ASK1 inhibitor compounds and uses thereof
Inventors
Assignees
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Publication Number
US-10150755-B2
Publication Date
2018-12-11
Expiration Date
Abstract
Described herein are compounds, including pharmaceutically acceptable salts, solvates, metabolites, prodrugs thereof, methods of making such compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat non-alcoholic steatohepatitis and other diseases characterized by dysfunctional tissue healing and fibrosis.
Core Innovation
The invention relates to a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, with constrained substituent variables including Z, R5, R25, R6, R8, R9, R13, and R14. The structural definition includes R5 selected from halogen and C1-6 alkyl, R25 selected from halogen, —N(R6)2, —C(=O)OR6, —C(=O)N(R6)2, —NR6C(=O)N(R6)2, and C1-9 heteroaryl options, and R6 selected from hydrogen, C1-C6 alkyl, —C1-C6 alkyl-O—C1-C6 alkyl, —C1-C6 alkyl-pyrazole, and C3-C8 cycloalkyl, with optional cyclization to form a C2-9 heterocycle or C2-9 heteroaryl selected from imidazolyl, pyrazolyl, and pyrrolyl.
The compound of Formula II further constrains the heteroaryl substitution pattern and the index values, with Z defined as C(R9)2, each R9 being hydrogen, n being 0, 1, or 2, and p being 0. The disclosed embodiments also include pharmaceutically acceptable salts or solvates, pharmaceutical compositions comprising the compounds and at least one pharmaceutically acceptable excipient, and treatment of non-alcoholic steatohepatitis in a subject by administering a therapeutically effective amount of the compound.
Claims Coverage
The independent claim coverage centers on a Formula II compound with tightly constrained substituent selections, together with pharmaceutically acceptable salts or solvates. Across the provided items, the inventive coverage also includes a selected compound set, with downstream claims directed to pharmaceutical compositions and treatment of non-alcoholic steatohepatitis. In total, the consolidated claim coverage identifies three core inventive features.
Formula II compound with constrained substituent sets
A compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from halogen and C1-6 alkyl; R25 is selected from halogen, —N(R6)2, —C(=O)OR6, —C(=O)N(R6)2, —NR6C(=O)N(R6)2, and C1-9 heteroaryl options; R6 is selected from hydrogen, C1-C6 alkyl, —C1-C6 alkyl-O—C1-C6 alkyl, —C1-C6 alkyl-pyrazole, and C3-C8 cycloalkyl, or two R6 on the same heteroatom cyclize to form a C2-9 heterocycle or C2-9 heteroaryl selected from imidazolyl, pyrazolyl, and pyrrolyl; Z is C(R9)2 with each R9 being hydrogen; n is 0, 1, or 2; and p is 0.
Selected compound set of Formula II derivatives
A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from a set, as recited in the independent claim text.
Pharmaceutical composition and non-alcoholic steatohepatitis treatment
A pharmaceutical composition comprising the claimed compound together with at least one pharmaceutically acceptable excipient, and a method of treating non-alcoholic steatohepatitis in a subject by administering a therapeutically effective amount of the compound or its pharmaceutically acceptable salt or solvate.
Overall, the claim coverage is directed to structurally constrained Formula II compounds, a selected compound set, and dependent composition and treatment coverage for non-alcoholic steatohepatitis.
Stated Advantages
Treatment of non-alcoholic steatohepatitis in a subject by administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or solvate.
Documented Applications
Pharmaceutical compositions comprising the compounds and at least one pharmaceutically acceptable excipient.
Treating non-alcoholic steatohepatitis in a subject by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or solvate.
ASK1 kinase enzymatic assay context, TNFα inhibition assessment in human PBMCs, MYLK/MLCK kinase assay context, and hERG QPatchHTX assessment.
Clinical trial design description for ASK1 inhibitors in human NASH.
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