Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
The instant application relates to deazapurines, thienopyrimidines and furopyrimidines with zinc-binding moiety based derivatives and their use in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.
1. A compound represented by formula XXIV:
or a pharmaceutically acceptable salt thereof, wherein:
G 1 is O;
G 4 is S;
R 8 is independently hydrogen, acyl, aliphatic or substituted aliphatic;
each R 1 and R 2 is independently selected from absent, hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, NO 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
p is 0, 1 or 2;
w is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
u is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
G 5 is —N(R 8 )—C 1 -C 4 alkyl;
G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, pyrazolyl, or benzimidazolyl; and
each R 6 is selected from absent, hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, NO 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
2. The compound of claim 1 , wherein u, p, w and n are each 0.
3. The compound of claim 1 , wherein G 5 is —N(R 8 )—CH 2 —.
4. The compound of claim 3 , wherein R 8 is hydrogen or methyl.
5. The compound of claim 1 , wherein:
n, u, p, w and n are each 0;
G 5 is —N(R 8 )—CH 2 —; and
R 8 is hydrogen or methyl.
6. The compound of claim 5 , wherein G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl.
7. The compound of claim 6 , wherein G 2 is selected from the group below:
wherein m is 0, 1, 2 or 3; and
R 3 is hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, NO 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
8. The compound of claim 7 , wherein m is 1 and R 3 is selected from the group consisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino and methylamino.
9. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
11. The pharmaceutical composition of claim 10 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition of claim 10 in the form of a tablet or a capsule.
13. The pharmaceutical composition of claim 10 , wherein the pharmaceutically acceptable carrier is an aqueous or non-aqueous solution, a suspension, an emulsion or an oil.
14. The pharmaceutical composition of claim 12 , wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, pyrazolyl, or benzimidazolyl.
15. The pharmaceutical composition of claim 14 , wherein G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl.
16. The pharmaceutical composition of claim 14 , wherein G 2 is selected from the group below:
wherein m is 0, 1, 2 or 3; and
R 3 is hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF 3 , CN, NO 2 , sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound selected from the compounds set forth in the table below or a pharmaceutically acceptable salt thereof:
53
54
69
70
71
72
73
74
75
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
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
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
211
212
213
214
215
18. The pharmaceutical composition of claim 16 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
19. The pharmaceutical composition of claim 17 in the form of a tablet or a capsule.
20. The pharmaceutical composition of claim 17 , wherein the pharmaceutically acceptable carrier is an aqueous or non-aqueous solution, a suspension, an emulsion or an oil.