WO2014111871A1

WO2014111871A1 - 4,5-dihydroisoxazole derivatives as nampt inhibitors

Info

Publication number: WO2014111871A1
Application number: PCT/IB2014/058315
Authority: WO
Inventors: Dinesh Chikkanna; Vinayak Khairnar; Sunil Kumar Panigrahi
Original assignee: Aurigene Discovery Technologies Limited
Priority date: 2013-01-17
Filing date: 2014-01-16
Publication date: 2014-07-24

Abstract

The present invention provides substituted 4,5-dihydroisoxazole derivatives of formula (I), which may be therapeutically useful, more particularly NAMPT inhibitors and in which R₁ R₂, Y, X, "Het" and "p" have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT) in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted 4,5-dihydroisoxazole derivatives of formula (I) or a pharmaceutically acceptable salts or stereoisomers or N-oxide thereof.

Description

4,5-DIHYDROISOXAZOLE DERIVATIVES AS NAMPT INHIBITORS

This application claims the benefit of Indian provisional application number 225/CHE/2013, filed on January 17, 2013 and Indian provisional application number 1130/CHE/2013, filed on March 15, 2013; which hereby incorporated by reference.

TECHNICAL FIELD

This invention pertains to compounds which inhibit the activity of NAMPT, compositions containing the compounds, and methods of treating diseases during which NAMPT is expressed.

BACKGROUND OF THE INVENTION

NAD⁺ (nicotinamide adenine dinucleotide) is a coenzyme that plays a critical role in many physiologically essential processes (Ziegkel, M. Eur. J. Biochem. 267 ^', 1550- 1564, 2000). NAD⁺ is necessary for several processes in signaling pathways including poly ADP-ribosylation in DNA repair, mono-ADP-ribosylation in both the immune system and G-protein-coupled signaling, deacylation mediated by sirtuins (Garten, A. et al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).

NAMPT (also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin) is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate- limiting enzyme in one of two pathways that salvage NAD⁺.

NAD⁺ Synthetase D

Nicotinic Acid Mononucleotide

(NAMN)

Increasing evidence suggests that NAMPT inhibitors have potential as anticancer agents. Cancer cells have a higher basal turnover of NAD⁺ and also display higher energy requirements compared with normal cells. Additionally, increased NAMPT expression has been reported in colorectal cancer (Van Beijnum, J. R. et al Int. J. Cancer 101, 118-127, 2002) and NAMPT is involved in angiogenesis (Kim, S. R. et al. Biochem. Biophys. Res. Commun. 357, 150-156, 2007). Small-molecule inhibitors of NAMPT have been shown to cause depletion of intracellular NAD⁺ levels and ultimately induce tumor cell death (Hansen, C M et al. Anticancer Res. 20, 4211-4220, 2000) as well as inhibit tumor growth in xenograft models (Olesen, U. H. et al Mol Cancer Ther. 9, 1609- 1617, 2010).

NAMPT inhibitors also have potential as therapeutic agents in inflammatory and metabolic disorders (Galli, M. et al Cancer Res. 70, 8-11 , 2010). For example, NAMPT is the predominant enzyme in T and B lymphocytes. Selective inhibition of NAMPT leads to NAD⁺ depletion in lymphocytes blocking the expansion that accompanies autoimmune disease progression whereas cell types expressing the other NAD⁺ generating pathways might be spared. A small molecule NAMPT inhibitor (FK866) has been shown to selectively block proliferation and induce apoptosis of activated T cells and was efficacious in animal models of arthritis (collagen-induced arthritis) (Busso, N. et al. Plos One 3, e2267, 2008). FK866 ameliorated the manifestations of experimental autoimmune encephalomyelitis (EAE), a model of T-cell mediated autoimmune disorders (Bruzzone, S et al. Plos One 4, e7897, 2009). NAMPT activity increases NF- kB transcriptional activity in human vascular endothelial cell, resulting in MMP-2 and MMP-9 activation, suggesting a role for NAMPT inhibitors in the prevention of inflammatory mediated complications of obesity and type 2 diabetes (Adya, R. et. al. Diabetes Care, 31, 758-760, 2008).

SUMMARY OF INVENTION

Provided herein are novel isoxazoline derivatives and pharmaceutical compositions thereof, which are useful as NAMPT inhibitors.

In one aspect of the present invention, it comprises compounds of formula (I):

wherein,

X is selected from Ό', 'S' or NCN; selected from hydrogen or alkyl;

wherein * indicates the point of attachment to 1 ;

Ri at each occurrence is independently selected from halogen, haloalkyl, haloalkyloxy, cyano, optionally substituted aryl, optionally substituted heterocyclyl, wherein the optional substituent is independently selected from one or more R₆;

or two adjacent Ri may be taken together with the atoms to which they are attached to form an optionally substituted 5-7 membered ring containing 1-2 hetero atoms independently selected from N, O and S in any stable combination; wherein the optional substituent is independently selected from one or more R₆;

R₂ is selected

substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-fused-heterocyclyl, optionally substituted heterocyclyl-fused-aryl or optionally substituted aryl-fused- heterocyclyl; wherein the optional substituent at each occurrence is independently selected from R7;

R3 is selected from hydrogen or alkyl;

R4 is selected from hydrogen or alkyl;

R5 is selected from optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-fused-aryl, optionally substituted aryl- fused-heterocyclyl, optionally substituted aryl-fused-cycloalkyl or optionally substituted cycloalkyl-fused-aryl; wherein the optional substituent, at each occurrence, is independently selected from one or more R₈;

or R4 and R5 may be taken together with the atoms to which they are attached to form an optionally substituted 3-14 membered mono or polycyclic ring containing 0-4 additional hetero atoms independently selected from N, O and S in any stable combination; R6 at each occurrence is selected from alkyl, -OR_c, halo, haloalkyl, hydroxyalkyl, -(CH₂)_mNR_aR_b or -(CO)NHR₃;

R7 is selected from heteroaryl, optionally substituted aryl, haloalkyl or - NHSO₂CH₃; wherein the optional substituent is alkoxy;

R₈ is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, -CO₂R₃ or cycloalkyl;

R_a and R_b are independently selected from hydrogen or alkyl;

R_c is selected from hydrogen, alkyl or arylalkyl;

n and p are independently selected from 0, 1 or 2;

m is selected from 1 or 2;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

In yet another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I), and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).

In yet another aspect, the present invention relates to the preparation of the compounds of formula (I).

In yet another aspect of the present invention, it provides novel 4,5- dihydroisoxazole derivatives of formula (I), which are useful for the inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) and to medical use of such 4,5-dihydroisoxazole derivatives.

DETAILED DESCRIPTION OF THE INVENTION

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 in order to facilitate the understanding of the present invention.

As used herein, the term "optionally substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, aryl, heterocyclyl, alkoxy, haloalkyl, haloalkoxy, cyano, carboxyl and aliphatic. It is understood that the substituent may be further substituted. As used herein, unless otherwise defined the term "alkyl" alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including Q-Cio straight or Q-Cio branched alkyl groups. Examples of "alkyl" include but are not limited to methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl and the like.

As used herein, the term "halo" or "halogen" alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.

As used herein, the term "haloalkyl" means alkyl substituted with one or more halogen atoms, where alkyl groups are as defined above. The term "halo" is used herein interchangeably with the term "halogen" means F, CI, Br or I. Examples of "haloalkyl" include but are not limited to trifiuoromethyl, difluoromethyl, 2, 2, 2-trifluoroethyl and the like.

"Alkoxy" refers to the group alkyl-O- or -O- alkyl, where alkyl groups are as defined above. Exemplary Ci-Cioalkyl group containing alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1 -propoxy, n-butoxy and t-butoxy and the like. An alkoxy group can be unsubstituted or substituted with one or more suitable groups or having linear or branched chain of alkyl chain.

"Haloalkoxy" refers to an alkoxy group, as defined above, wherein one or more of the alkoxy group's hydrogen atoms have been replaced with -F, -CI, -Br or -I. Examples of "haloalkoxy" include but are not limited to trifluoromethoxy, trifluoroethoxy and the like.

"Aryl" refers to aromatic hydrocarbon ring system of about 5 to 7 carbon atoms; wherein the said aryl group can be fused with other non aromatic hydrocarbon ring system of about 3 to 5 carbon atoms. Examples of a aryl group include, but are not limited to phenyl, 2,3-dihydro-lH-indene, tetrahydronaphthyl and the like. Unless otherwise specified, all aryl groups described herein may be substituted or unsubstituted.

"Heterocyclyl" refers to a saturated (i.e., "heterocycloalkyl"), partially saturated (i.e. , "heterocycloalkenyl"), or completely unsaturated (i.e. , "heteroaryl") monocyclic or polycyclic ring (include bridged, fused, and spirocyclic) system of 3 to 14 member having at least one heteroatom or heterogroup selected from -0-, -N-, -S-, N-oxide, or - CO-. Exemplary heterocyclyl groups include pyridine, furan, pyrazole, isoxazole, pyrrole, piperidine, piperazine, morpholine, imidazole, imidazo[l ,2-a]pyridine, phenyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1,2,3,4-tetrahydroisoquinoline, furan, pyridazine, pyrimidine, isoxazole, thiazole, pyrazole, thiophene, benzo[d]thiazole, pyrazine, benzo[b]thiophene, 1 ,3,4-thiadiazole, oxazole, imidazo[l,2-a]pyridine, isoquinoline, 2,3-dihydrobenzo[b][l ,4]dioxine, benzo[d]oxazole, quinoline, 2,3-dihydro- lH-indene, indazole, pyridine 1-oxide, l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine, isoindoline, 2,3-dihydro-lH-pyrrolo[3,4-c]pyridine, lH-pyrrolo[3,2-c]pyridine, 1H- benzo[d]imidazole, imidazo[l,2-a]pyrimidine, thieno[2,3-b]pyridine or furo[2,3- c]pyridine and the like. A heterocyclyl group can be unsubstituted or substituted with one or more suitable groups.

As used herein the term "cycloalkyl" alone or in combination with other term(s) means 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged and fused carbocyclyls.

"Aryl-fused-cycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein. Exemplary aryl-fused-cycloalkyl groups include 2,3-dihydro-lH-inden-l-yl, 1 ,2,3,4- tetrahydronaphth-l-yl and the like. An aryl-fused-cycloalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Cycloalkyl-fused-aryl" means a monocyclic cycloalkyl ring, such as cyclopentyl, fused to a aryl group, in which the aryl and cycloalkyl are as described herein. Exemplary cycloalkyl-fused-aryl groups include 2,3-dihydro-lH-inden-5-yl, l,2,3,4-tetrahydronaphth-5-yl and the like. A cycloalkyl-fused-aryl group can be unsubstituted or substituted with one or more suitable groups.

"Aryl-fused-heterocyclyl" means a monocyclic aryl ring, such as phenyl, fused to a heterocyclyl group, in which the aryl and heterocyclyl are as described herein. Exemplary aryl-fused-heterocycloalkyl groups include benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl, benzo[b]thiophen-2-yl, lH-benzo[d]imidazol-2-yl and the like. An aryl-fused-heterocyclyl group can be unsubstituted or substituted with one or more suitable groups.

"Heterocyclyl-fused-aryl" means a monocyclic heterocyclyl ring, such as pyrazole, piperidine or pyridyl, fused to an aryl group, in which the aryl and heterocyclyl are as described herein. Exemplary heterocyclyl-fused-aryl groups include benzo[d]oxazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, isoquinolin-5-yl, isoquinolin-6-yl, quinolin-7-yl, 2,3-dihydrobenzo[b][l ,4]dioxin-5-yl, indazol-5-yl and the like. An aryl-fused-heterocyclyl group can be unsubstituted or substituted with one or more suitable groups.

"Heterocyclyl-fused-heterocyclyl" means a monocyclic heterocyclyl ring, such as pyrazole, piperidine or pyridyl, fused to another heterocyclyl group, in which the heterocyclyl is as described herein. Exemplary heterocyclyl-fused-heterocyclyl groups include lH-pyrrolo[3,2-c]pyridine, imidazo[l,2-a]pyrimidine, thieno[2,3-b]pyridine or furo[2,3-c]pyridine and the like. A heterocyclyl-fused-heterocyclyl group can be unsubstituted or substituted with one or more suitable groups.

The term "fused" means that the second ring is attached or formed by having two adjacent atoms in common with the first ring. The term "fused" is equivalent to the term "condensed".

"Cyano" refers to an -CN group.

The term "heteroatom" as used herein designates a sulfur, nitrogen, or oxygen atom.

As used herein, the term 'compound(s)' comprises the compounds disclosed in the present invention.

As used herein, the term "comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

As used herein, the term "or" means "and/or" unless stated otherwise.

As used herein, the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.

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. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the term "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. As used herein, the term "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.

As used herein, the term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.

"Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

"N-oxides" are meant to comprise the compounds of Formula (I), (IA), (IB) and (IC), as illustrated herein, and the compounds of Table 1, wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.

The term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), (IA), (IB) and (IC), wherever they are chiral or when they bear one or more double bond. When the compounds of the formula (I), (IA), (IB) and (IC), and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers 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 or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers, including keto-enol tautomers; all tautomeric isomers are provided by this invention.

The present invention provides substituted 4,5-dihydroisoxazole derivatives of formula (I), which are useful for the inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPT).

The present invention further provides pharmaceutical compositions comprising the said substituted 4,5-dihydroisoxazole compounds and their derivatives as therapeutic agents.

In our invention to provide substituted 4,5-dihydroisoxazole compounds, the first embodiment of the present invention provides the structure of compounds as set forth in formula (I);

X is selected from Ό', 'S' or NCN;

Y is selected from hydrogen or alkyl;

wherein * indicates the point of attachment to 1 ;

R₂ is selected

optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-fused-heterocyclyl, optionally substituted heterocyclyl-fused-aryl or optionally substituted aryl-fused- heterocyclyl; wherein the optional substituent at each occurrence is independently selected from R₇;

R₃ is selected from hydrogen or alkyl;

R4 is selected from hydrogen or alkyl;

R₅ is selected from optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-fused-aryl, optionally substituted aryl- fused-heterocyclyl, optionally substituted aryl-fused-cycloalkyl or optionally substituted cycloalkyl-fused-aryl; wherein the optional substituent, at each occurrence, is independently selected from one or more Rs;

or R4 and R₅ may be taken together with the atoms to which they are attached to form an optionally substituted 3-14 membered mono or polycyclic ring containing 0-4 additional hetero atoms independently selected from N, O and S in any stable combination;

R6 at each occurrence is selected from alkyl, -OR_c, halo, haloalkyl, hydroxyalkyl, -(CH₂)_mNR_aR_b or -(CO)NHR₃ ;

R₇ is selected from heteroaryl, optionally substituted aryl, haloalkyl or - NHSO₂CH₃; wherein the optional substituent is alkoxy;

R_a and R_b are independently selected from hydrogen or alkyl;

R_c is selected from hydrogen, alkyl or arylalkyl;

n and p are independently selected from 0, 1 or 2;

m is selected from 1 or 2;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof. In another embodiment of the present invention, it provides the structure of compounds as set forth in formula (I A)

wherein,

Ri and R₂ are same as defined in formula 1 ;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

In yet another embodiment of the present invention, it provides the structure of compounds as set forth in formula (IB)

wherein,

Ri is selected from optionally substituted aryl or optionally substituted heterocyclyl;

Rzt, R₅ and n are same as defined in formula 1 ;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

In yet another embodiment of the present invention, it provides the structure of compounds as set forth in formula (IC)

wherein, R5 is heterocyclyl;

n is 0 or 1 ;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

In one embodiment, specifically provided are compounds of the formula (I) in which X is O.

In another embodiment, specifically provided are compounds of the formula (I) in which X is NCN.

In yet another embodiment, specifically provided are compounds of the formula (I) in which X is S.

In yet another embodiment, specifically provided are compounds of the formula (I) in which Y is hydrogen.

In yet another embodiment, specifically provided are compounds of the formula (I) in which Y is methyl.

In yet another embodiment, specifically provided are compounds of the formula

(I) in which

[_s and R₃ is hydrogen.

In yet another embodiment, specifically provided are compounds of the formula

(I) in which

and R₃ is methyl.

In yet another embodiment, specifically provided are compounds of the formula (I) in which p is 1.

In yet another embodiment, specifically provided are compounds of the formula (I) in which p is 2.

In yet another embodiment, specifically provided are compounds of the formula (I), (IA) and (IB) in which Ri is heterocyclyl. In yet another embodiment, specifically provided are compounds of the formula (I), (IA) and (IB) in which the above said heterocyclyl is selected from pyridine, furan, pyrazole, isoxazole, pyrrole, piperidine, piperazine, morpholine or imidazole.

In yet another embodiment, specifically provided are compounds of the formula (I), (IA) and (IB) in which Ri is phenyl.

In yet another embodiment, specifically provided are compounds of the formula (I) and (IA) in which R₂ is heterocyclyl, heterocyclyl-fused-heterocyclyl, heterocyclyl- fused-aryl or aryl-fused-heterocyclyl.

In yet another embodiment, specifically provided are compounds of the formula (I) and (IA) in which the above said heterocyclyl, heterocyclyl-fused-heterocyclyl, heterocyclyl-fused-aryl or aryl-fused-heterocyclyl is selected from

In yet another embodiment, specifically provided are compounds of the formula (IA) in which Ri is pyridine substituted with fluorine and R₂ is imidazo[l ,2-a]pyridine.

Another embodiment of the present invention provides a pharmaceutical composition comprising the compound as disclosed, and a pharmaceutically acceptable salt or stereoisomer or N-oxide thereof.

The compounds as disclosed in the present invention are formulated for pharmaceutical administration.

Yet another embodiment of the present invention provides use of the compounds as disclosed in the present invention useful in the treatment and prevention of diseases or disorder, caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT).

Diseases and/or disorders associated with elevated level of nicotinamide phosphoribosyltransferase (NAMPT) include, but are not limited to cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, skin cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, bladder cancer, leukemia, lymphoma, Hodgkin' s disease, viral infections including adult respiratory distress syndrome, ataxia telengiectasia, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, fibrotic diseases, dermatitis, atoptic dermatitis, psoriasis, ultra-violet induced skin damage, systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spodylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, restenosis, diabetes, glomerulonephritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, cancers of the brain and central nervous system, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck. The compounds of the present invention may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.

The pharmaceutical composition can be administered by oral, parenteral or inhalation routes. Examples of the parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and trans pulmonary administrations.

The MS (Mass Spectral) data provided in the examples were obtained using the equipment- API 2000 LC/MS/MS Triplequard,

Agilent Technologies/LC/MS/DVL/Singlequard,

Shimadzu LCMS-2020/Singlequard.

The NMR data provided in the examples were obtained using the equipment - ^lH NMR: Varian -400 MHz and Varian 300 MHz

The HPLC performed forthe provided examples using the equipements- AgilentTechnologies 1200 Series,

AgilentTechnologies 1100 Series,

Shimadzu (UFLC) Prominance,

Shimadzu Nexera-UHPLC.

The following abbreviations refer respectively to the definitions below:

NCS - N-Chlorosuccinimide; BOP Reagent - (Benzotriazol-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; DMSO - Dimethylsulfoxide; DIPEA - Ν,Ν-Diisopropylethylamine; HOBt - N- Hydroxybenzotriazole, NaHCC>3 - Sodium bicarbonate; NH₂OH.HCI - Hydroxylamine hydrochloride; EtOH - Ethanol; NaOCl - Sodium hypochlorite; Dioxane.HCl; - Hydrochloric acid in dioxane; K₂CO₃ - Potassium carbonate; Na₂SC¼ - Sodium sulphate; Na₂C0₃ - Sodium carbonate; DMP - Dess-Martin periodinane; Tetrakis - Tetrakis(triphenylphosphine)palladium(0); B(pin) - Bis(pinacolato)diboron, Pd(dppf)Ci₂ - [1 ,1 '-Bis (diphenylphosphino) ferrocene] dichloropalladium(II); H₂0 - water; br - Broad; A- Angstrom ; °C - Degree Celsius ; cone - Concentrated; CHCI₃ - Chloroform; CDCl₃//chloroform-d - Deuterated Chloroform; DMSO-d₆- Deuterated dimethylsulfoxide; CH₂C1₂ - DCM - Dichloromethane; DMF- N, N- Dimethylformamide;; Et₂0 - Diethyl ether; g- Gram; h - Hours; ^lH- Proton; HC1- Hydrochloric acid; Hz- Hertz; / - Coupling Constant; LC-MS - Liquid Chromatography- Mass Spectroscopy; HPLC - High-performance liquid chromatography; chiral HPLC - chiral high-performance liquid chromatography; MeOH - methanol; M - Molar; MHz - Mega Hertz (frequency); MS - Mass Spectroscopy; mrnol - Milli Mole; mL - Milli Litre; min - Minutes; mol - Moles; M⁺- Molecular ion; Ν- Normality; NMR - Nuclear Magnetic Resonance; Et₃N/TEA - Triethyl amine; ppm - Parts per million; rt/RT - Room temperature; s - Singlet; d - Doublet, t - Triplet; q - Quartet; m - Multiplet; dd - doublet of doublets; td - triplet of doublets; qd - quartet of doublets; ddd - doublet of doublet of doublets; dt - doublet of triplets; ddt - doublet of doublet of triplets; TLC - Thin Layer Chromatography; THF - Tetrahydrofuran; % - Percentage; μ - Micron; δ- Delta; anh. - anhydrous; PMS - Phenazine methosulfate; XTT - 2,3-Bis-(2-Methoxy-4- Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide; cDMEM - Dulbecco's Modified Eagle's Medium; FBS - Fetal bovine serum; NAM - Nam - Nicotinamide; NMN - Nmn - Nicotinamide mononucleotide; nm- nanometer; PRPP- Phosphoribosyl pyrophosphate; ATP - Adenosine triphosphate; BSA - Bovine serum albumin; DTT - Dithiothreitol; MgCl₂ - Magnesium chloride; IC₅₀ - Inhibitory concentration 50; RFU - relative fluorescence units and Tris - tris(hydroxymethyl)aminomethane.

General modes of preparation:

Compounds of this invention 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 vulnerable moieties may be protected and deprotected, as necessary.

Schemes:

General procedure for examples:

Scheme-1:

(ΙΑ')

Reagents and conditions: i) Method A or Method B; ii) Method C or Method D; iii) Method E or Method F.

Method A: NCS, DMF, RT, 3h, Et₃N, 0°C - RT, 36 h.

Method B: NaOCl, DCM, RT, 12 h.

Method C: 1,4 dioxane in HC1, dioxane, 0°C - RT, 12 h.

Method D: Ethereal HC1, Ether or 1,4 dioxane, 0°C - RT, 12 h.

Method E: EDCI.HC1, HOBt, DIPEA, DMF, RT, 16 h.

Method F: (BOP reagent or HATU), DIPEA, DMF, RT, 16 h.

Scheme-2:

Reagents and conditions: i) Method A or Method B; ii) Bis(pinacalato) diboran, KOAc, Pd(dppf)Ci₂ dcm complex,Dioxane,90°C,16h; iii) Method G or Method H or Method I; iv) Ri-Br, Pd(dppf)Cl₂ dcm complex, K₂C0₃, Dioxane:H₂0, 110°C, 12 h; v) Method C or Method D; vi) Method E or Method F.

Method A: NCS, DMF, RT, 3h, Et₃N ,0°C - RT, 36 h. Method B: NaOCl, DCM, rt, 12 h.

Method C: 1,4 dioxane in HC1, dioxane, 0°C - RT, 12 h.

Method D: Ethereal HC1, Ether or 1,4 dioxane, 0°C - RT, 12 h.

Method E: EDCI.HCl, HOBt, DIPEA, DMF, RT, 16 h.

Method F: (BOP reagent or HATU), DIPEA, DMF, RT, 16 h

Method G: RiB(pin) or R_!B(OH)₂, Pd(dppf)Cl₂, K₂C0₃, Dioxane:H₂0, 110°C, 12 h. Method H: RiB(pin) or R_!B(OH)₂, Tetrakis, Cs₂C0₃, DMF, 110°C, 12 h.

Method I: RiB(pin) or RiB(OH)₂, Tetrakis, Na₂C0₃, THF: H₂0, 100°C, 12 h.

Scheme-3:

Reagents and conditions: i) NCS, DMF, RT, 3h,Et₃N,0°C-RT, 36 h; ii) NH₂NH₂.H₂0, MeOH, 60°C, 3h; iii) EDCI.HCl, HOBt, Et₃N, DCM, rt, 16 h; iv) RiB(pin), Pd(dppf)Cl₂, Na₂C0₃, Dioxane:H₂0, 80°C, 13h.

Scheme-4:

Reagents and conditions: i) Method J or Method K; ii) Et₃N, DMAP, pyridine, 80 °C, 16h; iii) Et₃N, DMSO, rt, 12 h; iv) NaHC0₃, 0°C - RT, 12 h; v) Method J or Method K.

Method J: Et₃N, DMSO, RT, 16 h.

Method K: DMSO, RT, 16 h.

Scheme-5:

Reagents and conditions: i) NH₂OH.HCl, NaHC0₃, EtOH, RT, 30 min.; ii) NaOCl (6 ), DCM, RT, 12 h; iii) Method C or Method D; iv) Et₃N, DMSO, RT, 2 h.

Method C: 1,4 dioxane in HC1, dioxane, 0°C - RT, 12 h. Method D: Ethereal HC1, Ether or 1,4 dioxane, 0°C - RT, 12 h.

The specifics of the process for preparing compounds of the present invention are detailed in the experimental section.

In the following, the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention.

EXPERIMENTAL

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

Analysis for the compounds of the present invention unless mentioned, was conducted in the general methods well known to the person skilled in the art. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples, describing in detail the analysis of the compounds of the invention.

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 invention.

EXAMPLES

The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention.

Example-l:l-((5-(([l, l'-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(pyridin-3-yl) urea (±).

Step-1: Tert-butyl (2-(hydroxyimino) ethyl) carbamate (mixture of E and Z isomer).

Tert-butyl (2-oxoethyl)carbamate (18.5 g, 116 mmol), hydroxylamine hydrochloride (13.8 g, 232 mmol) and sodium bicarbonate (24.3 g, 232 mmol) were dissolved in ethanol (200 mL) and the reaction mixture was stirred for 12 h at room temperature. Solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate (100 mL) and washed with water (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure afforded the titled compound (18.5 g, crude) as liquid (mixture of E and Z isomer). The crude product was taken to the next step without any further purification.

Step-2: 2-(aUyloxy)-l , 1 ' -biphenyl.

Allyl iodide (6.4 g, 38.4 mmol) was added to a mixture of anhydrous potassium carbonate (13.2 g, 96 mmol) and biphenyl phenol (5.5 g, 32 mmol) in N,N- dimethylformamide (50 mL). The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate. Combined extracts were washed with water (2 x 30 mL) and dried. The solvent was evaporated to give residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 5/95) to give the titled compound (4.4 g, 65.6%) as a yellow liquid.

Step-3: Tert-butyl ((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (7.5 g, 43.05 mmol) in N,N-dimethylformamide (220 mL) was added N-chlorosuccinimide (6.5 g, 48.68 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h then cooled to 0 °C and added 2-(allyloxy)-l ,l'-biphenyl (9.0 g, 43.05 mmol) in one lot followed by dropwise addition of solution of triethylamine (6.43 mL, 47.4 mmol) in N,N-dimethylformamide (44 mL) over 30 min. The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured onto water at room temperature, extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 20/80) to give the titled compound (10 g, 72.9 %) as a liquid. LCMS: nt/z 282.9 [M-100] ⁺; H NMR (300 MHz, Chloroform-d) δ 7.54 - 7.46 (m, 2H), 7.40 (ddt, / = 8.1 , 6.0, 1.9 Hz, 2H), 7.35 - 7.27 (m, 3H), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.94 (dd, / = 8.6, 1.1 Hz, 1H), 4.87 (ddt, / = 10.6, 6.9, 3.5 Hz, 1H), 4.37 - 4.20 (m, 1 H), 4.21 - 4.05 (m, 1 H), 3.96 (dd, / = 10.2, 3.3 Hz, 1H), 3.81 (qd, / = 16.2, 6.3 Hz, 2H), 3.03 - 2.74 (m, 2H), 1.43 (d, / = 7.5 Hz, 9H).

Step-4: (5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

To a solution of tert-butyl ((5-(([l, l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl) methyl)carbamate (±) (7.5 g, 19.6 mmol) in 1 ,4-dioxane (10 mL) was added 4 N HC1 in 1 ,4-dioxane (40 mL) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. The solid precipitated out was filtered and triturated with diethyl ether to give titled compound (5.5 g, 88 %) as a solid.

Step-5: Phenyl pyridin-3-ylcarbamate.

To a solution of 3-aminopyridine (0.300 g, 3.19 mmol) in pyridine (5 mL) was added phenylchloroformate (0.600 g, 3.83 mmol) at 0 °C. The reaction mixture was stirred for 1 h then reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the titled compound (0.500 g, 73 %) as a solid.

Step-6: l -((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridin-3-yl)urea (±).

A solution of (5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.080 g, 0.283 mmol), phenyl pyridin-3-ylcarbamate (0.060 g, 0.283 mmol) and triethylamine (0.118 mL, 0.849 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (hexanes/ethyl acetate = 20/80) to give the titled compound (0.025 g, 21.9 %) as white solid. HPLC: 97.3 ; LCMS: nt/z 403.1 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.37 (d, / = 2.7 Hz, 1H), 8.26 (dd, / = 4.7, 1.5 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.65 - 7.58 (m, 2H), 7.49 (dd, / = 8.4, 6.8 Hz, 2H), 7.43 - 7.36 (m, 1H), 7.36 - 7.29 (m, 2H), 7.21 (dd, / = 8.4, 4.7 Hz, l H), 7.08 (td, / = 7.5, 1.0 Hz, 1H), 6.98 - 6.91 (m, 1H), 6.33 (s, lH), 4.94 (ddt, / = 11.5 , 6.0, 2.7 Hz, 1H), 4.24 (dd, / = 10.2, 3.0 Hz, 2H), 4.11 - 3.79 (m, 3H), 3.02 (dd, / = 17.3, 11.3 Hz, 1H), 2.89 (dd, / = 17.3, 6.4 Hz, lH).

Example-2: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridin-4-yl) urea (±).

Step-1: Phenyl pyridin-4-ylcarbamate.

To a solution of 4-aminopyridine (0.300 g, 3.19 mmol) in pyridine (5 mL) was added phenylchloroformate (0.600 g, 3.83 mmol) at 0 °C. The reaction mixture was stirred for 1 h then reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the titled compound (0.5 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridin-4-yl) urea (±).

A solution of (5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.050 g, 0.177 mmol) and phenyl pyridin-4-ylcarbamate (0.038 g, 0.177 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by Preparative TLC (hexanes/ethyl acetate = 20/80) to give the titled compound (0.015 g, 21.0 %) as white solid. HPLC: 97.3 %; LCMS: m/z 403.1 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.39 - 8.31 (m, 2H), 7.59 - 7.52 (m, 2H), 7.49 - 7.41 (m, 2H), 7.39 - 7.27 (m, 5H), 7.20 (s, 1H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 6.95 (dd, / = 8.7, 1.1 Hz, 1H), 5.03 - 4.84 (m, 2H), 4.20 (dd, / = 10.3, 3.2 Hz, 1H), 4.05 - 3.85 (m, 3H), 3.03 (dd, / = 17.3, 11.2 Hz, 1H), 2.89 (dd, / = 17.3, 6.6 Hz, 1H).

Further the enantiomeric mixture (2.0 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 2a & 2b). Method: Column: LUX AMYLOSE-2 AXIA PACKED (21.2 x 250 x 5u), n-hexane: ethanol: 40:60, Flow Rate: 20 mL/min. , Isocratic.

Example-2a: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridin-4-yl) urea .

Yield : 0.900 g ; Retention Time : 6.6 min.; HPLC: 99.1 ; LCMS: m/z 403.1 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.39 - 8.31 (m, 2H), 7.59 - 7.52 (m, 2H), 7.49 - 7.41 (m, 2H), 7.39 - 7.27 (m, 5H), 7.20 (s, 1H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 6.67 (dd, / = 8.7, 1.1 Hz, 1H), 5.03 - 4.84 (m, lH), 4.58 (m, 1H), 4.20 (dd, / = 10.3, 3.2 Hz, 1H), 4.05 - 3.85 (m, 3H), 3.03 (dd, / = 17.3, 11.2 Hz, 1H), 2.89 (dd, / = 17.3, 6.6 Hz, 1H). Example-2b: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridin-4-yl)urea .

Yield: 0.900g ; Retention Time :21.6 min.; HPLC: 99.1 ; LCMS: m/z 403.1 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.39 - 8.31 (m, 2H), 7.59 - 7.52 (m, 2H), 7.49 - 7.41 (m, 2H), 7.39 - 7.27 (m, 5H), 7.20 (s, 1H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 6.67 (dd, / = 8.7, 1.1 Hz, IH), 5.03 - 4.84 (m, IH), 4.58 (m, IH), 4.20 (dd, / = 10.3, 3.2 Hz, IH), 4.05 - 3.85 (m, 3H), 3.03 (dd, / = 17.3, 11.2 Hz, IH), 2.89 (dd, / = 17.3, 6.6 Hz, IH).

Example-3: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-2-cyano-3-(pyridin-4-yl) guanidine (±).

Step-1: Phenyl N'-cyano-N-(pyridin-4-yl) carbamimidate.

A solution of 4-aminopyridine (0.612 g, 6.5 mmol), diphenyl N-cyanocarbonimidate (1.540 g, 6.5 mmol) and triethylamine (1.0 mL, 6.5 mmol) in acetonitrile (15 mL) was stirred at 80 °C for 2h and allowed to stir at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate, washed with water. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/ dichloromethane = 10/90) to give titled compound (0.700 g, 47 %) as green thick mass. LCMS : m/z 239.10 [M+H] ⁺.

Step-2: l-((5-(([l , l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-2- cyano-3-(pyridin-4-yl) guanidine (±).

A solution of (5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.050 g, 0.177 mmol) and phenyl N'-cyano-N-(pyridin-4-yl)carbamimidate (0.042 g, 0.177 mmol) in acetonitrile (1 mL) was stirred at 80 °C for 12 h. The volatiles were evaporated completely under reduced pressure. The obtained residue was purified by preparative TLC (ethyl acetate/hexanes = 90/10) to give the titled compound (0.010 g, 13%) as off white solid. HPLC: 93.1 %; LCMS: m/z 426.9 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.58 (m, 2H), 7.80 (bs, IH), 7.43-7.19 (m, 8H), 7.10 (m, IH), 6.96 (m, IH), 5.84 (bs,lH), 5.36 (m, IH), 4.99 (m, IH), 4.23 -4.13 (m, IH), 4.03 -3.80 (m, 3H), 3.08-2.99 (m, IH), 2.90-2.84 (m, IH). Example-4: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-carboxamide (±).

Step-1: Phenyl ((5-(([l, l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

To a suspension of (5-(([l , l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine (±) (0.300 g, 1.06 mmol) and NaHC0₃ (0.267 g, 3.18 mmol) in THF (10 mL) was added phenylchloroformate (0.199 g, 1.27 mmol) at 0°C. The reaction mixture was stirred for 12 h at RT. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over Na₂S0₄ and evaporated under reduced pressure to give the titled compound (0.300 g, 70 ) as a liquid.

Step-2: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-6J- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide (±) .

A solution phenyl ((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.100 g, 0.249 mmol), 4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine (0.050 g, 0.373 mmol) and triethylamine (0.050 mL, 0.373 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over Na₂SC>4 and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.030 g, 27 %) as off white solid.HPLC: 99.13 ;LCMS: mJz 448.3 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 7.55 (dd, / = 8.0, 1.4 Hz, 2H), 7.41 (t, / = 7.6 Hz, 2H), 7.32 (ddt, / = 10.9, 7.2, 1.8 Hz, 3H), 7.13 (d, / = 5.3 Hz, 1H), 7.06 (td, / = 7.5, 1.1 Hz, 1H), 6.95 (d, / = 8.0 Hz, 1H), 6.76 (d, / = 5.2 Hz, 1H), 4.89 (td, / = 7.0, 3.2 Hz, 1H), 4.48 (d, / = 5.7 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.16 (dd, / = 10.2, 3.6 Hz, 1H), 4.13 - 3.91 (m, 3H), 3.65 (td, / = 5.8, 3.5 Hz, 2H), 3.01 (dd, / = 17.2, 11.2 Hz, 1H), 2.90 - 2.77 (m, 3H). Further the enantiomeric mixture (0.025 g) was separated by Chiral Preparative HPLC to give two separated enantiomers (example 4a & 4b). Method: Column: CHIRAL PAK IC-H (10mm x 250mm x5u), Hexane: IPA: Methanol: 1 :1 ) 90: 10, Flow Rate: 7 mL/Min), Isocratic.

Example-4a: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-carboxamide.

Yield :0.007 g ; Retention Time : 45.92 min. ; Chiral HPLC: 99.89 ; HPLC: 98.55 ; LCMS: m/z 448.3 [M+H] ⁺; H NMR (400 MHz, Chloroform-d) δ 7.55 (dd, / = 8.0, 1.4 Hz, 2H), 7.41 (t, / = 7.6 Hz, 2H), 7.32 (ddt, / = 10.9, 7.2, 1.8 Hz, 3H), 7.13 (d, / = 5.3 Hz, 1H), 7.06 (td, / = 7.5 , 1.1 Hz, 1H), 6.95 (d, / = 8.0 Hz, 1H), 6.76 (d, / = 5.2 Hz, 1H), 4.89 (td, / = 7.0, 3.2 Hz, 1H), 4.48 (d, / = 5.7 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.16 (dd, / = 10.2, 3.6 Hz, 1H), 4.13 - 3.91 (m, 3H), 3.65 (td, / = 5.8 , 3.5 Hz, 2H), 3.01 (dd, / = 17.2, 11.2 Hz, 1 H), 2.90 - 2.77 (m, 3H).

Example-4b: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-carboxamide.

Yield: 0.007 g ; Retention Time : 26.99 min. ; Chiral HPLC: 98.1 ; HPLC: 99.2 ; LCMS: m/z 448.3 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.55 (dd, / = 8.0, 1.4 Hz, 2H), 7.41 (t, / = 7.6 Hz, 2H), 7.32 (ddt, / = 10.9, 7.2, 1.8 Hz, 3H), 7.13 (d, / = 5.3 Hz, 1H), 7.06 (td, J = 7.5 , 1.1 Hz, 1H), 6.95 (d, / = 8.0 Hz, 1H), 6.76 (d, / = 5.2 Hz, 1H), 4.89 (td, / = 7.0, 3.2 Hz, 1H), 4.48 (d, / = 5.7 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.16 (dd, / = 10.2, 3.6 Hz, 1H), 4.13 - 3.91 (m, 3H), 3.65 (td, / = 5.8 , 3.5 Hz, 2H), 3.01 (dd, / = 17.2, 11.2 Hz, 1 H), 2.90 - 2.77 (m, 3H).

Example-5: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3,4-dihydro isoquinoline-2(lH)-carboxamide (±).

A solution phenyl ((5-(([l, l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.100 g, 0.249 mmol) and 1 , 2, 3, 4-tetrahydroisoquinoline (0.050 g, 0.373 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.030 g, 27 %) as off white solid. HPLC: 96.78%; LCMS: m/z 442.6 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 7.58 - 7.51 (m, 2H), 7.45 - 7.37 (m, 2H), 7.31 (dddd, / = 11.7, 5.5, 2.8, 1.8 Hz, 3H), 7.23 - 7.03 (m, 5H), 6.98 - 6.92 (m, 1H), 4.89 (ddt, / = 10.3, 6.7, 3.4 Hz, lH), 4.56 - 4.47 (m, 1H), 4.46 - 4.34 (m, 2H), 4.20 - 3.92 (m, 4H), 3.61 - 3.43 (m, 2H), 3.02 (dd, / = 17.3, 11.2 Hz, 1H), 2.91 - 2.78 (m, 3H).

Example-6: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridin-3-yl methyl) urea (±).

Phenyl ((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.100 g, 0.249 mmol) was reacted with pyridin-3- ylmethanamine (0.040 g, 0. 373 mmol) as described in the synthesis of example-5 to give the titled compound (0.027 g, 26 % ) as a white solid. LCMS: m/z 417.5 (M+H]⁺; HPLC: 97.46%; ^lU NMR (400 MHz, Chloroform-d) δ 8.47 (d, / = 8.2 Hz, 2H), 7.52 (ddt, / = 10.0, 7.7, 1.8 Hz, 3H), 7.44 - 7.37 (m, 2H), 7.37 - 7.24 (m, 3H), 7.15 - 7.02 (m, 2H), 6.98 - 6.91 (m, 1H), 4.89 (ddd, / = 11.6, 6.2, 3.0 Hz, 1H), 4.38 (d, / = 6.0 Hz, 1H), 4.30 (dd, / = 5.8, 3.2 Hz, 2H), 4.20 (dd, / = 10.2, 3.0 Hz, 1H), 4.04 (dd, / = 16.5, 8.2 Hz, 1H), 3.94 (dd, / = 10.2, 2.7 Hz, 1H), 3.80 - 3.68 (m, 2H), 2.98 (dd, / = 17.3, 11.4 Hz, 1H), 2.81 (dd, / = 17.3, 6.4 Hz, 1H).

Example-7: l-((3-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-5-yl) methyl)-3- (pyridin-3-yl) urea (±).

Step-1: 2-(2-bromophenoxy) acetaldehyde.

Titled compound was synthesized as per reported procedure in Chemistry-A European Journal, 18(11), 3286-3291, 2012.

Step-2: 2-(2-bromophenoxy) acetaldehyde oxime.

2-(2-bromophenoxy) acetaldehyde (1.24 g, 5.76 mmol), hydroxylamine hydrochloride (0.840 g, 12.1 mmol) and sodium bicarbonate (1.01 g, 12.1 mmol) were dissolved in ethanol (10 mL) and the reaction mixture was stirred at room temperature for 30 min. Solvent was removed under reduced pressure. The resulting residue was diluted with ethyl acetate (100 mL) and washed with water (2 x 100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (1.06 g, crude). The crude product was taken to the next step without further purification.

Step-3: tert-butyl allylcarbamate.

BocHN

To a suspension of ally amine (2.0 g, 35.08 mmol) in dichloromethane was added Boc- anhydride (8.4 g, 38.59 mmol), followed by triethylamine (5.3 g, 52.63 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure to give the residue. Residue was purified by column chromatography on silica gel (hexanes/ethyl acetate =hexanes/ ethyl acetate =90/10) to give the titled compound (2.2 g, 80 %) as a liquid.

Step-4: tert-butyl ((3-((2-bromophenoxy) methyl)-4, 5-dihydroisoxazol-5-yl) methyl) carbamate (±)

To a solution of 2-(2-bromophenoxy) acetaldehyde oxime (1.0 g, 4.340 mmol) and tert- butyl allylcarbamate (0.610 g, 3.910 mmol) in dichloromethane (10 mL) was added sodium hypochlorite (6%, aqueous solution) (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The layers were separated and organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 10/90) to give the titled compound (0.400 g, 25%) as off white solid. LCMS: m/z 330 [M-54]⁺ ; 1H NMR (400 MHz, Chloroform-d) δ 7.56 - 7.54 (dd, 1H), 7.28 - 7.25 (m, 1H), 6.96 (td, / = 8.3, 1.4 Hz, lH), 6.93 - 6.85 (m, 1H), 4.98 - 4.82 (m, 3H), 4.83 - 4.68 (m, lH), 3.41 (m,lH), 3.33 - 3.14 (m, 2H), 2.92 (dd, / = 17.6, 7.6 Hz, 1H), 1.46 - 1.40 (s, 9H).

Step-5:l-((3-((2-bromophenoxy) methyl)-4, 5-dihydroisoxazol-5-yl) methyl)-3-(pyridin- 3-yl) urea (±)

To a solution of tert-butyl ((3-((2-bromophenoxy) methyl)-4, 5-dihydroisoxazol-5-yl) methyl) carbamate (±) (0.4 g, 1.03 mmol) in 1 ,4-dioxane (5 mL) was added 4N HC1 in 1,4-dioxane (40 mL) at 0 °C. The reaction mixture was stirred for 2h at room temperature. The reaction mixture was evaporated under reduced pressure to give residue. The residue was triturated with diethyl ether to give (3-((2-bromophenoxy) methyl)-4, 5-dihydro isoxazol-5-yl) methanamine hydrochloride (±) (0.270 g, 91%) as a solid. A solution of above obtained (3-((2- bromophenoxy) methyl)-4, 5- dihydroisoxazol-5-yl) methanamine hydrochloride (±) (0.120 g, 0.42 mmol), phenyl pyridin-3-ylcarbamate (prepared in step-1 of example-1) (0.134 g, 0.63 mmol) and triethylamine (0.110 mL, 0.63 mmol) in DMSO (1 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 1/99) to give the titled compound (0.100 g, 83 %) as white solid. HPLC: 99.35 %; LCMS: m/z 405.4 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.51 (d, / = 2.6 Hz, 1H), 8.11 (dd, / = 4.7, 1.5 Hz, 1H), 7.92 - 7.82 (m, 1H), 7.56 (dd, / = 7.8, 1.6 Hz, 1H), 7.34 (td, / = 7.9, 7.5, 1.6 Hz, 1H), 7.28 - 7.14 (m, 2H), 6.91 (td, / = 7.7, 1.4 Hz, 1H), 6.48 (t, / = 5.9 Hz, 1H), 4.95 (s, 2H), 4.79 - 4.63 (m, 1H),3.36 - 3.09 (m, 2H), 3.23 - 3.12 (m, 1H), 2.90 (dd, / = 17.5, 7.5 Hz, 1H).

Example-8: l-((3-(([l, l'-biphenyl]-2-yloxy) methyl)-5-methyl-4, 5-dihydroisoxazol- 5-yl) methyl) -3 -(pyridin-3-yl) urea (±).

Step-1: 2-([l, l '-biphenyl]-2-yloxy) acetaldehyde oxime.

To a solution of 2-([l , l'-biphenyl]-2-yloxy) ethanol (3.8 g, 17.73 mmol) (synthesized as per reported procedure in Journal of the American Chemical Society, 127(44), 15521 - 15527, 2005) in dichloromethane (20 mL) was added Dess-Martin periodinane (9.7 g, 23.05 mmol) and stirred for 4 h at room temperature. Reaction mixture was filtered, washed with dichloromethane (2 x 20 mL). Collected filtrate was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated to give 2-([1 ,Γ- biphenyl]-2-yloxy)acetaldehyde (3.7 g, crude) as orange liquid.2-([l,l'-biphenyl]-2- yloxy)acetaldehyde] (2.6 g, 12.25 mmol) was reacted with hydroxylamine hydrochloride (1.78 g, 25.72 mmol) and sodium bicarbonate (2.1 g, 25.72 mmol) as described in the synthesis of step-2 of example-7 to give the titled compound (2.7 g, crude). The crude product was used as such for the next step without further purification. LCMS: m/z 228.1 [M+H] ⁺.

Step-2: tert-butyl (2-methylallyl) carbamate.

2-methylprop-2-en- 1 -amine (3.0 g, 42.18 mmol) was reacted with di-tert-butyl dicarbonate (10.0 g, 46.40 mmol) as described in the synthesis of step-3 of example-7 to give the titled compound (5.0 g, 69.4 %) as a solid. LCMS: m/z 172 [M+ H] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 4.89 - 4.76 (m, 2H), 4.65 (s, 1H), 3.67 (d, / = 6.3 Hz, 2H), 1.74 (d, / = 1.2 Hz, 3H), 1.46 (s, 9H).

Step-3:tert-butyl((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5- yl) methyl )carbamate (±).

2-([l, l '-biphenyl]-2-yloxy)acetaldehyde oxime (1.9 g, 8.36 mmol) was reacted with tert-butyl (2-methylallyl)carbamate (1.43 g, 8.360 mmol) as described in the synthesis of step-4 of example-7 to give the titled compound (0.8 g, 24 %) as a solid.LCMS: m/z 396 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.52 - 7.46 (m, 2H), 7.44 - 7.38 (m, 2H), 7.38 - 7.29 (m, 3H), 7.10 (td, / = 7.5, 1.1 Hz, 1H), 7.03 (dd, / = 8.1 , 1.1 Hz, 1H), 4.75 (q, / = 12.5 Hz, 3H), 3.37 - 3.15 (m, 2H), 2.83 (d, / = 17.6 Hz, 1H), 2.60 (d, / = 17.5 Hz, 1 H), 1.41 (s, 9H), 1.29 (s, 3H).

Step-4: l-((3-(([l ,l'4jiphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5- yl)methyl)-3-(pyridin-3-yl)urea (±).

tert-butyl ((3-(([l ,l'4jiphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5-yl) methyl) carbamate (±) (0.800 g, 2.020 mmol) was reacted with 4 N HC1 in 1 ,4-dioxane (5mL) as described in the synthesis of step-4 of example- 1 to give (3-(([l ,l'-biphenyl]-2- yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5-yl) methanamine hydrochloride (±) (0.579 g, crude). Above obtained (3-(([l, l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5- dihydroisoxazol-5-yl) methanamine hydrochloride (±) (0.100 g, 0.33 mmol) was further reacted with phenyl pyridin-3-ylcarbamate (prepared in step- 1 of example- 1) (0.072 g, 0.330 mmol) and triethylamine (0.110 mL, 0.630 mmol) as described in the synthesis of step-5 of example-7 to give the titled compound (0.026 g, 18.3 %) as a solid. HPLC: 99.64 ; LCMS: nt/z 417.1 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.38 - 8.30 (m, 1H), 8.25 (dd, / = 4.8, 1.5 Hz, 1H), 7.95 (ddd, / = 8.4, 2.8, 1.5 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.41 - 7.33 (m, 2H), 7.33 - 7.16 (m, 3H), 7.11 - 6.95 (m, 3H), 5.25 (t, / = 6.2 Hz, 1H), 4.74 (s, 2H), 3.56 (dd, / = 14.5, 7.5 Hz, 1H), 3.28 (dd, / = 14.5 , 5.0 Hz, 1H), 2.98 (d, / = 17.7 Hz, 1H), 2.68 (d, / = 17.7 Hz, 1H), 1.35 (s, 3H).

Example-9:l-((3-(([l, l'-biphenyl]-2-yloxy) methyl)-5-methyl-4, 5-dihydroisoxazol- 5-yl) methyl)-3-(pyridin-4-yl) urea (±).

(3-(([l , 1 '-biphenyl] -2-yloxy)methyl)-5 -methyl-4,5-dihydroisoxazol-5 -yl) methanamine hydrochloride (±) (0.050 g, 0.170 mmol) was reacted with phenyl pyridin-4-ylcarbamate (prepared in step- 1 of example-2) (0.037 g, 0.170 mmol) as described in the synthesis of step-5 of example-7 to give the titled compound (0.020 g, 27 %) as a solid. HPLC: 98.34 ; LCMS : nt/z All .2 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.42 - 8.29 (m, 2H), 7.50 - 7.41 (m, 2H), 7.40 - 7.19 (m, 7H), 7.07 (td, / = 7.5, 1.1 Hz, 1H), 6.98 (dd, / = 8.1 , 1.0 Hz, l H), 5.41 (d, / = 6.7 Hz, 1H), 4.73 (s, 2H), 3.56 (dd, / = 14.6, 7.4 Hz, 1H), 3.27 (dd, / = 14.5, 5.1 Hz, 1H), 2.97 (d, / = 17.8 Hz, lH), 2.69 (d, / = 17.7 Hz, 1H), 1.35 (s, 3H).

Example- 10: l-((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol- 5-yl)methyl)-3-(pyridin-3-ylmethyl) urea (±).

Step-1: Phenyl (pyridin-3-ylmethyl) carbamate.

To a suspension of pyridin-3-ylmethanamine (0.100 g, 0.926 mmol) and sodium bicarbonate (0.233 g, 2.780 mmol) in THF (5 mL) was added phenylchloroformate (0.174 g, 1.11 mmol) at 0 °C. The reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the titled compound (0.200 g, 90 %) as a liquid.

Step-2: l -((3-(([l, l '-biphenyl]-2-yloxy) methyl) -5 -methyl-4, 5-dihydroisoxazol-5-yl) methyl)- 3 -(pyridin- 3 -ylmethyl) urea (±).

(3-(([l , 1 '-biphenyl] -2-yloxy)methyl)-5 -methyl-4,5-dihydroisoxazol-5 -yl) methanamine hydrochloride (±) (0.050 g, 0.170 mmol) was reacted with phenyl (pyridin-3- ylmethyl) carbamate (0.040 g, 0.170 mmol) as described in the synthesis of step-5 of example-7 to give the titled compound (0.020 g, 26 %) as a solid. HPLC: 98.6 %; LCMS: mJz 430.9 [M+ H]⁺ ; ^lU NMR (400 MHz, Chloroform-d) δ 8.48 (dd, / = 5.2, 3.2 Hz, 2H), 7.57 (dt, / = 7.9, 2.0 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.44 - 7.37 (m, 2H), 7.37 - 7.28 (m, 3H), 7.22 - 7.15 (m, 1H), 7.1 1 - 6.98 (m, 2H), 4.76 - 4.61 (m, 4H), 4.36 (dd, / = 15.3, 6.1 Hz, 1H), 4.22 (dd, / = 15.3, 5.8 Hz, l H), 3.54 - 3.43 (m, 1H), 3.24 (dd, / = 14.5, 4.9 Hz, 1H), 2.91 (d, / = 17.6 Hz, 1H), 2.62 (d, / = 17.6 Hz, 1H), 1.37 - 1.15 (m, 3H). Further the enantiomeric mixture (0.020 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 10a & 10b). Method: Column: CHIRAL PAK IC-H (10 mm x 250 mm x5u), n-hexane: (ethanol: methanol): 90: 10, Isocratic Flow Rate: 7 mL/min

Example- 10a: l-((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol- 5-yl)methyl)-3-(pyridin-3-ylmethyl)urea.

Yield:0.002 g; Retention Time: 6.57 min ; Chiral HPLC: 98.52 ; HPLC: 97.45 ; LCMS: m/z 430.9 [M+H] ⁺.

Example- 10b : 1 -((3-(([l ,1 ' -biphenyl] -2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol- 5-yl)methyl)-3-(pyridin-3-ylmethyl)urea.

Yield: 0.002 g; Retention Time: 8.38 min.; Chiral HPLC: 96.8%; HPLC: 98.8 %; LCMS: m/z 430.9 [M+H] ⁺

Example-11: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-fluoropyridin-4-yl) urea (±)

Step-1: Phenyl (2-fluoropyridin-4-yl) carbamate

To a solution of 2-fluoropyridin-4-amine (0.500 g, 4.464 mmol) in pyridine (5 mL) was added phenyl chloro formate (0.73 lg, 4.67 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the titled compound (0.518 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(2- fluoropyridin-4-yl)urea (±)

A solution of (5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol), phenyl (2-fluoropyridin-4-yl)carbamate (0.130 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) in DMSO (2 mL) was stirred at room temperature for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (hexanes/ethyl acetate = 20/80) to give the titled compound (0.040 g, 20.22 %) as a solid. HPLC: 90.5 ; LCMS: mJz 421.5 [M+ H]⁺; H NMR (400 MHz, Chloroform-d) δ 7.92 (d, / = 5.7 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.48 - 7.39 (m, 2H), 7.40 - 7.28 (m, 3H), 7.16 (s, 1H), 7.14 - 7.03 (m, 2H), 7.00 - 6.92 (m, 2H), 4.99 - 4.82 (m, 2H), 4.32 - 4.17 (m, 1H), 4.03 - 3.84 (m, 3H), 3.04 (dd, / = 17.3, 1 1.3 Hz, 1H), 2.89 (dd, / = 17.4, 6.6 Hz, 1H).

Example- 12: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-chloropyridin-4-yl)urea (±)

Step-1: Phenyl (2-chloropyridin-4-yl) carbamate.

2-chloropyridin-4-amine (0.500 g, 4.464 mmol) was reacted with phenylchloroformate (0.838 g, 5.357 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-1 1 to give the titled compound (0.515 g) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l , l ' -biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (2-chloropyridin-4-yl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with phenyl(2-chloropyridin-4-yl)carbamate (0.140 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.010 g, 4.87 %) as a solid. HPLC: 98.9 ; LCMS: nt/z 437.8 [M+ H]⁺; 1 H NMR (400 MHz, Chloroform-d) δ 8.09 (d, / = 5.6 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.53 - 7.18 (m, 6H), 7.17 - 7.04 (m, 2H), 6.99 - 6.92 (m, 1H), 6.86 (d, / = 7.6 Hz, 1H), 5.02 - 4.89 (m, 1H), 4.68 (s, 1 H), 4.23 (dd, / = 10.5, 2.9 Hz, 1H), 4.08 - 3.79 (m, 3H), 3.04 (dd, / = 17.5, 11.4 Hz, 1H), 2.90 (dd, / = 17.3, 6.5 Hz, lH).

Example- 13: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methyl pyridin-4-yl) urea (±).

Step-1: Phenyl (2-methylpyridin-4-yl) carbamate.

2-methylpyridin-4-amine (0.150 g, 1.388 mmol) was reacted with phenylchloroformate (0.261 g, 1.665 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-1 1 to give the titled compound (0.210 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l , l ' -biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (2-methylpyridin-4-yl) urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (2-methylpyridin-4-yl)carbamate (0.130 g, 0.565mmol) and triethylamine (0.099 mL,0.706 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.020 g, 10.2 %) as a solid. HPLC: 92.15 ;LCMS: nt/z 416.9 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.23 (dd, / = 11.7, 5.7 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.55 - 7.46 (m, 2H), 7.44 - 7.13 (m, 4H), 7.13 - 6.98 (m, 2H), 6.99 - 6.82 (m, 1 H), 6.54 (s, 1 H), 5.00 - 4.82 (m, 1H), 4.36 (s, 1H), 4.32 - 4.14 (m, 1H), 4.04 (dd, / = 16.2, 7.1 Hz, 1H), 3.95 (dd, / = 10.3, 2.7 Hz, 1H), 3.84 (dd, / = 16.0, 4.4 Hz, 1H), 3.10 - 2.81 (m, 2H), 2.45 (d, / = 7.8 Hz, 3H). Further the enantiomeric mixture (0.150 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 13a & 13b). Method: Column: CHIRAL PAK AD-H (10 mm x 250mm x 5μ); n-hexane: (ethanol: methanol: 1 :1 ): 50:50, Isocratic.

Example- 13a: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methyl pyridin-4-yl) urea (±). Yield : 0.020 g ; Retention Time : 13.02 min.; Chiral HPLC: 95.93 ; HPLC: 98.6 ; LCMS: m/z 416.9 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.27 (d, / = 5.6 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.55 - 7.45 (m, 2H), 7.45 - 7.37 (m, 1H), 7.37 - 7.29 (m, 2H), 7.17 (d, / = 2.2 Hz, 1H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 7.00 (dd, / = 6.8, 1.4 Hz, 1H), 6.94 (dd, / = 8.6, 1.0 Hz, 1H), 6.20 (s, 1H), 5.01 - 4.91 (m, 1H), 4.25 (dd, / = 10.3, 2.8 Hz, 1H), 4.14 - 3.99 (m, 2H), 3.95 (dd, / = 10.4, 2.5 Hz, 1H), 3.89 - 3.77 (m, 1H), 3.02 (dd, / = 17.3, 11.4 Hz, 1H), 2.88 (dd, / = 17.3, 6.1 Hz, 1H), 2.47 (s, 3H).

Example- 13b: l-((5-(([l, l'-biphenyl]-2-yloxy) methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methyl pyridin-4-yl)urea.

Yield : 0.020 g ; Retention Time : 29.55 min.; Chiral HPLC: 91.10 ; HPLC: 98.8 ; LCMS: m/z 416.9 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.27 (d, / = 5.6 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.55 - 7.45 (m, 2H), 7.45 - 7.37 (m, 1H), 7.37 - 7.29 (m, 2H), 7.17 (d, / = 2.2 Hz, 1H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 7.00 (dd, / = 6.8, 1.4 Hz, 1H), 6.94 (dd, / = 8.6, 1.0 Hz, 1H), 6.50 (s, 1H), 4.96 - 4.91 (m, 1H), 4.35 (dd, / = 10.3, 2.8 Hz, 1H), 4.24 - 4.21 (m, 2H), 4.00 (dd, / = 10.4, 2.5 Hz, 1H), 3.96 - 3.82 (m, 2H), 3.02 (dd, / = 17.3, 11.4 Hz, 1H), 2.88 (dd, / = 17.3, 6.1 Hz, 1H), 2.47 (s, 3H).

Example- 14: l-((5-(([l, l'-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(3-cyanophenyl)urea (±).

To a solution of (5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) and 3-isocyanatobenzonitrile (0.080 g, 0.565 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (0.198 mL, 1.412 mmol) and stirred at 60 °C for 12 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (hexanes/ethyl acetate = 20/80) to give the titled compound (0.030 g, 14.9 %) as a solid. HPLC: 98.8 ; LCMS: m/z All A [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.69 (t, / = 1.9 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.52 - 7.42 (m,

3H), 7.42 - 7.21 (m, 4H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 6.95 (dd, / = 8.7, 1.1 Hz, 1H), 6.48 (s, 1H), 4.94 (ddt, / = 11.5, 6.0, 2.8 Hz, 1H), 4.38 (t, / = 5.8 Hz, 1H), 4.23 (dd, / = 10.4, 2.9 Hz, 1H), 4.08 - 3.91 (m, 2H), 3.86 (dd, / = 16.3, 4.6 Hz, 1H), 3.03 (dd, / = 17.3, 11.3 Hz, 1H), 2.89 (dd, / = 17.3, 6.3 Hz, 1H).

Example- 15: l-((5-(([l, l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(furan-2-ylmethyl) urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with 2- (isocyanatomethyl)furan (0.070 g, 0.565 mmol) and triethylamine (0.099 mL,0.706 mmol) as described in the synthesis of example- 14 to give the titled compound (0.020 g, 10.5 %) as a solid. HPLC: 98.67 ; LCMS: nt/z 405.9 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.60 - 7.49 (m, 2H), 7.46 - 7.37 (m, 2H), 7.37 - 7.28 (m, 3H), 7.25 (dd, / = 1.9, 0.9 Hz, 1 H), 7.06 (td, / = 7.5, 1.1 Hz, 1H), 6.94 (dd, / = 8.1 , 1.0 Hz, 1 H), 6.25 (dd, / = 3.2, 1.9 Hz, 1H), 6.13 (dq, / = 3.1 , 0.8 Hz, 1H), 4.88 (ddt, / = 11.5, 6.1 , 2.8 Hz, 1H), 4.42 (t, / = 5.7 Hz, 1H), 4.33 - 4.24 (m, 2H), 4.19 (dd, / = 10.2, 3.1 Hz, 1H), 4.08 - 3.96 (m, 1H), 3.92 (dd, / = 10.2, 2.7 Hz, lH), 3.84 - 3.72 (m, 2H), 2.97 (dd, / = 17.3 , 11.3 Hz, 1 H), 2.82 (dd, / = 17.3, 6.4 Hz, 1H).

Example- 16: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-cyanophenyl) urea (±).

Step-1: Phenyl (4-cyanophenyl) carbamate.

4-aminobenzonitrile (0.500 g, 4.232 mmol) was reacted with phenylchloroformate (0.795 g, 5.079 mmol) in pyridine (5 mL) as described in the synthesis of step- 1 of example-11 to give the titled compound (0.600 g) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(4- cyanophenyl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (4-cyanophenyl)carbamate (0.110 g, 0.471mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.080 g, 39.8 %) as a solid. HPLC: 95.0 ; LCMS: m/z 426.9 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 - 7.67 (m, 2H), 7.59 - 7.57 (m, 2H), 7.51 - 7.49 (m, 2H), 7.40 - 7.36 (m, 2H), 7.32 - 7.27 (m, 3H), 7.12 - 7.03 (m, 2H), 6.69 (t, / = 5.7 Hz, 1H), 4.83 (m, 1H), 4.15 - 3.98 (m, 2H), 3.94 (t, / = 5.5 Hz, 2H), 3.07 (dd, / = 17.3, 11.0 Hz, 1H), 2.82 (dd, / = 17.4, 7.5 Hz, 1H). Further the enantiomeric mixture (0.060 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 16a & 16b). Method: Column: LUX AMYLOSE-2 AXIA PACKED (21.2x250x5u), n-hexane: ethanol: 20:80, Flow Rate: 20 mL/Min.) , Isocratic.

Example- 16a: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-cyanophenyl) urea.

Yield : 0.025 g ; Retention Time : 6.33 min; Chiral HPLC: 99.30 ; HPLC: 98.85 ; LCMS: m/z 426.9 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.65 - 7.58 (m, 2H), 7.56 - 7.46 (m, 4H), 7.45 - 7.37 (m, 3H), 7.36 - 7.29 (m, 2H), 7.13 - 7.04 (m, 1H), 6.94 (d, / = 8.5 Hz, 1H), 6.34 (s, 1H), 5.00 - 4.88 (m, 1H), 4.25 (dd, / = 10.4, 2.8 Hz, 1H), 4.18 - 4.00 (m, 2H), 3.95 (dd, / = 10.4, 2.5 Hz, 1H), 3.83 (dd, / = 15.6, 3.9 Hz, 1H), 3.02 (dd, / = 17.3, 11.3 Hz, 1H), 2.88 (dd, / = 17.2, 6.2 Hz, 1H)

Example- 16b: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-cyanophenyl) urea .

Yield : 0.020 g ; Retention Time : 43.77 min.; Chiral HPLC: 97.8 ; HPLC: 98.86 ; LCMS: m/z 426.9 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d): δ 7.65 - 7.58 (m, 2H), 7.56 - 7.46 (m, 4H), 7.45 - 7.37 (m, 3H), 7.36 - 7.29 (m, 2H), 7.13 - 7.04 (m, 1H), 6.94 (d, / = 8.5 Hz, 1H), 6.34 (s, 1H), 5.00 - 4.88 (m, 1H), 4.25 (dd, / = 10.4, 2.8 Hz, 1H), 4.18 - 4.00 (m, 2H), 3.95 (dd, / = 10.4, 2.5 Hz, 1H), 3.83 (dd, / = 15.6, 3.9 Hz, 1H), 3.02 (dd, / = 17.3, 11.3 Hz, 1H), 2.88 (dd, / = 17.2, 6.2 Hz, 1H). Example- 17: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyrimidin-4-yl) urea (±).

Step-1: Phenyl pyrimidin-4-ylcarbamate.

Pyrimidin-4-amine (0.100 g, 1.053 mmol) was reacted with phenylchloroformate (0.198 g, 1.263 mmol) in pyridine (5 mL) as described in the synthesis of step- 1 of example-11 to give the titled compound (0.180 g,crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: 1 -((5-(([l , 1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyrimidin-4-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.150g, 0.471 mmol) was reacted with phenyl pyrimidin-4-ylcarbamate (0.101 g, 0.471 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.025 g, 13.17 %) as a solid. HPLC: 94.72%; LCMS: nt/z 404.1 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6): δ 9.79 (s, 1H), 8.73 (d, / = 1.2 Hz, 1 H), 8.49 (d, / = 5.8 Hz, 1H), 7.97 (d, / = 6.3 Hz, 1 H), 7.58 - 7.45 (m, 3H), 7.44 - 7.23 (m, 6H), 7.16 - 6.99 (m, 2H), 4.84 (ddt, / = 1 1.3, 7.9, 4.5 Hz, 1H), 4.14 - 3.92 (m, 5H), 3.08 (dd, / = 17.4, 10.9 Hz, 1 H), 2.83 (dd, / = 17.4, 7.5 Hz, 1H).

Example- 18: l-((5-(([l,l'-biphenyl]-2-yloxy) methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-fluorophenyl) urea (±)

Step-1: Phenyl (4-fluorophenyl) carbamate.

To a stirred solution of 4-fiuoroaniline (0.500 g, 4.505 mmol) in THF (10 mL) were added sodium bicarbonate (1.135 g, 13.514 mmol), followed by phenylchloroformate (0.846 g, 5.405 mmol) at 0 °C . The reaction mixture was stirred at room temperature for 30 min . The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 100 mL). Organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give the titled compound (0.800 g,crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l, l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl)methyl)-3- (4-fluorophenyl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (4-fiuorophenyl) carbamate (0.108 g, 0.471 mmol) and triethylamine (0.132 mL, 0.941 mmol)as described in the synthesis of step-2 of example-11 to give the titled compound (0.050 g, 25.33 %) as a solid. HPLC: 98.9 ; LCMS: nt/z 419.9 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.55 - 7.47 (m, 2H), 7.46 - 7.24 (m, 7H), 7.12 - 7.03 (m, 4H), 6.44 (t, / = 5.6 Hz, 1H), 4.88 - 4.77 (m, 1H), 4.16 - 3.99 (m, 2H), 3.92 (t, / = 5.4 Hz, 2H), 3.38 (q, / = 7.0 Hz, 1H), 2.82 (dd, / = 17.4, 7.5 Hz, 1H).

Example- 19: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-cyano-3-(trifluoromethyl)phenyl)urea (±).

Step-1: Phenyl (4-cyano-3-(trifluoromethyl) phenyl) carbamate.

4-amino-2-(trifluoromethyl)benzonitrile (0.500 g, 2.686 mmol) was reacted with phenylchloroformate (0.500 g, 3.224 mmol) in pyridine (5 mL) described in the synthesis of step-1 of example- 11 to give the titled compound (0.490 g,crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(4- cyano-3-(trifiuoro methyl) phenyl) urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (4-cyano-3-(trifiuoromethyl)phenyl)carbamate (0.140 g, 0.471 mmol) and triethylamine(0.198 mL, 1.412 mmol) as described in the synthesis of step-2 of example - 11 to give the titled compound (0.090 g, 38.7%) as a solid. HPLC: 97.9%; LCMS: nt/z 495.1 [M+H]⁺; H NMR (400 MHz, Chloroform-d) δ 7.81 (d, / = 2.1 Hz, l H), 7.64 - 7.48 (m, 4H), 7.46 - 7.35 (m, 5H), 7.21 (s, 1H), 7.12 - 7.04 (m, 1H), 6.94 (d, / = 8.4 Hz, 1H), 4.95 (ddd, / = 9.6, 6.4, 3.3 Hz, 2H), 4.22 (dd, / = 10.5 , 3.0 Hz, 1H), 4.03 - 3.88 (m, 3H), 3.15 - 2.97 (m, 1H), 2.91 (dd, / = 17.4, 6.6 Hz, 1H).

Example-20: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(6-chloro pyridazin-3-yl)urea (±).

Step-1: Phenyl (6-chloropyridazin-3-yl) carbamate.

6-chloropyridazin-3-amine (0.500 g, 4.464 mmol) was reacted with phenylchloroformate (0.725 g, 4.631 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-1 1 to give the titled compound (0.640 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l , l ' -biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (6-chloropyridazin-3-yl) urea (±)

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1 ) (0.150 g, 0.471 mmol) was reacted with phenyl (6-chloropyridazin-3-yl)carbamate (0.140 g, 0.565 mmol) and triethylamine(0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.120 g, 58.25 %) as a solid. HPLC: 97.25 %; LCMS: mJz 438.3 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.03 (d, / = 9.4 Hz, 1H), 7.79 (d, / = 9.4 Hz, 1H), 7.61 (t, / = 5.6 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.44 - 7.24 (m, 5H), 7.18 - 6.99 (m, 2H), ), 4.83 (ddt, / = 11.4, 7.7, 4.0 Hz, 1H), 4.16 - 3.90 (m, 4H), 3.08 (dd, / = 17.4, 11.0 Hz, 1H), 2.82 (dd, / = 17.4, 7.4 Hz, 1H).

Example-21: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-methyl pyrimidin-2-yl)urea (±).

Step-1: Phenyl (4-methylpyrimidin-2-yl) carbamate.

4-methylpyrimidin-2-amine(0.500 g, 4.464 mmol) was reacted with phenylchloroformate (0.861 g, 5.500 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 11 to give the titled compound (0.525g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(4- methylpyrimidin-2-yl) urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with phenyl (4-methylpyrimidin-2-yl)carbamate (0.130 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.020 g, 10.18 %) as a solid. HPLC: 95.2 ; LCMS: m/z All.9 [M+ H]⁺; H NMR (400 MHz, Chloroform-d) δ 9.53 (s, 1H), 8.32 (d, / = 5.1 Hz, 1H), 7.57 - 7.42 (m, 3H), 7.41 - 7.18 (m, 5H), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.96 (d, / = 8.2 Hz, 1H), 6.77 (d, / = 5.1 Hz, 1H), 4.88 (ddt, / = 11.3, 7.7, 4.2 Hz, 1H), 4.24 - 3.97 (m, 4H), 3.05 (dd, / = 17.3, 10.9 Hz, 1H), 2.90 (dd, / = 17.3, 7.2 Hz, 1H), 2.45 (s, 3H). Example-22: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyrimidin-2-yl)urea (±).

Step-1: Phenyl pyrimidin-2-ylcarbamate.

2-aminopyrimidine (0.200 g, 2.103 mmol) was reacted with phenylchloroformate (0.395 g, 2.523 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-11 to give the titled compound (0.450 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyrimidin-2-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.200 g, 0.627 mmol) was reacted with phenyl pyrimidin-2-ylcarbamate (0.162 g, 0.753 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.095 g, 37.54 %) as a solid. HPLC: 96.36 ; LCMS: nt/z 404.5 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.35 (t, / = 5.6 Hz, 1H), 8.52 (d, / = 4.9 Hz, 2H), 8.21 (s, 1H), 7.54 - 7.45 (m, 2H), 7.38 (dd, / = 8.4, 6.8 Hz, 2H), 7.30 (ddt, / = 12.2, 7.3, 2.1 Hz, 3H), 7.06 (td, / = 7.5, 1.1 Hz, 1H), 7.01 - 6.87 (m, 2H), 4.88 (ddd, / = 11.3, 7.2, 3.8 Hz, lH), 4.19 (dd, / = 16.5, 6.1 Hz, 1H), 4.09 (dt, / = 9.5, 4.7 Hz, 2H), 4.02 (dd, / = 10.1 , 4.1 Hz, lH), 3.06 (dd, / = 17.3, 11.0 Hz, 1H), 2.90 (dd, /= 17.3, 7.2 Hz, 1H).

Example-23: l-((5-((2-(furan-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(pyridin-4-yl) urea (±).

Step-1: tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl) carbamate (±).

Tert-butyl (2-(hydroxyimino) ethyl)carbamate (7.0 g, 32.85 mmol) was reacted with N- chlorosuccinimide (4.96 g, 37.12 mmol),l-(allyloxy)-2-bromobenzene(5.72 g, 32.85 mmol) (synthesized as per reported procedure in WO2011053821) and triethylamine (4.98 mL, 35.81 mmol) in N,N-dimethylformamide (150 mL) as described in the synthesis of step-3 of example-1 to give the titled compound (4.4 g, 31.6%) as a liquid. LCMS: m/z 286.9 [M-100] ^""^".Further the enantiomeric mixture (4.9 g) was separated by chiral preparative HPLC to give two separated enantiomers

Enantiomer-1: peak-1: tert-butyl ((5-((2-bromophenoxy) methyl)-4,5- dihydroisoxazol-3-yl) methyl) carbamate.(1.3 g).

Enantiomer-2: peak-2: tert-butyl ((5-((2-bromophenoxy) methyl)-4,5- dihydroisoxazol-3-yl) methyl) carbamate. (1.3 g).

Method: Column: LUX AMYLOSE-2; n-hexane (A): (ethanol: methanol) (B): (40:60); Flow Rate:

TIME %B FLOW

0 60 20

2 60 20

40 60 20

Step-2: (5-((2-bromophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (2.5 g, 6.49 mmol) was reacted with 4N HCl in 1 ,4-dioxane as described in the synthesis of step-4 of example-1 to give titled compound (1.7 g, 81.41 %) as a solid. Step-3: l-((5-((2-bromophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (pyridin-4-yl) urea (±).

(5-((2-bromophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (1.100 g, 3.420 mmol) reacted with phenyl pyridin-4-ylcarbamate (prepared in step-1 of example-2) (0.805 g, 3.750 mmol) and triethylamine (1.42 mL, 10.168 mmol) in DMSO (25 mL) as described in the synthesis of step-6 of example-1 to give the titled compound (0.500 g, 36.07 %) as white solid. LCMS: m/z 405.2 [M+H] ⁺. Step-4: l-((5-((2-(furan-3-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridin-4-yl)urea (±)

To a previously degassed solution of l-((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(pyridin-4-yl)urea (0.100 g, 0.248 mmol) in THF :water (3:1) (4 mL) was added furan-3-boronic acid (0.033 g, 0.298 mmol), followed by sodium carbonate (0.052 g, 0.496 mmol) and tetrakis (triphenylphosphine)palladium(O) (0.0143 g, 0.012 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 12 h at 100 °C. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (2 x 50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.009 g, 9.33 %) as a solid. HPLC: 95.91 %; LCMS: mJz 392.9 [M+ H]⁺; H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 5.8 Hz, 2H), 7.92 (dd, / = 1.6, 0.8 Hz, 1H), 7.48 (dq, / = 4.1 , 1.9 Hz, 2H), 7.32 - 7.19 (m, 3H), 7.11 - 6.99 (m, 2H), 6.96 - 6.88 (m, 1H), 6.79 (dd, / = 1.9, 0.8 Hz, 1H), 5.51 (s, 1H), 5.07 (td, / = 7.4, 3.7 Hz, 1H), 4.27 (dd, / = 10.4, 3.4 Hz, 1H), 4.19 (d, / = 5.1 Hz, 2H), 4.10 (dd, / = 10.4, 3.9 Hz, 1H), 3.27 - 3.04 (m, 2H).

Example-24: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2,6-dichloro pyridin-4-yl)urea (±).

Step-1: Phenyl (2, 6-dichloropyridin-4-yl) carbamate.

2,6-dichloropyridin-4-amine (0.100 g, 0.613 mmol) was reacted with sodium bicarbonate (0.155 g, 1.840 mmol) and phenylchloroformate (0.106 g, 0.675 mmol) at 0 °C in THF (5 mL) for 30 min as described in the synthesis of step-1 of example- 18 to give the titled compound (0.080 g, crude) as a solid. The crude product was taken to the next step without further purification.

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example- 1 ) (0.113 g, 0.354 mmol) was reacted with phenyl(2,6-dichloropyridin-4-yl)carbamate(0.100g, 0.354 mmol) and triethylamine(0.100 mL, 0.709 mmol) as described in the synthesis of step-2 of example - 11 to give the titled compound (0.080 g, 47.88 %) as a solid. HPLC: 97.75%; LCMS : nt/z 472.7 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.58 - 7.55(m, 2H), 7.47- 7.44 (m, 2H), 7.39 - 7.34 (m, 2H), 7.32 - 7.29 (m, 2H), 7.10 - 7.06 (m, 1H),7.25 (m, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 4.98 - 4.93 (m, 1H), 4.62 (m, 1H), 4.26 - 4.23 (m, 1H), 3.99- 3.87 (m, 2H), 3.88- 3.83 (m, 1H), 3.08 (dd, / = 17.3, 11.3 Hz, lH), 2.88 (dd, / = 17.2, 6.2 Hz, lH).

Example-25: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2,6-dimethoxy pyrimidin-4-yl) urea (±).

Step-1: Phenyl (2, 6-dimethoxypyrimidin-4-yl) carbamate.

To a solution of 2,6-dimethoxypyrimidin-4-amine (0.500 g, 3.223 mmol) in acetonitrile (5 mL) was added phenylchloroformate (0.252 g, 1.611 mmol) at room temperature and stirred for 12 h. The precipitate was filtered and washed with ethyl acetate (2 x 5 mL). Filtrate was evaporated and crude residue was triturated with diethyl ether (2 x 5 mL) to give the titled compound (0.230 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2,6-dimethoxy pyrimidin-4-yl) urea (±).

(5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314mmol) was reacted with phenyl (2,6-dimethoxypyrimidin-4-yl)carbamate (0.103 g, 0.376 mmol) and triethylamine (0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.030 g, 20.63 %) as a solid. HPLC: 97.3 %; LCMS: m/z 464.5 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.80 (s, 1H), 7.90 (s, 1H), 7.55 - 7.44 (m, 2H), 7.44 - 7.35 (m, 2H), 7.34 - 7.22 (m, 3H), 7.10 - 6.91 (m, 2H), 5.91 (s, 1H),4.88 (ddt, J = 10.9, 7.4, 3.9 Hz, 1H), 4.18 - 4.05 (m, 2H), 4.04 - 3.87 (m, 8H), 3.10 - 2.80 (m, 2H).

Example-26: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(3,5-dimethyl isoxazol-4-yl)urea (±).

Step-1: Phenyl (3, 5-dimethylisoxazol-4-yl) carbamate.

3, 5-dimethylisoxazol-4-amine (0.500 g, 4.459 mmol) was reacted with phenylchloroformate (0.349 g, 2.230 mmol) in acetonitrile (5 mL) as described in the synthesis of step-1 of example-25 to give the titled compound (0.300 g,crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (3,5-dimethylisoxazol-4-yl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314 mmol) was reacted with phenyl (3,5-dimethylisoxazol-4-yl)carbamate (0.087 g, 0.376 mmol) and triethylamine(0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example - 11 to give the titled compound (0.030 g, 22.75 %) as a solid. HPLC: 97.2 %; LCMS: m/z 421.5 [M+ H] ⁺; 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.55 - 7.45 (m, 2H), 7.44 - 7.25 (m, 5H), 7.15 - 7.01 (m, 2H), 6.59 (t, / = 5.7 Hz, 1H),4.82 (td, / = 11.2, 4.7 Hz, 1H), 4.05 (qd, / = 10.5, 4.6 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.04 (dd, / = 17.4, 10.9 Hz, 1H), 2.79 (dd, / = 17.4, 7.3 Hz, 1H), 2.21 (s, 3H), 2.05 (s, 3H), 2.36 - 2.30 (m, 3H).

Example-27: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(3-fluoropyridin-2-yl) urea (±).

Step-1: Phenyl (3-fluoropyridin-2-yl) carbamate.

3-fiuoro-2-aminopyridine (0.200 g, 1.784 mmol) was reacted with phenylchloroformate (0.335 g, 2.141 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 11 to give the titled compound (0.400 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(3- fluoropyridin-2-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.200 g, 0.627 mmol) was reacted with phenyl (3-fluoropyridin-2-yl)carbamate(0.175 g, 0.753mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.023 g, 8.72 %) as a solid. HPLC: 99.0 ; LCMS: m/z 420.8 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 9.57 (s, 1H), 7.99 (dd, / = 5.0, 1.4 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.44 - 7.35 (m, 3H), 7.34 - 7.22 (m, 3H), 7.15 - 7.01 (m, 2H), 7.02 - 6.86 (m, 2H), 4.88 (ddd, / = 11.3, 7.5, 3.8 Hz, 1H), 4.20 (dd, / = 16.5, 6.2 Hz, lH), 4.14 - 3.97 (m, 3H), 3.06 (dd, / = 17.3, 10.9 Hz, 1H), 2.90 (dd, / = 17.3, 7.1 Hz, 1H.)

Example-28: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(l-methyl-lH-pyrazol-4-yl)urea (±).

Step-1: Phenyl (l -methyl-lH-pyrazol-4-yl) carbamate.

1 -methyl- lH-pyrazol-4-amine (0.500 g, 5.148 mmol) was reacted with phenylchloroformate (0.403 g, 2.574 mmol) in acetonitrile (5 mL) as described in the synthesis of step-1 of example-25 to give the titled compound (0.280 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(l- methyl-lH-pyrazol-4-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314 mmol) was reacted with phenyl (l -methyl-lH-pyrazol-4-yl)carbamate (0.082 g, 0.376 mmol) and triethylamine(0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example - 11 to give the titled compound (0.025 g, 19.66 %) as a solid. HPLC: 98.86 ; LCMS: m/z 406.5 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.57 - 7.51 (m, 2H), 7.47 (s, 1H), 7.42 (dd, / = 8.4, 6.7 Hz, 2H), 7.37 - 7.28 (m, 4H), 7.06 (td, / = 7.5, 1.1 Hz, 1H), 6.94 (dd, / = 8.6, 1.1 Hz, 1H), 5.70 (s, 1H), 4.89 (ddd, / = 14.2, 6.4, 3.2 Hz, 1H), 4.30 (s, 1H), 4.17 (dd, / = 10.2, 3.4 Hz, 1H), 4.02 - 3.92 (m, 2H), 3.89 (d, / = 5.1 Hz, 1H), 2.99 (dd, / = 17.3, 11.2 Hz, 1H), 2.84 (dd, / = 17.3, 6.5 Hz, 1H), 1.63 - 1.52 (m, 3H).

Example-29: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(thiazol-2-yl) urea (±)

Step-1: Phenyl thiazol-2-ylcarbamate.

Thiazol-2-amine (0.500 g, 4.995 mmol) was reacted with phenylchloroformate (0.938 g, 5.994 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 11 to give the titled compound (0.625 g, crude) as a solid. The crude product was taken to the next step without further purification. Step-2: l -((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (thiazol-2-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example- 1 ) (0.150 g, 0.471 mmol) was reacted with phenyl thiazol-2-ylcarbamate (0.120 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example- 1 1 to give the titled compound (0.030 g, 15.6 %) as a solid. HPLC: 97.62 ; LCMS: nt/z 409.2 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 7.55 - 7.46 (m, 2H), 7.44 - 7.33 (m, 3H), 7.33 - 7.22 (m, 4H), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.97 - 6.91 (m, 1H), 6.84 (d, / = 3.6 Hz, 1H), 4.87 (ddt, / = 10.7, 7.0, 3.6 Hz, 1H), 4.21 - 3.89 (m, 4H), 3.48 (q, / = 7.0 Hz, l H), 3.11 - 2.80 (m, 2H).

Example-30: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(thiophen-2-yl)urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with 2- isocyanatothiophene (0.070 g, 0.565 mmol) and triethylamine (0.099 mL,0.706 mmol) as described in the synthesis of example- 14 to give the titled compound (0.300 g, 15.65 %) as a solid. HPLC: 96.24 ; LCMS: nt/z 407.8 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.60 - 7.51 (m, 2H), 7.44 (dd, / = 8.4, 6.7 Hz, 2H), 7.40 - 7.23 (m, 3H), 7.08 (td, / = 7.5, 1.0 Hz, 1H), 7.00 - 6.90 (m, 2H), 6.85 (dd, / = 5.6, 3.7 Hz, 1H), 6.65 - 6.58 (m, 1 H), 6.53 (s, 1 H), 4.91 (ddd, / = 14.3, 6.3, 3.1 Hz, 1H), 4.52 (s, 1H), 4.19 (dd, / = 10.2, 3.3 Hz, 1H), 4.08 - 3.84 (m, 3H), 3.10 - 2.75 (m, 2H).

Example-31: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(benzo[d]thiazol-6-yl)urea (±).

Step-1: Phenyl benzo[d]thiazol-6-ylcarbamate.

6-aminobenzothiazole (0.500 g, 3.329 mmol) was reacted with phenylchloroformate (0.625 g, 3.995 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-11 to give the titled compound (0.535 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[d]thiazol-6-yl)urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with phenyl benzo [d]thiazol-6-ylcarbamate (0.150 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.020 g, 92.7 %) as a solid. HPLC: 95.0 ; LCMS: mJz 459.3 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) 8.87 (s, 1H), 8.20 (d, / = 2.2 Hz, 1H), 7.98 (d, / = 8.7 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.50 (dd, / = 8.4, 6.8 Hz, 2H), 7.44 - 7.36 (m, 1H), 7.32 (ddd, / = 7.2, 4.3, 2.5 Hz, 2H), 7.16 (dd, / = 8.7, 2.2 Hz, 1H), 7.11 - 7.03 (m, 1H), 6.98 - 6.90 (m, 1H), 6.20 (s, 1H), 5.02 - 4.83 (m, 1H), 4.24 (dd, / = 10.2, 2.9 Hz, 1H), 4.11 (dd, / = 15.6, 7.3 Hz, 1H), 4.03 (s, lH), 3.95 (dd, / = 10.3, 2.6 Hz, lH), 3.84 (dd, / = 15.5, 4.0 Hz, 1H), 3.12 - 2.96 (m, 1H), 2.90 (dd, / = 17.2, 6.3 Hz, 1H).

Example-32: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyrazin-2-yl) urea (±).

To a solution of pyrazine-2-carboxylic acid (0.200 g, 1.61 mmol) was added DPPA (0.400 g, 0.900 mmol), followed by triethylamine (0.240 mL, 1.77 mmol) at room temperature. The resulting reaction mixture stirred for 30 min at room temperature and then stirred at 110 °C for 30 min. The reaction mixture was cooled to room temperature followed by addition of (5-(([l ,l '4jiphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.510 g, 1.61 mmol) and stirred for 16 h at room temperature. The residue obtained after evaporation of reaction mixture was purified by column chromatography on silica gel (methanol/dichloromethane = 3/97) to give the titled compound (0.015g, 2.0%) as a white solid. HPLC: 94.24 %; LCMS: nt/z 404.1 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.71 (s, 1H), 8.40 (d, / = 1.4 Hz, 1H), 8.17 (d, / = 2.8 Hz, 1H), 8.10 (dd, / = 2.8, 1.5 Hz, 1H), 7.58 - 7.43 (m, 2H), 7.39 (ddd, / = 7.6, 6.9, 1.1 Hz, 2H), 7.36 - 7.21 (m, 3H), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 7.00 - 6.89 (m, 1H), 4.90 (ddt, / = 11.0, 7.3, 4.0 Hz, 1H), 4.23 - 3.94 (m, 4H), 3.13 - 2.82 (m, 2H).

Example-33: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(6-chloro pyrazin-2-yl) urea (±).

Step-1: Phenyl (6-chloropyrazin-2-yl) carbamate.

6-chloro-2-aminopyrazine (0.200 g, 1.544 mmol) was reacted with phenylchloroformate (0.290 g, 1.853 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 1 1 to give the titled compound (0.400 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(6- chloropyrazin-2-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.200 g, 0.627 mmol) was reacted with phenyl(6-chloropyrazin-2-yl)carbamate (0.188 g, 0.753 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-1 lto give the titled compound (0.035g, 12.74 %) as a solid. HPLC: 96.02 %; LCMS: nt/z 437.8 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.50 (dd, / = 8.1 , 1.4 Hz, 2H), 7.40 (dd, / = 8.4, 6.8 Hz, 2H), 7.35 - 7.21 (m, 3H), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.98 - 6.91 (m, 1H), 4.93 (ddt, / = 10.7, 7.1 , 3.6 Hz, 1 H), 4.23 - 4.07 (m, 2H), 4.06 - 3.92 (m, 2H), 3.06 (dd, / = 17.3, 1 1.1 Hz, 1H), 2.91 (dd, / = 17.2, 6.8 Hz, 1H).

Example-34: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(benzo[b] thiophen-5-yl) urea (±).

Step-1: Phenyl benzo[b]thiophen-5-ylcarbamate.

5-aminobenzothiophene (0.200 g, 1.340 mmol) was reacted with phenylchloroformate (0.252 g, 1.608 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-1 1 to give the titled compound (0.380 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[b]thiophen-5-yl) urea (±)

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1 ) (0.200 g, 0.627 mmol) was reacted with phenyl benzo[b]thiophen-5-ylcarbamate (0.203 g, 0.753 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.115g, 40.06 %) as a solid. HPLC: 98.56 ; LCMS: nt/z 457.8 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.83 (d, / = 2.1 Hz, lH), 7.74 (dd, / = 8.6, 0.8 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.47 - 7.39 (m, 3H), 7.38 - 7.28 (m, 3H), 7.27 - 7.20 (m, 1H), 7.14 (dd, / = 8.6, 2.1 Hz, 1H), 7.06 (td, / = 7.5 , 1.1 Hz, 1H), 6.93 (dd, / = 8.7, 1.1 Hz, 1H), 6.31 - 6.22 (m, 1H), 4.90 (ddt, / = 11.7, 6.1 , 3.1 Hz, 1H), 4.31 (t, / = 5.9 Hz, 1H), 4.19 (dd, / = 10.2, 3.2 Hz, 1H), 4.05 (dd, / = 16.2, 6.9 Hz, 1H), 4.01 - 3.81 (m, 2H), 3.02 (dd, / = 17.3, 11.3 Hz, 1H), 2.88 (dd, / = 17.3, 6.4 Hz, 1H).

Example-35: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(l,3,4-thiadiazol-2-yl) urea (±).

Step-1: Phenyl 1 , 3, 4-thiadiazol-2-ylcarbamate.

l ,3,4-thiadiazol-2-amine (0.500 g, 4.944 mmol) was reacted with phenylchloroformate (0.387 g, 2.472 mmol) in acetonitrile (5 mL) as described in the synthesis of step-1 of example-25 to give the titled compound (0.250 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (l ,3,4-thiadiazol-2-yl)urea (±)

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314 mmol) was reacted with phenyl l ,3,4-thiadiazol-2-ylcarbamate (0.083 g, 0.376 mmol) and triethylamine (0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.030 g, 23.36 %) as a solid. HPLC: 98.9 ; LCMS: nt/z 410.5 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 11.37 (s, 1H), 8.71 (s, 1 H), 7.47 - 7.45 (m, 2H), 7.38 - 7.36 (m, 2H), 7.30 - 7.26 (m, 2H), 7.06 - 7.02 (m, 1H), 6.96 - 6.92 (m, 1H), 6.62 (bs, 1H), 4.91 (ddt, / = 10.7, 6.9, 3.6 Hz, 1H), 4.19 (dd, / = 10.3, 3.9 Hz, 1H), 4.09 (dd, / = 16.9, 5.6 Hz, 1H), 3.99- 3.93 (m, 2H), 3.02 (dd, / = 17.2, 11.1 Hz, 1H), 2.90 (dd, / = 17.3, 7.0 Hz, lH).

Example-36: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(6-cyanopyridin-3-yl) urea (±).

Step-1: Phenyl (6-cyanopyridin-3-yl) carbamate.

5-aminopicolinonitrile (0.500 g, 4.198 mmol) was reacted with phenylchloroformate (0.788 g, 5.038 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-1 1 to give the titled compound (0.605 g, crude) as a solid. The crude product was taken to the next step without further purification. Step-2: l-((5-(([l,r-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(6- cyanopyridin-3-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (6-cyanopyridin-3-yl)carbamate (0.140 g, 0.565mmol) and triethylamine (0.099 mL,0.706 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.030 g, 14.9 %) as a solid. HPLC: 97.6 ; LCMS: mJz 427.8 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.41 (d, / = 2.6 Hz, lH), 8.12 (dd, / = 8.6, 2.6 Hz, 1H), 7.62 - 7.51 (m, 3H), 7.46 (dd, / = 8.4, 6.7 Hz, 2H), 7.42 - 7.26 (m, 3H), 7.08 (t, / = 7.5 Hz, 1H), 6.94 (d, / = 8.3 Hz, 1H), 6.85 (s, 1H), 5.04 - 4.89 (m, 1H), 4.63 (d, / = 6.0 Hz, 1H), 4.25 (dd, / = 10.4, 2.8 Hz, 1H), 4.07 - 3.82 (m, 3H), 3.04 (dd, / = 17.4, 11.3 Hz, 1H), 2.90 (dd, / = 17.4, 6.4 Hz, 1H).

Example-37: l-((5-(([l l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(oxazol-2-yl)urea (±)

Step-1: Phenyl oxazol-2-ylcarbamate

Oxazol-2-amine (0.500 g, 5.952 mmol) was reacted with phenylchloroformate (1.118 g, 7.143 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 11 to give the titled compound (0.510 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (oxazol-2-yl)urea (±)

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl oxazol-2-ylcarbamate (0.120 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.020g, 10.83 %) as a solid. HPLC: 99.3 %; LCMS: nt/z 392.8 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.03 (s, 1H), 7.56 - 7.45 (m, 2H), 7.39 (dd, / = 8.4, 6.7 Hz, 2H), 7.35 - 7.15 (m, 4H), 7.13 - 7.01 (m, 1 H), 6.96 (d, / = 8.1 Hz, 1H), 6.89 (d, / = 1.0 Hz, 1H), 4.96 - 4.79 (m, 1H), 4.18 - 3.90 (m, 4H), 3.02 (dd, / = 17.2, 11.0 Hz, 1H), 2.87 (dd, / = 17.3, 7.1 Hz, 1H).

Example-38: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-chloro-6-methylpyrimidin-4-yl)urea (±).

Step-1: Phenyl (2-chloro-6-methylpyrimidin-4-yl) carbamate.

2-chloro-6-methylpyrimidin-4-amine (0.500 g, 3.484 mmol) was reacted with phenylchloroformate (0.654 g, 4.181 mmol) in pyridine (5 mL) as described in the synthesis of step- 1 of example- 11 to give the titled compound (0.490 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(2- chloro-6-methyl pyrimidin-4-yl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (2-chloro-6-methylpyrimidin-4-yl)carbamate (0.150 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.200 g, 94.06%) as a solid. HPLC: 97.36 %; LCMS: nt/z 452.8 [M+ H] ⁺; H NMR (400 MHz, DMSO-d6) 7.61 (s, 1H), 7.57 - 7.44

(m, 2H), 7.44 - 7.17 (m, 7H), 7.20 - 6.99 (m, 2H), 4.84 (ddt, / = 11.2, 7.8, 3.8 Hz, 1H), 4.16 - 3. 88 (m, 4H), 3.08 (dd, / = 17.4, 11.0 Hz, lH), 2.82 (dd, / = 17.3 , 7.4 Hz, 1H), 2.38 (s, 3H). Example-39: l-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(pyridin-4-yl)urea (±).

l-((5-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(pyridin-4-yl)urea (±) (prepared in step-3 of example-23) (0.100 g, 0.247 mmol) was reacted with (1 - methyl-lH-pyrazol-4-yl)boronic acid (0.037g, 0.296 mmol), tetrakis (triphenylphosphine)palladium(O) (0.014 g, 0.012 mmol) and sodium carbonate (0.052 g, 0.494 mmol) in THF :water (3 :1) (4 mL) as described in the synthesis of step-4 of example-23 to give the titled compound (0.011 g, 10.97 %) as a solid. HPLC: 94.74%; LCMS: m/z 406.9 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.37 (s, 2H), 7.87 (s, 1H), 7.68 (s, 1H), 7.47 - 7.30 (m, 3H), 7.26- 7.21 (m, 1H), 7.06 - 6.86 (m, 1H), 5.76 (s, 1H), 5.02 (t, / = 10.1 Hz, 1H), 4.35 (d, / = 11.1 Hz, 2H), 4.16 - 3.93 (m, 5H), 3.27 (d, / = 7.8 Hz, 1H), 3.14 (dd, / = 17.5, 11.8 Hz, lH).Further the enantiomeric mixture (0.190 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 39a & 39b). Method: Column: LUX AMYLOSE-2 AXIA PACKED (21.2mm x 250mm x5u); n-hexane (A): ethanol (B): (5:95), Flow Rate: 20 mL/min.

Example-39a: l-((5-((2-(l-methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(pyridin-4-yl)urea.

Yield: 0.035 g; HPLC: 98.60%; LCMS: m/z 407.2 [M+H] ⁺]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.39 - 8.31 (m, 2H), 8.05 (s, 1H), 7.90 (s, 1H), 7.59 (dd, / = 7.7, 1.7 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.17 (ddd, / = 8.7, 7.4, 1.7 Hz, lH), 7.10 - 7.02 (m, 1H), 7.01 - 6.87 (m, 2H), 5.06 - 4.97 (m, 1H), 4.12 (ddd, / = 18.7, 10.1, 4.8 Hz, 4H), 3.85 (s, 3H), 3.25 - 3.15 (m, 1H), 2.93 (dd, / = 17.2, 7.8 Hz, 1H).

Example-39b: l-((5-((2-(l-methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(pyridin-4-yl)urea.

Yield: 0.033 g, HPLC: 98.72%; LCMS: m/z 407.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.38 (d, / = 6.3 Hz, 2H), 8.05 (s, 1H), 7.90 (s, 1H), 7.59 (dd, / = 7.7, 1.7 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.17 (ddd, / = 8.7, 7.3, 1.7 Hz, 1H), 7.09 - 6.91 (m, 3H), 5.09 - 4.96 (m, 1H), 4.19 - 4.02 (m, 4H), 3.85 (s, 3H), 3.24 - 3.16 (m, 1H), 2.93 (dd, / = 17.2, 7.8 Hz, 1H).

Example-40: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(5-methylthiazol-2-yl)urea (±).

Step-1: Phenyl (5-methylthiazol-2-yl) carbamate.

5-methylthiazol-2-amine (0.500 g, 4.379 mmol) was reacted with phenylchloroformate (0.343 g, 2.190 mmol) Acetonitrile (5 mL) as described in the synthesis of step-1 of example-25 to give the titled compound (0.235g,crude ) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(5- methylthiazol-2-yl) urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314 mmol) was reacted with phenyl (5-methylthiazol-2-yl)carbamate (0.088 g, 0.376 mmol) and triethylamine (0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.040 g, 30.18 %) as a solid. HPLC: 98.32 ; LCMS: nt/z 423.5 [M+ H]⁺; H NMR (400 MHz, Chloroform-d) δ 9.48 (s, 1H), 7.55 - 7.47 (m, 2H), 7.46 - 7.35 (m, 2H), 7.35 - 7.29 (m, 3H), 7.04 (td, / = 7.5, 1.0 Hz, 1H), 6.99 - 6.87 (m, 2H), 4.86 (tt, / =

7.1 , 3.6 Hz, 1H), 4.17 - 3.87 (m, 4H), 3.01 (dd, / = 17.3, 11.1 Hz, 1H), 2.86 (dd, / =

17.3, 6.9 Hz, lH), 2.35 (dd, / = 1.3, 0.5 Hz, 3H).

Example-41: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(5-bromo-4-methylpyridin-2-yl)urea (±).

Step-1: Phenyl (5-bromo-4-methylpyridin-2-yl) carbamate.

5-bromo-4-methyl-2-aminopyridine (0.300 g, 1.604 mmol) was reacted with phenylchloroformate (0.301 g, 1.925 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 11 to give the titled compound (0.250g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2:l-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(5- bromo-4-methyl pyridin-2-yl) urea (±)

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.200 g, 0.627 mmol) was reacted with phenyl (5-bromo-4-methylpyridin-2-yl)carbamate (0.231 g, 0.753 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.080 g, 25.74 %) as a solid. HPLC: 98.66 %; LCMS: m/z 496.5 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 9.08 (s, 1H), 8.22 - 8.14 (m, 1H), 7.85 (s, 1H), 7.55 - 7.45 (m, 2H), 7.39 (ddt, / = 7.2, 6.0, 0.9 Hz, 2H), 7.35 - 7.23 (m, 3H), 7.05 (tt, / = 7.5, 1.0 Hz, 1H), 7.00 - 6.90 (m, 1H), 6.78 - 6.68 (m, 1H), 4.88 (ddt, / = 11.1, 7.5, 4.3 Hz, lH), 4.21 - 3.95 (m, 4H), 3.04 (dd, / = 17.3, 11.0 Hz, 1H), 2.89 (dd, / = 17.3, 7.1 Hz, 1H), 2.34 (d, / = 0.9 Hz, 3H).

Example-42: Methyl3-(3-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl)ureido) thiophene-2-carboxylate(±).

Step-1: Methyl 3-((phenoxycarbonyl) amino) thiophene-2-carboxylate.

Methyl 3-aminothiophene-2-carboxylate (0.300 g, 1.909 mmol) was reacted with phenylchloroformate (0.359 g, 2.290 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-11 to give the titled compound (0.500 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: Methyl 3-(3-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) ureido)thiophene-2-carboxylate (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.200 g, 0.627 mmol) was reacted with methyl 3-((phenoxycarbonyl)amino)thiophene-2-carboxylate (0.209 g, 0.753 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-l lto give the titled compound (0.095 g, 32.53 %) as a solid. HPLC: 95.02 %; LCMS: m/z 466.4 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 9.22 (s, 1H), 7.95 (d, / = 5.5 Hz, lH), 7.71 - 7.52 (m, 4H), 7.48 - 7.38 (m, 2H), 7.33 (td, / = 7.4, 1.7 Hz, 2H), 7.15 - 7.01 (m, 1H), 6.94 (d, / = 8.3 Hz, 1H),4.93 (ddt, / = 11.2, 5.6, 2.7 Hz, 1H), 4.25 (dd, / = 10.2, 2.9 Hz, 1H), 4.13 (dd, / = 15.9, 7.4 Hz, 1H), 4.03 - 3.81 (m, 4H), 3.78 (dd, / = 15.9, 4.5 Hz, 1H), 3.02 (dd, /= 17.3, 11.3 Hz, 1H), 2.85 (dd, / = 17.2, 5.8 Hz, 1H).

Example-43: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(5-methyl isoxazol-3-yl)urea (±).

Step-1: Phenyl (5-methylisoxazol-3-yl) carbamate.

5-methylisoxazol-3-amine (0.500 g, 5.097 mmol) was reacted with phenylchloroformate (0.399 g, 2.548 mmol) in acetonitrile (5 mL) as described in the synthesis of step-1 of example-25 to give the titled compound (0.240 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(5- methylisoxazol-3-yl) urea (±)

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314 mmol) was reacted with phenyl (5-methylisoxazol-3-yl)carbamate (0.082 g, 0.376 mmol) and triethylamine(0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.040 g, 31.38 %) as a solid. HPLC: 97.95 ; LCMS: nt/z 407.5 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.59 - 7.48 (m, 2H), 7.44 (ddd, / = 7.7, 6.9, 1.1 Hz, 2H), 7.39 - 7.25 (m, 3H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 7.03 - 6.92 (m, 1H), 6.02 (s, 1H), 4.90 (ddt, / = 10.8, 7.1 , 3.8 Hz, lH), 4.15 (dd, / = 10.2, 4.1 Hz, 1H), 4.10 - 3.95 (m, 3H), 3.05 (dd, / = 17.2, 11.1 Hz, 1H), 2.89 (dd, / = 17.3, 6.9 Hz, 1H), 2.37 (d, / = 0.9 Hz, 3H).

Example-44: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(3-methyl isoxazol-5-yl)urea (±).

Step-1: Phenyl (3-methylisoxazol-5-yl) carbamate.

3-methylisoxazol-5-amine (0.500 g, 5.097 mmol) was reacted with phenylchloroformate (0.399 g, 2.548 mmol) in acetonitrile (5 mL) as described in the synthesis of step-1 of example-25 to give the titled compound (0.200 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(3- methylisoxazol-5-yl) urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1 ) (0.100 g, 0.314 mmol) was reacted with phenyl (3-methylisoxazol-5-yl)carbamate (0.082 g, 0.376 mmol) and triethylamine(0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example - 11 to give the titled compound (0.018 g, 14.12 %) as a solid. HPLC: 97.81 ; LCMS : nt/z 407.5 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 7.65 (s, 1H), 7.60 - 7.50 (m, 2H), 7.52 - 7.40 (m, 2H), 7.39 - 7.28 (m, 3H), 7.06 (td, / = 7.5, 1.1 Hz, lH), 6.94 (dd, / = 8.7, 1.1 Hz, l H), 5.92 (s, 1H),5.01 - 4.91 (m, 1H), 4.27 (dd, / = 10.4, 2.9 Hz, 1 H), 4.03 - 3.82 (m, 3H), 3.00 (dd, / = 17.2, 11.3 Hz, 1H), 2.87 (dd, / = 17.2, 6.4 Hz, lH), 2.23 (s, 3H). Example-45: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(imidazo[l,2-a]pyridin-6-ylmethyl)urea (±).

Step-1: Phenyl (imidazo [l ,2-a]pyridin-6-ylmethyl)carbamate

Imidazo [l ,2-a]pyridin-6-ylmethanamine (0.500 g, 3.397 mmol) was reacted with phenylchloroformate (0.266 g, 1.699 mmol) in acetonitrile (5 mL) as described in the synthesis of step- 1 of example-25 to give the titled compound (0.210 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (imidazo[l ,2-a]pyridin-6-ylmethyl) urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1 ) (0.100 g, 0.314 mmol) was reacted with phenyl (imidazo[l ,2-a]pyridin-6-ylmethyl)carbamate (0.101 g, 0.376 mmol) and triethylamine (0.066 mL, 0.471 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.04g, 28.0 %) as a solid. HPLC: 97.42 ;LCMS: nt/z 456.5 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, / = 1.7 Hz, 1H), 7.64 - 7.50 (m, 3H), 7.44 - 7.41 (m, 4H), 7.39 - 7.19 (m, 3H), 7.08 (td, / = 7.5, 1.0 Hz, 1H), 6.94- 6.88 (m, 2H), 4.88 (ddd, / = 11.5, 6.0, 2.9 Hz, 1 H), 4.40 (d, / = 6.1 Hz, 1H), 4.37 - 4.13 (m, 3H), 4.04 (dd, / = 15.5, 7.1 Hz, 1H), 3.89 (dd, / = 10.2, 2.6 Hz, 1H), 3.83 - 3.64 (m, 2H), 2.96 (dd, / = 17.2, 11.4 Hz, 1 H), 2.77 (dd, / = 17.3, 6.2 Hz, 1H).

Example-46: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-methylthiazol-2-yl) urea (±).

Step-1: Phenyl (4-methylthiazol-2-yl) carbamate.

4-methylthiazol-2-amine (0.500 g, 4.382 mmol) was reacted with phenylchloroformate (0.823 g, 5.259 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-1 1 to give the titled compound (0.560 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(4- methylthiazol-2-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.15 g, 0.471 mmol) was reacted with phenyl (4-methylthiazol-2-yl)carbamate (0.130 g, 0.565 mmol) and triethylamine(0.099 mL,0.706 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.030 g, 15.1 %) as a solid. HPLC: 99.68 ; LCMS: nt/z 423.4 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.63 - 7.50 (m, 2H), 7.50 - 7.41 (m, 2H), 7.39 - 7.24 (m, 3H), 7.07 (td, / = 7.5, 1.0 Hz, 1H), 6.96 (d, / = 8.0 Hz, 1H), 6.38 (d, / = 1.3 Hz, 1H), 4.90 (ddt, / = 10.7, 7.1 , 3.7 Hz, l H), 4.21 - 3.92 (m, 4H), 3.05 (dd, / = 17.3, 11.1 Hz, 1H), 2.89 (dd, / = 17.3, 6.8 Hz, 1H), 2.33 (d, / = 1.1 Hz, 3H).

Example-47: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(5-(trifluoromethyl) isoxazol-3-yl)urea (±).

Step-1: Phenyl (5-(trifluoromethyl) oxazol-2-yl) carbamate.

5-(trifluoromethyl)oxazol-2-amine (0.500 g, 3.289 mmol) was reacted with phenylchloroformate (0.618 g, 3.947 mmol) in pyridine (5 mL) as described in the synthesis of step- 1 of example- 1 1 to give the titled compound (0.540 g, crude ) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(5- (trifluoromethyl) isoxazol-3-yl) urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1 ) (0.150 g, 0.471 mmol) was reacted with phenyl (5-(trifiuoromethyl)oxazol-2-yl)carbamate (0.140 g, 0.565 mmol) and triethylamine (0.099 mL,0.706 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.050 g, 23.0 %) as a solid. HPLC: 98.6 %; LCMS: mJz 4 460.8 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.31 (s, 1H), 8.34 (t, / = 5.8 Hz, 1H), 7.60 (q, / = 1.6 Hz, 1 H), 7.57 - 7.45 (m, 2H), 7.46 - 7.36 (m, 2H), 7.36 - 7.21 (m, 3H), 7.06 (td, / = 7.5, 1.1 Hz, 1 H), 6.95 (dd, / = 8.2, 1.1 Hz, 1H), 4.89 (ddt, / = 11.0, 7.3, 4.0 Hz, 1H), 4.19 - 4.05 (m, 2H), 4.05 - 3.85 (m, 2H), 3.01 (dd, / = 17.2, 11.0 Hz, 1 H), 2.85 (dd, / = 17.1 , 7.0 Hz, 1H).

Example-48: l-((5-(([l, l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(isoquinolin-5-yl) urea (±).

Step-1: Phenyl isoquinolin-5-ylcarbamate.

Isoquinolin-5-amine (0.150 g, 1.040 mmol) was reacted with phenylchloroformate (0.180 g, 1.144 mmol) and pyridine (0.251 mL, 3.120 mmol) in N,N-dimethylformamide (5 mL) to give the titled compound (0.500 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (isoquinolin-5-yl)urea (±)

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride^) (0.330 g, 1.035 mmol) was reacted with phenyl isoquinolin-5- ylcarbamate(0.274 g, 1.035mmol) and triethylamine (0.436 mL, 3.105 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.030 g, 6.4 %) as a solid. HPLC: 97.8%; LCMS: m/z 453.4 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 9.24 (d, / = 0.9 Hz, 1H), 8.40 (d, / = 6.0 Hz, 1H), 7.89 - 7.75 (m, 2H), 7.62 - 7.49 (m, 3H), 7.44 - 7.19 (m, 5H), 7.09 (td, / = 7.5, 1.1 Hz, 1H), 6.95 (dd, / = 8.3, 0.7 Hz, 1H), 6.42 (s, 1H), 4.90 (ddt, / = 11.7, 6.0, 2.9 Hz, 1H), 4.35 (s, 1H), 4.18 (dd, / =

10.2, 3.2 Hz, 1H), 4.12 - 3.86 (m, 3H), 3.00 (dd, / = 17.3, 11.2 Hz, 1H), 2.86 (dd, / =

17.3, 6.2 Hz, lH).

Example-49: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2,3-dihydro benzo[b][l,4]dioxin-6-yl)urea (±).

Step-1: Phenyl (2, 3-dihydrobenzo[b][l,4]dioxin-6-yl)carbamate.

2,3-dihydrobenzo[b][l,4]dioxin-6-amine (0.500 g, 3.307 mmol) was reacted with sodium bicarbonate (0.833 g, 9.921 mmol) and phenylchloroformate (0.570 g, 3.638 mmol) at 0 °C in THF (5 mL) for 30 min as described in the synthesis of step-1 of example- 18 to give the titled compound (0.700 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2,3-dihydrobenzo [b][l,4]dioxin-6-yl)urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)carbamate (0.128 g, 0.471 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.050 g, 23.13 %) as a solid. HPLC: 95.75 %; LCMS: m/z 460.2 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.58 - 7.50 (m, 2H), 7.46 - 7.38 (m, 2H), 7.38 - 7.28 (m, 3H), 7.06 (td, / = 7.5, 1.1 Hz, 1H), 6.94 (dd, / = 8.6, 1.1 Hz, 1H), 6.82 (d, / = 2.5 Hz, lH), 6.78 (d, / = 8.6 Hz, 1H), 6.68 (dd, / = 8.7, 2.5 Hz, 1H), 5.99 (s, 1H), 4.88 (ddt, / = 11.1, 6.4, 3.2 Hz, 1H), 4.31 (d, / = 6.0 Hz, 1H), 4.26 - 4.12 (m, 5H), 4.06 - 3.76 (m, 3H), 3.09 - 2.78 (m, 2H).

Example-50: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-chloro pyrimidin-4-yl)urea (±)

Step-1: Phenyl (2-chloropyrimidin-4-yl) carbamate.

2-chloropyrimidin-4-amine (0.500 g, 3.861 mmol) was reacted with phenylchloroformate (0.665 g, 4.247 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 11 to give the titled compound (0.700 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(2- chloropyrimidin-4-yl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with phenyl (2-chloropyrimidin-4-yl)carbamate (0.118 g, 0.471 mmol) and triethylamine(0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example - 11 to give the titled compound (0.015 g, 7.28 %) as a solid. HPLC: 91.06 %; LCMS: m/z 438.3 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.27 - 8.13 (m, 2H), 7.41 (d, / = 7.6 Hz, 2H), 7.32 (t, / = 7.5 Hz, 2H), 7.27 - 7.18 (m, 3H), 7.05 - 6.91 (m, 2H), 6.85 (d, / = 8.3 Hz, 1H), 4.89 - 4.79 (m, 1H), 4.12 - 3.84 (m, 4H), 3.01 - 2.90 (m, 1H), 2.80 (dd, / = 17.2, 6.5 Hz, 1H).

Example-51: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(thiophen-2-ylmethyl)urea (±).

Step-1: Phenyl (thiophen-2-ylmethyl) carbamate.

Thiophen-2-ylmethanamine (0.500 g, 4.417 mmol) was reacted with sodium bicarbonate (1.113 g, 13.251 mmol) and phenylchloroformate (0.761 g, 4.859 mmol) at 0° C in THF (5 mL) for 30 min as described in the synthesis of step-1 of example- 18 to give the titled compound (0.800 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (thiophen-2-ylmethyl)urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with phenyl (thiophen-2-ylmethyl)carbamate (0.110 g, 0.471 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.050 g, 25.21 %) as a solid. HPLC: 98.05 ; LCMS: nt/z 421.8 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.58 - 7.49 (m, 2H), 7.41 (tt, / = 6.8, 1.0 Hz, 2H), 7.37 - 7.27 (m, 3H), 7.15 - 7.10 (m, 1H), 7.06 (tt, / = 7.5 , 1.0 Hz, 1H), 6.94 (dd, / = 8.3, 1.1 Hz, 1H), 6.90 - 6.83 (m, 2H), 4.89 (ddd, / = 11.6, 6.1, 3.0 Hz, 1H), 4.54 - 4.38 (m, 2H), 4.21 (dd, / = 10.1 , 3.0 Hz, 1H), 4.06 (dd, / = 15.8 , 7.6 Hz, 1H), 3.92 (dd, / = 10.2, 2.6 Hz, 1H), 3.73 (dd, / = 15.8 , 4.3 Hz, 1H), 2.98 (dd, / = 17.3, 11.4 Hz, 1H), 2.84 (dd, / = 17.3, 6.3 Hz, 1H).

Example-52: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(benzo[d]oxazol-2-yl)urea (±).

Step-1: Phenyl benzo[d]oxazol-2-ylcarbamate.

Benzo[d]oxazol-2-amine (0.200 g, 1.493 mmol) was reacted with sodium bicarbonate (0.376 g, 4.478 mmol) and phenylchloroformate (0.234 g, 1.493 mmol) at 0 °C in THF (5 mL) for 30 min as described in the synthesis of step-1 of example- 18 to give the titled compound (0.800 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[d]oxazol-2-yl)urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1 ) (0.150 g, 0.471 mmol) was reacted with phenyl benzo[d]oxazol-2-ylcarbamate (0.120g, 0.471 mmol) and triethylamine (0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example-l lto give the titled compound (0.010 g, 4.80 %) as a solid. HPLC:95.5 ; LCMS: nt/z 443.4 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.00 (t, / = 5.8 Hz, 1H), 8.49 (s, 1H), 7.50 (ddd, / = 7.0, 4.4, 3.0 Hz, 3H), 7.46 - 7.35 (m, 3H), 7.31 (tdt, / = 7.8, 5.9, 2.0 Hz, 4H), 7.21 (td, / = 7.7, 1.3 Hz, 1H), 7.05 (td, / = 7.5, 1.1 Hz, l H), 6.96 (d, / = 8.0 Hz, 1H), 4.91 (ddt, / = 11.1 , 7.7, 4.0 Hz, 1H), 4.32 - 3.88 (m, 4H), 3.07 (dd, / = 17.3, 1 1.0 Hz, lH), 2.91 (dd, / = 17.2, 7.0 Hz, 1H).

Example-53:l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(quinolin-6-yl)urea (±)

Step-1: Phenyl quinolin-6-ylcarbamate.

6-aminoquinoline (0.066 g, 0.458 mmol) was reacted with phenylchloroformate (0.180 g, 1.144 mmol) and pyridine (0.251 mL, 3.120 mmol) in N,N-dimethylformamide (5 mL) to give the titled compound (0.030 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l , l ' -biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (quinolin-6-yl) urea (±)

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1 ) (0.150 g, 0.471 mmol) was reacted with phenyl quinolin-6-ylcarbamate (0.124 g, 0.471 mmol) and triethylamine(0.198 mL, 1.412 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.030 g, 14.09 %) as a solid. HPLC: 99.1 ; LCMS: nt/z 453.4 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.80 (dd, / = 4.3, 1.7 Hz, 1H), 8.1 1 - 7.91 (m, 3H), 7.71 - 7.57 (m, 2H), 7.52 (t, / = 7.6 Hz, 2H), 7.42 (ddd, / = 7.4, 4.9, 2.5 Hz, 2H), 7.39 - 7.31 (m, 3H), 7.09 (td, / = 7.4, 1.0 Hz, 1H), 6.97 (d, / = 8.4 Hz, 1H), 6.45 (s, 1H), 5.04 - 4.89 (m, 1 H), 4.26 (dd, / = 10.2, 2.9 Hz, 1H), 4.13 (dd, / = 15.9, 7.2 Hz, 1H), 3.98 (dd, / = 10.3, 2.6 Hz, 1H), 3.90 (dd, / = 15.9, 4.3 Hz, 1H), 3.06 (dd, / = 17.3, 11.3 Hz, 1H), 2.94 (dd, / = 17.2, 6.4 Hz, 1H).

Example-54:l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2,3-dihydro-iH-inden-l-yl)urea (±).

Step-1: Phenyl (2, 3-dihydro-lH-inden- l -yl) carbamate.

1 -aminoindane (0.1 10 g, 0.826 mmol) was reacted with phenylchloroformate (0.155 g, 0.991 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example- 1 1 to give the titled compound (0.210 g, crude) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-(2,3- dihydro-iH-inden-l-yl)urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.200 g, 0.627 mmol) was reacted with phenyl (2,3-dihydro-iH-inden-l-yl)carbamate (0.191 g, 0.753 mmol) and triethylamine(0.132 mL, 0.941 mmol) as described in the synthesis of step-2 of example - 11 to give the titled compound (0.07 Og, 25.27 %) as a solid.HPLC: 96.8 %; LCMS: m z 464.6 [M+ Na]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.48 (ddt, / = 6.2, 4.8, 1.5 Hz, 2H), 7.41 - 7.14 (m, 8H), 7.10 - 6.90 (m, 3H), 5.19 - 5.15 (m, 1H), 4.27 (dd, / = 18.1 , 8.5 Hz, 2H), 4.17 (ddd, / = 10.1, 5.7, 3.2 Hz, 1H), 3.95 (ddd, / = 10.2, 7.5, 2.7 Hz, 1H), 3.88 - 3.72 (m, 1H), 3.70 - 3.54 (m, 1H), 3.09 - 2.71 (m, 3H), 2.59 - 2.41 (m, 1H), 1.74 - 1.58 (m, 1H).

Example-55: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(iH-indazol-5-yl) urea (±).

Step-1: Phenyl lH-indazol-5-ylcarbamate.

To a solution of lH-indazol-5-amine (0.200 g, 1.502 mmol) in pyridine (5 mL), phenyl chloro formate (0.220 mL, 1.802 mmol) was added slowly at 0 °C and stirred at room temperature for 2 h. Then the reaction mixture was diluted with ice water to give solid, filtered and dried under vacuum. The crude compound obtained was purified on silica gel by column chromatography (methanol/dichloromethane = 3/97) to give titled compound (0.198 g, 52 %) as a solid. LCMS: m/z 254.0 [M+H] ⁺; ^lU NMR (400 MHz, DMSO-d6) δ 10.60 (s, lH), 8.60 (s, 1H), 8.18-8.05 (m, 2H), 7.80-7.70 (m, 1H), 7.34- 7.20 (m, 3H), 7.19-7.10 (m, 1H), 6.95-6.90 (m, 1H), 6.80-6.70 (m, 1H).

Step-2: l-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (iH-indazol-5-yl)urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.200 g, 0.627 mmol) was reacted with phenyl lH-indazol-5-ylcarbamate(0.191 g, 0.753 mmol) and triethylamine (0.170 mL, 1.250 mmol) in DMSO (5 mL) as described in the synthesis of step-2 of example- 11. The crude obtained was purified by preparative HPLC to give the titled compound (0.040 g, 14%) as a solid.

Preparative HPLC Method: Column: Agilent XDB CI 8 (9.4 X 250 mm, 5 micron); Water (A):: [Acetonitrile: methanol (1 :1 )](B); Flow Rate: 7 mL/min. LCMS: m/z 442.40 [M+ H]⁺; HPLC: 99.07 %; H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.68 (s, 1H), 7.96 (s, 1H), 7.88 (d, / = 1.9 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.41 (q, / = 8.6, 7.9 Hz, 3H), 7.36 - 7.25 (m, 4H), 7.13 (d, / = 8.1 Hz, 1H), 7.06 (t, / = 7.4 Hz, 1H), 6.46 (t, / = 5.6 Hz, 1H), 4.84 (dtd, / = 14.4, 7.8 , 6.5, 3.7 Hz, 1H), 4.14 - 3.98 (m, 2H), 3.95 (t, / = 5.4 Hz, 2H), 3.10 (dd, / = 17.4, 10.9 Hz, 1H), 2.85 (dd, / = 17.4, 7.4 Hz, 1H).

Example-56: l-((5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2,3-dihydro-iH-inden-5-yl)urea (±).

Step-1: Phenyl (2,3-dihydro- lH-inden-5-yl)carbamate .

To a solution of 2,3-dihydro-iH-inden-5-amine (0.300 g, 2.252 mmol) in pyridine (5 mL), phenyl chloroformate (0.340 mL, 2.703 mmol) was added slowly at 0 °C, stirred at room temperature for 2 h. Then the reaction mixture was diluted with ice water to give solid, filtered and dried under vacuum to give titled compound as crude (0.400 g, crude). This crude was used to next step without purification.

Step-2: l-((5-(([l , l ' -biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (2,3-dihydro-iH-inden-5-yl)urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl(2,3-dihydro-iH-inden-5-yl)carbamate (0.143 g, 0.565 mmol) and triethyl amine (1.300 mL, 0.942 mmol) in DMSO (5 mL) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.100 g, 48 %) as a solid. LCMS: m/z 442.45 [M+ H]⁺; HPLC: 95.52 %; ^lU NMR (400 MHz, Chloroform-d) δ 7.60 - 7.53 (m, 2H), 7.49 _ 7.40 (m, 2H), 7.39 - 7.31 (m, 3H), 7.18 (d, / = 2.0 Hz, 1 H), 7.14 (d, / = 8.0 Hz, 1H), 7.08 (tt, / = 7.5, 0.9 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.08 (s, 1H), 4.97 - 4.86 (m, 1H), 4.29 (d, / = 6.1 Hz, l H), 4.19 (dd, / = 10.2, 3.4 Hz, 1H), 4.09 - 3.83 (m, 2H), 3.02 (dd, / = 17.3 , 11.2 Hz, 1 H), 2.94 - 2.81 (m, 5H), 2.08 (p, / = 7.5 Hz, 2H).

Example-57: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridazin-4-yl) urea (±).

Step-1: phenyl pyridazin-4-ylcarbamate

To a solution of pyridazin-4-amine hydrochloride (0.090 g, 0.680 mmol) and pyridine (0.120 g, 1.500 mmol) in acetonitrile:THF (1 : 1) (10 mL) was added phenylchloroformate (0.090 mL, 0.750 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The reaction mixtures was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate/hexanes = 60/40) to give the titled compound (0.100 g, 68 ) as a solid.

Step-2: l-((5-(([l , l ' -biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (pyridazin-4-yl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl pyridazin-4-ylcarbamate (0.100 g, 0.470 mmol) and triethylamine (0.130 mL,0.940 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.060 g, 31 %) as a solid. HPLC: 98.08 %; LCMS : nt/z 404.1 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.45 (s, lH), 9.14 (dd, / = 2.8 , 1.0 Hz, 1H), 8.88 (dd, / = 6.0, 1.0 Hz, 1H), 7.76 (dd, / = 6.0, 2.8 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.44 - 7.22 (m, 5H), 7.12 (d, / = 8.2 Hz, lH), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.95 (t, / = 5.5 Hz, 1 H), 4.83 (dt, / = 11.3, 5.3 Hz, 1H), 4.16 - 3.99 (m, 2H), 3.95 (t, / = 4.2 Hz, 2H), 3.08 (dd, / = 17.4, 11.0 Hz, 1H), 2.82 (dd, / = 17.4, 7.5 Hz, 1H) .Example-58: l-((5-(([l, l'-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(pyrimidin-5-yl) urea (±).

Step-1: Phenyl pyrimidin-5-ylcarbamate.

To a solution of pyrimidin-5-amine (0.500 g, 5.260 mmol) and pyridine (0.630 g, 12.500 mmol) in acetonitrile (10 mL) was added phenylchloroformate (0.720 mL, 5.790 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate/hexanes = 60/40) to give the titled compound (0.100 g, 10 %) as a solid. LCMS: m/z 216.2 [M+ H] ⁺.

Step-2: l-((5-(([l , l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (pyrimidin-5-yl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.470 mmol) was reacted with phenyl pyrimidin-5-ylcarbamate (0.100 g, 0.470 mmol) and triethylamine (0.130 mL, 0.940 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.050 g, 26 %) as a solid. HPLC: 97.1 ; LCMS: m/z 404.4 [M+ H] ⁺; 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.88 (s, 2H), 8.79 (s, 1H), 7.55 - 7.46 (m, 2H), 7.44 - 7.36 (m, 2H), 7.36 - 7.25 (m, 3H), 7.12 (d, / = 8.1 Hz, lH), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.71 (t, / = 5.7 Hz, 1H), 4.82 (ddd, / = 11.0, 9.5, 5.4 Hz, lH), 4.16 - 3.98 (m, 2H), 3.93 (dd, / = 5.5, 1.4 Hz, 2H), 3.07 (dd, / = 17.4, 11.0 Hz, lH), 2.81 (dd, / = 17.4, 7.5 Hz, lH).

Example-59: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(4-methylpyridin-2-yl) urea (±).

To a solution of l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(5-bromo-4-methylpyridin-2-yl)urea (±) (prepared in step -2 of example - 41) (0.050 g, 0.101 mmol) in ethanol (20 mL), 10 % palladium on carbon (0.015 g) was added under inert atmosphere, then reaction mixture was stirred for 8 h under hydrogen gas(balloon) atmosphere. Then reaction mixture filtered through celite, the filtrate was concentrated under reduced pressure. The residue obtained was triturated with diethyl ether (2 X 10 mL) to give titled compound (0.015 g, 36%) as solid. LCMS: m/z 417.6 [M+ H]⁺;HPLC: 98.96 %; H NMR (400 MHz, Chloroform-d) δ 9.66 (s, 1H), 8.02 (d, / = 5.3 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.42 - 7.35 (m, 2H), 7.33 - 7.27 (m, 3H), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.95 (dd, / = 8.3, 1.2 Hz, 1H), 6.75 - 6.70 (m, 1H), 6.51 (s, 1H), 4.92 - 4.80 (m, lH), 4.25 - 3.95 (m, 4H), 3.06 (dd, / = 17.3, 10.9 Hz, 1H), 2.90 (dd, / = 17.4, 7.1 Hz, 1H), 2.30 (s, 3H).

Example-60: l-((5-(([l, l'-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(benzo[d]oxazol-5-yl) urea (±).

Step-1: phenyl benzo[d]oxazol-5-ylcarbamate

To a solution of benzo[d]oxazol-5-amine (1.0 g, 7.46 mmol) and sodium bicarbonate (1.9 g, 22.38 mmol) in THF (20 mL) was added phenylchloroformate (1.0 mL, 8.200 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate/hexanes = 60/40) to give the titled compound (1.5 g, 79 %) as a solid.

Step-2: l-((5-(([l , l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (benzo[d]oxazol-5-yl) urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl benzo[d]oxazol-5-ylcarbamate (0.120 g, 0.470 mmol) and triethylamine (0.130 mL, 0.940 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.050 g, 24 %) as a solid. HPLC: 96.19 ; LCMS: nt/z 443.1 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.65 (s, 1H), 7.96 (d, / = 2.1 Hz, 1 H), 7.63 (dd, / = 8.8, 0.6 Hz, lH), 7.57 - 7.45 (m, 2H), 7.46 - 7.36 (m, 2H), 7.36 - 7.22 (m, 4H), 7.12 (dd, / = 7.9, 1.1 Hz, 1H), 7.05 (td, / = 7.4, 1.1 Hz, 1H), 6.48 (t, / = 5.6 Hz, 1H), 4.90 - 4.76 (m, 1 H), 4.16 - 3.99 (m, 2H), 3.95 (t, / = 5.6 Hz, 2H), 3.09 (dd, / = 17.4, 10.9 Hz, 1 H), 2.84 (dd, / = 17.4, 7.5 Hz, 1H).

Example-61: l-((5-(([l, l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(4-cyano benzyl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.470 mmol) was reacted with phenyl 4-cyanobenzylcarbamate (0.120 g, 0.470 mmol) and triethylamine (0.130 mL, 0.940 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.050 g, 24 %) as a solid. HPLC: 97.78 ; LCMS: m/z 441.5 [M+H] ⁺; H NMR (400 MHz, Chloroform-d) δ 7.57 - 7.53 (m, 2H), 7.47 - 7.40 (m, 3H), 7.37 (ddd, / = 9.8, 5.1 , 2.2 Hz, 2H), 7.30 (dd, / = 7.6, 1.8 Hz, 2H), 7.24 (d, / = 8.0 Hz, 2H), 7.13 - 7.06 (m, 1 H), 7.00 - 6.95 (m, 1H), 4.98 - 4.84 (m, 1H), 4.48 - 4.31 (m, 1H), 4.31 - 4.18 (m, 1H), 4.04 (dd, / = 15.8, 7.6 Hz, 1 H), 3.93 (dd, / = 10.4, 2.5 Hz, 1H), 3.73 (dd, / = 15.7, 4.2 Hz, 1H), 3.63 (s, 1H), 2.98 (dd, / = 17.3, 11.4 Hz, 1H), 2.79 (dd, / = 17.3, 6.1 Hz, 1H).

Example-62: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(benzo[d]thiazol-5-yl)urea (±).

Step-1: phenyl benzo[d]thiazol-5-ylcarbamate

To a solution of benzo[d]thiazol-5 -amine (0.500 g, 3.329 mmol) in pyridine (5 mL) was added phenyl chloroformate (0.639 g, 3.995 mmol) at 0°C and further stirred for 12 h at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the titled compound (0.550 g, crude). The crude product was taken to the next step without further purification.

Step-2: 1 -((5-(([l , 1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[d]thiazol-5-yl)urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl benzo[d]thiazol-5-ylcarbamate (0.150 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.020 g, 9.3 %) as a solid. HPLC: 98.81 ; LCMS: nt/z 459.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.96 (s, 1H), 8.29 (d, / = 2.1 Hz, 1 H), 7.99 (d, / = 8.7 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.40 (dtd, / = 7.9, 6.6, 1.9 Hz, 3H), 7.35 - 7.24 (m, 3H), 7.12 (d, / = 8.0 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.55 (t, / = 5.6 Hz, 1H), 4.83 (q, / = 4.9, 3.3 Hz, 1H), 4.15 - 3.87 (m, 3H), 3.10 (dd, / = 17.3, 11.0 Hz, lH), 2.84 (dd, / = 17.4, 7.5 Hz, lH).

Example-63:l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(3-methyl pyridin-4-yl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (3-methylpyridin-4-yl)carbamate (0.140 g, 0.565 mmol) and triethylamine (0.099 mL,0.706 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.010 g, 4.87 %) as a solid.HPLC: 97.15 %; LCMS: m/z All .2 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.32 - 8.25 (m, 2H), 7.93 (d, / = 5.7 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.49 (t, / = 7.6 Hz, 2H), 7.42 - 7.30 (m, 3H), 7.07 (td, / = 7.5, 1.0 Hz, 1H), 6.94 (d, / = 8.4 Hz, 1H), 5.97 (s, 1H), 4.97 - 4.91 (m, 1H), 4.24 (dd, / = 10.2, 2.8 Hz, 1H), 4.12 (dd, / = 15.7, 7.3 Hz, 1H), 3.94 (dd, / = 10.2, 2.5 Hz, 1H), 3.79 (dd, / = 15.7, 4.0 Hz, 1H), 3.02 (dd, / = 17.2, 11.3 Hz, 1H), 2.86 (dd, / = 17.2, 5.9 Hz, 1H), 2.17 (s, 3H).

Example-64: 4-(3-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)ureido)pyridine 1-oxide (±).

To a stirred solution of l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridin-4-yl)urea (±) (0.100 g, 0.248 mmol) in dichloromethane (5 mL) was added meto-chloroperoxybenzoic acid (0.090 g, 0.370 mmol) at room temperature and further stirred for 4 h at room temperature. The reaction mixture was poured in to sodium bicarbonate solution and extracted with dichloromethane (3 x 15 mL). Dichloromethane layer dried and concentrated. The crude product purified by preparative HPLC to give titled compound (0.010 g, 10%) as a solid. HPLC: 95.5%; LCMS: m/z 419.5 [M+ H]⁺; H NMR (400 MHz, Chloroform-d) δ 10.02 (s, 1H), 8.04 (d, / = 6.8 Hz, 2H), 7.54 (m, 9 H), 7.06 (t, / = 7.5 Hz, 1H), 6.95 (d, / = 8.5 Hz, 1H), 6.52 (s, 1H), 4.85 (m, 1H), 4.32 - 3.8 (m, 4H), 2.96 (dd, / = 17.3, 11.1 Hz, lH), 2.82 (dd, / = 17.2, 6.9 Hz, 1H).

Example-65: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridazin-3-yl) urea (±).

Step-1: Phenyl pyridazin-3-ylcarbamate

To a solution of pyridazin-3-amine (0.100 g, 1.05 mmol) in pyridine (5 mL) was added phenylchloroformate (0.179 g, 1.150 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the titled compound (0.150 g, crude) as oil. The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l'4jiphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridazin-3-yl)urea (±).

(5-(([l ,l '4jiphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl pyridazin-3-ylcarbamate (0.120 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.020 g, 10.5 %) as a solid. HPLC: 95.96 ; LCMS : nt/z 404.1 M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 11.46 (s, 1H), 8.77 - 8.64 (m, 1H), 8.25 (s, 1 H), 7.74 - 7.16 (m, 9H), 7.05 (t, / = 7.4 Hz, 1H), 6.95 (d, / = 8.2 Hz, 1H), 4.87 (td, / = 11.0, 4.3 Hz, 1H), 4.24 - 3.95 (m, 4H), 3.15 - 2.84 (m, 2H).

Example-66: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(quinolin-7-yl) urea (±).

Step-1: Phenyl quinolin-7-ylcarbamate

To a solution of quinolin-7-amine (0.400 g, 2.770 mmol) in pyridine (5 mL) was added phenylchloroformate (0.380 mL, 3.00 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the titled compound (0.400 g, crude). The crude product was taken to the next step without further purification.

Step-2: l -((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (quinolin-7-yl)urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-d ydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.150 g, 0.471 mmol) was reacted with phenyl quinolin-7-ylcarbamate (0.140 g, 0.565 mmol) and triethylamine (0.099 mL, 0.706 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.010 g, 4.70 %) as a solid. HPLC: 98.53 ; LCMS: nt/z 453.4 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.85 (dd, / = 4.3, 1.8 Hz, 1H), 8.1 1 - 8.04 (m, 1H), 7.88 (dd, / = 8.9, 2.2 Hz, 1H), 7.79 - 7.69 (m, 2H), 7.66 - 7.59 (m, 2H), 7.53 - 7.47 (m, 1H), 7.41 - 7.36 (m, 1H), 7.33 - 7.29 (m, 2H), 7.29 - 7.27 (m, 1H), 7.06 (td, / = 7.5, 1.1 Hz, lH), 6.93 (dd, / = 8.7, 1.1 Hz, 1H), 6.67 (s, 1H), 4.93 (ddt, / = 11.5, 6.0, 2.8 Hz, 1H), 4.23 (dd, / = 10.2, 2.9 Hz, 1 H), 4.10 (dd, / = 15.9, 7.3 Hz, 1H), 3.97 - 3.82 (m, 2H), 3.03 (dd, / = 17.3, 1 1.3 Hz, 1H), 2.91 (dd, / = 17.3, 6.4 Hz, 1H).

Example-67: l-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(isoquinolin-7-yl) urea (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine chloride (±) (prepared in step-4 of example-1) (0.100 g, 0.313 mmol) was reacted with phenyl isoquinolin-7-ylcarbamate (0.083 g, 0.313 mmol) and triethylamine (0.096 g, 0.940 mmol) as described in the synthesis of step-2 of example- 11. The crude product was further purified by preparative HPLC to give the titled compound (0.002 g, 1.4 %) as a solid. HPLC: 96.43 ; LCMS: nt/z 453.4[M+ H]⁺; ^lU NMR (400 MHz, Chloroform- d) δ 9.12 (s, lH), 8.40 (s, 1H), 8.03 (s, 1H), 7.70 (d, / = 8.8 Hz, 1H), 7.63 - 7.59 (m, 2H), 7.56 - 7.46 (m, 4H), 7.42 - 7.36 (m, 1H), 7.32 (td, / = 7.3 , 1.7 Hz, 2H), 7.10 - 7.05 (m, 1H), 6.94 (dd, / = 8.6, 1.1 Hz, 1H), 6.60 (s, 1H), 4.96 - 4.90 (m, 1H), 4.23 (dd, / = 10.3, 3.0 Hz, 1H), 4.10 (dd, / = 16.1 , 7.0 Hz, 1H), 3.97 - 3.85 (m, 2H), 3.06 - 2.99 (m, 1H), 2.96 - 2.90 (m, 1H).

Preparative HPLC conditions: COLUMN: ZORBAX XDB-C18 (21.2 X 150 mm, 5 micron); 0.1 % TFA in water (A), acetonitrile (B); Flow: 20 ml/min. Time %B flow (ml/ min)

0 20 20

2 30 20

8 50 20

Example-68: 3-fluoro-/V-methyl-2'-((3-((3-(pyridin-4-yl) ureido) methyl)-4, 5- dihydroisoxazol-5-yl) methoxy)-[l, l '-biphenyl]-4-carboxamide (±).

Step-1: tert-butyl ((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l , l '-biphenyl]-2-yl) oxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)carbamate (±).

Tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in was reacted with (3- fluoro-4-(methylcarbamoyl)phenyl)boronic acid (0.307 g, 1.558 mmol) in the presence of sodium carbonate (0.275 g, 2.590 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.075 g, 0.065 mmol) in THF :water (3 :1 ) (13 mL) as described in the synthesis of step-4 of example-23 to give a crude. The crude was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.500 g, 84%) as a solid. LCMS: nt/z 458.1 [M+ H] ⁺.

Step-2: 2'-((3-(amino methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-3-fluoro-N-methyl- [1 , l '-biphenyl]-4-carboxamide hydrochloride (±).

tert-butyl((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,r-biphenyl]-2-yl) oxy) methyl) -4,5- dihydroisoxazol-3-yl) methyl) carbamate (±) (0.500 g, 4.0 mmol) was reacted with ethereal HQ (5 mL) in 1 ,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.300 g, 69 %) as a solid. LCMS: m/z 358.1 [M+H] ⁺. ^lU NMR (400 MHz, DMSO-d6) δ 8.52 (d, / = 6.7 Hz, 3H), 8.37 - 8.28 (m, 1H), 7.67 (t, / = 7.9 Hz, 1H), 7.51 - 7.34 (m, 4H), 7.17 (d, / = 8.5 Hz, 1H), 7.09 (t, / = 7.4 Hz, 1H), 4.96 (dtd, / = 11.1, 6.8, 4.0 Hz, 1H), 4.12 (qd, / = 10.5, 5.0 Hz, 2H), 3.74 (q, / = 5.8 Hz, 2H), 3.22 (dd, / = 17.6, 10.9 Hz, 1H), 3.12 - 2.87 (m, 1H), 2.80 (d, / = 4.5 Hz, 3H).

Step-3: 3-fluoro-N-methyl-2'-((3-((3-(pyridin-4-yl) ureido) methyl)-4, 5- dihydroisoxazol-5-yl) methoxy)-[l , l '-biphenyl]-4-carboxamide (±).

2'-((3-(amino methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-3-fluoro-N-methyl-[l , - biphenyl]-4-carboxamide hydrochloride (±) (0.050 g, 0.157 mmol) was reacted with phenyl pyridin-4-ylcarbamate (prepared in step-1 of example-2) (0.033 g, 0.157 mmol) and triethylamine (0.044 mL, 0.314 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.010 g, 13.1 ) as a solid. HPLC: 95.0 ;LCMS: m/z 478.40 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.37 - 8.28 (m, 2H), 8.25 (s, 1H), 7.66 (t, / = 8.1 Hz, 1H), 7.53 - 7.28 (m, 6H), 7.22 - 7.12 (m, 1H), 7.08 (td, / = 7.4, 1.0 Hz, 1H), 6.72 (t, / = 5.7 Hz, 1H), 4.93 - 4.77 (m, 1H), 4.13 (dd, / = 10.6, 3.7 Hz, 1H), 4.06 (dd, / = 10.5, 5.9 Hz, 1H), 3.97 (d, / = 5.6 Hz, 2H), 3.11 (dd, / = 17.4, 10.9 Hz, 1H), 2.91 - 2.82 (m, 1H), 2.79 (d, / = 4.6 Hz, 3H).

Example-69: 3-fluoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-[l, l'-biphenyl]-4-carboxamide (±).

2'-((3-(amino methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-3-fluoro-N-methyl-[l , - biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.150 g, 0.380 mmol) was reacted with phenyl (2-methylpyridin-4yl)carbamate (prepared in step- 1 of example- 13) (0.087 g, 0.380 mmol) and triethylamine (0.100 mL, 0.760 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.010 g, 5 %) as a solid. HPLC: 96.37%; LCMS: nt/z 492.3 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.26 (s, 1H), 8.16 (d, / = 5.7 Hz, 1H), 7.66 (t, / = 7.9 Hz, 1H), 7.53 - 7.30 (m, 4H), 7.25 (d, / = 2.1 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.13 - 7.00 (m, 1H), 6.70 (t, / = 5.7 Hz, 1H), 4.86 (s, 1H), 4.22 - 4.00 (m, 2H), 3.97 (d, / = 5.5 Hz, 2H), 3.11 (dd, / = 17.4, 10.9 Hz, 1H), 2.95 - 2.82 (m, 1H), 2.79 (d, / = 4.5 Hz, 3H), 2.36 (s, 3H).

Example-69a: 3-fluoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl) - 4, 5-dihydroisoxazol-5-yl) methoxy)-[l, l'-biphenyl]-4-carboxamide (enantiomer-1).

Step-l:tert-butyl((5-(((3'-fiuoro-4'-(methylcarbamoyl)-[l , 1 '-biphenyl]-2-yl) oxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)carbamate (enantiomer-1)

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate [enantiomer-1 : Peak- 1 ; (separated in step-1 of example-23)](0.500 g, 1.298mmol) was reacted with (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (0.307 g, 1.558 mmol) in the presence of sodium carbonate (0.275 g, 2.590 mmol) and tetrakis (triphenylphosphine) palladium(O) (0.075 g, 0.065 mmol) in THF :water (3 :1 ) (13 mL) as described in the synthesis of step-1 of example-68 to give titled compound (0.500 g, 84%) as a solid.

Step-2: 2'-((3-(amino methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-3-fluoro-N-methyl- [1 , l '-biphenyl]-4-carboxamide hydrochloride. (enantiomer-1)

tert-butyl((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,r-biphenyl]-2-yl) oxy) methyl) -4,5- dihydroisoxazol-3-yl) methyl)carbamate (single enantiomer) (0.500 g, 4.000 mmol) was reacted with ethereal HCl (5 mL) in 1 ,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.300 g, 69 %) as a solid. Step-3: 3-fluoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)-4, 5- dihydroisoxazol-5-yl) methoxy)-[l , l '-biphenyl]-4-carboxamide (enantiomer-1).

2'-((3-(amino methyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fluoro-N-methyl-[l , - biphenyl]-4-carboxamide hydrochloride (enantiomer-1) (0.400 g, 1.015 mmol) was reacted with phenyl (2-methylpyridin-4yl)carbamate (prepared in step-1 of example-13) (0.230 g, 1.015 mmol) and triethylamine (0.280 mL, 2.030 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.300 g, 60 ) as a solid. HPLC: 99.1 %; LCMS: nt/z 492.3 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.28 (d, / = 5.7 Hz, 1H), 7.85 (t, / = 8.1 Hz, 1H), 7.56 (dd, / = 8.2, 1.6 Hz, 1H), 7.45 - 7.29 (m, 3H), 7.25 - 7.13 (m, 2H), 7.14 - 7.02 (m, 1H), 6.95 (d, / = 8.2 Hz, 1H), 6.78 (s, 1H), 5.82 (t, / = 6.2 Hz, 1H), 4.89 (dd, / = 11.1 , 9.2 Hz, 1H), 4.33 (dd, / = 10.5, 2.1 Hz, 1H), 4.15 (dd, / = 17.0, 6.4 Hz, 1H), 4.06 (dd, / = 10.5, 1.7 Hz, 1H), 3.81 (dd, / = 17.0, 5.9 Hz, 1H), 3.15 (d, / = 4.8 Hz, 3H), 3.08 - 2.84 (m, 2H), 2.49 (s, 3H).

Example-69b: 3-fluoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)- 4, 5-dihydroisoxazol-5-yl) methoxy)-[l, l'-biphenyl]-4-carboxamide (enantiomer-2)

Step-1: tert-butyl ((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l, l '-biphenyl]-2-yl) oxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)carbamate (enantiomer-2).

Tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate [enantiomer-2: Peak-2; (separated in step-1 of example-23)] (0.500 g, 1.298 mmol) was reacted with (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (0.307 g, 1.558 mmol) in the presence of sodium carbonate (0.275 g, 2.590 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.075 g, 0.065 mmol) in THF :water (3:1) (13 mL) as described in the synthesis of step-1 of example-68 to give titled compound (0.500 g, 84%) as a solid.

Step-2: 2'-((3-(amino methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-3-fluoro-N-methyl- [1, l '-biphenyl]-4-carboxamide hydrochloride ((enantiomer-2).

Tert-butyl((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l, -biphenyl]-2-yl) oxy) methyl) -4,5- dihydroisoxazol-3-yl) methyl)carbamate (single enantiomer) (0.500 g, 4.000 mmol) was reacted with ether .HQ (5 mL) in 1,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.300 g, 69 %) as solid.

Step-3: 3-fiuoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)-4, 5- dihydroisoxazol-5-yl) methoxy)-[l , l '-biphenyl]-4-carboxamide (enatiomer-2).

2'-((3-(amino methyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fluoro-N-methyl-[l ,l'- biphenyl]-4-carboxamide hydrochloride (0.400 g, 1.015 mmol) was reacted with phenyl (2-methylpyridin-4yl)carbamate (prepared in step-1 of example-13) (0.230 g, 1.015 mmol) and triethylamine (0.280 mL, 2.030 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.250 g, 50 %) as a solid.HPLC: 97.2%; LCMS: nt/z 492.3 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.28 (d, / = 5.7 Hz, 1H), 7.85 (t, / = 8.1 Hz, 1H), 7.57 (dd, / = 8.1, 1.6 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.25 - 7.15 (m, 2H), 7.12 - 7.03 (m, 1H), 6.95 (d, / = 8.2 Hz, 1H), 6.76 (s, 1H), 5.80 (t, / = 6.2 Hz, 1H), 4.90 (t, / = 10.2 Hz, 1H), 4.34 (dd, / = 10.4, 2.0 Hz, 1H), 4.15 (dd, / = 16.9, 6.6 Hz, 1H), 4.06 (d, / = 10.2 Hz, 1H), 3.81 (dd, / = 16.9, 5.9 Hz, 1H), 3.21 - 3.10 (m, 3H), 3.07 - 2.84 (m, 2H), 2.50 (s, 3H).

Example-70: 3-fluoro-2'-((3-((3-(3-methoxypyridin-4-yl) ureido) methyl)-4, 5- dihydroisoxazol-5-yl)methoxy)-N-methyl- [1 ,1 ' -biphenyl] -4-carboxamide (±). Step-1: phenyl (3-methoxypyridin-4-yl) carbamate.

To a solution of 3-methoxypyridin-4-amine (0.300 g, 2.410 mmol) in pyridine (5 mL) was added phenylchloroformate (0.453 g, 2.900 mmol) at 0°C. The reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the titled compound (0.080 g, 11.8 %) as oil.

Step-2: 3-fluoro-2'-((3-((3-(3-methoxypyridin-4-yl) ureido) methyl)-4, 5- dihydroisoxazol-5-yl)methoxy)-N-methyl-[l ,r-biphenyl]-4-carboxamide (±).

A solution of (2'-((3-(amino methyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fluoro-N- methyl- [l ,l'-biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.100 g, 0.250 mmol), phenyl (3-methoxypyridin-4-yl)carbamate (0.067 g, 0.270 mmol) and triethylamine (0.105 mL, 0.750 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The obtained residue was Purified by column chromatography on silica gel (methanol/dichloromethane = 5/95) to give the titled compound (0.050 g, 27 %) as off white solid. HPLC: 98.69 ;

LCMS: m/z 508.2 [M+H] ⁺; 1H NMR (400 MHz, DMSO-d₆) δ 8.52 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.08 (d, / = 5.3 Hz, 1H), 8.01 (d, / = 5.3 Hz, 1H), 7.65 (t, / = 8.0 Hz, 1H), 7.47 - 7.35 (m, 5H), 7.17 - 7.14 (m, 1H), 7.10 - 7.04 (m, 1H), 4.91 - 4.81 (m, 1H), 4.16 - 4.03 (m, 2H), 3.98 (d, / = 5.6 Hz, 2H), 3.92 (s, 3H), 3.15 - 3.07 (m, 1H), 2.89 - 2.82 (m, 1H), 2.79 (d, / = 4.6 Hz, 3H). Example-71: 3-fluoro-N-methyl-2'-((3-((3-(pyridazin-4-yl)ureido)methyl)-4,5- dihydroisoxazol-5-yl)methoxy)-[l,l'-biphenyl]-4-carboxamide (±).

Step-1: 3-fiuoro-N-methyl-2'-((3-((3-(pyridazin-4-yl)ureido)methyl)-4,5- dihydroisoxazol-5-yl)methoxy)-[ 1 , 1 '-biphenyl]-4-carboxamide (±).

2'-((3 -(amino methyl)-4,5-dihydro isoxazol-5-yl)methoxy)-3-fluoro-N- methyl- [ 1 , 1 '- biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.100 g, 0.250 mmol) was reacted with phenyl pyridazin-4-ylcarbamate (prepared in step-1 of example-57) (0.053 g, 0.250 mmol) and triethylamine (0.050 mL, 0.375 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.020 g, 16.6 %) as a solid. HPLC: 98.89 ; LCMS: nt/z 479.3 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.03 (d, / = 2.8 Hz, 1H), 8.85 (dd, / = 6.0, 1.0 Hz, 1H), 7.97 (dd, / = 6.0, 2.8 Hz, 1 H), 7.82 (t, / = 8.1 Hz, 1 H), 7.53 (dd, / = 8.1 , 1.6 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.24 (dd, / = 12.5, 1.5 Hz, lH), 7.06 (td, / = 7.5, 1.0 Hz, 1H), 6.96 - 6.92 (m, 1H), 6.13 (t, / = 6.0 Hz, 1H), 4.96 - 4.84 (m, 1H), 4.29 (dd, / = 10.4, 2.3 Hz, lH), 4.16 (dd, / = 17.1 , 5.2 Hz, 1H), 4.05 (dd, / = 10.5, 1.9 Hz, 1H), 3.72 (dd, / = 17.1 , 4.5 Hz, 1 H), 3.14 - 3.06 (m, 3H), 3.05 - 2.82 (m, 2H).

Example-72: 3-fluoro-2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)-4, 5- dihydroisoxazol-5-yl) methoxy)-[l, l '-biphenyl]-4-carboxamide (±).

Step-1: tert-butyl ((5-(((4'-carbamoyl-3'-fluoro-[l , l ' -biphenyl]-2-yl) oxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

Tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in was reacted with (4- carbamoyl-3-fluorophenyl)boronic acid (0.413 g, 1.558 mmol) in the presence of sodium carbonate (0.275 g, 2.590 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.075 g, 0.065 mmol) in THF :water (3: 1) (13 mL) as described in the synthesis of step-4 of example-23 to give a crude. The crude was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.500 g, 84%) as a solid. Step-2: 2'-((3-(amino methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-3-fiuoro-[l, Γ- biphenyl]-4-carboxamide hydrochloride (±).

tert-butyl ((5-(((4'-carbamoyl-3'-fluoro-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)carbamate (±) (0.500 g, 4.000 mmol) was reacted with ethereal HCl (5 mL) in 1 ,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.200 g, 30 %) as a solid.

Step-3: 3-fluoro-2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)-4, 5-dihydroisoxazol- 5-yl) methoxy)-[l , l '-biphenyl]-4-carboxamide (±).

2'-((3-(aminomethyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-3-fluoro-[l , 1 '-biphenyl]-4- carboxamide hydrochloride (±) (0.075 g, 0.197 mmol) was reacted with phenyl (2- methylpyridin-4yl)carbamate (prepared in step-1 of example- 13) (0.068 g, 0.296 mmol) and triethylamine (0.055 mL, 0.394 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.020 g, 21 %) as a solid. HPLC: 99.3 %;

LCMS: m/z 478.5 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.15 (d, / = 5.7 Hz, 1H), 7.81 - 7.57 (m, 3H), 7.54 - 7.30 (m, 4H), 7.24 (s, 1H), 7.16 (t, / = 7.1 Hz, 2H), 7.07 (t, / = 7.5 Hz, 1H), 6.69 (t, / = 5.5 Hz, lH), 4.85 (s, 1H), 4.21 - 4.01 (m, 2H), 3.96 (d, / = 5.6 Hz, 2H), 3.11 (dd, / = 17.4, 10.8 Hz, 1H), 2.83 (dd, / = 17.0, 7.5 Hz, 1H), 2.35 (s, 3H). Example-73: 2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)-4, 5-dihydroisoxazol- 5-yl) methoxy)-[l, l'-biphenyl]-4-carboxamide (±).

Step-1: tert-butyl ((5-(((4'-carbamoyl-[l , l '-biphenyl]-2-yl) oxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) was reacted with (4- carbamoylphenyl)boronic acid (0.260 g, 1.560 mmol) in the presence of sodium carbonate (0.275 g, 2.59 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.075 g, 0.065 mmol) in THF :water (3: 1) (13 mL) as described in the synthesis of step-4 of example-23 to give a crude. The crude was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.500 g, 90%) as a solid.

Step-2: 2'-((3-(aminomethyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-[l, l '-biphenyl]-4- carboxamide hydrochloride (±).

tert-butyl ((5-(((4'-carbamoyl-[l, l '-biphenyl]-2-yl) oxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methyl)carbamate (±) (0.500 g, 1.170 mmol) was reacted with ethereal HC1 (5 mL) in 1 ,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.400 g, 94 %) as a solid.

Step-3: 2'-((3-((3-(2-methylpyridin-4-yl) ureido) methyl)-4, 5-dihydroisoxazol-5-yl) methoxy)-[l, l '-biphenyl]-4-carboxamide (±).

2'-((3 -(amino methyl)-4,5-dihydroisoxazol-5-yl) methoxy)- [1 , 1 '-biphenyl]-4- carboxamide hydrochloride (±) (0.200 g, 0.554 mmol) was reacted with phenyl (2- methylpyridin-4yl)carbamate (prepared in step-1 of example-13) (0.140 g, 0.609 mmol) and triethylamine (0.150 mL, 2.000 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.040 g, 15 %) as a solid. HPLC: 91.8 %; LCMS: mJz 460.4 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.27 (d, / = 5.7 Hz, 1H), 7.85 - 7.72 (m, 2H), 7.70 - 7.54 (m, 2H), 7.43 - 7.29 (m, 3H), 7.20 (dd, / = 5.8, 2.1 Hz, 1H), 7.08 (td, / = 7.5, 1.1 Hz, 1H), 6.95 (d, / = 8.2 Hz, 1H), 6.41 (s, 1H), 5.92 (s, lH), 5.70 (t, / = 6.2 Hz, 1H), 4.96 - 4.81 (m, 1H), 4.33 (dd, / = 10.4, 2.1 Hz, 1H), 4.16 - 3.92 (m, 2H), 3.71 (dd, / = 17.1, 6.0 Hz, 1H), 3.08 - 2.75 (m, 2H), 2.49 (s, 3H).

Example-74: l-((5-(((4'-methoxy-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(2-methylpyridin-4-yl)urea (±).

Step-1: tert-butyl ((5-(((4'-methoxy-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in THF: water (4:1) (12.5 mL) was added 4-methoxy phenylboronic acid (0.236 g, 1.557 mmol), followed by sodium carbonate (0.537 g, 3.894 mmol) and tetrakis(triphenylphosphine)palladium (0.149 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 80 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous and ethyl acetate layer were separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.420 g, 78 ) as a solid. LCMS: m/z 413.2 [M+ H] ⁺ Step-2: (5-(((4'-methoxy-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

tert-butyl ((5-(((4'-methoxy-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) carbamate (±) (0.420 g, 0.799 mmol) was reacted with 4N HCl in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.320 g, 93%) as a solid.

Step-3: l -((5-(((4'-methoxy-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methylpyridin-4-yl)urea (±).

A solution of (5-(((4'-methoxy-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (0.100 g, 0.286 mmol), phenyl (2-methylpyridin-4- yl)carbamate (prepared in step-1 of exampe-13) (0.070 g, 0.315 mmol) and triethylamine (0.086 g, 0.858 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2/98) to give the titled compound (0.030 g, 23 %) as a solid. HPLC: 96.79%; LCMS: nt/z 447.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.16 (d, / = 5.6 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.30 - 7.23 (m, 3H), 7.18 (dd, / = 5.7, 2.1 Hz, 1H), 7.08 (d, / = 8.3 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.97 - 6.93 (m, 2H), 6.69 (d, / = 5.6 Hz, 1H), 4.83 (dt, / = 11.0, 5.5 Hz, 1H), 4.08 (dd, / = 10.6, 3.8 Hz, 1H), 4.04 - 4.00 (m, 1H), 3.95 (t, / = 5.8 Hz, 2H), 3.75 (s, 3H), 3.09 (dd, / = 17.4, 11.0 Hz, 1H), 2.84 (dd, / = 17.4, 7.4 Hz, 1H), 2.36 (s, 3H). Example-75: l-((5-(((4'-methoxy-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydro- isoxazol-3-yl)methyl)-3-(pyridazin-4-yl)urea (±).

A solution of (5-(((4'-methoxy-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (0.100 g, 0.286 mmol), phenyl pyridazin-4- ylcarbamate (prepared in step-1 of example-57) (0.066 g, 0.315 mmol) and triethylamine (0.117 mL, 0.858 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane =2/98) to give the titled compound (0.060 g, 48 %) as a solid. HPLC: 98.31 %; LCMS: nt/z 434.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.11 (dt, / = 2.8, 0.9 Hz, 1H), 8.85 (dt, / = 6.0, 0.9 Hz, 1 H), 7.72 (ddd, / = 6.0, 2.8, 0.8 Hz, 1 H), 7.45 - 7.41 (m, 2H), 7.28 - 7.23 (m, 2H), 7.06 (dd, / = 8.5, 1.0 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.95 - 6.90 (m, 2H), 4.85 - 4.80 (m, 1 H) 4.09 - 3.94 (m, 4H), 3.73 (d, / = 0.8 Hz, 3H), 3.08 (dd, / = 17.4, 10.9 Hz, 1H), 2.82 (dd, / = 17.4, 7.5 Hz, 1H).

Example-76: l-(imidazo[l,2-a]pyridin-6-ylmethyl)-3-((5-((2-(pyridin-3- yl)phenoxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)urea (±).

Step-1: tert-butyl ((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±)

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.290 mmol) in 1 ,4-dioxane: water (4:1 ) (8 mL) was reacted with pyridin-3-ylboronic acid (0.314 g, 2.58 mmol) in the presence of potassium carbonate (0.530 g, 3.871 mmol) and l ,l '-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.105 g, 0.129 mmol) at 110 °C for 12 h as described in the synthesis of step-2 of example- 12 to give the titled compound (0.450 g, 91.8 %) as a solid.

Step-2: (5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±)

tert-butyl ((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl) carbamate (±) (0.450 g, 1.170 mmol) was reacted with 4 N HC1 in 1 ,4-dioxane (10 mL) at 0 °C as described in the synthesis of step-3 of example- 12 to give titled compound (0.250 g, crude).

Step-3: l-(imidazo[l ,2-a]pyridin-6-ylmethyl)-3-((5-((2-(pyridin-3-yl)phenoxy)methyl)- 4,5-dihydroisoxazol-3-yl)methyl)urea (±).

(5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.100 g, 0.280 mmol) was reacted with phenyl (imidazo[l ,2-a] pyridin-6-ylmethyl)carbamate (0.820 g, 0.308 mmol) and triethylamine (0.110 mL, 0.840 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.020 g, 15.6 %) as a solid. HPLC: 95.68 ; LCMS: nt/z 457.5 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d₆) δ 8.70 (dd, / = 2.3, 0.8 Hz, 1 H), 8.50 (dd, / = 4.8, 1.7 Hz, 1H), 8.37 (d, / = 1.5 Hz, 1H), 7.95 - 7.88 (m, 2H), 7.54 - 7.47 (m, 2H), 7.45 - 7.34 (m, 3H), 7.20 - 7.05 (m, 3H), 6.64 (t, / = 6.1 Hz, 1H), 6.37 (t, / = 5.8 Hz, 1H), 4.80 (dd, / = 10.9, 5.4 Hz, 1H), 4.21 (d, / = 6.0 Hz, 2H), 4.13 - 3.98 (m, 2H), 3.87 (dd, / = 5.9, 2.6 Hz, 2H), 3.05 (dd, / = 17.4, 1 1.0 Hz, 1 H), 2.77 (dd, / = 17.4, 7.2 Hz, 1H).

Example-77: l-(pyridazin-4-yl)-3-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)urea.

(5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dmydroisoxazol-3-yl)methanamine hydrochloride (±) (0.075 g, 0.210 mmol), phenyl pyridazin-4-ylcarbamate (prepared in step-1 of example-57) (0.045 g, 0.210 mmol) and triethylamine (0.088 mL, 0.630 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The obtained residue was purified by column chromatography on silica gel (methanol/dichloromethane = 5/95) to give the titled compound (0.020 g, 23.5 %) as white solid. HPLC: 98.92 ; LCMS: m/z 405.0M+H] ⁺; 1H NMR (400 MHz, DMSO- d6) 59.46 (s, 1H), 9.13 (dd, / = 2.8, 1.0 Hz, 1H), 8.87 (dd, / = 6.0, 1.0 Hz, 1H), 8.71 (dd, / = 2.3, 0.8 Hz, 1H), 8.50 (dd, / = 4.8, 1.6 Hz, lH), 7.92 (dt, / = 7.9, 2.0 Hz, 1H), 7.75 (dd, / = 6.0, 2.8 Hz, 1H), 7.46 - 7.35 (m, 3H), 7.15 (dd, / = 8.7, 1.1 Hz, 1H), 7.09 (td, / = 7.5, 1.0 Hz, 1H), 6.98 (t, / = 5.6 Hz, 1H), 4.85 (ddt, / = 11.1, 7.2, 4.3 Hz, 1H), 4.18 - 4.02 (m, 2H), 4.02 - 3.89 (m, 2H), 3.10 (dd, / = 17.4, 11.1 Hz, 1H), 2.83 (dd, / = 17.4, 7.3 Hz, 1H).

Example-78: l-((5-((2-(4-methoxvpyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(2-methylpyridin-4-yl)urea (±).

Step-1: tert-butyl ((5-((2-(4-methoxypyridin-3-yl) phenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl) carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in 1,4-dioxane: water (4:1) (15 mL) was added (4-methoxypyridin-3- yl)boronic acid (0.266 g, 1.687 mmol), followed by potassium carbonate (0.537 g, 3.894 mmol) and 1 ,1' -Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex(0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.330 g, 61 %) as a sticky solid. LCMS: m/z 413.5 [M+ H] ⁺

Step-2:(5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

tert-butyl ((5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.330 g, 0.799 mmol) was reacted with 4 N HC1 in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.230 g, 92%) as a solid.

Step-3: l-((5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2 -methyl pyridin-4-yl) urea (±).

A solution of (5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (0.060 g, 0.172 mmol), phenyl (2-methylpyridin-4- yl)carbamate (prepared in step-1 of exampe-13) (0.042 g, 0.189 mmol) and triethylamine (0.071 mL, 0.516 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2/98) to give the titled compound (0.010 g, 12.1 %) as a solid. HPLC: 92.69%; LCMS: nt/z 448.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.40 (d, / = 5.8 Hz, l H), 8.20 (s, l H), 8.17 (d, / = 5.6 Hz, 1H), 7.35 (ddd, / = 8.9, 7.5, 1.8 Hz, 1H), 7.25 (d, / = 2.1 Hz, 1H), 7.21 - 7.17 (m, 2H), 7.09 - 7.07 (m, 2H), 7.03 - 6.99 (m, 1H), 6.65 (t, / = 5.8 Hz, 1H), 4.76 - 4.70 (m, 1H), 4.04 - 3.96 (m, 2H), 3.86 (t, / = 6.2 Hz, 2H), 3.79 (s, 3H), 3.00 (dd, / = 17.4, 11.0 Hz, 1H), 2.66 (dd, / = 17.4, 11.0 Hz, 1H), 2.36 (s, 3H).

Example-79: l-((5-((2-(4-methoxypyridin-3-yl) phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(pyridazin-4-yl)urea (±).

A solution of (5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride^) (0.060 g, 0.172 mmol), phenyl pyridazin-4- ylcarbamate (prepared in step-1 of example-57) (0.040 g, 0.189 mmol) and triethylamine (0.071 mL, 0.516 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2.5/97.5) to give the titled compound (0.035 g, 47.1 %) as a solid. HPLC: 93.54%; LCMS: nt/z 434.85 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.12 (dd, / = 2.8, 1.0 Hz, 1H), 8.86 (dd, / = 6.0, 1.0 Hz, 1H), 8.39 (d, / =

5.7 Hz, 1H), 8.18 (s, 1H), 7.73 (dd, / = 6.0, 2.8 Hz, 1H), 7.33 (ddd, / = 9.0, 7.4, 1.8 Hz, 1H), 7.18 (dd, J = 7.5, 1.7 Hz, 1H), 7.09 - 7.06 (m, 2H), 7.02 - 6.97 (m, 1H), 6.91 (d, / =

5.8 Hz, 1H), 4.75 - 4.69 (m, 1 H), 4.03 - 3.85 (m, 4H), 3.77 (s, 3H), 3.00 (dd, / = 17.3 , 11.0 Hz, 1 H), 2.71 - 2.65 (m, 1H).

Example-80: l-((5-((2-(5-methylpyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

Step-1: tert-butyl ((5-((2-(5-methylpyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methyl)carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in was reacted with (5- methylpyridin-3-yl)boronic acid (0.213 g, 1.558 mmol) in the presence of sodium carbonate (0.275 g, 2.590 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.075 g, 0.065 mmol) in THF :water (3: 1) (13 mL) as described in the synthesis of step-4 of example-23 to give the titled compound (0.400 g, 77%) as a solid.

Step-2: (5-((2-(5-methylpyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

tert-butyl ((5-((2-(5-methylpyridin-3-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl) methyl) carbamate (±) (0.400 g, 1.000 mmol) was reacted with ethereal HC1 (5 mL) in 1,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.300 g, 89 %) as a solid.

Step-3: l-((5-((2-(5-methylpyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

(5-((2-(5-methylpyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.150 g, 0.449 mmol) was reacted with phenyl (2-methylpyridin-4- yl)carbamate (prepared in step-1 of exampe-13) (0.112 g, 0.490 mmol) and triethylamine (0.120 mL, 0.898 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.050 g, 26 %) as a solid. HPLC: 90.9 %; LCMS: m/z 432.2 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.02 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.46 - 8.36 (m, 1H), 8.25 (d, / = 5.6 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1 H), 7.38 (td, / = 8.1 , 7.5, 1.8 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.18 - 7.03 (m, 2H), 6.98 (d, / = 8.4 Hz, 1H), 6.44 (d, / = 9.4 Hz, 1H), 4.98 (dd, / = 11.9, 8.9 Hz, l H), 4.48 (dd, / = 15.0, 9.5 Hz, lH), 4.27 (dd, / = 10.7, 2.0 Hz, 1H), 4.14 (dd, / = 10.6, 1.7 Hz, l H), 3.86 (dd, / = 14.9, 2.5 Hz, 1 H), 3.36 (dd, / = 17.6, 8.7 Hz, 1H), 3.14 (dd, / = 17.6, 12.1 Hz, 1H), 2.47 (d, / = 1.3 Hz, 6H).

Example-81: l-((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

Step-1: tert-butyl ((5-((2-(2-fiuoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (1.250 g, 3.244 mmol) in 1 ,4-dioxane: water: ethanol (1.0: 0.25 : 0.082) (35 mL) was added (2-fluoropyridin-3-yl)boronic acid (0.551 g, 3.893 mmol), followed by potassium carbonate (1.342 g, 9.734 mmol) and 1,1 ' - Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.261 g, 0.324 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 1.5 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40mL). Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.562 g, 43 %) as a liquid. LCMS: m/z 302.1 [M+H- 100] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.20 (ddd, / = 4.8, 2.0, 1.0 Hz, 1 H), 7.79 (ddd, / = 9.3, 7.3, 2.0 Hz, 1H), 7.40 (ddd, / = 8.2, 7.4, 1.7 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.08 (td, / = 7.5, 1.0 Hz, lH), 6.97 (d, / = 8.3 Hz, lH), 5.33 (bs, lH), 4.87 (ddt, / = 11.1 , 7.4, 3.8 Hz, 1H), 4.17 - 4.05 (m, 2H), 3.95 (qd, / = 16.7, 6.2 Hz, 2H), 3.02 (qd, / = 17.4, 9.1 Hz, 2H), 1.46 (s, 9H).

Step-2: (5-((2-(2-fiuoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

tert-butyl ((5-((2-(2-fiuoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (0.560 g, 1.395 mmol) was reacted with 4 N HCl in 1,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.461 g, crude). The crude product was taken to the next step without further purification. LCMS : m/z 302.1 [M+H] ⁺.

Step-3: l-((5-((2-(2-fiuoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

(5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.100 g, 0.296 mmol) was reacted with phenyl (2-methylpyridin-4- yl)carbamate (prepared in step-1 of exampe-13) (0.108 g, 0.473 mmol) and N,N- diisopropylethylamine (0.157 mL, 0.888 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.032 g, 24.8 %) as a solid. HPLC: 96.78 %; LCMS: m/z 436.1 [M+ H] ⁺ ; 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, / = 5.7 Hz, 1H), 8.23 (dd, / = 5.0, 1.8 Hz, 1H), 7.98 (s, 1H), 7.85 (ddd, / = 9.4, 7.4, 2.0 Ηζ,ΙΗ), 7.42 - 7.29 (m, 2H), 7.29 (d, / = 2.1 Hz, 1H), 7.17 (dd, / = 5.8, 2.1 Hz, 1H), 7.11 (t, / = 7.4 Hz, lH), 6.97 (d, / = 8.3 Hz, lH), 5.99 (d, / = 8.5 Hz, lH), 4.95 - 4.89 (m, 1H), 4.43 (dd, / = 15.5, 9.1 Hz, 1H), 4.23 (dd, / = 10.5, 2.3 Hz, 1H), 4.11 (dd, / = 10.6, 1.8 Hz, 1H), 3.87 (dd, / = 15.4, 2.9 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.09-3.05 (m,lH), 2.47 (s, 3H). Further the enantiomeric mixture (0.030 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 81a & 81b). Method: Column: LUX AMYLOSE-2, n-hexane: ethanol:: ISOCRATIC (20:80);Flow Rate: 20 mL/Min).

Example-81a: l-((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea.

Yield: 0.007 g; Retention Time: 9.41 min.; Chiral HPLC: 99.33 ; HPLC: 98.70 ; LCMS: m/z 436.2 [M+ H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.28 (d, / = 5.7 Hz, 1H), 8.23-8.17 (m, 1H), 7.98 (s, 1H), 7.85 (ddd, / = 9.3, 7.4, 1.9 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.30 - 7.27 (m, 1H), 7.16 (dd, / = 5.6, 2.1 Hz, lH), 7.13 - 7.06 (m, 1H), 6.97 (d, / = 8.3 Hz, 1H), 5.97 (d, / = 7.8 Hz, 1H), 4.98 - 4.87 (m, 1H), 4.44 (dd, / = 15.4, 9.1 Hz, 1H), 4.23 (dd, / = 10.4, 2.3 Hz, 1H), 4.11 (dd, / = 10.5, 1.8 Hz, 1H), 3.85 (dd, / = 15.3, 2.8 Hz, 1H), 3.40-3.36 (m, 1H), 3.10-3.06 (m, 1H), 2.49 (s, 3H).

Example-81b: l-((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydro- isoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea.

Yield: 0.008 g; Retention Time: 7.01 min.; Chiral HPLC: 98.95 ; HPLC: 99.49 ; LCMS: m/z 436.5 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J = 5.7 Hz, 1H), 8.25 - 8.19 (m, 1H), 7.96 (s, 1H), 7.86 (ddd, J = 9.4, 7.3, 2.0 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.29 (d, J = 2.1 Hz, 1H), 7.16 (dd, J = 5.7, 2.1 Hz, 1H), 7.10 (td, J = 7.5, 1.0 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 5.98 (d, J = 8.3 Hz, 1H), 4.96 - 4.88 (m, 1H), 4.44 (dd, J = 15.4, 9.1 Hz, 1H), 4.23 (dd, J = 10.5, 2.4 Hz, 1H), 4.11 (dd, J = 10.5, 1.8 Hz, 1H), 3.85 (dd, J = 15.4, 2.8 Hz, 1H), 3.37-3.31 (m, 1H), 3.10-3.04 (dd, J = 17.5, 12.0 Hz, 1H), 2.48 (s, 3H).

Example-82: l-((5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5-dihydro- isoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

Step-1: tert-butyl ((5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (1.250 g, 3.244 mmol) in 1,4-dioxane: water: ethanol (1.0: 0.25: 0.082) (35 mL) was added (2-methoxypyridin-4-yl) boronic acid (0.741 g, 4.867 mmol), followed by potassium carbonate (1.342 g, 9.734 mmol) and 1,1 '-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.261 g, 0.324 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 2 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.602 g, 44 %) as a liquid. LCMS: nt/z 414.4 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.18 (dt, / = 5.4, 0.9 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.11 - 7.04 (m, 2H), 6.97 (dd, / = 8.3, 1.0 Hz, 1H), 6.91 (dt, / = 1.5, 0.9 Hz, 1H), 4.92 (tt, / = 7.3, 3.7 Hz, 1H), 4.75 (s, 1 H), 4.04 (dd, / = 10.2, 3.5 Hz, 1H), 3.99 (d, / = 1.0 Hz, 3H), 3.94 (d, / = 6.1 Hz, 2H), 3.05 (ddd, / = 17.3 , 11.2, 1.1 Hz, 1H), 2.91 (dd, / = 17.3, 7.3 Hz, 1 H), 1.44 (d, / = 0.9 Hz, 9H).

Step-2: (5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine dihydrochloride (±).

tert-butyl ((5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (0.600 g, 1.451 mmol) was reacted with4 N HC1 in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.502 g, crude). The crude product was taken to the next step without further purification. LCMS :

Step-3: l-((5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

(5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine dihydrochloride (±) (0.100 g, 0.296 mmol) was reacted with phenyl (2- methylpyridin-4-yl)carbamate (prepared in step-1 of exampe-13) (0.108 g, 0.473 mmol) and triethylamine (0.157 mL, 0.888 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.030 g, 22.7 %) as a solid. HPLC: 93.04 %; LCMS: nt/z 448.2 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.29 (d, / = 5.7 Hz, 1H), 8.21 (d, / = 5.4 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.32 (dt, / = 5.7, 1.6 Hz, 2H), 7.21 (dd, / = 5.7, 2.1 Hz, 1H), 7.16 - 7.14 (m, 2H), 6.97 (d, / = 8.9 Hz, 2H), 4.94 - 4.89 (m, 1H), 4.32 (dd, / = 10.4, 2.7 Hz, 1H), 4.15 (dd, / = 16.1 , 6.8 Hz, 1H), 4.01- 3.97 (m, 5H),2.98-2.92(m, 2H), 2.49 (s, 3H).

Example-83: l-((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

Step-1: tert-butyl ((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (1.250 g, 3.244 mmol) in 1 ,4-dioxane: water: ethanol (1.0: 0.25 : 0.08) (35 mL) was added (2-methoxypyridin-3-yl) boronic acid (0.740 g, 4.867 mmol), followed by potassium carbonate (1.340 g, 9.734 mmol) and 1 ,1 '-Bis (diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.260 g, 0.324 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 1.5 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.600 g, 44 %) as a liquid. LCMS: nt/z 414.3 [M+ H] ⁺; H NMR (400 MHz, Chloroform-d) δ 8.18 (ddd, / = 5.0, 2.0, 0.6 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.37 - 7.32 (m, 1H), 7.26 (d, / = 1.8 Hz, 1H), 7.06 (ddd, / = 8.4, 7.1 , 0.9 Hz, 1H), 6.99 - 6.92 (m, 2H), 4.83 (m, / = 10.9, 7.2, 3.7 Hz, 1H), 4.17 - 3.98 (m, 2H), 3.94 (d, / = 0.6 Hz, 3H), 3.83 (d, / = 6.0 Hz, 2H), 2.95 (dd, / = 17.2, 11.1 Hz, 1H), 2.80 (dd, / = 17.3, 6.9 Hz, 1H), 1.46 (s, 9H).

Step-2: (5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

tert-butyl ((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (0.600 g, 1.451 mmol) was reacted with 1,4-dioxane.HCl as described in the synthesis of step-4 of example-1 to give titled compound (0.500 g crude). The crude product was taken to the next step without further purification. LCMS: m/z 314.1 [M+H] ⁺

Step-3: l-((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

(5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.120 g, 0.343 mmol) was reacted with phenyl (2- methylpyridin-4-yl)carbamate (prepared in step-1 of exampe-13) (0.123 g, 0.548 mmol) and N,N-diisopropylethylamine (0.175 mL, 1.029 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.030 g, 22.7 %) as a solid. HPLC: 93.04 ; LCMS: m/z 448.2 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, / = 5.7 Hz, 1H), 8.22 (s, 1H), 8.17 (dd, / = 5.2, 1.9 Hz, 1H), 7.60 (dd, / = 7.2, 1.9 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.21 (td, / = 7.4, 1.9 Hz, 2H), 7.10 - 7.02 (m, 2H), 6.94 (d, / = 8.4 Hz, 1H), 4.97 - 4.83 (m, 1H), 4.26 (dd, / = 10.4, 2.5 Hz, 1H), 4.04 - 3.86 (m, 6H), 2.98 (qd, / = 17.2, 9.6 Hz, 2H), 2.50 (s, 3H). Further the enantiomeric mixture (0.040 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 83a & 83b). Method: Column: LUX AMYLOSE-2, n-hexane: ethanol:: ISOCRATIC (40:60);Flow Rate: 20 mL/min).

Example-83a: l-((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea.

Yield: 0.008 g; Retention Time: 7.09 min; Chiral HPLC: 99.54 ; HPLC: 99.52 ; LCMS: m/z 448.2 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, / = 5.6 Hz, 1H), 8.24 - 8.12 (m, 2H), 7.61 (dd, / = 7.2, 1.9 Hz, 1H), 7.37 (ddd, / = 17.5, 9.0, 1.9 Hz, 2H), 7.24 - 7.15 (m, 2H), 7.10 - 7.02 (m, 2H), 6.94 (d, / = 8.3 Hz, 1H), 4.98 - 4.77 (m, 1H), 4.26 (dd, / = 10.4, 2.5 Hz, 1H), 4.11 - 3.81 (m, 6H), 2.99 (qd, / = 17.2, 9.7 Hz, 2H), 2.50 (s, 3H).

Example-83b: l-((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea.

Yield: 0.009 g; Retention Time: 11.56 min.; Chiral HPLC: 99.71 ; HPLC: 98.35 ; LCMS: m/z 448.2 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, / = 5.7 Hz, 1H), 8.22 (s, 1H), 8.17 (dd, / = 5.2, 1.9 Hz, 1H), 7.60 (dd, / = 7.2, 1.9 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.21 (td, / = 7.4, 1.9 Hz, 2H), 7.10 - 7.02 (m, 2H), 6.94 (d, / = 8.4 Hz, 1H), 4.97 - 4.83 (m, 1H), 4.26 (dd, / = 10.4, 2.5 Hz, 1H), 4.04 - 3.86 (m, 6H), 2.98 (qd, / = 17.2, 9.6 Hz, 2H), 2.50 (s, 3H).

Example-84: l-((5-((2-(6-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methyl)-3-(2-methyl pyridin-4-yl) urea (±).

Step-1: tert-butyl ((5-((2-(6-fiuoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in 1,4-dioxane: water (4:1) (15 mL) was added (6-fiuoropyridin-3- yl)boronic acid (0.237 g, 1.687 mmol), followed by potassium carbonate (0.537 g, 3.894 mmol) and l ,l'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.450 g, 70 ) as a solid. Step-2: (5-((2-(6-fiuoropyridin-3-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

tert-butyl ((5-((2-(6-fluoropyridin-3-yl)-phenoxy)-methyl)-4,5-dihydroisoxazol-3-yl)- methyl) carbamate (±) (0.450 g, 0.962 mmol) was reacted with 4 N HC1 in 1 , 4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.350 g, 99%) as a solid.

Step-3: l -((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methylpyridin -4-yl) urea (±).

A solution of (5-((2-(6-fiuoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (0.350 g, 1.053 mmol), phenyl (2-methylpyridin-4- yl)carbamate (prepared in step-1 of exampe- 13) (0.281 g, 1.263 mmol) and Triethylamine (0.319 g, 3.159 mmol) in DMSO (10 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2.0/98.0) to give the titled compound (0.120 g, 26 %) as a solid. HPLC: 96.25%; LCMS: nt/z 436.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.35 (d, / = 2.6 Hz, 1H), 8.17 - 8.13 (m, 1H), 8.11 (dd, / = 8.2, 2.6 Hz, 1H), 7.40 (dh, / = 7.5, 1.7 Hz, 2H), 7.25 (d, / = 2.1 Hz, 1H), 7.21 (dd, / = 8.6, 2.9 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.09 (td, / = 7.4, 1.0 Hz, 1H), 6.68 (t, / = 5.6 Hz, 1H), 4.88 - 4.82 (m, 1H), 4.09 (qd, / = 10.5, 4.5 Hz, 2H), 3.96 (d, / = 6.1 Hz, 2H), 3.11 (dd, / = 17.5, 11.0 Hz, 1H), 2.83 (dd, / = 17.5, 7.3 Hz, 1H), 2.36 (s, 3H). Example-85: l-((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl)-3-(imidazo[l,2-a]pyridin-6-yl)urea (±).

Step-1: Phenyl imidazo [l,2-a]pyridin-6-ylcarbamate.

To a solution of imidazo[l,2-a]pyridin-6-amine (4.700 g, 35.298 mmol) (synthesis as per reported procedure in WO2003062241A1) as in pyridine (50 mL) was added phenylchloroformate (5.52 g, 35.298 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 14 h. The reaction mixture was diluted with water (50 mL) and extracted with chloroform (2 x 100 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure and purified by combifiash column chromatography to give the titled compound (2.500 g, 28%) as a solid. LCMS: m/z 254.45[M+H] ⁺; ^NMR (300 MHz, DMSO-d6) δ 10.25 (bs, 1H), 8.91 (s, 1H), 8.03 (s, 1H), 7.62 (m, 2H), 7.47 (m, 2H), 7.33 (m, 4H).

Step-2: l-((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(imidazo[l,2-a] pyridin-6-yl)urea (±).

(5-((2-(6-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine dihydrochloride (±) (prepared in step-2 of example-84) (O.lOOg, 0.300 mmol) was reacted with phenyl imidazo [1, 2-a] pyridin-6-ylcarbamate (0.072 g, 0.285 mmol) and N,N-diisopropylethylamine (0.121 mL, 0.712 mmol)) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.030 g, 23%) as a solid. HPLC:96.2 %; LCMS: m/z 461.1 [M+H] ⁺; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, / = 2.0 Hz, 1H), 8.69 (s, 1H), 8.36 (d, / = 2.5 Hz, 1H), 8.12 (td, / = 8.3, 2.6 Hz, 1H), 7.91 (s, 1H), 7.46 (d, / = 8.6 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.23 - 7.13 (m, 2H), 7.12 - 6.97 (m, 2H), 6.56 (t, / = 5.6 Hz, 1H), 4.84 (dt, / = 11.2, 5.6 Hz, 1H), 4.09 (qd, / = 10.6, 4.5 Hz, 2H), 3.97 (d, / = 5.6 Hz, 2H), 3.11 (dd, / = 17.5, 11.0 Hz, 1H), 2.83 (dd, / = 17.4, 7.2 Hz, 1H). Example-86: l-((5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(imidazo[l,2-a]pyridin-6-ylmethyl)urea (±).

Step-1: tert-butyl ((5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.600 g, 1.557 mmol) in was reacted with furan- 3-ylboronic acid (0.296 g, 2.648 mmol) in the presence of cesium carbonate (1.52 g, 4.672 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.179 g, 0.155 mmol) in N,N-dimethylformamide (10 mL) as described in the synthesis of step-4 of example-23 to give the titled compound (0.450 g, 76 %) as a solid. LCMS: m/z 272.9 [M-100] ⁺.

Step-2: (5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±).

tert-butyl ((5-((2-(furan-3-yl)-phenoxy)-methyl)-4,5-dihydroisoxazol-3-yl)-methyl) carbamate (±) (0.450 g, 1.209 mmol) was reacted with 4 N HCl in 1 ,4-dioxane (5 mL) in diethyl ether (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.300 g, crude ). LCMS: m/z 273.05 [M+H] ⁺(Free base)

Step-3: l-((5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (imidazo[l ,2-a]pyridin-6-ylmethyl)urea (±).

(5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)-methanamine hydrochloride (±) (0.100 g, 0.323 mmol) was reacted with phenyl (imidazo[l,2-a]pyridin-6- ylmethyl) carbamate (0.103 g, 0.388 mmol) and triethylamine (0.067 mL, 0.485 mmol)) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.005 g, 3.4%) as a solid. HPLC:91.08%;LCMS: nt/z 446.45 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (dd, / = 1.9, 1.0 Hz, 1H), 8.11 (dd, / = 1.6, 0.8 Hz, 1H), 7.91 (t, / = 1.0 Hz, 1H), 7.72 (t, / = 1.8 Hz, 1H), 7.63 (dd, / = 7.7, 1.7 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.26 (ddd, / = 8.8, 7.4, 1.8 Hz, 1H), 7.15 (dd, / = 9.3, 1.7 Hz, 2H), 7.09 - 6.98 (m, 3H), 6.65 (t, / = 5.9 Hz, 1H), 6.43 (t, / = 5.8 Hz, 1H), 5.01 -4.94 (m, / = 6.0 Hz, 1H), 4.24 - 4.12 (m, 2H), 4.09 - 3.97 (m, 2H), 3.48 - 3.40 (m, 2H), 3.21 - 3.11 (m, 1H), 2.86 (dd, / = 17.5 , 7.5 Hz, 1H).

Example-87: l-((5-((2-(furan-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(2-methyl pyridin-4-yl) urea (±).

(5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)-methanamine hydrochloride (±) (0.100 g, 0.324 mmol) was reacted with phenyl(2-methylpyridin-4- yl)carbamate (0.088 g, 0.389 mmol) and triethylamine (0.068 mL, 0.487 mmol)) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.005 g, 3.7%) as a solid.HPLC:92.0 %;LCMS: nt/z 407.45 [M+H] ⁺ ; 1H NMR (400 MHz, Chloroform-d) δ 8.26 (d, / = 5.7 Hz, 1 H), 7.92 (dd, / = 1.5, 0.8 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.25 - 7.20 (m, 2H), 7.06 - 6.99 (m, 2H), 6.93 (d, / = 8.1 Hz, 1H), 6.83 - 6.78 (m, 2H), 5.36 (s, 1H), 5.07-4.99 (m, 1H), 4.27 (dd, / = 10.3, 3.5 Hz, 1H), 4.19 (t, / = 5.6 Hz, 2H), 4.10 (dd, / = 10.4, 3.9 Hz, 1H), 3.26 - 3.04 (m, 2H), 2.46 (s, 3H).

Example-88: l-((5-((2-(3, 5-dimethylisoxazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

Step-1: tert-butyl ((5-((2-(3, 5-dimethylisoxazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step- 1 of example-23) (0.500 g, 1.298 mmol) in was reacted with (3,5- dimethylisoxazol-4-yl)boronic acid (0.347 g, 1.558 mmol) in the presence of sodium carbonate (0.275 g, 2.590 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.075 g, 0.065 mmol) in THF :water (3: 1) (13 mL) as described in the synthesis of step-4 of example-23 to give a crude. The crude was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.500 g, crude) as a solid. LCMS: m/z 402.00 [M+ H] ⁺.

Step-2: (5-((2-(3, 5-dimethylisoxazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

tert-butyl ((5-((2-(3,5-dimethylisoxazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.500 g, 1.25 mmol) was reacted with ethereal HC1 (5 mL) in 1,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.250 g, 60 %) as a solid. LCMS: m/z 301.3 [M+H] ⁺ (Free base).

Step-3: l-((5-((2-(3, 5-dimethylisoxazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3- yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

(5-((2-(3, 5-dimethylisoxazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.150 g, 0.445 mmol) was reacted with phenyl (2- methylpyridin-4-yl)carbamate (prepared in step-1 of exampe-13) (0.100 g, 0.445 mmol) and triethylamine (0.120 mL, 0.890 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.010 g, 5 %) as a solid. HPLC: 95.15 %; LCMS: m/z 436.45 [M+ H]⁺; H NMR (400 MHz, Chloroform-d) δ 8.32 (d, / = 5.7 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.23 (dd, / = 5.8, 2.2 Hz, 1H), 7.15 (dd, / = 7.5, 1.8 Hz, 1H), 7.07 (td, / = 7.4, 1.0 Hz, 1H), 6.94 (d, / = 8.3 Hz, 1H), 5.05 - 4.83 (m, 1H), 4.41 (s, 2H), 3.90 (d, / = 10.7 Hz, 1H), 3.86 (dd, / = 10.4, 2.5 Hz, 1H), 2.96 (dd, / = 10.2, 5.8 Hz, 2H), 2.51 (s, 3H), 2.30 (s, 3H), 2.16 (d, / = 4.4 Hz, 3H). Example-89: l-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(2-methylpyridin-4-yl)urea (±).

Step-1: tert-butyl ((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in l,4-dioxane:water(4:l) (10 mL) was added l-methyl-4-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-iH-pyrazole (0.405 g, 1.947 mmol), followed by potassium carbonate (0.537 g, 3.894 mmol) and l,l '-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 50 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.380 g, 69 ) as a sticky solid.

Step-2: (5 -((2-(l -methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5 -dihydroisoxazol-3 - yl)methanamine hydrochloride (±).

tert-butyl((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.380 g, 0.983 mmol) was reacted with 4 N HQ in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.320 g, 99%) as a solid. Step-3: l -((5-((2-(l-methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methylpyridin-4-yl)urea (±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)- methanamine hydrochloride (±) (0.500 g, 1.549 mmol) was reacted with phenyl (2- methylpyridin-4-yl)carbamate (prepared in step-1 of exampe-13) (0.530 g, 2.323 mmol) and triethylamine (0.87 mL, 6.196 mmol) in DMSO (5 mL) as described in the synthesis of step-2 of example- 1 1 to give the titled compound (0.400 g, 61 %) as a solid. LCMS: nt/z 421.2 [M+H]⁺; HPLC: 96.58 %; 1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.25 (d, / = 5.7 Hz, 1H), 7.86 (d, / = 0.7 Hz, 1H), 7.65 (s, 1H), 7.35 (dd, / = 7.6, 1.8 Hz, 1H), 7.28 (d, / = 2.1 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.13 - 7.10 (m, 1 H), 6.99 (td, / = 7.5, 1.1 Hz, 1H), 6.94 - 6.89 (m, 1 H), 5.69 - 5.56 (m, 1H), 5.08 - 4.96 (m, 1H), 4.43 - 4.28 (m, 2H), 4.08 (dd, / = 10.7, 2.3 Hz, 1H), 4.03 (dd, / = 15.3, 3.5 Hz, 1H), 3.98 (s, 3H), 3.52 - 3.05 (m, 2H), 2.47 (s, 3H). Further the enantiomeric mixture (0.300 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 89a & 89b). Method: Column: Cellulose-C4; n-hexane: ethanol: ISOCRATIC (20:80); Flow Rate: 7 mL/min).

Example-89a: l-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(2-methylpyridin-4-yl)urea.

Yield: 0.140 g; HPLC: 96.58 %; LCMS: nt/z 421.2 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1 H), 8.28 (d, / = 5.7 Hz, 1H), 7.88 (s, 1H), 7.67 (s, 1 H), 7.36 (dd, / = 7.5, 1.7 Hz, 1H), 7.31 (d, / = 2.1 Hz, lH), 7.25 - 7.22 (m, 1H), 7.13 (dd, / = 5.7, 2.1 Hz, 1H), 7.05 - 6.97 (m, 1 H), 6.96 - 6.90 (m, 1H), 5.58 (d, / = 7.2 Hz, 1H), 5.09 - 4.97 (m, 1H), 4.48 - 4.33 (m, 2H), 4.12 - 4.03 (m, 2H), 4.01 (s, 3H), 3.54 - 3.43 (m, 1H), 3.14 (dd, / = 17.5, 1 1.9 Hz, 1H), 2.49 (s, 3H).

Example-89b: l-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(2-methylpyridin-4-yl)urea.

Yield: 0.110 g; HPLC: 96.58 %; LCMS: nt/z 421.2 [M+ H]⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1 H), 8.27 (d, / = 5.6 Hz, 1H), 7.87 (s, 1H), 7.67 (s, 1 H), 7.36 (dd, / = 7.5, 1.7 Hz, 1H), 7.30 (d, / = 2.0 Hz, 1H), 7.24 (dd, / = 7.6, 1.7 Hz, 1H), 7.13 (dd, / = 5.7, 2.0 Hz, 1H), 7.00 (td, / = 7.5, 1.1 Hz, 1H), 6.93 (d, / = 8.2 Hz, 1H), 5.58 (d, / = 8.1 Hz, 1H), 5.12 - 4.84 (m, 1H), 4.45 - 4.33 (m, 2H), 4.15 - 4.04 (m, 2H), 4.00 (s, 3H), 3.53 - 3.44 (m, 1H), 3.14 (dd, / = 17.5, 12.0 Hz, 1H), 2.48 (s, 3H).

Example-90: l-(2-cyclopropylpyridin-4-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) urea (±).

Step-1: Phenyl (2-cyclopropylpyridin-4-yl) carbamate.

To a solution of 2-cyclopropylpyridin-4-amine (0.400 g,2.980 mmol) in acetonitrile (10 mL) was added phenylchloroformate (0.4 mL, 3.28 mmol) at room temperature. The reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the titled compound (0.500 g, 65%) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-(2-cyclopropylpyridin-4-yl)-3-((5-((2-(l -methyl- lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) urea (±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.310 mmol) was reacted with phenyl (2-cyclopropylpyridin-4-yl)carbamate (0.080 g, 0.310 mmol) and triethylamine (0.086 mL, 0.62 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.015 g, 10 %) as a solid. HPLC: 97.0 %; LCMS: m/z 447.2 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.39 (s, 1H), 8.24 (d, / = 5.6 Hz, lH), 7.89 (s, 1H), 7.68 (s, 1H), 7.38 (dd, / = 7.6, 1.8 Hz, 1H), 7.33 (d, / = 2.1 Hz, lH), 7.27 - 7.18 (m, 1H), 7.06 (dd, / = 5.6, 2.2 Hz, 1H), 7.02 (t, / = 7.5 Hz, 1H), 6.95 (d, / = 8.3 Hz, 1H), 5.58 (d, / = 8.5 Hz, 1H), 5.04 (dd, / = 12.5, 7.6 Hz, 1H), 4.50 - 4.30 (m, 2H), 4.22 - 4.05 (m, 2H), 4.02 (s, 3H), 3.33 (dd, / = 17.5, 8.2 Hz, 1H), 3.16 (dd, / = 17.6, 11.9 Hz, 1H), 1.98 (ddd, / = 13.3, 8.1, 4.9 Hz, 1H), 1.12 - 0.76 (m, 4H).

Example-91: l-(2-ethylpyridin-4-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) urea (±).

Step-1: phenyl (2-ethylpyridin-4-yl) carbamate.

To a solution of 2-ethylpyridin-4-amine hydrochloride (1.0 g, 6.25 mmol) and triethylamine (1.7 mL, 12.5 mmol) in acetonitrile (10 mL) was added phenylchloroformate (0.86 mL, 6.870 mmol) at 0 °C. The reaction mixture was stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate/hexanes = 60/40) to give the titled compound (1.0 g, 66 %) as a solid. LCMS: m/z 243.1 [M+H] ⁺; H NMR (300 MHz, Chloroform-d) δ 8.55 (d, / = 5.8 Hz, 1H), 8.42 (d, / = 5.7 Hz, 2H), 7.58 - 7.03 (m, 5H), 2.83 (dq, / = 15.1, 7.6 Hz, 2H), 1.31 (td, / = 7.7, 3.7 Hz, 3H).

Step-2: l-(2-ethylpyridin-4-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl) - 4, 5-dihydroisoxazol-3-yl) methyl) urea (±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.080 g, 0.248 mmol) was reacted with phenyl (2-ethylpyridin-4-yl)carbamate (0.060 g, 0.248 mmol) and triethylamine (0.07 mL, 0.495 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.02 g, 18 %) as a solid. HPLC: 93.74 %; LCMS: m z 435.2 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.31 (d, / = 5.7 Hz, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.43 - 7.31 (m, 2H), 7.27 - 7.20 (m, 1H), 7.14 (dd, / = 5.7, 2.1 Hz, 1H), 7.02 (td, / = 7.5, 1.1 Hz, 1H), 6.98 - 6.90 (m, 1H), 5.72 (dd, / = 8.2, 3.7 Hz, 1H), 5.04 (ddt, / = 10.8, 8.3, 2.5 Hz, 1H), 4.45 - 4.28 (m, 2H), 4.16 - 4.04 (m, 2H), 4.01 (s, 3H), 3.30 (dd, / = 17.5, 8.2 Hz, 1 H), 3.16 (dd, / = 17.5, 11.8 Hz, 1H), 2.77 (q, / = 7.6 Hz, 2H), 1.29 (t, / = 7.6 Hz, 3H).

Example-92: l-((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(pyridazin-4-yl)urea (±).

A solution of (5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.310 mmol), phenyl pyridazin-4-ylcarbamate (prepared in step-1 of example-57) (0.072 g, 0.341 mmol) and triethylamine (0.127 mL, 0.930 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2/98) to give the titled compound (0.033 g, 26.1 %) as a solid. HPLC: 96.39%; LCMS: nt/z 408.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.14 (dd, / = 2.8, 1.0 Hz, 1H), 8.88 (dd, / = 5.9, 1.0 Hz, 1H),

8.06 (s, 1H), 7.90 (d, / = 0.7 Hz, 1H), 7.75 (dd, / = 6.0, 2.8 Hz, 1 H), 7.59 (dd, / = 7.6,

1.7 Hz, 1H), 7.18 (ddd, / = 8.8, 7.2, 1.7 Hz, 1H), 7.1 1 - 7.00 (m, 2H), 6.97 (td, / = 7.5, 1.2 Hz, 1H), 5.07 - 4.99 (m, 1H), 4.13 (ddd, / = 17.2, 9.4, 4.8 Hz, 4H), 3.86 (s, 3H), 3.23 (dd, / = 17.4, 10.9 Hz, 1H), 2.94 (dd, / = 17.5, 7.8 Hz, 1H).

Example-93: l-(2-methoxypyridin-4-yl)-3-((5-((2-(l-methyl-iH-pyrazol-4- yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)urea (±).

Step-1: Phenyl (2-methoxypyridin-4-yl) carbamate.

To a solution of 2-methoxypyridin-4-amine (1.0 g, 7.992 mmol) in acetonitrile: THF (1 : 1) (20 mL) was added pyridine (1.390 g, 17.580 mmol), followed by added phenylchloroformate (1.450 g, 9.590 mmol) at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the titled compound (0.480 g, 25.0 %) as oil.

Step-2: l -(2-methoxypyridin-4-yl)-3-((5-((2-(l-methyl-iH-pyrazol-4-yl)

phenoxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)urea (±).

A solution of (5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.310 mmol), phenyl (2-methoxypyridin-4-yl)carbamate (0.080 g, 0.341 mmol) and Triethylamine (0.128 mL, 0.93 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the titled compound (0.008 g, 5.9 %) as a solid. HPLC: 98.22%; LCMS : nt/z 437.45 [M+ H]⁺; H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.97 (d, / = 5.8 Hz, 1H), 7.87 (d, / = 0.7 Hz, 1H), 7.65 (s, 1H), 7.36 (dd, / = 7.6, 1.8 Hz, 1 H), 7.25 - 7.19 (m, 1H), 7.03 - 6.96 (m, 2H), 6.95 - 6.90 (m, 1H), 6.86 (d, / = 1.9 Hz, 1H), 5.07 - 4.98 (m, 1H), 4.42 - 4.32 (m, 2H), 4.12 - 4.01 (m, 2H), 4.00 (s, 3H), 3.90 (d, / = 0.5 Hz, 3H), 3.32 (dd, / = 17.5, 8.3 Hz, lH), 3.13 (dd, / = 17.6, 1 1.9 Hz, 1H).

Preparative HPLC Method: Column: AG/PP/C18-15-035; 0.1 % TFA in Water (A): acetonitrile: methanol (1 : 1) (B).

TIME % B FLOW

0 30 20

2 40 20

8 60 20

Example-94: l-((5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±). Step-1: tert-butyl ((5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) was reacted with 2-(4- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazol-l -yl)ethanol (0.460 g, 1.948 mmol) in the presence of potassium carbonate (0.540 g, 3.9 mmol) and [1,1 '-bis (diphenylphosphino) ferrocene] dichloropalladium(II) complex with dichloromethane (0.106 g, 0.129 mmol) in 1 ,4-dioxane :water (3:1) (6 mL) as described in the synthesis of step-4 of example- 132 to give a crude. The crude was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.500 g, 92%) as a solid.

Step-2: 2-(4-(2-((3-(aminomethyl)-4, 5-dihydroisoxazol-5-yl) methoxy) phenyl)-lH- pyrazol-l-yl) ethanol hydrochloride (±).

tert-butyl((5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) carbamate (±) (0.5 g, 1.17 mmol) was reacted with ethereal HCl (5 mL) in 1 ,4-dioxane (5 mL) at 0 °C as described in the synthesis of step-4 of example- 1 to give titled compound (0.2 g, 47%) as a solid.

Step-3: l-((5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) urea (±).

2-(4-(2-((3-(aminomemyl)-4,5-dmydroisoxazol-5-yl)memoxy)phenyl)-lH-pyrazol-l - yl)ethanol hydrochloride (±) (0.100 g, 0.284 mmol) was reacted with phenyl (2- methylpyridin-4-yl)carbamate (prepared in step-1 of exampe-13) (0.065 g, 0.284 mmol) and triethylamine (0.08 mL, 0.568 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.020 g, 15 %) as a solid. HPLC: 99.2 ;LCMS: m/z 451.5 [M+H] ⁺; 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.41 (d, / = 6.8 Hz, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.77 - 7.63 (m, 1H), 7.60 (dd, / = 7.7, 1.7 Hz, 1H), 7.41 (t, / = 5.7 Hz, 1H), 7.23 (s, 1H), 7.17 (td, / = 7.8, 1.7 Hz, 1H), 7.10 (s, 1H), 7.05 (d, / = 8.1 Hz, 1H), 7.02 - 6.89 (m, 1H), 5.02 (dq, / = 11.2, 5.8 Hz, 1H), 4.92 (s, 1H), 4.13 (dt, / = 12.1, 6.0 Hz, 4H), 3.76 (d, / = 5.9 Hz, 2H), 3.23 (dd, / = 17.4, 10.9 Hz, 1H), 2.93 (dd, / = 17.5, 7.6 Hz, 1H), 2.56 (s, 4H).

Example-95: l-(isoquinolin-7-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl)

phenoxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)urea (±).

Step-1: Phenyl isoquinolin-7-ylcarbamate

To a solution of isoquinolin-7-amine (0.200 g, 1.390 mmol) and pyridine (0.329 g, 4.170 mmol) N,N-dimethylformamide (5 mL) was added phenylchloro formate (0.261 g, 1.670 mmol) at 0 °C. The reaction mixture was stirred for 6 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified by column chromatography (dichloromethane/methanol = 98/2) to give the titled compound (0.275 g, 75.1 %) as an oil.

Step-2: l-(isoquinolin-7-yl)-3-((5-((2-(l-methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)urea (±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.309 mmol) was reacted with phenyl isoquinolin-7-ylcarbamate (0.082 g, 0.309 mmol) and triethylamine (0.094 mL,0.929 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.060 g, 42.3 %) as a solid. HPLC: 97.93 %; LCMS: m/z 457.4 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.39 (s, 2H), 8.17 (d, / = 2.1 Hz, lH), 7.93 (s, 1H), 7.74 - 7.67 (m, 2H), 7.64 (dd, / = 8.9, 2.2 Hz, 1H), 7.56 (s, 1H), 7.38 (dd, / = 7.6, 1.7 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.01 (td, / = 7.5, 1.0 Hz, 1H), 6.97 - 6.91 (m, 1H), 5.60 - 5.52 (m, 1H), 5.05 (ddd, / = 11.5, 8.1, 4.1 Hz, 1H), 4.50 - 4.35 (m, 2H), 4.10 (ddd, / = 12.9, 7.7, 2.9 Hz, 2H), 4.03 (s, 3H), 3.34 (dd, / = 17.5, 8.1 Hz, 1H), 3.18 (dd, / = 17.5, 11.8 Hz, 1H).

Example-96: l-(benzo[b]thiophen-6-yl)-3-((5-((2-(l-methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)urea.

Step-1: tert-butyl benzo[b]thiophen-6-ylcarbamate.

To a previously degassed solution of 6-bromobenzo[b]thiophene (1.0 g, 4.694 mmol) in toluene (30 mL) was added tert-butyl carbamate (0.824 g, 7.042 mmol), followed by potassium carbonate (1.290 g, 9.388 mmol), Cul (0.044 g, 0.234 mmol) and Ni,N₂- dimethylcyclohexane-l ,2-diamine(0.066 g, 0.469 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 110 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (ethyl acetate/he xanes = 10/90) to give the titled compound (0.570 g, 48 %) as a solid. LCMS: m/z 150.2 [M-100] ⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.17 (s, 1H), 7.74 (d, / = 8.6 Hz, 1H), 7.57 (d, / = 5.5 Hz, 1H), 7.41 - 7.31 (m, 2H), 1.50 (s, 9H).

Step-2: Benzo[b]thiophen-6-amine hydrochloride.

tert-butyl benzo[b]thiophen-6-ylcarbamate (0.570 g, 0.962 mmol) was reacted with 4N HC1 in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.380 g, 89%) as solid. LCMS: nt/z 150.2 [M+ H] ⁺; 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 3H), 7.97 - 7.92 (m, 2H), 7.81 (d, / = 5.4 Hz, 1H), 7.49 (d, / = 5.4 Hz, 1H), 7.32 (dd, / = 8.5, 2.0 Hz, 1H).

Step-3: Phenyl benzo[b]thiophen-6-ylcarbamate.

To a solution of benzo[b]thiophen-6-amine hydrochloride (0.380 g, 2.046 mmol), in acetonitrile(5 mL) and THF (5 mL )were added pyridine (0.647 g, 8.184 mmol) and phenylchloroformate (0.372 g, 2.455 mmol) at 0 °C. The reaction mixture was stirred for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the titled compound (0.420 g, 76%) as a solid. The crude product was taken to the next step without further purification.

Step-4: l -(benzo[b]thiophen-6-yl)-3-((5-((2-(l -methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydro isoxazol-3-yl) methyl) urea (±).

A solution of (5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.055 g, 0.170 mmol), phenyl benzo[b]thiophen-6-ylcarbamate (0.055 g, 0.204 mmol) and Triethylamine (0.051 g, 0.510 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 3/97) to give the titled compound (0.036 g, 46.1 %) as a solid. HPLC: 98.26%; LCMS: m/z 462.1 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.18 (d, / = 1.9 Hz, 1H), 8.06 (s, 1H), 7.90 (d, / = 0.8 Hz, lH), 7.72 (d, / = 8.6 Hz, 1H), 7.59 (dd, / = 7.6, 1.7 Hz, 1H), 7.53 (d, / = 5.4 Hz, 1H), 7.32 (dd, / = 5.4, 0.9 Hz, 1H), 7.26 (dd, / = 8.6, 2.0 Hz, 1H), 7.17 (ddd, / = 8.7, 7.2, 1.7 Hz, 1H), 7.05 (dd, / = 8.3, 1.2 Hz, 1H), 6.96 (td, / = 7.4, 1.1 Hz, 1H), 6.59 (t, / = 5.6 Hz, 1H), 5.05 - 4.97 (m, 1H), 4.18 - 4.05 (m, 4H), 3.85 (s, 3H), 3.26 - 3.17 (m, 1H), 2.94 (dd, / = 17.5, 7.7 Hz, 1H).

Example-97: l-(iniidazo [1, 2-a] pyridin-6-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) urea (±).

Step-1: Phenyl imidazo [1, 2-a] pyridin-6-ylcarbamate .

To a solution of crude imidazo [l,2-a]pyridin-6-amine (4.7 g, 35.298mmol) (synthesis as per reported in WO2003062241Al)in pyridine (50 mL) was added phenylchloroformate (5.52 g, 35.298 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 14 h. The reaction mixture was diluted with water (50 mL) and extracted with chloroform (2 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure and purified by combiflash column chromatography to give the titled compound (2.5 g, 28%) as a solid. LCMS: m/z 254.45[M+H] ⁺; ^XHNMR (300 MHz, DMSO-d6) δ 10.25(bs, 1H), 8.91(s, 1H), 8.03(s, 1H), 7.62(m, 2H), 7.47(m, 2H), 7.33(m, 4H).

Step-2: l-(imidazo [1 , 2-a] pyridin-6-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) urea (±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.309 mmol) was reacted with phenyl imidazo [1, 2-a] pyridin-6-ylcarbamate (0.078 g, 0.309 mmol) and N,N-diisopropylethylamine (0.158 mL, 0.929 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.050 g, 38%) as a solid. HPLC: 99.44 %; LCMS: m/z 446.0 [M+H]⁺; ^lU NMR (600 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 7.47 (d, / = 9.5 Hz, 1H), 7.37 (d, / = 7.6 Hz, 1H), 7.23 (t, / = 8.2 Hz, 1H), 7.00 (t, / = 7.5 Hz, 1H), 6.93 (d, / = 8.3 Hz, 1H), 6.84 (d, / = 9.6 Hz, 1H), 5.63 (s, 1H), 5.07 - 4.97 (m, 1H), 4.36 - 4.30 (m, 2H), 4.10 - 4.06 (m, 2H), 3.97 (s, 3H), 3.28 (dd, / = 17.5, 8.0 Hz, 1H), 3.15 (dd, / = 17.5, 11.8 Hz, 1H). Further the enantiomeric mixture (0.045 g) was separated by chiral preparative HPLC to give two separated enantiomer (example 97a). Method: Column: CHIRAL PAK AD-H; Acetonitrile (A): 0.1 % Diethyl amine in IPA (B):: ISOCRATIC (20:80);Flow Rate: 5 mL/Min).

Example-97a: l-(imidazo [1, 2-a] pyridin-6-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) urea.

Yield: 0.012 g; Retention Time: 27.85 min.; Chiral HPLC: 99.17 %; HPLC: 99.04 %; LCMS: m/z 446.0[M+H]⁺; 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.93 - 7.89 (m, 2H), 7.59 (dd, / = 7.7, 1.6 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.19 - 7.14 (m, 1H), 7.07 - 6.94 (m, 3H), 6.63 (t, / = 5.7 Hz, 1H), 5.02- 4.95(m, 1H), 4.19 - 4.06 (m, 4H), 3.86 (d, / = 1.2 Hz, 3H), 3.21 (d, / = 10.9 Hz, 1H), 2.94 (dd, / = 17.5, 7.7 Hz, 1H).

Example-98: l-((5-((2-(iH-pyrazol-l-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methylpyridin-4-yl)urea (±).

Step-1: 2-(2, 2-dimethoxyethyl) isoindoline-1 , 3-dione.

To a solution of isobenzofuran-l , 3-dione (80.0g, 0.540 mol) in toluene (1000 mL) added 2, 2-dimethoxyethanamine (85.10 g, 0.811 mol), followed by N,N-diisopropylethylamine (0.187 mL, 1.080 mol) at room temperature. The reaction mixture was stirred at 120° C with dean stark apparatus for 16 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue obtained was diluted with in dichloromethane, filtered through pad of celite and dried over sodium sulfate and concentrated. The crude obtained was washed with petroleum ether to give the titled compound (100 g, 79%) as an off white solid. LCMS: m/z no ionization; ^lR NMR (300 MHz, Chloroform-d) δ 7.89 - 7.81 (m, 2H), 7.76 - 7.68 (m, 2H), 4.77 (td, / = 5.8, 0.8 Hz, 1H), 3.82 (dd, / = 5.8, 0.8 Hz, 2H), 3.38 (d, / = 0.9 Hz, 6H).

Step-2: 2-(l ,3-dioxoisoindolin-2-yl)acetaldehyde .

The solution of 2-(2, 2-dimethoxyethyl) isoindoline-1 , 3-dione (100 g, 0.425 mol) in IN HC1 (100 mL) stirred at 80° C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with water (2 x 200mL), followed by brine , dried over sodium sulfate and concentrated under vaccue to give the titled compound (60.0 g, 75% ) as off white solid. LCMS: m/z 190.1 [M+H] ⁺; H NMR (300 MHz, Chloroform-d) δ 9.66 (d, / = 0.8 Hz, 1H), 7.92 - 7.88 (m, 2H), 7.79 - 7.74 (m, 2H), 4.57 (d, / = 0.8 Hz, 2H).

Step -3: 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde oxime .

To a stirred solution of 2-(l , 3-dioxoisoindolin-2-yl) acetaldehyde (4.0 g, 21.15 mmol) in ethanol (40 mL) added hydroxylamine. HC1 (2.930 g, 42.305 mmol), followed by sodium bicarbonate (3.55 g, 42.305 mmol) at room temperature and stirred at room temperature for 16 h. Evaporated off the solvent, added water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with water (100 mL), followed by brine , dried over sodium sulfate and concentrated under vaccue to give the titled compound (3.2 g, 74%) as off white solid. LCMS: m/z 204.1 [M+H] ⁺; H NMR (300 MHz, DMSO-d6) δ 11.36 (s, 1H), 7.98 - 7.78 (m, 4H), 6.83 (t, / = 3.8 Hz, lH), 4.39 (dd, / = 3.9, 0.9 Hz, 2H).

Step-4: l-(2-(allyloxy)phenyl)-lH-pyrazole.

To a mixture of anhy. potassium carbonate (2.06 g, 14.99 mmol), 2-(lH-pyrazol-l-yl) phenol (synthesized as per reported procedure in Tetrahedron Letters, 52(52), 7171-7174 ,2011 and PCT Int. AppL, 2012102404 ) (1.2 g, 7.49 mmol),allyl bromide (0.996 g, 8.244 mmol) in acetone (20 mL) was stirred at 80 °C for 4 h. The reaction mixture was filtered and filtrate was concentrated to give titled compound (1.0 g, 66%) as a brown gummy liquid. LCMS: nt/z 201.0 [M+H] ⁺.

Step-5: 2-((5-((2-(lH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methyl) isoindoline- 1 , 3 -dione (±) .

To a solution of 2-(l ,3-dioxoisoindolin-2-yl)acetaldehyde oxime (1.2 g, 5.879 mmol) in N, N-dimethylformamide (20 mL) was added N-chlorosuccinimide (1.02 g, 7.643 mmol) at room temperature. After stirring at room temperature for 1 h, was added l-(2- (allyloxy)phenyl)-lH-pyrazole (1.29 g, 6.467 mmol) in one lot followed by drop wise addition of solution of triethylamine (1.6 mL, 11.75 mmol) in N,N-dimethylformamide (20 mL) over 10 min. The reaction mixture was stirred further for 16 h at room temperature. The reaction mixture was poured onto water extracted with ethyl acetate (50 mL) and washed with water (2 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the titled compound (0.600 g, 25 %) as an off white solid. LCMS: nt/z 402.8 [M+H] ⁺.

Step-6: (5-((2-(lH-pyrazol-l-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

To a solution of 2-((5-((2-(lH-pyrazol- l -yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methyl) isoindoline-l ,3-dione (±) (0.600 g, 1.4925 mmol) in methanol (10 mL) was added hydrazine hydrate (0.2 mL) at room temperature and stirred at 60° C for 3 h. Evaporated off the solvent, diluted with ethyl acetate (20 mL) and water (10 mL). Separated the organic layer and washed with brine, dried over sodium sulfate and concentrated. The residue obtained was treated with ethereal HC1 (10 mL) at 0 ° for lhr. The solid obtained was filtered and washed with ether (3 X 5 mL) and dried under vaccue to give the titled compound (0.200 g, 87%) as a white solid.

Step-7: l -((5-((2-(iH-pyrazol- l -yl) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)- 3-(2-methylpyridin-4-yl)urea (±)

A solution of (5-((2-(iH-pyrazol-l -yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (0.100 g, 0.323 mmol), phenyl (2-methylpyridin-4- yl)carbamate (prepared in step-1 of exampe-13) (0.086 g, 0.388 mmol) and triethylamine (0.098 g, 0.969 mmol) in DMSO (5 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the titled compound (0.025 g, 19 %) as a solid. HPLC: 96.47%; LCMS: nt/z 407.2 [M+ H]⁺; ^lU NMR (600 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.21 (d, / = 2.4 Hz, 1H), 8.18 (d, / = 5.6 Hz, 1 H), 7.72 - 7.68 (m, 2H), 7.35 (td, / = 7.9, 7.4, 1.7 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.20 (dd, / = 5.7, 2.1 Hz, 1H), 7.11 (td, / = 7.7, 1.3 Hz, l H), 6.72 (t, / = 5.6 Hz, 1H), 6.49 (t, / = 2.1 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.23 (dd, / = 10.5, 3.4 Hz, 1H), 4.13 (dd, / = 10.5, 5.6 Hz, 1H), 4.02 (dd, / = 5.7, 3.2 Hz, 2H), 3.15 (dd, / = 17.5, 11.1 Hz, 1H), 2.89 (dd, / = 17.6, 7.3 Hz, 1H), 2.36 (s, 3H).

Preparative HPLC method: XDB-C18 (21.2 x 150 mm, 5micron); 0.1 % TFA in Water (A): Acetonitrile (B); Flow Rate: 20.0 ml/min; GRADIENT: Time % of B FLOW

0 30 20.0

2 40 20.0

8 80 20.0

Example-99: l-((5-((2-(lH-pyrrol-l-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(2-methyl pyridin-4-yl) urea (±).

Step-1: l-(2-methoxyphenyl)-lH-pyrrole.

A solution of 2-aminophenol (5.0 g, 4.580 mmol) and 2, 5-dimethoxytetrahydrofuran (5.9 mL, 4.580 mmol) in acetic acid (75 mL) was heated at 100 °C for 15 min. The reaction mixture was diluted with ethyl acetate (250 mL). The organic phase was washed with water (2 x 100 mL), dried over sodium sulfate and concentrated under reduced pressure to give the titled compound (3.0 g, 40 %) as a liquid.

Step-2: l-(2-(allyloxy) phenyl) -lH-pyrrole.

Allyl bromide (3.4 g, 28.3 mmol) was added to a mixture of anhydrous potassium carbonate (7.8 g, 56.58 mmol) and l-(2-methoxyphenyl)-lH-pyrrole (3.0 g, 18.86 mmol) in N,N-dimethylformamide (30 mL). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate. Combined extracts were washed with water (2 x 30 mL) and dried. The solvent was evaporated to give residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 5/95) to give the titled compound (3.5 g, 93%) as a yellow liquid.

Step-3: tert-butyl ((5-((2-(lH-pyrrol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (2.5 g, 14.4 mmol) in N, N-dimethylformamide (100 mL) was added N-chlorosuccinimide (2.1 g, 15.84 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h, then cooled to 0 °C and added l-(2-(allyloxy) phenyl)- lH-pyrrole (3.5 g, 14.4 mmol) in one lot followed by drop wise addition of solution of triethylamine (2.2 mL, 15.84 mmol) in N,N-dimethylformamide (20 mL) over 10 min. The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured onto water at room temperature, extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 30/70) to give the titled compound (3.5 g, 58 %) as a solid.

Step-4: (5-((2-(lH-pyrrol-l-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

To a solution of tert-butyl((5-((2-(lH-pyrrol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl) methyl)carbamate (±) (3.5 g, 9.43 mmol) in 1,4-dioxane (5 mL) was added ethereal HC1 (5 mL) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. The solid precipitated out was filtered and triturated with diethyl ether to give titled compound (3.0 g, 98 %) as a solid.

Step-5: l-((5-((2-(lH-pyrrol-l-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)- 3-(2-methylpyridin-4-yl) urea (±).

(5-((2-(lH-pyrrol-l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.150 g, 0.550 mmol) was reacted with phenyl (2-methylpyridin-4- yl)carbamate (prepared in step-1 of exampe-13) (0.14 g, 0.61 mmol) and triethylamine (0.15 mL, 1.1 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.025 g, 11 %) as a solid. HPLC: 99.7 %; LCMS: m/z 406.18 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.26 (d, / = 5.6 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.21 (d, / = 2.1 Hz, 1H), 7.17 (t, / = 2.2 Hz, 2H), 7.09 - 6.95 (m, 3H), 6.46 (t, / = 2.2 Hz, 2H), 6.41 (s, 1H), 4.98 (dd, / = 11.4, 5.9 Hz, lH), 4.52 (s, 1H), 4.34 (td, / = 8.3, 5.8 Hz, 2H), 3.98 - 3.83 (m, 2H), 3.13 - 2.91 (m,2H), 2.48 (d, / = 3.2 Hz, 3H).

Example- 100: l-((5-(([l, l'-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-(2-methoxy pyrimidin-5-yl) urea (±).

Step-1: Phenyl (2-methoxypyrimidin-5-yl) carbamate.

2-methoxypyrimidin-5-amine (0.500 g, 4.0 mmol) was reacted with phenylchloroformate (0.55 mL, 4.400 mmol) in pyridine (5 mL) as described in the synthesis of step-1 of example-11 to give the titled compound (0.9 g, 92%) as a solid. The crude product was taken to the next step without further purification.

Step-2: l-((5-(([l , l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (2-methoxypyrimidin-5-yl) urea (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.150 g, 0.471 mmol) was reacted with phenyl (2-methoxypyrimidin-5-yl)carbamate (0.127 g, 0.470 mmol) and triethylamine (0.130 mL,0.940 mmol) as described in the synthesis of step-2 of example-1 1 to give the titled compound (0.05 g, 24%) as a solid. HPLC: 97.64 %; LCMS: m/z 434.1 [M+H]⁺; 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.62 (s, 2H), 7.55 - 7.46 (m, 2H), 7.44 - 7.36 (m, 2H), 7.36 - 7.25 (m, 3H), 7.12 (d, / = 8.1 Hz, 1H), 7.05 (td, / = 7.5, 1.1 Hz, 1H), 6.71 (t, / = 5.7 Hz, 1H), 4.82 (ddd, / = 11.0, 9.5, 5.4 Hz, 1H), 4.16 - 3.98 (m, 2H), 3.93 (dd, / = 5.5, 1.4 Hz, 2H), 3.86 (s, 3H), 3.07 (dd, / = 17.4, 11.0 Hz, 1H), 2.81 (dd, / = 17.4, 7.5 Hz, 1H).

Example- 101: l-(imidazo[l,2-a]pyridin-6-ylmethyl)-3-((5-((2-(l-methyl-iH-pyrazol- 4-yl)phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)urea (±).

A solution of (5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.310 mmol), phenyl (imidazo[l,2-a]pyridin-6-ylmethyl)carbamate (0.091 g, 0.341 mmol) and triethylamine (0.094 g, 0.930 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2.5/97.5) to give the titled compound (0.035 g, 24.5 %) as a solid. HPLC: 97.31 %; LCMS: m/z 460.2 [M+ H]⁺; ^lU NMR (400 MHz, Chloroform- d) δ 8.08 - 8.04 (m, 1H), 7.82 (d, / = 0.7 Hz, 1H), 7.66 (s, 1H), 7.58 (d, / = 1.1 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.38 (dd, / = 7.5, 1.7 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.05 (dd, / = 9.2, 1.7 Hz, 1H), 6.99 (dd, J = 7.6, 1.1 Hz, 1H), 6.94 - 6.89 (m, 1H), 5.00 (tt, / = 8.9, 2.7 Hz, 1H), 4.39 - 4.21 (m, 4H), 4.06 - 3.97 (m, 2H), 3.86 (s, 3H), 3.15 - 3.08 (m, 2H).

Example- 102: l-(2-methylpyridin-4-yl)-3-((5-((3-morpholinophenoxy)methyl)-4,5- dihydro isoxazol-3-yl)methyl)urea (±).

Step-1: 4-(3-(allyloxy)phenyl)moφholine.

To a solution of 3-morpholino phenol (2.0 g, 11.173 mmol) (synthesized as per procedure reported in Pet. Intl.Appl.2005123054) in acetone (40.0 mL), potassium carbonate (3.080 g, 22.346 mmol), sodium iodide (0.157 g, 1.117 mmol) and allyl bromide (1.620 g, 13.467 mmol) was added at 0°C under nitrogen atmosphere and was stirred at 60 °C for 16 h. Reaction mixture was cooled and filtered. Filtrate was concentrated under reduced pressure to give the titled compound (1.9 g, 77%) as a liquid. LCMS: mJz 220.55 [M+ H] ⁺.

Step-2: tert-butyl ((5-((3-mo holinophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

tert-butyl (2-(hydroxyimino) ethyl)carbamate (1.660 g, 9.543 mmol) was reacted with N- chlorosuccinimide (1.390 g, 10.410 mmol), 4-(3-(allyloxy)phenyl)moφholine (1.900 g, 8.675 mmol) and triethylamine (1.315 mL, 9.540 mmol) in N,N-dimethylformamide (30 mL) as described in the synthesis of step-3 of example- 1 to give the titled compound (0.600 g, 18%) as a sticky solid. LCMS: m/z 292.1 [M-100] ⁺

Step-3: (5-((3-moφholinophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±).

tert-butyl ((5-((3-moφholinophenoxy)-methyl)-4,5-dihydroisoxazol-3-yl)methyl) carbamate (±) (0.600 g, 1.530 mmol) was reacted with 4 N HC1 in 1,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.280 g, 55%) as sticky solid.

Step-4: l-(2-methylpyridin-4-yl)-3-((5-((3-mo holinophenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) urea (±).

A solution of (5-((3-mo holinophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.150 g, 0.457 mmol), phenyl (2-methylpyridin-4-yl)carbamate (prepared in step-1 of exampe-13) (0.112 g, 0.503 mmol) and triethylamine (0.198 mL, 1.371 mmol) in DMSO (5 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (20 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 3.5/96.5) to give the titled compound (0.012 g, 7 %) as a solid. HPLC: 95.57%; LCMS: m/z 426.2 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.17 (d, / = 5.7 Hz, 1H), 7.26 (d, / = 2.1 Hz, 1H), 7.19 (dd, / = 5.6, 2.2 Hz, 1H), 7.10 (t, / = 8.2 Hz, 1H), 6.75 (t, / = 5.7 Hz, 1H), 6.53 (dd, / = 8.2, 2.2 Hz, 1H), 6.46 (t, / = 2.4 Hz, 1H), 6.40 - 6.36 (m, 1H), 4.89 - 4.82 (m, 1H), 4.08 - 3.93 (m, 4H), 3.70 (dd, / = 6.1, 3.6 Hz, 4H), 3.18 - 3.11 (m, 1H), 3.08 (dd, / = 5.9, 3.8 Hz, 4H), 2.87 (dd, / = 17.4, 7.3 Hz, 1H), 2.36 (s, 3H).

Example-103: N-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydro isoxazol-3-yl) methyl)-3, 4-dihydroisoquinoline-2(lH)-carboxamide (±).

Step-1: Phenyl ((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

To a solution of (5-((2-(l-methyl-lH-pyrazol-4-yl)-phenoxy)-methyl)-4,5- dihydroisoxazol-3-yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.200 g, 0.619 mmol) in dry THF (10 mL) was added triethylamine (0.258 mL, 1.858 mmol), phenylchloroformate (0.116 g, 0.743 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate_, concentrated under reduced pressure to give the titled compound (0.080 g, crude) as a solid. The crude product was taken to the next step without further purification. Step-2: N-((5-((2-(l -methyl- lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3- yl) methyl)-3, 4-dihydroisoquinoline-2(lH)-carboxamide (±).

Phenyl ((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±) (0.080 g, 0.196 mmol) was reacted with 1 ,2,3,4- tetrahydroisoquinoline (0.028 g, 0.216 mmol) and N,N-diisopropylethylamine (0.100 mL, 0.590 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.055 g, 51 %) as a solid. HPLC: 95.64 %; LCMS: m/z 446.3 [M+H] ⁺ ; ^lU NMR (400 MHz, Chloroform-d) δ 7.87 (d, / = 0.7 Hz, 1H), 7.82 (s, 1H), 7.48 (dd, / = 7.6, 1.7 Hz, 1H), 7.23 - 7.07 (m, 5H), 7.00 (td, / = 7.5, 1.1 Hz, 1H), 6.91 (dd, / = 8.3, 1.1 Hz, 1H), 5.14 (t, / = 5.6 Hz, 1H), 5.03 (ddt, / = 11.0, 7.3, 3.7 Hz, 1H), 4.59 - 4.47 (m, 2H), 4.28 - 4.16 (m, 2H), 3.93 (s, 3H), 3.61 (q, / = 7.0 Hz, 2H), 3.20 (dd, / = 17.4, 11.2 Hz, 1H), 3.02 (dd, / = 17.4, 7.1 Hz, 1H), 2.88 - 2.82 (m, 2H).

Example-104: N-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine-2(lH)- carboxamide (±).

Phenyl ((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±) (0.250 g, 0.615 mmol) was reacted with 1, 2, 3, 4- tetrahydropyrrolo [1 , 2-a] pyrazine.TFA (synthesis as per WO2009090054A1 ) (0.145 g, 0.615 mmol) and triethylamine (0.25 mL, 1.845 mmol) as described in the synthesis of step-2 of example-11 to give the titled compound (0.04 g, 15 %) as a solid. HPLC: 95 %; LCMS: m/z 435.2 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 7.87 (d, / = 0.7 Hz, 1H), 7.79 (s, 1H), 7.46 (dd, / = 7.6, 1.7 Hz, 1H), 7.20 (ddd, / = 8.2, 7.4, 1.7 Hz, 1H), 7.00 (td, / = 7.5, 1.1 Hz, 1H), 6.91 (dd, / = 8.3, 1.1 Hz, 1H), 6.59 (dd, / = 2.7, 1.7 Hz, 1H), 6.15 (dd, / = 3.5, 2.7 Hz, 1H), 5.91 (dt, / = 3.6, 1.2 Hz, 1H), 5.34 - 5.24 (m, 1H), 5.03 (ddt, /= 10.7, 7.0, 3.4 Hz, 1H), 4.64 - 4.43 (m, 2H), 4.24 (dd, / = 10.3, 3.3 Hz, 1H), 4.21 - 4.14 (m, 2H), 4.08 (dd, / = 10.2, 3.6 Hz, 1H), 3.98 (t, / = 5.4 Hz, 2H), 3.95 (s, 3H), 3.81 (q, / = 5.4 Hz, 2H), 3.18 (dd, / = 17.3, 11.3 Hz, 1H), 3.01 (dd, / = 17.3, 7.0 Hz, 1H).

Example- 105: N-((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxamide(±).

A solution of crude phenyl ((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (0.080 g, 0.190 mmol), 4,5,6,7-tetrahydrothieno [3,2-c]pyridine hydrochloride (0.041 g, 0.235 mmol) and triethylamine (0.072 mL, 0.570 mmol) in DMSO (2 mL) was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 3/97) to give the titled compound (0.012 g, 17.1 %) as a solid. HPLC: 95.79%; LCMS: m/z 452.1 [M+ H]⁺; ^lU NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.90 (s, 1H), 7.58 (dd, / = 7.7, 1.7 Hz, 1H), 7.33 (d, / = 5.2 Hz, 1 H), 7.17 (ddd, / = 8.7, 7.4, 1.7 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.96 (td, / = 7.5, 1.2 Hz, 1H), 6.85 (d, / = 5.2 Hz, 1H), 5.01 - 4.90 (m, 1H), 4.42 (s, 2H), 4.14 - 3.96 (m, 4H), 3.85 (s, 3H), 3.63 (t, / = 5.6 Hz, 2H), 3.16 (dd, / = 17.5, 10.9 Hz, 1H), 2.85 (dd, / = 17.6, 7.7 Hz, 1H), 2.76 (t, / = 5.7 Hz, 2H).

Example-106: N-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) isoindoline-2-carboxamide (±).

Phenyl ((5-((2-(l-methyl-l H-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±) (0.100 g, 0.246 mmol) was reacted with isoindoline (0.033 g, 0.270 mmol) and N,N-diisopropylethylamine (0.126 mL, 0.738 mmol) as described in the synthesis of step-2 of example- 11 to give the titled compound (0.055 g, 51 %) as a solid. HPLC: 98.16 %; LCMS: nt/z 432.2 [M+H] ⁺ ; ^lU NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.87 (d, / = 0.9 Hz, 1H), 7.55 (dt, / = 7.6, 1.3 Hz, 1H), 7.33 - 7.23 (m, 4H), 7.13 (ddt, / = 9.3 , 7.2, 1.3 Hz, 1H), 7.04 - 6.99 (m, 1H), 6.93 (tt, / = 7.4, 1.1 Hz, 1H), 6.76 (t, / = 5.7 Hz, 1H), 4.99 - 4.90 (m, 1H), 4.57 (s, 4H), 4.14 - 3.99 (m, 4H), 3.82 (d, / = 1.1 Hz, 3H), 3.18 (dd, / = 17.6, 10.9 Hz, 1 H), 2.88 (dd, / = 17.6, 7.7 Hz, 1H).

Example- 107: N-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (±).

A stirred suspension of phenyl ((5-((2-(l-methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (0.090 g, 0.221 mmol) was reacted with 2,3- dihydro-lH-pyrrolo[3,4-c]pyridine dihydrochloride (0.062 g, 0.221 mmol) and triethylamine (0.090 mL, 0.664 mmol) as described in the synthesis of step-2 of example- 1 1 to give the titled compound (0.035 g, 36%) as a solid. HPLC: 94.6 %; LCMS: m/z 433.5 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.48 (d, / = 5.0 Hz, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.60 - 7.55 (m, 1H), 7.40 (d, / = 5.1 Hz, 1H), 7.16 (t, / = 7.8 Hz, 1H), 7.05 (d, / = 8.3 Hz, 1H), 6.96 (t, / = 7.5 Hz, 1H), 6.87 (t, / = 5.8 Hz, 1H), 4.98 (dq, / = 11.2, 5.8 Hz, 1H), 4.63 (d, / = 6.1 Hz, 4H), 4.12 (td, / = 10.3, 4.9 Hz, 2H), 4.05 (d, / = 5.8 Hz, 2H), 3.85 (s, 3H), 3.21 (dd, / = 17.6, 10.9 Hz, 1H), 2.91 (dd, J = 17.5, 7.7 Hz, 1H).

Example-108: 2-cyano-l-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) guanidine (enantiomer -1).

Step-1: Methyl N'-cyano-N-(2-methylpyridin-4-yl) carbamimidothioate.

To a solution of 2-methylpyridin-4-amine (1.0 g, 9.260 mmol), dimethyl cyanocarbonimidodithioate (1.550 g, 10.650 mmol) and DMAP (0.113 g, 0.926 mmol) in N,N-dimethylformamide (5 mL) was added NaH (60% mineral oil suspension) (0.530 g, 11.100 mmol) portion wise at 0 °C. The reaction mixture was stirred for 16 h at room temperature. To the reaction mixture added diethyl ether (50 mL) and stirred for 10 min. After decanting off the supernant phase the oily residue was stirred twice with ether (2 x 50 mL). After decanting the resulting semi solid was treated with water and filtered. The stirred ice cooled filtrate was treated with glacial acetic acid (5 mL) and the precipitate was collected by filtration and washed with water, small portions of ether, dried to give the titled compound (1.0 g, 52 %) as off white solid.

Step-2: tert-butyl ((5-((2-(l-methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) carbamate (enantiomer -1).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate [enantiomer-1 : peak-1 ; (separated in step-1 of example-23)] (0.500 g, 1.298 mmol) in 1 ,4-dioxane: water (4: 1) (10 mL) was added 1 - methyl-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-iH-pyrazole (0.405 g, 1.947 mmol), followed by potassium carbonate (0.537 g, 3.894 mmol) and 1 ,1 '-Bis (diphenylphosphino)ferrocene-palladium(II)dichloride dichloro methane complex (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 50 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous and ethyl acetate layer were separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.320 g, 61 %) as a sticky solid.

Step-3: (5-((2-(l -methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (enantiomer -1).

tert-butyl((5-((2-(l-methyl-iH^yrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (enantiomer - 1) (0.320 g, 0.828 mmol) was reacted with 4N HCl in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.270 g, 99%) as a solid.

Step-4: 2-cyano- l-((5-((2-(l -methyl- lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) guanidine (enantiomer -1)

A solution of (5-((2-(l -methyl- lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methanamine hydrochloride (enantiomer- 1) (O.lOOg, 0.309mmol), methylN'-cyano- N-(2-methylpyridin-4-yl)carbamimido thioate (0.072 g, 0.370 mmol), triethylamine (0.086 mL, 0.618 mmol) and DMAP (0.002 g, catalytic) in pyridine (3 mL) was heated 80 °C for 16 h. The reaction mixture was evaporated completely under reduced pressure. The obtained residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 4/96) to give the titled compound (0.03 g, 21 %) as off white solid. HPLC: 97.07 %;LCMS: m/z 445.2 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 5.6 Hz, 1H), 7.81 (s, 1H), 7.62 (s, 1H), 7.38 (dd, J = 7.6, 1.7 Hz, 1H), 7.24 - 7.17 (m, 2H), 7.13 (d, J = 5.4 Hz, 1H), 7.06 - 6.94 (m, 3H), 6.94 - 6.84 (m, 1H), 5.07 (td, J = 7.4, 3.5 Hz, 1H), 4.41 (d, J = 17.4 Hz, lH), 4.28 (dd, J = 10.4, 2.9 Hz, 1H), 4.19 - 3.97 (m, 2H), 3.80 (s, 3H), 3.22 (dd, / = 17.2, 1 1.4 Hz, 1H), 3.02 (dd, / = 17.3, 7.0 Hz, lH), 2.52 (s, 3H).

Example-109: l-((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)-3-(2-methylpyridin-4-yl) thiourea (enantiomer-1).

(5-((2-(l -methyl- lH-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (enantiomer-1) (0.100 g, 0.310 mmol) was reacted with 4- isothiocyanato-2-methylpyridine (0.093 g, 0.620 mmol) and triethylamine (0.086 mL, 0.620 mmol) as described in the synthesis of step-2 of example- 1 1 to give the titled compound (0.030 g, 22 %) as a solid. HPLC: 98.34 ; LCMS: m/z 437.5 [M+H] ⁺; ^lU NMR (400 MHz, DMSO-d6) δ 14.82 (s, 1H), 11.81 (s, 1H), 9.83 (s, 1H), 9.57 (t, / = 5.3 Hz, 1H), 8.58 - 8.34 (m, IH), 8.07 (d, / = 5.8 Hz, 1H), 7.90 (s, IH), 7.58 (dd, / = 7.7, 1.7 Hz, IH), 7.17 (td, / = 7.7, 7.3, 1.7 Hz, IH), 7.06 (d, / = 8.3 Hz, IH), 7.01 - 6.91 (m, IH), 5.05 (dt, / = 11.4, 5.9 Hz, IH), 4.62 - 4.43 (m, 2H), 4.13 (t, / = 4.9 Hz, 2H), 3.86 (s, 3H), 3.30 - 3.19 (m, IH), 3.04 - 2.87 (m, IH), 2.60 (s, 3H).

Example-110: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-lH-pyrrolo[3,2-c]pyridine-2-carboxamide(±).

Step-1: 1-tosyl-lH-pyrrolo [3,2-c]pyridine-2-carboxylic acid.

To as solution of l-tosyl-lH-pyrrolo[3,2-c]pyridine (5.0 g, 18.360 mmol) (synthesis as per reported in WO2012080450) in dry THF (75 mL) at -78 °C was added n-butyl lithium (2.5 M in hexane, 8.8 mL) drop wise under N₂ atmosphere. The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was poured into a round bottom flask containing dry ice and stirred for lh. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL). The THF layer was separated, the aqueous layer was filtered. The precipitate obtained was washed with water and dried to give titled compound (3.0 g, 52.0 ) as a solid.

Step-2: N-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-l - tosyl-lH-pyrrolo[3,2-c] pyridine-2-carboxamide (±).

To a solution of (5-(([l,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example- 1) (0.200 g, 0.627 mmol) and l-tosyl-lH-pyrrolo[3,2-c]pyridine-2-carboxylic acid (0.298 g, 0.942 mmol) in N,N- dimethylformamide (5 mL) was added of EDCI.HC1 (0.241 g, 1.258 mmol), HOBt (0.170 g, 1.258 mmol) and N,N-diisopropylethylamine (0.440 mL,2.500 mmol) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 50 mL) and washed with water (2 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the titled compound (0.200 g, 72.9 %) as crude. The crude product was taken to the next step without further purification.

Step-3: N-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-lH- pyrrolo[3,2-c]pyridine-2-carboxamide(±).

To a solution of N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-l-tosyl-lH-pyrrolo[3,2-c]pyridine-2-carboxarnide (±) (0.200 g, 0.340 mmol) in methanol: THF (1 : 1) (10 mL) was added cesium carbonate (0.336 g, 1.030 mmol) and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and residue obtained was purified by column chromatography on silica gel (dichloromethane/methanol = 92/8) to give the titled compound (0.035 g, 24 %) as an off white solid. LCMS: m z 427.35 [M+H] ⁺; HPLC: 98.6 ; H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 9.02 (t, / = 5.9 Hz, 1H), 8.94 (d, / = 1.0 Hz, 1H), 8.23 (d, / = 5.8 Hz, 1H), 7.57 - 7.45 (m, 2H), 7.41 - 7.21 (m, 7H), 7.17 - 6.97 (m, 2H), 4.92 - 4.75 (m, 1H), 4.22 - 3.99 (m, 4H), 3.20 - 3.02 (m, 1H), 2.84 (dd, / = 17.5, 7.6 Hz, 1H). Example-Ill: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-4-(lH-imidazol-l-yl) benzamide (±).

(5-(([l,l '4jiphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314 mmol) was reacted with 4- (lH-imidazol-l-yl)benzoic acid (0.059 g, 0.314 mmol) in the presence of EDCI.HCl (0.072 g, 0.376 mmol), HOBt (0.063 g, 0.470 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.941 mmol) in N,N-dimethylformamide (4 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.040 g, 28.3%) as a solid. LCMS: m/z 453.4 [M+H] ⁺; HPLC:98.45 %; H NMR (400 MHz, Chloroform-d) δ 7.93 (t, / = 1.1 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.56 - 7.51 (m, 2H), 7.48 - 7.43 (m, 2H), 7.39 (dd, / = 8.4, 6.9 Hz, 2H), 7.36 - 7.28 (m, 4H), 7.25 (t, / = 1.2 Hz, 1H), 7.07 (td, / = 7.5, 1.1 Hz, 1H), 6.96 (dd, / = 8.6, 1.0 Hz, 1H), 6.10 (s, 1H), 4.95 (ddd, / = 14.3, 6.4, 3.1 Hz, 1H), 4.27 - 4.15 (m, 2H), 4.10 (dd, / = 16.8, 4.9 Hz, 1H), 3.99 (dd, / = 10.3, 2.9 Hz, 1H), 3.05 (dd, / = 17.2, 11.3 Hz, 1H), 2.88 (dd, / = 17.2, 6.5 Hz, 1H).

Example-112: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-lH-indole-5-carboxamide (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydro- chloride (±) (prepared in step-4 of example-1) (0.100 g, 0.313 mmol) was reacted with lH-indole-5-carboxylic acid (0.075 g, 0.470 mmol) in the presence of EDCI.HCl (0.120 g, 0.627 mmol), HOBt (0.085 g, 0.627mmol) and N,N-diisopropylethylamine (0.23 mL, 1.255 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.040 g, 30 %) as a solid. LCMS: m/z 426.7 [M+H] ⁺; HPLC: 96.62 %; ^lU NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.64 (t, / = 5.8 Hz, 1H), 8.14 (d, / = 1.6 Hz, 1H), 7.64 (dd, / = 8.6, 1.7 Hz, 1H), 7.56 - 7.22 (m, 9H), 7.19 - 6.97 (m, 2H), 6.54 (t, / = 2.4 Hz, 1H), 4.82 (td, / = 12.1, 11.2, 5.3 Hz, 1H), 4.25 - 3.98 (m, 4H), 3.09 (dd, / = 17.4, 10.9 Hz, 1H), 2.84 (dd, / = 17.5, 7.6 Hz, 1H).

Example-113: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)benzo[b] thiophene-2-carboxamide(±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.313 mmol) was reacted with benzo[b]thiophene-2-carboxylic acid (0.083 g, 0.470 mmol) in the presence of EDCI.HCl (0.120 g, 0.627 mmol), HOBt (0.085g,0.627mmol) and N,N- diisopropylethylamine (0.23 mL, 1.255 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.075 g, 54.35%) as a solid. LCMS: m/z 443.2 [M+H] ⁺; HPLC: 97.68 %; H NMR (400 MHz, DMSO-d6) 5 9.14 (t, / = 5.8 Hz, lH), 8.11 (d, / = 0.8 Hz, 1H), 8.05 - 8.00 (m, 1H), 8.00 - 7.91 (m, 1H), 7.56 - 7.22 (m, 8 H), 7.17 - 7.00 (m, 2H), 4.93 - 4.77 (m, 1H), 4.22 - 3.99 (m, 4H), 3.10 (dd, / = 17.4, 10.9 Hz, 1H), 2.85 (dd, / = 17.4, 7.7 Hz, 1H), 1.39 - 0.86 (m, 1H).

Example-114: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine-6-carboxamide (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.314 mmol) was reacted with imidazo[l,2-a]pyridine-6-carboxylic acid (synthesized as per reported procedure mPCT Int. Appl, 2003070732) (0.050 g, 0.314 mmol) in the presence of EDCI.HCl (0.072 g, 0.376 mmol), HOBt (0.063 g, 0.470 mmol) and N,N-diisopropylethylamine (0.163 mL,0.941mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step- 2 of example-110 to give the titled compound (0.060 g, 45.0%) as a solid. LCMS: m/z 427.1 [M+H] ⁺; HPLC: 98.38 %; ¾ NMR (400 MHz, Chloroform-d) δ 8.60 (d, / = 1.5 Hz, 1H), 7.71 (d, / = 1.3 Hz, 1H), 7.61 (d, / = 9.5 Hz, 1H), 7.58 - 7.50 (m, 3H), 7.43 - 7.23 (m, 5H), 7.08 (t, / = 7.4 Hz, 1H), 6.96 (d, / = 8.5 Hz, 1H), 5.90 (s, 1H), 4.96 (s, 1H), 4.29 - 4.15 (m, 2H), 4.10 - 3.96 (m, 2H), 3.10 - 2.97 (m, 1H), 2.87 (dd, / = 17.1 , 6.3 Hz, 1H). Further the enantiomeric mixture (0.040 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 114 a & 114b). Method: Column: CHIRALPAK AD-H, n-hexane (A): (IPA: methanol) (B): 1 :1.

TIME %B FLOW (mL/min.)

0 50 7

20 50 7

Example-114a: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine-6-carboxamide.

Yield: 0.005 g; Retention Time: 19.358 min.; Chiral HPLC: 97.86%; HPLC: 98.6 %; LCMS: m/z 427.1 [M+H] ⁺

Example-114b: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine-6-carboxamide

Yield: 0.006 g; Retention Time: 25.25 min.; Chiral HPLC: 85 %; HPLC: 98.27 %; LCMS: m/z 427.1 [M+H] ⁺.

Example-115: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-lH-benzo[d] imidazole-5-carboxamide (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.313 mmol) was reacted with lH-benzo[d]imidazole-5-carboxylic acid (0.077g, 0.471 mmol) in the presence of EDCI.HC1 (0.120 g, 0.627 mmol), HOBt (0.085 g, 0.627 mmol) and N,N- diisopropylethylamine (0.23 mL, 1.255 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.030 g, 22.5 %) as a solid. LCMS: m/z 427.1 [M+H] ⁺; HPLC: 95.38 %; H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.81 (t, / = 5.6 Hz, 1H), 8.34 (d, / = 9.5 Hz, 1H), 8.27 - 8.04 (m, 1H), 7.89 - 7.56 (m, 2H), 7.54 - 7.21 (m, 7H), 7.18 - 6.97 (m, 2H), 4.90 - 4.76 (m, 1H), 4.22 - 3.98 (m, 4H), 3.09 (dd, / = 17.4, 10.9 Hz, 1H), 2.84 (dd, / = 17.5, 7.6 Hz,

1H).

Example-116: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-5-(4-methoxy phenyl) furan-2-carboxamide (±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.313 mmol) was reacted with 5- (4-methoxyphenyl)furan-2-carboxylic acid (0.082 g, 0.376 mmol) in the presence of EDCI.HC1 (0.090 g, 0.0.470 mmol), HOBt (0.063 g, 0.0.470 mmol) and N,N- diisopropylethylamine (0.16 mL,0.941 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.065 g, 43.0 %) as a solid. LCMS: m/z 483.4 [M+H] ⁺; HPLC: 96.17%; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (t, / = 6.0 Hz, 1H),7.91 - 7.82 (m, 2H), 7.55 - 7.46 (m, 2H), 7.43 - 7.23 (m, 5H), 7.19 (d, / = 3.6 Hz, 1H), 7.13 (dd, / = 8.0, 1.2 Hz, 1H), 7.10 - 7.00 (m, 3H), 6.97 (d, / = 3.6 Hz, 1H), 4.90 - 4.75 (m, 1H), 4.20 - 3.97 (m, 4H), 3.82 (s, 3H), 3.09 (dd, / = 17.5, 10.9 Hz, 1H), 2.84 (dd, / = 17.4, 7.8 Hz, 1H).

Example-117: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-6-(trifluoro methyl) benzo [b] thiophene-2-carboxamide(±).

(5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.050 g, 0.157 mmol) was reacted with 6-(trifluoromethyl) benzo[b]thiophene-2-carboxylic acid (0.057 g, 0.235 mmol) in the presence of EDCI.HC1 (0.060 g, 0.312 mmol), HOBt (0.042 g, 0.313 mmol) and N,N- diisopropylethylamine (0.12 mL,0.627 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.035 g, 43.75%) as a solid. LCMS: m/z 511.1 [M+H] ⁺; HPLC: 96.12 %; H NMR (400 MHz, DMSO-d6) δ 9.28 (t, / = 5.7 Hz, 1H), 8.63 - 8.55 (m, 1H), 8.25 - 8.13 (m, 2H), 7.74 (dd, / = 8.5, 1.7 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.43 - 7.22 (m, 5H), 7.16 - 7.01 (m, 2H), 4.92 - 4.78 (m, lH), 4.22 - 3.96 (m, 4H), 3.11 (dd, / = 17.5, 10.9 Hz, 1H), 2.85 (dd, / = 17.4, 7.7 Hz, 1H).

Example-118: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-lH-benzo[d] imidazole-2-carboxamide(±).

(5-(([l ,1 '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.100 g, 0.312 mmol) was reacted with lH-benzo[d]imidazole-2-carboxylic acid (0.076 g, 0.470 mmol) in the presence of EDCI.HCl (0.120 g, 0.627 mmol), HOBt (0.085 g, 0.627 mmol) and N,N- diisopropylethylamine (0.23 mL, 1.255 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.080 g, 60.15%) as a solid. LCMS: m/z 427.1 [M+H] ⁺; HPLC: 96.41 %; ^lU NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.29 (t, / = 6.0 Hz, 1H), 7.81 - 7.43 (m, 4H), 7.43 - 7.17 (m, 7H), 7.18 - 6.96 (m, 2H), 4.83 (dq, / = 11.4, 6.8, 5.9 Hz, lH), 4.27 - 3.98 (m, 4H), 3.09 (dd, / = 17.3, 10.8 Hz, 1H), 2.95 - 2.77 (m, 1H).

Example-119: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-6-(lH-imidazol-l-yl) nicotinamide (±).

(5-(([l ,l '-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (prepared in step-4 of example-1) (0.050 g, 0.157 mmol) was reacted with 6- (lH-imidazol-l-yl)nicotinic acid (0.030 g, 0.157 mmol) (synthesized as per reported procedure mWO2011094890) in the presence of EDCI.HCl (0.036 mg, 0.188 mmol), HOBt (0.038 g, 0.282 mmol) and N,N-diisopropylethylamine (0.147 mL, 0.847 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example - 110 to give the titled compound (0.015 g, 21.09 %) as a solid. LCMS: m/z 454.1 [M+H] ⁺; HPLC: 93.90 ; H NMR (400 MHz, Chloroform-d) δ 8.72 (d, / = 2.4 Hz, 1H), 8.44 (s, 1H), 8.20 - 8.09 (m, 1H), 7.71 (d, / = 1.9 Hz, lH), 7.61 - 7.48 (m, 2H), 7.48 - 7.15 (m, 6H), 7.15 - 6.91 (m, 2H), 6.01 (s, 1H), 5.05 - 4.88 (m, 1H), 4.31 - 4.16 (m, 2H), 4.17 - 3.96 (m, 2H), 3.14 - 2.82 (m, 2H).

Example- 120: N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-2-(methyl sulfona mido) isonicotinamide (±).

Step-1: N-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-2- aminoisonicotinamide (±).

5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.100 g, 0.314 mmol) was reacted with 2-aminoisonicotinic acid (0.065 g, 0.471 mmol) in the presence of EDCI.HCl (0.120 g, 0.627 mmol), HOBt (0.085 g, 0.627 mmol) and N,N-diisopropylethylamine (0.23 mL, 1.255 mmol) in N,N- dimethylformamide (5 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.060 g, 47.5 %) as a solid. LCMS: m/z 403.4 [M+H] ⁺.

Step-2: N-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-2- (methylsulfonamido) isonicotinamide (±).

To a stirred solution of N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-2-amino isonicotinamide (±) (0.050 g, 0.124 mmol) in pyridine (3 mL) was added methane sulphonyl chloride (0.042 g, 0.372 mmol) at 0 °C. The reaction mixture was warmed to room temperature and further stirred at 40 °C for 5h. The reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (20 ml x 2). Concentrated the organic layer to get crude compound which was further purified by column chromatography (100-200 mesh) on silica gel (dichloromethane/methanol = 95/5) to give the titled compound (0.020 g, 33.9 %) as a white solid. LCMS: m z 480.95 [M+H] ⁺; HPLC: 95.95 ; H NMR (400 MHz, DMSO- d6) δ 10.82 (s, 1H), 9.10 (d, / = 5.8 Hz, 1H), 8.41 (s, 1H), 7.56 - 7.45 (m, 2H), 7.47 - 7.25 (m, 7H), 7.18 - 7.01 (m, 2H), 4.90 - 4.78 (m, 1H), 4.07 (ddd, / = 25.3, 11.1 , 5.2 Hz, 4H), 3.42 - 3.34 (m, 3H), 3.08 (dd, / = 17.4, 11.0 Hz, 1H), 2.82 (dd, / = 17.4, 7.6 Hz, 1H).

PREPARATIVE HPLC PURIFICATION METHOD: COLUMN: XDB-C18 (21.20 x 150mm, 5micron); MOBILE PHASE: 0.1 % TFA in Water (A): Acetonitrile (B); Flow Rate: 20.0 ml/min

GRADIENT:

Time of B FLOW

0 20 20.0

2 30 20.0

8 80 20.0

Example- 121: N-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

(5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.310 mmol) was reacted with imidazo[l,2-a]pyridine-6-carboxylic acid (0.055 g, 0.341 mmol) in the presence of EDCI.HC1 (0.079g, 0.372 mmol), HOBt (0.054 g, 0.403 mmol) and N,N-diisopropylethylamine (0.293 mL, 1.55 mmol) in N,N-dimethylformamide (3 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.035 g, 26.24 %) as a solid. LCMS: m/z 431.1 [M+H] ⁺; HPLC: 97.50 ; H NMR (400 MHz, Chloroform-d) δ 8.80 (dd, / = 1.8, 1.0 Hz, 1H), 7.89 (d, / = 0.7 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.67 - 7.58 (m, 2H), 7.49 (dd, / = 9.4, 1.8 Hz, 1H), 7.41 (dd, / = 7.5, 1.8 Hz, 1H), 7.32 - 7.16 (m, 2H), 7.05 - 6.87 (m, 2H), 5.13 - 4.97 (m, 1H), 4.45 - 4.24 (m, 3H), 4.06 (dd, / = 10.4, 2.7 Hz, 1H), 3.90 (s, 3H), 3.20 - 2.98 (m, 2H).

Example- 122: N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,l'-biphenyl]-2- yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-6- carboxamide (±)

2'-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fiuoro-N-methyl-[l ,l'- biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.100 g, 0.250 mmol) was reacted with imidazo[l ,2-a]pyridine-6-carboxylic acid (0.045 g, 0.279 mmol) in the presence of EDCI.HC1 (0.057g, 0.300 mmol), HOBt (0.050 g, 0.380 mmol) and N,N-diisopropylethylamine (0.174 mL, 1.000 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.030 g,25 %) as a solid. LCMS: m/z 502.2 [M+H] ⁺; HPLC: 98.47 ; H NMR (400 MHz, DMSO-d6) δ 9.13 (t, / = 1.4 Hz, 1H), 8.95 (t, / = 5.7 Hz, 1H), 8.26 (s, 1H), 8.08 (d, / = 1.3 Hz, 1H), 7.70 - 7.58 (m, 4H), 7.50 - 7.33 (m, 4H), 7.20 - 7.01 (m, 2H), 4.94 - 4.80 (m, 1H),4.20 - 4.02 (m, 4H), 3.15 (dd, / = 17.5, 11.0 Hz, lH), 2.91 - 2.77 (m, 4H).

Example- 123: N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,l'-biphenyl]-2- yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl) methyl)imidazo[l,2-a]pyrimidine-6- carboxamide (±).

To a solution of 2'-((3-(amino methyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fluoro-N- methyl-[l ,l'-biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.150 g, 0.380 mmol) and imidazo[l ,2-a]pyridine-6-carboxylic acid (0.093 g, 0.570 mmol) (synthesis as per reported in WO2013127268 Al) in N,N-dimethylformamide (4 mL) was added EDCI (0.146 g, 0.76 mmol), HOBT (0.102 g, 0.760 mmol) and N,N- diisopropylethylamine (0.26 mL, 1.520 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 7/93) to give the titled compound (0.095 g, 50%) as a solid. HPLC: 98.78%; LCMS: m z 503.4 [M+H] ⁺; H NMR (400 MHz, DMSO-d6) δ 9.48 (d, / = 2.5 Hz, 1H), 9.13 (t, / = 5.7 Hz, 1H), 8.92 (d, / = 2.5 Hz, lH), 8.26 (d, / = 4.2 Hz, 1H), 8.05 (d, / = 1.5 Hz, 1H), 7.83 (d, / = 1.5 Hz, 1H), 7.66 (t, / = 8.0 Hz, 1H), 7.52 - 7.30 (m, 4H), 7.23 - 7.12 (m, 1H), 7.08 (td, / = 7.5, 1.0 Hz, 1H), 4.95 - 4.82 (m, 1H), 4.18 (d, / = 5.6 Hz, 2H), 4.11 (qd, / = 10.5, 4.8 Hz, 2H), 3.18 (dd, / = 17.5, 10.9 Hz, 1H), 2.87 (dd, / = 17.5, 7.4 Hz, 1H), 2.79 (d, / = 4.5 Hz, 3H).

Example- 124: N-((5-(((4'-carbamoyl-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide(±).

To a solution of 2'-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)-[l ,l'- biphenyl]-4-carboxamide hydrochloride (±) (0.150 g, 0.415 mmol) and imidazo[l ,2- a]pyridine-6-carboxylic acid (0.100 g, 0.650 mmol) in N,N-dimethylformamide (4.0 mL) added EDCI.HC1 (0.160 g, 0.830 mmol), HOBT (0.112 g, 0.830 mmol) and N,N- diisopropylethylamine (0.29 mL, 1.660 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3x50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 4/96) to give the titled compound (0.04 g, 20%) as a solid.HPLC: 97.15%; LCMS:m z 470.5 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.85 (dd, / = 1.8, 0.9 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.73 - 7.66 (m, 2H), 7.66 - 7.48 (m, 4H), 7.41 - 7.28 (m, 3H), 7.06 (td, / = 7.5, 1.0 Hz, 1H), 6.93 (d, / = 8.2 Hz, 1H), 6.50 (s, 1H), 5.67 (s, 1H), 5.00 - 4.76 (m, 1H), 4.31 (dd, / = 10.4, 2.5 Hz, 1H), 4.10 (dd, / = 17.0, 5.2 Hz, 1H), 3.96 (dd, / = 10.4, 2.3 Hz, 1H), 3.83 (dd, / = 16.9, 6.1 Hz, 1H), 3.01 (dd, / = 17.1, 11.3 Hz, 1H), 2.82 (dd, / = 17.2, 7.7 Hz, 1H).

Example- 125: N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,l'-biphenyl]-2- yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl) methyl)-lH-pyrrolo[3,2-c]pyridine-2- carboxamide (±).

2'-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fiuoro-N-methyl-[l ,l'- biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.100 g, 0.250 mmol) was reacted with lH-pyrrolo[3,2-c]pyridine-2-carboxylic acid (synthesized as per reported procedure in WO2005061498 Al) (0.120 g, 0.380 mmol) in the presence of EDCI.HC1 (0.097 g, 0.508 mmol), HOBt (0.069 g, 0.508 mmol) and N,N- diisopropylethylamine (0.18 mL, 1.016 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.040 g, 31.0 %) as a solid. LCMS: m/z 502.3 [M+H] ⁺; HPLC: 96.0 ; H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.03 (t, / = 5.9 Hz, 1H), 8.93 (d, / = 1.1 Hz, 1H), 8.31 - 8.16 (m, 2H), 7.66 (t, / = 7.9 Hz, 1H), 7.51 - 7.32 (m, 4H), 7.28 (s, 1H), 7.19 - 6.99 (m, 2H), 4.93 - 4.78 (m, 1H), 4.23 - 4.02 (m, 4H), 3.15 (dd, / = 17.5, 10.9 Hz, 1H), 2.83 (dd, / = 28.4, 6.1 Hz, 4H).

Example- 126: N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,l'-biphenyl]-2- yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)thieno[2,3-b]pyridine-2- carboxamide(±).

2'-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fiuoro-N-methyl-[l ,l'- biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.050 g, 0.127 mmol) was reacted with thieno[2,3-b]pyridine-2-carboxylic acid (0.034 g, 0.191 mmol) (synthesized as per reported procedure in PCT Int. Appl., 2004039366) in the presence of EDCI.HC1 (0.048 g, 0.254 mmol), HOBt (0.034 g, 0.254 mmol) and N,N- diisopropylethylamine (0.100 mL,0.510 mmol) in N,N-dimethylformamide (3 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.010 g, 15%) as a solid. LCMS: m/z 518.8 [M+H] ⁺; HPLC: 95.60%; H NMR (400 MHz, DMSO-d6) δ 9.26 (t, / = 5.7 Hz, 1H), 8.66 (dd, / = 4.6, 1.6 Hz, 1H), 8.39 (dd, / = 8.1 , 1.6 Hz, 1H), 8.26 (s, 1H), 8.10 (s, lH), 7.66 (t, / = 8.0 Hz, 1H), 7.53 - 7.31 (m, 5H), 7.16 (d, / = 8.4 Hz, 1H), 7.07 (t, / = 7.3 Hz, 1H), 4.87 (dtd, / = 10.9, 6.8, 3.7 Hz, 1H), 4.22 - 4.03 (m, 4H), 3.16 (dd, / = 17.4, 10.9 Hz, 1H), 2.88 (d, / = 7.5 Hz, 1H), 2.81 (d, / = 4.6 Hz, 3H).

Example- 127: N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,l'-biphenyl]-2- yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)thieno[2,3-c]pyridine-2- carboxamide(±).

2'-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fiuoro-N-methyl-[l , - biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.100 g, 0.254 mmol) was reacted with thieno[2,3-c]pyridine-2-carboxylic acid (0.068 g, 0.382 mmol) (synthesized as per reported procedure in PCT Int. Appl, 2004039366) in the presence of EDCI.HC1 (0.096 g, 0.510 mmol), HOBt (0.068 g, 0.510 mmol) and N,N- diisopropylethylamine (0.180 mL, 1.020 mmol) in N,N-dimethylformamide (3 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.030g,

23 %) as a solid. LCMS: m/z 519.1 [M+H] ⁺; HPLC: 98.65 %; H NMR (300 MHz, DMSO-d6) δ 9.42 - 9.28 (m, 2H), 8.53 (d, / = 5.5 Hz, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.94 (d, / = 5.6 Hz, 1H), 7.66 (t, / = 8.0 Hz, 1H), 7.42 (dt, / = 14.6, 8.7 Hz, 4H), 7.21 - 7.01 (m, 2H), 4.88 (m, 1H), 4.22 - 3.99 (m, 4H), 3.16 (dd, / = 17.4, 10.9 Hz, 1H), 2.84 (dd, / = 27.1, 6.1 Hz, 4H).

Example- 128: N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,l'-biphenyl]-2- yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)furo[2,3-c]pyridine-2- carboxamide(±).

2'-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fiuoro-N-methyl-[l ,l'- biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.100 g, 0.253 mmol) was reacted with furo[2,3-c]pyridine-2-carboxylic acid (synthesized as per reported procedure in PCT Int. Appl, 2012031197) (0.049 g, 0.304 mmol) in the presence of BOP reagent (0.134 g, 0.304 mmol) and N,N-diisopropylethylamine (0.131 mL, 0.759 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.020 g, 15.7 %) as a solid. HPLC: 98.01 %; LCMS: m/z 503.4 [M+H] ⁺; ^lU NMR (400 MHz, DMSO-d6) δ 9.34 (t, / = 5.9 Hz, 1H), 9.06 (s, 1H), 8.52 - 8.45 (m, 1H), 8.25 (d, / = 5.2 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.70 - 7.61 (m, 2H), 7.49 - 7.33 (m, 4H), 7.15 (d, / = 8.4 Hz, 1H), 7.07 (t, / = 7.6 Hz, 1H), 4.86 (q, J = 7.9, 6.5 Hz, 1H), 4.23 - 4.03 (m, 4H), 3.15 (dd, / = 17.5, 11.0 Hz, 1H), 2.90 - 2.82 (m, 1H), 2.79 (dd, / = 4.5, 1.6 Hz, 3H).

Example- 129: N-((5-(((4'-fluoro-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo [l,2-a]pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-(((4'-fluoro-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol- 3-yl) methyl) carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.050 g, 0.129 mmol) was reacted with (4- fluorophenyl)boronic acid (0.027 g, 0.194 mmol) in the presence of sodium carbonate (0.041 g, 0.386 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) in toluene: ethanol: water (3:2:1) (3.5 mL) as described in the synthesis of step-2 of example- 121 to give the titled compound (0.050 g, crude) as a solid.

Step-2: (5-(((4'-fiuoro-[l,r-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

tert-butyl((5-(((4'-fluoro-[l ,r-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.050 g, 0.125 mmol) was reacted with ethereal HCl (5 mL) in 1,4-dioxane (5 mL) at 0°C as described in the synthesis of step-3 of example- 121 to give titled compound (0.029 g, 90.6 %) as a solid.

Step-3: N-((5-(((4'-fluoro-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3-yl) methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±).

(5-(((4'-fiuoro-[l,r-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.029 g, 0.086 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.014 g, 0.861 mmol) in the presence of EDCI.HC1 (0.020 g, 0.103 mmol), HOBt (0.017 g, 0.129 mmol) and N,N-diisopropylethylamine (0.052mL, ,0.309 mmol) in N,N-dimethylformamide (1.0 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.005 g, 13.1 %) as a solid. LCMS: m/z 445.5 [M+H] ⁺; HPLC: 95.03 ; ^lU NMR (400 MHz, Chloroform-d) δ 8.72 (d, / = 1.7 Hz, 1H), 7.72 (s, 1H), 7.64 (d, / = 9.5 Hz, 2H), 7.58 - 7.41 (m, 2H), 7.41 - 7.28 (m, 3H), 7.17 - 7.02 (m, 3H), 6.96 (d, / = 8.1 Hz, 1H), 6.24 (s, 1H), 4.96 (td, / = 7.0, 3.4 Hz, 1H), 4.18 (dd, / = 9.7, 4.3 Hz, 3H), 4.04 (dd, / = 10.2, 3.3 Hz, 1H), 3.07 (dd, / = 17 Hz, 1H), 2.90 (dd, / = 17.2, 6.8 Hz, 1H).

Example- 130: N-((5-(((5-cyano-4'-fluoro-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5 dihydro isoxazol-3-yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-1: 3-bromo-4-hydroxybenzonitrile.

3-bromo-4-hydroxybenzaldehyde (1.0 g, 4.970 mmol) was reacted with hydroxylamine hydrochloride (0.520 g, 7.460 mmol) in DMSO (10 mL) at 90°C for 2 h. Then the reaction mixture cooled to room temperature and diluted with ice water and extracted with ethyl acetate (2 x 50 mL), separated the ethyl acetate layer and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give titled compound (0.960 g, 97%) as off white solid. LCMS: m/z 198.05 [M] ⁺; H NMR (300 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.05 (d, / = 2.1 Hz, 1H), 7.67 (dd, / = 8.5, 2.1 Hz, 1H), 7.06 (d, / = 8.5 Hz, 1H).

Step-2: 4-(allyloxy)-3-bromobenzonitrile.

3-bromo-4-hydroxybenzonitrile (0.950 g, 4.800 mmol) was reacted with ally bromide (0.700 g, 5.750 mmol), potassium carbonate (1.660 g, 12.000 mmol) and KI (0.016 g, 0.100 mmol) in acetone (20 mL) at reflux temperature for 2h. Then reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column (elution; 0-10% of gradient ethyl acetate in n-hexane) to give titled compound (1.0 g, 87%) as liquid. LCMS: m/z 236.0 [M-2] ⁺; HPLC: 96.60 %; H NMR (300 MHz, Chloroform-d) δ 7.84 (d, / = 2.0 Hz, 1H), 7.57 (dd, / = 8.6, 2.0 Hz, 1H), 6.92 (d, / = 8.6 Hz, 1H), 6.05 (ddt, / = 17.3, 10.2, 4.9 Hz, 1H), 5.59 - 5.26 (m, 2H), 4.68 (dt, / = 4.8, 1.6 Hz, 2H).

Step-3: tert-butyl ((5-((2-bromo-4-cyanophenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (0.878 g, 5.040 mmol) in N,N-dimethylformamide (30 mL) was added N-chlorosuccinimide (0.845 g, 6.300 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h then cooled to 0 °C and added 4-(allyloxy)-3-bromobenzonitrile (1.000 g, 4.200 mmol) in one lot followed by drop wise addition of triethylamine (1.470 mL, 10.500 mmol). The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate (2 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column (hexanes/ethyl acetate =50/50) to give the titled compound (0.600 g, 35%) as a liquid. LCMS: m z 310.0 [M -100] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 7.83 (d, / = 2.0 Hz, 1H), 7.59 (dd, / = 8.6, 2.1 Hz, 1H), 6.95 (d, / = 8.6 Hz, lH), 5.10 - 4.90 (m, 1H), 4.23 (dd, / = 10.2, 4.2 Hz, 2H), 4.18 - 4.07 (dd, / = 10.2, 4.2 Hz, 2H, 2H), 3.31 - 3.10 (m, 2H), 1.63 - 1.55 (m, 9H).

Step-4: 4-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-bromobenzonitrile hydrochloride (±).

To a solution of tert-butyl ((5-((2-bromo-4-cyanophenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl)carbamate (±) (0.600 g, 1.92 mmol) in 1 ,4-dioxane (10 mL) was added 4 N HC1 in 1 ,4-dioxane (10 mL) drop wise at 0 °C. Then reaction mixture was stirred for 12 h at room temperature. Then reaction mixture was concentrated under reduced pressure to give solid. This solid was triturated with dry diethyl ether (2 x 10 mL) to give titled compound (0.400 g, 88%) as solid. LCMS: m z 312.0 [M+2] ⁺; H NMR (300 MHz, Chloroform-d) δ 7.83 (q, / = 1.3 Hz, 1H), 7.59 (dq, / = 8.5, 1.4 Hz, 1H), 6.96 (d, / = 8.6 Hz, 1H), 5.03 (ddt, / = 10.9, 8.2, 4.3 Hz, 1H), 4.28 - 4.04 (m, 2H), 3.71 (d, / = 1.2 Hz, 2H), 3.66 (s, 2H), 3.20 (qd, / = 17.1, 8.6 Hz, 2H).

Step-5: N-((5-((2-bromo-4-cyanophenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide(±).

4-((3-(aminomemyl)-4,5-dmydroisoxazol-5-yl)memoxy)-3-bromobenzonitrile hydrochloride (±) (0.400 g, 1.290 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.250 g, 1.550 mmol) in the presence of HATU (0.736g, 1.930mmol) and N,N-diisopropylethylamine (0.600 mL, 3.230mmol) in N,N-dimethylformamide (10 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.200 g, 35%) as a solid. LCMS: m/z 454.0 [M+H] ⁺; ^lU NMR (300 MHz, Chloroform- d) δ 8.82 (d, / = 1.5 Hz, 1H), 8.18 (t, / = 5.7 Hz, 1H), 7.75 (d, / = 2.0 Hz, 1H), 7.65 (d, / = 1.4 Hz, 1H), 7.61 - 7.49 (m, 4H), 6.91 (d, / = 8.6 Hz, lH), 4.98 (ddt, / = 10.8, 7.3, 3.8 Hz, 1H), 4.18 (dd, / = 10.3, 3.8 Hz, 2H), 4.12 - 4.00 (m, 2H), 3.27 - 3.09 (m, 2H).

Step-6: N-((5-(((5-cyano-4'-fluoro-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±).

To a degassed solution of N-((5-((2-bromo-4-cyanophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±) (0.150 g, 0.330 mmol) in 1 ,4-dioxane: water (9:1) (20 mL) was added (4-fluorophenyl)boronic acid (0.056 g, 0.390 mmol), followed by potassium carbonate (0.153 g, 1.100 mmol) and [[1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.036 g, 0.044 mmol) at room temperature under inert atmosphere. Then resulting reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue obtained was purified by column chromatography on neutral alumina (dichloromethane/methanol = 90/5) to give the titled compound (0.030 g, 43%) as off white solid. LCMS: m z 470.1 [M+H] ⁺; HPLC: 96.15%; ^lU NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 7.72 (s, 1H), 7.66 (d, / = 5.4 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.55 (d, / = 2.1 Hz, 1H), 7.42 (dd, / = 8.4, 5.4 Hz, 2H), 7.36 - 7.29 (m, 1H), 7.08 (t, / = 8.5 Hz, 2H), 6.99 (d, / = 8.6 Hz, 1H), 6.40 (t, / = 5.5 Hz, 1H), 4.96 (ddt, / = 10.6, 6.9, 3.7 Hz, 1H), 4.28 - 4.18 (m, 2H), 4.16 - 4.04 (m, 2H), 3.19 - 3.04 (m, 1H), 2.87 (dd, / = 17.4, 7.1 Hz, 1H).

Example- 131: N-((5-(((3',5'-difluoro-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a] pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-(((3', 5'-difluoro-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) carbamate (±).

tert-butyl ((5-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.300g, 0.779 mmol) was reacted with (3,5- difluorophenyl)boronic acid (0.184 g, 1.165 mmol) in the presence of sodium carbonate (0.247 g, 2.330 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.089 g, 0.077 mmol) in ethanol:water:toluene (1 :2:8) (5.5 mL) as described in the synthesis of step-2 of example-121 to give the titled compound (0.300 g, crude) as a solid. LCMS: m/z 319.2 [M-100] ⁺.

Step-2: (5-(((3',5'-difluoro-[l ,l '-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

tert-butyl ((5-(((3', 5'-difluoro-[l, l '-biphenyl]-2-yl) oxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methyl)carbamate (±) (0.300 g, 0.717 mmol) was reacted with ethereal HC1 (5 mL) in 1 , 4-dioxane (5 mL) at 0° C as described in the synthesis of step-3 of example-121 to give titled compound (0.220 g, 58.5 %) as a solid. LCMS: m/z 319.2 [M+H] ⁺.

Step-3: N-((5-(((3',5'-difluoro-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±).

((5-(((3',5'-difluoro-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3-yl)- methanamine hydrochloride (±) (0.220 g, 0.617 mmol) was reacted with imidazo[l,2- a]pyridine-6-carboxylic acid (0.100 g, 0.617 mmol) in the presence of EDCI.HC1 (0.143 g, 0.741 mmol), HOBt (0.125 g, 0.926 mmol) and N,N-diisopropylethylamine (0.240 g, 1.857 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.102 g, 35.6 %) as a solid. LCMS: m/z 463.3 [M+H] ⁺; HPLC: 95.97 ; ^lU NMR (300 MHz, Chloroform-d) δ 8.80 (dd, / = 1.9, 0.9 Hz, 1H), 7.75 - 7.59 (m, 3H), 7.46 - 7.23 (m, 3H), 7.07 (dddd, / = 7.5, 5.1 , 2.9, 1.5 Hz, 3H), 6.96 (dd, / = 8.2, 1.1 Hz, 1H), 6.78 - 6.57 (m, 2H), 4.99 (ddt, / = 10.9, 7.1 , 3.3 Hz, 1H), 4.43 - 4.18 (m, 2H), 4.16 - 3.98 (m, 2H), 3.21 - 2.88 (m, 2H).

