Pyrrolopyrimidine compounds as kinase inhibitors
View Patent ↗Disclosed herein are compounds exemplified by the following structure Formula (I) that form covalent bonds with Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds of Formula (I). Methods of using the Btk inhibitors exemplified by the structure of Formula (I) are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
1. A compound having the structure of Formula (I):
wherein:
R 1 is halogen, —CN, —OH, —NH 2 , —SH, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted C 3 -C 8 cycloalkyl;
G is substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —SCH 3 , —N(R 21 )S(═O) 2 R 23 , S(═O) 2 N(R 21 )(R 22 ), —S(═O)R 23 , —S(═O) 2 R 23 , —C(═O)R 23 , —OC(═O)R 23 , —CO 2 R 21 , N(R 21 )(R 22 ), —C(═O)N(R 21 )(R 22 ), —N(R 21 )C(═O)R 23 , N(R 21 )C(═O)OR 22 , N(R 21 )C(═O)N(R 21 )(R 22 ), or L a —Ar;
L a is a bond, —CH 2 —, —CH(OH)—, —C(O)—, —CH 2 O—, —OCH 2 —, —SCH 2 , —CH 2 S—, —N(R 21 )—, —N(R 21 )C(O)—, —C(O)N(R 21 )—, —N(R 21 )C(O)N(R 21 )—, —O , —S—, —S(O)—, —S(O) 2 —, —N(R 21 )S(O) 2 —, or —S(O) 2 N(R 21 )—;
Ar is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
each R 24 is independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —SCH 3 , —N(R 21 )S(═O) 2 R 23 , S(═O) 2 N(R 21 )(R 22 ), —S(═O)R 23 , —S(═O) 2 R 23 , —C(═O)R 23 , —OC(═O)R 23 , —CO 2 R 21 , N(R 21 )(R 22 ), —C(═O)N(R 21 )(R 22 ), —N(R 21 )C(═O)R 23 , N(R 21 )C(═O)OR 22 , N(R 21 )C(═O)N(R 21 )(R 22 ), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl;
each R 21 and R 22 is independently H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
each R 23 is each independently substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
n is 0-4;
Y is an optionally substituted group selected from among C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene, C 6 -C 12 arylene, C 3 -C 12 heteroarylene, C 1 -C 6 alkyleneC 6 -C 12 arylene, C 1 -C 6 alkyleneC 3 -C 12 heteroarylene, C 1 -C 6 alkyleneC 3 -C 8 cycloalkylene, C 1 -C 6 alkyleneC 2 -C 7 heterocycloalkylene, C 3 -C 8 cycloalkylene, C 2 -C 7 heterocycloalkylene, fused C 3 -C 8 cycloalkyleneC 2 -C 7 heterocycloalkylene, and spiro C 3 -C 8 cycloalkyleneC 2 -C 7 heterocycloalkylene;
Z is —C(═O), —N(R a )C(═O), —S(═O) x , or —N(R a )S(═O) x , where x is 1 or 2, and R a is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl;
R 6 is H or L-J-W;
R 7 and R 8 are independently H or L-J-W; or R 7 and R 8 taken together form a bond;
L and J are each independently a bond, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted C 1 -C 6 heteroalkylene, substituted or unsubstituted C 2 -C 7 heterocycloalkylene, substituted or unsubstituted C 6 -C 12 arylene, substituted or unsubstituted C 3 -C 12 heteroarylene, —CO—, —O—, or —S—;
W is H, or NR 25 R 26 ; and
R 25 and R 26 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 -C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 3 -C 12 heteroaryl; or a pharmaceutically acceptable solvate, or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein G is L a —Ar.
3. The compound of claim 2 , wherein L a is —O—; and Ar is phenyl.
4. The compound of claim 3 , wherein Y is C 2 -C 7 heterocycloalkylene.
5. The compound of claim 4 , wherein Z is —C(═O).
6. The compound of claim 5 , wherein R 6 , R 7 , and R 8 are each H.
7. The compound of claim 5 , wherein R 6 and R 8 are H; and
R 7 is L-J-W.
8. The compound of claim 7 , wherein L is a bond, substituted or unsubstituted C 1 -C 6 alkylene, or substituted or unsubstituted C 3 -C 8 cycloalkylene; and J is a bond, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted C 1 -C 6 heteroalkylene, substituted or unsubstituted C 2 -C 7 heterocycloalkylene, substituted or unsubstituted C 6 -C 12 arylene, or substituted or unsubstituted C 3 -C 12 heteroarylene.
9. The compound of claim 8 , wherein L is a bond; J is —CH 2 —;
and W is NR 25 R 26 .
10. The compound of claim 9 , wherein R 25 is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; and R 26 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C i -C 6 heteroalkyl, substituted or unsubstituted C 2 C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 3 -C 12 heteroaryl.
11. The compound of claim 10 , wherein R 25 and R 26 are each CH 3 .
12. The compound of claim 10 , wherein R 25 is CH 3 and R 26 is cyclopropyl.
13. The compound of claim 3 , wherein Y is phenyl.
14. The compound of claim 13 , wherein Z is C(═O), NHC(═O), or N(CH 3 )C(═O).
15. The compound of claim 14 , wherein R 6 , R 7 , and R 8 are each H.
16. The compound of claim 14 , wherein R 6 and R 8 are H; and R 7 is L-J-W.
17. The compound of claim 16 , wherein L is a bond, substituted or unsubstituted C 1 -C 6 alkylene, or substituted or unsubstituted C 3 -C 8 cycloalkylene; and J is a bond, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 3 C 8 cycloalkylene, substituted or unsubstituted C 1 -C 6 heteroalkylene, substituted or unsubstituted C 2 -C 7 heterocycloalkylene, substituted or unsubstituted C 6 -C 12 arylene, or substituted or unsubstituted C 3 -C 12 heteroarylene.
18. The compound of claim 17 , wherein L is a bond; J is —CH 2 —; and
W is NR 25 R 26 .
19. The compound of claim 18 , wherein R 25 is H, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; and R 26 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 2 C 7 heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, or substituted or unsubstituted C 3 -C 12 heteroaryl.
20. The compound of claim 19 , wherein R 25 and R 26 are each CH 3 .
21. The compound of claim 19 , wherein R 25 is CH 3 and R 26 is cyclopropyl.
22. The compound of claim 1 , wherein n is 0.
23. The compound of claim 1 , wherein R 1 is —F, —Cl, —CH 3 , or —OCH 3 .
24. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound claim 1 , or a pharmaceutically acceptable salt, or pharmaceutically acceptable solvate.