WO2018050108A1 - 氘代3-(4,5-取代氨基嘧啶)苯基衍生物及其应用 - Google Patents

氘代3-(4,5-取代氨基嘧啶)苯基衍生物及其应用 Download PDF

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WO2018050108A1
WO2018050108A1 PCT/CN2017/102027 CN2017102027W WO2018050108A1 WO 2018050108 A1 WO2018050108 A1 WO 2018050108A1 CN 2017102027 W CN2017102027 W CN 2017102027W WO 2018050108 A1 WO2018050108 A1 WO 2018050108A1
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compound
cancer
egfr
pharmaceutically acceptable
mmol
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PCT/CN2017/102027
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English (en)
French (fr)
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朱永强
刘兆刚
冯超
胡诗合
陈浩
白恩赫
王佳
石晶淼
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江苏正大丰海制药有限公司
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Priority claimed from CN201610833361.3A external-priority patent/CN107840847A/zh
Priority claimed from CN201710413610.8A external-priority patent/CN108976229A/zh
Application filed by 江苏正大丰海制药有限公司 filed Critical 江苏正大丰海制药有限公司
Priority to ES17850310T priority Critical patent/ES2863925T3/es
Priority to US16/333,700 priority patent/US10654851B2/en
Priority to KR1020197007580A priority patent/KR102245280B1/ko
Priority to CN201780056474.XA priority patent/CN109689657B/zh
Priority to JP2019536634A priority patent/JP6746794B2/ja
Priority to EP17850310.8A priority patent/EP3498708B1/en
Priority to AU2017326029A priority patent/AU2017326029B2/en
Priority to CA3037097A priority patent/CA3037097C/en
Publication of WO2018050108A1 publication Critical patent/WO2018050108A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention belongs to the technical field of antitumor drugs, in particular to deuterated 3-(4,5-substituted aminopyrimidine) phenyl derivatives and their use in preparing antitumor drugs.
  • chemotherapy is the main treatment; chemotherapy drugs non-specifically block cell division and cause cell death. While killing tumor cells, they also greatly destroy the growth of normal human cells. Many adverse reactions. Many people are pessimistic and even give up treatment because of concerns about the serious side effects of chemotherapy. Coupled with the drug resistance of chemotherapy drugs, chemotherapy for non-small cell lung cancer (NSCLC) is not optimistic, and prolonging the chemotherapy cycle only increases the side effects. Did not increase the efficacy. At the same time, non-small cell lung cancer cells are not sensitive to chemotherapy and conventional chemotherapy, and the total response rate is only about 25%. Due to these reasons, the five-year survival rate of non-small cell lung cancer patients is less than 20%.
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • TKI small molecule tyrosine kinase inhibitor
  • MAb monoclonal antibody
  • Second-generation inhibitors such as afatinib and Dacomitinib, which are superior to the first generation, are characterized by increased recognition of EGFR, which can distinguish between tumor cells and normal cells, thus reducing side effects.
  • these molecules have poor selectivity for the T790M mutant of EGFR, resulting in a lower dose of clinical tolerance.
  • MTD maximum tolerated dose
  • the current EGFR-TKI still can not solve the clinical needs caused by drug resistance, and the existing drugs are mostly EGFR reversible or irreversible inhibitors with quinazoline or quinolinamide as the basic mother nucleus.
  • the toxic side effects caused by the poor selectivity of wild-type cells are also unavoidable. Therefore, new types, especially novel skeleton compounds, are urgently needed in clinical practice to solve problems such as drug resistance and poor selectivity.
  • the object of the invention can be achieved by the following measures:
  • the deuterated 3-(4,5-substituted aminopyrimidine)phenyl derivative of the present invention is a compound having the structure of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1, R 2 is selected from -CH 3 or -CD 3
  • R 3 and R 4 are selected from -CH 3 , CD 3 or H
  • at least one of R 1, R 2, R 3 and R 4 is -CD 3 .
  • R 1 is -CH 3 .
  • Step 1 Dissolving Compound II and 2,4-dichloropyrimidine in a solvent, and obtaining a III by nucleophilic substitution reaction in the presence of a Lewis acid, wherein the solvent is selected from the group consisting of ethylene glycol dimethyl ether (DME), toluene, Chlorobenzene or a mixture thereof; the Lewis acid is selected from the group consisting of aluminum trichloride or boron trifluoride;
  • DME ethylene glycol dimethyl ether
  • the Lewis acid is selected from the group consisting of aluminum trichloride or boron trifluoride;
  • Step 2 Intermediate III and 4-fluoro-2-methoxy-5-nitroaniline are dissolved in a solvent to obtain IV under the action of p-toluenesulfonic acid, wherein the solvent is selected from 1,4-dioxane, N,N-dimethylformamide (DMF) or a mixture thereof;
  • the solvent is selected from 1,4-dioxane, N,N-dimethylformamide (DMF) or a mixture thereof;
  • Step 3 Intermediate IV and an organic amine are dissolved in a solvent, and reacted under the action of DIPEA to obtain Intermediate V, wherein the solvent is selected from dimethyl benzoate (DMA), dimethylacetamide (DMAc), N, N- Dimethylformamide (DMF) or a mixture thereof;
  • the solvent is selected from dimethyl benzoate (DMA), dimethylacetamide (DMAc), N, N- Dimethylformamide (DMF) or a mixture thereof;
  • Step 4 The intermediate V is dissolved in a solvent, and the intermediate V is reduced to the intermediate VI using Pd/C as a reducing agent, wherein the solvent is selected from methanol or ethanol;
  • Step 5 Intermediate VI is reacted with chloropropionyl chloride in tetrahydrofuran/water as a solvent to obtain an intermediate compound. Without isolation, the reaction is carried out by directly adding sodium hydroxide to obtain a compound having the structure of formula (I).
  • Salts which may be formed by the compounds of the invention are also within the scope of the invention. Unless otherwise stated, the compounds of the invention are understood to include the salts thereof.
  • a compound of formula (I) is reacted with an amount of an equivalent amount of an acid or base, salted out in a medium, or lyophilized in an aqueous solution.
  • the basic fragments contained in the compounds of the present invention including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids.
  • Typical salts which may be formed include acetates, adipates, alginates, ascorbates, aspartates, benzoates, besylate, p-toluenesulfonate, hydrogen sulfate, Borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, ethane sulfonate, fumarate, Portuguese Heptanoate, glycerol phosphate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, lactate, maleate, methanesulfonate , naphthalene sulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate, phosphate, picrate, pi
  • the compound of the present invention which is obtained by the preparation, separation and purification in turn, has a weight content of 90% or more, for example, 95% or more, equal to or more than 99% ("very pure” compound), which is described in the text. Listed. Such "very pure” compounds of the invention are also contemplated herein as part of the present invention.
  • the invention also discloses the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation or prevention of a tumor drug.
  • Such tumors include, but are not limited to, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma, nasopharyngeal cancer.
  • One aspect of the invention provides a compound of formula (I) for use in the treatment or prevention of an EGFR mediated disease, disorder, disorder or condition mediated by EGFR or by an activating mutant or resistant mutant.
  • EGFR-mediated diseases, disorders, disorders, or conditions mediated by EGFR or by activating mutant or resistant mutants include, but are not limited to, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, breast cancer, prostate cancer, Liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal stromal tumor, leukemia, histiocytic lymphoma or nasopharyngeal carcinoma.
  • EGFRs in the form of activating mutant or resistant mutants include, but are not limited to, L858R activating mutants, Exon19 deletion activating mutants, and T790M resistant mutants.
  • the compounds of formula (I) of the present invention may be combined with other agents known to treat or ameliorate similar conditions.
  • the mode of administration and the dosage of the original drug remain unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
  • the compound of the formula (I) is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing both one or several known drugs and a compound of the formula (I).
  • Combination of drugs also includes the administration of a compound of formula (I) with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula (I) or a known drug may be lower than when they are administered alone.
  • Drugs or active ingredients which may be combined with a compound of formula (I) include, but are not limited to, the following:
  • the pharmaceutical or active ingredient that can be administered in combination with a compound of formula (I) includes, but is not limited to, the following: adiponectin, alendronate, interferon, atrexine, allopurinol , sodium bismuth citrate, palonosetron hydrochloride, hexamethylene melamine, aminoglutamine, amifostine, anrubicin, ampicillin, anatoxazole, dolasetron, aranesp, Arglabin, arsenic trioxide, anoxin, 5-azacytidine, azathioprine, BCG or tici BCG, betahidine, betamethasone acetate, betamethasone sodium phosphate inhibitor, bexarotene, bleomycin sulfate , Bromouridine, bortezomib, ceffizomib, busulfan, calcitonin, alemtuzumab injection, capecitabine, carboplatin, constance
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant or carrier.
  • pharmaceutically acceptable excipient or carrier refers to a pharmaceutically acceptable material, ingredient or medium, such as a liquid or solid filler, diluent, adjuvant, solvent or encapsulating material, including from an organ or part of the body. Carry or transport the main pharmaceutical agent to another organ or part of the body. Each carrier must be “acceptable” and compatible with other forms of pharmaceutical ingredients without harm to the patient.
  • Some examples of pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as wheat starch and potato starch starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Cellulose, cellulose acetate, powdered tragacanth, malt, gelatin, talcum powder; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil; glycols such as butanediol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and hydrogen Alumina; alginic acid; pyrogen-free water; physiological saline; Ringer's solution; ethanol; phosphate buffer, and other
  • the compounds of the present invention are administered to humans and animals as pharmaceutical agents, they can be administered by themselves or as a pharmaceutical composition.
  • a pharmaceutical composition for example, it comprises from 0.1% to 99.5%, preferably from 0.5% to 90%, of the active ingredient and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be administered by intravenous, intramuscular, intraperitoneal, subcutaneous, topical, oral, or other acceptable means.
  • the invention also provides a pharmaceutical pack or kit comprising one or more packages containing a pharmaceutical combination of one or more of the ingredients of the invention.
  • Optional such packages are produced in the form of announcements by government agencies, using or selling pharmaceuticals or biological products, using or selling therapeutic formulations for humans, in a published manner permitted in production regulations.
  • the deuterated compound of the present invention has an enzyme and cell level biological activity similar to AZD9291 and has lower cardiotoxicity.
  • the deuterated compounds of the present invention provide more options for novel antitumor drugs, and have good prospects for drug application.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the method for detecting the kinase activity of EGFR wild type, EGFR (T790M, L858R) double mutant and EGFR (L858R) single mutant was established by homogeneous time-resolved fluorescence (HTRF) method, and the inhibitory activity of the compound was determined.
  • HTRF homogeneous time-resolved fluorescence
  • the reaction solution 8uL configuration comprising 1 ⁇ enzymatic buffer (Cisbio, HTRF KinEASE TM -TK), 5mM MgCl2,1mM MnCl2,1mM DTT, 0.5 ⁇ M TK substrate-biotin (Cisbio, HTRF KinEASETM-TK) 10 ⁇ M ATP, graded concentrations Compound and 0.04 ng/ ⁇ L EGFR or 0.025 ng/ ⁇ L EGFR (T790M, L858R) or EGFR (L858R).
  • the compound was diluted to 9 concentrations three times from the reaction concentration of 1000 nM.
  • the DMSO concentration in the reaction system was 2%.
  • the enzyme and compound were pre-incubated for 15 minutes and then ATP and substrate were added to initiate the reaction. All enzyme catalyzed reactions were carried out at 25 ° C for 60 minutes. After the end of the enzyme-catalyzed reaction, 4 ⁇ L of TK antibody-cryptate and 4 ⁇ L of streptavidin-XL665 (reaction concentration: 62.5 nM) were added to the reaction mixture, and incubation was continued at 25 ° C for 60 minutes. After incubation the fluorescence detected in HTRF CLARIOstar (BMG LABTECH), and is calculated using GraphPad Prism 5.0 IC 50.
  • the deuterated compound of the present invention has an enzyme biological activity similar to that of AZD9291.
  • Test 1 EGFR wild-type cell phosphorylation test
  • the human squamous cell carcinoma cell line A431 expresses wild-type EGFR and is purchased from the Chinese Academy of Sciences cell bank. A431 was maintained in EMEM medium containing 10% fetal calf serum. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 . Endogenous p-EGFR in cell lysates was assayed according to the protocol described in the Phospho-EGFR HTRF kit (Cisbio, Cat. #64HR1PEG). 100 ⁇ L of the cells were seeded in a 96-well plate (50,000 cells/well), and cultured overnight at 37 ° C in a 5% CO 2 cell incubator.
  • a 4-fold diluted compound was added to the cells at a maximum concentration of 10 ⁇ M. After continuing to incubate for 2 hours, 100 ng/well of EGF was added and incubated at 37 ° C for 10 minutes, then the culture solution was discarded, and 25 ⁇ L/well of lysate was immediately added, and the cells were lysed at room temperature for 10 minutes, and then 12 ⁇ L/well was added to the Greiner white low.
  • detection antibodies Anti-phospho EGFR-d2 and Anti-EGFR-Tb
  • the human non-small cell lung cancer cell line HCC827 (Exon19 deletion EGFR, activated single mutant) was purchased from the Chinese Academy of Sciences cell bank. HCC827 was maintained in medium containing 10% fetal bovine serum RPMI 1640. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 . Endogenous p-EGFR in cell lysates was assayed according to the protocol described in the Phospho-EGFR HTRF kit (Cisbio, Cat. #64HR1PEG). 100 ⁇ L of the cells were seeded in a 96-well plate (50,000 cells/well), and cultured overnight at 37 ° C in a 5% CO 2 cell incubator.
  • a 4-fold diluted compound was added to the cells at a maximum concentration of 10 ⁇ M. After the culture was continued for 2 hours, the culture solution was discarded, and 25 ⁇ L/well of the lysate was immediately added, and the cells were lysed at room temperature for 10 minutes, and then 12 ⁇ L/well was added to a Greiner white low-volume 384-well plate, and a detection antibody (Anti-phospho EGFR-) was added. D2 and Anti-EGFR-Tb) were incubated at 25 ° C for 60 minutes. After incubation the fluorescence detected in HTRF CLARIOstar (BMG LABTECH), and is calculated using GraphPad Prism 5.0 IC 50.
  • Test 3 EGFR (T790M, L858R) double mutant cell phosphorylation test
  • the human non-small cell lung cancer cell line NCI-H1975 expresses the EGFR (T790M, L858R) double mutant and is purchased from the cell bank of the Chinese Academy of Sciences. NCI-H1975 was maintained in medium containing 10% fetal bovine serum RPMI 1640. The cells were grown at 37 ° C in a humidified incubator with 5% CO 2 . Endogenous p-EGFR in cell lysates was assayed according to the protocol described in the Phospho-EGFR HTRF kit (Cisbio, Cat. #64HR1PEG). 100 ⁇ L of the cells were seeded in a 96-well plate (50,000 cells/well), and cultured overnight at 37 ° C in a 5% CO 2 cell incubator.
