Plasma kallikrein inhibitors
The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing one or more disease states that could benefit from inhibition of plasma kallikrein, including hereditary angioedema, uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy and retinal vein occlusion. The compounds are selective inhibitors of plasma kallikrein.
1. A compound of the formula:
wherein {circle around (A)} is selected from
{circle around (B)} is selected from
V is CH or N;
X is CH or N;
Y is N, NO, NR x or C═O;
Z is NR 4 or CR 4 ;
E is N or CH;
Q is N or CH;
G is N or CR 7 ;
J is N or CR 7 ;
L is N or CR 7 ;
M is N or CR 8 ;
R 1 is selected from the group consisting of hydrogen, halo, cyano, R x , OR x and SO 2 R x ;
R 2 is hydrogen or halo;
R 3 is hydrogen or halo;
R 4 is hydrogen, R x , C 1-3 alkyl-OR x , C 1-3 alkyl-O—C 3-6 cycloalkyl or CH═CH 2 ;
R 5 is hydrogen or C 1-3 alkyl, which is optionally substituted with one to three substituents selected from halo and hydroxy;
R 6 is hydrogen or C 1-3 alkyl;
or R 5 and R 6 can be taken together with the carbon atom between them to form a C 3-6 cycloalkyl group;
each R 7 is independently selected from the group consisting of halo, R x , OR x , C 1-3 alkyl-OR x , NH(C═O)OR x and NH 2 ;
R 8 is selected from the group consisting of R x or OR x ;
or R 7 and R 8 can be taken together with the carbon atoms between them to form a 5-membered cycloalkyl or heterocyclyl group;
R 9 is hydrogen or C 1-3 alkyl;
R 10 is hydrogen, hydroxy or C 1-3 alkyl;
R x is hydrogen or C 1-6 alkyl, which is optionally substituted with one to four substituents selected from halo and hydroxy;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein E is CH and Z is CH; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein
wherein {circle around (A)} is
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein R 1 is selected from the group consisting of hydrogen, CH 3 , CHF 2 , CF 3 , OCHF 2 and SO 2 CH 3 ; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein R 4 is selected from the group consisting of cyano, CH 3 , CHF 2 , CH 2 OH, CH 2 OCH 3 , CH 2 OC(CH 3 ) 3 , CH 2 O(cyclopropyl), CH(OH)CF 3 , CH 2 C(CH 3 ) 2 OH, CD 2 OH, CH(CH 3 )OH; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 wherein R 5 is hydrogen, CH 3 or CH 2 OH; or a pharmaceutically acceptable salt thereof.
7. The compound of a claim 1 wherein X is N; Y is N; V is CH; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 wherein each R 7 is independently selected from the group consisting of hydrogen, chloro, fluoro, CH 3 , OCH 3 , CHF 2 , OCHF 2 , CH 2 OH, NH 2 and NH(C═O)OR x ; or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 selected from any one of compounds 1-228, or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
11. The composition of claim 10 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
12. A method for treating impaired visual activity, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, or bleeding from postoperative surgery in a mammal, comprising administering a composition of claim 10 to a mammal in need of thereof.
13. The method of claim 12 further comprising another agent selected from the group consisting of anti-inflammatory agents, anti-VEGF agents, immunosuppressive agents, anticoagulants, antiplatelet agents, and thrombolytic agents.
14. A method for treating uveitis, posterior uveitis, wet age related macular edema, diabetic macular edema, diabetic retinopathy or retinal vein occlusion in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.
15. A method of treating diabetic retinopathy or diabetic macular edema in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.
16. A method of treating retinal vein occlusion in a mammal comprising administering a composition of claim 10 to a mammal in need thereof.