Therapeutic compounds and methods of use thereof

Abstract

or a pharmaceutically acceptable salt thereof, wherein the variables X, Y1—Y5, R1, R2, R3, R4, and Het have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

1 - 2 . (canceled) 
     
     
         3 . A compound of formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , and R 3  are each independently selected from hydrogen, C 1 -C 6  alkyl, cyano, halo, and C 1 -C 6  haloalkyl; and R 4  and Z together with the benzene ring to which they are both attached form a 9- or 10-membered heterobicycle; 
 Het is 5- or 6-membered heteroaryl optionally substituted with one to three substituents each independently selected from C 1 -C 6  alkyl, cyano, halo, and C 1 -C 6  haloalkyl; 
 X is selected from —N(R 6 ) 2  and —N(R 7 ) 3   + − W, and amine oxides thereof; 
 Y 1  is —C(R 8 ) 2 —; and Y 2  is selected from —(C(R 8 ) 2 ) n —, —N(R 9 )—, —O—, —C(R 8 ) 2 —N(R 9 )—, —N(R 9 )—C(R 8 ) 2 —, —C(R 8 ) 2 —O—, and —O—C(R 8 ) 2 —; or 
 Y 1  is selected from —N(R 9 )— and —O—, and Y 2  is —(C(R 8 ) 2 ) n —; 
 n is selected from 0, 1, and 2; 
 Y 3  and Y 6  are each —C(R 8 ) 2 —; 
 Y 4  and Y 5  are each —C(R 8 )—; 
 each R 6  is independently selected from hydrogen, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkanoyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, and C 6 -C 12  aryl, wherein any C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkanoyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, and C 6 -C 12  aryl is optionally substituted with one or more groups independently selected from deuterium, halo, cyano, hydroxy, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkanoyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, C 3 -C 6  cycloalkyl, C 3 -C 6  halocycloalkyl, —NR a R b , —C(═O)NR a R b , R c , and phenyl, wherein any C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and C 1 -C 6  alkanoyl is optionally substituted with C 3 -C 6  cycloalkyl; or two R 6  groups together with the nitrogen to which they are both attached form a 4- to 10-membered heterocycle that is optionally substituted with one or more groups independently selected from deuterium, halo, cyano, hydroxy, C 1 -C 6  alkyl, and C 3 -C 6  cycloalkyl, which C 1 -C 6  alkyl, and C 3 -C 6  cycloalkyl is optionally substituted with one or more groups independently selected from hydroxy and halo; 
 each R 7  is independently selected from C 1 -C 6  alkyl; or two R 7  groups together with the nitrogen to which they are both attached form a 4- to 7-membered heterocycle; 
 each R 8  is independently selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 3 -C 6  cycloalkyl, benzyl, 5-15 membered heteroaryl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 3 -C 6  cycloalkoxy, hydroxy, halo, cyano, and -L-C6-C 12  aryl; wherein each C 3 -C 6  cycloalkyl, -L-C 6 -C 12  aryl, benzyl, 5-15 membered heteroaryl, and C 1 -C 6  alkoxy, is optionally substituted with one to three substituents R x  each independently selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, cyano, halo, hydroxy, C 3 -C 6  cycloalkoxy, C 3 -C 6  halocycloalkyl, —S(C 1 -C 6  alkyl), —S(O)(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), —NH 2 —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , 4-6 membered heterocycle, and C 1 -C 6  haloalkyl or two R 8  that are on adjacent carbons taken together form a double bond; and R 9  is selected from hydrogen, C 1 -C 6  alkyl and C 6 -C 12  aryl, which C 6 -C 12  aryl is optionally substituted with one to three substituents each independently selected from C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, cyano, halo, and C 1 -C 6  haloalkyl; or one R 8  or R 9  taken together with another R 8  or R 9  and the atoms to which they are attached form a 3-8 membered fused, bridged or spirocyclic ring, which 3-8 membered ring is optionally substituted with one to three substituents each independently selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, cyano, halo, and C 1 -C 6  haloalkyl; and L is selected from a bond, —O—, —S—, —S(O)—, and —S(O) 2 —; 
 each R a  and R b  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, and C 1 -C 6  alkanoyl; 
 each R c  is independently selected from 4-7 membered heterocycle that is optionally substituted with one or more groups independently selected from halo, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; and 
 W −  is a counterion, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 3 , which is a compound of formula Ib: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound of  claim 3 , which is a compound of formula Ic: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 3 , wherein one of Y 1  and Y 2  is —CH(R 8 )— and the other of Y 1  and Y 2  is —CH 2 —; R 8  is not H; Y 3  and Y 6  are each —CH 2 —; and Y 4  and Y 5  are each —CH—; or a pharmaceutically acceptable salt thereof. 
     
     
         7 - 11 . (canceled) 
     
     
         12 . The compound of  claim 6 , wherein R 8  is trifluoromethyl or phenyl that is optionally substituted with one to three substituents each independently selected from C 1 -C 6  alkyl, cyano, halo, and C 1 -C 6  haloalkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The compound of  claim 6 , wherein R 8  is trifluoromethyl or 3-trifluoromethylphenyl; or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 6 , wherein R 8  is phenyl that is optionally substituted with one to three substituents R x  each independently selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, cyano, halo, hydroxy, C 3 -C 6  cycloalkoxy, C 3 -C 6  halocycloalkyl, —S(C 1 -C 6  alkyl), —S(O)(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), —NH 2 —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , 4-6 membered heterocycle, and C 1 -C 6  haloalkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of  claim 6 , wherein R 8  is phenyl that is optionally substituted with one to three substituents R x  each independently selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, cyano, halo, and C 1 -C 6  haloalkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound of  claim 6 , wherein R 8  is phenyl that is optionally substituted with one to three substituents R x  each independently selected from the group consisting of F, Cl, CN, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy; or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The compound of  claim 6 , wherein R 8  is phenyl that is optionally substituted with one to three substituents R x  each independently selected from the group consisting of fluoro, chloro, trifluoromethyl, propyl, cyclopropyl, and trifluoromethoxy; or a pharmaceutically acceptable salt thereof. 
     
     
         18 - 47 . (canceled) 
     
     
         48 . A pharmaceutical composition comprising a compound of  claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         49 - 56 . (canceled) 
     
     
         57 . The compound of  claim 4 , wherein one of Y 1  and Y 2  is —CH(R 8 )— and the other of Y 1  and Y 2  is —CH 2 —; R 8  is not H; Y 3  and Y 6  are each —CH 2 —; and Y 4  and Y 5  are each —CH—; or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The compound of  claim 5 , wherein one of Y 1  and Y 2  is —CH(R 8 )— and the other of Y 1  and Y 2  is —CH 2 —; R 8  is not H; Y 3  and Y 6  are each —CH 2 —; and Y 4  and Y 5  are each —CH—; or a pharmaceutically acceptable salt thereof.