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WO2019001425A1 - 一种氘代奥斯替尼衍生物及其应用 - Google Patents

一种氘代奥斯替尼衍生物及其应用 Download PDF

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WO2019001425A1
WO2019001425A1 PCT/CN2018/092884 CN2018092884W WO2019001425A1 WO 2019001425 A1 WO2019001425 A1 WO 2019001425A1 CN 2018092884 W CN2018092884 W CN 2018092884W WO 2019001425 A1 WO2019001425 A1 WO 2019001425A1
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吴豫生
耿阳
孟庆国
梁阿朋
牛成山
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Deuracor Therapeutic Inc
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the field of medical technology, and in particular to a deuterated Osimintinib derivative for use as an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR related diseases, especially non-small cell lung cancer.
  • a deuterated Osimintinib derivative for use as an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR related diseases, especially non-small cell lung cancer.
  • Epidermal Growth Factor Receptor is a transmembrane protein tyrosine kinase of the erbB receptor family that binds to growth factor ligands (eg, epidermal growth factor (EGF)). Homogeneous dimerization can occur with additional EGFR molecules or with another family member (eg, erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4)). Homologous dimerization and/or heterodimerization of the erbB receptor results in phosphorylation of key tyrosine residues in the intracellular domain and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many human cancers, including lung cancer, head and neck cancer, and breast cancer.
  • Lung cancer is the world's highest incidence of cancer. It ranks first among all cancers in China, and it is also the cancer with the highest morbidity and mortality in China. About 30% of lung cancer patients in China have EGFR mutations, of which L858R and exon 19 deletion mutations account for more than 90%. These patients are more sensitive to EGFR inhibitors.
  • the existing first-generation EGFR inhibitors such as erlotinib and gefitinib have good curative effect on such patients, which can reduce tumors in more than 60% of patients and significantly prolong the progression-free survival of patients. .
  • the vast majority of patients will acquire resistance within 6-12 months. This resistance pattern is a further mutation of EGFR, which reduces its sensitivity to first-generation EGFR inhibitors.
  • T790M The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. 304, 1497-1500; New England Journal of Medicine 2004, 350, 2129-2139), from the original L- at this position. Threonine (T) is replaced by L-methionine (M), and the mutated EGF tyrosine kinase R no longer binds to gefitinib or erlotinib, thus making the first generation of EGFR inhibitors No longer effective, resulting in such patients currently in a state of no drug availability. Clinically, 50% of patients who developed resistance to first-generation EGFR inhibitors had EGFR T790M mutations. In the T790M mutant cell line H1975, first-generation EGFR inhibitors, such as gefitinib and erlotinib, were all greater than 3 [mu]M and were essentially inactive.
  • WO2013014448 discloses a pyrimidine derivative which can be used as an EGFR inhibitor and its use for treating cancer, the structure is as shown in the formula A, wherein G is selected from 4, 5, 6, 7-tetrahydropyrazolo[1,5-a]pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo[1,5 -a]pyridin-3-yl, R 2 is methyl or methoxy;
  • this drug cannot be used. Therefore, it is very necessary to optimize the structure of the drug, increase the half-life, reduce the toxicity of the drug, and increase the treatment window, so that more patients benefit.
  • CN104140418B discloses some methyl deuterated azinib (AZD9291) compounds having the structural formula shown in formula B, wherein R 1 , R 2 , R 3 , R 4 and R 5 are methyl or deuterated. methyl,
  • CN105237515 discloses an Osimertinib compound which only has a pyrimidine ring, and our study found that when the methyl group on the oxime is metabolized, a compound of the formula C is formed.
  • this compound still inhibits EGFR activity, it does not pass through the blood-brain barrier and enters the brain, thereby losing its effect on tumor patients with brain metastasis.
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 are each independently selected from methyl or deuterated methyl;
  • R 6 is selected from H or hydrazine.
  • the deuterated methyl group -CD 3 Preferably, the deuterated methyl group -CD 3.
  • the R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from methyl or -CD 3 .
  • At least one of R 1 , R 2 , R 3 , R 4 and R 5 is -CD 3 .
  • R 1 , R 2 , R 3 , R 4 and R 5 are -CD 3 .
  • the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate salt, a hydrogen sulfate salt, and a nitrate salt.
  • the organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, propylene Acid salt, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picric acid Salt, glutamate, ascorbate, camphorate, camphor sulfonate.
  • the inorganic acid salt is a hydrochloride or a sulfate; the organic acid salt is a methanesulfonate.
  • Another technical solution provided by the present invention is: a pharmaceutical composition comprising the compound of the above formula I and a pharmaceutically acceptable carrier.
  • the deuterated Ostinidil derivative provided by the present invention is a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, which inhibits one or more EGFR activation or resistance mutations, such as L858R activating mutant, Exon19 deletion EGFR activating mutant, T790M resistant mutant; this compound increases the inhibitory activity against mutations such as resistant EGFR T790M, and simultaneously reduces wild-type EGFR The inhibitory activity can be used to develop third-generation EGFR mutant selective inhibitors with higher activity, better selectivity, and lower toxicity.
  • the solvate referred to in the present invention means a complex of the compound of the present invention and a solvent. They either react in a solvent or precipitate out of the solvent or crystallize out.
  • a complex formed with water is referred to as a hydrate; others include an alcoholate, a ketone compound, and the like.
  • the solvates of the present invention include the compounds of the formula I of the present invention and salts thereof, and solvates of stereoisomers.
  • a stereoisomer as referred to in the present invention means that the compound of formula I in the present invention may contain one or more chiral centers and exist in different optically active forms. When the compound contains a chiral center, the compound contains the enantiomer.