  • a 4-fold diluted compound was added to the cells at a maximum concentration of 10 ⁇ M. After the culture was continued for 2 hours, the culture solution was discarded, and 25 ⁇ L/well of the lysate was immediately added, and the cells were lysed at room temperature for 10 minutes, and then 12 ⁇ L/well was added to a Greiner white low-volume 384-well plate, and a detection antibody (Anti-phospho EGFR-) was added. D2 and Anti-EGFR-Tb) were incubated at 25 ° C for 60 minutes. After incubation the fluorescence detected in HTRF CLARIOstar (BMG LABTECH), and is calculated using GraphPad Prism 5.0 IC 50.
  • the deuterated compound of the present invention has a cell-level biological activity similar to that of AZD9291.
  • HEK293 cells stably expressing the hERG channel were cultured in a 35 mm culture dish and placed in a 37 ° C / 5% CO 2 incubator for at least 24 hours before use in the experiment.
  • the cell culture medium was DMEM containing 10% fetal calf serum and 250 ⁇ g/mL G418.
  • the components of the extracellular fluid used in the whole cell patch clamp experiment were (mM): NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
  • the intracellular fluid (mM) was: K Aspartate, 130; MgCl 2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration).
  • the cells were given a 50 ms, -50 mV repolarization voltage, and the current recorded at this voltage was used as a baseline for calculating the hERG tail current.
  • the hERG tail current was stable for at least 3 minutes in the extracellular fluid prior to compound addition.
  • the hERG tail current amplitude change is less than ⁇ 5% after perfusion administration, it is considered that the drug action reaches a steady state.
  • Data acquisition and analysis were performed using the pCLAMP10.1 software program. Select 4 to 5 sweeps whose current is in a steady state before adding the compound, and calculate the peak average as the control current amplitude. After selecting the compound, the current is in the steady state of 4 to 5 sweeps, and the peak average value is calculated as the residual amplitude after the current is suppressed.
  • the inhibition rate of the test compound to hERG current is calculated according to the following equation:
  • % inhibition rate ⁇ 1 - (current residual amplitude) / (control current amplitude) ⁇ ⁇ 100
  • the inhibition rate (mean ⁇ standard deviation) of multiple concentrations of the test compound to hERG current was obtained, and the data was fitted using a logistic equation to obtain an IC 50 value.
  • the deuterated compounds of the invention have lower cardiotoxicity relative to AZD9291.

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Abstract

本发明公开了一类氘代3-（4,5-取代氨基嘧啶）苯基衍生物及其应用，其为具有式（I）结构的化合物或其药学上可接受的盐，这些化合物或其盐可通过某些突变形式的表皮生长因子受体而用于疾病或病况的治疗或预防，可以有效抑制多种肿瘤细胞的生长，并对EGFR、Her家族其他蛋白酶产生抑制作用，可用于制备抗肿瘤药物。

Description

氘代3-(4,5-取代氨基嘧啶)苯基衍生物及其应用 技术领域
本发明属于抗肿瘤药物技术领域，具体涉及氘代3-(4,5-取代氨基嘧啶)苯基衍生物及其在制备抗肿瘤药物中的应用。
背景技术
在传统的癌症治疗过程中，化疗为主要的治疗手段；化疗药物非特异性地阻断细胞分裂从而使细胞死亡，它们在杀死肿瘤细胞的同时，也大大破坏了人体正常细胞的生长，带来许多不良反应。很多人因为担忧化疗的严重副作用而使心情悲观甚至放弃治疗，再加上化疗药物的耐药性，使非小细胞肺癌(NSCLC)的化疗不容乐观，而延长化疗的周期只增加了毒副作用，并没有增加疗效。同时非小细胞肺癌的癌细胞对化疗、常规化疗不敏感，总缓解率也只有25％左右；由于这些原因的限制，非小细胞肺癌患者五年生存率低于20％。
在50％-80％的NSCLC病人中，他们的表皮生长因子受体(epidermal growth factor receptor，EGFR)都过度表达，从而引起癌变。靶向EGFR药物主要有两类：一类是作用于受体胞内区的小分子酪氨酸激酶抑制剂(TKI)；另一类是作用于受体胞外区的单克隆抗体(MAb)。已经应用于临床的第一代EGFR抑制剂如易瑞沙、埃罗替尼、拉帕替尼等，它们对于NSCLC肺癌的治疗取得了很大的成功，提高了非小细胞肺癌患者五年的生存率。同时，与化疗相比，它们的优势在于不会产生骨髓抑制，恶心和神经毒性等副作用；但它们在单独治疗时药效较低，且有非常明显的皮疹和腹泻等副作用，而且在使用一年后，患者对药物出现耐药性。研究认为EGFR基因T790M位点的突变是此类药物耐药的主要诱因，有临床案例数据显示，大约有50％的患者获得性耐药都源于T790M位点的突变所致。进一步研究证实，由于EGFR基因T790M突变，即编码的苏氨酸转变为甲硫氨酸，从而造成了空间位阻阻碍了抑制剂与ATP结合区结合最终导致了抑制剂活性丧失。目前也有研究显示T790M位点的突变不是直接影响抑制剂与EGFR的亲和性，而是突变导致EGFR与ATP的亲和性大大增加，使得抑制剂与EGFR的亲和性相对的大大降低了(抑制剂与ATP是竞争性结合)。第二代抑制剂如阿法替尼、Dacomitinib，它们优于第一代的特征在于对EGFR的识别性增加，可以辨别肿瘤细胞和正常细胞，这样副作用就会减少。但这些分子对EGFR的T790M突变体的选择性差，造成药物临床耐受剂量较低，在其最大耐受剂量(MTD)下，药物无法在体内达到其有效浓度而使得对多数耐药病人无效。
总之，目前的EGFR-TKI仍不能解决药物耐药性所引起的临床需求，而且现有的药物多是以喹唑啉或者喹啉胺类为基本母核的EGFR可逆或不可逆抑制剂，其对野生型细胞的选择性差带来的毒副作用也是不可避免的。因此，临床上迫切需要新类型，尤其是新颖骨架的化合物来解决耐药性、选择性差等问题。
发明内容
本发明的目的是提供一类氘代3-(4,5-取代氨基嘧啶)苯基衍生物。
本发明的目的可以通过以下措施达到：
本发明的氘代3-(4,5-取代氨基嘧啶)苯基衍生物为具有式(I)结构的化合物或其药学上可接受的盐，
Figure PCTCN2017102027-appb-000001
其中，R1,R2选自-CH3或-CD3，R3及R4选自-CH3、CD3或H，且R1,R2,R3及R4至少一个为-CD3。
进一步地，所述的具有式(I)结构的化合物，优选R1为-CH3。
本发明的化合物或其药学上可接受的盐，其中一些具体化合物选自：
Figure PCTCN2017102027-appb-000002
具有通式(I)的化合物制备路线如下所示：
Figure PCTCN2017102027-appb-000003
上述制备路线的具体步骤如下：
步骤1：将化合物II与2,4-二氯嘧啶溶于溶剂中，在路易斯酸的存在下，通过亲核取代反应得到III，其中溶剂选自乙二醇二甲醚(DME)、甲苯、氯苯或其混合；路易斯酸选自三氯化铝或三氟化硼；
步骤2：中间体III与4-氟-2-甲氧基-5-硝基苯胺溶于溶剂中，在对甲苯磺酸作用下得到IV，其中溶剂选自1,4-二氧六环、N,N-二甲基甲酰胺(DMF)或其混合；
步骤3：中间体IV与有机胺溶于溶剂，在DIPEA的作用下反应得到中间体V，其中溶剂选自己二酸二甲酯(DMA)、二甲基乙酰胺(DMAc)、N,N-二甲基甲酰胺(DMF)或其混合；
步骤4：将中间体V溶于溶剂，以Pd/C为还原剂，将中间体V还原为中间体VI，其中溶剂选自甲醇或乙醇；
步骤5：以四氢呋喃/水为溶剂，中间体VI与氯丙酰氯反应得到中间化合物，不分离，直接加氢氧化钠继续反应得到具有式(I)结构的化合物。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。例如，通式(I)的化合物与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以形成的典型的盐包括醋酸盐、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐、磺酸盐、酒石酸盐、硫氰酸盐。
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明还公开了所述通式(I)的化合物或其药学上可接受的盐在制备或预防肿瘤药物中的应用。
所述肿瘤包括但不限于非小细胞肺癌、小细胞肺癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌。
本发明的一个方面提供式(I)的化合物，用于治疗或预防由EGFR介导的或由激活突变体或抗性突变体形式的EGFR介导的疾病、障碍、紊乱或病况。
由EGFR介导的或由激活突变体或抗性突变体形式的EGFR介导的疾病、障碍、紊乱或病况包括但不限于非小细胞肺癌、小细胞肺癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌或鼻咽癌。
所述激活突变体或抗性突变体形式的EGFR包括但不限于L858R激活突变体、Exon19缺失激活突变体和T790M抗性突变体。
本发明通式(I)的化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量保持不变，而同时或随后服用式(I)的化合物。当式(I)化合物与其它一种或几种药物同时服用时，优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它一种或几种药物进行药物联用时，式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量低。可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限于以下物质：
雌激素受体调节剂、雄激素受体调剂、视网膜受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂，c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白体酶抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、ATK抑制剂、整联蛋白阻滞剂、干扰素、白介素-12、COX-2抑制剂、P53、P53激活剂、VEGF抗体和EGF抗体等。
在一个实施方案中，可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限于以下物质：阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、安磷汀、安柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠抑制剂、贝沙罗汀、硫酸博来霉素、 溴尿甘、硼替佐米、卡菲左米、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、乙烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligrand、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇抑制剂、17-立酶雌二醇、雌莫司汀磷酸钠、雌炔醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫西芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-嘧啶、阿糖呋喃糖胞噻啶-5呋喃硬质酰磷酸酯、福莫司汀、氟维司琼、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊、戈舍林瑞、盐酸拉格尼西陇、组胺瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、白细胞介素-2，内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑，酯化雌激素、6-巯基嘌呤、美司钠、氨甲喋呤、氨基乙酰丙酸甲酯、来替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-组、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷提曲赛、利比、依替磷酸铼-186、美罗华、力度伸-美、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁磷酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲胺碟呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福啶、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白稳定制剂、acolbifene、affinitak、氨基碟呤、阿佐昔芬、asoprisnil、阿他美坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克拉那托、环丙孕酮醋酸酯、地西他滨、DN-101/阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组胺瑞林水凝胶植入物、钬-166DOTMP、伊班磷酸、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MEP-PE、MX-6、那法瑞林、奈莫柔比星、新伐 司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、OS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素α、嘎唑呋林、tipifarnib、替拉孔明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanob、维替泊芬、长春氟宁、Z-100和唑来磷酸或他们的组合。
