Human plasma kallikrein inhibitors

A compound, or a pharmaceutically acceptable salt thereof, represented by formula XXVI:

• wherein:
• X represents C(NRaRb);
• —Y—R4 represents —((C1-C6)alkyl)-R4, —CH2C(O)—R4, —CH2NH-R4, —CH2N((C1-C6)alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2—R4, —NHC(O)—R4, —N((C1-C6)alkyl)-R4, —N((C1-C6)alkyl)CH2—R4, —N((CH2)2OH)—R4, —N[(C3-C8)cycloalkyl(C1-C6)alkyl]R4, —heterocyclyl-R4, —OR4, —OCH2—R4, —OC(O)—R4, —OC(O)NRaRb, —SCH2R4, or —SR4, wherein the (C1-C6)alkyl moiety of —((C1-C6)alkyl)-R4 is optionally substituted;
• Z is absent or represents halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, —SO2(C1-C6)alkyl, —SO2NH2, or (C3-C8)cycloalkyl;
• R1c represents halo, amino(C1-C6)alkyl, (C1-C6)alkoxy, cyano, —SO2CH3, formyl, acyl, —NH2, or optionally substituted aryl;
• R2 represents halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)fluoroalkyl, —OCH3, —Si(CH3)3, —CONH2, —C(O)OH, cyano, or phenyl;
• R3 represents —NH—, —O—, optionally substituted aryl, heteroaryl, phenyl, carbocyclyl, or heterocyclyl;
• R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, (C1-C6)alkyl, —CF3, —OCF3, (C1-C6)alkoxy, aryl, aryloxy, amino, amino(C1-C6)alkyl, —C(O)NH2, cyano, —NHC(O)(C1-C6)alkyl, -SO2(C1-C6)alkyl, and —SO2NH2;
• and
• R4 represents hydrogen, hydroxy, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C8)cycloalkyl, heterocyclyl(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, —CH2OH, —CH((C1-C6)alkyl)OH, —CH(NH2)CH((C1-C6)alkyl)2, optionally substituted aryl, optionally substituted aryl(C1-C6)alkyl, heteroaryl, optionally substituted heteroaryl(C1-C6)alkyl, —CH2S(C1-C6)alkyl, amino, or cyano;
• or —CH2-fused to the 4-position of the ring bearing Z to form a 5- to 7-membered heterocyclic ring with optional substituents;
• or, when R3 is phenyl, can represent —NH— fused to the position ortho to X on that phenyl;
• each Ra and Rb is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C3-C8)carbocyclyl, —C(═O)Rc, —C(═O)ORc, —C(═O)NRcRd, —C(═O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd;
• each Rc and Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8) carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl, or aryl(C1-C8)alkyl;
• n is 2 or 3;
• and
• the stereochemical configuration at any chiral center is R, S, or a mixture of R and S.