3-methyl-1 -(4-methyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo5-(((S )-3 -propionamidopyrrolidin-1 yl)methyl)-1 -(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-r/6): δ 0.97 (t, J = 7.6 Hz,3H), 1.08( d, J = 5.2 Hz, 3H), 1.65-1.69 (m,lH), 2.64 (q, 7=7.6Hz, 2H), 2.16 (m, 2H), 2.50-2.54 (m, 6H), 2.81 (m, 3H), 3.17 (s,3H), 3.73 (brs, 2H),4.21 (bs,lH), 5.09 (q,7=8.4Hz, 2H), 7.13 (d. 7=7.6Hz, 1H), 7.38 (t, 7=8.0Hz,lH), 7.55 (s,lH), 7.65 (d, 7=8.4Hz,lH), 8.01 (s,lH), 8.12 (s,lH), 8.30 (s,lH), 8.57 (s,lH), 11.72 (s,lH); ESI-MS (m/z) 600.21(M+H)+
90		Method C; A6/B10	N-(2-fluoro-5-({ 1 s,3s)-3-methyl-1 -(4mcthyl-4H-l,2,4-triazol-3yl)cyclobutyl)pheny l)-5 ((isobuty lamino)methyl)-2-oxo-1-(3,3,3trifluoroprop y 1 )-1,2-dihy dropyridinc - 3carboxamide: 'HNMR (400 MHz. DMSOd6): δ 0,87(d, J =6.6 Hz, 6H), 1.08(d, J =5.2 Hz, 3H), 1.64-1.74 (m, 1H), 2.31(d, J =6.3 Hz, 2H). 2.54 (m, Hz, 3H), 2.83-2.85 (m. 4H), 3.18(s, 3H), 3.59(s, 2H), 4.33(t, J =6.9 Hz, 2H), 7.05-7.07(m, 1H), 7.3 (dd. 71=8.5 Hz, 72=10.7Hz, 1H), 8.1 l(d, 7 =1.9 Hz, 1H). 8.30(s, 1H), 8.49 (dd, 7i=2.3 Hz, 72=7.6Hz,

127

Example No.	Structure	Method and Intermediate	Chemical Naine and Analytical data
			1H), 1H), 8.55 (d, 7=2.2 Hz.lH), 12.33 (s, 1H); ESI-MS (m/z) 563.6 (M+H)+
91	vN (/ i 1 θ-ΝΉΙ-Ν	Method C; A6/B10	N-(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4methyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)-5((neopentylamino)methyl)-2-oxo-1-(3,3,3trifluoropropyl)-1,2-dihydropyridine-3carboxamide: ’HNMR (400 MHz, DMSO76): δ 0.86 (d, 7 =6.6 Hz, 9H), 1.08(d, 7 =5.2 Hz, 3H), 2.2 (s, 2H), 2.51-2.54 (m, 4H), 2.812.84 (m, 4H), 3.18 (s, 3H), 3.57 (s, 2H), 4.33 (t, J =7 Hz, 2H), 7.03-7.07 (m, 1H), 7.3 (dd, 7i=8.7 Hz, 72=10.9Hz, 1H), 8.08 (d, 7 =1.6 Hz, 1H), 8.29(s, 1H), 8.50 (dd, 7i=2.3 Hz. 72 = 7.6Hz, 1H), 8.55 (d, 7=2.2 Ηζ,ΙΗ). 12.36(s, 1H); ESI-MS (m/z) 577.4 (M+H)+
92	\=Z σ '-CFj	Method C; A6/B8	5-(((2-Fluoro-2- methylpropyl)amino)methyl)-N-(2-fluoro-5((ls,3s)-3-methyl-l-(4-methyl-4H-l,2,4triazol-3-yI)cyclobutyl)phcnyl)-2-oxo-1 (2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide: fHNMR (400 MHz, DMSO7fi): δ 1.08(d, 7 =5.2 Hz, 3H), 1.28 (s, 3H), 1.33 (s, 3H), 2.53-2.61 (m, 5H), 2.76-2.78 (m, 2H), 3.18 (s, 3H), 3.62 (s, 2H), 5.09(q, 7=9.1 Hz, 2H), 7.06-7.08 (m, 1H), 7.31 (dd. 7i=8.5 Hz, 72= 10.7Hz, 1H), 8.03 (d, 7 =1.6 Hz. 1H), 8.30(s, 1H), 8.49 (dd, 7i= 2.2 Hz, 72=7.4Hz, 1H), 8.60 (d. 7 =2.5 Hz, 1H), 12.14 (s, 1H); ESI-MS (m/z) 567.2 (M+H)+

128

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
93		Method C; A6/B15	N-(2-fluoro-5-((ls,3s)-3-methyl-l-(4methyl-4H-l,2.4-triazo[-3yl)cyclobutyl)phenyl)-l-(4-nuorophenyl)-5((isobutylamino)methyl)-2-oxo-1,2dihydropyridinc-3-carboxamidc; ’HNMR (400 MHz. DMSO-d6): δ 0.88 (d, 7=6.6Hz, 6H), 1.08 (d, J = 5.5Hz, 3H), 1.67-1.73 (m, 1H), 2.37 (s, 2H), 2.55 (m. 3H), 2.78-2.80 (m, 2H), 3.19 (s, 3H), 3.65 (s, 2H), 7.05-7.08 (m. 1H), 7.28 (dd, 7î=10.7Hz, 72=8.5Hz, 1H), 7.40-7.45 (m, 2H), 7.57-7.59 (m. 2H), 8.02 (s, 1H), 8.30 (s, 1H), 8.49 (dd. 7i=7.4Hz, 72=2.2Hz, 1 H), 8.65(d, 7=2.2Hz, 1H), 12.24 (s, 1H); ESI-MS (m/z) 561.3 (M+H)+
94		Method C; A9/B8	5-((Isobutylamino)methyl)-N-(4-(3-methyl- 1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)pyridin-2-yl)-2-oxo-1-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DMSCW6) δ 0.86 (d. J = 4.0 Hz, 6H), 1.07-1.24 (m. 5H), 1.62-1.74 (m. 1H), 2.20-2.82 (m, 6H), 3.073.23 (m, 3H), 3.59 (s, 2H), 5.03-5.12 (m, 2H), 6.96-7.00, 7.07-7.11 (m, 1H), 8.04-8.10 (m, 1H), 8.23-8.36 (m, 3H), 8.60 (s, 1H), 11.22 (s, 1H);MS (m/z) 532.3 (M+H)+

Example 95

N-(3-(3,3-dimcthyl-l-(4-mcthyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-1 -(2.2.2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide

SUBSTITUTE SHEET (RULE 26)

129

Step-1: N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-tnazol-3-yl)cyclobutyl)phenyl)-2-oxo-l(2,2,2-trifluorocthyl)-5-vinyl-l,2-dihydropyridinc-3-carboxamide

To a stirred solution of 2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3carboxylic acid (500 mg, 2.02 mmol) in DMF ( 10 mL) was added HATU (923 mg., 2.42 mmol) and stirred at room température for 30 min. To this mixture were added DIPEA ( 1.04 mL, 6.07 mmol), 3-(3,3-dimcthyl-l-(4-mcthyl-4H-l,2,4-triazol-3-yl)cyclobutyl)aniiinc (518 mg, 2.02 mmol) and stirred for overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The residue obtained was purified by flash column chromatography to yield 830 mg of the desired compound. Ή NMR (400 MHz, DMSO-Æ) δ 1.06 (s, 3H), 1.12 (s, 3H), 2.58 (d. J = 12.4Hz, 2H), 2.90 (d, 7= 12.8Hz, 2H),3.22 (s, 3H),5.O3 (q, 7= 8.8 Hz, 2H), 5.30 (d, 7 = 10.8 Hz, 1H), 5.78 (d, 7 = 22.4 Hz, 1 H), 6.60- 6.67 (m, 1H), 7.06 (d, 7 = 7.6 Hz, 1H), 7.35 (t. 7= 8.0 Hz. 1H), 7.54-7.62 (m, 2H), 8.24 (d, 7 = 1.6 Hz, 1H), 8.32(s, 1H), 8.71 (s, 1H), 11.67 (s, 1H); ESI-MS (m/z) 486.3 (M+H)⁺

Step-2: N-(3-(3,3-dimethy I-1 -(4-methyI-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-formyl-2oxo-1-(2,2,2-trifluoroethyl)-l,2dihydropyridine-3-carboxamide

To a stirred solution of N-(3-(3,3-dimethyl-l-(4-mcthyl-4H-l,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 H?O (5.0 mL) were added NaIO+(733 mg. 3.42 mmol) followed by 1.0% OsOrint-BuOH (0.017 mL , 0.007 mmol). The réaction mixture was stirred at room température for overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was separated. dried over anhydrous sodium sulfate and concentrated to yield 710 mg of the desired compound. 'H NMR (400 MHz, DMSO-dô) δ 1.05 (s, 3H), 1 13 (s, 3H), 2.58 (d, 7 = 12.4Hz, 2H), 2.90 (d, J = 12.4Hz, 2H), 3.23 (s, 3H), 5.18 (q, 7 = 8.8 Hz. 2H), 7.07 (d. 7 = 8.0 Hz, 1H), 7.36 (t, 7 = 8.1 Hz, 1H), 7.55 (s, 1H), 7.61 (d, 7 = 8.4 Hz, 1H), 8.33 (s, 1H), 8.75 (d, 7 = 2.4 Hz, 1H). 8.95 (d, 7 = 2.0 Hz, 1H), 9.81 (s, 1H), 11.23 (s, 1H); ESI-MS (m/z) 488.2 (M+H)⁺

130

Step-3: N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isobutylamino)mcthyl)-2-oxo-l-(2,2,2-trifluorocthyl)-l,2-dihydropyridinc-3-carboxamidc To a stirred solution of N-(3-(3,3-dimethyl-l-(4-methyl-4H-1.2,4-triazol-3yl)cycIobutyl)phcnyl)-5-formyl-2-oxo-1-(2,2,2-trifluoroethyl)-1.2-dihydropyridine-35 carboxamide (100 mg, 0.20 mmol) and isobutylamine (72 mg, 0.61 mmol) in 1,2, dichloroethane (5.0 mL) was added drop of acelic acid and reflux for 4 h. The reaction mixture was brought to room température and then added sodium triacetoxy borohydridc (130 mg. 0.61 mmol) portion wise and stirred at room température for overnight. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic 10 layer was concentrated under reduced pressure and the obtained residue was purified by flash chromatography to yield 24 mg of thc desired product. 'HNMR (400 MHz, DMSO-76) δ 0 86 (d, J =8.0 Hz, 6H), 1.05 (s, 3H), 1.12 (s, 3H), 1.61-1.71 (m, IH), 2.27 (d, J =8.0 Hz, 2H), 2.57 (d. J =12.0 Hz. 2H). 2.89 (d. J =12.0 Hz, 2H), 3.22 (s, 3H), 3.56 (s, 2H), 5.08 (q, J =9.2 Hz, 2H), 7.04 (d, J =1.6 Hz, IH), 7.35 (t, J =7.6 Hz, IH), 7.56-7.58 (m. 2H), 7.99 (s, IH). 8.32 (s, 15 IH), 8.56(s, IH), 11.82 (s,lH); ESI-MS (m/z) 545.3 (M+H)⁺

The details of synthesis and analytical data of the examples prepared from the above mentioned methods are given below in Table-15.

Table-15: Structure, Chemical name, method, intermediate used and analytical data of Examples (96-151)

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
96	\ ΖΛ-νιΓ\-ν \=/ σ '-cf.	Method C; A11/B8	((S)-N-(3-(3,3-dimethyl-1 -(4-methyl-4Hl,2,4-triazol-3-yl)cycIobutyl) phenyl)-5-((3methylpiperidin-1 -yl)methyl)-2-oxo-1 (2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3carboxamide; 1HNMR (400 MHz, DMSO76) δ 0.85 (d, J =5.6 Hz, 3H), 1.06 (s, 3H), 1.09 (s, 3H), 1.58-1.90 (m, 5H), 2.53-2.57 (m, 2H), 2.58 (d, 7=12.4 Hz, 2H), 2.67-2.72 (m, 2H), 2.70 (d. 7=12.4 Hz, 2H), 3.16-3,18 (m. 2H), 3.22 (s, 3H), 5.06-5.12 (m, 2H), 7.05 (d, 7 =7.6 Hz. IH), 7.35 (t. 7 =7.6 Hz, IH), 7.567.57 (m. 2H), 8.00 (s, IH), 8.32 (s, IH), 8.47

131

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(s, IH). 11.79 (s, IH); ESI-MS (m/z) 571.7 (M+H)+
97	(j	Method C; A17/B8	5-((IsobutyIamino)methyl)-N-(3-(5-(4methyl-4H-l,2,4-triazoi-3- yl)spiro|2.3]hexan-5-yl)phenyl)-2-oxo-l(2,2,2-trinuoroelhyl)-1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz. DMSOd6): δ 0 44-0.48(m, 2H), 0.54-0.58 (m. 2H), 0.86 (d, 7=6.8 Hz, 6H), 1.65-1.68 (m, IH), 2.27-2.29 (m, 2H), 2.62-2.73 (m, 2H), 3.15(d, 7=10 Hz, 2H), 3.20 (s, 3H), 3.57 (s,2H), 5.055.12 (m, 2H), 7.07 (d, 7=7.6 Hz, IH). 7.367.40 (m. IH), 7.56 (s, IH), 7.61 (d, J=7.2 Hz, IH), 8.01 (s, IH), 8.39 (s, IH), 8.56 (s, IH). 11.84 (bs. 1 H); ESI MS (m/z) 543.4 (M+H)+
98		Method C; A17/B8	(S)-N-(3-(5-(4-methyl~4H-l,2,4-triazol-3yl)spiro[2.3]hexan-5-yl)phenyl)-5-((3methy Ipiperidin- 1 -y 1 )methy 1 )-2 -oxo-1 (2,2,2-trifluoroethyl)-1,2-dihydropyridine -3carboxamide: 'HNMR (400 MHz. DMSOd6): δ 0.44-0.48(m, 2H), 0.54-0.58(m. 2H), 0.82(d, 7=4 Hz. 3H), 1.24-1.50 (m, 2H), 1.581.67 (m, 4H), 1.84-1.90 (m. IH), 2.48-2.52 (m, 2H), 2.69-2.70 (m, 2H), 2.71-2.73 (m, 2H), 3.14-3.17 (m. 2H), 3.20 (s, 3H), 5.065.12 (m, 2H). 7.07 (d, 7=7.2 Hz, IH), 7.38 (t, 7=8 Hz, 1 H),7.58-7.60 (m, 2H), 8.00 (s, IH), 8.39 (s, IH), 8.46 (s, IH), 11.81(brs, 1H);ESI MS (m/z) 569.5 (M+H)+

132

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
99		Method C; A20/B8	(S)-N-(3-(3,3-difluoro-l-(4-methyl-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3mcthy Ipipcridin-1 -yl)mcthyl)-2-oxo-1 (2,2,2-trifluoroethyl)-1,2-dihydropyridi ne-3carboxamide: ’HNMR (400 MHz. DMSO-J6) δ 0.84 (d, J = 5.6 Hz,3H), 1.44-1.67 (m, 4H), 1.87 (m. IH), 2.50 - 2.52 (m, 2H). 2.72 (m, 2H), 3.26 (s, 3H), 3.32 (s, 2H), 3.393.42(m,2H),3.36-3.76(m, 2H), 5.05-5.12 (m, 2H), 7.11 (d. J=8.0Hz,lH). 7.40 (t. J= 8.0 Hz. IH), 7.54 (s,lH), 7.68 (d, J = 8 Hz, IH), 8.0 (s,lH), 8.41 (s, IH), 8.46 (s, IH) 11.81 (s, IH); ESI-MS (m/z) 579.24(M+H)+
100		Method C; A20/B8	N-(3-(3,3-difluoro-l -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-1-(2,2,2trifluoroethyl )-1,2-dihydropyridine-3carboxamide: ‘HNMR (400 MHz. DMSO-d6 ) δ 0.870 (d, J=6.4Hz, 6H), 1.64-1.71 (m, 1 H), 2.30 (d, J=6.0Hz, 2H), 3.23 (s. 3H), 3.33-3.45 (m, 2H), 3.59 (s, 2H), 3.33-3.76 (m, 2H), 5.05-5.12 (m, 2H), 7.11 (d, J = 7.6 Hz. IH), 7.40 (dJ=8.0Hz, IH), 7.53 (s, IH), 7.70 (d, J = 8.4 Hz, IH), 8.02 (s, IH), 8.41 (s, IH), 8.57 (d, J = 2.0 Hz, IH), 11.84 (s. IH); ESI-MS (m/z) 553.55 (M+H)+
101		Method C; A15/B8	5-((Isobutylamino)methyl)-N-(3-(2-(4- methyl-4H-l,2,4-triazol-3- yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-l(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz. DMSO-

133

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			d6)t δ 0.85 (d, J = 6.8Hz, 6H), 1.64 -1.66 (m, 1H), 1.68-1.74 (m, 2H), 1.90-1.92 (m, 2H), 1.98-2.01 (m. 2H), 2.26 -2.28 (m. 2H), 2.702.73 (m, 2H). 3.02-3.05 (m, 2H), 3.20 (s, 3H). 3.56-3.61 (m, 2H), 5.08 (q, J = 8.8 Hz, 2H), 6.98 (d. J = 8.0 Hz, 1H), 7.31 (t. J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 8.31 (s, 1H), 8.55 (s, 1H), 11.82(s, 1H); ESI-MS (m/z) 557.62 (M+H)+
102		Method C; A15/B8	(S)-N-(3-(2-(4-mcthyl-4H-l,2,4-triazol-3yl)spiro[3.3]heptan-2-yl)phenyl)-5-((3methylpiperidin-1 -yl)methyl)-2-oxo-1(2,2,2-trifluoroelhyl)-1,2-dihydropyridine-3carboxamide; 'HNMR (400 MHz, DMSOί/6): δ 0.81 (d. ./=5.6 Hz, 3H), 1.47-1.67 (m. 8H), 1.76-1.78 (m, 2H), 1.88-1.90 (m. 2H), 1.92-1.96 (m. 2H), 2.70-2.73(m. 4H), 3.023.05 (m, 3H), 3.21 (s, 3H), 5.11 (q, J = 9.2 Hz, 2H). 6.98 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1 H), 7.51 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 8.00 (s, 1H), 8.32 (s, 1H), 8.46 (s, 1H), 11.78 (s, 1H); ESI-MS (m/z) 583.40 (M+H)+
103		Method C; A17/B8	5-(((2-Ethylbutyl)amino)methyl)-N-(3-(5-(4methyl-4H-1,2,4-triazol-3- yl)Spiro[2.3]hexan-5-yl)phenyl)-2-oxo-l(2,2,2-trifluorocthyl)-l,2-dihydropyridinc-3carboxamide: ‘HNMR (400 MHz, DMSOd6): δ 0.44-0.47(m, 2H), 0.48-0.58 (m, 2H), 0.78-0.86(m. 6H), 1.24-1.29 (m, 4H), 1.311.35(m, 1H), 2.68 (d. J=9.6Hz, 2H), 2.71-2.73 (m, 2H), 3.15 (d, J=12.4 Hz, 2H), 3.20 (s, 3H),

134

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			3.57 (s, 2H), 5.05-5.09 (m, 2H), 7.07 (d. J=8 Hz, 1H), 7.38 (t, 7=8 Hz, 1 H), 7.56 (s, 1H), 7.61 (d, 7=8.8 Hz, 1H), 8.01 (s, 1H), 8.39 (s, 1H), 8.58 (s, 1H), 11.83 (brs, 1H); ESI MS (m/z) 571.6 (M+H)+
104	N N A ί Ο V=/ σ* t-CFj	Method C; AH / B8	N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)pheny 1)-5-(((2ethylbutyl)amino)methyl)-2-oxo-1-(2,2.2trifluoroethyl)- l,2-dihydropyridine-3carboxamide; 1HNMR (400 MHz. DMSOd6) δ 0.78-0.82 (m. 6H), 1.06 (s, 3H), 1.09 (s, 3H), 1.23-1.33 (m, 5H), 2.42-2.43 (m. 2H), 2.57 (d, 7 = 12.4 Hz, 2H), 2.90 ((d. 7=12.0 Hz, 2H), 3.22 (s, 3H). 3.68 (s, 2H), 5.09 (q.7 =8.8 Hz, 2H), 7.05 (d. 7 =7.6 Hz, 1H), 7.35 (t, 7 =8.0 Hz. 1H), 7.55-7.59 (m.2H), 8.04(s, 1H), 8.32 (s. 1H), 8.56 (s, 1H), 11.80 (s. 1H); ESIMS (m/z) = 573.6 (M+H)+
105		Method C A20 / B8	N-(3-(3,3-difl uoro-l-(4-methy I-4H-1,2,4triazol-3-yl)cyclobutyl)phcnyl)-5-(((2ethylbutyl)amino)methyl)-2-oxo-1-(2,2,2trifluoroethyl)-l,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz. DMSO-46) δ 0.79 (t. 7=6.8Hz, 6H), 1.23-1.33 (m, 5H), 2.36 (brs. 2H), 3.26 (s, 3H), 3.39-3.42 (m, 2H), 3.56 (s, 2H), 3.69-3.73 (m. 2H), 5.075.09 (m. 2H), 7.14 (d. 7 = 7.6 Hz. 1H). 7.40 (t. 7=7.6Hz, 1H), 7.52 (s, 1H), 7.71 (d, 7 = 6.8 Hz, 1H), 8.01 (s, 1H), 8.41 (s, 1H), 8.57(d. 7 = 2.0 Hz, 1H), 11.85 (s, 1H); ESI-MS (m/z) 581 (M+H)+

135

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
106	Y,/ ' ( Vnu j-n ü '-CF;	Method C; A17/B8	N-(3-(5-(4-methyl-4H-1,2,4-triazol-3yl)spiro[2.3]hexan-5-yl)phenyl)-5-(((2mcthylbutyl)amino)mcthyl)-2-oxo-1-(2,2,2trifluoroethyl)-l,2-dihydropyridine-3carboxamide (Isomer-1): *HNMR (400 MHz, DMSO-d6): δ 0.44-0.48(m, 2H), 0.540.58(m. 2H), 0.81-0.82(m. 3H), 0.84-0.86(m, 3H), i.06-1.09(m, 1H), 1.37-1.46(m. 2H), 2.26-2.39(m, 2H), 2.67-2.73(m, 2H), 3.153.17(m, 2H), 3.20(s, 3H), 3.57(s, 2H), 5.055.12(m, 2H), 7.07(d, 7=7.6 Hz, 1H), 7.38(t, 7=7.6Hz, 1H), 7.56(s, 1H), 7.60(d, J=8Hz, 1H), 8.00(s, 1H), 8.39(s, 1H), 8.56(s, 1H), 11.83(bs, 1H); ESI MS (m/z) 557.4 (M+H)+
107	' f TNH pN W 0 '-CF,	Method C A17/B8	N-(3-(5-(4-methyl-4H-l,2,4-triazol-3-yl) spiro[2.3]hexan-5-yl)phenyl )-5-(((2methylbutyl)amino)methyl)-2-oxo-1-(2,2,2lriiluoroethyl)-l,2-dihydropyridine-3carboxamidc (lsomcr-2): ‘HNMR (400 MHz, DMSO-d6): δ 0.54-0.55 (m, 2H), 0.56-0.58 (m, 2H), 0.81-0.82 (m, 3H), 0.84-0.86 (m, 3H), 1.05-1.12 (m, 1H), 1.37-1.46 (m, 2H), 2.28-2.42 (m. 2H), 2.65-2.72 (m, 2H), 3.153.17 (m. 2H), 3.20 (s, 3H), 3.59 (s, 2H), 5.055.12 (m, 2H), 7.07 (d, 7=8 Hz, 1H), 7.38 (t, 7=8Hz, 1H), 7.56 (s, 1H), 7.60 (d. 7=8Hz, 1H), 8.00 (s, 1H), 8.39 (s, 1H), 8.57 (s, 1H), 11.8 (brs, 1H); ESI MS (m/z) 557.6 (M+H)+
108	NN <-P vV ^cf,	Method C; A15/B8	5-(((Cyclopropylmethyl)amino)methyl)-N- (3-(2-(4-mcthyl-4H-l,2,4-triazol-3- yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-l-

136

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz, CDCh): δ 0.23-0.24 (m. 2H), 0.58-0.59 (m. 2H), 1.021.06 (m. IH), 1.80-1.86 (m. 2H), 1,99-2.06 (m, 4H), 2.59-2.65 (m, 2H), 2.81 -2.84 (m, 2H), 3.10-3.13 (m. 2H), 3.28 (s. 3H), 4.714.78 (m, 2H), 4.74 (q, J = 8.8 Hz, 2H), 6.97 (d, J = 8.0 Hz, IH), 7.26-7.30 (m, IH), 7.47 (d, J = 7.6 Hz, IH), 7.77 (s, IH), 7.82 (s. IH), 8.01 (s, IH), 8.63 (s, IH), 11.70 (s, IH); ESIMS (m/z) 555.38 (M+H)+
109		Method C; A18/B8	5-(((Cyclopropylmethyl)amino)methyl)-N(2-fluoro-5-(5-(4-methyl-4H-1.2,4-triazol-3y1)spiro[2.3]hexan-5-yl)pheny 0-2-oxo-1 (2,2,2-trifluoroethyl)-1.2-dihydropyridine-3carboxamide: ’HNMR (400 MHz, DMSOd6): δ 0.12-0.13(m, 2H), 0.40-0.49 (m, 4H), 0.57-0.611 (m, 2H), 0.85-0.91 (m. IH), 2.352.43 (m, 2H), 2.55-2.67 (m, 2H). 3.16-3.19 (m, 2H), 3.21 (s, 3H), 3.68 (s, 2H), 5.07-5.11 (m, 2H), 7.0-7.03 (m, IH), 7.30-7.35 (m, IH), 8.07 (s, IH), 8.41 (s, IH), 8.48-8.50 (m, IH), 8.62 (d. 7=2.4 Hz. IH), 12.15 (brs. IH); ESI MS (m/z) 559.39 (M+H)+
110		Method C; A12/B8	5-(((Cyclopropylmethyl)amino)methyl)-N(5-(3,3-dimethyl-1 -(4-methyl-4H-l .2,4triazol-3 - y l)cyclobu t yl )-2-flu oropheny 1 )-2oxo- l-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: ’HNMR (400 MHz. DMSO-dô) δ 0.15-0.16 (m, 2H), 0.44-0.45 (m, 2H), 0.91-1.20 (m, 7H), 2.57-

137

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			2.59 (m, 2H), 2.91 (d, J = 12.4 Hz, 2H), 3.24 (s, 3H), 3.49-3.51 (m, 2H), 3.72 (s, 2H), 5.11 (q, J = 8.8 Hz, 2H), 6.95 - 6.99 (m, 1H), 7.35 (t, J = 7.2 Hz. 1H), 7.58 (s, 1H), 8.06 (s. 1H), 8.33(s, 1H), 8.61 (s, 1H), 11.77 (s, 1H); ESIMS (m/z) 561.52 (M+H)+
111		Method C; Ail /B8	5-(((Cyclopropylmethyl)amino)methyl)-N(3-(3,3-dimethyl-1 -(4-methyl-4H-1.2,4triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz, DMSO-76) Ô 0.15-0.16 (m, 2H), 0.43-0.45 (m, 2H), 0.91 (m, 1H), 1.06 (s, 3H), 1.13 (s, 3H), 2.55-2.59 (m, 4H), 2.90 (d, J = 12.4 Hz, 2H), 3.23 (s, 3H), 3.72 ( s, 2H), 5.10 (q, J = 9.2 Hz, 2H), 7.05 (d, J = 1.6 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.58 (m. 2H), 8.06 (s, 1H), 8.33(s, 1H), 8.61 (s, 1H), 11.77 (s, 1H); ESI-MS (m/z) 543.9 (M+H)+
112		Method C; A12/B8	N-(5-(3,3-dimcthyl-l-(4-mcthyl-4H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((isobutylamino)methyl)-2-oxo-1-(2,2,2trifluorocthyl )-1,2-dihydropyridine-3 carboxamide: ‘HNMR (400 MHz. DMSO-76) ô 0.88 (d, J = 6.6 Hz, 6H), 1.05 (s, 3H), 1.14 (s, 3H), 1.69-1.71 (m, 1H), 2.35 (s, 2H), 2.54 (d, J= 12.6 Hz, 2H), 2.91 (d, J= 12.6 Hz, 2H), 3.23 (s, 3H), 3.65 (s, 2H), 5.10 (q, J = 9.2 Hz, 2H), 6.95-6.99 (m, 1H),7.29(t, 7 = 8.8, 1H), 8.06 (s, 1H), 8.34 (s, 1H), 8.46 (d, 7 = 7.4,

138

Example No.	Structure	Method and Intermédiare	Chemical Name and Analytical data
			1H), 8.63 (s, 1H), 12.11 (s, 1H), ESI-MS (m/z) 563.27 (M+H)+
113	x-CF,	Method C; A18/B8	N-(2-fluoro-5-(5-(4-methyl-4H-1.2.4-triazol3-yl)spiro[2.3]hexan-5-yl)phenyl)-5((isobutylamino)methyl)-2-oxo-1 -(2,2,2trinuoroethyl)-l,2-dihydropyridine-3carboxamide: ’HNMR (400 MHz, DMSOd6): δ 0.45-0.49(m, 2H), 0.56-0.60 (m. 2H), 0.87 (d, 7=6.4 Hz, 6H), 1.65-1.70 (m, 1H), 2.30-2.33 (m. 2H), 2.65-2.68(m,2H). 3.163.18 (m. 2H), 3.21 (s, 3H), 3.62 (s, 2H), 5.095.11 (m, 2H), 7.00 (s, 1H), 7.30-7.35 (m, 1H), 8.05 (s, 1H), 8.41 (s, 1H). 8.49 (t. 7=1.6Hz, 1H), 8.61 (s, 1H), 12.16 (s, 1H); ESI MS (m/z) 561.5 (M+H)+
114	N N A * Α-Λν ^=/ a ^cr3	Method C; AH / B8	N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobulyl)phenyl)-5((neopentylamino)methyl)-2-oxo-l-(2,2,2trifluoroethy 1)-1,2-dihy dropyridine-3 carboxamide; 1HNMR (400 MHz, DMSO76) S 0.86 (s, 9H), 1.08 (s, 3H), 1.19 (s, 3H), 2.21 (brs, 2H), 2.58 (d, 7 =12.4 Hz. 2H), 2.57 (d, 7=12.4Hz, 2H), 3.22 (s, 3H), 3.59 (s, 2H), 5.08 (q, 7 =8.8 Hz, 2H), 7.05 (d, 7 =7.6 Hz, 1H), 7.35 (t. J =7.6 Hz, 1H), 7.55-7.59 (m, 2H), 8.00 (s, 1H), 8.32 (s, 1H), 8.58 (s, 1H), 11.83 (s, 1H); ESI-MS (m/z) 559.6 (M+H)+
115	χ-ζ (ΓΑ-cf,	Method C; A14/B8	N-(2-chloro-5-(3,3-dimcthyl-l-(4-mcthyl4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isobulylamino)methyl)-2-oxo-1-(2,2,2trifluorocthyl)-1,2-dihydropyridinc-3-

139

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			carboxamide: 1HNMR (400 MHz, DMSO d6): δ 0.87 (d, J = 6.8 Hz, 6H), 1.06 (s, 3H), 1.14 (s, 3H), 1.72-1.65 (m, 1H), 2.31 (d, J = 5.6Hz, 2H), 2.54 (d, J = 12.4Hz. 2H), 2.92 (d, J = 12.8Hz, 2H), 3.24 (s, 3H), 3.60 (s, 2H), 5.10(q, J =8.0 Hz, 2H), 6.95-6.98 (m, 1H), 7.50 (d, 7= 8.4Hz, 1H), 8.05 (s, 1H), 8.35 (s, 1 H), 8.59 (d, J = 2.0 Hz, 1 H), 8.64 (d, J = 2.0 Hz, 1H), 12.25 (s, 1H); ESI-MS (m/z) 579.1 (M+H)+
116		Method C; A14/B8	N-(2-chloro-5 - ( 3,3 - d imethy 1-1 -(4-methy 14H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((neopentylamino)methyl)-2-oxo-1-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide: 1HNMR (400 MHz, DMSOdè): δ 0.86 (s, 9H), 1.06 (s, 3H), 1.14 (s, 3H), 2.21 (s, 2H), 2.54 (d, 7 = 12.4Hz, 2H), 2.92 (d, J = 12.8Hz, 2H), 3.24 (s, 3H), 3.59 (s, 2H), 5.10 (q, 7 =8.0 Hz, 2H), 6.98 (d, 7=8.0 Hz, 1H), 7.50 (d. 7 = 8.4Hz, 1H), 8.03 (s, 1H), 8.34 (s, 1H), 8.58 (d, 7= 2.0 Hz, 1H), 8.64 (s, 1H), 12.26 (s, 1H); ESI-MS (m/z) 593.1 (M+H)+
117		Method C; A12/B8	N-(5-(3,3-dimelhyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((ncopcntylamino)mcthyl)-2-oxo-1-(2,2,2trifl uoroethy 1)-1,2-dihydropyridine-3 carboxamide: 'HNMR (400 MHz, DMSOd6): δ 0.86 (s,9H), 1.05 (s,3H), 1.14 (s, 3H), 2.21 (s, 2H),2.53 (d, 7= 12.4 Hz, 2H), 2.90 (d, 7= 12.4 Hz, 2H), 2.23(s, 3H), 3.59 (brs, 2H),

140

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			5.06-5.13 (m, 2H), 6.96-6.99 (m, 1H),7.26- 7.31 (m, lH),8.O3(s, 1H), 8.33 (s, 1H), 8.46- 8.49 (m. 1H), 8.61 (s, 1H), 12.16 (s, 1H); ESI- MS (m/z) 577.4 (M+H) +
118	O * Ζλ	Method C; A11/B10	N-(3-(3,3-dimethyl-1 (4-methy 1-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-l -(3,3,3trilluoropropyl)-1,2-dihydropyridine-3carboxamide; 1HNMR (400 MHz, DMSO46) δ 0.87 (d. J =6.4 Hz, 6H), 1.06 (s, 3H), 1.09 (s, 3H), 1.66-1.72 (m, 1H), 2.32 (d, J = 12.3 Hz, 2H), 2.58 (d, 7=12.5 Hz, 2H). 2.812.91 (m, 4H), 3.23 (s, 3H), 3.60 (s, 2H), 4.32 (q, J =8.8 Hz, 2H), 7.05 (d, 7 =7.6 Hz. 1H), 7.35 (t, 7 =7.6 Hz, 1H), 7.56-7.59 (m, 2H), 8.09 (s, 1H), 8.32 (s, 1H), 8.54 (s, 1H), 12.03 (s. 1H); ESI-MS (m/z) = 559.4 (M+H)+
119	N N rV ïAL vC t A-N'hL·/ ^=/ <J	Method C; A11/B9	l-(Cyclopropylmethyl)-N-(3-(3,3-dimethyl- 1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phcnyl)-5((isobutylamino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz. DMSO-Jc,) δ 0.43-0.45 (m, 2H), 0.50-0.52 (m. 2H), 0.88 (d, J = 6.4 Hz, 6H), 1.06 (s. 3H), 1.13 (s, 3H), 1.74-1.76 (m, 1H), 2.35-2.37 (m, 2H), 2.50 (d, J = 12.4 Hz, 2H), 2.89 (d, 7 = 12.4 Hz, 2H). 3.23 (s. 3H), 3.63 (s, 3H), 3.94 (d, 7 = 7.1 Hz, 2H), 6.98-7.12 (m, 1H), 7.31-7.35 (m, 1H), 7.57-7.65 (m, 2H), 8.10 (s, 1H), 8.32 (s, 1H), 8.53 (s. 1H), 12.23 (s, 1H), ESI-MS (m/z) 517.4 (M+H)+

141

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
120	/•Z j 7k	Method C; A12/B10	N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((isobutylamino)methyl)-2-oxo-1 -(3,3,3trifluoropropyl)-l,2-dihydropyridine-3carboxamidc: 'HNMR (400 MHz, DMSO-d6) Ô 0.87 (d, J = 6.8 Hz, 6H), 1.11 (s, 3H), 1.14 (s, 3H), 1.50- 1.65 (m, 1H), 2.28 (d, J = 6.4 Hz, 2H), 2.40- 2.55 (m, 2H), 2.70- 2.90 (m, 4H), 3.33 (s, 3H), 3.56 (s, 2H), 4.30- 4.40 (m. 2H), 6.80- 7.00 (m, 1H), 7.28 (l. J = 9.2 Hz. 1H), 8.10 (s, 1H), 8.34 (s, 1H), 8.47- 8.65 (m, 2H), 12.37 (s, 1H); ESI-MS (m/z) 577.4 (M+H) +
121		Method C; A12/B10	N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobulyl)-2-iluorophenyl)-5((neopentylamino)methyl)-2-oxo-1-(3,3,3trinuoropropyl)-l,2-dihydropyridine-3carboxamide: ‘HNMR (400 MHz, DMSO-r/ô) δ 0.86 (s, 9H), 1.14 (s, 3H), 1.23 (s, 3H), 2.20 (s, 2H), 2.40- 2.55 (m, 2H), 2.70- 2.95 (m, 4H), 3.24 (s, 3H), 3.57 (s, 2H), 4.33 (t, J= 6.8 Hz, 2H), 6.90- 7.00 (m, 1 H), 7.20-7.35 (m, 1 H), 8.09 (s, 1 H), 8.33 (s, 1 H), 8.47- 8.65 (m, 1H), 8.56 (d. J = 2 Hz, 1H), 12.37 (s, 1H); ESI-MS (m/z) 591.4 (M+H)*
122	Nn fV M A V* O _/	Method C; Ail /B2	1 -(2,2-Difluorocthyl)-N-(3-(3,3-dimcthy 1-1 (4-methyl-4H-l ,2,4-triazol-3- yl )cyclobutyl)phenyl )-5 - ((isobutylamino)methyl)-2-oxo-1,2- dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-d6): δ 0.84-0.90 (m, 6H),

142

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			1.06 (s, 3H), 1.13 (s, 3H),1.34 (m, 1H), 2.292.33 (m, 2H), 2.57 (d, J= 12.4 Hz, 2H), 2.89 (d, J= 12.4 Hz, 2H),3.23 (s, 3H), 3.57 (s, 2H), 4.59 (m, 2H), 6.43(t, /=51.2 Hz.lH), 7.05 (d, J= 8 Ηζ,ΙΗ), 7.35 (t, /= 8 Hz.lH), 7.52 (s, IH), 8.59 (d,/= 8.8 Ηζ,ΙΗ), 8.01 (s, 1H),8.32 (s, 1H), 8.55 (s. 1H), 11.93 (s, 1H); ESI-MS (m/z) 527.4 (M+H) +
123	à	Method C; Ail / B8	N-(3-(3,3-Dimethy 1-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-5-((4-methyl.3-oxopiperazin-1 -yl)methyl)-2-oxo-1 -(2,2,2trifluoroethyl)-l,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz. DMSO-i/tf) Ô 1.06 (s, 3H), 1.13 (s, 3H), 2.52-2.70 (m, 4H), 2.82 (s, 3H), 2.87-2.92 (m, 2H). 3.00 (s, 2H), 3.22 (s, 3H), 3.25-3.34 (m. 2H), 3.45 (s, 2H). 5.04-5.13 (m. 2H), 7.04 (d, / = 8.0, 1H); 7.35 (t, J = 8.0, 1H); 7.56 (m, 2H), 8.05 (s, 1H), 8.32 (s. 1H), 8.49 (d, / = 2.4 Hz, 1H), 11.76 (s, 1H); ESI-MS (m/z) 586.4 (M+H)+
124		Method C; AH /Bll	l-(2-Cyclopropylethyl)-N-(3-(3,3-dimethyl- 1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phcnyl)-5- ((isobutylamino)methyl)-2-oxo-1,2- dihydropyridine-3-carboxamide: 'HNMR (DMSO-î/î, 400 MHz) δ 0.02-0.05 (m. 2H), 0.38-0.41 (m, 2H), 0.68-0.71 (m, 1H), 0.87 (d, / = 6.8 Hz, 6H), 1.06 (s, 3H), 1.13 (s, 3H), 1.34 (m, 2H), 1.66 - 1.62 (m, 1 H), 2.29 (d, / = 6.4 Hz, 2H). 2.57 (d. /= 12.4 Hz. 2H), 2.89 (d, J = 12.4 Hz. 2H), 3.23 (s, 3H), 3.57 (s, 2H),

143

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			4.14 (t, J = 6.8 Hz. 2H), 7.03 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 2 Hz, 2H), 8.06 (d, J = 2 Hz, 1H), 8.32 (s, 1H), 8.49 (d, 7= 2.40 Hz, 1H), 12.24 (s, 1 H). ESIMS (m/z) 531.2 [M+H]+
125		Method C; A18/B8	N-(2-fluoro-5-(5-(4-methyl-4H-1.2,4-triazol3-yl)spiro[2.3]hexan-5-yl)phenyl)-5((neopentylamino)methyl)-2-oxo-1-(2,2.2trifluoroethyl )-1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DMSOd6): S 0.47-0.49 (m, 2H), 0.57-0.59 (m, 2H), 0.89 (s, 9H), 2.50-2.53 (m, 2H), 2.65-2.68 (m, 2H), 3.16-3.18 (m. 2H), 3.21 (s, 3H), 3.34 (s, 2H), 5.07-5.144 (m, 2H), 7.03 (s, 1H), 7.317.35 (m, 1H). 8.07 (s, 1H), 8.41 (s. 1H), 8.48 (d, 7=5.6Hz, 1H), 8.66 (s, 1H), 12.15 (brs, 1H); ESI-MS (m/z) 575.4 (M+H)+
126		Method C; AH / B8	N-(3-(3,3-dimethyl-1 -(4-methyl-4H-1,2,4triazol-3-yi)cyclobutyl)phenyl)-5-(( 1 -inethyl4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1 H)-yl ) mcthyl)-2-oxo-1-(2,2,2-trifluorocthyl)-1,2dihydropyridine-3-carboxamide; 1HNMR (400 MHz, DMSO-d6)ô 1.05 (s, 3H), 1.12 (s, 3H), 2.57 (d, 7 = 11.9 Hz, 2H), 2.90 (d. J = 12.1 Hz, 2H), 3.22 (s, 3H), 3.68 (s, 4H), 3.78-3.81 (m, 5H), 5.10 (q, J =8.8 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 7.33 - 7.37 (m, 2H), 7.56- 7.58 (m, 2H), 8.11, (s, 1H), 8.32 (s, 1H), 8.53 (s, 1H), 11.79 (s, 1H); ESI-MS (m/z) 595.3(M+H) +

144

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
127		Method C; A13/B8	N-(3-(3,3-dimethyl-1 -(4-methyl-4H-1.2,4triazol-3-yl)cyclobutyl)-.5-fluorophenyl)-5((isobutylamino)mcthyl)-2-oxo-l -(2,2,2trifluoroethyl )-1,2-dihydropyridine-3carboxamidc; 1HNMR (400 MHz. DMSOd6) Ô 0.86 (d, J =6.0 Hz, 6H), 1.05 (s, 3H), 1.12 (s, 3H), 1.63-1.70 (m, 1H), 2.29 (d, J =5.6 Hz, 2H), 2.58 (d, J =12.0 Hz, 2H), 2.87 (d, J=\ 1.6 Hz, 2H), 3.25 (s, 3H), 3.58 (s, 2H), 5.08 (q. J =8.0 Hz. 2H), 6.91-6.93 (m, 1H), 7.13 (s, 1H). 7.66-7.68 (m, 1H), 8.03 (s, 1H), 8.34 (s, 1 H), 8.56 (s, 1 H), 11.92 (s, 1 H); ESIMS (m/z) 563.1 (M+H)+
128	XX	Method C; A11/B8	N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-5-((3-fluoro3-methylazetidin-1 -yl)mcthyl)-2-oxo-1 (2,2,2-triiluoroelhyl)-l,2-dihydropyridine-3carboxamide: 'HNMR (DMSO-Jô, 400 MHz) δ 1.17-1.19 (m, 9H), 2.70 (d. J = 12.5 Hz, 2H), 3.00 (d, J = 12.5 Hz, 2H), 3.28 (s, 3H), 3.363.42 (m. 4H), 3.58 (s, 2H), 4.76 (q, J = 8.5Hz, 2H), 7.01-7.03 (m. 2H), 7.54-7.55 (m, 2H), 7.86 (s, 1 H), 7.99 (s, 1 H), 8.62 (s, 1H), 11.68 (s, 1 H); ESI-MS M/Z = 561.3 [M+H]+
129	N N A t r?y_	Method C; Ail /B14	N-(3-(3,3-Dimethyl-l-(4-methyl-4H-1.2,4triazol-3-y 1 )cyclobutyl )phcnyl)-5((isobutylamino)melhyl)-2-oxo-l-(prop-2yn-1 -yl)-1,2-dihydropyridine-3carboxamide: 'HNMR ( DMSO d6. 400 MHz): δ 0.87 (d, J = 6.4 Hz, 6H), 1.06 (s, 3H), 1.13 (s, 3H), 1.65-1.70 (m, 1H), 2.29-2.32 (m,

145

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			2H), 2.55-2.60 (m, 2H), 2.87-2.92 (m, 2H), 3.23 (s, 3H), 3.51-3.59 (m, 2H), 4.92 (s, 2H), 7.02 (d, J = 7.6 Hz, IH); 7.34 (t, J = 8.0 Hz, IH); 7.58-7.62 (m, 2H), 8.11 (s, IH), 8.32 (s, IH), 8.514 (s, 1H), 12.03 (s, IH); MS (m/z): 501.4 (M+H)+
130		Method C; A13/B10	N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)-5-fluorophenyl)-5((isobutylamino)methyl)-2-oxo-1-(3,3,3trifluoropropyl)-l,2-dihydropyridine-3carboxamide; ’HNMR (400 MHz. DMSO-J6) δ 0.86 (d. J = 6.4 Hz, 6H), 1.05 (s, 3H), 1.23 (s. 3H). 1.69-1.71 (m, 1 H), 2.34 (s, 2H), 2.58 (d, J = 12.0 Hz.2H), 2.81-2.85 ( m, 4H), 3.25 (s, 3H), 3.61 (s, 2H), 4.32 (q, J = 8.0 Hz. 2H), 6.91(d. 7=8.0 Hz.lH), 7.13 (s, IH), 7.68 (d. 7 = 10.0 Hz, IH), 8.12 (s, IH), 8.34 (s, IH), 8.53 (d, 7 = 2.0 Hz.lH), 12.14 (s, IH); ESIMS (m/z) 577.3 (M+H)+
131		Method C; A12/B2	l-(2,2-Difluorocthyl)-N-(5-(3,3-dimcthyl-l(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)2-fluorophenyl)-5-((isobutylamino)methyl)2-oxo-1,2-dihydropyridinc-3-carboxamidc: ’HNMR (400 MHz, DMSO-d6): δ 0.84-0.89 (m, 6H),1.05 (s, 3H), 1.14 (s, 3H), 1.71 (brs, IH), 2.33-2.36 (m, 2H), 2.50-2.51 (m, 2H), 2.91 (d. 7= 12.4 Hz, 2H),3.24 (s, 3H), 3.64 (brs. 2H), 4.56-4.63 (m, 3H). 6.42(t, 7= 51.6 Hz, 1 H),6.95 -6.99 (m, IH), 7.26-7.31 (m, IH), 8.07 (s, 1H),8.34 (s, IH), 8.48 (m. IH),

