Inhibitors of Jun N-terminal kinase

摘要

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, Ca, Cb, Z, R5, 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.

主权项

1. 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 having a structure according to Formula (I):or a salt thereof,wherein:
ring A is 5-membered heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1or 2 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C3-C10-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR12, SR12, NR12R13, C(O)R14, C(O)NR12R13, OC(O)NR12R13 , C(O)OR12, NR15C(O)R14, NR15C(O)OR12, NR15C(O)NR12R13, NR15C(S)NR12R13, NR15S(O)2R14, S(O)2NR12R13, S(O)R14 and S(O)2R14; wherein:
R12, R13, and R15 are each independently selected from H, acyl, C1-C6-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, or R12 and R13, together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; andR14 is acyl, C1-C6-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl; Ca and Cb are carbon atoms, which are adjacent to each other and are part of ring A; Z is 5- or 6-membered heteroaryl selected from the group consisting of optionally substituted pyrazole, optionally substituted imidazole, optionally substituted triazole, optionally substituted oxazole, optionally substituted thiazole, optionally substituted oxadiazole, optionally substituted pyridine and optionally substituted pyrazine, with the proviso that when ring A is optionally substituted thiophene, then Z is not methyl-substituted thiazole or oxadiazole substituted with optionally substituted phenyl; R5 is selected from H, acyl, optionally substituted C1-C6 alkyl, and C3-C6 cycloalkyl; W is selected from C1-C4 alkylene, wherein the alkylene is optionally substituted with 1-4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C3-C6-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR42, SR42, NR42R43, C(O)R44, C(O)NR42R43, OC(O)NR42R43, C(O)OR42, NR45C(O)R44, C(O)OR42, NR45C(O)NR42R43, NR45C(S)NR42R43, NR45S(O)2R44S(O)2NR42R43, S(O)R44, and S(O)2R44, wherein:
R42, R43, and R45 are independently selected from H, acyl, C1-C6-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R42 and R43, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; andR44 is independently selected from acyl, C1-C6-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl; Cy is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1-6 substituents independently selected 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, ═O, CN, halogen, OR52, SR52, NR52R53, C(O)R54, C(O)NR52R53, OC(O)NR52R53, C(O)OR52, NR55C(O)R54, NR55C(O)OR52, NR55C(O)NR52R53, NR55C(S)NR52R53, NR55S(O)2R54, S(O)2NR52R53, S(O)R54 and S(O)2R54, wherein:
R52, R53 and R55 are independently selected from H, acyl, C1-C6-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R52 and R53, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring, wherein C1-C6-alkyl is optionally substituted with one or more substituents independently selected from halogen, 3 to 10 membered heterocycloalkyl, and heteroaryl; andR54 is independently selected from acyl, C1-C6-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, and wherein the compound according to Formula (I) exhibits the ability to inhibit c-Jun N-terminal kinase 3 (JNK3) in vitro, 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.