Heterocyclic compounds and uses thereof
Trisubstituted bicyclic heterocyclic compounds (e.g., chromenones and quinolines) and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
1. A compound of Formula I′ or Formula II′:
or a pharmaceutically acceptable form thereof,
wherein
W d is a 6-10 membered heteroaryl containing two or more nitrogen atoms;
wherein the heteroaryl is optionally substituted with R 1f , R 2f , R 3f , R 4f , and R 5f ;
each instance of R 1a is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, and (5-6 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S); wherein each of alkyl or heteroaryl is optionally substituted with one or more R 11 ;
each instance of R 11 is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, halo, OH, O(C 1 -C 8 alkyl), OCF 3 , OCF 2 H, OCFH 2 , NH 2 , NH(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl) 2 , haloalkyl, CN, NO 2 , CONH 2 , CONH(C 1 -C 8 alkyl), CON(C 1 -C 8 alkyl) 2 , COH, CO(C 1 -C 8 alkyl), COOH, COO(C 1 -C 8 alkyl), NHCO(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl)CO(C 1 -C 8 alkyl), (3-14 membered saturated, unsaturated, or aromatic carbocycle), and (3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of N, O, and S);
R 2a , R 3a , and R 4a each is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, halo, oxo, OH, O(C 1 -C 8 alkyl), OCF 3 , OCF 2 H, OCFH 2 , NH 2 , NH(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl) 2 , haloalkyl, CN, NO 2 , CONH 2 , CONH(C 1 -C 8 alkyl), CON(C 1 -C 8 alkyl) 2 , COH, CO(C 1 -C 8 alkyl), COOH, COO(C 1 -C 8 alkyl), NHCO(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl)CO(C 1 -C 8 alkyl), (3-14 membered saturated, unsaturated, or aromatic carbocycle), and (3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of N, O, and S);
R 1b , R 2b , R 3b , R 4b , and R 5b each is independently hydrogen or halogen;
R 1c is C 1 -C 8 alkyl;
R 2c is hydrogen or C 1 -C 8 alkyl;
R 1f is selected from the group consisting of NH 2 , NH(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl) 2 , hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, halo, OH, O(C 1 -C 8 alkyl), OCF 3 , OCF 2 H, OCFH 2 , haloalkyl, CN, NO 2 , CONH 2 , CONH(C 1 -C 8 alkyl), CON(C 1 -C 8 alkyl) 2 , COH, CO(C 1 -C 8 alkyl), COOH, COO(C 1 -C 8 alkyl), NHCO(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl)CO(C 1 -C 8 alkyl), (3-14 membered saturated, unsaturated, or aromatic carbocycle), and (3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of N, O, and S);
R 2f , R 3f , R 4f , and R 5f each is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, halo, OH, O(C 1 -C 8 alkyl), OCF 3 , OCF 2 H, OCFH 2 , NH 2 , NH(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl) 2 , haloalkyl, CN, NO 2 , CONH 2 , CONH(C 1 -C 8 alkyl), CON(C 1 -C 8 alkyl) 2 , COH, CO(C 1 -C 8 alkyl), COOH, COO(C 1 -C 8 alkyl), NHCO(C 1 -C 8 alkyl), N(C 1 -C 8 alkyl)CO(C 1 -C 8 alkyl), (3-14 membered saturated, unsaturated, or aromatic carbocycle), and (3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of N, O, and S); and
provided the compound is not
or an enantiomer, a mixture of enantiomers thereof.
2. The compound of claim 1 , which is a compound of Formula I′:
or a pharmaceutically acceptable form thereof.
3. The compound of claim 1 , which is a compound of Formula II′:
or a pharmaceutically acceptable form thereof.
4. The compound of claim 2 , wherein the compound of Formula I′ is a compound of formula I:
or a pharmaceutically acceptable form thereof.
5. The compound of claim 3 , wherein the compound of Formula II′ is a compound of formula II:
or a pharmaceutically acceptable form thereof.
6. The compound of claim 2 , wherein the compound of Formula I′ is a compound of the formula:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 2 , wherein the compound of Formula I′ is a compound of the formula:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable expedient.
12. The pharmaceutical composition of claim 11 , further comprises one or more therapeutic agent.