CN105884711A - Thiazole compounds, preparing method of thiazole compounds and application thereof in pharmacy - Google Patents

Abstract

The present invention discloses compounds represented by general formulas I and II or nitrogen oxides thereof, pharmaceutically acceptable salts or solvates, their preparation methods and their application in pharmacy, especially the application in anti-tumor. The results of pharmacodynamic experiments show that the compounds of formula I and formula II of the present invention have significant anti-tumor effects, especially significant anti-human multiple myeloma cells. Therefore, the compound of the present invention can be used to prepare medicines for preventing or treating tumor-related diseases.

Description

Thiazole compounds, their preparation method and their use in pharmacy

technical field

The invention relates to the field of pharmacy, in particular to thiazole compounds, their preparation method and their application in the preparation of drugs for preventing or treating tumor diseases.

This patent application claims the priority of the Chinese patent application (application number 201410062371.2, application date: February 25, 2014, name of invention: thiazole compounds, their preparation methods and their use in pharmaceuticals).

Background technique

Malignant tumors are major diseases that seriously threaten human health. The occurrence of tumors is characterized by the wrong response of cells themselves 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 the epigenetic environment. Even in 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. Currently, the clinically used antitumor drugs include cytotoxic drugs, kinase inhibitors, proteasome inhibitors, HDAC inhibitors, hedgehog inhibitors, and the like.

Heterocyclic compounds containing thiazole rings have broad-spectrum biological activities, such as local anesthesia, anticonvulsant, antiviral, antibacterial, antitumor and insecticidal effects.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)。 Other 2-position electron donating groups include substituted sulfhydryl groups (Bioorg Med Chem.21(24):7648-54) and methylene groups (Bioorg MedChem.20(7):2316-22). In addition, anti-tumor small molecules coupled with aromatic groups at the 2-position, 4-position and 5-position of thiazole have also been reported (WO2011137219A1, EP2606889A1, WO2013082324A1, EP2606889A1, US20120225880A1, WO2010083246A1).

Through the anti-tumor screening at the cellular level, we unexpectedly discovered a new class of thiazole compounds with anti-tumor activity.

Contents of the invention

The present invention discloses compounds represented by general formula I or II or nitrogen oxides thereof, pharmaceutically acceptable salts or solvates thereof:

in:

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 substituted aryl or heteroaryl, wherein Z 1 is} selected from halogen, nitrile, nitro, trifluoromethyl or -OR ₃ ;

R ₂ is -COR ₄ , -CONR ₅ R ₆ , Z ₂ substituted alkyl or halogen with 1 to 6 carbons;

R ₃ and R ₄ are alkyl, substituted alkyl, aryl or substituted aryl with 1 to 10 carbons;

R ₅ and R ₆ are independently selected from hydrogen atom, alkyl or substituted alkyl with 1 to 10 carbons, unsubstituted or one or more Z ₃ substituted aryl or heteroaryl, or R ₅ and R ₆ Together with an unsubstituted or substituted N atom, a 4- to 8-membered heterocyclic group is formed;

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 substituted alkyl group with 1 to 6 carbons;

R ₈ is an alkyl group with 1 to 6 carbons or one or more Z substituted alkyl groups with ₁ to 6 carbons;

Z ₄ is -NR ₉ R ₁₀ or -OR ₁₁ ;

R ₉ and R ₁₀ are independently selected from hydrogen atoms, alkyl groups or substituted alkyl groups with 1 to 6 carbons, or R ₉ and R ₁₀ together form a 3 to 8-membered cycloalkyl group, or R ₉ and R ₁₀ are combined with non- The substituted or substituted N atoms together form a 4-8 membered heterocycloalkyl group;

R ₁₁ is a hydrogen atom or an alkyl group having 1 to 6 carbons.

In the compound of formula I or II of the present invention:

X is preferably H, NO2 or CN _;

Y is preferably S, O, NH or NHCH ₂ ;

R1 is preferably phenyl or _pyridyl substituted by _one or more Z1, wherein Z1 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 with 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 pyridyl, wherein Z ₃ is as defined above.

More preferred compounds among the compounds of formulas I and II of the present invention are as follows:

Another object of the present invention is to provide the preparation method of formula I and formula II compound, as shown in the following reaction formula:

R ₁ , R ₄ , R ₅ , R ₆ , R ₇ and Y are as defined above for compounds of formula I and formula II.

Specifically include the following steps:

(1) compound III and R ₁ YH undergo nucleophilic substitution reaction under alkaline conditions to obtain compound Ia, the basic reagent used is selected from potassium carbonate, sodium carbonate, sodium methylate, sodium ethylate, preferably sodium methylate; The solvent is methanol, ethanol, acetonitrile, preferably methanol; the reaction time used is 1-24 hours; the temperature used is minus 20°C to 100°C, preferably 50°C to 70°C.

(2) With compound III as starting material, carry out nitration reaction to obtain formula IV compound, the nitrating reagent that adopts is selected from fuming nitric acid, concentrated nitric acid, concentrated nitric acid/concentrated sulfuric acid, preferred fuming nitric acid; The solvent that adopts is selected from acetic anhydride 1. 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.

(3) Nucleophilic substitution reaction between compound IV and R ₁ YH to prepare compound Ib.

(4) Compound I-b undergoes a reduction reaction to obtain I-c. The reducing agent used is selected from sodium borohydride, potassium borohydride, and lithium aluminum hydride, preferably sodium borohydride; the solvent used is selected from methanol, ethanol, tetrahydrofuran, preferably methanol; The reaction time used is 1-10 hours; the temperature used is minus 20°C to 100°C, preferably 0°C to 50°C.

(5) Compound I-c undergoes an esterification reaction to obtain Compound I-d. The acylating agent used is selected from acid anhydrides, acid chlorides, carboxylic acids, preferably acid anhydrides and acid chlorides; the base used is selected from triethylamine, 4-dimethylaminopyridine, carbonic acid Potassium, preferably 4-dimethylaminopyridine; The solvent used is selected from dichloromethane, chloroform, acetonitrile, preferably dichloromethane; The reaction time used is 1-24 hours; The temperature used is from minus 20°C to 100°C, preferably 25 °C to 100 °C.

(6) Compound I-b undergoes a reductive amination reaction to obtain I-e. The reducing agent used is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, preferably sodium nitrile borohydride; the solvent used is dichloro Methane, ethyl acetate, tetrahydrofuran, preferably dichloromethane; the reaction time used is 1-24 hours; the temperature used is minus 20°C to 100°C, preferably 25°C to 50°C.

(7) Nucleophilic substitution reaction occurs between compound V and R ₁ YH to obtain compound II, the basic reagent used is selected from potassium carbonate, sodium carbonate, sodium methylate, sodium ethylate, preferably sodium methylate; the solvent used is methanol, ethanol , acetonitrile, N, N-dimethylformamide, preferably methanol, N, N-dimethylformamide; the reaction time used is 1-24 hours; the temperature used is minus 20°C to 100°C, preferably 25°C to 70°C.

(8) With compound VI as starting material, carry out nitration reaction and make formula VII compound, the nitrating reagent that adopts is selected from fuming nitric acid, concentrated nitric acid, concentrated nitric acid/concentrated sulfuric acid, preferred fuming nitric acid; The solvent that adopts is selected from acetic anhydride , Trifluoroacetic anhydride, preferably trifluoroacetic anhydride; the reaction time used is 1-24 hours; the temperature used is from minus 50°C to 25°C, preferably minus 25°C to 0°C;

(9) Nucleophilic substitution reaction between compound VII and R ₁ YH to prepare compound VIII.

(10) Compound VIII reacts with CuCN to obtain compound IX, using N, N-dimethylsulfoxide, pyridine, acetone as a solvent, preferably N, N-dimethylamide; using a reaction time of 1-12 hours ; The temperature used is from 50°C to 150°C, preferably from 120°C to 140°C.

(11) Compound IX and nitrite are hydrolyzed with 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 a strong acid Aqueous solution, preferably 80% sulfuric acid aqueous solution; the adopted reaction time is 0.5-6 hours, preferably 0.5 hours; the adopted temperature is minus 20°C to 25°C, preferably 25°C.

(12) Compound X reacts with R ₅ R ₆ NH under the action of an acylating reagent to generate compound If. The acylating reagent is acetyl chloride, benzoyl chloride, oxalyl chloride, chloroacetyl chloride, trichloroacetyl chloride, phosphorus oxychloride, Preferred phosphorus oxychloride; Selected solvent is acetonitrile, acetone, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, preferably acetonitrile; The base that adopts is triethylamine, diisopropylethylamine, pyridine, preferably diisopropylethylamine Amine; the reaction time is 1-48 hours, preferably 5-12 hours; the temperature used is minus 20°C to 50°C, preferably 25°C.

The specific preparation method of the compound of formula I or formula II refers to the examples.

Another object of the present invention is to provide the use of the compound of formula I or II or its nitrogen oxide, pharmaceutically acceptable salt or solvate in the preparation of drugs for preventing and treating tumors. The results of pharmacodynamic experiments show that the compounds of the formulas I and II of the present invention have significant anti-tumor cell proliferation effects.

The following are some pharmacological experiments and results of the compounds of the present invention.

1. Experimental purpose: The effect of each compound on the proliferation activity of human multiple myeloma cell RPMI-8226 in vitro was determined by CCK-8 staining method, and the respective half inhibitory concentration IC ₅₀ was calculated.

2. Experimental materials: the compound of the present invention was dissolved in DMSO to make mother liquor, and diluted to an appropriate concentration with complete medium before use; reagent: CCK-8 kit was purchased from Nanjing Enjing Biotechnology Co., Ltd.; culture medium: RMPI-1640 culture Base was purchased from Gibco; fetal bovine serum: purchased from Gibco; 96-well cell culture plates were purchased from Costar.

3. Experimental method: take the cells with a living cell ratio of more than 90% for the experiment. The cell proliferation inhibition test used the EnoGeneCell ^TM Counting Kit-8 (CCK-8) cell viability detection kit. Cells were digested, counted, and made into a cell suspension with a concentration of 1×10 ⁵ cells/ml, and 100 μl of cell suspension was added to each well of a 96-well plate (1×10 ⁴ cells per well); the 96-well plate was placed at 37°C , 5% _CO incubator for 24 hours; dilute the drug to the required concentration with complete medium, add 100 μ L of corresponding drug-containing medium to each well, set up negative control group and vehicle control group simultaneously, and the positive drug is P5091 ( Cancer Cell 2012, 22, 345-358). 5 replicate wells in each group; place the 96-well plate in a 37°C, 5% CO ₂ incubator for 72 hours; add 10 μL CCK-8 solution to each well, incubate the culture plate in the incubator for 4 hours, and measure it with a microplate reader The OD value at 450nm, the inhibition rate was calculated and the IC ₅₀ value was calculated.

4. Experimental results: the inhibitory activity (IC ₅₀ ) of the compound of the present invention on the proliferation of human multiple myeloma RPMI-8226 cell line in vitro is shown in the table below.

compound _IC50 (μM) compound _IC50 (μM) compound _IC50 (μM) compound _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 1-22 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

The above test results show that the compounds of the present invention have different degrees of inhibitory effects on the growth of multiple myeloma cells, and it is particularly surprising that some compounds have stronger anti-tumor activity than the positive drug P5091. This result suggests that the compound of the present invention can be used to prepare antitumor drugs.

The compounds of the invention and their compositions can be used to prepare antitumor drugs. The tumors include but are not limited to the following:

Bone cancers, including, for example: sarcoma of bone origin (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant Giant cell tumor chordoma, osteochondroma (Gu hose type exostoses), benign chondroma, chondroblastoma, cartilaginous and tumor-like fibroma, osteoid osteoma and giant cell tumor.

Hematological cancers, including (for example): blood cancers such as acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndromes , Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.

Cancers of the nervous system, including, for example: cancers of the skull, such as bone cancer, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, such as meningioma, meningosarcoma, and glioma; Glioblastoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma , retinoblastoma, and congenital tumors; and spinal tumors such as neurofibromas, meningiomas, gliomas, and sarcomas.

Gastrointestinal neoplasms, including (for example): cancers of the esophagus, such as squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, such as tumors, lymphomas, and leiomyosarcoma; Glucagonomas, gastrinomas, carcinoid tumors, and vasoactive intestinal peptide tumors; small bowel cancers such as adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, Neurofibromas and fibromas; colorectal cancers such as adenocarcinoma, tubular adenocarcinoma, villous adenoma, hamartoma, and leiomyoma.

Cancers of the urological system, including (for example): renal cancers such as adenocarcinoma, Wilms tumor (Wilms tumor), lymphomas and leukemias; bladder and urethral 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 carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma tumors and lipomas.

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; pulmonary chondromatous malformation Tumors and mesotheliomas.

Liver cancer, including, for example: hepatocellular carcinoma, such as hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma and hemangioma.

Skin cancers, including, for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis.

The present invention also provides a pharmaceutical composition for preventing and treating tumors, which contains a therapeutically effective amount of the compound of formula I or II or its nitrogen oxide, pharmaceutically acceptable salt or solvate as an active ingredient and pharmaceutically acceptable Carrier. The pharmaceutical composition can be in the form of common pharmaceutical preparations such as ordinary tablets or capsules, sustained-release tablets or capsules, controlled-release tablets or capsules, granules, powders, syrups, oral liquids, and injections.

The dose of the compound of formula I or II or its nitrogen oxide, pharmaceutically acceptable salt or solvate in the pharmaceutical composition of the present invention varies with symptoms and age. For adults, during oral administration, the lower limit of one dose is 0.1 mg (preferably 1 mg), and the upper limit is 1000 mg (preferably 500 mg); during intravenous administration, the lower limit of one dose is 0.01 mg (preferably 0.1 mg), the upper limit is 500 mg (preferably 250 mg). Deviations from this dosage range can also be made according to the degree of the disease and the difference in the dosage form.

The compounds of the present invention may also be administered in combination with existing methods of treating cancer (for example, by chemotherapy, radiotherapy or surgery) when administered for therapy or prophylaxis. Therefore, the present invention also provides a method for treating cancer, comprising using a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form or preparation thereof to a patient, and simultaneously administering to the patient a therapeutically effective amount of one or more other cancer chemotherapeutic agents. For any particular patient, the particular drug 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 patient's age, Body weight, general health, sex and diet; timing of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment and similar factors well known in the medical art.

Examples of suitable chemotherapeutic agents include, but are not limited to, the following:

Alkylating agents: nitrogen mustards, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine, estramustine; ethyleneimines, thiotepa, imines Quinone; sulfonate and polyols, busulfan, dibromomannitol; nitrosoureas, cyclohexylnitrosourea, carmustine, pyrimidine nitrosourea, methyl cyclonitrosourea; triazene imidazoles , methazine; hydrazines, procarbazine.

Antimetabolites: pyrimidine antagonists, fluorouracil, cytarabine, furofluorouracil, bisfururouracil; purine antagonists, mercaptopurine, sodium sulfcaptopurine, azathioprine, thioguanine; folic acid antagonists, methotrexate , aminopterin.

Antitumor antibiotics: mitomycin C, bleomycin, actinomycin D, mithramycin, daunorubicin, doxorubicin, chromomycin A3, entomycin, neocarcinogen, anticancer Amycin, sudomycin.

Plant anticancer drugs: vincristine, colchicine, camptothecin, hydroxycamptothecin, cantharidin, indirubin.

Hormones: adrenocorticoids, prednisone, hydroprednisone, hydrocortisone, dexamethasone; estrogens, diethylstilbestrol, bromoacetylhexestrol; androgens and anabolic hormones, testosterone propionate, methyltestosterone, Nandrolone Phenylpropionate, Naphthoxydine, Tamoxifen.

Other types: cisplatin, interferon, L-asparaginase, hydroxyurea, propylimine, imimhydrazone, hematoporphyrin; immune agents.

detailed description

The content of the present invention is specifically described below by way of examples. In the present invention, the following examples are for better illustration of the present invention, and are not intended to limit the scope of the present invention.

Example 1

Preparation of 1-[5-(2,3-dichlorophenylthio)thiazol-2-yl]ethanone (I-1)

Add 2,3-dichlorothiophenol (120mg, 0.68mmol) and sodium methoxide (37mg, 0.68mmol) into dry methanol (6mL), and stir at room temperature for 20 minutes. 2-Acetyl-5-chlorothiazole (100mg, 0.48mmol) was added to the reaction solution, heated to 50°C, and the reaction solution continued to stir until the reaction was complete. The solvent was evaporated to dryness, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporation to dryness, the target compound (59 mg, yield 31%) was obtained by silica gel column chromatography. ¹ HNMR (CDCl ₃ , 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 C ₁₁ H ₇ NOS ₂ Cl ₂ +Nacacld 325.9244found 325.9246.

Example 2

Preparation of 1-[5-(3,4-dichlorophenylthio)thiazol-2-yl]ethanone (I-2)

The reaction steps refer to Example 1 to obtain the target compound (yield 26%). ¹ HNMR (CDCl ₃ , 500MHz) δ (ppm): 2.68 (s, 3H), 7.16-7.18 (m, 1H), 7.38-7.42 (m, 2H), 7.95 (s, 1H); ESI MSm/z 325.9 [M+Na] ⁺ ; HRMS for C _1m H ₇ NOS ₂ Cl ₂ +Na ccld 325.9244found 325.9246.

Example 3

Preparation of 1-[5-(2,6-dichlorophenylthio)thiazol-2-yl]ethanone (I-3)

The reaction steps refer to Example 1 to obtain the target compound (yield 43%). ¹ HNMR (CDCl ₃ , 500MHz): δ (ppm): 2.63 (s, 3H), 7.27-7.32 (m, 1H), 7.42-7.45 (m, 2H), 7.90 (s, 1H) ppm.ESIMS m/ z 303.9[M+H] ⁺ ; HRMS for C ₁₁ H ₇ NOS ₂ Cl ₂ +H cacld 303.9424found 303.9428.

Example 4

Preparation of 1-(5-chloro-4-nitrothiazol-2-yl)ethanone

The mixed solution of trifluoroacetic anhydride (6.3mL) and fuming nitric acid (2.1mL) was cooled to minus 20°C, stirred for 1 hour, and 2-acetyl-5-chlorothiazole (1.10g, 6.8mmol) was slowly added thereto trifluoroacetic anhydride (2 mL) solution. The reaction solution was continuously stirred at minus 20° C. for 2 hours. The reaction solution was concentrated, poured into ice water, extracted with ether, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporation to dryness, silica gel column chromatography gave a yellow solid (0.98 g, yield 73%). ¹ HNMR (CDCl ₃ , 300MHz): δ(ppm): 2.72(s, 3H); ESI MS m/z 204.9[MH] ⁺ ; HRMS for C ₅ H ₃ N ₂ O ₃ SCl-H cacld 204.9475found 204.9477.

Example 5

Preparation of 1-[5-(2,3-dichlorophenylthio)-4-nitrothiazol-2-yl]ethanone (I-4)

2,3-Dichlorothiophenol (94 mg, 0.53 mmol), sodium methoxide (29 mg, 0.53 mmol) were added to dry methanol (5 mL), and stirred at room temperature for 20 minutes. Then 1-(5-chloro-4-nitrothiazol-2-yl)ethanone (100 mg, 0.48 mmol) was added to the reaction solution, and stirring was continued at room temperature for 4 hours. The solvent was evaporated to dryness, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The target compound (129 mg, yield 76%) was obtained by silica gel column chromatography after spin-drying. ¹ HNMR (CDCl ₃ , 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 C ₁₁ H ₆ N ₂ O ₃ S ₂ Cl ₂ +Na ccld 370.9095found 370.9097.

Example 6

Preparation of 1-[5-(3,4-dichlorophenylthio)-4-nitrothiazol-2-yl]ethanone (I-5)

The reaction steps refer to Example 5 to obtain the target compound (yield 76%). ¹ HNMR (CDCl ₃ , 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 C ₁₁ H ₆ N ₂ O ₃ S ₂ Cl ₂ +Na ccld 370.9095found 370.9096.

Example 7

Preparation of 1-[5-(2,6-dichlorophenylthio)-4-nitrothiazol-2-yl]ethanone (I-6)

The reaction steps refer to Example 5 to obtain the target compound (yield 88%). ¹ HNMR (CDCl ₃ , 300MHz) δ (ppm): 2.67 (s, 3H), 7.46-7.59 (m, 3H); ESI MS m/z 371.0[M+Na] ⁺ ; HRMS for C ₁₁ H ₆ N ₂ O ₃ S ₂ Cl ₂ +Na ccld 370.9095found 370.9096.

Example 8

Preparation of 1-[5-(2,4-dichlorophenylthio)-4-nitrothiazol-2-yl]ethanone (I-7)

The reaction steps refer to Example 5 to obtain the target compound (yield 76%). ¹ HNMR (CDCl ₃ , 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 = 9 Hz); ESI MS m/z 370.9 [M+Na] ⁺ ; HRMS for C ₁₁ H ₆ N ₂ O ₃ S ₂ Cl ₂ +Na ccld370.9095found 370.9098.

Example 9

Preparation of 1-[5-(3,5-dichloropyridyl-4-thioxo)-4-nitrothiazol-2-yl]ethanone (I-8)

The reaction steps refer to Example 5 to obtain the target compound (50% yield). ¹ HNMR (CD ₃ OD, 300MHz) δ (ppm): 2.62(s, 3H), 8.84(s, 2H); ESI MS m/z 371.9[M+Na] ⁺ ; HRMS for C ₁₀ H ₅ N ₃ O ₃ S ₂ Cl ₂ +Na ccld 371.9047found 371.9049.

Example 10

Preparation of 1-[5-(3-methoxyphenylthio)-4-nitrothiazol-2-yl]ethanone (I-9)

The reaction steps refer to Example 5 to obtain the target compound (yield 88%). ¹ HNMR (CDCl ₃ , 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/z333 .0[M+Na] ⁺ ; HRMS for C ₁₂ H ₁₀ N ₂ O ₄ S ₂ +Na ccld 332.9980found 332.9983.

Example 11

Preparation of 1-[5-(3,4-dimethoxyphenylthio)-4-nitrothiazol-2-yl]ethanone (I-10)

The reaction steps refer to Example 5 to obtain the target compound (yield 32%). ¹ HNMR (CDCl ₃ , 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 C ₁₃ H ₁₂ N ₂ O ₅ S ₂ +H cacld341.0266found 341.0269.

Example 12

The preparation reaction steps of 1-[5-(4-nitrophenylthio)-4-nitrothiazol-2-yl]ethanone (I-11) refer to Example 5 to obtain the target compound (yield 90% ). ¹ HNMR (CDCl ₃ , 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 C ₁₁ H ₇ N ₃ O ₅ S ₂ +H ccld.325.9905found 325.9907.

Example 13

Preparation of 1-[5-(3,4-dichlorobenzylamino)-4-nitrothiazol-2-yl]ethanone (I-12)

3,4-Dichlorobenzylamine (128 mg, 0.73 mmol), 1-(5-chloro-4-nitrothiazol-2-yl)ethanone (100 mg, 0.48 mmol) were dissolved in isopropanol (2 mL), Heat to reflux. After the reaction, the solvent was evaporated to dryness, and the target compound (77 mg, yield 46%) was obtained by silica gel column chromatography. ¹ HNMR (CDCl ₃ , 300MHz) δ(ppm): 2.61(s, 3H), 4.58(d, 2H, J=6Hz), 7.2l(d, 1H, J=9Hz), 7.45-7.48(m, 2H ), 8.76 (brs, 1H); ESI MS m/z 346.0[M+H] ⁺ ; HRMS for C ₁₂ H ₉ Cl ₂ N ₃ O ₃ +H cacld.345.9820found345.9823.

Example 14

Preparation of 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]ethanol (I-13)

Sodium borohydride (11mg, 0.29mmol), 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]ethanone (100mg, 0.29mmol) Add methanol (2 mL), and stir at room temperature for 1 hour. Water was added to quench and the solvent was concentrated, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After spin-drying, the target compound (78 mg, yield 78%) was obtained by silica gel column chromatography. ¹ HNMR (CDCl ₃ , 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 C ₁₀ H ₇ Cl ₂ N ₃ O ₃ S ₂ +H calcd. 351.9384found 351.9387.

Example 15

Preparation of ethyl 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]acetate (I-14)

1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]ethanol (100mg, 0.28mmol), acetic anhydride (58mg, 0.57mmol), 4 -Dimethylaminopyridine (3 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL). Stir at room temperature for 1 hour, add water, extract with dichloromethane, combine organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate. After being spin-dried, the target compound (104 mg, 93%) was obtained by silica gel column chromatography. ¹ HNMR (CDCl ₃ , 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 . _{393.9490found 393.9495} .

Example 16

Preparation of ethyl 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]chloroacetate (I-15)

Referring to Example 15 for the reaction steps, the target compound was obtained (57% yield). ¹ HNMR (CDCl ₃ , 300MHz) δ (ppm): 1.72(d, 3H, J=7Hz), 4.10(s, 2H), 6.05(q, 1H, J=7Hz), 8.74(s, 2H); ESI MSm/z 427.9[M+H] ⁺ ; HRMS for C ₁₂ H ₈ Cl ₃ N ₃ O ₄ S ₂ +H calcd. 427.9100found 427.9104.

Example 17

Preparation of ethyl 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]propionate (I-16)

The reaction steps refer to Example 15 to obtain the target compound (yield 92%). ¹ HNMR (CDCl ₃ , 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).

Example 18

Preparation of ethyl 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]butanoate (I-17)

The reaction steps refer to Example 15 to obtain the target compound (yield 85%). ¹ HNMR (CDCl ₃ , 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 C ₁₄ H ₁₃ Cl ₂ N ₃ O ₄ S ₂ +Hcalcd.421.9803found 421.9807.

Example 19

Preparation of ethyl 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]benzoate (I-18)

The reaction steps refer to Example 15 to obtain the target compound (yield 78%). ¹ HNMR (CDCl ₃ , 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 C ₁₇ H ₁₁ Cl ₂ N ₃ O ₄ S ₂ +H calcd. 455.9646found 455.9649.

Example 20

Preparation of 1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]-N-methylethylamine (I-19)

Dissolve 1-[5-(3,4-dichlorobenzylamino)-4-nitrothiazol-2-yl]ethanone (80 mg, 0.23 mmol) in dichloromethane (1 mL), add dimethylamine (2M THF solution, 0.9mL, 1.82mmol), adding acetic acid to adjust the pH to 5-6. The reaction solution was stirred at room temperature until the starting material disappeared, then sodium cyanoborohydride (29 mg, 0.45 mmol) was added, and stirred at room temperature for 1 hour. Add water to quench, extract with dichloromethane, combine organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate. After spin-drying, silica gel column chromatography obtained the target compound (27 mg, yield 32%). ¹ HNMR (CDCl ₃ , 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/z 365.1 [M+H] ⁺ ; HRMS for C ₁₁ H ₁₀ Cl ₂ N ₄ O ₂ S ₂ +H calcd. 364.9700 found 364.9703.

Example 21

Preparation of N-benzyl-1-[5-(3,5-dichloropyridyl-4-thio)-4-nitrothiazol-2-yl]ethylamine (I-20)

The reaction steps refer to Example 20 to obtain the target compound (yield 61%). ¹ H NMR (CDCl ₃ , 500 MHz) 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 C ₁₇ H ₁₄ Cl ₂ N ₄ O ₂ S ₂ +H calcd. 441.0013 found 441.0016.

Example 22

Preparation of 1-[2-(2,3-dichlorophenylthio)-thiazol-5-yl]ethanone (II-1)

2,3-Dichlorothiophenol (120 mg, 0.68 mmol), sodium methoxide (37 mg, 0.68 mmol) were added to dry methanol (6 mL), and stirred at room temperature for 20 minutes. Then, 2-chloro-5-acetylthiazole (100 mg, 0.48 mmol) was added to the reaction liquid, and stirred at room temperature until the reaction was complete. The solvent was evaporated to dryness, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporation to dryness, the target compound (129 mg, yield 69%) was obtained by silica gel column chromatography. ¹ HNMR (CDCl ₃ , 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 C ₁₁ H ₇ Cl ₂ NOS ₂ +H calcd. 303.9424found 303.9427.

Example 23

Preparation of 1-[2-(3,4-dichlorophenylthio)-thiazol-5-yl]ethanone (II-2)

The reaction steps refer to Example 22 to obtain the target compound (yield 70%). ¹ HNMR (CDCl ₃ , 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 C ₁₁ H ₇ Cl ₂ NOS ₂ +Hcalcd.303.9424found 303.9427.

Example 24

Preparation of 1-[2-(2,6-dichlorophenylthio)-thiazol-5-yl]ethanone (II-3)

The reaction steps refer to Example 22 to obtain the target compound (yield 58%). ¹ HNMR (CDCl ₃ , 500MHz) δ (ppm): 2.49 (s, 3H), 7.39-7.42 (m, 1H), 7.52-7.53 (m, 2H), 8.10 (s, 1H).ESIMS m/z 303.9 [M+H] ⁺ ; HRMS for C ₁₁ H ₇ Cl ₂ NOS ₂ +H calcd.303.9424 found303.9427.

Example 25

Preparation of 1-[2-(2,4-dichlorophenylthio)-thiazol-5-yl]ethanone (II-4)

The reaction steps refer to Example 22 to obtain the target compound (yield 69%). ¹ HNMR (CDCl ₃ , 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 C ₁₁ H ₇ Cl ₂ NOS ₂ +Hcalcd.303.9424 found 303.9427.

Example 26

Preparation of 1-[2-(3-methoxyphenylthio)-thiazol-5-yl]ethanone (II-5)

The reaction steps refer to Example 22 to obtain the target compound (yield 71%). ¹ HNMR (CDCl ₃ , 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 C ₁₂ H ₁₁ NO ₂ S ₂ +H calcd.266.0309found 266.0311.

Example 27

Preparation of 1-[2-(3,4-dimethoxyphenylthio)-thiazol-5-yl]ethanone (II-6)

The reaction steps refer to Example 22 to obtain the target compound (yield 69%). ¹ HNMR (CDCl ₃ , 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 C ₁₃ H ₁₃ NO ₃ S ₂ +H calcd.296.0415 found 296.0417.

Example 28

Preparation of 1-[2-(4-nitrophenylthio)-thiazol-5-yl]ethanone (II-7)

The reaction steps refer to Example 22 to obtain the target compound (yield 87%). ¹ HNMR (CDCl ₃ , 500MHz) δ (ppm): 2.53 (s, 3H), 7.78 (m, 2H), 8.18 (s, 1H), 8.27 (m, 2H); ESI MS m/z281.0 [M +H] ⁺ ; HRMS for C ₁₁ H ₈ N ₂ O ₃ S ₂ +H calcd.281.0055 found 281.0057.

Example 29

Preparation of ]-[2-(3,5-dichloropyridyl-4-thio)-thiazol-5-yl]ethanone (II-8)

The reaction steps refer to Example 22 to obtain the target compound (yield 43%). ¹ HNMR (CDCl ₃ , 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 C ₁₀ H ₆ N ₂ OS ₂ +H calcd. 304.9377 found 304.9381.

Example 30

Preparation of 2,5-dibromo-4-nitrothiazole

Fuming nitric acid (13 mL) was added into trifluoroacetic anhydride (40 mL) at -20°C, and stirred at -20°C for 2 h. At the same temperature, slowly drop 2,5-dibromothiazole (14 g) into the reaction solution, and stir overnight at -20°C. The solvent was evaporated to dryness, water (100 mL) was slowly added, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ , the solvent was evaporated to dryness, beating with petroleum ether, and filtered to obtain 3.34 g of crude light yellow solid (yield 20%). ESI MS m/z 289.0[M+H] ⁺

Example 31

Preparation of 2-bromo-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole (I-21)

Dissolve 3,5-dichloro-4-mercaptopyridine (2.3g, 1.1eq) in 50mL of commercially available anhydrous methanol, add sodium methoxide (690mg, 1.1eq), stir at 40°C for 2h, add 2,5-di Bromo-4-nitrothiazole (3.34g), stirred at 40°C for 2.5h, evaporated to dryness, added 50mL of water, extracted with ethyl acetate, dried _over anhydrous _Na2SO4 , evaporated to dryness, and obtained the target by silica gel column chromatography Compound 2.57g (yield 83%). ¹ HNMR (CDCl ₃ , 300MHz) δ (ppm): 8.73 (s, 2H); ESI MS m/z 385.6 [M+H] ⁺

Example 32

Preparation of 5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-22)

2-Bromo-5-(3,5-dichloropyridyl)mercapto-4-nitrothiazole (100 mg) was dissolved in DMF (1 mL, analytical grade), and cuprous cyanide (41.6 mg, 1.8 eq) was added , stirred at 120°C (the oil bath was preheated in advance) for 1.5h, cooled to room temperature, added ethyl acetate (20mL) and stirred thoroughly, filtered to remove the precipitate, washed the organic phase twice with water, dried over anhydrous Na ₂ SO ₄ , evaporated to dryness, Methanol was added for shaking, and 30 mg of light yellow solid was obtained by filtration. (Yield 33%). ¹ HNMR (DMSO, 300MHz) δ (ppm): 8.95 (s, 2H), 8.52 (s, 1H), 8.17 (s, 1H); ESI MS m/z 349.1 [MH] ^-

Example 33

Preparation of N-methyl-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-23)

5-(3,5-dichloro-4-pyridyl)mercapto-4-nitrothiazole-2-carboxylic acid (100 mg) was suspended in MeCN (5 mL), and phosphorus oxychloride (0.037 mL, 1 .Seq), stirred at room temperature for 30min, added methylamine hydrochloride (22mg, 1.1eq) under ice-cooling, added dropwise diisopropylethylamine (0.237mL, 5eq), stirred at room temperature for 1.5h after completion, evaporated to dryness, Add ice water (15 mL), filter the obtained precipitate and wash twice with ether to obtain 22 mg of white powder (yield 21%). ¹ HNMR (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[ MH] ^-

Example 34

Preparation of N, N-diethyl-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-24)

5-(3,5-dichloro-4-pyridyl)mercapto-4-nitrothiazole-2-carboxylic acid (100mg) was suspended in MeCN (5mL), and phosphorus oxychloride (0.037mL, 1.5 eq), stirred at room temperature for 30min, added diethylamine hydrochloride (35mg, 1.1eq) under ice bath, added dropwise diisopropylethylamine (0.237mL, 5eq), stirred at room temperature overnight after completion, evaporated to dryness, added Ice water (15 mL) was placed at 0°C for crystallization, and the resulting precipitate was filtered and purified by preparative column chromatography to obtain 18 mg of white powder (yield 16%). ¹ HNMR (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] ⁺

Example 35

N-(1-methylpiperidin-4-yl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-25) preparation

Suspend 5-(3,5-dichloro-4-pyridyl)mercapto-4-nitrothiazole-2-carboxylic acid (50mg) in 3mL MeCN, add phosphorus oxychloride (0.02mL, 1.5eq) dropwise at room temperature , stirred at room temperature for 30min, added N-methyl-4-aminopiperidine (17.8mg, 1.1eq) under ice-cooling, added dropwise diisopropylethylamine (0.117mL, 5eq), stirred at room temperature for 1.5h after completion, evaporated Dry the solvent, add ice water (15mL), adjust the pH to 7 with saturated NaHCO ₃ , extract with ethyl acetate, wash with water, dry with anhydrous Na ₂ SO ₄ , evaporate the solvent to dryness, add diethyl ether to mash, filter the obtained solid and wash with diethyl ether , to obtain 30 mg of yellow powder (yield 47%). ¹ H NMR (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[MH] ^-

Example 36

Preparation of N-phenyl-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-26)

The reaction steps refer to Example 33 to obtain the target compound (yield 8%). ¹ HNMR (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[MH] ^-

Example 37

Preparation of N-benzyl-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-27)

5-(3,5-dichloro-4-pyridyl)mercapto-4-nitrothiazole-2-carboxylic acid (80 mg) was suspended in MeCN (3 mL), and phosphorus oxychloride (0.03 mL, 1.5 eq), add benzylamine (26.8mg, 1.1eq) under ice-cooling, drop diisopropylethylamine (0.19mL, 5eq), stir at room temperature overnight after completion, evaporate the solvent to dryness, add 15mL ice water, ethyl acetate Extracted, washed 5 times with 1N HCl, dried over anhydrous Na ₂ SO ₄ , evaporated to dryness, added diethyl ether and triturated to obtain 25 mg of light yellow powder (yield 25%). ¹ HNMR (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 MSm/z 438.8[MH] ^-

Example 38

Preparation of N-phenethyl-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-28)

The reaction steps refer to Example 37 to obtain the target compound (yield 22%). ¹ H NMR (DMSO, 300MHz) δ (ppm): 9.28 (s, 1H), 8.96 (s, 2H), 7.19 (s, 3H), 2.94 (s, 1H), 2.73 (s, 1H); ESIMS m/ z455.3[M+H] ⁺

Example 39

Preparation of N-(4-methoxyphenyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-29)

The reaction steps refer to Example 37 to obtain the target compound (yield 8%). ¹ HNMR (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[MH] ^-

Example 40

N-(3,4-dimethoxyphenyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-30) preparation

The reaction steps refer to Example 37 to obtain the target compound (yield 8%). ¹ H NMR (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 [MH] ^-

Example 41

N-(3-chloro-4-methoxyphenyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-31) preparation of

