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Publication Number
US-10696650-B2
Publication Date
2020-06-30
Expiration Date
Abstract
The present invention provides compounds useful as inhibitors of AHR, compositions thereof, and methods of using the same.
Core Innovation
The invention relates to compounds of formula IV-g and pharmaceutically acceptable salts thereof. The compounds comprise a heteroaryl ring designated as Hy that is a 5-6 membered heteroaryl ring having 1-2 nitrogens, and Ring B that is phenyl or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The scaffold includes variable substituents through Rx, R1, R2, and R3, with L1 as a covalent bond, L2 defined within the formula, and discrete parameters m, n, and p.
The patent content also shows structural examples and formula-based embodiments that vary the heteroaryl and ring substituent patterns while maintaining the defined scaffold. The examples include substituted heteroaryl carboxamide compounds and related intermediates, as well as pyrazole-3-carboxamide derivatives and representative AHR inhibitor compounds. Preparation and characterization are reported with methods such as 1H NMR, ES-LCMS, and product purity or mass information.
The invention further describes AHR inhibitor compounds, compositions, and structure-based chemical space defined by general scaffold formulas with heteroaryl group Hy, Ring A/B selections, linker definitions, and substituent sets. The document identifies AHR inhibition context, including DRE-regulated genes such as CYP1A1 and CYP1B1, and presents assay-related description for DRE-luciferase reporter readouts.
Claims Coverage
The consolidated claim coverage centers on one independent claim defining a compound of formula IV-g or a pharmaceutically acceptable salt thereof, with constrained heteroaryl ring definitions, linker constraints, and selectable substituent and integer parameters. Dependent claims narrow the scaffold by fixing p, selecting specific Hy rings, constraining Ring B, fixing R2 to hydrogen, and extending coverage to pharmaceutical compositions.
Constrained IV-g compound scaffold
A compound of formula IV-g or a pharmaceutically acceptable salt thereof, wherein Hy is a 5-6 membered heteroaryl ring having 1-2 nitrogens; Ring B is phenyl or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L1 is a covalent bond; and the structure is parameterized by R1, R2, R3, Rx, m, n, and p.
Defined substituent selections for R and related groups
Each Rx is independently hydrogen or C1-4 alkyl; each R1 is independently hydrogen, deuterium, or optionally substituted C1-6 aliphatic; each R is independently hydrogen, deuterium, or optionally substituted C1-6 aliphatic; and each of R2 and R3 is independently selected from R, halogen, cyano, nitro, and OR.
Discrete integer ranges for m, n, and p
Each of m and n is independently 1, 2, 3, 4, or 5, and p is 0, 1, 2, or 3.
Hy limited to named heteroaryl rings
Hy is one of pyrazolyl, imidazolyl, pyridinyl, or pyrazinyl.
Ring B limited to defined heteroaromatic composition
Ring B is a 5-6 membered monocyclic heteroaromatic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
R2 fixed to hydrogen
R2 is hydrogen.
Pharmaceutical composition including claimed compound
A pharmaceutical composition including a compound of claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
The claims coverage is anchored on the formula IV-g scaffold with defined Hy and Ring B ring classes, covalent linker L1, and constrained substituent and integer selections. The dependent claims further narrow p, Hy, Ring B, and R2, and include pharmaceutical composition coverage.
Stated Advantages
Provides compounds and pharmaceutically acceptable salts and compositions for an unmet need for AHR inhibitors.
Documented Applications
AHR inhibitor context for targeting AHR-driven, DRE-regulated genes including CYP1A1 and CYP1B1, with described pro-tumor and immunosuppressive roles involving Tregs/Tr1 and IDO/IL-10.
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