Prodrug forms of kinase inhibitors and their use in therapy

摘要

The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I:;
where: X is any negatively charged counterion; R1 is a group of the formula —(CH2)nTr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and —(CH2)nTr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R2, R3 and R4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or two of R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor.
;The compounds of the invention are useful in treating proliferative diseases such as cancer.

主权项

1. A compound Formula II: where: X− is a negatively charged counterion; Y is N or C—R7, where R7 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy and a group of Formula VIa, VIb, and VIc where * is the point of attachment to C, and where T is selected from the group consisting of O, NH, N(C1-C6 alkyl) and a direct link; m is an integer from 0 to 6; U is selected from the group consisting of OR44, CF3, OCF3, CN, NR45R46, pyrrolidinyl, piperidinyl, piperazinyl, N1-methylpiperazinyl, morpholinyl, CON(R47)(R48), SO2N(R49)(R50), N(R51)COR52, N(R53)SO2R54, COR55, SOR56, SO2R57 and COOR58; and R42, R43, R44, R45, R46, R47, R48 R49, R50, R51, R52, R53, R54, R55, R56, R57, R58 are independently selected from the group consisting of H and C1-C6 alkyl; Z is N or C—CN; n is an integer from 0 to 6; R1 is selected from a group of Formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IIIk, IIIl, IIIm, IIIn, IIIo, IIIp, or IIIq: where: * is the point of attachment to the quaternary nitrogen of the compound of Formula II; R8 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, CF3, OCF3, F, Cl, Br, I, NO2, CN, COOH, COO(C1-C6 alkyl), CONH2, CONH(C1-C6 alkyl), CON(C1-C6 alkyl)2, CO(C1-C6 alkyl), SO2NH2, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, SO2(C1-C6 alkyl) and a group of Formula VIa as defined above; where * is the point of attachment to a group of Formula IIIa-g or i-q; R9 is selected from the group consisting of H, C1-C6 alkyl and groups of Formula VIa as defined above; where * is the point of attachment to a group of Formula IIIc-f; h-j; or q; and R10 is selected from the group consisting of H and C1-C6 alkyl; R2 and R3 are independently selected from the group consisting of C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2CH2OH, and CH2CH2O(C1-C6 alkyl), or R2 and R3 may together with the nitrogen to which they are attached form a non-aromatic heterocyclic ring; R5 is selected from the group consisting of an aniline, an indole, an indoline, an amine, an aminoindole and an aminoindazole, each of which may be optionally substituted with one or more substituents selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF3, OH, NH2, NO2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, CONH2, CO(C1-C6 alkyl), SO2NH2 and SO2(C1-C6 alkyl); and R6 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, NH(C1-C6 alkyl), N(C1-C6alkyl)2 and a group of Formula Va or b where * is the point of attachment; V is selected from the group consisting of (CH2)k O, NH and N(C1-C6 alkyl); k is an integer from 0 to 6; and R41 is selected from the group consisting of H and C1-C6 alkyl.