Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
Inventors
Wang, Guoqiang • Shen, Ruichao • Long, Jiang • Ma, Jun • Xing, Xuechao • He, Yong • Granger, Brett • He, Jing • Wang, Bin • Or, Yat Sun
Assignees
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Publication Number
US-12018017-B2
Publication Date
2024-06-25
Expiration Date
Abstract
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, ester, stereoisomer, tautomer, solvate, hydrate, or combination thereof: which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcohol steatohepatitis disease (NASH).
Core Innovation
The invention relates to a method of treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a subject in need thereof by administering a therapeutically effective amount of a compound represented by Formula (I), or a pharmaceutically acceptable salt or ester thereof. Formula (I) is defined by structural variables including X1, X2, and X3, where each is independently N or C(R5), together with substituent groups R3, R4, R5, and R1/R2 selected from specified sets.
Within Formula (I), R3, R4, and R5 are each independently selected from hydrogen, halogen, —NO2, cyano, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, and optionally substituted C1-C8 alkoxyl. R1 and R2 are defined by broad substituent options including hydrogen, halogen, —NO2, cyano, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and N- and S-containing substituent patterns involving R6 and R7.
R6 and R7 are independently selected from hydrogen, C1-C15 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, with optional substitution or with R6 and R7 taken together with the nitrogen atom to form a heterocyclic. The disclosed embodiments further include stereochemically defined compounds within the Formula (I) framework, with substituent variants such as OH, F, CHF2, and nitrogen-containing cyclic or heterocyclic ring motifs, including named Formula (VIb-1), Formula (IVa-1), Formula (Va-1), and Formula (Vb) embodiments and specific depicted chemical structures.
Claims Coverage
The consolidated claim coverage identifies one independent treatment method. The claim covers administering a therapeutically effective amount of a Formula (I) compound, or a pharmaceutically acceptable salt or ester thereof, for treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, with the inventive scope defined by the Formula (I) substituent framework and dependent refinements to specific embodiments.
Treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis with Formula (I) compounds
A method of treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a subject in need thereof by administering a therapeutically effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt or ester thereof.
Formula (I) structural definition with X1, X2, X3 and R3, R4, R5
In Formula (I), X1, X2, and X3 are each independently N or C(R5), and R3, R4, and R5 are each independently selected from hydrogen, halogen, —NO2, cyano, optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, and optionally substituted C1-C8 alkoxyl.
R1 and R2 substituent range including nitrogen- and sulfur-containing groups
R1 is defined as R2, where R2 is selected from hydrogen, halogen, —NO2, cyano, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —N(R6)(R7), —S(O)2N(R6)(R7), —N(R6)C(O)(R7), and —N(R6)S(O)2(R7).
R6 and R7 optional heterocycle formation
R6 and R7 are independently selected from hydrogen, C1-C15 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, with optional substitution or with R6 and R7 taken together with the nitrogen atom to form a heterocyclic.
Specific Formula embodiments and depicted structures
Dependent refinements include Formula (VIb-1), Formula (IVa-1), Formula (Va-1), Formula (Vb), a depicted chemical structure shown in the images, and embodiments in which R1 is hydroxyl (OH) or R2 is selected from CH3, CF3, dimethylamino, or the depicted R2 substituent options.
The claims cover administration of a therapeutically effective amount of Formula (I) compounds, or pharmaceutically acceptable salts or esters, for treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. The inventive scope is defined by the Formula (I) substituent framework and narrowed in dependent claims by specific formula embodiments, depicted structures, and selected substituent constraints.
Stated Advantages
Treating non-alcoholic fatty liver disease.
Treating non-alcoholic steatohepatitis.
Preventing or treating ASK-1 mediated diseases, including hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and other ASK-1 mediated conditions.
Documented Applications
Treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a subject in need thereof by administering a therapeutically effective amount of a compound represented by Formula (I), or a pharmaceutically acceptable salt or ester thereof.
Preventing or treating ASK-1 mediated diseases, including hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), autoimmune, neurodegenerative, inflammatory, chronic kidney disease (CKD), cardiovascular, metabolic, and acute or chronic liver disease.
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