本发明还提供了一种药物组合物，该药物组合物包括所述式(I)的化合物或其药学上可接受的盐和药学上可接受的辅料或载体。这里所用的短语“药学上可接受的辅料或载体”是指药学接受的材料、成份或介质，如液体或固体填料、稀释剂、辅料、溶剂或封装材料，包括从一个器官或身体的某部分到另一个器官或身体的某部分携带或运输主要药学试剂。每个载体必须是“可以接受”，能兼容其他形式的药物成份而对病人不造成伤害。一些可作为药学上可以接受的载体的例子包括：糖，如乳糖、葡萄糖和蔗糖糖；淀粉，如小麦淀粉和马铃薯淀粉淀粉；纤维素及其衍生物，如钠羧甲基纤维素、乙基纤维素、醋酸纤维素，粉状西黄蓍胶、麦芽、明胶、滑石粉；辅料，如可可黄油和栓剂蜡；油，如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和豆油；甘醇，如丁二醇；多元醇，如甘油、山梨醇、甘露醇和聚乙二醇；酯，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；海藻酸；无热原水；生理盐水；林格氏液；乙醇；磷酸盐缓冲液，以及其他无毒的应用在药物制剂的可兼容物质。
当本发明的化合物作为药剂给人类和动物进行治疗时，它们可以本身或作为药物组合物而给药。例如，包含0.1％-99.5％(优选是0.5％-90％)的活性成分和药学上可接受的载体。
本发明的化合物可通过静脉注射，肌肉注射，腹腔注射，皮下注射，外用，口服，或其他可接受的办法来治疗疾病。
本发明还提供了药品包装或套件，包括一个或多个的包装，其中含有对本发明中一个或多个成分的药物组合。可选的此类包装以公告的形式由政府机构规范生产，以生产法规中许可的公开方法使用或销售药品或生物制品，使用或销售对人的治疗制剂。
与现有技术相比，本发明的有益效果为：
本发明的氘代化合物，具有与AZD9291相近的酶和细胞水平生物活性且具有更低的心脏毒性。本发明的氘代化合物为新型抗肿瘤药物提供了更多的选择，具有良好的药物应用前景。
具体实施方式
下面有代表性的例子旨在帮助阐述本发明，而不是有意也不应该被解释为限制本发明的范围。事实上，除了那些出现和描述于此的以外，本发明中文件的全部内容，包括依据此处引用的科技文献和专利的例子，以及由此产生的各种修饰和许多进一步变化对本专业内一般技术人员都是清晰明白的。还应当明白，这些参考文献的引用有助于陈述本文内容。
实施例1
Figure PCTCN2017102027-appb-000004
合成路线如下：
Figure PCTCN2017102027-appb-000005
化合物1
Figure PCTCN2017102027-appb-000006
取250mL单口烧瓶，分别加入N-甲基乙醇胺(10g，133.1mmol)，TEA(26.9g，266.3mmol)，乙腈(100mL)，然后将氯化苄(23.9g，139.8mmmol)在0℃下慢慢滴加到反应液中，并在室温下继续搅拌1h，TLC监测无原料剩余，减压蒸馏除去溶剂， 柱层析纯化得到21g无色液体即化合物1，收率95.5％。
化合物2
Figure PCTCN2017102027-appb-000007
取250mL茄型瓶，加入化合物1(21g，127.1mmol)，TEA(25.7g，254.2mmol)和DCM(100ml)，然后在0℃下滴加MsCl(14.6g，127.1mmol)。反应液在室温下搅拌3h，TLC监测已无原料剩余，减压蒸馏除去溶剂，柱层析纯化得到20g淡黄色液体即化合物2，收率85.6％。
化合物3
Figure PCTCN2017102027-appb-000008
取500mL封管，加入化合物2(20g，108.9mmol)，氨水215mL，混合液在40℃下搅拌过夜，TLC监测已无原料剩余，柱层析纯化得到15g无色液体即化合物3，收率为84％。
化合物4
Figure PCTCN2017102027-appb-000009
取500mL茄型瓶，加入化合物3(15g，91.3mmol)，DCM(200mL)，在室温下慢慢滴加Boc2O(19.9g，91.3mmol)，滴加完毕后混合液在室温下继续搅拌3h，TLC监测无原料剩余，减压蒸馏除去溶剂，柱层析纯化得到21g化合物4，为白色固体，产率为87％。
化合物5
Figure PCTCN2017102027-appb-000010
取100mL茄型瓶，加入化合物4(10g，37.8mmol)，DMF(40mL)，然后分批加入NaH(2.3g，56.7mmol)，搅拌30mins，加入TsOCD3(7.9g，41.6mmol)的DMF (10mL)溶液，然后室温下搅拌3h，TLC监测无原料剩余，加入150mL H2O淬灭，EA(50mL*3)萃取，合并有机相，brine洗，无水Na2SO4干燥，减压蒸馏出去溶剂，柱层析纯化得到8.5g即化合物5，为白色固体，收率为80％。
化合物6
Figure PCTCN2017102027-appb-000011
取250mL茄型瓶，加入化合物5(8.5g，30.18mmol)，THF(80ml)，冰浴下分批加入LiAlH4(3.4g，90.59mmol)，然后加热到60℃过夜，TLC监测无原料剩余，缓慢加入Na2SO4·10H2O淬灭，过滤除掉固体，收集滤液，减压蒸馏除去溶剂，柱层析纯化得到4.5g无色液体即化合物6，收率为76.3％。
化合物7
Figure PCTCN2017102027-appb-000012
取100mL茄型瓶，分别加入化合物6(4.5g，23mmol)，MeOH(50mL)，Pd(OH)2/C(200mg)，抽真空换氢气3次，室温下搅拌过夜，TLC监测已无原料剩余，过滤除掉Pd(OH)2/C，然后将反应液pH值调到酸性，减压蒸馏除去溶剂得到2.8g白色固体即化合物7，收率85.9％。
化合物8
Figure PCTCN2017102027-appb-000013
取250mL茄型瓶，分别加入2,4-二氯嘧啶(11.37g，76.33mmol)，三氯化铝(10.18g，76.33mmol)和100mL乙二醇二甲醚(DME)，室温下搅拌20分钟。然后分批加入化合物II(10.00g，63.61mmol)，升至80度反应6h。停止反应冷却至室温，加入100mL水，搅拌2h，过滤，固体用乙醇洗涤，真空干燥得红色粗品15.46克即化合物III，得 率90.1％。
取300mL1,4-二氧六环于500mL茄型瓶中，分别加入化合物III(20.00g，82.07mmol)，化合物4-氟-2-甲氧基-5-硝基苯胺(16.80g，90.28mmol)和对甲苯磺酸(17.17g，90.28mmol)。升至85度反应8h，冷却至室温，加水搅拌，并滴加40％氢氧化钠溶液至pH＝9.过滤，固体用乙醇洗涤，真空干燥后得黄色固体30.00g即化合物8，得率92.9％。
化合物9
Figure PCTCN2017102027-appb-000014
取120mL封管，加入化合物8(2g，4.77mmol)，7(810mg，5.72mmol)，DIPEA(1.23g，9.54mmol)，DMA(10mL)。然后封管140℃反应6h，TLC监测无原料剩余，将反应液冷却至室温，加入20mL水，析出固体，过滤，然后加入将滤饼加入2mL甲醇打浆洗涤，过滤、烘干得到1.7g红色固体即化合物9，收率70.6％。
化合物10
Figure PCTCN2017102027-appb-000015
取250mL单口烧瓶，加入化合物9(1.7g，3.37mmol)，Pd/C(200mg)，MeOH(100mL)，抽真空换氢气3次，室温下搅拌过夜，TLC监测已无原料剩余，过滤除掉Pd/C，减压蒸馏除去溶剂得到黄绿色固体，柱层析纯化，洗脱剂(DCM：MeOH：NH3H2O＝20:1:0.1)洗脱，得到1.2g黄绿色固体即化合物10，收率75％。
化合物11
Figure PCTCN2017102027-appb-000016
取20mL单口烧瓶，加入化合物10(500mg，1.05mmol)，DCM(30mL)，然后将3-氯丙酰氯(133.7mg，1.05mmol)，在0℃下慢慢滴加到反应液中，并在室温下继续搅拌30min，TLC监测无原料剩余，然后加入NaOH(168mg，4.2mmol)，升温到65℃搅拌过夜，HPLC监测无原料剩余，减压蒸馏除去溶剂，柱层析纯化，洗脱剂(DCM：MeOH＝10:1)洗脱得到280mg淡黄色固体即化合物11，收率为50.4％。
1H NMR(400MHz,CDCl3)δ10.19(s,1H),9.88(s,1H),9.12(s,1H),8.39(d,J＝5.3Hz,1H),7.85(d,J＝8.0Hz,1H),7.74(s,1H),7.26–7.14(m,2H),7.00(d,J＝7.0Hz,1H),6.82(s,1H),6.49(dd,J＝16.9,2.2Hz,1H),6.39(dd,J＝16.9,9.8Hz,1H),5.73(dd,J＝9.8,2.2Hz,1H),4.49–4.32(m,2H),3.91(s,3H),3.05(t,J＝6.0Hz,2H),2.95–2.87(m,2H),2.73(s,3H),2.39–2.23(m,7H),1.82(s,3H).LC-MS[M+H]+528.7
实施例2
Figure PCTCN2017102027-appb-000017
合成路线如下：
Figure PCTCN2017102027-appb-000018
化合物12
Figure PCTCN2017102027-appb-000019
取120mL封管，加入化合物8(500mg，1.19mmol)，N-甲基乙醇胺(107.26mg，1.42mmol)，DIPEA(307.59mg，2.38mmol)，DMA(5mL)。然后封管140℃反应6h，TLC监测无原料剩余，将反应液冷却至室温，加入20mL水，析出固体，过滤，然后加入将滤饼加入2mL甲醇打浆洗涤，过滤、烘干得到480mg红褐色固体即化合物12，收率85％。
化合物13
Figure PCTCN2017102027-appb-000020
取20mL茄型瓶，加入化合物12(450mg，1.05mmol)，TEA(159.39mg，1.57mmol)和DCM(5ml)。0℃下慢慢滴加MsCl(120.28mg，1.05mmol)，滴加完毕后在该温度下搅拌，1h后TLC监测已无原料剩余，减压蒸馏除去溶剂，柱层析纯化得到320mg红色固体即化合物13，收率55.15％。
化合物14
Figure PCTCN2017102027-appb-000021
取5mL封管，加入化合物13(220mg，0.40mmol)，氘代二甲胺(175.16mmg，2mmol)，DIPEA(103.39mg，0.8mmol)，THF(2mL)，80℃下搅拌过夜，TLC监测已无原料剩余，减压蒸馏除去溶剂得到红色固体，柱层析纯化，洗脱剂(DCM：MeOH：NH3H2O＝40:1:0.1)洗脱，得到90mg红色固体即化合物14，收率44.32％。
化合物15
Figure PCTCN2017102027-appb-000022
取250mL单口烧瓶，加入化合物14(90mg，0.18mmol)，Pd/C(30mg)，MeOH(10mL)，抽真空换氢气3次，室温下搅拌过夜，TLC监测已无原料剩余，过滤除掉Pd/C，减压蒸馏除去溶剂得到黄绿色固体，柱层析纯化，洗脱剂(DCM：MeOH：NH3H2O＝20:1:0.1)洗脱，得到40mg黄绿色固体即化合物15，收率46.53％。
化合物16
Figure PCTCN2017102027-appb-000023
取10mL单口烧瓶，加入化合物15(40mg，0.08mmol)，DCM(4mL)，然后将3-氯丙酰氯(10.63mg，0.08mmol)在0℃下慢慢滴加到反应液中，并在室温下继续搅拌30min，TLC监测无原料剩余，然后加入NaOH(16mg，0.4mmol)，升温到65℃搅拌过夜，HPLC监测无原料剩余，减压蒸馏除去溶剂，柱层析纯化，洗脱剂(DCM：MeOH：NH3H2O＝40:1:0.1)洗脱得到38mg淡黄色固体即化合物16，收率为89.34％。1H NMR(400MHz,CDCl3)δ10.12(s,1H),9.88(s,1H),9.10(s,1H),8.39(d,J＝5.2Hz,1H),7.86(d,J＝8.0Hz,1H),7.74(s,1H),7.19(dd,J＝17.1,6.5Hz,2H),7.00(d,J＝6.9Hz,1H),6.81(s,1H),6.46(d,J＝8.4Hz,2H),5.73(dd,J＝8.6,3.1Hz,1H),4.51–4.28(m,2H),3.90(s,3H),3.05(t,J＝5.6Hz,2H),2.98–2.87(m,2H),2.72(s,3H),2.31(dd,J＝16.4,11.2Hz,4H).LC-MS[M+H]+531.7
实施例3
Figure PCTCN2017102027-appb-000024
合成路线如下：
Figure PCTCN2017102027-appb-000025
化合物17
Figure PCTCN2017102027-appb-000026
取2L三颈瓶，分别加入CD3OH(15g，415.8mmol)，THF(600mL)。然后在-40℃下慢慢滴加n-BuLi(174.6mL，436.6mmol)。搅拌1h后滴加TsCl(79.3g，415.8mmol)的四氢呋喃溶液，滴加完毕后继续搅拌3h，TLC监测无原料剩余。加入600mLH2O淬灭，EA萃取(200mL*3)，brine洗涤，无水Na2SO4干燥，合并有机相，减压蒸馏除掉溶剂得到粗化合物，柱层析纯化得到73g白色固体即化合物17，收率92.7％。
化合物18
Figure PCTCN2017102027-appb-000027
取250mL茄型瓶，分别加入化合物17(8g，42.3mmol)，N-苄基乙醇胺(5.3g，35.2mmol)，三乙胺(9.8ml，70.4mmol)，四氢呋喃(100mL)。混合液在回流下反应8h， TLC监测无原料剩余，减压蒸馏除去溶剂，柱层析纯化得到5g无色粘稠液体即化合物18，收率84.4％。
化合物19
Figure PCTCN2017102027-appb-000028
取50mL茄型瓶，分别加入化合物18(3g，15.87mmol)，三乙胺(3.2g，31.74mmol)，二氯甲烷(20mL)，然后在0℃下慢慢滴加甲烷磺酰氯(2.18g，19.05mmol)，反应液在室温下搅拌3h，TLC监测无原料剩余，减压蒸馏除去溶剂得到淡黄色粘稠液体，柱层析纯化得到2.8g淡黄色液体即化合物19，收率71.6％。
化合物20
Figure PCTCN2017102027-appb-000029
取10mL封管，分别加入化合物19(2.8g，11.37mmol)，二甲胺溶液(1.5mL)，THF(3mL)。混合液在80℃下搅拌5h，TLC监测无原料剩余。加入5mL水稀释，乙酸乙酯(5mL*3)，合并有机相，饱和食盐水洗涤，无水Na2SO4干燥，减压蒸馏除去溶剂，中压制备纯化得到2g无色液体即化合物20，收率75％。
化合物21
Figure PCTCN2017102027-appb-000030
取100mL茄型瓶，分别加入化合物20(2g，10.2mmol)，10％钯碳(500mg)，甲醇(30mL)，35℃氢气下搅拌过夜，TLC监测无原料剩余，滤掉固体，在滤液中滴加HCl(in EA)至pH为酸性，减压蒸馏除去溶剂得到900mg白色固体即化合物21，收率62.3％。
化合物22
Figure PCTCN2017102027-appb-000031
取120mL封管，加入化合物8(965mg，2.3mmol)，21(467mg，2.76mmol)，二异丙基乙胺(1.18g，9.2mmol)，DMA(5mL)。然后封管140℃反应6h，TLC监测无原料剩余，将反应液冷却至室温，加入20mL水，析出固体，过滤，然后加入将滤饼加入2mL甲醇打浆洗涤，过滤、烘干得到900mg红色固体即化合物22，收率77.5％。
化合物23
Figure PCTCN2017102027-appb-000032
取250mL单口烧瓶，加入化合物22(900mg，1.78mmol)，Pd/C(300mg)，MeOH(100mL)，抽真空换氢气3次，室温下搅拌过夜，TLC监测已无原料剩余，过滤除掉Pd/C，减压蒸馏除去溶剂得到黄绿色固体，柱层析纯化，洗脱剂(DCM：MeOH：NH3H2O＝20:1:0.1)洗脱，得到600mg黄绿色固体即化合物23，收率71％。
