WO2018103663A1 - 一种取代的吡嗪甲酰胺类化合物及包含该化合物的组合物及其用途 - Google Patents

一种取代的吡嗪甲酰胺类化合物及包含该化合物的组合物及其用途 Download PDF

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WO2018103663A1
WO2018103663A1 PCT/CN2017/114810 CN2017114810W WO2018103663A1 WO 2018103663 A1 WO2018103663 A1 WO 2018103663A1 CN 2017114810 W CN2017114810 W CN 2017114810W WO 2018103663 A1 WO2018103663 A1 WO 2018103663A1
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compound
mmol
added
solution
pharmaceutically acceptable
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PCT/CN2017/114810
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French (fr)
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王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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Priority to CN201780004819.7A priority Critical patent/CN108419436B/zh
Publication of WO2018103663A1 publication Critical patent/WO2018103663A1/zh

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    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of medicine, and in particular to a substituted pyrazine carboxamide compound and a composition comprising the same and use thereof.
  • the epidermal growth factor receptors EGFR, ErbB-1, and HER1 are members of the ErbB receptor family, and the ErbB receptor family is the four closely related receptor tyrosine kinases EGFR (ErbB-1), HER2/c-neu ( ErbB-2), a subfamily of Her 3 (ErbB-3) and Her4 (ErbB-4).
  • EGFR is a cell surface receptor for members of the epidermal growth factor family (EGF family) of the extracellular protein ligand. Mutations that affect EGFR expression or activity may result in cancer. It has been reported that EGFR is unregulated in most solid tumors such as lung cancer, breast cancer and brain tumors. It is estimated that 30% of epithelial cancers are associated with mutations, amplification or dysregulation of EGFR or family members.
  • Treatments for inhibition of EGFR have been developed based on drugs or small molecule inhibitor drugs such as gefitinib and erlotinib.
  • gefitinib and erlotinib are beneficial for 10% to 40% of patients.
  • acquired resistance to gefitinib or erlotinib after a period of treatment has become a major clinical problem.
  • T790M which is the "guard" of EGFR.
  • these T790Ms targeting EGFR inhibitors also have relative inhibitory activity against wild-type EGFR, which limits clinical applications. Therefore, it is necessary to further develop more effective types of EGFR inhibitors that only target mutant proteins rather than wild-type proteins.
  • gefitinib, erlotinib and other EGFR inhibitors have achieved remarkable results in the treatment of advanced NSCLC with EGFR mutation, but subsequently found that EGFR-TKI is primary resistant in the treatment of NSCLC. Or secondary resistance, we are facing new challenges in the treatment of advanced NSCLC, and then carry out new exploration and find countermeasures.
  • the present invention discloses a substituted pyrazine carboxamide compound and a composition comprising the same and use thereof, which have better EGFR kinase inhibitory activity and/or have better pharmacodynamics/drug Generational kinetic properties that can be used to treat, prevent, and alleviate diseases mediated by EGFR kinase.
  • a substituted pyrazine carboxamide compound such as a pyrazine carboxamide compound of formula (I), or a crystalline form, a pharmaceutically acceptable salt, a prodrug, a hydrate or a solvent compound thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 and R 33 Each independently being hydrogen, deuterium, halogen or trifluoromethyl;
  • X 1 and X 2 are independently selected from the group consisting of "hydrogen (H), hydrazine (D), methyl, CH 2 D, CHD 2 , CD 3 , CH 2 CH 3 , CHDCH 3 , CHDCH 2 D, CHDCHD 2 , CHDCD 3, CD 2 CH 3, CD 2 CH 2 D, CD 2 CHD 2, CD 2 CD 3 " from the group consisting of;
  • Additional conditions are: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , At least one of R 33 , X 1 and X 2 is deuterated or deuterated.
  • X 1 is a methyl group which is deuterated one or more times.
  • X 2 is a methyl group which is deuterated one or more times.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content. More than 95%, more preferably more than 99%.
  • the strontium isotope content of strontium at each metamorphic position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. More preferably greater than 95%, more preferably greater than 99%.
  • the strontium isotope content of each of the deuterated positions of R 32 , R 33 , X 1 and X 2 is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, and even more preferably greater than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60 More preferably, more than
  • a pharmaceutically acceptable carrier is hydrated with a compound described in the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant
  • the solvates or solvates are mixed to form a pharmaceutical composition.
  • the invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a substituted pyrazine carboxamide compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof
  • a pharmaceutical composition of a stereoisomer, prodrug or isotopic variation comprising a pharmaceutically acceptable carrier and a substituted pyrazine carboxamide compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • it further comprises other therapeutic agents, which are drugs for cancer, cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases. .
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 1000 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • the present invention also discloses the use of a substituted pyrazine carboxamide compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, for the preparation of a therapeutic, prophylactic and mitigating protein kinase A pharmaceutical composition for the disease.
  • the compound of the present invention has excellent inhibitory activity against protein kinase (Kinase), particularly against EGFR kinase
  • the inhibitory activity and therefore the compound of the present invention and various crystal forms thereof, a pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for treatment and prevention And alleviation of diseases mediated by protein kinases (Kinase), particularly against EGFR kinases.
  • the compounds of the invention are useful in the treatment of diseases such as cancer, cell proliferative diseases, inflammation, infections, immune diseases, organ transplants, viral diseases, cardiovascular diseases or metabolic diseases.
  • the substituted pyrazine carboxamide compound disclosed in the present invention and the composition comprising the same have excellent inhibitory properties against EGFR kinase, and have better pharmacokinetic parameter characteristics, and can increase the drug concentration of the compound in the animal.
  • the substituted pyrazine carboxamides disclosed in the present invention and compositions comprising the same are useful for the treatment, prevention, and amelioration of kinase by protein kinases, particularly against EGFR kinases. disease.
  • the compound 2 (2 g, 10.7 mmol) was added to a solution of DMF (20 mL), and the mixture was cooled to 0 ° C in an ice water bath, then sodium hydride (NaH, 556 mg, 13.9 mmol) was added dropwise. After completion, stirring was continued at 0 ° C for 30 min, then a solution of Compound 1 (2.35 g, 10.7 mmol) in anhydrous DMF was slowly added dropwise and stirring was continued at 0 ° C for 2 hrs. Then, the reaction was quenched by the addition of water, and the mixture was stirred at room temperature for 10 min, and extracted with ethyl acetate. The organic phase was collected and purified to afford white solid (2.5 g).
  • Step 5 synthesizing compound 10
  • Trifluoroacetic acid (TFA, 1 mL) was added to a solution of compound 9 (65 mg, 105 ⁇ mol) in 5 mL of dichloromethane, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Triethylamine was neutralized and the product was used directly in the next step.
  • Example 2 was prepared as Compound 22, and the specific synthesis method was as follows:
  • Step 2 synthesizing compound 15;
  • Step 4 synthesizing compound 18
  • Step 7 synthesizing compound 21
  • Step 8 synthesizing compound 22
  • Example 3 was prepared as Compound 31, and the specific synthesis method was as follows:
  • Step 2 synthesizing compound 25;
  • Step 4 synthesizing compound 27;
  • Step 5 synthesizing compound 28;
  • Step 7 synthesizing compound 30;
  • Step 8 synthesizing compound 31;
  • Example 4 was prepared as Compound 38, and the specific synthesis method was as follows:
  • Step 2 synthesizing compound 33;
  • Step 4 synthesizing compound 35;
  • Step 5 synthesizing compound 36
  • Example 5 was prepared as Compound 50, and the specific synthesis method was as follows:
  • Step 4 synthesizing compound 44;
  • Step 5 synthesizing compound 45;
  • Step 8 synthesizing compound 49;
  • Step 9 synthesizing compound 50
  • Example 6 was prepared as Compound 55, and the specific synthesis method was as follows:
  • Step 3 synthesizing compound 53;
  • Step 5 synthesizing compound 54;
  • Trifluoroacetic acid (TFA, 1 mL) was added to a solution of compound 53 (65 mg, 105 ⁇ mol) in 5 mL of dichloromethane, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Triethylamine was neutralized and the product was used directly in the next step.
  • Step 6 synthesizing compound 55;
  • the biological evaluation of the compounds was carried out by evaluating the compounds of the invention in a number of tests to determine their biological activity. For example, the ability of a compound of the invention to inhibit a variety of protein kinases of interest can be tested. Some of the compounds tested showed potent inhibitory activity against EGFR kinase. Furthermore, anti-proliferative activity in some of these compounds was screened in human A431 skin cancer cells and human NCI-H1975 and HCC827 lung cancer cell lines, and the activity was demonstrated to be in the range of 1-50 nM. The cytotoxic or growth inhibitory effects of the compounds on the tumor cells of interest were evaluated.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. The solution was diluted in DMSO to a final concentration of 100 times the dilution. Dilute to 10 times the final concentration of the dilution solution with the buffer.
  • EGFR and EGFR [T790M/L858R] kinase assay After buffer preparation, the enzyme was mixed with different concentrations of pre-diluted compounds for 10 minutes, each double well. The corresponding substrate and ATP were added and reacted at room temperature for 20 minutes (in which a negative positive control was set). After the reaction is completed, the detection reagent is added, and after incubation at room temperature for 30 minutes, the machine is detected and data is collected. Data analysis and mapping according to Graphpad 5.0 software.
  • EGFR [d746-750] Kinase Assay: After the buffer was prepared, the mixed solution of the enzyme and the antibody was mixed with the different concentrations of the compound prepared by pre-dilution for 10 minutes, and the concentration was doubled. Kinase tracer 199 was added and incubated for 60 minutes at room temperature (where a negative positive control was set). After the reaction is completed, the machine is tested, the data is collected, and the analysis and mapping are performed according to the following formula.
  • IC 50 [(ABS test - ABS start) / (ABS control - ABS start)] x100
  • the substituted pyrazine carboxamides EGFR L858R/T790M mutants of Examples 1 to 6 (which are resistant to commercially available EGFR inhibitors) exhibited superiority to the non-deuterated compound ASP8273.
  • the inhibitory activity (the EGFR WT associated with the adverse reaction showed a lower inhibitory activity.
  • the compound of the present invention has a more potent inhibitory effect on EGFR L858R/T790M than the non-deuterated compound ASP8273. Excellent selectivity for EGFR WT.
  • Cell lines skin cancer cells A431; lung cancer cells HCC827; lung cancer cells NCI-H1975; all cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin.
  • test compound preparation The test compound was dissolved in DMSO to prepare a 20 mM stock solution and stored at -20 °C. The solution was diluted to a final concentration of 200 times with a DMSO gradient. When the drug is added, it is diluted with a cell culture medium to a 4-fold final concentration of the working solution.
  • MTS cell viability assay Trypsin digested logarithmic growth phase cells, inoculate 150 ⁇ l in 96-well plates at an optimized density, and add 4 ⁇ l of compound 50 ⁇ l/well diluted in the medium 24 hours later (see Table 2. for concentration settings). A well of the same volume of 0.5% DMSO was added as a control. After the cells were cultured for 72 hours, MTS was assayed for cell viability. The specific method is as follows: adherent cells, the medium is discarded, and a mixture containing 20 ⁇ l of MTS and 100 ⁇ l of the medium is added to each well. OD490 was detected after being placed in an incubator for 1-4 hours, with the OD650 value as a reference.
  • the GraphPad Prism software produced a dose-effect curve and calculated the IC 50 .
  • the results are shown in Table 2, where A represents IC 50 ⁇ 20 nM, B represents IC 50 of 20 nM ⁇ IC 50 ⁇ 23 nM, and C represents IC 50 of 23 nM ⁇ IC 50 ⁇ 25 nM, D indicates an IC 50 of 25 nM ⁇ IC 50 ⁇ 36 nM, and E indicates an IC 50 ⁇ 700 nM.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test. The drug was dissolved with PEG400 and dimethyl sulfoxide. Eyelid blood collection, the time of blood collection is 0.083 hours after administration, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 small Hours, 8 hours, 12 hours and 24 hours.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube to indicate the name and time point of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • Preparation of stock solution A certain amount of the powder of the compound example was accurately weighed and dissolved to 5 mM with DMSO, respectively.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-PD, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by simultaneously testing the compounds of the present invention and their compounds without deuteration.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in the table.
  • the undeuterated compound ASP8273 was used as a control in the table.
  • the compounds of the present invention significantly improved metabolic stability by comparison with the undeuterated compound ASP8273 in human and rat liver microsome experiments.

Abstract

本发明提供了一种取代的吡嗪甲酰胺类化合物及包含该化合物的组合物及其用途，所述取代的吡嗪甲酰胺类化合物为如式(I)所示的吡嗪甲酰胺化合物，或其晶型、药学上可接受的盐、前药，立体异构体、水合物或溶剂化合物。本发明公开的取代的吡嗪甲酰胺类化合物及包含该化合物的组合物对EGFR激酶具有优异的抑制性，同时具有更好的药代动力学参数特性，能够提高化合物在动物体内的药物浓度，以提高药物疗效和安全性。

Description

一种取代的吡嗪甲酰胺类化合物及包含该化合物的组合物及其用途 技术领域
本发明属于医药技术领域，尤其涉及取代的吡嗪甲酰胺类化合物及包含该化合物的组合物及其用途。
背景技术
表皮生长因子受体即EGFR、ErbB-1、HER1是ErbB受体家族的成员，ErbB受体家族是四种密切相关的受体酪氨酸激酶EGFR(ErbB-1)，HER2/c-neu(ErbB-2)，Her 3(ErbB-3)和Her4(ErbB-4)的亚家族。EGFR是胞外蛋白配体表皮生长因子家族(EGF家族)成员的细胞表面受体。影响EGFR表达或活性的突变可能导致癌症。据报道，在大多数实体瘤如肺癌、乳腺癌和脑瘤中EGFR处于无管制状态。据估计30％的上皮癌与EGFR或家族成员的突变、扩增或失调有关联。
基于通过抗体药或小分子抑制剂药物，例如吉非替尼和厄洛替尼，对EGFR的抑制的治疗方法已被研发出来。非小细胞肺癌的情况下，吉非替尼和厄洛替尼对10％～40％的病人有益处。然而，治疗一段时间后对吉非替尼或厄洛替尼的获得性耐药性成为主要的临床问题。研究证实，产生耐药性的一个主要原因是由于T790M的新突变，T790M是EGFR的“门卫”。然后，研发人员又研发了能T790M的抑制剂，如BIBW2992，并在临床试验中表现出优势。但是，这些以EGFR抑制剂为靶标的T790M对野生型EGFR也具有相对的抑制活性，这就限制了临床应用。所以，有必要进一步研发出更多仅靶向突变蛋白而非野生型蛋白的EGFR抑制剂的有效类型。
另外，吉非替尼、厄洛替尼等EGFR抑制剂(EGFR-TKI)针对EGFR突变晚期NSCLC虽然取得了令人瞩目的疗效，但是随后发现EGFR-TKI在治疗NSCLC时的原发性耐药或继发性耐药，是我们在治疗晚期NSCLC面临新的挑战，继而开展新的探索，寻找对策。
发明内容
针对以上技术问题，本发明公开了一种取代的吡嗪甲酰胺类化合物及包含该化合物的组合物及其用途，其具有更好的EGFR激酶抑制活性和/或具有更好药效学/药代动力学性能，可用于治疗、预防以及缓解由对EGFR激酶介导的疾病。
对此，本发明的技术方案为：
一种取代的吡嗪甲酰胺类化合物，如式(I)所示的吡嗪甲酰胺化合物，或其晶型、药学上可接受的盐、前药、水合物或溶剂化合物，
Figure PCTCN2017114810-appb-000001
其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32和R33各自独立地为氢、氘、卤素或三氟甲基；
X1、X2相互独立地选自由“氢(H)、氘(D)、甲基、CH2D、CHD2、CD3、CH2CH3、CHDCH3、CHDCH2D、CHDCHD2、CHDCD3、CD2CH3、CD2CH2D、CD2CHD2、CD2CD3”组成的组；
附加条件为：R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、X1和X2中至少一个是氘代的或氘。
作为本发明的进一步改进，X1为一次或多次氘代的甲基。
作为本发明的进一步改进，X2为一次或多次氘代的甲基。
作为本发明的进一步改进，所述化合物选自下组化合物或其药学上可接受的盐：
Figure PCTCN2017114810-appb-000002
Figure PCTCN2017114810-appb-000003
Figure PCTCN2017114810-appb-000004
作为本发明的进一步改进，氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量0.015％，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
在另一优选例中，氘在各氘代位置的氘同位素含量至少是大于天然氘同位素含量(0.015％)，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
具体地说，在本发明中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、X1和X2各氘代位置中氘同位素含量至少是5％，较佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
在另一选例中，式(I)中化合物的R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、X1和X2，至少其中一个R/X含氘，更佳地两个R/X含氘，更佳地三个R/X含氘，更佳地四个R/X含氘，更佳地五个R/X含氘，更佳地六个R/X含氘，更佳地七个R/X含氘，更佳地八个R/X含氘，更佳地九个R/X含氘，更佳地十个R/X含氘，更佳地十一个R/X含氘，更佳地十二个R/X含氘，更佳地十三个R/X含氘，更佳地十四个R/X含氘，更佳地十五个R/X含氘，更佳地 十六个R/X含氘，更佳地十七个R/X含氘，更佳地十八个R/X含氘，更佳地十九个R/X含氘，更佳地二十个R/X含氘，更佳地二十一个R/X含氘，更佳地二十二个R/X含氘，更佳地二十三个R/X含氘，更佳地二十四个R/X含氘，更佳地二十五个R/X含氘，更佳地二十六个R/X含氘，更佳地二十七个R/X含氘，更佳地二十八个R/X含氘，更佳地二十九个R/X含氘，更佳地三十个R/X含氘，更佳地三十一个R/X含氘，更佳地三十二个R/X含氘，更佳地三十三个R/X含氘，更佳地三十四个R/X含氘，更佳地三十五个R/X含氘。
作为本发明的进一步改进，将药学上可接受的载体与本发明第一方面中所述的化合物，或其晶型、药学上可接受的盐、前药，立体异构体、同位素变体水合物或溶剂合物进行混合，从而形成药物组合物。
本发明还公开了一种药物组合物，其含有药学上可接受的载体和如上所述的取代的吡嗪甲酰胺化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体、前药或同位素变体的药物组合物。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如2H，3H，13C，14C，15N，17O，18O，31P，32P，35S，18F以及36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易，是同位素中的首选。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用示例中的方案可以制备。
作为本发明的进一步改进，其还包含其他治疗药物，所述治疗药物为癌症、细胞增殖性疾病、炎症、感染、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病的药物。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
