US 11,685,721 B2
Human plasma kallikrein inhibitors
Pravin L. Kotian, Hoover, AL (US); Yarlagadda S. Babu, Birmingham, AL (US); Minwan Wu, Vestavia Hills, AL (US); Venkat R. Chintareddy, Vestavia Hills, AL (US); V. Satish Kumar, Birmingham, AL (US); and Weihe Zhang, Vestavia Hills, AL (US)
Assigned to BioCryst Pharmaceuticals, Inc., Durham, NC (US)
Filed by BioCryst Pharmaceuticals, Inc., Durham, NC (US)
Filed on Nov. 9, 2021, as Appl. No. 17/522,065.
Application 16/009,943 is a division of application No. 15/123,059, granted, now 10,125,102, previously published as PCT/US2015/019535, filed on Mar. 9, 2015.
Application 17/522,065 is a continuation of application No. 16/828,755, filed on Mar. 24, 2020, granted, now 11,192,861.
Application 16/828,755 is a continuation of application No. 16/009,943, filed on Jun. 15, 2018, granted, now 10,633,345.
Claims priority of provisional application 61/981,515, filed on Apr. 18, 2014.
Claims priority of provisional application 61/949,808, filed on Mar. 7, 2014.
Prior Publication US 2023/0056538 A1, Feb. 23, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 231/14 (2006.01); C07D 403/12 (2006.01); C07D 401/14 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 403/04 (2006.01); C07D 405/12 (2006.01); C07D 413/04 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01)
CPC C07D 231/14 (2013.01) [C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/12 (2013.01); C07D 405/12 (2013.01); C07D 413/04 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01)] 33 Claims
 
1. A compound, or a pharmaceutically acceptable salt thereof, represented by formula XXVI:

OG Complex Work Unit Chemistry
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.