Compounds that modulate intracellular calcium

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 or conditions that would benefit from inhibition of SOC channel activity.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 A is C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl or heteroaryl wherein C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, aryl or heteroaryl are independently optionally substituted with at least one R; or A is aryl or heteroaryl substituted with two R groups on adjacent carbon atoms wherein the two R groups and the carbon atoms to which they are attached form a C 4 -C 8 cycloalkyl or C 2 -C 8 heterocycloalkyl; 
 R is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C≡CH, —C≡CR 3 , C 1 -C 6 alkylenealkyne, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, phenyl, —NHS(═O) 2 R 3 , S(═O) 2 N(R 4 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 3 , —S(═O) 2 NHC(═O)R 4 , N(R 4 ) 2 , —N(R 4 )C(═O)R 3 , —CO 2 R 4 , —C(═O)R 3 , —OC(═O)R 3 , —C(═O)N(R 4 ) 2 , —SR 3 , —S(═O)R 3 , and —S(═O) 2 R 3 ; 
 J is a bond, NHS(═O) 2 , S(═O) 2 N(R 4 ), —C(═O), —C(═O)NHS(═O) 2 , —S(═O) 2 NHC(═O), N(R 4 ), —N(R 4 )C(═O), —CO 2 , —C(═O), —OC(═O), —C(═O)N(R 4 ), —S, —S(═O), and —S(═O) 2 , C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, or C 2 -C 6 heterocycloalkylene, wherein C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, and C 2 -C 6 heterocycloalkylene is optionally substituted with at least one R; 
 Q is selected from hydrogen, F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C≡CH, —C≡CR 3 , C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 6 heterocycloalkyl, aryl, heteroaryl, —NHS(═O) 2 R 3 , S(═O) 2 N(R 4 ) 2 , —C(═O)CF 3 , —C(═O)NHS(═O) 2 R 3 , —S(═O) 2 NHC(═O)R 4 , N(R 4 ) 2 , —N(R 4 )C(═O)R 3 , —CO 2 R 4 , —C(═O)R 3 , —OC(═O)R 3 , —C(═O)N(R 4 ) 2 , —SR 3 , —S(═O)R 3 , and —S(═O) 2 R 3 ; 
 R 1  is CO 2 R 2  or a carboxylic acid bioisostere, wherein R 2  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, phenyl or benzyl; 
 Z is O, S, NH, N—CN, or CHNO 2 ; 
 X is W-L-B, or B wherein B is optionally substituted with at least one R; 
 W is NR 2 , O or a bond; 
 L is methylene, ethylene substituted with at least one R, C 3 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, or C 2 -C 6 heterocycloalkylene, wherein methylene, C 3 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, C 1 -C 6 heteroalkylene, C 3 -C 6 cycloalkylene, and C 2 -C 6 heterocycloalkylene is optionally substituted with at least one R; 
 B is C 3 -C 10 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl or heteroaryl; 
 each R 3  is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; 
 each R 4  is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl; or 
 a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. 
 
     
     
         2 . The compound of  claim 1  wherein R 1  is CO 2 R 2 . 
     
     
         3 . The compound of  claim 1  wherein R 2  and Q are both hydrogen. 
     
     
         4 . The compound of  claim 1  wherein R 4  is hydrogen. 
     
     
         5 . The compound of  claim 1  wherein Z is O. 
     
     
         6 . The compound of  claim 1  wherein J is a bond. 
     
     
         7 . The compound of  claim 1  wherein A is aryl. 
     
     
         8 . The compound of  claim 7  wherein aryl is phenyl. 
     
     
         9 . The compound of  claim 8  wherein phenyl is substituted with at least one R. 
     
     
         10 . The compound of any of  claim 9  wherein R is selected from F, Cl, Br, I, or C 1 -C 6 alkyl. 
     
     
         11 . The compound of  claim 1  wherein A is heteroaryl. 
     
     
         12 . The compound of  claim 11  wherein heteroaryl is substituted with at least one R. 
     
     
         13 . The compound of  claim 1  wherein X is B. 
     
     
         14 . The compound of  claim 13  wherein B is heteroaryl. 
     
     
         15 . The compound of  claim 14  wherein heteroaryl is selected from benzoxazole, benzothiazole, benzimidazole, pyrazolopyridine, imidazopyridine, benzoxadiazole, benzothiadiazole, and benzotriazole. 
     
     
         16 . The compound of  claim 14  wherein B is substituted with at least one R. 
     
     
         17 . The compound of  claim 16  wherein R is selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C≡CH, —C≡CR 3 , C 1 -C 6 alkylenealkyne, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, tetrazolyl, C 2 -C 6 heterocycloalkyl, and phenyl. 
     
     
         18 . The compound of  claim 13  wherein B is C 3 -C 8 cycloalkyl. 
     
     
         19 . The compound of  claim 13  wherein B is C 2 -C 8 heterocycloalkyl. 
     
     
         20 . The compound of  claim 13  wherein B is aryl. 
     
     
         21 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable diluent, excipient, carrier or binder thereof. 
     
     
         22 . A method of modulating store-operated calcium (SOC) channel activity comprising contacting the SOC channel complex, or portion thereof, with a compound of  claim 1  or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         23 . A method for treating an autoimmune disease, heteroimmune disease or condition, or inflammatory disease in a mammal comprising administering to the mammal a compound of  claim 1  or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         24 . The method of  claim 23  wherein the autoimmune disease is inflammatory bowel disease, rheumatoid arthritis, myasthenia gravis, multiple sclerosis, Sjogren's syndrome, type I diabetes, lupus erythematosus, psoriasis, osteoarthritis, scleroderma, and autoimmune hemolytic anemia. 
     
     
         25 . The method of  claim 24  wherein the disease, disorder or condition is rheumatoid arthritis.