Di-substituted pyrazole compounds for the treatment of diseases
Inventors
Uesugi, Motonari • Kincaid, John • Huff, Joel
Assignees
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Publication Number
US-11339142-B2
Publication Date
2022-05-24
Expiration Date
Abstract
Provided herein are compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions in treating a condition, disease, or disorder associated with abnormal activation of the SREBP pathway, including metabolic disorders such as obesity, cancer, cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) wherein the compound is according to Formula (I).
Core Innovation
The invention relates to compounds represented by Formula (Ib), including stereoisomers, mixtures of stereoisomers, and pharmaceutically acceptable salts thereof. The compounds are defined by substituent options for R1a, R1b, R2, R2a, R2b, R3, R4, and R5/R6/R7, including patterns in which 0, 1, or 2 of X1-X4 are nitrogen and the remaining are CH or CR2b. Representative embodiments include Formula (I), Formula (Ib), and related sub-formula variants, together with defined substituent selections such as halo, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyalkyl, and optional substitution on cycloalkyl and heterocycloalkyl groups.
The disclosure states that the SREBP pathway regulates de novo lipogenesis and cholesterol synthesis, and identifies SREBP-1a, SREBP-1c, SREBP-2, SCAP, INSIG, and the Site-1 protease and Site-2 protease. The rationale presented is that inhibiting or otherwise modulating the SREBP pathway is directed to treating disorders associated with abnormal SREBP pathway activation. The compounds are also framed as SREBP-pathway-associated compounds and include pharmaceutical compositions with a pharmaceutically acceptable carrier.
The document also provides example compound structures, intermediates, and characterization data, including 1H NMR and LC/MS values, for specific substituted pyridinone-pyrazole, pyrazolyl-pyridinone, and related heteroaromatic compound examples. Therapeutic method statements are directed to increasing thermogenesis and/or reducing body weight, and to treatment of selected metabolic diseases and cancers.
Claims Coverage
The consolidated claim coverage centers on a Compound of Formula (Ib) defined by specific substituent and heteroatom-selection rules. One inventive feature group defines the structural scaffold, while dependent coverage refines substituent choices and extends to stereoisomers, pharmaceutically acceptable salts, pharmaceutical compositions, and therapeutic methods. In total, the claims present one core structural feature set with associated composition and use coverage.
Compound of formula (ib) with defined substituent pattern
A Compound of Formula (Ib) in which R1a, when present, is halo, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; R1b is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; R2 is where 0, 1, or 2 of X1-X4 are nitrogen and the remaining are CH or CR2b; R2a is —OR5, —S(O)R6, or —S(O)2R7; each R2b, when present, is independently halo, alkyl, haloalkyl, —NO2, or cyano; R3 is hydrogen, halo, alkyl, or haloalkyl; R4 is hydrogen, halo, alkyl, or haloalkyl; and R5, R6, and R7 are independently alkyl, haloalkyl, hydroxyalkyl, haloalkyl further substituted with 1 or 2 hydroxy, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, with optional substitution on cycloalkyl and heterocycloalkyl groups, and the compound includes stereoisomers, mixtures of stereoisomers, and pharmaceutically acceptable salts.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition including a compound of Formula (Ib), a stereoisomer, a mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Therapeutic use for srebp pathway-related disorders
A method of inhibiting or relieving a condition, disease, or disorder linked to abnormal activation of the SREBP pathway, or of increasing thermogenesis or reducing body weight, by administering an effective amount of the compound to treat listed metabolic and disease conditions, including cancers.
Overall, the claim set is built around a Formula (Ib) compound with defined R-group and heteroatom constraints, with coverage extended to stereoisomers and salts. The dependent claim family adds pharmaceutical composition coverage and method-of-use coverage for disorders associated with abnormal SREBP pathway activation, thermogenesis, and body-weight reduction.
Stated Advantages
The disclosure states a need for improved drug-like properties.
The compounds are described in terms of modulating the SREBP pathway for treating disorders associated with abnormal SREBP pathway activation.
The document describes deuteration to modulate pharmacokinetics/toxicity via kinetic isotope effects.
Documented Applications
Treating disorders associated with abnormal activation of the SREBP pathway.
Treating metabolic diseases, including obesity, metabolic syndrome, type 2 diabetes, dyslipidemia, and hypertension.
Treating cardiovascular disease and atherosclerosis.
Treating fatty liver disease, including NAFLD and nonalcoholic steatohepatitis.
Treating cancer, including hepatocellular carcinoma and glioblastoma multiforme.
Increasing thermogenesis and/or reducing body weight.
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