Inhibitors of bruton's tyrosine kinase
View Patent ↗Described herein are irreversible kinase inhibitor compounds exemplified by the following structure Formula (A2): methods for synthesizing such irreversible inhibitors, and methods for using such irreversible inhibitors in the treatment of a B cell proliferative disorder or a mast cell proliferative disorder.
1. A compound of Formula (A5) having the structure:
wherein:
R 1 is H, L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted alkenyl), L 2 -(substituted or unsubstituted cycloalkenyl), L 2 -(substituted or unsubstituted heterocycle), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 alkenyl);
R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl;
R 4 is L 3 -X-L 4 -G, wherein,
L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;
X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O) 2 , —NH, —NR 9 , —NHC(O), —C(O)NH, —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NH, —NHS(═O) 2 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 10 C(O)NR 10 —, heteroaryl, aryl, —NR 10 C(═NR 11 )NR 10 —, —NR 10 C(═NR 11 )—, —C(═NR 11 )NR 10 —, —OC(═NR 11 )—, or —C(═NR 11 )O—;
L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring;
G is
wherein,
R 6 , R 7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;
R 5 is H, halogen, -L 6 -(substituted or unsubstituted C 1 -C 3 alkyl), -L 6 -(substituted or unsubstituted C 2 -C 4 alkenyl), -L 6 -(substituted or unsubstituted heteroaryl), or -L 6 -(substituted or unsubstituted aryl), wherein L 6 is a bond, O, S, —S(═O), S(═o) 2 , NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), or —C(O)NH;
each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;
each R 10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or
two R 10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
R 9 and R 10 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or
each R 11 is independently selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 , —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl; or
pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein R 2 and R 3 are H.
3. The compound of claim 2 , wherein R 1 is L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl).
4. The compound of claim 3 having the structure
wherein each R a is independently H, halogen, —CF 3 , —CN, —NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), or -L a -(substituted or unsubstituted alkenyl), wherein L a is a bond, O, S, —S(═O), —S(═O) 2 , NH, C(O), CH 2 , —NHC(O)O, —NHC(O), or —C(O)NH.
5. The compound of claim 4 , wherein L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring.
6. The compound of claim 5 , wherein G is
7. The compound of claim 6 , wherein R 6 , R 7 , and R 8 are H.
8. The compound of claim 6 , wherein
R 7 and R 8 are H; and
R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
9. The compound of claim 8 , wherein R 6 is substituted lower alkyl.
10. The compound of claim 9 , wherein lower alkyl is substituted with a disubstituted amino group.
11. The compound of claim 6 , wherein
R 6 and R 8 are H; and
R 7 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
12. The compound of claim 11 , wherein R 7 is substituted lower alkyl.
13. The compound of claim 12 , wherein lower alkyl is substituted with a disubstituted amino group.
14. The compound of claim 5 , wherein G is
15. The compound of claim 14 , wherein R 6 is H.
16. The compound of claim 14 , wherein R 6 is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl.
17. The compound of claim 16 , wherein R 6 is substituted lower alkyl.
18. The compound of claim 17 , wherein lower alkyl is substituted with a disubstituted amino group.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
20. The pharmaceutical composition of claim 19 that is formulated for a route of administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration, or rectal administration.