U.S. patent application number 15/194795 was filed with the patent office on 2016-10-20 for substituted pyrazole 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, Nilesh Raghunath KHEDKAR, Kiran Chandrashekhar KULKARNI, Venkata P. PALLE, Zubair Abdul Wajid SHAIKH, Neelima SINHA.
Application Number | 20160304507 15/194795 |
Document ID | / |
Family ID | 48428566 |
Filed Date | 2016-10-20 |
United States Patent
Application |
20160304507 |
Kind Code |
A1 |
IRLAPATI; Nageswara Rao ; et
al. |
October 20, 2016 |
SUBSTITUTED PYRAZOLE 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) ; DESHMUKH; Gokul Keruji; (Pune,
IN) ; KHEDKAR; Nilesh Raghunath; (Pune, IN) ;
KULKARNI; Kiran Chandrashekhar; (Pune, IN) ; SHAIKH;
Zubair Abdul Wajid; (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: |
48428566 |
Appl. No.: |
15/194795 |
Filed: |
June 28, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14398161 |
Oct 31, 2014 |
9409898 |
|
|
PCT/IB2013/053446 |
May 1, 2013 |
|
|
|
15194795 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 19/02 20180101; C07D 413/14 20130101; A61P 9/00 20180101; A61P
11/06 20180101; C07D 401/14 20130101; A61P 17/06 20180101 |
International
Class: |
C07D 413/14 20060101
C07D413/14; C07D 401/14 20060101 C07D401/14 |
Foreign Application Data
Date |
Code |
Application Number |
May 2, 2012 |
IN |
6/KOL/2012 |
Dec 28, 2012 |
IN |
1474/KOL/2012 |
Claims
1. A compound having the Formula (I): ##STR00099## wherein, one of
A and B is N and the other is CR.sub.3; L is selected from
--C(O)NR.sub.11--, --CR.sub.aR.sub.bNR.sub.11-- and
--NR.sub.11CR.sub.aR.sub.b--; at each occurrence, R.sub.a and
R.sub.b are independently hydrogen, substituted or unsubstituted
alkyl or halogen; ring E is 5 membered non aromatic heterocyclic
ring selected from Formula (a) to (c) ##STR00100## at each
occurrence, X is selected from --C(O)--, --CR.sub.4R.sub.5-- and
--NR--; at each occurrence, Y is --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.9 and --C(O)R.sub.8; 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,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkoxy, --NR.sub.6R.sub.7, --NHC(O)R.sub.8, and
--C(O)OR.sub.9; or any two of adjacent R.sub.1 groups together with
the phenyl to which they are attached form substituted or
unsubstituted naphthalene ring; R.sub.2 is selected from halogen,
cyano, nitro, hydroxyl, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkoxy, --NR.sub.6R.sub.7, --NHC(O)R.sub.8, and
--C(O)OR.sub.9; R.sub.3 is selected from hydrogen, halogen, cyano,
nitro, hydroxyl, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, substituted or unsubstituted alkoxy,
substituted or unsubstituted haloalkoxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkoxy,
--NR.sub.6R.sub.7, --NHC(O)R.sub.8, and --C(O)OR.sub.9; 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.9, --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 selected
from substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, and
substituted or unsubstituted aryl; R.sub.9, which may be same or
different at each occurrence, is independently selected from
hydrogen, substituted or unsubstituted alkyl 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; at each
occurrence, R.sub.11 is independently hydrogen or substituted or
unsubstituted alkyl; and n is an integer ranging from 0 to 4, both
inclusive; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, having the Formula (II): ##STR00101##
or a pharmaceutically acceptable salt thereof; wherein ring E,
R.sub.1, R.sub.2, R.sub.3, L and `n` are as defined in claim-1.
3. The compound of claim 1, having the Formula-(III): ##STR00102##
or a pharmaceutically acceptable salt thereof; wherein ring E,
R.sub.1, R.sub.2, R.sub.3, L and `n` are as defined in claim-1.
4. The compound of claim 1, wherein ring E is selected from (a) to
(c) ##STR00103## wherein R, X and Y as defined in claim-1, and or a
pharmaceutically acceptable salt thereof.
5. The compound of claim 1, wherein L is selected from
--C(O)NR.sub.11--, --NR.sub.11C(O)-- and
--NR.sub.11CR.sub.aR.sub.b-- wherein R.sub.11, R.sub.a and R.sub.b
are independently a hydrogen or substituted or unsubstituted
alkyl.
6. The compound of claim 1, wherein R.sub.1 is same or different
and are 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; and `n` is 0, 1, 2, or 3.
7. 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 and
substituted or unsubstituted cycloalkyl.
8. The compound of claim 1, wherein R.sub.3 is selected from
hydrogen, halogen, cyano, nitro, hydroxyl, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted alkoxy and substituted or
unsubstituted cycloalkyl.
9. The compound of claim 1, wherein one of A and B is N and the
other is CH; L is --C(O)NH--, --NHC(O)-- or --NHCH.sub.2--; R.sub.1
is same or different and are independently selected from halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl and substituted or unsubstituted cycloalkyl; `n` is 0, 1,
2, or 3; R.sub.2 is halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl or substituted or
unsubstituted cycloalkyl; R.sub.3 is selected from hydrogen,
halogen or substituted or unsubstituted alkyl; and ring E is
selected from ##STR00104##
10. The compound of claim 1, which is selected from:
2,6-Difluoro-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3--
(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
2-Fluoro-6-methyl-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-y-
l)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
5-(3-Cyclopropyl-1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-1H-pyrazol-
-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
N-(6-(3-(Difluoromethyl)-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2--
yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;
5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(fluoromethyl)-1H-pyra-
zol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one; Methyl
3-(1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-p-
yrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate; Methyl
3-(1-(5-((2-chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-
-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;
2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5--
(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
2-Chloro-6-fluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-y-
l)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
2-Fluoro-6-methyl-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-y-
l)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
N-(6-(5-(Difluoromethyl)-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2--
yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;
5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(difluoromethyl)-1H-py-
razol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-3-(difluoromethyl)-1H-py-
razol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
N-(6-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-
-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;
2-Chloro-N-(6-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluo-
romethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-6-fluorobenzamide;
2,6-Difluoro-N-(6-(1',4',4'-trimethyl-5'-oxo-5-(trifluoromethyl)-4',5'-di-
hydro-1H,1'H-[3,3'-bipyrazol]-1-yl)pyridin-3-yl)benzamide;
2-Chloro-6-fluoro-N-(6-(1',4',4'-trimethyl-5'-oxo-5-(trifluoromethyl)-4',-
5'-dihydro-1H,1'H-[3,3'-bipyrazol]-1-yl)pyridin-3-yl)benzamide;
2-Fluoro-6-methyl-N-(6-(1',4',4'-trimethyl-5'-oxo-5-(trifluoromethyl)-4',-
5'-dihydro-1H,1'H-[3,3'-bipyrazol]-1-yl)pyridin-3-yl)benzamide;
2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-5--
(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
N-(6-(3-(4-Acetyl-5,5-dimethyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifl-
uoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;
N-(6-(3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-1H-pyra-
zol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;
5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-p-
yrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
5-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-
-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
1'-(5-(2,6-Difluorobenzyl)amino)pyridin-2-yl)-1,4,4-trimethyl-5'-(trifluo-
romethyl)-1H,1'H-[3,3'-bipyrazol]-5(4H)-one;
1'-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-1,4,4-trimethyl-5
(trifluoromethyl)-1H, 1'H-[3,3'-bipyrazol]-5(4H)-one;
3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-p-
yrazol-3-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one;
1-(5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1-
H-pyrazol-3-yl)-2,2-dimethyl-1,3,4-oxadiazol-3 (2H)-yl)ethanone;
N-(2,6-Difluorobenzyl)-6-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trif-
luoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine;
N-(6-(5-Cyclopropyl-3-(4-methyl-5-oxo-4,
5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluor-
obenzamide; N-(6-(3-Cyclopropyl-5-(4-methyl-5-oxo-4,
5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluor-
obenzamide;
2,6-Difluoro-N-(6-(5-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-
-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-methyl-1H-pyrazol-3-yl-
)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
(3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H--
pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol;
(3-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl-
)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol;
Methyl
3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyraz-
ol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;
2,6-Difluoro-N-(6-(3-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl-
)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;
3-(1-(5-(2,
6-Difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5--
methyl-4, 5-dihydroisoxazole-5-carboxamide; 2,
6-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(t-
rifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2-Chloro-6-fluoro-N-(5-(3-(4-methyl-5-oxo-4,
5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyrid-
in-2-yl)benzamide;
2-Fluoro-6-methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-y-
l)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2-Fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(tri-
fluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2,3-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5--
(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2,4,5-Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-
-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2,3,4-Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-
-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2,4-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5--
(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2,3-Dimethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5--
(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2-Chloro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(tri-
fluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
2-Methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(tri-
fluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
4-Ethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trif-
luoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;
N-(5-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromet-
hyl)-1H-pyrazol-1-yl)pyridin-2-yl)-2-naphthamide;
5-(1-(6-((2,6-Difluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-p-
yrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
5-(1-(6-((2-Chloro-6-fluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-
-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
5-(1-(6-((2-Fluoro-6-methylbenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-
-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;
N-(2,6-Difluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-
-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide and
N-(2-Chloro-6-fluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadia-
zol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide or
pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising one or more compounds
of Formula (I) according to claim 1 and one or more
pharmaceutically acceptable excipients.
12. 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.
13. The method of claim 12, 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.
14. The method of claim 12, wherein the disease is rheumatoid
arthritis, multiple sclerosis and psoriasis.
15. The method of claim 12, wherein the disease is allergic
disorders selected from asthma, chronic obstructive pulmonary
disorder (COPD) or respiratory disorders.
16. The method of claim 13, 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.
17. A process for the preparation of a compound of Formula (IIa):
##STR00105## wherein L is --NR.sub.11C(O)-- or
NR.sub.11CR.sub.aR.sub.b; ring E, A, B, R.sub.a, R.sub.b, R.sub.1,
R.sub.2, R.sub.3, R.sub.11 and `n` are as described herein above;
the process comprising the steps: a) oxidizing a compound of
Formula (10) where X is halogen, NO.sub.2, COOR' where R' is H,
alkyl etc., by using suitable oxidation agents to give compound of
Formula (11) in suitable solvent(s); ##STR00106## b) converting a
acid compound of Formula (11) to cyclized compound of compound of
Formula (12) by following acid ester formation then heterocyclic
ring formation using hydrazine hydrate followed by triphosgene
##STR00107## c) coupling of compound Formula (12) where X' is
halogen, with compound of Formula (6) where L' is C(O) or
CR.sub.aR.sub.b where R.sub.a, R.sub.b and R.sub.11 are hydrogen or
alkyl, to give compound of Formula (IIa) by using suitable reagents
and suitable solvent. ##STR00108##
18. The process for the preparation of compound claim 17, having
the Formula (IIa): ##STR00109## wherein L is --NR.sub.11C(O)-- or
NR.sub.11CR.sub.aR.sub.b; ring E, A, B, R.sub.a, R.sub.b, R.sub.1,
R.sub.2, R.sub.3, R.sub.11 and `n` are as described herein above;
the process comprising the steps: a) reducing a nitro group in
compound of Formula (12) where X' is NO.sub.2, by using suitable
reducing agent to give amino compound of Formula (13) where
R.sub.11 is hydrogen, in suitable solvent ##STR00110## b) coupling
of compound of Formula (13) with compound of Formula (8) by using
suitable amide coupling reagents or suitable reductive amidation
reagents to give compound of Formula (IIa) ##STR00111##
19. A process for the preparation of a compound of Formula (IIb):
##STR00112## wherein ring E, A, B, R.sub.1, R.sub.2, R.sub.3,
R.sub.11 and `n` are as described herein above; amide coupling of
compound Formula (12) where X' is COOR' where R' is H, alkyl etc.,
with compound of Formula (5a) to give compound of Formula (IIb) by
using suitable amide coupling methods ##STR00113##
Description
RELATED APPLICATIONS
[0001] The present application claims the benefit of priority to
Indian Provisional Patent Application No. 0006/KOL/2012, filed on
May 2, 2012 and 1474/KOL/2012, filed on Dec. 28, 2012. The entire
provisional specifications are incorporated herein by
reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The invention relates to substituted pyrazole 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
benefitted 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##
wherein, [0013] one of A and B is N and the other is CR.sub.3;
[0014] L is selected from --C(O)NR.sub.11--,
--CR.sub.aR.sub.bNR.sub.11-- and --NR.sub.11CR.sub.aR.sub.b--;
[0015] at each occurrence, R.sub.a and R.sub.b are independently
hydrogen, substituted or unsubstituted alkyl or halogen; [0016]
ring E is 5 membered non aromatic heterocyclic ring selected from
Formula (a) to (c)
[0016] ##STR00003## [0017] at each occurrence, X is selected from
--C(O)--, --CR.sub.4R.sub.5-- and --NR--; [0018] at each
occurrence, Y is --C(O)-- or --CR.sub.4R.sub.5--; [0019] provided
that both of X and Y are not simultaneously --C(O)--; [0020] 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.9 and --C(O)R.sub.8; [0021] 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,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkoxy, --NR.sub.6R.sub.7, --NHC(O)R.sub.8, and
--C(O)OR.sub.9; or any two of adjacent R.sub.1 groups together with
the phenyl to which they are attached form substituted or
unsubstituted naphthalene ring; [0022] R.sub.2 is selected from
halogen, cyano, nitro, hydroxyl, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkoxy, --NR.sub.6R.sub.7, --NHC(O)R.sub.8, and
--C(O)OR.sub.9; [0023] R.sub.3 is selected from hydrogen, halogen,
cyano, nitro, hydroxyl, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl, substituted or
unsubstituted alkoxy, substituted or unsubstituted haloalkoxy,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkoxy, --NR.sub.6R.sub.7, --NHC(O)R.sub.8, and
--C(O)OR.sub.9; [0024] 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.9,
--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; [0025] 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; [0026] R.sub.8, which may be same or
different at each occurrence, is independently selected from
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted cycloalkyl, and substituted
or unsubstituted aryl; [0027] R.sub.9, which may be same or
different at each occurrence, is independently selected from
hydrogen, substituted or unsubstituted alkyl and substituted or
unsubstituted aryl; [0028] 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; [0029] at each occurrence, R.sub.11 is independently
hydrogen or substituted or unsubstituted alkyl; and [0030] n is an
integer ranging from 0 to 4, both inclusive; [0031] or a
pharmaceutically acceptable salt thereof. [0032] According to one
embodiment, there are provided compounds having the Formula
(II):
[0032] ##STR00004## [0033] or a pharmaceutically acceptable salt
thereof; [0034] wherein ring E, R.sub.1, R.sub.2, R.sub.3, L and
`n` are as defined herein above. [0035] According to another
embodiment, there are provided compounds having Formula (III):
[0035] ##STR00005## [0036] or a pharmaceutically acceptable salt
thereof; [0037] wherein ring E, R.sub.1, R.sub.2, R.sub.3, L and
`n` are as defined herein above.
[0038] 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.
[0039] 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. [0040] According to one embodiment there are provided a
compound of Formula (I) wherein ring
##STR00006##
[0040] is selected from Formula (i) to (iv)
##STR00007## [0041] where R, R.sub.4, R.sub.5 and R.sub.10 are as
defined herein above. [0042] According to another embodiment there
are provided a compound of Formula (I) wherein ring
##STR00008##
[0042] is selected from Formula (v) to (vii)
##STR00009## [0043] where R, R.sub.4, and R.sub.5 are as defined
herein above. [0044] According to one embodiment there are provided
a compound of Formula (I) wherein ring
##STR00010##
[0044] is selected from Formula (viii) to (x)
##STR00011## [0045] where R, R.sub.4, and R.sub.5 are as defined
herein above.
[0046] According to another embodiment are provided compounds of
Formula (I), (II) and/or (III) in which L is selected from
--C(O)NR.sub.11--, --NR.sub.11C(O)-- and
--NR.sub.11CR.sub.aR.sub.b-- wherein R.sub.11, R.sub.a and R.sub.b
are independently a hydrogen or substituted or unsubstituted
alkyl.
[0047] According to another embodiment are provided compounds of
Formula (I), (II) and/or (III) in which R.sub.1 is same or
different and are 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; and `n` is 0, 1, 2, or 3.
[0048] According to another embodiment are provided compounds of
Formula (I), (II) and/or (III) 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 and
substituted or unsubstituted cycloalkyl.
[0049] According to another embodiment are provided compounds of
Formula (I), (II) and/or (III) in which R.sub.3 is selected from
hydrogen, halogen, cyano, nitro, hydroxyl, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted alkoxy and substituted or
unsubstituted cycloalkyl.
[0050] According to another embodiment are provided compounds of
Formula (I) in which one of A and B is N and the other is CH; L is
--C(O)NH--, --NHC(O)-- or --NHCH.sub.2--; R.sub.1 is same or
different and are independently selected from halogen, substituted
or unsubstituted alkyl, substituted or unsubstituted haloalkyl and
substituted or unsubstituted cycloalkyl; `n` is 0, 1, 2, or 3;
R.sub.2 is halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted haloalkyl or substituted or unsubstituted
cycloalkyl; R.sub.3 is selected from hydrogen, halogen or
substituted or unsubstituted alkyl; and ring E is selected from
##STR00012##
[0051] In another aspect, the invention provides a pharmaceutical
composition comprising at least one compound of Formula (I) and at
least one pharmaceutically acceptable excipient.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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.
[0056] In another aspect, there are provided processes for the
preparation of compounds of Formula (IIa):
##STR00013## [0057] wherein L is --NR.sub.11C(O)-- or
NR.sub.11CR.sub.aR.sub.b; [0058] ring E, A, B, R.sub.a, R.sub.b,
R.sub.1, R.sub.2, R.sub.3, R.sub.11 and `n` are as described herein
above; the process comprising the steps: [0059] a) oxidizing a
compound of Formula (10) where X' is halogen, NO.sub.2, COOR' where
R' is H, alkyl etc., by using suitable oxidation agents to give
compound of Formula (11) in suitable solvent(s);
[0059] ##STR00014## [0060] b) converting a acid compound of Formula
(11) to cyclized compound of compound of Formula (12) by following
acid ester formation then heterocyclic ring formation using
hydrazine hydrate followed by triphosgene
[0060] ##STR00015## [0061] c) coupling of compound Formula (12)
where X' is halogen, with compound of Formula (6) where L' is C(O)
or CR.sub.aR.sub.b where R.sub.a, R.sub.b and R.sub.11 are hydrogen
or alkyl, to give compound of Formula (IIa) by using suitable
reagents and suitable solvent.
##STR00016##
[0062] In another aspect, there are provided processes for the
preparation of compounds of Formula (IIb):
##STR00017## [0063] wherein ring E, A, B, R.sub.1, R.sub.2,
R.sub.3, R.sub.11 and `n` are as described herein above; amide
coupling of compound Formula (12) where X' is COOR' where R' is H,
alkyl etc., with compound of Formula (5a) to give compound of
Formula (IIb) by using suitable amide coupling methods
##STR00018##
[0064] In another aspect, there are provided processes for the
preparation of compounds of Formula (IIa):
##STR00019## [0065] wherein L is --NR.sub.11C(O)-- or
NR.sub.11CR.sub.aR.sub.b; [0066] ring E, A, B, R.sub.a, R.sub.b,
R.sub.1, R.sub.2, R.sub.3, R.sub.11 and `n` are as described herein
above; [0067] the process comprising the steps: [0068] a) reducing
a nitro group in compound of Formula (12) where X' is NO.sub.2, by
using suitable reducing agent to give amino compound of Formula
(13) where R.sub.11 is hydrogen, in suitable solvent
[0068] ##STR00020## [0069] b) coupling of compound of Formula (13)
with compound of Formula (8) by using suitable amide coupling
reagents or suitable reductive amidation reagents to give compound
of Formula (IIa)
##STR00021##
[0069] DETAILED DESCRIPTION OF THE INVENTION
Definitions and Abbreviations
[0070] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below.
[0071] 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.
[0072] The terms "halogen" or "halo" means fluorine, chlorine,
bromine, or iodine.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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.
[0078] 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.
[0079] 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.
[0080] The term "cycloalkyl" refers to a non-aromatic mono or
multicyclic ring system having 3 to 12 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Examples of multicyclic cycloalkyl groups include, but are not
limited to, perhydronapththyl, adamantyl and norbornyl groups,
bridged cyclic groups or spirobicyclic groups, e.g.,
spiro(4,4)non-2-yl and the like. Unless set forth or recited to the
contrary, all cycloalkyl groups described or claimed herein may be
substituted or unsubstituted.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] 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.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] A "3-12 membered cyclic ring" as used herein refers to a
monocyclic, bicyclic, polycyclic heteroaryl or heterocyclic ring
systems. Thease heteroaryl or heterocyclic ring as described
herein.
[0090] 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. 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] 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).
[0097] 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.
[0098] 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.
[0099] The term "subject" includes mammals, preferably humans and
other animals, such as domestic animals; e.g., household pets
including cats and dogs.
[0100] 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.
[0101] Unless otherwise stated, in the present application
"protecting group" refers to the groups intended to protect an
otherwise labile group, e.g., an amino group, a carboxy group and
the like, under specific reaction conditions. Various protecting
groups alongwith the methods of protection and deprotection are
generally known to a person of ordinary skilled in the art.
Incorporated herein in this regard as reference is Greene's
Protective Groups in Organic Synthesis, 4th Edition, John Wiley
& Sons, New York. In the present invention, preferred amino
protecting groups are t-butoxycarbonyl, benzyloxycarbonyl, acetyl
and the like; while preferred carboxy protecting groups are esters,
amides and the like.
[0102] Pharmaceutically Acceptable Salts:
[0103] 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.
[0104] 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
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] 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.
[0110] The pharmaceutical compositions may be administered in
conventional forms, for example, capsules, tablets, aerosols,
solutions, suspensions or products for topical application.
[0111] 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).
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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
[0116] 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.
[0117] 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.
[0118] 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.
[0119] The inflammatory bowel diseases also include Crohn's
disease, ulcerative colitis, indeterminate colitis, necrotizing
enterocolitis, and infectious colitis.
[0120] "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.
[0121] 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.
[0122] 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.
[0123] The compounds of this invention can be used to treat
subjects with immune disorders. As used herein, the term "immune
disorder" and like terms mean a disease, disorder or condition
caused by dysfunction or malfunction of the immune system as a
whole or any of its components including autoimmune disorders. Such
disorders can be congenital or acquired and may be characterized by
the component(s) of the immune system getting affected or by the
immune system or its components getting overactive. Immune
disorders include those diseases, disorders or conditions seen in
animals (including humans) that have an immune component and those
that arise substantially or entirely due to immune system-mediated
mechanisms. In addition, other immune system mediated diseases,
such as graft-versus-host disease and allergic disorders, will be
included in the definition of immune disorders herein. Because a
number of immune disorders are caused by inflammation or lead to
inflammation, there is some overlap between disorders that are
considered immune disorders and inflammatory disorders. For the
purpose of this invention, in the case of such an overlapping
disorder, it may be considered either an immune disorder or an
inflammatory disorder. An autoimmune disorder is a condition that
occurs when the immune system mistakenly attacks and destroys its
own body cells, tissues and/or organs. This may result in temporary
or permanent destruction of one or more types of body tissue,
abnormal growth of an organ, changes in organ function, etc. For
example, there is destruction of insulin producing cells of the
pancreas in Type 1 diabetes mellitus. Different autoimmune
disorders can target different tissues, organs or systems in an
animal while some autoimmune disorders target different tissues,
organs or systems in different animals. For example, the autoimmune
reaction is directed against the gastrointestinal tract in
Ulcerative colitis and the nervous system in multiple sclerosis
whereas in systemic lupus erythematosus (lupus), affected tissues
and organs may vary among individuals with the same disease. For
example, one person with lupus may have affected skin and joints
whereas another may have affected kidney, skin and lungs.
[0124] 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).
[0125] "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.
[0126] In another embodiment, the invention is directed to the
treatment of cancer by administering an effective amount of a
compound of the present invention.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] "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.
[0133] 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.
[0134] 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.
[0135] Under normal circumstances, when the endothelial cells
lining blood vessels are breached, platelets interact with von
Willebrand factor (vWF) via the membrane glycoprotein 1b complex to
help seal the breach. Glycoprotein 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).
[0136] 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.
[0137] "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
[0138] 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 A, B, L, R.sub.1, R.sub.2, R.sub.3, ring E and `n` are as
defined herein above. Starting materials are commercially available
or may be prepared by the procedures described herein or by the
procedures known in the art. Furthermore, in the following
synthetic schemes, where specific acids, bases, reagents, coupling
agents, solvents, etc., are mentioned, it is understood that other
bases, acids, reagents, coupling agents, solvents etc., known in
the art may also be used and are therefore included within the
scope of the present invention. Variations in reaction conditions
and parameters like temperature, pressure, duration of reaction,
etc., which may be used as known in the art are also within the
scope of the present invention. All the isomers of the compounds
described in these schemes, unless otherwise specified, are also
encompassed within the scope of this invention.
[0139] The compounds obtained by using the general reaction
sequences may be of insufficient purity. These compounds can be
purified by using any of the methods for purification of organic
compounds known in the art, for example, crystallization or silica
gel or alumina column chromatography using different solvents in
suitable ratios. Unless mentioned otherwise, room temperature (RT)
refers to a temperature in the range of 22 to 27.degree. C.
[0140] .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 nomenclature for the compounds of the
present invention was used according to ChemBioDraw Ultra 12.0
software.
##STR00022##
[0141] As depicted in synthetic Scheme-1, the synthesis of
compounds of the Formula (5), that served as precursor(s) of the
compounds of the invention (Ia) wherein A, B, R.sub.1, R.sub.2,
R.sub.3, ring E and `n` are as defined herein above, began with
cyclocondensation of hydrazine derivative(s) of the Formula (1)
with appropriately substituted 2,4-diones of the Formula (2) to
provide the pyrazole compounds of the Formula (3). Condensations of
this type typically afford compounds of the Formula (3) in a
regioselective manner as known in the art by using an acid catalyst
such as p-toluenesulfonic acid, hydrochloric acid, sulfuric acid
etc., and in suitable solvent. Compounds of the Formula (3)
undergoes oxidation reaction with suitable oxidants such as
potassium permanganate, ozone, sodium metaperiodate, ruthenium
chloride and the like; afforded compounds of the Formula (4). This
compound of the Formula (4) is further transformed to compounds of
the Formula (5) by following the procedure known in the art.
[0142] Compounds of the Formula (Ia) prepared by coupling of
halogen derivatives of the Formula (5) with amide/amine derivatives
of the Formula (6) in presence of suitable reagent and solvent.
[0143] Alternatively, nitro derivatives of the Formula (5) where X'
is nitro group; are transformed to amine derivatives of the Formula
(7) with hydrogen gas in the presence of metal catalysts known in
the art such as palladium on carbon, palladium hydroxide and the
like; Finally, compound of the Formula (7) is coupled with compound
of Formula (8) by reductive amination as per the methods known in
the art to obtain amino compound of Formula (Ia) where L is
NR.sub.11CR.sub.aR.sub.b. Compound of Formula (7) can also
converted to compound of Formula (Ia) where L is an amide linker,
by following suitable amide coupling reaction with compound of
Formula (8).
[0144] Alternatively, carboxylate derivatives of the Formula (5) is
coupled with amino compound of Formula (5a) to give compounds of
the Formula (Ib) where L is C(O)NR.sub.11.
##STR00023##
[0145] As described in synthetic Scheme-2, cyclocondensation of
hydrazine compound of the Formula (1) with appropriately
substituted enol ether(s) of the Formula (9) to provide the
pyrazole compound of the Formula (10) regioselectively (Synthesis,
2005, 16, 2744). The pyrazole compound of the Formula (10) is
converted to acid compound which further converted to compound of
Formula (12) by following the methods as described in the synthetic
Scheme-1. Finally compound of the Formula (IIa) where L is
--NR.sub.11C(O)-- or --NR.sub.11CR.sub.aR.sub.b-- or Formula (IIb)
where L is C(O)NR.sub.11, obtained from compound of formula (11) by
following the suitable reaction step(s) as described in the
synthetic Scheme-1.
##STR00024##
[0146] In another approach as described in the synthetic Scheme 3,
the halogen compound of Formula (10) undergoes carboxylation to
give acid or ester compound of the Formula (14). Alternatively,
compound of the Formula (10) is reacted with metal cyanides such as
zinc cyanide, copper cyanide, sodium cyanide, potassium
ferrocyanide or mixture(s) thereof; in presence of metal catalysts
like Pd.sub.2(dba).sub.3, Pd(PPh.sub.3).sub.4; in presence of
ligands such as bis(diphenylphosphino)ferrocene,
dibenzylideneacetone, xantphos or mixture(s) thereof. The said
transformation may also be carried out by other methods known in
the art. Compounds of the Formula (15) are converted to the
compounds of the Formula (16) and in turn to the compounds of the
invention of the Formula (I %) wherein A, B, R.sub.1, R.sub.2,
R.sub.3, ring E and `n` are as defined herein above, by following
the methods known in the art or as described in synthetic Scheme
1.
##STR00025##
[0147] Alternatively, as depicted in synthetic Scheme 4, compound
of the Formula (15) is converted to compound of the Formula (17) by
following the methods known in the art. Compound of the Formula
(17) is transformed to compound of the invention of the Formula
(IIb) wherein A, B, R.sub.1, R.sub.2, R.sub.3, ring E and `n` are
as defined herein above, by reacting with compounds of the Formula
(14) by amidation by following the methods described in the
synthetic Scheme 1 or as known in the art.
Experimental
[0148] 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.
[0149] 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-1
5-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1-
,3,4-oxadiazol-2(3H)-one
##STR00026##
[0151] Step-1:
5-Bromo-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine:
A mixture of 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (7.0 g,
34.0 mmol) and 5-bromo-2-hydrazinylpyridine hydrochloride (7.62 g,
34.0 mmol) in acetic acid (20 mL) was stirred at 70.degree. C. for
1.5 h. The reaction mixture was cooled to room temperature (RT) and
then diluted with ethyl acetate (200 mL) and basified with aqueous
sodium hydroxide solution (10%, pH 7-8). The resulting slurry was
filtered and the filtrate was washed with water (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
(silica gel, 20% ethyl acetate-hexanes as eluent) to afford 10 g
(82%) of the title compound as white semisolid. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.54 (brs, 1H), 8.02 (dd, J=2.5 & 8.5
Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 6.93 (s,
1H), 6.62 (d, J=3.5 Hz, 1H), 6.47 (dd, J=3.5 & 1.5 Hz, 1H);
ESI-MS (m/z) 358, 360 [(MH).sup.+, Br.sup.79,81].
[0152] Step-2:
1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic
acid: To a stirred solution of step-1 intermediate (10 g, 27.9
mmol) in acetone: water (1:1, 200 mL) at 0.degree. C. was drop-wise
added a solution of KMnO4 (30.9 g, 195 mmol) in water (50 mL). The
resulting mixture was stirred at room temperature for 15 min and
then at 60.degree. C. for 4 h. The reaction was cooled back down to
room temperature and 2-propanol (40 mL) was added to the above
mixture and stirring was continued for another 4 h at room
temperature. The reaction was filtered through celite and the
filtrate was evaporated under reduced pressure to dryness. The
residue was dissolved in 1N aqueous sodium hydroxide solution (300
mL) and washed with ethyl acetate-hexanes (10%). The aqueous layer
was acidified with aqueous hydrochloric acid (10%, pH 4.0) and then
extracted with ethyl acetate (3.times.100 mL). The combined organic
layers were washed with brine (100 mL), dried (Na.sub.2SO.sub.4)
and filtered. The filtrate was concentrated under vacuum to afford
6.0 g (64%) of the title compound as a white semi solid. ESI-MS
(m/z) 336, 338 [(MH).sup.+, Br.sup.79,81].
[0153] Step-3: Ethyl
1-(5-bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate:
To a stirred solution of step-2 intermediate (6.90 g, 20.53 mmol)
in ethanol (100 mL) at room temperature was added sulfuric acid (6
mL) drop-wise and the reaction was stirred at 100.degree. C. for 18
h. The reaction was cooled to room temperature and the solvent was
evaporated under vacuum. Water (100 mL) was added to the above
obtained residue, basified with aqueous sodium carbonate solution
(10%, 30 mL) and extracted with ethyl acetate (3.times.100 mL). The
combined organic layers were washed with water (100 mL), brine (100
mL), dried (Na.sub.2SO.sub.4) and filtered. The filtrate was
concentrated under vacuum to afford 6.0 g (80%) of the title
compound as a white semi-solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 8.72 (d, J=2.5 Hz, 1H), 8.38 (dd, J=2.5 & 8.5 Hz, 1H),
7.83 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 4.25 (q, J=7.0 Hz, 2H), 1.16
(t, J=7.0 Hz, 3H); ESI-MS (m/z) 364, 366 [(MH).sup.+,
Br.sup.79,81].
[0154] Step-4:
1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carbohydrazide:
A mixture of step-3 intermediate (6.0 g, 16.48 mmol) and hydrazine
hydrate (2.59 mL, 82 mmol) in ethanol (100 mL) was stirred at
100.degree. C. overnight. Reaction mixture was cooled down to room
temperature and the solvent was evaporated under vacuum. The
residue was triturated with toluene to obtain 4.0 g (70%) of title
compound as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 9.99 (s, 1H, D.sub.2O exchangeable), 8.64 (d, J=2.5 Hz,
1H), 8.30 (dd, J=2.5 & 8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H),
7.30 (s, 1H), 4.55 (brs, 2H, D.sub.2O exchangeable); ESI-MS (m/z)
350, 352 [(MH).sup.+, Br.sup.79,81].
[0155] Step-5:
5-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3,4-oxa-
diazol-2(3H)-one: To a stirred and (0.degree. C.) cooled solution
of step-4 intermediate (4.0 g, 11.43 mmol) and DIPEA (3.99 mL,
22.85 mmol) in DCM (50 mL) was added a solution of triphosgene
(1.35 g, 4.57 mmol) in DCM (20 mL) over a period of 10 min.
Reaction mixture was warmed to room temperature and stirred
overnight. The reaction was cooled to 0.degree. C. and quenched
with ice water (5 mL). Water (25 mL) was added to the above mixture
followed by DCM (100 mL). The layers were separated and the aqueous
layer was extracted with DCM (2.times.100 mL). The combined organic
layers were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was rotary evaporated to afford 3.0 g (70%)
of the title compound as pink semisolid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 12.95 (s, 1H, D.sub.2O exchangeable), 8.71
(d, J=2.5 Hz, 1H), 8.39 (dd, J=2.5 & 8.5 Hz, 1H), 7.90 (d,
J=8.5 Hz, 1H), 7.70 (s, 1H); ESI-MS (m/z) 376, 378 [(MH).sup.+,
Br.sup.79,81].
[0156] Step-6:
5-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-methyl--
1,3,4-oxadiazol-2(3H)-one: To a (0.degree. C.) cooled and stirred
solution of step-5 intermediate (3.0 g, 7.98 mmol) in DMF (25 mL)
was added potassium carbonate (1.0 g, 7.18 mmol) and methyl iodide
(0.50 mL, 7.98 mmol) and the reaction was stirred at room
temperature for 18 h. Ice cooled water (10 mL) was then added to
the above reaction mixture and the separated solid was filtered and
dried to afford 2.50 g (80%) of the desired product as a white
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.47 (d, J=2.0 Hz,
1H), 8.05 (dd, J=2.0 & 8.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H),
7.12 (s, 1H), 3.51 (s, 3H); ESI-MS (m/z) 390, 392 [(MH).sup.+,
Br.sup.79,81].
Intermediate-2
5-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1-
,3,4-oxadiazol-2(3H)-one
##STR00027##
[0158] Step-1:
1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
-pyrazol-5-ol: To a stirred solution of
1,1,1-trifluoro-4-(furan-2-yl)-4-methoxybut-3-en-2-one (129 g, 585
mmol; prepared by following the procedure described in Tett Lett.,
2002, 43, 8701) in chloroform (600 mL) was added solid
5-bromo-2-hydrazinylpyridine (prepared by the reaction of
2,5-dibromopyridine with hydrazine hydrate, 110.0 g, 585 mmol) in
10 portions at 0.degree. C. over a period of 30 min. The reaction
was stirred for 1 h at room temperature, and then at 50.degree. C.
for 36 h. The reaction was cooled to 0.degree. C. before the
addition of water (200 mL) and chloroform (500 mL). The layers were
separated and the aqueous layer was extracted with chloroform
(3.times.200 mL). The combined organic layers were washed with
brine (200 mL), dried (Na.sub.2SO.sub.4) and filtered. The filtrate
was rotary evaporated and the crude product was purified by flash
column chromatography (5% ethyl acetate-hexanes system as eluent)
to afford 90 g (40%) of the title compound as a white solid.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.17 (d, J=2.5 Hz, 1H),
7.96 (s, 1H, D.sub.2O Exchangeable), 7.75 (dd, J=2.5 & 8.5 Hz,
1H), 7.56 (d, J=1.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 6.76 (d, J=2.5
Hz, 1H), 6.54 (dd, J=1.5 & 2.5 Hz, 1H), 3.71 (d, J=18.5 Hz,
1H), 3.56 (d, J=18.5 Hz, 1H); ESI-MS (m/z) 376, 378 [(MH).sup.+,
Br.sup.79,81].
[0159] Step-2:
5-Bromo-2-(3-(furan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)
pyridine: To a (5.degree. C.) cooled solution of step-1
intermediate (80 g, 213 mmol) in benzene (600 mL) was added
SOCl.sub.2 (38.8 mL, 532 mmol). After stirring for 15 min at
5.degree. C., pyridine (51.6 mL, 638 mmol) was added at the same
temperature and the reaction was continued to stir for another 15
min. Ice cooled water (100 mL) was then added to the above reaction
mixture followed by ethyl acetate (300 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate
(2.times.200 mL). The combined organic layers were washed with
saturated aqueous NaHCO.sub.3 (300 mL), brine (200 mL), dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated
under vacuum to afford 70 g (92%) of the title compound as white
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.55 (d, J=1.5 Hz,
1H), 7.97 (dd, J=2.0 & 8.5 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H),
7.53 (d, J=1.5 Hz, 1H), 7.11 (s, 1H), 6.84 (d, J=3.0 Hz, 1H), 6.53
(dd, J=3.0 & 1.5 Hz, 1H); ESI-MS (m/z) 358, 360 [(MH).sup.+,
Br.sup.79,81].
[0160] Step-3:
Ethyl-1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxyla-
te: The title compound was prepared by following the similar
procedure described for step-3 of Intermediate-1 using above step-2
intermediate. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.59 (d,
J=2.5 Hz, 1H), 8.03 (dd, J=2.5 & 8.5 Hz, 1H), 7.87 (d, J=8.5
Hz, 1H), 7.37 (s, 1H), 4.46 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz,
3H); ESI-MS (m/z) 364, 366 [(MH).sup.+, Br.sup.79,81].
[0161] Step-4:
5-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl--
1,3,4-oxadiazol-2(3H)-one: The title compound was prepared by
following the similar procedure sequentially as described in
Step-4, Step-5, and Step-6 of Intermediate-1 using above step-3
intermediate. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.75 (d,
J=2.5 Hz, 1H), 8.38 (dd, J=2.5 & 8.5 Hz, 1H), 7.88 (d, J=8.5
Hz, 1H), 7.75 (s, 1H), 3.43 (s, 3H); ESI-MS (m/z) 390, 392
[(MH).sup.+, Br.sup.79,81].
Intermediate-3
6-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-
-1H-pyrazol-1-yl)nicotinic acid
##STR00028##
[0163] Step-1:
6-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl-
)-1H-pyrazol-1-yl)nicotinonitrile: In a sealed tube containing a
suspension of Intermediate-2 (1.0 g, 2.56 mmol), dicyanozinc (0.90
g, 7.69 mmol) in dioxane (8 mL) was purged nitrogen gas for 30 min
and, tetrakis(triphenylphosphine)palladium(0) (296 mg, 0.256 mmol)
was added. The resulting mixture was thoroughly deoxygenated by
purging nitrogen gas and the sealed tube was capped and stirred at
110.degree. C. for 5 h. The reaction mixture was cooled back down
to room temperature and ammonium hydroxide solution (1.0 mL) was
added followed by water (10 mL) and then diluted with 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 saturated aqueous NaHCO.sub.3 (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 (20% ethyl acetate-hexanes as eluent) to afford 850
mg (99%) of the title compound as white solid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 9.10 (d, J=2.5 Hz, 1H), 8.62 (dd, J=2.5 &
8.5 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 3.44 (s, 3H);
ESI-MS (m/z) 337 (MH).sup.+.
[0164] Step-2:
5-6-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluorometh-
yl)-1H-pyrazol-1-yl)nicotinic acid: In a sealed tube containing a
solution of
6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromet-
hyl)-1H-pyrazol-1-yl)nicotinonitrile (0.80 g, 2.37 mmol) in
methanesulfonic acid (5 mL, 77 mmol) and water (4 mL) was heated at
70.degree. C. for 6 h. The reaction mixture was then cooled to room
temperature and water (10 mL) was added to the above mixture
followed by ethyl acetate (50 mL). The layers were separated and
the aqueous layer was extracted with ethyl acetate (2.times.30 mL).
The combined organic layers were washed with saturated aqueous
NaHCO.sub.3 (30 mL), dried (Na.sub.2SO.sub.4) and filtered. The
filtrate was rotary evaporated to afford 500 mg (60%) of the title
compound as white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
13.71 (s, 1H, D.sub.2O exchangeable), 9.01 (d, J=2.5 Hz, 1H), 8.55
(dd, J=2.5 & 8.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.80 (s, 1H),
3.40 (s, 3H); ESI-MS (m/z) 356 (MH).sup.+.
Intermediate-4
3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5,5-dimeth-
ylisoxazol-4(5H)-one
##STR00029##
[0166] Step-1:
1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic
acid: The title compound was prepared from Step-2 of Intermediate-2
using potassium permanganate by following the similar procedure as
described in Step-2 of Intermediate-1. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 8.73 (d, J=2.5 Hz, 1H), 8.36 (dd, J=2.5 &
8.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.51 (s, 1H); ESI-MS (m/z)
336, 338 [(M).sup.+, Br.sup.79,81].
[0167] Step-2:
3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5,5-dimet-
hyl isoxazol-4(5H)-one: The title compound was prepared from
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic
acid by following the analogues procedure as described in
WO2012056748. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.60 (d,
J=2.5 Hz, 1H), 8.02 (dd, J=2.5 & 8.5 Hz, 1H), 7.92 (d, J=8.5
Hz, 1H), 7.52 (s, 1H), 1.53 (s, 6H); ESI-MS (m/z) 403, 405
[(MH).sup.+, Br.sup.79,81].
Intermediate-5
1'-(5-Bromopyridin-2-yl)-1,4,4-trimethyl-5'-(trifluoromethyl)-1H,1'H-[3,3'-
-bipyrazol]-5(4H)-one
##STR00030##
[0169] Step-1: Ethyl
3-(1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimet-
hyl-3-oxopropanoate: To (0.degree. C.) cooled and stirred solution
of
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic
acid (6.0 g, 17.85 mmol) in DCM (30 mL) was added oxalyl chloride
(4.69 mL, 53.6 mmol) followed by catalytic amount of DMF (0.14 mL,
1.78 mmol). The resulting mixture was warmed to room temperature
and then stirred for 1 h. Reaction mass was concentrated under
vacuum and the crude product was dried under vacuum.
[0170] To a freshly prepared solution of lithium diisopropyl amide
(prepared by the addition of n-butyl lithium (12.27 mL, 19.63 mmol)
to a solution of diisopropylamine (2.80 mL, 19.63 mmol) in THF (20
mL)) at -78.degree. C., was drop-wise added a solution of ethyl
isobutyrate (2.21 mL, 16.36 mmol) in THF (10 mL). The resulting
mixture was stirred at the same temperature for 1 h and then the
above prepared solution of
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbonyl
chloride (5.80 g, 16.36 mmol) in THF (20 mL) was drop-wise added.
The resulting mixture was stirred at -78.degree. C. for 30 min,
then gradually warmed to room temperature over 1 h and then stirred
for another 1 h at room temperature. The reaction was cooled to
0.degree. C. and then quenched with saturated ammonium chloride
solution (20 mL) and then diluted with ethyl acetate (100 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 rotary evaporated and the crude product was
purified by flash column chromatography (10% ethyl acetate in
hexanes as eluent) to afford 2.50 g (35%) of the title compound as
a white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.58 (d,
J=2.0 Hz, 1H), 8.02 (dd, J=2.0 & 8.0 Hz, 1H), 7.73 (d, J=8.0
Hz, 1H), 7.39 (s, 1H), 4.11 (q, J=7.0 Hz, 2H), 1.60 (s, 3H), 1.58
(s, 3H), 1.04 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 434, 436 [(MH).sup.+
Br.sup.79,81].
[0171] Step-2:
3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimet-
hyl-3-oxopropanehydrazide: A mixture of step-1 intermediate (2.40
g, 5.53 mmol) and hydrazine hydrate (0.87 mL, 27.6 mmol) in ethanol
(30 mL) was heated at 80.degree. C. overnight. The reaction mixture
was cooled to room temperature and the solvent was then evaporated
under vacuum. The residue was triturated with toluene to obtain 2.0
g (86%) of title compound as a white solid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 11.78 (s, 1H, D.sub.2O exchangeable), 8.72
(d, J=2.0 Hz, 1H), 8.38 (dd, J=2.0 & 8.0 Hz, 1H), 7.92 (d,
J=8.0 Hz, 1H), 7.54 (s, 1H), 1.42 (s, 6H); ESI-MS (m/z) 420, 422
[(MH).sup.+, Br.sup.79,81].
[0172] Step-3:
1'-(5-Bromopyridin-2-yl)-4,4-dimethyl-5'-(trifluoromethyl)-1H,1'H-[3,3'-b-
ipyrazol]-5(4H)-one: To a stirred and (0.degree. C.) cooled
solution of step-2 intermediate (2.0 g, 4.76 mmol) and DIPEA (1.66
mL, 9.52 mmol) in DCM (20 mL) was added a solution of triphosgene
(560 mg, 1.90 mmol) in DCM (5 mL) over a period of 10 min. The
reaction mixture was warmed to room temperature and then stirred
overnight. Reaction was cooled down to 0.degree. C. and then
quenched with ice water (5 mL). Water (25 mL) was added to the
reaction followed by DCM (50 mL). The layers were separated and the
aqueous layer was extracted with DCM (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 rotary evaporated
to afford 1.50 g (78%) of the title compound as semisolid.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.85 (s, 1H, D.sub.2O
exchangeable), 8.59 (d, J=2.0 Hz, 1H), 8.02 (dd, J=2.0 & 8.0
Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 1.60 (s, 6H); ESI-MS
(m/z) 402, 404 [(MH).sup.+, Br.sup.79,81].
[0173] Step-4:
1'-(5-Bromopyridin-2-yl)-1,4,4-trimethyl-5'-(trifluoromethyl)-1H,1'H-[3,3-
'-bipyrazol]-5(4H)-one: To a (0.degree. C.) cooled and stirred
solution of step-3 intermediate (1.50 g, 3.73 mmol) in DMF (10 mL)
was added potassium carbonate (619 mg, 4.48 mmol) and methyl iodide
(0.28 mL, 4.48 mmol) and the reaction was stirred at room
temperature for 18 h. Ice cooled water (10 mL) was added to the
above reaction mixture and the separated solid was filtered and
dried to afford 1.50 g (97%) of the desired product as a white
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.59 (d, J=2.0 Hz,
1H), 8.03 (dd, J=2.0 & 8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H),
7.32 (s, 1H), 3.44 (s, 3H), 1.55 (s, 6H); ESI-MS (m/z) 416, 418
[(MH).sup.+, Br.sup.79,81].
Intermediate-6
3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-1-
,2,4-oxadiazol-5(4H)-one
##STR00031##
[0175] Step-1:
1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide:
To a (0.degree. C.) cooled solution of
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic
acid (5.0 g, 14.88 mmol) in DCM (50 mL) was added oxalyl chloride
(3.91 mL, 44.6 mmol) followed by catalytic amount of DMF (0.14 mL,
1.78 mmol). The resulting mixture was stirred at room temperature
for 1 h. The excess of oxalyl chloride was removed under vacuum and
the residue was again diluted with DCM (100 mL). Aqueous ammonium
hydroxide solution (29.0 mL, 744 mmol) was added drop-wise to the
above mixture at 0.degree. C. and the reaction mixture was stirred
at room temperature overnight. The solvent was evaporated under
vacuum and concentrate was diluted with ethyl acetate (100 mL). 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 rotary evaporated to afford 4.0 g (80%) of the
title compound as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.73 (d, J=2.0 Hz, 1H), 8.41 (dd, J=2.0 & 8.0 Hz, 1H),
8.09 (s, 1H, D.sub.2O exchangeable), 7.97 (d, J=8.0 Hz, 1H), 7.70
(s, 1H, D.sub.2O exchangeable), 7.52 (s, 1H); ESI-MS (m/z) 335, 337
[(MH).sup.+, Br.sup.79,81].
[0176] Step-2:
1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbonitrile:
To a stirred and (0.degree. C.) cooled solution of step-1
intermediate (4.0 g, 11.94 mmol) in POCl.sub.3 (22.25 mL, 239 mmol)
was added pyridine (1.93 mL, 23.87 mmol). The resulting mixture was
warmed to room temperature and then stirred at 80.degree. C. for 3
h. The reaction was cooled to room temperature and the excess of
POCl.sub.3 was evaporated under vacuum. Water (50 mL) was added to
the above obtained residue, basified with aqueous saturated sodium
bicarbonate solution (50 mL) and extracted with ethyl acetate
(3.times.100 mL). The combined organic layers were washed with
water (50 mL), brine (50 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated under vacuum to afford 3.20
g (85%) of the title compound as a white solid. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.61 (d, J=2.0 Hz, 1H), 8.08 (dd, J=2.0
& 8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.26 (s, 1H); ESI-MS
(m/z) 317, 319 [(MH).sup.+, Br.sup.79,81].
[0177] Step-3:
1-(5-Bromopyridin-2-yl)-N-hydroxy-5-(trifluoromethyl)-1H-pyrazole-3-carbo-
ximidamide: A mixture of step-2 intermediate (150 mg, 0.473 mmol),
hydroxylamine hydrochloride (82 mg, 1.183 mmol) and
Na.sub.2CO.sub.3 (125 mg, 1.183 mmol) in ethanol (10 mL) was
stirred at 85.degree. C. for 6 h. Reaction mixture was cooled to
room temperature and the solvent was evaporated under vacuum. Water
(10 mL) was added to the obtained residue and extracted with ethyl
acetate (2.times.25 mL). The combined organic layers were washed
with water (20 mL), brine (20 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated under vacuum to afford 106
mg (64%) of the title compound as a white solid. .sup.1HNMR (400
MHz, DMSO-d.sub.6) .delta. 9.96 (s, 1H), 8.69 (d, J=2.0 Hz, 1H),
8.37 (dd, J=2.0 & 8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.23 (s,
1H), 5.93 (s, 2H); ESI-MS (m/z) 350, 352 [(MH).sup.+,
Br.sup.79,81].
[0178] Step-4:
3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxa-
diazol-5(4H)-one: To a stirred and (0.degree. C.) cooled solution
of step-3 intermediate (106 mg, 0.303 mmol) and DIPEA (0.106 mL,
0.606 mmol) in DCM (15 mL) was added drop-wise a solution of
triphosgene (35 mg, 0.121 mmol) in DCM (3 mL). The reaction was
stirred at room temperature for 1 h before quenching with ice water
(5 mL). Water (10 mL) was added to the above mixture followed by
DCM (25 mL). The layers were separated and the aqueous layer was
extracted with DCM (2.times.15 mL). The combined organic layers
were washed with brine (15 mL), dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was rotary evaporated to afford 100 mg (88%)
of the title compound as brown solid. ESI-MS (m/z) 376, 378
[(MH).sup.+, Br.sup.79,81].
[0179] Step-5:
3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl--
1,2,4-oxadiazol-5(4H)-one: To a (0.degree. C.) cooled and stirred
solution of step-4 intermediate (100 mg, 0.266 mmol) in DMF (3 mL)
was added potassium carbonate (73 mg, 0.532 mmol) and methyl iodide
(33 .mu.L, 0.532 mmol) and the reaction was stirred at room
temperature for 18 h. Ice cooled water (3 mL) was added to the
reaction and extracted with ethyl acetate (2.times.15 mL). The
combined organic layers were washed with water (3.times.10 mL),
brine (10 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 25 mg (24%) of the title compound
as white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.64 (d,
J=2.0 Hz, 1H), 8.07 (dd, J=2.0 & 8.0 Hz, 1H), 7.73 (d, J=8.0
Hz, 1H), 7.44 (s, 1H), 3.68 (s, 3H); ESI-MS (m/z) 390, 392
[(MH).sup.+, Br.sup.79,81].
Intermediate-7
1-(5-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dim-
ethyl-1,3,4-oxadiazol-3(2H)-yl)ethanone
##STR00032##
[0181] Step-1:
1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide:
A mixture of ethyl
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate
(33 g, 91 mmol) and hydrazine hydrate (17.07 mL, 544 mmol) in
ethanol (330 mL) was heated at 100.degree. C. overnight. The
reaction mixture was cooled back down to room temperature and the
solvent was evaporated under vacuum. The residue was triturated
with toluene to obtain 30 g (95%) of the title compound as a white
solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 9.97 (s, 1H,
D.sub.2O exchangeable), 8.72 (d, J=2.5 Hz, 1H), 8.40 (dd, J=2.5
& 8.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.54 (s, 1H), 4.58 (s,
2H, D.sub.2O exchangeable); ESI-MS (m/z) 350, 352 [(MH).sup.+,
Br.sup.79,81].
[0182] Step-2:
1-(5-Bromopyridin-2-yl)-N'-(propan-2-ylidene)-5-(trifluoromethyl)-1H-pyra-
zole-3-carbohydrazide: A solution of step-1 intermediate (1.0 g,
2.86 mmol) in acetone: hexane (1:1, 12 mL) was stirred at
70.degree. C. for 3 h. The reaction was then cooled to room
temperature and the solvent was evaporated under vacuum to afford
800 mg (72%) of the title compound as white solid. ESI-MS (m/z)
390, 392 [(MH).sup.+, Br.sup.79,81].
[0183] Step-3:
1-(5-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-di-
methyl-1,3,4-oxadiazol-3(2H)-yl)ethanone: A mixture of step-2
intermediate (800 mg, 2.05 mmol) and pyridine (0.33 mL, 4.1 mmol)
in acetic anhydride (8 mL) was stirred at 140.degree. C. for 3 h.
The reaction was then cooled to room temperature and the solvent
was evaporated under vacuum. The crude product was purified by
flash column chromatography (silica gel, ethyl acetate-hexanes
system as eluent) to afford 250 mg (28%) of the title compound as
white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.76 (d,
J=2.0 Hz, 1H), 8.36 (dd, J=2.0 & 8.0 Hz, 1H), 7.88 (d, J=8.0
Hz, 1H), 7.65 (s, 1H), 2.21 (s, 3H), 1.81 (s, 6H); ESI-MS (m/z)
432, 434[(MH).sup.+, Br.sup.79,81].
Intermediate-8
2-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,4-dimeth-
yl-4, 5-dihydrooxazole
##STR00033##
[0185] Step-1:
1-(5-Bromopyridin-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromet-
hyl)-1H-pyrazole-3-carboxamide: To (0.degree. C.) cooled solution
of
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic
acid (500 mg, 1.48 mmol), in DCM (20 mL) was added oxalyl chloride
(391 .mu.L, 4.46 mmol) followed by catalytic amount of DMF. The
resulting mixture was stirred at room temperature for 3 h. The
solvent and excess of oxalyl chloride was then removed under vacuum
and the resulting residue was dissloved in DCM (10 mL). A solution
of 2-amino-2-methylpropan-1-ol (0.35 mL, 3.72 mmol) in DCM (5 mL)
was then added to the above solution drop-wise at 0.degree. C. and
the resulting mixture was warmed to room temperature and then
continued stirring at the same temperature for 18 h. Water (10 mL)
was added to the above reaction followed by DCM (20 mL). The layers
were separated and the aqueous layer was extracted with DCM
(3.times.10 mL). The combined organic layers were washed with bine
(10 mL), dried (anhydrous Na.sub.2SO.sub.4) and filtered. The
filtrate was rotary evaporated and the crude product was purified
by flash column chromatography to afford 600 mg (99%) of the title
compound as white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
8.61 (d, J=2.0 Hz, 1H), 8.04 (dd, J=2.0 & 8.0 Hz, 1H), 7.75 (d,
J=8.0 Hz, 1H), 7.37 (s, 1H), 6.96 (s, 1H, D.sub.2O exchangeable),
3.73 (s, 2H), 1.44 (s, 6H); ESI-MS (m/z) 407, 409 [(MH).sup.+,
Br.sup.79,81].
[0186] Step-2:
2-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,4-dimet-
hyl-4,5-dihydrooxazole: To a stirred solution of step-1
intermediate (600 mg, 1.47 mmol) in DCM (15 mL) at room temperature
was added thionyl chloride (215 .mu.L, 2.95 mmol) drop-wise and the
resulting mixture was then stirred at room temperature for 24 h.
The reaction was then cooled to 0.degree. C., diluted with water
(20 mL) and the layers were separated. The aqueous layer was
extracted with DCM (10 mL). The combined organic layers were washed
with brine (10 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 310 mg (54%) of the title compound as
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.57 (d,
J=2.0 Hz, 1H), 8.00 (dd, J=2.0 & 8.0 Hz, 1H), 7.89 (d, J=8.0
Hz, 1H), 7.38 (s, 1H), 4.20 (s, 2H), 1.43 (s, 6H); ESI-MS (m/z)
389, 391 [(MH).sup.+, Br.sup.79,81]
Intermediate-9
5-(1-(5-Bromopyridin-2-yl)-3-cyclopropyl-1H-pyrazol-5-yl)-3-methyl-1,3,4-o-
xadiazol-2(3H)-one
##STR00034##
[0188] Step-1: Ethyl 4-cyclopropyl-2,4-dioxobutanoate: The title
compound was prepared by reacting 1-cyclopropylethanone with
diethyl oxalate by following the procedure described in
US20120115903.
[0189] Step-2: Ethyl 4-cyclopropyl-2-(methoxyimino)-4-oxobutanoate:
The title compound was prepared by reacting ethyl
4-cyclopropyl-2,4-dioxobutanoate with O-methylhydroxylamine
hydrochloride in ethanol-water (5:1) by following the procedure
described in WO2012022487.
[0190] Step-3: Ethyl
1-(5-Bromopyridin-2-yl)-3-cyclopropyl-1H-pyrazole-5-carboxylate: To
a stirred solution of ethyl
4-cyclopropyl-2-(methoxyimino)-4-oxobutanoate (420 mg, 1.97 mmol)
in acetic acid:2-methoxyethanol (6 mL, 2:1) was added
5-bromo-2-hydrazinylpyridine (370 mg, 1.97 mmol) at room
temperature. The resulting mixture was refluxed for 3 h. The
reaction mixture was cooled to room temperature and the solvent was
evaporated under vacuum. The crude product was purified by flash
column chromatography (silica gel, ethyl acetate-hexanes system) to
afford 220 mg (33%) of the title compound as pale yellow syrup.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.49 (d, J=2.0 Hz, 1H),
7.95 (dd, J=2.0 & 8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 6.56 (s,
1H), 4.30 (q, J=7.0 Hz, 2H), 2.04-1.98 (m, 1H), 1.29 (t, J=7.0 Hz,
3H), 1.02-0.97 (m, 2H), 0.83-0.79 (m, 2H); ESI-MS (m/z) 336, 338
[(MH).sup.+, Br.sup.79,81].
[0191] Step-4:
5-(1-(5-Bromopyridin-2-yl)-3-cyclopropyl-1H-pyrazol-5-yl)-3-methyl-1,3,4--
oxadiazol-2(3H)-one: The title compound was prepared from step-3
intermediate by following the procedure sequentially as described
in step-4, step-5 and step-6 of intermediate 1. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.38 (d, J=2.0 Hz, 1H), 7.93 (dd, J=2.0
& 8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 3.51 (s,
3H), 2.06-1.99 (m, 1H), 1.06-1.01 (m, 2H), 0.89-0.87 (m, 2H);
ESI-MS (m/z) 362, 364 [(MH).sup.+, Br.sup.79,81].
Intermediate-10
5-(1-(5-Bromopyridin-2-yl)-5-cyclopropyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-o-
xadiazol-2(3H)-one
##STR00035##
[0193] Step-1: Ethyl
1-(5-bromopyridin-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxylate: To
a stirred solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (0.378
g, 2.05 mmol) in acetic acid (5 mL) was added
5-bromo-2-hydrazinylpyridine (386 mg, 2.05 mmol) at room
temperature and the resulting mixture was refluxed for 2 h. The
reaction was then cooled to room temperature and the solvent was
evaporated under vacuum. The crude product was purified by flash
column chromatography (silica gel, ethyl acetate-hexane system as
eluent) to afford 300 mg (43%) of the title compound as pale yellow
syrup. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.55 (d, J=2.0 Hz,
1H), 7.98 (dd, J=2.0 & 8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H),
6.50 (s, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.70-2.64 (m, 1H), 1.40 (t,
J=7.0 Hz, 3H), 1.05-1.00 (m, 2H), 0.75-0.71 (m, 2H); ESI-MS (m/z)
336, 338 [(MH).sup.+ Br.sup.79,81].
[0194] Step-2:
5-(1-(5-Bromopyridin-2-yl)-5-cyclopropyl-1H-pyrazol-3-yl)-3-methyl-1,3,4--
oxadiazol-2(3H)-one: The title compound was prepared from step-1
intermediate by following the procedure sequentially as described
in step-4, step-5 and step-6 of intermediate-1. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.55 (d, J=2.0 Hz, 1H), 7.99 (dd, J=2.0
& 8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 6.41 (s, 1H), 3.55 (s,
3H), 2.80-2.73 (m, 1H), 1.09-1.03 (m, 2H), 0.77-0.74 (m, 2H);
ESI-MS (m/z) 362, 364 [(MH).sup.+, Br.sup.79,81].
Intermediate-11
5-(1-(5-Bromopyridin-2-yl)-5-methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadia-
zol-2(3H)-one
##STR00036##
[0196] Step-1:
Ethyl-1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxylate:
To a stirred solution of 5-bromo-2-hydrazinylpyridine (16.6 g, 89.0
mmol), in ethanol (5 mL) and acetic acid (10 mL) was added ethyl
2,4-dioxopentanoate (14.0 g, 89.0 mmol) drop-wise at 0.degree. C.
and the resulting mixture was stirred at 100.degree. C. for 2 h.
The reaction mixture was then cooled to room temperature and the
solvent was evaporated under vacuum. The residue was diluted with
water (50 mL) followed by ethyl acetate (100 mL). 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 rotary evaporated and the crude product was purified by flash
column chromatography (silica gel, ethyl acetate-hexanes system as
eluent) to afford 2.60 g (10%) of the title compound as white
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.51-8.50 (m, 1H),
7.96-7.93 (m, 2H), 6.71 (s, 1H), 4.41 (q, J=7.0 Hz, 2H), 2.67 (s,
3H), 1.41 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 310, 312 [(MH).sup.+,
Br.sup.79,81].
[0197] Step-2:
5-(1-(5-Bromopyridin-2-yl)-5-methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadi-
azol-2(3H)-one: The title compound was prepared from step-1
intermediate by following the procedure sequentially described in
step-4, step-5 and step-6 of Intermediate-1. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.53-8.52 (m, 1H), 7.98-7.93 (m, 2H), 6.62 (s,
1H), 3.53 (s, 3H), 2.72 (s, 3H); ESI-MS (m/z) 336, 338 [(MH).sup.+,
Br.sup.79,81]
Intermediate-12
Methyl
3-(1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-m-
ethyl-4,5-dihydroisoxazole-5-carboxylate
##STR00037##
[0199] Step-1:
1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde:
To a stirred solution of
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic
acid (6.20 g, 18.45 mmol), in DMF (50 mL) was successively added
EDC.HCl (4.24 g, 22.14 mmol), HOBT (3.11 g, 20.29 mmol),
N,O-dimethylhydroxylamine hydrochloride (2.70 g, 27.7 mmol) and
triethylamine (5.14 mL, 36.9 mmol). After stirring the reaction
mixture at 65.degree. C. for 12 h, the reaction was cooled to RT.
Water (60 mL) was added to the above reaction followed by ethyl
acetate (100 mL). The layers were separated and aqueous layer was
extracted with ethyl acetate (3.times.100 mL). The combined organic
layers were washed with water (100 mL), brine (100 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 4.20
g (60%) of the
1-(5-bromopyridin-2-yl)-N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyr-
azole-3-carboxamide as white solid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 8.74 (d, J=2.5 Hz, 1H), 8.37 (dd, J=2.5 &
8.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 3.77 (s, 3H),
3.34 (s, 3H); ESI-MS (m/z) 379, 381 [(MH).sup.+, Br.sup.79,81].
[0200] To a -78.degree. C. cooled and stirred solution of
1-(5-Bromopyridin-2-yl)-N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazol-
e-3-carboxamide (4.40 g, 11.61 mmol) in THF (35 mL) was added
DIBAL-H (1M, 29.9 mL, 29.9 mmol) over a period of 30 min. Reaction
was quenched at the same temperature with hydrochloric acid (10%)
and diluted with ethyl acetate (100 mL). The mixture was stirred at
room temperature for 2 h and then the layers were separated. 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 to
afford 2.60 g (70%) of the title compound as white solid.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 10.07 (s, 1H), 8.62 (d,
J=2.0 Hz, 1H), 8.08 (dd, J=2.0 & 8.0 Hz, 1H), 7.85 (d, J=8.0
Hz, 1H), 7.37 (s, 1H); ESI-MS (m/z) 320, 322 [(MH).sup.+,
Br.sup.79,81].
