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 compound represented by the 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), SO, or SO 2 ; B 3 is absent, O, NH, alkylamino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, or heterocyclic; B 4 is absent, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, heterocyclic, heteroaryl or aryl; R 20 , R 21 , R 22 are independently selected from R 1 ; R 7 is hydrogen, —OH, —O-aliphatic, —O-substituted aliphatic, —O-acyl or aliphatic, provided that when Y is absent, R 7 is absent; R′ is hydrogen or acyl; Q is absent or substituted or unsubstituted alkyl; Y is absent, N, or CH; R 1 is 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; and 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), SO 2 , N(R 8 ), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.
2. A compound according to claim 1 represented by formula (V):
or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is absent, O, S, aryl, heteroaryl, heterocyclic, 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), SO, or SO 2 ; B 3 is absent, O, NH, alkylamino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, or heterocyclic; B 4 is absent, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, heterocyclic, heteroaryl or aryl; M 1 is absent, C 1 -C 6 alkyl, O, S, SO, SO 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, SO, SO 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 Q, Y, R′, R 7 , R 20 , R 21 , R 22 and R 8 are as defined in claim 1 .
3. A compound according to claim 1 represented by formula (VI):
or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is absent, O, S, aryl, heteroaryl, heterocyclic, 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), SO, or SO 2 ; B 3 is absent, O, NH, alkylamino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, or heterocyclic; B 4 is absent, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, heterocyclic, heteroaryl or aryl; M 1 is absent, C 1 -C 6 alkyl, O, S, SO, SO 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, SO, SO 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 Q, Y, R′, R 7 , R 20 , R 21 , R 22 and R 8 are as defined in claim 1 .
4. A pharmaceutical composition comprising as an active ingredient a compound of claim 1 and a pharmaceutically acceptable carrier.
5. A compound represented by formula (IV):
or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is O or S; B 2 is absent or C 1 -C 6 alkyl; B 3 is absent, or C 1 -C 6 alkyl; B 4 is absent or C 1 -C 8 alkyl; R 20 , R 21 , R 22 are independently selected from R 1 ; R 7 is hydrogen, R 7 is hydrogen, —OH, —O-aliphatic, —O-substituted aliphatic, —O-acyl or an aliphatic group, provided that when Y is absent, R 7 is absent; R′ is hydrogen or acyl; Q is absent or substituted or unsubstituted alkyl; Y is absent or CH; R 1 is 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; and 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), SO 2 , N(R 8 ), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R 8 is hydrogen, acyl, aliphatic or substituted aliphatic.
6. A compound according to claim 5 represented by formula (V):
or a pharmaceutically acceptable salt or solvate thereof, wherein M 1 is absent, C 1 -C 6 alkyl, O, S, SO, SO 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, SO, SO 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 , Q, Y, R′, R 7 , R 20 , R 21 , R 22 and R 8 are as defined in claim 5 .
7. A compound according to claim 5 represented by formula (VI):
or a pharmaceutically acceptable salt or solvate thereof, wherein M 1 is absent, C 1 -C 6 alkyl, O, S, SO, SO 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, SO, SO 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 , Q, Y, R′, R 7 , R 20 , R 21 , R 22 and R 8 are as defined in claim 5 .
8. A compound according to claim 5 selected from the compounds delineated in the table below 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
50
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
94
96
97
98
99
100
101
108
109
110
111
112
113
149
151
153
155
157
158
159
160
161
162
163
164
165
166
167
168
197
198
199
200
206
207
208
9. A pharmaceutical composition comprising as an active ingredient a compound of claim 5 and a pharmaceutically acceptable carrier.
10. The compound of claim 1 represented by Formula VIII:
or a pharmaceutically acceptable salt or solvate thereof, wherein R 7 is H, OH or an aliphatic group; X 1 is O, S or NH; R a and R b are each hydrogen or are taken together with the carbon atom to which they are attached to form a carbonyl group; n is 0 to 9; and Q, Y, R 8 , R 4 , R 20 , R 21 and R 22 have the meanings set forth in claim 1 .
11. A compound according to claim 1 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
46
47
48
49
50
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
96
97
98
99
100
101
104
105
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
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
12. The compound of claim 1 represented by Formula X,
wherein
R a and R b are both hydrogen or R a and R b are taken together with the carbon atom to which they are attached to form —C(O)—;
R c is absent, alkyl, alkenyl or alkynyl;
R 9 is —OR′;
n is 0-7;
X 1 is O, S or NH;
G is Ar 1 , Ar 1 —X 2 or Ar 1 -alkyl-X 2 ;
Ar 1 is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
X 2 is O, S or NH; and
R 20 , R 21 , R 22 , Q, R 4 , R 8 , and R′ are as defined in claim 1 .