SUBSTITUTED PRYIDINONE COMPOUNDS AS CBL-B INHIBITORS

RELATED APPLICATIONS

This application claims the benefit of Indian Provisional Application No.202221046493 filed on August 16, 2022; which is hereby incorporated by reference in its entirety.

FILED OF THE INVENTION

The present patent application is directed to novel heterocyclic compounds which are useful as CBL inhibitors, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment or prevention of various diseases, conditions and/or disorders mediated by CBL-b.

BACKGROUND OF INVENTION CBL (Casitas B-lineage Lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase. CBL proteins are part of a family of ubiquitin ligases involved in cell signaling, protein ubiquitination, and degradation of protein substrates. The CBL proteins are a highly conserved family of proteins with three isoforms c-Cbl (also termed Cbl2, Cbl-SL, or RNF55), Cbl-b (also termed RNF56) and Cbl-3 (also called Cbl-3) [Keane et al., Oncogene, 18: 3365–3375, 1999; Keane et al., Oncogene, 10: 2367–2377, 1995; Kim et al., Gene, 239: 145–154, 1999].

All three mammalian Cbl proteins are RING-type E3 ligases containing an N-terminal tyrosine kinase binding (TKB) domain consisting of a four-helical bundle, a calcium binding EF-hand and a Src homology (SH2) domain, followed by a linker helical region and the RING domain, responsible for their catalytic function. Cbl-b ubiquitinates all three TAM family members, Tyro-3, Axl, and Mer, which is responsible for immunosuppressive and metastatic action. The unique feature of the TKB domain is that it recognizes specific substrates of Cbl-b, which is achieved by binding to proteins containing specific phosphorylated tyrosine-containing motifs, such as Syk and Zap-70, and a range of receptor tyrosine kinases. The interaction of proteins with the TKB domain of Cbl is mediated by 3 distinct subdomains consisting of a 4-helix bundle (4H), a calcium-binding EF hand, and a variant SH2 domain, all 3 of which are functionally required to form a unique PTB (phosphotyrosine-binding) module [Meng et al., Nature, 398(6722): 84-90, 1999]. SH2 domain within the TKB recognizes tyrosine-phosphorylated proteins for ubiquitin conjugation [Mohapatra et al., Biochim Biophys Acta., 1833 (1): 122-39, 2013]. A highly conserved α-helix of the L domain plays an important role in maintaining E3 activity [Zeng et al., Cell, 102(4): 533-9, 2000; Kassenbrock et al., J Biol Chem., 279(27): 28017-27, 2004]. The crystal structure shows that the L region contacts the TKB, RF, and E2 ubiquitin-conjugating enzymes. The RF domain has intrinsic E3 ubiquitin ligase activity and binds to ubiquitin-E2 for the transfer of ubiquitin to specific substrates [Budhidarmo et al., Trends Biochem Sci., 37(2): 58-65, 2012; Paolino et al., J Immunol., 186(4): 2138-47, 2011]. Recent studies indicates that the phosphorylation of Y363, located in the L region between TKB and RF domains, regulates the E3 activity of Cbl-b by 2 mechanisms: one is to remove the masking of the RF domain from the TKB domain, and the other is to form a surface to enhance binding affinity to E2s [Ryan et al., J Biol Chem., 285(31): 23687-98, 2010;].

Casitas B-lineage lymphoma proto-oncogene-b, a RING finger E3 ubiquitin-protein ligase, has been demonstrated to play a crucial role in establishing the threshold for T-cell activation and controlling peripheral T-cell tolerance via multiple mechanisms. In T cells, Cbl-b is predominantly expressed in peripheral T cells, whereas c-Cbl is mainly expressed in thymus, suggesting a distinct role of c-Cbl and Cbl-b in T-cell development and tolerance induction [Liu et al., Trends Immunol., 23(3): 140-3, 2002]. The E3 ubiquitin ligase cbl-b has been identified as a key intracellular checkpoint limiting T and NK cell activation. The blockade of cbl-b function by genetic deletion strongly enhances anti-tumor immune responses Cbl-b is expressed in all leukocyte subsets and regulates several signaling pathways in T cells, NK cells, B cells, and different types of myeloid cells. Cbl-b is thought to function largely by regulating T cell activity through degradation of phospho-inositol-3-kinase (PI-3-K) downstream of the CD28 costimulatory receptor. The role of Cbl-b in the negative regulation of T cell activation and tolerance induction are tightly controlled processes regulating immune responses to pathogens and tumors while preventing autoimmunity. Autoimmunity is mainly averted through central tolerance by negative selection of thymocytes carrying TCR for self-antigens.

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

Adoptive Cell Therapy (ACT) is used in otherwise treatment-resistant cancers, including metastatic melanomas, gliomas, and renal carcinomas. In ACT, NK cells or T cells

from a patient's own blood or tumor tissue are harvested, then grown into large numbers in the laboratory, and then the expanded cells are transferred back to the patient to enhance the patient’s immune system response to the cancer. In some versions of ACT, the T cells or NK cells are modified using genetic engineering to enable them to target the patient's cancer cells and kill the cancer cells more efficiently. Types of adoptive cell therapy include natural killer (NK) cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, engineered T-cell receptor therapy (TCR), and chimeric antigen receptor T-cell (CAR T) therapy. NK cell therapy uses NK cells, part of the innate immune system, and the first line of defense against infections and diseases, including cancer cells.

As genetic ablation of cbl-b is associated with spontaneous development of autoimmunity and increased susceptibility to experimental induction of autoimmune diseases [Bachmaier et al., Nature, 403(6766): 211–6, 2000] and it is not surprising that several groups later found links between genetic cbl-b variants and susceptibility to autoimmunity in an animal model for diabetes [Yokoi et al., Nat Genet., 31(4): 391–4, 2002] as well as in various human autoimmune diseases such as type 1 diabetes [Bergholdt et al., J Leukoc Biol., 77(4): 579–85, 2005], lupus erythematodes [Padilla et al., Lupus, 20(6): 628–35, 2011], asthma [Dewan et al., BMC Med Genet., 13: 95, 2012], and multiple sclerosis [Sawcer et al., Nature, 476(7359): 214– 9, 2011].

CBL inhibitors include small molecules, peptides, nucleic acids, or antibodies that inhibit the Cbl enzymes. Cbl enzymes include c-Cbl, Cbl-b, and Cbl-c. Cbl inhibitors for use in methods of treatment and compositions of the disclosure, include, but are not limited to, compounds and pharmaceutical compositions for cell-based immunotherapy. The Cbl inhibitors can be used in in-vivo treatment methods to modulate the immune system, such as increasing activation of T cells, NK cells, circulating T cells, tumor infiltrating lymphocytes and B cells, to increase engraftment of infused ex vivo expanded immune cells, or to increase the durability of response to the infused ex vivo expanded immune cells. In addition, the Cbl inhibitors can be used to help expand such immune cells in vitro or ex vivo to increase their growth and proliferation or to modulate the phenotype of the resulting expanded immune cells.

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

Currently, there is a largely unmet need for an effective way of treating disease and disorders associated with CBL-b inhibition includes but not limited to autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma. The improved therapeutic compounds, compositions and methods for the treatment for these disease and disorders are urgently required. CBL-b inhibition is an especially attractive target for cancer immunotherapy.

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

SUMMARY OF THE INVENTION

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

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein,

at each occurrence, R1 is selected independently from 3-15 membered heterocyclylC1- 8alkyl, 5-14 membered heteroarylC1-8alkyl and -[CHR]l-NR6R7; wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyC1-8alkyl, C1-8alkyl, – NHC(O)CH3, –NHC(O)CH2CH3 and –NHC(O)CH=CH2.;

Z is CH or N;

X is CH or N;

R is selected from hydrogen and C1-8alkyl;

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

ring A is 5-14 membered heteroaryl;

at each occurrence, R3 is C1-8alkyl;

R4 is selected from hydrogen and C1-8alkyl;

R5 is selected from C1-8alkyl and C3-12cycloalkyl; or

R4 and R5 joined together with the carbon atom to which they are attached, form a 3-15 membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl wherein 3-15

membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen and C1-8alkyl;

‘Y’ is absent or CR8R9;

R6 is selected from hydrogen and C1-8alkyl;

R7 is selected from C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxyC1-8alkyl, – CH2CH2NHC(O)CH=CH2, C3-12cycloalkyl, C3-12cycloalkylC1-8alkyl and 3-15 membered heterocyclylalkyl; wherein C3-12cycloalkyl and C3-12cycloalkylC1-8alkyl is optionally substituted with C1-8alkyl and haloC1-8alkyl;

R8 is hydrogen;

R9 is hydrogen;

R10 is selected from hydrogen and C1-8alkyl;

R11 is selected independently from C1-8alkyl, haloC1-8alkyl, C6-14aryl, C6-14arylC1-8alkyl, 3-15 membered heterocyclylC1-8alkyl, C3-12cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C6-14aryl, C6-14arylC1-8alkyl are optionally substituted with one or more substituents selected from halogen;

‘l’ is an integer ranging from 0 to 2, both inclusive;

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

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

‘r’ is an integer ranging from 0 to 4, both inclusive.

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

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

The compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein ‘Z’ is CH or N (according to an embodiment defined below), ‘n’ is 1 according to another embodiment defined below) and ‘X’ is CH or N (according to yet another embodiment defined below).

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

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

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7, 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl; wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyC1-8alkyl, C1-8alkyl, -NHC(O)CH3, –NHC(O)CH=CH2 and-NHC(O)CH2CH3.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7, wherein R, l, R6 and R7 are as defined in formula (I).

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

(I), in which R1 is 3-15 membered heterocyclylC1-8alkyl (e.g.
,

and 5-14 membered heteroarylC1-8alkyl

(e.g.
); wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro), oxo, hydroxyl, hydroxyC1-8alkyl (e.g. hydroxyl methyl), C1-8alkyl (e.g. methyl or isopropyl), -NHC(O)CH3, -NHC(O)CH2CH3 or –NHC(O)CH=CH2.

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

(I), in which R1 is a 3-15 membered heterocyclylC1-8alkyl (e.g.
,

) or 5-14 membered heteroarylC1-8alkyl

(e.g. ); wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from fluoro, oxo, hydroxyl, hydroxylmethyl, methyl, isopropyl, -NHC(O)CH3, -NHC(O)CH2CH3 or –NHC(O)CH=CH2.

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7. In this embodiment, R is hydrogen or C1-8alkyl; R6 is hydrogen or C1-8alkyl; R7 is C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxyC1-8alkyl, -CH2CH2NHC(O)CH=CH2, C3-12cycloalkyl, C3-12cycloalkylC1-8alkyl and 3-15 membered heterocyclylalkyl; wherein C3-12cycloalkyl and C3-12cycloalkylC1-8alkyl are substituted or unsubstituted with one or more substituents selected from C1-8alkyl and haloC1-8alkyl and ‘l’ is 1.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7. In this embodiment, R is hydrogen or C1-8alkyl (e.g. methyl); R6 is hydrogen or C1-8alkyl (e.g. methyl); R7 is C1-8alkyl (e.g. ethyl, isobutyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl or 3-methylbutan-2-yl), haloC1-8alkyl (e.g. difluoroethyl, 2-fluoro-2-methylpropyl, 1-fluoro-2,2-dimethylpropyl or 2-fluoro-2-methylbutyl), hydroxyC1-8alkyl (e.g. hydroxyethyl or 2-hydroxy-2-methylpropyl), C1- 8alkoxyC1-8alkyl (e.g. ethoxyethyl), -CH2CH2NHC(O)CH=CH2, 3-15 membered heterocyclylalkyl (e.g. methyloxetane), C3-12cycloalkyl (e.g. cyclopropyl or cyclobutyl) or C3- 12cycloalkylC1-8alkyl (e.g. methylcycloproyl); wherein the C3-12cycloalkyl and C3- 12cycloalkylC1-8alkyl are optionally substituted with one or more substituents selected from C1- 8alkyl (e.g. methyl) or haloC1-8alkyl (e.g. fluoromethyl) and ‘l’ is 1.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is -[CHR]l-NR6R7. In this embodiment, R is hydrogen or methyl; R6 is hydrogen or methyl; R7 is ethyl, isobutyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 2-ethylbutyl, 3-methylbutan-2-yl, difluoroethyl, 2-fluoro-2-methylpropyl, 1-fluoro-2,2-dimethylpropyl, 2-fluoro-2-methylbutyl, hydroxyethyl, 2-hydroxy-methylpropyl, ethoxyethyl, -CH2CH2NHC(O)CH=CH2, methyloxetane, 1-methylcyclopropyl, 1-methylcyclobutyl, cycloproylmethyl or 1-fluoromethyl cycloproylmethyl and ‘l’ is 1.

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

,

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

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

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

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

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

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

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

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which ‘m’ is 0 or 1.

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

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R2 is chloro, fluoro, –NHC(O)CH3 or –NHC(O)CH=CH2 and ‘m’ is 0 or 1.

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

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

(I), in which ring

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

(I), in which ring

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

(I), in which ring

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

(I), in which ring

According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is C1-8alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is methyl.

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

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

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

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

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

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

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 is hydrogen or C1-8alkyl (e.g. CH3).

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R5 is C1-8alkyl (e.g. CH3) or C3-12cycloalkyl (e.g. cyclobutyl).

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

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

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 joined together with the carbon atom to which they are attached, form a O

C3-12cycloalkyl (e.g.
), 3-15 membered heterocyclyl (e.g. ), or 3-15 membered

spirocyclyl (e.g.
), wherein C3-12cycloalkyl or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen (e.g. fluoro) or C1- 8alkyl (e.g. methyl or ethyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 joined together with the carbon atom to which they are attached, form a O

C3-12cycloalkyl (e.g.
), 3-15 membered heterocyclyl (e.g. ), or 3-15 membered

spirocyclyl (e.g.
), wherein C3-12cycloalkyl or 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from fluoro, methyl or ethyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R4 and R5 joined together with the carbon atom to which they are attached, form a

According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is hydrogen or C1-8alkyl (e.g. methyl).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is hydrogen or methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is hydrogen.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R10 is methyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C1-8alkyl, haloC1-8alkyl, C6-14aryl , C6-14arylC1-8alkyl-, 3-15 membered heterocyclylC1-8alkyl, C3-12cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein the C6-14aryl and C6-14arylC1-8alkyl are substituted or unsubstituted with one or more substituents selected from halogen.

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C1-8alkyl (e.g. methyl or ethyl).

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is haloC1-8alkyl (e.g. trifluoroethyl, difluoromethyl, difluoroethyl or trifluoropropyl).

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C3-12cycloalkyl (e.g. cyclopropyl).

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

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C3-8cycloalkylC1-8alkyl (e.g. cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl).

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

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

(I), in which R11 is 3-15 membered heterocyclylC1-8alkyl (e.g. ).

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

(I), in which R11 is .

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C6-14 aryl (e.g. phenyl); wherein the C6-14aryl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro).

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is C6-14 aryl (e.g. phenyl); wherein the C6-14aryl is optionally substituted with one or more substituents selected from fluoro.

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

(I), in which

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

(I), in which R11 is C6-14arylC1-8alkyl
wherein the C6-14arylC1-8alkyl is optionally substituted with one or more substituents selected from halogen (e.g. fluoro).

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

(I), in which R11 is C6-14arylC1-8alkyl
wherein the C6-14arylC1-8alkyl is optionally substituted with one or more substituents selected from fluoro.

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

(I), in which

According to yet another embodiment, specifically provided are compounds of formula (I), in which R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

.

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

‘Z’ is CH or N;

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or R4 and R5 joined together with the carbon atom to which they are attached, form a

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

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

‘Z’ is CH;

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or

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

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

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

‘Z’ is CH;

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or

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

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

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

‘Z’ is CH;

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or

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

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

According to an embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 10000 nM, preferably, less than 1000 nM, more preferably less than 100 nM, with respect to CBL family inhibitor activity.

Further embodiments relating to groups ring A, X, Y, Z, R1, R2, R3, R4, R5, R10, R11, n, m and r (and groups defined therein) are described hereinafter in relation to the compounds of formula (IA), (IB) or (IC). It is to be understood that these embodiments are not limited to use in conjunction with formula (IA), (IB) or (IC), but apply independently and individually to the compounds of formula (I).

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

Accordingly the invention provides a compound of formula (IA)

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, X, n, m and r are as defined in formula (I).

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

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

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

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, n, m and r are as defined in formula (I).

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

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

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

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein, R1, R2, R3, R4, R5, R10, R11, Y, n, m and r are as defined in formula (I).

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

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

It should be understood that the formulas (I), (IA), (IB) and (IC) structurally encompass all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

The terms “halogen” or “halo” means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).

The term “alkyl” refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. C1-8alkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term “C1-6alkyl” refers to an alkyl chain having 1 to 6 carbon atoms. The term “C1-4alkyl” refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.

The term “haloalkyl” refers to at least one halo group (selected from F, Cl, Br or I), linked to an alkyl group as defined above (i.e. haloC1-8alkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term “haloC1-4alkyl” refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.

The term “hydroxyalkyl” refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC1- 8alkyl). Examples of hydroxyalkyl moiety include, but are not limited to -CH2OH, -C2H4OH and –CH(OH)C2H4OH.

The term “alkoxy” denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C1-8 alkoxy). The representative examples of such groups are -OCH3 and -OC2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.

The term “alkoxyalkyl” or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. C1-8alkoxyC1-8alkyl or C1-8alkyloxyC1-8alkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH2OCH3 (methoxymethyl) and -CH2OC2H5 (ethoxymethyl). Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched.

The term “hydroxyC1-8alkyl” refers to a C1-8alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyC1-4alkyl). Examples of hydroxyC1-4alkyl moieties include, but are not limited to -CH2OH and -C2H4OH.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3-12cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term “C3-6cycloalkyl” refers to the cyclic ring having 3 to 6 carbon atoms. Examples of “C3- 6cycloalkyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e. C3-6cycloalkylC1-8alkyl). The

cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term “aryl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6-14aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term “arylalkyl” refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6- 14aryl) directly attached to an alkyl group (i.e. C6-14arylC1-8alkyl). The arylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term “heterocyclic ring” or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e.3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, oxetanyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term “heterocyclylalkyl” refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. heterocyclylC1-8alkyl). The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term “heteroaryl” unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl.

The term “heterarylalkyl” refers to a heteraryl ring radical directly bonded to an alkyl group (i.e. heteroarylC1-8alkyl). The heteroaryllalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term “pharmaceutically acceptable salt” includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.

The term “treating” or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c)

relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

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

A “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

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

The terms "salt" or "solvate", and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds.

PHARMACEUTICAL COMPOSITIONS

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

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

METHODS OF TREATMENT

The compounds of the present invention are particularly useful because they inhibit the activity of CBL-b, i.e., they prevent, inhibit, or suppress the action of CBL-b, and/or may elicit a CBL-b modulating effect. The compounds of the invention are therefore useful in the treatment of those conditions in which inhibition of CBL-b activity, and particularly CBL-b inhibition, is beneficial.

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

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

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

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

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

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

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

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

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

GENERAL METHODS OF PREPARATION

The compounds, described herein, including those of general formula (IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8 and IA-9), intermediates and specific examples are prepared through the synthetic methods as depicted in synthetic schemes 1-6. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling reagents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the present invention. The modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.

General Scheme

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

Synthetic scheme-1:

The esterification of compound of formula (1) yields ester compound of formula (2) [wherein R’ is C1-8alkyl]. The reaction is carried out in a suitable solvent. The suitable solvent used in the reaction may be methanol.

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

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

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

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

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

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

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

Synthetic scheme-2:

The hydrolysis reaction of compound of formula (3) [wherein R’ is C1-8alkyl] gives the compound of formula (10). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol or tetrahydrofuran or combination thereof.

The acid-amine coupling reaction of compound (10) with appropriate aromatic amines of compound of formula (9) gives the compound of formula (11). The reaction is carried out in a presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in a presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA. The reaction is carried out in a presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HCl, HOBt, DCC or T3P.

The Suzuki coupling reaction of compound of formula (11) and potassium vinyl trifluoroborate gives the compound of formula (12). The reaction is carried out in a presence of suitable base. The suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate or cesium carbonate. The reaction is carried out in a presence of suitable catalyst. The suitable catalyst used in the reaction may be selected from tetrakis (triphenylphosphine)palladium(0), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane, along with a suitable phosphine ligand, etc. The reaction may be carried out in a suitable solvent or mixture thereof. The suitable solvent may be selected from ethanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof.

The compound of formula (12) upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (13). The reaction is carried out in

presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be THF / water.

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

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

Synthetic scheme-3:

The Suzuki coupling reaction of compound of formula (3) [wherein R’ is C1-8alkyl] and potassium vinyl trifluoroborate gives the compound of formula (4). The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from potassium phosphate, potassium acetate, sodium, potassium tert-butoxide, sodium carbonate or cesium carbonate. The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be selected from tetrakis (triphenylphosphine)palladium(0), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane,

along with a suitable phosphine ligand, etc. The reaction may be carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be selected from ethanol, toluene, 1,4-dioxane, DMSO, water or a combination thereof.

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

The acid-amine coupling reaction of compound (14) with appropriate aromatic amines compound of formula (9) gives the compound of formula (15). The reaction is carried out in presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HCl, HOBt, DCC or T3P. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA.

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

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

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

suitable solvent used in the reaction may be selected from dichloromethane, dichloroethane or THF.

A general approach for the preparation of compounds of the general formula (IA-5, IA-6 and IA-7) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 4.

Synthetic scheme-4:

The Stille coupling reaction of compound of formula (3) and tributyl(1-ethoxyvinyl)tin gives the compound of formula (17). The reaction is carried out in presence of suitable catalyst. The suitable catalyst used in the reaction may be selected from tetrakis(triphenyl phosphine) palladium(0), dichlorobis(triphenyl phosphine)palladium(II), palladium acetate, along with a suitable phosphine ligand, etc. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from, 1,4-dioxane, DMSO or DMF.

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

The acid-amine coupling reaction of compound (18) with appropriate aromatic amines compounds of formula (9) gives the compound of formula (19). The reaction is carried out in presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HCl, HOBt, DCC or T3P. The reaction is carried out in presence

of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA.

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

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

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

Synthetic scheme-5:

The acid-amine coupling reaction of compound (14) with appropriate aromatic amines compound of formula (20) [wherein Q is C or N] gives the compound of formula (21). The reaction is carried out in presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HCl, HOBt, DCC or T3P. The reaction

is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA.

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

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

The compound of formula (23) on deprotection yields the compound of formula (IA-8). The reaction may be carried in presence of suitable acids. The suitable acids used in the reaction may be selected from hydrochloric acid and trifluoroacetic acid. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from methanol, ethanol, dichloroethane and 1,4- dioxane.

A general approach for the preparation of compounds of the general formula (IA-9) (wherein X, Y, Z, R2, R3, R4, R5, R6, R7, R10, R11, ‘m’ and ‘r’ are as defined in the description) is depicted in synthetic scheme 6.

Synthetic scheme-6:

The compound of formula (4) [wherein R’ is C1-8alkyl] upon oxidative cleavage using osmium tetra oxide and sodium periodate gives aldehyde compound of formula (5). The reaction is carried out in presence of suitable solvent or mixture thereof. The suitable solvent used in the reaction may be THF / water.

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

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

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

The acid-amine coupling reaction of compound of formula (27) with appropriate aromatic amine compound of formula (28) gives the compound of formula (29). The reaction

is carried out in presence of suitable coupling reagents. The suitable coupling reagents used in the reaction may be selected from HATU, EDC.HCl, HOBt, DCC or T3P. The reaction is carried out in presence of suitable solvent. The suitable solvent used in the reaction may be selected from dichloromethane, THF or dimethylformamide. The reaction is carried out in presence of suitable base. The suitable base used in the reaction may be selected from DIPEA or TEA.

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

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

EXPERIMENTAL SECTION

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulfate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.

WHAT IS CLAIMED IS:

1. A compound of formula (I)

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein,

at each occurrence, R1 is selected independently from 3-15 membered heterocyclylC1- 8alkyl, 5-14 membered heteroarylC1-8alkyl and –[CHR]l-NR6R7; wherein 3-15 membered heterocyclylC1-8alkyl and 5-14 membered heteroarylC1-8alkyl are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, hydroxyC1-8alkyl, C1-8alkyl, – NHC(O)CH3, –NHC(O)CH2CH3 and –NHC(O)CH=CH2.;

Z is CH or N;

X is CH or N;

R is selected from hydrogen and C1-8alkyl;

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

ring A is 5-14 membered heteroaryl;

at each occurrence, R3 is C1-8alkyl;

R4 is selected from hydrogen and C1-8alkyl;

R5 is selected from C1-8alkyl and C3-12cycloalkyl; or

R4 and R5 joined together with the carbon atom to which they are attached, form a 3-15 membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl wherein 3-15 membered heterocyclyl, C3-12cycloalkyl and 3-15 membered spirocyclyl are optionally substituted with one or more substituents selected from halogen and C1-8alkyl;

‘Y’ is absent or CR8R9;

R6 is selected from hydrogen and C1-8alkyl;

R7 is selected from C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxyC1-8alkyl, – CH2CH2NHC(O)CH=CH2, C3-12cycloalkyl, C3-12cycloalkylC1-8alkyl and 3-15 membered

heterocyclylalkyl; wherein C3-12cycloalkyl and C3-12cycloalkylC1-8alkyl is optionally substituted with C1-8alkyl and haloC1-8alkyl;

R8 is hydrogen;

R9 is hydrogen;

R10 is selected from hydrogen and C1-8alkyl;

R11 is selected independently from C1-8alkyl, haloC1-8alkyl, C6-14aryl, C6-14arylC1-8alkyl, 3-15 membered heterocyclylC1-8alkyl, C3-12cycloalkyl and C3-8cycloalkylC1-8alkyl; wherein C6- 14aryl, C6-14arylC1-8alkyl are optionally substituted with one or more substituents selected from halogen;

‘l’ is an integer ranging from 0 to 2, both inclusive;

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

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

‘r’ is an integer ranging from 0 to 4, both inclusive.

2. The compound of claim 1, having represented by formula (IA)

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, X, n, m and r are as defined in claim 1.

3. The compound of claim 1, having represented by formula (IB)

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein, R1, R2, R3, R4, R5, R10, R11, ring A, Y, n, m and r are as defined in claim 1.

4. The compound of claim 1, having represented by formula (IC)

or a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein, R1, R2, R3, R4, R5, R10, R11, Y, n, m and r are as defined in claim 1.

6. The compound according to any one of claims 1 to 5, wherein R2 is chloro, fluoro, – NHC(O)CH3 or –NHC(O)CH=CH2 and ‘m’ is 0 or 1.

7. The compound according to any one of claims 1 to 6, wherein R3 is methyl and ‘r’ is 1.

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

9. The compound according to any one of claims 1 to 8, wherein R4 is hydrogen or CH3.

10. The compound according to any one of claims 1 to 9, wherein R5 is CH3 or cyclobutyl.

11. The compound according to any one of claims 1 to 10, wherein R4 and R5 are CH3.

12. The compound according to any one of claims 1 to 8, wherein R4 and R5 joined together

13. The compound according to any one of claims 1 to 12, wherein R10 is hydrogen or methyl.

14. The compound according to any one of claims 1 to 4, wherein R11 is methyl, ethyl, difluoromethyl, difluoroethyl, trifluoroethyl, trifluoropropyl cyclopropyl, cyclopropylmethyl,

cyclopropylethyl or cyclobutylmethyl,

15. The compound according to any one of claims 1 to 3, wherein ring A
,

16. The compound according to any one of claims 1 to 3, wherein ring A is
.

17. The compound according to any one of claims 1, wherein ‘Z’ is C or N.

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

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

20. The compound according to claim 1, wherein

‘Z’ is CH or N;

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or

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

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl,

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

21. The compound according to claim 2, wherein

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or

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

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

22. The compound according to claim 3, wherein

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or

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

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

23. The compound according to claim 4, wherein

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

R3 is methyl;

Y is absent or CH2;

R4 is hydrogen or CH3;

R5 is CH3 or cyclobutyl; or

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

R10 is hydrogen or methyl;

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

cyclopropyl, cyclopropylmethyl, cyclopropylethyl or

‘l’ is 1;

‘n’ is 1;

‘m’ is 0 or 1; and

‘r’ is 1.

24. A compound selected from:

1-(Cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

1-(2,2-Difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-1-(2,2-Difluoroethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-1-(Cyclobutylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

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

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

N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(pyrrolidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-(morpholinomethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-((4,4-Difluoropiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 1-(Difluoromethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1, 2-dihydropyridine-3-carboxamide;

5-((3-Acetamidopiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

5-((3-Acetamidopiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

1-(2-Cyclopropylethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carboxamide;

(R)-5-((3-Fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-5-((3-Hydroxypyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-5-((3-Hydroxypyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-5-((3-Fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

1-(2-Cyclopropylethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-2-oxo-5-(piperidin-1-ylmethyl)-1,2-dihydropyridine-3-carbox amide;

(S)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide;

(S)-1-(Cyclopropylmethyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

(S)-1-(Cyclopropylmethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

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

(S)-1-(2-Cyclopropylethyl)-5-((3-fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-((4-Fluoropiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(R)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((2-methylmorpholino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-1-(2-Cyclopropylethyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

(S)-5-((3-Fluoropyrrolidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide;

5-((Isobutylamino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-((Isobutyl(methyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-(((oxetan-3-ylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-N-(2-fluoro-5-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-((3-Isopropylpiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

5-((3-Isopropylpiperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

(S)-5-((3-(hydroxymethyl)piperidin-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-(((2-Hydroxyethyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-(((2-Hydroxy-2-methylpropyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-(((2,2-Difluoroethyl)amino)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-N-(4-fluoro-3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-((4,4-Dimethyl-1,4-azasilinan-1-yl)methyl)-N-(3-(2-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)propan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-piperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-(((2-Hydroxy-2-methylpropyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-chloro-5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-chloro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1-methylcyclopropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((R)-3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1-methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-(((2-Ethylbutyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3-methylbutan-2-yl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((3-methylbutan-2-yl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

N-(5-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

N-(5-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

N-(3-(cyclobutyl(4-methyl-4H-1,2,4-triazol-3-yl)methyl)phenyl)-5-(((cyclopropylmethyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

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

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

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

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

N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-5-((tert-pentylamino)methyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

1-(Cyclopropylmethyl)-N-(2-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-((Ethylamino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

N-(3-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-chloro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(cyclopropylmethyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

1-(Cyclopropylmethyl)-5-(((cyclopropylmethyl)amino)methyl)-N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

1-(Cyclopropylmethyl)-5-(((cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

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

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

5-(((S)-3-Acrylamidopyrrolidin-1-yl)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

1-(2-Cyclopropylethyl)-5-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-5-(((S)-3-propionamidopyrrolidin-1-yl)methyl)-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

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

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

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

((S)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-((Isobutylamino)methyl)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-difluoro-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide; 5-((Isobutylamino)methyl)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

(S)-N-(3-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-(((2-Ethylbutyl)amino)methyl)-N-(3-(5-(4-methyl-4H-1,2,4-triazol-3-yl)Spiro[2.3]hexan-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

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

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

5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

N-(2-chloro-5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide;

1-(Cyclopropylmethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

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

1-(2,2-Difluoroethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((4-methyl-3-oxopiperazin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro pyridine-3-carboxamide;

1-(2-Cyclopropylethyl)-N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(5-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[2.3]hexan-5-yl)phenyl)-5-((neopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((1-methyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-fluoro-3-methylazetidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-Dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((1-methylcyclobutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

1-(2-Cyclopropylethyl)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((2-fluoro-2-methylpropyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutyl(methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

(S)-N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((3-methylpiperidin-1-yl)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-1-(oxetan-3-ylmethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-(1-(isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-1);

5-(1-(isobutylamino)ethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide (Isomer-2);

(+)N-(3-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(1-(isobutylamino)ethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

5-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(5-methyl-1H-imidazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-(3,3-dimethyl-1-(5-methyl-1H-imidazol-4-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

5-((Isobutylamino)methyl)-N-(3-(3-methyl-1-(5-methyl-1H-1,2,3-triazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide hydrochloride;

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

5-((Isobutylamino)methyl)-N-(3-((1r,3r)-3-methyl-1-(5-methyl-1H-1,2,3-triazol-4-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(3-acetamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide hydrochloride;

N-(3-acrylamido-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide 2,2,2-trifluoroacetate;

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

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

1-Ethyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-(((Cyclopropylmethyl)amino)methyl)-1-ethyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 5-(((3-Fluoro-3-methylbutyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

5-((Isobutylamino)methyl)-1-methyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

5-(((Cyclopropylmethyl)amino)methyl)-1-(2,2-difluoroethyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

1-(2,2-Difluoroethyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((3-fluoro-2,2-dimethylpropyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(2-fluoro-5-(2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(3,3,3-trifluoropropyl)-1,2-dihydropyridine-3-carboxamide;

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

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

1-Cyclopropyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((isobutylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-6-((isobutylamino)methyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide;

N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

N-(5-(6,6-dimethyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)-2-fluorophenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

5-((Isobutylamino)methyl)-N-(3-(6-methyl-2-(4-methyl-4H-1,2,4-triazol-3-yl)spiro[3.3]heptan-2-yl)phenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isobutylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-dimethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-(((3-fluoro-3-methylbutyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

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

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

N-(5-(3,3-diethyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-fluorophenyl)-5-((isopentylamino)methyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridine-3-carboxamide;

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

5-(((Cyclopropylmethyl)amino)methyl)-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

1-Cyclopropyl-N-(2-fluoro-5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((((1-(fluoromethyl)cyclopropyl)methyl)amino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide;

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

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

6-((Isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazine-2-carboxamide; and pharmaceutically acceptable salt thereof.

25. A compound of formula

or a pharmaceutically acceptable salt thereof.

26. A compound of formula

or a pharmaceutically acceptable salt thereof.

27. A compound of formula

or a pharmaceutically acceptable salt thereof.

28. A compound of formula

or a pharmaceutically acceptable salt thereof.

29. A compound of formula

or a pharmaceutically acceptable salt thereof.

30. A compound of formula

or a pharmaceutically acceptable salt thereof.

31. A compound of formula

or a pharmaceutically acceptable salt thereof.

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

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

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

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