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 furan, thiophene, pyrrole, pyridine, oxazole, thiazole, imidazole, thiadiazole, isoxazole, isothiazole, pyrazole, pyridazine, pyrimidine, pyrazine, oxadiazole, thiadiazole, triazole, indole, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzoxadiazole, benzothiadiazole, benzotriazole, pyrazolopyridine, imidazopyridine, pyrrolopyridine, pyrrolopyrimidine, indolizine, purine, furopyridine, thienopyridine, furopyrrole, furofuran, thienofuran, 1,4-dihydropyrrolopyrrole, thienopyrrole, thienothiophene, quinoline, isoquinoline, quinoxaline, furopyrazole, thienopyrazole, 1,6-dihydropyrrolopyrazole, C 3 -C 10 cycloalkyl, C 2 -C 8 cycloheteroalkyl, and naphthyl, wherein A is each optionally substituted with at least one R; 
 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; 
 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 B or W-L-B, wherein B is optionally substituted with at least one R; 
 W is NR 2 , O or a bond; 
 L is 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; 
 B is C 3 -C 10 cycloalkyl, C 2 -C 9 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 H. 
     
     
         3 . The compound of  claim 2  wherein R 4  is hydrogen. 
     
     
         4 . The compound of  claim 3  wherein J is a bond and Z is O. 
     
     
         5 . The compound of  claim 4  wherein X is B. 
     
     
         6 . The compound of  claim 5  wherein B is heteroaryl. 
     
     
         7 . The compound of  claim 6  wherein heteroaryl is selected from indole, benzothiophene, benzoxazole, benzofuran, benzothiazole, benzimidazole, benzoxadiazole, benzothiadiazole, benzotriazole, pyrazolopyridine, imidazopyridine, pyrrolopyridine, pyrrolopyrimidine, indolizine, and purine. 
     
     
         8 . The compound of  claim 7  wherein heteroaryl is benzofuran. 
     
     
         9 . The compound of  claim 8  wherein benzofuran is substituted with at least one R selected from F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OH, —OR 3 , —OCF 3 , —C≡CH, and C 1 -C 6 alkyl. 
     
     
         10 . The compound of  claim 8  wherein A is selected from thiophene, thiazole, pyridine, pyrimidine, indole, benzimidazole, benzothiazole, and isoquinoline. 
     
     
         11 . The compound of  claim 10  wherein thiophene, thiazole, pyridine, pyrimidine, indole, benzimidazole, benzothiazole, and isoquinoline is substituted with one R. 
     
     
         12 . The compound of  claim 11  wherein R is selected from F, Cl, Br, I, CF 3  or C 1 -C 6 alkyl. 
     
     
         13 . The compound of  claim 10  wherein A is pyrimidine. 
     
     
         14 . The compound of  claim 10  wherein A is benzothiazole. 
     
     
         15 . The compound of  claim 10  wherein A is isoquinoline. 
     
     
         16 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. 
       
     
     
         17 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. 
       
     
     
         18 . A compound selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. 
       
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable diluent, excipient, carrier or binder thereof. 
     
     
         20 . 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. 
     
     
         21 . A method of modulating calcium release activated calcium channel (CRAC) activity in a mammal comprising administering to the mammal a compound of  claim 1  or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound of  claim 1  modulates CRAC activity in the mammal. 
     
     
         22 . 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. 
     
     
         23 . The method of  claim 22  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. 
     
     
         24 . The method of  claim 22  wherein the heteroimmune disease or condition is graft-versus-host disease, graft rejection, atopic dermatitis, allergic conjunctivitis, organ transplant rejection, allogeneic or xenogenic transplantation, and allergic rhinitis. 
     
     
         25 . The method of  claim 22  wherein the inflammatory disease is uveitis, vasculitis, vaginitis, asthma, inflammatory muscle disease, dermatitis, interstitial cystitis, dermatomyositis, colitis, Crohn's disease, hepatitis, and chronic relapsing hepatitis. 
     
     
         26 . 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  claim 1  or a pharmaceutically acceptable salt or prodrug thereof.