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CN104844580B - Pyrimidines, its preparation method and medical usage - Google Patents

Pyrimidines, its preparation method and medical usage Download PDF

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CN104844580B
CN104844580B CN201510184234.0A CN201510184234A CN104844580B CN 104844580 B CN104844580 B CN 104844580B CN 201510184234 A CN201510184234 A CN 201510184234A CN 104844580 B CN104844580 B CN 104844580B
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amido
methyl
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pyrimidine
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CN104844580A (en
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赖宜生
杨凤娇
马骏
罗明昊
张姗
张奕华
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China Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

本发明属于药物领域，具体涉及一种具有式(I)结构特征的嘧啶类化合物、其立体异构体或其药学上可接受的盐、它们的制备方法以及在制备抗肿瘤药物中的应用。药理实验结果表明，该类化合物对表皮生长因子受体(EGFR)及其突变体具有良好的抑制作用，并且可以抑制多种肿瘤细胞的增殖，因此可作为EGFR抑制剂用于制备抗肿瘤药物。 The invention belongs to the field of medicines, and specifically relates to a pyrimidine compound having the structural characteristics of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, their preparation method and their application in the preparation of antitumor drugs. The results of pharmacological experiments show that the compounds have a good inhibitory effect on epidermal growth factor receptor (EGFR) and its mutants, and can inhibit the proliferation of various tumor cells, so they can be used as EGFR inhibitors for the preparation of antitumor drugs.

Description

嘧啶类化合物、其制备方法及医药用途Pyrimidine compound, its preparation method and medical application

技术领域technical field

本发明属于药物领域，具体涉及一种嘧啶类化合物、其制备方法以及医药用途，特别是在制备抗肿瘤药物中的应用。The invention belongs to the field of medicines, and in particular relates to a pyrimidine compound, its preparation method and medical application, especially the application in the preparation of antitumor drugs.

背景技术Background technique

蛋白酪氨酸激酶是细胞信号转导通路中的重要调控因子，在已知的518种蛋白激酶中，90种属于蛋白酪氨酸激酶。它能催化ATP上γ-磷酸转移到底物蛋白的酪氨酸残基上，促使激酶由非活化构象转变成活化构象，从而激活下游信号分子，进一步引发细胞的多种生物效应，在细胞生长、增殖、分化等过程中起着重要的作用(Oncogene，2000，19(49)：5548-5557)。在正常细胞中，蛋白酪氨酸激酶的催化活性受到严格的调控，但当其基因发生突变或其它变异时，酪氨酸激酶的功能便会因此失调，从而导致细胞增殖调节发生紊乱，进而诱导肿瘤的发生与发展。因此，近年来蛋白酪氨酸激酶已成为肿瘤分子靶向治疗的热门靶标。Protein tyrosine kinases are important regulatory factors in cell signal transduction pathways. Among the 518 known protein kinases, 90 belong to protein tyrosine kinases. It can catalyze the transfer of γ-phosphate on ATP to the tyrosine residue of the substrate protein, and promote the transformation of the kinase from an inactive conformation to an activated conformation, thereby activating downstream signaling molecules and further triggering various biological effects of cells. It plays an important role in processes such as proliferation and differentiation (Oncogene, 2000, 19(49): 5548-5557). In normal cells, the catalytic activity of protein tyrosine kinase is strictly regulated, but when its gene is mutated or otherwise altered, the function of tyrosine kinase will be out of balance, which will lead to the disorder of cell proliferation regulation, and then induce Tumor occurrence and development. Therefore, protein tyrosine kinases have become popular targets for tumor molecular targeted therapy in recent years.

表皮生长因子受体(EGFR)是一类重要的蛋白酪氨酸激酶ErbB家族，该家族包括erbB1(EGFR/HER1)、erbB2(HER2)、erbB3(HER3)、erbB4(HER4)四个成员。当EGFR胞外的受体与配体结合后，引起同源或异源二聚化，然后二聚体发生磷酸化作用，导致胞内酪氨酸激酶区被激活并结合一个ATP分子，促使胞内区的特定酪氨酸残基磷酸化，随后依次识别并结合具有PTB结构域或SH2结构域的接头蛋白(如Cbl、Shc、Grb2、Crk等)，进而激活下游信号分子。EGFR可以通过Ras/MAPK、c-Src和PI3K/Akt等多条信号通路对细胞功能进行调控(EMBOJ，2000，19(13)：3159-3167)。EGFR的功能异常与肺癌、乳腺癌、结肠癌、胃癌、肾癌、卵巢癌、前列腺癌、胶质母细胞瘤等多种肿瘤的发生发展密切相关(Clin Cancer Res，2006，12(18)：5268-5272)。因此，近年来靶向EGFR抗肿瘤药物深受人们关注。Epidermal growth factor receptor (EGFR) is an important protein tyrosine kinase ErbB family, which includes four members: erbB1 (EGFR/HER1), erbB2 (HER2), erbB3 (HER3), and erbB4 (HER4). When the EGFR extracellular receptor binds to the ligand, it causes homologous or heterologous dimerization, and then phosphorylation of the dimer causes the intracellular tyrosine kinase domain to be activated and bind an ATP molecule, prompting the cellular Specific tyrosine residues in the inner region are phosphorylated, and then sequentially recognize and bind adapter proteins with PTB domain or SH2 domain (such as Cbl, Shc, Grb2, Crk, etc.), thereby activating downstream signaling molecules. EGFR can regulate cell function through multiple signaling pathways such as Ras/MAPK, c-Src and PI3K/Akt (EMBOJ, 2000, 19(13): 3159-3167). Abnormal function of EGFR is closely related to the occurrence and development of lung cancer, breast cancer, colon cancer, gastric cancer, kidney cancer, ovarian cancer, prostate cancer, glioblastoma and other tumors (Clin Cancer Res, 2006, 12(18): 5268-5272). Therefore, antitumor drugs targeting EGFR have attracted much attention in recent years.

