CELL PROLIFERATION INHIBITORS AND CONJUGATES THEREOF

摘要

Disclosed herein are immunoconjugates comprising an inhibitor of Eg5 linked to an antigen binding moiety such as an antibody, that are useful for treating cell proliferative disorders. Also disclosed are novel inhibitors of Eg5 that can be used either alone or as part of an immunoconjugate to treat cell proliferation disorders. The Eg5 inhibitors include compounds of this formula as described herein:;;The invention further provides pharmaceutical compositions comprising these compounds and immunoconjugates, and compositions comprising the immunoconjugates or compounds with a therapeutic co-agent, and methods to use these compounds, conjugates and compositions for treating cell proliferation disorders.

主权项

1. An immunoconjugate of Formula (I): wherein Ab represents an antigen binding moiety; L represents a linking group that connects X to Ab; m is an integer from 1-4; n is an integer from 1 to 16; and X independently at each occurrence represents a group of Formula (II)that is connected by L to Ab,
wherein: Z is Nor CH; Ar1 is phenyl optionally substituted with up to three groups selected from halo, C1-3 alkyl, and C1-3 haloalkyl; Ar2 is phenyl or pyridinyl, and Ar2 is optionally substituted with up to two groups selected from halo, CN, C1-3 alkyl, hydroxyl, amino, and C1-3 haloalkyl; R1 is C1-6 alkyl, —(CH2)0-2—C3-6 cycloalkyl, or —(CH2)0-2—C4-7 heterocyclyl containing up to two heteroatoms selected from N, O and S as ring members, wherein each C1-6 alkyl, C3-6 cycloalkyl, or C4-7 heterocyclyl is optionally substituted with up to three groups selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, hydroxyl, amino, oxo, hydroxyl-substituted C1-4 alkyl, amino-substituted C1-4 alkyl, and COO(C1-4 alkyl); R2 is H or C1-4 alkyl; T is (CH2)1-3; Y is selected from C1-3 aminoalkyl, C4-6 heterocyclyl, and C3-6 cycloalkyl, wherein C1-3 aminoalkyl, C4-6 heterocyclyl, and C3-6 cycloalkyl are each optionally substituted with up to three groups selected from amino, oxo, halo, hydroxyl, C1-4 alkyl, C1-4 alkoxy, hydroxyl-substituted C1-4 alkyl, amino-substituted C1-4 alkyl, COOH, COO—(C1-4 alkyl), —C(═O)NH(C1-4 alkyl), —C(═O)N(C1-4alkyl)2, and C1-4 haloalkyl; A is NH, N(C1-4 alkyl), or a bond between the carbonyl in Formula (II) and Q; Q is selected from C1-4 alkyl, —O—C1-4alkyl, —(CH2)0-2—C4-6heterocyclyl, —(CH2)0-2—C3-6cycloalkyl, —(CH2)0-2—C5-6heteroaryl, and —(CH2)0-2-phenyl, and is optionally substituted with up to three groups selected from halo, hydroxyl, amino, —SH, —R, —OR, —SR, —SO2R, —NHR, —O-glucuronate, and —NR2, where each R is C1-6 alkyl optionally substituted with halo, —SH, —NH2, OMe, or —OH.