Polycyclic inhibitors of plasma kallikrein

A compound of formula (I):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• CyA is an 8- to 10-membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 10- to 14-membered tricyclic heteroarylene having 1-6 heteroatoms independently selected from oxygen, nitrogen, and sulfur, an 8- to 14-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 10- to 15-membered saturated or partially unsaturated tricyclic heterocyclyl having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein CyA is substituted with 0-6 —RA groups;
• each RA is independently selected from oxo, halogen, —CN, —C(O)R, —C(O)2R, —C(O)N(R)2, —NO2, —N(R)2, —N(R)C(O)R, —N(R)C(O)2R, —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 independently selected from oxygen, nitrogen, and sulfur, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 6- to 12-membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;
• X is —N═ or —NR—, wherein X is adjacent to the ring atom of CyA attached to the cyclopropyl ring;
• each RY and RY′ is independently selected from hydrogen, halogen, and an optionally substituted C1-6 aliphatic group;
• each Rx and Rx′ is independently selected from hydrogen, halogen, or —CN;
• CyB is selected from phenyl, 8- to 10-membered bicyclic aryl, a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 7- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein CyB is substituted with 0-5 —RB groups;
• or
• CyB and Rx, together with their intervening atoms, form a 6- to 12-membered spirocyclic ring system having 0-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the ring or rings formed by CyB and Rx may be substituted with 0-4 —RB groups;
• each RB is independently selected from oxo, halogen, —CN, —C(O)R, —C(O)2R, —C(O)N(R)2, —NO2, —N(R)2, —N(R)C(O)R, —N(R)C(O)2R, —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, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• L is an optionally substituted C1-3 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with —O—, —NRz—, —S—, —SO—, or —SO2—;
• or L is an optionally substituted 5- to 6-membered saturated or partially unsaturated heterocyclene, having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur;
• each Rz is independently selected from hydrogen, —(CH2)0-3OR, —(CH2)0-3C(O)OR, or an optionally substituted C1-6 aliphatic group;
• CyC is a 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 6- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein CyC is substituted with 0-6-LC-RC groups;
• each LC is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with —O— or —NR—;
• each RC is independently selected from halogen, —CN, —C(O)R, —C(O)2R, —C(O)N(R)2, —NO2, —N(R)2, —N(R)C(O)R, —N(R)C(O)2R, —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, CyD, or an optionally substituted group selected from C1-6 aliphatic;
• each CyD is independently selected from 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, or sulfur, a 5- to 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, phenyl, a 6- to 12-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a bridged bicycle, or a 6- to 12-membered saturated or partially unsaturated bicyclic spiroheterocyclyl having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur, wherein CyD is substituted with 0-4 -LD-RD groups;
• each LD is independently selected from a covalent bond or an optionally substituted C1-6 hydrocarbon chain, wherein 1 to 3 methylene units are optionally and independently replaced with —O— or —NR—;
• and
• each RD is independently selected from oxo, halogen, —CN, —C(O)R, —C(O)2R, —C(O)N(R)2, —NO2, —N(R)2, —N(R)C(O)R, —N(R)C(O)2R, —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, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.