Cell proliferation inhibitors and conjugates thereof
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.
1. A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
Z is CH;
Ar 1 is phenyl optionally substituted with up to three groups selected from halo, C1- 3 alkyl, and C haloalkyl;
Ar 2 is phenyl or pyridinyl, optionally substituted with up to two groups selected from halo, CN, C 1 . 3 alkyl, hydroxyl, amino, and C1.3 haloalkyl;
R I is —(CH 2 ) 0 —C 4 . 7 heterocyclyl, where the C 4 .7 heterocyclyl contains up to two heteroatoms selected from N, O and S as ring members, and C 4 .7 heterocyclyl and C 3 .7 cycloalkyl are each optionally substituted with up to three groups selected from halo, C 1 . 4 alkyl, C 1 . 4 alkoxy, hydroxyl, amino, oxo, hydroxyl-substituted C 1 . 4 alkyl, amino-substituted C 1 . 4 alkyl, C 1 . 4 haloalkyl, and COO(C 1 . 4 alkyl);
R 2 is H or C I14 alkyl;
T is —(CH 2 ) 1-3 —
Y is selected from Ci- 2 aminoalkyl, C 4 . 6 heterocyclyl, and C 3 . 6 cycloalkyl, wherein Ci- 2 aminoalkyl, C 4 . 6 heterocyclyl, and C 3 . 6 cycloalkyl are each optionally substituted with up to three groups selected from amino, oxo, halo, hydroxyl, C 1 . 4 alkoxy, hydroxyl-substituted C 1 . 4 alkyl, amino-substituted C 1 . 4 alkyl, COOH, COO—(C 1 . 4 alkyl), CONH(C 1 . 4 alkyl), CON(C 1 . 4 alkyl) 2 , and haloalkyl;
A is NH, N(C 1 . 4 alkyl), or a bond between the carbonyl in Formula (III) and Q;
Q is selected from C 1 . 4 alkyl, —(CH 2 )o- 2 -C 4 . 6 heterocyclyl, —(CH 2 )o- 2 -C 5 - 6 heteroaryl, and —(CH 2 )o- 2 -phenyl, and Q is optionally substituted with up to three groups selected from halo, hydroxyl, amino, —SH, —R, —OR, —SR, —SO 2 R, —NHR, and —NR 2 , where each R is C 1 . 6 alkyl optionally substituted with up to three groups selected from halo, —SH, —NH 2 , OMe, and —OH.
2. The compound of claim 1 , wherein R 1 is tetrahydropyranyl.
3. A compound of claim 1 , which is selected from:
Cmpd No.
Structure
12
15
17
18
19
23
24
32
37
38
39
46
47
48
53
56
57
58
65
66
68
69
70
74
82
83
84
85
86
87
88
89
92
93
97
98
107
108
109
110
111
113
114
115
116
117
118
119
120
121
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
5. A combination comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.