U.S. patent application number 15/186882 was filed with the patent office on 2016-10-20 for substituted pyridine compounds as crac modulators.
The applicant listed for this patent is LUPIN LIMITED. Invention is credited to Gokul Keruji DESHMUKH, Nageswara Rao IRLAPATI, Rajender Kumar KAMBOJ, Vijay Pandurang KARCHE, Venkata P. PALLE, Zubair Abdul Wajid SHAIKH, Neelima SINHA.
Application Number | 20160304506 15/186882 |
Document ID | / |
Family ID | 48428565 |
Filed Date | 2016-10-20 |
United States Patent
Application |
20160304506 |
Kind Code |
A1 |
IRLAPATI; Nageswara Rao ; et
al. |
October 20, 2016 |
SUBSTITUTED PYRIDINE COMPOUNDS AS CRAC MODULATORS
Abstract
The present invention relates to compounds described herein
Formula (I) and pharmaceutical acceptable salts thereof, which
modulate the activity of calcium release-activated calcium (CRAC)
channel. The invention also describes the compounds of Formula (I)
and pharmaceutical compositions containing such compounds thereof
for treating, managing, and/or lessening the severity of diseases,
disorders, syndromes or conditions associated with the modulation
of calcium release-activated calcium (CRAC) channel.
##STR00001##
Inventors: |
IRLAPATI; Nageswara Rao;
(Pune, IN) ; SHAIKH; Zubair Abdul Wajid; (Pune,
IN) ; KARCHE; Vijay Pandurang; (Pune, IN) ;
DESHMUKH; Gokul Keruji; (Pune, IN) ; SINHA;
Neelima; (Pune, IN) ; PALLE; Venkata P.;
(Pune, IN) ; KAMBOJ; Rajender Kumar; (Pune,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LUPIN LIMITED |
Mumbai |
|
IN |
|
|
Family ID: |
48428565 |
Appl. No.: |
15/186882 |
Filed: |
June 20, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14398154 |
Oct 31, 2014 |
9399638 |
|
|
PCT/IB2013/053440 |
May 1, 2013 |
|
|
|
15186882 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 9/00 20180101; C07D 413/04 20130101; C07D 417/14 20130101;
A61P 19/02 20180101; A61P 17/06 20180101; A61P 29/00 20180101; C07D
413/14 20130101 |
International
Class: |
C07D 413/14 20060101
C07D413/14; C07D 417/14 20060101 C07D417/14; C07D 413/04 20060101
C07D413/04 |
Foreign Application Data
Date |
Code |
Application Number |
May 2, 2012 |
IN |
6/KOL/2012 |
Claims
1. A compound having the Formula (I): ##STR00134## wherein, ring A
ismonocyclic heteroaryl provided that the ring A is not pyrazolyl;
ring E is a 5-membered non aromatic heterocyclic ring selected from
##STR00135## X, at each occurrence, is independently selected from
--C(O)--, --CR.sub.4R.sub.5-- and --NR--; Y, at each occurrence, is
independently --C(O)-- or --CR.sub.4R.sub.5--; provided that both
of X and Y are not simultaneously --C(O)--; R is selected from
substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, --C(O)NR.sub.6R.sub.7, --C(O)OR.sub.8
and --C(O)R.sub.9; ring W is selected from aryl or heteroaryl; L is
selected from --C(O)NR.sub.11--, --NR.sub.11C(O)-- and
--NR.sub.11CH.sub.2--; ring D is selected from ##STR00136## wherein
A.sub.1 and A.sub.2 are independently CR.sub.3 or N; G is selected
from S, NR.sub.12 and O; R.sub.1, which may be same or different at
each occurrence, is independently selected from halogen, cyano,
nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted haloalkoxy and substituted or
unsubstituted cycloalkyl; R.sub.2, which may be same or different
at each occurrence, is independently selected from halogen,
hydroxyl, cyano, nitro, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
haloalkoxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkoxy, --NR.sub.6R.sub.7 and
--NHC(O)R.sub.9; R.sub.3, which may be same or different at each
occurrence, is independently selected from hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkoxy, substituted or unsubstituted haloalkyl, substituted or
unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl,
--NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7 and --C(O)OR.sub.8;
R.sub.4 and R.sub.5, which may be same or different at each
occurrence, are independently selected from hydrogen, halogen,
--OR.sub.10, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl,
--C(O)OR.sub.8, --C(O)--NR.sub.6R.sub.7, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocyclyl; provided that, when any of R.sub.4 or
R.sub.5 in Y is --OR.sub.10 then R.sub.10 is not hydrogen; R.sub.6
and R.sub.7, which may be same or different at each occurrence, are
independently selected from hydrogen, substituted or unsubstituted
alkyl and substituted or unsubstituted cycloalkyl; or R.sub.6 and
R.sub.7, together with the nitrogen atom to which they are
attached, may form a substituted or unsubstituted, saturated or
unsaturated 3 to 12 membered cyclic ring, wherein the unsaturated
cyclic ring may have one or two double bonds; R.sub.8, which may be
same or different at each occurrence, is independently hydrogen,
substituted or unsubstituted alkyl; R.sub.9, which may be same or
different at each occurrence, is independently selected from
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, and substituted or unsubstituted aryl; R.sub.10 is
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocyclyl; R.sub.11, at each
occurrence, is independently selected from hydrogen, substituted or
unsubstituted alkyl and substituted or unsubstituted aryl; R.sub.12
is selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl and
substituted or unsubstituted heterocyclyl; `n` is an integer
ranging from 0 to 2, both inclusive; `p` is an integer ranging from
0 to 4, both inclusive; and `q` is an integer ranging from 1 to 2,
both inclusive; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, having Formula (II) ##STR00137## or a
pharmaceutically acceptable salt thereof, wherein, L is selected
from --C(O)NH--, --NHC(O)-- and --NHCH.sub.2--; ring W is selected
from aryl or heteroaryl; ring D, X, Y, R.sub.1, R.sub.2, R.sub.3,
`n`, `p`, and `q` are as defined in claim-1.
3. The compound of claim 1, having Formula (III) ##STR00138## or a
pharmaceutically acceptable salt thereof; wherein, L is selected
from --C(O)NH--, --NHC(O)-- and --NHCH.sub.2--; ring W is selected
from aryl or heteroaryl; ring D, X, Y, R.sub.1, R.sub.2, R.sub.3,
`n`, `p`, and `q` are as defined in claim-1.
4. The compound of claim 1, wherein ring ##STR00139## is selected
from Formula (i) to (iii) ##STR00140## wherein R, R.sub.4, and
R.sub.5 are as defined in claim-1.
5. The compound of claim 1, wherein ring ##STR00141## is selected
from Formula (iv) to (vii) ##STR00142## where R, R.sub.4, R.sub.5
and R.sub.10 are as defined claim 1.
6. The compound of claim 1, wherein L is --C(O)NR.sub.11--,
--NR.sub.11C(O)-- or --NR.sub.11CH.sub.2--; wherein R.sub.11 is
hydrogen or substituted or unsubstituted alkyl.
7. The compound of claim 1, wherein ring W is aryl wherein the aryl
is phenyl.
8. The compound of claim 1, wherein ring W is heteroaryl wherein
the heteroaryl is pyridyl, oxazolyl, isoxazolyl or
thiadiazolyl.
9. The compound of claim 1, wherein R.sub.1 is selected from
halogen, cyano, nitro, hydroxyl, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and
substituted or unsubstituted cycloalkyl; and `p` is 0, 1, 2, or
3.
10. The compound of claim 1, wherein ring D is ##STR00143## wherein
A.sub.1 and A.sub.2 are independently selected from CR.sub.3 or N;
R.sub.3 is hydrogen, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl and substituted or
unsubstituted cycloalkyl; and `q` is 1 or 2.
11. The compound of claim 1, wherein ring is ##STR00144## where G
is selected from S, NR.sub.12 and O; wherein R.sub.12 is hydrogen
or substituted or unsubstituted alkyl;
12. The compound of claim 1, wherein R.sub.3 is hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl and substituted or unsubstituted cycloalkyl; and `q` is 1
or 2.
13. The compound of claim 1, wherein R.sub.2 is selected from
halogen, hydroxyl, cyano, nitro, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy,
substituted or unsubstituted cycloalkyl, and --NR.sub.6R.sub.7
where R.sub.6 and R.sub.7 are independently a hydrogen or
substituted or unsubstituted alkyl; and `n` is 0, 1 or 2.
14. The compound of claim 1, having the Formula (IV): ##STR00145##
wherein R is substituted or unsubstituted alkyl; substituted or
unsubstituted haloalkyl, or substituted or unsubstituted
cycloalkyl; L is --C(O)NH--, --NHC(O)--, or --NHCH.sub.2--; ring W
is phenyl, pyridyl, oxazolyl, isoxazolyl or thiadiazolyl; R.sub.1
may be same or different and are independently a halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl or substituted or unsubstituted cycloalkyl; `p` is 1, 2,
or 3; ring D is ##STR00146## R.sub.3 is hydrogen, halogen,
substituted or unsubstituted alkyl; `q` is 1; R.sub.2 is halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, substituted or unsubstituted alkoxy, substituted or
unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl,
and --NR.sub.6R.sub.7 where R.sub.6 and R.sub.7 are independently a
hydrogen or substituted or unsubstituted alkyl; and `n` is 0, 1 or
2.
15. The compound of claim 1, which is selected from:
2,6-Difluoro-N-(4-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)pyridin-3-yl)phenyl)benzamide;
N-(4-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl) phenyl)-2,6-difluorobenzamide;
N-(2,6-Difluorophenyl)-4-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)pyridin-3-yl)benzamide;
N-(4-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)py-
ridin-3-yl)phenyl)-2,6-difluorobenzamide;
4-(2-cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrid-
in-3-yl)-N-(2,6-difluorophenyl)benzamide;
2,6-Difluoro-N-(4-(2-methoxy-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazo-
l-2-yl)pyridin-3-yl)phenyl)benzamide;
2,6-difluoro-N-(4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2--
(trifluoromethyl)pyridin-3-yl)phenyl) benzamide;
2,6-difluoro-N-(3-methyl-4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)-2-(trifluoromethyl)pyridin-3-yl)phenyl) benzamide;
2-Chloro-6-fluoro-N-(4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-y-
l)-2-(trifluoromethyl)pyridin-3-yl)phenyl)benzamide;
2,6-Difluoro-N-(4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2--
(methylamino)pyridin-3-yl)phenyl)benzamide;
2-Chloro-6-fluoro-N-(4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-y-
l)-2-(methylamino)pyridin-3-yl)phenyl)benzamide;
2-Fluoro-6-methyl-N-(4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-y-
l)-2-(methylamino)pyridin-3-yl)phenyl)benzamide;
2,6-Difluoro-N-(3-methyl-4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)-2-(methylamino)pyridin-3-yl)phenyl)benzamide;
2,6-Difluoro-N-(4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyr-
idin-3-yl)phenyl)benzamide;
2,6-Difluoro-N-(3-methyl-4-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)pyridin-3-yl)phenyl)benzamide;
N-(4-(4-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl)phenyl)-2,6-difluorobenzamide;
N-(2,6-Difluorophenyl)-4-(4-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)pyridin-3-yl)benzamide;
N-(4-(3-Ethyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
2-yl)phenyl)-2,6-difluorobenzamide;
N-(2,6-Difluorophenyl)-4-(3-ethyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)pyridin-2-yl)benzamide;
2,6-Difluoro-N-(4-(3-methyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)pyridin-2-yl)phenyl)benzamide;
N-(4-(5-Ethyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
2-yl)phenyl)-2,6-difluorobenzamide;
N-(2,6-Difluorophenyl)-4-(5-ethyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)pyridin-2-yl)benzamide;
2,6-Difluoro-N-(4-(6-methyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)pyridin-2-yl)phenyl)benzamide;
N-(4-(4-Chloro-6-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-
-2-yl)phenyl)-2,6-difluorobenzamide;
N-(4-(4-Ethoxy-6-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-
-2-yl)phenyl)-2,6-difluorobenzamide;
2,6-Difluoro-N-(4-(2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyr-
idin-4-yl)phenyl)benzamide;
2,6-Difluoro-N-(4-(4-methyl-6-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)pyridin-3-yl)phenyl)benzamide;
N-(4-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)
pyridin-3-yl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide;
N-(4-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl)-3-methylphenyl)-2, 6-difluorobenzamide;
N-(2'-ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[3,3'-bi-
pyridin]-6-yl)-2,6-difluorobenzamide;
N-(2'-ethyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[2,3'-bi-
pyridin]-5-yl)-2,6-difluorobenzamide;
N-(4-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)py-
ridin-3-yl)-3-methylphenyl)-2,6-difluorobenzamide;
N-(5-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)py-
ridin-3-yl)pyrazin-2-yl)-2, 6-difluorobenzamide;
2-Chloro-N-(5-(2-cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazo-
l-2-yl)pyridin-3-yl)pyrazin-2-yl)-6-fluorobenzamide;
N-(2'-Cyclopropyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[2-
,3'-bipyridin]-5-yl)-2,6-difluorobenzamide;
N-(2'-Cyclopropyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[3-
,3'-bipyridin]-6-yl)-2,6-difluorobenzamide;
2,6-Difluoro-N-(5-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2--
(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)benzamide;
2,6-Difluoro-N-(5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2'-(-
trifluoromethyl)-[3,3'-bipyridin]-6-yl)benzamide;
2,6-Difluoro-N-(5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2'-(-
trifluoromethyl)-[2,3'-bipyridin]-5-yl)benzamide;
5-(5-((2,6-Difluoro
benzyl)amino)-2'-ethyl-[2,3'-bipyridin]-5'-yl)-3-methyl-1,3,4-oxadiazol-2-
(3H)-one; 5-(6'-((2,6-Difluorobenzyl)
amino)-2-ethyl-[3,3'-bipyridin]-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
N-(2'-Ethyl-4-methyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-
-[2,3'-bipyridin]-5-yl)-2,6-difluorobenzamide;
N-(2'-Ethyl-4-methyl-5'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-
-[3,3'-bipyridin]-6-yl)-2,6-difluorobenzamide;
N-(2-Chloro-6-fluorophenyl)-5-(2-cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydr-
o-1,3,4-oxadiazol-2-yl)pyridin-3-yl)thiophene-2-carboxamide;
5-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrid-
in-3-yl)-N-(3-methylpyridin-4-yl)thiophene-2-carboxamide;
N-(2,6-Difluorophenyl)-5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)pyridin-3-yl)furan-2-carboxamide;
5-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrid-
in-3-yl)-N-(2,6-difluorophenyl)furan-2-carboxamide;
N-(4-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl)phenyl)-3,5-difluoroisonicotinamide;
N-(4-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl)phenyl)-2-fluoro-6-methylbenzamide;
2-Chloro-N-(4-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl-
) pyridin-3-yl)phenyl)-6-fluorobenzamide;
N-(4-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl) phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide;
N-(4-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl)phenyl)-3,5-dimethylisoxazole-4-carboxamide;
N-(4-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl) phenyl)-3-methylisonicotinamide;
N-(4-(5-(4,4-Dimethyl-5-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylpyridin-3-yl-
)phenyl)-2,6-difluorobenzamide;
2,6-Difluoro-N-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol--
2-yl)pyridin-3-yl)pyrazin-2-yl)benzamide;
2-Chloro-N-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl-
)pyridin-3-yl)pyrazin-2-yl)-6-fluorobenzamide;
2,6-Difluoro-N-(5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)pyridin-3-yl)pyrazin-2-yl)benzamide;
2,6-Difluoro-N-(5-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2--
(methylamino)pyridin-3-yl)pyrazin-2-yl)benzamide;
N-(2,6-Difluorophenyl)-5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)pyridin-3-yl)thiophene-2-carboxamide;
N-(2,6-Difluorophenyl)-5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-ox-
adiazol-2-yl)pyridin-3-yl)thiophene-2-carboxamide;
5-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrid-
in-3-yl)-N-(2,6-difluorophenyl)thiophene-2-carboxamide;
N-(2,6-Difluorophenyl)-5-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
-yl)-2-(trifluoromethyl)pyridin-3-yl)thiophene-2-carboxamide;
N-(2,6-Difluorophenyl)-5-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
-yl)-2-(methylamino)pyridin-3-yl)thiophene-2-carboxamide;
N-(2,6-Difluorophenyl)-1-methyl-5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-
-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1H-pyrrole-2-carboxamide;
N-(2,6-Difluorophenyl)-5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)pyridin-3-yl)-1-methyl-1H-pyrrole-2-carboxamide
N-(4-(4-Ethyl-6-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
2-yl)phenyl)-2,6-difluorobenzamide;
N-(4-(3-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
2-yl)phenyl)-2,6-difluorobenzamide;
N-(4-(3-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)
pyridin-2-yl)phenyl)-2,6-difluorobenzamide;
N-(4-(5-Cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)
pyridin-2-yl)phenyl)-2,6-difluorobenzamide and
N-(4-(6-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
3-yl)phenyl)-2,6-difluorobenzamide or pharmaceutically acceptable
salt thereof.
16. A pharmaceutical composition comprising one or more compounds
of Formula (I) according to claim 1, and one or more
pharmaceutically acceptable excipients.
17. A method of treating, 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.
18. The method of claim 17, 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.
19. The method of claim 17, wherein the disease is rheumatoid
arthritis, multiple sclerosis and psoriasis.
20. The method of claim 17, wherein the disease is allergic
disorders selected from asthma, chronic obstructive pulmonary
disorder (COPD) or respiratory disorders.
21. The method of claim 18, 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.
22. A process for the preparation of a compound of Formula (I):
##STR00147## where ring A, ring D, ring E, ring W, L, R.sub.1,
R.sub.2, R.sub.3, `n`, `p`, and `q` are as described herein above,
the process comprising the steps: a) coupling of a borate compound
of Formula (1) with halo compound of Formula (2) where X' is
halogen, to give compound of Formula (I) by using suitable reagents
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd.sub.2dba.sub.3,
Pd(PPh.sub.3).sub.4, or Pd(OAc).sub.2 and a suitable ligand
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), xanthophos, or
triphenylphosine ##STR00148## b) alternatively, coupling of a halo
compound of Formula (3) where X' is halogen, with compound of
Formula (2) where p is pinacolatoboronate or stannane, to give
compound of Formula (I) by using suitable reagents
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd.sub.2dba.sub.3,
Pd(PPh.sub.3).sub.4, or Pd(OAc).sub.2 and a suitable ligand
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), xanthophos, or
triphenylphosphine ##STR00149##
Description
RELATED APPLICATIONS
[0001] The present application is a Continuation of U.S.
application Ser. No. 14/398,154, filed Oct. 31, 2014, which is a
National Stage Application of PCT/IB2013/053440, filed May 1, 2013,
which claims the benefit of priority to Indian Provisional Patent
Application No. 0006/KOL/2012, filed on May 2, 2012 and which
applications are incorporated herein by reference. To the extent
appropriate, a claim of priority is made to each of the above
disclosed applications.
TECHNICAL FIELD OF THE INVENTION
[0002] The invention relates to substituted pyridine compounds,
pharmaceutically acceptable salts thereof and pharmaceutical
compositions for the treatment, 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,
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
[0003] 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. al., J. Immunol.,
183, 3454-3462, 2009), psoriasis, and cancer. An initial
inflammatory response to pathogens or injury is necessary and
required to fight infection or heal the wound, but sustained or
persistent inflammation can lead to any of the chronic disorders;
characterized by the production of inflammatory cytokines as,
specified above.
[0004] 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-.gamma., TNF-.alpha., 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.
[0005] Ca.sup.+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).
[0006] In immune cells, sustained Ca.sup.+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-.gamma.
(PLC-.gamma.). PLC-.gamma. hydrolyzes
phosphatidylinositol-3,4-biphosphate (PIP.sub.2) to the second
messengers, inositol-1,4,5-triphosphate (IP.sub.3) and
diacylglycerol (DAG). IP.sub.3 binds to IP.sub.3 receptors
(IP.sub.3R) in the membrane of the endoplasmic reticulum (ER) and
induces the release of ER Ca.sup.+2 stores into the cytoplasma. The
decrease in the Ca.sup.+2 concentration in the ER induces
store-operated Ca.sup.+2 entry (SOCE) through plasma membrane
Ca.sup.+2 channels. SOCE through highly Ca.sup.+2-selective
Ca.sup.+2 release-activated Ca.sup.+2 (hereinafter, CRAC) channels
constitutes the major pathway of intracellular Ca.sup.+2 entry in T
cells, B cells, macrophages, mast cells, and other cell types
(Parekh and Putney, Physiol. Rev., 85, 757-810, 2005).
[0007] The CRAC channel is comprised of two family proteins, one
which functions in sensing Ca.sup.+2 levels in the ER--the stromal
interacting molecules (STIM)-1 and -2 and the other which is a
pore-forming protein--Orai1, 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.sup.+2 binding motif. Depletion of Ca.sup.+2 from the ER causes
Ca.sup.+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.sup.+2 from the stores, they
aggregate in the vicinity of the STIM punctae. The eventual
increase in intracellular Ca.sup.+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, NF.kappa.B and Foxp3 (Fahmer
et. al., Immuno. Rev., 231, 99-112, 2009).
[0008] 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 STIM1 and Orai1 are
essential in in vitro tumor cell migration and in vivo tumor
metastasis. Thus the involvement of store operated Ca.sup.2+ entry
in tumor metastasis renders STIM1 and Orai1 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.
[0009] Recent literature reports the role of STIM1 and Orai1 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 STIM1-Orai1 mediated SOCE in thrombus
formation makes Orai1 a potential target for treatment of
thrombosis and related conditions (Gillo et. al., JBC, 285; 31,
23629-23638, 2010).
[0010] 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
benefited by the CRAC channel modulatory properties of the
compounds described herein.
[0011] Several compounds have been reported in the art as CRAC
channel modulators. For example, patent application publications
WO2005009539, WO2005009954, WO2006081391, WO2006081389,
WO2006034402, WO2006083477, WO2007087441, WO2007087442,
WO2007087429, WO2007089904, WO2009017819, WO2009076454,
WO2009035818, US20100152241, WO2010039238, WO2010025295,
WO2010027875, WO2011034962, WO2012151355, WO2013059666,
WO2013059677 disclose the compounds for modulating CRAC
channels.
SUMMARY OF THE INVENTION
[0012] In accordance with one aspect, the invention provides the
compounds of Formula (I):
##STR00002## [0013] wherein, [0014] ring A ismonocyclic
heteroarylprovided that the ring A is not pyrazolyl; [0015] ring E
is a 5-membered non aromatic heterocyclic ring selected from
[0015] ##STR00003## [0016] X, at each occurrence, is independently
selected from --C(O)--, --CR.sub.4R.sub.5-- and --NR--; [0017] Y,
at each occurrence, is independently --C(O)-- or
--CR.sub.4R.sub.5--; [0018] provided that both of X and Y are not
simultaneously --C(O)--; [0019] R is selected from substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heterocyclyl, --C(O)NR.sub.6R.sub.7, --C(O)OR.sub.8
and --C(O)R.sub.9; ring W is selected from aryl or heteroaryl; L is
selected from --C(O)NR.sub.11--, --NR.sub.11C(O)-- and
--NR.sub.11CH.sub.2--; [0020] ring D is selected from
[0020] ##STR00004## [0021] wherein A.sub.1 and A.sub.2 are
independently CR.sub.3 or N; [0022] G is selected from S, NR.sub.12
and O; [0023] R.sub.1, which may be same or different at each
occurrence, is independently selected from halogen, cyano, nitro,
hydroxyl, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted haloalkoxy and substituted or
unsubstituted cycloalkyl; [0024] R.sub.2, which may be same or
different at each occurrence, is independently selected from
halogen, hydroxyl, cyano, nitro, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted alkoxy, substituted or unsubstituted
haloalkoxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkoxy, --NR.sub.6R.sub.7 and
--NHC(O)R.sub.9; [0025] R.sub.3, which may be same or different at
each occurrence, is independently selected from hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkoxy, substituted or unsubstituted haloalkyl, substituted or
unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl,
--NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7 and --C(O)OR.sub.8; [0026]
R.sub.4 and R.sub.5, which may be same or different at each
occurrence, are independently selected from hydrogen, halogen,
--OR.sub.10, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl,
--C(O)OR.sub.8, --C(O)--NR.sub.6R.sub.7, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocyclyl; provided that, when any of R.sub.4 or
R.sub.5 in Y is --OR.sub.10 then R.sub.10 is not hydrogen; [0027]
R.sub.6 and R.sub.7, which may be same or different at each
occurrence, are independently selected from hydrogen, substituted
or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
or R.sub.6 and R.sub.7, together with the nitrogen atom to which
they are attached, may form a substituted or unsubstituted,
saturated or unsaturated 3 to 12 membered cyclic ring, wherein the
unsaturated cyclic ring may have one or two double bonds; [0028]
R.sub.8, which may be same or different at each occurrence, is
independently hydrogen, substituted or unsubstituted alkyl; [0029]
R.sub.9, which may be same or different at each occurrence, is
independently selected from substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, and substituted or
unsubstituted aryl; [0030] R.sub.10 is selected from hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl and substituted or unsubstituted
heterocyclyl; [0031] R.sub.11, at each occurrence, is independently
selected from hydrogen, substituted or unsubstituted alkyl and
substituted or unsubstituted aryl; [0032] R.sub.12 is selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl and substituted or
unsubstituted heterocyclyl; [0033] `n` is an integer ranging from 0
to 2, both inclusive; [0034] `p` is an integer ranging from 0 to 4,
both inclusive; and [0035] `q` is an integer ranging from 1 to 2,
both inclusive; [0036] or a pharmaceutically acceptable salt
thereof.
[0037] According to one embodiment, there are provided compounds
having the structure of Formula (II):
##STR00005## [0038] or its pharmaceutically acceptable salt
thereof; [0039] wherein, [0040] L is selected from --C(O)NH--,
--NHC(O)-- and --NHCH.sub.2--; [0041] ring W is selected from aryl
or heteroaryl; [0042] ring D, X, Y, R.sub.1, R.sub.2, R.sub.3, `n`,
`p`, and `q` are as defined above.
[0043] According to another embodiment, there are provided
compounds having the structure of Formula (III):
##STR00006## [0044] or its pharmaceutically acceptable salt
thereof; [0045] wherein, [0046] L is selected from --C(O)NH--,
--NHC(O)-- and --NHCH.sub.2--; [0047] ring W is selected from aryl
or heteroaryl; [0048] ring D, X, Y, R.sub.1, R.sub.2, R.sub.3, `n`,
`p`, and `q` are as defined above.
[0049] It should be understood that the Formula (I), Formula (II),
and Formula (III) structurally encompasses all tautomers,
stereoisomers, enantiomers and diastereomers, including isotopes
wherever applicable and pharmaceutically acceptable salts that may
be contemplated from the chemical structure of the genera described
herein.
[0050] The details of one or more embodiments of the invention set
forth in the below are illustrative in nature only and not intended
to limit to the scope of the invention. Other features, objects and
advantages of the inventions will be apparent from the description
and claims.
[0051] According to another embodiment there are provided a
compound of Formula (II) wherein ring
##STR00007##
is selected from Formula (i) to (iii)
##STR00008## [0052] where R, R.sub.4, and R.sub.5 are as defined
herein above.
[0053] According to another embodiment there are provided a
compound of Formula (III) wherein ring
##STR00009##
selected from Formula (iv) to (vii)
##STR00010## [0054] where R, R.sub.4, R.sub.5 and R.sub.10 are as
defined herein above.
[0055] According to another embodiment are provided compounds of
Formula (I), Formula (II) and/or Formula (III) in which L is
--C(O)NR.sub.11--, wherein R.sub.11 is hydrogen or substituted or
unsubstituted alkyl.
[0056] According to another embodiment are provided compounds of
Formula (I), Formula (II) and/or Formula (III) in which L is
--NR.sub.11C(O)-- wherein R.sub.11 is hydrogen or substituted or
unsubstituted alkyl.
[0057] According to another embodiment are provided compounds of
Formula (I), Formula (II) and/or Formula (III) in which L is
--NR.sub.11CH.sub.2-- wherein R.sub.11 is hydrogen or substituted
or unsubstituted alkyl.
[0058] According to another embodiment are provided compounds of
Formula (I), Formula (II) and/or Formula (III) in which ring W is
aryl wherein the aryl is phenyl; R.sub.1 is selected from halogen,
cyano, nitro, hydroxyl, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and
substituted or unsubstituted cycloalkyl; and `p` is 0, 1, 2, or
3.
[0059] According to another embodiment are provided compounds of
Formula (I), Formula (II) and/or Formula (III) in which ring W is
heteroaryl wherein the heteroaryl is pyridyl, oxazolyl, isoxazolyl
or thiadiazolyl; R.sub.1 is selected from halogen, cyano, nitro,
hydroxyl, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted haloalkoxy and substituted or
unsubstituted cycloalkyl; and `p` is 0, 1, or 2; According to
another embodiment are provided compounds of Formula (I), Formula
(II) and/or Formula (III) in which ring D is
##STR00011##
wherein A.sub.1 and A.sub.2 are independently CR.sub.3 or N;
R.sub.3 is hydrogen, halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl and substituted or
unsubstituted cycloalkyl; and `q` is 1 or 2.
[0060] According to another embodiment are provided compounds of
Formula (I), Formula (II) and/or Formula (III) in which ring D
is
##STR00012##
where G is selected from S, NR.sub.12 and O; wherein R.sub.12 is
hydrogen or substituted or unsubstituted alkyl; R.sub.3 is halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl and substituted or unsubstituted cycloalkyl and `q` is 1
or 2.
[0061] According to another embodiment are provided compounds of
Formula (I) in which R.sub.2 is selected from halogen, hydroxyl,
cyano, nitro, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted haloalkoxy, substituted or
unsubstituted cycloalkyl, and --NR.sub.6R.sub.7 where R.sub.6 and
R.sub.7 are independently a hydrogen or substituted or
unsubstituted alkyl; and `n` is 0, 1 or 2.
[0062] According to another embodiment are provided compounds of
Formula (IV):
##STR00013## [0063] wherein R is substituted or unsubstituted
alkyl; substituted or unsubstituted haloalkyl, or substituted or
unsubstituted cycloalkyl; L is --C(O)NH--, --NHC(O)--, or
--NHCH.sub.2--; ring W is phenyl, pyridyl, oxazolyl, isoxazolyl or
thiadiazolyl; R.sub.1 may be same or different and are
independently a halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl or substituted or
unsubstituted cycloalkyl; `p` is 1, 2, or 3;
[0063] ##STR00014## [0064] ring D is
##STR00015##
[0064] R.sub.3 is hydrogen, halogen, substituted or unsubstituted
alkyl; `q` is 1; R.sub.2 is halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy,
substituted or unsubstituted cycloalkyl, and --NR.sub.6R.sub.7
where R.sub.6 and R.sub.7 are independently a hydrogen or
substituted or unsubstituted alkyl; and `n` is 0, 1 or 2.
[0065] In another aspect, the invention provides a pharmaceutical
composition comprising at least one compound of Formula (I) and at
least one pharmaceutically acceptable excipient.
[0066] In another aspect of the invention, there is provided a
compound of Formula (I) useful in treating, managing and/or
lessening the severity of the diseases, disorders, syndromes or
conditions associated with the modulation of CRAC channel.
[0067] In another aspect, the invention provides a pharmaceutical
composition of a compound of Formula (I) useful in treating,
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.
[0068] 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.
[0069] 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-.gamma. and
TNF-.alpha. and the like, by regulating the cytokine signalling
pathway through calcineurin and NFAT cells.
[0070] In another aspect of the invention are processes for the
preparation of the compounds described herein.
[0071] In another aspect, there are provided processes for the
preparation compounds of Formula (I):
##STR00016##
where ring A, ring D, ring E, ring W, L, R.sub.1, R.sub.2, R.sub.3,
`n`, `p`, and `q` are as described herein above, the process
comprising the steps: [0072] a) coupling of a borate compound of
Formula (1) with halo compound of Formula (2) where X' is halogen,
to give compound of Formula (I) by using suitable reagents
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd.sub.2dba.sub.3,
Pd(PPh.sub.3).sub.4, or Pd(OAc).sub.2 and suitable ligand
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), xanthophos, or
triphenylphosphine
[0072] ##STR00017## [0073] b) alternatively, [0074] coupling of a
halo compound of Formula (3) where X' is halogen, with compound of
Formula (2) where p is pinacolatoboronate or stannane, to give
compound of Formula (I) by using suitable reagents
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd.sub.2dba.sub.3,
Pd(PPh.sub.3).sub.4, or Pd(OAc).sub.2 and a suitable ligand
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), xanthophos, or
triphenylphosphine
##STR00018##
[0074] DETAILED DESCRIPTION OF THE INVENTION
Definitions and Abbreviations
[0075] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below.
[0076] 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.
[0077] The terms "halogen" or "halo" means fluorine, chlorine,
bromine, or iodine.
[0078] Unless otherwise stated, in the present application "oxo"
means C(.dbd.O) group. Such an oxo group may be a part of either a
cycle or a chain in the compounds of the present invention.
[0079] 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.
[0080] 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), iso-propenyl,
2-methyl-1-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.
[0081] 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.
[0082] 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.
[0083] The term "alkenyloxy" refers to an alkenyl group attached
via an oxygen linkage. Non-limiting examples of such groups are
vinyloxy, allyloxy, 1-butenyloxy, 2-butenyloxy, isobutenyloxy,
1-pentenyloxy, 2-pentenyloxy, 3-methyl-1-butenyloxy,
1-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.
[0084] The term "alkynyloxy" refers to an alkynyl group attached
via an oxygen linkage. Non-limiting examples of such groups are
acetylenyloxy, propynyloxy, 1-butynyloxy, 2-butynyloxy,
1-pentynyloxy, 2-pentynyloxy, 3-methyl-1-butynyloxy, 1-hexynyloxy,
2-hexynyloxy, and the like. Unless set forth or recited to the
contrary, all alkynyloxy groups described or claimed herein may be
straight chain or branched, substituted or unsubstituted.
[0085] The term "cycloalkyl" refers to a non-aromatic mono or
multicyclic ring system having 3 to 12 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Examples of multicyclic cycloalkyl groups include, but are not
limited to, perhydronapththyl, adamantyl and norbomyl groups,
bridged cyclic groups or spirobicyclic groups, e.g.,
spiro(4,4)non-2-yl and the like. Unless set forth or recited to the
contrary, all cycloalkyl groups described or claimed herein may be
substituted or unsubstituted.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] The term "arylalkyl" refers to an aryl group as defined
above directly bonded to an alkyl group as defined above, e.g.,
--CH.sub.2C.sub.6H.sub.5 and --C.sub.2H.sub.4C.sub.6H.sub.5. Unless
set forth or recited to the contrary, all arylalkyl groups
described or claimed herein may be substituted or
unsubstituted.
[0094] A "3-12 membered cyclic ring" as used herein refers to a
monocyclic, bicyclic, polycyclic heteroaryl or heterocyclic ring
systems. These heteroaryl or heterocyclic ring as described
herein.
[0095] 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 --CF.sub.2--, --C(O)--, --S(O)--, S(O).sub.2,
--C(.dbd.N-alkyl)-, or --C(.dbd.N-cycloalkyl), etc. In addition
heterocyclic ring may also be fused with aromatic ring.
Non-limiting examples of heterocyclic rings include azetidinyl,
benzopyranyl, chromanyl, 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
indoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran
and the like.
[0096] The heterocyclic ring may be attached by any atom of the
heterocyclic ring 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; substituents may be on same or different ring
atom.
[0097] 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 by any
atom of the heteroaryl ring 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.
[0098] 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.
[0099] 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.
[0100] 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, halogen,
carboxyl, cyano, nitro, oxo (.dbd.O), thio (.dbd.S), alkyl,
haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring,
heterocyclylalkyl, heteroarylalkyl, --C(O)OR.sup.x, --C(O)R.sup.x,
--C(S)R.sup.x, --C(O)NR.sup.xR.sup.y,
--NR.sup.xC(O)NR.sup.yR.sup.z, --N(R.sup.x)S(O)R.sup.y,
--N(R.sup.x)S(O).sub.2R.sup.y, --NR.sup.xR.sup.y,
--NR.sup.xC(O)R.sup.y, --NR.sup.xC(S)R.sup.y,
--NR.sup.xC(S)NR.sup.yR.sup.z, --S(O).sub.2NR.sup.xR.sup.y,
--OR.sup.x, --OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--R.sup.xC(O)OR.sup.y, --R.sup.xC(O)NR.sup.yR.sup.z,
--R.sup.xC(O)R.sup.y, --SR.sup.x, and --S(O).sub.2R.sup.x; wherein
each occurrence of R.sup.x, R.sup.y and R.sup.z are independently
selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl,
alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heteroaryl,
heterocyclic ring, heterocyclylalkyl and heteroarylalkyl. The
aforementioned "substituted" groups cannot be further substituted.
For example, when the substituent on "substituted alkyl" is "aryl"
or "alkenyl", the aryl or alkenyl cannot be substituted aryl or
substituted alkenyl, respectively.
[0101] The term "stereoisomer" refers to a compound made up of the
same atoms bonded by the same bonds but having different
three-dimensional structures which are not interchangeable. The
three-dimensional structures are called configurations. As used
herein, the term "enantiomer" refers to two stereoisomers whose
molecules are nonsuperimposable mirror images of one another. The
term "chiral center" refers to a carbon atom to which four
different groups are attached. As used herein, the term
"diastereomers" refers to stereoisomers which are not enantiomers.
The terms "racemate" or "racemic mixture" refer to a mixture of
equal parts of enantiomers.
[0102] 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).
[0103] The term "treating" or "treatment" of a state, disease,
disorder, condition or syndrome includes: (a) 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.
[0104] 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.
[0105] The term "subject" includes mammals, preferably humans and
other animals, such as domestic animals; e.g., household pets
including cats and dogs.
[0106] A "therapeutically effective amount" means the amount of a
compound that, when administered to a subject for treating a
disease, disorder, syndrome or condition, is sufficient to cause
the effect in the subject which is the purpose of the
administration. The "therapeutically effective amount" will vary
depending on the compound, the disease and its severity and the
age, weight, physical condition and responsiveness of the subject
to be treated.
[0107] 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 along with 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.
[0108] Pharmaceutically Acceptable Salts:
[0109] The compounds of the invention may form salts with acid or
base. The compounds of invention may be 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 inorganic, organic acid addition salts formed by addition
of acids including hydrochloride salts. Non-limiting examples of
pharmaceutically acceptable salts are inorganic, organic base
addition salts formed by addition of bases. The compounds of the
invention may also form salts with amino acids. 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.
[0110] With respect to the overall compounds described by the
Formula (I), the invention extends to these stereoisomeric forms
and to mixtures thereof. To the extent prior art teaches synthesis
or separation of particular stereoisomers, the different
stereoisomeric forms of the invention may be separated from one
another by a method known in the art, or a given isomer may be
obtained by stereospecific or asymmetric synthesis or chiral HPLC
(high performance liquid chromatography. Tautomeric forms and
mixtures of compounds described herein are also contemplated.
Pharmaceutical Compositions
[0111] The invention relates to pharmaceutical compositions
containing the compound of Formula (I). In particular, the
pharmaceutical compositions contain a therapeutically effective
amount of at least one compound of Formula (I) and at least one
pharmaceutically acceptable excipient (such as a carrier or
diluent). Preferably, the pharmaceutical compositions include the
compound(s) described herein in an amount sufficient to modulate
the calcium release-activated calcium (CRAC) channel to treat CRAC
channel mediated diseases such as inflammatory diseases, autoimmune
diseases, allergic disorders, organ transplant, cancer and
cardiovascular disorders when administered to a subject.
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] The pharmaceutical compositions may be administered in
conventional forms, for example, capsules, tablets, aerosols,
solutions, suspensions or products for topical application.
[0117] 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).
[0118] Solid oral Formulations include, but are not limited to,
tablets, caplets, capsules (soft or hard gelatin), orally
disintegrating tablets, 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,
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.
[0119] 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.
[0120] 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.
[0121] 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
[0122] 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.
[0123] 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.
[0124] 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.
[0125] The inflammatory bowel diseases also include Crohn's
disease, ulcerative colitis, indeterminate colitis, necrotizing
enterocolitis, and infectious colitis.
[0126] "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.
[0127] 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.
[0128] In yet another embodiment, the invention is directed to the
treatment of "immune disorders" by administering an effective
amount of a compound of the present invention.
[0129] 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.
[0130] 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.
[0131] 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).
[0132] "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.
[0133] In another embodiment, the invention is directed to the
treatment of cancer by administering an effective amount of a
compound of the present invention.
[0134] It has been reported in the art that STIM1 and Orai1 are
essential in in vitro tumor cell migration and in vivo tumor
metastasis. Thus the involvement of store operated Ca.sup.2+ entry
in tumor metastasis renders STIM1 and Orai1 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.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] STIM1 is located on the endoplasmic reticulum (ER) and
functions as a calcium sensor. Orai1 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 Orai1 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.
[0139] "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.
[0140] In yet another embodiment, the invention is directed to the
treatment of "thrombocytopathies" by administering an effective
amount of a compound of the present invention.
[0141] 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.
[0142] Under normal circumstances, when the endothelial cells
lining blood vessels are breached, platelets interact with von
Willebrand factor (vWF) via the membrane glycoprotein Ib complex to
help seal the breach. Glycoprotein IIb/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).
[0143] 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. STIM1 is the the Ca(2+) sensor
in the endoplasmic reticulum (ER) membrane, whereas Orai1 is the
major store operated Ca(2+) (SOC) channel in the plasma membrane,
which play a key role in platelet SOCE.
[0144] "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
[0145] 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 4
wherein ring A, ring E, ring D, ring W, L, R.sub.1, R.sub.2,
R.sub.3, `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 acids, bases, 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.
