PROTEOLYSIS MODULATORS AND RELATED USES Russian patent published in 2023 - IPC C07D401/14 C07D403/12 C07D413/14 C07D417/12 C07D417/14 C07D471/04 C07K5/10 A61K38/07 A61P35/00 

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound having the chemical structure of ULM-L-PTM, or a pharmaceutically acceptable salt thereof, which can be used to degrade rat Kirsten sarcoma (KRas) protein. In this structure, (a) L is represented by the formula -(A^L)_q-, where q is an integer from 1 to 50; each A^L is independently selected from the group consisting of CR^L1R^L2, O, NR^L3, CO, C≡ C, C_3–11 heterocycloalkyl containing 1 or 2 N atoms, optionally substituted with 1-3 R^L1 and/or R^L2 groups , and phenyl optionally substituted with 1–3 R^L1 and/or R^L2 groups; and R^L1, R^L2 and R^L3 are each independently H or C_1–8 alkyl; (b) ULM is the following fragment; where W³ is selected from , 5–10-membered heteroaryl or phenyl, wherein the heteroaryl contains 1 or 2 atoms independently selected from N, O or S, and wherein the heteroaryl and phenyl are optionally substituted with 1 or 2 C_1-6 alkyls; R₉ and R₁₀ are independently hydrogen or C_1-6 alkyl; R₁₁ is or 5–10 membered heteroaryl optionally substituted with 1 or 2 C_1-6 alkyls, wherein the heteroaryl contains 1 or 2 atoms selected from N, O or S; R₁₂ is either H or C_1-6 alkyl; R₁₃ is either H, C_1-6 alkyl or C_1-6 alkylcarbonyl; each of R_14a, R_14b independently represents either H or C_1-6 alkyl; W⁵ is a 5–10 membered heteroaryl or phenyl, wherein the heteroaryl contains 1 or 2 atoms independently selected from N, O or S, and wherein the heteroaryl and phenyl are optionally substituted with 1 or 2 C_1-6 alkyls; R₁₅ is either H or 5–10 membered heteroaryl optionally substituted with 1 or 2 C_1-6 alkyls, wherein the heteroaryl contains 1 or 2 atoms selected from N, O or S; each R₁₆ is independently either C_1-6 alkyl or C_1-6 alkoxy; o is either 0, 1, 2, 3 or 4; (c) PTM is selected from PTM-III and PTM-IV; where is either phenyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1 N atom; X _PTM is N; R_PTM1A is NR _PTM9 R_PTM10, O-(C_3–6 heterocycloalkyl), wherein the heterocycloalkyl contains 1 N atom, -OC_1–4 alkyl-C_3–6 heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from C_1–6 alkyl or O-C_1–6 alkyl, wherein the heterocycloalkyl contains either 1 or 2 N atoms, etc.; R_PTM1B is H or; R_PTM9 and R_PTM10 are each independently H, phenyl, or C_1–6 alkyl optionally substituted with either 1 or 2 substituents independently selected from C(O)NH₂, C(O)N(C_1–6 alkyl) ₂ and C(O)N(H)(C_1–6 alkyl); R_PTM2 is H or (C=O)R _PTM2'; R_PTM2' is C_1–6 alkyl, C_2–6 alkene, -N(R_PTM8)₂ or -C(OH)₂; R_PTM3 is either phenyl or naphthalene, each independently substituted with either 1 or 2 substituents independently selected from OH, H and halo; R_PTM4A represents 1 or 2 substituents independently selected from OH, H and halo; R_PTM4B represents either Н or -CH₂CN; R_PTM8 represents H or С_1–6 alkyl; t represents 0, 1, 2, 3, 4, 5, 6; and represents the place of connection of L.

EFFECT: invention also relates to certain compounds, a pharmaceutical composition containing the proposed compounds and their use for treatment of the disease or disorder related to accumulation, aggregation and/or over-activation of KRas.

11 cl, 2 dwg, 14 tbl, 573 ex