146

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			8.61 (s, 1H), 12.22 (s, 1H); ESI-MS (m/z) 545.3 (M+H) +
132		Method C A12/B2	l-(2,2-Difluoroethyl)-N-(5-(3,3-dimethyl-l(4-methyI-4H-l,2,4-triazol-3-yl)cyc!obutyl)2-fluorophenyl)-5- ((neopentylamino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz. DMSO-d6): δ 0.87(d, J= 10.7 Hz. 9H),1.05(s, 3H), 1.12 (s, 3H), 2.27-2.29 (m, 2H),2.55-2.57 (m. 2H), 2.91(d, J= 12.6 Hz. 2H), 3.24 (s, 3H). 3.66 (s, 2H), 4.59-4.61 (m. 2H), 6.41-6.43 (m. lH),6.96-6.98(m, 1H), 7.29 (dd, Ji= 10.7 Hz, J2= 8.5 Hz 1H),8.O5 (s, 1H), 8.34 (s, 1 H), 8.47(dd, Ji= 7.4 Hz, J2= 2.2 Hz 1H),8.63 (s, 1H), 12.22 (s,lH); ESI-MS (m/z) 559.4 (M+H) +
133		Method C; Ail/B8	N-(3-(3,3-dimelhyl-1 -(4-methy 1-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-5-(((lmethylcyclobutyl)amino)methyl)-2-oxo-l(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DMSO¢/6):0 1.05 (s,3H), 1.12(s,3H), 1.67-1.69 (m, 4H), 1.93-1.95 (m, 2H), 2.57 (d, 7=12.4, 2H), 2.89 (d, 7=12.6, 2H), 3.22 (s, 3H), 3.51(s,2H), 4.05- 4.07(m, 2H), 5.08 (q, 7=9.1Hz, 2H), 7.04 (d, 7=8.0Hz, 1H), 7.20 (s, 1 H), 7.34-7.36 (m, 1H), 7.57 (t. 7=2.1Hz, 1H), 8.03(s, 1H), 8.32 (s, 1H), 8.57(d, 7=2.5Hz, 1H), 11.83 (s, 1H); ESI-MS (m/z) 557.4 (M+H)*

147

Example No.	Structure	Method and Intermediate	Chemical Name and Analyticai data
134		Method C; A12/B9	l-(Cyclopropylmethyl)-N-(5-(3,3-dimethyl- 1 -(4-methyl-4H-l ,2,4-triazol-3yl)cyclobutyl)-2-fluorophcnyl)-5((isobutylamino)methyl)-2-oxo-l,2dihydropyridinc-3-carboxamidc: 'HNMR (400 MHz, DMSO-d6): δ 0.42-0.46(m, 2H), 0.50-0.54(m, 2H), 0.89(d, 7=4 Hz,6H), 1,05(s, 3H), 1.14(s, 3H), 1.22-1.29(m, 1H), 1.701.72(m, 1H), 2.50-2.55(m, 4H), 2.90(d, 7=12 Hz, 2H), 3.23(s, 3H), 3.49(s, 2H), 3.94 (d, 7=8 Hz, 2H), 6.93-6.97 (m, 1H), 7.25-7.30(m, 1H), 7.99 (s, 1H), 8.13(s, 1H), 8.48-8.50(m, 1H), 8.56(s, 1H), 12.5(s, 1H); ESI MS (m/z) 535.6 (M+H)+
135	\ y—Zf n=/ σ ^CF^	Method C; Ail / B8	N-(3-(3,3-dimelhyl-l-(4-melhyl-4H-l,2,4triazol-3-yl)cyclobutyl)pheny!)-5-(((2-fluoro2-methylpropyI)amino)methyl)-2-oxo-1 -(2. 2,2-trinuoroethyl)-1,2-dihydropyridine-3carboxamidc: ‘HNMR (400 MHz. DMSO-76) δ 1.05 (s, 3H), 1.12 (s, 3H), , 1.28 (s. 3H), 1.33 (s, 3H), 2.57-2.59 (m, 4H), 2.89 (d, J = 12 Hz, 2H), 3.22 (s, 3H), 3.62 (s, 2H), 5.08 (q, 7 = 8.0 Hz. 2H), 7,03 (d, 7 = 8.0 Ηζ,ΙΗ), 7.35 (t, 7 = 8.0 Ηζ,ΙΗ), 7.57(s, J = 8.0 Hz, 2H), 8.00 (s, 1H), 8.32 (s, 1H), 8.57(s, 1H) 11.81 (s, 1H); ESI-MS (m/z) 563.3 (M+H)+
136		Method C; A12/B8	N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cycIobutyl)-2-fluorophenyI)-5(((2-fluoro-2-methylpropyl)amino)methyl)2-oxo-1 -(2.2,2-trifluoroethyl)-1.2dihydropyridine-3-carboxamide; 1HNMR

148

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(400 MHz, DMSO-76) δ 1.05 (s, 3H ), 1.14 (s, 3H), 1.28 (s, 3H), 1.33 (s, 3H), 2.58 (d, J =12.6 Hz. 2H). 2.91 (d, J =12.6 Hz. 2H ), 3.23 (s, 3H), 3.62 (s, 2H), 5.09 (q, J =9.1 Hz, 2H), 6.96-6.97 (m. IH), 7.26-7.28 (m. IH), 8.03 (s, IH), 8.32 (d. 7=8.0 Hz, IH), 8.47 (dd, 7i =7.4 Hz, 72=2.5Hz, IH), 8.61 (s, IH ) 12.14 (s, IH); ESI-MS (m/z) 581.6 (M+H)+
137		Method C; AI2/B11	l-(2-Cyclopropylethyl)-N-(5-(3,3-dimethyl1 -(4-mcthyl-4H-l ,2,4-triazoI-3yl)cyclobutyl)-2-fluorophenyl)-5((isobutylamino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide; 'HNMR (400 MHz. DMSO-76): δ 0.01 -0.02 (m, 2H), 0.35-0.40 (m, 2H), 0.65-0.71 (m.lH). 0.86 (d, J = 6.6 Hz, 6H), 1.05 (s, 3H), 1.14 (s, 3H), 1.57-1.67 (m, 3H), 2.30(d, J = 6.6 Hz, 2H), 2.54(d, J = 12.9 Hz. 2H), 2.90(d. 7 = 12.6 Hz, 2H),3.23 (s, 3H), 3.58 (s, 2H), 4.15(t, 7= 7.0 Hz, 2H), 6.92-6.95(m, IH) 7.25-7.79 (m, IH), 8.08 (d, 7=2.5Hz, IH), 8.33 (s, IH), 8.48-8.52 (m. 2H), 12.53 (s, IH); ESI-MS (m/z) 548.71 (M+H)+
138		Method C; A12/B11	l-(2-Cyclopropylethyl)-N-(5-(3,3-dimethyl- 1 -(4-methyl-4H-1,2.4-triazol-3yl)cyclobutyl)-2-fluorophcnyl)-5-(((2-fluoro2-methylpropyl)amino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide; 1 HNMR (400 MHz, DMSO-76): δ 0.36-0.40 (m, 2H), 0.01 - 0.02 (m. 2H), 0.65-0.73 (m.lH), 1.05 (s,3H), 1.14 (s, 3H), 1.28 (s, 3H), 1.33 (s,

149

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			3H), 1.62 (m, 2H), 2.54 (m, 4H), 2.90 (d, J = 12.6 Hz, 2H),3.23 (s, 3H), 3.62 (s, 2H), 4.15(t, J =7Hz,2H),6.92-6.96(m, 1H), 7.27 (dd, 7=10.9Hz 1H), 8.08 (d, J=1.9Hz 1H), 8.33 (s, 1 H), 8.50 (dd. J=7.6Hz 1 H), 8.53 (d, J=2.2Hz 1H), 12.54 (s, 1H); ESI-MS (m/z) 567.40 (M+H)+
139		Method C; Ail /B8	N-(3-(3,3-dimethyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-5((isopentylamino)methyl)-2-oxo-1-(2,2.2trifluoroethyl)-1,2-dihydropyridine-3carboxamide: 1HNMR (400 MHz, DMSOJ6) δ 0.85 (d, J = 6.6Hz, 6H ), 1.05 (s, 3H), 1.13 (s, 3H), 1.34 (q, J = 7.2 Hz, 2H). 1.601.62 (m, 1H), 2.54-2.57 (m, 4H), 2.89 (d, J = 12.6 Hz, 2H). 3.22 (s, 3H), 3.66 (s, 2H), 5.09 (q, J = 9.0 Hz, 2H). 7.05 (d. J = 8.0 Hz.lH), 7.35 (t, J = 7.8 Ηζ,ΙΗ), 7.55-7.58 (m, 2H), 8.05 (s, 1H), 8.32 (s, 1H), 8.58(d, J = 2.5 Ηζ,ΙΗ) 11.78 (s, 1H); ESI-MS (m/z) 559.4 (M+H)+
140	ο \=/ σ ^cf3	Method C; Example 97 ! Formaldéhyde	N-(3-(3,3-dimethyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phcnyl)-5((isobutyl(methyl)amino)methyl)-2-oxo-1 (2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide: ’HNMR (DMSO-dr„ 400 MHz) δ 0.84 (d, J = 8 Hz. 6H), 1.05 (s, 3H), 1.12 (s, 3H), 1.72-1.82 (m, 1 H), 2.08 (d, J = 8 Hz, 2H), 2.21 (s, 3H), 2.57 (d, J = 16 Hz. 2H), 2.89 (d, J = 16 Hz, 2H), 3.22 (s, 3H), 5.09 (t. J = 8 Hz, 2H), 7.05 (d, J = 8 Hz, 1H), 7.35 (t, J = 8 Hz,

150

Ex ample No.	Structure	Method and Intennediate	Chemical Name and Analytical data
			1H), 7.54-7.58 (m, 2H), 7.9-8.0 (m, 1H), 8.31 (s, 1 H), 8.49 (d, 7 = 2.4 Hz, 1 H), 11.80 (s, 1 H). ESI-MS (m/z) 559 |M+Hj+
141		Method C; A16/B8	N-(2-fluoro-5-(2-(4-methyl-4H-l,2,4-triazol3-yl)spiro[3.3Jheptan-2-yl)phenyl)-5((isobutylamino)methyl)-2-oxo-l-(2,2,2trifluoroethyl)- 1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DMSO76): δ 0.87(d. 7=6.6Hz, 6H), 1.65-1.79 (m,3H), 1.88-1.92 (m,2H), 2.0 -2.1 (m. 2H), 2.32 (q. 7=2.1Hz, 2H), 2.68 (d, 7=12.6Hz,2H), 3.05 (d, 7=12.4Hz. 2H), 3.21 (s,3H), 3.61 (s, 2H), 5.09 (q, 7 = 9.1 Hz, 2H), 6.93 (m, 1H), 7.27 (dd, 7i= 10.9Hz, 72= 8.7 Ηζ,ΙΗ), 8.04 (s,lH), 8.32 (s,lH),8.41 (dd, 7i=7.4Hz, 72 = 2.5 Hz, 1H), 8.61 (d, 7=2.5Hz, 1H), 12.12 (s.lH); ESI-MS (m/z) 575(M+H)+
142		Method C; AH / B8	N-(3-(3,3-dimethyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-5-(((( 1 (fluoromcthyl)cyclopropyl)mcthyl)amino)mc thyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: ‘HNMR (DMSO-7â, 400 MHz) δ 1.05 (s, 3H), 1.12 (s, 3H), 1.37 - 1.44 (m, 1H), 1.72 - 1.75 (m, 1H), 2.22-2.08 (m, 4H), 2.57 (d, J = 13 Hz, 2H), 2.73 (d, J = 23.8 Hz, 2H), 2.90 (d. J = 16 Hz, 2H), 3.22 (s, 3H), 3.64 (s, 2H), 5.09 (q. 7 = 9 Hz, 2H), 7.04 (d, 7 = 8 Hz, 1 H), 7.33-7.35 (m, 1H), 7.55-7.58 (m. 2H), 8.00-8.01 (m, 1H), 8.32 (s, 1H), 8.58 (d, 7 = 4 Hz, 1H), 11.82 (s, 1H). ESI-MS M/Z = 574.2 [M+H]+

151

Ex ample No.	Structure	Method and Intennediate	Chemical Name and Analytical data
143		Method C; Ail /B15	N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)phenyl )-1-(4fluorophcnyl)-5-(isobutyIamino)tncthyl)-2oxo-l,2-dihydropyridine-3-carboxamide: ’HNMR (400 MHz. DMSO-76): δ 0.87 (d, J=6.6Hz, 6H), 1.04(s, 3H), 1.11 (s, 3H), 1.621.72 (m, 1H), 2.32 (d. J=6.6Hz, 2H). 2.56 (d. J=12.6Hz, 2H), 2.88(d, J=12.6Hz. 2H), 3.21(s, 3H), 3.58(s, 2H), 7.00 (d, J=7.7Hz, 1H), 7.32 (t, J=8.2Hz, 1H), 7.42 (t, J=8.7Hz, 2H), 7.55-7.60 (m, 4H), 7.96(d, J=2.2Hz, 1 H), 8.30 (s, 1 H), 8.60(d, J=2.5Hz, 1 H), 11.97 (s, 1H); ESI-MS (m/z): 557.5 (M+H)+
144		Method C; A12/B8	(S)-N-(5-(3,3-dimethyl-1 -(4-methyl-4H1,2,4-triazol-3-yl)cyclobulyl)-2fluoropheny 1 )-5 -((3 - meth y Ipiperidin-1 yl)methyl)-2-oxo-l-(2,2,2-lrifluoroethyl)1,2-dihydropyridine-3-carboxamide: *HNMR (400 MHz, DMSO-7ft) δ 0.82 (d, J = 4.7 Hz, 3H), 1.05 (s, 3H), 1.14 (s, 3H), 1.61-1.64 (m, 4H), 1.86-1.88 (m, 1H), 2.55-2.75 (m, 6H), 2.91 (d, J= 12.1 Hz, 2H), 3.23 (s, 3H), 3.35 (s, 2H), 5.10 (q, J = 8.0 Hz, 2H), 6.95 - 6.99 (m, 1H), 7.28-7.29 (m, 1H), 8.02 (s, 1H), 8.33 (s, 1 H), 8.46-8.50 (m, 2H), 12.11 (s, 1 H), ESIMS (m/z) 589.3 (M+H)+
145		Method C; A12/B10	5-(((Cyclopropylmelhyl)amino)methyl)-N(5-(3,3-dimethyl-l -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2oxo-1-(3,3,3-trifluoropropyl)-1,2dihydropyridine-3-carhoxamide: *HNMR

152

Example No.	Structure	Method and Intennediate	Chemical Name and Analytical data
			(400 MHz. DMSO-î/6) δ 0.09-0.15 (m, 2H), 0.03- 0.05 (m, 2H), 0.85- 0.95 (m, IH), 1.05 (s, 3H), 1.14 (s, 3H), 2.41 (d, J = 6.9 Hz, 2H), 2.40- 2.55 (m, 2H), 2.75- 2.95 (m. 4H), 3.23 (s, 3H), 3.64 (s. 2H), 4.33 (t, J = 6.7 Hz, 2H), 6.90-7.00(m, IH), 7.28 (d, J= 10.6 Hz, IH), 8.14 (s, IH), 8.34 (s, IH), 8.47(d, J = 7.4 Hz, IH), 8.56 (d, 7 = 1.9 Hz, IH), 12.33 (s, IH); ESI-MS (m/z) 575.4 (M+H) +
146	mn rV X=/ \ Q CE}	Method C; A19/B8	N-(3-(3,3-dimcthyl-1 -(4-mcthyI-4H-1,2,4triazol-3-yl)cyclobutyl)phenyI)-5((isobutylamino)methyl)-N-methyl-2-oxo-l(2,2,2-lrifluoroelhyl)-l,2-dihydropyridine-3carboxamide: 'H NMR (400 MHz. DMSOd6): δ 0.90 (d, 7=6.3 Hz, 6H), 1.00 (s, 6H), 1.86 (m. IH), 2.43 (s, 2H), 2.45-2.50 (m. 2H), 2.75 - 2.79 (m, 2H). 3.12(s, 3H). 3.30(s, 3H), 3.75(s, 2H), 4.64(s, 2H), 6.95(s, IH), 7.1 l(d, J=7.7 Hz. 2H), 7.2l(d, 7=6.9 Hz, IH), 7.62(d, 7=19.2 Hz. 2H), 8.29(s, IH); ESI MS (m/z) 559.3 (M+H)+
147		Method C; A12/B8	N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2.4triazol-3-yl)cyclobutyl)phcnyl)-5((isopentylamino)methyl)-2-oxo-1-(2,2.2triHuoroethyl)-1,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz, DM S O-A) δ 0.85 (d, J = 6.6 Hz, 6H), 1.05 (s, 3H), 1.14 (s, 3H), 1.33 (q, 7 = 7.1 Hz, 2H), 1.59-1.61 (m, IH), 2.50 -2.52 (m, 4H), 2,89 (d, J = 12.4 Hz, 2H),3.23 (s, 3H), 3.63 (s, 2H), 5.09 (q. 7 = 7.1 Hz, 2H), 6.95 - 6.98 (m, IH), 7.26-7.28 (m,

153

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			1H), 8.05 (s, 1H), 8.34 (s, 1H), 8.47 (dd. J = 7.4 Hz & 7 = 2.5 Hz, 1 H), 8.61 (d, 7 = 2.5 Hz, 1H), 12.12 (s, 1H), ESI-MS (m/z) 577.2 (M+H)+
148		Method C; A12/B8	N-(5-(3,3-dimethyl-l-(4-methyl-4H-1,2,4triazol-3-yI)cyclobutyl)-2-fluorophenyl)-5((((i- (fluoromethyl)cyclopropyl)methyl)amino)me thyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: ’HNMR (400 MHz, DMSO-7ô) δ 1.04 (s, 3H), 1.14 (s, 3H), 1.39-1.41 (m, 1H), 1.72-1.75 (m. 1H), 2.11-2.15 (m, 4H). 2.54 (d, 7 = 12.9 Hz, 2H), 2.71 (d, J = 24.7 Hz, 2H), 2.91 (d. 7 = 12.6 Hz, 2H), 3.23 (s, 3H), 3.64 (s, 2H), 5.09 (q, J = 9.0 Hz, 2H), 6.95 - 6.97 (m, 1H), 7.28 (d, 7 = 8.8, 1H), 8.04 (s, 1H), 8.31 (s. 1H), 8.47 (s, 1H), 8.62 (s, 1H), 12.14 (s, 1H), ESI-MS (m/z) 593.1 (M+H)+
149		Method C; A16/B8	5-(((Cyclopropylmcthyl)amino)mcthyl)-N(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-l(2,2,2-trifluorocthyl)-1,2-d ihydropyridinc-3carboxamide: *HNMR (400 MHz, DMSO-dô) 0.13 (q, 7=4.6Hz, 2H), 0.41-0.45 (m. 2H), 0.85-0.94 (m,lH), 1.74 (m, 2H), 1.90 (t, 7= 7.14 Hz, 2H), 2.0 (t, 7=7.42 Hz, 2H), 2.44 (d, 7 = 6.59 Hz, 2H). 2.69 (d, 7=13.64 Hz. 2H), 3.05 (d, 7=12.36, 2H), 3.21 (s, 3H), 3.68 (s, 2H), 5.09 (q, 7 = 8.9 Hz, 2H), 6.91-6.95 (m, 1H), 7.28 (dd. 7i = 10.71 Hz, 72 = 8.79 Hz.

154

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			IH), 8.07 (s, IH), 8.32 (s, IH), 8.40 (dd, Ji = 7.42 Hz, Λ = 2.19 Hz, 1 H), 8.62 (d, J = 2.19 Hz, IH), 12.09 (s,lH); ESLMS (m/z) 573.25 (M+H)*
150	Ç (T ^CHF2	Method C; A12/B2	5-(((CyclopropyImethyl)amino)methyl)-l(2,2-difluoroethyl)-N-(5-(3,3-dimethyl-1 -(4methyL4H-l,2,4-triazol-3-yl)cyclobutyl)-2fluorophenyl)-2-oxo-1,2-dihydropyridine-3carboxamide: ‘HNMR (400 MHz, DMSOd6): δ 0.14-0.16(m, 2H), 0.44-0.46(m, 2H),0.89 (m, 1 H), 1.14 (s, 3H), 1.23 (s, 3H), 2.40-2.50 (m, 2H), 2.9l(d, J= 12.4 Hz, 2H), 3.23 (s, 3H),3.73 (s, 2H), 4.60 -4.65 (m, 2H),6.28-6.56 (m. IH), 6.96-6.98 (m. IH), 7.28(dd, Ji= 10.7 Hz, J2= 8.52 Ηζ,ΙΗ), 8.09 (s, 1 H), 8.34 (s, IH), 8.45-8.47 (m, IH), 8.62 (s, IH), 12.16 (s, IH); ESLMS (m/z) 543.3 (M+H)+
151		Method C; AH / B12	N-(3-(3,3-dimethyLl-(4-methyl-4H-1,2,4triazol-3-y[)cyclobutyl)phenyl)-5((isobutylamino)mcthyl)-1 -(oxctan-3ylmethyl)-2-oxo-l,2-dihydropyridine-3carboxamide: ’HNMR (400 MHz, DMSO d6, 400 MHz) δ 0.85 (d, J = 6.8 Hz, 6H), 1.05 (s, 3H), 1.12 (s, 3H), 1.59-1.71 (m, lH),2.26(d, J = 6.8 Hz, 2H), 2.56 (d, J = 12.4 Hz, 2H), 2.89 (d, J = 12.4 Hz, 2H), 3.22 (s, 3H), 3.423.54 (m, IH), 3.53 (s, 2H), 4.38 (d, J = 7.2 Hz, 2H, ), 4.42-4.47 (m, 2H), 4.59-4.65 (m. 2H), 7.03 (d, J = 8.0 Hz, IH); 7.33 (t, J = 8.0 Hz, IH); 7.52-7.57 (m, 2H), 8.09 (d, J = 2.8 Hz,

155

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			1H), 8.31 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 12.15 (s, 1 H); MS (m/z): 533.4 (M+H)+

Method D:

Example-152

5-( l-(Isobutylamino)ethy l)-N-(3-(( 1 s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4-triazol-35 yl)cyclobutyl)phenyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1)

Example-153

5-(l-(isobutylamino)ethyl)-N-(3-((ls,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-310 yl)cyclobulyl)phenyl)-2-oxo-l-(2.2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide (Isomer-2)

Step-1: Methyl 5-acetyl-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxylate O O

To a stirred solution of methyl 5-bromo-2-oxo-l-(2,2,2-trifluorocthyl)-l,2-dihydropyridinc-3carboxylatc (800 mg, 2.539 mmol) in 1,4-Dioxanc was degasscd using N₂ for 15 min. Tributyl(l-ethoxyvinyl)tin (943 pL, 2.793 mmol) and Pd(PPh3)2Cl₂ (89 mg, 0.126 mmol) were added to reaction mixture at room température under nitrogen atmosphère. The reaction mixture was heated to 120°C for overnight in a sealed tube. The reaction mixture was cooled to room température and then 2 M HCl (40 ml) was added to reaction mixture and stirred for 1 hr at room température. The reaction mixture was quenched with aqueous bicarbonate solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by flash chromalography to yield 450 mg of the desired

156 compound. Ή NMR (400 MHz, DMSO-J₆) δ 2.46 (s, 3H), 3.8 (s, 3H), 4.9-5.1 (m. 2H), 8.47 (d,/ = 2.4 Hz, 1H), 8.92 (d,/ = 2.4Hz, 1H)

Step-2: 5-Acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxylic acid

O O

To a stirred solution of 5-acetyl-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxylate (440 mg, 1.582 mmol) in THF/MeOH ( 10 mL) was added 2 mL of aqueous LiOH (199 mg, 4.748 mmol) and stirred at room température for ovemight. The reaction mixture was conccntratcd and the rcsiduc obtaincd was diluted with water and acidificd using IN HCl solution and extracted twice with ethyl acetate. The organic layer was concentrated under reduced pressure and dried to yield 270 mg desired product. ‘H NMR (400 MHz, DMSO-dô) δ 2.45 (s, 3H), 4.9- 5.2 (m, 2H), 8.57 (d, J = 2.4 Hz, 1H), 8.96 (d. J = 2.4 Hz, 1H), 13.03 (brs, 1H).

Step-3: 5-Acetyl-N-(3-((ls,3s)-3-methyl-l-(4-methyl-4H-1.2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide

To a stirred solution of 5-acetyl-2-oxo-1-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxylic acid (225 mg, 0.852 mmol) in DMF (4 mL) was added HATU (388 mg, 1.022 mmol) and stirred at room température for 30 min. To this mixture were added DIPEA (440 μΐ, 2.556 mmol) and 3-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl) cyclobutyl)aniline (206 mg, 0.852 mmol) and stirred for ovemight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphatc and concentrated. The obtained residue was purified by flash column chromatography to yield 191 mg of the desired compound. Ή NMR (400 MHz, DMSO-d₆) δ 1.08(d, / = 5.2 Hz, 3H), 2.4- 2.55 (m, 3H), 2.53 (s, 3H), 3.1- 3.25 (m, 2H), 3.17 (s, 3H), 5.17 (q, / = 8.8 Hz, 2H), 7.12 (d, / = 8 Hz, 1H), 7.38 (t. / = 8 Hz, 1H), 7.59 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 8.3 (s, 1H), 8.84 (d, J = 2.4 Hz, 1H), 8.99 (d./ = 2.4 Hz, 1 H), 11.35 (s, 1H).

Step-4: 5-(l-(Isobutylamino)ethyl)-N-(3-((l s,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazoI-3yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3~carboxamide (Isomer-1 ) & 5-( 1 -(isobutylamino)ethyl)-N-(3-(( 1 s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4

157 triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-tnfluoroethyl)-1.2-dihydropyndine-3carboxamidc (lsomcr-2)

To a stirred mixture of 5-acetyl-N-(3-(3-methyTl-(4-methyl-4H-l,2,4-triazol-3-yl) cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-l,2~dihydropyridine-3-carboxamide (100 mg, 0.205 mmol) and isobutyl amine hydrochloride (67 mg. 0.616 mmol) in THF were added triethylamine (288 pL, 2.05 mmol) and titanium isopropoxide (174 mg, 0,616 mmol) at room température. The reaction mixture was heated to 50°C for 4 h. The réaction mixture was brought to room température and then added sodium cyanoborohydride (39 mg, 0.616 mmol) and stirred at room température for overnight. The reaction mixture was quenched with saturated NHÆl solution and diluted with ethyl acelate. The réaction mixture was filtered. The organic layer was separated, conccntratcd and purified by flash chromatography to obtain 54 mg of the desired racemic product. The racemic product was purified by using SFC 0.1 % NH3 in Methanol to yield 21 mg of the desired Isomer-1 and 23 mg of desired Isomer-2.

Isomer-1: ‘HNMR (400 MHz, DMSO-î/₆) δ 0.83 (d, J = 6.4 Hz, 6H), 1.08 (d, J= 5.2 Hz, 3H). 1.26 (d, 7 = 6.4 Hz, 3H), 1.4- 1.55 (m. 1H), 1.9- 2.1 (m, 1H), 2.1- 2.3 (m, 1H), 2.40- 2.55 (m, 3H), 2.65- 2.8 (m, 2H), 3.17 (s, 3H), 3.5- 3.65 (m, 1H), 5.02- 5.20 (m. 2H), 7.1 (d. 7 = 8 Hz, 1H), 7.37 (t, 7 = 8 Hz, 1H), 7.60-7.80 (m, 2H), 8.02 (s, 1H), 8.3 (s, 1H),8.61 (s, 1H), 11.83 (s, 1H); ESI-MS (m/z) 545.31(M+H) ⁺

Isomer-2: 'HNMR (400 MHz, DMSO-A) Ô 0.6- 0.8 (m, 6H), 1.08 (d, J = 4.8 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H), 1.5- 1.65 (m, 1 H), 2- 2.15 (m, 1 H), 2.2- 2.3 (m, 1 H), 2.40 - 2.60 (m, 3H), 2.702.85 (m, 2H), 3.17 (s, 3H), 3.60- 3.75 (m, 1H), 4.9- 5.2 (m. 2H), 7.1 (d, 7 = 8 Hz, 1H), 7.37 (t, 7 = 8 Hz, 1H), 7.60- 7.80 (m, 2H), 8.04 (s, 1H), 8.3 (s, 1H), 8.62 (s, 1H), 11.81 (s, 1H); ESIMS (m/z) 545.3 (M+H) ⁺

The details of synthesis and analytical data of the cxamplcs prepared from the above mentioned methods are given below in Table-16.

Tahle-16: Structure, Chemical name, method, intermediate used and analytical dataof Examples (154-155)

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
154		Method D; Ail / Stcp-2 intermediate	(±)N-(3-(3,3-dimethyl-l-(4-mcthyl-4H1,2,4-triazol-3-yl)cyclobutyl)phcnyl)-5-( 1 (isobulylamino)ethyl)-2-oxo-1-(2,2,2trifluoroethyl )-1,2-dihydropyridine-3-

158

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
		of Example- 155	carboxamide: 'HNMR (DMSO-dtf, 400 MHz) δ 0.88-0.81 (m, 6H), 1.05 (s. 3H), 1.12 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.59-1.62 (m, 1H), 2.03-2.08 (m, 1H), 2.22-2.24 (m, 1H), 2.57 (d, J = 12 Hz, 2H), 2.89 (d, J = 12 Hz, 2H), 3.22 (s, 3H), 3.66-3.62 (m, 1H), 5.045.08 (m, 2H). 7.04 (d, J = 8.0 Hz, 1H), 7.35 (l, 7 = 8 Hz, 1 H), 7.54 (d, 7 = 8 Hz, 1H), 7.59 (s, 1H), 8.00 (s, 1H), 8.32 (s, 1H), 8.59 (d, 7=2.4 Hz, 1H), 11.83 (s, 1H). ESI-MS (m/z) 559.3 [M+HJ+
155		Method D; A12 / Slep-2 intermediate of Example155	(±)N-(5-(3,3-dimethyl-l-(4-methyl-4H- 1,2,4-triazol-3-yl)cyclobulyl)-2- fluorophenyi)-5-( 1 -(isobutylamino)ethyI)-2oxo-l-(2,2.2-trifluoroethyl)-l,2dihydropyridine-3-carboxamide: 'HNMR (DMSO-di, 400 MHz) δ 0.84-0.88 (m, 6H), 1.05 (s, 3H), 1.14 (s, 3H), 1.18-1.23 (m, 3H), 1.36-1.37 (m. 1H), 2.06-2.32 (m, 2H), 2.51 (d, 7 = 12.4 Hz. 2H), 2.89 (d, 7 = 12.4 Hz, 2H), 3.23 (s, 3H), 3.5-3.7 (m, 1H), 5.07-5.15 (m, 2H), 6.98-6.99 (m. 1H), 7.26-7.31 (m, 1H), 8.06-8.04 (m, 1H), 8.34 (s, 1H), 8.48 (d, 7 = 6.2 Hz, 1H), 8.64 (s, 1H), 12.15 (s, 1H); ESIMS (m/z) 577.3 [M+H]+

Method E:

Example-156

5-((lsobutylamino)methyl)-N-(3-((ls,3s)-3-methyl-l-(5-methyl-lH-imidazol-4-yl) cyclobutyl)phenyl)-2-oxo-l-(2,2.2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide

159

Step-1: N-(3-((ls,3s)-3-methyl-l-(5-methyl-l-tr!tyl-lH-imidazol-4-yl)cyclobutyl)phenyl)-2oxo-1 -(2,2,2-trifluorocthyl)-5-vinyl-1,2-dihydropyridinc-3-carboxamidc

To a stirred solution of 2-oxo-l-(2,2,2-trifluorocthyl)-5-vinyl-l,2-dihydropyridinc-3carboxylic acid (0.3 g, 1.21 mmol) in DMF (5 ml) at 0 °C was added HATU (0.69 g, 1.82 mmol). After 30 min, 3-((ls,3s)-3-methyl-l-(5-methyl-l-trityl-lH-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 température for 16 h. The reaction mixture was poured onto ice-cold water, precipitated solid was filtered and dried under vacuum to afford 0.8 g of the desired compound. ESI-MS (m/z) 713.3 (M+H) ⁺

Step-2: 5-Formyl-N-(3-(( 1 s,3s)-3-methyl-1 -(5-methyl-1-tri tyl- lH-imidazol-4yl)cyclobutyl)phenyl)-2-oxo-l-(2.2,2-trinuoroethyl)-l,2-dihydropyridine-3-carboxamide

To a stirred solution of N-(3-((ls,3s)-3-methyl-l-(5-methyl-l-trityl-lH-imidazol-4yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydropyridine-3carboxamide (0.8 g, 1.21 mmol) in THF (20 ml) and water (4 ml) was added NaKLi (0.85 g, 3.36 mmol) followed by OsÛ4 (1 % in f-BuOH, 0.0048 g, 0.0224 mmol, 0.5 ml). The reaction mixture was stirred at room température for 16 h. The réaction mixture was quenched with 10 % of sodium thiosulfate solution (25 mL) and extracted thrice with ElOAc. The organic layer was separated, dried over anhydrous Na2SO4, evaporated under reduced pressure to give crude compound. The crude compound was purified by combiflash chromatography to afford 0.550 g of the title compound. ESI-MS (m/z) 715.4 (M+H) ⁺

Step-3: 5-((Isobutylamino)methyl)-N-(3-((ls,3s)-3-methyl-l-(5-methyl-l-trityl-lH-imidazol4-yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydro pyridine-3-carboxamide

160

To a stirred solution of 5-formyl-N-(3-((ls,3s)-3-methyl-l-(5-methyl-l-trityl-lH-imidazol-4yl)cyclobutyl)phcnyl)-2-oxo-l-(2,2,2-trifluorocthyl)-l,2-dihydropyridinc-3-carboxamidc (0.3 g, 0.41 mtnol) in EDC (10 ml) was added isobutylamine (0.153 g, 2.09 mmol) and AcOH (0.125 g, 2.09 mmol) and heated at 80 °C for 3h. The reaction mixture was cooled to 0 °C, sodium triacetoxyborohydride (0.26 g, 1.25 mmol) was added and stirred at room température for 16 h. The reaction mixture was basified with sat. NaHCOa and extracted thrice with DCM. The organic layer was separated, dried over anhydrous NaiSO j, evaporated under reduced pressure to give crude compound. The crude compound was purified by comhiflash chromatography to afford 0.17 g of thc titlc compound. ESI-MS (m/z) 772 (M+H)⁺

Step-4: 5-((Isobutylamino)methyl)-N-(3-((ls,3s)-3-methyl-l-(5-methyl-lH-imidazol-4yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide

To a stirred solution of 5-((isobutylamino)methyl)-N-(3-(( ls,3s)-3-methyl-1 -(5-methyl-1 -trityllH-imidazol-4-yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamidc (0.15 g, 0.1943 mmol) in McOH (2 ml) at 0 °C was added 4M HCl in dioxanc (3 ml) and heated at 80 °C for 3h. The reaction mixture was concentrated, basified with sat NaHCOs and extracted with ElOAc (3 x 25 ml). The organic layer was separated. dried over anhydrous Na^SOa, evaporated under reduced pressure to give crude compound. The obtained compound was purified by combiflash chromatography to afford 0.05 g of the title compound. Ή NMR (DMSO-76. 400 MHz) δ 0.89 (d. J = 4 Hz, 6H), 1.04 (d. J = 5.2 Hz, 3H), 1.75-1.85 (m. IH), 1.91 (s, 3H). 2.32-2.34 (m, 3H), 2.46-2.50 (m, 2H), 2.74-2.79 (m. 2H), 3.77 (s, 2H), 5.09 (q. J = 9.0 Hz, 2H), 7.18 (d, J = 7.7 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.40 (s, 1 H), 7.57 (d, J = 8.0 Hz, IH), 7.66 (s, IH), 8.12 (s, IH), 8.65 (s, IH), 11.72 (s, IH); ESI-MS M/Z 530.4 (M+H)⁺

The details of synthesis and analytical data of the examples prepared from the above mentioned methods arc given below in Tahlc-17.

Table-17: Structure, chetnical name, method, intermediate used and analytical data of Examples (157-160)

161

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
157	0*^	Method E; A24/B8	N-(3-(3,3-dimethyl-1 -(5-methyl-1Himidazol-4-yl)cyclobutyl)phenyl)-5((isobutylamino)mcthyl)-2-oxo-1 -(2,2,2trifluoroethyl)-l,2-dihydropyridine-3carboxamidc: ‘HNMR (DMSO-rk 400 MHz) δ 0.89 (d, J = 8.0 Hz, 6H), 0.99-1.01 (m, 6H), 1.72-1.79 (m, 1H), 1.95 (s, 3H), 2.40-2.50 (m, 4H), 2.72 - 2.75 (m, 2H), 3.72 (s, 2H), 5.09(q, J = 8.0 Hz, 2H), 7.06 (d, 7 = 7.7 Hz, 1H), 7.26 (t. 7= 7.8 Hz, 1H), 7.38 (s, 1H), 7.50-7.55 (m, 2H), 8.07 (s, 1H), 8.63 (d, 7 = 2.5 Hz, 1H), 11.73 (s, 1 H); ESI-MS (m/z) 544.4 (M+H)+
158		Method E; A26/B8	5-((Isobutylamino)melhyl)-N-(3-(3-melhyl- 1 -(5-methyl-1 H-l ,2,3-triazol-4yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2tri fluoroethy 1 )-1,2-dihydropyridine- 3 carboxamide hydrochloride: ’HNMR (DMSO-dû, 400 MHz) δ 0.95 (d, 7 = 7.2 Hz, 6H), 1.06 (s, 3H), 1.09 (s, 3H), 2.07 (s, 3H), 2.55-2.58 (m, 2H), 2.76-2.79 (m, 4H), 2.892.92 (m, 2H). 4.07 (s, 2H), 5.11 (q,7 = 8.9 Hz, 2H), 7.05-7.07 (m, 1H), 7.28-7.32 (m, 1H), 7.49 (d, 7 = 7.8 Hz, 1 H), 7.63 (s, 1 H), 8.34 (s, 1H), 8.79 (d, 7 = 2 Hz 1H), 9.12 (bs, 2H), 11.61 (s, 1H); ESI-MS (m/z) 545.2 (M+H)+
159	(f ^C.fy	Method E; A25 / B8	5-((lsobutylamino)mcthyl)-N-(3-((ls,3s)-3methy 1-1 -(5-methyl-1 H-1,2,3-lriazol-4yl)cyclobutyl)phenyl)-2-oxo-1 -(2,2,2trifluoroethyl)-l,2-dihydropyridine-3carboxamide: ’HNMR (DMSO-rfû, 400 MHz) δ 0.87 (d, 7 = 4 Hz, 6H), 1.04 (d, 7 = 2 Hz,

162

Example No.	Structure	Method and Intermediate	Chemical Naine and Analytical data
			3H), 1.91 (s, 3H), 2.30-2.38 (m, 5H), 2.832.85 (m, 2H), 3.59 (s, 2H), 5.08 (q, J = 8.9 Hz, 2H), 7.13-7.15 (m, 1H), 7.30-7.34 (m, 2H), 7.54 (d, J = 8 Hz, 1H), 8.01 (s, 1H), 8.58 (d, J = 2 Hz 1 H), 11.8 (s, 1H), 14.31 (bs, 1 H); ESIMS M/Z 531 (M+H)+
160		Method E; A25/B8	5-((Isobutylamino)methyl)-N-(3-((lr,3r)-3methyl-1 -(5-methyl-1 H-1,2,3-triazol-4yl)cyclobutyl)phenyl)-2-oxo-1 -(2,2,2tri Π uoroethy 1 )-1,2-dih ydropyridine-3 carboxamide: ’HNMR (DMSO-ds, 400 MHz) δ 0.95 (d. J = 8 Hz, 6H), 1.04 (d, J = 2 Hz, 3H), 1.91 (s, 3H), 1.94-1.99 (m, 1H), 2.392.35 (m, 2H), 2.83-2.89 (m, 4H), 4.07 (s, 2H), 5.12 (q, J = 8 Hz. 2H), 7.15-7.17 (m, 1H), 7.31-7.35 (m, 1H), 7.55-7.57 (m. 1H), 7.63 (s, 1H), 8.22 (s, 1H), 8.77 (d. J = 2 Hz 1H), 11.6 (s, 1H), 14.37 (bs, 1H). ESI-MS M/Z = 531 (M+H)+

Method F:

Example-161

N-(3-acetamido-5-((ls,3s)-3-mcthyl-l-(4-mcthyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phcnyl)-5((isobutylamino)methy 1 )-2-oxo-1-(2,2,2-trifluoroeth y 1)-1,2-dihydropy ridine-3-carboxamide hydrochloride

Step-1: Methyl 5-formyl-2-oxo-1-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxylate

163

Ο

Το a stirred solution of methyl 2-oxo-l-(2,2,2-trifluoroethyl)-5-vinyl-l,2-dihydro pyridine-3carboxylatc (0.5 g, 1.92 mmol) in THF (8 ml) and water (2 ml) was added NalÛ4 (0.82 g, 3.83 mmol) followed by OsCL (1 % in i-BuOH, 0.97 ml, 0.038 mmol). The reaction mixture was stirred at room température for 3 h. The reaction mixture was quenched with 10 % of sodium thiosulfate solution (25 ml) and partitioned between EtOAc (3 x 50 ml) and water (25 ml). The organic layer was separated, dried over anhydrous Na₂SO4, evaporated under reduced pressure to afford 0.5 g of the title compound. ESI-MS (m/z) 264 (M+H)⁺

Sten-2: Mcthyl 5-((isobutylamino)mcthyl)-2-oxo-l-(2,2,2-trifluorocthyl)-l ,2-dihydropyridinc3-carboxylate

To a stirred solution of Methyl 5-formyl-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihy dropyridine-3carboxylale (0.5 g, 1.9 mmol) in DCE (10 ml) was added isobutylamine (0.94 ml, 9.5 mmol) and AcOH (0.53 ml, 9.5 mmol) and heated at 80 °C for 3h. The reaction mixture was cooled to 0 °C, sodium triacetoxy borohydride (1.2 g, 5.7 mmol) was added and stirred at room température for 16 h. The reaction mixture was basified with sat. NaHCO₃ and extracted thrice with DCM. The organic layer was separated, dried over anhydrous Na₂SO4, evaporated under reduced pressure to afford 0.52 g of the title compound. ESI-MS (m/z) 321 (M+H)⁺

Step-3 : Methyl 5-(((tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1 -(2,2,2tri fl uorocth y 1)-1,2-dihydropyridinc- 3 -carboxyl atc

Ο ύ

To a stirred solution of methyl 5-((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxylate (0.52 g, 1.62 mmol) in DCM (5 ml) was added trimethylamine (0.33 ml, 2.43 mmol) and (Boc)₂O (0.55 ml, 2.43 mmol) and stirred at room température for 16 h. The organic solvent was evaporated under reduced pressure to obtain compound. The obtained compound was purified by combiflash chromatography to afford 0.16 g of the title compound. ESI-MS (m/z) 421 (M+H)⁺

164

Step-4: 5-(( (Tert-butoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2.2-tnfluoroethyl)-1,2dihydropyridinc-3-carboxylic acid

To a stirred solution of methyl 5-(((tcrt-butoxycarbonyl)(isobutyl)amino)mcthyl)-2-oxo-l(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxylate (0.162 g, 0.38 mmol) in THF:MeOH:Water (1:1:0.5, 5 ml) was added lithium hydroxide (46 mg, 1.14 mmol) and stirred at room température for 16 h. The organic solvent was evaporated under reduced pressure. The obtained residue was acidified by IN HCl solution and extracted with ethyl acetate (3 x 10 ml). The organic layer dried over anhydrous Na₂SO4, evaporated under reduced pressure to obtain compound. The obtained compound was triturated with hexane solvent to afford 135 mg of the title compound. ^lH NMR (DMSO-7₀, 400 MHz) δ 0.81 (d, J = 4 Hz, 6H), 1.40 (s, 9H), 1.861.90 (m, 1H), 2.98-3.0 (m, 2H), 4.25 (s. 2H), 5.07 (q, J = 8 Hz. 2H), 8.09 (s, 1H), 8.39 (s. 1H), 13.8 (bs, 1H); ESI-MS (m/z) 407 (M+H)⁺

Stcp-5: Tcrt-butyl ((5-((3-amino-5-((ls,3s)-3-mcthyl-l-(4-mcthyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)carbamoyl)-6-oxo-l -(2,2,2-trifluoroethyl)-l,6-dihydropyridin-3yl)methyl)(isobutyl)carbamate

To a stirred solution of 5-((lr,3r)-3-methyl-l-(4-mcthyl-4H-l,2,4-triazol-3-yl)cy clobutyl)benzene-l,3-diamine (Intermediate A8) (0.1 g, 0.389 mmol), 5-(((tertbutoxycarbonyl)(isobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethy 1)-1,2dihydropyridine-3-carboxylic acid (0.0631 g, 0.155 mmol) in DMF (5 ml) was added 4methylmorpholine (0.428ml, 3.89 mmol) and then 50% solution of T₃P in DMF (0.371 ml, 0.583 mmol). The réaction mass was stirred at RT for 18 h. The reaction mass was diluted with brine solution (3 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer separated and dried over anhydrous Na₂SO4, evaporated under reduced pressure to afford crude compound which was purified by column to obtain 57 mg of required product as yellow solid. ESI-MS (m/z) 646 (M+H)⁺

165

Step-6: Tert-butyl ((5-((3-acetamido-5-((ls,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3yI)cyclobutyl)phcnyl)carbamoyl)-6-oxo-l-(2,2,2-trifluoroethyl)-l,6-dihydropyridin-3y 1 )methy l)(isobut y 1 )carbamate

To a stirred solution tert-butyl ((5-((3-amino-5-(( 1 s,3s)-3-mcthyl-l -(4-mcthy I-4H-1,2,4-triazol3-yl)cyclobutyl)phcnyl)carbamoyl)-6-oxo-l-(2,2,2-trifluoroethyl)-l,6-dihydropyridin-3yl)methyl)(isobutyl)carbamate (0.055g, 0.085 inmol) in DCM were added triethylamine (0.022 ml, 0.170 mmol) and then acetic anhydride (0.012 ml, 0.127 mmol). The reaction mass was stirred at room température for 18 hrs. The réaction mass was diluted with brinc 10 solution (3 ml) and extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous Na₂SO4, evaporated under reduced pressure to resuit crude compound which was purified by column to afford 60 mg of the desired product. ESI-MS (m/z) 688 (M+H)⁺ Step-7: N-(3-acetamido-5-((l s,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobuty])phenyl)-5-((isobutylamino)methyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,215 dihydropyridine-3-carboxamide hydrochloride

To a slirred solution N-(3-acrylamido-5-((ls,3s)-3-melhyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobuty1)phenyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (0.04 g) in DCM was added 4M hydrochloric acid in dioxane (1 ml) and was stirred at room température for 2 h. The solvent was evaporated under vacuum and the resulted solid was 20 washed with dicthyl ether and dried it to ohtain 31 mg of required product as yellow solid. 'H NMR (DMSO-ώ, 400 MHz) δ 0.96 (d. J = 4 Hz, 6H), 1.10-1.09 (m, 3H), 2.08 (s, 3H), 2.592.58 (m, 3H), 2.79-2.73 (m, 4H), 3.56 (s, 3H), 4.06-4.02 (m, 2H), 5.11 (q, J = 8 Hz. 2H), 7.35 (s, 1H), 7.41 (s, 1H), 8.04 (s, 1H), 8.32 (s, 1H), 8.78 (d, J = 4 Hz, 1H), 9.09 (bs, 2H), 9.18 (s, 1H), 10.17 (s, 1H). 11.66 (s, 1H); ESI-MS (m/z) 588 (M+H)⁺

The details of synthesis and analytical data of the example prepared from the above mentioned methods are given below in Table-18.