[0146] 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, RT (RT) refers to a
temperature in the range of 22 to 27.degree. C.
[0147] .sup.1H-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.
##STR00019##
[0148] 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.
[0149] 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.
[0150] The said reaction can be mediated by a suitable catalyst
known in the art such as Pd(PPh.sub.3).sub.2Cl.sub.2,
Pd.sub.2dba.sub.3, Pd(PPh.sub.3).sub.4, Pd(OAc).sub.2 or mixture(s)
thereof; a suitable ligand known in the art such as
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), xanthophos,
triphenylphosphine or mixture(s) thereof; in the presence of
suitable solvent using suitable base, preferably inorganic bases
such as alkalimetal carbonates like sodium carbonate, cesium
carbonate and phosphates like potassium phosphate or mixture(s)
thereof.
##STR00020##
[0151] 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) is prepared from the corresponding
halo derivatives via a metal catalysed boration reaction or known
methods in the art. The coupling reaction of haloderivatives 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). The
compounds of the Formula (6) can be converted to compounds of
Formula (I) by following the procedure known in the art.
##STR00021##
[0152] Another alternative approach is shown in Scheme 3 to prepare
compound of Formula (I) by reacting a borate compound of the
Formula (1) with halo compound of the Formula (7) followed by amide
coupling reaction. Alternatively, the compounds of the present
invention is prepared by reaction of halo derivatives of the
Formula (3) with stannane derivatives of the Formula (8) followed
by amide coupling reaction as depicted in Scheme 3. These coupling
reaction are carried out as per the methods known in the art or as
described in the Scheme 1. This compounds of the Formula (9) are
transformed to compound of Formula (I) using the techniques known
in the art.
[0153] For example, this amide coupling reaction of compounds of
the Formula (9) and Formula (9a) 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). 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: [0154]
(a) condensation of Y' and Y'' groups in the presence of a suitable
activating reagent used in peptide linkage syntheses, e.g.,
hydroxybenzotriazole and a coupling reagent like carbodiimides such
as EDC, DCC or mixture(s) thereof; or [0155] (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 [0156] (c) 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;
[0157] Such reactions are carried out in one or more suitable
solvents using suitable base for example triethylamine,
N-ethyldiisopropylamine; 4-dialkylaminopyridines like
4-dimethylaminopyridine, pyridine or mixture(s) thereof.
##STR00022##
[0158] Another alternative approach is shown in Scheme 4 to prepare
the compound of Formula (I) by reaction of borate/stannane
derivatives of the Formula (4) with the various halide derivatives
of the Formula (10) followed by successive heterocyclic ring
formation and coupling of the halo derivative (12) with either
boronic acid or alkyl zinc.
[0159] The coupling reaction of the halide derivatives of the
Formula (10) with borate/stannane derivatives of the Formula (4)
are carried out as per the methods known in the art or as described
in the Scheme 1 to afford compounds of the Formula (11). The
compounds of the Formula (11) can be converted to compounds of
Formula (12) by following the procedure known in the art. The
coupling reaction of halo derivatives of Formula (12) with the
corresponding boronic acids/alkyl zinc are carried out to afford
the compounds of the Formula (I) as per the methods known in the
art or as described in the Scheme 1.
Experimental
[0160] The invention is further illustrated by the following
examples which are provided merely to be exemplary of the invention
and do not limit the scope of the invention. The examples set forth
below demonstrate the synthetic procedures for the preparation of
the representative compounds. Certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the invention. The aforementioned
patents and patent applications are incorporated herein by
reference.
[0161] Unless otherwise stated, work-up implies the following
operations: distribution of the reaction mixture between the
organic and aqueous phase, separation of layers, drying the organic
layer over sodium sulfate, filtration and evaporation of the
organic solvent. Purification, unless otherwise mentioned, implies
purification by silica gel chromatographic techniques, generally
using ethyl acetate/petroleum ether mixture of a suitable polarity
as the mobile phase.
Intermediates
Intermediate 1a & 1b& 1c
5-(5-Bromo-6-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
(1a)
and
5-(5-(5-Aminopyrazin-2-yl)-6-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2-
(3H)-one (1b)
and
5-(6-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3--
methyl-1,3,4-oxadiazol-2(3H)-one (1c)
##STR00023##
[0162] Step-1: Ethyl 5-bromo-6-ethylnicotinate
[0163] Method-1: To a 0.degree. C. cooled solution of
ethyl-5,6-dibromonicotinate (1.0 g, 3.24 mmol, 1.0 eq., prepared by
following the procedure described in WO2011024004) in THF (10 mL)
was added [1,3-bis(diphenylphosphino)propane]dichloronickel (II)
(351 mg, 0.65 mmol, 0.2 eq) and the solution was stirred for 5 min.
Ethyl magnesium bromide (1M in THF, 3.88 mL, 3.88 mmol, 1.2 eq) was
then added drop-wise to the above mixture at 0.degree. C. The
resulting mixture was continued to stir at the same temperature for
3 h. Water (10 mL) was then added to the above mixture, followed by
ethyl acetate (20 mL). The layers were separated and the aqueous
layer was extracted with ethyl acetate (2.times.10 mL) and the
combined organic layers were washed with brine (20 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was evaporated and
the crude residue was purified by flash column chromatography
(silica gel, diethyl ether-hexane system as eluent) to afford 500
mg (60%) of the desired product as a white solid. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 9.06 (d, J=1.5 Hz, 1H), 8.40 (d, J=1.5 Hz,
1H), 4.42 (q, J=7.0 Hz, 2H), 3.05 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0
Hz, 3H), 1.28 (t, J=7.0 Hz, 3H); GC-MS (m/z) 257, 259 [M.sup.+,
Br.sup.79,81]
[0164] Method-2: A solution of ethyl-5,6-dibromonicotinate (6.0 g,
19.4 mmol, 1.0 eq; prepared by following the procedure described in
WO2011024004), ethylboronic acid (1.72 g, 23.3 mmol, 1.2 eq) and
potassium carbonate (8.0 g, 58.3 mmol, 3.0 eq) in 1,4-dioxane (10
mL) in a oven dried sealed tube was subjected to three cycles of
evacuation-backfilling with argon, and then
tetrakis(triphenylphosphine)palladium(0) (2.24 g, 1.94 mmol, 0.1
eq) was added. The sealed tube was sealed and the mixture was
stirred and heated in an oil bath to 110.degree. C. After three
days of stirring at the same temperature, the reaction was cooled
to RT and filtered through Celite.RTM.. The filtrate was evaporated
and the resultant residue was purified by flash column
chromatography (silica gel, ethyl acetate-hexane system as eluent)
to afford 1.90 g (38%) of the desired product as a white solid.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.06 (d, J=1.5 Hz, 1H),
8.40 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.05 (q, J=7.0 Hz,
2H), 1.43 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H); GC-MS (m/z)
257, 259 [M.sup.+, Br.sup.79 81].
Step-2: 5-Bromo-6-ethylnicotinohydrazide
[0165] A mixture of ethyl 5-bromo-6-ethylnicotinate (4.1 g, 15.8
mmol, 1.0 eq) and hydrazine hydrate (3.73 mL, 74.7 mmol, 4.7 eq) in
ethanol (30 mL) was heated to 80.degree. C. and further maintained
overnight. The reaction mixture was cooled to RT and the solvent
was removed on rotavapor. The residue was taken in ethyl acetate
(400 mL) and washed with water (2.times.100 mL), brine (100 mL),
dried (Na.sub.2SO.sub.4) and filtered. The filtrate was evaporated
under reduced pressure to afford 2.80 g (72%) of the desired
product as a white solid. .sup.1HNMR (400 MHz, DMSO) .delta. 9.99
(s, 1H, D.sub.2O exchangeable), 8.88 (d, J=1.5 Hz, 1H), 8.33 (d,
J=1.5 Hz, 1H), 4.62 (s, 2H, D.sub.2O exchangeable), 2.91 (q, J=7.0
Hz, 2H), 1.22 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 244, 246[(MH).sup.+,
Br.sup.79,81].
Step-3:
5-(5-Bromo-6-ethylpyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one
[0166] To a stirred and cooled (0.degree. C.) solution of
5-bromo-6-ethylnicotinohydrazide (2.50 g, 10.24 mmol, 1.0 eq) and
diisopropylethylamine (3.58 mL, 20.48 mmol, 2.0 eq) in DCM (20 mL)
was added a solution of triphosgene (1.21 g, 4.10 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
then diluted with DCM (50 mL) and washed with water (50 mL),
aqueous sodium bicarbonate (10%, 50 mL), brine (50 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was evaporated under
vacuum to afford 1.60 g (58%) of the desired product as a white
solid. .sup.1HNMR (400 MHz, DMSO) .delta. 8.83 (d, J=1.5 Hz, 1H),
8.25 (d, J=1.5 Hz, 1H), 2.92 (q, J=7.0 Hz, 2H), 1.21 (t, J=7.0 Hz,
3H); ESI-MS (m/z) 270, 272 [(MH).sup.+ Br.sup.79,81].
Step-4: Intermediate-1 a:
5-(5-Bromo-6-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0167] A mixture of
5-(5-Bromo-6-ethylpyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one (1.20 g,
4.44 mmol, 1.0 eq), methyl iodide (0.55 mL, 8.89 mmol, 2.0 eq) and
potassium carbonate (1.23 g, 8.89 mmol, 2.0 eq) in DMF (10 mL) was
stirred at RT for 4 h. Water (50 mL) was added to the reaction
mixture and the solid separated out was filtered. The residue was
washed with water (50 mL) and dried under vacuum to afford 800 mg
(63%) the Intermediate-1a as a white solid. .sup.1HNMR (400 MHz,
DMSO) .delta. 8.85 (d, J=1.5 Hz, 1H), 8.27 (d, J=1.5 Hz, 1H), 3.42
(s, 3H), 2.94 (q, J=7.0 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H); ESI-MS
(m/z) 284, 286 [(MH).sup.+, Br.sup.79,81].
Step-5: Intermediate-1b:
5-(5-(5-Aminopyrazin-2-yl)-6-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol--
2(3H)-one
[0168] To a solution of Intermediate-1a (1.0 g, 3.52 mmol, 1.0 eq)
and 5-(trimethyl stannyl)-pyrazine-2-amine (1.36 g, 5.28 mmol, 2.0
eq; prepared from 2-Amino-5-bromopyrazine by following the
procedure described in Chem. Eur. J. 2000, 6, 4132) in dioxane (10
mL) was added Pd(PPh.sub.3).sub.4 (200 mg, 0.17 mmol, 0.05 eq). The
resulting mixture was thoroughly deoxygenated by subjecting to
vacuum/nitrogen cycle three times and the reaction mixture was
stirred at 75.degree. C. for 15 h under nitrogen atmosphere. The
resulting mixture was cooled to RT and filtered through celite. The
filtrate was concentrated under vacuum and the crude product was
purified by flash column chromatography (silica gel, ethyl
acetate-hexanes system as eluent) to afford 510 mg (48%) the
Intermediate-1b as a white solid. ESI-MS (m/z) 299 (MH).sup.+.
Step-6: Intermediate-1c:
5-(6-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-
-methyl-1,3,4-oxadiazol-2(3H)-one
[0169] To a nitrogen purged solution of Intermediate-1a (6.50 g,
22.8 mmol, 1.0 eq) in dioxane (35 mL), bis(pinacolatodiboron) (7.55
g, 29.7 mmol, 1.1 eq), potassium acetate (3.37 g, 34.3 mmol, 1.5
eq), palladium acetate (514 mg, 2.28 mmol, 0.1 eq) and
1,1'-bis(diphenylphosphino)ferrocene (1.27 g, 2.28 mmol, 0.1 eq)
were sequentially added. The resulting mixture was stirred at
100.degree. C. for 12 h in sealed tube. The reaction was then
cooled to RT and filtered through celite. The filtrate was
concentrated under vacuum and the crude product was purified by
flash column chromatography (silica gel, ethyl acetate-hexanes
system as eluent) to afford 6.0 g (80%) of the Intermediate-1c as a
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.00 (d,
J=2.5 Hz, 1H), 8.45 (d, J=2.5 Hz, 1H), 3.52 (s, 3H), 3.14 (q, J=7.0
Hz, 2H), 1.37 (s, 12H), 1.28 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 332
(MH).sup.+.
[0170] The below intermediates in Table-1 were prepared by
following the similar procedure as described in Intermediate-1a or
Intermediate-1b or Intermediate-1c by using corresponding starting
materials.
TABLE-US-00001 TABLE 1 Intermediate No: IUPAC name Structure
.sup.1HNMR/ESI-MS Intermediate-2a: 5-(5- Bromo-6-methylpyridin-3-
yl)-3-methyl-1,3,4- oxadiazol-2(3H)-one ##STR00024## .sup.1HNMR
(400 MHz, DMSO) .delta. 8.82 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 1.5
Hz, 1H), 3.42 (s, 3H), 2.65 (s, 3H); ESI- MS (m/z) 270, 272
[(MH).sup.+ Br.sup.79,81]. Intermediate-2b: 5-(5-(5-
Aminopyrazin-2-yl)-6- methylpyridin-3-yl)-3-
methyl-1,3,4-oxadiazol- 2(3H)-one ##STR00025## .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.97 (d, J = 1.5 Hz, 1H), 8.20 (d, J = 1.0 Hz,
1H), 8.14 (d, J = 1.5 Hz, 1H), 8.12 (d, J = 1.0 Hz, 1H), 4.81 (s,
2H, D.sub.2O exchangeable), 3.53 (s, 3H), 2.71 (s, 3H); ESI-MS
(m/z) 285 (MH).sup.+ Intermediate-3a: 5-(5- Bromo-6-
cyclopropylpyridin-3-yl)- 3-methyl-1,3,4-oxadiazol- 2(3H)-one
##STR00026## .sup.1HNMR (400 MHz, DMSO) .delta. 8.75 (d, J = 2.0
Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 3.34 (s, 3H), 2.55-2.50 (m, 1H),
1.14-1.10 (m, 2H), 1.06-1.03 (m, 2H); ESI-MS (m/z) 296, 298
[(MH).sup.+ Br.sup.79,81] Intermediate-3b: 5-(5-(5-
Aminopyrazin-2-yl)-6- cyclopropylpyridin-3-yl)-
3-methyl-1,3,4-oxadiazol- 2(3H)-one ##STR00027## .sup.1HNMR (400
MHz, DMSO) .delta. 8.76 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 1.5 Hz,
1H), 8.02 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 6.73 (s,
D.sub.2O exchangeable, 2H), 3.40 (s, 3H), 2.41- 2.34 (m, 1H),
1.10-1.07 (m, 2H), 1.04- 0.97 (m, 2H); ESI-MS (m/z) 311 (MH).sup.+
Intermediate-3c: 5-(6- Cyclopropyl-5-(4,4,5,5- tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridin- 3-yl)-3-methyl-1,3,4-
oxadiazol-2(3H)-one ##STR00028## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.89 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 3.51
(s, 3H), 2.96-2.92 (m, 1H), 1.38 (s, 12H), 1.22-1.19 (m, 2H),
1.09-1.04 (m, 2H); ESI-MS (m/z) 344 (MH).sup.+
Intermediate-4:
5-(5-Bromo-6-methoxypyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00029##
[0171] Step-1: Methyl 5-bromo-6-methoxynicotinate
[0172] To a solution of ethyl-5,6-dibromonicotinate (5.0 g, 16.2
mmol, 1.0 eq) in methanol (5 mL) was added sodium methoxide (2.18
g, 40.5 mmol, 2.5 eq) and the resulting mixture was heated in a
sealed tube at 85.degree. C. for 48 h. The reaction was cooled back
down to RT and the solvent was evaporated under vacuum. The crude
residue was taken into water (20 mL) and ethyl acetate (50 mL). The
layers were separated and the aqueous layer was extracted with
ethyl acetate (2.times.50 mL). The combined organic layers were
washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and filtered.
The filtrate was evaporated and the resultant crude product was
purified by flash column chromatography (silica gel, ethyl
acetate:hexane system as eluent) to afford 1.55 g (39%) of the
desired product as a white solid. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.76 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 4.09 (s,
3H), 3.93 (s, 3H); ESI-MS (m/z) 246, 248 [(MH).sup.+,
Br.sup.79,81].
Step-2:
5-(5-Bromo-6-methoxypyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-o-
ne
[0173] The title compound was prepared from Step-1 Intermediate by
following the similar procedure sequentially as described in
Step-2, Step-3 and Step-4 of Intermediate-1a. ESI-MS (m/z) 286, 288
[(MH).sup.+, Br.sup.79,81].
Intermediate-5a:
5-(5-Bromo-6-(trifluoromethyl)pyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H-
)one
and
Intermediate-5b:
3-Methyl-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluorom-
ethyl)pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one
##STR00030##
[0174] Step-1: Ethyl-5-bromo-6-(trifluoromethyl)nicotinate
[0175] A solution of ethyl 5,6-dibromonicotinate (prepared by
following the procedure described in WO2011024004, 12 g, 38.8 mmol)
was reacted with methyl 2,2-difluoro-2-(fluorosulfonyl) acetate
(14.9 g, 78 mmol), copper iodide (9.62 g, 50.5 mmol) and HMPA (33.8
mL, 194 mmol), by following the similar procedure as described in
WO2009141398 to afford 11 g (95%) the desired product as a white
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.17 (d, J=1.5 Hz,
1H), 8.65 (d, J=1.5 Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0
Hz, 3H); ESI-MS (m/z) 298, 300[(MH).sup.+, Br.sup.79,81].
Intermediate-5a
[0176] The title compound was prepared from
ethyl-5-bromo-6-(trifluoromethyl)nicotinate by following the
similar procedure sequentially as described in step-1, step-2 and
step-3 of Intermediate-1a. .sup.1HNMR (400 MHz, DMSO) .delta. 9.08
(d, J=1.5 Hz, 1H), 8.66 (d, J=1.5 Hz, 1H), 3.45 (s, 1H); ESI-MS
(m/z) 325, 327 [(MH).sup.+, Br.sup.79, 81].
Intermediate-5b
[0177] To a nitrogen purged solution of Intermediate-5a (4.0 g,
12.3 mmol 1.0 eq) in dioxane (35 mL), bis(pinacolatodiboron) (3.76
g, 14.81 mmol, 1.1 eq), potassium acetate (2.42 g, 24.6 mmol, 2.0
eq), and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (0.504 g, 0.617
mmol) were sequentially added. The resulting mixture was heated to
100.degree. C. and further maintained for 12 h. The reaction
mixture was cooled to RT and filtered through celite. The filtrate
was concentrated under vacuum and the crude product was purified by
flash column chromatography (silica gel, ethyl acetate-hexanes
system as eluent) to afford 2.50 g (55%) of the desired compound as
a white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.15 (d,
J=1.5 Hz, 1H), 8.44 (d, J=1.5 Hz, 1H), 3.57 (s, 3H), 1.40 (s, 12H);
ESI-MS (m/z) 372 (MH).sup.+.
Intermediate-6a:
tert-Butyl-(3-bromo-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)py-
ridin-2-yl)(methyl)carbamate
And
Intermediate-6b:
5-(5-Bromo-6-(methylamino)pyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-on-
e
And
Intermediate-6c: tert-Butyl
(3-(5-aminopyrazin-2-yl)-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2--
yl)pyridin-2-yl)(methyl)carbamate
##STR00031##
[0178] Step-1: Ethyl-5-bromo-6-(methylamino)-nicotinate
[0179] A solution of ethyl 5,6-dibromonicotinate (prepared by
following the procedure described in WO2011024004, 5.0 g, 17.80
mmol) was reacted with methanamine (5 mL, 64.5 mmol 40% in water)
in THF (20 ml) by following the procedure described in WO201000475.
.sup.1HNMR (400 MHz, DMSO) .delta. 8.58 (d, J=2.0 Hz, 1H), 8.05 (d,
J=2.0 Hz, 1H), 7.21 (q, J=4.5 Hz, D.sub.2O exchangeable, 1H), 4.24
(q, J=7.0 Hz, 2H), 2.91 (d, J=4.5 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H);
GC-MS (m/z) 258, 260[(M).sup.+ Br.sup.79,81].
Step-2:
Ethyl-5-bromo-6-((tert-butoxycarbonyl)(methyl)amino)nicotinate
[0180] To a solution of ethyl 5-bromo-6-(methylamino)nicotinate
(4.50 g, 17.37 mmol) and triethylamine (9.68 mL, 69.5 mmol) in
acetonitrile (50 mL) was added Boc.sub.2O (16.1 ml, 69.5 mmol)
followed by DMAP (5 mg, 0.347 mmol). The resulting mixture was
heated to 85.degree. C. and maintained for 48 h. Reaction mixture
was then cooled to RT and the solvent was evaporated under vacuum.
The residue was taken in ethyl acetate (200 mL) and washed with
water (2.times.50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated under vacuum to afford 4.0
g (64%) of title compound as oily mass. HNMR (400 MHz, CDCl.sub.3)
.delta. 9.01 (d, J=2.0 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 4.43 (q,
J=7.0 Hz, 2H), 3.27 (s, 1H), 1.43 (t, J=7.0 Hz, 3H), 1.43 (s, 9H);
ESI-MS (m/z) 303, 305 [(M-55).sup.+, Br.sup.79,81].
Intermediate-6a
[0181] The title compound was prepared from Step-2 intermediate by
following the similar procedure sequentially as described in
step-2, step-3 and step-4 of Intermediate-1a. .sup.1HNMR (400 MHz,
DMSO) .delta. 8.85 (d, J=2.0 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 3.41
(s, 3H), 3.14 (s, 3H), 1.36 (s, 9H); ESI-MS (m/z) 329, 331
[(M-55).sup.+, Br.sup.79' 81].
Intermediate-6b
[0182] To a 0.degree. C. cooled solution of Intermediate-6a (1.0 g,
2.60 mmol) in DCM (10 mL) was added trifluoroacetic acid (1.0 mL,
12.98 mmol) and then stirred at RT for 16 h. The excess of
trifluoroacetic acid was evaporated under vacuum and the resulting
residue was triturated with hexane and diethyl ether to afford 500
mg (68%) of desired compound as a white solid. .sup.1HNMR (400 MHz,
DMSO) .delta. 8.41 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.16
(s, 1H), 3.35 (s, 3H), 2.90 (s, 3H); ESI-MS (m/z) 285, 287
[(MH).sup.+ Br.sup.79,81].
Intermediate-6c
[0183] To a nitrogen purged solution of Intermediate-6a (1.0 g,
2.60 mmol, 1.0 eq) in dioxane (10 mL) in a sealed tube 5-(trimethyl
stannyl)-pyrazine-2-amine (1.34 g, 5.19 mmol, 2.0 eq; prepared from
2-amino-5-bromopyrazine by following the procedure described in
Chem. Eur. J. 2000, 6, 4132) and Pd(PPh.sub.3).sub.4 (210 mg, 0.18
mmol, 0.05 eq) were sequentially added. The resulting mixture was
thoroughly deoxygenated by purging nitrogen gas for 15 min and the
reaction mixture was heated to 120.degree. C. and maintained for 48
h. The resulting mixture was then cooled to RT and filtered through
celite. The filtrate was concentrated under vacuum and the crude
product was purified by flash column chromatography (silica gel,
ethyl acetate-hexanes system as eluent) to afford 510 mg (50%) the
title compound as a white solid. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.88 (d, J=2.0 Hz, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.27 (d,
J=2.0 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 5.31 (s, 2H), 3.54 (s, 3H),
3.40 (s, 3H), 1.51 (s, 9H); ESI-MS (m/z) 400 (MH).sup.+
Intermediate-7:
5-(5-(4-Aminophenyl)-6-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)o-
ne
##STR00032##
[0184] Step-1: tert-Butyl
(4-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-3--
yl)phenyl)carbamate
[0185] To a solution of Intermediate-1a (2.30 g, 8.10 mmol, 1.0 eq)
and tert-butyl
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate
(2.58 g, 8.10 mmol, 1.0 eq; prepared from 4-bromoaniline by
following the procedure described in organic and biomolecular
chemistry, 2010, 8(15), 3457) in dioxane (25 mL) was added
Pd(PPh.sub.3).sub.2Cl.sub.2 (284 mg, 0.40 mmol). The resulting
mixture was thoroughly deoxygenated by subjecting to
vacuum/nitrogen cycle three times and the reaction mixture was
heated to 75.degree. C. and further maintained for 15 h under
nitrogen atmosphere. The resulting mixture was cooled to RT and
filtered through celite. The filtrate was concentrated under vacuum
and the crude product was purified by flash column chromatography
(silica gel, ethyl acetate-hexanes system as eluent) to afford 2.80
g (78%) of the desired compound as a white solid. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.96 (s, 1H), 7.89 (s, 1H), 7.48 (d, J=8.0
Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 6.75 (s, 1H), 3.51 (s, 3H), 2.84
(q, J=7.0 Hz, 2H), 1.58 (s, 9H), 1.23 (t, J=7.0 Hz, 3H); ESI-MS
(m/z) 397 (MH).sup.+
Step-2:
5-(5-(4-Aminophenyl)-6-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-
-2(3H)-one
[0186] To a 0.degree. C. cooled solution of above Step-1
intermediate (2.50 g, 6.31 mmol) in DCM (15 mL) was added
trifluoroacetic acid (15 mL) in drop wise manner and the resulting
mixture was stirred at RT for 2 h. The solvent was evaporated under
vacuum. Water (50 mL) was added to the above obtained residue and
basified with saturated aqueous sodium bicarbonate solution. The
resulting mixture was extracted with ethyl acetate (3.times.50 mL)
and the combined organic layers were washed with brine (50 mL),
dried (Na.sub.2SO.sub.4) and filtered. The filtrated was evaporated
under vacuum to afford 1.35 g (70%) of the desired product as a
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.95 (d, J=2.5 Hz,
1H), 7.90 (d, J=2.5 Hz, 1H), 7.13 (d, J=8.45 Hz, 2H), 6.77 (d,
J=8.5 Hz, 2H), 3.81 (s, 2H), 3.52 (s, 3H), 2.88 (q, J=7.5 Hz, 2H),
1.24 (t, J=7.5 Hz, 3H); ESI-MS (m/z) 297 (MH).sup.+.
Intermediate-8:
5-(5-Bromo-4-methylpyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00033##
[0188] The title compound was prepared by following the similar
procedure sequentially as described in step-2, step-3, and step-4
of Intermediate-1 using ethyl 5-bromo-4-methylpicolinate (prepared
by following the similar procedure as described in US2011212998).
.sup.1HNMR (400 MHz, DMSO) .delta. 8.79 (s, 1H), 7.93 (s, 1H), 3.34
(s, 3H), 2.45 (s, 3H); ESI-MS (m/z) 270, 272 [(MH).sup.+,
Br.sup.79,81].
Intermediate-9:
5-(6-Chloro-4-ethoxypyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00034##
[0189] Step-1: Ethyl 4-ethoxypicolinate
[0190] A solution of 4-chloropicolinic acid (1.0 g, 6.35 mmol) and
sulphuric acid (0.2 mL, 3.75 mmol) in ethanol (10 mL) was heated to
85.degree. C. and maintained for 16 h. Reaction mixture was cooled
to RT and the solvent was evaporated under vacuum. The residue was
taken into ethyl acetate (20 mL) and basified with aqueous
saturated sodium bicarbonate (pH 10, 20 mL). The layers were
separated and the organic layer was washed with brine (15 mL),
dried (Na.sub.2SO.sub.4) and filtered. The filtrate was
concentrated under vacuum to afford 1.0 g (69%) the title compound
as brown oily mass. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.54
(d, J=5.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 6.94 (dd, J=5.5&2.5
Hz, 1H), 4.47 (q, J=7.0 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 1.47-1.42
(m, 6H); GC-MS (m/z) 185 (M).sup.+.
Step-2: 4-Ethoxypicolinohydrazide
[0191] To a 0.degree. C. cooled solution of ethyl
4-ethoxypicolinate (5.0 g, 25.6 mmol) in ethanol (20 mL) was added
hydrazine hydrate (6.0 g, 120 mmol) drop-wise. After stirring for 2
h at RT, the separated out solid was filtered. The solid residue
was washed with water (50 mL) and dried to yield 5.80 g (99%) of
the title compound as white solid. .sup.1HNMR (400 MHz, DMSO)
.delta. 9.82 (brs, 1H, D.sub.2O exchangeable), 8.40 (d, J=5.5 Hz,
1H), 7.46 (d, J=2.5 Hz, 1H), 7.09 (dd, J=5.5 &2.5 Hz, 1H), 4.54
(brs, 2H, D.sub.2O exchangeable), 4.11 (q, J=7.0 Hz, 2H), 1.38 (t,
J=7.0 Hz, 3H); GC-MS (m/z) 181 (M).sup.+.
Step-3:
5-(4-Ethoxypyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0192] The title compound was prepared from
4-ethoxypicolinohydrazide by following the similar procedure
sequentially as described in step-3 and step-4 of Intermediate-1.
.sup.1HNMR (400 MHz, DMSO) .delta. 8.49 (d, J=5.5 Hz, 1H), 7.33 (d,
J=2.5 Hz, 1H), 7.13 (dd, J=5.5 & 2.5 Hz, 1H), 4.19 (q, J=7.0
Hz, 2H), 3.42 (s, 3H), 1.35 (t, J=7.0 Hz, 3H); GC-MS (m/z) 221
(M).sup.+.
Step-4:
4-Ethoxy-2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridi-
ne-oxide
[0193] A solution of
5-(4-ethoxypyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (200
mg, 0.90 mmol) and mCPBA (156 mg, 0.90 mmol) in DCM (5 mL) was
stirred at RT for 48 h. Ice water (10 mL) was added to the above
reaction mixture, basified with aqueous saturated sodium
bicarbonate solution (5 mL) and extracted with ethylacetate
(3.times.10 mL). The combined organic layers were washed with brine
(10 mL), dried (Na.sub.2SO.sub.4) and filtered. The filtrate was
concentrated under vacuum to afford 160 mg (75%) of title compound
as a white solid. HNMR (400 MHz, DMSO) .delta. 8.29 (d, J=5.5 Hz,
1H), 7.32 (d, J=2.5 Hz, 1H), 7.13 (dd, J=5.5& 2.5 Hz, 1H), 4.16
(q, J=7.0 Hz, 2H), 3.42 (s, 3H), 1.32 (t, J=7.0 Hz, 3H); GC-MS
(m/z) 237 (M).sup.+.
Step-5:
5-(6-Chloro-4-ethoxypyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-o-
ne
[0194] A mixture of
4-ethoxy-2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine-1-ox-
ide (1.0 g, 4.22 mmol) and phosphorous oxychloride (8 mL) was
heated to 80.degree. C. and maintained for 4 h. The excess of
phosphorous oxychloride was distilled under vacuum.
[0195] The resulting residue was taken in ice water, basified with
aqueous saturated sodium bicarbonate solution (10 mL) and extracted
with ethylacetate (3.times.20 mL). The combined organic layers were
dried (Na.sub.2SO.sub.4) and filtered. The filtrate was
concentrated under vacuum to afford 200 mg (19%) of the
Intermediate 9 as a white solid. .sup.1HNMR (400 MHz, DMSO) .delta.
7.33 (d, J=2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 4.24 (q, J=7.0 Hz,
2H), 3.43 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); GC-MS (m/z) 255, 257
[(M).sup.+, Cl.sup.35,37].
Intermediate-10a:
5-(4-Chloropyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
And
Intermediate-10b:
5-(4,6-Dichloropyridin-2-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00035##
[0196] Step-1: Ethyl-4-chloropicolinate
[0197] A mixture of 4-chloropicolinic acid (20 g, 127 mmol) and
thionyl chloride (200 mL) was heated to 100.degree. C. and
maintained for 6 h. The reaction was cooled to RT, and the excess
of thionyl chloride was removed under vacuum. To the above obtained
residue was then added ethanol (200 mL) at 0.degree. C. drop-wise
and the resulting mixture was stirred at RT for 20 h. The solvent
was evaporated under vacuum and the residue was taken in ethyl
acetate (1000 mL), washed with water (2.times.500 mL), saturated
sodium bicarbonate solution (2.times.500 mL), brine (500 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was evaporated to
yield 21.0 g (89%) the desired product as a semi solid. .sup.1HNMR
(400 MHz, DMSO) .delta. 8.66 (d, J=5.0 Hz, 1H), 8.13 (d, J=2.0 Hz,
1H), 7.49 (dd, J=5.0 &2.0 Hz 1H), 4.47 (q, J=7.0 Hz, 2H), 1.46
(t, J=7.0 Hz, 3H); GC-MS (m/z) 185, 187 [(M).sup.+,
Cl.sup.35,37].
Step-2: 4-Chloropicolinohydrazide
[0198] The title compound was prepared from
ethyl-4-chloroypicolinate by following the similar procedure as
described in step-2 of Intermediate-9. .sup.1HNMR (400 MHz, DMSO)
.delta. 10.05 (s, 1H, D.sub.2O exchangeable), 8.58 (d, J=5.0 Hz,
1H), 7.96 (d, J=2.0 Hz, 1H), 7.70 (dd, J=5.0 &2.0 Hz, 1H), 4.62
(s, 2H, D.sub.2O exchangeable); GC-MS (m/z) 171, 173 [(M).sup.+,
Cl.sup.35,37].
Intermediate-10a
[0199] The title compound was prepared from
4-ethoxypicolinohydrazide by following the similar procedure
sequentially as described in step-3 and step-4 of Intermediate-1.
.sup.1HNMR (400 MHz, DMSO) .delta. 8.69 (d, J=5.0 Hz, 1H), 7.94 (d,
J=2.0 Hz, 1H), 7.74 (dd, J=5.0 & 2.0 Hz, 1H), 3.44 (s, 3H);
GC-MS (m/z) 211, 213 [(M).sup.+, Cl.sup.35,37].
Intermediate-10b
4-Chloro-2-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine
1-oxide
[0200] To a 0.degree. C. cooled solution of Intermediate-10a (3.50
g, 16.5 mmol) in DCM (30 mL) was added urea hydrogen peroxide
(UHP)(3.11 g, 33.1 mmol) followed by drop-wise addition of
trifluoroacetic anhydride (4.67 ml, 33.1 mmol) and the resulting
mixture was stirred at RT for 16 h. The reaction mixture was
diluted with DCM (50 mL), basified with solid potassium carbonate
and the slurry was filtered. The filtrate was evaporated to yield
3.50 g (93%) of the desired product as a white solid. .sup.1HNMR
(400 MHz, DMSO) .delta. 8.42 (d, J=7.0 Hz, 1H), 7.94 (d, J=3.0 Hz,
1H), 7.74 (dd, J=7.0 & 3.0 Hz, 1H), 3.44 (s, 3H); GC-MS (m/z)
277, 279 [(M).sup.+, Cl.sup.35,37]. Further it was reacted with
POCl.sub.3 by following the similar procedure as described in
Step-5 of Intermediate-9. .sup.1HNMR (400 MHz, DMSO) .delta. 7.77
(d, J=1.5 Hz, 1H), 7.94 (d, J=1.5 Hz, 1H), 3.57 (s, 3H); GC-MS
(m/z) 246, 248 [(M).sup.+, Cl.sup.35,37].
Intermediate-11:
5-(5-Bromopyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00036##
[0201] Step-1:
5-(5-Bromopyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0202] The title compound was prepared by following the similar
procedure sequentially as described in step-2, step-3 and step-4 of
Intermediate-1a. .sup.1HNMR (400 MHz, DMSO) .delta. 8.94 (d, J=2.0
Hz, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.35 (dd, J=2.0 & 2.0 Hz, 1H),
3.43 (s, 3H); ESI-MS (m/z) 256, 258 [(MH).sup.+, Br.sup.79,81].
Intermediate-12:
5-(5-Bromo-4-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00037##
[0203] Step-1: Ethyl 5-bromo-4-ethylnicotinate
[0204] To a nitrogen purged and stirred solution of ethyl
5-bromo-4-iodonicotinate (2.50 g, 7.02 mmol, prepared by following
the procedure described in J. Am. Che. Soc., 2008, 130 (2),
472-480) in THF (10 mL) was added Pd(dba)2 (202 mg, 0.351 mmol).
The resulting mixture was cooled to 0.degree. C. and diethylzinc
(1M in THF, 10.54 mL, 10.54 mmol) was added drop-wise for 15 min.
The reaction was warmed to RT and stirred for 10 min. Reaction was
cooled to 0.degree. C. and quenched with 0.5 mL cold methanol. The
reaction mixture was diluted with ethyl acetate (20 mL) and
filtered through celite. The filtrate was evaporated and the crude
product was purified by flash column chromatography (silica gel,
EtOAc-hexane as eluent) to afford 0.95 g (52%) of the desired
product along with de-iodinated compound. HNMR (400 MHz,
CDCl.sub.3) .delta. 8.89 (s, 1H), 8.78 (s, 1H), 4.43 (q, J=7.0 Hz,
2H), 3.11 (q, J=7.5 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H), 1.25 (t, J=7.5
Hz, 3H); GC-MS (m/z) 257, 259 [(MH).sup.+, Br.sup.79,81].
Step-2:
5-(5-Bromo-4-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0205] The title compound was prepared from ethyl
5-bromo-4-ethylnicotinate by following the similar procedure
sequentially as described in step-2, step-3, and step-4 of
Intermediate-1a. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.87
(s, 1H), 8.78 (s, 1H), 3.44 (s, 3H), 3.06 (q, J=7.5 Hz, 2H), 1.18
(t, J=7.5 Hz, 3H); ESI-MS (m/z) 284, 286 [(MH).sup.+,
Br.sup.79,81].
Intermediate-13:
5-(2-Chloro-3-methylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00038##
[0206] Step-1:
5-(3-Chloropyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0207] The title compound was prepared from
ethyl-3-chloroisonicotinate (6.0 g, 32.3 mmol, prepared by
following the procedure described in WO2008024724) by following the
similar procedure sequentially as described in step-2, step-3 and
step-4 of Intermediate-1 (from). .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.76 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 7.69 (d, J=5.0 Hz,
1H), 3.58 (s, 3H); GC-MS (m/z) 111, 113 [M.sup.+,
Cl.sup.35,37].
Step-2:
3-Methyl-5-(3-methylpyridin-4-yl)-1,3,4-oxadiazol-2(3H)-one
[0208] To a stirred solution of step-1 intermediate (1.0 g, 4.73
mmol) in dioxane (30 mL), methylboronic acid (368 mg, 6.14 mmol),
potassium carbonate (1.96 g, 14.18 mmol) and Pd(PPh.sub.3).sub.4
(273 mg, 0.23 mmol) were sequentially added. The resulting mixture
was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle
three times and the reaction mixture was heated to 120.degree. C.
and maintained for 16 h under nitrogen atmosphere. The reaction
mixture was cooled to RT and filtered through celite. The filtrate
was concentrated under vacuum and the crude product was purified by
flash column chromatography (10% Ethyl acetate in hexanes) to
afford 0.86 g (95%) of the title compound as white solid. HNMR (400
MHz, CDCl.sub.3) .delta. 8.60 (m, 2H), 7.64 (d, J=5.0 Hz, 1H), 3.56
(s, 3H), 2.60 (s, 3H).
Step-3:
3-Methyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridi-
ne-1-oxide
[0209] To a stirred solution of step-2 intermediate (1.0 g, 5.23
mmol) in acetic acid (30 mL) was added hydrogen peroxide (0.321 mL,
10.46 mmol) drop-wise at RT and the reaction was heated to
80.degree. C. and maintained for 12 h. The resulting mixture was
cooled to RT and basified with solid potassium carbonate. The
resulting slurry was diluted with dichloromethane (50 mL) and
filtered. The filtrate was concentrated under vacuum to afford 800
mg (88%) of title compound as white solid. HNMR (400 MHz,
DMSO-d.sub.6) .delta. 8.34 (s, 1H), 8.19 (d, J=5.0 Hz, 1H), 7.67
(d, J=5.0 Hz, 1H), 3.43 (s, 3H), 2.45 (s, 3H).
Step-4:5-(2-Chloro-3-methylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-on-
e
[0210] A mixture of step-3 intermediate (0.800 g, 3.86 mmol) and
POCl.sub.3 (15 mL, 161 mmol) was heated at 100.degree. C. for 1 h.
Excess of POCl.sub.3 was distilled under reduced pressure and the
crude product was purified by flash column chromatography (silica
gel, 4% diethyl ether in hexanes) to afford 270 mg (25%) of the
desired compound as a white solid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 8.38 (d, J=5.0 Hz, 1H), 7.60 (d, J=5.0 Hz,
1H), 3.57 (s, 3H), 2.72 (s, 3H) ESI-MS (m/z) 226 (MH).sup.+
Intermediate-14a:
5-(2-Chloro-3-ethylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
And
Intermediate-14b:
5-(2-Chloro-5-ethylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00039##
[0211] Step-1: Ethyl-3-ethylisonicotinate
[0212] To a mixture of ethyl 3-chloroisonicotinate (6.0 g, 32.3
mmol, prepared by following the procedure described in
WO2008024724), and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (1.05
g, 1.29 mmol) in dioxane (40 mL) at RT was added drop-wise diethyl
zinc (1M in THF, 32.3 mL, 32.3 mmol). The resulting mixture was
thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle
three times and the reaction mixture was heated to 70.degree. C.
and maintained for 4 h under nitrogen atmosphere. The reaction
mixture was cooled to RT and then quenched with methanol (1 mL).
Water (10 mL) was added to the above mixture followed by ethyl
acetate (50 mL). The layers were separated and aqueous layer was
extracted with ethyl acetate (3.times.75 mL). The combined organic
layers were washed with 1N hydrochloric acid (50 mL), water (50
mL), brine (20 mL) dried (Na.sub.2SO.sub.4) and filtered. The
filtrate was concentrated under vacuum. The crude product was
purified by flash column chromatography to afford 2.30 g (40%) of
the title compound as colorless oil. HNMR (400 MHz, CDCl.sub.3)
.delta. 8.58 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 7.64 (d, J=5.0 Hz,
1H), 4.42 (q, J=7.5 Hz, 2H), 2.97 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.5
Hz, 3H) 1.26 (t, J=7.0 Hz, 3H); GC-MS (m/z) 179 (M).sup.+.
Step-2:
5-(3-Ethylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0213] The title compound was prepared from
ethyl-3-ethylisonicotinate by following the similar procedure
sequentially as described in step-2, step-3 and step-4 of
Intermediate-1a. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.63 (s,
1H), 8.59 (d, J=5.0 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 3.56 (s, 3H),
3.03 (q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H); GC-MS (m/z) 205
(M).sup.+
Step-3:
3-Ethyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-
e-1-oxide
[0214] To a stirred solution of step-2 intermediate (3.50 g, 17.1
mmol) in acetic acid (30 mL) was added hydrogen peroxide (0.62 mL,
20.4 mmol) drop-wise at RT and the resulting mixture was heated to
80.degree. C. and maintained for 12 h. The reaction was cooled to
RT and basified with solid potassium carbonate. The resulting
slurry was diluted with DCM (50 mL) and filtered. The filtrate was
concentrated under vacuum to afford 2.70 g (70%) of the title
compound as white solid. GC-MS (m/z) 221 (M).sup.+.
Step-4:
5-(2-Chloro-3-ethylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-on-
e and
5-(2-Chloro-5-ethylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0215] A mixture of
3-ethyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine-1-oxi-
de (330 mg, 1.50 mmol) and phosphorous oxychloride (2 mL, 21.4
mmol) was heated to 95.degree. C. and maintained for 8 h. Excess of
POCl.sub.3 was removed by distillation under reduced pressure and
the crude product was purified by flash column chromatography to
afford 80 mg (23%) of the Intermediate-14a as colorless oil along
with 80 mg (23%) of
5-(2-chloro-5-ethylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
(Intermediate-14b).
Intermediate-14a
[0216] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.57 (d, J=5.0 Hz,
1H), 7.64 (d, J=5.0 Hz, 1H), 3.57 (s, 3H), 2.17 (q, J=7.5 Hz, 2H),
1.25 (t, J=7.5 Hz, 3H); GC-MS 239, 141 [M.sup.+, Cl.sup.35,37]
Intermediate-14b
[0217] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.39 (s, 1H), 7.69
(s, 1H), 3.55 (s, 3H), 3.01 (q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz,
3H); GC-MS 239, 141 [M.sup.+, Cl.sup.35,37].
Intermediate-15:
5-(2-Chloro-6-methylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00040##
[0218] Step-1: t-Butyl-2-(2-chloro-6-methylisonicotinoyl)
hydrazinecarboxylate
[0219] To a stirred solution of 2-chloro-6-methylisonicotinic acid
(4.0 g, 23.3 mmol) in DMF (40 mL) was added successively tert-butyl
hydrazine carboxylate (3.0 g, 23.3 mmol), TBTU (6.0 g, 18.6 mmol)
and DIPEA (12.2 mL, 69.9 mmol). After stirring for 12 hat RT, water
(20 mL) was added to the reaction followed by ethyl acetate (50
mL). The layers were separated and the aqueous layer was extracted
with ethyl acetate (3.times.50 mL). The combined organic layers
were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated under vacuum to afford 3.0
g (45%) of the title compound as white solid. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.65 (s, D.sub.2O exchangeable, 1H), 7.48 (s,
1H), 7.42 (s, 1H), 6.77 (s, D.sub.2O exchangeable, 1H), 2.59 (s,
3H), 1.53 (s, 9H); GC-MS (m/z) 185 (M).sup.+
Step-2: 2-Chloro-6-methylisonicotinohydrazide
[0220] To a (0.degree. C.) cooled solution of step-1 intermediate
(3.0 g, 10.5 mmol) in DCM (15 mL) was added trifluoroacetic acid
(15 mL). After stirring for 2 hat RT, solvent was evaporated under
vacuum. Water (20 mL) was added to the resulting residue followed
by ethyl acetate (30 mL). The layers were separated and the aqueous
layer was extracted with ethyl acetate (2.times.50 mL). The
combined organic layers were washed with brine (20 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated
under vacuum and the crude product was purified by flash column
chromatography to afford 1.80 g (92%) of the title compound as
white solid.
Step-3:
5-(2-Chloro-6-methylpyridin-4-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-o-
ne
[0221] The title compound was prepared from
2-chloro-6-methylisonicotinohydrazide by following the similar
procedure sequentially as described in step-3 and step-4 of
Intermediate-1. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.65 (s,
1H), 7.58 (s, 1H), 3.43 (s, 3H), 2.55 (s, 3H); GC-MS (m/z) 225
(M).sup.+.
[0222] The below intermediates in Table-2 were prepared from
corresponding starting materials by following the similar procedure
as described in WO2012056478.
TABLE-US-00002 TABLE 2 Intermediate No: IUPAC name Structure
Intermediate-16: 2,6-Difluoro-N-(4-(4,4,5,5,-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) benzamide ##STR00041##
Intermediate-17: 2-Chloro-6-fluoro-N-(4-(4,4,5,5,-
tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzamide ##STR00042##
Intermediate-18: 2-Fluoro-6-methyl-N-(4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzamide ##STR00043##
Intermediate-19: 4-Methyl-N-(4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3-
thiadiazol-5-carboxamide ##STR00044## Intermediate-20:
N-(5-Bromopyridin-2-yl)-2,6- difluorobenzamide ##STR00045##
Intermediate-21: N-(6-Bromopyridin-3-yl)-2,6- difluorobenzamide
##STR00046## Intermediate-22: N-(5-Bromopyrazine-2-yl)-2,6-
difluorobenzamide ##STR00047## Intermediate-23:
N-(2,6-difluorophenyl)-5- (trimethylstannyl)thiophene-2-carboxamide
##STR00048## Intermediate-24: N-(2,6-difluorophenyl)-1-methyl-
5-(trimethylstannyl)-1H-pyrrole-2-carboxamide ##STR00049##
Intermediate-25:
N-(5-Chloropyrazine-2-yl)-2,6-difluorobenzamide
##STR00050##
[0224] To a 0.degree. C. cooled and stirred, solution of
2-chloro-6-fluorobenzoyl chloride (2.80 ml, 20.7 mmol) in DCM (50
mL) was added drop-wise a solution of 5-bromopyrazin-2-amine (5.41
g, 31.1 mmol) in DCM (5 mL) followed by pyridine (2.51 mL, 31.1
mmol). The resulting mixture was stirred at RT overnight. The
reaction was diluted with DCM (50 mL), and washed with water (20
mL), brine (20 mL), dried (Na.sub.2SO.sub.4) and filtered. The
filtrate was concentrated under vacuum and the crude product was
purified by flash column chromatography (silica gel, ethyl
acetate-hexanes system as eluent) to afford 3.50 g (51%) of the
intermediate 25 as a white solid. ESI-MS (m/z) 330.
Intermediate-26a:
N-(4-Bromo-3-methylphenyl)-2,6-difluorobenzamide
And
Intermediate-26b:
2,6-Difluoro-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)benzamide
##STR00051##
[0225] Step-1: N-(4-bromo-3-methylphenyl)-2,6-difluorobenzamide
[0226] The title compound was prepared by reacting
4-bromo-3-methylaniline (15 g, 81 mmol) with 2,6-difluorobenzoyl
chloride (6.76 mL, 53.7 mmol) in DCM (200 mL) by following the
similar procedure reported for Intermediate-25 to afford 12.0 g
(68%) the Intermediate-26a as a white solid. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 7.76 (s, 1H, D.sub.2O exchangeable), 7.57 (d,
J=2.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.43-7.39 (m, 1H), 7.31 (dd,
J=2.0& 8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 2H) 2.40 (s, 3H); ESI-MS
(m/z) 326, 328[(MH).sup.+ Br.sup.79,81].
Step-2:
2,6-Difluoro-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl)benzamide
[0227] To a stirred solution of step-1 intermediate (1.0 g, 3.07
mmol), bis(pinacolato)diboron (0.934 g 3.68 mmol) in dioxane (15
mL), potassium acetate (0.602 g, 6.13 mmol),
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (125 mg, 0.153 mmol) were
sequentially added. The resulting mixture was thoroughly
deoxygenated by subjecting to vacuum/nitrogen cycle three times and
the reaction mixture was heated at 120.degree. C. for 12 h under
nitrogen atmosphere. The reaction mixture was cooled to RT and
filtered through celite. The filtrate was concentrated under vacuum
and crude product was purified by column chromatography to afford
1.0 g (87%) of the intermediate 26bas a white solid. .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 7.78 (d, J=8.0 Hz, 1H), 7.64 (s, 1H),
7.46 (d, J=2.0 Hz, 1H), 7.42 (dd, J=8.0&2.0 Hz, 1H), 7.27 (m,
1H), 7.00 (t, J=8.0 Hz, 2H), 2.56 (s, 3H) 1.35 (s, 12H); ESI-MS
(m/z) 374 (MH).sup.+
Intermediate-27:
N-(2,6-Difluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zamide
##STR00052##
[0228] Step-1: 4-Bromo-N-(2,6-difluorophenyl)benzamide
[0229] To a 0.degree. C. cooled and stirred solution of
4-bromobenzoyl chloride (1.0 g, 4.56 mmol) in DCM (10 mL) was added
drop-wise a solution of 2,6-difluoroaniline (0.46 mL, 4.56 mmol) in
DCM (2 mL) followed by pyridine (0.48 mL, 5.47 mmol). The resulting
mixture was stirred at RT overnight. The reaction was diluted with
DCM (10 mL), washed with water (10 mL), brine (10 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated
under vacuum and the crude product was purified by flash column
chromatography (silica gel, ethyl acetate-hexanes system as eluent)
to afford 750 mg (53%) of the title product as a white solid.
.sup.1HNMR (400 MHz, DMSO) .delta. 10.25 (s, 1H), 7.93 (d, J=8.5
Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.45-7.38 (m, 1H), 7.23 (t, J=8.0
Hz, 2H), ESI-MS (m/z) 312, 314 [(MH).sup.+, Br.sup.79,81].
Step-2:
N-(2,6-Difluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
-yl)benzamide
[0230] To a stirred solution of step-1 intermediate (5.40 g, 17.3
mmol) in dioxane (50 mL),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.27
g, 20.7 mmol, potassium acetate (5.43 g, 55.4 mmol) and
[1,1'-bis(diphenyl phosphino)-ferrocene)dichloro palladium(II)
dichloro methane complex (0.706 g, 0.86 mmol) were sequentially
added. The resulting mixture was thoroughly deoxygenated by
subjecting to a vacuum/nitrogen cycle three times and then heated
at 100.degree. C. for 6 h under nitrogen atmosphere. The reaction
mixture was cooled to RT and filtered through celite. The filtrate
was concentrated under vacuum and the crude product was purified by
flash column chromatography (silica gel, ethyl acetate-hexanes
system as eluent) to afford 4.80 g (77%) the title compound as a
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.95-7.90 (m,
4H), 7.47 (s, 1H), 7.27-7.23 (m, 1H), 7.01 (t, J=8.0 Hz, 2H);
ESI-MS (m/z) 360 (MH).sup.+.
Intermediate-28: 5-Bromo-N-(2,6-difluorobenzyl)pyridin-2-amine
##STR00053##
[0232] To a solution of 5-bromopyridin-2-amine (3.04 g, 17.6 mmol),
in ethanol (10 mL), 2,6-difluorobenzaldehyde (1.92 mL, 17.59 mmol)
was added followed by the catalytic amount of acetic acid. The
resulting mixture was then refluxed for 16 h. Excess ethanol was
evaporated under vacuum. The residue was taken in dichloroethane
(20 mL) and sodium triacetoxyborohydride (14.91 g, 70.4 mmol), was
added and reaction was heated at 85.degree. C. for 16 h. The
reaction mixture was cooled to RT and diluted with DCM (50 mL)
followed by water (30 mL). The layers were separated and the
aqueous layer was extracted with DCM (3.times.50 mL). The combined
organic layers were washed with brine (50 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated
under vacuum to afford 1.50 g (29%) of the intermediate 28 as white
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.12 (d, J=2.5 Hz,
1H), 7.52 (dd, J=8.5&2.5 Hz, 1H), 7.29-7.22 (m, 1H), 6.91 (t,
J=8.0 Hz, 2H), 6.48 (d, J=8.5 Hz, 1H), 5.17 (s, D.sub.2O
exchangeable, 1H), 4.57 (s, 2H); ESI-MS 299, 301 [(MH).sup.+,
Br.sup.79,81].
Intermediate-29: 6-Bromo-N-(2,6-difluorobenzyl)pyridin-3-amine
##STR00054##
[0234] To a solution of 6-bromopyridin-3-amine (500 mg, 2.89 mmol),
in MeOH (3 mL), acetic acid (0.165 mL, 2.89 mmol),
2,6-difluorobenzaldehyde (0.31 mL, 2.89 mmol) was added. After
stirring the resulting mixture at RT for 12 h, sodium
cyanoborohydride (363 mg, 5.78 mmol) was added at 0.degree. C. and
resulting mixture was stirred at RT for 6 h. Solvent was evaporated
under vacuum. Residue was purified by column chromatography to
afford 200 mg (23%) of the title compound as white solid.
GC-MS-298, 300 [M.sup.+, Br.sup.79' 81]
Intermediate-30:
5-Bromo-N-(2-chloro-6-fluorophenyl)thiophene-2-carboxamide
##STR00055##
[0236] The title compound was prepared by following the analogous
procedure as described in WO2012056478. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 7.47 (d, J=4.0 Hz, 1H), 7.31 (bs, 1H),
7.30-7.22 (m, 2H), 7.15-7.11 (m, 2H); ESI-MS (m/z) 334
(MH).sup.+
Intermediate-31:
5-Bromo-N-(3-methylpyridin-4-yl)thiophene-2-carboxamide
##STR00056##
[0238] To a (0.degree. C.) cooled and stirred solution of
5-bromothiophene-2-carboxylic acid (1.91 g, 9.25 mmol) in DCM (20
mL) was added oxalyl chloride (4.05 mL, 46.2 mmol) followed by the
addition of catalytic amount of DMF. Reaction was allowed to stir
at 0.degree. C. for 2 h. The resulting reaction mixture was then
concentrated under vacuum, obtained residue was dissolved in DMF (2
mL) and added to a separately prepared (0.degree. C.) cooled
mixture containing 3-methylpyridin-4-amine (1.23 g, 11.37 mmol) and
sodium hydride (0.444 g, 18.49 mmol) in DMF (10 mL). After stirring
the reaction at RT overnight, quenched with ice cold water (20 mL),
followed by the addition of ethyl acetate (30 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate
(3.times.20 mL). The combined organic layers were washed with water
(2.times.50 mL), brine (20 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated under vacuum and the crude
product was purified by flash column chromatography (silica gel,
DCM-methanol system as eluent) to afford 1.10 g (40%) of the title
product as a white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
8.44 (d, J=5.5 Hz, 1H), 8.40 (s, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.70
(s, 1H), 7.40 (d, J=4.0 Hz, 1H), 7.13 (d, J=4.0 Hz, 1H), ESI-MS
(m/z) 297, 298 [(MH).sup.+ Br.sup.79, 81].
Intermediate-32:
5-bromo-N-(2,6-difluorophenyl)furan-2-carboxamide
##STR00057##
[0240] 5-Bromo-N-(2,6-difluorophenyl)furan-2-carboxamide: To a
solution of 5-bromofuran-2-carboxylic acid acid (2.0 g, 10.4 mmol)
in DMF (30 mL), 2,6-difluoroaniline (1.27 mL, 12.5 mmol), DIPEA
(3.66 mL, 20.9 mmol) and HATU (4.78 g, 12.5 mmol) were successively
added. The resulting mixture was stirred at RT for 3 h. The
reaction mixture was diluted with ethyl acetate (50 mL) followed by
water (30 mL). The layers were separated and the aqueous layer was
extracted with ethyl acetate (3.times.20 mL). The combined organic
layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated under vacuum. The crude
product was purified by flash column chromatography (silica gel,
20% ethyl acetate in hexane) to afford 400 mg (13%) of the title
compound as white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
7.57 (s, D.sub.2O exchangeable, 1H), 7.31-7.25 (m, 1H), 7.24 (d,
J=3.5 Hz, 1H), 7.01 (t, J=7.5 Hz, 2H), 6.54 (d, J=3.5 Hz, 1H);
ESI-MS (m/z) 302, 304 [(MH).sup.+ Br.sup.79,81].
Intermediate-33:
3-(5-Bromo-6-ethylpyridin-3-yl)-4,4-dimethylisoxazol-5 (4H)-one
##STR00058##
[0241] Step-1: Ethyl
3-(5-bromo-6-ethylpyridin-3-yl)-3-oxopropanoate
[0242] To a stirred solution of ethyl 5-bromo-6-ethylnicotinate
(1.1 g, 4.26 mmol) and ethyl acetate (1.25 mL, 12.79 mmol) in
anhydrous THF (10 mL) was added LiHMDS (1M in THF, 6.39 mL, 6.39
mmol) at -50.degree. C. over a period of 10 min. The reaction was
then stirred for 30 min at the same temperature and quenched with
acetic acid (2 mL). The reaction was basified with aqueous
saturated sodium bicarbonate solution (3 mL) followed by the
dilution with ethyl acetate (50 mL) and water (25 mL). The layers
were separated and the aqueous layer was extracted with ethyl
acetate (2.times.30 mL). The combined organic layers were washed
with brine (25 mL), dried (Na.sub.2SO.sub.4) and filtered. The
filtrate was rotary evaporated and the crude product was purified
by flash column chromatography (silica gel, ethyl acetate-hexanes
system as eluent) to afford 930 mg (72%) of the title compound as
white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 9.01 (d,
J=2.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 4.27 (s, 2H), 4.13 (q, J=7.0
Hz, 2H), 2.98 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H), 1.21 (t,
J=7.0 Hz, 3H); ESI-MS (m/z) 300, 302 [(MH).sup.+, Br.sup.79,81]
Step-2: Ethyl
3-(5-bromo-6-ethylpyridin-3-yl)-2,2-dimethyl-3-oxopropanoate
[0243] To a 0.degree. C. cooled and stirred suspension of sodium
hydride(60% dispersion inoil, 120 mg, 5 mmol), in DMF (3 mL) was
added ethyl 3-(5-bromo-6-ethylpyridin-3-yl)-3-oxopropanoate (0.5 g,
1.66 mmol) in DMF (7 mL) over a period of 15 min. The reaction
mixture was then stirred for 15 min at the same temperature and
Iodomethane (365 .mu.l, 5.83 mmol) was added to the above mixture.
The resulting mixture was then warmed to room temperature and
stirred for 3 h. The reaction mixture was diluted with water (30
mL) followed by ethyl acetate (50 mL). The layers were separated
and the aqueous layer was extracted with ethyl acetate (2.times.30
mL). The combined organic layers were washed with brine (20 mL),
dried (Na.sub.2SO.sub.4) and filtered. The filtrate was rotary
evaporated to afford 300 mg (54%) of the title compound as white
solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.77 (d, J=2.0
Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 2.96 (q,
J=7.0 Hz, 2H), 1.46 (s, 6H), 1.25 (t, J=7.0 Hz, 3H), 1.03 (t, J=7.0
Hz, 3H); ESI-MS (m/z) 328, 330 [(MH.sup.+, Br.sup.79,81].
Step-3:
3-(5-Bromo-6-ethylpyridin-3-yl)-4,4-dimethylisoxazol-5(4H)-one
[0244] To (0.degree. C.) cooled solution of ethyl
3-(5-bromo-6-ethylpyridin-3-yl)-2,2-dimethyl-3-oxopropanoate (320
mg, 0.97 mmol) in ethanol (7 mL) was added solution of
Hydroxylamine hydrochloride (81 mg, 1.17 mmol) in water (3 mL)
followed by a solution of KOH (120 mg, 2.14 mmol) in water (2 mL).
The resulting mixture was warmed to room temperature and stirred at
78.degree. C. for 1 h. The reaction was cooled back down to room
temperature and diluted with water (10 mL) followed by ethyl
acetate (50 mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (2.times.30 mL). The combined
organic layers were washed with brine (50 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was rotary evaporated
and the crude product was purified by flash column chromatography
to afford 130 mg (44%) of the title compound as white solid.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.92 (d, J=2.0 Hz, 1H),
8.34 (d, J=2.0 Hz, 1H), 2.98 (q, J=7.0 Hz, 2H), 1.55 (s, 6H), 1.25
(t, J=7.0 Hz, 3H); ESI-MS (m/z) 297, 299 [(MH).sup.+,
Br.sup.79,81]
Intermediate-34:
N-(6-bromo-4-methylpyridin-3-yl)-2,6-difluorobenzamide
##STR00059##
[0246] To a (0.degree. C.) cooled and stirred solution of
2,6-difluorobenzoyl chloride (357 .mu.L, 2.83 mmol) in DCM (5 mL)
was added 6-bromo-4-methylpyridin-3-amine (583 mg, 3.12 mmol)
followed by the addition of pyridine (344 .mu.L, 4.25 mmol). The
resulting mixture was then stirred at room temperature overnight.
