Inhibitors of receptor interacting protein kinase i for the treatment of disease

A method of inhibition of RIPK1 comprising contacting RIPK1 with a compound of structural Formula I:

• or a salt thereof, wherein:
• X is alkylene and is optionally substituted with one or more R7,
• or X is chosen from carbamoyl, carbonyl, and a bond;
• R1a and R1b, together with the intervening nitrogen, combine to form a pyrazoline, which is optionally substituted with one R3, and which is optionally substituted with one or more R4;
• R2 is chosen from hydrogen, hydroxy, cyano, and halo,
• or R2 is chosen from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which is optionally substituted with one or more R5;
• R3 is chosen from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one or more R6;
• each R4 is independently chosen from alkyl, halo, cyano, and hydroxy;
• each R5 is independently chosen from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl;
• two R5, together with the intervening atoms, optionally combine to form a cycloalkyl or heterocycloalkyl;
• each R6 is independently chosen from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy;
• and
• each R7 is independently chosen from alkyl, cyano, halo, and hydroxy.

A method of treatment of a RIPK1-mediated disease comprising the administration of a therapeutically effective amount of a compound as of structural Formula I:

• or a salt thereof, wherein:
• X is alkylene and is optionally substituted with one or more R7,
• or X is chosen from carbamoyl, carbonyl, and a bond;
• R1a and R1b, together with the intervening nitrogen, combine to form a pyrazoline, which is optionally substituted with one R3, and which is optionally substituted with one or more R4;
• R2 is chosen from hydrogen, hydroxy, cyano, and halo,
• or R2 is chosen from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which is optionally substituted with one or more R5;
• R3 is chosen from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one or more R6;
• each R4 is independently chosen from alkyl, halo, cyano, and hydroxy;
• each R5 is independently chosen from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl;
• two R5, together with the intervening atoms, optionally combine to form a cycloalkyl or heterocycloalkyl;
• each R6 is independently chosen from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy;
• and
• each R7 is independently chosen from alkyl, cyano, halo, and hydroxy, to a patient in need thereof.

A method of treatment of injury to the CNS comprising the administration of a therapeutically effective amount of a compound of structural Formula I:

• or a salt thereof, wherein:
• X is alkylene and is optionally substituted with one or more R7,
• or X is chosen from carbamoyl, carbonyl, and a bond;
• R1a and R1b, together with the intervening nitrogen, combine to form a pyrazoline, which is optionally substituted with one R3, and which is optionally substituted with one or ore R4;
• R2 is chosen from hydrogen, hydroxy, cyano, and halo,
• or R2 is chosen from alkyl, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, (cycloalkyl)oxy, (heterocycloalkyl)oxy, (aryl)oxy, (heteroaryl)oxy, (alkyl)carbonyl, (cycloalkyl)carbonyl, (heterocycloalkyl)carbonyl, (aryl)carbonyl, (alkyl)amino, (cycloalkyl)amino, (heterocycloalkyl)amino, (aryl)amino, and (heteroaryl)amino, any of which is optionally substituted with one or more R5;
• R3 is chosen from aryl, (aryl)oxy, heteroaryl, (heteroaryl)oxy, cycloalkyl, and heterocycloalkyl, any of which is optionally substituted with one or more R6;
• each R4 is independently chosen from alkyl, halo, cyano, and hydroxy;
• each R5 is independently chosen from halo, cyano, amido, alkyl, alkoxy, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, oxo, P(O)(CH3)2, SO2CH3, aryl optionally substituted with one or more alkyl, and heteroaryl optionally substituted with one or more alkyl;
• two R5, together with the intervening atoms, optionally combine to form a cycloalkyl or heterocycloalkyl;
• each R6 is independently chosen from halo, alkyl, cycloalkyl, cyano, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, and haloalkoxy;
• and
• each R7 is independently chosen from alkyl, cyano, halo, and hydroxy, to a patient in need thereof.