CN115448906B - A 2-anilinopyrimidine derivative and its preparation method and application - Google Patents

Abstract

The invention belongs to the field of medicines, and relates to a 2-anilinopyrimidine derivative, and a preparation method and application thereof. The 2-anilinopyrimidine derivative is a compound shown in a formula I, or a pharmaceutically acceptable salt or tautomer thereof or prodrug molecule thereof. Experiments show that the compound shown in the formula I has a certain inhibitory activity on an epidermal growth factor receptor, can effectively inhibit proliferation of various tumor cells, and has potential for research and development of tumor drugs.

Description

Translated fromChinese

一种2-苯胺基嘧啶类衍生物及其制备方法与应用A kind of 2-anilinopyrimidine derivative and its preparation method and application

技术领域Technical field

本发明属于医药领域，具体地，涉及一种具有EGFR和ALK抑制活性的2-苯胺基嘧啶类衍生物及其制备方法与应用。The invention belongs to the field of medicine. Specifically, it relates to a 2-anilinopyrimidine derivative with EGFR and ALK inhibitory activity and its preparation method and application.

背景技术Background technique

肿瘤分子靶向治疗是近几年发展迅速的一类新型肿瘤治疗手段，其原理是基于对肿瘤生长、发育密切相关的关键因子或蛋白通过靶向性的化学或生物学手段抑制达到选择性杀伤肿瘤细胞的一种治疗方法。相比于传统的抗癌小分子药物，肿瘤靶向药物具有针对性强、副作用相对较少和治疗效果好等特点，因此受到了广泛关注，肿瘤的靶向治疗也是肿瘤治疗的发展趋势之一。Tumor molecular targeted therapy is a new type of tumor treatment method that has developed rapidly in recent years. Its principle is to inhibit key factors or proteins closely related to tumor growth and development through targeted chemical or biological means to achieve selective killing of tumor cells. Compared with traditional anti-cancer small molecule drugs, tumor targeted drugs have the characteristics of strong targeting, relatively few side effects and good therapeutic effects, so they have received widespread attention. Targeted therapy of tumors is also one of the development trends of tumor treatment.

表皮生长因子受体(EGFR)是一种受体型酪氨酸蛋白激酶，在增殖、分化、凋亡以及血管生成等生命活动中发挥了重要作用，同时也被发现在多种肿瘤细胞如肺癌、乳腺癌、前列腺癌中存在过度活化或持续活化的情况。其中在肺癌患者中，EGFR的突变是最重要的驱动因子之一，尤其在亚洲人中其突变比例达到了50％以上。2003年上市的EGFR小分子抑制剂吉非替尼(Gefitinib)被用于非小细胞肺癌(NSCLC)晚期的治疗中，现在还常用作EGFR突变的NSCLC患者的一线用药。Epidermal growth factor receptor (EGFR) is a receptor-type tyrosine protein kinase that plays an important role in life activities such as proliferation, differentiation, apoptosis, and angiogenesis. It has also been found in a variety of tumor cells such as lung cancer. There is excessive activation or sustained activation in breast cancer and prostate cancer. Among lung cancer patients, EGFR mutation is one of the most important driving factors, especially in Asians, where the mutation rate reaches more than 50%. The EGFR small molecule inhibitor Gefitinib, which was launched in 2003, is used in the treatment of advanced non-small cell lung cancer (NSCLC), and is now often used as a first-line drug for NSCLC patients with EGFR mutations.

EGFR抑制剂发展至今按照上市药物分为了三代。第一代EGFR包括前面提到的Gefitinib还有Erlotinib、Icontinib等，其针对的是存在L858R或者del19突变的EGFR的NSCLC患者，获得了显著的临床疗效。但部分患者在使用药物的10～12个月后会产生耐药性，经过基因测序等可以发现其主要发生了T790M突变，超过50％的耐药患者发生了T790M的二次突变。为了解决第一代抑制剂耐药问题，发展了第二代EGFR抑制剂。第二代抑制剂属于不可逆抑制剂，其对野生型EGFR(EGFR^wt)也有较强的抑制作用，因此具有较大毒性。已经上市的第二代EGFR抑制剂包括Afatinib和Dacomtinib，但在临床最大耐受剂量(MTD)下，还是无法很好的解决T790M突变带来的耐药性问题。而真正解决T790M突变导致的耐药问题的则是第三代EGFR抑制剂，在2015年11月获得美国FDA加速批准上市的奥希替尼(Osimertinib)，其在临床上能够有效治疗T790M突变导致耐药的NSCLC患者，取得了较大成功。但不可避免的是部分受益患者在经过9～14个月治疗后又出现了新的耐药现象，经过研究发现，20～40％的患者是因为发生了C797S点突变导致了Osimertinib的耐药。C797S点突变指的是EGFR797位的半胱氨酸转变成丝氨酸，而797位又是Osimertinib与EGFR共价结合的重要位点之一，因此两者无法结合，最终导致Osimertinib的耐药。目前尚未有针对C797S突变的EGFR抑制剂上市，因此迫切需要对C797S具有高选择性的EGFR抑制剂解决三代抑制剂的耐药性问题。EGFR inhibitors have been divided into three generations according to the drugs on the market. The first generation of EGFR includes the aforementioned Gefitinib, Erlotinib, Icontinib, etc., which are targeted at NSCLC patients with EGFR mutations of L858R or del19, and have achieved significant clinical efficacy. However, some patients will develop drug resistance after 10 to 12 months of using the drug. After gene sequencing, it can be found that the main mutation is T790M, and more than 50% of resistant patients have a secondary mutation of T790M. In order to solve the drug resistance problem of the first generation of inhibitors, the second generation of EGFR inhibitors has been developed. The second generation of inhibitors is an irreversible inhibitor, which also has a strong inhibitory effect on wild-type EGFR (EGFR^wt ), so it has greater toxicity. The second generation of EGFR inhibitors that have been on the market include Afatinib and Dacomtinib, but at the clinical maximum tolerated dose (MTD), it is still unable to solve the drug resistance problem caused by the T790M mutation. The real solution to the drug resistance problem caused by T790M mutation is the third-generation EGFR inhibitor, Osimertinib, which was approved by the US FDA for accelerated marketing in November 2015. It can effectively treat NSCLC patients with drug resistance caused by T790M mutation in clinical practice and has achieved great success. However, it is inevitable that some patients who benefited from it will develop new drug resistance after 9 to 14 months of treatment. Studies have found that 20 to 40% of patients are resistant to Osimertinib due to the C797S point mutation. The C797S point mutation refers to the conversion of cysteine at position 797 of EGFR to serine, and position 797 is one of the important sites for covalent binding of Osimertinib and EGFR, so the two cannot bind, which ultimately leads to Osimertinib resistance. At present, there is no EGFR inhibitor targeting C797S mutation on the market, so there is an urgent need for EGFR inhibitors with high selectivity for C797S to solve the drug resistance problem of the third-generation inhibitors.

间变性淋巴瘤激酶(ALK)也属于受体型酪氨酸激酶，棘皮动物微管结合蛋白(EML4)和ALK融合基因突变生成的EML4-ALK嵌合蛋白会促使ALK的二聚化，导致相关信号通路持续激活，从而促进癌症的发生与发展。在NSCLC的吸烟患者中，有2.9％发生了EML4-ALK基因融合突变；在未吸烟的患者中，则有9.4％发生了EML4-ALK突变，因此ALK也是除EGFR突变外的主要突变类型之一。随着基因测序技术的发展，EGFR和ALK重排同时存在的情况被不断发现。有文献报道在对14名奥希替尼耐药的患者进行基因测序后发现有2名患者发生了EML4-ALK融合突变，这也暗示着，EGFR/ALK双靶点抑制剂未来不仅可以用于肺癌的靶点药物治疗，也有一定潜力用于解决EGFR的耐药性问题。Anaplastic lymphoma kinase (ALK) is also a receptor-type tyrosine kinase. The EML4-ALK chimeric protein generated by mutations in the echinoderm microtubule-binding protein (EML4) and the ALK fusion gene will promote the dimerization of ALK, leading to related Signaling pathways are continuously activated, thereby promoting the occurrence and development of cancer. Among smoking patients with NSCLC, 2.9% have EML4-ALK gene fusion mutations; among non-smoking patients, 9.4% have EML4-ALK mutations. Therefore, ALK is also one of the main mutation types in addition to EGFR mutations. . With the development of gene sequencing technology, the coexistence of EGFR and ALK rearrangements is constantly being discovered. There are reports in the literature that after gene sequencing of 14 osimertinib-resistant patients, 2 patients were found to have EML4-ALK fusion mutations. This also implies that EGFR/ALK dual-target inhibitors can not only be used for Target drug treatment of lung cancer also has certain potential to solve the problem of EGFR drug resistance.

发明内容Summary of the invention

本发明的目的是提供一类具有EGFR和ALK抑制活性的2-苯胺基嘧啶类衍生物抑制剂及其制备方法。The object of the present invention is to provide a type of 2-anilinopyrimidine derivative inhibitors with EGFR and ALK inhibitory activity and a preparation method thereof.

为了实现上述目的，本发明提供一种2-苯胺基嘧啶类衍生物，所述2-苯胺基嘧啶类衍生物为式I所示化合物，或其可药用盐或互变异构体或其前药分子；In order to achieve the above object, the present invention provides a 2-anilinopyrimidine derivative, which is a compound represented by formula I, or a pharmaceutically acceptable salt or tautomer thereof or its prodrug molecules;

其中：in:

R₁为R₁ is

R₂为R₂ is

R₃为氢、卤素(Cl或Br)、三氟甲基、硝基、取代或未取代C₁-C₆烷基、取代或未取代C₃-C₆环烷基、取代或未取代C₁-C₆烷氧基、取代或未取代C₃-C₆环烷氧基；R₃ is hydrogen, halogen (Cl or Br), trifluoromethyl, nitro, substituted or unsubstituted C₁ -C₆ alkyl, substituted or unsubstituted C₃ -C₆ cycloalkyl, substituted or unsubstituted C₁ -C₆ alkoxy, substituted or unsubstituted C₃ -C₆ cycloalkoxy;

X、Y、Z各自独立地为CH或N。优选地，X为N，Y、Z为CH。X, Y, and Z are each independently CH or N. Preferably, X is N, Y and Z are CH.

本发明中，所述药学上可接受的盐可以为无机酸盐或有机酸盐；具体地，所述无机酸盐选自下述任意一种无机酸形成的盐：盐酸、硫酸和磷酸；所述有机酸盐选自下述任意一种有机酸形成的盐：乙酸、三氟乙酸、丙二酸、柠檬酸和对甲苯磺酸。In the present invention, the pharmaceutically acceptable salt can be an inorganic acid salt or an organic acid salt; specifically, the inorganic acid acid salt is selected from the salts formed by any of the following inorganic acids: hydrochloric acid, sulfuric acid and phosphoric acid; The organic acid salt is selected from the salt formed by any of the following organic acids: acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.

本发明的化合物可以以不同的多晶型物形式存在。The compounds of the invention may exist in different polymorphic forms.

根据本发明一种优选实施方式，式I所示化合物选自下述任意一种：According to a preferred embodiment of the present invention, the compound represented by formula I is selected from any of the following:

本发明还提供所述2-苯胺基嘧啶类衍生物的制备方法，包括下述步骤：The invention also provides a method for preparing the 2-anilinopyrimidine derivatives, which includes the following steps:

式IA所示化合物与式IB所示化合物在酸性条件下、在溶剂中进行反应，获得式I所示化合物：The compound represented by formula IA and the compound represented by formula IB react under acidic conditions in a solvent to obtain the compound represented by formula I:

R₁、R₂、R₃、X、Y和Z如权利要求1所定义。R₁ , R₂ , R₃ , X, Y and Z are as defined in claim 1.

更具体地，可按照下述反应路线制备得到：More specifically, it can be prepared according to the following reaction route:

其中R₁、R₂、R₃、X、Y和Z如上所述。wherein R₁ , R₂ , R₃ , X, Y and Z are as described above.

反应路线主要包括以下反应步骤：The reaction route mainly includes the following reaction steps:

步骤a)式Ia所示化合物与含氟芳香环在碱性条件下发生取代反应得到式Ib所示化合物。优选地，反应以N,N-二甲基甲酰胺作溶剂，碳酸铯为碱试剂，反应温度为90℃，反应时间为24小时。Step a) The compound represented by formula Ia undergoes a substitution reaction with a fluorine-containing aromatic ring under alkaline conditions to obtain a compound represented by formula Ib. Preferably, the reaction uses N,N-dimethylformamide as solvent, cesium carbonate as base reagent, the reaction temperature is 90° C., and the reaction time is 24 hours.

步骤b)式Ib所示化合物在催化剂作用下与氢气发生还原反应得到式Ic所示化合物。优选地，反应在无水乙醇中进行；催化剂为10％的钯碳；反应温度为室温；反应时间为6小时。Step b) The compound represented by formula Ib undergoes a reduction reaction with hydrogen under the action of a catalyst to obtain the compound represented by formula Ic. Preferably, the reaction is carried out in absolute ethanol; the catalyst is 10% palladium on carbon; the reaction temperature is room temperature; and the reaction time is 6 hours.

步骤c)式Ic所示化合物在碱性条件下与相应的含脂肪杂环的乙醇衍生物的末端羟基发生亲核取代反应得到式Id所示化合物。优选地，反应所需碱为氢化钠；反应在无水乙醇中进行；反应温度为0℃；反应时间为8-12小时。Step c) The compound represented by formula Ic undergoes a nucleophilic substitution reaction with the terminal hydroxyl group of the corresponding aliphatic heterocycle-containing ethanol derivative under alkaline conditions to obtain the compound represented by formula Id. Preferably, the base required for the reaction is sodium hydride; the reaction is carried out in absolute ethanol; the reaction temperature is 0°C; the reaction time is 8-12 hours.

