IP Library › Granted Patent US 11,352,356

Granted Patent B2

US 11,352,356 · App. 16/908,497 · Granted Jun 7, 2022

Inhibitors of plasma kallikrein and uses thereof

Inventors: Nikolaos Papaioannou (Newton, MA); Sarah Jocelyn Fink (Arlington, MA); Thomas Allen Miller (Wakefield, MA); Gerald Wayne Shipps, Jr. (Stoneham, MA); Jeremy Mark Travins (Southborough, MA); David Edward Ehmann (Lexington, MA); Alastair Rae (Saffron Walden, GB); John Mark Ellard (Buntingford, GB)

Assignee: Takeda Pharmaceutical Company Limited

C07D471/04 A61P9/00 A61P29/00 C07D519/00

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Quick Facts

Patent No.: US 11,352,356
App. No.: 16/908,497
Granted: Jun 7, 2022
Kind: B2

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Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics for the same.

Claims (98)

1. A method of treating diabetic macular edema comprising administering to a patient in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

Cy A is selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclene 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 Cy A is substituted with 0-4 R A groups;

each R A is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 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;

Cy B 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 Cy B is substituted with 0-5 R B groups;

each R B is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to -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) 2 Q-, -QC(Q)-, —C(Q)Q-, —C(R) 2 QC(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);

R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen and C 1-6 aliphatic;

R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 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 C 1-6 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.

2. The method of claim 1 , wherein the compound is of Formula (IV):

or a pharmaceutically acceptable salt thereof,

wherein:

Cy A is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen and nitrogen, wherein Cy A is substituted with 0-3 R A groups;

L is selected from —NC(O)— and —C(O)N—;

R 6 , R 8 , and R 9 are independently selected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 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;

R 7 is —F, —Cl, or —Br;

W 4 is carbon or nitrogen;

R 10 and R 11 are each optionally present, and if present are independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 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;

R 13 is selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 2-6 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;

R 14 is optionally present, and if present and is selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 3-6 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 C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or 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;

3. The method of claim 1 , wherein the compound is of Formula (V):

or a pharmaceutically acceptable salt thereof,

wherein:

Cy A is a 5-membered heteroarylene having 1-4 nitrogens, wherein when Cy A comprises 3 nitrogens, Cy A is not

L is selected from —NC(O)— and —C(O)N—;

R 7 is —F, —Cl, or —Br;

R 10 is optionally present, and if present is selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 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;

R 11 is optionally present, and if present is selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 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;

R 13 is selected from —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- or 5-7-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;

4. The method of claim 1 , wherein L is selected from the group consisting of:

wherein # represents to point of attachment to Cy A .

5. The method of claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

Cy A 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 Cy A is substituted with 0-4 R A groups;

each R A is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 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;

Cy B 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 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 Cy B is substituted with 0-5 R B groups;

each R B is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 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;

R 1 and R 2 are independently selected from hydrogen and C 1-6 aliphatic;

R 6 and R 7 are independently selected from hydrogen, halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 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

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.

6. The method of claim 1 , wherein Cy A is selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 7- to to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur wherein Cy A is substituted with 0-4 R A groups.

7. The method of claim 1 , wherein Cy A is a 5-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy A is substituted with 0-2 R A groups.

8. The method of claim 1 , wherein Cy A is selected from the group consisting of:

wherein * represents to point of attachment to L.

9. The method of claim 1 , wherein the compound is of Formula (III-a) through (III-d):

or a pharmaceutically acceptable salt thereof,

wherein:

each R A is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 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;

Cy B 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 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 Cy B is substituted with 0-5 R B groups;

each R B is independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 3- to 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;

R 1 and R 2 are independently selected from hydrogen and C 1-6 aliphatic;

10. The method of claim 1 , wherein Cy B is a 7- to 10-membered bicyclic heteroaryl having 1-5 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein Cy B is substituted with 0-5 R B groups.

11. The method of claim 1 , wherein Cy B is

wherein:

W 1 , W 2 , W 3 , and W 4 are independently selected from carbon and nitrogen;

R 10 , R 11 , R 12 , R 13 , and R 14 are each optionally present when attached to a carbon atom, and if present correspond to an occurrence of R B independently selected from halogen, —CN, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —NO 2 , —N(R)—N(R) 2 , —N(R) 2 , —N(R)C(O)R, —N(R)C(O) 2 R, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —OR, —OC(O)R, —OC(O)N(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)N(R) 2 , —S(O) 2 N(R) 2 , or an optionally substituted group selected from C 1-6 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

12. The method of claim 1 , wherein Cy B is selected from the group consisting of:

13. The method of claim 1 , wherein Cy B is

wherein:

W 2 is selected from carbon, nitrogen, oxygen, and sulfur;

W 1 , W 3 , and W 4 are independently selected from carbon and nitrogen;

14. The method of claim 1 , wherein Cy B is selected from the group consisting of:

15. The method of claim 1 , wherein R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen, halogen, —CN, —N(R) 2 , —OR, or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, wherein each R is independently hydrogen or C 1-6 aliphatic.

16. The method of claim 1 , wherein R 6 is selected from hydrogen and halogen.

17. The method of claim 1 , wherein the compound is any one of compounds I-1 through I-303 as shown in Table 1, or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((3-chloroquinolin-6-yl)methyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 , wherein the compound is N-((7-bromoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((7-chloro-6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-(methoxymethyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

23. The method of claim 1 , wherein the compound is N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

24. The method of claim 1 , wherein the compound is N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

25. The method of claim 1 , wherein the compound is N-((7-bromo-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

26. The method of claim 1 , wherein the compound is N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.

27. The method of claim 1 , wherein the compound is N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6,7-dichloroimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

28. The method of claim 1 , wherein the compound is N-((7-chloro-8-fluoroimidazo[1,5-a]pyri din-1-yl)methyl)-1-((6-cyclopropylbenzofuran-2-yl)methyl)-1H-1,2,3 -triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

29. The method of claim 1 , wherein the compound is 4-(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-imidazole-2-carboxylic acid, or a pharmaceutically acceptable salt thereof.

Assignments (7)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 20, 2022

From: FINK, SARAH JOCELYN

To: BIODURO LLC

Reel/Frame 058712/0920 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 20, 2022

From: CHARLES RIVER DISCOVERY RESEARCH SERVICES UK LIMITED

To: CHARLES RIVER LABORATORIES, INC.

Reel/Frame 058712/0889 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 20, 2022

From: CHARLES RIVER LABORATORIES, INC.

To: SHIRE HUMAN GENETIC THERAPIES, INC.