Heterocyclic GLP-1 agonists
Inventors
Meng, Qinghua • XING, Weiqiang • Zhang, Haizhen • Lin, Xichen • Lei, Hui • Jennings, Andrew
Assignees
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Publication Number
US-11926626-B2
Publication Date
2024-03-12
Expiration Date
Abstract
This disclosure relates to GLP-1 agonists of Formula (I), including pharmaceutically acceptable salts and solvates thereof, and pharmaceutical compositions including the same.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof, defined by a multi-ring heteroaromatic scaffold with specified atom positions X1 through X8, including X3, X5, and X8 as C, X2 and X4 as N, X6 and X7 as CH, and X1 as CH or N, with optional single or double bond allowance as permitted by valence. The structure includes a carboxylic acid group where T1 is C(=O)OH and a variable T2 group that is hydrogen or (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl.
The Formula I definition further includes linker groups L1, L2, L3, L4, and L5 with enumerated bond and heteroatom-containing options, together with compatibility rules between L4 and L5. Ring A and Ring B are defined by attachment points and variable atom selections and substituent patterns through W1, W2, RY, RY1, RY2, B1 through B4, R1, R2, and R3, while Ring C is selected from phenyl, 5- to 6-membered heteroaryl, (C3-C6)cycloalkyl, (C5-C10)bicycloalkyl, 5- to 10-membered bicycloheteroaryl, and 3- to 6-membered heterocycloalkyl. The parameter b is an integer selected from 0-3, and each occurrence of Rb is independently selected from an enumerated set including alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cycloalkyl, and CN.
The provided content also describes compounds consistent with the claimed scaffold in example structures and identifies the compounds as GLP-1R modulators. The disclosure includes stated physiological effects and method-of-treatment language directed to type 1 diabetes mellitus, type 2 diabetes mellitus, obesity, and related metabolic or cardiovascular indications, including major adverse cardiovascular events (MACE).
Claims Coverage
The document provides one independent claim directed to a compound of Formula I, including pharmaceutically acceptable salt or solvate forms, with detailed constraints on the multi-ring scaffold. The inventive features center on the atom-type pattern, the T1/T2 groups, the linker framework L1-L5, and Ring A/B/C selection rules; additional dependent claims narrow linker choices, ring selections, substituent sets, and the integer parameter b.
Formula I compound with constrained atom positions
A compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein X3, X5, and X8 are C; X2 and X4 are N; X6 and X7 are CH; and X1 is CH or N, with an optional single or double bond as allowed by valence.
Carboxylic acid T1 and variable T2 substitution
T1 is C(=O)OH, and T2 is hydrogen or (C1-C6)alkyl optionally substituted with (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)haloalkoxy, S(O)2(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, with optional RT substitution.
Linker system L1 to L5 with compatibility rules
L1 is a bond or (C1-C3)alkylene optionally substituted with RL; L2 is a bond, —O—, —S(O)0-2—, or —NH—; L3 is —O—; and L4 and L5 are selected from enumerated carbon, oxygen, sulfur, nitrogen, carbonyl, and sulfoxide linkers with stated pairing constraints.
Ring A and Ring B structural definition
Ring A is defined by attachment points, W1/W2 selections, and RY substituent rules, including RY1 and RY2 together forming a (C1-C4)alkylene with optional replacement of one CH2 by O, S, NH, or N(C1-3 alkyl). Ring B is defined by B1 through B4 selections from CR1 or N with R1, R2, and R3 substituent options.
Ring C selection with parameter b and Rb substituents
Ring C is selected from phenyl, heteroaryl, cycloalkyl, bicycloalkyl, bicycloheteroaryl, and heterocycloalkyl classes, with each Rb independently selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, cycloalkyl, and CN, and b selected from 0-3.
Pharmaceutical composition with excipient
A pharmaceutical composition includes the compound of claim 1, or a pharmaceutically acceptable salt or solvate, together with a pharmaceutically acceptable excipient.
The claim coverage is directed to a tightly defined Formula I scaffold with constrained atom positions, T1/T2 substitution, linker definitions, and Ring A/B/C selection rules, with dependent narrowing of specific linker and ring choices and an excipient-containing pharmaceutical composition embodiment.
Stated Advantages
Modulation of GLP-1R for therapeutic treatment in GLP-1-associated diseases including type 1/2 diabetes mellitus and obesity-related conditions.
Reduced blood glucose, HbA1c, and glucagon as pharmacodynamic or clinical outcome targets.
BMI reduction and modulation of insulin and β-cells as outcome targets.
Cardiovascular risk reduction framed through MACE-related targets.
Support for combination therapy with other anti-obesity/anti-diabetic agents and agents supportive for NAFLD and NASH, including anti-emetic agents.
Modulates GLP-1R.
Modulates glucose and HbA1c.
Modulates insulin.
Reduces glucagon.
Reduces BMI.
Documented Applications
Treatment of GLP-1-associated diseases, including type 1 diabetes mellitus and type 2 diabetes mellitus.
Treatment of obesity and obesity-related conditions.
Treatment of metabolic syndrome.
Therapeutic use aimed at modulating insulin and β-cells, and targeting reductions in blood glucose, HbA1c, and glucagon.
Cardiovascular risk reduction framed via MACE-related targets.
Combination therapy use together with other anti-obesity, anti-diabetic, cardiovascular, and supportive agents, including agents for NAFLD and NASH.
Combination therapy including anti-emetic agents exemplified by 5-HT3 receptor antagonists.
Related metabolic/cardiovascular indications listed in the document, including major adverse cardiovascular events (MACE).
GLP-1 receptor agonist activity assessed using a cAMP assay in an HEK293/GLP1R/CRE-LUC system.
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