化合物24
Figure PCTCN2017102027-appb-000033
取20mL单口烧瓶，加入化合物23(300mg，0.63mmol)，THF(6mL)和H2O(1mL)，然后将3-氯丙酰氯(80.36mg，0.63mmol)在0℃下慢慢滴加到反应液中，并在室温下继续搅拌30min，TLC监测无原料剩余，然后加入NaOH(100.8mg，2.52mmol)，升温到65℃搅拌过夜，HPLC监测无原料剩余，减压蒸馏除去溶剂，柱层析纯化，洗脱剂(DCM：MeOH＝10:1)，洗脱得到170mg淡黄色固体即化合物24，收率51％。
1H NMR(400MHz,CDCl3)δ10.07(s,1H),9.87(s,1H),9.10(s,1H),8.39(d,J＝5.3Hz, 1H),7.85(d,J＝8.0Hz,1H),7.75(s,1H),7.25–7.14(m,2H),7.00(d,J＝7.0Hz,1H),6.80(s,1H),6.57–6.38(m,2H),5.74(dd,J＝8.2,3.8Hz,1H),4.49–4.30(m,2H),3.91(s,3H),3.05(t,J＝6.0Hz,2H),2.98–2.89(m,2H),2.42–2.21(m,13H).LC-MS[M+H]+528.7
实施例4
Figure PCTCN2017102027-appb-000034
合成路线如下：
Figure PCTCN2017102027-appb-000035
化合物25
Figure PCTCN2017102027-appb-000036
取1L单口烧瓶，分别加入N-甲基乙醇胺(40.0g，0.532mol)，三乙胺(80.8g，0.8mol)，二氯甲烷(500mL)，然后将氯化苄(67.4g，0.5mol)在0℃下慢慢滴加到反应液中，并在室温下搅拌过夜，TLC监测无原料剩余，加水200mL萃取分液，100mL二氯甲烷萃取水相。有机相饱和食盐水洗涤3次，无水硫酸钠干燥，减压浓缩，柱层析纯化得到73g无色液体即产物25，收率83.1％。
化合物26
Figure PCTCN2017102027-appb-000037
取1L单口烧瓶，分别加入25(71.0g，0.4mol)，二氯甲烷(400mL)，水浴下缓慢滴加氯化亚砜(76.7g，0.6mol)，室温反应12h，TLC监测反应液中已无原料剩余。减压浓缩，柱层析纯化得到60.0g淡黄色液体即产物26，收率为76.1％。
化合物27
Figure PCTCN2017102027-appb-000038
取2L单口烧瓶，分别加入26(60.0g，0.3mol)，氨水(1L)，混合液在40℃下搅拌过夜，TLC监测已无原料剩余。减压浓缩，柱层析纯化得到产物27为无色液体40.0g，收率为74.7％。
化合物28
Figure PCTCN2017102027-appb-000039
取1L茄型瓶，加入27(40.0g，0.3mol)，二氯甲烷(250mL)，在室温下缓慢滴加Boc2O(55.2g，0.3mol)，滴加完毕后混合液在室温下继续搅拌3h，TLC监测无原料剩余，减压蒸馏除去溶剂，柱层析纯化得到58.0g产物28，为无色液体，产率为86.7％。
化合物29
Figure PCTCN2017102027-appb-000040
取500mL茄型瓶，加入28(26.0g，98.3mmol)，N,N-二甲基甲酰胺(100mL)，冰浴下分批加入NaH(5.9g，147.5mmol)，搅拌30min，加入TsOCD3(27.9g，147.5mmol)的N,N-二甲基甲酰胺(10mL)溶液，然后室温下搅拌3h，TLC监测无原料剩余，加入300mL水淬灭，乙酸乙酯(100mL*3)萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，减压蒸馏出去溶剂，柱层析纯化得到21.0g即产物29，为白色固 体，收率为75.9％。
化合物30
Figure PCTCN2017102027-appb-000041
取250mL茄型瓶，分别加入29(21.0g，74.7mmol)，甲醇(100mL)，Pd/C(4.2g)，抽真空换氢气3次，40℃反应过夜，TLC监测已无原料剩余，过滤除掉Pd/C，减压蒸馏除去溶剂得到12.0g白色固体即产物30，收率84.0％。
化合物31
Figure PCTCN2017102027-appb-000042
取120mL封管，加入8(6.1g，14.5mmol)，30(5g，26.1mmol)，DIPEA(3.8g，29mmol)，DMAc(30mL)。然后封管140℃反应6h，TLC监测无原料剩余，将反应液冷却至室温，加入60mL水，析出固体，过滤，然后加入将滤饼加入20mL甲醇打浆洗涤，过滤、烘干得到7.0g红色固体即产物31，收率81.7％。
化合物32
Figure PCTCN2017102027-appb-000043
取250mL单口烧瓶，加入31(7.0g，12.5mmol)，Pd/C(1.4g)，甲醇(100mL)，抽真空换氢气3次，室温下搅拌过夜，TLC监测已无原料剩余，过滤除掉Pd/C，减压蒸馏除去溶剂得到黄绿色固体，柱层析纯化，洗脱剂(二氯甲烷：甲醇：氨水＝20:1:0.1)洗脱，得到3.5g黄绿色固体即产物32，收率50.9％。
化合物33
Figure PCTCN2017102027-appb-000044
取100mL单口烧瓶，加入32(1.1g，2.0mmol)，四氢呋喃(30mL)，水(3mL)，0℃下，将3-氯丙酰氯(274mg，2.2mmol)缓慢滴加到反应液中，并在室温下继续搅拌1h，TLC监测无原料剩余，然后加入NaOH(1.3g，31.4mmol)，升温到65℃搅拌过夜，HPLC监测无原料剩余，减压蒸馏除去溶剂，柱层析纯化，洗脱剂(二氯甲烷：甲醇：氨水＝40:1:0.1)洗脱得到800mg淡黄色固体即产物33，收率为66.4％。
化合物34
Figure PCTCN2017102027-appb-000045
取25mL单口烧瓶，加入33(320mg，0.5mmol)，二氯甲烷(3mL)，水(3mL)，室温下，将甲磺酸0.3mL缓慢滴加到反应液中，继续搅拌1h，减压蒸馏除去二氯甲烷，然后加入乙酸乙酯12.5mL和乙醇2.5mL，超声并室温搅拌析晶，抽滤，滤饼乙酸乙酯洗涤(2mL*2)滤饼干燥得到300mg黄色固体即产物34，收率为71.8％。
1H NMR(400MHz,DMSO)δ9.52(s,1H),8.83(s,1H),8.64(s,2H),8.35(s,1H),8.20(s,1H),7.45(d,J＝6.9Hz,1H),7.06(d,J＝5.7Hz,3H),6.86(dd,J＝16.9,10.3Hz,1H),6.25(d,J＝16.9Hz,1H),5.77(d,J＝11.7Hz,1H),4.38-4.23(m,2H),3.84(s,3H),3.29(d,J＝5.4Hz,2H),3.21-3.18(m,2H),2.97-2.92(m,2H),2.66(s,3H),2.19-2.11(m,2H),2.41(s,9H).
实施例5：制备的化合物的生物活性测试
1)此类化合物对EGFR野生型、EGFR(T790M，L858R)双突变型以及EGFR(L858R)单突变型的激酶活性IC50测试。上述激酶采购于英潍捷基(上海)贸易有限公司。
采用均相时间分辨荧光(HTRF)的方法建立EGFR野生型、EGFR(T790M，L858R)双突变型以及EGFR(L858R)单突变型的激酶活性检测方法，测定化合物的抑制活性。 配置8uL的反应液，包括1×enzymatic buffer(Cisbio,HTRF KinEASETM-TK)，5mM MgCl2，1mM MnCl2，1mM DTT，0.5μM TK substrate-biotin(Cisbio,HTRF KinEASETM-TK)10μM ATP，梯度浓度的化合物以及0.04ng/μL EGFR或者0.025ng/μL的EGFR(T790M，L858R)或EGFR(L858R)。化合物反应浓度为1000nM起3倍稀释9个浓度。反应体系中DMSO浓度为2％。酶和化合物预孵育15分钟，然后加入ATP和底物开始反应。所有酶催化反应都在25℃下进行60分钟。酶催化反应结束后，反应液中加入4μL TK antibody-cryptate和4μL streptavidin-XL665(反应浓度为62.5nM)，继续在25℃孵育60分钟。孵育结束后在CLARIOstar(BMG LABTECH)上检测HTRF荧光值，并使用GraphPad Prism 5.0计算IC50。
