OXAZOLE AND I SOXAZOLE CRAC MODULATORS
Related applications
The present application claims the benefit of priority to Indian Provisional Patent Application
Nos. 1215/KOL/2010, filed on October 30, 2010 and 0473/KOL/201 1, filed on April 1,
201 . The entire provisional specifications 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, prevention, 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 preparation 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 role in many diseases not only of the immune cells such as allergy, asthma,
arthritis, dermatitis, multiple sclerosis, systemic lupus but also organ transplant, diabetes,
cardiovascular disease, Alzheimer's disease, Parkinson's disease, inflammatory and/or
irritable bowel syndrome (Di Sabatino et. ah, 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, IL-28, IFN-g, TNF-a, etc., that have been implicated in
playing a role 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 signals have been shown to be essential for diverse cellular functions in different cell
types including differentiation, 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 be necessary for complete and
long-lasting 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-g (PLC-g) . PLC-g hydrolyzes
phosphatidylinositol-3,4-biphosphate (PIP2) to the second messengers, inositol- 1,4,5-
triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to IP3 receptors (IP3R) in the
membrane of the endoplasmic reticulum (ER) and induces the release of ER Ca stores into
4-9 • • the cytoplasma. The decrease in the Ca concentration in the ER induces store-operated
Ca+2 entry (SOCE) through plasma membrane Ca+2 channels. SOCE through highly Ca+2-
selective Ca+2 release-activated Ca+2 (hereinafter, CRAC) channels constitutes the major
4-9 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).
4-9 The CRAC channel is comprised of two family proteins, one which functions in sensing Ca
levels in the ER - the stromal interacting molecules (STIM)-l 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. Depletion of Ca+2 from the ER causes Ca+2 to
dissociate from STIM, which causes a conformational change that promotes oligomerization
and migration of STIM molecules to closely apposed 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 depletion of Ca from the stores,
they aggregate in the vicinity of the STIM punctae. The eventual increase in intracellular
Ca+2 concentration activates the calcineurin-NFAT pathway. NFAT activates transcription of
several genes including cytokine genes such as IL-2, etc along with other transcription
factors such as AP-1, NFKB and Foxp3 (Fahmer et. al., Immuno. Rev., 231, 99-1 12, 2009).
The role 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 STIMl 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 STIMl 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 role of STIMl and Orail in collagen dependent arterial
thrombosis in mice in vivo and that deficiency in either protects against collagen dependent
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 role of STIMl -
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 have 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
secretion of the cytokines involved in, as mentioned hereinbefore, inflammatory conditions,
cancer, allergic 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 have been reported in the art as CRAC channel modulators. For example,
patent application publications WO2005009954, WO2006081391, WO2006083477,
WO2007089904, WO2009017819, WO2010039238, WO2007087429, WO2007087441 and
WO2007087442 disclose substituted biaryl compounds for modulating CRAC channels.
Patent application publications WO2009076454, WO2010027875 and WO2006081389
WO2005009539, WO2005009954, WO2006034402, WO2009035818, US20 100 152241,
WO2010025295, WO201 1034962 disclose thiophene derivatives for modulating CRAC
channels.
Summary of the Invention
In accordance with one aspect, the invention provides the compounds of Formula (I):
wherein,
ring E is a 5-membered non aromatic heterocyclic ring selected from
(a) (b)
X, at each occurrence, is independently selected from -C(O)-, -CR-jRs- and -NR-;
Y, at each occurrence, is independently selected from -C(O)- and -CR R -;
R is selected from alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, -
C(0)NR<,R7, -C(0)OR6and -C(0 ) ;
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(0 )nR6, -NR6S(0) 2R , -NR (CR8R9)nC(0)OR , -N¾ 9), O)¾ , -
NR (CR8R9)nC(0)NR6R , -C(0)NR6R , -C(0)(0 )R6, -C(0)R6, -OC(0)R6, and -
OC(0)NR R ;
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(0)OR6, -NRsR , -C(0)R6, -NHS(0) 2R7
R3, which may be same or different at each occurrence, is independently selected from
hydrogen, halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, -NR R7, -NR6S(0) R , -
C(0)NR 6R7 and -C(0)0¾;
R4 and R5, which may be same or different at each occurrence, are independently selected
from hydrogen, halo, -ORj0, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, -(CR8R9)nC(0 )NR6R7, -C(0)R6 , and -(CR8R )nC(0 )OR6 ;
provided that, when any of or R in Y is -ORio then Ri0 is not hydrogen; or
R4 and R , 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 4 and R5 in X and any one of R4 and R 5 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 simultaneously -C(O)-;
ring D is selected from
wherein A1 and A2 are independently selected from C and N;
L is -C(0)NRu- or -NRnC(O)-;
G is selected from S, NRi2 and O;
Rii, at each occurrence, is independently selected from hydrogen, alkyl and aryl;
Ri2 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
Rio is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
, and R7, which may be same or different at each occurrence, are independently selected
from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; or and R , taken
together with the nitrogen atom to which they are attached to, may form a substituted or
unsubstituted 3- to 14- membered heterocyclic ring;
R and R9, which may be same or different at each occurrence, are independently selected
from hydrogen, halo, alkyl and alkoxy; or R 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 (=0), thio (=S), alkyl, haloalkyl, alkenyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic
ring, heterocyclylalkyl, heteroarylalkyl, -C(0)OR , -C(0)R x, -C(S)RX, -C(0)NR xR , -
NRxC(0)NR yRz, -N(Rx)S(0)R y, -N(Rx)S(0) 2Ry, -NR R , -NRxC(0)R , -NRxC(S)Ry, -
NRxC(S)NR R , -S(0) 2NRxR , -ORx, -OC(0)R x, -OC(0)NR xRy, -RxC(0)OR y, -
R C(0)NR R , -RxC(0)R , -SRX, and -S(0) 2Rx wherein each occurrence of Rx, R and R
are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and
heteroarylalkyl;
or a pharmaceutically acceptable salt 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 salt thereof;
wherein
ring selected from Formula (i) to (iv)
(i) (ii) (iii) v)
ring W, ring D, R, Ri, R2, R3, R , R , R10, 'p' and 'q' are as defined herein above.
According to another embodiment are provided compounds of Formula (lb):
or a pharmaceutically acceptable salt thereof;
wherein
ring ~N is selected from Formula (i) to (iv) as defined in Formula (la);
ring W, ring D, R, Rj, R2, R3, R4, R5, Rio, 'p' and 'q' are as defined herein above.
According to another embodiment are provided compounds of Formula (Ic):
or a pharmaceutically acceptable salt thereof;
wherein ring is selected from Formula (v) to (vii)
(v) (vi) (vii)
ring W, ring D, R, R , R2, R3, R , R5, 'p' and 'q' are as defined herein above.
According to another embodiment are provided compounds of Formula (Id):
or a pharmaceutically acceptable salt thereof;
wherein ring is selected from Formula (v) to (vii) as defined in Formula (Ic);
ring W, ring D, R, Ri, R2, R3, R4, R5, 'p' and 'q' are as defined herein above.
It should be understood that Formula (I), (la), (lb), (Ic), and (Id) structurally encompass all
N-oxides, 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), (lb), (Ic) and/or (Id)
in which ring D is
wherein A1 and A2 are independently selected from C and N; G is S or NRi2; 'q' is 1;
R3 and i2 are as defined herein above.
According to one sub embodiment are provided compounds of Formula (la), (lb), (Ic) and/or
(Id) in which ring W is aryl, heteroaryl or cycloalkyl.
According to another sub embodiment are provided compounds of Formula (la), (lb), (Ic)
and/or (Id) in which i is halo, hydroxyl, alkyl or alkoxy.
According to another sub embodiment are provided compounds of Formula (la), (lb), (Ic)
and/or (Id) in which R2 is hydrogen, halo, hydroxyl, alkyl, alkenyl, haloalkyl, alkoxy,
haloalkoxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkoxy, -C(0)OR , -NReR or -
C(0)R ; and R7 are as defined herein above.
According to another sub embodiment are provided compounds of Formula (la), (lb), (Ic)
and/or (Id) in which R3 is hydrogen, halo, hydroxy, alkyl, alkoxy, -C(0)NR 6R7 or -C(0)ORe ;
R6 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 secretion of cytokines,
for example IL-2, IL-4, IL-10, IL-13, IL-17, IL-21, IL-23, IL-28, IFN-g and TNF-cc and the
like, by regulating the cytokine signalling pathway through calcineurin and NFAT cells.
In another aspect of the invention are processes for the preparation of the compounds
described herein.
According to another embodiment are provided a process for the preparation 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, Rl R2, R3, p, q and n are as defined
herein above;
in presence of a catalyst selected from Pd(PPh3) Cl2, Pd2dba3, Pd(PPh3)4 or Pd(OAc)2
or a mixture thereof; a ligand selected from B AP, xanthophos or
triphenylphosphine or a mixture thereof and a base.
Detailed description of the invention
Definitions and Abbreviations:
Unless otherwise stated, the following terms used in the specification and claims have the
meanings given below.
For purposes of interpreting the specification, the following definitions 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, bromine, or iodine.
Unless otherwise stated, in the present application "oxo" means C(~ 0 ) group. Such an oxo
group may be a part of either a cycle or a chain in the compounds of the present 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 molecule 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. Unless set forth or recited to the contrary, all 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, "Ci-C 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, all alkylene groups described or claimed herein
may be straight chain or branched, substituted or unsubstituted.
The term "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), z'so-propenyl, 2-methyl-l- propenyl, 1-
butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all 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, all
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, all 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. Nonlimiting
examples of such groups are vinyloxy, allyloxy, 1-butenyloxy, 2-butenyloxy,
isobutenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-methyl- 1-butenyloxy, l-methyl-2-
butenyloxy, 2,3-dimethylbutenyloxy, 1-hexenyloxy and the like. Unless set forth or recited to
the contrary, all 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. Nonlimiting
examples of such groups are acetylenyloxy, propynyloxy, 1-butynyloxy, 2-
butynyloxy, 1-pentynyloxy, 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 norbornyl 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, all 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, all
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, all 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, all 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 have 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, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the
like. A perhaloalkyl refers to an alkyl having all 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, all
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, 2-hydroxypropyl, 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, all 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 -C2H4C H5. Unless set forth or recited to the
contrary, all 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, spirocyclic or bridged polycyclic 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, all
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
consists 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 quaternized, 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(=Ncycloalkyl),
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, perhydroazepinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl,
quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl,
thiazolidinyl, thiamorpholinyl, thiamorpholinyl 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 creation of a stable structure. Unless set forth or recited to the
contrary, all heterocyclyl groups described or claimed herein may be substituted or
unsubstituted.
The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to
14- membered 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 creation of a stable structure. Non-limiting examples of a heteroaryl ring
include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, 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, all 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 creation of a stable structure. Unless set forth or
recited to the contrary, all 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 creation of a stable structure. Unless set forth or recited
to the contrary, all 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(0)OR x, -C(0)R\ -C(S)R , -C(0)NR xRy, -NRxC(0)NR yR , -N(R )S(0)R y, -
N(Rx)S(0) 2Ry, -NRxRy, -NRxC(0)R y, -NRxC(S)R , -NRxC(S)NRyR , - S(0) 2NRxRy, -OR , -
OC(0)R , -OC(0)NR xR , -RxC(0)OR , -RxC(0)NR Rz, -R C(0)R y, -SRX, and -S(0) 2Rx;
wherein each occurrence of Rx, R and R are 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 contemplates various stereoisomers and mixtures thereof and includes
enantiomers and diastereomers. The invention also includes geometric 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 attachment 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 experience
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
regression 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 molecule; by way of
illustration that block or inhibit calcium release-activated calcium (CRAC) channel. Any
such modulation, whether it be partial or complete inhibition is sometimes referred to herein
as "blocking" and 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 animals, such as
domestic animals; 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, age, 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 salt 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, a-ketoglutarate, aglycerophosphate,
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 metal (for example,
sodium, potassium or lithium) or alkaline earth metal (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 stereospecific or asymmetric synthesis. Tautomeric forms and
mixtures of compounds described herein are also contemplated.
Unless otherwise stated, in the present 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 specific reaction conditions. Various protecting groups alongwith the methods of
protection and deprotection are generally known to a person of ordinary skilled in the art.
Incorporated herein in this regard as reference is Greene's Protective Groups in Organic
Synthesis, 4th Edition, John Wiley & Sons, New York. In the present invention, preferred
amino protecting groups are t-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 releaseactivated
calcium (CRAC) channel to treat CRAC channel mediated diseases such as
inflammatory diseases, autoimmune diseases, allergic 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, salt solutions, alcohols,
polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,
lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose,
magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of
cellulose, silicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and
diglycerides, 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 ingredient
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 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 forms, for example,
capsules, tablets, aerosols, solutions, suspensions or products for topical 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, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral,
intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such
as with a topical ointment).
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin),
dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like
are particularly suitable for oral application. Liquid formulations include, but are not limited
to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non¬
aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are
injectable solutions or suspensions formulation.
Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions,
soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions
or solutions.
For parenteral application, particularly suitable are injectable solutions or suspensions,
preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor
oil.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the
preparation is subdivided into unit doses containing appropriate quantities of the active
component. The unit dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, 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
depends, 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 preparation 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 result 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. All 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 present
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 immunologic process of
elimination 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
(prostaglandins, thromboxanes, leukotrienes, and other oxidized derivatives), other
inflammatory agents (e.g., reactive oxygen species), and adhesion molecules. 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 result from, or be triggered by, a dysregulation of the normal immune response.
The compound(s) of the present 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, gout, gouty arthritis, acute pseudogout,
Reiter's syndrome, ankylosing spondylitis, psoriatic arthritis, dermatomyositis; (pulmonary)
pleuritis, pulmonary fibrosis 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 vasculitis, angiogenesis, atherosclerosis, ischaemic heart
disease, thrombosis, myocardial infarction; (gastrointestinal) dysmotility, dysphagia,
inflammatory bowel diseases, pancreatitis, (genitourinary) interstitial cystitis, renal tubular
acidosis, urosepsis, (skin) purpura, vasculitis scleroderma, eczema, psoriasis, (neurologic)
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, (hematologic) chronic anemia, thrombocytopenia, (renal)
amyloidosis of the kidney, glomerulonephritis, kidney failure and other diseases such as
tuberculosis, leprosy, sarcoidosis, syphilis, Sjogren's syndrome, cystitis, fibromyalgia,
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.
"Allergic 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. Allergic diseases are characterized by excessive immunoglobulin E (IgE) production,
mast cell degranulation, tissue eosinophilia and mucus hypersecretion, 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. Allergic reactions can also result from food, insect
stings, and reactions to medications 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 allergic response
that is also called anaphylaxis. The main therapeutic interest around CRAC in allergic
disorders, originates from its role in lymphocytes and mast cells, CRAC activation being a
requirement for lymphocyte activation.
The compound(s) of the present invention are useful in treatment of allergic disorders
including, but not limited to, atopic dermatitis, atopic eczema, Hay fever, asthma, urticaria
(including chronic idiopathic urticaria), vernal conjunctivitis, allergic rhinoconjunctivitis,
allergic rhinitis (seasonal and perennial), sinusitis, otitis media, allergic bronchitis, allergic
cough, allergic 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 prevention of
"immune disorders" by administering an effective amount of a compound of the present
invention.
The compounds of this invention can be used to treat subjects with immune disorders. As
used herein, the term "immune disorder" and like terms 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 congenital 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 animals (including humans) that have 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 allergic disorders, will be included in the definition 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
inflammatory 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 result 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 producing cells of
the pancreas in Type 1 diabetes mellitus. Different autoimmune disorders can target different
tissues, organs or systems in an animal while some autoimmune disorders target different
tissues, organs or systems in different animals. For example, the autoimmune reaction is
directed against the gastrointestinal tract in Ulcerative colitis and the nervous system in
multiple sclerosis whereas in systemic lupus erythematosus (lupus), affected tissues and
organs may vary among individuals with the same disease. For example, one person with
lupus may have affected skin and joints whereas another may have affected kidney, skin and
lungs.
Specific 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, pemphigus 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
immune-mediated diabetes 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 blood (e.g., autoimmune hemolytic anemia, pernicious
anemia, and autoimmune thrombocytopenia) and autoimmune disorders of the blood vessels
(e.g., temporal arteritis, anti-phospholipid 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 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 predisposition towards it.
In another embodiment, the invention is directed to the treatment or prevention of cancer by
administering an effective amount of a compound of the present invention.
It has been reported in the art that STIM1 and Orail 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. ah, Cancer Cell, 1, 169-179, 2002,
Motiani et al, J. Biol. Chem., 285; 25, 19173-19183, 2010.
The compound(s) of the present 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. In yet another embodiment, the invention is directed to the treatment or
prophylaxis of allergic disorders by administering an effective amount of a compound of the
present invention.
In yet another embodiment, the invention is directed to the treatment or prophylaxis of
cardiovascular diseases or disorders by administering an effective amount of a compound of
the present invention.
The compounds of this invention can be used to treat subjects with cardiovascular disorders.
"Cardiovascular disorder" refers to a structural and functional 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 congenital or acquired. One of the main pathological feature of all these
diseases is clogged and hardened arteries, obstructing the blood flow to the heart. The effects
differ depending upon which vessels are clogged with plaque. The arteries carrying oxygen
rich blood, if clogged, result in coronary artery disease, chest pain or heart attack. If the
arteries reaching the brain are affected, it leads to transient ischemic 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 consequence 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 reticulum (ER) and functions as a calcium sensor.
Orail is a pore forming subunit of calcium channel located on the plasma membrane, the
depletion of calcium in the endoplasmic reticulum is sensed by STIM1, and calcium enters
via Orail to refill the endoplasmic reticulum. This pathway of filling the calcium is called
store operated calcium entry (SOCE), which plays an important role in calcium homeostasis,
cellular dysfunction and has a significant importance in cardiovascular diseases. In
cardiomyocytes, calcium is not only involved in excitation-contraction coupling but also acts
as a signalling molecule promoting cardiac hypertrophy. Hypertrophic hearts are susceptible
to abnormalities of cardiac rhythm and have 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 metabolic syndrome (MetS) swine coronary smooth muscle cells. The compound of this
invention can be used to treat neointimal hyperplasia, occlusive vascular diseases, MetS -
which is a combination of medical disorders including coronary artery disease, stroke and
type 2 diabetes, abdominal aortic aneurysm, angina, transient ischemic attack, stroke,
peripheral artery occlusive disease which includes inflammation, complement activation,
fibrinolysis, angiogenesis and/or diseases related to FXII- induced kinin formation such as
hereditary angioedema, bacterial infection of the lung, trypanosome infection, hypotensive
shock, pancreatitis, chagas disease, thrombocytopenia or articular gout, myocardial
infarction, portal 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, cerebral venous sinus
thrombosis ischemic cardiomyopathy, hypertrophic 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,
hemorrhagic stroke and ischemic 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 result of ruptured atherosclerotic
plaque which initiates thrombus formation. Platelet activation play an important role in
vascular inflammation leading 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 all 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 has
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 predisposition towards it.
In yet another embodiment, the invention is directed to the treatment or prevention of
"thrombocytopathies" by administering an effective amount of a compound of the present
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 congenital 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 dysfunction of platelets or coagulation system or diseases or
complications that arise as a result of partial or complete 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, ischemic cardiovascular diseases including
but not limited to myocardial ischemia, angina, ischemic cerebrovascular diseases including
but not limited to stroke, transient ischemia attack, cerebral venous sinus thrombosis (CVST)
and complications arising due to thrmobocytopathies. Besides this, the disorder related to
venous or arterial thrombus formation can be inflammation, complement 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 gout.
Under normal circumstances, when the endothelial cells lining blood vessels are breached,
platelets interact with von Willebrand factor (vWF) via the membrane glycoprotein lb
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 5-hydroxytryptamine (5-HT) - serotonin. All 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 negative 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 clot (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 inadequate 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 elevation 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 depletion.
STI 1 is the the Ca(2+) sensor in the endoplasmic reticulum (ER) membrane, whereas Orail
is the major store operated Ca(2+) (SOC) channel in the plasma membrane, which play a key
role 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 predisposition towards it.
General Methods of Preparation
The compounds of the present invention, including compounds of general formula (I) and
specific examples are prepared through the reaction sequences illustrated in synthetic
Schemes 1 to 5 wherein ring E, ring W, ring D, L, Rl 5 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 specific 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 present invention. Variations in reaction conditions and parameters like temperature,
pressure, duration of reaction, etc., which may be used as known in the art are also within the
scope of the present invention. All 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 temperature refers to a temperature in the range of 22 to 27 °C.
-NMR spectra of the compounds of the present invention were recorded using a
BRUCKNER instrument (model: Avance-III), 400 MHz. Liquid chromatography - mass
spectra (LCMS) of the compounds of the present 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 present invention were used according to
ChemBioDraw Ultra 12.0 software.
The compounds of formula (I) can be prepared by the reaction of borate derivative of formula
(1) with various halobenzamides of formula (2) as depicted in Scheme 1.
Alternatively, the compounds of the formula (I) can also be prepared by the reaction of the
halo derivatives of the formula (3) with borate/stannane derivatives 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)2Cl , Pd2dba3, Pd(PPh3)4, Pd(OAc)2 or mixture(s) thereof; a suitable ligand known
in the art such as 2,2'-bis(diphenylphosphino)-l , -binaphthyl (BGNAR), xanthophos,
triphenylphosphine or mixture(s) thereof; in the presence of a suitable base, preferably
inorganic bases such as alkalimetal carbonates like sodium carbonate, cesium 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).
In an alternative approach, the compounds of the present invention can also be prepared as
depicted in Scheme 2. Thus, the borate complex of formula (5) are prepared from the
corresponding halo derivatives via a metal catalysed boration reaction. As also known in the
art, such reactions are carried out in presence of a metal catalyst for example Pd(PPh )2Cl2,
Pd2dba3, PdCl2.dppf, Pd(PPh3) , 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 derivatives of the
formula (2) with borate derivatives 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
(I) by following the procedure known in the art.
Another alternative approach is shown in Scheme 3, where the compound of formula (I) can
be prepared by the reaction of the borate derivative of the formula (1) with the various halide
derivatives of the formula (7) followed by amide coupling reaction.
Alternatively, the compounds of the present invention are also prepared by the reaction of the
halo derivatives of the formula (3) with stannane derivatives 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
derivatives of the formula (7) with borate derivatives of the formula (1), or halo derivatives
of the formula (3) with stannane derivatives 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 present
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 present on either intermediate (9) or (9a). Such groups
are 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
carboxylic acid or an ester - present as either Y' or Y group is carried out using techniques
known in the art. However, in a few preferred aspects of the present 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 syntheses, e.g., hydroxybenzotriazole, 2-hydroxypyridine,
acetoneoxime and a coupling reagent like carbodiimides such as EDC, DCC or
mixture(s) thereof; or
(b) halogenation of the acid derivatives 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 derivatives 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 derivatives 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 derivatives at Y' or Y" of the compounds of the formula
(9) or (9a), with the corresponding acid chloride derivatives 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, N-ethyldiisopropylamine; 4-dialkylaminopyridines
dimethylaminopyridine, pyridine or mixture(s) thereof.
In another embodiment, the compounds of the present invention, wherein ring E is
dihydroisoxazols, 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, N-ethyldiisopropylamine; 4-dialkylaminopyridines like 4-
dimethylaminopyridine or a mixture thereof.
The compounds of Formula (10) are reduced to the corresponding aldehydes of the formula
( 11) with a reducing agent known in the art. Although not limited, such reducing agents
include alkyl- and alkoxy- metal hydrides like sodium bis(2-methoxyethoxy)aluminium
hydride, lithium aluminium hydride, diisobutylaluminium hydride or mixture(s) thereof.
Such reduction 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, ethanol,
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
(1 ) 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 acetates such as sodium acetate; alkali
metal hydroxides like potassium hydroxide, sodium hydroxide or mixture(s) thereof. Such a
reaction can be effected; in one or more solvent generally used in the art like alcohols such as
methanol, ethanol, 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 (Ie) or (If) 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-bromosuccinimide 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, ethanol, 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 derivatives 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 metal hydroxides like sodium hydroxide, potassium
hydroxide, lithium hydroxide and the like; or alkalineearth metal 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, ethanol, propanol, isobutanol; or mixtures thereof.
Accordingly, compound of formulae (Ih) can be prepared by following the procedure as
depicted in Scheme 5. Ester derivatives of the formula (14) are converted to the compounds
of the formula (Ih) by reduction processes known in the art by using suitable reducing 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, ethanol, propanol and the like; amides 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 and R are as defined herein above, in an appropriate solvent like
alcohols such as methanol, ethanol, 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 present invention is further illustrated by the following intermediates and examples with
detailed procedure to prepare 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
All intermediates used for the preparation of the compounds of the present 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 l a & l b
5,5-Dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)isoxazol-4(5 H)-one (la)
and
3-(3 -(5 -Aminopyrazin-2-yl)-4-methylphenyl)-5 ,5-dimethylisoxazol-4-(5H)-one (lb)
Step 1: 3-Bromo-4-methyl-[N-(methoxy)-N'-(methyl)]benzamide: To a solution of 3-bromo-
4-methylbenzoic 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 temperature 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 (2x50 mL). The combined organic
layers were washed with brine (50 mL), dried (Na2S0 ) 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, CDC13) d 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' 8 1] .
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 temperature over a period of 15-20 minutes and then stirred at room temperature 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 (Na2S0 )
and filtered. The filtrate was concentrated under vacuum to afford 0.58 g of the desired
product as a white solid. 1HNMR (400 MHz, CDC13) 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 1] .
Step 3 : (3-Bromo-4-methylphenyl)(3,3-dimethyloxiran-2-yl)methanone: 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 temperature. After stirring for 12 h at room
temperature 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 (Na2S0 4) 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, CDC13) d 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, 1H), 3.99 (s, 1H), 2.47 (s, 3H), 1.58 (s, 3H), 1.23 (s,
3H); ESI-MS (m/z) 269, 271 [(MH) +, Br79' 1] .
Step 4 : 3-(3-bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazol-4-ol: A mixture of
(3-bromo-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 temperature 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 (3><20 mL). The combined organic layers were washed with
water (20 mL), brine (20 mL), dried (Na2S0 4) and filtered. The filtrate was evaporated under
vacuum to afford 320 mg of the desired product as a white solid. 1HNMR (400 MHz, CDC13)
d 7.97 (d, J = 1.0 Hz, 1H), 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) +, Br79' 8 1].
Step 5: 3-(3-Bromo-4-methylphenyl)-5,5-dimethylisoxazol-4(5 H)-one: To a solution 3-(3-
bromo-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 temperature 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 (Na2S0 4) 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 (400 MHz, CDC13) d 8.29 (d, J = 1.0 Hz, 1H), 7.94 (dd, J =
1.0, 8.0 Hz, 1H), 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)+, Br79,81 ].
Step 6: 5,5-Dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)
isoxazol-4(5 H)-one :
General procedure for pinacolatodiboralane formation: To a solution of 3-(3-bromo-4-
methylphenyl)-5,5-dimethylisoxazol-4(5 H)-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)Cl 2 (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 overnight under nitrogen
atmosphere. The resulting mixture was cooled to room temperature 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 l a as a white solid. HNMR (400 MHz, CDC13) d 8.44 (d, J =2.0 Hz, 1H), 7.99
(dd, = 2.0, 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 2.55 (s, 3H), 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 H)-one: To a
solution of 5,5-dimethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)isoxazol-
4(5H)-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:H 20 (4:1, 100 mL) was added sodium bicarbonate (4.5 g, 54.1 mmol, 3.3 eq)
followed by Pd(PPh 3)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 atmosphere. The resulting mixture was cooled to
room temperature 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 l b as a white solid. 1HNMR (400 MHz, CDC13) d
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, D20 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
described in intermediate l a or intermediate lb:

Intermediate 13
4-Methoxy-5,5-dimethyl-3-(4-methyl-3 -(4,4,5 ,5-tetramethyl- 1,3,2-dioxaborolan-2-
yl)phenyl)-4,5-dihydroisoxazole
Intermediate 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 temperature for 20 min, methyl iodide (70 m , 1.09 mmol,
1.09 eq) was added to the above mixture and then continued stirring at room temperature 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
(Na2S0 4) and filtered. The filtrate was concentrated under vacuum to afford 200 mg of the
title product as syrupy oil. 1HNMR (400 MHz, CDC13) d 7.93 (d, J = 2.0 Hz, 1H), 7.62 (dd, J
= 8.0, 2.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 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)+, Br 9'8 1]
Step-2: 4-Methoxy-5,5-dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)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, CDC13) d
8.09 (d, J = 2.0 Hz,lH), 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, 12H), 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- 1,3,2-dioxaborolan-2-yl)phenyl)- 1,3,4-
oxadiazol-3(2 H)-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 overnight. The reaction mixture was cooled to room temperature 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 (Na2S0 4) and filtered. The
filtrate was evaporated under reduced pressure to afford 2.5 g (50%) of the desired product as
a white solid. 1HNMR (400 MHz, DMSO-^) d 9.84 (s, 1H, D 0 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, D20
exchangeable), 2.38 (s, 3H); ESI-MS (m/z) 229, 23 1 [(MH)+, Br79' 1] .
Step 2: l-(5-(3-Bromo-4-methylphenyl)-2,2-dimethyl-l,3,4-oxadiazol-3(2 H)-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, 2 1 eq) in hexane (10 mL), was added molecular sieves (500 mg) followed by
trifluoroacetic acid (2 mL) and the resulting mixture was refiuxed for 3 h. The reaction
mixture was cooled to room temperature and filtered. The filtrate was concentrated under
vacuum and the residue was taken in ethyl acetae (100 mL), washed with water (50 mL),
aqueous saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (Na2S0 4) 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- ) d
10.51 (s, 1H, D20 exchangeable), 8.02 (s, 1H), 7.75 (dd, j = 1.0, 8.0 Hz, 1H), 7.44 (d, J = 8.0
Hz, 1H), 2.40 (s, 3H), 2.01 (s, 3H), 1.94 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)+, Br79' 8 1] .
A mixture of 3-bromo-4-methyl-iV-(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 acetic anhydride was removed under vacuum after cooling the reaction mixture to room
temperature and the crude residue obtained was triturated with hexane to remove traces of
acetic anhydride present in the reaction mixture. The crude product was purified by flash
column chromatography (silica gel, 100-200 mesh, 13% ethyl acetate in hexane) to afford
800 mg of the desired product as an oil. 1HNMR (400 MHz, CDC13) d 7.97 (s, 1H), 7.65 (d,
J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 2.44 (s, 3H), 2.29 (s, 3H), 1.85 (s, 6H); ESI-MS
(m/z) 3 11, 313 [(MH)+, Br79' 1].
Step 3: 1-(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 H)-yl)ethanone: l-(5-(3-bromo-4-methylphenyl)-2,2-dimethyl-l ,3,4-
oxadiazol-3(2 H)-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)Cl 2 (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, CDC13) d 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)+.
Intermediate 15a & 15b
5-(3-Bromo-4-methylphenyl)-3-methyl-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)
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 overnight. The reaction mixture was cooled to room temperature 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 (Na2S0 4) 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- ) d 9.83 (s, 1H, D20 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, D20
exchangeable), 2.37 (s, 3H); ESI-MS (m/z) 229, 231 [(MH)+, Br79' 8 1] .
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 temperature. 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 (Na2S0 4) 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-i¾) d 12.66 (s, 1H, D20 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, 1H), 2.40 (s, 3H); ESI-MS (m/z) 255, 257 [(MH)+, Br79' 8 1] .
Step-3: 5-(3-Bromo-4-methylphenyl)-3-methyl-l,3,4-oxadiazol-2(3H)-one: A mixture of 5-
(3-bromo-4-methylphenyl)-l,3,4-oxadiazol-2(3H)-one (400 mg, 1.57 mmol, 1.0 eq), methyl
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 temperature 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 (2x20 mL). The combined organic layers were
washed with water (2 25 mL), brine (20 mL), dried (Na2S0 4) and filtered. The filtrate was
concentrated under vacuum to afford 400 mg of the desired product as a white solid. 'HNMR
(400 MHz, DMSO- ) d 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' 8 1] .
Step 4: 5-(3-(5-Aminopyrazin-2-yl)-4-methylphenyl)-3-methyl-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-amino-5-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 atmosphere. The resulting
mixture was cooled to room temperature 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 acetate-hexane mixture as eluent to afford 250 mg
of the intermediate 15b as a white solid. 1HNMR (400 MHz, DMSO- ) d 8.07 (s, 1H), 7.99
(s, 1H), 7.69 , J = 2.0 Hz, 1H), 7.64 (dd, J = 8.0, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H),
6.62 (s, 2H, D20 exchangeable), 3.36 (s, 3H), 2.35 (s, 3H); ESI-MS (m/z) 284 (MH)+.
The following intermediates 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
described in intermediate 5a or intermediate 15b:
Intermediates/IUPA
Structure 'HNMR /ESI-MS(MH)+
C name
'HNMR (400 MHz, DMSO-c*5) d 7.89
Intermediate 16a: 5- (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 8.0,
(3-Bromo-4-methyl 1.5 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H),
phenyl)-3-ethyl-l,3,4- 3.76 (q, J = 7.0 Hz, 2H), 2.40 (s, 3H),
oxadiazol-2(3H)-one 1.29 (t, J = 7.0 Hz, 3H); ESI-MS (m/z)
283, 285 [(MH)+
,Br 79' 8 1] .
'HNMR (400 MHz, DMSO-ί ) d 8.13
Intermediate 16b: 5-
(s, 1H), 7.98 (s, 1H), 7.77 (d, J = 1.0
(3-(5-Aminopyrazin-
Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.45
2-yl)-4-
(d, J = 8.0 Hz, 1H), 6.62 (s, 2H, D20
methylphenyl)-3-
exchangeable), 3.76 (q, J = 7.0 Hz,
ethyl-1 ,3,4-oxadiazol-
2H), 2.41 (s, 3H), 1.29 (t, J = 7.0 Hz,
2(3H)-one
3H); ESI-MS (m/z) 298 (MH)+
'HNMR (400 MHz, DMSO-i ) 7.91
Intermediate 17a: 5- (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 8.0,
(3-Bromo-4- 1.5 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H),
methylphenyl)-3- o= 3.69 (t, J = 7.0 Hz, 2H), 2.41 (s, 3H),
propyl- 1,3,4- 1.75-1.70 (m, 2H), 0.90 (t, J = 7.0 Hz,
oxadiazol-2(3H)-one 3H); ESI-MS (m/z) 296, 298 [(MH)+
,
Br 9' 8 1] .
'HNMR (400 MHz, CDC13) d 8.14 (s,
Intermediate 17b: 5-
1H), 8.09 (s, 1H), 7.86 (d, J 1.5 Hz,
(3-(5 -Aminopyrazin-
1H), 7.73 (dd, J = 8.0, 1.5 Hz, 1H),
2-yl)-4-
7.37 (d, J = 8.0 Hz, 1H), 3.74 (t, J =
methylphenyl)-3-
7.0 Hz, 2H), 2.43 (s, 3H), 1.87-1.78 (m,
propyl- 1,3,4-
2H), 0.98 (t, J = 7.0 Hz, 3H); ESI-MS
oxadiazol-2(3H)-one
(m/z) 312 (MH)+.
'HNMR (400 MHz, DMSO) d 7.89 (s,
Intermediate 18a : 5-
1H), 7.73 (dd, J = 8.0, 2.0 Hz, 1H),
(3-Bromo-4-
7.53 (d, J = 8.0 Hz, 1H), 3.40 (s, 3H),
ethylphenyl)-3-
2.75 (q, J = 7.5 Hz, 2H), .19 (t, J = 7.5
methyl- 1,3,4-
Hz, 3H); ESI-MS (m/z) 283, 285
oxadiazol-2(3H)-one
[(MH)+, Br79'8 1] .
'HNMR (400 MHz, DMSO- ) d 8.07
Intermediate 18b: 5- (s, 1H), 7.97 (s, 1H), 7.72 (dd, J =8.0,
(3-(5 -Aminopyrazin- 2.0 Hz, 1H), 7.67 (d, J =2.0 Hz, 1H),
2-yl)-4-ethylphenyl)- °=< 7.54 (d, J =8.0 Hz, 1H), 6.61 (s, 2H,
3-methyl- 1,3,4- D20 exchangeable), 3.40 (s, 3H), 2.75
oxadiazol-2(3 H)-one (q, J =7.5 Hz, 2H), 1.08 (t, J =7.5 Hz,
3H); ESI-MS (mix) 298 (MH)+.
Intermediate 19a: 5- 'HNMR (400 MHz, DMSO) d 7.91 (d,
(3-Bromo-4- J 2.5 Hz, 1H), 7.79 (dd, J =8.5, 2.0
methoxyphenyl)-3 - Hz, 1H), 7.28 (d, J =8.5 Hz, 1H), 3.93
methyl- 1,3,4- (s, 3H); ESI-MS (m/z) 285, 287
oxadiazol-2(3 H)-one [(MH) +, Br79,81 ] .
Intermediate 19b: 5- 'HNMR (400 MHz, DMSO-af<5) d 8.55
(3-(5-Aminopyrazin- (s, 1H), 8.21 (d, J =2.0 Hz, 1H), 8.01
2-yl)-4- (s, 1H), 7.73 (dd, J =8.0, 2.0 Hz, 1H),
methoxyphenyl)-3- 7.28 (d, J =8.0 Hz, 1H), 6.63 (s, 2H,
methyl- 1,3,4- D20 exchangeable), 3.94 (s, 3H), 3.39
oxadiazol-2(3 H)-one (s, 3H); ESI-MS (m/z) 300 (MH)+.
Intermediate 20a: 5- 'HNMR (400 MHz, CDC13) d 8.09 (d,
(3-Bromo-4- J =2.5 Hz, 1H), 7.76 (dd, J =8.5, 2.0
(difluoromethoxy)phe Hz, 1H), 7.30 (d, J =8.5 Hz, 1H), 6.60
nyl)-3 -methyl- 1,3,4- (t, J =72.5 Hz, 1H), 3.45 (s, 3H); ESIoxadiazol-
2(3 H)-one MS (m/z) 321, 323 [(MH) +, Br79'8 1].
'HNMR (400 MHz, DMSO- ) d 8.42
Intermediate 20b: 5-
(s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.03
(3-(5-Aminopyrazin-
(s, 1H), 7.80 (dd, J = 8.0, 2.0 Hz, 1H),
2-yl)-4- Y
7.53 (d, J = 8.0 Hz, 1H), 7.45 (t, J =
(difluoromethoxy)phe
72.5 Hz, 1H), 6.78 (s, 2H, D20
nyl)-3 -methyl- 1,3,4-
exchangeable), 3.41 (s, 3H); ESI-MS
oxadiazol-2(3 H)-one
(m/z) 336 (MH)+.
Intermediate 21a: 5- 'HNMR (400 MHz, CDC13) d 8.09 (d,
(3-Bromo-4- J = 2.0 Hz, 1H), 7.69 (dd, J = 8.0, 2.0
chlorophenyl)-3- x Hz, 1H), 7.55 (d, J = 8.0 Hz, lH), 3.50
methyl- 1,3,4- (s, 3H); ESI-MS (m/z) 289, 291
oxadiazol-2(3 H)-one [(MH)+, CI 35' 3 ]
Intermediate 21b: 5-
(3-(5-Aminopyrazin-
ESI-MS (m/z) 304, 306 [(MH)+, CI 35
-yl)-4-chlorophenyl)-
3 ]
3-methyl- 1,3,4-
oxadiazol-2(3 H)-one
Intermediate 22a: 5- 'HNMR (400 MHz, CDC13) d 8.05 (dd,
(3-Bromo-4- J = 6.5, 2.5 Hz, 1H), 7.77-7.73 (m,
fluorophenyl)-3- 1H), 7.21 (t, J = 8.5 Hz, 1H), 3.50 (s,
methyl-1,3,4- 3H); ESI-MS (m/z) 273, 275 [(MH)+,
oxadiazol-2(3 H)-one Br 9'8 1]
'HNMR (400 MHz, DMSO-i ) d 8.42
Intermediate 22b: 5-
(s, 1H), 8.32 (dd, J = 7.0, 2.5 Hz, 1H),
(3-(5-Aminopyrazin-
8.04 (s, 1H), 7.77-7.73 (m, 1H), 7.48
-yl)-4-fluorophenyl)- 0 ]
(dd, J = 8.5, 11.5 Hz, 1H), 6.86 (s, 2H,
3-methyl- 1,3,4-
D20 exchangeable), 3.41 (s, 3H); ESIoxadiazol-
2(3 H)-one
MS (m/z) 288 (MH)+
Intermediate 23a: 5- 'HNMR (400 MHz, DMSO- 5) d 7.84
(3-Bromo-2- (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz,
methylphenyl)-3- 1H), 7.32 (d, J 8.0 Hz, 1H), 3.42 (s,
methyl- 1,3,4- 3H), 2.62 (s, 3H); ESI-MS (m/z) 269,
oxadiazol-2(3 H)-one 271 [(MH)+, Br 79,81 ]
Intermediate 23b: 5-
(3-(5 -Aminopyrazin-
2-yl)-2-
ESI-MS (m/z) 284 (MH)+
methylphenyl)-3-
methyl- 1,3,4-
oxadiazol-2(3 H)-one
Intermediate 24a: 5-
'HNMR (400 MHz, CdCl3) d 7.71 (d, J
(3-Bromo-2-
= 8.0 Hz, 2H), 7.16 (t, J 8.0 Hz, IK),
ethylphenyl)-3-
3.53 (s, 3H), 3.16 (q, J = 7.5 Hz, 2H),
methyl- 1,3,4-
1.22 (t, J = 7.5 Hz, 3H)
oxadiazol-2(3 H)-one
Intermediate 24b: 5-
(3-(5-Aminopyrazin-
2-yl)-2-ethylphenyl)- ESI- MS (m/z) 298 (MH+)
3-methyl-l,3,4-
oxadiazol-2(3H)-one
Intermediate 25
5,5-Dimethyl-3 -(4-methy 1-3 -(4,4,5 ,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-4,5 -
dihydroisoxazole
Step 1: 3-(3-Bromo-4-methylphenyl)-5,5-dimethyl-4,5-dihydroisoxazole: To a mixture of 1-
(3-bromo-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 ethanol (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 resulting mixture was
stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (20
mL) followed by water (20 mL). The layers were separated and the organic layer was
extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with brine
(20 mL), dried (Na2S0 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. 1HNMR (400 MHz, CDC13) d 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)+, Br79'8 1].
Step 2: 5,5-Dimethyl-3-(4-methyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)-
4,5-dihydroisoxazole: 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, CDC13) d 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)-4,5-
dihydrooxazole
Step 1: 3-Bromo -N-(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 of 2-
amino-2-methylpropanol (1.44 mL, 15.1 1 mmol, 2.5 eq) in DCM (10 mL) drop wise for 15
min and then warmed to room temperature. After stirring for 24 h at room temperature, 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 (Na2S0 4) 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, DMSO-<¾ d 8.00 (d, J = 1.0 Hz, 1H), 7.70 (dd, J = 1.0, 8.0 Hz, 1H),
7.62 (s, 1H, D20 exchangeable), 7.40 (d, J = 8.0 Hz, 1H), 4.85 (t, J = 6.0 Hz, 1H, D20
exchangeable), 3.49 (d, J = 6.0 Hz, 2H), 2.37 (s, 3H), 1.28 (s, 6H); ESI-MS (m/z) 286, 288
[(MH)+, Br79'8 1] .
Step 2: 2-(3-Bromo-4-methylphenyl)-4,4-dimethyl-4,5-dihydrooxazole: 3-bromo-N-(lhydroxy-
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 temperature 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 (Na2S0 4)
and filtered. The filtrate was concentrated under vacuum to afford the 1.0 g of the desired
title product as a white solid. 'HNMR (400 MHz, CDC13) d 8.12 (d, J = 1.0 Hz, 1H), 7.75
(dd, = 1.0, 8.0 Hz, 1H), 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)Cl 2 (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. 1HNMR
(400 MHz, CDC13) d 8.28 (d, J = 1.0 Hz, 1H), 7.87 (dd, J = 1.0, 8.0 Hz, 1H), 7.18 (d, J = 8.0
Hz, 1H), 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 :
Step 1: 3-Bromo-4-methylbenzaldehyde oxime: To a stirred suspension of 3-bromo-4-
methylbenzaldehyde (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
temperature. 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 temperature, 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
(Na2S0 4) and filtered. The filtrate was evaporated under vacuum to afford 0.85 g of the title
product as a white solid. 1HNMR (400MHz, CDC13) d 8.08 (s, 1H), 7.87 (s, 1H, D20
exchangeable) 7.76 (d, J = 1.5 Hz, 1H), 7.43 (dd, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H),
2.44 (s, 3H); ESI-MS (m/z) 214, 216 [(MH)+, Br79' 8 1] .
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
temperature 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 , CDC13) d 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), 2.14-2.1 1
(m, 2H), 1.88-1.84 (m, 2H), 1.77-1.72 (m, 4H); ESI-MS (m/z) 294, 296 [(MH)+, Br79' 8 1] .
Step 3: 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: 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)Cl 2 (96 mg, 0.1 1 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, CDC13) d 7.88 (d, J = 1.5 Hz, 1H), 7.72 (dd, J = 8.0, 1.5 Hz, 1H),
7.18 (d, J = 8.0 Hz, 1H), 3.29 (s, 2H), 2.54 (s, 3H), 2.1 1-2.09 (m, 2H), 1.88-1.84 (m, 2H),
1.74-1.70 (m, 4H);ESI-MS (m/z) 342 (MH)+
The below intermediates 28 to 29 were prepared by following a procedure similar to that
described in intermediate 27:
Intermediates/IUPAC
Structure 'HNMR /ESI-MSCMH^
name
Intermediate 28: Methyl
1HNMR (400 MHz, CDC13) d 7.87 (d, J =
5-methyl-3 -(4-methyl-3 -
1.5 Hz, 1H), 7.59 (dd, J = 8.0, 1.5 Hz,
(4,4,5,5-tetramethyl-
1H), 7.33 (d, J = 8.0 Hz, 1H), 3.92 (d, J =
1,3,2-dioxaborolan-2-
17.0 Hz, 1H), 3.88 (s 3H), 3.26 (d, J =
yl)phenyl)-4,5-
17.0 Hz, 1H), 2.50 (s, 3H), 1.79 (s, 3H);
dihydroisoxazole-5 -
ESI-MS (m/z) 312, 314 [(MH)+, Br79,81 ]
carboxylate
Intermediate 29: (±)- 'HNMR (400 MHz,DMSO-d ) d 7.75 (d,
Ethyl 3-(3-bromo-4- 1.5 Hz, 1H), 7.52 (dd, J = 8.0, 1.5 Hz,
methylphenyl)-4,4- 1H), 7.43 (d, J = 8.0 Hz, 1H), 4.53 (s,
dimethyl-4,5- 1H), 4.10 (q, J = 7.0 Hz, 2H), 2.34 (s,
dihydroisoxazole-5 - 3H), 1.44 (s, 3H), 1.40 (s, 3H), 1.15 (t, J
carboxylate = 7.0 Hz, 3H); ESI- MS (m/z) 340, 342
[(MH+, Br 79'8 1]
Intermediate 30
3-(3-Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one
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 AIBN (21 mg, 0.13 mmol, 0.02 eq). The resulting mixture was stirred at room
temperature overnight. The reaction was diluted with chloroform (50 mL) and washed with
water (50 mL) and brine (50 mL). The organic layer was dried (Na2S0 4) 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. 1HNMR (400 MHz, CDC13) d 7.97 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.0, 2.0
Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.14 (s, 1H), 2.43 (s, 3H), 2.13-2.10 (m, 1H), 2.01-1.99 (m,
1H), 1.82-1.76 (m, 4H), 1.65-1.62 (m, 1H), 1.52-1.45 (m, 3H); ESI-MS (m/z) 386, 388, 390
[(MH)+ Br79' 8 1] .
Step 2: 3-(3-Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one: To a solution of
4-bromo-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 temperature and water (1 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 organic layers
were washed with water (2x10 mL), brine (15 mL), dried (Na2S0 ) 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-
(3-bromo-4-methylphenyl)-l-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 chromium 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,
CDC13) d 7.94 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.0, 2.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H),
4.82 (d, J = 10.0 Hz, 1H), 2.40 (s, 3H), 1.87-1.33 (m, 8H), 0.89-0.83 (m, 2H); ESI-MS (m/z)
324, 326 [(MH)+ Br79' 8 1] .
3-(3-Bromo-4-methylphenyl)-l-oxa-2-azaspiro[4.5]dec-2-en-4-one: 1HNMR (400 MHz,
CDC13) d 8.30 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.0, 2.0 Hz, 1H), 7.31 (d, J 8.0 Hz, 1H),
2.44 (s, 3H), 1.87-1 .42 (m, 10H); ESI-MS (m/z) 322, 324 [(MH)+ Br79' 1].
Intermediate 31
3-(3-Bromo-4-methylphenyl)-4-methyl- 1,2,4-oxadiazol-5 (4H)-one
Step-1: 3-Bromo-N-hydroxy-4-methylbenzimidamide: To a stirred solution of 3-bromo-4-
methylbenzonitrile (2.0 g, 10.2 mmol, 1.0 eq) in ethanol (20 mL) was added hydroxylamine
hydrochloride (1.77 g, 25.5 mmol, 2.5 eq) followed by a solution of sodium carbonate (2.70
g, 25.5 mmol, 2.5 eq) in water (2 mL). The resulting mixture was refluxed for 6 h. The
reaction was cooled to room temperature 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
(Na2S0 4) and filtered. The filtrate was rotary evaporated to afford 1.5 g of the title compound
as a white solid. 'HNMR (400 MHz, CDC13) d 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 = 8.0 Hz, 1H), 5.86 (s, 2H), 2.34 (s, 3H); ESI-MS (m/z)
229, 231 [(MH)+ Br79, 8 1] .
Step-2: 3-(3-Bromo-4-methylphenyl)-l,2,4-oxadiazol-5(4H)-one: To a 0 °C cooled solution
of 3-bromo-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 temperature for 3 h.
The reaction was cooled back down to room temperature 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 (Na S0 4) and filtered. The filtrate was evaporated under vacuum to
afford 250 mg of the title product as white solid. 1HNMR (400 MHz, DMSO-d 6) d 13.10 (s,
1H, D20 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)+, Br 9'8 1]
Step-3: 3-(3-Bromo-4-methylphenyl)-4-niethyl-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 temperature
overnight. 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 (2x20
mL) and the combined organic layers were washed with water (2x20 mL), brine (20 mL),
dried (Na2S0 4) 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- ) d
7.93 (d, J = 2.0 Hz,lH), 7.66 (dd, J = 7.5, 2.0 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 3.34 (s, 3H),
2.44 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)+, Br 9'8 1]
Intermediate 32
N-(5-Bromopyrazine-2-yl)-2,6-difluorobenzamide
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 N-bromosuccinimide (16.8 g, 94.6
mmol, 0.9 eq) portion wise and the resulting solution was stirred at the same temperature 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 (Na S0 4) 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. 1HNMR (400 MHz, CDC13) d 8.06
(s, 1H), 7.75 (s, 1H), 4.72 (brs, 2H, D20 exchangeable); ESI-MS (m/z) 174, 176 [(MH)+ Br79'
].
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 temperature for 15 h. The reaction was diluted with DCM (100 mL), and washed with
10% hydrochloric acid (100 mL), dried (Na2S0 ) 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, CDC13) d 9.47 (s, 1H), 8.62 (s, 1H, D20 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:
'HNMR (400 MHz, DMSO) d 11.40 (s,
Intermediate 34: N-
1H, D20 exchangeable), 9.23 (s, 1H),
(5-Bromopyrazine-2-
8.67 (s, 1H), 7.80 (q, J = 8.0 Hz, 1H),
yl)-2,4-
7.45-7.39 (m, 1H), 7.26-7.19 (m, 1H);
difluorobenzamide
ESI-MS (m/z) 314, 316 [(MH) + Br79' 8 1] .
'HNMR (400 MHz, DMSO) d 11.52 (s,
Intermediate 35: N-
1H, D20 exchangeable), 9.23 (s, 1H),
(5-Bromopyrazine-2-
—i
8.69 (s, 1H), 7.61-7.56 (m, 1H), 7.51-
yi)-2,5-
7.41 (m, 2H); ESI-MS (m/z) 314, 316
difluorobenzamide
[(MH) + Br79,81 ].
'HNMR (400 MHz, DMSO- 5) d 11.57
Intermediate 36: N-
(s, 1H, D20 exchangeable), 9.24 (s,
(5-Bromopyrazine-2-
1H,), 8.69 (s, 1H), 7.69-7.62 (m, 1H),
yi)-2,3-
7.54-7.50 (m, 1H), 7.38-7.33 (m, 1H);
difluorobenzamide
ESI-MS (m/z) 314, 316 [(MH) + Br79' 8 1]
'HNMR (400 MHz, DMSO-c/d) d 11.43
Intermediate 37: N-
(s, 1H, D20 exchangeable), 9.25 (s,
(5-bromopyrazin-2-
1H,), 8.72 (s, 1H), 7.90-7.85 (m, 2H),
yl)-3-
7.60-7.57 (m, 1H), 7.51-7.45 (m, 1H);
fluorobenzamide
ESI-MS (m/z) 296, 298 [(MH) + Br79, 8 1]
'HNMR (400 MHz, DMSO- ) d 11.37
Intermediate 38: N-
(s, 1H, D20 exchangeable), 9.24 (s,
(5-Bromopyrazine-2-
1H,), 8.70 (s, 1H), 8.14-8.10 (m, 2H),
yl)-4-
7.37 (t, J = 8.5 Hz, 2H); ESI-MS (m/z)
fluorobenzamide
296, 298 [(MH) + Br79' 8 1]
'HNMR (400 MHz, DMSO- ) 11.52
Intermediate 39: N-
(s, IH, D20 exchangeable), 9.22 (s,
(5-Bromopyrazine-2-
IH,), 8.70 (s, IH), 7.93-7.87 (m, IH),
yl)-2,4,5- B,_ \ - N
7.80-7.73 (m, IH); ESI-MS (m/z) 332,
trifluorobenzamide
334 [(MH)+ Br79' 8 1]
'HNMR (400 MHz, CDC13) 9.51 (s,
Intermediate 40: N- IH), 8.38 (s, IH, D20 exchangeable),
(5-Bromopyrazine-2- 8.14 (s, IH), 7.33 (t, J = 8.0 Hz, 2H),
yi)-2,3- 7.19 (t, J = 8.0 Hz, IH), 2.38 (s, 3H),
dimethylbenzamide 2.34 (s, 3H); ESI-MS (m/z) 306, 308
[(MH)+ Br79' 8 1] .
Intermediate 4 1: N- 'HNMR (400 MHz, DMSO d 11.59
(5-Bromopyrazine-2- (s, IH, D20 exchangeable), 9.26 (s,
yl)-4- —i IH,), 8.72 (s, IH), 8.21 (d, J = 8.0 Hz,
trifluoromethylbenza 2H), 7.92 (d, J = 8.0 Hz, IH); ESI-MS
mide (m/z) 346, 348 [(MH)+ Br79' 8 1]
'HNMR (400 MHz, CdCl3) d 9.48 (s,
Intermediate 42: NIH),
8.40-8.37 (m, 2H), 7.80 (d, J = 7.0
(5-Bromopyrazine-2-
'- - N Hz, IH), 7.74-7.72 (m, IH), 7.14 (t, J =
yl)-4-fluoro-3-
8.0 Hz, IH), 2.36 (s, 3H); ESI- MS
methylbenzamide
(m/z) 310, 312 [(MH)+, Br 9'8 1]
'HNMR (400 MHz, CDC13) d 9.50 (s,
Intermediate 43:N- 1H), 8.29 (s, 1H, D20 exchangeable),
(5-Bromopyrazine-2- 8.26 (s, 1H), 7.54 (d, J =7.5 Hz, 1H),
yl)-2- 7.43 (d, J =8.0 Hz, 1H), Ί . 2-1 (m,
methylbenzamide 2H), 2.46 (s, 3H); ESI-MS (m/z) 292,
294 [(MH) + Br79,81 ] .
'HNMR (400 MHz, DMSO-d 6) d 11.69
Intermediate 44: N- (s, 1H, D20 exchangeable), 9.25 (s, 1H),
(5-Bromopyrazine-2- 8.73 (s, 1H), 8.27 (s, 1H), 8.17 (d, J =
yl)-3-fluoro-5-triflu 8.0 Hz, 1H), 8.01 (d, J =8.0 Hz, 1H);
oromethylbenzamide ESI- MS (m/z) 364, 366 [(MH) +, Br
Intermediate 45
N-{5-Bromopyrazin-2-yl)-4-methyl- 1,2,3 -thiadiazole-5 -carboxamide
To a solution of 2-amino-5-bromopyrazine (1.0 g, 5.74 mmol, 1.2 eq) and 4-methyl- 1,2,3-
thiadiazole-5-carboxylic acid (690 mg, 4.79 mmol, 1.0 eq) in THF (20 mL) at room
temperature 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 temperature 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><20 mL). The combined organic layers were
washed with IN hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL),
brine (20 mL) dried (Na2SC4) and filtered. The filtrate was concentrated under vacuum and
the crude product was purified by flash column chromatography (silica gel) to afford 321 g
of the desired product as a white solid. 'HNMR (400 MHz, DMSO-t¾ d 11.91 (s, 1H, D 0
exchangeable), 9.20 (s, 1H), 8.72 (s, 1H), 2.83 (s, 3H); ESI-MS (m/z) 300, 302 [(MH)+, Br79'
Intermediate 46a and 46b
N-(4-bromophenyl)-2,6-difluorobenzamide (46a)
and
2,6-Difluoro -N-(4-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzamide (46b)
Step 1: N-(4-Bromophenyl)-2,6-difluorobenzamide: To a stirred and 0°C cooled solution of
4-bromoaniline (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 temperature 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
(Na2S0 4) 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- ) d 7.78 (brs, 1H, D20
exchangeable), 7.53-7.37 (m, 5H), 7.02-6.95 (m, 2H); ESI-MS (m/z) 312, 314 [(MH)+ Br79'
1].
Step 2: 2,6-Difluoro -N-(4-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)benzamide:
N-(4-Bromophenyl)-2,6-difluorobenzamide (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- ) d 10.92 (brs, 1H, D20 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
described in intermediate 46a or intermediate 46b:
'HNMR (400 MHz, CDC13) 7.63
(s, IH, D20 exchangeable), 7.51 (d,
Intermediate 48a: N-(4- J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz,
Bromophenyl)-2-fluoro- 2H), 7.31-7.26 (m, IH), 7.03 (d, J =
6-methylbenzamide 8.0 H , IH), 6.95 (t, J = 8.5 Hz,
IH), 2.43 (s, 3H); ESI-MS (m/z)
307, 309 [(MH)+, Br79'8 1]
'HNMR (400 MHz, CDC13) d 7.81
Intermediate 48b: 2- (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5
Fluoro-6-methyl-N-(4- Hz, 2H), 7.54 (s, IH, D20
(4,4,5,5-tetramethyl- exchangeable), 7.32-7.26 (m, IH),
1,3,2-dioxaborolan-2- 7.05 (d, J = 8.5 Hz, IH), 6.97 (t, J =
yl)phenyl)benzamide 8.0 Hz, IH), 2.46 (s, 3H), 1.34 (s,
12H); ESI-MS (m/z) 356 (MH)+.
Intermediate 49: 4-Ethyl-
N-(4-(4,4,5,5-
tetramethyl- 1,3,2- ESI-MS (m/z) 352 (MH)+.
dioxaborolan-2- -
yl)phenyl)benzamide
Intermediate 50
4-Methyl -N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l,2,3-thiadiazol-5-
carboxamide
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 temperature 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 temperature 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 (3x20 mL). The
combined organic layers were washed with IN hydrochloric acid (20 mL), saturated sodium
bicarbonate solution (20 mL), brine (20 mL) dried (Na2S0 4) 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
(400 MHz, CDC13) d 7.64 (brs, 1H, D20 exchangeable), 7.51-7.45 (m, 4H), 2.94 (s, 3H);
ESI-MS (m/z) 298, 300 [(MH)+ Br79' 1].
Step-2: 4-Methyl-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- 1,2,3-
thiadiazol-5-carboxamide: The title compound was prepared by the reaction of N-(4-
bromophenyl)-l,2,3-thiadiazol-5-carboxamide with bis(pinacolato)diboron by following the
procedure described for step 6 of intermediate 1. 'HNMR (400 MHz, CDC13) d 7.80 (d, J =
8.5 Hz, 2H), 7.61 (s, 1H, D20 exchangeable), 7.55 (d, J = 8.5 Hz, 2H), 2.94 (s, 3H), 1.32 (s,
12H); ESI-MS (m/z) 346 (MH)+.
Intermediate 51
N-(5-Bromopyridin-2-yl)-2,6-difluorobenzamide
To a mixture of 2-chloro-5-bromopyridine (370 mg, 1.9 mmol, 1.2 eq) and 2,6-
difluorobenzamide (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,Ndimethylethylene
diamine (0.1 mL, 1.05 mmol, 0.7 eq) were added sequentially. The
resulting mixture was stirred at reflux for 1 h. The reaction was cooled to room temperature,
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 ( a2S0 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. 1HNMR (400 MHz, DMSO-<¾ d
11.22 (s, 1H, D20 exchangeable), 8.70 (d, J = 2.5 Hz, 1H), 8.18 (dd, J = 8.0, 2.5 Hz, 1H),
7.67-7.59 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H); ESI-MS (m/z) 313, 315
[(MH)+ Br79' 8 1].
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 temperature and then stirred at the same temperature 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 ( a2S0 4) 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, CDC13) d 8.42 (d, J = 2.5 Hz, 1H), 8.1 8
(dd, J = 8.5, 2.5 Hz, 1H), 7.96 (brs, 1H, D20 exchangeable), 7.49 (d, J = 8.5 Hz, 1H), 7.46-
7.41 ( , 1H), 7.00 (t, J = 8.0 Hz, 2H); ESI-MS (m/z) 313, 315 [(MH)+ Br79' 8 1] .
Intermediate 53a : 5-bromo -N-(2,6-difluorophenyl)thiophene-2-carboxamide
and
Intermediate 53b: N-(2,6-difluorophenyl)-5-(trimethylstannyl)thiophene-2-carboxamide
Step 1: 5-Bromothiophene-2-carboxylic acid: To a 0 °C solution of 5-bromothiophene-2-
carboxaldehyde (5.0 g, 26.1 mmol) in acetone (50 mL) was added drop wise a freshly
prepared jone's reagent (25 mL) ( 25 g of chromium trioxide dissolved in 25 mL of cone
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 temperature for 4 h. Water (50 mL) was then
added to the above mixture followed by ethyl acetate (50 mL). The layers were separated and
the aqueous layer was extracted with ethyl acetate (2^50 mL). the combined extracts were
washed with water (50 mL), brine (50 mL), dried (Na2S0 4) 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) d 10.87 (brs, 1H, D20 Exchangeable), 7.63 (d, J = 4.0 Hz, 1H),
7.1 1 (d, J = 4.0 H , 1H).
Step 2: 5-Bromo-N-(2,6-difluorophenyl)thiophene-2-carboxamide To a 0 °C solution of 5-
bromothiophene-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
temperature 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, .2 eq) followed by pyridine (5 mL). The
reaction was gradually allowed to warm to room temperature and then stirred overnight at the
same temperature. The reaction was diluted with DCM (100 mL) and washed with water
(2x50 mL), 10% HCI (50 mL), brine (50 mL), dried (Na2S0 4) and filtered. The filtrate was
evaporated under vacuum to afford the 5 g (65%) of desired product as a white solid.
'HNMR (400 MHz, CDCI3) d 7.52 (s, 1H, D20 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 = 8.0 Hz, 2H); ESI-MS (m/z) 320, 322
[(MH)+, Br79' 8 1] .
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(PPh3)4 (454
mg, 0.39 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 atmosphere. The resulting mixture was cooled to room temperature 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)+] .
Intermediate 54
5-Bromo -N-(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 mineral oil, 0.44g, 18.49 mmol, 2.0
eq) and stirred for 1 h at room temperature. In a separate flask, to a solution of 5-
bromothiophene-2-carboxylic 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 temperature
for 2 h. The solvent and excess of oxalyl chloride were removed by evaporation 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 temperature overnight. 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 (Na2S0 4) 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. 1HNMR (400 MHz, CDC13) d
8.39 (d, J = 5.5 Hz, 1H), 8.36 (s, 1H), 8.05 (d, J = 5.5 Hz, 1H), 7.87 (s, 1H, D20
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' 8 1].
Intermediate-55a&55b
5-Bromo-N-(2,6-difluorophenyl)-3-methylthiophene-2-carboxamide (55a)
and
N-(2,6-Difluorophenyl)-3-methyl-5-(trimethylstannyl)thiophene-2-carboxamide (55b)
Step 1: 5-Bromo-3-methylthiophene-2-carbaldehyde: To 0 °C cooled solution of 3-
methylthiophene-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 temperature 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 (Na2S0 4) and filtered. The filtrate was
rotary evaporated to afford 11 g of the desired product as a brown solid. HNMR (400 MHz,
CDC13) d 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-carboxaldehyde by following the procedure
described for stepl of intermediate 53. 1HNMR (400 MHz, DMSO- ) d 13.20 (s, 1H, D20
Exchangeable), 7.20 (s, 1H), 2.43 (s, 3H);SI-MS (m/z) 221, 223 [(MH)+, Br79' 1] .
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, OMSO-d6) 9.78 (s, 1H, D20 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' 8 1] .
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
The title compound was prepared by following the procedure described for intermediate 53
from the corresponding starting materials. 1HNMR (400 MHz, CDC13) d 7.76 (s, 1H, D20
exchangeable), 7.60 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H), 7.24-7.16 (m, 1H), 6.93 (t,
J 8.5 Hz, 2H); ESI-MS (m/z) 318, 320 [(MH)+, Br79' 8 1] .
Intermediate 57
4-Bromo-N-(2,6-difluorophenyl)-3-methylthiophene-2-carboxamide
Step 1: Methyl 3-methylthiophene-2-carboxylate: To a solution of 3-Methylthiophene-2-
carboxylic acid (15 g, 105 mmol, 1.0 eq) in methanol (150 mL) was added cone 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 (Na2S0 4) and filtered.
The filtrate was evaporated under vacuum to afford 20 g (97%) of the desired product as a
oil. 'HNMR (400 MHz, CDC13) 7.38 (d, J = 5.0 Hz, 1H), 6.91 (d, J = 5.0 Hz, 1H), 3.85 (s,
3H), 2.55 (s, 3H); ESI- MS [(m/z) 157 (MH)+]
Step 2: Methyl 4-bromo-3-methylthiophene-2-carboxylate: A solution of methyl 3-
methylthiophene-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 temperature 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 temperature. 'HNMR (400 MHz,
CDC13) d 7.43 (s, 1H), 3.87 (s, 3H), 2.56 (s, 3H)
Step 3 : 4-Bromo -N-(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, 1.0 eq) followed by a solution of methyl-
4-bromo-3-methylthiophene-2-carboxylate (2.0 g, 8.58 mmol, 1.0 eq). The reaction was
allowed to come to room temperature and then stirred for 2 h at the same temperature. 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 (Na S0 4)
and filtered. The filtrate was rotary evaporated and the residue was purified by flash column
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) d 7.42 (s, 1H), 7.28-7.21 (m, 1H), 7.15
(s, 1H, D20 exchangeable), 7.03-6.94 (m, 2H), 2.56 (s, 3H); ESI-MS (m/z) 332, 334 [(MH)+,
Br79' 8 1] .
Intermediate 58a&58b
5-Bromo -N-(2,6-difluorophenyl)-l -methyl- lH-pyrrole-2-carboxamide (58a)
and
N-(2,6-Difluorophenyl)- 1-methyl-5-(trimethylstannyl)- H-pyrrole-2-carboxamide(58b)
Step-1: N-(2,6-Difluorophenyl)-l-methyl-lH-pyrrole-2-carboxamide: A mixture of 1-
methylpyrrol-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 temperature 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 temperature and stirred for 12 h. The reaction 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 HC1 (20 mL), brine (20 mL), dried
(Na2S0 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 of
N-(2,6-difluorophenyl)-l -methyl- lH-pyrrole-2-carboxamide (3.40 g, 14.39 mmol, 1.0 eq)
and NBS (2.70 g, 15.1 1 mmol, 1.05 eq) in DCM (30 mL) was stirred at room temperature 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
(Na2S04) 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) d 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 79'8 1]
Step-3 : N-(2,6-Difluorophenyl)- 1-methyl-5-(trimethylstannyl)- 1H-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(PPh 3)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 atmosphere. The resulting mixture was cooled to
room temperature 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
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-2,6-
difluorobenzamide
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-tetramethyl-l,3,2-
dioxaborolan-2-yl)phenyl)isoxazol-4(5 H)-one, Intermediate l a (419 mg, 1.27 mmol, 1.0 eq),
aq sodium carbonate solution (2N, 4 mL) and Pd(PPh3)2Cl2 (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
atmosphere. The reaction mixture was cooled to room temperature 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, OMSO-d6) d 11.82 (s, 1H, D20
exchangeable), 9.53 (s, 1H), 8.69 (s, 1H), 8.1 1 (d, J = 1.0 Hz, 1H), 7.99 (dd, J = 1.0, 8.0 Hz,
1H), 7.65-7.59 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 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:
Structure 1H NMR/ESI-MS(MH)+
IUPAC name
Example 2: N-(5-(5-
'HNMR (400 MHz, DMSO-i¾ d
(5,5-Dimethyl-4-oxo-
11.82 (s, 1H, D20 exchangeable),
4,5-dihydroisoxazol-
9.48 (s, 1H), 8.73 (s, 1H), 8.12 (s,
3-yl)-2-
1H), 8.00 (d, J =8.0 Hz, 1H), 7.55
methylphenyl)pyrazin °
(d, J =8.0 Hz, 1H), 2.86 (s, 3H),
-2-yl)-4-methyl-
2.45 (s, 3H), 1.44 (s, 6H); ESI-MS
1,2,3-thiadiazole-5-
(m/z) 423 (MH)+.
carboxamide
Example 3: N-(5'- 'HNMR (400 MHz, CDC13) d 8.00-
(5,5-Dimethyl-4-oxo- 7.98 (m, 2H), 7.70 (d, J =8.0 Hz,
4,5-dihydroisoxazol- 3H), 7.46-7.42 (m, 1H), 7.38-7.35
3-yl)-2'-methyl-[l,l'- (m, 3H), 7.02 (t, J =8.0 Hz, 2H),
biphenyl]-4-yl-2,6- 2.33 (s, 3H), 1.46 (s, 6H); ESI-MS

'HNMR (400 MHz, DMSO- ) d
11.19 (s, 1H, D20 exchangeable),
Example 7: N-(6-(5-
8.93 (s, 1H), 8.27 (dd, J = 8.5, 2.5
(5,5-dimethyl-4-oxo-
Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H),
4,5-dihydroisoxazol-
7.96 (s, 1H), 7.66-7.62 (m, 1H),
3-yl)-2-
7.58 (d, J = 8.5 Hz, 1H), 7.52 (d, J
ethylphenyl)pyridin-
= 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz,
3-yl)-2,6-
2H), 2.75 (q, J = 7.5 Hz, 2H), 1.42
difluorobenzamide
(s, 6H), 1.07 (t, J = 7.5 Hz, 3H);
ESI-MS (m/z) 450 (MH)+.
'HNMR (400 MHz, CDC13) d 9.76
Example 8: N-(5-(5- (s, 1H), 8.54 (s, 1H, D20
(5,5-dimethyl-4-oxo- exchangeable), 8.34 (s, 1H), 8.16
4,5-dihydroisoxazol- (dd, J = 8.0, 1.5 Hz, 1H), 8.07 (s,
3-yl)-2- 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.51-
isopropylphenyl)pyra 7.46 (m, 1H), 7.05 (t, J = 8.5 Hz,
zin-2-yl)-2,6- 2H), 3.25-3.18 (m, 1H), 1.43 (s,
difluorobenzamide 6H), 1.22 (d, J = 7.0 Hz, 6H); ESIMS
(m/z) 465 (MH)+.
Example 9: N-(5'- 'HNMR (400 MHz, CDC13) d 8.07
(5,5-dimethyl-4-oxo- (dd, J = 8.0, 1.5 Hz, 1H), 7.93 (s,
4,5-dihydroisoxazol- 1H), 7.71 (d, J = 8.0 Hz, 2H+1H
3-yl)-2'-isopropyl- D20 exchangeable), 7.49 (d, J = 8.0
[l,l'-biphenyl]-4-yl)- ~ 'N Hz, 1H), 7.46-7.42 (m, 1H), 7.33
2,6- (d, J = 8.0 Hz, 2H), 7.02 (t, J = 8.0
difluorobenzamide Hz, 2H), 3.15-3.08 (m, 1H), 1.46
(s, 6H), 1.18 (d, J = 7.0 Hz, 6H);

3-yl)-[l,l'-biphenyl]- 6H), 7.53 (t, J = 8.0 Hz, IH), 7.48-
4-yl)-2,6- 7.39 (m, 1H),7.01 (t, J 8.5 Hz,
difluorobenzamide 2H), 1.48 (s, 6H); ESI-MS (m/z)
421 (MH)+.
'HNMR (400 MHz, CDC13) d 9.76
Example 23: 2,6-
(s, IH), 8.61 (s, IH, D20
difluoro -N-(5-(5-(4-
exchangeable), 8.36 (s, IH), 7.79
methoxy-5,5-
(s, IH), 7.73 (dd, J 8.0, 1.0 Hz,
dimethyl-4,5-
1H), 7.52-7.45 (m, 1H), 7.37 (d, J =
dihydroisoxazol-3-
8.0 Hz, IH), 7.05 (t, J = 8.0 Hz,
yl)-2-
2H), 4.57 (s, IH), 3.43 (s, 3H), 2.43
methylphenyl)pyrazin
(s, 3H), 1.53 (s, 3H), 1.34 (s, 3H);
-2-yl)benzamide
ESI-MS (m/z) 453 (MH)+.
'HNMR (400 MHz, CDC13) 7.73
Example 24: 2,6- (s, IH, D20 exchangeable), 7.70 (d,
Difluoro-N-(5'-(4- J = 8.5 Hz, 2H), 7.65 (dd, J = 8.0,
methoxy-5,5- 1.5 Hz, IH), 7.60 (d, J = 1.5 Hz,
dimethyl-4,5- IH), 7.46-7.42 (m, IH), 7.36 (d, J =
dihydroisoxazol-3- 8.5 Hz, 2H), 7.32 (d, J = 8.0 Hz,
yl)-2'-methyl-[l,l'- IH), 7.02 (t, J = 8.0 Hz, 2H), 4.55
biphenyl]-4- (s, 1H), 3.43 (s, 3H), 2.31 (s, 3H),
yl)benzamide 1.53 (s, 3H), 1.34 (s, 3H); ESI-MS
(m/z) 451 (MH)+.
Example 25:N-(4'- 'HNMR (400 MHz, CDC13) d 8.04
(5,5-Dimethyl-4-oxo- (s, 1H), 8.00 (d, J = 8.0 Hz, IH),
4,5-dihydroisoxazol- 7.79 (s, IH, D20 exchangeable),
3-yl)-2'-methyl-[l ,r- 7.74 (d, J = 8.5 Hz, 2H), 7.48-7.42

Example 29: N-(3'- 'HNMR (400 MHz, CDC13) d 7.73
(5,5-Dimethyl-4-oxo- (s, IH, D20 exchangeable), 7.70 (d,
4,5-dihydroisoxazol- J = 8.5 Hz, 2H), 7.48-7.41 (m, 2H),
3-yl)-2'-methyl-[l,l - 7.35-7.33 (m, 4H), 7.02 (t, J = 8.5
biphenyl]-4-yl)-2,6- Hz, 2H), 2.25 (s, 3H), 1.50 (s, 6H);
difluorobenzamide ESI-MS (m/z) 435 (MH)+.
Example 30: N-(5-(3- 'HNMR (400 MHz, DMSO- )
(5,5-Dimethyl-4-oxo- 11.18 (s, IH, D20 exchangeable),
4,5-dihydroisoxazol- 8.93 (d, J = 2.5 Hz, IH), 8.26 (dd, J
3-yl)-2- = 9.5, 2.5 Hz, IH), 7.67-7.42 (m,
methylphenyl)pyridin 5H), 7.30 (t, J = 8.0 Hz, 2H), 3.34
-2-yl)-2,6- (s, 3H), 1.46 (s, 6H); ESI-MS (m/z)
difluorobenzamide 436 (MH)+.
'HNMR (400 MHz, CDC13) d 7.79
Example 31: N-(3'- (s, IH, D20 exchangeable), 7.72 (d,
(5,5-Dimethyl -4-oxo- J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz,
4,5-dihydroisoxazol- 2H), 7.52 (dd, J = 7.5, 1.5 Hz, IH),
3-yl)-2'-methoxy- 7.48 (dd, J = 7.5, 1.5 Hz, IH), 7.44-
[l,l'-biphenyl]-4-yl)- 7.39 (m, IH), 7.27 (t, J = 7.5 Hz,
2,6- IH), 7.01 (t, J = 8.5 Hz, 2H), 3.38
difluorobenzamide (s, 3H), 1.50 (s, 6H); ESI-MS (m/z)
451 (MH)+.
Example 32: N-(5-(5- 'HNMR (400 MHz, CDC13) d 9.78
(4-Acetyl-5,5-
F
(s, IH), 8.53 (s, IH, D20
dimethyl-4,5- z exchangeable), 8.41 (s, IH), 7.87
dihydro- 1,3,4- (s, IH), 7.80 (d, J 8.0 Hz, IH),
oxadiazol-2-yl)-2- 7.52-7.48 (m IH), 7.38 (d, J = 8.0

[l,l'-biphenyl]-4- (d, J = 8.0 Hz, IH), 7.36 (d, J = 8.5
yl)benzamide Hz, 2H), 7.22 (t, J = 8.0 Hz, 2H),
3.65 (t, J = 7.0 Hz, 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)+.
'HNMR (400 MHz, CDC13) d 7.74
(dd, J = 8.5, 2.0 Hz, IH), 7.71 (d, J
Example 36: N-(2'-
= 8.0 Hz, 2H+1H D20
Ethyl-5'-(4-methyl-5-
exchangeable), 7.67 (s, IH), 7.46-
oxo-4,5-dihydro-
7.42 ( , IH), 7.41 (d, J = 8.5 Hz,
1,3,4-oxadiazol-2-yl)-
IH), 7.32 (d, J = 8.0 Hz, 2H), 7.03
[l,l'-biphenyl]-4-yl)-
(t, J = 8.0 Hz, 2H), 3.49 (s, 3H),
2,6-
2.65 (q, J = 7.5 Hz, 2H), 1.12 (t, J =
difluorobenzamide
7.5 Hz, 3H); ESI-MS (m/z) 436
(MH)+.
'HNMR (400 MHz, CDC13) d 7.77
(dd, J = 8.0, 1.5 Hz, IH), 7.73 (d, J
Example 37: 2- = 8.5 Hz, 2H), 7.69 ( d, J = 1.5 Hz,
Chloro -N-(2'-ethyl-5'- IH), 7.62 (s, IH, D20
(4-methyl-5-oxo-4,5- exchangeable), 7.42 (d, J = 8.0 Hz,
dihydro- 1,3,4- IH), 7.42-7.37 (m, IH), 7.35 (d, J =
oxadiazol-2-yl)-[l , - 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz,
biphenyl] -4-yl)-6- IH), 7.14 (m, IH), 3.50 (s, 3H),
fluorobenzamide 2.66 (q, J = 7.5 Hz, 2H), 1.15 (t, J =
7.5 Hz, 3H); ESI- MS [(m/z) 452,
454 [(MH)+, CI 35' 37)
'HNMR (400 MHz, CDC13) d 7.76
(dd, J 8.5, 2.0 Hz, IH), 7.73 (d, J
Example 38: N-(2'-
= 8.0 Hz, 2H), 7.61 (s, IH, D20
Ethyl-5'-(4-methyl-5-
exchangeable), 7.42 (d, J = 8.5 Hz,
oxo-4,5-dihydro-
IH), 7.36-7.31 (m, 3H), 7.10 (d, J =
1,3,4-oxadiazol-2-yl)-
7.5 Hz, IH), 7.02 (t, J = 8.0 Hz,
[l,l'-biphenyl]-4-yl)-
2H), 3.51 (s, 3H), 2.68 (q, J = 7.5
2-fluoro-6-
Hz, 2H), 2.52 (s, 3H), 1.15 (t, J =
methylbenzamide
7.5 Hz, 3H); ESI-MS (m/z) 432
(MH)+.
Example 39: N-(2'-
'HNMR (400 MHz, CdCl3) d 7.78
Ethyl-5'-(4-methyl-5-
(dd, J = 8.5, 2.0 Hz, IH), 7.70-7.64
oxo-4,5-dihydro-
(m, 4H), 7.43 (d, J = 8.0 Hz, IH),
1,3,4-oxadiazol-2-yl)-
7.36 (d, J = 7.5 Hz, 2H), 3.50 (s,
[l,l'-biphenyl]-4-yl)-
3H), 3.03 (s, 3H) 2.66 (q, J = 7.5
4-methyl- 1,2,3-
Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H);
thiadiazole-5-
ESI-MS (m/z) 422 (MH)+
carboxamide
Example 40: 2,6- 'HNMR (400 MHz, CDC13) 7.81-
Difluoro -N-(2'- 7.77 (m, 2H), 7.72 (d, J = 8.5 Hz,
methoxy-5'-(4- 2H), 7.67 (brs, IH, D20
methyl-5-oxo-4,5- exchangeable), 7.56 (d, J - 8.5 Hz,
dihydro- 1,3,4- 2H), 7.47-7.42 (m, IH), 7.05 (d, J =
oxadiazol-2-yl)- [1, - 8.5 Hz, IH), 7.03 (t, J = 8.0 Hz,
biphenyl]-4- 2H), 3.89 (s, 3H), 3.49 (s, 3H);
yl)benzamide ESI-MS (m/z) 438 (MH)+

Example 44: N-(2'- 'HNMR (400 MHz, CDC13) 7.89
(Difluoromethoxy)- (d, J = 1.5 Hz, IH), 7.81-7.73 (m,
F 5'-(4-methyl-5-oxo- 4H), 7.52 (d, J = 8.5 Hz, 2H),
4,5-dihydro-l,3,4- 7.48-7.40 (m, IH), 7.33 (d, J = 8.5
oxadiazol-2-yl)-[ 1,1'- F Hz, IH), 7.02 (t, J = 8.5 Hz, 2H),
biphenyl]-4-yl)-2,6- 6.44 (t, J = 73 Hz, 1H), 3.49 (s,
difluorobenzamide 3H); ESI-MS (m/z) 474 (MH)+
Example 45:N-(2'-
1HNMR (400 MHz, CDC13) d 7.91
(Difluoromethoxy)-
(d, J = 2.0 Hz, IH), 7.84 (dd, J =
5'-(4-methyl-5-oxo-
8.5, 2.0 Hz, IH), 7.77 (s, IH, D 0
4,5-dihydro-l,3,4-
exchangeable), 7.71 (d, J - 8.5 Hz,
oxadiazol-2-yl)-[ 1,1'-
IH), 7.57 (d, J = 8.5 Hz, 2H), 7.36
biphenyl]-4-yl)-4-
(d, J = 8.5 Hz, IH), 6.47 (t, J = 73
methyl- 1,2,3 -
Hz, IH), 3.52 (s, 3H), 3.02 (s, 3H);
thiadiazole-5-
ESI-MS (m/z) 460 (MH)+
carboxamide
Example 46: N-(2'- 'HNMR (400 MHz, CDC13) d 7.82
Chloro-5'-(4-methyl- (d, J = 2.5 Hz, IH), 7.76-7.71 (m,
5-oxo-4,5 -dihydro- C 4H), 7.58 (d, J = 8.0 Hz, IH), 7.48
1,3,4-oxadiazol-2-yl)- (d, J = 8.5 Hz, 2H), 7.45-7.42 (m,
[l,l'-biphenyl]-4-yl)- F IH), 7.03 (d, J = 8.0 Hz, 2H), 3.50
2,6- (s, 3H); ESI-MS (m/z) 442, 444
difluorobenzamide [(MH)+, (CI 35' 37)]

4,5-dihydro- 1,3,4- = 7.0, 2.0 Hz, 1H), 7.48-7.49 (m,
oxadiazol-2-yl)-[ 1,1'- 1H), 7.43-7.42 (d, J = 7.0 Hz, 1H),
biphenyl]-4-yl)- 1,2,3- 7.37 (d, J = 8.5 Hz, 2H), 3.43 (s,
thiadiazole-5- 3H), 2.83 (s, 3H), 2.41 (s, 3H);
carboxamide ESI-MS (m/z) 408 (MH)+
Example 51: N-(2'-
HNMR (400 MHz, CDC13) d 7.78
ethyl-3'-(4-methyl-5-
(dd, J = 7.0, 2.5 Hz, 1H), 7.73 (s,
oxo-4,5-dihydro-
1H, D20 exchangeable), 7.67 (d, J
1,3,4-oxadiazol-2-yl)-
= 8.0 Hz, 2H), 7.37-7.32 (m, 4H),
[l,l'-biphenyl]-4-yl)-
3.54 (s, 3H), 3.02 (s, 3H), 2.92 (q, J
4-methyl-l,2,3-
= 7.5 Hz, 2H), 1.01 (t, J = 7.5 Hz,
thiadiazole-5-
3H); ESI- MS (m/z) 422 (MH)+
carboxamide
Example 52: N-(2'- 'HNMR (400 MHz, CDC13) d 7.93-
ethyl-3'-(4-methyl-5- 7.76 (m, 1H), 7.76-7.71 (m, 3H),
oxo-4,5-dihydro- 7.50-7.43 (m, 1H), 7.36-7.31 (m,
l,3,4-oxadiazol-2-yl)- 4H), 7.04 (t, J = 8.5 Hz, 2H), 3.54
[l,l'-biphenyl]-4-yl)- (s, 3H), 2.94 (q, J = 7.5 Hz, 2H),
2,6- 1.02 (t, J = 7.5 Hz, 3H); ESI- MS
difluorobenzamide (m/z) 435 (MH)+
Example 53: N-(5- 'HNMR (400 MHz, CDC13) d
(5,5-Dimethyl-4,5- 11.80 (brs, 1H, D20 exchangeable),
dihydroisoxazol-3- C 3 9.50 (s, 1H), 8.69 (s, 1H), 7.71 (s,
yl)-2- 1H), 7.67-7.60 (m, 2H), 7.42 (d, J =
methylphenyl)pyrazin 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz,
F
-2-yl)-2,6- 2H), 3.21 (s, 2H), 2.40 (s, 3H), 1.38
difluorobenzamide (s, 6H); ESI-MS (m/z) 423 (MH)+.
'HNMR (400 MHz, CDC13) d 9.75
Example 54: Methyl (s, 1H), 8.62 (s, 1H, D20
3-(3-(5-(2,6- exchangeable), 8.35 (s, 1H), 7.68
difluorobenzamido)p (d, J = 1.5 Hz, 1H), 7.65 (dd, J =
yrazin-2-yl)-4- 8.0, 1.5 Hz, 1H), 7.52-7.47 ( ,
methylphenyl)-5- 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.02
methyl-4,5- (t, J = 8.0 Hz, 2H), 3.90 (d, J = 17.0
dihydroisoxazole-5- Hz, 1H), 3.81 (s, 3H), 3.25 (d, J =
carboxylate 17.0 Hz, 1H), 2.43 (s, 3H), 1.72 (s,
3H); ESI-MS (m/z) 467 (MH)+.
