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 ():.
where:
R 1 is hydrogen or alkyl;
R 2 is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl, or heteroaralkyl optionally substituted with one or two substitutents independently selected from alkyl, alkoxy, or halo;
R 3 is alkyl or alkoxyalkyl;
R 4 is hydrogen or alkyl; or
R 3 and R 4 together with the carbon atom to which they are attached form cycloalkylene optionally substituted with one to four halo or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl, or haloalkyl;
R 5 is alkyl, haloalkyl optionally substituted with cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-X—R 9 (where X is —O—, —S—, —SO—, —SO 2 —, —CONH—, —NHCO—, or —NHSO 2 — and R 9 is alkyl, haloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl), or -(alkylene)-X 1 -(haloalkylene)-R 10 (where X 1 is —O—, —S—, —SO—, —SO 2 —, —CONH—, —NHCO—, or —NHSO 2 — and R 10 is cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), 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, or halo; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl, cycloalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo;
R 6 is haloalkyl;
R 7 is hydrogen or haloalkyl; and
R 8 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl attached via a carbon atom wherein the aromatic or alicyclic ring in R 8 is optionally substituted with one, two, or three R e independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl, or aminosulfonyl; or
a pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein R 1 is hydrogen and R 2 is cyclopropyl, 1-phenylethyl, or 1H-pyrazol-5-yl.
3. The compound of claim 1 wherein R 1 is hydrogen and R 2 is cyclopropyl.
4. The compound of claim 2 or 3 wherein R 3 is hydrogen and R 4 is alkyl.
5. The compound of claim 2 or 3 wherein R 3 is hydrogen and R 4 is methyl, ethyl, propyl or butyl.
6. The compound of claim 2 or 3 wherein R 3 is hydrogen and R 4 ethyl.
7. The compound of claim 2 or 3 wherein R 3 and R 4 are alkyl.
8. The compound of claim 2 or 3 wherein R 3 and R 4 are independently methyl or ethyl.
9. The compound of claim 2 or 3 wherein R 3 and R 4 are methyl.
10. The compound of claim 2 or 3 wherein R 3 and R 4 together with the carbon atom to which they are attached form cycloalkylene.
11. The compound of claim 2 or 3 wherein R 3 and R 4 together with the carbon atom to which they are attached form cyclopropylene.
12. The compound of any of the claims 2 - 11 wherein R 6 is haloalkyl and R 7 and R 8 are hydrogen.
13. The compound of any of the claims 2 - 11 wherein R 6 is 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl and R 7 and R 8 are hydrogen.
14. The compound of any of the claims 2 - 11 wherein R 6 is haloalkyl, R 7 is haloalkyl, and R 8 is hydrogen.
15. The compound of any of the claims 2 - 11 wherein R 6 is haloalkyl, R 7 is alkyl, and R 8 is hydrogen.
16. The compound of any of the claims 2 - 11 wherein R 6 is haloalkyl, R 7 is hydrogen, and R 8 is aryl optionally substituted with one, two, or three R e .
17. The compound of any of the claims 2 - 11 wherein R 6 is trifluoromethyl or difluoromethyl, R 7 is hydrogen, and R 8 is 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl.
18. The compound of any of the claims 2 - 11 wherein R 6 is haloalkyl, R 7 is hydrogen, and R 8 and R 8 is heteroaryl optionally substituted with one, two, or three R e .
19. The compound of any of the claims 2 - 18 wherein R 5 is cycloalkylalkyl optionally substituted with one, two, or three R a independently selected from alkyl or halo or an R c selected from aralkyl or heteroaralkyl.
20. The compound of any of the claims 2 - 18 wherein R 5 is 1-methylcyclopentylmethyl, 1-methylcyclohexyl, 1-methylcyclobutyl, 1-methyl-3,3-difluorocyclobutylmethyl, 1-methyl-4,4-difluorocyclohexylmethyl, 1-benzyl-cyclopropylmethyl, 1-thiazol-2-ylmethylcyclopropyl-methyl, or 1-methyl-3,3-difluorocyclopentylmethyl.
21. The compound of any of the claims 2 - 18 wherein R 5 is alkyl.
22. The compound of any of the claims 2 - 18 wherein R 5 is haloalkyl substituted with aryl, heteroaryl or heterocycloalkyl.
23. The compound of any of the claims 2 - 18 wherein R 5 is 2,2-difluoro-3-phenylpropyl, 2,2-difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholin-1-ylpropyl, 2,2-difluoro-3-pyridin-2-ylpropyl, 2,2-difluoro-3-pyridin-3-ylpropyl, or 2,2-dichloro-3-phenylpropyl.
24. The compound of any of the claims 2 - 18 wherein R 5 is -(alkylene)-S(O) 2 —R 9 where R 9 is alkyl.
25. The compound of any of the claims 2 - 18 wherein R 5 is methylsulfonylmethyl, ethylsulfonylmethyl, propyl-1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methysulfonylethyl, or 2-ethylsulfonylethyl.
26. The compound of any of the claims 2 - 18 wherein R 5 is -(alkylene)-S(O) 2 —R 9 where R 9 is is aryl or aralkyl optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halo; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo.
27. The compound of any of the claims 2 - 18 wherein R 5 is 2-difluoromethoxyphenyl-methanesulfonylmethyl, 2-phenylsulfonylethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylphenylmethanesulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-fluorophenylmethanesulfonylmethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, 2-, 3-, or 4-trifluoromethylphenylmethanesulfonyl-methyl, phenylmethanesulfonylmethyl, 2-(2-, 3-, or 4-trifluoromethylphenyl)sulfonylethyl, phenylmethanesulfonylmethyl, or 2-(2-, 3-, or 4-fluorophenyl)sulfonylethyl.
28. The compound of any of the claims 2 - 18 wherein R 5 is -(alkylene)-S(O) 2 —R 9 where R 9 is heteroaryl or heteroaralkyl optionally substituted with one, two, or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halo; or optionally substituted with one or two R b independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, halo alkoxy, halo, carboxy, or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO 2 R 11 (where R 11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein the aromatic or alicyclic ring in R c is optionally substituted with one, two, or three R d independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo.
29. The compound of any of the claims 2 - 18 wherein R 5 is pyridin-2-ylmethanesulfonyl-methyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 3-difluoro-methoxypyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxypyridin-3-ylmethane-sulfonylmethyl, 4-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 3-difluoromethoxy-pyridin-4-ylmethanesulfonylmethyl, pyrimidin-2-ylmethanesulfonylmethyl, pyrimidin-5-ylmethanesulfonylmethyl, 3-trifluoromethylpyridin-2-ylmethanesulfonylmethyl, 4-trifluoromethylpyridin-3-ylmethanesulfonylmethyl, 3,5-dimethylisoxazol-4-ylmethane-sulfonylmethyl, 2-fluorofuran-5-ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethane-sulfonylmethyl, furan-2-ylmethanesulfonylmethyl, 2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-4-ylethanesulfonylmethyl, 2-pyridin-3-yl-sulfonylethyl, 2-pyridin-4-ylsulfonylethyl, 3-pyridin-3-ylsulfonylpropyl, 1,3,5-triazin-2-yl-methanesulfonylmethyl, 1,3,4-thiadiazol-2-ylmethanesulfonylmethyl, oxazol-5-yl-methanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl, or thiazol-2-ylmethane-sulfonylmethyl.
30. The compound of any of the claims 2 - 18 wherein R 5 is -(alkylene)-S(O) 2 —R 9 where R 9 is cycloalkylalkyl.
31. The compound of any of the claims 2 - 18 wherein R 5 is cyclopropylmethanesulfonylmethyl.
32. A pharmaceutical composition comprising a compound of any of the claims 1 - 31 in admixture with one or more suitable excipients.
33. The compound of claim 1 wherein:
R 3 is alkyl and R 4 is alkyl.
34. The compound of claim 1 wherein:
R 3 and R 4 together with the carbon atom to which they are attached form cycloalkylene.
35. The compound of claim 1 wherein:
R 3 and R 4 together with the carbon atom to which they are attached form piperidin-4-yl substituted at the nitrogen atom with ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyran-4-yl.
36. The compound of claim 1 wherein:
R 6 is haloalkyl and R 7 and R 8 are hydrogen.
37. The compound of claim 1 wherein:
R 6 is haloalkyl, R 7 is haloalkyl, and R 8 are hydrogen.
38. The compound of claim 1 wherein:
R 6 is haloalkyl, R 7 is alkyl, and R 8 are hydrogen.
39. The compound of claim 1 wherein:
R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is 2-methylsulfonylethyl, R 6 is trifluoromethyl, R 7 is hydrogen and R 8 is 4-fluorophenyl, namely N-cyclopropyl-3-{4-methanesulfonyl-2-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethylamino]-butyrylamino}-2-oxo-pentanamide.
40. The compound of claim 39 which is N-cyclopropyl-3S-{4-methanesulfonyl-2S-[2,2,2-trifluoro-1S-(4-fluoro-phenyl)-ethylamino]-butyrylamino}-2-oxo-pentanamide.
41. The compound of claim 1 wherein:
R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is 2-phenylsulfonylmethyl, R 6 is trifluoromethyl, R 7 is hydrogen and R 8 is 4-fluorophenyl, namely N-cyclopropyl-3-{3-benzenesulfonyl-2-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethylamino]-propionylamino}-2-oxo-pentanamide.
42. The compound of claim 41 which is N-cyclopropyl-3S-{3-benzenesulfonyl-2R-[2,2,2-trifluoro-1S-(4-fluoro-phenyl)-ethylamino]-propionylamino}-2-oxo-pentanamide.
43. The compound of claim 1 wherein:
R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is cyclopropylmethylsulfonylmethyl, R 6 is perfluoropropyl, R 7 is hydrogen and R 8 is hydrogen, namely N-cyclopropyl-3-[3-cyclopropylmethanesulfonyl-2-(2,2,3,3,4,4,4-heptafluoro-butylamino)-propionylamino]-2-oxo-pentanamide.
44. The compound of claim 43 which is N-cyclopropyl-3S-[3-cyclopropylmethanesulfonyl-2R-(2,2,3,3,4,4,4-heptafluoro-butylamino)-propionylamino]-2-oxo-pentanamide.