第一代小分子EGFR抑制剂主要包括吉非替尼(gefitinib)、厄洛替尼(erlotinib)、拉帕替尼(lapatinib)和埃克替尼(icotinib)等。该类可逆的EGFR抑制剂主要是通过竞争性结合于激酶区域的ATP结合口袋，阻止ATP与EGFR结合，从而抑制其磷酸化，阻滞信号转导，进而诱导肿瘤细胞死亡。这些药物在临床治疗非小细胞肺癌、乳腺癌和胰腺癌等肿瘤中疗效突出。然而，临床研究表明，部分肿瘤患者在接受该类药物治疗一段时间后便发生EGFR二次突变和/或Met基因扩增、HGF过度表达等，从而产生获得性耐药(J BiomedBiotechnol，2011：165214)。其中，发生在EGFR激酶区域的T790M突变被认为是主要的耐药机制，该突变会阻碍抑制剂与激酶活性口袋结合，而增强ATP与活性口袋的结合(N Engl JMed，2005，352(8)：786-792；Proc Natl Acad Sci USA，2008，105(6)：2070-2075)。为此，人们开展了不可逆EGFR共价抑制剂研发。The first-generation small-molecule EGFR inhibitors mainly include gefitinib, erlotinib, lapatinib, and icotinib. This type of reversible EGFR inhibitor mainly binds to the ATP binding pocket of the kinase region through competitive binding, preventing ATP from binding to EGFR, thereby inhibiting its phosphorylation, blocking signal transduction, and inducing tumor cell death. These drugs have outstanding curative effects in the clinical treatment of tumors such as non-small cell lung cancer, breast cancer and pancreatic cancer. However, clinical studies have shown that some tumor patients undergo EGFR secondary mutations and/or Met gene amplification, HGF overexpression, etc. after receiving such drugs for a period of time, resulting in acquired drug resistance (J Biomed Biotechnol, 2011: 165214 ). Among them, the T790M mutation occurring in the EGFR kinase region is considered to be the main drug resistance mechanism, which will hinder the binding of the inhibitor to the kinase active pocket and enhance the binding of ATP to the active pocket (N Engl JMed, 2005, 352 (8) : 786-792; Proc Natl Acad Sci USA, 2008, 105(6): 2070-2075). To this end, people have carried out the development of irreversible EGFR covalent inhibitors.

不可逆EGFR抑制剂主要是通过亲电基团与EGFR激酶活性位点附近的Cys797巯基发生Michael加成而共价结合，从而占据ATP的结合口袋，阻止激酶激活。目前已有dacomitinib、neratinib、pelitinib、CO-1686和AZD9291等多个不可逆EGFR共价抑制剂进入临床研究，其中afatinib已于2013年7月被美国FDA批准上市，用于治疗转移性非小细胞肺癌。Irreversible EGFR inhibitors are covalently bound mainly through the Michael addition of the electrophilic group to the Cys797 thiol near the EGFR kinase active site, thereby occupying the ATP binding pocket and preventing kinase activation. At present, several irreversible EGFR covalent inhibitors such as dacomitinib, neratinib, pelitinib, CO-1686 and AZD9291 have entered clinical research, among which afatinib was approved by the US FDA in July 2013 for the treatment of metastatic non-small cell lung cancer .

不可逆抑制剂与靶蛋白发生共价结合虽然通常可以增强药效和延长作用时间，但当其亲电性过强会易于与非靶蛋白的亲核基团发生非特异性共价结合，从而产生脱靶现象。此外，当药物与底物蛋白发生不可逆的共价结合，会导致蛋白质的半抗原化，从而引起自身免疫反应(Chem Res Toxicol，2008，21(1)：84-92；Expert Opin Drug Discov，2012，7(7)：561-581)。Although covalent binding of irreversible inhibitors to target proteins can usually enhance drug efficacy and prolong action time, when their electrophilicity is too strong, they are prone to non-specific covalent binding with nucleophilic groups of non-target proteins, resulting in off-target Phenomenon. In addition, when the drug is irreversibly covalently bound to the substrate protein, it will lead to haptenization of the protein, thereby causing an autoimmune reaction (Chem Res Toxicol, 2008, 21(1): 84-92; Expert Opin Drug Discov, 2012 , 7(7):561-581).

值得一提的是，Taunton小组证实了含有α-氰基-α，β-不饱和羰基的化合物可以与p90核糖体S6蛋白激酶(RSK)发生可逆性共价结合，因此有助于克服或降低不可逆共价药物引发的不良反应(Nat Chem Biol，2012，8(5)：471-476)。It is worth mentioning that the Taunton group confirmed that compounds containing α-cyano-α, β-unsaturated carbonyl can reversibly bind to p90 ribosomal S6 protein kinase (RSK), thus helping to overcome or reduce Adverse reactions induced by irreversible covalent drugs (Nat Chem Biol, 2012, 8(5):471-476).

发明内容Contents of the invention

本发明公开了一种嘧啶类化合物、其立体异构体或其药学上可接受的盐以及医药用途。药理实验结果表明，该类化合物对表皮生长因子受体(EGFR)及其突变体具有良好的抑制活性，并可抑制多种肿瘤细胞的增殖。因此可作为EGFR激酶抑制剂用于制备抗肿瘤药物。The invention discloses a pyrimidine compound, its stereoisomer or its pharmaceutically acceptable salt and its medical use. The results of pharmacological experiments show that the compounds have good inhibitory activity on epidermal growth factor receptor (EGFR) and its mutants, and can inhibit the proliferation of various tumor cells. Therefore, it can be used as an EGFR kinase inhibitor to prepare antitumor drugs.

本发明公开式(I)所示的嘧啶类化合物、其立体异构体或其药学上可接受的盐：The present invention discloses a pyrimidine compound represented by formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:

其中：in:

R1代表C1-C8烷基、C3-C6环烷基、C5-C10芳基或C5-C10芳杂环基，所述的烷基、环烷基、芳基或芳杂环基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自：卤素、氰基、硝基、三氟甲基、C1-C8烷氧基、NR3R4、C(O)NR3R4或C(O)OR5；R 1 represents C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 5 -C 10 aryl or C 5 -C 10 aromatic heterocyclic group, the alkyl, cycloalkyl, aryl Or the aromatic heterocyclic group may be optionally monosubstituted to five substituted by the following identical or different substituents selected from the group consisting of: halogen, cyano, nitro, trifluoromethyl, C 1 -C 8 alkoxy, NR 3 R 4 , C(O)NR 3 R 4 or C(O)OR 5 ;

R2代表氢、卤素、NR3R4或OR5；R 2 represents hydrogen, halogen, NR 3 R 4 or OR 5 ;

R3和R4可相同或不同，任选自：氢、C1-C8烷基、或R3和R4与跟它们连接的氮原子一起形成5-7元杂环基团，该杂环基团可任选地包含一个或多个选自O、S或N的其它杂原子，并且该杂环基团可任选地由下述相同或不同的取代基单取代至五取代，所述取代基选自：卤素、氰基、硝基、羟基、三氟甲基、氨基、C1-C8烷基或C1-C8烷氧基；R 3 and R 4 may be the same or different, optionally selected from: hydrogen, C 1 -C 8 alkyl, or R 3 and R 4 form a 5-7 membered heterocyclic group together with the nitrogen atom attached to them, the heterocyclic group The cyclic group may optionally contain one or more other heteroatoms selected from O, S or N, and the heterocyclic group may optionally be monosubstituted to pentasubstituted by the following same or different substituents, The substituent is selected from: halogen, cyano, nitro, hydroxyl, trifluoromethyl, amino, C 1 -C 8 alkyl or C 1 -C 8 alkoxy;

R5代表氢、C1-C8烷基、C3-C6环烷基、C5-C10芳基或C5-C10芳杂环基，所述的烷基、环烷基、芳基或芳杂环基可任选地被下述相同或不相同的取代基单取代至五取代，所述的取代基选自：卤素、氰基、硝基、羟基、三氟甲基、氨基、C1-C8烷基或C1-C8烷氧基。R 5 represents hydrogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, C 5 -C 10 aryl or C 5 -C 10 aromatic heterocyclic group, said alkyl, cycloalkyl, The aryl or aromatic heterocyclic group may optionally be monosubstituted to pentasubstituted by the following identical or different substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, trifluoromethyl, Amino, C 1 -C 8 alkyl or C 1 -C 8 alkoxy.

进一步地，通式(I)所示的嘧啶类化合物、其立体异构体或其药学上可接受的盐，其特征在于：Further, the pyrimidine compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is characterized in that:

R1代表特戊基、环丙基、苯基、2-甲氧基苯基、4-三氟甲基苯基、吡唑基、吡咯基、咪唑基、呋喃基、吡啶基。R 1 represents p-amyl, cyclopropyl, phenyl, 2-methoxyphenyl, 4-trifluoromethylphenyl, pyrazolyl, pyrrolyl, imidazolyl, furyl, pyridyl.

R2代表N，N，N-三甲基乙二胺基、N-甲基哌嗪基、吗啉基。R 2 represents N,N,N-trimethylethylenediamine, N-methylpiperazinyl, morpholinyl.

具体来说，通式(I)所示的嘧啶类化合物、其立体异构体或其药学上可接受的盐选自下列化合物：Specifically, the pyrimidine compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds:

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-1)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-1);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-2-基)丙烯酰胺(LY-2)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(imidazol-2-yl)acrylamide (LY-2);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(呋喃-2-基)丙烯酰胺(LY-3)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(furan-2-yl)acrylamide (LY-3);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(2-甲氧基苯基)丙烯酰胺(LY-4)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(2-methoxyphenyl)acrylamide (LY-4);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡啶-2-基)丙烯酰胺(LY-5)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(pyridin-2-yl)acrylamide (LY-5);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡唑-3-基)丙烯酰胺(LY-6)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(pyrazol-3-yl)acrylamide (LY-6);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-4-基)丙烯酰胺(LY-7)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(imidazol-4-yl)acrylamide (LY-7);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-苯基丙烯酰胺(LY-8)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-phenylacrylamide (LY-8);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-环丙基丙烯酰胺(LY-9)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-cyclopropylacrylamide (LY-9);

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-特戊基丙烯酰胺(LY-10)；N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Pyrimidin-2-yl]amino]phenyl]-2-cyano-3-pentylacrylamide (LY-10);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-11)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-11);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-2-基)丙烯酰胺(LY-12)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-(imidazol-2-yl)acrylamide (LY-12);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-苯基丙烯酰胺(LY-13)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-phenylacrylamide (LY-13);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡啶-2-基)丙烯酰胺(LY-14)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-(pyridin-2-yl)acrylamide (LY-14);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(4-三氟甲基苯基)丙烯酰胺(LY-15)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-(4-trifluoromethylphenyl)acrylamide (LY-15);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(2-甲氧基苯基)丙烯酰胺(LY-16)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-(2-methoxyphenyl)acrylamide (LY-16);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(呋喃-2-基)丙烯酰胺(LY-17)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-(furan-2-yl)acrylamide (LY-17);

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-18)；N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino ]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-18);

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-2-基)丙烯酰胺(LY-19)；N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Cyano-3-(imidazol-2-yl)acrylamide (LY-19);

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(呋喃-2-基)丙烯酰胺(LY-20)；N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Cyano-3-(furan-2-yl)acrylamide (LY-20);

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(2-甲氧基苯基)丙烯酰胺(LY-21)；N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Cyano-3-(2-methoxyphenyl)acrylamide (LY-21);

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡啶-2-基)丙烯酰胺(LY-22)；N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Cyano-3-(pyridin-2-yl)acrylamide (LY-22);

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡唑-3-基)丙烯酰胺(LY-23)；N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Cyano-3-(pyrazol-3-yl)acrylamide (LY-23);

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-4-基)丙烯酰胺(LY-24)；N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Cyano-3-(imidazol-4-yl)acrylamide (LY-24);

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-环丙基丙烯酰胺(LY-25)。N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Cyano-3-cyclopropylacrylamide (LY-25).

下面药理实验中涉及的化合物代号等同于此处代号所对应的化合物。The compound codes involved in the following pharmacological experiments are equal to the compounds corresponding to the codes here.

本发明的另一目的在于提供通式(I)所示化合物的制备方法，其特征在于：2-硝基-5-氟苯甲醚经还原制得2-甲氧基-4-氟苯胺1，1经硝化得到2-甲氧基-4-氟-5-硝基苯胺2。2，4-二氯嘧啶与N-甲基吲哚在三氯化铝作用下偶联得到1-甲基-3-(2-氯嘧啶-4-基)吲哚3。3与2反应制得1-甲基-3-[[2-(2-甲氧基-4-氟-5-硝基)苯胺基]嘧啶-4-基]吲哚4，4与胺类化合物缩合制得中间体5，5经还原制得中间体6，6与氰基乙酸缩合得到中间体7，7在哌啶乙酸的催化下与醛类化合物缩合得到LY-1～LY-25；合成路线如下：Another object of the present invention is to provide the preparation method of the compound shown in general formula (I), it is characterized in that: 2-nitro-5-fluoroanisole is reduced to obtain 2-methoxy-4-fluoroaniline 1 , 1 is nitrated to obtain 2-methoxy-4-fluoro-5-nitroaniline 2. 2,4-dichloropyrimidine and N-methylindole are coupled under the action of aluminum chloride to obtain 1-methyl -3-(2-Chloropyrimidin-4-yl)indole 3. Reaction of 3 with 2 gives 1-methyl-3-[[2-(2-methoxy-4-fluoro-5-nitro) Anilino]pyrimidin-4-yl]indole 4,4 is condensed with amine compounds to obtain intermediate 5,5 is reduced to obtain intermediate 6,6 is condensed with cyanoacetic acid to obtain intermediate 7,7 is obtained in piperidine acetic acid Condensation with aldehyde compounds under the catalysis of LY-1～LY-25; the synthetic route is as follows:

其中，R1和R2的定义如权利要求1所述。Wherein, R 1 and R 2 are as defined in claim 1.