'HNMR (400 MHz, CDC13) d 7.70
Example 55: Methyl-
(d, J = 8.5 Hz, 2H), 7.58 (dd, J =
3-(4'-(2,6-
8.0, 1.5 Hz, 1H), 7.47 (d, J 1.5
difluorobenzmido)-6-
Hz, 1H), 7.49-7.40 (m, 1H), 7.33-
methyl-[l,l'-
7.29 (m, 3H), 7.03 (t, J = 8.0 Hz,
biphenyl]-3-yl)-5-
2H), 3.88 (d J = 17.0 Hz, 1H), 3.80
methyl-4,5-
(s, 3H), 3.22 (d, J = 17.0 Hz, 1H),
dihydroisoxazole-5-
2.30 (s, 3H), 1.72 (s, 3H); ESI-MS
carboxylate
(m/z) 465 (MH)+
'HNMR (400 MHz, DMSO- ) d
Example 56: 2,6-
11.17 (s, 1H, D20 exchangeable),
Difluoro -N-(2'-
8.92 (d, J = 2.0 Hz, 1H), 8.26 (dd, J
methyl-5'-(l-oxa-2-
= 8.5, 2.5 Hz, 1H), 7.66-7.59 (m,
azaspiro[4.4]non-2-
v 4H), 7.38 (d, J = 8.0 Hz, 1H), 7.30
en-3-yl)-[l,l'-
(t, J = 8.5 Hz, 2H), 2.37 (s, 3H),
biphenyl]-4-
1.92-1.89 (m, 2H), 1.78-1.72 (m,
yl)benzamide
6H); ESI-MS (m/z) 448 (MH)+.
'HNMR (400 MHz, DMSO-i/ )
Example 57: 2,6- 11.81 (s, 1H, D20 exchangeable),
Difluoro -N-(5-(2- 9.51 (s, 1H), 8.70 (s, 1H), 7.72 (s,
methyl-5-(l -oxa-2- 1H), 7.67 (dd, J = 8.0, 1.5 Hz, 1H),
azaspiro[4.4]non-2- 7.65-7.60 (m, 1H), 7.43 (d, J = 8.0
en-3- Hz, 1H), 7.27 (t, J = 8.5 Hz, 2H),
yl)phenyl)pyrazin-2- 2.41 (s, 3H), 1.95-1.91 (m, 2H),
yl)benzamide 1.80-1.67 (m, 6H); ESI-MS (m/z)
449 (MH)+.
Example 58: 2,6-
'HNMR (400 MHz, CDC13) d 7.99-
Difluoro -N-(2'-
7.97 ( , 2H), 7.70 (d, J = 8.5 Hz,
methyl-5'-(4-oxo-l-
2H+1H D20 exchangeable), 7.41-
oxa-2-
7.37 (m, 1H), 7.35 (d, J =7.5 Hz,
azaspiro[4.5]dec-2- ~
3H), 7.01 (t, J =8.0 Hz, 2H), 2.32
en-3-yl)-[l,l'-
(s, 3H), 1.85-0.82 (m, 10H); ESIbiphenyl]-
4-
MS (m/z) 475 (MH)+.
yl)benzamide
'HNMR (400 MHz, CDC13) d 9.75
Example 59: N-(5-(5-
(s, 1H), 8.66 (s, 1H), 8.34 (s, 1H,
(4,4-Dimethyl-4,5-
D20 exchangeable), 7.98 (s, 1H),
dihydrooxazol-2-yl)-
2-
7.90 (d, J =8.0 Hz, 1H), 7.51-7.47
methylphenyl)pyrazin
(m, 1H), 7.36 (d, J =8.0 Hz, 1H),
7.05 (t, . = 8.0 Hz, 2H), 4.1 1 (s,
e-2-yl)-2,6-
2H), 2.44 (s, 3H), 1.39 (s, 6H);
difluorobenzamide
ESI-MS (m/z) 423 (MH)+.
'HNMR (400 MHz, CDC13) d 8.70
Example 60: N-(5-(5- (d, J = 1.5 Hz, 1H), 8.39 (dd, J =
(4,4-dimethyl-4,5- 2.0, 8.5 Hz, 1H), 8.23 (s, 1H, D20
dihydrooxazol-2-yl)- CH exchangeable), 7.94 (s, 1H), 7.83
2- (d, J = 8.0 Hz, 1H), 7.46-7.40 (m,
methylphenyl)pyridin 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.02
-2-yl)-2,6- (t, J = 8.0 Hz, 2H), 4.09 (s, 2H),
difluorobenzamide 2.41 (s, 3H), 1.35 (s, 6H); ESI-MS
(m/z) 422 (MH)+.
'HNMR (400 MHz, CDC13) d 7.82-
Example 61: N-(5'-
7.80 (m, 2H), 7.77 (brs, 1H, D20
(4,4-dimethyl-4,5-
exchangeable), 7.68 (d, J 8.0 Hz,
dihydrooxazol-2-yl)-
2H), 7.48-7.40 (m, 1H), 7.35-7.29
2'-methyl-[l,l'-
(m, 3H), 7.02 (t, J = 8.0 Hz, 2H),
biphenyl]-4-yl)-2,6-
4.09 (s, 2H), 2.31 (s, 3H), 1.37 (s,
difluorobenzamide
6H); ESI-MS (m/z) 421 (MH)+.
Example 62: 2,6- 'HNMR (400 MHz, DMSO-d 6)
Difluoro -N-(2'- 10.95 (s, 1H, D20 exchangeable),
methyl-5 '-(4-methyl- 7.81 (d, J = 8.0 Hz, 2H), 7.66-7.60
5-oxo-4,5-dihydro- ( , 1H), 7.55-7.41 (m, 3H), 7.43
1,2,4-oxadiazol-3-yl)- (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0
[l,l'-biphenyl]-4- Hz, 2H), 3.24 (s, 3H), 2.35 (s, 3H);
yl)benzamide ESI-MS (m/z) 422 (MH)+
Example 63: 4- 'HNMR (400 MHz, DMSO-d 6) d
Methyl-N-(2'-methyl- 10.88 (s,lH, D20 exchangeable),
5'-(4-methyl-5-oxo- 7.8 (d, J = 8.5 Hz, 2H), 7.64 (dd, J
4,5-dihydro- 1,2,4- = 8.5, 1.5 Hz, 1H), 7.55 (d, J = 8.0
oxadiazol-3-yl)-[ 1,1'- Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H),
biphenyl]-4-yl)-l,2,3- 3.24 (s, 3H), 2.83 (s, 3H), 2.35 (s,
thiadiazole-5- 3H); ESI-MS (m/z) 406 (M-H)
carboxamide
'HNMR (400MHz, CDC13) d 7.71
Example 64: Ethyl 3- (d, J = 8.5 Hz, 2H), 7.52 (dd, J =
(4'-(2,6- 8.0, 1.5 Hz, 1H), 7.48 (d, J = 1.5
difluorobenzamido)- Hz, 1H), 7.47-7.41 (m, 1H), 7.31
6-methyl-[l ,r- (d, J = 8.5 Hz, 2H), 7.28 (d, J =8.0
biphenyl]-3-yl)-4,4- Hz, 1H), 7.03 (t, J = 8.0 Hz, 2H),
dimethyl-4,5- 4.22 (q, J =7.5 Hz, 2H), 2.29 (s,
dihydroisoxazole-5- 3H), 1.50 (s, 3H),1.49 (s, 3H), 1.21
carboxylate (t, J =7.5 Hz, 3H); ESI-MS (m/z)
493 (MH)+
'HNMR (400 MHz, CDC13) d 9.79
Example 65: N-(5-(5- (s, IH), 9.13 (d, J = 15 Hz, IH, D20
(5,5-Dimethyl-4-oxo- exchangeable), 8.47 (s, IH), 8.23-
4,5-dihydroisoxazol- 8.19 (m, 2H), 8.07 (d, J = 8.0 Hz,
3-yl)-2- IH), 7.62-7.56 (m, IH), 7.42 (d, J =
methylphenyl)pyrazin 8.0 Hz, IH), 7.36 (t, J = 8.0 Hz,
e-2-yl)-2- IH), 7.25-7.21 (m, IH), 2.46 (s,
fluorobenzamide 3H), 1.47 (s, 6H); ESI-MS (m/z)
419 (MH)+.
Example 66: N-(5-(5- 'HNMR (400 MHz, DMSO-i/6) d
(5,5-Dimethyl-4-oxo- 11.36 (s, IH, D20 exchangeable),
4,5-dihydroisoxazol- 9.52 (s, 1H), 8.68 (s, IH), 8.10 (s,
3-yl)-2- IH), 7.98 (d, J = 8.0 Hz, IH), 7.83

fluorobenzamide 2H), 2.45 (s, 3H), 1.43 (s, 6H);
ESI-MS (m/z) 419 (MH) +.
'HNMR (400 MHz, DMSO- 5) d
Example 70: N-(5-(5-
11.47 (s, IH, D20 exchangeable),
(5,5-Dimethyl-4-oxo-
9.50 (s, IH), 8.70 (s, IH), 8.1 1 (s,
4,5-dihydroisoxazol- ,
IH), 7.98 (dd , J = 8.0, 1.5 Hz, IH),
3-yl)-2-
7.96-7.89 (m, IH), 7.81-7.74 (m,
methylphenyl)pyrazin
IH), 7.54 (d, J = 8.0 Hz, IH), 2.44
e-2-yl)-2,4,5-
(s, 3H), 1.43 (s, 6H); ESI-MS (m/z)
trifluorobenzamide
455 (MH) +.
'HNMR (400 MHz, DMSO- ) d
Example 71: N-(5-(5- 11.26 (s, IH, D20 exchangeable),
(5,5 -Dimethyl-4-oxo- 9.55 (s, IH), 8.65 (s, IH), 8.1 1 (s,
4,5-dihydroisoxazol-
,
IH), 7.98 (dd , J = 8.0, 1.5 Hz, IH),
3-yl)-2- 7.54 (d, J = 8.0 Hz, IH), 7.34-7.30
methylphenyl)pyrazin (m, 2H), 7.22-7.19 (m, IH), 2.44
e-2-yl)-2,3- (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H),
dimethylbenzamide 1.43 (s, 6H); ESI-MS (m/z) 429
(MH) +.
Example 72: N-(5-(5- 'HNMR (400 MHz, DMSO- 5) d
(5,5-Dimethyl-4-oxo- 11.56 (s, IH, D20 exchangeable),
4,5-dihydroisoxazol- 9.55 (s, IH), 8.73 (s, IH), 8.25 (d, J
3-yl)-2- = 8.0 Hz, 2H), 8.13 (s, 1H), 7.99
methylphenyl)pyrazin 1 (dd, J = 8.0, 2.0 Hz, IH), 7.94 (d, J
e-2-yl)-4- = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz,
trifluoromethylbenza IH), 2.45 (s, 3H), 1.43 (s, 6H);
mide ESI-MS (m/z) 469 (MH) +.
'HNMR (400 MHz, CDC13) d 9.76
(s, IH), 8.50 (s, IH, D20
Example 73: N-(5-(5-
exchangeable), 8.44 (s, IH), 8.19
(5,5-Dimethyl-4-oxo-
(d, J = 1.5 Hz, IH), 8.08 (dd, J =
4,5-dihydroisoxazol-
8.0, 1.5 Hz, 1H), 7.84 ( d, J = 7.0
3-yl)-2-
Hz, 1H), 7.80-7.76 (m, 1H), 7.42
methylphenyl)pyrazin r
(d, J = 8.0 Hz, 1H), 7.14 (t, J = 8.5
e-2-yl)-4-fluoro-3-
Hz, 1H), 2.46 (s, 3H), 2.37 (s, 3H),
methylbenzamide
1.47 (s, 6H); ESI- MS (m/z) 433
(MH)+
'HNMR (400 MHz, DMSO-d6) d
Example 74: N-(5-(5-
11.26 ( s, IH, D20 exchangeable),
(5,5-Dimethyl-4-oxo-
9.54 (s, IH), 8.66 (s, IH), 8.10 ( d,
4,5-dihydroisoxazol-
J = 2.0 Hz, IH), 7.98 (dd, J = 8.0,
3-yl)-2-
~7V 1.5 Hz, IH), 7.56- 7.53 (m, 2H),
methylphenyl)pyrazin
7.45-7.41 (m, IH), 7.34- 7.29 (m,
e-2-yl)-2-
2H), 2.45 (s, 3H), 2.44 (s, 3H), 1.43
methylbenzamide
(s, 6H); ESI- MS (m/z) 415 (MH+)
'HNMR (400 MHz, CdCl3) d 9.78
Example 75: N-(5-(5-
( s, IH), 8.73 (s, IH, D20
(5,5-Dimethyl-4-oxoexchangeable),
8.50 (s, IH), 8.23 (
4,5-dihydroisoxazold,
J = 1.5 Hz, 1H), 8.12 ( dd, J =
3-yl)-2-
8.0, 1.5 Hz, 1H), 8.05 (s, 1H), 7.92
methylphenyl)pyrazin
I 0 ' (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.5
e-2-yl)-3-fluoro-5-
Hz, 1H), 7.45 ( d, J = 8.0 Hz, 1H),
trifluoromethylbenza
2.49 (s, 3H), 1.5 (s, 6H); ESI- MS
mide
(m/z) 487 (MH)+
Example 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 , -biphenyl]-4-yl)benzamide: To a stirred
solution of 3-bromo-4-methylbenzaldehyde (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(PPh 3)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 atmosphere. The reaction mixture was
cooled to room temperature 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.
HN R (400 MHz, DMSO-fi ) d 9.98 (s, 1H), 7.86 (s, 1H, D20 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'-((hydroxyimino)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 , -
biphenyl]-4-yl)benzamide (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 temperature for 1 h. The solvent was evaporated under vacuum and the
residue was diluted with water (10 mL) and extracted with ethyl acetate (3x20 mL). The
combined organic layers were dried (Na2S0 4) and filtered. The filtrate was rotary evaporated
to afford 650 g of the title compound as a white solid. 'HNMR (400 MHz, DMSO- ) d
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 : Methyl-3-(4'-(2,6-difluorobenzmido)-6-methyl-[ 1,1'-biphenyl]-3-yl)-5-(2-methoxy-
2-oxoethyl)-4,5-dihydroisoxazole-5-carboxylate: To a solution of 2,6-difluoro -N-(5'-
((hydroxyimino)methyl)-2'-methyl-[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
x , 0.6 mmol, 0.6 eq). The resulting mixture was heated to 70 °C for lh. The reaction was
then cooled down to room temperature 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 temperature 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 (Na2S0 ) 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. 'HNMR (400
MHz, CDC13) d 7.76 (s, 1H, D20 exchangeable), 7.70 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.0 Hz,
1H), 7.49 (s, 1H), 7.45-7.41 (m, 1H), 7.33-7.30 (m, 3H), 7.02 (t, J = 8.0 Hz, 2H), 4.02 (d, J =
17.0 Hz, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.49 (d, J = 17.0 Hz, 1H), 3.26 (d, J = 17.5 Hz, 1H),
2.98 (d, J = 17.5 Hz, 1H), 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-2-
oxoethyl)-4,5-dihydroisoxazole-5-carboxylate
The title compound was prepared by following the procedure similar to that described in
Example 76. *HNMR (400 MHz, DMSO- ) d 11.82 (s, IH, D20 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, J = 8.0 Hz, 2H), 3.96 (d, J = 17.0 Hz, IH), 3.71 (d, J = 17.0
Hz, IH), 3.71 (s, 3H), 3,61 (s, 3H), 3.20 (d, J = 17.0 Hz, IH), 3.13 (d, J 17.0 Hz, IH), 2.42
(s, 3H); ESI-MS (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-3-
yl)phenyl)pyrazin-2-yl)benzamide
The title compound was prepared by following 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) d 9.76 (s, IH), 8.56 (s, IH, D20 exchangeable), 8.40 (s, IH),
7.83 (d, J 2.0 Hz, IH), 7.43 (dd, J = 8.0, 2.0 Hz, IH), 7.52-7.49 (m, IH), 7.36 (d, J = 8.0
Hz, IH), 7.07 (t, J = 7.5 Hz, 2H), 5.14-5.13 (m, IH), 4.29 (d, J = 9.5 Hz, IH), 2.50-2.39 (m,
2H), 2.47 (s, 3H), 2.30-2.26 ( , IH), 2.17-2.12 (m, IH), 2.00-1.93 (m, 2H); ESI- MS (m/z)
463 (MH)+.
Example 78
2-Chloro -N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)benzamide
Intermediate 1b Example 78
To a 0°C cooled and stirred, solution of 2-chlorobenzoyl chloride (43 , 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 , 0.44 mmol, 1.3 eq). The resulting mixture
was stirred at room temperature for 15 h. The reaction was diluted with DCM (10 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 as eluent) to afford 50 mg of the title
product as a white solid. 'HNMR (400 MHz, CDC13) 9.78 (s, 1H), 8.80 (s, 1H, D20
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)+, CI 35'3 ].
The below Examples 79 to 83 were prepared by following a procedure similar to that
described in Example 78:
Example No:
Structure 1H NMR/ESI-MS(MH)+
IUPAC name
Example 79: N-(5- 'HNMR (400 MHz, CDC13) d 9.74
(5-(5,5-dimethyl-4- (s, 1H), 8.40 (s, 1H, D20
oxo-4,5-dihydro iso exchangeable), 8.37 (s, 1H), 8.17 (d,
xazol-3-yl)-2-methyl J = 1.5 Hz, 1H), 8.09 (dd, J = 8.0, 2.0
phenyl)pyrazin-2-yl) Hz, 1H), 7.64-7.59 (m, 2H), 7.46-
-2-fluoro-6-(tri fluo 7.42 (m, 2H), 2.47 (s, 3H), 1.48 (s,
romethyI)benzamide 6H); ESI-MS (m/z) 487 (MH)+
Example No:
Structure 1H NMR/ESI-MS(MH)+
IUPAC name
'HNMR (400 MHz, CDC13) d 9.79
Example 80: 2- (s, IH), 8.56 (s, IH, D20
Chloro-N-(5-(5-(5,5- exchangeable), 8.32 (s, IH), 8.16 (d,
dimethyl-4-oxo-4,5- J = 1.5 Hz, IH), 8.10 (dd, J = 8.0, 2.0
dihydroisoxazol-3 - Hz, IH), 7.43 (d, J = 8.0 Hz, IH),
yl)-2-methyl phenyl) 7.41-7.38 (m, IH), 7.31 (d, J = 8.0
pyrazin-2-yl)-6- Hz, IH), 7.14 (t, J = 8.0 Hz, IH),
fluorobenzamide 2.46 (s, 3H), 1.48 (s, 6H); ESI-MS
(m/z) 453, 455 [(MH)+,(C1 35'37)]
'HNMR (400 MHz, CDC13) d 10.48
Example 81: N-(5- (s, IH, D20 exchangeable), 9.83 (s,
(5-(5,5-dimethyl-4- IH), 8.46 (s, IH), 8.32 (dd, J = 1.5,
oxo-4,5- 7.5 Hz, IH), 8.20 (d, J = 2.0 Hz, IH),
dihydroisoxazol-3- 8.08 (dd, J = 8.0, 2.0 Hz, IH), 7.57
yl)-2- (ddd , J = 1.5, 7.5, 9.0 Hz, 1H), 7.42
methylphenyl)pyrazi (d, J = 8.0 Hz, IH), 7.17 (dt, J = 8.0,
n-2-yl)-2- 1.0 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H),
methoxybenzamide 4.13 (s, 3H), 2.47 (s, 3H), 1.48 (s,
6H); ESI-MS (m/z) 43 1 (MH)+
Example 82: N-(5- 'HNMR (400 MHz, DMSO- ) d
(5-(5,5-dimethyl-4- 10.81 (s, IH, D20 exchangeable),
oxo-4,5- 9.44 (s, IH), 8.59 (s, IH), 8.06 (d, J
dihydroisoxazol-3- = 2.0 Hz, IH), 7.96 (dd, J = 8.0, 2.0
yl)-2- Hz, IH), 7.51 (d, J = 8.0 Hz, IH),
methylphenyl)pyrazi 2.59-2.55 (m, 1H), 2.41 (s, 3H),
Example No:
Structure l NMR/ESI-MS(MH)+
IUPAC name
n-2- 1.85-1.64 (m, 5H), 1.46-1.37 (m,
yl)cyclohexanecarbo 2H), 1.42 (s, 6H), 1.39-1.18 (m, 3H);
xamide ESI-MS (m/z) 407 (MH)+
Example 83: N-(5- 'HNMR (400 MHz, CDC13) d 9.62
(5-(5,5-dimethyl-4- (s, 1H), 8.38 (s, 1H), 8.16 (d, J =2.0
oxo-4,5- Hz, 1H), 8.07 (dd, J =8.0, 2.0 Hz,
dihydroisoxazol-3 - 1H), 7.91 (brs, 1H, D20
yl)-2- exchangeable), 7.40 (d, J = 8.0 Hz,
n
methylphenyl)pyrazi 1H), 2.83-2.79 (m, 1H), 2.43 (s, 3H),
n-2- 2.04-1.93 (m, 4H), 1.84-1.79 (m,
yl)cyclopentanecarb 2H), 1.68-1.64 (m, 2H), 1.47 (s, 6H);
oxamide ESI-MS (m/z) 393 (MH)+
Example 84
N-(5-(2-(/ert-butyl)-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)-
2,6-difluorobenzamide
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-
( rt-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 temperature for 2 h. The reaction was diluted with DCM (100
mL), and washed with 10% hydrochloric acid (100 mL), dried (Na2S0 ) 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. 1HNMR (400 MHz, CDC13) d 9.72 (s, 1H), 8.55 (s, 1H, D 0 exchangeable),
8.28 (s, 1H), 8.14 (dd, J = 9.0, 2.5 Hz, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.52-7.45
(m, 1H), 7.07 (t, J = 8.5 Hz, 2H), 1.43 (s, 6H), 1.23 (s, 9H); ESI-MS (m/z) 479 (MH)+.
Example 85
N-(5-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)-2,6-
difluorobenzamide
The title compound was prepared by following a procedure similar to that described in
Example 84 by using intermediate 12b and 2,6-difluorobenzoyl chloride. 1HNMR (400 MHz,
CDC13) d 9.81 (s, 1H), 8.89 (s, 1H), 8.55 (s, 1H, D20 exchangeable), 7.98 (dd, J = 7.5, 1.5
Hz, 1H), 7.72 (dd, J = 7.5, 1.5 Hz, 1H), 7.54-7.47 ( , 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.07 (t, J
= 8.0 Hz, 2H), 3.57 (s, 3H), 1.54 (s, 6H); ESI-MS (m/z) 453 (MH)+.
