Fused amino pyridine as HSP90 inhibitors
The present invention relates to HSP90 inhibitors containing fused amino pyridine core that are useful as inhibitors of HSP90 and their use in the treatment of HSP90 related diseases and disorders such as cancer, an autoimmune disease, or a neurodegenerative disease.
1. A compound represented by formula I:
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein
U is N;
W is hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF 3 , NO 2 , CN, N 3 , sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl;
X is O, S, S(O), S(O) 2 , N(R 8 ), or C(O) where R 8 is hydrogen, acyl, aliphatic or substituted aliphatic;
Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl;
Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino;
Q is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or heterocycloalkyl;
V is hydrogen, straight- or branched-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl.
2. A compound represented by formula (II):
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein X 2 and X 5 are independently CH or N; R 21 -R 23 are independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxyl, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF 3 , NO 2 , CN, N 3 , substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; R 22 and R 23 can be taken together from the carbon to which they are attached to form a saturated or unsaturated fused 5-8 membered cyclic ring optionally substituted with 0-3 heteroatom; M 1 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl; M 2 is absent, O, S, SO, SO 2 , N(R 8 ), or C═O; M 3 is absent, C═O, O, S, SO, SO 2 or N(R 8 ); M 4 is hydrogen, halogen, CN, N 3 , hydroxy, substituted hydroxy, amino, substituted amino, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;
X is O, S, S(O), S(O) 2 , N(R 8 ), or C(O);
Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; and,
Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino.
3. A compound represented by formula (III):
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof, wherein X 1 -X 5 are independently N or CR 21 ; where R 21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF 3 , NO 2 , CN, N 3 , substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; M 1 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl; M 2 is absent, O, S, SO, SO 2 , N(R 8 ), or C═O; M 3 is absent, C═O, O, S, SO, SO 2 or N(R 8 ); M 4 is hydrogen, halogen, CN, N 3 , hydroxy, substituted hydroxy, amino, substituted amino, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;
X is O, S, S(O), S(O) 2 , N(R 8 ), or C(O);
Y is independently hydrogen, halogen, NO 2 , CN, or lower alkyl; and,
Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino.
4. A compound according to claim 2 represented by formula (IV):
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof, wherein X 2 and X 5 are independently CH or N; R 21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF 3 , NO 2 , CN, N 3 , substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Cy is a saturated or unsaturated fused 5-8 membered cyclic ring optionally substituted with 0-3 heteroatom; M 1 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl; M 2 is absent, O, S, SO, SO 2 , N(R 8 ), or C═O; M 3 is absent, C═O, O, S, SO, SO 2 or N(R 8 ); M 4 is hydrogen, halogen, CN, N 3 , hydroxy, substituted hydroxy, amino, substituted amino, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; and X, Y and Z are as previously defined in claim 2 .
5. A compound according to claim 2 represented by formula
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof, wherein X 2 and X 5 are independently CH or N; R 21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF 3 , NO 2 , CN, N 3 , substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Y 1 and Y 3 are independently O, S, N(R 8 ), CH(R 21 ); n is 1, 2, or 3; M 1 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl; M 2 is absent, O, S, SO, SO 2 , N(R 8 ), or C═O; M 3 is absent, C═O, O, S, SO, SO 2 or N(R 8 ); M 4 is hydrogen, halogen, CN, N 3 , hydroxy, substituted hydroxy, amino, substituted amino, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R 10 and R 20 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and X, Y and Z are as previously defined in claim 2 .
6. A compound according to claim 2 selected from the compounds delineated in Table A or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof:
TABLE A
Compound #
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
123
124
125
126
127
7. A pharmaceutical composition comprising as an active ingredient a compound of claim 2 and a pharmaceutical acceptable carrier.
8. A method of treating cell proliferative disorder that requires or is facilitated by expression of an HSP90 protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 7 , wherein said cell proliferative disorder is cancer.
9. The method of claim 8 , wherein said cancer selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, non-small cell lung cancer, ovarian cancer, prostate cancer, colon cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, renal cell carcinoma, gastric cancer, hepatocellular carcinoma, neuroblastoma, leukemia, lymphoma, vulvar cancer, Hodgkin's disease and Burkitt's disease.
10. A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a compound of claim 7 .
11. A compound according to claim 5 represented by formula (V):
or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof, wherein X 2 and X 5 are CH; R 21 is amino, substituted amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino; Y 1 and Y 3 are independently O, S, N(R 8 ), CH(R 21 ); n is 1; M 1 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; M 2 is N(R 8 ); M 3 is absent; M 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl; R 10 and R 20 are independently hydrogen, alkyl; X is O; Y is H; and Z is amino, substituted or unsubstituted alkylamino, or substituted or unsubstituted dialkylamino; R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.
12. A compound of claim 11 wherein Y 1 is O, Y 3 is O, R 10 is H, and R 20 is H.
13. A compound of formula:
Compound 111
or its pharmaceutically acceptable salts or solvate thereof.
14. A compound of formula:
Compound 118
or its pharmaceutically acceptable salts or solvate thereof.