The reaction steps refer to Example 37 to obtain the target compound (yield 29%). ¹ H NMR (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[MH] ^-

Example 42

Preparation of N-(3-methoxyphenyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-32)

The reaction steps refer to Example 37 to obtain the target compound (yield 29%). ¹ H NMR (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] ⁺

Example 43

Preparation of N-(2-methoxyphenyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-33)

The reaction steps refer to Example 37 to obtain the target compound (yield 13%). ¹ H NMR (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[MH] ^-

Example 44

N-(6-methoxypyridin-3-yl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-34) preparation

The reaction steps refer to Example 37 to obtain the target compound (yield 13%). ¹ H NMR (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 MSm/z455.9[MH] ^-

Example 45

N-[4-(3-dimethylaminopropoxy)phenyl]-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide ( I-35) Preparation

The reaction steps refer to Example 37 to obtain the target compound (yield 22%). ¹ HNMR (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, 6.4

Hz, 1H); ESI MS m/z 526.1[MH] ^-

Example 46

Preparation of N-(4-hydroxybenzyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-36)

The reaction steps refer to Example 37 to obtain the target compound (yield 26%). ¹ H 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); ESIMS m/z455.03[MH] ^-

Example 47

Preparation of N-(4-methylbenzyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-37)

The reaction steps refer to Example 37 to obtain the target compound (yield 23%). ¹ H 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] ⁺

Example 48

Preparation of N-(4-chlorobenzyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-38)

The reaction steps refer to Example 37 to obtain the target compound (yield 43%). ¹ H 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[MH] ^-

Example 49

Preparation of N-(4-fluorobenzyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-39)

The reaction steps refer to Example 37 to obtain the target compound (yield 48%). ¹ H 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=8.8 Hz, 2H), 4.36 (d, J=6.1Hz, 2H); ESI MS m/z457.0[MH] ^-

Example 50

Preparation of N-(3-fluorobenzyl)-5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-40)

The reaction steps refer to Example 37 to obtain the target compound (yield 51%). ¹ H 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] ^-

Example 51

{5-[(3,5-dichloro-4-pyridyl)mercapto]-4-nitrothiazol-2-yl}[1,2,3,4-tetrahydroisoquinolin-2-yl]ketone Preparation of (I-41)

The reaction steps refer to Example 37 to obtain the target compound (yield 44%). ¹ H 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/z 479.1[MH] ^-

Example 52

Preparation of N-{5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazol-2-yl}acetamide (I-42)

Step 1. Preparation of N-methoxycarbonyl-5-bromo-2-aminothiazole

200 mg of 5-bromo-2-aminothiazole was suspended in 10 mL of MeCN. 0.26mL methyl chloroformate (3eq) and 0.46mL triethylamine (3eq) were added dropwise at room temperature, stirred at room temperature for 3h, and the solvent was evaporated to dryness. Dissolve the obtained product in 2 mL of concentrated sulfuric acid, add 350 mg KNO ₃ (about 1.5 eq) in batches under ice bath, stir at 0°C for 3 h, pour the reaction solution into ice water, extract with ethyl acetate, wash with saturated NaHCO ₃ , dry Dry over Na ₂ SO ₄ , evaporate the solvent to dryness, and purify by preparative column chromatography (PE:EA 3:1) to obtain 80 mg of the target compound.

Step 2. Preparation of N-{5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazol-2-yl}acetamide

Dissolve 56mg of 3,5-dichloro-4-mercaptopyridine (crude product, about 1.1eq) in 3mL of anhydrous methanol, add 17mg of sodium methoxide (about 1.1eq), stir at 40°C for 30min, cool to room temperature, add 80mg of N- Methyl (5-bromo-4-nitro-2-thiazolyl)carbamate overnight at room temperature. The solvent was evaporated to dryness, 15 mL of water was added, extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ , and purified by preparative column chromatography (petroleum ether: ethyl acetate 5:1) to obtain 50 mg of the target compound with a yield of 12%. ¹ H NMR (300MHz, DMSO) δ12.28(s, 1H), 8.90(s, 2H), 4.75(s, 3H); ESI MS m/z403.2[M+Na] ⁺

Example 53

N-{5-[(3,5-dichloropyridin-4-yl)mercapto]-4-nitrothiazol-2-yl}propionamide (I-43)

The reaction steps refer to Example 53 to obtain the target compound (yield 8%). ¹ H 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/z 417.0[M+Na] ⁺

Example 54

Preparation of 1-[5-(2,4-difluorophenylthio)-4-nitrothiazol-2-yl]ethanone (I-44)

The reaction steps refer to Example 1 to obtain the target compound (yield 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] ⁺

Example 55

Preparation of 2-bromo-5-(2,4-difluorophenylmercapto)-4-nitrothiazole

The reaction steps refer to Example 31 to obtain the target compound (yield 66.4%). ¹ H 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 ).

Example 56

5-[(2,4-Difluoropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-45)

Using 2-bromo-5-(2,4-difluorophenylmercapto)-4-nitrothiazole as the raw material, the reaction procedure was referred to Example 32 to obtain the target compound (yield 25%). ¹ H 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).

Example 57

N-phenyl-5-[(2,4-difluoropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-46)

Using 5-[(2,4-difluoropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide as raw material, the reaction steps refer to Example 37. The target compound was obtained (total yield 14%). ¹ H 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).

Example 58

N-Benzyl-5-[(2,4-difluoropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide (I-47)

Using 5-[(2,4-difluoropyridin-4-yl)mercapto]-4-nitrothiazole-2-carboxamide as raw material, the reaction steps refer to Example 37. The target compound was obtained (total yield 4%). ¹ H 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).

Example 59

tablet

Compound I-7 (50g) prepared in Example 8, hydroxypropylmethylcellulose E (150g), starch (200g), an appropriate amount of povidone K30 and magnesium stearate (1g) were mixed, granulated, Tablets.

Claims (9)

1. the compound shown in formula I or II or its nitrogen oxides, pharmaceutically acceptable salt or solvate:

Wherein:

X is H, NO₂, halogen, CN ,-SCF₃Or-SO₂CF₃；

Y is S, NH, NHCH₂, O, SO or SO₂；

R₁Represent one or more Z₁Substituted aryl or heteroaryl, wherein, Z₁Selected from halogen, itrile group, nitro, trifluoromethyl Or-OR₃；

R₂For-COR₄、-CONR₅R₆, the Z of 1～6 carbon₂Substituted alkyl or halogen；

R₃And R₄It is the alkyl of 1～10 carbon, substituted alkyl, aryl or substituted aryl；

R₅、R₆Independently selected from hydrogen atom, the alkyl of 1～10 carbon or replace alkyl, non-substituted or one or more Z₃Take The aryl in generation or heteroaryl, or R₅、R₆4～8 yuan of heterocyclic radicals are formed together with non-substituted or substituted atom N；

Z₂For-OH ,-OCOR₇Or-NR₅R₆；

Z₃For halogen or-OR₈；

R₇It is alkyl or the replacement alkyl of 1～6 carbon；

R₈It is alkyl or one or more Z of 1～6 carbon of 1～6 carbon₄Substituted alkyl；

Z₄For-NR₉R₁₀Or-OR₁₁；

R₉、R₁₀Independently selected from hydrogen atom, the alkyl of 1～6 carbon or replacement alkyl or R₉、R₁₀Form one 3～8 together Unit's cycloalkyl or R₉、R₁₀4～8 yuan of Heterocyclylalkyls are formed together with non-substituted or substituted atom N；

R₁₁For hydrogen atom or the alkyl of 1～6 carbon.

2. compound as claimed in claim 1, it is characterised in that in described Formulas I or Formula II compound:

X preferred H, NO₂Or CN；

Y preferred S, O, NH or NHCH₂；

R₁The most one or more Z₁Substituted phenyl or pyridine radicals, wherein, Z₁Preferably halogen, itrile group or nitro；

R₂Preferably-COR₄Or-CONR₅R₆, wherein, R₄It is preferably the alkyl of 1～6 carbon；R₅、R₆Independently selected from hydrogen atom Or one or more Z₃Substituted phenyl or pyridine radicals, wherein, Z₃As defined in claim 1.

3. compound as claimed in claim 1, it is characterised in that described Formulas I or Formula II compound include following compound:

1-[5-(2,3-dichlorophenyl sulphur generation) thiazol-2-yl] ethyl ketone；

1-[5-(3,4-dichlorophenyl sulphur generation) thiazol-2-yl] ethyl ketone；

1-[5-(2,6-dichlorophenyl sulphur generation) thiazol-2-yl] ethyl ketone；

1-[5-(2,3-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(3,4-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(2,6-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(2,4-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(3-methoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(3,4-dimethoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(4-nitrobenzophenone sulphur generation)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(3,4-dichlorobenzyl amino)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethanol；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl acetate；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl chloroacetate；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl propionate；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl butyrate；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl benzoate；

1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base]-N-methyl ethyl-amine；

N-benzyl-1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethamine；

1-[2-(2,3-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone；

1-[2-(3,4-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone；

1-[2-(2,6-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone；

1-[2-(2,4-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone；

1-[2-(3-methoxyphenylthio)-thiazole-5-base] ethyl ketone；

1-[2-(3,4-dimethoxyphenylthio)-thiazole-5-base] ethyl ketone；

1-[2-(4-nitrobenzophenone sulphur generation)-thiazole-5-base] ethyl ketone；

1-[2-(3,5-dichloropyridine base-4-sulphur generation)-thiazole-5-base] ethyl ketone；

The bromo-5-of 2-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole；

5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-methyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N, N-diethyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(1-methyl piperidine-4-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-phenyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-benzyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-phenethyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(4-methoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(3,4-Dimethoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(3-chloro-4-methoxy phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(3-methoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(2-methoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(6-methoxypyridine-3-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-[4-(3-dimethylamino propoxyl group) phenyl]-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(4-hydroxybenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(4-methyl-benzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(4-chlorobenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(4-luorobenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-(3-luorobenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

{ 5-[(3,5-bis-chloro-4-pyridine radicals) sulfydryl]-4-nitrothiazole-2-base } [1,2,3,4-tetrahydroisoquinoline-2-base] ketone；

N-{5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-base } acetamide；

N-{5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-base } propionamide；

1-[5-(2,4-difluorophenylthio)-4-nitrothiazole-2-base] ethyl ketone；

5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-phenyl-5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-benzyl-5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-benzyl-5-[(2,6-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

N-benzyl-5-[(2,3-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

1-[5-(2,3-difluorophenylthio)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(2,6-difluorophenylthio)-4-nitrothiazole-2-base] ethyl ketone；

1-[5-(2-fluoro-4-chlorophenylthio)-4-nitrothiazole-2-base] ethyl ketone；

N-benzyl-5-[(2-fluoro-4-chloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide；

1-[5-(2,4-difluorophenylthio)-4-nitrothiazole-2-base] acetone.

4. the preparation method of compound described in claim 1, shown in following reaction equation:

Specifically include following steps:

(1) compound III prepares formula IV compound through nitration reaction；

(2) compound IV and R₁YH occurs nucleophilic substitution to prepare compound I-b；

In above-mentioned reaction equation, R₁、R₄As defined in claim 1 with Y.

5. the preparation method of compound described in claim 1, shown in following reaction equation:

Specifically include following steps:

(1) compound VI carries out nitration reaction and prepares Formula VII compound；

(2) compound VII and R₁YH occurs nucleophilic substitution to prepare compound VIII；

(3) compound VIII Yu CuCN reacts and obtains compound IX；

(4) compound IX and nitrous acid hydrochlorate occur diazol hydrolysis to obtain compounds X in acid flux material；

(5) compounds X and R₅R₆NH reacting generating compound I-f；

In above-mentioned reaction equation, R₁、R₅、R₆As defined in claim 1 with Y.

6. the Formulas I of claim 1 or Formula II compound or its nitrogen oxides, pharmaceutically acceptable salt or solvate are pre-in preparation Prevent or treat the application in tumor disease medicine.

Purposes the most according to claim 6, it is characterised in that be for preparing prevention or the medicine for the treatment of Huppert's disease disease Thing.

8. a prevention or the pharmaceutical composition for the treatment of tumor disease, it is characterised in that in described pharmaceutical composition containing treatment effectively The Formulas I of amount or II compound or its nitrogen oxides, pharmaceutically acceptable salt or solvate as active ingredient and pharmaceutically may be used The carrier accepted.

Pharmaceutical composition the most according to claim 8, it is characterised in that described pharmaceutical composition can be conventional tablet or capsule, Sustained-release tablet or capsule, Dospan or capsule, granule, powder, syrup, oral liquid or injection.