Dihydropyrazolopyrazinone derivative having MGAT2 inhibitory activity
Inventors
TATENO, Yusuke • Katou, Manabu • Wada, Toshihiro
Assignees
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Publication Number
US-12227509-B2
Publication Date
2025-02-18
Expiration Date
Abstract
The present invention provides a compound represented by a following formula.A compound represented by, wherein R1 is hydrogen, hydroxy, or the like;R2a and R2b may be taken together with an adjacent carbon atom to form ring B,ring B is a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;R3a is hydrogen, halogen, hydroxy, or the like;R3b is hydrogen, halogen, hydroxy, or the like;R4a is a group represented by formula: L3 is a single bond or substituted or unsubstituted alkylene,R7 is hydrogen, halogen, hydroxy, or the like, andR4b is halogen, cyano, carboxy, or the like, or its pharmaceutically acceptable salt.
Core Innovation
The invention relates to a compound represented by formula (I), including compounds defined by specific ring structures and substituent groups. The compound includes a ring B represented by a formula with R6 substituents and an integer n, and a substituent at R4a defined by a group represented by formulae that include a linkage through L3 and a group at R7 selected from halogen, sulfamoyl, alkyloxy, alkylsulfonyl, aromatic heterocyclyl, non-aromatic heterocyclyl, or sulfonamide-like fragments. The substituent R4b is defined to be alkyl, aromatic carbocyclyl, or aromatic heterocyclyl, and the compounds are also defined to include pharmaceutically acceptable salts.
The invention additionally covers R3a and R3b as hydrogen, and a compound class where R1 is hydrogen and where R2a and R2b are taken together with an adjacent carbon atom to form ring B. Ring B is represented by a specified ring formula with R6 substituents independently halogen or substituted or unsubstituted alkyloxy, and n is 1 or 2. The structural scope also includes expanded formula (I) embodiments with ring C selected as an aromatic carbocycle or aromatic heterocycle, and with R5 and m constrained by enumerated group options and an integer range.
The background/functional focus provided in the partial content states that the MGAT2 inhibitory activity is a key functional attribute of the formula (I) dihydropyrazolopyrazinone derivatives. Further, the partial content emphasizes reduced toxicity by avoiding an enone structure, and improved solubility and metabolic stability, including acid stability and reduced phototoxicity, hepatotoxicity, kidney toxicity, cardiovascular toxicity, gastrointestinal disorders, and drug interaction risk. The partial content additionally covers polymorphs and solid forms, including pharmaceutically acceptable salts, isotopes, radiolabeled compounds, and prodrugs.
Claims Coverage
The independent claims identified in the provided material cover a compound class represented by formula (I), with additional independent-claim coverage for pharmaceutical composition and treatment or prevention of MGAT2-associated disease. Across the claims, the main inventive features are the defined formula framework, ring B formation and substitution, the L3–R7 fragment in R4a, allowable R4b substituents, and expanded R1/R2a/R5/m definitions in broader embodiments.
Formula (I) compound with defined ring B and substituent groups
A compound represented by formula (I), wherein R1 is hydrogen; R2a and R2b are taken together with an adjacent carbon atom to form ring B; ring B is represented by formula with R6 substituents independently halogen or substituted or unsubstituted alkyloxy and n as 1 or 2; R3a and R3b are hydrogen; R4a is a group represented by a formula in which L3 is a single bond or substituted or unsubstituted alkylene and R7 is selected from halogen, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or a group represented by a sulfonamide-like formula; and R4b is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted aromatic heterocyclyl, or its pharmaceutically acceptable salt.
Formula (I) compound with expanded R1, R2a, R5, and ring C definitions
A compound represented by formula (I) wherein R1 is selected from hydrogen, hydroxy, carbamoyl, alkyl, alkylcarbonyl, alkyloxycarbonyl, alkylsulfonyl, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl, non-aromatic heterocyclyl, and corresponding carbonyl, oxycarbonyl, and sulfonyl variants; R2a is a group represented by formula with ring C being an aromatic carbocycle, aromatic heterocycle, non-aromatic carbocycle, or non-aromatic heterocycle; R5 substituents are each independently selected from halogen, hydroxy, cyano, carboxy, carbamoyl and related groups including sulfamoyl and alkyl/sulfonyl families; m is an integer of 1 to 5; R2b is substituted or unsubstituted alkyl or R2a and R2b are taken together with an adjacent carbon atom to form ring B; ring B is a substituted or unsubstituted non-aromatic carbocycle or non-aromatic heterocycle; R3a and R3b are hydrogen; and R4a and R4b are defined by the stated substituent options, with pharmaceutically acceptable salt forms included.
Sulfonamide-like sulfur-oxygen-nitrogen group in the R4a fragment
R4a is a group represented by formula in which L3 is a single bond or substituted or unsubstituted alkylene and R7 is selected from halogen, sulfamoyl, alkyloxy, alkylsulfonyl, aromatic heterocyclyl, non-aromatic heterocyclyl, or a group represented by sulfur-oxygen-nitrogen type formulas including 98S(=O)(98N98RN)98RS1 and related variants.
Pharmaceutical composition comprising the formula (I) compound
A pharmaceutical composition that includes the compound or a pharmaceutically acceptable salt of the compound together with a pharmaceutical additive.
Treatment or prevention of MGAT2-associated disease
A method of treating or preventing an MGAT2-associated disease by administering an effective amount of a compound or its pharmaceutically acceptable salt to a patient in need.
Overall, the claim coverage centers on a formula (I) compound class with defined ring B formation, constrained R-group substitutions, and sulfur-oxygen-nitrogen type R4a options, while broader embodiments add expanded R1, R2a, R5, and m definitions. The provided materials also include claim coverage for a pharmaceutical composition and a treatment or prevention method for MGAT2-associated disease.
Stated Advantages
Reduced toxicity by avoiding an enone structure.
Improved solubility and metabolic stability, including acid stability.
Reduced phototoxicity.
Reduced hepatotoxicity.
Reduced kidney toxicity.
Reduced cardiovascular toxicity.
Reduced gastrointestinal disorders.
Reduced drug interaction risk.
Oral absorbability and small clearance/distribution to targeted tissue.
Documented Applications
A method of treating or preventing an MGAT2-associated disease by administering an effective amount of a compound represented by formula (I) or its pharmaceutically acceptable salt to a patient in need [procedural detail omitted for safety].
A pharmaceutical composition that includes the compound represented by formula (I) or a pharmaceutically acceptable salt together with a pharmaceutical additive.
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