Macrocyclic compounds as KIF18a inhibitors

Abstract

The present disclosure provides macrocyclic compounds of formula (I), which are therapeutically useful as KIF18A inhibitors.(I) These compounds are useful in the treatment and / or prevention of diseases and / or disorders responsive to the inhibition of KIF18A activity. Compounds of the present disclosure are especially useful for treating cancer. The present disclosure also provides processes for the preparation of compounds of formula (I), as well as pharmaceutical formulations comprising at least one compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.

Description

MACROCYCLIC COMPOUNDS AS KIF18A INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Indian provisional application number 202341079320, filed on November 22, 2023, and Indian provisional application number 202441072285, filed on September 25, 2024, the specifications of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0002] This application relates to substituted macrocyclic compounds useful for the treatment of cancer and inflammatory diseases associated with KIF18A (kinesin family member 18A). The application also provides pharmaceutically acceptable compositions comprising compounds of formula (I) and methods of using said compositions in the treatment of diseases associated with KIF18A. BACKGROUND

[0003] A stable genome is critical for the survival and growth of all organisms. Equal partitioning of the genome during cell division is an absolute requirement for the maintenance of a stable genome in the cells. However, errors in the process of cell division can result in several defects in development and can lead to the formation of cancers in humans (Lengauer, C.; Kinzler, K. W.; Vogelstein, Nature 1998, 396, 643−649).

[0004] The mitotic spindle that is formed by dynamic microtubules plays a critical role in the accurate distribution of the genome during cell division. Several efforts have been made in the past to develop drugs that specifically target mitosis to inhibit cancer cell growth. To date, there are a number of antimitotic drugs that are approved for treating cancers in the clinic (Anna-Maria Olziersky, S Intidhar Labidi-Galy, Adv Exp Med Biol. 2017, 1002:125-152). One of the most important antimitotic drug class includes the microtubule targeting agents. These agents either stabilize microtubules or prevent microtubules from assembling during the metaphase stage of mitosis (Jackson, J. R.; Patrick, D. R.; Dar, M. M.; Huang, P. S., Nat. Rev. Cancer 2007, 7, 107−117).

[0005] The disruption of microtubule formation leads to mitotic arrest and death of cancer cells. Although microtubule targeting agents are used as standard-of-care medicines to treat multiple human cancer types, they also cause significant toxicities due to their effects on normal cells, including myelosuppression and neurotoxicity. In recent years, a new class of antimitotic drugs that target kinesins has been developed with the goal of improving the therapeutic index ascompared to existing antimitotic drugs in the clinic (Antiopi Voultsiadou, Vasiliki Sarli, Rev Recent Clin Trials, 2011 Sep;6(3):271-7).

[0006] Kinesins are microtubule stimulated ATP driven motor proteins that play a key role in the assembly and disassembly of microtubules. KIF18A, a member of the kinesin-8 family, plays a vital role in regulating the spindle length and the proper alignment of chromosomes at the spindle equator during metaphase. Knockdown of the KIF18A gene in a subset of cancer cell lines with chromosome instability showed a selective vulnerability at mitosis that was associated with spindle assembly checkpoint activation and formation of multipolar spindles that lead to the induction of apoptosis. However, knockdown of KIF18A in normal cells with a diploid genome did not show any of the effects observed in the cancer cells (Carolyn Marquis 1, Cindy L Fonseca 1, Katelyn A Queen 1, Lisa Wood 1, Sarah E Vandal 1, Heidi L H Malaby 1, Joseph E Clayton 2, Jason Stumpff 3, 2021 Feb 22;12(1):1213).

[0007] Further, mice with the KIF18A gene knockout are viable with defects only observed in the division of their germ cells (Liu, X.-s.; Zhao, X.-d.; Wang, X.; Yao, Y.-x.; Zhang, L.-l.; Shu, R.- z.; Ren, W.-h.; Huang, Y.; Huang, L.; Gu, M.-m.; Kuang, Y.; Wang, L.; Lu, S.-y.; Chi, J.; Fen, J.- s.; Wang, Y.-f.; Fei, J.; Dai, W.; Wang, Z.-G, Genes Cancer 2010, 1, 26−39). SUMMARY

[0008] Provided herein are compounds of formula (I) and pharmaceutical compositions thereof, which are capable of inhibiting KIF18A.

[0009] In one aspect of the present disclosure, a compound of formula (I):or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: each independently represents a single bond, a double bond, or a delocalized π bond; ring A represents 5-membered heteroarylenyl; X1and X2are each independently CR3or N;Y1, Y2, and Y3are each independently, CR5, C(R5)2, N, or NR5; R1is (C1-C6)alkyl, hydroxy(C1-C6)alkyl or (C3-C8)cycloalkyl; subscript ‘p’ and subscript ‘q’ are each independently 0, 1, or 2; each R2is independently (C1-C6)alkyl (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R3is independently hydrogen or (C1-C6)alkyl; each R4is independently (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R5is independently hydrogen or (C1-C6)alkyl, or two R5bonded to the same carbon atom are taken together to form oxo ; W1represents a bond, phenylene or 3- to 12-membered heterocycloalkylene, wherein phenylene and heterocycloalkylene are optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy; or iii) 3- to 10-membered heterocycloalkylene; W3represents a bond or 3- to 12-membered heterocycloalkylene, which is optionally substituted with (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; andRW2represents hydrogen, (C1-C6)alkyl, (C1-C6)acyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C6)alkyl.

[0010] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

[0011] In another aspect, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof for use as a medicament.

[0012] In another aspect, the present disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof for use in the treatment of disease mediated by KIF18A. The disease or disorder mediated by KIF18A is cancer.

[0013] In another aspect, the present disclosure relates to compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof for use in the treatment of cancer.

[0014] In another aspect, the present disclosure relates to compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the manufacture of a medicament for treatment of cancer.

[0015] In another aspect, the present disclosure provides a method of inhibiting KIF18 in a cell, comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0016] In another aspect, the present disclosure provides a method of treating a disease or condition mediated by KIF18A in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof or a pharmaceutically acceptable salt or a stereoisomer thereof. The disease or condition mediated by KIF18A is cancer.

[0017] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

[0018] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder mediated by KIF18A; wherein the disease or disorder is cancer.

[0019] In another aspect, the present disclosure relates to the preparation of compounds of formula (I).

[0020] In another aspect, the present disclosure provides therapeutic uses for compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, which are capable of inhibiting KIF18A. DETAILED DESCRIPTION

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated to facilitate the understanding of the present disclosure.

[0022] As used herein, the term “alkyl,” alone or in combination with other term(s), refers to saturated aliphatic hydrocarbon chains, including C1-C10 straight or C1-C10 branched alkyl chains, more preferably, C1-C6 straight or branched alkyl chains. Examples of “alkyl” include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and the like. The term “alkylene or alkylenyl” refers to an alkyl group, as defined above, linking at least two other groups (i.e., a divalent alkyl radical). The two moieties linked to the alkylene group can be linked to the same carbon atom or different carbon atoms of the alkylene group. The alkylene group preferably has C1-C8atoms and, more preferably, has C1-C3atoms.

[0023] As used herein, the term “alkenyl,” alone or in combination with other term(s), refers to an alkyl group as described above having at least one carbon-carbon double bond. The term “alkynyl,” alone or in combination with other term(s), refers to an alkyl group as described above having at least one carbon-carbon triple bond. The term “alkenylene or alkenylenyl” refers to an alkenyl group, as defined above, linking at least two other groups (i.e., a divalent alkenyl radical). The two moieties linked to the alkenylene group can be linked to the same carbon atom or different carbon atoms of the alkenylene group. The alkenylene group preferably has C2-C8 atoms and, more preferably, has C2-C6 atoms.

[0024] As used herein, the terms “halo” and “halogen,” alone or in combination with other term(s), mean fluorine, chlorine, bromine or iodine.

[0025] As used herein, the term “haloalkyl,” alone or in combination with other term(s), means alkyl substituted with one or more halogen atoms, wherein the alkyl groups and halogen atoms are as defined above. Examples of “haloalkyl” include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

[0026] As used herein, the terms “hydroxy” and “hydroxyl,” alone or in combination with other term(s), means –OH.

[0027] As used herein, the term “hydroxyalkyl,” alone or in combination with other term(s), refers to the group HO-alkyl-, wherein the alkyl and hydroxy groups are as defined herein.

[0028] As used herein the term “cycloalkyl,” alone or in combination with other term(s), means a -C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. A cycloalkyl may alternatively be polycyclic, containing more than one ring. Examples of polycyclic cycloalkyls include bridged, fused, and spirocyclic carbocyclyls, and the like. The term “cycloalkylene” refers to a divalent cycloalkyl group as defined herein.

[0029] As used herein, the term “cyclolalkyl,” alone or in combination with other term(s), means a cycloalkyl ring as defined above, linked to an alkyl moiety.

[0030] As used herein, the term “carbocyclyl,” alone or in combination with other term(s), includes “cycloalkyl”, “cycloalkenyl” and “aryl” groups which are as defined above. Examples of “carbocyclyl” include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, and naphthyl.

[0031] The term “heterocycloalkyl,” alone or in combination with other term(s), refers to a non- aromatic, saturated, or partially saturated monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2 and NH, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A monocyclic heterocycloalkyl may typically contain 3 to 7 ring atoms. Examples of “heterocycloalkyl” include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, azepanyl, and N-oxides thereof. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic heterocycloalkyls and the like. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups. The term “heterocycloalkylene” refers to a divalent heterocycloalkyl group as defined herein.

[0032] As used herein, the term “heteroaryl,” alone or in combination with other term(s), means a completely unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms / groups being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single-ring (monocyclic) or polycyclic ring system. Examples of “heteroaryl”include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl, and the like. As used herein, the term “heteroarylenyl” refers to a divalent heteroaryl group as defined herein.

[0033] As used herein, the term “heterocyclyl,” alone or in combination with other term(s), includes both “heterocycloalkyl” and “heteroaryl” groups which are as defined above. Examples of “heterocyclyl” include but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, indolyl, benzimidazolyl, benzothiazolyl, and the like.

[0034] The term “heteroatom,” as used herein, designates a sulfur, nitrogen, or oxygen atom.

[0035] As used in the above definitions, the term “optionally substituted” or “substituted” or “optionally substituted with suitable groups” refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocycloalkyl, heteroaryl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, arylalkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl (e.g., trifluoromethyl), amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, arylalkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, and phosphonic acid. It is understood that any substituent may be further substituted.

[0036] As used herein, the term “compound(s)” comprises the compounds disclosed in the present disclosure.

[0037] As used herein, the terms “comprise” and “comprising” are generally used in the sense of “include” and “including,” that is to say permitting the presence of one or more additional features or components. The term “including” as well as other forms thereof, such as “include”, “includes” and “included” is not limiting.

[0038] As used herein, the term “or” means “and / or” unless stated otherwise.

[0039] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0040] As used herein, the phrase “pharmaceutically acceptable excipient” refers to pharmaceutically substances such as a liquid or solid filler, diluent, solvent, or encapsulating material. By “pharmaceutically acceptable” it is meant that the substance is compatible with the other ingredients of a composition or formulation and not deleterious to the recipient thereof. Excipients are generally safe, non-toxic and neither biologically nor otherwise undesirable,including those which are acceptable for human pharmaceutical use as well as veterinary use. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd Ed. (Academic Press, 2020); Handbook of Pharmaceutical Excipients, 9th ed., Sheskey et al, Eds. (Pharmaceutical Press; 2020); Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0041] As used herein, “pharmaceutically acceptable salt(s)” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include non-toxic salts of the parent compound formed, for example, from non- toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by various chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.

[0042] As used herein, the terms “treat”, “treating,” and “treatment” refer to a method of alleviating or abrogating a disease and / or its attendant symptoms.

[0043] As used herein, the terms “prevent”, “preventing,” and “prevention” refer to a method of preventing the onset of a disease and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing,” and “prevention” also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease.

[0044] As used herein, the term “therapeutically effective amount” refers to that amount of the compound being administered sufficient to prevent development of, or to partially or completely alleviate one or more of the symptoms of, the condition or disorder being treated.

[0045] The term “stereoisomers” refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of formula (I), (I’), (IA), (IB), (IB’), (IC), (ID), (ID’), (IE), (IE’), (IF), and (IG) wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I), (I’), (IA), (IB), (IB’), (IC), (ID), (ID’), (IE), (IE’), (IF), and (IG) are chiral, they can exist in racemic or in optically active form. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and l-isomers and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation via recrystallization, chromatographic techniques (e.g., direct separation of enantiomers on chiral chromatographic columns), or any other appropriate method known in the art. Starting compounds of particular stereochemistry may be commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present disclosure may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as mixtures thereof.

[0046] The present disclosure provides compounds of formula (I), which are useful for the inhibition of KIF18A.

[0047] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of various embodiments disclosed herein. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present disclosure includes such modifications and variations and their equivalents. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments and is not to be construed as limiting the broader aspects of the present disclosure.

[0048] The embodiments below are illustrative of the present disclosure and are not intended to limit the claims to the specific embodiments exemplified.

[0049] In some embodiments, the present disclosure provides a compound of formula (I):or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: each independently represents a single bond, a double bond, or a delocalized π bond; ring A represents 5-membered heteroarylenyl;X1and X2are each independently CR3or N; Y1, Y2, and Y3are each independently, CR5, C(R5)2, N, or NR5; R1is (C1-C6)alkyl, hydroxy(C1-C6)alkyl or (C3-C8)cycloalkyl; subscript ‘p’ and subscript ‘q’ are each independently 0, 1, or 2; each R2is independently (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R3is independently hydrogen or (C1-C6)alkyl; each R4is independently (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R5is independently hydrogen or (C1-C6)alkyl, or two R5bonded to the same carbon atom are taken together to form oxo ; W1represents a bond, phenylene or 3- to 12-membered heterocycloalkylene, wherein phenylene and heterocycloalkylene are optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy; or iii) 3- to 10-membered heterocycloalkylene; W3represents a bond or 3- to 12-membered heterocycloalkylene, which is optionally substituted with (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; andRW2represents hydrogen, (C1-C6)alkyl, (C1-C6)acyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C6)alkyl.

[0050] In some embodiments, the present disclosure provides a compound of formula (I’):or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: each independently represents a single bond, a double bond, or a delocalized π bond; ring A represents 5-membered heteroarylenyl; X1and X2are each independently CR3or N; Y1and Y2are each independently, CR5, C(R5)2, N, or NR5; R1is (C1-C6)alkyl, hydroxy(C1-C6)alkyl or (C3-C8)cycloalkyl; subscript p and subscript q are each independently 0, 1, or 2; each R2is independently (C1-C6)alkyl (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R3is independently hydrogen or (C1-C6)alkyl; each R4is independently (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R5is independently hydrogen or (C1-C6)alkyl, or two R5bonded to the same carbon atom are taken together to form oxo ; W1represents a bond or 3- to 10-membered heterocycloalkylene, which is optionally substituted with (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replacedwith -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy; or iii) 3- to 10-membered heterocycloalkylene; W3represents a bond or 3- to 10-membered heterocycloalkylene, which is optionally substituted with (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; and RW2represents (C1-C6)alkyl, (C1-C6)acyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, or (C3- C6)cycloalkyl(C1-C6)alkyl.

[0051] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A represents 5-membered heteroarylenyl; X1and X2are each independently CH or N; R1is hydroxy(C1-C6)alkyl or (C3-C8)cycloalkyl; subscript ‘p’ is selected from 0, 1, and 2; each R2is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl or halo; W1represents a bond, phenylene or 3- to 12-membered heterocycloalkylene wherein heterocycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo or halo(C1-C6)alkyl; W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 6-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted withone or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 6-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy; or iii) 3- to 10-membered heterocycloalkylene; W3represents a bond or 3- to 12-membered heterocycloalkylene, which is optionally substituted with (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; and RW2represents hydrogen, (C1-C6)alkyl, (C1-C6)acyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C6)alkyl.

[0052] In some embodiments, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A represents 5-membered heteroarylenyl; X1is CH or N and X2is CH or N; R1is hydroxy(C1-C6)alkyl or (C3-C5)cycloalkyl; subscript ‘p’ is selected from 0, 1, and 2; each R2is independently (C1-C3)alkyl or halo; W1represents bond or 3- to 12-membered heterocycloalkylene, wherein heterocycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo or halo(C1-C6)alkyl; W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 6-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; orii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 6-membered heterocycloalkylene, and (C3- C6)cycloalkylene; or iii) 3- to 10-membered heterocycloalkylene; W3represents 3- to 12-membered heterocycloalkylene, which is optionally substituted with (C1-C6)alkyl, halo, or halo(C1-C6)alkyl; and RW2represents hydrogen, (C1-C3)alkyl, (C1-C3)acyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C3)alkyl.

[0053] In some embodiments, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A represents 5-membered heteroarylenyl; X1is CH and X2is CH or N; R1is hydroxy(C1-C4)alkyl or (C3-C5)cycloalkyl; subscript ‘p’ is selected from 0, or 1; each R2is independently (C1-C3)alkyl or halo; W1represents bond or 3- to 12-membered heterocycloalkylene, wherein heterocycloalkylene is optionally substituted with one or more substituents independently selected from halo or halo(C1-C6)alkyl; W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O- or -N(RW2)-; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O- or -N(RW2)-; or iii) 3- to 10-membered heterocycloalkylene;W3represents 3- to 12-membered heterocycloalkylene, which is optionally substituted with (C1-C3)alkyl, halo, or halo(C1-C3)alkyl; and RW2represents (C1-C3)alkyl, (C1-C3)acyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1- C3)alkyl.

[0054] In some embodiments, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A represents oxadiazola, triazola, thiazola, oxazola, isoxazola, pyrazola, imidazola or thiadiazola; X1is CH and X2is CH or N; R1is hydroxy(C1-C3)alkyl or (C3-C4)cycloalkyl; subscript ‘p’ is selected from 1; each R2is independently (C1-C2)alkyl or halo; W1represents a bond or 3- to 10-membered heterocycloalkylene, wherein heterocycloalkylene is optionally substituted with 1, 2 or 3 substituents independently selected from halo or halo(C1-C3)alkyl; W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with 3- to 6-membered heterocycloalkylene, or (C3-C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with 3- to 6-membered heterocycloalkylene, or (C3-C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy; or iii) 3- to 8-membered heterocycloalkylene; and W3represents 3- to 12-membered heterocycloalkylene, which is optionally substituted with (C1-C3)alkyl, or halo(C1-C3)alkyl.

[0055] In some embodiments, the present disclosure provides a compound of formula (IA):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W2, W3, X1, X2, Y1, Y2, Y3, R1, R2,and p are as described in classes and subclasses herein, both singly and in combination; W1ais O, NH or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1, and 2.

[0056] In some embodiments, the present disclosure provides a compound of formula (IB):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1, W2, W3, X1,X2, R1, R2,and p are as described in classes and subclasses herein, both singly and in combination.

[0057] In some embodiments, the present disclosure provides a compound of formula (IB’):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1, W2, W3, X1,X2, R1, R2,and p are as described in classes and subclasses herein, both singly and in combination.

[0058] In some embodiments, the present disclosure provides a compound of formula (IC):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W2, W3, X1, X2, R1, R2, and p are as described in classes and subclasses herein, both singly and in combination; W1ais O, NH, or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1 and 2.

[0059] In some embodiments, the present disclosure provides a compound of formula (ID):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1, W2, X1,X2, R1, R2,and p are as described in classes and subclasses herein, both singly and in combination; subscripts ‘m’ and ‘n’ are each independently selected from 0, 1 and 2.

[0060] In some embodiments, the present disclosure provides a compound of formula (ID’):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1, W2, X1,X2, R1, R2,and p are as described in classes and subclasses herein, both singly and in combination; subscripts ‘m’, ‘n’ and ‘r’ are each independently selected from 0, 1 and 2; Rw3is hydrogen, (C1-C6)alkyl, halo or halo(C1- C6)alkyl.

[0061] In some embodiments, the present disclosure provides a compound of formula (IE):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1, W2, X1, X2, R1, R2, and p are as described in classes and subclasses herein, both singly and in combination; subscripts ‘m’ and ‘n’ are each independently selected from 0, 1 and 2.

[0062] In some embodiments, the present disclosure provides a compound of formula (IE’):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1, W2, X1,X2, R1, R2,and p are as described in classes and subclasses herein, both singly and in combination; subscripts ‘m’, ‘n’ and ‘r’ are each independently selected from 0, 1 and 2; Rw3is hydrogen, (C1-C6)alkyl, halo or halo(C1- C6)alkyl.

[0063] In some embodiments, the present disclosure provides a compound of formula (IF):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W2, X1, X2, R1, R2, and p are as described in classes and subclasses herein, both singly and in combination; W1ais O, NH or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1 and 2.

[0064] In some embodiments, the present disclosure provides a compound of formula (IG):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W2, R1, R2, and p are as described in classes and subclasses herein, both singly and in combination; W1ais O, NH or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1 and 2.

[0065] In some embodiments, the ring

[0066] In some embodiments, the ring

[0067] In some embodiments, the ring

[0068] In some embodiments, ring A is oxadiazola (i.e., a divalent oxadiazole radical), triazola (i.e., a divalent triazole radical), thiazola (i.e., a divalent thiazole radical), oxazola (i.e., a divalent oxazole radical), isoxazola (i.e., a divalent isoxazole radical), pyrazola (i.e., a divalent pyrazoleradical), imidazola (i.e., a divalent imidazole radical) or thiadiazola (i.e., a divalent thiadiazole radical).

[0069] In some embodiments, ring A is oxadiazola, triazola, thiazola, oxazola, isoxazola, pyrazola or thiadiazola.

[0070] In some embodiments, ring A is oxadiazola, pyrazola, triazola, or thiadiazola.

[0071] In some embodiments, ring A is oxadiazola or triazola.

[0072] In some embodiments, ring A is oxadiazola.

[0073] In some embodiments, ring A is triazola.

[0074] In some embodiments, W1is a bond or 4- to 6-membered heterocycloalkylene.

[0075] In some embodiments, W1is a bond.

[0076] In some embodiments, W1is 4- to 6-membered heterocycloalkylene.

[0077] In some embodiments, W1is azetidina (i.e., a divalent azetidine radical), morpholina (i.e., a divalent morpholine radical), piperazina (i.e., a divalent piperazine radical), pyrrolidine (i.e., a divalent piperidine radical), piperidina (i.e., a divalent piperidine radical), phenylene (i.e., a divalent phenyl radical), or quinolina (i.e., a divalent quinoline radical).

[0078] In some embodiments, W1is a bond, azetidina, morpholina or piperazina.

[0079] In some embodiments, W1is morpholina or piperazina.

[0080] In some embodiments, W1is morpholina.

[0081] In some embodiments, W1is piperazina.

[0082] In some embodiments, W1is azetidina.

[0083] In some embodiments, W1is piperidina.

[0084] In some embodiments, W1is pyrrolidina.

[0085] In some embodiments, W1is phenylene.

[0086] In some embodiments, W1is quinolina.

[0087] In some embodiments, W3is a bond or 4- to 12-membered heterocycloalkylene.

[0088] In some embodiments, W3is 4- to 12-membered heterocycloalkylene.

[0089] In some embodiments, W3is a bond.

[0090] In some embodiments, W3is azetidina (i.e., a divalent azetidine radical), azaspiro-octana (i.e., a divalent azaspiro-octane radical), dioxino-pyridina (i.e., a divalent dioxino-pyridineradical), diazaspiro-nonana (i.e., a divalent diazaspiro-nonane radical) diazaspiro-decana (i.e., a divalent diazaspiro-decane radical), azaspiroun-decana (i.e., a divalent azaspiroun-decane radical)or piperidina (i.e., a divalent piperidine radical).

[0091] In some embodiments, W3is azetidina, azaspiro-octana, diazaspiro-nonana, diazaspiro- decana, azaspiroun-decana, or piperidina.

[0092] In some embodiments, W3is azetidina, azaspiro-octana or piperidina.

[0093] In some embodiments, W3is azetidina.

[0094] In some embodiments, W3is piperidina.

[0095] In some embodiments, W3is piperidina optionally substituted with methyl or trifluoromethyl.

[0096] In some embodiments, W1and W3are each piperidina.

[0097] In some embodiments, W1and W3are each independently piperidina and W2is 3 to 10 membered heterocycloalkylene.

[0098] In some embodiments, W1, and W3are each independently 3 to 12 membered heterocycloalkylene.

[0099] In some embodiments, W2is;

[0100] In some embodiments, R1is hydroxy(C1-C6)alkyl or (C1-C6)cycloalkyl.

[0101] In some embodiments, R1is hydroxy(C1-C6)alkyl or (C3-C6)cycloalkyl.

[0102] In some embodiments, R1is hydroxy(C1-C6)alkyl or cyclopropyl.

[0103] In some embodiments, R1is (C3-C6)cycloalkyl.

[0104] In some embodiments, R1is cyclopropyl.

[0105] In some embodiments, R1is hydroxy(C1-C6)alkyl.

[0106] In some such embodiments, R1is hydroxyethyl.

[0107] In some embodiments, R2is (C1-C6)alkyl or halo.

[0108] In some embodiments, R2is (C1-C3)alkyl or halo.

[0109] In some embodiments, R2is methyl or halo.

[0110] In some embodiments, R2is methyl or fluorine.

[0111] In some such embodiments, R2is methyl.

[0112] In some embodiments, R2is fluorine.

[0113] In some embodiments, X1and X2are each independently CH or N.

[0114] In some embodiments, X1is CH or N and X2is N

[0115] In some embodiments, X1is CH and X2is N.

[0116] In some embodiments, R2is (C1-C6)alkyl or halo, and subscript ‘p’ is 1.

[0117] In some embodiments, each of X1and X2is N.

[0118] In some embodiments, each of X1and X2is CH.

[0119] In some embodiments, each of Y1, Y2, and Y3are each independently, CR5, C(R5)2, N, or NR5; wherein R5is each independently hydrogen or (C1-C6)alkyl.

[0120] In some embodiments, each of Y1, Y2, and Y3are each independently, CR5or N; wherein R5is each independently hydrogen or (C1-C3)alkyl.

[0121] In some embodiments, each of Y1, Y2, and Y3are each independently CH or N.

[0122] In some embodiments, each of Y1, Y2, and Y3are CH.

[0123] In some embodiments, each of Y1and Y2are each independently CH ; Y3is N.

[0124] In some embodiments, each of Y1is CH; Y2and Y3are each independently N.

[0125] In some embodiments, W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O- or -N(RW2)-; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O- or -N(RW2)-.

[0126] In some embodiments, RW2represents hydrogen, (C1-C6)alkyl, (C1-C6)acyl, halo(C1- C6)alkyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C6)alkyl.

[0127] In some embodiments, RW2represents hydrogen, (C1-C3)alkyl, (C1-C3)acyl, halo(C1- C3)alkyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C3)alkyl.

[0128] In some embodiments, RW2represents (C1-C3)alkyl, (C1-C3)acyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C3)alkyl.

[0129] In some embodiments, W2represents 3- to 10-membered heterocycloalkylene.

[0130] In some embodiments, W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with 3- to 6-membered heterocycloalkylene, or (C3-C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one ormore methylene units of the alkenylenyl is optionally and independently replaced with 3- to 6-membered heterocycloalkylene, or (C3-C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy.

[0131] In some embodiments, W2represents: i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with (C3-C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1- C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with (C3-C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy.

[0132] In some embodiments, subscript ‘p’ is 0 or 1.

[0133] In some embodiments, subscript ‘p’ is 0.

[0134] In some embodiments, subscript ‘p’ is 1.

[0135] In one embodiment, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A represents 5-membered heteroarylenyl; X1is CH and X2is N; R1is hydroxyethyl or cyclopropyl; W1is piperidina or morpholina; W2represents: i) (C1-C5)alkylenyl, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2); or ii) (C2-C4)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C4)alkyl, halo and hydroxy, wherein one ormore methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-; or iii) 6-membered heterocycloalkylene; and W3represents 6-membered heterocycloalkylene, which is optionally substituted with methyl or trifluoromethyl; RW2is methyl or hydrogen.

[0136] In one embodiment, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: ring A represents 5-membered heteroarylenyl; X1is N and X2is N; R1is hydroxyethyl or cyclopropyl; W1represents piperidina or morpholina; W2represents: i) (C1-C5)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2); or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-; or iii) 6-membered heterocycloalkylene; and W3represents 6-membered heterocycloalkylene, which is optionally substituted with methyl or trifluoromethyl;

[0137] In some embodiments, RW2is methyl or hydrogen.

[0138] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0139] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomerthereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein (e.g., in unit dose form). Such compositions can be prepared using procedures well known in the pharmaceutical art. Compounds described in the present disclosure may be admixed with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutical composition typically includes one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. Examples of pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents, and the like.

[0140] The pharmaceutical compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present disclosure may be formulated so as to provide a desired release profile.

[0141] Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches, and lozenges.

[0142] Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.

[0143] Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.

[0144] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), for use in the treatment of a disease or disorder mediated by KIF18A.

[0145] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the treatment of cancer selected from hematological cancer, lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, a DNA damage repair pathway deficient cancer, homologous-recombination deficient cancer, triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

[0146] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof for use as a medicament.

[0147] As demonstrated in more detail below, compounds of formula (I) are useful as KIF18A inhibitors. Accordingly, the present disclosure provides methods of inhibiting KIF18A in a cell, comprising contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0148] Also provided are methods of inhibiting KIF18A in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof. In some embodiments, the effective amount is a therapeutically effective amount for treating a disease or condition mediated by KIF18A.

[0149] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof for use in the treatment of a disease or disorder mediated by KIF18A.

[0150] In some embodiments, the disease or disorder mediated by KIF18A is cancer.

[0151] In some embodiments, the cancer is hematological cancer, lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, a DNA damage repair pathway deficient cancer, or a homologous-recombination deficient cancer.

[0152] In some embodiments, the cancer is a triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

[0153] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof for use in the manufacture of a medicament for the treatment of cancer.

[0154] In some embodiments, the cancer is hematological cancer, lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, a DNA damage repair pathway deficient cancer, homologous-recombination deficient cancer, triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

[0155] In one aspect, the present disclosure provides a method of inhibiting KIF18A in a cell, comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0156] In one aspect, the present disclosure provides methods of treating a disease or condition mediated by KIF18A in a subject in need of such treatment. The methods comprise administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0157] In some embodiments, the disease or condition mediated by KIF18A is cancer. Accordingly, the present disclosure also provides compounds of formula (I), for use in the treatment of cancer.

[0158] In some embodiments, the cancer is selected from the group consisting of a hematological cancer, a lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, or prostate cancer, a DNA damage repair pathway deficient cancer, or a homologous- recombination deficient cancer.

[0159] In some embodiments, the cancer is a triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

[0160] In some embodiments, the cancer comprises cells that are positive for an inactivated TP53 gene and / or positive for at least one of an inactivated Rb gene, an amplified CCNE1 gene or overexpressed CCNE1 gene, an inactivated BRCA gene or a combination thereof.

[0161] In some embodiments, the cancer comprises cells that are positive for a mutant TP53 gene and / or comprises cells that are positive for an amplified CCNE1 gene, a silenced BRCA1 gene, a deficient Rb1 gene, or a combination thereof.

[0162] In some embodiments, the cancer is selected from the group consisting of a hematological cancer, a lymphatic cancer, and a cancer comprising cancer cells with a mutation in a gene encoding p53 (e.g., a loss of function mutation in the gene encoding p53).

[0163] In some embodiments, the cancer is a hematological cancer or a lymphatic cancer.

[0164] In some embodiments, the cancer is a DNA damage repair pathway deficient cancer and / or a homologous-recombination deficient cancer.

[0165] In some embodiments, the cancer is a DNA damage repair pathway deficient cancer.

[0166] In some embodiments, the cancer is a homologous-recombination deficient cancer.

[0167] In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the mutation in the gene encoding p53 is a loss of function mutation.

[0168] In some embodiment, the cancer is a triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

[0169] In some embodiments, the cancer comprises cells that are positive for an inactivated TP53 gene and / or positive for at least one of an inactivated Rb gene, an amplified CCNE1 gene or overexpressed CCNE1 gene product, an inactivated BRCA gene, or a combination thereof.

[0170] In some embodiments, the cancer comprises cells that are positive for a mutant TP53 gene and / or comprises cells that are positive for an amplified CCNE1 gene, a silenced BRCA1 gene, a deficient Rb1 gene, or a combination thereof.

[0171] In one aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for treating cancer.

[0172] In one aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for treating a disease or disorder mediated by KIF18A.

[0173] In one aspect, the disease or disorder is a cancer.

[0174] Administration of the compounds of the disclosure, in pure form or in an appropriate pharmaceutical composition, can be carried out using any acceptable route of administration. The route of administration may be any route which effectively transports the active compound of the present disclosure to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical. In some embodiments, the composition is administered by oral, parenteral or inhalation routes. Examples of parenteral administration include administration by injection, as well as percutaneous, transmucosal, transnasal and transpulmonary administration.

[0175] Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through dose ranging studies in humans based on preliminary evidence derived from animal studies. Preferably, doses are sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Varying modes of administration, dosage forms and suitable pharmaceutical excipients can be well used and adjusted by those skilled in the art.

[0176] In some embodiments, the subject is a human or other mammal.

[0177] In related embodiments, the disclosure provides the use of compounds of Formula (I) for the treatment of diseases and / or disorders responsive to the inhibition of KIF18A (e.g., for use in the methods described above), as well as in the manufacture of medicaments for treating suchdiseases and / or disorders. Typically, the symptoms of the disease are treated, improved, diminished and / or prevented by inhibition of KIF18A.

[0178] The compounds of the present disclosure may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials, as described above.

[0179] The compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also embraces isotopically labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the disclosure and their uses. Exemplary isotopes that can be incorporated in to compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as2H (“D”),3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I and125I. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and / or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0180] The present disclosure provides methods for the preparation of compounds of formula (I) according to the description provided herein using appropriate methods and / or materials. It is to be understood by those skilled in the art that known variations of the conditions and processes of the following procedures can be used to prepare these intermediates and compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present disclosure.

[0181] Compounds of this disclosure may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied; that reagents, solvents and reaction conditions may be substituted for those specifically mentioned; and that reactive moieties may be protected and deprotected, as necessary. As a nonlimiting example, compounds according to Formula (I) may be prepared according to Scheme 1 below.Scheme 1

[0182] Ring A in intermediate (iii) of Scheme 1 can be formed by reacting intermediate (i) having a reactive moiety RAawith intermediate (ii) having a reactive moiety RAb. Various reactive partners RAaand RAbmay be employed depending on the identity of ring A in Formula (I) as shown in Schemes 2a, 2b, and 2c. In schemes 2a, a hydrazide (ia) and a carboxylate (iia) may be used for forming intermediates according to formula (iiia-1), which may be converted to oxadizoles according to formula (iiia) via cyclodehydration employing Burgess reagent methyl N- (triethylammoniumsulfonyl)carbamate. Schemes 2b shows a first halide (ib-1) is reacted via Suzuki coupling with a boronate (ib-2) to form intermediate (ib), which can be reacted via aromatic nucleophilic substitution with a second halide (iib) to form pyrazoles according to formula (iiib). Schemes 2c shows a nitro-functionalized intermediate (iic-1) may be converted to azide (iic), which can be reacted via copper-catalyzed Huisgen cycloaddition with alkyne (ic) to form triazoles according to formula (iiic).Scheme 2aScheme 2c

[0183] Following formation of ring A, intermediates according to formula (iii), bearing reactive moieties RW1aand RW3amay be coupled to form intermediate (iv) having a reactive moiety R1a(e.g., a bromide). R1amay then be displaced with a sulfonamide R1SO2NH2to afford the product of Formula (I).

[0184] Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phases, separation of layers and drying the organic layer over anhydrous sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate / petroleum ether mixtures of a suitable polarity as the mobile phase. Some of the intermediates were taken to the next step based on TLC results, without further characterization, unless otherwise specified. Analysis for the compounds of the present disclosure, unless otherwise specified, was conducted using general methods well known to a person skilled in the art.

[0185] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further defined by reference to the following examples, describing in detail the analysis of the compounds of the disclosure, which are not construed to be viewed as limiting the scope of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.EXPERIMENTAL Abbreviations:

[0186] DMF-N,N-Dimethylformamide; ACN-Acetonitrile; EtOAc-Ethyl acetate; 9-BBN- 9- Borabicyclo[3.3.1]nonane; DIAD- Diisopropyl azodicarboxylate; LAH- Lithium aluminum hydride; CsF- Caesium Fluoride; TBAF- Tetrabutylammonium fluoride; NMP- N-Methyl-2- Pyrrolidone; PCy3 – tricyclohexylphosphane; THF-Tetrahydrofuran; DCM-Dichloromethane; MeOH-Methanol; EtOH-Ethanol; DMSO-dimethyl sulfoxide; MeI-Methyl iodide; EtI-Ethyl iodide; TEA (or) Et3N-Triethylamine; DIPEA- N,N-Diisopropylethylamine; K2CO3-Potassium carbonate; NaOAc-Sodium acetate; KOAc-Potassium acetate; NH4OH-Ammonium hydroxide; NH4Cl-Ammonium chloride; MHz-Megahertz; HATU-1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; FA-Formic acid; TFA- Trifluoroacetic acid; AcOH-Acetic acid; RT / rt-Room temperature; TFAA-Trifluoroacetic anhydride; Cs2CO3-Cesium carbonate; CuI-Copper iodide; K3PO4-Potassium phosphate; Pd(PPh3)4-Tetrakis(triphenylphosphine)palladium(0); NaOH-Sodium hydroxide; HCl- Hydrochloric acid; tBuXPhos-2-Di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl; Pd(OAc)2- Palladium acetate; Na2SO4-Sodium sulfate; Pd / C-Palladium on charcoal; DMP-Dess-Martin periodinane; ACN-Acetonitrile; DMAP-Dimethylaminopyridine; STAB-Sodium triacetoxy borohydride; h-hour; min-minute; TLC-Thin layer chromatography; LCMS-Liquid chromatography–mass spectrometry; HPLC-High-performance liquid chromatography; DMSO- d6-Deuterated dimethyl sulfoxide; Chloroform-d-Deuterated chloroform; NMR-Nuclear magnetic resonance; s-Singlet; d-Doublet; t-Triplet; m-multiplet; J-Coupling constant; Hz-Hertz; Int- Intermediate; H2-Hydrogen gas; tBuOK-Potassium tert-butoxide. Synthesis of Intermediates: Intermediate 1: Synthesis of 4-allylpiperidine hydrochloride

[0187] Step 1: Synthesis of Intermediate 1a. To a stirred solution of methyltriphenylphosphonium bromide (4.71 g, 13.2 mmol) in THF (10 mL) was added potassium 2-methylpropan-2-olate (1.97 g, 17.59 mmol) at 0 °C. After 1 h, tert-butyl 4-(2- oxoethyl)piperidine-1-carboxylate (2 g, 8.8 mmol) in THF (10 mL) was added dropwise to thereaction mixture at 0 °C. The resultant solution was brought to RT and stirred for 3 h. Then, the reaction mixture was quenched with water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford a crude mass which was purified by combi flash chromatography by eluting with 20% EtOAc / hexane to obtain a colourless oil. (1.6 g, 80.71% yield).1H NMR (CDCl3, 400 MHz): 5.82-5.73 (m, 1H), 5.06-4.99 (m, 2H), 4.19-4.10 (m, 2H), 2.69 (t, J = 12.2 Hz, 2H), 2.06-2.00 (m, 2H), 1.69-1.63 (m, 2H), 1.47 (s, 9H), 1.16-1.06 (m, 2H).

[0188] Step 2: Synthesis of Intermediate 1. To a stirred solution of Intermediate 1a (1.7 g, 7.54 mmol) in 1,4-dioxane (6 mL) was added 4.0 M HCl solution in dioxane (15 mL) and the resulting mixture was stirred under N2atmosphere for 2 h at RT. After completion of the reaction, the reaction mass was concentrated on rota vapor, washed with pentane, and dried under high vacuum to obtain a crude solid which was used for the next step without further purification (1.2 g crude yield). LC-MS: m / z 126.1 (M+H)+. Intermediate 2: Synthesis of 3-allylpiperidine hydrochloride

[0189] Step 1: Synthesis of Intermediate 2a. To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (4.8 g, 14.1 mmol) in THF (15 mL) was added potassium tert-butoxide (1.58 g, 14.1 mmol) at 0 °C and the mixture was stirred for 1 h at the same temperature. To the resultant solution, tert-butyl 3-formylpiperidine-1-carboxylate (1 g, 4.7 mmol) in THF (10 mL) was added dropwise at 0 °C. The reaction mixture was then brought to RT and stirred for 4 h. Completion of the reaction was monitored by TLC, showing consumption of the starting material. The reaction mass was then diluted with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to give the crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound as a yellow oil (0.9 g, 79% yield).1H NMR (DMSO-d6, 400 MHz): 6.43 (d, J = 12.8 Hz, 1H), 5.98 (d, J = 6.4 Hz, 1H), 4.62 (m, 1H), 4.13-4.02 (m, 1H), 3.82-3.72 (m, 2H), 3.54 (s, 1H), 3.43 (s, 2H), 3.32 (s, 3H), 2.72-2.68 (m, 1H), 1.39 (s, 9H).

[0190] Step 2: Synthesis of Intermediate 2b. To a stirred solution of Intermediate 2a (0.7 g, 2.9 mmol) in THF (10 mL) was added 2M HCl (2.2 mL) at 0 °C. Then, the reaction mixture was brought to RT and stirred for 3 h. After completion of the reaction, the reaction mass was extractedwith EtOAc followed by brine wash. The combined organic layer was dried over Na2SO4, and solvent was evaporated to give the title compound which was used for the next step without further purification (0.6 g crude yield).1H NMR (DMSO-d6, 400 MHz): 9.7 (s, 1H), 3.72 (bs, 2H), 2.85- 2.82 (m, 1H), 2.34-2.30 (m, 2H), 1.93-1.91 (m, 1H), 1.74-1.71 (m, 1H), 1.59-1.57 (m, 1H), 1.39 (s, 9H), 1.36-1.32 (m, 2H).

[0191] Step 3: Synthesis of Intermediate 2c. Intermediate 2c was prepared using a similar procedure described for the synthesis of Intermediate 1a.1H NMR (CDCl3, 400 MHz):5.82-5.73 (m, 1H), 5.06-5.04 (m, 1H), 5.01 (s, 1H), 3.94-3.89 (m, 1H), 2.77 (s, 1H), 2.01-1.95 (m, 2H), 1.85- 1.80 (m, 1H), 1.67-1.63 (m, 1H), 1.54-1.50 (m, 1H), 1.47 (s, 9H), 1.15-1.05 (m, 1H).

[0192] Step 4: Synthesis of Intermediate 2. Intermediate 2 was prepared using a similar procedure described for the synthesis of Intermediate 1. LC-MS: m / z 126.1 (M+H)+. Intermediate 3: Synthesis of 3-vinylpiperidine hydrochloride

[0193] Step 1: Synthesis of Intermediate 3a. Intermediate 3a was prepared using a similar procedure described for the synthesis of Intermediate 1a.1H NMR (CDCl3, 400 MHz): 5.77-5.69 (m, 1H), 5.11-5.02 (m, 2H), 3.99-3.95 (m, 2H), 2.78-2.74 (m, 1H), 2.51 (bs, 1H), 2.15 (s, 1H), 1.88-1.84 (m, 1H), 1.70-1.64 (m, 1H), 1.45 (s, 9H), 1.30-1.27 (m, 2H).

[0194] Step 2: Synthesis of Intermediate 3. Intermediate 3 was prepared using a similar procedure described for the synthesis of Intermediate 1.1H NMR (DMSO-d6, 400 MHz): 5.78- 5.70 (m, 1H), 5.09-5.02 (m, 2H), 3.99-3.95 (m, 2H), 2.78-2.74 (m, 1H), 2.59 (bs, 1H), 2.15 (s, 1H), 1.88-1.84 (m, 1H), 1.70-1.64 (m, 1H), 1.30-1.25 (m, 2H). Intermediate 4: Synthesis of 4-methyl-4-vinylpiperidine hydrochloride

[0195] Step 1: Synthesis of Intermediate 4a. To a stirred solution of tert-butyl 4- formylpiperidine-1-carboxylate (3 g, 14 mmol) in DMF (30 mL) was added potassium tert- butoxide (3.15 g, 28.1 mmol) followed by methyl iodide (4 g, 28.1 mmol) at 0 °C. The reactionmixture was then brought to RT and stirred for 12 h. Completion of the reaction was monitored by TLC, showing consumption of the starting material. The reaction mass was then quenched with a saturated ammonium chloride solution and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotavapor to give the crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound as a yellow oil (2.5 g, 59% yield). LC- MS: m / z 128.2, 172.1 (Boc pattern).

[0196] Step 2: Synthesis of Intermediate 4a. Intermediate 4a was prepared using a similar procedure described for the synthesis of Intermediate 1a.1H NMR (CDCl3, 400 MHz): 5.82-5.75 (m, 1H), 5.07-4.97 (m, 2H), 3.49-3.47 (m, 2H), 3.35-3.29 (m, 2H), 1.62-1.57 (m, 2H), 1.45 (s, 9H), 1.42-1.39 (m, 2H), 1.04 (s, 3H).

[0197] Step 3: Synthesis of Intermediate 4. Intermediate 4 was prepared using a similar procedure described for the synthesis of Intermediate 1.1H NMR (DMSO-d6, 400 MHz): 8.96 (bs, 2H), 5.83-5.76 (m, 1H), 5.11-5.04 (m, 2H), 3.04-3.01 (m, 2H), 2.90-2.87 (m, 2H), 1.78-1.72 (m, 2H), 1.62-1.55 (m, 2H), 1.02 (s, 3H). Intermediate 5: Synthesis of tert-butyl 4-vinylpiperidine-1-carboxylate

[0198] Synthesis of Intermediate 5. To a stirred solution of methyl triphenyl phosphonium bromide (125.62 g, 351.65 mmol) in THF (300 mL) was added t-BuOK, (52.61 g, 468.86 mmol) in portion wise manner at 0 °C under an atmosphere of nitrogen. The resultant reaction mixture was stirred for 1 h at 0 °C. Then tert-butyl 4-formylpiperidine-1-carboxylate (50.0 g, 234.43 mmol) was added at 0° C, then reaction mixture was stirred for 3 h at room temperature. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, reaction mixture was poured in ice cold water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford a title compound as a colourless liquid (20.0 g, 40.37%).1H NMR (CDCl3, 400 MHz): 5.82-5.75 (m, 1H), 5.07-4.97 (m, 2H), 3.49-3.47 (m, 2H), 3.35-3.29 (m, 2H), 1.62-1.57 (m, 2H), 1.45 (s, 9H), 1.42-1.39 (m, 2H).Intermediate 6: Synthesis of 3-allyloxy hydrochloride

[0199] Step 1: Synthesis of Intermediate 6a. To a stirred solution of 3-hydroxypiperidine-1- carboxylate (1 g, 4.96 mmol) in DMF (5 mL) was added NaH (0.18 g, 7.46 mmol) followed by allyl bromide (0.6 g, 4.96 mmol) at 0 °C. The reaction mixture was then brought to RT and stirred for 12 h. Completion of the reaction was monitored by TLC, showing consumption of the starting material. The reaction mass was then quenched with a saturated ammonium chloride solution and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to give the title compound which was used for the next step without further purification (0.9 g crude yield).1H NMR (DMSO- d6, 400 MHz): 5.92-5.85 (m, 1H), 5.27-5.21 (m, 1H), 5.13-5.10 (m, 1H), 4.04-3.93 (m, 2H), 3.60 (s, 1H) 3.29 (s, 3H), 1.81 (s, 1H), 1.65 (s, 2H), 1.49 (s, 1H), 1.45 (s, 9H), 1.23 (s, 1H).

[0200] Step 2: Synthesis of Intermediate 6 was prepared using a similar procedure described for the synthesis of Intermediate 1.1H NMR (DMSO-d6, 400 MHz): 5.93-5.86 (m, 1H), 5.27- 5.21 (m, 1H), 5.13-5.10 (m, 1H), 4.04-3.99 (m, 2H), 3.67 (s, 1H), 3.29-3.25 (m, 3H), 2.93-2.89 (m, 3H), 1.82-1.79 (m, 2H), 1.61-59 (m, 2H). Intermediate 7: Synthesis of 4-allyloxy hydrochloride

[0201] Step 1: Synthesis of Intermediate 7a. Intermediate 7a was prepared using a similar procedure described for the synthesis of Intermediate 6a.1H NMR (CDCl3, 400 MHz) : 5.92- 5.85 (m, 1H), 5.27-5.21 (m, 1H), 5.13-5.10 (m, 1H), 4.04-3.93 (m, 2H), 3.79 (bs, 2H) 3.54-3.50 (m, 1H), 3.13-3.06 (m, 2H), 1.81 (bs, 1H), 1.60-1.53 (m, 3H), 1.49 (s, 9H).

[0202] Step 2: Synthesis of Intermediate 7. Intermediate 7 was prepared using a similar procedure described for the synthesis of Intermediate 1.1H NMR (DMSO-d6, 400 MHz): 8.74(bs, 1H), 5.92-5.85 (m, 1H), 5.27-5.21 (m, 1H), 5.13-5.10 (m, 1H), 3.99-3.97 (m, 2H), 3.61-3.51 (m, 1H), 3.13 (bs, 2H), 2.96 (bs, 2H), 1.97-1.93 (m, 2H), 1.72-1.67 (m, 2H). Intermediate 8: Synthesis of 4-(allyloxy)-4-methylpiperidine hydrochloride

[0203] Step 1: Synthesis of Intermediate 8a. To a stirred solution of tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (30 g, 139.34 mmol) in DMF (300 mL) was added sodium hydride (6.4 g, 278.69 mmol) at 0 °C and stirred for 1 h. Then allyl bromide (84.29 g, 696.73 mmol) was added dropwise at 0 °C and stirred for 4 h at RT under nitrogen atmosphere. After completion of the reaction, reaction mass was quenched with saturated ammonium chloride solution, diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass, which was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (30.5 g, 85.72% yield).1H NMR (DMSO-d6, 400 MHz): 5.94-5.85 (s, 1H) 5.28- 5.23 (dd, 1H) 5.094-5.035 (dd, 1H) 3.87-3.85 (m, 2H) 3.57 (d, 2H) 3.041 (s, 2H) 1.66 (d, 2H) 1.39 (s, 9H) 1.38 (m, 2H) 1.13 (s, 3H).

[0204] Step 2: Synthesis of Intermediate 8. To a stirred solution of Int 8a (30.5 g, 119.43 mmol) in 1,4-dioxane (300 mL) was added 4M hydrogen chloride solution (4.0 M in dioxane) (150 mL) and stirred at RT for 3 h under nitrogen atmosphere. After completion of the reaction, 1,4-dioxane was evaporated on rota vapour and reaction mass was washed with diethyl ether and pentane, dried on rota vapour to afford title compound (25.9 g crude yield).1H NMR (DMSO-d6, 400 MHz): 9.12 (d, 2H) 5.95-5.86 (m, 1H) 5.30-5.29 (dd, 1H) 5.26-5.24 (dd, 1H) 3.87-3.85 (m, 2H) 3.05-3.02 (d, 2H) 2.89-2.86 (m, 2H) 1.87 (d, 2H) 1.70-1.66 (m, 2H) 1.16 (s, 3H).Intermediate 9: Synthesis of ethyl 6-azaspiro [2.5] octane-1-carboxylate hydrochloride

[0205] Step 1: Synthesis of Intermediate 9a. To a stirred solution of ethyl 2- (diethoxyphosphoryl) acetate (33.755 g, 150.56 mmol) in THF (200 mL) was added sodium hydride (3.13 g, 130.48 mmol) at 0 °C then reaction mixture was stirred for 1 h at 0 °C to room temperature. To the resultant mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (20 g, 100.37 mmol) at 0 °C. Reaction mixture was then stirred at room temperature for 16 h. After completion of the reaction, reaction mass was quenched with saturated NH4Cl solution, diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate and filtered then filtrate was evaporated on rota vapor to obtain crude mass, the crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (20 g, 73.98% yield). LC-MS: m / z 269.1 (M+H)+.

[0206] Step 2: Synthesis of Intermediate 9b. To stirred solution of TMSOI (16.34g, 37.128 mmol) in DMSO (100 mL), Potassium tert-butoxide (8.332 g, 74.25 mmol) at 0 °C and the reaction mass was stirred at RT for 90 min. Then, Int 9a (10 g, 37.13 mmol) was added at 0°C and the reaction mass was stirred at RT for 16 h. After completion of the reaction, reaction mass was diluted with ice cold water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass; the crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (4.8 g, 45.62% yield). LCMS: m / z 283.26 (M+H)+.

[0207] Step 3: Synthesis of Intermediate 9. Int 9 was synthesized using a similar procedure described for the synthesis of Int 8. LCMS: m / z 183.26 (M+H)+.Intermediate 10: Synthesis of 4-(allyloxy)-4-(trifluoromethyl)piperidine hydrogen chloride

[0208] Step 1: Synthesis of Intermediate 10a. Tetrabutylammonium fluoride (7.87 g, 30.11 mmol, 1M solution in tetrahydrofuran) was added to an ice-cooled solution of (trifluoromethyl)trimethylsilane (5.353 g, 37.64 mmol) and tert-butyl 4-oxo-1- piperidinecarboxylate (5 g, 25.094 mmol) in tetrahydrofuran (50 mL), and the reaction mixture was stirred at room temperature for 12 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi- flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (5.5 g, 81.40% yield).1H NMR (DMSO-d6, 400 MHz): 3.90 (d, J = 10.8 Hz, 2H), 2.95 (s, 2H), 1.66-1.53 (m, 2H), 1.56-1.48 (m, 2H),1.40 (s, 9H).

[0209] Step 2: Synthesis of Intermediate 10b. To a stirred solution of sodium hydride 60% dispersion in mineral oil (0.939 g, 40.85 mmol) in DMF (30 mL) was added Int.10a (5.5 g, 20.42 mmol) and stirred for 1 h. Then the reaction mixture was cooled to 0 °C and 3-bromoprop-1-ene (12.356 g, 102.12 mmol) was added to it. The reaction mixture was then stirred at room temperature for 3 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound as crude mass. The crude mass was used for next step without purification (6.5 g crude yield).1H NMR (DMSO-d6, 400 MHz): 5.90-5.88 (m, 1H), 5.36-5.30 (m, 1H), 5.20-5.16 (m, 1H), 4.12 (d, j=4.8Hz, 2H), 3.91 (d, j=10.8Hz, 2H), 2.88 (s, 2H), 1.99-1.95 (m, 2H), 1.62-1.55 (m, 2H), 1.40 (s, 9H).

[0210] Step 3: Synthesis of Intermediate 10. To a stirred solution of Int.10b (6.5 g, 21.013mmol) in 1,4 dioxane (30 mL) was added 4M HCl in dioxane (15 mL) in a dropwise manner at 0 °C under argon atmosphere. The reaction mixture was then brought to RT and stirred for 2h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuumpressure and washed with pentane to afford title compound (5.1 g crude yield).1H NMR (DMSO- d6, 400 MHz): 5.90-5.88 (m, 1H), 5.36-5.30 (m, 1H), 5.20-5.16 (m, 1H), 4.12 (d, J = 4.8 Hz, 2H), 3.27 (d, J = 12.8 Hz, 2H), 2.88 (s, 2H), 2.15-2.07(m, 4H). Intermediate 11: Synthesis of 4-(allyloxy)-1-(2-azido-5-bromophenyl)-4-(trifluoromethyl) piperidine

[0211] Step 1: Synthesis of Intermediate 11a. To a stirred solution of 4-bromo-2-fluoro-1- nitrobenzene (4.0 g, 18.18 mmol), Int 10 (6.7 g, 27.27 mmol) in DMF (20 mL) and K2CO3 (7.54 g, 54.55 mmol) were added. The reaction mixture was then heated with constant stirring at 120 °C for 16 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (6.5 g, 87.36% yield). LCMS: m / z 409.1(M+H)+.1H NMR (DMSO-d6, 400 MHz): 6.95-6.93 (m, 2H), 6.63-6.61 (d, 1H), 6.00-5.91 (m, 1H), 5.39-5.38 (d, 1H), 5.19-5.18 (d, 1H), 5.05 (s, 2H), 4.16 (s, 2H), 2.98 (s, 2H), 2.72-2.68 (m, 2H), 2.03-2.01 (m, 4H).

[0212] Step 2: Synthesis of Intermediate 11b. To a stirred solution of Int 11a (4.00 g, 9.78 mmol) in EtOH (60 mL) and H2O (15 mL) were added Fe powder (2.73 g, 48.88 mmol) followed by NH4Cl (2.61 g, 48.87 mmol). The reaction mixture was then heated with constant stirring at 60 °C for 16 h. After completion of the reaction, filtered through the celite bed and the solid phase was rinsed with DCM. The filtrate was concentrated on a rotary evaporator to obtain title compound which was used for next step without further purification (3.8g crude yield).1H NMR (DMSO-d6, 400 MHz): 720-7.17 (d, 1H), 7.14 (s, 1H), 6.96-6.94 (d, 1H), 6.01-5.92 (m, 1H), 5.40-5.35 (m, 1H), 5.25-5.21 (m, 1H), 4.20-4.12 (m, 2H), 3.29-3.26 (d, 2H), 2.95-2.89 (m, 2H), 2.15-2.09 (m, 4H). FT-IR: 2128.14 cm-1.

