WO2019080882A1 - Hdac抑制剂及其制备方法和用途 - Google Patents

Hdac抑制剂及其制备方法和用途

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Publication number
WO2019080882A1
WO2019080882A1 PCT/CN2018/111743 CN2018111743W WO2019080882A1 WO 2019080882 A1 WO2019080882 A1 WO 2019080882A1 CN 2018111743 W CN2018111743 W CN 2018111743W WO 2019080882 A1 WO2019080882 A1 WO 2019080882A1
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group
membered
formula
compound
hydrogen
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PCT/CN2018/111743
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English (en)
French (fr)
Inventor
李进
吴波
张登友
尚巳耘
楚洪柱
王稚京
吕开智
梁秋香
农云宏
陈伟
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成都先导药物开发有限公司
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Publication of WO2019080882A1 publication Critical patent/WO2019080882A1/zh

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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to HDAC inhibitors and methods for their preparation and use.
  • Tumor refers to the new body of the body that under the action of various tumorigenic factors, the local tissue cells lose their normal regulation at the genetic level, resulting in abnormal clonal proliferation.
  • the epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modification of other components in the chromatin high-level structure. These modifications alter the chromatin configuration, leading to changes in gene transcriptional regulation, and dysregulation of gene transcription. Cell proliferation is abnormal, resulting in tumor production.
  • Histone acetylation plays a central role in the transcriptional regulation of eukaryotic cells. Its role is regulated by a pair of functionally antagonistic protease histone acetyltransferases (HATs) and histone deacetylases (HDACs). In normal cells, this pair of enzymes is in a state of dynamic equilibrium. In general, increased levels of histone acetylation are associated with increased gene transcriptional activity, while too low levels of acetylation are associated with inhibition of gene expression. Studies have found that HDAC is overexpressed and recruited by transcription factors, leading to abnormal inhibition of specific genes, leading to tumors and other diseases; while inhibition of HDAC activity will cause growth inhibition and apoptosis of many cancer cells. Therefore, HDAC has become the latest and most popular target in the field of anti-tumor drug research and development.
  • HDAC inhibitors interfere with the function of histone deacetylases. They can generally be divided into two broad categories: NAD+-dependent enzymes and Zn2+ dependent enzymes. Zn2+-dependent proteases include HDACs I (including HDAC 1, 2, 3, and 8), II (including HDAC 4, 5, 6, 7, 9 and 11), IV (including HDAC 11) subfamilies; NAD+-dependent enzymes Mainly HDACs III subfamily.
  • the mechanism of action of HDAC inhibitors is to inhibit the expression of HDAC, block the gene expression due to HDAC recruitment dysfunction, and change the chromatin structure by changing the degree of acetylation of histones, thereby regulating gene expression to treat cancer.
  • HDAC inhibitors are tumor-specific and have cytotoxic effects on both proliferating and resting variant cells, whereas normal cells are more than 10 times more tolerant and do not cause normal cell growth arrest and apoptosis.
  • HDAC inhibitors There are currently five HDAC inhibitors on the market. SAHA, which was launched in 2006, targets Pan-HDAC; FK-288, which was launched in 2011, targets HDAC1 and HDAC2; PXD101, which was launched in 2014, targets HDAC1 and HDAC2; The target of this amine is HDAC1, HDAC2, HDAC3, HDAC10; LBH589, which was launched in 2015, targets HDAC (MOLT-4cells). These five HDAC inhibitors have certain problems in anticancer activity, toxic side effects, subtype selectivity, etc., and none of the five HDAC inhibitors target HDAC6.
  • the present invention provides a compound represented by the formula (I), or a crystal form thereof, or a hydrate thereof, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • n 0 to 10
  • L 1 represents no C 1 -C 10 alkylene group or C 1 -C 10 alkenyl group
  • Y is N or CR 2 , wherein R 2 is selected from hydrogen, halogen, hydroxy, amino, trifluoromethyl, cyano, C 1 -C 10 alkyl or C 1 -C 10 alkoxy;
  • X is O, S or NR 3 ; wherein R 3 is selected from hydrogen, C 1 -C 10 alkyl or C 1 -C 10 acyl;
  • R 1 is hydrogen, a C 1 -C 10 alkyl group, a C 3 -C 10 cycloalkane or a heterocycloalkane;
  • Ring A represents a 3 to 10 membered cycloalkane, a 3 to 10 membered heterocycloalkane, a 5 to 10 membered aryl group or a 5 to 10 membered heteroaryl group; wherein the A ring may be further substituted by 0 to 5 R 4 , wherein each R 4 is independently selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, —(CH 2 ) q R 5 , —(CH 2 ) q OR 5 , —(CH 2 ) q OCOR 5 , –(CH 2 ) q NR 5 R 6 , –(CH 2 ) q NR 5 COR 6 , –(CH 2 ) q COR 5 , –(CH 2 ) q COOR 5 ,–(CH 2 q CONR 5 R 6 , q is 0 to 10;
  • R 5 and R 6 are each selected from the group consisting of hydrogen, a C 1 - C 10 alkyl group, a 5 to 10 membered cycloalkane, a 5 to 10 membered heterocycloalkane, a 5 to 10 membered aryl group, or a 5 to 10 membered hetero An aryl group, wherein R 5 and R 6 may be further substituted by R 7 ;
  • R 7 is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 1 -C 10 alkylamino, -(CH 2 ) r OR 8 ; 0 to 10;
  • R 8 is selected from the group consisting of hydrogen and a C 1 -C 10 alkyl group.
  • the compound of the formula (I a) has a structure as shown in the formula (I a-1):
  • L 1 represents no, C 1 -C 5 alkylene or Where m is 0 to 3;
  • R 1 represents hydrogen, C 1 -C 5 alkyl
  • R 2 represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, —(CH 2 ) q R 5 , —(CH 2 ) q OR 5 , —(CH 2 ) q NR 5 R 6 , —(CH 2 ) q COR 5 , q is 0 to 5;
  • R 5 and R 6 are each selected from the group consisting of hydrogen, a C 1 - C 5 alkyl group, a 5 to 10 membered cycloalkane, a 5 to 10 membered heterocycloalkane, a 5 to 10 membered aryl group or a 5 to 10 membered hetero An aryl group, wherein R 5 and R 6 may be further substituted by R 7 ;
  • R 7 is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylamino, -(CH 2 ) r OR 8 ; 0 to 5;
  • R 8 is selected from the group consisting of hydrogen, C 1 -C 5 alkyl
  • Ring A represents a phenyl group, a 5-membered aromatic heterocyclic ring, a 6-membered aromatic heterocyclic ring, and a 10-membered aromatic heterocyclic ring.
  • the compound of the formula (I a) has a structure as shown in the formula (I a-2):
  • R 1 represents hydrogen or a halogen
  • ring A represents a phenyl group, a 5-membered aromatic heterocyclic ring, and a 6-membered aromatic heterocyclic ring.
  • the compound of the formula (I a) has a structure as shown in the formula (I a-3):
  • n 0, 1, 2, 3;
  • X represents hydrogen, halogen;
  • R 1 represents hydrogen, a C 1 -C 5 alkyl group, a 6-membered aryl group or a heteroaryl group;
  • R 3 represents hydrogen, C 1 -C 5 alkyl
  • R 2 represents hydrogen, halogen, trifluoromethyl, methoxy, —(CH 2 ) q R 5 , —(CH 2 ) q NR 5 R 6 , —(CH 2 ) q COR 5 , q is 0 to 5 ;
  • R 5 and R 6 are each selected from the group consisting of hydrogen, a C 1 -C 5 alkyl group, a 5- to 6-membered cycloalkane, a 5- to 6-membered heterocycloalkane, a 5- to 6-membered aromatic heterocyclic ring, and a phenyl group;
  • Ring A represents a phenyl group, a cyclohexane, a 5- to 6-membered heterocycloalkane, a 5- to 6-membered aromatic heterocyclic ring or a 10-membered aromatic heterocyclic ring.
  • the compound of the formula (I a) has a structure as shown in the formula (I a-4):
  • X represents O, S, and N; and ring A represents a phenyl group, a 5- to 6-membered aromatic heterocyclic ring, or a 10-membered aromatic heterocyclic ring.
  • L 1 represents no, C 1 -C 5 alkylene or Where m is 0 to 3;
  • R 1 represents hydrogen, C 1 -C 5 alkyl
  • R 2 represents hydrogen, halogen, trifluoromethyl, trifluoromethoxy, —(CH 2 ) q R 5 , —(CH 2 ) q OR 5 , —(CH 2 ) q NR 5 R 6 , —(CH 2 ) q COR 5 , q is 0 to 5;
  • R 5 and R 6 are each selected from the group consisting of hydrogen, a C 1 -C 5 alkyl group, a 5 to 10 membered cycloalkane 5 to 10 membered heterocycloalkane, a 5 to 10 membered aryl group or a 5 to 10 membered heteroaryl group. a base; wherein R 5 and R 6 may be further substituted by R 7 ;
  • R 7 is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylamino, -(CH 2 ) r OR 8 ; 0 to 5;
  • R 8 is selected from the group consisting of hydrogen, C 1 -C 5 alkyl
  • Ring A represents a phenyl group, a 5- to 6-membered aromatic heterocyclic ring or a 10-membered aromatic heterocyclic ring.
  • R 1 represents hydrogen or a halogen
  • ring A represents a phenyl group, a 5-membered aromatic heterocyclic ring, and a 6-membered aromatic heterocyclic ring.
  • n 0, 1, 2, 3;
  • X represents hydrogen, halogen;
  • R 1 represents hydrogen, a C 1 -C 5 alkyl group, a 6-membered aryl group or a heteroaryl group;
  • R 3 represents hydrogen, C 1 -C 5 alkyl
  • R 2 represents hydrogen, halogen, trifluoromethyl, methoxy, —(CH 2 ) q R 5 , —(CH 2 ) q NR 5 R 6 , —(CH 2 ) q COR 5 , q is 0 to 5 ;
  • R 5 and R 6 are each selected from the group consisting of hydrogen, a C 1 -C 5 alkyl group, a 5- to 6-membered cycloalkane, a 5- to 6-membered heterocycloalkane, a 5- to 6-membered aromatic heterocyclic ring, and a phenyl group;
  • Ring A represents a phenyl group, a cyclohexane, a 5- to 6-membered heterocycloalkane, a 5- to 6-membered aromatic heterocyclic ring or a 10-membered aromatic heterocyclic ring.
  • X represents O, S, and N; and ring A represents a phenyl group, a 5- to 6-membered aromatic heterocyclic ring, or a 10-membered aromatic heterocyclic ring.
  • the present invention also provides the use of the aforementioned compound, or a crystal form thereof, or a hydrate thereof, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the HDAC inhibitor .
  • the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease or a viral disease.
  • the cell proliferation disease is cancer.
  • the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, thyroid cancer.
  • the HDAC is HDAC6.
  • the present invention also provides a pharmaceutical composition which is a compound according to any one of claims 1 to 12, or a crystalline form thereof, or a hydrate thereof, or an optical isomer thereof, or a solvate thereof, Or a pharmaceutically acceptable salt thereof is a preparation prepared by adding an active ingredient together with a pharmaceutically acceptable adjuvant.
  • the preparation is an oral preparation, a transdermal absorption preparation or an injection preparation.
  • the present invention also provides the use of the aforementioned pharmaceutical composition for the preparation of a medicament for the HDAC inhibitor.
  • the medicament is a medicament for treating a cell proliferative disease, an autoimmune disease, an inflammation, a neurodegenerative disease or a viral disease.
  • the cell proliferation disease is cancer.
  • the cancer includes colon cancer, lung cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, thyroid cancer.
  • the HDAC is HDAC6.
  • n is 0, 1 , 2, or 3
  • L 1 is a C 1 -C 3 alkylene group or Y is N or CR 2
  • R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, trifluoromethyl, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy
  • X is O, S or NR 3
  • R 3 is selected from hydrogen, C 1 -C 3 alkyl or C 1 -C 3 acyl
  • R 1 is hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkane Or a 3 to 6 membered heterocycloalkane
  • ring A is a 3 to 10 membered cycloalkane, a 3 to 10 membered heterocycloalkane, a 5 to 10 membered aryl group or a 5 to 10 membered heteroaryl group, wherein the ring A is may be further substitute
  • amino, C 1 ⁇ C 3 alkyl group, C 1 ⁇ C 3 is Group, C 1 ⁇ C 3 alkylamino of, - (CH 2) r OR 8, r is 0 or 3, R 8 is selected from hydrogen, C 1 ⁇ C 10 alkyl group is.
  • n is 0 and L 1 is none or Y is N or CR 2 , R 2 is selected from hydrogen, halogen, trifluoromethyl, cyano, methyl, ethyl or methoxy, X is O, S or NR 3 , and R 3 is selected from hydrogen, methyl , ethyl, formyl or acetyl, R 1 is hydrogen, methyl, ethyl, ring A is a 5-6 membered cycloalkane, a 5 to 6 membered heterocycloalkane, a 5 to 6 membered aryl group, 9 a ⁇ 10-membered aryl group, a 5- to 6-membered heteroaryl group, and a 9- to 10-membered heteroaryl group, wherein the A ring may be further substituted by 1 to 3 R 4 , wherein each R 4 is independently selected from halogen, Cyano, trifluoromethyl, triflu
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L 1 represents no or R 1 is hydrogen, methyl, ethyl
  • ring A is phenyl, 5-membered nitrogen-containing aromatic heterocyclic ring, 6-membered nitrogen-containing aromatic heterocyclic ring, 10 membered nitrogen-containing aromatic heterocyclic ring
  • R 2 is hydrogen, halogen, trifluoro Methyl, trifluoromethoxy, -(CH 2 ) q R 5 , -(CH 2 ) q OR 5 , -(CH 2 ) q NR 5 R 6 , –(CH 2 ) q COR 5 , q is 0 1, 2 or 3
  • R 5 and R 6 are each selected from the group consisting of hydrogen, a C 1 - C 3 alkyl group, a 5 to 6 membered cycloalkane, a 5 to 6 membered heterocycloalkane, and a 5 to 6 membered aryl group.
  • R 5 and R 6 may be further substituted by R 7 , and R 7 is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy a C 1 -C 3 alkylamino group, -(CH 2 ) r OR 8 , wherein r is 0, 1, 2 or 3, and R 8 is selected from hydrogen, C 1 -C 3 alkyl;
  • L 1 represents no or R 1 is hydrogen, methyl, ethyl
  • ring A is phenyl, 5-membered nitrogen-containing aromatic heterocyclic ring, 6-membered nitrogen-containing aromatic heterocyclic ring, 10 membered nitrogen-containing aromatic heterocyclic ring
  • R 2 is hydrogen, halogen, trifluoro Methyl, trifluoromethoxy, -(CH 2 ) q R 5 , -(CH 2 ) q OR 5 , -(CH 2 ) q NR 5 R 6 , –(CH 2 ) q COR 5 , q is 0 1, 2 or 3
  • R 5 and R 6 are each selected from the group consisting of hydrogen, a C 1 - C 3 alkyl group, a 5 to 6 membered cycloalkane, a 5 to 6 membered heterocycloalkane, and a 5 to 6 membered aryl group.
  • R 5 and R 6 may be further substituted by R 7 , and R 7 is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy a C 1 -C 3 alkylamino group, -(CH 2 ) r OR 8 , wherein r is 0, 1, 2 or 3, and R 8 is selected from hydrogen, C 1 -C 3 alkyl;
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix C a to C b alkyl group indicates any alkyl group having "a" to "b" carbon atoms, including a linear alkyl group. And branched alkyl groups.
  • C 1 -C 4 alkyl means a straight-chain alkyl group and a branched alkyl group having 1 to 4 carbon atoms.
  • C a to C b alkoxy, C a to C b alkylamino, C a to C b acyl and the like respectively mean an alkyl group having "a" to "b" carbon atoms and a corresponding oxygen.
  • halogen means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • cycloalkyl or “cycloalkane” refers to a saturated ring or a non-aromatic unsaturated ring formed by all carbon atoms.
  • heterocyclic ring in the present invention means a saturated ring or a non-aromatic unsaturated ring containing at least one hetero atom; wherein the hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom.
  • aryl or "aromatic ring” means an aromatic unsaturated ring formed by an all carbon atom.
  • aromatic or aromatic heterocyclic ring in the present invention means an aromatic unsaturated ring containing at least one hetero atom; wherein the hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom.
  • alkylene means a hydrocarbon group respectively bonded to two atoms
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salt means the above compound or a stereoisomer thereof, an acid form and/or a base salt formed with an inorganic and/or organic acid and a base, and also a zwitterionic salt (internal salt), and also a quaternary ammonium salt.
  • an alkyl ammonium salt can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • the invention includes isotopically labeled compounds, which are the same as the compounds listed herein, but wherein one or more of the atoms are replaced by another atom, the atomic
  • the atomic mass or mass number is different from the atomic mass or mass number that is common in nature.
  • Isotopes which may be introduced into the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., 2H, 3H, 13C, 14C, 15N, 17O, 18O, 35S.
  • one or more compounds of the invention may be used in combination with one another.
  • the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition that modulates cellular function or treats a disease. If a group of compounds is used, the compounds can be administered to the subject simultaneously, separately or sequentially.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • the compound of the present invention has the functions of inducing differentiation, immunoregulation, blocking cell cycle, promoting apoptosis, and good HDAC6 subtype selectivity, and aims to have better curative effect on various cancers while overcoming the current Side effects of HDAC inhibitors such as anemia, ischemic stroke, deep vein thrombosis, thrombocytopenia, and vomiting.
  • the compounds of the present invention have HDAC inhibitory activity and can be used to treat diseases associated with abnormal HDAC activity.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • the structure of the compounds of the invention is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • the LC-MS was measured by Shimadzu LC-MS 2020 (ESI).
  • the HPLC was measured using Shimadzu High Pressure Liquid Chromatograph (Shimadzu LC-20A).
  • Reverse phase preparative chromatography was performed using a Gilson GX-281 reverse phase preparative chromatograph.
  • the thin layer chromatography silica gel plate is separated from the Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate by thin layer chromatography, and the specification is 0.4mm to 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as Anike Chemical, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • M is a mole per liter.
  • Room temperature is the most suitable reaction temperature, and is usually from 20 ° C to 30 ° C.
  • the overnight stay is usually 12 ⁇ 1 hour.
  • the intermediate 6a1 (500 mg, 1.51 mmol) was dissolved in methanol (4.00 mL) and water (4.00mL), and sodium hydroxide (181 mg, 4.53 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The aqueous layer was washed twice with ethyl acetate and then filtered with 1N hydrochloric acid. Several layers were combined, and the solvent was evaporated under reduced pressure to give crude compound (yield: 500 mg).
  • the intermediate 61a (500 mg, 1.58 mmol) was dissolved in chloroform (10.0 mL), oxalyl chloride (401 mg, 3.16 mmol) was added at 0 ° C, and the reaction was stirred at room temperature for 3.5 hours. After evaporating the solvent under reduced pressure, dichloromethane was evaporated. A solution of trimethylsilylated diazomethane cyclohexane (1.60 mL, 3.20 mmol, 2.0 M) was added at 0 ° C and the reaction was stirred for 2 hr. After completion of the reaction, the solvent was evaporated under reduced pressure.
  • the intermediate 61b (160 mg, 463 ⁇ mol) was dissolved in dichloromethane (3.00 mL) and methanol (3.00 mL), and aqueous aqueous hydroxylamine (306 mg, 9.27 mmol) and sodium hydroxide (55.6 mg, 1.39 mmol) were added and stirred at room temperature 3 hour. After evaporating the solvent under reduced pressure, it was purified by MPLC to give the product (30.0 mg, 83.2 ⁇ mol, yield 18%).
  • Example 62 The compound of Example 62 (173 mg, 483 ⁇ mol) was dissolved in methanol (10.0 mL), and palladium carbon (49.8 mg, 410 ⁇ mol) was added, and the reaction was stirred at room temperature under hydrogen for 2 hours. After evaporating the solvent under reduced pressure, it was purified by column chromatography to give the product (120 mg, 333 ⁇ mol, yield 69%).
  • the starting materials in the following tables are the starting materials, and the intermediates 11a2 to 11a7 are obtained according to the synthesis method of the intermediate 11a1.
  • the compounds 65 to 70 in the following table were obtained according to the synthesis method of the compound 64.
  • Methyl 2,2,2-trichloroacetimidate (6.60 g, 37.4 mmol) was added to acetic acid (50.0 mL), and 4-bromobenzene-1,2-diamine (7.00) was slowly added dropwise at 0 °C.
  • a solution of g, 37.4 mmol) in acetic acid (50.0 mL) was then stirred at room temperature overnight. After completion of the reaction, water was added, and the mixture was extracted twice with ethyl acetate. The organic layer was combined and washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (100 mL).
  • HDAC inhibitory activity of the compounds of the invention was tested by homogeneous time resolved fluorescence (HTRF).
  • HTRF homogeneous time resolved fluorescence
  • Example Activity (HDAC1) Activity (HDAC6) Example Activity (HDAC1) Activity (HDAC6) 1 +++ +++ 2 + +++ 3 +++ +++ 4 ++ +++ 5 +++ +++ 6 ++ +++ 7 ++ +++ 8 + + 9 + ++ 10 ++ +++ 11 + + 12 +++ +++ 13 +++ +++ 14 +++ +++ 15 +++ +++ 16 +++ +++ 17 +++ +++ 18 + + 19 ++ +++ 20 +++ +++ twenty one +++ +++ twenty two ++ +++ twenty three +++ +++ twenty four + + + 25 +++ +++ 26 +++ +++ 27 +++ +++ 28 ++ +++ 29 +++ +++ 30 + +++ 31 +++ +++ 32 + +++++
  • test results show that the compound of the present invention has good deacetylase inhibitory activity and can be effectively used for the treatment of diseases with abnormal histone deacetylase activity.
  • the membrane was placed in a primary antibody diluted in antibody dilution (5% skim milk) and allowed to stand overnight at 4 °C.
  • the TBST solution was washed three times at room temperature for 10 minutes each time.
  • the near-infrared labeled secondary antibody was added and gently shaken on a shaker at room temperature for 1 hour.
  • the fluorescence signal values were acquired on an Odyssey CLx near-infrared two-color fluorescence imaging system.
  • the inhibition of the compound was determined from the obtained data and plotted against the compound concentration to obtain a concentration response curve, and the EC 50 value was fitted according to a four-parameter model.
  • test results show that the compound of the present invention has a good inhibitory activity against HCT-116 cells.
  • novel compound of the formula I disclosed in the present invention exhibits good deacetylase inhibitory activity, and provides a novel treatment for diseases associated with abnormal histone deacetylase activity in clinical treatment. Medicinal may have good application prospects.

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Abstract

一种式(I)所示的化合物，含有式(I)化合物的药物组合物，以及该化合物和药物组合物在制备HDAC抑制剂类药物中的用途。化合物或其药物组合物可以用于制备治疗细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病的药物。

Description

HDAC抑制剂及其制备方法和用途 技术领域
本发明涉及HDAC抑制剂及其制备方法和用途。
背景技术
肿瘤是指机体在各种致瘤因子作用下，局部组织的细胞在基因水平上失去对其生长的正常调控，导致克隆性异常增生而形成的新生物。引起基因失活的外遗传机制主要包括DNA甲基化，组蛋白乙酰化和染色质高级结构中其他成分的修饰，这些修饰改变染色质构型，导致基因转录调节发生变化，基因转录的失调引起细胞增殖失常，从而导致肿瘤产生。
组蛋白乙酰化对于真核细胞的转录调控起核心作用。其作用受一对功能相互拮抗的蛋白酶组蛋白乙酰化转移酶(HATs)和组蛋白去乙酰化酶(HDACs)调控。在正常细胞中，这一对酶处于动态平衡状态。一般情况下，组蛋白乙酰化水平增强与基因转录活性增强有关，而乙酰化水平过低与基因表达抑制有关。研究发现，HDAC过度表达并被转录因子募集，导致特定基因的不正常抑制，从而导致肿瘤和其他疾病；而抑制HDAC的活性将引起许多癌细胞的生长抑制和凋亡。因此，HDAC已成为目前抗肿瘤药物研发领域最新和最热门的靶标。
HDAC抑制剂有干扰与组蛋白去乙酰化酶的功能。通常可分为两大类：NAD+-依赖性酶和Zn2+依赖性酶。Zn2+依赖性蛋白酶包括HDACs I(包括HDAC 1、2、3和8)、II(包括HDAC 4、5、6、7、9和11)、IV(包括HDAC 11)亚族；NAD+-依赖性酶主要是HDACs III亚族。HDAC抑制剂作用机制是通过抑制HDAC，阻断由于HDAC募集功能紊乱而导致的基因表达受抑，通过改变组蛋白的乙酰化程度来改变染色质结构，从而调控基因表达治疗癌症。它通过诱导肿瘤细胞的生长停滞、分化或凋亡对治疗血液系统肿瘤和实体瘤疗效显著。HDAC抑制剂具有肿瘤特异性，对增殖和静止的变异细胞均有细胞毒作用，而正常细胞对它有10倍以上的耐受，不会引起正常细胞的生长停滞和凋亡。
目前已经有五种HDAC抑制剂上市。2006年上市的SAHA，作用靶点为Pan-HDAC；2011年上市的FK-288，作用靶点为HDAC1、HDAC2；2014年上市的PXD101，作用靶点为HDAC1、HDAC2；2015年上市的西达本胺，作用的靶点为HDAC1、HDAC2、HDAC3、 HDAC10；2015年上市的LBH589，作用的靶点为HDAC(MOLT-4cells)。这五种HDAC抑制剂在抗癌活性、毒副作用、亚型选择性等方面存在一定的问题，且这五种HDAC抑制剂作用的靶点均无HDAC6。
因此，现在急需一种具有组蛋白去乙酰化酶抑制活性的新化合物。
发明内容
为了解决上述问题，本发明提供了式(I)所示的化合物、或其晶型、或其水合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐：
Figure PCTCN2018111743-appb-000001
其中，n为0～10；
L 1表示无或C 1～C 10的亚烷基或C 1～C 10的烯基；
Y为N或CR 2，其中R 2选自氢、卤素、羟基、氨基、三氟甲基、氰基、C 1～C 10的烷基或C 1～C 10的烷氧基；
X为O、S或NR 3；其中R 3选自氢、C 1～C 10的烷基或C 1～C 10的酰基；
R 1为氢、C 1～C 10的烷基、C 3～C 10的环烷烃或杂环烷烃；
环A表示3～10元的环烷烃、3～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基；其中A环可进一步被0～5个R 4取代，其中每个R 4分别独自选自卤素、氰基、硝基、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qOCOR 5、–(CH 2) qNR 5R 6、–(CH 2) qNR 5COR 6、–(CH 2) qCOR 5、–(CH 2) qCOOR 5、–(CH 2) qCONR 5R 6，q为0～10；
R 5、R 6分别选自氢、C 1～C 10的烷基、5～10元的环烷烃、5～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基，其中R 5、R 6可进一步被R 7取代；
R 7选自卤素、羟基、氨基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基、–(CH 2) rOR 8；其中r为0～10；。
R 8选自氢、C 1～C 10的烷基。
进一步地，所述化合物具有如式(Ⅰ a)或式(Ⅰ b)所示的结构：
Figure PCTCN2018111743-appb-000002
Figure PCTCN2018111743-appb-000003
进一步地，所述式(Ⅰ a)化合物具有如式(Ⅰ a-1)所示的结构：
Figure PCTCN2018111743-appb-000004
其中，L 1表示无、C 1～C 5的亚烷基或
Figure PCTCN2018111743-appb-000005
其中m为0～3；
R 1表示氢、C 1～C 5的烷基；
R 2表示氢、卤素、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0～5；
R 5、R 6分别选自氢、C 1～C 5的烷基、5～10元的环烷烃、5～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基；，其中R 5、R 6可进一步被R 7取代；
R 7选自卤素、羟基、氨基、C 1～C 5的烷基、C 1～C 5的烷氧基、C 1～C 5的烷氨基、–(CH 2) rOR 8；其中r为0～5；。
R 8选自氢、C 1～C 5的烷基；
环A表示苯基、5元芳杂环、6元芳杂环、10元芳杂环。
进一步地，所述式(Ⅰ a)化合物具有如式(Ⅰ a-2)所示的结构：
Figure PCTCN2018111743-appb-000006
其中，R 1表示氢、卤素；环A表示苯基、5元芳杂环、6元芳杂环。
进一步地，所述式(Ⅰ a)化合物具有如式(Ⅰ a-3)所示的结构：
Figure PCTCN2018111743-appb-000007
其中，n＝0、1、2、3；X表示氢、卤素；
R 1表示氢、C 1～C 5的烷基、6元的芳基或者杂芳基；
R 3表示氢、C 1～C 5的烷基；
R 2表示氢、卤素、三氟甲基、甲氧基、–(CH 2) qR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0～5；
R 5、R 6分别选自氢、C 1～C 5的烷基、5～6元环烷烃、5～6元杂环烷烃、5～6元芳杂环、苯基；
环A表示苯基、环己烷、5～6元杂环烷烃、5～6元芳杂环或者10元芳杂环。
进一步地，所述式(Ⅰ a)化合物具有如式(Ⅰ a-4)所示的结构：
Figure PCTCN2018111743-appb-000008
其中，X表示O、S、N；环A表示苯基、5～6元芳杂环或者10元芳杂环。
进一步地，所述式(Ⅰ a)为如下化合物之一：
Figure PCTCN2018111743-appb-000009
Figure PCTCN2018111743-appb-000010
Figure PCTCN2018111743-appb-000011
进一步地，所述式(Ⅰ b)化合物具有如式(Ⅰ b-1)所示的结构：
Figure PCTCN2018111743-appb-000012
其中，L 1表示无、C 1～C 5的亚烷基或
Figure PCTCN2018111743-appb-000013
其中m为0～3；
R 1表示氢、C 1～C 5的烷基；
R 2表示氢、卤素、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0～5；
R 5、R 6分别选自氢、C 1～C 5的烷基、5～10元的环烷烃5～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基；其中R 5、R 6可进一步被R 7取代；
R 7选自卤素、羟基、氨基、C 1～C 5的烷基、C 1～C 5的烷氧基、C 1～C 5的烷氨基、–(CH 2) rOR 8；其中r为0～5；
R 8选自氢、C 1～C 5的烷基；
环A表示苯基、5～6元芳杂环或10元芳杂环。
进一步地，所述式(Ⅰ b)化合物具有如式(Ⅰ b-2)所示的结构：
Figure PCTCN2018111743-appb-000014
其中，R 1表示氢、卤素；环A表示苯基、5元芳杂环、6元芳杂环。
进一步地，所述式(Ⅰ b)化合物具有如式(Ⅰ b-3)所示的结构：
Figure PCTCN2018111743-appb-000015
其中，n＝0、1、2、3；X表示氢、卤素；
R 1表示氢、C 1～C 5的烷基、6元的芳基或者杂芳基；
R 3表示氢、C 1～C 5的烷基；
R 2表示氢、卤素、三氟甲基、甲氧基、–(CH 2) qR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0～5；
R 5、R 6分别选自氢、C 1～C 5的烷基、5～6元环烷烃、5～6元杂环烷烃、5～6元芳杂环、苯基；
环A表示苯基、环己烷、5～6元杂环烷烃、5～6元芳杂环或者10元芳杂环。
进一步地，所述式(Ⅰ b)化合物具有如式(Ⅰ b-4)所示的结构：
Figure PCTCN2018111743-appb-000016
其中，X表示O、S、N；环A表示苯基、5～6元芳杂环或者10元芳杂环。
进一步地，所述式(Ⅰ b)为如下化合物之一：
Figure PCTCN2018111743-appb-000017
Figure PCTCN2018111743-appb-000018
本发明还提供了前述的化合物、或其晶型、或其水合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐在制备HDAC抑制剂类药物中的用途。
进一步地，所述药物是治疗细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病的药物。
进一步地，所述细胞增殖疾病为癌症。
进一步地，所述癌症包括结肠癌、肺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、甲状腺癌。
进一步地，所述HDAC为HDAC6。
本发明还提供了一种药物组合物，它是以权利要求1-12任一项所述的化合物、或其晶型、或其水合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
进一步地，所述制剂为口服制剂、透皮吸收制剂或注射制剂。
本发明还提供了前述的药物组合物在制备HDAC抑制剂类药物中的用途。
进一步地，所述药物是治疗细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病的药物。
进一步地，所述细胞增殖疾病为癌症。
进一步地，所述癌症包括结肠癌、肺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、甲状腺癌。
进一步地，所述HDAC为HDAC6。
在一些实施方案中，式(I)所示的化合物中，n为0、1、2或3，L 1为无、C 1～C 3的亚烷基或
Figure PCTCN2018111743-appb-000019
Y为N或CR 2，R 2选自氢、卤素、羟基、氨基、三氟甲基、氰基、C 1～C 3的烷基或C 1～C 3的烷氧基，X为O、S或NR 3，R 3选自氢、C 1～C 3的烷基或C 1～C 3的酰基，R 1为氢、C 1～C 3的烷基、C 3～C 6的环烷烃或3～6元的杂环烷烃，环A为3～10元的环烷烃、3～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基，其中A环可进一步被1～3个R 4取代，其中每个R 4分别独自选自卤素、氰基、硝基、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qOCOR 5、–(CH 2) qNR 5R 6、–(CH 2) qNR 5COR 6、–(CH 2) qCOR 5、–(CH 2) qCOOR 5、–(CH 2) qCONR 5R 6，q为0、1、2或3，R 5、R 6分别选自氢、C 1～C 3的烷基、5～6元的环烷烃、5～6元的杂环烷烃、5～6元的芳基或5～6元的杂芳基，其中R 5、R 6可进一步被R 7取代，R 7选自卤素、羟基、氨基、C 1～C 3的烷基、C 1～C 3的烷氧基、C 1～C 3的烷氨基、–(CH 2) rOR 8，r为0、1、2或3，R 8选自氢、C 1～C 10的烷基。
在一些实施方案中，式(I)所示的化合物中，n为0，L 1为无或
Figure PCTCN2018111743-appb-000020
Y为N或CR 2，R 2选自氢、卤素、三氟甲基、氰基、甲基、乙基或甲氧基，X为O、S或NR 3，R 3选自氢、甲基、乙基、甲酰基或乙酰基，R 1为氢、甲基、乙基，环A为5-6元的环烷烃、5～6元的杂环烷烃、5～6元的芳基、9～10元的芳基、5～6元的杂芳基、9～10元的杂芳基，其中A环可进一步被1～3个R 4取代，其中每个R 4分别独自选自卤素、氰基、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5、–(CH 2) qCOOR 5、–(CH 2) qCONR 5R 6，q为0、1、2或3，R 5、R 6分别选自氢、C 1～C 3的烷基、5～6元的环烷烃、5～6元的杂环烷烃、5～6元的芳基或5～6元的杂芳基，其中R 5、R 6可进一步被R 7取代，R 7选自卤素、羟基、氨基、C 1～C 3的烷基、C 1～C 3的烷氧基、C 1～C 3的烷氨基、–(CH 2) rOR 8，r为0、1、2或3，R 8选自氢、C 1～C 10的烷基。
在一些实施方案中，式(I)所示的化合物中，A环为
Figure PCTCN2018111743-appb-000021
Figure PCTCN2018111743-appb-000022
Figure PCTCN2018111743-appb-000023
在一些实施方案中，式(Ⅰ a-1)所示的化合物中，L 1表示无或
Figure PCTCN2018111743-appb-000024
R 1为氢、甲基、乙基，环A为苯基、5元含氮芳杂环、6元含氮芳杂环、10元含氮芳杂环，R 2为氢、卤素、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0、1、2或3，R 5、R 6分别选自氢、C 1～C 3的烷基、5～6元的环烷烃、5～6元的杂环烷烃、5～6元的芳基或5～6元的杂芳基，其中R 5、R 6可进一步被R 7取代，R 7选自卤素、羟基、氨基、C 1～C 3的烷基、C 1～C 3的烷氧基、C 1～C 3的烷氨基、–(CH 2) rOR 8，其中r为0、1、2或3，R 8选自氢、C 1～C 3的烷基；
在一些实施方案中，式(Ⅰ b-1)所示的化合物中，L 1表示无或
Figure PCTCN2018111743-appb-000025
R 1为氢、甲基、乙基，环A为苯基、5元含氮芳杂环、6元含氮芳杂环、10元含氮芳杂环，R 2为氢、卤素、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0、1、2或3，R 5、R 6分别选自氢、C 1～C 3的烷基、5～6元的环烷烃、5～6元的杂环烷烃、5～6元的芳基或5～6元的杂芳基，其中R 5、R 6可进一步被R 7取代，R 7选自卤素、羟基、氨基、C 1～C 3的烷基、C 1～C 3的烷氧基、C 1～C 3的烷氨基、–(CH 2) rOR 8，其中r为0、1、2或3，R 8选自氢、C 1～C 3的烷基；
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀C a～C b烷基表明任何含“a”至“b”个碳原子的烷基，包括直链烷基和支链烷基。因此，例如，C 1～C 4烷基是指包含1～4个碳原子的直链烷基和支链烷基。
本发明中，C a～C b烷氧基、C a～C b烷胺基、C a～C b酰基等分别是指含“a”至“b”个碳原子的烷基与对应的氧原子、氨基、酰基等相连形成的基团。
本发明中，卤素指氟原子、氯原子、溴原子、碘原子。
本发明中“环烷基”、“环烷烃”指全碳原子形成的饱和环或非芳香性的不饱和环。
本发明中的“杂环”、杂环烷烃”、杂环烷基”指包含至少一个杂原子的饱和环或非芳香性的不饱和环；其中杂原子指氮原子、氧原子、硫原子。
本发明中“芳基”、“芳环”指全碳原子形成的具有芳香性的不饱和环。
本发明中的“芳杂基”、芳杂环”指包含至少一个杂原子的具有芳香性的不饱和环；其中杂原子指氮原子、氧原子、硫原子。
本发明中“亚烷基”指分别与两个原子相连的碳氢基团；
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明的某些实施方式中，本发明包括了同位素标记的化合物，所述同位素标记化合物是指与本文中所列化合物相同，但是其中的一个或多个原子被另一个原子取代，该原子的原子质量或质量数不同于自然界中常见的原子质量或质量数。可以引入式(I)化合物中的同位素包括氢、碳、氮、氧、硫，即2H,3H、13C、14C、15N、17O、18O、35S。含有上述同位素和/或其它原子同位素的式(I)的化合物及其立体异构体，以及该化合物、立体异构体的可药用的盐均应包含在本发明范围之内。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
本发明所述的化合物，具有诱导分化、免疫调节、阻碍细胞周期、促进细胞凋亡的活性以及很好的HDAC6亚型选择性，旨在对各种癌症具有更好的疗效，同时克服目前的HDAC抑制剂的毒副作用，如贫血、缺血性中风、深部静脉血栓形成、血小板减少和呕吐等。
本发明所述的化合物具有HDAC抑制活性，可以用于治疗与HDAC活性异常相关的疾病。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
本发明化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3),氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
LC-MS的测定用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。
HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。
反相制备色谱使用Gilson GX-281反相制备色谱仪。
薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明，反应在氮气氛围下进行。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温。
实施例中无特殊说明，M是摩尔每升。
室温为最适宜的反应温度，通常为20℃～30℃。
过夜通常为12±1小时。
实施例1本发明中化合物的合成
通用合成路线1
Figure PCTCN2018111743-appb-000026
(1.1)中间体3a的合成：
Figure PCTCN2018111743-appb-000027
将4–溴–2–氟苯甲醛(100g,493mmol)和2–羟基乙酸甲酯(102g,1.13mol)溶于DMF(1.0L)中，在0℃下加入钠氢(59.2g,1.48mol,60％)，搅拌反应1小时后加入冰水(2.0L)，乙酸乙酯(1.0L)萃取4次，合并有机层并用饱和氯化钠溶液洗1次。减压蒸除溶剂，经柱层析纯化得中间体3a(22.0g,86.3mmol,产率18％)。
(1.2)中间体3b的合成：
以5–溴–2–氟苯甲醛和2–羟基乙酸甲酯为原料，按照中间体3a的合成方法，得到中间体3b(产率42％)。
(1.3)中间体3c的合成：
以4–溴–2–氟苯甲醛和2–巯基乙酸甲酯为原料，按照中间体3a的合成方法，得到中间体3c(产率94％)。
(1.4)中间体3d的合成：
以5–溴–2–氟苯甲醛和2–巯基乙酸甲酯为原料，按照中间体3a的合成方法，得到中间体3d(产率87％)。
(2.1)中间体4a的合成：
Figure PCTCN2018111743-appb-000028
将中间体3a(38.20g,151mmol)溶于甲苯(300mL)中，加入苄硫醇(24.50g,197.00mmol)、DIPEA(39.50g,306.00mmol,53.2mL)、4,5–双(二苯基膦)–9,9–二甲基氧杂蒽(8.90 g,15.40mmol)和三(二亚苄基丙酮)二钯(6.89g,7.53mmol)，回流反应过夜。反应后加入水(500mL)，乙酸乙酯(300mL)萃取2次，合并有机层后减压蒸除溶剂。经柱层析纯化后得中间体4a(27.00g,86.4mmol,产率57％)。
(2.2)中间体4b的合成：
以中间体3b为原料，按照中间体4a的合成方法，得到中间体4b(产率91％)。
(2.3)中间体4c的合成：
以中间体3c为原料，按照中间体4a的合成方法，得到中间体4c(产率89％)。
(2.4)中间体4d的合成：
以中间体3d为原料，按照中间体4a的合成方法，得到中间体4d(产率76％)。
(3.1)中间体6a1的合成：
Figure PCTCN2018111743-appb-000029
将中间体4a(600mg,2.01mmol)溶于乙酸(15.0mL)和水(5.00mL)中，分批加入N–氯代丁二酰亚胺(1.07g,8.00mmol)。搅拌反应2小时后加入水(20.0mL)。乙酸乙酯(30.0mL)萃取2次，合并有机层后用无水硫酸钠干燥。减压蒸除溶剂后，将残留物溶于二氯甲烷(10.0mL)。加入吡啶(470mg,6.00mmol)后室温搅拌反应4小时。减压蒸除溶剂，经柱层析纯化得中间体6a1(410mg,1.25mmol,产率62％)。
(3.2)中间体6a2～6a60的合成：
按照中间体6a1的合成方法，得到中间体6a2～6a60。
Figure PCTCN2018111743-appb-000030
Figure PCTCN2018111743-appb-000031
Figure PCTCN2018111743-appb-000032
Figure PCTCN2018111743-appb-000033
Figure PCTCN2018111743-appb-000034
Figure PCTCN2018111743-appb-000035
Figure PCTCN2018111743-appb-000036
1、化合物1的合成
Figure PCTCN2018111743-appb-000037
将中间体6a1(3.70g,11.20mmol)溶于二氯甲烷(15.0mL)和甲醇(15.0mL)中，加入羟胺水溶液(22.2mL,336.00mmol,50％)和氢氧化钠(1.34g,33.5mmol)后室温搅拌反应2小时。减压蒸除溶剂后经制备HPLC纯化得终产品(3.20g,9.15mmol,产率82％)。 1H NMR(400MHz,DMSO-d6)δ10.94(brs,2H),9.46(s,1H),8.00–7.96(m,1H),7.93(d,J＝8.4Hz,1H),7.71(dd,J＝8.4,1.6Hz,1H),7.58–7.53(m,1H),7.26–7.19(m,2H),7.15–7.09(m,2H),7.05–6.99(m,1H)；MS(ESI)m/z 333(M+1) +。
2、化合物2～60的合成
以中间体6a2～6a60为原料，按照化合物1的合成方法，得到下表中实施例2～60。
Figure PCTCN2018111743-appb-000038
Figure PCTCN2018111743-appb-000039
Figure PCTCN2018111743-appb-000040
Figure PCTCN2018111743-appb-000041
Figure PCTCN2018111743-appb-000042
Figure PCTCN2018111743-appb-000043
Figure PCTCN2018111743-appb-000044
3、化合物61的合成
(3.1)中间体61a的合成
Figure PCTCN2018111743-appb-000045
将中间体6a1(500mg,1.51mmol)溶于甲醇(4.00mL)和水(4.00mL)中，加入氢氧化钠(181mg,4.53mmol)后室温搅拌反应3小时。水层用乙酸乙酯洗2次后用1N盐酸调节 pH＝2，然后再用乙酸乙酯萃取2次。合并有几层并减压蒸除溶剂后得中间体61a粗品(500mg)。
(3.2)中间体61b的合成
Figure PCTCN2018111743-appb-000046
将中间体61a(500mg,1.58mmol)溶于氯仿(10.0mL)中，在0℃下加入草酰氯(401mg,3.16mmol)，室温搅拌反应3.5小时。减压蒸除溶剂后，残留物溶于四氢呋喃(4.92mL)和乙腈(5.0ml)。在0℃下加入三甲基硅烷化重氮甲烷环己烷溶液(1.60mL,3.20mmol,2.0M)并搅拌反应2小时。反应完成后减压蒸除溶剂，残留物溶于二氧六环(5.37mL)和水(5.37mL)中，加入碳酸银(158mg,948μmol)后于60℃下搅拌反应2小时。反应完成后冷却，用乙酸乙酯萃取2次，合并有机层后饱和氯化钠溶液洗，再加入无水硫酸镁干燥。减压蒸除溶剂后残留物溶于甲醇(10.0mL)，加入三甲基硅烷化重氮甲烷环己烷溶液(2.60mL,5.21mmol,2.0M)，搅拌反应30分钟后加入几滴乙酸淬灭反应。加入乙酸乙酯稀释溶液后用饱和氯化钠溶液洗，再加入无水硫酸镁干燥。减压蒸除溶剂，经柱层析纯化后得中间体61b(160mg,463μmol,产率29％)。
(3.3)化合物61的合成
Figure PCTCN2018111743-appb-000047
将中间体61b(160mg,463μmol)溶于二氯甲烷(3.00mL)和甲醇(3.00mL)中，加入羟胺水溶液(306mg,9.27mmol)和氢氧化钠(55.6mg,1.39mmol)后室温搅拌3小时。减压蒸除溶剂后，经MPLC纯化后得终产品(30.0mg,83.2μmol,产率18％)。 1H NMR(400MHz,DMSO–D6-d 6)δ10.69(brs,2H),9.02(s,1H),7.86(s,1H),7.72(d,J＝8.4Hz,1H),7.60(dd,J＝8.4,1.6Hz,1H),7.22-7.20(m,2H),7.09-7.07(m,2H),6.98(t,J＝7.2Hz,1H),6.82(s,1H),3.61(s,2H)；MS(ESI)m/z 347(M+1) +。
4、化合物62和63的合成
(4.1)中间体62a的合成
Figure PCTCN2018111743-appb-000048
将中间体6a1(2.90g,8.75mmol)溶于干燥的四氢呋喃(25.0mL)中，在0℃下分批加入 四氢铝锂(365mg,9.63mmol)。搅拌反应1小时后加入十水硫酸钠(3.00g)。减压蒸除溶剂后得中间体62a粗品(1.90g)。
(4.2)中间体62b的合成
Figure PCTCN2018111743-appb-000049
将中间体62a(1.90g,6.26mmol)溶于二氯甲烷(30.0mL)中，加入戴斯–马丁氧化剂(3.72g,8.77mmol)后室温搅拌反应4小时。减压蒸除溶剂后，经柱层析纯化得中间体62b(1.20g,3.98mmol,产率64％)。
(4.3)中间体46c的合成
Figure PCTCN2018111743-appb-000050
将钠氢(143mg,5.97mmol)溶于四氢呋喃(20.0mL)中，在0℃下加入2–(二甲氧基磷酰基)乙酸甲酯(1.34g,5.97mmol)后搅拌反应1小时。然后缓慢加入中间体62b(1.20g,3.98mmol)的四氢呋喃(20.0mL)溶液，室温搅拌反应4小时。减压蒸除溶剂后，经柱层析纯化得中间体62c(1.20g,3.10mmol,产率78％)。
(4.4)化合物62的合成
Figure PCTCN2018111743-appb-000051
将中间体62c(600mg,1.62mmol)溶于二氯甲烷(10.0mL)和甲醇(10.0mL)中，加入羟胺水溶液(1.61g,48.6mmol)和氢氧化钠(194mg,4.86mmol)后室温搅拌2小时。用1N盐酸调节pH至酸性，减压蒸除溶剂后经柱层析纯化得终产品(490mg,1.34mmol,产率83％)。 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.29(s,1H),9.25(s,1H),7.93(s,1H),7.83(d,J＝8.4Hz,1H),7.65(dd,J＝8.4,1.6Hz,1H),7.47(d,J＝15.6Hz,1H),7.31(s,1H),7.23(dd,J＝8.4,7.2Hz,2H),7.14–7.09(m,2H),7.05–6.99(m,1H),6.61(d,J＝15.6Hz,1H)；MS(ESI)m/z 359(M+1) +。
(4.5)化合物63的合成
Figure PCTCN2018111743-appb-000052
将实施例62化合物(173mg,483μmol)溶于甲醇(10.0mL)中，加入钯碳(49.8mg,410μmol)后在氢气下室温搅拌反应2小时。减压蒸除溶剂后，经柱层析纯化得终产品(120mg, 333μmol,产率69％)。 1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.18(s,1H),8.78(s,1H),7.90–7.84(m,1H),7.70(d,J＝8.4Hz,1H),7.60(dd,J＝8.4,1.6Hz,1H),7.23–7.19(m,2H),7.13–7.07(m,2H),7.02–6.98(m,1H),6.71(d,J＝0.8Hz,1H),3.04(t,J＝7.2Hz,2H),2.41(t,J＝7.2Hz,2H)；MS(ESI)m/z 361(M+1) +。
实施例2本发明中化合物的合成
通用合成路线2：
Figure PCTCN2018111743-appb-000053
(1.1)中间体9a的合成
Figure PCTCN2018111743-appb-000054
将5–溴苯并[d]噻唑(2.57g,12.0mmol)溶于干燥四氢呋喃(75.0mL)中，在–78℃下滴加六甲基二硅基胺基锂(17.0mL)后继续在–78℃下搅拌反应30分钟。滴加氰基甲酸酸乙酯(1.80g,18.2mmol)后继续在–78℃下搅拌反应30分钟。反应完成后加入饱和氯化铵溶液(50.0mL)淬灭并升至室温。乙酸乙酯(30mL)萃取3次，合并有机层后减压蒸除溶剂，经柱层析纯化得中间体9a(660mg,2.31mmol,产率19％)。
(1.2)中间体9b的合成
以6–溴苯并[d]噻唑和氰基甲酸酸乙酯为原料，按照中间体9a的合成方法，得到中间体9b(产率28％)。
(1.3)中间体9c的合成
以5–溴苯并[d]恶唑和氰基甲酸酸乙酯为原料，按照中间体9a的合成方法，得到中间体9c(产率25％)。
(2.1)中间体10a的合成
Figure PCTCN2018111743-appb-000055
将中间体9a(660mg,2.31mmol)、苄硫醇(3434mg,2.77mmol)、DIPEA(894mg,6.92mmol,1.21mL)、4,5–双(二苯基膦)–9,9–二甲基氧杂蒽(267mg,461μmol)和三(二亚苄基丙酮)二钯(211mg,231μmol)溶于甲苯(10.0mL)中，在氮气下回流反应5小时。冷却至室温后，加入乙酸乙酯(250mL)和水(250mL)，过滤除去不溶物。再加入乙酸乙酯(250mL)后依次用水、0.2N盐酸、饱和碳酸氢钠溶液和饱和氯化钠溶液洗。有机层加入无水硫酸钠干燥，减压蒸除溶剂后经柱层析纯化得中间体10a(530mg,1.61mmol,产率70％)。
(2.2)中间体10b的合成
以中间体9b为原料，按照中间体10a的合成方法，得到中间体10b(产率82％)。
(2.3)中间体10c的合成
以中间体9c为原料，按照中间体10a的合成方法，得到中间体10c(产率71％)。
(2.4)中间体11a1的合成
Figure PCTCN2018111743-appb-000056
将中间体10a(530mg,1.61mmol)溶于乙酸(9.0mL)和水(3.0mL)中，在0℃下加入N–氯代琥珀酰亚胺(859mg,6.44mmol)后继续在0℃下搅拌反应2小时。减压蒸除溶剂后加入乙酸乙酯和水，分出有机层后用无水硫酸镁干燥，再减压蒸除溶剂。将残留物溶于二氯甲烷(10.0mL)中，加入苯胺(164mg,1.76mmol)和吡啶(11.9g,150mmol,12.1mL)后室温搅拌过夜。反应完成后减压蒸除溶剂，加入二氯甲烷和水后分出有机层，加入无水硫酸镁干燥，再减压蒸除溶剂后经柱层析纯化得中间体11a(480mg,1.38mmol,产率86％)。
(2.5)中间体11a2～11a7的合成
以下表中的为原料，按照中间体11a1的合成方法，得到中间体11a2～11a7。
Figure PCTCN2018111743-appb-000057
Figure PCTCN2018111743-appb-000058
1、化合物64的合成
Figure PCTCN2018111743-appb-000059
将中间体11a(480mg,1.32mmol)溶于二氯甲烷(5.00mL)和甲醇(5.00mL)中，加入羟胺水溶液(875mg,26.5mmol)和氢氧化钠(159mg,3.97mmol)后室温搅拌反应3小时。减压蒸除溶剂后经MPLC纯化得终产品(364mg,1.04mmol,产率79％)。 1H NMR(400MHz,DMSO–d6)δ12.08(s,1H),10.46(s,1H),9.61(s,1H),8.42(d,J＝8.4Hz,1H),8.34(d,J＝2.0Hz,1H),7.90(dd,J＝8.4,2.0Hz,1H),7.30–7.19(m,2H),7.18–7.10(m,2H),7.06-7.01(m,1H)；MS(ESI)m/z 350(M+1) +。
2、化合物65～70的合成
以中间体11a2～11a7为原料，按照化合物64的合成方法，得到下表中化合物65～70。
Figure PCTCN2018111743-appb-000060
Figure PCTCN2018111743-appb-000061
实施例3、本发明化合物的制备
通用合成路线3：
Figure PCTCN2018111743-appb-000062
(1.1)中间体14a的合成
以5–溴–1H–吲哚–2–羧酸甲酯为原料，按照中间体4a的合成方法，得到中间体14a(产率60％)。
(1.2)中间体14b的合成
以6–溴–1H–吲哚–2–羧酸甲酯为原料，按照中间体4a的合成方法，得到中间体14b(产率72％)。
(1.3)中间体14c的合成
以5–溴–1–甲基–1H–吲哚–2–羧酸乙酯为原料，按照中间体4a的合成方法，得到中间体14c(产率71％)。
(1.4)中间体15a2～15a24的合成
以下表中的原料，按照中间体6a1的合成方法，得到中间体15a1～15a24。
Figure PCTCN2018111743-appb-000063
Figure PCTCN2018111743-appb-000064
Figure PCTCN2018111743-appb-000065
1、化合物71的合成
Figure PCTCN2018111743-appb-000066
将中间体15a1(480mg,1.28mmol)溶于乙醇(10.0mL)中，加入10％钯碳(330mg,2.74mmol)和甲酸铵(806mg,12.80mmol)后搅拌回流反应2小时。反应完成后过滤并减压蒸除溶剂，残留物溶于二氯甲烷(3.0mL)和甲醇(3.0mL)中，加入氢氧化钠(150mg,3.84mmol)和羟胺水溶液(1.32g,40.0mmol)后室温搅拌2小时。反应完成后减压蒸除溶剂，经MPLC纯化得终产品(123mg,351μmol,产率29％)。 1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),10.18(s,1H),9.25(s,1H),8.09(s,1H),7.59–7.47(m,2H),7.17(t,J＝7.6Hz,2H),7.10–7.04(m,3H),6.95(t,J＝7.2Hz,1H)；MS(ESI)m/z 332(M+1) +。
2、化合物72～94的合成
以中间体15a2～15a24为原料，按照化合物71的合成方法，得到下表中化合物72～94。
Figure PCTCN2018111743-appb-000067
Figure PCTCN2018111743-appb-000068
Figure PCTCN2018111743-appb-000069
Figure PCTCN2018111743-appb-000070
3、化合物95的合成
Figure PCTCN2018111743-appb-000071
将中间体15a1(210mg,554μmol)溶于二氯甲烷(3.00mL)和甲醇(3.00mL)中，加入氢氧化钠(66.5mg,1.66mmol)和羟胺水溶液(366mg,11.1mmol)后室温搅拌3小时。反应完成后减压蒸除溶剂，经制备型HPLC纯化得终产品(62.0mg,166.3μmol,产率30％)。 1H NMR(400MHz,DMSO–d6)δ12.43(s,1H),10.99(s,1H),10.19(s,1H),9.41(s,1H),7.96(s,1H),7.62(d,J＝8.8Hz,1H),7.54(d,J＝8.8Hz,1H),7.19(t,J＝7.6Hz,2H),7.08(d,J＝8.0 Hz,2H),6.98(t,J＝7.6s Hz,1H)；MS(ESI)m/z 366(M+1) +
4、化合物96～97的合成
以中间体15a8和15a18为原料，按照化合物79的合成方法，得到下表中化合物96～97。
Figure PCTCN2018111743-appb-000072
实施例4、本发明化合物的合成
通用合成路线4
Figure PCTCN2018111743-appb-000073
(1.1)中间体18a的合成
Figure PCTCN2018111743-appb-000074
将1H–吲哚–2–羧酸乙酯(1.89g,9.99mmol)溶于乙腈(200mL)中，加入1–氯甲基–4–氟–1,4–重氮化二环2.2.2辛烷双(四氟硼酸)盐(4.24g,12.0mmol)后室温搅拌反应24小时。减压蒸除溶剂后，经柱层析纯化得中间体18a(470mg,2.27mmol,产率22.71％)。
(1.2)中间体19a的合成
Figure PCTCN2018111743-appb-000075
将中间体18a(470mg,2.27mmol)溶于四氢呋喃(10.0mL)中，加入三氟乙酸(259mg,2.27mmol,320μL)和N–溴代琥珀酰亚胺后室温搅拌反应16小时。减压蒸除溶剂后，经柱层析纯化得中间体19a(640mg,2.24mmol,产率99％)。
(1.3)中间体20a的合成
以中间体19a为原料，按照中间体4a的合成方法，得到中间体20a(产率82％)。
(1.4)中间体21a1和21a2的合成
以下表中的原料，按照中间体6a1的合成方法，得到中间体21a1和21a2。
Figure PCTCN2018111743-appb-000076
1、化合物82和83的合成
以中间体21a1和21a2为原料，按照化合物79的合成方法，得到下表中化合物82和83。
Figure PCTCN2018111743-appb-000077
2、化合物100的合成
(1)中间体100a的合成
Figure PCTCN2018111743-appb-000078
将2,2,2–三氯乙酰亚氨酸甲酯(6.60g,37.4mmol)加入乙酸(50.0mL)中，在0℃下缓慢滴加4–溴苯–1,2–二胺(7.00g,37.4mmol)的乙酸(50.0mL)溶液，然后在室温下搅拌反应过夜。反应完成后加入水，用乙酸乙酯萃取2次，合并有机层后分别用水和饱和氯化钠溶液洗，加入无水硫酸钠干燥。减压蒸除溶剂，残留物溶于甲醇(100mL)后，在80℃下搅拌反应5小时。减压蒸除溶剂，加入乙酸乙酯溶解，依次用饱和碳酸氢钠溶液、饱和氯化钠溶液洗，加入无水硫酸钠干燥。减压蒸除溶剂后，经柱层析纯化得中间体100a(3.00g,11.8mmol,产率26％)。
(2)中间体100b的合成
Figure PCTCN2018111743-appb-000079
以中间体100a为原料，按照中间体4a的合成方法，得到中间体100b(产率76％)。
(3)中间体100c的合成
Figure PCTCN2018111743-appb-000080
以中间体100b为原料，按照中间体6a1的合成方法，得到中间体100c(产率62％)。
(4)化合物100的合成
Figure PCTCN2018111743-appb-000081
以中间体100c为原料，按照化合物79的合成方法，得到化合物84(产率43％)。 1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),11.91(s,1H),10.32(s,1H),9.42(s,1H),8.10–7.62(m,3H),7.25–6.95(m,5H)；MS(ESI)m/z 333(M+1) +。
以下通过试验例来具体说明本发明的有益效果：
试验例1HDAC1和HDAC6酶学检测方法
采用均相时间分辨荧光(HTRF)方法对本发明化合物的HDAC抑制活性进行检测。
使用酶缓冲液(50mM Tris-HCl pH 8.0,137mM NaCl,2.7mM KCl,1mM MgCl 2,0.01％Tween20)配制不同浓度的化合物溶液。使用检测缓冲液(Cisbio Bioassays#62SDBRDD)配制Streptavidin XL-665(Cisbio Bioassays#610SAXLA)和anti-H3K9me0-Eu(K)(Cisbio Bioassays#61KB0KAE)的检测混合物。
取4μL化合物溶液至反应板中，加入2μL HDAC溶液(终体系HDAC1：30ng/板；HDAC6：70ng/板)，室温孵育10分钟。加入4μL Histone H3(1-21)lysine 9 acetylated  biotinylated peptide(AnaSpec#AS-64361)，贴膜后在37℃下孵育60分钟。加入10μL检测混合物，室温孵育1小时，使用多功能酶标仪(Envision 2104)读取荧光信号。从所得数据确定化合物的抑制作用并将其与化合物浓度作图，得到浓度响应曲线，按照四参数模型拟合IC 50值。
按照上述方法对前述实施例制备的化合物进行HDAC1、HDAC6的酶活性检测，试验结果见表1，其中测定各化合物的IC 50按照说明分类。
表1、化合物对HDAC1和HDAC6的抑制活性
实施例 活性(HDAC1) 活性(HDAC6) 实施例 活性(HDAC1) 活性(HDAC6)
1 +++ +++ 2 + +++
3 +++ +++ 4 ++ +++
5 +++ +++ 6 ++ +++
7 ++ +++ 8 + +
9 + ++ 10 ++ +++
11 + + 12 +++ +++
13 +++ +++ 14 +++ +++
15 +++ +++ 16 +++ +++
17 +++ +++ 18 + +
19 ++ +++ 20 +++ +++
21 +++ +++ 22 ++ +++
23 +++ +++ 24 + +
25 +++ +++ 26 +++ +++
27 +++ +++ 28 ++ +++
29 +++ +++ 30 + +++
31 +++ +++ 32 + +++
33 + ++ 34 + +
35 ++ +++ 36 ++ +++
37 + + 38 + +
39 + + 40 +++ +++
41 +++ +++ 42 +++ +++
43 ++ ++ 44 ++ +++
45 ++ ++ 46 +++ +++
47 ++ ++ 48 ++ ++
49 ++ ++ 50 ++ ++
51 + + 52 ++ ++
53 ++ ++ 54 ++ +++
55 ++ ++ 56 ++ ++
57 ++ ++ 58 ++ ++
59 + ++ 60 ++ ++
61 ++ +++ 62 +++ ++
63 +++ +++ 64 + +++
65 + + 66 + +
67 + + 68 ++ ++
69 + + 70 ND ND
71 + +++ 72 + ++
73 ++ ++ 74 + +
75 + + 76 + +
77 + ++ 78 + ++
79 + ++ 80 + ++
81 + + 82 + ++
83 + + 84 + +
85 + ++ 86 + ++
87 + + 88 ++ +
89 + + 90 + +
91 + + 92 + +
93 + + 94 + +
95 + + 96 + +
97 + + 98 + +
99 + + 100 + +
注：，“+”表示IC 50为大于500nM小于10μM；“++”表示IC 50大于100nM小于500nM；“+++”表示IC 50小于100nM。ND:数据正在检测分析中。
试验结果表明，本发明化合物具有良好的去乙酰化酶抑制活性，可以有效用于与组蛋白去乙酰化酶活性异常疾病的治疗。
试验例2细胞生长抑制测定
将对数生长期的HCT-116细胞接种于12孔培养板中。待细胞贴壁过夜后，分别加入化合物处理细胞24小时。收取细胞，在冰浴下SDS裂解液裂解。取上述细胞裂解液进行SDS-PAGE电泳，用湿转系统将蛋白转移至PVDF膜上。加入TBST溶液(100mM Tris-HCl pH＝7.2-7.4，0.9％NaCl，0.2％Tween-20)配制的5％脱脂牛奶封闭液后，摇床室温封闭60分钟。将膜置于抗体稀释液(5％脱脂牛奶)稀释的一抗中，于4℃下过夜。用TBST溶液室温洗涤三次，每次10分钟。加入近红外标记标记的二抗，室温下于摇床上平缓摇动1小时。再用TBST溶液洗涤三次后，于Odyssey CLx近红外双色荧光成像系统获取荧光信号值。从所得数据确定化合物的抑制作用并将其与化合物浓度作图，得到浓度响应曲线，按照四参数模型拟合EC 50值。
按照上述方法对前述实施例制备的化合物进行细胞生长抑制检测，试验结果见表2，其中测定各化合物的EC 50按照说明分类。
表2化合物对HCT-116细胞的抑制活性
实施例 活性 实施例 活性 实施例 活性 实施例 活性
1 +++ 2 ++ 3 ++ 4 +++
5 +++ 6 ++ 7 ++ 8 +++
9 +++ 10 ++ 11 ++ 12 +++
13 +++ 14 ++ 15 +++ 16 +++
17 +++ 18 +++ 19 +++ 20 +++
21 +++ 22 ++ 23 ++ 24 +++
25 +++ 26 +++ 27 +++ 28 +++
29 +++ 30 ++ 31 ++ 32 ++
33 ++ 34 ++ 35 ++ 36 +++
37 ++ 38 ++ 39 ++ 40 ++
41 +++ 42 ++ 43 ++ 44 +++
45 ++ 46 +++ 47 ++ 48 ++
49 ++ 50 ++ 51 ++ 52 ++
53 ++ 54 ++ 55 ++ 56 ++
57 ++ 58 ++ 59 ++ 60 ++
61 +++ 62 +++ 63 +++ 64 ++
65 ++ 66 ++ 67 ++ 68 +
69 + 70 + 71 + 72 ++
73 + 74 + 75 + 76 ++
77 ++ 78 ++ 79 ++ 80 ++
81 ++ 82 ++ 83 ++ 84 ++
85 ++ 86 ++ 87 + 88 ++
89 ++ 90 + 91 ++ 92 ++
93 + 94 + 95 ++ 96 ++
97 ++ 98 ++ 99 ++ 100 ++
注：“+”表示EC 50大于50μM；“++”表示EC 50大于10μM小于50μM；；“+++”表示EC 50小10μM；ND:数据正在检测分析中。
试验结果表明，本发明化合物对HCT-116细胞具有良好的抑制活性。
综上所述，本发明公开的式Ⅰ所示的新化合物，表现出了良好的去乙酰化酶抑制活性，为临床治疗与组蛋白去乙酰化酶活性异常相关的疾病提供了一种新的药用可能，具有良好的应用前景。

Claims (24)

  1. 式(I)所示的化合物、或其晶型、或其水合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐：
    Figure PCTCN2018111743-appb-100001
    其中，n为0～10；
    L 1表示无或C 1～C 10的亚烷基或C 1～C 10的烯基；
    Y为N或CR 2，其中R 2选自氢、卤素、羟基、氨基、三氟甲基、氰基、C 1～C 10的烷基或C 1～C 10的烷氧基；
    X为O、S或NR 3；其中R 3选自氢、C 1～C 10的烷基或C 1～C 10的酰基；
    R 1为氢、C 1～C 10的烷基、C 3～C 10的环烷烃或3～10元的杂环烷烃；
    环A表示3～10元的环烷烃、3～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基；其中A环可进一步被0～5个R 4取代，其中每个R 4分别独自选自卤素、氰基、硝基、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qOCOR 5、–(CH 2) qNR 5R 6、–(CH 2) qNR 5COR 6、–(CH 2) qCOR 5、–(CH 2) qCOOR 5、–(CH 2) qCONR 5R 6，q为0～10；
    R 5、R 6分别选自氢、C 1～C 10的烷基、5～10元的环烷烃、5～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基，其中R 5、R 6可进一步被R 7取代；
    R 7选自卤素、羟基、氨基、C 1～C 10的烷基、C 1～C 10的烷氧基、C 1～C 10的烷氨基、–(CH 2) rOR 8；其中r为0～10。
    R 8选自氢、C 1～C 10的烷基。
  2. 根据权利要求1所述的化合物，其特征在于：所述式(I)化合物具有如式(Ⅰa)或式(Ⅰb)所示的结构：
    Figure PCTCN2018111743-appb-100002
  3. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰa)化合物具有如式(Ⅰa-1)所示的结构：
    Figure PCTCN2018111743-appb-100003
    其中，L 1表示无、C 1～C 5的亚烷基或
    Figure PCTCN2018111743-appb-100004
    其中m为0～3；
    R 1表示氢、C 1～C 5的烷基；
    R 2表示氢、卤素、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0～5；
    R 5、R 6分别选自氢、C 1～C 5的烷基、5～10元的环烷烃、5～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基，其中R 5、R 6可进一步被R 7取代；
    R 7选自卤素、羟基、氨基、C 1～C 5的烷基、C 1～C 5的烷氧基、C 1～C 5的烷氨基、–(CH 2) rOR 8；其中r为0～5；。
    R 8选自氢、C 1～C 5的烷基；
    环A表示苯基、5元芳杂环、6元芳杂环、10元芳杂环。
  4. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰa)化合物具有如式(Ⅰa-2)所示的结构：
    Figure PCTCN2018111743-appb-100005
    其中，R 1表示氢、卤素；环A表示苯基、5元芳杂环、6元芳杂环。
  5. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰa)化合物具有如式(Ⅰa-3)所示的结构：
    Figure PCTCN2018111743-appb-100006
    其中，n＝0、1、2、3；X表示氢、卤素；
    R 1表示氢、C 1～C 5的烷基、6元的芳基或者杂芳基；
    R 3表示氢、C 1～C 5的烷基；
    R 2表示氢、卤素、三氟甲基、甲氧基、–(CH 2) qR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5， q为0～5；
    R 5、R 6分别选自氢、C 1～C 5的烷基、5～6元环烷烃、5～6元杂环烷烃、5～6元芳杂环、苯基；
    环A表示苯基、环己烷、5～6元杂环烷烃、5～6元芳杂环或者10元芳杂环。
  6. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰa)化合物具有如式(Ⅰa-4)所示的结构：
    Figure PCTCN2018111743-appb-100007
    其中，X表示O、S、N；环A表示苯基、5～6元芳杂环或者10元芳杂环。
  7. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰa)为如下化合物之一：
    Figure PCTCN2018111743-appb-100008
    Figure PCTCN2018111743-appb-100009
    Figure PCTCN2018111743-appb-100010
    Figure PCTCN2018111743-appb-100011
  8. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰb)化合物具有如式(Ⅰb-1)所示的结构：
    Figure PCTCN2018111743-appb-100012
    其中，L 1表示无、C 1～C 5的亚烷基或
    Figure PCTCN2018111743-appb-100013
    其中m为0～3；
    R 1表示氢、C 1～C 5的烷基；
    R 2表示氢、卤素、三氟甲基、三氟甲氧基、–(CH 2) qR 5、–(CH 2) qOR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0～5；
    R 5、R 6分别选自氢、C 1～C 5的烷基、5～10元的环烷烃、5～10元的杂环烷烃、5～10元的芳基或5～10元的杂芳基；其中R 5、R 6可进一步被R 7取代；
    R 7选自卤素、羟基、氨基、C 1～C 5的烷基、C 1～C 5的烷氧基、C 1～C 5的烷氨基、–(CH 2) rOR 8；其中r为0～5；。
    R 8选自氢、C 1～C 5的烷基；
    环A表示苯基、5～6元芳杂环或10元芳杂环。
  9. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰb)化合物具有如式(Ⅰb-2)所示的结构：
    Figure PCTCN2018111743-appb-100014
    其中，R 1表示氢、卤素；环A表示苯基、5元芳杂环、6元芳杂环。
  10. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰb)化合物具有如式(Ⅰb-3)所示的结构：
    Figure PCTCN2018111743-appb-100015
    其中，n＝0、1、2、3；X表示氢、卤素；
    R 1表示氢、C 1～C 5的烷基、6元的芳基或者杂芳基；
    R 3表示氢、C 1～C 5的烷基；
    R 2表示氢、卤素、三氟甲基、甲氧基、–(CH 2) qR 5、–(CH 2) qNR 5R 6、–(CH 2) qCOR 5，q为0～5；
    R 5、R 6分别选自氢、C 1～C 5的烷基、5～6元环烷烃、5～6元杂环烷烃、5～6元芳杂环、苯基；
    环A表示苯基、环己烷、5～6元杂环烷烃、5～6元芳杂环或者10元芳杂环。
  11. 根据权利要求2所述的化合物，其特征在于：所述式(Ⅰb)化合物具有如式(Ⅰb-4)所示的结构：
    Figure PCTCN2018111743-appb-100016
    其中，X表示O、S、N；环A表示苯基、5～6元芳杂环或者10元芳杂环。
  12. 根据权利要求2所述的化合物物，其特征在于：所述式(Ⅰb)为如下化合物之一：
    Figure PCTCN2018111743-appb-100017
    Figure PCTCN2018111743-appb-100018
  13. 权利要求1-12任一项所述的化合物、或其晶型、或其水合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐在制备HDAC抑制剂类药物中的用途。
  14. 根据权利要求13所述的用途，其特征在于：所述药物是治疗细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病的药物。
  15. 根据权利要求14所述的用途，其特征在于：所述细胞增殖疾病为癌症。
  16. 根据权利要求15所述的用途，其特征在于：所述癌症包括结肠癌、肺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、甲状腺癌。
  17. 根据权利要求13-16任一项所述的用途，其特征在于：所述HDAC为HDAC6。
  18. 一种药物组合物，其特征在于：它是以权利要求1-12任一项所述的化合物、或其晶型、或其水合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐为活性成分，加上药学上可接受的辅料制备而成的制剂。
  19. 根据权利要求18所述的组合物，其特征在于：所述制剂为口服制剂、透皮吸收制剂或注射制剂。
  20. 权利要求18或19所述的药物组合物在制备HDAC抑制剂类药物中的用途。
  21. 根据权利要求20所述的用途，其特征在于：所述药物是治疗细胞增殖疾病、自身免疫疾病、炎症、神经变性疾病或病毒性疾病的药物。
  22. 根据权利要求21所述的用途，其特征在于：所述细胞增殖疾病为癌症。
  23. 根据权利要求22所述的用途，其特征在于：所述癌症包括结肠癌、肺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、甲状腺癌。
  24. 根据权利要求20-23任一项所述的用途，其特征在于：所述HDAC为HDAC6。
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