TETRAHYDRONAPHTHALENE AND TETRAHYDROISOQUINOLINE DERIVATIVES AS ESTROGEN RECEPTOR DESTROYERS Russian patent published in 2023 - IPC C07D417/14 C07D401/14 C07D403/14 A61K31/4725 A61P35/00 

FIELD: medicinal chemistry.

SUBSTANCE: bifunctional compounds used as modulators of the estrogen receptor (target protein). In particular, the present invention relates to bifunctional compounds having the chemical structure ULM-L-PTM, which contain at one end a ligand that binds to E3 ubiquitin ligase, and at the other end a fragment that binds to the target protein so that the target protein is located in the immediate vicinity of the ubiquitin ligase, with the implementation of destruction and inhibition of the target protein. In the general formula ULM-L-PTM: ULM is the chemical structure (a), W is selected from the group consisting of CH₂, CHR and C=O; each X is O; Z is O; G is H; Q₁, Q₂, Q₃ and Q₄ are independently N or C independently substituted with R or H; A is H or linear or branched C_1-6 alkyl; n is 1, 2 or 3; each R is independently selected from -OR', -NR'R", -CR'R"-, 6-membered aryl, 5- or 6-membered heteroaryl with one or two heteroatoms, linear or branched C_1-6alkyl, C_3-7cycloalkyl, C_3-7heterocyclyl with one, two or three heteroatoms, where one R is covalent-bonded to L; R' and R'' independently represent a bond or H; and is a bond that may or may not provide a stereospecific configuration; and where each ULM heteroatom is nitrogen; L is a chemical linker group represented by the formula -(A^L)_q-, wherein (A^L)_q is connected to ULM and PTM; q is 1, 2, 3 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; each A^L is independently selected from a bond, CR^L1R^L2, O, S, SO, SO ₂, NR^L3, CO, C≡C, C_3-11cycloalkyl, C_3-11heterocyclyl having 1 or 2 N or O atoms and optionally substituted with 1 R^L1 group, and 5- or 6-membered heteroaryl having 1, 2 or 4 N atoms; and each of R^L1, R^L2, R^L3, R^L4 and R^L5 independently represents H, halogen or C_1-8alkyl; PTM is the structure of formula (I_PTM), each X_PTM is independently CH or N; indicates the place of attachment L; R_PTM1 represents 1, 2 or 3 substitutions, each substitution is independently selected from OH, halogen and C_1-6alkoxy; R_PTM2 represents 1 or 2 substitutions, each substitution is independently selected from H, halogen, CF₃, linear or branched C_1-6alkyl, methoxy; R_PTM3 is 1 or 2 substitutions, each substitution is independently H or halogen; and R_PTM4 is H or methyl.

EFFECT: modulators of the estrogen receptor (target protein).

13 cl, 7 dwg, 544 ex

Formula (I_PTM)