[0213] Step 3: Synthesis of Intermediate 11. To a stirred solution of Int 11b (3.8 g, 10.02 mmol) in TFA (20 mL) was added sodium nitrite (0.89g, 13.03 mmol) in 20 mL water at 0 °C in dropwise manner and stirred at same temperature for 30 min. Then, sodium azide (0.85 g, 13.02 mmol) in 20 mL water was added dropwise manner and stirred at RT for 3 h. After completion of the reaction, reaction mass was quenched with saturated sodium bicarbonate solution at 0 °C and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain title compound (4.2 g crude yield). LC-MS: m / z 405.1 (M+H)+.

[0214] The intermediate in Table A was prepared according to the procedure described in Intermediate 11, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table A: I N AIntermediate 12: Synthesis of 2-vinylmorpholine hydrochloride

[0215] Step 1: Synthesis of Intermediate 12a. To a stirred solution of tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate (2 g, 9.2 mmol) in DCM (30 mL) was added Dess- Martin periodinane (4.7 g, 11 mmol) at 0 °C and the mixture was stirred for 30 min at the same temp. Then, the reaction mixture was brought to RT and stirred for 2 h. After completion of the reaction, the reaction mixture was quenched with a saturated sodium thiosulfate solution and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried overanhydrous sodium sulphate, filtered, and evaporated on rota vapor to give the title compound which was purified by combi flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (1.8 g, 90% yield). LC-MS: m / z 116.2 (Boc pattern)

[0216] Step 2: Synthesis of Intermediate 12b. Intermediate 12b was prepared using a similar procedure described for the synthesis of Intermediate 1a.1H NMR (CDCl3, 400 MHz): 5.84-5.77 (m, 1H), 5.40-5.24 (m, 2H), 3.96-3.91 (m, 3H), 3.58-3.54 (m, 1H), 2.98 (bs, 1H), 2.70 (s, 1H), 1.45 (s, 9H), 1.30-1.27 (m, 1H).

[0217] Step 3: Synthesis of Intermediate 12. Intermediate 12 was prepared using a similar procedure described for the synthesis of Intermediate 1.1H NMR (DMSO-d6, 400 MHz): 5.84- 5.77 (m, 1H), 5.40-5.24 (m, 2H), 3.96-3.91 (m, 3H), 3.58-3.54 (m, 1H), 2.98 (bs, 1H), 2.70 (s, 1H), 1.30-1.27 (m, 1H). Intermediate 13: Synthesis of 4-ethynyl-2-(3-vinylpiperidin-1-yl) pyrimidine

[0218] Step 1: Synthesis of Intermediate 13a. To a stirred solution of 2,4-dichloropyrimidine (30.0 g, 201.38 mmol), ethynyl triisopropylsilane (36.73 g, 201.383 mmol), in THF (300 mL) was added TEA (61.135 g, 101.19 mmol), Cuprous Iodide (3.835 g, 20.13 mmol), purged with N2gas for 15 mins followed by adding bis(triphenylphosphine)palladium dichloride (II) (14.135 g, 20.130 mmol). The resultant solution was then heated with constant stirring at 50 °C for 12 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (51 g, 85.88% yield). LCMS: m / z 295.1 (M+H)+.

[0219] Step 2: Synthesis of Intermediate 13b. To a stirred solution of 3-vinylpiperidine hydrochloride (16.27 g, 110.2 mmol) in DMF (10 mL) was added DIPEA (54.783 g, 423.87 mmol) followed by K2CO3(35.15 g, 138.20 mmol) and stirred for 15 min. Then, Int 13a (25 g, 84.774 mmol) was added and reaction mixture was heated with constant stirring at 120 °C for 12 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled waterand dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 2 % EtOAc / hexane as an eluent to afford title compound (28 g, 89.36% yield). LCMS: m / z 370.1 (M+H)+.

[0220] Step 3: Synthesis of Intermediate 13. To a stirred solution of Int 13b (28 g, 75.75 mmol) in THF (280 mL) was added TBAF (59.42 g, 227.25 mmol) at 0 °C dropwise under nitrogen atmosphere. The reaction mixture was under constant stirring maintained at RT for 3 h. The completion of the reaction was monitored using TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (13.0 g, 80.46 % yield). LCMS: 214.1 m / z (M+H)+.

[0221] The intermediates in Table B were prepared according to the procedure described in Intermediate 13, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table B: I B B BIntermediate 14: Synthesis of 2-(4-allylpiperidin-1-yl)-4-bromobenzoic acid

[0222] Step 1: Synthesis of Intermediate 14a. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (1.4 g, 6.0 mmol) in DMSO (10 mL) was added Intermediate 1 (1.16 g, 7.21 mmol) followed by K2CO3 (2.49 g, 18 mmol) at 0 °C and the mixture was stirred for 5 min at the same temperature. The reaction mixture was then heated at 140 °C for 16h. Completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic layer was washed with cold water followed by brine, dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain a crude oil which was purified by combi flash by eluting with 20%EtOAc / hexane to afford the title compound (1.4 g, 68.9% yield). LC-MS: m / z 337.90 (M+H)+.

[0223] Step 2: Synthesis of Intermediate 14. To a stirred solution of Int-14a (1.4 g, 4.14 mmol) in THF:MeOH:H2O (2:1:1, 12 mL) at 0 °C was added lithium hydroxide (2.08 g, 49.66 mmol) and the mixture was stirred for 5 min at the same temperature. The reaction mixture was then brought to room temperature and stirred for 24 h. Completion of the reaction was monitored by TLC. After completion of the reaction, solvents were evaporated in vacuo. The residue was diluted with water (10 mL) and acidified by 2N HCl to pH 5-6, extracted with ethyl acetate followed by cold brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain a pale brown solid (30 g crude yield). LCMS: m / z 323.90 (M+H)+.

[0224] The intermediates in Table C were prepared according to the procedure described for Intermediate 14, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table C: In N C- C- C- C- C-Intermediate 15: Synthesis of benzyl 4-(((tert-butoxycarbonyl) (cyclobutyl) amino) methyl)- 4-methylpiperidine-1-carboxylate

[0225] Step 1: Synthesis of Intermediate 15a. To a stirred solution of Cbz-4-formylpiperidine (20 g, 81 mmol) in DMF (50 mL) was added potassium 2-methylpropan-2-olate (18 g, 162 mmol) at 0 °C and stirred for 1 h at the same temperature. To the resultant mixture was added iodomethane (23 g, 162 mmol) and reaction mixture was brought to RT and stirred for 12 h. After completion of the reaction, reaction mass was diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; the crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (9.5 g, 45% yield). LCMS: m / z 262.1 (M+H)+.

[0226] Step 2: Synthesis of Intermediate 15b. To a stirred solution of Int 15a (8.5 g, 32.52 mmol) in methanol (50 mL) was added cyclobutanamine (2.3 g, 32.52 mmol) at 0 °C followed by ZnCl2(0.22 g, 1.62 mmol). Then reaction mixture was heated at 60 °C for 8 h. To this reaction mixture, sodium cyanoborohydride (2.65 g, 42.3 mmol) was added and then stirred at room temperature for another 12 h. After completion of the reaction, solvent was distilled under reduced pressure, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass, which was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (7.8 g, 76% yield). LC-MS: m / z 317.1 (M+H)+.

[0227] Step 3: Synthesis of Intermediate 15c. To a stirred solution of Int 15b (7.8 g, 24.6 mmol) in THF (50 mL) was added DMAP (3 g, 24.6 mmol) and TEA (7.48 g, 74 mmol) at 0 °C followed by (Boc)2O (8 g, 37 mmol). Then reaction mixture was stirred at RT for 12 h. After completion of the reaction, solvent was distilled under reduced pressure, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass, which was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (7.1 g, 69% yield).1H NMR (DMSO-d6, 400 MHz): 7.39-7.29 (m, 5H), 5.06 (s,2H), 3.77-3.75 (m, 1H), 3.70-3.67 (m, 1H), 3.08 (s, 4H), 2.27-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.59-1.48 (m, 2H), 1.45 (s, 9H), 1.35-1.28 (m, 2H), 1.21-1.17 (m, 2H).

[0228] Step 4: Synthesis of Intermediate 15. To a stirred solution of Int 15c (7.1 g, 17.44 mmol) in ethanol (10 mL) was added 10% palladium on carbon (0.4 g, 3.4 mmol) and the reaction mixture was stirred under hydrogen atmosphere for 24 h. After completion of reaction, reaction mixture was diluted with ethyl acetate and filtered through celite bed. Filtrate was collected and concentrated and dried under reduced pressure to obtain title compound (4.1 g crude) which was used for next step without further purification.1H NMR (DMSO-d6, 400 MHz): 3.77-3.75 (m, 1H), 3.70-3.67 (m, 1H), 3.08 (s, 4H), 2.27-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.59-1.48 (m, 2H), 1.45 (s, 9H), 1.35-1.28 (m, 2H), 1.21-1.17 (m, 2H). Intermediate 16: Synthesis of 1-(2-fluoro-4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole

[0229] To a stirred solution of 1,2-difluoro-4-nitrobenzene (1.5 g, 9.42 mmol) and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 11.31 mmol) in DMSO was added K2CO3 (3.9 g, 28.28 mmol) at RT. The reaction mixture was then stirred at 120 °C for 2 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine solution dried over anhydrous Na2SO4 filtered and concentrated on rotary evaporator to obtain crude mass, crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (1.2 g, 38% yield). LCMS: m / z 334 (M+H) +. Intermediate 17: Synthesis of 1-(tert-butoxycarbonyl)-5,5-difluoropiperidine-3-carboxylic acid

[0230] Step 1: Synthesis of Intermediate 17a. To a stirred solution of 1-tert-butyl 3-methyl 5- hydroxypiperidine-1,3-dicarboxylate (5 g, 19 mmol) in DCM (50 mL) was added slowly added Dess-Martin periodinane (16 g, 38 mmol). The mixture was stirred at RT for 12h and then filtered. The filtrate was washed with H2O and a saturated aqueous solution of Na2CO3. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by combi flash eluting with 20% EtOAc / hexane as an eluent to afford title compound (4.9 g, 98% yield). LCMS: m / z 158 (Boc pattern, M-100) +.

[0231] Step 2: Synthesis of Intermediate 17b. To a stirred solution of Int 17a (4.9 g, 19 mmol) in DCM (50 mL) cooled to -78° C and dropwise added DAST (2.0 g, 12.18 mmol). The mixture was stirred at RT for overnight and then H2O and DCM (30 mL) were added. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by combi flash eluting with 30% EtOAc / hexane as an eluent to afford title compound (4.9 g, 98% yield). LCMS: m / z 180 (Boc pattern, M-100) +.

[0232] Step 3: Synthesis of Intermediate 17. Intermediate 17 was synthesized using a similar procedure described in the synthesis of 14. LCMS: m / z 166 (Boc pattern, M-100) +. Intermediate 18: Synthesis of methyl 3-(piperidin-4-yloxy) propanoate hydrochloride

[0233] Step 1: Synthesis of Intermediate 18a. To a stirred solution of tert-butyl 4- hydroxypiperidine-1-carboxylate (2 g, 9.93 mmol) in DCM (20 mL) was added NMM (1.2 g, 11.92 mmol) at RT followed by methyl propiolate (1 g, 11.92 mmol) and stirred for 3 h at RT under nitrogen atmosphere. After completion of the reaction, the reaction mass was diluted with ice cold water and extracted with DCM followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (2.6 g, 92% yield).1H NMR (DMSO-d6, 400 MHz): 7.64 (d, 1H), 5.71 (d, 1H), 4.37-4.32 (m, 1H), 3.65-3.62 (m, 2H), 3.60 (s, 3H), 3.10-3.05 (m, 2H), 1.99- 1.88 (m, 2H), 1.50-1.47 (m, 2H), 1.45 (s, 9 H).

[0234] Step 2: Synthesis of Intermediate 18b. To a stirred solution of Intermediate 18a (2.6 g, 9.11 mmol) in EtOH (30 mL) was added 10% Pd / C (0.19 g, 1.82 mmol) and stirred under hydrogen gas atmosphere for 3 h at RT. After completion of the reaction, the reaction mixture was filtered through the celite pad to remove palladium carbon, filtrate was collected and concentrated on arotary evaporator to obtain title compound which was used for next step without further purification (2.5 g crude yield).1H NMR (CDCl3, 400 MHz): 3.76-3.70 (m, 7H), 3.50-3.46 (m, 1H), 3.15-3.08 (m, 2H), 2.62 (t, 2H), 1.83-1.79 (m, 2H), 1.56-1.53 (m, 2H), 1.45 (s, 9H).

[0235] Step 3: Synthesis of Intermediate 18. To a stirred solution of Intermediate 18b (2.5 g, 8.7 mmol) in dioxane (4 mL) was added 4 M HCl solution in dioxane (5 mL) and stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction, solvent was evaporated on a rotary evaporator and the reaction mass was washed with diethyl ether and pentane, and dried on a rotary evaporator to obtain title compound (2.2 g crude yield).1H NMR (CDCl3, 400 MHz): 3.76-3.70 (m, 7H), 3.50-3.46 (m, 1H), 3.15-3.08 (m, 2H), 2.62 (t, 2H), 1.83-1.79 (m, 2H), 1.56- 1.53 (m, 2H). Intermediate 19: Synthesis of 2-(1-(tert-butoxycarbonyl) piperidin-4-yl) acetic acid

[0236] Step 1: Synthesis of Intermediate 19a. To a stirred solution of Intermediate 9a (3 g, 11 mmol) in ethanol (10 mL) was added 10% palladium on carbon (2 g, 7.42 mmol) and stirred under hydrogen atmosphere for 4 h. After completion of reaction, reaction mixture was diluted with ethyl acetate and filtered through celite bed. Filtrate was concentrated and dried to obtain title compound which was used for next step without further purification (2.1 g crude). LC-MS: m / z 272.1 (M+H)+.

[0237] Step 2: Synthesis of Intermediate 19. To a stirred solution of Intermediate 19a (1 g, 3.68 mmol) in ethanol (2 mL), water (2 mL) and THF (4 mL) was added lithium hydroxide monohydrate (1.85 g, 44.21 mmol) at 0 °C and stirred for 16 h at RT. After completion of the reaction, reaction mass was concentrated then diluted with water and neutralized with 6N HCl solution then extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate and filtered then filtrate was evaporated on rotary evaporator to obtain title compound which was used for next step without further purification (1.1 g). LC-MS: m / z 242.1 (M+H)+.Intermediate 20: Synthesis of benzyl methyl((4-methylpiperidin-4-yl) methyl) carbamate hydrochloride

[0238] Step 1: Synthesis of Intermediate 20a. To a stirred solution of tert-butyl 4- formylpiperidine-1-carboxylate (5 g, 23.443 mmol) in DMF (20 mL) was added potassium 2- methylpropan-2-olate (5.261 g, 46.880 mmol) at 0 °C and stirred for 1 h at the same temperature. To the resultant solution was added iodomethane (6.655 g, 46.880 mmol) and reaction mixture was brought to RT and stirred for 12 h. After completion of the reaction, reaction mass was diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; the crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (4.7 g, 88.20% yield).1H NMR (CDCl3, 400 MHz): 3.142 (m, 2H), 1.95 (s, 1H), 1.915 (m, 1H), 1.476 (s, 9H), 1.470 (m, 1H), 1.428 (m, 1H), 4.28 (m, 1H), 1.104 (s, 3H). Step 2: Synthesis of Intermediate 20b. To a stirred solution of Int 20a (4.7 g, 20.678 mmol) in methanol (50 mL) was added methylamine (1.417 g, 24.814 mmol) at 0 °C followed by acetic acid (0.200 g, 3.330 mmol). Then reaction mixture was stirred for 12 h at room temperature. To this reaction mixture, was added sodium cyanoborohydride (3.249 g, 51.690 mmol) stirring continued at room temperature for another 16 h. After completion of the reaction, solvent was distilled under reduced pressure, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass, which was purified by combi- flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (4 g, 72.07% yield). LCMS: m / z 243.15 (M+H)+.

[0239] Step 3: Synthesis of Intermediate 20c. To a stirred solution of Int 20b (3.750 g, 13.971 mmol) in THF (50 mL) was added sodium hydroxide (1.118 g, 27.940 mmol) in water (10 mL) at 0 °C and stirred for 10 min at RT. Then, benzyl chloroformate (2.86 g, 16.76 mmol) was added to the reaction mixture and stirred for 16 h at room temperature. After completion of the reaction, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash.The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; the crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (4.8 g, 85.35% yield). LCMS: m / z 321.1 (M-56, Boc pattern).

[0240] Step 4: Synthesis of Intermediate 20. Int 20 was synthesized using a similar procedure described for the synthesis of Int 18. LCMS: m / z 277.1 (M+H)+. Intermediate 21: Synthesis of tert-butyl methyl ((4-methylpiperidin-4-yl) methyl) carbamate hydrochloride

[0241] Step 1: Synthesis of Intermediate 21a. Int 21a was synthesized using a similar procedure described for the synthesis of Int 20b. LCMS: m / z 277.15 (M+H)+.

[0242] Step 2: Synthesis of Intermediate 21b. Int 21b was synthesized using a similar procedure described for the synthesis of Int 15c. LCMS: m / z 321.1 (M-56, Boc pattern).

[0243] Step 3: Synthesis of Intermediate 21. Int 21 was synthesized using a similar procedure described for the synthesis of Int 15. LCMS: m / z 243.2 (M+H)+. Intermediate 22: Synthesis of 2-chloro-6-methylisonicotinohydrazide

[0244] To a stirred solution of methyl 2-chloro-6-methylisonicotinate (5.0 g, 26.93 mmol) in EtOH (20 mL) was added hydrazine hydrate (0.394 g, 3.04 mmol). The resultant solution was then refluxed with constant stirring for 12 h. Completion of the reaction was monitored by TLC. The resultant solution was directly evaporated to dryness and then, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound which was used for the next step without further purification(4.5 g crude).1H NMR (DMSO-d6, 400 MHz): 10.17 (s, bs, 1H), 7.63 -7.62 (m, 2H), 4.92 (s, bs, 2H), 2.52 -2.49 (m, 3H). LCMS: m / z 186.1(M+H)+. Intermediate 23: Synthesis of 2-chloro-5-methylisonicotinohydrazide

[0245] Step 1: Synthesis of Intermediate 23a. To a stirred solution of (5-bromo-2- chloroisonicotinic acid (15 g, 63.44 mmol) in DMF (150 mL) was added K2CO3 (26.3 g, 190.31 mmol) and stirred for 10 mins under inert condition followed by iodomethane (13.5 g, 95.15 mmol) at 0°C in dropwise manner. The resultant solution was stirred at room temperature for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice cold water. The title compound obtained as solid was filtered and dried and was used for further reaction without purification (7.7 g crude yield).1H NMR (CDCl3, 400 MHz): 7.69 (s, 1H), 8.64 (s, 1H), 4.00 (s, 3H).

[0246] Step 2: Synthesis of Intermediate 23b. To a stirred solution of Int 23a (7.7 g, 3.09 mmol), Methylboronic acid (2.76 g, 46.11 mmol) in toluene (126 mL) & water (6.3 mL) in a sealed tube was added K3PO4(22.84 g, 107.5 mmol) and degassed with argon for 10 min. Then, palladium diacetate (0.69 g, 3.07 mmol) and tricyclohexylphosphane (1.724 g, 6.14 mmol) was added and reaction mixture was heated to 100 °C for 16 h. The completion of the reaction was monitored by TLC showing that starting material was consumed, diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine solution dried over sodium sulphate filtered and concentrated to get crude mass. The crude mass was purified by combi-flash by eluting with 4.5% EtOAc / hexane as an eluent to afford title compound (3.26 g, 58.70% yield). LCMS: m / z 186.0 (M+H)+.

[0247] Step 3: Synthesis of Intermediate 23c. To a stirred solution of Int 23b (3.26 g, 17.56 mmol) in THF (65 mL), H2O (16.25 mL) was added LiOH. H2O (0.96 g, 22.83 mmol). The resultant solution was stirred at RT for 2 h. The completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and the remaining solution was acidified using 1N HCl solution and finally extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentratedunder reduced pressure to afford title compound (2.93 g crude yield). The crude mass was used for the next step without further purification. LCMS: m / z 172.0 (M+H)+.

[0248] Step 4: Synthesis of Intermediate 23d. To a stirred solution of Int. 23c (2.93 g, 3.09 mmol) in DMF (30 mL) in a two-neck round bottom flask, tert-butyl N-aminocarbamate (2.27 g, 17.17 mmol) was added and stirred for 5 min, then TBTU (4.39 g, 13.67 mmol) and DIPEA (6.623 g, 51.24 mmol) were added and stirred at room temperature for 16 h. The completion of the reaction was monitored by TLC showing that starting material was consumed, diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine solution dried over sodium sulphate filtered and concentrated to get crude mass. The crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound (3.2 g, 65.67 % yield). LCMS: m / z 286.1 (M+H)+.

[0249] Step 5: Synthesis of Intermediate 23. To a stirred solution of Int 23d (3.2 g, 11.20 mmol) in 1,4 dioxane (10 mL) was added 4M HCl in dioxane (25 mL) in a dropwise manner at 0 °C under argon atmosphere. The resultant mixture was then brought to RT and stirred for 2 h. The completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and washed with pentane to afford title compound (2.47 g crude yield). LCMS: m / z 186.1 (M+H)+.

[0250] The intermediates in Table E were prepared according to the procedure described in Intermediate 23, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table D: IIntermediate 24: Synthesis of 2-chloropyrimidine-4-carbohydrazide

[0251] A mixture of methyl 2-chloropyrimidine-4-carboxylate (2.8 g, 16.2 mmol) and hydrazine hydrate (0.80 g, 16.2 mmol) in methanol (50 mL) was stirred at 0 °C for 1 h. After completion of the reaction, the solid was collected by filtration and washed with hexane to afford the title compound as a yellow solid (1.7 g, 61% yield).1H NMR (DMSO-d6, 400 MHz):10.33(s, 1H), 8.97(d, J = 4.8 Hz, 1H), 7.96 (d, J = 4.8 Hz, 1H), 4.75 (s, 2H). LCMS: m / z 173.0 [M+H]+. Intermediate 25: Synthesis of tert-butyl 3-(3-(hydrazinecarbonyl) phenyl) piperidine-1- carboxylate

[0252] Step 1: Synthesis of Intermediate 25a. A suspension of 3-iodo methyl benzoate (5 g, 19 mmol), N-Boc-1,2,5,6-tetrahydropyridine-3-boronic acid pinacol ester (7 g, 22.9 mmol) and Cs2CO3 (12.4 g, 38.1 mmol) in toluene (20 mL) was purged with argon for 20 min. Then, Pd(dppf)Cl2 (1.4 g, 1.9 mmol) was added, and reaction mixture was heated at 90 °C for 12 h. After completion of the reaction, reaction mixture was filtered through celite bed, filtrate was collected and concentrated on rotary evaporator to get crude mass which was purified by combi flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound as a yellow viscous oil (5.4 g, 89% yield). LCMS: m / z 218 (M-Boc)+.

[0253] Step 2: Synthesis of Intermediate 25b. To a solution of intermediate 25a (5.4 g, 17 mmol) in THF:EtOAc (15 mL:5 mL) was added catalytic amount of acetic acid (0.5 mL) and 10% wetPd / C. Resultant solution was then subjected to autoclave at 40 °C at 100 psi pressure at hydrogen atmosphere for 48 h. After completion of the reaction, the reaction mixture was filtered through celite bed, filtrate was collected and concentrated on rotary evaporator to get crude mass which was used for next step without further purification (5 g crude yield).1H NMR (CDCl3, 400 MHz): 7.93-7.91 (m, 2H), 7.46-7.40 (m, 2H), 4.17-4.11 (m, 2H), 3.93 (s, 3H), 2.77-2.74 (m, 2H), 2.05- 2.00 (m, 1H), 1.81-1.76 (m, 1H), 1.73-1.64 (m, 3H), 1.48 (s, 9H).

[0254] Step 3: Synthesis of Intermediate 25. To a stirred solution of Int.25b (5 g, 15.6 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.64 g, 32.9 mmol) at RT. The resultant solution was then refluxed for 8 h under nitrogen atmosphere. After completion of the reaction, EtOH was evaporated on rotary evaporator and the reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain title compound which was used for next step without further purification (5.8 g crude yield). LC-MS: m / z 220.15 (M-100)+.1H NMR (DMSO-d6, 400 MHz): 9.75 (bs, 1H), 7.85 -7.82 (m, 2H), 7.50 -7.42 (m, 2H), 4.49 (bs, 1H), 4.01- 3.85 (m, 2H), 2.67 -2.61 (m, 2H), 2.60-2.51 (m, 1H), 1.91-1.62 (m, 3H), 1.47-1.44 (m,1H),1.38 (s, 9H). Intermediate 26: Synthesis of 4-bromo-2-(4-(methoxycarbonyl) piperidin-1-yl) benzoic acid

[0255] Step 1: Synthesis of Intermediate 26a. To a stirred solution of tert-butyl 4-bromo-2- fluorobenzoate (3.0 g, 10.90 mmol) in DMSO (10 mL) was added K2CO3(4.52 g, 32.7 mmol) followed by methyl piperidine-4-carboxylate (3.12 g, 21.80 mmol). The resultant solution was then heated with constant stirring at 140 °C for 16 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 15% EtOAc / hexane as an eluent to afford the title compound (3.8 g, 87.49% yield). LCMS: m / z 398.00 (M+H)+.

[0256] Step 2: Synthesis of Intermediate 26. To a stirred solution of Intermediate 26a (3.8 g, 9.54 mmol) in 1,4 dioxane (20 mL) was added Conc. HCl (4 mL) in a dropwise manner at 0 °Cunder argon atmosphere. The resultant solution was then brought to RT and stirred for 2 h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum and washed with pentane to afford the crude mass. The crude mass was purified by combi-flash by eluting with 1% MeOH / DCM as an eluent to afford the title compound (3.0 g, 91.89% yield). LCMS: m / z 341.90 (M+H)+. Intermediate 27: Synthesis of tert-butyl ((1-(5-bromo-2-(5-(2-chloropyridin-4-yl)-1,3,4- oxadiazol-2-yl) phenyl) piperidin-4-yl) methyl)carbamate

[0257] Step 1: Synthesis of Intermediate 27a. To a stirred solution of Intermediate C-3 (8.5 g, 20.56 mmol) in DMF (50 mL) was added TEA (6.24 g, 61.69 mmol) followed by HATU (11.72 g, 30.84 mmol) at 0 °C and the mixture was stirred for 15 min at the same temperature. Then, 2- chloroisonicotinohydrazide (4.23 g, 24.68 mmol) was added to the resultant mixture. The resultant solution was brought to RT and stirred for 12 h. Then, the reaction mixture was poured into ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford the title compound (8.2 g,70.34% yield). LCMS: m / z 568.10 (M+H)+.

[0258] Step 2: Synthesis of Intermediate 27. To a stirred solution of Intermediate 27a (0.30 g, 0.53 mmol) in THF (4 mL) was portion wise added Burgess reagent (0.13 g, 0.52 mmol) at 0 °C and the mixture was stirred for 5 min at the same temperature. The resultant mixture was then refluxed with constant stirring at 65 °C for 2 h. Completion of the reaction was monitored through TLC. Then, the reaction mixture was poured in water and extracted with EtOAc followed by a brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (0.12 g, 41.33 % yield). LCMS: m / z 550.05 (M+H)+.

[0259] The intermediates in Table E were prepared according to the procedure described in Intermediate 27, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table E: I N E EIntermediate 28: Synthesis of tert-butyl ((1-(5-bromo-2-(5-(2-chloropyrimidin-4-yl)-1,3,4- oxadiazol-2-yl) phenyl)-4-methylpiperidin-4-yl) methyl) (methyl)carbamate

[0260] Step 1: Synthesis of Intermediate 28a. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (24 g, 103 mmol) in DMSO (100 mL) was added K2CO3(43 g, 309 mmol) followed by tert-butyl (4-methylpiperidin-4-yl) methyl) carbamate (26 g, 114 mmol). The resultant mixture was then heated with constant stirring at 140 °C for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was used for next step without further purification (42 g crude). LCMS: m / z 441.7 (M+H)+.

[0261] Step 2: Synthesis of Intermediate 28b. To a stirred solution of Int 28a (41 g, 93 mmol) in DMF (40 mL) was added NaH (4.3 g, 186 mmol) followed by methyl iodide (27 g, 186 mmol) at0 °C. The reaction mixture was then brought to RT and stirred for 6 h. The completion of the reaction was monitored by TLC, showing consumption of the starting material. The reaction mass was then quenched with saturated ammonium chloride solution and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain title compound which was used for next step without further purification (41 g crude yield). LC-MS: m / z 455.3 (M+H)+.

