COMPOUNDS AND METHODS FOR IMPROVED CLEAVAGE OF TARGET PROTEINS Russian patent published in 2022 - IPC C07D401/14 C07D403/06 C07D403/14 C07D405/14 C07D413/14 C07D417/12 C07D417/14 A61K31/4025 A61K31/422 A61K31/427 A61K45/06 A61P1/04 A61P11/06 A61P15/00 A61P25/00 A61P25/28 A61P3/10 A61P35/00 A61P43/00 A61P9/00 A61P9/12 

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a bifunctional compound having the chemical structure ULM-L-PTM, where (a) PTM is a fragment directionally acting on protein, which is a small molecule, which binds to intracellular target protein; (b) L is a chemical linker group connecting ULM and the specified PTM, where the chemical linker group is represented by the chemical structure -A₁-...-A_q-, where q is an integer from 1 to 20; each A is independently selected from CR^L1R^L2, O, NR^L3, CO, C_3-11cycloalkyl optionally substituted with 1-6 R^L1 groups, C_3-11heterocyclyl optionally substituted with 1-6 R^L1 groups, 6-element aryl optionally substituted with 1-6 R^L1 and 5- or 6-element heteroaryl optionally substituted with 1-6 R^L1 groups; and R^L1, R^L2, R^L3, each independently, is H, halogen, C_1-8alkyl, OC_1-8alkyl, NHC_1-8alkyl, N(C_1-8alkyl)₂, OH, NH₂, CN, or CF₃; (c) ULM is a binding fragment of E3 ubiquitin ligase (hereinafter – ULM) of von Hippel-Lindau (VHL), having the chemical structure , where E is C=O; G is C=O; M is ; each R₉ and R₁₀ is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_1-6hydroxyalkyl, or C_1-6haloalkyl; R₁₁ is optionally substituted 5- or 6-element heteroaryl, optionally substituted 6-element aryl, or , , or ; each R₁₈ is independently halogen, C_1-6 alkoxy, cyano, or optionally substituted C_1-6 alkyl; and p from ULM is 0, 1, 2, 3, or 4; R₁₂ is H or optionally substituted C_1-6 alkyl; R₁₃ is H, optionally substituted C_1-6 alkyl, optionally substituted acetyl, or optionally substituted C_1-6 alkyl carbonyl, each R₁₄ is independently H, C_1-6 haloalkyl, or optionally substituted C_1-6 alkyl, where one R₁₄ is C_1-6 haloalkyl, or optionally substituted C_1-6 alkyl; R₁₅ is optionally substituted 5- or 6-element heteroaryl, optionally substituted 6-element aryl or ; each R₁₆ is independently halogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 haloalkyl, CN, or optionally substituted C_1-6haloalkoxy; o from ULM is equal to 0, 1, 2, 3, or 4; each heteroaryl and heterocyclyl has 1-3 heteroatoms independently selected from O, N, and S; and optionally substituted relates to optional substitutions by means of one or more elements independently selected from a group consisting of C_1-6 alkyl, C_1-6 alkoxy, =O, amino, amide, C_3-7 heterocycle, 6-element aryl, CN, halogen, COOH, hydroxyl, C_1-6 composite ester, C_1-6 acyl, and phenyl, or its pharmaceutically acceptable salt, where (i) target protein is selected from a group consisting of Ras, Raf, MEK, ERK path, estrogen receptor, and androgen receptor; or (ii) PTM is a compound, which targets human BET bromodomain-containing proteins, a compound, which targets RAF, a compound, which targets an estrogen receptor, a compound, which targets an androgen receptor, or a compound, which targets an epidermal growth factor receptor. The invention also relates to a pharmaceutical composition based on the above-mentioned bifunctional compound, a method for causing the cleavage of intracellular target protein in a cell, and a method for cleavage of intracellular target protein in a cell, based on the use of a compound of the above -mentioned structure or a composition based on it.

EFFECT: new heterocyclic compounds are obtained, which can be used as modulators of specific ubiquitination.

18 cl, 1 dwg, 4 tbl, 208 ex