Quinazoline based EGFR inhibitors containing a zinc binding moiety
The present invention relates to quinazoline containing zinc-binding moiety based derivatives of Formula (IV) below. These compounds have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and are useful in the treatment of EGFR-TK related diseases and disorders such as cancer. These compounds may further act as HDAC inhibitors.
1. A method of treating a cancer selected from breast cancer, hepatocellular carcinoma, colon cancer, head and neck cancer, renal carcinoma, lung cancer, prostate cancer, gastric carcinoma, leukemia and pancreatic cancer 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 pharmaceutically acceptable salt or solvate thereof, wherein B 1 is absent, O, S, aryl, heteroaryl, heterocylic, NH or alkylamino; B 2 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, heterocyclic, C(O), S(O), or S(O) 2 ; B 3 is absent, O, NH, alkylamino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkenyl, aryl, heteroaryl, or heterocyclic; B 4 is absent, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkenyl, heterocyclic, heteroaryl or aryl; R 20 , R 21 , and R 22 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF 3 , CN, N 3 , NO 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; Q is absent or substituted or unsubstituted alkyl: Y is absent, N, or CH; R′is hydrogen or acyl; R 4 is independently selected from hydrogen, hydroxy, amino, halogen, CF 3 , CN, N 3 , NO 2 , sulfonyl, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylheterocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, or alkynylheterocyclylalkynyl, which one or more methylenes can be interrupted or terminated by O, S, S(O), S(O) 2 , N(R 8 ), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; R 7 is hydrogen, —OH, —O-aliphatic, —O-substituted aliphatic, O-acyl or aliphatic, provided that when Y is absent, R 7 is absent; and R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.
2. The method according to claim 1 , wherein the compound is represented by formula (V):
or a pharmaceutically acceptable salt or solvate thereof, wherein M 1 is absent, C 1 -C 6 alkyl, O, S, S(O), S(O) 2 , NH, alkylamine, C(O), aryl, heteroaryl; M 2 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; M 3 is absent, C 1 -C 6 alkyl, O, S, S(O), S(O) 2 , NH, alkylamine, aryl, heteroaryl; M 4 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; M 5 is OH, SH, NR 7 R 8 , CO 2 R 8 , SOR 8 , SO 2 R 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, or heterocyclic; and B 1 , B 2 , B 3 , B 4 , R 20 , R 21 , R 22 , Q, Y, R′, R 7 , and R 8 are as defined in claim 1 .
3. The method according to claim 1 , wherein the compound is represented by formula (VI):
or a pharmaceutically acceptable salt or solvate thereof, M 1 is absent, C 1 -C 6 alkyl, O, S, S(O), S(O) 2 , NH, alkylamine, C(O), aryl, heteroaryl; M 2 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; M 3 is absent, C 1 -C 6 alkyl, O, S, S(O), S(O) 2 , NH, alkylamine, aryl, heteroaryl; M 4 is absent, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; M 5 is OH, SH, NR 7 R 8 , CO 2 R 8 , SOR 8 , SO 2 R 8 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, or heterocyclic; and B 1 , B 2 , B 3 , B 4 , R 20 , R 21 , R 22 , Q, Y, R′, R 7 , and R 8 are as defined in claim 1 .
4. A method of treating a cancer selected from breast cancer, hepatocellular carcinoma, colon cancer, head and neck cancer, renal carcinoma, lung cancer, prostate cancer, gastric carcinoma, leukemia and pancreatic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the compounds delineated in Table A or a pharmaceutically acceptable salt 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
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
5. The method of claim 1 , wherein the cancer is breast cancer, prostate cancer or non-small cell lung cancer.