Triazole-substituted arylamides as p2x3 and p2x2/3 modulators

Abstract

Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, R 1 is optionally substituted triazolyl, 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 - 61 . (canceled) 
     
     
         62 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof, 
       wherein:
 R 1  is optionally substituted triazolyl; 
 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; 
 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; 
 R 6  is:
 hydrogen; 
 C 1-6 alkyl; 
 C 1-6 alkyloxy; 
 halo; 
 C 1-6 haloalkyl; or 
 cyano; and 
 
 one or both of R 7  and R 8  is:
 hydrogen; 
 C 1-6 alkyl; 
 C 1-6 alkyloxy; 
 halo; 
 C 1-6 haloalkyl; or 
 cyano. 
 
 
     
     
         63 . The compound of  claim 62 , wherein R 2  is phenyl substituted once or twice with halo or methyl. 
     
     
         64 . The compound of  claim 62 , 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. 
     
     
         65 . The compound of  claim 62 , wherein, R 2  is pyridin 2-yl substituted with methyl or halo at the 5-position. 
     
     
         66 . The compound of  claim 62 , 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-pyridin-2-yl. 
     
     
         67 . The compound of  claim 62 , wherein R 6  is hydrogen. 
     
     
         68 . The compound of  claim 67 , wherein R 3  is hydrogen. 
     
     
         69 . The compound of  claim 68 , wherein R 4  is hydrogen or methyl. 
     
     
         70 . The compound of  claim 67 , wherein R 7  and R 8  are hydrogen. 
     
     
         71 . The compound of  claim 63 , wherein R 1  is triazolyl optionally substituted once or twice with any of 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. 
     
     
         72 . The compound of  claim 70 , wherein R 1  is triazolyl substituted with C 1-6 alkyl or halo-C 1-6 alkyl. 
     
     
         73 . The compound of  claim 70 , wherein R 1  is triazolyl optionally substituted once with methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 2,2-difluoroethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, isopropoxy, 1-methyl-azetidin-2-yl, 1-dimethylamino-ethyl or dimethylamino-methyl. 
     
     
         74 . The compound of  claim 70 , wherein R 4  and R 5  together with the atom to which they are attached form a cyclopropyl group. 
     
     
         75 . The compound of  claim 62 , 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. 
     
     
         76 . The compound of  claim 62 , wherein R 5  is: C 1-6 alkyloxy-C 1-6 alkyl; hydroxy-C 1-6 alkyl; heteroaryl, or heterocyclyl-C 1-6 alkyl. 
     
     
         77 . The compound of  claim 70 , 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. 
     
     
         78 . A pharmaceutical composition comprising:
 (a) a pharmaceutically acceptable carrier; and   (b) a compound of  claim 62 .   
     
     
         79 . A method for treating a urinary tract disease selected from reduced bladder capacity, frequenct micturition, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, prostatitits, pelvic pain syndrome, prostatodynia, cystitis, or idiophatic bladder hypersensitivity, said method comprising administering to a subject in need thereof an effective amount of a compound of  claim 62 . 
     
     
         80 . 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 62 . 
     
     
         81 . 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 62 .