Inhibitors of jun n-terminal kinase

Abstract

The present disclosure provides inhibitors of c-Jun N-terminal kinases (JNK) having a structure according to the following formula: or a salt or solvate thereof, wherein ring A, C a , C b , Z, R 5 , W and Cy are defined herein. The disclosure further provides pharmaceutical compositions including the compounds of the present disclosure and methods of making and using the compounds and compositions of the present disclosure, e.g., in the treatment and prevention of various disorders, such as Alzheimer's disease.

What is claimed is: 
     
         1 . A compound having a structure according to Formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt or solvate thereof, 
       wherein
 ring A is 5-membered heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C 3 -C 10 -cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR 12 , SR 12 , NR 12 R 13 , C(O)R 14 , C(O)NR 12 R 13 , OC(O)NR 12 R 13 , C(O)OR 12 , NR 15 C(O)R 14 , NR 15 C(O)OR 12 , NR 15 C(O)NR 12 R 13 , NR 15 C(S)NR 12 R 13 , NR 15 S(O) 2 R 14 , S(O) 2 NR 12 R 13 , S(O)R 14  and S(O) 2 R 14 ,
 wherein 
 R 12 , R 13  and R 15  are independently chosen from H, acyl, C 1 -C 6 -alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C 3 -C 8  cycloalkyl and 3- to 8-membered heterocycloalkyl, or R 12  and R 13 , together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and 
 R 14  is chosen from acyl, C 1 -C 6 -alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C 3 -C 8  cycloalkyl and 3- to 8-membered heterocycloalkyl; 
 
 C a  and C b  are carbon atoms, which are adjacent to each other and are part of ring A; 
 Z is 5- or 6-membered heteroaryl, with the proviso that
 (i) when ring A is thiophene, then Z is not a heteroaryl chosen from benzoimidazole, thiazole, and benzothiazole; 
 (ii) when ring A is thiazole, then Z is not benzoimidazole; 
 (iii) when ring A is thiophene, then Z is not substituted oxadiazole; and 
 (iv) when ring A is thiophene, then Z is not pyrimidinone; 
 
 R 5  is chosen from H, acyl, C 1 -C 6  alkyl, and C 3 -C 6  cycloalkyl; 
 W is chosen from C 1 -C 4  alkylene, wherein the alkylene is optionally substituted with 1-4 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C 3 -C 6 -cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR 42 , SR 42 , NR 42 R 43 , C(O)R 44 , C(O)NR 42 R 43 , OC(O)NR 42 R 43 , C(O)OR 42 , NR 45 C(O)R 44 , NR 45 C(O)OR 42 , NR 45 C(O)NR 42 R 43 , NR 45 C(S)NR 42 R 43 , NR 45 S(O) 2 R 44 , S(O) 2 NR 42 R 43 , S(O)R 44 , and S(O) 2 R 44 ,
 wherein 
 R 42 , R 43  and R 45  are members independently chosen from H, acyl, C 1 -C 6 -alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C 3 -C 8  cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R 42  and R 43 , together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and 
 R 44  is independently chosen from acyl, C 1 -C 6 -alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C 3 -C 8  cycloalkyl and 3- to 8-membered heterocycloalkyl; 
 
 Cy is chosen from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6 substituents independently chosen from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, CN, halogen, OR 52 , SR 52 , NR 52 R 53 , C(O)R 54 , C(O)NR 52 R 53 , OC(O)NR 52 R 53 , C(O)OR 52 , NR 55 C(O)R 54 , NR 55 C(O)OR 52 , NR 55 C(O)NR 52 R 53 , NR 55 C(S)NR 52 R 53 , NR 55 S(O) 2 R 54 , S(O) 2 NR 52 R 53 , S(O)R 54  and S(O) 2 R 54 ,
 wherein 
 R 52 , R 53  and R 55  are independently chosen from H, acyl, C 1 -C 6 -alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C 3 -C 8  cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R 52  and R 53 , together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and 
 R 54  is independently chosen from acyl, C 1 -C 6 -alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C 3 -C 8  cycloalkyl and 3- to 8-membered heterocycloalkyl.