Certain chemical entities, compositions and methods
Provided herein are substituted bicyclic compounds, e.g., compounds of Formula IV, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for inhibiting phosphatidyl inositol-3 kinase (PI3 kinase), e.g., for the treatment of various diseases and conditions associated with PI3 kinase activity, including but not limited to, cancer, inflammatory disease, immune disease, and respiratory disease.
1. A compound of Formula IV:
or a pharmaceutically acceptable salt thereof, wherein
W a 2 is CR 5 ;
W a 3 is CR 6 ;
W a 4 is CR 7 ;
W d is
R a is hydrogen, halo, phosphate, urea, carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl;
R 11 is hydrogen, alkyl, halo, amino, amido, hydroxy, or alkoxy;
R 12 is hydrogen, alkyl, cyano, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, amino, carboxylic acid, alkoxycarbonyl, or amido;
B is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II:
W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
q is an integer of 0, 1, 2, 3, or 4;
X is a bond or —(CH(R 9 )) z —;
Y is a bond, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 9 )—, —C(═O)—(CHR 9 ) z —, —C(═O)—, —N(R 9 )—C(═O)NH—, or —N(R 9 )C(R 9 ) 2 —;
each z is independently 1, 2, 3, or 4;
R 1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, or nitro;
R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl, or heteroaryl;
R 5 , R 6 , R 7 , and R 8 are independently hydrogen, C 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 5 cycloalkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 amido, amino, acyl, C 1 -C 4 acyloxy, C 1 -C 4 sulfonamido, halo, cyano, hydroxy, or nitro; and
each R 9 is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, or C 2 -C 10 heteroalkyl.
2. The compound of claim 1 , wherein the compound is of Formula V or Formula VI:
3. The compound of claim 1 , wherein the compound is of Formula VII:
4. The compound of claim 1 , wherein R 1 is selected from hydrogen, alkyl, and halo.
5. The compound of claim 4 , wherein R 1 is hydrogen, methyl, isopropyl, or fluoro.
6. The compound of claim 1 , wherein R 3 is —H, halo, alkyl, alkoxy, or cycloalkyl.
7. The compound of claim 6 , wherein R 3 is —H, —CH 3 , —CH 2 CH 3 , —CF 3 , —Cl, or —F.
8. The compound of claim 7 , wherein R 3 is methyl or chloro.
9. The compound of claim 1 , wherein R 5 is H, —CN, —NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —CF 3 , NO 2 , or halo.
10. The compound of claim 1 , wherein R 6 is H, —CN, —NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —CF 3 , NO 2 , or halo.
11. The compound of claim 1 , wherein R 7 is H, —CN, —NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —CF 3 , NO 2 , or halo.
12. The compound of claim 1 , wherein R 8 is H, —CN, —NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —CF 3 , NO 2 , or halo.
13. The compound of claim 1 , wherein X is —CH 2 — or —CH(CH 3 )—.
14. The compound of claim 13 , wherein —CH(CH 3 )— is in an (S) stereochemical configuration.
15. The compound of claim 1 , wherein X is —CH 2 — and Y is a bond.
16. The compound of claim 1 , wherein W c is aryl or heterocycloalkyl.
17. The compound of claim 1 , wherein W d is 4-amino-1H-pyrazolo[3,4-d]pyrimidin-1-yl,
6-amino-9H-purin-9-yl, or
7-amino-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl.
18. The compound of claim 1 , wherein W d is
19. The compound of claim 18 , wherein W d is
wherein R 11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and
R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
20. The compound of claim 19 , wherein the compound is of Formula 6-A:
21. The compound of claim 20 , wherein B is alkyl, amino, aryl, heteroalkyl, heteroaryl, heterocycloalkyl, or cycloalkyl.
22. The compound of claim 20 , wherein B is aryl, alkyl, cycloalkyl, heteroaryl, or heterocycloalkyl.
23. The compound of claim 22 , wherein B is optionally substituted phenyl, methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, optionally substituted pyridinyl, or tetrahydropyranyl.
24. The compound of claim 20 , wherein B is a moiety of Formula II:
wherein W c is phenyl;
R 1 is H, —F, —Cl, —CN, —CH 3 , isopropyl, —CF 3 , —OCH 3 , nitro, or phosphate;
R 2 is hydroxy or cyano; and
q is an integer of 0 or 1.
25. The compound of claim 20 , wherein R 12 is —I, —Br,
26. The compound of claim 25 , wherein R 12 is
27. A pharmaceutical composition comprising a compound of claim 1 , 19 , or 20 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
28. The compound of claim 1 , wherein the compound is of Formula 2-A:
29. The compound of claim 1 , wherein the compound is of Formula 2-B:
30. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
31. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
32. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
33. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
34. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
35. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: