Pyrazole-substituted arylamides as p2x3 and p2x2/3 antagonists

Abstract

Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, R 1 is optionally substituted pyrazolyl, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 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.

1 - 23 . (canceled) 
     
     
         24 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, 
       wherein:
 R 1  is optionally substituted pyrazol; 
 R 2  is optionally substituted phenyl, 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; 
 heteroaryl-C 1-6 alkyl; 
 heterocyclyl-C 1-6 alkyl; 
 aryl-C 1-6 alkyl; 
 aryloxy-C 1-6 alkyl; 
 —(CR a R b ) m —C(O)—R 8  wherein:
 m is 0 or 1; 
 R a  and R b  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; 
 
 
 
 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 , R 7  and R 8  each independently is:
 hydrogen 
 C 1-6 alkyl; 
 C 1-6 alkyloxy; 
 halo; 
 C 1-6 haloalkyl; or 
 cyano. 
 
 
     
     
         25 . The compound of  claim 24 , wherein R 1  is pyrazolyl optionally substituted with C 1-6 alkyl, halo-C 1-6 alkyl, hetero-C 1-6 alkyl, C 1-6 alkoxy, phenyl, heterocyclyl, C 3-6 -cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl or cyano. 
     
     
         26 . The compound of  claim 24 , wherein R 1  is pyrazolyl optionally substituted once with C 1-6 alkyl or halo-C 1-6 alkyl. 
     
     
         27 . The compound of  claim 24 , wherein R 2  is phenyl substituted at the 4-position with methyl or halo and optionally substituted at the 2- and 6-positions with halo. 
     
     
         28 . The compound of  claim 24 , 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. 
     
     
         29 . The compound of  claim 24 , wherein R 2  is pyridin 2-yl substituted with methyl or halo at the 5-position and optionally substituted with halo at the 3-position. 
     
     
         30 . The compound of  claim 24 , wherein R 2  is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridin-2-yl, 5-methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-ppyridin-2-yl. 
     
     
         31 . The compound of  claim 24 , wherein R 6 , R 7  and R 8  are hydrogen. 
     
     
         32 . The compound of  claim 24 , wherein R 3  is hydrogen. 
     
     
         33 . The compound of  claim 24 , wherein R 4  is hydrogen. 
     
     
         34 . The compound of  claim 24 , wherein R 4  is methyl. 
     
     
         35 . The compound of  claim 24 , wherein R 4  and R 5  together with the atom to which they are attached form a C 3-6  carbocyclic ring that is optionally substituted with hydroxy. 
     
     
         36 . The compound of  claim 24 , wherein R 5  is: C 1-6 alkyl; C 1-6 alkyloxy-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. 
     
     
         37 . The compound of  claim 24 , wherein R 5  is: C 1-6 alkyloxy-C 1-6 alkyl; hydroxy-C 1-6 alkyl; heteroaryl, or heterocyclyl-C 1-6 alkyl. 
     
     
         38 . The compound of  claim 24 , wherein R 5  is: hydroxymethyl, methoxymethyl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 6-methyl-pyridazin-3-yl, or 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl. 
     
     
         39 . The compound of  claim 24 , wherein said compound is of formula IIa or IIb: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 X is C; 
 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 
 
 R 1  and R 5  are as recited in  claim 24   
 
     
     
         40 . The compound of  claim 24 , wherein said compound is of formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 X is C; 
 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 
 
 R 1  and R 5  are as recited in  claim 24   
 
     
     
         41 . A pharmaceutical composition comprising:
 (a) a pharmaceutically acceptable carrier; and   (b) a compound of  claim 24 .   
     
     
         42 . 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 24 . 
     
     
         42 . 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 24 . 
     
     
         43 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, 
       wherein:
 R 1  is optionally substituted pyrazole; 
 R 2  is optionally substituted phenyl, 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: hydroxymethyl, methoxymethyl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 6-methyl-pyridazin-3-yl, or 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl 
 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 , R 7  and R 8  each independently is:
 hydrogen 
 C 1-6 alkyl; 
 C 1-6 alkyloxy; 
 halo; 
 C 1-6 haloalkyl; or 
 cyano.