FIELD: medicine; pharmaceutics.
SUBSTANCE: invention relates to a novel compound of Formula I having histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof, pharmaceutically acceptable salts, a pharmaceutical composition, an inhibition method and use in preparing a medicinal agent.
where each X1 - X4 is independently CA or N; A is H or halogen; L is C1-C2 alkylene; R1 is CF2H or CF3; B is (in this document Y1 is CR2 or each N, Y2 and Y3 is independently CR' or N and R' is H or C1-C5 alkyl) or (in this document Y1 is O or NR2); R2 is H or C1-C5 alkyl, where in C1-C5 alkyl at least one H can be substituted with OH or N(C1-C5 alkyl)2; R3 is halogen; C1-C5 alkyl; (in this document, a, b and c independently represent 0, 1, 2 or 3, where a and b cannot be 0 at the same time, and Z1 is CH2, NH or O); C4-C6 cycloalkenyl; C6-C12 aryl; 5–9 membered heteroaryl including at least one heteroatom selected from N, O and S; (in this document, each a or b independently represents integer 1 or 2); ; (in this document, each a independently represents integer 0, 1 or 2); or pyridinone; at least one H of R3 can each be independently substituted with halogen or -(CH2)n-Q1-Q2-Ra (in this document n equals 0 or 1); Q1 is a single bond, -SO2-, -NH-, -N(C1-C5 alkyl)-, -NHC(=O)-, -N(C1-C5 alkyl)C(=O)- or -C(=O)-; Q2 is a single bond, C1-C5 alkylene, -NH- or -N(C1-C5 alkyl)-; Ra is OH; C1-C5 alkyl; C1-C5 haloalkyl; -NR4R5 (in this document, each R4 and R5 independently represents H or C1-C5 alkyl); C1-C5 alkoxy; (in this document, each a and b is independently 1 or 2, M1 is CH2, O, NH or SO2 and M2 is CH or N); (in this document, M3 represents CH or N); diazabicycloheptane; or 5- or 6-membered heteroaryl, including 1–3 of N; and at least one H of Ra can each be independently substituted with OH; halogen; C1-C5 alkyl; (in this document, each a and b independently represents 0 or 1, but cannot be 0 at the same time, c equals 0 or 1, M4 is CH2, NH or O and at least one H of M4 can be substituted with halogen, C1-C5 alkyl, C3-C6 cycloalkyl or -C(=O)-O(C1-C5 alkyl)); -NR6R7 (in this document, each R6 and R7 is independently H or C1-C5 alkyl); -C(=O)-(C1-C5 alkyl); C(=O)-O(C1-C5alkyl); or -NH-C(=O)-O(C1-C5 alkyl).
EFFECT: novel compounds having selective inhibitory activity on HDAC6 are obtained.
12 cl, 189 tbl, 591 ex
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Authors
Dates
2024-04-19—Published
2021-07-13—Filed