CN106632060A - N-naphthylalkyl-substituted nitrogen-containing heterocyclic derivatives and preparation method and antitumor application thereof - Google Patents

N-naphthylalkyl-substituted nitrogen-containing heterocyclic derivatives and preparation method and antitumor application thereof Download PDF

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CN106632060A
CN106632060A CN201610871845.7A CN201610871845A CN106632060A CN 106632060 A CN106632060 A CN 106632060A CN 201610871845 A CN201610871845 A CN 201610871845A CN 106632060 A CN106632060 A CN 106632060A
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preparation
compound
methyl
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nmr
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孙宏斌
李明雷
陈超
徐畅
温小安
陈彩萍
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China Pharmaceutical University
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Abstract

The invention discloses compounds, nitric oxides thereof or pharmaceutically-acceptable salts or solvates shown in general formula I as well as a preparation method and application thereof to pharmacy, in particular to the antitumor aspect. Pharmacodynamic experiment results show that the compounds shown in the formula I are capable of reducing the level of a tumor-promoting factor Mem2 in tumor cells and have remarkable antitumor effect. Thus, the compounds can be applied to preparation of drugs for preventing or treating diseases related to tumors.

Description

The alkyl-substituted nitogen-contained heterocycle derivant of N- naphthalenes, preparation method and its anticancer usage
Technical field
The present invention relates to pharmaceutical field, and in particular to the alkyl-substituted nitogen-contained heterocycle derivant of N- naphthalenes, its preparation method and It is preventing or is treating the application in tumor disease medicine.
Patent application claims Chinese patent application (application number 201510735939.7, the applying date：October 30 in 2015 Day, invention and created name：The alkyl-substituted nitogen-contained heterocycle derivant of N- naphthalenes, preparation method and its anticancer usage) priority.
Background technology
Cancer is the public health problem of whole world serious concerns, be also the human health not yet captured biggest threat it One.Tumour is that the wrong responses for exchanging the signals such as ganglion cell's growth, differentiation, function and apoptosis with cell itself are characterized 's.At present, the antineoplastic for clinically using include cytotoxic drug, kinase inhibitor, proteasome inhibitor, Hdac inhibitor and hedgehog inhibitor etc..
Mdm2 is a ubiquitin ligase, and its vital function is to carry out poly ubiquitination to p53, promotes it to enter Proteasome is degraded.P53 is referred to as " the gene bodyguard " of cell, and p53 genes maintain stable low transcriptional level in normal cell, And concentration is low to being almost difficult to detect in cell, its main cause is ubiquitination degradations and functional transcription of the Mdm2 to p53 Inhibitory action (Cell Death Differ.2010,17 (1)：86-92).Cell activated by DNA damage, the former cancer factor, During the Pressure stimulations such as stimulation, the poor nutritional of active oxygen, p53 will be activated, and it is auxiliary that p53 that is stable and activating can just recruit some Transcription factor is attached to the expression of transcriptional control downstream gene in the specific region of DNA, produces a series of biological effect, adjusts Control growth, aging, apoptosis and the metabolism of cell.Research shows, Mdm2 overexpression in many tumor tissues, so that tumour is thin The functional transcription and level of p53 albumen has and significantly declines in born of the same parents, and then weakens inhibitory action of the p53 to tumour cell (Curr.Cancer Drug Targets 2005,5,3-8).Additionally, Mdm2 also produces cause by the approach that non-p53 is relied on Cancer acts on (Trends in Biochemical Sciences 2009,34 (6)：279-286), for example, Mdm2 can pass through poly Ubiquitination causes cancer suppressorfactor Rb PDs (Nature 1995,375,694-698；EMBO J.2005,24,160-169)； Mdm2 further promotes cell cycle progression (Nature 1995,375,691-694) by the functional transcription of activation E2F1；Mdm2 The proteasome that can promote cancer suppressorfactor p21 is degraded (EMBO J.2003,22,6365-6377) etc..In a word, Mdm2 is thin in regulation and control Key effect is played in born of the same parents' apoptosis and cell cycle progression, is the carcinogen of a confirmation.Therefore, the function of Mdm2 is suppressed to have Prestige becomes the new way of oncotherapy.
At present, the anti-cancer agent research based on Mdm2 is mainly developed Mdm2-p53 protein-protein interactions and is suppressed Agent (Curr.Med.Chem.2014；21(5)：553-74), and existing some Mdm2-p53 protein-protein interactions inhibitor (such as：AMG232, DS-3032b, MI-77301 etc.) enter clinical investigation phase.Although Mdm2-p53 protein-protein interactions Inhibitor shows certain antitumor action in clinical testing, but such inhibitor has obvious mechanism of action correlation Limitation, for example, the curative effect of such medicine highly relies on the state of p53, thus (swollen more than 50% to p53 mutated tumors P53 is to be mutated or lack in knurl) offer limited effectiveness (Cell Cycle 2011,10,1590-1598).Additionally, Mdm2-p53 eggs In vain-protein-interacting inhibitor is remarkably improved the expression of Mdm2 in cell, and (Mdm2 is the target gene of p53, the liter of p53 levels Height can promote on the contrary the expression of Mdm2), and increase the stability of Mdm2 by suppressing itself ubiquitination degraded of Mdm2, its knot Fruit be negative-feedback enhance the carcinogenic effect of Mdm2, and therefore and may produce drug resistance (Cell Cycle 2011,10, 1590-1598)。
In recent years, deubiquitinating enzymes USP7 is of concern as antineoplastic new target.USP7 can be general by going to Mdm2 Elementization and suppress the ubiquitination degraded of Mdm2, so as to improve its stability (Mol Cell.2004,26；13(6)：879-86).Grind Study carefully and show, USP7 overexpression (Nature 2008,455,813-818 in the tumour such as prostate cancer and Huppert's disease； Cancer Cell 2012,22,345-358).USP7 inhibitor can effectively reduce the content of Mdm2 in cell, and by p53 Rely on and the approach of non-p53 dependences plays effect (the Cancer Cell 2012,22,345-358 for suppressing tumour；Cell Death and Disease 2013,4, e867；Nat Cell Biol.2006,8 (10)：1064-73；Nature 2008, 455,813-818).Additionally, the present inventor and partner's research find that USP7 inhibitor can pass through to reduce the albumen water of N-Myc It is flat and play anti-neuroblastoma effect (Nature Medicine, 2016, doi：10.1038/nm.4180).Grinding at present USP7 inhibitor species it is less, and selective poor (Chinese pharmaceutical chemistry magazine 2013,23,486-492).Additionally, existing USP7 inhibitor is also unclear with the binding site of USP7 and the mode of action.Representational USP7 inhibitor includes P5091, its There is significant inhibitory action (Cancer Cell 2012,22,345-358) to Huppert's disease, but with larger poison Side effect, thus not yet enter clinical investigation phase.In fact, not yet there is any USP7 inhibitor to enter clinical research rank so far Section.
In sum, compared with Mdm2-p53 protein-protein interaction inhibitor, USP7 inhibitor can reduce Mdm2 Stability further reduces its content and plays antitumor action, and it is in terms of antitumor curative effect than Mdm2-p53 protein-protein phases Interaction inhibitor has more advantage.Clinically in the urgent need to safe and effective new USP7 inhibitor is used for antineoplaston.
The content of the invention
The present inventor based on USP7 Binding Capacities domain-Mdm2 peptides albumen eutectic structure (PLoS Biol, 2006,4 (2)： E27), using fragment method of formation, series of new compound has been designed and synthesized, by anti-tumor biological evaluation and effect Mechanism Study a, it was found that class has the active compound for anti tumor of brand new.It is thin that such compound can significantly reduce tumour The content of Mdm2 in born of the same parents, and with dose dependent.The invention discloses compound as shown in following formula I or its pharmaceutically can connect The salt received or solvate：
Wherein, W is independently chosen from CH, N or CR5；
X is O, N or S；
N is 0～5；
R1For H, straight or branched alkyl, the aryl or miscellaneous non-substituted or containing one or more substituents of 1～6 carbon Aryl, styryl, benzenesulfonyl, diarylmethyl, benzoyl or COOR9；
R2For H, NO2、NH2, halogen, CN, trifluoromethyl, formoxyl, CH (R6)NR7R8, 1～12 carbon straight or branched The straight or branched alkyl of 1～6 carbon that alkyl, hydroxyl replace, the aryl or heteroaryl of non-substituted or one or more replacements Base；
R3、R4It is independently chosen from H, NO2, halogen, CN, trifluoromethyl, COOR9, formoxyl, the straight or branched of 1～12 carbon Alkyl, CH (R6)NR7R8, it is non-substituted or one or more replace aryl or heteroaryl；
R5Selected from NO2, halogen, CN, trifluoromethyl, formoxyl, the straight or branched alkyl of 1～12 carbon, it is non-substituted or One or more aryl for replacing or heteroaryl；
R6For the alkyl of H or 1～6 carbon；
R7、R8It is independently chosen from straight or branched alkyl, the COR of H, 1～6 carbon10；
R9、R10It is independently chosen from H, the straight or branched alkyl of 1～12 carbon, non-substituted or one or more virtues for replacing Base or heteroaryl.
In the compound of the present invention, W preferred N or CH；
The preferred O of X；
N preferably 0～3；
R1It is preferred that aryl or heteroaryl non-substituted or containing one or more substituents；
R2It is preferred that CH (R6)NR7R8Or the straight or branched alkyl of 1～12 carbon, wherein, R6It is preferred that H；R7It is preferred that H；R8It is excellent Select the straight or branched alkyl of 1～6 carbon；
R3、R4The straight or branched alkyl of preferred H, 1～12 carbon alone.
Further, preferred compounds of the invention is as follows：
The compounds of this invention is also including the pharmaceutically acceptable salt of compound of formula I, chemical combination including but not limited to of the present invention The acid-addition salts that thing is formed with following acid：Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, Malaysia Acid, fumaric acid, malic acid, tussol, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, pamoic acid (handkerchief not acid), oxalic acid or amber Acid.
It is yet another object of the invention to provide prepared by compound of formula I or its pharmaceutically acceptable salt or solvate Purposes in the medicine of prevention and treatment tumour.Pharmacodynamic experiment result shows that the compound of the present invention has significantly anti-swelling Tumor cell proliferation is acted on.
It, in order to preferably illustrate the present invention, is not the model for limiting the present invention that the pharmacodynamics test of described below is Enclose.
The part pharmacological evaluation and result of the compounds of this invention is presented herein below.
【1】Cell in vitro activity pharmacological evaluation
1. experiment purpose：Human colon cancer cell HCT116 in-vitro multiplications are lived using CCK-8 Determination Stainings each compound The impact of property, and calculate respective half-inhibition concentration IC50。
2. experiment material：The compounds of this invention is configured to mother liquor with DMSO dissolvings, is diluted using front employing complete medium Into debita spissitudo；Reagent：CCK-8 kits build up bio tech ltd purchased from Nanjing；Culture medium：Modified form RMPI- 1640 culture mediums：Purchased from Hyclone companies；Class hyclone：Purchased from Hyclone companies；96 porocyte culture plates are purchased from Costar companies.
3. experimental technique：The cell that live cell fraction is taken up to more than 90% is tested.Cell inhibitory effect test is adopted EnoGeneCellTMCounting Kit-8 (CCK-8) cell viability detection kit.Cell dissociation, count, make concentration and be 3×104The cell suspension of individual/ml, 100 μ l cell suspensions are added (per hole 3 × 10 in 96 orifice plates per hole3Individual cell)；96 orifice plates are put In 37 DEG C, 5%CO2Cultivate 24 hours in incubator；Medicine is diluted to desired concn, 100 μ L are added per hole with complete medium The culture medium of corresponding drug containing, while negative control group is set up, vehicle control group.Per group of 5 multiple holes；96 orifice plates are placed in 37 DEG C, 5%CO2Cultivate 72 hours in incubator；10 μ L CCK-8 solution are added per hole, culture plate is incubated in incubator 3.5 Hour, the OD values at 450nm are determined with ELIASA, calculate the cell inhibitory rate under variable concentrations state and calculate IC50Value.
4. experimental result：Inhibitory activity of the compounds of this invention to human colon cancer cell HCT116 cell line in-vitro multiplications (IC50) see the table below.
Above-mentioned test result shows that growth of the compounds of this invention to tumour cell has different degrees of inhibitory action. Part of compounds shows the antitumor activity more higher than positive drug P5091.The result prompting the compounds of this invention can be used for Prepare antineoplastic.
【2】Normal cell toxicity pharmacological evaluation
With similar to the similar method of inhibiting tumour cells activity, from compound I-82 normal cell toxicity is carried out Pharmacological evaluation detects that experimental result is as follows：
As a result show, compound I-82 has certain selectivity to tumour cell and normal cell.Additionally, result table Bright, the antitumor activity of the compounds of this invention has certain p53 dependences.
The present inventor has further carried out the pharmacological evaluation inspection of normal cell toxicity from compound I-34, I-77, I-78 Survey.The compounds of this invention increases in vitro to human colon cancer cell HCT116 cell lines and Human umbilical vein endothelial cells HUVEC cell line Inhibitory activity (the IC for growing50) see the table below.
I-34 I-77 I-78 P5091
HCT116 5.06 11.15 6.58 10.54
HUVEC 16.39 27.45 20.49 11.29
As a result show, the compounds of this invention has certain selectivity, and its selectivity to tumour cell and normal cell Better than positive drug P5091.The result prompting the compounds of this invention has more preferable security and controls than existing USP7 inhibitor Treat window.Therefore, the compounds of this invention is expected to be used for preparing the antineoplastic with relatively low toxic and side effect.
【3】External molecular level pharmacological evaluation --- the horizontal checkout (Western blot) of tumour cell Mdm2
1. experiment purpose：Compound is determined using Western blot methods to contain Mdm2 in human colon cancer cell HCT116 The impact of amount
2. experiment material：The compounds of this invention is configured to mother liquor with DMSO dissolvings, is diluted using front employing complete medium Into debita spissitudo；Reagent is purchased from Sheng Xing biotech firms；Culture medium：Modified form RMPI-1640 culture mediums；Purchased from Hyclone companies； Class hyclone：Purchased from Hyclone companies；96 porocyte culture plates are purchased from Costar companies.
3. experimental technique：The cell that live cell fraction is taken up to more than 90% is tested.Cell dissociation, count, make it is dense Spend for the cell suspension of 100000/ml, 1000 μ l cell suspensions of every hole addition (every hole 2 × 10 in 12 orifice plates5Individual cell)；12 Orifice plate is placed in 37 DEG C, 5%CO2In incubator cultivate 24 hours it is adherent, suck upper strata culture medium；Medicine is diluted with complete medium To desired concn, the culture medium of the corresponding drug containing of 1000 μ L is added per hole, while negative control group is set up, vehicle control group. Per group of 3 multiple holes；12 orifice plates are placed in 37 DEG C, 5%CO2Cultivate 7 hours in incubator, remove upper strata culture medium；It is thin with PBS Cell pyrolysis liquid cell lysis are used after born of the same parents, albumen is extracted；
HCT-116 cells positive drug and compound I-82 are acted on, concentration selects 0 μM, 15 μM, 30 μM and 50 μM, phase Cell lysis after between seasonable, with 10% gel electrophoresis are separated.As a result show：With the rising of positive drug or compound I-82 concentration, (see accompanying drawing 1,2) protein level of Mdm2 significantly reduces.
Above Pharmacological test results show that the compounds of this invention has significant antitumor activity, part of compounds Antitumor activity is better than representational USP7 inhibitor P5091, and shows the security and therapeutic window higher than P5091.Machine Research processed shows that the antitumor activity of the compounds of this invention is at least part by reducing the protein level of Mdm2, raises p53 water Put down (see accompanying drawing 3), and then promote Apoptosis and realize.
Result above prompting the compounds of this invention can be used for preparing antineoplastic.The tumour is included but is not limited to such as Descend these：
Osteocarcinoma, including (such as)：Osteogenic sarcoma (osteosarcoma), fibrosarcoma, MFH, cartilage meat Knurl, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), Huppert's disease, malignant giant cell tumor chordoma, bone cartilage Knurl (turn round and look at hose epostoma), benign chondromas, chondroblastoma, cartilage and knurl sample fibroma, osteoidosteoma and big and small Born of the same parents' knurl.
Hematology's cancer, including (such as)：Hematologic cancers, such as acute myelogenous leukemia, chronic myelogenous leukemia, urgency Property lymphocytic series leukaemia, chronic lymphocytic system leukaemia, myeloproliferative disease, Huppert's disease and myelosis Abnormal syndrome, hodgkin's lymphomas (malignant lymphoma) and macroglobulinemia Waldenstron.
Nervous system cancer, including (such as)：Skull cancer, such as osteocarcinoma, hemangioma, granulation knurl, vitiligoidea and osteitis deformans； Meninx cancer, such as meningioma, meningosarcoma and glioma；The cancer of the brain, such as astrocytoma, medulloblastoma, neuroglia Matter knurl, ependymoma, gonioma (pinealoma), glioblastoma multiforme, Oligodendroglioma, nerve Sheath knurl, retinoblastoma and congenital tumor；And spinal cord knurl, such as fibroneuroma, meningioma, glioma and meat Knurl.
Stomach enteroncus, including (such as)：Esophagus cancer, such as squamous cell carcinoma, gland cancer, leiomyosarcoma and lymthoma；Cancer of the stomach, Such as tumour, lymthoma and leiomyosarcoma；Cancer of pancreas, such as duct adenocarcinoma, insulinoma, glucagonoma of pancreas, gastrinoma, class cancer Knurl and vasoactive intestinal peptide tumor；Carcinoma of small intestine, such as gland cancer, lymthoma, carcinoid tumor, Kaposi's sarcoma, liomyoma, hemangioma, Lipoma, fibroneuroma and fibroma；Colorectal cancer, such as gland cancer, tubule gland cancer, villous adenoma, hamartoma and liomyoma.
Urinary system cancer, including (such as)：Kidney, such as gland cancer, wilms' tumor (nephroblastoma), lymthoma and white Blood disease；Bladder and carcinoma of urethra, such as squamous cell carcinoma, divide a word with a hyphen at the end of a line thin bag cancer 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, such as squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma and Gland cancer；Bronchioalveolar carcinoma；Bronchial adenoma；Sarcoma；Lymthoma；CHL and celiothelioma.
Liver cancer, including (such as)：Hepatocellular carcinoma, such as hepatocellular carcinoma；Cholangiocarcinoma；Hepatoblastoma；Angiosarcoma；Liver cell Adenoma and hemangioma.
Cutaneum carcinoma, including (such as)：Chromoma, basal-cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, development Abnormality mole, lipoma, hemangioma, histiocytoma, cheloid, psoriasis.
Present invention also offers a kind of pharmaceutical composition of prevention and treatment tumour, wherein the Formulas I containing therapeutically effective amount Compound or its pharmaceutically acceptable salt or solvate are used as active ingredient and pharmaceutically acceptable carrier.The medicine Composition can be conventional tablet or capsule, sustained-release tablet or capsule, Dospan or capsule, granule, powder, syrup, Conventional dosage form on the galenic pharmacies such as oral liquid, injection.
The dosage of the compound or its pharmaceutically acceptable salt or solvate is with symptom in pharmaceutical composition of the present invention It is different with age etc. and different.Difference and formulation also dependent on disease degree different and deviate this dosage range.
When applying compound of the present invention and being prevented or treated tumour, also can be with the method (example of existing treating cancer Such as, by chemotherapy, radiotherapy or operation) it is administered in combination.Therefore, present invention also offers a kind of method for the treatment of cancer, including to Patient using therapeutically effective amount according to while compound of formula I or its pharmaceutically useful salt form or preparation to patient therapeuticallv The other antineoplastics of one or more of effective dose.For any specific patient, specific pharmaceutical combination and tool Depending on the treatment effective dose level of body need to be according to multiple factors, the factor include treated tumor type, feature and its Grade malignancy；The activity of the particular compound for being adopted；Age of patient, body weight, general health, sex and diet；Institute Using the administration time of particular compound, method of administration and excretion rate；It is similar to known to treatment duration and medical field Factor.
Can with the example of antineoplastic associated with the compounds of this invention including but not limited to it is following these：
Alkylating agent：Nitrogen mustards, endoxan, ifosfamide, melphalan, Chlorambucil, bendamustine, female does not take charge of Spit of fland；Ethylenimines, Tespamin, quinone imine；Sulphonic acid ester and polyalcohols, busulfan, dibromannitol；Nitrosoureas, ring Own nitrous, carmustine, nimustine, CH3-CCNU；Triazenes imidazoles, dacarbazine；Hydrazine, procarbazine.
Antimetabolite：Pyrimidine antagonists, fluorouracil, cytarabine, FT, Tegadifur；Purine is short of money Anti-agent, mercaptopurine, Sulfomercaprine Sodium, imuran, thioguanine；Antifol, methotrexate (MTX), aminopterin.
Antitumor antibiotics：Mitomycin C, bleomycin, actinomycin D, mithramycin, daunorubicin, adriamycin, color Mycin A3, enramycin, Neocarzinostatin, sarkomycin, M3.
Plant kind anti-cancer drugs：Vincristine, colchicin, camptothecine, HCPT, cantharidin, indigo red.
Hormone：Adrenocorticotropic hormone, metacortandracin, prednisolone, hydrocortisone, dexamethasone；Estrogen, oneself The female phenol of alkene, hexoestrol dibromoacetate；Androgen and anabolic hormone, testosterone propionate, methyltestosterone, Nandrolone Phenylpropionate, NSC-70735, three Atenolol.
Kinases inhibitor：It is various having listed and in the anti-tumor protein kinase inhibitor for grinding.
Histon deacetylase (HDAC) (HDAC) inhibitor：Vorinostat, chidamide, Belinostat, Panobinostat、Pracinostat、Entinostat.
Immune formulation：PD-1 antibody, PD-L1 antibody, PD-1 micromolecular inhibitors, PD-L1 micromolecular inhibitors.
Other types：Neoplatin, interferon, L-asparaginase, hydroxycarbamide, tetrahydroform, methyl GAG, haematoporphyrin.
It is a further object of the present invention to provide the synthetic method of such compound.By taking the synthesis of compound I-82 as an example, Its synthetic route is as follows：
To specifically include following steps：
(1) be there is into nucleophilic substitution in the basic conditions in compound A and B and compound C, the alkaline reagent of employing is obtained Selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, preferred potassium carbonate；Using solvent be selected from DMF, acetone, acetonitrile, preferably DMF；The reaction time for adopting is 1-24 hours；Temperature is adopted for subzero 20 DEG C to 120 DEG C, preferably 60 DEG C to 100 DEG C.
(2) there is the prepared compound D of reduction reaction in compound C, and the go back original reagent of employing is selected from sodium borohydride, hydroboration Potassium, Lithium Aluminium Hydride, preferred sodium borohydride；Using solvent selected from methanol, ethanol, tetrahydrofuran, preferred methyl alcohol；Using reaction Time is 0.5-10 hours；Temperature is adopted for subzero 20 DEG C to 100 DEG C, preferably 0 DEG C to 30 DEG C.
(3) with halide reagent there is substitution reaction generation compound E in compound D, and the halide reagent of employing is selected from tribromide Phosphorus, bromine, carbon tetrabromide, protochloride maple, preferred phosphorus tribromide；Using solvent be selected from dichloromethane, acetonitrile, ether, preferably Tetrahydrofuran；The reaction time for adopting is 1-24 hours；Temperature is adopted for subzero 20 DEG C to 60 DEG C, preferably 0 DEG C to 25 DEG C.
(4) with the heterocycle containing NH or heteroaromatic there is in the basic conditions the prepared compound of nucleophilic substitution in compound E F.Using alkaline reagent be selected from potassium carbonate, sodium carbonate, cesium carbonate, preferred potassium carbonate；The solvent for adopting is DMF, acetone, second Nitrile, preferred DMF；The reaction time for adopting is 1-24 hours；Temperature is adopted for subzero 20 DEG C to 120 DEG C, preferably 60 DEG C to 120 ℃。
(5) there is the prepared I-82 of reductive amination process in compound F, and the amination reagent for adopting is methylamine hydrochloride, methylamine alcohol Solution, preferred methylamine alcohol solution；The go back original reagent for adopting is sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, It is preferred that sodium borohydride；The solvent for adopting is methyl alcohol, ethanol, dichloromethane, tetrahydrofuran, preferred methyl alcohol；Using reaction time For 1-24 hours；Temperature is adopted for subzero 20 DEG C to 100 DEG C, preferably 25 DEG C to 50 DEG C.
Specific compounds process for production thereof is with reference to embodiment.
Description of the drawings
When Fig. 1 shows that positive drug p5091 acts on HCT-116 cells, intracellular Mdm2 levels reduce increasing with drug concentration Plus and reduce；
When Fig. 2 shows that compound I-82 acts on HCT-116 cells, intracellular Mdm2 levels reduce increasing with drug concentration And reduce；
Fig. 3 shows that compound I-41 is acted on after HCT-116 cell 2h, and Mdm2 is reduced in cell, and p53 levels are therewith after 8h Raise；
Fig. 4 is the nucleus magnetic hydrogen spectrum of compound I-82；
Fig. 5 is the nuclear-magnetism carbon spectrum of compound I-82.
Specific embodiment
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below be in order to The present invention is preferably illustrated, is not for limiting the scope of the present invention
Embodiment 1
The preparation of 6- benzyloxies-naphthalene -2- aldehyde (C)
6- hydroxyls-beta naphthal (150mg, 0.87mmol), potassium carbonate (361mg, 2.61mmol) are added into dry DMF (3mL) in, stir 30 minutes under room temperature.It is added dropwise after bromobenzyl (224mg, 155 μ L, 1.31mmol) in reactant liquor, is placed in 80 DEG C Oil bath, stirs complete to reaction.Add water and reaction is quenched, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, nothing Aqueous sodium persulfate is dried.It is evaporated rear silica gel column chromatography and obtains target compound (200mg, yield 88%).1H NMR (300MHz, DMSO- d6) δ 10.06 (s, 1H), 8.48 (s, 1H), 8.07 (d, J=9.0Hz, 1H), 7.92 (d, J=8.6Hz, 1H), 7.83 (d, J= 8.5Hz, 1H), 7.55 (s, 1H), 7.50 (d, J=6.7Hz, 2H), 7.45-7.21 (m, 4H), 5.25 (s, 2H).
Embodiment 2
The preparation of (6- benzyloxies-naphthalene -2- bases)-methyl alcohol (D)
6- benzyloxies-naphthalene -2- aldehyde (C) (200mg, 0.76mmol) is dissolved in dry THF (5mL), addition is dried boron Sodium hydride (43mg, 1.14mmol), stirs 2h complete to reaction under room temperature.Solvent is evaporated, is extracted with ethyl acetate, be associated with Machine layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be evaporated rear silica gel column chromatography obtain target compound D crude products (190mg, slightly Product yield 94%), direct plunge into the next step.
Embodiment 3
The preparation of 2- benzyloxies -6- bromomethyls-naphthalene (E)
(6- benzyloxies-naphthalene -2- bases)-methyl alcohol (D) (150mg, 0.57mmol) is dissolved in THF (5mL), under 0 DEG C of ice bath The dichloromethane solution (384mg, 135 μ L, 1.42mmol/mL) of phosphorus tribromide is added dropwise, room temperature is warmed naturally to, 4h is stirred.Plus Water quenching is gone out, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains target chemical combination Thing E crude products (110mg, crude yield 59%), direct plunge into the next step.
Embodiment 4
The preparation of 1- [(6- benzyloxies-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (F)
By 2- benzyloxies -6- bromomethyls-naphthalene (100mg, 0.31mmol), potassium carbonate (93mg, 0.67mmol), 2- formaldehyde - Imidazoles (48mg, 0.50mmol) is dissolved in DMF, stirs complete to reaction at 80 DEG C, is warmed to room temperature, and adds water and is quenched, ethyl acetate extraction Take, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains target compound F crude products (110mg, crude product Yield 94%), direct plunge into the next step.
Embodiment 5
The preparation of 1- { 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-82)
1- [(6- benzyloxies-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (100mg, 0.29mmol) is dissolved in and is dried first Alcohol, adds methylamine alcohol solution (0.5ml), adds excessive drying anhydrous sodium sulfate as attached water agent, is stirred overnight at room temperature；Filter off sulphur Sour sodium solid, adds in reactant liquor and is dried sodium borohydride solids (17mg, 0.44mmol), is stirred at room temperature complete to reaction.Will be molten Agent is evaporated, and is extracted with ethyl acetate, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column layer Analyse to obtain target compound I-1 (90mg, yield 86.2%).1H NMR (300MHz, DMSO-d6) δ 7.70 (d, J=8.9Hz, 2H), 7.56-7.18 (m, 9H), 7.03 (s, 1H), 6.91 (s, 1H), 5.36 (s, 2H), 5.19 (s, 2H), 3.85 (s, 2H), 2.47 (s, 3H).13CNMR (75MHz, CDCl3) δ 157.14,148.90,145.67,136.69,134.04,131.67, 129.35,128.82,128.61,128.05,127.72,127.51,125.66,125.26,120.82,119.72,107.14, 70.07,49.71,47.36,35.81.
Embodiment 6
The system of 1- { 1- { [6- (2- benzyl chloride epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-1) It is standby
With reference to the preparation method of the 1-82 of the description of embodiment 1～5, target compound I-1 (64mg, yield 63%) is obtained.1H NMR (300MHz, CDCl3) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.64-7.59 (m, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.29 (s, 3H), 7.22 (m, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 5.34 (s, 2H), 5.29 (s, 2H), 3.82 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ 156.81,146.32,134.00,131.95,129.42,129.06, 128.96,128.81,127.76,127.49,126.97,126.91,125.61,125.34,120.66,119.51,107.31, 67.18,49.62,47.79,36.10.
Embodiment 7
1- { 1- { [6- (3- methoxybenzyl epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-2) Preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-2 (85mg, yield 82%) is obtained.1H NMR (300MHz, CDCl3) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 7.36-7.25 (m, 2H), 7.21 (s, 2H), 7.04 (m, 3H), 6.96 (s, H), 6.84 (s, H), 5.33 (s, 2H), 5.15 (s, 2H), 3.80 (s, 3H) 3.11 (s, 2H), 2.44 (s, 3H).13C NMR (75MHz, CDCl3) δ 159.88,157.08,146.32,138.32,134.02,131.84, 129.66,129.34,128.86,127.70,127.48,125.63,125.29,120.66,119.66,113.51,113.01, 107.22,69.94,55.22,49.62,47.77,36.09.
Embodiment 8
The system of 1- { 1- { [6- (3- benzyl chloride epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-3) It is standby
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-3 (63mg, yield 43%) is obtained.1H NMR (300MHz, CDCl3) δ 7.69 (d, J=8.6Hz, 2H), 7.47 (d, J=8.8Hz, 2H), 7.40-7.06 (m, 6H), 7.01 (s, 1H), 6.89 (s, 1H), 5.33 (s, 2H), 5.14 (s, 2H), 3.80 (s, 2H), 2.43 (s, 3H).13C NMR (75MHz, CDCl3) δ 157.22,146.69,139.23,134.98,134.38,132.43,130.29,129.89,129.38, 128.57,128.12,127.95,127.84,126.06,125.80,125.77,121.09,119.94,107.65,69.61, 50.03,48.20,36.50.
Embodiment 9
The system of 1- { 1- { [6- (4- fluorine benzyloxies) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-4) It is standby
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-4 (90mg, yield 43%) is obtained.1H NMR (300MHz, CDCl3) δ 7.70 (d, J=8.3Hz, 2H), 7.45 (s, 2H), 7.42 (s, 1H), 7.26-7.16 (m, 3H), 7.08 (m, 2H), 7.02 (s, 1H), 6.89 (s, 1H), 5.33 (s, 2H), 5.12 (s, 2H), 3.81 (s, 2H), 2.44 (s, 3H).13C NMR (75MHz, CDCl3) δ 164.17,160.90,156.95,146.35,133.99,131.95,129.41, 129.29,127.68,127.48,125.64,125.36,120.65,119.60,115.64,115.36,107.20,69.39, 49.60,47.79,36.10.
Embodiment 10
1- { 1- { [6- (4- methylbenzyloxies) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N-'s methyl methylamines (I-5) Prepare
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-5 (67mg, yield 58%) is obtained.1H NMR (300MHz, CDCl3) δ 7.68 (dd, J=8.4,4.6Hz, 2H), 7.45 (s, 1H), 7.37 (d, J=7.8Hz, 2H), 7.23 (m, 5H), 7.01 (s, 1H), 6.89 (s, 1H), 5.32 (s, 2H), 5.13 (s, 2H), 3.80 (s, 2H), 2.44 (s, 3H), 2.37 (s, 3H).13C NMR (75MHz, CDCl3) δ 157.63,146.76,143.78,138.26,134.47,134.10, 132.18,129.71,129.23,128.10,128.06,127.90,126.05,125.67,121.07,120.18,107.58, 70.45,50.06,48.21,36.52,21.57.
Embodiment 11
The system of 1- { 1- { [6- (4- benzyl chloride epoxides) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-6) It is standby
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-6 (220mg, yield 76%) is obtained 。1H NMR (300MHz, CDCl3) δ 7.70 (d, J=8.3Hz, 2H), 7.46 (s, 1H), 7.39 (m, 4H), 7.21 (m, 3H), 7.02 (s, 1H), 6.90 (s, 1H), 5.35 (s, 2H), 5.15 (s, 2H), 3.82 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ 156.85,146.23,135.23,133.96,133.85,131.96,129.44,128.92,128.77, 128.65,127.69,127.52,125.64,125.37,120.68,119.55,107.23,69.28,49.62,47.74, 36.06.
Embodiment 12
1- { 1- { [6- (4- nitro benzyloxies) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N-'s methyl methylamines (I-7) Prepare
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-7 (60mg, yield 56%) is obtained.1H NMR (300MHz, CDCl3) δ 8.28 (d, J=8.5Hz, 2H), 7.70 (dd, J=19.8,8.8Hz, 4H), 7.32-7.11 (m, 4H), 7.03 (s, 1H), 6.91 (s, 1H), 5.36 (s, 2H), 5.30 (s, 2H), 3.83 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ 148.64,146.74,136.48,134.76,132.28,130.34,130.21,130.06, 129.80,128.27,128.10,126.45,123.32,122.65,121.94,117.18,109.91,71.32,52.24, 50.13,38.57.
Embodiment 13
The system of 1- { 1- { [6- (4- bromo-benzyloxys) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-8) It is standby
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-8 (105mg, yield 53%) is obtained 。1H NMR (300MHz, CDCl3) δ 7.68 (d, J=8.6Hz, 2H), 7.52 (d, J=8.1Hz, 2H), 7.45 (s, 1H), 7.34 (d, J=8.1Hz, 2H), 7.28-7.18 (m, 2H), 7.17 (s, 1H), 7.01 (s, 1H), 6.85 (d, J=17.8Hz, 1H), 5.33 (s, 2H), 5.22-5.02 (m, 2H), 3.75 (d, J=33.2Hz, 2H), 2.43 (s, 3H).13C NMR (75MHz, CDCl3) δ 157.25,146.71,136.18,134.37,132.43,132.15,129.87,129.48,129.35,128.10, 127.96,126.06,125.80,122.37,121.08,119.96,107.67,69.72,50.03,48.22,36.50.
Embodiment 14
The preparation of 1- { 1- { [6- (naphthalene -2- bases) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-9)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-9 (50mg, yield 66%) is obtained.1H NMR (300MHz, CDCl3) δ 7.95 (s, 1H), 7.87 (m, 3H), 7.72 (d, J=8.6Hz, 2H), 7.60 (d, J= 8.5Hz, 1H), 7.56-7.48 (m, 2H), 7.47 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 5.36 (s, 2H), 5.34 (s, 2H), 3.82 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ 157.16,146.28,134.20,134.04, 133.32,133.12,131.82,129.39,128.89,128.43,127.93,127.73,127.65,127.47,126.37, 126.27,126.11,125.65,125.30,125.24,120.67,119.71,107.32,61.62,49.64,47.70, 36.06.
Embodiment 15
The preparation of 1- { 1- [(6- isobutyl group epoxide naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-10)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-10 (66mg, yield 57%) is obtained 。1H NMR (300MHz, CDCl3) δ 7.69 (t, J=8.2Hz, 2H), 7.47 (d, J=11.2Hz, 1H), 7.27-7.08 (m, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 5.33 (s, 2H), 3.85 (d, J=6.5Hz, 2H), 3.81 (s, 2H), 2.44 (s, 3H), 2.20 (dd, J=15.8,9.2Hz, 1H), 2.12 (s, 1H), 1.08 (d, J=6.7Hz, 6H).13C NMR (75MHz, CDCl3) δ 157.62,146.42,134.14,131.51,129.16,128.61,127.56,127.47,125.62,125.19, 120.66,119.71,106.52,77.45,77.03,76.61,74.48,49.64,47.86,36.16,28.24,19.29.
Embodiment 16
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- propyl group -1H- imidazoles (I-11)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-11 (60mg, yield is obtained 53%).1H NMR (300MHz, CDCl3) δ 7.70 (dd, J=8.6,5.1Hz, 2H), 7.52-7.13 (m, 9H), 7.01 (d, J= 1.2Hz, 1H), 6.85 (d, J=1.3Hz, 1H), 5.18 (s, 4H), 2.67-2.59 (m, 2H), 1.82-1.69 (m, 2H), 0.95 (t, J=7.4Hz, 3H).13C NMR (75MHz, CDCl3) δ 157.14,148.62,136.71,134.02,131.77, 130.93,129.36,128.86,128.65,128.09,127.74,127.55,127.30,125.38,125.02,119.76, 107.14,70.09,49.53,28.84,21.31,13.95.
Embodiment 17
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- isopropyls -1H- imidazoles (I-12)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-12 (50mg, yield is obtained 66%).1H NMR (300MHz, CDCl3) δ 7.69 (dd, J=8.2,6.2Hz, 2H), 7.50-7.10 (m, 9H), 7.03-6.77 (m, 2H), 5.20 (s, 2H), 5.17 (s, 2H), 3.02 (tt, J=13.5,6.9Hz, 1H), 1.28 (d, J=6.8Hz, 6H).13C NMR (75MHz, CDCl3) δ 136.65,133.95,131.85,129.26,128.54,127.98,127.64,127.43, 127.26,127.14,125.80,125.24,124.85,119.67,119.49,115.46,107.13,70.02,49.21, 25.96,21.73.
Embodiment 18
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- methylols -1H- imidazoles (I-13)
Compound F (100mg, 0.29mmol) is dissolved in and is dried methyl alcohol (5mL), addition be dried sodium borohydride solids (17mg, 0.44mmol), it is stirred at room temperature complete to reaction.Solvent is evaporated, is extracted with ethyl acetate, merge organic layer, saturated aqueous common salt Washing, anhydrous sodium sulfate drying.The next step (160mg, crude yield 84%), silica gel can be direct plungeed into after being evaporated as crude product Column chromatography is obtained target compound sterling.1H NMR (300MHz, DMSO-d6) δ 7.78 (dd, J=8.7,2.8Hz, 1H), 7.67 (s, 1H), 7.50 (d, J=6.9Hz, 1H), 7.46-7.29 (m, 2H), 7.24 (dd, J=9.0,2.4Hz, 0H), 7.16 (s, 0H), 6.85 (s, 0H), 5.74 (s, 1H), 5.37 (s, 2H), 5.21 (s, 2H), 4.51 (s, 2H).13C NMR (75MHz, DMSO-d6) δ 156.88,147.59,137.31,134.03,133.11,129.71,128.83,128.74,128.27, 128.17,127.62,126.91,126.49,126.35,121.47,119.60,107.64,69.74,56.09,49.19.
Embodiment 19
The preparation of 1- [(6- methoxyl groups-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde
By 6- methoxyl groups -2- bromomethyls-naphthalene, 2- formaldehyde imidazoles, potassium carbonate is added and is dried in DMF, is stirred at 80 DEG C to anti- Should be complete.Add water and reaction is quenched, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying. Rear silica gel column chromatography is evaporated by target compound crude product (500mg, crude yield 33%).
Embodiment 20
The preparation of N- benzyl -1- { 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-14)
1- [(6- methoxyl groups-naphthalene -2- bases) methyl] -1H- imidazoles -2- formaldehyde (100mg, 0.38mmol) is dissolved in and is dried first Alcohol, is added dropwise benzylamine (44.26mg), adds excessive drying anhydrous sodium sulfate as attached water agent, is stirred overnight at room temperature；Filter off sodium sulphate Solid, adds in reactant liquor and is dried sodium borohydride solids (7.1mg), is stirred at room temperature complete to reaction.Solvent is evaporated, acetic acid is used Ethyl ester is extracted, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains target chemical combination Thing I-14 (120mg, yield 89%)1H NMR (300MHz, CDCl3) δ 7.66 (dd, J=14.4,8.7Hz, 2H), 7.39 (s, 1H), 7.35-7.05 (m, 8H), 7.01 (s, 1H), 6.90 (s, 1H), 5.29 (s, 2H), 3.91 (s, 3H), 3.84 (s, 2H), 3.79 (s, 2H), 3.46 (m, 1H).13C NMR (75MHz, CDCl3) δ 157.97,146.46,139.83,134.07,131.72, 129.28,128.70,128.55,128.36,128.22,127.58,127.44,127.11,127.01,125.71,125.35, 120.72,119.32,105.72,55.31,53.45,49.65,45.31.
Embodiment 21
The preparation of N- methyl isophthalic acids-{ 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-15)
With reference to the preparation method of the compound I-14 of the description of embodiment 20, target compound I-15 (80mg, yield is obtained 76%).1H NMR (300MHz, CDCl3) δ 7.69 (dd, J=12.6,8.7Hz, 2H), 7.44 (s, 1H), 7.20 (dd, J= 8.5,1.3Hz, 1H), 7.16 (dd, J=8.9,2.4Hz, 1H), 7.12 (s, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 5.33 (s, 2H), 3.91 (s, 3H), 3.80 (s, 2H), 2.43 (s, 3H).13C NMR (75MHz, CDCl3) δ 157.99,145.83, 134.09,131.60,129.26,128.70,127.64,127.53,125.66,125.28,120.80,119.37,105.71, 55.30,49.68,47.48,35.86.
Embodiment 22
The preparation of N- ethyl -1- { 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-16)
With reference to the preparation method of the compound I-14 of the description of embodiment 20, target compound I-16 (100mg, yield is obtained 90%).1H NMR (300MHz, CDCl3) δ 7.69 (dd, J=13.5,8.7Hz, 2H), 7.46 (s, 1H), 7.29-7.10 (m, 3H), 7.01 (s, 1H), 6.90 (s, 1H), 5.34 (s, 2H), 3.92 (s, 3H), 3.84 (s, 2H), 2.66 (q, J=7.1Hz, 2H), 1.08 (t, J=7.1Hz, 3H).13C NMR (75MHz, CDCl3) δ 157.96,146.74,134.06,131.77, 129.25,128.71,127.59,127.45,125.62,125.30,120.57,119.35,105.70,55.29,49.60, 45.86,43.84,15.11.
Embodiment 23
The preparation of N- isobutyl group -1- { 1- [(6- methoxynaphthalene -2- bases) methyl] -1H- imidazoles -2- bases } methylamine (I-17)
With reference to the preparation method of the compound I-14 of the description of embodiment 20, target compound I-17 (86mg, yield is obtained 71%).1H NMR (300MHz, CDCl3) δ 7.68 (dd, J=12.7,8.8Hz, 2H), 7.45 (s, 1H), 7.29-7.07 (m, 3H), 6.99 (s, 1H), 6.88 (s, 1H), 5.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 2H), 3.45 (s, 1H), 2.42 (d, J=6.7Hz, 2H), 1.70 (dt, J=13.2,6.6Hz, 1H), 0.87 (d, J=6.6Hz, 6H).13C NMR (75MHz, CDCl3) δ 157.96,146.50,134.07,131.75,129.24,128.71,127.59,127.35,125.68,125.36, 120.70,119.33,105.71,77.45,77.03,76.60,57.62,55.29,49.66,46.22,28.26,20.58.
Embodiment 24
The preparation of 6- { [2- (Methyaminomethyl) -1H- imidazoles -1- bases] methyl } Betanaphthol (I-18)
Compound I-15 (35mg) is dissolved in 2mL DCM, in -20 DEG C add phosphorus tribromide (4M, 2mL), after the completion of delay Slowly it is warmed to room temperature, 3.5h is stirred at room temperature, reactant liquor is poured in frozen water, with sodium acid carbonate neutrality, EA: THF=1: 1 extraction is neutralized to Take, anhydrous sodium sulfate drying, the target compound I-18 (32mg, yield 91%) of silica gel column chromatography purifying.1H NMR (300MHz, CDCl3) δ 7.69 (dd, J=12.6,8.7Hz, 1H), 7.44 (s, 0H), 7.20 (dd, J=8.5,1.3Hz, 1H), 7.16 (dd, J=8.9,2.4Hz, 0H), 7.12 (s, 0H), 7.00 (s, 1H), 6.89 (s, 0H), 5.33 (s, 1H), 3.91 (s, 2H), 3.80 (s, 1H), 2.43 (s, 2H).
Embodiment 25
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2,4,5- tri- bromo- 1H- imidazoles (I-20)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-20 (35mg, yield is obtained 42%).1H NMR (300MHz, CDCl3) δ 7.73 (d, J=8.6Hz, 2H), 7.57-7.17 (m, 9H), 5.34 (s, 2H), 5.20 (s, 2H).13C NMR (75MHz, CDCl3) δ 157.31,136.63,134.18,129.44,129.19,128.69,128.60, 128.05,127.80,127.48,125.92,124.78,119.89,118.70,117.12,107.12,105.67,70.07, 51.42.
Embodiment 26
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- dodecyls -1H- imidazoles (I-24)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-24 (30mg, yield is obtained 42%).1H NMR (300MHz, CDCl3) δ 7.71 (dd, J=8.5,5.2Hz, 2H), 7.53-7.31 (m, 7H), 7.20 (dd, J =19.7,5.9Hz, 2H), 7.03 (s, 1H), 6.87 (s, 1H), 5.19 (s, 4H), 2.73-2.61 (t, 2H), 1.72 (m, J= 7.6Hz, 2H), 1.29-1.20 (m, 16H), 0.90 (t, J=6.3Hz, 3H).13C NMR (75MHz, CDCl3) δ 157.14, 148.78,136.70,134.00,132.13,131.74,130.86,129.31,128.81,128.60,128.04,127.70, 127.49,127.24,125.38,124.99,119.72,107.13,70.07,49.54,31.86,29.56,29.44, 29.39,29.29,27.91,26.90,22.64,14.06.
Embodiment 27
1- { the preparations of 1- [(6- benzyloxy naphthalene -2- bases) methyl] the chloro- 1H- imidazoles (I-25) of -2- butyl -4- formoxyl -5-
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-25 (yield 42%) is obtained.1H NMR (300MHz, CDCl3) δ 9.78 (s, 1H), 7.68 (dd, J=8.6,3.6Hz, 2H), 7.39 (dq, J=19.1,7.1Hz, 6H), 7.19 (dd, J=12.0,7.1Hz, 3H), 5.67 (s, 2H), 5.17 (s, 2H), 2.73-2.57 (m, 2H), 1.67 (dt, J =15.4,7.6Hz, 2H), 1.33 (tt, J=11.4,5.7Hz, 2H), 0.86 (t, J=7.3Hz, 3H) .13C NMR (75MHz, CDCl3) δ 177.98,157.15,154.66,136.69,134.03,130.80,129.33,128.78,128.60,128.04, 127.76,127.50,125.08,124.76,124.35,119.75,114.59,107.12,70.07,48.30,29.18, 26.56,22.36,13.58.
Embodiment 28
1- { the preparations of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- propyl group -4- methyl isophthalic acids H- imidazoles (I-26)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-26 (yield 48%) is obtained.1H NMR (300MHz, CDCl3) δ 7.71 (d, J=8.5Hz, 2H), 7.50 (d, J=7.2Hz, 2H), 7.41 (dd, J=13.0, 5.5Hz, 4H), 7.26 (d, J=11.0Hz, 2H), 7.18 (d, J=8.4Hz, 1H), 6.56 (s, 1H), 5.19 (s, 2H), 5.11 (s, 2H), 2.73-2.61 (m, 2H), 2.23 (s, 3H), 1.30 (d, J=7.5Hz, 3H).13C NMR (75MHz, CDCl3)δ 157.06,148.94,136.70,136.07,133.95,131.94,129.32,128.83,128.61,128.04,127.63, 127.51,125.31,125.06,119.68,116.11,107.09,70.04,49.27,20.19,13.52,12.38.
Embodiment 29
1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- propyl group -1H- imidazoles -4, the preparation of 5- dicarboxylates (I-27)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-27 (23mg, yield is obtained 30%).1H NMR (300MHz, CDCl3) δ 7.68 (dd, J=8.6,4.0Hz, 2H), 7.40 (ddd, J=19.4,16.6, 7.2Hz, 6H), 7.24 (dd, J=8.9,2.4Hz, 1H), 7.21 (s, 1H), 7.14 (dd, J=8.5,1.6Hz, 1H), 5.53 (s, 2H), 5.18 (s, 2H), 4.44-4.35 (m, 2H), 4.22 (q, J=7.1Hz, 2H), 2.74-2.64 (m, 2H), 1.74 (dd, J=15.3,7.6Hz, 2H), 1.40 (t, J=7.1Hz, 3H), 1.18 (t, J=7.1Hz, 3H), 0.93 (t, J= 7.4Hz, 3H).13C NMR (75MHz, CDCl3) δ 163.04,160.60,157.11,151.82,136.69,133.96, 130.98,129.34,128.77,128.59,128.03,127.69,127.50,124.82,124.53,119.71,107.10, 70.05,61.20.48.32,29.12,21.24,14.25,13.83.
Embodiment 30
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -4- methyl -5- formoxyls -1H- imidazoles (I-28)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-28 (yield 42%) is obtained.1H NMR (300MHz, CDCl3) δ 9.86 (s, 1H), 7.72 (dd, J=8.6,4.0Hz, 2H), 7.61 (d, J=4.7Hz, 2H), 7.49 (d, J=7.0Hz, 2H), 7.46-7.28 (m, 4H), 7.27-7.18 (m, 2H), 5.60 (s, 2H), 5.19 (s, 2H), 2.53 (s, 3H).13C NMR (75MHz, CDCl3) δ 178.68,157.19,153.61,144.13,143.22,142.10, 142.05,136.67,134.17,130.94,129.46,128.79,128.61,128.04,127.66,127.51,126.69, 125.81,119.70,107.06,70.03,50.45,13.34.
Embodiment 31
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- imidazoles -4- Ethyl formates (I-29)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-29 (40mg, yield is obtained 68%).1H NMR (300MHz, CDCl3) δ 7.82 (s, 1H), 7.76-7.66 (m, 3H), 7.53-7.19 (m, 8H), 5.65 (s, 2H), 5.19 (s, 2H), 4.29 (dd, J=14.1,7.1Hz, 2H), 1.37-1.30 (m, 3H).13C NMR (75MHz, CDCl3)δ 160.27,157.15,142.13,137.92,136.71,134.10,131.39,129.42,128.83,128.59,128.01, 127.61,127.48,126.27,125.61,122.75,119.64,107.12,70.05,60.46,50.15,14.20.
Embodiment 32
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2,3- dicyanos -1H- imidazoles (I-30)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-30 (17mg, yield is obtained 31%).1H NMR (300MHz, DMSO-d6) δ 8.55 (s, 1H), 7.89-7.77 (m, 3H), 7.53-7.25 (m, 8H), 5.60 (s, 2H), 5.23 (s, 2H).13C NMR (75MHz, DMSO-d6) δ 157.32,144.06,137.25,134.49,131.93, 130.01,129.94,129.09,128.89,128.61,128.34,128.23,128.14,127.48,126.30,119.97, 112.82,108.92,107.76,69.81,51.28.
Embodiment 33
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- phenyl -1H- imidazoles (I-31)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-31 (10mg, yield is obtained 17%).1H NMR (300MHz, CDCl3) δ 7.71 (t, J=8.7Hz, 2H), 7.60 (dd, J=6.3,2.7Hz, 2H), 7.55- 7.28 (m, 10H), 7.21 (m, 3H), 7.02 (s, 1H), 5.35 (s, 2H), 5.20 (s, 2H).13C NMR (75MHz, CDCl3)δ 157.15,148.27,136.71,133.99,132.17,131.92,130.57,129.38,128.97,128.89,128.81, 128.62,128.55,128.05,127.75,127.50,125.34,124.92,121.30,119.73,107.16,70.08, 50.47.
Embodiment 34
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- nitros -1H- imidazoles (I-32)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound 1-32 (20mg, yield is obtained 36%).1H NMR (300MHz, CDCl3) δ 7.74 (dd, J=8.6,3.2Hz, 2H), 7.62 (s, 1H), 7.57-7.32 (m, 5H), 7.29 (dd, J=8.6,2.2Hz, 2H), 7.23 (d, J=2.0Hz, 1H), 7.18 (s, 1H), 7.09 (s, 1H), 5.72 (s, 2H), 5.20 (s, 2H).13C NMR (75MHz, CDCl3) δ 157.50,136.58,134.43,130.86,129.49, 129.22,128.75,128.62,128.41,128.07,127.50,127.13,125.73,125.60,120.03,114.57, 107.13,70.09,53.55.
Embodiment 35
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -2- formoxyls -1H- pyrroles (I-33)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-33 (yield 52%) is obtained.1H NMR (300MHz, CDCl3) δ 9.59 (d, J=0.8Hz, 1H), 7.73-7.64 (m, 2H), 7.57-7.46 (m, 3H), 7.46- 7.28 (m, 4H), 7.25-7.17 (m, 2H), 7.04-6.95 (m, 2H), 6.32-6.23 (m, 1H), 5.70 (s, 2H), 5.18 (s, 2H).13C NMR (75MHz, DMSO-d6) δ 179.95,156.79,137.34,134.11,133.94,132.77,131.52, 130.07,129.71,128.86,128.72,128.64,128.30,128.21,127.50,126.17,125.82,124.83, 119.56,110.43,107.66,69.75,51.31.
Embodiment 36
The preparation of 1- { 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- pyrroles's -2- bases }-N- methyl methylamines (I-34)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-34 (yield 74%) is obtained.1H NMR (300MHz, CDCl3) δ 7.67 (d, J=8.5Hz, 2H), 7.49 (d, J=7.1Hz, 1H), 7.40 (dd, J=18.2, 8.4Hz, 4H), 7.19 (dd, J=18.5,9.5Hz, 3H), 6.73 (s, 1H), 6.27 (s, 1H), 6.15 (s, 1H), 5.37 (s, 2H), 5.18 (s, 2H), 4.40-4.25 (m, 1H), 3.76 (s, 2H), 2.40 (s, 3H).13C NMR (75MHz, CDCl3)δ 156.91,136.76,133.84,133.39,129.33,128.90,128.57,127.98,127.49,126.66,125.10, 125.02,123.36,119.46,110.99,107.46,107.10,70.02,50.77,45.59,33.74.
Embodiment 37
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -4- formoxyls -1H- imidazoles (I-35)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-35 (yield 30%) is obtained.1H NMR (300MHz, CDCl3) δ 9.87 (s, 1H), 7.77-7.68 (m, 2H), 7.68-7.57 (m, 3H), 7.48 (d, J=7.1Hz, 2H), 7.45-7.31 (m, 3H), 7.29 (d, J=2.4Hz, 1H), 7.23 (dd, J=5.7,2.1Hz, 2H), 5.27 (s, 2H), (5.18 s, 2H).13C NMR (75MHz, CDCl3) δ 186.17,157.52,138.82,136.54,134.43,130.89, 129.53,129.42,129.42,128.81,128.64,128.64,128.22,128.22,128.11,128.11,127.53, 127.53,126.96,125.45,124.60,120.13,107.12,70.09,51.68.
Embodiment 38
1- 1- [6- (pyridin-4-yl methoxyl group) naphthalene -2- bases] methyl] and -1H- imidazoles -2- bases }-N- methyl methylamine (I- 39) preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-39 (yield 26%) is obtained.1H NMR (300MHz, CDCl3) δ 8.62 (d, J=6.0Hz, 2H), 7.69 (t, J=9.1Hz, 2H), 7.44 (s, 1H), 7.39 (d, 2H), 7.26-7.17 (m, 2H), 7.13 (d, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 5.34 (s, 2H), 5.19 (s, 2H), 3.80 (s, 2H), 2.43 (s, 3H).13C NMR (75MHz, CDCl3) δ 150.02,146.11,145.88,133.86,132.16, 129.62,129.03,127.70,127.56,127.53,125.62,125.46,121.46,120.72,119.33,107.24, 68.17,49.60,47.66,36.02.
Embodiment 39
1- 1- [6- (1,1- diphenylmethyl epoxide) naphthalene -2- bases] methyl] and -1H- imidazoles -2- bases }-N- methyl methylamine (I- 40) preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-40 (yield 82%) is obtained.1H NMR (300MHz, CDCl3) δ 7.66 (d, J=9.0Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 7.47 (d, J=7.1Hz, 3H), 7.41 (s, 1H), 7.31 (dddd, J=9.7,7.3,5.6,1.6Hz, 7H), 7.20 (d, J=2.2Hz, 1H), 7.14 (dd, J=6.7,1.8Hz, 2H), 7.00 (s, 1H), 6.86 (s, 1H), 6.36 (s, 1H), 5.30 (s, 2H), 3.79 (s, 2H), 2.43 (s, 3H), 2.19 (s, 2H).13C NMR (75MHz, CDCl3) δ 156.30,146.08,140.98,133.85,131.80, 129.26,128.79,128.63,128.41,128.10,127.81,127.76,127.67,127.49,126.85,125.89, 125.52,125.12,120.67,120.08,109.40,81.86,49.61,47.65,36.00.
Embodiment 40
(E) -1- { 1- { [6- (Chinese cassia tree epoxide) naphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamines (I-41) Prepare
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-41 (yield 48.04%) is obtained.1H NMR (300MHz, CDCl3) δ 7.71 (dd, J=8.6,5.2Hz, 2H), 7.45 (d, J=11.1Hz, 3H), 7.38-7.21 (m, 5H), 7.03 (s, 1H), 6.91 (s, 1H), 6.80 (d, J=16.0Hz, 1H), 6.48 (dt, J=16.0,5.7Hz, 1H), 5.30 (s, 2H), 4.82 (d, J=5.7Hz, 2H), 3.82 (s, 2H), 2.45 (s, 3H).13C NMR (75MHz, CDCl3) δ 134.02, 133.22,131.79,129.34,128.80,128.57,127.93,127.66,126.55,125.62,125.28,124.11, 120.67,119.62,107.05,68.67,49.62,47.79,36.09,29.65.
Embodiment 41
The preparation of 1- { 1- [(6- phenylsulfonyloxy naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-42)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-42 (yield 63.20%) is obtained.1H NMR (300MHz, CDCl3) δ 7.76 (d, J=7.5Hz, 2H), 7.65-7.55 (m, 3H), 7.43 (t, J=7.7Hz, 2H), 7.36 (s, 2H), 7.19 (d, J=5.8Hz, 1H), 7.00 (dd, J=8.9,2.2Hz, 1H), 6.93 (s, 1H), 6.80 (s, 1H), 5.30 (s, 2H), 3.70 (s, 2H), 2.34 (s, 3H).13C NMR (75MHz, CDCl3) δ 147.39,146.24, 135.40,134.96,134.27,132.87,131.77,129.67,129.16,128.74,128.47,127.73,125.78, 125.41,121.78,120.67,119.85,49.46,47.82,36.08.
Embodiment 42
1- { 1- { [6- (1- benzoyls) methoxynaphthalene -2- bases] methyl } -1H- imidazoles -2- bases }-N- methyl methylamine (I- 43) preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-43 (yield 48%) is obtained.1H NMR (300MHz, CDCl3) δ 8.03 (d, J=7.4Hz, 2H), 7.72-7.59 (m, 3H), 7.51 (t, J=7.6Hz, 2H), 7.38 (s, 1H), 7.27 (dd, J=8.9,2.3Hz, 1H), 7.12 (dd, J=14.0,5.3Hz, 2H), 7.02 (s, 1H), 6.81 (s, 1H), 5.38 (s, 2H), 5.20 (s, 2H), 3.01 (dq, J=20.5,6.9Hz, 1H), 1.26 (d, J=6.8Hz, 6H).13C NMR (75MHz, DMSO-d6) δ 156.50,152.59,134.86,134.24,133.89,133.05,129.69,129.28, 128.80,128.34,127.75,126.00,125.88,125.27,120.85,119.44,114.56,107.80,70.71, 49.11,25.50,22.11.
Embodiment 43
The preparation of 1- { 1- [(6- benzylthio naphthalene -2- bases) methyl] -1H- imidazoles -2- bases }-N- methyl methylamines (I-44)
A.6- bromo- 2- naphthoic acids (500mg, 1.99mmol) are dissolved in 20mL and are dried in methyl alcohol, the 1mL concentrated sulfuric acids are added dropwise, at 80 DEG C It is heated to reflux 2h complete to reaction.Solvent is evaporated, saturation NaHCO3After neutralization, it is extracted with ethyl acetate, merges organic layer, satisfies And brine It, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains the bromo- 2- naphthoic acids methyl esters crude products of 6-, direct plunges into down Step reaction.(520mg, crude yield 98%)
B. by the bromo- 2- naphthoic acids methyl esters (265mg, 1mmol) of 6-, diisopropyl ethyl amine (259mg, 350 μ L, 2mmol) is molten In 5mL anhydrous dioxanes, after benzenethiol (248mg, 235 μ L, 2mmol) is added dropwise, addition Pd2 (dba) 3 (46mg, 5%), (5%) 58mg, under argon gas protection, is heated to reflux 16h complete to reaction to Xantphos at 105 DEG C.Solvent is evaporated, second is used Acetoacetic ester is extracted, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains 6- benzyl sulphur Base -2- naphthoic acid methyl esters crude products, direct plunge into the next step.(300mg, crude yield 97%)
C. 6- benzylthios -2- naphthoic acid methyl esters (600mg, 1.95mmol) is dissolved in 8mL dry tetrahydrofurans, 0 DEG C of ice bath Lower addition Lithium Aluminium Hydride solid (148mg, 3.89mmol), warms naturally to that 2h is stirred at room temperature.Add water and be quenched, dichloromethane extraction Take, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains (6- benzylthio naphthalene -2- bases) methyl alcohol crude product, Direct plunge into the next step.(337mg, crude yield 62%)
D. by (6- benzylthio naphthalene -2- bases) methyl alcohol (337mg, 1.2mmol), triphenylphosphine (946mg, 3.61mmol) is dissolved in In dry methylene chloride, the dichloromethane solution of carbon tetrabromide (1.20g, 3.61mmol) is added dropwise under 0 DEG C of ice bath, is warmed naturally to 2h is stirred at room temperature.Add water and be quenched, dichloromethane extraction, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column layer Benzyl [(6- bromomethyls) naphthalene 2- yls] thioether crude product is analysed to obtain, the next step is direct plungeed into.(270mg, crude yield 65%)
E. reactions steps are obtained target compound I-44 (yields with reference to the preparation method of the I-82 of the description of embodiment 4～5 72%).1H NMR (300MHz, CDCl3) δ 7.62-7.54 (m, 3H), 7.32 (m, 2H), 7.26-7.10 (m, 6H), 6.94 (s, 1H), 6.82 (s, 1H), 5.27 (s, 2H), 4.13 (s, 2H), 3.72 (s, 2H), 2.35 (s, 3H).13C NMR (75MHz, CDCl3) δ 146.30,134.71,133.95,133.14,131.67,128.79,128.52,128.35,128.24,128.15, 128.02,127.62,127.26,127.17,125.48,125.32,120.72,49.60,47.81,38.73,36.10.
Embodiment 44
The preparation of 1- [(6- benzyloxy naphthalene -2- bases) methyl] -1H- pyrroles's -2- methyl formates (I-45)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-45 (yield 39%) is obtained.1H NMR (300MHz, CDCl3) δ 7.80-7.66 (m, 3H), 7.50-7.23 (m, 9H), 7.04 (dd, J=3.8,1.6Hz, 1H), 6.93 (s, 1H), 5.69 (s, 2H), 5.18 (s, 2H), 3.78 (s, 3H).
Embodiment 45
The preparation of 1- ((6- (benzyloxy) naphthalene -2- bases) methyl) -4- phenyl -1H- imidazoles (I-47)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-47 (yield 29%) is obtained.1H NMR (300MHz, CDCl3) δ 7.75 (t, J=8.4Hz, 4H), 7.63 (d, J=14.0Hz, 2H), 7.49 (d, J=7.3Hz, 2H), 7.42 (s, 2H), 7.40-7.32 (m, 4H), 7.28 (d, J=2.3Hz, 1H), 7.26-7.19 (m, 3H), 5.26 (s, 2H), 5.19 (s, 2H).
Embodiment 46
The preparation of 1- ((6- (benzyloxy) naphthalene -2- bases) methyl) -1H- imidazoles -4- Ethyl formates (I-48)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-48 (yield 33%) is obtained.1H NMR (300MHz, CDCl3) δ 7.96 (s, 1H), 7.87 (s, 1H), 7.80-7.62 (m, 3H), 7.48 (s, 2H), 7.40 (d, J= 7.6Hz, 4H), 7.22 (s, 2H), 5.43 (s, 2H), 5.19 (s, 2H), 4.27 (d, J=7.1Hz, 2H), 1.32 (t, J= 7.1Hz, 3H).
Embodiment 47
The preparation of 1- ((6- (benzyloxy) naphthalene -2- bases) methyl) -5- methyl isophthalic acids H- imidazoles -4- formaldehyde (I-50)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-50 (yield 43%) is obtained.1H NMR (300MHz, CDCl3) δ 10.00 (s, 1H), 7.85-7.65 (m, 2H), 7.65-7.25 (m, 8H), 7.18 (d, J= 8.4Hz, 2H), 5.23 (s, 2H), 5.20 (s, 2H), 2.51 (s, 3H).
Embodiment 48
The preparation of 1- ((6- (benzyloxy) naphthalene -2- bases) methyl) -1H- imidazoles -5- formaldehyde (I-51)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-51 (yield 41%) is obtained.1H NMR (300MHz, CDCl3) δ 9.79 (s, 1H), 7.77 (t, J=21.7Hz, 4H), 7.61 (s, 1H), 7.49 (d, J=6.6Hz, 2H), 7.46-7.26 (m, 4H), 7.22 (s, 2H), 5.64 (s, 2H), 5.19 (s, 2H).
Embodiment 49
1- (1- ((6- (benzyloxy) naphthalene -2- bases) methyl) the chloro- 1H- imidazol-4 yls of -2- butyl -5-)-N- methyl methylamines (I-55) preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-55 (yield 89%) is obtained.1H NMR (300MHz, CDCl3) δ 7.68 (dd, J=11.3,8.9Hz, 2H), 7.39 (ddd, J=19.5,17.0,7.2Hz, 5H), 7.27-7.14 (m, 3H), 7.11 (d, J=8.4Hz, 1H), 5.35 (s, 2H), 5.17 (s, 2H), 3.59 (s, 2H), 2.62- 2.46 (m, 2H), 2.35 (s, 3H), 1.76-1.54 (m, 2H), 1.37-1.30 (m, 2H), 0.85 (t, J=7.3Hz, 3H).
Embodiment 50
The preparation of 1- (1- ((6- (benzyloxy) naphthalene -2- bases) methyl) -1H- imidazol-4 yls)-N- methyl methylamines (I-56)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-56 (yield 76%) is obtained.1H NMR (300MHz, CDCl3) δ 7.73-7.23 (m, 10H), 7.20-6.81 (m, 3H), 5.21 (s, 1H), 5.13 (s, 2H), 5.09 (d, J=8.1Hz, 2H), 3.76 (s, 2H), 2.45 (s, 3H).
Embodiment 51
N- methyl isophthalic acids-(1- ((6- ((3- benzyloxy phenoxy bases) oxygen) naphthalene -2- bases) methyl) -1H- imidazol-4 yls) methylamine (I-57) Preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-57 (yield 73%) is obtained.1H NMR (300MHz, CDCl3) δ 7.74-7.63 (m, 2H), 7.44 (s, 1H), 7.40-7.25 (m, 3H) 7.25-7.06 (m, 6H), 7.04-6.93 (m, 4H), 6.88 (s, 1H), 5.31 (s, 2H), 5.13 (s, 2H), 3.79 (s, 2H), 2.45 (s, 1H), 2.42 (s, 3H).
Embodiment 52
1- (1- ((6- (3- (4- methoxyphenyls) propoxyl group) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases)-N- methyl first The preparation of amine (I-59)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-59 (yield 44%) is obtained.1H NMR (500MHz, CDCl3) δ 7.71 (d, J=8.4Hz, 2H), 7.49 (s, 1H), 7.27-7.02 (m, 6H), 6.97-6.81 (m, 3H), 5.38 (s, 2H), 4.10 (s, 2H), 3.89 (s, 2H), 3.83 (s, 3H), 2.92 (s, 1H), 2.84 (s, 2H), 2.50 (s, 3H), 2.18 (s, 2H).
Embodiment 53
1- (1- ((6- (benzyloxy) naphthalene -2- bases) methyl) -4- methyl isophthalic acid H- imidazoles -5- bases)-N- methyl methylamines (I-60) Preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-60 (yield 53%) is obtained.1H NMR (300MHz, CDCl3) δ 7.76-7.03 (m, 12H), 5.34 (s, 2H), 5.16 (s, 2H), 3.60 (s, 2H), 3.08 (s, 0H), 2.35 (s, 3H), 2.23 (s, 3H).
Embodiment 54
N- ((1- ((6- ((4- bromobenzyls) oxygen) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases) methyl)-N- methyl benzamides (I-61) preparation
A is obtained compound I-8 (yield 53%) with reference to the preparation method of the I-82 of the description of embodiment 1～5.1H NMR (300MHz, CDCl3) δ 7.68 (d, J=8.6Hz, 2H), 7.52 (d, J=8.1Hz, 2H), 7.45 (s, 1H), 7.34 (d, J= 8.1Hz, 2H), 7.28-7.18 (m, 2H), 7.17 (s, 1H), 7.01 (s, 1H), 6.85 (d, J=17.8Hz, 1H), 5.33 (s, 2H), 5.22-5.02 (m, 2H), 3.75 (d, J=33.2Hz, 2H), 2.43 (s, 3H).
Benzoic acid (5.59mg, 0.0458mmol) is dissolved in dichloromethane (2mL) by b, and EDCI is successively added under room temperature (8.78mg, 0.0458mmol), HOBT (6.188mg, 0.0458mmol), adds triethylamine (12.75 μ L, 0.0916mmol), It is eventually adding compound I-8 (20mg, 0.0458mmol).It is stirred at room temperature complete to reaction.Add water and reaction is quenched, use ethyl acetate Extraction, merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.It is evaporated rear silica gel column chromatography and obtains target compound I- 61 (20mg, yields 81%).1H NMR (300MHz, CDCl3) δ 8.10 (d, J=7.5Hz, 1H), 7.66 (t, J=7.7Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 7.45 (d, J=7.5Hz, 1H), 7.33 (dd, J=16.1,8.0Hz, 3H), 7.18 (d, J=6.0Hz, 5H), 7.05-6.91 (m, 3H), 5.53 (s, 2H), 5.14 (s, 2H), 4.99 (s, 2H), 2.95 (s, 3H).
Embodiment 55
N- ((1- ((6- ((4- bromobenzyls) oxygen) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases) methyl)-N- methylacetamides (I-62) preparation
With reference to the preparation method of the I-61 of the description of embodiment 54, target compound I-62 (yield 84%) is obtained.1H NMR (300MHz, CDCl3) δ 7.67 (d, J=8.5Hz, 2H), 7.52 (d, J=8.3Hz, 2H), 7.46-7.20 (m, 4H), 7.20- 6.91 (m, 4H), 5.37 (s, 2H), 5.11 (s, 2H), 4.73 (s, 2H), 2.86 (d, J=9.7Hz, 3H), 1.69 (s, 3H).
Embodiment 56
N- ((1- ((6- ((4- bromobenzyls) oxygen) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases) methyl)-N- methylbutyryl amine (I-63) preparation
With reference to the preparation method of the I-61 of the description of embodiment 54, target compound I-63 (yield 88%) is obtained.1H NMR (300MHz, CDCl3) δ 7.85 (d, J=8.7Hz, 2H), 7.72 (d, J=8.4Hz, 2H), 7.54 (d, J=8.4Hz, 2H), 7.41 (dd, J=35.8,4.3Hz, 5H), 7.17 (s, 1H), 5.57 (s, 2H), 5.31 (s, 2H), 4.93 (s, 2H), 3.05 (s, 3H), 2.00 (s, 2H), 1.63 (d, J=7.3Hz, 2H), 0.95 (t, J=7.4Hz, 3H).
Embodiment 57
N- ((1- ((6- ((4- bromobenzyls) oxygen) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases) methyl)-N-METHYLFORMAMIDE (I-64) preparation
With reference to the preparation method of the I-61 of the description of embodiment 54, target compound I-64 (yield 86%) is obtained.1H NMR (300MHz, CDCl3) δ 8.05 (s, 1H), 7.88 (d, J=9.4Hz, 2H), 7.72 (d, J=8.4Hz, 2H), 7.56 (t, J= 10.2Hz, 3H), 7.48-7.33 (m, 3H), 7.16 (s, 1H), 5.54 (s, 2H), 5.31 (s, 2H), 4.85 (s, 2H), 3.06 (s, 3H).
Embodiment 58
The preparation of N- methyl isophthalic acids-(1- (4- (naphthalene -2- methoxyl groups) benzyl) -1H- imidazoles -2- bases) methylamine (I-65)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-65 (yield 84%) is obtained.1H NMR (300MHz, CDCl3) δ 7.92-7.81 (m, 4H), 7.58-7.44 (m, 3H), 7.03 (dd, J=24.6,7.8Hz, 5H), 6.84 (s, 1H), 5.23 (s, 2H), 5.15 (s, 2H), 3.82 (d, J=9.0Hz, 2H), 2.45 (s, 3H), 2.36 (s, 1H).
Embodiment 59
The preparation of 1- ((6- (benzyloxy) naphthalene -2- bases) methyl) -1H- imidazoles -2- amine (I-69)
The preparation method of the compound F for a. describing with reference to embodiment 1～4, is obtained compound I-32 (yield 36%).1H NMR (300MHz, CDCl3) δ 7.74 (dd, J=8.6,3.2Hz, 2H), 7.62 (s, 1H), 7.57-7.32 (m, 5H), 7.29 (dd, J=8.6,2.2Hz, 2H), 7.23 (d, J=2.0Hz, 1H), 7.18 (s, 1H), 7.09 (s, 1H), 5.72 (s, 2H), 5.20 (s, 2H).
The preparation method of the compound D for b. describing with reference to embodiment 2, obtains target compound I-69 (yield 56%).1H NMR (300MHz, CDCl3) δ 7.72 (dd, J=8.6,3.4Hz, 2H), 7.60 (s, 1H), 7.41 (ddd, J=19.6,14.8, 7.0Hz, 5H), 7.31-7.14 (m, 5H), 5.71 (s, 2H), 5.18 (s, 2H).
Embodiment 60
1- (1- ((6- (4- bromobenzene ethyoxyls) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases)-N-'s methyl methylamines (I-71) Prepare
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-71 (yield 51%) is obtained.1H NMR (300MHz, DMSO-d6) δ 7.76 (dd, J=8.7,4.3Hz, 2H), 7.60 (s, 1H), 7.50 (d, J=8.3Hz, 2H), 7.35-7.25 (m, 4H), 7.20-7.07 (m, 1H), 6.82 (s, 1H), 5.36 (s, 2H), 4.29 (t, J=6.7Hz, 2H), 3.67 (s, 2H), 3.07 (t, J=6.7Hz, 2H), 2.25 (s, 3H).
Embodiment 61
1- (1- ((6- (3- (4- bromobenzenes) propoxyl group) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases)-N- methyl methylamine (I- 72) preparation
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-72 (yield 62%) is obtained.1H NMR (300MHz, DMSO-d6) δ 7.76 (d, J=8.8Hz, 2H), 7.61 (s, 1H), 7.47 (d, J=8.3Hz, 2H), 7.29 (dd, J=11.2,2.1Hz, 2H), 7.22 (d, J=8.3Hz, 2H), 7.17 (dd, J=9.0,2.5Hz, 1H), 7.14 (d, J= 0.9Hz, 1H), 6.82 (d, J=0.9Hz, 1H), 5.36 (s, 2H), 4.06 (t, J=6.3Hz, 2H), 3.67 (s, 2H), 2.76 (t, J=7.6Hz, 2H), 2.25 (s, 3H), 2.11-2.01 (m, 2H).
Embodiment 62
The preparation of N- ((1- ((6- benzyloxy naphthalene -2- bases) methyl) -1H- imidazoles -2- bases) methyl) propyl group -1- amine (I-74)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-74 (yield 50%) is obtained.1H NMR (300MHz, CDCl3) δ 7.69 (d, J=8.3Hz, 1H), 7.48 (d, J=7.1Hz, 2H), 7.44-7.31 (m, 2H), 7.22 (d, J=3.6Hz, 1H), 7.00 (s, 1H), 6.89 (s, 1H), 5.35 (s, 1H), 5.25-5.15 (m, 1H), 2.58 (t, J =7.0Hz, 1H), 1.47 (dd, J=14.6,7.2Hz, 1H), 0.88 (t, J=7.4Hz, 1H).
Embodiment 63
The preparation of N- ((1- ((6- benzyloxy naphthalene -2- bases) methyl) -1H- imidazoles -2- bases) methyl) butyl -1- amine (I-75)
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-75 (yield 56%) is obtained.1H NMR (300MHz, CDCl3) δ 7.70 (d, J=7.9Hz, 2H), 7.49 (d, J=7.0Hz, 3H), 7.46-7.27 (m, 4H), 7.26-7.19 (m, 2H), 7.06 (s, 1H), 6.95 (s, 1H), 5.44 (s, 2H), 5.24-5.12 (m, 2H), 4.02 (s, 2H), 2.92-2.74 (m, 2H), 1.71-1.50 (m, 2H), 1.34 (td, J=14.6,7.1Hz, 2H), 0.88 (t, J=7.3Hz, 3H)。
Embodiment 64
The system of N- methyl isophthalic acids-(1- ((6- (3- phenylpropyl alcohol epoxides) naphthalene -2- bases) methyl) -1H- imidazoles -2- bases) methylamine (I-77) It is standby
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-77 (yield 67%) is obtained.1H NMR (300MHz, CDCl3) δ 7.69 (d, J=8.7Hz, 1H), 7.52-7.27 (m, 2H), 7.23 (dd, J=10.2,5.9Hz, 2H), 7.10 (s, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 5.33 (s, 1H), 4.06 (dd, J=12.7,6.4Hz, 1H), 3.84 (s, 1H), 3.17 (s, 1H), 2.87 (t, J=7.5Hz, 1H), 2.46 (s, 2H), 2.23-2.11 (m, 1H).
Embodiment 65
N, N- dimethyl -4- (3- ((6- ((2- ((methylamine) methyl) -1H- imidazoles -1- bases) methyl) naphthalene -2- bases) oxygen) third Base) aniline (I-78) preparation
A. the bromo- 3- phenyl-propanes (2g, 10mmol) of 1- are dissolved in into DCM, under condition of ice bath, add the μ L of the concentrated sulfuric acid 700, dense nitre 1400 μ L of acid, magnetic agitation 4h under the conditions of 0 DEG C, reaction is complete.Add water and reaction is quenched, extracted with DCM, merge organic layer, washing Organic phase, saturated common salt water washing, organic phase anhydrous sodium sulfate drying.Solvent is evaporated rear silica gel column chromatography and obtains compound 1- (3- bromopropyls) -4- nitrobenzene (1.032g, yield 43%).
B. 1- (3- bromopropyls) -4- nitrobenzene (73mg, 0.3mmol) will be dissolved in and will be dissolved in absolute ethyl alcohol, add reduced iron powder (50mg, 0.9mmol), adds the 2MHCl aqueous solution, and 2h is stirred at room temperature, and reaction is complete.Iron powder in reactant liquor is filtered, decompression The ethanol in filtrate is distilled, ethyl acetate extraction is added, merges organic layer, wash organic phase, saturated common salt water washing is organic Mutually use anhydrous sodium sulfate drying.Solvent is evaporated rear silica gel column chromatography and obtains compound 4- (3- bromopropyls) aniline (18mg, yield 28%)
C. 4- (3- bromopropyls) aniline (60mg, 0.28mmol) is dissolved in into dry DMF (5mL), adds K2CO3(116mg, 0.84mmol), iodomethane (44 μ L, 0.7mmol) is dropwise instilled, is stirred at room temperature to reaction completely, add excessive ammonia that iodine is quenched Methane, by the K in reactant liquor2CO3Filter out, add ethyl acetate extraction, merge organic layer, 20mL water is added in organic phase, Washing organic phase 4 times, uses afterwards saturated common salt water washing, organic phase anhydrous sodium sulfate drying.Solvent is evaporated rear silica gel column layer Analyse to obtain the bromo- 3- of compound 1- (4-N, N- dimethylamino) phenyl-propane (61mg, yield 91%)
The preparation method of the I-82 for d. describing with reference to embodiment 1～5, is obtained target compound I-78 (yield 59%).1H NMR (300MHz, CDCl3) δ 7.66 (d, J=8.7Hz, 2H), 7.43 (s, 1H), 7.18 (d, J=8.7Hz, 2H), 7.09 (d, J =8.6Hz, 3H), 7.00 (s, 1H), 6.88 (s, 1H), 6.70 (d, J=8.5Hz, 2H), 5.32 (s, 2H), 4.05 (t, J= 6.3Hz, 2H), 3.81 (s, 2H), 2.90 (s, 6H), 2.75 (t, J=7.4Hz, 2H), 2.44 (s, 3H), 2.13 (dd, J= 13.7,6.9Hz, 2H).
Embodiment 66
4- ((6- ((2- ((methylamine) methyl) -1H- imidazoles -1- bases) methyl) naphthalene -2- bases) oxygen) methyl butyrate (I-79) Prepare
With reference to the preparation method of the I-82 of the description of embodiment 1～5, target compound I-79 (yield 59%) is obtained.1H NMR (300MHz, CDCl3) δ 7.66 (t, J=9.0Hz, 2H), 7.42 (s, 1H), 7.24-7.07 (m, 3H), 7.01 (s, 1H), 6.90 (s, 1H), 5.32 (s, 2H), 4.10 (s, 2H), 3.82 (s, 2H), 2.80 (d, J=4.8Hz, 3H), 2.43 (s, 3H), 2.41 (d, J=7.5Hz, 2H), 2.19 (s, 2H).
Embodiment 66
The preparation of 1- ((6- benzyloxy naphthalene -2- bases) methyl) -2- ethyls -4- methyl isophthalic acids H- imidazoles (I-81)
With reference to the preparation method of the compound F of the description of embodiment 1～4, target compound I-81 (yield 49%) is obtained.1H NMR (300MHz, CDCl3) δ 7.71 (d, J=8.5Hz, 2H), 7.50 (d, J=7.2Hz, 2H), 7.41 (dd, J=13.0, 5.5Hz, 4H), 7.26 (d, J=11.0Hz, 2H), 7.18 (d, J=8.4Hz, 1H), 6.56 (s, 1H), 5.19 (s, 2H), 5.11 (s, 2H), 2.73-2.61 (m, 2H), 2.23 (s, 3H), 1.30 (d, J=7.5Hz, 3H).
Embodiment 67
The preparation of Pharmaceutical composition：Tablet
Compound I-82 (1g) is mixed with lactose (23g) and microcrystalline cellulose (5.7g) with mixer.Compressed with roller bearing Machine is compressing by gained mixture, is worth flake sheeted product.The laminar sheeted product is ground with beater grinder Grinds, make gained granular material pass through 20 mesh sieves.By a light silicon dioxide (0.3g) and magnesium stearate (0.3g) In being added to screened material, and mix.Gained mix products pelleter compressing tablet, prepares tablet.
Embodiment 68
The preparation of Pharmaceutical composition：Gelatine capsule agent
Compound I-82 (1g) and microcrystalline cellulose (0.35g) and lactose (0.15g) are pelletized with water, then by the particle Mix with hinge sodium carboxymethylcellulose (0.04g) and magnesium stearate (0.01g).Gained mix products filling gelatine capsule, system Standby gelatine capsule agent.

Claims (6)

1. the compound or pharmaceutically acceptable salt or solvate shown in formula I：
Wherein, W is independently chosen from CH, N or CR5；
X is O, N or S；
N is 0～5；
R1For H, 1～6 carbon from chain or branched alkyl, non-substituted or aryl or heteroaryl containing one or more substituents, Styryl, benzenesulfonyl, diarylmethyl, benzoyl or COOR9；
R2For H, NO2、NH2, halogen, CN, trifluoromethyl, formoxyl, CH (R6)NR7R8, 1～12 carbon straight or branched alkane The straight or branched alkyl of 1～6 carbon that base, hydroxyl replace, the aryl or heteroaryl of non-substituted or one or more replacements；
R3、R4It is independently chosen from H, NO2, halogen, CN, trifluoromethyl, COOR9, formoxyl, the straight or branched alkyl of 1～12 carbon, CH(R6)NR7R8, it is non-substituted or one or more replace aryl or heteroaryl；
R5Selected from NO2, it is halogen, CN, trifluoromethyl, formoxyl, the straight or branched alkyl of 1～12 carbon, non-substituted or one Or multiple substituted aryl or heteroaryl；
R6For the alkyl of H or 1～6 carbon；
R7、R8Be independently chosen from H, 1～6 carbon from chain or branched alkyl, COR10；
R9、R10Be independently chosen from H, the straight or branched alkyl of 1～12 carbon, non-substituted or one or more aryl for replacing or Heteroaryl.
2. compound as claimed in claim 1, it is characterised in that in the compound of formula I：
W preferred N or CH；
The preferred O of X；
N preferably 0～3；
R1It is preferred that aryl or heteroaryl non-substituted or containing one or more substituents；
R2It is preferred that CH (R6)NR7R8Or the straight or branched alkyl of 1～12 carbon, wherein, R6It is preferred that H；R7It is preferred that H；R8It is preferred that 1～6 The straight or branched alkyl of individual carbon；
R3、R4The straight or branched alkyl of preferred H, 1～12 carbon alone.
3. compound as claimed in claim 1, it is characterised in that the Formulas I includes following compound：
4. the compound of formula I of claim 1 or its pharmaceutically acceptable salt or solvate are preparing prevention or are treating tumour Application in disease medicament.
5. it is a kind of prevention or treat tumor disease pharmaceutical composition, it is characterised in that in described pharmaceutical composition containing treatment The compound of formula I of effective dose or its pharmaceutically acceptable salt or solvate are used as active ingredient and pharmaceutically acceptable load Body.
6. pharmaceutical composition according to claim 5, 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.
CN201610871845.7A 2015-10-30 2016-09-27 N-naphthylalkyl-substituted nitrogen-containing heterocyclic derivatives and preparation method and antitumor application thereof Pending CN106632060A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115572247A (en) * 2022-10-21 2023-01-06 中国药科大学 A retinoid K 3 Derivatives and medical use thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115572247A (en) * 2022-10-21 2023-01-06 中国药科大学 A retinoid K 3 Derivatives and medical use thereof
CN115572247B (en) * 2022-10-21 2023-08-11 中国药科大学 Vitamin K 3 Derivatives and medical use thereof

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