OA16396A

OA16396A - Oxazoline and isoxazoline derivatives as CRAC modulators.

Info

Publication number: OA16396A
Application number: OA1201300176
Authority: OA
Inventors: Gokul Keruji Deshmukh; Nageswara Rao Irlapati; Vijay Pandurang Karche; Santosh Madhukar Jachak; Neelima Sinha; Venkata P. Palle; Rajender Kumar Kamboj
Original assignee: Lupin Limited
Priority date: 2010-10-30
Filing date: 2011-10-31
Publication date: 2015-10-07

Abstract

The present invention relates to compounds of Formula (I) along with processes for their preparation that are useful for treating, preventing and/or managing the diseases, disorders, syndromes or conditions associated with the modulation of CRAC. The invention further relates to methods of treating, preventing, managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of CRAC of Formula (I).

Description

OXAZOLINE AND ISOXAZOLINE DERIVATIVES AS CRAC MODULATORS

Related applications

The présent application daims the benefit of priority to Indian Provisionai Patent Application Nos. 1215/KOL/2010, fîled on October 30, 2010 and 0473/KOL/2011, filed on April 1, 2011. The entire provisionai spécifications are incorporated herein by reference.

Technical field of the invention

The invention relates to heterocyclic compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, prévention, management, and/or lessening of severity of diseases, disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel. The invention also relates to methods of treating, preventing, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the modulation of CRAC. The invention also relates to processes for the préparation of the compounds of the invention.

Background of the invention

Inflammation is the response by the body to infection, irritation or injury; wherein the immune cells of the body are activated in response to any of these stimuli. Inflammation plays a key rôle in many diseases not only of the immune cells such as allergy, asthma, arthritis, dermatitis, multiple sclerosis, systemic lupus but also organ transplant, diabètes, cardiovascular disease, Alzheimer’s disease, Parkinson’s disease, inflammatory and/or irritable bowel syndrome (Di Sabatino et. al., J. Immunol., 183, 3454-3462, 2009), psoriasis, and cancer. An initial inflammatory response to pathogens or injury is necessary and required to fight infection or heal the wound, but sustained or persistent inflammation can lead to any of the chronic disorders; characterized by the production of inflammatory cytokines as, specified above.

Inflammation is characterized by the production of different cytokines such as IL-2, IL-4, IL-10. IL-13, IL-17, IL-21, IL-23, 1L-28, IFN-γ, TNF-α, etc., that hâve been implicated in playing a rôle in different diseases. Any drug which can modulate the production of these cytokines would help alleviate the disease symptoms and may also cure it.

Ca⁺² signais hâve been shown to be essential for diverse cellular functions in different cell types including différentiation, effector functions, and gene transcription in cells of the immune System as well as regulating the cytokine signaling pathway through calcineurin and nuclear factor of activated T cells (NFAT).

In immune cells, sustained Ca⁺² influx has been shown to bc necessary for complété and longlasting activation of calcineurin-NFAT pathways, essential for cytokine production. Engagement of receptors such as T-cell antigen receptor (TCR), the B-cell antigen receptor (BCR), and the Fc receptors (FcR) on mast cells, macrophages, and NK cells, leads to the tyrosine phosphorylation and activation of phospholipase C-γ (PLC-γ). PLC-γ hydrolyzes phosphatidylinositol-3,4-biphosphate (PIP2) to the second messengers, inositol-1,4,5triphosphate (IP3) and diacylglycérol (DAG). IP3 binds to IP3 receptors (IP3R) in the membrane of the endoplasmic réticulum (ER) and induces the release of ER Ca⁺² stores into the cytoplasma. The decrease in the Ca concentration in the ER induces store-operated Ca entry (SOCE) through plasma membrane Ca⁺² channels. SOCE through highly Ca⁺²- sélective Ca⁺² releaseactivated Ca (hereinafter, CRAC) channels constitutes the major pathway of intracellular Ca entry in T cells, B cells, macrophages, mast cells, and other cell types (Parekh and Putney, Physiol. Rev., 85, 757-810, 2005).

The CRAC channel is comprised of two family proteins, one which functions in sensing Ca⁺²levels in the ER - the stromal interacting molécules (STIM)-1 and -2 and the other which is a pore-forming protein - Orail, 2 and 3. The STIM proteins are single transmembrane proteins localized on the ER membrane with their N-termini oriented toward the lumen and containing an EF-hand Ca⁺² binding motif. Déplétion of Ca⁺² from the ER causes Ca⁺² to dissociate from STIM, which causes a conformational change that promûtes oligomérization and migration of STIM molécules to closely apposcd ER-plasma membrane junctions. At the junctions, the STIM oligomers interact with the Orai proteins. In resting cells, Orai channels are dispersed across the plasma membrane and on déplétion of Ca⁺² from the stores, they aggregate in the vicinity of the STIM punctae. The eventual increase in intracellular Ca concentration activâtes the calcineurin-NFAT pathway. NFAT activâtes transcription of several genes including cytokine genes such as 1L-2, etc along with other transcription factors such as AP-1, NFkB and Foxp3 (Fahmer et. al., Immuno. Rev., 231, 99-112, 2009).

The rôle of CRAC channel in different diseases such as allergy, inflammatory bowel disease, thrombosis and breast cancer has been reported in literature (Parekh, Nat. Rev., 9, 399 - 410,

2010). It has been reported in the art that ST1M1 and Orail are essential in in vitro tumor cell migration and in vivo tumor metastasis. Thus the involvement of store operated Ca entry in tumor metastasis renders STIM1 and Orail proteins potential targets for cancer therapy (Yang

et.al., Cancer Cell, 15, 124-134, 2009). Additional literature available on the involvement of CRAC channel in cancer are Abeele et. al., Cancer Cell, 1, 169-179, 2002, Motiani et al., J. Biol. Chem., 285; 25, 19173-19183,2010.

Recent literature reports the rôle of STIM1 and Orail in collagen dépendent arterial thrombosis in mice in vivo and that deficiency in either protects against collagen dépendent arterial thrombus formation as well as brain infarction (Varga-Szabo et. al., J. Exp. Med., 205, 1583-1591, 2008; Braun et. al., Blood, 113, 2056-2063, 2009). The rôle of STIM1-Orail mediated SOCE in thrombus formation makes Orail a potential target for treatment of thrombosis and related conditions (Gillo et. al., JBC, 285; 31, 23629-23638, 2010).

As the Orai pore channel proteins hâve been shown to be essential for transmitting the signal induced by the binding of antigens to the cellular receptors on the immune cells, a potential Orai channel interacting drug would be able to modulate the signaling thereby impacting the sécrétion of the cytokines involved in, as mentioned hereinbefore, inflammatory conditions, cancer, allergie disorders, immune disorders, rheumatoid arthritis, cardiovascular diseases, thrombocytopathies, arterial and/or venous thrombosis and associated or related conditions which can be benefitted by the CRAC channel modulatory properties of the compounds described herein.

Several compounds hâve been reported in the art as CRAC channel modulators. For example, patent application publications W02005009954, W02006081391, W02006083477,

W02007089904, W02009017819, WO2010039238, W02007087429, W02007087441 and W02007087442 disclose substituted biaryl compounds for modulating CRAC channels.

Patent application publications W02009076454, WO2010027875 and W02006081389 W02005009539, W02005009954, W02006034402, W02009035818, US20100152241,

W02010025295, WO2011034962 disclose thiophene dérivatives for modulating CRAC channels.

Summary of the Invention

In accordance with one aspect, the invention provides the compounds of Formula (I):

(RJ, (I) wherein, ring E is a 5-membered non aromatic heterocyclic ring selected from

and

(b)

X, at each occurrence, is independently selected from -C(O)-, -CR4R5- and -NR-;

Y, at each occurrence, is independently selected from -C(O)- and -CR4R5-;

R is selected from alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, C(O)NR₆R₇, -C(O)OR₆ and -C(O)R_fi;

ring W is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

Ri, which may be same or different at each occurrence, is independently selected from halo, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, -S(O)_nR₆, -NR₆S(O)₂R₇, -NR₆(CR₈R₉)_nC(O)OR₆, -NR₆(CR₈R₉)_nC(O)R₆, NR₆(CRKR9)_nC(O)NR₆R₇, -C(O)NR₆R₇, -C(O)(O)R₆, -C(O)R₆, -OC(O)R₆, and -OC(O)NR₆R₇;

R₂, which may be same or different at each occurrence, is independently selected from hydrogen, halo, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, -C(O)ORè, -NR₆R₇, -C(O)Rf„ -NHS(O)₂R₇and -NHC(O)R₆;

R₃, which may be same or different at each occurrence, is independently selected from hydrogen, halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, -NRûR₇, -NR6S(O)₂R₇, -C(O)NRôR₇ and C(O)OR₆;

R4 and R5, which may be same or different at each occurrence, are independently selected from hydrogen, halo, -ORjo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -(CR_gR₉)„C(O)NR₆R₇, -C(O)R₆, and -(CR₈R₉)_nC(O)OR₆ ;

provided that, when any of R4 or R5 in Y is -ORio then Rio is not hydrogen; or

R4 and R5, taken together with the carbon atom to which they are attached to, may form a substituted or unsubstituted 3- to 7- membered carbocyclic or heterocyclic ring; or any one of R4 and R5 in X and any one of R4 and R5 in Y combined together, when they are attached to carbon atoms, may form a 4- to 7- membered substituted or unsubstituted heterocyclic ring;

provided that both of X and Y are not simultaneousiy -C(O)-;

ring D is selected from

wherein A¹ and A² are independently selected from C and N;

L is -C(O)NR| r or -NRnC(O)-;

G ïs selected from S, NR12 and O;

Rn, at each occurrence, is independently selected from hydrogen, alkyl and aryl;

R12 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;

Rjois selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;

R₆ and R7, which may be same or different at each occurrence, are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; or R₍₎ and R7, taken together with the nitrogen atom to which they are attached to, may form a substituted or unsubstituted 3- to 14membered heterocyclic ring;

Rg and Rq, which may be same or different at each occurrence, are independently selected from hydrogen, halo, alkyl and alkoxy; or Rg and Rt>, taken together with the carbon atom they are attached to, may form a 3- to 6- membered cyclic ring wherein the cyclic ring may be carbocyclic or heterocyclic;

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

p îs an integer ranging from 0 to 5, both inclusive;

q is an integer ranging from 1 to 4, both inclusive; and wherein alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, aryl, heteroaryl, heterocyclyl, wherever they occur may optionally be substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, oxo (=O), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(O)OR^X, -C(O)R^X, -C(S)R^X, -C(O)NR^xR^y, -NR^xC(O)NR^yR^z, -N(R^x)S(O)R^y, N(R^x)S(O)2R^y, -NR^xR^y, -NR^xC(O)R^y, -NR^xC(S)R^y, -NR^xC(S)NR^yR^z, -S(O)2NR^xR^y, -OR^X, OC(O)R^X, -OC(O)NR^xR^y, -R^xC(O)OR^y, -R^xC(O)NR^yR^z, -R^xC(O)R^y, -SR^X, and -S(O)₂R^X,· wherein each occurrence of R^x, R^y and R^z are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and heteroarylalkyl;

or a pharmaceutically acceptable sait thereof.

The below embodiments, which are illustrative in nature only and are not intended to limit the scope of the invention.

According to one embodiment are provided compounds of Formula (la):

or a pharmaceutically acceptable sait thereof;

wherein ring °'N is selected from Formula (i) to (iv)

ring W, ring D, R, Ri, R₂, R3, R4, Rs, Rio, ‘p’ and ‘q’ are as defined herein above.

According to another embodiment are provided compounds of Formula (Ib):

or a pharmaceutically acceptable sait thereof;

wherein ring °~N is selected from Formula (i) to (iv) as defined in Formula (la);

ring W, ring D, R, R_b R₂, R3, R4, R₅, Rio, ‘p’ and ‘q’ are as defined herein above.

According to another embodiment are provided compounds of Formula (le):

or a pharmaceutically acceptable sait thereof;

wherein ring N is selected from Formula (v) to (vii)

ring W, ring D, R, R_b R2, R3, R4, R5, ‘p* and ‘q’ are as defined herein above.

According to another embodiment are provided compounds of Formula (Id):

(Id» or a pharmaceutically acceptable sait thereof;

('Vv wherein ring N is selected from Formula (v) to (vii) as defined in Formula (le);

ring W, ring D, R, R_u R2, Ri, R.i, R5, ‘p’ and ‘q’ are as defined herein above.

It should be understood that Formula (I), (la), (1b), (le), and (Id) structurally encompass ail Noxides, tautomers, stereoisomers and pharmaceutically acceptable salts that may be contemplated from the chemical structures described herein.

According to sub embodiment are provided compounds of Formula (la), (Ib), (le) and/or (Id) in which ring D is

wherein A¹ and A² are independently selected from C and N; G is S or NR12; ‘q’ is 1 ; R3 and R(2are as defined herein above. W '

According to one sub embodiment are provided compounds of Formula (la), (lb), (le) and/or (Id) in which ring W is aryl, heteroaryl or cycloalkyl.

According to another sub embodiment are provided compounds of Formula (la), (Ib), (le) and/or (Id) in which R| is halo, hydroxyl, alkyl or alkoxy.

According to another sub embodiment are provided compounds of Formula (la), (Ib), (le) and/or (Id) in which R₂ is hydrogen, halo, hydroxyl, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, -C(O)ORô, -NR₆R7 or -C(O)R6i Rô and R7 are as defined herein above.

According to another sub embodiment are provided compounds of Formula (la), (Ib), (le) and/or (Id) in which R3 is hydrogen, halo, hydroxy, alkyl, alkoxy, -C(O)NRôR7 or -C(O)ORe ; Rù and R7 are as defined herein above.

In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient.

In another aspect of the invention, there is provided a compound of Formula (I) useful in treating, preventing, managing and/or lessening the severity of the diseases, disorders, syndromes or conditions associated with the modulation of CRAC channel.

In another aspect, the invention provides a pharmaceutical composition of a compound of Formula (I) useful in treating, preventing, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the modulation of CRAC channel in a subject in need thereof by administering to the subject, one or more compounds described herein in an amount.

In another aspect, the invention provides a method of modulating ion channel activity, for example, CRAC channel, by administering effective amount of a compound of Formula (I) and/or pharmaceutically acceptable salts.

In another aspect, the invention provides a method of modulating the sécrétion of cytokines, for example IL-2, IL-4, IL-10, IL-13, IL-17, IL-21, IL-23, IL-28, IFN-γ and TNF-α and the like, by regulating the cytokine signalling pathway through calcineurin and NFAT cells.

In another aspect of the invention are processes for the préparation of the compounds described herein. Ά?

According to another embodiment are provided a process for the préparation compounds of

Formula (I):

comprising reacting a compound of Formula (1) with a compound of Formula (2)

wherein X' is halo; ring E, ring D, ring W, L, R), Ri, Rj, p, q and n are as defined herein above;

in presence of a catalyst selected from Pd(PPh3)2Ch, Pdîdbaj, Pd(PPhj)4 or Pd(OAc)2 or a mixture thereof; a ligand selected from BINAP, xanthophos or triphenylphosphine or a mixture thereof and a base.

Detailed description of the invention

Définitions and Abbreviations:

Uniess otherwise stated, the following terms used in the spécification and daims hâve the meanings given below.

For purposes of interpreting the spécification, the following définitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

The terms halogen or halo means fluorine, chlorine, bromîne, or iodine.

Uniess otherwise stated, in the présent application “oxo” means C(=O) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the présent invention.

The term alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molécule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t-butyl) and the like. Uniess set forth or recited to the contrary, ail alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term alkylene refers to a saturated divalent hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone. In particular, C1-C5 alkylene means a saturated divalent hydrocarbon radical with one to six carbon atoms e.g. methylene (-CH2-), ethylene (-CH2-CH2-), 2,2-dimethylethylene, n-propylene, 2-methylpropylene, and the like. Unless set forth or recited to the contrary, ail alkylene groups described or claimed herein may be straight chain or branched, substituted or unsubstituted,

The tenu alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2butenyl and the like. Unless set forth or recited to the contrary, ail alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond. Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, ail alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term alkoxy refers to an alkyl group attached via an oxygen linkage. Non-limiting examples of such groups are methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, ail alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term alkenyloxy refers to an alkenyl group attached via an oxygen linkage. Non-limiting examples of such groups are vinyloxy, allyloxy, 1-butenyloxy, 2-butenyloxy, isobutenyloxy, 1pentenyloxy, 2-pentenyloxy, 3-methyl-1-butenyloxy, 1-methyl-2-butenyloxy, 2,3dimethylbutenyloxy, 1-hexenyloxy and the like. Unless set forth or recited to the contrary, ail alkenyloxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term “alkynyloxy” refers to an alkynyl group attached via an oxygen linkage. Non-limiting examples of such groups are acetylenyloxy, propynyloxy, 1-butynyloxy, 2-butynyloxy, 1pentynyloxy, 2-pentynyloxy, 3-methyl-1-butynyloxy, 1-hexynyloxy, 2-hexynyloxy, and the like.

The term cycloalkyl refers to a non-aromatic mono or multicyclic ring System having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbomyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, ail cycloalkyl groups described or claimed herein may be substituted or unsubstituted.

The term cycloalkoxy refers to an cycloalkyl, defined herein, group attached via an oxygen linkage. Non-limiting examples of such groups are cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like. Unless set forth or recited to the contrary, ail alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term cycloalkenyl refers to a non-aromatic mono or multicyclic ring System having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, ail cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.

The term cycloalkylalkyl refers to a cycloalkyl group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to the contrary, ail cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term haloalkyl refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. Preferably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can hâve one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chioromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having ail hydrogen atoms replaced with halogen atoms.

The term haloalkoxy refers to an haloalkyl, defined herein, group attached via an oxygen linkage. Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy. Unless set forth or recited to the contrary, ail haloalkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

The term hydroxyalkyl refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl. Non-limiting examples of a hydroxyalkyl include 2- hydroxyethyl, 3-hydroxypropyl, 2hydroxypropyl, and the like.

The term aryl refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic Systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, ail aryl groups described or claimed herein may be substituted or unsubstituted.

The term arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H4C6H5. Unless set forth or recited to the contrary, ail arylalkyl groups described or claimed herein may be substituted or unsubstituted.

A carbocyclic ring or carbocycle as used herein refers to a 3- to 10- membered saturated or unsaturated, monocyclic, fused bicyclic, spirocycüc or bridged polycyclîc ring containing carbon atoms, which may optionally be substituted, for example, carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, aryl, naphthyl, adamentyl etc. Unless set forth or recited to the contrary, ail carbocyclic groups or rings described or claimed herein may be aromatic or non aromatic.

The term heterocyclic ring or heterocyclyl ring or heterocyclyl, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consiste of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring Systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with -C(O)-, -C(=N-alkyl)-, or -C(=N-cycloalkyl), etc. Non-limiting examples of heterocyclic rings include azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, benzopyranyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydro azepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl y/ sulfoxide, thiamorpholinyl sulfone and the like. The heterocyclic ring may be attached to the main structure at any heteroatom or carbon atom that results in the création of a stable structure. Unless set forth or recited to the contrary, ail heterocyclyl groups described or claimed herein may be substituted or unsubstituted.

The term heteroaryl unless otherwise specîfied, refers to a substituted or unsubstituted 5- to 14membered aromatic heterocyclic ring with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring System. The heteroaryl ring may be attached to the main structure at any heteroatom or carbon atom that results in the création of a stable structure. Non-limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indoiyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like. Unless set forth or recited to the contrary, ail heteroaryl groups described or claimed herein may be substituted or unsubstituted.

The term heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the création of a stable structure. Unless set forth or recited to the contrary, ail heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.

The term heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the création of a stable structure. Unless set forth or recited to the contrary, ail heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.

Unless otherwise specified, the term substituted as used herein refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety. Such substituents include, but are not limited to hydroxy, halo, carboxyl, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, amino, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(O)OR^X, -C(O)R^X, C(S)R*, -C(O)NR^xR^y, -NR^xC(O)NR^yR^z, -N(R^x)S(O)R^y, -N(R^x)S(O)2R^y, -NR^xR^y, -NR^xC(O)R^y, NR^xC(S)R^y, -NR^xC(S)NR^yR^z, - S(O)2NR^xR^y, -OR^X, -OC(O)R^X, -OC(O)NR^xR^y, -R^xC(O)OR^y, R^xC(O)NR^yR^z, -R^xC(O)R^y, -SR^X, and -S(O)₂R^X; wherein each occurrence of R^x, R^y and R^z are (vS' independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and heteroarylalkyl.

The phrase “may optionally be substituted” refers to a moiety or group that may or may not be substituted. For example, optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted and unsubstituted aryl radicals.

A stereoisomer refers to a compound having the same atoms bonded through the same bonds but having different three-dimensional orientations, which are not interchangeable. The invention contemplâtes various stereoisomers and mixtures thereof and includes enantiomers and diastereomers. The invention also includes géométrie isomers “E” or “Z” or cis or trans configuration in a compound having either a double bond or having substituted cycloalkyl ring System.

A Tautomer refers to a compound that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachaient of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (I).

The term treating or treatment of a state, disease, disorder, condition or syndrome includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet expérience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) relieving the disease, i.e., causing régression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The term modulate or “modulating” or “modulation” refers to a decrease or inhibition in the amount, quality, or effect of a particular activity, function or molécule; by way of illustration that block or inhibit calcium release-activated calcium (CRAC) channei. Any such modulation, whether it be partial or complété inhibition is sometimes referred to herein as blocking and vt/ corresponding compounds as blockers. For example, the compounds of the invention are useful as modulators of the CRAC channel.

The term subject includes mammals, preferably humans and other animais, such as domestic animais; e.g., household pets including cats and dogs.

A therapeutically effective amount refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect, The therapeutically effective amount will vary depending on the compound, the disease and its severity, âge, weight, physical condition and responsiveness of the subject to be treated,

Pharmaceutically Acceptable Salts:

The compounds of the invention may form salts. In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable sait may be appropriate. Non-limiting examples of pharmaceutically acceptable salts are organic acid addition salts formed by addition of acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorate, α-ketoglutarate, a-glycerophosphate, formate, fumarate, propionate, glycolate, lactate, pyruvate, oxalate, maleate, and salicylate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate, carbonate salts, hydrobromate and phosphoric acid.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali métal (for example, sodium, potassium or lithium) or alkaline earth métal (for example calcium) salts of carboxylic acids can also be made.

With respect to the overall compounds described by the Formula (I) the invention extends to stereoisomeric forms and to mixtures thereof. The different stereoisomeric forms of the invention may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospeciftc or asymmctric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.

Unless otherwise stated, in the présent application “protecting group” refers to the groups intended to protect an otherwise labile group, e.g., an amino group, a carboxy group and the like, under spécifie reaction conditions. Various protecting groups alongwith the methods of protection and deprotection are generally known to a person of ordinary skilled in the art. lncorporated herein in this regard as référencé is Greene's Protective Groups in Organic x)/~

Svnthesis, 4th Edition, John Wiley & Sons, New York. In the présent invention, preferred amino protecting groups are r-butoxycarbonyl, benzyloxycarbonyl, acetyl and the like; while preferred carboxy protecting groups are esters, amides and the like.

Pharmaceutical Compositions:

The invention relates to pharmaceutical compositions containing the compound of Formula (I).

In particular, the pharmaceutical compositions contain a therapeutically effective amount of at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate the calcium release-activated calcium (CRAC) channel to treat CRAC channel mediated diseases such as inflammatory diseases, autoimmune diseases, allergie disorders, organ transplant, cancer and cardiovascular disorders when administered to a subject.

The compound of the invention may be incorporated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes a pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.

Examples of suitable carriers include, but are not limited to, water, sait solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnésium carbonate, sugar, cyclodcxtrin, amylose, magnésium stéarate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglyceridcs, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingrédient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For example, the active compound can be mixed with a carrier, or diluted by a v|/~ carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

The pharmaceutical compositions may be administered in conventional fonns, for example, capsules, tablets, aérosols, solutions, suspensions or products for topicai application.

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parentéral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topicai (such as with a topicai ointment).

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingrédient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the lîke are particularly suitable for oral application. Liquid formulations include, but are not limited to, syrups, émulsions, soft gelatin and stérile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parentéral application, particularly suitable are injectable solutions or suspensions formulation.

Liquid formulations include, but are not limited to, syrups, émulsions, suspensions, solutions, soft gelatin and stérile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

For parentéral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

The pharmaceutical préparation is preferably in unit dosage form. In such form, the préparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged préparation, the package containing discrète quantities of préparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

For administration to human patients, the total daily dose of the compounds of the invention dépends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose préparation may be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, and most typically 10 mg to 500 mg, according to the potency of the active component or mode of administration.

Suitable doses of the compounds for use in treating the diseases disorders, syndromes and conditions described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to resuit in a desired therapeutic benefit without causing unwanted side effects for the patient. For example, the daily dosage of the CRAC channel modulator can range from about 0.1 to about 30.0 mg/kg. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. Ail changes and modifications are envisioned within the scope of the invention.

Method of treatment

In a further embodiment, the invention is directed to the treatment or prophylaxis of inflammatory conditions by administering an effective amount of a compound of the présent invention.

Inflammation is part of the normal host response to infection and injury or exposure to certain substances prone to cause it. Inflammation begins with the immunologie process of élimination of invading pathogens and toxins to repair damaged tissue. Hence, these responses are extremely ordered and controlled. However, excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases and is characterized by the production of inflammatory cytokines, arachidonic acid-derived eicosanoids (prostaglandine, thromboxanes, leukotrienes, and other oxidized dérivatives), other inflammatory agents (e.g., reactive oxygen species), and adhesion molécules. As used herein, the term “inflammatory conditions” is defined as a disease or disorder or abnormality characterized by involvement of inflammatory pathways leading to inflammation, and which may resuit from, or be triggered by, a dysrégulation of the normal immune response.

The compound(s) of the présent invention are useful in treatment of inflammatory conditions including, but not limited to, diseases of many body Systems such as (musculoskeletal) arthritis, myositis, rheumatoid arthritis, osteoarthritis, goût, gouty arthritis, acute pseudogout, Reiter’s syndrome, ankylosing spondylitis, psoriatic arthritis, dermatomyositis; (pulmonary) pleuritis, pulmonary fibrosîs or nodules, restrictive lung disease, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), (cardiovascular) aortic valve stenosis, restenosis, arrhythmias, coronary arteritis, myocarditis, pericarditis, Raynaud’s phenomenon, systemic vasculîtis, angiogenesîs, atherosclerosis, ischaemic heart disease, thrombosis, myocardial infarction; (gastrointestinal) dysmotility, dysphagia, inflammatory bowel diseases, pancreatitis, (genitourinary) interstitial cystitis, rénal tubular acidosis, urosepsis, (skin) purpura, vasculîtis scleroderma, eczema, psoriasis, (neurologie) central nervous System disorders, cranial and peripheral neuropathies, peripheral neuropathy, radiculopathy, spinal cord or cauda equina compression with sensory and motor loss, multiple sclerosis (MS) (mental) cognitive dysfunction, Alzheimer's disease, (neoplastic) lymphoma, inflammation associated with cancer, (ophthalmologic) iridocyclitis, keratoconjunctivitis sicca, uveitis, (hématologie) chronic anémia, thrombocytopénie, (rénal) amyloidosis of the kidney, glomerulonephritis, kidney failure and other diseases such as tuberculosis, leprosy, sarcoidosis, syphilis, Sjôgren’s syndrome, cystitis, ftbromyalgia, fibrosis, septic shock, endotoxic shock, surgical complications, systemic lupus erthymotosus (SLE), transplantation associated arteriopathy, graft vs. host reaction, allograft rejection, chronic transplant rejection.

The inflammatory bowel diseases also include Crohn's disease, ulcerative colitis, indeterminate colitis, necrotizing enterocolitis, and infectious colitis.

“Allergie disorders” is defined as disorders/diseases that are caused by a combination of genetic and environmental factors resulting in a hypersensitivity disorder of the immune System. Allergie diseases are characterized by excessive immunoglobulin E (IgE) production, mast cell degranulation, tissue eosinophilia and mucus hypersécrétion, resulting in an extreme inflammatory response. These responses also take place during infection with multicellular parasites, and are linked to the production of a characteristic set of cytokines by T helper (Th) 2 cells. For example asthma is a chronic inflammatory condition of the lungs, characterized by excessive responsiveness of the lungs to stimuli, in the form of infections, allergens, and environmental irritants. Allergie reactions can also resuit front food, insect stings, and reactions to médications like aspirin and antibiotics such as penicillin. Symptoms of food allergy include abdominal pain, bloating, vomiting, diarrhea, itchy skin, and swelling of the skin during hives. Food allergies rarely cause respiratory (asthmatic) reactions, or rhinitis. Insect stings, antibiotics, and certain medicines produce a systemic allergie response that is also called anaphylaxis. The main therapeutic interest around CRAC in allergie disorders, originates froin its rôle in lymphocytes and mast cells, CRAC activation being a requirement for lymphocyte activation. '

The compound(s) of the présent invention are useful in treatment of allergie disorders including, but not limited to, atopie dermatitîs, atopie eczema, Hay fever, asthma, urticaria (including chronic idiopathic urticaria), vemal conjunctivîtis, allergie rhinoconjunctivitis, allergie rhinitis (seasonal and perennial), sinusitis, otitis media, allergie bronchitis, allergie cough, allergie bronchopulmonary aspergillosis, anaphylaxis, drug reaction, food allergies and reactions to the venom of stinging insects.

In yet another embodiment, the invention is directed to the treatment or prévention of “immune disorders” by administering an effective amount of a compound of the présent invention.

The compounds of this invention can be used to treat subjects with immune disorders. As used herein, the term immune disorder and like tenus mean a disease, disorder or condition caused by dysfunction or malfunction of the immune System as a whole or any of its components including autoimmune disorders. Such disorders can be congénital or acquired and may be characterized by the component(s) of the immune System getting affected or by the immune System or its components getting overactive. Immune disorders include those diseases, disorders or conditions seen in animais (including humans) that hâve an immune component and those that arise substantially or entirely due to immune system-mediated mechanisms. In addition, other immune System mediated diseases, such as graft-versus-host disease and allergie disorders, will be included in the définition of immune disorders herein. Because a number of immune disorders are caused by inflammation or lead to inflammation, there is some overlap between disorders that are considered immune disorders and inflainmatory disorders. For the purpose of this invention, in the case of such an overlapping disorder, it may be considered either an immune disorder or an inflammatory disorder. An autoimmune disorder is a condition that occurs when the immune System mistakenly attacks and destroys its own body cells, tissues and/or organs. This may resuit in temporary or permanent destruction of one or more types of body tissue, abnormal growth of an organ, changes in organ function, etc. For example, there is destruction of insulin producîng cells of the pancréas in Type 1 diabètes mellitus. Different autoimmune disorders can target different tissues, organs or Systems in an animal whîle some autoimmune disorders target different tissues, organs or Systems in different animais. For example, the autoimmune reaction is directed against the gastrointestinal tract in Ulcerative colitis and the nervous System in multiple scierosis whereas in systemic lupus erytheinatosus (lupus), affected tissues and organs may vary among individuals with the saine disease. For example, one person with lupus may hâve affected skin and joints whereas another may hâve affected kidney, skin and lungs. W^-

Spécifie autoimmune disorders that may be ameliorated using the compounds and methods of this invention include without limitation, autoimmune disorders of the skin (e.g., psoriasis, dermatitis herpetiformis, pemphîgus vulgaris, and vitiligo), autoimmune disorders of the gastrointestinal System (e.g., Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis), autoimmune disorders of the endocrine glands (e.g., Type 1 or immunemediated diabètes mellitus, Grave's disease. Hashimoto’s thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland), autoimmune disorders of multiple organs (including connective tissue and musculoskeletal System diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome), autoimmune disorders of the nervous System (e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barre, and autoimmune uveitis), autoimmune disorders of the biood (e.g., autoimmune hemolytîc anémia, pemicious anémia, and autoimmune thrombocytopenia) and autoimmune disorders of the blood vessels (e.g., temporal arteritis, antiphospholipid syndrome, vasculitides such as Wegener's granulomatosis, and Behcet' s disease).

Treatment of an immune disorder herein refers to administering a compound or a composition of the invention alone or in combination with other agents to a subject, who has an immune disorder, a sîgn or symptom of such a disease or a risk factor towards such a disease, with a purpose to cure, relieve, alter, affect, or prevent such disorder or sign or symptom of such a disease, or the prédisposition towards it.

In another embodiment, the invention is directed to the treatment or prévention of cancer by administering an effective amount of a compound of the présent invention.

It has been reported in the art that STIM1 and Orai 1 are essential in in vitro tumor cell migration and in vivo tumor metastasis. Thus the involvement of store operated Ca²⁺ entry in tumor metastasis renders STIM1 and Orail proteins potential targets for cancer therapy (Yang et.al., Cancer Cell, 15, 124-134, 2009). Additional literature available on the involvement of CRAC channel in cancer are Abeele et. al., Cancer Cell, 1, 169-179, 2002, Motiani et al., J. Biol. Chem., 285; 25, 19173-19183,2010.

The compound(s) of the présent invention may be useful in treatment of cancers and/or its metastasis including, but not limited to, breast cancer, lung cancer, pancreatic cancer, ovarian cancer, colon cancer, neck cancer, kidney cancer, bladder cancer, thyroid, blood cancer, skin cancer and the like. Ln yet another embodiment, the invention is directed to the treatment or -V ~ prophylaxie of allergie disorders by administering an effective amount of a compound of the présent invention.

In yet another embodiment, the invention is directed to the treatment or prophylaxie of cardiovascular diseases or disorders by administering an effective amount of a compound of the présent invention.

The compounds of this invention can be used to treat subjects with cardiovascular disorders. “Cardiovascular disorder” refers to a structural and fonctional abnormality of the heart and blood vessels, comprised of diseases including but not limited to, atherosclerosis, coronary artery disease, arrhythmia, heart failure, hypertension, diseases of the aorta and its branches, disorders of the peripheral vascular System, aneurysm, endocarditis, pericarditis, heart valve disease. It may be congénital or acquired. One of the main pathological feature of ail these diseases is clogged and hardened arteries, obstructing the blood flow to the heart. The effects dififer depending upon which vessels are clogged with plaque. The arteries carrying oxygen rich blood, if clogged, resuit in coronary artery disease, chest pain or heart attack. If the arteries reaching the brain are affected, it leads to transient ischémie attack or stroke. If the vessels in arms or legs are affected, leads to peripheral vascular disease. Because a number of cardiovascular diseases may also be related to or arise as a conséquence of thrombocytopathies, there is some overlap between disorders that are considered under heading cardiovascular disorders and thrmobocytopathies. For the purpose of this invention, in the case of such an overlapping disorder, it may be considered either a cardiovascular disorder or a thrombocytopathy.

STIM1 is located on the endoplasmic réticulum (ER) and fonctions as a calcium sensor. Orail is a pore forming subunit of calcium channel located on the plasma membrane, the déplétion of calcium in the endoplasmic réticulum is sensed by STIMI, and calcium enters via Orail to refill the endoplasmic réticulum. This pathway of filling the calcium is called store operated calcium entry (SOCE), which plays an important rôle in calcium homeostasis, cellular dysfonction and has a significant importance in cardiovascular diseases. In cardiomyocytes, calcium is not only involved in excitation-contraction couplîng but also acts as a signalling molécule promoting cardiac hypertrophy. Hypertrophie hearts are susceptible to abnormalities of cardiac rhythm and hâve impaired relaxation. Vascular smooth muscle cells (VSMCs) are responsible for the maintenance of vascular tone. VSMCs disorders, usually manifested as a phenotype change, are involved in the pathogenesis of major vascular diseases such as atherosclerosis, hypertension and restenosis. SOCE was also found increased in mctabolic syndrome (MetS) swine coronary smooth muscle cells. The compound of this invention can be used to treat neointimal '1 hyperplasia, occlusive vascular diseases, Mets - which is a combination of medical disorders including coronary artery disease, stroke and type 2 diabètes, abdominal aortic aneurysm, angina, transient ischémie attack, stroke, peripheral artery occlusive disease which includes inflammation, complément activation, fibrinolysis, angiogenesis and/or diseases related to FXIIinduced kinin formation such as hereditary angioedema, bacterial infection of the lung, trypanosome infection, hypotensive shock, pancreatitis, chagas disease, thrombocytopenia or articular goût, myocardial infarction, portai vein thrombosis which leads to hypertension, pulmonary hypertension, deep vein thrombosis, jugular vein thrombosis, systemic sepsis, pulmonary embolism, and papilledema, Budd-Chiari syndrome, Paget-Schroetter disease, cérébral venous sinus thrombosis ischémie cardiomyopathy, hypertrophie cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Prinzmetal angina, angina pectoris, chronic venous insufficiency, acute coronary syndrome, endocarditis, conceptual apraxia, pulmonary valve stenosis, thrombophlebitis, ventricular tachycardia, temporal arteritis, tachycardia, paroxysmal atrial fibrillation, persistent atrial fibrillation, permanent atrial fibrillation, respiratory sinus arrhythmia, carotid artery dissection, cerebrovascular diseases include, hémorrhagie stroke and ischémie stroke (where the thrombo-inflammatory cascade results in infarct growth), cardiomegaly, endocarditis, pericarditis, pericardial effusion. Valvular heart disease, vascular diseases or vascular inflammation is the resuit of ruptured atherosclerotic plaque which initiâtes thrombus formation. Platelet activation play an important rôle in vascular inflammation lcading to myocardial infarction and ischaemic stroke, the compound of this invention will prevent platelet activation and plaque formation and would also be useful to treat ail peripheral vascular diseases (PVD), pulmonary thromboembolism, and venous thrombosis.

“Treatment of cardiovascular disorders” herein refers to administering a compound or a composition of the invention alone or in combination with other agents to a subject, who lias a cardiovascular disease, a sign or symptom of such a disease or a risk factor towards such a disease, with a purpose to cure, relieve, alter, affect, or prevent such disorder or sign or symptom of such a disease, or the prédisposition towards it.

In yet another embodiment, the invention is directed to the treatment or prévention of “thrombocytopathies” by administering an effective amount of a compound of the présent invention.

Thrombocytopathies: The compounds of this invention can be used to treat subjects with thrombocytopathies. Thrombocytopathy is an abnormality of platelets or its functions. It may be congénital or acquired. It may cause a thrombotic or a bleeding tendency or may be part of a wider disorder such as myelodysplasia. Thrombocytopathies include such vascular disorders that arise due to dysfonction of platelets or coagulation system or diseases or complications that arise as a resuit of partial or complété restriction of blood flow to different organs or Systems due to such thrombocytopathies. Thrombocytopathies will thus include without limitation; diseases due to superficial vein thrombosis, diseases due to deep vein thrombosis, diseases due to arterial thrombosis, peripheral vascular diseases, thrombophilia, thrombophlebitis, embolisms, thromboembolism, ischémie cardiovascular diseases including but not limited to myocardial ischemia, angina, ischémie cerebrovascular diseases including but not limited to stroke, transient ischemia attack, cérébral venous sinus thrombosis (CVST) and complications arising due to thrmobocytopathies. Besides this, the disorder related to venous or arterial thrombus formation can be inflammation, complément activation, fibrinolysis, angiogenesis and/or diseases related to FXII- induced kinin formation such as hereditary angioedema, bacterial infection of the lung, trypanosome infection, hypotensitive shock, pancreatitis, chagas disease, thrombocytopenia or articular goût.

Under normal circumstances, when the endothélial cells lining blood vessels are breached, platelets interact with von Willebrand factor (vWF) via the membrane glycoprotein 1b complex to help seal the breach. Glycoprotein Ilb/Ia complex attracts other platelets, which combine to form aggregates. The platelets contain granules which break down to release fibrinogen, vWF, platelet-derived growth factor adenosine 5-diphosphate (ADP), calcium and 5hydroxytryptamine (5-HT) - serotonin. Ail this helps to promote the formation of a haemostatic plug (primary haemostasis). Activated platelets also synthesise thromboxane A2 from arachidonic acid as well as presenting negatively charged phospholipids on the outer leaflet of the platelet membrane bilayer. This négative surface provides binding sites for enzymes and cofactors of the coagulation system. The total effect is therefore to stimulate the coagulation system to form a clôt (secondary haemostasis).

Thus physiological platelet activation and thrombus formation are essential to stop bleeding in case of vascular injury, whereas under pathological conditions this may lead to vessel occlusion due to inadéquate triggering of the same process in diseased vessels leading to thrombosis, thromboembolism or tissue ischemia of vital organs. A central step in platelet activation is agonist-induced élévation of the intracellular Ca(2+) concentration. This happens on the one hand through the release of Ca(2+) from intracellular stores and on the other hand through Ca(2+) influx from the extracellular space. In platelets, the major Ca(2+) influx pathway is through store operated Ca(2+) entry (SOCE), induced by store déplétion. STIM1 is the the/iAZ

Ca(2+) sensor in the endoplasmic réticulum (ER) membrane, whereas Orail is the major store operated Ca(2+) (SOC) channel in the plasma membrane, which play a key rôle in platelet SOCE.

Treatment of thrombocytopathy herein refers to administering a compound or a composition of the invention alone or in combination with other agents to a subject, who has a thrombocytopathy, a sign or symptom or complication of such a disease or a risk factor towards such a disease, with the purpose to cure, relieve, alter, affect, or prevent such a disorder or sign or symptom, or the prédisposition towards it.

General Methods of Préparation

The compounds of the présent invention, including compounds of general formula (I) and spécifie examples are prepared through the reaction sequences illustrated in synthetic Schemes 1 to 5 wherein ring E, ring W, ring D, L, R], R2, R3, ‘n’ ‘p’ and ‘q’ are as defined herein above. Starting materials are commercially available or may be prepared by the procedures described herein or by the procedures known in the art. Furthermore, in the following synthetic schemes, where spécifie acids, bases, reagents, coupling agents, solvents, etc., are mentioned, it is understood that other bases, acids, reagents, coupling agents, solvents etc., known in the art may also be used and are therefore included within the scope of the présent invention. Variations in reaction conditions and parameters like température, pressure, duration of reaction, etc., which may be used as known in the art are also within the scope of the présent invention. Ail the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

The compounds obtained by using the general reaction sequences may be of insufficient purity. These compounds can be purified by using any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. Unless mentioned otherwise, room température refers to a température in the range of 22 to 27 °C.

'H-NMR spectra of the compounds of the présent invention were recorded using a BRUCKNER instrument (model: Avance-Ill), 400 MHz. Liquid chromatography - mass spectra (LCMS) of the compounds of the présent invention were recorded using Agilent ion trap model 6320 and Thermo Scientific Single Quad model MSQ plus instruments. IUPAC nomencleature for the compounds of the présent invention were used according to ChemBioDraw Ultra 12.0 software. '

Scti«m« 1

<Ί «>

X* to hafogcn, Pto pitiBcqtaiDbMonate Oi tlHiiUh*;

The compounds of formula (I) can be prepared by the reaction of borate dérivative of formula (1 ) with various halobenzamides of formula (2) as depicted in Scheme 1.

Altematively, the compounds of the formula (I) can also be prepared by the reaction of the halo dérivatives of the formula (3) with borate/stannane dérivatives of the formula (4) as shown in Scheme 1. The same transformation may also be carried out by other suitable coupling methods known in the art.

The said reaction can be mediated by a suitable catalyst known in the art such as Pd(PPh3)₂Cl₂, Pd₂dba3, Pd(PPh₂)4, Pd(OAc)₂ or mixture(s) thereof; a suitable ligand known in the art such as 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (BINAP), xanthophos, triphenylphosphine or mixture(s) thereof; in the presence of a suitable base, preferably inorganic bases such as alkalimetal carbonates like sodium carbonate, césium carbonate and phosphates like potassium phosphate or mixture(s) thereof. As also known from the art, such reactions are effected in the solvents like ethers such as tetrahydrofuran, dioxane, and the like; hydrocarbons like toluene; amides such as DMA, DMF and the like; sulfoxides like dimethylsulfoxide; halogenated hydrocarbons like DCM or mixture(s) thereof to afford the compounds of the formula (I).

191

Sctwn* 1

(»)

Q « H. ÇH or

(1)

In an alternative approach, the compounds of the présent invention can also be prepared as depicted in Scheme 2. Thus, the borate complex of formula (5) are prepared from the corresponding halo dérivatives via a métal catalysed boration reaction. As also known in the art, such reactions are carried out in presence of a métal catalyst for example Pd(PPh₃)₂Cl₂, Pd₂dba₃, w

PdCh.dppf, Pd(PPh3)4, Pd(OAc)2 in suitable solvent(s) for example ethers like THF, dioxane and the like; hydrocarbons like toluene; amides such as DMF, DMA and the like; sulfoxides like dimethylsulfoxide. The coupling reaction of halobenzamide dérivatives of the formula (2) with borate dérivatives of the formula (5) are carried out by following the methods known in the art or as described in the Scheme 1 to afford the compounds of the formula (6). This compounds of the formula (6) can be converted to compounds of formula (1) by following the procedure known in the art.

ftchvnw 3

Vatflntf NHRii.wCOOH.COOÉlkyiatCOCl Ul

Y*to COOK. COOwttyf. COCl; or

Another alternative approach is shown in Scheme 3, where the compound of formula (I) can be prepared by the reaction of the borate dérivative of the formula (1) with the various halide dérivatives of the formula (7) followed by amide coupling reaction.

Altematively, the compounds of the présent invention are also prepared by the reaction of the halo dérivatives of the formula (3) with stannane dérivatives of the formula (8) followed by amide coupling reaction as shown in Scheme 3. The same transformation may also be carried out by other suitable coupling methods known in the art. The coupling reaction of the halide dérivatives of the formula (7) with borate dérivatives of the formula (1), or halo dérivatives of the formula (3) with stannane dérivatives of the formula (8) are carried out as per the methods known in the art or as described in the Scheme 1 to afford compounds of the formula (9). This compounds of the formula (9) are transformed to compound of formula (I) using the techniques known in the art.

For example, compounds of the formula (9) are transformed to the compounds of the présent invention by coupling with the other intermediate (9a) by amide coupling reaction, i.e., formation of an amide linkage. Such amide coupling reaction is carried out by condensing an amino group or a protected amino group with a carboxylate group like carboxylic acid or an activated carboxylic acid or an ester présent on either intermediate (9) or (9a). Such groups are 3^/^ represented by Y' and Y on intermediate (9) and (9a). Condensation of an amino group or a protected amino group with a carboxylate group - like carboxylic acid or an activated carboxytic

H acid or an ester - présent as either Y' or Y group is carried out using techniques known in the art. However, in a few preferred aspects of the présent invention, such amide coupling reactions are accomplished in either of the following ways - when Y' is an amino group or a protected amino group and Y is a carboxylate group like carboxylic acid or an activated carboxylic acid or an ester group - or when Y' is an carboxylate group like carboxylic acid or an activated carboxylic acid or an ester group and Y amino group or a protected amino group:

(a) condensation of Y' and Y groups in the presence of a suitable activating reagent used in peptide linkage synthèses, e.g., hydroxybenzotriazole, 2-hydroxypyridine, acetoneoxime and a coupling reagent like carbodiimides such as EDC, DCC or mixture(s) thereof; or (b) halogénation of the acid dérivatives at Y' or Y of the compounds of formula (9) or (9a) with thionyl chloride, oxalyl chloride and the like followed by condensation with the amino or protected amino group at Y or Y', respectively; or (c) mixed anhydride formation of the acid dérivatives at Y' or Y of the compounds of the formula (9) or (9a) with isobutylchloroformate, ethylchloroformate and the like or mixture(s) thereof followed by condensation with the amino or protected amino group at Y or Y' of the compounds of formula (9a) or (9), respectively; or (d) reaction at Y' or Y of the compounds of formula (9) or (9a) with corresponding amine dérivatives at Y' or Y of the compounds of formula (9a) or (9) respectively, in presence of trimethyl aluminium; or (e) amide coupling of the amine dérivatives at Y' or Y of the compounds of the formula (9) or (9a), with the corresponding acid chloride dérivatives at Y or Y' of the compounds of formula (9a) or (9), respectively.

Such reactions are carried out in one or more solvents known in the art for example, chlorinated solvents; DCM, chloroform and the like; ethers such as diethyl ether, THF and the like; amides such as DMF, DMA and the like; or a mixture thereof; in the presence of a suitable base like triethylamine, /V-ethyldiisopropylamine; 4-dialkylaminopyridines like 4-dimethylaminopyridine, pyridine or mixture(s) thereof. ’W'—

In another embodiment, the compounds of the présent invention, wherein ring E is dîhydroisoxazols, can be prepared as described in synthetic Scheme 4. The compounds of formula (6), wherein Q = Oalkyl/OH, are then converted to the Weinreb amide of formula (10) by the reaction with N, O-dimethylhydroxylamine hydrochloride in presence of an activating reagent like hydroxybenzotriazole, 2-hydroxypyridine, acetoneoxime or mixture(s) thereof; and a coupling reagent like carbodiimides such as EDC, DCC or mixture(s) thereof. Such reactions are carried out in one or more solvents known in the art for example, chlorinated solvents; DCM, chloroform and the like; ethers such as diethyl ether, THF and the like; amides such as DMF, DMA and the like; or a mixture thereof; and in the presence of a suitable base like triethylamine, /V-ethyldiisopropylamine; 4-dialkylaminopyridines like 4-dimethylaminopyridine or a mixture thereof.

The compounds of Formula (10) are reduced to the corresponding aldéhydes of the formula (11) with a reducing agent known in the art. Although not limited, such reducing agents include alkyland alkoxy- métal hydrides like sodium bis(2-methoxyethoxy)aluminium hydride, lithium aluminium hydride, diisobutylaluminium hydride or mixture(s) thereof. Such réduction of the compounds of formula (10) are carried out in one or more solvents like ethers such as diethyl ether, THF and the like; alcohols such as methanol, éthanol, isopropanol and the like; amides such as DMF, DMA and the like; chlorinated solvents such as DCM, chloroform and the like; or mixture(s) thereof.

The compounds of formula (11) are converted to the corresponding oximes of the formula (12) by the processes known in the art. Preferably, compounds of the formula (11) are treated with hydroxylamine hydrochloride in the presence of bases. Any base known in the art can be used for the said reaction, for example, alkalimetal acétates such as sodium acetate; alkali métal q/~~ hydroxides like potassium hydroxide, sodium hydroxide or mixture(s) thereof. Such a réaction can be effected; in one or more solvent generally used in the art like alcohols such as methanol, éthanol, isopropanol, butanol or mixture(s) thereof under the conditions generally used in the art.

The reaction of the oximes of formula (12) with substituted alkenes of formula (13) or cyclic alkene (13a) to afford compound of formulae (le) or (lf) respectively. This reaction can be carried out as per the processes known in the art in presence of one or more halogenating reagents or oxidizing agents. Although not limited, halogenating reagents like Nhalosuccinimide such as N-bromosuccinimîde or N-chlorosuccinimide, sodium hypochlorite. Oxidizing agents like magtrieve are used as known from the art. Such reactions are effected in one or more solvents like nitriles such as acetonitrile; ketones such as acetone; alcohols such as methanol, éthanol, propanol, butanol and the like; ethers such as diethyl ether, THF and the like; amides: DMF, DMA and the like; sulfoxides like dimethylsulfoxide; hydrocarbons such as hexane, toluene and the like; halogenated hydrocarbons such as DCM, chloroform and the like or mixture(s) thereof.

Compound of formulae (Ig) can be prepared by following the procedure as depicted in Scheme 5. The ester dérivatives of the formula (14) are converted to the compounds of the formula (Ig) by the hydrolysis processes known in the art. Thus, the hydrolysis can be carried out in presence of acids such as trifluoroacetic acid, hydrochloric acid and the like; or mixtures thereof or bases such as alkali métal hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; or alkalineearth métal hydroxides such as barium hydroxide and the like; or mixtures thereof. Such hydrolysis reactions can be carried out in a suitable solvent like ethers such as diethyl ether, tetrahydrofuran and the like; protic solvents like water, methanol, éthanol, propanol, isobutanol; or mixtures thereof. (A-—-

Accordingly, compound of formulae (Ih) can be prepared by following the procedure as depicted in Scheme 5. Ester dérivatives of the formula (14) are converted to the compounds of the formula (Ih) by réduction processes known in the art by using suitable reducîng agent such as lithium aluminium hydride, diisobutylaluminium hydride, sodium borohydride and in suitable solvent like ethers such as diethyl ether, THF, and the like; alcohols such as methanol, éthanol, propanol and the like; amîdes such as dimethylformamide, dimethylacetamide and the like; sulfoxides like dimethylsulfoxide; hydrocarbons such as hexane, toluene and the like; chlorinated solvents like DCM or mixture(s) thereof.

Accordingly, compound of formulae (II) can be prepared by following the procedure as depicted in Scheme 5. Compounds of the formula (14) are treated with a compound of the formula (15) where 1¾ and R5 are as defined herein above, in an appropriate solvent like alcohols such as methanol, éthanol, isopropanol and the like; ethers such as diethyl ether, tetrahydrofuran and the like; hydrocarbons such as benzene, toluene and the like; or mixture(s) thereof.

The présent invention is further illustrated by the following intermediates and examples with detailed procedure to préparé them, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only.

Intermediates

Ail intermediates used for the préparation of the compounds of the présent invention, were prepared by approaches reported in the literature or by methods known in the art of organic chemistry. Detailed experimental procedures for synthesis of the corresponding intermediates are given below:

Intermediate 1 a & 1 b

5,5-Dimethyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)isoxazol-4(5//)-one (la) and

3-(3-(5-Aminopyrazin-2-yl)-4-methylphenyl)-5,5-dimethylisoxazol-4-(5H)-one (lb) --32

Step 1: 3-Bromo-4-methyl-[N-(methoxy)-N’-(methyl)]benzamide: To a solution of 3-bromo-4methylbenzoic acid (10 g, 46.5 mmol) in DCM, N-methyl-N’-methoxyamine hydrochloride (4.5 g, 46.5 mmol, 1.0 eq), EDC. HCl (9.80 g, 51.1 mmol, 1.1 eq), HOBT (6.91 g, 51.15 mmol, 1.1 eq) and triethylamine (13 mL, 93 mmol, 2 eq) were added successively. The resulting mixture was stirred at room température for 3h. The reaction mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2^50 mL). The combincd organic layers were washed with brine (50 mL), dried (NaîSO4) and filtered. The filtrate was concentrated under reduced pressure to afford 6.80 g of the desired 3-bromo-4-methyl-[N-(methoxy)-N’-(methyl)]benzamide. 'HNMR (400 MHz, CDClj) δ 7.88 (s, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.26 (d,J= 8.0 Hz, 1H), 3.55 (s, 3H), 3.35 (s, 3H), 2.42 (s, 3H); ESI-MS (m/z) 258, 260 [(MH)⁺, Br⁷⁹'⁸¹].

Step 2: l-(3-Bromo-4-methylphenyl)-3-methylbut-2-en-l-one: To a stirred and cooled (at -20°C) solution of 3-bromo-4-methyl-[N-(methoxy)-N’-(methyl)]benzamide (600 mg, 2.32 mmol, 1.0 eq) in THF (5 mL) a solution of isopropenylmagnesium bromide in THF (0.5 M, 5.6 mL, 2.79 mmol, 1.2 eq) was added. The resulting reaction mixture was allowed to warm to room température over a period of 15-20 minutes and then stirred at room température for 2 h. The reaction mixture was cooled to 0 °C before being quenched with saturated ammonium chloride solution (3 mL). The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (10 mL), dried (NaiSCL) and filtered. The filtrate was concentrated under vacuum to afford 0.58 g of the desired product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 8.07 (d,J= 1.0 Hz, 1H), 7.75 (dd, J = 1.0, 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 2.43 (s, 3H), 2.20 (s, 3H), 2.01 (s, 3H); ESI-MS (m/z) 253, 255 [(MH)⁺, Br⁷⁹’⁸'].

Step 3: (3-Bromo-4-methylphenyl)(3,3-dimethyIoxiran-2-yI)rnethanone: To a cooled solution (at 0°C) of l-(3-bromo-4-methylphenyl)-3-methylbut-2-en-l-one (1.50 g, 5.92 mmol, 1.0 eq) in DCM (100 mL), w-chloroperbenzoic acid (77%, 4.30 g, 17.78 mmol, 3.0 eq) was added portion wise and then allowed to warm to room température. After stirring for 12 h at room température water was added to the reaction mixture and the layers were separated. The organic layer was washed with saturated aqueous solution of sodium bicarbonate (3x50 mL) followed by brine (50 mL) and then dried (Na₂SÛ4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexane) to afford 1.60 g of the desired product, as a white solid. 'HNMR (400 MHz, CDCI3) Ô 8.13 (d, J = 1.5 Hz, 1H), 7.81 (dd, J= 1.5, 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1 H), 3.99 (s, 1H), 2.47 (s, 3H), 1.58 (s, 3H), 1.23 (s, 3H); ES1-MS (m/z) 269,271 [(MH)⁺, Br⁷⁹'⁸¹].

Step 4: 3-(3-bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazol-4-ol: A mixture of (3bromo-4-methylphenyl)(3,3-dimethyloxiran-2-yl)methanone (500 mg, 1.85 mmol, 1.0 eq) and hydroxylamine hydrochloride (500 mg, 7.19 mmol, 3.9 eq) in a 5:3 volummetric mixture of methanol and pyridine was heated at gentle reflux for 12 h. The resulting mixture was cooled to room température and the solvent was evaporated under vacuum. The residue was taken in water (10 mL) acidified with glacial acetic acid and stirred for 10 min. Ethyl acetate (50 mL) was added to the above mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried (Na₂SO4) and filtered. The filtrate was evaporated under vacuum to afford 320 mg of the desired product as a white solid. ’HNMR (400 MHz, CDClj) δ 7.97 (d, J = 1.0 Hz, IH), 7.65 (dd, J= 1.0, 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.78 (s, 1H), 2.42 (s, 3H), 1.51 (s, 3H), 1.31 (s, 3H); ESI-MS (m/z) 284, 286 [(MH)⁺, Br^79,81].

Step 5: 3-(3-Bromo-4-methylphenyl)-5,5-dimethylisoxazol-4(5f/)-one: To a solution 3-(3bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazol-4-ol (1,80 g, 6.42 mmol) in glacial acetic acid (70 mL), chromium trioxide (640 mg, 6.42 mmol, 1.0 eq), water (4 mL) and concentrated sulfuric acid (0.8 mL) were successively added and the resulting mixture was stirred at 100°C for 30 min. The reaction was cooled to room température and poured into water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 2% ethyl acetate in hexane) to afford the 800 mg of the desired product as a white solid. 'HNMR aJ~~ (400 MHz, CDC1₃) δ 8.29 (d, J = 1.0 Hz, I H), 7.94 (dd, J = 1.0, 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1H), 2.44 (s, 3H), 1.46 (s. 3H), 1.24 (s, 3H); ESI-MS (m/z) 282, 284 [(MH)⁺, Br^79,81].

Step 6: 5,5-Dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) isoxazol-4(5//)-one:

General procedure for pinacolatodiboralane formation'. To a solution of 3-(3-bromo-4methyiphenyl)-5,5-dimethylisoxazol-4(57Z)-one (180 mg, 0.64 mmol, 1.0 eq) in dioxane (10 mL), successively bis(pinacolato)diboron (243 mg, 0.95 mmol, 1.5 eq), potassium acetate (187 mg, 1.91 mmol, 3 eq) and Pd(dppf)C12 (26 mg, 0.031 mmol, 0.05 eq) were added. The resulting solution was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and the reaction mixture was then heated at 100°C ovemight under nitrogen atmosphère. The resulting mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 6% ethyl acetate in hexane) to afford 140 mg of the intermediate la as a white solid. ‘HNMR (400 MHz, CDClj) δ 8.44 (d, J = 2.0 Hz, 1 H), 7.99 (dd, J = 2.0, 8.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 2.55 (s, 3 H), 1.44 (s, 6H), 1.33 (s, 12H); ESI-MS (m/z) 330 (MH)⁺.

Step 7: 3-(3-(5-Aminopyrazin-2-yl)-4-methylphenyl)-5,5-dimethylisoxazol-4(5//)-one: To a solution of 5,5-dimethyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yi)phenyl)isoxazol-4(5//)one (5.4 g, 16.4 mmol, 1.0 eq) and 2-amino-5-bromopyrazine (2.8 g, 16.4 mmol, 1.0 eq), in THF:H₂O (4:1, 100 mL) was added sodium bicarbonate (4.5 g, 54.1 mmol, 3.3 eq) followed by Pd(PPh3)₄ (0.95 g, 0.82 mmol, 0.05 eq). The resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and the reaction mixture was heated at 75 °C for 15 h under nitrogen atmosphère. The resulting mixture was cooled to room température and filtered through celite, The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane) to afford 1.5 g of the intermediate lb as a white solid. 'HNMR (400 MHz, CDCI3) δ 8.14 (s, 1H), 8.12 (s, 1H), 8.08 (d, J = 1.5 Hz, 1H), 8.01 (dd, J = 7.5, 1.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.73 (s, 2H, D₂O exchangeable), 2.41 (s, 3H), 1,46 (s, 6H); ESI-MS (m/z) 297 (MH)⁺.

The below intermediates 2 to 12b were prepared by following a procedure similar to that described in intermediate la or intermediate lb:

Intermediates/IUPAC name

Structure

‘HNMR/ESI-MS (MH)⁺

Intermediate 2: 3-(4-Ethyl3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2yl)phenyl)-5,5dimethylisoxazol-4(5//)one	-O	’HNMR (400 MHz, CDCla) δ 8.46 (d, J= 2.0 Hz, 1 H), 8.04 (dd, J = 8.0, 2.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 2.94 (q, J = 7.5 Hz, 1H), 1.45 (s, 6H), 1.35 (s, 12H), 1.20 (t, J= 7.5 Hz, 3H); ESI-MS (m/z) 344 (MH)⁺.
Intermediate 3: 3-(4- Isoproyl-3-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2-yl)phenyi)5,5-dimethylisoxazol4(5Z/)-one		’HNMR (400 MHz, CDC1₃) δ 8.43 (s, 1H), 8.08 (dd, J= 8.5, 2.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 3.15-3.08 (m, 1H), 1.45 (s, 6H), 1.35 (s, 12H), 1.23 (d, J = 7.0 Hz, 6H); ESI-MS (m/z) 358 (MH)⁺.
Intermediate 4a: 3-(3Bromo-4-(/e?7butyl)phenyl)-5,5dimethylisoxazol-4(5H)one	/0'	’HNMR (400 MHz, CDCI3) δ 8.36 (d, J = 2.0 Hz, 1 H), 7.99 (dd, J= 8.5, 2.0/7z, 1H), 7.55 (d,J = 8.5 Hz, 1H), 1.55 (s, 9H), 1.49 (s, 6H); ESI-MS (m/z) 324, 326 [(MH)⁺, Br⁷⁹'⁸¹]
Example 4b: 3-(3-(5Ami nopyrazin-2-yl )-4(tert-butyl)phenyl)-5,5 dimethy!isoxazol-4(5H)one	_Γ N Pc	’HNMR (400 MHz, CDCI3) δ 8.08 (dd, J= 8.5,2.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 1 H), 4.63 (s, 2H, D2O exchangeable), 1.44 (s, 6H), 1.24 (s, 9H); ESI-MS (m/z) 339 (MH)⁺.
Intermediate 5: 3-(3-(5- Aminopyrazin-2-yl)-4chlorophenyl)-5,5-di methylisoxazol-4(5H)-one	—(T^-NHj J 'n f o	ESI- MS (m/z) 317, 319 [(MH)⁺, Cl ³⁵’³⁷]

Intermediate 6: 3-(4Fluoro-3-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan2-yl)phenyl)-5,5-dimethyl isoxazol-4(5H)-one	_o —	'HNMR (400 MHz, CDC1₃) Ô 8.49 (dd, J = 5.5, 2.5 Hz, 1H), 8.20-8.15 (m, 1 H), 7.13 (t, J = 8.5 Hz, 1H), 1.47 (s,6H), 1.37 (s, 12H); ESI-MS (m/z) 334 (MH)⁺.
Intermediate 7a: 3-(4- Methoxy-3-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)5,5-dimethylisoxazol4(5H)-one	PCH> .	‘HNMR (400 MHz, CDC1₃) δ 8.41 (d, J =2.5 Hz, 1H), 8.15 (dd, J = 8.5, 2.5 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 1.45 (s, 6H), 1.36 (s, 12H); ESI-MS (m/z) 346 (MH)⁺.
Intermediate 7b: 3-(3-(5Aminopyrazin-2-yl)-4methoxyphenyl)-5,5dimethylisoxazol-4(5H)one	p^CHf_l i P—NHj —Tn	'HNMR (400 MHz, CDCI3) δ 8.59 (s, 1H), 8.52 (s, 1H), 8.11- 8.09 (m, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.06 (d,J=8.5 Hz, 1H), 4.65 (s, 2H, D2O exchangeable), 3.93 (s,3H), 1.46 (s, 6H); ESI- MS (m/z) 313 (MH)⁺
Intermediate 8: H-(4-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yI)-2(4,4,5,5-tetramethyl-l ,3,2dioxaborolan-2yl)phenyl)acetamide	,0 HN-C /=< **·» O’®' /O	'HNMR (400 MHz, CDCI3) δ 8.52 (d, J= 8.5 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1 H), 8.08 (dd, J = 8.5, 2.0 Hz, 1H), 7.75 (s, 1H, D₂O exchangeable), 2.27 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 325, 327 [(MH)⁺, Br⁷⁹’⁸¹]
Intermediate 9: 5,5Dimethyl-3-(3-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2yl)phenyl)isoxazol-4(5H)one	₀ To	'HNMR (400 MHz, CDCI3) δ 8.51 (s, 1H), 8.15 (td, J =7.5, 1.0 Hz, 1H), 7.90 (td, J =7.5, 1.0 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 1.47 (s, 6H), 1.35 (s, 12H); ESI-MS (m/z) 316 (MH)⁺.

Intermediate 10: 5,5Dimethyl-3-(3-methyl-4(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2yl)phenyl)isoxazoi-4(5H)one		'HNMR (400 MHz, CDCls) δ 7.87-7.79 (m, 3H), 2.56 (s, 3H), 1.45 (s, 6H), 1.35 (s, 12H); ESIMS (m/z) 330 (MH)⁺.
Intermediate 11: 5,5Dimethyl-3-(2-methyl-3(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2yl)phenyl)isoxazol-4(5H)one		'HNMR (400 MHz, CDCI3) δ 7.87 (dd, J =8.0, 1.5 Hz, 1H), 7.48 (dd, J = 8.0, 1.5 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1 H), 2.53 (s, 3H), 1.48 (s,6H), 1.35 (s, 12H); ESI-MS (m/z) 330 (MH)⁺.
Intermediate 12a: 3-(3- Bromo-2-methoxyphenyl)5,5-dimethylisoxazol4(5H)-one		'HNMR (400 MHz, CDCI3) δ 7.68 (dd, ./=8.0, 1.5 Hz, 1H), 7.57 (dd, J= 8.0, 1.5 Hz, 1H), 7.09 (t, J =8.0 Hz, 1 H), 3.88 (s, 3H), 1.49 (s, 6H); ESI-MS (m/z) 298,300 [(MH)⁺, Br⁷⁹’⁸¹]
Intermediate 12b: 3-(3-(5aminopyrazin-2-yl)-2methoxyphenyl)-5,5dimethylisoxazol-4(5H)one	-J .0 cQ[	'HNMR (400 MHz, CDCI3) δ 8.65 (s, 1H), 8.12 (s, 1H), 7.86 (dd, J =8.0, 1.5 Hz, 1H), 7.61 (dd,J=8.0, 1.5 Hz, 1H), 7.33 (t, J =8.0 Hz, 1 H), 3.55 (s, 3H), 1.52 (s, 6H); ESI-MS (m/z) 313 (MH)⁺

Intermediate 13

4-Methoxy-5,5-dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-

4,5-dihydroisoxazole χζ---38

Intermedlate 13

Step-1: 3-(3-Bromo-4-methylphenyl)-4-methoxy-5,5-dimethyl-4,5-dihydroisoxazole: To a 0 °C cooled solution of 3-(3-bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazol-4-ol (240 mg, 0,84 mmol, 1.0 eq, prepared hereinbefore in step-4 of intermediate 1) in DMF (3 mL) was added sodium hydride (60% dispersion in oil, 43 mg, 1.09 mmol, 1.3 eq) in one portion. After stirring at the same température for 20 min, methyl iodide (70 pL, 1.09 mmol, 1.09 eq) was added to the above mixture and then continued stirring at room température for 1 h. Water (5 mL) was added to the reaction mixture followed by ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x10 mL) and the combined organic layers were washed with water (2x10 mL), brine (10 mL), dried (NaiSOi) and filtered. The filtrate was concentrated under vacuum to afford 200 mg of the title product as syrupy oil. ^lHNMR (400 MHz, CDC1₃) Ô 7.93 (d, J = 2.0 Hz, 1 H), 7.62 (dd, J = 8.0, 2.0 Hz, I H), 7.29 (d, J = 8.0 Hz, 1 H), 4.52 (s, 1H), 3.46 (s, 3H), 2.44 (s, 3H), 1.54 (s, 3H), 1.35 (s, 3H); ESI-MS (m/z) 298, 300 [(MH)⁺, Br⁷⁹’⁸¹]

Step-2: 4-Methoxy-5,5-dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyI-1,3,2-dioxaborolan-2yl)phenyl)-4,5-dihydroisoxazole: The title compound was prepared by following the general procedure described hereinbefore for step-6 of intermediate 1. 'HNMR (400 MHz, CDCIj) ô 8.09 (d, J = 2.0 Ηζ,ΙΗ), 7.73 (dd, J = 8.0, 2.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.58 (s, 1H), 3.42 (s, 3H), 2.55 (s, 3 H), 1.54 (s, 3H) 1.34 (s, I2H), 1.31 (s, 3H); ESI- MS (m/z) 346 (MH)⁺

Intermediate 14 l-(2,2-Dimethyl-5-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyI)-l,3,4oxadiazol-3(2H)-yl)^ethanone

Step 1: 3-Bromo-4-methylbenzohydrazide: A mixture of methyl-3-bromo-4-methylbenzoate (5.0 g, 21.8 mmol, 1.0 eq) and hydrazine hydrate (5 mL, 99 mmol, 4.5 eq) in methanol (50 mL) was heated to 80°C ovemight. The reaction mixture was cooled to room température and filtered. The filtrate was evaporated under vacuum. The residue was taken in ethyl acetate (100 mL) and ,

washed with water (2x50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under reduced pressure to afford 2.5 g (50%) of the desired product as a white solid. ’HNMR (400 MHz, DMSO-ίήί) δ 9.84 (s, 1H, DO exchangeable), 8.02 (d, J= 1.0 Hz, 1H), 7.74 (dd, J = 1.0, 8.0 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 3.35 (s, 2H, D₂O exchangeable), 2.38 (s, 3H); ES1-MS (m/z) 229, 231 [(MH)⁺, Br⁷⁹·⁸¹].

Step 2: l-(5-(3-Bromo-4-methylphenyl)-2,2-dimethyl-l,3,4-oxadiazol-3(2//)-yl)ethanone: To a mixture of 3-bromo-4-methylbenzohydrazide (2.0 g, 8.72 mmol, 1.0 eq) and acetone (10 mL, 172 mmol, 21 eq) in hexane (10 mL), was added molecular sieves (500 mg) followed by trifluoroacetic acid (2 mL) and the resulting mixture was refluxed for 3 h. The reaction mixture was cooled to room température and filtered. The filtrate was concentrated under vacuum and the residue was taken in ethyl acetae (100 mL), washed with water (50 inL), aqueous saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under reduced pressure to afford the 2.10 g of the 3-bromo-4-methyl-N’(propan-2-ylidene)benzohydrazide. ’HNMR (400 MHz, DMSO-î/λ) δ 10.51 (s, 1H, D₂O exchangeable), 8.02 (s, l H), 7.75 (dd, J = 1.0, 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 2.40 (s, 3H), 2.01 (s, 3H), 1,94 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)⁺, Br^79,8'].

A mixture of 3-bromo-4-methyl-jV’-(propan-2-ylidene)benzohydrazide (2.0 g, 7.46 mmol), as obtained hereinbefore, and acetic anhydride (30 mL) was refluxed for one hour. The excess of acetîc anhydride was removed under vacuum after cooling the reaction mixture to room température and the crude residue obtained was triturated with hexane to remove traces of acetic anhydride présent in the reaction mixture. The crude product was purified by flash column chromatography (siiica gel, 100-200 inesh, 13% ethyl acetate in hexane) to afford 800 mg of the desired product as an oil. ’HNMR (400 MHz, CDClj) δ 7.97 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1 H), 2.44 (s, 3H), 2.29 (s, 3H), 1.85 (s, 6H); ESI-MS (m/z) 311, 313 [(MH)⁺, Br⁷⁹·⁸¹].

Step 3: l-(2,2-Dimethyl-5-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)1,3,4-oxadiazol-3(2//)-yl)ethanone: 1 -(5-(3-bromo-4-methylphenyl)-2,2-dimethyl-1,3,4oxadiazol-3(2Z7)-yl)ethanone (400 mg, 1.28 mmol, 1.0 eq) was reacted with bis(pinacolato) diboron (480 mg, 1.92 mmol, 1.5 eq) and Pd(dppf)Cl₂ (52 mg, 0.064 mmol, 0.05 eq) by following the procedure described hereinbefore in step 6 of intermediate 1 to afford 120 mg of the intermediate 2 as a white solid. ’HNMR (400 MHz, CDClj) δ 8.12 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 2.57 (s, 3H), 2.31 (s, 3H), 1.86 (s, 6H), 1.36 (s, 6H), 1.26 (s, 6H); ESI-MS (m/z) 359 (MH)⁺. --40

Intermediate 15a & 15b

5-(3-Bromo-4-methylphenyl)-3-methyi-l,3,4-oxadiazol-2(3H)-one ( 15a) and

5-(3-(5-Aminopyrazine-2-yl)-4-methylphenyl)-3-methyl-l,3,4-oxadiazol-2(3H)-one (15b)

IntomMdtflt· 1 S*

Step 1: 3-Bromo-4-methylbenzohydrazide: A mixture of methyl-3-bromo-4-methylbenzoate (5.0 g, 21.8 mmol, 1.0 eq) and hydrazine hydrate (5 mL, 99 mmol, 4.5 eq) in methanol (50 mL) was heated to 80°C ovemight. The reaction mixture was cooled to room température and filtered. The filtrate was evaporated under vacuum. The residue was taken in ethyl acetate (100 mL) and washed with water (2*50 mL), brine (50 mL), dried (Na₂SÛ4) and filtered. The filtrate was evaporated under reduced pressure to afford 2,5 g (50%) of the desired product as a white solid. ^lHNMR (400 MHz, DMSCW6) δ 9.83 (s, 1H, D₂O exchangeable), 8.01 (d, J = 2.0 Hz, 1H), 7.74 (dd, J= 8.0, 2.0 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 4.50 (s, 2H, D₂O exchangeable), 2.37 (s, 3H); ESI-MS (m/z) 229, 231 [(MH)⁺, Br⁷⁹·⁸¹].

Step-2: 5-(3-Bromo-4-methylphenyl)-l,3,4-oxadiazol-2(3H)-one: To a stirred and cooled (0 °C) solution of 3-bromo-4-methylbenzohydrazide (3.0 g, 13.1 mmol, 1.0 eq) and diisopropylethyl amine (4.6 mL, 26.8 mmol, 2.0 eq) in DCM (20 mL) was added a solution of triphosgene (1.55 g, 5.2 mmol, 0.4 eq) in DCM (10 mL) over a period of 10 min. The resulting mixture was stirred for 1 h at the same température. The reaction mixture was diluted with DCM (50 mL) and washed with water (50 mL), aqueous sodium bicarbonate (10%, 50 mL), brine (50 mL), dried (Na₂SO4) and filtered. The filtrated was evaporated under vacuum to afford 3.0 g of the desired product as a white solid. ’hNMR (400 MHz, DMSO-t/6) δ 12.66 (s, 1H, D₂O exchangeable), 7.90 (d, J= 2.0 Hz, 1H), 7.69 (dd, J= 8.0, 2.0 Hz, 1H), 7.52 (d, J= 8.0 Hz, IH), 2.40 (s, 3H); ESI-MS (m/z) 255, 257 [(MH)⁺, Br⁷⁹'⁸¹].

Step-3: 5-(3-Bromo-4-methylphenyl)-3-methyl-l,3,4-oxadiazol-2(3H)-one: A mixture of 5-(3bromo-4-methylphenyl)-l,3,4-oxadiazol-2(3H)-one (400 mg, 1.57 mmol, 1.0 eq), inethyl iodide (0.2 mL, 3.15 mmol, 2.0 eq) and potassium carbonate (210 mg, 3.15 mmol, 2.0 eq) in DMF (10 mL) was stirred at room température for 24 h. Water (50 mL) was added to the reaction mixture followed by ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2*20 mL). The combined organic layers were washed with water (2*25 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 400 mg of the desired product as a white solid. ’HNMR (400 MHz, DMSO-r/6) Ô 7.90 (d, J= 2.0 Hz, 1H), 7.70 (dd, J= 8.0, 2.0 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 3.40 (s, 3H), 2.41 (s, 3H); ESI-MS (m/z) 269, 271[(MH)⁺, Br⁷⁹’⁸¹].

Step 4: 5-(3-(5-Aminopyrazin-2-yl)-4-methylphenyl)-3-nriethyl-l,3,4-oxadiazol-2(3H)-one: To a solution of 5-(3-bromo-4-methylphenyl)-3-methyl-l,3,4-oxadiazol-2(3H)-one (500 mg, 1.76 mmol) and 5-(trimethyl stannyl)-pyrazine-2-amine (683 mg, 2.65 mmol, prepared from 2-amino5-bromopyrazine by following the procedure described in Chem. Eur. J. 2000, 6, 4132) in THF (10 mL) was added Pd(PPh3)4 (100 mg, 0.088 mmol). The resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and the reaction mixture was heated at 75 °C for 15 h under nitrogen atmosphère. The resulting mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography over silica gel using ethyl acetatehexane mixture as eluent to afford 250 mg of the intermediate 15b as a white solid. 'HNMR (400 MHz, DMSO-J6) Ô 8.07 (s, 1 H), 7.99 (s, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 7.64 (dd, J = 8.0, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.62 (s, 2H, D₂O exchangeable), 3.36 (s, 3H), 2.35 (s, 3H); ESIMS (m/z) 284 (MH)⁺.

The following intermediatcs were prepared by following the above procedure from the corresponding starting materials.

The below intermediates 16a to 24b were prepared by following a procedure similar to that described in intermediate 15a or intermediate 15b:

Intermediates/IUPA

C name

Structure 'HNMR/ESI-MS(MH)⁺

Intermediate 16a: 5(3-Bromo-4-methyl phenyl)-3-ethyl-1,3,4oxadiazol-2(3 H)-one	n-n -J	'HNMR (400 MHz, DMSO-i/6) δ 7.89 (d,J= 1.5 Hz, 1 H), 7.69 (dd, J= 8.0, 1.5 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 3.76 (q, J= 7.0 Hz, 2H), 2.40 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 283,285 [(MH)⁺,Br ⁷⁹’⁸¹].
Intermediate 16b: 5(3-(5-Aminopyrazin2-yl)-4methylphenyl)-3ethyl-1,3,4-oxadiazol2(3H)-one		‘HNMR (400 MHz, DMSO-cfô) δ 8.13 (s, 1 H), 7.98 (s, 1 H), 7.77 (d, J = 1.0 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 6.62 (s, 2H, D₂O exchangeable), 3.76 (q, J= 7.0 Hz, 2H), 2.41 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 298 (MH)⁺
Intermediate 17a: 5(3-Bromo-4methylphenyl)-3propyl-1,3,4oxadiazol-2(3H)-one	a	'HNMR (400 MHz, DMSO-i/6) Ô 7.91 (d, J = 1.5 Hz, 1 H), 7.69 (dd, J = 8.0, 1.5 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 3.69 (t, J = 7.0 Hz, 2H), 2.41 (s, 3H), 1.75-1.70 (m, 2H), 0.90 (t, J= 7.0 Hz, 3H); ESI-MS (m/z) 296, 298 [(MH)⁺, Br⁷⁹·⁸¹].
Intermediate 17b: 5(3-(5-Aminopyrazin2-yl)-4methyiphenyl)-3propyl-1,3,4oxadiazol-2(3H)-one		'HNMR (400 MHz, CDCI3) δ 8.14 (s, 1 H), 8.09 (s, 1 H), 7.86 (d, J = 1.5 Hz, 1 H), 7.73 (dd, J = 8.0, 1.5 Hz, 1 H), 7.37 (d, J =8.0 Hz, 1H), 3.74 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.87-1.78 (m, 2H), 0.98 (t, J= 7.0 Hz, 3H); ESI-MS (m/z) 312 (MH)⁺.

Intermediate 18a: 5(3-Bromo-4ethylphenyl)-3methyl-1,3,4oxadiazol-2(3H)-one		^lHNMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.73 (dd, J = 8.0, 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 3.40 (s, 3H), 2.75 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 283, 285 [(MH)⁺, Br^79,81].
Intermediate 18b: 5(3-(5-Aminopyrazin2 -yl)-4- ethylpheny 1 )3-methyl-1,3,4oxadiazol-2(37/)-one		‘HNMR (400 MHz, DMSO-i/6) Ô 8.07 (s, 1H), 7.97 (s, 1H), 7.72 (dd, J= 8.0, 2.0 Hz, 1H), 7.67 (d, J -2.0 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1 H), 6.61 (s, 2H, D2O exchangeable), 3.40 (s, 3H), 2.75 (q, J - 7.5 Hz, 2H), 1.08 (t, J =1.5 Hz, 3H); ESI-MS (m/z) 298 (MH)⁺.
Intermediate 19a: 5(3-Bromo-4methoxyphenyl)-3methyl-1,3,4oxadiazol-2(3//)-one	/	'HNMR (400 MHz, DMSO) δ 7.91 (d, J = 2.5 Hz, 1 H), 7.79 (dd, J = 8.5, 2.0 Hz, 1 H), 7.28 (d, J = 8.5 Hz. 1H), 3.93 (s, 3H); ESI-MS (m/z) 285, 287 [(MH)⁺, Br⁷⁹¹⁸¹].
Intermediate 19b: 5(3-(5-Aminopyrazin- 2-yl)-4methoxyphenyl)-3methyl-1,3,4oxadiazol-2(3//)-one		‘HNMR (400 MHz, DMSO-î/6) δ 8.55 (s, 1 H), 8.21 (d, J=2.0/7z, 1H), 8.01 (s, 1 H), 7.73 (dd, J = 8.0, 2.0 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 6.63 (s, 2H, D2O exchangeable), 3.94 (s, 3H), 3.39 (s, 3H); ESI-MS (m/z) 300 (MH)⁺,
Intermediate 20a: 5(3-Bromo-4(difluoromethoxy)phe nyl)-3-methyl-1,3,4oxadîazol-2(3//)-one	V n-n /	'HNMR (400 MHz, CDC1₃) δ 8.09 (d, J = 2.5 Hz, 1H), 7.76 (dd, J= 8.5, 2.0 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 6.60 (t, J - 72.5 Hz, 1H), 3.45 (s, 3H); ESIMS (m/z) 321, 323 [(MH)⁺, Br⁷⁹’⁸¹].

Intermediate 20b: 5(3-(5-Aminopyrazin2-yl)-4(difluoromethoxy)phe nyl)-3-methyl-l ,3,4oxadiazol-2(3/7)-one		'HNMR (400 MHz, DMSO-î/6) δ 8.42 (s, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 8.03 (s, 1 H), 7.80 (dd, J = 8.0, 2.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.45 (t, J = 72.5 Hz, 1 H), 6.78 (s, 2H, D₂O exchangeable), 3.41 (s, 3H); ESI-MS (m/z) 336 (MH)*.
Intermediate 21a: 5(3-Bromo-4chlorophenyl)-3methyl-1,3,4oxadiazol-2(3/?)-one	/	‘HNMR (400 MHz, CDC1₃) δ 8.09(dT J = 2.0 Hz, 1 H), 7.69 (dd, J = 8.0, 2,0 Hz, 1H), 7.55 (d, J =8.0 Hz, lH), 3.50 (s, 3H); ESI-MS (m/z) 289, 291 [(MH)*, Cl³⁵¹³⁷]
Intermediate 21b: 5(3-(5-Aminopyrazin2-yl)-4-chlorophenyl)3-methyl-1,3,4oxadiazol-2(3/7)-one		ESI-MS (m/z) 304, 306 [(MH)*, Cl^3S· ³⁷1
Intermediate 22a: 5(3-Bromo-4fluorophenyl)-3methyl-1,3,4oxadiazol-2(3/7)-one	N-N /	^lHNMR (400 MHz, CDCI3) δ 8.05 (dd, J = 6.5, 2.5 Hz, 1H), 7.77-7.73 (m, 1 H), 7.21 (t, J =8.5 Hz, 1H), 3.50 (s, 3H); ESI-MS (m/z) 273, 275 [(MH)*, Br^79,81]
Intermediate 22b: 5(3-(5-Am inopyrazi n2-yI)-4-fluorophenyl)3-methyI-1,3,4oxadiazol-2(3/7)-one		'HNMR (400 MHz, DMSO-î/6) δ 8.42 (s, 1 H), 8.32 (dd, J = 7.0, 2.5 Hz, 1 H), 8.04 (s, 1H), 7.77-7.73 (m, 1H), 7.48 (dd, J = 8.5, 11.5 Hz, 1 H), 6.86 (s, 2H, D₂O exchangeable), 3.41 (s, 3H); ESI- MS (m/z) 288 (MH)*

Intermediate 23a: 5(3-Bromo-2methylphenyl)-3methyl-1,3,4oxadiazol-2(377)-one		'HNMR (400 MHz, DMSO-c/6) δ 7.84 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1H), 7.32 (d, J =8.0 Hz, 1 H), 3.42 (s, 3H), 2.62 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)⁺, Br^79,81]
Intermediate 23b: 5(3-(5-Aminopyrazin2-yl)-2methylphenyl)-3meth yl-1,3,4oxadiazol-2(3//)-one		ESI-MS (m/z) 284 (MH)⁺
Intermediate 24a: 5(3-Bromo-2ethylphenyl)-3methyl-1,3,4oxadiazol-2(3/7)-one		'HNMR (400 MHz, CdClj) Ô 7.71 (d, J = 8.0 Hz, 2H), 7,16 (t, J = 8.0 Hz, 1 H), 3.53 (s, 3H), 3.16 (q, J= 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H)
Intermediate 24b: 5(3-(5-Aminopyrazin2-yl)-2-ethylphenyl)3-methyl-l,3,4oxadiazol-2(3f/)-one		ESI- MS (m/z) 298 (MH⁺)

Intermediate 25

5,5-Dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4,5dihydroisoxazole

Step 1: 3-(3-Bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazole: To a mixture of l-(3bromo-4-methylphenyl)-3-methylbut-2-en-l-one, (prepared herein before in step 2 of intermediate 1; 1.0 g, 3.95 mmol, 1.0 eq), and hydroxylamine hydrochloride (330 mg, 4.74 — mmol, 1.2 eq) in éthanol (10 mL) at 0°C, was added an aqueous solution of potassium hydroxide (IN, 4 mL) until the pH of the reaction was basic. The resuiting mixture was stirred at room température for 4 h. The reaction mixture was diluted with ethyl acetate (20 mL) followed by water (20 mL). The layers were separated and the organîc layer was extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SC>4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc in hexane) to afford 250 mg of the desired product as a white solid. ’HNMR (400 MHz, CDCI3) δ 7.79 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H),

7.27 (d, J= 8.0 Hz, 1H), 3.08 (s, 2H), 2.43 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 268, 270 [(MH)⁺,

Step 2: 5,5-Dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4,5dihydroisoxazole: 3-(3-bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazole (250 mg, 0.93 mmol, 1.0 eq) was reacted with bis(pinacolato)diboron by following the procedure described hereinbefore in step 6 of intermediate 1 to afford 200 mg of the desired product as a white solid. ’HNMR (400 MHz, CDCI3) δ 7.91 (s, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.16 (s, 2H), 2.57 (s, 3H), 1.49 (s, 6H), 1.36 (s, 12H); ESI-MS (m/z) 316 (MH)⁺.

Intermediate 26

4,4-Dimethyl-2-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4,5dihydrooxazole tHümeocModboronl

Step 1: 3-Bromo-7V-(l-hydroxy-2-methylpropan-2-yl)-4-methylbenzamide: To a stirred 0°C cooled solution of 3-bromo-4-methylbenzoyl chloride (prepared from the corresponding carboxylic acid; 1.40 g, 6.04 mmol, 1.0 eq) in DCM (10 mL), was added a solution of2-amino-

2-methylpropanol (1.44 mL, 15.11 mmol, 2.5 eq) in DCM (10 mL) drop wise for 15 min and then warmed to room température. After stirring for 24 h at room température, the reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with water (20 mL) followed by brine (20 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum to afford the 1.7 g of the desired product as a white solid. 'HNMR (400 MHz, DMSOd₆) δ 8.00 (d, J= 1.0 Hz, 1H), 7.70 (dd, J= 1.0, 8.0 Hz, 1H), 7.62 (s, 1H, D₂O exchangeable),

7.40 (d, J= 8.0 Hz, 1H), 4.85 (t, J= 6.0 Hz, 1H, D₃O exchangeable), 3.49 (d, J= 6.0 Hz, 2H), 2.37 (s, 3H), 1.28 (s, 6H); ESI-MS (m/z) 286, 288 [(MH)⁺, Br⁷⁹’⁸¹].

Step 2: 2-(3-Bromo-4-methylphenyl)-4,4-dimethyl-4,5-dihydrooxazole: 3-bromo-N-( 1 -hydroxy-

2- methylpropan-2-yl)-4-methylbenzamide (1.7 g, 6.04 mmol, 1.0 eq) was treated with thionyl chloride (0.9 mL, 12.08 mmol, 2.0 eq) and the neat reaction mixture was stirred at room température for 12 h. The mixture is diluted with diethyl ether (50 mL) and the precipitated solid was filtered and washed with diethyl ether (20 mL). The solid collected was dissolved in sodium hydroxide solution (IN, 15 mL) and extracted with diethyl ether (2x20 mL). The combined organic layers were washed with brine (20mL), dried (NaîSC^) and filtered. The filtrate was concentrated under vacuum to afford the 1.0 g of the desired title product as a white solid. ¹HNMR (400 MHz, CDClj) δ 8.12 (d, J = 1.0 Hz, 1 H), 7.75 (dd, J = 1.0, 8.0 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1H), 4.09 (s, 2H), 2.42 (s, 3H), 1.37 (s, 6H); ESI-MS (m/z) 268, 270 [(MH)⁺, Br⁷⁹’⁸¹].

Step 3: 2-(3-bromo-4-methylphenyl)-4,4-dimethyl-4,5-dihydrooxazole (600 mg, 2.23 mmol, 1.0 eq) was reacted with bis(pinacolato)diboron (850 mg, 3.35 mmol, 1.5 eq) and Pd(dppf)Cl2 (90 mg, 0.11 mmol, 0.05 eq) by following the procedure described hereinbefore in step 6 of intermediate 1 to afford 700 mg of the desired product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 8.28 (d, J = 1.0 Hz, 1 H), 7.87 (dd, J = 1.0, 8.0 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 4.07 (s, 2H), 2.55 (s, 3H), 1.36 (s, 6H), 1.33 (s, 12H); ESI-MS (m/z) 316 (MH)⁺.

Intermediate 27

3- (4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxazorolan-2-yl)phenyl)-1 -oxa-2-azaspiro[4,4]non-2- ene:

CMj btefpInBealitodbMonl P<XdppOCi,

Step 1: 3-Bromo-4-methylbenzaldehyde oxime: To a stirred suspension of 3-bromo-4methylbenzaldehyde (1.0 g, 5 mmol, 1.0 eq) in methanol (50 mL) was added a solution hydroxylamine hydrochloride (434 mg, 6.3 mmol, 1.2 eq) in water (2 mL) at room température. The resulting solution was cooled to 0 °C and then treated with an aqueous solution of sodium carbonate (2M, 2 mL). After stirring for 1 h at room température, the solvent was removed under vacuum. The residue was taken into ethyl acetate (20 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine (15 mL), dried (Na₃SO4) and filtered. The filtrate was evaporated under vacuum to afford 0.85 g of the title product as a white solid. ’HNMR (400MHz, CDC1₃) δ 8.08 (s, 1H), 7.87 (s, 1H, D₂O exchangeable) 7.76 (d, 1.5 Hz, 1H), 7.43 (dd, 8.0 Hz, 1H), 7.27 (d, ./ = 8.0 Hz, 1H), 2.44 (s, 3H); ESI-MS (m/z) 214, 216 [(MH)⁺, Br⁷⁹’ ^8I].

Step 2: 3-(3-Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4,4]non-2-ene: To a solution of 3-bromo-

4-methylbenzaldehyde oxime (0.85 g, 4 mmol, 1.0 eq) in THF (50 mL) was added pyridine (0.2 mL, 2.4 mmol, 0.6 eq) followed by N-chlorosuccinimide (530 mg, 4 mmol, 1.0 eq) and the resulting mixture was refluxed for 1 h. The reaction was cooled to room température before the addition of a solution of methlenecyclopentane (0.42 mL, 4 mmol, 1.0 eq) in THF (5 mL) followed by triethyl amine (0.94 mL, 7 mmol, 1.7 eq). The resulting solution was refluxed for 1 h. The solvent was evaporated under vacuum and usual work up afforded 690 mg of the title product as a white solid. ’HNMR (400MHz, CDCI3) δ 8.09 (s, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.24 (d, J= 8.0 Hz, 1H), 3.22 (s, 2H), 2.41 (s, 3H), 2.14-2.11 (m, 2H), 1.88-1.84 (m, 2H), 1.77-1.72 (m, 4H); ESI-MS (m/z) 294, 296 [(MH)⁺, Br⁷⁹’⁸¹].

Step 3: 3-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxazorolan-2-yl)phenyl)-1 -oxa-2azaspiro[4,4]non-2-ene: 3-(3;Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4,4]non-2-ene (690 mg, 2 mmol, 1.0 eq) was reacted with bis(pinacolatodiboron) (720 mg, 3 mmol, 1.2 eq) and and Pd(dppf)Cl₂ (96 mg, 0.11 mmol, 0.05 eq) by following the procedure described hereinbefore in step 6 of intermediate 1 to afford 640 mg of the desired product as a white solid. ’HNMR (400MHz, CDCb) δ 7.88 (d, J = 1.5 Hz, 1 H), 7.72 (dd, J = 8.0, 1.5 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 3.29 (s, 2H), 2.54 (s, 3H), 2.11 -2.09 (m, 2H), 1.88-1.84 (m, 2H), 1.74-1.70 (m, 4H);ESI-MS (m/z) 342 (MH)¹

The bclow intermediates 28 to 29 were prepared by following a procedure similar to that described in intermediate 27:

Intermediates/IUPAC name

Structure

^lHNMR/ESI-MS(MH)⁺

Intermediate 28: Methyl 5 -methy 1 -3 -(4-methyl -3 (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2yl)phenyl)-4,5dihydroisoxazole-5carboxylate		’HNMR (400 MHz, CDCI3) δ 7.87 (d, J = 1.5 Hz, 1H), 7.59 (dd, J = 8.0, 1.5 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 3.92 (d, J = 17.0 Hz, 1H), 3.88 (s\ 3H), 3.26 (d, J = 17.0 Hz, 1H), 2.50 (s, 3H), 1.79 (s, 3H); ESI-MS (m/z) 312, 314 [(MH)⁺, Br⁷⁹’⁸¹]
Intermediate 29: (±)Ethyl 3-(3-bromo-4methylphenyl)-4,4dimethyl-4,5dihydroisoxazole-5carboxylate	CZ/^Br 1Γ ⁰	’HNMR (400 MHz,DMSO-d₆) δ 7.75 (d, 1.5 Hz, 1H), 7.52 (dd, J = 8.0, 1.5 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 4.53 (s, 1H), 4.10 (q, J = 7.0 Hz, 2H), 2.34 (s, 3H), 1.44 (s, 3H), 1.40 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H); ESI- MS (m/z) 340, 342 [(MH⁺, Br ⁷⁹’⁸¹]

Intermediate 30

3-(3-Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one

N9SMJ0N

Slêp I

Step 1: 4-Bromo-3-(3-bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-ene: To a solution of 3-(3-bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-ene (2.0 g, 6.49 mmol, 1.0 eq) (prepared by following the procedure described for step-2 of the intermediate 27 by the reaction of 3-methyl-4-methylbenzaldehyde oxime with methylenecyclohexane) in chloroform (20 mL) was added NBS (1.15 g, 6.49 mmol, 1.0 eq) followed by catalytic amount of A1BN (21 mg, 0.13 10 mmol, 0.02 eq). The resulting mixture was stirred at room température ovemight. The reaction was diluted with chloroform (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (silica gel, ethyl acetate and hexane) to afford 600 mg of the title product as a white solid. ’HNMR (400 MHz, CDCh) δ 7.97 (d, J = 2.0 Hz, 1 H), 7.65 (dd, J = 8.0, 2.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 5.14 (s, 1 H), 2.43 (s,

3H), 2.13-2.10 (m, IH), 2.01-1.99 (m, IH), 1.82-1.76 (m, 4H), 1.65-1.62 (m, IH), 1.52-1.45 (m, 3H); ESI-MS (m/z) 386, 388, 390 [(MH)⁺ Br⁷⁹’⁸¹].

Step 2: 3-(3-Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one: To a solution of 4bromo-3-(3-bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-ene (500 mg, 1.29 mmol, 1.0 eq) in DMSO (8 mL) was added sodium bicarbonate (218 mg, 2.59 mmol, 2.0 eq) followed by sodium iodide (289 mg, 1.93 mmol, 1.5 eq). The resulting mixture was stirred at 100 °C for 5 h. The reaction was cooled to room température and water (15 mL) was added to the above reaction mixture followed by ethyl acetate (15 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organîc layers were washed with water (2x10 mL), brine (15 mL), dried (NaiSCL) and filtered. The filtrate was evaporated under vacuum.

The crude product was purified with column chromatography (silica gel, ethyl acetate and hexane) to afford the desired product 170 mg of the title product along with 100 mg of the 3-(3bromo-4-methylphenyl)-1 -oxa-2-azaspiro(4.5]dec-2-en-4-ol. The 3-(3-bromo-4-methylphenyl)l-oxa-2-azaspiro[4.5]dec-2-en-4-ol was again converted to the title product by the oxidation with chromîum trioxide by following the procedure described for step-5 of the intermediate 1.

3-(3-bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-ol: 'HNMR (400 MHz, CDCI3) δ 7.94 (d, J = 2.0 Hz, 1 H), 7.63 (dd, J = 8.0, 2.0 Hz, 1 H), 7.23 (d, J - 8.0 Hz, 1 H), 4.82 (d, J = 10.0 Hz, IH), 2.40 (s, 3H), 1.87-1.33 (m, 8H), 0.89-0.83 (m, 2H); ESI-MS (m/z) 324, 326 [(MH)⁺Br⁷⁹·⁸¹].

3-(3-Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one: ’HNMR (400 MHz, CDCij) δ 8.30 (d, J = 2.0 Hz, IH), 7.95 (dd, 8.0, 2.0 Hz, IH), 7.31 (d, J = 8.0 Hz, IH), 2.44 (s, 3H), 1.87-1.42 (m, 10H); ESI-MS (m/z) 322, 324 [(MH)⁺ Br⁷⁹’⁸¹].

Intermediate 31

3-(3-Bromo-4-methylphenyl)-4-methyl-1,2,4-oxadiazol-5(4H)-one

HjNOH

Slep-1

Mol/KjCOj

Biep-3

Step-1: 3-Bromo-N-hydroxy-4-methylbenzimidamide: To a stirred solution of 3-bromo-4methylbenzonitrile (2.0 g, 10.2 mmol, 1.0 eq) in éthanol (20 mL) was added hydroxylamine hydrochloride (1.77 g, 25.5 mmol, 2.5 eq) followed by a solution of sodium carbonate (2,70

25.5 mmol, 2.5 eq) in water (2 mL). The resulting mixture was refluxed for 6 h. The reaction was cooled to room température and the solvent was removed under vacuum. The residue was taken in DCM (100 mL) and washed with water (30 mL), brine (30 mL), dried (Na2SÛ4) and filtered. The filtrate was rotary evaporated to afford 1.5 g of the title compound as a white solid. ’HNMR (400 MHz, CDCh) δ 9.70 (s, 1H), 7.86 (d,J = 1.5 Hz, 1H), 7.59 (dd,J=7.5, 1.5 Hz, 1H), 7.34( d, J= Ü.QHz, 1H), 5.86 (s, 2H), 2.34 (s, 3H); ESI-MS (m/z) 229, 231 [(MH)⁺ Br^79,81].

Step-2: 3-(3-Bromo-4-methylphenyl)-l,2,4-oxadiazol-5(4H)-one: To a 0 °C cooled solution of 3bromo-N-hydroxy-4-methylbenzimidamide (500 mg, 2.18 mmol, 1.0 eq) in DCM ( 10 mL) was added triphosgene (250 mg, 0.87 mmol, 0.4 eq) followed by diisopropylethylamine (0.76 mL, 4.46 mmol, 2 eq). The resulting mixture was stirred at room température for 3 h. The reaction was cooled back down to room température and quenched with water (5 mL) followed by dilution with DCM. The layers were separated and the organic layer was washed with brine (10 mL), dried (Na2SÜ4) and filtered. The filtrate was evaporated under vacuum to afford 250 mg of the title product as white solid. ‘HNMR (400 MHz, DMSO-dô) δ 13.10 (s, 1H, D2O exchangeable), 8.01 (d, J =1.5 Hz, 1H), 7.74 (dd, J= 8.0, 1.5 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H) 2.42 (s, 3H); ESI-MS (m/z) 255, 257 [(MH)⁺, Br⁷⁹’⁸¹]

Step-3: 3-(3-Bromo-4-methylphenyl)-4-methyl-l,2,4-oxadiazol-5(4H)-one: To a stirred solution of 3-(3-bromo-4-methylphenyl)-l,2,4-oxadiazol-5(4H)-one (1.5 g, 5.92 mmol, 1.0 eq) in DMF (10 mL) was added methyl iodide (0.73 mL, 11.85 mmol, 2,0 eq) and potassium carbonate (1.6 g, 11.85 mmol, 2.0 eq) and the reaction was stirred at room température ovemight. Water (20mL) was added to the reaction mixture followed by ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2*20 mL) and the combined organic layers were washed with water (2x20 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane System as eluent) to afford 1.35 g of the title product as a white solid. 'HNMR (400 MHz, DMSO-ίήί) δ 7.93 (d, J = 2.0 7fe,lH), 7.66 (dd, J= 7.5, 2.0 Hz, 1H), 7.60 (d, J= 7.5 Hz, 1 H), 3.34 (s, 3H), 2.44 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)⁺, Br⁷⁹’⁸¹]

Intennediate 32

N-(5-Bromopyrazine-2-yl)-2,6-difluorobenzamide\xx

NBS

Step-1

Inletmtdinh 32

Step 1: 2-Amino-5-bromopyrazine: To a 0°C cooled and stirred solution of 2-aminopyrazine (10 g, 105 mmol, 1.0 eq) in DCM (1000 mL) was added A-bromosuccinimide (16.8 g, 94.6 mmol, 0.9 eq) portion wîse and the resulting solution was stirred at the same température for 30 min. The reaction mixture was filtered while keeping the filtrate at 0°C and cold water (500 mL) was added to the filtrate. The layers were separated and the organic layer was washed with brine (200 mL), dried (Na₂SÛ4) and filtered. The filtrate was concentrated under vacuum. The crude product was purified by re-crystallization using DCM and hexane to afford 12 g of the desired product as a pale yellow solid. ’HNMR (400 MHz, CDCI3) δ 8.06 (s, 1H), 7.75 (s, 1H), 4.72 (brs, 2H, D₂O exchangeable); ESI-MS (m/z) 174, 176 [(MH)⁺ Br⁷⁹·⁸¹].

Step 2: N-(5-Bromopyrazine-2-yl)-2,6-difluorobenzamide: To a 0°C cooled and stirred, solution of 2,6-difluorobenzoyl chloride (5.7 g, 36.2 mmol, 0.9 eq) in DCM (200 mL) was added drop wise a solution of 2-amino-5-bromopyrazine (7.0 g, 40.2 mmol, 1.0 eq) in DCM (50 mL) followed b pyridine (3.1 g, 36.2 mmol, 0.9 eq). The resulting mixture was stirred at room température for 15 h. The reaction was diluted with DCM (100 mL), and washed with 10% hydrochloric acid (100 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to afford 6.0 g of the title product as a yellow solid. ’HNMR (400 MHz, CDCI3) δ 9.47 (s, 1H), 8.62 (s, 1H, D₂O exchangeable), 8.24 (s, 1H), 7.53-7.45 (m, 1H), 7.03 (t, J= 8.0 Hz, 2H); ESI-MS (m/z) 314, 316 [(MH)⁺ Br⁷⁹’⁸¹].

The below intermediates 33 to 44 were prepared by following a procedure similar to that described in intermediate 32:

Intermediates/IUPA C naine

Structure 'HNMR/ESI-MS

MH⁺

Intermediate 33: N(5-Bromopyrazin-2yl)-2fluorobenzamide		’HNMR (400 MHz, CDCla) δ 9.51 (s, 1H), 9.08 (d,J = 15 Hz, 1H, D₂O exchangeable), 8,40 (s, 1H), 8.17 (dt, J = 1.5, 8.0 Hz, 1H), 7.62-7.56 (m, 1H), 7.35 (t,J=7.5 Hz, 1H), 7.23 (dd, J = 9.0, 12.5 Hz, 1H) ; ESI-MS (m/z) 296, 298 [(MH)⁺ Br^79,81].
Intermediate 34: N(5-Bromopyrazine-2yl)-2,4difluorobenzamide		’HNMR (400 MHz, DMSO) δ 11.40 (s, 1H, D₂O exchangeable), 9.23 (s, 1H), 8.67 (s, 1 H), 7.80 (q, J = 8.0 Hz, 1 H), 7.45-7.39 (m, 1H), 7.26-7.19 (m, 1H); ESI-MS (m/z) 314, 316 [(MH)⁺ Br⁷⁹·⁸¹].
Intermediate 35: N(5-Bromopyrazine-2yl)-2,5difluorobenzamide	F	’HNMR (400 MHz, DMSO) δΊ 1.52 (s, 1H, D₂O exchangeable), 9.23 (s, 1H), 8.69 (s, 1H), 7.61-7.56 (m, 1H), 7.517.41 (m, 2H); ESI-MS (m/z) 314, 316 [(MH)⁺ Br⁷⁹’⁸¹].
Intermediate 36: N(5-Bromopyrazine-2yl)-2,3difluorobenzamide		’HNMR (400 MHz, DMSO-î/6) δ 11.57 (s, 1 H, D₂O exchangeable), 9.24 (s, 1H,), 8.69 (s, 1H), 7.69-7.62 (m, 1H), 7.54-7.50 (m, 1H), 7.38-7.33 (m, 1H); ESI-MS (m/z) 314, 316 [(MH)⁺ Br⁷⁹’⁸¹]
Intermediate 37: N(5-bromopyrazin-2yl)-3fluorobenzamide		’HNMR (400 MHz, DMSO-îM) δ 11.43 (s, 1 H, D₂O exchangeable), 9.25 (s, 1H,), 8.72 (s, 1H), 7.90-7.85 (m, 2H), 7.60-7.57 (m, 1H), 7.51-7.45 (m, 1H); ESI-MS (m/z) 296, 298 [(MH)⁺ Br⁷⁹·⁸¹]

Intermediate 38: N(5-Bromopyrazîne-2- yl)-4fluorobenzamide		‘HNMR (400 MHz, DMSO-î/6) δ 11.37 (s, 1H, D₂O exchangeable), 9.24 (s, 1 H,), 8.70 (s, 1H), 8.14-8.10 (m, 2H), 7.37 (t, J= 8.5 Hz, 2H); ESI-MS (m/z) 296, 298 [(MH)⁺Br^79,81]
Intermediate 39: N(5 - B romopyrazi ne-2yl)-2,4,5trifluorobenzamide		‘HNMR (400 MHz, DMSO-i/6) δ 11.52 (s, 1 H, D2O exchangeable), 9.22 (s, IH,), 8.70 (s, 1H), 7.93-7.87 (m, 1H), 7.80-7.73 (m, 1H); ESI-MS (m/z) 332, 334 [(MH)⁺ Br⁷⁹’⁸¹]
Intermediate 40: V(5-Bromopyrazine-2yl)-2,3dimethylbenzamide		‘HNMR (400 MHz, CDCI3) δ 9.51 (s, 1H), 8.38 (s, 1H, D2O exchangeable), 8.14 (s, IH), 7.33 (t, J= 8.0 Hz, 2H), 7.19 (t,J= 8.0 Hz, lH),2.38(s, 3H), 2.34 (s, 3H); ESI-MS (m/z) 306, 308 [(MH)⁺ Br⁷⁹’⁸¹].
Intermediate 41 : N(5-Bromopyrazine-2yl)-4trifluoromethylbenza mide		‘HNMR (400 MHz, DMSO-J6) δ 11.59 (s, 1 H, D₂O exchangeable), 9.26 (s, 1 H,), 8.72 (s, 1 H), 8.21 (d, J = 8.0 Hz, 2H), 7.92 (d, J= 8.0 Hz, 1 H); ESI-MS (m/z) 346, 348 [(MH)⁺ Br⁷⁹’⁸¹]
Intermediate 42: N(5-Bromopyrazine-2yl)-4-fluoro-3methylbenzami de		‘HNMR (400 MHz, CdCl₃) δ 9.48 (s, IH), 8.40-8.37 (m, 2H), 7.80 (d, J= 7.0 Hz, 1 H), 7.74-7.72 (m, 1 H), 7.14 (t, J = 8.0 Hz, IH), 2.36 (s, 3H); ESI- MS (m/z) 310, 312 [(MH)⁺, Br⁷⁹¹⁸¹ ]

Intermediate 43: /V(5-Bromopyrazine-2yl)-2methylbenzamide		’HNMR (400 MHz, CDCEVô 9.50 (s, IH), 8.29 (s, 1H, D₂O exchangeable), 8.26 (s, 1 H), 7.54 (d, J = 7.5 Hz, 1 H), 7.43 (d, J= 8.0 Hz, 1 H), 7.32-7.26 (m, 2H), 2.46 (s, 3H); ESI-MS (m/z) 292, 294 [(MH)⁺ Br^79,81].
Intermediate 44: Λ/(5-Bromopyrazine-2yl)-3-fluoro-5-triflu oromethylbenzamide		’HNMR (400 MHz, DMSO-d₆) δ 11.69 (s, 1 H, D₂O exchangeable), 9.25 (s, 1 H), 8.73 (s, 1 H), 8.27 (s, 1 H), 8.17 (d, J = 8.0 Hz, 1H), 8.01 (d, J =3.0 Hz, 1H); ESI- MS (m/z) 364, 366 [(MH)⁺, Br 79,81]

Intermediate 45 /V-(5-Bromopyrazin-2-yl)-4-methyl-l,2,3-thiadiazoIe-5-carboxamide

To a solution of 2-amino-5-bromopyrazine (1.0 g, 5.74 mmol, 1.2 eq) and 4-methyl-1,2,3thiadiazole-5-carboxylic acid (690 mg, 4.79 mmol, 1.0 eq) in THF (20 mL) at room température was sequentially added EDC. HCl (970 mg, 7.18 mmol, 1.5 eq), HOBT (1.37g, 7.18 mmol, 1.5 eq) and diisopropylethyl amine (1.23 mL, 9.58 mmol, 2.0 eq). The resulting solution was stirred at the same température for 24 h. Water (30 mL) was added to the reaction mixture followed by 10 ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with IN hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL) dried (Na₂SO₄) and filtered, The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel) to afford 321 mg of the desired product as a white solid. ’HNMR 15 (400 MHz, DMSO-r/rt) δ 11.91 (s, 1 H, D₂O exchangeable), 9.20 (s, 1H), 8.72 (s, 1H), 2.83 (s,

3H); ESI-MS (m/z) 300, 302 [(MH)⁺, Br⁷⁹'⁸¹].

Intermediate 46a and 46b

N-(4-bromophenyl)-2,6-difluorobenzamide (46a) vf' and

2,6-Difluoro-/V-(4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (46b)

Intormedl·!· 4U lrriarm*dlat«44b

Step 1 : N-(4-Bromophenyl)-2,6-difluorobenzamide: To a stirred and 0°C cooled solution of 4bromoaniline (1.0 g, 5.8 mmol, 1.0 eq) and pyridine (0.61 mL, 7 mmol, 1.2 eq) in DCM (20 mL) was added drop wise a solution of 2,6-difluorobenzoyl chloride (0.8 mL, 6.4 mmol, 1.1 eq) in DCM (5 mL). After stirring the resulting mixture at the same température for 1 h, the solvent was removed under vacuum. The residue was taken into ethyl acetate (20 mL) and water (20 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2x20 mL) and the combined organic layers were washed with brine (20 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum to afford 1.20 g of the desired product as a white solid. ’HNMR (400 MHz, DMSO-</₆) δ 7.78 (brs, 1H, D₂O exchangeable), 7.53-7.37 (m, 5H), 7.02-6.95 (m, 2H); ESI-MS (m/z) 312, 314 [(MH)⁺ Br^79,81].

Step 2: 2,6-Difluoro-/V-(4-(4,4,5,5,-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)benzamide: 7V(4-Bromophenyl)-2,6-difiuorobenzamide (5.0 g, 16.1 mmol, 1.0 eq) was reacted with bis(pinacolato)diboron (4.88 g, 19.2 mmol, 1.2 eq) by following the procedure described in step 6 of intermediate 1 to afford 4.20 g of the desired product as a white solid. ’HNMR (400 MHz, DMSO-Jfl) δ 10.92 (brs, 1H, D₂O exchangeable), 7.72-7.64 (m, 4H), 7.62-7.56 (m, 1H), 7.26 (t, J= 8.0 Hz, 2H), 1.29 (s, 12H); ESI-MS (m/z) 360 (MH)⁺.

The below intermediates 47a to 49 were prepared by following a procedure similar to that described in intermediate 46a or intermediate 46b:

Intcrmediates/IUPAC name

Structure

‘HNMR/ESI-MS MH⁺

Intermediate 47a: N-(4- Bromophenyl)-2-chloro- 6-fluorobenzamide	-oAb	’HNMR (400 MHz, DMSO-^) 5 10.95 (s, 1H, D₂O exchangeable), 7.68 (d, J= 8.5 Hz, 2H) 7.59-7.53 (m, 3H), 7.46 (d, J = 8.0 Hz, 1 H), 7.42-7.33 (m, 1H); ESl- MS (m/z) 327,329 [(MH)⁺, Br⁷⁹’⁸¹]
Intermediate 47b: 2Chloro-6-fluoro-7V-(4(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2yl)phenyl)benzamide		’HNMR (400 MHz, CDC1₃) δ 7.81 (d, J= 8.5 Hz, 2H), 7.63 (d, J= 8.5 Hz, 2H), 7.56 (s, 1 H, D₂O exchangeable), 7.38-7.32 (m, 1H), 7.25 ( d, 1 H), 7.09 (t, J = 8.5 Hz, 1H), 1.35 (s, 12H); ESI- MS (m/z) 376 (MH)⁺
Intermediate 48a: N-(4- Bromophenyl)-2-fluoro- 6-methylbenzamide	^b-	’HNMR (400 MHz, CDCI3) δ 7.63 (s, 1H, D₂O exchangeable), 7.51 (d, J= 8.5 Hz, 2H), 7.45 (d, J= 8.5 Hz, 2H), 7.31 -7.26 (m, 1 H), 7.03 (d, J = 8.0 Hz, 1H), 6.95 (t, J =8.5 Hz, 1H), 2.43 (s, 3H); ESI-MS (m/z) 307, 309 [(MH)⁺, Br⁷⁹’⁸¹]
Intermediate 48b: 2- Fluoro-6-methyl-N-(4(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2yl )phenyl )benzam ide		’HNMR (400 MHz, CDCI3) δ 7.81 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.54 (s, 1H, D₂O exchangeable), 7.32-7.26 (m, 1H), 7.05 (d, J = 8.5 Hz, 1 H), 6.97 (t, J = 8.0 Hz, 1H), 2.46 (s, 3H), 1.34 (s, 12H); ESI-MS (m/z) 356 (MH)⁺.

Intermediate 49: 4-EthylJV-(4-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2yl)phenyl )benzam ide

ESI-MS (m/z) 352 (MH)⁺.

Intermediate 50

4-Methyl-/V-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l,2,3-thiadiazol-5carboxamide

HjC

IrilarTTWdlat· 60

Step-1: N-(4-Bromophenyl)-l,2,3-thiadiazol-5-carboxamide: To a solution of 4-bromoaniline (820 mg, 4.79 mmol, 1.0 eq) and 4-methyl-l,2,3-thiadiazole-5-carboxylic acid (690 mg, 4.79 mmol, 1.0 eq) in THF (20 mL) at room température was sequentially added EDC. HCl (970 mg, 7.18 mmol, 1.5 eq), HOBT (1.37g, 7.18 mmol, 1.5 eq) and diisopropylethyl amine (1.23 mL, 9.58 mmol, 2.0 eq). The resulting solution was stirred at the same température for 24 h. Water (30 mL) was added to the reaction mixture followed by ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3^x20 mL). The combined organic layers were washed with IN hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL) dried (NaiSO^) and fîltered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel) to afford 321 mg of the desired product as a white solid. ’HNMR (400 MHz, CDCI3) δ 7.64 (brs, 1H, D₂O exchangeable), 7.51-7.45 (m, 4H), 2.94 (s, 3H); ESI-MS (m/z) 298, 300 [(MH)⁺ Br⁷⁹' ^8,J.

Step-2: 4-Methyl-N-(4-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)phenyl)-l,2,3-thiadiazol-5carboxamide: The title compound was prepared by the reaction of N-(4-bromophenyl)-1,2,3thiadiazol-5-carboxamide with bis(pinacolato)diboron by following the procedure described for step 6 of intermediate 1. ’HNMR (400 MHz, CDCI3) δ 7.80 (d, J= 8.5 Hz, 2H), 7.61 (s, 1H, D2O exchangeable), 7.55 (d, J= 8.5 Hz, 2H), 2.94 (s, 3H), 1.32 (s, 12H); ESI-MS (m/z) 346 (MH)'._W--59

Intermediate 51

AL(5-Bromopyridin-2-yl)-2,6-difluorobenzamide

To a mixture of 2-chloro-5-bromopyridine (370 mg, 1.9 mmol, 1.2 eq) and 2,6difluorobenzamide (250 mg, 1.5 mmol, 1.0 eq) in dioxane (10 mL), copper iodide (151 mg, 0.75 mmol, 0.5 eq), potassium phosphate (670 mg, 3.15 mmol, 2.1 eq) and N,N-dimethylethylene diamine (0.1 mL, 1.05 mmol, 0.7 eq) were added sequentially. The resulting mixture was stirred at reflux for 15 h. The reaction was cooled to room température, filtered to remove the solid components and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with water (20 mL), brine (20 mL), dried (Na₂SC>4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate and hexane) to afford 300 mg of the solid product as a white solid. 'HNMR (400 MHz, DMSO-</₀) δ 11.22 (s, 1H, D₂O exchangeable), 8.70 (d, J = 2.5 Hz, 1 H), 8.18 (dd, J = 8.0, 2.5 Hz, 1 H), 7.67-7.59 (m, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 2H); ESI-MS (m/z) 313, 315 [(MH)⁺ Br⁷⁹’⁸¹].

Intermediate 52

N-(6-Bromopyridin-3-yl)-2,6-difluorobenzamide

To a (0 °C) cooled and stirred solution of 2-bromo-5-aminopyridine (2.0 g, 11.56 mmol, 1.0 eq) in DCM (25 mL) was added sequentially 2,6-difluorobenzoyl chloride (1.44 mL, 11.56 mmol, 1.0 eq) and pyridine (1.19 mL, 13.87 mmol, 1.2 eq). The resulting mixture was allowed to warm to room température and then stirred at the same température for 30 min. Reaction was diluted with DCM (30 mL) and washed with water (20 mL), saturated aqueous sodium bicarbonate solution (30 mL), brine (20 mL), dried (Na₂SO4) and filtered. The filtrate was rotary evaporated and the residue was triturated with hexane to afford 3.4 g of the desired product as a white solid. 'HNMR (400 MHz, CDCIj) δ 8.42 (d, J = 2.5 Hz, 1 H), 8.18 (dd, J = 8.5, 2.5 Hz, 1 H), 7.96 (brs,

1H, D₂O exchangeable), 7.49 (d, J = 8.5 Hz, 1H), 7.46-7.41 (m, 1H), 7.00 (t, J = 8.0 Hz, 2H);

ESI-MS (m/z) 313, 315 [(MH)⁺ Br⁷⁹'⁸¹].

Intermediate 53a: 5-bromo-A/-(2,6-difluorophenyl)thiophene-2-carboxamide and

Intermediate 53b: N-(2,6-difluorophenyl)-5-(trimethylstannyl)thiophene-2-carboxamide (COC0y«t DMF

Marmedlat· U· intenmdW* S3b

Step 1: 5-Bromothiophene-2-carboxylic acid: To a 0 °C solution of 5-bromothiophene-2carboxaldehyde (5.0 g, 26.1 mmol) in acetone (50 mL) was added drop wise a ffeshly prepared jone’s reagent (25 mL) ( 25 g of chromium trioxide dissolved in 25 mL of cône sulfuric acid, is added slowly to 75 mL of water that had been cooled to 0 °C and stirring) and the resulting mixture was stirred at room température for 4 h. Water (50 mL) was then added to the above 10 mixture followed by ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x50 mL). the combined extracts were washed with water (50 mL), brine (50 mL), dried (Na₂SO4) and filtered. The filtrate was evaporated under vacuum, to afford

5.2 g (95 ) of the desired product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 10.87 (brs, III, D₂O Exchangeable), 7.63 (d, J= 4.0 Hz, 1H), 7.11 (d, J= 4.0 Hz, 1H).

Step 2: 5-Bromo-N-(2,6-difluorophenyl)thiophene-2-carboxamide To a 0 °C solution of 5bromothiophene-2-carboxylic acid (5.20 g, 25 mmol, 1.0 eq) in DCM (60 mL) was added drop wise a solution of oxalyl chloride (16 g, 125 mmol, 5 eq) in DCM (20 mL) followed by a catalytic amount of DMF (0.5 mL). The resulting mixture was stirred for 2 h at room température and then the solvent, excess of oxalyl chloride were removed under vacuum. To the residue obtained above was taken into DCM (50 mL) cooled to 0 °C, then added a solution of

2,6-difluoroaniline (4.0 g, 31 mmol, 1.2 eq) followed by pyridine (5 mL). The reaction was gradually allowed to warm to room température and then stirred ovemight at the same température. The reaction was diluted with DCM (100 mL) and washed with water (2^χ50 mL), 10% HCl (50 mL), brine (50 mL), dried (Na₂SÛ4) and filtered. The filtrate was evaporated under vacuum to afford the 5 g (65%) of desired product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 7.52 (s, 1H, D₂O Exchangeable), 7.43 (d, J = 4.0 Hz, 1H), 7.24-7.17 (m, 1H), 7.06 (d, J = 4.0 Hz, 1H), 6.94 (t, J= 8.0Hz, 2H); ESI-MS (m/z) 320, 322 [(MH)⁺, Br⁷⁹’⁸'].

Step 3: N-(2,6-Difluorophenyl)-5-(trimethylstannyl)thiophene-2-carboxamide: To a solution of

5-bromo-N-(2,6-difluorophenyl)thiophene-2-carboxamide (2.50 g, 7.86 mmol, 1.0 eq) and hexamethylditin (1.63 mL, 7.86 mmol, 1.0 eq) in dioxane (40 mL) was added Pd(PPha)4 (454 mg, 0.39 mmol, 0.05 eq). The resulting mixture was thoroughly deoxygenated by subjccting to vacuum/nitrogen cycle three times and the reaction mixture was heated at 75 °C for 15 h under nitrogen atmosphère. The resulting mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate-hexane mixture as eluent) to afford 1.0 g (31 %) of the desired product as a pale yellow solid. ESI-MS (m/z) 404 [(MH)⁺J.

Intermediate 54

5-Bromo-A-(3-methylpyridin-4-yl)thiophene-2-carboxamide

To a solution of 3-methylpyridine-4-amine (1.23g, 11.37 mmol, 1.2 eq) in DMF (5 mL) at 0 °C was added solid sodium hydride (60% suspension in minerai oil, 0.44g, 18.49 mmol, 2.0 eq) and stirred for 1 h at room température. In a separate flask, to a solution of 5-bromothiophene-2carboxylic acid (1.91 g, 9.25 mmol, 1.0 eq) in DCM ( 10 mL) was added oxalyl chloride (4.0 mL,

46.2 mmol, 5.0 eq) at 0 °C and then stirred at the same température for 2 h. The solvent and excess of oxalyl chloride were removed by évaporation under vacuum. The residue was dissolved in DMF (2 mL) and added to the above mixture at 0 °C and the resulting mixture was stirred at room température ovemight. Water (10 mL) was added to the reaction followed by ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with water (2x20 mL), brine (20 mL), dried (Na₂SÛ4) and filtered. The filtrate was concentrated under vacuum and purified by column chromatography (silica gel, DCM:MeOH System) to afford 1.0 g of the desired product as a white solid. ¹ HNMR (400 MHz, CDClj) δ 8.39 (d, J = 5.5 Hz, 1 H), 8.36 (s, 1 H), 8.05 (d, J =

5.5 Hz, 1H), 7.87 (s, 1H, D₂O exchangeable), 7.40 (d, J = 4.0 Hz, 1H), 7.09 (d, J - 4.0 Hz, 1H), 2.29 (s, 3H); ESI-MS (m/z) 297, 299 [(MH)⁺ Br⁷⁹’⁸¹].

Intermediate-55a&55b

5-Bromo-N-(2,6-difluorophcnyl)-3-methylthiophene-2-carboxamide (55a) and

A-(2,6-Difluorophenyl)-3-methyl-5-(trimethylstannyl)thiophene-2-carboxamide (55b)

(COC^cet DMF

COOH

Step t

kittrrnfdMH* SS*

MvjSnSnM*] Pd(PPhj)_A

B4»p4

IntirmedUta Mb

Step 1: 5-Bromo-3-methylthiophene-2-carbaldehyde: To 0 °C cooled solution of 3methylthiophene-2-carbaldehyde (10,0 g, 79.3 mmol, 1.0 eq) in DCM (100 mL) was added drop wise a solution of bromine (12.6 g, 79.3 mmol, 1.0 eq) and the resulting mixture was stirred 70 °C for 4 h. The reaction was cooled to room température and diluted with DCM (100 mL). The resulting organic layer was washed with water (100 mL), saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried (Na₂SO4) and filtered. The filtrate was rotary evaporated to afford 11 g of the desired product as a brown solid. ’HNMR (400 MHz, CDCI3) δ 9.87 (s, 1H), 6.93 (s, 1H), 2.51 (s, 3H); ESI-MS (m/z) 205, 207 [(MH)⁺, Br⁷⁹’⁸¹].

Step 2: 5-Bromo-3-methylthiophene-2-carboxylic acid: The title compound was prepared from the 5-bromo-3-methylthiophene-2-carboxaIdehyde by following the procedure described for stepl of intermediate 53. 'HNMR (400 MHz, DMSO-î/a) δ 13.20 (s, 1H, D₂O Exchangeable), 7.20 (s, 1H), 2.43 (s, 3H);S1-MS (m/z) 221,223 [(MH)⁺, Br⁷⁹’⁸¹],

Step 3: 5-Bromo-N-(2,6-difluorophenyl)-3-methylthiophene-2-carboxamide: The title compound was prepared by following the procedure described for step 2 of the intermediate 53. 'HNMR (400 MHz, DMSO-î/a) δ 9.78 (s, 1H, D₂O Exchangeable), 7.41-7.34 (m, 1H), 7.20-7.15 (m, 3H), 2.43 (s, 3H); ESI-MS (m/z) 332, 334 [(MH)⁺, Br⁷⁹'⁸¹].

Step-4: N-(2,6-Difluorophenyl)-3-methyl-5-(trimethylstannyl)thiophene-2-carboxamide: The title compound was prepared by following the procedure described hereinbefore for step 3 of intermediate 53. ESI-MS (m/z) 418 (MH)⁺.

Intermediate 56

4-Bromo-N-(2,6-difluorophenyl)thiophene-2-carboxamide (COCr^cel DMF

Intwmedüil* 54

The title compound was prepared by following the procedure described for intermediate 53 from the corresponding starting materials. *HNMR (400 MHz, CDCI3) δ 7.76 (s, IH, D₂O exchangeable), 7.60 (d, 1.5 Hz, IH), 7.46 (d, J= 1.5 Hz, IH), 7.24-7.16 (m, IH), 6.93 (t, J =

8.5 Hz, 2H); ESI-MS (m/z) 318, 320 [(MH)⁺, Br⁷⁹’⁸'].

Intermediate 57

4-Bromo-N-(2,6-difluorophenyl)-3-methylthiophene-2-carboxamide

Intervrwdlal* ¢7

Step 1: Methyl 3-methylthiophene-2-carboxyIate: To a solution of 3-Methylthiophene-2carboxylic acid (15 g, 105 mmol, 1.0 eq) in methanol (150 mL) was added conc sulfuric acid (7.5 mL) drop wise and refluxed for 12 h. The solvent was evaporated under vacuum and the residue was taken into ethyl acetate (200 mL), washed with water (2x50 mL), saturated aqueous sodium bicarbonate solution (2x50 mL), brine (50 mL), dried (Na₂SO4) and filtered. The filtrate was evaporated under vacuum to afford 20 g (97%) of the desired product as a oil. ’HNMR (400 MHz, CDCI3) δ 7.38 (d, J= 5.0 Hz, IH), 6.91 (d, J= 5.0 Hz, IH), 3.85 (s, 3H), 2.55 (s, 3H); ESIMS [(m/z) 157 (MH)⁺]

Step 2: Methyl 4-bromo-3-methylthiophene-2-carboxylate: A solution of methyl 3methylthiophene-2-carboxylate (20 g, 103 mmol, 1.0 eq) and sodium hydroxide (12.3 g, 307 mmol, 3 eq) in acetic acid (75 mL) was heated to 60 °C. Bromine (46.9 g, 294 mmol, 2.85 eq) was added drop wise at such a rate so as to maintain the température of the reaction mixture at <85 °C. The resulting mixture was stirred at 85 °C for 6 h. The solution was then allowed to cool to 50 °C and zinc dust (15.4 g, 236 mmol, 2.3 eq) was added in 3 gram portions to the reaction such that the exotherm was controlled to remain below 85 °C. The resulting mixture was stirred at 85 °C for 1 h, and then filtered hot through a small bed of celite. Water (300 mL) was added and the mixture was extracted with hexane (300 mL). The organic phase was washed with water, then concentrated to dryness to give 27 g (89%) an off white oil which slowly crystallized upon standing at room température. ’HNMR (400 MHz, CDCI3) δ 7.43 (s, IH), 3.87 (s, 3H), 2.56 (s, 3H)

Step 3: 4-Bromo-7V-(2,6-difluorophenyl)-3-methylthiophene-2-carboxamide: To a 0 °C solution of 2,6-difluoroaniline (1.10 g, 8.58 mmol, 1.0 eq) in DCM (20 mL) was added drop wise trimethyl aluminium (2 M in toluene, 4,3 mL, LO eq) followed by a solution of methyl-4bromo-3-methylthiophene-2-carboxylate (2.0 g, 8.58 mmol, LO eq). The reaction was allowed to corne to room température and then stirred for 2 h at the same température. The reaction was quenched with water (10 mL) followed by the addition of DCM (20 mL). The layers were separated, and the organic layer was washed with brine (15 mL), dried (Na₂SO4) and filtered. The filtrate was rotary evaporated and the residue was purified by flash colurnn chromatography (silica gel, 30% ethyl acetate in hexane) to afford 1.0 g (35%) of the desired product as a brown solid. ‘HNMR (400 MHz, CDC1₃) Ô 7.42 (s, 1H), 7.28-7.21 (m, 1H), 7.15 (s, 1H, D₂O exchangeable), 7,03-6.94 (m, 2H), 2.56 (s, 3H); ESI-MS (m/z) 332, 334 [(MH)⁺, Br^79,81].

Intermediate 58a&58b

5-Bromo-/V-(2,6-difluorophenyl)-l -methyl-1 H-pyrrole-2-carboxamide (58a) and

N-(2,6-Difluorophenyl)-1 -methyl-5-(trimethylstannyl)-1 H-pyrrole-2-carboxamide(58b)

Internwdlttt Ma

Step-1: N-(2,6-Difluorophenyl)-l-methyl-lH-pyrrole-2-carboxamide: A mixture of 1methylpyrrol-2-carboxylic acid (1.0 g, 7.99 mmol, 1.0 eq) and thionyl chloride (9.5 g, 80 mmol, 10 eq) was refluxed for 3 h. The reaction was cooled to room température and excess of thionyl chloride was removed under vacuum. The resulting residue was co-distilled with benzene to remove the traces of thionyl chloride. The residue was dissolved in DCM (10 mL), cooled to 0 °C and a solution of 2,6-difluoroaniline (1.0 g, 7.99 mmol, 1.0 eq) in DCM (2 mL) was added drop wise followed by the addition of pyridine (1.0 g, 12.79 mmol, 1.5 eq). The reaction was warmed to room température and stirred for 12 h. The réaction was diluted with DCM (50 mL), and water (30 mL) was added to the reaction mixture. The layers were separated and the organic layer was washed with IN HCl (20 mL), brine (20 mL), dried (Na₂SC>4) and filtered. The filtrate was concentrated under vacuum. The crude product was used for the next step. ESI-MS (m/z) 237 (MH)⁺.

Step-2: 5-Bromo-N-(2,6-difluorophenyl)-l-methyl-lH-pyrrole-2-carboxamide: A mixture ofN(2,6-difluorophenyl)-l-methyI-lH-pyrrole-2-carboxamide (3.40 g, 14.39 mmol, 1.0 eq) and NBS (2.70 g, 15.11 mmol, 1.05 eq) in DCM (30 mL) was stirred at room température for 12 h. Water (50 mL) was added to the reaction followed by DCM (100 mL) and the layers were separated. The organic layer was washed with water (50 mL), brine (50 mL), dried (NaîSCl·;) and filtered. The filtrate was rotary evaporated and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane System as eluent) to afford 3.30 g of the title product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 7.25-7.18 (m, 1H), 6.98 (t, J= 8.0 Hz, 2H), 6.82 (d, J= 4.0 Hz, 1H), 6.27 (d, J= 4.0 Hz, 1H), 3.97 (s, 3H); ESI-MS (m/z) 315, 317 [(MH)⁺, Br ⁷⁹'⁸¹]

Step-3: N-(2,6-Difluorophenyl)-l-methyl-5-(trimethylstannyl)-lH-pyrrole-2-carboxamide: To a solution of 5-bromo-N-(2,6-difluorophenyl)-l-methyl-lH-pyrrole-2-carboxamide (1.20 g, 3.81 mmol, 1.0 eq) and hexamethylditin (1.25 g, 3.81 mmol, 1.0 eq) in dioxane (15 mL) was added Pd(PPh3)4 (220 mg, 0.19 mmol, 0.05 eq). The resulting mixture was thoroughly deoxygenated by subjecting to a vacuum/nitrogen cycle three times and the reaction mixture was heated at 75 °C for 15 h under nitrogen atmosphère. The resulting mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was used for next step without further purification. ESI-MS (m/z) 400 (MH)⁺,

Examples

Example 1 /V-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-2,6difluorobenzamide

GtiiïipU 1

To a stirred solution of N-(5-Bromopyrazine-2-yl)-2,6-difluorobenzamide, Intermediate 32, (400 mg, 1.27 mmol, 1.0 eq) in dioxane (10 mL), 5,5-Dimethyl-3-(4,4,5,5-tctramethyl-l,3,2dioxaborolan-2-yl)phenyi)isoxazol-4(5//)-one, Intermediate la (419 mg, 1.27 mmol, 1.0 eq), aq sodium carbonate solution (2N, 4 mL) and Pd(PPli3)2C12 (44 mg, 0.063 mmol, 0.05 eq) were sequentially added. The resulting mixture was thoroughly deoxygenated by subjecting to a vacuum/nitrogen cycle three times and then heated at 100°C for 24 h under nitrogen atmosphère. The reaction mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 30% ethyl acetate in hexane) to afford 200 mg of the desired product as a white solid. 'HNMR (400 MHz, DMSO-ίή,) δ 11.82 (s, 1H, D₂O exchangeable), 9.53 (s, 1H), 8.69 (s, 1H), 8.11 (d, J = 1.0 Hz, 1 H), 7.99 (dd, J = 1.0, 8.0 Hz, 1 H), 7.65-7.59 (m, 1 H), 7.54 (d, J = 8.0 Hz, IH), 7.27 (t, J= 8.0 Hz, 2H), 2.44 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.

The below Examples 2 to 75 were prepared from the corresponding intermediates by following a procedure similar to that described in Example 1 :

Example No: 1UPAC name	Structure	'H NMR/ESI-MS(MH)⁺
Example 2: //-(5-(5- (5,5-Dimethyl-4-oxo- 4,5-dihydroisoxazol- 3-yl)-2methylphenyi)pyrazin -2-yl)-4-methyll,2,3-thiadiazole-5carboxamide	/'V A-nh L	'HNMR (400 MHz, DMSO-i/_rt) δ 11.82 (s, IH, D₂O exchangeable), 9.48 (s, 1 H), 8.73 (s, IH), 8.12 (s, IH), 8.00 (d, J = 8.0 Hz, 1H),7.55 (d,J=8.0Hz, 1 H), 2.86 (s, 3H), 2.45 (s, 3H), 1.44 (s, 6H); ESI-MS (m/z) 423 (MH)⁺.
Example 3://-(5’(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2’-methyl-[l,l’- biphenyl]-4-yl-2,6difluorobenzamide	F	‘HNMR (400 MHz, CDC1₃) δ 8.007.98 (m, 2H), 7.70 (d, J= 8.0 Hz, 3H), 7.46-7.42 (m, IH), 7.38-7.35 (m, 3H), 7.02 (t, J= 8.0 Hz, 2H), 2.33 (s, 3 H), 1.46 (s, 6H); ESI-MS (m/z) 435 (MH)⁺.
Example 4: //-(5-(5- (5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2- methylphenyl)pyridin -2-yl)-2,6difluorobenzamide	F	‘HNMR (400 MHz, DMSO-î/î) δ 11.2 (s, 1 H, D₂O exchangeable), 8.94 (s, 1 H), 8.28 (d, J = 8.0 Hz, IH), 8.05 (s, IH), 7.93 (d, J= 8.0 Hz, IH), 7.63 (d, J= 8.0 Hz, 2H), 7.49 (d, J= 8.0 Hz, IH), 7.30 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H), 1.42 (s, 6H); ESI-MS (m/z) 436 (MH)⁺.

Example 5:/V-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2- ethylphenyl)pyrazin- 2-yl)-2,6- difluorobenzamide	φν_/^Ν=\_ \ / 0 F	'HNMR (400 MHz, DMSO-î/₆) δ 11.82 (s, 1 H, D₂O exchangeable), 9.51 (s, 1H), 8.63 (s, 1H), 8.03-8.01 (m, 3H), 7.64-7.60 (m, 1H), 7.56 (d, J = 8.0 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 2H), 2.76 (q, J= 7.5 Hz, 2H), 1.41 (s, 6H), 1.09 (t,J=7.5//z, 3H); ESI-MS (m/z) 451 (MH)⁺.
Example 6: N-(5'(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2’-ethyl-[1,1'biphenyl]-4-yl)-2,6difluorobenzamide	/Ό F	'HNMR (400 MHz, DMSO-t/6) δ 10.94 (s, 1 H, D₂O exchangeable), 7.94 (dd, J= 8.0, 2.0 Hz, 1H), 7.817.78 (m, 3H), 7.63-7.59 (m, 1H), 7.51 (d, J=8.0Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.28 (t, J= 8.0 Hz, 2H), 2.62 (q, J - 7.5 Hz, 2H), 1.41 (s, 6H), 1.06 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 449 (MH)⁺.
Example 7: /7-(6-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2ethylphenyljpyridin3-yl)-2,6difluorobenzamide	F	'HNMR (400 MHz, DMSO-ί/β) δ 11.19 (s, 1 H, D₂O exchangeable), 8.93 (s, 1I I), 8.27 (dd, J= 8.5, 2.5 Hz, 1H), 7.98 (d,J= 1.5 Hz, 1H), 7.96 (s, 1H), 7.66-7.62 (m, 1H), 7.58 (d, J = 8.5 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 2H), 2.75 (q, J= 7.5 Hz, 2H), 1.42 (s, 6H), 1.07 (t, J= 7.5 Hz, 3H); ESI-MS (m/z) 450 (MH)⁺.
Example 8: N-(5-(5- (5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2isopropylphenyl)pyra	Κ^Φ	'HNMR (400 MHz, CDC1₃) δ 9.76 (s, 1 H), 8.54 (s, 1H, D₂O exchangeable), 8.34 (s, 1H), 8.16 (dd,J = 8.0,1.5 Hz, 1H), 8.07 (s, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.51 -

zin-2-yl)-2,6- d i fluorob enzam ide		7.46 (m, 1H), 7.05 (t, J= 8.5 Hz, 2H), 3.25-3.18 (m, 1H), 1.43 (s, 6H), 1.22 (d,./ = 7.0 Hz, 6H); ESIMS (m/z) 465 (MH)⁺.
Ex ample 9:7V-(5'(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2'-isopropyl[ 1,1 ’-biphenyl]-4-yl)2,6difluorobenzamide	ΛΓ	’HNMR (400 MHz, CDC1₃) δ 8.07 (dd, J =8.0, 1.5 Hz, 1H), 7.93 (s, 1H), 7.71 (d, J=8.0 Hz, 2H+1H D₂O exchangeable), 7.49 (d, J= 8.0 Hz, 1 H), 7.46-7.42 (m, 1H), 7.33 (d, J =8.0/*, 2H), 7.02 (t,J=8.0 Hz, 2H), 3.15-3.08 (m, 1H), 1.46 (s, 6H), 1.18 (d, J = 7.0 Hz, 6H); ESI-MS (m/z) 463 (MH)⁺.
Example 10: 7V-(2‘(tert-butyl)-5'-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3yl)-[ 1,1 '-biphenyl]-4yi)-2,6difluorobenzamide	₀	’HNMR (400 MHz, CDC1₃) δ 8.01 (dd, J = 8.5, 2.0 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 7.68 (brs, D₂O exchangeable, 1H), 7.63 (d, J= 8.0 Hz, 2H), 7.62 (d, J= 8.5 Hz, 1H), 7.45-7.41 (m, 1 H), 7.27 (d, J= 8.0 Hz, 2H), 7.02 (t, J= 8.0 Hz, 2H), 1.43 (s, 6H), 1.22 (s, 9H); ESI-MS (m/z) 477 (MH)⁺.
Example 11 : N-(2’chloro-5'-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3yl)-[ 1,1 -biphenyl]-4yi)-2,6difluorobenzamide	Cl -H Ao F	’HNMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H, D₂O Exchangeable), 8.03-7.97 (m, 2H), 7.83 (dd, J = 8.5, 1.5 Hz, 2H), 7.76 (d, J= 8.5 Hz, 1H), 7.64-7.59 (m, 1H), 7.527.47 (m, 2H), 7.28 (t, J= 8.0 Hz, 2H) 1.45 (s, 3H), 1.43 (s, 3H); ESIMS [(m/z) 455, 457 [(MH)⁺, Cl ³⁵‘ 37)

Example 12://-(5-(5- (5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2fluorophenyl)pyrazin- 2-yl)-2,6- d i fl uorobenzamîde	F	’HNMR (400 MHz, DMSO-î/î) δ 11.89 (s, 1 H, D2O exchangeable), 9.58 (s, 1H), 8.92 (s, IH), 8.65 (dd, J =7.5, 2.5 Hz, 1H), 8.15-8.11 (m, 1 H), 7.66-7.57 (m, 2H), 7.27 (t, J = 8.0 Hz, 2H), 1.45 (s, 6H); ESI-MS (m/z) 441 (MH)⁺.
Example 13://-(5'- (5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2'-fluoro-[l,l'biphenyl]-4-yl)-2,6difluorobenzamide		’HNMR (400 MHz, DMSO-ί/ό) Ô 10.98 (s, 1H, D₂O exchangeable), 8.12 (dd, J= 8.0, 2.0 Hz, 1H), 8.037.99 (m, 1 H), 7.83 (d, J = 8.5 Hz, 2H), 7.63-7.59 (m, 3H), 7.51 (dd, J = 11.0, 8.5, Hz, 1 H), 7.27 (t, J = 8.0 Hz, 2H), 1.43 (s, 6H); ESI-MS (m/z) 439 (MH)⁺.
Example 14: //-(5-(5(5,5-dimethyl-4-oxo4,5 - di hydroisoxazol3-yl)-2metho xyphenyl )pyraz in-2-yl)-2,6difluorobenzamide	0 F	’HNMR (400 MHz, CDCI3) δ 9.76 (s, 1H), 8.81 (s, 1H), 8.62 (d,J = 2.0 Hz, IH), 8.60 (s, 1H, D₂O exchangeable), 8.17 (dd, J= 8.0, 2.0¾ 1 H), 7.49-7.45 (m, IH), 7.10 (d, J = 8.0 Hz, 1 H), 7.04 (t, J = 8.0 Hz, 2H), 3.95 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 453 (MH)⁺.
Example 15: N-(5'(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2'-methoxy[1,1 -biphenyl]-4-yl)2,6difluorobenzamide		’HNMR (400 MHz, CDC1₃) δ 8.148.11 (m,3H), 7.77 (s, IH, D₂O exchangeable), 7.72 (d, J= 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.467.42 (m, 1 H), 7.07 (d, J= 8.0 Hz, IH), 7.03 (t, J= 8.0 Hz, 2H), 3.90 (s, 3H), 1.49 (s, 6H); ESI-MS (m/z) 451 (MH)⁺.

Example 16:7V-(5’(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2'-methoxy[1,1 -biphenyl]-4-yl)4-methyl-1,2,3 thiadiazole-5carboxamide	b	'HNMR (400 MHz, DMSO-î/î) δ 10.84 (s, 1H, D₂O exchangeable), 7.99 (dd, J = 8.5, 2.0 Hz, 1 H), 7.92 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 2H), 7.52 (d, J= 8.5 Hz, 2H), 7.29 (d, J =8.5 Hz, 1 H), 3.85 (s, 3H), 2.83 (s, 3H), 1.41 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.
Example 17: W-(5-(5- (5,5-dimethyl-4-oxo- 4,5-dihydroisoxazol- 3-yl)-2- methoxyphenyl)pyrid in-2-yl)-2,6difluorobenzamide	\ O /Sj'^N F	‘HNMR (400 MHz, CDC1₃) δ 8.68 (d, J = 2.5 Hz, 1 H), 8.51 (d, J = 2.5 Hz, 1H), 8.42 (dd, J= 8.5, 2.5 Hz, 1 H), 8.12 (dd, J = 8.5, 2.5 Hz, 1 H), 7.95 (s, 1H, D₂O exchangeable), 7.88 (d, J = 8.5 Hz, 1 H), 7.48-7.41 (m, 1H), 7.08 (d, J= 8.5 Hz, 1H), 7.02 (t, J =8.0 Hz, 2H), 3.92 (s, 3H), 1.46 (s, 6H); ESI-MS (m/z) 452 (MH)⁺.
Example 18:7/-(6-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methoxyphenyl)pyrid in-3-yl)-2,6difluorobenzamide	f	'HNMR (400 MHz, CDC1₃) Ô 8.67 (d, J = 2.5 Hz, 1H), 8.49 (d, J= 2.5 Hz, 1H), 8.39 (dd, J= 8.5, 2.5 Hz, 1 H), 8.10 (dd, J = 8.5, 2.5 Hz, 1H), 7.97 (s, 1H, D₂O exchangeable), 7.84 (d, J= 8.5 Hz, 1H), 7.44-7.40 (m, 1 H), 7.06 (d,J= 8.5 Hz, 1H), 7.70 (t,J= 8.0 Hz, 2H), 3.90 (s, 3H), 1.44 (s, 6H); ESI-MS (m/z) 452 (MH)⁺.
Example 19: W-(2’acetamido-5'-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-		'HNMR (400 MHz, DMSO-ίήί) δ 11.95 (s, 1 H, D₂O exchangeable), 9.34 (s, 1 H, D₂O exchangeable), 7.96-7.92 (m, 2H), 7.82-7.78 (m,

yl)-[l,l'-biphenyl]-4yi)-2,6difluorobenzamide		3H), 7.65-7.57 (m, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 1.96 (s, 3H), 1.42 (s, 6H); ESI-MS (m/z) 478 (MH)⁺.
Example 20: /7-(5-(3(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)phenyl)pyrazin- 2-yl)-2,6difluorobenzamide		’HNMR (400 MHz, CDC1₃) Ô 9.75 (s, 1H), 8.76 (s, 1H), 8.73 (t,J = 1.5 Hz, 1 H), 8.41 (s, IH, D₂O exchangeable), 8.20-8.14 (m, 2H), 7.62 (t, J = 8.0 Hz, 1 H), 7.51 -7.47 (m, 1H), 7.06 (t, J= 8.5 Hz, 2H), 1.55 (s, 6H); ESI-MS (m/z) 423 (MH)⁺
Example 21 :/7-(6-(3- (5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)phenyl)pyridin- 3-yl)-2,6difluorobenzamide		’HNMR (400 MHz, CDC1₃) δ 8.718.69 (m, 2H), 8.45 (dd, J = 8.5,2.5 Hz, 1 H), 8.13 (dd, J = 8.0, 1.5 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1 H), 7.76 (s, 1H, D₂O exchangeable), 7.58 (t, J = 8.0 Hz, 1 H), 7.48-7.44 (m, 1 H), 7.03 (t, J =8.5 Hz, 2H), 1.49 (s, 6H); ESI-MS (m/z) 422 (MH)⁺.
Example22:/7-(3(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl )-[ 1,1 ’-biphenyl]4-yl)-2,6difluorobenzamide		’HNMR (400 MHz, CDCI3) δ 8.33 (t, J = 1.5 Hz, 1H), 8.07 (td, J = 8.0, 1.5 Hz, 1H), 7.74-7.63 (m, 6H), 7.53 (t, J= 8.0 Hz, 1H), 7.487.39 (m, 1 H),7.01 (t, J =8.5 Hz, 2H), 1.48 (s, 6H); ESI-MS (m/z) 421 (MH)⁺.
Example 23: 2,6- difluoro-77-(5-(5-(4methoxy-5,5dimethyl-4,5dihydroisoxazol-3-	/O' F	’HNMR (400 MHz, CDCI3) δ 9.76 (s, 1 H), 8.61 (s, 1H, D₂O exchangeable), 8.36 (s, IH), 7.79 (s, IH), 7.73 (dd, J =8.0, 1.0 Hz, 1 H), 7.52-7.45 (m, 1 H), 7.37 (d, J =

yl)-2- methylphenyl)pyrazin -2-yl)benzamide		8.0 Hz, 1H), 7.05 (t, J= 8.0 Hz, 2H), 4.57 (s, 1H), 3.43 (s, 3H), 2.43 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H); ESI-MS (m/z) 453 (MH)⁺.
Example 24; 2,6- Difluoro-N-(5'-(4methoxy-5,5- dimethyI-4,5dihydroisoxazol-3yl)-2'-methyl-[l,l'biphenyl]-4yl)benzamide	^F\. Zo f	'HNMR (400 MHz, CDC1₃) 5 7.73 (s, 1 H, D2O exchangeable), 7.70 (d, J= 8.5 Hz, 2H), 7.65 (dd, J= 8.0, 1.5 Hz, 1H), 7.60 (d, J= 1.5¾ 1H), 7.46-7.42 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.32 (d, J= 8.0 Hz, 1 H), 7.02 (t, J = 8.0 Hz, 2H), 4.55 (s, 1 H), 3.43 (s, 3H), 2.31 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H); ESI-MS (m/z) 451 (MH)⁺.
Example 25: N-(4'(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2'-methyl-[l,rbiphenyl]-4-yl)-2,6difluorobenzamide		‘HNMR (400 MHz, CDCI3) δ 8.04 (s, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.79 (s, 1H, D₂O exchangeable), 7.74 (d, J= 8.5 Hz, 2H), 7.48-7.42 (m, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1 H), 7.04 (t, J = 8.5 Hz, 2H), 2.37 (s, 3H), 1.51 (s, 6H); ESI-MS (m/z) 435 (MH)⁺.
Example 26: N-(5-(4(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2methylphenyl)pyrazin -2-yl)-2,6difluorobenzamide		'HNMR (400 MHz, CDCI3) δ 9.78 (s, 1H), 8.56 (s, 1H, D₂O exchangeable), 8.38 (s, 1H), 8.08 (s, 1H), 8.06 (d, J =8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1 H), 7.51 -7.46 (m, 1H), 7.05 (t, J =8.5 Hz, 2H), 2.48 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 437 (MH)⁺

Example 27: A-(5-(4(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)pyridin -2-yl)-2,6difluorobenzamide		'HNMR (400 MHz, CDC1₃) δ 8.71 (d, J = 2.0 Hz, 1 H), 8.44 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 8,01 (d,J = 8.5 Hz, 1H), 7.51-7.42 (m,3H), 7.04 (t, J =8.5 Hz, 2H), 2.44 (s, 3H), 1.46 (s, 6H); ESI-MS (m/z) 436 (MH)⁺.
Example 28: /9-(5-(3(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2- methylphenyl)pyrazin -2-yl)-2,6difluorobenzamide		‘HNMR (400 MHz, DMSO-i/_fi) δ 11.82 (s, 1H, D₂O exchangeable), 9.48 (s, 1H), 8.62 (s, 1H), 7.64-7.56 (m, 3H), 7.49 (t, J = 7.5 Hz, 1H), 7.27 (t, J= 8.0 Hz, 2H), 2.26 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.
Example 29: /9-(3'(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2'-methyl-[l,l'biphenyl]-4-yl)-2,6difluorobenzamide		'HNMR (400 MHz, CDCI₃) δ 7.73 (s, 1H, D₂O exchangeable), 7.70 (d, J= 8.5 Hz, 2H), 7,48-7.41 (m, 2H), 7.35-7.33 (m, 4H), 7.02 (t, J= 8.5 Hz, 2H), 2.25 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 435 (MH)⁺.
Example 30:79-(5-(3(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)pyridin -2-yl)-2,6difluorobenzamide		'HNMR (400 MHz, DMSO-J₆) δ 11.18 (s, 1 H, D₂O exchangeable), 8.93 (d, J =2.5 Hz, 1H), 8.26 (dd, J = 9.5, 2.5 Hz, 1H), 7.67-7.42 (m, 5H), 7.30 (t, J= 8.0 Hz, 2H), 3.34 (s, 3H), 1.46 (s, 6H); ESI-MS (m/z) 436 (MH)⁺.
Example 31: A-(3'(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2'-methoxy[l,l’-biphenyl]-4-yl)-	^fii	'HNMR (400 MHz, CDC1₃) δ 7.79 (s, 1 H, D₂O exchangeable), 7.72 (d, J= 8.5 Hz, 2H), 7.62 (d, J= 8.5 Hz, 2H), 7.52 (dd, J = 7.5, 1.5 Hz, 1 H), 7.48 (dd, J = 7.5, 1.5 Hz, 1 H), 7.44-

2,6- difluorobenzamide		7.39 (m, 1H), 7.27 (t, J =1.5 Hz, 1 H), 7.01 (t, J = 8.5 Hz, 2H), 3.38 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 451 (MH)⁺.
Example 32: 79-(5-(5(4-Acetyl-5,5dimethyl-4,5dihydro-1,3,4oxadiazol-2-yl)-2methylphenyl) pyrazin-2-yl)-2,6difluorobenzamide	«Ach,	’HNMR (400 MHz, CDClj) δ 9.78 (s, 1 H), 8.53 (s, 1H, D₂O exchangeable), 8.41 (s, IH), 7.87 (s, 1H), 7.80 (d, J =8.0 Hz, 1H), 7.52-7.48 (m 1H), 7.38 (d,J= 8.0 Hz, 1H), 7.06 (t, J= 8.5 Hz, 2H), 2.46 (s, 3H), 2.30 (s, 3H), 1.86 (s, 6H); ESI-MS (m/z) 466 (MH)⁺.
Example 33: 2,6- Difluoro-7V-(2'methyl-5'-(4-methyl5-oxo-4,5-dihydro1,3,4-oxadiazol-2-yl)[ 1, l’-biphenyl]-4yl)benzamide	1 F	’HNMR (400 MHz, DMSO-Jô) δ 10.95 (s, 1H, D₂O exchangeable), 7.81 (d, J = 8.5 Hz, 2H), 7.70 (dd, J = 8.0, 1.5 Hz, 1H), 7.66-7.61 (m, 1H), 7.59 (d, J= 1.5 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 2H), 7.28 (t, J= 8.0 Hz, 2H), 3.41 (s, 3H), 2.33 (s, 3H); ESI-MS (m/z) 422 (MH)⁺.
Example 34: N-(5'(4-Ethyl-5-oxo-4,5dihydro-1,3,4oxadiazol-2-yl)-2‘methyl-[ 1, Γbiphenyl]-4-yl)-2,6difluorobenzamide		’HNMR (400 MHz, DMSO-J6) δ 10.95 (s, 1H, D₂O exchangeable), 7.80 (d, J = 8.5 Hz, 2H), 7.70 (dd, J = 8.0, 1.5 Hz, 1H), 7.65-7.59 (m, 1H), 7.58 (d, J= 1.5 Hz, IH), 7.50 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 2H), 7.28 (t, J= 8.0 Hz, 2H), 3.77 (q, J =7.0 Hz, 2H), 2.32 (s, 3H), 1.29 (t, J=7.0/7z, 3H); ESIMS (m/z) 436 (MH)⁺.

Example 35: 2,6- Difluoro-N-(2'methyl-5'-(5-oxo-4propyl-4,5-dihydro1,3,4-oxadiazol-2-yl)[l,l'-biphenyl]-4yl)benzamide		‘HNMR (400 MHz, DMSO-rfô) δ 10.95 (s, IH, D2O exchangeable), 7.76 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 8.0, 1.5 Hz, IH), 7.59-7.53 (m, IH), 7.53 (d,J = 1.5 Hz, IH), 7.46 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 2H), 7.22 (t, J= 8.0 Hz, 2H), 3.65 (t, J =l.QHz, 2H), 2.27 (s, 3H), 1.68 (q, J = 7.0 Hz, 2H), 0.86 (t, J= 7.0 Hz, 3H); ESI-MS (m/z) 450 (MH)⁺.
Example 36: N-(2'- Ethyl-5'-(4-methyl-5oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)[l,l'-biphenyl]-4-yl)- 2,6difluorobenzamide		‘HNMR (400 MHz, CDCI3) δ 7.74 (dd, J = 8.5, 2.0 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 2H+1H D₂O exchangeable), 7.67 (s, 1 H), 7.467.42 (m, IH), 7.41 (d,J=8.5Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2H), 7.03 (t, J =8.0 Hz, 2H), 3.49 (s, 3H), 2.65 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 436 (MH)⁺.
Example 37:2Chloro-7V-(2'-ethyl-5'(4-methyl-5-oxo-4,5dihydro-1,3,4oxadiazol-2-yl)-[ 1,1'biphenyl]-4-yl)-6fluorobenzamide	1 Cl	'HNMR (400 MHz, CDCI3) δ 7.77 (dd, J = 8.0, 1.5 Hz, I H), 7.73 (d, J = 8.5 Hz, 2H), 7.69 ( d, J = 1.5 Hz, IH), 7.62 (s, IH, D₂O exchangeable), 7.42 (d, J - 8.0 Hz, IH), 7.42-7.37 (m, IH), 7.35 (d,J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz, IH), 7.14(m, 1 H), 3.50 (s, 3H), 2.66 (q, J = 7.5 Hz, 2H), 1.15 (t, J = 7.5 Hz, 3H); ESI- MS [(m/z) 452, 454 [(MH)⁺, Cl ³⁵¹³⁷)

νίζ—

Example 38: N-(2’- Ethyl-5'-(4-methyl-5oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)[1,1 ’-biphenyl ]-4-yl )2-fluoro-6methylbenzamide		'HNMR (400 MHz, CDCI₃) Ô 7.76 (dd, J = 8.5,2.0 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 2H), 7.61 (s, 1H, D₂O exchangeable), 7.42 (d, J= 8.5 Hz, 1 H), 7.36-7.31 (m,3H), 7.10 (d,J= 7.5 Hz, 1 H), 7.02 (t, J =8.0 Hz, 2H), 3.51 (s, 3H), 2.68 (q,J=7.5 Hz, 2H), 2.52 (s,3H), 1.15 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 432 (MH)⁺.
Example 39: W-(2’Ethyl-5'-(4-methyl-5oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)[l,l’-biphenyl]-4-yl)4-methyl-1,2,3thiadiazole-5carboxamide		'HNMR (400 MHz, CdCl₃) δ 7.78 (dd, J = 8.5, 2.0 Hz, 1 H), 7.70-7.64 (m, 4H), 7.43 (d, J = 8.0 Hz, 1 H), 7.36 (d, J=7.5//z,2H), 3.50 (s, 3H), 3.03 (s,3H) 2.66 (q,J=7.5 Hz,2H), 1.14 (t, J = 7.5//z, 3H); ESI-MS (m/z) 422 (MH)⁺
Example 40: 2,6- Difluoro-/V-(2'methoxy-5'-(4methyl-5-oxo-4,5dihydro-1,3,4oxadiazol-2-yl)-[ 1,1 'biphenyl]-4yl)benzamide	N	'HNMR (400 MHz, CDC1₃) δ 7.817.77 (m, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.67 (brs, 1H, D₂O exchangeable), 7.56 (d, J= 8.5 Hz, 2H), 7.47-7.42 (m, 1 H), 7.05 (d, J = 8.5 Hz, 1H), 7.03 (t,J= 8.0Z/z, 2H), 3,89 (s,3H), 3.49 (s,3H); ESI-MS (m/z) 438 (MH)⁺
Example 41: 2- Chloro-6-fluoro-./V- (2'-methoxy-5'-(4methyl-5-oxo-4,5dîhydro-1,3,4oxadiazol-2-yl)-[ 1,1 '-	o«V t Ci	'HNMR (400 MHz, CDC1₃) δ 7.81- 7.76 (m, 2H), 7.71 (d, J= 8.5 Hz, 2H), 7.55 (m, 3H), 7.40-7.35 (m, 1H), 7.28 (d, J= 8.5 Λ/ζ, 1H), 7,11 (dt, J =8.5, 1.0 Hz, 1H), 7.05 (d,J = 8.5 Hz, 1 H), 3.89 (s, 3H), 3.49 (s,

biphenyl]-4yl)benzamide		3H); ESI-MS (m/z) 454, 456 [(MH)⁺, (Cl³⁵'³⁷)]
Example 42: 2- Fluoro-yV-(2'methoxy-5'-(4methyl-5-oxo-4,5dihydro-1,3,4oxadiazol-2-yl)-[ 1,1 biphenyl]-4-yl)-6methylbenzamide		’HNMR (400 MHz, CDC1₃) δ 7.817.77 (m, 2H), 7.72 (d, J= 8.5 Hz, 2H), 7.56-7.54 (m, 3H), 7.34-7.28 (m, 1H), 7.08-6.97 (m, 3H), 3,89 (s, 3H), 3.49 (s,3H), 2.49 (s, 3H); ESI-MS (m/z) 434 (MH)⁺.
Example 43:4-Ethyl- W-(2'-methoxy-5'-(4methyl-5-oxo-4,5dihydro-1,3,4- oxadiazol-2-yl)-[ 1, Γbiphenyl]-4yl)benzamide		’HNMR (400 MHz, CDCI3) δ 7.85 (s, 1H, D₂O exchangeable), 7.837.81 (m, 3H), 7.77 (dd, J= 8.5, 2.0 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7,04 (d, J = 8.0 Hz, 1 H), 3.88 (s, 3H), 3.49 (s, 3H), 2.73 (q, J = 7.5 Hz, 1 H), 1.28 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 430 (MH)⁺.
Example 44: jV-(2‘- (Difluoromethoxy)5'-(4-methyl-5-oxo4,5-dihydro-l,3,4oxadiazol-2-yl)-[ 1,1'bîphenyl]-4-yl)-2,6di fl uorobenzamide	F Ίί 1 F	’HNMR (400 MHz, CDCI3) δ 7.89 (d, J= 1.5 Hz, 1H), 7.81-7.73 (m, 4H), 7.52 (d, J = 8.5 Hz, 2H), 7.48-7.40 (m, 1 H), 7.33 (d, J= 8.5 Hz, 1 H), 7.02 (t, J= 8.5 Hz, 2H), 6.44 (t, J= 73 Hz, 1 H), 3.49 (s, 3H); ESI-MS (m/z) 474 (MH)⁺
Example 45: N-(2'~ (Dîfluoromethoxy)5'-(4-methyl-5-oxo4,5-dihydro-l,3,4oxadiazol-2-yl)-[ 1,1'- biphenyl]-4-yl)-4-	JPli y-f' \|N °%-^N ° S-N 1	’HNMR (400 MHz, CDCI3) δ 7.91 (d, J =2.0 Hz, 1H), 7.84 (dd, J = 8.5, 2.0 Hz, 1H), 7.77 (s, 1H, D₂O exchangeable), 7.71 (d, J= 8.5 Hz, 1 H), 7.57 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1 H), 6.47 (t, J =73

Λ-—

methyi-1,2,3 thiadiazole-5carboxamide		Hz, 1H), 3.52 (s, 3H), 3.02 (s, 3H); ESI-MS (m/z) 460 (MH)⁺
Example 46: N-(2'- Chloro-5'-(4-methyl- 5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)- [1 ,l’-biphenyl]-4-yl)- 2,6- difluorobenzamide	1 F	'HNMR (400 MHz, CDC1₃) δ 7.82 (d, J= 2.5 Hz, 1H), 7.76-7.71 (m, 4H), 7.58 (d, J= 8.0 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 2H), 7.45-7.42 (m, 1 H), 7.03 (d, J = 8.0 Hz, 2H), 3.50 (s, 3H); ESI-MS (m/z) 442,444 [(MH)⁺, (Cl ³⁵’³⁷)]
Example 47: N-(2'Chloro-5'-(4-methyl- 5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)[l,r-biphenyl]-4-yl)4-methyl-l,2,3thiadiazole-5carboxamide	ja p~a ^0=an^{n 0} s-^N 1	^lHNMR (400 MHz, CDC1₃) δ 7.81 (d, J= 2.0/7z, 1H), 7.41 (dd,J = 8.5, 2.0 Hz, 1H), 7.69 (d, J =8.5 Hz, 2H), 7.63 (s, 1H, D₂O exchangeable), 7.59 (d, J= 8.5 Hz, 1 H), 7.50 (d, J = 8.5 Hz, 2H), 3.50 (s, 3H), 3.00 (s, 3H); ESI-MS (m/z) 428, 430 [(MH)⁺(Cl ³⁵’ ³⁷)]
Example 48: 2,6- Difluoro-7V-(2'methyl-3'-(4-methyl5-oxo-4,5-dihydro1,3,4-oxadiazol-2-yl)[l,l'-biphenyl]-4yl)benzamide		'HNMR (400 MHz, DMSO-î/6) δ 10.94 (s, 1 H, D₂O exchangeable, 7.79 (d, J = 8.5 Hz, 2H), 7.72 (dd, J = 7.0, 2.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.46-7.40 (m, 2H), 7.36 (d, J= 8.5 Hz, 2H), 7.26 (t, J= 8.0 Hz, 2H), 3.43 (s,3H), 2.41 (s, 3H); ESI-MS (m/z) 422 (MH)⁺.
Example 49: 2- Chloro-6-fluoro-N(2’-methyl-3’-(4methyl-5-oxo-4,5dihydro-1,3,4oxadiazol-2-yl)-[ 1, Γ-		'HNMR (400 MHz, DMSO-c/6) δ 10.93 (s, 1H, D₂O exchangeable, 7.79 (d, J= 8.5 Hz, 2H), 7.72 (dd, J = 7.0, 2.0 Hz, 1H), 7.60-7.54 (m, 1 H), 7.48-7.37 (m, 4H), 7.36 (d, J= 8.5 Hz, 2H), 3.43 (s, 3H), 2.41 (s,

biphenyl]-4yl)benzamide		3H); ESI-MS (m/z) 438,440 [(MH)⁺, Cl ³⁵’³⁷]
Example 50: 4Methyl-7V-(2'-methyl3'-(4-methyl-5-oxo4,5-dihydro-l ,3,4oxadîazol-2-yI)-[ 1, Γbiphenyl]-4-yl)-1,2,3 thiadiazole-5carboxamide	\ H r·	’HNMR (400 MHz, DMSO-//6) δ 10.87 (s, 1H, D2O exchangeable, 7.78 (d, J= 8.5 Hz, 2H), 7.72 (dd, J = 7.0, 2.0 Hz, 1 H), 7.48-7.49 (m, 1 H), 7.43-7.42 (d,J= 7.0 Hz, 1H), 7.37 (d, J= 8.5 Hz, 2H), 3.43 (s, 3H), 2.83 (s, 3H), 2.41 (s, 3H); ESI-MS (m/z) 408 (MH)⁺
Example 51 : N-(2'ethyl-3'-(4-methyI-5oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)[l,l’-biphenyl]-4-yl)4-methyl-1,2,3thiadiazole-5carboxamide		’HNMR (400 MHz, CDCI3) Ô 7.78 (dd, J= 7.0, 2.5 Hz, 1H), 7.73 (s, 1 H, D2O exchangeable), 7.67 (d, J = 8.0 Hz, 2H), 7.37-7.32 (m, 4H), 3.54 (s, 3H), 3.02 (s, 3H), 2.92 (q, J = 7.5 Hz, 2H), 1.01 (t, J= 7.5 Hz, 3H); ES1- MS (m/z) 422 (MH)⁺
Example 52:7V-(2’ethyl-3 '-(4-methyl-5 oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)[l,r-biphenyl]-4-yl)2,6di fl uorobenzami de		’HNMR (400 MHz, CDClj) Ô 7.937.76 (m, 1H), 7.76-7.71 (m, 3H), 7.50-7.43 (m, 1H), 7.36-7.31 (m, 4H), 7.04 (t, J= 8.5 Hz, 2H), 3.54 (s, 3H), 2.94 (q, J= 7.5 Hz, 2H), 1.02 (t, J= 7.5 Hz, 3H); ESI- MS (m/z) 435 (MH)⁺
Example 53:7V-(5- (5,5-Dimethyl-4,5- dihydroisoxazol-3- yl)-2methylphenyl)pyrazin -2-yl )-2,6-	gh₃ y? F	’HNMR (400 MHz, CDCI3) δ 11.80 (brs, 1H, D2O exchangeable), 9.50 (s, 1H), 8.69 (s, 1H), 7.71 (s, 1H), 7.67-7.60 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.26 (t, J =8.0 Hz, 2H), 3.21 (s, 2H), 2.40 (s, 3H), 1.38

difluorobenzamide		(s, 6H); ESI-MS (m/z) 423 (MH)⁺.
Example 54: Methyl 3-(3-(5-(2,6di fl uorob en zam ido)p yrazin-2-yl)-4methylphenyl)-5methyl-4,5dihydroisoxazole-5carboxylate	MtOOC'l''*	‘HNMR (400 MHz, CDC1₃) δ 9.75 (s, 1 H), 8.62 (s, 1H, D₂O exchangeable), 8.35 (s, 1H), 7.68 (d, J = 1.5 Hz, 1 H), 7.65 (dd, J = 8.0, 1.5 Hz, 1H), 7.52-7.47 (m, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.02 (t, J = 8.0 Hz, 2H), 3.90 (d, J = 17.0 Hz, 1 H), 3.81 (s, 3H), 3.25 (d, J = 17.0 Hz, 1H), 2.43 (s, 3H), 1.72 (s, 3H); ESI-MS (m/z) 467 (MH)⁺.
Example 55: Methyl3-(4’-(2,6difluorobenzmido)-6methyl-[l,l’biphenyl]-3-yl)-5methyl-4,5dihydroisoxazole-5carboxylate	ÿ-oVp L ^N MeOGC-yd	‘HNMR (400 MHz, CDCI3) δ 7.70 (d, J = 8.5 Hz, 2H), 7.58 (dd, J = 8.0, 1.5 Hz, 1 H), 7.47 (d, J= 1.5 Hz, 1H), 7.49-7.40 (m, 1H), 7.33- 7.29 (m, 3H), 7.03 (t, 8.0 Hz, 2H), 3.88 (dJ= 17.0 Hz, lH),3.80 (s, 3H), 3.22 (d, J= 17.0 Hz, 1H), 2.30 (s, 3H), 1.72 (s, 3H); ESI-MS (m/z) 465 (MH)⁺
Example 56: 2,6- Difluoro-W-(2'methyl-5'-(l -oxa-2azaspiro[4.4]non-2en-3-yl)-[l,rbiphenyl]-4yl)benzamide		‘HNMR (400 MHz, DMSO-î^) δ 11.17 (s, 1 H, D₂O exchangeable), 8.92 (d, 2.0 Hz, 1 H), 8.26 (dd, J = 8.5, 2.5 Hz, 1H), 7.66-7.59 (m, 4H), 7.38 (d, J = 8.0 Hz, 1 H), 7.30 (t, J= 8.5 Hz, 2H),2.37(s, 3H), 1.92-1.89 (m, 2H), 1.78-1.72 (m, 6H); ESI-MS (m/z) 448 (MH)⁺.
Example 57: 2,6- Difluoro-H-(5-(2methyl-5-( 1 -oxa-2azaspiro[4.4]non-2-	C<-	‘HNMR (400 MHz, DMSO-i/_ft) δ 11.81 (s, 1H, D₂O exchangeable), 9.51 (s, 1 H), 8.70 (s, 1H), 7.72 (s, 1 H), 7.67 (dd, J = 8.0, 1.5 Hz, 1 H),

en-3- yl)phenyl)pyrazin-2- yl)benzamide		7.65-7.60 (m, 1H), 7.43 (d, J= 8.0 Hz, 1 H), 7.27 (t, J = 8.5 Hz, 2H), 2.41 (s, 3H), 1.95-1.91 (m, 2H), 1.80-1.67 (m, 6H); ESI-MS (m/z) 449 (MH)⁺.
Example 58: 2,6- Difluoro-7V-(2'methyl-5'-(4-oxo-loxa-2azaspiro[4.5]dec-2en-3-yi)-[ 1,1 'biphenyl]-4yl)benzamide		'HNMR (400 MHz, CDC1₃) δ 7.997.97 (m, 2H), 7.70 (d, J = 8.5 Hz, 2H+1H D₂O exchangeable), 7.417.37 (m, 1H), 7.35 (d, J = 7.5 Hz, 3H), 7.01 (t, J= 8.0 Hz, 2H), 2.32 (s, 3H), 1.85-0.82 (m, 10H); ESIMS (m/z) 475 (MH)⁺.
Example 59:7V-(5-(5(4,4-Dimethyl-4,5dihydrooxazol-2-yl)2methylphenyi)pyrazin e-2-yl)-2,6difluorobenzamide		'HNMR (400 MHz, CDC1₃) δ 9.75 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H, D₂O exchangeable), 7.98 (s, 1H), 7.90 (d, J = 8.0 Hz, 1 H), 7.51 -7.47 (m, 1H), 7.36 (d, J =8.0 Hz, 1H), 7.05 (t, J =8.0 Hz, 2H), 4.11 (s, 2H), 2.44 (s, 3H), 1.39 (s, 6H); ESI-MS (m/z) 423 (MH)⁺.
Example 60:2V-(5-(5(4,4-dîmethyl-4,5dihydrooxazol-2-yl)2methylphenyl)pyridin -2-yl)-2,6di fl uorobenzamide	T Φ	'HNMR (400 MHz, CDClj) δ 8.70 (d, J= 1.5 Hz, 1H), 8.39 (dd, J = 2.0,8.5 Hz, 1 H), 8.23 (s, 1H, D₂0 exchangeable), 7.94 (s, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.46-7.40 (m, 2H), 7.31 (d, J = 8.0 Hz, 1 H), 7.02 (t, J = 8.0 Hz, 2H), 4.09 (s, 2H), 2.41 (s, 3H), 1.35 (s, 6H); ESI-MS (m/z) 422 (MH)⁺.

Example 61: 7V-(5’- (4,4-dimethyl-4,5dihydrooxazol-2-yl)- 2’-methyl-[l,rbiphenyl]-4-yl)-2,6difluorobenzamide	_ ch, ^m S—.	’HNMR (400 MHz, CDCI3) Ô 7.827.80 (m, 2H), 7.77 (brs, 1 H, D₂O exchangeable), 7.68 (d, J - 8.0 Hz, 2H), 7.48-7.40 (m, IH), 7.35-7.29 (m, 3H), 7.02 (t, J = 8.0 Hz, 2H), 4.09 (s,2H), 2.31 (s,3H), 1.37 (s, 6H); ESI-MS (m/z) 421 (MH)⁺.
Example 62: 2,6- Difluoro-7V-(2'methyl-5'-(4-methyl5-oxo-4,5-dihydro1,2,4-oxadiazol-3-yl)[l,l'-biphenyl]-4yl)benzamide		'HNMR (400 MHz, DMSO-dû) δ 10.95 (s, IH, D₂O exchangeable), 7.81 (d, J= 8.0 Hz, 2H), 7.66-7.60 (m, IH), 7.55-7.41 (m, 3H), 7.43 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 3.24 (s, 3H), 2.35 (s, 3H); ESI-MS (m/z) 422 (MH)⁺
Example 63: 4Methyl-/V-(2'-methyl 5'-(4-methyl-5-oxo4,5-dihydro-l,2,4oxadiazol-3-yl)-[ 1,1'biphenyl]-4-yl)-1,2,3thiadiazoie-5carboxamide	Ο·<_ο.Η 0	’HNMR (400 MHz, DMSO-d₆) δ 10.88 (s,lH, D₂O exchangeable), 7.8 (d, J= 8.5 Hz, 2H), 7.64 (dd, J = 8.5, 1.5 Hz, IH), 7.55 (d, 7=8.0 Hz, 2H), 7.44 (d, 7= 8.5 Hz, 2H), 3.24 (s, 3H), 2.83 (s, 3H), 2.35 (s, 3H); ESI-MS (m/z) 406 (M-H)
Example 64: Ethyl 3(4'-(2,6difluorobenzamido)6-methyl-[ 1,1'biphenyl]-3-yl)-4,4dimethyl-4,5dîhydroisoxazole-5carboxylate		’HNMR (400MHz, CDCI3) δ 7.71 (d, 7= 8.5 Hz, 2H), 7.52 (dd, 7 = 8.0, 1.5 Hz, IH), 7.48 (d,7=1.5 Hz, IH), 7.47-7.41 (m, 1 H), 7.31 (d, 7 = 8.5 Hz, 2H), 7.28 (d, 7= 8.0 Hz, 1 H), 7.03 (t, 7= 8.0 Hz, 2H), 4.22 (q, 7= 7.5 Hz, 2H), 2.29 (s, 3H), 1.50 (s, 3H),1.49 (s, 3H), 1.21 (t, 7= 7.5 Hz, 3H); ESI-MS (m/z) 493 (MH)⁺

Example 65:77-(5-(5- (5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)pyrazin e-2-yl)-2fluorobenzamide	,ch> fYA p 'Z-NH V	’HNMR (400 MHz, CDC1₃) δ 9.79 (s, 1H), 9.13 (d, J= 15 Hz, 1H, D₂0 exchangeable), 8.47 (s, 1 H), 8.238.19 (m, 2H), 8.07 (d, 7=8.0 Hz, 1H), 7.62-7.56 (m, 1H), 7.42 (d, 7 = 8.0 Hz, 1H), 7.36 (t, J= 8.0 Hz, 1H), 7.25-7.21 (m, 1H), 2.46 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 419(MH)⁺.
Example 66:77-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methyl pheny l)pyrazi n e-2-yl)-2,4difluorobenzamide		’HNMR (400 MHz, DMSO-76) δ 11.36 (s, 1H, D₂O exchangeable), 9.52 (s, 1H), 8.68 (s, 1H), 8.10 (s, 1 H), 7.98 (d, J = 8,0 Hz, 1 H), 7.83 (q, 7=8.0 Hz, 1H), 7.54 (d,7=8.0 Hz, 1H), 7.48-7.42 (m, 1H), 7.26 (t, 7 = 8.0 Hz, 1H), 2.44 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.
Example 67:77-(5-(5(5,5-Dimethyl-4-oxo4,5-dîhydroisoxazol- 3-yl)-2methylphenyl)pyrazin e-2-yl)-2,5difluorobenzamide		’HNMR (400 MHz, DMSO-76) δ 11.46 (s, IH, D₂O exchangeable), 9.51 (s, 1 H), 8.69 (s, 1 H), 8.11 (d, 7 = 1.5 Hz, 1H), 7.99 (dd, 7= 8.0, 1.5 Hz, 1H), 7.64-7.59 (m, 1H), 7.54 (d, 7 = 8.0 Hz, 1H), 7.50-7.44 (m, 1H), 7.26 (t, 7= 8.0 Hz, 2H), 2.44 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.
Example 68:77-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2methylphenyl)pyrazin e-2-yl)-2,3-	fC^N=\ F	’HNMR (400 MHz, DMSO-76) δ 11.52 (s, 1 H, D₂O exchangeable), 9.52 (s, 1H), 8.69 (s, 1H), 8.11 (s, 1 H), 7.99 (dd, 7 = 8.0, 1.6 Hz, 1 H), 7.67 (q, 7 = 9.0 Hz, 1 H), 7.57-7.53 (m, 2H), 7.40-7.34 (m, 1 H), 2.44

difluorobenzamide		(s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.
Example 69: 7/-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)pyrazin e-2-yl)-4fluorobenzamide		‘HNMR (400 MHz, DMSO-i/6) δ 11.33 (s, 1H, D2O exchangeable), 9.52 (s, 1H), 8.70 (s, 1H), 8.16 (dd, J= 8.4, 11.0 Hz, 2H), 8.12 (s, 1H), 7.98 (d, J= 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1 H), 7.40 (t, J = 10.0 Hz, 2H), 2.45 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 419 (MH)⁺.
Example 70:2V-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2methylphenyl )p yrazi n e-2-yl)-2,4,5trifluorobenzamide		‘HNMR (400 MHz, DMSO-i/6) δ 11.47 (s, 1 H, D2O exchangeable), 9.50 (s, 1H), 8.70 (s, 1H), 8.11 (s, 1 H), 7.98 (dd, J = 8.0, 1.5 Hz, 1 H), 7.96-7.89 (m, 1H), 7.81-7.74 (m, 1H), 7.54 (d, J= 8.0 Hz, 1H), 2.44 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 455 (MH)⁺.
Example 71: 7V-(5-(5- (5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2methylphen yl)pyrazi n e-2-yl)-2,3- di methylbenzamide		‘HNMR (400 MHz, DMSO-rfô) δ 11.26 (s, 1H, D2O exchangeable), 9.55 (s, 1H), 8.65 (s, 1H), 8.11 (s, 1H), 7.98 (dd,J=8.0,1.5 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.34-7.30 (m,2H), 7.22-7.19 (m, 1H), 2.44 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 429 (MH)⁺.
Example 72:7V-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2methylphenyl)pyrazin	-φο'	'HNMR (400 MHz, DMSO-c/ά) δ 11.56 (s, 1 H, D2O exchangeable), 9.55 (s, 1H), 8.73 (s, 1H), 8.25 (d, J = 8.0 Hz, 2H), 8.13 (s, 1 H), 7.99 (dd, J = 8.0, 2.0 Hz, 1 H), 7.94 (d, J

e-2-yl)-4trifluoromethylbenza mi de		= 8.0 Hz, 2H), 7.54 (d, J= 8.0 Hz, 1 H), 2.45 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 469 (MH)⁺.
Example 73: /9-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazoi3-yl)-2methy 1 pheny 1 )p yr azi n e-2-yl)-4-fluoro-3methylbenzamide	CK, (Mv ⁰ °^c	’HNMR (400 MHz, CDC1₃) δ 9.76 (s, 1H), 8.50 (s, 1H, D₂O exchangeable), 8.44 (s, 1H), 8.19 (d,J= 1.5 Hz, 1H), 8.08 (dd, J= 8.0, 1.5 Hz, I H), 7.84 ( d, J = 7.0 Hz, 1H), 7.80-7.76 (m, 1H), 7.42 (d, J=8.0Hz, 1H), 7.14 (t, 7=8.5 Hz, 1H), 2.46 (s, 3H), 2.37 (s, 3H), 1.47 (s, 6H); ESI- MS (m/z) 433 (MH)⁺
Example 74:/9-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazoI- 3-yl)-2methyl phenyl)pyrazi n e-2-yl)-2methylbenzamide		’HNMR (400 MHz, DMSO-d₆) δ 11.26 ( s, 1 H, D₂O exchangeable), 9.54 (s, 1 H), 8.66 (s, 1H), 8.10 (d, J =2.0 Hz, 1H), 7.98(dd, J = 8.0, 1.5 Hz, 1H), 7.56- 7.53 (m, 2H), 7.45-7.41 (m, 1H), 7.34- 7.29 (m, 2H), 2.45 (s, 3H), 2.44 (s, 3H), 1.43 (s, 6H); ESI- MS (m/z) 415 (MH⁺)
Example 75:79-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2methylphenyl)pyrazin e-2-yl)-3-fluoro-5tri fl uoromethy ib enza mide	° ^F -p	’HNMR (400 MHz, CdCl₃) δ 9.78 (s, 1H), 8.73 (s, 1H, D₂O exchangeable), 8.50 (s, 1H), 8.23 ( d,J = \.5Hz, 1H), 8.12 (dd,7 = 8.0, 1.5 Hz, 1H), 8.05 (s, 1 H), 7.92 (d, 7= 8.5 Hz, 1 H), 7.61 (d, 7=7.5 Hz, 1 H), 7.45 ( d, J = 8.0 Hz, 1 H), 2.49 (s, 3H), 1.5 (s, 6H); ESI- MS (m/z) 487 (MH)⁺

Ex ample 76

Methyl-3-(4’-(2,6-difluorobenzmido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-5-(2-methoxy-2-oxoethyl)4,5-dihydroisoxazole-5-carboxylate

Step-1: 2,6-Difluoro-N-(5'-formyl-2'-methyl-[l,r-biphenyl]-4-yl)benzamide: To a stirred solution of 3-bromo-4-inethylbenzaldehyde (1.40 g, 7.0 mmol, 1.0 eq) in dioxane (20 mL), the borate intermediate 46b (2.52 g, 1.27 mmol, 1.0 eq), aq sodium carbonate solution (2N, 10 mL) and Pd(PPh₃)₂Cl₂ (246 mg, 0.35 mmol, 0.05 eq) were sequentially added. The resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and then heated at 100°C for 24 h under nitrogen atmosphère. The reaction mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane System as eluent) to afford 1.70 g of the desired product as a white solid. ’HNMR (400 MHz, DMSO-i7_tf) Ô 9.98 (s, 1H), 7.86 (s, 1H, D₂O exchangeable), 7.77-7.71 (m, 4H), 7.46-7.39 (m, 2H), 7.34 (d, J= 8.5 Hz, 1H), 7.00 (t, J= 8.0 Hz, 2H), 2.36 (s, 3H); ESI-MS (m/z) 352 (MH)⁺.

Step-2: 2,6-Difluoro-N-(5'-((hydroxyîmino)methyl)-2'-methyl-[ l, 1 -biphenyl]-4-yl) benzamide: To a 0 °C cooled solution of 2,6-difluoro-N-(5'-formyl-2'-methyl-[l,r-biphenyl]-4yljbenzamîde (683 mg, 1 mmol, 1.0 eq) in methanol (30 mL) and hydroxylamine hydrochloride (168 mg, 2.4 mmol, 2.5 eq) in water (1 mL) was added drop wise a solution of sodium carbonate (123 mg, 1.14 mmol, 1.1 eq) in water (1.0 mL). The resulting mixture was stirred at room température for 1 h. The solvent was evaporated under vacuum and the residue was diluted with water (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic layers were drîed (Na₂SO₄) and filtered. The filtrate was rotary evaporated to afford 650 mg of the title compound as a white solid. ’HNMR (400 MHz, DMSO-^) δ 8.13 (s, 1H), 7.71-7.68 (m, 3H), 7.48-7.43 (m, 3H), 7.35-7.28 (m, 3H), 7.03 (t, J = 8.0 Hz, 2H), 2.29 (s, 3H); ESI-MS (m/z) 367 (MH)⁺.

Step-3: MethyI-3-(4’-(2,6-difluorobenzmido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-5-(2-methoxy-2oxoethyl)-4,5-dihydroisoxazole-5-carboxylate: To a solution of 2,6-difluoro-V-(5^l((hydroxyimino)methyl)-2'-methyl-[l,l'-biphenyl]-4-yl)benzamide (400 mg, 1.0 mmol, 1.0 eq) in THF (15 mL) was added NCS (173 mg, 1.3 mmol, 1.3 eq) followed by pyridine (60 pL, 0.6 mmol, 0.6 eq). The resulting mixture was heated to 70 °C for lh. The reaction was then cooled down to room température and dimethyl 2-methylenesuccinate (0.14 mL, 1.0 mmol, 1.0 eq) was added to the above mixture followed by triethyl amine (0.27 mL, 1.7 mmol, 1.7 eq). The resulting mixture was then further heated to 70 °C for 2h. The reaction was cooled back down to room température and water (30 mL) was then added followed by ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate and hexane System as eluent) to afford 510 mg of the desired product as a white solid. ^lHNMR (400 MHz, CDCI3) δ 7.76 (s, II I, D₂O exchangeable),

7.70 (d, J= 8.5 Hz, 2H), 7.58 (d, J = 8.0 Hz, IH), 7.49 (s, IH), 7.45-7.41 (m, IH), 7.33-7.30 (m, 3H), 7.02 (t, J = 8.0 Hz, 2H), 4.02 (d, J = 17.0 Hz, 1 H), 3.81 (s, 3H), 3.70 (s, 3H), 3.49 (d, J = 17.0 Hz, IH), 3.26 (d, J= 17.5 Hz, IH), 2.98 (d, 7 = 17.5 Hz, IH), 2.30 (s, 3H); ESI-MS (m/z) 523 (MH)⁺.

Example 77

Methyl 3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-(2-methoxy-2oxoethyl)-4,5-dihydroisoxazole-5-carboxylate

COOMe

The title compound was prepared by following the procedure similar to that described in Example 76. ‘HNMR (400 MHz, DMSO-J(5) δ 11.82 (s, IH, D₂O exchangeable), 9.51 (s, IH),

8.71 (s, IH), 7.75 (d, J= 1.5 Hz, IH), 7.71 (dd, J= 8.0, 1.5 Hz, IH), 7.65-7.60 (m, IH), 7.46 (d, J =8.0 Hz, IH), 7.27 (t, 7= 8.0 Hz, 2H), 3.96 (d, 7 = 17.0 Hz, 1 H), 3.71 (d,7 = 17.0 Hz, IH),

3.71 (s, 3H), 3,61 (s, 3H), 3.20 (d. 7= 17.0 Hz, IH), 3.13 (d, 7= 17.0 Hz, 1H),2.42 (s, 3H); ESIMS (m/z) 525 (MH)⁺.

Example 77A

2,6-Difluoro-N-(5-(2-methyl-5-(4-oxo-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3yl)phenyl)pyrazin-2-yl)benzamide

The title compound was prepared by foilowing the procedure similar to that described in Example 76 by using cyclohex-2-en-l-one in place of dimethyl 2-methylenesuccinate in step-3. 'HNMR (400 MHz, CDC1₃) δ 9.76 (s, 1H), 8.56 (s, 1H, D₂O exchangeable), 8.40 (s, IH), 7.83 (d, J = 2.0 Hz, 1H), 7.43 (dd, J= 8.0, 2.0 Hz, 1H), 7.52-7.49 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 7.5 Hz, 2H), 5.14-5.13 (m, 1H), 4.29 (d, J = 9.5 Hz, 1H), 2.50-2.39 (m, 2H), 2.47 (s, 3H), 2.30-2.26 (m, 1H), 2.17-2.12 (m, 1H), 2.00-1.93 (m, 2H); ESI- MS (m/z) 463 (MH)⁺.

Example 78

2-Chloro-/V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)benzamide

Intermediate 1b

To a 0°C cooled and stirred, solution of 2-chlorobenzoyl chloride (43 pL, 0.34 mmol, 1.0 eq) in DCM (2 mL) was added drop wise a solution of Intermediate lb, (100 mg, 0.34 mmol, 1.0 eq) in DCM (5 mL) followed by pyridine (47 pL, 0.44 mmol, 1.3 eq). The resulting mixture was stirred at room température for 15 h. The reaction was diluted with DCM (10 mL), and washed with 10% hydrochloric acid (5 mL), dried (Na₂SC>4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane as eluent) to afford 50 mg of the title product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 9.78 (s, 1H), 8.80 (s, 1H, D₂O exchangeable), 8.39 (s, 1H), 8.19 (d, J= 2.0 Hz, 1H), 8.09 (dd, J = 8.0, 2.0 Hz, 1H), 7.84 (dd, J= 7.0, 1.5 Hz, 1H), 7.52-7.40 (m, 4H), 2.47 (s, 3H), 1.48 (s, 6H); ESI- MS (m/z) 435, 437 [(MH)⁺, Cl ³⁵'³⁷].

The below Examples 79 to 83 were prepared by foilowing a procedure similar to that described in Example 78: v-—

Example No: IUPAC name	Structure	*H NMR/ESI-MS(MH)⁺
Example 79:7V-(5(5-(5,5-dimethyl-4oxo-4,5-dihydro iso xazol-3-yl)-2-methyl phenyl)pyrazin-2-yl) -2-fluoro-6-(tri fluo rom ethyl )benzamide	~7\r F	’HNMR (400 MHz, CDC1₃) δ 9.74 (s, IH), 8.40 (s, IH, D₂0 exchangeable), 8.37 (s, IH), 8.17 (d, J = 1.5 Hz, 1 H), 8.09 (dd, J = 8.0, 2.0 Hz, IH), 7.64-7.59 (m, 2H), 7.46- 7.42 (m, 2H), 2.47 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 487 (MH)⁺
Example 80: 2Chloro-V-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3yl)-2-methyl phenyl) pyrazin-2-yl)-6fluorobenzamide		‘HNMR (400 MHz, CDCI3) δ 9.79 (s, IH), 8.56 (s, IH, D₂0 exchangeable), 8.32 (s, IH), 8.16 (d, J = 1.5 Hz, 1 H), 8.10 (dd, J = 8.0, 2.0 Hz, I H), 7.43 (d, J = 8.0 Hz, 1 H), 7.41-7.38 (m, IH), 7.31 (d, J=8.0 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 1 H), 2.46 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 453, 455 [(MH)⁺,(C1³⁵³⁷)]
Example 81 : /V-(5(5-(5,5-dimethyl-4oxo-4,5dihydroisoxazol-3yl)-2methyl phen yl)p yrazi n-2-yl)-2methoxybenzamide		’HNMR (400 MHz, CDCI3) δ 10.48 (s, IH, D₂O exchangeable), 9.83 (s, IH), 8.46 (s, IH), 8.32 (dd,J= 1.5, 7.5 Hz, 1 H), 8.20 (d, J = 2.0 Hz, 1 H), 8.08 (dd, J= 8.0, 2.0 Hz, IH), 7.57 (ddd, J = 1.5, 7.5, 9.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.17 (dt, J = 8.0, 1.0 Hz, 1 H), 7.09 (d, J= 8.5 Hz, IH), 4.13 (s, 3H), 2.47 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 431 (MH)⁺
Example 82: JV-(5(5-(5,5-dimethyl-4oxo-4,5dihydroisoxazol-3-		’HNMR (400 MHz, DMSO-î/6) Ô 10.81 (s, 1 H, D₂O exchangeable), 9.44 (s, 1 H), 8.59 (s, 1 H), 8.06 (d, J = 2.0 Hz, l H), 7.96 (dd, J= 8.0, 2.0

Example No: IUPAC name	Structure	'h NMR/ESI-MS(MH)⁺
yl)-2methylphenyl)pyrazi n-2yl)cyclohexanecarbo xamide		Hz, IH), 7.51 (d, .7=8.0 Hz, 1H), 2.59-2.55 (m, 1 H), 2.41 (s,3H), 1.85-1.64 (m, 5H), 1.46-1.37 (m, 2H), 1.42 (s, 6H), 1.39-1.18 (m, 3H); ESI-MS (m/z) 407 (MH)⁺
Example 83: A-(5(5-(5,5-dimethyl-4oxo-4,5dihydroisoxazol-3yl)-2methyl phenyl )pyrazi n-2yljcyclopentanecarb oxamide		'HNMR (400 MHz, CDC1₃) δ 9.62 (s, 1 H), 8.38 (s, 1 H), 8.16 (d, J = 2.0 Hz, 1H), 8.07 (dd, J= 8.0, 2.0 Hz, 1H), 7.91 (brs, 1H, D₂O exchangeable), 7.40 (d, J= 8.0 Hz, 1H), 2.83-2.79 (m, 1H), 2.43 (s, 3H), 2.04-1.93 (m, 4H), 1.84-1.79 (m, 2H), 1.68-1.64 (m, 2H), 1.47 (s, 6H); ESI-MS (m/z) 393 (MH)⁺

Example 84

A-(5-(2-(/e/7-butyl)-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)-2,6difluorobenzamide

InUrmedlite 4ϋ

Exemple M

To a 0°C cooled and stirred, solution of 2,6-difluorobenzoyl chloride (0.083 mL, 0.66 mmol, 1.5 eq) in DCM (200 mL) was added drop wise a solution of 3-(3-(5-aminopyrazin-2-yl)-4-(?er/butyl)phenyl)-5,5-dimethylisoxazol-4(5H)-one, Intermediate 4b, (150 mg, 0.44 mmol, 1.0 eq) in

DCM (50 mL) followed by pyridine (0.053 mL, 0.66 mmol, 1.5 eq). The resulting mixture was stirred at room température for 2 h. The reaction was diluted with DCM (100 mL), and washed with 10% hydrochloric acid (100 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel,

10% ethyl acetate in hexane) to afford 40 mg of the title product as a white solid. ’HNMR (400 MHz, CDC1₃) 5 9.72 (s, IH), 8.55 (s, IH, D₂O exchangeable), 8.28 (s, IH), 8.14 (dd, J= 9.0, 2.5 Hz, IH), 7.86 (s, IH), 7.70 (d, J =8.5 Hz, IH), 7.52-7.45 (m, IH), 7.07 (t, J= 8.5 Hz, 2H), 1.43 (s, 6H), 1.23 (s, 9H); ESI-MS (m/z) 479 (MH)⁺.

Example 85 /V-(5-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)-2,6difluorobenzamide

The title compound was prepared by foliowing a procedure similar to that described in Example

84 by using intermediate 12b and 2,6-difluorobenzoyl chloride. ’HNMR (400 MHz, CDCI3) δ

9.81 (s, IH), 8.89 (s, IH), 8.55 (s, IH, D₂O exchangeable), 7.98 (dd, J = 7.5, 1.5 Hz, IH), 7.72 (dd, J = 7.5, 1.5 Hz, IH), 7.54-7.47 (m, IH), 7.39 (t, J= 7.5 Hz, IH), 7.07 (t, J = 8.0 Hz, 2H), 3.57 (s, 3H), 1.54 (s, 6H); ESI-MS (m/z) 453 (MH)⁺.

Example 86

7V-(5-(2-chloro-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazïn-2-yl)-2,6difluorobenzamide

The title compound was prepared by foliowing a procedure similar to that described in Example by using intermediate 5 and 2,6-difluorobenzoyl chloride.¹ HNMR (400 MHz, CDCI3) δ 9.78 20 (s, 1 H), 8.68 (s, 1 H), 8.58 (s, 1 H, D₂O exchangeable), 8.29 (d, J = 1.5 Hz, 1 H), 8.15 (dd, J = 8.0,

1.5 Hz, IH), 7.76 (d, J = 8.0 Hz, IH), 7.51-7.43 (m, IH), 7.04 (t, J = 8.5 Hz, 2H) 1.49 (s, 6H); ESI- MS (m/z) 457,459 (MH)⁺, Cl ³⁵’³⁷]

Example 87-96

The below Examples 87 to 96 were prepared by foliowing a procedure similar to that described 25 in Example 84 by taking the corresponding intermediate and suitably substituted benzoyl chloride as given in the Scheme below. M-'92

I

Intermediate 15b-20b, 22b, 24b

Example : IC PAC name	Structure	‘HNMR/ESI-MS (MH)⁺
Example 87: 2,6- Difluoro-H-(5-(2methyl-5-(4methyl-5-oxo-4,5dihydro-1,3,4oxadiazol-2yl )phenyl)pyrazi n- 2-yl)benzamide		'HNMR (400 MHz, DMSO-î/6) 6 11.84 (s, 1H, D₂O exchangeable), 9.53 (s, 1H), 8.73 (s, 1H), 7.89 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.657.59 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.27 (t, J= 8.5 Hz, 2H), 3.42 (s, 3H), 2.46 (s, 3H); ESI-MS (m/z) 424 (MH)⁺.
Example 88: N-(5(5-(4-Ethyl-5-oxo4,5-dihydro-l,3,4oxadiazol-2-yl)-2methy 1 pheny 1 )p yraz in-2-yl)-2,6difluorobenzamide		'HNMR (400 MHz, DMSO-rf6) δ 11.84 (s, 1H, D₂O exchangeable), 9.53 (s, IH), 8.73 (s, 1H), 7.89 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.657.59 (m, 1H), 7.56 (d, J = 8.0 Hz, 1 H), 7,27 (t, J= 8.5 Hz, 2H), 3.78 (q, J= 7.0 Hz, 2H), 2.45 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 438 (MH)⁺.
Example 89: 2,6- Difluoro-N-(5-(2methyl-5-(5-oxo-4propyl-4,5-dihydro- l,3,4-oxadiazol-2yl)phenyl)pyrazin2-yl)benzamide	II	'HNMR (400 MHz, DMSO-t/6) δ 11.84 (s, 1H, D₂O exchangeable, 9.53 (s, 1H), 8.73 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 8.0, 2.0 Hz, 1H), 7.66-7.59 (m, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.27 (t, J= 8.5 Hz, 2H), 3.71 (t, J= 7.0 Hz, 2H), 2.46 (s, 3H), 1.74 (q, J = 7.0 Hz, 2H), 0.91 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 452

AJ--93

Example : HJ PAC namc	Structure	'HNMR/ESI-MS (MH)⁺
		(MH)⁺.
Example 90: JV-(5(2-Ethyl-5-(4methyl-5-oxo-4,5 dîhydro-1,3,4oxadiazol-2yl)phenyl)pyrazin2-yl)-2,6difluorobenzamide	Άίύ	‘HNMR (400 MHz, CDC1₃) δ 9.78 (s, 1H), 8.62 (s, 1H, D₂O exchangeable), 8,39 (s, 1H), 7.867.83 (m, 2H), 7.53-7.46 (m, 2H), 7.07 (t, J = 8.5 Hz, 2H), 3.51 (s, 3H), 2.80 (q, J = 7.0 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 438 (MH)⁺
Example 91:2- Chloro-H-(5-(2ethyl-5-(4-methyl5-oxo-4,5-dihydrol,3,4-oxadiazol-2yl )phenyl)pyrazin2-yl)-6fluorobenzamide	o-ÇC ^N Λρ 1 c/	'HNMR (400 MHz, CdCl₃) δ 9.78 (s, 1H)), 8.38 (s, 1H, D₂O exchangeable), 8.37 (s, 1H), 7.86 (d, J = 1.5 Hz, 1 H), 7.84 (s, 1 H), 7.48 (d, J = 8.5 Hz, 1H), 7.47-7.41 (m, 1H), 7.32 (d, J= 8.5 Hz, 1H), 7.18-7.14 (td, J = 8.5, 1.0 Hz, 1H), 3.51 (s, 3H), 2.82-2.78 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H);ESI-MS (m/z) 454, 456 [(MH)⁺, Cl^35,37]
Example 92: 7/-(5(2-Ethyl-5-(4methyl-5-oxo-4,5 dihydro-1,3,4oxadiazol-2yl)phenyl)pyrazin2-yl)-2-fluoro-6methylbenzamide		'HNMR (400 MHz, CDC1₃) δ 9.78 (s, 1H), 8.45 (s, 1H, D₂O exchangeable), 8.31 (s, 1H), 7.857.82 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.38-7.32 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 8.5 Hz, 1 H), 3.50 (s, 3H), 2.80 (q, J= 7.5 Hz, 2H), 2.52 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H); ES1- MS (m/z) 434 (MH)⁺

Example : IUPAC name	Structure	'HNMR/ESI-MS (MH)⁺
Example 93: 2,6- Difluoro-7V-(5-(2methoxy-5-(4methyl- 5 -oxo -4,5 dihydro-1,3,4oxadiazol-2yl)phenyl)pyrazin2-yl)benzamide		'HNMR (400 MHz, DMSO-î/6) δ 11.78 (s, 1 H, D2O exchangeable), 9.53 (s, 1H), 9.01 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.88 (dd, J= 8.0, 2.0 Hz, 1H), 7.66-7.59 (m, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 8.5 Hz, 2H), 3.99 (s, 3H), 3.41 (s, 3H); ESIMS (m/z) 440 (MH)⁺.
Example 94: 2,6Difluoro-A-(5-(2fluoro-5-(4-methyl5-oxo -4,5 -dihydrol,3,4-oxadiazol-2yl)phenyl)pyrazin2-yl)benzamide	1 F	'HNMR (400 MHz, CDCI3) δ 9.80 (s, 1H), 8.83 (t, J= \,5 Hz, IH), 8.62 (dd, J= 7.0, 2.0 Hz, 1H), 8.49 (s, 1H, D₂O exchangeable), 7.90-7.86 (m, I H), 7.54-7.47 (m, 1 H), 7.31 (dd, J = 11.0, 9.0 Hz, 1 H), 7.07 (t, J = 8.5 Hz, 2H), 3.52 (s, 3H); ESI-MS (m/z) 428 (MH)⁺.
Example 95: JV-(5(2(difluoromethoxy)5-(4-methyl-5-oxo4,5-dihydro-I,3,4oxadiazol-2yl)phenyl)pyrazin2-yl)-2,6difluorobenzamide	v ZwÔ 1 ^F	'HNMR (400 MHz, CDCI3) δ 9.82 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H, D₂O exchangeable), 8.43 (d, J = 2.5 Hz, 1H), 7.91 (dd, J = 8.5, 2.5 Hz, 1H), 7.54-7.50 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.08 (t, J= 8.5 Hz, 2H), 6.64 (t, y = 73 Hz, 1H), 3.52 (s, 3H); ESI-MS (m/z) 476 (MH)⁺.
Example 96: N-(5- (2-ethyl-3-(4methyl-5-oxo-4,5dihydro-1,3,4oxadiazol-2-		'HNMR (400 MHz, CDCI3) δ 9.78 (s, 1H), 8.44 (s, 1H), 8.38 (d, J= 1.5 Hz, 1H), 7.89 (dd, J = 7.5, 1.5 Hz, 1H), 7.54-7.41 (m, 3H), 7.08 (t, J = 8.5 Hz, 2H), 3.55 (s, 3H), 3.03 (q, J =

Examplc : IUPAC nanie	Structure	'HNMR/ESI-MS (MH)⁺
yl)phenyl)pyrazin- 2-yl)-2,6- difluorobenzamide		7.5 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H); ESI- MS (m/z) 438 (MH)⁺

Examples 97-118

HOOC

Intermediate 1 fib, 22b

HOOC

(COCI)₂, cal DMF or SOCI₂ pyridlne O

O^

Method A: To a stirred and cooled (0 °C) solution of a corresponding substituted pyridine carboxylic acid (0.44 mmol, 1.3 eq) in DCM (5 mL) was added oxalyl chloride (1.5 eq) followed by a catalytic amount of DMF. The resulting mixture was stirred at the same température for 2 h. The solvent and the excess of oxalyl chloride were removed under vacuum and the residue was dissolved in DCM. The resulting acid chloride solution was cooled to 0 °C, and a solution of aminopyrazine intermediate (1.0 eq) in DCM was added followed by pyridine (1.5 eq). The reaction mixture was stirred at room température for 15 h. The reaction was diluted with DCM (10 mL) and the organic layer was washed with water (5 mL), brine (5 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane) to afford the desired product as a soiid.

Method B: A mixture of a corresponding substituted pyridine carboxylic acid (0.37 mmol, 1.3 eq) and thionyl chloride (2 mL) was refluxed for 2 h. The excess of thionyl chloride was removed by évaporation under reduced pressure. The resulting acid chloride in DCM (3 mL) was added drop wise to a stirred and cooled (0 °C) solution of aminopyrazine intermediate (1.0 eq) ' and pyridine (1.5 eq) in DCM (5 mL), The resulting mixture was stirred at room température for 15 h. Work up and isolation as described in method A afforded the desired product as a white solid.

The below Examples-97 to 118 were prepared by following a procedure similar to that described 5 in method A or method B by using corresponding intermediates 1 b, 7b, 18b or 22b.

Example No: IUPAC name	Structure	’HNMR ESI-MS (MH)⁺
Example 97: W-(5-(5- (5,5-Dimethyl-4-oxo4,5-dihydroisoxazol-3- yi)-2- methy Ipheny l)pyrazi n- 2-yi)picolinamide		’HNMR (400 MHz, DMSO-ί/ό) δ 10.75 (s, 1H, D2O exchangeable), 9.61 (s, 1H), 8.80 (d, J =4.5 Hz, 1H), 8.72(s, 1 H), 8.26 (d, J=8.0 Hz, 1 H), 8.15 (t, J = 8.0 Hz, 1H), 8.12 (s, 1 H), 7.99 (d, J =8.0 Hz, 1 H), 7.77 (t, J = 5.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H), 1.43 (s, 6H); ESI-MS (m/z) 402 (MH)⁺.
Example 98: H-(5-(5- (5,5-Dimethyl-4-oxo- 4,5-dihydroisoxazol-3- yi)-2- methyl phenyl )pyrazin- 2-yl)nicotinamide		’HNMR (400 MHz, CDC1₃) δ 9.76 (s, 1H), 9.22 (d, J = 1.5, Hz, 1H), 8.86 (dd, J =4.5, 1.5 Hz, 1H), 8.61 (s, 1H, D₂O exchangeable), 8.49 (s, 1H), 8.31 (td, J = 8.0, 2.0 Hz, 1H), 8.21 (d, ./=2.0 Hz, 1H), 8.10 (dd, J = 8.0,2.0 Hz, 1H), 7.53 (ddd, J = 8.0, 4.5, 1.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 402 (MH)⁺
Example 99:7/-(5-(5- (5,5-Dimethyl-4-oxo- 4,5-dihydroisoxazol-3-	/ 0	’HNMR (400 MHz, CDCI3) δ 9.76 (s, 1H), 8.87 (dd, J = 1.5,4.5 Hz, 2H), 8.63 (s, 1H,D₂O

yl)-2- methylphenyl)pyrazin- 2-yl)isonicotinamide		exchangeable), 8.47 (s, 1 H), 8.19 (s, 1 H), 8.08 (dd, J = 8.0, 2.0 Hz, IH), 7.80 (dd, J = 1.5, 4.5 Hz, 2H), 7.42 (d, J =8.0 Hz, IH), 2.46 (s, 3H), 1.47 (s, 6H); ESIMS (m/z) 402 (MH)⁺
Example 100: /7-(5-(5(5,5-Dimethyl-4-oxo4,5-dihydroîsoxazol-3- yi)-2- methylphenyl)pyrazin- 2-yl)-2methylnicotinamide		’HNMR (400 MHz, CDC1₃) δ 9,76 (s, IH), 8.65 (dd,J=5.0, 1.5 Hz, IH), 8.40 (s, IH), 8.39 (s, IH, D2O exchangeable), 8.19 (d, J = 1.5 Hz, IH), 8.09 (d, J = 8.0, 1.5 Hz, IH), 7.90 (dd, J= 7.5, 1.5 Hz, IH), 7.43 (d, .7=8.0 Hz, IH), 7.18-7.15 (m, IH), 2.80 (s, 3H), 2.47 (s, 3H), 1.48 (s, 6H); ESIMS (m/z) 416 (MH)⁺.
Example 101:6- Chloro-7V-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)- 2-methylphenyl) pyrazin-2yl)nicotinamide	AoVæ —pd	’HNMR (400 MHz, CDC1₃) δ 9.75 (s, 1 H), 8.98 (d, J = 2.5 Hz, IH), 8.53 (s, IH, D₂O exchangeable), 8.48 (s, IH), 8.26 (dd, .7=8.0, 2.5 Hz, IH), 8.20 (d, J =2.0 Hz, 1 H), 8,10 (dd, .7= 8.0, 2.0 Hz, IH), 7.53 (d, J= 8.0 Hz, IH), 7.44 (d, J =8.0 Hz, IH), 2.47 (s, 3H), 1.48 (s, 6H); ESIMS (m/z) 436, 438 [(MH)⁺, Cl³⁵· ³⁷1
Example 102: 6- Chloro-#-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)- 2-methylphenyl)	(ί^ΓΛ—Z^N=\ Cl, Zo'	’HNMR (400 MHz, CDCI3) δ 9.75 (s, IH), 8.78 (s, 1 H), 8.75 (s, IH, D₂O exchangeable), 8.70 (d, J =4.5 Hz, 1 H), 8.47 (s, IH), 8.19 (d, J =2.0 Hz, IH), 8.10 (dd, J =

pyrazin-2-yl) isonicotinamide		8.0, 2.0 Hz, 1 H), 7.74 (d, 7= 4.5 Hz, 1 H), 7.43 (d, 7 = 8.0 Hz, 1 H), 2.47 (s, 3H), 1.47 (s, 6H); ESIMS (m/z) 436, 438 [(MH)⁺, Cl^{351 37}1
Example 103: 3,5Dichloro-/V-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)2-methylphenyl) pyrazin-2yl)isonicotinamide	7~V/^N=\ Cl 7'ο·^Ν cf	’HNMR (400 MHz, CDC1₃) δ 9.74 (s, 1 H), 8.63 (s, 2H), 8.46 (s, 1H), 8.19 (s, 1H+1H, D₂O exchangeable), 8.10 (d, 7= 8.0, 1.5 Hz, 1H), 7.43 (d, 7 =8.0 Hz, 1H), 2.47 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 470, 472, 474 [(MH)⁺, Cl³⁵¹³⁷]
Example 104: 4- Chloro-/V-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)- 2-methylphenyl) pyrazin-2yl)nicotinamide		’HNMR (400 MHz, CDCI₃) δ 9.76 (s, 1 H), 9.05 (s, 1 H), 8.67 (d, 7 = 5.5 Hz, 2H), 8.47 (s, 1H), 8.20 (s, 1 H), 8.10 (dd, 7= 8.0, 2.0 Hz, 1H), 7.48 (d, 7 =5.5 Hz, 1H), 7.43 (d, 7=8.0 Hz, 1H), 2.47 (s, 3H), 1.46 (s, 6H); ESI-MS (m/z) 436, 438 [(MH)⁺, Cl ³⁵’³⁷]
Example 105:77-(5-(5(5,5-dimethyl-4-oxo- 4,5-dihydroisoxazol-3yl)-2-methylphenyl) pyrazin-2-yt)-6methylnicotinamide	“P	’HNMR (400 MHz, CDClj) δ 9.77 (s, 1H), 9.09 (d, J =2.0 Hz, 1 H), 8,56 (s, 1H, D₂O exchangeable), 8.47 (s, 1H), 8.20 (d, J =2.0 Hz, 1H), 8.18 (dd, 7 = 8.0,2.0 Hz, 1 H), 8.09 (dd,7 = 8.0, 2.0 Hz, 1 H), 7.43 (d, 7=8.0 Hz, 1H), 7.35 (d, 7 =8.0 Hz, 1H), 2.68 (s, 3H), 2.47 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 416 (MH)⁺

Example 106: 5- Chloro-W-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)- 2-methylphenyl) pyrazin-2-yl) nicotinamide		’HNMR (400 MHz, CDCI₃) δ 9.77 (s, IH), 9.09 (s, IH), 8.83 (d, J =2.5 Hz, IH), 8.68 (s, IH, D₂O exchangeable), 8.52 (d, J= 1.5 Hz, 1 H), 8.33 (t, J= 2.0 Hz, IH), 8.23 (d, 7 = 1.5 Hz, 1 H), 8.12 (dd, 7=8.0, 1.5 Hz, IH), 7.46 (d,7 = 8.0 Hz, 1 H), 2.50 (s, 3H), 1.49 (s, 6H); ESI-MS (m/z) 436, 438 [(MH)⁺, Cl ^3Î’³⁷]
Example 107: //-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroîsoxazol-3yl)-2methylphenyl)pyrazin2-yl)-3-fluoroiso nicotinamide	7ό·^ν /	’HNMR (400 MHz, CDClj) δ 9.76 (s, IH), 9.07 (d, 7= 12.5 Hz, IH), 8.73 (d,7 =2.0Hz, IH), 8.69 (dd, 7= 5.0, 1.0 Hz, IH), 8.49 (s, I H), 8.20 (d, 7 = 2.0 Hz, 1 H), 8.09 (dd, 7= 8.0, 2.0 Hz, IH), 8.05 (dd,7 =6.5, 5.0Hz, IH), 7.43 (d,7=8.0 Hz, IH), 2.46 (s, 3H), 1.47 (s, 6H); ESI- MS (m/z) 420 (MH)⁺
Example 108:7V-(5-(5(5,5-dimethyl-4-oxo- 4,5-dihydroisoxazol-3yl )-2-methylphenyl ) pyrazin-2-yl)-5fluoronicotinamide		’HNMR (400 MHz, CDC1₃) δ 9.77 (s, IH), 9.19 (d,7= 13.5 Hz, D2O exchangeable, IH), 8.71 (dt, 7= 7.5, 2.0 Hz, 1 H), 8.51 (s, 1 H), 8.47-8.45 (m, IH), 8.21 (d,7 = 2.0 Hz, 1 H), 8.10 (dd, 7 = 8.0, 2.0 Hz, IH), 7.50-7.47 (m, IH), 7.43 (d,7= 8.0 Hz, IH), 2.47 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 420 (MH)⁺.
Example 109:H-(5-(5- (5,5-dimethyl-4-oxo-		’HNMR (400 MHz, CDC1₃) δ 9.79 (s, IH), 9.23 (d,7= 14Hz,

100

4,5-dihydroisoxazol-3yl)-2-methylphenyl) pyrazin-2-yl)-2fluoronicotinamide		D₂O exchangeable, 1H), 8.72 (dt, J = 8.0, 2.0 Hz, 1 H), 8.53 (s, 1 H), 8.48 (d,J=4.5 Hz, 1H), 8.23 (s, 1 H), 8.11 (dd, J= 8.0, 2.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H), 1.50 (s,6H); ESI-MS (m/z) 420 (MH)⁺
Example 110: 2- Chloro-N-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)- 2-methylphenyl) pyrazin-2yl)isonicotinamide	7^^	436'HNMR (400 MHz, CDClj) δ 9.77 (s, 1H), 8.67 (dd, J= 1.0, 5.0 Hz, 1 H), 8.63 (s, 1H, D₂O exchangeable), 8.52 (s, 1H), 8.23 (d, .7= 2.0 Hz, 1H), 8.13 (dd, J= 8.0,2.0 Hz, 1 H), 7.90 (dd,J = 1.5, 1.0 Hz, 1H), 7.75 (dd,J= 5.0, 1.0 Hz, 1H), 7.46 (d, J =8.0 Hz, 1 H), 2.46 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 436, 438 [(MH)⁺, Cl ³⁵’³⁷]
Example 111:2- Chloro-H-(5-(5-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)2-methylphenyl) pyrazin-2-yl)-6methylisonicotinamide		‘HNMR (400 MHz, CDC1₃) δ 9.74 (s, 1H), 8.56 (s, 1H, D₂O exchangeable), 8.49 (s, 1H), 8.20 (d, J= 2.0 Hz, 1H), 8.10 (dd, J = 8.0, 2.0 Hz, 1H), 7.64 (s, 1H), 7.58 (s, 1 H), 7.44 (d, J =8.0 Hz, 1 H), 2.67 (s,3H), 2.47 (s, 3H), 1.46 (s, 6H); ESI-MS (m/z) 450, 452 [(MH)⁺, Cl^3S·³⁷]
Example 112:7V-(5-(5(5,5-dimethyl-4-oxo- 4,5-dihydroisoxazol-3yl)-2-methylphenyl)		'HNMR (400 MHz, CDCI3) δ 9.75 (s, 1 H), 8.66 (s, 1H, D₂O exchangeable), 8.48 (s, 1H), 8.47 (d, J = 5.0 Hz, 1 H), 8.20 (s, 1H),

101

pyrazin-2-yl)-2fluoroisonicotinamide		8.10 (d, J = 8.0 Hz, 1H), 7.69 (d, J =5.0 Hz, 1 H), 7.48 (s, 1H), 7.43 (d, J= 8.0 Hz, 1 H), 2.47 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 420 (MH)⁺
Example 113: A-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yl)-2-methylphenyl) pyrazin-2-yl)-2methylnicotïnamide		'HNMR (400 MHz, CDCI3) δ 9.76 (s, 1H), 8.66 (dd, J= 1.5,5.0 Hz, 1H), 8.40 (s, 1 H), 8.39 (s, 1H, D₂O exchangeable), 8.19 (d, J = 2.0 Hz, 1 H), 8.09 (dd, J= 8.0, 2.0 Hz, 1 H), 7.90 (dd, J= 1.5, 7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.29-7.23 (m, 1H), 2.80 (s, 3H), 2.47 (s, 3H), 1.48 (s, 6H); ESIMS (m/z) 416 (MH)⁺
Example 114:/V-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yl ) -2 -methyl ph enyl ) pyrazin-2-yl)-3,5-di fluoroisonicotinamide		'HNMR (400 MHz, CDCI3) δ 9.75 (s, 1 H), 8.57 (s, 2H+1H, D₂O exchangeable), 8.49 (s, 1 H), 8.21 (d, J = 2.0 Hz, I H), 8.12 (dd, J =8.0, 2.0 Hz, 1H), 7.45 (d,J = 8.0 Hz, 1 H), 2.48 (s, 3H), 1.49 (s, 6H); ESI-MS (m/z) 438 (MH)⁺
Example 115: H-(5-(5- (5,5-dimethyl-4-oxo- 4,5-dihydroisoxazol-3yl )-2-methylphenyl) pyrazin-2-yl)-3- methylisonicotinamide	Λύ	'HNMR (400 MHz, CDCIj) δ 9.77 (s, 1H), 8.65 (s, 1H), 8.65 (d, J= 5.0 Hz, 1H), 8.47 (s, 1H), 8.29 (s, 1H, D₂O exchangeable), 8.21 (d, J =2.0 Hz, 1H), 8.12 (dd, J = 8.0, 2.0 Hz, 1H), 7.47-7.44 (m, 2H), 2.58 (s, 3H), 2.49 (s, 3H), 1.49 (s, 6H); ESI-MS (m/z) 416 (MH)⁺

rvv'’

102

Example 116:7V-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yl)-2-methoxy phenyl)pyrazin-2-yl)3,5-difluoro isonicotinamide		’HNMR (400 MHz, CDCI₃) δ 9.71 (s, 1H), 8.87 (s, 1 H), 8.63 (d, J= 2.5 Hz, 1 H), 8.54 (s, 2H), 8.41 (s, 1H, D₂O exchangeable), 8.17 (dd, J = 8.5, 2.5 Hz, 1 H), 7.10 (d, J= 8.5 Hz, 1 H), 3.95 (s, 3H), 2.03 (s, 3H); ESI-MS (m/z) 454 (MH)⁺
Example 117: N-(5-(2ethyl -5 - (4-m ethy 1-5 oxo-4,5-dihydro-1,3,4oxadiazol-2yl)phenyl)pyrazin-2yl)-3,5-difluoro isonicotinamide	f ^F	’HNMR (400 MHz, CDC1₃) δ 9.73 (s, 1 H), 8.57 (s, 2H), 8.45 (d, J= \.QHz, 1H+1H,D₂O exchangeable), 7.87-7.84 (m, 2H), 7.49 (d, J = 8.5 Hz, 1H), 3.51 (s, 3H), 2.80 (q, J =7.5 Hz, 2H), 1.18 (t, J =7.5 Hz, 3 H); ESI-MS (m/z) 439 (MH)⁺
Example 118: 3,5- Difluoro-/V-(5-(2fluoro-5-(4-methyl-5oxo-4,5-dihydro-1,3,4oxadiazol-2yl)phenyl)pyrazin-2yl)isonicotinamide	F 0<.n oC*¹ f	’HNMR (400 MHz, CDC1₃) δ 9.77 (s, 1H), 8.87 (t, J = \ .5Hz, 1H), 8.62 (dd, J =7.0, 2.0 Hz, 1H), 8.57 (s, 2H), 8.48 (s, 1H, D₂O exchangeable), 7.91-7.87 (m, 1H), 7.32 (dd, J = 11.0, 9.0 Hz, 1 H), 3.53 (s,3H); ESI-MS (m/z) 429 (MH/.

Example 119

N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)benzofuran-2-carboxamide --103

The title compound was prepared by following a procedure similar to that described in method B of Examples 97 to 118 by using Intermediate lb and benzofuran-2-carboxylic acid. ’HNMR (400 MHz, CDC1₃) δ 9.79 (s, 1H), 9.04 (s, 1H, D₂O exchangeable), 8.50 (s, 1H), 8.21 (d, J = 2.0 Hz, 1 H), 8.09 (dd, J = 8.0, 2.0 Hz, 1 H), 7.74 (d, J = 7.5 Hz, 1 H), 7.70 (s, 1 H), 7.59 (dd, J = 8.5, 1.0 Hz, 1 H), 7.51 (dt, J = 7.5, 1.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 1 H), 7.36 (dt, J = 8.0, 1.0 Hz, 1 H), 2.48 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 441 (MH)⁺.

Example 120

2,6-Difluoro-7V-(5-(2-methyl-5-(4-oxo-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)phenyl)pyrazin-2- yl)benzamide

Step-1: 3-(3-(5-Aminopyrazin-2-yl)-4-methyiphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one: To a solution of intermediate 30 (100 mg, 0.311 mmol, 1.0 eq) and 5-(trimethyl stannyl)-pyrazine-2amine (prepared from 2-amino-5-bromopyrazine by following the procedure described in Chem. Eur. J. 2000, 6, 4132) (241 mg, 0.93 mmol, 3 eq) in dioxane (5 mL) was added Pd(PPhî)4 (18 mg, 0.015 mmol, 0.05 eq). The resulting mixture was thoroughly deoxygenated by subjecting to a vacuum/nitrogen cycle three times and the reaction mixture was heated at 75 °C for 15 h under nitrogen atmosphère. The resulting mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel using ethyl acetate-hexane mixture as eluent) to afford 44 mg of the title compound as a white solid. ’HNMR (400 MHz, CDCI3) δ 9.72 (s, 1H), 8.55 (s, 1H, D₂O exchangeable), 8.16 (s, 1H), 8.13 (s, 1H), 8.08 (d, J= 2.0 Hz, 1H), 8.01 (dd, J = 8.0, 2.0 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 4.64 (s, 2H, D₂O exchangeable), 2.42 (s, 3H), 1.86-1.65 (m, 10H); ESI-MS (m/z) 337 (MH)⁺.

Step-2: 2,6-Difluoro-/V-(5-(2-methyl-5-(4-oxo-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)phenyl) pyrazin-2-yl)benzamide: To a 0°C cooled and stirred, solution of 2,6-difluorobenzoyl chloride (0.013 mL, 0.11 mmol, 1.0 eq) in DCM (3 mL) was added drop wise a solution of 3-(3-(5aminopyrazin-2-yl)-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one (40 mg, 0.11 mmol,

104

1.0 eq) in DCM (2 mL) followed by pyridine (0.01 mL, 0.11 mmol, 1.0 eq). The resulting mixture was stirred at room température ovemight. The reaction was diluted with DCM (5 mL), and washed with 10% hydrochloric acid (5 mL), dried (Na₂S0.4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane) to afford 8 mg of the title product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 9.76 (s, IH), 8.51 (s, 1H, D₂O exchangeable), 8.41 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 7.5 Hz, IH), 7.51-7.47 (m, 1H,) 7.42 (d, J = 7.5 Hz, 1H), 7.06 (t, J = 8.0 Hz, 2H), 2.48 (s, 3H), 1.82-0.87 (m, 10H); ESI-MS (m/z) 477 (MH)⁺.

Example 121

7V-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylphenyl)pyrazine-2-carboxamide

1. socij ² nh₂

HO

Slep-2

Exùmpl· 121

Step-1: 5-Chloro-N-(2,6-difluorophenyl)pyrazine-2-carboxamide: A mixture of 5hydroxypyrazine-2-carboxylic acid (500 mg, 3.57 mmol, 1.0 eq), thionyl chloride (5 mL) and DMF (0.3 mL) was refluxed for 15 h. The excess of thionyl chloride was removed under vacuum and the residue was taken in THF (5 mL). The resulting mixture was cooled to 0 °C and a solution of 2,6-difluoroaniline (0.58 mL, 5.35 mmol, 1.5 eq) was added to the above mixture followed by triethyl amine (0.75 mL, 5.35 mmol, 1.5 eq). After stirring for 3 h at room température, the reaction was diluted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), 2N HCl (10 mL), dried (Na₂SO₄) and filtered. The filtrate was concentrated under vacuum. The crude product was purified with flash column chromatography (silica gel, ethyl acetate and hexane System as eluent) to afford 500 mg of the title product as a white solid. ‘HNMR (400 MHz, DMSO-î/6) δ 10.67 (s, IH, D?O exchangeable), 9.11 (s, IH), 9.98 (s, IH), 7.47-7.41 (m, IH), 7.26-7.21 (m, 2H); ESI-MS (m/z) 270, 272 [(MH)⁺, Cl³⁵¹³⁷]

Step-2: ?V-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methyl phenyl) pyrazine-2-carboxamide: To a solution of intermediate la (100 mg, 0.30 mmol, 1.0 eq) and 5-chloro-N-(2,6-difluorophenyl)pyrazine-2-carboxamide (61 mg, 0.30 mmol, 1.0 eq), in THF:H₂O (4:1, 5 mL) was added sodium bicarbonate (38 mg, 0.45 mmol, 1.5 eq) followed by

Pd(PPh₃)4 ( 17 mg, 0.015 mmol, 0.05 eq). The resulting mixture was thoroughly deoxygenated by —.

105 subjecting to a vacuum/nitrogen cycle three times and the reaction mixture was heated at 75 °C for 15 h under nitrogen atmosphère. The resulting mixture was cooled to rooin température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane) to afford 50 mg of the title product as a white solid. 'HNMR (400 MHz, CDC1₃) δ 9.59 (s, IH), 9.26 (s, IH, D₂O exchangeable), 8.82 (s, IH), 8.29 (d, J= 2.0 Hz, IH), 8.18 (dd, J= 8.0, 2.0Hz, IH), 7.50 (d, J = 8.0 Hz, lH), 7.31-7.28 (m, 1 H), 7.07 (t,J=8.0tfz, 2H), 2.53 (s, 3H), 1.51 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.

Example 122

4-(2,6-Difluorobenzamido)-3'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 '-biphenyl]-2carboxylic acid

Step-1: Ethyl-2-bromo-5-(2,6-difluorobenzamido)benzoate: To a 0°C cooled and stirred, solution of 2,6-difluorobenzoyl chloride (0.5 mL, 4.11 mmol, 1.0 eq) in DCM (5 mL) was added drop wise a solution of ethyl-2-bromo-5-aminobenzoate (1.0 g, 4.11 mmol, 1.0 eq) in DCM (5 mL) followed by pyridine (0.43 mL, 4.93 mmol, 1.2 eq). The resulting mixture was stirred at room température for 15 h. The reaction was diluted with DCM (15 mL), and washed with 10% hydrochloric acid (10 mL), dried (Na₂SO.i) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane as eluent) to afford 500 mg of the title product as a white solid. ’HNMR (400 MHz, CDC1₃) δ 8.23 (s, IH, D₂O exchangeable), 7.97 (d, J= 2.5 Hz, IH), 7.73 (dd, J= 8.5, 2.5 Hz, IH), 7.60 (d, J= 8.5 Hz, IH), 7.41-7.34 (m, IH), 6.92 (t, J = 8.0 Hz, 2H); ESI-MS (m/z) 384,386 [(MH)⁺ Br⁷⁹’⁸¹].

Step-2: Ethyl 4-(2,6-difluorobenzamido)-3’-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1 ,Tbiphenyl]-2-carboxylate; To a solution of ethyl-2-bromo-5-(2,6-difluorobenzamido) benzoate (180 mg, 0.47 mmol, 1.0 eq), in dioxane (5 mL), successively intermediate 9 (150 mg, 0.47

106 mmol, 1.0 eq) sodium carbonate (100 mg, 0.95 mmol, 2 eq) and Pd(PPh3)₂Cl₂ (33 mg, 0.047 mmol, 0.1 eq) were added. The resulting solution was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three tirnes and the reaction mixture was then heated at 120°C in microwave (Biotage) for 30 min. The resulting mixture was cooled to room température, diluted S with ethyl acetate (10 mL) and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane System as eluent) to afford 90 mg of the title compound as a white solid. ’HNMR (400 MHz, CDC1₃) δ 8.13-8.09 (m, 2H), 8.05-8.01 (m, 2H), 7.88 (s, IH, D₂O exchangeable), 7.52-7.42 (m, 4H), 7.04 (t, J= 8.0 Hz, 2H), 4.14 (q, J= 7.0 Hz, 2H), 1.49 (s, 6H), 10 1.09 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 493 (MH)⁺.

Step-3: 4-(2,6-Difluorobenzamido)-3'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazoi-3-yl)-[ 1,Tbiphenyl]-2-carboxylic acid: A solution of ethyl 4-(2,6-difluorobenzamido)-3'-(5,5-dimethyl-4oxo-4,5-dihydroisoxazol-3-yl)-[l,l'-biphenyl]-2-carboxylate (80 mg, 0.16 mmol) in a mixture of dioxane and 2N HCl (5 mL, 1:1 (v/v)) was refluxed for 15 h. The solvent was removed under 15 vacuum and the residue was purified by column chromatography (silica gel, DCM: MeOH as eluent) to afford 30 mg of the desired product as a white solid. ’HNMR (400 MHz, CDCI3) δ 8.12-8.09 (m, 3H), 8.06 (d, J = 2.0 Hz, IH), 7.96 (s, IH, D₂O exchangeable), 7.51-7.41 (m, 4H), 7.03 (t, J= 8.0 Hz, 2H), 1.46 (s, 6H); ESI-MS (m/z) 465 (MH)⁺.

Example 123

7V-(5'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-hydroxy-[ 1,1 '-biphenyl]-4-yl)-2,6difluorobenzamide

OMe

Exemple 16

BBij/DCM

To a 0 °C cooled and stirred solution of Example 15 (60 mg, 0.13 mmol, 1.0 eq) in DCM (2 mL) was added drop wise boron tribromide (IM in DCM, 0.20 mL, 1.5 eq) and then allowed to warm to 10 °C. After stirring for lh, boron tribromide (1M in DCM, 0.20 mL, 1.5 eq) was again added to the reaction and then continued to stir at 10 °C for another 2h. The reaction was quenched with methanol (1 mL) at 0 °C and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate (5 mL) and washed with water (3 mL), brine (3 mL), dried (Na₂SOj) and filtered. The filtrate was evaporated under vacuum and the crude product was purified by column chromatography (silica gel, ethyl acetate and hexane as eluent) to afford 45 mg of the desired

107 product as a white solid. ‘HNMR (400 MHz, DMSO-î/6) δ 10.89 (s, 1H, D₂O exchangeable), 10.29 (s, 1H, D₂O exchangeable), 7.93 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.0, 2.0 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.65-7.59 (m, 1 H), 7.57 (d, J = 8.5 Hz, 2H), 7.27 (t, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1 H), 1.40 (s, 6H); ESI-MS (m/z) 437 (MH)⁺.

Example 124

JV-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-hydroxyphenyl)pyrazin-2-yl)-2,6difluorobenzamide

The title compound was prepared by following a procedure similar to that described in Example 123 by using Example 14. *HNMR (400 MHz, CDC1₃) δ 13.13 (s, 1H, D₂O exchangeable), 9.60 (s,lH), 9.00 (s, 1H), 8.68 (s, 1H), 8.61 (s, 1H, D₂O exchangeable), 8.11 (dd, J = 8.5, 2.0 Hz, 1 H), 7.58-7.43 (m, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 7,06 (t, J = 8.0 Hz, 2H), 1.49 (s, 6H); ESI- MS (m/z) 439 (MH)⁺.

Examples 125 to 133

General procedure for the O-alkylation of the compounds of examples 123 and 124:

OH

Ixirnpki 124 * nd 124 «X/XjCOj

OA

To a stirred solution of hydroxyl compound of Example 123 or Example 124 (1.0 eq) in acetone (5 mL) was added potassium carbonate (1.0 eq) and the corresponding alkyl halide (1.0-3.0 eq) and the resulting mixture was refluxed ovemight. The reaction was cooled to room température and then filtered. The solid residue was washed with acetone and the combined filtrâtes were evaporated under vacuum. The crude residue was purified with flash column chromatography (silica gel, ethyl acetate : hexane as eluent) to afford the desired product as white solid. λλζ-—’

108

Example No: IUPAC namc	Structure	¹ HNMR/ESI-MS (MH)⁺
Ex ample 125: jV-(5'- (5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yl)-2'-isopropoxy-[ 1,1'- biphenyl]-4-yl)-2,6difluorobenzamide		‘HNMR (400 MHz, CDCI₃) δ 8.12 (d, J = 2.0 Hz, 1 H), 8.07 (dd, J= 8.5, 2.0 Hz, 1H), 7.71-7.68 (m, 2H+1H, D₂O exchangeable), 7.61 (d, J= 8.5 Hz, 2H), 7.47-7.42 (m, 1H), 7.06 (d, J= 8.5 Hz, 1H), 7.03 (t, J= 8.0 Hz, 2H), 4.65-4.61 (m, 1H), 1.48 (s, 6H), 1.33 (d, 7=6.0 Hz, 6H); ESI-MS (m/z) 479 (MH)⁺.
Example 126: jV-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yi)-2isopropoxyphenyl)pyraz in-2-yl)-2,6difluorobenzamide		'HNMR (400 MHz, CDC1₃) δ 9.76 (s, 1 H), 8.90 (s, 1H), 8.66 (d,7 = 2.0 Hz, 1 H), 8.49 (s, 1H, D₂O exchangeable), 8.13 (dd, 7= 8.5, 2.0 Hz, 1 H), 7.50-7.44 (m, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.05 (t, 7 = 8.0 Hz, 2H), 4.78-4.72 (m, 1H), 1.48 (s, 6H), 1.40 (d, 7=6.0 Hz, 6H); ESI-MS (m/z) 481 (MH)⁺.
Example 127: H-(5'(5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yl)-2'-isobutoxy-[ 1,1 '- biphenyl]-4-yl)-2,6dîfluorobenzamide	₁1 Φ'^Ν ° F	'HNMR (400 MHz, CDCI3) δ 8.09 (d, 7 = 2.0 Hz, 1 H), 8.06 (dd, 7 = 8.5,2.0 Hz, 1H), 7.70-7.66 (m, 2H+1 H, D₂O exchangeable), 7.59 (d, 7= 8.5 Hz, 2H), 7.43-7.40 (m, 1 H), 7.02 (d, 7 = 8.5 Hz, 1 H), 7.00 (t, 7= 8.0 Hz, 2H), 3.79 (d, 7= 6.5 Hz, 2H), 2.09-2.02 (m, 1H), 1.46 (s, 6H), 0.98 (d, 7= 6.5 Hz, 6H); ESIMS (m/z) 493 (MH)⁺.

109

Example 128: 79-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yl)-2isobutoxyphenyl)pyrazin -2-yl)-2,6difluorobenzamide	t ·ψ	'HNMR (400 MHz, CDC1₃) δ 9.75 (s, 1H), 8.87 (s, 1 H), 8.63 (d,J= 2.0 Hz, IH), 8.47 (s, 1H, D₂O exchangeable), 8.12 (dd, J= 8.5, 2.0 Hz, 1H), 7.50-7.42 (m, 1H), 7.07 (d, J = 8.5 Hz, 1 H), 7.00 (t, J = 8.0 Hz, 2H), 3.88 (d, J= 6.5 Hz, 2H), 2.16-2.09 (m, 1H), 1.46 (s, 6H), 1.01 (d, J= 6.5 Hz, 6H); ESIMS (m/z) 495 (MH)⁺.
Example 129:79-(5'- (5,5-dimethyl-4-oxo- 4,5-dihydroisoxazol-3yl)-2'-ethoxy-[l,l'biphenyl]-4-yl)-2,6di fl uorob enzam ide		'HNMR (400 MHz, CDC1₃) δ 8.11 (d, J = 2.0 Hz, 1 H), 8.07 (dd, J = 8.5,2.0 Hz. 1 H), 7.71-7.68 (m, 2H+1H, D₂O exchangeable), 7.61 (d, J= 8.5 Hz, 2H), 7.47-7.42 (m, 1H), 7.03 (d, J = 8.5 Hz, 1H), 7.02 (t, J = 8.0 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 1.47 (s, 6H), 1.40 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 465 (MH)⁺.
Example 130:79-(5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol-3yl)-2ethoxyphenyl)pyrazin-2yi)-2,6difluorobenzamide	F	‘HNMR (400 MHz, CDCI3) δ 9.76 (s, 1H), 8,91 (s, 1 H), 8.67 (d,J = 2.0 Hz, 1 H), 8.44 (s, 1H, D₂O exchangeable), 8.14 (dd, J= 8.5, 2.0 Hz, 1H), 7.50-7.46 (m, 1H), 7.09 (d, J = 8.5 Hz, 1 H), 7.05 (t, J = 8.0 Hz, 2H), 4.21 (q, J = 6.5 Hz, 2H), 1.48 (t, J= 6.5 Hz, 3H), 1.48 (s, 6H); ESI-MS (m/z) 467 (MH)⁺.
Example 131 : 79-(5- (5,5-dimethyl-4-oxo- 4,5-dihydroisoxazol-3-		'HNMR (400 MHz, CdCl₃) δ 8.12 (d, J = 2.5 Hz, 1 H), 8.09 (dd, J = 8.5, 2.5 Hz, 1H), 7.72-7.69 (m,

110

yl)-2'-propoxy-[l ,Γbiphenyl]-4-yI)-2,6difluorobenzamide		3H), 7.62 (d, J= 8.5 Hz, 2H), 7.48- 7.41 (m, 1H), 7.05-7.01 (m, 3H), 4.02 (q, J= 6.5 Hz, 2H), 1.83-1.78 (m, 2H), 1.48 (s, 6H), 1.02 (t,7 = 6.5 Hz, 3H); ESI- MS (m/z)479 (MH)⁺
Example 132: N-(2'- (allyloxy)-5'-(5,5dimethyl-4-oxo-4,5dihydroisoxazol-3-yl)[1,1 '-b iphenyl ]-4-yl )2,6-difluorobenzamide		'H NMR (400 MHz, CDC1₃) δ 8.11 (d, J= 2.5 Hz, 1H), 8.07 (dd, 7 = 8.5,2.5 Hz, 1H), 7.71-7.68 (m, 3H), 7.61 (d, 7 = 8.0 Hz, 2H), 7.48-7.39 (m, 1H), 7.05-6.99 (m, 3H), 6.055.95 (m, IH), 5.39-5.24 (m, 2H), 4.63-4.61 (m, 2H), 1.46 (s, 6H); ESI-MS (m/z) 477 (MH)⁺
Example 133: N-(2'(cyclopentyl oxy)-5 '(5,5-dimethyl-4-oxo- 4.5- dihydroisoxazol-3yl)-[ 1,1 -b iphenyl ]-4-yl)- 2.6- difluorobenzamide	9	’HNMR (400 MHz, CdCl₃) δ 8.10 (d, 7 = 2.5 Hz, 1 H), 8.06 (dd, 7 = 8.5, 2.5 Hz, 1H), 7.68 (d,7=8.5 Hz, 2H), 7.58 (d, 7= 8.5 Hz, 2H), 7.48-7.41 (m, 1H), 7.05-7.02 (m, 3H), 4.87-4.85 (m, 1H), 1.92-1.82 (m, 4H), 1.79-1.70 (m, 2H), 1.591.64 (m, 2H), 1.47 (s, 6H); ESI-MS (m/z) 505 (MH)⁺

Example 134

H-(2'-Amino-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 '-biphenyl]-4-yl)-2,6difluorobenzamide

A solution of Example 19 (50 mg, 0.10 mmol) in a mixture of dioxane and methanol (5 mL, 1:1 (v/v)) was heated to 70 °C for 12 h. The solvent was removed under vacuum and the residue was mj—'

111 taken in water (5 mL) and ethyl acetate (5 mL). The mixture was basified with saturated aqueous solution of sodium bicarbonate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄) and filtered. The filtrate was rotary evaporated and the crude product was purified with column chromatography (silica gel, DCM:MeOH as eluent) to afford 20 mg of the desired product as a white solid. 'HNMR (400 MHz, DMSO-î/6) δ 10.92 (s, IH, D₂O exchangeable), 7.80 (d, J = 8.5 Hz, 2H), 7.71 (dd, J = 8.5, 2.0 Hz, IH), 7.64-7.56 (m, IH), 7.41 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 6.84 (d, J = 8.5 Hz, IH), 5.48 (s, 2H, D₂O exchangeable), 1.35 (s, 6H); ESI-MS (m/z) 436 (MH)⁺.

Example 135

7V-(5'-(5,5-DimethyI-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-(methylamino)-[ 1,1 ’-biphenyl ]-4-y 1 )-

2,6-difluorobenzamide

To a 0 °C solution of Example 134 (50 mg, 0.11 mmol, 1.0 eq) in methanol (5 mL) was added formaldéhyde (37% aqueous solution) (10 pL, 0.12 mmol, 1.1 eq). After stirring for 30 min at room température, sodium cyanoborohydride (8 mg, 0.14 mmol, 1.2 eq) was added to the above reaction mixture followed by a catalytic amount of acetic acid. The resulting mixture was stirred at room température for 12 h. The solvent was removed under vaccum and the residuc was dissolvcd in ethyl acetate (10 mL) and washed with water (5 mL), brine (5 mL), dried (Na₂SO₄) and filtered. The filtrate was evaporated under vacuum and the crude product was purified by column chromatography (silica gel, DCM:MeOH as eluent) to afford 8 mg of title compound 'HNMR (400 MHz, CDCI3) δ 8.07 (dd, J= 8.5, 2.0 Hz, IH), 7.87 (d, J= 2.0 Hz, IH), 7.45-7.09 (m, 3H), 7.46-7.43 (m, 3H), 7.04 (t, J= 8.0 Hz, 2H), 6.72 (d, J= 8.5 Hz, IH), 4.33 (s, IH, D2O exchangeable), 2.86 (s, 3H), 1.45 (s, 6H); ESI-MS (m/z) 450 (MH)⁺.

Example 136

JV-(5'-(5,5-Dimethyi-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-(dimethylamino)-[ l, 1 ’-biphenyl]-4-yl)-

2,6-difluorobenzamide

F

112

The title compound was prepared by following a procedure similar to that described in Example 135 by using Example 134 (yîeld: 10 mg) ^!HNMR (400 MHz, CDCI3) δ 8.01 (dd, J = 8.5, 2.0 Hz, 1 H), 7.97 (d, J = 2.0 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 2H), 7.65 (s, 1 H, D₂O exchangeable), 7.61 (d, J= 8.5 Hz, 2H), 7.48-7.41 (m, 1H), 7.06-7.00 (m, 3H), 2.64 (s, 6H), 1.45 (s, 6H); ESI-MS (m/z) 464 (MH)⁺.

Example 137 f/ï/S)-7V-(5-(5-(5,5-Dimethyl-4-hydroxy-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2yl)-2,6-difluorobenzamide

To a solution of Example 1 (100 mg, 0.23 mmol, 1.0 eq) in methanol (5 mL) at room température was added sodium borohydride (13 mg, 0.34 mmol, 1.5 eq) portion wise. After stirring for 10 min at the same température, the solvent was removed under vacuum. Water (3 mL) was added to the above obtained residue followed by ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2*10 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum. The crude product was triturated with hexane and dried to afford 90 mg of the desired product as a white solid. 'HNMR (400 MHz, DMSO-Jî) δ 11.81 (s, IH, D₂O exchangeable), 9.51 (s, 1 H), 8.69 (s, 1 H), 7.86 (d, J = 1.5 Hz. 1 H), 7.77 (dd, J = 8.0, 1.5 Hz, 1 H), 7.64-7.60 (m, IH), 7.44 (d, J = 8.0 Hz, IH), 7.27 (t, J = 8.0 Hz, 2H), 5.95 (d, J = 8.0 Hz, IH, D₂O exchangeable), 4.92 (d, J = 8.0 Hz, IH), 2.42 (s, 3H), 1.18 (s, 6H); ESI-MS (m/z) 439 (MH)⁺.

Example 138 (7ï/S)-/V-(5-(2-Methyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)pyrazin-2-yl)l,2,3,4-tetrahydronaphthalene-2-carboxamide

The title compound was prepared by following a procedure similar to that described in method B of Examples 97 to 118 by using intermediate 23b and l,2,3,4-tetrahydronaphthalene-2- vy^-·

113 carboxylic acid.’HNMR (400 MHz, CDC1₃) δ 9.71 (s, 1H), 8.35 (s, 1H), 8.08 (s, 1H, D₂O exchangeable), 7.87 (dd, J= 8.0, 1.5 Hz, 1H), 7.54 (dd, J= 8.0, 1.5 Hz, 1H), 7,43 (t, J= 8.0 Hz, 1H), 7.19-7.14 (m, 4H), 3.55 (s, 3H), 3.24-2.81 (m, 5H), 2.56 (s, 3H), 2.33-2.28 (m, 1H), 2.102.03 (m, 1H); ESI- MS (m/z) 442 (MH)⁺

Example 139

3-(4’-(2.6-Difluorobenzamido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-5-methyl-4,5-dihydroisoxazole-5carboxyiic acid

To a solution of Example 55 (50 mg, 0.1 mmol, 1.0 eq) in THF (2 mL) was added a solution of lithium hydroxide (13 mg, 0.32 mmol, 3.0 eq) in water (1 mL) at room température. The resulting solution was then stirred at the same température for 4 h. The solvent was removed under vacuum and the residue was taken in water (3 mL) and acidified with 10% aqueous hydrochloric acid to p^H=2.0, and then extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum to afford 35 mg of the desired product as a white solid. ’HNMR (400 MHz, CDCI3) δ 7.74 (s, 1H, D₂O exchangeable), 7.71 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.46-7.41 (m, 1H), 7.32 (d, 7=8.5/*. 3H), 7.02 (t,J=8.0/*, 2H), 3.87 (d, J = 17.5 Hz, 1 H), 3.31 (d, J = 17.5 Hz, 1 H), 2.30 (s, 3H), 1.77 (s, 3H); ESI-MS (m/z) 451 (MH)⁺.

Examples 140-142

The below examples were prepared by following a procedure similar to that described in Example 139 by using Example 54 to préparé Example 140, Example 76 to préparé Example 141 Example 77 to préparé Example 142.

Examplc No: HJPAC name	Structure	’HNMR/ESI-MS (MH)⁺
Example 140: 3-(3(5-(2,6difluorobenzamido)	pV? Hooc-y*o	’HNMR (400 MHz, CDCI3) δ 9.79 (s, 1H), 9.09 (s, 1H, D₂O exchangeable), 8.37 (s, 1H), 7.66

114

Example No: IUPAC name	Structure	’HNMR/ESI-MS (MH)⁺
pyrazin-2-yl)-4- methylphenyl)-5methyl-4,5dihydroisoxazole-5carboxylîc acid		(s, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.52-7.44 (m, I H), 7.35 (d, 7=8.0 Hz. 1 H), 7.04 (t, 7 = 8.0 Hz, 2H), 3.88 (d, 7= 17.0 Hz, 1H), 3.29 (d, 7 = 17.0 Hz, 1 H), 2.43 (s, 3H), 1.74 (s, 3H); ESI-MS (m/z) 453 (MH)⁺.
Example 141: 5- Carboxymethy 1 -3 (4’-(2,6difluorobenzmido)6-methyl-[I,l’biphenyl]-3-yl)-4,5dihydroisoxazole-5carboxylic acid	χφ ° p HOOC'fcoOH	’HNMR (400 MHz, DMSO-76) Ô 13.22 (s, 1H, D₂O exchangeable), 12.56 (s, 1H, D₂O exchangeable), 10.91 (s, 1H, D₂O exchangeable), 7.77 (d,7= 8.5 Hz, 2H), 7.60-7.56 (m, 2H), 7.49 (s, 1H), 7.45 (d,7 = 1.5 Hz, IH), 7.40-7.37 (m, 3H), 7.26 (t, 7= 8.0 Hz, 2H), 3.87 (d, 7 = 17.5 Hz, I H), 3.58 (d, 7= 17.5 Hz, 1 H), 2.98 (s, 2H), 2.28 (s, 3H); ESI-MS (m/z) 495 (MH)\
Example 142: 5- (Carboxymethyl)-3(3-(5-(2,6difluorobenzamido) pyrazin-2-yl)-4methylphenyl)-4,5dihydroisoxazole-5carboxylic acid	rP HOOC COOH	’HNMR (400 MHz, DMSO-76) δ 13.29 (s, 1 H, D₂O exchangeable), 12.58 (s, 1H, D₂O exchangeable), 11.82 (s, 1H, D₂O exchangeable), 9.51 (s, 1H), 8.71 (s, 1H), 7.76 (s, 1H), 7.71 (dd, 7=8.0, 1,5 Hz, 1H), 7.65-7.60 (m, 1H), 7.45 (d, 7 = 8.0 Hz, 1 H), 7.27 (t, 7= 8.0 Hz, 2H), 3.92 (d, 7= 17.0 Hz, 1H), 3,61 (d,7= 17.0 Hz, lH),3.00(s, 2H), 2.42 (s, 3H); ESI-MS (m/z) 495 (M-H).

115

Example 143

2,6-Difluoro-/V-(5 ’-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2’-methyl-[ 1,1 biphenyl]-4-yl)benzamide

To a solution of Example 55 (50 mg, 0.10 mmol, 1.0 eq) in methanol (5 mL), was added sodium borohydride (11 mg, 0.3 mmol, 3 eq) portion wise. The resulting solution was stirred at room température for lh. The solvent was removed under vacuum and the residue was taken in ethyl acetate (10 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO4) and filtered. The filtrate was concentrated under vacuum to afford 40 mg of the desired product as a white solid. *HNMR (400 MHz, CDClj) δ 7.74 (s, 1H, D₂O exchangeable), 7.70 (d, 8.5 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.46-7.43 (m,

H), 7.32 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1 H), 7.02 (t, J = 8.0 Hz, 2H), 3.72 (d, J = 12 Hz, 1H), 3.57 (d, J= M Hz, 1H), 3.48 (d, J= 17.0 Hz, 1H), 3.02 (d, J= 17.0 Hz, 1H), 2.29 (s, 3H), 1.23 (s, 3H); ESI-MS (m/z) 437 (MH)⁺.

Examples 144-146

The below examples were prepared by following a procedure similar to that described in Example 143 by using Example 54 to préparé Example 144, Example 76 to préparé Example 145 Example 77 to préparé Example 146.

Example No: IUPAC name	Structure	‘HNMR/ESI-MS (MH)⁺
Example 144: 2,6Difluoro-ZZ-fS-ÎS-fS(hydroxymethyl)-5methyl-4,5dihydroisoxazol-3-yl)- 2- methylphenyl)pyrazin-	l ^N/—T~O HO '	'HNMR (400 MHz, CDC1₃) δ 9.75 (s, 1 H), 8.70 (s, 1H, D₂O exchangeable), 8.35 (s, 1 H), 7.67 (s, 1 H), 7.63 (d,/=8.0½. 1H), 7.52-7.45 (m, 1H), 7.34 (d, J= 8.0 Hz, 1 H), 7.05 (t, J = 8.0 Hz, 2H), 3.75-3.71 (m, 1H), 3.61-3.50 (m,

116

Examplc No: IUPAC namc	Structure	’HNMR/ESI-MS (MH)⁺
2-yl)benzamide		1H), 3.50 (d, J= 17.0 Hz, 1H), 3.04 (d, J = 17.0 Hz, 1 H), 2.42 (s, 3H), 1.43 (s, 3H); ESI-MS (m/z) 439 (MH)⁺.
Example 145: 2,6- Difluoro-W-(5’-(5-(2hydroxyethyl)-5- (hydroxymethyl)-4,5dihydroisoxazol-3-yl)- 2*-methyl-[l,l’- biphenyl]-4yl)benzamide	λοΎΡ	’HNMR (400 MHz, DMSO-t/6) 6 10.92 (s, 1H, D2O exchangeable), 7.78 (d, J= 8.5 Hz, 2H), 7.65-7.53 (m, 2H), 7.43-7.35 (m, 4H), 7.27 (d, J = 8.0 Hz, 2H), 5.04 (t, J = 6.0 Hz, 1 H), 4.51 (t, J = 5.0 Hz, 1 H), 3.52 (dd, J = 6.5, 5.0 Hz, 2H), 3.42 (d, J= 6.0 Hz, 2H), 3.28 (s, 2H), 2.27 (s, 3H), 1.90-1.82 (m, 2H); ESI-MS (m/z) 467 (MH)⁺.
Example 146:W-(5-(5(5,5bis(hydroxymethyl)4,5-dihydroisoxazol-3yl)-2methylphenyl )pyrazîn2-yl)-2,6difluorobenzamide	xxvpp A /~rc> OH OH	’HNMR (400 MHz, DMSO-î/6) δ 11.80 (s, 1 H, D2O exchangeable), 9.51 (s, 1H), 8.69 (s, 1H), 7.73 (d, J= Ï.5 Hz, IH), 7.67 (dd,J=8.0, 1.5 Hz, 1H), 7.64-7.58 (m, 1H), 7.43 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 2H), 5.01 (t, J= 6.0 Hz, 1 H), 3.49 (dd, J =6.0, 1.0 Hz, 4H), 3.48 (s, 4H), 3.27 (s, 2H), 2.41 (s, 3H); ESI-MS (m/z) 469 (MH)⁺.

117

Example 147

7V-Cyclopropyl-3-(4’-(2,6-difluorobenzamido)-6-methyl-[l,l ’-biphenyl]-3-yl)-5-methyl-4,5dihydroisoxazole-5-carboxamide

To a solution of Example 139 (200 mg, 0.44 mmol, 1.0 eq), in acetonitrile (10 mL) was added thionyl chloride (0.3 mL, 4.4 mmol, 10 eq) and the resulting solution was refluxed for 2 h. The solvent and the excess of thionyl chloride was removed under vacuum and dried. The residue was dissolved in DCM (10 mL) cooled to 0 °C and cyclopropyl amine (30 pL, 0.44 mmol, 1.0 eq) and triethyl amine (0.6 mL, 3.52 mmol, 8 eq) were added sequentially. The resulting solution 10 was stirred at room température for 1 h. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (silica gel, 40% ethyl acetate in hexane) to afford 90 mg of the desired product as a white solid. ’HNMR (400 MHz, CDC1₃) δ 7.78 (s, IH, D₂O exchangeable), 7.71 (d, J = 8.5 Hz, 2H), 7.52 (dd, J= 8.0, 1.5 Hz, IH), 7.48 (d, J= 1.5 Hz, IH), 7.46-7.41 (m, IH), 7.33-7.29 (m, 3H), 7.02 (t, J = 8.0 Hz, 2H), 6.91 (d,J=3.0//z, IH, 15 D₂O exchangeable), 3.82 (d, J= 17.5 Hz, IH), 3.22 (d, J= 17.5 Hz, IH), 2.74-2.69 (m, IH), 2.30 (s, 3H), 1.69 (s, 3H), 0.89-0.74 (m, 2H), 0.54-0.50 (m, 2H); ESI-MS (m/z) 490 (MH)⁺.

Examples 148-153

The below Examples 148 to 153 were prepared by foliowing a procedure similar to that described in Example 147 by using Example 139 or Example 140 and appropriate amine.

Example No: IUPAC nanie	Structure	’HNMR/ESI-MS (MH)⁺
Example 148: 3-(4’(2,6difluorobenzamido)-6methyl-[ 1,1 ’-biphenyl]3-yl)-5-methyl-4,5dihydroisoxazole-5carboxamide	ΧΟ-Φ ⁰ / H/J	'HNMR (400 MHz, CDCI3) δ 7.76 (s, IH, D₂O exchangeable), 7.71 (d, J = 8.5 Hz, 2H), 7.53 (dd, J = 8.0, 1.5 Hz, IH), 7.48 (d,J= 1.5 Hz, IH), 7.46-7.41 (m, IH), 7.337.30 (m, 3H), 7.02 (t, J= 8.0 Hz, 2H), 6.82 (s, IH, D₂O exchangeable), 5.52 (s, 1 H, D₂O

118

		exchangeable), 3.84 (d, J- 17.0 Hz, 1 H), 3.24 (d, J = 17.0 Hz, 1 H), 2.30 (s, 3H), 1.74 (s, 3H); ESIMS (m/z) 450 (MH)⁺.
Example 149: 3-(3-(5(2,6Difluorobenzamido)pyr azin-2-yl)-4methylphenyl)-/V,5dimethyl-4,5dîhydroisoxazole-5 carboxamide	⁰ F VH HN ¹ \	'HNMR (400 MHz, CDC1₃) δ 9.76 (s, IH), 8.46 (s, IH, D₂O exchangeable), 8.39 (s, 1 H), 7.70 (d, J = 1.5 Hz, 1 H), 7.60 (dd, J = 8.0, 1.5 Hz, IH), 7.54-7.46 (m, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.06 (t, J= 8.0 Hz, 2H), 6.91-6.89 (m, 1 H, D₂O exchangeable), 3.85 (d, J = 17.0Hz, IH), 3.25 (d, J= 17.0 Hz, 1 H), 2.82 (d, J = 5.0 Hz, 3H), 2.43 (s, 3H), 1.72 (s, 3H); ESIMS (m/z) 466 (MH)⁺.
Example 150: 3-(4'(2,6Difluorobenzamido)-6methyl-[ 1,1 ’-biphenyl]3-yl)-N,jV,5-trimethyl4,5-dihydroisoxazole5-carboxamide	Ο Γ’ν y—h o —N ¹ X	'HNMR (400 MHz, CDCI3) δ 7.76 (s, IH, D₂O exchangeable), 7.70 (d, J = 8.5 Hz, 2H), 7.57 (dd, J = 8.0, 1.5 Hz, IH), 7.51 (d, J= 1.5 Hz, IH), 7.46-7.41 (m, IH), 7.33- 7.29 (m, 3H), 7.02 (t, J= 8.0 Hz, 2H), 4.34 (d, J = 17.0//z, IH), 3.29 (s, 3H), 3.14 (d, J = 17.0/fe, IH), 2.97 (s,3H), 2.30 (s, 3H), 1.69 (s, 3H); ESI-MS (m/z) 478 (MH)⁺.
Example 151 : N- Cyclopropyl-3-(3-(5(2,6difluorobenzamido)pyr azin-2-yl)-4-	kA? 0. y-+-o	'HNMR (400 MHz, CDCI3) δ 9.76 (s, IH), 8.52 (s, IH, D₂O exchangeable), 8.38 (s, 1 H), 7,69 (d,J= 1.5 Hz, IH), 7.60 (dd,J = 8.0, 1.5 Hz, IH), 7.54-7.46 (m,

119

inethylphenyl)-5methyl-4,5dihydroisoxazole-5carboxamide		IH), 7.36 (d,7 =8.0½ 1 H), 7.06 0,7 = 8.0 Hz, 2H), 6.91-6.89 (m, IH, D₂O exchangeable), 3.85 (d, J = 17.0½ 1 H), 3.24 (d, 7= 17.0 Hz, 1 H),2.74-2.70(m, IH), 2.43 (s, 3H), 1.70 (s, 3H), 0.81-0.75 (m, 2H), 0.55-0.52 (m, 2H); ESI-MS (m/z) 492 (MH)⁺.
Example 152: 2,6- Difluoro-7V-(2'-methyl5'-(5-methyl-5-(4methylpiperazine-1 carbonyl)-4,5dihydroisoxazol-3-yl)[l,l'-biphenyl]-4yl)benzamide	XoVp 0 /	’HNMR (400 MHz, CDClj) δ 7.91 (s, IH, D₂O exchangeable), 7.71 (d, 7= 8.5 Hz, 2H), 7.55 (dd, 7 = 8.0, 1.5½ IH), 7.51 (d,7= 1.5 Hz, IH), 7.46-7.41 (m, IH), 7.337.29 (m,3H), 7.02 0,7=8.0½ 2H), 4.42-4.35 (m, 2H), 4.20-4.17 (m, 1 H), 3.83-3.78 (m, IH), 3.533.48 (m, 1 H), 3.17-3.08 (m,3H), 2.85-2.80 (m, IH), 2.67-2.63 (m, IH), 2.57 (s, 3H), 2.31 (s, 3H), 1.69 (s, 3H); ESI-MS (m/z) 533 (MH)⁺.
Example 153: 2,6- Difluoro-/V-(5-(2methyl-5-(5-methyl-5(4-methylpiperazine-1 carbonyl)-4,5dihydroisoxazoi-3yl)phenyl)pyrazin-2yl)benzamide	ξ f 0 Γ / o O Γ	*HNMR (400 MHz, CDClj) δ 9.76 (s, 1 H), 8.55 (s, IH, D₂O exchangeable), 8.38 (s, IH), 7.72 (d, J = 1.5 Hz, 1 H), 7.65 (dd, 7 = 8.0, 1.5½ 1 H), 7.52-7.47 (m, 1 H), 7.36 (d, 7 = 8.0 Hz, 1 H), 7.06 0,7=8.0½ 2H), 4.41 (d,7 = 17.0½ 1 H), 4.08-4.04 (m, IH), 3.77-3.73 (m, 2H), 3.60-3.55 (m, IH), 3.15 (d, 7= 17.0½ IH), 2.49-2.43 (m, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 1.69 (s, 3H); ES1-

120

MS (m/z) 535 (MH)⁺.

Example 154

5-(2-Amino-2-oxoethyl)-3-(4’-(2,6-difluorobenzamido)-6-methyl-[l,l ’-biphenyl]-3-yl)-4,5 dihydroisoxazole-5-carboxamide

A solution of Example 76 (200 mg, 0.4 mmol, 1.0 eq), and aqueous ammonia (33%, 5 mL) in THF (5 mL) was stirred at room température for 12 h. The solvent was removed under vacuum and the crude residue was purified by préparative HPLC to afford 30 mg of the desired product as a white soiid. 'HNMR. (400 MHz, DMSO-c/6) δ 13.22 (s, 1H, D₂O exchangeable), 12.56 (s, 1H, D₂O exchangeable), 10.92 (s, 1H, D₂O exchangeable), 7.70 (d, J = 8.5 Hz, 2H), 7.54-7.50 (m, 2H), 7.42-7.33 (m, 2H), 7.19-7.14 (m, 2H), 3.70 (d, J = 17.5 Hz, 1H), 3.57 (d, J = 17.5 Hz, 1H), 2.86 (d, J = 15.0 Hz, 1H), 2.67 (d, J= 15.0 Hz, 1H), 2.23 (s, 3FI); ESI-MS (m/z) 493 (MH)⁺.

Example 155

3-(4’-(2,6-Dtfluorobenzamido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-/V-methyl-5-(2-(methylamino)-2oxoethyi)-4,5-dihydroîsoxazole-5-carboxamide

The title compound was prepared by foilowing a procedure similar to that described in Example 154 by using Example 76 and methylamine. 'HNMR (400 MHz, DMSO-î/6) δ 10.92 (s, 1H, D₂O exchangeable), 7.98 (q, J = 4.5 Hz, 1H, D₂O exchangeable), 7.84 (q, J = 4.5 Hz, 1H, D₂O exchangeable), 7.78 (d, J= 8.5 Hz, 2H), 7.63-7.58 (m, 1H), 7.57 (dd, J= 8.0, 1.5 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J =8.5 Hz, 2H), 7.27 (t, J =8.0 Hz, 2H), 3.84 (d, J = \Ί.5Ηζ, 1 H), 3.61 (d, J =

17.5 Hz, 1 H), 2.75 (d, J = 15.0 Hz, 1 H), 2.69 (d, J = 15.0 Hz, 1 H), 2.59 (d, J = 4.5 Hz, 3H), 2.52 (d, J= 4.5 Hz, 3H), 2.28 (s, 3H); ESI-MS (m/z) 521 (MH)⁺.

Examples 156-169

General procedure for the synthesis of compounds of the présent invention:

121

To a stirred solution of any one of boronate dérivatives of intermediates la, 2, 6, 7a, 9 or 11 (1.0 eq) in dioxane (10 mL), any one of halo intermediates of 53a, 54, 55, 56, 57 or 58 (1.0 eq), aq sodium carbonate solution (2M, 4 mL) and Pd(PPh3)₂Cl₂ (0.05 eq) were sequentially added. The 5 resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and then heated at 130 °C for 30 min in microwave (Biotage). The reaction mixture was cooled to room température and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane) to afford the desired product as a solid.

The below examples were prepared by following a procedure similar to that described in above mentîoned general procedure.

Example No: IUPACName	Structure	‘HNMR/ESI-MS (MH)⁺
Example 156: N-(2,6- Difluorophenyl)-5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)thiophe ne-2-carboxamide	F	'HNMR (400 MHz, CDC1₃) δ 8.20 (d, J= 1.5 Hz, IH), 8.05 (dd, J= 8.0, 1.5 Hz, IH), 7.72 (d, J =4.0 Hz, IH), 7.42 (d, J= 8.0Hz, IH), 7.33 (s, IH, D2O exchangeable), 7.28-7.22 (m, 1 H), 7.16 (d, J = 4.0 Hz, 1 H), 7.00 (t, J = 8.0 Hz, 2H), 2.51 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 441 (MH)⁺

122

Example 157:7V-(2,6Difluorophenyl)-5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2ethylphenyl)thiophen e-2-carboxamide		’HNMR (400 MHz, CDC1₃) δ 8.13 (d, J= 1.5 Hz, 1H), 8.09 (dd, J= 8.0, 1.5 Hz, 1H), 7.70 (d, J =3.5 Hz, IH), 7.43 (d, J= 8.0 Hz, 1H), 7.32 (s, 1H, D₂O exchangeable), 7.27-7.22 (m, 1H), 7.10 (d, 7= 3.5 Hz, 1 H), 7.00 (t, J= 8.0 Hz, 2H), 2.80 (q, J = 7.5 Hz, 2H), 1.47 (s, 6H), 1.21 (t, J = 7.5 Hz, 3H); ESIMS (m/z) 455 (MH)⁺
Example 158: 5-(5(5,5-Dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2-ethylphenyl)N-(3-methylpyridin- 4-yl)thiophene-2carboxamide	y?^{N 0}	’HNMR (400 MHz, CDC1₃) δ 8.48 (d, J =5.5 Hz, 1H), 8.43 (s, 1H), 8.25 (d, J = 5.5 Hz, 1 H), 8.15 (d, J = 1.5 Hz, 1 H), 8.12 (dd, 7= 8.0, 1.5 Hz, 1H), 7.71 (s, 1H,D₂O exchangeable), 7.68 (d, J= 4.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.14 (t, J =4.0 Hz, 1H), 2.82 (q, .7=7.5 Hz, 2H), 2.37 (s, 3H), 1.49 (s, 6H), 1.23 (t, 7= 7.5 7/z, 3H); ESI-MS (m/z) 434 (MH)⁺
Example 159: N-(2,6Di fluorophenyl)-5 -(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2fluorophenyl)thiophe ne-2-carboxamide	F F	’HNMR (400 MHz, CDC1₃) δ 8.51 (dd, J = 7.5, 5.0 Hz, 1 H), 8.15-8.11 (m, 1 H), 7.74 (d, J = 4.0 Hz, 1 H), 7.58 (d, 7 = 4.0½. 1H), 7.33 (s, 1H, D₂O exchangeable), 7.31-7.25 (m, 2H), 7.03 (t, J= 7.5 Hz, 2H), 1.52 (s, 6H); ESI-MS (m/z) 445 (MH)⁺

123

Example 160:/7-(2,6- Difluorophenyl)-5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2- methoxyphenyl)thiop hene-2-carboxamide	0- . « -	’HNMR (400 MHz, CDC1₃) δ 8.53 (s, IH), 8.13 (dd, J=9.0, 2.0 Hz, 1 H), 7.72 (d, 7 = 4.0 Hz, 1 H), 7.60 (d,7= 4.0Hz, IH), 7.36 (s, IH, D₂O exchangeable), 7.28-7.21 (m, 1 H), 7.11 (d, 7 = 9.0 Hz, 1 H), 7.03 (t, 7= 7.5 Hz, 2H), 4.05 (s, 3H), 1.50 (s, 6H); ESI-MS (m/z) 457 (MH)⁺
Example 161:77-(2,6- Difluorophenyl)-5-(3(5,5-dimethyl-4-oxo4,5-dihydroîsoxazol- 3-yl)-2inethyl phenyl)thiophe ne-2-carboxamîde		’HNMR (400 MHz, CDCI3) δ 7.70 (d, 7= 3.5 Hz, 1 H), 7.52 (t,7=7.5 Hz, 2H), 7.36 (t, 7= 7.5 Hz, IH), 7.32 (s, IH, D₂O exchangeable) 7.28-7.22 (m, 1 H), 7.08 (d, 7= 4.0 Hz, 1 H), 7.03 (t, 7= 8.0 Hz, 2H), 2.39 (s, 3H), 1.51 (s, 6H); ESI-MS (m/z) 441 (MH)⁺
Example 162: //-(2,6Difluorophenyl)-5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)-3methylthiophene-2carboxamide	9? Χό	’HNMR (400 MHz, CDCI3) δ 8.18 (d, 7 = 1.5 Hz, 1 H), 8.03 (dd, 7 = 8.0, 1.5 Hz, IH), 7.39 (d, 7= 8.0 Hz, IH), 7.26-7.21 (m, IH), 7.13 (s, IH, D₂O exchangeable), 7.03-6.98 (m, 3H), 2.63 (s, 3H), 2.51 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 455 (MH)⁺

124

Example 163:7/-(2,6- Difluorophenyl)-5-(3(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)phenyl)-3methylthiophene-2carboxamide		'HNMR (400 MHz, CDC1₃) δ 8.40 (t, J = 1.5 Hz, 1 H), 8.09 (d, J = 7.5 Hz, 1 H), 7.73 (d, J = 7.5 Hz, 1 H), 7.52 (t, J =7.5 Hz, 1 H), 7.26-7.20 (m, 2H),7.13(s, IH,D₂O exchangeable), 7.00 (t, J= 8.0 Hz, 2H), 2.62 (s, 3 H), 1.50 (s, 6H); ESI-MS (m/z) 441 (MH)⁺
Example 164:7/-(2,6D i fl uorophenyl )-4-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methoxyphenyl)thiop hene-2-carboxamide	O-N Îg Q F	'HNMR (400 MHz, CDC1₃) δ 8.27 (d, J =2.0 Hz, IH), 8.10 (dd, J= 9.0, 2.0 Hz, 1 H), 8.04 (d, J = 1.0 Hz, IH), 7.88 (d, J = 1.0 Hz, IH), 7.41 (s, IH, D₂O exchangeable), 7.26-7.21 (m, 1 H), 7.08 (d, J = 9.0 Hz, IH), 7.02 (t, J = 7.5 Hz, 2H), 3.96 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 457 (MH)⁺
Example 165:7/-(2,6- Difluorophenyl)-4-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)-3methylthîophene-2carboxamide	'b-N L/ï f	‘HNMR (400 MHz, CDC1₃) δ 8.05 (dd, J = 7.5, 1.5 Hz, 1 H), 7.90 (d, J = 1.5 Hz, IH), 7.39 (d, J = 8.0 Hz, IH), 7.26-7.20 (m, 2H), 7.19 (s, IH, D₂O exchangeable), 7.01 (t, J= 8.0 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 455 (MH)⁺

125

Example 166: N-(2,6- Difluorophenyl)-4-(3(5,5-dimethyi-4-oxo4,5-dihydroisoxazol- 3-yl)phenyl)-3methylthiophene-2carboxamide		‘HNMR (400 MHz, CDC1₃) δ 8.168.13 (m, 2H), 7.56 (td, J = 7.5, 1.0 Hz, 1 H), 7.49 (dt, J = 7.5, 1.0 Hz, IH), 7.41 (s, 1H), 7.27-7.22 (m, 1H), 7.21 (s, 1H, D₂O exchangeable), 7.03 (t, J= 8.0 Hz, 2H), 2.57 (s, 3H), 1.51 (s, 6H); ESI-MS (m/z) 441 (MH)⁺
Example 167: N-(2,6difluorophenyl)-5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol- 3-yl)-2methylphenyl)-!methyi-1 H-pyrrole-2carboxamide		'HNMR (400 MHz, CDCI3) Ô 8.09 (dd, J = 8.5, 2.0 Hz, 1 H), 8.01 (d, J = 2.0 Hz, 1H), 7.42 (d,J=8.5 Hz, 1 H), 7.26-7.19 (m, 2H), 7.02 (t, J = 7.5 Hz, 2H), 6.92 (d, J= 4.0 Hz, 1H), 6.18 (d, J =4.0 Hz, 1 H), 3.72 (s, 3H), 2.25 (s,3H), 1.47 (s, 6H); ESI-MS (m/z) 438 (MH)⁺
Example 168: N-(2,6di fl uorophenyl)- 5 - (5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2methoxyphenyl)-1 methyl-1 H-pyrrole-2carboxamide	0-	‘HNMR (400 MHz, CDCI3) δ 8.21 (dd, J = 8.5, 2.0 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1H), 7.27-7.18 (m, 2H), 7.08 (d, J= 8.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 2H), 6.92 (d, J= 4.0 Hz, 1H), 6.25 (d, J =4.0 Hz, 1 H), 3.91 (s, 3H), 3.77 (s,3H), 1.49 (s, 6H); ESI-MS (m/z) 453 (MH)⁴

126

Example 169:79-(2,6difluorophenyl)-5-(5(5,5-dimethyl-4-oxo4,5-dihydroisoxazol3-yl)-2-ethylphenyl)1 -methyl-1 H-pyrrole2-carboxamide

0, N-\J1 Γ tO ' W

’HNMR (400 MHz, CDC1₃) 6 8.13 (dd, J = 8.5, 2.0 Hz, 1 H), 7.99 (d, J = 2.0 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.88 (d, J = 1.0 Hz, 1 H), 7.307.19 (m, 2H), 7.03 (t, J= 7.5 Hz, 2H), 6.92 (d, 7=4.0 Hz, 1 H), 6.18 (d, 7 =4.0 Hz, 1 H), 3.70 (s, 3H), 2.56 (q, 7= 7.5 Hz, 2), 1.48 (s, 6H), 1.42 (t, 7=7.5 Hz, 3H); ESI-MS (m/z) 452 (MH)⁺

Examples 170-177

General procedure for the synthesis of compounds of the présent invention:

intermediate 15a, 18a-24a

intermediate 53b, 55b

Pd(PPh₃)₄

Dioxane

To a stirred solution of any one of bromo intermediate of 15a or 18a to 24a (1.0 eq) in dioxane (10 mL), any one of stananne dérivative of intermediate 53b or 55b (LO eq) and Pd(PPh₃)4 (0.05 eq) were sequentially added. The resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and then heated at 130 °C for 30 min in microwave (Biotage). The reaction mixture was cooled to room température and filtered through celite. The 10 filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate & hexane) to afford the desired product as a solid.

The below examples were prepared by following a procedure similar to that described in above mentioned general procedure.

127

Exemple No/ IUPAC nanie	Structure	‘HNMR/ESI-MS (MH)⁺
Example 170: 77-(2,6Difluorophenyl)-5-(2methyl-5-(4-methyl5-oxo-4,5-dihydrol,3,4-oxadiazol-2yl )phenyl) thîophene2-carboxamide		’HNMR (400 MHz, CDC1₃) δ 7.88 (d, J =2.0Hz, IH), 7.73 (dd,J = 8.0,2.0¾ IH), 7.70 (d, J =4.0 Hz, IH), 7.40 (d, J= 8.0 Hz, IH), 7.33 (s, IH, D2O exchangeable) 7.27-7.21 (m, IH), 7.13 (d, J =4.0 Hz, 1 H), 7.00 (t, J= 8.5 Hz, 2H), 3.49 (s, 3H), 2.50 (s, 3H); ESI-MS (m/z) 428 (MH)⁺
Example 171:N-(2,6- Difluorophenyl)-5-(2ethyl-5-(4-methyI-5oxo-4,5-dihydrol,3,4-oxadiazol-2yl )phenyl)thiophene2-carboxamide		’HNMR (400 MHz, CDCI3) δ 7.84 (d, J = 2.0 Hz, 1 H), 7.79 (dd, J = 8.0, 2.0 Hz, 1 H), 7.70 (d, J = 4.0 Hz, IH), 7.44 (d, J = 8.0 Hz, IH), 7.34 (s, 1 H, D₂O exchangeable) 7.27-7.23 (m, IH), 7.10 (d, J= 4.0 Hz, IH), 7.00 (t, J = 8.5 Hz, 2H), 3.50 (s, 3H), 2.81 (q, J =7.5 Hz, 2H), l .22 (t, J = 7.5 Hz, 3H); ESIMS (m/z) 442 (MH)⁺
Example 172:27-(2,6- Difluorophenyl)-5-(2fluoro-5-(4-methyl-5oxo-4,5-dihydrol,3,4-oxadîazol-2yl)phenyl)thiophene2-carboxamide	F	’HNMR (400 MHz, DMSO-r/6) δ 10.34 (s, IH, D₂O exchangeable), 8.18 (dd, J = 7.5, 2.0 Hz, 1 H), 8.08 (d, J = 4.0, Hz, IH), 7.87-7.83 (m, 2H), 7.60 (dd,J= 11.0, 8.5 Hz, 1 H), 7.46-7.40 (m, 1 H), 7.24 (t, J = 8.5 Hz, 2H), 3.43 (s, 3H); ESI-MS (m/z) 432 (MH)⁺

128

Exemple No/ IUPAC namc	Structure	'HNMR/ESI-MS (MH)⁺
Example 173: 5-(2(Difluoromethoxy)-5(4-methyl-5-oxo-4,5dihydro-1,3,4oxadiazoI-2yl)phenyl)-N-(2,6d i fl uorophenyl )thi oph ene-2-carboxamide	1	¹ HNMR (400 MHz, CDC1₃) δ 8.18 (d, J = 2.0 Hz, 1 H), 7.82 (dd, J = 8.5, 2.0 Hz, 1H), 7.71 (d, 7=4.0 Hz, 1 H), 7.54 (d, 7 = 4.0 Hz, 1 H), 7.38 (d, 7= 8.5 Hz, 1 H), 7.33 (s, 1H, D₂O exchangeable) 7.31-7.23 (m, 1H), 7.02 (t, 7= 8.5 Hz, 2H), 6.66 (t, 7= 73 Hz, 1 H), 3.53 (s, 3H); ESI-MS (m/z) 480 (MH)⁺
Example 174:7V-(2,6Difluorophenyl)-5-(2methoxy-5-(4-methyl5-oxo-4,5-dihydrol,3,4-oxadiazol-2yl)phenyl)-3methylthiophene-2carboxamide	\ 0 jîXî ° JrS 1	'HNMR (400 MHz, CDC1₃) δ 8.17 (d, J = 2.5 Hz, 1 H), 7.80 (dd, 7 = 8.5, 2.5 Hz, 1H), 7.44 (s, 1H), 7.257.22 (m, 1H), 7.18 (s, 1H, D₂O exchangeable), 7.10 (d, 7= 8.5 Hz, 1 H), 7.03 (t, 7 = 8.5 Hz, 2H), 4.06 (s, 3H), 3.53 (s,3H), 2.64 (s, 3H); ESI-MS (m/z) 458 (MH)⁺
Example 175: 5-(2- Chloro-5-(4-methyl5-oxo-4,5-dihydrol,3,4-oxadiazol-2yl)phenyl)-/V-(2,6difluorophenyl)thioph ene-2-carboxamide	a 1	'HNMR (400 MHz, CDCl₃) δ 8.04 (d, 7 = 2.0 Hz, 1 H), 7.77 (dd, 7 = 8.5, 2.0 Hz, 1H), 7.73 (d,7=3.5 Hz, 1 H), 7.63 (d, 7 = 8.5 Hz, 1 H), 7.45 (d, 7= 3.5 Hz, 1H), 7.34 (s, 1 H, D₂O exchangeable) 7.29-7.24 (m, 1 H), 7.03 (t, 7 = 8.5 Hz, 2H), 3.53 (s, 3H); ESI-MS (m/z) 448 (MH)⁺

129

Examplc No/ IUPAC namc	Structure	'HNMR/ESI-MS (MH)⁺
Example 176:7V-(2,6Difluorophenyl)-5-(2methyl-3-(4-methyl5-oxo-4,5-dihydrol,3,4-oxadiazol-2yl)phenyl)thiophene2-carboxamide		‘HNMR (400 MHz, CDC1₃) δ 7.84 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 4.0 Hz, 1 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.38 (t, J =7.5 Hz, 1H), 7.32 (s, 1H, D₂O exchangeable) 7.28-7.23 (m, 1H), 7.08 (d, J= 4.0 Hz, 1H), 7.03 (t, J =8.5 Hz, 2H), 3.56 (s, 3H), 2.62 (s, 3H); ESI-MS (m/z) 428 (MH)⁺
Example 177: //-(2,6difluorophenyl)-5-(2ethyl-3 -(4-methyl-5 oxo-4,5-dihydrol,3,4-oxadiazol-2y l)phenyl )th i ophene2-carboxamide		'HNMR (400 MHz, CDC1₃) δ 7.85 (dd, J = 8.0, 1.0 Hz, 1 H), 7.71 (d, J = 3.5 Hz, 1H), 7.50 (dd,J=8.0, 1.0 Hz, 1 H), 7.37 (d, J =8.0 Hz, 1H), 7.35 (s, 1 H, D₂O exchangeable), 7.31-7.25 (m, 1H), 7.08 (à, J =3.5 Hz, 1 H), 7.03 (t, J = 8.0 Hz, 2H), 3.54 (s, 3H), 3.06 (q, J =7.0 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H); ESIMS (m/z) 442 (MH)⁺

Biological assays and utility:

The CRAC channel modulatory activity of the compounds were thus evaluated by measuring the sécrétion of IL-2 by antigen stimulated T-celis in vitro. Altematively, such activity can also be 5 evaluated by assay methods known to one skilled in the art.

In vitro assay

Example-178

Inhibition of IL-2 sécrétion: Jurkat T cells were seeded at a density of 0.5 to 1 million cells per well in RPMI medium. Test compounds from this invention were added to the cells at different

130 concentrations. This was followed by the addition of PHA, a T cell mitogen after 10 minutes. The cells were then incubated for 20 to 24 hours in a CO₂ incubator at 37°C. After incubation with the compounds, cells were centrifuged, collected the supematant and processed for ELISA to quantitate the amount of IL-2 secreted. A commercial ELISA kit (R&D Systems, Inc. Minneapolis, MN, USA) was used to estimate the IL-2 concentrations. Amount of IL-2 secreted by cells stimulated with PHA was considered as a 100% maximal signal and the decrease in amount of IL-2 secreted by cells treated with the test compounds was expressed as percent inhibition of the maximal signal. The dose response data was analyzed using 4-parametric sigmoidal dose response (variable slope) curve - fit.

In the above IL-2 assay, compounds of the invention were found to hâve IC50 (nM) values as shown below:

IC₅o(nM)	Examples
<100 nM	3, 16, 19, 29, 33, 34,40,46, 80, 87, 93, 114, 135, 157, 158, 160, 171, 173, 176
100 nM - 1000 nM	4, 7, 8, 11, 18, 23,24,31, 113,53,58,61, 67, 78, 103, 107, 121, 126, 132, 136, 138,
> 1000 nM	10, 17, 69, 145

Thus, compounds of the invention are shown to inhîbit IL-2 sécrétion.

Example-179

SOCE inhibition: Jurkat E6.1 cells were seeded at a density of 1 - 2 x 10⁵ cells per well in calcium-4 dye prepared in calcium free HBSS (Sigma, USA). Test compounds from this invention were added to the cells at different concentrations. This was followed by the addition of thapsigargin (TG), a SERCA inhibitor, to empty the stores of calcium. Calcium chloride was added to the cells after 10-30 min to induce calcium influx and the fluorescence was measured for 10 min using the FLIPR-Tetra détection system. Fluorescence was also measured using a plate reader at 485nm excitation and 520nm émission (Synergy2, Biotek, USA) after 30 - 90 minutes of calcium addition. Fluorescence observed in cells treated with Thapsigargin and calcium chloride solution was considered 100% maximal signal and the reduced fluorescent

131 signal observed in the presence of test compounds was expressed as percent inhibition of the maximal signal. The dose response data was analyzed using 4-parametric sigmoidal dose response (variable slope) curve - fit.

In the above SOCE inhibition assay, compounds of the présent invention showed activity against SOCE as given below:

IC₅o(nM)	Examples
<1000 nM	15,41, 135,160, 176

Thus, compounds of the invention are shown to hâve CRAC channel modulation activity by inhibition of SOCE.

Example-180

NFAT Transcriptional Activity: HEK 293 cells were stably transfected with a NFAT-Luc reporter gene. 30,000 - 80,000 cells were seeded per well. Test compounds from this invention were added to the cells at different concentrations. Thapsigargin (TG) was added after 10 mins and the cells were incubated for 4 - 8 h. NFAT transcriptional activity was measured using BrightGlo reagent (Promega USA). Luminescence observed in cells treated with thapsigargin was considered 100% maximal signal and the reduced fluorescent signal observed in the presence of test compounds was expressed as percent inhibition of the maximal signal. The data was analyzed using 4-parametric sigmoidal dose response (variable slope) curve-fit.

In the above NFAT transcriptional activity assay, compounds of the présent invention showed activity as given below:

IC₅₀(nM)	Examples
<500 nM	29, 50, 135, 176

Thus, compounds of the invention are shown to inhibit NFAT transcription activity.

Thus, the in vitro screening assays showed that the compounds of invention inhibit CRAC channel activity.

132

Example-181

Effect of compounds of the présent invention on ovalbumin induced (Dclayed Type Hypersensitivity) DTH model:

Intradermal injections of émulsions containing Freund's complété adjuvant (FCA), heat killed Mycobacterium tuberculosis (4mg/ml) in complété Freund’s adjuvant and Ovalbumin (lOmg/ml) were given to female Lewis rats (n = 6 each group) on day 0 at the base of the tail. On day 7, Ovalbumin (20mg/ml) was injected into the right ear of the animais. 24 h post injection of Ovalbumin, ear swelling induced due to antigenic challenge was assessed using Vernier calipers. Animais were treated with either vehîcle or test compounds orally once a day from day 0 till day 8.

Compounds of the présent invention showed efficacy in suppressing ear swelling in the animais on antigenic challenge.

Example-182

Effect of compounds of the présent invention on Collagen Induced Arthritis (CIA):

Female Lewis rats (n = 6 each group) were given intradermal injections (at the base of the tail) of émulsions containing porcine Collagen-II (2mg/ml) and incomplète Freund’s adjuvant on day 0 and day 7. Animais were observed for disease progression from day 10 onwards till day 35. Disease was scored as: 0 - Normal, 1 - Swelling and erythema limited to one or two digits only, 2 - Swelling and erythema in more than two digits or erythema and mild swelling extending from ankle to the tarsals, 3 - Erythema and moderate swelling extending from ankles to the metatarsals, 4 - Erythema and severe swelling encompassing the ankles foot and digits and or ankylosis of the limb. Animais were dosed with either vehicle or test compounds orally once a day from day 0 till day 35.

Compounds of the présent invention were found to reduce arthritis in these animais.

As mentioned hereinbefore, the CRAC channel is involved with numerous biological responses through various Ca²⁺ signaling pathways. The compounds of the présent invention are therefore useful for the treatment and/or prophylaxis of, although not limited to, inflammatory conditions, cancer, rheumatoid arthritis, allergie disorders, immune disorders, cardiovascular diseases, thrombocytopathies and ail related conditions which can be benefitted by the CRAC channel modulatory properties of the compounds described herein. iv—

133

The compounds of the présent invention can be administered to a warm-blooded animal, including human being, for the treatment and/or prophylaxie of one or many diseases or disorders mentioned hereinabove which can be benefitted by the CRAC channel modulatory properties of the compounds described herein. The compounds may be formulated according to 5 the methods known in the art as well as by new methods and may be administered to the body System via gastro-intestinal tract as well as via other routes known to a person skilled in the art. Thus, administration of the compounds of the présent invention via oral route, parentéral route, inhalation and /or topical applications are within the scope of this application. Any combination of a compound of the présent invention with excipients and/or other therapeutic agents known in 10 the art for the said conditions, diseases and/or disorders are also encompassed by the présent invention.

Ail patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for ail purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.

Although certain embodiments and examples hâve been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and examples without departing from the teachings thereof. Ail such modifications are intended to be encompassed within the below daims of the invention. 4^—

9 avr 20131

67 53

134

Claims

1. A compound of Formula (I):

II) wherein, ring E is a 5-membered non aromatic heterocyclic ring selected from / and (b)

X, at each occurrence, is independently selected from -C(O)-, -CR4R5- and -NR-;

Y, at each occurrence, is independently selected from -C(O)- and -CR4R5-;

R is selected from alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)NR₆R₇, -C(O)OR6and -C(O)Rû;

ring W is selected from aryl, heteroaryl, cycloalkyl and.heterocyclyl;

Ri, which may be same or different at each occurrence, is independently selected from halo, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, -S(O)_nR₆, -NR₆S(O)₂R₇, -NR6(CR₈R9)_nC(O)OR₆, -NR₆(CR₈R₉)_nC(O)R₆, NR₆(CR₈R9)_nC(O)NR₆R₇, -C(O)NR₆R₇, -C(O)(O)R₆, -C(O)R₆, -OC(O)R₆, and -OC(O)NR₆R₇;

R₂, which may be same or different at each occurrence, is independently selected from hydrogen, halo, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, -C(O)ORô, -NRùR₇, -C(O)Rô, -NHS(O)₂R₇and -NHC(O)R₆;

R₃, which may be same or different at each occurrence, is independently selected from hydrogen, halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, -NR&R₇, -NRéS(O)₂R₇, C(O)NR₆R₇ and -C(O)OR₆;

R₄ and R5, which may be same or different at each occurrence, are independently selected from hydrogen, halo, -ORjo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -(CR₈R9)nC(O)NR6R₇, -C(O)Rfi, and -(CR₈R9)_nC(O)OR₆ ;

provided that, when any of R4 or R 5 in Y is -OR10 then Rio is not hydrogen; or

135

R4 and Rs, taken together with the carbon atom to which they are attached to, may form a substituted or unsubstituted 3- to 7- membered carbocyclic or heterocyclic ring; or any one of R4 and R5 in X and any one of R4 and R5 in Y combined together, when they are attached to carbon atoms, may form a 4- to 7- membered substituted or unsubstituted heterocyclic ring in order to give a bicyclic heterocyclic ring;

provided that both of X and Y are not simultaneously -C(O)-;

ring D is selected from

1 *7 whereinA and A are independently selected from C and N;

G is selected from S, NRt₂ and O;

L is -C(O)NR| 1- or -NR, ,C(O)-;

R] 1, at each occurrence, is independently selected from hydrogen, alkyl and aryl;

R]₂ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;

Riois selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;

Rô and R7, which may bc same or different at each occurrence, are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; or R/, and R7, taken together with the nitrogen atom to which they are attached to, may form a substituted or unsubstituted 3to 14- membered heterocyclic ring;

Rg and Ro, which may be same or different at each occurrence, are independently selected from hydrogen, halo, alkyl and alkoxy; or Rg and R9, taken together with the carbon atom they are attached to, may form a 3- to 6- membered cyclic ring wherein the cyclic ring may be carbocyclic or heterocyclic;

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

p is an integer ranging from 0 to 5, both inclusive;

q is an integer ranging from 1 to 4, both inclusive; and wherein alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, aryl, heteroaryl, heterocyclyl, wherever they occur may optionally be substituted with one or more substituents independently selected from hydroxy, halo, cyano, nitro, oxo (=O), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl,

136 cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(O)OR^X, -C(O)R^X, -C(S)R^X, -C(O)NR^xR^y, -NR^xC(O)NR^yR^z, -N(R^x)S(O)R^y, N(R^x)S(O)2R^y, -NR^xR^y, -NR^xC(O)R^y, -NR^xC(S)R^y, -NR^xC(S)NR^yR^z, -S(O)2NR^xR^y, -OR^X, OC(O)R^X, -OC(O)NR^xR^y, -R^xC(O)OR^y, -R^xC(O)NR^yR^z, -R^xC(O)R^y, -SR^X, and -S(O)₂R^X,· wherein each occurrence of R^x, R^y and R^z are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and heteroarylalkyl;

or a pharmaceutically acceptable sait thereof or streoisomers thereof.

2. The compound of claim 1 having the Formula (la):

or a pharmaceutically acceptable sait thereof;

wherein ring is selected from Formula (i) to (iv)

Rio ring W, ring D, R, R|, R₂, R3, R4, R5, Rjq, ‘p’ and ‘q’ are as defined claim 1.

3. The compound of claim 1 having the Formula (Ib):

or a pharmaceutically acceptable sait thereof;

wherein ring ^U'N is selected from Formula (i) to (iv) o

(li) (iii) ring W, ring D, R, R|, R₂, R3, R4, R5, Rio, ‘p’ and ‘q’ are as defined in claim 1.

4. The compound of claim 1 having the Formula (le):

137 <lc>

or a pharmaceutically acceptable sait thereof; r°p wherein ring N is selected from Formula (v) to (vii) O-? ^RHN'^N ^R5 . Λ H o^n'^N t R R N ^and > r; (V) (vi) (vü)

5 ring W, ring D, R, R_h R2, R3, R₄, R₅, ‘p’ and ‘q’ are as defined in claim 1.

5. The compound of claim 1 having the Formula (Id):

(Id) or a pharmaceutically acceptable sait thereof;

v ^ff wherein ring N is selected from Formula (v) to (vii)

o-T ^R<~An'^N ^R5 A p-Y o+z R O-? ^and R< ^Rs 10 (v) (vi) (vii)

ring W, ring D, R, Ri, R2, R3, R4, R5, ‘p’ and ‘q’ are as defined in claim 1.

6. The compound of claim 1, wherein ring E is non aromatic heterocyclic ring selected from (a) (b)

X, at each occurrence, is independently selected from -C(O)-, -CR4R5- and -NR-;

Y, at each occurrence, is independently selected from C(O) and -CR4R5-;

R is selected from alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl; —138

R4 and R.5, which may be same or different at each occurrence, are independently selected from hydrogen, halo, OR10, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -(CR8R9)_nC(O)NRûR7, -C(O)Râ, and -(CReR9)_nC(O)OR6 ; or

R4 and R5, taken together with the carbon atom to which they are attached to, may form a substituted or unsubstituted 3- to 7- membered carbocyclic or heterocyclic ring; or any one of R4 and R5 in X and any one of Ri and R5 in Y combined together, when they are attached to carbon atoms, may form a 4- to 7- membered substituted or unsubstituted heterocyclic ring in order to give a bicyclic heterocyclic ring.

7. The compound of claim 1, wherein ring D is

1 *5 wherein A and A are independently selected from C and N ;

G îs selected from S and NRi₂; R₃ is as defined in claim 1.

Rj₂ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl.

8. The compound of claim 1, wherein ring W is selected from aryl, heteroaryl and cycloalkyl.

9. The compound of claim 1, wherein L is -C(O)NRn- or -NRuC(O)-; where Rh is hydrogen or alkyl.

10. The compound of claim 1, wherein ring E is selected from:

ring W is aryl or heteroaryl;

R is alkyl; R₃ is hydrogen or alkyl;

Ri is halo or alkyl;

R4 and R5, which may be same or different at each occurrence, are independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -(CReRgÎnCtOjNRôR?, and (CR₈R9)nC(O)OR₆ ; ‘n’ is 0 or 1 ;

R4 and R5, taken together with the carbon atom to which they are attached to, may form a substituted or unsubstituted 3- to 7- membered carbocyclic or heterocyclic ring; or

139

L is -C(O)NRi j- or -NR],C(O)-;

Rj i is selected from hydrogen or alkyl;

ring D and R₂ are as defined in claim 1.

11. The compound of claim 1, which is selected from:

7V-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-

2,6-difluorobenzamide,

7V-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-4methyl-l,2,3-thiadiazole-5-carboxamide,

7V-(5’-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2’-methyl-[l,l ’-biphenyl]-4-yl-

2,6-difluorobenzamide,

7/-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyridin-2-yl)-

2,6-difluorobenzamide,

7V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)pyrazin-2-yl)-2,6difluorobenzamide, ?/-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-ethyl-[ 1,1 '-biphenyl]-4-yl)-2,6difluorobenzamide,

2V-(6-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)pyridin-3-yl)-2,6difluorobenzamide,

7V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-isopropylphenyl)pyrazin-2-yl)-

2,6-difluorobenzamide,

7V-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2^,-isopropyl-[ 1,1 '-biphenyl]-4-yl)-

2,6-difluorobenzamide, ?/-(2'-(tert-butyl)-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 ’-biphenyl]-4-yl)-

2,6-difluorobenzamide,

7V-(2'-chloro-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[l,r-biphenyl]-4-yl)-2,6di fl uorobenzamide,

7/-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-fluorophenyl)pyrazin-2-yl)-2,6difluorobenzamide,

7V-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-fluoro-[ 1,1 '-biphenyl]-4-yl)-2,6difluorobenzamide, ---140

77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)-

2.6- difIuorobenzamide,

77-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methoxy-[ 1,1 ’-biphenyl]-4-yl)-

2.6- difluorobenzamide,

77-(5'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methoxy-[ 1,1 ’-biphenyl ]-4-y l)-4methyl-1,2,3-thiadiazole-5-carboxamide,

77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyridin-2-yl)-

2,6-difluorobenzamide,

77-(6-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyridin-3-yl)-

2,6-difluorobenzamide,

77-(2^,-acetamido-5’-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 ’-bi phenyl]-4-y I )-

2,6-difluorobenzamide,

77-(5-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyI)pyrazin-2-yl)-2,6d i fi uorob enzamîde,

77-(6-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyridin-3-yl)-2,6difluorobenzamide,

77-(3'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 '-biphenyl]-4-yl)-2,6difluorobenzamide,

2.6- difluoro-77-(5-(5-(4-methoxy-5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-2- m ethyl phenyl )pyrazi n-2-yl )benzam ide,

2.6- Difluoro-N-(5'-(4-methoxy-5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-2'-methyl-[l,rbiphenyl]-4-yl)benzamide,

77-(4'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methyl-[ 1,1 '-biphenyl]-4-yl)-2,6difluorobenzamide,

77-(5-(4-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-

2,6-difluorobenzamide,

77-(5-(4-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyridin-2-yl)-

2,6-difluorobenzamide,

77-(5-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-

2,6-difluorobenzamide, ---141

A-(3'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2^,-methyl-[ 1,1 ’-bi phenyl ]-4-yl )-2,6 difluorobenzamide,

7V-(5-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyridin-2-yl)-

2,6-difluorobenzamide, jV-(3’-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methoxy-[ 1,1 '-bi phenyl]-4-yl)-

2.6- difluorobenzamide,

7V-(5-(5-(4-Acetyl-5,5-dimethyl-4,5-dihydro-l,3,4-oxadiazol-2-yl)-2-methylphenyl) pyrazin-2-yl)-2,6-difluorobenzamide,

2.6- Difluoro-A-(2^,-methyl-5’-(4-inethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1biphenyl]-4-yl)benzamide,

N-(5'-(4-Ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2'-methyl-[ 1,1 ’-biphenyIJ-4-yl)-

2.6- di fl uorobenzami de,

2.6- Difluoro-N-(2'-methyl-5'-(5-oxo-4-propyl-4,5-dihydro-l ,3,4-oxadiazol-2-yl)-[ 1,1'biphenyl]-4-yl)benzamide,

7V-(2'-Ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1 '-biphenyl]-4-yl)-

2,6-di fluorobenzamide,

2-Chloro-A-(2'-ethyl-5'-(4-mcthyl-5-oxo-4,5-dihydiO-1,3,4-oxadiazol-2-yl)-[ 1,1'biphenyl]-4-yl)-6-fluorobenzamide,

A-(2'-Ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1 '-bi phenyl ] -4-yl )2-fluoro-6-methylbenzamîde, /V-(2'-Ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1 ’-biphenyl]-4-yl)4-methyl-l,2,3-thiadiazole-5-carboxamide,

2.6- Difluoro-A-(2'-methoxy-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1'biphenyl]-4-yl)benzamide,

2-Chloro-6-fluoro-A-(2'-mcthoxy-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)[1,1 '-biphenyl]-4-yl)benzamide,

2-Fluoro-7V-(2'-methoxy-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yI)-[l,l'biphenyl]-4-yl)-6-methylbenzamide,

4-Ethyi-A-(2'-methoxy-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1'biphenyl]-4-yl)benzamide, —142

A-(2^,-(Difluoromethoxy)-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[ Ι,Γbiphenyl]-4-yl)-2,6-difluorobenzamide,

79-(2'-(Difluorornethoxy)-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1'biphenyl]-4-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide,

79-(2'-Chloro-5'-(4-methyl-5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2-yl)-[ 1,1 ’-bi phenyl]-4-yl)-

2,6-difluorobenzamide,

A-(2’-Chloro-5'-(4-mcthyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1 '-biphcnyl ] -4-yl )4-methyI-1,2,3-thiadiazole-5-carboxamide,

2.6- Difluoro-A-(2^,-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1’biphenyl]-4-yl)benzamide,

2-Chloro-6-fluoro-N-(2'-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)[1,1 '-biphenyl]-4-yl)benzamide,

4-Methyl-H-(2'-methyl-3^,-(4-methyl-5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2-yl)-[ 1, Γbiphenyl]-4-yl)-1,2,3-thiadiazole-5-carboxamide,

N-(2'-ethyl-3'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-biphenyl]-4-yl)-4methyl-l,2,3-thiadiazole-5-carboxamide,

A-(2'-ethyl-3’-(4-inethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[ 1,1 '-biphenyl]-4-yl)-

2,6-difluorobenzamide,

79-(5-(5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2,6difluorobenzamide,

Methyl 3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-methyl-4,5dihydroisoxazole-5-carboxylate,

Methyl-3-(4’-(2,6-difluorobenzmido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-5-methyl-4,5dihydroisoxazole-5-carboxylate,

2.6- DifIuoro-79-(2'-methyl-5'-( 1 -oxa-2-azaspiro[4.4]non-2-en-3-yl)-[ 1,1 ’-biphenyl]-4yl)benzamide,

2.6- DifluoiO-7V-(5-(2-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)phenyl)pyrazin-2yl)benzamide,

2.6- Difluoro-79-(2'-methyl-5'-(4-oxo-1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl)-[ 1,1 ’-biphenyl]-

4-yl)benzamide, ---143

77-(5-(5-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-methylphenyl)pyrazine-2-yl)-2,6difluorobenzamide,

77-(5-(5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2-methylphenyl)pyridin-2-yl)-2,6difluorobenzamide,

77-(5’-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2’-methyl-[ 1,1 ’-biphenyl]-4-yl)-2,6difluorobenzamide,

2,6-Difluoro-77-(2'-methyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[ 1,1'biphenyl]-4-yl)benzamide,

4-Methyl-7V-(2'-methyl-5'-(4-methyl-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-[l,rbiphenyl]-4-yl)-l,2,3-thiadiazole-5-carboxamide,

Ethyl 3-(4'-(2,6-difluorobenzamido)-6-methyl-[ 1,1 '-biphenyl]-3-yl)-4,4-dimethyl-4,5dihydroisoxazole-5-carboxylate,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazo!-3-yl)-2-methylphenyl)pyrazine-2-yl)2-fl uorob enzamide,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-

2.4- difluorobenzamide,

2.5- difluorobenzamide,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)2,3 -di fluorobenzam ide,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)4-fluorobenzamîde,

2.4.5- trifluorobenzamide,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)2,3-dimethylbenzamide,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)4-trifluoromethylbenzamide,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)4-fluoro-3-methylbenzamide, vv-—

144

2- methylbenzamide,

77-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yi)-2-methylphenyl)pyrazine-2-yl)-

3- fluoro-5-trifluoromethylbenzamide,

Methyl-3-(4’-(2,6-difluorobenzmido)-6-methyl-[l,r-biphenyl]-3-yl)-5-(2-methoxy-2oxoethyl)-4,5-dihydroisoxazole-5-carboxylate,

Methyl 3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-(2-methoxy-2oxoethyI)-4,5-dihydroisoxazole-5-carboxylate,

2.6- Difluoro-N-(5-(2-methyl-5-(4-oxo-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3- yl) phenyl)pyrazin-2-yl)benzamide,

2-Chloro-77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylphenyl)pyrazin-2-yl)benzamide,

77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2fluoro-6-(trifluoromethyl)benzamide,

2-Chloro-77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl) pyrazin-2-yl) -6-fluorobenzamide,

77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2methoxybenzamide,

77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)cyclohexanecarboxamide,

77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)cyclopentanecarboxamide,

77-(5-(2-(/er/-butyl)-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2yl)-2,6-difluorobenzamide,

77-(5-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)-

2.6- difIuorobenzamide,

77-(5-(2-chloro-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)-

2.6- difluorobenzamide,

2.6- Difluoro-77-(5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2- yl)phenyl)pyrazin-2-yl)benzamide,

145

N-(5-(5-(4-Ethyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-2-methyIphenyl)pyrazin-2-yl)-

2,6-difluorobenzamide,

2.6- Difluoro-N-(5-(2-methyl-5-(5-oxo-4-propyl-4,5-dihydro-l,3,4-oxadiazol-2- yl)phenyl) pyrazin-2-yl)benzamide,

7/-(5-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)pyrazin-2-yl)-

2.6- difluorobenzamide,

2-Chloro-7/-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2-yl)phenyl) pyrazin-2-yl)-6-fluorobenzamide,

7/-(5-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2-yl)phenyl)pyrazin-2-yl)2-fluoro-6-methylbenzamide,

2.6- Difluoro-7/-(5-(2-methoxy-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2- yl ) phenyl)pyrazi n-2-y 1 )b enzam ide,

2.6- Difluoro-7/-(5-(2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2- yl)phenyl)pyrazin-2-yl)benzamide, jⁱV-(5-(2-(diiluoromethoxy)-5-(4-inethyl-5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2yl)phenyl)pyrazin-2-yl)-2,6-difluorobenzamide,

N-(5-(2-ethyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)pyrazin-2-yl)-

2.6- di fl uorobenzani id e,

7/-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methyiphenyl)pyrazin-2yl)picolinamide,

7/-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)nicotinamide,

7/-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)isonicotinamide,

7/-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2methylnicotinamide,

6-Chloro-7/-(5-(5-(5,5-dimethyl-4-oxo-4,5-dîhydroisoxazol-3-yl)-2- methylphenyl)pyrazin-2-yl)nicotinamide,

6-Chloro-7/-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazoI-3-yl)-2methylphenyl)pyrazin-2-yl)isonicotinamide, ------146

3,5-Dichloro-7V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2- methylphenyl)pyrazîn-2-yl)isonicotinamide,

4- Chloro-7V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2- methylphenyl)pyrazin-2-yl)nicotinamide, jV-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-6m ethyl nicotin amide,

5- Chloro-7V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2- methylphenyl)pyrazin-2-yl)nicotinamide,

7V-(5-(5-(5,5-dimethyi-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-3fluoroisonicotinamide, /7-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-5fluoronicotinamide, /7-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2fluoronicotinamide,

2-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methyiphenyl)pyrazin-2-yl)isonicotinamide,

2-Chloro-/7-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylphenyl)pyrazin-2-yl)-6-methylisonicotinamide, /7-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2fluoroisonicotinamide,

7V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2methylnicotinamide,

77-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-

3,5-difluoroisonicotinamide, /7-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methyIphenyl)pyrazin-2-yl)-3methylisonicotinamide, /7-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)-

3,5-difluoroisonicotinamide, /V-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yi)phenyl)pyrazin-2-yl)-

3,5-difluoroisonicotinamide, -147

3.5- Difluoro-7V-(5-(2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2- yl)phenyl)pyrazin-2-yl)isonicotinamide,

N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)benzofuran-2-carboxamide,

2.6- Difluoro-A-(5-(2-methyl-5-(4-oxo-l-oxa-2-azaspiro[4.5]dœ-2-cn-3- yl )phenyl)pyrazi n-2 - yl )benzam i de,

N-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylphenyl)pyrazine-2-carboxamide,

4-(2,6-Difluorobenzamido)-3'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ I, Γbiphenyl]-2-carboxylic acid,

JV-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-y])-2'-hydroxy-[ 1,1 ’-b iphenyl ] -4-yl ) -

2,6-difluorobenzamide, ^-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-hydroxyphenyl)pyrazin-2-yl)-

2,6-difluorobenzamide,

V-(5^,-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-isopropoxy-[ 1,1 ’-biphenyl]-4-yl)-

2,6-difluorobenzamide,

A/-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-isopropoxyphenyl)pyrazin-2yl)-2,6-difluorobenzamide, /V-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-isobutoxy-[ 1,1 '-bi pheny 1 ] -4-y I )-

2,6-difluorobenzamide, /V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-isobutoxyphenyl)pyrazin-2-yl)-

2,6-difluorobenzamide,

7V-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-ethoxy-[ 1,1 ’-biphenyl]-4-yl)-2,6difluorobenzamide,

7V-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yI)-2-ethoxyphenyl)pyrazin-2-yl)-

2,6-difluorobenzamide,

7V-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2’-propoxy-[ 1,1 ’-biphenylj-4-yl)-

2,6-difluorobenzamide,

V-(2'-(allyloxy)-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 '-biphenyl]-4-yl)-

2,6-difluorobenzamide,

148

7V-(2'-(cyclopentyloxy)-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 ’-b i phenyl] 4-yl)-2,6-difluorobenzamide, yV-(2'-amino-5^,-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[ 1,1 '-biphenyl]-4-yl)-2,6difluorobenzamide,

7V-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-(methylamino)-[ 1,1 '-biphenyl]-4yl)-2,6-difluorobenzamide, jV-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2*-(dimethylamino)-[l,r-biphenyl]4-yl)-2,6-difluorobenzamide, (7ï/5)-77-(5-(5-(5,5-Dimethyl-4-hydroxy-4,5-dihydroisoxazol-3-yl)-2-methylphenyl) pyrazine-2-yl)-2,6-difluorobenzamide,

77-(5-(2-Methyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)pyrazin2yl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide

3-(4’-(2.6-Difluorobenzamido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-5-methyl-4,5dihydroisoxazole-5-carboxylic acid,

3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-methyl-4,5dihydroisoxazole-5-carboxylic acid,

5-Carboxymethyl-3-(4’-(2,6-difluorobenzmido)-6-methyl-[ l, 1 ’-biphenyl]-3-yl)-4,5dihydroisoxazoie-5-carboxylic acid,

5-(Carboxymethyl)-3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-4,5dihydroisoxazole-5-carboxylic acid,

2.6- Difluoro-//-(5’-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2’-inethyl[1,1 ’-biphenyl]-4-yl)benzamide,

2.6- Difluoro-7V-(5-(5-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2methylphenyl)pyrazin-2-yl)benzamide,

2.6- Difluoro-jV-(5’-(5-(2-hydroxyethyl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2’methyl-[ 1,1 ’-biphenyl]-4-yl)benzamide,

77-(5-(5-(5,5-bis(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2yl)-2,6-difluorobenzamide,

7V-Cyclopropyl-3-(4’-(2,6-difluorobenzamido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-5-methyl-

4,5-dihydroisoxazoie-5-carboxamide,

149

3-(4’-(2,6-difluorobenzamido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-5-methyl-4,5dihydroisoxazole-5-carboxamide,

3-(3-(5-(2,6-Difluorobenzamido)pyrazin-2-yi)-4-methylphenyl)-7V,5-dimethyl-4,5dihydroisoxazoie-5-carboxamide,

3-(4-(2,6-Difluorobenzamido)-6-methyl-[ 1,1 ’-biphenyl]-3-yl)-M 7V,5-trimethyl-4,5dihydroisoxazole-5-carboxamide

7V-Cyclopropyl-3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-methyl-

4,5-dihydroisoxazole-5-carboxamide,

2.6- Difluoro-7V-(2^,-methyl-5'-(5-methyl-5-(4-methylpiperazine-l-carbonyl)-4,5dihydroisoxazol-3-yl)-[ 1,1 '-biphenyl]-4-yl)benzamide,

2.6- Difluoro-jV-(5-(2-methyi-5-(5-methyl-5-(4-methylpiperazine-l-carbonyl)-4,5- dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)benzamide,

5-(2-Amino-2-oxoethyI)-3-(4’-(2,6-difluorobenzamido)-6-methyl-[ 1,1 ’-biphenyi]-3-yl)-

4,5-dihydroisoxazole-5-carboxamide,

3-(4’-(2,6-difluorobenzamido)-6-methyl-[l, 1 ’-biphenyl]-3-yl)-V-mcthyl-5-(2(methylamino)-2-oxoethyl)-4,5-dihydroisoxazole-5-carboxamide,

V-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylphenyl)thiophene-2-carboxamide,

JV-(2,6-Difluorophenyl)-5-(5-(5,5-dîmethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2ethylphenyl)thiophene-2-carboxamide,

5-(5-(5,5-Dirnethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)-N-(3-methylpyridin-

4-yl)thiophene-2-carboxamide,

AL(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2fl uoroph en yl)thiophen e-2- carboxam id e,

7V-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methoxyphenyl)thiophene-2-carboxamide,

AL(2,6-Difluorophenyl)-5-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylphenyl)thiophene-2-carboxamide,

7V-(2,6-Difluorophenyi )-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylpbenyl)-3-methylthiophene-2-carboxamide, u ____

150 /V-(2,6-Difluorophenyl)-5-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phcnyl)-3methylthiophene-2-carboxamide,

77-(2,6-Difluorophenyl)-4-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methoxyphenyl)thiophene-2-carboxamide,

77-(2,6-Difluorophenyl)-4-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methylphenyl)-3-methylthiophene-2-carboxamide,

77-(2,6-Difluorophenyl)-4-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)-3methylthiophene-2-carboxamide,

77-(2,6-difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methyiphenyl)-1 -methyl-1 H-pyrrole-2-carboxamide,

77-(2,6-difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2methoxyphenyl)-1 -methyl-1 H-pyrrole-2-carboxamide,

77-(2,6-difluorophenyl)-5-(5-(5,5-dîmethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2ethylphenyl)-1 -methyl-1 H-pyrrole-2-carboxamide,

77-(2,6-Difluorophenyl)-5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2yl)phenyl)thiophene-2-carboxamide,

N-(2,6-Difluorophenyl)-5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2yl)phenyl)thiophene-2-carboxamide,

77-(2,6-Difluorophenyl)-5-(2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2yl)phenyl)thiophene-2-carboxamide,

5-(2-(Difluoromethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)-N(2,6-difluorophenyl)thiophene-2-carboxamide,

77-(2,6-Difluorophenyl)-5-(2-methoxy-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2yl)phenyl)-3-methylthiophene-2-carboxamide,

5-(2-Chloro-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)-77-(2,6difluorophenyl)thiophene-2-carboxamide, /7-(2,6-Difluorophenyl)-5-(2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2yl )phenyl )th iophen e-2-carboxamide and /7-(2,6-difluorophenyl)-5-(2-ethyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2yl)phenyl)thiophene-2-carboxamide or pharmaceutically acceptable sait thereof.

151

12. A pharmaceutical composition comprising one or more compounds of Formula (I) according to claim 1, and one or more pharmaceutically acceptable excipients.

13. Use of of a compound of claim 1 or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for treating, preventing, managing and/or lessening diseases or disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel in a subject in need thereof.

14. The use of claim 13, wherein the diseases, disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel are selected from the group consisting of inflammatory diseases, autoimmune diseases, allergie disorders, organ transplant, cancer and cardiovascular disorders.

15. The use of claim 13, wherein the disease is rheumatoid arthritis, multiple sclerosis and psoriasis.

16. The use of claim 13, wherein the disease is allergie disorders selected from asthma, chronic obstructive pulmonary disorder (COPD) or respiratory disorders.

17. The use of claim 14, wherein inflammatory diseases are selected from rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases, pancreatitis, peripheral neuropathy, multiple sclerosis (MS) and inflammation associated with cancer.

18. A process for the préparation of a compound of Formula (I):

comprising reacting a compound of Formula (1 ) with a compound of Formula (2) wherein X' is halo;

ring E is a 5-membered non aromatic heterocyclic ring selected from

152 and (b)

X, at each occurrence, is independently selected from -C(O)-, -CR4R5- and -NR-;

Y, at each occurrence, is independently selected from C(O) and -CR4R5-;

R is selected from alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, C(O)NR₆R₇, -C(O)OR₆and -C(O)R₆;

ring W is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl;

Ri, which may be same or different at each occurrence, is independently selected from halo, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, -S(O)_nR₆, -NR₆S(O)₂R₇, -NRé(CR8R₉)_nC(O)0R₆, -NR₆(CR₈R₉)_nC(O)R₆, NR₆(CR₈R₉)_nC(O)NR₆R₇, -C(O)NR₆R₇, -C(O)(O)R₆, -C(O)R₆, -OC(O)R₆, and -OC(O)NR₆R₇;

R₂, which may be same or different at each occurrence, is independently selected from hydrogen, halo, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, -C(O)ORô, -NRôR₇, -C(O)Rû, -NHS(O)₂R₇and -NHC(O)R₆;

Rj, which may be same or different at each occurrence, is independently selected from hydrogen, halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, -NR(,R₇, -NR6S(O)₂R₇, C(O)NR6R₇ and -C(O)0R₆;

R4 and R5, which may be same or different at each occurrence, are independently selected from hydrogen, halo, OR10, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -(CR₈R₉)nC(O)NR₆R₇, -C(O)R_f) , and -(CR₈R₉)nC(O)ORs ; or when any of R4 or R5 in Y is OR10 then Rio is not hydrogen;

R4 and R5, taken together with the carbon atom to which they are attached to, may form a substituted or unsubstituted 3- to 7- membered carbocyclic or heterocyclic ring; or any one of R4 and R5 in X and any one of R4 and R5 in Y combined together, when they are attached to carbon atoms, may form a 4- to 7- membered substituted or unsubstituted heterocyclic ring in order to give a bicyclic heterocyclic ring;

provided that both of X and Y are not simultaneously -C(O)-;

ring D is selected from —

153 wherein A¹ and A² are independently selected from C and N;

G is selected from S, NRi₂ and O; L is -C(O)NR| i- or-NR| iC(O)-;

Ru, at each occurrence, is independently selected from hydrogen, alkyl and aryl;

Rio is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;

Ré and R7, which may be same or different at each occurrence, are independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; or Ré and R7, taken together with the nitrogen atom to which they are attached to, may form a substituted or unsubstituted 3to 14- membered heterocyclic ring;

R₈ and Rç>, which may be same or different at each occurrence, are independently selected from hydrogen, halo, alkyl and alkoxy; or R« and Rq, taken together with the carbon atom they are attached to, may form a 3- to 6- membered cyclic ring wherein the cyclic ring may be carbocyclic or heterocyclic;

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

p is an integer ranging from 0 to 5, both inclusive; and q is an integer ranging from 1 to 4, both inclusive;

in presence of a catalyst selected from Pd(PPh₃)₂Cl₂, Pd₂dba₃, Pd(PPh₃)4 or Pd(OAc)₂ or a mixture thereof; a ligand selected from BINAP, xanthophos or triphenylphosphine or a mixture thereof and a base, -u-— On ... „ «