Thiazole and oxazole-substituted arylamides as p2x3 and p2x2/3 antagonists

Abstract

Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, R 1 is a group of formula A or formula B, and X, R 2 , R 3 , R 4 , R 5 , R 6 , R a and R b are as defined herein. Also provided are methods of using the compounds for treating diseases mediated by a P2X 3 and/or a P2X 2/3 receptor antagonist and methods of making the subject compounds.

1 - 53 . (canceled) 
     
     
         54 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 R 1  is a group of formula A or formula B; 
 
       
         
           
           
               
               
           
         
         wherein:
 X is —S— or —O—; and 
 R a  and R b  each independently is:
 hydrogen; 
 C 1-6 alkyl; 
 C 1-6 alkoxy; 
 C 1-6 alkylsulfonyl-C 1-6 alkyl; 
 halo-C 1-6 alkyl; 
 halo-C 1-6 alkoxy; 
 hetero-C 1-6 alkyl; 
 C 3-6 -cycloalkyl; 
 C 3-6 cycloalkyl-C 1-6 alkyl; 
 aminocarbonyl; 
 C 1-6 alkoxycarbonyl; or 
 cyano; 
 or R a  and R b  together with the atom to which they are attached may form a phenyl group that is optionally substituted; 
 
 
         R 2  is:
 optionally substituted phenyl; 
 optionally substituted pyridinyl; 
 optionally substituted pyrimidinyl; 
 optionally substituted pyridazinyl; or 
 optionally substituted thiophenyl; 
 
         R 3  is:
 hydrogen; 
 C 1-6 alkyl; 
 hetero-C 1-6 alkyl; or 
 cyano; 
 
         R 4  is:
 hydrogen; 
 C 1-6 alkyl; or 
 hetero-C 1-6 alkyl; 
 
         or R 3  and R 4  together with the atom to which they are attached may form a C 3-6  carbocyclic ring; 
         R 5  is:
 C 1-6 alkyl; 
 hetero-C 1-6 alkyl; 
 halo-C 1-6 alkyl; 
 N—C 1-6 alkylamino; 
 N,N-di-(C 1-6 alkyl)-amino; 
 C 3-7 cycloalkyl; 
 aryl; 
 heteroaryl; 
 heterocyclyl; 
 C 3-7 cycloalkyl-C 1-6 alkyl; 
 aryl-C 1-6 alkyl; 
 heteroaryl-C 1-6 alkyl; 
 heterocyclyl-C 1-6 alkyl; 
 heterocyclyloxy; 
 aryloxy-C 1-6 alkyl; 
 —(CR c R d ) m —C(O)—R 8  wherein:
 m is 0 or 1; 
 R c  and R d  each independently is:
 hydrogen; or 
 C 1-6 alkyl; and 
 
 R 8  is:
 hydrogen; 
 C 1-6 alkyl; 
 hetero-C 1-6 alkyl; 
 C 3-7 cycloalkyl; 
 aryl; 
 heteroaryl; 
 heterocyclyl; 
 C 3-7 cycloalkyl-C 1-6 alkyl; 
 aryl-C 1-6 alkyl; 
 heteroaryl-C 1-6 alkyl; 
 heterocyclyl-C 1-6 alkyl; 
 C 3-7 cycloalkyloxy; 
 aryloxy; 
 heteroaryloxy; 
 heterocyclyloxy; 
 C 3-7 cycloalkyloxy-C 1-6 alkyl; 
 aryloxy-C 1-6 alkyl; 
 heteroaryloxy-C 1-6 alkyl; 
 heterocyclyloxy-C 1-6 alkyl; or 
 —NR 9 R 10 , wherein: 
  R 9  is: 
  hydrogen; or 
  C 1-6 alkyl; and 
  R 10  is: 
  hydrogen; 
  C 1-6 alkyl; 
  hetero-C 1-6 alkyl; 
  C 3-7 cycloalkyl; 
  aryl; 
  heteroaryl; 
  heterocyclyl; 
  C 3-7 cycloalkyl-C 1-6 alkyl; 
  aryl-C 1-6 alkyl; 
  heteroaryl-C 1-6 alkyl; or 
  heterocyclyl-C 1-6 alkyl; and 
 
 
 
         or R 4  and R 5  together with the atom to which they are attached may form a C 3-6  carbocyclic ring that is optionally substituted with hydroxy; 
         or R 4  and R 5  together with the atom to which they are attached may form a C 4-6  heterocyclic ring containing one or two heteroatoms each independently selected from O, N and S; 
         or R 3 , R 4  and R 5  together with the atom to which they are attached may form a six-membered heteroaryl containing one or two nitrogen atoms, and which is optionally substituted with halo, amino or C 1-6 alkyl; and 
         R 6  is:
 hydrogen; 
 C 1-6 alkyl; 
 C 1-6 alkyloxy; 
 halo; 
 C 1-6 haloalkyl; 
 halo-C 1-6 alkoxy; or 
 cyano. 
 
       
     
     
         55 . The compound of  claim 54 , wherein R 2  is phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2-position with halo. 
     
     
         56 . The compound of  claim 54 , wherein R 2  is pyridin 2-yl substituted with methyl or halo at the 5-position. 
     
     
         57 . The compound of  claim 54 , wherein, R 2  is 4-methyl-phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-fluoro-phenyl, 4-chloro-2-fluoro-phenyl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl, or 2-chloro-4-methyl-phenyl. 
     
     
         58 . The compound of  claim 57 , wherein R 6  is hydrogen. 
     
     
         59 . The compound of  claim 58 , wherein R 3  is hydrogen. 
     
     
         60 . The compound of  claim 58 , wherein R 4  is hydrogen. 
     
     
         61 . The compound of  claim 58 , wherein R 4  is methyl. 
     
     
         62 . The compound of  claim 54 , wherein R 1  is a group of formula A. 
     
     
         63 . The compound of  claim 54 , wherein X is S. 
     
     
         64 . The compound of  claim 54 , wherein one of R a  and R b  is hydrogen and the other is: hydrogen; C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkylsulfonyl-C 1-6 alkyl; halo-C 1-6 alkyl; halo-C 1-6 alkoxy; hetero-C 1-6 alkyl; C 3-6 -cycloalkyl; C 3-6 cycloalkyl-C 1-6 alkyl; aminocarbonyl; C 1-6 alkoxycarbonyl; or cyano. 
     
     
         65 . The compound of  claim 54 , wherein one of R a  and R b  is hydrogen and the other is C 1-6 alkyl. 
     
     
         66 . The compound of  claim 54 , wherein R 5  is: C 1-6 alkyloxy-C 1-6 alkyl; hydroxy-C 1-6 alkyl; heteroaryl, or heterocyclyl-C 1-6 alkyl. 
     
     
         67 . The compound of  claim 54 , wherein R 5  is hydroxymethyl, methoxymethyl, pyrazin-2-yl or 5-methyl-pyrazin-2-yl. 
     
     
         68 . The compound of  claim 54 , wherein said compound is of formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 R 11  and R 12  each independently is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy, halo, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, hetero-C 1-6 alkyl, C 1-6 alkylsulfonyl or cyano; and 
 X, R 4 , R 5 , R a  and R b  are as recited in claim  1 . 
 
     
     
         69 . The compound of  claim 54 , wherein said compound is of formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 R 11  and R 12  each independently is hydrogen, C 1-6 alkyl, C 1-6 alkyloxy, halo, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, hetero-C 1-6 alkyl, C 1-6 alkylsulfonyl or cyano; and 
 X, R 4 , R 5 , R a  and R b  are as recited in claim. 
 
     
     
         70 . A pharmaceutical composition comprising:
 (a) a pharmaceutically acceptable carrier; and   (b) a compound of  claim 54 .   
     
     
         71 . 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 54 . 
     
     
         72 . A method for treating a respiratory disorder selected from chronic obstructive pulmonary disorder (COPD), asthma, and bronchospasm, said method comprising administering to a subject in need thereof an effective amount of a compound of  claim 54 . 
     
     
         73 . A method for treating a gastrointestinal disorder selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, and pain associated with GI distension, said method comprising administering to a subject in need thereof an effective amount of a compound of  claim 54 .