US2013123265A1PendingUtilityA1
Compounds that modulate intracellular calcium
Est. expiryDec 12, 2027(~1.4 yrs left)· nominal 20-yr term from priority
A61P 37/02A61P 35/00A61P 3/10A61P 37/08A61P 7/06A61P 29/00A61P 27/02A61P 25/00A61P 11/02A61K 31/381A61K 31/4439C07D 401/12C07D 413/14A61P 19/02C07D 207/456C07D 495/04A61P 1/00C07D 401/14C07D 333/68C07D 403/04A61P 11/00A61P 13/12C07D 231/40A61K 45/06C07D 213/55C07D 333/74C07D 333/38A61P 17/00C07D 409/12C07D 401/04A61K 31/415A61K 31/444A61K 31/5025C07D 231/38C07D 213/80C07D 413/04A61P 17/06A61P 19/10A61K 31/506A61P 1/16A61K 31/4436C07D 261/18
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Claims
Abstract
Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases, disorders or conditions that would benefit from inhibition of SOC channel activity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
wherein:
L is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 5 ;
V is a bond, O, —(C(R 6 ) 2 ) n —O or NR 1 ;
W is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl; wherein when Y is S and X is CR 3 then V and W are absent;
X is N or CR 3 ;
Y is O, S or NR 3 , with the proviso that if Y is S, then X is not CH;
R is CO 2 R 1 , a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or benzyl;
R 2 and R 4 are independently an aryl, or a heteroaryl, wherein R 2 and R 4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
n is an integer from 1-6;
R 5 is selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 25 —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 6 is independently hydrogen, F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; and
R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, substituted or unsubstituted aryl or benzyl.
2 . The compound of claim 1 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl or iso-propyl.
3 . The compound of claim 1 or 2 , wherein:
R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
4 . The compound of claim 1 or 2 , wherein:
R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from:
5 . The compound of any of claim 1 , 2 , or 4 , wherein:
R 4 is substituted with at least one substituent selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
6 . The compound of claim 1 , wherein:
R 4 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
7 . The compound of claims 1 - 6 , wherein:
R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
8 . The compound of any claims 1 - 6 , wherein:
R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
9 . The compound of any of claims 1 - 6 and 8 , wherein:
R 2 is substituted with one or more of the substituents selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 25 —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
10 . The compound of claim 1 , wherein:
R 2 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
11 . The compound of any of claims 1 - 10 , wherein:
R 1 is hydrogen.
12 . The compound of any of claims 1 - 11 , wherein:
X is N and Y is O.
13 . The compound of any of claims 1 - 11 , wherein:
X is N and Y is CR 3 , wherein R 3 is selected from H or methyl.
14 . The compound of any of claims 1 - 11 , wherein:
X is CR 3 and Y is O, wherein R 3 is selected from H or methyl.
15 . The compound of any of claims 1 - 11 , wherein:
X is CR 3 and Y is NR 3 , wherein each R 3 is independently selected from H or methyl.
16 . A compound of Formula (II), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
wherein:
L is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 5 ;
V is a bond, 0, —(C(R 6 ) 2 ) n —O or NR 1 ;
W is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl;
X is N or CR 3 ;
Y is N or CR 3 ;
R is CO 2 R 1 , a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or benzyl;
R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one R 5 ;
R 4 is an aryl, optionally substituted with at least one R 5 ;
each R 5 is independently selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 6 is independently selected from hydrogen, from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
n is an integer from 1-6;
each R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; and
R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, substituted or unsubstituted aryl or benzyl.
17 . The compound of claim 16 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl or iso-propyl.
18 . The compound of claim 16 or 17 , wherein:
R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
19 . The compound of claim 16 or 17 , wherein:
R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from:
20 . The compound of any of claims 16 , 17 , and 19 , wherein:
R 4 is substituted with at least one substituent selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
21 . The compound of claim 16 , wherein:
R 4 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
22 . The compound of any of claims 16 - 21 , wherein:
R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
23 . The compound of any of claims 16 - 21 , wherein:
R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
24 . The compound of any of claims 16 - 21 and 23 , wherein:
R 2 is substituted with one or more of the substituents selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
25 . The compound of claim 16 , wherein:
R 2 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
26 . The compound of any of claims 16 - 25 , wherein:
R 1 is hydrogen.
27 . The compound of any of claims 16 - 26 , wherein:
X is N and Y is CR 3 , wherein R 3 is selected from H or methyl.
28 . The compound of any of claims 16 - 26 , wherein:
X is N and Y is N.
29 . The compound of any of claims 16 - 26 , wherein:
X is CR 3 and Y is CR 3 , wherein each R 3 is independently selected from H or methyl.
30 . The compound of any of claims 16 - 26 , wherein:
X is CR 3 and Y is N, wherein R 3 is selected from H or methyl.
31 . A compound of Formula (III), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
wherein:
L is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 10 ;
V is a bond, O, —(C(R 3 ) 2 ) n —O or NR 1 ;
W is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl
R is CO 2 R 1 , a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or benzyl;
R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
R 4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 3 is independently selected from hydrogen, from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
n is an integer from 1 to 6;
R 10 is independently selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; and
R 5 , R 6 and R 7 are independently selected from a hydrogen, —OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, substituted or unsubstituted aryl or benzyl.
32 . The compound of claim 31 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl or iso-propyl.
33 . The compound of claim 31 or 32 , wherein:
R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
34 . The compound of claim 31 or 32 , wherein:
R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from:
35 . The compound of any of claims 31 , 32 , and 34 , wherein:
R 4 is substituted with at least one substituent selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
36 . The compound of claim 31 , wherein:
R 4 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
37 . The compound of any of claims 31 - 36 , wherein:
R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
38 . The compound of any of claims 31 - 36 , wherein:
R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
39 . The compound of any of claims 31 - 36 and 37 , wherein:
R 2 is substituted with one or more of the substituents selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
40 . The compound of claim 31 , wherein:
R 2 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
41 . The compound of any of claims 31 - 40 , wherein:
R 1 is hydrogen.
42 . A compound of Formula (IV), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
wherein:
L is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl is optionally substituted with at least one R 10 ;
V is a bond, O, —(C(R 7 ) 2 ) n —O or NR 1 ;
W is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl;
X is N or CR 3 ;
Y is O, S, NR 3 or —CR 5 ═CR 6 —;
R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
R 4 is an aryl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 7 is independently selected from hydrogen, from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
n is an integer from 1-6;
each R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
R 10 is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, substituted or unsubstituted aryl or benzyl; and
R 5 and R 6 are independently selected from a hydrogen, —OH, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, substituted or unsubstituted aryl or benzyl.
43 . The compound of claim 42 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl or iso-propyl.
44 . The compound of claim 42 or 43 , wherein:
R 4 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
45 . The compound of claim 42 or 43 , wherein:
R 4 is an optionally substituted heterocycle wherein the heterocycle is selected from:
46 . The compound of any of claims 42 , 43 , and 45 , wherein:
R 4 is substituted with at least one substituent selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
47 . The compound of claim 42 , wherein:
R 4 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
48 . The compound of any of claims 42 - 47 , wherein:
R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
49 . The compound of any of claims 42 - 47 , wherein:
R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
50 . The compound of any of claims 42 - 47 and 49 , wherein:
R 2 is substituted with one or more of the substituents selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
51 . The compound of claim 42 , wherein:
R 2 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
52 . The compound of any of claims 42 - 51 , wherein:
R 1 is hydrogen.
53 . The compound of any of claims 42 - 51 , wherein:
X is N and Y is S.
54 . A compound of Formula (V), or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof:
wherein:
V is a bond, O, —(C(R 6 ) 2 ) m —O or NR 1 ;
W is a bond, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl;
n=1 or 2;
m is an integer from 1-6;
R is CO 2 R 1 , a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or benzyl;
R 2 is an aryl, or a benzothienyl, wherein the aryl or benzothienyl is optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
R 4 is selected from H, F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 6 is independently selected from hydrogen, from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; and
each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl.
55 . The compound of claim 54 , wherein:
R 1 is hydrogen, methyl, ethyl, n-propyl or iso-propyl.
56 . The compound of claim 54 or 55 , wherein:
R 4 is a substituent selected from H, F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl or C 1 -C 6 haloalkyl.
57 . The compound of any of claim 54 or 55 , wherein:
R 4 is one or more substituents selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
58 . The compound of any of claims 54 - 57 , wherein:
R 2 is a phenyl, optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 8 , —OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 -fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 haloalkyl.
