Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators

Abstract

The invention is concerned with the compounds of formula I or II: and salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I or II as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

We claim: 
     
         1 . A compound of formula II: 
       
         
           
           
               
               
           
         
         wherein:
 (1) A is 
 
       
       
         
           
           
               
               
           
         
         
           B is B 1  and R 5  is R 5a ; or 
           (2) A is 
         
       
       
         
           
           
               
               
           
         
         
           B is B 2  and R 5  is R 5b ; or 
           (3) A is 
         
       
       
         
           
           
               
               
           
         
         
           B is B 3  and R 5  is R 5a ; or 
           (4) A is 
         
       
       
         
           
           
               
               
           
         
         
           B is B 4  and R 5  is R 5a ; or 
           (5) A is 
         
       
       
         
           
           
               
               
           
         
         
           B is B 1  and R 5  is R 5a ; or 
           (6) A is 
         
       
       
         
           
           
               
               
           
         
         
           B is B 5  and R 5  is R 5a ; or 
           (7) A is 
         
       
       
         
           
           
               
               
           
         
         
           B is B 3  and R 5  is R 5a ; 
           B is a 5-membered heteroaryl comprising 2 or 3 nitrogen atoms in the ring that is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —CN, and NR 6   2  (C 3 -C 7 )cycloalkyl; 
           R 1  is a phenyl or 5-membered heteroaryl, wherein R 1  is optionally substituted with one or more groups independently selected from halogen, —CN, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl; 
           R 2  is halogen, (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2  is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl; 
           each R 3a  is independently selected from H, halogen and (C 1 -C 6 )alkyl; 
           one R 3b  group is halogen, —CN, or (C 1 -C 6 )alkyl and the remaining R 3b  groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
 one R 3b ′ group is halogen, (C 1 -C 6 )alkyl, —CN, or (C 1 -C 6 )haloalkyl and the remaining R 3b ′ groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl; 
 
           two R 3c  groups attached to different non-adjacent carbon atoms or adjacent carbon atoms are combined to form a (C 1 -C 4 )alkyl linker or a (C 1 -C 2 )alkyl-O-(C 1 -C 2 )alkyl linker, wherein the (C 1 -C 4 )alkyl linker or (C 1 -C 2 )alkyl-O-(C 1 -C 2 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3c  groups are independently selected from H, halogen and (C 1 -C 6 )alkyl; 
           each R 3d  group is independently selected from H, halogen, (C 1 -C 6 )alkyl, and —CN, wherein any (C 1 -C 6 )alkyl of R 3d  is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl; 
           one R 3e  group is halogen, —CN or (C 1 -C 6 )alkyl and the remaining R 3e  groups are independently selected from H, (C 1 -C 6 )alkyl and (C 1 -C 6 )haloalkyl;
 two R 3f  groups attached to the same carbon atom are combined to form a (C 2 -C 4 )alkyl linker, wherein the (C 2 -C 4 )alkyl linker is optionally substituted with one or more groups independently selected from halogen and (C 1 -C 6 )alkyl, and the remaining R 3f  groups are independently selected from H, halogen and (C 1 -C 6 )alkyl; 
 
           R 4  is H, (C 1 -C 6 )alkyl or (C 1 -C 6 )haloalkyl; 
           R 5  is R 5a  or R 51 ); 
           R 5 a is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a  is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl-O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, oxo and —O—(C 1 -C2)alkyl-O- optionally substituted with one or more halogen, which —O—(C 1 -C 2 )alkyl-O- group is bonded to two adjacent carbon atoms of any phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 4, 5, 6 or 7-membered heterocycle or (C 3 -C 8 )cycloalkyl of R 5a ; 
           R 5b  is a phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 5, 6, 7 or 8-membered heterocycle, wherein any phenyl, 5-membered heteroaryl, 6-membered heteroaryl or 4, 6, 7 or 8-membered heterocycle of R 5b  is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl optionally substituted with one or more halogen, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —OH, —S(C 1 -C 6 )alkyl, —S(C 1 -C 6 )haloalkyl, and NR 6   2 , and wherein any 5-membered heterocycle of R 5b  is substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —CN, (C 3 -C 7 )cycloalkyl, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )haloalkyl, —S(C 1 -C 6 )alkyl and —S(C 1 -C 6 )haloalkyl; and 
           each R 6  is independently H or (C 1 -C 6 )alkyl; 
           or pharmaceutically acceptable a salt thereof. 
         
       
     
     
         2 . The compound of  claim 1 , wherein:
 (1) A is   
       
         
           
           
               
               
           
         
         B is B 1  and R 5  is R 5a ; or
 (2) A is 
 
       
       
         
           
           
               
               
           
         
         B is B 2  and R 5  is R 5b ; or 
         (3) A is 
       
       
         
           
           
               
               
           
         
         B is B 3  and R 5  is R 5a ; or 
         (4) A is 
       
       
         
           
           
               
               
           
         
         B is B 4  and R 5  is R 5a ; or 
         (5) A is 
       
       
         
           
           
               
               
           
         
         B is B 1  and R 5  is R 5a ; or 
         (6) A is 
       
       
         
           
           
               
               
           
         
         B is B 5  and R 5  is R 5a ; or 
         (7) A is 
       
       
         
           
           
               
               
           
         
         B is B 3  and R 5  is R. 
       
     
     
         3 . The compound of  claim 1  wherein each R 3a  is independently H or F. 
     
     
         4 . The compound of  claim 1  wherein one R 3a  is F and the remaining R 3a  groups are H. 
     
     
         5 . The compound of  claim 1  wherein each R 3a  is H. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is (C 1 -C 6 )alkyl or CN, wherein any (C 1 -C 6 )alkyl of R 2  is optionally substituted with one or more groups independently selected from halogen, —OH and —O(C 1 -C 6 )alkyl. 
     
     
         7 . The compound of  claim 1 , wherein R 2  is —CH 3 , —CH 2 OH, —CHF 2 , —CH 2 OCH 3  or CN. 
     
     
         8 . The compound of  claim 1 ,wherein R 2  is —CH 3 . 
     
     
         9 . The compound of  claim 1 ,wherein B is a pyrazolyl or triazolyl, each of which is optionally substituted with one or more groups independently selected from halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl. 
     
     
         10 . The compound of  claim 1 , wherein B is: 
       
         
           
           
               
               
           
         
         wherein each R Z1  is independently selected from H, halogen, (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl. 
       
     
     
         11 . The compound of  claim 1 , wherein one R 3b  group is F and the remaining R 3b  groups are H, and one R 3b ′ group is F and the remaining R 3b ′ groups are H. 
     
     
         12 . The compound of  claim 1 , wherein
 (1) the A group   
       
         
           
           
               
               
           
         
         is: 
       
       
         
           
           
               
               
           
         
         (2) the A group 
       
       
         
           
           
               
               
           
         
         is: 
       
       
         
           
           
               
               
           
         
         and 
         (3) the A group 
       
       
         
           
           
               
               
           
         
         is: 
       
       
         
           
           
               
               
           
         
       
     
     
         13 . A pharmaceutical composition, comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         14 . A method for treating a respiratory disorder in a mammal comprising, administering a compound of  claim 1  or a pharmaceutically acceptable salt thereof to the mammal.