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 (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 —NR c C(O)R d ; or two geminal occurrences of R 1 taken together with the carbon to which they are attached represent —C(O)—; or two vicinal or geminal occurrences of R 1 taken together form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring;

W is —C(O)NH— or —C(O)N(R c )—;

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 , or —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;

can represent

r is 0, 1, 2, or 3;

n is an integer from 0 to 6;

p is 0, 1, or 2; and

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.

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

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

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

5. The method of claim 1 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is reperfusion injury.

6. The method of claim 1 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is acute myocardial infarction.

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

8. The method of claim 1 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is blood loss during cardiopulmonary bypass.

9. The method of claim 1 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, and proliferative retinopathy.

10. The method of claim 1 , wherein R 1 represents —OH, —OR c , —NH 2 , —NHR c , —NR c R d , alkyl, aryl, heteroaryl, halo, haloalkyl, cycloalkyl, —OC(O)R c , —NHC(O)R c , or —NR c C(O)R d ; or two geminal occurrences of R 1 taken together with the carbon to which they are attached represent —C(O)—; or two vicinal or geminal occurrences of R 1 taken together form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring.

11. The method of claim 1 , wherein V represents optionally substituted aryl.

12. The method of claim 1 , wherein Z is absent, or wherein Z represents one or more substituents independently selected from the group consisting of halo, haloalkyl, —NO 2 , and —CN.

13. The method of claim 1 , wherein 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 )—, or —C(NHC(O)NR c R d )—.

14. The method of claim 1 , wherein R 3 represents optionally substituted aryl or optionally substituted heteroaryl.

15. The method of claim 1 , wherein R 3a is absent or represents halo, alkyl, —CF 3 , —OCF 3 , aryl, heteroaryl, —C(O)NH 2 , cyano, —NHC(O)alkyl, —SO 2 alkyl, —SO 2 NH 2 , —NO 2 , —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 , —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 , or —(CF 2 ) r CF 3 .

16. The method of claim 1 , wherein Y represents a bond.

17. The method of claim 1 , wherein R 4 represents H, (cycloalkyl)alkyl, or (cyclopropyl)(C 1 -C 6 )alkyl.

18. 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, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, diabetic retinopathy, diabetic macular edema, and brain edema.

19. The method of claim 18 , wherein the disease or condition characterized by unwanted plasma kallikrein activity is selected from the group consisting of hereditary angioedema.

20. A method of preventing hereditary angioedema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of 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 —NR c C(O)R d ; or two geminal occurrences of R 1 taken together with the carbon to which they are attached represent —C(O)—; or two vicinal or geminal occurrences of R 1 taken together form an optionally substituted fused or spirocyclic carbocyclic or heterocyclic ring;

W is —C(O)NH— or —C(O)N(R c )—;

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 , or —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;

can represent

r is 0, 1, 2, or 3;

n is an integer from 0 to 6; and

p is 0, 1, or 2.