Modulators of the integrated stress pathway

Abstract

Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases; disorders and conditions.

1 .- 53 . (canceled) 
     
     
         54 . A method of making a compound of formula (1-6): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, comprising: 
         (i) contacting a compound of formula (1-1): 
       
       
         
           
           
               
               
           
         
         
           with a compound of formula (1-2): 
         
       
       
         
           
           
               
               
           
         
         
           to make a compound of formula (1-3): 
         
       
       
         
           
           
               
               
           
         
         
           follow by a hydrolysis step to make a compound of formula (1-4): 
         
       
       
         
           
           
               
               
           
         
       
       and
 (ii) contacting the compound of formula (1-4) with a compound of formula (1-5): 
 
       
         
           
           
               
               
           
         
         
           thereby making the compound of formula (1-6); wherein: 
         
       
       
         
           
           
               
               
           
         
         
           D is 
           L 1  is CH 2 O —* or CH 2 OCH 2 —*, L 2  is selected from CH 2 O —*, CH 2 O CH 2 —*, or —O—, and “-*” indicates the attachment point to A or Z, respectively; 
           R 1  is hydrogen or C 1 -C 6  alkyl; 
           A is phenyl or 5-6-membered heteroaryl, wherein the phenyl or 5-6-membered heteroaryl is substituted with 0-5 R Y ; 
           Z is hydrogen, phenyl, or 5-6-membered heteroaryl, wherein each phenyl or 5-6-membered heteroaryl is substituted with 0-5 R Y ; 
           each R X  is independently selected from the group consisting of C 1 -C 6  alkyl, hydroxy-C 1 -C 6  alkyl, halo-C 1 -C 6  alkyl, amino-C 1 -C 6  alkyl, cyano-C 1 -C 6  alkyl, oxo, halo, cyano, —OR A , —NR B R C , —NR B C(O)R D , —C(O)NR B R C , —C(O)R D , —C(O)OH, —C(O)OR D , —SR E , —S(O)R D , and —S(O) 2 R D ; 
           each R Y  is independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, hydroxy-C 1 -C 6  alkyl, halo-C 1 -C 6  alkyl, halo-C 1 -C 6  alkoxy, amino-C 1 -C 6  alkyl, cyano-C 1 -C 6  alkyl, oxo, halo, cyano, —OR A , —NR B R C , —N B C(O)R D , —C(O)NR B R C , —C(O)R D , —C(O)OH, —C(O)OR D , —S(R F ) m , —S(O)R D , —S(O) 2 R D , and G 1 ; or 
           2 R Y  groups on adjacent atoms, together with the atoms to which they are attached form a 3-7-membered fused cycloalkyl, 3-7-membered fused heterocyclyl, aryl, or 5-6 membered fused heteroaryl substituted with 0-5 R X ; 
           each G 1  is independently 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl, wherein each 3-7-membered cycloalkyl, 3-7-membered heterocyclyl, aryl, or 5-6-membered heteroaryl is substituted with 0-3 R Z ; 
           each R Z  is independently selected from the group consisting of C 1 -C 6  alkyl, hydroxy-C 1 -C 6  alkyl, halo-C 1 -C 6  alkyl, halo, cyano, —OR A , —NR B R C , N B C(O)R D , —C(O)NR B R C , —C(O)R D , —C(O)OH, —C(O)OR D , and —S(O) 2 R D ; 
           R A  is, at each occurrence, independently hydrogen, C 1 -C 6  alkyl, halo-C 1 -C 6  alkyl, —C(O)NR B R C , —C(O)R D , —C(O)OH, or —C(O)OR D ; 
           each of R B  and R C  is independently hydrogen or C 1 -C 6  alkyl; or 
           R B  and R C  together with the atom to which they are attached form a 3-7-membered heterocyclyl ring substituted with 0-3 R Z ; 
           each R D  is independently C 1 -C 6  alkyl or halo-C 1 -C 6  alkyl; 
           each R E  is independently hydrogen C 1 -C 6  alkyl, or halo-C 1 -C 6  alkyl; 
           each R F  is independently hydrogen, C 1 -C 6  alkyl, or halo; and 
           m is 1, 3, or 5. 
         
       
     
     
         55 . The method of  claim 54 , wherein D is substituted with 0 or 1 R X . 
     
     
         56 . The method of  claim 54 , wherein D is 
       
         
           
           
               
               
           
         
       
     
     
         57 . The method of  claim 54 , wherein D is 
       
         
           
           
               
               
           
         
       
     
     
         58 . The method of  claim 57 , wherein R X  is oxo or —OH. 
     
     
         59 . The method of  claim 54 , wherein R 1  is hydrogen. 
     
     
         60 . The method of  claim 54 , wherein A is phenyl, pyridyl, or isoxazolyl, each of which is substituted with 0-2 R Y  groups. 
     
     
         61 . The method of  claim 54 , wherein A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         62 . The method of  claim 54 , wherein W is oxadiazolyl, imidazolyl, or triazolyl. 
     
     
         63 . The method of  claim 54 , wherein W is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         64 . The method of  claim 54 , wherein Z is phenyl or pyridyl, each of which is substituted with 0-2 R Y  groups. 
     
     
         65 . The method of  claim 54 , wherein Z is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         66 . The method of  claim 54 , wherein Z is hydrogen. 
     
     
         67 . The method of  claim 54 , wherein each R Y  is independently selected from the group consisting of chloro, fluoro, —CF 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —OCH 3 , —OCH(CH 3 ) 2 , —CN, and G 1 , wherein G 1  is cyclopropyl; or
 2 R Y  groups on adjacent atoms, together with the atoms to which they are attached, form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is substituted with 0-5 R X , wherein each R X  is independently fluoro. 
 
     
     
         68 . The method of  claim 54 , wherein:
 R 1  is hydrogen;   A and W are each independently phenyl, pyridyl, oxadiazolyl, imidazolyl, triazolyl, or isoxazolyl, each of which is optionally substituted with 1-5 R Y  groups;   Z is hydrogen, phenyl, or pyridyl, wherein phenyl or pyridyl is substituted with 0-5 R Y  groups;   each R X  is fluoro, oxo, or —OH;   each R Y  is independently chloro, fluoro, —CF 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —OCH 3 , —OCH(CH 3 ) 2 , —CN, or -G 1 ; or   2 R Y  groups on adjacent atoms, together with the atoms to which they are attached form a furanyl, pyrrolyl, or dioxolanyl ring, each of which is substituted with 0-2 R X ; and   G 1  is cyclopropyl.   
     
     
         69 . The method of  claim 54 , wherein the compound of formula (1-6) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutical acceptable salt thereof.