Example 86
N-(5-(2-chloro-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)-2,6-
difluorobenzamide
The title compound was prepared by following a procedure similar to that described in
Example 84 by using intermediate 5 and 2,6-difluorobenzoyl chloride. 1HNMR (400 MHz,
CDC13) d 9.78 (s, 1H), 8.68 (s, 1H), 8.58 (s, 1H, D20 exchangeable), 8.29 (d, J = 1.5 Hz,
1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.51-7.43 (m, 1H), 7.04 (t, J =
8.5 Hz, 2H) 1.49 (s, 6H); ESI- MS (m/z) 457, 459 (MH)+, CI 35,37]
Example 87-96
The below Examples 87 to 96 were prepared by following a procedure similar to that
described in Example 84 by taking the corresponding intermediate and suitably substituted
benzoyl chloride as given in the Scheme below.
b
Example : IUPAC
Structure 1HNMR/ESI-MS (MH)+
name
Example 87: 2,6- 'HNMR (400 MHz, DMSO- ) d
Difluoro-N-(5-(2- 11.84 (s, 1H, D 0 exchangeable),
methyl-5-(4- 9.53 (s, 1H), 8.73 (s, 1H), 7.89 (s,
methyl-5-oxo-4,5- 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.65-
dihydro- 1,3,4- 7.59 (m, 1H), 7.56 (d, J = 8.0 Hz,
oxadiazol-2- 1H), 7.27 (t, J = 8.5 Hz, 2H), 3.42 (s,
yl)phenyl)pyrazin- 3H), 2.46 (s, 3H); ESI-MS (m/z) 424
2-yl)benzamide (MH)+.
Example 88: N-(5- 'HNMR (400 MHz, DMSO- ) d
(5-(4-Ethyl-5-oxo- 11.84 (s, 1H, D20 exchangeable),
4,5-dihydro-l,3,4- 9.53 (s, 1H), 8.73 (s, 1H), 7.89 (s,
oxadiazol-2-yl)-2- 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.65-
methylphenyl)pyraz 7.59 (m, 1H), 7.56 (d, J = 8.0 Hz,
in-2-yl)-2,6- 1H), 7.27 (t, J = 8.5 Hz, 2H), 3.78 (q,
Example : IUPAC
Structure 1HNMR/ESI-MS (MH)+
name
difluorobenzamide J = 7.0 Hz, 2H), 2.45 (s, 3H), 1.30 (t,
J = 7.0 Hz, 3H); ESI-MS (m/z) 438
(MH)+.
'HNMR (400 MHz, DMSO-i/<5) d
11.84 (s, IH, D20 exchangeable,
Example 89: 2,6-
9.53 (s, IH), 8.73 (s, IH), 7.90 (d, J
Difluoro-N-(5-(2-
= 2.0 Hz, IH), 7.80 (dd, J = 8.0, 2.0
methyl-5-(5-oxo-4-
Hz, IH), 7.66-7.59 (m, IH), 7.56 (d,
propyl-4,5-dihydro-
J = 8.0 Hz, IH), 7.27 (t, J = 8.5 Hz,
l,3,4-oxadiazol-2- ¾
2H), 3.71 (t, J = 7.0 Hz, 2H), 2.46 (s,
yl)phenyl)pyrazin-
3H), 1.74 (q, J = 7.0 Hz, 2H), 0.91 (t,
2-yl)benzamide
J = 7.0 Hz, 3H); ESI-MS (m/z) 452
(MH)+.
Example 90: N-(5- 'HNMR (400 MHz, CDC13) d 9.78
(2-Ethyl-5-(4- (s, IH), 8.62 (s, IH, D20
methyl-5-oxo-4,5- exchangeable), 8.39 (s, IH), 7.86-
dihydro- 1,3,4- - 7.83 (m, 2H), 7.53-7.46 (m, 2H),
oxadiazol-2- 7.07 (t, J = 8.5 Hz, 2H), 3.51 (s, 3H),
yl)phenyl)pyrazin- 2.80 (q, J = 7.0 Hz, 2H), 1.18 (t, J =
2-yl)-2,6- 7.5 Hz, 3H); ESI-MS (m/z) 438
difluorobenzamide (MH)+
Example 91: 2- 'HNMR (400 MHz, CdCl3) d 9.78 (s,
Chloro -N-(5-(2- IH)), 8.38 (s, IH, D20
ethyl-5-(4-methyl- exchangeable), 8.37 (s, IH), 7.86 (d,
5-oxo-4,5-dihydro- J = 1.5 Hz, IH), 7.84 (s, IH), 7.48 (d,
Example : IUPAC
Structure 1HNMR/ESI-MS (MH)+
name
l,3,4-oxadiazol-2- J = 8.5 Hz, IH), 7.47-7.41 (m, IH),
yl)phenyl)pyrazin- 7.32 (d, J= 8.5 Hz, IH), 7.18-7.14
2-yl)-6- (td, J = 8.5, 1.0 Hz, IH), 3.51 (s,
fluorobenzamide 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)+, CI35'37]
'HNMR (400 MHz, CDC13) d 9.78
Example 92: N-(5-
(s, IH), 8.45 (s, IH, D20
(2-Ethyl-5-(4-
exchangeable), 8.31 (s, IH), 7.85-
methyl-5-oxo-4,5-
7.82 (m, 2H), 7.47 (d, J = 8.5
dihydro- 1,3,4-
Hz,lH), 7.38-7.32 (m, IH), 7.10 (d, J
oxadiazol-2-
= 7.5 Hz, IH), 7.02 (t, J = 8.5 Hz,
yl)phenyl)pyrazin-
IH), 3.50 (s, 3H), 2.80 (q, J = 7.5 Hz,
2-yl)-2-fluoro-6-
2H), 2.52 (s, 3H), 1.17 (t, J = 7.5 Hz,
methylbenzamide
3H); ESI- MS (m/z) 434 (MH)+
Example 93: 2,6- 'HNMR (400 MHz, DMSO-i/6) d
Difluoro -N-(5-(2- 11.78 (s, IH, D20 exchangeable),
methoxy-5-(4- 9.53 (s, IH), 9.01 (s, IH), 8.28 (d, J
methyl-5-oxo-4,5- = 2.0 Hz, IH), 7.88 (dd, J = 8.0, 2.0
dihydro- 1,3,4- Hz, IK), 7.66-7.59 ( , IH), 7.39 (d,
oxadiazol-2- J = 8.0 Hz, IH), 7.27 (t, J = 8.5 Hz,
yl)phenyl)pyrazin- 2H), 3.99 (s, 3H), 3.41 (s, 3H); ESI-
2-yl)benzamide MS (m/z) 440 (MH)+.

Examples 97-1 18
Intermediate 18b, 22b
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
temperature 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 temperature 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 (Na2S0 4) 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 solid.
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 evaporation 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
temperature 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 in method A or method B by using corresponding intermediates lb, 7b, 18b or 22b.

Example 119
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)benzofuran-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 l b and benzofuran-2-carboxylic acid.
'HNMR (400 MHz, CDC13) 9.79 (s, 1H), 9.04 (s, 1H, D20 exchangeable), 8.50 (s, 1H),
8.21 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.0, 2.0 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.70 (s, 1H),
7.59 (dd, J = 8.5, 1.0 Hz, 1H), 7.51 (dt, J = 7.5, 1.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.36
(dt, J = 8.0, 1.0 Hz, 1H), 2.48 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 441 (MH)+.
Example 120
2,6-Difluoro -N-(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-methylphenyl)-l -oxa-2-azaspiro[4.5]dec-2-en-4-one:
To a solution of intermediate 30 (100 mg, 0.31 1 mmol, 1.0 eq) and 5-(trimethyl stannyl)-
pyrazine-2-amine (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(PPh 3)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 atmosphere. The resulting mixture was cooled to
room temperature 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, CDC13) d 9.72 (s, 1H), 8.55 (s, 1H, D20 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, D20 exchangeable), 2.42 (s, 3H), 1.86-1.65 (m, 10H); ESI-MS (m/z) 337 (MH)+.
Step-2: 2,6-Difluoro -N-(5-(2-methyl-5-(4-oxo-l-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, 0.1 1 mmol, 1.0 eq) in DCM (3 mL) was added drop wise a solution of 3-
(3-(5-aminopyrazin-2-yl)-4-methylphenyl)- 1-oxa-2-azaspiro[4.5]dec-2-en-4-one (40 mg,
0.1 1 mmol, 1.0 eq) in DCM (2 mL) followed by pyridine (0.01 mL, 0.1 1 mmol, 1.0 eq). The
resulting mixture was stirred at room temperature overnight. 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) d 9.76 (s, 1H), 8.51 (s, 1H, D20
exchangeable), 8.41 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 7.5 Hz, 1H), 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
N-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazine-2-carboxamide
Example 121
Step-1: 5-Chloro-N-(2,6-difluorophenyl)pyrazine-2-carboxamide: A mixture of 5-
hydroxypyrazine-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 temperature, the reaction was diluted with ethyl acetate (15 mL). The organic layer was
washed with water (10 mL), 2N HC1 (10 mL), dried (Na2S0 4) 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. 1HNMR (400 MHz, DMSO- ) d 10.67 (s, 1H, D20
exchangeable), 9.1 1 (s, 1H), 9.98 (s, 1H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 2H); ESI-MS
(m/z) 270, 272 [(MH)+, CI 35>37]
Step-2: N-(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 l a (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:H20 (4:1, 5 mL) was added sodium bicarbonate (38 mg, 0.45 mmol,
1.5 eq) followed by Pd(PPh 3)4 (17 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 atmosphere. The resulting
mixture was cooled to room temperature 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) d 9.59 (s, 1H), 9.26 (s, 1H, D20 exchangeable),
8.82 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.18 (dd, J = 8.0, 2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H),
7.31-7.28 (m, 1H), 7.07 (t, J = 8.0 Hz, 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)-[l ,1'-
biphenyl]-2-carboxylic 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, 4.1 1 mmol, 1.0 eq) in DCM (5 mL) was
added drop wise a solution of ethyl-2-bromo-5-aminobenzoate (1.0 g, 4.1 1 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 temperature for 15 h. The reaction was diluted with DCM (15 mL), and
washed with 10% hydrochloric acid (10 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 as eluent) to afford 500 mg of the title
product as a white solid. 1HNMR (400 MHz, CDC13) d 8.23 (s, 1H, D20 exchangeable), 7.97
(d, J = 2.5 Hz, 1H), 7.73 (dd, J = 8.5, 2.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.41-7.34 (m,
1H), 6.92 (t, J = 8.0 Hz, 2H); ESI-MS (m/z) 384, 386 [(MH)+ Br79, 1] .
Step-2: Ethyl 4-(2,6-difluorobenzamido)-3'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-
[l,l'-biphenyl]-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 mmol, 1.0 eq) sodium carbonate (100 mg, 0.95 mmol, 2 eq) and Pd(PPh 3)2Cl2 (33
mg, 0.047 mmol, 0.1 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
120°C in microwave (Biotage) for 30 min. The resulting mixture was cooled to room
temperature, diluted 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. 1HNMR (400 MHz, CDC13) d 8.13-8.09 (m, 2H), 8.05-8.01
(m, 2H), 7.88 (s, 1H, D20 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), 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-dihydroisoxazol-3-yl)-[ ,1'-
biphenyl]-2-carboxylic acid: A solution of ethyl 4-(2,6-difluorobenzamido)-3'-(5,5-dimethyl-
4-oxo-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 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, CDC13) d 8.12-8.09 (m, 3H), 8.06 (d, J = 2.0 Hz, 1H), 7.96 (s, 1H, D20
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
N-(5'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-hydroxy-[l,l'-biphenyl]-4-yl)-2,6-
difluorobenzamide
Example 15 xamp e
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 (1M 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 (Na2S0 4) 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 product as a white solid. 1HNMR (400 MHz, DMSO- ) d 10.89
(s, 1H, D20 exchangeable), 10.29 (s, 1H, D20 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, 1H), 7.57 (d, J = 8.5 Hz,
2H), 7.27 (t, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 1.40 (s, 6H); ESI-MS (m/z) 437
(MH)+.
Example 124
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-hydroxyphenyl)pyrazin-2-yl)-2,6-
difluorobenzamide
The title compound was prepared by following a procedure similar to that described in
Example 123 by using Example 14. 1HNMR (400 MHz, CDC13) d 13.13 (s, 1H, D20
exchangeable), 9.60 (s,lH), 9.00 (s, 1H), 8.68 (s, 1H), 8.61 (s, 1H, D20 exchangeable), 8.1 1
(dd, J = 8.5, 2.0 Hz, 1H), 7.58-7.43 (m, 1H), 7.14 (d, J = 8.5 Hz, 1H), 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:
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 overnight. The reaction was cooled to
room temperature and then filtered. The solid residue was washed with acetone and the
combined filtrates 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.
Example No: IUPAC
Structure 'HNMR /ESI-MS (MH)+
name
'HNMR (400 MHz, CDC13) d 8.12
(d, J = 2.0 Hz, 1H), 8.07 (dd, J =
Example 125: N-(5'-
8.5, 2.0 Hz, 1H), 7.71-7.68 (m,
(5,5-dimethyl-4-oxo-
- 2H+1H, D20 exchangeable), 7.61
4,5-dihydroisoxazol-3-
(d, J = 8.5 Hz, 2H), 7.47-7.42 (m,
yl)-2'-isopropoxy-[ 1,1'-
1H), 7.06 (d, J = 8.5 Hz, 1H), 7.03
biphenyl]-4-yl)-2,6-
(t, J = 8.0 Hz, 2H), 4.65-4.61 (m,
difluorobenzamide
1H), 1.48 (s, 6H), 1.33 (d, J = 6.0
Hz, 6H); ESI-MS (m/z) 479 (MH)+.
'HNMR (400 MHz, CDC13) d 9.76
Example 126: N-(5-(5- (s, 1H), 8.90 (s, 1H), 8.66 (d, J =
(5,5-dimethyl-4-oxo- 2.0 Hz, 1H), 8.49 (s, 1H, D20
4,5-dihydroisoxazol-3- ~( exchangeable), 8.13 (dd, J = 8.5,
yl)-2- 2.0 Hz, 1H), 7.50-7.44 (m, 1H),
isopropoxyphenyl)pyraz 7.10 (d, J = 8.5 Hz, 1H), 7.05 (t, J =
in-2-yl)-2,6- 8.0 Hz, 2H), 4.78-4.72 (m, 1H),
difluorobenzamide 1.48 (s, 6H), 1.40 (d, J = 6.0 Hz,
6H); ESI-MS (m/z) 481 (MH)+.

7.0 Hz, 3H); ESI-MS (m/z) 465
(MH)+.
'HNMR (400 MHz, CDC13) d 9.76
Example 130: N-(5-(5- (s, 1H), 8.91 (s, 1H), 8.67 (d, J =
(5,5-dimethyl-4-oxo- 2.0 Hz, 1H), 8.44 (s, 1H, D20
4,5-dihydroisoxazol-3- ( exchangeable), 8.14 (dd, J = 8.5,
yl)-2- 2.0 Hz, 1H), 7.50-7.46 (m, 1H),
ethoxyphenyl)pyrazin-2- 7.09 (d, J = 8.5 Hz, 1H), 7.05 (t, J =
yl)-2,6- 8.0 Hz, 2H), 4.21 (q, J 6.5 Hz,
difluorobenzamide 2H), 1.48 (t, J = 6.5 Hz, 3H), 1.48
(s, 6H); ESI-MS (m/z) 467 (MH)+.
'HNMR (400 MHz, CdCl3) d 8.12
(d, J = 2.5 Hz, 1H), 8.09 (dd, J =
Example 131 : JV-(5'-
8.5, 2.5 Hz, 1H), 7.72-7.69 (m,
(5,5-dimethyl-4-oxo-
3H), 7.62 (d, J = 8.5 Hz, 2H), 7.48-
4,5-dihydroisoxazol-3-
7.41 (m, 1H), 7.05-7.01 (m, 3H),
yl)-2'-propoxy-[l,l'-
4.02 (q, J = 6.5 Hz, 2H), 1.83 -1.78
biphenyl]-4-yl)-2,6-
(m, 2H), 1.48 (s, 6H), 1.02 (t, J =
difluorobenzamide
6.5 Hz, 3H); ESI- MS (m/z)479
(MH)+
Example 132 :N-(2'- Ή NMR (400 MHz, CDC13) d 8.1 1
(d, J = 2.5 Hz, 1H), 8.07 (dd, J = (allyloxy)-5'-(5,5-
dimethyl-4-oxo-4,5- 8.5, 2.5 Hz, 1H), 7.71-7.68 (m, 3H),
dihydroisoxazol-3 -yl)- 7.61 (d, J = 8.0 Hz, 2H), 7.48-7.39
[l,l'-biphenyl]-4-yl)- (m, 1H), 7.05-6.99 (m, 3H), 6.05-
2,6-difluorobenzamide 5.95 (m, 1H), 5.39-5.24 (m, 2H),
4.63-4.61 (m, 2H), 1.46 (s, 6H);
Example 134
N-(2'-Amino-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[l , -biphenyl]-4-yl)-2,6-
difluorobenzamide
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 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 (Na S0 4) 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, DMSOd6)
10.92 (s, 1H, D20 exchangeable), 7.80 (d, J 8.5 Hz, 2H), 7.71 (dd, J = 8.5, 2.0 Hz,
1H), 7.64-7.56 (m, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 6.84 (d, J = 8.5 Hz,
1H), 5.48 (s, 2H, D20 exchangeable), 1.35 (s, 6H); ESI-MS (m/z) 436 (MH)+.
Example 135
N-(5'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-(methylamino)-[l , -biphenyl]-4-
yl)-2,6-difluorobenzamide
To a 0 °C solution of Example 134 (50 mg, 0.1 1 mmol, 1.0 eq) in methanol (5 mL) was
added formaldehyde (37% aqueous solution) (10 m , 0.12 mmol, 1.1 eq). After stirring for 30
min at room temperature, 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 temperature for 12 h. The solvent was removed under vaccum
and the residue was dissolved in ethyl acetate (10 mL) and washed with water (5 mL), brine
(5 mL), dried (Na2S0 ) 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, CDC13) d 8.07 (dd, J = 8.5, 2.0 Hz, 1H), 7.87 (d,
J = 2.0 Hz, 1H), 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, 1H), 4.33 (s, 1H, D20 exchangeable), 2.86 (s, 3H), 1.45 (s, 6H); ESI-MS (m/z) 450
(MH)+.
Example 136
N-(5'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-(dimethylamino)-[l , -biphenyl]-4-
yl)-2,6-difluorobenzamide
The title compound was prepared by following a procedure similar to that described in
Example 135 by using Example 134 (yield: 10 mg) 'HNMR (400 MHz, CDC13) d 8.01 (dd, J
= 8.5, 2.0 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.65 (s, 1H, D20
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
^-N -(5-(5-(5,5-Dimethyl-4-hydroxy
2-yl)-2,6-difluorobenzamide
To a solution of Example 1 (100 mg, 0.23 mmol, 1.0 eq) in methanol (5 mL) at room
temperature was added sodium borohydride (13 mg, 0.34 mmol, 1.5 eq) portion wise. After
stirring for 10 min at the same temperature, 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 0 mL). The combined
organic layers were washed with brine (10 mL), dried (Na S0 4) 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-a¾ d 11.81 (s, 1H,
D 0 exchangeable), 9.51 (s, 1H), 8.69 (s, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 8.0, 1.5
Hz, 1H), 7.64-7.60 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 2H), 5.95 (d, J = 8.0
Hz, 1H, D20 exchangeable), 4.92 (d, J = 8.0 Hz, 1H), 2.42 (s, 3H), 1.18 (s, 6H); ESI-MS
(m/z) 439 (MH)+.
Example 138
^-N -(5-(2-Methyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)pyrazin-2-
yl)- 1,2,3 ,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 1,2,3,4-
tetrahydronaphthalene-2-carboxylic acid. 1HNMR (400 MHz, CDC13) d 9.71 (s, 1H), 8.35 (s,
1H), 8.08 (s, 1H, D20 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), 2.10-2.03 (m, 1H); ESI- MS (m/z) 442 (MH)+
Example 139
3-(4'-(2.6-Difluorobenzamido)-6-methyl-[l , -biphenyl]-3-yl)-5-methyl-4,5-
dihydroisoxazole-5-carboxylic 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 temperature. The
resulting solution was then stirred at the same temperature 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 =2.0, and then extracted with ethyl acetate (2x10 mL). The combined
organic layers were washed with brine (10 mL), dried (Na2S0 4) and filtered. The filtrate was
concentrated under vacuum to afford 35 mg of the desired product as a white solid. 'HNMR
(400 MHz, CDC13) d 7.74 (s, 1H, D20 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, J = 8.5 Hz, 3H), 7.02 (t, J = 8.0 Hz,
2H), 3.87 (d, J = 17.5 Hz, 1H), 3.31 (d, J = 17.5 Hz, 1H), 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 prepare Example 140, Example 76 to prepare Example
141 Example 77 to prepare Example 142.
Example No:
Structure 'HNMR /ESI-MS (MH)+
IUPAC name
3H); ESI-MS (m/z) 495 (MH)+.
'HNMR (400 MHz, OMS - 6 d
Example 142: 5- 13.29 (s, 1H, D20 exchangeable),
(Carboxymethyl)-3- 12.58 (s, 1H, D 0 exchangeable),
11.82 (s, 1H, D2(3-(5-(2,6- 0 exchangeable),
difluorobenzamido) 9.51 (s, 1H), 8.71 (s, 1H), 7.76 (s,
pyrazin-2-yl)-4- 1H), 7.71 (dd, J = 8.0, 1.5 Hz,
methylphenyl)-4,5- 1H), 7.65-7.60 (m, 1H), 7.45 (d, J
dihydroisoxazole-5- = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz,
carboxylic acid 2H), 3.92 (d, J = 17.0 Hz, 1H),
3.61 (d, J = 17.0 Hz, 1H), 3.00 (s,
2H), 2.42 (s, 3H); ESI-MS (m/z)
495 (M-H).
•
Example 143
2,6-Difluoro -N-(5'-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2'-methyl-[l , -
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 temperature 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 (Na2S0 4) and filtered. The filtrate was concentrated under vacuum
to afford 40 mg of the desired product as a white solid. 1HNMR (400 MHz, CDC13) d 7.74 (s,
1H, D20 exchangeable), 7.70 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.46-
7.43 (m, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.02 (t, J 8.0 Hz, 2H), 3.72
(d, J = 12 Hz, 1H), 3.57 (d, J = 12 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 prepare Example 144, Example 76 to prepare Example
145 Example 77 to prepare Example 146.
Example No: IUPAC
Structure 1HNMR /ESI-MS (MH)+
name
'HNMR (400 MHz, CDC13) d 9.75
(s, 1H), 8.70 (s, 1H, D20
Example 144: 2,6-
exchangeable), 8.35 (s, 1H), 7.67
Difluoro -N-(5-(5-(5-
(s, 1H), 7.63 (d, J = 8.0 Hz, 1H),
(hydroxymethyl)-5-
7.52-7.45 (m, 1H), 7.34 (d, J 8.0
methyl-4,5-
Hz, 1H), 7.05 (t, J = 8.0 Hz, 2H),
dihydroisoxazol-3 -yl)-
2-
3.75-3.71 (m, 1H), 3.61-3.50 (m,
1H), 3.50 (d, J = 17.0 Hz, 1H),
methylphenyl)pyrazin-
3.04 (d, J = 17.0 Hz, 1H), 2.42 (s,
2-yl)benzamide
3H), 1.43 (s, 3H); ESI-MS (m/z)
439 (MH)+.
Example 147
N-Cyclopropyl-3-(4'-(2,6-difluorobenzamido)-6-methyl-[l , -biphenyl]-3-yl)-5-methyl-4,5-
dihydroisoxazole-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 ,
0.44 mmol, 1.0 eq) and triethyl amine (0.6 mL, 3.52 mmol, 8 eq) were added sequentially.
The resulting solution was stirred at room temperature 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. 1HNMR
(400 MHz, CDC13) d 7.78 (s, 1H, D20 exchangeable), 7.71 (d, J = 8.5 Hz, 2H), 7.52 (dd, J =
8.0, 1.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.46-7.41 (m, 1H), 7.33-7.29 (m, 3H), 7.02 (t, J =
8.0 Hz, 2H), 6.91 (d, J = 3.0 Hz, 1H, D 0 exchangeable), 3.82 (d, J = 17.5 Hz, 1H), 3.22 (d, J
= 17.5 Hz, 1H), 2.74-2.69 (m, 1H), 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 following a procedure similar to that
described in Example 147 by using Example 139 or Example 140 and appropriate amine.

'HNMR (400 MHz, CDC13) d 9.76
(s, 1H), 8.55 (s, 1H, D20
exchangeable), 8.38 (s, 1H), 7.72
Example 153: 2,6-
(d, J = 1.5 Hz, 1H), 7.65 (dd, J =
Difluoro -N-(5-(2-
8.0, 1.5 Hz, 1H), 7.52-7.47 (m,
methy1-5 -(5-methyl-5 -
1H), 7.36 (d, J = 8.0 Hz, 1H), 7.06
(4-methylpiperazine- 1
(t, J 8.0 Hz, 2H), 4.41 (d, J =
carbonyl)-4,5-
17.0 Hz, 1H), 4.08-4.04 (m, 1H),
dihydroisoxazol-3-
3.77-3.73 ( , 2H), 3.60-3.55 (m,
yl)phenyl)pyrazin-2-
1H), 3.15 (d, J = 17.0 Hz, 1H),
yl)benzamide
2.49-2.43 (m, 4H), 2.43 (s, 3H),
2.31 (s, 3H), 1.69 (s, 3H); ESIMS
(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 temperature for 12 h. The solvent was removed under
vacuum and the crude residue was purified by preparative HPLC to afford 30 mg of the
desired product as a white solid. 1HNMR (400 MHz, DMSO- ) d 13.22 (s, 1H, D20
exchangeable), 12.56 (s, 1H, D20 exchangeable), 10.92 (s, 1H, D20 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, 3H); ESI-MS (m/z) 493 (MH)+.
Example 155
3-(4'-(2,6-Difluorobenzamido)-6-methyl-[l ,1'-biphenyl]-3-yl )-N -methyl-5-(2-
(methylamino)-2-oxoethyl)-4,5-dihydroisoxazole-5-carboxamide
The title compound was prepared by following a procedure similar to that described in
Example 154 by using Example 76 and methylamine. 1HNMR (400 MHz, DMSO-i/<5) d
10.92 (s, 1H, D20 exchangeable), 7.98 (q, J = 4.5 Hz, 1H, D20 exchangeable), 7.84 (q, J =
4.5 Hz, 1H, D20 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
17.5 Hz, 1H), 3.61 (d, J = 17.5 Hz, 1H), 2.75 (d, J = 15.0 Hz, 1H), 2.69 (d, J = 15.0 Hz, 1H),
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 present invention:
intermediate 1a, 2, 6,7a, 9, 1 intermediate 53a, 54-58 Examples 156-169
To a stirred solution of any one of boronate derivatives of intermediates 1a, 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(PPli3) Cl (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 temperature 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
above mentioned general procedure.
Example No: 1HNMR/ESI-MS
Structure
IUPAC Name (MH)+
'HNMR (400 MHz, CDC13) d 8.20
Example 156: N-(2,6- (d, J = 1.5 Hz, 1H), 8.05 (dd, J =
Difluorophenyl)-5 -(5- 8.0, 1.5 Hz, 1H), 7.72 (d, J = 4.0
(5,5-dimethyl-4-oxo- Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H),
4,5-dihydroisoxazol- 7.33 (s, 1H, D20 exchangeable),
3-yl)-2- 7.28-7.22 (m, 1H), 7.16 (d, J = 4.0
methylphenyl)thiophe Hz, 1H), 7.00 (t, J = 8.0 Hz, 2H),
ne-2-carboxamide 2.51 (s, 3H), 1.50 (s, 6H); ESI-MS
(m/z) 441 (MH)+
'HNMR (400 MHz, CDC13) d 8.13
(d, J = 1.5 Hz, 1H), 8.09 (dd, J =
Example 157: N-(2,6-
8.0, 1.5 Hz, 1H), 7.70 (d, J = 3.5
Difluorophenyl)-5-(5-
Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H),
(5,5-dimethyl-4-oxo-
7.32 (s, 1H, D20 exchangeable),
4,5-dihydroisoxazol-
3-yl)-2- -
7.27-7.22 (m, 1H), 7.10 (d, J =3.5
Hz, 1H), 7.00 (t, J = 8.0 Hz, 2H),
ethylphenyl)thiophen
2.80 (q, J =7.5 Hz, 2H), 1.47 (s,
e-2-carboxamide
6H), 1.21 (t, J = 7.5 Hz, 3H); ESIMS
(m/z) 455 (MH)+

'HNMR (400 MHz, CDC13) d 8.53
Example 160: N -(2,6- (s, IH), 8.13 (dd, J = 9.0, 2.0 H ,
Difluorophenyl)-5-(5- IH), 7.72 (d, J 4.0 Hz, IH), 7.60
(5,5-dimethyl -4-oxo- (d, J 4.0 Hz, IH), 7.36 (s, IH,
4,5-dihydroisoxazol- D20 exchangeable), 7.28-7.21 (m,
3-yl)-2- IH), 7.1 1 (d, J = 9.0 Hz, IH), 7.03
methoxyphenyl)thiop (t, J = 7.5 Hz, 2H), 4.05 (s, 3H),
hene-2-carboxamide 1.50 (s, 6H); ESI-MS (m/z) 457
(MH) +
'HNMR (400 MHz, CDC13) d 7.70
Example 161 : N -(2,6-
(d, J = 3.5 Hz, IH), 7.52 (t, J = 7.5
Difluorophenyl)-5 -(3 -
Hz, 2H), 7.36 (t, J = 7.5 Hz, IH),
( ,5-dimethyl-4-oxo-
7.32 (s, IH, D20 exchangeable)
4,5-dihydroisoxazol-
7.28-7.22 (m, IH), 7.08 (d, J = 4.0
3-yl)-2-
Hz, IH), 7.03 (t, J = 8.0 Hz, 2H),
methylphenyl)thiophe
2.39 (s, 3H), 1.51 (s, 6H); ESI-MS
ne-2-carboxamide
(m/z) 441 (MH)+
Example 162: vV-(2,6- 'HNMR (400 MHz, CDC13) d 8.18
Difluorophenyl)-5-(5- (d, J = 1.5 Hz, 1H), 8.03 (dd, J =
(5,5-dimethyl-4-oxo- 8.0, 1.5 Hz, 1H), 7.39 (d, J = 8.0
4,5-dihydroisoxazol- V__/ < ~ Hz, 1H), 7.26-7.21 (m, 1H), 7.13 (s,
3-yl)-2- 1H, D20 exchangeable), 7.03-6.98
methylphenyl)-3- (m, H), 2.63 (s, 3H), 2.51 (s, 3H),
methylthiophene-2- 1.48 (s, 6H); ESI-MS (m/z) 455
carboxamide (MH)+
'HNMR (400 MHz, CDC13) d 8.40
Example 163: N-(2,6-
(t, J = 1.5 Hz, 1H), 8.09 (d, J = 7.5
Difluorophenyl)-5 -(3 -
Hz, IH), 7.73 (d, J =7.5 Hz, IH),
(5,5-dimethyl-4-oxo-
7.52 (t, J =7.5 Hz, IH), 7.26-7.20
4,5-dihydroisoxazol-
(m, 2H), 7.13 (s, IH, D20
3-yl)phenyl)-3-
exchangeable), 7.00 (t, J = 8.0 Hz,
methylthiophene-2-
2H), 2.62 (s, 3H), 1.50 (s, 6H);
carboxamide
ESI-MS (m/z) 441 (MH)+
'HNMR (400 MHz, CDCI3) d 8.27
Example 164: _V-(2,6- (d, J = 2.0 Hz, 1H), 8.10 (dd, J =
Difluorophenyl)-4-(5- 9.0, 2.0 Hz, 1H), 8.04 (d, J = 1.0
(5,5-dimethyl-4-oxo- Hz, 1H), 7.88 (d, J = 1.0 Hz, 1H),
4,5-dihydroisoxazol- 7.41 (s, 1H, D20 exchangeable),
3-yl)-2- 7.26-7.21 (m, 1H), 7.08 (d, J =9.0
methoxyphenyl)thiop Hz, 1H), 7.02 (t, J =7.5 Hz, 2H),
hene-2-carboxamide 3.96 (s, 3H), 1.48 (s, 6H); ESI-MS
(m/z) 457 (MH) +
Example 165: JV-(2,6- 'HNMR (400 MHz, CDC13) d 8.05
Difluorophenyl)-4-(5- (dd, J =7.5, 1.5 Hz, 1H), 7.90 (d, J
(5,5-dimethyl-4-oxo- = 1.5 Hz, 1H), 7.39 (d, J = 8.0 Hz,
4,5-dihydroisoxazol- 1H), 7.26-7.20 (m, 2H), 7.19 (s, 1H,
3-yl)-2- S' o D20 exchangeable), 7.01 (t, J =8.0
methylphenyl)-3- Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H),
methylthiophene-2- 1.47 (s, 6H); ESI-MS (m/z) 455
carboxamide (MH)+

'HNMR (400 MHz, CDC13) 8.13
(dd, J = 8.5, 2.0 Hz, 1H), 7.99 (d, J
Example 169:N-(2,6-
2.0 Hz, 1H), 8.04 (d, J = 8.5 Hz,
difluorophenyl)-5 -(5-
1H), 7.88 (d, J = 1.0 Hz, 1H), 7.30-
(5,5-dimethyl-4-oxo-
7.1 (m, 2H), 7.03 (t, J = 7.5 Hz,
4,5-dihydroisoxazol-
2H), 6.92 (d, J = 4.0 Hz, 1H), 6.18
3-yl)-2-ethylphenyl)-
(d, J = 4.0 Hz, 1H), 3.70 (s, 3H),
1-methyl- 1H-pyrrole-
2.56 (q, J = 7.5 Hz, 2), 1.48 (s, 6H),
2-carboxamide
1.42 (t, J = 7.5 Hz, 3H); ESI-MS
(m/z) 452 (MH)+
Examples 170-177
General procedure for the synthesis of compounds of the present invention:
i
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 derivative of intermediate 53b or 55b (1.0 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 temperature
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) 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.
Example No/
Structure ^NMR/ESI-MS (MH)+
IUPAC name
'HNMR (400 MHz, CDC13) 7.88
Example 170: N-(2,6- (d, J = 2.0 Hz, 1H), 7.73 (dd, J =
Difluorophenyl)-5-(2- 8.0, 2.0 Hz, 1H), 7.70 (d, J = 4.0
methyl-5-(4-methyl- Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H),
5-OCO -4,5-dihydro- 7.33 (s, 1H, D20 exchangeable)
l,3,4-oxadiazol-2- 7.27-7.21 (m, 1H), 7.13 (d, J = 4.0
yl)phenyl)thiophene- Hz, 1H), 7.00 (t, J = 8.5 Hz, 2H),
2-carboxamide 3.49 (s, 3H), 2.50 (s, 3H); ESI-MS
(m/z) 428 (MH)+
'HNMR (400 MHz, CDC13) d 7.84
(d, J = 2.0 Hz, 1H), 7.79 (dd, J =
Example 171: N-(2,6-
8.0, 2.0 Hz, 1H), 7.70 (d, J = 4.0
Difluorophenyl)-5-(2-
Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H),
ethyl-5-(4-methyl-5-
7.34 (s, 1H, D20 exchangeable)
oxo-4,5-dihydro-
7.27-7.23 (m, 1H), 7.10 (d, J = 4.0
l,3,4-oxadiazol-2- ¾
Hz, 1H), 7.00 (t, J = 8.5 Hz, 2H),
yl)phenyl)thiophene-
3.50 (s, 3H), 2.81 (q, J = 7.5 Hz,
2-carboxamide
2H), 1.22 (t, J = 7.5 Hz, 3H); ESIMS
(m/z) 442 (MH)+
Example No/
Structure HNMR/ESI-MS (MH)+
IUPAC name
'HNMR (400 MHz, DMSO- ) d
Example 172: _V-(2,6-
10.34 (s, 1H, D20 exchangeable),
Difluorophenyl)-5-(2-
8.18 (dd, J = 7.5, 2.0 Hz, 1H), 8.08
fluoro-5-(4-methyl-5-
(d, J = 4.0, Hz, 1H), 7.87-7.83 (m,
oxo-4,5-dihydro-
2H), 7.60 (dd, J = 11.0, 8.5 Hz,
l,3,4-oxadiazol-2-
1H), 7.46-7.40 (m, 1H), 7.24 (t, J =
yl)phenyl)thiophene-
8.5 Hz, 2H), 3.43 (s, 3H); ESI-MS
2-carboxamide
(m/z) 432 (MH)+
'HNMR (400 MHz, CDC13) d 8.18
Example 173: 5-(2-
(d, J = 2.0 Hz, 1H), 7.82 (dd, J =
(Difluoromethoxy)-5-
8.5, 2.0 Hz, 1H), 7.71 (d, J = 4.0
(4-methyl-5-oxo-4,5-
Hz, 1H), 7.54 (d, J = 4.0 Hz, 1H),
dihydro- 1,3,4-
7.38 (d, J = 8.5 Hz, 1H), 7.33 (s,
oxadiazol-2-
1H, D20 exchangeable) 7.31-7.23
yl)phenyl)-N-(2,6-
(m, 1H), 7.02 (t, J 8.5 Hz, 2H),
difluorophenyl)thioph
6.66 (t, J = 73 Hz, 1H), 3.53 (s,
ene-2-carboxamide
3H); ESI-MS (m/z) 480 (MH)+
Example No/
Structure ^NMR/ESI-MS (MH)+
IUPAC name
Example 174: N-(2,6- 'HNMR (400 MHz, CDC13) d 8.17
Difluorophenyl)-5-(2- (d, J = 2.5 Hz, IH), 7.80 (dd, J =
methoxy-5-(4-methyl- 8.5, 2.5 Hz, 1H), 7.44 (s, 1H), 7.25-
5-oxo-4,5-dihydro- 7.22 (m, 1H), 7.18 (s, 1H, D20
l,3,4-oxadiazol-2- exchangeable), 7.10 (d, J = 8.5 Hz,
yl)phenyl)-3- 1H), 7.03 (t, J = 8.5 Hz, 2H), 4.06
methylthiophene-2- (s, 3H), 3.53 (s, 3H), 2.64 (s, 3H);
carboxamide ESI-MS (m/z) 458 (MH)+
'HNMR (400 MHz, CDC13) d 8.04
Example 175: 5-(2- (d, J = 2.0 Hz, IH), 7.77 (dd, J =
Chloro-5 -(4-methyl- 8.5, 2.0 Hz, 1H), 7.73 (d, J = 3.5
5-oxo-4,5-dihydro- Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H),
l,3,4-oxadiazol-2- 7.45 (d, J = 3.5 Hz, 1H), 7.34 (s,
yl)phenyl )-N -(2,6- 1H, D20 exchangeable) 7.29-7.24
difluorophenyl)thioph ( , 1H), 7.03 (t, J = 8.5 Hz, 2H),
ene-2-carboxamide 3.53 (s, 3H); ESI-MS (m/z) 448
(MH)+
Example No/
Structure 1HNMR/ESI-MS (MH)+
IUPAC name
'HNMR (400 MHz, CDC13) d 7.84
Example 176: N-(2,6- (d, J =7.5 Hz, 1H), 7.72 (d, J =4.0
Difluorophenyl)-5-(2- Hz, 1H), 7.53 (d, J =7.5 Hz, 1H),
methyl-3-(4-methyl- 7.38 (t, J = 7.5 Hz, 1H), 7.32 (s,
5-oxo-4,5-dihydro- 1H, D20 exchangeable) 7.28-7.23
l,3,4-oxadiazol-2- (m, 1H), 7.08 (d, J =4.0 Hz, 1H),
yl)phenyl)thiophene- 7.03 (t, J = 8.5 Hz, 2H), 3.56 (s,
2-carboxamide 3H), 2.62 (s, 3H); ESI-MS (m/z)
428 (MH)+
'HNMR (400 MHz, CDC13) d 7.85
(dd, J =8.0, 1.0 Hz, 1H), 7.71 (d, J
Example 177: N-(2,6-
= 3.5 Hz, 1H), 7.50 (dd, J =8.0, 1.0
difluorophenyl)-5-(2-
Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H),
ethyl-3-(4-methyl-5-
7.35 (s, 1H, D20 exchangeable),
oxo-4,5-dihydro-
7.31-7.25 (m, 1H), 7.08 (d, J = 3.5
l,3,4-oxadiazol-2-
Hz, 1H), 7.03 (t, J = 8.0 Hz, 2H),
yl)phenyl)thiophene-
3.54 (s, 3H), 3.06 (q, J = 7.0 Hz,
2-carboxamide
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 secretion of IL-2 by antigen stimulated T-cells in vitro. Alternatively, such activity can
also be evaluated by assay methods known to one skilled in the art.
In vitro assay
Example- 78
Inhibition of IL-2 secretion: 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 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 C0 2 incubator at 37°C. After
incubation with the compounds, cells were centrifuged, collected the supernatant 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 have IC50 (nM) values as
shown below:
Thus, compounds of the invention are shown to inhibit IL-2 secretion.
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 detection system. Fluorescence
was also measured using a plate reader at 485nm excitation and 520nm emission (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 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 present invention showed activity
against SOCE as given below:
Thus, compounds of the invention are shown to have 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 present invention
showed activity as given below:
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.
Example-181
Effect of compounds of the present invention on ovalbumin induced (Delayed Type
Hypersensitivity) DTH model:
Intradermal injections of emulsions containing Freund's complete adjuvant (FCA), heat killed
Mycobacterium tuberculosis (4mg/ml) in complete 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 animals. 24 h post
injection of Ovalbumin, ear swelling induced due to antigenic challenge was assessed using
Vernier calipers. Animals were treated with either vehicle or test compounds orally once a
day from day 0 till day 8.
Compounds of the present invention showed efficacy in suppressing ear swelling in the
animals on antigenic challenge.
Example- 182
Effect of compounds of the present invention on Collagen Induced Arthritis (CIA):
Female Lewis rats (n = 6 each group) were given intradermal injections (at the base of the
tail) of emulsions containing porcine Collagen-II (2mg/ml) and incomplete Freund's adjuvant
on day 0 and day 7. Animals 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. Animals were dosed with either vehicle or test
compounds orally once a day from day 0 till day 35.
Compounds of the present invention were found to reduce arthritis in these animals.
As mentioned hereinbefore, the CRAC channel is involved with numerous biological
responses through various Ca signaling pathways. The compounds of the present invention
are therefore useful for the treatment and/or prophylaxis of, although not limited to,
inflammatory conditions, cancer, rheumatoid arthritis, allergic disorders, immune disorders,
cardiovascular diseases, thrombocytopathies and all related conditions which can be
benefitted by the CRAC channel modulatory properties of the compounds described herein.
The compounds of the present invention can be administered to a warm-blooded animal,
including human being, for the treatment and/or prophylaxis 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 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 present invention via oral route,
parenteral route, inhalation and /or topical applications are within the scope of this
application. Any combination of a compound of the present invention with excipients and/or
other therapeutic agents known in the art for the said conditions, diseases and/or disorders are
also encompassed by the present invention.
All patents, patent applications and publications cited in this application are hereby
incorporated by reference in their entirety for all purposes to the same extent as if each
individual patent, patent application or publication were so individually denoted.
Although certain embodiments and examples have 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. All
such modifications are intended to be encompassed within the below claims of the invention.
