Tead inhibitors and methods of use

Abstract

The present disclosure provides, in part, compounds of formula (I): wherein the variables are as defined herein, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat physiological disorders, such as proliferative disorders, mediated by TEA domain transcription factors.

Description

TEAD INHIBITORS AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 624,647, filed on January 24, 2024, the entire contents of which are incorporated herein by reference.SUMMARY OF THE DISCLOSURE

[0002] Disclosed herein, in certain embodiments, are compounds of formula (I) or formula (I- 1), e.g., compounds of formula (la), formula (la- 1), formula (lb), formula (Ib-1 ), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le) and / or formula (Ie-1) or pharmaceutically acceptable salts thereof. Additionally, disclosed herein, in certain embodiments, are compositions comprising a compound of formula (I) or formula (I- 1), e.g., compounds of formula (la), formula (la-1), formula (lb), formula (Ib-1 ), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le) and / or formula (Ie-1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further disclosed herein, in certain embodiments, are methods of inhibiting abnormal transcriptional enhanced associate (TEA) domain transcription factor (TEAD) transcriptional complex activity and thus treating certain diseases or disorders such as cancer characterized by abnormal TEAD transcriptional complex activity (e.g., hyperactivation).

[0003] Disclosed herein, in certain embodiments, are compounds of formula (I):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0004] Also, disclosed herein, in certain embodiments, are compounds of formula (1-1):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0005] Also, disclosed herein, in certain embodiments, are compounds of formula (la):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0006] Also, disclosed herein, in certain embodiments, are compounds of formula (lb):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0007] Also, disclosed herein, in certain embodiments, are compounds of formula (la- 1):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0008] Also, disclosed herein, in certain embodiments, are compounds of formula (Ib-1):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0009] Also, disclosed herein, in certain embodiments, are compounds of formula (Ic):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0010] Also, disclosed herein, in certain embodiments, are compounds of formula (Id):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0011] Also, disclosed herein, in certain embodiments, are compounds of formula (le):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0012] Also, disclosed herein, in certain embodiments, are compounds of formula (Ic-1):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0013] Also, disclosed herein, in certain embodiments, are compounds of formula (Id-1):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0014] Also, disclosed herein, in certain embodiments, are compounds of formula (Ie-1):or pharmaceutically acceptable salts thereof, wherein the variables are as defined herein.

[0015] In some embodiments, the compounds of formula (I), formula (I- 1), formula (la), formula (la-1 ), formula (lb), formula (Ib-1), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le) or formula (Ie-1) are selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof.

[0016] Also provided herein, in certain embodiments, are pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] Further disclosed herein, in certain embodiments, are methods of treating a disease or condition mediated by TEAD activity (e.g., dysregulation) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein or a pharmaceutical composition disclosed herein. In some embodiments, the disease or condition is a cancer characterized by abnormal TEAD transcriptional complex activity (e.g., hyperactivation).BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The disclosure can be more completely understood with reference to the following drawings.

[0019] FIG. 1 is a diagram showing the domain architecture of human TEAD1, TEAD2, TEAD3, and TEAD4. The percent values represent the identity of the N-terminal DNA binding domain (DNA-BD) and C -terminal YAP / TAZ binding domain (Y AP / TAZ-BD) of TEAD2-4 compared to the respective binding domains of TEAD 1. Post translation modifications including palmitoylation and phosphorylation as well as the p38 binding D domain of DNA-BD are also shown.

[0020] FIG. 2A is a diagram showing the upstream signaling and downstream transcriptional outputs of TEAD in cancer biology, which regulate critical functions in tumorigenesis, stem cell maintenance, cancer immunology , and metabolism, as well as formation of signaling feedback loops. Oncogenic signal transduction pathways include EGFR signaling, TGFβ signaling, WNt signaling, GPCR signaling, and cancer genes (indicated with *), such as KRAS, BRAF, LKB1, APC, and GNAQ / 11.

[0021] FIG. 2B is a diagram showing the role of TEAD in multiple stages of tumori genesis.DETAILED DESCRIPTION

[0022] Provided herein, in certain embodiments, are compounds and compositions, e.g., compounds of formula (I) or formula (I- 1), e.g., compounds of formula (la), formula (la-1), formula (lb), formula (Ib-1). formula (Ic). formula (Ic-1). formula (Id), formula (Id-1), formula (le) and / or formula (Ie-1), or pharmaceutically acceptable salts thereof. Further provided herein, in certain embodiments, are compositions comprising a compound of formula (I) or formula (I- 1), e.g.. compounds of formula (la), formula (la-1), formula (lb), formula (Ib-1), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le) and / or formula (Ie-1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Also provided herein, in certain embodiments, are methods of use of compounds and compositions disclosed herein. The contemplated compounds and compositions disclosed herein are inhibitors of transcriptional enhancer factor domain (TEAD) activity and thus are useful in methods of treating certain diseases or disorders such as cancer characterized by abnormal TEAD transcriptional complex activity (e.g., hyperactivation).Certain Terminology

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. Generally, nomenclatures utilized in connection with, and techniques of, immunology, oncology, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well-known and commonly used in the art. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0024] The articles “a” and “an” are used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.Chemical Definitions

[0025] Definitions of specific functional groups and chemical terms are described in more detail below.

[0026] In some embodiments, compounds described herein comprise one or more asymmetric centers, and thus exist in various isomeric forms, e.g.. enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0027] In some embodiments, compounds described herein also comprise one or more isotopic substitutions. For example, in some embodiments, H is in any isotopic form, including1H.2H (D or deuterium), and3H (T or tritium); C is any isotopic form, including12C,13C, and14C; O is in any isotopic form, including16O and18O; F is in any isotopic form, including18F and19F; and the like.

[0028] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example. “C1-6alkyl” is intended to encompass. C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0029] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1-C20 alkyl"). In some embodiments, an alky l group has 1 to 10 carbon atoms (“C1-C10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-C9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-C7 alkyl”). In some embodiments, an alky l group has 1 to 6 carbon atoms (“C1-C6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of C1-C6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0030] As used herein, “alkylene,” refers to a divalent radical of an alkyd group. When a range or number of carbons is provided for a particular “alky lene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. In some embodiments, “alkylene” group is substituted or unsubstituted with one or more substituents as described herein.

[0031] As used herein, “heteroaryl” refers to a monovalent radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits.

[0032] As used herein, “heteroarylene” refers to a divalent radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroarylene” or “5-6 membered heteroarylene”). In some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits.

[0033] In some embodiments, a heteroary l or heteroaiylene group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroary l” or “5-6 membered heteroarylene”). In some embodiments, the 5-6membered heteroaryl or 5-6 membered heteroarylene has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl or 5-6 membered heteroarylene has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl or 5-6 membered heteroarylene has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0034] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazoly 1, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing tw o heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6- membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.

[0035] Exemplary 5-membered heteroarylene groups containing one heteroatom include, without limitation, pyrrolylene, furanylene and thiophenylene. Exemplary 5-membered heteroary lene groups containing two heteroatoms include, without limitation, imidazolylene, pyrazolylene, oxazolylene, isoxazolylene, thiazolylene, and isothiazolylene. Exemplary 5- membered heteroarylene groups containing three heteroatoms include, without limitation, triazolylene, oxadiazolylene, and thiadiazolylene. Exemplary 5-membered heteroarylene groups containing four heteroatoms include, without limitation, tetrazolylene. Exemplary 6-membered heteroarylene groups containing one heteroatom include, without limitation, pyridinylene. Exemplary 6-membered heteroarylene groups containing two heteroatoms include, without limitation, pyridazinylene, pyrimidinylene, and pyrazinylene. Exemplary 6-membered heteroary lene groups containing three or four heteroatoms include, without limitation, triazinylene and tetrazinylene, respectively.

[0036] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C5-C7cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cycloheptanes, cyclohexanes, cyclopentanes, cyclobutanes, and cyclopropanes.

[0037] The term “carbocyclyl” or “carbocyclic” refers to a radical of an aromatic or non- aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“3-10 membered carbocyclic ring”) and zero heteroatoms in the aromatic or non-aromatic ring system. In some embodiments, “carbocyclyl” or “carbocyclic” ring is a “3-7 membered carbocyclic ring.”

[0038] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”). and is saturated or is partially unsaturated. In some embodiments, heterocyclyl bicyclic ring systems include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more phenyl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring.” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably.

[0039] In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-6 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen.oxygen, and sulfur (‘"5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0040] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. In some embodiments, hetero is applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalky l; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0041] The terms “halo’" and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo. -Br), and iodine (iodo. -I). In certain embodiments, the halo group is either fluoro or chloro.

[0042] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0043] The term “oxo” as used herein refers to =0.

[0044] In general, the term “substituted,” whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by- rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0045] Nitrogen atoms are substituted or unsubstituted as valency permits, and include primary-, secondary, tertiary, and quaternary nitrogen atoms.

[0046] These and other exemplary substituents are described in more detail in the Detailed Description. Examples, and Claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.Other Definitions

[0047] As used herein, “pharmaceutically acceptable excipient” refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient(s). Exemplary pharmaceutical excipients include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient acceptability. They may also assist in product identification or enhance the overall safety or function of the product during storage or use.

[0048] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0049] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant,child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient.” “individual” and “subject” are used interchangeably herein. None of the terms require the supervision of medical personnel.

[0050] The terms “disease”, “disorder”, and “condition” are used interchangeably herein.

[0051] As used herein, and unless otherwise specified, the terms “treat.” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slow s the progression of the disease, disorder or condition.

[0052] As used herein, and unless otherwise specified, a “therapeutically effective amount” or an “effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount or an effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. In some embodiments, the term “therapeutically effective amount” or “effective amount” encompasses an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.Compounds

[0053] Disclosed herein, in certain embodiments, are compounds of formula (I):, or pharmaceutically acceptable salts thereof. wherein:X is selected from the group consisting of NRa, O, and S;Y and Z are each independently selected from N and CR4;Ring A is selected from 3-6 membered saturated heterocyclyl and 3-10 membered carbocyclyl, wherein the 3-6 membered saturated heterocyclyl has one. two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S;Ring B is a 5-10 membered heteroarylene having one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S; wherein the 5-10 membered heteroarylene is optionally substituted;R1is 3-10 membered heterocyclyl or -(C1-C4alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl has one. two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S and is optionally substituted, wherein the C1-C4alkylene is optionally substituted; each R2is independently selected from the group consisting of halogen, -C1-C6alkyl, and -C1-C6haloalkyl; or two R2attached to the same carbon atom, together with the carbon atom to which they are attached, combine to form cyclopropyl as valency permits; each R3is independently selected from halogen and -C1-C6alkyl; each R4is independently selected from halogen and -C1-C6alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; andRais selected from hydrogen and -C1-C6alkyl; provided that when Ring A is phenyl, Ring B is not 1,3,4-oxadiazolylene or tetrazolylene, and provided that when Z is N, Y is N.

[0054] Also disclosed herein, in certain embodiments, are compounds of formula (I-1):. or pharmaceutically acceptable salts thereof, wherein:Y and Z are each independently selected from N and CR4;W is selected from CH2and O;Ring A is selected from 3-6 membered saturated heterocyclyl and 3-10 membered carbocyclyl, wherein the 3-6 membered saturated heterocyclyl has one. two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S;Ring B is a 5-6 membered monocy clic heteroarylene having one, two, three, or four heteroatoms each independently selected from the group consisting of N. O, and S: wherein the 5-6 membered monocyclic heteroarylene is optionally substituted; each R2is independently selected from the group consisting of halogen. -C1-C6alkyl, and -C1-C6haloalkyl; or two R2attached to the same carbon atom, together with the carbon atom to which they are attached, combine to form cyclopropyl as valency permits; each R3is independently selected from halogen and -C1-C6alkyl; each R4is independently selected from halogen and -C1-C6alkyl; each R5is independently selected from hydrogen and halogen; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; t is 1, 2, or 3; u is 0, 1, or 2;v is 0, 1, or 2;Rais selected from hydrogen and -C1-C6alky l; andReis C1-C6alkyl, provided that when Ring A is phenyl, Ring B is not 1,3,4-oxadiazolylene or tetrazolylene, and provided that when Z is N. Y is N.

[0055] In some embodiments, Ring A is selected from phenyl and C5-C7 cycloalkyl. In some embodiments. Ring A is phenyl. In some embodiments. Ring A is C5-C7 cycloalkyl.

[0056] In some embodiments. Ring A is selected from the group consisting of phenyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[l.l.l]pentanyl, and azetidinyl. In some embodiments, Ring is selected from the group consisting of cyclopentyl, cyclohexyl, and cycloheptyl. In certain embodiments, Ring A is cyclohexyl.

[0057] In some embodiments, the compounds are compounds of formula (la): , or pharmaceutically acceptable salts thereof.

[0058] In some embodiments, the compounds are compounds of formula (lb):, or pharmaceutically acceptable salts thereof.

[0059] In some embodiments, the compounds are compounds of formula (la- 1):or pharmaceutically acceptable salts thereof.

[0060] In some embodiments, the compounds are compounds of formula (Ib-1):, or pharmaceutically acceptable salts thereof.

[0061] In some embodiments, the compounds are compounds of formula (Ic): or pharmaceutically acceptable salts thereof.

[0062] In some embodiments, the compounds are compounds of formula (Id) or (le):pharmaceutically acceptable salts thereof.

[0063] In some embodiments, the compounds are compounds of formula (Id):, or pharmaceutically acceptable salts thereof.

[0064] In some embodiments, the compounds are compounds of formula (le):, or pharmaceutically acceptable salts thereof.

[0065] In some embodiments, the compounds are compounds of formula (Ic-1):, or pharmaceutically acceptable salts thereof.

[0066] In some embodiments, the compounds are compounds of formula (Id-1) or (Ie-1):or, or pharmaceutically acceptable salts thereof.

[0067] In some embodiments, the compounds are compounds of formula (Id-1):, or pharmaceutically acceptable salts thereof.

[0068] In some embodiments, the compounds are compounds of formula (Ie-1): , or pharmaceutically acceptable saltsthereof.

[0069] In some embodiments, Ring B is 5-6 membered monocyclic heteroarylene that is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from halogen and -C1-C6alkyl. In some embodiments, Ring B is 5-6 membered heteroarylene that is unsubstituted.

[0070] In some embodiments, Ring B is selected from the group consisting of oxadiazolylene. imidazolylene, pyrazolylene, triazolylene, and tetrazolylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from halogen and C1-C6alkyl. In certain embodiments, Ring B is selected from oxadiazolylene and imidazolylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from halogen and C1-C6alkyl.

[0071] In some embodiments, Ring B is selected from the group consisting of oxadiazolylene. imidazolyl ene, pyrazolylene, triazolylene, and tetrazolylene, each of which is unsubstituted. In certain embodiments, Ring B is selected from oxadiazolylene and imidazolylene, each of which is unsubstituted.

[0072] In some embodiments, Ring B is selected from the group consisting of

[0073] In some embodiments, R1is 5 to 6-membered heterocyclyl having one or two heteroatoms, wherein the 5 to 6-membered heterocyclyl is optionally substituted with 1, 2. or 3 substituents each independently selected from C1-C6alkyl and oxo. In some embodiments, R1is -(C1-C4alkylene)-(5 to 6-membered heterocyclyl having one or two heteroatoms, wherein the 5 to 6-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from C1-C6alkyl and oxo.

[0074] In some embodiments, R1iswherein u is 0. 1 , or 2.

[0075] In some embodiments, R1is

[0076] In some embodiments, R1is

[0077] In some embodiments, Reis methyl. In some embodiments, u is 0 and Reis methyl.

[0078] In some embodiments, each R2is independently selected from the group consisting of fluoro, methyl, and trifluoromethyl. In some embodiments, each R2is fluoro. In some embodiments, each R2is methyl.

[0079] In some embodiments, R3is C1-C6alkyl. In some embodiments, R3is methyl.

[0080] In some embodiments, Z is CH. In some embodiments. Z is N.

[0081] In some embodiments, m is 1 or 2. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0082] In some embodiments, n is 0. In some embodiments, n is 1. and R3is C1-C6alkyl, e.g.. methvl.

[0083] In some embodiments, t is 1.

[0084] In some embodiments, u is 0.

[0085] In some embodiments, v is 1.

[0086] In some embodiments, W is CH2. In some embodiments, W is O.

[0087] In some embodiments, Rais hydrogen.

[0088] In some embodiments, Ring A is phenyl and Ring B is not 1 ,2,4-oxadiazolylene.

[0089] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof.Table 1. List of compounds.Compound SynthesisGeneral Synthetic Schemes

[0090] Exemplary methods for preparing compounds described herein (e.g.. a compound of formula (I), formula (1-1 ), formula (la), formula (la- 1 ), formula (lb), formula (Ib-1 ), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le), or formula (Ie-1 )) are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the scope of the disclosure, and should not be regarded in any manner as limiting the scope or the spirit of the claimed invention.Scheme AScheme BScheme CScheme DScheme EScheme F

[0091] In addition to the general synthetic schemes, specific syntheses of the compounds disclosed herein are set forth in the various Examples.Pharmaceutical Compositions and Routes of Administration

[0092] Disclosed herein, in certain embodiments, are pharmaceutical compositions comprising: (a) a compound disclosed herein (e.g., a compound of formula (I), formula (I- 1), formula (la), formula (la-1 ), formula (lb), formula (Ib-1), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le), or formula (Ie-1) or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient. In some embodiments, the excipient is selected from: inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. In some embodiment, the pharmaceutical compositions are administered alone or in combination with other therapeutic agents. Such compositions are prepared in any suitable manner.

[0093] In some embodiments, the pharmaceutical compositions are administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery- inserted cylindrical polymer.

[0094] One mode for administration is parenteral, particularly by injection. In some embodiments, the forms in which the novel compositions of the present disclosure are incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oik or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also used for injection. In some embodiments, ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils are employed. In some embodiments, the proper fluidity is maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In some embodiments, the prevention of the action of microorganisms is brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0095] Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously stenle-filtered solution thereof.

[0096] Oral administration is another route for administration of the compounds disclosed herein. In some embodiments, administration is via capsule or enteric coated tablets, or the like. In some embodiments, in making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that is in the form of a capsule, sachet, paper or other container. In some embodiments, when the excipient serves as a diluent, it is in the form of a solid, semi- solid, or liquid material (as above), which acts as a vehicle, earner or medium for the activeingredient. Thus, in some embodiments, the compositions are e in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0097] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. In some embodiments, the formulations additionally include; lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0098] In some embodiments, the compositions of the disclosure are formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). In some embodiments, such transdermal patches are used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts. The construction and use of transdermal patches for the delivery' of pharmaceutical agents is well known in the art. In some embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0099] The compositions are preferably formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantify of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, theage, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0100] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. In some embodiments, when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0101] In some embodiments, the tablets or pills of the present disclosure are coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, in some embodiments, the tablet or pill comprises an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. In some embodiments, the two components are separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. In some embodiments, a variety of materials are used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0102] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. In some embodiments, the liquid or solid compositions contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In some embodiments, compositions in pharmaceutically acceptable solvents are nebulized by use of inert gases. In some embodiments, nebulized solutions are inhaled directly from the nebulizing device or the nebulizing device is attached to a facemask tent, or intermittent positive pressure breathing machine. In some embodiments, solution, suspension, or powder compositions are administered, orally or nasally, from devices that deliver the formulation in an appropriate manner.Methods of Treatment

[0103] Disclosed herein, in certain embodiments, are methods of treating a disease or disorder modulated by abnormal activity of a TEAD isoform (e.g., TEAD1 and / or TEAD4) (e.g., hyperactivation of TEAD transcriptional complex) in an individual in need thereof, comprisingadministering to the individual a compound of formula (I), formula (1-1), formula (la), formula (la-1), formula (lb), formula (Ib-1), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le) or formula (Ie-1), or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of a compound of formula (I), formula (1-1), formula (la), formula (la-1). formula (lb), formula (Ib-1). formula (Ic). formula (Ic-1). formula (Id), formula (Id-1), formula (le), or formula (Ie-1), or a pharmaceutically acceptable salt thereof).

[0104] TEA domain transcription factors (TEADs) are downstream effectors of the Hippo signaling pathway. Currently, four isoforms of TEAD have been identified - TEAD1, TEAD2, TEAD3, and TEAD4. The TEAD isoforms share highly similar structures. The N-terminus of the four isoforms share a highly conserved 68-amino acid TEA / ATTS DNA-binding domain, which binds to the MCAT element (50 -CATTCCA / T-30). The C -terminus contains the transactivation domain which recruits transcriptional coactivators YAP / TAZ.

[0105] The expression of TEAD proteins is up-regulated in many cancer types including gastric, colorectal, breast, and prostate cancers. TEAD hyperactivation plays a role in tumor progression, metastasis, cancer metabolism, immunity, and dmg resistance and is correlated with poor survival in patients.

[0106] Selective binding of TEAD 1 and / or TEAD4 is beneficial for optimizing anti-tumor efficacy while minimizing undesired effects. Inhibition of TEADS has been associated with off- target toxicity (e.g., kidney toxicity), while inhibition of TEAD2 may be pro-proliferative.

[0107] In some embodiments, the compounds disclosed herein selectively bind one or more TEAD isoforms. In certain embodiments, the compounds disclosed herein selectively bind TEAD1. In certain embodiments, the compounds disclosed herein selectively bind TEAD4. In certain embodiments, the compounds disclosed herein selectively bind TEAD1 and TEAD4. In some embodiments, the binding selectivity for TEAD1 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold over TEAD2 and / or TEADS. In some embodiments, the binding selectivity for TEAD4 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold over TEAD2 and / or TEADS.

[0108] In some embodiments, the compounds disclosed herein are useful as a medical therapy for treating a disease or condition mediated by hyperactivation of YAP / TAZ-TEAD (e.g., TEAD1 and / or TEAD4) transcriptional co-activator complex. In some embodiments, the compounds disclosed herein are useful as a medical therapy for treating a disease or condition characterized by the hyperactivation of TEAD (e.g., TEAD1, TEAD2, TEADS, and TEAD4 isoforms). In some embodiments, the disease or condition is characterized by the overexpression or genomic fusion or amplification of TEAD. TEAD1 and TEAD4 experience recunent onco-fusions; for example, TEAD1-PARVA. These fusions drive higher expression of TEADs and may result in enhanced transcription of TEAD-target genes. Amplifications (genomic copy number gains) of TEAD4 occur in diverse cancers as part of the 12p13 locus in, e.g., ovarian and uterine carcinoma as well as testicular germ cell tumors. These genomic amplifications of TEAD4 are associated with strong increase in its mRNA expression and may drive high TEAD- YAP / TAZ transcriptional activity.

[0109] In certain embodiments, the TEAD isoform is TEAD1. In certain embodiments, the TEAD isoform is TEAD4. In some embodiments, the disease, disorder or condition is a cancer characterized by abnormal TEAD transcriptional complex activity' (e.g., hyperactivation). Such cancers include but are not limited to breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular cancer, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastomas. In some embodiments, the cancer is selected from pancreatic adenocarcinoma, hepatocellular cancer, breast cancer, and malignant mesothelioma. In certain embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is malignant mesothelioma.

[0110] Also provided herein is a compound or pharmaceutically acceptable salt disclosed herein, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

[0111] In another aspect, provided herein is use of a compound or pharmaceutically acceptable salt disclosed herein, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a disease or disorder mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

[0112] In some embodiments, the cancer is a breast cancer. In some embodiments, the cancer is a lung cancer. In some embodiments, the cancer is a gastric cancer. In some embodiments, the cancer is a colorectal cancer. In some embodiments, the cancer is a prostate cancer. In some embodiments, the cancer is a head and neck cancer. In some embodiments, the cancer is a renal cell carcinoma. In some embodiments, the cancer is a medulloblastoma. In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the cancer is a hepatocellular cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a metastatic breast cancer. In some embodiments, the cancer is a metastatic lung cancer. In some embodiments, the cancer is a metastatic gastric cancer. In some embodiments, the cancer is a metastatic colorectal cancer. In some embodiments, the cancer is a metastatic prostate cancer. Insome embodiments, the cancer is a metastatic head and neck cancer. In some embodiments, the cancer is a metastatic renal cell carcinoma. In some embodiments, the cancer is a metastatic mesothelioma. In some embodiments, the cancer is a metastatic pancreatic cancer. In some embodiments, the cancer is a metastatic hepatocellular cancer.

[0113] In some embodiments, the disclosure provides for compounds of formula (I), formula (1-1). formula (la), formula (la- 1), formula (lb), formula (Ib-1), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le), or formula (Ie-1) for modulating TEAD activity. In some embodiments, the disclosure provides for pharmaceutically acceptable salts of compounds of formula (I), formula (1-1), formula (la), formula (la- 1), formula (lb), formula (Ib-1), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le), or formula (Ie-1) for modulating TEAD activity.

[0114] In some embodiments, the disclosure provides for compounds of formula (I), formula (1-1), formula (la), formula (la-1), formula (lb), formula (Ib-1), formula (Ic), formula (Ic-1), formula (Id), formula (Id-1), formula (le), or formula (Ie-1) or pharmaceutically acceptable salts thereof for use in medical therapy.

[0115] In some embodiments, the compounds and pharmaceutically acceptable salts thereof or pharmaceutical compositions disclosed herein are administered alone or in combination with one or more other therapeutic agents. In some embodiments, the other therapeutic agent is any suitable chemotherapeutic agent. In some embodiments, the one or more other therapeutic agents are selected from modulators of other transcription factors. In some embodiments, the modulators of other transcription factors are selected from modulators of YAP, modulators of EGFR, or modulators of MEK.

[0116] In some embodiments, the one or more other therapeutic agents are administered concurrently with the compounds or pharmaceutically salts thereof or pharmaceutical compositions disclosed herein. In some embodiments, the one or more other therapeutic agents are administered sequentially with the compounds or pharmaceutically salts thereof or pharmaceutical compositions disclosed herein. In some embodiments, the one or more other therapeutic agents are administered before the compounds or pharmaceutically salts thereof or pharmaceutical compositions disclosed herein. In some embodiments, the one or more other therapeutic agents are administered after the compounds or pharmaceutically salts thereof or pharmaceutical compositions described disclosed.EXAMPLES

[0117] The present disclosure will be further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the disclosure in any way.

[0118] While specific embodiments of the invention have been described here in for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.AbbreviationsAnalytical Methods

[0119] Commercially available starting materials, reagents and dry solvents were used as supplied. Flash column chromatography or glass column chromatography was performed using Merck silica gel 230-400 mesh size. Flash chromatography was also performed on combi-flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.Liquid Chromatography-Mass Spectrometry MethodsMETHOD-A

[0120] Method Name: - UC02 FAR1, Machine Details: - Water Acquity UPLC- H Class equipped with PDA and Acquity SQ detector, Column: Waters X-bridge Cl 8, 50*2. 1 mm, 2.5 micron, Column temperature: 35 °C, Auto sampler temperature: 15 °C. Mobile Phase A; 0. 1 % Formic acid in Milli Q water (PH = 2.70), Mobile Phase B: 0. 1% Formic acid in Milli Q water: Acetonitrile (10:90); Mobile phase gradient details: : T = 0 min (97% A, 3% B) flow : 0.8 rnL / min; T = 0.75 min (97% A, 3% B) flow : 0.8 mL / min; gradient to T = 2.7 min (2% A, 98% B) flow : 0.8 mL / min; gradient to T = 3 min (0% A, 100% B) flow : 1 rnL / min; T = 3.5 min (0% A, 100% B) flow : 1 mL / min; gradient to T= 3.51 min (97% A, 3% B) flow : 0.8 mL / min; end of run at T = 4 min (97% A, 3% B), Flow rate: 0.8 mL / min. Flow rate:- 0.8 mL / min, Run Time:- 4 min, UV Detection Method:- PDA, Wavelength:- 200-500 nm; Mass parameter: Probe: -ESI, Mode of Ionisation; - positive and negative, Cone voltage: -30 V and 10 V. capillary voltage: - 3.0 KV, Extractor Voltage: - 1 V, Rf Lens: - 0. 1 V, Temperature of source:-120 °C, Temperature of Desolvation:- 400 °C. Cone Gas Flow: - 100 L / hour, Desolvation Gas flow:-800 L / hour.METHOD-B

[0121] Method Name:-UC03_ABR2, Machine Details: - Waters Acquity Ultraperfomance LC connected with PDA and equipped with SQ detector, Column: Waters X-bridge C18, 50*4.6 mm, 3.5 micron, Column temperature: 35 °C, Auto sampler temperature: 15 °C, Mobile Phase A: 5 mM Ammonium Bicarbonate (pH = 8.00) in Milli Q water, Mobile Phase B: Acetonitrile; Mobile phase gradient details: T = 0 min (97% A. 3% B) Flow rate = 1.0 mL / min. T = 0.20 min (97% A, 3% B) Flow rate = 1.0 rnL / min; gradient to T = 2.70 min (20% A, 80% B) Flow rate = 1.0 mL / min; gradient to T = 3.0 min (0% A, 100% B) Flow rate = 1.2 mL / min; T = 3.50 min (0% A, 100% B) Flow rate = 1.2 rnL / min; T = 3.51 min (97% A, 3% B) Flow rate = 1.0 mL / min; end of run at T = 4.0 min (97% A, 3% B) Flow rate = 1.0 mL / min, Run Time:- 4 min, UV Detection Method:- PDA, Wavelength:- 195 nm - 500 nm; Mass parameter: Probe:-ESI, Mode of Ionisation: - Positive and Negative, Cone voltage :-30 and 10 V, capillary voltage:- 3.0 KV,Extractor Voltage:-2 V, Rf Lens:- 0.1 V, Temperature of source:-120 °C, Temperature of Probe:- 400 °C, Cone Gas Flow:- 100 L / Hr, Desolvation Gas flow:-800 L / Hr.High-performance liquid chromatography MethodsMethod-A

[0122] Method Name: - HP04 BR1 Machine Details: - Water alliance e2695 with 2998 PDA detector, Column temperature: 25 °C, Auto sampler temperature: 25 °C, Mobile Phase A: 0.1% ammonium hydroxide solution in HPLC water Mobile Phase B: 100% ACETONITRILE;Mobile phase gradient details: T = 0 min (10% A, 90% B) flow : 1 mL / min; T = 7 min (90% A, 10% B) flow : 1 mL / min; gradient to T = 9 min (100% A, 0% B) flow : 1 mL / min; gradient to T = 14 min (100% A, 0% B) flow : 1 mL / min; T = 14.01 min (10% A, 90% B) flow : 1 mL / min; gradient to T= 17 min (10% A, 90% B) flow : 1 mL / min; end of run at T = 17 min (10% A, 90% B), Flow rate: 1 mL / min, Run Time:- 17 min, UV Detection Method: - PDA.Method-B

[0123] Method Name: - HP05 TF ARI. Machine Details: AGILENT TECHNOLOGY 1260 infinity series with PDA detector, Column temperature: 25 °C, Auto sampler temperature: 25 °C, Mobile Phase A; 0.05% Trifluoroacetic acid in HPLC water Mobile Phase B: 100% Acetonitrile; Mobile phase gradient details T = 0 min (90% A, 10% B) flow: 1 mL / min; T = 7 min (10% A, 90% B) flow : 1 mL / min; gradient to T = 9 min (0% A, 100% B) flow : 1 mL / min; gradient to T = 14 min (0% A, 100% B) flow' : 1 mL / min; T = 14.01 min (90% A, 10% B) flow : 1 mL / min; gradient to T= 17 min (90% A, 10% B) flow : 1 mL / min; end of run at T = 17 min (90% A. 10% B), Flow rate: 1 mL / min, Run Time:- 17 min, UV Detection Method;- PDA.Method-C

[0124] Method Name; HP06 TFAR1 Machine Details: - AGILENT TECHNOLOGY 1100 series with PDA detector, Column temperature; 25 °C, Auto sampler temperature: 25 °C, Mobile Phase A: 0.05% Trifluoroacetic acid in HPLC water Mobile Phase B: 100% Acetonitrile;Mobile phase gradient details T = 0 min (90% A, 10% B) flow: 1 mL / min; T = 7 min (10% A, 90% B) flow: 1 mL / min; gradient to T = 9 min (0% A, 100% B) flow: 1 mL / min; gradient to T = 14 min (0% A, 100% B) flow; 1 mL / mm; T = 14.01 min (90% A, 10% B) flow; 1 mL / min; gradient to T= 17 min (90% A, 10% B) flow: 1 mL / min; end of run at T = 17 min (90% A, 10% B), Flow rate: 1 mL / min, Run Time: - 17 min, UV Detection Method: - PDANMR

[0125] 1H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker Avance-400 instrument operating at 400 MHz using the stated solvent at room temperature unless otherw ise stated. Samples w ere prepared as solutions in a suitable deuterated solvent and referenced to the appropriate internal non-deuterated solvent peak or tetramethylsilane.Chemical shifts were recorded in ppm (5) downfield of tetramethylsilane. In all NMR data w ere consistent with the proposed structures. Characteristic chemical shifts (5) are given in parts-per- million using conventional abbreviations for designation of major peaks: e.g., s = singlet; d = doublet; t = triplet; q = quartet; dd = doublet of doublets; dt = doublet of triplets; m = multiplet; br = broad; br s = broad singlet.Purification methods

[0126] Preparative purification by reversed phase HPLCPreparatory HPLC Method-A

[0127] Biotage-FC-01 with binary pump with UV / Visible wave-length detector, Column: YMC, 120 g, 50 pm, column temperature; room temp., mobile phase A: 0. 1% formic acid in water, mobile phase B: Acetonitrile; mobile phase gradient details: t = 0.01 min (100% A, 0% B); t = 3 min (85% A, 15% B); gradient to t = 25 min (55% A, 45% B); t = 35 min (0% A, 100% B); gradient to end of run at t = 45 min (100% A, 0% B); flow rate: 80 mL / min, analysis time 45 min.Synthesis:

[0128] Several methods for the chemical synthesis of compounds of the present application are described herein. These and / or other well-known methods may be modified and / or adapted in various ways to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure.General Scope of the Work:

[0129] The following compounds were prepared according to the methods described below inExample 1 - Example 33 below.EXAMPLE 1 - Preparation of (3-(5-(2-((4,4-difhiorocyclohexyl) amino) pyridin-3-yl)- l,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 1, Compound 2, Compound 3)Step 1 : Synthesis of Intermediate 1-Al: Methyl 2-((4,4-difluorocyclohexyl) amino) nicotinate:

[0130] To a stirred solution of Methyl 2-chloronicotinate (CAS:40134-18-7) (5.0 g, 26.93 mmol, 1.0 eq) in DMSO (50 mL) was added Et3N (10.88 g, 107.72 mmol, 4.0 eq) and stirred for10 min. at rt. After 10 minutes, 4,4-difluorocyclohexan-l-amine hydrochloride (6.93 g, 40.37 mmol, 1.5 eq) was added to the reaction mixture and stirred at 140 °C for 16 h. The reaction wasmonitored through the TLC (Using 10% EtOAc: hexane as a mobile phase) which showed complete consumption of SM. The reaction w as diluted with water (50 mL) and extracted with EtOAc (2 x 200 mL). The separated combined organic layers were dried over anhydrous Na2SO4, concentrated under reduced pressure to afford the title compound as methyl 2-((4.4- difluorocyclohexyl) ammo) nicotinate (2.0 g, 7.39 mmol. Yield: 27.47%) (Note: crude obtained w as used as such for next step without any further purification)LCMS (Method A): 2.165 mm, 80.24%, 254.0 nm, MS: ES+ m / z 270.85 [M+1]Step 2: Synthesis of Intermediate 1-A2: 2-((4.4-difluorocvclohexyl) amino) nicotinohydrazide:

[0131] To a stirred solution of methyl 2-((4.4-difluorocyclohexyl) amino) nicotinate Intermediate 1-Al (2.0 g, 7.39 mmol, 1.0 eq) in MeOH (20 mL) was added Hydrazine hydrate (3.69 g, 73.8 mmol, 10.0 eq) and stirred at 90 °C for 16 h. The completion of reaction was indicated by TLC (70% EtOAc: hexane as a mobile phase) and resulting reaction mixture was concentrated under reduced pressure to afford the crude. The crude residue was further diluted with water (50 mL) and extracted with 10% MeOH: DCM, (100 mL), combined organic layers were dried over anhydrous Na2SO4, concentrated under reduced pressure to afford the title compound 2-((4,4-difluorocyclohexyl) amino) nicotinohydrazide as off w hite solid (Intermediate 1-A2) (1.2 g, 4.43 mmol, Yield; 63.15%). (Note: crude obtained was used as such for next step without any further purification)LCMS (Method A): 1.129 min, 88.95%. 254.0 nm, MS: ES+ m / z 271.15 [M+1]Step 3; Synthesis of Intermediate 1-A3: 2-((4,4-difluorocvclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide:

[0132] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (1.05 g, 7.34 mmol, 2.0 eq) in DMF (10 mL) were added EDC.HC1 (4.25 g, 22. 16 mmol, 6.0 eq), HOBt (3.41 g, 22.18 mmol, 6.0 eq) and DIPEA (3.81 g, 29.53 mmol, 8.0 eq) at 0 °C. The resulting reaction mixture w as stirred at rt for 20 minutes, followed by addition of 2-((4,4-difluorocyclohexyl) amino) nicotinohydrazide (Intermediate 1-A2) (1.0 g, 3.69 mmol. 1.0 eq) and reaction mixture was stirred at rt for 6 h. The completion of reaction was monitored by TLC (0.5:9.5 MeOH: DCM, as a mobile phase) then the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (2 x 100 mL). The separated organic layers were washed with ice-cold water (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude which was purified by flash column chromatography using silica gel 230-400 mesh size. The gradient 2.5% MeOH in DCM provided the title compound 2-((4.4-difluorocyclohexyl) amino)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) nicotine hydrazide as a yellow solid (0.40 g, 1.01 mmol, Yield: 27.34%).1H NMR (DMSO-d6, 400 MHz): δ ppm 10.38 (s, 1H), 9.59 (s, 1H), 8.21 - 8.17 (m, 2H), 8.00- 7.98 (m, 2H), 6.60 (dd, J = 7.6, 4.8 Hz, 1H), 4.13-4.09 (m, 1H), 3.22 (t, J = 6.8 Hz, 2H), 2.02- 1.89 (m, 8H), 1.52-1.48 (m, 2H), 1.38 (s, 3H).LCMS (Method A): 1.365 min, 92.71%, 254.0 nm, MS:ES+ m / z 396.27 (M+l)Step 4: Synthesis of 3-(5-(2-((4,4-difluorocvclohexyl) amino) pyridin-3-yl)-1.3.4-oxadiazol-2- vl)-3-methvlpyrrolidin-2-one (Compound 1);

[0133] To a stirred solution of 2-((4,4-difluorocyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (Intermediate 1-A3) (0.20 g, 0.50 mmol, 1.0 eq) in DCM (2 mL) were added Et3N (0. 153 g, 0.60 mmol. 3.0 eq) and 4-Toluenesulfonyl chloride (0.97 g, 0.60 mmol, 1 .2 eq) then resulting reaction mixture was stirred at rt for 2 h. The completion of reaction was monitored by TLC (0.5:9.5 MeOH: DCM as a mobile phase). After completion, reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL x 2). The separated organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the cmde as a yellow oil. The crude was purified by flash column chromatography with using silica gel (230-400 mesh) and gradient 90% EtOAc in hexane afforded the title compound as a yellow solid (0.110 g, 0.29 mmol, Yield: 57.89%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.31 (dd, J = 4.8, 2.0Hz, 1H), 8.19 (s, 1H), 8.07 (dd, J = 7.6, 2.0 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H). 6.79 (dd, J = 8.0, 4.8 Hz, 1H), 4.28-4.26 (m, 1H), 3.44-3.36 (m, 2H), 2.78-2.71 (m, 1H), 2.24- 2.18 (m, 1H), 2.07-2.01 (m, 6H), 1.66-1.49 (m, 5H).LCMS (Method A): 1.812 min, 100%. 254.0 nm, MS: ES+ m / z 378.27 [M+1]HPLC (Method A): 5.811 min, 95.24%, 210 nmStep 5: Chiral separation of racemate Compound 1; Synthesis of 3-(5-(2-((4,4- difluorocyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 2 and Compound 3)

[0134] COLUMN ID: CHIRALPAK IA 250X50 mm 5 um

[0135] MOBILE PHASE A: 0.1% M. NH3in Heptane

[0136] MOBILE PHASE B; 0.1% M. NH3IN IPA-ACN (50-50)

[0137] FLOW RATE (ML / MIN); 40

[0138] INSTRUMENT ID: PHP-04-AGILENT 1260 SERIES, INFINITY-II WITH 2489 UVDetector

[0139] METHOD; TIME; FLOW; %A; %B (0.01:40:70:30), (40:40:70:30)

[0140] Input Quantity; 0.100 g.

[0141] Output Quantity: Compound 2 = 0.035 (%Yield = 35.00%) and Compound 3 = 0.036 g (%Yield = 36.00 %)Compound 21H NMR (DMSO-d6, 400 MHz): δ ppm, 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (brs, 1H), 8.07 (dd, J= 7.6, 1.6 Hz, 1H), 7.79 (d. J 7.2 Hz, 1H), 6.80-6.77 (m, 1H), 4.26 (brs. 1H), 3.43-3.36 (m. 2H), 2.78-2.71 (m. 1H), 2.25-2.18 (m. 1H), 2.07-2.02 (m. 6H), 1.63-1.60 (m. 5H).LCMS (Method A): 1.987 min, 100.00 %. 254.0 nm, MS: ES+ m / z 378.32 [M+1]HPLC (Method B): 7.07 min, 99.56 %, 254 nmCHIRAL HPLC: 2.74 min, 100.00%, 262 nmCompound 31H NMR (DMSO-d6, 400 MHz): δ ppm. 8.31 (dd, J = 4.8, 2.0 Hz, 1H), 8.19 (brs, 1H), 8.07 (dd,J = 8.0. 2.0 Hz. 1H), 7.79 (d. J 7.2 Hz. 1H), 6.79 (dd, J 7.6. 4.8 Hz. 1H), 4.28-4.27 (m. 1H),3.44-3.36 (m, 2H), 2.78-2.73 (m, 1H), 2.25-2.18 (m, 1H), 2.08-1.99 (m, 6H), 1.66-1.60 (m, 5H).LCMS (Method A): 1.988 min. 100%, 254.0 nm. MS: ES+ m / z 378.32 [M+1JHPLC (Method B): 7.10 min, 95.57%, 210.0 nmCHIRAL HPLC: 3.35 min, 100%, 250.0 nmEXAMPLE 2 - Preparation of 3-(5-(2-(cyclohexylamino) pyridin-3-yl)-l,3,4-oxadiazol-2- yl)-3-methylpyrrolidin-2-one (Compound 4)Step 1 : Synthesis of Intermediate 4-B1 methyl 2-(cyclohexvlamino)nicotinate

[0142] To a solution of methyl 2-chloronicotinate (CAS:40134-18-7) (5.0 g, 29. 1 mmol. 1.0 eq), and cyclohexanamine (CAS: 108-91-8) (8.6 g, 87.42 mmol, 3.0 eq) in DMSO (50 mL), was added triethyl amine (12.2 mL, 87.42 mmol, 3.0 eq) and reaction mixture was stirred at rt for 10 min. after 10 min, the reaction temperature increases up to 160 °C and stirring was continued for4 h. The reaction was monitored by TLC (20% EtOAc in hexane as mobile phase). After completion, the resulting reaction mixture was cool to rt and diluted by water (50 mL). The resulting reaction mixture was extracted with diethyl ether (2 x 200 mL) and combined organiclayers were dried over Na2SO4then concentrated under reduced pressure to afford the crude (4.0 g). The obtained crude material was purified by manual column chromatography using silica gel (100-200 mesh) as stationary phase and gradient 35% EtOAc in hexane afforded the title compound methyl 2-(cyclohexyl amino) nicotinate (3.6 g, 15.3 mmol, Yield; 52.94%)1H NMR (DMSO-d6, 400 MHz): δ ppm 8.29-8.27 (m, 1H), 8.07 (dd, J = 7.6. 1.6Hz. 1H), 7.92 (d, J = 7.6 Hz, 1H), 6.61-6.58 (m, 1H), 4.05-3.98 (m, 1H), 3.81 (s, 3H), 1.94-1.91 (m, 2H), 1.70- 1.66 (m, 2H), 1.59-1.56 (m, 1H), 1.42-1.23 (m, 5H).LCMS (Method A): 1.925 min, 99.90%, 254.0 nm, MS: ES+ m / z 235.10 [M+1]Step 2; Synthesis of Intermediate 4-B2:2-(cvclohexvlamino)nicotinohydrazide:

[0143] To a solution of methyl 2-(cyclohexylamino) nicotinate (Intermediate 4-B1) (2.0 g, 8.53 mmol, 1.0 eq), in methanol (40.0 mL), was added NH2NH2.H2O (1.92 g, 38.41 mmol, 4.5 eq) at rt then resulting reaction mixture was stirred at 90 °C for 16 h. The progress of reaction was monitored on TLC (20% EtOAc in hexane as mobile phase). After completion, the resulting reaction mixture was cool to rt and concentrated to obtain the residue. The residue was diluted by addition of water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude (2.0 g). The obtained crude material was purified by manual flash column chromatography using silica gel (100-120 mesh) as stationary phase and gradient 50% EtOAc in hexane afforded the title compound methyl 2-(cyclohexyl amino) nicotinate (Intermediate 4-B2) (1.8 g. 7.68 mmol, Yield: 90.45%)1H NMR (DMSO-d6, 400 MHz): δ ppm 9.72 (s. 1H), 8.28 (d. J = 7.6 Hz. 1H), 8.12-8.11 (m, 1H), 7.81 (dd, J = 7.2, 1.2 Hz, 1H), 6.51-6.48 (m 1H), 4.48 (s, 2H), 3.93-3.91 (m, 1H), 1.92- 1.89 (m, 2H), 1.68-1.65 (m, 2H), 1.58-1.54 (m, 1H), 1.40-1.18 (m, 5H).LCMS (Method A): 1.140 min, 98.28%, 254.0 nm, MS: ES+ m / z 235.10 [M+1]Step 3: Synthesis of Intermediate 4-B3:2-(cvclohexvlamino)-N'-(3-methvl-2-oxopvrrolidine-3- carbonvl) nicotinohydrazide

[0144] To a solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.366 g, 2.134 mmol, 1.2 eq) in DMF (5.0 mL) was added HATU (1.2 g, 3.01 mmol, 1.5 eq), DIPEA (1.1 mL, 6.40 mmol, 3.0 eq) and reaction mixture was stirred at 0 °C for 15 min, followed by drop wise addition of 2-(cyclohexylamino)nicotinohydrazide (Intermediate 4-B2) (0.500 g, 2.134 mmol, 1.0 eq) and stirred the reaction mixture at rt for 4 h. The reaction was monitored by TLC (EtOAc: hexane; 8:2 as mobile phase). After completion, the resulting reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 150 mL) then dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.3 g). The obtained crude material was purified by flash column chromatography using silica (100-200 mesh) as stationary phase and gradient 10% MeOH in DCM afforded the title compound 2-(cyclohexylamino)-N'-(3- methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (0. 150 g. 0.417 mmol, Yield: 19.5%).LCMS (Method A): 1.296 min, 87.01%, 254.0 nm, MS: ES+ m / z 360.17 [M+1]Step 4: Synthesis of 3-(5-(2-(cyclohexylamino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3- methylpyrrolidin-2-one (Compound 4)

[0145] To a solution of 2-(cyclohexylamino)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (Intermediate 4-B3) (0.130 g, 0.361 mmol. 1.0 eq) in DCM (1.5 mL), was added tri ethyl amine (0.109 g, 1.08 mmol, 3.0 eq) and then reaction mixture was stirred at 0 °C followed by addition of TosCl (0.082 g, 0.433 mmol, 1.2 eq) and further stirred at 0 °C for 15 min then rt for 3 h. The reaction was monitored on TLC (EtOAc: hexane; 8:2 as mobile phase). After completion of reaction, the resulting reaction mixture was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.080 g crude. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary' phase and gradient 70% ethyl acetate in hexane afforded the title compound 3-(5-(2-(cyclohexylamino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (0.055 g, 0.161 mmol, Yield: 38.73%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.29 (dd, J = 4.8, 1.6Hz, 1H), 8.19 (s, 1H). 8.04 (dd J = 7.6, 1.6 Hz, 1H), 7.79 (d, J = 7.2Hz. 1H), 6.73 (dd, J = 7.6, 4.8 Hz, 1H), 4.12-4.10 (m, 1H), 3.44-3.30 (m, 2H), 2.78-2.67 (m, 1H), 2.24-2.18 (m, 1H), 1.98-1.95 (m, 2H), 1.71-1.70 (m, 2H), 1.60 (s. 4H), 1.45-1.43 (m. 5H).LCMS (Method A): 1.741 min, 100 %, 345 nm, MS: ES+ m / z 342.21 [M+1]HPLC (Method A): 7.274 mm, 100 %, 254 nmChiral HPLC: Peak-1 :6.27 min, 50.41 % and Peak-2: 7.04 min, 49.58 %, 262 nmEXAMPLE 3 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)- l,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 5)Step 1 : Synthesis of Intermediate 5-Al: 4.4-dimethylcyclohexan-l-one oxime

[0146] To a stirred solution of 4,4-dimethylcyclohexan-l-one (CAS:4255-62-3) (1.0 g, 7.92 mmol, 1.0 eq) in EtOH (5 mL) and water (6 mL) was added NH2OH.HCI (0.715 g, 10.30 mmol,1.3 eq) and Na2CO3(1.09 g, 10.30 mmol, 1.3 eq.) at rt. The resulting reaction mixture was allowed to stirred at 80 °C for 2 h. The progress of reaction was monitored by TLC (10%EtOAc: hexane). After completion, the resulting reaction mixture was concentrated and residue was diluted with water (15 mL) then extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude(1.05 g). The obtained crude material was purified by trituration with n-pentane (20 mL) to afford the title compound 4,4-dimethylcyclohexan-l-one oxime (0.910 g. 6.44 mmol, Yield;81.25%).1H NMR (DMSO-d6, 400 MHz) δ ppm, 2.55 (t, J = 6.8 Hz, 2H). 2.27 (J = 6.4 Hz. 2H), 1.51-1.43(m. 4H), 1.01 (s. 6H). Note: -OH, proton might exchange in CDCbLCMS (Method A): 1.797 min, 99.02%. 210 nm, MS: ES+ m / z 142.0 [M+1]Step 2: Synthesis of Intermediate 5-A2: 4,4-dimethylcyclohexan-l-amine

[0147] To a stirred solution of 4,4-dimethylcyclohexan-l-one oxime (Intermediate 5-Al) (5.8 g, 21.88 mmol. 1.0 eq) in THF (60 mL). was added LAH (1 M in THF. 21.8 mL. 21.88 mmol.1.0 eq) at 0 °C dropwise under nitrogen atmosphere and reaction temp, was maintained at 0 °Cfor 15 min. After 15 min. reaction mixture allows to refluxed for 4 h. The reaction progress was monitored by TLC (100% EtOAc as mobile phase). After completion, the resulting reaction mixture was cooled to rt then 1 M NaOH solution (30 mL) was added dropwise and filtered through celite bed, wash the bed with ethyl acetate (50 mL) twice. Combined filtrate was extracted with ethyl acetate (3 x 50 mL) and combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude (5.1 g). The obtained crude material was purified by flash column chromatography using silica gel (100-200 mesh) as stationary' phase and gradient 5% MeOH in DCM afforded the title compound 4,4-dimethylcyclohexan-l-amine (Intermediate 5-A2) (1.5 g, 11.78 mmol, Yield: 28.73%)1H NMR (DMSO-d6, 400 MHz): δ 2.51-2.42 (m, 2H), 1.54-1.51 (m, 2H), 1.32-1.29 (m, 2H), 1.18-1.13 (m, 4H). 0.86 (s. 6H). (Note: Exchangeable protons might be exchanged in DMSO moisture.)Step 3: Synthesis of Intermediate 5-B1 : methyl 2-l(4.4-dimethylcyclohexyl) amino) nicotinate

[0148] To a stirred solution of Methyl 2-Chloronicotinate (CAS: 40134-18-7) (2.0 g. 1 1.02 mmol, 1.0 eq) and 4,4-dimethylcyclohexan-l-amine (Intermediate 5-B1) (1.4 g, 11.02 mmol, 1.0 eq) in DMSO (14 mL), was added Triethylamine (4.6 mL, 33.10 mmol, 3.0 eq) and stirring was continued at rt. After 5 min. reaction mixture was stirred at 160 °C for 2 h. The reaction progress was monitored on TLC (30% EtOAc in hexane as mobile phase). After completion of reaction, the resulting reaction mixture was cooled to rt and diluted by water (20 mL), extracted with diethyl ether (3 x 100 mL) then combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the cmde (1.37 g). The obtained crude material was purified by flash column chromatography using silica gel (100-120 mesh) as stationary phase and gradient 2-3% EtOAc in hexane afforded the title compound methyl 2-((4.4- dimethylcyclohexyl) amino) nicotinate Intermediate 5-B1 (0.920 g, 3.50 mmol, Yield: 32.85%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.27 (d, J = 4.8 Hz. 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.09 (brs, 1H), 6.65 (t, J = 6.8 Hz, 1H), 3.96-3.95 (m, 1H), 3.88 (s, 3H), 1.82-1.78 (m, 2H), 1.51-1.23 (m, 6H), 0.94 (d, J= 6.4 Hz, 6H)LCMS (Method A): 2.482 min, 100%, 254.0 nm, MS: ES+ m / z 262.8 [M+1]Step 4: Synthesis of Intermediate 5-B2: 2-((4,4-dimethylcyclohexyl) amino) nicotinohydrazide

[0149] To a solution of methyl 2-((4,4-dimethylcyclohexyl) amino) nicotinate (Intermediate 5- Bl) (0.70 g, 2.67 mmol, 1.0 eq) in MeOH (7 mL), was added hydrazine hydrate (1.33 g, 26.71 mmol, 10.0 eq) at rt, then the reaction mixture was heated up to 90 °C for 8 h. The completion of reaction was monitored by TLC (30% EtOAc in hexane as mobile phase). After completion, theresulting reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4further concentrated under reduced pressure to afford the crude (0.610 g). The obtained crude material was purified by flash column chromatography using silica gel (100-200 mesh) as stationary phase and gradient 15-16% EtOAc in hexane afforded the title compound methyl 2-((4.4- dimethyl cyclohexyl) amino) nicotinate (Intermediate 5-B2) (0.520 g, 1.98 mmol. Yield: 74.28%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.72 (s, 1H), 8.29 (d, J = 6.8 Hz, 1H), 8.11 (dd, J =4.8, 1.6 Hz, 1H), 7.81 (dd, J = 7.6, 1.6Hz, 1H), 6.49 (dd, J = 7.6, 4.8 Hz, 1H), 4.44 (s, 2H), 3.87 (brs, 1H), 1.80-1.74 (m, 2H), 1.39-1.24 (m, 6H), 0.93 (d, J = 3.2 Hz, 6H).LCMS (Method A): 1.405 min, 99.22%, 254 nm, MS: ES+ m / z 263.15 [M+1]Step 5: Synthesis of Intermediate 5-B3: 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide

[0150] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.163 g, 1. 144 mmol, 1.2 eq), in DMF (2.5 mL), was added DIPEA (0.49 mL, 2.862 mmol, 3 eq) and HATU (0.543 g, 1.431 mmol, 1.5 eq) at rt. The reaction mixture was stirred for 15 min. at same temperature. After 15 min., methyl 2-((4,4-dimethylcyclohexyl) amino) nicotinate (Intermediate 5-B2) (0.250 g, 0.954 mmol, 1.0 eq) was added and reaction mixture was stirred for 8 h at rt. The reaction progress was monitored on TLC (3% MeOH in DCM mobile phase) and after completion of reaction, water (20 mL) was added and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.230 g crude. The obtained crude material was purified by manual column chromatography using silica gel (100-200 mesh) as stationary phase and gradient 2% MeOH in DCM afforded the title compound 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.160 g, 0.412 mmol, Yield: 10.88%)LCMS (Method A): 1.569 min, 66.27%. 254 nm, MS: ES+ m / z 388.27 [M+1]Step 6: Synthesis of 3-(5-(2-((4,4-dimethylcvylohexyl) amino) pyridin-3-vl)-1,3,4-oxadiazol-2- yl)-3-methylpyrrolidin-2-one (Compound 5)

[0151] To a stirred solution 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (0140 g, 0.3617 mmol, 1.0 eq) in DCM (2 mL), was added triethylamine (0.15 mL, 1.085 mmol, 3 eq), tosyl chloride (0.082 g, 0.434 mmol, 1.2 eq) at 0 °C and reaction mixture was stirred at rt for 2 h. The reaction was monitored by TLC (1% MeOH in DCM as mobile phase). After TLC indicate the complete consumption of startingmaterial, water (10 mL) was added and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.087 g). The crude was purified by flash column chromatography using silica gel (100-200 mesh) as stationary phase and gradient 1 % MeOH in DCM afforded the title compound 3-(5-(2- ((4.4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methyl pyrrolidin-2-one (Compound 5) (0.0485 g, 0.131 mmol. Yield: 36.09%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.28 (dd, J = 4.8, 1.6 Hz, 1H), 8. 19 (brs, 1H), 8.04 (dd, J = 7.6, 2.0 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 6.73 (dd, J = 7.6, 4.8 Hz, 1H), 4.05 (brs, 1H), 3.44-3.37 (m, 2H), 2.76-2.73 (m, 1H), 2.23-2.19 (m, 1H), 1.88-1.84 (m, 2H), 1.60 (s, 3H), 1.50-1.41 (m, 4H), 1.35-1.32 (m, 2H), 0.95 (d, J = 5. 6 Hz, 6H).LCMS (Method A): 2.109 min, 99.12%, 254.0 nm, MS: ES+ m / z 370.27 [M+1]HPLC (Method B): 8.24 min, 99.25%, 254.0 nm,Chiral HPLC: Peak-1 : 5.10 min, 49.56%, 235.0 nm, Peak-2: 5.68 min, 50.22%, 235.0 nm.EXAMPLE 4 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)- l,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 6, Compound 7)

[0152] Compound 5 racemate (-39.2 mg) was subjected to chiral separation by chiral SFC and both enantiomers were separated.

[0153] COLUMN ID: Hypersil Chiral-ICT (250mm x 50mm x 5μm)

[0154] MOBILE PHASE A; 0. 1 % M.NH3IN HEPTANE

[0155] MOBILE PHASE B: 0.1 % N.NH3IN MeOH: MTBE (50:50)

[0156] INSTRUMENT ID: PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UVDETECTOR

[0157] FLOW RATE(ML / MIN): 40

[0158] Input Quantity: 39.2 mg

[0159] Output Quantity; Compound 6-12.42 mg, Compound 7-10.54 mg.Compound 61H NMR (DMSO-d6, 400 MHz): δ 8.28 (dd, J = 8.8, 1.6Hz, 1H), 8.19 (s, 1H), 8.03 (dd, J = 8.0, 2.0 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 6.73 (dd, J= 7.6, 4.8 Hz, 1H), 4.10-4.05 (m, 1H), 3.43 -3.40 (m, 2H), 2.78 - 2.73 (m, 1H). 2.24-2.19 (m, 1H). 1.88-1.84 (m, 2H). 1.60 (s, 3H). 1.47-1.41 (m, 4H), 1.35 - 1.23 (m, 2H), 0.95 (d, J = 5.2 Hz, 6H).LCMS (Method A): 2.241 min, 100%, 254.0 nm, MS: ES+ m / z 370.4 [M+1]HPLC (Method B): 8.508 mm, 100%. 254.0 nmChiral HPLC: 5.21 min, 100 %, 235 nmCompound 71H NMR (DMSO-d6, 400 MHz): δ ppm, 5 8.28 (dd, J = 8.8, 1.6 Hz, 1H), 8.18 (s, 1H), 8.03 (dd, J= 7.6, 1.6 Hz, 1H), 7.81 (d. J = 7.6 Hz, 1H), 6.73 (dd, J= 7.6, 4.8 Hz. 1H), 4.07 (hrs, 1H), 3.43 - 3.40 (m, 2H), 2.78 - 2.71 (m, 1H), 2.24-2.18 (m, 1H), 1.88-1.84 (m, 2H), 1.60 (s, 3H), 1.50-1.41 (m, 4H), 1.35 - 1.22 (m, 2H), 0.95 (d, J = 5.6 Hz, 6H).LCMS (Method A): 2.240 mm, 100%, 254.0 nm, MS: ES+ m / z 370.4 [M+1]HPLC (Method B): 8.512 min, 99.81%. 254.0 nmChiral HPLC (Method C): 5.75 min. 95.15%, 235 nmEXAMPLE 5 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpiperidin-2-one (Compound 8)Step 1 : Synthesis of Intermediate 8-A2: Diethyl 2-(3-(l,3-dioxoisoindolin-2-yl) propyl)-2- methylmal onate:

[0160] To a stirred solution of Diethyl 2-methylmalonate (CAS:609-08-5) (10.0 g, 57.47 mmol, 1.0 eq) in THF (100 mL) was added NaH (60%) (2.52 g, 105 mmol, 1.1 eq) portion wise by maintaining the reaction temperature at 0 °C. After complete addition of NaH, the reaction was stirred at rt for 1 h and then 2-(3-bromopropyl) isoindoline-1, 3-dione (15.40 g, 57.47 mmol.1.0 eq) was added. The resulting reaction mixture was stirred at 70 °C for 16 h. The reaction was monitored by TLC (EtOAc: hexane: 1 :9 as mobile phase) which confirmed that the reaction got completed after 16 h. The crude mixture was allowed to cooled to rt then poured into ice-cold water (100 mL) and extracted with EtOAc (2 x 150 mL). The separated organic layers were dried over Na2SO4. concentrated under vacuum to afford the crude (22.0 g). The crude was purified by column chromatography with using Silica-Gel (60-120 mesh size) as stationary phase and gradient 5% EtOAc in hexane afforded the title compound diethyl 2-(3-(1,3- dioxoisoindolin-2-yl) propyl)-2-methylmalonate (7.0 g, 19.38 mmol, Yield: 33.73%).1H NMR (DMSO-d6, 400 MHz): δ ppm 7.89- 7.83 (m, 4H), 4.09- 4.04 (m, 4H), 3.57 (t, J = 6.8Hz, 2H), 1.79- 1.74 (m, 2H), 1.56 - 1.50 (m, 2H), 1.27 (s, 3H), 1.10 (t, J = 7.2 Hz, 6H).LCMS (Method A): 2.229 min, 79.54%, 210.0 nm, MS: ES+ m / z 362.28 [M+1]Step 2: Synthesis of Intermediate 8-A3: Ethyl 3-methvl-2-oxopiperidine-3-carboxylate:

[0161] To a stirred solution of diethyl 2-(3-(1,3-dioxoisoindolin-2-yl) propyl)-2- methylmalonate (Intermediate 8-A2) (2.0 g, 5.53 mmol, 1.0 eq) in Ethanol (50 mL) was added Hydrazine hydrate (0.27 g, 5.40 mmol, 1.0 eq) and stirred the reaction at 80 °C for 16 h. The reaction was monitored on TLC (using MeOH: DCM: 1:9 as mobile phase) which confirmed that the reaction got completed after 16 h. After completion of reaction the reaction mixture was filtered and filtrate was evaporated under reduced pressure to afford the residue which was diluted with water (20 mL) and extracted with 5% MeOH in DCM (2 x 50 mL). The separated organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the title compound as crude Ethyl 3-methyl-2-oxopiperidine-3-carboxylate (0.80 g. 4.31 mmol. Yield: 78.43%). (Note: crude compound was used as such for next step without further purification).1H NMR (DMSO-d6, 400 MHz): δ ppm 7.63 (brs, 1H), 4.14- 4.02 (m, 4H), 1.73- 1.66 (m, 4H), 1.32 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H).Step 3: Synthesis of 3-methyl-2-oxopiperidine-3-carboxylic acid (Intermediate 8-A4):

[0162] To a stirred solution of Ethyl 3-methyl-2-oxopiperidine-3-carboxylate (1.0 g, 6.36 mmol, 1.0 eq) in MeOH (10 mL) was added NaOH (1.27 g, 31.75 mmol, 5.0 eq) in water (3 mL). The resulting reaction mixture was stirred at rt for 16 h. The reaction was monitored on TLC (using MeOH: DCM: 2:8 as mobile phase) which confirmed that the reaction got completed after 16 h. The reaction mixture was acidified with 1 N HC1 (till pH~4). and concentrated under reduced pressure to afford the title compound 3-methyl-2-oxopiperidine-3- carboxylic acid (0.80 g, 5.09 mmol, Yield: 94.28%).LCMS (Method A): 0.803 min, 80.70%, 210.0 nm, MS: ES+ m / z 158.22 [M+1]Step 4: Synthesis of (Intermediate 8-A5): 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopiperidine-3-carbonyl) nicotinohydrazide:

[0163] To a stirred solution of 3-methyl-2-oxopiperidine-3-carboxylic acid (Intermediate 8- A4) (0.1 g, 0.70 mmol, 1.0 eq) in DMF (2 mL) were added EDC.HC1 (0.43, 2.24 mmol, 6.0 eq), HOBt (0.35, 2.28 mmol, 6.0 eq) and DIPEA (0.39 g, 3.02 mmol, 8.0 eq). The resulting reaction mixture was stirred at rt for 10 min. and then 2-((4,4-dimethylcyclohexyl) amino) nicotinohydrazide (Intermediate 5-B2) (0. 10 g, 0.38 mmol, 1.0 eq) was added to the reaction mixture and stirred again at rt for 6 h. The reaction was monitored by TLC (using MeOH: DCM : 0.5: 9.5 as mobile phase) which confirmed that the reaction got completed after 6 h. After completion reaction mixture was diluted with ice cold water (10 mL) and extracted with EtOAc (2 x 20 mL). The separated organic layers were dried over anhydrous sodium sulfate.concentrated under vacuum to afford the crude (0. 19 g) as a yellow oil. The resulting crude was purified by flash column chromatography using silica gel (230-400 mesh size) and gradient 5% MeOH in DCM afforded the title compound 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl- 2-oxopiperidine-3 -carbonyl) nicotinohydrazide (0.14 g, 0.34 mmol. Yield: 93.33%). (Note: Few impurities still observed after column purification and we have forwarded this for next step without further purification ).LCMS (Method A): 1.725 mm, 54.68%, 254.0 nm, MS: ES+ m / z 402.39 [M+1]Step 5: Synthesis of 3-(5-(2-((4,4-dimethYlcyclohexyl) amino) pvridin-3-yl)-1,3,4-oxadiazol-2- yl)-3-methvlpiperidin-2-one (Compound 8)

[0164] To a stirred solution of 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopiperidine-3-carbonyl) nicotinohydrazide (Intermediate 8-A5), (0.13 g, 0.32 mmol, 1.0 eq) in DCM (2 mL) were added Et3N (0.09 g, 0.97 mmol, 3.0 eq) and 4-Toluenesulfonyl chloride (0.07 g, 0.38 mmol, 1.2 eq). The resulting reaction mixture was stirred at rt for 2 h. The reaction was monitored by TLC (using MeOH: DCM:0.5:9.5 as mobile phase) which confirmed that the reaction got completed after 2 h. The reaction was diluted with w ater (10 mL) and extracted with DCM (2 x 20 mL). The separated organic layers were dried over anhydrous Na2SO4, concentrated under reduced pressure to afford the cmde (0. 190 g) as a yellow' oil. The crude was purified by flash column chromatography with using Silica Gel (230-400 mesh size) and gradient 100% EtOAc afforded the pure title compound 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpiperidin-2-one (Compound 8) (0.028 g, 0.073 mmol, Yield: 22.58%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.28 (dd, J = 4.8, 1.6 Hz, 1H), 8.03 (dd, J = 7. 6, 2.0 Hz, 1H), 7.91 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 6.73 (dd, J = 7.6, 4.8 Hz, 1H), 4.07-4.05 (m, 1H), 3.29-3.26 (m, 2H). 2.37-2.32 (m, 1H). 1.96-1.91 (m, 1H). 1.88 - 1.84 (m, 4H), 1.67 (s. 3H), 1.52- 1.41 (m, 3H), 1.35- 1.26 (m, 3H), 0.95 (d, J = 6.0 Hz, 6H).LCMS (Method A): 2.257 min, 97.71%, 254 nm. MS: ES+ m / z 384.49 [M+1]HPLC (Method A): 7.725 min, 96.66%, 254.0 nmCHIRAL HPLC; 2.123 min, 50.46%, 2.322 min, 49.54%. 356.0 nmEXAMPLE 6 - Preparation of 3-(5-(2-((4,4-difluorocyclohexyl) amino) pyridin-3-yl)- 1,3,4- oxadiazol-2-yl)-3-methylpiperidin-2-one (Compound 9)Step 1 : Synthesis of Intermediate 9-AL (methyl 2-((4.4-difluorocyclohexyl) amino) nicotinate:

[0165] To a stirred solution of Methyl 2-chloronicotinate CAS:40134-18-7 (1.0 g, 5.82 mmol,1.0 eq) in DMSO (10 mL) were added 4,4-difluorocyclohexan-l-amine hydrochlorideCAS;675112-70-6 (1.19 g. 6.98 mmol, 1.2 eq) and Et3N (1.17 g, 11.58 mmol, 2.0 eq). The resulting reaction mixture was stirred at 160 °C for 2 h. The reaction was monitored on TLC(using EtOAc: hexane; 8:2 as mobile phase), after completion the resulting reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.65 g crude. The obtained crude material was purified by flash column chromatography using silica (230-400 mess) as stationary phase and gradient 10% EtOAc in hexane afforded the title compound (methyl 2-((4,4-difluorocyclohexyl) amino) nicotinate (0.40 g, 1.47 mmol, Yield:25.29%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.31 (d, J = 4.8, 2.0 Hz, 1H), 8.10 (d, J 7.6, 2.0 Hz.1H), 7.89 (d, J = 7.6 Hz. 1H), 6.66-6.63 (m, 1H), 4.19-4.16 (m, 1H), 3.82 (s, 3H), 2.05-1.95 (m,6H), 1.59-1.55 (m. 2H).LCMS (Method A): 2.250 min, 97.96 %, 254.0 nm, MS: ES+ m / z 271.49 [M+1]Step 2; Synthesis of Intermediate 9-A2: 2-((4,4-difluorocyclohexyl) amino) nicotinohydrazide

[0166] To a stirred solution of (methyl 2-((4,4-difluorocyclohexyl) amino) nicotinateIntermediate 9-Al (0 40 g 1 47 mmol) in MeOH (4 mL) was added Hydrazine hydrate (0 73 g14.59 mmol, 10.0 eq) at rt and reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored on TLC (100% EtOAc as mobile phase) which confirmed that the reaction got completed after 16 h. The resulting reaction mixture was concentrated under reduced pressure and extracted with DCM (3 x 30 mL), the combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the title compound 2-((4.4- difluorocyclohexyl) amino) ni cotinohydrazide (0.2 g, 0.740 mmol, 50.00%).1H NMR (DMSO-d6, 400 MHz): δ ppm 9.77 (brs, 1H), 8.34 (d, J = 7.2 Hz, 1H). 8.15 (dd, J 4.8, 1.6 Hz, 1H), 7.85 (dd, J = 7.6, 1.6 Hz, 1H), 6.55 (dd, J = 7.6, 4.8 Hz.. 1H), 4.46 (s, 2H), 4.10-4.08 (m, 1H), 2.02-1.93 (m, 6H), 1.55-1.48 (m, 2H)LCMS (Method A): 1.483 min, 91.89%, 254.0 nm, MS: ES+ m / z 271.19 [M+H]Step 3: Synthesis of Intermediate 9-A3:2-((4,4-difluorocyclohexyl) amino)-N'-(3-methyl-2- oxopiperidine-3-carbonyl) nicotinohydrazide:

[0167] To a stirred solution of 3-methyl-2-oxopiperidine-3-carboxylic acid (Intermediate 8- A4) (0.22 g, 1.40 mmol, 2.0 eq) in DMF (4 mL) were added EDC.HC1 (0.80 g, 4.18 mmol, 6.0 eq), HOBt (0.56 g, 4.21 mmol, 6.0 eq) and DIPEA (0.72 g, 5.58 mmol, 8.0 eq) under Nitrogen. The resulting reaction mixture was stirred at rt for 10 min, followed by addition of 2-((4,4- difluorocyclohexyl) amino) ni cotinohydrazide (Intermediate 9-A2) (0.19 g, 0.70 mmol, 1.0 eq) and stirred the reaction at rt for 6 h. The reaction was monitored on TLC (05% MeOH in DCM as mobile phase). After completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 20 mL). The separated organic layers were dried over Na2SO4. further concentrated under reduced pressure to afford the crude as a yellow oil. The crude was purified by flash column chromatography using silica gel (230-400 mesh size) as a stationary phase and gradient 100% EtOAc afforded the title compound 2-((4,4-difluorocyclohexyl) amino)-N'-(3- methyl-2-oxopiperidine-3-carbonyl) nicotinohydrazide (0.13 g. 0.31 mmol, yield: 45%).LCMS (Method A): 1.621 min, 75.52 %, 254.0 nm, MS: ES+ m / z 410.29 [M+1]Step 4; Synthesis of 3-(5-(2-((4.4-difluorocyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2- vl)-3-methylpiperidin-2-one (Compound 9):

[0168] To a stirred solution of 2-((4,4-difluorocyclohexyl) amino)-N'-(3-methyl-2- oxopiperidine-3-carbonyl) ni cotinohydrazide (Intermediate 9- A3) (0.12 g, 0.29 mmol, 1.0 eq) in DCM (2 mL) were added Et3N (0.08 g, 0.79 mmol, 3.0 eq) and 4-toluenesulfonylchloride (0.06 g, 0.35 mmol, 3.0 eq) under nitrogen atmosphere. The reaction mixture was stirred at rt for 3 h. and monitored by TLC (5% MeOH in DCM as mobile phase). After completion, the crude mixture was diluted with water (10 mL) and extracted with DCM (2 × 15 mL). The separatedorganic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude (0.20 g), which was purified by flash column chromatography using silica gel (230-400 mesh) and gradient 80% EtOAc in hexane afforded the title compound 3-(5- (2-((4,4-difluorocyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpiperidin-2- one (0.023 g. 0.05 mmol, Yield: 20.05%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.31 (dd. J = 4.4, 1.6Hz, 1H). 8.07 (dd, J = 7. 6.1.6 Hz, 1H), 7.91 (brs, 1H), 7.81 (d, J = 7.6 Hz, 1H), 6.80-6.77 (m, 1H), 4.28-4.27 (m, 1H), 3.37 (brs, 2H), 2.35-2.32 (m, 1H), 2.07-2.02 (m, 6H), 1.99- 1.91 (m, 1H), 1.87- 1.84 (m, 2H), 1.67 (s, 3H), 1.64-1.62 (m, 2H).LCMS (Method A): 2.04 mm, 95.04%, 254.0 nm, MS: ES+ m / z 391.94 [M+1],HPLC (Method A): 6.39 min, 95.53%, 254.0 nmCHIRAL HPLC: Peak-1 : 2.096 mm, 48.94 %, Peak-2: 2.443 min, 48.61 %, at 350.0 nmEXAMPLE 7 - Preparation of 2-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1 ,3,4-oxadiazol-2-yl)-2-methylmorpholin-3-one (Compound 10)Step 1: Synthesis of Synthesis of Intermediate 10-C1: diethyl 2-(2-((tert-butoxy carbonyl) amino) ethoxy)-2-methylmalonate.

[0169] To a stirred solution of tert-butyl (2-hydroxyethyl) carbamate (CAS: 29263-94-3) (5.0 g, 31.00 mmol. 1.0 eq) in THF (50.0 mL) under nitrogen atmosphere was added NaH (1.86 g,46.50 mmol, 1.5 eq, 60%) and resulting reaction mixture was stirred at 0 °C for 1 h. To thissolution diethyl 2-bromo-2-methylmalonate (CAS: 29263-94-3) (11.78 g, 46.50 mmol, 1.5 eq) was added at 0 °C and the resulting mixture was stirred at 0 °C to rt for 6 h. The TLC indicated completion of reaction (20% EtOAc in hexane as a mobile phase). After completion, w ater (100 mL) was added and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated under high vacuum to obtained the crude product. The obtained crude material w as purified by flash column chromatography using silica gel (100- 200 mesh) as stationary phase and gradient 18-20% EtOAc in hexane afforded the title compound diethyl 2-(2-((tert-butoxy carbonyl) amino) ethoxy)-2-methylmalonate. (0.67 g, 2.009 mmol, Yield: 10.17%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 6.74 (s, 1H). 4. 19 - 4. 10 (m, 4H), 3.45 (t, J 6.0 Hz. 2H), 3.06 (q. J = 6.0 Hz. 2H), 1.50 (s. 3H), 1.36 (s, 9H), 1.19 (t, J = 6.8 Hz, 6H).LCMS (Method A): 2.216 min, 60.95%, 220.0 nm. MS: ES+ m / z 334.3 [M+1],Step 2; Synthesis of Intermediate 10-C2: diethyl 2-(2-aminoethoxy)-2-methylmalonate hydrochloride

[0170] To a solution of diethyl 2-(2-((tert-butoxy carbonyl) amino) ethoxy)-2-methylmalonate (Intermediate 10-C1) (0.67 g, 20.0 mmol, 1.0 eq) in DCM (14.0 mL), was added 4.0 M HC1 In dioxane (6.7 mL, 10 v) under nitrogen atmosphere at 0 °C and reaction mixture was stirred at rt for 1 h. The reaction was monitored by TLC (10% MeOH: DCM as mobile phase). After completion, the resulting reaction mixture was concentrated under reduced pressure to afford Ethyl 4-amino-2-methyl-2-(4-oxo-8-(4-(trifluoromethyl) phenyl) quinazolin-3(4H)-yl) butanoate hydrochloride Intermediate 10-C3 as HC1 salt. (Note: crude was forwarded as such for next step without any further purification) (0.65 g, 2.786 mmol, Yield: Quantitative)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.01 (brs, 2H), 4.20 (q, J =7.2 Hz, 4H), 3.74 (t, J = 5.2 Hz, 2H), 3.57 (s, 2H), 2.98-2.97 (m, 2H), 1.56 (s, 3H), 1.21 (t, J = 7.2 Hz, 6H).LCMS (Method A): 1.482 min, 83.53%, 210.0 nm, MS: ES+ m / z 234.27 [M+1],Step 3: Synthesis of Intermediate 10-B3: Ethyl 2-methyl-3-oxomorpholine-2-carboxvlate.

[0171] To a solution of Ethyl 4-amino-2-methyl-2-(4-oxo-8-(4-(trifluoromethyl) phenyl) quinazolin-3(4H)-yl) butanoate hydrochloride (Intermediate 10-C2) (0.650 g, 2.78 mmol, 1.0 eq) in DMF (7.0 mL) was added K2CO3(3.84 g, 27.80 mmol. 10.0 eq) and reaction mixture was stirred at rt for 16 h. The progress was monitored on TLC (using 10% MeOH in DCM as mobile phase). After the completion of reaction, the resulting reaction mixture was diluted with (20 mL) water and extracted with 10% MeOH in DCM (3 x 20 mL) and combined organic layers were dried over Na2SO4then concentrated under reduced pressure to afford 0.80 g crude. Theobtained crude material was purified by reversed phase column chromatography using (C18 silica gel) as stationary phase. The gradient 15-20% ACN in water (0.1% FA) afforded the title compound Ethyl 2-methyl-3-oxomorpholine-2-carboxylate. (0.250 g, 1.336 mmol, Yield: 55.42%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 5 8.25 (hrs, 1H). 4.17 - 4.09 (m, 2H), 3.95 - 3.89 (m, 1H), 3.84 - 3.79 (m, 1H), 3.35 - 3.29 (m, 1H), 3.24 - 3.18 (m, 1H), 1.44 (s, 3H). 1.19 (L J = 7.2 Hz, 3H).LCMS (Method A): 1.375 min, 100%. 210.0 nm, MS: ES+ m / z 188.09 [M+1]Step 4; Synthesis of Intermediate 10-A4: 2-methyl-3-oxomorpholine-2-carboxylic acid.

[0172] To a solution of Ethyl 2-methyl-3-oxomorpholine-2-carboxylate Intermediate 10-A4 (0.25 g, 1.33 mmol, 1.0 eq), in MeOH (5.0 mL), was added solution of NaOH (0.26 g, 6.67 mmol, 5.0 eq) in water (2.5 mL) and reaction mixture was stirred for 4 h at rt. The progress was monitored on TLC (10% MeOH in DCM as mobile phase). After the completion of reaction, the resulting reaction mixture was concentrated under vacuum and then dilute with 1 N HC1 solution then pH was adjusted to (~3) and extracted with 10% MeOH in DCM, the organic layer was concentrated under reduced pressure to afford the title compound 2-methyl-3-oxomorpholine-2- carboxylic acid. (0.300 g, 1.885 mmol. Yield: Quantitative)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.18 (s, 1H), 3.96 - 3.90 (m, 1H), 3.81 - 3.76 (m, 1H), 3.30 - 3.27 (m, 1H), 3.21 - 3.15 (m, 1H), 1.39 (s, 3H). Note: -COOH proton might be exchanged.LCMS (Method A): 0.352 min, 100.0%, 210.0 nm, MS: ES+ m / z 160.0 [M+1]Step 5: Synthesis of Intermediate 5-BL Methyl 2-((4,4-dimethylcyclohexyl) amino) nicotinate

[0173] To a stirred solution of 4,4-dimethylcyclohexan-l -amine (Intermediate 5-A2) (0.556 g, 4.37 mmol, 1.5 eq), and methyl 2-chloronicotinate (CAS:40134-18-7) (0.500 g, 2.91 mmol, 1.0 eq) in DMSO (5.0 mL) was added Et3N (1.21 mL, 8.70 mmol, 3.0 eq) at rt. The reaction mixture was stirred at 140 °C for 6 h. The reaction was monitored on TLC (using 20% EtOAc in hexane as mobile phase). After the completion of reaction, the resulting reaction mixture was cooled to rt and diluted with water (20 mL) then extracted with EtOAc (2 x 50 mL). Combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude (0.60 g). The obtained crude material was purified by flash column chromatography using silica gel (230- 400 mesh) as stationary phase and gradient 10-20% EtOAc in hexane afforded the title compound Methyl 2-((4,4-dimethylcyclohexyl) amino) nicotinate (0.220 g, 0.838 mmol, Yield: 28.78%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.27 (dd, J = 4.8, 2.0 Hz, 1H), 8.07 (dd, J 8.0, 2.0Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 6.58 (dd, J = 7.6, 4.8 Hz, 1H), 3.97 - 3.95 (m, 1H), 3.81 (s, 3H), 1.81 - 1.77 (m, 2H), 1.47 - 1.36 (m, 4H), 1.32 - 1.25 (m, 2H), 0.93 (d, J = 6.4 Hz, 6H).LCMS (Method A): 2.56 min, 100%, 254.0 nm, MS: ES+ m / z 264.28 [M+1]Step 6: Synthesis of Intermediate 5-B2: Methyl 2-((4.4-dimethylcyclohexyl) amino) nicotinate

[0174] To a solution of Methyl 2-((4,4-dimethylcyclohexyl) amino) nicotinate (Intermediate 5-B1) (0.220 g, 0.838 mmol, 1.0 eq) in MeOH (2.0 mL) was added hydrazine hydrate (0.8 mL, 16.60 mmol, 20.0 eq) at rt and the reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored on TLC (80% EtOAc in hexane as mobile phase). After completion the resulting reaction mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with 10% methanol in DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the title compound Methyl 2-((4,4-dimethylcyclohexyl) amino) nicotinate (Intermediate 5-B2) (0.200 g, 0.762 mmol, Yield: 90.91%)1H NMR (DMSO-d6, 400 MHz): δ ppm 9.71 (s, 1H), 8.28 (d. J = 7.6 Hz. 1H), 8.10 (dd, J = 4.8. 2.0 Hz, 1H), 7.80 (dd, J = 7.6, 1.6 Hz, 1H), 6.48 (dd, J = 7.6, 4.8 Hz, 1H), 4.44 (s, 2H), 3.90 3.86 (m, 1H), 1.80 - 1.76 (m, 2H), 1.39 - 1.32 (m, 3H), 1.29 - 1.22 (m, 3H), 0.92 (s, 6H).LCMS (Method A): 1.614 mm, 97.85 %, 254.0 nm, MS: ES+ m / z 263.33 [M+1]Step 7: Synthesis of Intermediate 10-A5: N'-(2-((4,4-dimethylcvclohexyl) amino) nicotinoyl)-2- methyl-3-oxomorpholine-2-carbohydrazide

[0175] To a solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (Intermediate 10-A4) (0.135 g, 0.855 mmol, 1.5 eq), in DMF (2.0 mL) was added DIPEA (0.5 mL, 2.85 mmol, 5.0 eq), EDC.HC1 (0.272 g, 1.42 mmol, 2.5 eq) and HOBt (0.259 g, 1.71 mmol, 3.0 eq) at rt. The resulting reaction mixture was stirred for 15 min at same temperature, followed by the addition of 2 Methyl 2-((4,4-dimethylcyclohexyl) amino) nicotinate (Intermediate 5-B2) (0.150 g, 0.57 mmol, 1.0 eq) dropwise (in DMF (2 mL)) and stirred again at rt for 16 h. The progress was monitored on TLC (10% MeOH in DCM mobile phase). After completion of reaction, as indicated by TLC the reaction mixture was diluted with water 10 mL and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0. 150 g crude. The obtained crude material was purified by trituration (DCM: pentane 1: 10) to afford the title compound N'-(2-((4,4-dimethylcyclohexyl) amino) nicotinoyl)-2-methyl-3-oxomorpholine-2-carbohydrazide (0.110 g, 0.272 mmol, Yield: 47.68%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 5 9.77 (s, 1H), 8.17 - 8.16 (m, 2H), 7.96 (d, J 6.8 Hz. 1H), 7.62 - 7.61 (m, 1H), 6.55 - 6.49 (m, 1H), 5.79-5.77 (m, 1H), 3.89 - 3.85 (m, 2H), 2.99 - 2.94 (m, 2H), 2.32 - 2.22 (m, 1H), 2.21 - 2.13 (m, 3H), 1.90-1.77 (m, 2H), 1.51 - 1.49 (m, 1H), 1.47 - 1.44 (m. 1H), 1.39 - 1.36 (m, 2H), 1.30-1.23 (m, 2H), 0.98-0.94 (m, 6H).LCMS (Method A): 1.60 min, 72.66%, 254 nm, MS: ES+ m / z 404.4 [M+1]Step 8: Synthesis of 2-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2- yl)-2-methylmorpholin-3-one (Compound 10)

[0176] To a stirred solution of N'-(2-((4.4-dimethylcyclohexyl) amino) nicotinoyl)-2-methyl- 3-oxomorpholine-2-carbohydrazide (0.100 g, 0.247 mmol, 1.0 eq) in DCM (1.0 mL) was added Et3N (0.10 mL, 0.743 mmol, 3.0 eq) and tosyl chloride (0.094 g, 0.494 mmol, 2.0 eq) at it The reaction mixture was stirred at same temperature for 2 h. The reaction progress was monitored by TLC (5% MeOH in DCM as mobile phase). After 2 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford (0.08 g) the crude. The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary' phase and gradient 70-80% EtOAc in hexane afforded the tittle compound 2-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-methylmorpholin-3-one (Compound 10) (0.015 g, 0.0389 mmol. Yield: 15.70%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 5 8.56 (d, J = 2.4 Hz, 1H), 8.30 (dd, J 4.8, 2.0 Hz,1H), 8.07 (dd, J = 7.6, 1.6 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 6.75-6.72 (m, 1H), 4.07 - 4.06 (m, 1H), 3.98 - 3.92 (m, 2H), 3.48 - 3.43 (m, 1H), 3.36 - 3.33 (m, 1H), 1.89 - 1.85 (m, 5H), 1.53 - 1.41 (m, 4H), 1.35 - 1.32 (m, 2H). 0.95 (d, J = 6.0 Hz, 6H).LCMS (Method A): 2.257 min, 99.20%, 254.0 nm, MS: ES+ m / z 386.49 [M+1]HPLC (Method A): 8.21 min, 98.03%, 254.0 nmChiral HPLC: (Peak-1): 1.814 min, 49.06%, 230.0 nm; (Peak-2): 2.180 min, 48.91%, 230.0 nmEXAMPLE 8 - Preparation of 2-(5-(2-((4,4-difhiorocyclohexyl) amino) pyridin-3-yl)- 1,3,4- oxadiazol-2-yl)-2-methylmorpholin-3-one (Compound 11)Step 1 : Synthesis of Intermediate 11 -Al : N'-(2-((4.4-difluorocyclohexyl) amino) nicotinoyl)-2- methyl-3-oxomorpholine-2-carbohydrazide

[0177] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (Intermediate 10- A4) (0.399 g, 2.50 mmol, 4.0 eq) in DMF (2.0 mL) was added DIPEA (0.42 mL, 2.84 mmol, 4.0 eq), EDC.HC1 (0.296 g, 1.50 mmol, 2.5 eq) and HOBt (0.284 g, 1.86 mmol, 3.0 eq) at rt. The reaction mixture was stirred for 15 min at same temperature, followed by the addition of DMF (2 mL) solution of 2-((4,4-difluorocyclohexyl) amino) nicotinohydrazide (Intermediate 9-A2) (0. 170 g, 0.62 mmol, 1.0 eq) dropwise and reaction mixture was further stirred at rt for 16 h. The progress was monitored on TLC (10% MeOH in DCM as mobile phase). After 16 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water 10 mL and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.120 g). The obtained crude material was purified by trituration with pentane (10 ml) to afford the title compound N'-(2- ((4.4-difluorocyclohexyl) amino) nicotinoyl)-2-methyl-3-oxomorpholine-2-carbohydrazide (0.110 g, 0.267 mmol, Yield: 42.51%)1H NMR (DMSO-d6, 400 MHz): δ, 10.38 (brs, 1H), 9.80 (s, 1H). 8.22 - 8.10 (m, 3H). 8.00 (d, J = 6.8 Hz, 1H), 6.62 (dd, J = 7.6, 4.8 Hz, 1H), 4.12 - 4.11 (m, 1H), 3.91 - 3.88 (m, 2H), 3.09 - 3.03 (m, 1H), 2.02 - 2.00 (m, 6H), 1.52 - 1.45 (m, 5H), 1.24-1.17 (m, 1H).LCMS (Method A): 1.616 min, 67.40%, 254 nm, MS: ES+ m / z 411.93 [M+1],Step 2: Synthesis of 2-(5-(2-((4.4-difluorocyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2- yl)-2-methylmorpholin-3-one (Compound 11)

[0178] To a stirred solution of N'-(2-((4,4-difluorocyclohexyl) amino) nicotinoyl)-2-methyl-3- oxomorpholine-2-carbohydrazide (0.100 g, 0.243 mmol, 1.0 eq) in DCM (1.0 mL) was addedEt3N (0.10 mL, 0.729 mmol, 3.0 eq) and tosyl chloride (0.091 g, 0.477 mmol, 2.0 eq) at rt. The reaction mixture was stirred at rt for 2 h and the progress was monitored on TLC (using 5%MeOH in DCM as mobile phase). After 2 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water 10 mL and extracted with DCM (3 x 10 mL).The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the (0.08 g) crude. The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 85% EtOAc in hexane afforded the title compound 2-(5-(2-((4,4-difluorocyclohexyl) amino) pyridin-3-yl)-l,3,4-oxadiazol-2-yl)-2- methylmorpholin-3-one (Compound 11) (0.039 g. 0.0991 mmol, Yield: 40.79%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 6 8.56 (d, J = 2.8 Hz, 1H), 8.34 (dd, J 4.8, 2.0 Hz,1H), 8.11 (dd, J 7.6, 2.0 Hz. 1H), 7.77 (d. J 7.2 Hz. 1H), 6.80 (dd, J 7.6, 4.8 Hz. 1H), 4.294.26 (m, 1H), 3.97 - 3.91 (m, 2H), 3.48 - 3.43 (m, 1H), 2.08 1.99 (m, 7H), 1.85 (s, 3H), 1.681.62 (m, 2H).LCMS (Method A): 1.966 min, 99.33%, 254.0 nm, MS: ES+ 394.61 [M+1]HPLC (Method A): 7.03 min, 98.78%, 254.0 nmChiral HPLC: (Peak-1): 5.17 min, 50.23%, 260.0 nm; (Peak-2): 7.09 mm, 49.29%, 260.0 nmEXAMPLE 9 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino)-6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 12)Step 1 : Synthesis of Intermediate 12-Al : methyl 2-((4,4-dimethylcyclohexyl) amino)-6- methylnicotinate

[0179] To a stirred solution of methyl 2-chloro-6-methylnicotinate (CAS: 53277-47-7) (0.5 g, 2.693 mmol, 1.0 eq) and 4,4-dimethylcyclohexan-1 -amine (Intermediate 5-A2) (0.514 g, 4.04 mmol, 1.5 eq) in DMSO (5 mL) was added Et3N (0.81 g, 8.07 mmol, 3.0 eq) at rt, the reaction mixture was stirred at 100 °C for 5 h and progress was monitored on TLC (30% EtOAc in hexane as mobile phase). After completion, as indicated by TLC the resulting reaction mixture was cooled to rt, then diluted with water (30 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na2SO4and then concentrated under reduced pressure to afford the crude. The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 2-3% EtOAc in hexane afforded the title compound methyl 2-((4,4-dimethylcyclohexyl) amino)-6-methylnicotinate (Intermediate 12-Al) (0.240 g, 0.868 mmol, Yield: 32.24%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 7.96-7.92 (m, 2H), 6.45 (d, J = 8.0 Hz, 1H), 4.01-3.99 (m, 1H), 3.76 (s, 3H), 2.33 (s, 3H), 1.82-1.77 (m, 2H), 1.44-1.26 (m, 6H), 0.96-0.91 (m, 6H).LCMS (Method A): 2.997 min, 100%, 254.0 nm, MS: ES+ m / z 278.24 [M+1]Step 2: Synthesis of Intermediate 12-A2:2-((4.4-dimethvlcyclohexyl) amino)-6- methylnicotinohydrazide

[0180] To a stirred solution of methyl 2-((4,4-dimethylcyclohexyl) amino)-6-methylnicotinate (Intermediate 12-Al) (0.19 g, 0.687 mmol, 1.0 eq) in MeOH (1.9 mL) was added hydrazine hydrate (0.343 g. 6.874 mmol. 10.0 eq) at rt and reaction mixture was heated up to 90 °C for 1.5 h. The reaction progress was monitored by TLC (30% EtOAc in hexane as mobile phase). After completion, the resulting reaction mixture was concentrated under reduced pressure then diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford 0.2 g crude. The crude was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase and gradient 5-10% EtOAc in hexane afforded the title compound 2-((4,4- dimethylcyclohexyl) amino)-6-methylnicotinohydrazide (0.185 g, 0.669 mmol, Yield: 97.37%)LCMS (Method A): 1.716 min, 97.43%, 254.0 nm, MS: ES+ m / z 277.24 [M+1]Step 3 Synthesis of Intermediate 12-A3: 2-((4.4-dimethylcyclohexyl) amino)-6-methyl-N'-(3- methyl-2-oxopyrrolidine-3-carbonvl) nicotinohvdrazide

[0181] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.17 g, 1.195 mmol, 2.0 eq) in DMF (1.6 mL) was added DIPEA (0.385 g, 2.989 mmol, 5.0 eq), EDC.HC1(0.571 g, 2.989 mmol, 5.0 eq) and HOBt (0.548 g, 3.586 mmol, 6.0 eq) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C followed by addition of 2-((4,4-dimethylcyclohexyl) amino)-6-methylnicotinohydrazide (Intermediate 12-A2) (0.165 g, 0.597 mmol, 1.0 eq) and stirred at rt for 9 h. The reaction progress was monitored by TLC (using 10% MeOH in DCM as a mobile phase). After completion, the resulting reaction mixture was diluted in water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude. The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 5-10% MeOH in DCM afforded the title compound 2-((4,4-dimethylcyclohexyl) amino)-6-methyl-N'- (3-methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.1 g, 0.249 mmol. Yield: 41.72%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 10.20 (s. 1H), 9.51 (s, 1H), 8.27 (s, 1H). 7.97 (s, 1H). 7.88 (d, J 8.0 Hz. 1H), 6.40-6.38 (m, 1H), 3.93 (brs, 1H), 3.22 (t, J = 6.8 Hz, 2H), 2.56-2.54 (m, 1H), 2.30 (s, 3H), 1.95-1.88 (m, 1H), 1.79-1.77 (m, 2H), 1.41-1.24 (m, 9H), 0.92 (d, J = 2.0 Hz, 6H)LCMS (Method A): 1.753 mm, 86.35%, 254.0 nm, MS: ES+ 402.44 [M+1]Step 4: Synthesis of 3-(5-(2-((4,4-dimethylcvclohexyl) amino)-6-methylpyridin-3-yl)-1,3,4- oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 12)

[0182] To a stirred solution to 2-((4,4-dimethylcyclohexyl) amino)-6-methyl-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (0. 1 g, 0.249 mmol, 1.0 eq) in DCM (1.0 mL) was added Et3N (0.20 g, 1.995 mmol, 8.0 eq) and tosyl chloride (0.142 g. 0.748 mmol, 3.0 eq) at room temperature. The reaction mixture w as stirred for 2 h at rt and progress was monitored by TLC (using 5% MeOH in DCM as mobile phase). After completion, the reaction mixture w as diluted with water (15 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude. The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 5% MeOH in DCM afforded the title compound 3-(5-(2-((4,4- dimethylcyclohexyl) amino)-6-methylpyridin-3-yl)-l,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2- one (0.042 g. 0.109 mmol, Yield: 43.97%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.17 (s, 1H). 7.91 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 6.60 (d. J=7.6Hz, 1H). 4.10-4.08 (m, 1H). 3.44-3.33 (m, 2H). 2.76-2.70 (m, 1H). 2.38 (s, 3H), 2.23-2.17 (m, 1H), 1.87-1.83 (m, 2H), 1.59 (s, 3H), 1.51-1.41 (m, 4H), 1.35-1.29 (m, 2H), 0.95 (d, J = 3.6 Hz, 6H).LCMS (Method A): 2.418 min, 100%, 254 nm, MS: ES+ m / z 384.39 [M+1],HPLC (Method A): 8.693 mm, 100%, 254 nm.Chiral HPLC: Peak-1 : 2.007 min, 50.18%, 356 nm; Peak-2: 2.1 19 min. 49.82%, 356 nmEXAMPLE 10 - Preparation of 3-(5-(2-((4,4-difhiorocyclohexyl) amino)-6-methylpyridin-3-yl)-1,3;4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 13)Step 1 : Synthesis of Intermediate 13-Al : methyl 2-((4.4-difluorocyclohexyl) amino)-6- methvlnicotinate

[0183] To a stirred solution of 4,4-difluorocyclohexan-l -amine hydrochloride (CAS: 675112-70-6) (2.77 g, 16.16 mmol, 3.0 eq) and methyl 2-chloro-6-methylnicotinate (CAS:53277-47-7)(1.0 g, 5.387 mmol, 1.0 eq) in DMSO (10.0 mL) was added Et3N (4.5 mL, 32.32 mmol, 6.0 eq) at rt. The reaction mixture was stirred at 140 °C for 16 h and reaction progress was monitored byTLC (20% EtOAc in hexane as mobile phase). After completion of reaction, the resulting reaction mixture was cooled to rt then diluted with water (20 mL) and extracted with EtOAc (3 x30 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude (1.2 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 20-25%EtOAc in hexane afforded the title compound Methyl 2-((4,4-difluorocyclohexyl) amino)-6- methylnicotinate (Intermediate 13-Al) (0.350 g, 1.231 mmol. Yield: 22.85%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 7.98 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 4.20-4.18 (m, 1H), 3.79 (s, 3H), 2.35 (s, 3H), 2.03 - 1.96 (m, 6H), 1.59 - 1.55 (m, 2H).LCMS (Method A): 2.474 min, 98.16%, 254.0 nm, MS: ES+ m / z 285.41 [M+1],Step 2: Synthesis of Intermediate 13-A2: 2-((4.4-difluorocyclohexyl) amino )-6- methylnicotinohydrazide

[0184] To a solution of Methyl 2-((4,4-difluorocyclohexyl) amino)-6-methylnicotinate (Intermediate 13-Al) (0.350 g, 1.231 mmol, 1.0 eq) in MeOH (3.5 mL) was added Hydrazine hydrate (1.09 mL, 24.66 mmol, 20.0 eq) at rt and the reaction mixture was heated up to 90 °C for 16 h. The reaction progress was monitored on TLC (5% MeOH in DCM as mobile phase). After completion, the resulting reaction mixture was concentrated under reduced pressure and quenched with water (10 mL), extracted with 5% methanol in DCM (3 x 10 mL) and combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the cmde 2-((4,4-difluorocyclohexyl) amino)-6-methylnicotinohydrazide (Intermediate 13-A2) (0.320 g, 1.195 mmol, Yield: 91.43%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.74 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.01 (d, J 2.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 4.47 (brs, 2H), 4.07-4.05 (m, 1H), 2.13 (s, 3H), 2.03 - 1.97 (m, 6H), 1.51 - 1.48 (m, 2H).LCMS (Method A): 1.519 mm, 97.02%, 254.0 nm, MS: ES+ m / z 285.29 [M+1]Step 3: Synthesis of Intermediate 13-A3: 2-((4.4-difluorocyclohexyl) amino)-6-methyl-N'-(3- methyl-2-oxopyrrolidine-3-carbonyl) nicotinohvdrazide

[0185] To a solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.563 g, 3.93 mmol, 4.0 eq), in DMF (5.0 ml) was added DIPEA (0.85 mL, 4.90 mmol. 5.0 eq), EDC.HC1 (0.470 g, 2.40 mmol, 2.5 eq) and HOBt (0.449 g, 2.90 mmol, 3.0 eq) at 0 °C then stirred for 15 min at the same temperature followed by the addition of 2-((4,4-difluorocyclohexyl)amino)-6- methylni cotinohydrazide (Intermediate 13-A2) (0.280 g, 0.98 mmol, 1.0 eq) dropwise (in DMF) at 0 °C. After completion of addition reaction mixture was stirred at rt for 16 h. The progress was monitored on TLC (5% MeOH in DCM mobile phase). After 16 h TLC indicates the completion of reaction so resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to get the crude (0.30 g). The obtained crude material was purified by trituration with pentane (10 ml) to afford the title compound 2-((4,4-difluorocyclohexyl) amino)-6-methyl-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.260 g, 0.244 mmol, Yield: 64.00%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 5 10.29 (s, 1H), 9.59 (s, 1H), 8.38 (s, 1H), 7.96 - 7.85 (m, 2H), 6.44 (d. J 7.6Hz, 1H), 4.13-4.12 (m, 1H), 3.21 (t, J = 6.4 Hz, 2H), 2.31 (s, 3H), 2.10 - 1.87 (m, 7H), 1.54 - 1.47 (m, 2H), 1.37 (s, 3H), 1.28 - 1.19 (m, 1H).LCMS (Method A): 1.697 min, 91.84%, 254 nm, MS: ES+ m / z 410.29 [M+1]Step 4: Synthesis of 3-(5-(2-((4.4-difluorocvclohexyl) amino)-6-methylpvridin-3-yl)-1.3.4- oxadiazol-2-vl)-3-methvlpyrrolidin-2-one (Compound 13)

[0186] To a stirred solution of 2-((4,4-difluorocyclohexyl) amino)-6-methyl-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.250 g, 0.61 mmol, 1.0 eq) in DCM (2.5 mL) was added Et3N (0.25 mL. 1.80 mmol, 3.0 eq) and tosyl chloride (0. 173 g, 0.91 mmol, 1.5 eq) at rt, then reaction mixture was stirred at same temperature for 2 h. The reaction was monitored by TLC (100% EtOAc as mobile phase). After 2 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.30 g crude. The crude was purified by manual column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 90% EtOAc in hexane afforded the tittle compound 3-(5-(2-((4,4-difluorocyclohexyl) amino)-6-methylpyridin-3-yl)-l,3,4-oxadiazol-2- yl)-3-methyl pyrrolidin-2-one (Compound 13) (0.194 g. 0.498 mmol, Yield: 81.17%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 5 8.17 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H). 7.76 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 7.6 Hz. 1H), 4.30 - 4.27 (m, 1H), 3.45 - 3.38 (m, 2H), 2.77 - 2.70 (m, 1H), 2.40 (s, 3H), 2.24 - 2.17 (m, 1H), 2.08 - 2.00 (m, 6H), 1.66 - 1.62 (m, 2H), 1.59 (s, 3H).LCMS (Method A): 2.320 min, 99.35%. 254.0 nm, MS: ES+ m / z 392.24 [M+1]HPLC (Method A): 7.973 min, 100%, 254.0 nmChiral HPLC: (Peak-1): 2.015 min, 49.97%. 350.0 nm; (Peak-2); 2.220 min, 50.03%, 350.0 nmEXAMPLE 11 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino)-5-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 14)Step 1 : Synthesis of Intermediate 14-AL methyl 2-chloro-5-methylnicotinate

[0187] To a solution of 2-chloro-5-methylnicotinic acid (CAS: 66909-30-6) (5.0 g, 29.14 mmol, 1.0 eq) and K2CO3(6.00 g, 43.71 mmol, 1.5 eq) in DMF (100 mL) was added Methyl iodide (6.00 mL, 87.42 mmol, 3.0 eq) and reaction mixture was stirred at rt for 16 h. The reaction was monitored on TLC (20% EtOAc in hexane as mobile phase). After completion of reaction, the resulting reaction mixture was diluted with water (40 mL) and extracted withEtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4and then concentrated under reduced pressure to afford the title compound Methyl 2-chloro-5- methylnicotinate Intermediate 14-Al (5.0 g. 25.93 mmol. Yield: 92.44%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.43 - 8.42 (m, 1H), 8.09 - 8.08 (m, 1H). 3.87 (s, 3H),2.33 (s. 3H)LCMS (Method A): 1.847 min, 100%, 254.0 nm, MS: ES+ m / z 186.36 [M+1]Step 2; Synthesis of Intermediate 14-A2: methyl 2-((4,4-dimethylcvclohexyl) amino)-5-methyl nicotinate

[0188] To a solution of 4,4-dimethylcyclohexan-1-amine (Intermediate 5-A2) (1.64 g, 12.93 mmol, 1.2 eq) and Methyl 2-chloro-5 -methylnicotinate (Intermediate 14-Al) (2.0 g, 10.77 mmol, 1.0 eq) in DMSO (20.0 mL) was added DIPEA (6.94 g, 53.85 mmol, 5.0 eq) at rt. Afterthe addition, the reaction mixture was stirred at 120 °C for 16 h. The reaction was monitored on TLC (20% EtOAc in hexane as mobile phase). After completion of the reaction, the resulting reaction mixture was cooled to rt then diluted with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude (1.2 g). The obtained cmde material was purified by flash column chromatography using silica gel (230-400 mesh) as a stationary' phase. The gradient 15-20% EtOAc in hexane afforded the title compound methyl 2-((4,4-dimethylcyclohexyl) amino)-5- methylnicotinate (0.35 g, 1.26 mmol, Yield: 11.75%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.13 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 7.2Hz, 1H), 3.93 - 3.91 (m, 1H), 3.81 (s, 3H). 2.16 (s, 3H), 1.81 - 1.77 (m. 2H), 1.46- 1.37 (m, 4H), 1.36-1.24 (m, 2H), 0.93 (d, J = 4.8 Hz, 6H).LCMS (Method A):2.314 min, 90.12%, 254.0 nm, MS: ES+ m / z 276.99 [M+1]Step 3; Synthesis of Intermediate 13-A3: 2-((4,4-dimethylcyclohexyl) amino)-5 -methyl nicotinohydrazide

[0189] To a solution of methyl 2-((4,4-dimethylcyclohexyl) amino)-5-methylnicotinate (Intermediate 14-A2) (0.330 g, 1.19 mmol, 1.0 eq) in MeOH (4.0 mL) was added hydrazine hydrate (1.16 mL, 23.80 mmol, 20.0 eq) at rt then the reaction mixture was heated at 90 °C for 16 h. The reaction was monitored on TLC (100% EtOAc as mobile phase). After completion, the resulting reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with water (10 mL). extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the title compound 2-((4,4-dimethylcyclohexyl) amino)-5-methylnicotinohydrazide (0.3 g, 1.08 mmol, Yield: 90.91%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.66 (s, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 1.6 Hz. 1H), 7.68 (d, J = 2.0 Hz. 1H), 4.43 (s, 2H), 3.84-3.82 (m, 1H), 2.10 (s, 3H), 1.79 - 1.75 (m, 2H), 1.39-1.23 (m. 6H), 0.92 (d. J = 2.0 Hz. 6H).LCMS (Method A): 1.718 min, 99.58%. 254.0 nm, MS: ES+ m / z 277.11 [M+1]Step 4; Synthesis of Intermediate 14-A4: 2-((4,4-dimethylcyclohexyl) amino)-5-methyl-N'-(3- methyl-2-oxopyrrolidine-3-carbonyl) nicotinohy drazide

[0190] To a solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.620 g, 4.34 mmol. 4.0 eq), in DMF (2.0 mL) was added DIPEA (0.559 g, 4.34 mmol, 4.0 eq), EDC.HC1 (0.51 g, 2.71 mmol, 2.5 eq) and HOBt (0.49 g, 3.25 mmol, 3.0 eq) at rt. The reaction mixture was stirred for 15 min at rt followed by the addition of 2-((4,4-dimethylcyclohexyl) amino)-5-methylnicotinohydrazide (Intermediate 14-A3) (0.300 g, 1.08 mmol, 1.0 eq) in DMF (1.0 mL) dropwise and further stirred at rt for 6 h. The progress was monitored on TLC (using 100% EtOAc as a mobile phase). After 6 h, TLC indicates the completion of the reaction then water (20 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude. The obtained crude material was purified by trituration with n-pentane: DCM (10: 1) to afford the title compound 2-((4,4-dimethylcyclohexyl) amino)-5-methyl-N'-(3-methyl-2-oxopyrrolidine-3- carbonyl) nicotinohydrazide (0.250 g, 0.622 mmol, Yield: 57.36%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 10.27 (s, 1H), 9.56 (s, 1H), 8.03 - 7.97 (m, 2H), 7.91 (d, J = 7.2Hz, 1H) 7.85 (d, J = 1.6 Hz, 1H), 3.84 (brs, 1H), 3.22 (t, J = 6.8 Hz, 2H). 2.56 - 2.51 (m. 1H), 2.13 (s. 3H), 1.95 - 1.89 (m. 1H), 1.78 - 1.76 (m, 2H). 1.38 - 1.35 (m. 6H), 1.32-1.16 (m, 3H), 0.92 (s, 3H), 0.91 (s, 3H)LCMS (Method A): 1.759 min, 95.33%, 220 nm, MS: ES+ 402.08 [M+1]Step 5: Synthesis of Intermediate 14: 3-(5-(2-((4,4-dimethylcyclohexyl) amino)-5- methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 14)

[0191] To a stirred solution of 2-((4,4-difluorocyclohexyl) amino)-6-methyl-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.25 g, 0.62 mmol, 1.0 eq) in DCM (2.5 mL), was added Et3N (0.50 g, 4.90 mmol, 8.0 eq) and tosyl chloride (0.353 g, 1.80 mmol, 3.0 eq) at rt and stirred for 2 h. The reaction was monitored on TLC (using 100% EtOAc as mobile phase). After 2 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.280 g). The crude w as purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 80-90% EtOAc in hexane afforded the title compound 3-(5-(2- ((4,4-dimethylcyclohexyl) amino)-5-methylpyridin-3-yl)-l,3,4-oxadiazol-2-yl)-3- methylpyrrolidin-2-one (Compound 14) (0.235 g, 0.612 mmol, Yield: 96.32%)1H NMR (DMSO-d6, 400 MHz): δ ppm: 5 8.17 - 8.13 (m, 2H), 7.86 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 7.2 Hz. 1H), 4.01 (brs, 1H), 3.46 - 3.37 (m, 2H), 2.78 - 2.72 (m, 1H), 2.21 (s, 4H), 1.87 - 1.83 (m, 2H), 1.60 (s, 3H), 1.51-1.40 (m, 4H), 1.34-1.27 (m, 2H), 0.95 (s, 3H), 0.94 (s, 3H).LCMS (Method A): 2.098 min, 99.70%, 254.0 nm, MS: ES+ m / z 384.36 [M+1]HPLC (Method A): 7.67 min, 98.68%, 254.0 nmChiral HPLC: (Peak-1): 1.924 min, 50.03%, 234.0 nm; (Peak- 2): 2.124 min, 49.97%, 234.0 nmEXAMPLE 12 - Preparation of 3-(5-(2-((4,4-difluorocyclohexyl) amino)-5-methyl pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 15)Step 1 : Synthesis of Intermediate 14-Al : methyl 2-chloro-5-methvlnicotinate

[0192] To a stirred solution of 2-chloro-5 -methylnicotinic acid (CAS: 66909-30-6) (5.0 g,29.14 mmol, 1.0 eq) and K2CO3(5.63 g, 40.79 mmol, 1.5 eq) in DMF (35 mL) was addedMethyl iodide (5.44 mL, 87.42 mmol, 3.0 eq) at rt. After the addition of Mel, the reaction mixture was stirred for 16 h at ambient temperature. The reaction was monitored on TLC (20%EtOAc in hexane as mobile phase). After the completion of reaction, the resulting reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4then concentrated under reduced pressure to afford the title compound Methyl 2-chloro-5-methylnicotinate (4.8 g, 25.86 mmol, Yield: 88.74%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.42 (dd, J = 2.4, 0.8 Hz, 1H), 8.09 (dd, J = 2.4, 0.8Hz, 1H), 3.87 (s, 3H), 2.33 (s, 3H),LCMS (Method A): 1.868 mm, 98.90%, 254.0 nm, MS: ES+ m / z 185.99 [M+1]Step 2: Synthesis of Intermediate 15-Al : methyl 2-((4.4-difluorocyclohexyl) amino)-5-methvl nicotinate

[0193] To a solution of 4,4-difluorocyclohexan-l -amine hydrochloride (CAS: 675112-70-6)(3.68 g, 21.55 mmol, 2.0 eq) and methyl 2-chloro-5-methylnicotinate (Intermediate 14-Al) (2.0g, 10.77 mmol, 1.0 eq) in DMSO (20 mL), was added Et?N (7.49 mL, 53.85 mmol, 5.0 eq) at rt.After the addition reaction mixture was heated for 160 °C for 2 h. The reaction was monitored by TLC (40% EtOAc in hexane as mobile phase). After the completion of reaction, the resulting reaction mixture was cooled to rt and diluted with water (50 mL) then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude (0.6 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 20-25% EtOAc in hexane afforded the title compound methyl 2-((4,4-difluorocyclohexyl) amino)-5- methylnicotinate (0.140 g, 0.739 mmol, Yield: 4.57%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.16 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 4.15-4.13 (m, 1H), 3.81 (s, 3H), 2.18 (s, 3H). 2.03 - 1.94 (m, 6H). 1.57 - 1.53 (m, 2H).LCMS (Method A): 2.324 min, 95.02 %, 254.0 nm, MS: ES+ m / z 285.24 [M+H]Step 3: Synthesis of Intermediate 15-A2: 2-((4,4-difluorocyclohexyl) amino)-5-methyl nicotinohydrazide

[0194] To a solution of Methyl 2-((3,3-difluorocyclohexyl) amino) nicotinate Intermediate 15- Al (0.170 g, 0.59 mmol, 1.0 eq) in MeOH (2.0 mL) was added Hydrazine hydrate (0.5 mL, 11.90 mmol, 20.0 eq) at rt and reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored on TLC (5% MeOH in DCM as mobile phase), after completion the resulting reaction mixture was concentrated under reduced pressure and extracted with 10% methanol in DCM (3 x 20 mL) and combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the title compound 2-((4,4-difluorocyclohexyl) amino)-5- methylnicotinohydrazide (0.130 g. 0.457 mmol, Yield: 76.47%) (Note: The obtained crude material was used as such for next step).1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.74 (s, 1H). 8.09 (d, J = 7.6 Hz, 1H), 8.01 (d, J 2.0 Hz. 1H), 7.73 (d. J = 2.0 Hz. 1H), 4.47 (s. 2H), 4.07-4.05 (m, 1H), 2.13 (s, 3H), 2.03-1.97 (m, 6H), 1.51 - 1.48 (m, 2H).LCMS (Method A): 1.519 min, 97.02 %, 254.0 nm, MS: ES+ m / z 285.29 [M+1]Step 4: Synthesis of Intermediate 15-A3: 2-((4,4-difluorocyclohexyl) amino)-5-methyl-N'-(3- methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide

[0195] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.257 g, 1.800 mmol, 4.0 eq) in DMF (3.0 mL) was added DIPEA (0.39 mL, 2.25 mmol, 5.0 eq), EDC.HC1 (0.218 g, 1.14 mmol, 2.5 eq) and HOBt (0.206 g, 1.35 mmol, 3.0 eq) at 0 °C. The reactionmixture was stirred for 15 min at 0 °C, followed by the addition of 2-((4,4-difluorocyclohexyl) amino)-5-methylnicotinohydrazide (Intermediate 15-A3) (0.130 g, 0.45 mmol, 1.0 eq) and allowed to stirred at rt for 16 h. The progress was monitored on TLC (5% MeOH in DCM mobile phase). After 16 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water and extracted with 10% methanol in DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0. 110 g). The obtained crude material was purified by trituration with pentane (15 ml) to afford the title compound 2-((4.4-difluorocyclohexyl) amino)-5-methyl-N'-(3-methyl- 2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.100 g. 0.244 mmol. Yield: 54.00%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 5 10.32 (brs. 1H), 9.58 (s, 1H), 8.06 (d, J 1.6 Hz,1H), 7.97 - 7.87 (m, 3H), 4.08 - 4.04 (m, 1H). 3.22 (t. J = 6.8 Hz. 1H), 2.14 (s. 3H), 2.01 - 1.93(m, 5H), 1.95 - 1.89 (m, 2H), 1.52-1.48 (m, 2H), 1.38 (s, 3H), 1.29 - 1.24 (m, 2H).LCMS (Method A): 1.600 min, 95.71%, 254 nm, MS: ES+ m / z 410.49 [M+1]Step 5: Synthesis of 3-(5-(2-((4,4-difluorocyclohexyl) amino)-5-methylpyridin-3-yl)-1.3.4- oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 15)

[0196] To a stirred solution of 2-((4,4-difluorocyclohexyl) amino)-5-methyl-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.100 g, 0.24 mmol, 1.0 eq) in DCM (1.0 mL) was added Et3N (0.1 mL, 0.72 mmol, 3.0 eq) and tosyl chloride (0.068 g, 0.36 mmol, 1.5 eq) at rt. The reaction mixture was stirred al rt for 2 h. and monitored on TLC (5% MeOH in DCM as mobile phase). After 2 h. TLC indicates the completion of reaction so resulting reaction mixture was diluted with water (20 mL) and extracted with 10% methanol in DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.110 g). The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 70-80% EtOAc in hexane afforded the title compound 3-(5-(2-((4,4-difluorocyclohexyl) amino)-5-methylpyridin-3-yl)-l,3,4-oxadiazol-2- yl)-3-methylpyrrolidin-2-one (0.069 g, 0.176 mmol, Yield: 72.18%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 5 8.17 - 8.16 (m, 2H), 7.90 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 4.24-4.23 (m, 1H), 3.44 - 3.37 (m, 2H), 2.78 - 2.72 (m, 1H), 2.23 - 2.18 (m, 4H), 2.06 - 2.00 (m, 6H), 1.60 (s, 5H).1H NMR (MeOD-d4, 400 MHz): δ ppm, 5 8.11 (dd, J = 2.4, 0.8 Hz, 1H), 7.99 (dd, J = 20, 7.2 Hz. 1H), 4.25-4.15 (m, 1H), 3.61 - 3.52 (m, 2H), 2.95 - 2.88 (m, 1H), 2.39 - 2.33 (m, 1H), 2.28 (s, 3H). 2.15 - 2.00 (m, 6H). 1.77-1.73 (m, 5H).LCMS (Method A): 1.998 min, 100%. 254.0 nm, MS: ES+ m / z 392.39 [M+1]HPLC (Method A): 6.67 min, 100%, 254.0 nmChiral HPLC: (Peak-1): 1.800 min, 49.94%. 263.0 nm; (Peak-2): 1.956 min, 50.06%, 263.0 nmEXAMPLE 13 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino)-4-methylpyridin-3-yl)-l,3;4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 16)Step 1 : Synthesis of Intermediate 16-A5: methyl 2-chloro-4-iodonicotinate

[0197] To a stirred solution of 2-chloro-4-iodonicotinic acid (CAS:544671-78-5) (8.5 g, 30.03 mmol 1.0 eq) in DMF (85 mL) was added K2CO3(6.21 g, 45.06 mmol, 1.5 eq) at room temperature followed by addition of Methyl iodide (12.79 g, 90. 11 mmol 3.0 eq) and reaction mixture was stirred at rt for 4 h. The reaction was monitored by TLC (10% ethyl acetate in hexane as a mobile phase), after completion the resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude (9.0 g).The obtained crude material was purified by trituration with n-pentane (40 mL) to afford the title compound methyl 2-chloro-4-iodonicotinate (8.0 g, 26.93 mmol, Yield: 89.68%).1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 5.2 Hz, 1H), 8.04 (d, J = 5.2 Hz, 1H), 3.94 (s, 3H).LCMS (Method A): 2.039 min, 100%, 254.0 nm, MS: ES+ 298.15 m / z [M+1]Step 2: Synthesis of Intermediate 16-Al : Methyl 2-chloro-4-methvlnicotinate

[0198] To a stirred solution of methyl 2-chloro-4-iodonicotinate (Intermediate 16-A5) (8.0 g, 26.89 mmol, 1.0 eq) in DMF (80 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (CAS:823-96-l) (6.72 g, 53.78 mmol 2.0 eq) at rt, followed by addition of K2CO3(14.8 g, 107.5 mmol 4.0 eq) and reaction mixture was purged using N2 (g). The catalyst Pd(PPh3)4(3.10 g, 26.89 mmol 0. 1 eq) was added to this reaction mixture at room temperature and heated under stirring up to 1 10 °C for 120 min. The reaction was monitored by TLC (10% ethyl acetate in hexane as a mobile phase), after completion the resulting reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude (9.0 g). The obtained crude material was purified by flash column chromatography using silica gel (230- 400 mesh size) and gradient 0-5% ethyl acetate in hexane afforded the title compound methyl 2- chloro-4-methylnicotinate (2.0 g, 10.77 mmol, Yield: 40.01%).1H NMR (DMSO-d6, 400 MHz): 5 8.38 (d, J= 4.8 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 3.92 (s, 3H), 2.31 (s, 3H)LCMS (Method A): 1.830 min, 96.68 %, 254.0 nm, MS: ES+ m / z 185.79 [M+1]Step 3: Synthesis of Intermediate 16-A2: methyl 2-((4.4-dimethylcyclohexyl) amino)-4-methyl nicotinate

[0199] To a stirred solution of methyl 2-chloro-6-methylbenzoate (1.0 g, 5.40 mmol 1.0 eq) and 4,4-dimethylcyclohexan-l-amine (Intermediate 5-A2) (1.37 g, 10.81 mmol 2.0 eq) in DMSO (10 mL) was added DIPEA (6.97 g, 54.05 mmol 10.0 eq) at rt. The reaction mixture was heated up to 140 °C and stirred for 16 h. The reaction progress was monitored by TLC (30% ethyl acetate as a mobile phase), after completion the resulting reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over Na2SO4. filtered and concentrated under reduced pressure to afford the crude product (1.3 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) and gradient 15% EtOAc in hexane afforded the title compoundmethyl 2-((4,4-dimethylcyclohexyl) amino)-4-methylnicotinate (0.15 g, 0.543 mmol. Yield: 10.07%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.02 (d, J = 5.2 Hz. 1H), 7.30 (d, J = 7.2 Hz. 1H), 6.44 (d, J = 5.2 Hz, 1H), 3.90-3.88 (m, 1H), 3.83 (s, 3H), 2.33 (s, 3H), 1.77-1.73 (m, 2H), 1.45-1.35 (m, 4H), 1.30-1.26 (m, 2H), 0.93 (d, J = 6.0Hz, 6H).LCMS (Method A): 2.156 min, 94.51%, 254.0 nm, MS:ES+ m / z 277.06 [M+1]

[0200] Step 4: Synthesis of Intermediate 16-A3: 2-((4.4-dimethylcyclohexyl) amino)-4-methyl nicotinohydrazide

[0201] To a stirred solution of methyl 2-((4,4-dimethylcyclohexyl) amino)-4-methylnicotinate (Intermediate 16-A2) (0.15 g, 0.543 mmol 1.0 eq) in MeOH (2 mL) was added hydrazine hydrate monohydrate (CAS:7803-57-8) solution (1.35 g, 27.17 mmol, 50.0 eq) at rt. The reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored by TLC (80% EtOAc in hexane as a mobile phase), after completion the resulting reaction mixture was poured into 50 mL water extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (0.2 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) and gradient 50% EtOAc in hexane afforded the title compound 2-((4,4- dimethylcyclohexyl) amino)-4-methylnicotinohydrazide (0.1 g, 0.362 mmol, Yield: 66.67%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.44 (s, 1H), 7.86 (d, J = 5.2 Hz, 1H), 6.37 (d, J 5.2 Hz, 1H), 5.54 (d, J = 8.0 Hz, 1H), 4.57 (brs, 1H), 3.78-3.76 (m, 1H), 2.12 (s, 3H), 1.73-1.70 (m, 2H), 1.39-1.30 (m, 4H), 1.27-1.21 (m, 3H), 0.92 (A,J = 4.4Hz, 6H).LCMS (Method A): 1.576 min, 84.09%, 254 nm, MS: ES- m / z 275.71 [M-l]Step 5; Synthesis of Intermediate 16-A4: -2-((4,4-dimethylcyclohexyl) amino)-4-methyl-N'-(3- methyl-2-oxopvrrolidine-3-carbonyl) nicotinohydrazide

[0202] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.186 g, 1.304 mmol 4.0 eq) in DMF (2 mL) was added DIPEA (0.210 g, 1.63 mmol, 5.0 eq), EDC.HC1 (CAS: 25952-53-8) (0.155 g, 0.815 mmol, 2.5 eq) and HOBt (0.149 g, 0.978 mmol, 3.0 eq) at 0 °C under nitrogen atmosphere. To this reaction mixture 2-((4,4-dimethylcyclohexyl) amino)-4- methylnicotinohydrazide (Intermediate 16-A3) (0.09 g, 0.326 mmol, 1.0 eq) was added and reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC (100% EtOAc as a mobile phase), after completion the resulting reaction mixture was poured into water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers w ere dried over Na2SO4. filtered and concentrated under reduced pressure to afford the crude product (0.08 g). Theobtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) and gradient 70% EtOAc in hexane afforded the title compound 2-((4,4- dimethyl cyclohexyl) amino)-4-methyl-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.045 g, 0. 112 mmol, Yield; 34.42%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 10.15 (s. 1H), 9.66 (s, 1H), 7.98 (s, 1H), 7.89 (d, J = 5.2 Hz, 1H), 6.37 (d, J = 5.2 Hz, 1H), 6.13 (d. J = 7.2 Hz. 1H), 3.78-3.77 (m. 1H), 3.23 (t, J = 6.8 Hz, 2H), 2.59-2.54 (m, 1H), 2,14 (s, 3H), 1.96-1.90 (m, 1H), 1.77-1.73 (m, 2H), 1.42-1.34 (m, 7H), 1.27-1.20 (m, 2H), 0.92 (d, J = 3.2 Hz, 6H).LCMS (Method A): 1.680 mm, 100%, 254 nm, MS: ES+ m / z 402.56 [M+1]Step 6: - Synthesis of 3-(5-(2-((4.4-dimethylcyclohexyl) amino)-4-methylpyridin-3-vl)-L3.4- oxadiazol-2-vl)-3-methylpyrrolidin-2-one (Compound 16)

[0203] To a stirred solution of 2-((4,4-dimethyl cyclohexyl) amino)-4-methyl-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (Intermediate 16-A4) (0.045 g, 0.112 mmol 1.0 eq) in DCM (2 mL) was added p -Toluene sulfonyl chloride (0.053 g, 0.280 mmol, 2.5 eq) and Et3N (0.0566 g, 0.561 mmol, 5.0 eq) under nitrogen atmosphere and stirred at rt for 1 h. The reaction was monitored by TLC (5% MeOH in DCM as a mobile phase), after completion the resulting reaction mixture was poured into water (50 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude (0.05 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) and gradient 3% MeOH in DCM afforded the title compound 3-(5-(2-((4,4-dimethylcyclohexyl) amino)-4-methylpyridin-3-yl)-1,3,4- oxadiazol-2-yl)-3-methylpyrrolidin-2-one (0.015 g, mmol, Yield: 34.90%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.19 (s, 1H), 8.09 (d, J= 4.8 Hz, 1H), 7.94 (d, J= 7.2 Hz, 1H), 6.57 (d, .J 5.6 Hz. 1H), 4.05-3.98 (m, 1H), 3.41-3.36 (m, 1H), 2.78-2.67 (m, 1H), 2.44 (s, 3H), 2.26-2.19 (m, 1H), 1.83-1.80 (m, 2H), 1.60 (s, 3H), 1,45-1.39 (m, 4H), 1.33-1.32 (m, 1H), 1.29-1.22 (m. 2H), 0.94 (d. J=5.2 Hz, 6H).LCMS (Method A): 1.974 min, 98.28%, 254 nm. MS: ES+ m / z 384.35 [M+1]HPLC (Method A): 5.609 min, 97.07%, 254 nmChiral HPLC: 2.168 min, 47.79%, 233 nm; 2.27 min, 47.88%, 233 nmEXAMPLE 14 - Preparation of 3-(5-(3-((4,4-dimethylcyclohexyl) amino) pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 17)

[0204] Step 1 : Synthesis of Intermediate 17-Al: methyl 3-((4,4-dimethylcyclohexyl) amino) pyrazine-2-carboxylate

[0205] To a stirred solution of methyl 3-chloropyrazine-2-carboxylate (CAS: 27825-21-4) (0.8 g, 4.310 mmol, 1.0 eq) and 4,4-dimethylcyclohexan-l -amine (Intermediate 5-A2) (0.822 g.6.465 mmol, 1.5 eq) in DMSO (8 mL) was added Et3N (1.30 g, 12.93 mmol, 3.0 eq) at rt and reaction mixture was stirred for 2 h al 100 °C. The reaction was monitored on TLC (30% EtOAc in hexane as mobile phase), after completion the resulting reaction mixture was cooled to rt and diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4then concentrated under reduced pressure to afford the crude. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 20% EtOAc in hexane afforded the title compound methyl 3-((4,4-dimethylcyclohexyl) amino) pyrazine-2-carboxylate (0.548 g, 2.08 mmol. Yield:44.89%)LCMS (Method A): 2.572 mm, 95.42 %, 254 nm, MS: (ES+) m / z 264.33 [M+1]Step 2: Synthesis of Intermediate 17-A2: 3-((4.4-dimethylcyclohexyl) amino) pyrazine-2- carbohydrazide

[0206] To a solution of methyl 3-((4,4-dimethylcyclohexyl) amino) pyrazine-2-carboxylate Intermediate 17-A2 (0.540 g, 2.05 mmol, 1.0 eq) in MeOH (5.4 mL) was added Hydrazine hydrate (1.02 g, 20.5 mmol, 10.0 eq) at rt and reaction mixture was heated up to 90 °C for 1.5 h. The reaction was monitored on TLC (30% EtOAc in hexane as mobile phase), after completion the resulting reaction mixture was concentrated under reduced pressure and diluted with water (15 mL) then extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the crude (0.6 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 20% EtOAc in hexane afforded the title compound 3-((4,4- dimethylcyclohexyl) amino) pyrazine-2-carbohydrazide (0.5 g, 1.89 mmol, Yield: 92.59%)1H NMR (DMSO-d6, 400 MHz): δ ppm 9.88 (s, 1H), 8.70 (d, J = 7.6 Hz, 1H), 8.20 (d, J = Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 4.51 (d, J = 4.4 Hz, 2H), 3.86-3.84 (m, 1H), 1.81-1.77 (m, 2H), 1.48-1.37 (m, 4H), 1.31-1.25 (m, 2H), 0.95-0.90 (m, 6H).LCMS (Method A): 2.106 min, 100%, 254.0 nm, MS: ES+ m / z 264.28 [M+1]Step 3 Synthesis of Intermediate 17-A3; 3-((4.4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) pyrazine-2-carbohydrazide

[0207] To a solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.544 g, 3.802 mmol, 2.0 eq) in DMF (5 mL) was added DIPEA (1.23 g, 9.505 mmol, 5.0 eq), EDC.HC1 (0.908 g, 4.752 mmol, 2.5 eq) and HOBt (0.872 g, 5.703 mmol. 3.0 eq) at 0 °C. After 15 min of stirring at 0 °C, 3-((4,4-dimethylcyclohexyl) amino) pyrazine-2 -carbohydrazide (Intermediate 17-A2) (0.5 g, 1.901 mmol, 1.0 eq) was added and stirred at rt for 16 h. The reaction progress was monitored on TLC (using 10 % MeOH in DCM as a mobile phase) which indicated that the reaction was completed after 16 h. The resulting reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude. The obtained crude material was purified by trituration with n-pentane (30 mL) to afford the title compound 3-((4,4- dimethylcyclohexyl) amino)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) pyrazine-2- carbohydrazide (0.425 g, 1.094 mmol. Yield: 57.62%)LCMS (Method A);2.016 min, 100%, 210.0 nm, MS; ES+ m / z 389.39 [M+1]Step 4: Synthesis of 3-(5-(3-((4,4-dimethylcyclohexyl) amino) pyrazin-2-yl)-1.3,4-oxadiazol- 2-yl)-3-methylpyrrolidin-2-one (Compound 17)

[0208] To a stirred solution of 3-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) pyrazine-2-carbohydrazide (0.425 g, 1.095 mmol, 1.0 eq) in DCM (4.2 mL) was added Et3N (0.884 g, 8.76 mmol, 8.0 eq) and tosyl chloride (0.623 g, 3.28 mmol. 3.0 eq) at room temperature. The reaction mixture was stirred at it for 1 h. The reaction was monitored on TLC (10% MeOH in DCM as mobile phase), after completion the Reaction mass was diluted with water (15 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.5 g crude. The crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 0-80% EtOAc in hexane afforded the title compound 3- (5-(3-((4,4-dimethylcyclohexyl) amino) pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-3-methyl pyrrolidine-2-one (0.267 g, 0.72 mmol, Yield: 65.88%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.31 (d, J = 2.4 Hz, 1H) , 8.21 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 4.02-4.00 (m, 1H), 3.42-3.33 (m, 2H), 2.74-2.66 (m, 1H), 2.26-2.19 (m, 1H), 1.91-1.84 (m, 2H), 1.60 (s, 3H). 1.56-1.48 (m, 2H). 1.44-1.37 (m, 2H). 1.35- 1.28 (m, 2H), 0.95 (d, J = 7.6 Hz, 6H).LCMS (Method A):2.224 min, 96.97%, 265 nm, MS:ES+ m / z 371.4 [M+1]HPLC (Method A): 8.68 mm, 96.77%, 254.0 nmChiral HPLC: Peak-1 : 1.977 min, 49. 14%, 220 nm; Peak-2: 166 min, 48.80%, 220 nmEXAMPLE 15 - Preparation of 3-(5-(3-((4,4-imethylcyclohexyl) amino) pyrazin-2-yl)- 1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 18, Compound 19)Chiral Separation of Compound 18 & Compound 19:

[0209] Compound 17 racemate (0.1 g) was subjected to chiral separation by chiral SFC. Both the enantiomers were separated and label as Compound 18 i.e. Compound 17-Peak-l (first eluted); Compound 19 i.e. Compound 17-Peak-2 (second eluted).

[0210] COLUMN ID: YMC CELLULOSE SC, 250 mm X 20 mm x 5um

[0211] MOBILE PHASE A: 0. 1% M.NH3 IN HEPTANE IPA ACN (70:30) -90 10

[0212] MOBILE PHASE B; NA

[0213] FLOW RATE (ML / MIN): 20

[0214] INSTRUMENT ID: PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UVDETECTOR

[0215] METHOD: TIME; FLOW: %A; %B (0.01: 25:: 20 ; 20 : : 100 : 0)

[0216] Input Quantity : 0.1 g.

[0217] Output Quantity: Compound 18=0.037 g (%Yield=37%) and Compound 19= 0.032 g (%Yield=32%)Compound 181H NMR (DMSO-d6, 400 MHz): δ ppm, 8.32 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 7.99 (d, J 2.4 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 4.02-4.01 (m, 1H), 3.44-3.29 (m, 2H), 2.75-2.68 (m, 1H), 2.27-2.20 (m, 1H), 1.87-1.84 (m, 2H), 1.61 (s, 3H), 1.56-1.48 (m, 2H), 1.45-1.41 (m, 2H), 1.36- 1.23 (m, 2H), 0.96 (d, J = 7.6 Hz, 6H)LCMS (Method A): 2.35 min, 100%, 254.0 nm, MS: ES+ 371.53 [M+1]HPLC (Method A): 8.63 min, 100%, 254.0 nmChiral HPLC: 1.977 mm, 98.87%, 260.0 nmCompound 191H NMR (DMSO-d6, 400 MHz): δ ppm, 8.32 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 7.2Hz, 1H), 4.03-4.01 (m, 1H), 3.44-3.29 (m, 2H), 2.75-2.68 (m, 1H), 2.27-2.20 (m, 1H), 1.88-1.84 (m, 2H), 1.61 (s, 3H), 1.56-1.49 (m, 2H), 1.45-1.42 (m, 2H), 1.36- 1.23 (m, 2H), 0.96 (d, J - 7.6 Hz, 6H)LCMS (Method A): 2.35 min, 100%, 254.0 nm, MS: ES+ 371.53 [M+1]HPLC (Method A): 8.63 min, 100%, 254.0 nmChiral HPLC: 2.163 min, 100%, 260.0 nmEXAMPLE 16 - Preparation of 3-(5-(3-((4,4-difluorocyclohexyl) amino) pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 20)Step 1 : Synthesis of Intermediate 20-Al: methyl 3-((4.4-difluorocyclohexyl) amino) pyrazine-2- carboxylate

[0218] To a stirred solution of methyl 3-chloropyrazine-2-carboxylate (CAS: 27825-21-4) (0.5 g, 2.693 mmol. 1.0 eq) and 4,4-difluorocyclohexan-1-amine hydrochloride (CAS: 675112-70-6)(1.38 g, 8.081 mmol, 3.0 eq) in DMSO (5 mL) was added Et3N (3.0 mL, 21.55 mmol, 8.0 eq) at rt and reaction mixture was stirred at 140 °C for 2 h. The reaction was monitored on TLC (30%EtOAc in hexane as a mobile phase), after completion the resulting reaction mixture was cooled to rt and diluted with water (30 mL) then extracted with diethyl ether (3 x 30 mL). The combined organic layers were dried over Na2SO4. concentrated under reduced pressure to get the crude (0.4 g). The obtained crude material was triturated by n-pentane (30 ml) to afford the title compound methyl 3-((4,4-difluorocyclohexyl) amino) pyrazine-2-carboxylate (0.253 g,0.932 mmol, Yield: 32.19%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.35 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H),7.89-7.81 (m, 1H), 4.14-4.11 (m, 1H), 3.86 (s. 3H), 2.06-1.93 (m. 6H), 1.63-1.61 (m. 2H).LCMS (Method A): 1.975 min, 94.23%, 254.0 nm, MS: ES+ m / z 272.09 [M+1]Step 2: Synthesis of Intermediate 20-A2:3-((4.4-difluorocyclohexyl) amino) pyrazine-2- carbohydrazide

[0219] To a stirred solution of methyl 3-((4,4-difluorocyclohexyl) amino) pyrazine-2- carboxylate (Intermediate 20-Al) (0.233 g, 0.859 mmol, 1.0 eq) in MeOH (2.33 mL) was added hydrazine hydrate (0.429 g, 8.597 mmol, 10.0 eq) at rt and reaction mixture was heated up to 90 °C for 1.5 h. The reaction was monitored on TLC (50% EtOAc in hexane as mobile phase). After completion, the resulting reaction mixture was concentrated under reduced pressure and residue was diluted with water (15 mL) then extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.2 g). The obtained crude material was purified by trituration with n-pentane (20 ml) to afford the title compound 3-((4,4-difluorocyclohexyl) amino) pyrazine-2-carbohydrazide (Intermediate 20-A2) (0.125 g, 0.460 mmol, Yield: 53.65%)1H NMR (DMSO-d6, 400 MHz): δ ppm 9.95 (brs, 1H), 8.74 (d, J = 7.2 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 4.53 (s, 2H), 4.13-4.06 (m, 1H), 2.03-1.99 (m, 6H), 1.58-1.56 (m, 2H).LCMS (Method A): 1.709 min, 97.98 %, 254.0 nm, MS: ES+ m / z 272.09 [M+1]Step 3 Synthesis of Intermediate 20- A3: 3-((4.4-difluorocyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) pyrazine-2-carbohydrazide

[0220] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.105 g, 0.738 mmol, 2.0 eq) in DMF (1 mL) was added DIPEA (0.238 g, 1.845 mmol, 5.0 eq), EDC.HC1 (0.176 g, 0.922 mmol, 2.5 eq) and HOBt (0.169 g, 1.107 mmol. 3.0 eq) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C followed by addition of 3-((4,4-difluorocyclohexyl) amino) pyrazine-2-carbohydrazide (Intermediate 20- A2) (0.1 g, 0.369 mmol, 1.0 eq) and stirred further at rt for 16 h. The progress was monitored on TLC (5% MeOH in DCM as a mobile phase). After 16 h, TLC indicates the completion of the reaction. The resulting reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.2 g). The obtained crude material was purified by trituration with n-pentane (20 mL) to afford the title compound 3-((4,4-difluorocyclohexyl) amino)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) pyrazine-2-carbohydrazide (0.09 g, 0.227 mmol, Yield: 61.59%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 10.45 (s. 1H), 9.55 (s, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8.33 (d, J = 2.4Hz, 1H). 7.98 (s. 1H). 7.85 (d, J = 2.4 Hz, 1H). 4.11-4.04 (m, 1H). 3.21 (t. J = 6.4 Hz, 2H), 2.03-1.99 (m, 6H), 1.59-1.57 (m, 2H), 1.38 (s, 3H), 1.28-1.22 (m, 2H).LCMS (Method A):1.832 min, 78.54%, 254.0 nm, MS: ES+ m / z 397.34 [M+1]Step 4: Synthesis of 3-(5-(3-((4,4-difluorocyclohexyl) amino) pyrazin-2-yl)-1.3,4-oxadiazol-2- vl)-3-methylpyrrolidin-2-one (Compound 20)

[0221] To a stirred solution of 3-((4,4-difluorocyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) pyrazine-2-carbohydrazide (0.075 g, 0.189 mmol, 1.0 eq) in DCM (0.75 mL) was added Et3N (0.152 g, 1.513 mmol, 8.0 eq) and tosyl chloride (0.107 g, 0.567 mmol, 3.0 eq) al room temperature and stirred at rt for 1 h. The reaction was monitored on TLC (5% MeOH in DCM as mobile phase), after completion the reaction mixture was diluted with water (15 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.06 g). The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 5% MeOH in DCM afforded the title compound 3-(5-(3-((4,4- difluorocyclohexyl) amino) pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 20) (0.015 g, 0.039 mmol, Yield: 20.95%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.35 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 4.24-4.23 (m, 1H), 3.43-3.38 (m, 2H), 2.75-2.69 (m, 1H), 2.27-2.20 (m, 1H), 2.08-2.03 (m, 6H), 1.68-1.66 (m, 2H), 1.61 (s. 3H).LCMS (Method A): 1.972 min, 99.65%, 260.0 nm, MS: ES+ m / z 379.5 [M+1]HPLC (Method A): 6.80 min, 100%, 260.0 nmChiral HPLC: Peak-l : 1.914 min, 49.97%, 261 nm; Peak-2: 2.156 min, 50.03%, 261 nmEXAMPLE 17 - Preparation of 3-methyl-3-(5-(2-((4-methylcyclohexyl) amino) pyridin-3- yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2-one (Compound 21)Step 1 : Synthesis of Intermediate 21-B1 Methyl 2-((4-methylcvclohexvl) amino) nicotinate

[0222] To a stirred solution of 4-methylcyclohexan-1-amine (CAS: 6321-23-9) (5.0 g, 43.96 mmol, 1.2 eq) and methyl 2-chloronicotinate (CAS:40134-18-7) (6.8 g, 36.63 mmol, 1.0 eq) inDMSO (50 mL), was added Et3N (15.4 mL, 109.8 mmol, 3.0 eq) at rt then reaction mixture was stirred for 2 h at 160 °C. The reaction was monitored by TLC (5% EtOAc in hexane as mobile phase). After completion, the reaction mixture was cooled at rt and diluted with water (50 mL).The resulting reaction mixture was extracted with diethyl ether (3 x 100 mL) and combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude(4.9 g). The obtained crude material was purified by flash column chromatography using silica gel (60-120 mesh) as a stationary phase and gradient 2-3% EtOAc in hexane afforded the title compound Methyl 2-((4-methylcyclohexyl) amino) nicotinate (Intermediate 21-B1) (3.4 g, 13.69 mmol, Yield: 31.06%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.28-8.26 (m, 2H), 8.21 (d, J 7.2 Hz, 1H), 8.08-8.04(m, 2H), 7.80 (d, J 7.6 Hz, 1H), 6.60-6.56 (m, 2H), 4.28-4.27 (m, 1H), 3.92-3.87 (m, 1H), 3.83(s, 3H), 3.80 (s, 3H), 2.00-1.98 (m, 2H) 1.74-1.67 (m, 4H), 1.62-1.39 (m, 5H), 1.38-1.37 (m,1H), 1.26-1.11 (m. 4H), 1.08-0.99 (m. 2H), 0.92-0.87 (m. 6H).LCMS (Method A): 2. 139 min, 53.98 %, 254.0 nm, MS: ES+ m / z 249.26 (M+l), 2.277 min, 45.14%, 254.0 nm, MS: ES+ m / z 249.25. [M+1]Step 2: Synthesis of Intermediate 21-B2: 2-((4-methylcyclohexyl) amino) nicotinohydrazide

[0223] To a stirred solution of Methyl 2-((4-methylcyclohexyl) amino) nicotinate (Intermediate 21-B1) (3.4 g, 13.69 mmol, 1.0 eq) in MeOH (34 mL), was added hydrazine hydrate (6.84 g, 136.9 mmol, 10.0 eq) at rt and reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored by TLC (30% EtOAc in hexane as mobile phase). After completion, reaction mixture was concentrated under reduced pressure to obtained the residue which was dissolved in water (50 mL) and extracted with EtOAc (3 x 50 mL) and combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford 2.9 g cmde. The obtained crude material was purified by flash column chromatography using silica gel (60-120 mesh) as stationary phase and gradient 18% EtOAc in hexane afforded the title compound 2-((4- methylcyclohexyl) amino) nicotinohydrazide (2.5 g, 9.66 mmol. Yield: 73.52%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.72 (d, J = 9.2 Hz, 2H), 8.67 (d, J = 8.0 Hz, 1H), 8.14-8.10 (m, 3H), 7.84 (dd, J = 7.6, 1.6 Hz, 1H), 7.80 (dd, J = 7.6, 2.0 Hz, 1H), 6.50-6.47 (m, 2H), 4.46-4.43 (m, 4H), 4.21-4.19 (m, 1H), 3.82-3.79 (m, 1H), 2.00-1.97 (m, 2H), 1.70-1.68 (m, 4H), 1.59-1.48 (m, 5H), 1.38-1.36 (m, 1H), 1.22-1.11 (m, 4H), 1.07-1.01 (m, 2H), 0.91-0.88 (m, 6H). (Due to Cis and trans isomer mixture all protons show double integration).LCMS (Method A): 1.278 min, 46.90%, 254.0 nm, MS: ES+ m / z 249.20 [M+1] and 1.327 min, 50.98%, 254.0 nm. MS: ES+ m / z 249.20 [M+1]Step 3 Synthesis of Intermediate 21-B3;N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((4-methyl cyclohexyl)amino)nicotinohydrazide

[0224] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.864 g, 6.048 mmol, 1 .0 eq) in DMF (15 mL), was added DIPEA (3.1 mL, 181 .4 mmol, 3 eq) and HATU (4.5 g, 12.09 mmol, 2 eq) at rt and reaction mixture was stirred for 15 min at same temperature. After 15 min, 2-((4-methylcyclohexyl) amino) nicotinohydrazide (Intermediate 21-B2) (1.5 g, 6.048 mmol, 1.0 eq) was added and reaction mixture was stirred for 8 h at rt. The progress was monitored on TLC (100% EtOAc mobile phase) After completion, water (50 mL) was added and reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 1.89 g cmde. The obtained crude material was purified by flash column chromatography using silica gel (100-200 mesh) as stationary phase (desired product was eluted in 100% EtOAc as mobile phase) to afford N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((4-methylcyclohexyl) amino) nicotinohydrazide (0.260 g, 0.6933 mmol, Yield: 11.55%)LCMS (Method A): 1.363 min, 45.86%, 254.0 nm, MS: ES+ m / z 374.32 (M+l ) and 1.408 min, 53.29%, 254.0 nm, MS: ES+ m / z 374.32 [M+1]Step 4: Synthesis of 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2- vl)-3-methylpyrrolidin-2-one (Compound 21)

[0225] To a solution N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((4-methylcyclohexyl) amino) nicotinohydrazide (0.420 g, 1.126 mmol, 1.0 eq) in DCM (4.2 mL). was added triethyl amine (0.47 mL, 3.378 mmol, 3.0 eq) and tosyl chloride (0.256 g, 1.351 mmol. 1.2 eq) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction was monitored by TLC (using 100% EtOAc as mobile phase). After TLC indicate the completion of reaction water (20 mL) was added and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.510 g crude. The crude was purified by flash column chromatography using silica gel (100-200 mesh) as stationary phase (desired product was eluted in 100% EtOAc in DCM as mobile phase) to afford the title compound 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3- methylpyrrolidin-2-one (Compound 21) (0.310 g, 0.873 mmol, Yield: 77.69%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.29-8.27 (m, 1H), 8.18 (hrs, 1H), 8.06-8.02 (m, 2H), 6.73 (dd, J = 8.0. 4.2 Hz. 1H), 3.99-3.97 (m, 1H), 3.46-3.34 (m, 2H), 2.77-2.72 (m, 1H), 2.24- 2.19 (m, 1H), 2.07-2.05 (m, 1H), 1.80-1.67 (m, 3H), 1.58 (d, J= 8.0 Hz, 4H). 1.45-1.39 (m, 1H). 1.28-1.22 (m, 2H), 1.09-1.06 (m, 1H), 0.94-0.90 (m, 3H). Note: Mixture of Cis and trans isomer present in compound.LCMS (Method A): Peak-1 : 1.845 min, 66.32 %, 254.0 nm, MS: ES+ m / z 356.37 [M+1]; Peak-2: 1.964 min, 33.68%, 254.0 nm, MS: ES+ m / z 356.37 [M+1]HPLC (Method A): Peak-1: 8.23 min, 47.41%, 254.0 nm; Peak-2: 8.43 min, 52.19%, 254.0 nmChiral HPLC: Peak-1 : 5.40 min, 24.07%, 355 nm; Peak-2: 5.85 min, 23.63%, 355 nm; Peak-3:6.84 mm, 26.36%, 355 nm; Peak-4: 7.29 min, 25.87%, 355 nmEXAMPLE 18 - Preparation of 3-methyl-3-(5-(2-((4-methylcyclohexyl) amino) pyridin-3- yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2-one (Compound 22, Compound 23, Compound 24, Compound 25)Step 1 : Chiral separation

[0226] Cis trans mixture of Compound 21 was subjected to chiral SFC separation and 4 isomers were separated.

