Chemical compounds, compositions and methods for kinase modulation
Substituted isoquinolinone compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
1. A compound of formula (Ib):
or a pharmaceutically acceptable form thereof, wherein
B is hydrogen, or a moiety of Formula II:
wherein W c is 6-membered aryl or cycloalkyl;
q is an integer of 0, 1, 2, 3, or 4;
X is absent or —(CH(R 9 )) z —, and z is an integer of 1, 2, 3, or 4;
Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —C(═O)(CHR 9 ) z —, —N(R 9 )—, —N(R 9 )—C(═O)NH—, or —N(R 9 )C(R 9 ) 2 —, and z is an integer of 1, 2, 3, or 4;
R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
each R 2 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
R 3 is aryl, alkenyl, cyano, or amino, or R 3 is a heteroatom selected from N, S, and O, wherein the heteroatom has a covalent bond either directly or through a C 1 -C 6 alkyl group to an aryl, heteroaryl or heterocyclyl; wherein each of the above substituents can be substituted with 0, 1, 2, or 3 R 13 ;
R 5 , R 6 , R 7 , and R 8 are independently hydrogen, halo, cyano, alkyl, or amino;
each R 9 is independently hydrogen, alkyl, or heterocycloalkyl;
W d is
R 12 is hydrogen, alkyl, haloalkyl, alkynyl, alkenyl, halo, —C(O)NH 2 , NH 2 , cyano, aryl, heteroaryl, nonaromatic heterocyclyl, or cycloalkyl;
R a′ is hydrogen, alkyl, —NH 2 , cyano, or halogen; and
each R 13 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halogen.
2. The compound of claim 1 , wherein R 3 is aryl.
3. The compound of claim 2 , wherein the aryl is phenyl.
4. The compound of claim 3 , wherein R 3 is
5. The compound of claim 1 , wherein R 3 is alkenyl.
6. The compound of claim 5 , wherein the alkenyl is ethenyl.
7. The compound of claim 1 , wherein R 3 is a heteroatom selected from N, S, and O, and the heteroatom has a covalent bond directly to heterocyclyl.
8. The compound of claim 1 , wherein B is:
9. The compound of claim 8 , wherein q is 0.
10. The compound of claim 8 , wherein R 1 is hydrogen.
11. The compound of claim 1 , wherein Y is —N(R 9 )—.
12. The compound of claim 1 , wherein X is —(CH(R 9 )) z —.
13. The compound of claim 12 , wherein z is 1.
14. The compound of claim 1 , wherein R 9 is hydrogen or alkyl.
15. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable form thereof.
16. The compound of claim 15 , wherein the compound is
or a pharmaceutically acceptable form thereof.
17. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.
18. A method of inhibiting a phosphoinositide 3-kinase (PI3K) in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .