IP Library › Granted Patent US 11,787,796

Granted Patent B2

US 11,787,796 · App. 17/024,437 · Granted Oct 17, 2023

Plasma Kallikrein inhibitors and uses thereof

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

C07D471/04 C07D519/00

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Quick Facts

Patent No.: US 11,787,796
App. No.: 17/024,437
Granted: Oct 17, 2023
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 (95)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

Cy A 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 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, 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;

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

each R B is independently selected from halogen, —CN, oxo, —C(R)═N(R), —C(O)R, —C(O) 2 R, —C(O)N(R) 2 , —C(═N(R))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, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 8- to 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur;

L is an optionally substituted C 1-6 hydrocarbon chain, wherein 1 to 3 methylene units are independently replaced with —Cy-, —O—, —NR—, —C(O)—, —C(O)NR—, —NRC(O)—, —S(O) 2 NR—, —NRS(O) 2 —, or —S(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 1 and R 2 are independently selected from hydrogen, halogen, —OR, —SR, —N(R) 2 , and optionally substituted C 1-6 aliphatic; wherein R 1 may be taken together with a monocyclic Cy 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 3 , R 4 , R 5 , 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, 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;

R 6 is an optionally substituted C 1-6 aliphatic;

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;

with the proviso that:

the compound is other than 3-chloro-4-[[5-[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-benzenepropanoic acid and N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

2. The compound of claim 1 , wherein Cy A is selected from a 5-membered heteroarylene having 1-4 heteroatoms independently selected from oxygen and nitrogen and an 8-membered partially unsaturated bicyclic heterocyclylene having 2-3 heteroatoms selected from oxygen and nitrogen, wherein Cy A is substituted with 0-3 R A groups.

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

wherein * represents the point of attachment to L.

4. The compound of claim 1 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof,

wherein:

represents a single or double bond;

X is selected from C and N;

each W is independently selected from CR A , CH, N, and O;

R 4 is selected from hydrogen, halogen, —CN, —C(O)OR, or an optionally substituted group selected from C 1-6 aliphatic, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

R 6 is C 1-6 aliphatic; and

each R is independently hydrogen or an optionally substituted C 1-6 aliphatic;

with the proviso that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

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

wherein represents a single or double bond;

each X is independently N or C;

each Y is independently CR A , CH, or N;

Z is CH 2 or O;

R A is selected from an optionally substituted group selected from C 1-6 aliphatic, 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;

R 6 is C 1-6 aliphatic.

6. The compound of claim 1 , wherein the compound is of Formula (III-a), Formula (III-b), Formula (III-c), Formula (III-d), Formula (III-e), Formula (III-f), or Formula (III-g):

or a pharmaceutically acceptable salt thereof,

wherein:

R 6 is C 1-6 aliphatic;

with the proviso that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

7. The compound of claim 1 , wherein the compound is of Formula (IV-a), Formula (IV-b), Formula (IV-c), or Formula (IV-d):

or a pharmaceutically acceptable salt thereof,

wherein:

R 6 is C 1-6 aliphatic.

8. The compound of claim 1 , wherein L is selected from —(C(R) 2 ) m NR(C(R) 2 ) m -#, —(C(R) 2 ) m NRC(O)(C(R) 2 ) m -#, —(C(R) 2 ) m C(O)NR(C(R) 2 ) m -#, —NRC(O)NR-#, —(C(R) 2 ) m OC(O)NR(C(R) 2 ) m -#, —O(C(R) 2 ) m NRC(O)-#, —O(C(R) 2 ) m NRS(O) 2 -#, —(C(R) 2 ) m S(O) 2 NR(C(R) 2 ) m -#, and —(C(R) 2 ) m NRS(O) 2 (C(R) 2 ) m -#, wherein each R is independently hydrogen or optionally substituted C 1-6 aliphatic, each m is independently 0, 1 or 2, and #represents the point of attachment to Cy A .

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

or a pharmaceutically acceptable salt thereof,

wherein:

Q is selected from —C(R) 2 —, —C(O)—, and —S(O) 2 —;

R B is selected from halogen, —CN, —OR, —N(R) 2 , —N(R)CN, —C(═N(R))N(R) 2 , —S(O)R, —S(O) 2 R, —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, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 8- to 10-membered spirocyclic heterocyclyl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur, wherein each R is independently hydrogen or optionally substituted C 1-6 aliphatic;

R 6 is C 1-6 aliphatic;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic;

n is 0 or 1; and

p is 0, 1, or 2;

with the proviso that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

10. The compound of claim 9 , wherein Cy A is selected from the group consisting of:

wherein * represents the point of attachment to L.

11. The compound of claim 1 , wherein the compound is of Formula (III-a-i), Formula (III-b-i), Formula (III-c-i), Formula (III-d-i), Formula (III-e-i), Formula (III-f-i), or Formula (III-g-i):

or a pharmaceutically acceptable salt thereof,

wherein:

Q is selected from —C(R) 2 —, —C(O)—, and —S(O) 2 —;

R 6 is C 1-6 aliphatic; and

p is 0, 1, or 2;

with the proviso that the compound is other than N-(furan-2-ylmethyl)-N,3,5-trimethyl-1-((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-pyrazole-4-sulfonamide.

12. The compound of claim 1 , wherein the compound is of Formula (IV-a-i), Formula (IV-b-i), Formula (IV-c-i), Formula (IV-d-i), Formula (IV-e-i), Formula (IV-f-i), or Formula (IV-g-i):

or a pharmaceutically acceptable salt thereof,

wherein:

Q is selected from —C(R) 2 —, —C(O)—, and —S(O) 2 —;

p is 0, 1, or 2;

R 6 is C 1-6 aliphatic.

13. The compound of claim 1 , wherein Cy B 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 Cy B is substituted with 0-5 R B groups.

14. The compound of claim 13 , wherein Cy B is selected from the group consisting of:

15. The compound of claim 1 , wherein R 6 is C 1-6 cycloalkylaliphatic.

16. The compound of claim 1 , wherein R 6 is cyclopropyl.

17. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 1 , further comprising a pharmaceutically acceptable excipient.

19. The compound of claim 1 , wherein R 3 , R 5 , and R 7 are hydrogen.

20. The compound of claim 1 , wherein L is selected from —NRC(O)-# and —C(R) 2 NRC(O)-#, wherein each R is independently selected from hydrogen and optionally substituted C 1-6 aliphatic and #represents the point of attachment to Cy A .

Assignments (7)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 21, 2022

From: FINK, SARAH JOCELYN

To: BIODURO LLC

Reel/Frame 058726/0395 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 21, 2022

From: ELLARD, JOHN MARK; RAE, ALASTAIR

To: CHARLES RIVER DISCOVERY RESEARCH SERVICES UK LIMITED

Reel/Frame 058726/0408 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 21, 2022

From: PAPAIOANNOU, NIKOLAOS; TRAVINS, JEREMY MARK; FINK, SARAH JOCELYN

To: SHIRE HUMAN GENETIC THERAPIES, INC.