Compounds as GLP-1R agonists
Inventors
REEVES, Corey • Romero, F. Anthony • Jones, Christopher T. • Fenaux, Martijn • Luehr, Gary W.
Assignees
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Publication Number
US-12024507-B2
Publication Date
2024-07-02
Expiration Date
Abstract
The present application provides compounds that may be used as a glucagon-like peptide-1 receptors (GLP-1R) agonist, or pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions containing such compounds, or pharmaceutically acceptable salts thereof. Methods of preparing these compounds and compositions, and methods of using these compounds and compositions to treat or prevent a disease or a condition mediated by GLP-1R, are also provided.
Core Innovation
The disclosure relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, with defined structural variables X, Y, n, R1 through R7, Ring A, Ring B, and a linking group L. Ring A is a 5- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or C6-C14 aryl, and Ring B is a C3-C10 cycloalkyl, C6-C14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each optionally substituted by specified groups. The linking group L connects Ring A and Ring B through a bond, oxygen-containing, alkylene-containing, or amine-containing options with attachment-point semantics.
The compound definition further constrains R1 as —C1-C6 alkylene-R5, with R5 being a 5 to 6-membered heteroaryl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. R2, R3, and R4 are selected from hydrogen, oxo, or C1-C6 alkyl, with R3 and R4 optionally taken together with the carbon atoms to form C3-C6 cycloalkyl optionally substituted by halo or C1-C3 alkyl. R7 includes selected structural options, including an —C(O)NH—R8 form, and R8 is hydrogen, —OH, —S(O)2—C1-C6 alkyl, or C1-C6 alkyl optionally substituted by halo.
The disclosure also describes therapeutic use of the compounds for treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) by administering a therapeutically effective amount to an individual in need. It further includes pharmaceutical compositions, manufacture of a medicament for GLP-1R-mediated disease, and exemplified disease scope including liver disease, diabetes, and cardiometabolic disease. Additional disclosed forms include salts, solvates, N-oxides, tautomers, stereoisomers, isotopically labeled compounds, metabolites, combination therapy concepts, and kit or article of manufacture concepts.
Claims Coverage
Independent coverage centers on the compound of formula (I) and pharmaceutically acceptable salts thereof, with broad structural definition through X, Y, n, R1-R7, Ring A, Ring B, and the linker L. The consolidated claim coverage also includes a selected-group compound claim and a therapeutic-use claim for GLP-1R-mediated disease treatment. In total, three inventive feature groupings are supported across the inputs.
Formula (I) compound scaffold
A compound of formula (I), or a pharmaceutically acceptable salt thereof, with X being N or CH, Y being N or CR4, n being 0 or 1, R being hydrogen, and R1 through R7 defined by the stated structural options.
Ring A and ring B definitions
Ring A is 5- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, or C6-C14 aryl, and Ring B is C3-C10 cycloalkyl, C6-C14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each optionally substituted by specified groups.
Linking group L connecting ring A and ring B
L is a bond, —O—, C1-C6 alkylene, *—O—C1-C6 alkylene-**, *—C1-C6 alkylene-O—**, or *-NR6—C1-C6 alkylene-**, with attachment points to ring A and ring B and defined optional substitution patterns on the alkylene portion.
Selected group of compounds
A compound selected from the stated group of compounds, including Compounds 1-18, or a pharmaceutically acceptable salt thereof.
GLP-1R-mediated disease treatment
A method for treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) by administering a therapeutically effective amount of the compound to an individual in need.
The claims collectively cover a broad formula (I) chemical genus, a selected group of specific compounds, and therapeutic use in GLP-1R-mediated disease treatment. The structural coverage is defined by the stated ring systems, substituent constraints, and connecting linker L.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) by administering a therapeutically effective amount of the compound to an individual in need.
Treating liver disease, including primary biliary cirrhosis, primary sclerosing cholangitis, drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extra-hepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha-1-antitrypsin deficiency.
Treating diabetes and cardiometabolic disease.
Use in the manufacture of a medicament for GLP-1R-mediated disease.
Combination therapy for GLP-1R-mediated indications with other antidiabetic, antiobesity, and NASH agents.
Kits and articles of manufacture associated with the claimed compounds.
GLP-1R cell assay using a TR-FRET cAMP readout.
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