[0201] Step-2:
1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde
oxime: To a (0.degree. C.) cooled solution of
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde
(2.60 g, 8.12 mmol) in methanol (30 mL) was added a solution of
hydroxylamine hydrochloride (0.847 g, 12.19 mmol) in water (5 mL)
followed by a solution of sodium carbonate (0.517 g, 4.87 mmol) in
water (2 mL). The reaction mixture was warmed to room temperature
and then stirred for 1 h. The reaction mixture was diluted with
water (20 mL) and diluted with ethyl acetate (100 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 concentrated under vacuum to afford 2.60 g (96%) as
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.57 (d,
J=2.0 Hz, 1H), 8.23 (s, 1H), 7.98 (dd, J=2.0 & 8.0 Hz, 1H),
7.78 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.19 (s, 1H), ESI-MS (m/z)
335, 337 [(MH).sup.+, Br.sup.79,81].
[0202] Step-3: Methyl
3-(1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl--
4,5-dihydroisoxazole-5-carboxylate: To a stirred solution of step-2
intermediate (3.0 g, 8.95 mmol) in THF(100 mL) was added NCS (1.79
g, 13.43 mmol) and pyridine (434 .mu.L, 5.37 mmol) at 0.degree. C.
and then stirred at 60.degree. C. for 3 h. The reaction was then
cooled back down to 0.degree. C., methyl methacrylate (1.43 mL,
13.43 mmol) and triethylamine (2.49 mL, 17.91 mmol) were added
sequentially to the above mixture and the resulting mixture was
stirred at 45.degree. C. for 6 h. The reaction mixture was cooled
to room temperature and then diluted with water (50 mL) followed by
ethyl acetate (100 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 rotary evaporated
and the crude product was purified by flash column chromatography
(silica gel, ethyl acetate-hexanes system as eluent) to afford 2.0
g (51%) of the title compound as white solid. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.58 (d, J=2.0 Hz, 1H), 8.01-7.98 (dd, J=2.0
& 8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 4.00 (d,
J=17.0 Hz, 1H), 3.81 (s, 3H), 3.36 (d, J=17.0 Hz, 1H), 1.74 (s,
3H); ESI-MS (m/z) 433, 435 [(MH).sup.+, Br.sup.79,81].
Intermediate-13a
1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylic
acid
And
Intermediate-13b
1-(5-Bromopyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic
acid
##STR00038##
[0204] Step-1: Ethyl 4-(furan-2-yl)-2,4-dioxobutanoate: To a
(0.degree. C.) cooled and stirred suspension of sodium hydride (60%
suspension in mineral oil, 5.45 g, 136 mmol) in THF (100 mL) was
added drop-wise a solution of diethyl oxalate (12.4 mL, 91 mmol)
over a period of 30 min. The resulting mixture was then warmed to
room temperature and then continued stirring for 30 min at the same
temperature. A solution of 1-(furan-2-yl)ethanone (5.0 g, 45.4
mmol) in THF (25 mL) was then added to the above mixture at room
temperature and the resulting mixture was slowly warmed to
50.degree. C. and continued stirring at the same temperature for 5
h. The reaction mixture was cooled down to room temperature and
then quenched with aqueous hydrochloric acid (10%, 10 mL) followed
by the addition of water (50 mL) and ethyl acetate (100 mL). 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 rotary evaporated to afford 9.54 g (100%) of the
title compound as semisolid. ESI-MS (m/z) 211 [(MH).sup.+
[0205] Step-2:
1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylic
acid and
1-(5-Bromopyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic
acid: A mixture of ethyl 4-(furan-2-yl)-2,4-dioxobutanoate (1.0 g,
4.76 mmol) and 5-bromo-2-hydrazinylpyridine (895 mg, 4.76 mmol) in
acetic acid (6 mL) and ethanol (6 mL) was heated at 100.degree. C.
for 1 h. The reaction mixture was cooled to room temperature and
the solvent was evaporated under vacuum. The crude product was
purified by flash column chromatography to afford 60 mg (4%) of
intermediate 13a and 200 mg (12%) of the intermediate 13b as white
solids.
Intermediate-13a
1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylic
acid
[0206] .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.3.25 (s, 1H,
D.sub.2O exchangeable), 8.67 (d, J=2.0 Hz, 1H), 8.35 (dd, J=8.0
& 2.0 Hz, 1H), 7.76-7.72 (m, 2H), 7.17 (s, 1H), 6.67-6.66 (m,
1H), 6.56-6.55 (m, 1H); ESI-MS (m/z) 334, 336 [(MH).sup.+,
Br.sup.79,81].
Intermediate-13b
1-(5-Bromopyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic
acid
[0207] .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.3.68 (s, 1H,
D.sub.2O exchangeable), 8.66 (d, J=2.0 Hz, 1H), 8.35 (dd, J=8.0
& 2.0 Hz, 1H), 7.80-7.74 (m, 2H), 7.28 (s, 1H), 6.99-6.98 (m,
1H), 6.64-6.63 (m, 1H); ESI-MS (m/z) 334, 336 [(MH).sup.+,
Br.sup.79,81].
Intermediate-14
5-(1-(5-Bromopyridin-2-yl)-5-(difluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,-
3,4-oxadiazol-2(3H)-one
##STR00039##
[0209] Step-1:
1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-N-methoxy-N-methyl-1H-pyrazole-5-c-
arboxamide: To a stirred solution of
1-(5-bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylic
acid (500 mg, 1.49 mmol) in THF (10 mL) was successively added
EDC.HCl (430 mg, 2.24 mmol), HOBT (344 mg, 2.24 mmol),
N,O-dimethylhydroxylamine hydrochloride (219 mg, 2.24 mmol) and
triethylamine 417 .mu.L, 2.99 mmol). The resulting mixture was
stirred at room temperature for 16 h. The reaction was then diluted
with water (10 mL) followed by ethyl acetate (10 mL). The layers
were separated and the aqueous layer was extracted with ethyl
acetate (3.times.25 mL). The combined organic layers were washed
with brine (20 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 300 mg (7%) of the desired product as
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.01 (d,
J=2.0 Hz, 1H), 7.96-7.89 (m, 2H), 7.53-7.50 (m, 1H), 6.83-6.82 (m,
2H), 6.53-6.52 (m, 1H), 3.48 (s, 3H), 3.36 (s, 3H); (ESI-MS (m/z)
377, 379 [(MH).sup.+, Br.sup.79,81]
[0210] Step-2:
1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carbaldehyde:
To a -78.degree. C. cooled and stirred solution of step-1
intermediate (10.0 g, 26.5 mmol) in THF (40 mL) was added drop-wise
DIBAL-H (1M in THF, 53.0 mL, 53.0 mmol) over a period of 30 min.
The reaction was gradually warmed to room temperature and stirred
overnight. The reaction was then cooled to 0.degree. C. and
quenched with aqueous hydrochloric acid (10%, 50 mL) followed by
the addition of water (50 mL) and ethyl acetate (100 mL). 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 rotary evaporated and the crude product was
purified by flash column chromatography to afford 1.50 g (17%) of
the title compound as white solid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 10.43 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.34
(dd, J=8.0 & 2.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.84-7.83 (m,
1H), 7.44 (s, 1H), 7.08-7.07 (m, 1H), 6.67-6.65 (m, 1H). (ESI-MS
(m/z) 318, 320 [(MH).sup.+, Br.sup.79,81]
[0211] Step-3:
5-Bromo-2-(5-(difluoromethyl)-3-(furan-2-yl)-1H-pyrazol-1-yl)pyridine:
To a cooled (-35.degree. C.) and stirred solution of step-2
intermediate (4.0 g, 12.57 mmol) in DCM (100 mL) was added DAST
(4.15 mL, 31.4 mmol) drop-wise and the reaction was gradually
warmed to room temperature and then stirred at the same temperature
overnight. The reaction mixture was diluted with water (50 mL)
followed by DCM (50 mL). The layers were separated and the aqueous
layer was extracted with DCM (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 rotary evaporated and the crude
product was purified by flash column chromatography to afford 2.70
g (63%) of the title compound as white solid. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 8.64 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.0 &
2.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.84-7.83 (m, 1H), 7.77 (t,
J=50 Hz, 1H), 7.29 (s, 1H), 7.07-7.06 (m, 1H), 6.66-6.65 (m, 1H);
(ESI-MS (m/z) 340, 342 [(MH).sup.+, Br.sup.79,81].
[0212] Step-4:
5-(1-(5-Bromopyridin-2-yl)-5-(difluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1-
,3,4-oxadiazol-2(3H)-one: The title compound was prepared from
step-3 intermediate by following the similar procedure sequentially
as described in step-4, step-5 and step-6 of intermediate-1.
.sup.1HNMR (400 MHz, Cd.sub.3CN) .delta. 8.60 (d, J=2.0 Hz, 1H),
8.17 (dd, J=8.0 & 2.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.72 (t,
J=50 Hz, 1H), 7.28 (s, 1H), 3.45 (s, 3H); (ESI-MS (m/z) 372, 374
[(MH).sup.+, Br.sup.79,81].
Intermediate-15
5-(1-(5-Bromopyridin-2-yl)-3-(difluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1,-
3,4-oxadiazol-2(3H)-one
##STR00040##
[0214] The title compound was prepared from Intermediate 13b by
following the similar procedure as described in Intermediate-14.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.66 (d, J=2.0 Hz, 1H),
8.36 (dd, J=8.0 &2.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.42 (s,
1H), 7.23 (t, J=50 Hz, 1H), 3.40 (s, 3H); (ESI-MS (m/z) 372, 374
[(MH).sup.+, Br.sup.79,81].
Intermediate-16
5-(1-(5-Bromopyridin-2-yl)-5-(fluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,-
4-oxadiazol-2(3H)-one
##STR00041##
[0216] Step-1:
(1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazol-5-yl)methanol:
To a stirred solution of
1-(5-bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carbaldehyde
(5.0 g, 15.72 mmol) in THF (40 mL) was added borane-THF complex
(1M, 31.4 mL, 31.4 mmol) drop-wise at 0.degree. C. over a period of
15 min. The reaction was gradually warmed to room temperature and
then stirred at the same temperature for 2 h. The reaction was
cooled to 0.degree. C. and then quenched with ice cold water (10
mL) followed by the addition of ethyl acetate (50 mL). 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 (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 (silica gel, ethyl acetate-hexanes
system as eluent) to afford 2.0 g (40%) of the title compound as
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.48 (d,
J=2.0 Hz, 1H), 8.0 (d, J=8.0 Hz, 1H), 8.00 (dd, J=8.0 & 2.0 Hz,
1H), 7.53-7.51 (m, 1H), 6.79-6.78 (m, 1H), 6.65 (s, 1H), 6.52-6.50
(m, 1H), 5.28 (s, 1H), 4.76 (s, 2H); ESI-MS (m/z) 320, 322
[(MH).sup.+, Br.sup.79,81]
[0217] Step-2:
5-Bromo-2-(5-(fluoromethyl)-3-(furan-2-yl)-1H-pyrazol-1-yl)pyridine:
To a (-78.degree. C.) cooled and stirred solution of step-1
intermediate (2.0 g, 6.25 mmol) in DCM (30 mL) was drop-wise added
DAST (1.65 mL, 12.49 mmol) and the reaction was then warmed to
-40.degree. C. and then stirred for 2 h at that temperature. The
reaction was diluted with water (30 mL) at -40.degree. C. followed
by the addition of DCM (50 mL). The layers were separated and the
aqueous layer was extracted with DCM (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 rotary evaporated
and the crude product was purified by flash column chromatography
to afford 1.10 g (54%) of the title compound as white solid.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.62 (d, J=2.0 Hz, 1H),
8.25 (dd, J=8.0 & 2.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.81 (m,
1H), 7.00-6.99 (m, 1H), 6.97 (s, 1H), 6.65-6.63 (m, 1H), 5.93 (d,
J=50 Hz, 2H); (ESI-MS (m/z) 322, 324 [(MH).sup.+,
Br.sup.79,81].
Intermediate-17
5-Hydrazinyl-2-nitropyridine hydrochloride
##STR00042##
[0219] Step-1: tert-butyl
1-(6-nitropyridin-3-yl)hydrazinecarboxylate: To a nitrogen purged
solution of 5-bromo-2-nitropyridine (50 g, 246 mmol) and tert-butyl
hydrazinecarboxylate (26.0 g, 197 mmol) in toluene (500 mL) in a
sealed tube, cesium carbonate (93.0 g, 286 mmol), dppf (20.48 g,
36.9 mmol) and Pd.sub.2(dba).sub.3 (15.79 g, 17.24 mmol) were
sequentially added. The resulting mixture was thoroughly
deoxygenated by flushing nitrogen gas for 15 min and the resulting
mixture was stirred at 100.degree. C. for 5 h. The reaction mixture
was cooled to room temperature and then filtered through celite.
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 23.0 g (38%) of the
title compound as a yellow solid. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 9.0 (d, J=2.5 Hz, 1H), 8.36 (dd, J=2.5 & 8.5 Hz, 1H),
8.22 (d, J=8.5 Hz, 1H), 4.47 (s, 2H, D.sub.2O exchangeable) 1.61
(s, 9H); GCMS (m/z) 154 (M-Boc).sup.+
[0220] Step-2: 5-Hydrazinyl-2-nitropyridine hydrochloride: To
(0.degree. C.) cooled solution of tert-butyl
1-(6-nitropyridin-3-yl)hydrazinecarboxylate (5.0 g, 19.67 mmol) in
dry 1,4-dioxane (250 mL) was added aqueous hydrochloric acid (2N,
98 mL). After stirring for 16 h at 25.degree. C., the solvent was
evaporated under vacuum. The residue was triturated with hexane and
dried under vacuum to afford 2.70 g (89%) of the title compound as
pink solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.10.75 (brs,
2H, D.sub.2O exchangeable), 9.75 (s, 1H, D.sub.2O exchangeable),
8.32 (d, J=8.5 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 7.55(dd, J=2.5
& 8.5 Hz, 1H).
Intermediate-18
5-(1-(6-Aminopyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1-
,3,4-oxadiazol-2(3H)-one
##STR00043##
[0222] Step-1:
3-(Furan-2-yl)-1-(6-nitropyridin-3-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-
-pyrazol-5-ol: To a stirred solution of Intermediate-17, (17.0 g,
89 mmol) in ethanol (50 mL) was added DIPEA (31.2 mL, 178 mmol) at
0.degree. C. and stirred for 30 min. The resulting mixture was
added drop-wise to a 0.degree. C. cooled solution of
1,1,1-trifluoro-4-(furan-2-yl)-4-methoxybut-3-en-2-one (23.5 g, 107
mmol) in ethanol (20 mL). The resulting mixture was warmed to room
temperature and then stirred at 45.degree. C. overnight. The
solvent was removed under reduced pressure and the residue was
purified by flash column chromatography (silica gel, 30% ethyl
acetate-hexanes system as eluent) to afford 12.0 g (30%) of the
title compound as a pink solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 9.03 (s, 1H, D.sub.2O exchangeable), 8.65 (d, J=2.5 Hz,
1H), 8.34 (d, J=8.5 Hz, 1H), 8.02 (dd, J=2.5 & 8.5 Hz, 1H),
7.94 (d, J=1.5 Hz, 1H), 7.12 (d, J=3.0 Hz, 1H), 6.72 (dd, J=1.5
& 3.0 Hz, 1H), 4.00 (d, J=19.0 Hz, 1H), 3.66 (d, J=19.0 Hz,
1H); ESI-MS (m/z) 343 (MH).sup.+.
[0223] Step-2:
5-(3-(Furan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-nitropyridine:
To a (0.degree. C.) cooled solution of step-1 intermediate (1.50 g,
4.38 mmol) in DCM (15 mL) was added SOCl.sub.2 (0.70 mL, 9.64
mmol). After stirring for 15 min at 0.degree. C., pyridine (0.88
mL, 10.9 mmol) was added at the same temperature and the resulting
mixture was stirred for 30 min at 0.degree. C. The solvent was
removed under reduced pressure and the residue was dissolved in ice
cooled water (30 mL) and ethyl acetate (25 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
saturated aqueous NaHCO.sub.3 solution (50 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 1.0 g (74%) of the title compound as a white solid.
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.94 (d, J=2.5 Hz, 1H),
8.45 (d, J=8.5 Hz, 1H), 8.30 (dd, J=2.5 & 8.5 Hz, 1H), 7.56 (d,
J=1.5 Hz, 1H), 7.27 (s, 1H), 6.89 (d, J=3.0 Hz, 1H), 6.56 (dd,
J=1.5 & 3.0 Hz, 1H); ESI-MS (m/z) 325 (MH).sup.+.
[0224] Step-3:
1-(6-Nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic
acid: The title compound was prepared by reacting step-2
intermediate (4.0 g, 12.34 mmol) with potassium permanganate (13.0
g, 83 mmol) by following the similar procedure as described in
Step-2 of Intermediate-1 to afford 3.0 g (80%) of the desired
product as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 8.99 (d, J=1.5 Hz, 1H), 8.60-8.57 (m, 2H), 7.71 (s, 1H);
ESI-MS (m/z) 302 (MH).sup.+.
[0225] Step-4: tert-Butyl
2-(1-(6-nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbonyl)
hydrazinecarboxylate: To a stirred solution of step-3 intermediate
(2.50 g, 8.27 mmol) in DCM (25 mL) was successively added EDC.HCl
(2.37 g, 12.41 mmol), HOBT (0.634 g, 4.14 mmol) and
tert-butylhydrazine carboxylate (1.093 g, 8.27 mmol). After
stirring at room temperature for 6 h, the reaction mixture was
diluted with water (10 mL) and dichloromethane (30 mL). The layers
were separated and aqueous layer was extracted with dichloromethane
(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
rotary evaporated and the crude product was purified by flash
column chromatography to afford 2.0 g (58%) of the title compound
as a white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.89 (d,
J=2.5 Hz, 1H), 8.53 (s, 1H, D.sub.2O exchangeable), 8.49 (d, J=8.5
Hz, 1H), 8.27 (dd, J=2.5 & 8.5 Hz, 1H), 7.85 (s, 1H, D.sub.2O
exchangeable), 7.51 (s, 1H), 1.51 (s, 9H); ESI-MS (m/z) 317
(M-Boc).sup.+.
[0226] Step-5:
1-(6-Nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide:
To a (0.degree. C.) cooled solution of step-4 intermediate (2.0 g,
4.80 mmol) in dichloromethane (25 mL) was added drop-wise
trifluoroacetic acid (3.70 mL, 48.0 mmol). After stirring the
reaction mixture at room temperature for 18 h, the solvent was
evaporated under reduced pressure. The crude product was triturated
with diethyl ether to obtain 1.32 g (87%) of the title compound as
semi solid. The residue was used for next step without further
purification. ESI-MS (m/z) 317 (MH).sup.+.
[0227] Step-6:
3-Methyl-5-(1-(6-nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)--
1,3,4-oxadiazol-2(3H)-one: The title compound was prepared from
step-5 intermediate by following the similar procedure sequentially
as described in Step-5 and Step-6 of Intermediate-1. .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 8.91 (d, J=2.5 Hz, 1H), 8.48 (d,
J=8.5 Hz, 1H), 8.31(dd, J=2.5 & 8.5 Hz, 1H), 7.37 (s, 1H), 3.53
(s, 3H); ESI-MS (m/z) 398 (M+acetonitrile).
[0228] Step-7:
5-(1-(6-Aminopyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl--
1,3,4-oxadiazol-2(3H)-one: To a 0.degree. C. cooled and stirred
solution of Step-6 intermediate (500 mg, 1.40 mmol) in ethanol (10
mL) and hydrochloric acid (1M, 0.5 mL) was added iron powder (800
mg, 14 mmol, 10 eq) portion-wise. The resulting mixture was then
stirred at 95.degree. C. for 2 h. The reaction was then cooled down
to 0.degree. C., poured in ice water and basified with aqueous
ammonia solution followed by the addition of ethyl acetate (20 mL).
The layers were separated and the aqueous layer was extracted with
ethyl acetate (2.times.25 mL). The combined organic layers were
washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and filtered.
The filtrate was rotary evaporated to afford 400 mg (87%) of the
title product as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.06 (d, J=2.0 Hz, 1H),
7.62 (s, 1H), 7.55 (dd, J=2.5, 8.5 Hz, 1H), 6.61 (s, 2H, D.sub.2O
exchangeable), 6.55 (d, J=8.5 Hz, 1H), 3.41 (s, 3H); ESI-MS (m/z)
327 (MH).sup.+.
EXAMPLES
Example-1
2,6-Difluoro-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(-
trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide
##STR00044##
[0230] To a nitrogen purged solution of Intermediate-1 (200 mg,
0.51 mmol) in dioxane (5 mL), was added potassium phosphate (268
mg, 1.54 mmol), 2,6-difluorobenzamide (161 mg, 1.02 mmol),
trans1,2-diaminocyclohexane (25 .mu.L, 0.205 mmol) and copper(I)
iodide (39 mg, 0.205 mmol) sequentially. The resulting mixture was
thoroughly deoxygenated by purging nitrogen gas for 15 min and then
the resulting mixture was stirred at 110.degree. C. for (30
min.times.2) in a microwave (Biotage). The reaction mixture was
cooled down to room temperature and then filtered through celite.
The filtrate was evaporated and the crude product was purified by
flash column chromatography (silica gel, 30% ethyl acetate-hexanes
system as eluent) to afford 45 mg (18%) of the desired product as
white solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.55 (d,
J=2.5 Hz, 1H), 8.50 (dd, J=2.5 & 8.5 Hz, 1H), 7.97 (s, 1H,
D.sub.2O exchangeable), 7.91 (d, J=8.5 Hz, 1H), 7.52-7.48 (m, 1H),
7.12 (s, 1H), 7.06 (t, J=8.5 Hz, 2H), 3.49 (s, 3H); ESI-MS (m/z)
467 (MH).sup.+.
Example-2
2-Fluoro-6-methyl-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl-
)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide
##STR00045##
[0232] The title compound was prepared by following the similar
procedure as described in Example-1 by using Intermediate-1 and
2-fluoro-6-methylbenzamide. .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.55 (s, 1H, D.sub.2O exchangeable), 8.50 (d, J=8.5 Hz,
1H), 7.91-7.88 (m, 2H), 7.38-7.32 (m, 1H), 7.12 (s, 1H) 7.10 (d,
J=8.0 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 3.49 (s, 3H), 2.50 (s, 3H);
ESI-MS (m/z) 463 (MH).sup.+.
Example-3
5-(3-Cyclopropyl-1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-1H-pyrazol--
5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00046##
[0234] In a microwave vial containing toluene (10 mL) and cesium
carbonate (360 mg, 1.104 mmol) was purged nitrogen gas for 30 min
and then Intermediate-9 (200 mg, 0.552 mmol),
(2,6-difluorophenyl)methanamine (95 mg, 0.663 mmol) and BINAP (34.4
mg, 0.055 mmol) were sequentially added. The resulting mixture was
thoroughly deoxygenated by purging nitrogen gas for another 15 min
and then Pd.sub.2(dba).sub.3 (37.9 mg, 0.041 mmol) was added to the
above mixture. Microwave vial was then sealed and kept in microwave
reactor and stirred at 125.degree. C. for 1 h. The reaction mixture
was cooled to room temperature and filtered through celite. 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 12 mg (5%) of the title compound as
white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.78 (s,
1H), 7.47-7.42 (m, 2H), 7.22-7.13 (m, 3H), 6.71 (s, 1H), 6.11 (brs,
1H, D.sub.2O exchangeable), 4.34 (d, J=4.0 Hz, 2H), 3.34 (s, 3H),
2.10-1.90 (m, 1H), 0.95-0.93 (m, 2H), 0.80-0.76 (m, 2H); ESI-MS
(m/z) 425 (MH).sup.+
[0235] The below Examples 4 to 7 given in Table-1 were prepared by
following the similar procedure as described in Example-3 by using
appropriate intermediate of Intermediate-12, Intermediate-15 or
Intermediate-16 and appropriate amine or amide Intermediate.
TABLE-US-00001 TABLE 1 Example No: IUPAC name Structure
.sup.1H-NMR/ESI-MS Example-4: N-(6-(3- (Difluoromethyl)-5-(4-
methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-1H-
pyrazol-1-yl)pyridin-3- yl)-2,6- difluorobenzamide ##STR00047##
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.38 (s, 1H), 8.74 (d,
J = 2.0 Hz, 1H), 8.41 (dd, J = 8.0 & 2.0 Hz, 1H), 7.92 (d, J =
8.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.40 (s, 1H), 7.31 (t, J = 8.0 Hz,
2H), 7.23 (t, J = 50 Hz, 1H), 3.40 (s, 3H); ESI- MS (m/z) 449
(MH).sup.+ Example-5: 5-(1-(5- ((2,6- Difluorobenzyl)amino)
pyridin-2-yl)-5- (fluoromethyl)-1H- pyrazol-3-yl)-3-methyl-
1,3,4-oxadiazol-2(3H)- one ##STR00048## .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 7.90 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.0
Hz, 1H), 7.48-7.40 (m, 1H), 7.29 (dd, J = 8.0 & 2.0 Hz, 1H),
7.15 (t, J = 8.0 Hz, 2H), 7.01 (s, 1H), 6.70 (t, J = 5.0 Hz, 1H,
D.sub.2O exchangeable), 5.83 (d, J = 50 Hz, 2H), 4.37 (d, J = 5.0
Hz, 2H), 3.35 (s, 3H); ESI-MS (m/z) 417 (MH).sup.+ Example-6:
Methyl 3- (1-(5-((2,6- difluorobenzyl)amino) pyridin-2-yl)-5-
(trifluoromethyl)-1H- pyrazol-3-yl)-5-methyl- 4,5-dihydroisoxazole-
5-carboxylate ##STR00049## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 7.91 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H),
7.46-7.42 (m, 1H), 7.40 (s, 1H), 7.25-7.23 (dd, J = 2.0 & 8.0
Hz, 1H), 7.15 (t, J = 8.0 Hz, 2H), 6.85 (t, J = 5.0 Hz, 1H,
D.sub.2O exchangeable), 4.36 (d, J = 5.0 Hz, 2H), 3.83 (d, J = 17.0
Hz, 1H), 3.69 (s, 3H), 3.44 (d, J = 17.0 Hz, 1H), 1.59 (s, 3H);
ESI-MS (m/z) 496 (MH).sup.+ Example-7: Methyl 3-
(1-(5-((2-chloro-6- fluorobenzyl)amino) pyridin-2-yl)-5-
(trifluoromethyl)-1H- pyrazol-3-yl)-5-methyl- 4,5-dihydroisoxazole-
5-carboxylate ##STR00050## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 7.59 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H),
7.45-7.39 (m, 3H), 7.33-7.26 (m, 2H), 6.75 (t, J = 5.0 Hz, 1H,
D.sub.2O exchangeable), 4.42 (d, J = 5.0 Hz, 2H), 3.85 (d, J = 17.0
Hz, 1H), 3.71 (s, 3H), 3.46 (d, J = 17.0 Hz, 1H), 1.61 (s, 3H);
ESI-MS (m/z) 512, 514 [(MH).sup.+, Cl.sup.35,37]
Example-8
2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(-
trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide
##STR00051##
[0237] To a nitrogen purged solution of Intermediate-2 (2.0 g, 5.13
mmol) in dioxane (8 mL) in a microwave vial was added cesium
carbonate (3.34 g, 10.25 mmol), 2,6-difluorobenzamide (1.05 g, 6.66
mmol) and xantphos (445 mg, 0.77 mmol) sequentially. The resulting
mixture was thoroughly deoxygenated by purging nitrogen gas for 15
min and then palladium (II) acetate (115 mg, 0.513 mmol) was added
to the above reaction mixture. Microwave vial was sealed and kept
in microwave (Biotage) and heated to 125.degree. C. and maintained
for 1 h. The reaction mixture was cooled to room temperature and
filtered through celite. The filtrate was evaporated and the crude
product was purified by flash column chromatography (silica gel,
40% ethyl acetate-hexanes system as eluent) to afford 790 mg (33%)
of the desired product as white solid. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.65 (d, J=2.5 Hz, 1H), 8.50 (dd, J=2.5 &
8.5 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.90 (s, 1H, D.sub.2O
exchangeable), 7.54-7.47 (m, 1H), 7.28 (s, 1H), 7.07 (t, J=8.5 Hz,
2H), 3.55 (s, 3H); ESI-MS (m/z) 467 (MH)+.
[0238] The below Examples 9 to 32 given in Table-2 were prepared by
following the similar procedure as described in Example-8 by using
corresponding Intermediate (Intermediate 2, 4, 5, 6, 7, 8, 9, 10,
11, 14, 15) and appropriate amine or amide Intermediate.
TABLE-US-00002 TABLE 2 Example No: IUPAC name Structure
.sup.1H-NMR/ESI-MS Example-9: 2-Chloro-6- fluoro-N-(6-(3-(4-
methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-
2-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)pyridin- 3-yl)benzamide
##STR00052## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.65 (d, J =
2.5 Hz, 1H), 8.49 (dd, J = 2.5 & 8.5 Hz, 1H), 7.96 (d, J = 8.5
Hz, 1H), 7.80 (s, 1H, D.sub.2O exchangeable), 7.46-7.42 (m, 1H),
7.32 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H),
3.55 (s, 3H); ESI-MS (m/z) 483 (MH).sup.+ Example-10: 2-Fluoro-
6-methyl-N-(6-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-
2-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)pyridin- 3-yl)benzamide
##STR00053## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.65 (d, J =
2.5 Hz, 1H), 8.49 (dd, J = 2.5 & 8.5 Hz, 1H), 7.94 (d, J = 8.5
Hz, 1H), 7.79 (s, 1H, D.sub.2O exchangeable), 7.39-7.34 (m, 1H),
7.28 (s, 1H), 7.12 (d, J = 7.5 Hz 1H) 7.04 (t, J = 7.5 Hz, 1H),
3.55 (s, 3H), 2.52 (s, 3H); ESI-MS (m/z) 463 (MH).sup.+ Example-11:
N-(6-(5- (Difluoromethyl)-3-(4- methyl-5-oxo-4,5-
dihydro-1,3,4-oxadiazol- 2-yl)-1H-pyrazol-1- yl)pyridin-3-yl)-2,6-
difluorobenzamide ##STR00054## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.40 (s, 1H, D.sub.2O exchangeable), 8.01 (d, J = 2.0 Hz,
1H), 8.03 (dd, J = 8.0 & 2.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H),
7.83 (t, J = 50 Hz, 1H), 7.69-7.61 (m, 1H), 7.35 (s, 1H), 7.30 (t,
J = 8.0 Hz, 2H), 3.43 (s, 3H); ESI-MS (m/z) 449 (MH).sup.+
Example-12: 5-(1-(5- ((2,6-Difluorobenzyl) amino)pyridin-2-yl)-5-
(difluoromethyl)-1H- pyrazol-3-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)-
one ##STR00055## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.91
(d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 50 Hz,
1H), 7.48-7.41 (m, 1H), 7.30 (dd, J = 8.0 & 2.0 Hz, 1H), 7.24
(s, 1H), 7.15 (t, J = 8.0 Hz, 2H), 6.78 (t, J = 5.0 Hz, 1H,
D.sub.2O exchangeable), 4.38 (d, J = 5.0 Hz, 2H), 3.41 (s, 3H);
ESI-MS (m/z) 435 (MH).sup.+ Example-13: 5-(1-(5- ((2,6-
Difluorobenzyl)amino) pyridin-2-yl)-3- (difluoromethyl)-1H-
pyrazol-5-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)- one ##STR00056##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.87 (d, J = 2.0 Hz, 1H),
7.52 (d, J = 8.0 Hz, 1H), 7.32-7.25 (m, 1H), 7.19 (dd, J = 8.0
& 2.0 Hz, 1H), 7.05 (s, 1H), 6.93 (t, J = 8.0 Hz, 2H), 6.76 (t,
J = 50 Hz, 1H), 4.50 (s, 2H), 3.48 (s, 3H); ESI-MS (m/z) 435
(MH).sup.+ Example-14: N-(6-(3- (5,5-Dimethyl-4-oxo-4,5-
dihydroisoxazol-3-yl)-5- (trifluoromethyl)-1H-
pyrazol-1-yl)pyridin-3- yl)-2,6- difluorobenzamide ##STR00057##
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.35 (s, 1H, D.sub.2O
exchangeable), 8.82 (d, J = 2.5 Hz, 1H), 8.47 (dd, J = 2.5 &
8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.69-7.63 (m, 1H), 7.62 (s,
1H), 7.31 (t, J = 7.5 Hz, 2H) 1.46 (s, 6H); ESI-MS (m/z) 480
(MH).sup.+ Example-15: 2-Chloro- N-(6-(3-(5,5-dimethyl-4-
oxo-4,5-dihydroisoxazol- 3-yl)-5-(trifluoromethyl)-
1H-pyrazol-1-yl)pyridin- 3-yl)-6-fluorobenzamide ##STR00058##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.67 (d, J = 2.5 Hz, 1H),
8.51 (dd, J = 2.5 & 8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.95
(s, 1H, D.sub.2O exchangeable), 7.50 (s, 1H), 7.43- 7.40 (m, 1H),
7.31 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 1.53 (s, 6H);
ESI-MS (m/z) 496, 497 [(MH).sup.+, Cl.sup.35,37] Example-16: 2,6-
Difluoro-N-(6-(1',4',4'- trimethyl-5'-oxo-5-
(trifluoromethyl)-4',5'- dihydro-1H,1'H-[3,3'-
bipyrazol]-1-yl)pyridin- 3-yl)benzamide ##STR00059## .sup.1HNMR
(400 MHz, DMSO-d.sub.6) .delta. 11.36 (s, 1H, D.sub.2O
exchangeable), 8.84 (d, J = 2.0 Hz, 1H), 8.41 (dd, J = 2.0 &
8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.53 (s,
1H), 7.31 (t, J = 8.0 Hz, 2H) 3.34 (s, 3H), 1.45 (s, 6H); ESI-MS
(m/z) 493 (MH).sup.+ Example-17: 2-Chloro- 6-fluoro-N-(6-(1',4',4'-
trimethyl-5'-oxo-5- (trifluoromethyl)-4',5'- dihydro-1H,1'H-[3,3'-
bipyrazol]-1-yl)pyridin- 3-yl)benzamide ##STR00060## .sup.1HNMR
(400 MHz, DMSO-d.sub.6) .delta. 11.38 (s, 1H, D.sub.2O
exchangeable), 8.83 (d, J = 2.0 Hz, 1H), 8.42 (dd, J = 2.0 &
8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.64-7.58 (m, 1H), 7.53 (s,
1H), 7.51 (d, J = 8.0 Hz, 1H) 7.45 (t, J = 8.0 Hz, 1H) 3.34 (s,
3H), 1.45 (s, 6H); ESI-MS (m/z) 509 (MH).sup.+ Example-18:
2-Fluoro- 6-methyl-N-(6-(1',4',4'- trimethyl-5'-oxo-5-
(trifluoromethyl)-4',5'- dihydro-1H,1'H-[3,3'-
bipyrazol]-1-yl)pyridin- 3-yl)benzamide ##STR00061## .sup.1HNMR
(400 MHz, DMSO-d.sub.6) .delta. 11.19 (s, 1H, D.sub.2O
exchangeable), 8.84 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 2.0 &
8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.46- 7.42 (m,
1H), 7.22-7.18 (m, 2H), 3.34 (s, 3H), 2.36 (s, 3H), 1.45 (s, 6H);
ESI-MS (m/z) 489 (MH).sup.+ Example-19: 2,6- Difluoro-N-(6-(3-(4-
methyl-5-oxo-4,5- dihydro-1,2,4-oxadiazol-
3-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)pyridin- 3-yl)benzamide
##STR00062## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.42 (s,
1H, D.sub.2O exchangeable), 8.85 (d, J = 2.0 Hz, 1H), 8.45 (dd, J =
2.0 & 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H),
7.70- 7.62 (m, 1H), 7.32 (t, J = 8.0 Hz, 2H), 3.52 (s, 3H); ESI-MS
(m/z) 467 (MH).sup.+ Example-20: N-(6-(3-(4-
Acetyl-5,5-dimethyl-4,5- dihydro-1,3,4-oxadiazol-
2-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)pyridin- 3-yl)-2,6-
difluorobenzamide ##STR00063## .sup.1HNMR (400 MHz, CDCl.sub.3)
.delta. 8.63 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 2.0 & 8.0 Hz,
1H), 8.13 (s, 1H, D.sub.2O exchangeable), 7.90 (d, J = 8.0 Hz, 1H),
7.53-7.46 (m, 1H), 7.29 (s, 1H), 7.06 (t, J = 8.0 Hz, 2H), 2.31 (s,
3H), 1.91 (s, 6H); ESI-MS (m/z) 509 (MH).sup.+ Example-21: N-(6-(3-
(4,4-Dimethyl-4,5- dihydrooxazol-2-yl)-5- (trifluoromethyl)-1H-
pyrazol-1-yl)pyridin-3- yl)-2,6- difluorobenzamide ##STR00064##
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.39 (s, 1H, D.sub.2O
exchangeable), 8.78 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 2.0 &
8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.68-7.63 (m, 1H), 7.54 (s,
1H), 7.31 (t, J = 8.0 Hz, 2H), 4.15 (s, 2H), 1.31 (s, 6H); ESI-MS
(m/z) 466 (MH).sup.+ Example-22: 5-(1-(5- ((2,6-Difluorobenzyl)
amino)pyridin-2-yl)-5- (trifluoromethyl)-1H-
pyrazol-3-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)- one ##STR00065##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.97 (d, J = 2.5 Hz, 1H),
7.58 (d, J = 8.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.21-7.18 (m, 2H),
6.94 (t, J = 8.0 Hz, 2H), 4.51 (s, 2H), 3.53 (s, 3H); ESI-MS (m/z)
453 (MH).sup.+ Example-23: 5-(1-(5- ((2-Chloro-6-
fluorobenzyl)amino) pyridin-2-yl)-5- (trifluoromethyl)-1H-
pyrazol-3-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)- one ##STR00066##
.sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.97 (d, J = 2.5 Hz, 1H),
7.58 (d, J = 8.5 Hz, 1H), 7.30-7.20 (m, 5H), 7.08-7.06 (m, 1H),
4.58 (s, 2H), 3.53 (s, 3H); ESI-MS (m/z) 469, 471 [(MH).sup.+,
Cl.sup.35,37] Example-24: 1'-(5-((2,6- Difluorobenzyl)amino)
pyridin-2-yl)-1,4,4- trimethyl-5'- (trifluoromethyl)-1H,1'H-
[3,3'-bipyrazol]-5(4H)- one ##STR00067## .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 7.92 (d, J = 2.5 Hz, 1H), 7.56 (d, J = 8.5
Hz, 1H), 7.47-7.42 (m, 1H), 7.41 (s, 1H), 7.28 (dd, J = 2.5 &
8.5 Hz, 1H), 7.16 (t, J = 8.0 Hz, 2H), 6.83 (t, J = 5.5 Hz, 1H,
D.sub.2O exchangeable), 4.38 (d, J = 5.5 Hz, 2H), 3.33 (s, 3H),
1.41 (s, 6H); ESI-MS (m/z) 479 (MH).sup.+ Example-25: 1'-(5-((2-
Chloro-6- fluorobenzyl)amino) pyridin-2-yl)-1,4,4-trimethyl-
5'-(trifluoromethyl)- 1H,1'H-[3,3'-bipyrazol]- 5(4H)-one
##STR00068## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.95 (d, J
= 2.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.48-7.39 (m, 2H), 7.41
(s, 1H), 7.33-7.28 (m, 2H), 6.74 (t, J = 5.0 Hz, 1H, D.sub.2O
exchangeable), 4.42 (d, J = 5.0 Hz, 2H), 3.33 (s, 3H), 1.41 (s,
6H); ESI-MS (m/z) 495, 497 [(MH).sup.+, Cl.sup.35,37] Example-26:
3-(1-(5- ((2,6- Difluorobenzyl)amino) pyridin-2-yl)-5-
(trifluoromethyl)-1H- pyrazol-3-yl)-4-methyl-
1,2,4-oxadiazol-5(4H)- one ##STR00069## .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 7.96 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.63
(d, J = 8.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.28 (dd, J = 2.0 & 8.0
Hz, 1H), 7.16 (t, J = 8.0 Hz, 2H), 6.92 (t, J = 5.0 Hz, 1H,
D.sub.2O exchangeable), 4.39 (d, J = 5.0 Hz, 2H), 3.47 (s, 3H);
ESI-MS (m/z) 453 (MH).sup.+ Example-27: 1-(5-(1-(5- ((2,6-
Difluorobenzyl)amino) pyridin-2-yl)-5- (trifluoromethyl)-1H-
pyrazol-3-yl)-2,2- dimethyl-1,3,4- oxadiazol-3(2H)- yl)ethanone
##STR00070## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 7.96 (d, J =
2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.32-7.28 (m, 1H), 7.21 (s,
1H), 7.17 (dd, J = 2.0 & 8.0 Hz, 1H), 6.94 (t, J = 8.0 Hz, 2H),
4.51 (s, 2H), 2.31 (s, 3H), 1.89 (s, 6H); ESI-MS (m/z) 495
(MH).sup.+ Example-28: N-(2,6- Difluorobenzyl)-6-(3-
(4,4-dimethyl-4,5- dihydrooxazol-2-yl)-5- (trifluoromethyl)-1H-
pyrazol-1-yl)pyridin-3- amine ##STR00071## .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 7.93 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.0
Hz, 1H), 7.50-7.43 (m, 1H), 7.41 (s, 1H), 7.26 (dd, J = 2.0 &
8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 2H), 6.82 (t, J = 5.0 Hz, 1H,
D.sub.2O exchangeable), 4.38 (d, J = 5.0 Hz, 2H), 4.12 (s, 2H),
1.29 (s, 6H); ESI-MS (m/z) 452 (MH).sup.+ Example-29: N-(6-(5-
Cyclopropyl-3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-
2-yl)-1H-pyrazol-1- yl)pyridin-3-yl)-2,6- difluorobenzamide
##STR00072## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.32 (s,
1H, D.sub.2O) .delta. exchangeable), 8.83 (d, J = 2.0 Hz, 1H), 8.40
(dd, J = 2.0 & 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.67-7.63
(m, 1H), 7.31 (t, J = 8.0 Hz, 2H), 6.64 (s, 1H), 3.41 (s, 3H),
2.67-2.59 (m, 1H), 1.02-0.97 (m, 2H), 0.81-0.77 (m, 2H); ESI-MS
(m/z) 439 (MH).sup.+ Example-30: N-(6-(3- Cyclopropyl-5-(4-
methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol- 2-yl)-1H-pyrazol-1-
yl)pyridin-3-yl)-2,6- difluorobenzamide ##STR00073## .sup.1HNMR
(400 MHz, DMSO-d.sub.6) .delta. 11.25 (s, 1H, D.sub.2O
exchangeable), 8.65 (d, J= 2.0 Hz, 1H), 8.32 (dd, J = 2.0 & 8.0
Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.67-7.60 (m, 1H), 7.29 (t, J =
8.0 Hz, 2H), 6.84 (s, 1H), 3.39 (s, 3H), 2.07-1.98 (m, 1H),
1.01-0.96 (m, 2H), 0.83-0.79 (m, 2H); ESI-MS (m/z) 439 (MH).sup.+
Example-31: 2,6- Difluoro-N-(6-(5-methyl- 3-(4-methyl-5-oxo-4,5-
dihydro-1,3,4-oxadiazol- 2-yl)-1H-pyrazol-1- yl)pyridin-3-
yl)benzamide ##STR00074## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.29 (s, 1H, D.sub.2O exchangeable), 8.80 (d, J = 2.0 Hz,
1H), 8.39 (dd, J = 2.0 & 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H),
7.68-7.6 (m, 1H), 7.30 (t, J = 8.0 Hz, 2H), 6.81 (s, 1H), 3.41 (s,
3H), 2.62 (s, 3H); ESI-MS (m/z) 413 (MH).sup.+ Example-32: 5-(1-(5-
((2,6-Difluorobenzyl) amino)pyridin-2-yl)-5-
methyl-1H-pyrazol-3-yl)- 3-methyl-1,3,4- oxadiazol-2(3H)-one
##STR00075## .sup.1HNMR (400 MHz, CDCl.sub.3) 7.93 (d, J = 2.0 Hz,
1H), 7.65 (d, J = 8.0 Hz, 1H), 7.31-7.23 (m, 1H), 7.19 (dd, J = 2.0
& 8.0 Hz, 1H), 6.93 (t, J = 8.0 Hz, 2H), 6.56 (s, 1H), 4.51 (d,
J = 6.0 Hz, 2H), 4.31 (t, J = 6.0 Hz, 1H, D.sub.2O exchangeable),
3.50 (s, 3H), 2.58 (s, 3H); ESI-MS (m/z) 399 (MH).sup.+
Example-33
(3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-p-
yrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol
##STR00076##
[0240] To a stirred and cooled (0.degree. C.) solution of Example-6
(30 mg, 0.061 mmol) in methanol (3 mL) was added NaBH.sub.4 (5 mg,
0.121 mmol). The resulting mixture was warmed to room temperature
and then stirred for 3 h at the same temperature. Reaction was then
diluted with water (3 mL) followed by ethyl acetate (5 mL). The
layers were separated and the aqueous layer was extracted with
ethyl acetate (2.times.5 mL). The combined organic layers were
washed with brine (3 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 20 mg (70%) of the
title compound as white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 7.93 (d, J=2.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.49-7.45
(m, 1H), 7.35 (s, 1H), 7.24 (dd, J=2.0 & 8.0 Hz, 1H), 7.18 (t,
J=8.0 Hz, 2H), 6.82 (t, J=8.0 Hz, 1H), 5.14 (t, J=5.0 Hz, 1H), 4.38
(d, J=5.0 Hz, 2H), 3.86-3.47 (m, 3H), 3.05 (d, J=17.0 Hz, 1H), 1.32
(s, 3H); ESI-MS (m/z) 468 (MH).sup.+
Example-34
(3-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-
-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol
##STR00077##
[0242] The title compound was prepared by following the similar
procedure as described in Example-33 using Example-7. .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 7.99 (d, J=2.0 Hz, 1H), 7.46 (d,
J=8.0 Hz, 1H), 7.30-7.23 (m, 2H), 7.21 (s, 1H), 7.18 (dd, J=8.0
& 2.0 Hz, 1H), 7.07-7.02 (m, 1H), 4.57 (s, 2H), 3.75 (d, J=12.0
Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 3.56 (d, J=17.0 Hz, 1H), 3.16 (d,
J=17.0 Hz, 1H), 1.44 (s, 3H); ESI-MS (m/z) 485, 487 [(MH).sup.+,
Cl.sup.35,37]
Example-35
Methyl
3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-
-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate
##STR00078##
[0244] Step-1:
2,6-Difluoro-N-(6-(3-formyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyri
din-3-yl) benzamide: In a sealed tube containing a dioxane (20 mL)
and cesium carbonate (2.54 g, 7.81 mmol) was purged with nitrogen
gas for 10 min and then
1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde
(prepared in step-1 of the intermediate-12; 1.0 g, 3.12 mmol),
2,6-difluorobenzamide (736 mg, 4.69 mmol) and xanthphos (180 mg,
0.31 mmol) were sequentially added. The resulting mixture was
thoroughly deoxygenated by purging nitrogen gas for another 15 min
and then palladium (II) acetate (35 mg, 0.15 mmol) was added to the
above mixture. The sealed tube was capped and stirred at
130.degree. C. for 6 h. The reaction mixture was then cooled to
room temperature and filtered through celite. 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 700 mg (56%) of the title compound as white
solid. .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 10.09 (s, 1H), 8.63
(d, J=2.0 Hz, 1H), 8.60 (dd, J=2.0 & 8.0 Hz, 1H), 8.00 (brs,
1H, D.sub.2O Exchangeable), 7.93 (d, J=8.0 Hz, 1H), 7.59-7.53 (m,
1H), 7.36 (s, 1H), 7.09 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 397
(MH).sup.+
[0245] Step-2: 2,
6-Difluoro-N-(6-(3-((hydroxyimino)methyl)-5-(trifluoromethyl)-1H-pyrazol--
1-yl)pyridin-3-yl)benzamide: To (0.degree. C.) cooled solution of
the above Step-1 intermediate (900 mg, 2.27 mmol) in methanol (10
mL) was added solution of hydroxylamine hydrochloride (237 mg, 3.41
mmol) in water (5 mL) followed by a solution of sodium carbonate
(241 mg, 2.27 mmol) in water (2 mL). The resulting mixture was then
stirred at room temperature for 2 h. The reaction was then diluted
with water (20 mL) followed by 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 (25 mL), dried (Na.sub.2SO.sub.4) and filtered. The
filtrate was concentrated under vacuum to afford 900 mg (96%) of
the desired product as white solid. ESI-MS (m/z) 412 (MH).sup.+
[0246] Step-3: Methyl
3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyraz-
ol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate: To a stirred
solution of the above Step-2 intermediate (900 mg, 2.18 mmol) in
THF (25 mL) were added NCS (438 mg, 3.28 mmol) and pyridine (124
.mu.L, 1.53 mmol) at 0.degree. C. and then stirred at 45.degree. C.