CLAIMS
1. A compound of Formula (I):
wherein,
ring E is a 5-membered 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, cycloalkenyl, aryl, heteroaryl,
heterocyclyl, -C(0)NR6R7, -C(0)OR6and -C(0 )R ;
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(0) nR6, -NR6S(0) 2R7, -NR6(CR8R9)nC(0)OR ,
NR (CR8R9)nC(0)R6, -NR (CR R )nC(0)NR 6R7, -C(0)NR6R7, -C(0)(0)R , -C(0)R6, -
OC(0)R6, and -OC(0)NR R7;
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(0 )OR6, -NR6R7, -C(0)R6, -
NHS(0 )2R and -NHC(0 )R«;
R3, which may be same or different at each occurrence, is independently selected
from hydrogen, halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, -NR6R7, -NR S(0 )2R ,
-C(0)NR6R and -C(0)OR6;
and R5, which may be same or different at each occurrence, are independently
selected from hydrogen, halo, -ORi0, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, -(CR R9)nC(0)NR6R , -C(0 )R6 , and -(CR8R9)nC(0 )OR6 ;
provided that, when any of or R5 in Y is -OR10 then Rio is not hydrogen; or
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 R 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
wherein A1 and A2 are independently selected from C and N;
G is selected from S, NR[2 and O;
L is -C(0 )NRi or-NRnC(O)-;
Rii, at each occurrence, is independently selected from hydrogen, alkyl and aryl;
R 2 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
Rio is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
R and R , which may be same or different at each occurrence, are independently
selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; or ¾ and R ,
taken together with the nitrogen atom to which they are attached to, may form a substituted
or unsubstituted 3- to 14- membered heterocyclic ring;
R and R , which may be same or different at each occurrence, are independently
selected from hydrogen, halo, alkyl and alkoxy; or R 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 (=0), thio (=S), alkyl, haloalkyl, alkenyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic
ring, heterocyclylalkyl, heteroarylalkyl, -C(0)OR , -C(0)R x, -C(S)RX, -C(0)NR xRy, -
NR C(0)NR R , -N(Rx)S(0)R , -N(Rx)S(0) 2Ry, -NRxR , -NRxC(0)R , -NR"C(S)R , -
NRxC(S)NR Rz, -S(0) 2NRxR , -ORx, -OC(0)R x, -OC(0)NR xR , -RxC(0)OR , -
RxC(0)NR yR , -RxC(0)R y, -SRX, and -S(0) 2Rx wherein each occurrence of Rx, R and R
are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl,
cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl ring and
heteroarylalkyl;
or a pharmaceutically acceptable salt thereof or streoisomers thereof.
2. The compound of claim 1 having the Formula (la):
or a pharmaceutically acceptable salt thereof;
wherein ring ~ is selected from Formula (i) to (iv)
ring W, ring D, R, Rl 5 R2, R3, R4, R5, Rio, 'p' and 'q' are as defined claim 1.
3. The compound of claim 1 having the Formula (lb):
(lb)
or a pharmaceutically acceptable salt thereof;
Y' XV
wherein ring ~ is selected from Formula (i) to (iv)
ring W, ring D, R, Rj, R2, R3, R4, R5, Rj0, 'p' and 'q' are as defined in claim 1.
4. The compound of claim 1 having the Formula (Ic):
or a pharmaceutically acceptable salt thereof;
wherein ring selected from Formula (v) to (vii)
(v) (vi) (vii)
ring W, ring D, R, Ri, R2, R3, R4, R5, 'p' and 'q' are as defined in claim 1.
5. The compound of claim 1 having the Formula (Id):
or a pharmaceutically acceptable salt thereof;
wherein ring
VN
v
is selected from Formula (v) to (vii)
(v) (vi) v
ring W, ring D, R, R , R2, R3, , 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
(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 -CR Rs-;
R is selected from alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl;
4 and R5, which may be same or different at each occurrence, are independently
selected from hydrogen, halo, ORi0, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, -(CR R )nC(0)NR 6R7, -C(0)R , and -(CR8R9)nC(0)OR ; or
R and R , 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 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.
7. The compound of claim 1, wherein ring D is
1 wherein A and A are independently selected from C and N ;
G is selected from S and NRi2; R 3 is as defined in claim 1.
R12 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(0)NRn- or -NRnC(O)-; where R is
hydrogen or alkyl.
10. The compound of claim 1, wherein ring E is selected from:
ring W is aryl or heteroaryl;
Ris alkyl; R3 is hydrogen or alkyl;
Ri is halo or alkyl;
and R , which may be same or different at each occurrence, are independently
selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -(CR R9)nC(0)NR6R ,
and -(CR R9)nC(0)OR6 ; 'n' is 0 or 1;
R 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
Lis -C(0)NR - or-NR C(0 )-;
Ri 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:
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2,6-difluorobenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-4-
methyl-l,2,3-thiadiazole-5-carboxamide,
N-(5'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methyl-[l , -biphenyl]-4-yl-
2,6-difluorobenzamide,
N-(5-(5 -(5 ,5-Dimethyl-4-oxo-4,5 -dihydroisoxazol-3-yl)-2-methylphenyl)pyridin-2-yl)-
2,6-difluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)pyrazin-2-yl)-2,6-
difluorobenzamide,
N- 5'-(5 ,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3 -yl)-2'-ethyl- [1,1 '-biphenyl]-4-yl)-2,6-
difluorobenzamide,
N-(6-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)pyridin-3-yl)-2,6-
difluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-isopropylphenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-isopropyl-[l ,1'-biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(2'-(tert-butyl)-5'-(5 ,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3 -yl)- [1,1'-biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(2'-chloro-5 '-(5,5-dimethyl-4-oxo-4,5 -dihydroisoxazol-3 -yl)- [1,1'-biphenyl]-4-yl)-2,6-
difluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-fluorophenyl)pyrazin-2-yl)-2,6-
difluorobenzamide,
N-(5 '-(5 ,5-dimethyl-4-oxo-4,5 -dihydroisoxazol-3-yl)-2'-fluoro- [1,1 '-biphenyl]-4-yl)-2,6-
difluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methoxy-[l , -biphenyl]-4-yl)-
2,6-difluorobenzamide,
7V-(5'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methoxy-[l , -biphenyl]-4-yl)-4-
methyl-l,2,3-thiadiazole-5-carboxamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyridin-2-yl)-
2,6-difluorobenzamide,
N-(6-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyridin-3-yl)-
2,6-difluorobenzamide,
N-(2'-acetamido-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[l , -biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(5-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)-2,6-
difluorobenzamide,
N-(6-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyridin-3-yl)-2,6-
difluorobenzamide,
N- '-(5 ,5-dimethyl-4-oxo-4,5 -dihydroisoxazol-3-yl)- [1,1 '-biphenyl]-4-yl)-2,6-
difluorobenzamide,
2,6-difluoro-N-(5-(5-(4-methoxy-5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)benzamide,
2,6-Difluoro-N-(5'-(4-methoxy-5,5-dimethyl-4,5-dihydroisoxazol-3-yl)-2'-methyl-[l,l'-
biphenyl]-4-yl)benzamide,
yV-(4'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methyl-[l,l'-biphenyl]-4-yl)-2,6
difluorobenzamide,
N-(5-(4-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
N-(5-(4-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyridin-2-yl)-
2,6-difluorobenzamide,
N-(5-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
N-(3 '-(5,5-Dimethyl-4-oxo-4,5 -dihydroisoxazol-3-yl)-2'-methyl- [1,1'-biphenyl]-4-yl)-2,6
difluorobenzamide,
N-(5-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyridin-2-yl)-
2,6-difluorobenzamide,
N-(3'-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-methoxy-[l , -biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(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-N-(2'-methyl-5,-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-
biphenyl]-4-yl)benzamide,
N-(5'-(4-Ethyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-2'-methyl-[l,l'-biphenyl]-4-yl)-
2,6-difluorobenzamide,
2,6-Difluoro-N-(2'-methyl-5,-(5-oxo-4-propyl-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-
biphenyl]-4-yl)benzamide,
N-(2'-Ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-biphenyl]-4-yl)-
2,6-difluorobenzamide,
2-Chloro-N-(2'-ethyl-5*-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-
biphenyl]-4-yl)-6-fluorobenzamide,
N-(2'-Ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-biphenyl]-4-yl)-
2-fluoro-6-methylbenzamide,
N-(2'-Ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-o'xadiazol-2-yl)- [1,1 '-biphenyl]-4-yl)-
4-methyl- 1,2,3-thiadiazole-5-carboxamide,
2,6-Difluoro-N-(2'-methoxy-5'-(4-methyl-5-oxo-4,5-dihydro-l ,3,4-oxadiazol-2-yl)-[ 1,1'-
biphenyl]-4-yl)benzamide,
2-Chloro-6-fluoro-N-(2'-methoxy-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-
[1,1 '-biphenyl]-4-yl)benzamide,
2-Fluoro-N-(2'-methoxy-5'-(4-methyl-5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)-[ 1,1'-
biphenyl]-4-yl)-6-methylbenzamide,
4-Ethyl-N-(2'-methoxy-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l , -
biphenyl]-4-yl)benzamide,
N-(2'-(Difluoromethoxy)-5'-(4-methyl-5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)-[l ,1'-
biphenyl]-4-yl)-2,6-difluorobenzamide,
N-(2'-(Difluoromethoxy)-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l , -
biphenyl]-4-yl)-4-methyl- 1,2,3-thiadiazole-5-carboxamide,
N-(2'-Chloro-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l ,-biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(2'-Chloro-5'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l ,-biphenyl]-4-yl)-
4-methyl- 1,2,3 -thiadiazole-5-carboxamide,
2,6-Difluoro-N-(2,-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-
bipheny1] -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-N-(2'-methyl-3,-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-[l,l'-
biphenyl]-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)-4-
methyl-1,2,3-thiadiazole-5-carboxamide,
N-(2'-ethyl-3 -(4-methyl-5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)- [1,1-biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(5-(5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2,6-
difluorobenzamide,
Methyl 3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-methyl-4,5-
dihydroisoxazole-5-carboxylate,
Methyl-3-(4'-(2,6-difluorobenzmido)-6-methyl-[l,l'-biphenyl]-3-yl)-5-methyl-4,5-
dihydroisoxazole-5-carboxylate,
2,6-Difluoro-N-(2'-methyl-5'-(l -oxa-2-azaspiro[4.4]non-2-en-3-yl)-[ 1,1'-biphenyl]-4-
yl)benzamide,
2,6-Difluoro-N-(5-(2-methyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)phenyl)pyrazin-2-
yl)benzamide,
2,6-Difluoro-N-(2,-methyl-5'-(4-oxo-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-[l,l'-biphenyl]-
4-yl)benzamide,
V-(5-(5-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-2-methylphenyl)pyrazine-2-yl)-2,6-
difluorobenzamide,
N-(5-(5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2-methylphenyl)pyridin-2-yl)-2,6-
difluorobenzamide,
N- 5' -(4,4-dimethyl-4,5 -dihydrooxazol-2-yl)-2' -methyl-[1,1' -biphenyl] -4-yl)-2,6-
difluorobenzamide,
2,6-Difluoro-N-(2,-methyl-5,-(4-methyl-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-[l,l'-
biphenyl]-4-yl)benzamide,
4-Methyl-N-(2'-methyl-5 ,-(4-methyl-5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)-[ 1,1'-
biphenyl]-4-yl)- 1,2,3-thiadiazole-5-carboxamide,
Ethyl 3-(4,-(2,6-difluorobenzamido)-6-methyl-[l,l'-biphenyl]-3-yl)-4,4-dimethyl-4,5-
dihydroisoxazole-5-carboxylate,
V-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2-fluorobenzamide,
7V-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2.4-difluorobenzamide,
iV-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2.5-difluorobenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2,3-difluorobenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
4-fluorobenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2,4,5-trifluorobenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2,3-dimethylbenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
4-trifluoromethylbenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
4-fluoro-3-methylbenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
2-methylbenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazine-2-yl)-
3-fluoro-5-trifluoromethylbenzamide,
Methyl-3-(4'-(2,6-difluorobenzmido)-6-methyl-[l,l'-biphenyl]-3-yl)-5-(2-methoxy-2-
oxoethyl)-4,5-dihydroisoxazole-5-carboxylate,
Methyl 3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-(2-methoxy-2-
oxoethyl)-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-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)benzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2
fluoro-6-(trifluoromethyl)benzamide,
2-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)
pyrazin-2-yl) -6-fluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2
methoxybenzamide,
N-(5-(5 -(5,5-dimethyl-4-oxo-4,5 -dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)cyclohexanecarboxamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)cyclopentanecarboxamide,
N-(5-(2-(ter/-butyl)-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2-
yl)-2,6-difluorobenzamide,
N-(5-(3 -(5 ,5-Dimethyl-4-oxo-4,5 -dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)
2,6-difluorobenzamide,
N-(5-(2-chloro-5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
2,6-Difluoro-iV-(5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
yl)phenyl)pyrazin-2-yl)benzamide,
N-(5-(5-(4-Ethyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-2-methylphenyl)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,
N-(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-N-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)
pyrazin-2-yl)-6-fluorobenzamide,
N-(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-N-(5-(2-methoxy-5-(4-methyl-5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-
yl)phenyl)pyrazin-2-yl)benzamide,
2,6-Difluoro-N-(5-(2-fluoro-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
yl)phenyl)pyrazin-2-yl)benzamide,
N-(5-(2-(difluoromethoxy)-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
yl)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-difluorobenzamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)picolinamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)nicotinamide,
N-(5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)isonicotinamide,
N-(5 -(5 -(5 ,5-Dimethyl-4-oxo-4,5 -dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2
methylnicotinamide,
6-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)nicotinamide,
6-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)isonicotinamide,
3,5-Dichloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)isonicotinamide,
4-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)nicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-6-
methylnicotinamide,
5-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)nicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-y l)-3 -
fluoroisonicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-5-
fluoronicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2-
fluoronicotinamide,
2-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)isonicotinamide,
2-Chloro-N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)-6-methylisonicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2-
fluoroisonicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-2-
methylnicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-
3,5-difluoroisonicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-yl)-3-
methylisonicotinamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-methoxyphenyl)pyrazin-2-yl)-
3,5-difluoroisonicotinamide,
N-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)pyrazin-2-yl)-
3,5-difluoroisonicotinamide,
3.5- Difluoro -N -(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-2-
yl)benzofuran-2-carboxamide,
2.6- Difluoro -N -(5-(2-methyl-5-(4-oxo-l-oxa-2-azaspiro[4.5]dec-2-en-3-
yl)phenyl)pyrazin-2-yl)benzamide,
V-(2,6-Difl uorophenyl)-5-(5-(5,5-dimethyl-4 -oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazine-2-carboxamide,
4-(2,6-Difluorobenzamido)-3'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[l,l'-
biphenyl]-2-carboxylic acid,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-hydroxy-[l ,r-biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-hydroxyphenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
iV-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-isopropoxy-[l ,r-biphenyl]-4-yl)-
2,6-difluorobenzamide,
jV-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-isopropoxyphenyl)pyrazin-2-
yl)-2,6-difluorobenzamide,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-isobutoxy-[l ,r-biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-isobutoxyphenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-ethoxy-[l,l'-biphenyl]-4-yl)-2,6-
difluorobenzamide,
N-(5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethoxyphenyl)pyrazin-2-yl)-
2,6-difluorobenzamide,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-propoxy-[l , -biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(2'-(allyloxy)-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[l,l'-biphenyl]-4-yl)-
2,6-difluorobenzamide,
N-(2'-(cyclopentyloxy)-5'-(5,5-diniethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-[l , -biphenyl]-
4-yl)-2,6-difluorobenzamide,
N-(2'-amino-5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3 -yl)- [1,1'-biphenyl]-4-yl)-2,6-
difluorobenzamide,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-(methylamino)-[ 1,1'-biphenyl]-4-
yl)-2,6-difluorobenzamide,
N-(5'-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2'-(dimethylamino)-[l , -biph^
4-yl)-2,6-difluorobenzamide,
S -N-(5-(5-(5,5-Dimethyl-4-hycftoxy-4,5-dihydroisoxazol-3-yl)-2-methy^
pyrazine-2-yl)-2,6-difluorobenzamide,
N-(5-(2-Methyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl)pyrazin-
2yl)- 1,2,3,4-tetrahydronaphthalene-2-carboxamide
3-(4'-(2.6-Difluorobenzamido)-6-methyl-[l,l'-biphenyl]-3-yl)-5-methyl-4,5-
dihydroisoxazole-5-carboxylic acid,
3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-methyl-4,5-
dihydroisoxazole-5-carboxylic acid,
5-Carboxymethyl-3-(4 '-(2,6-difluorobenzmido)-6-methyl- [1,1' -biphenyl]-3-yl)-4,5-
dihydroisoxazole-5-carboxylic acid,
5-(Carboxymethyl)-3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-4,5-
dihydroisoxazole-5 -carboxylic acid,
2,6-Difluoro-N-(5'-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2'-methyl-
[1,1 '-biphenyl]-4-yl)benzamide,
2,6-Difluoro-N -(5-(5-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)pyrazin-2-yl)benzamide,
2,6-DifluoGo-N -(5'-(5-(2-hydroxyethyl)-5-(hydroxynlethyl)-4,5-dihydroisoxazol-3-yl)-2 ,
methyl-[1,1' -biphenyl]-4-yl)benzamide,
N -(5-(5-(5,5-bis(hydroxymethyl)-4,5-dihydroisoxazol-3-yl)-2-methylphenyl)pyrazin-2-
yl)-2,6-difluorobenzamide,
N -Cyclopropyl-3 -(4 ' -(2,6-difluorobenzamido)-6-methyl- [1,1' -biphenyl] -3-yl)-5-methyl-
4,5-dihydroisoxazole-5-carboxamide,
3-(4 '-(2,6-difluorobenzamido)-6-methyl- [1,1'-biphenyl]-3-yl)-5-methyl-4,5-
dihydroisoxazole-5-carboxamide,
3-(3-(5-(2,6-Difluorobenzamido)pyrazin-2-yl)-4-methylphenyl )-N ,5-dimethyl-4,5-
dihydroisoxazole-5-carboxamide,
3-(4'-(2,6-Difluorobenzamido)-6-methyl- [1,1'-biphenyl]-3-y\)-N, N,5 -trimethyl-4,5-
dihydroisoxazole-5 -carboxamide
N-Cyclopropyl-3-(3-(5-(2,6-difluorobenzamido)pyrazin-2-yl)-4-methylphenyl)-5-methyl
4.5-dihydroisoxazole-5-carboxamide,
2.6-Difluoro-N -(2'-methyl-5'-(5-methyl-5-(4-methylpiperazine-l-carbonyl)-4,5-
dihydroisoxazol-3-yl)-[l , -biphenyl]-4-yl)benzamide,
2,6-Difluoro-N -(5-(2-methyl-5-(5-methyl-5-(4-methylpiperazine-l-carbonyl)-4,5-
dihydroisoxazol-3-yl)phenyl)pyrazin-2-yl)benzamide,
5-(2-Amino-2-oxoethyl)-3 -(4 '-(2,6-difluorobenzamido)-6-methy 1- [1,1'-biphenyl]-3-yl)-
4,5-dihydroisoxazole-5-carboxamide,
3-(4' -(2,6-difluorobenzamido)-6-methyl- [1,1'-biphenyl]-3-yl)-N -methyl-5-(2-
(methylamino)-2-oxoethyl)-4,5-dihydroisoxazole-5-carboxamide,
N-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
ethylphenyl)thiophene-2-carboxamide,
5-(5-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylphenyl)-N-(3-methylpyridin-
4-yl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
fluorophenyl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methoxyphenyl)thiophene-2-carboxamide,
N-(2,6-DifluorophenyI)-5-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)-3-methylthiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazo}-3-yl)phenyl)-3-
methylthiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-4-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methoxyphenyl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-4-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)-3-methylthiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-4-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)phenyl)-3-
methylthiophene-2-carboxamide,
N-(2,6-difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methylphenyl)-1-methyl- 1H-pyrrole-2-carboxamide,
N-(2,6-difluorophenyl)-5-(5-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
methoxyphenyl)- 1-methyl- 1H-pyrrole-2-carboxamide,
N-(2,6-difluorophenyl)-5-(5-(5 ,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-2-
ethylpheny1)- -methyl-1H-pyrrole-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
yl)phenyl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
yl)phenyl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(2-fluoro-5-(4-niethyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
yl)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-carboxaniide,
N-(2,6-Difluorophenyl)-5-(2-methoxy-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
yl)phenyl)-3-methylthiophene-2-carboxamide,
5-(2-Chloro-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl )-N -(2,6-
difluorophenyl)thiophene-2-carboxamide,
N-(2,6-Difluorophenyl)-5-(2-methyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-
y1)phenyl)thiophene-2-carboxamide and
N-(2,6-difluorophenyl)-5-(2-ethyl-3-(4-methyl-5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-
yl)phenyl)thiophene-2-carboxamide
or pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising one or more compounds of Formula (I)
according to claim 1, and one or more pharmaceutically acceptable excipients.
13. A method of 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 wherein the method comprises
administering to the subject a therapeutically effective amount of a compound of
claim 1 or a pharmaceutically acceptable salt thereof.
14. The method 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, allergic disorders, organ transplant, cancer and cardiovascular disorders.
15. The method of claim 13, wherein the disease is rheumatoid arthritis, multiple
sclerosis and psoriasis.
16. The method of claim 13, wherein the disease is allergic disorders selected from
asthma, chronic obstructive pulmonary disorder (COPD) or respiratory disorders.
17. The method 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 preparation 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
X, at each occurrence, is independently selected from -C(O)-, -CR4R5- and
Y, at each occurrence, is independently selected from C(O) and -CP R5-;
R is selected from alkyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,
heterocyclyl, C(0)NR R7, -C(0)OR and -0(0)¾;
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(0) nR6, -NR6S(0) 2R , -NR6(CR R9)nC(0)OR 6,
NR6(CR8R9)nC(0)R , -NR (CR R9)nC(0)NR R , -C(0)NR R , -C(0)(0 )R6, -C(0)R6, -
OC(0)R 6, and -OC(0)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(0)ORe, -NR^, -C(0)R6, -
NHS(0) 2R7 and -NHC(0)R 6;
R3, which may be same or different at each occurrence, is independently selected
from hydrogen, halo, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy, -NR6R , -NR6S(0) R ,
-C(0)NR 6R7 and -C(0)OR6;
and R5, which may be same or different at each occurrence, are independently
selected from hydrogen, halo, ORi0, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, -(CR8R9)nC(0 )NR6R , -C(0)R 6 , and -(CR8R )„C(0)OR ; or
when any of R or R in Y is ORi0 then R10 is not hydrogen;
R 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
wherein A1 and A2 are independently selected from C and N;
G is selected from S, NR 2 and O; L is -C(0)NR - or-NRnC(O)-;
ii, at each occurrence, is independently selected from hydrogen, alkyl and aryl;
Ri is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
Rio is 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 R ,
taken together with the nitrogen atom to which they are attached to, may form a substituted
or unsubstituted 3- to 14- membered heterocyclic ring;
R8 and R9, which may be same or different at each occurrence, are independently
selected from hydrogen, halo, alkyl and alkoxy; or R8 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; 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 BI AP, xanthophos or
triphenylphosphine or a mixture thereof and a base.