2, 4-pyrimidinediamine compounds and prodrugs thereof and their uses

A compound of formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• Y is oxygen or sulfur;
• Z1, Z2, and Z3 are independently selected from CH and N, provided that at least one of Z1 Z2 and Z3 is N;
• R1 is hydrogen or C1-C6 alkyl;
• R2 and R3 are independently selected from hydrogen, halogen, C1-C6 alkyl, and halo(C1-C6 alkyl), or R2 and R3 together with the carbon to which they are attached form C3-C6 cycloalkyl;
• R4 is hydrogen, halogen, cyano, nitro, C1-C6 alkyl, or halo(C1-C6 alkyl);
• R5 is C1-C6 alkyl, —N(R7)2, aryl optionally substituted with 1, 2, 3, or 4 R6 groups, heteroaryl optionally substituted with 1, 2, 3, or 4 R6 groups, cycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R6 groups, or heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R6 groups, in which
• each R6 is independently selected from deuterium, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), C1-C6 alkoxy, halo(C1-C6 alkoxy), amino, (C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, hydroxy(C1-C6 alkyl), (C1-C6 alkoxy)C1-C6 alkyl, amino(C1-C6 alkyl), ((C1-C6 alkyl)amino)(C1-C6 alkyl), (di(C1-C6 alkyl)amino)(C1-C6 alkyl), —C(O)OH, —C(O)NH2, C3-C8 cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, or two R6 groups form a spiro-fused C3-C6 cycloalkyl, a spiro-fused heterocycloalkyl, oxo, ═CH2, or ═CH(C1-C6 alkyl);
• and
• each R7 is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6 alkyl), hydroxy(C1-C6 alkyl), (C1-C6 alkoxy)C1-C6 alkyl, aryl, heteroaryl, heterocycloalkyl, (aryl)C1-C6 alkyl, (heteroaryl)C1-C6 alkyl, and (heterocycloalkyl)C1-C6 alkyl;
• wherein the arylene is further substituted with 0, 1, 2, 3, or 4 R9, where each R9 is independently selected from halogen, cyano, C1-C6 alkyl, halo(C1-C6 alkyl), C1-C6 alkoxy, and halo(C1-C6 alkoxy), or R9 and R5 together with the carbons to which they are attached form C5-C10 heterocycloalkyl;
• and
• the heteroarylene is further substituted with 0, 1, 2, 3, or 4 R10, where each R10 is independently selected from halogen, cyano, C1-C6 alkyl, halo(C1-C6 alkyl), C1-C6 alkoxy, and halo(C1-C6 alkoxy), or R10 and R5 together with the carbons to which they are attached form C5-C10 heterocycloalkyl,
• provided the compound is not
• N4-(3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine,
• N4-(2,2-dimethyl-3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine,
• N4-(2,2-dimethyl-3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(4-(4-methylpiperazin-1-yl)phenyl)-2,4-pyrimidinediamine, or
• N4-(3,4-dihydro-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-5-fluoro-N2-(4-ethoxycarbonylpiperazin-1-yl(phenyl))-2,4-pyrimidinediamine.