[0262] Step 3: Synthesis of Intermediate 28c. To a stirred solution of Int 28b (41 g, 90 mmol) in THF:MeOH:H2O (2:1:1, 400 mL) at 0 °C was added lithium hydroxide (38 g, 900 mmol) and stirred for 5 min at the same temperature. The reaction mixture was then brought to room temperature and stirred for 12 h. The completion of the reaction was monitored by TLC. After completion of the reaction, solvents were evaporated in vacuo. The residue was diluted with water (10 mL) and acidified by using saturated citric acid solution to pH 5-6, extracted with ethyl acetate followed by cold brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain title compound as a pale brown solid (39 g crude yield). LCMS: m / z 441.3 (M+H)+.

[0263] Step 4: Synthesis of Intermediate 28d. To a stirred solution of Int.28c (4 g, 9 mmol) in DMF (20 mL) was added TEA (2.8 g, 27 mmol) followed by HATU (5.2 g, 13.6 mmol) at 0 °C and stirred for 10 min. After 10 min, 2-chloropyrimidine-4-carbohydrazide (1.9 g, 11 mmol) was added to the resultant mixture and the resultant mixture was stirred at RT for 12 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (1.5 g, 28% yield). LCMS: m / z 596.75 (M+H)+.

[0264] Step 5: Synthesis of Intermediate 28. Int 28 was synthesized using a similar procedure described for the synthesis of Int 27. LCMS: m / z 578.75 (M+H)+. Int.28’ was also synthesized by the similar procedure as of Int.28. LCMS: m / z 563.2 (M+H)+.

[0265] The intermediates in Table F were prepared according to the procedure described in Intermediate 28, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table F: IF FIntermediate 29: Synthesis of 44-bromo-54,7-dimethyl-7-aza-3 (2,5)-oxadiazola-2(2,4)- pyridina-1(1,3), 5(1,4)-dipiperidina-4(1,2)-benzenacyclooctaphaneStep 1: Synthesis of Intermediate 29a. Intermediate 29a was synthesized from similar procedure reported for intermediate 26

[0266] Step 2: Synthesis of Intermediate 29b. To a stirred solution of Int 29a (0.6 g, 1.25 mmol) and tert-butyl 3-formylpiperidine-1-carboxylate (0.32 g, 1.5 mmol) in EtOH (10 mL) and THF (2 mL) was added AcOH (5 mL). The resultant solution was stirred at RT for 12 h. Further, sodium triacetoxy borohydride (1.2 g, 5.75 mmol) was added and again stirred for 4 h. The completion of the reaction was monitored using TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound. (0.7 g, 95.23% yield). LCMS: m / z 673.15 (M+H)+.

[0267] Step 3: Synthesis of Intermediate 29c. To a stirred solution of Int 29b (0.7 g, 1.03 mmol) in 1,4-dioxane (3 mL) was added 4M dioxane HCl (3 mL). The resultant solution was stirred at RT for 2 h. The completion of the reaction was monitored using TLC. The resultant mixture was concentrated under high vacuum, then triturated with diethyl ether and decanted. The obtainedsolid was dried under high vacuum to afford title compound which was used for next step without further purification. (0.9 g crude product). LCMS: m / z 573.10 (M+H)+.

[0268] Step 4: Synthesis of Intermediate 29. To a stirred solution of Int 29c (1.4 g, 2.29 mmol) in DMSO (6 mL) was added CsF (1.04 g, 6.88 mmol). The reaction mixture was then heated with constant stirring at 140 °C for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi- flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound. (0.60 g, 48.67% yield). LCMS: m / z 537.05 (M+H)+. Intermediate 30: Synthesis of 2-(2-(4-allylpiperidin-1-yl)-4-bromophenyl)-5-(2- chloropyridin-4-yl)-1,3,4-oxadiazola

[0269] Step 1: Synthesis of Intermediate 30a. Intermediate 30a was prepared using a similar procedure described for the synthesis of Intermediate 27a. LC-MS: m / z 478.95 (M+H)+.

[0270] Step 2: Synthesis of Intermediate 30. A mixture of Intermediate 30a (3.6 g, 7.53 mmol) in POCl3(20 mL) was heated at 90 °C for 2 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into cold water and quenched with a saturated solution of sodium carbonate to pH 8-9. Then, the mixture was extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford the title compound (2.8 g, 81% yield). LCMS: m / z 459.2 (M+H)+.

[0271] The intermediates in Table G were prepared according to the procedure described in Intermediate 30, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table G: I N G G G GIntermediate 31: Synthesis of 2-(2-(4-(allyloxy)-4-methylpiperidin-1-yl)-4-bromophenyl)-5- (2-chloropyrimidin-4-yl)-1,3,4-oxadiazole

[0272] Step 1: Synthesis of Intermediate 31a. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (21 g, 90.112 mmol) in DMSO (250 mL) was added potassium carbonate (37.36 g, 138.2 mmol) and Int 12 (20.73 g, 191.7 mmol) and the reaction mass was heated at 140 °C for16 h. After completion of the reaction, reaction mass was diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass; the crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (25.5 g, 76.24% yield). LC-MS: m / z 368.26 (M+H)+.

[0273] Step 2: Synthesis of Intermediate 31b. To a stirred solution of Int 31a (25.5 g, 69.24 mmol) in THF (200 mL), MeOH (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (29.05 g, 692.43 mmol) and reaction mixture was stirred at RT for 12 h. After completion of the reaction, reaction mass was evaporated using rota vapor, adjusted to pH 6 using 2N HCl solution, extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain title compound (27.5 g crude yield). LC-MS: m / z 354.2389 (M+H)+.

[0274] Step 3: Synthesis of Intermediate 31c. To a stirred solution of Int 31b (14 g, 39.52 mmol) in dry DMF (150 mL) under inert atmosphere was added DIPEA (15.32 g, 129.25 mmol) followed by PyAOP (24.72 g, 47.42 mmol) at RT. The resulting mixture was stirred at RT for 5 min. Then, 2-chloropyrimidine-4-carbohydrazide, Int 9 (6.82g, 39.52 mmol) was added and the resultant mixture was stirred at RT for 2 h. After completion of the reaction, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass; the crude mass was purified by combi-flash by eluting with 30%-40% EtOAc / hexane as an eluent to afford title compound (6.4 g, 31.83% yield). LC-MS: m / z 508.79 (M+H)+.

[0275] Step 4: Synthesis of Intermediate 31. To a stirred solution of Int 31c (6.4g, 12.58 mmol) in THF (60 mL) was added Burgess reagent (7.98 g, 75.47 mmol) at 0 °C. The resultant mixture was stirred at 65 °C for 1 h. Then, reaction mixture was brought to room temperature. After completion of the reaction, reaction mass was added with water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass; the crude mass was purified by combi- flash by eluting with 30%-40% EtOAc / hexane as an eluent to afford title compound (5.8 g, 93.95% yield). LC-MS: m / z 490.78 (M+H)+.

[0276] The intermediate in Table H was prepared according to the procedure described in Intermediate 31, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table H: IIntermediate 32: Synthesis of methyl 1-(5-bromo-2-(5-(2-chloropyridin-4-yl)-1,3,4- oxadiazol-2-yl) phenyl) piperidine-4-carboxylate

[0277] Step 1: Synthesis of Intermediate 32a. Intermediate 32a was prepared using a similar procedure described for the synthesis of Intermediate 27a. LC-MS: m / z 494.95 (M+H)+.

[0278] Step 2: Synthesis of Intermediate 32. Intermediate 32 was prepared using a similar procedure described for the synthesis of Intermediate 27. LC-MS: m / z 476.90 (M+H)+. Intermediate 33: Synthesis of methyl 1-(5-bromo-2-(5-(2-chloro-6-methylpyridin-4-yl)-1,3,4- oxadiazol-2-yl) phenyl) piperidine-4-carboxylate

[0279] Step 1: Synthesis of Intermediate 33a. Intermediate 33a was prepared using a similar procedure described for the synthesis of Intermediate 27a. LC-MS: m / z 508.95 (M+H)+.

[0280] Step 2: Synthesis of Intermediate 33. Intermediate 33 was prepared using a similar procedure described for the synthesis of Intermediate 27. LC-MS: m / z 490.90 (M+H)+.Intermediate 34: Synthesis of tert-butyl ((1-(5-bromo-2-(5-(2-chloropyridin-4-yl)-1,3,4- oxadiazol-2-yl) phenyl)-4-methylpiperidin-4-yl) methyl) (methyl) carbamate

[0281] To a stirred solution of Intermediate E-1 (2 g, 3.5 mmol) in DMF (15 mL) was added NaH (0.21 g, 5.2 mmol) followed by methyl iodide (0.6 g, 4.96 mmol) at 0 °C. The reaction mixture was then brought to RT and stirred for 2 h. Completion of the reaction was monitored by TLC, showing consumption of the starting material. The reaction mass was then quenched with a saturated ammonium chloride solution and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain the title compound which was used for the next step without further purification (2 g crude yield). LC-MS: m / z 576.10 (M+H)+. Intermediate 35: Synthesis of 44-bromo-7-aza-3(2,5)-oxadiazola-2(2,4)-pyridina- 1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclooctaphan-8-one

[0282] Step 1: Synthesis of Intermediate 35a. To a stirred solution of Intermediate 27 (0.38 g, 0.69 mmol) in DMSO (5 mL) was added DIPEA (0.27 g, 2.08 mmol) followed by methyl piperidine-3-carboxylate (0.15 g, 1.03 mmol). The resultant solution was then heated with constant stirring at 140 °C for 16 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, andconcentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (0.22 g, 48 % yield). LCMS: m / z 655.20 (M+H)+.

[0283] Step 2: Synthesis of Intermediate 35b. To a stirred solution of Intermediate 35a (0.21 g, 0.32 mmol) in THF (2 mL), MeOH (2 mL), H2O (2 mL) was added LiOH.H2O (0.28 g, 6.52 mmol). The resultant solution was stirred at RT for 16 h. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum pressure and the remaining solution was neutralized using saturated citric acid solution and subsequently extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (0.4 g crude) which used in the next reaction without purification. LCMS: m / z 641.15 (M+H)+.

[0284] Step 3: Synthesis of Intermediate 35c. To a stirred solution of Intermediate 35b (0.4 g, 0.61 mmol) in dioxane (5 mL) was added 4 M HCl solution in dioxane (3 mL) and the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and washed with pentane to afford the title compound which was dried under high vacuum and used for the next step without further purification (0.4 g crude product). LCMS: m / z 541.10 (M+H)+.

[0285] Step 4: Synthesis of Intermediate 35. To a stirred solution of Intermediate 35c (0.4 g, 0.72 mmol) was added TEA (0.219 g, 2.16 mmol) followed by HATU (0.41 g, 1.08 mmol) at 0 °C and the mixture was stirred for 10 min at the same temperature. Then, the reaction mixture was brought to room temperature and stirred for 12 h. After completion of the reaction, the reaction mass was poured into ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to give the crude mass which was purified by combi-flash chromatography by using 50% EtOAc / hexane as an eluent to afford the title compound (0.06 g, 15% yield). LCMS: m / z 523.10 (M+H)+.Intermediate 36: Synthesis of N-(7-methyl-8-oxo-7-aza-3 (2,5)-oxadiazola-2 (2,4)-pyridina-1 (1,3), 5 (1,4)-dipiperidina-4 (1,2)-benzenacyclooctaphane-44-yl) cyclopropanesulfonamide

[0286] Step 1: Synthesis of Intermediate 36a. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (10 g, 42.9 mmol) in DMSO (10 mL) was added K2CO3(17.8 g, 128.7 mmol) followed by addition of tert-butyl (4-methylpiperidin-4-yl) carbamate (11.1 g, 47.2 mmol). The reaction mixture was heated under constant stirring at 140 °C for 16 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by washing with brine. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (11.5 g, 62.7% yield). LC-MS: m / z 429.00 (M+H)+.

[0287] Step 2: Synthesis of Intermediate 36b. To a stirred solution of Int 36a (11 g, 25.7 mmol) in DMF (100 mL), NaH (1.2 g, 41.5 mmol) was added at 0 °C and stirred for 5 min. After that Iodomethane (7.3 g, 51.5 mmol) was added. Reaction mixture was stirred at RT for 2 h. After completion of reaction, reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4and evaporated to dryness to afford title compound which was used for next step without further purification (11 g crude). LC-MS: m / z 433.4 (M+H)+.

[0288] Step 3: Synthesis of Intermediate 36c. To a stirred solution of Int 36b (11 g, 24.9 mmol) in THF (50 mL), MeOH (25 mL), H2O (25 mL) and LiOH. H2O (6.3 g, 149.5 mmol) were added. The reaction mixture was stirred at RT for 12 h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and the resultant mixture was neutralised using 1N HCl and then extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound which was used for next step without further purification (10.5 g crude). LC-MS: m / z 429.2 (M+H)+.

[0289] Step 4: Synthesis of Intermediate 36d. To a stirred solution of Int 36c (10.5 g, 24.6 mmol) in DMF (50 mL) was added TEA (7.5 g, 73.7 mmol) followed by addition of HATU (18.7 g, 49.1 mmol), and stirred for 15 min. Then, 2-chloroisonicotinohydrazide (5.1 g, 29.5 mmol) was added to the reaction mixture and the resultant solution was stirred at RT for 12 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to title compound. (9.5 g, 66.6% yield). LC-MS: m / z 582.2 (M+H)+.

[0290] Step 5: Synthesis of Intermediate 36e. To a stirred solution of Int 36d (9.5 g 16.3 mmol) in THF (100 mL) was added burgess reagent (7.8 g, 32.7 mmol) in portion wise manner. The reaction mixture was then refluxed with constant stirring at 65°C for 3 h. Completion of the reaction was monitored through TLC. Then, reaction mixture was poured in water and extracted with EtOAc followed by a brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound which was used for next step without further purification (9.5 g crude). LC-MS: m / z 564.4 (M+H)+.

[0291] Step 6: Synthesis of Intermediate 36f. To a stirred solution of Intermediate 36e (9.5 g, 16.9 mmol) in DMSO (100 mL) was added DIPEA (6.6 g, 50.6 mmol) followed by addition of methyl piperidine-3-carboxylate (3.6 g, 25.3 mmol). The reaction mixture was then heated with constant stirring at 140 °C for 48 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound. (6 g, 53.1% yield). LC- MS: m / z 671.6 (M+H)+.

[0292] Step 7: Synthesis of Intermediate 36g. To a stirred solution of Int.36f (6 g 8.9 mmol) in THF (15 mL), MeOH (7.5 mL), H2O (7.5 mL) and LiOH.H2O (2.3 g, 53.7 mmol) were added. The reaction mixture was stirred at RT for 12h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and the remaining solution was neutralised using 1N HCL and finally extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound (5 g crude). LC-MS: m / z 657.3 (M+H)+.

[0293] Step 8: Synthesis of Intermediate 36h. To a solution of Int.36g (4 g, 6.1 mmol) in 4M- HCl in 14-dioxane (40 mL) was stirred at RT for 2 h. Completion of the reaction was monitored using TLC. The resultant mixture was concentrated under high vacuum, then triturated with diethyl ether and de-canned. The obtained solid was dried under high vacuum to afford title compound (4 g crude yield). LC-MS: m / z 557.3 (M+H)+.

[0294] Step 9: Synthesis of Intermediate 36. To a stirred solution of Int.36h (0.5 g, 1 mmol) in DMF (5 mL) was added DIPEA (0.45 g, 4.5 mmol) followed by T3P (3 g, 9 mmol). The reaction mixture was stirred at RT for 5 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (0.1 g, 15.51% yield). LC- MS: m / z 537.2 (M+H)+.

[0295] The intermediates in Table I were prepared according to the procedure described in Intermediate 35, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table I: I N I- I-I-Intermediate 37: Synthesis of 44-bromo-54, 7-dimethyl-7-aza-3 (2,5)-oxadiazola-2 (2,4)- pyrimidina-1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclooctaphan-8-one

[0296] Step 1: Synthesis of Intermediate 37a. Int 37a was synthesized using a similar procedure described for the synthesis of Int 36f. LCMS: m / z 684.00 (M+H)+.

[0297] Step 2: Synthesis of Intermediate 37b. Int 37b was synthesized using a similar procedure described for the synthesis of Int 36g. LCMS: m / z 670.84 (M+H)+.

[0298] Step 3: Synthesis of Intermediate 37c. Int 37c was synthesized using a similar procedure described for the synthesis of Int 36h. LCMS: m / z 570.84 (M+H)+.

[0299] Step 4: Synthesis of Intermediate 37. Int 37 was synthesized using a similar procedure described for the synthesis of Int 28d. LCMS: m / z 552.75 (M+H)+.

[0300] The intermediates in Table J were prepared according to the procedure described in Intermediate 37, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table J:Intermediate 38: Synthesis of 44-bromo-54,7-dimethyl-7-aza-3(2,5)-oxadiazola-2(2,4)- pyridina-5(1,4)-piperidina-1(1,3)-pyrrolidina-4(1,2)-benzenacyclooctaphan-8-one

[0301] Step 1: Synthesis of Intermediate 38a. Intermediate 38a was synthesized using a similar procedure described in the synthesis of Int 36h.LCMS: m / z 476.30 (M+H) +.

[0302] Step 2: Synthesis of Intermediate 38b. Intermediate 38b was synthesized using a similar procedure described in the synthesis of Int 36d. LCMS: m / z 673.6 (M+H)+.

[0303] Step 3: Synthesis of Intermediate 38c. Intermediate 38c was synthesized using a similar procedure described in the synthesis of Int 36h. LCMS: m / z 573.6 (M+H)+.

[0304] Step 4: Synthesis of Intermediate 38. To a stirred solution of Int 38c (1.4 g, 2.29 mmol) in DMSO (6 mL) was added CsF (1.04 g, 6.88 mmol). The reaction mixture was then heated with constant stirring at 140 °C for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi- flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound. (0.60 g, 48.67% yield). LCMS: m / z 537.3 (M+H)+.

[0305] The intermediates in Table K were prepared according to the procedure described in the synthesis of Intermediate 38, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table K:Intermediate 39: Synthesis of 44-bromo-54,7-dimethyl-7-aza-3(2,5)-oxadiazola-2(2,4)- pyridina-1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacycloheptaphan-6-one

[0306] Step 1: Synthesis of Intermediate 39a. To a stirred solution of 1-(tert-butoxycarbonyl)- 4-methylpiperidine-4-carboxylic acid (10.5 g, 43.15 mmol) in DMF (200 mL) was added K2CO3(6.5 g, 47.47 mmol) followed by MeI (12.25 g, 86.31 mmol) and stirred at RT for 16 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain title compound which was purified by combi-flash by eluting with 30 % EtOAc / hexane as an eluent (11.10 g, 99.95 % yield). LCMS: m / z 158.1 (M+H)+

[0307] Step 2: Synthesis of Intermediate 39b. To a stirred solution of Int 39a (11 g, 42.74 mmol) in DCM (50 mL) was added 4M dioxane HCl (20 mL) in dropwise manner at 0oC and stirred at RT for 8 h. After completion of the reaction, solvent was evaporated under reduced pressure to obtain the residue which was washed with pentane and then dried under high vacuum to afford title compound which was used for next step without further purification (12 g crude). (1H NMR DMSO-d6, 400 MHz):8.97 (bs, 1H), 3.67 (s, 1H), 3.16-3.17 (m, 2H), 2.85-2.83 (m, 2H), 2.07-2.04 (m, 2H),1.68-1.65 (m, 2H), 1.19 (s, 3H).

[0308] Step 3: Synthesis of Intermediate 39c. To a stirred solution of 4-bromo-2-fluorobenzoic acid (6 g, 27.39 mmol) and Int 39b (12 g, 76.94 mmol) in DMSO (70 mL) was added K2CO3(11.35 g, 86.19 mmol) at RT. Reaction mixture was then stirred at 120 °C for 16 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain crude mass, which was purified by eluting with 30 % EtOAc / hexane as an eluent to afford title compound (4.8 g, 49.19 % yield). LCMS: m / z 356.1 (M+H)+.

[0309] Step 4: Synthesis of Intermediate 39d. To a stirred solution of Int 39c (1.1 g, 3.08 mmol) in DMF (20 mL) was added TEA (0.937 g, 9.26 mmol) followed by HATU (1.76 g, 4.63 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, 2-chloroisonicotinohydrazide (0.689 g, 4.01mmol) was added to the resultant solution and reaction mixture was stirred at RT for 12 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain crude mass, which was purified by eluting with 30 % EtOAc / hexane as an eluent to afford title compound (0.99 g, 62.89 % yield). LCMS: m / z 509.1 (M+H)+.

[0310] Step 5: Synthesis of Intermediate 39e. To a stirred solution of Int 39d (0.96 g, 1.88 mmol) in THF (20 mL) was added Burgess reagent (1.8 g, 7.53 mmol) at 0 °C. Reaction mixture was then stirred at 65°C for 1 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain title compound, which was used for next step without further purification (1 g crude). LCMS: m / z 491.1 (M+H)+.

[0311] Step 6: Synthesis of Intermediate 39f. To a stirred solution of Int 39e (0.5 g, 101 mmol) and tert-butyl methyl (piperidin-3-yl) carbamate (0.327 g, 1.52 mmol) in DMF (10 mL) was added K2CO3 (0.463 g, 3.05 mmol) at RT. Reaction mixture was then stirred at 140 °C for 16 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain title compound, which was used for next step without further purification (0.85 g crude). LCMS: m / z 569.2 (M+H)+.

[0312] Step 7: Synthesis of Intermediate 39g. To a stirred solution of Int 39f (0.850 g, 1.26 mmol) in MeOH:THF (2 mL:20 mL) was added LiOH.H2O. (0.533 g, 12.69 mmol) in water (5 mL). Reaction mixture was then stirred at RT for 48 h. After completion of the reaction, solvents were evaporated under reduced pressure. The residue was collected and dissolved in ice cold water, acidified with 1N HCl solution and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain title compound, which was used for next step without further purification (0.8 g crude). LCMS: m / z 655.3 (M+H)+.

[0313] Step 8: Synthesis of Intermediate 39h. Intermediate 39h was synthesized using a similar procedure as described in the synthesis of Int29c. LCMS: m / z 555.3 (M+H)+.

[0314] Step 9: Synthesis of Intermediate 39. Intermediate 39 was synthesized using a similar procedure as described in the synthesis of Int 39d. LCMS: m / z 537.2 (M+H)+.

[0315] The intermediate in Table L was prepared according to the procedure described in the synthesis of Intermediate 39, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table L: I n LIntermediate 40: Synthesis of (E)-44-bromo-6-oxa-3(2,5)-oxadiazola-2(2,4)-pyridina-1(1,3)- piperidina-5(1,3)-azetidina-4(1,2)-benzenacyclodecaphan-7-ene

[0316] Step 1: Synthesis of Intermediate 40a. To a stirred solution of sodium hydride 60% dispersion in mineral oil (1.99 g, 86.60 mmol) in THF (30 mL) was added tert-butyl 3- hydroxyazetidine-1-carboxylate (5.0 g, 28.86 mmol) and stirred for 15 min. Then, the reaction mixture was cooled to 0 °C and 3-bromoprop-1-ene (6.985 g, 57.73 mmol) was added to it. The resultant mixture was then stirred at room temperature for 12 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (3.8 g, 56.85% yield).1H NMR (DMSO-d6, 400 MHz): 5.95-5.88 (m, 1H), 5.34-5.28 (m, 1H), 5.24-5.21 (m, 1H), 4.29-4.26 (m, 1H), 4.10-4.01 (m, 2H), 3.95-3.93 (m, 2H), 5.95-5.88 (m, 1H), 3.88-3.84 (m, 2H), 1.45 (s, 9H).

[0317] Step 2: Synthesis of Intermediate 40b. To a stirred solution of Int. 40a (3.8 g, 17.87 mmol) in 1,4 dioxane (15 mL) was added 4M HCl in dioxane (10 mL) in a dropwise manner at 0 °C under argon atmosphere. The reaction mixture was then brought to RT and stirred for 2 h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and washed with pentane to afford title compound which was used for next step without further purification (3.5 g crude yield). LCMS: m / z 114.1(M+H)+.

[0318] Step 3: Synthesis of Intermediate 40c. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (5.0 g, 21.45 mmol) in DMSO (8 mL) was added K2CO3 (8.96 g, 64.36 mmol) followed by Int.40b (3.21 g, 21.45 mmol). The reaction mixture was then heated under constant stirring at 140 °C for 3 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (5.0 g, 71.44% yield). LCMS: m / z 328.0(M+H)+.

[0319] Step 4: Synthesis of Intermediate 40d. To a stirred solution of Int. 40c (2.0 g, 6.131 mmol) in THF (8mL), MeOH (8 mL), H2O (8 mL) and NaOH (1.22 g, 30.65 mmol) were added. The reaction mixture was stirred at RT for 12 h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and the remaining solution was neutralised using saturated citric acid solution and extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound (2.5 g crude yield). LCMS: m / z 314.00 (M+H)+.

[0320] Step 5: Synthesis of Intermediate 40e. To a stirred solution of Int. 40d (2.3 g, 7.368 mmol) in DMF (5 mL) was added TEA (2.237 g, 22.10 mmol) followed by HATU (4.2 g, 11.05 mmol) at 0 °C and stirred for 10 min. After 10 min, 2-chloroisonicotinohydrazide (1.517 g, 8.842 mmol) was added to the reaction mixture. The reaction mixture was stirred at RT for 12 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to affordcrude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (2.7 g, 78.68% yield). LCMS: m / z 466.95 (M+H)+.

[0321] Step 6: Synthesis of Intermediate 40f. To a stirred solution of Int.40e (2.5 g, 5.368 mmol) in THF (10 mL) was added burgess reagent (3.198 g, 13.42 mmol) in portion wise manner. The reaction mixture was then refluxed with constant stirring at 65 °C for 1 h. The completion of the reaction was monitored through TLC. Then, reaction mixture was poured in water and extracted with EtOAc followed by a brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound (1.8 g, 74.90 % yield). LCMS: m / z 448.90 (M+H)+.

[0322] Step 7: Synthesis of Intermediate 40g. To a stirred solution of Int.40f (1.5 g, 3.35 mmol) in NMP (5 mL) was added DIPEA (2.165 g, 16.75 mmol) followed by 3-allylpiperidine hydrochloride (0.65 g, 4.019 mmol). The reaction mixture was then heated with constant stirring at 140 °C for 48 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (0.5 g, 27.82% yield). LCMS: m / z 536.10(M+H)+.

[0323] Step 8: Synthesis of Intermediate 40. To a stirred solution of Int.40g (0.1 g, 0.186 mmol) in DCM (10 mL) was added Grubbs catalyst 2nd generation (0.032 g, 0.03 mmol) and resultant solution was stirred at 40 °C for 12 h. After completion of reaction, the reaction mixture was filtered using celite bed. The filtrate was evaporated to get crude mass. The crude mass was purified by combi flash using 20%EtOAc / hexane to afford title compound (0.24 g, 63.45% yield). LCMS: m / z 508.05 (M+H) +. Intermediate 41: Synthesis of (Z)-44-bromo-3(2,5)-oxadiazola-2(2,4)-pyridina-1(1,3),5(1,4)- dipiperidina-4(1,2)-benzenacyclooctaphan-7-ene

[0324] Step 1: Synthesis of Intermediate 41a. To a stirred solution of Intermediate 30 (0.6 g, 1.34 mmol) in DMSO (5 mL) was added DIPEA (0.50 g, 3.91 mmol) followed by Intermediate-3 (0.29 g, 1.96 mmol). The resultant solution was then heated with constant stirring at 140 °C for 24 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (0.4 g, 57% yield). LCMS: m / z 534.10 (M+H)+.

[0325] Step 2: Synthesis of Intermediate 41. To a stirred solution of 41a (0.4 g, 0.75 mmol) in DCM (10 mL) was added Grubbs second generation catalyst (0.127 g, 0.15 mmol) and the resultant suspension was refluxed for 6 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was filtered on celite bed, the filtrate was collected and evaporated on rota vapor. The crude mass was purified by combi flash by eluting with 20% EtOAc / hexane as an eluent to afford the desired product (0.21 g, 55.4% yield). LCMS: m / z 506.05 (M+H)+.

[0326] The intermediates in Table M were prepared according to the procedure described in Intermediate 41, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table M: I N M MM M M M MIntermediate 42: Synthesis of 2-(2-(4-(allyloxy) piperidin-1-yl)-4-bromophenyl)-5-(2- chloropyridin-4-yl)-1,3,4-oxadiazole

[0327] Step 1: Synthesis of Intermediate 42a. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (1.4 g, 6.0 mmol) in DMSO (10 mL) was added 4-allyloxypiperidine hydrochloride (1.16 g, 7.21 mmol) followed by adding K2CO3(2.49 g, 18 mmol) at 0 °C and stirred for 5 min at the same temperature. The reaction mixture was then heated at 140 °C and 16h. Completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water and extracted with ethyl acetate. The organic layer was washed with cold water followed by brine, dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude oil which was purified by combi flash by eluting with 20%EtOAc / hexane to afford the title compound (1.4 g, 68.9% yield). LC-MS: m / z 354.24 (M+H)+.

[0328] Step 2: Synthesis of Intermediate 42b. To a stirred solution of Int-42a (1.4 g, 4.14 mmol) in THF:MeOH:H2O (2:1:1, 12 mL) at 0 °C was added lithium hydroxide (2.08 g, 49.66 mmol) and stirred for 5 min at the same temperature. The reaction mixture was then brought to room temperature and stirred for 24 h. Completion of the reaction was monitored by TLC. After completion of the reaction, solvents were evaporated in vacuo. The residue was diluted with water (10 mL) and acidified by 2N HCl to pH 5-6, extracted with ethyl acetate followed by cold brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain pale brown solid (2 g crude yield). LCMS: m / z 340.05 (M+H)+.

[0329] Step 3: Synthesis of Intermediate 42c. Intermediate 42c was synthesized using a similar procedure described in the synthesis of 40e. LC-MS: m / z 494.95 (M+H)+.

[0330] Step 4: Synthesis of Intermediate 42. Intermediate 42 was synthesized using a similar procedure described in the synthesis of 40f. LC-MS: m / z 476.95 (M+H)+.Intermediate 43: Synthesis of 2-(2-(4-(allyloxy) piperidin-1-yl)-4-bromophenyl)-5-(2- fluoropyridin-4-yl)-1,3,4-oxadiazole

[0331] Step 1: Synthesis of Intermediate 43a. Int 43a was synthesized using a similar procedure described for the synthesis of Int 28d. LCMS: m / z 477.05 (M+H)+.

[0332] Step 2: Synthesis of Intermediate 43. Int 43 was synthesized using a similar procedure described for the synthesis of Int 28. LCMS: m / z 459.05 (M+H)+. Intermediate 44: Synthesis of 2-(2-(4-(allyloxy)-4-methylpiperidin-1-yl)-4-bromophenyl)-5- (2-chloropyrimidin-4-yl)-1,3,4-oxadiazole

[0333] Step 1: Synthesis of Intermediate 44a. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (21 g, 90.112 mmol) in DMSO (250 mL) was added potassium carbonate (37.36 g, 138.2 mmol) and Int 8 (20.73 g, 191.7 mmol) and the reaction mass was heated at 140 °C for 16 h. After completion of the reaction, reaction mass was diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass; the crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (25.5 g, 76.24% yield). LC-MS: m / z 368.26 (M+H)+.

[0334] Step 2: Synthesis of Intermediate 44b. To a stirred solution of Int 44a (25.5 g, 69.24 mmol) in THF (200 mL), MeOH (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (29.05 g, 692.43 mmol) and reaction mixture was stirred at RT for 12 h. After completion of the reaction, reaction mass was evaporated using rota vapor, adjusted to pH 6 using 2N HCl solution, extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain title compound (27.5 g crude yield). LC-MS: m / z 354.2389 (M+H)+.

[0335] Step 3: Synthesis of Intermediate 44c. To a stirred solution of Int 44b (14 g, 39.52 mmol) in dry DMF (150 mL) under inert atmosphere was added DIPEA (15.32 g, 129.25 mmol) followed by PyAOP (24.72 g, 47.42 mmol) at RT. The resulting mixture was stirred at RT for 5 min. Then, 2-chloropyrimidine-4-carbohydrazide, (6.82g, 39.52 mmol) was added and the resultant mixture was stirred at RT for 2 h. After completion of the reaction, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass; the crude mass was purified by combi-flash by eluting with 30%-40% EtOAc / hexane as an eluent to afford title compound (6.4 g, 31.83% yield). LC-MS: m / z 508.79 (M+H)+.

[0336] Step 4: Synthesis of Intermediate 44. To a stirred solution of Int 44c (6.4g, 12.58 mmol) in THF (60 mL) was added Burgess reagent (7.98 g, 75.47 mmol) at 0 °C. The resultant mixture was stirred at 65 °C for 1 h. Then, reaction mixture was brought to room temperature. After completion of the reaction, reaction mass was added with water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass; the crude mass was purified by combi- flash by eluting with 30%-40% EtOAc / hexane as an eluent to afford title compound (5.8 g, 93.95% yield). LC-MS: m / z 490.78 (M+H)+.

[0337] The intermediate in Table N was prepared according to the procedure described in Intermediate 44, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table N: I N NIntermediate 45: Synthesis of (Z)-44-bromo-6-oxa-3(2,5)-oxadiazola-2(2,4)-pyridina- 1,5(1,4)-dipiperidina-4(1,2)-benzenacyclodecaphan-8-ene

[0338] Step 1: Synthesis of Intermediate 45a. Int 45a was synthesized using a similar procedure described in the synthesis of Int.40g. LCMS: m / z 564.15 (M+H)+.

[0339] Step 2: Synthesis of Intermediate 45. Int 45 was synthesized using a similar procedure described in the synthesis of Int.40. LCMS: m / z 536.10 (M+H) +. Intermediate 46: Synthesis of (Z)-2-hydroxy-N-(6-oxa-3 (2,5)-oxadiazola-2 (2,4)-pyridina-1,5 (1,4)-dipiperidina-4(1,2)-benzenacyclononaphan-8-en-44-yl)ethane-1-sulfonamide

[0340] Step 1: Synthesis of Intermediate 46a. To a stirred solution of Int 43 (0.50 g, 1.08 mmol) and tert-butyl 4-vinylpiperidine-1-carboxylate, Int 5 (0.27 g, 1.30 mmol) in DCM (50 mL) was added Grubbs catalyst 2nd generation (0.13 g, 0.21 mmol) and reaction mixture was stirred at 40 °C for 12 h. After completion of reaction, the resultant solution was filtered using celite bed. The organic layer was evaporated to get crude mass. The crude mass was purified by combi flash using 30% EtOAc / hexane to afford title compound (0.35 g, 50.35 %). LCMS: m / z 644.05 (M+H)+.

[0341] Step 2: Synthesis of Intermediate 46b. To a stirred solution of Int 46a (0.2 g, 0.3 mmol) in DCM (20 mL) was added TFA (0.5 mL) in a dropwise manner at 0 °C under argon atmosphere. The resultant solution was stirred at same temperature for 0.5 h. The completion of the reaction was monitored using TLC. The reaction mixture was concentrated under reduced pressure and washed with pentane to afford title compound which was used for next step without further purification (0.1 g crude). LCMS: m / z 542.2 (M+H)+.

[0342] Step 3: Synthesis of Intermediate 46c. To a stirred solution of Int 46b (0.1 g, 0.18 mmol) in DMSO (3 mL) was added Caesium fluoride (0.08 g, 0.55 mmol). The resultant mixture was then heated with constant stirring at 100 ℃ for 12 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (0.12 g, 54.09% yield). LCMS: m / z 522.15 (M+H)+.

[0343] Step 4: Synthesis of Intermediate 46. To a stirred solution of Int 46c (0.05g, 0.09 mmol), 2-hydroxyethane sulphonamide (0.014 g, 0.11 mmol) in 1,4 dioxane (3 mL) in a sealed tube was added K3PO4 (0.61 g, 0.28 mmol) and degassed with argon for 10 min. Then, palladium (II)(π- cinnamyl) chloride dimer (0.002g, 0.01 mmol) and tBuXPhos (0.004 g, 0.02 mmol) were added and reaction mixture was heated to 90 °C for 3 h. The completion of the reaction was monitored by TLC showing that starting material was consumed, reaction mixture was filtered through celite bed, diluted with water and extracted with EtOAc. The organic layer was washed with brine solution dried over sodium sulphate filtered and concentrated to get crude mass. The crude mass was purified by combi-flash by eluting with 10% MeOH / DCM as an eluent to afford title compound (0.052 g, 95.59 % yield). LCMS: m / z 567.20(M+H)+.

[0344] The intermediate in Table O was prepared according to the procedure described in Intermediate 46, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table O: I N OIntermediate 47: Synthesis of (Z)-2-hydroxy-N-(54-methyl-6-oxa-3(2,5)-oxadiazola-2(2,4)- pyrimidina-1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclononaphan-8-en-44-yl) ethane-1- sulfonamide

[0345] Step 1: Synthesis of Intermediate 47a. Int 47a was synthesized using a similar procedure described for the synthesis of Int 40g. LCMS: m / z 565.504 (M+H)+.

[0346] Step 2: Synthesis of Intermediate 47b. Int 47b was synthesized using a similar procedure described for the synthesis of Int 40. LCMS: m / z 537.45 (M+H) +.

[0347] Step 3: Synthesis of Intermediate 47. Int 47 was synthesized using a similar procedure described for the synthesis of Int 46. LCMS: m / z 581.68 (M+H)+.

[0348] The intermediates in Table P were prepared according to the procedure described in Intermediate 47, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table P:Intermediate 48: Synthesis of 44-bromo-7-aza-3(2,5)-oxadiazola-2(2,4)-pyridina- 1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclooctaphan-6-one

[0349] Step 1: Synthesis of Intermediate 48a. To a stirred solution of Intermediate 32 (0.85 g, 1.77 mmol) in DMSO (5 mL) was added DIPEA (0.69 g, 5.33 mmol) followed by tert-butyl (piperidin-3-ylmethyl)carbamate (0.572 g, 2.66 mmol). The resultant solution was then heated with constant stirring at 140 °C for 16 h. Completion of the reaction was monitored by TLC. Then,the reaction mixture was poured into ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 40% EtOAc / hexane as an eluent to afford the title compound (0.7 g, 60 % yield). LCMS: m / z 657.15 (M+H)+.

[0350] Step 2: Synthesis of Intermediate 48b. To a stirred solution of Intermediate 48a (0.45 g, 0.67 mmol) in THF (2 mL), MeOH (2 mL), H2O (2 mL) was added LiOH. H2O (0.16 g, 6.72 mmol). The resultant solution was stirred at RT for 2 h. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum pressure and the remaining solution was neutralized using saturated citric acid solution and subsequently extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound (0.42 g crude) which used for further reaction without purification. LCMS: m / z 643.15 (M+H)+.

[0351] Step 3: Synthesis of Intermediate 48c. To a stirred solution of Intermediate 48b (0.42 g, 0.61 mmol) in dioxane (5 mL) was added 4 M HCl solution in dioxane (3 mL) and the mixture was stirred at RT for 2 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under vacuum and washed with pentane to afford the title compound which was used for the next step without further purification (0.4 g crude product). LCMS: m / z 443.10 (M+H)+.

[0352] Step 4: Synthesis of Intermediate 48. To a stirred solution of Intermediate 48c (0.4 g) in DMF (5 mL) was added TEA (0.219 g, 2.16 mmol) followed by HATU (0.41 g, 1.08 mmol) at 0 °C and the mixture was stirred for 10 min at the same temperature. Then, the reaction mixture was brought to room temperature and stirred for 12 h. After completion of the reaction, the reaction mass was poured into ice cold water and extracted with ethyl acetate followed by brine wash. Collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to give the crude mass which was purified by combi-flash chromatography by using 5% MeOH / DCM as an eluent to afford the title compound (0.22 g, 56.84% yield). LCMS: m / z 523.10 (M+H)+.Intermediate 49: Synthesis of 44-bromo-6-oxa-3 (2,5)-oxadiazola-1(3,1),5(1,4)-dipiperidina- 2(1,3),4(1,2)-dibenzenacyclononaphan-9-one

[0353] Step 1: Synthesis of Intermediate 49a. To a stirred solution of tert-butyl 4-bromo-2- fluorobenzoate (1.7 g, 6.18 mmol) in DMF (5 mL) was added K2CO3(1.71 g, 12.35 mmol) followed by methyl 3-(piperidin-4-yloxy) propanoate, Int.18 (1.157 g, 6.179 mmol). The resultant solution was then heated with constant stirring at 140 °C for 5 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 15% EtOAc / hexane as an eluent to afford tert- butyl 4-bromo-2-(4-(3-methoxy-3-oxopropoxy) piperidin-1-yl) benzoate (1.4 g, 51.22% yield). LCMS: m / z 442.05(M+H)+.

[0354] Step 2: Synthesis of Intermediate 49b. To a stirred solution of Int.49a (1.3 g, 2.94 mmol) in 1,4 dioxane (10 mL) was added 4M HCl in dioxane (10 mL) in a dropwise manner at 0 °C under argon atmosphere. The resultant solution was then brought to RT and stirred for 24 h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and washed with pentane to afford title compound which was used for next step without further purification (1.0 g crude yield). LCMS: m / z 385.95 (M+H)+.

[0355] Step 3: Synthesis of Intermediate 49c. To a stirred solution of Int.49b (0.9 g, 2.33 mmol) in DMF (4 mL) was added TEA (0.707 g, 7 mmol) followed by HATU (1.772 g, 4.66 mmol) at 0 °C and stirred for 10 min. After 10 min, Int.25 (0.89 g, 2.8 mmol) was added to the resultant mixture and stirred at RT for 12 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash byeluting with 20% EtOAc / hexane as an eluent to afford title compound (0.45 g, 28.1% yield). LCMS: m / z 687.05 (M+H)+.

[0356] Step 4: Synthesis of Intermediate 49d. To a stirred solution of Int. 49c (0.42 g, 0.61 mmol) in THF (4 mL) was added burgess reagent (0.365 g, 1.52 mmol) in portion wise manner. The resultant mixture was then refluxed with constant stirring at 65 °C for 2 h. Completion of the reaction was monitored through TLC. Then, the reaction mixture was poured in water and extracted with EtOAc followed by a brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound (0.33 g, 80.66 % yield). LCMS: m / z 669.15(M+H)+.

[0357] Step 5: Synthesis of Intermediate 49e. To a stirred solution of Int. 49d (0.33 g, 0.493 mmol) in THF (2 mL), MeOH (2 mL), H2O (2 mL) was added LiOH. H2O (0.236 g, 9.860 mmol). The resultant solution was stirred at RT for 1h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and the remaining solution was neutralised using saturated citric acid solution and finally extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound (0.31 g crude yield). The title compound was used for next step without further purification. LCMS: m / z 655.05 (M+H)+.

[0358] Step 6: Synthesis of Intermediate 49f. To a stirred solution Int 49e (0.31 g, 0.47 mmol) in dioxane (2 mL) was added 4 M HCl solution in dioxane (2 mL) and stirred at RT for 0.5 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under vacuum pressure and washed with pentane to afford title compound which was used for next step without further purification. LCMS: m / z 554.95 (M+H)+.

[0359] Step 7: Synthesis of Intermediate 49. To a stirred solution of Int.49f (0.25 g, 0.45 mmol) in DMF (5 mL) was added TEA (0.182 g, 1.80 mmol) followed by HATU (0.257 g, 0.67 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, reaction mixture was brought to room temperature and stirred for 0.5 h. After completion of reaction, reaction mass was poured into ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to get crude mass which was purified by combi-flash chromatography by using 100% EtOAc as an eluent to afford title compound (0.11 g, 45.48% yield). LCMS: m / z 539.05(M+H)+.Intermediate 50: Synthesis of 25-bromo-3(2,5)-oxadiazola-4(4,2)-pyridina-1(1,4),5(1,3)- dipiperidina-7(3,1)-pyrrolidina-2(1,2)-benzenaheptaphan-6-one

[0360] Step 1: Synthesis of Intermediate 50a. Int 50a was synthesized using a similar procedure described for the synthesis of Int 49f. LCMS: m / z 474.0 (M+H)+.

[0361] Step 2: Synthesis of Intermediate 50b. Int 50b was synthesized using a similar procedure described for the synthesis of Int 49c. LCMS: m / z 685.15 (M+H) +.

[0362] Step 3: Synthesis of Intermediate 50c. Int 50c was synthesized using a similar procedure described for the synthesis of Int 49f. LCMS: m / z 585.15 (M+H)+.

[0363] Step 4: Synthesis of Intermediate 50. Int 50 was synthesized using a similar procedure described for the synthesis of Int 46c. LCMS: m / z 549.10 (M+H)+.

[0364] The intermediates in Table Q were prepared according to the procedure described in the synthesis of Intermediate 50, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table Q:Intermediate 51: Synthesis of 44-bromo-6-oxa-3(2,5)-oxadiazola-1(3,1),5(1,4)-dipiperidina- 2(1,3),4(1,2)-dibenzenacyclononaphane

[0365] Step 1: Synthesis of Intermediate 51a. Int 51a was prepared using a similar procedure described for the synthesis of Int 49c. LCMS: m / z 641.10 (M+H)+.

[0366] Step 2: Synthesis of Intermediate 51b. Int 51b was prepared using a similar procedure described for the synthesis of Int 40f. LCMS: m / z 623.15 (M+H)+.

[0367] Step 3: Synthesis of Intermediate 51c. To a stirred solution of Int.51b (0.75 g, 1.2 mmol) in THF (10 mL) was added 9-BBN (0.48 g, 4.01 mmol) and reaction mixture was stirred at 65 °C for 12 h. Reaction mixture was then cooled down and stirred at RT for 4 h. Then, 6N NaOH solution (0.32 g, 8.02 mmol) and 30% H2O2 (0.14 g, 4.01 mmol) solution was added to the reaction mixture at 0 °C and stirred for 4 h. Then, the reaction mixture was quenched with saturated solution of sodium bisulfite and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound (0.45 g, 68% yield). LCMS: m / z 641.10 (M+H)+.

[0368] Step 4: Synthesis of Intermediate 51d. To a stirred solution of Int.51c (0.45 g, 0.7 mmol) in DCM (10 mL) was added TEA (0.21 g, 2.1 mmol) followed by MsCl (0.32 g, 2.8 mmol) at 0 °C. Reaction mixture was brought to RT and stirred for 6 h. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound (0.7 g crude yield). LCMS: m / z 719.3 (M+H)+.

[0369] Step 5: Synthesis of Intermediate 51e. Int 51d was prepared using a similar procedure described for the synthesis of Int 40b. LCMS: m / z 619.3 (M+H)+.

[0370] Step 6: Synthesis of Intermediate 51. To a stirred solution of Int.51e (0.5 g, 0.81 mmol) in THF (10 mL) in a sealed tube was added TEA (0.32 g, 3.2 mmol) at 0 °C. Reaction mixture was heated at 80 °C and stirred for 12 h. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi flash by eluting with 90% EtOAc / hexane as an eluent to afford title compound (0.23 g, 54% yield). LCMS: m / z 523.10 (M+H)+. Intermediate 52: Synthesis of 44-bromo-6-oxa-3(2,5)-oxadiazola-1(1,4)-piperazina-2(2,4)- pyridina-5(1,4)-piperidina-4(1,2)-benzenacyclononaphane

[0371] Step 1: Synthesis of Intermediate 52a. Int 52a was synthesized using a similar procedure described in the synthesis of Int.40g. LCMS: m / z 625.2 (M+H)+.

[0372] Step 2: Synthesis of Intermediate 52b. Int 52b was synthesized using a similar procedure described in the synthesis of Int.51c. LCMS: m / z 643.15 (M+H)+.

[0373] Step 3: Synthesis of Intermediate 52c. Int 52c was synthesized using a similar procedure described in the synthesis of Int.51d. LCMS: m / z 721.15 (M+H)+.

[0374] Step 4: Synthesis of Intermediate 52d. Int 52d was synthesized using a similar procedure described in the synthesis of Int.51e. LCMS: m / z 621.05 (M+H)+.

[0375] Step 5: Synthesis of Intermediate 52. To a stirred solution of Int 52d (0.15 g, 0.24 mmol) in THF (5 mL) was added TEA (0.12 g, 1.20 mmol). The reaction mixture was then heated under constant stirring at 65 °C for 72 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under vacuum pressure and washed with pentane to afford title compound which was used for next step without further purification (0.18 g crude yield). LCMS: m / z 525.2 (M+H)+Intermediate 53: Synthesis of 34-bromo-5-oxa-9-aza-2(2,5)-oxadiazola-1(4,2)-pyridina- 4(1,4)-piperidina-3(1,2)-benzenacyclononaphane

[0376] Step 1: Synthesis of Intermediate 53a. To a stirred solution of tert-butyl 4- hydroxypiperidine-1-carboxylate (6.0 g, 29.81 mmol) in dioxane (30 mL) was added tBuOK (0.06g, 0.53 mmol) followed by acrylonitrile (8.067 g, 152.036 mmol). The reaction mixture was then heated with constant stirring at 90 °C for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 40% EtOAc / hexane as an eluent to afford title compound (6.2 g, 81.77% yield). LCMS: m / z 155.00 (M+H-100)+.

[0377] Step 2: Synthesis of Intermediate 53b. To a stirred solution of Int 53a (6.2 g, 24.378 mmol) in DCM (20 mL) was added TFA (6 mL) in a dropwise manner at 0 °C under argon atmosphere. The resultant solution was then brought to RT and stirred for 2 h. The completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and washed with pentane to afford title compound (7g crude). LCMS: m / z 155(M+H)+.

[0378] Step 3: Synthesis of Intermediate 53c. To a stirred solution of Int 53b (7 g, 27.862 mmol) in NMP (30 mL) was added DIPEA (18.006 g, 139.310 mmol) followed by methyl 4-bromo-2- fluorobenzoate (12.986 g, 55.725 mmol). The resultant solution was stirred at 120 °C for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound (5.5 g, 53.75% yield). LCMS: m / z 367 (M+H)+.

[0379] Step 4: Synthesis of Intermediate 53d. To a stirring solution of Int 53c (1.0 g, 2.722 mmol) in methanol (10 mL) was added nickel chloride hexahydrate (0.324 g, 1.360 mmol), BOC anhydride (0.891 g, 4.080) followed by NaBH4 (0.2 g, 5.44 mmol) portion wise at 0 °C. The resultant mixture was then stirred at RT for 2 h. The completion of the reaction was monitored through TLC. Then, the reaction mixture was poured in ice water and extracted with EtOAc followed by a brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound (0.6 g, 46.74 % yield). LCMS: m / z 471.38 (M+H)+.

[0380] Step 5: Synthesis of Intermediate 53e. To a stirred solution of Int 53d (0.6 g, 1.272 mmol) in ethanol (6 mL) was added hydrazine hydrate (0.319 g, 6.360 mmol) and the resultant solution was heated with constant stirring at 90 °C for 12 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound which was used for next step without further purification (0.5 g crude). LCMS: m / z 471.38 (M+H)+.

[0381] Step 6: Synthesis of Intermediate 53f. To a stirred solution of 2-fluoroisonicotinic acid (0.108 g, 0.764 mmol) in DMF (3 mL) was added TEA (0.344 g, 3.39 mmol), EDCI (0.163g, 0.840 mmol) and HOBt (0.065 g, 152.055 mmol) at 0 °C and stirred for 10 min. Then, Int 53e (0.4 g, 0.849 mmol) was added and reaction mixture was stirred at RT for 3 h. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound which was used for next step without further purification (0.25 g crude). LCMS: m / z 658.2(M+H)+.

[0382] Step 7: Synthesis of Intermediate 53g. To a stirred solution of Int 53f (0.2 g, 0.336 mmol) in THF (4 mL) was portion wise added burgess reagent (0.160 g, 0.670 mmol). The resultantmixture was then refluxed with constant stirring at 65 °C for 2 h. The completion of the reaction was monitored through TLC. Then, reaction mixture was poured in water and extracted with EtOAc followed by a brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (0.05 g, 25.81 % yield). LCMS: m / z 576.05(M+H)+.

[0383] Step 8: Synthesis of Intermediate 53h. To a stirred solution of Int 53g (0.05 g, 0.087 mmol) in 1,4 dioxane (1 mL) was added 4 M dioxane HCl (1 mL) in a dropwise manner at 0 °C under argon atmosphere. The resultant solution was then brought to RT and stirred for 3 h. The completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and washed with pentane to afford title compound which was used for next step without further purification (0.08 g). LCMS: m / z 476.1 (M+H)+.

[0384] Step 9: Synthesis of Intermediate 53. To a stirred solution of Int 53h (0.04 g, 0.084 mmol) in NMP (3 mL) was added DIPEA (18.006 g, 139.310 mmol). The resultant solution was stirred at 140 °C for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (0.03 g, 78.26% yield). LCMS: m / z 458.00 (M+H)+. Intermediate 54: Synthesis of 34-bromo-5-oxa-10-aza-2(2,5)-oxadiazola-1(4,2)-pyridina- 4(1,4)-piperidina-3(1,2)-benzenacyclodecaphane

[0385] Step 1: Synthesis of Intermediate 54a. To a stirred solution of 4-pyridinol (2 g, 21 mmol) and t-butyl (4-hydroxybutyl) carbamate (4.8 g, 25.23 mmol) in dry THF (20 mL) was added PPh3 (8.3 g, 31.5 mmol) and DIAD (6.4 g, 31.5 mmol) under inert atmosphere at 0 °C. Reaction mixture was then stirred at RT for 16 h. After completion of the reaction, reaction mixture was quenchedwith water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain crude mass, which was purified by eluting with 90 % EtOAc / hexane as an eluent to afford title compound (2 g, 36 % yield). LCMS: m / z 267.1 (M+H)+.

[0386] Step 2: Synthesis of Intermediate 54b. To a stirred solution Int 54a (2 g, 7.51 mmol) in EtOH (40 mL) was added 4M dioxane HCl solution (1.4 mL) followed by platinum oxide (0.51 g, 2.25 mmol) under inert atmosphere at 0 °C. Reaction mixture was then stirred at 40 °C under hydrogen atmosphere for 16 h. After completion of the reaction, reaction mixture was filtered on celite bed. Filtrate was collected and concentrated under reduced pressure to afford title compound which was used for next step without further purification (1.6 g crude). LCMS: m / z 273.2 (M+H)+.

[0387] Step 3: Synthesis of Intermediate 54c. To a stirred solution of Int 54b (1.6 g, 5.88 mmol) in NMP (15 mL) was added DIPEA (3.62 g, 28.02 mmol) followed by addition of methyl 4-bromo- 2-fluorobenzoate (2 g, 8.8 mmol). The resultant solution was then heated with constant stirring at 140 °C for 16 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (1 g, 84% yield). LCMS: m / z 485.20 (M+H)+.

[0388] Step 4: Synthesis of Intermediate 54d. To a stirred solution of Int 54c (1 g, 2 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.3 g, 6.18 mmol) The resultant solution was then refluxed for 6 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% MeOH / DCM as an eluent to afford title compound (0.36 g, 35% yield). LCMS: m / z 485.10 (M+H)+.

[0389] Step 5: Synthesis of Intermediate 54e. To a stirred solution of 2-fluoroisonic acid (0.15 g, 1.01 mmol) in DMF (5 mL) was added TEA (0.22 g, 2.2 mmol) followed by HATU (0.55 g, 1.44 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, Int 54d (0.35 g, 0.72 mmol) was added to the resultant solution and reaction mixture was stirred at RT for 12 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filteredand concentrated on rotary evaporator to obtain crude mass, which was purified by eluting with 10% MeOH / DCM as an eluent to afford title compound (0.2 g, 46 % yield). LCMS: m / z 608.3 (M+H)+.

[0390] Step 6: Synthesis of Intermediate 54f. Intermediate 54f was synthesized using a similar procedure as described in the synthesis of Int 39e. LCMS: m / z 590.2 (M+H)+.

[0391] Step 7: Synthesis of Intermediate 54g. Intermediate 54g was synthesized using a similar procedure as described in the synthesis of Int 39b. LCMS: m / z 490.2 (M+H)+.

[0392] Step 8: Synthesis of Intermediate 54. Intermediate 54 was synthesized using a similar procedure as described in the synthesis of Int 53. LCMS: m / z 470.2 (M+H)+. Intermediate 55: Synthesis of 44-bromo-26-methyl-7-aza-3(2,5)-oxadiazola-2(2,4)-pyridina- 1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclooctaphan-6-one

[0393] Step 1: Synthesis of Intermediate 55a. Intermediate 55a was prepared using a similar procedure described for the synthesis of Intermediate 48a. LCMS: m / z 671.15 (M+H)+.

[0394] Step 2: Synthesis of Intermediate 55b. Intermediate 55b was prepared using a similar procedure described for the synthesis of Intermediate 48b. LCMS: m / z 657.15 (M+H)+.

[0395] Step 3: Synthesis of Intermediate 55c. Intermediate 55c was prepared using a similar procedure described for the synthesis of Intermediate 48c. LCMS: m / z 557.10 (M+H)+.

[0396] Step 4: Synthesis of Intermediate 55. Intermediate 55 was prepared using a similar procedure described for the synthesis of Intermediate 48. LCMS: m / z 537.10 (M+H)+.Intermediate 56: Synthesis of 4-bromo-2-(4-(((tert-butoxycarbonyl) (methyl) amino) methyl) piperidin-1-yl) benzoic acid

[0397] Step 1: Synthesis of Intermediate 56a. To a stirred solution of Intermediate C-3 (1 g, 2.42 mmol) in DMF (5 mL) was added NaH (0.2 g, 6.04 mmol) followed by methyl iodide (1 g, 7.25 mmol) at 0 °C. The reaction mixture was then brought to RT and stirred for 2 h. Completion of the reaction was monitored by TLC, showing consumption of the starting material. The reaction mass was then quenched with a saturated ammonium chloride solution and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to give the crude mass which was purified by combi flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (0.81 g, 76% yield). LC-MS: m / z 441.05 (M+H)+.

