US 12,221,441 B2
Plasma kallikrein inhibitors and uses thereof
Nikolaos Papaioannou, Newton, MA (US); Jeremy Mark Travins, Southborough, MA (US); Sarah Jocelyn Fink, Arlington, MA (US); John Mark Ellard, Buntingford (GB); and Alastair Rae, Saffron Walden (GB)
Assigned to Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed by Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed on Aug. 16, 2023, as Appl. No. 18/234,608.
Application 18/234,608 is a division of application No. 17/024,437, filed on Sep. 17, 2020, granted, now 11,787,796.
Claims priority of provisional application 62/902,353, filed on Sep. 18, 2019.
Prior Publication US 2023/0391773 A1, Dec. 7, 2023
Int. Cl. C07D 471/04 (2006.01); A61P 9/00 (2006.01); A61P 29/00 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [C07D 519/00 (2013.01)] 19 Claims
 
1. A method of treating a plasma kallikrein-mediated disease or disorder using a compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
CyA is selected from a 5-membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and a 7- to 10-membered partially unsaturated bicyclic heterocyclylene 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, and an optionally substituted group selected from C1-6 aliphatic, phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur;
CyB is selected from phenyl, a 5- to 6-membered monocyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered partially unsaturated bicyclic carbocyclyl, a 10-membered bicyclic aryl, a 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and a 12-membered tricyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein CyB is substituted with 0-5 RB groups;
each RB is independently selected from halogen, —CN, oxo, —C(R)═N(R), —C(O)R, —C(O)2R, —C(O)N(R)2, —C(═N(R))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, and an optionally substituted group selected from C1-6 aliphatic, phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, a 3-to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and an 8- to 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur;
L is an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are independently replaced with -Cy-, —O—, —NR—, —C(O)—, —C(O)NR—, —NRC(O)—, —S(O)2NR—, —NRS(O)2—, or —S(O)2—;
-Cy- is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
R1 and R2 are independently selected from hydrogen, halogen, —OR, —SR, —N(R)2, and optionally substituted C1-6 aliphatic; wherein R1 may be taken together with a monocyclic CyA to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;
R3, R4, R5, and R7 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, and an optionally substituted group selected from C1-6 aliphatic, phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur;
R6 is 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, and an optionally substituted group selected from C1-6 aliphatic, phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and a 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 a 3- to 7-membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and a 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; and
n is 0 or 1;
with the proviso that:
(a) at least one of R3, R4, R5, R6 and R7 is C1-6 aliphatic or halogen; and
(b) the compound is other than N-[1-[(6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, N-[1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-5-methyl-1H-pyrazol-3-yl]-3-pyridinecarboxamide, 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-benzenepropanoic acid, 2-[(6,8-dichloroimidazo[1,2-a]pyridin-2-yl)methyl]-4-methyl-N-phenyl-5-thiazolecarboxamide, and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.