Biphenyl and phenyl-pyridine amides as p2x3 and p2x2/3 antagonists

Abstract

Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, R 1 is optionally substituted phenyl or optionally substituted pyridinyl, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 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 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is: 
 optionally substituted thienyl; 
 optionally substituted pyrimidinyl; or, 
 optionally substituted pyridazinyl; 
 R 2  is:
 hydrogen; or, 
 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 3-7 cycloalkyl; 
 heteroaryl; 
 heterocyclyl; 
 heterocyclyl-C 1-6 alkyl; or, 
 C 3-7 cycloalkyl-C 1-6 alkyl; 
 
 or R 2  and R 3  together form a C 3-7 cycloalkyl; 
 R 4  is:
 hydrogen; 
 C 1-6 alkyl; 
 C 3-7 cycloalkyl; 
 C 3-7 cycloalkyl-C 1-6 alkyl; or, 
 pyrimidinyl; 
 
 R 5  is:
 C 1-6 alkyl; 
 C 1-6 alkoxy; 
 C 3-7 cycloalkyl; 
 C 1-6 alkoxy-C 1-6 alkyl; 
 amino-C 1-6 alkyl; 
 oxetanyl optionally substituted once or twice with C 1-6 alkyl; 
 phenyl optionally substituted once or twice with a group or groups independently selected from C 1-6 alkyl, halo, halo-C 1-6 alkyl and C 1-6 alkoxy; 
 thienyl optionally substituted once or twice with a group or groups independently selected from C 1-6 alkyl and C 1-6 alkoxy; 
 furanyl optionally substituted once or twice with C 1-6 alkyl; 
 thiazolyl optionally substituted once or twice with C 1-6 alkyl; 
 oxazolyl optionally substituted once or twice with C 1-6 alkyl; 
 isoxazolyl optionally substituted once or twice with a group or groups independently selected from C 1-6 alkyl and phenyl; 
 pyrazolyl optionally substituted once or twice with C 1-6 alkyl; 
 thiadiazolyl optionally substituted once with C 1-6 alkyl; 
 tetrahydropyranyl; 
 morpholinyl; 
 piperidinyl optionally substituted with C 1-6 alkyl or acetyl; 
 pyrimidinyl; or, 
 pyridinyl optionally substituted once or twice with C 1-6 alkyl; and 
 
 R 6 , R 7  and R 8  each independently is:
 hydrogen; or, 
 halo. 
 
 
     
     
         2 . The compound of  claim 1  wherein R 7 , R 8  and R 9  are hydrogen. 
     
     
         3 . The compound of  claim 2  wherein R 1  is pyrimidin-2-yl substituted at the 5-position with methyl or halo. 
     
     
         4 . The compound of  claim 3  wherein R 1  is 5-methyl-pyrimidin-2-yl. 
     
     
         5 . The compound of  claim 3  wherein R 1  is pyrimidin-2-yl substituted with halo at the 5-position. 
     
     
         6 . The compound of  claim 2  wherein R 2  is hydrogen. 
     
     
         7 . The compound of  claim 2  wherein R 2  is methyl. 
     
     
         8 . The compound of  claim 2  wherein R 3  is C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkylsulfanyl-C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, amino-C 1-6 alkyl, N—C 1-6 alkyl-amino-C 1-6 alkyl, N,N,-di-C 1-6 alkyl-amino-C 1-6 alkyl, C 3-7 cycloalkyl, optionally substituted phenyl, heteroaryl, or heterocyclyl-C 1-6 alkyl. 
     
     
         9 . The compound of  claim 8  wherein R 3  is C 1-6 alkyloxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, heteroaryl or heterocyclyl-C 1-6 alkyl. 
     
     
         10 . The compound of  claim 9  wherein R 3  is methoxymethyl. 
     
     
         11 . The compound of  claim 9  wherein R 3  is hydroxymethyl. 
     
     
         12 . The compound of  claim 9  wherein R 3  is heteroaryl selected from pyridinyl, pyrimidinyl, or pyrazinyl, each of which may be optionally substituted once or twice with methyl. 
     
     
         13 . The compound of  claim 9  wherein R 3  is hydroxymethyl, methoxymethyl, pyrazin-2-yl or 5-methyl-pyrazin-2-yl. 
     
     
         14 . The compound of  claim 2  wherein R 1  is pyridazin-3-yl. 
     
     
         15 . The compound of  claim 14  wherein R 1  is pyridazin-3-yl substituted at the 6-position with methyl or halo. 
     
     
         16 . The compound of  claim 2  wherein R 1  is thienyl. 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1  and at least one pharmaceutical acceptable carrier, diluent or excipient. 
     
     
         18 . A method of modulating P2X 3  and P2X 2/3  receptor activity in a subject, said method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
     
     
         19 . A method of  claim 18  wherein the subject suffers from a pain condition selected from the group consisting of poisoning, neuritis, neuralgias, interstitial cystitis, nerve injury, ischemic injury, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, cancer pain, pain due to burns, pain associated with irritable bowel syndrome, a viral infection, a parasitic infection, a bacterial infection, a post-traumatic injury, a migraine headache or a cluster headaches.