Table-18: Structure. Chemical name, method, intermediate used and analytical data of Example162

166

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
162	_ΛΗΝ rfA	Method F; A8/B8 Acryloyl chloride	N-(3-acrylamido-5-((Is,3s)-3-methyl-l-(4methyl-4H-1,2,4-triazol-3yl)cyclobutyl )phcnyl)-5 ((isobutylamino)methyl)-2-oxo-1 -(2,2,2trifluorocthyl)-1,2-dihydropyridine-3carboxamidc 2,2,2-trifluoroacctatc: 'HNMR (DMSO-d6, 400 MHz) δ 0.95 (d, J = 8 Hz, 6H), 1.08 (d, J = 2 Hz, 3H), 1.91-1.99 (m, 1H), 2.57-2.59 (m, 2H), 2.64-2.66 (m, 1H), 2.78-2.84 (m. 4H), 3.22 (s, 3H), 4.09-4.07 (m. 2H), 5.13 (q. J = 8 Hz, 2H), 5.75-5.78 (m, 1H), 6.23-6.28 (m, 1H), 6.38-6.45 (m, 1H), 7.35 (s, 1H), 7.38 (s,lH), 8.14 (s, 1H), 8.208.21 (m, 1H), 8.43 (s, 1H), 8.61 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.91 (bs. 1H), 10.27 (s. 1H), 11.67 (bs, 1H); ESI-MS (m/z) 600 (M+H)+

The details of synthesis and analytical data of the cxamples synthesized from the abovemenlioned methods are given below in Table-19.

Table-19: Structure, method. intermediates used, Chemical name and analytical data of 5 Examples (163-205)

Examplc No.	Structure	Method and Intermediate	Chemical Name and Analytical data
163	nn fV aîX	Method C; AH /B16	N-(3-(3,3-dimcthyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)phenyl)-6((isobutylamino)methyl)-3-oxo-4-(2,2,2trifluorocthyl)-3,4-dihydropyrazinc-2carboxamideJHNMR (400 MHz , DMSO de) δ 0.89 (d, J = 8.0 Hz, 6H), 1.05 (s, 3H), 1.13 (s, 3H), 1.67-1.79 (m. 1H), 2.41 (d. J = 8.0 Hz,

167

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			2H), 2.55 (d. J = 12.0 Hz. 2H), 2.89 (d, J = 12.0 Hz, 2H), 3.22 (s, 3H), 3.92 (s, 2H), 5.065.15 (m. 2H), 7.05 (d, J = 8.0 Hz, 1H); 7.35 (t, J = 8.0 Hz, 1H); 7.52 (s, 1H), 7.71 (d. J = 8.0 Hz, 1H), 8.32 (s, 1H), 8.46 (s, 1H), 10.58 (s, 1H); ESI-MS (m/z) 546.46 (M+H)+
164		Method C; A12/B18	N-(5-(3,3-dimethyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-Ιέ thyl-5-((isobutylamino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide: *HNMR (400 MHz, DMSO-d6) δ 0.89 (d, J = 6.6 Hz, 6H),1.05 (s, 3H), 1.14(s, 3H), 1.31(t, 7=7.14 Hz, 3H), 1.77-1.82 (m, 1H), 2.41-2.44 (m, 2H), 2.52-2.57 (m, 2H), 2.91 (d, 7=12.6 Hz, 2H), 3.23 (s, 3H), 3.69 (s, 2H), 4.11 (q, 7=7.11 Hz, 2H), 6.95 (dq, 7/=8.6 Hz, J2= 2.5 Hz, 1H), 7.27 (dd, 71=10.7 Hz, 72=8.5Hz, 1H), 8.15 (d, 7=1 7Hz, 1 H), 8.34( s, 1 H), 8.5 (dd, 7i=7.6 Hz, 72=2.3Hz, 1H), 8.56 (d, 7=2.2Hz, 1H), 12.50 (s, 1H); ESI-MS (m/z) 509.3 (M+H)+
165		Method C; A6/B18	l-Ethyl-N-(2-fluoro-5-((ls,3s)-3-methyl-l(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyI)phcnyl)-5-(((( 1(fluoromethyl)cyclopropyl)methyl)amino)me thyl)-2-oxo-1,2-dihydropyridine-3carboxamide; ‘HNMR (400 MHz, DMSO-Æ) δ 1.08(d, 7=5 Hz, 3H), 1.32-1.35 (m, 3H), 1.39-1.43 (m,lH), 1.74-1.76 (m,lH), 2.112.15 (m, 4H), 2.53-2.55 (m, 3H), 2.70-2.77 (m, 4H), 3.18 (s,3H), 3.62 (s, 2H), 4.10 (q, 7=7.01 Hz, 2H), 7.02-7.04 (m, 1H), 7.29 (dd.

168

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			7/=10.7Hz. 72=8.8Hz, 1H), 8.09 (d, 7=1.92Hz, 1H), 8.29 (s, 1H), 8.51-8.53 (m, 2H), 12.55 (s, 1H); ESI-MS (m/z) 525.3 (M+H)+
166		Method C; A6/B18	5-(((Cyclopropylmethyl)amino)methyl)-lethyl-N-(2-fluoro-5-((ls,3s)-3-methyl-l-(4methyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-l,2dihydropyridine-3-carboxamide: ‘HNMR (400 MHz. DMSO-ί/ό) δ 0.84 - 0.88 (m, 2H),0.42-0.44 (m, 2H), O.93-O.96(m. 1H), 1.08(d, 7=5.2Hz, 3H), 1.32-1.35(m. 3H), 2.52-2.54(m. 5H). 2.78(d. 7=3.6Hz, 2H), 3.19(s, 3H), 3.68(s, 2H), 4.1 l(q, 7=7.14Hz, 2H), 7.07-7.09(m. 1H), 7.28-7.32(m, 1H), 8.14(d, 7=2.2Hz, 1H), 8.30(s, 1H), 8.508.53(m, 2H), 12.49(s, 1H); ESI-MS (m/z) 493.3 (M+H)+
167		Method C; A6/B8	5-(((3-Fluoro-3-methylbutyl)amino)methyl)N-(2-fluoro-5-(( ls.3s)-3-mcthyl-l-(4methyl-4H-1.2.4-triazol-3- yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2trifluorocthyl)-l,2-dihydropyridinc-3- carboxamide: ESI-MS (m/z) 581.38 (M+H)+
168		Method C; A12/B15	N-(5-(3,3-dimcthyl-l-(4-mcthyl-4H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-l(4-fluorophenyl)-5-((isobutylamino)melhyl)2-oxo-1,2-dihydropyridinc-3-carboxamide: ‘HNMR (400 MHz, DMSO-i/6) δ 0.89 (d, J= 6.59Hz, 6H), 0.93 (d, 7= 6.59Hz, 1H), 1.05 (s, 3H), 1.14 (s, 3H), 1.75 (s, 1H), 2.51-2.54 (m.

169

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			4H), 2.91 (d, J= 12.64Hz, 2H), 3.24 (s, 3H), 3.70 (s, 2H), 6.94-6.97 (m, 1H), 7.26 (dd, 7=10.71Hz & 8.52Hz, 1H), 7.40-7.44 (m, 2H), 7.57-7.60 (m. 2H), 8.05 (s, 1H), 8.34 (s, 1 H), 8.47 (dd, 7=7.42Hz & 2.47Hz, I H), 8.67 (s, 1H), 12.22 (s, 1H); ESI-MS (m/z) 575.3 (M+H)+
169	<<	Method C; A12/B19	N-(5-(3,3-dimethyl-l-(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-1 (4-nuorobenzyl)-5-((isobutylamino)methyl)2-oxo-1,2-dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-76) δ 0.86 (d, 7= 6.59Hz, 6H), 1.05 (s, 3H), 1.13 (s, 3H), 1.661.70 (m, 1H), 1.91 (s, 2H), 2.53-2.55 (m,4H), 2.90 (d, 7= 12.91 Hz, 2H), 3.22(s, 3H), 3.62(s, 1H), 5.28(s, 2H), 6.93-6.97 (m, 1H), 7.187.29 (m, 2H), 7.27 (dd, 7= 10.71Hz &8.79Hz, 1 H), 7.42 (dd. 7= 8.79Hz & 5.49Hz, 2H), 8.22 (s, 1H), 8.33 (s, 1H), 8.46 (dd. 7= 7.55Hz & 2.33Hz, 1H). 8.56 (s, 1H), 12.37 (s, 1H); ESIMS (m/z) 589.3 (M+H)+
170	nn rf vU ' ô-âîÎ	Method C; A5/B17	5-((Isobutylamino)methyl)-1 -methyl-N-(3((ls,3s)-3-mcthyl-l-(4-mcthyl-4H-l,2,4triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-Je) δ 0.89 (d. 7=6.4 Hz. 6H), 1.08 (d. J=5.49Hz, 3H), 1.75-1.80 (m. 1H), 2.51-2.70 (m, 5H), 2.80-2.86 (m, 2H), 3.17 (s, 3H), 3.63(s, 2H), 3.73 (s, 2H), 7.10(d, 7=7.42Hz, 1H). 7.37(1, 7=7.97Hz, 1H), 7.55 (s, 2H), 7.65 (d, 7=8.24Hz, 1H), 8.13(s, 1H),

170

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			8.29(s, 1H), 8.54(s, 1H), 12.18 (s, 1H); ESIMS (m/z): 463.5 (M+H)+
171	A	Method C; A6/B2	5-(((Cyclopropylmelhyl)amino)methyl)-l(2,2-dinuoroethyl)-N-(2-fluoro-5-((ls,3s)-3methyl-1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-l,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-J6) Ô 0.12 (t, 7=4.94Hz, 2H), 0.39-0.44 (m, 2H), 0.83-0.93 (m, 1H), 1.08(d, 7=5.22Hz, 3H), 2.40 (d. J=6.59Hz, 2H), 2.52-2.56(m, 4H), 2.76-2.78 (m. 2H), 3.18 (s, 3H), 3.64 (s, 2H), 4.56-4.64 (m, 2H). 6.27-6.56 (m, 1H), 7.05-7.33 (m, 1H), 7.287.33 (m, 1 H), 8.05 (d, 7=2.19Hz, 1 H), 8.30 (s, 1H), 8.48-8.58 (m. 1H), 8.58 (d. J=2.4Hz, 1H), 12.21 (s, 1H); ESI-MS (m/z) 529.43 (M+H)+
172	0	Method C; A6/B8	5-(((3-Fluoro-2,2- dimethylpropyl)amino)methyl)-N-(2-fluoro5-((ls,3s)-3-mcthyl-l-(4-mcthyl-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide: ESI-MS (m/z) 581.35 (M+H)+
173		Method C; A6/B2	1 -(2,2-DifluoroethyI)-N-(2-fluoro-5-(( 1 s,3s)3-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((((l- (fluoromethyl)cyclopropyl)melhyl)amino)me thyl)-2-oxo-l,2-dihydropyridinc-3carboxamide: 'HNMR (400 MHz, DMSO-dô) δ 1.08 (d, 7=5.5Hz, 3H), 1.34-1.46 (m. 1H), 1.70-1.77 (m. 1H), 2.11-2.19 (m, 4H), 2.54 (q,

171

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			7=1.9Hz, 4H), 2.69-2.78 (m, 4H), 3.18 (s, 3H), 3.63 (s, 2H), 4.56-4.64 (m, 2H), 6.416.55 (m, IH), 7.04-7.08 (m, IH), 7.28-7.33 (m, IH), 8.04 (d, 7=1.9Hz, IH), 8.30 (s, IH), 8.50-8.5l(m. IH). 8.59 (d, 7 = 2.5Hz, IH), 12.24 (s, IH); ESI-MS (m/z) 561.36 (M+H)+
174	'Υνί'	Method C; A12/B8	N-(5-(3,3-dimethyl-l-(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5(((3-fluoro-2,2dimethylpropyl)amino)methyl)-2-oxo-l(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide; ESI-MS (m/z) 595.36 (M+H)+
175	F	Method C; A16/B8	N-(2-fluoro-5-(2-(4-methyl-4H-l,2,4-triazol3-yl)spiro[3.3]heptan-2-yl)phenyl)-5-((((l(fluoromcthyl)cyclopropyl)mcthyl)amino)mc thyl)-2-oxo-l-(2,2,2-trifluoroethyl)-1.2dihy drop yridine-3 -carbo xamide : ‘HNMR (400 MHz, DMSO-dô) δ 1.30-1.44 (m, IH), 1.70-1.80(m. 3H), 1.90 (t, 7=7.28Hz, 2H), 2.0 (t, 7=7.28Hz, 2H), 2.11-2.22 (m, 4H), 2.672.70 (m. 4H). 3.05 (d, 7=12.36 Hz. 2H), 3.21(s, 3H), 3.64(s, 2H), 5.09(q, 7=8.97Hz, 2H), 6.91-6.95 (m, IH), 7.27 (dd, 71=10.71Hz, 72= 8.79 Hz, IH). 8.04 (s, IH), 8.32 (s, 1 H), 8.41 (dd,7i=7.55 Hz.72=2.33Hz, 1 H), 8.61 (d, 7 = 2.47 Hz, 1 H), 12.13 (s, 1 H); ESI-MS (m/z) 605(M+H)+
176		Method C; A16/B8	N-(2-fluoro-5-(2-(4-methy1-4H-l,2,4-triazol- 3-yl)spiro[3.3]heptan-2-yl)phenyl)-5((isopentylamino)methyl)-2-oxo-1-(2,2,2trifluorocthyl)-l,2-dihydropyridinc-3-

172

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			carboxamide:'HNMR (400 MHz, DMSO-d6) 0.8(d, 7=8.0Hz, 6H), 1.30-1.39 (m,2H), 1.581.65(m, 1H), 1.72-1.88 (m,2H), 1.88-2.0 (m,4H), 1.99-2.02 (m,2H), 2.63-2.70 (m,2H),3.05 (d, 7=12.36Hz,2H), 3.20 (s,3H), 3.73 (s,2H), 5.10 (q, 7=8.88 Hz,2H), 6.936.96 (m,lH), 7.28 (dd, 7j=10.71Hz, 72=8.52 Ηζ,ΙΗ), 8.10(s,lH), 8.31(d. 7= 8.79 Ηζ,ΙΗ), 8.39 (dd. 7/=7.28Hz, 72=2.06Hz,l H), 8.64(d, 7=2.1Hz, !H),12.06(s,lH); ESI-MS (m/z) 589.45 (M+H)+
177		Method C; A5/B8	5-((((1- (Fluoromethy l)cyc lopropy 1 ) methy 1 )amino )m ethyl)-N-(3-((ls,3s)-3-methyl-l-(4-methyl4H-1,2,4-triazol-3-y l)cyc!obulyl)phenyl)-2oxo-l-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: ‘HNMR (400 MHz, DMSO-d6) δ 1.07 (d, 7 = 5.22 Hz, 3H), 1.41-1.43 (m, 1H), 1.71-1.73 (m, 1H), 2.13-2.15 (m, 4H), 2.52-2.54 (m. 2H), 2.72 2.75 (m, 5H), 3.17 (s, 3H), 3.64 (s, 2H), 5.08 (q, 7= 9.07 Hz, 2H), 7.09 (d, 7 = 7.6 Hz. 1H), 7.37 (t, J = 7.97 Hz, 1H), 7.56 (s. 1H), 7.65 (d. 7= 8.24 Hz, 1 H), 8.01 (s, 1H), 8.29 (s, 1H), 8.58 (d, 7 = 2.74 Hz, 1 H), 11.82 (s, 1 H); ESIMS (m/z) 561.30 (M+H)+
178	Ά'	Method C; A6/B6	N-(2-fluoro-5-(( ls,3s)-3-methyl-1 -(4methyl-4H-l,2,4-triazol-3yl)cyclobuty l )pheny l)-5-((« 1 (fluoiOmethyl)cyclopropyI)methyl)amino)me thyl)-2-oxo-l-(3,3.3-trifluoropropyl)-l,2-

173

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			dihydropyridine-3-carboxatnide: 'HNMR (400 MHz, DMSO-Je) δ 1.08 (d, J = 5.22 Hz, 3H), 1.37-1.39 (m. 1H), 1.71-1,74 (m, 1H), 2.14-2.16 (m, 4H), 2.52-2.54 (m, 3H), 2.63 2.66 (m, 2H), 2.80-2.82 (m, 4H), 3.18 (s, 3H), 3.62 (s. 2H), 4.33 (t, J = 7.00 Hz. 2H). 7.057.09 (m, 1H), 7.30 (dd, J = 10.71 Hz, & 8.79 Hz, 1H), 8.11 (d, J = 2.47 Hz, 1H), 8.29 (s, 1H), 8.50 (dd, J = 7.55 Hz, & 2.33 Hz, 1H), 8.55 (d, 7 = 2.47 Hz. 1H). 12.35 (s, 1H); ESIMS (m/z) 593.31 (M+H)*
179		Method C; A12/B15	5-(((Cyclopropylmethyl)amino)methyl)-N(5-(3,3-dimethyl-1 -(4-methyl-4 H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-l(4-iluorophenyl)-2-oxo-1.2-dihydropyridine3-carboxamide: 'HNMR (400 MHz, DMSO76) δ 0.18-0.19 (m, 2H), 0.46-0.47 (m. 2H), 0.84-0.89 (m, 1H), 1.05 (s, 3H), 1.15 (s, 3H), 2.50-2.58 (m, 4H), 2.91 (d, 7=12.64 Hz, 2H),3.24 (s,3H), 3.79 (s,2H), 6.94-6.98 (m,lH), 7.23-7.28 (m,lH), 7.41-7.48 (m, 2H), 7.58-7.61 (m. 2H),8.08 (s, 1H),8.34 (s. 1H), 8.46 (dd, 7 =7.55 Hz & 2.33 Ηζ,ΙΗ), 8.69 (d, 7 = 2.47Hz, 1H), 12.19 (s, 1H); ESI-MS (m/z) 573.1 (M+H)+
180		Method C; A12/B15	N-(5-(3,3-dimcthyl-l-(4-mcthyl-4H-l,2,4triazol-3-yl)cyclobulyl)-2-fluorophenyl)-5<(((1(fluoromethyl)cyclopropyl)methyl)amino)me thyl)-l-(4*nuorophenyl)-2-oxo-1,2dihydropyridine-3-carboxamide: 'HNMR

174

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			(400 MHz, DMSOv/6) δ l .05 (s, 3H), 1.14 (s, 3H), 1.42-1.45 (m,lH), 1.72-1.77 (m,lH), 2.15-2.18 (m.4H), 2.52-2.56 (m, 2H), 2.76 (d, J = 24.7Hz, 2H), 2.91 (d, J = 12.9Hz, 2H), 3.24 (s, 3H), 3.66 (s, 2H),6.94-6.95 (m.lH),7.25 (dd, J=10.9Hz,8.7Hz,lH), 7.42 (l, J = 8.65Hz, 2H), 7.57-7.61 (m, 2H), 8.0 (d, J = 2.5 Hz. 1H), 8.33 (s, 1H), 8.49 (dd, J = 2.22 Hz, 7.49 Hz, 1H), 8.66 (d. J = 2.7Hz, 1H), 12.27 (s, 1H); ESI-MS (m/z) 605.1 (M+H)+
181		Method B; A6/B7	1 -Cyclopropyl-N-(2-fluoro-5-(( 1 s,3s)-3melhyl-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide: ’HNMR (400 MHz, DMSO-r/ô) δ 0,80 (d, J =6.5 Hz, 6H), 0.97-0.99 (m, 2H), 1.07-1.11 (m, 5H), 1.66-1.74 (m, 1H), 2.37 (bs, 2H), 2.52-2.55 (m, 3H), 2.78 (d, J =3.84 Hz, 2H), 3.19 (s, 3H), 3.47-3.54 (m, 1H), 3.64 (s, 2H), 7.057.08 (m, 1H), 7.31 (dd, J =10.71 Hz and J =8.79 Hz, 1H), 7.96 (s, 1H), 8.30 (s, 1 H), 8.49-8.51 (m, 2H), 12.50 (s,lH); ESI-MS (m/z) 507.2 (M+H)+
182		Method C; A12/B16	N-(5-(3,3-dimcthyl- l-(4-mcthyl-4H-1,2,4lriazol-3-yl)cyclobutyl)-2-fluorophenyl)-6((isobutylamino)methyl)-3-oxo-4-(2,2,2trifluoroethyl)-3,4-dihydropyrazine-2carboxamide: ^NMR (400 MHz, DMSO de) δ 0.88 (d, J = 8.0 Hz, 6H), 1.05 (s, 3H), 1.13

Example No.	Structure	Method and Intermediate	Chemical Name and Analyticai data
			(s, 3H), 1.63-1.75 (m, 1H), 2.35 (d, J = 8.0 Hz, 2H), 2.55 (d, J = 12.0 Hz, 2H), 2.91 (d, J = 12.0 Hz. 2H), 3.26 (s, 3H), 3.86 (s, 2H), 5.055.14 (m, 2H). 7.11-7.16 (m, 1H), 7.29 (t. J = 8.0 Hz, 1H), 7.79-7.84 (m, 1H), 8.33 (s, 1H), 8.47 (s, 1 H), 10.36 (s, 1H); MS (m/z): 564.38 (M+H)+
183		Method C; A28 ! B8	N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4triazol-3-yl)spiro[3.3]heptan-2-yl)-2fluorophenyl)-5-((isobutylamino)methyl)-2oxo-l-(2,2.2-trifIuoroethyl)-l,2dihydropyridine-3-carboxamide: JHNMR (400 MHz. DMSO-d6) δ 0.87 (d. 7= 6.59 Hz, 6H), 1.03 (s, 6H), 1.66-1.69 (m. 1H). 1.77 (s, 2H), 1.87 (s, 2H), 2.27- 2.29 (m, 2H), 2.712.73 (m,2H), 3.06-3.08 (m, 2H), 3.20 (s, 3H), 3.60 (s, 2H). 5.09(q. 7=8.97 Hz, 2H), 6.926.94(m, 1H), 7.27(dd, 71=10.71 Hz, 72= 8.8 Hz, 1H), 8.04(s, 1H), 8.3 l(s, 1H), 8.40 (dd. 71=7.42 Hz, 72= 2.11 Hz, 1H), 8.60 (s, 1H), 12.13 (s, 1H); ESI-MS (m/z) 603.44(M+H)+
184		Method C; A28/B8	5-(((Cyclopropylmethyl)amino)methyl)-N(5-(6,6-dimcthyl-2-(4-mcthyl-4H-1,2,4triazol-3-yl)spiro[3.3]heptan-2-yl)-2fluorophenyl)-2-oxo-1 -(2,2,2-trifluoroethyl)l,2-dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-dr,) δ 0.10-0.14 (m 2H), 0.40-0.44 (m, 2H), 0.89-0.94(m, 1H), 1.03 (s,6H), 1.77 (s.2H), 1.87 (s,2H), 2.42 (d, 7=5.5 Hz. 2H), 2.72 (d, 7=12.09 Hz. 2H). 3.08(d, 7= 12.4 Hz, 2H), 3.20 (s, 3H), 3.67 (s.

176

Ex ample No.	Structure	Method and Intennediate	Chemical Name and Analytical data
			2H), 5.09 (q, J = 9.07 Hz, 2H), 6.91-6.94 (m, IH), 7.27(dd, 7i=10.7 Hz,72= 8.5 Hz, IH), 8.06 (s, IH), 8.32 (d. J = 4.67 Hz, IH), 8.40 (dd, Ji= 7.4 Hz, 72= 2.19 Hz, IH), 8.61(d, J= 2.19Hz, IH), 12,11 (s, IH); ESI-MS (m/z) 601.44(M+H)+
185		Method C; A28 ! B8	N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4triazol-3-yl)spiro[3.3Jheptan-2-yl)-2fluoropheny 1 )-5 -(((( 1 (fluoromethyl)cyclopropyl)methyl)amino) methyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-l ,2dihydropyridine-3 -carboxamide : 1 HNMR (400 MHz, DMSO-de) δ 1.02 (s, 6H). 1.401.47 (m,lH), 1.72-1.74 (m,3H), 1.87 (s, 2H), 2.11-2.20 (m, 4H), 2.70-2.76 (m, 4H), 3.07 (d, 7=12.09 Hz,2H), 3.20 (s, 3H), 3.65 (s, 2H), 5.09 (q. 7 = 8.88 Hz, 2H), 6.89-6.93 (m, 1 H), 7.27 (dd, 7i = 10.71 Hz, J2 = 8.79 Hz, IH), 8.03 (d, 7= 11.81Hz, 1 H), 8.29-8.32 (m, IH), 8.41 (dd. 7i = 7.5 Hz. J2 = 2.33 Hz, IH), 8.61 (d, J = 2.47 Hz, IH), 12.13 (s, IH); ESI-MS (m/z) 633.68 (M+H)+
186		Method C; A28 ! B8	N-(5-(6,6-dimethyl-2-(4-mcthyl-4H-1,2,4triazol-3-yl)spiro[3.3]heptan-2-yl)-2fluorophenyl)-5-(((3-fluoro-3methylbutyl)amino)methyl)-2-oxo-1-(2,2,2trifluoroethyl)-1,2-dihydropyridine-3carboxamide: ESI-MS (m/z) 635.45(M+H)+
187		Method C; A28 / B8	N-(5-(6,6-dimethyl-2-(4-methyl-4H-l,2,4triazol-3-yl)spiro[3.3Jheptan-2-yl)-2fl uorophcny 1) - 5-( (isopenty lamino)mcthy 1 )-2-

177

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			oxo-1 -(2,2.2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz. DMSO-dô) 5 0.86 (d, 7=8.0Hz, 6H), 1.02 (s, , 6H). 1.32-1.40 (m,2H), 1.571.67 (m,lH), 1.78(s,2H), 1.85(s.2H), 2.57 2.70 (m. 2H), 2.73-3.03 (m,2H), 3.04 (d, /=13.74 Hz. 2H), 3.20 (s, 3H), 3.68 (s,2H), 5.09 (q, J = 8.88 Hz, 2H), 6.90-6.93 (m,lH), 7.27 (dd, //=10.71Hz, J2= 8.52Hz.lH), 8.07 (s,lH), 8.31 (t. /=4.39Hz,lH), 8.39 (dd, /;= 7.28 Hz, J2 = 2.06 Hz, 1H), 8.62 (d. J=2.19Hz, 1 H),l2.09(s,l H); ESI-MS (m/z) 617(M+H)+
188		Method C; A28 / B8	N-(5-(6,6-dimethyl-2-(4-methyl-4H-l,2,4triazol-3-yl)spiro[3.3]heptan-2-yI)-2fluorophenyl)-5-(((3-fluoro-2,2dimethylpropyl)amino)methyl)-2-oxo-1 (2,2,2-triiluoroethyl)-1.2dihydropyridine-3carboxamide: ESI-MS (m/z) 635.45 (M+H)+
189		Method C; A6/B8	N-(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4mcthyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((((l(fluoromethyl)cyclopropyl)methyl)amino)me thyl )-2-oxo-1 -(2,2,2 t rifl uorocthyl )-1,2dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-de) d 1.07 (d. J = 4.95 Hz, 3H), 1.39-1.44 (m. 1H), 1.72-1.74 (m, 1H), 2.12-2.14 (m. 4H), 2.54-2.56 (m. 3H), 2.73 2.75 (m. 4H), 3.18 (s, 3H), 3.65 (s, 2H), 5.09 (q, J = 8.98 Hz, 2H), 7.06-7.09 (m, 1H), 7.31(dd, /i = 10.72 Hz, /2 = 8.8 Hz. 1H), 8.05 (s, 1H), 8.30 (s. 1H), 8.49 ((dd, /1 = 7.42 Hz.

178

Example No.	Structure	Method and Intennediate	Chemical Name and Analytical data
			72 = 2.2 Hz, 1H), 8.62 (d, J = 2.2Hz. 1H), 12.13 (s, IH); ESI-MS (m/z) 579.36 (M+H)+
190		Method C; A29/B8	5-((Isobutylamino)methyl)-N-(3-(6-methyl2-(4-methyl-4H-1,2,4-triazol-3yl)spirol3.3]heptan-2-yl)phenyl)-2-oxo-l(2,2,2-lrifluoroethyl)-1,2-dihydropyridine-3carboxamide: 'H NMR (400 MHz. DMSOd6) δ 0.87 (d, J = 8 Hz, 6H), 0.99 (d, 7=4.0 Hz, 3H), 1.52-1.58(m, 1H), 1.60-1.68 (m, 2H), 2.01-2.07(m. 1 H), 2.1l-2.22(m, 2H), 2.402.50 (m, 2H), 2.59-2.66 (m, 2H). 2.95-3.08 (m, 2H), 3.20 (s, 3H), 3.59 (s, 2H), 5.05-5.09 (m, 2H), 6.98 (d, 7=8 Hz, 1H), 7.33(1,7=8 Hz, 1 H), 7.49(s, 1 H), 7.57(d, 7=8 Hz. 1 H), 8.01 (s, lH),8.31(s, lH),8.57(s, 1H), 11.79 (brs, 1H); ESI-MS (m/z) 571.38 (M+H)+
191	σ x.cFj	Method C; A30/B8	N-(2-fluoro-5-(6-mcthyl-2-(4-mcthyl-4Hl,2,4-triazol-3-yl)spiro[3.3]heptan-2yl)phenyl)-5-((isobutylamîno)methyl)-2-oxo1 -(2,2,2-trifluorocthy 1)-1,2-dihydropyridinc3-carboxamide: ESI-MS (m/z) 589.45 (M+H)+
192		Method C; A3O/B8	5-(((Cyclopropylmethyl)amino)methyl)-N(2-fluoro-5-(6-methyl-2-(4-methyl-4H-l,2,4triazol-3-y l)spiro[3.3Jhcptan-2-yl)phcnyl)-2oxo-1-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: ESI-MS (m/z) 587.33 (M+H)+
193	1 O-^w σ	Method C; A27 / B8	N-(5-(3,3-diethyl-1 -(4-methyl-4H-1,2,4triazol-3-y 1 )cyclob ut yl )-2-fluoropheny 1 )-5 ((isobutylamino)methyl)-2-oxo-1-(2,2,2-

179

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			trifluoroethyl)-l,2-dihydropyridine-3carboxamide: ’HNMR (400 MHz. DMSO-7ô) δ 0.69-0.74 (m, 6H), 0.87 (d, J = 6.6 Hz, 6H), 1.34-1.46 (m, 4H), 1.69-1.71(m. 1H), 2.332.44 (m, 4H), 2.81 (d, J = 12.0 Hz, 2H), 3.23 (s, 3H), 3.63 (s, 2H), 5.09 (q,7 = 8.8 Hz, 2H), 6.97-6.98 (m. 1H), 7.27-7.29 (m. 1H), 8.05 (s, 1H), 8.31 (d, 7 = 8.52 Hz, 1H. 8.46 (dd, 7 = 7.28 Hz, & 1.78 Hz, 1H), 8.62 (s, 1H), 12.11 (s, 1H); ESI-MS (m/z) 591,41 (M+H)+
194		Method C; A12/B8	N-(5-(3,3-dimethyl-l-(4-methyl-4H-1,2,4- triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5(((3-fluoro-3-methylbutyl)amino)methyl)-2oxo-1 -(2,2,2-trifluoroethyl)-1,2- dihydropyridine-3-carboxamide: ESI-MS (m/z) 595.35 (M+H)+
195		Method C; A27/B8	N-(5-(3,3-diethyl-l-(4-methyl-4H-l ,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((((1- (fluoromethyl)cyclopropyl)methyl)amino)me thyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-1.2dihydropyridine-3-carboxamide: 'HNMR (400 MHz, DMSO-de) δ 0.69-0.74 (m, 6H), 1.34-1.46 (m, 5H), 1.71-1.74 (m, 1H), 2.142.19 (m, 4H), 2.43-2.46 (m, 2H), 2.76 (d, 7 = 24.4 Hz, 2H), 2.82 (d, J = 12.3 Hz, 2H), 3.23 (s, 3H), 3.64 (s, 2H), 5.09 (q, J = 8.8 Hz, 2H), 6.97-6.98 (m, 1 H), 7.25-7.30 (m, 1 H), 8.04 (s, 1H), 8.31 (s, 1H), 8.47 (d, 7 = 5.4 Hz, 1H), 8.61 (d, 7= 1.9 Hz, 1H), 12.14 (s, 1H); ESIMS (m/z) 621.38 (M+H)+

180

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
1%		Method C; A3O/B8	N-(2-fluoro-5-(6-methyl-2-(4-methyl-4Hl,2,4-triazol-3-yl)spiro[3.3]heptan-2yl)phcnyl)-5-((((l- ( fluoromethyl)c yclopropy 1 ) methy 1) amino) me thyl)-2-oxo-l-(2,2,2-trifluorocthyl)-l ,2dihydropyridinc-3-carboxamidc: ESI-MS (m/z) 619.45 (M+H)+
197		Method C; A3O/B8	5(((3-Fluoro-3-methylbutyl) amino)methyl)N-(2-fluoro-5-(6-methyl-2-(4-methyl-4Hl,2,4-triazol-3-yl)spiro[3.3]heptan-2yl)phenyl)-2-oxo-1-(2,2,2-tri fluoroethyl)l,2-dihydropyridine-3-carboxamide: ESI- MS (m/z) 621.45 (M+H)+
198		Method C; A27 / B8	5-(((Cyclopropylmethyl)amino)methyl)-N(5-(3,3-dicthyl-l-(4-mcthyl-4H-l, 2,4- triazol3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-l(2,2,2-trinuoroethyl)-l,2-dihydropyridine-3carboxamide: ‘HNMR (400 MHz, DMSOd6): δ 0.08-0.12 (m, 2H), 0.38-0.43 (m,2H), 0.67-0.74 (m, 6H), 0.84-0.89 (m,lH), 1.331.47 (m, 4H), 2.38-2.44 (m, 4H), 2.83 (d, J = 12.0 Hz. 2H), 3.23 (s, 3H), 3.63 (s, 2H), 5.09 (q, J = 8.0 Hz. 2H), 6.97-6.98 (m, IH), 7.277.29 (m, IH), 8.05 (s, IH), 8.32 (s, IH), 8.47 (dd, J = 7.55 Hz, & 2.06 Hz, IH), 8.60 (d, J = 2.0 Hz. IH), 12.13 (s, IH); ESI-MS (m/z) 589.34 (M+H)+
199	nN rV ‘<w 'Y & '-CF;	Method C; A27 / B8	N-(5-(3,3-dicthyl-1 -(4-mcthyl-4 H-1,2,4triazol-3-yl)cyclobutyl)-2-fiuorophenyl)-5((isopentylamino)melhyi)-2-oxo-l-(2,2.2tri fluorocthyl )-1,2-dihydropyridinc-3 -

181

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			carboxamide: ’HNMR (400 MHz. DMSO-d6) δ 0.67-0.74 (m. 6H), 0.87 (d, J = 6.7 Hz, 6H), 1.31-1.46 (m, 4H), 1.41-1.44 (m. 2H), 1.58 1.66 (m, 1H), 2.33-2.44 (m, 4H), 2.83 (d, J = 12.4 Hz, 2H), 3.23 (s, 3H), 3.65 (s, 2H), 5.09 (q, J = 8.8 Hz, 2H), 6.97-6.98 (m, 1H). 7.277.29 (m. 1H). 8.06 (s, 1H), 8.32 (d, J = 8.52 Hz, 1H), 8.46 (d. J = 5.5 Hz, 1H), 8.61 (s, 1H), 12.10 (s, 1H); ESI-MS (m/z) 605.45 (M+H)+
200		Method C; A3O/B8	N-(2-iluoro-5-(6-methyl-2-(4-methyl-4Hl,2,4-triazol-3-yl)spiro[3.3]heptan-2yl)phenyl)-5-((isopentylamino)methyl)-2oxo-1 -(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide: ESI-MS (m/z) 603.45 (M+H)+
201		Method C; A6/B15	5-(((Cyclopropylmcthyl)amino)mcthyl)-N(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4-methyl4H-1,2,4-triazol-3-yl)cyclobutyl (phenyl )-1 (4-fluorophcnyl)-2-oxo-l,2-dihydropyridine3-carboxamide: ESI-MS (m/z) 559.48 (M+H)+
202		Method C; A6/B15	N-(2-iluoro-5-(( 1 s,3s)-3-methy l-1 -(4methyl-4H-l,2,4-triazol-3- yl)cyclobutyl)phenyl)-5-((((I-(fluoromethyl)cyclopropyl)methyl)amino)methyl)1 -(4-nuorophenyl)-2-oxo-1,2- dihydropyridmc-3-carboxamidc: ESI-MS (m/z) 591.38 (M+H)+

182

Ex ample No.	Structure	Method and Intermediate	Chemical Name and Analytical data
203	* ΛΧ-νέΆ-ν	Method B; A6/B7	1 -Cyclopropyl-N-(2-fluoro-5-(( 1 s,3s)-3methyl-l-(4-methy]-4H-l ,2,4-triazoi-3y 1 )cy c lobuty 1 )phcny 1 )-5 -( ( (( 1 (fluoromethyl )cyclopropyl)methyl)amino) me thyl)-2-oxo-l,2-dihydropyridine-3carboxamide: 'HNMR (400 MHz. DMSO-76) δ 0.95-0.99 (m. 2H), 1.08-1.12 (m. 5H), 1.391.47 (m, 1H), 1.70-1.76 (m, 1H), 2.11-2.19 (m, 4H), 2.53-2.55 (m, 3H), 2.65-2.69 (m. 1H), 2.75-2.78(m, 3H), 3.19 (s, 3H). 3.473.54 (m, 1H), 3.62 (s, 2H), 7.02-7.06 (m. 1H), 7.30 (dd, 7 = 10.9 Hz and 7 =8.7 Hz, 1 H), 7.91 (d, 7=2.2 Hz. 1H), 8.29 (s, 1H), 8.50-8.54 (m, 2H), 12.54 (s,lH); ESI-MS (m/z) 537.3 (M+H)+
204		Method C; A30/B8	5-(((3-Fluoro-2.2- dimelhylpropyl)amino)methyl)-N-(2-nuoro5-(6-methyl-2-(4-methyl-4H-l,2,4-triazol-3yl)spiro[3.3Jhcptan-2-yl)-phcnyl)-2-oxo-l(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide: ESI-MS (m/z) 621.40 (M+H)+
205	«Vif o S-.U - q·^.	Method C; A6/B16	N-(2-fluoro-5-((ls,3s)-3-methyl-l-(4mcthyl-4H-1,2,4-triazol-3y l)cyclobutyl )pheny 1 ) -6((isobutylamino)methyl)-3-oxo-4-(2,2,2trifluoroethyl)-3,4-dihydropyrazine-2carboxamide: 'HNMR (400 MHz. DMSO-*) δ 0.88 (d, 7 = 8.0 Hz, 6H), 1.07 (d. 7 = 4.0 Hz, 3H), 1.22-1.24 (m, 1H), 1.64-1.76 (m, 1H), 2.36 (d. 7 = 8.0 Hz, 2H), 2.54 (m, 3H), 2.772.81 (m. 2H), 3.21 (s, 3H), 3.87 (s, 2H), 5.05-

183

Example No.	Structure	Method and Intermediate	Chemical Name and Analytical data
			5.14 (m, 2H), 7.17-7.23 (m, 1H), 7.31 (t, J = 8.0 Hz. 1 H); 7.84- 7.88 (m. 1 H), 8.30 (s, 1 H), 8.47 (s, 1H). 10.36 (s, 1H); ESI-MS (m/z) 550.41 (M+H)+
206	1	Method C; A5/B16	6-((lsobutylamino)methyl)-N-(3-((ls,3s)-3methyl-1 -(4-methy 1-4H- l,2,4-triazol-3yl)cyclobutyl)phenyl)-3-oxo-4-(2,2,2trifluoiOethyl)-3,4-dihydropyrazine-2carboxamide: ’HNMR (400 MHz. DMSO-dd) δ 0.88 (d. J = 8.0 Hz, 6H), 1.07 (d, J = 4.0 Hz. 3H), 1.64-1.76 (m, 1 H), 2.35 (d, J = 8.0 Hz, 2H), 2.53 (m. 3H), 2.78-2.80 (m, 2H), 3.17 (s, 3H), 3.86 (s, 2H). 5.05-5.14 (m. 2H), 7.1 l(d, 7 = 8.0 Hz, 1H), 7.37 (t, 7 = 8.0 Hz, 1 H); 7.57 (s, 1H), 7.73-7.77 (m. 1H), 8.29 (s, 1H), 8.44 (s, 1H), 10.56 (s, 1H); ESI-MS (m/z) 532.32 (M+H)+

PHARMACOLOGICAL ACTIVITY

Cbl-b phosphorylation inhibition assav:

The assay measures ability of test compounds to inhibit SRC kinase-mediated 5 phosphorylation of a truncated version of His-tagged Cbl-b protein containing residues 36-427. This TR-FRET assay is performcd in a 384 wcll plate at room température in a lüpl réaction volume with buffer containing 50mM HEPES pH 7.5, 5mM mgC12, ImM DTT, O.lmg/ml BSA. Candidate compounds (1% DMSO final) were preincubated with 30nM Cbl-b (Accession number NP_733762.2) for one hour followed by an additional one hour in the presence of 30nM of GST-tagged SRC kinase (Accession number NP_005408.1) with ΙΟΟμΜ ATP (final concentrations). Following. incubation, lOul of a mixture containing 3.75nM Anli-His XL665 antibody (CisBio) and 1:200 TK-Cryptate Antihody (CisBio HTRF TK kit) prepared in détection buffer, was added to the reaction. The plate was incubated for one hour at room température followed by ovemight in cold and fluorescence signal was measured with excitation of 337nm and dual émission of 665 and 620nm on Artémis HRTF reader. Signal was

184 expressed as HTRF ratio (fluorescence intensity @665nm/fluorescence intensity @620nm x 10000). The resulting data wcrc analyscd and 1C50 values wcrc determined using nonlincar régression analysis, variable slope fïtting (GraphPad Prism version 8.4.3).

The IC50 (nM) values of some of the compounds are sel forth in Table-20 wherein “A” 5 refers to an IC50 value of less than 100 nM, “B” refers to IC50 value in range of 100.01 to 500.0 nM. “C” refers to IC50 value in range of 500.01 to 1000.0 nM and “D” refers to IC50 values more than 1000.1 nM.

Table-20:

Sr. No.	Compound No.	Cbl-b Phosphorylation inhibition
@luM	@30uM	ICso(nM)
1.	Example 1	48.8	79.3	D
2.	Ex ample 2	63.5	68.8	A
3.	Examplc 3	70.2	72.2	B
4.	Example 4	54.0	78.1	C
5.	Example 5	70.5	79.0	B
6.	Examplc 6	48.6	78.8	D
7.	Example 7	17.3	56.5	D
8.	Example 8	47,7	75.6	D
9.	Examplc 9	69.6	71.1	A
10.	Example 10	63.9	-	B
11.	Example 11	50.1	75.4	D
12.	Example 12	36.2	36.1	D
13.	Example 13	51.2	69.8	D
14.	Examplc 14	26.9	74.0	D
15.	Example 15	55.2	79.0	C
16.	Example 16	21.6	72.2	D
17.	Example 17	40.7	76.3	D
18.	Examplc 18	55.6	74.5	C
19.	Examplc 19	47.7	75.6	D
20.	Example 20	23.0	65.7	D
21.	Example 21	75.3	69.5	B
22.	Ex ample 22	52.4	-	D
23.	Example 23	75.6	73.9	B

185

Sr. No.	Compound No.	Cbl-b Phosphorylation inhibition
@luM	@30uM	ICsoinM)
24.	Example 24	64.5	88.6	B
25.	Example 25	60.0	70.1	B
26.	Example 26	61.6	75.0	B
27.	Example 27	58.8	65.3	C
28.	Example 28	23.5	66.6	D
29.	Examplc 29	46.1	62.1	D
30.	Example 30	62.6	82.0	B
31.	Example 31	52.5	81.2	C
32.	Example 32	69.1	86.3	A
33.	Example 33	49.4	71.2	D
34.	Example 34	77.4	72.2	A
35.	Example 35	50.3	77.8	D
36.	Example 36	52.9	83.6	C
37.	Example 37	72.7	70.5	A
38.	Example38	65.3	75.8	B
39.	Example 39	40.7	83.4	D
40.	Example 40	75.1	75.1	B
41.	Example 41	56.1	78.9	C
42.	Example 42	57.6	71.0	B
43.	Example 43	70.2	82.9	B
44.	Example 44	34.3	75.2	D
45.	Example 45	50.5	74.4	C
46.	Example 46	34.6	77.9	D
47.	Examplc 47	83.2	70.5	A
48.	Examplc 48	77.2	75.6	A
49.	Example 49	87.6	88.9	A
50.	Example 50	79.3	83.4	A
51.	Example51	76.9	83.0	A
52.	Example 52	80.7	75.5	A
53.	Examplc 53	81.4	87.2	A
54.	Ex amp le 54	76.2	77.5	A

186

Sr. No.	Compound No.	Cbl-b Phosphorylation inhibition
@ luM	@30uM	ICso(nM)
55.	Example55	76.0	83.4	A
56.	Example 56	73.8	83.4	A
57.	Example 57	83.5	79.0	A
58.	Example 58	71.0	82.0	A
59.	Example 59	51.5	80.0	C
60.	Examplc 60	67.5	82.5	B
61.	Example 61	65.5	80.0	B
62.	Example 62	38.7	79.2	D
63.	Example 63	87.5	88.4	B
64.	Example 64	53.1	73.7	C
65.	Example 65	73.9	86.2	B
66.	Example 66	57.3	70.5	B
67.	Example 67	65.6	75.4	B
68.	Example 68	79.9	85.4	A
69.	Examplc 69	61.2	69.5	B
70.	Example 70	74.8	84.6	A
71.	Example 71	75.0	81.8	B
72.	Example 72	61.2	77.3	B
73.	Example 73	68.1	78.0	A
74.	Example 74	74.7	83.8	A
75.	Example 75	66.5	71.0	B
76.	Example 76	73.5	80.3	A
77.	Example77	62.2	-	B
78.	Examplc 78	71.2	72.8	B
79.	Examplc 79	86.3	69.3	A
80.	Example 80	86.7	81.0	A
81.	Example 81	51.1	73.4	B
82.	Example 82	60.6	73.2	B
83.	Example 83	73.5	79.5	A
84.	Examplc 84	73.7	78.7	A
85.	Example 85	54.9	72.7	B

187

Sr. No.	Compound No.	Cbl-b Phosphorylation inhibition
@luM	@30uM	ICiotnM)
86.	Example 86	62.1	80.2	C
87.	Example 87	57.8	70.0	C
88.	Example 88	74.1	80.1	A
89.	Example 89	34.9	61.2	D
90.	Example 90	74.5	73.1	A
91.	Examplc 91	69.1	80.7	A
92.	Example 92	58.3	62.9	B
93.	Example 93	60.1	67.2	C
94.	Example 94	62.1	79.2	B
95.	Example 95	66.7	69.9	B
96.	Ex ample 96	47.8	68.6	A
97.	Ex ample 97	60.0	74.3	B
98.	Example 98	73.5	80.4	A
99.	Example 99	65.5	70.5	B
100.	Examplc 100	58.0	70.4	B
101.	Example 101	57.5	72.1	C
102.	Example 102	59.0	71.5	C
103.	Example 103	62.2	-	B
104.	Example 104	72.4	66.4	A
105.	Example 105	73.1	88.1	B
106.	Example 106	59.0	72.5	B
107.	Example 107	53.0	77.5	C
108.	Example 108	55.4	65.4	C
109.	Examplc 109	66.2	74.9	B
110.	Examplc 110	63.3	72.7	B
111.	Example 111	63.2	81.0	B
112.	Example 112	64.1	70.8	B
113.	Example 113	64.7	76.6	B
114.	Example 114	76.5	80.1	B
115.	Examplc 115	82.6	82.6	A
116.	Example 116	79.6	83.1	A

