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WO2015127797A1 - 噻唑类化合物、其制备方法及其在制药中的用途 - Google Patents

噻唑类化合物、其制备方法及其在制药中的用途 Download PDF

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Publication number
WO2015127797A1
WO2015127797A1 PCT/CN2014/090466 CN2014090466W WO2015127797A1 WO 2015127797 A1 WO2015127797 A1 WO 2015127797A1 CN 2014090466 W CN2014090466 W CN 2014090466W WO 2015127797 A1 WO2015127797 A1 WO 2015127797A1
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WIPO (PCT)
Prior art keywords
indolyl
nitrothiazole
nitrothiazol
carboxamide
ethanone
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PCT/CN2014/090466
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English (en)
French (fr)
Inventor
孙宏斌
宋洁梅
陈超
王锦政
徐畅
温小安
顾伟
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中国药科大学
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Publication of WO2015127797A1 publication Critical patent/WO2015127797A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/58—Nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to the field of pharmacy, in particular to a thiazole compound, a preparation method thereof and application thereof in preparing a medicament for preventing or treating tumor diseases.
  • Tumors are major diseases that seriously threaten human health. Tumors are characterized by the cell's own erroneous response to signals that regulate cell growth, differentiation, function, and apoptosis. It is now believed that most tumors are caused by changes in multiple genes and epigenetic environments. Even for the same type of tumor, the types of malignant cell populations are different, have different genetic changes, and change with the development of the disease.
  • anti-tumor drugs used in clinical practice include cytotoxic drugs, kinase inhibitors, proteasome inhibitors, HDAC inhibitors, hedgehog inhibitors and the like.
  • the thiazole ring-containing heterocyclic compound has a broad spectrum of biological activities such as local anesthesia, anticonvulsant, antiviral, antibacterial, antitumor and insecticidal effects.
  • Many of the thiazole compounds having antitumor activity contain a 2-position free or substituted amino group (US20130317218A1, WO2013082324A1, CN102964343A, US20120225880A1, CN102070556A, WO2010083246A1, US20050234033A1, WO2005035541A1, WO2004074283A1, WO2000075120A1).
  • Other 2-position electron donating groups also include substituted sulfhydryl groups (Bioorg Med Chem.
  • the present invention discloses a compound of the formula I and II or an oxynitride, pharmaceutically acceptable salt or solvate thereof:
  • X is H, NO 2 , halogen, CN, -SCF 3 or -SO 2 CF 3 ;
  • Y is S, NH, NHCH 2 , O, SO or SO 2 ;
  • R 1 represents one or more Z 1 substituted aryl or heteroaryl groups, wherein Z 1 is selected from halogen, nitrile, nitro, trifluoromethyl or -OR 3 ;
  • R 2 is -COR 4 , -CONR 5 R 6 , a Z 2 -substituted alkyl group of 1 to 6 carbons or a halogen;
  • R 3 and R 4 are an alkyl group of 1 to 10 carbons, a substituted alkyl group, an aryl group or a substituted aryl group;
  • R 5 and R 6 are independently selected from a hydrogen atom, an alkyl or substituted alkyl group of 1 to 10 carbons, an unsubstituted or one or more Z 3 -substituted aryl or heteroaryl group, or R 5 , R 6 Forming a 4-8 membered heterocyclic group together with an unsubstituted or substituted N atom;
  • Z 2 is -OH, -OCOR 7 or -NR 5 R 6 ;
  • Z 3 is halogen or -OR 8 ;
  • R 7 is an alkyl group or a substituted alkyl group of 1 to 6 carbons
  • R 8 is an alkyl group of 1 to 6 carbons or one or more Z 4 -substituted alkyl groups of 1 to 6 carbons;
  • Z 4 is -NR 9 R 10 or -OR 11 ;
  • R 9 and R 10 are independently selected from a hydrogen atom, an alkyl group of 1 to 6 carbons or a substituted alkyl group, or R 9 and R 10 together form a 3 to 8 membered cycloalkyl group, or R 9 , R 10 and The substituted or substituted N atoms together form a 4-8 membered heterocycloalkyl group;
  • R 11 is a hydrogen atom or an alkyl group of 1 to 6 carbons.
  • X is preferably H, NO 2 or CN
  • Y is preferably S, O, NH or NHCH 2 ;
  • R 1 is preferably one or more Z 1 substituted phenyl or pyridyl groups, wherein Z 1 is preferably halogen, nitrile or nitro;
  • R 2 is preferably -COR 4 or -CONR 5 R 6 , wherein R 4 is preferably an alkyl group of 1 to 6 carbons; R 5 and R 6 are independently selected from a hydrogen atom or one or more Z 3 -substituted phenyl groups. Or a pyridyl group, wherein Z 3 is as defined above.
  • Another object of the present invention is to provide a process for the preparation of compounds of formula I and formula II, as shown in the following scheme:
  • R 1 , R 4 , R 5 , R 6 , R 7 and Y are as defined above for the compounds of formula I and formula II.
  • the alkaline reagent used is selected from the group consisting of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, preferably sodium methoxide;
  • the solvent is methanol, ethanol, acetonitrile, preferably methanol;
  • the reaction time is from 1 to 24 hours;
  • the temperature is from 20 ° C to 100 ° C, preferably from 50 ° C to 70 ° C.
  • the nitrating agent used is selected from the group consisting of fuming nitric acid, concentrated nitric acid, concentrated nitric acid/concentrated sulfuric acid, preferably fuming nitric acid;
  • the solvent used is selected from acetic anhydride.
  • Trifluoroacetic anhydride preferably trifluoroacetic anhydride; a reaction time of from 1 to 24 hours; a temperature of from 50 ° C to 25 ° C, preferably from 25 ° C to 0 ° C.
  • the compound Ib is obtained by subjecting compound IV to R 1 YH by nucleophilic substitution reaction.
  • the reducing agent used is selected from the group consisting of sodium borohydride, potassium borohydride, lithium aluminum hydride, preferably sodium borohydride;
  • the solvent used is selected from the group consisting of methanol, ethanol, tetrahydrofuran, preferably methanol;
  • the reaction time employed is from 1 to 10 hours; the temperature is from 20 ° C to 100 ° C, preferably from 0 ° C to 50 ° C.
  • Compound Ic is esterified to obtain compound Id, and the acylating agent used is selected from the group consisting of an acid anhydride, an acid chloride, a carboxylic acid, preferably an acid anhydride and an acid chloride; the base used is selected from the group consisting of triethylamine, 4-dimethylaminopyridine, and carbonic acid. Potassium, preferably 4-dimethylaminopyridine; the solvent used is selected from the group consisting of dichloromethane, chloroform, acetonitrile, preferably dichloromethane; the reaction time is from 1 to 24 hours; the temperature is from minus 20 ° C to 100 ° C, preferably 25 °C to 100 °C.
  • nucleophilic substitution reaction of compound V with R 1 YH to obtain compound II the alkaline reagent used is selected from the group consisting of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, preferably sodium methoxide; the solvent used is methanol and ethanol. , acetonitrile, N,N-dimethylformamide, preferably methanol, N,N-dimethylformamide; the reaction time is from 1 to 24 hours; the temperature is from minus 20 ° C to 100 ° C, preferably 25 ° C to 70 ° C.
  • the nitrating agent used is selected from the group consisting of fuming nitric acid, concentrated nitric acid, concentrated nitric acid/concentrated sulfuric acid, preferably fuming nitric acid;
  • the solvent used is selected from acetic anhydride. , trifluoroacetic anhydride, preferably trifluoroacetic anhydride;
  • the reaction time used is 1-24 hours; the temperature used is minus 50 ° C to 25 ° C, preferably minus 25 ° C to 0 ° C;
  • Compound VII is obtained by subjecting compound VII to nucleophilic substitution reaction with R 1 YH.
  • Compound IX and nitrite are hydrolyzed by diazonium salt in an acidic solvent to obtain compound X.
  • the nitrite is sodium nitrite, potassium nitrite, calcium nitrite, preferably sodium nitrite; the solvent used is strong acid.
  • An aqueous solution preferably an 80% aqueous solution of sulfuric acid; a reaction time of 0.5 to 6 hours, preferably 0.5 hours; and a temperature of from 20 to 25 ° C, preferably 25 ° C.
  • phosphorus oxychloride Preference is given to phosphorus oxychloride; the solvent chosen is acetonitrile, acetone, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, preferably acetonitrile; the base used is triethylamine, diisopropylethylamine, pyridine, preferably diisopropyl Amine; reaction time is 1-48 hours, preferably 5-12 hours; use temperature is below 20 ° C to 50 ° C, preferably 25 ° C.
  • a further object of the invention is to provide the use of a compound of formula I and II, or an oxynitride, pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the prophylaxis and treatment of a tumor.
  • Pharmacodynamic experiments showed that the compounds of the formula I and II of the present invention have significant anti-tumor cell proliferation effects.
  • the compound of the present invention is prepared by dissolving in DMSO to prepare a mother liquid, and is diluted to a proper concentration by using a complete medium before use; reagent: CCK-8 kit is purchased from Nanjing Enjing Biotechnology Co., Ltd.; culture medium: RMPI-1640 culture Base purchased from Gibco; fetal bovine serum: purchased from Gibco; 96-well cell culture plates purchased from Costar.
  • the compounds of the invention and compositions thereof are useful in the preparation of anti-tumor drugs.
  • Such tumors include, but are not limited to, the following:
  • Bone cancer including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignancy Giant cell tumor chordoma, osteochondroma (Gu-hose exogenous osteophytes), benign chondroma, chondroblastoma, cartilage and tumor-like fibroids, osteoid osteoma and giant cell tumor.
  • osteogenic sarcoma osteosarcoma
  • fibrosarcoma malignant fibrous histiocytoma
  • chondrosarcoma chondrosarcoma
  • Ewing's sarcoma malignant lymphoma
  • multiple myeloma multiple myeloma
  • malignancy Giant cell tumor chordoma reticulocyte sarcom
  • Hematological cancers including, for example, hematological cancers such as acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndromes , Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.
  • hematological cancers such as acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndromes , Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.
  • Nervous system cancers including, for example, skull cancers such as bone cancer, hemangioma, granuloma, xanthoma, and deformed osteitis; meningeal carcinomas such as meningiomas, meningiomas, and gliomas; brain cancers such as stars Cell tumor, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma, oligodendroglioma, schwannomas , retinoblastoma and congenital tumors; and myeloma, such as fibrone, meningiomas, gliomas and sarcomas.
  • skull cancers such as bone cancer, hemangioma, granuloma, xanthoma, and deformed osteitis
  • meningeal carcinomas such as meningiomas, meningiomas, and gliomas
  • Gastrointestinal tumors including, for example, esophageal cancers such as squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; gastric cancer, such as tumors, lymphomas, and leiomyosarcomas; pancreatic cancers such as ductal adenocarcinoma, islet tumors, pancreas Glucagonoma, gastrinoma, carcinoid tumor and vasoactive intestinal peptide tumor; small bowel cancer, such as adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, Fibrosarcoma and fibroids; colorectal cancers such as adenocarcinoma, tubular adenocarcinoma, villous adenoma, hamartoma, and leiomyomas.
  • Urinary system cancers including, for example, kidney cancers such as adenocarcinoma, Wilms' tumor (kidney cell tumor), lymphoma and leukemia; bladder and urinary tract cancers such as squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; Prostate cancer, such as adenocarcinoma and sarcoma; testicular cancer, such as seminoma, teratoma, embryonal cancer, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroids, fibroadenomas, adenoma Tumor and lipoma.
  • kidney cancers such as adenocarcinoma, Wilms' tumor (kidney cell tumor), lymphoma and leukemia
  • bladder and urinary tract cancers such as squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma
  • Prostate cancer such as adenocarcinoma and
  • Lung cancer including, for example, bronchial carcinoma, such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma; bronchioloalveolar carcinoma; bronchial adenoma; sarcoma; lymphoma; Tumor and mesothelioma.
  • bronchial carcinoma such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma
  • bronchioloalveolar carcinoma bronchial adenoma
  • sarcoma sarcoma
  • lymphoma such as lymphoma
  • Tumor and mesothelioma such as bronchial carcinoma, such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, and adenocarcinoma
  • bronchioloalveolar carcinoma such as bronchial adenoma
  • Liver cancer includes, for example, hepatocellular carcinoma, such as hepatocellular carcinoma; cholangiocarcinoma; hepatic blastoma; angiosarcoma; hepatocellular adenoma and hemangiomas.
  • Skin cancer includes, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic sputum, lipoma, hemangioma, cutaneous fibroids, keloid, psoriasis.
  • the present invention also provides a pharmaceutical composition for preventing and treating a tumor comprising a therapeutically effective amount of a compound of formula I or II or an oxynitride thereof, a pharmaceutically acceptable salt or solvate thereof as an active ingredient, and pharmaceutically acceptable a.
  • the pharmaceutical composition may be in the form of a conventional tablet or capsule, a sustained release tablet or capsule, a controlled release tablet or capsule, a granule, a powder, a syrup, an oral solution, an injection, or the like.
  • the dose of the compound of the formula I and II or the nitrogen oxide, pharmaceutically acceptable salt or solvate thereof in the pharmaceutical composition of the present invention varies depending on the symptoms and age.
  • the lower limit of one dose is 0.1 mg (preferably 1 mg)
  • the upper limit is 1000 mg (preferably 500 mg); when administered intravenously, the lower limit of one dose is 0.01 mg (preferred 0.1 mg), the upper limit is 500 mg (preferably 250 mg).
  • This dosage range can also be deviated depending on the degree of disease and the type of the dosage form.
  • Administration of the compounds of the invention for treatment or prophylaxis can also be combined with existing methods of treating cancer (e.g., by chemotherapy, radiation therapy, or surgery).
  • the invention therefore also provides a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound according to formula (I) or (II) or a pharmaceutically acceptable salt form or formulation thereof, while administering to the patient therapeutically effective A quantity of one or more other cancer chemotherapeutic agents.
  • the particular pharmaceutical combination and the particular therapeutically effective dosage level will depend on a number of factors, including the type and severity of the tumor being treated; the activity of the particular compound employed; the age of the patient, Body weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment and similar factors well known in the medical arts.
  • chemotherapeutic agents include, but are not limited to, the following:
  • Alkylating agents nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine, estramustine; ethyleneimine, thiotepa, imine ⁇ ; sulfonate and polyols, busulfan, dibromomannitol; nitrosourea, cyclohexyl nitrite, carmustine, pyrimidine nitrosourea, nitrosourea; triazolidine , amidamine; steroids, procarbazine.
  • Antimetabolites pyrimidine antagonists, fluorouracil, cytarabine, furosemide, difurfuryluracil; sputum antagonists, sputum, sodium sulfonate, azathioprine, thioguanine; folic acid antagonists, methotrexate , ammonia pterin.
  • Antitumor antibiotics mitomycin C, bleomycin, actinomycin D, mithramycin, daunorubicin, doxorubicin, chromomycin A3, enmycin, neocarcin, anticancer Taxomycin, albinomycin.
  • Plant anticancer drugs vincristine, colchicine, camptothecin, hydroxycamptothecin, cantharidin, indirubin.
  • Hormones adrenocortical hormone, prednisone, prednisone, hydrocortisone, dexamethasone; estrogen, diethylstilbestrol, bromoacetyl estrone; androgen and anabolic hormone, testosterone propionate, methyltestosterone, Nandrolone phenylpropionate, naphthyloxyquine, tamoxifen.
  • 2,3-Dichlorothiophenol 120 mg, 0.68 mmol
  • sodium methoxide 37 mg, 0.68 mmol
  • 2-Acetyl-5-chlorothiazole 100 mg, 0.48 mmol was added to the reaction mixture, and the mixture was heated to 50 ° C, and the mixture was stirred until the reaction was completed.
  • the solvent was evaporated to dryness. After evaporation to dryness, silica gel column chromatography wasield.
  • reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with saturated NaHCO 3
  • the Na 2 SO 4 was dried, and the solvent was evaporated to dryness, and purified by column chromatography (PE: EA 3:1) to give 80 mg of the title compound.

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Abstract

本发明公开了如通式I和II所示的化合物或其氮氧化物、药学上可接受的盐或溶剂化物、其制备方法以及在制药中的用途，尤其是在抗肿瘤中的应用。药效学实验结果表明，本发明的式I和式II化合物具有显著的抗肿瘤作用，尤其是具有显著的抗人多发性骨髓瘤细胞的作用。因此本发明化合物可以用于制备预防或治疗肿瘤相关疾病的药物。

Description

噻唑类化合物、其制备方法及其在制药中的用途 技术领域
本发明涉及制药领域，具体涉及噻唑类化合物、其制备方法及其在制备预防或治疗肿瘤疾病药物中的应用。
本专利申请要求中国专利申请(申请号201410062371.2，申请日：2014年02月25日，发明创造名称：噻唑类化合物、其制备方法及其在制药中的用途)的优先权。
背景技术
恶性肿瘤是严重威胁人类健康的重大疾病。肿瘤的发生是以细胞自身对调节细胞生长、分化、功能及凋亡等信号的错误应答为特征的。现在认为多数肿瘤是多种基因和后生环境的改变引起的。即使同一种类型的肿瘤，其恶性细胞群种类也是不同的，有着不同的遗传改变，并且随着疾病的发展而改变。目前，在临床上使用的抗肿瘤药物包括细胞毒类药物、激酶抑制剂、蛋白酶体抑制剂、HDAC抑制剂、hedgehog抑制剂等。
含噻唑环的杂环化合物具有广谱的生物活性，如局麻、抗惊厥、抗病毒、抗菌、抗肿瘤和杀虫等作用。许多具有抗肿瘤活性的噻唑化合物均含有2位游离或取代的氨基(US20130317218A1,WO2013082324A1,CN102964343A,US20120225880A1,CN102070556A，WO2010083246A1,US20050234033A1,WO2005035541A1,WO2004074283A1,WO 2000075120A1)。其它的2位给电子基还包括取代的巯基(Bioorg Med Chem.21(24):7648-54)和亚甲基(Bioorg Med Chem.20(7):2316-22)等。此外，噻唑2位、4位和5位偶联有芳香基团的抗肿瘤小分子也有报道(WO2011137219A1,EP2606889A1,WO2013082324A1,EP2606889A1,US20120225880A1,WO2010083246A1)。
通过细胞水平的抗肿瘤筛选，我们意外地发现了具有抗肿瘤活性的一类新型噻唑类化合物。
发明内容
本发明公开了如通式I和II所示的化合物或其氮氧化物、药学上可接受的盐或溶剂化物：
Figure PCTCN2014090466-appb-000001
其中：
X为H、NO2、卤素、CN、-SCF3或-SO2CF3；
Y为S、NH、NHCH2、O、SO或SO2；
R1代表一个或多个Z1取代的芳基或杂芳基，其中，Z1选自卤素、腈基、硝基、三 氟甲基或-OR3；
R2为-COR4、-CONR5R6、1～6个碳的Z2取代的烷基或卤素；
R3和R4为1～10个碳的烷基、取代的烷基、芳基或取代的芳基；
R5、R6独立地选自氢原子、1～10个碳的烷基或取代烷基、非取代的或一个或多个Z3取代的芳基或杂芳基，或者R5、R6与非取代或取代的N原子一起形成一个4～8元杂环基；
Z2为-OH、-OCOR7或-NR5R6；
Z3为卤素或-OR8；
R7为1～6个碳的烷基或取代烷基；
R8为1～6个碳的烷基或1～6个碳的一个或多个Z4取代的烷基；
Z4为-NR9R10或-OR11；
R9、R10独立地选自氢原子、1～6个碳的烷基或取代烷基、或者R9、R10一起形成一个3～8元环烷基、或者R9、R10与非取代或取代的N原子一起形成一个4～8元杂环烷基；
R11为氢原子或1～6个碳的烷基。
在本发明式I和II化合物中：
X优选H、NO2或CN；
Y优选S、O、NH或NHCH2；
R1优选一个或多个Z1取代的苯基或吡啶基，其中，Z1优选卤素、腈基或硝基；
R2优选-COR4或-CONR5R6，其中，R4优选为1～6个碳的烷基；R5、R6独立地选自氢原子或一个或多个Z3取代的苯基或吡啶基，其中，Z3如上述所定义。
本发明式I和II化合物中更优选的化合物如下：
Figure PCTCN2014090466-appb-000002
Figure PCTCN2014090466-appb-000003
Figure PCTCN2014090466-appb-000004
Figure PCTCN2014090466-appb-000005
Figure PCTCN2014090466-appb-000006
Figure PCTCN2014090466-appb-000007
Figure PCTCN2014090466-appb-000008
Figure PCTCN2014090466-appb-000009
Figure PCTCN2014090466-appb-000010
本发明的另一目的是提供了式I及式II化合物的制备方法，如下反应式所示：
Figure PCTCN2014090466-appb-000011
R1、R4、R5、R6、R7和Y上述式I和式II化合物中所定义。
具体包括以下步骤：
(1)将化合物III与R1YH在碱性条件下发生亲核取代反应制得化合物I-a,采用的碱性试剂选自碳酸钾、碳酸钠、甲醇钠、乙醇钠，优选甲醇钠；采用的溶剂为甲醇、乙醇、乙腈，优选甲醇；采用的反应时间为1-24小时；采用温度为零下20℃至100℃，优选50℃至70℃。
(2)以化合物III为起始原料，进行硝化反应制得式IV化合物,采用的硝化试剂选自发烟硝酸、浓硝酸，浓硝酸/浓硫酸，优选发烟硝酸；采用的溶剂选自醋酸酐、三氟醋酸酐，优选三氟醋酸酐；采用的反应时间为1-24小时；采用的温度为零下50℃至25℃，优选零下25℃至0℃。
(3)将化合物IV与R1YH发生亲核取代反应制得化合物I-b。
(4)化合物I-b发生还原反应制得I-c，采用的还原试剂选自硼氢化钠、硼氢化钾、四氢铝锂，优选硼氢化钠；采用的溶剂选自甲醇、乙醇、四氢呋喃，优选甲醇；采用的反应时间为1-10小时；采用温度为零下20℃至100℃，优选0℃至50℃。
(5)化合物I-c发生酯化反应制得化合物I-d，采用的酰化试剂选自酸酐、酰氯、羧酸，优选酸酐和酰氯；采用的碱选自三乙胺、4-二甲氨基吡啶、碳酸钾，优选4-二甲氨基吡啶；采用的溶剂选自二氯甲烷、氯仿、乙腈，优选二氯甲烷；采用的反应时间为1-24小时；采用温度为零下20℃至100℃，优选25℃至100℃。
(6)化合物I-b发生还原胺化反应制得I-e，采用的还原试剂为硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠，优选腈基硼氢化钠；采用的溶剂为二氯甲烷、乙酸乙酯、四氢呋喃，优选二氯甲烷；采用的反应时间为1-24小时；采用温度为零下20℃至100℃，优选25℃至50℃。
(7)将化合物V与R1YH发生亲核取代反应制得化合物II，采用的碱性试剂选自碳酸钾、碳酸钠、甲醇钠、乙醇钠，优选甲醇钠；采用的溶剂为甲醇、乙醇、乙腈、N,N-二甲基甲酰胺，优选甲醇、N,N-二甲基甲酰胺；采用的反应时间为1-24小时；采用温度为零下20℃至100℃，优选25℃至70℃。
(8)以化合物VI为起始原料，进行硝化反应制得式VII化合物，采用的硝化试剂选自发烟硝酸、浓硝酸，浓硝酸/浓硫酸，优选发烟硝酸；采用的溶剂选自醋酸酐、三氟醋酸酐，优选三氟醋酸酐；采用的反应时间为1-24小时；采用的温度为零下50℃至25℃，优选零下25℃至0℃；
(9)将化合物VII与R1YH发生亲核取代反应制得化合物VIII。
(10)化合物VIII与CuCN发生反应得到化合物IX，采用溶剂为N,N-二甲酰胺、二甲亚砜、吡啶、丙酮，优选N,N-二甲酰胺；采用反应时间为1-12小时；采用温度为50℃至150℃，优选120℃至140℃。
(11)化合物IX与亚硝酸酸盐在酸性溶剂中发生重氮盐水解反应得到化合物X，亚硝酸盐采用亚硝酸钠、亚硝酸钾、亚硝酸钙，优选亚硝酸钠；采用的溶剂为强酸水溶液，优选80％硫酸水溶液；采用反应时间为0.5-6小时，优选0.5小时；采用温度为零下20℃至25℃，优选25℃。
(12)化合物X与R5R6NH在酰化试剂作用下反应生成化合物I-f，酰化试剂采用乙酰氯、苯甲酰氯、草酰氯、氯乙酰氯、三氯乙酰氯、三氯氧磷，优选三氯氧磷；所选溶剂为乙腈、丙酮、二氯甲烷、氯仿、四氢呋喃、乙醚，优选乙腈；采用的碱为三乙胺、二异丙基乙胺、吡啶，优选二异丙基乙胺；反应时间为1-48小时，优选5-12小时；采用温度为零下20℃至50℃，优选25℃。
具体的式I和式II化合物的制备方法参照实施例。
本发明的又一目的是提供了式I和II化合物或其氮氧化物、药学上可接受的盐或溶剂化物在制备预防和治疗肿瘤的药物中的用途。药效学实验结果表明，本发明式I及II化合物具有显著的抗肿瘤细胞增殖作用。
下面是本发明的化合物的部分药理实验及结果。
1.实验目的：采用CCK-8染色法测定各化合物对人多发性骨髓瘤细胞RPMI-8226体外增殖活性的影响，并计算各自的半数抑制浓度IC50。
2.实验材料：本发明化合物用DMSO溶解配制成母液，使用前采用完全培养基稀释成适当浓度；试剂：CCK-8试剂盒购自南京恩晶生物科技有限公司；培养基：RMPI-1640培养基购自Gibco公司；胎牛血清：购自Gibco公司；96孔细胞培养板购自Costar公司。
3.实验方法：取活细胞比例达90％以上的细胞进行实验。细胞增殖抑制试验采用EnoGeneCellTM Counting Kit-8(CCK-8)细胞活力检测试剂盒。细胞消化、计数、制成浓度为1×105个/ml的细胞悬液,96孔板中每孔加入100μl细胞悬液(每孔1×104个细胞)；96孔板置于37℃，5％CO2培养箱中培养24小时；用完全培养基稀释药物至所需浓度，每孔加入100μL相应的含药物的培养基，同时设立阴性对照组，溶媒对照组，阳性药为P5091(Cancer Cell 2012,22,345–358)。每组5个复孔；96孔板置于37℃，5％CO2培养箱中培养72小时；每孔加入10μL CCK-8溶液,将培养板在培养箱内孵育4小时,用酶标仪测定在450nm处的OD值，计算抑制率并计算出IC50值。
4.实验结果：本发明化合物对人多发性骨髓瘤RPMI-8226细胞株体外增殖的抑制活性(IC50)见下表。
化合物 IC50(μM) 化合物 IC50(μM) 化合物 IC50(μM) 化合物 IC50(μM)
I-1 87.60 I-8 20.97 I-15 15.47 II-2 82.55
I-2 123.29 I-9 43.38 I-16 28.35 II-3 91.36
I-3 114.36 I-10 5.86 I-17 14.39 II-4 47.27
I-4 5.03 I-11 2.45 I-18 17.30 II-5 79.20
I-5 4.69 I-12 44.27 I-19 14.57 II-6 129.55
I-6 6.86 I-13 23.39 I-20 14.00 II-7 25.33
I-7 2.64 I-14 20.55 II-1 87.20 II-8 22.57
I-21 20.30 I-22 12.38 I-23 >100 I-24 49.71
I-25 40.85 I-26 12.38 I-27 6.03 I-28 24.73
I-29 12.44 I-30 10.61 I-31 23.14 I-32 12.21
I-33 46.12 I-34 10.97 I-35 11.27 I-36 11.46
I-37 6.22 I-38 6.18 I-39 6.07 I-40 6.11
I-41 11.18 I-42 47.71 I-43 24.73 I-44 11.8
P5091 11.72            
上述测试结果显示，本发明化合物对多发性骨髓瘤细胞的生长具有不同程度的抑制作用，尤其令人惊讶的是，部分化合物显示了比阳性药P5091更强的抗肿瘤活性。该结果提示本发明化合物可以用于制备抗肿瘤药物。
本发明所述的化合物及其组合物可用于制备抗肿瘤药物。所述肿瘤包括但不限于如下这些：
骨癌，包括(例如)：骨源性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞瘤脊索瘤、骨软骨瘤(顾软管型外生骨疣)、良性软骨瘤、成软骨细胞瘤、软骨及瘤样纤维瘤、骨样骨瘤和巨细胞瘤。
血液科癌症，包括(例如)：血液癌症，如急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞系白血病、慢性淋巴细胞系白血病、骨髓增生性疾病、多发性骨髓瘤和骨髓增生异常综合征、霍奇金氏淋巴瘤(恶性淋巴瘤)和瓦尔登斯特伦巨球蛋白血症。
神经系统癌症，包括(例如)：头骨癌，如骨癌、血管瘤、肉芽瘤、黄瘤和畸形性骨炎；脑膜癌，如脑膜瘤、脑膜肉瘤和神经胶质瘤；脑癌，如星形细胞瘤、成神经管细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性成胶质细胞瘤、少突神经胶质细胞瘤、神经鞘瘤、成视网膜细胞瘤和先天性肿瘤；以及脊髓瘤，如纤维神经瘤、脑膜瘤、神经胶质瘤和肉瘤。
胃肠瘤，包括(例如)：食道癌症，如鳞状细胞癌、腺癌、平滑肌肉瘤和淋巴瘤；胃癌，如肿瘤、淋巴瘤和平滑肌肉瘤；胰腺癌，如导管腺癌、胰岛瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤和血管活性肠肽瘤；小肠癌，如腺癌、淋巴瘤、类癌瘤、卡波济氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、纤维神经瘤和纤维瘤；大肠癌，如腺癌、小管腺癌、绒毛状腺瘤、错构瘤和平滑肌瘤。
泌尿系统癌症，包括(例如)：肾癌，如腺癌、维尔姆斯瘤(肾母细胞瘤)、淋巴瘤和白血病；膀胱和尿道癌，如鳞状细胞癌、移行细胞癌和腺癌；前列腺癌，如腺癌和肉瘤；睾丸癌，如精原细胞瘤、畸胎瘤、胚胎性癌、畸胎瘤、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤和脂肪瘤。
肺癌，包括(例如)：支气管癌，如鳞状细胞癌、未分化小细胞癌、未分化大细胞癌和腺癌；细支气管肺泡癌；支气管腺瘤；肉瘤；淋巴瘤；肺软骨瘤性错构瘤和间皮瘤。
肝癌，包括(例如)：肝细胞癌，如肝细胞癌；胆管癌；肝胚细胞瘤；血管肉瘤；肝细胞腺瘤和血管瘤。
皮肤癌，包括(例如)：恶性黑素瘤、基底细胞癌、鳞状细胞癌、卡波济氏肉瘤、发育异常性痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、银屑病。
本发明还提供了一种预防和治疗肿瘤的药物组合物，其中含有治疗有效量的式I或II化合物或其氮氧化物、药学上可接受的盐或溶剂化物作为活性成份和药学上可接受的载体。所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、颗粒剂、散剂、糖浆剂、口服液、注射剂等制剂学上常规的制剂形式。
本发明药物组合物中式I和II化合物或其氮氧化物、药学上可接受的盐或溶剂化物的剂量随症状和年龄等不同而不同。对成人而言，在口服给药时，一次给药量的下限是0.1mg(优选1mg)，上限是1000mg(优选500mg)；在静脉给药时，一次给药量的下限是0.01mg(优选0.1mg)，上限是500mg(优选250mg)。也可根据疾病程度的不同和剂型的不同而偏离此剂量范围。
施用本发明所述化合物进行治疗或预防时，也可与现有治疗癌症的方法(例如，通过化疗、放疗或手术)组合施用。因此本发明还提供了一种治疗癌症的方法，包括向患者使用治疗有效量的根据发明式(I)或(II)的化合物或其可药用的盐形式或制剂，同时向患者施用治疗有效量的一种或多种其他的癌症化疗剂。对于任何具体的患者，具体的药物组合形式及具体的治疗有效剂量水平需根据多重因素而定，所述因素包括所治疗的肿瘤类型和严重程度；所采用的具体化合物的活性；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体化合物的给药时间、给药途径和排泄率；治疗持续时间及医疗领域公知的类似因素。
合适的化疗剂的例子包括但不限于以下这些：
烷化剂：氮芥类，环磷酰胺、异环磷酰胺、美法仑、苯丁酸氮芥、苯达莫司汀、雌莫司汀；乙撑亚胺类，塞替哌、亚胺醌；磺酸酯及多元醇类，白消安、二溴甘露醇；亚硝基脲类，环己亚硝、卡氮芥、嘧啶亚硝脲、甲环亚硝脲；三氮烯咪唑类，甲氮咪胺；肼类，甲基苄肼。
抗代谢药：嘧啶拮抗剂，氟尿嘧啶、阿糖胞苷、呋氟尿嘧啶、双呋氟尿嘧啶；嘌呤拮抗剂，巯嘌呤、磺巯嘌呤钠、硫唑嘌呤、硫鸟嘌呤；叶酸拮抗剂，甲氨蝶呤、氨蝶呤。
抗肿瘤抗生素：丝裂霉素C、博来霉素、放线菌素D、光神霉素、柔红霉素、阿霉素、色霉素A3、恩霉素、新制癌素、抗癌霉素、素道霉素。
植物类抗癌药：长春新碱、秋水仙碱、喜树碱、羟基喜树碱、斑蝥素、靛玉红。
激素：肾上腺素皮质激素，泼尼松、氢化泼尼松、氢化可的松、地塞米松；雌激素，己烯雌酚、溴乙酰己烷雌酚；雄激素及同化激素，丙酸睾丸酮、甲睾酮、苯丙酸诺龙、萘氧啶、三苯氧胺。
其他类型：顺氯氨铂、干扰素、左旋门冬酰胺酶、羟基脲、丙亚胺、丙咪腙、血卟啉；免疫制剂。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中，以下所述的实施例是为了更 好的阐述本发明，并不是用来限制本发明的范围。
实施例1
1-[5-(2,3-二氯苯基硫代)噻唑-2-基]乙酮(I-1)的制备
将2,3-二氯苯硫酚(120mg,0.68mmol)、甲醇钠(37mg,0.68mmol)加入干燥的甲醇(6mL)中，室温下搅拌20分钟。向反应液中加入2-乙酰基-5-氯噻唑(100mg,0.48mmol)，加热至50℃，反应液继续搅拌直至反应完全。将溶剂蒸干，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥。蒸干后硅胶柱层析得目标化合物(59mg,收率31％)。1HNMR(CDCl3,300MHz)δ(ppm):2.71(s,3H),6.90-6.93(d,1H,J＝9Hz),7.08-7.13(t,1H),7.34-7.36(d,1H,J＝6Hz),8.02(s,1H)；ESI MS m/z 325.9[M+Na]+；HRMS for C11H7NOS2Cl2+Na cacld 325.9244 found 325.9246.
实施例2
1-[5-(3,4-二氯苯基硫代)噻唑-2-基]乙酮(I-2)的制备
反应步骤参照实施例1，得目标化合物(收率26％)。1HNMR(CDCl3,500MHz)δ(ppm):2.68(s,3H),7.16-7.18(m,1H),7.38-7.42(m,2H),7.95(s,1H)；ESI MS m/z 325.9[M+Na]+；HRMS for C11H7NOS2Cl2+Na cacld 325.9244found 325.9246.
实施例3
1-[5-(2,6-二氯苯基硫代)噻唑-2-基]乙酮(I-3)的制备
反应步骤参照实施例1，得目标化合物(收率43％)。1HNMR(CDCl3,500MHz):δ(ppm):2.63(s,3H),7.27-7.32(m,1H),7.42-7.45(m,2H),7.90(s,1H)ppm.ESI MS m/z303.9[M+H]+；HRMS for C11H7NOS2Cl2+H cacld 303.9424 found 303.9428.
实施例4
1-(5-氯-4-硝基噻唑-2-基)乙酮的制备
将三氟乙酸酐(6.3mL)、发烟硝酸(2.1mL)的混合溶液降温至零下20℃，搅拌1小时，向其中缓慢加入2-乙酰基-5-氯噻唑(1.10g,6.8mmol)的三氟乙酸酐(2mL)溶液。反应液继续在零下20℃搅拌2小时。将反应液浓缩、倒入冰水中，用乙醚萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥。蒸干后硅胶柱层析得黄色固体(0.98g,收率73％)。1HNMR(CDCl3,300MHz):δ(ppm):2.72(s,3H)；ESI MS m/z 204.9[M-H]+；HRMS for C5H3N2O3SCl-H cacld 204.9475 found 204.9477.
实施例5
1-[5-(2,3-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮(I-4)的制备
将2,3-二氯苯硫酚(94mg,0.53mmol)、甲醇钠(29mg,0.53mmol)加入干燥的甲醇(5mL)，室温下搅拌20分钟。然后向反应液中加入1-(5-氯-4-硝基噻唑-2-基)乙酮(100mg,0.48mmol)，室温下继续搅拌4小时。将溶剂蒸干，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥。旋干后硅胶柱层析得目标化合物(129mg,收率76％)。 1HNMR(CDCl3,500MHz)δ(ppm):2.67(s,3H),7.37-7.40(m,1H),7.72-7.73(m,2H)；ESI MS m/z 371.0[M+Na]+；HRMS for C11H6N2O3S2Cl2+Na cacld 370.9095 found 370.9097.
实施例6
1-[5-(3,4-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮(I-5)的制备
反应步骤参照实施例5，得目标化合物(收率76％)。1HNMR(CDCl3,300MHz)δ(ppm):2.66(s,3H),7.52-7.56(dd,1H,J＝3,6Hz),7.64-7.66(d,1H,J＝6Hz),7.80-7.81(d,1H,J＝3Hz)；ESI MS m/z 371.0[M+Na]+；HRMS for C11H6N2O3S2Cl2+Na cacld 370.9095 found 370.9096.
实施例7
1-[5-(2,6-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮(I-6)的制备
反应步骤参照实施例5，得目标化合物(收率88％)。1HNMR(CDCl3,300MHz)δ(ppm):2.67(s,3H),7.46-7.59(m,3H)；ESI MS m/z 371.0[M+Na]+；HRMS for C11H6N2O3S2Cl2+Na cacld 370.9095 found 370.9096.
实施例8
1-[5-(2,4-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮(I-7)的制备
反应步骤参照实施例5，得目标化合物(收率76％)。1HNMR(CDCl3,300MHz)δ(ppm):2.65(s,3H),7.41-7.44(m,1H),7.66-7.67(d,1H,J＝3Hz),7.70-7.73(d,1H,J＝9Hz)；ESI MS m/z 370.9[M+Na]+；HRMS for C11H6N2O3S2Cl2+Na cacld 370.9095 found370.9098.
实施例9
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙酮(I-8)的制备
反应步骤参照实施例5，得目标化合物(收率50％)。1HNMR(CD3OD,300MHz)δ(ppm):2.62(s,3H),8.84(s,2H)；ESI MS m/z 371.9[M+Na]+；HRMS for C10H5N3O3S2Cl2+Na cacld 371.9047 found 371.9049.
实施例10
1-[5-(3-甲氧基苯基硫代)-4-硝基噻唑-2-基]乙酮(I-9)的制备
反应步骤参照实施例5，得目标化合物(收率88％)。1HNMR(CDCl3,300MHz)δ(ppm):2.65(s,3H),3.85(s,3H),7.10-7.27(m,3H),7.43-7.49(m,1H)；ESI MS m/z 333.0[M+Na]+；HRMS for C12H10N2O4S2+Na cacld 332.9980 found 332.9983.
实施例11
1-[5-(3,4-二甲氧基苯基硫代)-4-硝基噻唑-2-基]乙酮(I-10)的制备
反应步骤参照实施例5，得目标化合物(收率32％)。1HNMR(CDCl3,300MHz)δ(ppm):2.65(s,3H),3.88(s,3H),3.95(s,3H),6.97(d,1H,J＝6Hz),7.10(s,1H),7.26(d,1H,J＝6Hz)；ESI MS m/z 341.0[M+H]+；HRMS for C13H12N2O5S2+H cacld 341.0266 found 341.0269.
实施例12
1-[5-(4-硝基苯基硫代)-4-硝基噻唑-2-基]乙酮(I-11)的制备反应步骤参照实施例5，得目标化合物(收率90％)。1HNMR(CDCl3,300MHz)δ(ppm):2.67(s,3H),7.92(d,2H,J＝9Hz),8.41(d,2H,J＝9Hz)；ESI MS m/z 326.0[M+H]+；HRMS for C11H7N3O5S2+H cacld.325.9905 found 325.9907.
实施例13
1-[5-(3,4-二氯苯甲基氨基)-4-硝基噻唑-2-基]乙酮(I-12)的制备
将3,4-二氯苄胺(128mg,0.73mmol)、1-(5-氯-4-硝基噻唑-2-基)乙酮(100mg,0.48mmol)溶于异丙醇(2mL)，加热回流。反应结束后，将溶剂蒸干，硅胶柱层析得目标化合物(77mg,收率46％)。1HNMR(CDCl3,300MHz)δ(ppm):2.61(s,3H),4.58(d,2H,J＝6Hz),7.21(d,1H,J＝9Hz),7.45-7.48(m,2H),8.76(brs,1H)；ESI MS m/z 346.0[M+H]+；HRMS for C12H9Cl2N3O3+H cacld.345.9820 found 345.9823.
实施例14
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙醇(I-13)的制备
将硼氢化钠(11mg,0.29mmol)、1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙酮(100mg,0.29mmol)加入甲醇(2mL)中，室温下搅拌1小时。加水淬灭并将溶剂浓缩，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥。旋干后经硅胶柱层析得目标化合物(78mg,收率78％)。1HNMR(CDCl3,500MHz)δ(ppm):1.61(d,3H,J＝5Hz),3.08(s,1H),5.07(q,1H,J＝5Hz),8.71(s,2H)；ESI MS m/z 351.9[M+H]+；HRMS for C10H7Cl2N3O3S2+H calcd.351.9384 found 351.9387.
实施例15
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙酸乙酯(I-14)的制备
将1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙醇(100mg,0.28mmol)、醋酸酐(58mg,0.57mmol)、4-二甲氨基吡啶(3mg,0.03mmol)溶于二氯甲烷(3mL)。室温搅拌1小时，加水，二氯甲烷萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥。旋干后经硅胶柱层析得目标化合物(104mg,93％)。1HNMR(CDCl3,300MHz)δ(ppm):1.64(d,3H,J＝6Hz),2.07(s,3H),5.94(q,1H,J＝6Hz),8.71(s,2H)；ESI MS m/z 393.9[M+H]+；HRMS for C12H9Cl2N3O4S2+H calcd.393.9490 found 393.9495.
实施例16
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]氯乙酸乙酯(I-15)的制备
反应步骤参照实施例15，得目标化合物(收率57％)。1HNMR(CDCl3,300MHz)δ(ppm):1.72(d,3H,J＝7Hz),4.10(s,2H),6.05(q,1H,J＝7Hz),8.74(s,2H)；ESI MS m/z427.9[M+H]+；HRMS for C12H8Cl3N3O4S2+H calcd.427.9100 found 427.9104.
实施例17
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]丙酸乙酯(I-16)的制备
反应步骤参照实施例15，得目标化合物(收率92％)。1HNMR(CDCl3,300MHz)δ(ppm):1.11(t,3H,J＝5Hz),1.67(d,3H,J＝5Hz),2.36(q,2H,J＝5Hz),5.98(q,1H,J＝5Hz).
实施例18
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]丁酸乙酯(I-17)的制备
反应步骤参照实施例15，得目标化合物(收率85％)。1HNMR(CDCl3,500Hz)δ(ppm):0.91(t,3H,J＝7Hz),1.59-1.67(m,5H),2.32(t,2H,J＝7Hz),5.98(q,1H,J＝6Hz),8.72(s,2H)；ESI MS m/z 422.0[M+H]+；HRMS for C14H13Cl2N3O4S2+H calcd.421.9803 found421.9807.
实施例19
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]苯甲酸乙酯(I-18)的制备
反应步骤参照实施例15，得目标化合物(收率78％)。1HNMR(CDCl3,300MHz)δ(ppm):1.79(d,3H,J＝7Hz),6.20(q,1H,J＝7Hz),7.41-7.46(m,2H),7.57-7.62(m,1H),7.96-7.98(m,2H),8.68(s,2H)；ESI MS m/z 456.0[M+H]+；HRMS for C17H11Cl2N3O4S2+H calcd.455.9646 found 455.9649.
实施例20
1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]-N-甲基乙胺(I-19)的制备
将1-[5-(3,4-二氯苯甲基氨基)-4-硝基噻唑-2-基]乙酮(80mg,0.23mmol)溶于二氯甲烷(1mL)，加入二甲胺(2M的THF溶液，0.9mL,1.82mmol)，加入醋酸调pH至5～6。反应液室温搅拌直至原料消失，加入氰基硼氢化钠(29mg,0.45mmol)，室温搅拌1小时。加入水淬灭，用二氯甲烷萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥。旋干后硅胶柱层析得目标化合物(27mg,收率32％)。1HNMR(CDCl3,500MHz)δ(ppm):1.44(d,3H,J＝7Hz),2.41(s,3H),3.89(q,1H,J＝7Hz),8.70(s,2H)；ESI MS m/z365.1[M+H]+；HRMS for C11H10Cl2N4O2S2+H calcd.364.9700 found 364.9703.
实施例21
N-苄基-1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙胺(I-20)的制备
反应步骤参照实施例20，得目标化合物(收率61％)。1HNMR(CDCl3,500MHz)δ(ppm):1.47(d,3H,J＝6Hz),1.82(brs,1H),3.76(s,2H),4.06(q,1H,J＝6Hz),7.18-7.20(m,2H),7.27-7.30(m,3H),8.72(s,2H)；ESI MS m/z 441.0[M+H]+；HRMS for C17H14Cl2N4O2S2+H calcd.441.0013found 441.0016.
实施例22
1-[2-(2,3-二氯苯基硫代)-噻唑-5-基]乙酮(II-1)的制备
将2,3-二氯苯硫酚(120mg,0.68mmol)、甲醇钠(37mg,0.68mmol)加入干燥的甲醇(6mL)，室温下搅拌20分钟。然后向反应液中加入2-氯-5-乙酰基噻唑(100mg,0.48mmol)，室温搅拌直至反应完全。将溶剂蒸干，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥。蒸干后经硅胶柱层析得目标化合物(129mg,收率69％)。1HNMR(CDCl3,300MHz)δ(ppm):2.51(s,3H),7.27-7.33(m,1H),7.60-7.68(m,2H),8.14(s,1H)；ESI MS m/z 303.9[M+H]+；HRMS for C11H7Cl2NOS2+H calcd.303.9424 found303.9427.
实施例23
1-[2-(3,4-二氯苯基硫代)-噻唑-5-基]乙酮(II-2)的制备
反应步骤参照实施例22，得目标化合物(收率70％)。1HNMR(CDCl3,500MHz)δ(ppm):2.50(s,3H),7.50(dd,1H,J＝2,8Hz),7.55(d,1H,J＝8Hz),7.77(d,1H,J＝2Hz),8.12(s,1H)；ESI MS m/z 303.9[M+H]+；HRMS for C11H7Cl2NOS2+H calcd.303.9424found303.9427.
实施例24
1-[2-(2,6-二氯苯基硫代)-噻唑-5-基]乙酮(II-3)的制备
反应步骤参照实施例22，得目标化合物(收率58％)。1HNMR(CDCl3,500MHz)δ(ppm):2.49(s,3H),7.39-7.42(m,1H),7.52-7.53(m,2H),8.10(s,1H).ESI MS m/z 303.9[M+H]+；HRMS for C11H7Cl2NOS2+H calcd.303.9424found 303.9427.
实施例25
1-[2-(2,4-二氯苯基硫代)-噻唑-5-基]乙酮(II-4)的制备
反应步骤参照实施例22，得目标化合物(收率69％)。1HNMR(CDCl3,300MHz)δ(ppm):2.50(s,3H),7.36(dd,1H,J＝2,8Hz),7.60(d,1H,J＝2Hz),7.68(d,1H,J＝8Hz),8.12(s,1H)；ESI MS m/z 303.9[M+H]+；HRMS for C11H7Cl2NOS2+H calcd.303.9424found303.9427.
实施例26
1-[2-(3-甲氧基苯基硫代)-噻唑-5-基]乙酮(II-5)的制备
反应步骤参照实施例22，得目标化合物(收率71％)。1HNMR(CDCl3,300MHz)δ(ppm):2.48(s,3H),3.83(s,3H),7.04-7.07(m,1H),7.20-7.27(m,2H),7.37-7.42(m,1H),8.11(s,1H)；ESI MS m/z 266.0[M+H]+；HRMS for C12H11NO2S2+H calcd.266.0309 found266.0311.
实施例27
1-[2-(3,4-二甲氧基苯基硫代)-噻唑-5-基]乙酮(II-6)的制备
反应步骤参照实施例22，得目标化合物(收率69％)。1HNMR(CDCl3,300MHz)δ(ppm):2.46(s,3H),3.88(s,3H),3.93(s,3H),6.95(d,1H,J＝8Hz),7.13(d,1H,J＝2Hz), 7.26-7.29(m,1H),8.09(s,1H)；ESI MS m/z 296.0[M+H]+；HRMS for C13H13NO3S2+H calcd.296.0415 found 296.0417.
实施例28
1-[2-(4-硝基苯基硫代)-噻唑-5-基]乙酮(II-7)的制备
反应步骤参照实施例22，得目标化合物(收率87％)。1HNMR(CDCl3,500MHz)δ(ppm):2.53(s,3H),7.78(m,2H),8.18(s,1H),8.27(m,2H)；ESI MS m/z 281.0[M+H]+；HRMS for C11H8N2O3S2+H calcd.281.0055 found 281.0057.
实施例29
1-[2-(3,5-二氯吡啶基-4-硫代)-噻唑-5-基]乙酮(II-8)的制备
反应步骤参照实施例22，得目标化合物(收率43％)。1HNMR(CDCl3,300MHz)δ(ppm):2.53(s,3H),8.10(s,1H),8.67(s,2H)；ESI MS m/z 304.9[M+H]+；HRMS for C10H6N2OS2+H calcd.304.9377 found 304.9381.
实施例30
2,5-二溴-4-硝基噻唑的制备
将-20℃下将发烟硝酸(13mL)加入三氟乙酸酐(40mL)中，-20℃搅拌2h。同样温度下，缓慢将2,5-二溴噻唑(14g)滴入反应液，-20℃搅拌过夜。蒸干溶剂，缓慢加入水(100mL)，乙酸乙酯萃取，无水Na2SO4干燥，蒸干溶剂，石油醚打浆，抽虑得粗品淡黄色固体3.34g(收率20％)。ESI MS m/z 289.0[M+H]+
实施例31
2-溴-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑(I-21)的制备
将3,5-二氯-4-巯基吡啶(2.3g，1.1eq)溶于50mL市售无水甲醇中，加入甲醇钠(690mg,1.1eq)，40℃搅拌2h，加入2,5-二溴-4-硝基噻唑(3.34g)，40℃搅拌2.5h，蒸干溶剂，加入50mL水，乙酸乙酯萃取，无水Na2SO4干燥，蒸干溶剂，经硅胶柱层析得目标化合物2.57g(收率83％)。1HNMR(CDCl3,300MHz)δ(ppm):8.73(s,2H)；ESI MS m/z385.6[M+H]+
实施例32
5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-22)的制备
将2-溴-5-(3,5-二氯吡啶基)巯基-4-硝基噻唑(100mg)溶于DMF(1mL,分析纯)中，加入氰化亚铜(41.6mg,1.8eq)，120℃搅拌(油浴事先预热)1.5h，冷却至室温，加入乙酸乙酯(20mL)充分搅拌，过滤除去沉淀，有机相水洗两次，无水Na2SO4干燥，蒸干溶剂，加入甲醇震荡，抽虑得淡黄色固体30mg。(收率33％)。1HNMR(DMSO,300MHz)δ(ppm):8.95(s,2H),8.52(s,1H),8.17(s,1H)；ESI MS m/z 349.1[M-H]-
实施例33
N-甲基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-23)的制备
将5-(3,5-二氯-4-吡啶基)巯基-4-硝基噻唑-2-羧酸(100mg)悬浮于MeCN(5mL)，室温滴入三氯氧磷(0.037mL,1.5eq)，室温搅拌30min，冰浴下加入甲胺盐酸盐(22mg,1.1eq)，滴入二异丙基乙胺(0.237mL,5eq)，完成后室温搅拌1.5h，蒸干溶剂，加冰水(15mL)，抽虑所得沉淀用乙醚洗两次，得白色粉末22mg(收率21％)。1HNMR(DMSO,300MHz)δ(ppm):9.09(d,J＝5.2Hz,1H),8.96(s,2H),2.73(d,J＝4.8Hz,3H)；ESI MS m/z 362.6[M-H]-
实施例34
N,N-二乙基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-24)的制备
将5-(3,5-二氯-4-吡啶基)巯基-4-硝基噻唑-2-羧酸(100mg)悬浮于MeCN(5mL)，室温滴入三氯氧磷(0.037mL,1.5eq)，室温搅拌30min，冰浴下加入二乙胺盐酸盐(35mg,1.1eq)，滴入二异丙基乙胺(0.237mL,5eq)，完成后室温搅拌过夜，蒸干溶剂，加冰水(15mL)，置于0℃析晶，抽虑所得沉淀通过制备柱层析纯化得白色粉末18mg(收率16％)。1HNMR(DMSO,300MHz)δ(ppm):8.95(s,2H),3.56–3.54(m,4H),1.32–1.15(m,6H)；ESI MS m/z 405.1[M]+
实施例35
N-(1-甲基哌啶-4-基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-25)的制备
将5-(3,5-二氯-4-吡啶基)巯基-4-硝基噻唑-2-羧酸(50mg)悬浮于3mL MeCN，室温滴入三氯氧磷(0.02mL,1.5eq)，室温搅拌30min，冰浴下加入N-甲基-4-氨基哌啶(17.8mg,1.1eq)，滴入二异丙基乙胺(0.117mL,5eq)，完成后室温搅拌1.5h，蒸干溶剂，加冰水(15mL)，用饱和NaHCO3调pH至7，乙酸乙酯萃取，水洗，无水Na2SO4干燥，蒸干溶剂，加入乙醚捣碎，抽虑所得固体用乙醚洗，得黄色粉末30mg(收率47％)。1HNMR(DMSO,300MHz)δ(ppm):9.22(s,1H),8.95(s,2H),3.95(s,1H),3.10(m,4H),2.72(s,3H),1.96(m,4H)；ESI MS m/z 446.1[M-H]-
实施例36
N-苯基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-26)的制备
反应步骤参照实施例33，得目标化合物(收率8％)。1HNMR(DMSO,300MHz)δ(ppm):11.08(s,1H),9.00(s,2H),7.77(d,J＝7.9Hz,2H),7.36(t,J＝7.6Hz,2H),7.16(t,J＝7.2Hz,1H)；ESI MS m/z 425.0[M-H]-
实施例37
N-苄基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-27)的制备
将5-(3,5-二氯-4-吡啶基)巯基-4-硝基噻唑-2-羧酸(80mg)悬浮于MeCN(3mL)，室温滴入三氯氧磷(0.03mL,1.5eq)，冰浴下加入苄胺(26.8mg,1.1eq)，滴入二异丙基乙胺(0.19mL,5eq)，完成后室温搅拌过夜，蒸干溶剂，加15mL冰水，乙酸乙酯萃取，1N HCl洗5次，无水Na2SO4干燥，蒸干溶剂，加入乙醚研磨得淡黄色粉末25mg(收 率25％)。1HNMR(DMSO,300MHz)δ(ppm):9.76(t,J＝5.9Hz,1H),8.97(s,2H),7.34–7.20(m,5H),4.40(d,J＝6.1Hz,2H)；ESI MS m/z 438.8[M-H]-
实施例38
N-苯乙基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-28)的制备
反应步骤参照实施例37，得目标化合物(收率22％)。1HNMR(DMSO,300MHz)δ(ppm):9.28(s,1H),8.96(s,2H),7.19(s,3H),2.94(s,1H),2.73(s,1H)；ESI MS m/z455.3[M+H]+
实施例39
N-(4-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-29)的制备
反应步骤参照实施例37，得目标化合物(收率8％)。1HNMR(DMSO,300MHz)δ(ppm):10.96(s,1H),8.98(s,2H),7.66(d,J＝9.0Hz,2H),6.91(d,J＝9.1Hz,2H),3.72(s,3H)；ESI MS m/z 455.0[M-H]-
实施例40
N-(3,4-二甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-30)的制备
反应步骤参照实施例37，得目标化合物(收率8％)。1HNMR(DMSO,300MHz)δ(ppm):10.93(s,1H),7.40(m,2H),6.90(m,1H),3.60(m,6H)；ESI MS m/z 484.9[M-H]-
实施例41
N-(3-氯-4-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-31)的制备
反应步骤参照实施例37，得目标化合物(收率29％)。1HNMR(DMSO,300MHz)δ(ppm):11.15(s,1H),9.00(s,2H),7.90(s,1H),7.70(m,1H),7.15(m,1H),3.91(s,3H)；ESI MS m/z 488.8[M-H]-
实施例42
N-(3-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-32)的制备
反应步骤参照实施例37，得目标化合物(收率29％)。1HNMR(DMSO,300MHz)δ(ppm):11.03(s,1H),8.97(s,2H),7.40(m,2H),7.23(m,1H),6,71(m,1H),3.98(s,3H)；ESI MS m/z 479.4[M+Na]+
实施例43
N-(2-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-33)的制备
反应步骤参照实施例37，得目标化合物(收率13％)。1HNMR(DMSO,300MHz)δ(ppm):9.80(s,1H),9.00(s,2H),7.85(m,1H),7.10(m,3H),3.88(s,3H)；ESI MS m/z 454.7[M-H]-
实施例44
N-(6-甲氧基吡啶-3-基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-34)的制备
反应步骤参照实施例37，得目标化合物(收率13％)。1HNMR(DMSO,300MHz)δ (ppm):11.15(s,1H),9.00(s,2H),8.49(m,1H),8.05(s,1H),6.86(s,1H),3.88(s,3H)；ESI MS m/z 455.9[M-H]-
实施例45
N-[4-(3-二甲胺基丙氧基)苯基]-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-35)的制备
反应步骤参照实施例37，得目标化合物(收率22％)。1HNMR(DMSO,300MHz)δ(ppm):10.97(s,1H),8.99(s,2H),7.66(d,J＝8.6Hz,2H),6.92(d,J＝8.6Hz,2H),3.98(t,J＝6.1Hz,1H),2.46(d,J＝6.9Hz,1H),2.24(s,6H),1.87(dd,J＝13.1,6.4Hz,1H)；ESI MS m/z526.1[M-H]-
实施例46
N-(4-羟基苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-36)的制备
反应步骤参照实施例37，得目标化合物(收率26％)。1H NMR(300MHz,DMSO)δ9.62(t,J＝6.3Hz,1H),9.27(s,1H),8.95(s,1H),7.08(d,J＝8.3Hz,1H),6.66(d,J＝8.4Hz,1H),4.26(d,J＝6.1Hz,1H)；ESI MS m/z455.03[M-H]-
实施例47
N-(4-甲基苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-37)的制备
反应步骤参照实施例37，得目标化合物(收率23％)。1H NMR(300MHz,DMSO)δ9.69(t,J＝6.0Hz,1H),8.95(s,1H),7.18–7.03(m,4H),4.33(d,J＝6.1Hz,2H),1.21(s,3H)；ESI MS m/z 477.0[M+Na]+
实施例48
N-(4-氯苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-38)的制备
反应步骤参照实施例37，得目标化合物(收率43％)。1H NMR(300MHz,DMSO)δ9.76(s,1H),8.95(s,1H),7.32(m,4H),4.37(s,2H)；ESI MS m/z 474.2[M-H]-
实施例49
N-(4-氟苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-39)的制备
反应步骤参照实施例37，得目标化合物(收率48％)。1H NMR(300MHz,DMSO)δ9.75(t,J＝6.1Hz,1H),8.95(s,1H),7.32(dd,J＝8.3,5.8Hz,2H),7.10(t,J＝8.8Hz,2H),4.36(d,J＝6.1Hz,2H)；ESI MS m/z457.0[M-H]-
实施例50
N-(3-氟苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-40)的制备
反应步骤参照实施例37，得目标化合物(收率51％)。1H NMR(300MHz,DMSO)δ9.76(t,J＝6.1Hz,1H),8.95(s,1H),7.33(dd,J＝14.2,7.8Hz,1H),7.34(s,1H)7.12(m,2H),4.40(d,J＝6.1Hz,2H)；ESI MS m/z 481.0[M+Na]-
实施例51
{5-[(3,5-二氯-4-吡啶基)巯基]-4-硝基噻唑-2-基}[1,2,3,4-四氢异喹啉-2-基]酮(I-41)的制备
反应步骤参照实施例37，得目标化合物(收率44％)。1H NMR(300MHz,DMSO)δ9.66(d,J＝8.9Hz,1H),9.07(s,2H),7.56–6.81(m,4H),5.20(m,1H),2.80(m,2H),2.02(m,2H),1.31(m,2H)；ESI MS m/z479.1[M-H]-
实施例52
N-{5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-基}乙酰胺(I-42)的制备
步骤1.N-甲氧羰基-5-溴-2-氨基噻唑的制备
将200mg 5-溴-2-氨基噻唑悬浮于10mL MeCN。室温下滴入0.26mL氯甲酸甲酯(3eq)0.46mL三乙胺(3eq)，室温搅拌3h，蒸干溶剂。将所得产物溶于2mL浓硫酸，冰浴下，分批加入350mg KNO3(约1.5eq)，0℃搅拌3h，将反应液倒入冰水中，乙酸乙酯萃取，饱和NaHCO3洗，无水Na2SO4干燥，蒸干溶剂，制备柱层析纯化(PE:EA 3:1)得80mg目标化合物。
步骤2.N-{5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-基}乙酰胺的制备
56mg 3,5-二氯-4-巯基吡啶(粗品，约1.1eq)溶于3mL无水甲醇中，加入17mg甲醇钠(约1.1eq)，40℃搅拌30min，冷却至室温，加入80mg N-(5-溴-4-硝基-2-噻唑基)氨基甲酸甲酯，室温过夜。蒸干溶剂，加入15mL水，乙酸乙酯萃取，无水Na2SO4干燥，制备柱层析纯化(石油醚:乙酸乙酯5:1)得目标化合物50mg，收率12％。1H NMR(300MHz,DMSO)δ12.28(s,1H),8.90(s,2H),4.75(s,3H)；ESI MS m/z403.2[M+Na]+
实施例53
N-{5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-基}丙酰胺(I-43)
反应步骤参照实施例53，得目标化合物(收率8％)。1H NMR(300MHz,DMSO)δ12.61(s,1H),8.93(s,2H),4.16(q,J＝7.1Hz,2H),1.20(t,J＝7.1Hz,3H)；ESI MS m/z417.0[M+Na]+
实施例54
1-[5-(2,4-二氟苯基硫代)-4-硝基噻唑-2-基]乙酮(I-44)的制备
反应步骤参照实施例1，得目标化合物(收率77.4％)。1H NMR(300MHz,DMSO)δ7.96(dd,J＝14.9,8.3Hz,1H),7.65(td,J＝9.2,2.3Hz,1H),7.42–7.32(m,1H),2.54(s,3H).ESI MS m/z338.9[M+Na]+
实施例55
2-溴-5-(2,4-二氟苯基巯基)-4-硝基噻唑的制备
反应步骤参照实施例31，得目标化合物(收率66.4％)。1H NMR(300MHz,DMSO)δ7.98(dd,J＝15.0,8.4Hz,1H),7.66(td,J＝9.2,2.5Hz,1H),7.37(td,J＝8.5,1.7Hz,1H).
实施例56
5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-45)
以2-溴-5-(2,4-二氟苯基巯基)-4-硝基噻唑为原料，反应步骤参照实施例32，得目标化合物(收率25％)。1H NMR(300MHz,DMSO)δ8.46(s,1H),8.12(s,1H),7.99(dd,J＝14.9,8.4Hz,1H),7.67(td,J＝9.2,2.3Hz,1H),7.40(dd,J＝11.6,5.1Hz,1H).
实施例57
N-苯基-5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-46)
以5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺为原料，反应步骤参照实施例37。得目标化合物(总收率14％)。1H NMR(300MHz,DMSO)δ11.00(s,1H),8.01(dd,J＝14.9,8.4Hz,1H),7.77(d,J＝7.9Hz,2H),7.69(td,J＝9.2,2.4Hz,1H),7.45–7.37(m,1H),7.35(t,J＝7.8Hz,2H),7.15(t,J＝7.3Hz,1H).
实施例58
N-苄基-5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺(I-47)
以5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺为原料，反应步骤参照实施例37。得目标化合物(总收率4％)。1H NMR(300MHz,DMSO)δ9.70(t,J＝6.1Hz,1H),7.99(dt,J＝8.3,6.7Hz,1H),7.72–7.63(m,1H),7.39(td,J＝8.4,2.2Hz,1H),7.31–7.25(m,5H),4.40(d,J＝6.2Hz,2H).
实施例59
片剂
将实施例8中制得的化合物I-7(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合，制粒，压片。

Claims (9)

  1. 通式I或II所示的化合物或其氮氧化物、药学上可接受的盐或溶剂化物：
    Figure PCTCN2014090466-appb-100001
    其中：
    X为H、NO2、卤素、CN、-SCF3或-SO2CF3；
    Y为S、NH、NHCH2、O、SO或SO2；
    R1代表一个或多个Z1取代的芳基或杂芳基，其中，Z1选自卤素、腈基、硝基、三氟甲基或-OR3；
    R2为-COR4、-CONR5R6、1～6个碳的Z2取代的烷基或卤素；
    R3和R4为1～10个碳的烷基、取代的烷基、芳基或取代的芳基；
    R5、R6独立地选自氢原子、1～10个碳的烷基或取代烷基、非取代的或一个或多个Z3取代的芳基或杂芳基，或者R5、R6与非取代或取代的N原子一起形成一个4～8元杂环基；
    Z2为-OH、-OCOR7或-NR5R6；
    Z3为卤素或-OR8；
    R7为1～6个碳的烷基或取代烷基；
    R8为1～6个碳的烷基或1～6个碳的一个或多个Z4取代的烷基；
    Z4为-NR9R10或-OR11；
    R9、R10独立地选自氢原子、1～6个碳的烷基或取代烷基、或者R9、R10一起形成一个3～8元环烷基、或者R9、R10与非取代或取代的N原子一起形成一个4～8元杂环烷基；
    R11为氢原子或1～6个碳的烷基。
  2. 如权利要求1所述的化合物，其特征在于，所述式I和式II化合物中：
    X优选H、NO2或CN；
    Y优选S、O、NH或NHCH2；
    R1优选一个或多个Z1取代的苯基或吡啶基，其中，Z1优选卤素、腈基或硝基；
    R2优选-COR4或-CONR5R6，其中，R4优选为1～6个碳的烷基；R5、R6独立地选自氢原子或一个或多个Z3取代的苯基或吡啶基，其中，Z3如权利要求1中所定义。
  3. 如权利要求1所述的化合物，其特征在于，所述式I和式II化合物包括以下化合物：
    1-[5-(2,3-二氯苯基硫代)噻唑-2-基]乙酮；
    1-[5-(3,4-二氯苯基硫代)噻唑-2-基]乙酮；
    1-[5-(2,6-二氯苯基硫代)噻唑-2-基]乙酮；
    1-[5-(2,3-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(3,4-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(2,6-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(2,4-二氯苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(3-甲氧基苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(3,4-二甲氧基苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(4-硝基苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(3,4-二氯苯甲基氨基)-4-硝基噻唑-2-基]乙酮；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙醇；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙酸乙酯；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]氯乙酸乙酯；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]丙酸乙酯；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]丁酸乙酯；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]苯甲酸乙酯；
    1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]-N-甲基乙胺；
    N-苄基-1-[5-(3,5-二氯吡啶基-4-硫代)-4-硝基噻唑-2-基]乙胺；
    1-[2-(2,3-二氯苯基硫代)-噻唑-5-基]乙酮；
    1-[2-(3,4-二氯苯基硫代)-噻唑-5-基]乙酮；
    1-[2-(2,6-二氯苯基硫代)-噻唑-5-基]乙酮；
    1-[2-(2,4-二氯苯基硫代)-噻唑-5-基]乙酮；
    1-[2-(3-甲氧基苯基硫代)-噻唑-5-基]乙酮；
    1-[2-(3,4-二甲氧基苯基硫代)-噻唑-5-基]乙酮；
    1-[2-(4-硝基苯基硫代)-噻唑-5-基]乙酮；
    1-[2-(3,5-二氯吡啶基-4-硫代)-噻唑-5-基]乙酮；
    2-溴-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑；
    5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-甲基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N,N-二乙基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(1-甲基哌啶-4-基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-苯基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-苄基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-苯乙基-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(4-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(3,4-二甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(3-氯-4-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(3-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(2-甲氧基苯基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(6-甲氧基吡啶-3-基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-[4-(3-二甲胺基丙氧基)苯基]-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(4-羟基苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(4-甲基苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(4-氯苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(4-氟苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-(3-氟苄基)-5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    {5-[(3,5-二氯-4-吡啶基)巯基]-4-硝基噻唑-2-基}[1,2,3,4-四氢异喹啉-2-基]酮；
    N-{5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-基}乙酰胺；
    N-{5-[(3,5-二氯吡啶-4-基)巯基]-4-硝基噻唑-2-基}丙酰胺；
    1-[5-(2,4-二氟苯基硫代)-4-硝基噻唑-2-基]乙酮；
    5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-苯基-5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-苄基-5-[(2,4-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-苄基-5-[(2,6-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    N-苄基-5-[(2,3-二氟吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    1-[5-(2,3-二氟苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(2,6-二氟苯基硫代)-4-硝基噻唑-2-基]乙酮；
    1-[5-(2-氟-4-氯苯基硫代)-4-硝基噻唑-2-基]乙酮；
    N-苄基-5-[(2-氟-4-氯吡啶-4-基)巯基]-4-硝基噻唑-2-甲酰胺；
    1-[5-(2,4-二氟苯基硫代)-4-硝基噻唑-2-基]丙酮。
  4. 权利要求1所述化合物的制备方法，如下反应式所示：
    Figure PCTCN2014090466-appb-100002
    具体包括以下步骤：
    (1)化合物III经硝化反应制得式IV化合物；
    (2)化合物IV与R1YH发生亲核取代反应制得化合物I-b；
    上述反应式中，R1、R4和Y如权利要求1中所定义。
  5. 权利要求1所述化合物的制备方法，如下反应式所示：
    Figure PCTCN2014090466-appb-100003
    具体包括以下步骤：
    (1)化合物VI进行硝化反应制得式VII化合物；
    (2)化合物VII与R1YH发生亲核取代反应制得化合物VIII；
    (3)化合物VIII与CuCN发生反应得到化合物IX；
    (4)化合物IX与亚硝酸酸盐在酸性溶剂中发生重氮盐水解反应得到化合物X；
    (5)化合物X与R5R6NH反应生成化合物I-f；
    在上述反应式中，R1、R5、R6和Y如权利要求1中所定义。
  6. 权利要求1的式I或式II化合物或其氮氧化物、药学上可接受的盐或溶剂化物在制备预防或治疗肿瘤疾病药物中的应用。
  7. 根据权利要求6所述的用途，其特征在于是用于制备预防或治疗多发性骨髓瘤疾病的药物。
  8. 一种预防或治疗肿瘤疾病的药物组合物，其特征在于，所述药物组合物中含有治疗有效量的式I或II化合物或其氮氧化物、药学上可接受的盐或溶剂化物作为活性成份和药学上可接受的载体。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述药物组合物可以是普通片剂或胶囊、缓释片剂或胶囊、控释片剂或胶囊、颗粒剂、散剂、糖浆剂、口服液或注射剂。
PCT/CN2014/090466 2014-02-25 2014-11-06 噻唑类化合物、其制备方法及其在制药中的用途 WO2015127797A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11273154B2 (en) * 2017-03-03 2022-03-15 Progenra, Inc. Azole compounds as ubiquitin-specific protease USP7 inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105884711A (zh) * 2014-12-16 2016-08-24 中国药科大学 噻唑类化合物、其制备方法及其在制药中的用途
CN110437173A (zh) * 2019-08-26 2019-11-12 浙江工业大学 一种含噻唑环的二苯乙烯类化合物及其合成方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074283A1 (en) * 2003-02-21 2004-09-02 Pfizer Inc. N-heterocyclyl-substituted amino-thiazole derivatives as protein kinase inhibitors
CN101115749A (zh) * 2004-12-17 2008-01-30 安姆根有限公司 氨基嘧啶化合物和使用方法
WO2009017822A2 (en) * 2007-08-02 2009-02-05 Amgen Inc. Pi3 kinase modulators and methods of use
CN102070556A (zh) * 2010-12-29 2011-05-25 湖南大学 5-苄基-4-烷基-2-芳氨基噻唑及其制备与应用
CA2793697A1 (en) * 2010-04-30 2011-11-03 Merck Sharp & Dohme Corp. Inhibitors of phosphoinositide dependent kinase 1 (pdk1)
EP2606889A1 (en) * 2011-12-21 2013-06-26 Telik, Inc. Substituted Thiazoles as VEGFR2 kinase Inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125875B2 (en) * 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2007073497A2 (en) * 2005-12-22 2007-06-28 Icagen, Inc. Calcium channel antagonists
US8680139B2 (en) * 2009-04-01 2014-03-25 Progenra Anti-neoplastic compounds, compositions and methods
CN104003956A (zh) * 2013-02-27 2014-08-27 中国药科大学 噻唑类化合物、其制备方法与其在制药中的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074283A1 (en) * 2003-02-21 2004-09-02 Pfizer Inc. N-heterocyclyl-substituted amino-thiazole derivatives as protein kinase inhibitors
CN101115749A (zh) * 2004-12-17 2008-01-30 安姆根有限公司 氨基嘧啶化合物和使用方法
WO2009017822A2 (en) * 2007-08-02 2009-02-05 Amgen Inc. Pi3 kinase modulators and methods of use
CA2793697A1 (en) * 2010-04-30 2011-11-03 Merck Sharp & Dohme Corp. Inhibitors of phosphoinositide dependent kinase 1 (pdk1)
CN102070556A (zh) * 2010-12-29 2011-05-25 湖南大学 5-苄基-4-烷基-2-芳氨基噻唑及其制备与应用
EP2606889A1 (en) * 2011-12-21 2013-06-26 Telik, Inc. Substituted Thiazoles as VEGFR2 kinase Inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11273154B2 (en) * 2017-03-03 2022-03-15 Progenra, Inc. Azole compounds as ubiquitin-specific protease USP7 inhibitors

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