Heterocyclic compounds and uses thereof
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the heterocyclic entities, and methods of using these chemical entities for treating diseases and conditions associated with PI3 kinase activity are described herein.
1. A method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase), comprising: contacting the PI3 kinase with a therapeutically effective amount of a compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein
W 1 is CR 3 ,
W 2 is CR 4 ,
W 3 is N;
W 4 is N;
W 5 is CR 7 ;
W 6 is CR 8 ;
R 1 and R 2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
R 3 is amido of formula —C(O)N(R) 2 or —NHC(O)R, wherein R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heteroalicyclic; or wherein said (R) 2 may be taken together with the nitrogen to which they are attached to form an optionally substituted 4-, 5-, 6-, 7-, or 8-membered ring;
R 4 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
or R 3 and R 4 taken together form a cyclic moiety; and
R 5 , R 7 , and R 8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
2. The method of claim 1 , wherein the contacting of the PI3 kinase with the compound comprises contacting a cell that expresses the PI3 kinase.
3. The method of claim 1 , wherein the PI3 kinase is PI3 kinase alpha.
4. The method of claim 2 , further comprising administering a second therapeutic agent to the cell.
5. The method of claim 1 ,
wherein the contacting of the PI3 kinase with the compound is in a subject suffering from a cancer selected from the group consisting of: breast invasive carcinoma, prostate adenocarcinoma, colon adenocarcinoma, thyroid carcinoma, bladder urothelial carcinoma, lung adenocarcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, testicular germ cell tumors, lung squamous cell carcinoma, stomach adenocarcinoma, glioblastoma multiforme, liver hepatocellular carcinoma, pancreatic adenocarcinoma, esophageal carcinoma, brain lower grade glioma, head and neck squamous cell carcinoma, rectum adenocarcinoma, cholangiocarcinoma, mesothelioma, breast cancer, lung cancer, gastric cancer, and uterine cancer.
6. The method of claim 1 , wherein
W 1 is CR 3 ;
W 2 is CR 4 ;
W 3 is N;
W 4 is N;
W 5 is CR 7 ;
W 6 is CR 8 ;
R 1 and R 2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 3 is amido of formula —C(O)N(R) 2 or —NHC(O)R, wherein R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heteroalicyclic; or wherein said (R) 2 may be taken together with the nitrogen to which they are attached to form an optionally substituted 4-, 5-, 6-, or 7-membered ring, and
R 4 , R 7 , and R 8 are each hydrogen.
7. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 5 , wherein
W 1 is CR 3 ;
W 2 is CR 4 ;
W 3 is N;
W 4 is N;
W 5 is CR 7 ;
W 6 is CR 8 ;
R 1 and R 2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 3 is amido of formula —C(O)N(R) 2 or —NHC(O)R, wherein R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heteroalicyclic; or wherein said (R) 2 may be taken together with the nitrogen to which they are attached to form an optionally substituted 4-, 5-, 6-, or 7-membered ring, and
R 4 , R 7 , and R 8 are each hydrogen.
9. The method of claim 5 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. The method of claim 5 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
11. The method of claim 5 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
12. The method of claim 5 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
13. The method of claim 5 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The method of claim 5 , wherein the cancer is breast cancer.
15. The method of claim 5 , wherein the cancer is lung cancer.
16. The method of claim 15 , wherein the lung cancer is non-small cell lung cancer.
17. The method of claim 15 , wherein the lung cancer is small cell lung cancer.
18. The method of claim 5 , wherein the cancer is gastric cancer.
19. The method of claim 5 , wherein the cancer is uterine cancer.
20. The method of claim 10 , wherein the cancer is breast cancer.
21. The method of claim 11 , wherein the cancer is breast cancer.
22. The method of claim 12 , wherein the cancer is breast cancer.
23. The method of claim 13 , wherein the cancer is breast cancer.
24. The method of claim 10 , wherein the cancer is uterine cancer.
25. The method of claim 11 , wherein the cancer is uterine cancer.
26. The method of claim 12 , wherein the cancer is uterine cancer.
27. The method of claim 4 , wherein the second therapeutic agent is an inhibitor of Ras oncogenic isoforms.
28. The method of claim 5 , wherein the therapeutically effective amount is from about 0.05 to about 7 g/day.
29. The method of claim 5 , wherein the therapeutically effective amount is from about 0.05 to about 2.5 g/day.
30. The method of claim 5 , further comprising administering a second therapeutic agent to the subject.
31. The method of claim 30 , wherein the second therapeutic agent is a chemotherapeutic agent.