Saturated bicyclic heterocyclic derivatives as SMO antagonists
Inventors
Branca, Danila • Ferrigno, Federica • Hernando, Jose Ignacio Martin • Jones, Philip • Kinzel, Olaf • Malancona, Savina • Muraglia, Ester • Palumbi, Maria Cecilia • Pescatore, Giovanna • Scarpelli, Rita
Assignees
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Publication Number
US-8470823-B2
Publication Date
2013-06-25
Expiration Date
Abstract
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.
Core Innovation
The invention concerns compounds of structural formula I defined by multiple variable indices, including m and n each independently 1 or 2, w, y and z each independently 0, 1 or 2, and x being 0 or 1. The structure includes a defined group A as C3-7 cycloalkyl or fluoroC3-7 cycloalkyl, and a moiety L having selectable sub-structures incorporating (X/O)a, (NR7)b, (O)c, (CR8R9)d, and (NR7)e.
Substituents R1 through R11 are defined broadly, with R1 and R2 each selected from specified alkyl/haloalkyl variants or ring systems, and each of R3, R4, R5 and R6 independently selected from defined substituted functional classes. R7 is hydrogen or C1-6 alkyl, while R8 and R9 are independently hydrogen, C1-6 alkyl or C1-6 alkoxy types or haloC1-6 alkyl, and R10 and R11 include functional groups and optionally substituted ring systems.
The inventive concept is also expressed through related embodiments, including pharmaceutically acceptable salts, stereoisomers and tautomers of the formula I compounds, and additional structural embodiments such as formula II. The scope extends to crystalline and stereochemical variations while retaining the defined structural framework and substituent patterns.
Claims Coverage
The provided claim set includes independent claims directed to a compound of structural formula I and to a specific named compound. Across the claims, the structural scope is defined by the variable indices and the selectable sets for groups A, L, and R1–R11, together with coverage of pharmaceutically acceptable salts, stereoisomers, and tautomers.
Compound of structural formula I with defined indices and substituent sets
A compound of structural formula I in which m and n are independently 1 or 2, w, y and z are independently 0, 1 or 2, and x is 0 or 1; wherein A is C3-7 cycloalkyl or fluoroC3-7 cycloalkyl and L is —(X/O)a(NR7)b(O)c(CR8R9)d(NR7)e— with a, b, c, d, and e each defined as in the claim; wherein R1–R11 and X are each defined by the specified ranges and group selections; and wherein the compound is a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
Specific named bicyclic heterocyclic compound
8a-methyl-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-N-(1-phenyl-1H-pyrazol-5-yl)hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxamide, together with pharmaceutically acceptable salts, stereoisomers or tautomers thereof.
The claim coverage is anchored by broad structural formula I scope with extensive variable-index substitution patterns and a separate independent claim directed to a particular named compound, each explicitly extending to pharmaceutically acceptable salts, stereoisomers, and tautomers.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating diseases with abnormal hedgehog activation by inhibiting the Sonic Hedgehog (Hh) pathway using Smoothened (Smo) antagonists.
Cancer treatment, including basal cell carcinoma, medulloblastoma, prostate cancer, pancreatic cancer, breast cancer, colon cancer, small cell lung cancer, and upper GI tract cancers.
Treating psoriasis.
Treating angiogenesis-related conditions.
Combination therapy with other anti-cancer and/or radiotherapeutic agents for hedgehog pathway inhibition-related treatment.
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