[发明专利]组蛋白脱乙酰酶抑制剂

摘要

本发明涉及组蛋白脱乙酰酶的抑制。本发明提供了用于抑制组蛋白脱乙酰酶酶活性的化合物和方法。本发明还提供了用于治疗细胞增殖性疾病和不良状态的组合物和方法。本发明的一个方面提供了下式(1)的化合物，其中T、A和X的定义如文中所述。

主权项

1.式(1)的化合物：或其N-氧化物、水合物、溶剂化物、可药用盐、络合物或前药，或其外消旋或非消旋混合物、非对映异构体、对映异构体或互变异构体，其中T为NH₂或OH；A选自亚芳基、亚杂芳基、亚环烷基和亚杂环基，它们中的每一个均为任选取代的；且X为：(a)其中Y＝N或CH，n¹＝0-4，且Z¹选自R⁹-、R¹³-C(O)-、R¹³-C(S)-、R⁷-N(R²)-、R⁶-O-、R¹⁰-S-、R¹³-S(O)_1-2、R⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹¹-C(O)-N(R²)-、R¹³-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹²-O-C(O)-N(R²)-、R⁸-N(R²)-C(O)-O-、R⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R⁵-N(R²)-C(O)-N(R²)-、R⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R⁵-NH-C(N(R²))-NH-、R⁵-S(O)_0-2-N(R²)-、R⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-；条件是：如果n¹为1或2且Z¹为R⁹-、R¹³-C(O)-、R⁷-N(R²)-、R⁶-O-、R¹⁰-S-、R¹³-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹¹-C(O)-N(R²)-、R¹³-N(R²)-C(O)-、R¹²-O-C(O)-N(R²)-、R⁸-N(R²)-C(O)-O-、R⁵-S(O)₂-N(R²)-或R⁵-N(R²)-S(O)₂-，则A不是噻吩基、噻二唑基、噻唑基、嘧啶基、吡嗪基、哒嗪基、吡啶基、三嗪基或四嗪基；(b)其中Y＝N或CH，n²＝0或2-4，且Z²选自R¹⁵-、R¹⁵-C(O)-、R¹³-C(S)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R¹⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R¹⁵-N(R²)-C(O)-N(R²)-、R¹⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R¹⁵-NH-C(N(R²))-NH-、R¹⁵-S(O)_0-2-N(R²)-、R¹⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-；条件是：如果n²为2且Z²为R¹⁵-、R¹⁵-C(O)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-S(O)₂-N(R²)-或R¹⁵-N(R²)-S(O)₂-，则A不是噻吩基、噻二唑基、噻唑基、嘧啶基、吡嗪基、哒嗪基、吡啶基、三嗪基或四嗪基；(c)其中n³＝0-4，且Z³选自R¹⁵-、R¹⁵-C(O)-、R¹³-C(S)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R¹⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R¹⁵-N(R²)-C(O)-N(R²)-、R¹⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R¹⁵-NH-C(N(R²))-NH-、R¹⁵-S(O)_0-2-N(R²)-、R¹⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-，条件是：如果n³为2且Z³为R¹⁵-、R¹⁵-C(O)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-S(O)₂-N(R²)-或R¹⁵-N(R²)-S(O)₂-，则A不是苯基、噻吩基、噻二唑基、噻唑基、嘧啶基、吡嗪基、哒嗪基、吡啶基、三嗪基或四嗪基；(d)其中n⁴＝0、2、3或4，且Z⁴选自R¹⁵-、R¹⁵-C(O)-、R¹³-C(S)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R¹⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R¹⁵-N(R²)-C(O)-N(R²)-、R¹⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R¹⁵-NH-C(N(R²))-NH-、R¹⁵-S(O)_0-2-N(R²)-、R¹⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-，条件是：如果n⁴为2且Z⁴为R¹⁵-、R¹⁵-C(O)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-S(O)₂-N(R²)-或R¹⁵-N(R²)-S(O)₂-，则A不是苯基、噻吩基、噻二唑基、噻唑基、嘧啶基、吡嗪基、哒嗪基、吡啶基、三嗪基或四嗪基；(e)其中n⁵＝1-4，n⁶＝1-4，n⁷＝1-4，Z⁵选自R¹⁵-、R¹⁵-C(O)-、R¹³-C(S)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R¹⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R¹⁵-N(R²)-C(O)-N(R²)-、R¹⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R¹⁵-NH-C(N(R²))-NH-、R¹⁵-S(O)_0-2-N(R²)-、R¹⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-；Z⁶选自R¹⁵-、R¹⁵-C(O)-、R¹³-C(S)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R¹⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R¹⁵-N(R²)-C(O)-N(R²)-、R¹⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R¹⁵-NH-C(N(R²))-NH-、R¹⁵-S(O)_0-2-N(R²)-、R¹⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-；且Z⁷选自R¹⁵-、R¹⁵-C(O)-、R¹³-C(S)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R¹⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R¹⁵-N(R²)-C(O)-N(R²)-、R¹⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R¹⁵-NH-C(N(R²))-NH-、R¹⁵-S(O)_0-2-N(R²)-、R¹⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-；或(f)其中Z⁸选自R¹⁵-、R¹⁵-C(O)-、R¹³-C(S)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-S-、R¹⁵-S-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-C(S)-O-、R¹⁵-O-C(S)-、R¹⁵-C(S)-S-、R¹⁵-S-C(S)-、R¹⁵-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-、R¹⁵-O-C(O)-O-、R¹⁵-O-C(O)-S-、R¹⁵-S-C(O)-O-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-O-C(S)-O-、R¹⁵-O-C(S)-S-、R¹⁵-S-C(S)-O-、R¹⁵-O-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-O-、R¹⁵-S-C(O)-S-、R¹⁵-S-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-S-、R¹⁵-S-C(S)-S-、R¹⁵-N(R²)-C(O)-N(R²)-、R¹⁵-N(R²)-C(S)-N(R²)-、R¹⁵-N(R²)-C(S)-S-、R¹⁵-S-C(S)-N(R²)-、R¹⁵-NH-C(N(R²))-NH-、R¹⁵-S(O)_0-2-N(R²)-、R¹⁵-N(R²)-S(O)_0-2-和R¹⁵-N(R²)-S(O)_0-2-N(R²)-，条件是：如果Z⁸为R¹⁵-、R¹⁵-C(O)-、R¹⁵-N(R²)-、R¹⁵-O-、R¹⁵-S-、R¹⁵-S(O)_1-2、R¹⁵-C(O)-O-、R¹⁵-O-C(O)-、R¹⁵-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-、R¹⁵-O-C(O)-N(R²)-、R¹⁵-N(R²)-C(O)-O-、R¹⁵-S(O)₂-N(R²)-或R¹⁵-N(R²)-S(O)₂-，则A不是苯基、噻吩基、噻二唑基、噻唑基、嘧啶基、吡嗪基、哒嗪基、吡啶基、三嗪基或四嗪基，其中每个R²独立地选自氢、(C₁-C₅烷基)-、Ar-(C₀-C₄烷基)-、Het-(C₀-C₄烷基)-、Hca-(C₀-C₄烷基)-、Cak-(C₀-C₄烷基)-、R¹⁴-CO-、R¹⁴-SO2-、R¹⁴-CO-NH-和R¹⁴-CO-O-，其中每个烷基均为任选取代的；每个R⁵独立地选自H-、任选取代的(C₁-C₆烃基)-、Ar-(C₁-C₆烃基)-、Het-(C₁-C₆烃基)-、Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-；每个R⁶独立地选自H-；取代的(C₁-C₆烃基)-，条件是如果所述(C₁-C₆烃基)仅具有一个取代基，则该取代基不是卤素或氨基；Hca-(C₀-C₁或C₃-C₆烃基)-；以及Cak-(C₀-C₆烃基)-；每个R⁷独立地选自H、任选取代的(C₁-C₆烃基)-、Hca-(C₀-C₁或C₃-C₆烃基)-和Cak-(C₀-C₆烃基)-；每个R⁸独立地选自任选取代的(C₁-C₆烃基)-、Ar-(C₁-C₆烃基)-、Het-(C₁-C₆烃基)-、Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-，条件是R⁸不能是2-(吗啉-4-基)乙基；每个R⁹独立地选自Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-；每个R¹⁰独立地选自H-、Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-；每个R¹¹独立地选自H-、(C₁-C₆烃基)-、Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-；每个R¹²独立地选自任选取代的(C₁-C₆烃基)-、Ar-(C₁-C₆烃基)-、Het-(C₁-C₆烃基)-、Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-；每个R¹³独立地选自H-、任选取代的(C₁-C₆烃基)-、Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-；每个R¹⁴独立地选自Ar-和任选取代的(C₁-C₆烃基)-；且每个R¹⁵独立地选自H-、任选取代的(C₁-C₆烃基)-、Ar-(C₀-C₆烃基)-、Het-(C₀-C₆烃基)-、Hca-(C₀-C₆烃基)-和Cak-(C₀-C₆烃基)-；其中任一(C₁-C₆烃基)-部分为任选取代的，且每一Ar独立地为任选取代的芳基，每一Het独立地为任选取代的杂芳基，每一Hca独立地为任选取代的杂环烷基，且每一Cak独立地为任选取代的环烷基。