188

Sr. No.	Compound No.	Cbl-b Phosphorylation inhibition
@luM	@30uM	TCso(nM)
117.	Example 117	81.1	73.8	A
118.	Example 118	57.4	70.0	C
119.	Example 119	55.6	72.6	C
120.	Example 120	74.0	76.4	B
121.	Example 121	67.8	81.2	B
122.	Example 122	68.1	69.9	B
123.	Example 123	38.5	78.9	D
124.	Example 124	72.4	77.6	B
125.	Example 125	68.2	79.2	B
126.	Example 126	29.6	57.9	D
127.	Ex ample 127	72.1	78.9	B
128.	Ex ample 128	12.4	61.8	D
129.	Example 129	77.8	78.7	B
130.	Example 130	53.8	71.8	C
131.	Examplc 131	70.0	65.1	B
132.	Example 132	58.6	75.6	B
133.	Example 133	78.7	93.9	B
134.	Example 134	47.0	71.6	D
135.	Example 135	43.2	73.2	D
136.	Example 136	50.8	72.1	C
137.	Example 137	61.0	72.9	B
138.	Example 138	45.0	72.2	D
139.	Example 139	78.5	84.9	B
140.	Examplc 140	41.7	74.8	D
141.	Examplc 141	77.8	84.9	B
142.	Example 142	65.2	80.5	B
143.	Ex ample 143	37.1	72.5	D
144.	Ex ample 144	68.2	81.7	B
145.	Ex ample 145	69.5	82.7	B
146.	Examplc 146	30.5	76.1	D
147.	Example 147	65.1	75.3	B

189

Sr. No.	Compound No.	Cbl-b Phosphorylation inhibition
@luM	@30uM	IC50(nM)
148.	Example 148	68.6	71.5	B
149.	Example 149	48.5	73.4	C
150.	Example 150	59.3	72.7	B
151.	Ex ample 151	62.7	73.7	B
152.	Example 152	70.8	74.1	A
153.	Examplc 153	66.3	-	B
154.	Example 154	83.6	88.2	A
155.	Example 155	78.5	85.6	A
156.	Example 156	75.6	85.7	B
157.	Ex ample 157	40.1	81.9	D
158.	Example 158	68.6	72.5	B
159.	Example 159	69.5	64.0	B
160.	Example 160	88.6	89.8	A
161.	Example 161	84.3	94.9	B
162.	Examplc 162	59.1	64.3	B
163.	Example 163	33.40	67.35	D
164.	Ex ample 164	73.26	78.52	A
165.	Ex ample 165	66.66	75.55	A
166.	Example 166	76.14	65.33	B
167.	Examplc 168	43.15	63.95	D
168.	Example 169	69.38	80.33	B
169.	Example 170	68.05	74.22	A
170.	Examplc 171	46.87	68.55	B
171.	Example 173	75.00	81.14	A
172.	Example 175	73.95	79.17	A
173.	Example 176	53.87	79.47	C
174.	Example 177	56.79	75.29	B
175.	Example 178	60.97	61.39	B
176.	Example 179	17.82	57.61	D
177.	Example 180	34.75	56.68	D

190

Sr. No.	Compound No.	Cbl-b Phosphorylation inhibition
@luM	@30uM	ICso(nM)
178.	Example 181	61.24	74.04	A
179.	Example 182	25.90	61.96	D
180.	Example 183	76.46	68.95	B
181.	Example 184	34.01	55.46	D
182.	Example 185	25.31	58.60	D
183.	Example 187	82.98	68.47	A
184.	Example 189	81.09	83.46	A
185.	Example 190	63.86	82.64	B
186.	Example 192	38.73	78.91	D
187.	Ex ample 194	41.44	74.95	D
188.	Example 197	43.85	73.61	D
189.	Examplc 198	42.22	82.52	D
190.	Example 200	42.45	74.45	D
191.	Example 201	48.51	77.48	C
192.	Examplc 202	76.60	78.61	A
193.	Ex ample 204	33.98	-	D
194.	Example 205	14.22	51.75	D

(-): Not determined

Although the invention herein has been described with reference to particular embodiments, it is to be underslood thaï lhese embodiments are merely illustrative of the principlcs and applications of thc présent invention. It is thcrcforc to bc understood lhat 5 numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised withoul departing from the spiril and scope of the présent invention as described above.

Ail 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 10 specifically and individually indicated to be incorporated herein by reference.

Claims (10)

l. A compound of formula (l): (I) or a stereoisomer, or a pharmaceutically acceptable sait thereof, wherein, at each occurrence, R! is selected independently from 3-15 membered heterocyclyiCi. salkyl, 5-14 membered heteroarylCi-salkyl and -[CHR]i-NR6R7; wherein the 3-15 membered heterocyclylCusalkyl and 5-14 membered heteroarylCi-salkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyCj-salkyl, Ci-salkyl, NHC(O)CH3, -NHC(O)CH2CH3 and -NHC(O)CH=CH2 ; Z is CH or N; X is CH or N; R is selected from hydrogenand Ci-salkyl; at each occurrence, R2 is selected independently from halogen, -NHC(O)CH3 and NHC(O)CH=CH2; ring A is 5-14 membered heteroaryl; at each occurrence, R3 is C t-salkyl; R4 is selected from hydrogen and C i-salkyI; Rs is selected from Ci-salkyI and C3-i2cycloalkyl; or R4 and R5joined together with the carbon atom to which they are attached, form a 3-15 membered heterocyclyl, C3-i2cycloalkyl and 3-15 membered spirocyclyl, wherein the 3-15 membered heterocyclyl, C3-i2cycloalkyi and 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen and C i-salkyl; Ύ’ is absent or CRSR9; R6 is selected from hydrogen and Cuealkyl; R7 is selected from Ci-salkyl, haloCi-salkyl, hydroxyCi-salkyl, Ci.galkoxyCi-salkyl, CH2CH2NHC(O)CH=CH2, C3-i2cycloalky!, C3-i2cycloalkylCi-8alkyl and 3-15 membered heterocycly lalky I; wherein C3.|2cycloalkyl and C3-i3cycloalky ICi-salkyl is optionally substituted with Cusalkyl and haloCi-ealkyl; R8 is hydrogen; R9 is hydrogen;

1 -Cyclopropy l-N-(2-fl uoro-5-(( 1 s,3s)-3-methy I-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-l ,2-dihydropyridine-3-carboxamide;

20 N-(5-(3,3-dimethy 1-1 -(4-methy 1-4H-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-l,2,4-triazol-3-yl)spiro[3,3]heptan-2-yl)-2fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1 -(2,2,2-trifluoroethyr)-l ,2-dihydropyridine3-carboxamide;

25 5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(6,6-dimethy1-2-(4-methyl-4H-l ,2,4triazol-3-yl)spiro[3.3]heptan-2-yl)-2-fluorophenyl)-2-oxo-l-(2,2,2-trifluoroethy 1)-1,2dihydropyridine-3-carboxamide;

N-(5-(6,6-dimethyl-2-(4-methyl-4H-l ,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2fluoropheny 1)-5-(((( 1 -(fluoromethy! )cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,230 trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2fluoropheny l)-5-(((3-fluoro-3-methy!butyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2dihydropyridine-3-carboxamide;

N-(5-(6,6-dimethyl-2-(4-methyl-4H-l,2,4-triazol-3-y!)spiro[3.3]heptan-2-yl)-2fluorophenyl)-5-((ïsopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ^-dihydropyridineS-carboxamide;

N-(5-(6,6-dimethyl-2-(4-methyl-4H-l,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-25 fl uorophenyl)-5-(((3-fluoro-2,2-dimethylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethy ΟΙ,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(( l s,3s)-3-methy I-1 -(4-methy l-4H-1,2,4-triazol-3yl)cyclobutyl)pheny 1)-5-(((( l-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-l(2,2,2-tr ifl uoroethy l )-1,2-dihydropyridine-3-carboxamide;

10 5-((lsobutylamino)methyl)-N-(3-(6-methyl-2-(4-methyl-4H-l,2,4-triazol-3yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-l -(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-l ,2,4-triazol-3-y!)spiro[3.3]heptan-2y l)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethy l)-l,2-dihydropyridine-315 carboxamide;

1 -(2,2-Difl uoroethy l)-N-(2-fluoro-5-(( 1 s,3s)-3-methy I-1 -(4-methyl-4H-l,2,4-triazol-3y l)cyclobutyl)pheny 1)-5-(((( 1-(fl uoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-l ,2dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethy 1-1 -(4-methy 1-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5(((3-fluoro-2,2-dimethylpropy l)amino)methyl)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2dihydropyridine-3-carboxamide;

2I0

N-(2-fluoro-5-(2-(4-methyl-4H-l,2,4-triazol-

1 - Ethy l-N-(2-fl uoro-5-(( 1 s,3s)-3-methy 1-1 -(4-methy I-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-(((( l-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-l ,2dihydropyridine-3-carboxamide;

1 -(2,2-Difluoroethy l)-N-(5-(3,3-dimethy1-1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)-2-fluorophenyl)-5-((neopentylamino)methyl)-2-oxo-l,2-dihydropyridine-3carboxamide;

N-(3-(3,3-dimethy I-1 -(4-methyl-4H-1,2,4-triazol-3-y l)cyclobuty l)pheny 1)-5-((( 1 methylcyclobutyl)amino)methyl)-2-oxo-l -(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

l-(Cyclopropylmethyl)-N-(5-(3,3-dimethyl-i-(4-methyI-4H-l,2,4-triazol-3yl)cyclobutyl)-2-fl uoropheny l)-5-((isobuty!amino)methyl)-2-oxo-1,2-dihydropyridine-3carboxamide;

N-(3-(3,3-dimethy I-1 -(4-methy 1-4H-1,2,4-triazol-3-y l)cyclobuty l)pheny I )-5-(((2fluoro-2-methylpropy l)amino)methyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide;

N-(5-(3,3-dimethy 1-1 -(4-methy 1-4H-1,2,4-triazol-3-y l)cyclobutyl)-2-fl uoropheny l)-5(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide;

207 l

-(2-Cyclopropy lethy l )-N-(5-(3,3-dimethy I-1 -(4-methy I-4H-1,2,4-triazol-3yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-l,2-dihydropyridine-3carboxamide;

l-(2-Cyclopropylethyl)-N-(5-(3,3-dimethyi-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyl)-2-fluorophenyl)-5-(((2-fiuoro-2-inethylpropyl)amino)methyl)-2-oxo-l,2dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethyl-l-(4-methy I-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isobutyl(methyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

N-(2-fluoro-5-(2-(4-methyl-4H-l,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethy 1-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pheny 1)-5-((((1( fl uoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethyl-1 -(4-methy I-4H-1,2,4-triazol-3-y l)cyclobuty l)pheny 1)-1 -(4fluorophenyl)-5-(isobutylamino)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

(S)-N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)-2fluoropheny l)-5-((3-methy Ipiperidin-1 -y l)methy l)-2-oxo-1 -(2,2,2-trifluoroethyl )-1,2dihydropyridine-3-carboxamide;

1 -(2,2-Difluoroethy l)-N-(5-(3,3-dimethy I-1 -(4-methy I-4H-1,2,4-triazol-3y l)cyclobuty I )-2-(1 uoropheny l)-5-((isobuty lam ino)methy l)-2-oxo-1,2-dihydropy ridine-3carboxamide;

1 -(2,2-Difl uoroethy I )-N-(3-(3,3-dimethy I-1 -(4-methy I-4H-1,2,4-triazoî-3yl)cyc1obutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-l ,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-Dimethyl-l-(4-methy I-4H-1,2,4-triazol-3-yl)cyclobutyl)pheny 1)-5-((4methyl-3-oxopiperazin-l -y l)methyl)-2-oxo-1-(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3carboxamide;

l-(2-Cyclopropylethyl)-N-(3-(3,3-dimethy1-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobuty1)phenyl)-5-((isobutylamino)methyl)-2-oxo-l ,2-dihydropyridine-3-carboxamide;

206

N-(2-fluoro-5-(5-(4-methyl-4H-l,2,4-tnazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5((neopentyiamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethy I-1 -(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pheny 1)-5-(( 1 methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5( 1 H)-y l)methyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethy I-1 -(4-methy I-4H-1,2,4-triazol-3-yl)cyclobuty l)-5-fluoropheny l)-5((isobutylaiïiino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethy 1-1 -(4-methy 1-4H-1,2,4-triazol-3-y l)cyclobutyl )pheny 1)-5-((3fluoro-3-methy lazetidin-1 -y l)methy I )-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide;

N-(3-(3,3-Dimethy 1-1 -(4-methy i-4 H-1,2,4-triazol-3-yl)cyclobutyl)pheny l)-5((isobutylam ino)methy l)-2-oxo-1 -(prop-2-y η-1 -y 1)-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethy 1-1-(4-methy I-4H-1,2,4-triazol-3-yl)cyclobutyl)-5-fl uoropheny l)-5((isobutylamino)methyl)-2-oxo-l-(3,3,3-trifIuoropropyl)-l,2-dihydropyridine-3-carboxamide;

1 -(Cyclopropy Imethy l)-N-(3-(3,3-dimethy 1-1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2.4-triazol-3-yl)cyclobutyl)-2-fiuorophenyl)-5((isobuty lamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-l,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((neopentylamino)methyl)-2-oxo-l -(3,3,3-trifluoropropyl)-l,2-dihydropyridine-3carboxamide;

1 -(Cyclopropy Imethy l)-5-(((cyclopropy Imethy l)amino)methyl)-l\l-(3-(3-methy 1-1 -(4methyl-4H-l ,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

l-(Cyclopropylmethyl)-5-(((cyclopropy Imethy l)amino)methyl)-N-(2-fluoro-5-(( 1 s,3s)3-methy 1-1 -(4-methyl-4H-1,2,4-triazol-3-y l)cyclobuty l)pheny l)-2-oxo-1,2-dihydropyridine-3carboxamide;

N-(2-chioro-5-(( I s,3s)-3-methy I-1 -(4-methy I-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2dihydropyridine-3-carboxamide;

N-(2-chloro-5-(( 1 s,3s)-3-methy I-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)l,2-dihydropyridine-3-carboxamide;

203 l-(Cyclopropylmethyl)-N-(3-(3-methyl-l -(4-methyl-4H-l,2,4-tnazol-3yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-l,2-dihydropyridine-3carboxamide;

1 -(2-Cyclopropy lethy l)-N-(3-(2-methy 1-1 -(4-methy 1-4H-1,2,4-triazol-3-y l)propan-2yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)-l,2-dihydropyridine-3-carboxamide;

(R)-5-((3-Fluoropyrrol idin-1-y l)methy l)-N-(3-(2-methyl-1-(4-methy I-4H-1,2,4-triazol3-yl)propan-2-yl)pheny l)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3-carboxamide;

(S)-5-((3-Hydroxypyrrolidin- l-yl)methyl)-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4triazol-3-y l)propan-2-y l)pheny l)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3carboxamide;

(S)-5-((3-HydroxypynOlidin-l-yl)methyl)-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4triazol-3-yl)propan-2-yl)phenyl)-2-oxo-l-{2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

(S)-5-((3-Fluoropyrrolidin-l-yl)methyl)-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol3-y l)propan-2-y l)phenyl)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3-carboxamide;

l-(2-Cyclopropylethyl)-N-(3-(3-((4-methyl·4H-l,2,4-triazol-3-yl)methyl)oxetan-3yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)-l,2-dihydropyridine-3-carbox amide;

198 (S)-N-(3-(2-methyl-l-(4-methy 1-4H-1,2,4-tnazol-3-yl)propan-2-yl)pheny 1)-5-((3methylpiperidin-1 -y l)methy l)-2-oxo-1 -(3,3,3-trifluoropropy I)-1,2-dihydropyridine-3carboxamide;

(S)-l-(Cyclopropylmethyl)-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3yl)phenyl)-5-((3-methylpiperidin-l-yl)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

(S)-1 -(Cyclopropylmethy l)-N-(3-(2-methy 1-1 -(4-methy 1-4H-1,2,4-triazol -3-y 1 )propan2-yl)phenyl)-5-((3-methylpiperidin-l-yl)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

(R)-N-(3-(2-methyl-l-(4-methyl-4H-1,2,4-triazol-3-yI)propan-2-yl)phenyl)-5-((3methylpiperidin-1 -yl)methyl)-2-oxo-l-(2,2,2-trifluoroethy!)-l,2-dihydropyridine-3carboxamide;

(S)-N-(3-(2-methyl-1-(4-methy 1-4H-1,2,4-triazol-3-yl)propan-2-yl)pheny 1)-5-((2methylmorpholino)methy l)-2-oxo-1 -(2,2.2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide;

(S)-l-(2-Cyclopropylethyl)-5-((3-fluoropyrrolidin-l-yl)methyl)-N-(3-(2-methyi-l-(4methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

1 -(Difluoromethy l)-N-(3-(2-methy I-1 -(4-methy I-4H-1,2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)-1,2-dihydropyridine-3-carboxamide;

1 -(2,2-Difluoroethy l)-N-(3-(2-methyl-1 -(4-methyl-4H-1,2,4-triazoi-3-y l)propan-2yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)-l,2-dihydropyridine-3-carboxamide;

(S)-l-(2,2-Difluoroethyl)-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phenyl)-5-((3-methylpiperidin-l-yl)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

l-Cyclopropyl-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)2-oxo-5-(piperidin-1 -ylmethy 1)-1,2-dihydropyridine-3-carboxamide;

N-(3-(( 1 s,3 s)-3-methy 1-1-(4-methyl-4H-1,2,4-triazol-3-yl Jcyclobuty l)pheny l)-2-oxo-5(piperidin-1 -y Imethyl)-! -(2,2,2-trifluoroethyl )-l ,2-dihydropyridine-3-carboxamide;

(S)-1 -(Cyclobuty Imethy l)-N-(3-(2-methy 1-1 -(4-methyl-4H-1,2,4-triazol-3-yl)propan2-yl)phenyl)-5-((3-methylpiperidin-l-yl)methyl)-2-oxo-l,2-dihydropyridine-3-carboxainide;

(S)-N-(3-(2-methyl-1 -(4-methyl-4H-1,2,4-triazol-3-yI)propan-2-y l)phenyl )-5-((3methylpiperidin-l-yl)methy1)-2-oxo-l-(2,2.2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

197 l-(Cyclopropylmethyl)-N-(3-(3-((4-methyl-4H-l,2,4-triazol-3-yl)methyl)oxetan-3y I )pheny l)-2-oxo-5-(piperidin-1 -y Imethy I )-1,2-dihydropyridine-3-carboxamide;

N-(3-(3-((4-methyl-4H-l ,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5(piperidin-l-ylmethyl)-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxamide;

N-(3-(2-methyl-l-(4-methyl-4H-l ,2,4-triazol-3-y1)propan-2-yl)phenyl)-2-oxo-5(pyrrolidin-l-ylmethyl)-l -(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-5(morpholinomethyI)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

3-yl)spiro[3.3]heptan-2-yl)phenyl)-5(((( l -(fl uoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(2-(

3.

The compound according to claim l, wherein R¹ is

194

4-methyl-4H-l,2,4-triazol-3-yl)spiro[3,3]heptan-2-yI)phenyl)-55 ((isopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethy!)-l,2-dihydropyridme-3-carboxamide;

4. The compound according to claim I, wherein R⁴ and R⁵ joined together with the carbon atom to which they are attached, form a

5-(((3-Fluoro-2,2-dimethylpropyl)amino)methy[)-N-(2-fluoro-5-(6-methyl-2-(4methyl-4H-1,2,4-triazol-3-y l)spiro[3.3]heptan-2-y l)-pheny 1 )-2-oxo-1 -(2,2,2-trifluoroethy I )20 l,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4-methy I-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-6-((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4dihydropyrazine-2-carboxamide; or

5-(((Cyclopropy Imethy l)amino)methy !)-N-(2-fluoro-5-(( l s,3s)-3-methy I-1 -(4-methy l10 4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-l -(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4-methy I-4H-1,2,4-triazol-3y l)cyclobutyl)pheny 1)-5-(((( l-(fluoro-methyl)cyclopropyl)methyl)amino)methyl)-l -(4fluoropheny l)-2-oxo-1,2-dihydropyridine-3-carboxamide;

15 1 -Cyclopropyl-N-(2-fl uoro-5-(( 1 s,3s)-3-methy I-1 -(4-methyl-4H-1,2,4-triazol-3y l)cyclobutyl)pheny 1)-5-(((( i-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2dihydropyridine-3-carboxamide;

5-(((Cyclopropy Imethy l)amino)methy I )-N-(5-(3,3-diethy l-1 -(4-methy I-4H-1,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-l -(2,2,2-trifluoroethy!)-l,2-dihydropyridine-3carboxamide;

N-(5-(3,3-diethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-55 ((isopentylamino)methyl)-2-oxo-l -(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-l ,2,4-triazol-3-yl)spiro[3.3]heptan-2y l)phenyl)-5-((isopentyIamino)methyl)-2-oxo-l -(2,2,2-trifluoroethyl )- l,2-dihydropyridine-3carboxamide;

5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide;

N-(5-(3,3-diethyi-l -(4-methy 1-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-520 ((isobuty lamino)methyl)-2-oxo-1-(2,2,2-trifluoroethy I)-1,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-1 -(4-methyl-4 H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5(((3-fIuoro-3-methy lbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethy I)-1,2-dihydropyridine3-carboxamide;

N-(5-(3,3-diethyl-1 -(4-methy 1-4H-1,2,4-triazol-3-y l)cyclobuty I )-2-fluorophenyl )-525 (((( l-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-l -{2,2,2-trifluoroethyl)-l ,2dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H-l,2,4-triazol-3-yl)spiro[3.3]heptan-2y l)pheny 1)-5-((((1-(fluoromethy1)cyclopropyl)methyl)amino)methyl)-2-oxo-l -(2,2,2t ri fl uoroethy l)-l ,2-dihydropyridine-3-carboxamide;

30 5-(((3-Fluoro-3-methylbutyl)amino)methyl)-N-(2-fluoro-5-(6-methyl-2-(4-methyl-4H1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-l -(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide;

5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-l-(4-fluorophenyl)-2-oxo-l ,2-dihydropyridine-3carboxamide;

15 N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((((1-(fluoromethy l)cyclopropyl)methyl)amino)inethyl)-l-(4-fluorophenyr)-2-oxo-1,2dihydropy ridine-3-carboxam ide;

5-(((( l-(Fluoromethyl)cyclopropyl)methyl)amino)methyl)-N-(3-((l s,3s)-3-methyl-l(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroetbyl )-1,2dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methy I-1 -(4-methy 1-4H-1,2,4-triazol-310 y l)cyclobutyl)pheny 1)-5-(((( 1 -(fluoromethy l)cyclopropyl)methy i)amino)methyl)-2-oxo-1 (3,3,3-tritluoropropyl)-l,2-dihydropyridine-3-carboxamide;

5-(((3-Fluoro-2,2-dimethylpropyl)amino)methyl)-N-(2-fluoro-5-((ls,3s)-3-methyl-l(4-methy I-4H-1,2,4-triazol-3-y l)cyc!obuty l)pheny l)-2-oxo-1 -(2,2,2-trifluoroethy I )-1,2dihydropyridine-3-carboxamide;

5-(((Cyc lopropy Imethy l)amino)methy 1)-1 -(2,2-difluoroethy l)-N-(2-fluoro-5-(( 1 s,3s)3-methy 1-1-(4-mcthy I-4H-1,2,4-triazol-3-y l)cyclohutyl)phcnyl)-2-oxo-1,2-dihydropyridine-3carboxamide;

5-(( Isobuty lamino)methy 1)-1 -methy l-N-(3-(( 1 s,3s)-3-methy 1-1 -(4-methy 1-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

5-(((3-Fluoro-3-methylbutyl)amino)methyl)-N-(2-fluoro-5-((ls,3s)-3-methyl-l -(4methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-tri fl uoroethy 1)-1,2dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-1 -(4-methy 1-4H-1,2,4-triazol-3-y l)cyclobuty l)-2-fluoropheny 1)-1 (4-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-l ,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-l(4-fluorobenzyl)-5-((isobutylamino)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

5-(((Cyclopropylmethyl)amino)methyl)-l-ethyl-N-(2-fluoro-5-((ls,3s)-3-methyl-l-(4methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

5-((Isobuty laminojmethy l)-N-(3-(( I r,3r)-3-methyl-1 -(5-methy I-1 H-1,2,3-triazol-4yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethylj-l ,2-dihydropyridine-3-carboxamide;

N-(3-acetamido-5-((l s,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3y l)cyclobuty l)phenyl)-5-((isobuty laminojmethy l)-2-oxo-1 -(2,2,2-trifluoroethy Ij-1,2dihydropyridine-3-carboxamide hydrochlorîde;

209

N-(3-acry lamido-5-(( l s,3s)-3-methy l-l -(4-methy I-4H-1,2,4-tnazol-3yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2dihydropyridine-3-carboxamide 2,2,2-trifluoroacetate;

N-(3-(3,3-dimethy 1-1 -(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6((isobutyiamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide;

N-(5-(3,3-dimethyl-1 -(4-methy I-4H-1,2,4-triazol-3-yl )cyclobutyl)-2-fluorophenyl)-1 ethyl-5-((isobutylamino)methyl)-2-oxo- l,2-dihydropyridine-3-carboxamide;

5-((Isobuty lam ino)methy l)-N-(3-((l s,3s)-3-methy l-1 -(5-methy I-1 H-1,2,3-triazol-4yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxamide;

5-((lsobuty laminojmethy l)-N-(3-(3-methyl-1 -(5-methy 1-1 H-1,2,3-triazol-4y Ijcyclobutyljpheny l)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3-carboxamide hydrochlorîde;

5-(( Isobutylamino)methy l)-N-(3-(( 1 s,3s)-3-methy 1-1 -(5-methyi-1 H-imidazol-4yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dÎhydropyridine-3-carboxamide;

N-(3-(3,3-dimethy 1-1-(5-methy 1-1 H-imidazol-4-yl jcyclobuty 1 jpheny l)-5((isobuty Iamino)methyl)-2-oxo-1 -(2,2,2-trifluoroethy Ij-1,2-dihydropyridine-3-carboxam ide;

5-( l -(isobuty lami nojethyl)-N-(3-(( l s,3s)-3-methyl-I -(4-methy I-4H-1,2,4-triazol-3yl)cyclobutyljphenylj-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide (lsomer-2);

(+)N-(3-(3,3-dimethyl-1 -(4-methy l-4H-1,2,4-triazol-3-yl jcyclobuty l jpheny I j-5-( 1 (isobuty lamino)ethy l)-2-oxo- 1-(2,2,2-trifluoroethy I )-1,2-dihydropyridine-3-carboxamide;

(+)N-(5-(3,3-dimethyl-l-(4-methyl-4H-I,2,4-triazol-3-yl)cyclobutyi)-2-fluorophenyl)5-(l-(isobutylaminojethy l)-2-oxo-l-(2,2,2-tnfluoroethyl)-i,2-dihydropyridine-3-carboxamide;

5-( l -(isobutylaminojethy l)-N-(3-(( l s,3s)-3-methy l-1 -(4-methy l-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide (Isomer-1);

5-(((Cyciopropylmethyl)amino)methylj-l-(2,2-difluoroethyij-N-(5-(3,3-dimethyl-l(4-methyl-4H-l ,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-l,2-dihydropyridine-3carboxamide;

N-(3-(3,3-dimethyl-1 -(4-methy I-4H-1,2,4-triazol-3-y l)cyclobuty l)phenyl )-5((isobutylamino)methyl)-l-(oxetan-3-ylmethyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

5-(((Cyclopropylmethyljamino)methylj-N-(2-fluoro-5-(2-(4-methyl-4H-l,2,4-tnazol3-yljspiro[3.3]heptan-2-yljphenylj-2-oxo-l-(2,2,2-trifluoroethylj-l,2-dihydropyridine-3carboxamide;

5-(((Cyclopropylniethyl)amino)methyl)-N-(5-(3,3-dimethyl-l-(4-methy I-4H-1,2,4triazoi-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1-(3,3,3-trifluoropropy 1)-1,2-dihydropyridine3-carboxamide;

N-(3-(3,3-dimethy I-1 -(4-methy 1-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isobutylamino)methyl)-N-rnethyl-2-oxo-l -(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

N-(3-(3,3-dimethyl-1 -(4-methy 1-4 H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((Îsopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethy0-1,2-dihydropyridme-3-carboxamide;

N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((((1 -(fl uoromethyl)cyclopropyl)methy l)amino)methyl)-2-oxo-l -(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxam ide;

208

5-(((Cyclopropylmethyl)amino)methyl)-N-(3-(3,3-dimethyl-1-(4-methy 1-4 H-1.2,4triazol-3-y l)cyclobuty I )pheny l)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3carboxamide;

N-(5-(3,3-dimethy 1-1-(4-methy I-4H-1,2,4-triazol-3-yl)cyclobuty 1)-2-11 uorophenyl)-5((isobutylamino)methyl)-2-oxo-]-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5((isobutylam ino)methy l)-2-oxo-1 -(2,2,2-trifluoroethy I )-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethy 1-1-(4-methy l-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((neopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(2-chloro-5-(3,3-dimethy 1-1-(4-methy 1-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isobuty lamino)methyl)-2-oxo-1-(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3-carboxamide;

N-(2-chloro-5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((neopentylamino)methyl)-2-oxo-l -(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethy I-1 -(4-methy I-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5((neopentylamino)methyl)-2-oxo-l-(2,2.2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethy I-1 -(4-methy I-4H-1,2,4-triazol-3-yl)cyc!obutyl)phenyl)-5((isobutylamino)methyl)-2-oxo-l-(3,3,3-trifluoropropyl)-l,2-dihydropyridine-3-carboxamide;

5-(((Cyclopropylmethyl)amino)methyl)-N-(5-(3,3-dimethyl-l-(4-methyl-4H-l,2,4triazol-3-yl)cyclobutyl)-2-fluorophenyl)-2-oxo-1 -(2,2,2-trïfluoroethyl)-l ,2-dihydropyridine-3carboxamide;

5-(((Cyclopropylmethyl)amino)methy1)-N-(2-fluoro-5-(5-(4-methyl-4H-l ,2,4-triazol3-yl)spiro[2.3]hexan-5-y l)pheny l)-2-oxo-l-(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3carboxamide;

205

5-(((Cyclopropylmethyl)amino)methyl)-N-(3-(2-(4-methy 1-4H-1,2,4-triazol-3y l)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-l-( 2,2,2-trifluoroethy l)-l,2-dihydropyridine-3carboxamide;

5-(((2-Ethy Ibuty l)amino)methy I )-N-(3-(5-(4-methy I-4H-1,2,4-triazol-3y l)Spiro[2.3]hexan-5-y 1 )pheny I)-2-oxo-1 -(2,2,2-trifluoroethyl )-1,2-dihydropyridine-3carboxamide;

N-(3-(3,3-dimethyi-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2ethylbutyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-difhioro-1-(4-methyl-4H-l,2,4-triazol-3-yI)cyclobutyl)phenyl)-5-(((2ethylbutyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(5-(4-methyl-4H-1,2,4-triazo!-3-yi)spiro[2.3]hexan-5-yl)pheny 1)-5-(((2methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethy l)-l,2-dihydropyridine-3carboxamide (lsomer-1 );

N-(3-(5-(4-methyl-4H-l,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)pheny 1)-5-(((2methylbuty1)amino)methyl)-2-oxo-l-(2,2.2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide (Isomer-2);

5-((Isobutylamino)methyl)-N-(3-(2-(4-methyl-4H-l,2,4-triazol·3-yl)spiro[3.3]heρtan2-yl)pheny l)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-N-(3-(2-(4-methy!-4H-l,2,4-triazol-3-yl)spiro[3.3 ]heptan-2-yl)pheny 1)-5-((3methylpiperidin-1 -y 1 )methy l)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropy ridine-3carboxamide;

5-((!sobutylamino)methyl)-N-(3-(5-(4-methyl-4H-l,2,4-tnazol-3-yl)spiro[2.3]hexan5-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

(S)-N-(3-(5-(4-methyi-4H-l,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5-((3methylpiperidin-1-y I)methy1 )-2-oxo-l -(2,2,2-trifluoroethy l)-l ,2-dihydropyridine-3carboxamide;

(S)-N-(3-(3,3-dinuoro-1-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)pheny 1)-5-((3methylpiperidin-1-y l)methyl)-2-oxo-i-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

N-(3-(3,3-difluoro-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5((isobutylamino)methy l)-2-oxo-1-(2,2,2-trifluoroethyi)-l ,2-dihydropyridine-3-carboxamide;

5-((lsobutylamino)methy l)-N-(4-(3-methy 1-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)pyridin-2-yl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3carboxamide;

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)-l,2-dihydropyridine-3-carboxamide;

((S)-N-(3-(3,3-dimethy 1-1-(4-methy I-4H-1.2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3methylpiperidin-l-yl)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3carboxamide;

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5-(((2-Fhioro-2-methylpropyl)amino)methyl)-N-(2-f!uoro-5-((ls,3s)-3-methyl-l-(4methyl-4H-1,2,4-triazol-3-y l)cyclobuty l)pheny l)-2-oxo-1 -(2,2.2-trifluoroethy 1 )-1.2dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methy 1-1 -(4-methy I-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-l-(4-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-l ,2dihydropyridîne-3-carboxamide;

5-((Isobutylamino)methyl)-N-(3-((ls,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3y l)cyclobutyl)pheny l)-2-oxo-1 -(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide;

l-(2-Cyclopropylethyl)-5-((isobutylamino)methyl)-N-(3-((ls,3s)-3-methyl-l-(4methyl-4H-l ,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

N-(3-(( ls,3R)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo5-(((S)-3-propionamidopy rrolidin-1 -y l)methy 1)-1 -(2,2,2-trifiuoroethyl)-1,2-dihydropyridine3-carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methy 1-1 -(4-methy 1-4H-1,2,4-triazoi-3y1)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methy 1-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(3,3.3-trifluoropropyl)-1,2dihydropyridine-3-carboxamide;

5-(((S)-3-AcrylamidopynOlidin-l-yl)methyl)-N-(3-((ls,3R)-3-methyl-l-(4-methyl-4Hl.2,4-triazol-3-yl)cyclobutyl)phenyI)-2-oxo-1-(2,2,2-tri fluoroethyi)-l,2-dihydropyridine-3carboxamide;

5-(((2-Fluoro-2-methylpropyl)amino)methyl)-N-(3-((l s,3s)-3-methy 1-1-(4-methy 1-4Hl,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3carboxamide;

N-(3-fl uoro-5-(( 1 s,3s)-3-methy I-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-1,2dihydropyridine-3-carboxamide;

N-(2-chloro-5-(3-methyl-1 -(4-methyl-4H-1,2,4-triazol-3-y l)cyclobuty l)pheny l)-l(cyclopropylmethyl)-5-((isobutylamino)methyl)-2-oxo-l ,2-dihydropyridine-3-carboxamide;

5-((Ethylamino)methyl)-N-(2-fluoro-5-(( ls,3s)-3-methyl-l-(4-methyl-4H-l,2,4triazol-3-y l)cyc!obuty l)phenyl)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide;

5-(((CyclopropyImethyl)amino)methyl)-N-(2-fluoro-5-((ls,3s)-3-methyl-l-(4-methy I4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-l,2-dihydropyridine3-carboxamide;

l-(Cyclopropylmethyl)-N-(2-fluoro-5-(3-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

5-(((2-Ethoxyethyl)amino)methyl)-N-(2-fluoro-5-((l s, 3s)-3-methy 1-1 -(4-methy 1-4H1,2,4-triazol-3-yi)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methy 1-1 -(4-methy 1-4 H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-(((2-hydroxy-2-methylpropyi)amino)methyl)-2-oxo-1-(2,2,2trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-((ls,3s)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3yl)cyclobutyl)pheny 1)-5-((( I -methy Icyclobuty l)amino)methy l)-2-oxo-1 -(2,2,2-trifluoroethy ΟΙ ,2-dihydropyridine-3-carboxamide;

202

N-( 2-fl uoro-5-(( l s,3s)-3-methy l-l -(4-methy I-4H-1,2,4-tnazol-3yl)cyclobutyl)phenyl)-2-oxo-5-((tert-pentylamino)methyl)-l -(2,2,2-trifluoroethyl)-l ,2dihydropyridine-3-carboxamide;

l-(Cyclopropylmethyl)-5-((isobutylamino)methyl)-N-(3-(3-methy1-l-(4-methyl-4Hl,2,4-triazol-3-yl)cyclobutyl) phenyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

N-(3-(( l s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4-triazol-3-yi)cyc!obutyl)phenyl)-5((neopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

5-(((2-Ethy lbutyl)amino)methy l)-N-(3-(( 1 s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

N-(3-(( ls,3s)-3-methy 1-1-(4-methy 1-4 H-1,2,4-triazol-3-yl)cyclobuty I )phenyl)-5-(((3methy lbutan-2-y l)amino)methy l)-2-oxo-1 -(2,2,2-trifluoroethyl )-1,2-dihydropyridine-3carboxamide (Isomer-1 );

N-(3-(( 1 s,3s)-3-methy 1-1 -(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3methylbutan-2-yl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3carboxamide (lsomer-2);

N-(3-(( 1 s,3s)-3-methy I-1 -(4-methy I-4H-1,2,4-triazol-3-yl)cyciobutyl)phenyl)-5-(((2methylbuty l)amino)methyl)-2-oxo-1-(2,2,2-tri fl uoroethyl)-!,2-dihydropyridine-3carboxamide (Isomer-1);

201

N-( 3-(( l s,3s)-3-methy I-1 -(4-methy I-4H-1,2,4-tnazol-3-yl)cyclobutyl)phenyl)-5-(((2methylbutyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)- l,2-dihydropyridine-3carboxamide (Isomer-2);

N-(3-(cyclobutyl(4-methyl-4H-l,2,4-triazoi-3-yl)methyl)phenyl)-5((Îsobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxamide ( Isomer-1 );

N-(3-(cyclobutyl(4-methyl-4H-l,2,4-triazol-3-y!)methyl)phenyl)-5((isobuty lamino)methy l)-2-oxo-1 -(2,2,2-trifluoroethy I)-1,2-dihydropyridine-3-carboxamide (lsomer-2);

N-(5-(cyclobutyl(4-methyl-4H-l,2,4-triazo!-3-yl)methyl)-2-fluorophenyl)-5((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxamide (Isomer-1 );

N-(5-(cycIobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl )-2-11 uorophenyl)-5((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3-carboxamide (lsomer-2);

N-(3-(cyclobutyl(4-methyl-4H-l,2,4-triazol-3-y!)methyl)phenyl)-5(((cyclopropylmethyl)amino)methyI)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2-dihydropyridine-3carboxamide (Isomer-1);

N-(3-(cyclobuty l(4-methy I-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5(((cyclopropylmethy])amino)niethyl)-2-oxo-l-(2,2,2-trifluoroethy l)-l,2-dihydropyridine-3carboxamide (lsomer-2);

N-(2-fluoro-5-(( 1 s,3s)-3-methyl-1 -(4-methy I-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((neopentylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethy 1)-1,2dihydropyridine-3-carboxamide;

5-(((2-Hydroxy-2-methylpropyl)amino)methyl)-N-(3-((ls,3s)-3-methyl-l-(4-methyl4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine3-carboxamide;

N-(2-chloro-5-(( l s,3R)-3-methy l-1 -(4-methy l-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-l-yl)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)l,2-dihydropyridine-3-carboxamide;

N-(2-chloro-5-(( l s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l ,2dihydropyridine-3-carboxamide;

Ν-(3-(( Is,3s)-3-methyl-l-(4-methy 1-4H-1,2,4-triazol-3-yl)cyclobutyi)pheny 1)-5-(((1methylcyclopropyl)amino)methyl)-2-oxo- l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

N-(3-(( I s,3S)-3-methy I-1 -(4-methy I-4H-1,2,4-triazol-3-y l)cyc lobuty l)phenyl)-5-(((R)3-methy Ipiperidin-1 -y l)methy l)-2-oxo-1 -(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3carboxamide;

N-(3-(( 1 s,3s)-3-methy I-1 -(4-methy I-4H-1,2,4-triazol-3-yl)cyclobutyl)pheny 1)-5-((( 1 methylcyclobutyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

5-((Isobutylamino)methy l)-N-(3-(( 1 s,3s)-3-methyl-l -(4-methy I-4H-1,2,4-triazol-3y l)cyclobuty l)pheny l)-2-oxo-1 -(2,2,2-trifl uoroethy 1)-1,2-dihydropyridine-3-carboxamide;

N-(3-((ls,3R.)-3-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)3-pi peridi η-1 -y l)methyl)-2-oxo-1 -(2,2,2-trifl uoroethy I)-1,2-dihydropy ridine-3-carboxamide;

N-(2-fluoro-5-(( 1 s,3s)-3-methy I-1 -(4-methy 1-4H-1,2,4-triazol-3yl)cyclobutyl)phenyl)-5-((îsobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethy 1)-1,2dihydropyridine-3-carboxamide;

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N-(2-fl uoro-5-((l s,3 R)-3-methy l-l -(4-methy I-4H-1,2,4-tnazol-3yl)cyclobutyl)phenyl)-5-(((S)-3-methylpîperidin-l-yl)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)l,2-dihydropyridine-3-carboxamide;

5-((4,4-Dimethy 1-1,4-azasilinan- 1-y l)methy I )-N-(3-(2-methy I-1 -(4-methyl-4H-1,2,4triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3carboxamide;

5-(((2,2-Difluoroethyl)amino)methyl)-14-(3-(2-methyl-l -(4-methyl-4H-l ,2,4-triazol-3y l)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethy l)-l,2-dihydropyridine-3-carboxamide;

(S)-N-(4-fluoro-3-(2-methyl-1 -(4-methy I-4H-1,2,4-triazol-3-yl)propan-2-y l)phenyl)-5((3-methy Ipiperidin-1 -yl )methy l)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3carboxamide;

5-(((2-Hydroxy-2-methy lpropyl)amino)methy 1)-14-(3-(2-methyl-l -(4-methy 1-4H1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

5-(((2-Hydroxyethyl )amino)methyl)-N-(3-(2-methy 1-1-(4-methy 1-4H-1,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-l -(2,2,2-trifluoroethy l)-l,2-dihydropyridine-3-carboxamide;

5-(( 3-I sopropy I p iperidi η-1 -yl )methy l)-N-(3-(2-methy l-1 -(4-methy I-4H-1,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)- l,2-dihydropyridine-3-carboxamide (Isomer-2);

(S)-5-((3-(hydroxymethyl)pÎpendin-1-yl)methyl)-N-(3-(2-methyl-l-(4-methyl-4H1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

5-((3-Isopropylpiperidin-1 -yl)methyl)-N-(3-(2-methyl-1 -(4-methy I-4H-1,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-l-(2,2.2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide (lsomer-l );

5-((Isobutyl(methyl)amino)methyl)-N-(3-(2-methy 1-1-(4-methy 1-4H-1,2,4-triazol-3yl)propan-2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-(((oxetan-3ylmethyl)amino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(2-methyl-l-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5((isobutylamino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

199 (S)-N-(2-fluoro-5-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-5((3-methy lpiperidin-l-y l)methyl)-2-oxo-l-(2,2,2-trifluoroethy I)- l,2-dihydropyridine-3carboxamide;

5-((lso butylamino)methyl)-N-(3-(2-methy l-l-(4-methy 1-4H-1,2,4-triazol-3-yl)propan2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

5-((4-Fluoropiperidin-l-yl)methyl)-N-(3-(2-methyl-I-(4-methyl-4H-l,2,4-triazoI-3yl)propan-2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

(R)-N-(3-(2-methy 1-1-(4-methy l-4H-l,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((2methylmorpholino)methyl)-2-oxo-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3carboxamide;

(S)-l-(2-Cyclopropylethyl)-N-(3-(2-methy!-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan2-yl)phenyl)-5-((3-methylpiperidin-l-yl)methyl)-2-oxo-l,2-dihydropyridine-3-carboxamide;

(S)-5-((3-FluoiOpynOlidin-l-yl)methyl)-N-(3-(2-methyl-1-(4-methy I-4H-1,2,4-triazol3-yl)propan-2-yl)phenyl)-2-oxo-l-(3,3,3-trifluoropropyl)-l,2-dihydropyridine-3-carboxamide;

5-((3-Acetamidopiperidin-1 -y l)methy l)-N-(3-(2-methy 1-1 -(4-methy I-4H-1,2,4-triazol3-yl)propan-2-yl)phenyl)-2-oxo-l -(2.2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide (Isomer-2);

5-((3-Acetamidopiperidin-l-yl)methyl)-N-(3-(2-methyl-l-(4-methyl-4H-l ,2,4-triazoi3-yl)propan-2-yl)phenyl)-2-oxo-l-(2,2,2-trifluoroethyl)- l,2-dihydropyridine-3-carboxamide ( Isomer-1 );

5-((4,4-Difluoropiperidin-l-yl)methyl)-N-(3-(2-methyl-l-(4-methyl-4H-1,2,4-triazol3-y l)propan-2-y l)phenyl)-2-oxo-1 -(2,2,2-trifluoroethy 1)-1,2-dihydropyridine-3-carboxamide;

5 5. The compound according to claim 1, wherein R¹¹ is methyl, ethyl, difluoromethyl.

difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl,

5 R¹⁰ is selected from hydrogen and Ci-salkyi;

R¹¹ is selected independently from Ci._salkyl, haloCi-ealkyl, Cô-uaryl, Cô-uaryICi-salkyl, 3-15 membered heterocyclylCi-salkyl, C₃-i2cycloalkyl and Cs-scycloalkylCi-galkyl; wherein the Câ-uaryl, Cô-^arylCi-salkyl are optionally substituted with one or more substituents selected from halogen;

10 Ί’ is an integer ranging from 0 to 2, both inclusive;

‘m’ is an integer ranging from 0 to 4, both inclusive;

‘n’ is an integer ranging from 1 to 3, both inclusive; and ‘r’ is an integer ranging from 0 to 4, both inclusive.

15 2. The compound of claim 1, having represented by formula (1 A), (IB) or (IC):

(IA)

(IB)

193

or a stereoisomer, or a pharmaceutically acceptable sait thereof.

6-((lsobutylamino)methy l)-N-(3-(( 1 s,3s)-3-methyl-1 -(4-methyl-4H-1,2,4-triazol-325 yl)cyclobutyl)phenyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; and pharmaceutically acceptable sait thereof.

6.

The compound according to claim 1, wherein ring A is

7. The compound according to claim 1, wherein ‘Z’ is CH or N;

195

‘X’ isCHorN;

R² is chloro, fluoro,-NHC(O)CH₃ or-NHC(O)CH=CH₂;

ΙΟ

R³ is methyl;

Y is absent or CH₂;

R⁴ is hydrogen or CH₃;

R⁵ is CHa or cyclobutyl; or

R⁴ and R⁵joined together with the carbon atom to which they are attached, form a

R¹⁰ is hydrogen or methyl;

196

R' is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyimethyl, ' ' , ^F or :

F .

T is l ;

‘n’ is 1;

‘m’ is 0 or 1; and ‘r’ is 1.

8. The compound according to claim 1 is l-(Cyciopropylmethyl)-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)-l,2-dihydropyridine-3-carboxamide;

N-(3-(2-methyl-1 -(4-methyl-4H-1,2,4-triazol-3-yl )propan-2-y l)pheny l)-2-oxo-5(piperidin-l-ylmethyl)-l-(2,2,2-trifluoroethyl)-l,2-dihydropyridine-3-carboxamide;

l-Cyclopropyl-N-(3-(2-methyl-l-(4-methyl-4H-l,2,4-triazol-3-yl)propan-2yl)phenyl)-2-oxo-5-(piperidin-l-ylmethyl)-l,2-dihydropyridine-3-carboxamide;

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient wherein the pharmaceutically acceptable excipient is a 30 carrier or diluent.

10. A compound according to claim 1 for use in treating or preventing a CBL-b mediated disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is cancer.