for 2 h. The reaction was cooled to 0.degree. C., methyl
methacrylate (350 .mu.L, 3.28 mmol) was then added to the above
mixture followed by triethyl amine (610 .mu.L, 4.38 mmol). The
resulting mixture was stirred at 40.degree. C. for 4 h. The
reaction was then cooled down to room temperature and diluted with
water (50 mL) followed by ethyl acetate (25 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate
(2.times.25 mL). The combined organic layers were washed with brine
(20 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 660 mg, (59%) of the title compound as white
solid. .sup.1HNMR (400 MHz, DMSO) .delta. 11.37 (s, 1H, D.sub.2O
exchangeable), 8.79 (d, J=2.0 Hz, 1H), 8.44 (dd, J=2.0 & 8.0
Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.69-7.62 (m, 1H), 7.56 (s, 1H),
7.33 (t, J=8.0 Hz, 2H), 3.90 (d, J=17.0 Hz, 1H), 3.72 (s, 3H), 3.51
(d, J=17.0 Hz, 1H), 1.62 (s, 3H). ESI-MS (m/z) 510 (MH).sup.+
Example-36
2,6-Difluoro-N-(6-(3-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-
-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide
##STR00079##
[0248] The title compound was prepared from Example-35 by following
the similar procedure as described in Example-33. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.56 (m, 1H), 8.54 (d, J=2.0 Hz, 1H),
7.85-7.83 (m, 2H), 7.54-7.47 (m, 1H), 7.29 (s, 1H), 7.07 (t, J=8.0
Hz, 2H), 3.79 (d, J=12.0 Hz, 1H), 3.36 (d, J=12.0 Hz, 1H), 3.61 (d,
J=17.0 Hz, 1H), 3.20 (d, J=17.0 Hz, 1H), 1.47 (s, 3H); ESI-MS (m/z)
482 (MH)+
Example-37
3-(1-(5-(2,6-Difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazo-
l-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxamide
##STR00080##
[0250] To a solution of from Example-35 (100 mg, 0.19 mmol) in
methanol was added a solution of ammonia in methanol (5 mL) and the
resulting solution was heated to 100.degree. C. and further
maintained for 16 h. The reaction was cooled to room temperature
and the solvent was evaporated under reduced pressure. The crude
product was triturated with 10% ethyl acetate in hexane (10 mL) to
afford 50 mg (50%) of the title compound as white solid. .sup.1HNMR
(400 MHz, DMSO-d.sub.6) .delta. 11.00 (s, 1H), 8.00 (d, J=2.0 Hz,
1H), 8.44-8.41 (dd, J=2.0 & 8.0 Hz, 1H), 7.94 (d, J=8.0 Hz,
1H), 7.69-7.65 (m, 1H), 7.64 (brs, 1H, D.sub.2O exchangeable), 7.54
(s, 1H), 7.44 (brs, 1H, D.sub.2O exchangeable), 7.33-7.29 (t, J=8.0
Hz, 2H), 3.81 (d, J=17.0 Hz, 1H), 3.37 (d, J=17.0 Hz, 1H), 1.58 (s,
3H); ESI-MS (m/z) 495 (MH).sup.+
Example-38
2,6-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(-
trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide
##STR00081##
[0252] To a stirred solution of Intermediate-18 (75 mg, 0.230 mmol)
in DCM (2 mL) was added 2,6-difluorobenzoyl chloride (29 .mu.L,
0.230 mmol), pyridine (37 .mu.L, 0.460 mmol) followed by DMAP (5.62
mg, 0.046 mmol). After stirring the above reaction mixture at room
temperature for 16 h, the reaction was diluted with DCM (10 mL),
washed with aqueous hydrochloric acid (10%, 10 mL) brine (10 mL),
dried (Na.sub.2SO.sub.4) and filtered. The filtrate was evaporated
and the crude product was purified by flash column chromatography
to afford 25 mg (20%) of the desired product as white solid.
.sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.80 (s, 1H, D.sub.2O
exchangeable), 8.66 (d, J=2.5 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.20
(dd, J=2.5 & 8.5 Hz, 1H), 7.77 (s, 1H), 7.65-7.57 (m, 1H), 7.25
(t, J=8.5 Hz, 2H), 3.43 (s, 3H); ESI-MS (m/z) 467 (MH)+.
[0253] The below Examples 39 to 50 given in Table-3 were prepared
by following the similar procedure as described in Example-38 by
using Intermediate-18 and appropriate acid chloride.
TABLE-US-00003 TABLE 3 Example No: IUPAC name Structure
.sup.1H-NMR/ESI-MS Example-39: 2- Chloro-6-fluoro-N-(5-
(3-(4-methyl-5-oxo- 4,5-dihydro-1,3,4- oxadiazol-2-yl)-5-
(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide
##STR00082## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.82 (s,
1H, D.sub.2O exchangeable), 8.66 (d, J = 2.5 Hz, 1H), 8.42 (d, J =
8.5 Hz, 1H), 8.20 (dd, J = 2.5 & 8.5 Hz, 1H), 7.78 (s, 1H),
7.59-7.54 (m, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.39 (t, J = 7.5 Hz,
1H), 3.43 (s, 3H); ESI-MS (m/z) 483, 485 [(MH).sup.+,
Cl.sup.35,37]. Example-40: 2-Fluoro- 6-methyl-N-(5-(3-(4-
methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-
(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide
##STR00083## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 10.63 (s,
1H, D.sub.2O exchangeable), 9.13 (d, J = 2.5 Hz, 1H), 8.65 (dd, J =
2.5 & 8.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H),
7.50-7.42 (m, 3H), 3.45 (s, 3H); ESI- MS (m/z) 483 (MH).sup.+.
Example-41: 2-Fluoro- N-(5-(3-(4-methyl-5- oxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-
yl)benzamide ##STR00084## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.32 (s, 1H, D.sub.2O exchangeable), 8.66 (d, J = 2.0 Hz,
1H), 8.42 (d, J = 8.0 Hz, 1H), 8.19 (dd, J = 2.0 & 8.0 Hz, 1H),
7.78 (s, 1H), 7.76-7.72 (m, 1H), 7.65-7.59 (m, 1H), 7.39- 7.32 (m,
2H), 3.43 (s, 3H); ESI-MS (m/z) 449 (MH).sup.+ Example-42: 2,3-
Difluoro-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-
yl)benzamide ##STR00085## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
9.19 (d, J = 12.0 Hz, 1H), 8.61 (d, J = 12.0 Hz, 1H), 8.54 (d, J =
2.0 Hz, 1H), 7.96-7.92 (m, 2H), 7.46-7.43 (m, 1H), 7.33-7.28 (m,
2H), 3.55 (s, 3H); ESI-MS (m/z) 467 (MH).sup.+ Example-43: 2,4,5-
Trifluoro-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-
yl)benzamide ##STR00086## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.45 (s, 1H, D.sub.2O exchangeable), 8.67 (d, J = 2.0 Hz,
1H), 8.39 (d, J = 8.0 Hz, 1H), 8.20 (dd, J= 2.0 & 8.0 Hz, 1H),
7.95-7.89 (m, 1H), 7.80-7.73 (m, 1H), 7.78 (s, 1H) 3.43 (s, 3H);
ESI-MS (m/z) 485 (MH).sup.+ Example-44: 2,3,4-
Trifluoro-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-
yl)benzamide ##STR00087## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.51 (s, 1H, D.sub.2O exchangeable), 8.68 (d, J = 2.0 Hz,
1H), 8.39 (d, J = 8.0 Hz, 1H), 8.20 (dd, J = 2.0 & 8.0 Hz, 1H),
7.79 (s, 1H), 7.67-7.60 (m, 1H), 7.52-7.42 (m, 1H), 3.43 (s, 3H);
ESI-MS (m/z) 485 (MH).sup.+ Example-45: 2,4- Difluoro-N-(5-(3-(4-
methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-
(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide
##STR00088## .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.34 (s,
1H, D.sub.2O exchangeable), 8.65 (d, J = 2.0 Hz, 1H), 8.41 (d, J =
8.0 Hz, 1H), 8.18 (dd, J = 2.0 & 8.0 Hz, 1H), 7.85-7.80 (m,
1H), 7.78 (s, 1H), 7.47-7.44 (m, 1H), 7.27-7.24 (m, 1H), 3.43 (s,
3H); ESI-MS (m/z) 467 (MH).sup.+ Example-46; 2,3-
Dimethyl-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-
yl)benzamide ##STR00089## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.25 (s, 1H, D.sub.2O exchangeable), 8.62 (d, J = 2.0 Hz,
1H), 8.44 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 2.0 & 8.0 Hz, 1H),
7.78 (s, 1H), 7.33-7.29 (m, 2H), 7.21-7.18 (m, 1H), 3.44 (s, 3H),
2.30 (s, 3H), 2.28 (s, 3H); ESI-MS (m/z) 459 (MH).sup.+ Example-47:
2- Chloro-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-
yl)benzamide ##STR00090## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.50 (s, 1H, D.sub.2O exchangeable), 8.64 (d, J = 2.0 Hz,
1H), 8.42 (d, J = 8.0 Hz, 1H), 8.18 (dd, J = 2.0 & 8.0 Hz, 1H),
7.78 (s, 1H), 7.65 (dd, J = 2.0 & 7.0 Hz, 1H), 7.58-7.56 (m,
1H), 7.54-7.50 (m, 1H), 7.48- 7.44 (m, 1H), 3.43 (s, 3H); ESI-MS
(m/z) 465, 467 [(MH).sup.+, Cl.sup.35,37] Example-48: 2-
Methyl-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-
oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-
yl)benzamide ##STR00091## .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 11.24 (s, 1H, D.sub.2O exchangeable), 8.63 (d, J = 2.0 Hz,
1H), 8.43 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 2.0 & 8.0 Hz, 1H),
7.77 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.43-7.39 (m, 1H),
7.32-7.28 (m, 2H), 3.43 (s, 3H), 2.42 (s, 3H); ESI-MS (m/z) 445
(MH).sup.+ Example-49: 4-Ethyl- N-(5-(3-(4-methyl-5-
oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-5- (trifluoromethyl)-1H-
pyrazol-1-yl)pyridin-2- yl)benzamide ##STR00092## .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.81 (s, 1H, D.sub.2O exchangeable), 8.62
(d, J = 8.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 2.0
& 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz,
2H), 7.27 (s, 1H), 3.55 (s, 3H), 2.76 (q, J = 7.0 Hz, 2H), 1.28 (t,
J = 7.0 Hz, 3H); ESI- MS (m/z) 459 (MH).sup.+ Example-50: N-(5-(3-
(4-Methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-
(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)-2-naphthamide
##STR00093## .sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 8.96 (s, 1H,
D.sub.2O exchangeable), 8.68 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 2.0
Hz, 1H), 8.51-8.50 (m, 1H), 8.03-8.01 (m, 4H), 7.98-7.94 (m, 2H),
7.68- 7.60 (m, 2H), 3.56 (s, 3H); ESI-MS (m/z) 481 (MH).sup.+
Example-51
5-(1-(6-((2,6-Difluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-py-
razol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00094##
[0255] To a stirred solution of Intermediate-18 (100 mg, 0.307
mmol) in methanol (5 mL), containing molecular sieves (100 mg), was
added 2, 6-difluorobenzaldehyde (97 mg, 0.61 mmol) and acetic acid
(35 .mu.L, 0.61 mmol). The reaction was stirred at room temperature
for 18 h. Sodium cyanoborohydride (38.5 mg, 0.613 mmol) was then
added to the above mixture. The resulting mixture was stirred at
room temperature for 18 h and then filtered. The solid obtained was
washed with methanol and purified by preparative HPLC to obtain 80
mg (55%) of the title compound as white solid. .sup.1HNMR (400 MHz,
CDCl.sub.3) .delta. 8.22 (d, J=2.5 Hz, 1H), 7.57 (dd, J=2.5 &
8.5 Hz, 1H), 7.33-7.25 (m, 1H), 7.20 (s, 1H), 6.92 (t, J=7.5 Hz,
2H), 6.63 (d, J=8.5 Hz, 1H), 5.57 (s, 1H), 4.68 (d, J=6.5 Hz, 2H),
3.53 (s, 3H); ESI-MS (m/z) 453 (MH)+.
Example-52
5-(1-(6-((2-Chloro-6-fluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)--
1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00095##
[0257] The title compound was prepared by following the similar
reductive amination procedure as described in Example-51 using
Intermediate-18 and 2-chloro-6-fluorobenzaldehyde. .sup.1HNMR (400
MHz, DMSO-d.sub.6) .delta. 8.20 (d, J=2.5 Hz, 1H), 7.64 (s, 1H),
7.59 (dd, J=2.5 & 8.5 Hz, 1H), 7.50-7.48 (m, 1H), 7.46-7.37 (m,
1H), 7.39 (s, 1H), 7.26-7.22 (m, 1H), 6.66 (d, J=8.5 Hz, 1H), 4.63
(s, 2H), 3.42 (s, 3H); ESI-MS (m/z) 469, 471 [(MH).sup.+,
Cl.sup.35,37]
Example-53
5-(1-(6-((2-Fluoro-6-methylbenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)--
1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one
##STR00096##
[0259] The title compound was prepared by following the similar
reductive amination procedure as described in Example-51 using
Intermediate-18 and 2-fluoro-6-methylbenzaldehyde. .sup.1HNMR (400
MHz, CDCl.sub.3) .delta. 8.24 (d, J=2.5 Hz, 1H), 7.50 (dd, J=2.5
& 8.5 Hz, 1H), 7.23-7.17 (m, 1H), 7.20 (s, 1H), 7.02 (d, J=7.0
Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 6.50 (d, J=8.5 Hz, 1H), 4.88 (s,
1H), 4.64 (s, 2H), 3.53 (s, 3H), 2.46 (s, 3H); ESI-MS (m/z) 449
(MH).sup.+
Example-54
N-(2,6-Difluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2--
yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide
##STR00097##
[0261] A stirred suspension of Intermediate-3 (0.40 g, 1.12 mmol)
and SOCl.sub.2 (3.29 mL, 45.0 mmol) was heated to 90.degree. C. and
maintained for 4 h. Excess of SOCl.sub.2 was evaporated. The
residue was azeotroped with toluene and dissolved in DCM (20 mL)
and 2,6-difluoroaniline (160 mg, 1.23 mmol), pyridine (0.273 mL,
3.38 mmol) and DMAP (0.014 g, 0.113 mmol) were sequentially added
at 0.degree. C. to the above solution. The reaction was then warmed
to room temperature and then stirred for 18 h at the same
temperature. Reaction was cooled back down to 0.degree. C. and ice
water (10 mL) was added. The separated solid was filtered and dried
under vacuum to afford 70 mg (13%) of the desired product as a
white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 10.58 (s,
1H, D.sub.2O exchangeable), 9.13 (d, J=2.5 Hz, 1H), 8.65 (dd, J=2.5
& 8.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.50-7.42
(m, 1H), 7.24 (t, J=8.0 Hz, 2H), 3.45 (s, 3H); ESI-MS (m/z) 467
(MH).sup.+.
Example-55
N-(2-Chloro-6-fluorophenyl)-6-(3-(4-methyl-5-oxo-4,
5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicot-
inamide
##STR00098##
[0263] The title compound was prepared by reacting Intermediate-3
with 2-chloro-6-fluoroaniline, by following the similar procedure
as described in Example-54. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.63 (s, 1H, D.sub.2O exchangeable), 9.13 (d, J=2.5 Hz,
1H), 8.65 (dd, J=2.5 & 8.5 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H),
7.82 (s, 1H), 7.50-7.42 (m, 3H), 3.45 (s, 3H); ESI-MS(m/z) 483
(MH).sup.+.
Biological Assays and Utility:
[0264] 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-56
[0265] 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.
[0266] In the above IL-2 assay, compounds of the invention were
found to have IC.sub.50 (nM) values as shown below:
TABLE-US-00004 IC.sub.50 (nM) Examples <100 nM 8, 9, 10, 11. 12,
14, 15, 18, 22, 23, 32, 33, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48 51, 52, 53, 55 100 nM-1000 nM 1, 2, 3, 5, 6, 7,16, 17,
19, 20, 21, 24, 25, 34, 35 26, 27, 28, 29, 30, 49, 50, 54 >1000
nM 4, 13, 31
[0267] Thus, compounds of the invention are shown to inhibit IL-2
secretion.
Example-57
[0268] 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 percentage inhibition
of the maximal signal. The dose response data was analysed using
4-parametric sigmoidal dose response (variable slope)
curve-fit.
[0269] 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-58
[0270] 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
minutes 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.
[0271] 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.
[0272] Thus, the in vitro screening assays showed that the
compounds of invention inhibit CRAC channel activity.
[0273] 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
benefitted by the CRAC channel modulatory properties of the
compounds described herein.
[0274] The compounds of the present invention can be administered
to a warm-blooded animal, including human being, for the treatment
and/or prophylaxis of one or many diseases or disorders mentioned
hereinabove which can be benefitted by the CRAC channel modulatory
properties of the compounds described herein. The compounds may be
formulated according to the methods known in the art as well as by
new methods and may be administered to the body system via
gastro-intestinal tract as well as via other routes known to a
person skilled in the art. Thus, administration of the compounds of
the present invention via oral route, parenteral route, inhalation
and/or topical applications are within the scope of this
application. Any combination of a compound of the present invention
with excipients and/or other therapeutic agents known in the art
for the said conditions, diseases and/or disorders are also
encompassed by the present invention.
[0275] 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.
[0276] 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.
* * * * *