  • the invention includes mixtures of the two isomers and isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula I contains more than one chiral center, diastereomers may be present.
  • Stereoisomers of the invention include resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • a prodrug as referred to in the present invention refers to a parent compound which includes a known amino protecting group and a carboxy protecting group, which are hydrolyzed under physiological conditions or released by an enzymatic reaction.
  • Specific prodrug preparation methods can be referred to the prior art (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. ChemLett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • a compound of the formula I according to the invention may be administered in a suitable dosage form with one or more pharmaceutical carriers.
  • dosage forms include those suitable for oral, rectal, topical, intraoral, and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • compositions of this invention may be formulated, quantified, and administered in a manner consistent with medical practice.
  • the "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the deuterated Ostinidil derivative provided by the invention can be used for preparing drugs for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, etc. It is especially useful for the treatment of non-small cell lung cancer caused by EGFR mutations, including sensitive mutations (such as L858R mutation or deletion of exon 19) and drug resistance mutations (such as EGFR T790M mutation).
  • the invention provides a compound of formula I of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for use in the modulation of EGFR tyrosine kinase activity or in the treatment of EGFR The application of drugs for related diseases.
  • the modulating EGFR tyrosine kinase activity or treating an EGFR-related disease refers to treating cancer, diabetes, an immune system disease, a neurodegenerative disease, or a cardiovascular disease.
  • the invention provides the use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, for the manufacture of a medicament for the treatment of non-small cell lung cancer.
  • the deuterated Ostinidyl derivatives of the present invention are particularly useful for the preparation of a medicament for the treatment of cancer, such as non-small cell lung cancer.
  • the compound of the formula I of the present invention can be used as a single therapeutic drug in anticancer therapy, or can be used in addition to conventional Surgical or radiation therapy or a combination of chemotherapy or immunotherapy.
  • the above therapy and the EGFR inhibitor of the present invention can be administered in parallel, simultaneously, sequentially, or separately.
  • the medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases of the present invention may further comprise any one or more of the following drugs in addition to the EGFR inhibitor of the present invention: gefitinib, erg Lotitinib, ectatinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panituzumab, pertuzumab , zarumimumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tancomycin, aspironmycin, IPI-504, NVP-AUY922.
  • Target compound 1 the structural formula is:
  • the synthetic route is:
  • Target compound 1 Under a nitrogen atmosphere, 540 mg of TRN15801-1, 574 mg of TRN158-c, 30 ml of DCE, 20 ml of 2-pentanol and 374 mg of p-toluenesulfonic acid were sequentially added to a 100 ml single-mouth bottle. The oil bath was heated to 80 ° C for overnight reaction; TLC detection TRN158-c disappeared, the reaction solution was cooled to room temperature, poured into a mixture of ice water and DCM, and the aqueous layer was washed twice with DCM, then the DCM layer was combined with saturated brine. After washing twice, then drying and drying the organic layer; passing the column to obtain 200 mg of a brown solid, the analytical data of the compound is as follows:
  • Target compound 2 the structural formula is as follows:
  • the synthetic route is as follows:
  • TRN15801-1 500 mg, 2.02 mmol was added to a reaction flask, then 10 ml of isopropanol was added, followed by TRN158-d (416 mg, 2.2 mmol) and p-toluenesulfonic acid monohydrate (475 mg, 2.5 mmol). Then, under reflux with argon, a reflux reaction was added overnight. The reaction solution was cooled to room temperature, and then a part of the solvent was concentrated, then placed in an ice bath, and then allowed to stand for crystallized, filtered, and the filter cake was washed twice with acetonitrile and dried to give 524 mg of product. MS+1: 401.3.
  • the compound TRN15802 (400 mg, 0.88 mmol) was added to a three-necked flask, and then 20 ml of anhydrous dichloromethane and diisopropylethylamine (206 mg, 1.6 mmol) were added, and then cooled to 0 degree under argon atmosphere. Then, 5 ml of acryloyl chloride (90 mg, 1 mmol) in anhydrous dichloromethane was added dropwise, and the addition was completed in about 30 minutes. After the addition, the temperature was automatically raised to room temperature overnight.
  • Target compound 3 the structural formula is as follows:
  • the synthetic route is as follows:
  • the intermediate TRN158-e was purchased from the BEHRINGER Reagent Company.
  • the synthetic route of the intermediate TRN158-f is as follows:
  • Target compound 4 the structural formula is:
  • the synthetic route is:
  • TRN15804-2, TRN15804-3, TRN15804-4 and TRN15804 was carried out in accordance with the corresponding steps in Example 2.
  • the analytical data of the synthesized target compound TRN15804 is as follows:
  • the methanesulfonate salt of the compound TRN15801 was synthesized, and the synthesis route was as follows:
  • EGFR T790M/L858R kinase double mutant EGFR kinase
  • EGFR WT wild type EGFR kinase
  • the compound to be tested was separately prepared into a 10 mM (mmol/L) DMSO solution, and the control compound AZD9291 was formulated into a 1 mM (mmol/L) DMSO solution;
  • test compound solution Serially dilute the test compound solution to 12 concentrations (or other desired test concentration) on a 384-well plate of TECAN EVO200 by 3-fold dilution;
  • the well plate was incubated at room temperature for 90 minutes, and then the test reaction was terminated by adding 40 ⁇ L of stop buffer (containing 0.5 M EDTA);
  • test compounds in Table 3 are as follows.
  • Control compound 2 is a compound disclosed in the authorization publication number CN105237515B, and its structural formula is:
  • Control compound 3 is a compound disclosed in the authorization publication number CN104140418B, and its structural formula is:
  • Control Compound 1 (AZD9291, trade name: Ostinib) is as follows:
  • Example 1 of the present invention had better kinase activity than Comparative Compound 1, Control Compound 2 and Control Compound 3.
  • Test methods and procedures are carried out using methods well known to those skilled in the art, and the reagents used in the methods are commercially available.
  • test plate was incubated at room temperature for 30 minutes to stabilize the luminescence signal.
  • the IC50 was calculated using XLFIT (V5.3.1.3) software.
  • the compound of Example 1 of the present invention exhibited strong inhibitory activity against EGFR mutant cells (H1975, PC-9), compared with the control compound 1 and the control compound 2 and the control compound 3.
  • the compounds of the invention have a higher inhibitory activity on the growth of EGFR mutant cells.
  • Reducing Coenzyme II (NADPH) is required: 10 ⁇ l of 20 mg of liver microparticles per ml is mixed with 10 mmol of reduced coenzyme II (NADPH) to incubate. Finally, the concentrations of liver microparticles and reduced coenzyme II (NADPH) were set at 0.5 mg per ml and 1 mmol, respectively.
  • Reducing Coenzyme II is not required: 10 ⁇ l of 20 mg of liver microparticles per ml and 40 ⁇ l of ultrapure water are added to incubate. The final concentration of liver particles is 0.5 mg per ml.
  • the peak area was determined from the extracted ion chromatogram.
  • the slope value K is determined by a linear regression of the natural logarithm of the percentage of parent drug residue versus the incubation time curve.
  • in vitro half-life (in vitro t 1/2 ) is calculated by the following formula:
  • control compound 2 and the control compound 3 in Table 7 have the same structural formula as in Table 3.
  • the compound of Example 1 of the present invention has better metabolic stability in human liver microparticles than AZD9291 and Comparative Compound 2 and Control Compound 3. This indicates that the compounds of the present invention have better pharmacokinetic stability and in vivo activity in humans, and are very suitable for subsequent drug development.
  • the compounds provided in the above examples of the invention can be used to prepare EGFR inhibitors.
  • the compounds provided in the examples of the present invention can be used for the preparation of a medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases.
  • the EGFR-related diseases are selected from the group consisting of cancer, diabetes, immune system diseases, neurodegenerative diseases, and cardiovascular diseases.
  • the compounds provided in the examples of the present invention can be used for the preparation of a medicament for treating non-small cell lung cancer.
  • the compounds provided in the examples of the present invention may be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition.

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Abstract

本发明公开了一种式Ⅰ所示的氘代奥斯替尼(Osimertinib)衍生物、其药学上可接受的盐、立体异构体、溶剂化物或前药，其中的各符号如权利要求中所定义。本发明的氘代奥斯替尼衍生物可以抑制一种或多种EGFR的激活或抗性突变，可用于EGFR敏感型突变癌症的治疗，是一种理想的由EGFR突变导致的疾病的治疗药物。

Description

一种氘代奥斯替尼衍生物及其应用 技术领域
本发明涉及医药技术领域，具体涉及用作EGFR抑制剂的氘代奥斯替尼(Osimertinib)衍生物及其在制备用于调节EGFR酪氨酸激酶活性或治疗EGFR相关疾病，尤其是非小细胞肺癌的药物中的应用。
背景技术
表皮生长因子受体EGFR(Epidermal Growth Factor Receptor)是erbB受体家族的跨膜蛋白酪氨酸激酶的一种，当其与生长因子配体(例如表皮生长因子(EGF))结合时，受体可以与附加的EGFR分子发生同源二聚，或者与另一家族成员(例如erbB2(HER2)、erbB3(HER3)、或者erbB4(HER4))发生异源二聚。erbB受体的同源二聚和/或异源二聚导致胞内域中关键酪氨酸残基的磷酸化，并且导致对参与细胞增殖和生存的许多细胞内信号传导通路的刺激。erbB家族信号传导的失调促进增殖、侵入、转移、血管生成和肿瘤细胞生存，并且已在许多的人类癌症中(包括肺癌、头颈部癌和乳腺癌等)得到描述。
肺癌是全球发病率最高的癌症，在中国肺癌发病率位居所有癌症中第一位，也是中国发病率和死亡率最高的癌症。在中国的肺癌病人中，大约30％的病人具有EGFR突变，其中L858R和外显子19缺失突变占大约90％以上，这类病人对EGFR抑制剂更为敏感。现有已上市第一代EGFR抑制剂如厄洛替尼、吉非替尼等对这类病人有较好的疗效，能够使其中60％以上的病人肿瘤缩小，明显延长病人的无进展生存期。但绝大多数病人在6-12个月会获得耐药，这种耐药模式是EGFR的进一步突变，这就降低了其对第一代EGFR抑制剂的敏感性。这些突变中最常见的是所谓的“gatekeeper”突变T790M(Science,2004,Vol.304,1497-1500；New England Journal of Medicine 2004,350, 2129-2139)，由原来在该位点的L-苏氨酸(T)为L-甲硫氨酸(M)替代，变异后的EGF酪氨酸激酶R不再与吉非替尼、厄洛替尼结合，从而使第一代EGFR抑制剂将不再起效，导致这类病人目前处于无药可用的状态。临床发现对第一代EGFR抑制剂产生耐药的病人中有50％检测都有EGFR T790M突变。在T790M突变细胞系H1975中，第一代EGFR抑制剂，如吉非替尼和厄洛替尼，均大于3μM，基本没有活性。
为了提高对耐药EGFR T790M等突变的抑制活性，WO2013014448公开了可作为EGFR抑制剂的嘧啶衍生物及其治疗癌症的用途，结构如式A所示，其中，G选自4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基、1H-吲哚-3-基、1-甲基-1H-吲哚-3-基或吡唑并[1,5-a]吡啶-3-基，R 2为甲基或甲氧基；
Figure PCTCN2018092884-appb-000001
WO2013014448中已成功上市的化合物(AZD9291)的结构式为：
Figure PCTCN2018092884-appb-000002
于2015年11月13日获美国FDA加速批准(商品名TagAsso，AZD9291，Osimertinib)上市，用于治疗表皮生长因子受体EGFR T790M突变阳性的晚期非小细胞肺癌患者。但是，Osimertinib(AZD9291，TagAsso)的半衰期较短，使用剂量较高，一些代谢产物由于对野生型EGFR的过分抑制或激活，在临床应用过程中，导致不良反应，最常见的不良反应(≧25％)为腹泻、皮疹、干皮肤及指甲毒性。这也限制了应用此药物的治疗窗口，对一些不太敏感的病人，由于治疗窗口的限制， 而导致治疗效果较差。同时，对于一些太敏感的病人，由于过大的副作用，而导致不能使用此药物治疗。因此，非常有必要对该药的结构进行优化，增加半衰期，降低药物毒性，增加治疗窗口，从而让更多的患者受益。
截至目前，CN104140418B公开了一些甲基氘代的奥斯替尼(AZD9291)化合物，结构式如式B所示，其中，R 1、R 2、R 3、R 4和R 5为甲基或氘代甲基，
Figure PCTCN2018092884-appb-000003
虽然CN104140418B公开的这些化合物提高了奥斯替尼(Osimertinib)的半衰期，但是，通过已有文献的报道和我们的研究发现，Osimertinib与靶点EGFR激酶的结合模式中，嘧啶环部分与EGFR激酶的铰链区结合(hige-binding)，一旦嘧啶环部分被代谢成其他形式，就会导致Osimertinib与EGFR激酶的结合变弱或不能结合而失去活性。CN105153122报道了甲基氘代和吲哚环全氘代的AZD9291化合物，此类化合物虽然也能增加Osimertinib的半衰期，但是由于氘代的位点太多，在生产制备时，必然价格高昂，增加了生产研发成本，从而导致患者的支出增加。CN105237515公开了只氘代嘧啶环的Osimertinib化合物，我们研究发现，当吲哚上的甲基被代谢掉后生成式C所示化合物，
Figure PCTCN2018092884-appb-000004
此化合物虽然仍有抑制EGFR活性，但是其不能通过血脑屏障，进入 大脑，从而对脑部转移的肿瘤患者失去效果。
因此，有必要开发既能增加Osimertinib的半衰期，又能很好的降低毒副作用，又能透过血脑屏障，进入大脑，对脑部肿瘤转移的患者有效的药物。
发明内容
本发明提供了如式Ⅰ所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2018092884-appb-000005
其中：
R 1、R 2、R 3、R 4、R 5各自独立地选自甲基或氘代甲基；
R 6选自H或氘。
优选地，所述氘代甲基为-CD 3。所述R 1、R 2、R 3、R 4、R 5各自独立地选自甲基或-CD 3。
所述R 1、R 2、R 3、R 4、R 5中至少一个为-CD 3。
所述R 1、R 2、R 3、R 4、R 5中有1～3个为-CD 3。
式Ⅰ所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，其中，所述化合物任选自下述结构式表示的化合物：
Figure PCTCN2018092884-appb-000006
其中，所述的药学上可接受的盐为无机酸盐或有机酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。
优选地，所述的无机酸盐为盐酸盐或硫酸盐；所述的有机酸盐为甲磺酸盐。
本发明提供的另一个技术方案是：一种药物组合物，包含上述式Ⅰ所示化合物以及药学上可接受的载体。
本发明提供的氘代奥斯替尼衍生物，为式Ⅰ所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，该化合物可以抑制一种或多种EGFR的激活或抗性突变，例如L858R激活突变体、Exon19缺失EGFR激活突变体、T790M抗性突变体；该化合物提高了对耐药EGFR T790M等突变的抑制活性，并且同时降低了对野生型EGFR的抑制活性，可用于开发活性更高、选择性更好、毒性更低的第三代EGFR突变体选择性抑制剂。
本发明中所提及的溶剂化物是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，与水形成的配合物称为水合物；其他还包括醇合物、酮合物等。本发明所述的溶剂化物包括本发明式Ⅰ所示的化合物及其盐、立体异构体的溶剂化物。
本发明所提及的立体异构体是指本发明中式Ⅰ所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本技术领域已知的方法拆分，例如结晶以及手性色谱等方法。当式Ⅰ所示的化合物含有多于一个手性中心时，可以存在非对应异构体。本发明的立体异构体包括拆分过的光学纯的特定异构体以及非对应异构体的混合物。非对映异构体可以由本技术领域已知方法拆分，比如结晶以及制备色谱。
本发明所提及的前药是指包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到的母体化合物。具体的前药制备方法可参照现有技术(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.ChemLett.1994,4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
在实际应用中，可将本发明的式Ⅰ化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，与一种或多种药用载体制成适合 的剂型施用。这些剂型包括适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)等。
本发明的药物组合物可以以符合医学实践规范的方式配制，定量和给药。给予化合物的“有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
本发明提供的氘代奥斯替尼衍生物，可用于制备调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病方面的药物，如癌症、糖尿病、免疫系统疾病、神经退行性疾病或心血管疾病等，尤其适用于由EGFR突变，包括敏感型突变(如L858R突变或外显因子19缺失)和耐药性突变(如EGFR T790M突变)，引起的非小细胞肺癌的治疗药物。
因此，另一方面，本发明提供了本发明的式Ⅰ化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备用于调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病的药物方面的应用。
在一个实施方案中，所述调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病是指治疗癌症、糖尿病、免疫系统疾病、神经退行性疾病或心血管疾病。
在另一个实施方案中，本发明提供了本发明的式Ⅰ化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药在制备治疗非小细胞肺癌的药物方面的应用。本发明的氘代奥斯替尼衍生物尤其适用于制备治疗癌症，如非小细胞肺癌的药物。
本发明的式Ⅰ化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，在抗癌治疗中可以作为单独治疗的药物应用，或者除此之外还可以与常规的手术或放射疗法或化学疗法或免疫疗法联合应用。上述疗法与本发明的EGFR抑制剂可以并列地、同时地、序贯地、或分别地给药。
本发明的用于调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病的药物，除本发明的EGFR抑制剂之外，还可以包含以下药物中的任意一种或多种：吉非替尼、厄洛替尼、埃克替尼、拉帕替尼、XL647、NVP-AEE-788、ARRY-334543、凡德他尼、PF00299804、西妥昔单抗、 帕尼突单抗、帕妥珠单抗、扎鲁木单抗、尼妥珠单抗、MDX-214、CDX-110、IMC-11F8、CNF2024、坦螺旋霉素、阿螺旋霉素、IPI-504、NVP-AUY922。
具体实施方式
下面结合具体实施例对本发明的技术方案作进一步的说明。
实施例1
目标化合物1，结构式为：
Figure PCTCN2018092884-appb-000007
合成路线为：
Figure PCTCN2018092884-appb-000008
具体合成步骤如下：
1)化合物TRN158-a的合成：在氮气保护下，向1升三口瓶中依次加入18克5-溴-2,4-二氯嘧啶和180毫升无水四氢呋喃，降至-60℃，滴加异丙基氯化镁的四氢呋喃溶液393毫升，用时40分钟；之后升温至-30℃反应1小时，在-30℃下滴加氘水20毫升，用时20分钟，之后缓慢升至室温反应1小时；反应结束后，向反应液中加1升乙酸乙酯搅拌10分钟，过滤，滤液旋干；所得粗品经硅胶柱层析得3.07g白色固体；MS+1：151。
2)化合物TRN158-b的合成：在氮气保护下，向1升三口瓶中依次加入4克钠氢和600毫升无水四氢呋喃，降温至0℃，向反应液中滴加9.75克吲哚的四氢呋喃溶液60毫升，滴加完毕后逐渐升温至室 温，搅拌1个小时；降温至0℃，向反应液中滴加14.5克氘代碘甲烷，滴加完毕后逐渐升温至室温搅拌过夜；TLC检测原料消失，向反应液加入冰水和EA，水层再用EA洗涤2次，然后合并EA层用饱和食盐水洗涤2次，然后干燥旋干有机层；过柱子得到10.5克无色液体；该化合物的分析数据如下：
1H-NMR(400MHz，CDCl 3)δ：7.63(d,J＝8.64,1H)；7.30(dd,J＝0.76,J＝9.0,1H)；7.21(t,J＝16.24,1H)；7.09(t,J＝15.88,1H)；7.00(d,3.08,1H)；6.46(dd,J＝0.76,J＝3.84,1H)；MS+1：135。
3)化合物TRN15801-1的合成：在氮气保护下，向100毫升单口瓶中依次加入3.76克TRN158-a、40毫升DME、4.06克无水氯化铁和2.8克TRN158-b，在60℃下反应过夜；TLC检测TRN158-b消失，将反应液降到室温，倒入冰水和EA的混合液中，水层再用EA洗涤2次，然后合并EA层用饱和食盐水洗涤2次，然后干燥旋干有机层；过柱子得到0.746克黄色固体；该化合物的分析数据如下：
1H-NMR(400MHz，CDCl 3)：δ：8.42(s,1H)；8.28-8.34(m,J＝22.76,1H)；7.92(s,1H)；7.30-7.40(m,J＝41.32,3H)；MS+1：248。
4)目标化合物1的合成：在氮气保护下，向100毫升单口瓶中依次加入540毫克TRN15801-1、574毫克TRN158-c、30毫升DCE、20毫升2-戊醇和374毫克对甲苯磺酸，油浴加热到80℃反应过夜；TLC检测TRN158-c消失,反应液降到室温，倒入冰水和DCM的混合液中,水层再用DCM洗涤2次，然后合并DCM层用饱和食盐水洗涤2次，然后干燥旋干有机层；过柱子得到200毫克褐色固体，该化合物的分析数据如下：
1H-NMR(400MHz，CDCl 3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；8.06(dd,J＝2.92,J＝8.64,1H)；7.72(s,1H)；7.39(dd,J＝1.84,J＝9.24,1H)；7.23-7.30(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71(dd,J＝2.20,J＝11.92,1H)；3.88(s,3H)；2.89(t,J＝11.2,2H)；2.70(s,3H)；2.26-2.29(m,8H)；MS+1：504，为目标化合物1。
实施例2
目标化合物2，结构式如下所示：
Figure PCTCN2018092884-appb-000009
合成路线如下：
Figure PCTCN2018092884-appb-000010
化合物TRN15802-2的合成：
将化合物TRN15801-1(500mg,2.02mmol)加入到反应瓶中，然后加入10毫升异丙醇，再加入TRN158-d(416mg,2.2mmol)和一水合对甲苯磺酸(475mg,2.5mmol)，然后氩气保护下，加入回流反应过夜。将反应液降到室温，然后浓缩掉部分溶剂，然后放入冰浴中，静置析晶，过滤，滤饼用乙腈洗2次，干燥得到524mg产物。MS+1：401.3。
化合物TRN15802-3的合成：
将化合物TRN15802-2(520mg,1.3mmol)、N,N,N’-三甲基乙二胺(265mg,2.6mmol)和碳酸钾(359mg,2.6mmol)加入到反应瓶中，然后再加入10毫升N-甲基吡咯烷酮，120度反应5小时，将反应液将至室温，然后倒入冰水中，搅拌30分钟，然后过滤，收集滤饼， 用甲基叔丁基醚洗涤两次，干燥，得到500mg产品。MS+1:483.3。
化合物TRN15802-4的合成：
将化合物TRN15802-3(500mg,1.03mmol)加入到三口瓶中，然后加入10毫升的乙醇和10毫升的饱和氯化铵水溶液，然后加入铁粉(560mg,10mmol)。加热回流反应8小时，然后将反应液降温至室温，过滤，滤液浓缩干，加入50毫升二氯甲烷，然后用水洗涤一遍，用饱和食盐水洗涤一遍，干燥有机相，有机相浓缩，得到420mg产品。MS+1：453.3。
化合物TRN15802的合成：
将化合物TRN15802(400mg,0.88mmol)加入到三口瓶中，再加入20毫升的无水二氯甲烷和二异丙基乙胺(206mg,1.6mmol)，然后氩气保护下，降温到0度，然后滴加丙烯酰氯(90mg,1mmol)的无水二氯甲烷溶液5毫升，大约30分钟加完，加完后，自动升至室温过夜。将反应液倒入冰水中，然后用二氯甲烷萃取三次(每次20毫升二氯甲烷)，合并有机相，有机相用饱和食盐水洗涤一遍，有机相干燥，浓缩过柱子，得到245mg产品。该化合物的分析数据如下：
1H-NMR(400MHz，CDCl 3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；8.06(dd,J＝2.92,J＝8.64,1H)；7.72(s,1H)；7.39(dd,J＝1.84,J＝9.24,1H)；7.23-7.30(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71(dd,J＝2.20,J＝11.92,1H)；2.89(t,J＝11.2,2H)；2.70(s,3H)；2.26-2.29(m,8H)；MS+1：507.3。
化合物TRN158-d的合成参考专利文献CN105237515B的制备方法合成。
实施例3
目标化合物3，结构式如下所示：
Figure PCTCN2018092884-appb-000011
合成路线如下：
Figure PCTCN2018092884-appb-000012
中间体TRN158-e采购自百灵威试剂公司。
中间体TRN158-f的合成路线如下：
Figure PCTCN2018092884-appb-000013
化合物3的合成：
将化合物1(5g，71mmol)加入到三口瓶中，然后在0度下，加入100毫升的乙醇，三乙胺(7.2g，71mmol)，苯甲醛(7.5g，71mmol)。在0度下滴加钛酸四异丙酯(21.6g，76mmol)，加完后，缓慢升至室温过夜。次日，将反应液将至0度，分批加入硼氢化钠(2.8g，74mmol)2个小时内加完，加完后，在0度继续反应4个小时，加入饱和氯化铵水溶液淬灭反应，过滤，滤液浓缩，然后用二氯甲烷萃取三次，合并有机相，然后过柱子得到4.6g油状物产物。MS+1:125.1。
化合物5的合成：
将化合物3(4.6g，36.8mmol)和化合物4(5.3g，36.8mmol)加入到反应瓶中，然后再加入30毫升乙醇，在0度下滴加30毫升的 氢氧化钠水溶液(1.5g，36.9mmol),加完后，将反应液缓慢加热到回流，反应3小时。将反应将至室温，然后浓缩反应液，用二氯甲烷萃取，有机相干燥，浓缩，将粗品过柱子得到3.1g油状产物。MS+1：196.2。
化合物TRN158-f的合成：
将化合物5(3.1g，15.8mmol)加入到反应瓶中，然后加入100毫克的湿钯碳，然后在氢气氛围下反应过夜，将反应液过滤，滤液旋干得到1.2g油状产物。MS+1：106.1。
化合物TRN15803-2、TRN15803-3,、TRN15803-4和TRN15803的合成操作过程参照实施例2中的相应步骤进行合成。合成的目标化合物TRN15803的分析数据如下：
1H-NMR(400MHz，CDCl 3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；8.06(dd,J＝2.92,J＝8.64,1H)；7.72(s,1H)；7.39(dd,J＝1.84,J＝9.24,1H)；7.23-7.30(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71(dd,J＝2.20,J＝11.92,1H)；3.88(s,3H)；2.89(t,J＝11.2,2H)；2.26-2.29(m,8H)；MS+1：507.3。
实施例4
目标化合物4，结构式为：
Figure PCTCN2018092884-appb-000014
合成路线为：
Figure PCTCN2018092884-appb-000015
中间体TRN158-g的合成参照专利CN105237515B的制备方法合成。
化合物TRN15804-2、TRN15804-3,、TRN15804-4和TRN15804的合成操作参照实施例2中的相应步骤进行合成。合成的目标化合物TRN15804的分析数据如下：
1H-NMR(400MHz，CDCl 3)：δ：10.18(br,1H)；9.85(s,1H)；9.12(br,1H)；8.38(s,1H)；8.06(dd,J＝2.92,J＝8.64,1H)；7.72(s,1H)；7.39(dd,J＝1.84,J＝9.24,1H)；7.23-7.30(m,2H)；6.79(s,1H)；6.33-6.48(m,,2H)；5.71(dd,J＝2.20,J＝11.92,1H)；3.88(s,3H)；2.89(t,J＝11.2,2H)；2.70(s,3H)；2.26-2.29(m,2H)；MS+1：510.3。
参照上述实施例的合成方法，又分别制备了一系列具体的化合物。见表1所示。
实施例5-实施例12
实施例5-12合成的目标化合物及其表征数据，具体见表1所示。
表1
Figure PCTCN2018092884-appb-000016
Figure PCTCN2018092884-appb-000017
Figure PCTCN2018092884-appb-000018
Figure PCTCN2018092884-appb-000019
实施例13
合成化合物TRN15801的甲磺酸盐，合成路线如下：
Figure PCTCN2018092884-appb-000020
具体操作过程：将化合物TRN15801(100mg，0.2mmol)加入到反应瓶中，然后加入10毫升的乙腈，再加入甲磺酸(20mg)，然后加热回流反应3小时，然后降至室温，过滤得产物96毫克。
效果实验例
实验例1
采用以上实施例提供的化合物，对野生型EGFR和突变型EGFR激酶的活性抑制作用进行了检测。
测定了待测物对双突变型EGFR激酶(EGFR T790M/L858R激酶)、野生型EGFR激酶(EGFR WT)活性的抑制作用。检测中所用的野生型EGFR和突变型EGFR(T790M/L858R)激酶均购自Carna Bioscience(卡纳生物科学)。
实验过程如下：
一、待测化合物的准备
1、将待测的化合物分别配制成10mM(mmol/L)的DMSO溶液，对照样化合物AZD9291配制成1mM(mmol/L)的DMSO溶液；
2、通过3-倍稀释，将待测化合物溶液连续稀释到12个浓度(或别的所需的测试浓度)在TECAN EVO200的384孔板上；
3、使用Echo550转移20nL待测化合物溶液到384孔板上(Coring3570)。使用DMSO作为空白对照。
二、进行酶测试
1、准备含有酶、基质、辅因子的1.3X酶溶液，如下表2所示；
2、在室温下，每个孔板的孔中加入15μL的1.3X酶溶液培养30分钟；
3、加入5μL的4X ATP溶液开始测试反应，最终每个孔中的溶液体积应为20μL，含有的成分如下表2所示；
4、孔板在室温下培养90分钟，然后加入40μL的终止缓冲液(含有0.5M EDTA)终止测试反应；
5、使用EZ检测分析每个孔的实验数据。
表2 酶测试中酶溶液参数表
Figure PCTCN2018092884-appb-000021
三、数据分析
1、使用read转化率(CR)，根据如下公式计算抑制比率：
Figure PCTCN2018092884-appb-000022
2、按照如下公式，使用XLFit(equation 201)计算IC50和Ki值，
Figure PCTCN2018092884-appb-000023
部分化合物的检测结果如下表3所示。
表3 野生型EGFR和突变型EGFR激酶的活性抑制检测结果
Figure PCTCN2018092884-appb-000024
Figure PCTCN2018092884-appb-000025
表3中各检测化合物分别如下。
本发明实施例1化合物结构式为：
Figure PCTCN2018092884-appb-000026
对照化合物2为授权公告号为CN105237515B中公开的化合物，其结构式为：
Figure PCTCN2018092884-appb-000027
对照化合物3为授权公告号为CN104140418B中公开的化合物，其结构式为：
Figure PCTCN2018092884-appb-000028
对照化合物1(AZD9291，商品名：奥斯替尼)结构如下：
Figure PCTCN2018092884-appb-000029
从表3的检测数据可以看出，本发明实施例1的化合物比对照化合物1、对照化合物2和对照化合物3均有更好的激酶活性。
实验例2
化合物对细胞生长抑制活性测试。测试方法和步骤采用本领域技术人员熟知的方法进行，方法中所用试剂均可市购得到。
测试方法：
2.1实验步骤：
(1)使用Echo(非接触式纳升级声波移液系统)取40nL待测化合物溶液到测试板。
(2)将细胞配制成25000cell/mL的溶液，然后取40μL到指定的384孔测试板上。
(3)培养板在37℃，5％的二氧化碳，95％的湿度下培养72小时。
(4)每孔中加入40μL的
Figure PCTCN2018092884-appb-000030
试剂。
(5)将测试板在室温下，孵育30分钟，以稳定发光信号。
(6)密封测试板，以1000转/分钟的离心速度去除气泡。
(7)将测试板在摇床上摇动1分钟。
(8)读取测试板数据。
2.2数据处理
(1)使用下面的公式计算残留率：
Figure PCTCN2018092884-appb-000031
S：测试样品读数；
V：空白样读数；
M：AZD9291测试样(1μM用于测试PC-9和H1975，30μM用于 A431测试)读数；
使用XLFIT(V5.3.1.3)软件计算IC50。
检测结果如表4所示：
表4 化合物对细胞抑制活性
Figure PCTCN2018092884-appb-000032
表4中的对照化合物1、对照化合物2和对照化合物3的结构式与表3中相应化合物相同。
从表4可以看出，本发明的实施例1化合物对EGFR突变型细胞(H1975、PC-9)表现出较强的抑制活性，与对照化合物1以及对照化合物2和对照化合物3相比，本发明的化合物对EGFR突变型细胞生长有更高的抑制活性。
实验例3
化合物体外代谢稳定性实验研究，测试方法和步骤采用本领域技术人员熟知的方法进行，方法中所用试剂均可市购得到。
测试方法：
3.1实验设计：
(1)本实验的主要溶液按照下表配置。
表5
试剂 备用浓度 体积 最终浓度
磷酸缓冲液 200mM 200μL 100mM
超纯水 - 106μL -
氯化镁溶液 50mM 40μL 5mM
(2)按照如下方法分别进行两个测试实验：
a)需要还原型辅酶Ⅱ(NADPH)：取20毫克每毫升的肝微粒10微升与10毫摩尔的还原型辅酶Ⅱ(NADPH)混合孵化。最终将肝微粒和还原型辅酶Ⅱ(NADPH)的浓度分别设定在0.5毫克每毫升和1毫摩尔。
b)不需要还原型辅酶Ⅱ(NADPH)：取20毫克每毫升的肝微粒10微升与40微升的超纯水加入到一起孵化。肝微粒的最终浓度为0.5毫克每毫升。
(3)分别加入4微升的200微摩尔的内控化合物或需要测试的化合物开始测试实验。在本研究中，以戊脉安(Verapamil)作为阳性控制样。需测试的化合物或内控化合物的浓度最终为2微摩尔。
(4)在0、15、30、45和60分钟，取少量孵化液用于测试。将取的少量孵化液用4倍体积的冷乙腈稀释，用IS(100纳摩尔阿普唑仑(alprazolam)、200纳摩尔的柳胺苄心定(labetalol)、200纳摩尔咖啡碱(caffeine)和2微摩尔的酮洛芬(ketoprofen))停止此反应。样品离心分离40分钟，取100微升少量滤液和100微升超纯水混合，然后用液质/质谱分析。
(5)数据分析
所有记录数据都记录在微软excel表中。
从提取的离子色谱图确定峰面积。斜率值K是由母体药物残留百分率的自然对数与孵育时间曲线的线性回归确定的。
体外(in vitro)半衰期(in vitro t 1/2)由下面公式计算：
体外半衰期＝-(0.693/k)。
体外t 1/2(min)转化为体外固有清除率(体外CL int(in vitro CL int)，μL/min/mg蛋白)使用以下方程(重复测定的平均值)进行：
Figure PCTCN2018092884-appb-000033
将体外t 1/2(min)转换成放大的内在清除率(放大CL int，以mL/min/kg)使用下列方程(重复测定的平均值)：
Figure PCTCN2018092884-appb-000034
表6 肝微粒体内清除率预测的换算系数
Figure PCTCN2018092884-appb-000035
a.Iwatsubo等，Davies and Morris,1993,10(7)pp 1093-1095
b.Barter等，2007,Curr Drug Metab,8(1),pp 33-45；Iwatsubo等，1997,JPET,283pp462-469.
3.2实验结果
体外肝微粒代谢稳定性实验结果如下表7所示：
表7 化合物体外肝微粒代谢稳定性
Figure PCTCN2018092884-appb-000036
Figure PCTCN2018092884-appb-000037
表7中的对照化合物2、对照化合物3结构式同表3中相应化合物。
从表7的实验数据可以明显的看出，本发明中实施例1的化合物比AZD9291以及对照化合物2和对照化合物3在人肝微粒中具有更好的代谢稳定性。这就预示着本发明中的化合物在人体中有更好的药代稳定性和体内活性，非常适合进行后续的药物研发。
本发明以上实施例所提供的化合物可以用于制备EGFR抑制剂。
本发明实施例所提供的化合物可以用于制备调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病的药物。其中，EGFR相关疾病选自癌症、糖尿病、免疫系统疾病、神经退行性疾病和心血管疾病。
本发明实施例所提供的化合物可以用于制备治疗非小细胞肺癌的药物。
本发明实施例所提供的化合物可以与药学上可接受的载体混合，制备成一种药物组合物。
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效变换，或直接或间接运用在其他相关的技术领域，均包括在本发明的专利保护范围内。

Claims (12)

  1. 式Ⅰ所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
    Figure PCTCN2018092884-appb-100001
    其中：
    R 1、R 2、R 3、R 4、R 5各自独立地选自甲基或氘代甲基；
    R 6选自H或氘。
  2. 根据权利要求1所述的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述R 1、R 2、R 3、R 4、R 5各自独立地选自甲基或-CD 3。
  3. 根据权利要求2所述的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述R 1、R 2、R 3、R 4、R 5中至少一个为-CD 3。
  4. 根据权利要求3所述的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述R 1、R 2、R 3、R 4、R 5中有1～3个为-CD 3。
  5. 根据权利要求1所述的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物任选自下述结构式表示的化合物：
    Figure PCTCN2018092884-appb-100002
  6. 根据权利要求1-5任一所述的化合物，其中，所述的药学上可接受的盐为无机酸盐或有机酸盐，所述无机酸盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐；所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐。
  7. 根据权利要求6所述的化合物，其中，所述的无机酸盐为盐酸盐或硫酸盐；所述的有机酸盐为甲磺酸盐。
  8. 一种药物组合物，包含权利要求1-7中任一项所述的化合物以及药学上可接受的载体。
  9. 权利要求1-7中任一项所述的化合物在制备EGFR抑制剂中的应用。
  10. 权利要求1-7中任一项所述的化合物在制备用于调控EGFR酪氨酸激酶活性或治疗EGFR相关疾病的药物中的应用。
  11. 根据权利要求10所述的应用，其中，所述疾病选自癌症、糖尿病、免疫系统疾病、神经退行性疾病和心血管疾病。
  12. 权利要求1-7中任一项所述的化合物在制备用于治疗非小细胞肺癌的药物中的应用。
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