[0227] COLUMN ID: CHIRALPAK IG (250X50 mm 5um)

[0228] MOBILE PHASE A: 0.1 % M.NH3 IN HEPTANE

[0229] MOBILE PHASE B; 0.1 % M.NH3 IN HEPTANE

[0230] INSTRUMENT ID: PHP-04-AGILENT 1260 SERIES INFINITY-II WITH UVDETECTOR

[0231] FLOW RATE(ML / MIN): 40

[0232] Input Quantity: 100 mg

[0233] Output Quantity: Compound 22 11.17 mg, Compound 23 =15.5 mg, Compound 24=13.1 mg, Compound 25 = 16.11 mgCompound 221H NMR (DMSO-d6, 400 MHz): δ ppm, 8.28 (dd, J = 4.8, 2.0 Hz, 1H), 8.19 (s, 1H), 8.07-8.03 (m. 2H), 6.73 (dd, J = 7.6, 4.8 Hz, 1H), 4.39-3.37 (m, 1H), 3.44-3.34 (m, 2H), 2.77-2.74 (m,1H), 2.25-2.20 (m, 1H), 1.80-1.77 (m, 2H), 1.67-1.52 (m, 8H), 1.27-1.21 (m, 2H), 0.93 (d, J6.4 Hz, 3H).LCMS (Method A): 1.866 min, 100%, 254.0 nm, MS: ES+ m / z 356.32 [M+1]HPLC (Method A): 5.584 min, 99.72%, 254.0 nmChiral HPLC: 5.43 min, 100%, 355 nmCompound 231H NMR (DMSO-d6, 400 MHz): δ ppm, 8.28 (dd, J = 4.8, 2.0 Hz, 1H), 8.19 (s, 1H), 8.06-8.03 (m. 2H), 6.73 (dd, J = 7.6, 4.8 Hz, 1H), 4.38-3.37 (m. 1H), 3.44-3.33 (m. 2H) 2.79-2.72 (m, 1H), 2.25-2.18 (m, 1H), 1.80-1.77 (m, 2H), 1.67-1.51 (m 8H), 1.27-1.19 (m, 2H), 0.93 (d, J = 6.4 Hz, 3H).LCMS (Method A): 1.965 min, 99.35%, 254.0 nm, MS: ES+ m / z 356.27 [M+1]HPLC (Method A): 5.583 min, 99.52%, 254.0 nmChiral HPLC: 5.89 min, 97.95%, 355 nmCompound 241H NMR (DMSO-d6, 400 MHz): 8.29 (dd, J = 4.8, 2.0 Hz, 1H), 8.18 (s, 1H), 8.03 (dd, J 7.6, 2.0 Hz, 1H), 7.67 (d. J = 7.2 Hz. 1H), 6.73 (dd, J = 7.6, 4.8 Hz, 1H), 4.00-3.96 (m. 1H), 3.43- 3.38 (m, 2H), 2.77-2.70 (m, 1H), 2.24-2.17 (m, 1H), 2.07-2.05 (m. 2H), 1.74-1.71 (m 2H), 1.59 (s, 3H), 1.43-1.41 (s, 1H), 1.33-1.22 (m, 2H), 1.12-1.06 (m, 2H), 0.91 (d, J = 6.8 Hz, 3H).LCMS (Method A):2.086 min, 99.71%, 254.0 nm, MS: ES+ m / z 356.32 [M+1]HPLC (Method A):5.906 min, 99.71%, 254.0 nmChiral HPLC: 6.89 min, 100%, 355 nmCompound 251H NMR (DMSO-d6, 400 MHz): δ ppm, 8.28 (dd, J = 4.8, 1.6 Hz, 1H), 8.18 (s, 1H). 8.03 (dd. J = 7.6, 1.6 Hz, 1H). 7.67 (d, J = 7.2 Hz, 1H). 6.73 (dd. J = 7.6, 4.8 Hz, 1H). 4.00-3.96 (m, 1H). 3.43-3.37 (m, 2H), 2.77-2.70 (m, 1H), 2.24-2.18 (m, 1H), 2.07-2.05 (m, 2H), 1.74-1.71 (m, 2H), 1.59 (s, 3H), 1.43-1.41 (m, 1H), 1.32-1.23 (m, 2H), 1.12-1.03 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H).LCMS (Method A):2.083 min, 100%, 254.0 nm, MS: ES+ m / z 356.37 [M+1]HPLC (Method A): 8.39 min, 99.52%, 254.0 nmChiral HPLC: 7.35 min, 100%, 355 nmEXAMPLE 19 - Preparation of 3-methyl-3-(5-(2-((4-(trifluoromethyl) cyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2-one (Compound 26)Step 1 : Synthesis of Intennediate 26-Al: methyl 2-((4-(trifluoromethyl)cyclohexyl) amino) nicotinate

[0234] To a stirred solution of methyl 2-chloronicotinate CAS: 40134-18-7 (0.50 g, 2.693 mmol, 1.0 eq). 4-(trifluoromethyl) cyclohexan-1-amine (CAS:58665-70-6) (0.54 g, 3.232 mmol.1.2 eq) and Et3N (0.81 g, 8.081 mmol, 3.0 eq) in DMSO (5 mL) and the resulting reaction mixture was heated at 140 °C for 4 h. The reaction was monitored on TLC (using EtOAc: hexane; 2.0:8.0 as mobile phase) which confirmed that the reaction got completed after 4 h of stirring at 140 °C. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.540 g crude. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (10%EtOAc: hexane) to yielding methyl 2-((4-(trifluoromethyl) cyclohexyl) amino) nicotinate (0.20 g, 0.661 mmol. Yield: 24.55%).1H NMR (DMSO-d6, 400 MHz): δ ppm. 8.30 (dd. J = 8.4, 1. 6 Hz. 1H), 8.25 (d. J= 6.8 Hz. 1H),8.10 (dd, J= 7.6, 2.0 Hz, 1H), 6.65 - 6.62 (m, 1H), 4.38-4.34 (m, 1H), 3.84 (s, 3H), 2.49 - 2.39(m, 1H), 1.91-1.87 (m, 2H), 1.80 - 1.76 (m, 2H), 1.72-1.63 (m, 2H), 1.51-1.40 (m, 2H).LCMS (Method A): 2.366 min, 91.66%, 345.0 nm, MS: ES+ rn / z 303.1 [M+1]Step 2: Synthesis of Intermediate 26- A2 : 2-((4-(trifluoromethyl)cyclohexyl)amino)nicotino- hydrazide

[0235] To a stirred solution of methyl 2-((4-(trifluoromethyl) cyclohexyl) amino) nicotinate (Intermediate 26-Al) (0.20 g, 0.662 mmol, 1.0 eq) and hydrazine hydrate (0.16 g, 3.311 mmol, 5.0 eq) in EtOH (2 mL) was stirred at 80 °C for 5 h. After completion of reaction as indicated by TLC (using EtOAc: hexane; 8:2 as mobile phase) the resulting reaction mixture was concentrated under reduced pressure to obtained the crude. The obtained residue was diluted with water (10 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the title compound 2-((4- (trifluoromethyl) cyclohexyl) amino) nicotinohydrazide (0.220 g, 2.307 mmol, Yield: Quantitative).LCMS (Method A): 1.347 min, 96.95%, 254.0 nm. MS: ES+ m / z 303.1 [M+1]Step 3; Synthesis of Intermediate 26-A3:N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((4-(trifluoro methyl)cyclohexyl)amino)nicotinohydrazide

[0236] To a stirred solution of 2-((4-(trifluoromethyl) cyclohexyl) amino) nicotinohydrazide Intermediate 26-A2 (0.250 g, 0.826 mmol, 1.0 eq), HATU (0.471 g, 1.240 mmol, 1.5 eq) and DIPEA (0.320 g, 2.480 mmol, 3.0 eq) in DMF (2.5 mL) was stirred at 0 °C for 10 Min. followed by addition of 3 -methyl-2-oxopyrrolidine-3 -carboxylic acid (0.295 g, 2.067 mmol, 2.5 eq) at 0 °C. The resulting reaction mixture was stirred at rt for 2 h. The completion of reaction was indicated by TLC (100% EtOAc as mobile phase) and resulting reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.220 g). The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase The 10% MeOH in DCM eluent afforded the title compound N'-(3- methyl-2-oxopyrrolidine-3-carbonyl)-2-((4-(trifluoromethyl) cyclohexyl) amino) nicotinohydrazide (0.090 g, 0.210 mmol, Yield: 25.46%).LCMS (Method A): 1.484 min, 88.36%, 254.0 nm, MS: ES+ m / z 428.28 (M+l)Step 4: Synthesis of 3-methvl-3-(5-(2-((4-(trifluoromethvl)cvclohexvl)amino)pvridin-3-vl)-1,3,4- oxadiazol-2-yl)pyrrolidin-2-one (Compound 26)

[0237] To a stirred solution of N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((4- (trifluoromethyl) cyclohexyl) amino) nicotinohydrazide (Intermediate 26- A3) (0.14 g, 0.327 mmol, 1.0 eq) and tosyl chloride (0.075 g, 0.393 mmol, 1.2 eq) in DCM (2 mL) was added Et3N (0. 10 g, 0.982 mmol. 3.0 eq) at rt. The resulting reaction mixture was stirred at rt for 1 h.Completion of the reaction was indicated by TLC (using 8.0:2.0 EtOAc: hexane as mobile phase). The resulting reaction mixture was diluted with water (7 mL) and extracted with EtOAc(3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.20 g). The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (100% EtOAc) to afford the title compound 3-methyl-3-(5-(2-((4-(trifluoromethyl) cyclohexyl) amino) pyridin-3- yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2-one (0.065 g, 0.158 mmol, Yield: 48.46%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.30 (dd, J = 4.8, 2.0 Hz, 1H), 8.19 (s, 1H), 8.10-8.05(m, 2H), 6.77 (dd, J= 7.6, 4.8 Hz, 1H), 4.68 - 4.43 (m, 1H), 3.44-3.34 (m, 2H), 2.79-2.73 (m,1H), 2.46-2.41 (m, 1H), 2.25-2.19 (m, 1H), 1.99-1.93 (m, 2H), 1.82-1.68 (m, 4H), 1.61 (s, 3H),1.58-1.52 (m, 2H).LCMS (Method A): 2.003 min, 99.52%. 254.0 nm, MS: ES+ m / z 410. 1[M+1]HPLC (Method A): 5.83 min, 97.81%, 254.0 nmEXAMPLE 20 - Preparation of 3-methyl-3-(5-(2-((1-(2,2,2-trifluoroethyl) azetidin-3-yl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2-one (Compound 27)Step 1 : Synthesis of Intermediate 27-Al : methyl 2-((l-(2.2.2-trifluoroethyl) azetidin-3-yl) amino) nicotinate

[0238] To a stirred solution of 1 -(2,2,2-trifluoroethyl) azeti din-3 -amine (0.646 g, 4. 19 mmol, 1.2 eq), methyl 2-chloronicotinate (CAS:40134-18-7) (0.60 g, 3.49 mmol, 1.0 eq) and Et3N (1.05 g, 10.48 mmol. 3.0 eq) in DMSO (6 rnL) was stirred at 150 °C for 8 h. The completion of reaction was indicated by TLC (EtOAc: hexane; 2.0:8.0 as mobile phase). After completion, the resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 rnL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (35% EtOAc in hexane) to afford the title compound methyl 2-((1-(2.2.2-trifluoroethyl) azetidin-3-yl) amino) nicotinate (0.023 g, 0.08 mmol. Yield: 1.90%).LCMS (Method A): 1.392 min, 95.52%, 254.0 nm, MS: ES+ m / z 290.1 [M+1]Step 2: Synthesis of Intermediate 27-A2: 2-((1-(2.2.2-trifluoroethyl) azetidin-3-yl) amino) nicotinohydrazide

[0239] To a stirred solution of methyl 2-((1 -(2,2,2-trifluoroethyl) azetidin-3-yl) amino) nicotinate (Intermediate 27-Al) (0.100 g, 0.345 mmol, 1.0 eq) and Hydrazine hydrate (0.560 g, 1.728 mmol, 5.0 eq) in EtOH (1 mL) was stirred at 80 °C for 3 h. The reaction was monitored on TLC (100% EtOAc; as mobile phase). After 3 h, the reaction mixture was concentrated and diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.680 g). The obtained crude material was purified by reversed phase flash column chromatography using C18 silica as stationary phase (35% ACN in water) to afford the title compound 2-((1 -(2,2,2- trifluoroethyl) azetidin-3-yl) amino) nicotinohydrazide (0.050 g, 0. 172 mmol, Yield; 50.00%).LCMS (Method A): 0.339 min, 99.67%, 254.0 nm, MS: ES+ m / z 289.8 [M+1]Step 3; Synthesis of Intermediate 27-A3:N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)amino)nicotinohydrazide

[0240] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.066 g, 0.466 mmol, 1.5 eq), HATU (0.198 g, 0.622 mmol, 2.0 eq) and DIPEA (0.120 g, 0.933 mmol, 3.0 eq) in DMF (1 mL) was stirred at 0 °C for 10 min. After 10 minutes, the 2-((1 -(2,2,2-trifluoroethyl) azeti din-3 -yl) amino) nicotinohydrazide (0.090 g, 0.311 mmol, 1.0 eq) was added to the reaction mixture and stirred at rt for 1 h. The progress of reaction was monitored on TLC (MeOH: DCM; 0.5: 9.5 as mobile phase) and after completion reaction mixture was diluted with water (5 mL).extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the title compound N'-(3-methyl-2- oxopyrrolidine-3-carbonyl)-2-((1-(2,2,2-trifluoroethyl) azeti din-3-yl) amino) nicotinohydrazide in quantitative yield. (0.140 g, 0.337 mmol, Yield: Quantitative).LCMS (Method A): 1.039 min, 88.54%, 254.0 nm, MS: ES+ m / z 415.32 [M+1]Step 4: Synthesis of 3-methyl-3-(5-(2-(1l-(2,2,2-trifluoroethyl) azetidin-3-yl)amino) pyridin-3- yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2-one (Compound 27)

[0241] To a stirred solution of N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-((l -(2,2,2- trifluoroethyl) azetidin-3-yl) amino) nicotinohydrazide (Intermediate 27-A3) (0. 12 g, 0.289 mmol, 1.0 eq) and tosyl chloride (0.066 g, 0.347 mmol, 1.2 eq) in DCM (2 mL) was added Et3N (0.087 g, 0.868 mmol, 3.0 eq) and stirred at rt for 1 h. The reaction was monitored on TLC (using EtOAc: hexane; 8.0:2.0 as mobile phase), after completion the resulting reaction mixture was diluted with water (8 mL) and extracted with 10% IP A in DCM (3 x 15 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0. 115 g). The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (05% MeOH in DCM) to afford the title compound 3-methyl-3-(5-(2-((1-(2,2,2-trifluoroethyl) azetidin-3-yl) amino) pyridin-3-yl)-1,3,4- oxadiazol-2-yl) pyrrolidin-2-one (0.065 g. 0.163 mmol. Yield: 56.63%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 8.10 (s, 1H). 7.86 (dd, J = 7.6. 1.6 Hz, 1H). 6.86-6.83 (m, 1H). 4.03-3.95 (m, 2H). 3.65-3.63 (m, 1H). 3.58-3.53 (m, 1H). 3.40-3.37 (m, 2H), 3.28-3.10 (m, 3H), 2.74 - 2.67 (m, 1H), 2.51-2.18 (m, 1H), 1.59 (s, 3H).Note: One proton might be exchanged with deuterated solvent)LCMS (Method A): 1.349 min, 98.13%, 254.0 nm, MS: ES+ m / z 397.17 [M+1]HPLC (Method A): 4.107 min, 96.54%, 254.0 nmEXAMPLE 21 - Preparation of 3-methyl-3-(5-(2-(spiro [2.5] octan-6-ylamino) pyridin-3- yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2-one (Compound 28)

[0242] Step 1 ; Synthesis of Intermediate 28-A2; spiro [2.5] octan-6-amine

[0243] To a stirred solution of spiro [2.5] octan-6-one (9.0 g, 72.58 mmol, 1.0 eq.) in MeOH(90 mL), were added ammonium acetate (55.8 g, 725.8 mmol, 10 eq) and NaCN(BH3) (45.5 g,725.8 mmol, 10 eq) at rt. The resulting reaction mixture was allowed to stirred at 60 °C for 2 h.After completion of reaction as indicated by TLC (2% MeOH in DCM) the resulting reaction mixture was cooled to rt, diluted with DCM (180 mL) then water (100 mL) was added and extracted with DCM (3 x 150 mL). The combined DCM layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (21.3 g). The obtained crude material was purified by flash column chromatography using silica gel (100-120 mesh) as stationary phase and gradient 5% MeOH in DCM afforded the title compound Intermediate 28-A2 spiro[2.5] octan-6-amine (4.1 g, 32.74 mmol, Yield: 45.55%). (Note: crude compound used as such for the next step without further purification)Step 2; Synthesis of Intermediate 28-B1; methyl 2-(spiro [2,5] octan-6-ylamino) nicotinate

[0244] To a solution of Methyl 2-Chloronicotinate (CAS; 40134-18-7) (1.0 g, 5.83 mmol, 1.0 eq), and spiro [2.5] octan-6-amine (Intermediate 28-A2) (1.46 g, 11.67 mmol, 2.0 eq) in DMSO(10 mL), was added triethyl amine (2.45 mL, 17.51 mmol, 3.0 eq) at rt and stirred for 2 h at 160°C. The reaction was monitored on TLC (30% EtOAc in hexane as mobile phase). To this reaction mixture water (20 mL) was added and extracted with diethyl ether (3 x 100 mL). Thecombined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the (0.471 g) crude. The obtained crude material was purified by flash column chromatography using silica gel (100-120 mesh) as stationary phase and gradient 10% EtOAc in hexane afforded the title compound methyl 2-(spiro [2.5] octan-6-ylamino) nicotinate (Intermediate 28-B1) (0.169 g. 0.65 mmol. Yield: 8.45%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.29 (dd, J = 4.8, 2.0 Hz, 1H), 8.08 (dd, J 8.0, 2.0 Hz, 1H), 7.97 (d, J = 7.6Hz, 1H), 6.60 (dd, J = 8.0, 4.8 Hz, 1H), 4. 13-4.07 (m, 1H), 3.82 (s, 3H), 1.94-1.90 (m, 2H), 1.64-1.59 (m, 2H), 1.48-1.39 (m, 2H), 1.12-1.09 (m, 2H), 0.33-0.29 (m, 4H).LCMS (Method A): 2.423 min, 95.06%, 254.0 nm, MS: ES+ m / z 260.7 [M+1]Step 3: Synthesis of Intermediate 28-B2: 2-(spiro [2.5] octan-6-ylamino) nicotinohydrazide

[0245] To a stirred solution of methyl 2-(spiro [2.5] octan-6-yl amino) nicotinate (Intermediate 28-B1) (0.165 g, 0.63 mmol, 1.0 eq) in MeOH (1.6 mL), was added Hydrazine hydrate (0.317 g, 6.30 mmol. 10.0 eq), at rt and reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored by TLC (30% EtOAc in hexane as mobile phase). After completion, the reaction mixture was concentrated under reduced pressure and diluted with water (20 mL) then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4. concentrated under reduced pressure to afford the crude (0. 182 g). The obtained crude material was purified by flash column chromatography using silica gel (100-200 mesh) as stationary phase and gradient 19% EtOAc in hexane afforded the title compound 2-(spiro [2.5] octan-6-ylamino) nicotinohydrazide (Intermediate 28-B2) (0.143 g, 0.55 mmol, Yield: 86.66%)1H NMR (DMSO-d6, 400 MHz): δ ppm, , 9.73 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8. 12 (dd, J = 4.8, 1.6 Hz 1H), 7.82 (dd, J = 7. 6, 1.6 Hz, 1H), 6.50 (dd, J = 7.6, 4.8 Hz, 1H), 4.45 (hrs, 2H), 4.02-4.01 (m, 1H), 1.92-1.88 (m, 2H), 1.57-1.50 (m, 2H), 1.43-1.38 (m, 2H), 1.14-1.10 (m, 2H), 0.31-0.21 (m, 4H).LCMS (Method A): 1.416 min, 93.92%, 254 nm, MS: ES+ m / z 261.15 [M+1]Step 4: Synthesis of Intermediate 28-B3: N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-(spiro[2.5] octan-6-ylamino) nicotinohydrazide

[0246] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.060 g, 0.419 mmol, 1.0 eq.) in DMF (1.0 mL), was added DIPEA (0.218 mL, 1.258 mmol, 3 eq.) and HATU (0.240 g, 0.629 mmol, 1.5 eq.) at rt. The reaction mixture was stirred for 15 min at the same temperatures. After 15 min, 2-(spiro [2.5] octan-6-ylamino) nicotinohydrazide (Intermediate 28- B2) (0.140 g, 0.503 mmol, 1.2 eq.) was added and stirred at rt for 8 h. The progress of reactionwas monitored by TLC (using 100% EtOAc as mobile phase). After completion of reaction water (20 mL) was added and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.080 g crude. The obtained crude material was purified by flash column chromatography using silica gel (100-200 mesh) as stationary phase and gradient 80% EtOAc in hexane afforded the title compound N'-(3- methyl-2-oxopyrrolidine-3-carbonyl)-2-(spiro [2.5] octan-6-ylamino) nicotinohydrazide (0.063 g, 0.1632 mmol, Yield: 30.40%).1H NMR (DMSO-d6, 400 MHz): δ 10.34 (s, 1H), 9.56 (s, 1H), 8.22 - 8.18 (m, 2H), 7.99-7.95 (m, 2H), 6.55 (dd, J = 8.0, 4.8 Hz, 1H), 4.04-4.02 (m, 1H), 3.22 (t, J = 6.8 Hz, 2H), 1.96-1.89 (m. 3H), 1.63 (t, J= 11.6Hz. 2H), 1.39 (s. 5H), 1.24 - 1.23 (m, 1H), 1.08-1.00 (m, 2H), 0.31- 0.28 (m, 2H), 0.24-0.21 (m, 2H).LCMS (Method A): 1.530 min, 94.78%. 254 nm, MS: ES+ m / z 386.37 [M+1]Step 5; Synthesis of 3-methyl-3-(5-(2-(spiro [2.5] octan-6-ylamino) pyridin-3-vl)-l,3,4- oxadiazol-2-vl) pyrrolidin-2-one (Compound 28)

[0247] To a stirred solution N'-(3-methyl-2-oxopyrrolidine-3-carbonyl)-2-(spiro [2.5] octan-6- ylamino) nicotinohydrazide (0.060 g, 0.155 mmol, 1.0 eq.) in DCM (1 mL), were added triethyl amine (0.065 mL, 0.467 mmol, 3 eq.) and tosyl chloride (0.035 g, 0.186 mmol, 1.2 eq.) at 0 °C. Then reaction mixture was stirred at rt for 2 h. The reaction progress was monitored on TLC (100% EtOAc in hexane as mobile phase). After TLC indicate the complete consumption of starting material, water (10 mL) was added and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.058 g). The cmde was purified by flash column chromatography using silica gel (100- 200 mesh) as stationary phase and gradient 1% MeOH in DCM afforded the title compound 3- methyl-3-(5-(2-(spiro [2.5] octan-6-ylamino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl) pyrrolidin-2- one (0.0183 g, 0.049 mmol. Yield: 31.57%)1H NMR (DMSO-d6, 400 MHz): δ ppm δ 8.30 (dd, J = 4.8. 2.0 Hz. 1H), 8.19 (s. 1H), 8.05 (dd, J = 7.6, 1.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 6.74 (dd, J = 7.6, 4.8 Hz, 1H), 4.21-4.20 (m, 1H), 3.44 - 3.37 (m, 2H), 2.77-2.73 (m, 1H), 2.25-2.18 (m, 1H), 1.99 - 1.96 (m, 2H), 1.60 - 1.49 (m, 7H), 1.21-1.16 (m, 2H), 0.34-0.24 (m, 4H).LCMS (Method A): 1.958 min, 97.28%, 254.0 nm, MS: ES+ m / z 368.32 (M+l)HPLC (Method B): 6.012 mm, 96.93%, 254.0 nm,Chiral HPLC: Peak-1 : 5.28 min, 51.08%, 262.0 nm; Peak-2: 5.71 min, 46.18%, 262.0 nmEXAMPLE 22 - Preparation of 3-(5-(2-(cycloheptylamino) pyridin-3-yl)-1,3,4-oxadiazol-2- yl)-3-methylpyrrolidin-2-one (Compound 29)Step 1 ; Synthesis of Intermediate 29-B1 methyl 2-(cycloheptylamino)nicotinate

[0248] To a stirred solution of methyl 2-chloronicotinate (CAS No: 40134-18-7) (3.0 g, 17.54 mmol 1.0 eq) in DMSO (30 mL), was prepared in 100 mL of RBF at room temperature. To this reaction solution, cycloheptanamine (CAS: 5452-35-7) (3.96 g. 35.08 mmol, 2.0 eq) and triethyl amine (5.31 g, 52.62 mmol, 3.0 eq)) were added at rt under nitrogen atmosphere. The reaction mixture was heated up to 160 °C and further stirred for 2 h at 160 °C. The reaction was monitored by TLC (50% EtOAc: hexane as a mobile phase). After completion, water (100 mL) was added and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (5.6 g). The obtained crude material was purified by flash column chromatography using silica gel(230-400 mesh size) as stationary phase and gradient 5-10 % EtOAc in hexane afforded the title compound methyl 2-(cycloheptylamino) nicotinate (2.0 g, 8.05 mmol, Yield: 46.06%).1H NMR (DMSO-d6, 400 MHz): δ ppm), 8.28 (dd, J = 4.8, 2.0Hz, 1H), 8.07 (dd, J = 4.0, 2.0Hz, 1H), 7.98 (d. J = 7.6Hz, 1H), 6.59 (dd, J = 8.0, 4.8 Hz, 1H), 4.24-4.19 (m. 1H), 3.89 (s,3H), 1.92-1.89 (m, 2H), 1.60-1.45 (m, 10H).LCMS (Method A): 2.305 min, 89.51%. 254 nm, MS: ES+ m / z 249.15 [M+1],Step 2: Synthesis of Intermediate 29-B2: - 2-(cycloheptylamino)nicotinohydrazide

[0249] To a stirred solution of methyl 2-( cycloheptylamino) nicotinate (Intermediate 29-B1) (1.5 g, 6.04 mmol 1.0 eq) in MeOH (15 mL), was added hydrazine hydrate (CAS: 10217-52-4) (3.02 g, 60.4 mmol, 10.0 eq) at rt and reaction mixture was stirred at 90 °C for 16 h. The progress of reaction was monitored by TLC (70% EtOAc in hexane as a mobile phase). After completion, water (100 mL) was added and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (2.5 g). The obtained crude material was purified by flash column chromatography using silica gel (60-120 mesh size) as stationary phase and gradient 50% EtOAc in hexane afforded the title compound 2-(cycloheptylamino) nicotinohydrazide (0.45 g, 1.81 mmol, Yield: 30.0%).1H NMR (DMSO-d6, 400 MHz): δ ppm 9.72 (s, 1H), 8.34 (d. J = 7.6 Hz. 1H), 8.12 (dd, J 4.8. 2.0 Hz, 1H), 7.81 (dd, J = 7.6, 2.0 Hz, 1H), 6.49 (dd, J = 7.6, 4.8 Hz, 1H), 4.48 (brs, 2H), 4.15- 4.11 (m, 1H), 1.92-1.86 (m, 2H), 1.59-1.44 (m, 10H).LCMS (Method A): 1.236 min, 100%, 254 nm, MS: ES+ m / z 248.80 [M+1]Step 3: Synthesis of Intermediate 29-B3:2-(cvcloheptylamino)-N'-(3-methvl-2-oxopvrrolidine-3- carbonvl) nicotinohydrazide

[0250] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.37 g, 2.60 mmol, 1.5 eq) in DMF (4.5 mL), was added DIPEA (0.66 g, 5.19 mmol, 3.0 eq) and HATU (0.98 g, 2.59 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred for 5 min., finally 2- (cycloheptylamino) ni cotinohydrazide (0.43 g, 1.73 mmol 1.0 eq) was added at 0 °C. and reaction mixture was stirred at rt for 2 h. The progress was monitored by TLC (70% EtOAc: hexane as a mobile phase). After completion, water (50 mL) was added and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude (0.80 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 50% EtOAc in hexane afforded the title compound 2-(cycloheptylamino)-N'- (3-methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.15 g, 0.40 mmol, Yield: 23.20%).1H NMR (DMSO-d6, 400 MHz): δ ppm 10.31 (brs, 1H), 9.56 (brs,1H), 8.23-8.17 (m, 2H), 7.97- 7.95 (m, 2H), 6.54 (dd, J = 8.0, 4.8 Hz, 1H), 4.14-4.12 (m, 1H), 3.50 (s, 1H), 3.22 (t, J = 6.4 Hz, 2H), 1.95-1.89 (m, 3H), 1.59-1.45 (m, 10H), 1.38 (s, 3H).LCMS (Method A): 1.371 min, 90.89%, 254 nm, MS: ES+ m / z 374.27 [M+1]Step 4: Synthesis of 3-(5-(2-(cycloheptylamino) pvridin-3-yl)-1,3,4-oxadiazol-2-yl)-3- methylpyrrolidin-2-one (Compound 29)

[0251] To a stirred solution of 2-(cycloheptylamino)-N'-(3-methyl-2-oxopyrrolidine-3- carbonyl) ni cotinohydrazide (Intermediate 29-B3) (0.15 g, 0.40 mmol 1.0 eq) in (1.5 mL) DCM, was prepared in 25 mL of glass RBF at room temperature. To this reaction solution triethyl amine (0.121 g, 1.2 mmol 3.0 eq) was added and reaction mixture was stirred at rt for 2 h. The reaction was monitored by TLC (100% EtOAc as a mobile phase). After completion, water (50 mL) was added and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (0. 17 g). The obtained crude material was purified by flash column chromatography using silica gel 230-400 mesh size as stationary phase and gradient 70% EtOAc in hexane afforded the title compound 3-(5-(2-(cycloheptylamino) pyridin-3-yl)-l,3,4-oxadiazol-2-yl)-3-methylpyrrolidin- 2-one (0.042 g, 0.118 mmol, Yield: 29.42%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.29 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (s, 1H), 8.04 (dd, J = 7.6, 1.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 6.73 (dd, J = 7.6, 4.8 Hz, 1H), 4.34-4.30 (m, 1H), 2.78-2.71 (m, 1H), 2.24-2.18 (m, 1H), 1.98-1.94 (m, 1H), 1.66-1.51 (m, 13H). Note: Three protons merged in DMSO Solvent / moisture peak.1H NMR (MeOD-d4, 400 MHz): δ ppm 8.23 (dd, J= 5.2, 2.0 Hz, 1H), 8. 15 (d, J = 7.6 Hz, 1H), 6.73 (dd, J = 7.6, 4.8 Hz 1H), 4.35-4.31 (m, 1H), 3.60-3.52 (m, 2H), 2.94-2.87 (m, 1H), 2.39- 2.33 (m, 1H), 2.08-2.02 (m, 2H), 1.74-1.62 (m, 13H). Note: 2H-Exchanged in MeOD NMR.LCMS (Method A): 1.859 min, 100%, 254 nm, MS: ES+ m / z 356.52 (M+l)HPLC:(Method A): 5.040 min., 99.40%, 254 nmChiral HPLC: Peak-1 : 5.50 min. 50.05%, 356 nm. Peak-2: 6.04 min, 49.80%, 356 nmEXAMPLE 23 - Preparation of 3-(5-(2-((4,4-difluorocycloheptyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 30)Step 1; Synthesis of Intermediate 30-Al: Ethyl 5,5-difluoro-2-oxocycloheptane-l-carboxylate.

[0252] To a stirred solution of 4,4-difluorocyclohexan-1-one (CAS: 22515-18-0) (10.0 g,74.55 mmol, 1.0 eq) in DCM (100 mL) was prepared in 500 mL of RBF at -10 °C temperature.To this stirring solution boron trifluoride etherate (Et2O.BF3) (13.66 g, 96.92 mmol, 1.3 eq) was added and stirred the reaction for 10 min at same temperature. Finally, ethyl diazoacetate (11.04 g, 96.92 mmol, 1.3 eq) in DCM (50.0 mL) were added at same temperature under nitrogen atmosphere. After 1 h of stirring at -10 °C the resulting reaction mixture was allowed to warm up to rt for 2 h. The reaction was monitored by TLC (using 15% EtOAc as a mobile phase).After completion of reaction, the resulting reaction mixture was diluted with 30% K2CO3solution (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product(15.0 g). The obtained crude material was purified by flash column chromatography, gradient 0-5% EtOAc in hexane afforded the title compound Ethyl 5,5-difluoro-2-oxocycloheptane-1- carboxylate (10 g, 45.41 mmol, Yield: 60.91%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 4.22 - 4. 10 (m, 2H), 2.58 - 2.51 (m, 1H), 2.45 - 2.40 (m, 1H), 2.39 - 2.37 (m, 1H), 2.30 - 2.15 (m, 1H), 2.06 - 2.04 (m, 3H), 1.99 - 1.78 (m, 1H), 1.27-1.18 (m, 4H),Mass: MS: ES+ m / z 221.2 (M+l) and m / z 219.2 (M-1)Step 2: Synthesis of Intermediate 30- A2: 4.4-difluorocycloheptan-1-one

[0253] To a stirred solution of Ethyl 5,5-difluoro-2-oxocycloheptane-1-carboxylate (Intermediate 30-Al) (10.0 g, 45.40 mmol, 1.0 eq) in 3.0 M HC1 (25.0 mL) was reflux 16 h. The reaction was monitored by TLC (using 15% EtOAc as a mobile phase) which confirmed that the reaction got completed after 16 h of stirring. The resulting reaction mixture was diluted with NaHCO3solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4. filtered and concentrated under reduced pressure to afford the crude 4,4-difluorocycloheptan-l-one (5.0 g, 33.78 mmol, Yield: 74.32%). (Note: crude was used as such for next step without any purification).1H NMR (DMSO-d6, 400 MHz): δ ppm, 4.40 - 4.24 (m, 2H), 2.63 - 2.56 (m, 2H), 2.26 - 2. 10 (m. 3H), 1.93 - 1.87 (m, 1H), 1.38 - 1.23 (m, 2H).Step 3; Synthesis of Intermediate 30- A3: 4,4-difluorocycloheptan-1-amine.

[0254] To a stirred solution of 4,4-difluorocycloheptan-l-one (Intermediate 30-A2) (5.0 g, 33.74 mmol, 1.0 eq) in MeOH (10.0 mL) was added ammonium acetate (NEhOAc) (26.0 g, 337.4 mmol. 10.0 eq) and stirred at rt for 30 min. followed by the addition of sodium cyano borohydride (NaBH3CN) portion wise (6.30 g, 101.2 mmol, 3.0 eq) and further stirred the reaction for 16 h at same temperature. The reaction was monitored by TLC (5% MeOH in DCM as a mobile phase). After completion the resulting reaction mixture was diluted with 10% Na2CO3solution (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as crude 4,4-difluorocycloheptan-l -amine. (4.0 g, 26.81 mmol, Yield: 79.45%). (Note: The crude compound was used as such for next step without any further purification).LCMS (Method A): 0.455 min, 83.95%, MS: ES+ m / z 150.29 [M+1]Step 4: Synthesis of Intermediate 30-BL Methyl 2-((4,4-difluorocycloheptyl) amino) nicotinate

[0255] To a solution of 4,4-difluorocycloheptan-1-amine (Intermediate 30-A3) (2.57 g, 17.227 mmol, 2.0 eq) and methyl 2-chloronicotinate (CAS:40134-18-7) (1.60 g, 8.60 mmol, 1.0 eq) in DMSO (20.0 mL), was added Et3N (3.59 mL, 25.8 mmol. 3.0 eq) at rt and reaction mixture was stirred at 160 °C for 6 h. The reaction was monitored by TLC (40% EtOAc in hexane as mobilephase). After completion, the resulting reaction mixture was cooled at rt and diluted with 10% Na2CO3solution (50.0 mL). The resulting reaction mixture was extracted with EtOAc (3 x 50 rnL) and combined organic layers were dried over Na2SO4then concentrated under reduced pressure to afford 2.0 g crude. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase. The gradient 20-25% EtOAc in hexane afforded the title compound Methyl 2-((4,4-difluorocycloheptyl) amino) nicotinate (Intermediate 30-B1) (0.80 g, 2.852 mmol, Yield: 16.79%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.30 (dd, J = 4.4, 2.0 Hz, 1H), 8.09 (dd, J = 8.0, 2.0 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 8.0, 4.8 Hz, 1H), 4.27 - 4.23 (m, 1H), 3.82 (s, 3H), 2.17 - 2.01 (m, 5H), 1.95 - 1.89 (m, 1H). 1.69 - 1.60 (m, 4H).LCMS (Method A): 2.171 min, 98.51 %, 254.0 nm, MS: ES+ m / z 285.56 [M+1]Step 5: Synthesis of Intermediate 30-B2: 2-((4-methylcyclohexyl) amino) nicotinohydrazide

[0256] To a solution of Methyl 2-((4,4-difluorocycloheptyl) amino) nicotinate (Intermediate 30-B1) (0.780 g, 2.74 mmol, 1.0 eq) in MeOH (8.0 mL), was added hydrazine hydrate (2.74 g, 54.8 mmol, 20.0 eq) at rt then the reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored by TLC (5% MeOH in DCM as mobile phase). After completion, reaction mixture was concentrated under reduced pressure and diluted with water (20.0 mL) extracted with 10% MeOH in DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford 0.80 g crude. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 90% EtOAc in hexane afforded the title compound 2-((4,4- difluorocycloheptyl) amino) nicotinohydrazide (Intermediate 21-B2) (0.50 g, 1.75 mmol, Yield: 62.50%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.77 (s, 1H), 8.38 (d, J = 7.2 Hz, 1H), 8.13 (dd, J =4.8. 1.6Hz, 1H), 7.84 (dd, J = 8.0, 2.0 Hz, 1H), 6.53 (dd, J = 7.6, 4.8 Hz, 1H), 4.47 (s, 2H), 4.19 - 4.15 (m, 1H), 2.16 - 2.02 (m, 5H). 1.99 - 1.87 (m. 1H), 1.66 - 1.62 (m. 4H).LCMS (Method A): 1.161 min, 95.45 %, 254.0 nm. MS: ES+ m / z 284.86 [M+1]Step 6; Synthesis of Intermediate 30-B3: 2-((4,4-difluorocycloheptvl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide

[0257] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.302 g, 2. 11 mmol, 1.2 eq) in DMF (5.0 mL), was added DIPEA (0.68 rnL, 5.28 mmol, 3.0 eq) and HATH (1.67 g, 4.40 mmol, 2.5 eq) in reaction mixture at 0 °C and stirred for 15 min. followed by addition of 2-((4,4-difluorocycloheptyl) amino) nicotinohydrazide (Intermediate 30-B2) (0.500g, 1.76 mmol, 1.0 eq) dropwise and further stirred at 0 °C to rt for 6 h. The progress was monitored on TLC (5% MeOH in DCM as a mobile phase). After 6 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water (20.0 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.60 g crude. The obtained crude material was purified by reversed phase flash column chromatography using (Cl 8 silica gel) as stationary phase (desired product was eluted in 20-30% ACN in water (0.1% FA as mobile phase) to afford the title compound 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2-oxopyrrolidine-3- carbonyl) nicotinohydrazide (0.340 g, 0.830 mmol, Yield: 41.66%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 10.89 (brs, 1H), 9.84 (brs. 1H), 8.27 (dd, J = 4.8, 1.6 Hz. 1H), 8.23-8.19 (m. 1H), 8.00 - 7.98 (m. 2H), 6.67 (dd, J = 7.6, 4.8 Hz, 1H), 4.19 (brs, 1H), 3.08 (s, 1H), 2.88 (s, 2H), 2.13 - 2.00 (m, 8H), 1.98 - 1.91 (m, 1H), 1.63 - 1.47 (m, 5H). (Note: NMR was impure)LCMS (Method A): 1.342 min, 16.89%, 254 nm, MS: ES+ m / z 410.22 [M+1],Step 7: Synthesis of 3-(5-(2-((4,4-difluorocycloheptyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2- yl)-3-methylpyrrolidin-2-one (Compound 30)

[0258] To a stirred solution of 2-((4,4-dimethylcyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.340 g, 0.83 mmol, 1.0 eq) in DCM (5.0 mL), was added Et3N (0.34 mL, 2.40 mmol, 3.0 eq) and tosyl chloride (0.189 g, 0.99 mmol, 1.2 eq) at 0 °C and reaction mixture was stirred at rt for 2 h. The reaction was monitored on TLC (5% MeOH in DCM as mobile phase). After 2 h, TLC indicates the completion of reaction so resulting reaction mixture was diluted with water (20 mL) and extracted with 10% MeOH in DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.2 g). The crude was purified by purified by reversed phase flash column chromatography using (Cl 8 silica gel) as stationary phase and gradient 50-60% ACN in water (0.1% FA) afforded the title compound 3-(5-(2-((4,4- difluorocycloheptyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 30) (0.021 g, 0.0537 mmol, Yield: 6.46%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (s, 1H), 8.06 (dd, J = 7.6, 1.6 Hz, 1H). 7.84 (d, J = 7.2 Hz, 1H). 6.77 (dd. J = 8.0, 4.8 Hz, 1H). 4.35-4.34 (m, 1H). 3.44 - 3.40 (m, 2H), 2.78 - 2.71 (m, 1H), 2.25 - 2.23 (m, 2H), 2.21 - 2.09 (m, 4H), 2.04 - 1.95 (m, 1H), 1.72 - 1.67 (m, 3H), 1.63 - 1.60 (m, 4H).LCMS (Method A): 2.001 min, 100.0%, 254.0 nm, MS: ES+ m / z 392.22 [M+1]HPLC (Method A): 6.99 min, 100.0%, 254.0 nmChiral HPLC: Peak-1 : 5.88 min. 24.76%, 260.0 nm; Peak-2: 6.14 min, 21.27%, 260.0 nm; Peak-3: 6.22 mm, 28.53%, 260.0 nm; Peak-4: 7.09 mm, 25.42%, 260.0 nmEXAMPLE 24 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 31)Step 1: Synthesis of Intermediate 31-B1: methyl 2-(cyclopentylamino)nico tinate

[0259] To a stirred solution of methyl 2-chloronicotinate (CAS: 40134-18-7) (1.0 g, 5.847 mmol, 1 eq) and Cyclopentanamine (CAS-1003-03-8) (1.0 g, 11.69 mmol, 2.0 eq) in DMSO (10 mL), was added triethyl amine (2.6 mL, 17.543 mmol, 3.0 eq) at rt and reaction mixture was stirred at 160 °C for 8 h. The reaction was monitored on TLC (30% EtOAc in hexane as mobile phase). After 8 h., the reaction mixture was cooled at rt, diluted by water (10 mL) and extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried over Na2SO4. concentrated under reduced pressure to afford 2.0 g crude The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase.The desired product was eluted in 5% EtOAc in hexane as a mobile phase to afford methyl 2-(cyclopentyl amino) nicotinate (0.57 g, 2.59 mmol, Yield: 44.40%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.30 (dd, J = 4.8, 2.0 Hz, 1H), 8.06 (dd, J = 8.0, 2.0Hz, 1H), 7.93 (d, J = 6.8 Hz, 1H), 6.62-6.59 (m, 1H), 4.40-4.35 (m, 1H), 3.81 (s, 3H), 1.98-1.95(m. 2H), 1.71-1.57 (m, 4H), 1.47-1.41 (m. 2H).LCMS (Method A): 1.602 min, 100%, 254.0 nm, MS: ES+ m / z 221.10 [M+1]Step 2: Synthesis of Intermediate 31-B2- 2-(cyclopentylamino)nicotinohydrazide

[0260] To a stirred solution of methyl 2-(cyclopenlyIamino) nicotinate (Intermediate 31-B1) (0.55 g, 2.5 mmol, 1.0 eq) in MeOH (5.5 mL), was added hydrazine hydrate (1.25 g, 25.0 mmol, 10.0 eq) at rt and reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored on TLC (50% EtOAc in hexane as mobile phase). After completion, reaction mixture was concentrated under reduced pressure then water (20 mL) was added and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4further concentrated under reduced pressure to afford 0.6 g crude. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase. The desired product was eluted in 90% EtOAc in hexane as mobile phase to afford 2-(cyclopentylamino) nicotinohydrazide (0.320 g, 1.98 mmol, Yield: 58.18%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.73 (s, 1H). 8.28 (d, J = 6.8 Hz, 1H), 8.14-8.12 (m, 1H), 7.81 (d. J = 7.6. 2.0 Hz, 1H). 6.52-6.49 (m, 1H). 4.44 (s. 2H), 4.33-4.25 (m. 1H), 1.99-1.92 (m, 2H), 1.71-1.57 (m, 4H), 1.42-1.36 (m, 2H)LCMS (Method A): 0.986 mm, 99.78%, 254 nm, MS: ES+ m / z 221.10 [M+1]Step 3: Synthesis of Intermediate 31-B3: 2-(cyclopenlylamino)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide

[0261] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.3 g. 2.09 mmol, 1.0 eq) in DMF (3 mL), was added DIPEA (1.1 mL, 6.29 mmol, 3 eq) and HATU (1.1 g, 3.146 mmol, 1.5 eq) at rt and reaction mixture was stirred for 15 min. After 15 min., 2- (cy cl openly lamino) nicotinohydrazide (Intermediate 31-B2) (0.50 g, 2.299 mmol, 1.1 eq) was added and reaction mixture was stirred again at rt for 5 h. The progress was monitored on TLC (using 5% MeOH in DCM mobile phase). After 5 h TLC indicates the completion of reaction so resulting reaction mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.5 g crude. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase. The desired product was eluted in 7% MeOH in DCM as mobile phase to afford the title compound 2-(cyclopentylamino)-N'-(3-methyl-2-oxopyrrolidine-3- carbonyl) nicotinohydrazide (0.11 g, 0.318 mmol, Yield: 15.20%)LCMS (Method A): 1.204 min, 64.62%, 254 nm, MS: ES+ m / z 346.2 [M+1]Step 4: Synthesis of 3-(5-(2-(cyylopentvlamino) pvridin-3-yl)-1,3.4-oxadiazol-2-yl)-3- methylpyrrolidin-2-one (Compound 31)

[0262] To a stirred solution of 2-(cyclopentylamino)-N'-(3-methyl-2-oxopyrrolidine-3- carbonyl) nicotinohydrazide (Intermediate 31-B3) (0.09 g, 0.260 mmol, 1.0 eq) in DCM (1.0 mL), was added Tri ethyl amine (0.10 mL, 0.782 mmol, 3.0 eq) and tosyl chloride (0.064 g, 0.339 mmol, 1.3 eq) at 0 °C and reaction mixture was stirred at rt for 2 h. The reaction was monitored on TLC (70% EtOAc in hexane as mobile phase). After completion water (50 mL) was added and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0. 1 g crude. The crude was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 60% EtOAc in hexane afforded the title compound 3-(5-(2-(cyclopentylamino) pyridin- 3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (0.028 g, 0.085 mmol, Yield: 32.82%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.31-8.29 (m, 1H), 8.19 (s, 1H), 8.03 (dd, J 7.6 2.0 Hz, 1H), 7.81 (d, J= 6.8 Hz, 1H), 6.76-6.73 (m, 1H), 4.49-4.44 (m, 1H), 3.43-3.39 (m, 2H), 2.77-2.67 (m, 1H), 2.24-2.18 (m, 1H), 2.05-2.01 (m, 2H), 1.74-1.71 (m, 2H), 1.68-1.61 (m, 2H), 1.59 (s, 3H), 1.53-1.47 (s, 2H).LCMS (Method A): 1.574 min, 100%. 210.0 nm, MS: ES+ m / z 328.16 [M+1]HPLC (Method A): 4.879 mm, 98.84%, 254.0 nm,CHIRAL HPLC: Peak-1: 5.42 min, 48.96 %, 260.0 nm; Peak-2: 5.84 min, 50.42 %, 260.0 nmEXAMPLE 25 - Preparation of 3-(5-(2-((3,3-difluorocyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-3-methylpyrrolidin-2-one (Compound 32)Step 1 : Synthesis of Intermediate 32-A1 Benzyl (3,3-difluorocyclohexyl) carbamate.

[0263] To a stirred solution of Benzyl (3-oxocyclohexyl) carbamate (CAS:320590-29-2) (5.0 g, 20.219 mmol, 1.0 eq) in DCM (80 mL) was prepared in 250 mL RBF at 0 °C followed by the dropwise addition of DAST (4.0 mL, 30.320 mmol, 1.5 eq) and stirred the reaction for 4 h at ambient temperature. The reaction was monitored by TLC (using 25% EtOAc in hexane as a mobile phase) After completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (5 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product. The obtained crude material was purified by flash column chromatography (using 230-400 mesh silica and 20-25%EtOAc in hexane gradient) to afford the title compound Benzyl (3,3-difluorocyclohexyl) carbamate (3.0 g, 11.14 mmol, Yield: 55.10%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 7.44 - 7.29 (m, 6H), 5.01 (s, 2H), 3.54 - 3.46 (m, 1H), 2.33 - 2.21 (m, 1H), 1.99 - 1.95 (m, 1H), 1.82 - 1.60 (m, 4H), 1.40 - 1.37 (m, 1H), 1.23 - 1.20 (m, 1H).LCMS (Method A): 2.329 min, 98.28%, 210 nm, MS: ES+ m / z 270.10 [M+1]Step 2: Synthesis of Intermediate 32-A2: 3.3-difluorocyclohexan-1-amine hydrochloride

[0264] To a stirred solution of Benzyl (3,3-difluorocyclohexyl) carbamate (3.0 g, 11.123 mmol, 1.0 eq) in MeOH (40.0 mL) was prepared in 100 mL RBF at ambient temperature, were added formic acid (0.041 mL, 1.120 mmol, 0.1 eq) and 10% of Pd / C (6.0 g, 200% w / w) at same temperature. The resulting mixture was stirred under H2 atmosphere for 12 h at ambient temperature. The reaction was monitored by TLC (using 5% DCM: MeOH as a mobile phase) which confirmed that the reaction got completed after 12 h of stirring to rt. The resulting reaction mixture was filtered off and the filtrate was directly concentrated under reduced pressure to afford the crude product. The obtain crude was diluted with MeOH (20 mL) and 4.0 M HC1 in dioxane (60.0 mL, 20 v) was added and stirred at 0 °C to rt for 6 h. The reaction was monitored by TLC (using 10% DCM: MeOH as a mobile phase) After completion of reaction resulting mixture was directly concentrated under reduce pressure to afford the crude 3,3- difluorocyclohexan-l-amine hydrochloride (3.2 g, 18.6 mmol, Yield; Quantitative). (Note; The crude compound was used as such for next step without any further purification.)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.15 (s, 2H). 3.17 (s, 1H), 2.40-2.37 (m, 1H), 2.02 1.83 (m, 5H), 1.44 - 1.36 (m, 2H).Step 3; Synthesis of Intermediate 32- A3; Methyl 2-((3,3-difluorocyclohexyl) amino) nicotinate

[0265] To a stirred solution of 3,3-difluorocyclohexan-1-amine hydrochloride (Intermediate 32-A2) (3.2 g, 18.64 mmol, 1.0 eq), and methyl 2-chloronicotinate (CAS:40134-18-7) (3.8 g, 22.360 mmol, 1.2 eq) in DMF (35.0 mL), was added K2CO3(7.71 g, 55.92 mmol, 3.0 eq) at rt and stirred at 160 °C for 8 h. The reaction was monitored on TLC (40% EtOAc in hexane as mobile phase). After completion of reaction, the resulting reaction mixture was cooled to rt and diluted with water (50 mL) then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4then concentrated under reduced pressure to afford 2.6 g crude. The obtained crude material was purified by flash column chromatography using silica gel (230- 400 mesh) as stationary phase and gradient 20-25% EtOAc in hexane afforded the titlecompound Methyl 2-((3,3-difluorocyclohexyl) amino) nicotinate (Intermediate 32-A3) (0.2 g, 0.739 mmol, Yield: 3.97%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.31 (dd, .7 = 4.4, 1.6 Hz, 1H), 8.10 (dd, ,7 7.6, 2.0Hz, 1H), 8.00 (d, J = 7.6Hz, 1H), 6.65 (dd, 7.6, 4.8 Hz, 1H), 4.36 - 4.34 (m, 1H), 3.82 (s, 3H), 2.39 - 2.33 (m, 1H), 2.00 - 1.76 (m, 5H), 1.55 - 1.46 (m, 2H).LCMS (Method A):2.268 min, 100%, 254.0 nm, MS: ES+ m / z 270.70 [M+1]Step 4: Synthesis of Intermediate 32- A4: 2-((3.3-difluorocyclohexyl) amino) nicotinohydrazide

[0266] To a stirred solution of Methyl 2-((3,3-difluorocyclohexyl) amino) nicotinate (Intermediate 32-A3) (0.160 g, 0.890 mmol, 1.0 eq) in MeOH (8.0 mL), was added Hydrazine hydrate (0.378 g. 11.830 mmol, 20.0 eq) at rt and reaction mixture was heated up to 90 °C for 16 h. The reaction was monitored on TLC (5% MeOH in DCM as mobile phase). After completion, the reaction mixture was concentrated under reduced pressure and extracted with 10% MeOH in DCM (3 x 20 mL) and combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the title compound 2-((3,3-difluorocyclohexyl) amino) nicotinohydrazide (Intermediate 32-A4) (0. 160 g, 0.519 mmol, Yield: Quantitative) (Note crude was used as such for next step without any further purification.)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.77 (s, 1H), 8.34 (d, J = 7.6 Hz. 1H), 8.16 (dd, J = 4.8, 1.6 Hz, 1H), 7.85 (dd, .7 = 7.6, 2.0 Hz, 1H), 6.56 (dd, .7 = 7.6, 4.8 Hz, 1H), 4.46 (brs, 2H), 4.26 - 4.19 (m, 1H), 2.39 - 2.35 (m, 1H), 1.99 - 1.96 (m, 1H), 1.91 - 1.86 (m, 2H), 1.83 - 1.74 (m, 2H), 1.53 - 1.47 (m, 1H), 1.43 - 1.38 (m, 1H).LCMS (Method A): 1.197 min, 100%, 210.0 nm, MS: ES+ m / z 271.10 [M+1]Step 5: Synthesis of Intermediate 32-A5: 2-((3,3-difluorocyclohexyl) amino)-N'-(3-methyl-2- oxopvrrolidine-3-carbonvl) nicotinohydrazide

[0267] To a stirred solution of 3-methyl-2-oxopyrrolidine-3-carboxylic acid (0.158 g, 1.1 mmol, 2.0 eq) in DMF (2 mL), was added DIPEA (0.38 rnL, 2.2 mmol. 4.0 eq), EDC.HC1 (0.316 g. 1.65 mmol. 3.0 eq) and HOBt (0.336 g, 2.20 mmol, 4.0 eq) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C followed by the addition of 2-((3,3-difluorocyclohexyl) amino) nicotinohydrazide (Intermediate 32- A4) (0.150 g, 0.55 mmol, 1.0 eq) dropwise (in 2 mL of DMF) over 5 min. and further stirred at rt for 16 h. The progress was monitored on TLC (using 5% MeOH in DCM mobile phase). After completion water (30.0 mL) was added and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.20 g crude. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase.The gradient 90-100% EtOAc in hexane afforded the title compound 2-((3,3-difluorocyclohexyl) amino)-N'-(3-methyl-2-oxopyrrolidine-3-carbonyl) nicotinohydrazide (0.140 g, 0.354 mmol, Yield: 59.81%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 10.37 (s, 1H), 9.57 (s, 1H), 8.23-8.21 (m, 2H), 8.01 - 7.98 (m, 2H), 6.61 (dd, J = 7.6, 4.8 Hz, 1H), 4.26 - 4.24 (m, 1H), 3.22 (t, J = 6.8 Hz, 2H), 2.57 - 2.49 (m, 1H), 2.38 - 2.33 (m, 1H), 1.99 - 1.88 (m, 4H), 1.85 - 1.77 (m, 2H), 1.51 - 1.41 (m, 1H), 1.38 - 1.26 (m, 1H), 1.24 (s, 3H).LCMS (Method A): 1.381 min, 91.55%. 254 nm, MS: ES+ m / z 396.32 [M+1]Step 6; Synthesis of 3-(5-(2-((3.3-difluorocyclohexyl) amino) pyridin-3-yl)-1,3,4-oxadiazol-2- yl)-3-methylpyrrolidin-2-one (Compound 32)

[0268] To a stirred solution of 2-((3,3-difluorocyclohexyl) amino)-N'-(3-methyl-2- oxopyrrolidine-3-carbonyl) ni cotinohydrazide (0.130 g, 0.32 mmol, 1.0 eq) in DCM (1.5 mL), was added Et3N (0.13 mL, 0.097 mmol, 3.0 eq) and tosyl chloride (0.093 g, 0.48 mmol, 1.2 eq) at 0 °C and reaction mixture was stirred at rt for 2 h. The reaction was monitored on TLC (5% MeOH in DCM as mobile phase). After completion, the resulting reaction mixture was diluted with water (30 mL) and extracted with 10% methanol in DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0. 150 g cmde. The crude was purified by purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase The gradient 80-90% EtOAc in hexane afforded the tittle compound 3-(5-(2-((3.3-difluorocyclohexyl) amino) pyridin-3-yl)-l,3,4-oxadiazol-2-yl)-3- methylpyrrolidin- 2-one (0.101 g, 0.267 mmol. Yield: 75.59%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.32 (dd, J = 4.8, 2.0 Hz, 1H), 8.19 (s, 1H), 8.07 (dd, J = 7.6, 2.0 Hz, 1H), 7.85 (d, J = 7. 6 Hz, 1H), 6.79 (dd, J = 7.6 4.8 Hz, 1H), 4.41 - 4.39 (m, 1H), 3.34 - 3.32 (m, 2H), 2.78 - 2.71 (m, 1H), 2.51 - 2.43 (m, 1H), 2.25 - 2.18 (m, 1H), 2.03 - 1.81 (m. 5H), 1.60 (s, 3H), 1.57 - 1.50 (m, 2H).LCMS (Method A): 1.986 min, 99.55%, 254.0 nm, MS: ES+ 378.62 [M+1]HPLC (Method A): 6.009 mm, 99.73%, 254.0 nmChiral HPLC: (Peak-1): 5.31 min, 25.01%, 352.0 nm; (Peak-2): 5.67 min, 25.16%, 352.0 nm;(Peak -3): 5.92 min, 25.61%, 352.0 nm; (Peak-4); 6.64 min. 24.69%, 352.0 nmEXAMPLE 26 - Preparation of 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-2H- tetrazol-2-yl)-3-methylpyrrolidin-2-one (Compound 33)Step 1- Synthesis of Intermediate 36-B1 1-benzyl-3-melhylpyrrolidin-2-one

[0269] To a stirred solution of l-benzylpyrrolidin-2-one (1.5 g, 8.57 mmol, 1.0 eq) in THF (15 mL) was added n-BuLi (1.6 M solution in hexane) (6.4 mL. 10.2 mmol, 1.2 eq) dropwise at -78°C over 30 min. followed by dropwise addition of Mel (2.43 g, 17.1 mmol, 2.0 eq) at -78 °C.The reaction mixture was stirred for 2 h at same temperature and monitored by TLC (usingEtOAc: hexane 30% as mobile phase). After completion the resulting reaction mixture was quenched with saturated NH4CI solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to obtained the crude material. The crude was purified by normal phase column chromatography on silica gel (230:400 mesh) and gradient 20% EtOAc in hexane afforded the title compound 1- benzyl-3-methylpyrrolidin-2-one (1.0 g, Yield: 61.73%).*H NMR (DMSO-d6, 400 MHz): δ ppm 7.38-7.20 (m, 5H), 4.38 (s, 2H), 3.18-3.14 (m, 2H), 2.47-2.41 (m, 1H), 2.21-2.16 (m, 1H), 1.56-1.51 (m, 1H), 1.11 (d, J = 7.2 Hz, 3H).LCMS (Method A): 1.867 mm, 85.14%, 254.0 nm, MS (ES+) m / z 190.3 [M+1],Step 2- Synthesis of Intermediate 36-B2: 1-benzyl-3-bromo-3-methylpvrrolidin-2-one

[0270] To a stirred solution of 1-benzyl-3-methylpyrrolidin-2-one (0.5 g. 2.64 mmol, 1.0 eq) in THF (5 mL) was added EDA (1.0 M solution in hexane) (5.2 mL, 5.28 mmol, 2.0 eq) dropwise at -78 °C and reaction mixture was stirred for 1 h at same temperature, followed by addition of TMSC1 (0.57 g, 5.28 mmol, 2.0 eq) dropwise at -78 °C and reaction mixture was further stirred for 1 h at same temperature. The reaction mixture was allowed to warm up to 0 °C then NBS (0.94 g, 5.28 mmol, 2.0 eq) was added and progress was monitored by TLC (30% EtOAc in hexane as mobile phase). After 1 h, the resulting reaction mixture was diluted with saturated NH4Cl solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4and concentrated to afford the crude material. The crude compound was purified by flash column chromatography on silica gel (230:400 mesh) and gradient 20% EtOAc in hexane afforded the title compound l-benzyl-3-bromo-3- methylpyrrolidin-2-one (0.2 g, Yield: 28.23%).1H NMR (DMSO-d6, 400 MHz): δ ppm 7.38-7.23 (m, 5H), 4.57 (d, J = 14.8 Hz, 1H), 4.30 (d, J = 15.2 Hz, 1H), 3.21-3.18 (m, 2H), 2.45-2.43 (m, 1H), 2.31-2.26 (m, 1H), 1.85 (s, 3H).LCMS (Method A): 2.056 min, 73.04%, 215.0 nm, MS (ES+) m / z 268.1, 270.1 [M, M+2],Step 3: Synthesis of Intermediate 33-B1 : 3-bromo-3-methylpyrrolidin-2-one

[0271] To a solution of 1-benzyl-3-bromo-3-methylpyrrolidin-2-one (1.0 g, 3.72 mmol, 1.0 eq) in toluene (10 mL) was added triflic acid (2.23 g, 14.9 mmol, 4.0 eq) and reaction mixture heated at 190 °C for 25 min in Microwave. After 25 min, TLC (50% EtOAc in hexane as mobile phase) indicate the completion of reaction, the resulting reaction mixture was diluted with saturated NaHCO3solution (230 mL) and extracted with EtOAc (2 x 330 mL). The combined organic layers were dried over Na2SO4and evaporated to get the crude material. The crude obtained was purified by flash column chromatography on silica (230:400 mesh) and gradient 50% EtOAc in hexane afforded the title compound 3-bromo-3-methylpyrrolidin-2-one (8.0 g, Yield: Quantitative). (Note: 1 g x 12 reactions were performed parallelly and combined crude material purified together)1H NMR (DMSO-d6, 400 MHz): δ ppm 8.13 (s, 1H), 3.23-3.14 (m, 2H), 2.45-2.44 (m, 1H), 2.28-2.21 (m, 1H), 1.76 (s, 3H).LCMS (Method A): 1.446 min, 99.83%, 235.0 nm, MS (ES+): 178.0 [M+1],Step 4- Synthesis of Intermediate 33-Al : 2-((4,4-dimethylcyclohexyl) amino) nicotinonitrile

[0272] To a stirred solution of 2-chloronicotinonitrile (1.0 g, 5.38 mmol, 1.0 eq) in DMSO (10 mL) was added 4,4-dimethylcyclohexan-1-amine (Intermediate 5-A2; 0.82 g, 6.46 mmol, 1.2 eq) and Et3N (1.63 g, 16.1 mmol, 3.0 eq) at rt and heated at 100 °C for 4 h. The reaction was monitored on TLC (30% EtOAc in hexane). After completion of the reaction, the resulting mixture was partitioned between water (30 mL) and ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na2SO4and solvent was removed in vacuum to get the crude material. The crude material was purified by normal phase column chromatography on silica (230:400 mesh) and gradient 18% EtOAc in hexane afforded the title compound 2-((4,4- dimethylcyclohexyl) amino) nicotinonitrile (0.6 g, Yield: 36.25%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.25 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.86 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.60 (dd, J = 7.6, 4.8 Hz, 1H), 3.93-3.87 (m, 1H), 1.64- 1.58 (m, 4H), 1.38-1.35 (m, 2H), 1.28-1.20 (m, 2H), 0.94 (s, 3H). 0.90 (s, 3H).LCMS (Method A):2.545 min, 98.70%, 254.0 nm, MS (ES+) m / z 230.12 [M+1]Step 5; Synthesis of Intermediate 33-A2: N-(4,4-dimethvlcvclohexvl)-3-(2H-tetrazol-5-vl) pyridin-2-amine

[0273] To a stirred solution of 2-((4,4-dimethylcyclohexyl) amino) nicotinonitrile (0.6 g, 2.61 mmol, 1.0 eq) in DMF (6 mL) was added NaN3(0.44 g. 6.80 mmol, 2.6 eq) and NH4Cl (0.41 g, 7.84 mmol, 3.0 eq) at rt. The reaction mixture was heated at 130 °C for 16 h and progress was monitored on TLC (30% EtOAc in hexane). After completion, the resulting mixture was acidified with 1 N HC1, precipitates formed was filtered then solid collected and dried under reduced pressure to afford the title compound N-(4.4-dimethylcyclohexyl)-3-(2H-tetrazol-5-yl) pyridin-2-amine (0.35 g, Yield: 49.12%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.76 (brs, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.21 (dd, J = 5.2, 1.6 Hz, 1H), 6.93 (dd, J = 7.2, 5.6 Hz, 1H), 4.02 (s, 1H), 1.91-1.87 (m, 2H), 1.60-1.51 (m, 2H), 1.47-1.43 (m, 2H), 1.38-1.31 (m, 2H), 0.97 (s, 3H), 0.95 (s, 3H). Note: One proton might be exchanged in DMSO Moisture.LCMS (Method A): 1.766 mm. 100%, 254.0 nm, MS (ES+) m / z 273.19 [M+1] ,Step 6- Synthesis of 3-(5-(2-((4.4-dimethylcyclohexyl)amino)pyridin-3-yl)-2H-tetrazol-2-yl)-3- methylpyrrolidin-2-one (Compound 33)

[0274] To a stirred solution of N-(4,4-dimethylcyclohexyl)-3-(2H-tetrazol-5-yl) pyridin-2- amine (0.25 g, 0.91 mmol, 1.0 eq) in ACN (2.5 mL) was added 3-bromo-3-methylpyrrolidin-2- one (0.32 g, 1.83 mmol, 2.0 eq), K2CO3(0.25 g, 1.83 mmol, 2.0 eq) and KI (0.30 g, 1.83 mmol, 2.0 eq) at rt. The reaction mixture was heated at 100 °C for 8 h and monitored on TLC (70% EtOAc in hexane). After completion of the reaction, the resulting mixture was partitioned between water (40 mL) and ethyl acetate (3 x 40 mL). The combined organic layers were dried over Na2SO4and solvent was removed in vacuum to get the crude material. The crude material was purified by normal phase flash column chromatography on silica (230:400 mesh) and gradient 40% EtOAc in hexane afforded the title compound 3-(5-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-2H-tetrazol-2-yl)-3-methylpyrrolidin-2-one (0.11 g, Yield: 32.43%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.51 (s, 1H), 8.27 (dd, J = 7.6, 2.0 Hz, 1H), 8.22 (dd, J = 4.8 Hz, 2.0 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 6.71 (dd, J = 7.6, 4.8 Hz, 1H), 4.04 (hrs, 1H), 3.51-3.43 (m, 2H), 2.93-2.86 (m, 1H), 2.58-2.50 (m, 1H), 1.96 (s, 3H), 1.89-1.85 (m, 2H), 1.48- 1.40 (m, 4H), 1.34-1.27 (m, 2H), 0.95 (s, 3H). 0.94 (s, 3H).LCMS (Method A): 2.020 min, 97.25%. 210.0 nm, MS (ES+) m / z 370.48 [M+1]HPLC (Method A): 95.80%, 6.05 min at 220 nmChiral HPLC: Peak-1: 49.87%, RT 1.778 min at 256 nm; Peak-2: 50.00%, RT = 1.843 min at256 nmEXAMPLE 27 - Preparation of 3-(5-(2-((4,4-difluorocyclohexyl) amino) pyridin-3-yl)-2H- tetrazol-2-yl)-3-methylpyrrolidin-2-one (Compound 34)Step 1- Synthesis of Intermediate 34-Al: 2-((4.4-difluorocyclohexyl) amino) nicotinonitrile

[0275] To a stirred solution of 2-chloronicotinonitrile (1.0 g, 5.38 mmol, 1.0 eq) in DMSO (10 mL) was added 4,4-difluorocyclohexan-l -amine hydrochloride (1.1 g, 6.46 mmol, 1.2 eq) andEt3N (2.72 g, 26.9 mmol, 5.0 eq) at rt and reaction mixture was heated at 120 °C for 8 h. The reaction was monitored on TLC (30% EtOAc in hexane). After completion of the reaction, the resulting mixture was partitioned between water (80 mL) and ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4and solvent was removed in vacuum to get the crude material. The crude material was purified by flash column chromatography on silica(230:400 mesh) and gradient 20% EtOAc in hexane afforded the title compound (0.9 g,52.56%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.29 (dd, J= 4.8, 1.8 Hz, 1H), 7.90 (dd, J= 7.6, 1.6Hz,1H), 6.91 (d, J = 8.0 Hz, 1H), 6.66 (dd, J= 7.6, 5.2 Hz, 1H), 4.17-4.10 (m, 1H), 2.05 - 1.92 (m,3H), 1.89-1.87 (m. 3H), 1.76 - 1.66 (m, 2H).LCMS (Method A): 2.075 min, 100%, 220.0 nm, MS (ES+) m / z 238.77 [M+1] ,Step 2: Synthesis of Intermediate 34- A2: N-(4.4-difluorocyclohexyl)-3-(2H-tetrazol-5-yl) pyridin-2-amine

[0276] To a stirred solution of 2-((4,4-difluorocyclohexyl) amino) nicotinonitrile (0.9 g, 3.79 mmol, 1.0 eq) in DMF (9 mL) was added NaN3(0.64 g, 9.86 mmol, 2.6 eq) and NH4CI (0.60 g, 11.3 mmol, 3.0 eq) at rt and reaction was heated up to 120 °C for 12 h. The reaction was monitored on TLC (50% EtOAc in hexane). After completion of the reaction, the resulting mixture was acidified with 1 N HC1 precipitates formed was filtered then solid was collected and dried under reduced pressure to afford the title compound N-(4,4-difluorocyclohexyl)-3- (2H-tetrazol-5-yl) pyridin-2-amine (0.5 g, 1.78 mmol, Yield: 47.03%).LCMS (Method A): 1.592 min, 62.50%, 254.0 nm, MS (ES+) m / z 281.19 [M+1],Step 3: Synthesis of 3-(5-(2-((4.4-difluorocyclohexyl) amino) pyridin-3-yl)-2H-tetrazol-2-yl)-3- methylpyrrolidin-2-one (Compound 34)

[0277] To a stirred solution of N-(4,4-difluorocyclohexyl)-3-(2H-tetrazol-5-yl) pyridin-2- amine (0.5 g, 1.78 mmol, 1.0 eq) in ACN (5.0 mL) was added 3-bromo-3-methylpyrrolidin-2- one (0.63 g, 3.56 mmol, 2.0 eq), K2CO3(0.49 g. 3.56 mmol, 2.0 eq) and KI (0.59 g, 3.56 mmol, 2.0 eq) at rt. The reaction was heated at 100 °C for 8 h and monitored on TLC (50% EtOAc in hexane). After completion of the reaction, the resulting mixture was partitioned between water (30 mL) and ethyl acetate (2 x 40 mL). The combined organic layer was dried over Na2SO4and solvent was removed in vacuum to get the crude material. The crude material was purified by flash column chromatography on silica (230:400 mesh) and gradient 40% EtOAc in hexane afforded the title compound 3-(5-(2-((4,4-difluorocyclohexyl) amino) pyridin-3-yl)-2H-tetrazol- 2-yl)-3-methylpyrrolidin-2-one (0.042 g, Yield: 6.24%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.52 (s, 1H), 8.31-8.25 (m, 2H), 7.41 (d, J = 7.2 Hz, 1H), 6.77 (dd, J = 7.6, 4.8 Hz, 1H), 4.24 (brs, 1H), 3.53 - 3.41 (m, 2H), 2.92 - 2.85 (m, 1H), 2.58 - 2.53 (m. 1H), 2.08-1.99 (m, 6H), 1.96 (s, 3H), 1.63-1.62 (m, 2H).LCMS (Method A): 1.733 min. 98.94%, 220.0 nm, MS (ES+) m / z 378.73 [M+1] ,HPLC (Method A): 97.52%, 5.551 min at 210 nmChiral HPLC: Peak-1 : 49.79%, RT 1.681 min at 250 nm; Peak-2: 50.01%, RT = 1.817 min at250 nmEXAMPLE 28 - Preparation of 3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2,3-triazol-1-yl) pyrrolidin-2-one (Compound 35)Synthesis of Intermediate 35-A2Step la: Synthesis of Intermediate 35-A2: 3-azidopvrrolidin-2-one

[0278] To a solution of 2-oxopyrrolidin-3-yl 4-methylbenzenesulfonate (0.05 g, 0.195 mmol.1.0 eq) in acetone (4 mL) was added KI (cat.) and NaN3(0.022 g, 0.352 mmol, 1.8 eq) in H2O (1 mL) at room temperature and stirred the reaction mixture at 60-65 °C for 7 h. The completion of reaction was monitored on TLC (EtOAc 100% as mobile phase). After completion, the reaction mixture was diluted with water (5 mL) and extracted with chloroform (2 x 5 mL). Combined organic layers were dried over Na2SO4and concentrated to afford 0.08 g cmde. The obtained crude material was purified by trituration using n-pentane (2 mL) to afford the title compound 3- azidopyrrolidin-2-one (0.019 g, 0.151 mmol, Yield: 76.92%).1H NMR (CDCh, 400 MHz): δ ppm, 6.19 (brs, 1H), 4.13 (t, J= 8.0 Hz. 1H), 3.51 - 3.32 (m,2H), 2.52 - 2.34 (m, 1H), 2.08 - 1.99 (m, 1H).Step 1 : Synthesis of Intermediate 35-A3: 3-(trimethylsilyl) ethynyl) pyridine-2-amine

[0279] To a solution of 3-iodopyridin-2-amine CAS: 104830-06-0 (5.0 g. 22.73 mmol, 1.0 eq), in Et3N (20 mL) was added CuI (0.413 g, 2. 173 mmol, 0.1 eq) followed by purged with N2gas, were added PdCl2(PPh3)2 (0.823 g, 1.137 mmol, 0.05 eq) and dropwise ethynyltrimethyl silane (CAS: 1066-54-2) (3.49 g, 35.64 mmol, 1.64 eq) at 0 °C and stirred the reaction at rt under nitrogen atmosphere for 6 h. The reaction was monitored on TLC (using EtOAc: hexane; 30% as mobile phase) which confirmed that the reaction got completed after 6 h. The resulting reaction mixture was filter through celite and wash with ether, now that organic layer was wash with sat. NH4CI solution (100 mL) and the organic layer was separated and dried over Na2SO4and concentrated under reduced pressure to afford 5.5 g. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (15% ethyl acetate in hexane) to yielding 3 -(trimethyl silyl) ethynyl) pyridine-2-amine (2.4 g, 12.61 mmol, Yield: 55.49%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 7.96 (d, J= 3.2 Hz, 1H), 7.51 (dd, J=7.2, 1.2 Hz, 1H), 6.52 (dd, J=7.2, 4.8 Hz, 1H), 6.10 (s, 2H), 0.23 (s, 9H).LCMS (Method A): 1.628 min, 99.81%, 327 nm, MS: ES+ 191.10 (M+l)Step 2: Synthesis of Intermediate 35-A4: 3-ethynyl pyridin-2-amine

[0280] To a solution of 3-(trimethylsilyl) ethynyl) pyridine-2-amine (2.4 g, 12.61 mmol, 1 .0 eq) in THE (24 rnL) was added TBAF (CAS:429-41-4) (2.4 rnL, 1.702 mmol, 0.13 eq) dropwise and stirred the reaction at rt under nitrogen atmosphere for 1 h. The progress of reaction was monitored on TLC (EtOAc: hexane; 50% as mobile phase). After completion, the resulting reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). Combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (2 g). The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase and gradients 30% ethyl acetate in hexane afforded the title compound 3-ethynyl pyridin-2-amine (1.0 g, 8.46 mmol. Yield: 67.12%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 7.96 (dd, J = 4.8. 1.6 Hz, 1H), 7.54 (dd, J = 7.2. 1.6 Hz, 1H), 6.53 (dd, J = 7.6, 4.8 Hz, 1H), 6.13 (s, 2H), 4.43 (s, 1H).LCMS (Method A): 0. 197 min, 90.20%, 254 nm, MS: ES+ m / z 118.89 [M+1]Step 3; Synthesis of Intermediate 35-A5; 3-(4-(2-aminopyridin-3-yl)-1H-1,2,3-triazol-1- yl)pyrrolidin-2-one

[0281] To a solution of 3-azidopyrrolidin-2-one (Intermediate 35-A2) (0.39 g, 3.09 mmol, 1 .0 eq) intBuOH (3.9 mL) was added 3-ethynyl pyridin-2-amine (Intermediate 35-A4) (0.365 g, 3.09 mmol, 1.0 eq) and Cui (cat.) at rt. The reaction mixture was stirred at 80 °C for 16 h. The completion of reaction was indicated by TLC (5% MeOH: DCM as mobile phase) so after completion, resulting mixture was filtered through celite pad and filtrate was evaporated to afford the crude (0.5 g). The obtained crude material was purified by flash column chromatography using silica (60-120 mesh) as stationary phase and gradient 15% MeOH in DCM afforded the title compound 3-(4-(2-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl) pyrrolidin- 2-one (0.1 g. 0.409 mmol. Yield: 13.24%).1H NMR (DMSO-d6, 400 MHz); δ ppm, 8.77 (s, 1H). 8.41 (s, 1H). 7.97 (d, J = 3.6 Hz, 1H). 7.90 (d, J= 7.6 Hz, 1H), 6.97 (s, 2H), 6.66 (dd, J= 7.2, 4.8 Hz, 1H), 5.49 (t, J = 9.2 Hz, 1H), 3.46 - 3.39 (m, 1H), 2.77 - 2.67 (m, 1H), 2.61 - 2.56 (m, 1H). (Note: 1H merge with DMSO moisture peak)LCMS (Method A): 1.63 min, 97.38%, 254 nm, MS: ES+ m / z 245.2 [M+1]Step 4: Synthesis of 3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2,3- triazol-1-yl) pyrrolidin-2-one (Compound 35)

[0282] To a solution of 3-(4-(2-aminopyridin-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-2-one (0.37 g, 1.515 mmol. 1.0 eq) in DCM (3.7 mL) was added (4-(trifluoromethyl)phenyl)boronic acid (CAS; 128796-39-4) (0.43 g, 2.27 mmol, 1.5 eq), copper(II)acetate (0.33 g, 1.818 mmol, 1.2 eq) and pyridine (0.359 g, 4.545 mmol, 3.0 eq) then resulting mixture was stirred at rt under O2atmosphere for 16 h, The progress of reaction was monitored on TLC (using 5% MeOH: DCM as mobile phase). After completion, the reaction mixture was filtered through celite bed and filtrate was concentrated to afford the crude (0.9 g). The obtained crude material was purified by prep HPLC purification (gradient H2O: ACN) to afford the title compound 3-(4-(2-((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2,3-triazol-1-yl) pyrrolidin-2-one one (0.008 g, 0.021 mmol, Yield: 1.36%).1H NMR (MeOD-d4, 400 MHz): δ ppm, 8.64 (s, 1H), 8.25 (d, J = 3.6 Hz, 1H), 8.05 (dd, J = 7.6,1.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 6.96 (dd, J= 4.8, 7.6 Hz, 1H), 5.59 (t, J = 8.8 Hz, 1H), 3.69 - 3.50 (m, 2H), 2.94 - 2.90 (m. 1H), 2.87 - 2.75 (m, 1H) (Note: 2H protons exchanged in MeOD-d4).1H NMR (DMSO-d6, 400 MHz): δ ppm, 10.86 (s, 1H), 8.98 (s, 1H), 8.43 (s, 1H), 8.29 (d, J3.2 Hz , 1H), 8.17 (d, J = 6.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.04(dd, J= 4.8, 7.6 Hz, 1H), 5.56 (t, J = 9.2 Hz, 1H), 3.49 - 3.40 (m, 2H), 2.80 - 2.76 (m, 1H);(Note: one proton merged in DMSO solvent peak).LCMS (Method A): 2.343 min, 95. 10%, 254 nm, MS: ES+ m / z 389.22 [M+1]HPLC (Method A): 8.34 min, 97.16%, 210.0 nmChiral HPLC: Peak-1 3.75 min, 47.96%, 300 nm; Peak-2 = 4.48 mm, 51.57%, 300 nmEXAMPLE 29 - Preparation of 3-methyl-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2,3-triazol-1-yl) pyrrolidin-2-one (Compound 36)Step 1 : Synthesis of Intermediate 36-Al : tert-butyl 3-methyl-2-oxopvrrolidine-1-carboxylate

[0283] To a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (CAS:85909-08-6) (0.5 g,2.69 mmol, 1.0 eq) in THF (8.5 mL) was added LiHMDS (0.3 mL, 2.83 mmol. 1.05 eq) dropwise at -78 °C and stirred the reaction for 15 min. After 15 min, Mel (0.3 mL, 2.97 mmol.1.01 eq) was added at -30 °C dropwise and allow the reaction mixture to warm up to room temperature then stirred for 2 h. The progress of reaction was monitored on TLC (using EtOAcin Hexene (3:7) as mobile phase). After completion, resulting reaction mixture was diluted with saturated NH4CI solution (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layer were dried over Na2SO4and concentrated to get the cmde (0.510 g). The obtained crude material was purified by column chromatography using silica gel 230-400 mesh size and gradient 0-30% EtOAc in hexane afforded the title compound tert-butyl 3-methyl-2- oxopyrrolidine-1 -carboxylate (0.128 g, 0.643 mmol. Yield: 23.80%).1H NMR (CDCl3, 400 MHz): δ ppm, 3.80-3.75 (m, 1H), 3.62-3.55 (m, 1H), 2.62 - 2.52 (m. 1H), 2.26 - 2.18 (m, 1H), 1.70 - 1.58 (m, 1H), 1.54 (s, 9H), 1.24 (d, J = 7.2Hz, 3H).Step 2: Synthesis of Intermediate 36- A2: tert-butyl 3-bromo-3-methyl-2-oxopyrrolidine-1- carboxvlate

[0284] To a solution of tert-butyl 3 -methyl-2-oxopyrrolidine-1-carboxylate (1.0 g, 5.02 mmol, 1.0 eq) in THE (10 mL) was added LIHMDS (10.00 mL, 10.01 mmol, 2.0 eq) at -78 °C and stirred the reaction for 15 min. followed by addition of TMSC1 (1.09 g, 10.0 mmol, 2.0 eq) at same temperature. The reaction was stirred for 30 min. and NBS (1.77 g. 10.0 mmol. 2.0 eq) was added then stirring was continued at rt for 3 h. The reaction progress was monitored by TLC (using EtOAc: Hexene (3:7) as mobile phase). After completion, reaction mixture was diluted with saturated NH4CI solution (20 mL) and extracted with EtOAc (3 x 20 mL), combined organic layers were dried over Na2SO4and solvent was evaporated to afford the (1.0 g) crude. The obtained crude material was purified by flash column chromatography using silica 60-120 mesh size and gradient 0-30% EtOAc in hexane afforded the tittle compound tert-butyl 3- bromo-3-methyl-2-oxopyrrolidine-1-carboxylate (0.700 g, 2.51 mmol, Yield: 50.11%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 3.79-3.72 (m, 2H), 2.52-2.47 (m, 1H), 2.16-2.08 (m, 1H), 1.93 (s, 3H), 1.56 (s, 9H).Step 3: Synthesis of Intermediate 36- A3: tert-butyl 3-azido-3-methvl-2-oxopyrrolidine-l- carboxvlate

[0285] To a solution of tert-butyl 3-bromo-3-methyl-2-oxopyrrolidine-l-carboxylate (Intermediate 36-A2) (1.4 g, 5.035 mmol, 1.0 eq) in acetone (112 mL) was added NaN3(0.654 g, 10.07 mmol, 2.0 eq) in H2O (28 mL) and KI (cat.) then stirred at 60 °C for 3 h. The progress of reaction was monitored by TLC (EtOAc: Hexene (3:7) as mobile phase). After completion, the resulting reaction mixture was diluted with water (20 mL) and extracted with chloroform (3 x 20 mL) then combined organic layers were dried over Na2SO4and concentrated to afford the crude (1.5 g). The obtained crude material was purified by flash column chromatography using silicagel 60-120 mesh size and gradient 0-30% EtOAc in hexane afforded the title compound tert- butyl 3-azido-3-methyl-2-oxopyrrolidine-1-carboxylate (0.6 g, 2.49 mmol, Yield: 49.61%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 3.60 (t, J = 6.8 Hz, 2H), 2.06-1.99 (m, 1H), 1 .96 - 1 .89 (m, 1H), 1.46 (s, 12H).Step 4: Synthesis of Intermediate 36- A4: tert-butyl 3-(4-(2-aminopyridin-3-yl)-1H-1.2.3-triazol- 1 -yl)-3-methvl-2-oxopvrrolidine-1-carboxylate

[0286] To a solution of tert-butyl 3-azido-3-methyl-2-oxopyrrolidine-1-carboxylate (0.57 g, 2.30 mmol, 1.0 eq) intBuOH (6 mL) was added 3-ethynyl pyridin-2-amine (Intermediate 35-A4) (0.280 g, 2.30 mmol. 1.0 eq) and CuI (cat.) and stir the reaction mixture at 80 °C for 16 h. The reaction was monitored by TLC (5% MeOH: DCM as mobile phase). After completion, the reaction mixture was directly concentrated to afford the (0.6 g) crude. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as stationary phase and gradient 0-15% MeOH in DCM afforded the title compound tert-butyl 3-(4-(2- aminopyridin-3-yl)-1H-1,2,3 -triazol-1-yl)-3 -methy 1-2-oxopyrrolidine-1-carboxylate (0.017 g, 0.047 mmol, Yield: 2.0%).LCMS (Method A): 1.324 min, 13.06%, 220 nm, MS: ES+ m / z 359.2 [M+1],Step 5: Synthesis of Intermediate 36-A5: tert-butvl 3-methyl-2-oxo-3-(4-(2-((4-(trifluoromethvl) phenyl) amino) pvridin-3-vl)-1H-1,2,3-triazol-l 1yl) pvrrolidine-1-carboxylate

[0287] To a solution of tert-butyl 3-(4-(2-aminopyridin-3-yl)-1H-1.2.3-triazol-l-yl)-3-methyl- 2-oxopyrrolidine-1-carboxylate (0.52 g, 1.45 mmol, 1.0 eq) in DCM (6 mL) was added (4- (trifluoromethyl)phenyl)boronic acid (CAS: 128796-39-4) (0.549 g, 2.90 mmol, 2.0 eq), copper(II)acetate (0.525 g, 2.90 mmol, 2.0 eq) and DIPEA (0.562 g, 4.35 mmol, 3.0 eq) at rt and stirred the reaction under O2gas atmosphere for 16 h. The reaction was monitored by TLC (using 5% MeOH: DCM as mobile phase). After completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4and evaporated to afford the title compound tert-butyl 3-methyl-2-oxo-3-(4- (2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2,3-triazol-1-yl) pyrrolidine-1- carboxylate (0.540 g, 1.07 mmol. Yield: 74.07%).LCMS (Method A): 2.915 min, 50.55%. 254 nm, MS: ES+ m / z 503.49 [M+1]+Step 6: Synthesis of 3-methvl-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2.3-triazol-1-yl) pyrrolidin-2-one (Compound 36)

[0288] To a solution of tert-butyl 3-methyl-2-oxo-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2,3-triazol-1-yl) pyrrolidine- 1 -carboxylate (0.53 g, 1.054 mmol, 1.0 eq) in 4M HC1 in 1,4 dioxane (5 mL) was stirred at rt for 3 h. The reaction was monitored on TLC(using 5% MeOH: DCM as mobile phase). After completion, the reaction mixture was concentrated to afford the (0.6 g) crude. The Crude product was purified by the prep HPLC purification (ACN: H2O) to afford the title compound 3-methyl-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-1,2,3-triazol-l-yl) pyrrolidin-2-one (0.017 g, 0.042 mmol,Yield: 4.01%).1H NMR (MeOD-d4, 400 MHz): δ ppm. 8.75 (s, 1H), 8.24 (dd, J = 5.6, 1.6 Hz. 1H), 8.09 (dd, J7.6, 1.6 Hz, 1H). 7.96 (d, J = 8.8 Hz, 2H). 7.59 (d, J= 8.8 Hz, 2H). 6.98-6.95 (m, 1H). 3.66-3.49 (m, 2H), 3.15-3.07 (m, 1H), 2.66-2.59 (m, 1H), 1.95 (s, 3H). (Note: Two protons exchanged in MeOD NMR)LCMS (Method A): 2.449 min, 96.14%, 254 nm, MS: ES+ rn / z 403.47 [M+1]HPLC (Method A): 8.79 min, 98.99%, 354 nmEXAMPLE 30 - Preparation of 3-(4-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)- 1H- imidazol-1-yl)-3-methylpyrroIidin-2-one (Compound 37)Step 1- Synthesis of (Intermediate 37-Al) 3-bromo-N-(4,4-dimethylcyclohexyl) pyridin-2- amine

[0289] To a stirred solution of 4,4-dimethylcyclohexan-1 -one (CAS:4255-62-3) (10.0 g, 79.239 mmol, 1.0 eq) in DCM (100 mL) was added 3-bromopyridin-2-amine (CAS: 13534-99-1) (13.70 g, 79.239 mmol, 1.0 eq) and AcOH (9.50 g, 158.478 mmol, 2.0 eq) at rt and reaction mixture was stirred at rt for 2 h. followed by addition of NaBH(OAc)2(25.07 g, 118.85 mmol.1.5 eq) portion wise. The reaction mixture was stirred for 16 h at rt. The reaction was monitored by TLC (using 1% EtOAc: hexane as mobile phase), after completion the resulting reaction mixture was quenched with water (200 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford crude. The obtained crude was purified by flash column chromatography using silica (230-400 mesh) and gradient 0.5% EtOAc in hexane afforded the title compound 3-bromo-N- (4,4-dimethylcyclohexyl) pyridin-2-amine (1.0 g, 3.53 mmol, Yield: 4.46%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 7.99 (dd, J = 4.8, 1.2 Hz, 1H), 7.71 (dd, J = 7.6, 1.6 Hz, 1H), 6.45 (dd, J = 7.6, 4.8 Hz, 1H), 5.70 (d, J = 8.0 Hz, 1H), 3.84-3.80 (m, 1H), 1.70-1.66 (m. 2H), 1.59-1.49 (m. 2H), 1.38-1.35 (m. 2H), 1.29-1.22 (m. 2H), 0.94 (s, 3H), 0.91 (s, 3H).LCMS: 2.863 min, 98.92%, 254.0 nm, MS (ES+) m / z 285.6 [M+2]+.Step 2- Synthesis of (Intermediate 37-A2) N-(4.4-dimethylcyclohexyl)-3-(4,4.5.5-tetramethyl-1.3,2-dioxaborolan-2-yl) pyridin-2-amine

[0290] To a stirred solution of 3-bromo-N-(4,4-dimethylcyclohexyl) pyridin-2-amine (Intermediate 37-Al) (1.2 g, 4.24 mmol, 1.0 eq) in DMSO (12 mL) was added B2Pin2(CAS:73183-34-3) (4.29 g, 16.96 mmol, 4.0 eq) and KO Ac (0.706 g, 7.208 mmol, 1.7 eq) at rt. Followed by addition of PdCl2(dppf) (0.309 g, 0.424 mmol, 0.1 eq) under N2 atmosphere. The resulting reaction mixture was stirred at 95 °C for 16 h and monitored by TLC (30% EtOAc in hexane as mobile phase), after completion the resulting reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (30 mL x 3). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.970 g). The obtained crude material was purified by flash column chromatography using silica gel (100-200 mesh) and gradient 10% EtOAc in hexane afforded the title compound N-(4,4- dimethylcyclohexyl)-3-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl) pyridin-2-amine (Intermediate 37-A2) (0.070 g, 0.212 mmol, Yield: 5.02%).LCMS (Method A): 1.94 min. 34.45 %, 220.0 nm, MS: ES+ m / z 249 [M+1] (Corresponding Boronic Acid mass observed)Step 3: Synthesis of (Intermediate 37-A3):tert-butyl 3-(4-(2-((4,4-dimethylcyclohexyl) amino) pvridin-3-yl)-1H-imidazol-1-yl)-3-methyl-2-oxopyrrolidine-1-carboxylate

[0291] To a stirred solution of N-(4,4-dimethylcyclohexyl)-3-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)pyridin-2-amine (Intermediate 37-A2) (0.7 g, 2.121 mmol, 1.0 eq), tert-butyl 3-(4-bromo-1H-imidazol-1-yl)-3-methy1-2-oxopyrrolidine-1-carboxylate (Intermediate 41 -D2) (0.876 g, 2.545 mmol, 1.2 eq) and K3PO4(1.34 g. 6.363 mmol, 3.0 eq) in dioxane (5.6 mL) and water (1.4 mL) under N2 purging for 10 min. followed by the addition of PdCl2(dppf) (0.310 g, 0.424 mmol, 0.2 eq) and resulting reaction mixture was stirred at 100 °C for 2 h. The reaction was monitored by TLC (30% EtOAc in hexane as mobile phase). After completion, the resulting reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford the crude (0.130 g). The obtained crude material was purified by flash column chromatography using silica gel (100-200 mesh) as stationary phase and gradient 50% EtOAc in hexane afforded the title compound tert-butyl 3-(4-(2-((4,4-dimethylcyclohexyl) amino) pyridin- 3-yl)-1H-imidazol-1-yl)-3-methyl-2-oxopyrrolidine-l-carboxylate (0.060 g, 0.128 mmol, Yield: 12.8%).LCMS (Method A): 2. 100 min. 96.90 %, 345.0 nm, MS: ES+ m / z 468.4 [M+1]Step 4: Synthesis of 3-(4-(2-((4.4-dimethylcyclohexyl) amino) pyridin-3-yl)-1H-imidazol-1-yl)-3-methylpyrrolidin-2-one (Compound 37)

[0292] To a solution of tert-butyl 3-(4-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1H- imidazol-l-yl)-3-methyl-2-oxopyrrolidine-1-carboxylate (Intermediate 37-A3) (0.060 g, 0.128 mmol, 1.0 eq) in DCM (0.6 mL) was added 4 M HC1 in dioxane (0.6 mL) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction was monitored on TLC (30% ethyl acetate in hexane as mobile phase). After completion of reaction the resulting reaction mixture was diluted by DCM (5 mL) and basified by aq. NaHCO3solution (2 mL). The combined organic layer was separate out and dried by Na2SO4, concentrated under reduced pressure, to afford the title compound 3-(4-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1H-imidazol-1-yl)-3-methylpyrrolidin-2-one (Compound 37) (0.009 g, 0.0245 mmol, Yield: 19.23%).1H NMR (MeOD-d4, 400 MHz): δ ppm, 7.96 (d, J = 1.6 Hz, 1H), 7.86 (dd, J 4.8, 1.6 Hz,1H), 7.70 (dd, J = 7.6, 2.0 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 6.56 - 6.53 (m, 1H), 4.63 (s, 1H), 3.52-3.50 (m, 2H), 2.74-2.69 (m, 1H), 2.59-2.53 (m, 1H), 1.92-1.89 (m, 2H), 1.81 (s, 3H) 1.54-1.47 (m, 4H), 1.42-1.35 (m, 2H), 1.00 (s, 3H), 0.98 (s, 3H). Note: Two protons exchanged in MeOD NMR.LCMS (Method A): 1 .783 min, 99.63%, 354.0 nm, MS: ES+ m / z 368.34 (M+l)HPLC (Method A): 6.903 min, 97.07%, 254.0 nm.Chiral HPLC (Method A): Peak 01- 2.226 min, 48.30%, 254.0 nm, Peak 02- 2.268 min, 50.57%,254.0 nm.EXAMPLE 31 - Preparation of 3-(3-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)-3-methylpyrrolidin-2-one (Compound 38)

[0293] Step 1 : Synthesis of Intermediate 33-AL 2-((4,4-dimethylcyclohexyl) amino) nicotinonitrile.

[0294] To a stirred solution of 4,4-difluorocyclohexan-1-amine hydrochloride (CAS: 675112- 70-6) (0.822 g. 6.46 mmol, 1.2 eq) and 2-chloronicotinonitrile (CAS: 6602-54-6) (1.0 g, 5.38 mmol, 1.0 eq) in DMSO (10.0 mL) was added Et3N (2.24 mL, 16.14 mmol, 3.0 eq) at rt and stirred at 120 °C for 4 h. The TLC (20% EtOAc in hexane as mobile phase) indicated the completion of reaction. The resulting reaction mixture was cooled to rt and diluted with w ater (50 mL) then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to afford the crude (1.2 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 20-25% EtOAc in hexane afforded the title compound 2-((4,4- dimethylcyclohexyl) amino) nicotinonitrile (0.8 g, 3.488 mmol, Yield: 48.33%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.26 (dd, J = 4.8, 0.8 Hz, 1H), 7.86 (dd, J = 7.6, 1.2 Hz, 1H), 6.72 (d, J = 8.0 Hz. 1H), 6.60 (dd, J = 7.2, 4.8 Hz, 1H), 3.95 - 3.85 (m, 1H), 1.64 - 1.59 (m, 4H), 1.38 - 1.35 (m, 2H). 1.28 - 1.20 (m, 2H). 0.93 (d, J = 13.6 Hz. 6H).LCMS (Method A): 2.620 min, 99.50%. 254.0 nm, MS: ES+ m / z 230.71 [M+1],Step 2: Synthesis of Intermediate 38-A1 2-((4,4-dimethylcyclohexyl) amino)-N-hydroxy nicotinimidamide

[0295] To a stirred solution of 2-((4,4-dimethylcyclohexyl) amino)-N- hydroxynicotinimidamide (Intermediate 33-Al) (0.800 g, 3.34 mmol, 1.0 eq) in dioxane: water (8 mL; 2 mL) was added hydroxylamine hydrochloride (NH2OH.HCI) (0.936 g, 13.48 mmol, 4.0 eq) and followed by the portion wise addition of NaHCO3(1. 132 g. 13.48 mmol, 4.0 eq) at rt. The reaction mixture was heated up to 70 °C for 6 h and monitored by TLC (50% EtOAc in hexane as mobile phase). After completion of reaction, resulting reaction mixture was diluted with water (10 mL) white precipitate formation was observed which was filtered and dried under reduced pressure to afford the title compound 2-((4,4-dimethylcyclohexyl) amino)-N- hydroxynicotinimidamide (0.5 g, 1.905 mmol, Yield: 54.63%). (Note: The obtained crude material was used as such for next step without further purification)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.86 (s, 1H), 8.24 (d, J = 7.6 Hz. 1H), 7.98 (dd, J =4.8, 1.2 Hz, 1H), 7.73 (dd, J = 7.6, 1.6 Hz, 1H), 6.51 (dd, J = 7.6, 4.8 Hz, 1H), 5.89 (s, 2H), 3.89 (brs, 1H), 1.81 - 1.78 (m, 2H), 1.41 - 1.27 (m, 6H), 0.93 (d, J = 2.0 Hz, 6H).LCMS (Method A): 1.689 min, 100%, 230.0 nm, MS: ES+ m / z 263.46 [M+1]Step 3: Synthesis of Intermediate 38: 3-(3-(2-((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,2,4 -oxadiazol-5-yl)-3-methylpyrrolidin-2-one (Compound 38)

[0296] To a stirred solution of 2-((4,4-dimethylcyclohexyl) amino)-N- hydroxynicotinimidamide (Intermediate 38-Al) (0.500 g, 1.90 mmol, 1.0 eq) and 3-methyl-2- oxopyrrolidine-3-carboxylic acid (0.271 g, 1.90 mmol, 1.0 eq) in dioxane (5.0 mL) was added EDC.HCl (1.45 g, 7.62 mmol, 4.0 eq) and HOBt (1.16 g, 7.62 mmol, 4.0 eq) at rt, then reaction mixture was heated up to 70 °C for 6 h. The reaction was monitored on TLC (100% EtOAc in hexane as mobile phase). After completion, the resulting reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the crude (0.250 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 60-70% EtOAc in hexane afforded the title compound 3-(3-(2- ((4,4-dimethylcyclohexyl) amino) pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-methylpyrrolidin-2-one (Compound 38). (0.136 g, 0.365 mmol, Yield: 19.17%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.27 - 8.22 (m, 3H), 7.07 (d, J = 7.2 Hz, 1H), 6.73 (dd, J = 8.0. 4.8 Hz. 1H). 4.05 - 4.04 (m. 1H). 3.46 - 3.40 (m. 2H), 2.80 - 2.73 (m. 1H), 2.30 - 2.23(m, 1H), 1.88 - 1.84 (m, 2H), 1.63 (s. 3H), 1.51 1.39 (m, 4H), 1.35 1.28 (m, 2H), 0.94 (d, J = 4.8 Hz, 6H).LCMS (Method A): 2.226 mm, 100%, 254 nm, MS: ES+ m / z 370.66 [M+1]HPLC (Method A): 7.446 min, 99.76%, 265.0 nmChiral HPLC: (Peak-1): 1.735 min, 50.01%. 345.0 nm; (Peak-2): 1.860 min, 49.99%, 345.0 nmEXAMPLE 32 - Preparation of 3-(3-(2-((4,4-difhiorocyclohexyl) amino) pyridin-3-yl)- 1,2,4-oxadiazol-5-yl)-3-methylpyirolidin-2-one (Compound 39)Step 1 ; Synthesis of Intennediate 34-A1: 2-((4.4-difluorocvclohexvl) amino) malononitrile.

[0297] To a stirred solution of 4,4-difluorocyclohexan-l -amine hydrochloride (CAS: 675112- 70-6) (1.10 g, 6.40 mmol, 1.2 eq) and 2-chloronicotinonitrile (CAS: 6602-54-6) (1.0 g. 5.38 mmol, 1.0 eq) in DMSO (10.0 mL) was added Et3N (3.75 mL, 26.90 mmol, 5.0 eq) at it. After the addition, the reaction mixture was stirred at 160 °C for 6 h. The reaction was monitored on TLC (30% EtOAc in hexane as mobile phase). After completion, the resulting reaction mixture was cooled to rt then diluted with water (30 mL) and extracted with EtOAc (3 x 40 mL) The combined organic layers were dried over Na2SO4. concentrated under reduced pressure to afford the crude (0.8 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 15% EtOAc in hexane afforded the title compound 2-((4,4-difluorocyclohexyl) amino) malononitrile (0.550 g, 2.318 mmol, Yield: 32.12%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.29 (dd, J = 4.8, 1.6 Hz, 1H), 7.90 (dd, J = 7.6, 1.6 Hz, 1H), 6.91 (d. J = 7.6Hz. 1H), 6.67-6.64 (m. 1H), 4.17 - 4.10 (m, 1H), 2.05 - 1.86 (m, 6H), 1.76 - 1.69 (m, 2H).LCMS (Method A): 2.071 mm, 98.28%. 254.0 nm, MS: ES+ m / z 238.32 [M+1],Step 2: Synthesis of Intermediate 39-A1 : 2-((4,4-difluorocyclohexyl) amino)-N-hvdroxy nicotinimidamide.

[0298] To a stirred solution of 2-((4,4-difluorocyclohexyl) amino) malononitrile (Intermediate 34-Al) (0.5 g, 2.10 mmol, 1.0 eq) in dioxane: water (5 mL: 2 mL) was added hydroxylamine hydrochloride (NH2OH.HCI) (0.583 g, 8.40 mmol, 4.0 eq), followed by the addition of NaHCO3(0.705 g, 8.40 mmol. 4.0 eq) portion wise at rt and reaction mixture was heated up to 70 °C for 6 h. The reaction was monitored on TLC (50% EtOAc in hexane as mobile phase), after completion the resulting reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford the crude (0.4 g). The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 40-50% EtOAc in hexane afforded the title compound 2-((4,4-difluorocyclohexyl) amino)-N- hydroxynicotinimidamide (Intermediate 39-Al) (0.250 g, 0.924 mmol, Yield: 43.89%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.93 (s, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.02 (dd, J =4.8, 1.6Hz, 1H), 7.78 (dd, J = 8.0 1.6Hz, 1H), 6.57 (dd, J = 7.6, 4.8 Hz, 1H), 5.94 (s, 2H), 4.14 - 4.12 (m, 1H), 2.13 - 1.91 (m, 6H), 1.54 - 1.49 (m. 2H).LCMS (Method A): 1.508 min, 100%. 254.0 nm, MS: ES+ m / z m / z 271.34 [M+1]Step 3: Synthesis of 3-(2-((4.4-difluorocyclohexyl) amino) pyridin-3-yl)-1.2,4-oxadiazol-5-yl)-3-methylpyrrolidin-2-one (Compound 39)

[0299] To a stirred solution of 2-((4.4-difluorocyclohexyl) amino)-N- hydroxynicotinimidamide (Intermediate 39-Al) (0.240 g, 0.887 mmol, 1.0 eq) and 3-methyl-2- oxopyrrolidine-3-carboxylic acid (0. 126 g, 0.887 mmol, 1.0 eq) in dioxane (2.5 mL) was added EDC.HC1 (0.677 g, 3.54 mmol, 4.0 eq) and HOBt (0.541 g, 3.54 mmol, 4.0 eq) at rt and heated up to 70 °C for 6 h. The reaction w as monitored on TLC (100% EtOAc in hexane as mobile phase), after completion the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL) combined organic layers were dried over Na2SO4, further concentrated under reduced pressure to afford 0. 150 g crude. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase and gradient 80-90% EtOAc in hexane afforded the title compound 3-(2-((4,4-difluorocyclohexyl) amino) pyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-methylpyrrolidin-2-one. (0.95 g, 0.250 mmol, Yield: 28.35%)1H NMR (DMSO-d6, 400 MHz): δ ppm, 8.30 - 8.24 (m, 3H), 7.06 (d, J 6.8 Hz, 1H), 6.78 (dd,J = 8.0, 5.2 Hz, 1H), 4.27 - 4.25 (m, 1H), 3.45 - 3.37 (m, 2H), 2.79 - 2.72 (m, 1H), 2.30 - 2.23(m, 1H), 2.07 1.99 (m, 6H), 1.63 (s, 5H).LCMS (Method A): 2.029 min, 99.49%, 260 nm, MS: ES+ m / z 378.68 [M+1]HPLC (Method A): 6.591 mm, 97.22%, 254.0 nmChiral HPLC: Peak-1 : 1.672 min, 49.40%, 340.0 nm; Peak-2: 1.859 min, 49.36%, 340.0 nmEXAMPLE 33 - Preparation of 3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1-yl) pyrrolidin-2-one (Compound 40)Step 1 : Synthesis of Intermediate 40-Al: 3-bromo-N-(4-(trifluoromethvl) phenyl) pyridin-2- amine

[0300] To a stirred solution of 3-bromopyridin-2-amine (CAS: 13534-99-l) (2.0 g, 11.56 mmol, 1.0 eq) in toluene (20 mL), was added CS2CO3(11.24 g, 34.68 mmol, 3.0 eq) followed by addition of 1 -iodo-4-(trifluoromethyl) benzene (CAS:455-13-0) (3.14 g, 11.56 mmol, 1.0 eq) at rt and purged under nitrogen gas for 10 minutes. After 10 min, Pd(OAc)2(0.25 g, 1.55 mmol,0. 1 eq) and Xantphos (1.0 g. 1.73 mmol, 0. 15 eq) was added and the resulting reaction mixture was heated at 100 °C for 4 h. The progress of reaction was monitored by TLC (10% EtOAc in hexane as mobile phase). After completion, the reaction mixture was poured in water (70 mL) and extract it with EtOAc (70 mL). Organic layer was dried over Na2SO4and evaporate under vacuum to afford the crude product. The crude was purified by flash column chromatography(silica 60-120 mesh) and gradient 100% hexane afforded the title compound 3-bromo-N-(4- (trifluoromethyl) phenyl) pyridin-2-amine (2.4 g, 7.56 mmol, Yield: 66.66%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.60 (s, 1H), 8.21 (dd, .7 = 4.4, 1.2 Hz, 1H), 8.02 (dd, .7 = 7.6, 1.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.61 (d. J = 8.4 Hz, 2H), 6.89-6.86 (m, 1H).LCMS (Method A): 2.807 min, 97.63%, 254.0 nm, MS: ES+ m / z 319.0 [M+2],Step 2: Synthesis of Intermediate 40-A2:3-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)-N-(4-(trifluoromethyl) phenyl) pyridin-2-amine

[0301] To a stirred solution of 3-bromo-N-(4-(trifluoromethyl) phenyl) pyridin-2-amine (Intermediate 40-Al) (2.3 g, 7.25 mmol, 1.0 eq) in dioxane (25 mL), was added KO Ac (2.11 g, 21.67 mmol, 3.0 eq) followed by addition of B2Pin2(CAS:73183-34-3) (2.20 g, 8.70 mmol, 1.2 eq) at rt and purged under nitrogen gas for 10 minutes. The addition of Pd(dppf)Cl2(0.526 g, 0.725 mmol, 0.1 eq) was completed and stirred at 95 °C for 4 h. The reaction was monitored by TLC (using 20% EtOAc in hexane as mobile phase) After completion, the resulting reaction mixture poured in water (70 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were dried over Na2SO4and evaporate under vacuum to get the crude. The crude was purified by flash column chromatography using 100-200 silica and gradient 5% EtOAc in hexane afforded the title compound 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl) phenyl) pyridin-2-amine (1.0 g, 2.74 mmol, Yield: 37.87%)1H NMR (DMSO-d6, 400 MHz): δ ppm 8.82 (s, 1H), 8.36 (dd, J = 4.8, 2.0Hz, 1H), 7.95 - 7.89(m, 3H), 7.64 (d, J = 8.4 Hz, 2H), 6.90 (dd, J = 6.8, 4.8 Hz, 1H), 1.37 (s, 12H)LCMS (Method A): 1.786 min, 93.33%, 254.0 nm, MS: ES+ m / z 283.11 (M-82) (mass of corresponding boronic acid observed).Step 3; Synthesis of Intermediate 40-A3: 2-oxopyrrolidin-3-yl methane sulfonate

[0302] To a stirred solution of 3-hydroxypyrrolidin-2-one (CAS: 15166-68-4) (2.0 g, 19.78 mmol, 1.0 eq) in DCM (20 mL), was added Et3N (2.99 g, 29.67 mmol, 1.5 eq) at room temperature, followed by addition of Methane sulfonyl chloride (2.6 g, 23.73 mmol, 1.2 eq) at 0 °C. The resulting reaction mixture was stirred at rt for 1 h. The reaction was monitored by TLC (using 60% EtOAc in hexane as mobile phase) which confirmed that the reaction got completed after 1 h of stirring at rt. The resulting reaction mixture poured in water (40 mL) and extracts it with DCM (3 x 40 mL). The organic layers were dried over Na2SO4and evaporate under vacuum to afford 2-oxopyrrolidin-3-yl methanesulfonate (1.9 g, 10.60 mmol. Yield: 53.67%). (Note: Crude further used in next step without purification and characterization)Step 4: Synthesis of Intermediate 40-A4: 3-(4-bromo-1H-imidazol-1-yl) pyrrolidin-2-one

[0303] To a stirred solution of 4-bromo-1H-imidazole (CAS:2302-25-2) (1.54 g. 10.61 mmol, 1 .0 eq) in DMF (30 mL), was added CS2CO3(6.91 g, 21 .22 mmol, 2.0 eq) at room temperature and reaction mixture stirred at 60 °C for 1 h. After cool the reaction mixture at rt, was added 2- oxopyrrolidin-3-yl methane sulfonate (Intermediate 40- A3) (1.9 g, 10.61 mmol, 1.0 eq) and further stirred at 80 °C for 3 h. The reaction was monitored by TLC (using 100% EtOAc as mobile phase) which confirmed that the reaction got completed after 3 h of stirring at 80 °C. The resulting reaction mixture poured in cold water (30 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was dried over Na2SO4and evaporate under vacuum to get the cmde. The crude was purified by flash column chromatography using silica 60-120 mesh size and gradient 5% MeOH in DCM to afford the tittle compound 3-(4-bromo- 1H-imidazol-1-yl) pyrrolidin-2- one (0.6 g, 2.60 mmol, Yield: 24.59%).1H NMR (DMSO-d6, 400 MHz): δ ppm 8.24 (s, 1H), 7.71 (s, 1H), 7.39 (s, 1H), 4.98 (t, J = 9.6 Hz, 1H), 3.35-3.23 (m, 2H), 2.50-2.25 (m, 2H).LCMS (Method A): 0.871 min, 86.18%, 220.0 nm, MS: ES+ m / z 231.9 [M+2],Step 5: Synthesis of 3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1- yl) pyrrolidin-2-one (Compound 40)

[0304] To a stirred solution of 3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-N-(4- (trifluoromethyl) phenyl) pyridin-2-amine (Intermediate 40- A2) (0.4 g, 1.09 mmol, 1.0 eq) in dioxane (3.2 mL) and water (0.8 mL) were prepared in 30 mL glass vial at room temperature. To this reaction solution, CS2CO3(1.0 g, 3.29 mmol, 3.0 eq) was added at room temperature. Then 3-(4-bromo-1H-imidazol-l-yl) pyrrolidin-2-one (Intermediate 40-A4) (0.25 g, 1.09 mmol, 1.0 eq) was added at rt followed by purging under nitrogen gas for 10 minutes. Finally, Pd(dppf)Cl2(0.079 g, 0.109 mmol, 0.1 eq) was added and reaction mixture was stirred at 100 °C for 16 h. The reaction was monitored by TLC (20% EtOAc in hexane as mobile phase) which confirmed that the reaction got completed after 16 h of stirring at 100 °C. The resulting reaction mixture poured in water (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were dried over Na2SO4and evaporate under vacuum to get crude. The crude was purified by flash column chromatography using Silica 230-400 and gradient 5% MeOH in DCM afforded the title compound 3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1-yl) pyrrolidin-2-one (0.078 g, 0.201 mmol, Yield: 18.35%)1H NMR (DMSO-d6, 400 MHz): δ ppm 1 1.95 (s, 1H), 8.31 (s, 1H), 8.17-8.15 (m, 1H), 8.088.05 (m, 2H), 8.00-7.96 (m, 3H), 7.63 (d, J = 8.4 Hz, 2H), 6.94-6.91 (m, 1H), 5.12 (t, J 9.6Hz, 1H), 3.44 - 3.33 (m, 2H), 2.69-2.64 (m, 1H), 2.44-2.38 (m, 1H).1H NMR (MeOD-d4, 400 MHz): δ ppm 8.14 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 - 7.93 (m, 2H), 7.90(d, J = 8.4 Hz, 2H), 7.73 (d, J = 0.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.90-6.87 (m, 1H), 5.19(t, J = 9.6 Hz, 1H). 3.61 - 3.49 (m, 2H). 2.87 - 2.80 (m, 1H), 2.57 - 2.49 (m. 1H).LCMS (Method A): 2.086 min, 100%. 254.0 nm, MS: ES+ m / z 388.12 [M+1],HPLC (Method A): 8.40 min, 100%, 210.0 nmEXAMPLE 34 - Preparation of 3-methyl-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1-yl) pyrrolidin-2-one (Compound 41)Step 1 : Synthesis of Intermediate 41-D1 Tert-butyl 3-(4-bromo-1H-imidazol-1-yl)-2- oxopvrrolidine-1-carboxylate

[0305] To a solution of 3-(4-bromo-1H-imidazol-1-yl) pyrrolidin-2-one (Intermediate 40-A4)(2.40 g, 10.432 mmol 1.0 eq) and (Boc)2O (3.41 g, 15.648 mmol, 1.5 eq) in DCM (24 rnL) was added DMAP (0.318 g 2.607 mmol, 0.25 eq) under a nitrogen atmosphere then reaction mixture was stirred for 2 h at rt. The reaction was monitored by TLC (5% MeOH: DCM mobile phase).After completion, the resulting reaction mixture was diluted with water (100 mL) and extractedwith DCM (3 x 100 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford the crude (3.5 g). The obtained crude material was purified by manual column chromatography using silica (100-200 mesh) as stationary phase and gradient 2% MeOH in DCM afforded the title compound tert-butyl 3-(4-bromo-1H-imidazol-l- yl)-2-oxopyrrolidine-1-carboxylate (2.5 g. 7.571 mmol. Yield: 72.58%).LCMS (Method A): 1.805 min, 89.13%, 254.0 nm, MS: ES+ m / z 332.11 [M+2]Step 2; Synthesis of (Intermediate 41 -D2): tert-butyl 3-(4-bromo-1H-imidazol-1-yl)-3-methyl-2- oxopyrrolidine-1-carboxylate

[0306] To a solution tert-butyl 3-(4-bromo-1H-imidazol-l-yl)-2-oxopyrrolidine-1-carboxylate (Intermediate 41 -DI) (1.5 g, 4.55 mmol, 1.0 eq), LiHMDS (2 M in THE) (4.54 mL, 9.118 mmol, 2.0 eq) in THE (15 mL) was added at -78 °C and for 30 min at same temperature. The Methyl iodide (1.2 g, 9.11 mmol, 2.0 eq) was added at -78 °C and stirred for another 1 h. After 1 h the reaction mixture was allow ed to warm up to rt and further stirred for 12 h. The reaction was monitored on TLC (5% MeOH in DCM as mobile phase). After completion of reaction, the resulting reaction mixture was quenched with sat. aq. NH4CI (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure to afford 0.5 g crude. The obtained crude material was purified by manual column chromatography using silica (100-200 mesh) as stationary phase and gradient 2% MeOH in DCM afforded the tittle compound tert-butyl 3-(4-bromo-1H-imidazol-l-yl)-2- oxopyrrolidine-1 -carboxylate (0.35 g, 1.016 mmol, Yield: 22.38%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 7.85 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 3.77-3.69 (m, 2H), 2.62-2.53 (m, 1H), 2.34-2.28 (m, 1H), 1.69 (s, 3H), 1.47 (s, 9H).LCMS (Method A): 1.953 min, 85.60%, 220.0 nm, MS: ES+ m / z 345.97 [M+2]Step 3: Synthesis of Intermediate 41-D3: tert-butyl 3-methyl-2-oxo-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1-yl) pyrrolidine-1-carboxylate

[0307] To a stirred solution of tert-butyl 3-(4-bromo-1H-imidazol-1-yl)-3-methyl-2- oxopyrrolidine-1 -carboxylate (Intermediate 41-D2) (0.30 g, 0.87 mmol, 1.0 eq) in dioxane: H2O (4: 1 mL) was prepared in 25 mL of glass RBF at room temperature. To this reaction solution, 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl) phenyl) pyridin-2-amine (Intermediate 40-A2) (0.412 g, 1.13 mmol, 1.3 eq) and CS2CO3(0.85 g, 2.61 mmol, 3.0 eq) was added at rt under nitrogen atmosphere. Finally, Pd(dppf)Cl2(0.063 g, 0.087 mmol, 0.1 eq) was added, follow ed by nitrogen gas purging (5 min.) and stirred at 90 °C for 2 h. The reaction was monitored by TLC (50% EtOAc in hexane as a mobile phase) which confirmed that the reactiongot completed after 2 h at 90 °C. The resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried overNa2SO4, filtered and concentrated under reduced pressure to afford the crude product (0.5 g). The obtained crude material was purified by flash column chromatography and gradient 30% ethyl acetate in hexane afforded the title compound tert-butyl 3-methyl-2-oxo-3-(4-(2-((4- (trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1-yl) pyrrolidine-1-carboxylate (0.26 g, 0.518 mmol, Yield: 59.48%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 11.90 (s, 1H), 8.22 (s, 1H), 8.17-8.16 (m, 2H), 8.09 (d, J= 7.2 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 6.95-6.92 (m, 1H), 3.87-3.74 (m. 2H), 2.73-2.68 (m. 1H), 2.44-2.33 (m. 1H) 1.80 (s, 3H), 1.48 (s, 9H).LCMS (Method A): 2.844 min, 93.55%, 254.0 nm, MS: ES+ m / z 502.54 (M+l)Step 4: Synthesis of 3-methyl-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H- imidazol-1-yl) pyrrolidin-2-one (Compound 41)

[0308] To a stirred solution of tert-butyl 3-methyl-2-oxo-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1-yl) pyrrolidine- 1 -carboxylate (0.25 g, 0.49 mmol, 1.0 eq) in dioxane (2.5 mL) was prepared in 25 mL of glass RBF at room temperature. To this reaction solution, 4 M HC1 in dioxane (2.49 mL, 2.49 mmol, 5.0 eq) was added dropwise at 0 °C under nitrogen atmosphere. Then the resulting reaction mixture was stirred at rt for 2 h. The progress of reaction was monitored by TLC (50% EtOAc in hexane as a mobile phase). After completion, the resulting reaction mixture was concentrated under reduced pressure and basified with sat. NaHCO3solution (50 mL) then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (0.25 g). The obtained crude material was purified by trituration using DCM (1 mL) and Pentane (10 mL) to obtain the title compound 3-methyl-3-(4-(2-((4-(trifluoromethyl) phenyl) amino) pyridin-3-yl)-1H-imidazol-1-yl) pyrrolidin-2-one (0.124 g, 0.298 mmol. Yield: 59.97%).1H NMR (DMSO-d6, 400 MHz): δ ppm, 11.96 (s. 1H), 8.31 (s. 1H), 8.16 (s, 2H), 8.11-8.08 (m, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 6.94-6.91 (m, 1H), 3.38-3.34 (m, 2H), 2.70-2.63 (m, 1H), 2.47-2.41 (m, 1H), 1.71 (s, 3H).1H NMR (MeOD-d4, 400 MHz): 8.13 (dd, J = 4.8, 1.6 Hz, 1H), 8.06 (s, 1H), 7.96 (dd, J 7.6, 1.6 Hz, 1H), 7.90 (d,J= 8.4 Hz, 2H), 7.83 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.90-6.87 (m, 1H), 3.51 (dd, J = 5.2 Hz, 2H), 2.78-2.71 (m, 1H), 2.61-2.55 (m, 1H), 1.83 (s, 3H). Note: Two protons exchanged in MeOD NMR.LCMS (Method A): 2.154 min, 99.55%. 210.0 nm, MS: ES+ m / z 402.27 [M+1]HPLC (Method A): 8.69 mm, 100%, 210 nmChiral HPLC: 7.34 min, 50.22%, and 7.47 min, 48.64%, 300 nmEXAMPLE 35 - Preparation of 3-(4-(2-(cyclohexylamino) phenyl)-1H-imidazol-1-yl)-3- methylpyrrolidin-2-one (Compound 42)

[0309] Step 1 : Synthesis of Intermediate 42-B1 : N-cyclohexyl-2-(4,4.5.5-tetramethyl-1.3,2- dioxaborolan-2-yl) aniline

[0310] To a stirred solution of cyclohexanone (CAS: 108-94-1) (0.738 g, 6.84 mmol, 1.0 eq) inMeOH (10 mL) was added 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (CAS:191171-55-8) (1.5 g, 6.84 mmol, 1.0 eq) at rt. The resulting mixture was stirred at same temperature for 1 h. After 1 h, NaCN(BH3) (0.711 g, 13.68 mmol, 2.0 eq) was added and the reaction mixture was stirred again at room temperature for 16 h. The reaction was monitored byTLC (EtOAc: hexane (0.1 :0.9) as mobile phase). After completion, the resulting reaction mixture was concentrated under a vacuum to get the crude. The obtained crude material was purified by flash column chromatography using silica gel (60-120 mesh) as stationary phase and gradient 100% hexane afforded the title compound N-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) aniline (1.03 g, 3.419 mmol, Yield: 49.98%).1H NMR (DMSO-d6, 400 MHz): δ ppm: 7.40 (dd, .7 = 7.2. 1.2 Hz, 1H), 7.24 - 7.20 (m, 1H),6.56 (d, J= 8.4 Hz, 1H), 6.48 (t, J = 7.6 Hz, 1H), 5.88 (d, J = 8.0Hz, 1H), 1.84 1.83 (m, 2H),1.64-1.62 (m, 2H), 1.52-1.31 (m, 4H), 1.29-1.16 (m, 14H). (Note: 1H-proton merged in DMSO moisture peak).LCMS (Method C): 1.387 min, 100%, 210.0 nm, MS: ES+ m / z 220.15 (M+1 , corresponding boronic acid mass observed)Step 2; Synthesis of Intermediate 42- A2: tert-butyl 3-(4-(2-(cyclohexylamino) phenyl)-1H- imidazol-1-yl)-3-methyl-2-oxopyrrolidine-1-carboxylate

[0311] To a stirred solution of N-cyclohexyl-2-(4,4.5.5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (0.4 g. 1.32 mmol. 1.0 eq), tert-butyl 3-(4-bromo-1H-imidazol-1-yl)-3-methyl-2- ox opyrrolidine-1 -carboxylate (0.457 g, 1.32 mmol, 1.0 eq) and CS2CO3(1.3 g, 3.984 mmol, 2.0 eq) in dioxane (3.2 mL) and water (0.8 mL), was added Pd(dppf)Cl2(0.485 g, 0.664 mmol, 0.5 eq) under N2 atmosphere. The resulting mixture was stirred at 60 °C in microwave for 30 min. The reaction progress was checked by TLC (using EtOAc: hexane (0.2:0.8) as mobile phase), after 30 min. resulting reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic phases were dried over Na2SO4and concentrated under reduced pressure to afford crude. The obtained crude material was purified by flash column chromatography using silica gel (60-120 mesh) as stationary phase and gradient 30% EtOAc in hexane afforded the title compound tert- butyl 3-(4-(2-(cyclohexylamino) phenyl)-1H-imidazol- 1-yl)-3-methyl-2-oxopyrrolidine-1-carboxylate (0.12 g, 0.273 mmol, Yield: 20.61%).1H NMR (DMSO-d6, 400 MHz): δ ppm: 8.08 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.44 (d, J= 7.6 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 6.49 (t, J = 7.6Hz, 1H), 3.95 (s, 2H), 3.82 - 3.74 (m, 2H), 2.67 - 2.65 (m, 1H), 2.43 - 2.33 (m, 2H), 1.95 - 1.92 (m, 2H), 1.76 - 1.16 (m, 18H).LCMS (Method A): 2.114 min, 98.83%, 254.0 nm, MS: ES+ m / z 439.48 [M+1]Step 3: 3-(4-(2-(cyclohexylamino) phenvl)-1H-imidazol-1-yl)-3-methylpyrrolidin-2-one(Compound 42)

[0312] To a stirred solution of tert-butyl 3-(4-(2-(cyclohexylamino) phenyl)-1H-imidazol-1- yl)-3-methyl-2-oxopyrrolidine-l-carboxylate (Intermediate 42-A2) (0.155 g, 0.353 mmol, 1.0 eq) in DCM (10 mL) was added 4 N HC1 in dioxane (3.0 mL) and stirred reaction mixture for 3 h. The reaction was monitored on TLC (using EtOAc: hexane; 0.2:0.8 as mobile phase). After completion, the reaction mixture was concentrated under reduced pressure and triturated by Et20 to obtained the crude. The crude was further purified by reversed phase prep HPLC (ACN: H2O) to afford the title compound 3-(4-(2-(cyclohexylamino) phenyl)- IH-imidazol-l -yl)-3- methylpyrrolidin-2-one (0.067 g, 0.197 mmol. Yield: 56.01%)1H NMR (DMSO-d6, 400 MHz): δ ppm: 11.36 (brs, 1H), 8.69 (brs, 1H), 8.48 (s, 1H), 8.16 (s.1H), 7.71 (d, J= 7.6 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.17 (s, 1H), 3.39 - 3.35 (m, 3H), 2.71 - 2.68(m, 1H), 2.50 - 2.43 (m, 1H), 1.96 - 1.94 (m, 2H), 1.72 - 1.68 (m, 5H), 1.58 - 1.55 (m, 1H),1.37 - 1.13 (m. 5H).1H NMR (MeOD-d4, 400 MHz): δ ppm: 8.77 (s, 1H), 8.19 (s. 1H), 7.81 - 7.79 (m, 1H), 7.577.51 (m, 3H), 3.58 - 3.54 (m, 2H). 3.47 - 3.45 (m, 1H). 2.87 - 2.79 (m, 1H), 2.67 - 2.63 (m.1H), 2.06 - 2.04 (m, 2H), 1.89 - 1.83 (m, 5H), 1.71 1.68 (m, 1H), 1.54 - 1.37 (m, 2H), 1.331.23 (m, 3H). Note: 2H-Proton exchanged in MeOD NMR.LCMS (Method A): 1.633 min, 100%, 254.0 nm, MS: ES+ 339.36 [M+1]HPLC (Method A): 8.22 min, 100%, 254.0 nmEXAMPLE 36 - Preparation of 3-(4-(2-((4,4-difhiorocyclohexyl) amino) phenyl)-1H- imidazol-1-yl)-3-methylpyrroIidin-2-one (Compound 43)Step 1 ; Synthesis of Intermediate 43-B1: N-(4,4-difluorocyclohexyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

[0313] To a stirred solution of 4,4-difluorocyclohexanone (CAS: 371-90-4) (1.0 g. 4.56 mmol,1.0 eq) in MeOH (10 mL) was added 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) aniline(CAS: 191171-55-8) (0.612 g, 4.56 mmol, 1.0 eq). The resulting mixture was stirred at rt for 1 h. then NaCN(BH3) (0.474 g. 9.12 mmol, 2.0 eq) was added and reaction mixture was stirred at rtfor 16 h. The reaction was monitored on TLC (using EtOAc: hexane - 0. 1:0.9 as mobile phase). After 16 h, the resulting cmde reaction mixture was concentrated under vacuum to get the crude. The obtained crude material was purified by column chromatography using silica gel (60-120 mesh) and gradient 2% EtOAc in hexane afforded the title compound N-(4,4- difluorocyclohexyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.81 g, 2.41 mmol. Yield: 52.67%).1H NMR (DMSO-d6, 400 MHz): δ ppm: 7.43 (dd. J = 6.0, 1.2 Hz, 1H), 7.28 - 7.24 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.60 - 6.48 (m, 1H), 5.87 (d, J = 8.4 Hz, 1H), 3.64 - 3.63 (m, 1H), 2.04 - 1.91 (m, 6H), 1.55 - 1.50 (m, 2H), 1.23 (s, 12H).LCMS (Method A): 3.042 min, 32.03%, 254.0 nm, MS: ES+ m / z 338.31 [M+1]+(Note: Due to FA buffer in LCMS we have observed corresponding Boronic Acid m / z 256.2 atRT=1.569 min, @254.0 nm)Step 2: Synthesis of Intermediate 42- A2 - tert-butyl 3-(4-(2-((4,4-difluorocyclohexyl) amino) phenyl)- 1H-imidazol- 1 -yl)-3-methyl-2-oxopyrrolidine-1-carboxylate

[0314] To a stirred solution of N-(4,4-difluorocyclohexyl)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (Intermediate 43-B1) (0.195 g, 0.581 mmol, 1.0 eq), tert-butyl 3-(4- bromo-1H-imidazol-1-yl)-3-methyl-2-oxopyrrolidine-l-carboxylate (Intermediate 41-D2) (0.2 g, 0.581 mmol, 1 .0 eq) and CS2CO3(0.572 g, 1 .761 mmol, 3.0 eq) in dioxane : H2O (8:2) (2 mL) was added Pd(dppl)C12 (0.021 g, 0.029 mmol, 0.5 eq) and purge with N2for 5 minutes. The resulting mixture was stirred at 60 °C in micro wave for 30 min. The reaction progress was monitored on TLC (using EtOAc: hexane; 3:7 as mobile phase) and after completion, crude mixture was diluted with water (15 mL) and extracted with EtOAc (50 mL). The organic phases were dried over Na2SO4and concentrated under reduced pressure to afford the crude. The obtained crude material was purified by flash column chromatography using silica gel (60-120 mesh) as stationary phase and gradient 25% EtOAc in hexane afforded the title compound tert- butyl 3-(4-(2-((4.4-difluorocyclohexyl) amino) phenyl)-1H-imidazol-l-yl)-3-methyl-2- oxopyrrolidine-1-carboxylate (Intermediate 43-A2) (0.018 g, 0.037 mmol, Yield: 6.40%).LCMS (Method A): 2.228 min, 94.21%, 254.0 nm, MS: ES+ m / z 475.6 [M+1]Step 3: Synthesis of 3-(4-(2-((4,4-difluorocyclohexyl) amino) phenyl)-1H-imidazol-1-yl)-3- methylpyrrolidin-2-one (Compound 43)

[0315] To a solution of tert-butyl 3-(4-(2-((4,4-difluorocyclohexyl) amino) phenyl)-1H- imidazol-1-yl)-3-methyl-2-oxopyrrolidine-1-carboxylate (Intermediate 43-A2) (0.11 g, 0.232 mmol, 1.0 eq) in DCM (10 mL) was added 4 M HC1 in dioxane (3.0 mL) and stirred at rt for 5 h.The reaction was monitored on TLC (EtOAc 100% as mobile phase) which confirmed that the reaction got completed after 5 h. The reaction mixture was concentrated under reduced pressure and triturated by Et2O then further purified by reversed phase prep HPLC (ACN: H2O) to afford the tittle compound 3-(4-(2-((4,4-difluorocyclohexyl) amino) phenyl)- 1H-imidazol-1-yl)-3- methylpyrrolidin-2-one (0.042 g, 0.112 mmol, Yield: 48.39%)1H NMR (DMSO-d6, 400 MHz): δ ppm: 9. 19 (brs, 1H), 8.50 (s, 1H). 8.02 (s, 1H), 7.34 - 7.28 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 3.53 - 3.37 (m, 3H), 2.76 - 2.61 (m, 3H), 2.03 - 1.88 (m, 6H), 1.74 (s, 3H), 1.56 - 1.53 (m, 2H).1H NMR (MeOD-d4, 400 MHz): δ ppm: 9.03 (s, 1H), 7.98 (d, .7 = 1.2 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 3.58 - 3.54 (m, 3H), 2.83 - 2.78 (m, 1H), 2.67 - 2.63 (m. 1H), 2.11 - 2.09 (m, 4H), 1.98 - 1.89 (m, 5H), 1.69 - 1.64 (m, 2H). Note: Two Proton exchanged in MeOD and Two protons are merged in MeOD Solvent peak.LCMS (Method A): 1.691 min, 97.60%. 254.0 nm, MS: ES+ 375.37 [M+1]HPLC (Method A): 7.79 min, 96.95%, 254.0 nm

[0316] Compounds 16a, 25a, 26a, 32a, 37a, 37b, 37c, and 41a of Table 1 may be prepared by synthetic methods similar to the Examples described above with modifications apparent to those skilled in the art.Biological ExamplesEXAMPLE 37 - NCI-H226 Proliferation and Cell Viability Assay

[0317] Cell proliferation of a TEAD dependent NF2-null mesothelioma cell line, NCI-H226 was assayed using the CellTiter-Glo® 2.0 protocol.

[0318] a) CellTiter-Glo® 2.0 (Promega #G9243). The effect of the TEAD inhibitors disclosed herein on cell proliferation was determined in TEAD 1 -genetically dependent cell line NCI-H226 (responder cell line). Cells were seeded in 96-well plates (Thermo Scientific #167008) in growth media (RPMI-1640, Gibco #61870-010) for NCI-H226 with 10% Heat Inactivated Fetal Bovine Semm (Gibco 10500-064) at 800 (NCI-H226) cells per well at 37°C, 5% CO2, humidified incubator; 24 hours later, fresh growth media containing test compound or DMSO vehicle was added and incubated with the cells for 144 hrs. TEAD inhibitor stocks were made al a 1000X fold excess in DMSO, and a dose response test compound dose range of 10,000 to 0. 1 nM was used. Each treatment was carried out in triplicate. After 144 hrs of treatment, relative cell viability numbers were determined using the CellTiter-Glo 2.0 assay following the manufacturer’s instructions. Test plates and CellTiter-Glo 2.0 reagent were allowed to equilibrate to room temperature. CellTiter-Glo 2.0 reagent was added at 1: 1 reagent to mediaratio to the 96-well cell plates, plates were placed on a plate shaker for 2 minutes and then incubated at room temperature for a further 10 minutes to allow complete cell lysis to occur. The mix was then transferred to white, 96-well luminometer assay plates (Greiner Bio One #655075). Luminescence was quantified using a CLARIOStar Plus multi-mode plate reader (BMG Labtech) in luminescence detection mode with the recommended settings (ultra-Glo pre- set: emission 545-50nm with autofocus and enhanced dynamic range on). Relative cell density was expressed as a function of inhibitor concentration, with respect to DMSO-only control wells. Data plotted using GraphPad Prism.

[0319] For EC50data “A” indicates a value of less than 0.2 μM; the symbol “B” indicates a value in the range of from 0.2 μM up to 1 μM; and the symbol “C” indicates a value of greater than 1 μM. ND: no data.

[0320] Table 2. Cytotoxic potency measured by CTG assay for H226-responder cell line.

Claims

CLAIMSWhat is claimed is:

1. A compound having the chemical formula (I):, or a pharmaceutically acceptable salt thereof, wherein:X is selected from the group consisting of NRa, O, and S;Y and Z are each independently selected from N and CR4;Ring A is selected from 3-6 membered saturated heterocyclyl and 3-10 membered carbocyclyl, wherein the 3-6 membered saturated heterocyclyl has one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S;Ring B is a 5-10 membered heteroarylene having one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S; wherein the 5-10 membered heteroarylene is optionally substituted;R1is 3-10 membered heterocyclyl or -(C1-C4alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl has one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S and is optionally substituted, wherein the C1-C4alkylene is optionally substituted; each R2is independently selected from the group consisting of halogen, -C1-C6alkyl, and -C1-C6haloalkyl; or two R2attached to the same carbon atom, together with the carbon atom to which they are attached, combine to form cyclopropyl as valency permits; each R3is independently selected from halogen and -C1-C6alkyl;each R4is independently selected from halogen and -C1-C6alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; andRais selected from hydrogen and -C1-C6alkyl provided that when Ring A is phenyl. Ring B is not 1,3,4-oxadiazolylene or tetrazolylene, and provided that when Z is N. Y is N.

2. A compound having the chemical formula (I- 1):or a pharmaceutically acceptable salt thereof, wherein;Y and Z are each independently selected from N and CR4;W is selected from CH2and ORing A is selected from 3-6 membered saturated heterocyclyl and 3-10 membered carbocyclyl, wherein the 3-6 membered saturated heterocyclyl has one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S;Ring B is a 5-6 membered monocyclic heteroaiyiene having one, two, three, or four heteroatoms each independently selected from the group consisting of N, O, and S; wherein the 5-6 membered monocyclic heteroaiy iene is optionally substituted; each R2is independently selected from the group consisting of halogen, -C1-C6alkyl, and -C1-C6haloalkyl; or two R2attached to the same carbon atom, together with the carbon atom to which theyare attached, combine to form cyclopropyl as valency permits; each R3is independently selected from halogen and -C1-C6alkyl; each R4is independently selected from halogen and -C1-C6alkyd; each R5is independently selected from hydrogen and halogen; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; t is 1, 2, or 3; u is 0, 1, or 2; v is 0, 1, or 2;Rais selected from hydrogen and -C1-C6alkyl; andR6is C1-C6alkyl, provided that when Ring A is phenyl, Ring B is not 1,3,4-oxadiazolylene or tetrazolylene, and provided that when Z is N, Y is N.

3. The compound of claim 1 or 2, wherein Ring A is selected from phenyl and C5-C7cycloalkyl.

4. The compound of claim 1 or 2, wherein Ring A is selected from the group consisting of phenyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentanyl, and azetidinyl,5. The compound of any one of claims 1, 3, and 4 , wherein the compound is a compound of formula (la):or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 and 3-5, wherein the compound is a compound of formula (Ib): or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 2-4. wherein the compound is a compound of formula (la-1): , or a pharmaceutically acceptablesalt thereof.

8. The compound of any one of claims 2-4 and 7, wherein the compound is a compound of formula (Ib-1):or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1 , 3, and 4, wherein the compound is a compound of formula (Ic): or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1, 3, 4, and 9, wherein the compound is a compound of formula (Id) or (le):pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 2-4, wherein the compound is a compound offormula (Ic-1):, or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 2-4 and 11, wherein the compound is a compound of formula (Id-1) or (Ie-1):or or a pharmaceutically acceptable saltthereof.

13. The compound of any one of claims 1-12, wherein Ring B is 5-6 membered monocyclic heteroarylene that is optionally substituted with 1. 2, 3, or 4 substituents each independently selected from halogen and -C1-C6alkyl.

14. The compound of any one of claims 1-13, wherein Ring B is selected from the group consisting of oxadiazolylene, imidazolylene, pyrazolylene, triazolylene, and tetrazolylene, each of which is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from halogen and C1-C6alkyl.

15. The compound of any one of claims 1-13, wherein Ring B is selected from the group consisting of oxadiazolylene, imidazolylene, pyrazolylene, triazolylene, and tetrazolylene, each of which is unsubstituted.

16. The compound of any one of claims 1, 3-6, 9, 10, and 13-15, wherein R1is 5 to 6- membered heterocyclyl having one or two heteroatoms, wherein the 5 to 6-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents each independently selected from C1-C6alkyl and oxo.

17. The compound of any one of claims 1, 3-6, 9, 10, and 13-15, wherein R1is -(C1- C4alkylene)-(5 to 6-membered heterocyclyl having one or two heteroatoms, wherein the 5 to 6- membered heterocyclyl is optionally substituted with 1. 2, or 3 substituents each independently selected from C1-C6alkyl and oxo.

18. The compound of any one of claims 1, 3-6, 9, 10, and 13-17, wherein R1is;, wherein u is 0, 1, or 2.

19. The compound of any one of claim 1, 2-6, 9, 10, and 13-17, wherein R1is20. The compound of any one of claims 1, 2-6, 9, 10, and 13-17, wherein R1is21. The compound of claim 19 or 20, wherein u is 0 and Reis methyl.

22. The compound of any one of claims 1-21, wherein each R2is independently selected from the group consisting of fluoro, methyl, and trifluoromethyl.

23. The compound of any one of claims 1-22, wherein Y is N.

24. The compound of any one of claims 1 -4 and 9-22, wherein Z is CH.

25. The compound of any one of claims 1-4 and 9-22. wherein Z is N.

26. The compound of any one of claims 1-6, 9, 10, and 13-25, wherein m is 1 or 2.

27. The compound of any one of claims 1-26, wherein n is 0.

28. The compound of any one of claims 1-26, wherein n is 1, and R3is C1-C6alkyl.

29. The compound of any one of claims 2-4. 7, 8, 11-17, and 22-28 wherein t is 1.

30. The compound of any one of claims 2-4, 7, 8, 11 -29, wherein u is 0.

31. The compound of any one of claims 2-4. 7, 8, 11-17, and 22-30, wherein v is 1.

32. The compound of any one of claims 2-4, 7, 8, 11-17, and 20-31, wherein W is CH2.

33. The compound of any one of claims 1-32. wherein Rais hydrogen.

34. The compound of any one of claims 1-33, wherein Ring A is phenyl and Ring B is not 1,2,4-oxadiazolylene.

35. The compound of claim 1, wherein the compound is selected from a compound of Table 1 or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition, comprising: (a) a compound or a pharmaceutically acceptable salt thereof of any one of claims 1-35; and (b) a pharmaceutically acceptable excipient.

37. A method of treating a disease or condition mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof, comprising: administering to the subject a therapeutically-effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-35, or a pharmaceutical composition of claim 36.

38. The method of claim 37, wherein the disease or condition is a cancer characterized byhyperactivation of a TEAD isoform selected from TEAD1 and TEAD4.

39. The method of claim 38, wherein the cancer is selected from the group consisting of; a breast cancer, a lung cancer, a gastric cancer, a colorectal cancer, a pancreatic cancer including pancreatic adenocarcinoma, a mesothelioma including malignant mesothelioma, a hepatocellular cancer, a prostate cancer, a head and neck cancer, a renal cell carcinoma, and a medulloblastoma.

40. The method of any one of claims 37-39. wherein the therapeutically-effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-35, or the pharmaceutical composition of claim 36, is administered in combination with one or more other therapeutic agents.

41. A compound or pharmaceutically acceptable salt of any one of claims 1-35, or the pharmaceutical composition of claim 36, for use in treating a disease or condition mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

42. The compound or pharmaceutically acceptable salt or pharmaceutical composition for use of claim 41, wherein the disease or condition is a cancer characterized by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4.

43. The compound or pharmaceutically acceptable salt or pharmaceutical composition for use of claim 42, wherein the cancer is selected from the group consisting of: a breast cancer, a lung cancer, a gastric cancer, a colorectal cancer, a pancreatic cancer including pancreatic adenocarcinoma, a mesothelioma including malignant mesothelioma, a hepatocellular cancer, a prostate cancer, a head and neck cancer, a renal cell carcinoma, and a medulloblastoma.

44. Use of a compound or pharmaceutically acceptable salt of any one of claims 1-35, or a pharmaceutical composition of claim 36 in the manufacture of a medicament for treating a disease or condition mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof.

45. The use of claim 44, wherein the disease or condition is a cancer characterized by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4.

46. The use of claim 45, wherein the cancer is selected from the group consisting of; a breast cancer, a lung cancer, a gastric cancer, a colorectal cancer, a pancreatic cancer includingpancreatic adenocarcinoma, a mesothelioma including malignant mesothelioma, a hepatocellular cancer, a prostate cancer, a head and neck cancer, a renal cell carcinoma, and a medulloblastoma.

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