Heterocyclic compounds and uses thereof
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 (Ia):
or a pharmaceutically acceptable form thereof, wherein:
W 5 is N 4 or CR 4 ;
R 4 is hydrogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety;
Cy is aryl or heteroaryl substituted by 0-4 occurrences of R 3 ;
R 1 is -(L) n -R 1′ ;
each L is independently absent, alkylene, or —O—;
R 1′ is —(C═O)—NR a1 R a2 ;
R a1 and R a2 are each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or R a1 and R a2 are taken together with nitrogen to form a cyclic moiety;
R 2 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, or heteroaryl;
each R 3 is independently alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, 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 —;
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) 13 , —C(═O)—N(R 9 )—, —N(R 9 )—C(═O)NH—, —N(R 9 )C(R 10 ) 2 —, —C(═O)—N(R 9 )—(CHR 10 ) z —, or —P(═O)R 2 —;
each z is an integer of 1, 2, 3, or 4;
n is an integer of 0, 1, 2, 3, or 4;
each R 9 is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, aryl, or heteroaryl;
W d is
wherein W d is optionally substituted with one or more R b , R 11 , R 12 , and R 13 ;
each R b is independently hydrogen, halo, phosphate, urea, carbonate, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl; and
each R 10 , R 11 , R 12 , and R 13 is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, haloalkyl, cyano, hydroxyl, nitro, phosphate, urea, carbonate, or NR′R″ wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
2. The compound of claim 1 , wherein n is 1, 2, or 3.
3. The compound of claim 1 , wherein L is absent.
4. The compound of claim 1 , wherein R a2 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or acyl.
5. The compound of claim 1 , wherein R a1 and R a2 are taken together with the nitrogen to which they are attached to form a cyclic moiety.
6. The compound of claim 1 , wherein W 5 is N or W 5 is CR 4 and R 4 is hydrogen.
7. The compound of claim 1 , wherein X is —(CH(R 10 )) z — and z is 1 or 2.
8. The compound of claim 1 , wherein Y is absent, —O—, —N(R 9 )—, or —S(═O) 2 —.
9. The compound of claim 1 , wherein Cy is phenyl substituted with 1 occurrence of R 3 .
10. The compound of claim 1 , wherein R 3 is halo, alkyl, haloalkyl, acyl, or heteroaryl.
11. The compound of claim 1 , wherein W d is:
12. The compound of claim 11 , wherein R 12 is hydrogen, halo, haloalkyl, cyano, amino, or amido.
13. The compound of claim 1 , wherein the compound of Formula (Ia) is a compound of Formula (IIIa):
or a pharmaceutically acceptable form thereof, wherein:
W 1 is N or CR 14 , W 2 is N or CR 6 , W 3 is N or CR 7 , and W 4 is N or CR 8 , wherein no more than two N atoms are adjacent; and
R 6 , R 7 , R 8 and R 14 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R″, wherein R′ and R″ are taken together with nitrogen to form a cyclic moiety.
14. The compound of claim 13 , wherein R a1 and R a2 are taken together with nitrogen to form a cyclic moiety.
15. The compound of claim 14 , wherein the cyclic moiety is 5- or 6-membered.
16. The compound of claim 13 , wherein n is 1 and L is alkylene.
17. The compound of claim 13 , wherein W 1 is CR 14 , W 2 is CR 6 , W 3 is CR 7 , and W 4 is CR 8 .
18. The compound of claim 13 , wherein R 8 is hydrogen or alkyl.
19. The compound of claim 1 , wherein X is —CH 2 —, —CH(CH 3 )—, —CH(C 6 H 5 )—, or —CH(CH 2 CH 3 )—.
20. The compound of claim 19 , wherein the CH carbon of —CH(CH 3 )—or —CH(CH 2 CH 3 )—has a predominately (S) stereochemical configuration.
21. The compound of claim 1 , wherein X—Y is —CH 2 —N(CH 3 )—, or —CH 2 —N(CH 2 CH 3 )—.
22. The compound of claim 1 , wherein the compound of Formula (Ia) is a compound of Formula (V):
or a pharmaceutically acceptable form thereof.
23. The compound of claim 22 , or a pharmaceutically acceptable form thereof, wherein:
R 1 is -(L) n -R 1′ ;
each L is independently —O or alkylene;
R 1′ is —(C═O)—NR a1 R a2 ;
W d is:
R 12 is hydrogen, halo, haloalkyl, cyano, amino, or amido; and
n is 0, 1, 2, 3, or 4.
24. A pharmaceutical composition comprising a compound according to claim 1 , and one or more pharmaceutically acceptable excipients.
25. The compound of claim 1 , which is:
or a pharmaceutically acceptable form thereof.
26. The compound of claim 1 , which is:
or a pharmaceutically acceptable form thereof.