Indole, indazole and benzimidazole arylamides as p2x3 and p2x2/3 antagonists

Abstract

Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X 3 and/or a P2X 2/3 receptor antagonists and methods of making the compounds.

What is claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 R 1  is: C 1-6 alkyl; or halo; 
 R 2  is: C 3-6 cycloalkyl; C 1-6 alkoxy-C 1-6 alkyl; hydroxy-C 1-6 alkyl; or heteroaryl-C 1-6 alkyl; 
 R 3  is: C 1-6 alkyl; hydroxy-C 1-6 alkyl; C 1-6 alkoxy-C 1-6 alkyl; halo-C 1-6 alkyl; C 3-6 cycloalkyl; C 3-6 cycloalkyl-C 1-6 alkyl; phenyl optionally substituted with halo, C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl; or phenyl-C 1-6 alkyl wherein the phenyl portion thereof is optionally substituted with halo, C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl; 
 R 4  and R 5  each independently is: hydrogen; or fluoro; 
 X is: N; or CR a  wherein R a  is C 1-6 alkyl or halo. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R 4  and R 5  are hydrogen. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is methyl. 
     
     
         4 . The compound of  claim 2 , wherein R 2  is: cyclopropyl; 2-methoxy-1-methyl-ethyl; 2-hydroxy-1-methyl-ethyl; 5-methylpyrazin-2-yl-methyl; 1-pyrazin-2-yl-ethyl; pyrimidin-5-yl-methyl; 6-methyl-pyridazin-3-yl-methyl; pyridazin-3-yl-methyl; 5-methyl-pyrimidin-yl-methyl; or 2-methyl-pyrimidin-5-yl-methyl. 
     
     
         5 . The compound of  claim 2 , wherein R 2  is 2-hydroxy-1-methyl-ethyl; 5-methylpyrazin-2-yl-methyl; or 1-pyrazin-2-yl-ethyl. 
     
     
         6 . The compound of  claim 2 , wherein R 3  is C 1-6 alkyl; halo-C 1-6 alkyl; phenyl optionally substituted with C 1-6 alkyl; or phenyl-C 1-6 alkyl wherein the phenyl portion thereof is optionally substituted with C 1-6 alkyl. 
     
     
         7 . The compound of  claim 2 , wherein R 3  is isopropyl, isobutyl, n-propyl, 3-methyl-butyl, 222-trifluoroethyl, 2-methoxyethyl, phenyl, benzyl, 2-methyl-phenyl; 4-methyl-phenyl; or 2-isopropyl-phenyl. 
     
     
         8 . The compound of  claim 2 , wherein R 3  is isopropyl, isobutyl, n-propyl, or 3-methyl-butyl. 
     
     
         9 . The compound of  claim 2 , wherein R 3  is phenyl, 2-methyl-phenyl; 4-methyl-phenyl; or 2-isopropyl-phenyl. 
     
     
         10 . The compound of  claim 2 , wherein X is —N—. 
     
     
         11 . The compound of  claim 2 , wherein X is —CR a —. 
     
     
         12 . The compound of  claim 11 , wherein R a  is hydrogen or halo. 
     
     
         13 . The compound of  claim 2 , wherein R a  is hydrogen. 
     
     
         14 . The compound of  claim 1 , wherein said compound is selected from:
 3-Isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide; and   3-Isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide.   
     
     
         19 . A pharmaceutical composition comprising:
 (a) a pharmaceutically acceptable carrier; and   (b) a compound of  claim 1 .   
     
     
         20 . A method for treating a pain condition selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury, or pain associated with irritable bowel syndrome, said method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .