ASK1 inhibitor compounds and uses thereof
Inventors
Assignees
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Publication Number
US-11434249-B1
Publication Date
2022-09-06
Expiration Date
Abstract
Described herein are compounds, including pharmaceutically acceptable salts and solvates 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 compounds having the structure of Formula (I), including pharmaceutically acceptable salts and solvates thereof, and related Formula (Ia), (Ib), and (Ic) embodiments. The compounds define multiple substituent variables R1 through R14, together with parameters p and q, and p is 0, 1, 2, or 3, with some embodiments reciting q as 0, 1, or 2. The disclosed compound family includes structural examples in which R4 varies across heteroaryl and fused heteroaryl-cycloalkyl motifs, including triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole ring systems.
Within Formula (I), R1 and R3 are independently selected from hydrogen, halogen, and C1-6 alkyl, or R2 and R3 are combined to form a phenyl ring. R2 is selected from hydrogen, halogen, —OR6, —N(R6)2, C1-6 alkyl, C2-9 heterocycle, and C6-10 aryl, with optional substitution by one, two, or three substituents selected from —C(=O)R14 and —N(R13)C(=O)R14. R4 is C1-9 heteroaryl optionally substituted with one, two, or three substituents selected from C1-6 alkyl and C3-8 cycloalkyl, while R5, R6, R13, and R14 are constrained to the stated selection sets.
The embodiments further emphasize Formula (Ia), Formula (Ib), and Formula (Ic) compounds in which the R4 position is the main locus of variation. In the provided examples, R4 includes triazole, imidazole, oxazole, isoxazole, oxadiazole, tetrazole, and fused heteroaryl-cycloalkyl motifs, and R5a is fixed as hydrogen in some examples. The disclosure also frames the compounds as ASK1 inhibitor compounds for treating non-alcoholic steatohepatitis (NASH), with the broader therapeutic context also referencing non-alcoholic fatty liver disease (NAFLD).
Claims Coverage
The claim coverage centers on one independent Formula (I) compound claim, including pharmaceutically acceptable salts or solvates, with constrained substituent variables and p limited to 0, 1, 2, or 3. Across the consolidated input, the independent claim is supported by the same core feature set: the Formula (I) scaffold, defined substituent classes for R1, R2, R3, R4, R5, R6, R13, and R14, and optional phenyl ring formation by combining R2 and R3.
Formula (I) compound scaffold with constrained substituents
A compound having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is independently selected from hydrogen, halogen, and C1-6 alkyl; R2 is selected from hydrogen, halogen, —OR6, —N(R6)2, C1-6 alkyl, C2-9 heterocycle, and C6-10 aryl, with optional substitution by one, two, or three substituents selected from —C(=O)R14 and —N(R13)C(=O)R14; R3 is selected from hydrogen, halogen, and C1-6 alkyl; R4 is C1-9 heteroaryl optionally substituted with one, two, or three substituents selected from C1-6 alkyl and C3-8 cycloalkyl; each R5 is independently selected from halogen, —CN, and C1-6 alkyl; each R6 is independently selected from hydrogen and C1-6 alkyl; R13 is independently selected from hydrogen, C1-6 alkyl, and C3-8 cycloalkyl; each R14 is independently selected from C1-6 alkyl and C3-8 cycloalkyl; and p is 0, 1, 2, or 3.
R2 and R3 phenyl ring formation
R2 and R3 may be combined to form a phenyl ring.
R2 fixed to hydrogen
A compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen.
R2 restricted to heterocycle or aryl with optional carbonyl-linked substituents
A compound of claim 1, including a pharmaceutically acceptable salt or solvate form, wherein R2 is selected from C2-9 heterocycles or C6-10 aryl groups optionally substituted with one to three substituents selected from —C(=O)R14 and —N(R13)C(=O)R14.
R4 triazole embodiment with optional alkyl and cycloalkyl substitution
A specified compound from claim 1 provided as a pharmaceutically acceptable salt or solvate, where the compound includes an R4 triazole optionally substituted with one or two groups selected from C1-6 alkyl and C3-8 cycloalkyl.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable excipient.
Treatment of non-alcoholic steatohepatitis
A method of treating non-alcoholic steatohepatitis in a subject by administering a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or solvate form.
Overall, the claims cover Formula (I) compounds with tightly defined substituent classes and p limited to 0, 1, 2, or 3, including optional phenyl ring formation by combining R2 and R3 and R4 as optionally substituted C1-9 heteroaryl. Dependent claims further narrow R2 and R4 and also recite a pharmaceutical composition and treatment of non-alcoholic steatohepatitis.
Stated Advantages
The patent states treatment of non-alcoholic steatohepatitis in a subject by administering a therapeutically effective amount of the defined Formula (I) compound, or a pharmaceutically acceptable salt or solvate.
Documented Applications
A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable excipient.
A method of treating non-alcoholic steatohepatitis in a subject by administering a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or solvate form.
Methods of treating non-alcoholic steatohepatitis by administering therapeutically effective amounts of Formula (I), Formula (Ia), Formula (Ib), or Formula (Ic) compounds, or pharmaceutically acceptable salts or solvates, to a subject in need thereof.
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