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 having the structure of Formula (V): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is aryl or heteroaryl wherein aryl or heteroaryl is optionally substituted with at least one R 3 ; 
 wherein aryl is selected from phenyl and napthyl, 
 wherein heteroaryl is selected from furan, thiophene, pyrrole, oxazole, thiazole, isothiazole, imidazole, isoxazole, pyrazole, oxadiazole, thiadiazole, benzothiazole, benzoxazole, benzofuran, and indole; 
 R 2  is phenyl or pyridyl wherein each is optionally substituted with at least one R 4 ; each 
 R 3  is independently selected from F, Cl, Br, I, CH 3 , Et, CH 2 F, CHF 2  or CF 3 ; 
 each R 4  is independently selected from F, Cl, Br, I, CH 3 , CH 2 F, CHF 2  or CF 3 ; 
 R 5  is H, CH 3 , Et, isopropyl or allyl; 
 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 
 
       
     
     
         2 . The compound of  claim 1  wherein R 2  is phenyl. 
     
     
         3 . The compound of  claim 1  wherein R 2  is pyridyl. 
     
     
         4 . The compound of any one of  claims 1 - 3  wherein each R 4  is independently selected from F and CH 3 . 
     
     
         5 . The compound of any one of  claims 1 - 3  wherein each R 4  is F. 
     
     
         6 . The compound of any one of  claims 1 - 5  wherein R 1  is aryl. 
     
     
         7 . The compound of  claim 6  wherein R 1  is phenyl. 
     
     
         8 . The compound of any one of  claims 1 - 5  wherein R 1  is heteroaryl. 
     
     
         9 . The compound of  claim 8  wherein R 1  is thiazolyl. 
     
     
         10 . The compound of  claim 9  wherein R 1  is unsubstituted thiazolyl. 
     
     
         11 . The compound of  claim 8  wherein R 1  is pyridyl. 
     
     
         12 . The compound of  claim 11  wherein R 1  is unsubstituted pyridyl. 
     
     
         13 . The compound of any one of  claims 1 - 12  wherein R 5  is CH 3 . 
     
     
         14 . The compound of any one of  claims 1 - 12  wherein R 5  is Et. 
     
     
         15 . The compound of any one of  claims 1 - 12  wherein R 5  is allyl. 
     
     
         16 . A compound of Formula V selected from 2,6-difluoro-N-(5-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)benzamide; 2,4,6-trifluoro-N-(5-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)benzamide; 2-fluoro-N-(5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)thiophen-2-yl)-6-methylbenzamide; N-(5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)-2,4,6-trifluorobenzamide; 2,4,6-trifluoro-N-(5-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)benzamide; 2,4-difluoro-N-(5-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)benzamide; 2,6-difluoro-N-(5-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)benzamide; N-(5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)thiophen-2-yl)-2,6-difluorobenzamide; 2,6-difluoro-N-(5-(3-(thiazol-2-yl)-1-vinyl-1H-pyrazol-5-yl)thiophen-2-yl)benzamide; 2,3,6-trifluoro-N-(5-(1-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrazol-5-yl)thiazol-2-yl)benzamide; 2,6-difluoro-N-(5-(1-methyl-3-(5-methyl-1,2,4-oxadiazol -3-yl)-1H-pyrazol -5-yl)thiazol -2-yl)benzamide; 2,6-difluoro-N-(4-methyl-5-(1-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrazol-5-yl)thiazol-2-yl)benzamide; 2-fluoro-6-methyl-N-(5-(1-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrazol-5-yl)thiazol-2-yl)benzamide; 2,3,6-trifluoro-N-(5-(1-methyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)thiazol-2-yl)benzamide; 2,6-difluoro-N-(5-methyl-2-(oxazol-2-yl)-4,5′-bithiazol-2′-yl)benzamide. 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable diluents, excipient, or binder, and a compound of any one of  claims 1 - 16  or a pharmaceutically acceptable salt, pharmaceutically acceptable pro-drug, or pharmaceutically acceptable solvate thereof. 
     
     
         18 . A method for 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 or pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable pro-drug thereof according to any one of  claims 1 - 16 . 
     
     
         19 . A method of modulating store-operated calcium (SOC) channel activity comprising contacting the SOC channel complex, or portion thereof, with a compound or pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable pro-drug thereof according to any one of  claims 1 - 16 . 
     
     
         20 . The method of  claim 19 , wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephrititis, uvetis, 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, schleroderma, osteoporosis, eczema, organ transplant reject, allogeneic or xenogeneic transplantation, graft rejection, graft-versus host disease, lupus erythematosus, type 1 diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, hepatitis and atopic dermatitis, asthma, psoriasis, multiple schlerosis, Sjorgren's syndrome, and autoimmune diseases or disorders.