US 11,807,605 B2
Human plasma kallikrein inhibitors
Pravin L. Kotian, Hoover, AL (US); Yarlagadda S. Babu, Birmingham, AL (US); V. Satish Kumar, Birmingham, AL (US); Weihe Zhang, Vestavia Hills, AL (US); and Lakshminarayana Vogeti, Lawrence, KS (US)
Assigned to BioCryst Pharmaceuticals, Inc., Durham, NC (US)
Filed by BioCryst Pharmaceuticals, Inc., Durham, NC (US)
Filed on Jul. 13, 2021, as Appl. No. 17/374,335.
Application 17/374,335 is a continuation of application No. 16/718,537, filed on Dec. 18, 2019, granted, now 11,066,360.
Application 16/718,537 is a continuation of application No. 15/764,071, granted, now 10,562,850, previously published as PCT/US2016/054619, filed on Sep. 30, 2016.
Claims priority of provisional application 62/235,754, filed on Oct. 1, 2015.
Prior Publication US 2022/0098151 A1, Mar. 31, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/14 (2006.01); A61K 31/444 (2006.01); C07D 207/16 (2006.01); C07D 401/12 (2006.01); C07D 409/14 (2006.01); C07D 207/24 (2006.01); A61P 7/00 (2006.01); A61P 17/10 (2006.01); A61P 17/00 (2006.01)
CPC C07D 207/16 (2013.01) [A61P 7/00 (2018.01); A61P 17/00 (2018.01); A61P 17/10 (2018.01); C07D 207/24 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 409/14 (2013.01)] 35 Claims
 
1. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:

OG Complex Work Unit Chemistry
wherein, independently for each occurrence:
R1 represents —OH, —ORc, —NH2, —NHRc, —NRcRd, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, —C(O)Rc, —C(O)OH, —C(O)ORc, —OC(O)Rc, —C(O)NH2, —C(O)NHRc, —C(O)NRcRd, —NHC(O)Rc, or —NRcC(O)Rd;
W is —C(O)NH—;
R2 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, —NO2, —CN, —C(O)Rc, —C(O)OH, —C(O)ORc, —OC(O)Rc, —C(O)NH2, —C(O)NHRc, —C(O)NRcRd, —NHC(O)Rc, —N(Rc)C(O)Rd, —OS(O)p(Rc), —NHS(O)p(Rc), and —NRcS(O)p(Rc);
X represents —C(NH2)—, —C(NH(Rc))—, —C(NRcRd)—, —C(NHS(O)pRc)—, —C(NHC(O)Rc)—, —C(NHC(O)NH2)—, —C(NHC(O)NHRc)—, —C(NHC(O)NRcRd)—, —C(OH) —C(O(alkyl))—, —C(N3)—, —C(CN)—, —C(NO2)—, —C(S(O)nRa)—, —C[—C(═O)Rc]—, —C[—C(═O)NRcRd]—, —C[—C(═O)SRc]—, —C[—S(O)Rc]—, —C[—S(O)2Rc]—, —C[S(O)(ORc)]—, —C[—S(O)2(ORc)]—, —C[—SO2NRcRd]—, —C(halogen)-, —C(alkyl), —C((cycloalkyl)alkyl), —C(alkenyl)-, —C(alkynyl)-, or —C(aralkyl)-;
R3 represents optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
R3a is absent or represents one or more substituents independently selected from the group consisting of halo, hydroxy, alkyl, —CF3, —OCF3, alkoxy, aryl, heteroaryl, aryloxy, amino, aminoalkyl, —C(O)NH2, cyano, —NHC(O)alkyl, -SO2alkyl, —SO2NH2, cycloalkyl, —(CH2)rORa, —NO2, —(CH2)rNRaRb, —(CH2)rC(O)Ra, —NRaC(O)Rb, —C(O)NRcRd, —NRaC(O)NRcRd, —C(═NRa)NRcRd, —NHC(═NRa)NRcRd, —NRaRb, —SO2NRcRd, —NRaSO2NRcRd, —NRaSO2alkyl, —NRaSO2Ra, —S(O)pRa, —(CF2)rCF3, —NHCH2Ra, —OCH2Ra, —SCH2Ra, —NH(CH2)2(CH2)rRa, —O(CH2)2(CH2)rRa, and —S(CH2)2(CH2)rRa;
Y represents a bond; or —Y—R4 represents optionally substituted -alkylene-R4, —CH2C(O)—R4, —CH2NH—R4, —CH2N(alkyl)-R4, —CRaRb—R4, —NH—R4, —NHCH2-R4, —NHC(O)—R4, —N(alkyl)-R4, —N(alkyl)CH2-R4, —N((CH2)2OH)—R4, —N((cycloalkyl)alkyl)R4, -heterocyclyl-R4, —OR4, —OCH2-R4, —OC(O)—R4, —OC(O)NRaRb, —SCH2R4, or —SR4;
R4 represents hydrogen, hydroxy, optionally substituted alkyl, cycloalkyl, (heterocycloalkyl)alkyl, (cycloalkyl)alkyl, —CH2OH, —CH(alkyl)OH, —CH(NH2)CH(alkyl)2, aryl, aralkyl, heteroaryl, heteroaralkyl, —CH2S(alkyl), amino, or cyano; or —(CRaRb)r(CRaRb)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 R3 is phenyl, R4 can represent —NRa— fused to the position ortho to X on that phenyl;
each Ra and Rb is independently H, alkyl, alkenyl, alkynyl, aralkyl, (cycloalkyl)alkyl, —C(═O)Rc, —C(═O)ORc, —C(═O)NRcRd, —C(═O)SRc, —S(O)Rc, —S(O)2Rc, —S(O)(ORc), or —SO2NRcRd;
Rc and Rd 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 Rc and Rd can be taken together to form an optionally substituted heterocyclic ring;
r is 0, 1, 2, or 3;
n is an integer from 0 to 6; and
p is 0, 1, or 2.