Water (5 mL) was added to the above mixture and then extracted with
DCM (3.times.10 mL). The combined organic layers were washed with
10% aq.HCl (10 mL), dried (Na.sub.2SO.sub.4) and filtered. The
filtrate was concentrated under vacuum to afford 650 mg (70%) of
the title compound as a white solid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 10.56 (s, 1H, D.sub.2O exchangeable), 8.41
(s, 1H), 7.66 (s, 1H), 7.65-7.58 (m, 1H), 7.27 (t, J=7.0 Hz, 2H),
2.27 (m, 3H); (ESI-MS (m/z) 327, 329 [(MH).sup.+,
Br.sup.79,81].
Intermediate-35: N-(5-Bromo-4-methylpyridin-2-yl)-2,
6-difluorobenzamide
##STR00060##
[0248] To a (0.degree. C.) cooled and stirred solution of
2,6-difluorobenzoyl chloride (500 mg, 2.83 mmol) in DCM (10 mL) was
added 4-bromo-3-methylaniline (632 mg, 3.40 mmol) followed by the
addition of pyridine (275 .mu.L, 3.40 mmol). The resulting mixture
was warmed to room temperature and stirred overnight. Water (10 mL)
was then added to the above mixture and extracted with DCM
(3.times.20 mL). The combined organic layers were washed with 10%
aq.HCl (10 mL), dried (Na.sub.2SO.sub.4) and filtered. The filtrate
was concentrated under vacuum to afford 250 mg (28%) of the title
compound as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.44 (s, 1H, D.sub.2O exchangeable), 8.53 (s, 1H), 7.63
(s, 1H), 7.61-7.54 (m, 1H), 7.21 (t, J=7.0 Hz, 2H), 2.41 (m, 3H);
(ESI-MS (m/z) 327, 329 [(MH).sup.+ Br.sup.79,81]
EXAMPLES
General Procedure for the Coupling Reaction
##STR00061##
[0250] Method-A: To a nitrogen purged stirred solution of halo
intermediate mentioned in above scheme (1.0 eq) in dioxane (5 mL)
in a microwave tube, borate intermediate (1.0 eq) mentioned in
above scheme, aqueoussodium carbonate solution (2N) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.05 eq) were sequentially added. The
resulting mixture was thoroughly deoxygenated by purging nitrogen
for a period of 15 minutes and then heated to 130.degree. C. and
maintained for 30 min in microwave (Biotage). The reaction mixture
was cooled to RT 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
system as eluent) to afford the desired product as a white
solid.
[0251] Method-B: To a nitrogen purged and stirred solution of halo
intermediate (1.0 eq) mentioned in above scheme in dioxane (5 mL)
in a sealed tube, borate intermediate (1.0 eq) mentioned in above
scheme, aqueoussodium carbonate solution (2N) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.05 eq) were sequentially added. The
resulting mixture was thoroughly deoxygenated by purging nitrogen
for a period of 15 minutes and then heated to 130.degree. C. and
further maintained for 18 h. The reaction mixture was cooled to RT
and filtered through celite. The filtrate was concentrated under
vacuum and the crude product was purified by flash column
chromatography (silica gel, ethyl acetate-hexanes system as
eluent)/preparative HPLC to afford the desired product as a white
solid.
[0252] Method-C: To a stirred solution of halo intermediate (0.1
eq) mentioned in above scheme in dioxane (5 mL) in a round bottomed
flask, borate intermediate (0.1 eq) mentioned in above-scheme,
aqueous solution of Na.sub.2CO.sub.3 (2M) and
bis(triphenylphosphine)palladium(II) chloride (0.05 eq) were
sequentially added. The resulting mixture was thoroughly
deoxygenated by subjecting to vacuum/nitrogen cycle three times and
the reaction mixture was refluxed for 24 h under nitrogen
atmosphere. The reaction mixture was cooled to RT and then filtered
through celite. The filtrate was concentrated under vacuum and
crude product was purified with column chromatography (silica gel,
ethyl acetate-hexanes system as eluent)/preparative HPLC to afford
the title compound as a white solid.
Examples 1-27
[0253] The below Examples of 1 to 27 in Table-3 were prepared by
following any of the general procedures described in Method-A,
Method-B or Method-C by using appropriate intermediates.
TABLE-US-00003 TABLE 3 Example No: IUPAC name Structure
.sup.1HNMR/ESI-MS Example-1: 2,6- Difluoro-N-(4-(2-
methyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 3-yl)phenyl)benzamide ##STR00062##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.94 (d, J = 2.0 Hz, 1H),
7.94 (d, J = 2.0 Hz, 1H), 7.94 (s, D.sub.2O exchangeable, 1H), 7.78
(d, J = 8.5 Hz, 2H), 7.48-7.43 (m, 1H), 7.37 (d, J = 8.5 Hz, 2H),
7.03 (t, J = 8.0 Hz, 2H), 3.52 (s, 3H), 2.60 (s, 3H); ESI-MS (m/z)
423 (MH).sup.+. Example-2: N-(4-(2- ethyl-5-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)phenyl)-2,6-
difluorobenzamide ##STR00063## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.99 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.91
(s, D.sub.2O exchangeable, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.45 (m,
1H), 7.35 (d, J = 8.5 Hz, 1H), 7.03 (t, J = 8.0 Hz, 2H), 3.52 (s,
3H), 2.86 (q, J = 7.0 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H); ESI-MS
(m/z) 436(M).sup.+ Example-3: N-(2,6- Difluorophenyl)-4-(2-
ethyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)benzamide ##STR00064## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.05 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.94
(d, J = 2.0 Hz, 1H), 7.52 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H),
7.32-7.25 (m, 1H), 7.04 (t, J = 8.0 Hz, 2H), 3.53 (s, 3H), 2.85 (q,
J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 437
(MH).sup.+ Example-4: N-(4-(2- Cyclopropyl-5-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)phenyl)-2,6-
difluorobenzamide ##STR00065## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.86 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H),
7.7-7.77 (m, 3H), 7.51-7.47 (m, 3H), 7.04 (t, J = 8.0 Hz, 2H), 3.51
(s, 3H), 2.18- 2.14 (m, 1H), 1.26-1.25 (m, 2H), 1.01-0.98 (m, 2H);
ESI-MS (m/z) 449 (MH).sup.+ Example-5: 4-(2- cyclopropyl-5-(4-
methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)-N-(2,6- difluorophenyl)benzamide ##STR00066## .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.90 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.5
Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.55
(s, 1H), 7.30-7.24 (m, 1H), 7.03 (t, J = 8.0 Hz, 2H), 3.52 (s, 3H),
2.11-2.04 (m, 1H), 1.29-1.26 (m, 2H), 1.09-0.98 (m, 2H); ESI- MS
(m/z) 449 (MH).sup.+ Example-6: 2,6- Difluoro-N-(4-(2-
methoxy-5-(4-methyl- 5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-
yl)pyridin-3- yl)phenyl)benzamide ##STR00067## .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.60 (d, J = 2.5 Hz, 1H), 8.03 (d, J = 2.5 Hz,
1H), 7.80 (s, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz,
2H), 7.45 (m, 1H), 7.03 (t, J = 8.0 Hz, 2H), 4.05 (s, 3H), 3.51 (s,
3H); ESI-MS (m/z) 439(MH).sup.+ Example-7: 2,6-
difluoro-N-(4-(5-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-2- (trifluoromethyl)pyridin- 3- yl)phenyl)benzamide
##STR00068## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.13 (s, 1H),
8.14 (s, 1H), 7.83 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.47 (m, 1H),
7.39 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 8.0 Hz, 2H), 3.56 (s, 3H);
ESI-MS (m/z) 477 (MH).sup.+ Example-8: 2,6- difluoro-N-(3-methyl-
4-(5-(4-methyl-5-oxo- 4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-
(trifluoromethyl)pyridin- 3- yl)phenyl)benzamide ##STR00069##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.16 (s, 1H), 8.06 (s,
1H), 7.70 (s, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.43- 7.46 (m, 1H),
7.15 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 8.0 Hz 2H), 3.56 (s, 3H),
2.10 (s, 3H); ESI-MS (m/z) 491(MH).sup.+ Example-9: 2-Chloro-
6-fluoro-N-(4-(5-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-2- (trifluoromethyl)pyridin- 3- yl)phenyl)benzamide
##STR00070## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.13 (d, J =
1.5 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H),
7.67 (s, D.sub.2O exchangeable, 1H), 7.43-7.38 (m, 3H), 7.30 (d, J
= 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz 1H), 3.56 (s, 3H); ESI-MS (m/z)
493(MH).sup.+ Example-10: 2,6- Difluoro-N-(4-(5-(4-
methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-2-
(methylamino)pyridin- 3-yl)phenyl)benzamide ##STR00071## .sup.1HNMR
(400 MHz, DMSO) .delta. 10.97 (s, 1H), 8.44 (d, J = 2.0 Hz, 1H),
7.82 (d, J = 8.5 Hz, 2H), 7.65-7.58 (m, 1H), 7.48 (d, J = 2.0 Hz,
1H), 7.43 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 8.0 Hz, 2H), 6.56 (q, J
= 4.5 Hz 1H), 3.36 (s, 3H), 2.83(d, J = 4.5 Hz, 3H); ESI-MS (m/z)
438 (MH).sup.+ Example-11: 2- Chloro-6-fluoro-N-(4-
(5-(4-methyl-5-oxo- 4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-
(methylamino)pyridin- 3-yl)phenyl)benzamide ##STR00072## .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 8.60 (s, 1H), 7.78 (d, J = 8.5 Hz,
2H), 7.66 (s, 1H), 7.61 (s, D.sub.2O exchangeable, 1H), 7.44 (d, J
= 8.5 Hz, 2H), 7.41-7.39 (m, 1H), 7.33-7.27 (m, 1H), 7.17-7.13 (m,
1H), 5.04 (brs, 1H), 3.48 (s, 3H), 3.04 (d, J = 4.5 Hz, 3H); ESI-MS
(m/z) 454, 456 [(MH).sup.+, Cl .sup.35,37] Example-12: 2-Fluoro-
6-methyl-N-(4-(5-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-2- (methylamino)pyridin- 3-yl)phenyl)benzamide
##STR00073## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.60 (d, J =
2.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.71 (s, 1H), 7.67 (d, J =
2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.33-7.31 (m, 1H), 7.10(d, J
= 7.5 Hz, 1H), 7.00 (t, J = 8.5 Hz, 1H), 5.12 (q, J = 4.5 Hz 1H),
3.47 (s, 3H), 3.05 (d, J = 4.5 Hz, 3H), 2.51 (s, 3H); ESI-MS (m/z)
434(MH).sup.+ Example-13: 2,6- Difluoro-N-(3-methyl-
4-(5-(4-methyl-5-oxo- 4,5-dihydro-1,3,4- oxadiazol-2-yl)-2-
(methylamino)pyridin- 3-yl)phenyl)benzamide ##STR00074## .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 8.63 (d, J = 2.0 Hz, 1H), 7.69 (brs,
2H), 7.60 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.5& 2.0 Hz, 1H),
7.49-7.43 (m, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.05 (t, J = 8.0 Hz,
2H), 4.55 (q, J = 4.5 Hz, 1H), 3.48 (s, 3H), 3.02 (d, J = 4.5 Hz,
3H), 2.17 (s, 3H); ESI-MS (m/z) 452 (MH).sup.+ Example-14: 2,6-
Difluoro-N-(4-(5-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 3-yl)phenyl)benzamide ##STR00075##
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.01 (s, D.sub.2O
exchangeable, 1H), 9.10 (d, J = 2.0 Hz, 1H), 8.94 (d, J = 2.0 Hz,
1H), 8.35 (t, J = 2.0 Hz, 1H), 7.89-7.84 (m, 4H), 7.66-7.55 (m,
1H), 7.26 (t, J = 8.0 Hz, 2H), 3.46 (s, 3H); ESI-MS (m/z) 409
(MH).sup.+ Example-15: 2,6- Difluoro-N-(3-methyl-
4-(5-(4-methyl-5-oxo- 4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)phenyl)benzamide ##STR00076## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.06 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.07
(dd, J = 2.0 & 2.0 Hz 1H), 7.76 (s, D.sub.2O exchangeable, 1H),
7.69 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.0 & 2.0 Hz 1H),
7.46-7.49 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 8.0 Hz
2H), 3.55 (s, 3H), 2.33 (s, 3H); ESI-MS (m/z) 423(MH).sup.+
Example-16: N-(4-(4- Ethyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 3-yl)phenyl)-2,6- difluorobenzamide
##STR00077## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 10.28 (s,
D.sub.2O exchangeable, 1H), 8.88 (s, 1H), 8.53 (s, 1H), 8.12 (d, J
= 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.42-7.46 (m, 1H), 7.24
(t, J = 8.0 Hz, 2H), 3.45 (s, 3H), 2.86 (q, J = 7.5 Hz, 2H), 0.98
(t, J = 7.5 Hz, 3H); ESI-MS (m/z) 437 (MH).sup.+ Example-17:
N-(2,6- Difluorophenyl)-4-(4- ethyl-5-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)benzamide
##STR00078## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 10.28 (s,
D.sub.2O exchangeable, 1H), 8.88 (s, 1H), 8.53 (s, 1H), 8.12 (d, J
= 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.42-7.46 (m, 1H), 7.24
(t, J = 8.0 Hz, 2H), 3.45 (s, 3H), 2.86 (q, J = 7.5 Hz, 2H), 0.98
(t, J = 7.5 Hz, 3H); ESI-MS (m/z) 437 (MH).sup.+ Example-18:
N-(4-(3- Ethyl-4-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 2-yl)phenyl)-2,6- difluorobenzamide
##STR00079## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.66 (d, J =
5.0 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 5.0 Hz, 1H),
7.70 (s, D.sub.2O exchangeable, 1H), 7.58 (d, J = 8.5 Hz, 2H),
7.29- 7.24 (m, 1H), 7.04 (t, J = 8.0 Hz, 2H), 3.58 (s, 3H), 3.01
(q, J = 7.5 Hz, 2H), 1.10(t, J = 7.5 Hz, 3H); ESI-MS (m/z) 437
(MH).sup.+ Example-19: N-(2,6- Difluorophenyl)-4-(3-
ethyl-4-(4-methyl-5- oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
2-yl)benzamide ##STR00080## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.66 (d, J = 5.0 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.71
(d, J = 5.0 Hz, 1H), 7.70 (s, D.sub.2O exchangeable, 1H), 7.58 (d,
J = 8.5 Hz, 2H), 7.29- 7.24 (m, 1H), 7.04 (t, J = 7.5 Hz 2H), 3.58
(s, 3H), 3.01 (q, J = 7.5 Hz, 2H), 1.10(t, J = 7.5 Hz, 3H); ESI-MS
(m/z) 437 (MH).sup.+ Example-20: 2,6- Difluoro-N-(4-(3-
methyl-4-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 2-yl)phenyl)benzamide ##STR00081##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.64 (d, J = 5.0 Hz, 1H),
7.82(s, D.sub.2O exchangeable, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.64
(d, J = 5.0 Hz, 1H), 7.54(d, J = 8.5 Hz, 2H), 7.44- 7.47 (m, 1H),
7.05 (t, J = 8.0 Hz, 2H), 3.58 (s, 3H), 2.60 (s, 3H); ESI-MS (m/z)
423 (MH).sup.+ Example-21: N-(4-(5- Ethyl-4-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin- 2-yl)phenyl)-2,6-
difluorobenzamide ##STR00082## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.73 (s, 1H), 8.20-8.15 (m, 3H), 8.07 (d, J = 8.5 Hz, 2H),
7.51 (s, D.sub.2O exchangeable, 1H), 7.31-7.23 (m, 1H), 7.04 (t, J
= 8.0 Hz, 2H), 3.60 (s, 3H), 3.09(q, J = 7.5 Hz, 2H), 1.33 (t, J =
7.5 Hz, 3H); ESI-MS (m/z) 437 (MH).sup.+ Example-22: N-(2,6-
Difluorophenyl)-4-(5- ethyl-4-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 2-yl)benzamide ##STR00083## .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.73 (s, 1H), 8.20-8.15 (m, 3H), 8.07 (d,
J = 8.5 Hz, 2H), 7.51 (s, D.sub.2O exchangeable, 1H), 7.31-7.23 (m,
1H), 7.04 (t, J = 7.5 Hz, 2H), 3.60 (s, 3H), 3.09(q, J = 7.5 Hz,
2H), 1.33 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 437 (MH).sup.+
Example-23: 2,6- Difluoro-N-(4-(6- methyl-4-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
2-yl)phenyl)benzamide ##STR00084## .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 11.01 (s, D.sub.2O exchangeable, 1H), 8.17
(d, J = 8.5 Hz, 2H), 7.98 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.60
(m, 1H), 7.56 (s, 1H), 7.29 (t, J = 8.0 Hz, 2H), 3.46 (s, 3H), 2.63
(s, 3H); ESI-MS (m/z) 423 (MH).sup.+ Example-24: N-(4-(4-
Chloro-6-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 2-yl)phenyl)-2,6- difluorobenzamide
##STR00085## .sup.1HNMR (400 MHz, DMSO) .delta. 11.07 (s, 1H), 8.32
(d, J = 1.5 Hz, 1H), 8.23 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 1.5 Hz,
1H), 7.85 (d, J = 8.5 Hz, 2H), 7.63 (m, 1H), 7.28 (m, 2H), 3.47 (s,
3H); ESI-MS (m/z) 443, 445 [(MH).sup.+, Cl .sup.35,37]. Example-25:
N-(4-(4- Ethoxy-6-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 2-yl)phenyl)-2,6- difluorobenzamide
##STR00086## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.08 (d, J =
8.5 Hz, 2H), 7.79 (s, D.sub.2O exchangeable, 1H), 7.78 (d, J = 8.5
Hz, 2H), 7.43-7.46 (m, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.30 (d, J =
2.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H),
3.58 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 453 (MH).sup.+
Example-26: 2,6- Difluoro-N-(4-(2-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)pyridin- 4-yl)phenyl)benzamide
##STR00087## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.79 (d, J =
5.0 Hz, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H),
7.80 (s, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.66 (dd, J = 5.0, 1.5 Hz,
1H), 7.49-7.46 (m, 1H), 7.05 (t, J = 8.0 Hz, 2H), 3.59 (s, 3H);
ESI- MS (m/z) 409 (MH).sup.+ Example-27: 2,6- Difluoro-N-(4-(4-
methyl-6-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 3-yl)phenyl)benzamide ##STR00088##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.56(s, 1H), 7.84 (s, 1H),
7.95 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.45-7.49 (m, 1H), 7.38 (d,
J = 8.5 Hz, 2H), 7.04(t, J = 8.0 Hz, 2H), 3.56 (s, 3H), 2.41 (s,
3H); ESI-MS (m/z) 423(MH).sup.+
Example-28
N-(4-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyr-
idin-3-yl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide
##STR00089##
[0255] The title compound was prepared by the reacting
Intermediate-3a with Intermediate-19 by following the general
procedure described in Method C. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.87 (d, J=2.0 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.78 (s,
1H), 7.73 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 3.51 (s, 3H),
3.02 (s, 3H), 2.15-2.11 (m, 1H), 1.28-1.24 (m, 2H), 1.02-0.9 (m,
2H); ESI-MS (m/z) 434 (M).sup.+.
Examples 29-41a, 41b, 41c
##STR00090##
[0256] The below Examples mentioned in Table-4 were prepared by
following the general procedure described in Method A, Method B or
Method C by using appropriate intermediates.
TABLE-US-00004 TABLE 4 Example No: IUPAC name Structure
.sup.1HNMR/ESI-MS Example-29: N-(4-(2- Ethyl-5-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)-3-methylphenyl)- 2,6-difluorobenzamide. ##STR00091##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.01 (d, J = 2.0 Hz, 1H),
7.83-7.82 (m, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.5, 2.0
Hz, 1H), 7.49- 7.41 (m, 1H), 7.13 (d, J = 8.5 Hz, 1H), 7.03 (t, J =
8.0 Hz, 2H), 3.52 (s, 3H), 2.65 (q, J = 7.0 Hz, 2H), 2.10 (s, 3H),
1.17 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 451 (MH).sup.+. Example-30:
N-(2'- ethyl-5'-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-[3,3'- bipyridin]-6-yl)-2,6- difluorobenzamide
##STR00092## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.05 (d, J =
2.5 Hz, 1H), 8.83 (s, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.20 (d, J =
2.5 Hz, 1H), 7.90 (d, J = 2.5 Hz, 1H), 7.78(dd, J = 8.5 &2.5
Hz, 1H), 7.52-7.44 (m, 1H), 7.05 (t, J = 8.0 Hz, 2H), 3.54 (s, 3H),
2.84 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H); ESI-MS (m/z)
438 (MH).sup.+ Example-31: N-(2'- ethyl-5'-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-[2,3'- bipyridin]-5-yl)-2,6-
difluorobenzamide ##STR00093## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.04 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.5 Hz, 1H), 8.49
(dd, J = 8.5 & 2.5 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.96 (s,
1H), 7.52-7.48 (m, 2H), 7.07 (t, J = 8.0 Hz, 2H), 3.53 (s, 3H),
2.99 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H); ESI-MS (m/z)
438 (MH).sup.+ Example-32: N-(4-(2- Cyclopropyl-5-(4-
methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)-3-methylphenyl)- 2,6-difluorobenzamide ##STR00094##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.89 (d, J = 2.0 Hz, 1H),
7.81 (d, J = 2.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.55 (dd, J = 8.0
& 2.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H),
7.04 (t, J = 8.0 Hz, 2H), 3.51 (s, 3H), 2.19 (s, 3H), 1.83- 179 (m,
1H), 1.26-1.20 (m, 2H), 1.00-0.89 (m, 2H); ESI-MS (m/z) 462
(M).sup.+ Example-33: N-(5-(2- Cyclopropyl-5-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)pyrazin-2-yl)-2,6-
difluorobenzamide ##STR00095## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.84 (d, J = 1.0 Hz, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.65
(s, 1H), 8.56 (d, J = 1.0 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H),
7.55-7.48 (m, 1H), 7.10 (t, J = 8.0 Hz, 2H), 3.53 (s, 3H),
2.31-2.24 (m, 1H), 1.33-1.28 (m, 2H), 1.10-1.07 (m, 2H); ESI-MS
(m/z) 451 (MH).sup.+ Example-34: 2- Chloro-N-(5-(2-
cyclopropyl-5-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 3-yl)pyrazin-2-yl)-6- fluorobenzamide
##STR00096## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.85 (s, 1H),
8.95 (d, J = 2.0 Hz, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.13 (d, J =
2.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.16 (t,
J = 8.5 Hz, 1H), 3.53 (s, 3H), 2.32-2.27 (m, 1H), 1.33-1.26 (m,
2H), 1.06-1.06 (m, 2H); ESI-MS (m/z) 467, 469[(MH).sup.+, Cl
.sup.35,37] Example-35: N-(2'- Cyclopropyl-5'-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)-[2,3'- bipyridin]-5-yl)-2,6-
difluorobenzamide ##STR00097## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.91 (s, 1H), 8.79 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.12
(s, 1H), 7.86 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52-7.49 (m, 1H),
7.08 (t, J = 8.0 Hz, 2H), 3.52 (s, 3H), 2.29-2.33 (m, 1H),
1.31-1.28 (m, 2H), 1.05- 1.04 (m, 2H); ESI-MS (m/z) 450 (MH).sup.+
Example-36: N-(2'- Cyclopropyl-5'-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)-[3,3'- bipyridin]-6-yl)-2,6-
difluorobenzamide ##STR00098## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.01 (s, 1H), 8.91(d, J = 2.0 Hz, 1H), 8.55 (d, J = 8.0 Hz,
1H), 8.32 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.0 & 2.0 Hz, 1H),
7.87 (d, J = 2.0 Hz, 1H), 7.51-7.44 (m, 1H), 7.05 (t, J = 8.0 Hz,
2H), 3.53 (s, 3H), 2.07- 2.02 (m, 1H), 1.31-1.27 (m, 2H), 1.06-1.02
(m, 2H); ESI-MS (m/z) 450 (MH).sup.+ Example-37: 2,6-
Difluoro-N-(5-(5-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-2- (trifluoromethyl)pyridin- 3-yl)pyrazin-2-
yl)benzamide ##STR00099## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
9.84 (d, J = 2.0 Hz, 1H), 9.22 (d, J = 2.0 Hz, 1H), 8.57 (s, 1H),
8.50 (d, J = 1.5 Hz, 1H), 8.40 (d, J = 1.5 Hz, 1H), 7.55-7.49 (m,
1H), 7.09(t, J = 8.5 Hz, 2H), 3.58 (s, 3H); ESI-MS (m/z)
479(MH).sup.+ Example-38: 2,6- Difluoro-N-(5'-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)-2'- (trifluoromethyl)-[3,3'-
bipyridin]-6- yl)benzamide ##STR00100## .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 9.18 (d, J = 1.5 Hz, 1H), 8.71 (s, D.sub.2O
exchangeable, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 2.5 Hz,
1H), 8.14 (d, J = 1.5 Hz, 1H), 7.81 (dd, J = 8.5 & 2.5 Hz, 1H),
7.51- 7.48 (m, 1H), 7.06 (t, J = 8.0 Hz, 2H), 3.58 (s, 3H); ESI-MS
(m/z) 478(MH).sup.+ Example-39: 2,6- Difluoro-N-(5'-(4-
methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-2'-
(trifluoromethyl)-[2,3'- bipyridin]-5- yl)benzamide ##STR00101##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.18 (s, 1H), 8.81 (s,
1H), 8.52 (d, J = 6.5 Hz, 1H), 8.37 (brs, 1H), 7.98 (s, 1H),
7.59-7.51 (m, 2H), 7.07 (t, J = 8.0 Hz, 2H), 3.57 (s, 3H); ESI- MS
(m/z) 478(MH).sup.+ Example-40: 5-(5- ((2,6- Difluorobenzyl)amino)-
2'-ethyl-[2,3'- bipyridin]-5'-yl)-3- methyl-1,3,4-
oxadiazol-2(3H)-one ##STR00102## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 8.85 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.98
(d, J = 2.0 Hz, 1H), 7.46-7.44 (m, 1H), 7.41 (d, J = 8.5 Hz, 1H),
7.18-7.13 (m, 3H), 6.64 (t, J = 5.5 Hz, 1H), 4.37 (d, J = 5.5 Hz,
2H), 3.42 (s, 3H), 2.93 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz,
3H) ESI-MS (m/z) 424 (MH).sup.+ Example-41a: 5-(6'- ((2,6-
Difluorobenzyl)amino)- 2-ethyl-[3,3'- bipyridin]-5-yl)-3-
methyl-1,3,4- oxadiazol-2(3H)-one ##STR00103## .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.97 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.0 Hz,
1H), 7.87 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 6.5, 2.0 Hz, 1H),
7.32-7.24 (m, 1H), 7.24 (s, D.sub.2O exchangeable, 1H), 6.95 (t, J
= 4.0 Hz, 2H), 6.63 (d, J = 6.5 Hz, 1H), 4.68 (d, J = 6.0 Hz, 2H)
3.52 (s, 3H), 2.86 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H);
ESI- MS (m/z) 424 (MH).sup.+ Example-41b: N-(2'-
Ethyl-4-methyl-5'-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-[2,3'- bipyridin]-5-yl)-2,6- difluorobenzamide
##STR00104## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 10.63 (s,
1H, D.sub.2O exchangeable), 8.96 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H),
8.09 (d, J = 2.0 Hz, 1H), 7.66 (s, 1H), 7.65-7.61 (m, 1H), 7.29 (t,
J = 8.0 Hz, 2H), 3.43 (s, 3H), 2.94 (q, J = 7.0 Hz, 2H), 2.37 (s,
3H), 1.19 (t, J = 7.0 Hz, 3H); ESI-MS (m/z) 452 (MH).sup.+
Example-41c: N-(2'- Ethyl-4-methyl-5'-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)-[3,3'- bipyridin]-6-yl)-2,6-
difluorobenzamide ##STR00105## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.24 (s, 1H, D.sub.2O exchangeable), 9.09 (d, J = 2.0 Hz,
1H), 8.50 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H),
7.53-7.45 (m, 1H), 7.06 (t, J = 8.0 Hz, 2H), 3.54 (s, 3H), 2.75-
2.59 (m, 2H), 2.22 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H); ESI-MS (m/z)
452 (MH).sup.+
Example-42
N-(2-Chloro-6-fluorophenyl)-5-(2-cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-
-1,3,4-oxadiazol-2-yl)pyridin-3-yl)thiophene-2-carboxamide
##STR00106##
[0258] The title compound was prepared by following the similar
procedure as described in general procedure of Method-Cby using
Intermediate-3c and intermediate-30 .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.90 (d, J=2.0 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H),
7.76 (d, J=3.5 Hz, 1H), 7.42 (s, 1H), 7.33-7.24 (m, 3H), 7.18-7.16
(m, 1H), 3.53 (s, 3H), 2.42-2.36 (m, 1H), 1.32-1.26 (m, 2H),
1.11-1.08 (m, 2H); ESI-MS (m/z) 470, 472[(M).sup.+,
Cl.sup.35,37].
Example-43
5-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridi-
n-3-yl)-N-(3-methylpyridin-4-yl)thiophene-2-carboxamide
##STR00107##
[0260] The title compound was prepared by following the similar
procedure as described in general procedure of Method-B by using
Intermediate-3c and Intermediate-31. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.92 (d, J=2.0 Hz, 1H), 8.48 (brs, 1H), 8.42
(brs, 1H), 8.20 (brs, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.86 (bs, 1H),
7.75 (d, J=3.5 Hz, 1H), 7.33 (d, J=3.5 Hz, 1H), 3.53 (s, 3H), 2.42
(s, 3H), 2.38-2.32 (m, 1H), 1.33-1.30 (m, 2H), 1.11-1.07 (m, 2H);
ESI-MS (m/z) 433 (M).sup.+.
Example-44
N-(2,6-Difluorophenyl)-5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxad-
iazol-2-yl)pyridin-3-yl)furan-2-carboxamide
##STR00108##
[0262] The title compound was prepared by following the similar
procedure as described in general procedure of Method-C by using
Intermediate-1c and Intermediate-32. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 9.03 (d, J=2.5 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H),
7.67 (s, D.sub.2O exchangeable, 1H), 7.53 (d, J=3.5 Hz, 1H),
7.32-7.27 (m, 1H), 7.03 (t, J=8.0 Hz, 2H), 6.88 (d, J=3.5 Hz, 1H),
3.55 (s, 3H), 3.14 (q, J=7.5 Hz, 2H), 1.45 (t, J=7.5 Hz, 3H);
ESI-MS (m/z) 427 (MH).sup.+.
Example-45
5-(2-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridi-
n-3-yl)-N-(2,6-difluorophenyl)furan-2-carboxamide
##STR00109##
[0264] The title compound was prepared by following the similar
procedure as described in general procedure of Method C by using
Intermediate-3c and Intermediate-32. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.90 (d, J=2.5 Hz, 1H), 8.27 (d, J=2.5 Hz, 1H),
7.73 (s, D.sub.2O exchangeable, 1H), 7.44 (d, J=3.5 Hz, 1H),
7.33-7.26 (m, 1H), 7.04 (t, J=8.0 Hz 2H) 7.01 (d, J=2.5 Hz, 1H),
3.54 (s, 3H), 2.49-2.43 (m, 1H), 1.36-1.32 (m, 2H), 1.17-1.13 (m,
2H); ESI-MS (m/z) 439 (MH).sup.+.
Example-46
N-(4-(2-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-3-
-yl)phenyl)-3,5-difluoroisonicotinamide
##STR00110##
[0266] To a solution of Intermediate-7 (200 mg, 0.67 mmol, 1.2 eq)
and 3,5-difluoroisonicotinic acid (161 mg, 1.01 mmol, 1.5 eq) in
DCM (20 mL) at RT was sequentially added EDC.HCl (194 mg, 1.01
mmol, 1.5 eq), HOBT (155 mg, 1.01 mmol, 1.5 eq) and triethylamine
(0.18 mL, 1.35 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 DCM (30 mL). The layers were separated
and the aqueous layer was extracted with DCM (3.times.20 mL). The
combined organic layers were washed with saturated sodium
bicarbonate solution (20 mL), brine (20 mL) dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated
under vacuum and the crude product was purified by flash column
chromatography (silica gel, ethylacetate-hexanes system as eluent)
to afford 40 mg (14%) of the desired product as a white solid. HNMR
(400 MHz, CDCl.sub.3) .delta. 9.00 (d, J=2.0 Hz, 1H), 8.53 (s, 2H),
8.00 (s, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.38
(d, J=8.5 Hz, 2H), 3.52 (s, 3H), 2.86 (q, J=7.5 Hz, 2H), 1.24 (t,
J=7.5 Hz, 3H); ESI-MS (m/z) 438 (MH).sup.+
[0267] The below Examples-47 to 52 given in Table-5 were prepared
by following the similar procedure as described in Example-46 by
using Intermediate-7 and appropriate acid intermediate.
TABLE-US-00005 TABLE 5 Example No: IUPAC name Structure
.sup.1HNMR/ESI-MS Example-47: N-(4-(2- Ethyl-5-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)phenyl)-2-fluoro-6- methylbenzamide ##STR00111## .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 9.00 (d, J = 2.5 Hz, 1H), 7.92 (d, J
= 2.5 Hz, 1H), 7.7 (d, J = 8.5 Hz, 2H), 7.69 (s, 1H), 7.35 (d, J =
8.5 Hz, 2H), 7.32-7.31 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.02 (t,
J = 8.0 Hz, 1H), 3.55 (s, 3H), 2.87 (q, J = 7.5 Hz, 2H), 2.52 (s,
3H), 1.25 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 433 (MH).sup.+
Example-48: 2-Chloro- N-(4-(2-ethyl-5-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)phenyl)-6-
fluorobenzamide ##STR00112## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.00 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 2.5 Hz, 1H), 7.78
(d, J = 8.5 Hz, 1H), 7.68 (s, D.sub.2O exchangeable, 1H), 7.43-7.39
(m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H),
7.16-7.12 (m, 1H), 3.53 (s, 3H), 2.87 (q, J = 7.5 Hz, 2H), 1.26 (t,
J = 7.5 Hz, 3H); ESI-MS (m/z) 453, 455 [(MH).sup.+, Cl.sup.35,37]
Example-49: N-(4-(2- Ethyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- yl)phenyl)-4-methyl- 1,2,3-thiadiazole-5-
carboxamide ##STR00113## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
9.02 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.75 (s,
D.sub.2O exchangeable, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.39 (d, J =
8.5 Hz, 2H), 3.53 (s, 3H), 3.02 (s, 3H), 2.86 (q, J = 7.5 Hz, 2H),
1.25 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 423(MH).sup.+ Example-50:
N-(4-(2- Ethyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 3-yl)phenyl)-3,5- dimethylisoxazole-4-
carboxamide ##STR00114## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
9.00 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 2.5 Hz, 1H), 7.68 (d, J =
8.5 Hz, 2H), 7.43 (s, 1H), 7.35 (d, J = 8.5 Hz, 2H), 3.52 (s, 3H),
2.86 (q, J = 7.5 Hz, 2H), 2.72 (s, 3H), 2.55 (s, 3H), 1.24 (t, J =
7.5 Hz, 3H); ESI-MS (m/z) 420(MH).sup.+ Example-51: N-(4-(2-
Ethyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)phenyl)-3- methylisonicotinamide ##STR00115## .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 9.01 (d, J = 2.0 Hz, 1H), 8.59-8.57 (m,
2H), 7.92 (d, J = 2.0 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J = 8.5 Hz,
2H), 7.40- 7.38 (m, 3H), 3.53 (s, 3H), 2.87 (q, J = 7.5 Hz, 2H),
2.53 (s, 3H), 1.25 (t, J = 7.5 Hz, 3H); ESI-MS (m/z) 416
(MH).sup.+
Example-52
N-(4-(5-(4,4-Dimethyl-5-oxo-4,5-dihydroisoxazol-3-yl)-2-ethylpyridin-3-yl)-
phenyl)-2,6-difluorobenzamide
##STR00116##
[0269] The title compound was prepared by the reaction of
Intermediate-33 with Intermediate-16 by following the similar
procedure as described in method B. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 10.99 (s, 1H, D.sub.2O exchangeable), 8.96
(d, J=2.0 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H),
7.64-7.59 (m, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.28 (t, J=8.0 Hz, 2H),
2.82 (q, J=7.0 Hz, 2H), 1.58 (s, 6H), 1.20 (t, J=7.0 Hz, 3H);
ESI-MS (m/z) 450 (MH).sup.+
Example-53
2,6-Difluoro-N-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
-yl)pyridin-3-yl)pyrazin-2-yl)benzamide
##STR00117##
[0271] To a 0.degree. C. cooled and stirred solution of
2,6-difluorobenzoyl chloride (118 mg, 0.67 mmol, 1.0 eq) in DCM (2
mL) was added drop-wise a solution of Intermediate-1b, (200 mg,
0.67 mmol, 1.0 eq) in DCM (2 mL) followed by pyridine (63.6 mg,
0.80 mmol, 1.2 eq). The resulting mixture was stirred at RT
overnight. The reaction was diluted with DCM (10 mL), and washed
with water (5 mL), brine (5 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated under vacuum and the crude
product was purified by flash column chromatography (silica gel,
ethyl acetate-hexane system as eluent) to afford 45 mg (15%) of the
example-53 as a white solid. HNMR (400 MHz, CDCl.sub.3) .delta.
9.82 (d, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.44
(d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.53 (m, 1H), 7.09 (t,
J=8.0 Hz, 2H), 3.54 (s, 3H), 2.99 (q, J=7.5 Hz, 2H), 1.31 (t, J=7.5
Hz, 3H); ESI-MS (m/z) 439 (MH).sup.+.
Example-54
2-Chloro-N-(5-(2-ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-
pyridin-3-yl)pyrazin-2-yl)-6-fluorobenzamide
##STR00118##
[0273] The title compound was prepared by following the similar
procedure as described in Example-53 by using Intermediate-1b and
2-chloro-6-fluorobenzoyl chloride. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.83 (s, 1H), 9.08 (s, 1H), 8.62 (s, D.sub.2O exchangeable,
1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.45 (m, 1H) 7.33 (d, J=8.0 Hz,
1H), 7.16 (t, J=8.0 Hz, 1H), 3.55 (s, 3H), 3.00 (q, J=7.5 Hz, 2H),
1.31 (t, J=7.5 Hz, 3H); ESI-MS (m/z) 455, 457 [(MH).sup.+,
Cl.sup.35,37]
Example-55
2,6-Difluoro-N-(5-(2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol--
2-yl)pyridin-3-yl)pyrazin-2-yl)benzamide
##STR00119##
[0275] The title compound was prepared by following the similar
procedure as described in Example-53 by using Intermediate-2band
2,6-difluorobenzoyl chloride followed by Boc deprotection using
trifluroacitic acid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.82
(s, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.18 (s 1H),
7.52 (m, 1H), 7.08 (t, J=8.0, 2H), 3.56 (s, 3H), 2.74 (s, 3H);
ESI-MS (m/z) 425 (MH).sup.+
Example-56
2,6-Difluoro-N-(5-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-(-
methylamino)pyridin-3-yl)pyrazin-2-yl)benzamide
##STR00120##
[0277] The title compound was prepared by following the similar
procedure as described in Example-53 by using Intermediate-6c and
2,6-difluorobenzoyl chloride.
[0278] .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.68 (s, 1H), 9.20
(q, J=4.5 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H),
8.64 (s, 1H), 8.24 (s, 1H), 7.50 (m, 1H), 7.08 (t, J=8.0 Hz, 2H),
3.51 (s, 3H), 3.18 (d, J=4.5 Hz, 3H); ESI-MS (m/z) 440
(MH).sup.+
General Procedure for the Synthesis of Example 57-63
##STR00121##
[0280] To a nitrogen purged and stirred solution of any one of
bromo Intermediate 1a, 2a, 3a, 5a, or 6b (1.0 eq) in dioxane (10
mL), any one of stananne derivative of Intermediate-23 or
Intermediate-24 (1.0 eq) and Pd(PPh.sub.3).sub.4 (0.05 eq) were
sequentially added. The resulting mixture was thoroughly
deoxygenated by purging nitrogen gas for 15 min and then heated to
130.degree. C. and maintained for 30 min in microwave (Biotage).
The reaction mixture was cooled to RT and filtered through celite.
The filtrate was concentrated under vacuum and the crude product
was purified by flash column chromatography (silica gel, ethyl
acetate-hexanes system as eluent) to afford the desired product as
a solid. The Examples 57-63 given in Table-6 were prepared by
following this procedure using appropriate intermediates.
TABLE-US-00006 TABLE 6 Example No: IUPAC name Structure
.sup.1HNMR/ESI-MS Example-57: N-(2,6- Difluorophenyl)-5-(2-
ethyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin-
3-yl)thiophene-2- carboxamide ##STR00122## .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 9.03 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.0 Hz,
1H), 7.73 (d, J = 3.5 Hz, 1H), 7.34 (s, 1H), 7.32-7.24 (m, 1H),
7.18 (d, J = 3.5 Hz, 1H), 7.034, J = 8.0 Hz, 2H), 3.50 (s, 3H),
3.03 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); ESI-MS (m/z)
443 (MH).sup.+ Example-58: N-(2,6- Difluorophenyl)-5-(2-
methyl-5-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)pyridin- 3-yl)thiophene-2- carboxamide ##STR00123##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.98 (d, J = 2.0 Hz, 1H),
8.11 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.38 (s, 1H),
7.28 (m, 1H), 7.22 (d, J = 4.0 Hz, 1H), 7.03 (t, J = 8.0 Hz, 2H),
3.52 (s, 3H), 2.77 (s, 3H); ESI-- MS (m/z) 429 (MH).sup.+.
Example-59: 5-(2- Cyclopropyl-5-(4- methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)-N-(2,6-
difluorophenyl)thio- phene-2-carboxamide ##STR00124## .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 8.89 (d, J = 2.0 Hz, 1H), 8.02 (d, J
= 2.0 Hz, 1H), 7.74 (d, J = 3.5 Hz, 1H), 7.33 (s, 1H), 7.32-7.24
(m, 2H), 7.01 (t, J = 8.5 Hz, 2H), 3.53 (s, 3H), 2.41- 2.35 (m,
1H), 1.32-1.26 (m, 2H), 1.10-1.06 (m, 2H); ESI-MS (m/z) 455
(MH).sup.+ Example-60: N-(2,6- Difluorophenyl)-5-(5-
(4-methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-2-
(trifluoromethyl)pyridin- 3-yl)thiophene-2- carboxamide
##STR00125## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.16 (d, J =
2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H),
7.39 (s, D.sub.2O exchangeable, 1H), 7.29 (m, 1H), 7.26 (d, J = 4.0
Hz, 1H), 7.03 (t, J = 8.0 Hz 2H), 3.60 (s, 3H); ESI-MS (m/z)
483(MH).sup.+ Example-61: N-(2,6- Difluorophenyl)-5-(5-
(4-methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-2-
(methylamino)pyridin- 3-yl)thiophene-2- carboxamide ##STR00126##
.sup.1HNMR (400 MHz, DMSO) .delta. 10.29 (s, D.sub.2O exchangeable,
1H), 8.50 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 1.5 Hz, 1H), 7.70 (s,
1H), 7.47-7.42 (m, 2H), 7.24 (t, J = 8.0 Hz, 2H), 6.97 (q, J = 4.5
Hz, D.sub.2O exchangeable, 1H), 3.35 (s, 3H), 2.88 (d, J = 4.5 Hz,
3H); ESI-MS (m/z) 444 (MH).sup.+ Example-62: N-(2,6-
Difluorophenyl)-1- methyl-5-(2-methyl-5- (4-methyl-5-oxo-4,5-
dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)-1H-pyrrole-2-
carboxamide ##STR00127## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
9.02 (d, J = 2.5 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.31 (s,
D.sub.2O exchangeable, 1H), 7.23 (m, 1H), 7.01 (t, J = 8.0 Hz, 2H),
6.94 (d, J = 4.5 Hz, 1H), 6.23 (d, J = 4.5 Hz, 1H), 3.73 (s, 3H),
3.53 (s, 3H), 2.51(s, 3H); ESI-MS (m/z) 426(MH).sup.+ Example-63:
N-(2,6- Difluorophenyl)-5-(2- ethyl-5-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)pyridin- 3-yl)-1-methyl-1H-
pyrrole-2-carboxamide ##STR00128## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.07 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H), 7.27
(s, 1H), 7.24-7.21 (m, 1H), 7.02 (t, J = 8.0 Hz, 2H), 6.94 (d, J =
4.0 Hz, 1H), 6.23 (d, J = 4.0 Hz, 1H), 3.72 (s, 3H), 3.53 (s, 3H),
2.77 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); ESI-MS (m/z)
440 (MH).sup.+
Example-64
N-(4-(4-Ethyl-6-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-2-
-yl)phenyl)-2,6-difluorobenzamide
##STR00129##
[0282] To a nitrogen purged and stirred solution of Example-24 (100
mg, 0.226 mmol) and ethylboronic acid (0.025 g, 0.339 mmol) in
dioxane (5 ml) in a sealed tube, potassium carbonate (94 mg, 0.67
mmol) and Pd(Ph.sub.3P).sub.4 (13 mg, 0.011 mmol) were sequentially
added. The resulting mixture was thoroughly deoxygenated by
nitrogen gas for 15 min and then heated to 130.degree. C. and
maintained for 16 h. The reaction mixture was cooled to RT and
filtered through celite. The filtrate was concentrated under vacuum
and the crude product was purified by flash column chromatography
(silica gel, ethyl acetate-hexanes system as eluent) to afford 24
mg (24%) of the desired product as a white solid. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 7.90 (d, J=1.5 Hz, 1H), 7.83 (d, J=8.5 Hz,
2H), 7.79 (s, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.53 (d, J=1.5 Hz, 1H),
7.51-7.43 (m, 1H), 7.05 (t, J=8.0 Hz, 2H), 3.59 (s, 3H), 3.00 (q,
J=7.5 Hz, 2H), 1.40 (t, J=7.5 Hz, 3H); ESI-MS (m/z) 437
(MH).sup.+.
Example-65
N-(4-(3-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-2-
-yl)phenyl)-2,6-difluorobenzamide
##STR00130##
[0283] Step-1:
Ethyl-5-bromo-6-(4-(2,6-difluorobenzamido)phenyl)nicotinate
[0284] To a nitrogen gas purged solution of
ethyl-5,6-dibromonicotinate (5.0 g, 16.18 mmol, prepared by
following the procedure described in WO2011024004) in dioxane (50
mL), in a sealed tube was added Intermediate-16 (5.81 g, 16.18
mmol) and potassium carbonate (4.47 g, 32.4 mmol). The resulting
mixture was thoroughly deoxygenated by purging nitrogen gas for 15
min and then tetrakis(triphenylphosphine)palladium(0) (0.93 g, 0.81
mmol) was added to the above mixture. The resulting mixture was
then heated to 120.degree. C. and maintained for 16 h. The reaction
was cooled to RT and filtered through celite. The filtrate was
concentrated under vacuum and the crude product was purified by
flash column chromatography (silica gel, ethyl acetate-hexanes
system as eluent) to afford 3.20 g (43%) of the title compound as
white solid. HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.05 (s,
D.sub.2O exchangeable, 1H), 9.11 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.0
Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.62-7.59
(m, 1H), 7.28 (t, J=8.0 Hz, 2H), 4.38 (q, J=7.0 Hz, 2H), 1.35 (t,
J=7.0 Hz, 3H); ESI-MS (m/z) 461, 463 [(MH).sup.+,
Br.sup.79,81].
Step-2: 5-Bromo-6-(4-(2,6-difluorobenzamido)phenyl)nicotinic
acid
[0285] To a 0.degree. C. cooled solution of step-1 intermediate
(1.0 g, 2.62 mmol) in ethanol (20 mL) was added a solution of
sodium hydroxide (0.315 g, 7.87 mmol) in water (10 mL) and stirred
the reaction at RT for 4 h. The solvent was evaporated under vacuum
and the residue was taken in water (10 mL), acidified with 10% HCl
(2 mL). The precipitated solid was filtered and dried under vacuum
to yield 0.88 g (93%) of the title compound as a white solid.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.03 (s, D.sub.2O
exchangeable, 1H), 9.03 (d, J=1.5 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H),
7.81 (d, J=8.5 Hz, 2H), 7.72 (d, J=8.5 Hz, 2H), 7.63-7.57 (m, 1H),
7.22 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 431, 432 [(MH).sup.+,
Br.sup.79,81].
Step-3:
N-(4-(3-bromo-5-(hydrazinecarbonyl)pyridin-2-yl)phenyl)-2,6-difluo-
robenzamide
[0286] To a stirred solution of step-2 intermediate (200 mg, 0.46
mmol), in DCM (5 mL) EDC.HCl (133 mg, 0.69 mmol), HOBT (0.031 g,
0.231 mmol) and hydrazine hydrate (22 .mu.L, 0.693 mmol) were
successively added. After stirring at RT for 16 h, water (10 mL)
was added to the reaction followed by DCM (20 mL). The layers were
separated and aqueous layer was extracted with DCM (3.times.10 mL).
The combined organic layers were washed with bine (20 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated
under vacuum to afford 180 mg (87%) of the title compound as a
white solid. HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.03 (s,
D.sub.2O exchangeable, 1H), 10.11 (s, D.sub.2O, exchangeable, 1H),
9.02 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 7.82 (d, J=8.5 Hz,
2H), 7.72 (d, J=8.5 Hz, 2H), 7.65-7.58 (m, 1H), 7.28 (t, J=8.0 Hz,
2H), 4.64 (brs, D.sub.2O exchangeable, 2H); ESI-MS (m/z) 446, 448
[(MH).sup.+, Br.sup.79,81].
Step-4:
N-(4-(3-Bromo-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)p-
yridin-2-yl)phenyl)-2,6-difluorobenzamide
[0287] The title compound was prepared from step-3 intermediate by
following the similar procedure as described in step-3 and step-4
of intermediate-1a. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
11.05 (s, D.sub.2O exchangeable, 1H), 9.11 (d, J=1.5 Hz, 1H), 8.56
(d, J=1.5 Hz, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H),
7.65-7.57 (m, 1H), 7.28 (t, J=8.0 Hz, 2H), 3.92 (s, 3H); (ESI-MS
(m/z) 488, 490 [(MH).sup.+ Br.sup.79 81].
Step-5:
N-(4-(3-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)p-
yridin-2-yl)phenyl)-2,6-difluorobenzamide
[0288] To a nitrogen gas purged solution of step-4 intermediate
(105 mg, 0.21 mmol) in dioxane (2 mL) in a microwave tube was added
ethylboronic acid (19 mg, 0.26 mmol) and potassium carbonate (60
mg, 0.43 mmol). The resulting mixture was thoroughly deoxygenated
by purging nitrogen gas for 15 min and then
tetrakis(triphenylphosphine)palladium(0) (12 mg, 10.77 .mu.mol) was
added. The reaction mixture was heated at 100.degree. C. for 2 h in
a microwave reactor. The reaction mixture was cooled to RT diluted
with dioxane (5 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-hexanes
system as eluent) to afford 25 mg (26%) the title compound as a
white solid. HNMR (400 MHz, CDCl.sub.3) .delta. 8.95 (d, J=2.0 Hz,
1H), 8.06 (d, J=2.0 Hz, 1H), 7.84 (s, D.sub.2O exchangeable, 1H),
7.75 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.50-7.42 (m, 1H),
7.03 (t, J=8.0 Hz, 2H), 3.56 (s, 3H), 2.80 (q, J=7.5 Hz, 2H), 1.23
(t, J=7.5 Hz, 3H); ESI-MS (m/z) 437 (MH).sup.+
Example-66
N-(4-(3-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyr-
idin-2-yl)phenyl)-2,6-difluorobenzamide
##STR00131##
[0290] The title compound was prepared by following the similar
procedure as described in step-5 of Example-65 using step-4
intermediate of Example-65 and cyclopropylboronic acid. .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 8.93 (d, J=2.0 Hz, 1H), 7.78-7.76 (m,
4H), 7.75 (s, D.sub.2O exchangeable, 1H), 7.66 (d, J=2.0 Hz, 1H),
7.49-7.45 (m, 1H), 7.05 (t, J=8.0 Hz, 2H), 3.55 (s, 3H), 2.12-2.08
(m, 1H), 1.10-1.05 (m, 2H), 0.84-0.80 (m, 2H); ESI-MS (m/z) 449
(MH).sup.+
Example-67
N-(4-(5-Cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyr-
idin-2-yl)phenyl)-2,6-difluorobenzamide
##STR00132##
[0291] Step-1:3-Bromo-5-(ethoxycarbonyl)pyridine-1-oxide
[0292] To a stirred solution of ethyl 5-bromonicotinate (2.0 g,
8.69 mmol) in acetic acid (50 mL) was added urea hydrogen peroxide
(4.09 g, 43.5 mmol) at 0.degree. C. After that the reaction mixture
was heated to 80.degree. C. and further maintained for 18 h. The
reaction was cooled to 0.degree. C. and basified with solid sodium
carbonate (till whole acetic acid layer was covered) and diluted
with DCM (50 mL). The resulting suspension was then filtered and
the filtrate was evaporated. The crude product was triturated with
hexane (10 mL) to afford 2.0 g (93%) of the desired product as a
white solid. GC-MS (m/z) 245, 247[M.sup.+, Br.sup.79,81].
Step-2: Ethyl-2,5-dibromonicotinate
[0293] To a 0.degree. C. cooled solution of step-1 intermediate
(12.0 g, 48.8 mmol) in toluene (150 mL) was added phosphorous
oxybromide (13.9 g, 48.8 mmol) drop-wise. The resulting mixture was
heated to 65.degree. C. and maintained for 2 h, then cooled to
0.degree. C., poured into crushed ice followed by the addition of
ethyl acetate (50 mL). The mixture was basified (pH 8) using
aqueous 10% sodium carbonate solution. The layers were separated
and the aqueous layer was extracted with ethyl acetate (2.times.100
mL). The combined organic layers were washed with brine (100 mL),
dried (Na.sub.2SO.sub.4) and filtered. The filtrate was evaporated
and the crude product was purified by flash column chromatography
(silica gel, EtOAc-Hexane as eluent) to afford 7.0 g (46%) of the
desired product as a white solid. HNMR (400 MHz, CDCl.sub.3)
.delta. 8.56 (d, J=2.5 Hz, 1H), .delta. 8.19 (d, J=2.5 Hz, 1H),
4.44 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 308,
312[(MH).sup.+, Br.sup.79,81].
Step-3:
Ethyl-5-bromo-2-(4-(2,6-difluorobenzamido)phenyl)nicotinate
[0294] The title compound was prepared by by following the general
procedure described in Method B using ethyl 2,5-dibromonicotinate
(6.40 g, 20.7 mmol) and Intermediate-16 (7.44 g, 20.7 mmol) to
afford 4.30 g (45%) of the desired product as a white solid.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.77 (d, J=2.5 Hz, 1H),
8.58 (d, J=2.5 Hz, 1H), 8.02 (s, D.sub.2O exchangeable, 1H) 7.69
(d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.48-7.41 (m, 1H), 7.02
(t, J=8.0 Hz, 2H), 4.25 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H);
ESI-MS (m/z) 461, 463[(MH).sup.+, Br.sup.79,81].
Step-4:
N-(4-(5-Bromo-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)p-
yridin-2-yl)phenyl)-2,6-difluorobenzamide
[0295] The title compound was prepared from
ethyl-5-bromo-2-(4-(2,6-difluorobenzamido)phenyl)nicotinate by
following the similar procedure sequentially as described in
step-2, step-3, and step-4 of Intermediate-1a. ESI-MS (m/z) 487,
489[(MH).sup.+, Br.sup.79,81].
Step-5:
N-(4-(5-Cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol--
2-yl)pyridin-2-yl)phenyl)-2,6-difluorobenzamide
[0296] To a nitrogen gas purged solution of ethyl
N-(4-(5-bromo-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin--
2-yl)phenyl)-2,6-difluorobenzamide (60 mg, 0.12 mmol), in dioxane
(4 mL) in a sealed tube was added cyclopropylboronic acid (16 mg,
0.18 mmol) followed by sodium carbonate (34 mg, 0.24 mmol). The
resulting mixture was thoroughly deoxygenated by purging nitrogen
gas for 15 min and then tetrakis(triphenylphosphine)palladium(0)
(14 mg, 0.012 mmol) was added to the above mixture. The reaction
was heated to 100.degree. C. and maintained for 18 h. The reaction
mixture was then cooled to RT, diluted with EtOAc (5 mL) and
filtered through celite. The filtrate was concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (silica gel, 20% ethyl acetate-hexane system) to
afford 15 mg (27%) of the title compound as a white solid. HNMR
(400 MHz, CDCl.sub.3) .delta. 8.61 (d, J=2.5 Hz, 1H), 7.77 (s,
D.sub.2O exchangeable, 1H) 7.71 (d, J=8.5 Hz, 2H), 7.65 (d, J=2.5
Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.47-7.43 (m, 1H), 7.03 (t, J=8.0
Hz, 2H), 3.45 (s, 3H), 2.03-1.99 (m, 1H), 1.17-1.12 (m, 2H),
0.85-0.82 (m, 2H); ESI-MS (m/z) 449 (MH).sup.+
Example-68
N-(4-(6-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridin-3-
-yl)phenyl)-2,6-difluorobenzamide
##STR00133##
[0297] Step-1: Ethyl-5-bromo-2-ethylnicotinate
[0298] A nitrogen purged and stirred solution of ethyl
2,5-dibromonicotinate (2.5 g, 8.09 mmol) and Pd(dba).sub.2 (233 mg,
0.405 mmol) in THF (10 mL), cooled in ice bath (0.degree. C.) was
added a solution of diethylzinc (1M in THF 9.71 mL, 9.71 mmol)
drop-wise for 15 min. The resulting mixture was warmed to RT and
then stirred for 10 min. Reaction mixture was again cooled to
0.degree. C. and then quenched with 0.5 mL cold methanol. Reaction
content was diluted with ethyl acetate (20 mL) and filtered through
celite. The filtrate was rotary evaporated and the crude product
was purified by flash column chromatography (silica gel, 3%
EtOAc-hexanes as eluent) to afford 0.5 g (24%) of the title product
as a white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.71 (d,
J=2.0 Hz, 1H), 8.28 (d, J=2.0 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 3.14
(q, J=7.5 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H);
ESI-MS (m/z) 258, 260 [(MH).sup.+ Br.sup.79,81].
Step-2:
5-(5-Bromo-2-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
[0299] The title compound was prepared from
ethyl-5-bromo-2-ethylnicotinate by following the procedure
sequentially as described in step2, step-3 and step-4 of
Intermediate-1a. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.80
(d, J=2.5 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H), 3.44 (s, 3H) 3.05 (q,
J=7.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H); ESI-MS (m/z) 284, 286
[(MH).sup.+, Br.sup.79,81]
Step-3:
N-(4-(6-Ethyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)p-
yridin-3-yl)phenyl)-2,6-difluorobenzamide
[0300] The title compound was prepared by reacting
5-(5-bromo-2-ethylpyridin-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
and Intermediate-16 by following the general procedure for coupling
reaction as described in Method A. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 10.98 (s, D.sub.2O exchangeable, 1H), 9.00
(d, J=2.5 Hz, 1H), 8.26 (d, J=2.5 Hz, 1H), 7.85-7.80 (m, 4H),
7.63-7.59 (m, 1H), 7.28 (t, J=8.0 Hz, 2H), 3.46 (s, 3H), 3.13 (q,
J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H); ESI-MS (m/z) 437
(MH).sup.+
Biological Assays and Utility:
[0301] 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-69
[0302] 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 CO.sub.2 incubator at 37.degree. C. After incubation
with the compounds, cells were centrifuged, the supernatant was
collected and processed for ELISA to quantitate the amount of IL-2
secreted. A commercial ELISA kit (R&D Systems, Inc.
Minneapolis, Minn., 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.
[0303] In the above IL-2 assay, compounds of the invention were
found to have IC.sub.50 (nM) values as shown below:
TABLE-US-00007 IC.sub.50 (nM) Examples <100 nM 2, 4, 6, 7, 10,
11, 12, 15, 29, 30, 32, 33, 35, 36, 37, 41, 42, 43, 54, 57, 59, 60,
61, 100 nM-1000 nM 1, 3, 5, 8, 9, 13, 16, 27, 28, 31, 34, 38, 39,
40, 46, 47, 48, 49, 53, 55, 58, 62, 41B, 66, >1000 nM 14, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 44, 45, 50, 51, 56, 63, 41A,
64, 65, 67, 68
[0304] Thus, compounds of the invention are shown to inhibit IL-2
secretion.
Example-70
[0305] SOCE inhibition: Jurkat E6.1 cells were seeded at a density
of 1-2.times.10.sup.5 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 485 nm
excitation and 520 nm 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.
[0306] In the above SOCE inhibition assay, compounds of the present
invention showed activity less than <1000 nM against SOCE. Thus,
compounds of the invention are shown to have CRAC channel
modulation activity by inhibition of SOCE.
Example-71
[0307] NFAT Transcriptional Activity: HEK 293 cells were stably
co-transfected with a NFAT-FireflyLuciferase and Tk-Renilla
Luciferase reporter genes 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. The NFAT-Firefly luciferase
and Tk-Renilla luciferase activity was measured using Dual-Glo
reagent (Promega USA). The Renilla luciferase activity was used for
protein normalization. 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.
[0308] In the above NFAT transcriptional activity assay, compounds
of the present invention showed activity less than <1000 nM.
Thus, compounds of the invention are shown to inhibit NFAT
transcription activity.
[0309] Thus, the in vitro screening assays showed that the
compounds of invention inhibit CRAC channel activity.
[0310] As mentioned hereinbefore, the CRAC channel is involved with
numerous biological responses through various Ca.sup.2+ 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
benefited by the CRAC channel modulatory properties of the
compounds described herein.
[0311] 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 benefited 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.
[0312] 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.
[0313] 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.
* * * * *