[0398] Step 2: Synthesis of Intermediate 56. Intermediate 56 was prepared using a similar procedure described for the synthesis of Intermediate 14. LCMS: m / z 427.05 (M+H)+. Intermediate 57: Synthesis of 44-bromo-7-methyl-7-aza-3(2,5)-oxadiazola-2(2,4)-pyridina- 1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclooctaphane

[0399] Step 1: Synthesis of Intermediate 57a. Intermediate 57a was prepared using a similar procedure described for the synthesis of Intermediate 27a. LCMS: m / z 582.05 (M+H)+.

[0400] Step 2: Synthesis of Intermediate 57b. Intermediate 57b was prepared using a similar procedure described for the synthesis of Intermediate 27. LCMS: m / z 562.05 (M+H)+.

[0401] Step 3: Synthesis of Intermediate 57c. Intermediate 57c was prepared using a similar procedure described for the synthesis of Intermediate 48a. LCMS: m / z 641.4 (M+H)+.

[0402] Step 4: Synthesis of Intermediate 57d. To a stirred solution of Intermediate 57c (0.5 g, 0.78 mmol) in DCM (10 mL) was added Dess-Martin periodinane (0.4 g, 0.93 mmol) at 0 °C and the mixture was stirred for 30 min at the same temp. Then, the reaction mixture was brought to RT and stirred for 12 h. After completion of the reaction, the reaction mixture was quenched with a saturated sodium thiosulfate solution and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass which was purified by combi flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (0.45 g, 90% yield). LC-MS: m / z 639.15 (M+H)+.

[0403] Step 5: Synthesis of Intermediate 57e. Intermediate 57e was prepared using a similar procedure described for the synthesis of Intermediate 48c. LCMS: m / z 539.15 (M+H)+.

[0404] Step 6: Synthesis of Intermediate 57. To a stirred solution of Intermediate 57e (0.2 g, 0.37 mmol) in EtOH:THF (3:1, 4 mL) was added DIPEA (0.05 g, 0.37 mmol) at 00C and reaction mixture was stirred at room temperature for 12 h. Formation of imine was monitored by TLC. Then, STAB (0.16 g, 0.74 mmol) was added portionwise at 00C and the reaction mixture was stirred at RT for 12 h. After completion of the reaction, the reaction mass was diluted with water and extracted with Methanol / DCM followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass which was purified by combi flash by eluting with 10% MeOH / DCM as an eluent to afford the title compound (0.07 g, 36% yield). LC-MS: m / z 523.1 (M+H)+. Intermediate 58: Synthesis of N-(tert-butoxycarbonyl)-N-(cyclopropylmethyl) glycine

[0405] Step 1: Synthesis of Intermediate 58a. To a stirred solution of (tert-butoxycarbonyl) glycine (1.0 g, 5.70 mmol) in DMF (5 mL) was added K2CO3 (1.18 g, 8.56 mmol) followed by iodomethane (1.620 g, 11.416mmol) at 0°C in a dropwise manner. The resultant solution was stirred at RT for 3 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound which was used for the next step without purification(1.0 g crude).1H NMR (DMSO-d6, 400 MHz): 7.22 (t, J = 6.2 Hz, 1H), 3.68 (d, J = 6.4 Hz, 2H), 3.62 (s, 3H), 1.38 (s, 9H).

[0406] Step 2: Synthesis of Intermediate 58b. To a stirred solution of Intermediate 58a (0.1 g, 0.53 mmol) in DMF (3 mL) was added sodium 2-methylpropane-2-olate (0.102 g, 1.05 mmol) followed by (bromomethyl)cyclopropane (0.143 g, 1.05 mmol) at 0°C in a dropwise manner. The resultant solution was stirred at 50°C for 30 min. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound which was used for the next step without purification (0.12 g crude).1H NMR (DMSO-d6, 400 MHz): 3.90 (d, J = 7.2 Hz, 2H), 3.68 – 3.62 (m, 5H), 1.38 (s, 9H), 1.34-1.31 (m, 1H), 0.53 – 0.49 (m, 2H), 0.27- 0.26 (m, 2H).

[0407] Step 3: Synthesis of Intermediate 58. To a stirred solution of Intermediate 58b (0.12 g, 0.493 mmol) in THF (2 mL), MeOH (2 mL), H2O (2 mL) was added LiOH.H2O (0.207 g, 4.93 mmol). The resultant solution was stirred at RT for 2 h. Completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum and the remaining solution was neutralized using saturated citric acid solution and finally extracted using EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the title compound which was used for the next step without purification (0.1 g crude).1H NMR (DMSO-d6, 400 MHz): 12.47 (s, 1H), 3.90 (d, J = 7.2 Hz, 2H), 3.08 (d, J = 6.8 Hz, 2H), 3.68-3.62 (m, 5H), 1.38 (s, 9H), 1.34-1.31 (m, 1H), 0.42-0.39 (m, 2H), 0.17-0.16 (m, 2H). Intermediate 59: Synthesis of 34-bromo-9-(cyclopropylmethyl)-6,9-diaza-2 (2,5)-oxadiazola- 1 (4,2)-pyridina-4 (1,4)-piperidina-3 (1,2)-benzenacyclononaphan-7-one

[0408] Step 1: Synthesis of Intermediate 59a. To a stirred solution of Intermediate 27 (0.3 g, 0.36 mmol) in dioxane (5 mL) was added 4 M HCl solution in dioxane (2 mL) and the mixture was stirred at RT for 0.5 h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and washed with pentane to afford the title compound which was used for the next step without purification (0.25 g). LCMS: m / z 449.95(M+H)+.

[0409] Step 2: Synthesis of Intermediate 59b. To a stirred solution of N-(tert-butoxycarbonyl)- N-(cyclopropylmethyl)glycine (0.1 g, 0.43 mmol) in DMF (2 mL) was added TEA (0.132 g, 1.30 mmol) followed by HATU (0.249 g, 0.65 mmol) at 0 °C and the mixture was stirred for 10 min. After 10 min, Intermediate 59a (0.196 g, 0.43 mmol) was added to the resultant solution and the mixture was stirred at RT for 0.5 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford the title compound (0.18 g, 62% yield). LCMS: m / z 661.15 (M+H)+.

[0410] Step 3: Synthesis of Intermediate 59c. To a stirred solution of Intermediate 59b (0.18 g, 0.30 mmol) in dioxane (5 mL) was added 4 M HCl solution in dioxane (2 mL) and the mixture was stirred at RT for 0.5 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and washed with pentane to afford title compound which was used for the next step without purification (0.15 g crude product). LCMS: m / z 561.05 (M+H)+.

[0411] Step 4: Synthesis of Intermediate 59. To a stirred solution of Intermediate 59c (0.15 g, 0.268 mmol) in DMSO (4 mL) was added DIPEA (0.139 g, 1.070mmol). The resultant solution was then heated with constant stirring at 140 °C for 24 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 40% EtOAc / hexane as an eluent to afford the title compound (0.07 g, 50 % yield). LCMS: m / z 523.05 (M+H)+.Intermediate 60: Synthesis of 34-bromo-9-(cyclopropylmethyl)-5-oxa-9-aza-2(2,5)- oxadiazola-1(4,2)-pyridina-4(1,4)-piperidina-3(1,2)-benzenacyclononaphane

[0412] Step 1: Synthesis of Intermediate 60a. To a stirred solution of t-butyl (4- hydroxypiperidine)-1- carboxylate (10 g, 49.7 mmol) in dry THF (100 mL) was added KOH (0.3 g, 5 mmol) followed by ethyl acrylate (15 g, 149 mmol) under inert atmosphere at 0 °C. Reaction mixture was then stirred at RT for 16 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain crude mass, which was purified by eluting with 30 % EtOAc / hexane as an eluent to afford title compound (7 g, 68.33 % yield). LCMS: m / z 246.1, 201.1 (Boc pattern).

[0413] Step 2: Synthesis of Intermediate 60b. To a stirred solution Int 60a (4.5 g, 15 mmol) in dry THF (50 mL) was added LAH (1.13 g, 30 mmol) under inert atmosphere at 0 °C and stirring continued for another 2 h. After completion of the reaction, reaction mixture was quenched with aqueous sodium sulphate solution, filtered on celite bed. Filtrate was collected and concentrated under reduced pressure to afford title compound which was used for next step without further purification (4 g crude). LCMS: m / z 204.1, 160.1 (Boc pattern).

[0414] Step 3: Synthesis of Intermediate 60c. To a stirred solution of Int 60b (4 g, 15.4 mmol) in DCM (5 mL) was added TFA (5 mL) at 0 °C. The resultant solution was stirred at RT for 2 h. The completion of the reaction was monitored by TLC. Then, solvents were concentrated under reduced pressure to afford title compound which was used for next step without further purification (3.5 g crude). LCMS: m / z 160.1 (M+H)+.

[0415] Step 4: Synthesis of Intermediate 60d. Intermediate 60d was synthesized using a similar procedure described in the synthesis of Int 54c. LCMS: m / z 372.1 (M+H)+.

[0416] Step 5: Synthesis of Intermediate 60e. To a stirred solution of Int 60d (2 g, 5.4 mmol) in DCM (20 mL) was added TEA (1.63 g, 16.11 mmol) followed by MsCl (0.92 g, 8.1 mmol) at at 0 °C. The resultant solution was then stirred at RT for 2 h. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer wasdried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound, which was used for next step without further purification (2.9 g crude). LCMS: m / z 450.10 (M+H)+.

[0417] Step 6: Synthesis of Intermediate 60f. To a stirred solution of Int 60e (2.9 g, 6.44 mmol) in THF (20 mL) was added DIPEA (2.5 g, 19.3 mmol) followed by cyclopropyl methanamine (1.37 g, 19.3 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, reaction mixture was stirred at RT for 48 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford title compound, which was used for next step without further purification (3 g crude). LCMS: m / z 425.1 (M+H)+.

[0418] Step 7: Synthesis of Intermediate 60g. To a stirred solution of Int 60f (1.5 g, 3.52 mmol) in DCM (15 mL) was added TEA (1.1 g, 10.57 mmol) followed by Boc2O (1.15 g, 5.3 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, reaction mixture was stirred at RT for 4 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude mass, which was purified by eluting with 40 % EtOAc / hexane as an eluent to afford title compound (0.75 g, 40.5 % yield). LCMS: m / z 525.2 (M+H)+.

[0419] Step 8: Synthesis of Intermediate 60h. Intermediate 60h was synthesized using a similar procedure described in the synthesis of Int 54d. LCMS: m / z 525.3 (M+H)+.

[0420] Step 9: Synthesis of Intermediate 60i. Intermediate 60i was synthesized using a similar procedure described in the synthesis of Int 54e. LCMS: m / z 648.4 (M+H)+.

[0421] Step 10: Synthesis of Intermediate 60j. Intermediate 60j was synthesized using a similar procedure as described in the synthesis of Int 39e. LCMS: m / z 630.2 (M+H)+.

[0422] Step 11: Synthesis of Intermediate 60k. To a stirred solution of Int 60j (0.2 g, 0.36 mmol) in DCM (5 mL) was added 4M HCl in dioxane solution (1 mL) at 0 °C. The resultant solution was stirred at RT for 2 h. Completion of the reaction was monitored by TLC. Then, solvents were concentrated under reduced pressure to afford title compound which was used for next step without further purification (0.2 g crude). LCMS: m / z 530.2 (M+H)+.

[0423] Step 12: Synthesis of Intermediate 60. Intermediate 60 was synthesized using a similar procedure as described in the synthesis of Int 54. LCMS: m / z 510.2 (M+H)+.Intermediate 61 (mixture of two racemic regioisomers): Synthesis of 44-bromo-3 (2,5)- oxadiazola-2 (2,4)-pyridina-1 (1,3), 5 (1,4)-dipiperidina-4 (1,2)-benzenacyclooctaphanol

[0424] To a mixture of Intermediate 41 (0.3 g, 0.592 mmol) in THF (6 mL), borane- tetrahydrofuran complex (1 M in THF, 1.18 mL, 1.18 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. To the reaction mixture, hydrogen peroxide (30 % in H2O, 1 mL) and 2 N NaOH (2 mL) were added at 0 °C and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was quenched with ice-cold water followed by extraction with ethyl acetate. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to a give crude mass which was purified by combi-flash column chromatography using ethyl acetate in hexane to afford the title compound (0.220 g, 73% yield). LC-MS: m / z 525.2 (M+H)+. Intermediate 62: Synthesis of 1-(4-(5-(4-(cyclopropanesulfonamido)-2-(4- ((cyclopropylamino)methyl)-4-methylpiperidin-1-yl) phenyl)-1,3,4-oxadiazol-2-yl) pyridin- 2-yl) piperidine-3-carboxylic acid

[0425] Step 1: Synthesis of Intermediate 62b. To a stirred solution of Int 20a (4.7 g, 20.678 mmol) in methanol (50 mL) was added cyclopropanamine (1.417 g, 24.814 mmol) at 0 °C followed by acetic acid (0.200 g, 3.330 mmol). Then reaction mixture was stirred for 12 h at room temperature. To this reaction mixture, was added sodium cyanoborohydride (3.249 g, 51.690 mmol) stirring continued at room temperature for another 16 h. After completion of the reaction, solvent was distilled under reduced pressure, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried overanhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; which was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (4 g, 72.07% yield). LC-MS: m / z 269.2 (M+H)+.

[0426] Step 2: Synthesis of Intermediate 62c. To a stirred solution of Int 62b (3.750 g, 13.971 mmol) in THF (50 mL) was added sodium hydroxide (1.118 g, 27.940 mmol) in water (10 mL) at 0 °C and stirred for 10 min at RT. Then, benzyl chloroformate (2.86 g, 16.76 mmol) was added to the reaction mixture and stirred for 16 h at room temperature. After completion of the reaction, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; the crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (4.8 g, 85.35% yield). LC-MS: m / z 303.2 (M+H)+.

[0427] Step 3: Synthesis of Intermediate 62d. To a stirred solution Int 62c (4.7 g, 11.676 mmol) in DCM (50 mL) was added TFA (20 mL) at 0 °C and then stirred at RT for 1 h. After completion of the reaction, reaction mass was concentrated on rotary evaporator to afford title compound (3.5 g crude). LC-MS: m / z 303.1 (M+H)+.

[0428] Step 4: Synthesis of Intermediate 62e. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (3.5 g, 15.019 mmol) in DMSO (50 mL) was added Int 62d (5.45 g, 18.023 mmol) followed by dipotassium carbonate at 0 °C. Then reaction mixture was stirred at 140 °C for 16 h. After completion of the reaction, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass, the crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (4.5 g, 58.13% yield). LC-MS: m / z 515.1 (M+H)+.

[0429] Step 5: Synthesis of Intermediate 62f. To a stirred solution of Int 62e (4.5 g, 8.73 mmol) in methanol (10 mL), water (10 mL) and THF (45 mL) was added lithium hydroxide monohydrate (2.198 g, 41.960 mmol) at 0 °C. Reaction mixture was then brought to RT and stirred for 16 h at RT. After completion of the reaction, reaction mass was concentrated then diluted with water and acidified with 2N HCl solution and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain title compound (3.0 g). LC-MS: m / z 501.1 (M+H)+.

[0430] Step 6: Synthesis of Intermediate 62g. To a stirred solution Int 62f (2.9 g, 5.783 mmol) in DMF (20 mL) was added triethylamine (1.754 g, 17.350 mmol) followed by HATU (3.299 g, 8.670 mmol) at 0 °C and stirred for 30 min at the same temperature. Then, 2-chloroisonicotinohydrazide (1.191 g, 6.94 mmol) was added to the resultant solution and reaction mixture was stirred at RT for 12 h. After completion of the reaction, reaction mass was diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; the crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (2.9 g, 76.55% yield). LC-MS: m / z 556.1 (M+H)+.

[0431] Step 7: Synthesis of Intermediate 62h. To a stirred solution of Int 62g (2.8 g, 4.275 mmol) in THF (60 mL) was added burgess reagent (2.037 g, 8.550 mmol) and reaction mixture was stirred at 65°C for 1 h. After completion of the reaction, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain title compound (2.6 g). LC-MS: m / z 638.1 (M+H)+.

[0432] Step 8: Synthesis of Intermediate 62i. To a stirred solution of Int 62h (2.6 g, 4.081 mmol) in DMSO (26 mL) was added methyl piperidine-3-carboxylate (1.224 g, 8.550 mmol) followed by DIPEA (1.583 g, 12.240 mmol) at 0 °C. Reaction mixture was then stirred at 140 °C for 48 h. After completion of the reaction, reaction mass was diluted with ice cold water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; the crude mass was purified by combi-flash by eluting with 30% EtOAc / hexane as an eluent to afford title compound (1.7 g, 56.00% yield). LC-MS: m / z 743.2 (M+H)+.

[0433] Step 9: Synthesis of Intermediate 62j. To a stirred solution of Int 62i (1.7 g, 2.286 mmol) and cyclopropanesulfonamide (0.415 g, 3.428 mmol) in 1,4-dioxane (17 mL) was added tBuXPhos (0.097 g, 0.220 mmol) and K3PO4(1.213 g, 5.710 mmol) and purged with argon for 15 min. Then palladium (II)(π-cinnamyl) chloride dimer (0.059 g, 0.110 mmol) was added, and reaction mixture was heated at 90 °C for 4 h. After completion of reaction, reaction mass extracted with ethyl acetate and water followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rotary evaporator to obtain crude mass; the crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (1.7 g, 94.86% yield). LC-MS: m / z 784.05 (M+H)+.

[0434] Step 10: Synthesis of Intermediate 62k. Int 62k was synthesized using a similar procedure described in the synthesis of Int 44b. LC-MS: m / z 770.3 (M+H)+.

[0435] Step 11: Synthesis of Intermediate 62. To a stirred solution of Int 62k (0.8 g, 1.04 mmol) in ethanol (10 mL) and THF (5 mL) was added 10% palladium on carbon (0.22 g, 2.077 mmol) and the reaction mixture was stirred under hydrogen atmosphere at RT for 24 h. After completionof reaction, reaction mixture was diluted with ethyl acetate and filtered through celite bed. Filtrate was collected and concentrated and dried under reduced pressure to obtain title compound (0.45 g crude) which was used for next step without further purification. LC-MS: m / z 636.1 (M+H)+.

[0436] The intermediate in Table R was prepared according to the procedure described in Intermediate 62, except isopropyl amine was used instead of cyclopropylamine in step 1. Table R: IIntermediate 63: Synthesis of benzyl ((1-(3-(5-(2-chloropyridin-4-yl)-1,3,4-oxadiazol-2-yl)-6- (cyclopropanesulfonamido) pyridin-2-yl)-4-methylpiperidin-4-yl) methyl) (methyl) carbamate

[0437] Step 1: Synthesis of Intermediate 63a. To a stirred solution of benzyl methyl((4- methylpiperidin-4-yl) methyl) carbamate (8.33 g, 30.17 mmol) in ACN (20 mL) was added DIPEA (9.74 g, 75.42 mmol) followed by 2,6-difluoronicotinic acid (4.0 g, 25.14 mmol) at 0 °C. The reaction mixture was stirred at RT for 5h. The completion of the reaction was monitored by TLC. The reaction mixture was poured into water and extracted with ethyl acetate. The collected organic layer was washed with brine solution and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash chromatography by eluting with 15-20% EtOAc / hexane as an eluent to afford title compound (6 g, 57.44% yield). LCMS: m / z 416.10(M+H)+.

[0438] Step 2: Synthesis of Intermediate 63b. To a stirred solution of Int 63a (6 g, 14.43 mmol) and 2-chloroisonicotinohydrazide (3 g, 17.32 mmol) in DMF (30 mL) was added TEA (5.14 g, 51 mmol) followed by HATU (12.9 g, 34 mmol) at 0 °C and stirred for 10 min at the same temperature. The reaction mixture was brought to RT and stirred for 4h. After completion of the reaction, reaction mass was poured to ice cold water and extracted with ethyl acetate. The collected organic layer was washed with brine solution and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash chromatography by eluting with 30-40% EtOAc / hexane to afford title compound (6 g, 73% yield). LCMS: m / z 569.10 (M+H)+.

[0439] Step 3: Synthesis of Intermediate 63c. To a stirred solution of Int 63b (5 g, 8.78 mmol) in THF (30 mL) was added burgess reagent (6.28 g, 26.36 mmol) in portion wise manner. The reaction mixture was then refluxed with constant stirring at 65°C for 3 h. The completion of the reaction was monitored through TLC. The reaction mixture was poured to water and extracted with EtOAc. The collected organic layer was washed with brine solution and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash chromatography by eluting with 10-30% EtOAc / hexane to afford title compound (4 g, 82.62 % yield). LCMS: m / z 551.2(M+H)+.

[0440] Step 4: Synthesis of Intermediate 63. To a stirred solution of Int 63c (4 g, 7.25 mmol) in DMSO (20 mL) was added Cesium fluoride (7.09 g, 21.77 mmol) followed by cyclopropane sulfonamide (1.05 g, 8.71 mmol). The reaction mixture was then heated with constant stirring at 120 °C for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with brine solution and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 40-60% EtOAc / hexane as an eluent to afford title compound (3g, 63.37% yield). LCMS: m / z 651.91(M-H)+.Intermediate 65: Synthesis of N-(3-(4-(allyloxy) piperidin-1-yl)-4-(4-(2-(3-vinylpiperidin-1- yl) pyridin-4-yl)-1H-pyrazol-1-yl) phenyl)cyclopropanesulfonamide

[0441] Step 1: Synthesis of Intermediate 64. To a stirred solution of 2-fluoro-4-iodopyridine (6.5 g, 29.14 mmol) in DMSO (50 mL), 3-vinylpiperidine hydrochloride (3.8 g, 34.97 mmol) and potassium carbonate (12 g, 87.44 mmol) were added, and reaction mixture was heated at 1200C for 12 h. progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with EtOAc followed by brine wash. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by combi flash eluting with 5% EtOAc / hexane as an eluent to afford the title compound (8.1 g, 88% yield). LCMS: m / z 315.0 (M+H)+.

[0442] Step 2: Synthesis of Intermediate 65a. To a stirred solution of Int 64 (4 g ,12.73 mmol) and Int 16 (5 g, 15.27 mmol) in dioxane (40 mL) and water (20 mL), Na2CO3(3.3 g, 31.83 mmol), Pd (PPh3)4 (1.17 g, 1.019 mmol) were added and purged with argon for 15 min. Then, the reaction mixture was stirred at 100 °C for 6 h. After completion of the reaction, reaction mass was filtered on celite bed, filtrate collected, diluted with water and extracted with EtOAc followed by brine wash. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by combi flash eluting with 40% EtOAc / hexane as an eluent to afford title compound (3.6 g, 40% yield). LCMS: m / z 394 (M+H)+.

[0443] Step 3: Synthesis of Intermediate 65b. To a stirred solution of Int 65a (1.4 g ,3.55 mmol) and Int 7 (1.5 g, 10.67 mmol) in DMF was added K2CO3 (1.4 g ,10.67 mmol) at RT. Reaction mixture was then stirred at 110 °C for 16 h in microwave. The reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by combi flash eluting with 40% EtOAc / hexane as an eluent to afford title compound (0.8 g, 61% yield). LCMS: m / z 515.4 (M+H)+.

[0444] Step 4: Synthesis of Intermediate 65c. To a stirred solution of Int 65b (0.1 g, 0.194 mmol) in ethanol (12 ml) was added iron powder (0.065 g, 1.160 mmol). Then the temperature was raised to 50-55 °C, ammonium chloride (0.031 g 0.580 mmol) was dissolved in water, and the reaction was refluxed at 85 °C for 2 h. After the reaction, the iron powder was removed by filtration, the filter cake was washed twice with of ethyl acetate, and the filtrate was collected and concentrated under reduced pressure to obtain residue which was diluted in water and extracted with EtOAc followed by brine wash. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford title compound which was used for next step without further purification (0.1 g crude yield). LCMS: m / z 485.3(M+H)+.

[0445] Step 5: Synthesis of Intermediate 65. Int 65c (0.100 g, 0.206 mmol) in DCM (10 mL) was added pyridine (0.049 g, 0.619 mmol) followed by cyclopropane sulfonyl chloride (0.109 g, 0.776 mmol) at RT. Reaction mixture was then stirred for 5 h at RT. The reaction mixture was quenched with water and extracted with DCM followed by brine wash. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford title compound which was used for next step without further purification (0.1 g crude yield). LCMS: m / z 589.2 (M+H)+. Intermediate 66: Synthesis of 1-(4-(5-(6-(cyclopropanesulfonamido)-2-(4-methyl-4- ((methylamino)methyl) piperidin-1-yl) pyridin-3-yl)-1,3,4-oxadiazol-2-yl) pyridin-2-yl) piperidine-3-carboxylic acid

[0446] Step 1: Synthesis of Intermediate 66a. To a stirred solution of Int 63 (2.5 g, 3.88 mmol) in DMSO (20 mL) was added DIPEA (1.18 g, 9.20 mmol) followed by methyl piperidine-3- carboxylate (0.65 g, 4.59 mmol). The reaction mixture was then heated with constant stirring at 140 °C for 16 h. The completion of the reaction was monitored by TLC. Then the reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with brine solution and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 30-50% EtOAc / hexane as an eluent to afford title compound (2g, 68.76 % yield). LCMS: m / z 758.7 (M+H)+.

[0447] Step 2: Synthesis of Intermediate 66b. To a stirred solution of Int 66a (2 g, 2.63 mmol) in THF (5 mL), MeOH (20 mL), H2O (5 mL) was added LiOH.H2O (0.189 g, 7.90 mmol). Thereaction mixture was stirred at RT for 2 h. The completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and neutralised using saturated citric acid solution. Reaction mixture was extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound which was used for next step without purification (1.6g crude). LCMS: m / z 744.5 (M+H)+.

[0448] Step 3: Synthesis of Intermediate 66. The solution of Int 66b (0.45 g, 0.60 mmol) in TFA (1.5 mL) was heated at 60 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated under vacuum pressure and washed with pentane to afford the title compound which was used for next step without purification (0.3 g crude). LCMS: m / z 611.7(M+H)+. Intermediate 67: Synthesis of 1-azido-4-bromo-2-fluorobenzene

[0449] A solution of 4-bromo-2-fluoroaniline (20 g, 105.25 mmol) in TFA (80 mL) was stirred for 15 min till the solution became clear. To the solution, sodium nitrite (9.44 g, 136.82 mmol) solution in water (40 mL) was added and stirred at RT for 1 h under nitrogen atmosphere. Then, sodium azide (8.895 g, 136.820 mmol) solution in water (40 mL) was added and stirred at RT for 3 h under nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through the celite pad, and the solid phase was rinsed with MeOH. The filtrate was concentrated on a rotary evaporator to afford title compound (25 g crude product). The title compound was used for next step without further purification.1H NMR (DMSO-d6, 400 MHz): 7.90 (dd, 1H), (s, 1H), 7.45 (dd, 1H),7.29 (t, 1H). Intermediate 68: Synthesis of (34Z,8Z)-44-bromo-54-methyl-31H-6-oxa-2(2,4)-pyrimidina- 1(1,3),5(1,4)-dipiperidina-3(4,1)-triazola-4(1,2)-benzenacyclononaphan-8-ene

[0450] Step 1: Synthesis of Intermediate 68a. To a stirred solution of Int 13 (4.5 g, 21.099 mmol) in THF (40 mL) was added Int 67 (6.836 g, 31.647 mmol), tertiary butanol (40 mL), water (40 mL), copper sulphate pentahydrate (2.634 g, 10.55 mmol). Then, sodium ascorbate (6.27 g, 31.640mmol) was portion wise at 0 °C. The resultant solution was then stirred at RT for 12 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20 % EtOAc / hexane as an eluent to title compound (5.5 g, 60.72% yield). LCMS: m / z 429.1(M+H)+.

[0451] Step 2: Synthesis of Intermediate 68b. To a stirred solution of Int 8 (0.893 g, 4.658 mmol) in DMF (10 mL) was added K2CO3 (1.609 g, 11.640 mmol) at 0 °C and stirred for 15 min. Then, Int 68a (1.0 g, 2.329 mmol) was added to the reaction mixture and the resultant solution was heated with constant stirring at 120 °C for 12 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (1.20 g, 91.27% yield). LCMS: m / z 564.30 (M+H)+.

[0452] Step 3: Synthesis of Intermediate 68. To a stirred solution of Int 68b (0.800 g, 1.417 mmol) in DCM (100 mL) was added Grubbs catalyst 2nd generation (0.241 g, 0.280 mmol) and resultant solution was stirred at 40 °C for 12 h. After completion of reaction, the resultant solution was filtered on celite bed. The filtrate evaporated on rotary evaporator to get crude mass. The crude mass was purified by column chromatography using 6%EtOAc / Hexane to afford titled compound (0.4 g, 52.62 %). LCMS: m / z 536.10 (M+H) +.

[0453] The intermediates in Table S were prepared according to the procedure described in Intermediate 68, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.SIntermediate 69: Synthesis of 2-hydroxy-N-((34Z,8Z)-54-(trifluoromethyl)-31H-6-oxa-2(2,4)- pyrimidina-1(1,3),5(1,4)-dipiperidina-3(4,1)-triazola-4(1,2)-benzenacyclononaphan-8-en-44- yl) ethane-1-sulfonamide

[0454] Step 1: Synthesis of Intermediate 69a. Intermediate 69a was synthesized using a similar procedure described in the synthesis of Int 68a. LCMS: m / z 618.00 (M+H)+.

[0455] Step 2: Synthesis of Intermediate 69b. Intermediate 69b was synthesized using a similar procedure described in the synthesis of Int 68. LCMS: m / z 590.00 (M+H)+.

[0456] Step 3: Synthesis of Intermediate 69. A mixture of Intermediate 69b (0.85 g, 1.43 mmol), 2-hydroxyethane-1-sulfonamide (0.21 g, 1.72 mmol) in dioxane (15 mL) in a sealed tube was added K3PO4(0.76 g, 3.59 mmol) and degassed with argon for 10 min. Then, palladium (II)(π- cinnamyl) chloride dimer (0.037 g, 0.07 mmol) and tBuXPhos (0.06 g, 0.14 mmol) were added and the reaction mixture was heated to 90°C for 3 h. The completion of the reaction was monitored by TLC. After completion of the reaction, reaction mass was diluted with water and extracted with EtOAc followed by brine wash. The organic layer was dried over sodium sulphate, filtered, and concentrated to get crude mass which was purified by combi flash by eluting with 60% EtOAc / hexane as an eluent to afford title compound. LCMS: m / z 635.5 (M+H) +. The intermediates in Table T were prepared according to the procedure described in Intermediate 69, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table T:Intermediate 70: Synthesis of (Z)-44-bromo-54,7-dimethyl-31H-7-aza-2(2,4)-pyridina- 1(1,3),5(1,4)-dipiperidina-3(4,1)-triazola-4(1,2)-benzenacyclooctaphan-8-one

[0457] Step 1: Synthesis of Intermediate 70a. To a stirred solution of 2-fluoro-4-iodopyridine (15 g, 67.27 mmol) in DMSO (50 mL) was added K2CO3(27.90 g, 201.80 mmol) followed by addition of methyl piperidine-3-carboxylate (14.45 g, 100.90 mmol). The reaction mixture was then heated with constant stirring at 120 °C for 20 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (18.0 g, 77.30% yield). LCMS: m / z 347.00 (M+H)+.

[0458] Step 2: Synthesis of Intermediate 70b. To a stirred solution of Int 70a (10 g, 28.89 mmol) and ethynyltriisopropylsilane (7.90 g, 43.33 mmol) in THF (100 mL) was purged under argon and added TEA (8.77 g, 86.66 mmol) followed by addition of CuI (0.55 g, 2.88 mmol) and dichlorobis (triphenylphosphine)palladium(II) (2.03 g, 2.88 mmol) was added and the resultant solution was then heated with constant stirring at 50 °C for 4 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (15.00 g, 99.37% yield). LCMS: m / z 401.60 (M+H)+.

[0459] Step 3: Synthesis of Intermediate 70c. Int 70c was synthesized using a similar procedure described for the synthesis of Int 13. LCMS: m / z 245.30 (M+H)+.

[0460] Step 4: Synthesis of Intermediate 70d. Int 70d was synthesized using a similar procedure described for the synthesis of Int 68a. LCMS: m / z 462.20 (M+H)+.

[0461] Step 5: Synthesis of Intermediate 70e. To a stirred solution of Int 70d (4.20 g, 9.12 mmol) in DMSO (15 mL) was added DIPEA (3.62 g, 28.02 mmol) followed by addition of tert-butyl methyl (4-methylpiperidin-4-yl) methyl) carbamate (3.32 g, 13.69 mmol). The resultant solution was then heated with constant stirring at 140 °C for 36 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford title compound (2.5 g, 40.14% yield). LCMS: m / z 682.20 (M+H)+.

[0462] Step 6: Synthesis of Intermediate 70f. Int 70f was synthesized using a similar procedure described for the synthesis of Int 36c. LCMS: m / z 668.20 (M+H)+.

[0463] Step 7: Synthesis of Intermediate 70g. Int 70g was synthesized using a similar procedure described for the synthesis of Int 36h. LCMS: m / z 568.20 (M+H)+.

[0464] Step 8: Synthesis of Intermediate 70. Int 70 was synthesized using a similar procedure described for the synthesis of Int 36d. LCMS: m / z 550.20 (M+H)+. Intermediate 71: Synthesis of 2-hydroxy-N-((34Z,7Z)-54-methyl-31H-2(2,4)-pyrimidina- 1(1,3),5(1,4)-dipiperidina-3(4,1)-triazola-4(1,2)-benzenacyclononaphan-7-en-44-yl) ethane- 1-sulfonamide

[0465] Step 1: Synthesis of Intermediate 71a. To a stirred solution of (methoxymethyl)triphenyl phosphonium chloride (36.19 g, 105.58 mmol) in THF (100 mL) was added potassium tert- butoxide (11.84 g, 105.58 mmol) at 0 °C and the mixture was stirred for 1 h at the same temperature. To the resultant solution, Int 20a (12 g, 52.79 mmol) in THF (20 mL) was added dropwise at 0 °C. The reaction mixture was then brought to RT and stirred for 12 h. The completion of the reaction was monitored by TLC, showing consumption of the starting material. The reaction mass was then diluted with water and extracted with EtOAc followed by brine wash. The collectedorganic layer was dried over anhydrous sodium sulphate, filtered, and evaporated on rota vapor to obtain crude mass. The crude mass was purified by combi-flash by eluting with 20% EtOAc / hexane as an eluent to afford the title compound (10 g, 66.67% yield).1H NMR (CDCl3, 400 MHz): 6.26 (d, J = 12 Hz, 1H), 5.82 (d, J = 8 Hz, 1H), 3.75-3.72 (m, 2H), 3.56 (s, 3H), 3.53- 3.50 (m, 2H), 1.55-1.50 (m, 2H), 1.48-1.46 (m, 9 H), 1.42-1.36 (m, 2H), 1.11 (s, 3H). LC-MS: m / z 256.1 (M+H)+.

[0466] Step 2: Synthesis of Intermediate 71b. To a stirred solution of Intermediate 71a (10 g, 39.15 mmol) in THF (50 mL) was added 2M HCl (33.4 mL) at 0 °C. Then, the reaction mixture was brought to RT and stirred for 2 h. After completion of the reaction, the reaction mass was extracted with EtOAc followed by brine wash. The organic layer was dried over Na2SO4,and solvent was evaporated to get crude mass which was used for next step without further purification (7.2 g crude yield). LC-MS: m / z 242.1 (M+H)+.

[0467] Step 3: Synthesis of Intermediate 71c. Intermediate 71c was prepared using a similar procedure described for the synthesis of Int 12b.1H NMR (CDCl3, 400 MHz):5.85-5.78 (m, 1H), 5.09-5.01 (m, 2H), 3.57-3.54 (m, 2H), 3.27-3.20 (m, 2H), 2.06-2.03 (m, 2H), 1.47 (s, 9H), 1.44- 1.37 (m, 2H), 1.33-1.28 (m, 2H), 0.95 (s, 3H).

[0468] Step 4: Synthesis of Intermediate 71d. Intermediate 71d was prepared using a similar procedure described for the synthesis of Int 12. LC-MS: m / z 140.1 (M+H)+.

[0469] Step 5: Synthesis of Intermediate 71e. Intermediate 71e was prepared using a similar procedure described for the synthesis of Int 11a. LC-MS: m / z 339.1 (M+H)+.

[0470] Step 6: Synthesis of Intermediate 71f. Int 71f was synthesized using a similar procedure described for the synthesis of Int 11b. LCMS: m / z 309.1 (M+H)+.

[0471] Step 7: Synthesis of Intermediate 71g. Int 71g was synthesized using a similar procedure described for the synthesis of Int 11. LCMS: m / z 335.0 (M+H)+.

[0472] Step 8: Synthesis of Intermediate 71h. Int 71h was synthesized using a similar procedure described for the synthesis of Int 68a. LCMS: m / z 562.4 (M+H)+.

[0473] Step 9: Synthesis of Intermediate 71i. Int 71i was synthesized using a similar procedure described for the synthesis of Int 68. LCMS: m / z 534.4 (M+H)+.

[0474] Step 10: Synthesis of Intermediate 71. Int 71 was synthesized using a similar procedure described for the synthesis of Int 69. LCMS: m / z 579.4 (M+H)+.Intermediate 72: Synthesis of N-((34Z, 8Z)-54-methyl-31H-6-oxa-2(2, 4), 4(5, 4)- dipyrimidina-1(1, 3), 5(1, 4)-dipiperidina-3 (4,1)-triazolacyclononaphan-8-en-42-yl) cyclopropanesulfonamide

[0475] Step 1: Synthesis of Intermediate 72a. To a stirred solution of 2,4-dichloropyrimidine 5 amine (3 g, 18.3 mmol) in THF (30 mL) was added TEA (5.5 g, 55 mmol) followed by Int 8 (3.5 g, 18.3 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, the reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator to obtain crude mass, which was purified by eluting with 40% EtOAc / hexane as an eluent to afford title compound (3.5 g, 67.7 % yield). LCMS: m / z 283.1 (M+H)+.

[0476] Step 2: Synthesis of Intermediate 72b. Int 72b was synthesized using a similar procedure described for the synthesis of Int 11. LCMS: m / z 309.1 (M+H)+.

[0477] Step 3: Synthesis of Intermediate 72c. Int 72c was synthesized using a similar procedure described for the synthesis of Int 68a. LCMS: m / z 522.3 (M+H)+.

[0478] Step 4: Synthesis of Intermediate 72d. Int 72d was synthesized using a similar procedure described for the synthesis of Int 68. LCMS: m / z 494.3 (M+H)+.

[0479] Step 5: Synthesis of Intermediate 72. To a stirred solution of Int 72d (0.2 g, 0.40 mmol) in DMSO (2 mL) was added Cs2CO3(0.4 g, 1.21 mmol) followed by cyclopropane sulfonamide (0.1 g, 0.81 mmol). The resultant solution was then heated with constant stirring at 120 °C for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was poured into ice water and extracted with ethyl acetate. The collected organic layer was washed with brine solution and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude mass. The crude mass was purified by combi-flash by eluting with 40% EtOAc / hexane as an eluent to afford title compound (0.09 g, 38.4% yield). LCMS: m / z 579.4 (M-H)+.Intermediate 73: Synthesis of 2-hydroxy-N-((34Z, 9Z)-54-methyl-31H-7-oxa-1 (4,2)- morpholina-2 (2,4)-pyrimidina-5 (1,4)-piperidina-3 (4,1)-triazola-4 (1,2)- benzenacyclodecaphan-9-en-44-yl) ethane-1-sulfonamide

[0480] Step 1: Synthesis of Intermediate 73a. Int 73a was synthesized using a similar procedure described for the synthesis of Int 8a. LCMS: m / z 214.1, 170.2 (Boc pattern).

[0481] Step 2: Synthesis of Intermediate 73b. Int 73b was synthesized using a similar procedure described for the synthesis of Int 8. LCMS: m / z 170.05 (M+H)+.

[0482] Step 3: Synthesis of Intermediate 73c. Int 73c was synthesized using a similar procedure described for the synthesis of Int 11a. LCMS: m / z 369.2 (M+H)+.

[0483] Step 4: Synthesis of Intermediate 73d. Int 73d was synthesized using a similar procedure described for the synthesis of Int 11b. LCMS: m / z 339.1 (M+H)+.

[0484] Step 5: Synthesis of Intermediate 73e. Int 73e was synthesized using a similar procedure described for the synthesis of Int 11. LCMS: m / z 365.2 (M+H)+.

[0485] Step 6: Synthesis of Intermediate 73f. Int 73f was synthesized using a similar procedure described for the synthesis of Int 68a. LCMS: m / z 580.4 (M+H)+.

[0486] Step 7: Synthesis of Intermediate 73g. Int 73g was synthesized using a similar procedure described for the synthesis of Int 68. LCMS: m / z 552.3 (M+H)+.

[0487] Step 8: Synthesis of Intermediate 73. Int 73 was synthesized using a similar procedure described for the synthesis of Int 69. LCMS: m / z 597.3 (M+H) +.Intermediate 73’: Synthesis of 2-hydroxy-N-((34Z,9Z)-54-(trifluoromethyl)-31H-7-oxa-1(4,2)- morpholina-2(2,4)-pyrimidina-5(1,4)-piperidina-3(4,1)-triazola-4(1,2)- benzenacyclodecaphan-9-en-44-yl)ethane-1-sulfonamide: Int 73’ was synthesized using a similar procedure described for the synthesis of Int 73. LCMS: m / z 651.2 (M+H)+. Intermediate 74: Synthesis of N-((34Z, 8Z)-54-methyl-31H-6-oxa-2 (2,4)-pyrimidina-4 (3,2)- pyridina-1 (1,3), 5(1,4)-dipiperidina-3 (4,1)-triazolacyclononaphan-8-en-46-yl) cyclopropanesulfonamide

[0488] Step 1: Synthesis of Intermediate 74a. To a stirred solution of 2,6-difluoro 3- nitropyridine (2.4 g, 15 mmol) in DMF (20 mL) was added K2CO3(6.2 g, 45 mmol) followed by Int 8(2.9 g, 15 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, reaction mixture was stirred at RT for 12 h. After completion of the reaction, reaction mixture was quenched with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain crude mass, which was purified by eluting with 10% EtOAc / hexane as an eluent to afford title compound (1.8 g, 40.7 % yield). LCMS: m / z 283.1 (M+H)+.

[0489] Step 2: Synthesis of Intermediate 74b. To a stirred solution of Int 74a (1 g, 3.4 mmol) in EtOH (5 mL) and AcOH (5 mL) was added zinc powder (1.1 g, 17 mmol) at 0 °C and stirred for 10 min at the same temperature. Then, reaction mixture was stirred at 75 °C for 16 h. After completion of the reaction, reaction mixture was filtered on celite bed. Filtrate was collected and concentrated in vacuo, diluted with water and extracted with EtOAc followed by brine wash. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated on rotary evaporator to obtain title compound, which was purified used for next step without further purification (1 g crude). LCMS: m / z 266.2 (M+H)+.

[0490] Step 3: Synthesis of Intermediate 74c. Int 74c was synthesized using a similar procedure described for the synthesis of Int 11. LCMS: m / z 292.3 (M+H)+.

[0491] Step 4: Synthesis of Intermediate 74d. Int 74d was synthesized using a similar procedure described for the synthesis of Int 68a. LCMS: m / z 505.5 (M+H)+.

[0492] Step 5: Synthesis of Intermediate 74e. Int 74e was synthesized using a similar procedure described for the synthesis of Int 68. LCMS: m / z 477.4 (M+H)+.

[0493] Step 6: Synthesis of Intermediate 74. Int 74 was synthesized using a similar procedure described for the synthesis of Int 72. LCMS: m / z 578.4 (M+H)+. Intermediate 75: Synthesis of (E)-2-hydroxy-N-(54-(trifluoromethyl)-6-oxa-3(2,5)- oxadiazola-2(2,4)-pyrimidina-1 (1,3), 5 (1,4)-dipiperidina-4(1,2)-benzenacyclononaphan-8- en-44-yl) ethane-1-sulfonamide

[0494] Step 1: Synthesis of Intermediate 75a. To a stirred solution of methyl 4-bromo-2- fluorobenzoate (6.0 g, 25.74 mmol) in DMSO (40 mL) was added K2CO3 (10.67 g, 77.24 mmol) followed by Int. 8’ (6.32 g, 25.74 mmol). The reaction mixture was then heated with constant stirring at 140 °C for 5 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 2% EtOAc / hexane as an eluent to afford title compound (6.0 g, 55.19% yield). LCMS: m / z 422.0 (M+H)+.

[0495] Step 2: Synthesis of Intermediate 75b. To a stirred solution of Int. 75a (6.0 g, 14.21 mmol) in THF (30 mL), MeOH (15 mL), H2O (30 mL) and LiOH. H2O (1.22 g, 30.65 mmol) was added. The reaction mixture was stirred at RT for 12 h. The completion of the reaction was monitored using TLC. The reaction mixture was concentrated under vacuum pressure and the remaining solution was neutralised using saturated citric acid solution and finally extracted usingEtOAc followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound (5.8 g crude yield). The title compound was used for next step without further purification. LCMS: m / z 409.80 (M+H)+.

[0496] Step 3: Synthesis of Intermediate 75c. To a stirred solution of Int. 75b (5.0 g, 12.24 mmol) in DMF (20 mL) was added TEA (4.96 g, 48.99 mmol) followed by T3P (19.486 g, 61.24 mmol) at 0 °C and stirred for 5 min at the same temp. Then, 2-chloropyrimidine-4-carbohydrazide (2.536 g, 14.69 mmol) was added to the reaction mixture. The reaction mixture was stirred at RT for 2 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate followed by brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 50% EtOAc / hexane as an eluent to afford title compound (3.2 g, 46.43% yield). LCMS: m / z 564.00 (M+H)+.

[0497] Step 4: Synthesis of Intermediate 75d. To a stirred solution of Int. 75c (3.2 g, 5.686 mmol) in THF (30 mL) was added burgess reagent (3.387 g, 14.21 mmol) in portion wise manner. The reaction mixture was then refluxed with constant stirring at 65 °C for 1 h. Completion of the reaction was monitored through TLC. Then, reaction mixture was poured in water and extracted with EtOAc followed by a brine wash. The collected organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford title compound (3.0 g crude yield). The title compound was used for next step without further purification. LCMS: m / z 545.95 (M+H)+.

[0498] Step 5: Synthesis of Intermediate 75e. To a stirred solution of Int. 75d (3.0 g, 5.506 mmol) in NMP (20 mL) was added DIPEA (2.847 g, 22.02 mmol) followed by 3-vinylpiperidine hydrochloride (0.976 g, 6.607 mmol). The reaction mixture was then heated with constant stirring at 140 °C for 12 h. Completion of the reaction was monitored by TLC. Then, the reaction mixture was poured in ice water and extracted with ethyl acetate. The collected organic layer was washed with chilled water and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude mass. The crude mass was purified by combi-flash by eluting with 10% EtOAc / hexane as an eluent to afford title compound (3.2 g, 93.80% yield). LCMS: m / z 621.10 (M+H)+.

[0499] Step 6: Synthesis of Intermediate 75f. To a stirred solution of Int.75e (2.0 g, 3.228 mmol) in DCM (200 mL) were added Grubbs catalyst 2nd generation (0.548 g, 0.640 mmol) and reaction mixture was stirred at 40 °C for 12 h. After completion of reaction, the reaction mixture wasfiltered using celite bed and filtrate was evaporated to get crude mass. The crude mass was purified by combi flash using 20% EtOAc / hexane to afford title compound (0.85 g, 44.52% yield). LCMS: m / z 592.90 (M+H) +.

[0500] Step 7: Synthesis of Intermediate 75. A mixture of Intermediate 75f (0.85 g, 1.43 mmol), 2-hydroxyethane-1-sulfonamide (0.21 g, 1.72 mmol) in dioxane (15 mL) in a sealed tube was added K3PO4(0.76 g, 3.59 mmol) and degassed with argon for 10 min. Then, palladium (II)(π- cinnamyl) chloride dimer (0.037 g, 0.07 mmol) and tBuXPhos (0.06 g, 0.14 mmol) were added and the reaction mixture was heated to 90°C for 3 h. The completion of the reaction was monitored by TLC. After completion of the reaction, reaction mass was diluted with water and extracted with EtOAc followed by brine wash. The organic layer was dried over sodium sulphate, filtered, and concentrated to get crude mass which was purified by combi flash by eluting with 60% EtOAc / hexane as an eluent to afford title compound. LCMS: m / z 636.15 (M+H)+. Intermediate 76: Synthesis of 25-bromo-7-oxa-3(2,5)-oxadiazola-4(4,2)-pyridina-1(1,4)- piperidina-6(1,3)-azetidina-2(1,2)-benzenacyclooctaphan-5-oneThe procedure for preparation of intermediate 76 was similar to the preparation of intermediate 27 and 35.Example 1: Synthesis of N-(8-oxo-7-aza-3(2,5)-oxadiazola-2(2,4)-pyridina-1(1,3),5(1,4)- dipiperidina-4(1,2)-benzenacyclooctaphane-44-yl) cyclopropanesulfonamide (Compound 1)

[0501] To a mixture of Intermediate 35 (0.06 g, 0.115 mmol), cyclopropane sulfonamide (0.021 g, 0.17 mmol) in dioxane (3 mL) in a sealed tube was added K3PO4(0.061 g, 0.28 mmol) and the mixture was degassed with argon for 10 min. Then, palladium (II)(π-cinnamyl) chloride dimer (0.003 g, 0.05 mmol) and tBuXPhos (0.01 g, 0.1 mmol) were added and the reaction mixture was heated to 90°C for 4 h. Completion of the reaction was monitored by TLC showing that starting material was consumed. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc followed by brine wash. The combined organic layer was dried over sodium sulphate, filtered, and concentrated to give the crude mass which was purified by prep-HPLC to afford the title compound (0.018 g, 27% yield).1H NMR (CD3OD, 400 MHz): 8.32- 8.31 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.5 (s, 1H), 7.39-7.37 (m, 1H), 7.18 (d, J = 2 Hz, 1H), 7.08-7.05 (m, 1H), 3.93-3.88 (m, 2H), 3.74-3.70 (m, 2H), 3.60-3.56 (m, 1H), 3.17 (d, J = 2.4 Hz, 1H), 3.14 (s, 2H), 2.78 (s, 1H), 2.72-2.68 (m, 3H), 2.59 (s, 1H), 2.05 (s, 1H), 1.90-1.86 (m, 2H), 1.73 (s, 4H), 1.70 (s, 1H), 1.16-1.13 (m, 2H), 1.06-1.02 (m, 2H). LCMS: 564.3 (M+H)+

[0502] The compounds in Table 1 were prepared according to the procedure described in Example 1, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table 1:Example 2: Synthesis of N-(3(2,5)-oxadiazola-2(2,4)-pyridina-1(1,3),5(1,4)-dipiperidina- 4(1,2)-benzenacyclooctaphane-44-yl) cyclopropanesulfonamide (Compound 16)

[0503] To a stirred solution of compound 7 (0.45 g, 0.82 mmol) in EtOH:THF (1:1, 10 mL) was added 10% wet Pd / C. The reaction flask was equipped with hydrogen balloon and the mixture was stirred for 24 h at room temperature. The reaction mixture was then filtered on celite bed, the filtrate was collected and concentrated under reduced pressure to afford a crude mass which was purified by prep-HPLC to afford the title compound (0.1 g, 22% yield).1H NMR (CDCl3, 400 MHz): 8.32-8.30 (m, 2H), 7.39-7.38 (m, 1H), 7.08-7.07 (m, 1H), 6.91-6.89 (m, 1H), 6.51(s, 1H), 4.45-4.35 (m 1H), 3.95-3.85 (m, 1H), 3.37-3.32 (m, 2H), 3.25-3.15 (m, 1H), 2.97-2.93 (m, 1H), 2.85-2.81(m, 1H), 2.75-2.70 (m, 1H), 2.63-2.60 (m, 1H), 1.95-1.90 (m, 1H), 1.87-1.85 (m, 2H), 1.80-1.75 (m, 1H), 1.70-1.60 (m, 3H), 1.50-1.45 (m, 5H), 1.40-1.35 (m, 2H), 1.34-1.30 (m, 4H), 1.07-1.05 (m, 2H). LC-MS: m / z 549.4 (M+H)+.

[0504] The racemic mixture of compound-16 was separated by chiral HPLC using i cellulose-c (250 mm x 4.6 mm, 5µ) column with a mobile phase of n-hexane and 0.1% HCOOH in [EtOH:MeOH (80:20)] using a flow rate of 1.0 mL / min

[0505] Compound 17 (Isomer 1 of Compound 16): First eluting peak (ee>99%):1H NMR (CDCl3, 400 MHz): 8.32-8.30 (m, 2H), 7.39-7.38 (m, 1H), 7.08-7.07 (m, 1H), 6.91-6.89 (m, 1H), 6.51(s, 1H), 4.45-4.35 (m 1H), 3.95-3.85 (m, 1H), 3.37-3.32 (m, 2H), 3.25-3.15 (m, 1H), 2.97- 2.93 (m, 1H), 2.85-2.81(m, 1H), 2.75-2.70 (m, 1H), 2.63-2.60 (m, 1H), 1.95-1.90 (m, 1H), 1.87-1.85 (m, 2H), 1.80-1.75 (m, 1H), 1.70-1.60 (m, 3H), 1.50-1.45 (m, 5H), 1.40-1.35 (m, 2H), 1.34- 1.30 (m, 4H), 1.07-1.05 (m, 2H). LC-MS: m / z 549.4 (M+H)+.

[0506] Compound 18 (Isomer 2 of Compound 16): Second eluting peak (ee>99%):1H NMR (CDCl3, 400 MHz): 8.32-8.30 (m, 2H), 7.39-7.38 (m, 1H), 7.08-7.07 (m, 1H), 6.91-6.89 (m, 1H), 6.51(s, 1H), 4.45-4.35 (m 1H), 3.95-3.85 (m, 1H), 3.37-3.32 (m, 2H), 3.25-3.15 (m, 1H), 2.97- 2.93 (m, 1H), 2.85-2.81(m, 1H), 2.75-2.70 (m, 1H), 2.63-2.60 (m, 1H), 1.95-1.90 (m, 1H), 1.87- 1.85 (m, 2H), 1.80-1.75 (m, 1H), 1.70-1.60 (m, 3H), 1.50-1.45 (m, 5H), 1.40-1.35 (m, 2H), 1.34- 1.30 (m, 4H), 1.07-1.05 (m, 2H). LC-MS: m / z 549.4 (M+H)+.

[0507] The compounds in Table 2 were prepared according to the procedure described in Example 2, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table 2:Example 3: N-(hydroxy-3(2,5)-oxadiazola-2(2,4)-pyridina-1(1,3),5(1,4)-dipiperidina-4(1,2)- benzenacyclooctaphane-44-yl)cyclopropanesulfonamide (Compound 27 to 32, Mixture of regioisomers)

[0508] Compounds 27 to 32 were prepared using a similar procedure as described in Example 1 and without isolation subjected to chiral separation of isomers.

[0509] Two regioisomers (peak 1 and peak 2) were separated by prep-HPLC as compound 27 to 32 using Luna, omega ps C18 (250 x 21.2 mm, 5µ) column with a mobile phase of ACN:MeOH (1:1) and 0.05% TFA in H2O using a flow rate of 15 mL / min.

[0510] Peak 1 (mixture of compounds 27Aand 27B) were again subjected for prep-HPLC purification to separate two racemic isomers as compound 27A and compound 27B using Triart C-18 ExRS (250 x 20 mm, 5µ) column with a mobile phase of ACN:EtOH (3:1) and 0.1% FA in H2O using a flow rate of 15 mL / min.

[0511] Peak 2 (mixture of compounds 29 to 32) were separated by chiral HPLC to separate four stereoisomers as compounds 29 to 32 using Regis, i Cellulose-C (250 x 21.2 mm, 5µ) column with a mobile phase of n-hexane and 0.1% HCOOH in [EtOH:MeOH (80:20)] using a flow rate of 15 mL / min.

[0512] Characterization data for all the separated isomers are provided in Table 3.Table 3:Example 4: (E)-N-(6-oxa-1(4,2)-morpholina-3(2,5)-oxadiazola-2(2,4)-pyridina-5(1,4)- piperidina-4(1,2)-benzenacyclononaphan-8-en-44-yl)-2-hydroxyethane-1-sulfonamide (Compound 33)

[0513] Compound 33 was prepared using a similar procedure as described in Example 1.1H NMR (CD3OD, 400 MHz): 8.36 (d, J = 5.2 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 4 Hz, 1H), 7.21-7.18 (m, 2H), 7.08-7.04 (m, 1H), 6.35-6.33 (m, 2H), 4.56-4.48 (m, 2H), 4.09-4.05 (m, 1H), 3.98-3.95 (m, 3H), 3.80-3.72 (m, 2H), 3.42-3.40 (m, 2H), 3.00-2.95 (m, 2H), 2.89-2.86 (m, 2H), 2.59-2.56 (m, 2H), 2.30 (bs, 4H), 2.05-2.00 (m, 2H). LCMS m / z: 569.2 (M+H)+.

[0514] The compounds in Table 4 were prepared according to the procedure described in Example 4, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions.Table 4Example 5: Synthesis of (Z)-N-(6-oxa-3(2,5)-oxadiazola-2(2,4)-pyridina-1,5(1,4)- dipiperidina-4(1,2)-benzenacyclodecaphan-8-en-44-yl)-2-hydroxyethane-1-sulfonamide (Compound 116)

[0515] A mixture of Intermediate 45 (0.06 g, 0.115 mmol), 2-hydroxy ethane-1-sulfonamide (0.021 g, 0.17 mmol) in dioxane (3 mL) in a sealed tube was added K3PO4 (0.061 g, 0.28 mmol) and degassed with argon for 10 min. Then, palladium (II)(π-cinnamyl) chloride dimer (0.003 g, 0.05 mmol) and tBuXPhos (0.01 g, 0.1 mmol) were added and the reaction mixture was heated to 90°C for 4 h. The completion of the reaction was monitored by TLC showing that starting material was consumed. After completion of the reaction, reaction mass was diluted with water and extracted with EtOAc followed by brine wash. The organic layer was dried over sodium sulphate, filtered, and concentrated to get crude mass which was purified by prep-HPLC to afford title compound (0.018 g, 27% yield).1H NMR (CD3OD, 400 MHz): 8.23 (d, J = 6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.51-7.50 (m, 1H), 7.13 (d, J = 4 Hz, 1H), 7.03-7.01 (m, 1H), 5.82-5.76 (m, 1H), 5.70-5.63 (m, 1H), 4.33(d, J = 16 Hz, 1H), 3.98-3.94 (m, 4H), 3.52-3.48 (m, 1H), 3.42-3.38 (m, 3H), 3.28-3.22 (m, 2H), 2.80 (t, J= 12 Hz, 2H), 2.15-2.08 (m, 4H), 1.95-1.86 (m, 3H), 1.73- 1.65 (m, 2H), 1.48-1.40 (m, 2H). LCMS: 581.20 (M+H)+

[0516] The compounds in Table 5 were prepared according to the procedure described in Example 5, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table 5: . 1 11 1 11 11 1 111 1 11 1 11 11 1 11 1 1Example 6: N-(6-oxa-3(2,5)-oxadiazola-2(2,4)-pyrimidina-1,5(1,4)-dipiperidina-4(1,2)- benzenacyclodecaphane-44-yl)-2-hydroxyethane-1-sulfonamide (Compound 145)

[0517] To a stirred solution of compound 116(0.45 g, 0.82 mmol) in EtOH:THF (1:1, 10 mL) was added 10% wet Pd / C. The reaction flask was equipped with hydrogen balloon and stirred for 24 h at room temperature. The reaction mixture was then filtered on celite bed, filtrate collected and concentrated under reduced pressure to afford crude mass which was purified by prep-HPLC to afford the title compound (0.1 g, 22% yield).1H NMR (DMSO-d6, 400 MHz): 8.56 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.36-7.35 (m, 1H), 7.31 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.03-7.01 (m, 1H), 4.37 ((d, J = 12.8 Hz, 2H), 3.97 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 10.4 Hz, 2H), 3.39 (t, J = 6.0Hz, 2H), 3.21-3.14 (m, 4H), 2.78 (t, J = 10.8Hz 2H), 2.11 (d, J = 13.2 Hz, 2H), 1.70-1.53 (m, 6H), 1.47-1.30 (m, 8H). LCMS: m / z 583.4 (M+H)+.

[0518] The compounds in Table 6 were prepared according to the procedure described in Example 6, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table 6: 11 1 11 11 1 11 11 11 11 11Example 7: Synthesis of N-(7-cyclopropyl-54-methyl-8-oxo-7-aza-3(2,5)-oxadiazola-2(2,4)- pyridina-1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclooctaphane-44-yl) cyclopropanesulfonamide (Compound 160)

[0519] To a stirred solution of Int 62 (0.150 g, 0.236 mmol) in DMF (2 mL) was added triethylamine (0.072 g, 0.700 mmol) followed by HATU (0.369 g, 0.940 mmol) at 0 °C. Reaction mixture was brought to RT and stirred for 16 h. After completion of the reaction, reaction mass diluted with ice cold water and extracted with ethyl acetate followed by, filtered, and evaporated on rotary evaporator to obtain crude mass, crude mass was purified by combi flash chromatography onto 4 g flash column by eluted with ethyl acetate. Then purified by prep-HPLC using 0.1% formic acid in water and acetonitrile mobile phase to afford title compound (0.012 g, 8.23% yield).1H NMR (CD3OD, 400 MHz): 8.07 (d, J = 8 Hz, 1H), 8.015 (d, J = 4 Hz, 1H), 7.78 (s, 1H), 7.58- 7.56 (m, 1H), 7.31 (s, 1H), 7.15 (d, J = 8 Hz, 1H), 4.92 (d, J = 12Hz, 1H), 4.50 (d, J = 12 Hz, 1H), 4.2 (d, J = 8 Hz, 2H), 4.02 (d, J = 12 Hz, 4H), 3.89 (s, 2H), 3.73 (d, J = 4 Hz, 1H), 3.33-3.32 (m, 3H), 3.06-3.03 (m, 1H), 2.76-2.73 (m, 2H), 2.165 (d, J = 8 Hz, 2H), 1.92 (d, J = 12 Hz, 3H), 1.405-1.36 (m, 3H), 1.35 (d, J = 4 Hz, 2H), 1.12-1.10 (m, 2H), 1.07-1.03 (m, 3H), 0.92 (d, J = 4 Hz, 1H). LC-MS: m / z 618.4 (M+H)+.

[0520] The compounds in Table 7 were prepared according to the procedure described in Example 7, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table 7: . 1 1Example 8: Synthesis of N-((34Z,8Z)-31H-6-oxa-2(2,4)-pyridina-1(1,3),5(1,4)-dipiperidina- 3(4,1)-pyrazola-4(1,2)-benzenacyclononaphan-8-en-44-yl)cyclopropanesulfonamide (Compound 163)

[0521] Example 8 was synthesized using a similar procedure described in the synthesis of Intermediate 40.1H NMR (DMSO-d6, 400 MHz): 9.88 (bs, 1H), 8.98 (s, 1H), 8.12 (s, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.47 (d, J = 8.8 Hz 1H), 6.99 (s, 1H), 6.97 (d, J = 2 Hz, 2H), 6.8 (d, J = 5.2 Hz, 1H), 5.68-5.65 (m, 1H), 5.35 (t, J = 18 Hz, 1H), 4.71 (d, J = 13.6 Hz, 1H), 4.31-4.26 (m, 1H), 3.98 (m, 1H), 3.86-3.81 (m, 1H), 4.28-4.26 (m, 1H), 4.12-3.98 (m, 1H), 3.66-3.63 (m, 1H), 3.49- 3.41 (m, 1H), 3.16-3.13 (m, 1H), 2.89-2.80 (m, 2H),2.38-2.33 (m,2H),2.08-1.99 (m, 2H), 1.99- 1.93 (m, 2H),1.63-1.60 (m, 1H), 1.57-1.55 (m, 2H),1.55-1.50 (m, 2H), 0.98-0.86 (d, 4H). LCMS: m / z 561.3(M+H)+. Example 9: N-(6-methyl-7-oxo-6-aza-3(2,5)-oxadiazola-4(4,2)-pyridina-1(1,4),5(1,3)- dipiperidina-2(1,2)-benzena-8(1,2)-cyclopropanaoctaphane-25-yl) cyclopropanesulfonamide (Compound 164)

[0522] Example 9 was prepared using a similar procedure described for the synthesis of Example 1, except cyclopropane sulfonamide was used instead of 2-hydroxy ethane-1-sulfonamide. LC- MS: m / z 590.0 (M+H)+Two diastereomers were separated by prep-HPLC as peak 1 (164A) and peak 2 (164B) using Kinetex Evo C18 (250 x 21.2 mm, 5µ) column with a mobile phase of 0.1% FA in H2O and Acetonitrile using a flow rate of 16 mL / min. Peak 1 (Isomer 1 of Compound 164):1H NMR (DMSO-d6, 400 MHz): 10.28 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.18-7.13 (m, 3H), 7.03 (dd, J = 8.8, 2.0 Hz, 1H), 4.65-4.60 (m, 1H), 4.05-3.98 (m, 1H), 3.63-3.60 (m, 1H), 3.55-3.48 (m, 2H), 3.30-3.15 (m, 3H), 3.09 (s, 3H), 2.85-2.78 (m, 1H), 2.65-2.60 (m, 1H), 2.19-2.12 (m, 1H), 2.03-1.75 (m, 5H), 1.72-1.65 (m, 1H), 1.50- 1.42 (m, 1H), 1.35-1.28 (m, 1H), 1.18-1.00 (m, 5H), 0.90-0.86 (m, 1H). LC-MS: m / z 590.0 (M+H)+Peak 2 (Isomer 2 of Compound 164):1H NMR (DMSO-d6, 400 MHz): 10.28 (s, 1H), 8.31(d, J = 4 Hz, 1H), 8.01 (d, J = 8 Hz, 1H), 7.27-7.24 (m, 2H), 7.04-7.00 (m, 2H), 5.00-4.96 (m, 1H),4.18- 4.17 (m, 1H), 3.88 (d, J = 8 Hz, 1H), 3.42-3.36 (m, 1H), 3.28 (s, 1H), 2.92 (s, 1H), 2.88 (s, 3H), 2.78-2.75 (m, 2H), 2.62-2.55 (m, 2H), 2.49-2.39 (m, 2H), 2.14-2.11 (m, 1H), 2.01-1.99 (m, 1H), 1.91-1.88 (m, 1H), 1.74 (s, 1H), 1.56 (s, 1H), 1.32 (d, J = 12 Hz, 1H), 1.16 (m, 1H), 1.02-0.98 (m, 2H), 0.90-0.86 (m, 1H), 0.67-0.64 (m, 1H). LC-MS: m / z 590.3 (M+H)+.Example 10: Synthesis of (Z)-N-(54-methyl-8-oxo-31H-7-aza-2(2,4)-pyridina-1(1,3),5(1,4)- dipiperidina-3(4,1)-triazola-4(1,2)-benzenacyclooctaphane-44-yl) cyclopropanesulfonamide (Compound 165)

[0523] Example 10 was prepared using a similar procedure described for the synthesis of Example 1, except cyclopropane sulfonamide was used instead of 2-hydroxy ethane-1- sulfonamide.1H NMR (DMSO-d6, 400 MHz): 9.32 (d, J = 12.4 Hz, 2H), 8.27 (s, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.27 (s, 1H), 7.16-7.12 (m, 2H), 4.82-4.75 (m, 2H), 4.10-3.92 (m, 4H), 3.78- 3.69 (m, 2H), 3.61-3.52 (m, 2H), 2.98-2.85 (m, 3H), 2.78-2.72 (m, 1H), 2.10-1.98 (m, 2H), 1.81- 1.62 (m, 4H), 1.58-1.46 (m, 2H), 1.38-1.32 (m, 1H), 1.15 (s, 3H), 0.98 (s, 1H). LCMS: m / z 591.60 (M+H)+

[0524] The racemic compound 165 was separated by chiral HPLC using Cellulose-4 (250 x 21.2 mm, 5µ) column with a mobile phase of hexane and 0.1% FA in EtOH using a flow rate of 15 mL / min.

[0525] Compound 165A (Isomer 1 of Compound 165). First eluting peak (165A, ee 98%):1H NMR (DMSO-d6, 400 MHz): 9.32 (d, J = 12.4 Hz, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.32-7.22 (m, 1H), 7.19-7.16 (m, 1H), 7.12-7.03 (m, 2H), 4.82-4.75 (m, 1H), 4.10-3.92 (m, 2H), 3.78-3.69 (m, 2H), 3.61-3.52 (m, 2H), 3.49-3.40 (m, 2H), 2.98-2.85 (m, 4H), 2.75-2.72 (m, 1H), 2.10-1.98 (m, 2H), 1.81-1.62 (m, 5H), 1.55-1.46 (m, 2H), 1.38-1.05 (m, 4H), 0.98 (s, 3H). LCMS: m / z 591.60 (M+H)+

[0526] Compound 165B (Isomer 2 of Compound 165). Second eluting peak (165B, ee 95%):1H NMR (DMSO-d6, 400 MHz): 9.32 (d, J = 12.4 Hz, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.32-7.22 (m, 1H), 7.19-7.16 (m, 1H), 7.12-7.03 (m, 2H), 4.82-4.75 (m, 1H), 4.10-3.92 (m, 2H), 3.78-3.69 (m, 2H), 3.61-3.52 (m, 2H), 3.49-3.40 (m, 2H), 2.98-2.85 (m, 4H), 2.75-2.72 (m, 1H), 2.10-1.98 (m, 2H), 1.81-1.62 (m, 5H), 1.55-1.46 (m, 2H), 1.38-1.05 (m, 4H), 0.98 (s, 3H). LCMS: m / z 591.60 (M+H)+. Example 11: Synthesis of 2-hydroxy-N-((34Z, 8Z)-26-methyl-31H-6-oxa-2 (2,4)-pyrimidina-1 (1,3), 5 (1,4)-dipiperidina-3 (4,1)-triazola-4 (1,2)-benzenacyclononaphan-8-en-44-yl) ethane- 1-sulfonamide (Compound 166)

[0527] Example 11 was prepared using a similar procedure described for the synthesis of Example 1.1H NMR (DMSO-d6,400 MHz): 10.01 (bs, 1H), 9.24 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.08 (s, 1H), 7.07-7.03 (m, 2H), 5.76-5.68 (m, 1H), 5.38-5.33 (m, 1H), 4.78-4.69 (m, 2H), 4.34-4.28 (m, 1H), 3.77 (t, J = 6.4 Hz, 2H), 3.69-3.65 (m, 1H), 3.50-3.40 (m, 1H), 3.19-3.10 (m, 1H), 2.98-2.91 (m, 1H), 2.86-2.71 (m, 2H), 2.69-2.60 (m, 2H), 2.50-2.40 (m, 2H), 2.37 (s, 3H), 2.25-2.15 (m, 1H), 2.02-1.95 (m, 1H), 1.79-1.70 (m, 3H), 1.55-1.49 (m, 3H), 1.45-1.34 (m, 2H). LCMS: m / z 581.3 (M+H)+.

[0528] The racemic compound 166 was separated by chiral HPLC using Cellulose-4 (250 x 21.2 mm, 5µ) column with a mobile phase of hexane and EtOH using a flow rate of 15 mL / min.

[0529] Compound 166A (Isomer 1 of Compound 166). First eluting peak (166A, ee>99%):1H NMR (DMSO-d6, 400 MHz): 9.24 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.08 (s, 1H), 7.07-7.03 (m, 2H), 5.73-5.68 (m, 1H), 5.38-5.33 (m, 1H), 4.78-4.66 (m, 2H), 4.34-4.28 (m, 1H), 3.77 (t, J = 6.4 Hz, 2H), 3.70-3.65 (m, 1H), 3.50-3.40 (m, 1H), 3.19-3.10 (m, 1H), 2.98-2.91 (m, 1H), 2.86-2.71 (m, 2H), 2.69-2.60 (m, 2H), 2.50-2.40 (m, 2H), 2.37 (s, 3H), 2.25-2.15 (m, 1H), 2.02-1.95 (m, 1H), 1.79-1.70 (m, 3H), 1.55-1.49 (m, 3H), 1.45-1.34 (m, 2H). LCMS: m / z 581.3 (M+H)+.

[0530] Compound 166B (Isomer 2 of Compound 166). Second eluting peak (166B, ee>97%):1H NMR (DMSO-d6, 400 MHz): 9.24 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.08 (s, 1H), 7.07-7.03 (m, 2H), 5.73-5.68 (m, 1H), 5.38-5.33 (m, 1H), 4.78-4.66 (m, 2H), 4.34-4.28 (m, 1H), 3.77 (t, J = 6.4 Hz, 2H), 3.70-3.65 (m, 1H), 3.50-3.40 (m, 1H), 3.19-3.10 (m, 1H), 2.98-2.91 (m, 1H), 2.85-2.71 (m, 2H), 2.69-2.60 (m, 2H), 2.50-2.40 (m, 2H), 2.37 (s, 3H), 2.25-2.15 (m, 1H), 2.02-1.95 (m, 1H), 1.79-1.70 (m, 3H), 1.55-1.49 (m, 3H), 1.45-1.34 (m, 2H). LCMS: m / z 581.4 (M+H)+. Example 12: Synthesis of 2-hydroxy-N-(54-methyl-6-oxa-3(2,5)-oxadiazola-2(2,4)- pyrimidina-1(1,3),5(1,4)-dipiperidina-4(1,2)-benzenacyclononaphane-44-yl)ethane-1- sulfonamide (Compound 167)

[0531] Compound 167 was prepared using a similar procedure described for the synthesis of Example 2.1H NMR (CDCl3, 400 MHz): 8.48 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.83-6.80 (m, 1H), 4.55-4.51 (m, 2H), 4.15 (t, J = 5.2 Hz, 2H), 3.61-3.56 (m, 2H), 3.52-3.43 (m, 2H), 3.37 (t, J = 6 Hz, 3H), 3.17-3.16 (m, 1H), 3.07-3.01 (m, 2H), 2.79-2.76 (m, 1H), 2.11 (s, 1H), 2.06 (s, 1H), 1.99-1.95 (m, 4H), 1.77 (m, 2H),1.60 (s, 1H), 1.55-1.53 (m, 2H), 1.31-1.28 (m, 2H). LCMS m / z: 584.30 (M+H)+.

[0532] The racemic compound 167 was separated by chiral HPLC using i cellulose-c (250 mm x 4.6 mm, 5µ) column with a mobile phase of n-hexane and 0.1% HCOOH in [EtOH:MeOH (80:20)] using a flow rate of 1.0 mL / min.

[0533] Compound 167A (Isomer 1 of Compound 167). First eluting peak (167A, ee 99%):1H NMR (DMSO-d6, 400 MHz): 8.57-8.55 (d, J = 4.8 Hz, 1H), 7.95-7.93 (d, J = 8.8 Hz, 1H), 7.34- 7.33 (d, J = 4.8 Hz, 1H), 7.01 (s, 1H), 6.91-6.88 (m, 1H), 4.46 (m, 2H), 3.78-3.74 (t, J = 6.4 Hz,2H), 3.53 (s, 3H), 3.36-3.36 (m, 2H), 3.34-3.34 (m, 2H), 3.29-3.26 (m, 1H), 3.11 (m, 1H), 2.96- 2.91 (m, 2H), 2.08 (s, 1H), 1.83 (m, 1H), 1.82 (m, 1H), 1.78 (m, 2H), 1.70 (m, 3H), 1.56-1.53 (m, 2H), 1.44 (m, 3H). LCMS: m / z 584.30 (M+H)+

[0534] Compound 167B (Isomer 2 of Compound 167). Second eluting peak (167B, ee 93%):1H NMR (DMSO-d6, 400 MHz): 8.57-8.55 (d, J = 4.8 Hz, 1H), 7.95-7.93 (d, J = 8.4 Hz, 1H), 7.34- 7.32 (d, J = 4.8 Hz, 1H), 7.01 (s, 1H), 6.90-6.87 (dd, 1H), 4.46-4.43 (d, J = 9.6 Hz, 2H), 3.78-3.74 (t, J = 6.6 Hz, 2H), 3.53-3.51 (d, J = 7.2 Hz, 2H), 3.74-3.34 (m, 4H), 3.31 (m, 1H), 2.12 (m, 1H), 2.99-2.98 (m, 1H), 2.91 (m, 2H), 2.08 (m, 1H), 1.83-1.82 (m, 2H), 1.78 (m, 2H), 1.70 (m, 3H), 1.55-1.51 (m, 2H), 1.46-1.43 (m, 3H). LCMS: m / z 584.30 (M+H)+. The compounds in Table 8 were prepared according to the procedure described in Example 13, using appropriate variations in reactants, quantities of reagents, solvents, and reaction conditions. Table 8:

[0535] Although the present disclosure has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present disclosure encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. For example, the compounds in the Table-9 below which can be prepared by following similar procedure as described in aboveSchemes / Examples with suitable modifications known to the one ordinary skilled in the art are also included in the scope of the present disclosure. Table 9:BIOLOGY KIF18A Biochemical assay:

[0536] A microtubule-stimulated ATPase activity assay was used to measure KIF18A enzyme activity after treatment with compounds according to the present disclosure. The assay measuresADP formed from the ATPase reaction. Compounds were serially diluted 1:3 in a 10-point titration. Buffer consisting of 15 mM Tris, pH 7.5, 10 mM MgCl2, 0.01% Pluronic F-68, 1 µM Taxol was prepared.5 µL of a test compound (concentrations per serial dilution) was added to a 384-well white microplate well, followed by 5 µL of 10 nM Recombinant Human KIF18A protein expressed in E.coli and purified by affinity chromatography in-house and 30 µg / mL pig microtubules (Cytoskeleton Inc). The resulting reaction mixtures were incubated for 30 minutes at room temperature on a plate shaker at 200 rpm. Then, 5 µL of ATP (at Km 20 µM) was added to the reaction mixture and incubated for another 30 minutes at room temperature on a plate shaker at 200 rpm. Then 25 µL of ADP-GloTMreagent (Promega Inc) was added to the reaction and incubated for 40 minutes at room temperature on a plate shaker at 200 rpm. Then, 50 µL of detection reagent (KDR) was added to the reaction mixture (Maintain 1:1:2 for the reaction mixture: ADP Glo: KDR). The plate was read in luminescence mode using a Victor Nivo microplate reader. IC50values of the compounds were determined by fitting the dose-response data to sigmoidal curve fitting equation using GraphPad Prism software V9.

[0537] The compounds were screened by the above-mentioned assay procedure, and the KIF18A % inhibition values for certain exemplary compounds at 10µM are compiled in Table 10 below. Table 10: CC

[0538] IC50 values of certain exemplary compounds are summarized in the below table, wherein “A” refers to an IC50 value less than 0.5 μM, “B” refers to an IC50 value in range of 0.5 μM to 1.0 μM and “C” refers to an IC50 value greater than 1.0 μM. The results are summarized in Table 11 below. Table 11: CoCIncorporation by Reference

[0539] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents

[0540] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

We Claim:

1. A compound of formula (I):or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: each independently represents a single bond, a double bond, or a delocalized π bond; ring A represents 5-membered heteroarylenyl; X1and X2are each independently CR3or N; Y1, Y2, and Y3are each independently, CR5, C(R5)2, N, or NR5; R1is (C1-C6)alkyl, hydroxy(C1-C6)alkyl or (C3-C8)cycloalkyl; subscript ‘p’ and subscript ‘q’ are each independently 0, 1, or 2; each R2is independently (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R3is independently hydrogen or (C1-C6)alkyl; each R4is independently (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, hydroxy(C1-C6)alkyl, 5- to 6-membered heteroaryl, cyano, carboxamido, or halo; each R5is independently hydrogen or (C1-C6)alkyl, or two R5bonded to the same carbon atom are taken together to form oxo; W1represents a bond, phenylene or 3- to 12-membered heterocycloalkylene, wherein phenylene and heterocycloalkylene are optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; W2represents:i) (C1-C8)alkylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy; or ii) (C2-C8)alkenylenyl, which is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, halo and hydroxy, wherein one or more methylene units of the alkenylenyl is optionally and independently replaced with -C(O)-, -O-, -N(RW2)-, 3- to 7-membered heterocycloalkylene, or (C3- C6)cycloalkylene, and wherein the cycloalkylene is optionally substituted with one or more substituents selected from (C1-C6)alkyl, halo and hydroxy; or iii) 3- to 10-membered heterocycloalkylene; W3represents a bond or 3- to 12-membered heterocycloalkylene, which is optionally substituted with (C1-C6)alkyl, halo, halo(C1-C6)alkyl or hydroxy; and RW2represents hydrogen, (C1-C6)alkyl, (C1-C6)acyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, or (C3-C6)cycloalkyl(C1-C6)alkyl.

2. The compound according to claim 1, wherein ring A is oxadiazola, triazola, thiazola, oxazola, isoxazola, pyrazola, imidazola or thiadiazola.

3. The compound according to claim 2, wherein ring A is oxadiazola, triazola, thiazola, oxazola, isoxazola, pyrazola or thiadiazola.

4. The compound according to any one of claims 1 to 3, having a formula (IA):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1ais O, NH, or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1, and 2.

5. The compound according to any one of claims 1 to 3, having a formula (IB):, or a pharmaceutically acceptable salt or a stereoisomer thereof.

6. The compound according to any one of claims 1 to 3, having a formula (IC):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1ais O, NH or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1, and 2.

7. The compound according to any one of claims 1 to 3, having a formula (ID):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein subscripts ‘m’ and ‘n’ are each independently selected from 0, 1, and 2.

8. The compound according to any one of claims 1 to 3, having a formula (IE):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein subscripts ‘m’ and ‘n’ are each independently selected from 0, 1, and 2.

9. The compound according to any one of claims 1 to 3, having a formula (IF):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1ais O, NH or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1, and 2.

10. The compound according to any one of claims 1 to 3, having a formula (IG):, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein W1ais O, NH or CH2, and subscripts ‘m’ and ‘n’ are each independently selected from 0, 1, and 2.

11. The compound according to any one of claims 1 to 10, wherein the ring12. The compound according to any one of claims 1 to 10, wherein W1is 4- to 6-membered heterocycloalkylene.

13. The compound according to any one of claims 1 to 10, wherein W1is azetidina, morpholina, piperazina, pyrrolidina piperidina, phenylene, or quinolina.

14. The compound according to any one of claims 1 to 10, wherein W3is 4- to 12-membered heterocycloalkylene.

15. The compound according to any one of claims 1 to 10, wherein W3is azetidina, azaspiro- octana, dioxino-pyridina, diazaspiro-nonana, diazaspiro-decana, azaspiroun-decana or piperidina.

16. The compound according to any one of claims 1 to 10, wherein W2is:n the asterisk marks the point of attachment to W1.

17. The compound according to any one of claims 1 to 10, wherein R1is hydroxy(C1-C6)alkyl or cyclopropyl.

18. The compound according to any one of claims 1 to 10, wherein R1is cyclopropyl.

19. The compound according to any one of claims 1 to 10, wherein R1is hydroxy(C1-C6)alkyl.

20. The compound according to any one of claims 1 to 11, wherein R2is (C1-C6)alkyl or halo.

21. The compound according to any one of claims 1 to 20, selected from:or a pharmaceutically acceptable salt or a stereoisomer thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

23. The pharmaceutical composition of claims 1 to 22, for use in the treatment of a disease or disorder mediated by KIF18A.

24. The pharmaceutical composition for use of claim 23, wherein the disease or disorder is cancer selected from hematological cancer, lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, a DNA damage repair pathway deficient cancer, homologous-recombination deficient cancer, triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

25. A compound of claims 1 to 21, for use as a medicament.

26. A compound according to any one of claims 1 to 21, for use in the treatment of a disease or disorder mediated by KIF18A, wherein the disease or disorder mediated by KIF18A is cancer.

27. A compound according to any one of claims 1 to 21, for use in the treatment of cancer.

28. The compound according to claim 27, wherein the cancer is hematological cancer, lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, a DNA damage repair pathway deficient cancer, or a homologous-recombination deficient cancer.

29. The compound according to claim 27, wherein the cancer is a triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

30. A compound according to any one of claims 1 to 21, for use in the manufacture of a medicament for the treatment of cancer.

31. The compound according to claim 30, wherein the cancer is hematological cancer, lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, a DNA damage repair pathway deficient cancer, homologous-recombination deficient cancer, triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

32. A method of inhibiting KIF18A in a cell, comprising contacting the cell with a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or a stereoisomer thereof.

33. A method of treating a disease or condition mediated by KIF18A in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or a stereoisomer thereof.

34. The method according to claim 33, wherein the disease or condition mediated by KIF18A is cancer.

35. The method according to claim 34, wherein the cancer is hematological cancer, lymphatic cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, prostate cancer, a DNA damage repair pathway deficient cancer, or a homologous-recombination deficient cancer.

36. The method according to claim 34, wherein the cancer is a triple-negative breast cancer (TNBC), a non-luminal breast cancer, a high-grade serous ovarian cancer (HGSOC), or serous endometrial cancer.

37. The method according to any one of claims 34 to 36, wherein the cancer comprises cells that are positive for an inactivated TP53 gene and / or positive for at least one of an inactivated Rb gene, an amplified CCNE1 gene or overexpressed CCNE1 gene, an inactivated BRCA gene or a combination thereof.

38. The method according to any one of claims 34 to 37, wherein the cancer comprises cells that are positive for a mutant TP53 gene and / or comprises cells that are positive for an amplified CCNE1 gene, a silenced BRCA1 gene, a deficient Rb1 gene, or a combination thereof.

39. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

40. Use of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder mediated by KIF18A.

41. The use according to claim 40, wherein the disease or disorder is cancer.

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