Atf6 inhibitors and uses thereof

Abstract

Compounds as inhibitors of Activating Transcription Factor 6 (ATF6) are provided. The compounds may find use as therapeutic agents for the treatment of diseases or disorders mediated by ATF6 and may find particular use in the treatment of viral infections, neurodegenerative diseases, vascular diseases, or cancer.

1 .- 112 . (canceled) 
     
     
         113 . A method of preparing a compound of Formula (A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         one of G 1  and G 2  is N and one of G 1  and G 2  is CR d ,
 wherein R d  is H or C 1 -C 6 alkyl; 
 
         R 1  is H, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl; or R 1  is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6  haloalkyl; 
         R 8  is H or C 1 -C 6 alkyl, 
         n is 0 or 1; 
         L is —CH 2 — or is absent; 
         R 2 , R 3 , R 4 , R 5 , and R 6  are each independently H, halo, CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, provided that either at least two of R 2 , R 3 , R 4 , R 5 , and R 6  are other than H, or that one of R 2 , R 3 , R 4 , R 5 , and R 6  is cyano; 
         or R 2 , R 4 , R 5 , and R 6  are each independently H, halo, CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl and R 3  is taken together with an R 1  and the atoms to which they are attached to form a 5- or 6-membered ring, wherein the 5- or 6-membered ring is unsubstituted or substituted with one to three groups selected from the group consisting of halo, CN, OH, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; 
         A is 
       
       
         
           
           
               
               
           
         
         
           wherein --- indicates that 
         
       
       
         
           
           
               
               
           
         
         
            is attached in either an E or Z configuration; 
         
         R a  and R b  are each independently H, C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, 6-membered aryl, or 5- or 6-membered heteroaryl, wherein each C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, 6-membered aryl, or 5- or 6-membered heteroaryl of R a  and R b  is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 alkyl, or is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; 
         R c  is C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, 6-membered aryl, or 5- or 6-membered heteroaryl, wherein each C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, 6-membered aryl, or 5- or 6-membered heteroaryl of R c  is unsubstituted or substituted with one to four groups selected from the group consisting of OH, halo, and C 1 -C 6 alkyl; 
         R e  is H, or C 1 -C 6 alkyl;
 provided that when A is 
 
       
       
         
           
           
               
               
           
         
         
            and R a  is H, methyl, ethyl, n-Pr, i-Pr, i-Bu, 2-thiofuryl, 2-furyl, unsubstituted phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-fluorophenyl, or 2,4-dichlorophenyl, at least one of (i.)-(ix.) applies:
 (i.) G 2  is N; 
 (ii.) n is 1, L is absent, and R 1  is C 1 -C 6 alkyl; 
 (iii.) n is 0, L is absent, and at least one of R 2 , R 3 , R 4 , R 5 , and R 6  is halo, CN, or C 1 -C 6 haloalkyl; 
 (iv.) n is 1, and R 3  is taken together with R 1  and the atoms to which they are attached to form a 5- or 6-membered ring; 
 (v.) one of R 2 , R 3 , R 4 , R 5 , and R 6  is CN; 
 (vi.) R 4  and R 5  are each independently Cl, Br, I, CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; 
 (vii.) one of R d  and R 7  is C 1 -C 6 alkyl; 
 (viii.) R 2  and R 3  are each Cl; and 
 (ix.) at least one of R 2 , R 3 , R 4 , R 5 , and R 6  is F, Br, I, CN, or C 1 -C 6 haloalkyl and R a  is H or 2-thiofuryl; 
 
           provided that when A is 
         
       
       
         
           
           
               
               
           
         
         
            and n is 1, then R 1  is other than H; 
           provided that when A is 
         
       
       
         
           
           
               
               
           
         
         
            n is 0 and L is absent, then R a  is other than H; 
           provided that when A is 
         
       
       
         
           
           
               
               
           
         
         
            and R e  is methyl, then R a  is other than unsubstituted phenyl; 
           provided that when A is 
         
       
       
         
           
           
               
               
           
         
         
            n is 1 and L is absent, then R 1  is other than H; 
         
         and 
         R 7  is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
 provided that when R d  is C 1 -C 6 alkyl, R 7  is H, and when R 7  is C 1 -C 6 alkyl, R d  is H, comprising: 
 
         (i) reducing a compound of Formula (1), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  R 7 , L, G 1  and G 2  are as defined in Formula (A), to a primary amine of Formula (2) in the presence of a reducing agent; 
       
       
         
           
           
               
               
           
         
         (ii) optionally converting the primary amine of Formula (2) to a secondary amine of Formula (3) by an alkylating agent; and 
       
       
         
           
           
               
               
           
         
         (iii) reacting the primary amine of Formula (2) or the secondary amine of Formula (3) with an acid of Formula (4), wherein A is as defined in Formula (A), to obtain the compound of Formula (A) 
       
       
         
           
           
               
               
           
         
       
     
     
         114 . The method of  claim 113 , further comprising:
 reducing the carbonyl group of a compound of Formula (5) to obtain a compound of Formula (6), wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are as defined in Formula (A), and   
       
         
           
           
               
               
           
         
         reacting the compound of Formula (6) with a nitro compound of Formula (7), wherein R 7 , G 1  and G 2  are as defined in Formula (A), to obtain the compound of Formula (1), wherein n is 1 and L is absent 
       
       
         
           
           
               
               
           
         
       
     
     
         115 . The method of  claim 113 , further comprising:
 reacting a compound of Formula (8), wherein R 2 , R 3 , R 4 , R 5 , and R 6  are as defined in Formula (A) and X is halogen, with a nitro compound of Formula (7), wherein R 7 , G 1  and G 2  are as defined in Formula (A), to obtain the compound of Formula (1), wherein L is absent   
       
         
           
           
               
               
           
         
       
     
     
         116 . The method of  claim 113 , further comprising:
 reacting a compound of Formula (9), wherein R 2 , R 4 , R 5 , and R 6  are as defined in Formula (A), with a nitro compound of Formula (7), wherein R 7 , G 1  and G 2  are as defined in Formula (A), to obtain the compound of Formula (1), wherein L is absent, R 3  is taken together with R 1  and the atoms to which they are attached to form a 5-membered cycloalkyl   
       
         
           
           
               
               
           
         
       
     
     
         117 . The method of  claim 113 , further comprising:
 reacting a compound of Formula (10), wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are as defined in Formula (A) and X is halogen, with a nitro compound of Formula (7), wherein R 7 , G 1  and G 2  are as defined in Formula (A), to obtain the compound of Formula (1), wherein n is 1 and L is —CH 2 —