Cathepsin cysteine protease inhibitors
View Patent ↗This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
1. A compound of the formula:
wherein R 1 is halo;
R 2 is halo;
R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, aryl or heteroaryl;
or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
2. The compound of claim 1 wherein R 1 is fluoro or chloro; or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
3. The compound of claim 2 wherein R 2 is fluoro or chloro; or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
4. The compound of claim 3 wherein R 3 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
5. The compound of claim 4 wherein R 3 is C 1-6 haloalkyl; or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
6. The compound of claim 4 wherein R 3 is 2,2,2-trifluoroethyl; or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
7. The compound of claim 1 which is:
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)phenyl]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising a compound of claim 1 and another agent selected from the group consisting of: an organic bisphosphonate, a selective estrogen receptor modulator, an estrogen receptor beta modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent, vitamin D, a synthetic Vitamin D analogue, a Nonsteroidal anti-inflammatory drug, a selective cyclooxygenase-2 inhibitor, an inhibitor of interleukin-1 beta, a LOX/COX inhibitor and the pharmaceutically acceptable salts and mixtures thereof.