1211399-87-9

Upstream product

• 138775-03-8 (S)-4-(benzyloxycarbonyl)-1-(tert-butyloxycarbonyl)-piperazine-2-carboxylic acid 
• 155-09-9 trans-2-phenylcyclopropylamine 
• 3721-28-6 (1S,2R)-tranylcypromine 
• 220241-67-8 C₄H₆O₆*C₉H₁₁N 
• 1329683-16-0 C₂₂H₂₅N₃O₃ 
• 32315-10-9 bis(trichloromethyl) carbonate 
• 1329683-24-0 C₂₁H₂₂Cl₂N₄O₂ 
• 1329683-22-8 C₂₂H₂₀Cl₂N₄O₃ 
• 1329683-20-6 C₁₅H₁₇N₃O₂ 
• 1329683-18-2 C₂₃H₂₃N₃O₄ 
• 1211399-89-1 (8aS)-2-[(1S,2R)-2-phenylcyclopropyl]tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-dione hydrochloride 
• 41195-90-8 1,2-dichloro-3-isocyanatobenzene 

Relevant academic research and scientific papers

Identification of MK-5710 ((8aS)-8a-methyl-1,3-dioxo-2-[(1S,2R)-2- phenylcyclo- propyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydro-imidazo[1,5-a] pyrazine-7(1H)-carboxamide), a potent smoothened antagonist for use in Hedgehog pathway dependent malignancies, Part 2

The Hedgehog (Hh-) signaling pathway is a key developmental pathway which gets reactivated in many human tumors, and smoothened (Smo) antagonists are emerging as novel agents for the treatment of malignancies dependent on the Hh-pathway, with the most advanced compounds demonstrating encouraging results in initial clinical trials. A novel series of potent bicyclic hydantoin Smo antagonists was reported in the preceding article, these have been resolved, and optimized to identify potent homochiral derivatives with clean off-target profiles and good pharmacokinetic properties in preclinical species. While showing in vivo efficacy in mouse allograft models, unsubstituted bicyclic tetrahydroimidazo[1,5-a]pyrazine-1,3(2H,5H)-diones were shown to epimerize in plasma. Alkylation of the C-8 position blocks this epimerization, resulting in the identification of MK-5710 (47) which was selected for further development.

SATURATED BICYCLIC HETEROCYCLIC DERIVATIVES AS SMO ANTAGONISTS

The present invention relates to compounds of formula I: and pharmaceutically acceptable salts or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smoantagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.