步骤d)式Ie所示化合物在碱性条件下与相应的包含R₂基团的末端伯胺发生亲核取代反应得到式If所示化合物。优选地，反应所需碱可以从三乙胺、二异丙基乙基胺、氨水、甲醇钠、乙醇胺、叔丁醇钠、叔丁醇钾、四丁基碘化铵等中选择一种或多种；反应温度为80℃；反应时间为0.5-3小时。Step d) The compound represented by the formula Ie undergoes a nucleophilic substitution reaction with the corresponding terminal primary amine containing the R₂ group under alkaline conditions to obtain the compound represented by the formula If. Preferably, the base required for the reaction can be selected from triethylamine, diisopropylethylamine, ammonia, sodium methoxide, ethanolamine, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium iodide, etc. or Various; reaction temperature is 80℃; reaction time is 0.5-3 hours.

步骤e)式If所示化合物在酸性条件下与式Id化合物的末端伯胺发生取代反应得到式I所示化合物。优选地，反应所需酸为对甲苯磺酸一水化合物；反应在2-戊醇中进行；反应温度为90℃；反应时间为5小时。Step e) The compound represented by formula If undergoes a substitution reaction with the terminal primary amine of the compound represented by formula Id under acidic conditions to obtain the compound represented by formula I. Preferably, the acid required for the reaction is p-toluenesulfonic acid monohydrate; the reaction is carried out in 2-pentanol; the reaction temperature is 90°C; the reaction time is 5 hours.

在不描述起始原料合成及中间体的情况下，化合物是可以商业购买的或利用标准方法或利用本文实施例的扩展方法利用可商业化购买的化合物来制备。Without describing starting material synthesis and intermediates, the compounds are commercially available or prepared using commercially available compounds using standard methods or using extended methods of the examples herein.

本发明的再一个目的是提供式Ⅰ所示化合物及其药学上可接受的盐的应用。具体地，本发明所述的2-苯胺基嘧啶类衍生物可应用于制备下述产品：Another object of the present invention is to provide the use of compounds represented by formula I and pharmaceutically acceptable salts thereof. Specifically, the 2-anilinopyrimidine derivatives of the present invention can be used to prepare the following products:

1)表皮生长因子受体(EGFR)抑制剂；1) Epidermal growth factor receptor (EGFR) inhibitors;

2)间变性淋巴瘤激酶(ALK)抑制剂；2) Anaplastic lymphoma kinase (ALK) inhibitors;

3)真核生物肿瘤细胞增殖抑制剂；3) Eukaryotic tumor cell proliferation inhibitors;

4)真核生物肿瘤细胞转移抑制剂；4) Eukaryotic tumor cell metastasis inhibitor;

5)血管生成抑制剂；5) Angiogenesis inhibitors;

6)预防和/或治疗肿瘤的药物。6) Drugs to prevent and/or treat tumors.

所述表皮生长因子受体(EGFR)包括但不限于EGFR^L858R、EGFR^del19、EGFR^L858R/T790M、EGFR^del19/T790M、EGFR^{L858R/T790M/C797S}和EGFR^{del19/T790M/C797S}中至少一种。The epidermal growth factor receptor (EGFR) includes, but is not limited to, at least one of EGFR^L858R , EGFR^del19 , EGFR^L858R/T790M , EGFR^del19/T790M , EGFR^{L858R/T790M/C797S} and EGFR^{del19/T790M/C797S} .

所述间变性淋巴瘤激酶(ALK)包括但不限于ALK^wt、ALK^L1196M和EML4-ALK中至少一种。The anaplastic lymphoma kinase (ALK) includes, but is not limited to, at least one of ALK^wt , ALK^L1196M and EML4-ALK.

所述真核生物优选为哺乳动物；所述肿瘤细胞优选为癌细胞；更优选地，所述癌细胞为白血病癌细胞、淋巴瘤细胞、肺癌细胞、乳腺癌细胞、卵巢癌细胞、宫颈癌细胞、人脑胶质瘤细胞、黑色素癌细胞、胶质母细胞瘤细胞、鼻咽癌细胞、肝癌细胞、脑癌细胞、胰腺癌细胞、子宫癌细胞、睾丸癌细胞、皮肤癌细胞、胃癌细胞、结肠癌细胞、膀胱癌细胞或直肠癌细胞。The eukaryotes are preferably mammals; the tumor cells are preferably cancer cells; more preferably, the cancer cells are leukemia cancer cells, lymphoma cells, lung cancer cells, breast cancer cells, ovarian cancer cells, and cervical cancer cells. , human brain glioma cells, melanoma cancer cells, glioblastoma cells, nasopharyngeal cancer cells, liver cancer cells, brain cancer cells, pancreatic cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer cells, Colon, bladder or rectal cancer cells.

所述白血病癌细胞具体为人慢性粒细胞白血病(CML)细胞系K562；所述淋巴瘤细胞具体为人组织细胞淋巴瘤细胞U937；所述肺癌细胞具体为人肺癌细胞株HCC827；所述乳腺癌细胞具体为人乳腺癌细胞MCF-7、T47D和MDA-MB-231；所述卵巢癌细胞具体为A2780；所述宫颈癌细胞具体为人宫颈癌细胞系Hela；所述人脑胶质瘤细胞具体为U251；所述黑色素癌细胞具体为A375；所述胶质母细胞瘤细胞具体为人胶质母细胞瘤细胞A172和人脑星形胶质母细胞瘤细胞U-118MG；所述鼻咽癌细胞具体为鼻咽癌细胞株CNE-2；所述肝癌细胞为具体人肝癌细胞HepG2。The leukemia cancer cells are specifically human chronic myeloid leukemia (CML) cell line K562; the lymphoma cells are specifically human histiocytic lymphoma cells U937; the lung cancer cells are specifically human lung cancer cell line HCC827; the breast cancer cells are specifically human breast cancer cells MCF-7, T47D and MDA-MB-231; the ovarian cancer cells are specifically A2780; the cervical cancer cells are specifically human cervical cancer cell line Hela; the human brain glioma cells are specifically U251; the melanoma cancer cells are specifically A375; the glioblastoma cells are specifically human glioblastoma cells A172 and human brain astrocytic glioblastoma cells U-118MG; the nasopharyngeal cancer cells are specifically nasopharyngeal cancer cell line CNE-2; and the liver cancer cells are specifically human liver cancer cells HepG2.

所述肿瘤为癌，所述癌具体为白血病、淋巴瘤、肺癌、黑色素癌、胶质母细胞瘤、宫颈癌、鼻咽癌、肝癌、乳腺癌、脑癌、胰腺癌、卵巢癌、子宫癌、睾丸癌、皮肤癌、胃癌、结肠癌、膀胱癌或直肠癌。The tumor is cancer, and the cancer is specifically leukemia, lymphoma, lung cancer, melanoma cancer, glioblastoma, cervical cancer, nasopharyngeal cancer, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, and uterine cancer. , testicular cancer, skin cancer, stomach cancer, colon cancer, bladder cancer or rectal cancer.

本发明还提供一种产品，其活性成分为所述的2-苯胺基嘧啶类衍生物；所述产品为以下中的至少一种：The present invention also provides a product, the active ingredient of which is the 2-anilinopyrimidine derivative; the product is at least one of the following:

1)表皮生长因子受体(EGFR)抑制剂；1) Epidermal growth factor receptor (EGFR) inhibitors;

2)间变性淋巴瘤激酶(ALK)抑制剂；2) anaplastic lymphoma kinase (ALK) inhibitors;

3)真核生物肿瘤细胞增殖抑制剂；3) Eukaryotic tumor cell proliferation inhibitor;

4)真核生物肿瘤细胞转移抑制剂；4) Eukaryotic tumor cell metastasis inhibitor;

5)血管生成抑制剂；5) Angiogenesis inhibitors;

6)预防和/或治疗肿瘤的药物。6) Drugs to prevent and/or treat tumors.

对各产品的限定与前述相同，在此不再赘述。The limitations on each product are the same as above and will not be repeated here.

本发明结构式Ⅰ所示化合物或其药学上可接受的盐也可用于制备预防和/或治疗肿瘤的药物。以结构式Ⅰ所示的化合物或其药学上可接受的盐为有效成分制备的预防和/或治疗肿瘤的药物，也属于本发明的保护范围。The compound represented by the structural formula I of the present invention or its pharmaceutically acceptable salt can also be used to prepare drugs for preventing and/or treating tumors. Medicines for preventing and/or treating tumors prepared using the compound represented by structural formula I or its pharmaceutically acceptable salt as active ingredients also fall within the scope of the present invention.

用式Ⅰ所示化合物或其药学上可接受的盐制备的表皮生长因子(EGFR)抑制剂、间变性淋巴瘤激酶(ALK)抑制剂、真核生物肿瘤细胞增殖抑制剂以及预防和/或治疗肿瘤的药物可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织；或是被其他物质混合或包裹后导入机体。Epidermal growth factor (EGFR) inhibitors, anaplastic lymphoma kinase (ALK) inhibitors, eukaryotic tumor cell proliferation inhibitors and prevention and/or treatment prepared by using the compound represented by formula I or its pharmaceutically acceptable salts Tumor drugs can be introduced into the body through injection, spray, intranasal drip, eye drop, penetration, absorption, physical or chemical mediated methods, such as muscle, intradermal, subcutaneous, vein, mucosal tissue; or after being mixed or wrapped with other substances Import into the body.

需要的时候，在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。When necessary, one or more pharmaceutically acceptable carriers may be added to the above-mentioned drugs, including conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

用结构式Ⅰ所示化合物或其药学上可接受的盐制备的预防和/或治疗肿瘤药物可以制成注射液、片剂、粉剂、颗粒剂、胶囊、口服液、膏剂、霜剂等多种形式。上述各种剂型的药物均可以按照药学领域的常规方法制备。Preventive and/or therapeutic tumor drugs prepared from compounds represented by structural formula I or pharmaceutically acceptable salts thereof can be made into various forms such as injections, tablets, powders, granules, capsules, oral liquids, ointments, creams, etc. . The drugs in various dosage forms mentioned above can be prepared according to conventional methods in the pharmaceutical field.

本发明提供的化合物经过测试证明可以抑制多种肿瘤细胞的生长，以及对EGFR家族蛋白酶产生抑制作用，尤其能够有效抑制EGFR蛋白激酶耐药突变体的活性，例如EGFR^{del19/T790M/C797S}和EGFR^{L858R/T790M/C797S}，可以克服现有第三代EGFR抑制剂药物例如Osimertinib等诱发的NSCLC患者的临床耐药。同时对ALK^wt具有较好的抑制效果。本发明提供的化合物原料易得，制备方法简单，实验证明其有良好的抗癌效果，在抗肿瘤药物设计研发领域有着良好的应用前景。The compounds provided by the present invention have been tested and proved to be able to inhibit the growth of various tumor cells, as well as inhibit the EGFR family proteases, and can especially effectively inhibit the activity of EGFR protein kinase resistant mutants, such as EGFR^{del19/T790M/C797S} and EGFR^{L858R/T790M/C797S} , and can overcome the clinical drug resistance of NSCLC patients induced by existing third-generation EGFR inhibitors such as Osimertinib. At the same time, it has a good inhibitory effect on ALK^wt . The raw materials of the compounds provided by the present invention are easy to obtain, the preparation method is simple, and experiments have shown that it has a good anti-cancer effect, and has a good application prospect in the field of anti-tumor drug design and development.

本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。Other features and advantages of the present invention will be described in detail in the following detailed description.

具体实施方式Detailed ways

下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式，然而应该理解，可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。Preferred embodiments of the invention will be described in more detail below. Although preferred embodiments of the present invention are described below, it should be understood that the present invention may be implemented in various forms and should not be limited to the embodiments set forth herein.

下述实施例中所述实验方法，如无特殊说明，均为有机合成的常规方法；所述试剂和生物材料，如无特殊说明，均从商业途径获得。The experimental methods described in the following examples, unless otherwise stated, are all conventional methods of organic synthesis; the reagents and biological materials, unless otherwise stated, are all obtained from commercial sources.

实施例1Example 1

5-氯-N²-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基-N⁴-苯基嘧啶-2,4-二胺5-Chloro-N² -((2-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-4-yl)oxy)phenyl-N⁴ -phenylpyrimidine-2 ,4-diamine

实施例1AExample 1A

2-氟-4-(3-甲氧基-4-硝基苯氧基)吡啶2-Fluoro-4-(3-methoxy-4-nitrophenoxy)pyridine

将2,4-二氟吡啶(0.500g，4.34mmol)用25mL的N,N-二甲基甲酰胺溶解，加入碳酸铯(2.831g，8.68mmol)和3-甲氧基-4-硝基苯酚(0.73g，4.34mmol)，升温至90℃，反应时间24个小时。反应完成后用乙酸乙酯和水进行萃取，有机层用水层多次萃取，直至无色，收集有机层，通过硅胶柱色谱分离纯化，得淡黄色固体0.841g，产率73.7％。化合物核磁表征数据：¹H NMR(400MHz,Chloroform-d)δ8.17(d,J＝5.8Hz,1H),8.00(d,J＝8.9Hz,1H),6.84(s,2H),6.74(dd,J＝8.9,2.3Hz,1H),6.52(s,1H),3.96(s,3H).¹³C NMR(101MHz,CDCl₃)δ166.73,166.61,166.33,163.97,158.54,155.30,149.28,149.10,128.19,111.38,111.26,111.22,105.63,98.60,98.19,56.87.。Dissolve 2,4-difluoropyridine (0.500g, 4.34mmol) with 25mL of N,N-dimethylformamide, and add cesium carbonate (2.831g, 8.68mmol) and 3-methoxy-4-nitro Phenol (0.73g, 4.34mmol), heated to 90°C, reaction time 24 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The organic layer was extracted with the water layer several times until colorless. The organic layer was collected and separated and purified by silica gel column chromatography to obtain 0.841g of a light yellow solid with a yield of 73.7%. Compound NMR characterization data:¹ H NMR (400MHz, Chloroform-d) δ8.17 (d, J = 5.8Hz, 1H), 8.00 (d, J = 8.9Hz, 1H), 6.84 (s, 2H), 6.74 ( dd, J＝8.9, 2.3Hz, 1H), 6.52 (s, 1H), 3.96 (s, 3H).¹³ C NMR (101MHz, CDCl₃ ) δ 166.73, 166.61, 166.33, 163.97, 158.54, 155.30, 149.28, 149.10 ,128.19,111.38,111.26,111.22,105.63,98.60,98.19,56.87..

实施例1BExample 1B

4-((2-氟吡啶-4-基)氧基)-2-甲氧基苯胺4-((2-fluoropyridin-4-yl)oxy)-2-methoxyaniline

用10mL的无水乙醇溶解实施例1A(0.841g，3.18mmol)，加入含有55％水的10％的钯碳试剂(0.170g，原料的20％)，用氢气置换空气，重复多次确保氢气置换完全，在室温下反应6小时。反应完成后使用硅藻土过滤除去多余的钯碳，收集滤液，减压旋蒸除去溶剂，得到淡黄色浓稠液态产物0.547g，产率70.7％。化合物核磁表征数据：¹H NMR(400MHz,DMSO-d6)δ8.07(d,J＝5.8Hz,1H),6.82(dd,J＝5.8,1.0Hz,1H),6.72–6.65(m,2H),6.56–6.50(m,2H),4.80(s,2H),3.74(s,3H).¹³C NMR(101MHz,DMSO)δ170.03,169.91,166.17,163.87,149.16,148.98,147.48,143.54,136.32,113.96,113.09,110.65,110.62,104.76,96.59,96.17,56.03.Dissolve Example 1A (0.841g, 3.18mmol) with 10 mL of absolute ethanol, add 10% palladium-carbon reagent (0.170g, 20% of raw materials) containing 55% water, replace the air with hydrogen, repeat several times to ensure hydrogen The replacement was complete and the reaction was carried out at room temperature for 6 hours. After the reaction is completed, use diatomaceous earth to filter to remove excess palladium carbon, collect the filtrate, and evaporate the solvent under reduced pressure to obtain 0.547g of a light yellow thick liquid product with a yield of 70.7%. Compound NMR characterization data:¹ H NMR (400MHz, DMSO-d6) δ8.07 (d, J＝5.8Hz, 1H), 6.82 (dd, J＝5.8, 1.0Hz, 1H), 6.72–6.65 (m, 2H ),6.56–6.50(m,2H),4.80(s,2H),3.74(s,3H).¹³ C NMR(101MHz,DMSO)δ170.03,169.91,166.17,163.87,149.16,148.98,147.48,143.54,136.32 ,113.96,113.09,110.65,110.62,104.76,96.59,96.17,56.03.

实施例1CExample 1C

2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯胺2-Methoxy-4-((2-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-4-yl)oxy)aniline

先用8mL的N,N-二甲基甲酰胺溶解1-羟乙基-4-甲基哌嗪(0.389g，2.69mmol)，在0℃条件下乙醇溶液中搅拌10分钟后，加入60％的氢化钠(0.112g，2.81mmol)，搅拌20分钟后让其缓慢升温，1小时后，用4mL的N,N-二甲基甲酰胺溶解实施例1B(0.547g，2.25mmol)并加入反应液中，温度上升至室温时，过夜。反应完成后用乙酸乙酯和水萃取，水层用乙酸乙酯多次萃取，收集有机层，通过硅胶柱色谱分离纯化，得到淡黄色油状产物0.572g，产率71.1％。化合物核磁表征数据：¹H NMR(400MHz,CDCl₃)δ7.92(d,J＝5.9Hz,1H),6.65(s,1H),6.49(d,J＝9.2Hz,3H),6.10(d,J＝2.0Hz,1H),4.35(t,J＝5.7Hz,2H),3.77(s,3H),2.73(d,J＝5.8Hz,2H),2.51(d,J＝33.7Hz,8H),2.26(s,3H).First dissolve 1-hydroxyethyl-4-methylpiperazine (0.389g, 2.69mmol) in 8 mL of N,N-dimethylformamide. After stirring in the ethanol solution at 0°C for 10 minutes, add 60% of sodium hydride (0.112g, 2.81mmol), stir for 20 minutes and allow it to slowly heat up. After 1 hour, dissolve Example 1B (0.547g, 2.25mmol) with 4mL of N,N-dimethylformamide and add it to the reaction Liquid, when the temperature rises to room temperature, stay overnight. After the reaction is completed, extract with ethyl acetate and water. The aqueous layer is extracted with ethyl acetate multiple times. The organic layer is collected and separated and purified by silica gel column chromatography to obtain 0.572g of a light yellow oily product with a yield of 71.1%. Compound NMR characterization data:¹ H NMR (400MHz, CDCl₃ ) δ7.92 (d, J = 5.9 Hz, 1H), 6.65 (s, 1H), 6.49 (d, J = 9.2 Hz, 3H), 6.10 (d ,J＝2.0Hz,1H),4.35(t,J＝5.7Hz,2H),3.77(s,3H),2.73(d,J＝5.8Hz,2H),2.51(d,J＝33.7Hz,8H ),2.26(s,3H).

实施例1DExample 1D

2,5-二氯-N-苯基嘧啶-4-胺2,5-Dichloro-N-phenylpyrimidin-4-amine

用5mL的二甲基亚砜溶解2,4,5-三氯嘧啶(0.500g，2.73mmol)，加入少量的四丁基碘化铵，待溶液变为黄色后再加入苯胺(0.281g，3.00mmol)及三乙胺(0.302g，3.00mmol)，升温至80℃，过夜反应。反应完成后用乙酸乙酯和水萃取，多次用乙酸乙酯重复萃取水层，收集有机层，用硅胶柱分离产物，得黄色固体产物0.455g，产率85.1％。化合物核磁表征数据：¹H NMR(400MHz,DMSO-d6)δ9.53(s,1H),7.58(dd,J＝8.6,1.1Hz,2H),7.46–7.31(m,2H),7.19(d,J＝7.4Hz,1H).¹³C NMR(101MHz,DMSO)δ157.64,157.38,155.84,137.88,129.00,125.46,123.93,114.05.Dissolve 2,4,5-trichloropyrimidine (0.500g, 2.73mmol) with 5mL of dimethyl sulfoxide, add a small amount of tetrabutylammonium iodide, wait until the solution turns yellow, then add aniline (0.281g, 3.00 mmol) and triethylamine (0.302g, 3.00mmol), raise the temperature to 80°C, and react overnight. After the reaction is completed, extract with ethyl acetate and water, repeatedly extract the aqueous layer with ethyl acetate several times, collect the organic layer, and separate the product with a silica gel column to obtain 0.455g of yellow solid product with a yield of 85.1%. Compound NMR characterization data:¹ H NMR (400MHz, DMSO-d6) δ9.53 (s, 1H), 7.58 (dd, J = 8.6, 1.1Hz, 2H), 7.46–7.31 (m, 2H), 7.19 (d , J=7.4Hz, 1H).¹³ C NMR (101MHz, DMSO) δ157.64,157.38,155.84,137.88,129.00,125.46,123.93,114.05.

5-氯-N²-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基-N⁴-苯基嘧啶-2,4-二胺5-Chloro-N² -((2-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-4-yl)oxy)phenyl-N⁴ -phenylpyrimidine-2 ,4-diamine

将实施例1C(0.171g，0.477mmol)、实施例1D(0.137g，0.572mmol)及其他试剂包括三(二亚苄基丙酮)二钯(0.022g，2.39x10-3 mmol)、1,1'-联萘-2,2'-双二苯膦(0.030g，47.7×10^-3mmol)和叔丁醇钾(0.077g，0.687mmol)放入封管中，氩气保护，加入5mL的1,4-二氧六环后再用氩气通入溶液中除气。120℃条件下反应24小时，反应完成后用乙酸乙酯和水进行萃取，收集有机层用硅胶柱方法分离产物，收集淡黄色固体产物0.151g，产率56.3％。核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ8.30(d,J＝8.6Hz,1H),8.09(s,1H),7.99(d,J＝5.9Hz,1H),7.59(d,J＝7.6Hz,2H),7.49(s,1H),7.38(t,J＝7.9Hz,2H),7.17(t,J＝7.4Hz,1H),7.09(s,1H),6.63–6.57(m,2H),6.55(d,J＝2.2Hz,1H),6.19(d,J＝2.1Hz,1H),4.41(t,J＝5.8Hz,2H),3.85(s,3H),2.77(t,J＝5.8Hz,2H),2.53(d,J＝40.1Hz,8H),2.28(s,3H).¹³C NMR(101MHz,CDCl₃)δ167.51,165.54,157.65,155.86,154.32,149.03,148.27,147.86,137.72,128.91,126.61,124.61,122.26,119.72,112.62,107.09,103.77,97.19,63.62,57.10,55.90,54.96,53.38,45.99.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺562.2333，实测值562.2289。Example 1C (0.171g, 0.477mmol), Example 1D (0.137g, 0.572mmol) and other reagents included tris(dibenzylideneacetone)dipalladium (0.022g, 2.39x10-3 mmol), 1,1 '-Binaphthyl-2,2'-bisdiphenylphosphine (0.030g, 47.7×10^-3 mmol) and potassium tert-butoxide (0.077g, 0.687mmol) were placed in a sealed tube, protected by argon, and 5 mL of After removing 1,4-dioxane, argon gas was passed into the solution to degas. React for 24 hours at 120°C. After the reaction is completed, extract with ethyl acetate and water. Collect the organic layer and separate the product using a silica gel column. 0.151g of the light yellow solid product is collected, with a yield of 56.3%. The nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ8.30 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 5.9 Hz, 1H), 7.59 ( d,J＝7.6Hz,2H),7.49(s,1H),7.38(t,J＝7.9Hz,2H),7.17(t,J＝7.4Hz,1H),7.09(s,1H),6.63– 6.57(m,2H),6.55(d,J＝2.2Hz,1H),6.19(d,J＝2.1Hz,1H),4.41(t,J＝5.8Hz,2H),3.85(s,3H), 2.77(t,J＝5.8Hz,2H),2.53(d,J＝40.1Hz,8H),2.28(s,3H).¹³ C NMR (101MHz, CDCl₃ )δ167.51,165.54,157.65,155.86,154.32, 149.03,148.27,147.86,137.72,128.91,126.61,124.61,122.26,119.72,112.62,107.09,103.77,97.19,63.62,57.10,55.90,54.96,53.38,45. 99. High resolution mass spectrometry HRMS (ESI) m/z calculated value [M+H]⁺ 562.2333, measured value 562.2289.

实施例2Example 2

(2-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷(2-((5-chloro-2-((2-methoxy-4-((2-(2-(4-methylpiperazin-1-yl))ethoxy)pyridin-4-yl) Oxygen)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

实施例2与实施例1合成方法基本一致，将实施例1D中的苯氨换成2-(二甲基氧磷基)苯胺，其余合成步骤及条件与实施例1基本一致。核磁表征及高分辨质谱数据如下：¹HNMR(400MHz,Chloroform-d)δ10.78(s,1H),8.50(ddd,J＝8.6,4.4,1.1Hz,1H),8.31–8.25(m,1H),8.05(s,1H),7.92(d,J＝5.9Hz,1H),7.43(s,2H),7.28–7.19(m,1H),7.05(tdd,J＝7.5,2.4,1.1Hz,1H),6.57(d,J＝2.3Hz,2H),6.47(d,J＝2.2Hz,1H),6.13(d,J＝2.1Hz,1H),4.34(s,2H),3.79(s,3H),2.69(s,2H),2.57–2.45(m,4H),2.44–2.33(m,4H),2.21(d,J＝2.5Hz,3H),1.78(s,3H),1.75(s,3H).¹³C NMR(101MHz,CDCl₃)δ167.95,167.44,165.50,165.45,157.34,155.92,154.87,149.18,148.37,147.84,147.68,145.67,143.57,119.87,114.80,113.12,112.48,107.05,104.37,103.83,97.18,63.58,57.04,55.89,54.90,53.31,45.92,18.87,18.16.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺638.2411，实测值638.2369。The synthesis method of Example 2 is basically the same as that of Example 1. The aniline in Example 1D is replaced by 2-(dimethylphosphoryl)aniline. The remaining synthesis steps and conditions are basically the same as those of Example 1. The nuclear magnetic characterization and high-resolution mass spectrometry data are as follows:¹ HNMR (400MHz, Chloroform-d) δ10.78 (s, 1H), 8.50 (ddd, J = 8.6, 4.4, 1.1Hz, 1H), 8.31–8.25 (m, 1H) ),8.05(s,1H),7.92(d,J＝5.9Hz,1H),7.43(s,2H),7.28–7.19(m,1H),7.05(tdd,J＝7.5,2.4,1.1Hz, 1H),6.57(d,J＝2.3Hz,2H),6.47(d,J＝2.2Hz,1H),6.13(d,J＝2.1Hz,1H),4.34(s,2H),3.79(s, 3H),2.69(s,2H),2.57–2.45(m,4H),2.44–2.33(m,4H),2.21(d,J＝2.5Hz,3H),1.78(s,3H),1.75(s ,3H).¹³ C NMR (101MHz, CDCl₃ ) δ167.95,167.44,165.50,165.45,157.34,155.92,154.87,149.18,148.37,147.84,147.68,145.67,143.57,119.87,11 4.80,113.12,112.48,107.05,104.37 ,103.83,97.18,63.58,57.04,55.89,54.90,53.31,45.92,18.87,18.16. High resolution mass spectrometry HRMS (ESI) m/z calculated value [M+H]⁺ 638.2411, measured value 638.2369.

实施例3Example 3

(6-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷(6-((5-chloro-2-((2-methoxy-4-((2-(2-(4-methylpiperazin-1-yl))ethoxy)pyridin-4-yl) Oxygen)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

部分合成路线如下：Part of the synthesis route is as follows:

实施例3AExample 3A

5-碘基-6-氨基喹喔啉5-iodo-6-aminoquinoxaline

用5mL的1,4-二氧六环加水溶液(4:1)溶解6-氨基喹喔啉(0.100g,0.689mmol)，在0℃条件下，先加入碳酸氢钠(0.144g,1.722mmol)和入碘单质(0.437g,1.722mmol)，搅拌半小时后，转移至室温4小时；反应完全后用水和乙酸乙酯萃取，收集有机层，用硅胶柱分离产物，得深黄色固体0.122g。化合物核磁表征数据：¹H NMR(400MHz,Chloroform-d)δ8.74(d,J＝2.0Hz,1H),8.53(d,J＝2.0Hz,1H),7.83(d,J＝9.0Hz,1H),7.31–7.22(m,1H).¹³C NMR(101MHz,CDCl₃)δ171.21,149.46,145.51,144.22,141.27,138.61,130.30,120.70,67.08.Dissolve 6-aminoquinoxaline (0.100g, 0.689mmol) with 5mL of 1,4-dioxane in water (4:1). At 0°C, first add sodium bicarbonate (0.144g, 1.722mmol). ) and iodine element (0.437g, 1.722mmol), stir for half an hour, and then transfer to room temperature for 4 hours; after the reaction is complete, extract with water and ethyl acetate, collect the organic layer, and separate the product with a silica gel column to obtain 0.122g of a dark yellow solid. . Compound NMR characterization data:¹ H NMR (400MHz, Chloroform-d) δ8.74 (d, J = 2.0Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 7.83 (d, J = 9.0Hz, 1H),7.31–7.22(m,1H).¹³ C NMR (101MHz, CDCl₃ ) δ171.21,149.46,145.51,144.22,141.27,138.61,130.30,120.70,67.08.

实施例3BExample 3B

5-二甲基氧磷基-6-氨基喹喔啉5-Dimethylphosphooxy-6-aminoquinoxaline

实施例3A(0.100g,0.37mmol)、二甲基氧膦(0.043g,0.55mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.021g,0.037mmol)，醋酸钯(0.008g,0.037mmol)和磷酸钾(0.117g,0.550mmol)放入封管中，氩气保护。加入2mL的N,N-二甲基甲酰胺和0.4mL的水后再次进行氩气保护，密封，120℃条件下，反应过夜。反应完成后用乙酸乙酯和水萃取，收集有机层，通过硅胶柱色谱方法分离产物，得黄色固体产物0.112g。化合物核磁表征数据：¹H NMR(400MHz,Chloroform-d)δ8.63–8.40(m,2H),7.84(s,1H),7.03(d,J＝4.6Hz,1H),2.04–1.95(m,6H).¹³C NMR(101MHz,CDCl₃)δ155.72,145.78,143.13,139.74,137.63,134.05,134.03,124.88,124.79,20.21,19.49.Example 3A (0.100g, 0.37mmol), dimethylphosphine oxide (0.043g, 0.55mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.021g, 0.037mmol) ), palladium acetate (0.008g, 0.037mmol) and potassium phosphate (0.117g, 0.550mmol) were placed in a sealed tube and protected by argon. After adding 2 mL of N,N-dimethylformamide and 0.4 mL of water, the mixture was protected by argon again, sealed, and allowed to react overnight at 120°C. After the reaction is completed, extract with ethyl acetate and water, collect the organic layer, and separate the product through silica gel column chromatography to obtain 0.112g of a yellow solid product. Compound NMR characterization data:¹ H NMR (400MHz, Chloroform-d) δ8.63–8.40 (m, 2H), 7.84 (s, 1H), 7.03 (d, J = 4.6Hz, 1H), 2.04–1.95 (m ,6H).¹³ C NMR (101MHz, CDCl₃ ) δ155.72,145.78,143.13,139.74,137.63,134.05,134.03,124.88,124.79,20.21,19.49.

实施例3CExample 3C

(6-((2,5-二氯-4-基)氨基)喹喔啉-5-基)二甲基氧磷(6-((2,5-dichloro-4-yl)amino)quinoxalin-5-yl)dimethylphosphonoxide

实施例3C的合成方法参照实施例1D，将苯胺换成实施例3B，其他反应条件和实施例1D合成条件基本一致。化合物核磁表征数据：¹H NMR(400MHz,Chloroform-d)δ13.22(s,1H),9.15(dd,J＝9.5,4.2Hz,1H),8.81–8.78(m,1H),8.74(d,J＝1.8Hz,1H),8.27(d,J＝0.9Hz,1H),8.25(d,J＝9.6Hz,1H),2.12(dd,J＝14.3,0.8Hz,7H).¹³C NMR(101MHz,CDCl₃)δ157.26,156.90,156.90,156.37,155.99,155.00,147.84,143.63,143.61,139.44,139.37,133.98,133.96,125.68,125.59,116.46,20.72,19.99.The synthesis method of Example 3C is similar to that of Example 1D, except that aniline is replaced by Example 3B. The other reaction conditions are basically the same as those of Example 1D. Compound NMR characterization data:¹ H NMR (400MHz, Chloroform-d) δ13.22 (s, 1H), 9.15 (dd, J = 9.5, 4.2Hz, 1H), 8.81–8.78 (m, 1H), 8.74 (d ,J＝1.8Hz,1H),8.27(d,J＝0.9Hz,1H),8.25(d,J＝9.6Hz,1H),2.12(dd,J＝14.3,0.8Hz,7H).¹³ C NMR (101MHz, CDCl₃ )δ157.26,156.90,156.90,156.37,155.99,155.00,147.84,143.63,143.61,139.44,139.37,133.98,133.96,125.68,125.59,116.46, 20.72,19.99.

实施例3Example 3

(6-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷(6-((5-chloro-2-((2-methoxy-4-((2-(2-(4-methylpiperazin-1-yl))ethoxy)pyridin-4-yl) Oxygen)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

实施例1C(0.144g,0.402mmol)、实施例3C(0.147g,0.402mmol)、对甲苯磺酸一水化合物(0.153g,0.804mmol)用6mL的2-戊醇溶解，在90℃条件下反应5小时。反应完成后用乙酸乙酯和水萃取，多次用乙酸乙酯对水层进行萃取，收集有机层，用硅胶柱分离产物，得黄色固体产物80mg。化合物核磁表征数据：¹H NMR(400MHz,Chloroform-d)δ12.75(s,1H),9.13(dd,J＝9.5,4.1Hz,1H),8.75(s,1H),8.72(s,1H),8.35–8.29(m,1H),8.19(s,1H),8.13(d,J＝9.5Hz,1H),7.98(d,J＝5.9Hz,1H),7.51(s,1H),6.67–6.64(m,2H),6.54(dd,J＝5.9,2.2Hz,1H),6.17(d,J＝2.1Hz,1H),4.40(t,J＝5.7Hz,2H),3.87(s,3H),2.80–2.55(m,11H),2.38(s,3H),2.14(s,3H),2.11(s,3H).¹³C NMR(101MHz,CDCl₃)δ167.47,165.43,157.22,155.89,155.80,149.31,148.90,148.88,148.64,147.90,143.86,143.80,143.35,142.96,139.27,139.20,132.98,132.95,126.82,126.73,126.50,119.88,112.62,112.49,111.60,108.01,107.16,103.99,97.23,63.44,56.84,55.98,54.55,52.42,45.27,20.76,20.03.Example 1C (0.144 g, 0.402 mmol), Example 3C (0.147 g, 0.402 mmol), p-toluenesulfonic acid monohydrate (0.153 g, 0.804 mmol) were dissolved in 6 mL of 2-pentanol and reacted at 90°C for 5 hours. After the reaction was completed, it was extracted with ethyl acetate and water. The water layer was extracted with ethyl acetate several times, the organic layer was collected, and the product was separated with a silica gel column to obtain 80 mg of a yellow solid product. Compound NMR characterization data:¹ H NMR (400 MHz, Chloroform-d) δ12.75 (s, 1H), 9.13 (dd, J = 9.5, 4.1 Hz, 1H), 8.75 (s, 1H), 8.72 (s, 1H), 8.35–8.29 (m, 1H), 8.19 (s, 1H), 8.13 (d, J = 9.5 Hz, 1H), 7.98 (d, J = 5.9 Hz, 1H), 7 .51(s,1H),6.67–6.64(m,2H),6.54(dd,J＝5.9,2.2Hz,1H),6.17(d,J＝2.1Hz,1H),4.40(t,J＝5.7Hz,2H),3.87(s,3H),2.80–2.55(m,11H),2.38(s,3H),2.14(s,3H),2.11(s,3H).¹³ C NMR(101MHz,CDCl₃ )δ167.47,165.43,157.22,155.89,155.80,149.31,148.90,148.88,148.64,147.90,143.86,143.80,143.35,142.96,139.27,139.20,132.98,132.9 5,126.82,126.73,126.50,119.88,112.62,112.49,111.60,108.01,107.16,103.99,97.23,63.44,56.84,55.98,54.55,52.42,45.27,20.76,20.03.

实施例4Example 4

5-氯-4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N-(2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2-胺5-Chloro-4-(1-(ethylsulfonyl)-1H-indol-3-yl)-N-(2-methoxy-4-((2-(2-(4-methylpiperidine) Azin-1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)pyrimidin-2-amine

部分合成路线如下：Some of the synthetic routes are as follows:

实施例4AExample 4A

3-(2,5-二氯嘧啶-4-基)-1H-吲哚3-(2,5-Dichloropyrimidin-4-yl)-1H-indole

用6mL的四氢呋喃溶解吲哚(1.28g,10.79mmol)，0℃下将甲基溴化镁(3.37mL,10.78mmol)缓慢滴加进去，搅拌30分钟；再加入2,4,5-三氯嘧啶(1g,5.4mmol)，室温下搅拌1小时，升温至60℃后继续搅拌1.5小时。反应结束后，待冷却至室温后滴加634μL的乙酸(11.06mmol)、9.9mL水及2mL的四氢呋喃，在60℃搅拌20分钟。收集有机层，加入11mL的庚烷后产生白色固体，收集产物1.51g。化合物核磁表征数据：¹H NMR(400MHz,DMSO-d6)δ8.69(d,J＝1.4Hz,2H),8.50(d,J＝6.9Hz,1H),7.55(s,1H),7.24(d,J＝0.6Hz,2H).Dissolve indole (1.28g, 10.79mmol) in 6mL of tetrahydrofuran, slowly add methylmagnesium bromide (3.37mL, 10.78mmol) dropwise at 0°C, and stir for 30 minutes; then add 2,4,5-trichloro Pyrimidine (1g, 5.4mmol) was stirred at room temperature for 1 hour. After the temperature was raised to 60°C, stirring was continued for 1.5 hours. After the reaction was completed, after cooling to room temperature, 634 μL of acetic acid (11.06 mmol), 9.9 mL of water, and 2 mL of tetrahydrofuran were added dropwise, and the mixture was stirred at 60° C. for 20 minutes. The organic layer was collected, and 11 mL of heptane was added to produce a white solid. 1.51 g of the product was collected. Compound NMR characterization data:¹ H NMR (400MHz, DMSO-d6) δ8.69 (d, J = 1.4Hz, 2H), 8.50 (d, J = 6.9Hz, 1H), 7.55 (s, 1H), 7.24 ( d,J＝0.6Hz,2H).

实施例4BExample 4B

3-(2,5-二氯嘧啶-4-基)-1-(乙基磺酰基)-1H-吲哚3-(2,5-Dichloropyrimidin-4-yl)-1-(ethylsulfonyl)-1H-indole

用1.5mL的四氢呋喃溶解实施例4A(0.100g,0.379mmol)，0℃下加入氢化钠(0.037g,0.946mmol)，关闭制冷后3个小左右后加入乙基磺酰氯(0.058g,0.454mmol)，室温条件下过夜。反应完成后用乙酸乙酯和水萃取，收集有机层，通过硅胶柱色谱方法分离产物，得淡黄色固体产物0.155g。化合物核磁表征数据：¹H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.57(s,1H),8.37(d,J＝7.9Hz,1H),7.92(d,J＝8.2Hz,1H),7.46(dd,J＝13.1,7.8Hz,2H),3.87–3.71(m,2H),1.11(t,J＝7.3Hz,3H).Dissolve Example 4A (0.100g, 0.379mmol) with 1.5mL of tetrahydrofuran, add sodium hydride (0.037g, 0.946mmol) at 0°C, turn off the refrigeration and add ethylsulfonyl chloride (0.058g, 0.454mmol) about 3 hours later ) at room temperature overnight. After the reaction is completed, extract with ethyl acetate and water, collect the organic layer, and separate the product through silica gel column chromatography to obtain 0.155g of a light yellow solid product. Compound NMR characterization data:¹ H NMR (400MHz, DMSO-d6) δ8.91 (s, 1H), 8.57 (s, 1H), 8.37 (d, J = 7.9Hz, 1H), 7.92 (d, J = 8.2 Hz,1H),7.46(dd,J＝13.1,7.8Hz,2H),3.87–3.71(m,2H),1.11(t,J＝7.3Hz,3H).

实施例4Example 4

5-氯-4-(1-(乙基磺酰基)-1H-吲哚-3-基)-N-(2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2-胺5-Chloro-4-(1-(ethylsulfonyl)-1H-indol-3-yl)-N-(2-methoxy-4-((2-(2-(4-methylpiperidine) Azin-1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)pyrimidin-2-amine

实施例4的合成方法参照实施例3，将实施例3C换成实施例4B，其他反应条件和实施例3合成条件基本一致。核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ8.48(d,J＝0.8Hz,2H),8.41(d,J＝0.8Hz,2H),7.99(d,J＝6.0Hz,2H),7.76(s,1H),7.44–7.34(m,2H),6.68(d,J＝2.4Hz,2H),6.59–6.54(m,1H),6.19(d,J＝2.1Hz,1H),4.41(t,J＝5.7Hz,2H),3.91(s,3H),3.42(q,J＝7.4Hz,2H),2.79–2.54(m,10H),2.38(s,3H),1.30–1.27(m,4H).¹³CNMR(101MHz,CDCl₃)δ167.42,165.46,158.19,149.30,148.82,147.90,134.87,130.44,128.74,126.33,125.55,124.07,123.37,119.70,112.94,112.75,107.21,103.95,97.29,63.52,56.90,56.02,54.63,52.57,49.01,45.37,8.12.For the synthesis method of Example 4, refer to Example 3, replace Example 3C with Example 4B, and other reaction conditions are basically the same as the synthesis conditions of Example 3. The nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ8.48 (d, J = 0.8Hz, 2H), 8.41 (d, J = 0.8Hz, 2H), 7.99 (d, J = 6.0Hz, 2H),7.76(s,1H),7.44–7.34(m,2H),6.68(d,J＝2.4Hz,2H),6.59–6.54(m,1H),6.19(d,J＝2.1Hz,1H ),4.41(t,J＝5.7Hz,2H),3.91(s,3H),3.42(q,J＝7.4Hz,2H),2.79–2.54(m,10H),2.38(s,3H),1.30 –1.27(m,4H).¹³ CNMR(101MHz,CDCl₃ )δ167.42,165.46,158.19,149.30,148.82,147.90,134.87,130.44,128.74,126.33,125.55,124.07,123.37,119 .70,112.94,112.75,107.21, 103.95,97.29,63.52,56.90,56.02,54.63,52.57,49.01,45.37,8.12.

实施例5Example 5

5-氯-N²-(2-甲氧基-4-((2-(2-吗啉乙氧基)吡啶-4-基)氧基)苯基)-N⁴-苯基嘧啶-2,4-二胺5-Chloro-N² -(2-methoxy-4-((2-(2-morpholinoethoxy)pyridin-4-yl)oxy)phenyl)-N⁴ -phenylpyrimidine-2 ,4-diamine

合成方法参考实施例1，产率61.2％。核磁表征及高分辨质谱数据如下：¹H NMR(400MHz,Chloroform-d)δ8.29(d,J＝8.7Hz,1H),8.07(s,1H),7.99(d,J＝5.9Hz,1H),7.57(d,J＝8.0Hz,2H),7.51(s,1H),7.37(t,J＝7.9Hz,2H),7.14(d,J＝11.5Hz,2H),6.63–6.52(m,3H),6.19(d,J＝2.1Hz,1H),4.41(s,2H),3.84(s,3H),3.73–3.68(m,4H),2.74(t,J＝5.7Hz,2H),2.53(dd,J＝5.7,3.7Hz,4H).¹³C NMR(101MHz,CDCl₃)δ167.57,165.49,157.64,155.89,154.28,149.08,148.28,147.86,137.75,128.88,126.63,124.60,122.31,119.80,112.60,107.16,105.08,103.77,97.17,66.83,63.32,57.58,55.90,53.92.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺549.2017，实测值549.1949。The synthesis method is as shown in Example 1, with a yield of 61.2%. The NMR characterization and high-resolution mass spectrum data are as follows:¹ H NMR (400 MHz, Chloroform-d) δ8.29 (d, J = 8.7 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 5.9 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.14 (d, J = 11.5 Hz, 2H), 6.63–6.52 (m, 3H), 6.19 (d, J = 2.1 Hz, 1H), 4.41 (s, 2H), 3.84 (s, 3H), 3.73–3.68 (m, 4H), 2.74 (t, J = 5.7 Hz, 2H), 2.53 (dd, J = 5.7, 3.7 Hz, 4H).¹³ C NMR (101 MHz, CDCl₃ ) δ 167.57, 165.49, 157.64, 155.89, 154.28, 149.08, 148.28, 147.86, 137.75, 128.88, 126.63, 124.60, 122.31, 119.80, 112.60, 107.16, 105.08, 103.77, 97.17, 66.83, 63.32, 57.58, 55.90, 53.92. High resolution mass spectrometry HRMS (ESI) m/z calculated value [M+H]⁺ 549.2017, found value 549.1949.

实施例6Example 6

(2-((5-氯-2-((2-甲氧基-4-((2-(2-吗啉乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷(2-((5-chloro-2-((2-methoxy-4-((2-(2-morpholineethoxy)pyridin-4-yl)oxy)phenyl)amino)pyrimidine -4-yl)amino)phenyl)dimethylphosphine oxide

合成方法参考实施例2，产率63.3％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ10.78(s,1H),8.54–8.45(m,1H),8.28(d,J＝9.5Hz,1H),8.05(s,1H),7.92(d,J＝5.9Hz,1H),7.45(s,2H),7.22(d,J＝14.0Hz,1H),7.06(ddt,J＝8.8,6.7,1.6Hz,1H),6.58(s,2H),6.48(d,J＝2.2Hz,1H),6.14(d,J＝2.2Hz,1H),4.35(t,J＝5.7Hz,2H),3.79(s,3H),3.65–3.58(m,4H),2.68(t,J＝5.7Hz,2H),2.46(s,4H),1.79(s,3H),1.75(s,3H).¹³C NMR(101MHz,CDCl₃)δ167.49,165.46,157.33,155.93,154.86,149.21,148.36,147.85,143.59,132.25,129.67,126.65,123.17,122.80,121.02,119.90,112.48,107.11,106.76,103.84,97.15,66.80,63.31,57.55,55.90,53.89,18.85,18.14.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺625.2095，实测值625.2046。The synthesis method refers to Example 2, the yield is 63.3%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ10.78 (s, 1H), 8.54–8.45 (m, 1H), 8.28 (d, J) ＝9.5Hz,1H),8.05(s,1H),7.92(d,J＝5.9Hz,1H),7.45(s,2H),7.22(d,J＝14.0Hz,1H),7.06(ddt,J ＝8.8,6.7,1.6Hz,1H),6.58(s,2H),6.48(d,J＝2.2Hz,1H),6.14(d,J＝2.2Hz,1H),4.35(t,J＝5.7Hz ,2H),3.79(s,3H),3.65–3.58(m,4H),2.68(t,J＝5.7Hz,2H),2.46(s,4H),1.79(s,3H),1.75(s, 3H).¹³ C NMR (101MHz, CDCl₃ ) δ167.49,165.46,157.33,155.93,154.86,149.21,148.36,147.85,143.59,132.25,129.67,126.65,123.17,122.80,121 .02,119.90,112.48,107.11,106.76, 103.84,97.15,66.80,63.31,57.55,55.90,53.89,18.85,18.14. High resolution mass spectrometry HRMS (ESI) m/z calculated value [M+H]⁺ 625.2095, measured value 625.2046.

实施例7Example 7

(6-((5-氯-2-((2-甲氧基-4-((2-(2-(4-甲基哌嗪-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷(6-((5-chloro-2-((2-methoxy-4-((2-(2-(4-methylpiperazin-1-yl))ethoxy)pyridin-4-yl) Oxygen)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

合成方法参考实施例3，产率38.1％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ12.75(s,1H),9.13(dd,J＝9.5,4.1Hz,1H),8.73(d,J＝11.2Hz,2H),8.36–8.28(m,1H),8.19(s,1H),7.98(dd,J＝5.9,1.4Hz,2H),7.51(s,1H),6.64(s,2H),6.55(dd,J＝5.9,2.2Hz,1H),6.18(d,J＝2.1Hz,1H),4.42(t,J＝5.7Hz,3H),3.87(s,3H),3.71(d,J＝4.6Hz,4H),2.77(d,J＝5.7Hz,2H),2.55(s,4H),2.12(d,J＝14.3Hz,6H).¹³C NMR(101MHz,CDCl₃)δ167.47,165.43,157.21,155.89,155.80,149.30,148.63,147.90,143.35,142.96,132.96,132.94,126.82,126.73,126.50,119.87,112.61,108.01,107.17,103.99,97.23,66.71,63.18,57.55,55.97,53.85,20.76,20.03.The synthesis method is as shown in Example 3, with a yield of 38.1%. The nuclear magnetic resonance characterization data are as follows:¹ H NMR (400 MHz, Chloroform-d) δ12.75 (s, 1H), 9.13 (dd, J = 9.5, 4.1 Hz, 1H), 8.73 (d, J = 11.2 Hz, 2H), 8.36-8.28 (m, 1H), 8.19 (s, 1H), 7.98 (dd, J = 5.9, 1.4 Hz, 2H), 7.51 (s, 1H), 6.64 ( s, 2H), 6.55 (dd, J = 5.9, 2.2 Hz, 1H), 6.18 (d, J = 2.1 Hz, 1H), 4.42 (t, J = 5.7 Hz, 3H), 3.87 (s, 3H), 3.71 (d, J = 4.6 Hz, 4H), 2.77 (d, J = 5.7 Hz, 2H), 2.55 (s, 4H), 2.12 (d, J = 14.3 Hz, 6H).¹³ C NMR (101 MHz, CDCl₃ ) δ 167.47, 165.43, 157.21, 155.89, 155.80, 149.30, 148.63, 147.90, 143.35, 142.96, 132.96, 132.94, 126.82, 126.73, 126.50, 119.87, 112.61, 108.01, 107.17, 103.99, 97.23, 66.71, 63.18, 57.55, 55.97, 53.85, 20.76, 20.03.

实施例8Example 8

5-氯-N⁴-(1-(乙基磺酰基)-1H-吲哚-3-基)-N²-(2-甲氧基-4-((2-(2-吗啉乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺5-Chloro-N⁴ -(1-(ethylsulfonyl)-1H-indol-3-yl)-N² -(2-methoxy-4-((2-(2-morpholinoethoxy) yl)pyridin-4-yl)oxy)phenyl)pyrimidine-2,4-diamine

合成方法参考实施例4，产率22.4％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ8.49–8.44(m,2H),8.40(s,2H),7.97(dd,J＝12.6,7.0Hz,2H),7.76(s,1H),7.47–7.32(m,2H),6.67(dd,J＝4.7,2.3Hz,2H),6.56(dd,J＝5.9,2.2Hz,1H),6.20(d,J＝2.1Hz,1H),4.45(t,J＝5.6Hz,2H),3.89(s,3H),3.76–3.70(m,4H),3.41(q,J＝7.4Hz,2H),2.81(t,J＝5.6Hz,2H),2.60(d,J＝4.7Hz,4H),1.29(t,J＝7.4Hz,3H).¹³C NMR(101MHz,CDCl₃)δ167.46,165.36,158.18,157.90,156.95,149.31,148.80,147.91,134.87,130.45,128.73,126.34,125.54,124.05,123.38,119.73,118.15,116.52,112.94,112.72,107.28,103.94,97.28,66.55,63.04,57.50,56.01,53.79,49.01,8.12.The synthesis method refers to Example 4, the yield is 22.4%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ8.49–8.44 (m, 2H), 8.40 (s, 2H), 7.97 (dd, J) ＝12.6,7.0Hz,2H),7.76(s,1H),7.47–7.32(m,2H),6.67(dd,J＝4.7,2.3Hz,2H),6.56(dd,J＝5.9,2.2Hz, 1H),6.20(d,J＝2.1Hz,1H),4.45(t,J＝5.6Hz,2H),3.89(s,3H),3.76–3.70(m,4H),3.41(q,J＝7.4 Hz, 2H), 2.81 (t, J = 5.6Hz, 2H), 2.60 (d, J = 4.7Hz, 4H), 1.29 (t, J = 7.4Hz, 3H).¹³ C NMR (101MHz, CDCl₃ ) δ167.46,165.36,158.18,157.90,156.95,149.31,148.80,147.91,134.87,130.45,128.73,126.34,125.54,124.05,123.38,119.73,118.15,116 .52,112.94,112.72,107.28,103.94,97.28,66.55,63.04, 57.50,56.01,53.79,49.01,8.12.

实施例9Example 9

5-氯-N²-(2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)-N⁴-苯基嘧啶-2,4-二胺5-Chloro-N² -(2-methoxy-4-((2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)-N⁴ -Phenylpyrimidine-2,4-diamine

合成方法参考实施例1，产率60.8％，核磁表征及高分辨质谱数据如下：¹H NMR(400MHz,Chloroform-d)δ8.26(d,J＝8.5Hz,1H),8.03(s,1H),7.97(d,J＝5.8Hz,1H),7.59–7.46(m,3H),7.33(t,J＝7.7Hz,2H),7.14(d,J＝11.0Hz,2H),6.62–6.48(m,3H),6.19(s,1H),4.42(t,J＝5.4Hz,2H),3.80(s,3H),2.89(t,J＝5.4Hz,2H),2.64(s,4H),1.78(s,4H).¹³C NMR(101MHz,CDCl₃)δ167.54,165.42,157.58,155.84,154.25,149.01,148.21,147.84,137.73,128.85,126.58,124.56,122.30,119.72,112.57,107.14,105.02,103.73,97.19,64.50,55.87,54.88,54.48,23.40.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺533.2068，实测值533.2021The synthesis method refers to Example 1. The yield is 60.8%. The nuclear magnetic characterization and high-resolution mass spectrometry data are as follows:¹ H NMR (400MHz, Chloroform-d) δ8.26 (d, J=8.5Hz, 1H), 8.03 (s, 1H) ),7.97(d,J＝5.8Hz,1H),7.59–7.46(m,3H),7.33(t,J＝7.7Hz,2H),7.14(d,J＝11.0Hz,2H),6.62–6.48 (m,3H),6.19(s,1H),4.42(t,J＝5.4Hz,2H),3.80(s,3H),2.89(t,J＝5.4Hz,2H),2.64(s,4H) ,1.78(s,4H).¹³ C NMR (101MHz, CDCl₃ ) δ167.54,165.42,157.58,155.84,154.25,149.01,148.21,147.84,137.73,128.85,126.58,124.56,122.30,11 9.72,112.57,107.14,105.02 ,103.73,97.19,64.50,55.87,54.88,54.48,23.40. High-resolution mass spectrometry HRMS (ESI) m/z calculated value [M+H]⁺ 533.2068, measured value 533.2021

实施例10Example 10

(2-((5-氯-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷(2-((5-chloro-2-((2-methoxy-4-((2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-yl)oxy)oxy)benzene base)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

合成方法参考实施例2，产率59.2％，核磁表征及高分辨质谱数据如下：¹H NMR(400MHz,Chloroform-d)δ10.77(s,1H),8.45(dd,J＝8.4,4.3Hz,1H),8.23(d,J＝9.4Hz,1H),7.99(s,1H),7.87(d,J＝5.9Hz,1H),7.40(d,J＝19.0Hz,2H),7.23–7.12(m,1H),7.06–6.96(m,1H),6.56–6.49(m,2H),6.46–6.39(m,1H),6.11(d,J＝2.1Hz,1H),4.34(t,J＝5.7Hz,2H),3.73(s,3H),2.79(s,2H),2.55(s,4H),1.71(d,J＝13.2Hz,10H).¹³C NMR(101MHz,CDCl₃)δ167.52,165.40,157.37,155.98,154.91,149.19,148.38,147.87,143.65,132.28,129.63,126.71,123.24,122.68,121.09,119.84,112.52,107.19,106.84,103.86,97.25,64.32,55.93,54.87,54.48,23.42,18.90,18.19.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺609.2146，实测值609.2089。The synthesis method is as in Example 2, with a yield of 59.2%. The nuclear magnetic resonance characterization and high-resolution mass spectrum data are as follows:¹ H NMR (400 MHz, Chloroform-d) δ10.77 (s, 1H), 8.45 (dd, J = 8.4, 4.3 Hz, 1H), 8.23 (d, J = 9.4 Hz, 1H), 7.99 (s, 1H), 7.87 (d, J = 5.9 Hz, 1H), 7.40 (d, J = 19.0 Hz, 2H), 7.23-7.12 (m, 1 H), 7.06–6.96 (m, 1H), 6.56–6.49 (m, 2H), 6.46–6.39 (m, 1H), 6.11 (d, J = 2.1 Hz, 1H), 4.34 (t, J = 5.7 Hz, 2H), 3.73 (s, 3H), 2.79 (s, 2H), 2.55 (s, 4H), 1.71 (d, J = 13.2 Hz, 10H).¹³ C NMR (101 MHz, CDCl₃ ) δ 167.52, 165.40, 157.37, 155.98, 154.91, 149.19, 148.38, 147.87, 143.65, 132.28, 129.63, 126.71, 123.24, 122.68, 121.09, 119.84, 112.52, 107.19, 106.84, 103.86, 97.25, 64.32, 55.93, 54.87, 54.48, 23.42, 18.90, 18.19. High resolution mass spectrometry HRMS (ESI) m/z calculated value [M+H]⁺ 609.2146, found value 609.2089.

实施例11Example 11

(6-((5-氯-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷(6-((5-chloro-2-((2-methoxy-4-((2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-yl)oxy)oxy)benzene base)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

合成方法参考实施例3，产率50.6％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ12.70(s,1H),9.07(dd,J＝9.5,4.1Hz,1H),8.69(d,J＝9.7Hz,2H),8.25(d,J＝9.4Hz,1H),8.11(s,1H),8.06(d,J＝9.5Hz,1H),7.90(d,J＝5.9Hz,1H),7.48(s,1H),6.62–6.57(m,2H),6.51(s,1H),6.15(d,J＝2.2Hz,1H),4.71–4.62(m,2H),3.82(s,3H),3.37–3.30(m,2H),3.20(s,4H),2.06(d,J＝14.2Hz,6H),1.99(s,4H).¹³C NMR(101MHz,CDCl₃)δ167.62,164.28,157.11,155.79,155.67,149.31,148.71,148.42,147.92,143.77,143.72,143.49,143.05,139.11,139.05,132.90,128.76,126.67,126.59,126.46,125.79,119.82,112.43,111.51,107.89,107.68,103.89,97.16,61.74,56.00,54.27,53.91,23.23,20.71,19.98.The synthesis method refers to Example 3, the yield is 50.6%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ12.70 (s, 1H), 9.07 (dd, J=9.5, 4.1Hz, 1H), 8.69(d,J＝9.7Hz,2H),8.25(d,J＝9.4Hz,1H),8.11(s,1H),8.06(d,J＝9.5Hz,1H),7.90(d,J＝5.9 Hz,1H),7.48(s,1H),6.62–6.57(m,2H),6.51(s,1H),6.15(d,J＝2.2Hz,1H),4.71–4.62(m,2H),3.82 (s,3H),3.37–3.30(m,2H),3.20(s,4H),2.06(d,J＝14.2Hz,6H),1.99(s,4H).¹³ C NMR (101MHz, CDCl₃ ) δ167.62,164.28,157.11,155.79,155.67,149.31,148.71,148.42,147.92,143.77,143.72,143.49,143.05,139.11,139.05,132.90,128.76,126 .67,126.59,126.46,125.79,119.82,112.43,111.51,107.89, 107.68,103.89,97.16,61.74,56.00,54.27,53.91,23.23,20.71,19.98.

实施例12Example 12

5-氯-N⁴-(1-(乙基磺酰基)-1H-吲哚-3-基)-N²-(2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺5-Chloro-N⁴ -(1-(ethylsulfonyl)-1H-indol-3-yl)-N² -(2-methoxy-4-((2-(2-(pyrrolidine- 1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)pyrimidine-2,4-diamine

合成方法参考实施例4，产率51.5％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ8.51–8.45(m,2H),8.39(d,J＝7.2Hz,2H),7.96(dd,J＝7.0,3.5Hz,2H),7.76(s,1H),7.45–7.32(m,2H),6.70–6.64(m,2H),6.58(dd,J＝5.9,2.2Hz,1H),6.21(d,J＝2.1Hz,1H),4.75(t,J＝5.1Hz,2H),3.91(s,3H),3.48–3.18(m,8H),2.07(s,4H),1.29(t,J＝7.4Hz,3H).¹³C NMR(101MHz,CDCl₃)δ167.69,164.30,158.18,157.90,156.99,149.34,148.67,147.98,134.87,130.44,128.71,126.46,125.56,124.05,123.33,119.67,118.20,116.51,112.95,112.65,107.83,103.90,97.27,61.59,56.07,54.24,53.93,49.02,23.29,8.11,1.00.The synthesis method refers to Example 4, the yield is 51.5%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ8.51–8.45 (m, 2H), 8.39 (d, J = 7.2Hz, 2H), 7.96(dd,J＝7.0,3.5Hz,2H),7.76(s,1H),7.45–7.32(m,2H),6.70–6.64(m,2H),6.58(dd,J＝5.9,2.2Hz, 1H),6.21(d,J＝2.1Hz,1H),4.75(t,J＝5.1Hz,2H),3.91(s,3H),3.48–3.18(m,8H),2.07(s,4H), 1.29 (t, J=7.4Hz, 3H).¹³ C NMR (101MHz, CDCl₃ ) δ167.69,164.30,158.18,157.90,156.99,149.34,148.67,147.98,134.87,130.44,128.71,126.46,125 .56,124.05,123.33 ,119.67,118.20,116.51,112.95,112.65,107.83,103.90,97.27,61.59,56.07,54.24,53.93,49.02,23.29,8.11,1.00.

实施例13Example 13

5-氯-N²-(2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)-N⁴-苯基嘧啶-2,4-二胺5-Chloro-N² -(2-methoxy-4-((2-(2-(piperidin-1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)-N⁴ -Phenylpyrimidine-2,4-diamine

合成方法参考实施例1，产率46.4％，核磁表征及高分辨质谱数据如下：¹H NMR(400MHz,Chloroform-d)δ8.28(d,J＝8.7Hz,1H),8.05(s,1H),7.98(d,J＝5.9Hz,1H),7.58–7.54(m,2H),7.49(s,1H),7.38–7.32(m,3H),7.18–7.10(m,4H),6.60(t,J＝2.8Hz,2H),6.52(dd,J＝5.9,2.2Hz,1H),6.19(d,J＝2.2Hz,1H),4.42(s,2H),3.82(s,3H),2.74(s,2H),2.50(s,5H),1.60(d,J＝5.6Hz,4H),1.42(d,J＝5.1Hz,2H).¹³C NMR(101MHz,CDCl₃)δ167.48,165.56,157.66,155.87,154.29,149.07,148.35,147.89,137.78,128.85,128.60,126.60,124.55,122.28,119.92,119.80,112.56,107.05,103.75,97.20,63.54,57.75,55.88,53.48,25.67,24.10.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺547.2224，实测值547.2161。The synthesis method is as in Example 1, with a yield of 46.4%. The NMR characterization and high-resolution mass spectrometry data are as follows:¹ H NMR (400 MHz, Chloroform-d) δ8.28 (d, J = 8.7 Hz, 1H), 8.05 (s, 1H), 7.98 (d, J = 5.9 Hz, 1H), 7.58–7.54 (m, 2H), 7.49 (s, 1H), 7.38–7.32 (m, 3H), 7.18–7.10 (m, 4H), 6.60 (t, J = 2.8 Hz, 2H), 6.52 (dd, J = 5.9, 2.2 Hz, 1H), 6.19 (d, J = 2.2 Hz, 1H), 4.42 (s, 2H), 3.82 (s, 3H), 2.74 (s, 2H), 2.50 (s, 5H), 1.60 (d, J = 5.6 Hz, 4H), 1.42 (d, J = 5.1 Hz, 2H).¹³ C NMR (101 MHz, CDCl₃ ) δ 167.48, 165.56, 157.66, 155.87, 154.29, 149.07, 148.35, 147.89, 137.78, 128.85, 128.60, 126.60, 124.55, 122.28, 119.92, 119.80, 112.56, 107.05, 103.75, 97.20, 63.54, 57.75, 55.88, 53.48, 25.67, 24.10. High resolution mass spectrometry HRMS (ESI) m/z calculated value [M+H]⁺ 547.2224, found value 547.2161.

实施例14Example 14

(2-((5-氯-2-((2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷(2-((5-chloro-2-((2-methoxy-4-((2-(2-(piperidin-1-yl)ethoxy)pyridin-4-yl)oxy)oxy)benzene base)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

合成方法参考实施例2，产率40.3％，核磁表征及高分辨质谱数据如下：¹H NMR(400MHz,Chloroform-d)δ10.79(s,1H),8.49(dd,J＝8.5,4.4Hz,1H),8.27(d,J＝9.5Hz,1H),8.04(s,1H),7.92(d,J＝5.9Hz,1H),7.44(s,2H),7.22(ddd,J＝14.0,7.7,1.6Hz,1H),7.06(dd,J＝7.6,2.2Hz,1H),6.57(d,J＝6.7Hz,2H),6.47(dd,J＝5.7,2.2Hz,1H),6.13(d,J＝2.2Hz,1H),4.36(d,J＝5.9Hz,2H),3.78(s,3H),2.69(s,3H),2.45(s,4H),1.76(d,J＝13.1Hz,6H),1.53(d,J＝5.6Hz,5H),1.35(s,2H).¹³C NMR(101MHz,CDCl₃)δ167.72,164.43,157.34,155.99,154.80,149.27,148.28,147.94,147.78,143.62,132.23,129.72,126.80,123.08,122.70,121.07,119.89,112.45,107.64,106.93,103.83,97.11,61.12,56.51,55.97,53.92,23.42,22.42,18.92,18.21.高分辨质谱HRMS(ESI)m/z计算值[M+H]⁺623.2302，实测值623.2257。The synthesis method refers to Example 2. The yield is 40.3%. The NMR characterization and high-resolution mass spectrometry data are as follows:¹ H NMR (400MHz, Chloroform-d) δ10.79 (s, 1H), 8.49 (dd, J=8.5, 4.4Hz ,1H),8.27(d,J＝9.5Hz,1H),8.04(s,1H),7.92(d,J＝5.9Hz,1H),7.44(s,2H),7.22(ddd,J＝14.0, 7.7,1.6Hz,1H),7.06(dd,J＝7.6,2.2Hz,1H),6.57(d,J＝6.7Hz,2H),6.47(dd,J＝5.7,2.2Hz,1H),6.13( d,J＝2.2Hz,1H),4.36(d,J＝5.9Hz,2H),3.78(s,3H),2.69(s,3H),2.45(s,4H),1.76(d,J＝13.1 Hz, 6H), 1.53 (d, J = 5.6Hz, 5H), 1.35 (s, 2H).¹³ C NMR (101MHz, CDCl₃ ) δ 167.72, 164.43, 157.34, 155.99, 154.80, 149.27, 148.28, 147.94, 147.78 ,143.62,132.23,129.72,126.80,123.08,122.70,121.07,119.89,112.45,107.64,106.93,103.83,97.11,61.12,56.51,55.97,53.92,23.42,22 .42,18.92,18.21. High-resolution mass spectrometry HRMS (ESI) Calculated m/z value [M+H]⁺ 623.2302, measured value 623.2257.

实施例15Example 15

(6-((5-氯-2-((2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷(6-((5-chloro-2-((2-methoxy-4-((2-(2-(piperidin-1-yl)ethoxy)pyridin-4-yl)oxy)oxy)benzene base)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

合成方法参考实施例3，产率42.5％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ12.76(s,1H),9.14(dd,J＝9.5,4.1Hz,1H),8.79–8.69(m,2H),8.32(d,J＝8.4Hz,1H),8.20(s,1H),8.16–8.12(m,1H),7.99(d,J＝6.0Hz,1H),7.51(s,1H),6.66(d,J＝8.1Hz,2H),6.54(dd,J＝5.8,2.1Hz,1H),6.18(d,J＝2.2Hz,1H),4.42(t,J＝5.9Hz,3H),3.87(s,3H),3.64(s,3H),2.76(s,3H),2.52(s,5H),2.13(d,J＝14.3Hz,6H),1.62–1.57(m,5H),1.43(d,J＝6.0Hz,3H).¹³C NMR(101MHz,CDCl₃)δ167.43,165.47,157.24,155.90,155.81,149.31,148.91,148.71,147.94,143.81,143.34,142.97,139.28,132.99,126.83,126.47,119.91,112.61,108.01,107.11,103.99,97.25,63.31,57.60,55.97,54.66,25.47,23.96,20.77,20.04.The synthesis method is as shown in Example 3, with a yield of 42.5%. The nuclear magnetic resonance characterization data are as follows:¹ H NMR (400 MHz, Chloroform-d) δ12.76 (s, 1H), 9.14 (dd, J = 9.5, 4.1 Hz, 1H), 8.79-8.69 (m, 2H), 8.32 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H), 8.16-8.12 (m, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 6.66 (d, J = 8.1H z, 2H), 6.54 (dd, J = 5.8, 2.1 Hz, 1H), 6.18 (d, J = 2.2 Hz, 1H), 4.42 (t, J = 5.9 Hz, 3H), 3.87 (s, 3H), 3.64 (s, 3H), 2.76 (s, 3H), 2.52 (s, 5H), 2.13 (d, J = 14.3 Hz, 6H), 1.62–1.57 (m, 5H), 1.43 (d, J = 6.0 Hz, 3H).¹³ C NMR (101 MHz, CDCl₃ ) δ 167.43, 165.47, 157.24, 155.90, 155.81, 149.31, 148.91, 148.71, 147.94, 143.81, 143.34, 142.97, 139.28, 132.99, 126.83, 126.47, 119.91, 112.61, 108.01, 107.11, 103.99, 97.25, 63.31, 57.60, 55.97, 54.66, 25.47, 23.96, 20.77, 20.04.

实施例16Example 16

5-氯-N⁴-(1-(乙基磺酰基)-1H-吲哚-3-基)-N²-(2-甲氧基-4-((2-(2-(哌啶-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺5-Chloro-N⁴ -(1-(ethylsulfonyl)-1H-indol-3-yl)-N² -(2-methoxy-4-((2-(2-(piperidine- 1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)pyrimidine-2,4-diamine

合成方法参考实施例4，产率38.8％，核磁表征数据如下：：¹H NMR(400MHz,Chloroform-d)δ8.49–8.44(m,2H),8.40–8.36(m,2H),7.98–7.93(m,2H),7.76(s,1H),7.39(dddd,J＝28.0,8.2,7.2,1.2Hz,2H),6.67(dd,J＝4.6,2.3Hz,2H),6.57(dd,J＝5.9,2.1Hz,1H),6.19(d,J＝2.1Hz,1H),4.76(t,J＝5.0Hz,2H),3.90(s,3H),3.42(q,J＝7.3Hz,2H),3.27(t,J＝5.0Hz,2H),3.06(s,3H),1.96(s,4H),1.58(s,2H),1.28(d,J＝7.3Hz,3H).¹³C NMR(101MHz,CDCl₃)δ167.68,164.30,158.17,157.89,156.99,149.33,148.66,148.00,134.87,130.45,128.71,126.46,125.55,124.03,123.32,119.66,118.21,116.49,112.95,112.66,107.79,103.89,97.21,60.80,56.35,56.06,53.82,49.03,23.14,22.24,8.11.The synthesis method refers to Example 4, the yield is 38.8%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ8.49–8.44(m,2H),8.40–8.36(m,2H),7.98– 7.93(m,2H),7.76(s,1H),7.39(dddd,J＝28.0,8.2,7.2,1.2Hz,2H),6.67(dd,J＝4.6,2.3Hz,2H),6.57(dd, J＝5.9,2.1Hz,1H),6.19(d,J＝2.1Hz,1H),4.76(t,J＝5.0Hz,2H),3.90(s,3H),3.42(q,J＝7.3Hz,¹³ C NMR (101MHz, CDCl₃ ) δ167.68,164.30,158.17,157.89,156.99,149.33,148.66,148.00,134.87,130.45,128.71,126.46,125.55,124.03,123.32,119.6 6,118.21,116.49,112.95,112.66,107.79,103.89 ,97.21,60.80,56.35,56.06,53.82,49.03,23.14,22.24,8.11.

实施例17Example 17

(2-((5-溴-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)胺基)嘧啶-4-基)胺基)苯基)二甲基氧磷(2-((5-bromo-2-((2-methoxy-4-((2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-yl)oxy)oxy)benzene base)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

合成方法参考实施例10，产率38.8％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ10.62(s,1H),8.45(dd,J＝8.5,4.3Hz,1H),8.34(d,J＝8.6Hz,1H),8.24–8.20(m,1H),7.97(d,J＝5.9Hz,1H),7.54–7.45(m,2H),7.34–7.26(m,1H),7.16–7.06(m,1H),6.65–6.58(m,2H),6.55(dd,J＝5.9,2.2Hz,1H),6.19(s,1H),4.56(t,J＝5.4Hz,2H),3.86(s,3H),3.09(d,J＝5.9Hz,2H),2.90(s,4H),1.91(s,4H),1.83(d,J＝13.1Hz,6H).¹³CNMR(101MHz,CDCl₃)δ167.61,165.02,157.92,157.84,156.80,149.16,148.31,147.90,143.57,143.55,132.16,132.13,129.58,129.48,126.73,123.69,123.62,122.98,122.86,121.64,120.69,119.80,112.53,107.40,103.84,97.22,95.45,63.35,55.95,54.51,54.34,23.38,18.80,18.09,0.99.The synthesis method refers to Example 10, the yield is 38.8%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ10.62 (s, 1H), 8.45 (dd, J=8.5, 4.3Hz, 1H), 8.34(d,J＝8.6Hz,1H),8.24–8.20(m,1H),7.97(d,J＝5.9Hz,1H),7.54–7.45(m,2H),7.34–7.26(m,1H) ,7.16–7.06(m,1H),6.65–6.58(m,2H),6.55(dd,J＝5.9,2.2Hz,1H),6.19(s,1H),4.56(t,J＝5.4Hz,2H ),3.86(s,3H),3.09(d,J＝5.9Hz,2H),2.90(s,4H),1.91(s,4H),1.83(d,J＝13.1Hz,6H).¹³ CNMR( 101MHz, CDCl₃ )δ167.61,165.02,157.92,157.84,156.80,149.16,148.31,147.90,143.57,143.55,132.16,132.13,129.58,129.48,126.73,123.69, 123.62,122.98,122.86,121.64,120.69,119.80,112.53 ,107.40,103.84,97.22,95.45,63.35,55.95,54.51,54.34,23.38,18.80,18.09,0.99.

实施例18Example 18

(6-((5-溴-2-((2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)氨基)嘧啶-4-基)氨基)喹喔啉-5-基)二甲基氧磷(6-((5-bromo-2-((2-methoxy-4-((2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine

合成方法参考实施例11，产率35.6％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ12.57(s,1H),8.98(dd,J＝9.5,4.1Hz,1H),8.73(dd,J＝14.8,1.9Hz,2H),8.29(s,2H),8.12(d,J＝9.5Hz,1H),7.97(d,J＝5.9Hz,1H),7.53(s,1H),6.62(d,J＝7.6Hz,2H),6.54(dd,J＝5.9,2.2Hz,1H),6.18(d,J＝2.2Hz,1H),4.53(t,J＝5.5Hz,2H),3.86(s,3H),3.05(t,J＝5.6Hz,2H),2.85(s,4H),2.12(d,J＝14.3Hz,6H),1.88(s,4H).¹³CNMR(101MHz,CDCl₃)δ167.52,165.09,158.76,157.67,156.75,149.25,148.93,148.91,148.58,147.92,143.86,143.81,143.32,142.99,139.34,139.27,132.75,132.73,127.12,127.03,126.47,119.81,112.77,112.60,111.87,107.34,103.96,97.26,96.61,63.54,55.98,54.58,54.35,23.38,20.77,20.04.The synthesis method refers to Example 11, the yield is 35.6%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ12.57 (s, 1H), 8.98 (dd, J=9.5, 4.1Hz, 1H), 8.73(dd,J＝14.8,1.9Hz,2H),8.29(s,2H),8.12(d,J＝9.5Hz,1H),7.97(d,J＝5.9Hz,1H),7.53(s,1H ),6.62(d,J＝7.6Hz,2H),6.54(dd,J＝5.9,2.2Hz,1H),6.18(d,J＝2.2Hz,1H),4.53(t,J＝5.5Hz,2H ),3.86(s,3H),3.05(t,J＝5.6Hz,2H),2.85(s,4H),2.12(d,J＝14.3Hz,6H),1.88(s,4H).¹³ CNMR( 101MHz, CDCl₃ )δ167.52,165.09,158.76,157.67,156.75,149.25,148.93,148.91,148.58,147.92,143.86,143.81,143.32,142.99,139.34,139.27, 132.75,132.73,127.12,127.03,126.47,119.81,112.77 ,112.60,111.87,107.34,103.96,97.26,96.61,63.54,55.98,54.58,54.35,23.38,20.77,20.04.

实施例19Example 19

5-溴-N⁴-(1-(乙基磺酰基)-1H-吲哚-3-基)-N²-(2-甲氧基-4-((2-(2-(吡咯烷-1-基)乙氧基)吡啶-4-基)氧基)苯基)嘧啶-2,4-二胺5-Bromo-N⁴ -(1-(ethylsulfonyl)-1H-indol-3-yl)-N² -(2-methoxy-4-((2-(2-(pyrrolidine- 1-yl)ethoxy)pyridin-4-yl)oxy)phenyl)pyrimidine-2,4-diamine

合成方法参考实施例12，产率37.1％，核磁表征数据如下：¹H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.47(d,J＝8.5Hz,1H),8.38(s,1H),8.26(d,J＝7.9Hz,1H),8.00–7.91(m,2H),7.79(s,1H),7.38(d,J＝28.2Hz,2H),6.65(d,J＝9.7Hz,2H),6.56(dd,J＝5.8,2.0Hz,1H),6.20(d,J＝2.1Hz,1H),4.83–4.69(m,2H),3.89(s,3H),3.42(t,J＝7.1Hz,4H),3.32(s,2H),2.09(d,J＝3.4Hz,4H),1.28(t,J＝7.4Hz,3H).¹³C NMR(101MHz,CDCl₃)δ167.67,164.20,160.79,158.34,158.26,149.31,148.67,147.97,134.89,130.11,128.71,126.40,125.51,123.99,123.03,119.62,117.65,112.99,112.64,107.86,107.04,103.88,97.30,61.31,56.08,54.18,53.80,49.02,23.27,8.14.The synthesis method refers to Example 12, the yield is 37.1%, and the nuclear magnetic characterization data are as follows:¹ H NMR (400MHz, Chloroform-d) δ8.58 (s, 1H), 8.47 (d, J = 8.5Hz, 1H), 8.38 ( s,1H),8.26(d,J＝7.9Hz,1H),8.00–7.91(m,2H),7.79(s,1H),7.38(d,J＝28.2Hz,2H),6.65(d,J ＝9.7Hz,2H),6.56(dd,J＝5.8,2.0Hz,1H),6.20(d,J＝2.1Hz,1H),4.83–4.69(m,2H),3.89(s,3H),3.42 (t, J＝7.1Hz, 4H), 3.32 (s, 2H), 2.09 (d, J＝3.4Hz, 4H), 1.28 (t, J＝7.4Hz, 3H).¹³ C NMR (101MHz, CDCl₃ )δ167.67,164.20,160.79,158.34,158.26,149.31,148.67,147.97,134.89,130.11,128.71,126.40,125.51,123.99,123.03,119.62,117.65,112 .99,112.64,107.86,107.04,103.88,97.30,61.31,56.08 ,54.18,53.80,49.02,23.27,8.14.

测试例1、MTT法细胞增殖抑制活性测试Test Example 1: MTT method cell proliferation inhibition activity test

体外细胞增殖抑制实验采用MTT法，采用以下5种细胞系：BaF3_EGFR^dTC(dTC代表del19/T790M/C797S三突变)、BaF3_EGFR^LTC(LTC代表L8585R/T790M/C797S三突变)、H1975(EGFR的L858R/T790M突变型)、H820(EGFR的del19/T790M突变型)、A549(EGFR野生型)。The in vitro cell proliferation inhibition experiment used the MTT method and used the following five cell lines: BaF3_EGFR^dTC (dTC represents the del19/T790M/C797S triple mutation), BaF3_EGFR^LTC (LTC represents the L8585R/T790M/C797S triple mutation), H1975 (the L858R/EGFR triple mutation) T790M mutant), H820 (del19/T790M mutant of EGFR), A549 (EGFR wild type).

其中两类BaF3细胞为悬浮细胞，用含有10％胎牛血清(体积分数)及1％的puro的PRIM-1640培养液，在37℃乙基5％的CO₂(体积分数)条件下常规培养。。Two types of BaF3 cells were suspension cells, cultured in PRIM-1640 medium containing 10% fetal bovine serum (volume fraction) and 1% puro, at 37°C and 5% CO₂ (volume fraction).

其他为贴壁细胞，其中A549用含体积分数为10％胎牛血清的F12K培养液，H1975和H820采用10％胎牛血清的PRIM-1640培养液。Others are adherent cells, of which A549 uses F12K culture medium containing 10% fetal bovine serum, and H1975 and H820 use PRIM-1640 culture medium containing 10% fetal bovine serum.

具体操作如下：The specific operations are as follows:

将所有化合物配置成浓度为10mM的DMSO(二甲基亚砜)溶液，然后通过梯度稀释法得到一系列浓度逐渐降低的化合物溶液。All compounds were prepared into DMSO (dimethyl sulfoxide) solutions with a concentration of 10 mM, and then a series of compound solutions with gradually decreasing concentrations were obtained by gradient dilution.

培养细胞，取对数期的细胞，计数后将肿瘤细胞以每孔1.2×10⁴-1.5×10⁴个(悬浮细胞)或者6×10³-9×10³个(贴壁细胞)的密度稀释，之后加入99μL含有细胞的培养基接种于96孔板中。接下来是加药步骤，对于悬浮细胞，铺板4小时后进行加药；对于贴壁细胞，则需细胞贴壁后加药，一般为铺板后12-16小时加药。之后每孔加1μL的化合物溶液，因此化合物终浓度相当于原浓度稀释100倍，每个浓度设置3个复孔，IC₅₀测试时设置8～9个浓度梯度。同时实验加入两个阳性药组，分别是第一代EGFR抑制剂Gefinitinb和具有三突变EGFR抑制活性的Brigatinib；以及设置对照组和空白组，都是加入1μL的纯DMSO溶液。所有处理后的细胞培养3天后，向化合物组和对照组每孔加入10μL的5mg/mL的MTT的PBS溶液，空白组则不加。然后继续培养4小时。之后悬浮细胞的需线进行离心处理，而贴壁细胞则无须离心；吸除每孔的培养基，再加入100μL的DMSO溶液；之后分别在微量振荡器上振荡5分钟及摇床上摇5分钟；最后使用酶标仪测试490nm处OD值，从而计算处不同浓度下化合物对肿瘤细胞的抑制率(Inh％)，再通过绘制抑制率-浓度曲线获得IC₅₀值。测试结果如表1所示，可以看到大部分化合物都具有一定的肿瘤细胞抑制活性，其中11、12、17、18等化合物表现较好，对大部分肿瘤细胞都有不错的抑制活性，其IC₅₀值达到了微摩尔级。Culture the cells, take the cells in the logarithmic phase, and count the tumor cells at a density of 1.2×10⁴ -1.5×10⁴ (suspended cells) or 6×10³ -9×10³ (adherent cells) per well. After dilution, 99 μL of culture medium containing cells was added and seeded in a 96-well plate. The next step is to add the drug. For suspended cells, add the drug 4 hours after plating; for adherent cells, add the drug after the cells adhere, usually 12-16 hours after plating. Then add 1 μL of compound solution to each well, so the final concentration of the compound is equivalent to diluting 100 times the original concentration. Three duplicate wells are set for each concentration. 8 to 9 concentration gradients are set for the IC₅₀ test. At the same time, two positive drug groups were added to the experiment, namely the first-generation EGFR inhibitor Gefinitinb and Brigatinib with triple-mutant EGFR inhibitory activity; and a control group and a blank group were set up, both of which added 1 μL of pure DMSO solution. After all treated cells were cultured for 3 days, 10 μL of 5 mg/mL MTT in PBS solution was added to each well of the compound group and control group, but not to the blank group. Then continue culturing for 4 hours. After that, the suspended cells need to be centrifuged, but the adherent cells do not need to be centrifuged; aspirate the culture medium from each well, and then add 100 μL of DMSO solution; then shake for 5 minutes on a micro shaker and 5 minutes on a shaker; Finally, use a microplate reader to test the OD value at 490 nm to calculate the inhibitory rate (Inh%) of the compound on tumor cells at different concentrations, and then obtain the IC₅₀ value by drawing the inhibition rate-concentration curve. The test results are shown in Table 1. It can be seen that most compounds have a certain inhibitory activity on tumor cells. Among them, compounds such as 11, 12, 17, and 18 perform better and have good inhibitory activity against most tumor cells. The IC₅₀ value reaches the micromolar level.

抑制率公式如下：Inh％＝(对照组OD₄₉₀-实验组OD₄₉₀)/(对照组OD₄₉₀-空白组OD₄₉₀)×100％。The inhibition rate formula is as follows: Inh% = (OD₄₉₀ of the control group - OD₄₉₀ of the experimental group)/(OD₄₉₀ of the control group - OD₄₉₀ of the blank group) × 100%.

实验后获得了本发明制备的化合物的体外细胞增殖抑制活性，结果如表1、表2所示。After the experiment, the in vitro cell proliferation inhibitory activity of the compound prepared by the present invention was obtained. The results are shown in Table 1 and Table 2.

表1实施例制备的化合物的体外肿瘤细胞增殖抑制活性Table 1 In vitro tumor cell proliferation inhibitory activity of the compounds prepared in Examples

表2部分实施例制备的化合物的体外肿瘤细胞增殖抑制活性Table 2 In vitro tumor cell proliferation inhibitory activity of compounds prepared in some examples

注：IC₅₀表示半数抑制浓度Note: IC₅₀ represents the half inhibitory concentration

测试例2、EGFR酶抑制活性实验Test Example 2, EGFR enzyme inhibitory activity experiment

以EGFR为研究对象，测试化合物对L858R/T790M/C797S的亚型以及野生型的抑制活性，该项测试与上海睿智化学研究有限公司负责和桑迪亚医药技术(上海)有限责任公司都有合作，采用了Mobility Shift Assay方法(仪器迁移率改变法)。基本操作流程如下：首先将化合物用缓冲液配置成化合物溶液，并转移至微孔板中；用缓冲液配置激酶溶液，往化合物租、阳性对照租加入激酶溶液，阴性对照组加入缓冲液；室温下反应10分钟；用缓冲液将ATP和底物配置成混合液，再滴入各组中；室温下再反应60分钟；用缓冲液配置反应终止液，并加入各组中；使用Caliper仪器读取数据，计算抑制率。Taking EGFR as the research object, the inhibitory activity of compounds against L858R/T790M/C797S isoforms and wild type was tested. This test was conducted in cooperation with Shanghai Ruizhi Chemical Research Co., Ltd. and Sandia Pharmaceutical Technology (Shanghai) Co., Ltd. , using the Mobility Shift Assay method (instrumental mobility change method). The basic operation process is as follows: first, use buffer to prepare the compound solution and transfer it to the microplate; use buffer to prepare the kinase solution, add the kinase solution to the compound and positive control, and add buffer to the negative control; room temperature React at room temperature for 10 minutes; use buffer to prepare a mixture of ATP and substrate, and drop it into each group; react at room temperature for another 60 minutes; use buffer to prepare a reaction stop solution, and add it to each group; use a Caliper instrument to read Get the data and calculate the inhibition rate.

表3所有实施例的EGFR^LTC酶抑制活性Table 3 EGFR^LTC enzyme inhibitory activity of all examples

表4部分实施例的EGFR^wt酶抑制活性Table 4 EGFR^wt enzyme inhibitory activity of some examples

表5部分实施例的EGFR^LTC酶抑制活性Table 5 EGFR^LTC enzyme inhibitory activity of some examples

测试例3、ALK酶抑制活性实验Test Example 3, ALK enzyme inhibitory activity experiment

该项ALK抑制活性测试与桑迪亚医药技术(上海)有限责任公司合作，采用了Mobility Shift Assay方法(仪器迁移率改变法)对ALK靶点抑制活性进行测试。测试方法与EGFR酶抑制活性测试基本一致。This ALK inhibitory activity test was conducted in cooperation with Sandia Pharmaceutical Technology (Shanghai) Co., Ltd., and the Mobility Shift Assay method (instrument mobility change method) was used to test the ALK target inhibitory activity. The test method is basically consistent with the EGFR enzyme inhibitory activity test.

表6实施例的ALK酶抑制活性ALK enzyme inhibitory activity of Table 6 Examples

以上已经描述了本发明的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。The embodiments of the present invention have been described above. The above description is illustrative, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims (9)

1. 2-anilinopyrimidine derivatives or pharmaceutically acceptable salts thereof, wherein the 2-anilinopyrimidine derivatives are compounds shown in a formula I;

the compound shown in the formula I is selected from any one of the following:

。

2. the 2-anilinopyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;

the inorganic acid salt is selected from any one of the following inorganic acid salts: hydrochloric acid, sulfuric acid, and phosphoric acid;

the organic acid salt is selected from any one of the following organic acid salts: acetic acid, trifluoroacetic acid, malonic acid, citric acid and p-toluenesulfonic acid.

3. A process for the preparation of a 2-anilinopyrimidine derivative according to any one of claims 1 to 2, comprising the steps of:

reacting a compound shown in a formula IA with a compound shown in a formula IB in a solvent under an acidic condition to obtain a compound shown in a formula I:

R₁ 、R₂ 、R₃ x, Y and Z are as defined in claim 1.

4. Use of a 2-anilinopyrimidine derivative according to any one of claims 1 to 2 for the preparation of the following products:

1) An Epidermal Growth Factor Receptor (EGFR) inhibitor;

2) Anaplastic Lymphoma Kinase (ALK) inhibitors;

3) Eukaryotic tumor cell proliferation inhibitors;

4) An inhibitor of eukaryotic tumor cell metastasis;

5) An angiogenesis inhibitor;

6) A medicament for preventing and/or treating tumors.

5. The use according to claim 4, wherein,

the Epidermal Growth Factor Receptor (EGFR) is EGFR^L858R 、EGFR^del19 、EGFR^L858R/T790M 、EGFR^del19/T790M 、EGFR^{L858R/T790M/C797S} And EGFR (epidermal growth factor receptor)^{del19/T790M/C797S} At least one of (a) and (b);

the Anaplastic Lymphoma Kinase (ALK) is ALK^wt 、ALK^L1196M And at least one of EML 4-ALK;

the eukaryote is a mammal;

the tumor cells are cancer cells; the cancer cells are leukemia cancer cells, lymphoma cells, lung cancer cells, breast cancer cells, ovarian cancer cells, cervical cancer cells, human brain glioma cells, melanin cancer cells, glioblastoma cells, nasopharyngeal cancer cells, liver cancer cells, brain cancer cells, pancreatic cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, stomach cancer cells, colon cancer cells, bladder cancer cells or rectal cancer cells;

the tumor is a carcinoma.

6. The use according to claim 5, wherein,

the leukemia cancer cells are human Chronic Myelogenous Leukemia (CML) cell line K562;

the lymphoma cell is human histiocyte lymphoma cell U937;

the lung cancer cell is a human lung cancer cell strain HCC827;

the breast cancer cells are human breast cancer cells MCF-7, T47D and MDA-MB-231;

the ovarian cancer cell is A2780;

the cervical cancer cells are human cervical cancer cell line Hela;

the human brain glioma cell is U251;

the melanocyte is A375;

the glioblastoma cells are human glioblastoma cell A172 and human brain astrocyte tumor cell U-118MG;

the nasopharyngeal carcinoma cell is a nasopharyngeal carcinoma cell line CNE-2;

the liver cancer cell is human liver cancer cell HepG2;

the cancer is leukemia, lymphoma, lung cancer, melanin cancer, glioblastoma, cervical cancer, nasopharyngeal cancer, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, gastric cancer, colon cancer, bladder cancer or rectal cancer.

7. A product comprising the 2-anilinopyrimidine derivative according to any one of claims 1 to 2 as an active ingredient; the product is at least one of the following:

1) An Epidermal Growth Factor Receptor (EGFR) inhibitor;

2) Anaplastic Lymphoma Kinase (ALK) inhibitors;

3) Eukaryotic tumor cell proliferation inhibitors;

4) An inhibitor of eukaryotic tumor cell metastasis;

5) An angiogenesis inhibitor;

6) A medicament for preventing and/or treating tumors.

8. The product of claim 7, wherein,

the Epidermal Growth Factor Receptor (EGFR) is EGFR^L858R 、EGFR^del19 、EGFR^L858R/T790M 、EGFR^del19/T790M 、EGFR^{L858R/T790M/C797S} And EGFR (epidermal growth factor receptor)^{del19/T790M/C797S} At least one of (a) and (b);

the Anaplastic Lymphoma Kinase (ALK) is ALK^wt 、ALK^L1196M And at least one of EML 4-ALK;

the eukaryote is a mammal;

the tumor cells are cancer cells; the cancer cells are leukemia cancer cells, lymphoma cells, lung cancer cells, breast cancer cells, ovarian cancer cells, cervical cancer cells, human brain glioma cells, melanin cancer cells, glioblastoma cells, nasopharyngeal cancer cells, liver cancer cells, brain cancer cells, pancreatic cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, stomach cancer cells, colon cancer cells, bladder cancer cells or rectal cancer cells;

the tumor is a carcinoma.

9. The product of claim 8, wherein,

the leukemia cancer cells are human Chronic Myelogenous Leukemia (CML) cell line K562;

the lymphoma cell is human histiocyte lymphoma cell U937;

the lung cancer cell is a human lung cancer cell strain HCC827;

the breast cancer cells are human breast cancer cells MCF-7, T47D and MDA-MB-231;

the ovarian cancer cell is A2780;

the cervical cancer cells are human cervical cancer cell line Hela;

the human brain glioma cell is U251;

the melanocyte is A375;

the glioblastoma cells are human glioblastoma cell A172 and human brain astrocyte tumor cell U-118MG;

the nasopharyngeal carcinoma cell is a nasopharyngeal carcinoma cell line CNE-2;

the liver cancer cell is human liver cancer cell HepG2;

the cancer is leukemia, lymphoma, lung cancer, melanin cancer, glioblastoma, cervical cancer, nasopharyngeal cancer, liver cancer, breast cancer, brain cancer, pancreatic cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, gastric cancer, colon cancer, bladder cancer or rectal cancer.