Human plasma kallikrein inhibitors

1. 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 formula II, or a pharmaceutically acceptable salt thereof:

wherein:

X represents CH, C(OH), C(O(C 1 -C 6 )alkyl), —C(NH 2 ), —C(NR a R b ), —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[(C 1 -C 5 )alkyl], —C[(C 4 -C 5 )carbocyclyl], —C[(C 1 -C 8 )substituted alkyl], —C[(C 2 -C 8 )alkenyl], —C[(C 2 -C 8 )substituted alkenyl], —C[(C 2 -C 8 )alkynyl], —C[(C 2 -C 8 )substituted alkynyl], —C[aryl(C 1 -C 5 )alkyl] or N;

—Y—R 4 represents —((C 1 -C 6 )alkyl)-R 4 , —CH 2 C(O)—R 4 , —CH 2 NH-R 4 , —CH 2 N((C 1 -C 6 )alkyl)-R 4 , —CR a R b —R 4 , —NH—R 4 , —NHCH 2 —R 4 , —NHC(O)—R 4 , —N((C 1 -C 6 )alkyl)-R 4 , —N((C 1 -C 6 )alkyl)CH 2 —R 4 , —N((CH 2 ) 2 OH)—R 4 , —N[(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl]R 4 , -heterocyclyl-R 4 , —OR 4 , —OCH 2 —R 4 , —OC(O)—R 4 , —SCH 2 R 4 , or —SR 4 , wherein the (C 1 -C 6 )alkyl moiety of —((C 1 -C 6 )alkyl)-R 4 is optionally substituted;

Z is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, —CF 3 , —OCF 3 , (C 1 -C 6 )alkoxy, aryl, aryloxy, amino, amino(C 1 -C 6 )alkyl, —C(O)NH 2 , cyano, —NHC(O)(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, —SO 2 NH 2 , (C 3 -C 5 )cycloalkyl, (CH 2 ) r OR a , N 02 , (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 -(C 1 -C 6 )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 ; or alternatively Z is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;

R 1c represents halo, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, cyano, —C(═NH)NH 2 , —CONR a R b , —(C 1 -C 6 )alkylCONR a R b , —SO 2 CH 3 , formyl, acyl, —NH 2 , —C(═NH)NH(OH), —C(═NH)NH(C(O)O—(C 1 -C 6 )alkyl), —C(═NH)NH(C(O)O—(C 1 -C 6 )haloalkyl), —C(═NH)NH(C(O)S—(C 1 -C 6 )alkyl), —C(═NH)NH(C(O)(OCH(C 1 -C 6 )alkyl)OC(O)(C 1 -C 6 )alkyl), optionally substituted aryl, or optionally substituted heteroaryl;

R 2 represents halo, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, —OCH 3 , —Si(CH 3 ) 3 , —CONH 2 , —C(O)OH, cyano, or phenyl;

R 3 represents —NH—, —O—, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;

R 3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C 1 -C 6 )alkyl, —CF 3 , —OCF 3 , (C 1 -C 6 )alkoxy, aryl, aryloxy, amino, amino(C 1 -C 6 )alkyl, —C(O)NH 2 , cyano, —NHC(O)(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, —SO 2 NH 2 , (C 3 -C 8 )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 -(C 1 -C 6 )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 , or S(CH 2 ) 2 (CH 2 ) r R a ; or alternatively R 3a is a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of N, O, and S;

R 4 represents hydrogen, hydroxy, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 8 )cycloalkyl, heterocyclyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, —CH 2 OH, —CH((C 1 -C 6 )alkyl)OH, —CH(NH 2 )CH((C 1 -C 6 )alkyl) 2 , optionally substituted aryl, optionally substituted aryl(C 1 -C 6 )alkyl, heteroaryl, optionally substituted heteroaryl(C 1 -C 6 )alkyl, —CH 2 S(C 1 -C 6 )alkyl, amino, or cyano;

each R a and R b is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl(C 1 -C 8 )alkyl, (C 3 -C 8 )carbocyclyl, —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 ;

each R c and R d is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 ) carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O)n(C 1 -C 8 )alkyl, or aryl(C 1 -C 8 )alkyl; or when R and R d are bonded to a common nitrogen atom, then they may form a 3- to 7-membered heterocyclic ring wherein optionally a carbon atom of said heterocyclic ring may be replaced with —O—, —S— or —NR a —;

n is 2 or 3;

r is independently for each occurrence 0, 1, 2, or 3;

p is independently for each occurrence 0, 1, or 2; and

the stereochemical configuration at any chiral center is R, S, or a mixture of R and S.

2. The method of claim 1 , wherein X represents CH, C(OH), C(O(C 1 -C 6 )alkyl), —C(NH 2 ), —C(NR a R b ), —C(halogen), —C[(C 2 -C 8 )alkenyl], —C[(C 2 -C 8 )substituted alkenyl], or N.

3. The method of claim 1 , wherein X represents CH.

4. The method of claim 1 , wherein —X—Y— represents —CHNHCH 2 —, —C(OH)CH 2 CH 2 —, or —CHOCH 2 —.

5. The method of claim 1 , wherein R 3 represents phenylene-R 3a .

6. The method of claim 1 , wherein —R 3 —R a represents

7. The method of claim 1 , wherein R 4 is cyclopropyl.

8. The method of claim 1 , wherein R 3 is phenyl, and R 3a is ortho, meta, or para —OH.

9. The method of claim 1 , wherein R 3 is phenyl, and R 3a is meta or para —NH 2 .

10. The method of claim 1 , wherein R 3 is phenyl, and R 3a is meta or para —CN.

11. The method of claim 1 , wherein Z is absent, or represents fluoro or chloro.

12. The method of claim 1 , wherein Z represents 2-F, 4-F, 5-F, 6-F, 6-Cl, or 5-(C 3 -C 8 )cycloalkyl.

13. The method of claim 1 , wherein R 1c represents aminomethyl.

14. The method of claim 1 , wherein R 1c represents cyano.

15. The method of claim 1 , wherein R 1c represents —SO 2 CH 3 .

16. The method of claim 1 , wherein R 2 is —CH 3 , —CF 3 , tert-butyl, cyclopropyl, —OCH 3 , —Si(CH 3 ) 3 , —CONH 2 , cyano, or phenyl.

17. The method of claim 1 , wherein the compound of formula (II) is selected from the group consisting of:

18. The method of claim 1 , wherein the compound of formula (II) has the structure:

19. The method of claim 1 , wherein the compound of formula (II) is the (+)-enantiomer.

20. The method of claim 18 , wherein the compound of formula (II) is the (−)-enantiomer.

21. The method of claim 18 , wherein the compound of formula (II) is a hydrochloride salt.

22. The method of claim 18 , wherein the compound of formula (II) is a bis(hydrochloride) salt.

23. The method of claim 19 , wherein the compound of formula (II) is a hydrochloride salt.

24. The method of claim 19 , wherein the compound of formula (II) is a bis(hydrochloride) salt.

25. The method of claim 20 , wherein the compound of formula (II) is a hydrochloride salt.

26. The method of claim 20 , wherein the compound of formula (II) is a bis(hydrochloride) salt.

27. The method 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.

28. The method of claim 1 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema.

29. The method of claim 1 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema.

30. The method of claim 18 , 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.

31. The method of claim 18 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema.

32. The method of claim 18 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema.

33. The method of claim 19 , 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.

34. The method of claim 19 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is angioedema.

35. The method of claim 19 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is hereditary angioedema.

36. The method of claim 24 , 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.

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

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