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 —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;

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.

2. The compound 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.

3. The compound of claim 2 , wherein R 1 represents —OH, —OR c , —NH 2 , alkyl, aryl, halo, haloalkyl, cycloalkyl, or —OC(O)R; and n is 1 or 2.

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

R 1 represents —OH, -O((C 1 -C 6 )alkyl), —OC(O)((C 1 -C 6 )alkyl), —NH 2 , or (C 1 -C 6 )alkyl.

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:

(a) one occurrence of R 1 represents —OH or —OR c ; and the other occurrence of R 1 represents aryl or heteroaryl;

(b) one occurrence of R 1 represents —OH or —OR c ; and the other occurrence of R 1 represents haloalkyl;

(c) both occurrences of R 1 are halo; or

(d) the two geminal occurrences of R 1 taken together with the carbon to which they are attached represent —C(O)—.

7. The compound of claim 3 , wherein n is 2; the two occurrences of R 1 are vicinal; and the two vicinal occurrences of R 1 taken together form an optionally substituted fused carbocyclic ring.

8. 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 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —CN, —NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, —C(O)OH, —C(O)O(C 1 -C 6 )alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 )alkyl, and —C(O)N((C 1 -C 6 )alkyl) 2 .

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

10. The compound 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.

11. The compound of claim 10 , wherein Z represents one instance of halo.

12. The compound 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 )—.

13. The compound of claim 12 , wherein X represents —C(NH 2 )—; —C(NH(cycloalkyl)alkyl)-; —C(NH(C 1 -C 6 )alkyl)-; —C(NHS(O) p (C 1 -C 6 )alkyl)-, wherein p is 1 or 2; optionally substituted —C(NHC(O)NH(aryl))-; optionally substituted C(NHC(O)NH(heteroaryl))-; or —C(NHC(O)((C 1 -C 6 )alkyl))-.

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

15. The compound of claim 14 , wherein R 3 represents phenyl, 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; or wherein R 3 represents pyridyl.

16. The compound 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 .

17. The compound of claim 1 , wherein Y represents a bond.

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

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

20. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition, comprising a compound of claim 19 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

22. The compound of claim 8 wherein R2 represents (halo)aryl or (halo)heteroaryl.

23. The compound of claim 11 wherein Z represents one instance of fluoro.