US 12,441,724 B2
Inhibitors of plasma kallikrein and uses thereof
Nikolaos Papaioannou, Newton, MA (US); Sarah Jocelyn Fink, Arlington, MA (US); Thomas Allen Miller, Wakefield, MA (US); Gerald Wayne Shipps, Jr., Stoneham, MA (US); Jeremy Mark Travins, Southborough, MA (US); David Edward Ehmann, Lexington, MA (US); Alastair Rae, Saffron Walden (GB); and John Mark Ellard, Buntingford (GB)
Assigned to Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed by Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed on Apr. 20, 2022, as Appl. No. 17/724,753.
Application 17/724,753 is a division of application No. 16/908,497, filed on Jun. 22, 2020, granted, now 11,352,356.
Application 16/908,497 is a division of application No. 16/299,996, filed on Mar. 12, 2019, granted, now 10,730,874, issued on Aug. 4, 2020.
Claims priority of provisional application 62/757,728, filed on Nov. 8, 2018.
Claims priority of provisional application 62/642,376, filed on Mar. 13, 2018.
Prior Publication US 2023/0078513 A1, Mar. 16, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 471/04 (2006.01); A61K 31/437 (2006.01); A61K 31/498 (2006.01); A61K 31/4985 (2006.01); A61K 31/519 (2006.01); A61K 31/53 (2006.01); A61K 31/5355 (2006.01); A61P 9/00 (2006.01); A61P 29/00 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [A61P 9/00 (2018.01); A61P 29/00 (2018.01); C07D 519/00 (2013.01)] 29 Claims
 
1. A method of treating hereditary angioedema comprising administering to a patient in need thereof a compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
CyA is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 7- to 10-membered bicyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein CyA is substituted with 0-4 RA groups;
each RA is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)2R, —C(O)N(R)2, —NO2, —N(R)—N(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)2R, —N(R)C(O)N(R)2, —N(R)S(O)2R, —OR, —OC(O)R, —OC(O)N(R)2, —SR, —S(O)R, —S(O)2R, —S(O)N(R)2, —S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur;
CyB is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-5 heteroatoms selected from oxygen, nitrogen, and sulfur, and 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein CyB is substituted with 0-5 RB groups;
each RB is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)2R, —C(O)N(R)2, —NO2, —N(R)—N(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)2R, —N(R)C(O)N(R)2, —N(R)S(O)2R, —OR, —OC(O)R, —OC(O)N(R)2, —SR, —S(O)R, —S(O)2R, —S(O)N(R)2, —S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur;
L is selected from -QC(R)2—, —C(R)2Q-, -QC(Q)-, —C(Q)Q-, —C(R)2QC(O)—, and —C(O)QC(R)2—, wherein each Q is independently a monovalent or divalent group as valency allows, selected from the group consisting of O, N(R), and (S);
R1, R2, R3, and R4 are independently selected from hydrogen and C1-6 aliphatic;
R5, R6, R7, R8, and R9 are independently selected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)2R, —C(O)N(R)2, —NO2, —N(R)—N(R)2, —N(R)2, —N(R)C(O)R, —N(R)C(O)2R, —N(R)C(O)N(R)2, —N(R)S(O)2R, —OR, —OC(O)R, —OC(O)N(R)2, —SR, —S(O)R, —S(O)2R, —S(O)N(R)2, —S(O)2N(R)2, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur; and
each R is independently hydrogen, —CN, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur;
or two R groups on the same carbon or nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
with the proviso that the compound is other than N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-2-((3-chloroquinolin-6-yl)methyl)isonicotinamide.