Inhibitors of plasma kallikrein
The present invention provides compounds that inhibit the activity of plasma kallikrein (PK) and methods of preventing and treating the formation of thrombin during or after a PK dependent disease or condition, for example, after fibrinolysis treatment.
1. A compound having the formula:
wherein
Ar is a bond or an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine;
the subscript m is an integer of from 0 to 5;
each R a is independently selected from the group consisting of cycloalkyl, (C 1 -C 8 )haloalkyl, halogen, —OH, —OR 1 , —OSi(R 1 ) 3 , —OC(O)O—R 1 , —OC(O)R 1 , —OC(O)NHR 1 , —OC(O)N(R 1 ) 2 , —SH, —SR 1 , —S(O)R 1 , —S(O) 2 R 1 , —SO 2 NH 2 , —S(O) 2 NHR 1 , —S(O) 2 N(R 1 ) 2 , —NHS(O) 2 R 1 , —NR 1 S(O) 2 R 1 , —C(O)NH 2 , —C(O)NHR 1 , —C(O)N(R 1 ) 2 , —C(O)R 1 , —C(O)H, —C(═S)R 1 , —NHC(O)R 1 , —NR 1 C(O)R 1 , —NHC(O)NH 2 , —NR 1 C(O)NH 2 , —NR 1 C(O)NHR 1 , —NHC(O)NHR 1 , —NR 1 C(O)N(R 1 ) 2 , —NHC(O)N(R 1 ) 2 , —CO 2 H, —CO 2 R 1 , —NHCO 2 R 1 , —NR 1 CO 2 R 1 , —R 1 , —CN, —NO 2 , —NH 2 , —NHR 1 , —N(R 1 ) 2 , —NR 1 S(O)NH 2 , —NR 1 S(O) 2 NHR 1 , —NH 2 C(═NR 1 )NH 2 , —N═C(NH 2 )NH 2 , —C(═NR 1 )NH 2 , —NH—OH, —NR 1 —OH, —NR 1 —OR 1 , —N═C═O, —N═C═S, —Si(R 1 ) 3 , —NH—NHR 1 , —NHC(O)NHNH 2 , NO, —N═C═NR 1 and —S—CN, wherein each R 1 is independently alkyl;
L is a linking group selected from the group consisting of a bond, CH 2 and SO 2 ;
Q a , Q b , and Q c are each members independently selected from the group consisting of N, S, O and C(R q ) wherein each R q is independently selected from the group consisting of H, C 1-8 alkyl, halo and phenyl, and the ring having Q a , Q b , Q c and Y as ring vertices is a five-membered ring having two double bonds;
Y is a member selected from the group consisting of C and N;
when Ar is a bond, m is 1;
when Ar is an aromatic ring, m is an integer of from 0-5; and
pharmaceutically acceptable salts thereof.
2. A compound of claim 1 , wherein Ar is an aromatic ring selected from the group consisting of benzene, pyridine and pyrimidine.
3. A compound of claim 1 , wherein Ar is a bond and m is 1.
4. A compound of claim 1 , having a formula Ia:
5. A compound of claim 2 , wherein L is a bond and Y is N.
6. A compound of claim 2 , wherein L is a bond, Y is N and Ar is a benzene ring.
7. A compound of claim 6 , wherein Q a , Q b and Q c are each independently C(R q ).
8. A compound of claim 6 , wherein Q b is N.
9. A compound of claim 2 , wherein Y is C; Q a is S and Ar is selected from phenyl or pyridyl.
10. A compound of claim 9 , wherein Q c is C.
11. A compound of claim 2 , wherein L is CH 2 and Y is N.
12. A compound of claim 11 , wherein Q a is C.
13. A compound of claim 12 , wherein Q b and Q c are each independently selected from the group consisting of N and C(R q ).
14. A compound of claim 12 , wherein Ar is benzene or pyridine.
15. A compound of claim 2 , wherein L is a bond and Y is C.
16. A compound of claim 15 , wherein Q b is O; and Q a and Q c are each C(R q ).
17. A compound of claim 2 , wherein L is SO 2 and Y is N.
18. A compound of claim 2 , wherein each R a is independently selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxy, aryl, aryl(C 1 -C 8 alkyl), halogen, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —CN, —C(═O)(C 1 -C 8 alkyl), —(C═O)NH 2 , —(C═O)NH(C 1 -C 8 alkyl), —C(═O)N(C 1 -C 8 alkyl) 2 , —OH, —COOH, —COO(C 1 -C 8 alkyl), —OCO(C 1 -C 8 alkyl), —O(C═O)O(C 1 -C 8 alkyl)-NO 2 , —SH, —S(C 1 -C 8 alkyl), —NH(C═O)(C 1 -C 8 alkyl), —NH(C═O)O(C 1 -C 8 alkyl), —O(C═O)NH(C 1 -C 8 alkyl), —SO 2 (C 1 -C 8 alkyl), —NHSO 2 (C 1 -C 8 alkyl) and —SO 2 NH(C 1 -C 8 alkyl).
19. A compound of claim 18 , wherein each R a is independently selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxy, phenyl, phenyl(C 1 -C 8 alkyl), halogen, —CN, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —(C═O)CH 3 , —(C═O)NH 2 , —OH, —COOH, —COO(C 1 -C 8 alkyl), —OCO(C 1 -C 8 alkyl), —O(C═O)O(C 1 -C 8 alkyl), —NO 2 , —SH, —S(C 1 -C 8 alkyl), and —NH(C═O)(C 1 -C 8 alkyl).
20. A compound of claim 19 , wherein R a is halogen.
21. A compound of claim 2 , selected from the group consisting of:
22. A compound having the formula II:
wherein
the subscript m is an integer of from 0 to 5;
the subscript n is an integer of from 0 to 4;
the subscript q is an integer of from 0 to 1;
L is a linking group selected from the group consisting of a bond, CH 2 and SO 2 ;
each of R b and R c is independently selected from the group consisting of cycloalkyl, (C 1 -C 8 )haloalkyl, halogen, —OH, —OR 2 , —OSi(R 2 ) 3 , —OC(O)O—R 2 , —OC(O)R 2 , —OC(O)NHR 2 , —OC(O)N(R 2 ) 2 , —SH, —SR 2 , —S(O)R 2 , —S(O) 2 R 2 , —SO 2 NH 2 , —S(O) 2 NHR 2 , —S(O) 2 N(R 2 ) 2 , —NHS(O) 2 R 2 , —NR 2 S(O) 2 R 2 , —C(O)NH 2 , —C(O)NHR 2 , —C(O)N(R 2 ) 2 , —C(O)R 2 , —C(O)H, —C(═S)R 2 , —NHC(O)R 2 , —NR 2 C(O)R 2 , —NHC(O)NH 2 , —NR 2 C(O)NH 2 , —NR 2 C(O)NHR 2 , —NHC(O)NHR 2 , —NR 2 C(O)N(R 2 ) 2 , —NHC(O)N(R 2 ) 2 , —CO 2 H, —CO 2 R 2 , —NHCO 2 R 2 , —NR 2 CO 2 R 2 , —R 2 , —CN, —NO 2 , —NH 2 , —NHR 2 , —N(R 2 ) 2 , —NR 2 S(O)NH 2 , —NR 2 S(O) 2 NHR 2 , —NH 2 C(═NR 2 )NH 2 , —N═C(NH 2 )NH 2 , —C(═NR 2 )NH 2 , —NH—OH, —NR 2 —OH, —NR 2 —OR 2 , —N═C═O, —N═C═S, —Si(R 2 ) 3 , —NH—NHR 2 , —NHC(O)NHNH 2 , NO, —N═C═NR 2 and —S—CN, wherein each R 2 is independently alkyl;
when q is 0, Z is a member selected from the group consisting of O, S and NR d wherein R d is H or C 1 -C 8 alkyl;
when q is 1, Z is N; and
pharmaceutically acceptable salts thereof.
23. A compound of claim 22 , wherein the subscript q is 0 and Z is selected from the group consisting of O, S and NH.
24. A compound of claim 23 , wherein the subscript n is an integer of from 0 to 2.
25. A compound of claim 24 , wherein Z is O or S.
26. A compound of claim 22 , wherein the subscript q is 1.
27. A compound of claim 26 , wherein L is selected from the group consisting of —CH 2 — and —SO 2 —.
28. A compound of claim 27 , wherein the subscript m is 0.
29. A compound of claim 22 , wherein R b and R c are each independently selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxy, phenyl, phenyl (C 1 -C 8 alkyl), halogen, —CN, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —(C═O)CH 3 , —(C═O)NH 2 , —OH, —COOH, —COO(C 1 -C 8 alkyl), —OCO(C 1 -C 8 alkyl), —O(C═O)O(C 1 -C 8 alkyl)-NO 2 , —SH, —S(C 1 -C 8 alkyl), and —NH(C═O)(C 1 -C 8 alkyl).
30. A compound of claim 22 , selected from the group consisting of:
31. A pharmaceutical composition comprising a compound of claim 1 , in combination with a pharmaceutically acceptable excipient.
32. A method of treating thrombosis in a subject having thromboisis, said method comprising administering to said subject a compound of claim 1 .
33. A method of treating a plasma kallikrein dependent disease or condition in a subject having a disease or condition selected from the group consisting of stroke, inflammation, pain, acute myocardial infarction, deep vein thrombosis (DVT), post fibrinolytic treatment conditions, angina, angioedema, sepsis, arthritis, blood loss during cardiopulmonary bypass, inflammatory bowel disease, and diabetes, said method comprising administering to said subject a compound of claim 1 .