Human plasma kallikrein inhibitors

1. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:

wherein, independently for each occurrence:

R 1 represents —OH, —OR c , —NH 2 , —NHR c , —NR c R d , alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, —C(O)R c , —C(O)OH, —C(O)OR c , —OC(O)R c , —C(O)NH 2 , —C(O)NHR c , —C(O)NR c R d , —NHC(O)R c , or —NRcC(O)R d ;

W is —C(O)NH—;

R 2 represents optionally substituted aryl or heteroaryl;

V represents optionally substituted aryl or heteroaryl;

Z is absent or represents one or more substituents independently selected from the group consisting of halo, haloalkyl, —NO 2 , —CN, —C(O)R c , —C(O)OH, —C(O)OR c , —OC(O)R c , —C(O)NH 2 , —C(O)NHR c , —C(O)NR c R d , —NHC(O)R c , —N(R c )C(O)R d , —OS(O) p (R c ), —NHS(O) p (R c ), and —NR c S(O) p (R c );

X represents —C(NH 2 )—, —C(NH(R c ))—, —C(NR c R d )—, —C(NHS(O) p R c )—, —C(NHC(O)R c )—, —C(NHC(O)NH 2 )—, —C(NHC(O)NHR c )—, —C(NHC(O)NR c R d )—, —C(OH) —C(O(alkyl))—, —C(N 3 )—, —C(CN)—, —C(NO 2 )—, —C(S(O) n R a )—, —C[—C(═O)R c ]—, —C[—C(═O)NR c R d ]—, —C[—C(═O)SR c ]—, —C[—S(O)R c ]—, —C[—S(O) 2 R c ]—, —C[S(O)(OR c )]—, —C[—S(O) 2 (OR c )]—, —C[—SO 2 NR c R d ]—, —C(halogen)-, —C(alkyl), —C((cycloalkyl)alkyl), —C(alkenyl)-, —C(alkynyl)-, or —C(aralkyl)-;

R 3 represents optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

R 3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, alkyl, —CF 3 , —OCF 3 , alkoxy, aryl, heteroaryl, aryloxy, amino, aminoalkyl, —C(O)NH 2 , cyano, —NHC(O)alkyl, -SO 2 alkyl, —SO 2 NH 2 , cycloalkyl, —(CH 2 ) r OR a , —NO 2 , —(CH 2 ) r NR a R b , —(CH 2 ) r C(O)R a , —NR a C(O)R b , —C(O)NR c R d , —NR a C(O)NR c R d , —C(═NR a )NR c R d , —NHC(═NR a )NR c R d , —NR a R b , —SO 2 NR c R d , —NR a SO 2 NR c R d , —NR a SO 2 alkyl, —NR a SO 2 R a , —S(O) p R a , —(CF 2 ) r CF 3 , —NHCH 2 R a , —OCH 2 R a , —SCH 2 R a , —NH(CH 2 ) 2 (CH 2 ) r R a , —O(CH 2 ) 2 (CH 2 ) r R a , and —S(CH 2 ) 2 (CH 2 ) r R a ;

Y represents a bond; or —Y—R 4 represents optionally substituted -alkylene-R 4 , —CH 2 C(O)—R 4 , —CH 2 NH—R 4 , —CH 2 N(alkyl)-R 4 , —CR a R b —R 4 , —NH—R 4 , —NHCH 2 -R 4 , —NHC(O)—R 4 , —N(alkyl)-R 4 , —N(alkyl)CH 2 -R 4 , —N((CH 2 ) 2 OH)—R 4 , —N((cycloalkyl)alkyl)R 4 , -heterocyclyl-R 4 , —OR 4 , —OCH 2 -R 4 , —OC(O)—R 4 , —OC(O)NR a R b , —SCH 2 R 4 , or —SR 4 ;

R 4 represents hydrogen, hydroxy, optionally substituted alkyl, cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, —CH 2 OH, —CH(alkyl)OH, —CH(NH 2 )CH(alkyl) 2 , aryl, aralkyl, heteroaryl, heteroaralkyl, —CH 2 S(alkyl), amino, or cyano; or —(CR a R b ) r (CR a R b ) p — fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents; or,

when R 3 is phenyl, R 4 can represent —NR a — fused to the position ortho to X on that phenyl;

each R a and R b is independently H, alkyl, alkenyl, alkynyl, aralkyl, (cycloalkyl)alkyl, —C(═O)R c , —C(═O)OR c , —C(═O)NR c R d , —C(═O)SR c , —S(O)R c , —S(O) 2 R c , —S(O)(OR c ), or —SO 2 NR c R d ;

R c and R d represent, independently for each occurrence, optionally substituted alkyl, alkenyl, alkynyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, —C(O)alkyl, or —S(O) p (alkyl); or R c and R d can be taken together to form an optionally substituted heterocyclic ring;

r is 0, 1, 2, or 3;

n is an integer from 0 to 6; and

p is 0, 1, or 2.

2. The compound of claim 1 , wherein R 1 represents —OH, —OR c , alkyl, aryl, haloalkyl, or cycloalkyl;

Z is absent or represents one or more occurrences of halo;

X represents —C(NH 2 )—, —C(NH(R c ))—, —C(NHS(O) p R c )—, or —C(NHC(O)R c )—;

R 3 represents optionally substituted aryl or heteroaryl;

R 3a is absent or represents one or more substituents independently selected from the group consisting of alkyl and cyano;

—Y—R 4 represents -alkylene-R 4 or —N(alkyl)-R 4 ; and

R 4 represents cycloalkyl.

3. The compound of claim 1 , wherein R 1 represents —OH, —O((C 1 -C 6 )alkyl), (C 1 -C 6 )alkyl, haloalkyl, cycloalkyl, or aryl.

4. The compound of claim 3 , wherein n is 1; and

R 1 represents —OH, —CH 3 —OCH 2 CH 2 CH 3 , —OCH 2 CH 3 , or —OCH 3 .

5. The compound of claim 3 , wherein n is 2; and the two occurrences of R 1 are geminal.

6. The compound of claim 5 , wherein R 1 represents —OH, —OCH 3 , —CH 3 , —CF 3 , cyclopropyl, or phenyl.

7. The compound of claim 5 , wherein:

(a) one occurrence of R 1 represents —OH or —O((C 1 -C 6 )alkyl); and the other occurrence of R 1 represents aryl or cycloalkyl;

(b) one occurrence of R 1 represents —OH or —O((C 1 -C 6 )alkyl); and the other occurrence of R 1 represents alkyl or haloalkyl; or

(c) both occurrences of R 1 are halo.

8. The compound of claim 5 , wherein:

(a) one occurrence of R 1 represents —OH or —OCH 3 ; and the other occurrence of R 1 represents phenyl or cyclopropyl; or

(b) one occurrence of R 1 represents —OH or —OCH 3 ; and the other occurrence of R 1 represents —CH 2 CH 3 or —CF 3 .

9. The compound of claim 1 , wherein R 2 represents aryl or heteroaryl, substituted by one or more substituents selected from the group consisting of —OH, halo, —NH 2 , —CN, —NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, —C(O)OH, and —C(O)O(C 1 -C 6 )alkyl.

10. The compound of claim 1 , wherein R 2 represents (halo)aryl or (halo)heteroaryl.

11. The compound of claim 10 , wherein R 2 represents phenyl, pyridyl, or thiophenyl substituted by one occurrence of halo.

12. The compound of claim 1 , wherein V represents optionally substituted aryl.

13. The compound of claim 12 , wherein Z represents halo or Z is absent.

14. The compound of claim 12 , wherein Z represents one instance of halo.

15. The compound of claim 1 , wherein X represents —CH, —C(NH 2 )—, —C(NH(R c ))—, —C(NHS(O) p R c )—, or —C(NHC(O)RF c )—.

16. The compound claim 15 , wherein X represents —C(NH 2 )—;

—C(NH(C 1 -C 6 )alkyl)—; —C(NHS(O) p (C 1 -C 6 )alkyl)—, wherein p is 1 or 2; or

—C(NHC(O)((C 1 -C 6 )alkyl))—.

17. The compound of claim 1 , wherein R 3 represents aryl or heteroaryl optionally substituted by one or more substituents independently selected from the group consisting of cyano, halo, —NO 2 , (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl.

18. The compound of claim 17 , wherein R 3 represents phenyl or pyridyl, optionally substituted by one or more substituents selected from the group consisting of —CN, halo, —NO 2 , (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl.

19. The compound of claim 1 , wherein R 3a is absent or represents cyano or (C 1 -C 6 )alkyl.

20. The compound of claim 1 , wherein Y represents -alkylene-R 4 or —NH—R 4 .

21. The compound of claim 20 , wherein R 4 represents cycloalkyl or (cycloalkyl)(C 1 -C 6 )alkyl.

22. The compound of claim 1 , selected from the following table:

23. A pharmaceutical composition, comprising a compound of claim 1 ;

and a pharmaceutically acceptable carrier.

24. A method of treating a disease or condition characterized by unwanted plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 ; wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy.

25. The method of claim 24 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema.

26. The method of claim 24 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema.

27. The compound of claim 1 , wherein:

R 1 represents —OH, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —F, —CF 3 , phenyl, or cyclopropyl;

R 2 represents substituted phenyl or pyridyl substituted by one instance of chloro;

R 3 represents optionally substituted phenyl or pyridyl;

r 3a is absent or represents one or more substituents independently selected from the group consisting of cyano and —CH 3 ;

V represents optionally substituted phenyl;

Y—R 4 represents CH 2 CH 2 -cyclopropyl or —NHCH 2 -cyclopropyl;

X represents —C(NH 2 )—, —C(NH(R c ))—, —C(NHS(O) p R c )—, or —C(NHC(O)R c ;

Z represents halo; and

R c represents alkyl.

28. The compound of claim 27 , wherein:

Z is one instance of F or Z is absent.

29. The compound of claim 27 , wherein n is 1; and

R 1 represents —OCH 3 or —OCH 2 CH 3 .

30. The compound of claim 27 , wherein n is 2; and the two occurrences of R 1 are geminal.

31. The compound of claim 30 , wherein R 1 independently represents —OH, —OCH 3 , —CF 3 , or phenyl.

32. The method of claim 25 , wherein the compound is selected from the following table:

33. The method of claim 26 , wherein the compound is selected from the following table:

34. A method of preventing hereditary angioedema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

35. The method of claim 34 , wherein the compound is selected from the following table: