# US 9,040,556 B2 · Fused amino pyridine as HSP90 inhibitors

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- Number: US 9,040,556 B2
- Document ID: US9040556B2
- Status: Granted
- Kind: B2
- Application number: 14/054,273
- Filed: 2013-10-15
- Published: 2014-08-07
- Granted: 2015-05-26
- Earliest claimed: 2007-03-20
- Assignees: Curis, Inc.
- Applicants: Curis, Inc.
- Inventors: Xiong Cai; Changgeng Qian; Haixiao Zhai
- Web page: https://patentgrep.com/patent/US9040556B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 31/04: Antibacterial agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

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.

## Claims

### Claim 1

A method of treating inflammatory diseases or immune system disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by formula I:
or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, prodrug or solvate 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, CF3, NO2, CN, N3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl;
X is absent, O, S, S(O), S(O)2, N(R8), C(O), CF2, C(R8) or C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl in which one or more methylene can be interrupted or terminated by O, S, SO, SO2, N(R8), C(O), where R8 is hydrogen, acyl, aliphatic or substituted aliphatic;
Y is independently hydrogen, halogen, NO2, 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, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO2, N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; substituted or unsubstituted cycloalkyl; where R8 is hydrogen, acyl, aliphatic or substituted aliphatic.

### Claim 2

A method of treating inflammatory diseases or immune system disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by formula (II):
or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X2 and X5 are independently CH or N; R21-R23 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, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; R22 and R23 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; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C═O; M3 is absent, C═O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;
X is absent, O, S, S(O), S(O)2, N(R8), C(O), CF2, C(R8) or C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl in which one or more methylene can be interrupted or terminated by O, S, SO, SO2, N(R8), C(O);
Y is independently hydrogen, halogen, NO2, CN, or lower alkyl;
Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and,
R8 is hydrogen, acyl, aliphatic or substituted aliphatic.

### Claim 3

A method of treating inflammatory diseases or immune system disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by formula (III):
or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X1-X5 are independently N or CR21, where R21 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, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C═O; M3 is absent, C|O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;
X is absent, O, S, S(O), S(O)2, N(R8), C(O), CF2, C(R8) or C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl in which one or more methylene can be interrupted or terminated by O, S, SO, SO2, N(R8), C(O);
Y is independently hydrogen, halogen, NO2, CN, or lower alkyl;
Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and,
R8 is hydrogen, acyl, aliphatic or substituted aliphatic.

### Claim 4

A method of treating inflammatory diseases or immune system disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by formula (IV):
or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X2 and X5 are independently CH or N; R21 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, CF3, NO2, CN, N3, 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; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; M2 is absent, O, S, SO, SO2, N(R8), or C═O; M3 is absent, C═O, O, S, SO, SO2 or N(R8); M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;
X is absent, O, S, S(O), S(O)2, N(R8), C(O), CF2, C(R8) or C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl in which one or more methylene can be interrupted or terminated by O, S, SO, SO2, N(R8), C(O);
Y is independently hydrogen, halogen, NO2, CN, or lower alkyl;
Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and,
R8 is hydrogen, acyl, aliphatic or substituted aliphatic.

### Claim 5

A method of treating inflammatory diseases or immune system disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by formula (V):
or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein X2 and X5 are independently CH or N; R21 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, CF3, NO2, CN, N3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Y1 and Y3 are independently O, S, N(R8), CH(R21);
n is 1, 2, or 3; M1 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl;
M2 is absent, O, S, SO, SO2, N(R8), or C═O; M3 is absent, C═O, O, S, SO, SO2 or N(R8);
M4 is hydrogen, halogen, CN, N3, hydroxy, substituted hydroxy, amino, substituted amino, CF3, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R10 and R20 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
X is absent, O, S, S(O), S(O)2, N(R8), C(O), CF2, C(R8) or C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl in which one or more methylene can be interrupted or terminated by O, S, SO, SO2, N(R8), C(O);
Y is independently hydrogen, halogen, NO2, CN, or lower alkyl;
Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and,
R8 is hydrogen, acyl, aliphatic or substituted aliphatic.

### Claim 6 (depends on 1)

The method according to claim 1, wherein said compound is selected from the compounds delineated in Table A or a geometric isomer, enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, prodrug or solvate 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

### Claim 7 (depends on 1)

The method according to claim 1, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said inflammatory disease or immune system disorder is Psoriasis.

### Claim 9 (depends on 2)

The method according to claim 2, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 10 (depends on 9)

The method according to claim 9, wherein said inflammatory disease or immune system disorder is Psoriasis.

### Claim 11 (depends on 3)

The method according to claim 3, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 12 (depends on 11)

The method according to claim 11, wherein said inflammatory disease or immune system disorder is Psoriasis.

### Claim 13 (depends on 4)

The method according to claim 4, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 14 (depends on 13)

The method according to claim 13, wherein said inflammatory disease or immune system disorder is Psoriasis.

### Claim 15 (depends on 5)

The method according to claim 5, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 16 (depends on 15)

The method according to claim 15, wherein said inflammatory disease or immune system disorder is Psoriasis.

### Claim 17 (depends on 6)

The method according to claim 6, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 18 (depends on 17)

The method according to claim 17, wherein said inflammatory disease or immune system disorder is Psoriasis.

### Claim 19

A method of treating inflammatory diseases or immune system disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 20 (depends on 19)

The method according to claim 19, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 21 (depends on 20)

The method according to claim 20, wherein said inflammatory disease or immune system disorder is Psoriasis.

### Claim 22

A method of treating inflammatory diseases or immune system disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 23 (depends on 22)

The method according to claim 22, wherein said inflammatory disease or immune system disorder is selected from Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease, Colitis, Ulcerosa, Alcoholic hepatitis, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain and Systemic Lupus Erythematosus.

### Claim 24 (depends on 23)

The method according to claim 23, wherein said inflammatory disease or immune system disorder is Psoriasis.