Substituted benzimidazoles as PI3 kinase inhibitors
The present invention provides substituted benzimidazole compounds of Formula I: wherein the variables R 1 , R 2 , W 1 , W 2 , W 3 , W 4 , W 5 , W 6 , W a , W b , W c and W d are defined herein. The compounds are useful as phosphoinositide 3-kinase (PI3 kinase) inhibitors.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
W 1 is N, NR 3 or CR 3 ; W 2 is N, NR 4 or CR 4 ; W 3 is N, NR 5 or CR 5 ; W 4 is N or NR 6 ; wherein no more than two N atoms are adjacent;
W 5 is N or NR 7 ; W 6 is N or CR 8 ; W a is CH; W b is CH; W c is NR 10 ; W d is N;
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 and R 4 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;
wherein R 4 is optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; wherein said substituents are optionally further substituted with one or more of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea or carbonate;
or R 3 and R 4 taken together form a cyclic moiety;
R 5 is hydrogen;
R 6 , 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 or carbonate; and
R 10 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 or carbonate.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound has the Formula:
3. The compound or pharmaceutically acceptable salt of claim 2 , wherein W 2 is CR 4 and R 4 is optionally substituted 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.
4. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 4 is optionally substituted aryl, heteroaryl, or heterocycloalkyl.
5. The compound or pharmaceutically acceptable salt of claim 4 , wherein R 4 is optionally substituted heterocycloalkyl.
6. The compound or pharmaceutically acceptable salt of claim 5 , wherein R 4 is 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, or 8-membered heterocycloalkyl.
7. The compound or pharmaceutically acceptable salt of claim 5 , wherein the optionally substituted heterocycloalkyl is morpholinyl, piperazinyl, azetidinyl, pyrrolidinyl, or piperidinyl.
8. The compound or pharmaceutically acceptable salt of claim 5 , wherein R 1 is hydrogen.
9. The compound or pharmaceutically acceptable salt of claim 8 , wherein R 2 is NH 2 .
10. The compound or pharmaceutically acceptable salt of claim 1 , wherein W 2 is CR 4 .
11. The compound or pharmaceutically acceptable salt of claim 10 , wherein R 4 is optionally substituted aryl, heteroaryl, or heterocycloalkyl.
12. The compound or pharmaceutically acceptable salt of claim 1 , wherein W 3 is CR 5 .
13. The compound or pharmaceutically acceptable salt of claim 1 , wherein W 4 is N.
14. The compound or pharmaceutically acceptable salt of claim 1 , wherein W 5 is N.
15. The compound or pharmaceutically acceptable salt of claim 1 , wherein W 2 and W 3 are CH.
16. The compound or pharmaceutically acceptable salt of claim 1 , wherein W 6 is CR 8 .
17. The compound or pharmaceutically acceptable salt of claim 1 , wherein W c is NR 10 and R 10 is alkyl or hydrogen.
18. The compound or pharmaceutically acceptable salt of claim 1 , wherein W 1 is CR 3 .
19. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is amino.
20. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is hydrogen.
21. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is selected from the group consisting of: