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.

1 . (canceled) 
     
     
         2 : 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 triazole optionally substituted with alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, —R a , —OR a , —SR a , ═O, ═NR a , ═N—OR a , —NR a R b , -halogen, —SiR a R b R c , —OC(O)R a , —C(O)R e , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR c C(O)R e , —NR c C(O)NR a R b , —NR c C(S)NR a R b , —NR c C(O)OR a , —NR c C(NR a R b )═NR d , —S(O)R e , —S(O) 2 R e , —S(O) 2 NR a R b , —NR c S(O) 2 R a , —CN, —NO 2 , —N 3 , —CH(Ph) 2 , fluoro(C 1 -C 4 )alkoxy, and fluoro(C 1 -C 4 )alkyl,
 wherein 
 R a , R b , R c , R d  and R e  each independently hydrogen, C 1 -C 24  alkyl, C 3 -C 10  cycloalkyl, C 1 -C 24  heteroalkyl, C 3 -C 10  heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; and wherein where two R groups are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring 
 
 R 5  is chosen from H, acyl, substituted or unsubstituted 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; 
 
 wherein the aryl groups are chosen from 5-, 6- or 7-membered, aromatic carbocyclic group having a single ring or being fused to other aromatic or non-aromatic rings; and wherein the heteroaryl groups are chosen from polyunsaturated, 5-, 6- or 7-membered aromatic moiety containing at least one heteroatom chosen from N, O, S, Si and B, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quarternized, and wherein the heteroaryl groups can be a single ring or be fused to other aryl, heteroaryl, cycloalkyl or heterocycloalkyl rings. 
 
       
     
     
         3 : The compound of  claim 2 , wherein the compound has a structure according to Formula (IV), Formula (V), Formula (VI) or Formula (VII): 
       
         
           
           
               
               
           
         
         or a salt or solvate thereof, 
         wherein
 R 2  and R 2a  are independently chosen from H, C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, 2- to 4-membered heteroalkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, CN, and halogen; 
 
       
       
         
           
           
               
               
           
         
         
           wherein the moiety 
           wherein R 4  is chosen from H, C 1 -C 4  alkyl, C 1 -C 4  alkenyl, C 1 -C 4  alkynyl, C 1 -C 4  haloalkyl, C 3 -C 6  cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR 17 , SR 17  and NR 17 R 18 , wherein
 R 17  and R 18  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 17  and R 18 , together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring. 
 
         
       
     
     
         4 : The compound of  claim 2 , wherein ring A is chosen from thiophene, thiazole, and pyrazole, wherein the thiophene, the thiazole, or the pyrazole is optionally substituted with 1 or 2 substituents chosen from C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, C 1 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, 2- to 4-membered heteroalkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, CN, and halogen. 
     
     
         5 : The compound of  claim 3 , wherein the compound has a structure according to Formula (IVa), Formula (Va), Formula (VIa) or Formula (VIIa): 
       
         
           
           
               
               
           
         
         or a salt or solvate thereof,
 wherein R 4  is chosen from H, methyl, and cyclopropyl. 
 
       
     
     
         6 : The compound of  claim 2 , wherein W is methylene (—CH 2 —). 
     
     
         7 : The compound of  claim 2 , wherein R 5  is H. 
     
     
         8 : The compound of  claim 2 , wherein Cy is chosen from phenyl, naphthyl, quinoline, isoquinoline, quinoxaline, quinazoline, 3,4-dihydroquinolin-2-one, 3,4-dihydro-1,5-naphthyridin-2-one, and 3,4-dihydro-1,6-naphthyridin-2-one, each optionally substituted with 1-6 substituents independently chosen from C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl, C 1 -C 6 -haloalkyl, 2- to 6-membered heteroalkyl, C 3 -C 12 -cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- or 6-membered 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 . 
     
     
         9 : The compound of  claim 8 , wherein Cy is optionally substituted quinolone. 
     
     
         10 : The compound of  claim 8 , wherein Cy is optionally substituted isoquinoline. 
     
     
         11 : The compound of  claim 8 , wherein Cy is optionally substituted 3,4-dihydroquinolin-2-one. 
     
     
         12 : The compound of  claim 11 , wherein the Cy is 3,4-dihydroquinolin-2-one substituted with at least one C 1 -C 6 -haloalkyl. 
     
     
         13 : The compound of  claim 8 , wherein Cy is optionally substituted 3,4-dihydro-1,6-naphthyridin-2-one. 
     
     
         14 : The compound of  claim 8 , wherein Cy is optionally substituted 3,4-dihydro-1,5-naphthyridin-2-one. 
     
     
         15 : The compound of  claim 14 , wherein Cy is unsubstituted 3,4-dihydro-1,5-naphthyridin-2-one. 
     
     
         16 : The compound of  claim 2 , which is N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-7-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. 
     
     
         17 : The compound of  claim 2 , which is N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)acetamide. 
     
     
         18 : A method of treating a neurodegenerative disease, the method comprising:
 administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound of  claim 2 .   
     
     
         19 : The method of  claim 18 , wherein the neurodegenerative disease is chosen from Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, Parkinson's disease, Down syndrome, dementia, mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), traumatic brain injuries, cerebral ischemic brain damage, ischemic or hemorrhaging stroke, hereditary cerebral hemorrhage with amyloidosis of the dutch-type, and cerebral amyloid angiopathy. 
     
     
         20 : The method of  claim 18 , wherein said neurodegenerative disease is Alzheimer's disease, diffuse Lewy body type of Alzheimer's disease, or mild cognitive impairment (MCI), and the mammalian subject is a human.