本发明还公开了如上所述的取代的吡嗪甲酰胺化合物，或其晶型、药学上可接受的盐、水合物或溶剂化合物的用途，用于制备治疗、预防以及缓解由对蛋白激酶介导的疾病的药物组合物。
由于本发明化合物具有优异的对蛋白激酶(Kinase)的抑制活性，特别是针对EGFR激酶具有很好 的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由对蛋白激酶(Kinase)，特别是针对EGFR激酶介导的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：癌症、细胞增殖性疾病、炎症、感染、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病等。
本发明的有益效果为：
本发明公开的取代的吡嗪甲酰胺类化合物及包含该化合物的组合物对EGFR激酶具有优异的抑制性，同时具有更好的药代动力学参数特性，能够提高化合物在动物体内的药物浓度，以提高药物疗效和安全性；本发明公开的取代的吡嗪甲酰胺类化合物及包含该化合物的组合物可用于治疗、预防以及缓解由对蛋白激酶(Kinase)，特别是针对EGFR激酶介导的疾病。
具体实施方式
下面结合本发明的较优的实施例作进一步的详细说明。
应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
中间体(化合物3)的合成。
Figure PCTCN2017114810-appb-000005
在氮气氛围下，将化合物2(2g，10.7mmol)加入到DMF(20mL)溶液中，冰水浴冷却至0℃下，然后慢慢滴加氢化钠(NaH，556mg，13.9mmol)，滴加完毕后继续在0℃下搅拌30min，然后慢慢滴加化合物1(2.35g,10.7mmol)的无水DMF溶液，继续在0℃下搅拌2hrs。然后加入水淬灭反应，在室温下搅拌10min，乙酸乙酯萃取，收集有机相过柱纯化得白色固体2.5g，收率为64.1％。
实施例1制备化合物11
Figure PCTCN2017114810-appb-000006
具体步骤如下：
步骤1：合成化合物6；
氮气氛围下，将4mL Ti(Oi-Pr)4加入至化合物4(500mg,2.27mmol)和化合物5(328mg,3.41mmol)的混合液中，室温下搅拌过夜，加入15mL乙醇随后加入NaCNBH3(713mg,11.35mmol)，将此反应物在室温下继续搅拌2小时，倒入混有5g硅藻土的水(10mL)，搅拌30分钟后过滤，收集有机相，旋干，通过柱色谱分离纯化得到目标产物化合物6为黄色固体220mg，收率为32.4％。LC-MS(APCI):m/z＝299.4(M+1)+。
步骤2：合成化合物7；
将化合物6(120mg,402μmol)，甲醛(98mg,1.21mmol,37％水溶液)，1滴CH3COOH的甲醇溶液(5mL)在室温下搅拌10分钟，加入NaCNBH3(93mg,1.5mmol)，继续搅拌2小时，加入碳酸氢钠饱和溶液，用二氯甲烷萃取，收集有机相过柱纯化得目标产物化合物7为黄色固体，共110mg，收率为87.3％。LC-MS(APCI):m/z＝313.5(M+1)+；1HNMR(CDCl3,400MHz)(δ/ppm)8.03(d,J＝8.8Hz,2H),6.77(d,J＝9.2Hz,2H),3.12-3.07(m,3H),2.93(m,J＝12.8Hz,2H),2.66(s,3H),1.95-1.91(m,2H),1.57-1.46(m,2H)。
步骤3：合成化合物8；
将化合物7(110mg,352μmol)，铁粉(197mg,3.52mmol)，氯化铵(94mg,1.76mmol)的乙醇/水(10mL/5mL)溶液加热至90℃，并反应2小时后冷却至室温，过滤，收集有机相移除乙醇 后用饱和碳酸氢钠溶液稀释，用二氯甲烷萃取后收集有机相得到化合物8为白色固体，共90mg，收率为90.9％。LC-MS(APCI):m/z＝283.4(M+1)+。
步骤4：合成化合物9；
将N,N-二异丙基乙胺(DIPEA，0.5mL)加入至化合物8(90mg,319μmol)和化合物3(154mg,414μmol)的DMF(N,N-二甲基甲酰胺，1.5mL)溶液中。加热至140℃后反应1.5小时，冷却至室温，减压抽干，用薄层色谱分离纯化得到目标产物化合物9为黄色固体，共65mg，收率为33.2％。LC-MS(APCI):m/z＝617.4(M+1)+。
步骤5：合成化合物10；
将三氟乙酸(TFA，1mL)加入至化合物9(65mg,105μmol)的5mL二氯甲烷溶液中，室温下搅拌1小时，减压移除溶剂，将残余物溶于20mL二氯甲烷并用0.5mL三乙胺中和，产物直接用于下一步。LC-MS(APCI):m/z＝517.3(M+1)+。
步骤6：合成化合物11；
将冷却至-10℃丙烯酰氯(11mg,125μmol)的二氯甲烷(0.1mL)溶液加入上一步溶液中，室温下搅拌1小时，加入饱和碳酸氢钠溶液搅拌10分钟，用二氯甲烷萃取，收集有机相过柱纯化得目标产物化合物11为黄色固体，共27mg，收率为45.8％。LC-MS(APCI):m/z＝571.5(M+1)+；1HNMR(CDCl3,500MHz)(δ/ppm)10.59(d,J＝15.0Hz,1H),7.59(br s,1H),7.42(d,J＝8.0Hz,2H),6.90(d,J＝8.0Hz,2H),6.52-6.35(m,2H),5.73-5.67(m,1H),5.56-5.54(m,1H),5.43(br s,1H),3.94-3.83(m,2H),3.81-3.73(m,2H),3.68(d,J＝11.5Hz,2H),2.70(t,J＝12.5Hz,2H),2.63(q,J＝7.5Hz,2H),2.58-2.53(m,1H),2.52(s,3H),2.39-2.19(m,2H),2.00(d,J＝11.5Hz,2H),1.80-1.70(m,2H),1.18(t,J＝7.5Hz,3H)。
实施例2制备化合物22，具体合成方法如下：
Figure PCTCN2017114810-appb-000007
步骤1：合成化合物13；
氢气氛围下，将200mg Pd(OH)2加入化合物12(750mg,3.84mmol)的10mL甲醇溶液中，搅拌过夜，硅藻土过滤，移除溶剂得到目标产物化合物13为白色固体，共380mg，收率为94.1％。1HNMR(CDCl3,300MHz)(δ/ppm)3.74-3.70(m,1H),1.92-1.88(m,2H),1.39(t,J＝6.6Hz,2H)。
步骤2：合成化合物15；
将化合物14(500mg,3.5mmol)，化合物13(373mg,3.54mmol)和碳酸钾(979mg,7.09mmol)的DMF(10mL)溶液在室温下搅拌16小时，加水稀释后用二氯甲烷萃取，收集有机相过柱纯化得目标产物为黄色固体，共720mg，收率为89.9％。LC-MS(APCI):m/z＝226.4(M+1)+。
步骤3：合成化合物16；
将化合物15(500mg,2.21mmol)的二氯甲烷(20mL)溶液冷却至0℃后加入800mg分子筛和N-甲基氧化吗啉(NMO,388mg,3.31mmol)，继续加入过钌酸四内胺(39mg,110μmol)，在0℃下搅拌15分钟后转移至室温环境中继续搅拌90分钟，过滤掉分子筛，收集有机相，过柱纯化得目标产物为黄色固体，共320mg，收率为64.6％。LC-MS(APCI):m/z＝225.4(M+1)+；1HNMR(CDCl3,300MHz)(δ/ppm)8.18(d,J＝5.4Hz,2H),6.86(d,J＝6Hz,2H),2.62(s,4H)。
步骤4：合成化合物18；
将化合物17(402mg,4.01mmol)加入至化合物16(300mg,1.34mmol)的甲苯(10mL)溶液中，加热至回流温度并反应15分钟，减压蒸馏移除甲苯，冷却至室温后加入四氢呋喃(THF)和二氯甲烷(DCM)各5mL，再滴加3滴乙酸和氰基硼氢化钠(252mg,4.01mmol)后继续反应1小时，加入饱和碳酸氢钠溶液后用二氯甲烷萃取，收集有机相过柱纯化得目标产物为黄色固体，共 100mg，收率为24.2％。LC-MS(APCI):m/z＝309.4(M+1)+；1HNMR(CDCl3,300MHz)(δ/ppm)8.11(d,J＝5.7Hz,2H),6.80(d,J＝5.4Hz,2H),2.99-2.80(m,1H),2.52-2.49(m,8H),1.97-1.94(m,2H),2.32(s,3H),1.59(t,J＝6.9Hz,2H)。
步骤5：合成化合物19；
合成方法与实施例1步骤3一致，不同之处在于用化合物18代替化合物7，最终得到目标产物为白色固体86mg，收率为95.6％。LC-MS(APCI):m/z＝279.4(M+1)+。
步骤6：合成化合物20；
合成方法与实施例1步骤4一致，不同之处在于用化合物19代替化合物8，最终得到目标产物为黄色固体72mg，收率为38.1％。LC-MS(APCI):m/z＝613.5(M+1)+。
步骤7：合成化合物21；
合成方法与实施例1步骤5一致，不同之处在于用化合物20代替化合物9，最终得到目标产物直接用于下一步。LC-MS(APCI):m/z＝513.4(M+1)+。
步骤8：合成化合物22；
合成方法与实施例1步骤6一致，不同之处在于用化合物21代替化合物10，最终得到目标产物为黄色固体27mg，收率为40.9％。LC-MS(APCI):m/z＝567.4(M+1)+；1HNMR(CDCl3,300MHz)(δ/ppm)10.60(d,J＝9.0Hz,1H),7.60(br s,1H),7.45(d,J＝9.0Hz,2H),6.91(d,J＝9.0Hz,2H),6.52-6.38(m,2H),5.77-5.72(m,1H),5.59-5.57(m,1H),5.35(br s,1H),3.92-3.68(m,4H),3.08-2.94(m,8H),2.70-2.66(m,2H),2.61(s,3H),2.35-2.24(m,3H),2.06-2.00(m,2H),1.78-1.72(m,2H),1.21(t,J＝7.2Hz,3H)。
实施例3制备化合物31，具体合成方法如下：
Figure PCTCN2017114810-appb-000008
步骤1：合成化合物24；
将化合物23(75mg,0.55mmol)加入至化合物4(1.1g,5.0mmol)和CDCl3(80mL)的混合溶液中，室温下搅拌过夜，用二氯甲烷稀释后，依次用10mL水和10mL0.5N盐酸溶液洗涤，收集有机相得到目标产物为黄色固体，共0.89g，收率为80％。LC-MS(APCI):m/z＝225(M+1)+；1HNMR(CDCl3,300MHz)(δ/ppm)8.17(d,J＝5.4Hz,2H),6.86(d,J＝5.4Hz,2H),3.81(s,4H)。
步骤2：合成化合物25；
将化合物24(0.8g，3.57mmol)的甲醇(20mL)溶液置于冰水中冷却后，缓慢加入硼氢化钠(NaBH4,136g,3.57mmol)，搅拌1小时后，加水10mL淬灭反应，继续在室温下搅拌20分钟，加入20mL水和30mL乙酸乙酯，用乙酸乙酯萃取，收集有机相得到目标产物为黄色固体，共740mg，收率为92.5％。LC-MS(APCI):m/z＝227(M+1)+。
步骤3：合成化合物26；
氮气氛围下，依次将吡啶(0.86g,4.5mmol)，对甲基苯酰氯(TsCl,0.86g,4.5mmol)加入至化合物25(0.77g,3mmol)的二氯甲烷(20mL)溶液中，室温下搅拌过夜，加入30mL水和30mL二氯甲烷，收集有机相后依次用水，盐水洗涤后用无水硫酸钠干燥，收集有机相过柱纯化得目标产物为黄色固体，共510mg，收率为45％。LC-MS(APCI):m/z＝381(M+1)+；1HNMR(CDCl3,300MHz)(δ/ppm)8.08(d,J＝5.4Hz,2H),7.81(d,J＝5.4Hz,2H),7.35(d,J＝4.8Hz,2H),6.78(d,J＝5.7Hz,2H),3.91(s,2H)3.01(s,2H)2.46(s,3H)。
步骤4：合成化合物27；
氮气氛围下，依次将化合物26(1.14mg,3mmol)，化合物17(1.5g,15mmol)，K2CO3(2.6g,15mmol)，DMF(6mL)加入至一个三颈圆底烧瓶中，加热至120℃并搅拌反应过夜，加入20mL 二氯甲烷和40mL水，有机相用无水硫酸钠干燥后过滤，收集有机相过柱纯化得目标产物为黄色固体，共620mg，收率为66％。LC-MS(APCI):m/z＝309(M+1)+；1HNMR(CDCl3,300MHz)(δ/ppm)8.10(d,J＝5.7Hz,2H),6.80(d,J＝5.7Hz,2H),3.96(d,J＝7.8Hz,2H),2.96(d,J＝7.8Hz,2H),2.65(br s,4H),2.50(d,J＝10.2Hz,4H),2.32(s,3H)。
步骤5：合成化合物28；
合成方法与实施例1步骤3一致，不同之处在于用化合物27代替化合物7，最终得到目标产物为白色固体450mg，收率为80％。LC-MS(APCI):m/z＝278(M+1)+。
步骤6：合成化合物29；
合成方法与实施例1步骤4一致，不同之处在于用化合物28代替化合物8，最终得到目标产物为黄色固体200mg，收率为33％。LC-MS(APCI):m/z＝613(M+1)+；1HNMR(CDCl3,300MHz)(δ/ppm)10.59(d,J＝9.0Hz,1H),7.62(br s,1H),7.45(d,J＝8.4Hz,2H),6.91(d,J＝8.4Hz,2H),5.50(br s,1H),5.40(br s,1H),3.71-3.58(m,6H),3.10-3.04(m,8H),2.71(q,J＝7.5Hz,2H),2.64(s,3H),2.47-2.41(m,2H),1.49(s,9H),1.21(t,J＝7.5Hz,3H)。
步骤7：合成化合物30；
合成方法与实施例1步骤5一致，不同之处在于用化合物29代替化合物9，最终得到目标产物直接用于下一步。
步骤8：合成化合物31；
合成方法与实施例1步骤6一致，不同之处在于用化合物30代替化合物10，最终得到目标产物为黄色固体38mg，收率为22％。LC-MS(APCI):m/z＝567(M+1)+；1HNMR(CDCl3,400MHz)(δ/ppm)10.59(d,J＝11.2Hz,1H),7.59(br s,1H),7.43(d,J＝8.4Hz,2H),6.90(d,J＝8.4Hz,2H),6.49-6.36(m,2H),5.74-5.67(m,1H),5.57-5.55(m,1H),5.41(br s,1H),3.94-3.73(m,4H),3.68(d,J＝12.4Hz,2H),3.11-2.95(m,8H),2.71-2.62(m,7H),2.45-2.37(m,1H),2.30-2.22(m,2H),1.18(t,J＝11.2Hz,3H)。
实施例4制备化合物38，具体合成方法如下：
Figure PCTCN2017114810-appb-000009
步骤1：合成化合物32；
氮气氛围下，将4mL的Ti(Oi-Pr)4加入至化合物4(500mg,2.27mmol)与1-叔丁氧羰基哌嗪(328mg,3.41mmol)的混合物中，在室温下搅拌过夜，依次加入15mL乙醇和NaCNBH3(713mg,11.35mmol)，继续搅拌2小时后倒入10水和5g硅藻土，搅拌30分钟后过滤，减压移除溶剂，柱色谱分离纯化得到目标产物为换色固体，共220mg，收率为32.4％。LC-MS(APCI):m/z＝391.4(M+1)+。
步骤2：合成化合物33；
合成方法与实施例1步骤5一致，不同之处在于用化合物32代替化合物9，最终得到目标产物直接用于下一步。
步骤3：合成化合物34；
将化合物33(210mg,725μmol)甲醛(94mg,1.09mmol,37％溶于5mL MeOD)和乙酸(1滴)的混合溶液在室温下搅拌10分钟后加入NaCNBD3(68mg,1.09mmol)，继续在室温下搅拌2小时后，移除溶剂，残留物加入饱和碳酸氢钠溶液，用二氯甲烷萃取后收集有机相过柱纯化得黄色固体190mg，收率为85.4％。LC-MS(APCI):m/z＝308.4(M+1)+。
步骤4：合成化合物35；
将化合物34(190mg,619μmol)，铁粉(173mg,3.10mmol)和氯化铵(165mg,310mmol)的EtOH/H2O(15mL/5mL)加热至90℃并反应2小时，待反应液恢复至室温后移除溶剂，加入10mL饱和碳酸氢钠溶液，用二氯甲烷萃取后收集有机相最终得到目标产物为白色固体150mg，收率为87.5％。LC-MS(APCI):m/z＝278.4(M+1)+。
步骤5：合成化合物36；
将化合物35(150mg,542μmol)和化合物3(200mg,703μmol)溶于2mL DMF中后，加入0.9mL DIPEA，在140℃下微波反应1.5小时。待反应体系冷却至室温后减压干燥，过柱纯化后最终得到目标产物110mg，收率为34％。LC-MS(APCI):m/z＝612.8(M+1)+。
步骤6：合成化合物37；
合成方法与实施例1步骤5一致，不同之处在于用化合物36代替化合物9，最终得到目标产物直接用于下一步。LC-MS(APCI):m/z＝512.7(M+1)+。
步骤7：合成化合物38；
合成方法与实施例1步骤6一致，不同之处在于用化合物37代替化合物10，最终得到目标产物为黄色固体56mg，收率为55.2％。LC-MS(APCI):m/z＝566.7(M+1)+；1HNMR(CDCl3,500MHz)(δ/ppm)10.59(d,J＝15.0Hz,1H),7.59(br s,1H),7.42(d,J＝8.0Hz,2H),6.90(d,J＝8.0Hz,2H),6.52-6.35(m,2H),5.73-5.67(m,1H),5.56-5.54(m,1H),5.43(br s,1H),3.94-3.83(m,2H),3.81-3.73(m,2H),3.68(d,J＝11.5Hz,2H),3.04-2.75(m,8H),2.70(t,J＝12.5Hz,2H),2.63(q,J＝7.5Hz,2H),2.58-2.53(m,1H),2.39-2.19(m,2H),2.00(d,J＝11.5Hz,2H),1.80-1.70(m,2H),1.18(t,J＝7.5Hz,3H)。
实施例5制备化合物50，具体合成方法如下：
Figure PCTCN2017114810-appb-000010
步骤1：合成化合物41；
依次将化合物39(2.82g,20mmol)，化合物40(2.02g,20mmol)和碳酸钾(4.14g,30mmol)加入至装有50mL DMF的圆底烧瓶后，室温下搅拌过夜，加水稀释后过滤，干燥得到棕色固体3.8g，收率为85.5％。LC-MS(APCI):m/z＝223(M+1)+。
步骤2：合成化合物42；
合成方法与实施例3步骤5一致，不同之处在于用化合物41代替化合物27，最终得到目标产物为白色固体1.92g，收率为99％。LC-MS(APCI):m/z＝193(M+1)+。
步骤3：合成化合物43；
氮气氛围下，将装有20mL***的圆底烧瓶于冰盐浴中冷却至0℃，加入化合物42(1.92g，10mmol)后，继续缓慢加入氘代盐酸溶液(0.85mL,10mmol)搅拌30分钟后过滤，并用***洗涤滤饼，干燥后得到白色固体2.2g；将此白色固体加入至10mL的氘水中，于150℃下微波反应4小时后，加入氢氧化钠溶液(3mol/L,5mL)，用乙酸乙酯萃取后依次用水、饱和食盐水洗涤，收集有机相过柱纯化得白色固体0.8g，收率为42％。LC-MS(APCI):m/z＝197(M+1)+。
步骤4：合成化合物44；
氮气保护下，依次将化合物43(0.8g,4.2mmol)，20mL二氯甲烷和三乙胺(TEA,1.1g,5mmol))加入至一个圆底烧瓶中，待其完全溶解后冰水浴冷却，缓慢滴加(Boc)2O(1.1g,5mmol)，滴加完成后将反应体系恢复至室温并反应16小时后，加50mL水和50mL二氯甲烷，收集有机相过柱纯化得白色固体480mg，收率为39％。LC-MS(APCI):m/z＝297(M+1)+。
步骤5：合成化合物45；
将化合物44(480mg,1.6mmol)的20mL二氯甲烷溶液冷却至0℃后，依次加入800mg 4A分子筛和N-甲基-N-氧化吗啉(NMO,282mg,2.4mmol)和过钌酸四内胺(28mg,80μmol)。将该反应液在0℃下反应15分钟后恢复至室温后继续反应90分钟，过滤收集有机相过柱纯化得白色固体300mg，收率为62.5％。LC-MS(APCI):m/z＝295(M+1)+；1HNMR(400MHz,CDCl3)δ/ppm 6.37(br,1H),3.53(t,J＝6.0Hz,4H),2.56(t,J＝6.0Hz,4H),1.53(s,9H)。
步骤6：合成化合物47；
将化合物46(295mg,1mmol)加入至化合物45(400mg,4mmol)的甲苯(10mL)溶液中，加热至回流后反应15分钟，减压移除甲苯，室温下加入THF/DCM(5mL/5mL)后，继续加入3滴乙酸和氰基硼氢化钠(NaBH3CN,252mg,4mmol)后搅拌1小时，加入饱和碳酸氢钠溶液后用二氯甲烷萃取，收集有机相过柱纯化得白色固体190mg，收率为50％。LC-MS(APCI):m/z＝379.(M+1)+。
步骤7：合成化合物48；
合成方法与实施例1步骤5一致，不同之处在于用化合物47代替化合物9，最终得到目标产物110mg，收率为80％。LC-MS(APCI):m/z＝279(M+1)+。
步骤8：合成化合物49；
将化合物48(278mg,1mol)和化合物3(445mg,1.2mol)溶于5mL DMF中后，加入1.3g N-乙基二异丙胺(DIPEA)，在140℃下微波反应1.5小时。待反应体系冷却至室温后减压干燥，过柱纯化后最终得到目标产物200mg，收率为33％。LC-MS(APCI):m/z＝613(M+1)+。
步骤9：合成化合物50；
氮气保护下，将化合物49(180mg,0.3mmol)溶于二10mL氯甲烷中，冷却至0℃，滴加三氟乙酸(TFA,3.1g，27.2mmol)，恢复至室温并反应1小时；加入50mL二氯甲烷后冷却至，滴加三乙胺(5.6mL,40.4mmol)，冷却至-10℃，逐滴加入丙烯酰氯(30mg，0.33mmol)并在该温度下反应10分钟后，加入水淬灭反应，分离有机相，并依次用水和饱和碳酸氢钠溶液洗涤，收集有机相过柱纯化得黄色固体产物38mg，收率为22％。LC-MS(APCI):m/z＝567(M+1)+；1HNMR(CDCl3,500MHz)(δ/ppm)10.59(d,J＝15.0Hz,1H),7.59(br s,1H),6.52-6.35(m,2H),5.73-5.67(m,1H),5.56-5.54(m,1H),5.43(br,1H),3.94-3.83(m,2H),3.81-3.73(m,2H),3.68(d,J＝11.5Hz,2H),3.04-2.75(m,8H),2.70(t,J＝12.5Hz,2H),2.63(q,J＝7.5Hz,2H),2.58-2.53(m,1H),2.52(s,3H),2.39-2.19(m,2H),2.00(d,J＝11.5Hz,2H),1.80-1.70(m,2H),1.18(t,J＝7.5Hz,3H)。
实施例6制备化合物55，具体合成方法如下：
Figure PCTCN2017114810-appb-000011
步骤1：合成化合物51；
将化合物6(120mg,402μmol)，氘代甲醛(98mg,1.21mmol,20％重水溶液)，1滴CD3COOD加入到氘代甲醇(5mL)中，室温下搅拌10分钟，加入NaBD3CN(97mg,1.5mmol)，继续搅拌2小时，加入碳酸氢钠饱和溶液，用二氯甲烷萃取，收集有机相过柱纯化得目标产物化合物7为黄色 固体，共110mg，收率为87.3％。LC-MS(APCI):m/z＝313.5(M+1)+；1HNMR(CDCl3,400MHz)(δ/ppm)8.03(d,J＝8.8Hz,2H),6.77(d,J＝9.2Hz,2H),3.12-3.07(m,3H),2.93(m,J＝12.8Hz,2H),1.95-1.91(m,2H),1.57-1.46(m,2H)。
步骤2：合成化合物52；
将化合物51(110mg,352μmol)，铁粉(197mg,3.52mmol)，氯化铵(94mg,1.76mmol)的乙醇/水(10mL/5mL)溶液加热至90℃，并反应2小时后冷却至室温，过滤，收集有机相移除乙醇后用饱和碳酸氢钠溶液稀释，用二氯甲烷萃取后收集有机相得到化合物8为棕色固体，共90mg，收率为90.9％。LC-MS(APCI):m/z＝286.4(M+1)+。
步骤3：合成化合物53；
将N,N-二异丙基乙胺(DIPEA，0.5mL)加入至化合物52(90mg,319μmol)和化合物3(154mg,414μmol)的DMF(N,N-二甲基甲酰胺，1.5mL)溶液中。加热至140℃后反应1.5小时，冷却至室温，减压抽干，用薄层色谱分离纯化得到目标产物化合物9为黄色固体，共65mg，收率为33.2％。LC-MS(APCI):m/z＝620.4(M+1)+。
步骤5：合成化合物54；
将三氟乙酸(TFA，1mL)加入至化合物53(65mg,105μmol)的5mL二氯甲烷溶液中，室温下搅拌1小时，减压移除溶剂，将残余物溶于20mL二氯甲烷并用0.5mL三乙胺中和，产物直接用于下一步。LC-MS(APCI):m/z＝520.3(M+1)+。
步骤6：合成化合物55；
将冷却至-10℃丙烯酰氯(11mg,125μmol)的二氯甲烷(0.1mL)溶液加入上一步溶液中，室温下搅拌1小时，加入饱和碳酸氢钠溶液搅拌10分钟，用二氯甲烷萃取，收集有机相过柱纯化得目标产物化合物11为黄色固体，共27mg，收率为45.8％。LC-MS(APCI):m/z＝571.5(M+1)+；1HNMR(CDCl3,500MHz)(δ/ppm)10.59(d,J＝15.0Hz,1H),7.59(br s,1H),7.42(d,J＝8.0Hz,2H),6.90(d,J＝8.0Hz,2H),6.52-6.35(m,2H),5.73-5.67(m,1H),5.56-5.54(m,1H),5.43(br s,1H),3.94-3.83(m,2H),3.81-3.73(m,2H),3.68(d,J＝11.5Hz,2H),2.70(t,J＝12.5Hz,2H),2.63(q,J＝7.5Hz,2H),2.58-2.53(m,1H),2.39-2.19(m,2H),2.00(d,J＝11.5Hz,2H),1.80-1.70(m,2H),1.18(t,J＝7.5Hz,3H)。
化合物的生物活性测试
化合物的生物评价是采用将本发明的化合物在多个测试中进行评价以确定它们的生物学活性。 例如，可测试本发明化合物抑制多种关注的蛋白激酶的能力。一些测试的化合物对EGFR激酶显示出强效的抑制活性。此外，在人A431皮肤癌细胞及人NCI-H1975和HCC827肺癌细胞细胞系中，筛选一些这些化合物中的抗增殖活性，且证明活性在1-50nM范围。评价所述化合物在关注的肿瘤细胞上的细胞毒性或生长抑制作用。
(1)激酶抑制作用
化合物配制：受试化合物溶于DMSO配成20mM母液。在DMSO中梯度稀释成100倍终浓度的稀释液。加药时用缓冲液稀释成10倍终浓度的稀释液。
EGFR及EGFR[T790M/L858R]激酶检测：配制缓冲液后，将酶与预先稀释配制的不同浓度化合物混合10分钟，每个浓度双复孔。加入对应底物及ATP，室温反应20分钟(其中设置阴阳性对照)。反应完毕加入检测试剂，室温孵育30分钟后上机检测，采集数据。根据Graphpad 5.0软件进行数据分析及拟图。
EGFR[d746-750]激酶检测：配制缓冲液后，将酶和抗体的混合溶液与预先稀释配制的不同浓度化合物混合10分钟，每个浓度双复孔。加入Kinase tracer 199，室温孵育60分钟(其中设置阴阳性对照)。反应完毕后上机检测，采集数据，按照下式进行分析及拟图。
IC50＝[(ABS测试-ABS开始)/(ABS对照-ABS开始)]x100
实施例1～6合成得到的取代的吡嗪甲酰胺类化合物的激酶抑制作用归纳于如下表1所示：
表1：实施例1～6的取代的吡嗪甲酰胺类化合物的激酶抑制作用分析表
实施例编号 EGFR(L858R/T790M)IC50(nM) WT/LT
ASP8273 0.9～1.0 15倍
实施例1 1.0～2.0 >50倍
实施例2 0.3～0.9 >50倍
实施例3 0.3～0.9 >50倍
实施例4 0.3～0.9 >50倍
实施例5 0.3～0.9 >50倍
实施例6 0.3～0.9 >50倍
如表1所示，实施例1～6的取代的吡嗪甲酰胺类化合物EGFR L858R/T790M突变体(其对可商购的EGFR抑制剂具有抗性)表现出比未氘代化合物ASP8273更优良的抑制活性(，与不良反应相关的EGFR WT表现出更低的抑制活性。由此可见，与未氘代化合物ASP8273相比，本发明化合物对EGFR L858R/T790M具有更强效的抑制作用以及优于EGFR WT的优异选择性。
(2)细胞毒性实验
细胞系：皮肤癌细胞A431；肺癌细胞HCC827；肺癌细胞NCI-H1975；均用含10％胎牛血清、100U/ml青霉素、100μg/ml链霉素的RPMI1640培养基培养。
化合物配制：受试化合物溶于DMSO配成20mM保存液，-20℃保存。用DMSO梯度稀释成200倍终浓度的保存液。加药时用再用细胞培养基稀释成4倍终浓度的工作液。
MTS细胞活力检测：胰酶消化对数生长期细胞，按已优化的密度接种150μl于96孔板，24小时后加入培养基稀释的4倍浓度化合物50μl/孔(浓度设置见表2.)。以加入同样体积的0.5％DMSO的孔作为对照。细胞继续培养72小时后，MTS检测细胞活力。具体方法如下：贴壁细胞，弃去培养基，每孔加入含20μl MTS和100μl培养基的混合液。放入培养箱继续培养1-4小时后检测OD490，以OD650值作为参考。GraphPad Prism软件制作量效曲线并计算IC50，结果详见表2所示,其中A表示IC50≤20nM，B表示IC50为20nM<IC50≤23nM，C表示IC50为23nM<IC50≤25nM，D表示IC50为25nM<IC50≤36nM，并且E表示IC50≥700nM。
表2：实施例1～6的取代的吡嗪甲酰胺类化合物的细胞毒性实验分析表
Figure PCTCN2017114810-appb-000012
实验结果表明本发明的化合物对肺癌细胞H1975和HCC827具有比未氘代ASP8273更强效的活性以及优于皮肤癌细胞A431的优异选择性。(3)大鼠中的药代动力学评价
8只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组4只，单次口服给予5mg/kg剂量的(a)对照组：N-(3-(2-(4-乙酰哌嗪-1-基)2-甲氧基苯胺基)-5-三氟甲基嘧啶基-4胺基)苯基丙烯酰胺；(b)试验组：实施例1-9，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小 时、8小时、12小时和24小时。
大鼠吸入***后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL1％肝素盐溶液。使用前，试管于60℃烘干过夜。在随后一个时间点血样采集完成之后，大鼠***麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，表明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验结果表明，相对于对照化合物，本发明化合物在动物体内具有更好的药物动力学，因而具有更好的药效学和治疗效果。
(4)代谢稳定性评价
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的化合物实施例的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH7.4)的配制：取预先配好的0.5M磷酸二氢钾150mL和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生***溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-PD，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸***和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH 7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生***置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生***溶液，作为0min样 品。再向孵育板每孔加入80μL的NADPH再生***溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS***检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t1/2和CLint，其中V/M即等于1/蛋白浓度。
对本发明化合物及其没有氘代的化合物同时测验比较，评价其在人和大鼠肝微粒体的代谢稳定性。作为代谢稳定性的指标的半衰期及肝固有清除率如表所示。表中采用未经氘代的化合物ASP8273作为对照品。如表3所示，在人和大鼠肝微粒体实验中，通过与未经氘代的化合物ASP8273对照，本发明化合物可以明显改善代谢稳定性。
表3：实施例1～6的取代的吡嗪甲酰胺类化合物的代谢稳定性作用分析表
Figure PCTCN2017114810-appb-000013
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (6)

  1. 一种取代的吡嗪甲酰胺类化合物，其特征在于：如式(I)所示的吡嗪甲酰胺化合物，或其晶型、药学上可接受的盐、水合物或溶剂化合物，
    Figure PCTCN2017114810-appb-100001
    其中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32和R33各自独立地为氢、氘、卤素或三氟甲基；
    X1、X2相互独立地选自由“氢(H)、氘(D)、甲基、CH2D、CHD2、CD3、CH2CH3、CHDCH3、CHDCH2D、CHDCHD2、CHDCD3、CD2CH3、CD2CH2D、CD2CHD2、CD2CD3”组成的组；
    附加条件为：R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、X1和X2中至少一个是氘代的或氘。
  2. 根据权利要求1所述的取代的吡嗪甲酰胺类化合物，其特征在于：X1、X2相互独立地选自一次或多次氘代的甲基。
  3. 根据权利要求1所述的取代的吡嗪甲酰胺类化合物，其特征在于：所述化合物选自下组化合物或其药学上可接受的盐：
    Figure PCTCN2017114810-appb-100002
    Figure PCTCN2017114810-appb-100003
  4. 一种药物组合物，其特征在于：其含有药学上可接受的载体和如权利要求1～3任意一项所述的取代的吡嗪甲酰胺化合物，或其晶型、药学上可接受的盐、水合物或溶剂合物、立体异构体、前药或同位素变体的药物组合物。
  5. 根据权利要求4所述的药物组合物，其特征在于：其还包含其他治疗药物，所述治疗药物为治疗癌症、细胞增殖性疾病、炎症、感染、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病的药物。
  6. 一种如权利要求1～5任意一项所述的取代的吡嗪甲酰胺化合物，或其晶型、药学上可接受的盐、水合物或溶剂化合物的用途，其特征在于：用于制备治疗、预防以及缓解由对表皮生长因子突变引起的疾病的药物组合物。
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