Example- 132: N-((5-(((4'-methoxy-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

(5-(((4'-methoxy-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3-yl)- methanamine hydrochloride (±) (0.100 g, 0.286 mmol) was reacted with imidazo[l,2- a]pyridine-6-carboxylic acid (0.065 g, 0.401 mmol) in the presence of EDCI.HC1 (0.065 g, 0.343 mmol), HOBt (0.050 g, 0.378 mmol) and N,N-diisopropylethylamine (0.148 mL,, 0.857 mmol) in N,N-dimethylformamide (3 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.030 g, 22 %) as a solid. LCMS: m/z 457.35 [M+H] ⁺; HPLC: 97.99 ; H NMR (400 MHz, DMSO-d6) δ 9.14 (d, / = 1.7 Hz, 1H), 8.95 (t, / = 5.7 Hz, 1H), 8.08 (s, 1H), 7.68 - 7.61 (m, 3H), 7.47 - 7.42 (m, 2H), 7.28 (td, / = 6.8, 6.0, 1.9 Hz, 2H), 7.09 (d, / = 8.5 Hz, 1H), 7.02 (t, / = 7.2 Hz, 1H), 6.96 - 6.91 (m, 2H), 4.86 (d, / = 15.7 Hz, 1H), 4.17 (d, / = 5.7 Hz, 2H), 4.10 - 4.00 (m, 2H), 3.76 (s, 3H), 3.12 (dd, / = 17.4, 10.9 Hz, 1H), 2.86 (dd, / = 17.4, 7.6 Hz, 1H). Example- 133: N-((5-((2-(lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide(±).

Step-1: 2-((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)isoindoline- 1,3-dione (±).

To a solution of 2-(2-(methylamine) ethyl) isoindoline- 1 , 3-dione (0.500 g, 2.475 mmol) in N, N-dimethylformamide (5 mL) was added N-chlorosuccinimide (0.460 g, 3.674 mmol) at room temperature. After stirring for 2 h at room temperature was added 1 - (allyloxy)-2-bromobenzene (0.574 g, 2.694 mmol), followed by triethylamine (0.371 g, 3.674 mmol). The resulting reaction mixture was stirred for 16 h at room temperature. After the completion of the reaction, added water and extracted by ethyl acetate, washed with brine, dried over sodium sulfate and evaporated solvent. Crude obtained was triturated with diethyl ether to give the titled compound (0.270 g, 27%) as an off white solid. LCMS: m/z 417.0 [M+2] ⁺; ^lU NMR (300 MHz, DMSO-d6) δ 7.96 - 7.84 (m, 4H), 7.54 (dd, / = 7.9, 1.6 Hz, 1H), 7.32 (ddd, / = 8.8, 7.4, 1.6 Hz, 1H), 7.09 (dd, / = 8.3, 1.4 Hz, 1H), 6.89 (td, / = 7.6, 1.4 Hz, 1H), 4.94 (ddt, / = 11.1, 8.0, 3.8 Hz, 1H), 4.54 (s, 2H), 4.19 - 4.00 (m, 2H), 3.30 - 3.19 (m, 1H), 3.02 (dd, / = 17.4, 7.2 Hz, 1H).

Step-2: (5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methanamine (±).

To a solution of 2-((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3- yl)methyl)isoindo line- 1 , 3-dione (±) (1.0 g, 2.408 mmol) in methanol (10 mL) was added hydrazine hydrate (0.241g, 4.816 mmol) at room temperature and stirred at 60° C for 3 h. Evaporated off the solvent, diluted with ethyl acetate (20 mL) and water (10 mL). Separated the organic layer and washed with brine, dried over sodium sulfate and concentrated to give the titled compound (0.600 g, 87%) as colorless gummy liquid. LCMS: m/z no ionization ; H NMR (300 MHz, Chloroform-d) δ 7.53 (dd, / = 7.9, 1.6 Hz, 1H), 7.20 (dd, / = 7.8, 1.4 Hz„ 1H), 6.88 (ddd, / = 17.3, 7.9, 1.4 Hz, 2H), 5.01 (tt, / = 8.8, 4.5 Hz, 1H), 4.11 (d, / = 4.5 Hz, 2H), 3.69 - 3.61 (m, 2H), 3.26 - 3.12 (m, 2H).

Step-3: N-((5-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)imidazo[l ,2- a]pyridine-6-carboxamide (±) .

(5-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine (±) (0.600 g, 2.104 mmol) was reacted with imidazo[l,2-a]pyridine-6-carboxylic acid (0.375 g, 2.314 mmol) in the presence of EDCI.HC1 (0.605 g, 3.156 mmol), HOBt (0.014 mg, 0.105 mmol) and triethylamine (0.873 mL, 6.313 mmol) in dichloromethane (10 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.500 g, 55%) as a solid. LCMS: m/z 430.95 [M+2] ⁺; H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 9.01 (d, / = 6.3 Hz, 1H), 8.08 (s, lH), 7.72 - 7.59 (m, 3H), 7.55 (d, / = 7.9 Hz, 1H), 7.33 (t, / = 8.0 Hz, 1H), 7.11 (d, / = 8.3 Hz, 1H), 6.89 (t, / = 7.8 Hz, 1H), 4.92 (d, / = 10.1 Hz, 1H), 4.27 (d, / = 5.7 Hz, 2H), 4.21 - 4.03 (m, 2H), 3.21 (dd, / = 17.6, 11.0 Hz, 1H), 3.01 (dd, / = 17.6, 7.2 Hz, 1H).

Step-4: N-((5-((2-(lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine- 6 -carboxamide (±).

To a previously degassed solution of N-((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±) (0. 200 g, 0.466 mmol) in 1,4-dioxane: water (3:2) (5 mL) in 100 ml sealed tube was added 4- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.108 g, 0.559 mmol), sodium carbonate (0.148 g, 1.398 mmol). Again degassed the solution with argon for 10 min and was added [l ,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.017g, 0.023 mmol) and stirred at 80° C for 13 h. The reaction mixture was cooled to room temperature, evaporated off the solvent, added water and extracted with chloroform (2 x 10 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude obtained was purified by column chromatography on silica gel (chloroform/methanol = 92/8) to give the titled compound (0.030 g, 16%) as off-white solid LCMS: nt/z 417.3 [M+H] ⁺; HPLC: 97.61 %; H NMR (300 MHz, DMSO-d6) δ 12.89 (s, 1H), 9.13 (s, 1H), 8.99 (t, / = 5.9 Hz, 1H), 8.18 - 7.94 (m, 3H), 7.65 (d, / = 8.9 Hz, 4H), 7.21 - 6.91 (m, 3H), 5.02 (d, / = 8.1 Hz, 1H), 4.26 (d, / = 5.6 Hz, 2H), 4.21 - 4.01 (m, 2H), 3.26 - 3.15 (m, 1 H), 2.93 (dd, / = 17.4, 7.4 Hz, 1H).

Example- 134: N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,l'-biphenyl]-2- yl)oxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)imidazo[l,2-a]pyridine-7- carboxamide (±).

2'-((3-(amino methyl)-4,5-dihydroisoxazol-5-yl)methoxy)-3-fluoro-N- methyl- [ 1 ,1'- biphenyl]-4-carboxamide hydrochloride (±) (prepared in step-2 of example 68) (0.050 g, 0.127 mmol) was reacted with imidazo[l ,2-a]pyridine-7-carboxylic acid (0.034 g, 0.191 mmol) in the presence of EDCI.HCl (0.048 g, 0.254 mmol), HOBt (0.034 g, 0.254 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.510 mmol) in N,N- dimethylformamide (3 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.035 g, 55.5 %) as a solid. LCMS: m/z 502.1 [M+H] ⁺; HPLC: 99.65 %; H NMR (400 MHz, DMSO-d6) δ 9.05 (t, / = 5.8 Hz, 1H), 8.63 (dd, / = 7.1 , 0.9 Hz, 1H), 8.30 (d, / = 20.8 Hz, 1H), 8.18 - 8.12 (m, 1H), 8.11 - 8.05 (m, 1H), 7.74 (d, / = 1.1 Hz, 1H), 7.67 (t, / = 8.1 Hz, 1H), 7.52 - 7.34 (m, 4H), 7.32 (dd, / = 7.1 , 1.7 Hz, 1H), 7.17 (d, / = 8.2 Hz, 1H), 7.08 (td, / = 7.4, 1.0 Hz, 1H), 4.87 (dtd, / = 10.9, 6.8, 3.7 Hz, 1 H), 4.24 - 4.03 (m, 4H), 3.16 (dd, / = 17.4, 10.9 Hz, 1H), 2.88 (d, / = 7.5 Hz, 1H), 2.81 (d, / = 4.6 Hz, 3H).

Example- 135: N-((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (Enatiomer-1 of Example-121).

Step-1: tert-butyl ((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (enantiomer - 1).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate [enantiomer-1 : Peak-1 ; (separated in step-1 of example-23)] (0.500 g, 1.298 mmol) in 1 ,4-dioxane: water (4: 1) (10 mL) was added 1 - methyl-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-iH-pyrazole (0.405 g, 1.947 mmol), followed by potassium carbonate (0.537g, 3.894 mmol) and 1 ,1 '-Bis (diphenylphosphino)ferrocene-palladium(II)dichloride dichloro methane complex (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 50 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water (2 x 50 mL), brine solution. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.320 g, 61 %) as a sticky solid.

Step-2: (5-((2-(l -methyl-iH-pyrazol-4-yl) phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (enantiomer -1 ).

tert-butyl ((5-((2-(l-methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (enantiomer- 1) (0.320 g, 0.828 mmol) was reacted with 4 N HQ in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.270 g, 99%) as a solid.

Step-3: N-((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (enatiomer- 1).

(5-((2-(l -methyl-iH-pyrazol-4-yl) phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methan- amine hydrochloride (enantiomer- 1) (0.270 g, 0.838 mmol) was reacted with imidazo[l ,2-a]pyridine-6-carboxylic acid (0.193 g, 1.173 mmol) in the presence of EDCI.HC1 (0.193 g, 1.193 mmol), HOBt (0.147 g, 1.809 mmol) and N,N- diisopropylethylamine (0.729 mL, 4.190 mmol) in N,N-dimethylformamide (8 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.140 g, 39 %) as a solid. LCMS: m/z 431.3 [M+H] ⁺; HPLC: 99.66 %; Chiral HPLC: 99.61 %; H NMR (400 MHz, DMSO-d6) δ 9.13 (t, / = 1.4 Hz, 1H), 8.99 (t, / = 5.7 Hz, 1H), 8.08 - 8.06 (m, 2H), 7.90 (s, 1H), 7.68 - 7.63 (m, 3H), 7.58 (dd, / = 7.7, 1.7 Hz, 1 H), 7.17 (ddd, / = 8.7, 7.3, 1.7 Hz, 1H), 7.05 (dd, / = 8.3, 1.2 Hz, 1H), 6.96 (td, / = 7.5, 1.2 Hz, 1H), 5.02 (dq, / = 7.3, 3.5, 2.7 Hz, 1H), 4.26 (d, / = 5.7 Hz, 2H), 4.12 (qd, / = 10.4, 5.0 Hz, 2H), 3.85 (s, 3H), 3.25 (dd, / = 17.5, 10.9 Hz, 1H), 2.94 (dd, / = 17.6, 7.7 Hz, lH).

Example- 136: N-((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (Enantiomer-2 of Example-121).

Step-1: tert-butyl ((5-((2-(l-methyl-iH-pyrazol-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (enantiomer-2).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy) methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate [enantiomer-2: Peak-2; (separated in step-1 of example-23)] (0.500 g, 1.298 mmol) in 1 ,4-dioxane: water (4: 1) (10 mL) was added 1 - methyl-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-iH-pyrazole (0.405 g, 1.947 mmol), followed by potassium carbonate (0.537 g, 3.894mmol) and 1 ,1 '-Bis (diphenylphosphino)ferrocene-palladium(II)dichloride dichloro methane complex (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 50 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.380 g, 69 %) as a sticky solid.

Step-2: (5-((2-(l -methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (enantiomer-2).

tert-butyl ((5 -((2-(l -methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5 -dihydroisoxazol-3 - yl)methyl)carbamate (enantiomer-2) (0.380 g, 0.983 mmol) was reacted with 4N HQ in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.320 g, 99%) as a solid.

Step-3: N-((5-((2-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide(enantiomer-2).

(5-((2-(l -methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (enantiomer-2) (0.320 g, 0.993 mmol) was reacted with imidazo[l ,2-a]pyridine-6-carboxylic acid (0.225 g, 1.390 mmol) in the presence of EDCI.HC1 (0.228 g, 1.191 mmol), HOBt (0.174 g, 1.290 mmol) and Ν,Ν- diisopropylethylamine (0.864 mL, 4.965 mmol) in Ν,Ν-dimethylformamide (10 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.135 g, 31 %) as a solid. LCMS: m z 431.3 [M+H] ⁺; HPLC: 98.69 %; Chiral HPLC: 99.07%; ^lU NMR (400 MHz, DMSO-d6) δ 9.13 (d, / = 1.4 Hz, 1H), 8.99 (t, / = 5.8 Hz, 1H), 8.08 - 8.05 (m, 2H), 7.90 (s, 1H), 7.67 - 7.62 (m, 3H), 7.58 (dd, J = 7.7, 1.7 Hz, 1 H), 7.17 (td, / = 7.8, 7.2, 1.7 Hz, 1H), 7.05 (d, / = 8.2 Hz, 1H), 6.98 - 6.92 (m, 1H), 5.05 - 4.98 (m, 1H), 4.26 (d, / = 5.7 Hz, 2H), 4.16 - 4.07 (m, 2H), 3.85 (s, 3H), 3.25 (dd, / = 17.5, 10.9 Hz, 1H), 2.94 (dd, / = 17.5, 7.7 Hz, 1H).

Example- 137: N-((5-((4-cyano-2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydro isoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

To a degassed solution of N-((5-((2-bromo-4-cyanophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide(±) (0.300 g, 0.660 mmol) in 1,4-dioxane: water (9:1) (20 mL) was added l -methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.165 g, 0.790 mmol), followed by potassium carbonate (0.229 g, 1.650 mmol) and [[l ,l'-Bis(diphenylphosphino) ferrocene] dichloropalladium(II) complex with dichloromethane (0.054 g, 0.070 mmol) at room temperature under inert atmosphere. Then resulting reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue obtained was purified by column chromatography on neutral alumina (dichloromethane/methanol = 99.5/0.5) to give the titled compound (0.120 g, 40 %) as off white solid .LCMS: m/z 456.2 [M-H] ⁺; HPLC: 95.25%; H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 7.89 (s, 1H), 7.72 (d, / = 1.8 Hz, 2H), 7.69 - 7.65 (m, 2H), 7.63 (d, / = 9.4 Hz, 1H), 7.52 (ddd, / = 8.6, 7.1, 1.9 Hz, 2H), 7.41 (t, / = 5.9 Hz, 1H), 6.95 (d, / = 8.6 Hz, 1H), 5.08 (ddt, / = 10.3, 6.4, 2.9 Hz, 1H), 4.45 (dd, / = 16.9, 5.7 Hz, 1H), 4.36 (dd, / = 10.3, 2.7 Hz, 1H), 4.28 (dd, / = 16.9, 5.9 Hz, 1H), 4.11 (dd, / = 10.3, 3.2 Hz, 1H), 3.92 (s, 3H), 3.33 - 3.18 (m, 1H), 3.04 (dd, / = 17.4, 7.2 Hz, 1H).

Example- 138: N-((5-((2-(l-ethyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide(±).

Step-1 : 1 -ethyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole.

To a solution of 4-(4,4,5,5-tetramemyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.194 g, 1.000 mmol) in acetonitrile (10 mL) was added cesium carbonate (0.652 g, 2.0 mmol), followed by ethyl iodide (0.187 g, 1.2 mmol) at room temperature and stirred at 80°C for 16 h. After the completion of reaction, cooled to room temperature filtered through pad of celite and evaporated off the filtrate to give the titled compound (0.180 g) as a crude. LCMS: m/z 223.1 [M+H] ⁺. ^lU NMR (600 MHz, Chloroform-d) δ 7.79 (d, / = 4.5 Hz, 1H), 7.71 (d, / = 4.6 Hz, 1H), 4.19 (q, / = 7.2 Hz, 2H), 1.71 (t, / = 7.2 Hz, 3H), 1.33 (d, / = 4.9 Hz, 12H).

Step-2: N-((5-((2-(l -ethyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±).

To a previously degassed solution of N-((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±) (prepared in step-3 of example- 133) (0.200 g, 0.466 mmol) in 1,4-dioxane: water (3:2) (5 mL) in 100 ml sealed tube was added l-ethyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH- pyrazole (0.124 g, 0.559 mmol) and sodium carbonate (0.148 g, 1.398 mmol). Again degassed the solution with argon for 10 min and was added [Ι ,Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.017g, 0.023 mmol) and stirred at 80° C for 13 h. The reaction mixture was cooled to room temperature, evaporated off the solvent, added water and extracted with chloroform (2 x 10 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude obtained was purified by column chromatography on silica gel (Chloroform/Methanol = 96/4) to give the titled compound (0.035 g, 17%) as off-white solid. LCMS: m/z 445.4 [M+H] ⁺; HPLC: 95.23 %; ^lU NMR (300 MHz, Chloroform-d) δ 8.84 - 8.80 (m, 1H), 7.93 (d, / = 0.7 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.62 (d, / = 8.8 Hz, 2H), 7.54 (dd, / = 9.6, 1.8 Hz, 1H), 7.42 (dd, / = 7.6, 1.7 Hz, 1H), 7.36 (s, 1H), 7.24 - 7.16 (m, 1H), 7.04 - 6.97 (m, 1H), 6.91 (d, / = 8.1 Hz, 1H), 5.13 - 5.00 (m, 1H), 4.43 (dd, / = 16.7, 5.6 Ηζ,ΙΗ), 4.34 - 4.26 (m, 2H), 4.17 (q, / = 7.3 Hz, 2H), 4.06 (dd, / = 10.4, 2.8 Hz, lH), 3.29 - 2.98 (m, 2H), 1.48 (t, / = 7.3 Hz, 3H).

Example- 139: N-((5-((2-(l-isopropyl-lH-pyrazol-4-yl) phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-1 : 1 -isopropyl-4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazole .

To a solution of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.194 g, 1.000 mmol) in acetonitrile (10 mL) was added cesium carbonate (0.652 g, 2.000 mmol), followed by 2-bromopropane (0.189 g, 1.538 mmol) at room temperature and stirred at 80°C for 4 h. After the completion of reaction, cooled to room temperature filtered through pad of celite and evaporated off the filtrate to give the titled compound (0.200 g) as crude. LCMS: m/z 237.2 [M+H] ⁺; H NMR (300 MHz, Chloroform-d) δ 7.89 (s, 2H), 4.61 - 4.44 (m, 1H), 1.50 (d, / = 6.6 Hz, 6H), 1.32 (d, / = 3.1 Hz, 12H).

Step-2: N-((5-((2-(l-isopropyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl) imidazo [l,2-a]pyridine-6-carboxamide (±).

N-((5-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)imidazo[l,2- a]pyridine-6-carboxamide (±) (prepared in step-3 of example-133) (0.130 g, 0.302 mmol) in 1 ,4-dioxane was treated with l-isopropyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.086 g, 0.363 mmol) as described in the step-2 of example-138 to give the titled compound (0.040 g, 29%) as off-white solid. LCMS: m/z 459.2 [M+H] ⁺; HPLC: 91.26 %; H NMR (300 MHz, Chloroform-d) δ 8.87 (d, / = 2.0 Hz, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.73 - 7.65 (m, 2H), 7.62 (d, / = 1.7 Hz, 3H), 7.42

(dd, / = 7.6, 1.8 Hz, 1H), 7.24 - 7.17 (m, 1H), 6.99 (t, / = 7.5 Hz, 1H), 6.90 (d, / Hz, 1H), 5.05 (dd, / = 10.8, 6.0 Hz, 1H), 4.48 (dt, / = 13.7, 6.7 Hz, 2H), 4.30 (dd, / = 10.4, 2.8 Hz, 1H), 4.15 (dd, / = 16.9, 5.8 Hz, 1H), 4.05 (dd, / = 10.3, 2.8 Hz, 1H), 3.22 (dd, / = 17.2, 11.3 Hz, 1H), 3.05 (dd, / = 17.0, 6.8 Hz, 1H), 1.50 (d, / = 6.7 Hz, 6H).

Example- 140: N-((5-(((l-methyl-iH-indazol-4-yl)oxy)methyl)-4,5-dihydroisoxazol- 3-yl) methyl) imidazo [1,2-a] pyridine-6-carboxamide (±).

Step-1 : 4-(allyloxy)- 1 -methyl-iH-indazole.

Allyl iodide (0.408 g, 2.432 mmol) was added to a solution of 1 -methyl- lH-indazol-4-ol (0.300 g, 2.027 mmol) (Synthesized as per reported procedure in J.Med. Chem. 55(8),3975-3991, 2002) in acetone (10.0 mL) and potassium carbonate (0.839 g, 6.081 mmol) at 0°C under nitrogen atmosphere and the reaction mixture was heated to 60 °C for 16 h. The resulting mixture was cooled and filtered. Filtrate was concentrated under reduced pressure to give residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 15/85) to give the titled compound (0.275 g, 71 ) as a liquid. LCMS: m/z 189.2 [M+ H]⁺.

Step-2: tert-butyl ((5-(((l-methyl-iH-indazol-4-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

tert-butyl (2-(hydroxyimino) ethyl)carbamate (0.254 g, 1.462 mmol) was reacted with N- chlorosuccinimide (0.233 g, 1.752 mmol), 4-(allyloxy)-l-methyl-lH-indazole (0.275 g, 1.462 mmol) and triethylamine 0.221 mL, 1.608 mmol) in N,N-dimethylformamide (10 mL) as described in the synthesis of step-3 of example- 1 to give the titled compound (0.130 g, 18%) as a sticky solid. LCMS: m/z 261.1 [M-100] ⁺.

Step-3: (5-(((l-methyl-iH-indazol-4-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

tert4jutyl((5-(((l-methyl-iH-indazol-4-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.130 g, 0.362 mmol) was reacted with 4N HQ in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.080 g, 75%) as a solid.

Step-4: N-((5-(((l-methyl-iH-indazol-4-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a] pyridine-6-carboxamide (±).

(5-(((l-methyl-iH-indazol-4-yl)oxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.080 g, 0.269 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.052 g, 0.323 mmol) in the presence of BOP reagent (0.130 g, 0.295 mmol) and Ν,Ν-diisopropylethylamine (0.14 mL, 0.807 mmol) in Ν,Ν- dimethylformamide (3 mL) at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (30 mL) and washed with water (4 x 30 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 3/97) to give titled compound (0.012 g, 8.0 %) as a solid. LCMS: m/z 405.3 [Μ+Η] ⁺; HPLC: 88.52 %; 1H NMR (400 MHz, DMSO-d6) 5 9.15 (t, / = 1.4 Hz, 1H), 9.04 (t, / = 5.8 Hz, 1H), 8.10 - 8.06 (m, 1H), 7.99 (d, / = 0.9 Hz, 1H), 7.69 - 7.60 (m, 3H), 7.30 - 7.25 (m, 1H), 7.17 (d, / = 8.4 Hz, 1H), 6.57 (d, / = 7.6 Hz, 1H), 5.02 - 4.92 (m, 1H), 4.30 - 4.14 (m, 4H), 3.99 (s, 3H), 3.25 - 3.19 (m, 1H), 3.00 (dd, / = 17.5, 7.2 Hz, 1H).

Example- 141: N-((5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide(±).

To a solution of 2-(4-(2-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)phenyl)- lH-pyrazol-l-yl)ethanol hydrochloride (±) (0.100 g, 0.284 mmol) and imidazo[l ,2- a]pyridine-6-carboxylic acid (0.070 g, 0.426 mmol) in N,N-dimethylformamide (4 mL) was added EDCI (0.110 g, 0.568 mmol), HOBT (0.077 g, 0.568 mmol) and N,N- diisopropylethylamine (0.2 mL, 1.136 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 4/96) to give the titled compound (0.015 g, 11 %) as a solid. HPLC: 95.5%: LCMS: m/z 461.1 [M+H] ⁺; 1H NMR (400 MHz, Chloroform- d) δ 8.57 (d, / = 1.3 Hz, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.68 (t, / = 5.9 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.56 - 7.35 (m, 3H), 7.25 - 7.14 (m, 1H), 7.00 (t, / = 7.5 Hz, 1H), 6.92 (d, / = 8.4 Hz, 1H), 5.13 - 4.94 (m, 1H), 4.42 (dd, / = 16.1, 6.3 Hz, 1H), 4.37 - 4.26 (m, 4H), 4.26 - 4.14 (m, 2H), 4.09 (dt, / = 11.5, 4.5 Hz, 2H), 3.31 - 3.02 (m, 2H).

Example- 142: N-((5-((2-(l-(2-(dimethylamino)ethyl)-lH-pyrazol-4-yl)

phenoxy)methyl)-4,5-dihydro isoxazol-3-yl)methyl)imidazo[l,2-a]pyridine-6- carboxamide (±).

Step -1 : N, N-dimethyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)ethanamine —

4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.200 g, 1.025 mmol) in acetonitrile (10 mL) was treated with cesium carbonate (0.668 g, 2.051 mmol) and 2- chloro-N,N-dimethylethanamine hydrochloride (0.221 g, 1.538 mmol) 80° C for 4h as described in the synthesis of step-1 of example- 139 to give the titled compound (0.200 g, crude). LCMS: m z 266.2 [M+H] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 7.89 (d, / = 1.9 Hz, 2H), 4.23 (t, /= 6.9 Hz, 2H), 2.77 (t, / = 6.8 Hz, 2H), 1.40 - 1.20 (m, 18H). Step-2: N-((5-((2-(l-(2-(dimemylamino)ethyl)-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) meth l)imidazo[l ,2-a]pyridine-6-carboxamide (±).

N-((5-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)imidazo[l,2- a]pyridine-6-carboxamide (±) (prepared in step-3 of example-133) (0.130 g, 0.302 mmol) was treated with N,N-dimethyl-l-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazol-l-yl)methanamine (0.960 g, 0.363 mmol) as described in the synthesis of step-2 of example-138 to give the titled compound (0.040 g, 27%) as an off white solid .LCMS: m/z 488.2 [M+H] ⁺; HPLC: 97.47 %; ^lU NMR (300 MHz, Chloroform-d) δ 8.54 (s, 1H), 7.93 (d, / = 9.8 Hz, 3H), 7.69 (s, 2H), 7.58 (d, / = 9.4 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.22 - 7.13 (m, 1H), 6.97 (t, / = 7.5 Hz, 1H), 6.88 (d, / = 8.2 Hz, 1H), 5.05 (ddd, / = 11.1 , 7.8, 2.5 Hz, 1H), 4.34 (dd, / = 8.8, 6.2 Hz, 3H), 4.24 (p, / = 5.8 Hz, 2H), 4.10 (dd, / = 10.5, 2.4 Hz, 1H), 3.30 - 2.94 (m, 3H), 2.75 (dt, / = 12.6, 5.6 Hz, 1H), 2.22 (s, 6H).

Example- 143: N-((5-((3-(l-methyl-iH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a] pyridine-6-carboxamide (±).

Step-1: l-(allyloxy)-3-bromobenzene.

Potassium carbonate (7.970 g, 57.796 mmol), sodium iodide (0.432 g, 2.889 mmol) and Allyl bromide (4.190 g, 34.678 mmol) was added to a solution of 3-bromophenol (5.0 g, 28.898 mmol) in acetone (40.0 mL) at 0 °C under nitrogen atmosphere and it was heated to 60 °C for 16 h. The reaction mixture was cooled and filtered. Filtrate was concentrated under reduced pressure to give the titled compound (6.0 g, 97%) as a liquid.

Step-2: tert-butyl ((5-((3-bromophenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

tert-butyl (2-(hydroxyimino) ethyl)carbamate (1.790 g, 10.325 mmol) was reacted with N-chlorosuccinimide (1.5 g, 11.632 mmol), l -(allyloxy)-3-bromobenzene (2.0 g, 9.386 mmol) and triethylamine (1.0 g, 10.846 mmol) in N,N-dimethylformamide (30 mL) as described in the synthesis of step-3 of example- 1 to give the titled compound (0.950 g, 26%) as a sticky solid. LCMS: m/z 286.1 [M-100] ⁺.

Step-3: (5-((3-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±).

tert-butyl ((5-((3-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (0.950 g, 2.467 mmol) was reacted with 4N HC1 in 1 ,4-dioxane as described in the synthesis of step-4 of example-1 to give titled compound (0.600 g, 75%) as sticky solid. LCMS: m/z 287.1 [M+H] ⁺ (free base).

Step-4: N-((5-((3-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)imidazo[l ,2- a]pyridine-6-carboxamide (±).

(5-((3-bromophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.300 g, 0.932 mmol) was reacted with imidazo[l,2-a]pyridine-6-carboxylic acid (0.181 g, 1.119 mmol) in the presence of BOP reagent (0.452 g, 1.025 mmol) and Ν,Ν- diisopropylethylamine (0.359 g, 2.790 mmol) in Ν,Ν-dimethylformamide (10 mL) at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2/98) to give titled compound (0.250 g, 62 %) as a solid. LCMS: m/z 429.3 [M+H] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 8.83 (m, 1H), 7.73 - 7.62 (m, 3H), 7.44 (dd, / = 9.4, 1.8 Hz, 1H), 7.15 - 7.04 (m, 2H), 6.90 - 6.79 (m, 2H), 5.07 - 4.98 (m, 1H), 4.43 (d, / = 5.3 Hz, 2H), 4.06 (d, / = 4.7 Hz, 2H), 3.25 (dd, / = 17.3, 10.7 Hz, 1H), 3.09 (dd, / = 17.3, 7.2 Hz, 1H).

Step-5: N-((5-((3-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo [1,2-a] ridine-6-carboxamide (±).

To a previously degassed solution of N-((5-((3-bromophenoxy)methyl)-4,5- dmydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±) (0.250 g, 0.582 mmol) in 1 ,4-dioxane: water (4: 1) (15 mL) was added l -methyl-4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-iH-pyrazole (0.157 g, 0.757 mmol), followed by potassium carbonate (0.240 g, 1.746 mmol) and l, l ' -Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.047 g, 0.058 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 6 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Ethyl acetate layer was separated and the combined ethyl acetate layers were washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (methanol/dichloromethane = 5.5/94.5) to give the titled compound (0.060 g, 24 ) as a solid. LCMS: nt/z 431.1 [M+ Η] ⁺. ; HPLC: 95.97 ; ^lU NMR (400 MHz, DMSO-d6) δ 9.15 (t, / = 1.4 Hz, 1H), 9.02 (t, / = 5.8 Hz, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.70 - 7.59 (m, 3H), 7.23 (t, / = 8.2 Hz, 1H), 7.16 - 7.11 (m, 2H), 6.78 - 6.72 (m, 1H), 4.91 (ddd, / = 11.0, 8.8 , 5.1 Hz, 1H), 4.27 (d, / = 5.7 Hz, 2H), 4.11 - 4.01 (m, 2H), 3.85 (s, 3H), 3.21 (dd, / = 17.5, 10.8 Hz, 1H), 2.92 (dd, / = 17.5, 7.3 Hz, 1 H).

Example- 144: N-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-7-carboxamide (±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.070g, 0.217 mmol) was reacted with imidazo[l,2-a]pyridine-7-carboxylic acid (synthesis as per reported in PCT Int. AppL, 2010043377) (0.053 g, 0.326 mmol) in the presence of EDCI.HC1 (0.083 g, 0.435 mmol), HOBt (0.059 g, 0.435 mmol) and N,N- diisopropylethylamine(0.16 mL, 0.870 mmol) in N,N-dimethylformamide (3 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.045 g, 43%) as a solid. LCMS: m/z 431.1 [M+H] ⁺; HPLC: 97.88 %; H NMR (400 MHz, DMSO-d6) δ 9.09 (t, / = 5.7 Hz, lH), 8.67 - 8.62 (m, 1H), 8.18 (d, / = 1.4 Hz, 1H), 8.10 (d, / = 4.8 Hz, 2H), 7.93 (s, lH), 7.76 (d, / = 1.1 Hz, 1H), 7.61 (dd, / = 7.7, 1.7 Hz, 1H), 7.34 (dd, / = 7.1, 1.8 Hz, 1H), 7.19 (ddd, / = 8.7, 7.3, 1.7 Hz, lH), 7.10 - 7.05 (m, 1H), 7.02 - 6.95 (m, 1H), 5.10 - 4.99 (m, 1H), 4.28 (d, / = 5.7 Hz, 2H), 4.15 (qd, / = 10.4, 4.9 Hz, 2H), 3.88 (s, 3H), 3.28 (dd, / = 17.5, 10.9 Hz, 1H), 2.97 (dd, / = 17.6, 7.7 Hz, lH). Example- 145: N-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) furo[3,2-c]pyridine-2-carboxamide(±).

To a solution of (5-((2-(l-methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.309 mmol) and furo[3,2-c]pyridine-2-carboxylic acid (0.076 g, 0.460 mmol) in N,N-dimethylformamide (4 mL) was added EDCI (0.120 g, 0.618 mmol), HOBT (0.083 g, 0.618 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.236 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (250 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3 x50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 5/95) to give the titled compound (0.020 g, 15%) as a solid.HPLC: 94.9 %; LCMS: m/z 432.1 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.04 (d, / = 1.0 Hz, 1H), 8.62 (d, / = 5.8 Hz, 1H), 7.85 (d, / = 0.8 Hz, 1H), 7.80 (s, 1H), 7.56 (d, / = 1.0 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.20 (ddd, / = 8.1 , 7.4, 1.7 Hz, 1H), 7.00 (td, / = 7.5, 1.1 Hz, 1H), 6.92 (dd, / = 8.4, 1.1 Hz, 1H), 5.08 (tt, / = 7.5, 3.7 Hz, lH), 4.43 - 4.37 (m, 2H), 4.24 (dd, / = 10.2, 3.7 Hz, 1H), 4.11 (dd, / = 10.3, 4.1 Hz, 1H), 3.96 (s, 3H), 3.23 (dd, / = 17.3, 11.2 Hz, 1H), 3.05 (dd, / = 17.3, 7.3 Hz, 1H).

Example- 146: N-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) furo[2,3-c]pyridine-2-carboxamide (±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.100 g, 0.309 mmol) was reacted with furo[2,3-c]pyridine-2-carboxylic acid (0.060 g, 0.371 mmol) in the presence of BOP reagent (0.164 g, 0.371 mmol) and N,N-diisopropylethylamine (0.159 mL, 0.927 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.100 g, 75.0 %) as a solid.HPLC:99.08%; LCMS: m/z 432.1 [M+H] + ; ^lU NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 8.49 (d, / = 5.3 Hz, 1H), 7.84 (d, / = 0.7 Hz, 1H), 7.78 (s, 1H), 7.60 (dd, / = 5.3, 1.1 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.32 (t, / = 5.9 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.98 (td, / = 7.5, 1.1 Hz, 1H), 6.92 - 6.86 (m, 1H), 5.06 (ddt, / = 11.1, 7.4, 3.8 Hz, 1H), 4.38 (d, / = 5.9 Hz, 2H), 4.22 (dd, / = 10.2, 3.6 Hz, 1H), 4.08 (dd, / = 10.3, 4.0 Hz, 1H), 3.94 (s, 3H), 3.20 (dd, / = 17.3, 11.2 Hz, 1H), 3.03 (dd, / = 17.3, 7.2 Hz, 1H).

Example- 147: N-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl)thieno[2,3-b]pyridine-2-carboxamide(±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.050 g, 0.155 mmol) was reacted with thieno[2,3-t>]pyridine-2-carboxylic acid (synthesis as per reported in WO2004039366) (0.042 g, 0.233 mmol) in the presence of EDCI.HCl (0.059 g, 0.310 mmol), HOBt (0.042 g, 0.310 mmol) and N,N-diisopropylethylamine (0.11 mL,0.621 mmol) in N,N-dimethylformamide (3 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.012 g, 8.6 %) as a solid. LCMS: m/z 447.90[M+H] ⁺; HPLC: 95.62%; H NMR (400 MHz, DMSO-d6) δ 9.29 (t, / = 5.8 Hz, 1H), 8.66 (dt, / = 4.6, 1.2 Hz, 1H), 8.40 (dd, / = 8.1, 1.6 Hz, 1H), 8.08 (d, / = 15.6 Hz, 2H), 7.90 (d, / = 0.8 Hz, 1H), 7.58 (dd, / = 7.7, 1.7 Hz, 1H), 7.51 (ddd, / = 8.1 , 4.6, 0.8 Hz, 1H), 7.20 - 7.11 (m, 1H), 7.05 (dd, / = 8.3, 1.1 Hz, 1H), 6.96 (td, / = 7.4, 1.1 Hz, 1H), 5.10 - 4.96 (m, 1H), 4.26 (d, / = 5.8 Hz, 2H), 4.13 (qd, / = 10.4, 5.1 Hz, 2H), 3.85 (s, 3H), 3.28 - 3.19 (m, 1H), 2.94 (dd, / = 17.5, 7.8 Hz, 1H).

Example- 148: N-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) thieno[2,3-c]pyridine-2-carboxamide(±).

(5-((2-(l -methyl- lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (prepared in step-2 of example-89) (0.200 g, 0.621 mmol) was reacted with thieno[2,3-c]pyridine-2-carboxylic acid (synthesis as per reported in WO2004039366) (0.167 g, 0.931 mmol) in the presence of EDCI.HCl (0.239 g, 1.242 mmol), HOBt (0.168 g, 1.242 mmol) and N,N-diisopropylethylamine (0.45 mL,2.483 mmol) in N,N-dimethylformamide (3 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.060 g,21.66 %) as a solid. LCMS: m/z 448.3 [M+H] ⁺; HPLC: 94.53 %; H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.55 (d, / = 5.5 Hz, 1H), 7.91 (d, / = 0.8 Hz, 1H), 7.83 (d, / = 0.8 Hz, 1H), 7.78 - 7.65 (m, 2H), 7.49 (d, / = 5.9 Hz, 1H), 7.42 (dd, / = 7.6, 1.7 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.00 (td, / = 7.5, 1.1 Hz, 1H), 6.90 (dd, / = 8.3, 1.1 Hz, 1H), 5.06 (ddd, / = 8.7, 6.9, 3.2 Hz, 1H), 4.41 (dd, / = 16.7, 5.6 Hz, 1H), 4.35 - 4.24 (m, 2H), 4.06 (dd, / = 10.4, 3.0 Hz, 1H), 3.92 (s, 3H), 3.22 (dd, / = 17.3, 11.5 Hz, 1H), 3.06 (dd, / = 17.2, 6.9 Hz, lH).

Example- 149: N-((5-(l-(2-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-l:tert-butyl ((5-(l-(2-bromophenoxy) ethyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

tert-butyl (2-(hydroxyimino) ethyl)carbamate (1.4 g, 7.046 mmol) was reacted with N- chlorosuccinimide (1.060 g, 7.962 mmol), l-bromo-2-(but-3-en-2-yloxy) benzene (1.60 g,7.046 mmol) (synthesized as per reported procedure in WO2011053821, Chem. Eur. journal 11, 5397-5407,2005) and triethylamine (1.08 mL,7.750 mmol) in N,N- dimethylformamide (25 mL) as described in the synthesis of step-3 of example- 1 to give the titled compound (0.800 g, 28.4%) as a liquid. LCMS: m/z 300.0 [M -100] ⁺.

Step-2: tert-butyl ((5-(l-(2-(l-methyl-lH-pyrazol-4-yl) phenoxy) ethyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-(l-(2-bromophenoxy) ethyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±) (0.400 g, 1.001 mmol) in toluene: water: ethanol (8:2:1) (14 mL) was added 1-methyl pyrazole-4-boronic acid pinacol ester (0.312 g, 1.502 mmol), followed by potassium carbonate (0.415 g, 3.005 mmol) and 1,1 '- bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.073 g, 0.100 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 5 h at 95°C. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (2 x 40 mL). The combined ethyl acetate layer was washed with water, brine solution (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 75/25) to give the titled compound (0.250 g, 62 %) as a liquid. LCMS: m z 401.55 [M+H] ⁺; H NMR (400 MHz, Chloroform-d) δ 7.91(s, 1H), 7.83- 7.79 (m, 1H), 7.74 (s, 1H), 7.54- 7.44 (m, 1H), 7.21 - 7.16 (m, 1H), 7.02 - 6.97 (m, 1H), 4.80 - 4.76 (m, 1H), 4.60 - 4.45 (m, 1H), 4.06 - 4.04 (m, 2H), 3.98 (s, 3H), 3.11 - 2.90(m,lH), 2.89 - 2.80 (m, 1H), 1.47 (s, 9H),1.41 - 1.35 (m, 3H).

Step-3: (5-(l-(2-(l-methyl-lH-pyrazol-4-yl) phenoxy) ethyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

tert-butyl ((5-(l-(2-(l-methyl-lH-pyrazol-4-yl) phenoxy) ethyl)-4, 5-dihydroisoxazol-3- yl) methyl) carbamate (±) (0.250 g, 0.624 mmol) was reacted with 4 N HC1 in 1 ,4- dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.201 g, crude) The crude product was taken to the next step without further purification.

Step-4: N-((5-(l-(2-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±).

To a stirred solution of imidazo [1, 2-a] pyridine-6-carboxylic acid (0.048 g, 0.296 mmol) and (5-(l-(2-(l-methyl-lH-pyrazol-4-yl) phenoxy) ethyl)-4, 5-dihydroisoxazol-3- yl) methanamine hydrochloride (±) (0.100 g, 0.296 mmol) in N,N-dimethylformamide (5.0 mL) was added EDCI.HC1 (0.063 g, 0.326 mmol), HOBt (0.052 g, 0.385 mmol) and triethylamine (0.123 mL, 0.890 mmol) at 0°C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 14 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate (2 x 20 mL) and washed with water (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 6/94) to give the titled compound (0.025g, 19%) as a solid. HPLC: 96.53 %; LCMS: m/z 445.0 [M+H] ⁺; H NMR (400 MHz, Chloroform-d) δ 8.91 (s, 1H), 8.69 (s, 1H), 7.89 - 7.59 (m, 5H), 7.42 - 7.38 (m, 2H), 7.23 - 7.19 (m, 1H), 7.10 - 6.94 (m, 2H), 4.85 - 4.45 (m, 2H), 4.19 - 4.16 (m, 2H), 3.95 - 3.92 (m, 3H), 3.18 - 3.07(m, lH), 2.89 - 2.80 (m, 1H), 1.56 - 1.35 (m, 3H).

Example- 150: iV-((5-((2-(iH-pyrazol-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo [l,2-a]pyridine-6-carboxamide(±).

Step-1: tert-butyl ((5-((2-(iH-pyrazol-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.298 mmol) in 1 ,4-dioxane: water (4: 1) (15 mL) was added (iH-pyrazol-5-yl)boronic acid (0.188 g, 1.687 mmol), followed by potassium carbonate (0.537 g, 3.894 mmol) and 1 ,1 ' -Bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (methanol/dichloromethane = 3/97) to give the titled compound (0.340 g, 70 %) as a sticky solid.

Step-2: (5-((2-(iH-pyrazol-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) .

tert4jutyl((5-((2-(iH-pyrazol-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl) carbamate (±) (0.340 g, 0.911 mmol) was reacted with 4N HQ in 1 ,4-dioxane as described in the synthesis of step-4 of example- 1 to give titled compound (0.230 g, 92%) as a solid. LCMS: m/z 273.2 [M+H] ⁺(Free base).

Step-3: N-((5-((2-(iH-pyrazol-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l ,2-a] pyridine-6-carboxamide(±).

(5-((2-(lH-pyrazol-5-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.120 g, 0.389 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.075 g, 0.467 mmol) in the presence of BOP reagent (0.189 g, 0.427 mmol) and Ν,Ν-diisopropylethylamine (0.337 mL, 1.945 mmol) in Ν,Ν- dimethylformamide (5 mL) at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 2.5/97.5) to give the titled compound (0.025 g, 15 %) as a sticky solid. LCMS: m z 417.3 [M+H] ⁺; HPLC: 95.95 %; H NMR (400 MHz, DMSO-d6) δ 12.82 (d, / = 13.5 Hz, 1H), 9.08 (s, 1H), 8.94 (d, / = 5.5 Hz, 1H), 8.05 - 8.00 (m, 1H), 7.88(s, 1H), 7.72 - 7.56 (m, 4H), 7.22 (s, lH), 7.04 (dd, / = 42.6, 16.8 Hz, 2H), 6.70 (d, / = 21.8 Hz, 1H), 4.95 (s, 1H), 4.22 - 4.02 (m, 4H), 3.15 (dd, / = 13.4, 4.3 Hz, lH), 2.90 (dd, / = 17.5, 7.2 Hz, 1H).

Example- 151: N-((5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo [1,2-a] pyridine-6-carboxamide (±).

Step-1: l-(2-methoxyphenyl)-lH- imidazole.

In a seal tube vessel, 2-bromoanisol (4.0 g, 21.38 mmol) was reacted with imidazole (1.61 g, 23.52 mmol) in the presence of hexamethylenetetramine (HMTA) (0.150 g, 1.07 mmol), Cul (0.204 g, 1.07 mmol) and potassium carbonate (5.9 g, 42.77 mmol) in N, N- dimethylformamide (30 mL) at 100 °C for 6 h. Then reaction mixture cooled to room temperature and diluted with ice water extracted with ethyl acetate (3 x 50 mL), separated the ethyl acetate layer and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude. This crude was purified by column chromatography on silica gel (dichloromethane/methanol = 95/5) to give titled compound (2.0 g, 54%) as a solid.LCMS: m z 175.05 [M+H] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 7.80 - 7.74 (m, 1H), 7.40 - 7.30 (m, 1H), 7.27 (ddd, / = 8.6, 3.9, 1.8 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.04 (ddq, / = 9.7, 6.1 , 2.2, 1.8 Hz, 2H), 3.95 - 3.75 (m, 3H).

Step-2: 2-(lH-imidazol-l-yl) phenol.

To a solution of l-(2-methoxyphenyl)-lH- imidazole (1.3 g, 7.46 mmol) in dry dichloromethane (20 mL) was added boron tribromide (1.8 mL, 14.92 mmol) (diluted with 10 mL of dry dichloromethane) slowly at -10 °C and the resulting mixture was stirred for 8 h at room temperature. Then reaction mixture was diluted with dichloromethane (50 mL) and washed with 10% sodium bicarbonate solution, separated the dichloromethane layer, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (dichloromethane/methanol = 94/6) to give titled compound (0.510 g, 46 %) as a solid.LCMS: m/z 161.0 [M+H] ⁺; 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.93 (s, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.33 (dd, J = 7.8, 1.7 Hz, 1H), 7.22 (td, J = 7.8, 1.7 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.90 (td, J = 7.6, 1.4 Hz, 1H). Step-3: l-(2-(allyloxy) phenyl)- 1H- imidazole.

2-(lH-imidazol-l-yl) phenol (0.500 g, 3.120 mmol) was reacted with ally bromide (0.320 g, 3.740 mmol) in the presence of potassium carbonate (1.29 g, 9.36 mmol) and KI (0.052 g, 0.312 mmol) in acetone (50 mL) at reflux temperature for 8 h. Then reaction mixture was cool to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (dichloromethane/methanol = 97/3) to give titled compound (0.215 g, 35%) as a solid. LCMS: m z 201.1 [M+H] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 7.90 - 7.80 (s, 1H), 7.40 - 7.30 (m, 1H), 7.27 (ddd, / = 8.6, 3.9, 1.8 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.04 (ddq, / = 9.7, 6.1, 2.2, 1.8 Hz, 2H),6.00-5.80 (m, 1H), 5.40-5.20 (m, 2H), 4.60-4.50(m, 2H).

Step-4: tert-butyl ((5-((2-(l H-imidazol- 1 -yl)phenoxy)methyl)-4,5 -dihydroisoxazol-3 - yl)methyl)carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (0.750 g, 4.305 mmol) in N, N-dimethylformamide (20 mL) was added N-chlorosuccinimide (0.650 g, 4.865 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h then cooled to 0 °C and added l-(2-(allyloxy) phenyl)- lH-imidazole (0.862 g, 4.305 mmol) in one lot followed by drop wise addition of solution of triethylamine (0.66 mL, 4.720 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured into water at room temperature, extracted with ethyl acetate (2 x 50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue obtained was purified by column chromatography on silicagel (dichloromethane/methanol = 97/3) to give titled compound (0.400 g, 25%) as a solid. LCMS: m/z 373.3 [M+H] ⁺. Step-5: (5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

To a solution of tert-butyl((5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (0.400 g, 1.074 mmol) in diethyl ether (20 mL) was added ethereal HC1 (10 mL) at 0 °C under inert atmosphere, and then stirred for 12 h at room temperature. Then reaction mixture concentrated under reduced pressure to give solid. This solid was triturated with dry diethyl ether (2 x lOmL) to give titled compound (0.200 g, 61 %) as solid. LCMS: m/z 273.1 [M+ H] ⁺ (Free base).

Step-6: N-((5-((2-(lH midazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine- 6 -carboxamide (±).

(5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.130 g, 0.421 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.102 g, 0.631 mmol) in the presence of EDCI.HC1 (0.162 g, 0.842mmol), HOBt (0.114 g, 0.842 mmol) and N,N-diisopropylethylamine (0.31 mL, 1.684 mmol) in N,N-dimethylformamide (4 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.050 g, 29 %) as a solid. LCMS: m/z 416.9 [M+H] ⁺; HPLC: 96.69 %; H NMR (400 MHz, Chloroform-d) δ 9.08 (dt, / = 1.8, 1.0 Hz, 1H), 8.89 (t, /= 6.0 Hz, 1H), 7.90 (dt, /= 9.5, 1.3 Hz, 1H), 7.86 - 7.82 (m, 1H), 7.70 - 7.60 (m, 3H), 7.37 - 7.26 (m, 2H), 7.12 - 7.02 (m, 3H), 6.97 (dt, / = 8.3, 1.0 Hz, 1H), 4.93 (ddd, / = 8.6, 6.6, 3.6 Hz, 1H), 4.40 (dd, / = 16.7, 5.8 Hz, 1H), 4.31 (dd, / = 10.4, 2.1 Hz, 1H), 4.20 - 4.09 (m, 1H), 3.97 (dd, / = 10.3, 1.5 Hz, 1H), 3.22 - 3.02 (m, 1H), 2.89 (dd, / = 17.3, 6.5 Hz, 1H). Further the enantiomeric mixture (0.040 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 151a & 151b). Method: Column: Cellulose-C4, n-hexane (A): ethanol (B), Isocratic (20:80), Flow Rate: 7 mL/min. Example- 151a: N-((5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide.

Yield:0.010 g; HPLC: 95.95 ; LCMS: m/z 417.5 [M+H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 9.11 (s, 1H), 8.90 (s, 1H), 7.92 (d, / = 9.1 Hz, 1H), 7.86 (s, 1H), 7.74 - 7.61 (m, 3H), 7.40 - 7.29 (m, 2H), 7.10 (dd, / = 15.6, 8.0 Hz, 3H), 7.00 (d, / = 8.3 Hz, 1H), 4.95 (dd, / = 11.8, 6.4 Hz, 1 H), 4.50 - 4.38 (m, 1H), 4.34 (dd, / = 10.4, 2.0 Hz, 1H), 4.18 (dd, / = 16.6, 5.9 Hz, 1H), 4.00 (d, / = 10.3 Hz, 1H), 3.16 (dd, / = 17.2, 11.8 Hz, 1H), 2.91 (dd, / = 17.3, 6.4 Hz, 1H).

Example- 151b: N-((5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide.

Yield: 0.005 g; HPLC: 93.43 %;; LCMS: m/z 417.5 [M+H] ⁺ ; 1H NMR (400 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.90 (t, / = 5.8 Hz, 1H), 7.92 (dd, / = 9.3, 1.7 Hz, 1H), 7.86 (s, 1H), 7.73 - 7.61 (m, 3H), 7.40 - 7.29 (m, 2H), 7.16 - 7.04 (m, 3H), 7.00 (dd, / = 8.2, 1.3 Hz, 1H), 4.95 (dd, / = 11.8, 6.5 Hz, 1H), 4.48 - 4.27 (m, 2H), 4.18 (dd, / = 16.7, 6.2 Hz, 1H), 4.00 (dd, / = 10.3 , 1.6 Hz, 1H), 3.16 (dd, / = 17.2, 11.8 Hz, 1H), 2.91 (dd, / = 17.3, 6.5 Hz, 1H).

Example- 152: N-((5-((2-(lH-pyrrol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

To a solution of (5-((2-(lH-pyrrol-l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.240 g, 0.880 mmol) and imidazo[l ,2-a]pyridine-6- carboxylic acid (0.216 g, 1.320 mmol) in N,N-dimethylformamide (4 mL) was added EDCI (0.340 g, 1.760 mmol), HOBT (0.240 g, 1.760 mmol) and N,N- diisopropylethylamine (0.460 mL, 2.640 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3x50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 4/96) to give the titled compound (0.030 g, 8 %) as a solid. HPLC: 99.8 %; LCMS : m/z 416.4 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.65 (dd, / = 1.8, 1.0 Hz, 1H), 7.71 (d, / = 1.3 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.35 (dd, / = 9.4, 1.8 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.28 - 7.22 (m, 2H), 7.10 - 6.95 (m, 2H), 6.31 (t, / = 2.2 Hz, 2H), 6.23 (s, 1H). 4.99 (d, / = 8.8 Hz, 1H), 4.50 (dd, / = 16.5, 6.9 Hz, 1H), 4.39 - 4.23 (m, 1H), 4.17 (dd, / = 16.1, 4.2 Hz, 1H), 4.06 - 3.86 (m, 1H), 3.12 (dd, / = 17.3, 11.7 Hz, 1H), 3.02 - 2.80 (m, 1H).

Example- 153: N-((5-((2-(iH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

(5-((2-(iH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (prepared in step-6 of example-98) (0.100 g, 0.323 mmol) was reacted with imidazo[l ,2-a]pyridine-6-carboxylic acid (0.062 g, 0.388 mmol) in the presence of BOP reagent (0.171g, O.388mmol) and N,N-diisopropylethylamine (0.168 mL, 0.969 mmol) in N,N-dimethylformamide (3 mL) at room temperature for 16h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (30 mL) and washed with water (4 x 30 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (methanol/dichloromethane = 4/96) to give titled compound (0.048 g, 35%) as a solid. LCMS: m/z 417.1 [Μ+Η] ⁺; HPLC: 92.30 %; H NMR (600 MHz, DMSO-d6) δ 9.15 (t, / = 1.4 Hz, 1H), 8.99 (t, / = 5.7 Hz, 1H), 8.22 (d, / = 2.5 Hz, 1H), 8.12 - 8.07 (m, lH), 7.72 - 7.61 (m, 5H), 7.34 (ddd, / = 9.0, 7.4, 1.7 Hz, 1H), 7.26 (dd, / = 8.4, 1.3 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.50 (t, / = 2.1 Hz, 1H), 4.94 (dp, / = 10.7, 3.5 Hz, 1H), 4.24 - 4.20 (m, 3H), 4.13 (dd, / = 10.5, 5.9 Hz, 1H), 3.23 - 3.14 (m, 1H), 2.90 (dd, / = 17.6, 7.4 Hz, 1H). Further the enantiomeric mixture (0.048 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 153a & 153b). Method: Column: CHIRAL PAK AD-H, n-hexane (A): ethanol (B), ISOCRATIC (40:60); Flow Rate: 6 mL/min.

Example- 153a: N-((5-((2-(iH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide .

Yield: 0.009 g; HPLC: 96.52 %; Chiral HPLC: 98.19%; LCMS: m/z 417.3 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO-d6) δ 9.13 (t, / = 1.3 Hz, 1H), 8.96 (t, / = 5.7 Hz, 1H), 8.20 (d, / = 2.5 Hz, 1H), 8.08 (d, / = 1.2 Hz, 1H), 7.73 - 7.60 (m, 5H), 7.37 - 7.29 (m, 1H), 7.25 (dd, / = 8.4, 1.3 Hz, 1H), 7.15 - 7.04 (m, 1H), 6.49 (t, / = 2.1 Hz, 1H), 4.97 - 4.89 (m, 1H), 4.23 (dd, / = 10.1, 4.2 Hz, 3H), 4.12 (dd, / = 10.6, 5.9 Hz, 1H), 3.21 - 3.09 (m, 1H), 2.89 (dd, / = 17.5, 7.5 Hz, 1H).

Example- 153b: N-((5-((2-(iH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide .

Yield: 0.009 g; HPLC: 98.19%; Chiral HPLC: 98.18%;; LCMS: m/z 417.4 ; ^lU NMR (400 MHz, DMSO-d6) δ 9.13 (t, / = 1.4 Hz, 1H), 8.96 (t, / = 5.6 Hz, 1H), 8.20 (d, / = 2.4 Hz, 1H), 8.12 - 8.03 (m, 1H), 7.72 - 7.58 (m, 5H), 7.33 (td, / = 7.9, 7.3, 1.7 Hz, 1H), 7.25 (dd, / = 8.5, 1.4 Hz, 1H), 7.09 (td, / = 7.7, 1.4 Hz, 1H), 6.49 (t, / = 2.1 Hz, 1H), 4.96 - 4.86 (m, 1H). 4.27 - 4.17 (m, 3H), 4.12 (dd, / = 10.6, 5.8 Hz, 1H), 3.18 (dd, / = 17.6, 11.1 Hz, 1H), 2.89 (dd, / = 17.5, 7.4 Hz, 1H).

Example- 154: N-((5-((2-(pyrimidin-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo [l,2-a]pyridine-6-carboxamide (±).

Step-l:tert-butyl ((5-((2-(pyrimidin-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) .

To a previously degassed solution of tert-butyl((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.290 mmol) in toluene : ethanol (1 :1) (10 mL) was added pyrimidin-5-yl boronic acid (0.240 g, 1.930 mmol), followed by potassium carbonate (0.530 g, 3.870 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.150 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 12 h at 1 10 °C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 50/50) to give the titled compound (0.150 g, 30.1 %) as a solid. ¾ NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.91 (d, / = 0.8 Hz, 2H), 7.46 - 7.36 (m, 2H), 7.17 - 7.12 (m, 1H), 7.01 (d, / = 8.2 Hz, 1H), 5.97 (s, 1H), 4.94 (ddd, / = 10.9, 7.7, 3.2 Hz, 1H), 4.30 - 4.23 (m, 1H), 4.09 (dd, / = 10.4, 2.7 Hz, 1H), 4.03 (d, / = 6.2 Hz, 2H), 3.11 (dd, / = 17.5, 11.4 Hz, 1H), 3.00 (dd, / = 17.5, 7.7 Hz, 1H), 1.45 (s, 9H).

Step-2: (5-((2-(pyrimidin-5-yl)phenoxy)methyl)-4,5-dmydroisoxazol-3-yl)methanamine hydrochloride (±) .

tert-butyl((5-((2-(pyrimidin-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.150 g, 0.39 mmol) was reacted with 4 N HCl in 1 ,4-dioxane as described in the synthesis of step-2 of example- 130 to give titled compound (0.075 g, crude).

Step-3: N-((5-((2-(pyrimidin-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±).

(5-((2-(pyrimidin-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.075 g, 0.233 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.045 g, 0.280 mmol) in the presence of EDCI.HCl (0.053 g, 0.280 mmol), HOBt (0.048 g, 0.349 mmol) and N,N-diisopropylethylamine (0.129 g, 0.932 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.020 g, 20.0 %) as a solid. HPLC: 98.64 %; LCMS: m/z 429.1 [M+H] +; ^lU NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 8.99 (d, / = 1.6 Hz, 1H), 8.94 (s, 1H), 8.70 (t, / = 5.9 Hz, 1H), 7.76 (dd, / = 9.4, 1.8 Hz, 1H), 7.72 - 7.60 (m, 3H), 7.41 (ddd, / = 16.7, 7.8, 1.7 Hz, 2H), 7.14 (t, / = 7.5 Hz, 1H), 6.98 (d, / = 8.3 Hz, lH), 5.00 (ddt, / = 11.2, 6.6, 2.0 Hz, lH), 4.41 (dd, / = 16.7, 5.9 Hz, 1H), 4.33 - 4.19 (m, 2H), 4.10 (dd, / = 10.3, 1.9 Hz, 1H), 3.48 (q, / = 7.0 Hz, 1H), 3.25 (dd, / = 17.5, 11.9 Hz, 1H), 3.06 (dd, / = 17.5, 6.9 Hz, 1H).

Example- 155 : N-((5-((2-(pyridin-3 -yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methyl) imidazo[l,2-a] pyridine-6-carboxamide (±) Step-1: tert-butyl ((5-((2-(pyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.290 mmol) in 1 ,4-dioxane: water (4:1) (8 mL) was reacted with pyridin-3-ylboronic acid (0.314 g, 2.580 mmol) in the presence of potassium carbonate (0.530 g,3.871 mmol) and [1,1 '-Bis (diphenylphosphino) ferrocene] dichloropaUadium (II) (0.105 g, 0.129 mmol) at 110 °C for 12 h as described in the synthesis of step-2 of example-121 to give the titled compound (0.450 g, 91.8 %) as a solid.

tert-butyl ((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.450 g, 1.170 mmol) was reacted with 4 N HQ in 1 ,4-dioxane (10 mL) at 0 °C as described in the synthesis of step-3 ofexample-121 to give titled compound (0.250 g, crude ).

Step-3: N-((5-((2-(pyridin-3-yl) phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±).

(5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.700 g, 0.196 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.035 g, 0.216 mmol) in the presence of EDCI.HC1 (0.045 g, 0.235mmol), HOBt (0.040 g, 0.294 mmol) and N,N-diisopropylethylamine (0.126 g, 0.980 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.015 g, 18 ) as a solid. LCMS: m/z 428.1 [M+H] ⁺; HPLC: 98.5 %; H NMR (400 MHz, Chloroform-d) δ 9.42 (s, 1H), 9.08 - 9.01 (m, 1H), 8.85 (dd, / = 2.2, 0.9 Hz, 1H), 8.53 (dd, / = 4.9, 1.6 Hz, 1H), 7.90 - 7.77 (m, 2H), 7.71 - 7.57 (m, 3H), 7.45 (dd, / = 7.9, 5.0 Hz, 1H), 7.37 (t, / = 7.6 Hz, 2H), 7.14 - 7.05 (m, 1H), 6.95 (d, / = 8.1 Hz, 1H), 4.98 (dd, / = 11.8, 7.0 Hz, 1H), 4.43 (dd, / =

16.3, 6.9 Hz, 1H), 4.30 - 4.18 (m, 2H), 4.08 (dd, / = 10.4, 1.6 Hz, 1H), 3.30 - 3.08 (m, 2H).

Further the enantiomeric mixture (0.680 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 155a & 155b). Method: Column: CELLULOSE C-4, n-hexane (A): methanol (B): ISOCRATIC (10:90), Flow: 6 mL/min.

Example- 155a: N-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide.

Yield: 0.300 g; HPLC: 98.72%; LCMS: m/z 428.50 [M+H] ⁺ ; H NMR (600 MHz, Chloroform-d) δ 9.41 (t, / = 6.1 Hz, 1H), 9.05 - 8.99 (m, 1H), 8.84 - 8.78 (m, 1H), 8.49 (dd, / = 4.9, 1.6 Hz, 1H), 7.84 (dd, / = 9.5, 1.8 Hz, lH), 7.77 (dt, / = 7.9, 1.9 Hz, 1H), 7.67 - 7.57 (m, 3H), 7.42 (dd, / = 7.9, 4.9 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.06 (td, / = 7.6, 1.1 Hz, 1H), 6.91 (d, / = 8.1 Hz, 1H), 4.94 (ddt, / = 10.6, 6.7, 1.9 Hz, 1H), 4.38 (dd, / =

16.4, 6.8 Hz, 1H), 4.24 - 4.15 (m, 2H), 4.04 (dd, / = 10.3, 1.7 Hz, 1H), 3.25 - 3.05 (m, 2H).

Example- 155b : N-((5-((2-(pyridin-3 -yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methyl) imidazo[l,2-a] pyridine-6-carboxamide.

Yield: 0.210 g; Chiral HPLC: 98.39%; HPLC: 99.17 %; LCMS: m/z 428.50 [M+H] ⁺ ; ^lU NMR (600 MHz, Chloroform-d) δ 9.42 (t, / = 6.1 Hz, 1H), 9.05 (t, / = 1.3 Hz, 1H), 8.84 (d, / = 2.1 Hz, 1H), 8.52 (dd, / = 4.9, 1.6 Hz, 1H), 7.86 (dd, / = 9.5, 1.8 Hz, 1H), 7.80 (dt, / = 7.9, 1.9 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.45 (dd, / = 8.0, 5.0 Hz, 1H), 7.39 - 7.32 (m, 2H), 7.09 (td, / = 7.5, 1.0 Hz, 1H), 6.94 (d, / = 8.2 Hz, 1H), 4.97 (ddt, / = 10.3, 6.7, 1.9 Hz, 1H), 4.42 (dd, / = 16.4, 6.9 Hz, 1H), 4.27 - 4.19 (m, 2H), 4.07 (dd, / = 10.3, 1.6 Hz, 1H), 3.23 (dd, / = 17.5, 12.0 Hz, 1H), 3.13 (dd, / = 17.5, 6.9 Hz, 1H).

Example- 156: N-((5-((2-(6-methylpyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-((2-(6-methylpyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methyl)carbamate (+).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step- 1 of example-23) (0.200 g, 0.519 mmol) in l ,4-dioxane:water (3 : 1) (10 mL) was added 2-methyl-5-(4 ,4,5,5- tetramethyl- l ,3-dioxolan-2-yl)pyridine (0.125 g, 0.571 mmol), followed by potassium carbonate (0.215 g, 1.550 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.060g, 0.052mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (2 x 50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate / hexanes = 0/100 to 80/20) to give the titled compound (0.0198 g, 96 ) as a solid. LCMS: nt/z 397.8 [M+ H] ⁺.

Step-2: (5-((2-(6-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) .

To a solution of tert-butyl ((5-((2-(6-methylpyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±) (0.190 g, 0.478 mmol) in diethyl ether (10 mL) was added ethereal HC1 (5 mL) at 0°C under inert atmosphere, and then stirred for 12 h at room temperature. Then reaction mixture concentrated under reduced pressure to give solid. This solid was triturated with dry diethyl ether (2 x lOmL) to give titled compound (0.150 g, 94%) as solid.LCMS: nt/z 298.1 [M+ H] ⁺ (Free base).

Step-3: N-((5-((2-(6-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a] pyridine-6-carboxamide (±).

(5-((2-(6-methylpyridin-3-yl)phenoxy)methyl)-4,5-dmydroisoxazol-3-yl)methanamine hydrochloride (±) (0.159 g, 0.476 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.092 g, 0.572 mmol) in the presence of EDCI.HC1(0.183 g, 0.952 mmol), HOBt (0.128 g, 0.952 mmol) and N,N-diisopropylethylamine (0.34 mL, 1.910 mmol) in N,N-dimethylformamide (4 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (O. lOOg, 47.61 %) as a solid. LCMS: m/z 442.1 [M+H] ⁺; HPLC: 98.88 ; 1H NMR (400 MHz, Chloroform-d) δ 9.75 (t, / = 6.1 Hz, 1H), 9.08 (dt, / = 1.9, 1.0 Hz, 1H), 8.74 (dd, / = 2.3, 1.0 Hz, 1H), 7.90 (dt, / = 9.5, 1.3 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.65 - 7.56 (m, 2H), 7.38 - 7.29 (m, 3H), 7.09 (tt, / = 7.6, 1.1 Hz, 1H), 6.95 - 6.90 (m, 1H), 4.99 (dd, / = 11.6, 7.2 Hz, 1H), 4.50 (dd, / = 16.2, 7.2 Hz, 1H), 4.25 - 4.13 (m, 2H), 4.08 (dd, / = 10.4, 1.6 Hz, 1H), 3.29 - 3.10 (m, 2H), 2.61 (s, 3H).

Example- 157: N-((5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide (±) .

To a suspension of imidazo [1,2- a] pyridine-6-carboxylic acid (0.076 g, 0.471 mmol) and (5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine dihydrochloride (±) (0.150 g, 0.428 mmol) in N,N-dimethylformamide (4 mL) was added EDCI.HC1 (0.099 g, 0.514 mmol), HOBt (0.081 g, 0.600 mmol) and N,N-diisopropylethylamine (0.200 mL, 1.286 mmol) at 0°C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate (2 x 20 mL). The combined ethyl acetate layer was washed with water, brine solution (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (methanol/dichloromethane = 6/94) to give the titled compound (0.080 g, 42%) as a solid. HPLC: 96.59 %; LCMS: m/z 458.2 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.80 (dt, / = 1.6, 0.8 Hz, 1H), 8.20 - 8.17 (m, 1H), 7.74 - 7.63 (m, 3H), 7.44 - 7.31 (m, 3H), 7.12 - 7.06 (m, 2H), 6.99 - 6.90 (m, 2H), 6.62 - 6.54 (m, 1H),4.97 (ddd, / = 10.7, 7.0, 3.4 Hz, 1H), 4.36 - 4.15 (m, 3H), 4.09 - 4.02 (m, lH),3.94(s,3H), 3.12 (dd, / = 17.2, 11.3 Hz, 1H), 2.97 (dd, /

Hz, 1H).

Example- 158: N-((5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide(±).

(5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.150 g, 0.428 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.097 g, 0.600 mmol) in the presence of EDCI.HC1 (0.098 g, 0.513 mmol), HOBt (0.075 g, 0.556 mmol) and N,N-diisopropylethylamine (0.165 g, 1.284 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.040 g, 20 %) as a solid. LCMS: m/z 458.2 [M+H] ⁺; HPLC: 96.00 ; H NMR (400 MHz, DMSO-d6) δ 9.14 (t, / = 1.4 Hz, 1H), 8.95 (t, / = 5.7 Hz, 1H), 8.40 (d, / = 5.7 Hz, 1H), 8.20 (s, 1H), 8.08 (d, / = 1.3 Hz, 1H), 7.68 - 7.59 (m, 3H), 7.35 (ddd, / = 9.2, 7.5, 1.8 Hz, 1H), 7.19 (dd, J = 7.5, 1.8 Hz, 1H), 7.09 (dd, / = 7.1, 3.8 Hz, 2H), 7.01 (td, J = 7.4, 1.0 Hz, 1H), 4.78 - 4.69 (m, 1H), 4.14 - 3.94 (m, 4H), 3.79 (s, 3H), 3.04 (dd, / = 17.4, 10.9 Hz, 1H), 2.73 (dd, / = 17.5, 7.3 Hz, 1H).

Example- 159: N-((5-((2-(2-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

To a suspension of imidazo [1 , 2-a] pyridine-6-carboxylic acid (0.079 g, 0.488 mmol) and (5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine dihydrochloride (±) (0.150 g, 0.444 mmol) in N,N-dimethylformamide (4 mL) was added EDCI.HC1 (0.102 g, 0.532 mmol), HOBt (0.084 g, 0.621 mmol) and N,N-diisopropylethylamine (0.230 mL, 1.332 mmol) at 0°C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 14 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate (2 x 20 mL). The combined ethyl acetate layer was washed with water, brine solution (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (methanol/dichloromethane =5/95) to give the titled compound (0.060 g, 30%) as a solid. HPLC: 98.98 %; LCMS: m/z 446.1 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 9.01 (t, / = 1.4 Hz, 1H), 8.24 - 8.15 (m, 2H), 7.82 - 7.75 (m, 2H), 7.68 - 7.60 (m, 3H), 7.42 - 7.26 (m, 3H), 7.06 (tt, / = 7.6, 0.6 Hz, lH), 6.90 (d, / = 8.4 Hz, 1H), 4.90 (ddt, / = 11.7, 7.1, 2.2 Hz, 1H), 4.62 (dd, / = 16.4, 7.7 Hz, 1H), 4.13 - 4.01 (m, 3H), 3.18 (qd, / = 17.5, 9.4 Hz, 2H). Further the enantiomeric mixture (0.040 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 159a & 159b). Method: Column: CHIRALPAK AD-H; n-hexane (A): ethanol (B), Isocratic (40:60); Flow Rate: 5 mL/Min).

Example-159a: N-((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide.

Yield: 0.015 g; Retention Time: 13.44 min.; Chiral HPLC: 99.74 %; HPLC: 99.21 %; LCMS: m/z 446.55 [M+ H] ⁺; H NMR (400 MHz, Chloroform-d) δ 9.02 (t, / = 1.3 Hz, 1H), 8.27 - 8.15 (m, 2H), 7.84 - 7.76 (m, 2H), 7.71 - 7.61 (m, 3H), 7.40 (td, / = 8.0, 1.8 Hz, 1H), 7.33 (ddd, / = 7.1, 5.0, 1.9 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.08 (dd, / = 8.0, 7.0 Hz, 1H), 6.92 (d, / = 8.2 Hz, 1H), 4.93 (dt, / = 9.5, 2.2 Hz, 1H), 4.64 (dd, / = 16.4, 7.6 Hz, 1H), 4.16 - 4.04 (m, 3H), 3.30 - 3.11 (m, 2H).

Example- 159b: N-((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide .

Yield: 0.016 g; Retention Time: 16.34 min ; Chiral HPLC: 99.60 %;HPLC: 99.40 %; LCMS: m/z 446.60 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 9.02 (t, / = 1.3 Hz, 1H), 8.23 (s, 1H), 8.20 - 8.16 (m, 1H), 7.85 - 7.75 (m, 2H), 7.70 - 7.62 (m, 3H), 7.43 - 7.37 (m, 1H), 7.33 (ddd, / = 7.1, 4.9, 1.8 Hz, 1H), 7.29 (d, / = 1.8 Hz, 1H), 7.08 (td, / = 7.5, 1.0 Hz, 1H), 6.92 (d, / = 8.2 Hz, 1H), 4.92 (ddd, / = 11.5, 5.8, 3.6 Hz, 1H), 4.64 (dd, / = 16.4, 7.5 Hz, 1H), 4.15 - 4.04 (m, 3H), 3.19 (qd, / = 17.5, 9.4 Hz, 2H).

Example- 160: N-((5-((2-(5-methylpyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

To a solution of (5-((2-(5-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (0.150 g, 0.449 mmol) and imidazo[l ,2-a]pyridine-6- carboxylic acid (0.110 g, 0.670 mmol) in N,N-dimethylformamide (3 mL) was added EDCI.HC1 (0.170 g, 0.898 mmol) HOBT (0.120 g, 0.898 mmol) and N,N- diisopropylethylamine (0.31 mL, 1.790 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (250 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 4/96) to give the titled compound (0.070 g, 35%) as a solid. HPLC: 97.26 %; LCMS: m/z 442.2 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 9.58 (s, 1H), 9.09 - 9.02 (m, 1H), 8.64 (s, 1H), 8.35 (d, / = 2.0 Hz, 1H), 7.87 (dd, / = 9.4, 1.7 Hz, 1H), 7.72 - 7.55 (m, 4H), 7.40 - 7.31 (m, 2H), 7.08 (t, / = 7.5 Hz, 1H), 6.92 (d, / = 8.6 Hz, 1H), 5.04 - 4.89 (m, 1H), 4.46 (dd, / = 16.1 , 7.1 Hz, 1H), 4.28 - 4.14 (m, 2H), 4.06 (d, / = 10.2 Hz, 1H), 3.19 (qd, / = 17.6, 9.4 Hz, 2H), 2.42 (s, 3H).

Example- 161: N-((5-((2-(2-methoxypyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

To a suspension of imidazo [1,2-a] pyridine-6-carboxylic acid (0.076 g, 0.471 mmol) and (5-((2-(2-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.150 g, 0.428 mmol) in N,N-dimethylformamide (4 mL) was added EDCI (0.099 g, 0.514 mmol), HOBt (0.081 g, 0.600 mmol) and N,N- diisopropylethylamine (0.20 mL, 1.286 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate (2 x 20 mL). The combined ethyl acetate layer was washed with water, brine solution (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (methanol/dichloromethane =6/94) to give the titled compound (0.061 g, 30%) as a solid. HPLC: 95.69 %; LCMS: m/z 458.3 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.89 (dd, / = 1.8, 1.0 Hz, 1H), 8.12 (dd, / = 5.1 , 1.9 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.60 (dd, / = 9.4, 1.8 Hz, 2H), 7.56 - 7.51 (m, 2H), 7.36 (ddd, / = 8.1 , 7.4, 1.8 Hz, 1 H), 7.07 (td, / = 7.5, 1.0 Hz, 1H), 6.97 - 6.92 (m, 2H), 6.90 (s, 1H), 4.91 (ddt, / = 11.6, 6.1 , 3.0 Hz, lH), 4.31 (dd, / = 17.5 , 6.1 Hz, 1H), 4.19 (dd, / = 10.2, 3.2 Hz, 1H), 3.98 (dd, / = 10.2, 2.8 Hz, 1H), 3.91 (d, / = 0.5 Hz, 3H), 3.77 (dd, / = 17.5, 4.7 Hz, 1H), 3.01 (dd, / = 17.0, 11.3 Hz, 1H), 2.82 (dd, / = 17.0, 6.3 Hz, 1H).

Further the enantiomeric mixture (0.050 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 161 a & 161 b). Method: Column: CHIRALPAK AD-H; n-hexane (A): ethanol (B), Isocratic (40:60); Flow Rate: 5 mL/Min.

Example- 161a: N-((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide.

Yield: 0.014 g; Retention Time: 10.11 min. ; Chiral HPLC: 99.55 ; HPLC: 97.45 ; LCMS: m/z 458.50 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.89 (dd, / = 1.9, 1.0 Hz, 1H), 8.12 (dd, / = 5.0, 1.9 Hz, 1H), 7.74 - 7.64 (m, 3H), 7.62 - 7.51 (m, 2H), 7.36 (ddd, / = 8.2, 7.4, 1.8 Hz, 1H), 7.24 (d, / = 1.8 Hz, 1H), 7.06 (td, / = 7.5, 1.1 Hz, 1H), 6.98 - 6.91 (m, 2H), 6.88 (t, / = 5.4 Hz, 1H), 4.90 (ddt, / = 1 1.7, 6.1 , 2.9 Hz, 1H), 4.33 - 4.16 (m, 2H), 3.97 (dd, / = 10.2, 2.7 Hz, 1H), 3.76 (dd, / = 17.5, 4.7 Hz, 3H), 3.49 (t, / = 7.0 Hz, 1H), 3.00 (dd, / = 17.0, 11.3 Hz, 1H), 2.81 (dd, / = 17.0, 6.2 Hz, 1H). Example- 161b: N-((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide.

Yield: 0.015 g; Retention Time: 15.66 min. ; HPLC: 99.35 ; HPLC: 98.30 ; LCMS : m/z 458.25 [M+ H] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.89 (t, / = 1.3 Hz, 1H), 8.12 (dd, / = 5.1, 1.9 Hz, 1H), 7.74 - 7.65 (m, 3H), 7.62 - 7.48 (m, 2H), 7.40 - 7.32 (m, 1H), 7.24 (d, / = 1.8 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.98 - 6.91 (m, 2H), 6.88 (s, 1H), 4.90 (ddt, / = 11.6, 5.9, 2.8 Hz, 1H), 4.32 - 4.17 (m, 2H), 3.97 (dd, / = 10.2, 2.8 Hz, 1H), 3.89(s,3H),3.76 (dd, / = 17.4, 4.6 Hz, 1H),3.01 (dd, / = 17.0, 11.3 Hz, 1H), 2.81 (dd, / = 17.0, 6.2 Hz, lH).

Example- 162: N-((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

(5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dmydroisoxazol-3-yl)methanamine hydrochloride (±) (prepared in step-2 of example-84) (0.300 g, 0.809 mmol) was reacted with imidazo[l ,2-a]pyridine-6-carboxylic acid (0.172 g, 1.067 mmol) in the presence of BOP reagent (0.393 g, 0.889 mmol) and N,N-diisopropylethylamine (0.313 g, 2.427 mmol) in N,N-dimethylformamide (6 mL) at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 3/97) to give titled compound (0.180 g, 49 %) as a solid. LCMS: m/z 446.3 [M+H] ⁺; HPLC: 97.25 ; ^lU NMR (400 MHz, Chloroform-d) δ 8.99 (dd, / = 2.0, 1.0 Hz, 1H), 8.44 (d, / = 2.4 Hz, 1H), 8.34 - 8.28 (m, 1H), 7.91 (td, / = 8.1 , 2.5 Hz, 1H), 7.76 - 7.61 (m, 4H), 7.40 - 7.30 (m, 2H), 7.11 - 7.03 (m, 2H), 6.96 (d, / = 8.3 Hz, 1H), 4.98 (ddt, / = 11.7, 7.0, 2.3 Hz, 1H), 4.40 (dd, / = 16.7, 5.9 Hz, 1H), 4.28 - 4.19 (m, 2H), 4.08 (dd, / = 10.3, 2.1 Hz, 1H), 3.22 (dd, / = 17.4, 11.7 Hz, 1H), 3.06 (dd, / = 17.4, 7.0 Hz, 1H).

Further the enantiomeric mixture (0.180 g) was separated by chiral preparative HPLC to give two separated enantiomers (example 162a & 162b). Method: Column: CELLULOSE -C4, n-hexane (A): ethanol (B), Isocratic (50:50), Flow Rate: 7 mL/Min. Example-162a: N-((5-((2-(6-fluoropyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide.

Yield: 0.050 g; LCMS: m/z 446.3 [M+H] ⁺; HPLC: 98.19 ; Chiral HPLC: 96.52%; H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.00 (t, / = 5.7 Hz, 1H), 8.37 (d, / = 2.6 Hz, 1H), 8.16 - 8.11 (m, 2H), 7.71 (dd, / = 20.6, 9.9 Hz, 3H), 7.40 (ddd, / = 7.7, 6.2, 1.8 Hz, 2H), 7.23 (dd, / = 8.5, 2.9 Hz, 1H), 7.17 (d, / = 8.7 Hz, 1H), 7.09 (t, / = 7.5 Hz, 1H), 4.89 - 4.84 (m, 1H), 4.19 - 4.05 (m, 4H), 3.14 (dd, / = 17.5, 11.0 Hz, 1H), 2.84 (dd, / = 17.5, 7.5 Hz, 1H).

Example- 162b: N-((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo [l,2-a]pyridine-6-carboxamide. Yield: 0.050 g; LCMS: m z 446.3 [M+H] ⁺; HPLC: 98.19 ; Chiral HPLC: 96.52%; ^lU NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.00 (t, / = 5.7 Hz, 1H), 8.37 (d, / = 2.6 Hz, 1H), 8.16 - 8.11 (m, 2H), 7.71 (dd, / = 20.6, 9.9 Hz, 3H), 7.40 (ddd, / = 7.7, 6.2, 1.8 Hz, 2H), 7.23 (dd, / = 8.5, 2.9 Hz, 1H), 7.17 (d, / = 8.7 Hz, 1H), 7.09 (t, / = 7.5 Hz, 1H), 4.89 - 4.84 (m, 1H), 4.19 - 4.05 (m, 4H), 3.14 (dd, / = 17.5, 11.0 Hz, 1H), 2.84 (dd, / = 17.5, 7.5 Hz, lH).

Example- 163: N-((5-((2-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo [l,2-a]pyridine-6-carboxamide(±).

Step-1: tert-butyl ((5-((2-(6-(trifiuoromethyl)pyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±).

To a previously degassed solution of tert-butyl((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.500 g, 1.290 mmol) in 1,4-dioxane: water (3:1) (10 mL) was added (6-(trifluoromethyl) pyridin- 3-yl)boronic acid (0.370 g, 1.930 mmol), followed by potassium carbonate (0.530 g, 3.870 mmol) and Pd(dppf)Cl₂-CH₂Cl₂ (0.105 g, 0.129 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 12 h at 110 °C. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 80/20) to give the titled compound (0.500 g, 85.0 %) as a solid.

Step-2: (5-((2-(6-(trifluoromemyl)pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine dihydrochloride (±).

tert-butyl ((5-((2-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl) carbamate (±) (0.500 g, 1.107 mmol) was reacted with 4N HC1 in 1 ,4- dioxane as described in the synthesis of step-2 of example- 130 to give the titled compound (0.300 g, crude).

Step-3: N-((5-((2-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo [l,2-a]pyridine-6-carboxamide (±).

(5-((2-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (0.120 g, 0.280 mmol) was reacted with imidazo[l ,2- a]pyridine-6-carboxylic acid (0.055 g, 0.339 mmol) in the presence of EDCI.HCl (0.065 g, 0.339 mmol), HOBt (0.058 g, 0.339 mmol) and N,N-diisopropylethylamine (0.144 g, 1.120 mmol) in N,N-dimethylformamide (2 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.020 g, 14.2 %) as a solid. LCMS: m/z 496.2 [M+H] ⁺; HPLC: 99.26 ; H NMR (400 MHz, Chloroform-d) δ 8.98 (dd, / = 1.9, 1.0 Hz, 1H), 8.89 (d, / = 2.0 Hz, 1H), 8.79 (s, 1H), 8.00 - 7.94 (m, 1H), 7.83 (d, / = 8.1 Hz, 1H), 7.74 (dd, / = 9.5, 1.8 Hz, 1H), 7.66 (d, / = 1.3 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.44 - 7.36 (m, 1H), 7.34 (dd, / = 7.6, 1.7 Hz, 1H), 7.10 (td, / = 7.6, 1.0 Hz, 1H), 6.96 (dd, / = 8.4, 1.0 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.53 (dd, / = 16.1 , 7.5 Hz, lH), 4.24 - 4.10 (m, 3H), 3.28 (dd, / = 17.6, 11.9 Hz, 1H), 3.14 (dd, / = 17.7, 7.4 Hz, 1H).

Example- 164: N-((5-((2-(6-(benzyloxy)pyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±) and

Example- 165: N-((5-((2-(6-hydroxypyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazole ,2-aJ pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-((2-(6-(benzyloxy)pyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) carbamate (±).

To a degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl)carbamate (±) (prepared in step- 1 of example-23) (0.500g, 1.300 mmol) in l ,4-dioxane:water (9: 1) (10 mL) was added 2-(benzyloxy) -5 -(4,4,5, 5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)pyridine (0.605 g, 1.950 mmol), followed by potassium carbonate (0.537g, 3.890 mmol) and l ,l ' -Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.106 g, 0.130 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate = 60/40) to give titled compound (0.500 g, 78%) as a solid. LCMS: nt/z 490.4 [M+ H] ⁺.

Step-2: (5-((2-(6-(benzyloxy)pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±) (2a) and 5-(2-((3-(aminomethyl)-4,5- dihydroisoxazol-5-yl)methoxy)phenyl)pyridin-2-ol hydrochloride^) (2b).

To a solution of tert-butyl((5-((2-(6-(benzyloxy)pyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) carbamate (±) (0.500 g, 1.021 mmol) in diethyl ether (20 mL) was added ethereal HC1 (20 mL) at 0°C under inert atmosphere, and then stirred for 12 h at room temperature. Then reaction mixture concentrated under reduced pressure to give solid. This solid was triturated with dry diethyl ether (2 x 10 mL) to give the mixture of titled compound 2a & 2b as crude compound (0.300 g, 69%) as solid.

2a: LCMS: nt/z 390.1 [M+ H] ⁺ (Free base).

2b: LCMS: nt/z 300.1 [M+ H] ⁺ (Free base).

Step-3: N-((5-((2-(6-(benzyloxy)pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide(±) (3a) and

N-((5-((2-(6-hydroxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l ,2-a] pyridine- 6 -carboxamide (±) (3b).

The crude mixture of 2a & 2b (0.350 g, 0.822 mmol) was reacted with imidazo[l,2- a]pyridine-6-carboxylic acid (0.199 g, 1.232 mmol) in the presence of EDCI.HC1 (0.316g, 1.643mmol), HOBt (0.222 g, 1.643 mmol) and N,N-diisopropylethylamine (0.59 mL,3-287 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110. The crude was separated by column chromatography to give the titled compound 3a (0.020g) and 3b (0.100 g) as a solid.

3a(Example-164): LCMS: m/z 534.2 [M+H] ⁺; HPLC: 95.26%; H NMR (400 MHz, DMSO-d6) 5 9.13 (s,lH), 8.94 (t, / = 5.6 Hz, 1H), 8.31 (t, / = 1.8 Hz, 1H), 8.06 (d, / = 1.3 Hz, 1H), 7.90 (dt, / = 8.6, 1.9 Hz, 1H), 7.68 - 7.57 (m, 3H), 7.49 - 7.42 (m, 2H), 7.41 - 7.27 (m, 5H), 7.13 (d, / = 8.2 Hz, 1H), 7.05 (t, / = 7.5 Hz, 1H), 6.92 (dd, / = 8.6, 1.3 Hz, 1H), 5.38 (d, / = 1.4 Hz, 2H), 4.86 (dt, / = 10.4, 4.9 Hz, 1H), 4.24 - 3.96 (m, 4H), 3.22 - 3.08 (m, 1H), 2.86 (dd, / = 17.2, 7.1 Hz, 1H).

3b(Example-165): LCMS: m/z 444.2 [M+H] ⁺; HPLC: 97.97%; H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H),9.14 (d, / = 1.4 Hz, lH), 8.97 (t, / = 5.8 Hz, 1H), 8.08 (s, 1H), 7.65 (ddd, / = 11.5, 6.0, 2.4 Hz, 4H), 7.50 (d, / = 2.7 Hz, 1H), 7.40 - 7.20 (m, 2H), 7.11 - 6.92 (m, 2H), 6.36 (d, / = 9.5 Hz, 1H), 4.87 (dq, / = 14.5, 5.5 Hz, 1H), 4.19 (d, / = 5.5 Hz, 2H), 4.07 (qd, / = 10.4, 4.6 Hz, 2H), 3.22 - 3.09 (m, 2H), 2.87 (dd, / = 17.5, 7.6 Hz, 1H).

Example- 166: N-((5-((2-(2-methylpyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-((2-(2-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol- 3-yl)methyl)carbamate (±).

In a sealed tube, a degassed solution of tert-butyl ((5-((2 jromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step- 1 of example-23) (0.200 g, 0.519 mmol) in 1 ,4-dioxane: water (9: 1) (10 mL) was added 2-methyl-3-(4,4,5,5- tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridine (0.125 g, 0.571 mmol), followed by potassium carbonate (0.108 g, 0.780 mmol) and l, l ' -Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.042 g, 0.0520 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (dichloromethane/methanol = 96/4) to give titled compound (0.195g, 94%) as a solid. LCMS: nt/z 398.2 [M+ H] ⁺.

Step-2: (5-((2-(2-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

To a solution of tert-butyl ((5-((2-(6-methylpyridin-3-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) carbamate (±) (0.200 g, 0.532 mmol) in diethyl ether (lOmL) was added ethereal HC1 (5 mL) at 0 °C under inert atmosphere, and then stirred for 12 h at room temperature. Then reaction mixture concentrated under reduced pressure to give solid. This solid was triturated with dry diethyl ether (2 x 10 mL) to give titled compound (0.160 g, 96%) as solid. LCMS: nt/z 298.1 [M+ H] ⁺ (Free base).

Step-3: N-((5-((2-(2-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±).

(5-((2-(2-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.160 g, 0.479 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.116 g, 0.719 mmol) in the presence of EDCI.HC1 (0.184 g, 0.958 mmol), HOBt (0.129 g, 0.958 mmol) and Ν,Ν-diisopropylethylamine (0.35mL, 1.917 mmol) in N,N-dimethylformamide (5 mL) as described in the synthesis of step-2 of example-110 to give the titled compound (0.130 g, 61 %) as a solid. LCMS: m/z 442.2 [M+H] ⁺; HPLC: 96.94%; H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.92 (t, / = 5.7 Hz, lH), 8.42 (dd, / = 4.9, 1.8 Hz, 1H), 8.11 (d, / = 1.3 Hz, 1H), 7.71 (d, / = 1.4 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.52 (dd, / = 7.7, 1.8 Hz, 1H), 7.39 (ddd, / = 8.6, 7.3, 1.9 Hz, 1H), 7.26 (dd, / = 7.7, 4.9 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.09 - 7.01 (m, 1H), 4.80 - 4.63 (m, 1H), 4.03 (q, / = 5.5, 4.9 Hz, 4H), 3.04 (dd, / = 17.5, 11.0 Hz, 1H), 2.66 (dd, / = 17.6, 6.9 Hz, lH), 2.27 (s, 3H).

Example- 167: N-((5-((2-(2-methylpyridin-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a] pyridine-6-carboxamide (±).

Step-1: 2-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) pyridine.

To a previously degassed solution of 4-bromo-2-methylpyridine (0.500 g, 2.906 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2^,-bi(l,3,2-dioxaborolane) (0.812 g, 3.997 mmol), potassium acetate (0.854 g, 8.720 mmol) in 1 ,4-dioxane (5mL) in 50 mL sealed tube was added [l ,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.021 g, 0.029 mmol) and stirred at 80°C 4 h. Evaporated off the solvent and purified column chromatography on silica gel (ethyl acetate/ pet ether = 30/70) to give the titled compound (0.250 g, 39%) as a off white solid .LCMS : m/z 220.1 [M+H] ⁺.

Step-2: tert-butyl ((5-((2-(2-methylpyridin-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol- 3-yl)methyl)carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.300 g, 0.780 mmol) in 1 ,4-dioxane: water (4:1) (12 mL) was reacted with 2-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)pyridine (0.188 g, 0.858 mmol) in the presence of sodium carbonate (0.248 g, 2.342 mmol) and l,l '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.028 g, 0.039 mmol) at 80 °C for 4 h as described in the synthesis of step-2 of example- 121 to give the titled compound (0.210 g, 68 %) as a solid. LCMS: m/z 398.60 [M+H] ⁺; H NMR (300 MHz, Chloroform-d) δ 8.52 (d, / = 5.2 Hz, 1H), 7.38 (d, / = 7.8 Hz, 1H), 7.32 (t, / = 8.6 Hz, 3H), 7.08 (t, / = 7.5 Hz, 1H), 6.96 (d, / = 8.3 Hz, 1H), 4.90 (tt, / = 7.2, 3.6 Hz, 1H), 4.46 (s, 1H), 4.15 (dd, / = 10.0, 3.9 Hz, 1H), 4.02 (dd, / = 10.1 , 3.6 Hz, lH), 3.89 (dd, / = 10.2, 6.2 Hz, 1H), 3.54 - 3.43 (m, 1H), 3.03 (dd, / = 17.4, 11.1 Hz, 1H), 2.83 (dd, / = 17.4, 7.1 Hz, lH), 2.62 (s, 3H), 1.42 (s, 9H).

Step-3: (5-((2-(2-methylpyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

4N HC1 in 1, 4-dioxane (2mL) was added to a solution of tert-butyl ((5-((2-(2- methylpyridin-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (0.210 g, 1.564 mmol) in methanol (3 mL) at room temperature. After stirring for 2 h at room temperature, reaction mixture was evaporated off and triturated with diethyl ether to give the titled compound (0.190 g, crude) as an off white hygroscopic solid. LCMS: m/z 298.1 /M+H] ⁺; ^lU NMR (300 MHz, DMSO-d6) δ 8.78 (d, / = 6.1 Hz, 1H), 8.44 (s, 3H), 8.08 (s, 1H), 8.02 (s, 1H), 7.65 - 7.52 (m, 2H), 7.28 (d, / = 8.3 Hz, 1H), 7.24 - 7.16 (m, 1H), 5.00 (m, lH), 4.29 - 4.11 (m, 2H), 3.80 (d, / = 5.7 Hz, 2H), 3.24 (dd, / = 17.6, 11.0 Hz, 1H), 2.96 (dd, / = 17.6, 7.6 Hz, 1H), 2.75 (s, 3H).

Step-4: N-((5-((2-(2-methylpyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a] Pyridine-6-carboxamide (±).

(5-((2-(2-methylpyridin-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.100 g, 0.299 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.058 g, 0.359 mmol) in the presence of EDCI.HC1 (0.074 g, 0.389 mmol), HOBt (0.008 g, 0.059 mmol) and triethylamine (0.045 g, 0.449 mmol) in dichloromethane (2 mL) as described in the step-2 of example- 110 to give the titled compound (0.052 g, 39%) as a solid. LCMS: m/z 442.5 [M+H] ⁺; HPLC: 99.09 %; H NMR (300 MHz, Chloroform-d) δ 8.81 (s, 1H), 8.47 (d, / = 5.2 Hz, 1H), 7.67 (t, / = 12.5 Hz, 3H), 7.45 - 7.37 (m, 2H), 7.32 (d, / = 6.1 Hz, 3H), 7.08 (t, / = 7.6 Hz, 1H), 6.96 (d, / = 8.2 Hz, 1H), 6.46 (s, 1H), 4.94 (s, 1H), 4.19 (dd, / = 13.1 , 4.8 Hz, 3H), 4.09 - 4.01 (m, 1H), 3.16 - 3.01 (m, 1H), 2.94 - 2.81 (m, 1H), 2.58 (s, 3H).

Example- 168: N-((5-((2-(pyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-((2-(pyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl) methyl) carbamate (±).

tert-butyl ((5-((2-bromophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.700g, 1.817 mmol) in THF: water (2: 1) (12 mL) was reacted with pyridin-4-ylboronic acid (0.246 g, 1.998 mmol) in the presence of sodium carbonate (0.578 g,5.451mmol) and l ,l '-bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.066 g, 0.090 mmol) at 80 °C for 4 h as described in the synthesis of step-2 of example- 121 to give the titled compound (0.600 g, 86 %) as an off white solid. LCMS: m/z 384.60 [M+H] ⁺; ^lU NMR (300 MHz, DMSO-d6) δ 9.03 - 8.91 (m, 2H), 8.25 - 8.15 (m, 2H), 7.70 - 7.53 (m, 2H), 7.36 - 7.16 (m, 2H), 5.01 (td, / = 12.4, 4.9 Hz, 1H), 4.46 (s, 1H), 4.23 (d, / = 4.9 Hz, 2H), 3.81 (q, / = 5.8 Hz, 2H), 3.35 - 3.14 (dd, / = 17.7, 7.7 Hz, 1H), 3.01 (dd, / = 17.7, 7.7 Hz, 1H), 1.42 (s, 9H).

Step-2: (5-((2-(pyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) .

4 N HC1 in 1,4-dioxane (2 mL) was added to a solution of tert-butyl ((5-((2-(pyridin-4- yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (0.600 g, 1.564 mmol) in methanol (3 mL) at room temperature. After stirring for 2 h at room temperature, reaction mixture was evaporated off and triturated with diethyl ether to give the titled compound (0.470 g, 94 %) as an off white hygroscopic solid. LCMS: m/z 284.1 M+H] ⁺; H NMR (300 MHz, DMSO-d6) δ 9.03 - 8.91 (m, 2H), 8.56 (s, 3H), 8.25 - 8.15 (m, 2H), 7.70 - 7.53 (m, 2H), 7.36 - 7.16 (m, 2H), 5.01 (td, / = 12.4, 4.9 Hz, 1H), 4.23 (d, / = 4.9 Hz, 2H), 3.81 (q, / = 5.8 Hz, 2H), 3.35 - 3.14 (dd, / = 17.7, 7.7 Hz, 1H), 3.01 (dd, / = 17.7, 7.7 Hz, 1H).

Step-3: N-((5-((2-(pyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

(5-((2-(pyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.200 g, 0.520 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.101 g, 0.624 mmol) in the presence of EDCI.HCl (0.149 g, 0.780 mmol), HOBt (0.040 g, 0.026 mmol) and triethylamine (0.157 g, 1.561 mmol) in dichloromethane (5 mL) as described in the step-2 of example- 110 to give the titled compound (0.060 g, 27%) as anoff white solid. LCMS: m/z 428.1 [M+H] ⁺; HPLC: 98.71 %; ^lU NMR (300 MHz, Chloroform-d) δ 8.82 (dt, / = 1.9, 0.9 Hz, 1H), 8.65 - 8.55 (m, 2H), 7.74 - 7.63 (m, 3H), 7.46 (ddd, / = 6.3, 3.8, 1.3 Hz, 3H), 7.43 - 7.38 (m, 1H), 7.37 - 7.31 (m, 1H), 7.14 - 7.06 (m, 1H), 6.97 (d, / = 8.3 Hz, 1H), 6.48 (t, / = 5.7 Hz, 1H), 4.95 (ddt, / = 10.8, 7.0, 3.2 Hz, 1H), 4.21 (td, / = 8.0, 6.7, 4.2 Hz, 2H), 4.06 (dd, / = 10.3, 3.1 Hz, 1H), 3.10 (dd, / = 17.3, 11.1 Hz, 2H), 2.87 (dd, / = 17.3, 7.5 Hz, 1H).

Example- 169: N-((5-((2-(pyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a] pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-((2-(pyridin-2-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (prepared in step-1 of example-23) (0.400g, 1.038 mmol) in toluene: ethanol (9.5:0.5) (5 mL) was added 2-(tributylstannyl)pyridine (0.420 g, 1.142 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (0.120 g, 0.104 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 48 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40mL). Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 30/70) to give the titled compound (0.106 g, 26 %) as a liquid. LCMS: m/z 384.3 [M+H] ⁺ ; ^lU NMR (600 MHz, Chloroform-d) δ 8.72 - 8.68 (m, 1H), 7.80 - 7.77 (m, 1H), 7.76 - 7.72 (m, 2H), 7.39 - 7.33 (m, 1H), 7.23 - 7.19 (m, 1H), 7.13 - 7.09 (m, 1H), 7.00 - 6.95 (m, 1H), 4.96 - 4.90 (m, 1H), 4.76 (bs, 1H),4.20 - 4.15 (m, 2H), 3.95 - 3.87 (m, 2H), 3.06 - 2.99 (m, 1H), 2.93 - 2.85 (m, 1H), 1.44 (s, 9H).

Step-2: (5-((2-(pyridin-2-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

tert-butyl ((5-((2-(pyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±) (0.103 g, 0.268 mmol) was reacted with 4 N HCl in 1 ,4-dioxaneas described in the step-4 of example- 1 to give titled compound (0.080 g, crude). LCMS: m/z 284.2 [M+H] ⁺. The crude product was taken to the next step without further purification.

Step-3: N-((5-((2-(pyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide(±).

To a suspension of (5-((2-(pyridin-2-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.075 g, 0.234 mmol) in N,N-dimethylformamide (2 mL) was added imidazo[l ,2-a]pyridine-6-carboxylic acid (0.038 g, 0.234 mmol), EDCI (0.049 g, 0.258 mmol), HOBt (0.041 g, 0.304 mmol) and triethylamine (0.098 mL, 0.703 mmol) at 0°C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 14 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate (2 x 20 mL). The combined ethyl acetate was washed with water, brine solution (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combi flash column chromatography (methanol/dichloromethane = 6/94) to give the titled compound (0.034 g, 34%) as a solid. HPLC: 95.12%; LCMS: nt/z 428.1 [M+H] ⁺; 1H NMR (600 MHz, Chloroform-d) δ 8.71 - 8.64 (m, 2H), 7.78 - 7.67 (m, 3H), 7.64 (dd, / = 7.6, 1.8 Hz, 1H), 7.61 - 7.55 (m, 2H), 7.42 (dd, / = 9.5, 1.8 Hz, 1H), 7.36 (ddd, / = 8.9, 7.5, 1.8 Hz, 1H), 7.24 (td, / = 4.9, 2.5 Hz, 1H), 7.13 (bs, 1H), 7.07 (td, / = 7.5, 1.0 Hz, 1 H), 6.99 (d, / = 8.2 Hz, lH), 4.96 (ddt, / = 11.6, 6.0, 3.0 Hz, l H), 4.42 (dd, / = 16.3, 6.7 Hz, 1H), 4.22 - 4.06 (m, 3H), 3.09 (dd, / = 17.2, 11.2 Hz, 1H), 2.93 (dd, / = 17.2, 5.9 Hz, 1H).

Example- 170: N-((5-((2-(5-fluoropyridin-2-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-((2-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenoxy)methyl)- 4,5-dihydro isoxazol-3-yl)methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-bromophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (1.0 g, 2.596 mmol) in 1 ,4-dioxane (20 mL) was added bis(pinacalato)diboran (1.320 g, 5.192 mmol), followed by potassium acetate (0.764 g, 7.788 mmol) and l ,l '-Bis(diphenylphosphino) ferrocene -palladium (Il)dichloride dichloromethane complex (0.211 g, 0.259 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.850 g, 75 %) as a liquid. LCMS: mJz 433.1 [M+ H] ⁺.

Step-2: tert-butyl ((5-((2-(5-fiuoropyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (0.200 g, 0.462 mmol) in 1,4-dioxane: water (4: 1) (10 mL) was added 2-bromo-5- fluoropyridine (0.082 g, 0.462 mmol), followed by potassium carbonate (0.191 g, 1.386 mmol) and l, -bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloro methane complex (0.037 g, 0.046 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous and ethyl acetate layer were separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (ethyl acetate/hexanes = 45/55) to give the titled compound (0.085 g, 45 %) as a sticky solid. LCMS: m/z 402.2 [M+ H] ⁺. Step-3: (5-((2-(5-fiuoropyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

Tert-butyl ((5-((2-(5-fiuoropyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (0.085 g, 0.211 mmol) was reacted with 4 N HC1 inl ,4 dioxane as described in the step-4 of example- 1 to give titled compound (0.060 g, 83 %) as sticky solid. Step-4: N-((5-((2-(5-fluoropyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine- 6 -carboxamide (±).

(5-((2-(5-fluoropyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.060 g, 0.177 mmol) was reacted with imidazo[l,2-a]pyridine-6- carboxylic acid (0.037 g, 0.230 mmol) in the presence of BOP reagent (0.093 g, 0.212 mmol) and Ν,Ν-diisopropylethylamine (0.068 g, 0.531 mmol) in Ν,Ν- dimethylformamide (3 mL) at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (30 mL) and washed with water (4 x 30 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (methanol/dichloromethane = 4/96) to give titled compound (0.014 g, 17%) as a solid. LCMS: m/z 446.1 [M+H] ⁺; HPLC: 97.65 %; H NMR (400 MHz, DMSO-d6) δ 9.13 (t, / = 1.4 Hz, 1H), 8.97 (t, / = 5.8 Hz, 1H), 8.63 (d, / = 3.0 Hz, 1H), 8.13 - 8.07 (m, 1H), 7.96 (dd, / = 8.9, 4.6 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.70 - 7.60 (m, 3H), 7.40 (ddd, / = 8.9, 7.5, 1.8 Hz, 1H), 7.16 (d, / = 8.2 Hz, 1H), 7.08 (t, / = 7.5 Hz, 1H), 4.91 (dq, / = 11.0, 5.0 Hz, 1H), 4.21 - 4.16 (m, 3H), 4.12 (dd, / = 10.6, 5.6 Hz, 1H), 3.22 - 3.11 (m, 1H), 2.90 (dd, / = 17.5, 7.7 Hz, 1H).

Example- 171: N-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) furo[2,3-c] pyridine-2-carboxamide (±).

To a suspension of furo[2,3-c] pyridine-2-carboxylic acid (0.030 g, 0.471 mmol), 5-((2- (pyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine dihydrochloride (±) (0.050 g, 0.156 mmol) in N,N-dimethylformamide (2 mL) was added BOP reagent (0.076 g, 0.172 mmol) and N,N-diisopropylethylamine (0.200 mL, 1.286 mmol) at -5°C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 14 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate (2 x 15 mL). The combined ethyl acetate layer was washed with water, brine solution (2 x 5 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (methanol/dichloromethane = 4/96) to give the titled compound (0.012 g, 21%) as a solid. HPLC: 94.23 %; LCMS: mJz 430.2 [M+2] ⁺; 1H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 7.72 - 7.52 (m, 5H), 7.48 (s, 1H), 7.21 - 7.07 (m, 3H), 6.76 (td, / = 7.5, 1.1 Hz, 1H), 6.67 (d, / = 8.1 Hz, 1H), 4.99 (ddt, / = 10.7, 7.3, 4.0 Hz, 1H), 4.45 (dd, / = 17.2, 5.8 Hz, 1H), 4.32 (dd, / = 17.2, 5.3 Hz, 1H), 3.36 (dt, / = 13.2, 3.8 Hz, lH), 3.29 - 3.15 (m, 2H), 2.94 (dd, / = 17.3, 6.7 Hz, 1H).

Example- 172: N-((5-((4-cyano-2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

To a previously degassed solution of N-((5-((2-bromo-4-cyanophenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±) (0.150 g, 0.330 mmol) in 1 ,4-dioxane: water (9:1) (20 mL) was added (6-fiuoropyridin-3-yl)boronic acid (0.070 g, 0.490 mmol), followed by potassium carbonate (0.153 g, 1.100 mmol) and [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloro methane (0.036 g, 0.044 mmol) at room temperature under inert atmosphere. Then resulting reaction mixture was stirred for 16 h at 90 °C. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue obtained was purified by column chromatography on neutral alumina (dichloromethane/methanol = 95/5) to give the titled compound

(0.020 g, 33%) as off white solid. LCMS: m/z 471.1 [M+ H] ⁺; HPLC: 96.06%; H NMR (400 MHz, DMSO-d6) δ 9.20 (d, / = 1.5 Hz, 1H), 9.01 (t, / = 5.6 Hz, 1H), 8.48 (d, / = 2.5 Hz, 1H), 8.24 (td, / = 8.2, 2.5 Hz, 1H), 8.14 (d, / = 1.3 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.73 (d, / = 1.3 Hz, 1H), 7.69 (d, / = 1.5 Hz, 2H), 7.41 (d, / = 8.6 Hz, 1H), 7.34 (dd, / = 8.6, 2.8 Hz, 1H), 4.95 (dd, / = 16.5, 11.0 Hz, 1H), 4.32 (dd, / = 10.6, 3.5 Hz, 2H), 4.24 (dd, / = 16.8, 5.8 Hz, 2H), 3.22 (dd, / = 17.5, 11.1 Hz, 1H), 2.90 (dd, / = 17.6, 7.3 Hz, 1H).

Example- 173: N-((5-((2-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenoxy)methyl)- 4,5-dihydroisoxazol-3-yl) methyl)imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-1: tert-butyl ((5-((2-(l-methyl-6-oxo-l ,6-dihydropyridin-3-yl)phenoxy)methyl)- 4,5-dihydroisoxazol-3-yl) methyl)carbamate (±).

To a previously degassed solution of tert-butyl ((5-((2-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)carbamate (±) (0.200 g, 0.462 mmol) in 1,4-dioxane: water (4: 1) (10 mL) was added 5-bromo-l - methylpyridin-2(lH)-one (0.086 g, 0.462 mmol), followed by potassium carbonate (0.191 g, 1.386 mmol) and [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (0.037 g, 0.046 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was filtered through celite pad and it was washed with ethyl acetate (2 x 40 mL). Filtrate was concentrated and resulting mixture was dissolved in ethyl acetate and water. Aqueous, ethyl acetate layer was separated. The combined ethyl acetate layer was washed with water, brine solution (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (ethyl acetate/he xanes = 45/55) to give the titled compound (0.090 g, 47 %) as a sticky solid. LCMS: m/z 313.2 [M-100] ⁺.

Step-2: 5-(2-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)phenyl)-l- methylpyridin-2(iH)-one hydrochloride (±).

tert-butyl((5-((2-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl)carbamate (±) (0.090 g, 0.217 mmol) was reacted with 4 N HCl in 1,4-dioxane as described in the step-4 of example- 1 to give titled compound (0.060 g, 78%) as sticky solid.

Step-3: N-((5-((2-(l-methyl-6-oxo-l ,6-dihydropyridin-3-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl) methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

5-(2-((3-(aminomethyl)-4,5-dihydroisoxazol-5-yl)methoxy)phenyl)-l -methylpyridin- 2(iH)-one hydrochloride (±) (0.060 g, 0.171 mmol) was reacted with imidazo[l ,2- a]pyridine-6-carboxylic acid (0.036 g, 0.222 mmol) in the presence of BOP reagent (0.093 g, 0.205 mmol) and Ν,Ν-diisopropylethylamine (0.066 g, 0.513 mmol) in DMF (3 mL) at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (30 mL) and washed with water (4 x 30 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combifiash column chromatography (methanol/dichloromethane = 4/96) to give the titled compound (0.008 g, 10%) as a solid. LCMS: m z 458.1 [Μ+Η] ⁺; HPLC: 97.80 %; H NMR (400 MHz, DMSO-d6) δ 9.13 (t, / = 1.4 Hz, 1H), 8.96 (t, / = 5.7 Hz, 1H), 8.08 (d, / = 1.3 Hz, 1H), 7.89 (d, / = 2.6 Hz, 1H), 7.71 - 7.58 (m, 4H), 7.37 - 7.24 (m, 2H), 7.09 (d, / = 8.2 Hz, 1H), 7.02 (t, / = 7.5 Hz, 1H), 6.41 (d, / = 9.4 Hz, 1H), 4.95 - 4.81 (m, 1H), 4.18 (d, / = 5.7 Hz, 2H), 4.08 (qd, / = 10.5, 4.8 Hz, 2H), 3.48 (s, 3H), 3.16 (dd, / = 17.5, 10.8 Hz, 1H), 2.88 (dd, / = 17.5, 7.6 Hz, 1H).

Example- 174: N-((5-((2-(4-methylpiperazin-l-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide(±).

Step-1: 2-(4-methylpiperazin-l-yl) phenol.

To a solution of l -(2-methoxyphenyl)-4-methylpiperazine (4.7 g, 22.8 mmol) (synthesized as per reported procedure in J. Org.Chem. 58,5101-5106, 1993) in dichloromethane (100 mL) was added a solution of boron tribromide (5.4 mL, 57.0 mmol) in dichloromethane (50 mL) at -20 °C temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding sodium bicarbonate solution (100 mL), extracted with dichloromethane (2 xlOO mL). The combined organic phase was dried over sodium sulfate and evaporated under reduced pressure to afford the titled compound (4.4 g, 99%) as a solid. LCMS: m/z 193.2 [M+H] ⁺.

Step-2: l-(2-(allyloxy) phenyl)-4-meth lpiperazine.

Allyl bromide (4.16 g, 34.370 mmol) was added to a mixture of anhydrous potassium carbonate (4.7 g, 34.370 mmol), 2-(4-methylpiperazin-l-yl) phenol (4.4 g, 22.9 mmol) and KI (0.100 g) in acetone (50 mL). The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate. Combined extracts were washed with water (2 x 30 mL) and dried. The solvent was evaporated to give residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 5/95) to give the titled compound (4.3 g, 81%) as a yellow liquid. LCMS: m/z 233.10 [M+H] ⁺.

Step-3: tert-butyl ((5-((2-(4-methylpiperazin-l-yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (±) (3.0 g, 17.24 mmol) in N, N-dimethylformamide (125 mL) was added N-chlorosuccinimide (2.6 g, 19.48 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h then cooled to 0 °C and added l-(2-(allyloxy) phenyl)-4-methylpiperazine (4.0 g, 17.24 mmol) in one lot followed by drop wise addition of solution of triethylamine (2.6 mL, 18.96 mmol) in N,N-dimethylformamide (25 mL) over 10 min. The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured onto water at room temperature, extracted with ethyl acetate (100 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 50/50) to give the titled compound (4.0 g, 57 %) as a solid. LCMS: nt/z 405.2 [M+H] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 7.12 - 6.84 (m, 4H), 5.23 (s, 1H), 4.98 (ddd, / = 10.7, 8.0, 4.0 Hz, 1H), 4.34 - 3.97 (m, 6H), 3.80 (d, / = 13.9 Hz, 1H), 3.66 - 3.39 (m, 3H), 3.39 - 2.92 (m, 6H), 1.42 (s, 9H).

Step-4: (5-((2-(4-methylpiperazin-l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

To a solution of tert-butyl ((5-((2-(4-methylpiperazin-l -yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±) (4.0 g, 9.9 mmol) in 1 , 4-dioxane (10 mL) was added ethereal HC1 (10 mL) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. The solid precipitated out was filtered and triturated with diethyl ether to give titled compound (3.3 g, 98 %) as a solid.

Step-5: N-((5-((2-(4-methylpiperazin- l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) imidazo [1 , 2-a] pyridine-6-carboxamide (±).

To a solution of (5-((2-(4-methylpiperazin-l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol- 3-yl) methanamine hydrochloride (±) (0.150 g, 0.440 mmol) and imidazo[l ,2-a]pyridine- 6-carboxylic acid (0.107 g, 0.660 mmol) in N,N-dimethylformamide (4 mL) was added EDCI.HC1 (0.170 g, 0.880 mmol), HOBT (0.120 g, 0.880 mmol) and N,N- diisopropylethylamine (0.300 mL, 1.760 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (250 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 4/96) to give the titled compound (0.080 g, 40 %) as a solid. HPLC: 91.6 %; LCMS: nt/z 449.2 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform- d) δ 8.83 (dd, / = 1.8, 1.0 Hz, 1 H), 7.70 (d, / = 1.3 Hz, 1H), 7.66 (dd, / = 1.3, 0.7 Hz, 1H), 7.60 (dt, / = 9.5, 0.8 Hz, 1H), 7.49 (dd, / = 9.5, 1.8 Hz, 1H), 7.09 (td, / = 7.7, 1.7 Hz, lH), 7.05 - 6.96 (m, 2H), 6.92 (dt, / = 8.0, 1.6 Hz, 2H), 5.04 (tt, / = 9.6, 3.0 Hz, 1H), 4.65 (dd, / = 17.3, 6.2 Hz, 1H), 4.36 (dd, / = 17.3, 5.0 Hz, 1H), 4.26 (dd, / = 10.4, 3.0 Hz, 1H), 4.22 - 4.01 (m, 3H), 3.95 (d, / = 13.7 Hz, 1H), 3.65 - 3.52 (m, 2H), 3.31 (dd, / = 10.9, 2.5 Hz, 2H), 3.28 - 3.22 (m, 2H), 3.18 (s, 3H), 2.99 - 2.86 (m, 1H).

Example- 175: N-((5-((2-(4-methylpiperazin-l-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl) imidazo [l,2-a]pyridine-7-carboxamide (±).

(5-((2-(4-methylpiperazin-l -yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.070 g, 0.206 mmol) was reacted with imidazo[l ,2-a]pyridine-7- carboxylic acid (0.050 g, 0.31 mmol) in the presence of EDCI.HCl (0.080 g, 0.412 mmol), HOBt (0.056 g, 0.412 mmol) and N,N-diisopropylethylamine (0.150 mL, 0.824 mmol) in N,N-dimethylformamide (3 mL) as described in the step-2 of example- 110 to give the titled compound (0.015 g, 16.3%) as a solid. LCMS: nt/z 449.2 [M+H] ⁺; HPLC: 96.67%; 1 H-NMR(400 MHz, Chloroform-d) δ 8.19 - 8.14 (m, 2H), 7.72 (d, / = 43.3 Hz, 2H), 7.42 (t, / = 5.7 Hz, 1H), 7.30 (dd, / = 7.2, 1.5 Hz, 1H), 7.09 - 7.01 (m, 1 H), 6.98 (td, / = 7.6, 1.5 Hz, l H), 6.93 - 6.86 (m, 2H), 5.02 (t, / = 9.7 Hz, 1H), 4.60 (dd, / = 16.9, 6.1 Hz, 1H), 4.42 (dd, / = 17.0, 5.3 Hz, 1 H), 4.24 - 4.00 (m,4H), 3.83 (d, / = 12.7 Hz, 1H), 3.59 - 3.42 (m, 4H), 3.33 - 3.14 (m, 6H), 3.00 (t, / = 12.1 Hz, 1H).

Example- 176: N-((5-((2-(piperidin-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-1: 2-(piperidin- l -yl) phenol.

To a solution of l-(2-methoxyphenyl) piperidine (/. Org. Chem., 58, 5101 -5106, 1993) (2.4 g, 12.5 mmol) in dichloromethane (100 mL) was added a solution of boron tribromide (5.4 mL, 57.0 mmol) in dichloromethane (50 mL) at -20 °C temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by adding sodium bicarbonate solution (100 mL), extracted with dichloromethane (2 x 100 mL). The combined organic phase was dried over sodium sulfate and evaporated under reduced pressure to afford the titled compound (1.6 g, 72%) as a solid. LCMS: nt/z 178.1 [M+H] ⁺.

Step-2: l -(2-(allyloxy) phenyl) piperidine.

Allyl bromide (1.6 g, 13.500 mmol) was added to a mixture of anhydrous potassium carbonate (1.860 g, 13.5 mmol), 2-(piperidin- l-yl) phenol (1.6 g, 9.0 mmol) and KI (0.100 g) in acetone (50 mL). The reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate. Combined extracts were washed with water (2 x 30 mL) and dried. The solvent was evaporated to give residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 5/95) to give the titled compound (1.6 g, 81 %) as a yellow liquid. LCMS: mJz 218.3 [M+H] ⁺.

Step-3: tert-butyl ((5-((2-(piperidin-l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (±) (1.3 g, 7.37 mmol) in N, N-dimethylformamide (50 mL) was added N-chlorosuccinimide (1.1 g, 8.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h then cooled to 0 °C and added l -(2-(allyloxy)phenyl) piperidine (1.6 g, 7.370 mmol) in one lot followed by drop wise addition of solution of triethylamine (1.1 mL, 8.100 mmol) in N,N-dimethylformamide (10 mL) over 10 min. The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured onto water at room temperature, extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 30/70) to give the titled compound (1.2 g, 42 %) as a solid. LCMS: m/z 390.2 [M+H] ⁺.

Step-4: (5-((2-(piperidin- l-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

To a solution of tert-butyl ((5-((2-(piperidin-l -yl) phenoxy) methyl)-4, 5- dihydroisoxazol-3-yl) methyl)carbamate (±) (1.2 g, 3.08 mmol) in 1 ,4-dioxane (5 mL) was added ethereal HC1 (5 mL) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. The solid precipitated out was filtered and triturated with diethyl ether to give titled compound (1.0 g, 98 %) as a solid. LCMS: m/z 290.2 [M+H] ⁺.

Step-5: N-((5-((2-(piperidin- l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) imidazo [1 , 2-a] pyridine-6-carboxamide (±).

To a solution of (5-((2-(piperidin- l -yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.150 g, 0.476 mmol) and imidazo[l ,2-a]pyridine-6- carboxylic acid (0.116 g, 0.710 mmol) in N,N-dimethylformamide (4 mL) added EDCI (0.180 g, 0.950 mmol), HOBT (0.130 g, 0.950 mmol) and N,N-diisopropylethylamine (0.330 mL, 1.900 mmol) at 0 °C. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (250 mL). The organic phase was washed with aqueous sodium bicarbonate solution (50 mL), brine (3 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 4/96) to give the titled compound (0.08 g, 40 %) as a solid. HPLC: 95.2 ; LCMS: m/z 434.5 [M+H] ⁺; ^lU NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.74 (d, / = 7.8 Hz, 1H), 7.63 (d, / = 1.3 Hz, 1H), 7.46 (d, / = 9.4 Hz, lH), 7.36 (dd, / = 9.4, 1.8 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.10 - 6.88 (m, 4H), 5.09 (ddt, / = 10.4, 5.0, 2.8 Hz, 1H), 4.81 (dd, / = 15.5, 8.0 Hz, 1H), 4.32 (dd, / = 15.3, 2.5 Hz, 1H), 4.15 (d, / = 2.8 Hz, 2H), 3.26 (dd, / = 16.8, 10.6 Hz, 1H), 3.19 - 3.06 (m, 3H), 2.56 (dd, / = 10.2, 6.6 Hz, 2H), 1.83 - 1.66 (m, 3H), 1.53 (q, / = 5.6 Hz, 3H).

Example-177: N-((5-((2-morpholinophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide (±).

Step-1: 2-morpholinophenol.

To a solution of 4-(2-methoxyphenyl) morpholine (J.Org. Chem. 58, 5101-5106, 1993) (2.5 g, 12.945 mmol) in dried dichloromethane (25 mL) was added boron tribromide (1M solution in dichloromethane) (5.52 ml, 32.363 mmol) drop wise at -5° C. Reaction mixture was allowed to room temperature for 14 h. Reaction mixture quenched with saturated sodium bicarbonate at 0 °C. Extracted with dichloromethane (2 x 100 mL), the combined dichloromethane layer was washed with water; brine solution (2 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue obtained was triturated with diethyl ether: pentane (4:6), followed by dichloromethane: pentane (2:8). Formed precipitate was collected by filtration and dried in vacuum (2.0 g, 86.6%) as a solid. LCMS: m/z 180.1 [M+H] ⁺; H NMR (400 MHz, Chloroform-d) δ 7.26 - 7.08(m, 2H), 6.98-6.87 (m, 2H),3.88 - 3.86 (m, 4H), 2.90 - 2.88 (m, 4H).

Step-2: 4-(2-(allyloxy) phenyl) morpholine.

To a mixture of anhydrous potassium carbonate (4.620 g, 33.478 mmol), 2- mo holinophenol (2.0 g, 11.159 mmol) and KI (0.185 g, 1.115 mmol) in acetone (100 mL) was added allyl iodide (1.2 mL, 13.391 mmol). The reaction mixture was stirred at 70 °C for 14 h. concentrated under reduced pressure to give a residue. The obtained residue was dissolved in 100 mL mixture of water: diethyl ether (1 :1) and ether layer was separated. Again aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined diethyl ether and washed with water, brine solution (2 x 40 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by combiflash column chromatography (ethyl acetate/hexanes = 10/90) to give the titled compound (1.110 g, 45%) as a liquid. LCMS: m/z 220.1 [M+H] ⁺; 1H NMR (300 MHz, Chloroform-d) δ 7.26 - 6.92 (m, 4H), 6.09 (ddt, / = 17.3, 10.3, 5.0 Hz, 1H), 5.43(dq, / = 17.2, 1.7 Hz, 1H), 5.28 (dq, / = 10.6, 1.5 Hz, 1H), 4.58 (dt, / = 5.0, 1.7 Hz, 2H), 3.94 - 3.81 (m, 4H), 3.16 - 3.02 (m, 4H).

Step-3: tert-butyl ((5-((2-mo holinophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

tert-butyl (2-(hydroxyimino) ethyl)carbamate (0.870 g, 5.016 mmol) was reacted with N- chlorosuccinimide (0.671 g, 5.017 mmol), 4-(2-(allyloxy) phenyl) morphline (1.101 g, 5.016 mmol) and triethylamine (0.760 mL, 5.518 mmol) in N,N-dimethylformamide (10 mL) as described in the step-3 of example-174 to give the titled compound (0.982 g, 50%) as a liquid. LCMS: m/z 392.4 [M+2] ⁺ ; 1H NMR (400 MHz, Chloroform-d) δ 7.27 - 6.95 (m, 3H), 6.95 - 6.83 (m, 1H), 5.45 (s, 1H), 5.00 (td, / = 6.8, 4.0 Hz, 1H), 4.20 - 4.04 (m, 4H), 3.91 - 3.81 (m, 4H), 3.21 - 3.10 (m, 3H), 3.09 - 2.97 (m, 1H), 2.78 (d, / = 29.5 Hz, 2H), 1.43 (d, / = 22.3 Hz, 9H).

Step-4: (5-((2-moφholinophenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±).

tert-butyl ((5-((2-moφholinophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (0.980 g, 2.503 mmol) was reacted with 4 N HCl in 1,4-dioxane as described in the step-4 of example-174 to give titled compound (0.820 g, crude). The crude product was taken to the next step without further purification. Step-5: Ν-((5-((2-ηιοφ1ιο1ίηορ1ΐ6ηοχγ)ηΐ6ΐ1ιγ1)-4,5-(ϋ1ιγάΓθί8θχ ζο1-3- yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±).

To a suspension of imidazo[l,2-a]pyridine-6-carboxylic acid (0.089 g, 0.549 mmol), (5- ((2-morpholinophenoxy) methyl)-4,5-dihydroisoxazol-3-yl) methanamine hydrochloride (±) (0.200 g, 0.549 mmol) in N,N-dimethylformamide (5.0 mL) was added EDCI.HCl (0.127 g, 0.658 mmol), HOBt (0.111 g, 0.823 mmol) and N,N-diisopropylethylamine (0.212 mL, 1.647 mmol) at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at room temperature for 14 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate (2 x 20 mL). The combined ethyl acetate layer was washed with water, brine solution (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC method to give the titled compound (0.025 g, 21.1 %) as solid. HPLC: 99.33%; LCMS: m/z 436.4 [M+H] ⁺ ; 1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 7.68 - 7.64 (m, 1H), 7.47 (d, / = 9.4 Hz, 1H), 7.40 (s, 1H), 7.32 (d, / = 10.1 Hz, 2H), 7.06 (dt, / = 20.3, 7.5 Hz, 2H), 6.93 (dd, / = 16.3, 8.0 Hz, 2H), 5.12-5.07 (m, 1H), 4.69 (dd, / = 15.8, 7.2 Hz, 1H), 4.41 - 4.31 (m, 1H), 4.15 (s, 2H), 3.88 - 3.72 (m, 4H), 3.25 (dt, /= 20.1 , 10.3 Hz, 3H), 3.11 (dd, /= 17.0, 5.4 Hz, 1H), 2.75 (d, / = 10.3 Hz, 2H).

Preparative HPLC purification method:

Column: AG/AD/PP/C18-15/033; Mobile Phase: 0.1 % TFA in Water (A), Acetonitrile (B); Flow Rate: 20 mL/min.

TIME %B

0 10

2 20

6 40

Example- 178: N-((5-((3-morpholinophenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a] pyridine-6-carboxamide (±).

(5-((3-ηιοφ1ιο1ίηορ1ΐ6ηοχγ)ηΐ6ΐ1ιγ1)-4,5-(ϋ1ιγάΓθί8θχ ζο1-3-γ1)ηΐ6ΐ1ι η ηιίη6

hydrochloride (±) (0.130 g, 0.396 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.077 g, 0.475 mmol) in the presence of BOP reagent (0.192 g, 0.435 mmol) and Ν,Ν-diisopropylethylamine (0.153g, 1.188 mmol) in N,N-dimethyl formamide (3 mL) at room temperature for 16h. The reaction mixture was diluted with water (10 mL) extracted with ethyl acetate (30 mL) and washed with water (4 x 30 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give titled compound (0.025 g, 15 %) as a solid. LCMS: nt/z 436.2 [M+H] ⁺; HPLC: 98.37 %; 1H NMR (400 MHz, DMSO-d6) δ 9.14 (t, / = 1.3 Hz, 1H), 9.01 (t, / = 5.7 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.70 - 7.60 (m, 3H), 7.09 (t, / = 8.2 Hz, 1H), 6.52 (dd, / = 8.2, 2.3 Hz, 1H), 6.45 (t, / = 2.3 Hz, 1H), 6.41 - 6.35 (m, 1H), 4.86 (ddd, / = 11.0, 6.8, 4.1 Hz, 1H), 4.25 (d, / = 5.7 Hz, 2H), 3.99 (qd, / = 10.5, 4.9 Hz, 2H), 3.69 (dd, / = 5.9, 3.8 Hz, 4H), 3.18 (dd, / = 17.5, 10.9 Hz, 1H), 3.06 (t, / = 4.8 Hz, 4H), 2.90 (dd, / = 17.4, 7.3 Hz, 1H).

PREPARATIVE HPLC PURIFICATION METHOD:

COLUMN: XDB-C18 (21.20 x 150mm, 5 micron); MOBILE PHASE: (A): 0.1 % TFA in Water; (B): acetonitrile.FLOW RATE: 20.0 ml/min

GRADIENT:

Time % of B FLOW

0 20 20.0

2 30 20.0

8 80 20.0

Example- 179: N-((5-((4-(trifluoromethoxy)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo [l,2-a]pyridine-6-carboxamide(±).

Step-1: l -(allyloxy)-4-(trifluoro methoxy) benzene.

Allyl iodide (5.66 g, 33.7 mmol) was added to a mixture of anhydrous potassium carbonate (4.650 g, 33.7 mmol) and 4-(trifluoro methoxy) phenol (4.0 g, 22.47 mmol) in acetone (50 mL). The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate. Combined extracts were washed with water (2 x 30 mL) and dried. The solvent was evaporated to give the titled compound (4.0 g, crude) as a yellow liquid . The crude product was taken to the next step without further purification.

Step-2: tert-butyl((5-((4-(trifiuoromethoxy)phenoxy)methyl)-4,5 -dihydroisoxazol-3 - yl)methyl)carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (1.59 g, 9.16 mmol) in N, N-dimethylformamide (50 mL) was added N-chlorosuccinimide (1.380 g, 10.350 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h then cooled to 0 °C and added l -(allyloxy)-4-(trifluoro methoxy)benzene (2.090 g, 9.16 mmol) in one lot followed by drop wise addition of solution of triethylamine (1.010 g, 10.070 mmol) in N,N-dimethylformamide (20 mL) over 30 min. The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured onto water at room temperature, extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 50/50) to give the titled compound (1.2 g, 34.2%) as a liquid. LCMS: m/z no ionization; ^lU NMR (400 MHz, Chloroform-d) δ 7.19 - 7.11 (m, 2H), 6.93 - 6.85 (m, 2H), 4.96 (ddt, / = 10.3, 5.0, 2.8 Hz, 2H), 4.17 - 3.95 (m, 4H), 3.18 (dd, / = 17.3, 10.7 Hz, 1H), 3.08 - 2.94 (m, 1H), 1.45 (s, 9H).

Step-3: (5-((4-(trifluoromethoxy)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methanamine hydrochloride (±).

To a solution of tert-butyl ((5-((4-(trifiuoromethoxy)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)carbamate (±) (1.2 g, 3.070 mmol) in 1 ,4-dioxane (10 mL) was added 4 N HCl in 1,4-dioxane (10 mL) at 0 °C. The reaction mixture was stirred for 12 h at room temperature. The solid precipitated out was filtered and triturated with diethyl ether to give titled compound (1.0 g, crude).

Step-4: N-((5 -((4-(trifiuoromethoxy)phenoxy)methyl)-4,5-dihydroisoxazol-3 - yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±).

(5-((4-(trifiuoro methoxy) phenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (0.100 g, 0.306 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.054 g, 0.336 mmol) (synthesized as per reported procedure in WO1070732) in the presence of EDCI.HC1 (0.071 g, 0.367 mmol), HOBt (0.064 g, 0.459 mmol) and N,N-diisopropylethylamine (0.158 g, 1.220 mmol) in N,N- dimethylformamide (2 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.030 g, 23.0 %) as a solid. LCMS: m z 435.3 [M+H] ⁺; HPLC: 99.40 ; 1H NMR (400 MHz, Chloroform-d) δ 8.83 (dd, / = 1.9, 1.0 Hz, 1H), 7.73 (d, / = 1.3 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.44 (dd, / = 9.5, 1.8 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.91 - 6.87 (m, 2H), 6.84 (d, / = 5.5 Hz, 1H), 5.08 - 4.97 (m, 1H), 4.45 - 4.41 (m, 2H), 4.12 - 4.00 (m, 2H), 3.25 (dd, / = 17.3, 10.8 Hz, 1H), 3.10 (dd, / = 17.3, 7.2 Hz, 1H).

Example- 180: N-((5-((2-(trifluoromethyl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l,2-a]pyridine-6-carboxamide (±).

Step-1: l-(allyloxy)-2-(trifluoromethyl) benzene.

Allyl iodide (4.65 g, 27.7 mmol) was added to a mixture of anhydrous potassium carbonate (3.8 g, 27.7 mmol) and 2-(trifluoromethyl)phenol (3.0 g, 18.5 mmol) in acetone (50 mL). The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was poured onto ice water, extracted with ethyl acetate. Combined extracts were washed with water (2 x 30 mL) and dried. The solvent was evaporated to give the titled compound (3.1 g, crude) as a yellow liquid. The crude product was taken to the next step without further purification.

Step-2: tert4jutyl((5-((2-(trifiuoromethyl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±).

To a solution of tert-butyl (2-(hydroxyimino) ethyl)carbamate (1.72 g, 9.8 mmol) in N, N-dimethylformamide (50 mL) was added N-chlorosuccinimide (1.47 g, 11.07 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h then cooled to 0 °C and added l-(allyloxy)-2-(trifiuoromethyl)benzene (2.0 g, 9.80 mmol) in one lot followed by drop wise addition of solution of triethylamine (1.08 g, 10.78 mmol) in N,N-dimethylformamide (20 mL) over 30 min. The reaction mixture was stirred further for 36 h at room temperature. The reaction mixture was poured onto water at room temperature, extracted with ethyl acetate (50 mL) and washed with water (4 x 50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes = 50/50) to give the titled compound (1.0 g, 27.0%) as a liquid. ^lU NMR (400 MHz, Chloroform-d) δ 7.60 - 7.55 (m, 1H), 7.54 - 7.44 (m, 1H), 7.09 - 6.95 (m, 2H), 5.05 - 4.89 (m, 2H), 4.23 - 4.08 (m, 4H), 3.22 - 3.12 (m, 2H), 1.45 (s, 9H).

Step-3: (5-((2-(trifluoromethyl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±).

tert-butyl((5-((2-(trifluoromethyl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)carbamate (±) (1.0 g, 2.670 mmol) was reacted with 4N HC1 in 1 ,4-dioxane as described in the synthesis of step-2 of example- 130 to give titled compound (0.59 g, crude). The crude product was taken to the next step without further purification.

Step-4: N-((5-((2-(trifiuoromethyl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)imidazo[l,2-a] pyridine- 6 -carboxamide (±).

(5-((2-(trifluoromethyl)phenoxy)methyl)-4,5-dmydroisoxazol-3-yl)methanamine hydrochloride (±) (0.100 g, 0.321 mmol) was reacted with imidazo[l ,2-a]pyridine-6- carboxylic acid (0.056 g, 0.35 mmol) (synthesized as per reported procedure in WO1070732) in the presence of EDCI.HC1 (0.073 g, 0.385 mmol), HOBt (0.066 g, 0.480 mmol) and N,N-diisopropylethylamine (0.165 g, 1.280 mmol) in N,N- dimethylformamide (2 mL) as described in the synthesis of step-2 of example- 110 to give the titled compound (0.015 g, 11.0 %) as a solid. LCMS: m z 419.3 [M+H] ⁺; HPLC: 97.33 ; 1H NMR (400 MHz, Chloroform-d) δ 8.83 (t, / = 1.4 Hz, 1H), 7.72 (d, / = 1.3 Hz, lH), 7.69 - 7.61 (m, 2H), 7.58 - 7.54 (m, 1H), 7.54 - 7.41 (m, 2H), 7.05 (t, / = 7.7 Hz, 1H), 6.99 (d, / = 8.3 Hz, 1H), 6.75 (s, 1H), 5.11 - 5.01 (m, 1H), 4.45 (d, / = 5.2 Hz, 2H), 4.27 (dd, / = 10.1 , 3.8 Hz, 1H), 4.10 (dd, / = 10.1 , 3.0 Hz, 1H), 3.31 - 3.18 (m, 2H).

Example- 181: N-((5-((4-chlorophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide (±).

Step -1 : 1 - (allylo xy) -4-chlorobenzene .

To a solution of 4-chloro phenol (2.0 g, 15.556 mmol) in acetone (40.0 mL) was added potassium carbonate (6.441 g, 46.670 mmol), KI (0.251 g, 1.555 mmol) and allyl bromide (1.480 mL, 17.112 mmol) at 0 C under nitrogen atmosphere and it was stirred at 60 C for 14 h. The resulting mixture was concentrated under reduced pressure to give a residue. The obtained residue was dissolved in 100 mL mixture of water: diethyl ether (1 :1) and separated ether layer. Aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined diethyl ether and washed with water, brine solution (2 x 40 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the titled compound (2.6 g, crude) as a liquid. ^lU NMR (300 MHz,

Chloroform-d) δ 7.25 - 7.20 (m, 2H), 6.85 - 6.82 (m, 2H), 6.08 - 5.96 (m, 1H), 5.43 - 5.26 (m, 2H), 4.52 - 4.49 (m, 2H). Step-2: tert-butyl ((5-((4-chlorophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) carbamate (±).

tert-butyl (2-(hydroxyimino) ethyl)carbamate (1.2 g, 6.888 mmol) was reacted with N- chlorosuccinimide (1.010 g, 6.888 mmol), l-(allyloxy)-4-chlorobenzene (1.160 g,6.888mmol) (synthesized as per reported procedure inWO2011053821 ) and triethylamine (1.150 mL, 7.750 mmol) in N,N-dimethylformamide (20 mL) as described in the step-3 of example- 1 to give the titled compound (0.500 g, 21 %) as a liquid. LCMS: mJz 241.0 [M-100] ⁺; ^lU NMR (300 MHz, Chloroform-d) δ 7.26 - 7.22 (m, 2H), 6.85 - 6.82 (m, 2H), 4.96-4.93 (m, 1H), 4.10-3.98 (m, 4H), 3.16-3.12 (m, 1H), 3.05-3.02 (m, 1H), 1.45 (s, 9H).

Step-3: (5-((4-chlorophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methanamine hydrochloride (±).

tert-butyl ((5-((4-chlorophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)carbamate (±) (0.130 g, 0.381 mmol) was reacted with 4 N HC1 in 1,4-dioxane as described in the step-4 of example- 1 to give titled compound (0.100 g, crude). The crude product was taken to the next step without further purification.

Step-4: N-((5-((4-chlorophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide (±).

To a suspension of imidazo [1, 2-a] pyridine-6-carboxylic acid (0.058 g, 0.360 mmol) and (5-((4-chlorophenoxy) methyl)-4,5-dihydroisoxazol-3-yl)methanamine hydrochloride (±) (O.lOOg, 0.360 mmol) in N,N-dimethylformamide (2.0 mL) was added EDCI (0.083 g, 0.432 mmol), HOBt (0.073 g, 0.541 mmol) and N,N- diisopropylethylamine (0.123 mL, 1.082 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 14 h. The resulting mixture was poured onto ice water, extracted with ethyl acetate (2 x 20 mL). The combined ethyl acetate layer was washed with water, brine solution (2 x 10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (methanol/dichloromethane = 7/93) to give the titled compound (0.025 g, 17.1%) as a solid. HPLC: 96.6%; LCMS: m/z 385.25 [M+H] ⁺ ; 1H NMR (400 MHz, Chloroform-d) δ 8.83 - 8.81 (m, 1H), 7.74 - 7.61 (m, 2H), 7.42 (dd, / = 9.4, 1.8 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.85 - 6.79 (m, 2H), 6.77 (s, 2H), 5.05 - 4.98 (m, 1H), 4.43 (d, / = 5.3 Hz, 2H), 4.08-4.00 (m, 2H), 3.27 (dd, / = 17.3, 10.7 Hz, 1H), 3.12 (dd, / = 17.4, 7.1 Hz, 1H).

Biology:

Cytotoxicity Assay in MiaPaCa-2:

MiaPaCa-2 Cells (ATCC) were seeded in 96 well plates (Costar clear flat bottom) at a density of 3000 cells/well and allowed to settle overnight. Test compounds were dissolved in dimethyl sulphoxide (DMSO- Sigma Aldrich, D2650) and incubated with MiaPaCa-2 cells for 72 h. Post 72h, 50μ1 XTT (lmg/mL; Invitrogen, X 6493) and PMS (8 μΜ; Sigma Aldrich, P9625) reagents were added to the cells in 100 μΐ of cDMEM (Sigma Aldrich-D5648) + 10% FBS (Hyclone-5430088-03) + IX Pen Strep (Sigma Aldrich-P0781). After 1 hour incubation with XTT and PMS absorbance was monitored with Spectramax M3 (Molecular Device). IC₅₀ values were plotted using Graphppad prism software (Graphpad Inc, La Jola, CA USA).

IC₅₀ values of the compounds are indicated in Table 1 wherein "A" refers to an IC₅₀ value in range of 0.0001 to 3.00 μΜ, "B" refers to IC50 value in range of 3.001 to 10.0 μΜ and "C" refers to IC₅₀ value of greater than 10 μΜ.

Nampt Fluorescence assay:

The enzymatic assay was standardized using in-house recombinant Nampt wild type protein from E.coli expression & NAM (Cat # 47865-U) as a substrate. The product NMN formed after enzymatic reaction was derivatized to a fluorescent derivative through sequentially reacting with acetophenone/KOH and formic acid. The derivatized fluorescent NMN derivative was detected at 382 nm excitation wavelength and a 445 nm emission wavelength. The final assay conditions were 50 ng Nampt, 2 μΜ Nam (Km cone), 0.4 mM PRPP (Cat # P8296), 2 mM ATP (Cat # A7699), 0.02% BSA, 2 mM DTT, 12 mM MgCl₂, 50 mM Tris HC1 pH-7.5, 2% DMSO (25 μΐ, reaction volume: 15 minutes pre -incubation of enzyme with compound & 15 minutes incubation for the complete reaction) in 96 well Black plate. The florescence was measured (Excitation at 382 nm & Emission at 445 nm) using Victor³ V fluorimeter. The data is calculated using the RFU values. The final concentration of DMSO was 2 % in the assay. Each individual IC50 was determined using 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response (variable slope).

IC₅₀ values of the compounds are indicated in Table 1 wherein "A" refers to an IC₅₀ value in range of 0.0001 to 0.005 μΜ, "B" refers to IC₅₀ value in range of 0.0051 to 0.01 μΜ and "C" refers to IC₅₀ value in range of 0.011 to 0.2 μΜ.

Table 1: Biochemical assay and cell proliferation assay result

- c 98 B A

- c 99 A A

- c 100 - C

C A 101 A Aa - B 102 B Ab - C 103 C C c C 104 - C c C 105 A C

A A 106 A Aa A A 107 C Ab B A 108 B A

- C 109 A A

- C 110 A A

C A 111 A Aa c C 112 - Ab - C 113 B A c C 114 A A c C 114a A A

- C 114b A A c C 115 C C

- C 116 - C - C 117 - C

A A 118 - C

- C 119 A A

- C 120 - C

- C 121 A A

- C 122 C A

- A 123 C C

- C 124 A A

- C 125 A A

A A 126 B A

- C 127 A A

C C 128 C A

C C 129 A A

- C 130 C A c C 131 A A

- C 132 A A

- C 133 -

A A 134 - Ca A A 135 B Ab A A 136 B A

- C 137 B A - C 138 C A

- c 139 c A

- c 140 c A

- c 141 c B

A A 142 - A

- C 143 c B

- C 144 - C

- C 145 - C

C C 146 B A

- C 147 B A

- c 148 A A

- c 149 - A

- A 150 C A

- B 151 B A

B B 151a - C

C C 151b B A

A A 152 A A

C C 153 A A

- C 153a B A

- C 153b - -

- C 154 C A - C 155 B A

A A 155a C A

- A 155b A A

- C 156 C A

- C 157 A A

A A 158 B B

A A 159 A A

B A 159a A Aa B A 159b A Cb A A 160 B A

B C 161 C A

A A 161a B A

B A 161b B -

B A 162 A A

A A 162a B A

A A 162b A A

A A 163 C A

A A 164 B B

B B 165 C C

B A 166 B A

B A 167 - A 81 C A 168 C A

81a B A 169 c A

81b C - 170 c A

82 A A 171 B A

83 A A 172 B A

83a A A 173 C A

83b C - 174 B A

84 A A 175 - C

85 B A 176 C A

86 C A 177 A A

87 B A 178 C B

88 A A 179 - C

89 A A 180 - C

89a A A 181 - C

Claims

We claim:

1. A compound of formula (I),

wherein,

X is selected from Ό', 'S' or NCN;

selected from hydrogen or alkyl;

wherein * indicates the point of attachment to 1 ;

R₂ is selected

substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-fused-heterocyclyl, optionally substituted heterocyclyl-fused-aryl or optionally substituted aryl-fused- heterocyclyl; wherein the optional substituent at each occurrence is independently selected from R₇;

R3 is selected from hydrogen or alkyl;

R4 is selected from hydrogen or alkyl; R5 is selected from optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-fused-aryl, optionally substituted aryl- fused-heterocyclyl, optionally substituted aryl-fused-cycloalkyl or optionally substituted cycloalkyl-fused-aryl; wherein the optional substituent, at each occurrence, is independently selected from one or more Rs;

R6 at each occurrence is selected from alkyl, -OR_c, halo, haloalkyl, hydroxyalkyl, -(CH₂)_mNR_aR_b or -(CO)NHR₃;

Rs is selected from halogen, cyano, alkyl, haloalkyl, alkoxy, -CO₂R₃ or cycloalkyl;

R_a and R_b are independently selected from hydrogen or alkyl;

R_c is selected from hydrogen, alkyl or arylalkyl;

n and p are independently selected from 0, 1 or 2;

m is selected from 1 or 2;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

2. The compound according to Claim 1 , having the formula (IA):

wherein,

Ri and R₂ are same as defined in Claim 1 ;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

3. The compound according to Claim 1 or Claim 2, wherein Ri is heterocyclyl.

4. The compound according to Claim 3, wherein heterocyclyl is pyridine, furan, pyrazole, isoxazole, pyrrole, piperidine, piperazine, morpholine or imidazole.

5. The compound according to Claim 1 or Claim 2, wherein Ri is phenyl.

6. The compound according to Claim 1 or Claim 2, wherein R₂ is heterocyclyl, heterocyclyl-fused-heterocyclyl, heterocyclyl- fused-aryl or aryl-fused- heterocyclyl.

7.

8. The compound according to Claim 1 , having the formula (IB):

wherein,

Rzt, R₅ and n are same as defined in Claiml ;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

9. The c

wherein,

R5 is heterocyclyl;

n is 0 or 1 ;

or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

10. A compound selected from the group consisting of

Ex No. IUPAC NAME l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridin-3-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-a

(pyridin-4-yl)urea; l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-b

(pyridin-4-yl)urea; l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-2- cyano-3-(pyridin-4-yl)guanidine (±);

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-6,7- dihydrothieno [3 ,2-c]p yr idine- 5 (4H) -carboxamide (±) ;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-6,7-a

dihydrothieno [3 ,2-c]p yr idine- 5 (4H) -carboxamide ;

N-((5-(([l, -biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-6,7-b

dihydrothieno [3 ,2-c]p yr idine- 5 (4H) -carboxamide ;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3,4- dihydroisoquinoline-2(l H)-carboxamide (±) ; l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridin-3-ylmethyl)urea (±); l -((3-((2-bromophenoxy)methyl)-4,5-dihydroisoxazol-5-yl)methyl)-3- (pyridin-3-yl)urea (±); l -((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5- yl)methyl)-3-(pyridin-3-yl)urea (±); l -((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5- yl)methyl)-3-(pyridin-4-yl)urea (±); 0 l -((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5- yl)methyl)-3-(pyridin-3-ylmethyl)urea (±); l -((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5-a

yl)methyl)-3-(pyridin-3-ylmethyl)urea; l -((3-(([l,l'-biphenyl]-2-yloxy)methyl)-5-methyl-4,5-dihydroisoxazol-5-b

yl)methyl)-3-(pyridin-3-ylmethyl)urea; l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2-fluoropyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2-chloropyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2-methylpyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-a

(2-methylpyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-b

(2-methylpyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (3-cyanophenyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (furan-2-ylmethyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (4-cyanophenyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-a

(4-cyanophenyl)urea; l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-b

(4-cyanophenyl)urea; l -((5-(([l, -biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyrimidin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (4-fluorophenyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (4-cyano-3-(trifluoromethyl)phenyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (6-chloropyridazin-3-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (4-methylpyrimidin-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyrimidin-2-yl)urea (±); l -((5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2,6-dichloropyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2,6-dimethoxypyrimidin-4-yl)urea (±) ; l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (3,5-dimethylisoxazol-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (3-fluoropyridin-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (1 -methyl- lH-pyrazol-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (thiazol-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (thiophen-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[d]thiazol-6-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyrazin-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (6-chloropyrazin-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[b]thiophen-5-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (l,3,4-thiadiazol-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (6-cyanopyridin-3-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (oxazol-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2-chloro-6-methylpyrimidin-4-yl)urea (±); l -((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridin-4-yl)urea (±); l -((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol- a

3 -yl)methyl)-3 -(pyridin-4-yl)urea; l -((5-((2-(l-methyl-lH-pyrazol-4-yl) phenoxy) methyl)-4,5-dihydroisoxazol-b

3 -yl)methyl)-3 -(pyridin-4-yl)urea; l -((5-(([l, -biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (5-methylthiazol-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (5-bromo-4-methylpyridin-2-yl)urea (±); methyl 3-(3-((5-(([l ,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)ureido)thiophene-2-carboxylate (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (5-methylisoxazol-3-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (3-methylisoxazol-5-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (imidazo[l ,2-a]pyridin-6-ylmethyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (4-methylthiazol-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- ( 5 - (tr iflu oromethyl) isoxazol-3-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (isoquinolin-5-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2-chloropyrimidin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (thiophen-2-ylmethyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[d]oxazol-2-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (quinolin-6-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2,3-dihydro-l H-inden- l-yl)urea (±);

-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (lH-indazol-5-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (2,3-dihydro-lH-inden-5-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridazin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyrimidin-5-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (4-methylpyridin-2-yl) urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[d]oxazol-5-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (4-cyanobenzyl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (benzo[d]thiazol-5-yl)urea (±);

-((5-(([l, l '-biphenyl]-2-yloxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3- (3-methylpyridin-4-yl) urea (±);

4-(3-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)ureido)pyridine 1 -oxide (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (pyridazin-3-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (quinolin-7-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3- (isoquinolin-7-yl)urea (±);

3-fluoro-N-methyl-2'-((3-((3-(pyridin-4-yl)ureido)methyl)-4,5- dihydroisoxazol-5-yl) methoxy)-[l,l'-biphenyl]-4-carboxamide (±);

3-fluoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl)ureido)methyl)-4,5- dihydroisoxazol-5-yl)methoxy)-[l,l'-biphenyl]-4-carboxamide (±);

3-fluoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl)ureido)methyl)-4,5- a

dihydroisoxazol-5 -yl)methoxy)- [ 1 , 1 '-biphenyl] -4-carboxamide ;

3-fluoro-N-methyl-2'-((3-((3-(2-methylpyridin-4-yl)ureido)methyl)-4,5-b

dihydroisoxazol-5 -yl)methoxy)- [ 1 , 1 '-biphenyl] -4-carboxamide ;

3-fluoro-2'-((3-((3-(3-methoxypyridin-4-yl)ureido)methyl)-4,5- dihydroisoxazol-5-yl)methoxy)-N-methyl-[l ,l'-biphenyl]-4-carboxamide (±);

3-fluoro-N-methyl-2'-((3-((3-(pyridazin-4-yl)ureido)methyl)-4,5- dihydroisoxazol-5-yl)methoxy)-[l,l'-biphenyl]-4-carboxamide (±);

3-fluoro-2'-((3-((3-(2-methylpyridin-4-yl)ureido)methyl)-4,5-dihydroisoxazol- 5 -yl)methoxy)- [ 1 , 1 '-biphenyl] -4-carboxamide (±) ;

2'-((3-((3-(2-methylpyridin-4-yl)ureido)methyl)-4,5-dihydroisoxazol-5- yl)methoxy)-[l,l'-biphenyl]-4-carboxamide (±); l -((5-(((4'-methoxy-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(2-methylpyridin-4-yl)urea (±); l -((5-(((4'-methoxy-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl)-3-(pyridazin-4-yl)urea (±); l -(imidazo[l,2-a]pyridin-6-ylmethyl)-3-((5-((2-(pyridin-3-

76

yl)phenoxy)methyl)-4 ,5 -dihydroisoxazol-3 -yl)methyl)urea (±) ; l -(pyridazin-4-yl)-3-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-

77

dihydroisoxazol-3-yl)methyl)urea (±); l -((5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

78

yl)methyl)-3-(2-methylpyridin-4-yl)urea (±); l -((5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

79

yl)methyl)-3-(pyridazin-4-yl)urea (±); l -((5-((2-(5-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

80

yl)methyl)-3-(2-methylpyridin-4-yl)urea (±); l -((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl)

81

methyl)-3-(2-methylpyridin-4-yl) urea (±); l -((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl)

81 a

methyl)-3-(2-methylpyridin-4-yl) urea; l -((5-((2-(2-fluoropyridin-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl)

81b

methyl)-3-(2-methylpyridin-4-yl) urea; l -((5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5 -dihydroisoxazol-3 -

82

yl) methyl)-3-(2-methylpyridin-4-yl) urea (±); l -((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5 -dihydroisoxazol-3 -

83

83a

yl) methyl)-3-(2-methylpyridin-4-yl) urea; l -((5-((2-(2-methoxypyridin-3-yl) phenoxy) methyl)-4, 5 -dihydroisoxazol-3 -

83b

yl) methyl)-3-(2-methylpyridin-4-yl) urea; l -((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

84

yl)methyl)-3-(2-methylpyridin-4-yl)urea (±); l -((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

85

yl)methyl)-3-(imidazo[l ,2-a]pyridin-6-yl)urea (±); l -((5-((2-(furan-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-

86

(imidazo[l ,2-a]pyridin-6-ylmethyl)urea (±); l -((5-((2-(furan-3-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)-3-

87

(2-methylpyridin-4-yl) urea (±); l -((5-((2-(3,5-dimethylisoxazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

88

yl)methyl)-3-(2-methylpyridin-4-yl)urea (±); l -((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

89

89 a

yl)methyl)-3-(2-methylpyridin-4-yl)urea; l -((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

89b

yl)methyl)-3-(2-methylpyridin-4-yl)urea;

1 -(2-cyclopropylpyridin-4-yl)-3-((5-((2-(l-methyl- lH-pyrazol-4-

90

yl)phenoxy)methyl)-4 ,5 -dihydroisoxazol-3 -yl)methyl)urea (±) ;

1 -(2-ethylpyridin-4-yl)-3-((5-((2-(l -methyl- 1 H-pyrazo 1-4- yl)phenoxy)methyl)-

91

4,5 -dihydroisoxazol-3 -yl)methyl)urea (±) ; l -((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

92

yl)methyl)-3-(pyridazin-4-yl)urea (±); l -(2-methoxypyridin-4-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-

93

yl)phenoxy)methyl)-4 ,5 -dihydroisoxazol-3 -yl)methyl)urea (±) ;

94 l -((5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)phenoxy)methyl)-4,5- dihydroisoxazol-3-yl)methyl)-3-(2-methylpyridin-4-yl)urea (±); l -(isoquinolin-7-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-

95

4,5 -dihydroisoxazol-3 -yl)methyl)urea (±) ; l -(benzo[b]thiophen-6-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-

96

yl)phenoxy)methyl)-4 ,5 -dihydroisoxazol-3 -yl)methyl)urea (±) ; l -(imidazo [1 , 2-a] pyridin-6-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl)

97

phenoxy) methyl)-4, 5 -dihydroisoxazol-3 -yl) methyl) urea (±); l -(imidazo [1 , 2-a] pyridin-6-yl)-3-((5-((2-(l-methyl-lH-pyrazol-4-yl)

97 a

phenoxy) methyl)-4, 5 -dihydroisoxazol-3 -yl) methyl) urea; l -((5-((2-(lH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

98

yl)methyl)-3-(2-methylpyridin-4-yl)urea (±);

1 -((5 -((2-( 1 H-pyrrol- 1 -yl)phenoxy)methyl)-4 ,5 -dihydroisoxazol-3 -yl)methyl)-

99

3-(2-methylpyridin-4-yl)urea (±); l -((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-3-

100

(2-methoxypyrimidin-5-yl)urea (±); l -(imidazo[l,2-a]pyridin-6-ylmethyl)-3-((5-((2-(l-methyl-lH-pyrazol-4-

101

yl)phenoxy)methyl)-4 ,5 -dihydroisoxazol-3 -yl)methyl)urea (±) ; l -(2-methylpyridin-4-yl)-3-((5-((3-mo holinophenoxy)methyl)-4,5-

102

dihydroisoxazol-3-yl)methyl)urea (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

103

yl)methyl)-3,4-dihydroisoquinoline-2(lH)-carboxamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

104

yl)methyl)-3,4-dmydropyrrolo[l,2-a]pyrazine-2(lH)-carboxarnide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

105

yl)methyl)-6J-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide (±); N-((5-((2-(l-methyl-l H-pyrazol-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-

106

3-yl) methyl) isoindoline-2-carboxamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

107

yl)methyl)-lH-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (±);

2-cyano-l-((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-

108

dihydroisoxazol-3-yl)methyl)-3-(2-methylpyridin-4-yl)guanidine; l -((5-((2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

109

yl)methyl)-3-(2-methylpyridin-4-yl)thiourea;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-lH-

110

pyrrolo[3,2-c]pyridine-2-carboxamide(±);

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-4-

111

(lH-imidazol-l-yl)benzamide (±);

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-lH-

112

indole-5-carboxamide (±);

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)

113

b enzo [b ] thiophene-2-carboxamide(±) ;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-

114

yl)methyl)imidazo[l,2-a] pyridine-6-carboxamide (±);

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)

114a

imidazo [ 1 ,2-a]pyridine-6-carboxamide ;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)

114b

imidazo [ 1 ,2-a]pyridine-6-carboxamide ;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-lH-

115

benzo[d] imidazole-5-carboxamide (±);

116 N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-5- (4-methoxyphenyl) furan-2-carboxamide (±);

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-6-

117

(trifluoromethyl) benzo [b] thiophene-2-carboxamide (±);

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-lH-

118

b enzo [d] imidazole-2-carboxamide (±) ;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-6-

119

( 1 H-imidazol- 1 -yl)nicotinamide (±) ;

N-((5-(([l,l'-biphenyl]-2-yloxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-2-

120

(methyl sulfonamide)) isonicotinamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

121

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-

122

dihydroisoxazol-3-yl) methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-

123

dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyrimidine-6-carboxamide (±);

N-((5-(((4'-carbamoyl-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-

124

3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-

125

dihydroisoxazol-3-yl)methyl)-lH-pyrrolo[3,2-c]pyridine-2-carboxamide (±);

N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-

126

dihydroisoxazol-3-yl)methyl)thieno[2,3-b]pyridine-2-carboxamide (±);

N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-

127

dihydroisoxazol-3-yl)methyl)thieno[2,3-c]pyridine-2-carboxamide (±);

N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-

128

dihydroisoxazol-3-yl)methyl)furo[2,3-c]pyridine-2-carboxamide (±); N-((5-(((4'-fluoro-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3-yl)

129

methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-(((5-cyano-4'-fluoro-[l,l'-biphenyl]-2-yl)oxy)methyl)-4,5-

130

dihydroisoxazol-3 -yl)methyl)imidazo [1 ,2-a]pyridine-6 -carboxamide ;

N-((5-(((3',5'-difluoro-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-

131

3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-(((4'-methoxy-[l ,l'-biphenyl]-2-yl)oxy)methyl)-4,5-dihydroisoxazol-3-

132

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

133

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-(((3'-fluoro-4'-(methylcarbamoyl)-[l,r-biphenyl]-2-yl)oxy)methyl)-4,5-

134

dihydroisoxazol-3 -yl)methyl)imidazo [1 ,2-a]pyridine-7 -carboxamide (±) ;

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

135 yl)methyl)irnidazo[l,2-a]pyridine-6-carboxamide (Enatiomer-1 of Example- 121);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

136 yl)methyl)irnidazo[l,2-a]pyridine-6-carboxamide (Enatiomer-2 of Example- 121);

N-((5-((4-cyano-2-(l-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-

137

dihydroisoxazol-3-yl)methyl)irnidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(l-ethyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

138

yl)methyl)irnidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(l-isopropyl-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-

139

dihydroisoxazol-3-yl)methyl)irnidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-(((l-methyl-lH-indazol-4-yl)oxy)methyl)-4,5-dihydroisoxazol-3-

140

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±); N-((5-((2-(l-(2-hydroxyethyl)-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-

141

dihydroisoxazol-3-yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(l-(2-(dimethylamino)ethyl)-lH-pyrazol-4-yl)phenoxy)methyl)-4,5-

142

dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((3-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

143

yl)methyl) imidazo [1 ,2-a] pyridine-6-carboxamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

144

yl)methyl)imidazo[l,2-a]pyridine-7-carboxamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

145

yl)methyl)furo[3,2-c]pyridine-2-carboxamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

146

yl)methyl)furo[2,3-c]pyridine-2-carboxamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

147

yl) methyl)thieno[2,3-b]pyridine-2-carboxamide (±);

N-((5-((2-(l-methyl-l H-pyrazol-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

148

yl)methyl)thieno[2,3-c]pyridine-2-carboxamide (±);

N-((5-(l-(2-(l-methyl-lH-pyrazol-4-yl)phenoxy)ethyl)-4,5-dihydroisoxazol-3-

149

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(lH-pyrazol-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

150

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

151

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

151a

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide;

151b N-((5-((2-(lH-imidazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide;

N-((5-((2-(lH-pyrrol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)

152

imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(lH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

153

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(lH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

153a

yl)methyl)imidazo [1 ,2-a]pyridine-6-carboxamide;

N-((5-((2-(lH-pyrazol-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

153b

yl)methyl)imidazo [1 ,2-a]pyridine-6-carboxamide;

N-((5-((2-(pyrimidin-5-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)

154

imidazo [l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

155

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

155a

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

155b

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(6-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

156

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(2-methoxypyridin-4-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-

157

yl) methyl) imidazo [1, 2-a] pyridine-6-carboxamide (±);

N-((5-((2-(4-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)

158

methyl) imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(2-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)

159

methyl) imidazo[l,2-a]pyridine-6-carboxamide (±); N-((5-((2-(2-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)

159a

methyl) imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(2-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)

159b

methyl) imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(5-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

160

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(2-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

161

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(2-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

161a

yl)methyl)imidazo [1 ,2-a]pyridine-6-carboxamide;

N-((5-((2-(2-methoxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

161b

yl)methyl)imidazo [1 ,2-a]pyridine-6-carboxamide;

N-((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

162

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

162a

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide;

N-((5-((2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

162b

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide;

N-((5-((2-(6-(trifluoromethyl)pyridin-3-yl)phenoxy)methyl)-4,5-

163

dihydroisoxazol-3-yl)methyl) imidazo [l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(6-(benzyloxy)pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

164

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(6-hydroxypyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

165

yl)methyl)imidazo[l,2-a] pyridine-6-carboxamide (±);

166 N-((5-((2-(2-methylpyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3- yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(2-methylpyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

167

yl)methyl) imidazo[l ,2-a] pyridine-6-carboxamide (±);

N-((5-((2-(pyridin-4-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

168

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(pyridin-2-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

169

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(5-fluoropyridin-2-yl) phenoxy) methyl)-4, 5-dihydroisoxazol-3-yl)

170

methyl) imidazo [1, 2-a] pyridine-6-carboxamide (±);

N-((5-((2-(pyridin-3-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

171

yl)methyl)furo[2,3-c]pyridine-2-carboxamide (±);

N-((5-((4-cyano-2-(6-fluoropyridin-3-yl)phenoxy)methyl)-4,5-

172

dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenoxy)methyl)-4,5-

173

dihydroisoxazol-3-yl)methyl)imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(4-methylpiperazin-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-

174

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(4-methylpiperazin-l-yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)

175

methyl) imidazo[l,2-a]pyridine-7-carboxamide (±);

N-((5-((2-(piperidin-l -yl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)

176

imidazo[l,2-a]pyridine-6-carboxamide (±);

N-((5-((2-mo holinophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl)

177

imidazo [1 , 2-a] pyridine-6-carboxamide (±);

N-((5-((3-mo holinophenoxy)methyl)-4,5-dihydroisoxazol-3-

178

yl)methyl)imidazo[l,2-a]pyridine-6-carboxamide (±); N-((5-((4-(trifluoromethoxy)phenoxy)methyl)-4,5-dihydroisoxazol-3-

179

yl)methyl) imidazo[l ,2-a]pyridine-6-carboxamide (±);

N-((5-((2-(trifluoromethyl)phenoxy)methyl)-4,5-dihydroisoxazol-3-yl)methyl)

180

imidazo[l,2-a]pyridine-6-carboxamide (±) and

N-((5-((4-chlorophenoxy) methyl)-4, 5-dihydroisoxazol-3-yl) methyl) imidazo

181

[1, 2-a] pyridine-6-carboxamide (±); or a pharmaceutically acceptable salt or a stereoisomer or a N-oxide thereof.

11. A pharmaceutical composition comprising at least one compound according to any one of Claims 1 to 10 and/or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of Claim 11 further comprising at least one additional pharmaceutical agent wherein the said additional pharmaceutical agent is an anticancer agent, chemotherapy agent, or antiproliferative compound.

13. A compound according to any one of the Claims 1 to 10 or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

14. The compound according to any one of the Claims 1 to 10 for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide.

15. A method of inhibiting Nicotinamide phosphoribosyltransferase in a patient by administering therapeutically effective amount of at least one compound of any one of Claims 1 to 10.

16. A method of treating, preventing, inhibiting or eliminating a disease or condition in a patient by inhibiting NAMPT in said patient by administering a therapeutically effective amount of at least one compound of any one of Claims 1 to 10, wherein said disease or condition is selected from the group consisting of cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, skin cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, bladder cancer, leukemia, lymphoma, Hodgkin' s disease, viral infections including adult respiratory distress syndrome, ataxia telengiectasia, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, fibrotic diseases, dermatitis, atoptic dermatitis, psoriasis, ultra-violet induced skin damage, systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spodylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, restenosis, diabetes, glomerulonephiritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, cancers of the brain and central nervous system, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck.