IP Library › Granted Patent US 10,329,260
Granted Patent B2
US 10,329,260 · App. 15/977,129 · Granted Jun 25, 2019

Human plasma kallikrein inhibitors

View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,329,260
App. No.
15/977,129
Granted
Jun 25, 2019
Kind
B2
Abstract

Disclosed are compounds of formula I as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also disclosed are pharmaceutical compositions comprising at least one such compound, and methods involving use of the compounds and compositions in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.

Claims (124)

1. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

2. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

8. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

9. The compound of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

15. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

16. The compound of claim 15 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 15 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 15 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 15 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 15 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 15 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

22. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

23. The compound of claim 22 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 22 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25. The compound of claim 22 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 22 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 22 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 22 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

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

(+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 30 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

32. The compound of claim 30 , wherein the compound is:

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

33. The compound of claim 32 , wherein the compound is (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.

34. The compound of claim 32 , wherein the compound is (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.

35. The compound of claim 32 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

36. The compound of claim 35 , wherein the pharmaceutically acceptable salt thereof is a bis(hydrochloride) salt.

37. The compound of claim 8 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

38. The compound of claim 8 , wherein the compound is:

(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl)propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

39. The compound of claim 38 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

40. The compound of claim 15 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

41. The compound of claim 15 , wherein the compound is:

(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphenyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

42. The compound of claim 41 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

43. The compound of claim 22 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

44. The compound of claim 22 , wherein the compound is:

(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)methyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-(pyridin-2-yl)propyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

(−)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynaphthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 44 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.

Assignments (8)
SECURITY INTEREST Recorded Jan 23, 2026
From: BIOCRYST PHARMACEUTICALS, INC.
To: WILMINGTON TRUST, NATIONAL ASSOCIATION
Reel/Frame 074485/0651 →
TERMINATION AND RELEASE OF SECURITY INTEREST IN PATENT COLLATERAL RECORDED AT REEL 063363/FRAME 0873 Recorded Oct 8, 2025
From: BIOPHARMA CREDIT PLC
To: BIOCRYST PHARMACEUTICALS, INC.
Reel/Frame 073056/0492 →
PATENT SECURITY AGREEMENT Recorded Apr 19, 2023
From: BIOCRYST PHARMACEUTICALS, INC.
To: BIOPHARMA CREDIT PLC
Reel/Frame 063363/0873 →
RELEASE OF GRANT OF SECURITY INTEREST IN PATENTS Recorded Apr 18, 2023
From: ATHYRIUM OPPORTUNITIES III CO-INVEST 1 LP
To: BIOCRYST PHARMACEUTICALS, INC.
Reel/Frame 063362/0550 →
SECURITY INTEREST Recorded Dec 17, 2020
From: BIOCRYST PHARMACEUTICALS, INC.
To: ATHYRIUM OPPORTUNITIES III CO-INVEST 1 LP
Reel/Frame 054800/0634 →
RELEASE OF SECURITY INTEREST Recorded Dec 16, 2020
From: MIDCAP FINANCIAL TRUST, AS AGENT
To: BIOCRYST PHARMACEUTICALS, INC.; MDCP, LLC
Reel/Frame 054774/0446 →
SECURITY INTEREST Recorded Aug 9, 2018
From: BIOCRYST PHARMACEUTICALS, INC.; MDCP, LLC
To: MIDCAP FINANCIAL TRUST, AS AGENT
Reel/Frame 046599/0580 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2018
From: KOTIAN, PRAVIN L.; BABU, YARLAGADDA S.; WU, MINWAN; CHINTAREDDY, VENKAT R.; KUMAR, V. SATISH; ZHANG, WEIHE
To: BIOCRYST PHARMACEUTICALS, INC.
Reel/Frame 045797/0458 →