Substituted Urea eIF2alpha Kinase Activators

摘要

This disclosure relates to substituted urea eIF2α kinase activators including methods of making and using the same. For example, such activators can include cycloalkyl aryl ureas, which activate at least one eIF2α kinase. These compounds may be useful for treatment of diseases such as, for example, cancer, hemolytic anemia not caused by infectious agents, Wolcott-Rallison syndrome, neurodegenerative disease, tuberous sclerosis complex, fragile-X syndrome, autism spectrum disorder, and ribosomal defect disease.

主权项

1. A compound of Formula (III): or a pharmaceutically acceptable salt thereof,
wherein: Z, Z1, and Z2 are each independently selected from the group consisting of: NH, O, and S; R1 is XR3; each R2 is independently selected from the group consisting of: unsubstituted or substituted C1-6alkyl; unsubstituted or substituted C2-6alkenyl; unsubstituted or substituted C2-6alkynyl; unsubstituted or substituted heteroaryl; unsubstituted or substituted heterocycle; C1-6haloalkyl; C1-6alkoxy; C1-6haloalkoxy; halo; —CN; —SR4; —SO2NR4; —COR4; —OCOR4; —CO2R4; —CONHNR4R5; —OCONR4R5; —NO2; —NR4R5; guanidine; —NR4COR5; —NR4SO2R5; —CONR4R5; —OH; C1-6alkylamino optionally substituted with a group consisting of: —OH, C1-6alkoxy, —NR4R5, —COOH, substituted or unsubstituted C1-6alkyl, —NR4SO2R5, —CONR4R5, halo, aryl, heterocycle, and heteroaryl; (C2-6alkenyl)-O—; C1-6alkylsulfinyl; (aryl)-O—; (aryl)-(C═O)—; (aryl)NR4—; (aryl)SO2NR4—; (heterocyclyl)-O—; (heterocyclyl)NR4—; (heterocyclyl)-(C═O)—; (heteroaryl)-O—; (heteroaryl)NR4—; (heteroaryl)-(C═O)—; (heteroaryl)SO2NR4—; O—(CH2)2-4-heterocycle; O—(CH2)2-4—NR4R5; O—(CH2)2-4-heteroaryl; X is selected from the group consisting of: NR4, O, and S(O)p; m is an integer from 1 to 5; n is an integer from 0 to 2; p is an integer from 0 to 2; R3 is selected from the group consisting of: unsubstituted or substituted heteroaryl; and wherein R2a and R4a are independently selected from the group consisting of: H; halo; unsubstituted or substituted C1-6alkyl; unsubstituted or substituted C1-6alkenyl; unsubstituted or substituted C1-6alkynyl; C1-6haloalkyl; CONR4R5; CONH(C1-6alkyl)heterocyclyl; CONH(C1-6alkyl)carbocyclyl; CONH(C1-6alkyl)aryl; CONH(C1-6alkyl)heteroaryl; NR4R5; (C1-6alkyl)NR4R5; (C1-6alkoxy)NR4R5; (C1-6alkyl)heterocyclyl; (C1-6alkyl)carbocyclyl; C1-6aralkyl; C1-6heteroaralkyl; (C1-6alkoxy)heterocyclyl; (C1-6alkoxyl)carbocyclyl; (C1-6alkoxyl)aryl; (C1-6alkoxyl)heteroaryl; NR4COR5; COOR4; C1-6haloalkoxy; C1-6alkylamino optionally substituted with a group consisting of: —OH, C1-6alkoxy, —NR4R5, —COOH, substituted or unsubstituted C1-6alkyl, —NR4SO2R5, —CONR4R5, halo, aryl, heterocycle, and heteroaryl; (C2-6alkenyl)-O—; C1-6alkylsulfinyl; (aryl)-O—; (aryl)-(C═O)—; (aryl)NR4—; (aryl)SO2NR4—; (heterocyclyl)-O—; (heterocyclyl)NR4—; (heterocyclyl)-(C═O)—; (heteroaryl)-O—; (heteroaryl)NR4—; (heteroaryl)-(C═O)—; (heteroaryl)SO2NR4—; O—(CH2)2-4-heterocycle; O—(CH2)2-4—NR4R5; O—(CH2)2-4-heteroaryl; R1a, R3a, and R5a are independently selected from the group consisting of: H; Cl; Br; I; unsubstituted or substituted C1-6alkyl; C1-6haloalkyl; CONR4R5; CONH(C1-6alkyl)heterocyclyl; NR4R5; (C1-6alkyl)NR4R5; (C1-6alkoxy)NR4R5; (C1-6alkyl)heterocyclyl; (C1-6alkoxy)heterocyclyl; NR4COR5; COOR4; C1-6haloalkoxy; C1-6alkylamino optionally substituted with a group consisting of: —OH, C1-6alkoxy, —NR4R5, —COOH, substituted or unsubstituted C1-6alkyl, —NR4SO2R5, —CONR4R5, halo, aryl, heterocycle, and heteroaryl; (C2-6alkenyl)-O—; C1-6alkylsulfinyl; (aryl)-O—; (aryl)-(C═O)—; (aryl)NR4—; (aryl)SO2NR4—; (heterocyclyl)-O—; (heterocyclyl)NR4—; (heterocyclyl)-(C═O)—; (heteroaryl)-O—; (heteroaryl)NR4—; (heteroaryl)-(C═O)—; (heteroaryl)SO2NR4—; O—(CH2)2-4-heterocycle; O—(CH2)2-4—NR4R5; O—(CH2)2-4-heteroaryl; each R4 and R5 is independently selected from the group consisting of: H and unsubstituted or substituted C1-6alkyl; and each R6 is selected from the group consisting of: H, halo, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C2-6alkenyl, unsubstituted or substituted C2-6alkynyl, (C1-6alkoxy), —OH, —CONR4R5, —CONR7R8, —CN, —SR4, —SO2NR4, —COR4, —CO2R4, —CONHNR4R5, —OCONR4R5, —NO2, —NR4R5, guanidine, —NR4COR5, (C1-6alkoxy)NR4R5, unsubstituted or substituted carbocyclyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, C1-6alkylamino optionally substituted with a group consisting of: —OH, C1-6alkoxy, —NR4R5, —COOH, substituted or unsubstituted C1-6alkyl, —NR4SO2R5, —CONR4R5, halo, aryl, heterocycle, and heteroaryl; (C2-6alkenyl)-O—; C1-6alkylsulfinyl; (aryl)-O—; (aryl)-(C═O)—; (aryl)NR4—; (aryl)SO2NR4—; (heterocyclyl)-O—; (heterocyclyl)NR4—; (heterocyclyl)-(C═O)—; (heteroaryl)-O—; (heteroaryl)NR4—; (heteroaryl)-(C═O)—; (heteroaryl)SO2NR4—; O—(CH2)2-4-heterocycle; O—(CH2)2-4—NR4R5; O—(CH2)2-4-heteroaryl; each R7 is independently selected from the group consisting of: H and unsubstituted or substituted C1-6alkyl; and each R8 is independently selected from the group consisting of: H, unsubstituted or substituted C1-6alkyl, carbocyclyl, (C1-6alkyl)carbocyclyl, (C1-6alkoxy)carbocyclyl, aryl, (C1-6alkyl)aryl, (C1-6alkoxy)aryl, heterocyclyl, (C1-6alkyl)heterocyclyl, (C1-6alkoxy)heterocyclyl, heteroaryl, (C1-6alkyl)heteroaryl, and (C1-6alkoxy)heteroaryl.