Heterocyclic compounds and uses thereof
Heterocyclic entities that modulate PI3 kinase activity, pharmaceutical compositions containing the isoquinolone entities, and methods of using these chemical entities for treating diseases and conditions associated with P13 kinase activity are described herein.
1. A compound of Formula I-A or Formula I-B:
or a pharmaceutically acceptable salt thereof, wherein
W 1 is N or CR 5 , W 2 is N or CR 6 , W 3 is N or CR 7 , W 4 is N or CR 8 , wherein no more than two N atoms are adjacent;
R 1 is -(L ) n —R 1′ ;
L is —S—, —N(R 2 )—, —C(R 3 ) 2 —, or —O—;
n is 0 or 1;
when n is 0, R 1′ is hydrogen, alkyl, heterocycloalkyl, aryl, alkoxy, amino, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
when n is 1, R 1′ is amino, alkoxy, alkyl, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
R 4 , R 5 , 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, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
X is absent or is —(CH(R 10 )) z —and z is an integer of 1, 2, 3, or 4;
Y is absent, —O—, —S—, —S(═O)—, —S(═O) 2 —, —N(R 9 )—, —C(═O)—(CHR 10 ) z —, —C(═O)—, —N(R 9 )—C(═O)—, —N(R 9 )—C(═O)NH—,or —N(R 9 )C(R 10 ) 2 —;
each instance of R 2 and R 9 is independently hydrogen, C 1 -C 10 alkyl, C 3 —C 7 cycloalkyl, heterocycloalkyl, C 2 —C 10 heteroalkyl, aryl, or heteroaryl;
each instance of R 3 and R 10 is independently hydrogen, alkyl, aryl, heteroaryl, or halo; and
wherein each instance of R a is independently hydrogen or alkyl;
wherein R 11 is H, alkyl, halo, amino, amido, hydroxyl, or alkoxy, and
R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid acycloxy, alkoxycarbonyl, or amido.
2. The compound of claim 1 wherein
W 1 is N, W 2 is CR 6 , W 3 is CR 7 , W 4 is CR 8 ;
W 1 is CR 5 , W 2 is N, W 3 is CR 7 , W 4 is CR 8 ;
W 1 is CR 5 , W 2 is CR 6 , W 3 is N, W 4 is CR 8 ;
W 1 is N, W 2 is CR 6 , W 3 is N, W 4 is CR 8 ;
W 1 is N, W 2 is N, W 3 is CR 7 , W 4 is CR 8 ;
W 1 is N, W 2 is CR 6 , W 3 is CR 7 , W 4 is N;
W 1 is CR 5 , W 2 is N, W 3 is N, W 4 is CR 8 ;
W 1 is CR 5 , W 2 is N, W 3 is CR 7 , W 4 is N;
W 1 is CR 5 , W 2 is CR 6 , W 3 is N, W 4 is N; or
W 1 is CR 5 , W 2 is CR 6 , W 3 is CR 7 , W 4 is CR 8 .
3. The compound of claim 2 wherein the compound of Formula I-A is a compound of Formula XV-A or the compound of Formula I-B is a compound of Formula XV-B:
4. The compound of claim 1 wherein n is 0 and R 1′ is hydrogen, amino, alkoxy, alkyl, heterocycloalkyl, aryl, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
5. The compound of claim 1 wherein n is 1 and R 1′ is amino, alkoxy, alkyl, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
6. The compound of claim 5 wherein n is 1 and R 1′ is alkyl which is substituted with heterocycloalkyl or R 1′ is NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
7. The compound of claim 1 wherein R 8 is hydrogen, alkyl,halo.
8. The compound of claim 7 wherein R 8 is alkyl substituted with one or more fluoro.
9. The compound of claim 1 wherein X is —CH 2 —,—CH(CH 3 )—, —CH(C 6 H 5 )—or —CH(CH 2 CH 3 )—.
10. The compound of claim 1 wherein Y is absent, —O—, —N(R 9 )—, —N(R 9 )C(R 10 ) 2 —, or —S(═O) 2 —.
11. The compound of claim 1 wherein W d is:
12. The compound of claim 11 wherein R 11 is amino.
13. The compound of claim 11 wherein R 12 is a monocyclic heteroaryl, a bicyclic heteroaryl, or a heterocycloalkyl.
14. The compound of claim 1 having a structure of Formula XVI-A:
15. The compound of claim 12 having a structure of Formula XVIII-A:
16. A composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .
17. The composition of claim 16 wherein the composition is a liquid, solid, semi-solid, gel, or an aerosol form.
18. The compound of claim 1 , wherein the compound is: