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 (XIV),
or a pharmaceutically acceptable salt or prodrug thereof, wherein
n is 0, 1, 2, 3 or 4;
p is 0, 1 or 2;
G 1 is CR 1 , S, O, NR 10 or NS(O) 2 R 10 ,
G 2 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic;
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;
R 10 is selected from hydrogen, hydroxy, amino, alkoxy, alkylamino, dialkylamino, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
B is selected from the group consisting of
d and e are independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;
R 100 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloalkyl; and
C is
where R 33 is selected from hydrogen and C 1 -C 8 -alkyl.
2. The compound of claim 1 , wherein G 2 is selected from the group below:
wherein m is 0, 1, 2 or 3;
R 3 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, and
R 8 is as defined in claim 1 .
3. A compound represented by formula XXII,
or a pharmaceutically acceptable salt or prodrug thereof, wherein
n is 0, 1, 2, 3 or 4;
p is 0, 1 or 2,
G 1 is CR 1 , S, O, NR 10 or NS(O) 2 R 10 ;
G 2 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or, substituted or unsubstituted heterocyclic;
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;
R 10 is selected from hydrogen, hydroxy, amino, alkoxy, alkylamino, dialkylamino, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic;
t, v and w are independently 0, 1, 2 or 3;
u is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
G 4 is NR 8 , S or O;
G 5 is absent, C 1 -C 8 alkyl or a C 1 -C 8 alkyl interrupted by one or more O, S, S(O), SO 2 , N(R 8 ), C(O);
G 6 is selected from CR 1 and NR 8 ;
G 7 is selected from —CR 1 , —NR 8 , S and O; and
R 5 and R 6 are independently selected from 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.
4. The compound of claim 3 , wherein G 2 is selected from the group below:
wherein m is 0, 1, 2 or 3;
R 3 is selected from 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; and
R 8 is as defined in claim 3 .
5. A pharmaceutical composition comprising as an active ingredient a compound of claim 1 and a pharmaceutically acceptable carrier.
6. A method of treating a PI3K related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 5 .
7. A method of treating an mTOR-mediated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 5 .
8. A method of treating an HDAC-mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 5 .
9. A method of treating a disease mediated by both PI3K and HDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 5 .
10. The compound of claim 1 , wherein G 2 is
wherein
m is 0, 1, 2 or 3;
R 3 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; and
R 8 is as defined in claim 1 .
11. The compound of claim 1 , wherein R 33 is hydrogen.
12. The compound of claim 1 , wherein R 100 is hydrogen or methyl.
13. The compound of claim 3 , wherein G 2 is
wherein
m is 0, 1, 2 or 3;
R 3 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, and
R 8 is as defined in claim 3 .
14. A pharmaceutical composition comprising as an active ingredient a compound of claim 3 and a pharmaceutical acceptable carrier.
15. The compound of claim 3 , wherein G 2 is selected from the group below:
wherein
m is 1;
R 3 s selected from the group consisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino and methylamino; and
R 8 is as defined in claim 3 .
16. The compound of claim 1 , wherein G 2 is selected from the group below:
wherein
m is 1;
R 3 is selected from the group consisting of hydroxy, hydroxymethyl, amino, acylamino, acetylamino and methylamino; and
R 8 is as defined in claim 1 .
17. A compound selected from the compounds delineated in Table A or a pharmaceutically acceptable salt, or prodrug thereof:
TABLE A
Compound No.
Structure
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
41
42
43
44
46
47
48
49
50
51
52
101
102
103
104
171
172
175
203
204
207
210
18. A pharmaceutical composition comprising as an active ingredient a compound of claim 17 and a pharmaceutically acceptable carrier.