Claims for Patent: 10,329,260

Summary for Patent: 10,329,260

Title:	Human plasma kallikrein inhibitors
Abstract:	Disclosed are compounds of formula I ##STR00001## 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.
Inventor(s):	Kotian; Pravin L. (Hoover, AL), Babu; Yarlagadda S. (Birmingham, AL), Wu; Minwan (Vestavia Hills, AL), Chintareddy; Venkat R. (Vestavia Hills, AL), Kumar; V. Satish (Birmingham, AL), Zhang; Weihe (Vestavia, AL)
Assignee:	BioCryst Pharmaceuticals, Inc. (Durham, NC)
Application Number:	15/977,129
Patent Claims:	1. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ##STR00594## ##STR00595## 2. The compound of claim 1, wherein the compound is ##STR00596## or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, wherein the compound is ##STR00597## or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1, wherein the compound is ##STR00598## or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, wherein the compound is ##STR00599## or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, wherein the compound is ##STR00600## or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, wherein the compound is ##STR00601## or a pharmaceutically acceptable salt thereof. 8. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ##STR00602## ##STR00603## 9. The compound of claim 8, wherein the compound is ##STR00604## or a pharmaceutically acceptable salt thereof. 10. The compound of claim 8, wherein the compound is ##STR00605## or a pharmaceutically acceptable salt thereof. 11. The compound of claim 8, wherein the compound is ##STR00606## or a pharmaceutically acceptable salt thereof. 12. The compound of claim 8, wherein the compound is ##STR00607## or a pharmaceutically acceptable salt thereof. 13. The compound of claim 8, wherein the compound is ##STR00608## or a pharmaceutically acceptable salt thereof. 14. The compound of claim 8, wherein the compound is ##STR00609## or a pharmaceutically acceptable salt thereof. 15. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ##STR00610## ##STR00611## 16. The compound of claim 15, wherein the compound is ##STR00612## or a pharmaceutically acceptable salt thereof. 17. The compound of claim 15, wherein the compound is ##STR00613## or a pharmaceutically acceptable salt thereof. 18. The compound of claim 15, wherein the compound is ##STR00614## or a pharmaceutically acceptable salt thereof. 19. The compound of claim 15, wherein the compound is ##STR00615## or a pharmaceutically acceptable salt thereof. 20. The compound of claim 15, wherein the compound is ##STR00616## or a pharmaceutically acceptable salt thereof. 21. The compound of claim 15, wherein the compound is ##STR00617## or a pharmaceutically acceptable salt thereof. 22. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ##STR00618## ##STR00619## 23. The compound of claim 22, wherein the compound is ##STR00620## or a pharmaceutically acceptable salt thereof. 24. The compound of claim 22, wherein the compound is ##STR00621## or a pharmaceutically acceptable salt thereof. 25. The compound of claim 22, wherein the compound is ##STR00622## or a pharmaceutically acceptable salt thereof. 26. The compound of claim 22, wherein the compound is ##STR00623## or a pharmaceutically acceptable salt thereof. 27. The compound of claim 22, wherein the compound is ##STR00624## or a pharmaceutically acceptable salt thereof. 28. The compound of claim 22, wherein the compound is ##STR00625## 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)met- hyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino)(phenyl)met- hyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamin- o)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamin- o)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphe- nyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-hydroxyphe- nyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)me- thyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl)(cyclopropylmethoxy)me- thyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)me- thyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethoxy)me- thyl)-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)(cyclopropylmethylamin- o)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethylamin- o)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)(cyclopropylmethylamin- o)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)(cyclopropylmethylamin- o)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)me- thyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropylmethoxy)me- thyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropy- l)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-phenylpropy- l)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamin- o)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl)(cyclopropylmethylamin- o)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)ph- enyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(phenyl)methyl)ph- enyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropy- l)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(3-(3-cyclopropyl-1-hydroxy-1-phenylpropy- l)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphe- nyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(3-hydroxyphe- nyl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-methoxynap- hthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-car- boxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino)(2-m- ethoxynaphthalen-1-yl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyraz- ole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-ami- no)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(3-((4-aminophenyl)(cyclopropylmethyl-ami- no)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)m- ethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(3-((3-aminophenyl)(cyclopropyl-methoxy)m- ethyl)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)met- hyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-2-yl)met- hyl)-phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)met- hyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(3-((cyclopropylmethoxy)(pyridin-3-yl)met- hyl)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)met- hyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethoxy)(pyridin-3-yl)met- hyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (+)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynap- hthalen-1-yl)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; (-)-1-(3-(Aminomethyl)phenyl)-N-(3-((cyclopropylmethylamino)(2-methoxynap- hthalen-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.