CN105884711A - Thiazole compounds, preparing method of thiazole compounds and application thereof in pharmacy - Google Patents
Thiazole compounds, preparing method of thiazole compounds and application thereof in pharmacy Download PDFInfo
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- CN105884711A CN105884711A CN201410796279.9A CN201410796279A CN105884711A CN 105884711 A CN105884711 A CN 105884711A CN 201410796279 A CN201410796279 A CN 201410796279A CN 105884711 A CN105884711 A CN 105884711A
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- nitrothiazole
- dichloropyridine
- sulfydryl
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Abstract
The invention discloses thiazole compounds or nitric oxide and medically-acceptable salt or solvate of the thiazole compounds, a preparing method of the thiazole compounds and application of the thiazole compounds in pharmacy, especially the application in tumor suppression. Pharmacodynamic experiment results show that the compounds in the general formulas I and II shown in the description have a remarkable tumor suppression effect and especially have a remarkable human multiple myeloma cell suppression effect. Thus, the compounds can be used for preparing medicine for preventing or treating diseases related to tumors.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to thiazole compound, its preparation method and prevent in preparation
Or the application in treatment tumor disease medicine.
Patent application claims Chinese patent application (application number 201410062371.2, the applying date: 2014
02 month 25 days, invention and created name: thiazole compound, its preparation method and the purposes in pharmacy thereof)
Priority.
Background technology
Malignant tumour is the major disease of serious threat human health.Tumour is to regulation with cell self
The wrong responses of the signals such as cell growth, differentiation, function and apoptosis is characterized.It is presently believed that most tumors is
The change of several genes and rear raw environment causes.Even if same type of tumour, its malignant cell group's kind
Also it is different, has different hereditary changes, and change along with advancing of disease.At present, in clinic
The antineoplastic of upper use includes cytotoxic drug, inhibitors of kinases, proteasome inhibitor, HDAC
Inhibitor, hedgehog inhibitor etc..
Heterocyclic compound containing thiazole ring has the biologically active of wide spectrum, such as local anaesthesia, anticonvulsion, antiviral, anti-
The effects such as bacterium, antitumor and desinsection.Many have the thiazolium compounds of antitumor activity all contain 2 free or
Substituted amino (US20130317218A1, WO2013082324A1, CN102964343A,
US20120225880A1, CN102070556A, WO2010083246A1, US20050234033A1,
WO2005035541A1, WO2004074283A1, WO 2000075120A1).Other 2 give electronics
Base also includes substituted sulfydryl (Bioorg Med Chem.21 (24): 7648-54) and methylene (Bioorg Med
Etc. Chem.20 (7): 2316-22).Additionally, thiazole 2,4 and 5 couplings have the anti-swollen of aromatic group
The little molecule of knurl also have been reported that (WO2011137219A1, EP2606889A1, WO2013082324A1,
EP2606889A1, US20120225880A1, WO2010083246A1).
By the anti-tumor i n vitro test of cellular level, it is our surprising discovery that a class with antitumor activity is novel
Thiazole compound.
Summary of the invention
The invention discloses the compound as 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, nitre
Base, 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
Or multiple Z3Substituted aryl or heteroaryl, or R5、R6Formed together with non-substituted or substituted atom N
One 4～8 yuan of heterocyclic radical；
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、R10Together
Form 3～8 yuan of cycloalkyl or R9、R10One is formed together with non-substituted or substituted atom N
4～8 yuan of Heterocyclylalkyls；
R11For hydrogen atom or the alkyl of 1～6 carbon.
In formula I or 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 nitre
Base；
R2Preferably-COR4Or-CONR5R6, wherein, R4It is preferably the alkyl of 1～6 carbon；R5、R6Independent
Ground is selected from hydrogen atom or one or more Z3Substituted phenyl or pyridine radicals, wherein, Z3As defined above.
In formula I and II compound, preferred compound is as follows:
It is a further object of the present invention to provide Formulas I and the preparation method of Formula II compound, shown in following reaction equation:
R1、R4、R5、R6、R7Defined in Formulas I above-mentioned with Y and Formula II compound.
Specifically include following steps:
(1) by compound III and R1YH occurs nucleophilic substitution to prepare compound I-a in the basic conditions,
The alkaline reagent used is selected from potassium carbonate, sodium carbonate, sodium methoxide, caustic alcohol, preferably sodium methoxide；Use is molten
Agent is methyl alcohol, ethanol, acetonitrile, preferably methyl alcohol；The reaction time used is 1-24 hour；Employing temperature is
Subzero 20 DEG C to 100 DEG C, preferably 50 DEG C to 70 DEG C.
(2) with compound III as initiation material, carry out nitration reaction and prepare formula IV compound, the nitrification of employing
Reagent is selected from fuming nitric aicd, red fuming nitric acid (RFNA), red fuming nitric acid (RFNA)/concentrated sulfuric acid, preferably fuming nitric aicd；The solvent used is selected from
Acetic anhydride, trifluoro-acetic anhydride, preferably trifluoro-acetic anhydride；The reaction time used is 1-24 hour；Use
Temperature is subzero 50 DEG C to 25 DEG C, the most subzero 25 DEG C to 0 DEG C.
(3) by compound IV and R1YH occurs nucleophilic substitution to prepare compound I-b.
(4) compound I-b occurs reduction reaction to prepare I-c, and the original reagent of going back of employing is selected from sodium borohydride, boron
Hydrofining, Lithium Aluminium Hydride, preferably sodium borohydride；The solvent selected from methanol of employing, ethanol, oxolane, excellent
Select methyl alcohol；The reaction time used is 1-10 hour；Using temperature is subzero 20 DEG C to 100 DEG C, preferably 0
DEG C to 50 DEG C.
(5) compound I-c occur esterification prepare compound I-d, the acylating reagent of employing selected from acid anhydrides,
Acyl chlorides, carboxylic acid, preferred anhydrides and acyl chlorides；The alkali used is selected from triethylamine, DMAP, potassium carbonate,
Preferably DMAP；The solvent used is selected from dichloromethane, chloroform, acetonitrile, preferably dichloromethane；
The reaction time used is 1-24 hour；Using temperature is subzero 20 DEG C to 100 DEG C, and preferably 25 DEG C to 100
℃。
(6) compound I-b occur reductive amination process prepare I-e, employing go back original reagent be sodium borohydride,
Sodium cyanoborohydride, sodium triacetoxy borohydride, preferably itrile group sodium borohydride；The solvent used is dichloromethane
Alkane, ethyl acetate, oxolane, preferably dichloromethane；The reaction time used is 1-24 hour；Use
Temperature is subzero 20 DEG C to 100 DEG C, preferably 25 DEG C to 50 DEG C.
(7) by compound V and R1YH occurs nucleophilic substitution to prepare compound II, the alkalescence examination of employing
Agent is selected from potassium carbonate, sodium carbonate, sodium methoxide, caustic alcohol, preferably sodium methoxide；The solvent used is methyl alcohol, second
Alcohol, acetonitrile, DMF, preferably methyl alcohol, DMF；During the reaction used
Between be 1-24 hour；Using temperature is subzero 20 DEG C to 100 DEG C, preferably 25 DEG C to 70 DEG C.
(8) with compound VI as initiation material, carry out nitration reaction and prepare Formula VII compound, the nitre of employing
Change reagent selected from fuming nitric aicd, red fuming nitric acid (RFNA), red fuming nitric acid (RFNA)/concentrated sulfuric acid, preferably fuming nitric aicd；The solvent choosing used
From acetic anhydride, trifluoro-acetic anhydride, preferably trifluoro-acetic anhydride；The reaction time used is 1-24 hour；Use
Temperature be subzero 50 DEG C to 25 DEG C, the most subzero 25 DEG C to 0 DEG C；
(9) by compound VII and R1YH occurs nucleophilic substitution to prepare compound VIII.
(10) compound VIII Yu CuCN reacts and obtains compound IX, and employing solvent is N, N-diformazan
Acid amides, dimethyl sulfoxide, pyridine, acetone, preferably N, N-diformamide；Using the reaction time is 1-12 hour；
Using temperature is 50 DEG C to 150 DEG C, preferably 120 DEG C to 140 DEG C.
(11) compound IX and nitrous acid hydrochlorate occur diazol hydrolysis to obtain compound in acid flux material
X, nitrite uses natrium nitrosum, potassium nitrite, calcium nitrite, preferably natrium nitrosum；The solvent used
For strong acid aqueous solution, preferably 80% aqueous sulfuric acid；Using the reaction time is 0.5-6 hour, and preferably 0.5 is little
Time；Using temperature is subzero 20 DEG C to 25 DEG C, preferably 25 DEG C.
(12) compounds X and R5R6NH is reacting generating compound I-f, acylating reagent under acylating reagent effect
Use chloroacetic chloride, chlorobenzoyl chloride, oxalyl chloride, chloracetyl chloride, trichloro-acetic chloride, POCl3, preferably trichlorine
Oxygen phosphorus；Selected solvent is acetonitrile, acetone, dichloromethane, chloroform, oxolane, ether, preferably acetonitrile；
The alkali used is triethylamine, diisopropylethylamine, pyridine, preferably diisopropylethylamine；Reaction time is 1-48
Hour, preferably 5-12 hour；Using temperature is subzero 20 DEG C to 50 DEG C, preferably 25 DEG C.
The preparation method of concrete Formulas I or Formula II compound is with reference to embodiment.
Formulas I or II compound or its nitrogen oxides, pharmaceutically acceptable are it is yet another object of the invention to provide
Salt or solvate purposes in the medicine of preparation prevention and treatment tumour.Pharmacodynamic experiment result shows, this
Invention Formulas I and II compound have significant anti-tumour cell proliferative effect.
Part pharmacological evaluation and the result of the compound of the present invention are presented herein below.
1. experiment purpose: use each compound of CCK-8 Determination Staining to people's multiple myeloma cells
The impact of RPMI-8226 in-vitro multiplication activity, and calculate respective half-inhibition concentration IC50。
2. experiment material: the compounds of this invention DMSO dissolves and is configured to mother liquor, uses front employing to train completely
Foster base is diluted to debita spissitudo；Reagent: CCK-8 kit is purchased from En Jing bio tech ltd, Nanjing；
Culture medium: RMPI-1640 culture medium is purchased from Gibco company；Hyclone: purchased from Gibco company；96
Porocyte culture plate is purchased from Costar company.
3. experimental technique: take live cell fraction and reach the cell of more than 90% and test.Cell inhibitory effect is tested
Use EnoGeneCellTMCounting Kit-8 (CCK-8) cell viability detection kit.Cell dissociation,
Counting, making concentration is 1 × 105The cell suspension of individual/ml, in 96 orifice plates, every hole adds 100 μ l cell suspensions
(every hole 1 × 104Individual cell)；96 orifice plates are placed in 37 DEG C, 5%CO2Incubator is cultivated 24 hours；It is finished
Full culture medium dilution medicine is to desired concn, and every hole adds the culture medium of the 100 corresponding drug containing of μ L, simultaneously
Setting up negative control group, Vehicle controls group, positive drug is P5091 (Cancer Cell 2012,22,345-358).
The often multiple hole of group 5；96 orifice plates are placed in 37 DEG C, 5%CO2Incubator is cultivated 72 hours；Every hole adds 10 μ L
CCK-8 solution, hatches culture plate in incubator 4 hours, measures the OD value at 450nm with ELIASA,
Calculate inhibiting rate and calculate IC50Value.
4. experimental result: the compounds of this invention is to people's Huppert's disease RPMI-8226 cell line in-vitro multiplication
Inhibitory activity (IC50) see table.
| 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 |
Above-mentioned test result shows, the growth of multiple myeloma cells is had in various degree by the compounds of this invention
Inhibitory action, especially it is surprising that part of compounds shows higher anti-more swollen than positive drug P5091
Tumor activity.This result prompting the compounds of this invention may be used for preparing antineoplastic.
Compound of the present invention and combinations thereof thing can be used for preparing antineoplastic.Described tumour include but not
Be limited to following these:
Osteocarcinoma, including (such as): osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma cell
Knurl, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), Huppert's disease, evil
Property giant-cell tumor chordoma, osteochondroma (turn round and look at hose epostoma), benign chondromas, chondroblast
Knurl, cartilage and knurl sample fibroma, osteoidosteoma and giant-cell tumor.
Hematology's cancer, including (such as): hematologic cancers, such as acute myelogenous leukemia, chronic myelognous
Leukaemia, acute lymphoblastic system leukaemia, chronic lymphocytic system leukaemia, myeloproliferative disease, many
Send out property myeloma and myelodysplastic syndrome, hodgkin's lymphomas (malignant lymphoma) and Walden this
Special human relations macroglobulinemia.
Nervous system cancer, including (such as): skull cancer, as osteocarcinoma, hemangioma, granulation knurl, vitiligoidea and
Osteitis deformans；Meninx cancer, such as meningioma, meningosarcoma and glioma；The cancer of the brain, as astrocytoma,
Medulloblastoma, glioma, ependymoma, gonioma (pinealoma), polymorphy become
Spongiocytoma, Oligodendroglioma, neurinoma, retinoblastoma and congenital tumor；
And spinal cord knurl, such as fibroneuroma, meningioma, glioma and sarcoma.
Stomach and intestine knurl, including (such as): esophagus cancer, such as squamous cell carcinoma, gland cancer, leiomyosarcoma and pouring
Bar knurl；Cancer of the stomach, such as tumour, lymthoma and leiomyosarcoma；Cancer of pancreas, such as duct adenocarcinoma, insulinoma, pancreas
Glucagonoma, gastrinoma, carcinoid tumor and vasoactive intestinal peptide tumor；Carcinoma of small intestine, as gland cancer, lymthoma,
Carcinoid tumor, Kaposi's sarcoma, liomyoma, hemangioma, lipoma, fibroneuroma and fibroma；Greatly
Intestinal cancer, such as gland cancer, tubule gland cancer, villous adenoma, hamartoma and liomyoma.
Urinary system cancer, including (such as): kidney, as gland cancer, wilms' tumor (nephroblastoma),
Lymthoma and leukaemia；Bladder and carcinoma of urethra, such as squamous cell carcinoma, transitional cell carcinoma and gland cancer；Prostate cancer,
Such as gland cancer and sarcoma；Carcinoma of testis, as seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma,
Sarcoma, interstitial cell cancer, fibroma, adenofibroma, adenomatoid tumor and lipoma.
Lung cancer, including (such as): bronchiolar carcinoma, as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated greatly
Cell cancer and gland cancer；Bronchioalveolar carcinoma；Bronchial adenoma；Sarcoma；Lymthoma；Chondroma of lung paramnesia
Knurl and celiothelioma.
Liver cancer, including (such as): hepatocellular carcinoma, such as hepatocellular carcinoma；Cholangiocarcinoma；Hepatoblastoma；Blood vessel
Sarcoma；Adenoma and hemangioma.
Cutaneum carcinoma, including (such as): chromoma, basal-cell carcinoma, squamous cell carcinoma, card ripple Ji Shi
Sarcoma, dysplasia mole, lipoma, hemangioma, histiocytoma, cheloid, psoriasis.
Present invention also offers a kind of prevention and the pharmaceutical composition for the treatment of tumour, wherein contain therapeutically effective amount
Formulas I or II compound or its nitrogen oxides, pharmaceutically acceptable salt or solvate are as active ingredient and medicine
Acceptable carrier on.Described pharmaceutical composition can be conventional tablet or capsule, sustained-release tablet or capsule,
System conventional on the galenic pharmacies such as Dospan or capsule, granule, powder, syrup, oral liquid, injection
Agent form.
Formulas I or II compound or its nitrogen oxides, pharmaceutically acceptable salt or molten in pharmaceutical composition of the present invention
The dosage of agent compound is different with the difference such as symptom and age.For adult, when oral administration, once give
The lower limit of dose is 0.1mg (preferably 1mg), and the upper limit is 1000mg (preferably 500mg)；Give at vein
During medicine, the lower limit of single administration amount is 0.01mg (preferably 0.1mg), and the upper limit is 500mg (preferably 250mg).
This dosage range is deviateed also dependent on the difference of disease degree and the difference of formulation.
Use compound of the present invention when treating or prevent, it is possible to the method (example of existing treatment cancer
As, by chemotherapy, radiotherapy or operation) combined administration.Therefore present invention also offers a kind of side treating cancer
Method, including to patient use therapeutically effective amount according to invention formula (I) or the compound of (II) or it is pharmaceutically acceptable
Salt form or preparation, simultaneously to one or more other the cancer chemotherapeutic agent of patient therapeuticallv's effective dose.
Any concrete patient, concrete pharmaceutical combination and concrete treatment effective dose level are needed according to many
Depending on weight factor, described factor includes treated tumor type and the order of severity；The particular compound used
Activity；The age of patient, body weight, general health, sex and diet；The particular compound used
Administration time, method of administration and excretion rate；Similar factor known to treatment duration and medical field.
Suitably the example of chemotherapeutics include but not limited to following these:
Alkylating agent: nitrogen mustards, endoxan, ifosfamide, melphalan, Chlorambucil, bendamustine
Spit of fland, Estramustine；Ethylenimine class, Tespamin, quinone imine；Sulphonic acid ester and polyalcohols, busulfan, two
Bromine mannitol；Nitrosoureas, hexamethylene nitrous, carmustine, nimustine, CH3-CCNU；Triazenes
Imidazoles, dacarbazine；Hydrazine, procarbazine.
Antimetabolite: Pyrimidine antagonists, fluorouracil, cytarabine, FT, Tegadifur；
Purine antagonist, mercaptopurine, Sulfomercaprine Sodium, imuran, thioguanine；Antifol, first ammonia butterfly
Purine, aminopterin.
Antitumor antibiotics: mitomycin C, bleomycin, actinomycin D, mithramycin, daunorubicin,
Adriamycin, chromomycin A3, enramycin, Neocarzinostatin, sarkomycin, M3.
Plant anticarcinogen: vincristine, colchicin, camptothecine, HCPT, cantharidin, indigo are beautiful
Red.
Hormone: adrenocorticotropic hormone, metacortandracin, prednisolone, hydrocortisone, dexamethasone；
Estrogen, diethylstilbestrol, hexoestrol dibromoacetate；Androgen and anabolic hormone, testosterone propionate, methyltestosterone,
Nandrolone Phenylpropionate, NSC-70735, TAM.
Other types: neoplatin, interferon, L-asparaginase, hydroxycarbamide, tetrahydroform, methyl GAG,
Haematoporphyrin；Immune formulation.
Detailed description of the invention
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below is
In order to preferably illustrate the present invention, it is not for limiting the scope of the present invention.
Embodiment 1
The preparation of 1-[5-(2,3-dichlorophenyl sulphur generation) thiazol-2-yl] ethyl ketone (I-1)
By 2,3-thiophenol dichlorobenzene (120mg, 0.68mmol), sodium methoxide (37mg, 0.68mmol) add
In the methyl alcohol (6mL) being dried, stir 20 minutes under room temperature.2-acetyl group-5-diuril is added in reactant liquor
Azoles (100mg, 0.48mmol), is heated to 50 DEG C, and reactant liquor continues stirring until reaction is complete.By solvent
Being evaporated, be extracted with ethyl acetate, merge organic layer, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried.It is evaporated
Rear silica gel column chromatography obtains target compound (59mg, yield 31%).1HNMR(CDCl3, 300MHz) and 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 325.9244found 325.9246.
Embodiment 2
The preparation of 1-[5-(3,4-dichlorophenyl sulphur generation) thiazol-2-yl] ethyl ketone (I-2)
Reactions steps, with reference to embodiment 1, obtains target compound (yield 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 C1mH7NOS2Cl2+Na cacld 325.9244found 325.9246.
Embodiment 3
The preparation of 1-[5-(2,6-dichlorophenyl sulphur generation) thiazol-2-yl] ethyl ketone (I-3)
Reactions steps, with reference to embodiment 1, obtains target compound (yield 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/z 303.9[M+H]+；HRMS for C11H7NOS2Cl2+H cacld 303.9424found 303.9428.
Embodiment 4
The preparation of 1-(5-chloro-4-nitrothiazole-2-base) ethyl ketone
The mixed solution of TFAA (6.3mL), fuming nitric aicd (2.1mL) is cooled to subzero 20 DEG C,
Stir 1 hour, be slowly added to the trifluoroacetic acid of 2-acetyl group-5-diuril azoles (1.10g, 6.8mmol) wherein
Acid anhydride (2mL) solution.Reactant liquor continues to stir 2 hours at subzero 20 DEG C.Reactant liquor is concentrated, pours ice into
In water, extracting with ether, merge organic layer, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried.It is evaporated rear silicon
Plastic column chromatography obtains yellow solid (0.98g, yield 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.
Embodiment 5
The preparation of 1-[5-(2,3-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone (I-4)
By 2,3-thiophenol dichlorobenzene (94mg, 0.53mmol), sodium methoxide (29mg, 0.53mmol) add dry
Dry methyl alcohol (5mL), stirs 20 minutes under room temperature.Then in reactant liquor, add 1-(5-chloro-4-nitro thiophene
Azoles-2-base) ethyl ketone (100mg, 0.48mmol), continues stirring 4 hours under room temperature.Solvent is evaporated, uses second
Acetoacetic ester extracts, and merges organic layer, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried.It is spin-dried for rear silica gel column layer
Analyse to obtain target compound (129mg, yield 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 370.9095found 370.9097.
Embodiment 6
The preparation of 1-[5-(3,4-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone (I-5)
Reactions steps, with reference to embodiment 5, obtains target compound (yield 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 370.9095found 370.9096.
Embodiment 7
The preparation of 1-[5-(2,6-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone (I-6)
Reactions steps, with reference to embodiment 5, obtains target compound (yield 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 370.9095found 370.9096.
Embodiment 8
The preparation of 1-[5-(2,4-dichlorophenyl sulphur generation)-4-nitrothiazole-2-base] ethyl ketone (I-7)
Reactions steps, with reference to embodiment 5, obtains target compound (yield 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
370.9095found 370.9098.
Embodiment 9
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl ketone (I-8)
Reactions steps, with reference to embodiment 5, obtains target compound (yield 50%).1HNMR(CD3OD, 300
MHz) δ (ppm): 2.62 (s, 3H), 8.84 (s, 2H)；ESI MS m/z 371.9[M+Na]+；HRMS for
C10H5N3O3S2Cl2+Na cacld 371.9047found 371.9049.
Embodiment 10
The preparation of 1-[5-(3-methoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (I-9)
Reactions steps, with reference to embodiment 5, obtains target compound (yield 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 332.9980found 332.9983.
Embodiment 11
The preparation of 1-[5-(3,4-dimethoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (I-10)
Reactions steps, with reference to embodiment 5, obtains target compound (yield 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
341.0266found 341.0269.
Embodiment 12
The preparation reactions steps of 1-[5-(4-nitrobenzophenone sulphur generation)-4-nitrothiazole-2-base] ethyl ketone (I-11) is with reference to implementing
Example 5, obtains target compound (yield 90%).1HNMR(CDCl3, 300MHz) and 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.325.9905found 325.9907.
Embodiment 13
The preparation of 1-[5-(3,4-dichlorobenzyl amino)-4-nitrothiazole-2-base] ethyl ketone (I-12)
By 3,4-dichloro-benzylamine (128mg, 0.73mmol), 1-(5-chloro-4-nitrothiazole-2-base) ethyl ketone (100mg,
0.48mmol) it is dissolved in isopropanol (2mL), is heated to reflux.After reaction terminates, solvent is evaporated, silicagel column
Chromatograph to obtain target compound (77mg, yield 46%).1HNMR(CDCl3, 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 C12H9Cl2N3O3+H cacld.345.9820found
345.9823.
Embodiment 14
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethanol (I-13)
By sodium borohydride (11mg, 0.29mmol), 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole
-2-base] ethyl ketone (100mg, 0.29mmol) adds in methyl alcohol (2mL), stirs 1 hour under room temperature.Add
Shrend is gone out and by solvent concentration, is extracted with ethyl acetate, and merges organic layer, and saturated aqueous common salt washs, anhydrous sulphur
Acid sodium is dried.Target compound (78mg, yield 78%) is obtained through silica gel column chromatography after being spin-dried for.1HNMR
(CDCl3, 500MHz) and δ (ppm): 1.61 (d, 3H, J=5Hz), 3.08 (s, 1H), 5.07 (q, 1H, J=5
Hz), 8.71 (s, 2H)；ESI MS m/z 351.9[M+H]+；HRMS for C10H7Cl2N3O3S2+H calcd.
351.9384found 351.9387.
Embodiment 15
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl acetate (I-14)
By 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethanol (100mg, 0.28mmol),
Acetic anhydride (58mg, 0.57mmol), DMAP (3mg, 0.03mmol) are dissolved in dichloromethane
(3mL).Being stirred at room temperature 1 hour, add water, dichloromethane extracts, and merges organic layer, and saturated common salt is washed
Washing, anhydrous sodium sulfate is dried.Target compound (104mg, 93%) is obtained through silica gel column chromatography after being spin-dried for.1HNMR
(CDCl3, 300MHz) and δ (ppm): 1.64 (d, 3H, J=6Hz), 2.07 (s, 3H), 5.94 (q, 1H, J=6
Hz), 8.71 (s, 2H)；ESI MS m/z 393.9[M+H]+；HRMS for C12H9Cl2N3O4S2+H calcd.
393.9490found 393.9495.
Embodiment 16
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl chloroacetate (I-15)
Reactions steps, with reference to embodiment 15, obtains target compound (yield 57%).1HNMR(CDCl3, 300
MHz) δ (ppm): 1.72 (d, 3H, J=7Hz), 4.10 (s, 2H), 6.05 (q, 1H, J=7Hz), 8.74 (s,
2H)；ESI MSm/z427.9[M+H]+；HRMS for C12H8Cl3N3O4S2+H calcd.427.9100
found 427.9104.
Embodiment 17
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl propionate (I-16)
Reactions steps, with reference to embodiment 15, obtains target compound (yield 92%).1HNMR(CDCl3, 300
MHz) 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).
Embodiment 18
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl butyrate (I-17)
Reactions steps, with reference to embodiment 15, obtains target compound (yield 85%).1HNMR(CDCl3, 500Hz) and 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.421.9803found 421.9807.
Embodiment 19
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethyl benzoate (I-18)
Reactions steps, with reference to embodiment 15, obtains target compound (yield 78%).1HNMR(CDCl3, 300
MHz) 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.455.9646found 455.9649.
Embodiment 20
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base]-N-methyl ethyl-amine (I-19)
By molten for 1-[5-(3,4-dichlorobenzyl amino)-4-nitrothiazole-2-base] ethyl ketone (80mg, 0.23mmol)
In dichloromethane (1mL), add dimethylamine (THF solution of 2M, 0.9mL, 1.82mmol), add
Enter acetic acid and adjust pH to 5～6.Reactant liquor is stirred at room temperature until raw material disappears, addition sodium cyanoborohydride (29mg,
0.45mmol), 1 hour it is stirred at room temperature.Add shrend to go out, extract with dichloromethane, merge organic layer, full
And brine It, anhydrous sodium sulfate is dried.It is spin-dried for rear silica gel column chromatography and obtains target compound (27mg, receipts
Rate 32%).1HNMR(CDCl3, 500MHz) and 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
C11H10Cl2N4O2S2+H calcd.364.9700found 364.9703.
Embodiment 21
The preparation of N-benzyl-1-[5-(3,5-dichloropyridine base-4-sulphur generation)-4-nitrothiazole-2-base] ethamine (I-20)
Reactions steps, with reference to embodiment 20, obtains target compound (yield 61%).1HNMR(CDCl3, 500
MHz) δ (ppm): 1.47 (d, 3H, J=6Hz), 1.82 (brs, 1H), 3.76 (s, 2H), 4.06 (q, 1H, J=6
Hz), 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.441.0013 found 441.0016.
Embodiment 22
The preparation of 1-[2-(2,3-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone (II-1)
By 2,3-thiophenol dichlorobenzene (120mg, 0.68mmol), sodium methoxide (37mg, 0.68mmol) add
The methyl alcohol (6mL) being dried, stirs 20 minutes under room temperature.Then in reactant liquor, add 2-chloro-5-acetyl group
Thiazole (100mg, 0.48mmol), is stirred at room temperature until reacting complete.Solvent is evaporated, uses ethyl acetate
Extraction, merges organic layer, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried.Obtain through silica gel column chromatography after being evaporated
Target compound (129mg, yield 69%).1HNMR(CDCl3, 300MHz) and 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.303.9424found 303.9427.
Embodiment 23
The preparation of 1-[2-(3,4-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone (II-2)
Reactions steps, with reference to embodiment 22, obtains target compound (yield 70%).1HNMR(CDCl3, 500
MHz) 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.303.9424found 303.9427.
Embodiment 24
The preparation of 1-[2-(2,6-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone (II-3)
Reactions steps, with reference to embodiment 22, obtains target compound (yield 58%).1HNMR(CDCl3, 500
MHz) 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.303.9424 found
303.9427.
Embodiment 25
The preparation of 1-[2-(2,4-dichlorophenyl sulphur generation)-thiazole-5-base] ethyl ketone (II-4)
Reactions steps, with reference to embodiment 22, obtains target compound (yield 69%).1HNMR(CDCl3, 300
MHz) 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.303.9424 found 303.9427.
Embodiment 26
The preparation of 1-[2-(3-methoxyphenylthio)-thiazole-5-base] ethyl ketone (II-5)
Reactions steps, with reference to embodiment 22, obtains target compound (yield 71%).1HNMR(CDCl3, 300
MHz) 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.266.0309found 266.0311.
Embodiment 27
The preparation of 1-[2-(3,4-dimethoxyphenylthio)-thiazole-5-base] ethyl ketone (II-6)
Reactions steps, with reference to embodiment 22, obtains target compound (yield 69%).1HNMR(CDCl3, 300
MHz) 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.
Embodiment 28
The preparation of 1-[2-(4-nitrobenzophenone sulphur generation)-thiazole-5-base] ethyl ketone (II-7)
Reactions steps, with reference to embodiment 22, obtains target compound (yield 87%).1HNMR(CDCl3, 500
MHz) 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.
Embodiment 29
]-[2-(3,5-dichloropyridine base-4-sulphur generation)-thiazole-5-base] preparation of ethyl ketone (II-8)
Reactions steps, with reference to embodiment 22, obtains target compound (yield 43%).1HNMR(CDCl3, 300
MHz) 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.
Embodiment 30
The preparation of 2,5-bis-bromo-4-nitrothiazoles
To at-20 DEG C, fuming nitric aicd (13mL) be added in TFAA (40mL) ,-20 DEG C of stirrings
2h.At same temperature, slowly by 2,5-bis-bromo thiazole (14g) instills reactant liquor, and-20 DEG C are stirred overnight.Steam
Dry solvent, is slowly added to water (100mL), and ethyl acetate extracts, anhydrous Na2SO4It is dried, solvent evaporated,
Petroleum ether is pulled an oar, and filters to obtain crude pale yellow solid 3.34g (yield 20%).ESI MS m/z 289.0[M+H]+
Embodiment 31
The preparation of the bromo-5-of 2-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole (I-21)
By 3,5-bis-chloro-4-mercaptopyridine (2.3g, 1.1eq) is dissolved in 50mL commercial anhydrous methyl alcohol, adds first
Sodium alkoxide (690mg, 1.1eq), 40 DEG C of stirring 2h, addition 2,5-bis-bromo-4-nitrothiazole (3.34g), 40 DEG C
Stirring 2.5h, solvent evaporated, add 50mL water, ethyl acetate extracts, anhydrous Na2SO4It is dried, is evaporated
Solvent, obtains target compound 2.57g (yield 83%) through silica gel column chromatography.1HNMR(CDCl3, 300MHz) and δ
(ppm): 8.73 (s, 2H)；ESI MS m/z 385.6[M+H]+
Embodiment 32
The preparation of 5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-22)
Bromo-for 2-5-(3,5-dichloropyridine base) sulfydryl-4-nitrothiazole (100mg) is dissolved in DMF, and (1mL divides
Analyse pure) in, addition cuprous cyanide (41.6mg, 1.8eq), 120 DEG C of stirring (oil bath preheats in advance) 1.5h,
It is cooled to room temperature, adds ethyl acetate (20mL) and be sufficiently stirred for, be filtered to remove precipitation, organic phase washing two
Secondary, anhydrous Na2SO4It is dried, solvent evaporated, adds methyl alcohol concussion, filter to obtain faint yellow solid 30mg.(receive
Rate 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]-
Embodiment 33
The preparation of N-methyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-23)
5-(3,5-bis-chloro-4-pyridine radicals) sulfydryl-4-nitrothiazole-2-carboxylic acid (100mg) is suspended in MeCN
(5mL), room temperature instills POCl3 (0.037mL, 1.Seq), and 30min is stirred at room temperature, and adds first under ice bath
Amine hydrochlorate (22mg, 1.1eq), instills diisopropylethylamine (0.237mL, 5eq), is stirred at room temperature after completing
1.5h, solvent evaporated, with frozen water (15mL), filter gained precipitation ether and wash twice, obtain white powder 22mg
(yield 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]-
Embodiment 34
The preparation of N, N-diethyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-24)
5-(3,5-bis-chloro-4-pyridine radicals) sulfydryl-4-nitrothiazole-2-carboxylic acid (100mg) is suspended in MeCN
(5mL), room temperature instills POCl3 (0.037mL, 1.5eq), and 30min is stirred at room temperature, and adds two under ice bath
Ethylamine hydrochloride (35mg, 1.1eq), instills diisopropylethylamine (0.237mL, 5eq), and after completing, room temperature is stirred
Mix overnight, solvent evaporated, with frozen water (15mL), it is placed in 0 DEG C of crystallization, filters gained and precipitate by preparing post
Chromatographic purifying obtains white powder 18mg (yield 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]+
Embodiment 35
N-(1-methyl piperidine-4-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-'s nitrothiazole-2-formamide (I-25)
Preparation
5-(3,5-bis-chloro-4-pyridine radicals) sulfydryl-4-nitrothiazole-2-carboxylic acid (50mg) is suspended in 3mL MeCN,
Room temperature instills POCl3 (0.02mL, 1.5eq), and 30min is stirred at room temperature, and adds N-methyl-4-ammonia under ice bath
Phenylpiperidines (17.8mg, 1.1eq), instills diisopropylethylamine (0.117mL, 5eq), is stirred at room temperature after completing
1.5h, solvent evaporated, with frozen water (15mL), use saturated NaHCO3Adjusting pH to 7, ethyl acetate extracts,
Washing, anhydrous Na2SO4It is dried, solvent evaporated, adds ether and smash to pieces, filter gained solid ether and wash,
Obtain yellow powder 30mg (yield 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]-
Embodiment 36
The preparation of N-phenyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-26)
Reactions steps, with reference to embodiment 33, obtains target compound (yield 8%).1HNMR (DMSO, 300
MHz) 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/z425.0[M-H]-
Embodiment 37
The preparation of N-benzyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-27)
5-(3,5-bis-chloro-4-pyridine radicals) sulfydryl-4-nitrothiazole-2-carboxylic acid (80mg) is suspended in MeCN
(3mL), room temperature instills POCl3 (0.03mL, 1.5eq), adds benzylamine (26.8mg, 1.1eq) under ice bath,
Instill diisopropylethylamine (0.19mL, 5eq), stirred overnight at room temperature after completing, solvent evaporated, add 15mL
Frozen water, ethyl acetate extracts, and 1N HCl washes 5 times, anhydrous Na2SO4It is dried, solvent evaporated, adds ether
Grind to obtain pale yellow powder 25mg (yield 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]-
Embodiment 38
The preparation of N-phenethyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-28)
Reactions steps, with reference to embodiment 37, obtains target compound (yield 22%).1HNMR (DMSO, 300
MHz) 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]+
Embodiment 39
The system of N-(4-methoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-29)
Standby
Reactions steps, with reference to embodiment 37, obtains target compound (yield 8%).1HNMR (DMSO, 300
MHz) δ (ppm): 10.96 (s, 1H), 8.98 (s, 2H), 7.66 (d, J=9.0Hz, 2H), 6.91 (d, J=9.1
Hz, 2H), 3.72 (s, 3H)；ESI MS m/z 455.0[M-H]-
Embodiment 40
N-(3,4-Dimethoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-30)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 8%).1HNMR (DMSO, 300
MHz) 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]-
Embodiment 41
N-(3-chloro-4-methoxy phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-31)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 29%).1HNMR (DMSO, 300
MHz) 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]-
Embodiment 42
The system of N-(3-methoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-32)
Standby
Reactions steps, with reference to embodiment 37, obtains target compound (yield 29%).1HNMR (DMSO, 300
MHz) 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]+
Embodiment 43
The system of N-(2-methoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-33)
Standby
Reactions steps, with reference to embodiment 37, obtains target compound (yield 13%).1HNMR (DMSO, 300
MHz) 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]-
Embodiment 44
N-(6-methoxypyridine-3-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-34)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 13%).1HNMR (DMSO, 300
MHz) 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[M-H]-
Embodiment 45
N-[4-(3-dimethylamino propoxyl group) phenyl]-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formyl
The preparation of amine (I-35)
Reactions steps, with reference to embodiment 37, obtains target compound (yield 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=13.1,6.4
Hz, 1H)；ESI MS m/z 526.1[M-H]-
Embodiment 46
N-(4-hydroxybenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-36)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 26%).1H NMR (300MHz,
DMSO) δ 9.62 (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[M-H]-
Embodiment 47
N-(4-methyl-benzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-37)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 23%).1H NMR (300MHz,
DMSO) δ 9.69 (t, J=6.0Hz, 1H), 8.95 (s, 1H), 7.18-7.03 (m, 4H), 4.33 (d, J=6.1
Hz, 2H), 1.21 (s, 3H)；ESI MS m/z 477.0[M+Na]+
Embodiment 48
N-(4-chlorobenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-38)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 43%).1H NMR (300MHz,
DMSO) δ 9.76 (s, 1H), 8.95 (s, 1H), 7.32 (m, 4H), 4.37 (s, 2H)；ESI MS m/z 474.2
[M-H]-
Embodiment 49
N-(4-luorobenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-39)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 48%).1H NMR (300MHz,
DMSO) δ 9.75 (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]-
Embodiment 50
N-(3-luorobenzyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-40)
Preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 51%).1H NMR (300MHz,
DMSO) δ 9.76 (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]-
Embodiment 51
{ 5-[(3,5-bis-chloro-4-pyridine radicals) sulfydryl]-4-nitrothiazole-2-base } [1,2,3,4-tetrahydroisoquinoline-2-base] ketone
(I-41) preparation
Reactions steps, with reference to embodiment 37, obtains target compound (yield 44%).1H NMR (300MHz,
DMSO) δ 9.66 (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]-
Embodiment 52
N-{5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-base } preparation of acetamide (I-42)
The preparation of the bromo-thiazolamine of step 1.N-methoxycarbonyl group-5-
Bromo-for 200mg 5-thiazolamine is suspended in 10mL MeCN.0.26mL chlorine is instilled under room temperature
Methyl formate (3eq) 0.46mL triethylamine (3eq), is stirred at room temperature 3h, solvent evaporated.Products therefrom is molten
In the 2mL concentrated sulfuric acid, under ice bath, it is dividedly in some parts 350mg KNO3(about 1.5eq), 0 DEG C of stirring 3h, will
Reactant liquor is poured in frozen water, and ethyl acetate extracts, saturated NaHCO3Wash, anhydrous Na2SO4It is dried, is evaporated
Solvent, prepares column chromatography purifying (PE: EA 3: 1) and obtains 80mg target compound.
Step 2.N-{5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-base } preparation of acetamide
56mg 3,5-bis-chloro-4-mercaptopyridine (crude product, about 1.1eq) is dissolved in 3mL absolute methanol, adds
Enter 17mg sodium methoxide (about 1.1eq), 40 DEG C of stirring 30min, be cooled to room temperature, add 80mg N-(5-
Bromo-4-nitro-2-thiazolyl) methyl carbamate, ambient temperature overnight.Solvent evaporated, adds 15mL water, second
Acetoacetic ester extracts, anhydrous Na2SO4It is dried, prepares column chromatography purifying (petroleum ether: ethyl acetate 5: 1) and obtain mesh
Mark compound 50mg, yield 12%.1H NMR (300MHz, DMSO) δ 12.28 (s, 1H), 8.90 (s, 2H),
4.75 (s, 3H)；ESI MS m/z403.2[M+Na]+
Embodiment 53
N-{5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-base } propionamide (I-43)
Reactions steps, with reference to embodiment 53, obtains target compound (yield 8%).1H NMR (300MHz,
DMSO) δ 12.61 (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]+
Embodiment 54
The preparation of 1-[5-(2,4-difluorophenylthio)-4-nitrothiazole-2-base] ethyl ketone (I-44)
Reactions steps, with reference to embodiment 1, obtains target compound (yield 77.4%).1H NMR (300MHz,
DMSO) δ 7.96 (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]+
Embodiment 55
The preparation of the bromo-5-of 2-(2,4-difluorophenyl sulfydryl)-4-nitrothiazole
Reactions steps, with reference to embodiment 31, obtains target compound (yield 66.4%).1H NMR (300MHz,
DMSO) δ 7.98 (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).
Embodiment 56
5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-45)
With the bromo-5-of 2-(2,4-difluorophenyl sulfydryl)-4-nitrothiazole for raw material, reactions steps reference embodiment 32,
Obtain target compound (yield 25%).1H NMR (300MHz, DMSO) δ 8.46 (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=11.6,5.1
Hz, 1H).
Embodiment 57
N-phenyl-5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-46)
With 5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide for raw material, reactions steps reference
Embodiment 37.Obtain target compound (total recovery 14%).1H NMR (300MHz, DMSO) δ 11.00 (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).
Embodiment 58
N-benzyl-5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide (I-47)
With 5-[(2,4-difluoro pyridine-4-base) sulfydryl]-4-nitrothiazole-2-formamide for raw material, reactions steps reference
Embodiment 37.Obtain target compound (total recovery 4%).1H NMR (300MHz, DMSO) δ 9.70 (t, J=
6.1Hz, 1H), 7.99 (dt, J=8.3,6.7Hz, 1H), 7.72-7.63 (m, 1H), 7.39 (td, J=8.4,2.2
Hz, 1H), 7.31-7.25 (m, 5H), 4.40 (d, J=6.2Hz, 2H).
Embodiment 59
Tablet
By the compound I-7 (50g) prepared in embodiment 8, HPMC E (150g), starch
(200g), PVP K30 is appropriate and magnesium stearate (1g) mixes, and pelletizes, compressing tablet.
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.
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