表1体外酶学活性测试数据(IC50，nM)
Figure PCTCN2017102027-appb-000046
本发明的氘代化合物，具有与AZD9291相近的酶生物活性。
2)EGFR野生型，EGFR Exon19缺失(激活单突变体)以及EGFR(T790M，L858R)双突变型细胞磷酸化测试
测验1：EGFR野生型细胞磷酸化测验
人皮肤鳞状细胞癌细胞系A431表达野生型EGFR，从中国科学院细胞库购买。将A431维持在含有10％胎牛血清的EMEM培养基中。使细胞在有5％CO2的加湿培养箱中于37℃生长。依照Phospho-EGFR HTRF kit(Cisbio，货号#64HR1PEG)中描述的方案，检测细胞裂解液中内源性p-EGFR。将100μL细胞接种于96孔板中(50000细胞/孔)，于37℃，5％CO2细胞培养箱中培养过夜。将连续4倍稀释的化合物加入细胞中，反应最高浓度为10μM。继续培养2小时后，加入100ng/孔的EGF于37℃培养10分钟，然后弃去培养液，并立即加入25μL/孔裂解液，于室温裂解细胞10分钟，然后取12μL/孔加入Greiner白色低体积384孔板中，加入检测抗体(Anti-phospho EGFR-d2以及Anti-EGFR-Tb)，在25℃孵育60分钟。孵育结束后在CLARIOstar(BMG LABTECH)上检测HTRF荧光值，并使用GraphPad Prism 5.0计算IC50。
测验2：Exon19缺失EGFR(激活单突变体)细胞磷酸化测验
人非小细胞肺癌细胞系HCC827(Exon19缺失EGFR，激活单突变体)从中国科学院细胞库购买。将HCC827维持在含有10％胎牛血清RPMI1640培养基中。使细胞在有5％CO2的加湿培养箱中于37℃生长。依照Phospho-EGFR HTRF kit(Cisbio，货号 #64HR1PEG)中描述的方案，检测细胞裂解液中内源性p-EGFR。将100μL细胞接种于96孔板中(50000细胞/孔)，于37℃，5％CO2细胞培养箱中培养过夜。将连续4倍稀释的化合物加入细胞中，反应最高浓度为10μM。继续培养2小时后弃去培养液，并立即加入25μL/孔裂解液，于室温裂解细胞10分钟，然后取12μL/孔加入Greiner白色低体积384孔板中，加入检测抗体(Anti-phospho EGFR-d2以及Anti-EGFR-Tb)，在25℃孵育60分钟。孵育结束后在CLARIOstar(BMG LABTECH)上检测HTRF荧光值，并使用GraphPad Prism 5.0计算IC50。
测验3：EGFR(T790M，L858R)双突变型细胞磷酸化测验
人非小细胞肺癌细胞系NCI-H1975表达EGFR(T790M，L858R)双突变型，从中国科学院细胞库购买。将NCI-H1975维持在含有10％胎牛血清RPMI1640培养基中。使细胞在有5％CO2的加湿培养箱中于37℃生长。依照Phospho-EGFR HTRF kit(Cisbio，货号#64HR1PEG)中描述的方案，检测细胞裂解液中内源性p-EGFR。将100μL细胞接种于96孔板中(50000细胞/孔)，于37℃，5％CO2细胞培养箱中培养过夜。将连续4倍稀释的化合物加入细胞中，反应最高浓度为10μM。继续培养2小时后弃去培养液，并立即加入25μL/孔裂解液，于室温裂解细胞10分钟，然后取12μL/孔加入Greiner白色低体积384孔板中，加入检测抗体(Anti-phospho EGFR-d2以及Anti-EGFR-Tb)，在25℃孵育60分钟。孵育结束后在CLARIOstar(BMG LABTECH)上检测HTRF荧光值，并使用GraphPad Prism 5.0计算IC50。
表2细胞水平EGFR野生及突变体磷酸化测试(IC50，nM)
Figure PCTCN2017102027-appb-000047
本发明的氘代化合物，具有与AZD9291相近的细胞水平生物活性。
3)制备的化合物对hERG钾离子通道作用的测试
稳定表达hERG通道的HEK293细胞培养于35mm培养皿中，在37℃/5％CO2培养箱中放置至少24小时后用于实验。细胞培养基为含有10％胎牛血清和250μg/mL G418的DMEM。
全细胞膜片钳实验所用细胞外液的成分为(mM)：NaCl,137；KCl,4；CaCl2,1.8；MgCl2,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含0.3％DMSO。细胞内液(mM)为：K Aspartate,130；MgCl2,5；EGTA 5；HEPES,10；Tris-ATP 4；pH 7.2(KOH滴定)。
每次实验取出一个培养皿，用细胞外液清洗两次，放置于倒置显微镜载物台上。全细胞膜片钳实验在室温下进行，所用硼硅玻璃微电极尖端电阻为3～5MΩ。全细胞记录 模式后，将膜电位钳制在-80mV，每隔30s给予细胞+50mV去极化电压刺激，持续2s后复极化至-50mV，持续3s，即可引出hERG尾电流。去极化电压刺激前，先给予细胞50ms，-50mV复极化电压，该电压下记录的电流作为计算hERG尾电流的基线。加入化合物前，hERG尾电流在细胞外液中至少稳定记录3分钟。灌流给药后当hERG尾电流幅值变化小于<5％时，被认为药物作用达到稳态。数据采集和分析使用pCLAMP10.1软件程序。选取加入化合物前电流处于稳态的4～5个sweep，计算峰值平均值，作为对照电流幅值。选取加入化合物后电流处于稳态的4～5个sweep，计算峰值平均值，作为电流被抑制后的剩余幅值。待测化合物对hERG电流的抑制率依据以下方程进行计算：
％抑制率＝{1-(电流剩余幅值)/(对照电流幅值)}×100
依据上述计算方法得到待测化合物多个浓度对hERG电流的抑制率(平均值±标准差)后，使用logistic方程对数据进行拟合，得到IC50值。
表3化合物在细胞水平对hERG钾离子通道抑制的IC50(μM)
Compound ID IC50
AZD9291 0.37
11 1.85
16 2.67
24 1.97
本发明的氘代化合物，相对于AZD9291具有更低的心脏毒性。

Claims (10)

  1. 具有式(I)结构的化合物或其药学上可接受的盐，
    Figure PCTCN2017102027-appb-100001
    其中，R1,R2选自-CH3或-CD3，R3及R4选自-CH3、-CD3或-H，且R1,R2,R3及R4至少一个为-CD3。
  2. 根据权利要求1所述的具有式(I)结构的化合物或其药学上可接受的盐，其特征在于R1为-CH3。
  3. 化合物或其药学上可接受的盐，其中化合物选自：
    Figure PCTCN2017102027-appb-100002
  4. 根据权利要求1～3中任意一项所述的具有式(I)结构的化合物或其药学上可接受的盐，其特征在于，所述的药学上可接受的盐选自醋酸盐、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐、磺酸盐、酒石酸盐或硫氰酸盐。
  5. 一种药物组合物，其包括权利要求1～4中任意一项所述具有式(I)结构的化合物或 其药学上可接受的盐，以及药学上可接受的辅料。
  6. 权利要求1～4中任意一项所述的具有式(I)结构的化合物或其药学上可接受的盐在制备治疗或预防肿瘤药物方面的用途。
  7. 根据权利要求6所述的用途，其特征在于，所述的肿瘤选自非小细胞肺癌、小细胞肺癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌或鼻咽癌。
  8. 权利要求1～4中任意一项所述的具有式(I)结构的化合物或其药学上可接受的盐在制备用于治疗或预防由EGFR介导的或由激活突变体或抗性突变体形式的EGFR介导的疾病、障碍、紊乱或病况的药物的用途。
  9. 根据权利要求8所述的用途，其特征在于，所述的由EGFR介导的或由激活突变体或抗性突变体形式的EGFR介导的疾病、障碍、紊乱或病况选自非小细胞肺癌、小细胞肺癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌或鼻咽癌。
  10. 根据权利要求8所述的用途，其特征在于，所述的激活突变体或抗性突变体形式的EGFR选自L858R激活突变体、Exon19缺失激活突变体和T790M抗性突变体。
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