Granted Patent B2

US 11,370,803 · App. 17/024,189 · Granted Jun 28, 2022

Inventors: Nikolaos Papaioannou (Newton, MA); Jeremy Mark Travins (Southborough, MA); Sarah Jocelyn Fink (Arlington, MA); John Mark Ellard (Buntingford, GB); Alastair Rae (Saffron Walden, GB)

Assignee: Takeda Pharmaceutical Company Limited

C07D519/00

Abstract

Claims (63)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

Het A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, a 5- to 6-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, a 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and a 7- to 10-membered bicyclic heteroarylene having 1-5 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het 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, 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, or sulfur;

L is an optionally substituted C 1-6 hydrocarbon chain, wherein 1-3 methylene units are independently replaced with —Cy—, —C(R) 2 ——O—, —NR—, —C(O)—, —S(O) 2 —, —C(O)NR—, —NRC(O)—, —S(O) 2 NR—, and —NRS(O) 2 —;

—Cy— is 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclylene, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;

R′ and R″ are independently selected from hydrogen, halogen, —OR, —NR 2 , —SR, and optionally substituted C 1-6 aliphatic; wherein R′ may be taken together with a monocyclic Het A to form an optionally substituted fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur;

R 1 , R 2 , R 3 , R 4 , 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, 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, or sulfur;

each R is independently hydrogen 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, or 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, or sulfur, and 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; and

n is 0 or 1.

2. The compound according to claim 1 , wherein when L is —(CR 2 ) m NRC(O)— and m is 0 to 2, one of the following (a), (b), or (c) applies:

(a) n is 0;

(b) at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is CN; or

(c) R 1 is an optionally substituted saturated monocyclic heterocycle comprising 1-3 nitrogen atoms, with the proviso that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl) methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-l-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-(( 4 -(((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

3. The compound according to claim 1 , wherein L is selected from the group consisting of —C(R) 2 NRC(O)-#, —C(R) 2 C(O)NRC(R) 2 -#, —C(R) 2 NRC(O)C(R) 2 -#, —C(R) 2 NRC(R) 2 -#, —C(R) 2 C(R) 2 NRC(R) 2 -#, —C(O)NRC(R) 2 -#, —C(R) 2 C(O)NR-#, —NRC(O)C(R) 2 -#, —CR 2 C(O)NRC(R) 2 -#, —SO 2 NRC(R) 2 -#, and —C(R) 2 NRSO 2 -#, wherein # represents the point of attachment to Het A .

4. The compound according to claim 1 , wherein when L is —C(R) 2 NRC(O)-# or —C(R) 2 C(O)NR-#, one of the following (a), (b), or (c) applies:

(a) n is 0;

(b) at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is CN; or

(c) R 1 is an optionally substituted saturated monocyclic heterocycle comprising 1-3 nitrogen atoms, with the proviso that the compound is not N-((7-chloroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-morpholinoimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(( 6-cyclopropyl-8-(2-oxopyrrolidin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(2-oxooxazolidin-3-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, or 4-(2-((4- (((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)morpholine-2-carboxylic acid.

5. The compound according to claim 1 , wherein the compound has a structure of Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I-d),

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein the compound has a structure of Formula (II):

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein the compound has a structure of Formula (II-a) or Formula (II-b):

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein R′ is taken together with a monocyclic Het A to form an optionally substituted fused ring and the compound has a structure of Formula (III):

wherein R fus is fused with Het A to form a fused 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur,

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein the compound has a structure of Formula (III-a) or Formula (III-b):

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide (I-4),

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-sulfonamide (I-5),

7-chloro-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-6),

7-chloro-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-8-fluoroimidazo[1,5-a]pyridine-1-sulfonamide (I-7),

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxamide (I-8),

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-5-(6-cyclopropylimidazo[1,2-a]pyridin-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carboxamide (I-9),

N-((7-cyanoimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-carboxamide (I-10),

1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-11),

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethan-1-amine (I-12),

2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)acetamide (I-13),

methyl 2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylate (I-14),

2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridine-8-carboxylic acid (I-15),

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethan-1-amine (I-16),

ethyl 3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoate (I-17a),

3-(2-((4-((((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-6-cyclopropylimidazo[1,2-a]pyridin-8-yl)propanoic acid (I-17b),

1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-l-yl)-N-((1-((6-cyclopropyl-8-(4H-1,2,4-triazol-4-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)methanamine (I-18),

2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-(1-(1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethyl)acetamide (I-19),

N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropyl-8-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (I-20);

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein Het A is a 5-membered monocyclic heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein Het A is substituted with 0-2 R A groups.

11. The compound according to claim 1 , wherein Het A is selected from:

wherein * represents to point of attachment to L.

12. The compound according to claim 1 , wherein a single instance of R A is C 1-6 aliphatic substituted with halogen.

13. The compound of claim 1 , wherein the compound is selected from:

2-(7-chloroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)acetamide (I-1),

1-(7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)-N-((1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-2,2,2-trifluoroethan-1-amine (I-2),

7-chloro-N-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-8-fluoroimidazo[1,5-a]pyridine-1-carboxamide (I-3),

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

15. A method of treating a plasma kallikrein-mediated disease or disorder comprising administering to a patient in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein the disease or disorder is hereditary angioedema or diabetic macular edema.

17. A method of treating hereditary angioedema or diabetic macular edema comprising administering to a patient in need thereof a compound of claim 1 , or pharmaceutically acceptable salt thereof.

Assignments (8)

Cited By (2)

US 12,221,441 US 12,441,724