Human plasma kallikrein inhibitors
Disclosed are compounds of formula I as described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one compound of the invention, and methods involving use of the compounds and compositions of the invention in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.
1. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
2. The compound of claim 1 , wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
3. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
4. The compound of claim 3 , wherein the compound is (+)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino) (phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
5. The compound of claim 3 , wherein the compound is (−)-1-(3-(aminomethyl)phenyl)-N-(5-(((cyclopropylmethyl)amino) (phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
6. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
7. The compound of claim 6 , wherein the compound is (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl) (cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
8. The compound of claim 6 , wherein the compound is (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl) (cyclopropylmethylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
9. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
10. The compound of claim 9 , wherein the compound is (+)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino) (2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
11. The compound of claim 9 , wherein the compound is (−)-1-(3-(aminomethyl)phenyl)-N-(5-((cyclopropylmethylamino) (2-hydroxyphenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
12. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
13. The compound of claim 12 , wherein the compound is (+)-1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl) (cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
14. The compound of claim 12 , wherein the compound is (−)-1-(3-(aminomethyl)phenyl)-N-(5-((3-aminophenyl) (cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
15. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
16. The compound of claim 15 , wherein the compound is (+)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl) (cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
17. The compound of claim 15 , wherein the compound is (−)-1-(3-(aminomethyl)phenyl)-N-(5-((4-cyanophenyl) (cyclopropylmethoxy)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
18. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
19. The compound of claim 18 , wherein the compound is (+)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl) propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
20. The compound of claim 18 , wherein the compound is (−)-1-(3-(aminomethyl)phenyl)-N-(5-(3-cyclopropyl-1-hydroxy-1-(pyridin-3-yl) propyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
21. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
22. The compound of claim 21 , 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; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
23. The compound of claim 21 , 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; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
24. The compound of claim 1 , wherein the compound is
and wherein the pharmaceutically acceptable salt thereof is a hydrochloride salt.
25. The compound of claim 24 , wherein the compound is (+)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl) propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.
26. The compound of claim 24 , wherein the compound is (−)-N-(5-(1-amino-3-cyclopropyl-1-(pyridin-2-yl) propyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; and wherein the pharmaceutically acceptable salt thereof is a di-hydrochloride salt.