Alpha ketoamide compounds as cysteine protease inhibitors
View Patent ↗The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.
1. A compound of Formula (II):
wherein:
R 5 is alkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-X—R 9 (where X is —S— or —SO 2 — and R 9 is alkyl, cycloalkylalkyl, aryl, aralkyl or heteroaralkyl) or haloalkyl optionally substituted with cycloalkyl, wherein the aromatic or alicyclic ring in R 5 is optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, halo or —SO 2 R 11 (where R 11 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl);
R 6 is haloalkyl; and
R 8 is hydrogen or aryl, wherein the aromatic ring in R 8 is optionally substituted with one, two, or three R e independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl, alkylsulfonylamino, aminocarbonyl, or aminosulfonyl; or
a pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein R 5 is -(alkylene)-S—R 9 .
3. The compound of claim 1 , wherein R 5 is -(alkylene)-SO 2 —R 9 .
4. The compound of claim 1 , wherein the compound is selected from:
5. The compound of claim 1 , wherein the compound is selected from:
6. A compound of Formula (III):
wherein:
R 1 is hydrogen;
R 2 is cycloalkyl or aralkyl;
R 3 is hydrogen or alkyl;
R 4 is alkyl; or
R 3 and R 4 together with the carbon atom to which they are attached form cycloalkylene;
R 5 is alkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-X—R 9 (where X is —S— or —SO 2 — and R 9 is alkyl, cycloalkylalkyl, aryl, aralkyl or heteroaralkyl) or haloalkyl optionally substituted with cycloalkyl wherein the aromatic or alicyclic ring in R 5 is optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, halo or —SO 2 R 11 (where R 11 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl);
R 6 is haloalkyl; and
R 8 is hydrogen or aryl, wherein the aromatic ring in R 8 is optionally substituted with one, two, or three R e independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl, alkylsulfonylamino, aminocarbonyl, or aminosulfonyl; or
a pharmaceutically acceptable salts thereof.
7. The compound of claim 6 , wherein R 5 is -(alkylene)-S—R 9 .
8. The compound of claim 6 , wherein R 5 is -(alkylene)-SO 2 —R 9 .
9. The compound of claim 6 , wherein the compound is selected from:
10. The compound of claim 6 , wherein the compound is selected from: