WO2015085860A1 - 杂环羟肟酸类化合物及其药用组合物和应用 - Google Patents

杂环羟肟酸类化合物及其药用组合物和应用 Download PDF

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WO2015085860A1
WO2015085860A1 PCT/CN2014/092104 CN2014092104W WO2015085860A1 WO 2015085860 A1 WO2015085860 A1 WO 2015085860A1 CN 2014092104 W CN2014092104 W CN 2014092104W WO 2015085860 A1 WO2015085860 A1 WO 2015085860A1
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蒋晟
涂正超
白进红
邱亚涛
孙巧
李西才
周学让
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广州康缔安生物科技有限公司
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    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon 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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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of chemical medicine, and in particular to a heterocyclic hydroxamic acid compound having the structural features of the formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof and a prodrug molecule thereof, which comprises the compound Pharmaceutical compositions and the use of these compounds or compositions in the preparation of a medicament.
  • Histone deacetylases are a group of organisms that regulate glycoplasty, transcriptional activation or inhibition, cell cycle, cell differentiation, and apoptosis by inducing histone deacetylation at the level of cellular chromatin.
  • the enzyme of the effect in particular, is related to the regulation of transcriptional expression of the gene after activation of the cell.
  • Histone acetylation and deacetylation of chromatin is one of the key links regulating gene expression, and abnormal gene expression is the molecular biological basis for tumors and some genetic and metabolic diseases.
  • the degree of histone acetylation is coordinated by histone acetylase (HAT) and histone deacetylase (HDAC).
  • the occurrence of tumors is closely related to the imbalance of acetylation and deacetylation of the lysine residues at the N-terminus of nucleosome core histones.
  • its dynamic balance is maintained by both HAT and HDAC.
  • HAT and HDAC In the active region of chromatin gene transcription, the acetylation activity of its core histones is increased; on the contrary, in the inactive regions of gene transcription, the degree of acetylation is low.
  • Class I includes HDAC1, HDAC2, HDAC3 and HDAC8, which are only present in the nucleus
  • Class II includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10 and HDAC11 shuttle between the nucleus and the cytoplasm during signal transduction
  • Class III is SIRT1-SIRT7 is very different from the first two types, and its activity is not dependent on Zn 2+ , and It is dependent on Coenzyme I (NAD), which has at least 7 subtypes that are not inhibited by Class I and II HDAC inhibitors
  • Class IV is HDAC11, which contains catalytic sites for Class I and Class II HDACs.
  • I, II and IV are classical families and are Zn 2+ -dependent HDAC.
  • the vast majority of HDAC inhibitors currently in clinical research are capable of inhibiting multiple subtypes of HDAC, which are often part of the Zn 2+ -dependent HDAC family.
  • Histone deacetylase inhibitors are a class of compounds that inhibit the activity of HDACs.
  • HDAC inhibitors increase the level of chromatin histone acetylation, thus leading to the activation of specific genes such as p21, p53, etc., which in turn leads to terminal differentiation of cells or apoptosis of cancer cells. Therefore, HDAC has become one of the most popular targets in the development of cancer chemotherapy drugs.
  • Histone deacetylase inhibitors generally include a zinc ion binding region, a linking region and a surface recognition region. The direct action of the inhibitor with zinc ions is necessary to produce inhibitory activity.
  • HDAC inhibitors mainly include the following four categories: (1) short-chain fatty acids such as butyric acid, phenylbutyric acid and its salts; (2) hydroxamic acids, which are the most widely studied HDAC inhibitors to date.
  • SAHA suberoylanilide hydroxamic acid
  • TSA trichostatin A
  • cyclic tetrapeptides are the most complex type of inhibition a cyclic amino acid macrocycle in the molecule of a cyclic peptide inhibitor as a hydrophobic surface recognition region, an alkyl chain as a linking region, and an alkyl chain terminal
  • a zinc ion binding group such as trapoxin, HC-toxon, Apicidin, FK228 and Largazole, etc.
  • benzamide compounds such compounds are less active than the general hydroxamic acid and cyclic peptide compounds, However, it has a higher selectivity for class I HDACs.
  • Histone deacetylase inhibitors have the advantage of low cytotoxicity compared to traditional anti-tumor drugs.
  • SAHA Merck's suberoylanilide hydroxamic acid
  • Zolinza vorinostat
  • CCL metastatic cutaneous T-cell lymphoma
  • the natural product FK228 was marketed as the injectable drug Istodax (romidepsin), and also used to treat cutaneous T lymphoma (CTCL), which became the second listed histone deacetylase inhibitor after Zolinza.
  • CTCL cutaneous T lymphoma
  • the FDA approved its treatment of peripheral T-cell lymphoma (PTCL).
  • the invention provides a histone deacetylase inhibitor of a heterocyclic hydroxamic acid compound, which solves the problems of inaccurate curative effect and large toxic side effect of the existing medicine.
  • the present invention also provides a method for preparing a histone deacetylase inhibitor of the heterocyclic hydroxamic acid, and a pharmaceutical use.
  • the present invention provides a heterocyclic hydroxamic acid compound having the chemical structure represented by Formula I, and a pharmaceutically acceptable salt, isomer, racemate, prodrug or solvent thereof.
  • X is optionally N, O or S, and X is substituted by 0-1 substituents which are C 1 -C 10 alkyl;
  • W, Y, Z are optionally CH or N;
  • the R 1 group is selected from:
  • the R 2 group is selected from:
  • the R 3 group is selected from:
  • n is an integer from 0-6;
  • the R 4 and R 5 groups are selected from:
  • R 4 and R 5 forms a five-, six-, seven-, or eight-membered heterocyclic ring structure
  • X 1 , Y 1 is selected from N, O, S, CH; n 2 , and n 3 is 0, 1, 2 or 3;
  • the R 6 group is selected from:
  • the R 7 group is selected from:
  • the heteroaryl group is selected from the group consisting of pyridine, pyrazole, pyrazine, pyrrole, imidazole, furan, thiophene, benzofuran, benzothiophene;
  • the side chain of the alkylamine is at the 4, 5, 6 or 7 position of the anthracene ring.
  • the invention also provides a process for the preparation of a heterocyclic hydroxamic acid compound of formula I, which process comprises the steps of:
  • R 1 , R 2 , R 3 , R 4 , R 5 are as defined in claim 1;
  • the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, borane, potassium borohydride, lithium borohydride, sodium borohydride, lithium tetrahydrogenate, sodium borohydride, and the organic base is selected from the group consisting of imidazole.
  • halogenated alkane is selected from the group consisting of methyl iodide, ethyl iodide, ethyl bromide, 2-iodoethanol, 2 - bromoethanol, 2-chloroethanol, bromobutane, bromopentane, bromohexane, bromoheptane, bromooctane, bromodecane, bromoquinane, halogenated C3 to C9 cycloalkyl, halogenated C4 ⁇ C9 heterocycloal
  • the invention also provides a process for the preparation of a compound of formula II, the process comprising the steps of:
  • the necessary organic solvent may be selected from the group consisting of dichloromethane, tetrahydrofuran (THF), dimethylformamide (DMF), ethylene glycol dimethyl ether, 1,2-dichloroethane, ortho-benzene.
  • Dimethyl diformate (DMP) methanol, ethanol, petroleum ether, n-hexane or diethyl ether
  • essential inorganic base may be selected from sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, calcium carbonate
  • the acid may be selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid or nitric acid.
  • the reducing agent may be sodium cyanoborohydride, sodium borohydride, borane, potassium borohydride, lithium borohydride, sodium borohydride, lithium tetrahydrogenate, sodium borohydride or lanthanide. nickel.
  • Another object of the invention is to provide the use of the above compounds.
  • the present invention also relates to the use of an effective amount of the above compounds for the treatment of lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer Transitional proliferative diseases such as epithelial cell carcinoma, leukemia and cervical cancer.
  • heterocyclic hydroxamic acid compound and the pharmaceutically acceptable salt thereof according to the invention can effectively inhibit the growth of various tumor cells and inhibit the action of histone deacetylase, and can be used for preparing antitumor drugs.
  • the compounds and pharmaceutically acceptable salts thereof of the present application are useful in the preparation of transitional proliferative diseases such as tumors in humans and other mammals.
  • heterocyclic hydroxamic acid compound and pharmaceutically acceptable salt thereof according to the invention can be used for treating mammalian diseases related to histone deacetylase dysregulation including cancer, neurodegenerative diseases, AIDS, Alzheimer's disease, Malaria and diabetes.
  • alkyl means a straight or branched, C 1 ⁇ n of the aliphatic saturated hydrocarbon alkyl 1-n carbon atoms is represented, including straight and branched chains such as "C 1 ⁇ 12 alkyl group” It is meant that the group is an alkyl group and the number of carbon atoms in the carbon chain of the alkyl group is between 1 and 12. It should be noted that when the number of carbon atoms is not particularly limited, it means only the number of carbon atoms of the alkyl moiety specified therein, and does not include the number of carbon atoms on the substituent of the alkyl group.
  • salts refers to salts which, within the scope of sound medical judgment, are suitable for contact with mammalian, particularly human, tissues without undue toxicity, irritation, allergic response, etc., and which are commensurate with a reasonable benefit/risk ratio, Pharmaceutically acceptable salts such as amines, carboxylic acids and other types of compounds are well known in the art.
  • isomer refers to two or more compounds that have the same molecular composition but differ in structure and properties.
  • racemate refers to an equimolar mixture of an optically active chiral molecule and its enantiomer. It is composed of the same amount of molecules with opposite optical rotation and the same optical rotation. The optical rotation is due to these molecules. The interaction between the two cancels each other and is therefore not optical.
  • solvate refers to a mixture of a compound and a solvent, for example, a crystalline form is a solvate.
  • prodrug refers to a compound that produces a parent compound of the above formula by rapid conversion in vivo by hydrolysis in blood.
  • any variable e.g., R1, R2, etc.
  • the definition of each occurrence thereof is independent of the definition of each occurrence.
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. in case The ring system is polycyclic, which means that such a bond is only attached to any suitable carbon atom adjacent to the ring.
  • alkyl means a straight or branched, C 1 ⁇ n of the aliphatic saturated hydrocarbon alkyl 1-n carbon atoms is represented, including straight and branched chains such as "C 1 ⁇ 12 alkyl group” It is meant that the group is an alkyl group and the number of carbon atoms in the carbon chain of the alkyl group is between 1 and 12. It should be noted that when the number of carbon atoms is not particularly limited, it means only the number of carbon atoms of the alkyl moiety specified therein, and does not include the number of carbon atoms on the substituent of the alkyl group.
  • Cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • heteroaryl denotes a stable monocyclic ring of up to 6 atoms in the ring or up to 6 atomic bicyclic carbon rings in each ring, at least one of which is an aromatic ring and contains from 1 to 4 Heteroatoms from O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, thiazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrole Base, pyridyl.
  • heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group.
  • heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or a hetero atom-containing ring.
  • halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or substituted.
  • (C1-C6)alkyl may be one, two, Or three substituents selected from the group consisting of OH, halogen, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidinyl and the like.
  • the invention includes the free forms of Formula I, as well as pharmaceutically acceptable salts and stereoisomers.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form” refers to an amine compound in a non-salt form. Included are pharmaceutically acceptable salts including not only the exemplary salts of the particular compounds described herein, but also all of the typical pharmaceutically acceptable salts of the free forms of the compounds of formula I.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the salt is treated by a suitable alkaline dilute aqueous solution such as a dilute aqueous solution of sodium hydroxide, a dilute aqueous solution of sodium carbonate, a dilute aqueous ammonia solution and a dilute aqueous solution of potassium hydrogencarbonate to regenerate the free form.
  • a suitable alkaline dilute aqueous solution such as a dilute aqueous solution of sodium hydroxide, a dilute aqueous solution of sodium carbonate, a dilute aqueous ammonia solution and a dilute aqueous solution of potassium hydrogencarbonate to regenerate the free form.
  • the free form is in some physical properties such as in a polar solvent.
  • the solubility in the solution is somewhat different from its respective salt form, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • salts of the compounds are formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, sulfuric acid, Salts of hydrobromic acid, sulfamic acid, phosphoric acid, nitric acid, etc., also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, acetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, Acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, fumaric acid, 2-acetoxy-benzoic acid, fumaric acid, A salt prepared from toluenesulfonic acid, methane
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like.
  • a pharmaceutically acceptable salt of an organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin, such as refined ammonia Acid, beet, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine , N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, methyl glucosamine, histidine, lysine, isopropylamine, morpholine, piperidine, polyamine resin, Rucaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • the present application provides a method for treating a proliferative disease or condition, such as a tumor in a human or other mammal, using a compound of formula (I) and a pharmaceutically acceptable salt thereof.
  • the compounds designed herein and pharmaceutically acceptable salts thereof can be used to treat or control lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, gastric cancer, pancreatic cancer, Transitional proliferative diseases such as breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, leukemia and cervical cancer.
  • the compounds designed herein and pharmaceutically acceptable salts thereof can be used with cytotoxic/cytostatics, estrogen receptor modulators, androgen receptor modulators, currently in use or at developmental stages, Retinoid receptor modulators, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, interference Cell cycle checkpoint drugs and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit Inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histone deacetylase inhibitors, proteasome inhibitors, CDK inhibitors, Bcl-2 family protein inhibition Agent, MDM2 family protein inhibitor, IAP family protein
  • a method of treating breast cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a method of treating respiratory cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, small cell & non-small cell lung cancer, bronchial adenocarcinoma, and pleural pulmonary blastoma.
  • a method of treating brain cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, brain stem and sub-glial glioma, cerebellum and cerebral astrocytoma, ependymoma, and neuroectoderm and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to, cervical cancer, endometrial cancer, ovarian cancer, vaginal cancer and vulvar cancer, and intrauterine tumors.
  • a method of treating digestive tract cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, anal cancer, colon cancer, colonic straight cancer, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.
  • a method of treating urinary tract cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, and urethral cancer.
  • a method of treating an ocular cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • these include, but are not limited to, intraocular melanoma and retinoblastoma.
  • liver cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • hepatoma hepatocellular carcinoma with or without fibrotic changes
  • cholangiocarcinoma intrahepatic cholangiocarcinoma
  • mixed hepatocellular cholangiocarcinoma mixed hepatocellular cholangiocarcinoma.
  • a method of treating skin cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • squamous cell carcinoma Kaposi's sarcoma
  • malignant melanoma Merck's cell skin cancer
  • non-melanoma cell carcinoma include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck's cell skin cancer, and non-melanoma cell carcinoma.
  • a method of treating head and neck cancer in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof as referred to in the present application.
  • These include, but are not limited to, laryngeal, hypopharyngeal, nasopharynx, oropharyngeal cancer, and lip and oral cancer.
  • a method of treating lymphoma in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a method of treating a sarcoma of a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as contemplated by the present application.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as contemplated by the present application.
  • these include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • a method of treating leukemia in a human or other mammal using a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable salt thereof, as referred to herein.
  • these include, but are not limited to, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the compounds of the invention may be administered to a mammal, preferably a human, alone or in combination with a pharmaceutically acceptable receptor, adjuvant or diluent, in accordance with standard pharmaceutical techniques.
  • the compound can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally and topically, ocularly, pulmonaryly, nasally, or parenterally.
  • the dosage range is from 0.1 to 500 mg/day/kg body weight orally.
  • a suitable mode of administration is daily single dose administration or multiple administrations twice, three times, four times, or the like, or administration using a sustained release technique.
  • the preferred dosage range is from 0.1 to 1500 mg/day/kg body weight.
  • the dose is 1 to 500 mg.
  • the daily dose for adult patients can be as low as 0.1 mg/day.
  • the dosage range is from 0.1 to 500 mg/day/kg body weight in an intravenous dose.
  • a suitable mode of administration is daily single dose administration or multiple administrations twice, three times, four times, or the like, or administration using a sustained release technique.
  • the preferred dosage range is from 0.1 to 1500 mg/day/kg body weight.
  • the dose is 1 to 500 mg.
  • the daily dose for adult patients can be as low as 0.1 mg/day.
  • the pharmaceutical composition containing the active ingredient can be formulated into a form suitable for oral administration, such as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or Soft capsules, or syrups or elixirs.
  • the composition intended for oral administration can be prepared according to any method known in the art of pharmaceutical composition manufacture, and in order to provide a pharmaceutically refined and palatable preparation, the composition may contain one or more selected from the group consisting of sweetness Agents for flavors, flavors, colorants and preservatives. Tablets contain the active ingredient with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch. Or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or coated by known techniques to mask the unpleasant taste of the drug or to prolong disintegration and absorption in the gastrointestinal tract and thus provide a drug effect that lasts longer.
  • a water-soluble taste-masking raw material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose may be employed, or a delayed starting material such as ethylcellulose or cellulose acetate butyrate may be employed.
  • the dosage form of the tablet may be 0.1 mg/tablet, 0.2 mg/tablet, 0.25 mg/tablet, 0.5 mg/tablet, 1 mg/tablet, 2 mg/tablet, 5 mg/tablet, 10 mg/tablet, 25 mg/tablet, 50 mg/tablet, 100 mg/tablet, and 250 mg/tablet.
  • Other dosage forms such as capsules can be used for similar dosage references.
  • Intestinal enzyme nulating Intestinal enzyme nulating
  • the preparation for oral use can also be formulated into a hard gelatin capsule in which the active ingredient is mixed in an inert solid diluent such as calcium carbonate, sodium carbonate or kaolin; or a soft gelatin capsule in which the active ingredient is mixed in a water-soluble carrier
  • an inert solid diluent such as calcium carbonate, sodium carbonate or kaolin
  • a soft gelatin capsule in which the active ingredient is mixed in a water-soluble carrier
  • a water-soluble carrier for example, polyethylene glycol or an oily medium such as peanut oil, liquid paraffin or olive oil.
  • the aqueous suspension contains the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, or gum arabic; such aqueous suspensions may also contain a Or a plurality of preservatives such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose, saccharin Or aspartame.
  • An oily suspension can be prepared by suspending the active ingredient in a vegetable oil, for example, peanut oil, sesame oil, coconut oil, or olive oil, a mineral oil such as liquid paraffin.
  • a vegetable oil for example, peanut oil, sesame oil, coconut oil, or olive oil, a mineral oil such as liquid paraffin.
  • Such oily suspensions may contain a thickening agent such as beeswax, paraffin wax or cetyl alcohol.
  • Sweetening agents and flavoring agents as described above may be added to provide a formulation suitable for oral administration.
  • These compositions can be stored by the addition of an anti-oxidant such as butylated hydroxyanisole or a tocopherol.
  • Dispersible powders or granules are suitable for the preparation of aqueous suspensions by the addition of water to provide active ingredients in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by the examples referred to above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be present. These compositions can be stored by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil such as peanut oil or olive oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin and esters or liposomes derived from a mixture of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation of the partial esters and alkylene oxides.
  • the product is, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweeteners, flavoring agents, antioxidants, and preservatives.
  • Syrups and elixirs may be prepared using sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain wetting agents, flavoring agents, coloring agents, antioxidants, and preservatives.
  • compositions of the invention may be formulated as sterile injectable solutions.
  • Water, Ringer's solution and isotonic sodium chloride solution can be employed in acceptable vehicles and solvents.
  • Such sterile injectables can also be formulated as a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is first dissolved in a mixture of soybean oil and lecithin, and then the oil solution is placed in a mixture of water and glycerin and treated to form a microemulsion.
  • Such pharmaceutical compositions can be formulated in the form of a sterile injectable solution or oily suspension for intramuscular or subcutaneous administration.
  • This suspension can be prepared according to the known techniques using the dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injectable preparation may also be presented as a sterile injectable solution or suspension in a non-pharmaceutically acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • non-volatile oils are conventionally employed as a solvent or suspension medium.
  • any non-irritating, non-volatile oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid have been found to be useful in injectable formulations.
  • the compounds of formula (I) may be combined with other agents known to treat or ameliorate similar conditions.
  • the mode of administration & dosage of the original drug remains unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
  • a pharmaceutical composition comprising both one or several known drugs and a compound of the formula (I).
  • Combination of drugs also includes the administration of a compound of formula (I) with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula (I) or a known drug may be lower than when they are administered alone.
  • Drugs or active ingredients which may be combined with a compound of formula I include, but are not limited to:
  • the drug that can be administered in combination with a compound of formula (I) includes, but is not limited to, adiponectin, alendronate, interferon, atranoxine, allopurinol, sodium allopurinate , palonosetron hydrochloride, hexamethylene melamine, aminoglumidine, amifostine, amrubicin, amsacrine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, arba Nuoxin, 5-azacytidine, azathioprine, BCG, betahidine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromide, bortezomib, busulfan , calcitonin, alemzumab injection, capecitabine, carboplatin, cisplatin, constance, cefesone, sir, interleukin
  • the conventional post-treatment method is: after the reaction is completed, an appropriate amount of water is added to the reaction liquid, the organic phase and the aqueous phase are separated, and the organic phase is combined; if necessary, 5% HCl is sequentially used.
  • the solution and/or saturated NaSO 4 are dried, filtered, and dried under reduced pressure to give a crude product which is purified by column chromatography to give the final product.
  • the biochemical activity of a compound is determined based on its degree of inhibition of the deacetylation of the HDAC enzyme. After incubation with a fluorescently labeled substrate containing an acetylated lysine side chain and HDAC enzyme, the fluorescent substrate is deacetylated. After the deacetylated fluorescently labeled substrate is cleaved by the enzyme, a fluorescent substance is released, which generates an emission light of 460 nm under excitation of 360 nm light.
  • reaction concentration 20M
  • HDAC enzyme is diluted to the appropriate concentration
  • the compounds to be tested are added at different concentrations, reacted at 37 ° C for 30 minutes, and then the same volume of 2 is added.
  • concentration of substrate developer was incubated for 15 minutes at room temperature. Finally, the reading was measured with a microplate reader. The excitation light was 360 nm, the emission was 460 nm, and the data was processed with Prime 4 software.
  • the IC 50 in the above table refers to the inhibitor concentration (50% inhibitory concentration) when it is inhibited by half.
  • the above compound has a remarkable activity of inhibiting the deacetylation of the HDAC enzyme as compared with the positive control (SAHA).
  • the structure of the compound of the present invention is compared with the related related compounds, and the results of the enzyme activities are shown in Table 2, showing significant advantages ranging from several times to several tens of times.
  • the introduction of a side chain at positions 4, 5, 6, and 7 of the oxime can improve its activity on histone deacetylase. Compared with the existing compounds, the activity can be increased by more than 10 times.
  • An alkyl or alkane substituent may be introduced at the 1, 2 and 3 positions of the anthracene ring, and its activity on histone deacetylase is substantially equal to or better than that of the parent compound.
  • the introduction of other cyclic structures at the 2,3 position of the indole ring is substantially equivalent to the parent compound in the activity of the histone deacetylase.
  • the introduction of a substituent on the double bond is slightly less active against the histone deacetylase than the parent compound.
  • the intermediate benzene ring introduces a fluorine or nitrogen-containing hetero atom, and its activity on histone deacetylase is substantially equivalent to that of the parent compound.
  • the anthracene ring can be substituted with benzofuran or benzothiophene, which has substantially equivalent activity to histone deacetylases as the parent compound.
  • the principle of the MTT method is that the yellow thiazole blue can enter the cell through the cell membrane, and the amber dehydrogenase in the living cell mitochondria can reduce the exogenous MTT to the blue-violet needle-like Formazan crystal which is hardly soluble in water and deposit on the cell.
  • the crystal can be dissolved by dimethyl sulfoxide (DMSO), and the light absorption value is detected by an enzyme-linked immunosorbent detector at a wavelength of 490 nm / 570 nm, which can indirectly reflect the number of cells.
  • DMSO dimethyl sulfoxide
  • the cancer cell lines used were Hela (human cervical cancer cells), MCF-7 (human breast cancer cells), BGC-823 (human gastric cancer cells), A549 (human lung cancer cells), HT1080 (human fibers).
  • Sarcoma cells A431 (human epidermal squamous cell carcinoma cells), DU145 (human prostate cancer cells), U937 (human leukemia cells), Pac-1 (human pancreatic cancer cells), MOLT-4 (human acute lymphoblastic leukemia) Cells); cultured in DMEM + 10% FBS medium or 1640 + 10% FBS, respectively.
  • Negative control group 190 ⁇ l cell suspension + 10 ⁇ l 2% DMSO (final concentration of DMSO 0.1%)
  • Positive control group 190 ⁇ l cell suspension + 10 ⁇ l of different concentrations of compound
  • the cells were seeded in a 96-well plate at a dose of 1500 cells/well, 190 ⁇ l/well, and cultured overnight at 37 ° C in a 5% CO 2 incubator;
  • the GI 50 in the above table indicates the concentration of 50% growth inhibition required for cell growth inhibition.
  • the above drugs have a significant activity of inhibiting the growth of the listed tumor cells as compared with the positive control (SAHA).
  • the compounds of the present invention show significant advantages over the existing compounds, and the results of tumor cell activity are shown in Table 4.
  • the introduction of a side chain at the 4, 5, 6, and 7 positions of guanidine can greatly enhance the activity of its anti-tumor cells. Compared with the existing compounds, the activity can be increased by 10 to 100 times or more.
  • An alkyl or alkane substituent may be introduced at the 1, 2 and 3 positions of the anthracene ring, and the activity against the tumor cells is substantially equal to or better than that of the parent compound.
  • the introduction of other cyclic structures at the 2,3 position of the anthracene ring is substantially equivalent to that of the parent compound.
  • the introduction of a substituent on the double bond is slightly less active against the tumor cells than the parent compound.
  • the intermediate benzene ring introduces a fluorine or nitrogen-containing hetero atom, and its activity against tumor cells is substantially equivalent to that of the parent compound.
  • the anthracene ring may be substituted by benzofuran or benzothiophene, and its activity against tumor cells is substantially equivalent to that of the parent compound.
  • HCT116 cells 5 ⁇ 10 6 HCT116 cells were inoculated into the right anterior iliac crest of BALB/C nude mice.
  • the tumors grew to a size of 100-200 mm3, they were administered orally in groups, and 3 dose groups, 10 mg/kg, 20 mg/kg, and 40 mg were set.
  • /kg, iv, qd, 8-10/group the animal weight was weighed every two days, and the tumor volume was measured (the initial tumor volume and body weight were recorded on the day of grouping).

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Abstract

本发明公开了一种具有通式I的杂环羟肟酸类化合物及其药学上可接受的酸或碱盐或立体异构体。本发明涉及的化合物及其药学上可接受的盐可以有效抑制多种肿瘤细胞的生长，并对组蛋白去乙酰化酶产生抑制作用，可用于制备抗肿瘤药物。

Description

杂环羟肟酸类化合物及其药用组合物和应用 技术领域
本发明属于化学医药领域，具体地涉及具有式(I)结构特征的杂环吲哚羟肟酸类化合物或其药学上可接受的盐或立体异构体及其前药分子,含有这种化合物的药物组合物和这些化合物或组合物在制备药物中的应用。
背景技术
组蛋白去乙酰化酶(HDACs)是一组在细胞染色质水平、通过诱导组蛋白去乙酰化来调控包括染色质重组、转录活化或抑制、细胞周期、细胞分化及细胞凋亡等一系列生物学效应的酶，特别是与细胞活化后的基因转录表达调控有关。染色质的组蛋白乙酰化和去乙酰化是调节基因表达的关键环节之一，而异常的基因表达是肿瘤及一些遗传和代谢疾病发生的分子生物学基础。组蛋白的乙酰化程度，有组蛋白乙酰化酶(HAT)和组蛋白去乙酰化酶(HDAC)协调控制的。肿瘤的发生与核小体核心组蛋白N-端的赖氨酸残基的乙酰化和去乙酰化的失衡有密切关系。在体内,其动态平衡是由HAT和HDAC共同维持。在染色质基因转录活跃区，其核心组蛋白的乙酰化活性增高；相反，在基因转录非活跃区，其乙酰化程度偏低。
目前已知组蛋白去乙酰化酶有18个不同的亚型，按种系分为4大类：I类包括HDAC1、HDAC2、HDAC3和HDAC8，只存在于细胞核中；II类包括HDAC4、HDAC5、HDAC6、HDAC7、HDAC9、和HDAC10和HDAC11，在信号转导过程中穿梭于细胞核与细胞质之间；III类是SIRT1-SIRT7与前两类有很大的区别，其活性不是依赖Zn2+，而是依赖辅酶I(NAD)，至少有7种亚型，它不能被I，II类HDAC抑制剂所抑制；和Ⅳ类是HDAC11,包含有I类和II类HDACs的催化位点。其中Ⅰ、Ⅱ、Ⅳ为经典家族，是Zn2+依赖性的HDAC。目前临床研究的绝大多数HDAC抑制剂能够抑制HDAC的多个亚型，这些亚型往往属于Zn2+依赖性的HDAC家族。
组蛋白去乙酰化酶抑制剂(HDAC inhibitor，HDACIs)则是一类抑制HDACs活性的化合物。实验证明，HDAC抑制剂会使染色质组蛋白乙酰化水平提高，因此导致特定基因激活表达如p21、p53等，相应的导致细胞的末端分化或癌细胞的凋亡。因此，HDAC已成为目前肿瘤化疗药物研发领域最热门的靶标之一。
组蛋白去乙酰化酶抑制剂一般包括锌离子结合区，连接区和表面识别区三个部分。抑制剂与锌离子的直接作用是产生抑制活性所必须的。HDAC抑制剂主要包括以下四类：(1)短链脂肪酸，如丁酸，苯丁酸及其盐类化合物；(2)羟肟酸类，这是迄今研究最广泛的一类HDAC抑制剂，如辛二酰苯胺异羟肟酸(suberoylanilide hydroxamic acid，SAHA)和曲古抑菌素A(trichostatin A，TSA)；(3)环四肽类，环肽类化合物是结构最为复杂的一类抑制剂，环肽类抑制剂的分子中氨基酸大环作为疏水的表面识别区，烷基链作为连接区，烷基链末端连 接着一个锌离子结合基团，如trapoxin，HC-toxon，Apicidin，FK228和Largazole等；(4)苯甲酰胺类化合物，这类化合物的活性比一般的羟肟酸类和环肽类化合物低，但是对Ⅰ类HDAC具有较高的选择性。如MS-275，CI-994等。作为新一代靶向抗肿瘤药物！与传统的抗肿瘤药物相比,组蛋白去乙酰化酶抑制剂具有低细胞毒性的优势。2006年，美国FDA批准默克公司的辛二酰苯胺异羟肟酸(suberoylanilide hydroxamic acid，SAHA)以vorinostat(Zolinza)上市，用于治疗转移性皮肤T细胞淋巴瘤(CTCL)，这是第一个面世的组蛋白去乙酰化酶抑制剂类抗肿瘤药物。2009年天然产物FK228以注射用药物Istodax(romidepsin)上市，也于治疗皮肤T淋巴细胞瘤(CTCL)，成为继Zolinza之后，第二个上市的组蛋白去乙酰化酶抑制剂。2011年FDA批准其治疗外周T细胞淋巴瘤(PTCL)。
由于目前已上市的组蛋白去乙酰化酶抑制剂类药物的疗效不确切、毒副作用较大。因此需要一种新的低毒高效的组蛋白去乙酰化酶抑制剂以克服现有药物耐受并提高临床效果,本发明因此而来。
发明内容
本发明提供一种杂环吲哚羟肟酸类化合物的组蛋白去乙酰化酶抑制剂，用以解决现有药物疗效不确切、毒副作用较大的缺陷等问题。本发明还提供该种杂环吲哚羟肟酸类的组蛋白去乙酰化酶抑制剂的制备方法，以及药物用途。
首先，本发明提供了具有通式I所示的化学结构的杂环吲哚羟肟酸类化合物，及其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物：
Figure PCTCN2014092104-appb-000001
其中，
X任选为N,O或S，且X被0-1个取代基取代，所述取代基为C1-C10烷基；
W,Y,Z任选为CH或N；
R1基团任选自：
2)氢；
2)C1-C12烷基；
3)-CH2-O-(C1-C12烷基)；
4)-CH2-NH-(C1-C12烷基)；
5)-CH2-S-(C1-C12烷基)；
6)C6-C12芳基；
7)杂芳基；
8)-CH2-(C6-C12芳基)或-CH2-杂芳基；
上述的C6-C12芳基，杂芳基，-CH2-C6-C12芳基，-CH2-杂芳基，含有或不含有1个或多个取代基，其取代基选自卤素、氨基、羟基、硝基、氰基、C1-C12烷基、C1-C12烷氧基、氨基C1-C12烷基、C1-C12酰基、C1-C12酰氧基、硫代C1-C12烷基、羧基或苯基；
R2基团任选自：
1)氢；2)卤素；3)C1～C5烷基；4)C3～C6环烷基；5)C1～C5含氟烷基；
R3基团任选自：
2)氢；2)C1～C10烷基；3)C3～C9环烷基；4)C4～C9杂环烷基；5)C6-C12芳基；6)C6-C12杂芳基；7)C6-C12芳烷基；8)C6-C12杂芳烷基；9)-(CH2)nC(O)R6；10)-(CH2)-OC(O)R6；11)C1-C12酰基；12)–(CH2)nR7；13)C1-C12烷羟基
n为0-6的整数；
R4,R5基团任选自：
1)氢；2)卤素；3)C1～C5烷基；4)C1-C12烷羟基；5)C1～C5含氟烷基；6)芳基或7)R4和R5形成五元、六元、七元或八元杂环结构
Figure PCTCN2014092104-appb-000002
其中X1,Y1任选自N,O,S,CH；n2,n3为0、1、2或3；
R6基团任选自：
1)氢；2)C1～C6烷基；3)C3～C9环烷基；4)C4～C9杂环烷基；5)C6-C12芳基；6)杂芳基；
R7基团任选自：
1)C1～C6烷基醚；2)C1～C6烷基硫醚；3)C1～C6烷基胺；4)C1～C6烷基磺酰胺基；
所述杂芳基选自吡啶,吡唑,吡嗪,吡咯,咪唑,呋喃,噻吩,苯并呋喃,苯并噻吩；
烷基胺的側链是在吲哚环的4,5,6或7位上。
本发明还提供制备式I所示的杂环吲哚羟肟酸类化合物的方法，该方法包括如下步骤：
(1)将式II化合物和式III化合物在还原剂的作用下进行缩合反应，得到式IV化合物；反应过程如下所示：
Figure PCTCN2014092104-appb-000003
(2)将式IV化合物在碱性作用下与R3X进行缩合反应，得到式V化合物；反应过程如下所示：
Figure PCTCN2014092104-appb-000004
(3)将式IV化合物或式V化合物在碱性作用下与羟氨进行缩合反应，得到式I化合物；反应过程如下所示：
Figure PCTCN2014092104-appb-000005
其中，
R1、R2、R3、R4、R5同权利要求1中所述；
进一步地，所述的还原剂选自氰基钠硼氢,硼氢化钠,硼烷,硼氢化钾,硼氢化锂,硼氢化钠,四氢铝锂,醋酸钠硼氢；有机碱选自咪唑、三乙胺、二异丙基乙胺、哌啶、二甲基吡啶、LiHMDS、NaHMDS、KHMDS、N-甲基吗啉、DABCO,碳酸钾,碳酸钠,碳酸镁,碳酸钙,碳酸铯,氢氧化钠,氢氧化钾,氢氧化锂,氢氧化铯,氢氧化镁,氢氧化钙或吡啶；所述的卤代烷烃选自碘甲烷,碘乙烷,溴乙烷,2-碘乙醇,2-溴乙醇,2-氯乙醇,溴丁烷,溴戊烷,溴己烷,溴庚烷,溴辛烷,溴壬烷,溴奎烷,卤代C3～C9环烷基,卤代C4～C9杂环烷基,卤代C6-12芳基,卤代C6-12杂芳基,卤代C6-12芳烷基(如苄基),卤代C6-12杂芳烷基(如吡啶甲基),X(CH2)nC(O)R6,X(CH2)-OC(O)R6,或卤代酰基。
本发明还提供制备通式II化合物的方法，该方法包括如下步骤：
(1)杂环醛与硝基甲烷反应得到化合物a，反应过程如下所示：
Figure PCTCN2014092104-appb-000006
(2)化合物a和还原剂反应得通式II化合物；反应过程如下所示：
Figure PCTCN2014092104-appb-000007
上述的合成反应过程中，必要的有机溶剂可以选自二氯甲烷、四氢呋喃(THF)、二甲基甲酰胺(DMF)、乙二醇二甲醚、1,2-二氯乙烷、邻苯二甲酸二甲酯(DMP)、甲醇、乙醇、石油醚、正己烷或乙醚；必要的无机碱可以选自氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钠、碳酸钙；必要的酸可以选自三氟乙酸、盐酸、硫酸或硝酸。所述的还原剂可以是氰基钠硼氢,硼氢化钠,硼烷,硼氢化钾,硼氢化锂,硼氢化钠,四氢铝锂,醋酸钠硼氢或镭尼 镍。
本发明的另一目的是提供以上述化合物的应用。
上述化合物及其药学上可接受的盐或立体异构体或其前药分子在制备治疗或预防肿瘤的药物中的应用。
本发明还涉及了利用有效剂量的上述化合物可以用于治疗淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、白血病和宫颈癌等过渡增殖性疾病。
本发明涉及的杂环吲哚羟肟酸类化合物及其药学上可接受的盐,可以有效抑制多种肿瘤细胞的生长,并对组蛋白去乙酰化酶产生抑制作用,可用于制备抗肿瘤药物。如本领域人员所理解的,本申请所涉及的化合物及其药学可接受的盐可用于制备治疗人类及其它哺乳动物的肿瘤等过渡增殖性疾病。
本发明涉及的杂环吲哚羟肟酸类化合物及其药学上可接受的盐可以用于治疗组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、艾滋病、老年痴呆、疟疾和糖尿病。
应当说明的是，本文所使用相关术语诸如“烷基”“芳基”“杂芳基”“卤素”“酰基”等等与所属领域中所述术语的一般含义无明显不同。
例如，术语“烷基”指直链或支链，C1～n烷基则表示1-n个碳原子的饱和的脂烃基，包括直链和支链，例如“C1～12烷基”指的是该基团为烷基，且烷基的碳链上碳原子的数量在1-12之间。应当说明的是，当没有特别限制其碳原子数时，仅指其中指明的烷基部分的碳原子数，而并不包括烷基的取代基上碳原子数。
本领域的普通技术人员应当知道下列术语或缩写的含义。
术语“药物上可接受的盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐，比如胺、羧酸和其它类型化合物的医学上可接受的盐在所属领域中是被熟知的。
术语“异构体”是指分子组成相同、但结构和性质不同的两种或多种化合物。
术语“外消旋体”是指一种具有旋光性的手性分子与其对映体的等摩尔混合物，它由旋光方向相反、旋光能力相同的分子等量混合而成，其旋光性因这些分子间的作用而相互抵消，因而是不旋光的。
术语“溶剂合物”是指化合物与溶剂组成的混合物，例如结晶体即是一种溶剂合物。
术语“前体药物”指通过在血液中水解而活体内快速转化产生具有上述化学式的母体化合物的化合物。
具体实施方式
本发明所述化合物中,当任何变量(例如R1,R2等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果 环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域的普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料,容易的合成目标化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
应当说明的是，本文所使用相关术语诸如“烷基”“芳基”“杂芳基”“卤素”“酰基”等等与所属领域中所述术语的一般含义无明显不同。
例如，术语“烷基”指直链或支链，C1～n烷基则表示1-n个碳原子的饱和的脂烃基，包括直链和支链，例如“C1～12烷基”指的是该基团为烷基，且烷基的碳链上碳原子的数量在1-12之间。应当说明的是，当没有特别限制其碳原子数时，仅指其中指明的烷基部分的碳原子数，而并不包括烷基的取代基上碳原子数。“环烷基”指的是具有特定碳原子数的单环饱和的脂烃基。例如“环烷基”包括环丙基,甲基-环丙基,2,2-二甲基-环丁基,2-乙基-环戊基,环己基等。
本文所使用术语“杂芳基”代表环中多达6个原子的稳定的单环或每个环中多达6个原子双环碳环,其中至少一个环为芳香环且含有1-4个选自O,N和S的杂原子。本定义范围内的杂芳基包括但不限于:咪唑基、噻唑基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、吡嗪基、哒嗪基、嘧啶基、吡咯基、吡啶基。对于于“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。在杂芳基取代基是双环的且含有一个环为非芳香性或不含有杂原子的例子中,应理解各自经芳香环或含杂原子环连接。
正如本领域技术人员所理解的,本文中所用“卤素”意指包括氯,氟,溴和碘。
除非另有定义,烷基,环烷基,芳基,杂芳基和杂环基取代基可为未被取代的或取代的.例如,(C1-C6)烷基可被一个,两个,或三个选自OH,卤素,烷氧基,二烷基氨基或杂环基例如吗啉基,哌啶基等取代基取代。
本发明包括式I的游离形式,也包括药学上可接受的盐及立体异构体。文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括药学上可接受的盐不仅包括本文所述特定化合物的示例性盐,也包括所有式I化合物游离形式的典型的药学上可接收的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,通过适当的碱稀水溶液如氢氧化钠稀水溶液,碳酸钠稀水溶液,,稀氨水溶液及碳酸氢钾稀水溶液处理该盐使游离形式再生.游离形式在某些物理性质如在极性溶剂中的溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规无毒盐包括得自无机酸例如盐酸、硫酸、 氢溴酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、乙酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、2-乙酰氧基-苯甲酸、富马酸、对甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明的化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂,例如精氨酸、甜菜、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、甲基葡萄糖胺、组氨酸、赖氨酸、异丙基胺、吗啉、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
在一个实施方案中,本申请提供了一种利用具有式(I)的化合物及其药学可接受的盐治疗人或其它哺乳动物肿瘤等过渡增殖性疾病或症状。
在一个实施方案中,本申请所设计的化合物及其药学可接受的盐可以用于治疗或控制淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、白血病和宫颈癌等过渡增殖性疾病。
在一个实施方案中,本申请所设计的化合物及其药学可接受的盐可以与目前应用的或处于开发阶段的细胞毒素/细胞抑制剂、雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂、细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组蛋白去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、COX-2抑制剂、整联蛋白阻滞剂、P53激活剂、VEGF抗体、EGF抗体等药物联合用药增加其临床效果。
本申请所涉及的化合物及其药学可接受的盐可根据下面的方法用于治疗下列的疾病以及下面没有列出的其它疾病:
1)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的乳腺癌的方法。包括但不局限于侵袭性导管癌、侵袭性小叶癌、原位管癌和原位小叶癌。
2)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的呼吸道癌的方法。包括但不局限于小细胞&非小细胞肺癌、支气管腺癌和胸膜肺母细胞瘤。
3)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的脑癌的方法。包括但不局限于脑干和眼下神经胶质瘤、小脑和大脑星形细胞瘤、室管膜细胞瘤以及神经外胚层和松果体瘤。
4)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的雌、雄性生殖器官的肿瘤的方法。雄性生殖器官的肿瘤包括但不局限于前列腺和睾丸癌。雌性生殖器官的肿瘤包括但不局限于宫颈癌、子宫内膜癌、卵巢癌、阴道癌和外阴癌以及子宫内瘤。
5)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的消化道癌的方法。包括但不局限于肛门癌、结肠癌、结肠直道癌、食道癌、胃癌、胰腺癌、直肠癌、小肠癌、和唾腺癌。
6)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的尿道癌的方法。包括但不局限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌、和尿道癌。
7)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的眼癌的方法。包括但不局限于眼内黑素瘤和视网膜细胞瘤。
8)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的肝癌的方法。包括但不局限于肝细胞瘤(具有或不具有纤维板变化的肝细胞癌)、胆管癌(肝内胆管癌)和混合的肝细胞性胆管癌。
9)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的皮肤癌的方法。包括但不局限于扁平细胞癌、卡波济氏肉瘤、恶性黑色素瘤、默克氏细胞皮肤癌、和非黑素瘤细胞癌。
10)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的头颈癌的方法。包括但不局限于喉、下咽、鼻咽、口咽癌以及唇和口腔癌。
11)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的淋巴瘤的方法。包括但不局限于AIDS相关的淋巴瘤、非何杰金淋巴瘤、皮肤T细胞淋巴瘤、全身T细胞淋巴瘤、何杰金淋巴瘤和中枢神经系统淋巴瘤。
12)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的肉瘤的方法。包括但不局限于软组织肉瘤、骨肉瘤、恶性纤维性组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
13)一种利用包含本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐的药用组合物治疗人或其它哺乳动物的白血病的方法。包括但不局限于急性骨髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性骨髓性白血病以及多毛细胞白血病。
服用方式与剂量范围
根据标准药学技术,本发明化合物可单独偶或在药用组合物中与药学上可接受的受体、辅料或稀释剂组合给予哺乳动物,优选人。可口服或皮下、肌注、腹膜内、静脉、直肠及局部、眼睛、肺部、鼻腔、胃肠外给予化合物。
在一个实施方案中,利用式(I)化合物治疗或控制癌症等患者时,服用剂量范围为在口服0.1～500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日两次、三次、四次等多次给药或利用缓释技术给药。对于大型哺乳动物,其优选剂量范围为0.1～1500毫克/天/公斤体重。对于平均体重为70公斤的病人,其剂量为1～500毫克。对于一些特别高活性化合物,成年病人每日剂量可低达0.1毫克/天。
在一个实施方案中,利用式(I)化合物治疗或控制癌症等患者时,服用剂量范围为在静脉注射0.1～500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日两次、三次、四次等多次给药或利用缓释技术给药。对于大型哺乳动物,其优选剂量范围为0.1～1500毫克/天/公斤体重。对于平均体重为70公斤的病人,其剂量为1～500毫克。对于一些特别高活性化合物,成年病人每日剂量可低达0.1毫克/天。
剂型
这种含有活性成分的药用组合物可制成适于口服给药形式,例如片剂、含片、锭剂、水或油混悬液、可分散粉剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、或糖浆剂或酊剂。可根据药用组合物制造领域中任何已知方法制备预期口服给以予的组合物,并且为提供药学上精制的及适口的制剂,这种组合物可含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的药剂。片剂含有活性成分与无毒的适用于制造片剂的药学上可接受的辅料。这些辅料可为例如,惰性稀释剂如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；制粒剂(granulating)和崩解剂如微晶纤维素、交联羧甲纤维素钠、玉米淀粉或海藻酸；粘合剂例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；及润滑剂例如硬脂酸镁、硬脂酸或滑石粉。片剂可不包衣或通过已知技术包衣从而掩盖药物的不良味道或延长在胃肠道中崩解和吸收且因而提供持续更长时间的药物效应。例如,可采用水溶性掩盖味道的原料例如羟丙基-甲基纤维素或羟丙纤维素,或采用延时原料例如乙基纤维素、醋酸丁酸纤维素。片剂剂型可为0.1毫克/片、0.2毫克/片、0.25毫克/片、0.5毫克/片、1毫克/片、2毫克/片、5毫克/片、10毫克/片、25毫克/片、50毫克/片、100毫克/片、和250毫克/片。其它剂型如胶囊等可作相似剂量参考。道肠酶nulating)
口服使用的制剂也可制成硬明胶胶囊剂,其中活性成分混合于惰性固体稀释剂,例如碳酸钙、碳酸钠或白陶土中；或制成软明胶胶囊剂,其中活性成分混合于水溶性载体例如聚乙烯二醇或油性介质如花生油、液体石蜡或橄榄油中。
水混悬液含有与适于制造水混悬液的辅料混合的活性材料。这种辅料为助悬剂例如羧甲纤维素钠、甲基纤维素、羟丙基-甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、或阿拉伯胶；此水混悬液也可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂例如蔗糖、糖精或阿司帕坦。
可通过将活性成分混悬与植物油例如,花生油、麻油、椰子油、或橄榄油中,矿物油例如液体石蜡制备油性混悬液。这种油性混悬液可含有增稠剂例如蜂蜡、固体石蜡或鲸蜡醇。可加入上文所述的甜味剂和调味剂以提供适合口服的制剂。可通过加入抗氧化剂例如丁羟茴醚或a生育酚储存这些组合物。这体酸素钠
可分散粉剂或颗粒剂适于通过加入水制备水混悬液而提供与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性成分。适当的分散剂或湿润剂及助悬剂已通过上文涉及的例子说明。也可存在其他辅料例如甜味剂、调味剂和着色剂。这些组合物可通过加入抗氧化剂例如抗坏血酸而储存。
本发明组合物可制成水包油乳状液的形式。油相可为植物油例如花生油或橄榄油,或矿物油例如液体石蜡或其混合物。适当的乳化剂可为天然存在的磷脂例如大豆卵磷脂及酯类或得自脂肪酸和己糖醇酐混合的偏脂例如脱水山梨糖醇单油酸酯,及所述偏酯和烯化氧的缩合产物例如聚氧乙烯脱水山梨糖醇单油酸酯。此乳剂也可含甜味剂、调味剂、抗氧化剂和防腐剂。
可使用甜味剂例如甘油、丙二醇、山梨醇、或蔗糖制备糖浆剂和酊剂。这种制剂也可含有湿润剂、调味剂、着色剂、抗氧化剂和防腐剂。
本发明组合物可制成无菌注射的水溶液。在可接受的载体和溶剂中可采用水、林格氏液和等渗氯化钠溶液。
这种无菌可注射剂也可制成活性成分溶于油相中的无菌可注射水包油微乳剂。例如,首先将活性成分溶于豆油和卵磷脂的混合物中,然后将油溶液放入水和甘油的混合物中并处理而制成微乳剂。
这种药用组合物可制成用于肌内或皮下给药的无菌可注射溶液或油状混悬液形式。可根据已知技术使用上文中提到的分散剂或湿润剂及助悬剂制备这种混悬液。无菌可注射制剂也可制成在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如作为在1,3-丁二醇中的溶液。另外,常规采用非挥发油作为溶剂或混悬介质。为此目的,可采用任何无刺激性的非挥发油包括合成的甘油一酯或甘油二酯。另外,发现在可注射制剂中使用脂肪酸例如油酸。
药物代谢物及前药
本申请所涉及的化合物及其药学上可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学上可接受的盐的结构的前药,也包括本申请的专利要求中。
联合用药
式(I)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式(I)化合物。当式I化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它其它一种或几种药物进行联用时,式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式I化合物进行药物联用的药物或活性成分包括但不局限为:
细胞毒素/细胞抑制剂、雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂、细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组蛋白去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、COX-2抑制剂、整联蛋白阻滞剂、P53激活剂、VEGF抗体、EGF抗体等。
在一个实施方案中,可以与式(I)化合物进行药物联用的药物包括但不局限为:阿地白介素、阿仑瞵酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射液、卡培他滨、卡铂、顺铂、康士德、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米送、磷酸地塞米送、戊酸雌二醇、地尼白介素2、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、壳聚糖复合物、拉步立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃胞塞啶-5’-硬脂磷酸酯、福莫司汀、氟维司群、丙钟球蛋白、吉西他滨、吉妥单抗、伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤体纸、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素α2、干扰素α-2A、干扰素α-2B、干扰素α-n1、干扰素α-n3、干扰素β、干扰素γ-1a、白细胞介素-2、内含子A、易瑞沙、依立替康凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-巯基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢化可的松口服溶液剂、奥沙利铂、紫杉醇、多西他塞、卡巴他塞、泼尼松磷酸钠、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸皮鲁卡品、毗柔比星、普卡霉素、卜吩姆钠、泼尼莫司汀、泼尼松、司替泼尼松龙、倍美力、丙卡巴齐、重组人类红细胞生成素、雷替曲塞、利比、依替瞵酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、沙莫司亭、司莫司汀、西佐喃、奥布佐生、唬钠甲强龙、帕福斯酸、链佐星、氯化锶-89、左 旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁瞵酸、拓扑替康、托瑞米芬、托西莫单抗、曲瑞妥珠单抗、曲奥舒凡、维甲酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、吉西他滨、阿霉素-MTC、伊班瞵酸、兰乐肽、拉索昔芬、米泼昔芬、米诺屈酸酯、脂质体MTP-PE、那法瑞林、诺拉曲特、紫杉醇聚谷氨酸酯、西奥骨化醇、埃罗替尼、紫杉醇脂质体、tipifarnib、SAHA、替拉扎明、伐普肽、vatalanib、维替泊芬、长春氟宁或它们的组合。
为了更好的说明本发明的技术内容，下面结合具体实例对本发明作进一步阐述,但该实施例并非用于限制本发明的保护范围。
应当说明的是，下述实施例中，常规后处理方法是：反应完成后，在反应液中加入适量的水，分离有机相和水相，合并有机相；如有需要，依次使用5％HCl溶液和/或饱和NaSO4干燥，过滤之后减压选干，得到粗产物，再经过柱层析分离纯化之后得到最终产物。
实施例1
Figure PCTCN2014092104-appb-000008
步骤1.(E)-4-(2-硝基乙烯基)-1H-吲哚
Figure PCTCN2014092104-appb-000009
吲哚-4-甲醛(1g,6.89mmol)和(NH4)2OAc(266mg,3.44mmol)溶于硝基甲烷(16 ml)中,然后向溶液中加入乙酸楚(6.9ml,6.9mmol).在110℃条件下,反应12h,旋干反应液,剩余物用水稀释,然后加入乙酸乙酯(30mL×3)萃取,有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，硅胶柱层析得到桔红色固体600mg，产率60％。1H NMR(400MHz,CDCl3),δ8.51(br,1H),8.21(d,J＝15.6Hz,1H),7.89(s,1H),7.70(d,J＝15.2Hz,1H),7.49(d,J＝8.4Hz,1H),7.44(dd,J＝1.6,8.4Hz,1H),7.35(t,J＝2.8Hz,1H),6.68(t,J＝2.2Hz,1H)ppm.MS(EI,m/z):189(M++1).步骤2.4-(2-硝乙基)-1H-吲哚
Figure PCTCN2014092104-appb-000010
(E)-4-(2-硝基乙烯基)-1H-吲哚(988mg,5.25mmol)溶于MeOH/THF(1:1,20mL)中,0℃时分批加入NaBH4(875mg,23.09mmol).加完后,移去冰浴,反应液在室温下搅拌半小时。蒸干溶剂，硅胶柱层析得到黄色油状液体体798mg，产率80％。1H NMR(400MHz,CDCl3):δ8.28(br,1H),7.34(d,J＝8.0Hz,1H),7.27-7.25(m,1H),7.16(t,J＝7.6Hz,1H),6.96(d,J＝7.2Hz,1H),6.59(s,1H),4.72(t,J＝7.6Hz,2H),3.63(t,J＝7.8Hz,2H)ppm.MS(EI,m/z):191(M++1).
步骤3.4-(2-氨乙基)-1H-吲哚
Figure PCTCN2014092104-appb-000011
将催化量的Raney-Ni在95％乙醇(6ml)加入到4-(2-硝乙基)-1H-吲哚(500mg,2.63mmol)和水合肼(0.38ml,7.89mmo)在95％乙醇(7ml)的溶液中。回流12h后,过滤除去固体,蒸干溶剂，硅胶柱层析得到棕色固体331mg，产率78％。1H NMR(400MHz,CDCl3):δ8.59(br,1H),7.27(d,J＝8.8Hz,1H),7.19(t,J＝2.6Hz,1H),7.14(t,J＝7.6Hz,1H),6.95(d,J＝7.2Hz,1H),6.59(s,1H),3.13-3.04(m,4H)ppm.MS(EI,m/z):161(M++1).
步骤4.(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)丙烯酸甲酯
Figure PCTCN2014092104-appb-000012
向4-(2-氨乙基)-1H-吲哚(393mg,2.45mmol)甲醇溶液中(20ml)分批慢慢加入(E)-3-(4-甲醛基苯基)丙烯酸甲酯(389mg,2.04mmol)和醋酸(0.12ml,2.04mmol)。五分钟后,加入NaBH3CN(257mg,4.08mmol)。反应2h后,用饱和NaHCO3淬灭反应液,然后加入乙酸乙酯(30mL×3)萃取,有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，硅胶柱层析得到黄色液体(698mg,85％)。1H NMR(400MHz,CDCl3):δ8.26(br,1H),7.67(d,J＝16.0Hz,1H),7.44(d,J＝8.0Hz,2H),7.29-7.26(m,3H),7.20(t,J＝2.8Hz,1H),7.13(t,J＝7.6Hz,1H),6.95(d,J＝6.8Hz,1H),6.59(s,1H),6.41(d,J＝16.0Hz,1H),3.83(s,2H),3.80(s,3H),3.14(t,J＝7.0Hz,2H),3.04(t,J＝6.8Hz,2H)ppm.MS(EI,m/z):335(M++1).HRMS(ESI):calcd for C21H22N2O2[MH+]335.1681,found 335.1682.
步骤5.(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000013
在冰浴条件下,向(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)丙烯酸甲酯(202mg,0.6mmol)的甲醇(1.5ml)溶液中加入新制的2M NH2OH甲醇溶液(3ml,6mmol)和KOH(58mg,0.91mmol,87％w/w)甲醇溶液(1.5ml).室温反应12h后,蒸干溶剂，硅胶柱层析得到淡黄色固体141mg，产率70％。1H NMR(400MHz,MeOD):δ7.56-7.52(m,3H),7.35(d,J＝8.0Hz,2H),7.27(d,J＝8.4Hz,1H),7.22(d,J＝3.2Hz,1H),7.03(t,J＝7.6Hz,1H),6.85(d,J＝7.2Hz,1H),6.50-6.44(m,2H),3.93(s,2H),3.31-3.09(m,4H)ppm.13C NMR(125MHz,MeOD):δ162.1,136.9,135.4,133.8,132.0,126.8,126.6,125.1,124.7,121.5,118.4,116.0,114.8,107.0,96.3,49.2,45.9,29.2ppm.HRMS(ESI):calcd for C20H22N3O2[MH+]336.1634,found 336.1635.
实施例2
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
Figure PCTCN2014092104-appb-000014
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.0(s,NH),8.0(brs,NH),7.66-7.50(m,4H),7.37(d,J＝8.0Hz,2H),7.28(d,J＝8.0Hz,2H),7.25(d,J＝3.2Hz,1H),7.03(t,J＝7.6Hz,1H),3.93(s,2H),3.31-3.09(m,4H),1.71(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1792.
实施例3
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000015
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.0(brs,NH),8.01(brs,NH),7.56-7.52(m,3H),7.35(d,J＝8.0Hz,2H),7.27(d,J＝8.4Hz,1H),7.22(d,J＝3.2Hz,1H),7.03(t,J＝7.6Hz,1H),6.85(d,J＝7.2Hz,1H),6.50-6.44(m,2H),3.93(s,2H),3.11-3.02(m,4H),2.30(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1792.
实施例4
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000016
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.1(brs,NH),8.03(brs,NH),7.59-7.55(m,3H),7.38(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),7.25(d,J＝7.2Hz,1H),7.03(d,J＝15.6Hz,1H),6.85(d,J＝7.2Hz,1H),6.53(d,J＝15.6Hz,1H),3.96(s,2H),3.19-3.12(m,4H),2.41(q,J＝6.8Hz,2H),1.08(t,J＝6.8Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947,found 364.1948.
实施例5
(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000017
合成方法如实施例1。
1H NMR(400MHz,CDCl3):δ8.24(br,1H),7.69(d,J＝16.0Hz,1H),7.45(d,J＝8.0Hz,2H),7.30-7.26(m,3H),7.18-7.12(m,2H),6.91(d,J＝6.8Hz,1H),6.46-6.42(m,2H),3.84(s,3H),3.76(s,2H),3.54(t,J＝5.2Hz,2H),3.12-3.08(m,2H),2.95-2.91(m,2H),2.75(t,J＝5,2Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896,found 380.1896.
实施例6(E)-3-(4-((2-(2-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000018
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.55-7.53(m,3H),7.37(d,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.12(d,J＝3.2Hz,1H),7.00(t,J＝13.6Hz,1H),6.93(d,J＝3.2Hz,1H),6.52(t,J＝13.6Hz,1H),3.97(s,2H), 3.35-3.19(m,4H)2.89(s,3H)ppm.13C NMR(125MHz,MeOD):δ162.2,136.7,135.7,133.9,132.3,126.9,126.6,125.6,124.8,121.7,118.6,116.2,114.9,107.1,49.5,45.8,29.5,18.9ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1789.
实施例7(E)-3-(4-((2-(2-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000019
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.01(brs,NH),7.56-7.52(m,3H),7.36(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),7.12(s,1H),7.00(d,J＝13.6Hz,1H),6.52(d,J＝13.6Hz,1H),3.98(s,2H),3.36-3.20(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1789.
实施例8(E)-N-羟基-3-(4-((2-(1,2,3,4-四氢环戊烷并[b]吲哚-8-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000020
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.03(brs,NH),7.59-7.55(m,3H),7.38(d,J＝8.2Hz,2H),7.25(d,J＝8.2Hz,2H),7.33(d,J＝15.6Hz,1H),6.55(d,J＝15.6Hz,1H),3.95(s,2H),3.16-3.05(m,4H),2.45-2.60(m,4H),2.06(brs,OH),1.88(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found 376.1948.
实施例9(E)-3-(4-((2-(苯并呋喃-4-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000021
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.02(brs,NH),7.53(d,J＝13.6Hz,1H),7.49-7.35(m,3H),7.28(d,J＝8.0Hz,2H),7.15(d,J＝8.0Hz,2H),6.55(d,J＝13.6Hz,1H),4.01(brs,NH),3.93(s,2H),3.15-3.04(m,4H),3.01(t,J＝6.6Hz,2H),2.45(t,J＝6.6Hz,2H),2.02(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]337.1474,found 337.1476.
实施例10(E)-3-(4-((2-(苯并噻吩-4-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000022
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.00(brs,NH),8.00(brs,NH),7.55(d,J＝13.8Hz,1H),7.28(d,J＝8.2Hz,2H),7.13-7.07(m,3H),7.05(d,J＝8.2Hz,2H),6.88(d,J＝13.8Hz,1H),3.93(s,2H),3.86(s,2H),3.70(s,2H),3.00(t,J＝6.8Hz,2H),2.72(t,J＝6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C20H20N2O2S[MH+]353.1245,found 353.1246.
实施例11(E)-3-(4-(((2-(苯并呋喃-4-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000023
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.54(d,J＝13.8Hz,1H),7.26(d,J＝8.2Hz,2H),7.15-7.08(m,3H),7.06(d,J＝8.2Hz,2H),6.85(d,J＝13.8Hz,1H),3.85(s,2H),3.33(t,J＝7.6Hz,2H),3.00(t,J＝7.8Hz,2H),2.92(t,J＝6.8Hz,2H),2.70(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H23N2O3[MH+]351.1630,found 351.1629.
实施例12(E)-3-(4-(((2-(苯并噻吩-4-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000024
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.55(d,J＝13.8Hz,1H),7.25(d,J＝8.0Hz,2H),7.20-7.00(m,5H),7.06(d,J＝8.0Hz,2H),6.85(d,J＝13.8Hz,1H),3.81(s,2H),2.89(t,J＝6.8Hz,2H),2.71(t,J＝6.8Hz,2H),2.02(brs,OH)ppm.HRMS(ESI):calcd for C21H23N2O2S[MH+]367.1402,found 367.1401.
实施例13(E)-3-(4-(((2-(苯并呋喃-4-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000025
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.56(d,J＝13.8Hz,1H),7.26(d,J＝8.0Hz,2H),7.21-7.03(m,5H),7.05(d,J＝8.0Hz,2H),6.85(d,J＝13.8Hz,1H),3.85(s,2H),2.88(t,J＝6.8Hz,2H),2.70(t,J＝6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found 381.1735.
实施例14(E)-3-(4-(((2-(苯并噻吩-4-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000026
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.00(brs,NH),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.20(d,J＝8.0Hz,2H),7.11-7.03(m,3H),7.01(d,J＝8.0Hz,2H),6.84(d,J＝13.6Hz,1H),4.21(t,J＝6.6Hz,2H),3.83(s,2H),2.89(m 2H),2.85(t,J＝6.6Hz,2H),2.67(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N2O3S[MH+]397.1580,found 397.1581.
实施例15(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000027
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.01(m,3H),7.01(d,J＝8.0Hz,2H),6.84(d,J＝13.6Hz,1H),3.83(s,2H),3.21(t,J＝6.6Hz,2H),2.89(m 2H),2.85(t,J＝6.6Hz,2H),2.67(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N3O2S[MH+]394.1511,found 394.1511.
实施例16(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000028
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.20(d,J＝8.0Hz,2H),7.10-7.05(m,3H),7.07(d,J＝8.0Hz,2H),6.85(d,J＝13.6Hz,1H),4.00(brs,NH),3.90(s,2H),3.06(t,J＝6.8Hz,2H),2.88(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.43(m,2H),2.02(brs,OH),1.79(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found 391.2057.
实施例17(E)-N-羟基-3-(4-((2-(2,3,4,5-四氢-1H-吡啶并[3,4-b]吲哚-9-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000029
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),7.00-6.91(m,3H),6.84(d,J＝13.6Hz,1H),4.00(brs,2H),3.85(s,2H),3.08(t,J＝6.8Hz,2H),2.88(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.59(m,2H),2.00(brs,OH),1.80(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found 391.2055.
实施例18(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000030
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.03(brs,NH),7.57(d,J＝13.6Hz,1H),7.22(d,J＝8.0Hz,2H),7.15-7.10(m,3H),7.10(d,J＝8.0Hz,2H),6.88(d,J＝13.6Hz,1H),4.01(t,J＝7.2Hz,2H),3.88(s,2H),2.88(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.98(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found 392.1897.
实施例19(E)-N-羟基-3-(4-((2-(2,3,4,5-四氢吡喃并[3,2-b]吲哚-9-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000031
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.23(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),7.00-6.90(m,3H),6.85(d,J＝13.6Hz,1H),4.00(t,J＝7.2Hz,2H),3.85(s,2H),2.88(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.59(m,2H),2.01(brs,OH),1.98(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found 392.1896.
实施例20(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000032
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.53(d,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.05(m,3H),7.01(d,J＝8.0Hz,2H),6.85(d,J＝13.6Hz,1H),3.81(s,2H),2.98(t,J＝7.0Hz,2H),2.88(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.96(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found 408.1668.
实施例21(E)-3-(4-((2-(9H-咔唑胺-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000033
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.05(brs,NH),7.55(d,J＝13.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.42(d,J＝7.2Hz,1H),7.19(d,J＝8.2Hz,2H),7.17-7.00(m,5H),7.01(d,J＝8.2Hz,2H),6.85(d,J＝13.6Hz,1H),3.86(s,2H),2.89(t,J＝6.2Hz,2H),2.67(t,J＝6.2Hz,2H)ppm.HRMS(ESI):calcd for C24H24N3O2[MH+]386.1790,found 386.1791.
实施例22(E)-3-(4-((2-(9H-吡啶并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基- 丙烯酰胺
Figure PCTCN2014092104-appb-000034
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.57(d,J＝7.0Hz,1H),8.03(brs,NH),7.75(d,J＝7.2Hz,1H),7.55(d,J＝13.6Hz,1H),7.38(m,1H),7.18(d,J＝8.2Hz,2H),7.22-7.05(m,3H),7.01(d,J＝8.2Hz,2H),6.85(d,J＝13.6Hz,1H),3.81(s,2H),2.83(t,J＝6.2Hz,2H),2.66(t,J＝6.2Hz,2H)ppm.HRMS(ESI):calcd for C23H23N4O2[MH+]387.1743,found 387.1742.
实施例23(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000035
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.00(brs,NH),7.53(t,J＝13.6Hz,1H),7.20(d,J＝8.0Hz,2H),7.13-7.07(m,3H),7.02(d,J＝8.0Hz,2H),6.83(t,J＝13.6Hz,1H),3.90(s,2H),3.80(m,2H),2.88(t,J＝6.2Hz,2H),2.78(t,J＝6.6Hz,2H),2.67(t,J＝6.2Hz,2H)2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found 394.2053.
实施例24(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-8-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000036
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.05(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.11(m,2H),7.02(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.67(d,J＝8.6Hz,1H),6.16(s,1H),3.88(m,2H),3.82(s,2H),2.88(t,J＝6.2Hz,2H),2.67(t,J＝6.2Hz,2H),2.59(m,2H),2.04(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found 376.1948.
实施例25(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯 酰胺
Figure PCTCN2014092104-appb-000037
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.00(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.12-7.10(m,2H),7.01(d,J＝8.0Hz,2H),6.89(t,J＝13.6Hz,1H),6.67(d,J＝7.2Hz,1H),6.16(s,1H),3.87(s,2H),3.61(s,3H),2.89-2.67(m,4H),2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1948.
实施例26(E)-3-(4-((2-(1-甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000038
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.00(brs,NH),7.53(t,J＝13.6Hz,1H),7.17(d,J＝8.0Hz,2H),7.12-7.00(m,3H),7.01(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.82(d,J＝7.2Hz,1H),6.48(d,J＝7.2Hz,1H),3.81(s,2H),3.60(s,3H),2.88-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790found350.1791.
实施例27(E)-3-(4-((2-(2-叔丁基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000039
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.03-6.93(m,3H),7.03(d,J＝8.0Hz,2H),6.86(t,J＝13.6Hz,1H),6.27(s,1H),3.87(s,2H),2.89-2.67(m,4H),2.00(brs,NH),1.38(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found 392.2261.
实施例28(E)-3-(4-((2-(2-羟乙基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000040
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.03-6.93(m,3H),7.01(d,J＝8.0Hz,2H),6.84(t,J＝13.6Hz,1H),6.13(s,1H),3.85(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.78(t,J＝6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found 380.1897.
实施例29(E)-3-(4-((2,3-二甲基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000041
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.10(m,2H),7.01(d,J＝8.0Hz,2H),6.84(t,J＝13.6Hz,1H),6.68(d,J＝8.6Hz,1H),3.83(s,2H),2.88-2.67(m,4H),2.38(s,3H),2.35(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1948.
实施例30(E)-3-(4-((2-(2-苯基-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000042
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.05(brs,NH),7.55(t,J＝13.6Hz,1H),7.48-7.25(m,5H),7.20(d,J＝8.0Hz,2H),7.19-7.08(m,3H),7.06(d,J＝8.0Hz,2H),6.86(t,J＝13.6Hz,1H),6.46(s,1H),3.85(s,2H),2.89-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found 412.1948.
实施例31(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-4-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000043
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.06(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.03-6.93(m,3H),7.01(d,J＝8.0Hz,2H),6.84(t,J＝13.6Hz,1H),6.15(s,1H),3.82(s,2H),2.86-2.67(m,4H),2.00(brs,NH),1.58(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found 394.2053.
实施例32(E)-3-(4-((2-(1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺]
Figure PCTCN2014092104-appb-000044
1H NMR(400MHz,MeOD):δ7.60(d,J＝8.0Hz,2H),7.56(d,J＝15.5Hz,1H),7.46-7.42(m,3H),7.34(d,J＝8.5Hz,1H),7.22(d,J＝2.5Hz,1H),6.98(d,J＝8.5Hz,1H),6.50(d,J＝16.0Hz,1H),6.39(s,1H),4.12(s,2H),3.20(t,J＝7.8Hz,2H),3.03(t,J＝7.8Hz,2H)ppm.13C NMR(125MHz,MeOD):δ164.5,139.1,135.6,135.4,134.3,129.8,128.5,127.9,126.9,124.8,121.5,119.6,118.1,111.1,100.6,50.8,49.4,32.7ppm.HRMS(ESI):calcd for C20H22N3O2[MH+]336.1634,found 336.1633.
实施例33(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
Figure PCTCN2014092104-appb-000045
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(s,NH),8.01(brs,NH),7.62-7.46(m,3H),7.31(d,J＝8.0Hz,1H),7.28(d,J＝7.6Hz,2H),7.07(d,J＝8.0Hz,1H),7.03(d,J＝7.6Hz,2H),6.78(s,1H),3.93(s,2H),3.30-3.07(m,4H),1.72(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1791.
实施例34(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000046
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.55-7.50(m,3H),7.36(d,J＝8.0Hz,2H),7.28(d,J＝8.4Hz,1H),7.23(s,1H),7.05(t,J＝7.6Hz,1H),6.86(d,J＝7.2Hz,1H),6.50-6.44(m,2H),3.92(s,2H),3.10-3.01(m,4H),2.31(s,3H)ppm.13C NMR(125MHz,MeOD):δ162.7,136.6,135.9,133.7,132.3,126.8,126.7,125.5,124.9,121.8,118.8,116.3,114.7,107.1,51.2,49.5,45.5,29.6ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1791.
实施例35(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000047
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.02(brs,NH),7.59-7.53(m,3H),7.37(d,J＝8.2Hz,2H),7.27(d,J＝8.2Hz,2H),7.25(s,1H),7.13(d,J＝15.6Hz,1H),6.85(d,J＝7.2Hz,1H),6.53(d,J＝15.6Hz,1H),3.96(s,2H),3.19-3.12(m,4H),2.42(q,J＝6.8Hz,2H),1.09(t,J＝6.8Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947,found 364.1946.
实施例36(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000048
合成方法如实施例1。
1H NMR(400MHz,CDCl3):δ8.12(br,1H),7.68(d,J＝16.0Hz.1H),7.42(d,J＝8.0Hz,2H),7.37(s,1H),7.30-7.24(m,2H),7.19(t,J＝2.6Hz,1H),6.96(dd,J＝1.2,8.4Hz,1H),6.46(d,J＝2.0Hz,1H),6.41(d,J＝16.0Hz,1H),3,81(s,3H),3.72(s,2H),3.54(t,J＝5.4Hz,2H),2.91-2.87(m,2H),2.84-2.80(m,2H),2.72(t,J＝5.2Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896,found 380.1896.
实施例37(E)-3-(4-((2-(2-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000049
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.00(brs,NH),7.54-7.52(m,3H),7.38(d,J＝8.0Hz,2H),7.20(d,J＝8.0Hz,2H),7.12(s,1H),7.00(t,J＝13.6Hz,1H),6.93(d,J＝3.2Hz,1H),6.52(t,J＝13.6Hz,1H),3.90(s,2H),3.35-3.19(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1789.
实施例38(E)-3-(4-((2-(2-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000050
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.97(brs,NH),8.00(brs,NH),7.55-7.50(m,3H),7.33(d,J＝8.0Hz,2H),7.20(d,J＝8.0Hz,2H),7.12(s,1H),7.10(d,J＝13.6Hz,1H),6.52(d,J＝13.6Hz,1H),3.98(s,2H),3.36-3.20(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1788.
实施例39(E)-N-羟基-3-(4-((2-(1,2,3,4-四氢环戊烷并[b]吲哚-9-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000051
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.59-7.52(m,3H),7.38(d,J＝8.2Hz,2H),7.25(d,J＝8.2Hz,2H),7.33(d,J＝15.6Hz,1H),6.55(d,J＝15.6Hz,1H),3.93(s,2H),3.15-3.03(m,4H),2.61-2.43(m,4H),2.02(brs,OH),1.89(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found 376.1946.
实施例40(E)-3-(4-((2-(苯并呋喃-5-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000052
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.54(d,J＝13.6Hz,1H),7.48-7.35(m,3H),7.27(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,2H),6.58(d,J＝13.6Hz,1H),4.02(brs,NH),3.92(s,2H),3.15-3.06(m,4H),3.02(t,J＝6.6Hz,2H),2.47(t,J＝6.6Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O3[MH+]337.1474,found 337.1475.
实施例41(E)-3-(4-((2-(苯并噻吩-5-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000053
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.00(brs,NH),7.55(d,J＝13.8Hz,1H),7.28(d,J＝8.2Hz,2H),7.15-7.07(m,3H),7.03(d,J＝8.2Hz,2H),6.89(d,J＝13.8Hz,1H),3.93(s,2H),3.86(s,2H),3.70(s,2H),3.01(t,J＝6.8Hz,2H),2.73(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.13C NMR(125MHz,MeOD):δ161.7,144.1,136.1,135.6,133.3,132.3,127.6,126.3,125.9,123.2,120.1,119.7,118.9,114.2,107.8,54.8,49.5,47.2,34.2ppm.HRMS(ESI):calcd for C20H21N2O2S[MH+]353.1245,found 353.1243.
实施例41(E)-3-(4-(((2-(苯并呋喃-5-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000054
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.53(d,J＝13.8Hz,1H),7.26(d,J＝8.2Hz,2H),7.15-7.07(m,3H),7.05(d,J＝8.2Hz,2H),6.87(d,J＝13.8Hz,1H),3.85(s,2H),3.32(t,J＝7.6Hz,2H),3.01(t,J＝7.8Hz,2H),2.92(t,J＝6.8Hz,2H),2.71(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]351.1630,found 351.1633.
实施例42(E)-3-(4-(((2-(苯并噻吩-5-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯 酰胺
Figure PCTCN2014092104-appb-000055
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J＝13.8Hz,1H),7.26(d,J＝8.2Hz,2H),7.20-7.00(m,5H),7.07(d,J＝8.2Hz,2H),6.86(d,J＝13.8Hz,1H),3.82(s,2H),2.88(t,J＝6.8Hz,2H),2.70(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H22N2O2S[MH+]367.1402,found 367.1400.
实施例43(E)-3-(4-(((2-(苯并呋喃-5-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000056
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.02(brs,NH),7.55(d,J＝13.8Hz,1H),7.25(d,J＝8.0Hz,2H),7.22-7.03(m,5H),7.07(d,J＝8.0Hz,2H),6.86(d,J＝13.8Hz,1H),3.86(s,2H),2.89(t,J＝6.8Hz,2H),2.71(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found 381.1733.
实施例44(E)-3-(4-(((2-(苯并噻吩-5-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000057
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.02(brs,NH),7.57(d,J＝13.6Hz,1H),7.23(d,J＝8.0Hz,2H),7.15-7.03(m,3H),7.04(d,J＝8.0Hz,2H),6.88(d,J＝13.6Hz,1H),4.23(t,J＝6.6Hz,2H),3.85(s,2H),2.89(m2H),2.86(t,J＝6.6Hz,2H),2.68(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N2O3S[MH+]397.1580,found 397.1580.
实施例45(E)-3-(4-((2-(8H-呋喃并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000058
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.41(s,1H),7.37(d,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.03(m,2H),7.01(d,J＝8.0Hz,2H),6.85(d,J＝13.6Hz,1H),6.38(d,J＝7.2Hz,1H),3.82(s,2H),2.87(m 2H),2.66(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H21N3O3[MH+]375.1505,found 375.1504.
实施例46(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000059
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.06(m,3H),7.03(s,1H),7.01(d,J＝8.0Hz,2H),6.85(d,J＝13.6Hz,1H),3.82(s,2H),3.20(t,J＝6.6Hz,2H),2.90(m 2H),2.88(t,J＝6.6Hz,2H),2.67(m,2H),2.00(brs,OH)ppm.13C NMR(125MHz,MeOD):δ161.1,143.9,136.2,135.6,133.3,132.6,127.9,126.2,126.0,123.2,120.0,119.3118.9,108.3,72.3,54.8,48.6,36.6,34.2,31.6ppm.HRMS(ESI):calcd for C22H24N3O2S[MH+]394.1511,found 394.1510.
实施例47(E)-N-羟基-3-(4-((2-(6,7,8,9-四氢-5H-咔唑胺-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000060
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.55(d,J＝15.6Hz,1H),7.18(d,J＝8.2Hz,2H),7.05-7.00(m,2H),7.01(d,J＝8.2Hz,2H),6.85(d,J＝15.6Hz,1H),6.57(s,1H),3.86(s,2H),2.88(m,2H),2.67(m,2H),2.59(t,J＝6.2Hz,2H),2.43(t,J＝6.2Hz,2H),1.56-1.58(m,4H)ppm.HRMS(ESI):calcd for C24H28N3O2[MH+]390.2103,found 390.2104.
实施例48(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-5-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000061
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.20(d,J＝8.0Hz,2H),7.10-7.05(m,2H),7.07(d,J＝8.0Hz,2H),7.03(s,1H),6.85(d,J＝13.6Hz,1H),4.00(brs,NH),3.82(s,2H),3.06(t,J＝6.8Hz,2H),2.88(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.79(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found 391.2056.
实施例49(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000062
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.56(d,J＝13.6Hz,1H),7.22(d,J＝8.0Hz,2H),7.17-7.13(m,3H),7.10(s,1H),7.08(d,J＝8.0Hz,2H),6.88(d,J＝13.6Hz,1H),3.96(t,J＝7.2Hz,2H),3.83(s,2H),2.88(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.98(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found 392.1897.
实施例50(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000063
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.03(brs,NH),7.55(d,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.08(m,2H),7.05(s,1H),7.01(d,J＝8.0Hz,2H),6.86(d,J＝13.6Hz,1H),3.82(s,2H),2.93(t,J＝7.0Hz,2H),2.88(t,J＝6.6Hz,2H),2.66(t,J＝6.6Hz,2H),2.43(m,2H),2.00(brs,OH),1.95(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found 408.1666.
实施例51(E)-3-(4-((2-(9H-咔唑胺-3-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000064
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.06(brs,NH),7.58(d,J＝7.6Hz,1H),7.55(d,J＝13.6Hz,1H),7.42(s,1H),7.40(d,J＝7.2Hz,1H),7.19(d,J＝8.2Hz,2H),7.17-7.00(m,4H),7.01(d,J＝8.2Hz,2H),6.85(d,J＝13.6Hz,1H),3.85(s,2H),2.88(t,J＝6.2Hz,2H),2.67(t,J＝6.2Hz,2H)ppm.HRMS(ESI):calcd for C24H24N3O2[MH+]386.1790,found 386.1791.
实施例52(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000065
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.54(t,J＝13.6Hz,1H),7.20(d,J＝8.0Hz,2H),7.05-7.03(m,2H),7.01(d,J＝8.0Hz,2H),6.83(t,J＝13.6Hz,1H),6.57(s,1H),3.88(s,2H),3.81(m,2H),2.88(t,J＝6.2Hz,2H),2.78(t,J＝6.6Hz,2H),2.67(t,J＝6.2Hz,2H)2.31(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found 394.2053.
实施例53(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000066
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),7.01-6.95(m,2H),6.85(t,J＝13.6Hz,1H),6.56(s,1H),6.16(s,1H),3.85(m,2H),3.81(s,2H),2.88(t,J＝6.2Hz,2H),2.67(t,J＝6.2Hz,2H),2.59(m,2H),2.04(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found 376.1948.
实施例54(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000067
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.56(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),7.00-6.91(m,2H),6.89(t,J＝13.6Hz,1H),6.56(s,1H),6.16(s,1H),3.86(s,2H),3.60(s,3H),2.88-2.67(m,4H),2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1948.
实施例55(E)-3-(4-((2-(1-甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000068
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.12-7.05(m,2H),7.03(s,1H),7.01(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.82(d,J＝7.2Hz,1H),6.48(d,J＝7.2Hz,1H),3.81(s,2H),3.60(s,3H),2.88-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790found 350.1791.
实施例56(E)-3-(4-((2-(2-叔丁基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000069
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.01(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),7.01-6.95(m,2H),6.93(s,1H),6.86(t,J＝13.6Hz,1H),6.13(s,1H),3.83(s,2H),2.89-2.67(m,4H),2.00(brs,NH),1.35(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found392.2261.
实施例57(E)-3-(4-((2-(2-羟乙基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000070
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.03-6.98(m,3H),7.01(d,J＝8.0Hz,2H),6.94(s,1H),6.84(t,J＝13.6Hz,1H),6.13(s,1H),3.85(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.78(t,J＝6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found 380.1895.
实施例58(E)-3-(4-((2,3-二甲基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000071
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),7.01-6.97(m,2H),6.84(t,J＝13.6Hz,1H),6.57(s,1H),3.83(s,2H),2.88-2.67(m,4H),2.37(s,3H),2.34(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1948.
实施例59(E)-3-(4-((2-(2-苯基-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000072
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.05(brs,NH),7.55(t,J＝13.6Hz,1H),7.48-7.22(m,5H),7.40(s,1H),7.19(d,J＝8.0Hz,2H),7.30-7.10(m,2H),7.05(d,J＝8.0Hz,2H),6.86(t,J＝13.6Hz,1H),6.43(s,1H),3.85(s,2H),2.89-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found 412.1948.
实施例60(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000073
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.06(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.06-7.02(m,2H),7.01(d,J＝8.0Hz,2H),6.94(s,1H),6.83(t,J＝13.6Hz,1H),6.13(s,1H),3.82(s,2H),2.86-2.67(m,4H),2.00(brs,NH),1.54(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found 394.2051.
实施例61(E)-3-(4-((2-(1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000074
合成方法如实施例1。1H NMR(400MHz,MeOD):δ7.56(d,J＝15.6Hz,1H),7.50(d,J＝8.2Hz,1H),7.26(s,1H),7.25-7.19(m,3H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,1H),6.84(d,J＝15.6Hz,1H),4.10(s,2H),3.18(t,J＝7.8Hz,2H),3.00(t,J＝7.8Hz,2H)ppm.13C NMR(125MHz,MeOD):δ164.3,139.1,135.6,135.4,134.1,129.8,128.7,127.9,126.9,124.8,121.6,119.6,118.3,111.1,100.6,50.9,49.6,32.9ppm.HRMS(ESI):calcd for C20H22N3O2[MH+]336.1634,found 336.1634.
实施例62(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
Figure PCTCN2014092104-appb-000075
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(s,NH),8.04(brs,NH),7.50-7.27(m,3H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.86(m,1H),6.56(s,1H),6.45(d,J＝7.6Hz,1H),3.89(s,2H),2.88-2.68(m,4H),1.72(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1790.
实施例63(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000076
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.02(brs,NH),7.55(d,J＝13.8Hz,1H),7.50(d,J＝8.2Hz,1H),7.28(d,J＝7.8Hz,1H),7.26(s,1H),7.22(d,J＝7.2Hz,2H),7.06(d,J＝7.2Hz,2H),6.86(d,J＝8.2Hz,1H),6.84(d,J＝13.8Hz,1H),6.45(d,d,J＝7.8Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.27(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1792.
实施例64(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000077
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.06(brs,NH),7.57(d,J＝8.6Hz,1H),7.53(d,J＝15.6Hz,1H),7.28(d,J＝7.8Hz,2H),7.25(s,1H),7.20(d,J＝8.2Hz,2H),7.08(d,J＝8.2Hz,2H),6.86(d,J＝8.6Hz,1H),6.83(d,J＝15.6Hz,1H),3.62(s,2H),2.89-2.78(m,4H),2.40(q,J＝6.8Hz,2H),1.00(t,J＝6.8Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947,found364.1948.
实施例65(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000078
合成方法如实施例1。1H NMR(400MHz,CDCl3):δ8.12(br,1H),7.66(d,J＝16.0Hz.1H),7.40(d,J＝8.0Hz,2H),7.27(d,J＝7.2Hz,2H),7.26(s,1H),7.19(d,J＝8.0Hz,2H),6.86(d,J＝8.0Hz,1H),6.45(d,J＝7.2Hz,1H),6.42(d,J＝16.0Hz,1H),3.72(s,2H),3.56(t,J＝5.4Hz,2H),2.89(m,2H),2.80(m,2H),2.70(t,J＝5.2Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896,found 380.1895.
实施例66(E)-3-(4-((2-(2-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000079
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.01(brs,NH),7.56-7.50(m,3H),7.38(d,J＝8.2Hz,2H),7.19(d,J＝8.0Hz,2H),7.10(s,1H),7.05(t,J＝13.6Hz,1H),6.90(m,1H),6.52(t,J＝13.6Hz,1H),3.88(s,2H),3.30-3.15(m,4H)2.80(s,3H)ppm.13C NMR(125MHz,MeOD):δ162.0,136.5,135.5,133.6,132.1,126.9,126.2,125.6,124.6,121.6,118.7,116.2,114.8,107.0,49.9,45.6,29.6,18.9ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1788.
实施例67(E)-3-(4-((2-(2-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000080
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.01(brs,NH),7.52-7.48(m,3H),7.32(d,J＝8.0Hz,2H),7.20(d,J＝8.0Hz,2H),7.13(s,1H),7.11(d,J＝13.6Hz,1H),6.58(d,J＝13.6Hz,1H),3.96(s,2H),3.33-3.20(m,4H)2.80(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1789.
实施例68(E)-N-羟基-3-(4-((2-(1,2,3,4-四氢环戊烷并吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000081
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.01(brs,NH),7.57-7.50(m,3H),7.36(d,J＝8.2Hz,2H),7.22(d,J＝8.2Hz,2H),7.31(d,J＝15.6Hz,1H),6.58(d,J＝15.6Hz,1H),3.90(s,2H),3.10-3.03(m,4H),2.60-2.41(m,4H),2.01(brs,OH),1.88(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found 376.1948.
实施例69(E)-3-(4-((2-(苯并呋喃-6-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000082
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.08(brs,NH),7.57(d,J＝13.6Hz,1H),7.49-7.36(m,3H),7.29(d,J＝8.0Hz,2H),7.15(d,J＝8.0Hz,2H),6.59(d,J＝13.6Hz,1H),4.03(brs,NH),3.93(s,2H),3.15-3.05(m,4H),3.00(t,J＝6.6Hz,2H),2.48(t,J＝6.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O3[MH+]337.1474,found 337.1475.
实施例70(E)-3-(4-((2-(苯并噻吩-6-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000083
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.00(brs,NH),7.54(d,J＝13.8Hz,1H),7.26(d,J＝8.2Hz,2H),7.17-7.09(m,3H),7.04(d,J＝8.2Hz,2H),6.88(d,J＝13.8Hz,1H),3.91(s,2H),3.80(s,2H),3.70(s,2H),3.00(t,J＝6.8Hz,2H),2.71(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O2S[MH+]353.1245,found 353.1246.
实施例71(E)-3-(4-(((2-(苯并呋喃-6-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000084
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.00(brs,NH),7.55(d,J＝13.8Hz,1H),7.28(d,J＝8.2Hz,2H),7.18-7.07(m,3H),7.04(d,J＝8.2Hz,2H),6.85(d,J＝13.8Hz,1H),3.82(s,2H),3.30(t,J＝7.6Hz,2H),3.00(t,J＝7.8Hz,2H),2.92(t,J＝6.8Hz,2H),2.70(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]351.1630,found 351.1631.
实施例72(E)-3-(4-(((2-(苯并噻吩-6-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000085
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.00(brs,NH),7.56(d,J＝13.8Hz,1H),7.23(d,J＝8.2Hz,2H),7.21-7.03(m,5H),7.07(d,J＝8.2Hz,2H),6.85(d,J＝13.8Hz,1H),3.80(s,2H),2.89(t,J＝6.8Hz,2H),2.71(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H22N2O2S[MH+]367.1402,found 367.1401.
实施例73(E)-3-(4-(((2-(苯并呋喃-6-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000086
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.01(brs,NH),7.55(d,J＝13.8Hz,1H),7.27(d,J＝8.0Hz,2H),7.23-7.04(m,5H),7.05(d,J＝8.0Hz,2H),6.85(d,J＝13.8Hz,1H),3.85(s,2H),2.88(t,J＝6.8Hz,2H),2.72(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found 381.1735.
实施例74(E)-3-(4-(((2-(苯并噻吩-6-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000087
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.05(brs,NH),7.56(d,J＝13.6Hz,1H),7.23(d,J＝8.0Hz,2H),7.16-7.03(m,3H),7.05(d,J＝8.0Hz,2H),6.87(d,J＝13.6Hz,1H),4.22(t,J＝6.6Hz,2H),3.85(s,2H),2.88(m2H),2.85(t,J＝6.6Hz,2H),2.66(m,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C22H24N2O3S[MH+]397.1580,found 397.1581.
实施例75(E)-3-(4-((2-(8H-呋喃并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000088
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),7.98(brs,NH),7.54(d,J＝13.6Hz,1H),7.40(s,1H),7.36(d,J＝7.2Hz,1H),7.17(d,J＝8.0Hz,2H),7.15-7.03(m,2H),7.00(d,J＝8.0Hz,2H),6.84(d,J＝13.6Hz,1H),6.38(d,J＝7.2Hz,1H),3.81(s,2H),2.87(m 2H),2.64(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H21N3O3[MH+]375.1505,found 375.1504.
实施例76(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000089
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.53(d,J＝13.6Hz,1H),7.17(d,J＝8.0Hz,2H),7.15-7.06(m,3H),7.02(s,1H),7.00(d,J＝8.0Hz,2H),6.86(d,J＝13.6Hz,1H),3.81(s,2H),3.21(t,J＝6.6Hz,2H),2.90(m2H),2.83(t,J＝6.6Hz,2H),2.62(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N3O2S[MH+]394.1511,found 394.1511.
实施例77(E)-N-羟基-3-(4-((2-(6,7,8,9-四氢-5H-咔唑胺-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000090
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.00(brs,NH),7.55(d,J＝15.6Hz,1H),7.18(d,J＝8.2Hz,2H),7.05-7.00(m,2H),7.01(d,J＝8.2Hz,2H),6.85(d,J＝15.6Hz,1H),6.57(s,1H),3.86(s,2H),2.88(m,2H),2.67(m,2H),2.59(t,J＝6.2Hz,2H),2.43(t,J＝6.2Hz,2H),1.56-1.58(m,4H)ppm.HRMS(ESI):calcd for C24H28N3O2[MH+]390.2103,found 390.2105.
实施例78(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-6-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000091
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.22(d,J＝8.0Hz,2H),7.13-7.09(m,2H),7.06(d,J＝8.0Hz,2H),7.02(s,1H),6.85(d,J＝13.6Hz,1H),4.01(brs,NH),3.81(s,2H),3.08(t,J＝6.8Hz,2H),2.87(t,J＝6.6Hz,2H),2.66(t,J＝6.6Hz,2H),2.42(m,2H),2.00(brs,OH),1.77(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found 391.2055.
实施例79(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000092
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.03(brs,NH),7.55(d,J＝13.6Hz,1H),7.23(d,J＝8.0Hz,2H),7.17-7.12(m,3H),7.10(s,1H),7.08(d,J＝8.0Hz,2H),6.86(d,J＝13.6Hz,1H),3.93(t,J＝7.2Hz,2H),3.82(s,2H),2.87(t,J＝6.6Hz,2H),2.66(t,J＝6.6Hz,2H),2.42(m,2H),2.00(brs,OH),1.97(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found 392.1895.
实施例80(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000093
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.16-7.09(m,2H),7.06(s,1H),7.02(d,J＝8.0Hz,2H),6.85(d,J＝13.6Hz,1H),3.82(s,2H),2.93(t,J＝7.0Hz,2H),2.88(t,J＝6.6Hz,2H),2.66(t,J＝6.6Hz,2H),2.46(m,2H),2.00(brs,OH),1.95(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found 408.1668.
实施例81(E)-3-(4-((2-(9H-咔唑胺-2-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000094
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.05(brs,NH),7.59(d,J＝7.6Hz,1H),7.54(d,J＝13.6Hz,1H),7.43(s,1H),7.40(d,J＝7.2Hz,1H),7.18(d,J＝8.2Hz,2H),7.16-7.00(m,4H),7.03(d,J＝8.2Hz,2H),6.86(d,J＝13.6Hz,1H),3.81(s,2H),2.85(t,J＝6.2Hz,2H),2.66(t,J＝6.2Hz,2H)ppm.HRMS(ESI):calcd for C24H24N3O2[MH+]386.1790,found 386.1791.
实施例82(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000095
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.98(brs,NH),8.02(brs,NH),7.55(t,J＝13.6Hz,1H),7.21(d,J＝8.0Hz,2H),7.07-7.05(m,2H),7.02(d,J＝8.0Hz,2H),6.86(t,J＝13.6Hz,1H),6.58(s,1H),3.88(s,2H),3.82(m,2H),2.87(t,J＝6.2Hz,2H),2.77(t,J＝6.6Hz,2H),2.66(t,J＝6.2Hz,2H)2.31(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found 394.2050.
实施例83(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000096
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.08(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),7.02-6.97(m,2H),6.85(t,J＝13.6Hz,1H),6.58(s,1H),6.19(s,1H),3.83(m,2H),3.80(s,2H),2.86(t,J＝6.2Hz,2H),2.65(t,J＝6.2Hz,2H),2.58(m,2H),2.03(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found 376.1946.
实施例84(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000097
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.58(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),7.03-6.93(m,2H),6.88(t,J＝13.6Hz,1H),6.57(s,1H),6.18(s,1H),3.86(s,2H),3.61(s,3H),2.89-2.68(m,4H),2.31(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1949.
实施例85(E)-3-(4-((2-(1-甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000098
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.56(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.14-7.06(m,2H),7.04(s,1H),7.02(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.81(d,J＝7.2Hz,1H),6.48(d,J＝7.2Hz,1H),3.81(s,2H),3.61(s,3H),2.88-2.66(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790found 350.1791.
实施例86(E)-3-(4-((2-(2-叔丁基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000099
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),7.02-6.97(m,2H),6.91(s,1H),6.85(t,J＝13.6Hz,1H),6.13(s,1H),3.83(s,2H),2.89-2.64(m,4H),2.00(brs,NH),1.33(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found 392.2262.
实施例87(E)-3-(4-((2-(2-羟乙基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000100
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.08-7.04(m,3H),7.00(d,J＝8.0Hz,2H),6.94(s,1H),6.84(t,J＝13.6Hz,1H),6.16(s,1H),3.83(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.76(t,J＝6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found 380.1897.
实施例88(E)-3-(4-((2,3-二甲基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000101
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),7.00-6.96(m,2H),6.83(t,J＝13.6Hz,1H),6.58(s,1H),3.83(s,2H),2.88-2.65(m,4H),2.37(s,3H),2.32(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1946.
实施例89(E)-3-(4-((2-(2-苯基-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000102
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.48-7.21(m,5H),7.42(s,1H),7.17(d,J＝8.0Hz,2H),7.31-7.11(m,2H),7.04(d,J＝8.0Hz,2H),6.88(t,J＝13.6Hz,1H),6.45(s,1H),3.85(s,2H),2.89-2.67(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found412.1947.
实施例90(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-6-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000103
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.07-7.03(m,2H),7.01(d,J＝8.0Hz,2H),6.96(s,1H),6.82(t,J＝13.6Hz,1H),6.13(s,1H),3.81(s,2H),2.87-2.66(m,4H),2.00(brs,NH),1.54(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found394.2053.
实施例91(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000104
合成方法如实施例1。1H NMR(400MHz,MeOD):δ7.66-7.55(m,3H),7.36(d,J＝8.0Hz,2H),7.28(d,J＝8.4Hz,1H),7.24(d,J＝3.2Hz,1H),7.05(t,J＝7.6Hz,1H),6.86(d,J＝7.2Hz,1H),6.53-6.45(m,2H),3.95(s,2H),3.32-3.08(m,4H)ppm.13CNMR(125MHz,MeOD):δ162.3,136.9,135.3,133.8,132.0,126.9,126.5,125.1,124.9,121.5,118.5,116.1,114.3,107.0,96.3,49.3,45.8,29.3ppm.HRMS(ESI):calcd for C20H22N3O2[MH+]336.1634,found 336.1633.
实施例92(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)氨基)甲基)苯基)-N-羟基-丁烯酰胺
Figure PCTCN2014092104-appb-000105
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(s,NH),8.03(brs,NH),7.68-7.53(m,4H),7.38(d,J＝8.0Hz,2H),7.27(d,J＝8.0Hz,2H),7.23(d,J＝3.2Hz,1H),7.02(t,J＝7.6Hz,1H),3.91(s,2H),3.30-3.07(m,4H),1.71(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1790.
实施例93
(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)甲氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000106
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.02(brs,NH),7.58-7.52(m,3H),7.37(d,J＝8.0Hz,2H),7.27(d,J＝8.4Hz,1H),7.23(d,J＝3.2Hz,1H),7.02(t,J＝7.6Hz,1H),6.86(d,J＝7.2Hz,1H),6.51-6.45(m,2H),3.95(s,2H),3.11-3.02(m,4H),2.32(s,3H)ppm.13C NMR(125MHz,MeOD):δ162.5,136.6,135.9,133.8,132.4,126.9,126.7,125.4,124.9,121.6,118.7,116.5,114.9,107.3,51.5,49.6,45.6,29.6ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found350.1791.
实施例94(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000107
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.01(brs,NH),7.58-7.53(m,3H),7.38(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),7.26(d,J＝7.2Hz,1H),7.06(d,J＝15.6Hz,1H),6.85(d,J＝7.2Hz,1H),6.56(d,J＝15.6Hz,1H),3.93(s,2H),3.19-3.12(m,4H),2.45(q,J＝6.8Hz,2H),1.09(t,J＝6.8Hz,2H)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947,found 364.1946.
实施例95(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)2-羟乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000108
合成方法如实施例1。1H NMR(400MHz,CDCl3):δ8.27(br,1H),7.68(d,J＝16.0Hz,1H),7.46(d,J＝8.0Hz,2H),7.30-7.26(m,3H),7.19-7.13(m,2H),6.92(d,J＝6.8Hz,1H),6.48-6.40(m,2H),3.83(s,3H),3.76(s,2H),3.52(t,J＝5.2Hz,2H),3.12-3.06(m,2H),2.95-2.90(m,2H),2.75(t,J＝5.2Hz,2H)ppm.HRMS(ESI):calcd  for C22H26N3O3[MH+]380.1896,found 380.1895.
实施例96(E)-3-(4-((2-(2-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000109
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.00(brs,NH),7.99(brs,NH),7.56-7.52(m,3H),7.38(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),7.15(d,J＝3.2Hz,1H),7.02(t,J＝13.6Hz,1H),6.92(d,J＝3.2Hz,1H),6.53(t,J＝13.6Hz,1H),3.92(s,2H),3.36-3.20(m,4H)2.88(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1788.
实施例97(E)-3-(4-((2-(2-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000110
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.96(brs,NH),8.00(brs,NH),7.58-7.52(m,3H),7.37(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),7.10(s,1H),7.01(d,J＝13.6Hz,1H),6.53(d,J＝13.6Hz,1H),3.98(s,2H),3.36-3.20(m,4H)2.90(s,3H)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790,found 350.1791.
实施例98(E)-3-(4-((2-(苯并呋喃-7-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000111
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.49-7.37(m,3H),7.29(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,2H),6.56(d,J＝13.6Hz,1H),4.00(brs,NH),3.92(s,2H),3.16-3.07(m,4H),3.02(t,J＝6.6Hz,2H),2.46(t,J＝6.6Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O3[MH+]337.1474,found 337.1474.
实施例99(E)-3-(4-((2-(苯并噻吩-7-取代)乙氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000112
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.00(brs,NH),8.00(brs,NH),7.55(d,J＝13.8Hz,1H),7.28(d,J＝8.2Hz,2H),7.13-7.07(m,3H),7.05(d,J＝8.2Hz,2H),6.88(d,J＝13.8Hz,1H),3.93(s,2H),3.86(s,2H),3.70(s,2H),3.00(t,J＝6.8Hz,2H),2.72(t,J＝6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C20H21N2O2S[MH+]353.1245,found 353.1244.
实施例100(E)-3-(4-(((2-(苯并呋喃-7-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000113
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.01(brs,NH),7.55(d,J＝13.8Hz,1H),7.26(d,J＝8.2Hz,2H),7.17-7.09(m,3H),7.08(d,J＝8.2Hz,2H),6.87(d,J＝13.8Hz,1H),3.85(s,2H),3.33(t,J＝7.6Hz,2H),3.00(t,J＝7.8Hz,2H),2.92(t,J＝6.8Hz,2H),2.72(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N4O2[MH+]351.1630,found 351.1629.
实施例101(E)-3-(4-(((2-(苯并噻吩-7-取代)乙基(甲基)氨基)甲基)苯基)-N-羟基丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.02(brs,NH),8.00(brs,NH),7.56(d,J＝13.8Hz,1H),7.25(d,J＝8.0Hz,2H),7.23-7.06(m,5H),7.03(d,J＝8.0Hz,2H),6.85(d,J＝13.8Hz,1H),3.81(s,2H),2.89(t,J＝6.8Hz,2H),2.71(t,J＝6.8Hz,2H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C21H22N2O2S[MH+]367.1402,found 367.1402.
实施例102(E)-3-(4-(((2-(苯并呋喃-6-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000115
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.01(brs,NH),7.56(d,J＝13.8Hz,1H),7.27(d,J＝8.0Hz,2H),7.24-7.07(m,5H),7.03(d,J＝8.0Hz,2H),6.86(d,J＝13.8Hz,1H),3.85(s,2H),2.88(t,J＝6.8Hz,2H),2.70(t,J＝6.8Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25N2O4[MH+]381.1736,found 381.1733.
实施例103(E)-3-(4-(((2-(苯并噻吩-7-取代)乙基(2-羟乙基)氨基)甲基)苯基)-N-羟基丙烯酰胺
Figure PCTCN2014092104-appb-000116
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.01(brs,NH),8.03(brs,NH),7.55(d,J＝13.6Hz,1H),7.22(d,J＝8.0Hz,2H),7.13-7.06(m,3H),7.02(d,J＝8.0Hz,2H),6.86(d,J＝13.6Hz,1H),4.23(t,J＝6.6Hz,2H),3.82(s,2H),2.87(m2H),2.83(t,J＝6.6Hz,2H),2.66(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N2O3S[MH+]397.1580,found 397.1580.
实施例104(E)-3-(4-((2-(3,8-呋喃并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000117
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.38(d,J＝7.2Hz,1H),7.18(d,J＝8.0Hz,2H),7.06-6.91(m,3H),7.00(d,J＝8.0Hz,2H),6.86(d,J＝13.6Hz,1H),6.32(d,J＝7.2Hz,1H),3.81(s,2H),2.88(m 2H),2.68(m,2H),2.05(brs,OH)ppm.HRMS(ESI):calcd for C22H21N3O3[MH+]375.1505,found 375.1505.
实施例105(E)-3-(4-((2-(3,8-二氢噻吩并[2,3-b]吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000118
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.16-7.03(m,3H),7.01(d,J＝8.0Hz,2H),6.85(d,J＝13.6Hz,1H),3.83(s,2H),3.21(t,J＝6.6Hz,2H),2.89(m2H),2.83(t,J＝6.6Hz,2H),2.66(m,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H24N3O2S[MH+]394.1511,found 394.1512.
实施例107(E)-N-羟基-3-(4-((2-(6,7,8,9-四氢-5H-咔唑胺-7-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000119
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.97(brs,NH),8.01(brs,NH),7.55(d,J＝15.6Hz,1H),7.18(d,J＝8.2Hz,2H),7.13-7.05(m,3H),7.00(d,J＝8.2Hz,2H),6.85(d,J＝15.6Hz,1H),3.91(s,2H),2.89(m,2H),2.67(m,2H),2.58(t,J＝6.2Hz,2H),2.42(t,J＝6.2Hz,2H),1.58(m,4H)ppm.HRMS(ESI):calcd for C24H28N3O2[MH+]390.2103,found 390.2102.
实施例108(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢-1H-吡啶并[2,3-b]吲哚-8-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000120
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(d,J＝13.6Hz,1H),7.22(d,J＝8.0Hz,2H),7.17-7.08(m,3H),7.05(d,J＝8.0Hz,2H),6.85(d,J＝13.6Hz,1H),4.00(brs,NH),3.90(s,2H),3.08(t,J＝6.8Hz,2H),2.89(t,J＝6.6Hz,2H),2.65(t,J＝6.6Hz,2H),2.43(m,2H),2.01(brs,OH),1.78(m,2H)ppm.HRMS(ESI):calcd for C23H27N4O2[MH+]391.2056,found391.2055.
实施例109(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢吡喃并[2,3-b]吲哚-8-取代)乙氨基)甲 基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000121
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.03(brs,NH),7.56(d,J＝13.6Hz,1H),7.22(d,J＝8.0Hz,2H),7.15-7.10(m,3H),7.07(d,J＝8.0Hz,2H),6.87(d,J＝13.6Hz,1H),4.01(t,J＝7.2Hz,2H),3.88(s,2H),2.86(t,J＝6.6Hz,2H),2.67(t,J＝6.6Hz,2H),2.43(m,2H),2.00(brs,OH),1.96(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O3[MH+]392.1896,found 392.1896.
.实施例110(E)-N-羟基-3-(4-((2-(2,3,4,9-四氢硫代吡喃并[2,3-b]吲哚-8-取代)乙氨基)甲基)苯基)-丙烯酰胺
Figure PCTCN2014092104-appb-000122
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.01(brs,NH),7.55(d,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.15-7.07(m,3H),7.02(d,J＝8.0Hz,2H),6.86(d,J＝13.6Hz,1H),3.81(s,2H),2.98(t,J＝7.0Hz,2H),2.86(t,J＝6.6Hz,2H),2.66(t,J＝6.6Hz,2H),2.42(m,2H),2.00(brs,OH),1.95(m,2H)ppm.HRMS(ESI):calcd for C23H26N3O2S[MH+]408.1667,found 408.1667.
实施例111(E)-3-(4-((2-(9H-咔唑胺-1-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000123
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.03(brs,NH),7.56(d,J＝13.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.41(d,J＝7.2Hz,1H),7.21(d,J＝8.2Hz,2H),7.19-7.05(m,5H),7.01(d,J＝8.2Hz,2H),6.85(d,J＝13.6Hz,1H),3.86(s,2H),2.89(t,J＝6.2Hz,2H),2.67(t,J＝6.2Hz,2H)ppm.HRMS(ESI):calcd for C24H24N3O2[MH+]386.1790,found 386.1791.
实施例112(E)-3-(4-((2-(2-(2-羟乙基)-3-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000124
合成方法如实施例1。1H NMR(400MHz,MeOD):δ9.99(brs,NH),8.01(brs,NH),7.55(t,J＝13.6Hz,1H),7.21(d,J＝8.0Hz,2H),7.13-7.07(m,3H),7.02(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),3.90(s,2H),3.81(m,2H),2.88(t,J＝6.2Hz,2H),2.78(t,J＝6.6Hz,2H),2.66(t,J＝6.2Hz,2H)2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052,found 394.2052.
实施例113(E)-3-(4-((2-(2,3-二氢-1H-吡咯并[1,2-a]吲哚-5-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000125
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.08(brs,NH),7.56(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.14-7.11(m,2H),7.02(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.67(d,J＝8.6Hz,1H),6.16(s,1H),3.88(m,2H),3.82(s,2H),2.88(t,J＝6.2Hz,2H),2.67(t,J＝6.2Hz,2H),2.59(m,2H),2.04(m,2H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C23H26N3O2[MH+]376.1947,found 376.1948.
实施例114(E)-3-(4-((2-(1,2-二甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000126
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.13-7.09(m,2H),7.01(d,J＝8.0Hz,2H),6.88(t,J＝13.6Hz,1H),6.65(d,J＝7.2Hz,1H),6.16(s,1H),3.87(s,2H),3.60(s,3H),2.89-2.67(m,4H),2.30(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1947.
实施例115(E)-3-(4-((2-(1-甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000127
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.13-7.00(m,3H),7.01(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.81(d,J＝7.2Hz,1H),6.46(d,J＝7.2Hz,1H),3.81(s,2H),3.60(s,3H),2.88-2.65(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C21H24N3O2[MH+]350.1790found 350.1792.
实施例116(E)-3-(4-((2-(2-叔丁基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000128
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.05-6.95(m,3H),7.02(d,J＝8.0Hz,2H),6.86(t,J＝13.6Hz,1H),6.25(s,1H),3.87(s,2H),2.89-2.67(m,4H),2.00(brs,NH),1.39(s,9H)ppm.HRMS(ESI):calcd for C24H30N3O2[MH+]392.2260found392.2260.
实施例117(E)-3-(4-((2-(2-羟乙基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000129
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.05(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.05-6.96(m,3H),7.01(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.15(s,1H),3.85(s,2H),3.80(m,2H),2.88-2.67(m,4H),2.79(t,J＝6.6Hz,1H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O3[MH+]380.1896found 380.1895.
实施例118(E)-3-(4-((2,3-二甲基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000130
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.05(brs,NH),8.03(brs,NH),7.55(t,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.15-7.11(m,2H),7.01(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.67(d,J＝8.6Hz,1H),3.83(s,2H),2.88-2.67(m,4H),2.39(s,3H),2.35(s,3H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C22H26N3O2[MH+]364.1947found 364.1947.
实施例119(E)-3-(4-((2-(2-苯基-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000131
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.03(brs,NH),7.56(t,J＝13.6Hz,1H),7.49-7.27(m,5H),7.22(d,J＝8.0Hz,2H),7.20-7.10(m,3H),7.05(d,J＝8.0Hz,2H),6.87(t,J＝13.6Hz,1H),6.45(s,1H),3.85(s,2H),2.87-2.66(m,4H),2.00(brs,NH)ppm.HRMS(ESI):calcd for C26H26N3O2[MH+]412.1947found412.1946.
实施例120(E)-3-(4-((2-(2-(2-羟丙基-2取代)-1H-吲哚-7-取代)乙氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000132
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.03(brs,NH),8.05(brs,NH),7.55(t,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.06-6.96(m,3H),7.01(d,J＝8.0Hz,2H),6.85(t,J＝13.6Hz,1H),6.15(s,1H),3.82(s,2H),2.86-2.67(m,4H),2.00(brs,NH),1.59(s,6H)ppm.HRMS(ESI):calcd for C23H28N3O3[MH+]394.2052found394.2051.
实施例121(E)-3-(5-((2-(1H-吲哚-4-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000133
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.79(s,1H),8.03(brs,NH),7.77(d,J＝13.6Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,1H),7.45(d,J＝13.6Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝7.4Hz,1H),7.03(m,1H),6.86(d,J＝6.6Hz,1H),6.45(d,J＝6.0Hz,1H),3.89(s,2H),2.96-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1587.
实施例123(E)-3-(4-((2-(1H-吲哚-4-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000134
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.82(d,J＝13.8Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.16(d,J＝8.8Hz,1H),7.03(m,1H),6.86(d,J＝7.8Hz,1H),6.78(d,J＝8.8Hz,1H),6.72(s,1H),6.67(d,J＝13.8Hz,1H),6.45(d,J＝6.0Hz,1H),3.82(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1541.
实施例124(E)-3-(4-((2-(1H-吲哚-4-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000135
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.03(m,1H),6.99(d,J＝8.8Hz,1H),6.95(d,J＝8.6Hz,1H),6.89(s,1H),6.86(d,J＝8.4Hz,1H),6.84(d,J＝13.6Hz,1H),6.45(d,J＝6.0Hz,1H),3.86(s,2H),2.92-2.75(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found 354.1542.
实施例125(E)-3-(5-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基
Figure PCTCN2014092104-appb-000136
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.79(s,1H),8.03(brs,NH),7.78(d,J＝14.6Hz,1H),7.74(d,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,1H),7.45(d,J＝14.6Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝7.4Hz,1H),7.03(m,1H),6.86(d,J＝6.6Hz,1H),6.45(d,J＝6.0Hz,1H),3.68(t,J＝6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found 381.1849.
实施例126(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000137
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.83(d,J＝13.8Hz,1H),7.26(d,J＝6.0Hz,1H),7.21(d,J＝8.6Hz,1H),7.15(d,J＝8.8Hz,1H),7.03(m,1H),6.86(d,J＝7.8Hz,1H),6.79(d,J＝8.8Hz,1H),6.73(s,1H),6.69(d,J＝13.8Hz,1H),6.46(d,J＝6.0Hz,1H),3.65(t,J＝6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1803.
实施例127(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000138
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.00(brs,NH),7.55(d,J＝13.2Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.03(m,1H),6.99(d,J＝7.8Hz,1H),6.95(d,J＝7.8Hz,1H),6.89(s,1H),6.86(d,J＝7.8Hz,1H),6.84(d,J＝13.2Hz,1H),6.45(d,J＝6.0Hz,1H),3.65(t,J＝6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1801.
实施例128(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000139
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.60(d,J＝8.6Hz,1H),8.28(brs,NH),7.55(d,J＝13.6Hz,1H),7.28(d,J＝8.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.96(d,J＝6.6Hz,2H),6.84(d,J＝13.6Hz,1H),6.73(d,J＝6.6Hz,2H),3.90(s,2H),2.88-2.67(m,4H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found 337.1587.
实施例129(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000140
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.61(d,J＝8.0Hz,1H),8.01(brs,NH),7.82(d,J＝14.6Hz,1H),7.28(d,J＝8.0Hz,1H),7.22(d,J＝6.6Hz,1H),7.16(d,J＝7.6Hz,1H),6.78(d,J＝7.6Hz,1H),6.72(s,1H),6.67(d,J＝14.6Hz,1H),6.45(d,J＝6.6Hz,1H),3.83(s,2H),2.90-2.69(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H20FN4O2[MH+]355.1492found 355.1493.实施例130(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000141
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.60(d,J＝8.8Hz,1H),8.02(brs,NH),7.55(d,J＝13.6Hz,1H),7.28(d,J＝8.8Hz,1H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.96(d,J＝6.6Hz,2H),6.84(d,J＝13.6Hz,1H),6.73(d,J＝6.6Hz,1H),3.63(t,J＝5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝5.6Hz,2H),2.00(brs,OH)ppm HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found 381.1849.
实施例131(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-4-取代)乙基(2--羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000142
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.60(d,J＝8.0Hz,1H),8.00(brs,NH),7.82(d,J＝13.6Hz,1H),7.28(d,J＝8.0Hz,1H),7.16(d,J＝7.6Hz,1H),6.90(d,J＝6.6Hz,1H),6.78(d,J＝7.6Hz,1H),6.72(s,1H),6.67(d,J＝13.6Hz,1H),6.48(d,J＝6.6Hz,1H),3.63(t,J＝5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found 399.1755.
实施例132(E)-3-(4-((2-(苯并呋喃-4-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000143
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.00(brs,NH),7.84(d,J＝13.6Hz,1H),7.52(d,J＝6.2Hz,1H),7.24(d,J＝8.0Hz,1H),7.16(d,J＝6.8Hz,1H),7.14(m,1H),6.99(d,J＝7.0Hz,1H),6.78(d,J＝8.8Hz,1H),6.72(s,1H),6.67(d,J＝13.6Hz,1H),6.60(d,J＝7.2Hz,1H),3.81(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found 355.1381.
实施例133(E)-3-(4-((2-(苯并噻吩-3-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000144
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.02(brs,NH),7.68(d,J＝6.0Hz,1H),7.55(d,J＝13.6Hz,1H),7.40(d,J＝6.6Hz,1H),7.29(d,J＝6.6Hz,1H),7.26(m,1H),7.19(d,J＝5.6Hz,1H),6.99(d,J＝6.8Hz,1H),6.95(d,J＝6.8Hz,1H),6.89(s,1H),6.82(d,J＝13.6Hz,1H),3.81(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found 371.1152.
实施例134(E)-3-(5-((2-(1H-吲哚-5-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000145
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.76(s,1H),8.01(brs,NH),7.76(d,J＝13.6Hz,1H),7.72(d,J＝7.8Hz,1H),7.52(d,J＝7.8Hz,1H),7.46(d,J＝13.6Hz,1H),7.26(d,J＝6.0Hz,1H),7.21(d,J＝7.4Hz,1H),7.02(m,1H),6.85(d,J＝6.6Hz,1H),6.43(d,J＝6.0Hz,1H),3.88(s,2H),2.97-2.76(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1585.
实施例135(E)-3-(4-((2-(1H-吲哚-5-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000146
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.01(brs,NH),7.82(d,J＝13.8Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.16(d,J＝8.8Hz,1H),7.03(m,1H),6.86(d,J＝7.8Hz,1H),6.78(d,J＝8.8Hz,1H),6.72(s,1H),6.67(d,J＝13.8Hz,1H),6.45(d,J＝6.0Hz,1H),3.82(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1540.
实施例136(E)-3-(4-((2-(1H-吲哚-5-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000147
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.56(d,J＝13.6Hz,1H),7.28(d,J＝6.0Hz,1H),7.23(d,J＝8.6Hz,1H),7.03(m,1H),6.99(d,J＝8.8Hz,1H),6.93(d,J＝8.6Hz,1H),6.89(s,1H),6.85(d,J＝8.4Hz,1H),6.80(d,J＝13.6Hz,1H),6.46(d,J＝6.0Hz,1H),3.83(s,2H),2.90-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found 354.1541.
实施例137(E)-3-(5-(((2-(1H-吲哚-5-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000148
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.76(s,1H),8.02(brs,NH),7.75(d,J＝14.6Hz,1H),7.70(d,J＝7.8Hz,1H),7.51(d,J＝7.8Hz,1H),7.45(d,J＝14.6Hz,1H),7.26(d,J＝6.0Hz,1H),7.22(d,J＝7.4Hz,1H),7.01(m,1H),6.83(d,J＝6.6Hz,1H),6.47(d,J＝6.0Hz,1H),3.67(t,J＝6.6Hz,2H),3.61(s,2H),2.69-2.65(m,4H),2.53(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found 381.1847.
实施例138(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000149
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.00(brs,NH),7.82(d,J＝13.8Hz,1H),7.27(d,J＝6.0Hz,1H),7.20(d,J＝8.6Hz,1H),7.16(d,J＝8.8Hz,1H),7.01(m,1H),6.87(d,J＝7.8Hz,1H),6.77(d,J＝8.8Hz,1H),6.73(s,1H),6.66(d,J＝13.8Hz,1H),6.42(d,J＝6.0Hz,1H),3.63(t,J＝6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.53(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1802.
实施例139(E)-3-(4-(((2-(1H-吲哚-5-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000150
合成方法如实施例1。
1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.05(brs,NH),7.56(d,J＝13.2Hz,1H),7.27(d,J＝6.0Hz,1H),7.23(d,J＝8.6Hz,1H),7.05(m,1H),6.97(d,J＝7.8Hz,1H),6.93(d,J＝7.8Hz,1H),6.88(s,1H),6.83(d,J＝7.8Hz,1H),6.81(d,J＝13.2Hz,1H),6.48(d,J＝6.0Hz,1H),3.62(t,J＝6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.57(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1802.
实施例140(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基氨基)甲基)苯基)-N-羟基 -丙烯酰胺
Figure PCTCN2014092104-appb-000151
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.58(s,1H),8.26(brs,NH),7.55(d,J＝13.6Hz,1H),7.28(s,1H),7.19(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.96(d,J＝6.6Hz,2H),6.86(d,J＝13.6Hz,1H),6.73(d,J＝6.6Hz,2H),3.91(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found 337.1586.
实施例141(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基氨基)甲基)吡啶-3-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000152
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.69(s,1H),8.58(s,1H),7.86(d,J＝8.2Hz,1H),7.56(d,J＝13.6Hz,1H),7.50(d,J＝8.2Hz,1H),7.28(s,1H),6.96(d,J＝6.6Hz,2H),6.83(d,J＝13.6Hz,1H),6.72(d,J＝6.6Hz,2H),4.12(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C18H20N5O2[MH+]338.1539,found 338.1537.
实施例142(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000153
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.60(s,1H),8.00(brs,NH),7.81(d,J＝14.6Hz,1H),7.29(s,1H),7.23(d,J＝6.6Hz,1H),7.18(d,J＝7.6Hz,1H),6.81(d,J＝7.6Hz,1H),6.73(s,1H),6.67(d,J＝14.6Hz,1H),6.43(d,J＝6.6Hz,1H),3.82(s,2H),2.90-2.69(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H20FN4O2[MH+]355.1492found 355.1491.
实施例143(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000154
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.61(s,,1H),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.28(s,,1H),7.19(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.97(d,J＝6.6Hz,2H),6.84(d,J＝13.6Hz,1H),6.73(d,J＝6.6Hz,1H),3.63(t,J＝5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.53(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found 381.1847.
实施例144(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000155
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.75(s,1H),8.56(s,1H),8.01(brs,NH),7.78(d,J＝13.6Hz,1H),7.72(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.47(d,J＝13.6Hz,1H),7.28(s,1H),7.02(d,J＝6.6Hz,1H),6.75(d,J＝6.6Hz,1H),3.60(t,J＝5.6Hz,2H),3.58(s,2H),2.69-2.65(m,4H),2.53(t,J＝5.6Hz,2H),2.00(brs,OH)ppm HRMS(ESI):calcd for C20H24N5O3[MH+]382.1801,found 382.1802.
实施例145(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基(2--羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000156
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.61(s,1H),8.00(brs,NH),7.82(d,J＝13.6Hz,1H),7.28(d,J＝8.0Hz,1H),7.16(d,J＝7.6Hz,1H),6.92(d,J＝6.6Hz,1H),6.78(d,J＝7.6Hz,1H),6.72(s,1H),6.67(d,J＝13.6Hz,1H),6.47(d,J＝6.6Hz,1H),3.65(t,J＝5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.53(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found 399.1753.
实施例146(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-5-取代)乙基(2--羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000157
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.62(s,1H),8.00(brs,NH),7.56(d,J＝13.6Hz,1H),7.28(s,1H),7.05(d,J＝6.6Hz,1H),6.98(d,J＝7.6Hz,1H),6.93(d,J＝7.6Hz,1H),6.88(s,1H),6.82(d,J＝13.6Hz,1H),6.49(d,J＝6.6Hz,1H),3.62(t,J＝5.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.57(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found 399.1753.
实施例147(E)-3-(4-((2-(苯并呋喃-5-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000158
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.82(d,J＝13.6Hz,1H),7.52(d,J＝6.2Hz,1H),7.37(d,J＝8.2Hz,1H),7.35(s,1H),7.16(d,J＝6.8Hz,1H),7.05(d,J＝7.0Hz,1H),6.78(d,J＝8.2Hz,1H),6.72(s,1H),6.67(d,J＝13.6Hz,1H),6.62(d,J＝7.2Hz,1H),3.81(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found 355.1383.
实施例148(E)-3-(4-((2-(苯并呋喃-5-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000159
合成方法如实施例1。1H NMR(400MHz,MeOD):1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.55(d,J＝13.6Hz,1H),7.52(d,J＝6.2Hz,1H),7.37(d,J＝7.6Hz,1H),7.33(s,1H),7.06(d,J＝7.3Hz,1H),6.99(d,J＝7.0Hz,1H),6.96(d,J＝7.0Hz,1H),6.89(s,1H),6.83(d,J＝13.6Hz,1H),6.67(d,J＝7.2Hz,1H),3.82(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found 355.1382.
实施例149(E)-3-(4-((2-(苯并噻吩-5-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000160
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.82(d,J＝13.6Hz,1H),7.80(d,J＝6.6Hz,1H),7.66(s,1H),7.40(d,J＝6.2Hz,1H),7.29(d,J＝6.2Hz,1H),7.18(d,J＝6.6Hz,1H),7.16(d,J＝6.8Hz,1H),6.79(d,J＝6.8Hz,1H),6.73(s,1H),6.65(d,J＝13.6Hz,1H),3.81(s,2H),2.89-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found 371.1150.
实施例150(E)-3-(4-((2-(苯并噻吩-5-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000161
合成方法如实施例1。1H NMR(400MHz,MeOD):1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.81(d,J＝8.0Hz,1H),7.64(s,1H),7.56(d,J＝13.8Hz,1H),7.41(d,J＝6.0Hz,1H),7.29(d,J＝6.2Hz,1H),7.17(d,J＝8.2Hz,1H),6.99(d,J＝7.0Hz,1H),6.96(d,J＝7.0Hz,1H),6.89(s,1H),6.83(d,J＝13.8Hz,1H),3.83(s,2H),2.89-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]371.1151found 371.1149.
实施例151(E)-3-(5-((2-(1H-吲哚-6-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000162
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.78(s,1H),8.05(brs,NH),7.76(d,J＝13.6Hz,1H),7.72(d,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,1H),7.46(d,J＝13.6Hz,1H),7.27(d,J＝6.0Hz,1H),7.20(d,J＝7.4Hz,1H),7.05(m,1H),6.89(d,J＝6.6Hz,1H),6.47(d,J＝6.0Hz,1H),3.89(s,2H),2.96-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1586.
实施例152(E)-3-(6-((2-(1H-吲哚-6-取代)乙氨基)甲基)吡啶基-3-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000163
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.67(s,1H),8.01(brs,NH),7.87(d,J＝7.8Hz,1H),7.53(d,J＝13.6Hz,1H),7.48(d,J＝7.8Hz,1H),7.27(d,J＝6.2Hz,1H),7.20(d,J＝7.8Hz,1H),7.03(m,1H),6.87(d,J＝6.8Hz,1H),6.82(d,J＝13.6Hz,1H),6.46(d,J＝6.0Hz,1H),4.13(s,2H),2.98-2.78(m,4H),2.00(brs,OH)ppmHRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found 337.1585.
实施例153(E)-3-(4-((2-(1H-吲哚-6-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000164
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.00(brs,NH),7.80(d,J＝13.8Hz,1H),7.25(d,J＝6.0Hz,1H),7.21(d,J＝8.6Hz,1H),7.15(d,J＝8.8Hz,1H),7.00(m,1H),6.85(d,J＝7.8Hz,1H),6.76(d,J＝8.8Hz,1H),6.70(s,1H),6.65(d,J＝13.8Hz,1H),6.45(d,J＝6.0Hz,1H),3.81(s,2H),2.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1542.
实施例154(E)-3-(4-((2-(1H-吲哚-6-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000165
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.06(brs,NH),8.00(brs,NH),7.53(d,J＝13.6Hz,1H),7.26(d,J＝6.0Hz,1H),7.21(d,J＝8.6Hz,1H),7.03(m,1H),6.99(d,J＝8.8Hz,1H),6.93(d,J＝8.6Hz,1H),6.89(s,1H),6.86(d,J＝8.4Hz,1H),6.81(d,J＝13.6Hz,1H),6.42(d,J＝6.0Hz,1H),3.83(s,2H),2.92-2.75(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found 354.1542.
实施例155(E)-3-(5-(((2-(1H-吲哚-6-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000166
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.79(s,1H),8.02(brs,NH),7.76(d,J＝14.6Hz,1H),7.72(d,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,1H),7.42(d,J＝14.6Hz,1H),7.27(d,J＝6.0Hz,1H),7.20(d,J＝7.4Hz,1H),7.03(m,1H),6.86(d,J＝6.6Hz,1H),6.45(d,J＝6.0Hz,1H),3.68(t,J＝6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝6.2Hz,2H),2.00(brs,OH)ppm HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found 381.1848.
实施例156(E)-3-(4-(((2-(1H-吲哚-6-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000167
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.01(brs,NH),7.85(d,J＝13.8Hz,1H),7.28(d,J＝6.0Hz,1H),7.21(d,J＝8.6Hz,1H),7.13(d,J＝8.8Hz,1H),7.00(m,1H),6.86(d,J＝7.8Hz,1H),6.79(d,J＝8.8Hz,1H),6.72(s,1H),6.66(d,J＝13.8Hz,1H),6.48(d,J＝6.0Hz,1H),3.63(t,J＝6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.53(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1801.
实施例157(E)-3-(4-(((2-(1H-吲哚-4-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000168
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.00(brs,NH),7.55(d,J＝13.2Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.03(m,1H),6.99(d,J＝7.8Hz,1H),6.95(d,J＝7.8Hz,1H),6.89(s,1H),6.86(d,J＝7.8Hz,1H),6.84(d,J＝13.2Hz,1H),6.45(d,J＝6.0Hz,1H),3.65(t,J＝6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1801.
实施例158(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000169
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.07(brs,NH),8.61(d,J＝8.6Hz,1H),8.29(brs,NH),7.55(d,J＝13.6Hz,1H),7.28(d,J＝8.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.96(d,J＝6.6Hz,2H),6.85(d,J＝13.6Hz,1H),6.75(d,J＝6.6Hz,2H),3.88(s,2H),2.88-2.67(m,4H),2.01(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found 337.1585.
实施例159(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基氨基)甲基)吡啶-3-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000170
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.66(s,1H),8.61(d,J＝8.6Hz,1H),7.82(d,J＝8.2Hz,1H),7.57(d,J＝13.6Hz,1H),7.52(d,J＝8.2Hz,1H),7.28(d,J＝8.6Hz,1H),6.96(d,J＝6.6Hz,2H),6.86(d,J＝13.6Hz,1H),6.75(d,J＝6.6Hz,2H),4.12(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C18H20N5O2[MH+]338.1539,found 338.1537.
实施例160(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000171
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.60(d,J＝8.0Hz,1H),8.00(brs,NH),7.80(d,J＝14.6Hz,1H),7.26(d,J＝8.0Hz,1H),7.20(d,J＝6.6Hz,1H),7.16(d,J＝7.6Hz,1H),6.79(d,J＝7.6Hz,1H),6.72(s,1H),6.65(d,J＝14.6Hz,1H),6.46(d,J＝6.6Hz,1H),3.82(s,2H),2.90-2.69(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H20FN4O2[MH+]355.1492found 355.1492.
实施例161(E)-3-(4-((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000172
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.61(d,J＝8.8Hz,1H),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.28(d,J＝8.8Hz,1H),7.19(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.96(d,J＝6.6Hz,2H),6.82(d,J＝13.6Hz,1H),6.71(d,J＝6.6Hz,1H),3.62(t,J＝5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found 381.1849.
实施例212(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000173
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.76(s,1H),8.58(d,J＝8.8Hz,1H),8.01(brs,NH),7.73(d,J＝13.6Hz,1H),7.70(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.43(d,J＝13.6Hz,1H),7.24(d,J＝8.8Hz,1H),7.02(d,J＝6.6Hz,1H),6.71(d,J＝6.6Hz,1H),3.63(t,J＝5.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.56(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H24N5O3[MH+]382.1801,found 382.1801.
实施例162(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基(2--羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000174
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.61(d,J＝8.0Hz,1H),8.03(brs,NH),7.81(d,J＝13.6Hz,1H),7.27(d,J＝8.0Hz,1H),7.16(d,J＝7.6Hz,1H),6.90(d,J＝6.6Hz,1H),6.78(d,J＝7.6Hz,1H),6.72(s,1H),6.67(d,J＝13.6Hz,1H),6.48(d,J＝6.6Hz,1H),3.64(t,J＝5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found 399.1753.
实施例163(E)-3-(4-(((2-(1H吡咯并[2,3-b]吡啶-6-取代)乙基(2--羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000175
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.62(d,J＝8.0Hz,1H),8.00(brs,NH),7.56(d,J＝13.6Hz,1H),7.21(d,J＝8.0Hz,1H),7.03(d,J＝6.6Hz,1H),6.99(d,J＝7.6Hz,1H),6.93(d,J＝7.6Hz,1H),6.85(s,1H),6.80(d,J＝13.6Hz,1H),6.48(d,J＝6.6Hz,1H),3.63(t,J＝5.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.52(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H24FN4O3[MH+]399.1754found 399.1753.
实施例164(E)-3-(4-((2-(苯并呋喃-6-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000176
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.02(brs,NH),7.83(d,J＝13.6Hz,1H),7.51(d,J＝6.2Hz,1H),7.45(d,J＝8.2Hz,1H),7.28(s,1H),7.17(d,J＝6.8Hz,1H),6.99(d,J＝8.2Hz,1H),6.78(d,J＝7.0Hz,1H),6.72(s,1H),6.69(d,J＝13.6Hz,1H),6.65(d,J＝6.2Hz,1H),3.82(s,2H),2.89-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found 355.1382.
实施例165(E)-3-(4-((2-(苯并呋喃-6-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000177
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.05(brs,NH),7.59(d,J＝13.8Hz,1H),7.53(d,J＝6.6Hz,1H),7.45(d,J＝7.6Hz,1H),7.29(s,1H),7.06(d,J＝7.6Hz,1H),6.99(d,J＝6.2Hz,1H),6.96(d,J＝6.2Hz,1H),6.89(s,1H),6.83(d,J＝13.8Hz,1H),6.66(d,J＝7.2Hz,1H),3.83(s,2H),2.90-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found 355.1381.
实施例166(E)-3-(4-((2-(苯并噻吩-6-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000178
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.03(brs,NH),7.83(d,J＝13.6Hz,1H),7.75(d,J＝6.6Hz,1H),7.72(s,1H),7.41(d,J＝6.2Hz,1H),7.29(d,J＝6.2Hz,1H),7.19(d,J＝6.6Hz,1H),7.15(d,J＝6.8Hz,1H),6.80(d,J＝6.8Hz,1H),6.72(s,1H),6.66(d,J＝13.6Hz,1H),3.80(s,2H),2.85-2.63(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found 371.1151.
实施例167(E)-3-(4-((2-(苯并噻吩-6-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000179
合成方法如实施例1。1H NMR(400MHz,MeOD):1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.75(d,J＝8.0Hz,1H),7.72(s,1H),7.55(d,J＝13.8Hz,1H),7.40(d,J＝6.2Hz,1H),7.29(d,J＝6.2Hz,1H),7.19(d,J＝8.2Hz,1H),7.03(d,J＝7.0Hz,1H),6.98(d,J＝7.0Hz,1H),6.89(s,1H),6.84(d,J＝13.8Hz,1H),3.82(s,2H),2.89-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]371.1151found 371.1148.
实施例168(E)-3-(5-((2-(1H-吲哚-7-取代)乙氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000180
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.79(s,1H),8.03(brs,NH),7.77(d,J＝13.6Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,1H),7.45(d,J＝13.6Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝7.4Hz,1H),7.03(m,1H),6.86(d,J＝6.6Hz,1H),6.45(d,J＝6.0Hz,1H),3.89(s,2H),2.96-2.77(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586found337.1587.
实施例169(E)-3-(4-((2-(1H-吲哚-7-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000181
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.00(brs,NH),7.83(d,J＝13.8Hz,1H),7.27(d,J＝6.0Hz,1H),7.21(d,J＝8.6Hz,1H),7.16(d,J＝8.8Hz,1H),7.03(m,1H),6.88(d,J＝7.8Hz,1H),6.75(d,J＝8.8Hz,1H), 6.70(s,1H),6.63(d,J＝13.8Hz,1H),6.49(d,J＝6.0Hz,1H),3.82(s,2H),2.89-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found354.1542.
实施例170(E)-3-(4-((2-(1H-吲哚-7-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000182
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.01(brs,NH),7.57(d,J＝13.6Hz,1H),7.23(d,J＝6.0Hz,1H),7.20(d,J＝8.6Hz,1H),7.01(m,1H),6.99(d,J＝8.8Hz,1H),6.93(d,J＝8.6Hz,1H),6.89(s,1H),6.85(d,J＝8.4Hz,1H),6.81(d,J＝13.6Hz,1H),6.45(d,J＝6.0Hz,1H),3.85(s,2H),2.92-2.75(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H21FN3O2[MH+]354.1540found 354.1542.
实施例171(E)-3-(5-(((2-(1H-吲哚-7-取代)乙基)(2-羟乙基)氨基)甲基)吡啶基-2-取代)-N-羟基-丙烯酰胺
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.78(s,1H),8.05(brs,NH),7.78(d,J＝14.6Hz,1H),7.72(d,J＝7.8Hz,1H),7.50(d,J＝7.8Hz,1H),7.46(d,J＝14.6Hz,1H),7.27(d,J＝6.0Hz,1H),7.21(d,J＝7.4Hz,1H),7.03(m,1H),6.86(d,J＝6.6Hz,1H),6.45(d,J＝6.0Hz,1H),3.66(t,J＝6.6Hz,2H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848found 381.1847.
实施例172(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)(2-羟乙基)氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000184
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.02(brs,NH),7.85(d,J＝13.8Hz,1H),7.27(d,J＝6.0Hz,1H),7.21(d,J＝8.6Hz,1H),7.13(d,J＝8.8Hz,1H),7.03(m,1H),6.86(d,J＝7.8Hz,1H),6.75(d,J＝8.8Hz,1H),6.70(s,1H),6.67(d,J＝13.8Hz,1H),6.46(d,J＝6.0Hz,1H),3.63(t,J＝6.6Hz,2H),3.61(s,2H),2.69-2.65(m,4H),2.53(t,J＝6.2Hz,2H),2.00(brs,OH) ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1802.
实施例173(E)-3-(4-(((2-(1H-吲哚-7-取代)乙基)(2-羟乙基)氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000185
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.12(brs,NH),8.01(brs,NH),7.55(d,J＝13.2Hz,1H),7.27(d,J＝6.0Hz,1H),7.22(d,J＝8.6Hz,1H),7.05(m,1H),6.99(d,J＝7.8Hz,1H),6.93(d,J＝7.8Hz,1H),6.89(s,1H),6.85(d,J＝7.8Hz,1H),6.80(d,J＝13.2Hz,1H),6.45(d,J＝6.0Hz,1H),3.66(t,J＝6.6Hz,2H),3.60(s,2H),2.69-2.65(m,4H),2.55(t,J＝6.2Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C22H25FN3O3[MH+]398.1802found 398.1801.
实施例174(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-4-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000186
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.08(brs,NH),8.59(s,1H),8.52(s,1H),8.09(brs,NH),7.55(d,J＝13.6Hz,1H),7.19(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.99(d,J＝6.6Hz,2H),6.85(d,J＝13.6Hz,1H),6.78(d,J＝6.6Hz,2H),3.83(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found 337.1588.
实施例175(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-5-取代)乙基氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000187
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.09(brs,NH),8.62(s,1H),8.09(brs,NH),7.55(d,J＝13.6Hz,1H),7.29(s,1H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.93(d,J＝6.6Hz,2H),6.85(d,J＝13.6Hz,1H),6.78(d,J＝6.6Hz,2H),3.88(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found 337.1586.
实施例176(E)-3-(4-((2-(1H吡咯并[3,2-b]吡啶-7-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000188
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.60(d,J＝8.2Hz,1H),8.20(brs,NH),7.28(d,J＝8.2Hz,1H),7.55(d,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.98(d,J＝6.6Hz,2H),6.83(d,J＝13.6Hz,1H),6.79(d,J＝6.6Hz,2H),3.83(s,2H),2.88-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C19H21N4O2[MH+]337.1586,found 337.1584.
实施例177(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-4-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000189
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.60(s,1H),8.57(s,1H),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.96(d,J＝6.6Hz,2H),6.84(d,J＝13.6Hz,1H),6.71(d,J＝6.6Hz,1H),3.63(t,J＝5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found 381.1847.
实施例178(E)-3-(4-((2-(1H吡咯并[2,3-c]吡啶-5-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000190
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.10(brs,NH),8.62(s,1H),8.00(brs,NH),7.55(d,J＝13.6Hz,1H),7.29(s,1H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.95(d,J＝6.6Hz,2H),6.83(d,J＝13.6Hz,1H),6.70(d,J＝6.6Hz,1H),3.65(t,J＝5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found 381.1848.
实施例178(E)-3-(4-((2-(1H吡咯并[3,2-b]吡啶-7-取代)乙基)(2-羟乙基)氨基)甲基)苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000191
合成方法如实施例1。1H NMR(400MHz,MeOD):δ10.11(brs,NH),8.60(d,J＝8.6Hz,1H),8.06(brs,NH),7.55(d,J＝13.6Hz,1H),7.28(d,J＝8.6Hz,1H),7.18(d,J＝8.0Hz,2H),7.01(d,J＝8.0Hz,2H),6.97(d,J＝6.6Hz,2H),6.82(d,J＝13.6Hz,1H),6.75(d,J＝6.6Hz,1H),3.67(t,J＝5.6Hz,1H),3.62(s,2H),2.69-2.65(m,4H),2.55(t,J＝5.6Hz,2H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C21H25N4O3[MH+]381.1848,found 381.1849.
实施例179(E)-3-(4-((2-(苯并呋喃-7-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000192
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.01(brs,NH),7.83(d,J＝13.6Hz,1H),7.53(d,J＝6.2Hz,1H),7.32(d,J＝8.2Hz,1H),7.19(d,J＝6.8Hz,1H),7.09(m,1H),7.05(d,J＝8.0Hz,1H),6.80(d,J＝8.2Hz,1H),6.77(s,1H),6.70(d,J＝13.6Hz,1H),6.66(d,J＝7.2Hz,1H),3.80(s,2H),2.87-2.66(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380found 355.1380.
实施例180(E)-3-(4-((2-(苯并呋喃-7-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000193
合成方法如实施例1。1H NMR(400MHz,MeOD):1H NMR(400MHz,MeOD):δ8.02(brs,NH),.57(d,J＝13.6Hz,1H),7.52(d,J＝6.6Hz,1H),7.32(d,J＝7.6Hz,1H),7.09m,1H),7.05(d,J＝7.2Hz,1H),6.99(d,J＝7.0Hz,1H),6.96(d,J＝7.0Hz,H),6.89(s,1H),6.83(d,J＝13.6Hz,1H),6.65(d,J＝6.6Hz,1H),3.82(s,2H),.88-2.68(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]355.1380ound 355.1383.
实施例181(E)-3-(4-((2-(苯并噻吩-7-取代)乙氨基)甲基)2-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000194
合成方法如实施例1。1H NMR(400MHz,MeOD):δ8.06(brs,NH),7.83(d,J＝13.6Hz,1H),7.62(d,J＝6.6Hz,1H),7.40(d,J＝6.6Hz,1H),7.29(d,J＝6.6Hz,1H),7.27(m,1H),7.19(d,J＝6.2Hz,1H),7.18(d,J＝6.6Hz,1H),7.16(d,J＝6.2Hz,1H),6.79(d,J＝6.2Hz,1H),6.72(s,1H),6.67(d,J＝13.6Hz,1H),3.83(s,2H),2.89-2.66(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O2S[MH+]371.1151found 371.1153.
实施例182(E)-3-(4-((2-(苯并噻吩-7-取代)乙氨基)甲基)3-氟苯基)-N-羟基-丙烯酰胺
Figure PCTCN2014092104-appb-000195
合成方法如实施例1。1H NMR(400MHz,MeOD):1H NMR(400MHz,MeOD):δ8.02(brs,NH),7.63(d,J＝8.0Hz,1H),7.55(d,J＝13.8Hz,1H),7.40(d,J＝6.0Hz,1H),7.29(d,J＝6.2Hz,1H),7.27(m,1H),7.17(d,J＝8.2Hz,1H),7.00(d,J＝7.0Hz,1H),6.95(d,J＝7.0Hz,1H),6.89(s,1H),6.84(d,J＝13.8Hz,1H),3.82(s,2H),2.89-2.67(m,4H),2.00(brs,OH)ppm.HRMS(ESI):calcd for C20H20FN2O3[MH+]371.1151found 371.1150.
实施例183HDAC生化活性的测定
1.测定原理：化合物生化活的性测定是根据其抑制HDAC酶的去乙酰化作用程度来确定的。用荧光标记的含有乙酰化的赖氨酸侧链的底物和HDAC酶作用之后，该荧光底物被去乙酰化。去乙酰化后的荧光标记底物被酶裂解后，释放出荧光物质，该荧光物质在360nm光的激发下产生460nm的发射光。
2.具体步骤：HDAC的底物用反应缓冲液稀释至200M(反应浓度为20M)，将HDAC酶稀释至适当浓度，加入不同浓度待测化合物，37℃反应30分钟，然后加入相同体积的2倍浓度底物发展液(developer)，室温孵育15分钟，最后用微孔板读板仪测定读数，激发光为360nm，发射光为460nm，数据用Prime 4软件处理。
3.检测结果(如表1所示)与分析：
表1
Figure PCTCN2014092104-appb-000196
Figure PCTCN2014092104-appb-000197
Figure PCTCN2014092104-appb-000198
Figure PCTCN2014092104-appb-000199
Figure PCTCN2014092104-appb-000200
Figure PCTCN2014092104-appb-000201
Figure PCTCN2014092104-appb-000202
上表中IC50是指被抑制一半时抑制剂的浓度(50％inhibitory concentration)。
从上表中结果可以看出：上述的化合物与阳性对照(SAHA)相比，具有显著的抑制HDAC酶的去乙酰化作用的活性。
本发明化合物结构与现有的相关化合物相比，酶活性结果见表2，显示出显著优势，相差几倍到数十倍。
表2 酶活性结果比较表
Figure PCTCN2014092104-appb-000203
Figure PCTCN2014092104-appb-000204
在吲哚的4,5,6,7位引入侧链可以很好的提高其对组蛋白去乙酰化酶的活性。与现有化合物相比,其活性可以提高10倍以上。吲哚环的1,2及3位上可以引入烷基或烷烃基取代基,其对组蛋白去乙酰化酶的活性与母体化合物基本相当或更好。在吲哚环的2,3位上引入引入其它环状结构,其对组蛋白去乙酰化酶的活性与母体化合物基本相当。双键上引入取代基其对组蛋白去乙酰化酶的活性比母体化合物稍弱。中间苯环引入氟或含氮杂原子,其对组蛋白去乙酰化酶的活性与母体化合物基本相当。吲哚环可以被苯并呋喃或苯并噻吩取代,其对组蛋白去乙酰化酶的活性与母体化合物基本相当。
实施例184检测化合物对癌细胞活性实验
1.实验原理：化合物抑制癌细胞生长用MTT方法来检测。MTT法的原理是，黄色的噻唑兰可透过细胞膜进入细胞内，活细胞线粒体中的琥珀脱氢酶能使外源性MTT还原为难溶于水的蓝紫色的针状Formazan结晶并沉积在细胞中，结晶能被二甲基亚砜(DMSO)溶解，用酶联免疫检测仪在490nm/570nm波长处检测其光吸收值，可间接反映细胞数量。
2.实验材料：所使用的癌细胞系为Hela(人宫颈癌细胞)，MCF-7(人乳腺癌细胞)，BGC-823(人胃癌细胞)，A549(人肺癌细胞)，HT1080(人纤维肉瘤细胞)，A431(人表皮鳞状细胞癌细胞)，DU145(人前列腺癌细胞)，U937(人白血病细胞)，Pac-1(人胰腺癌细胞)，MOLT-4(人急性淋巴母细胞白血病细胞)；分别用DMEM+10％FBS培养基培养或者使用1640+10％FBS培养。
3.实验方法与结果分析：
实验组：190μl细胞悬液+10μl不同浓度的药物(终浓度为10-5～10-10M)
空白对照组：200μl PBS
阴性对照组：190μl细胞悬液+10μl 2％DMSO(DMSO终浓度为0.1％)
阳性对照组：190μl细胞悬液+10μl不同浓度的化合物
a).细胞接种于96孔板，接种量为1500个/孔，190μl/孔，37℃5％的CO2培养箱培养过夜；
b).次日每孔加入10μl不同药物，药物终浓度为10-5～10-10M，设三个平行孔；37℃、5％的CO2培养箱孵育72小时；
c).每孔加入20μl 5mg/ml的MTT，37℃5％的CO2培养箱孵育4小时；
d).弃上清，每孔加入100μl的DMSO，振荡；
e).570nm读数，计算细胞存活率，根据结果计算GI50，得下表3。
表3
Figure PCTCN2014092104-appb-000205
Figure PCTCN2014092104-appb-000206
Figure PCTCN2014092104-appb-000207
Figure PCTCN2014092104-appb-000208
Figure PCTCN2014092104-appb-000209
Figure PCTCN2014092104-appb-000210
Figure PCTCN2014092104-appb-000211
上表中GI50表示的是细胞50％生长抑制所需的药物浓度(50％growth inhibition)。
从上表中结果可以看出：上述的药物与阳性对照(SAHA)相比，具有显著的抑制所列肿瘤细胞生长的活性。
本发明化合物与现有的化合物相比，显示出显著优势，对肿瘤细胞活性结果见表4。
表4
Figure PCTCN2014092104-appb-000212
Figure PCTCN2014092104-appb-000213
在吲哚的4,5,6,7位引入侧链可以很好的提高其抗肿瘤细胞的的活性。与现有化合物相比,其活性可以提高10到100倍以上。吲哚环的1,2及3位上可以引入烷基或烷烃基取代基,其抗肿瘤细胞的活性与母体化合物基本相当或更好。在吲哚环的2,3位上引入引入其它环状结构,其对抗肿瘤细胞的活性与母体化合物基本相当。双键上引入取代基其对抗肿瘤细胞的活性比母体化合物稍弱。中间苯环引入氟或含氮杂原子,其对抗肿瘤细胞的活性与母体化合物基本相当。吲哚环可以被苯并呋喃或苯并噻吩取代,其对抗肿瘤细胞的活性与母体化合物基本相当。
实施例185检测化合物1-1对裸鼠体内肿瘤的抑制实验
5×106个HCT116细胞接种到BALB/C裸鼠的右前腋下,待瘤体增长至100-200mm3大小时分组口服给药,设3个剂量组,10mg/kg,20mg/kg,和40mg/kg,iv,qd,8～10只/组,每两天称取一次动物体重,量取瘤体积(分组当天记录初始瘤体积和体重)。瘤体积计算公式为:V＝π/6*a*b*b.结果发现化合物1-1对动物体重无明显影响,均表现出良好的体内抑制肿瘤生长活性。该化合物均能完全抑制肿瘤的生长。
Figure PCTCN2014092104-appb-000214
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在 不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (11)

  1. 具有通式I所示的化学结构的杂环羟肟酸类化合物，及其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物：
    Figure PCTCN2014092104-appb-100001
    其中，
    X任选为N,O或S，且X被0-1个取代基取代，所述取代基为C1-C10烷基；
    W,Y,Z任选为CH或N；
    R1基团任选自：
    1)氢；
    2)C1-C12烷基；
    3)-CH2-O-(C1-C12烷基)；
    4)-CH2-NH-(C1-C12烷基)；
    5)-CH2-S-(C1-C12烷基)；
    6)C6-C12芳基；
    7)杂芳基；
    8)-CH2-(C6-C12芳基)或-CH2-杂芳基；
    上述的C6-C12芳基，杂芳基，-CH2-(C6-C12芳基)，-CH2-杂芳基，含有或不含有1个或多个取代基，其取代基选自卤素、氨基、羟基、硝基、氰基、C1-C12烷基、C1-C12烷氧基、氨基C1-C12烷基、C1-C12酰基、C1-C12酰氧基、硫代C1-C12烷基、羧基或苯基；
    R2基团任选自：
    1)氢；2)卤素；3)C1～C5烷基；4)C3～C6环烷基；5)C1～C5含氟烷基；
    R3基团任选自：
    1)氢；2)C1～C10烷基；3)C3～C9环烷基；4)C4～C9杂环烷基；5)C6-C12芳基；6)C6-C12杂芳基；7)C6-C12芳烷基；8)C6-C12杂芳烷基；9)-(CH2)nC(O)R6；10)-(CH2)-OC(O)R6；11)C1-C12酰基；12)–(CH2)nR7；13)C1-C12烷羟基
    n为0-6的整数；
    R4,R5基团分别任选自：
    1)氢；2)卤素；3)C1～C5烷基；4)C1-C12烷羟基；5)C1～C5含氟烷基；6)芳基或7)R4和R5形成五元、六元、七元或八元杂环结构
    Figure PCTCN2014092104-appb-100002
    其中X1,Y1任选自N,O,S,CH；n2,n3分别任选自0、1、2或3；
    R6基团任选自：
    1)氢；2)C1～C6烷基；3)C3～C9环烷基；4)C4～C9杂环烷基；5)C6-C12芳基；6)杂芳基；
    R7基团任选自：
    1)C1～C6烷基醚；2)C1～C6烷基硫醚；3)C1～C6烷基胺；4)C1～C6烷基磺酰胺基；
    所述杂芳基选自吡啶、吡唑、吡嗪、吡咯、咪唑、呋喃、噻吩、苯并呋喃或苯并噻吩；
    烷基胺的側链是在吲哚环的4,5,6或7位上。
  2. 根据权利要求1的所述的杂环羟肟酸类化合物，其特征在于，所述X任选为N,O或S；W,Y,Z为CH；R1为氢或C1-C5烷基；R2为氢、F；R3为氢、C1-C5烷基或羟乙基。
  3. 根据权利要求2的所述的杂环羟肟酸类化合物，其特征在于，其中
    R4,R5基团分别任选自：1)氢；2)C1～C5烷基；3)C1～C5羟烷基。
  4. 根据权利要求3的所述的杂环羟肟酸类化合物，其特征在于，该杂环羟肟酸类化合物为：
    Figure PCTCN2014092104-appb-100003
    Figure PCTCN2014092104-appb-100004
    Figure PCTCN2014092104-appb-100005
    Figure PCTCN2014092104-appb-100006
    Figure PCTCN2014092104-appb-100007
    Figure PCTCN2014092104-appb-100008
    Figure PCTCN2014092104-appb-100009
    Figure PCTCN2014092104-appb-100010
    Figure PCTCN2014092104-appb-100011
  5. 根据权利要求2的所述的杂环羟肟酸类化合物，其特征在于，R4与R5基团形成的环状结构为以下结构之一:
    Figure PCTCN2014092104-appb-100012
  6. 根据权利要求1所述的杂环羟肟酸类化合物，其特征在于，该化合物选自：
    Figure PCTCN2014092104-appb-100013
    Figure PCTCN2014092104-appb-100014
    Figure PCTCN2014092104-appb-100015
    Figure PCTCN2014092104-appb-100016
    Figure PCTCN2014092104-appb-100017
    Figure PCTCN2014092104-appb-100018
    Figure PCTCN2014092104-appb-100019
    Figure PCTCN2014092104-appb-100020
    Figure PCTCN2014092104-appb-100021
    Figure PCTCN2014092104-appb-100022
    Figure PCTCN2014092104-appb-100023
    Figure PCTCN2014092104-appb-100024
  7. 一种治疗肿瘤的药用组合物，其活性成分包括权利要求1-6任一项所述的杂环羟肟酸类化合物或其药学上可接受的盐或立体异构体或其前药分子。
  8. 权利要求1～6中任一项所述的杂环羟肟酸类化合物在制备预防或者治疗与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病药物中的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症。
  10. 根据权利要求9所述的应用，其特征在于，所述的癌症为淋巴瘤、非小细胞肺癌、小细胞肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、白血病和宫颈癌等中的任一种。
  11. 根据权利要求8所述的应用，其特征在于，所述与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病还包括神经变性疾病、艾滋病、老年痴呆、疟疾和糖尿病。
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