59 . The compound of any of claims 54 - 57 , wherein:
R 2 is an optionally substituted heterocycle wherein the heterocycle is selected from:
60 . The compound of any of claims 54 - 57 and 59 , wherein:
R 2 is substituted with one or more of the substituents selected from —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , or —S(═O) 2 R 8 .
61 . The compound of claim 54 , wherein:
R 2 is selected from phenyl; 2-fluorophenyl; 3-fluorophenyl; 4-fluorophenyl; 2-chlorophenyl; 3-chlorophenyl; 4-chlorophenyl; 2,4-dichlorophenyl; 2,3-dichlorophenyl; 3,4-dichlorophenyl; 3,5-dichlorophenyl; 2-bromophenyl; 3-bromophenyl; 4-bromophenyl; 2-iodophenyl; 3-iodophenyl; 4-iodophenyl; 2-methylphenyl; 3-methylphenyl; 4-methylphenyl; 2,4-dimethylphenyl; 2,3-dimethylphenyl; 3,4-dimethylphenyl; 3,5-dimethylphenyl; 2-trifluoromethylphenyl; 3-trifluoromethylphenyl; and 4 -trifluoromethylphenyl.
62 . The compound of any of claims 54 - 61 , wherein R 1 is hydrogen.
63 . The compound of any of claims 54 - 62 , wherein n=2.
64 . A method of modulating store-operated calcium (SOC) channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of any of claim 1 , 16 , 31 , 42 or 54 , or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
65 . The method of claim 64 , wherein contacting occurs in vitro.
66 . The method of claim 64 , wherein contacting occurs in vivo.
67 . The method of any of claims 64 - 66 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of the store operated calcium channel complex selected from stromal interaction molecules (STIM) family of proteins.
68 . The method of claim 67 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of STIM1 or STIM2.
69 . The method of any of claims 64 - 68 , wherein modulating store operated calcium channel activity with a compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits store-operated calcium entry (SOCE).
70 . The method of any of claims 64 - 69 , wherein the store operated calcium channel complex is calcium-release activated calcium (CRAC) channel complex.
71 . The method of claim 70 , wherein modulating calcium release activated calcium (CRAC) activity with a compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits the electrophysiological current (I CRAC ) associated with activated CRAC channels.
72 . A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of any of claim 1 , 16 , 31 , 42 or 54 , or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
73 . The method of claim 72 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one component of the calcium release activated (CRAC) channel complex selected from stromal interaction molecules (STIM) family of proteins.
74 . The method of claim 73 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with STIM1 or STIM2.
75 . The method of any of claims 72 - 74 wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits store-operated calcium entry (SOCE).
76 . The method of any of claims 72 - 75 , wherein modulating calcium release activated calcium (CRAC) channel activity with a compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits the electrophysiological current (I CRAC ) directly associated with activated CRAC channels.
77 . The method of any of claims 72 - 76 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits SOCE with an IC 50 below about 10 μM.
78 . The method of any of claims 72 - 77 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits electrophysiological current (I CRAC ) associated with activated CRAC channels at a concentration below about 10 μM.
79 . A method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of any of claim 1 , 16 , 31 , 42 or 54 , or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
80 . The method of claim 79 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 modulates the activity of, modulates an interaction of, or binds to, or interacts with a mammalian STIM1 protein, or a mammalian STIM2 protein.
81 . The method of claim 79 or claim 80 , wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, psoriasis, multiple sclerosis, Sjogren's syndrome, and autoimmune diseases or disorders.
82 . The method of claim 81 wherein the disease, disorder, or condition is rheumatoid arthritis.
83 . The method of claim 81 wherein the disease, disorder, or condition is psoriasis.
84 . The method of claim 81 wherein the disease, disorder, or condition is organ transplant rejection.
85 . The method of claim 81 wherein the disease, disorder, or condition is multiple sclerosis.
86 . The method of claim 81 wherein the disease, disorder, or condition is inflammatory bowel disease.
87 . The method of claim 86 wherein the inflammatory bowel disease is ulcerative colitis.
88 . The method of any of claims 79 - 87 , further comprising administering to the mammal a second therapeutic agent.
89 . The method of claim 88 , wherein the second therapeutic agent is selected from immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2-specific inhibitors, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, anti-TNF-α agents, abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, and anticholinergics.
90 . The method of claim 89 , wherein the second therapeutic agent is selected from tacrolimus, cyclosporin, rapamicin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720, prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone, aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398, leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, infliximab, etanercept, adalimumab, abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta-agonists, theophylline, and anticholinergics.
91 . A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering a compound of any of claim 1 , 16 , 31 , 42 or 54 , or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
92 . The method of claim 91 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 modulates an interaction of, or modulates the level of, or binds to, or interacts with a mammalian STIM1 protein, or a mammalian STIM2 protein.
93 . A method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of NFAT in a mammal comprising administering a compound of any of claim 1 , 16 , 31 , 42 or 54 , or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
94 . The method of claim 93 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 modulates an interaction of, or modulates the level of, or binds to, or interacts with a mammalian STIM1 protein or a mammalian STIM2 protein.
95 . The method of claim 94 , wherein the cytokine is selected from IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-1α, IL-1β, IL-1 RA, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), oncostatin M, erythropoietin, leukemia inhibitory factor (LIF), interferons, gamma-interferon (γ-IFN), B7.1 (CD80), B7.2 (B70, CD86), TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail, and migration inhibitory factor (MIF).
96 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of any of claim 1 , 16 , 31 , 42 or 54 , or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
97 . Use of a compound of any of claim 1 , 16 , 31 , 42 or 54 , or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, for the formulation of a medicament for the modulation of store operated calcium (SOC) channel activity in a subject or for the treatment of a disease or condition in a subject that would benefit from the modulation of store operated calcium (SOC) channel activity.
98 . The use of claim 97 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits store operated calcium entry (SOCE).
99 . The use of claim 97 or claim 98 , wherein the store operated calcium channel activity is calcium release activated calcium channel activity.
100 . An article of manufacture, comprising packaging material, a compound of any of claim 1 , 16 , 31 , 42 or 54 , or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, which is effective for inhibiting calcium release-activated calcium (CRAC) channel activity, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from the inhibition of calcium release-activated calcium (CRAC) channel activity, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for the inhibition of calcium release-activated calcium (CRAC) channel activity, or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from the inhibition of calcium release-activated calcium (CRAC) channel activity.
101 . The article of manufacture of claim 100 , wherein the compound of any of claim 1 , 16 , 31 , 42 or 54 inhibits store operated calcium entry (SOCE).
102 . The compound of claim 1 having the structure of Formula (VI):
wherein:
Z is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl; wherein C 1 -C 6 alkyl and C 1 -C 6 heteroalkyl are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 .
R is CO 2 R 1 , a carboxylic acid bioisostere, an optionally substituted heteroaryl, or an optionally substituted heterocycloalkyl;
R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or benzyl;
R 2 and R 4 are independently an aryl, or a heteroaryl, wherein R 2 and R 4 are independently optionally substituted with at least one substituent selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 8 heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —N(R 9 )S(═O) 2 N(R 9 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(═O)R 8 , —N(R 9 ) 2 , —N(R 9 )C(═O)R 8 , —N(R 9 )C(═O)N(R 9 ) 2 , —N(R 9 )C(═O)OR 8 , —CO 2 R 9 , —C(═O)R 8 , —OC(═O)R 8 , —OC(═O)N(R 9 ) 2 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , and —S(═O) 2 R 8 ;
each R 8 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; and
each R 9 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl.
103 . The compound of claim 102 wherein X is C 1 -C 6 alkyl.
104 . The compound of claim 103 wherein X is CH 3 .
105 . The compound of claim 103 wherein X is CH 2 CH 3 .
106 . The compound of any of claims 102 - 105 wherein X is substituted with a substituent selected from F, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 8 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 heteroalkyl.
107 . The compound of any of claims 102 - 106 wherein the substituent is selected from F, Cl, Br, and I.
108 . The compound of claim 102 having the structure
109 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of any of claims 102 - 108 or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
110 . A method of modulating store-operated calcium (SOC) channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of any of claims 102 - 109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
111 . A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering a compound of any of claims 102 - 109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
112 . A method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of any of claims 102 - 109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
113 . A method of inhibiting store-operated calcium entry (SOCE) activation of nuclear factor of activated T cells (NFAT) in a mammal comprising administering a compound of any of claims 102 - 109 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
114 . A method of decreasing cytokine expression by inhibiting the store-operated calcium entry activation of NFAT in a mammal comprising administering a compound of any ofCited by (0)
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