Therapeutic compounds and methods of use thereof

Abstract

The invention provides a method of treating a disease or condition in a mammal by administering a compound having the general formula I:or a pharmaceutically acceptable salt thereof, wherein the variables RAA, n, ring A, X1, L, m, X2, R2, R3, R4, R5, X, and R6 have the meaning as described herein.

We claim: 
     
         1 . A method of treating a disease or condition in a mammal selected from the group consisting of pain, depression, cardiovascular diseases, respiratory diseases, and psychiatric diseases, and combinations thereof, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a salt thereof; wherein 
         each R AA  is independently selected from the group consisting of F, Cl, Br, I, —CN, —OR A1 , —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said 6-12 membered aryl and 5-12 membered heteroaryl of R AA  is optionally substituted with from 1 to 5 substitutents independently selected from the group consisting of F, Cl, Br, I, C 1-4  alkyl, C 1-4  haloalkyl, and C 1-4 (halo)alkoxy; R A1  is selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 1-8  haloalkyl, C 3-8  cycloalkyl, phenyl and benzyl; R A2  is selected from the group consisting of C 1-8  alkyl that is optionally substituted with one or more substituents selected from oxo (═O), fluoro, amino, C 1-4  alkylamino and di(C 1-4 alkyl)amino; X KA  is selected from the group consisting of absent, —C(═O)—, and C 1-4  alkylene; wherein any C 1-4  alkylene of X RA  is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, and phenyl that is optionally substituted with 1 to 5 substitutents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4  alkyl, C 1-4  haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4  alkylamino and C 1-4  dialkylamino; 
         n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
         ring “A” is a 3-15 membered carbocyclyl, a 6-12 membered aryl, a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl; 
         X 1  and X 2  are each independently selected from the group consisting of absent, —S—, —O— and —N(R X )— wherein R x  is H, C 1-8  alkyl, or C 1-8  haloalkyl, and wherein if the subscript m is 0 then one of X 1  or X 2  is absent; 
         L is C 1-6  alkylene, wherein L is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of C 1-4  alkyl, C 1-4  alkoxy, halo, oxo (═O), and C 1-4  haloalkyl; wherein any two substituents attached to the same atom on L are optionally combined to form a 3- to 5-membered carbocyclic ring; 
         m is 0 or 1; 
         R 2  is selected from the group consisting of F, Cl, Br, I, and C 3-8  cycloalkyl; 
         R 4  is selected from the group consisting of F, Cl, Br, I, and C 1-8  haloalkyl; 
         and R 5  are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8  alkyl, C 3-8  cycloalkyl, C 1-8  haloalkyl and C 1-8  alkoxy; 
         X is selected from the group consisting of O, S, S═O, SO 2 , N(R N ), C═O, CH 2 , and C═S, wherein R N  is selected from the group consisting of H, C 1-6  alkyl and acyl; 
         ring “B” is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, wherein ring B is optionally substituted with one or more groups independently selected from C 1-4  alkyl; and 
         R 6  is hydrogen or C 1-6  alkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Id): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Ie): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein ring “B” is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl. 
     
     
         6 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Ik): 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Im): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (In): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Io): 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Ip): 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Iq): 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Ir): 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , wherein the compound of formula (I) is a compound of formula (Is): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein wherein n is 2, 3, 4, or 5. 
     
     
         15 . The method of  claim 1 , wherein ring “A” is a 6-15 membered carbocycle, a 6-10 membered aryl, or a 4-6 membered heterocycle. 
     
     
         16 . The method of  claim 1 , wherein ring “A” is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 1 , wherein the group 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 1 , wherein X 1  is absent; X 2  is —O—; m is 1; and -(L)- is an optionally substituted C 1-4  alkylene. 
     
     
         19 . The method of  claim 1 , wherein wherein:
 ring “A” is a 6-15 membered carbocycle, a 6-10 membered aryl, or a 4-6 membered heterocycle;   X 1  is absent;   X 2  is —O—;   m is 1; and   -(L)- is an optionally substituted C 1-4  alkylene.   
     
     
         20 . The method of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of: