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 method of treating a disease or disorder mediated by one or more of PI3K, mTOR and HDAC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (XXIV),
or a pharmaceutically acceptable salt thereof, wherein:
G 1 is O;
G 4 is S;
each R 1 and R 2 is 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;
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;
R 8 is hydrogen or aliphatic
G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, pyridopyrrolyl, pyrrolyl, pyrazolyl, or benzimidazolyl; and
each R 6 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.
2. The method of claim 1 , wherein u, p, w and n are each 0.
3. The method of claim 1 , wherein G 5 is —N(R 8 )—CH 2 — or —N(R 8 )—CH(CH 3 )—.
4. The method of claim 3 , wherein R 8 is hydrogen or methyl.
5. The method of claim 1 , wherein:
u, p, w and n are each 0;
G 5 is —N(R 8 )—CH 2 — or —N(R 8 )—CH(CH 3 )—; and
R 8 is hydrogen or methyl.
6. The method of claim 5 , wherein G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl.
7. The method 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 method 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 method of claim 1 , wherein the compound of Formula (XXIV) is represented by the formula:
wherein G 2 is as defined in claim 1 .
10. The method of claim 9 , wherein G 2 is optionally substituted phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl or benzimidazolyl.
11. The method of claim 10 , 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.
12. A method of treating a disease or disorder mediated by one or more of PI3K, mTOR and HDAC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the compounds set forth in the table below or a pharmaceutically acceptable salt thereof:
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13. The method of claim 1 , wherein said disease or disorder is a cell proliferative disorder.
14. The method of claim 13 , wherein said cell proliferative disorder is selected from the group consisting of papilloma, blastoglioma, Kaposi's sarcoma, melanoma, non-small cell lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neck cancer, bladder cancer, breast cancer, lung cancer, colorectal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease and Burkitt's disease.
15. The method of claim 1 , wherein the disease or disorder is mediated by PI3K.
16. The method of claim 1 , wherein the disease or disorder is mediated by mTOR.
17. The method of claim 1 , wherein the disease or disorder is mediated by HDAC.
18. The method of claim 1 , wherein the disease or disorder is mediated by PI3K and HDAC.
19. A method of treating a disease or disorder mediated by one or more of PI3K, mTOR and HDAC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the compounds set forth in the table below or a pharmaceutically acceptable salt thereof:
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