本发明的进一步目的在于提供一种药物组合物，由治疗上有效量的权利要求1-5中任一项的化合物或其药学上可接受的载体或者辅料组成。A further object of the present invention is to provide a pharmaceutical composition, which consists of a therapeutically effective amount of the compound of any one of claims 1-5 or its pharmaceutically acceptable carrier or adjuvant.

本发明的再一个目的是提供具有通式(I)的化合物或其立体异构体或其药学上可接受的盐以及由它们构成的组合物在抗肿瘤方面的应用，其中所述的肿瘤为非小细胞肺癌、乳腺癌、胃癌、直肠癌、肝癌、前列腺癌、膀胱癌及卵巢癌、头颈部肿瘤或胶质母细胞瘤。Another object of the present invention is to provide the compound with general formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof and the application of the composition composed of them in anti-tumor, wherein said tumor is Non-small cell lung cancer, breast cancer, stomach cancer, rectal cancer, liver cancer, prostate cancer, bladder cancer and ovarian cancer, head and neck cancer or glioblastoma.

所述的化合物包括通式(I)所示化合物的构象异构体、旋光异构体、外消旋体、非对映异构体或互变异构体，以及任何上述形式的混合体。The compound includes conformational isomers, optical isomers, racemates, diastereoisomers or tautomers of the compound represented by the general formula (I), and any mixture of the above forms.

具体实施方式detailed description

为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。In order to further clarify the present invention, a series of examples are given below, these examples are completely illustrative, they are only used to specifically describe the present invention, and should not be construed as limiting the present invention.

实施例1Example 1

2-甲氧基-4-氟苯胺(1)的制备Preparation of 2-methoxy-4-fluoroaniline (1)

将2-硝基-5-氟苯甲醚(1.00g，5.81mmol)和5％钯碳(0.62g，0.29mmol)加入35mLTHF中，室温下通入氢气搅拌5h，抽滤，旋干溶剂，得浅黄色固体0.80g，收率97％。2-nitro-5-fluoroanisole (1.00g, 5.81mmol) and 5% palladium carbon (0.62g, 0.29mmol) were added to 35mLTHF, hydrogen was passed through at room temperature and stirred for 5h, suction filtered, and the solvent was spin-dried. 0.80 g of a light yellow solid was obtained, with a yield of 97%.

2-甲氧基-4-氟-5-硝基苯胺(2)的制备Preparation of 2-methoxy-4-fluoro-5-nitroaniline (2)

冰浴下，将1(1.00g，5.42mmol)分批溶于6.50mL浓硫酸中，分批加入NaNO3(0.46g，5.41mmol)，继续搅拌4小时，2％NaOH溶液调中性，二氯甲烷萃取，旋干溶剂，得橙红色固体0.64g，收率64％。Under ice-cooling, 1 (1.00g, 5.42mmol) was dissolved in 6.50mL concentrated sulfuric acid in batches, NaNO 3 (0.46g, 5.41mmol) was added in batches, and stirring was continued for 4 hours. After extraction with methyl chloride, the solvent was spin-dried to obtain 0.64 g of an orange-red solid, with a yield of 64%.

1-甲基-3-(2-氯嘧啶-4-基)吲哚(3)的制备Preparation of 1-methyl-3-(2-chloropyrimidin-4-yl)indole (3)

将2，4-二氯嘧啶(1.00g，6.71mmol)溶于25mL乙二醇二甲醚中，冰浴冷却，分批加入AlCl3(0.98g，7.42mmol)，控温低于10℃下，加入N-甲基吲哚(0.83mL，6.74mmol)，撤去冰浴，回流反应2h，冷却至室温，倒入200mL冰水中，搅拌30min，抽滤，水洗，乙腈重结晶，干燥得乳白色固体0.88g，收率54％。Dissolve 2,4-dichloropyrimidine (1.00g, 6.71mmol) in 25mL of ethylene glycol dimethyl ether, cool in an ice bath, add AlCl 3 (0.98g, 7.42mmol) in batches, and control the temperature below 10°C , add N-methylindole (0.83mL, 6.74mmol), remove the ice bath, reflux for 2h, cool to room temperature, pour into 200mL of ice water, stir for 30min, filter with suction, wash with water, recrystallize with acetonitrile, and dry to obtain a milky white solid 0.88g, yield 54%.

1-甲基-3-[2-[(2-甲氧基-4-氟-5-硝基)苯胺基]嘧啶-4-基]吲哚(4)的制备Preparation of 1-methyl-3-[2-[(2-methoxy-4-fluoro-5-nitro)anilino]pyrimidin-4-yl]indole (4)

将3(0.90g，3.71mmol)、2(0.69g，3.72mmol)和一水合对甲苯磺酸(0.84g，4.44mmol)溶于30mL仲戊醇中，回流2.5h，冷却至室温，析出黄色固体，抽滤，乙醇洗涤，干燥得黄色固体1.23g，收率85％。Dissolve 3 (0.90g, 3.71mmol), 2 (0.69g, 3.72mmol) and p-toluenesulfonic acid monohydrate (0.84g, 4.44mmol) in 30mL of sec-amyl alcohol, reflux for 2.5h, cool to room temperature, and a yellow color precipitates The solid was suction filtered, washed with ethanol, and dried to obtain 1.23 g of a yellow solid, with a yield of 85%.

1-甲基-3-[[2-[2-甲氧基-4-(N，N，N’-三甲基乙二胺基)-5-硝基]苯胺基]嘧啶-4-基]吲哚(5a)制备1-methyl-3-[[2-[2-methoxy-4-(N,N,N'-trimethylethylenediamine)-5-nitro]anilino]pyrimidin-4-yl ]Indole (5a) preparation

4(0.50mg，1.31mmol)和N，N，N’-三甲基乙二胺(0.16mL，1.30mmol)加入仲丁醇和DIPEA(0.55mL，3.22mmol)，通入N2，回流过夜反应，冷却至室温，抽滤，得红色固体0.48g，收率80％，mp：143～145。ESI-MS：476.4[M+H]+。4 (0.50mg, 1.31mmol) and N,N,N'-trimethylethylenediamine (0.16mL, 1.30mmol) were added with sec-butanol and DIPEA (0.55mL, 3.22mmol), and N 2 was introduced, and the reaction was refluxed overnight , cooled to room temperature, and suction filtered to obtain 0.48 g of a red solid, with a yield of 80%, and mp: 143-145. ESI-MS: 476.4 [M+H] + .

1-甲基-3-[[2-[2-甲氧基-4-(N，N，N’-三甲基乙二胺基)-5-氨基]苯胺基]嘧啶-4-基]吲哚(6a)制备1-methyl-3-[[2-[2-methoxy-4-(N,N,N'-trimethylethylenediamino)-5-amino]anilino]pyrimidin-4-yl] Indole(6a) Preparation

5a(0.50mg，1.13mmol)和5％钯-碳(0.11g，0.06mmol)加入四氢呋喃，通入氢气，室温反应4h，抽滤，旋干滤液得黄色固体590mg，收率98％。5a (0.50mg, 1.13mmol) and 5% palladium-carbon (0.11g, 0.06mmol) were added into tetrahydrofuran, hydrogen was introduced, reacted at room temperature for 4h, suction filtered, and the filtrate was spin-dried to obtain 590mg of a yellow solid, yield 98%.

1-甲基-3-[[2-[2-甲氧基-4-(N，N，N’-三甲基乙二胺基)-5-氰基乙酰胺基]苯胺基]嘧啶-4-基]吲哚吲哚(7a)的制备1-methyl-3-[[2-[2-methoxy-4-(N,N,N'-trimethylethylenediamine)-5-cyanoacetamido]anilino]pyrimidine- Preparation of 4-yl]indole indole (7a)

氰基乙酸(190mg，2.24mmol)、EDC·HCl(859mg，4.48mmol)和6a(0.59g，1.12mmol)加入DMF和DIPEA(1.20mL，6.72mmol)，室温反应4h，加水稀释，超声搅拌，抽滤，水洗干燥得灰白色固体0.45g，收率78％，mp：124～126℃。ESI-MS：513.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.21(s，6H)，2.26(t，2H，J＝6.36Hz)，2.71(s，3H)，2.92(t，2H，J＝6.38Hz)，3.86(s，3H)，3.95(s，3H)，3.96(s，2H)，7.03(s，1H)，7.17(t，1H，J＝7.47Hz)，7.25(d，1H，J＝5.46Hz)，7.27(d，1H，J＝7.86Hz)，7.56(d，1H，J＝7.8Hz)，7.90(s，1H)，8.22(d，1H，J＝7.62Hz)，8.33(d，1H，J＝5.34Hz)，8.67(s，1H)，8.99(s，1H)，10.32(s，1H).Cyanoacetic acid (190mg, 2.24mmol), EDC·HCl (859mg, 4.48mmol) and 6a (0.59g, 1.12mmol) were added to DMF and DIPEA (1.20mL, 6.72mmol), reacted at room temperature for 4h, diluted with water, stirred ultrasonically, Suction filtration, washing with water and drying gave 0.45 g of off-white solid, yield 78%, mp: 124-126°C. ESI-MS: 513.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.21 (s, 6H), 2.26 (t, 2H, J=6.36Hz), 2.71 (s, 3H), 2.92(t, 2H, J=6.38Hz), 3.86(s, 3H), 3.95(s, 3H), 3.96(s, 2H), 7.03(s, 1H), 7.17(t, 1H, J=7.47Hz), 7.25(d, 1H, J=5.46Hz), 7.27(d, 1H, J=7.86Hz), 7.56(d, 1H, J=7.8Hz), 7.90(s, 1H) , 8.22(d, 1H, J=7.62Hz), 8.33(d, 1H, J=5.34Hz), 8.67(s, 1H), 8.99(s, 1H), 10.32(s, 1H).

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-1)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-1)

7(0.03g，0.06mmol)溶于5mL乙腈，加入吡咯甲醛(5.60mg，0.06mmol)和催化量的哌啶醋酸，室温反应4h，加水，搅拌，抽滤干燥得橘色固体0.02g，收率58％，mp：131～133℃。ESI-MS：590.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.12(s，6H)，2.27(s，2H)，2.72(s，3H)，2.98(s，2H)，3.87(s，3H)，3.95(s，3H)，6.47(s，1H)，7.12(s，2H)，7.23(s，2H)，7.37(s，2H)，7.52(d，1H，J＝7.86Hz)，7.95(s，1H)，8.15(s，1H)，8.26(d，1H，J＝7.50Hz)，8.34(d，1H，J＝4.56Hz)，8.59(s，1H)，9.18(s，1H)，10.0(s，1H)，12.01(s，1H).7 (0.03g, 0.06mmol) was dissolved in 5mL of acetonitrile, added pyrrole formaldehyde (5.60mg, 0.06mmol) and a catalytic amount of piperidine acetic acid, reacted at room temperature for 4h, added water, stirred, and dried by suction to obtain 0.02g of an orange solid. Rate 58%, mp: 131-133°C. ESI-MS: 590.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.12(s, 6H), 2.27(s, 2H), 2.72(s, 3H) , 2.98(s, 2H), 3.87(s, 3H), 3.95(s, 3H), 6.47(s, 1H), 7.12(s, 2H), 7.23(s, 2H), 7.37(s, 2H), 7.52(d, 1H, J=7.86Hz), 7.95(s, 1H), 8.15(s, 1H), 8.26(d, 1H, J=7.50Hz), 8.34(d, 1H, J=4.56Hz), 8.59(s, 1H), 9.18(s, 1H), 10.0(s, 1H), 12.01(s, 1H).

实施例2Example 2

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-2-基)丙烯酰胺(LY-2)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(imidazol-2-yl)acrylamide (LY-2)

参照LY-1的制备方法，由7a与咪唑-2-甲醛反应制得黄色粉末状固体，收率73％，mp：137～139℃。ESI-MS：591.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.11(s，6H)，2.28(br，2H)，2.72(s，3H)，2.99(br，2H)，3.88(s，3H)，3.90(s，3H)，7.14(br，2H)，7.24(br，2H)，8.06(br，2H)，8.26(d，1H，J＝6.93Hz)，8.34(m，1H)，8.59(s，1H)，9.19(s，1H)，10.24(br，1H).Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with imidazole-2-carbaldehyde, the yield was 73%, and mp: 137-139°C. ESI-MS: 591.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.11(s, 6H), 2.28(br, 2H), 2.72(s, 3H) , 2.99(br, 2H), 3.88(s, 3H), 3.90(s, 3H), 7.14(br, 2H), 7.24(br, 2H), 8.06(br, 2H), 8.26(d, 1H, J =6.93Hz), 8.34(m, 1H), 8.59(s, 1H), 9.19(s, 1H), 10.24(br, 1H).

实施例3Example 3

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(呋喃-2-基)丙烯酰胺(LY-3)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(furan-2-yl)acrylamide (LY-3)

参照LY-1的制备方法，由7a与呋喃-2-甲醛反应制得黄色粉末状固体，收率81％，mp：174～176℃。ESI-MS：591.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.11(s，6H)，2.45(m，2H)，2.72(s，3H)，2.99(m，2H)，3.88(s，3H)，3.91(s，3H)，6.87(m，1H)，7.14(m，2H)，7.24(m，2H)，7.46(d，1H，J＝3.54Hz)，7.52(d，1H，J＝7.98Hz)，7.99(s，1H)，8.08(s，1H)，8.21(s，1H)，8.26(d，1H，J＝8.10Hz)，8.33(d，1H，J＝5.31Hz)，8.60(s，1H)，9.16(s，1H)，10.26(s，1H).Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with furan-2-carbaldehyde, the yield was 81%, and mp: 174-176°C. ESI-MS: 591.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.11(s, 6H), 2.45(m, 2H), 2.72(s, 3H) , 2.99(m, 2H), 3.88(s, 3H), 3.91(s, 3H), 6.87(m, 1H), 7.14(m, 2H), 7.24(m, 2H), 7.46(d, 1H, J =3.54Hz), 7.52(d, 1H, J=7.98Hz), 7.99(s, 1H), 8.08(s, 1H), 8.21(s, 1H), 8.26(d, 1H, J=8.10Hz), 8.33(d, 1H, J=5.31Hz), 8.60(s, 1H), 9.16(s, 1H), 10.26(s, 1H).

实施例4Example 4

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(2-甲氧基苯基)丙烯酰胺(LY-4)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(2-methoxyphenyl)acrylamide (LY-4)

参照LY-1的制备方法，由7a与2-甲氧基苯甲醛反应制得黄色粉末状固体，收率73％，mp：197～199℃。ESI-MS：631.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.29(s，2H)，2.42(s，2H)，2.98(s，4H)，3.73(s，4H)，3.80(s，3H)，3.87(s，3H)，7.15(br，2H)，7.24(br，2H)，7.49(s，1H)，7.59(s，1H)，7.90(s，1H)，8.01(s，2H)，8.27(s，1H)，8.34(s，1H)，8.60(s，1H)，8.83(s，1H)，9.30(s，1H)，10.01(s，1H).Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with 2-methoxybenzaldehyde, the yield was 73%, and mp: 197-199°C. ESI-MS: 631.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 1.29(s, 2H), 2.42(s, 2H), 2.98(s, 4H) , 3.73(s, 4H), 3.80(s, 3H), 3.87(s, 3H), 7.15(br, 2H), 7.24(br, 2H), 7.49(s, 1H), 7.59(s, 1H), 7.90(s, 1H), 8.01(s, 2H), 8.27(s, 1H), 8.34(s, 1H), 8.60(s, 1H), 8.83(s, 1H), 9.30(s, 1H), 10.01 (s, 1H).

实施例5Example 5

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡啶-2-基)丙烯酰胺(LY-5)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(pyridin-2-yl)acrylamide (LY-5)

参照LY-1的制备方法，由7a与吡啶甲醛反应制得黄色粉末状固体，收率78％，mp：194～196℃。ESI-MS：602.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.11(s，6H)，2.27(br，2H)，2.74(s，3H)，3.00(br，2H)，3.90(s，3H)，3.92(s，3H)，7.16(br s，2H)，7.21～7.28(m，2H)，7.56(d，1H，J＝8.04Hz)，8.00(s，1H)，8.29(m，1H)，8.38(s，1H)，8.56(s，1H)，8.82(s，1H)，9.23(s，1H)，10.34(s，1H).Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with pyridine formaldehyde, the yield was 78%, and mp: 194-196°C. ESI-MS: 602.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.11(s, 6H), 2.27(br, 2H), 2.74(s, 3H) , 3.00(br, 2H), 3.90(s, 3H), 3.92(s, 3H), 7.16(br s, 2H), 7.21～7.28(m, 2H), 7.56(d, 1H, J=8.04Hz) , 8.00(s, 1H), 8.29(m, 1H), 8.38(s, 1H), 8.56(s, 1H), 8.82(s, 1H), 9.23(s, 1H), 10.34(s, 1H).

实施例6Example 6

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡唑-3-基)丙烯酰胺(LY-6)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(pyrazol-3-yl)acrylamide (LY-6)

参照LY-1的制备方法，由7a与吡唑-3-甲醛反应制得黄色粉末状固体，收率73％，mp：223～225℃。ESI-MS：590.3[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.13(s，6H)，2.21(br，2H)，2.74(s，3H)，2.99(br，2H)，3.89(s，3H)，3.93(s，3H)，7.14(br s，2H)，7.16(m，2H)，7.22(d，1H，J＝7.83Hz)，7.25(d，1H，J＝4.65Hz)，7.54(d，1H，J＝7.86Hz)，7.99(d，1H，J＝7.80Hz)，8.22(s，1H)，8.56(d，1H，J＝6.93Hz)，8.35(d，1H，J＝5.19Hz)，8.67(s，1H)，9.19(s，1H)，10.44(s，1H).Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with pyrazole-3-carbaldehyde, the yield was 73%, and mp: 223-225°C. ESI-MS: 590.3[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.13(s, 6H), 2.21(br, 2H), 2.74(s, 3H) , 2.99(br, 2H), 3.89(s, 3H), 3.93(s, 3H), 7.14(br s, 2H), 7.16(m, 2H), 7.22(d, 1H, J=7.83Hz), 7.25 (d, 1H, J=4.65Hz), 7.54(d, 1H, J=7.86Hz), 7.99(d, 1H, J=7.80Hz), 8.22(s, 1H), 8.56(d, 1H, J= 6.93Hz), 8.35(d, 1H, J=5.19Hz), 8.67(s, 1H), 9.19(s, 1H), 10.44(s, 1H).

实施例7Example 7

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-4-基)丙烯酰胺(LY-7)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-(imidazol-4-yl)acrylamide (LY-7)

参照LY-1的制备方法，由7a与咪唑-4-甲醛反应制得黄色粉末状固体，收率65％，mp：210～212℃。ESI-MS：591.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.12(s，6H)，2.26(m，2H)，2.72(s，3H)，2.99(m，2H)，3.87(s，3H)，3.92(s，3H)，7.13～7.16(m，2H)，7.20～7.25(m，1H)，7.52(d，1H，J＝7.68Hz)，7.96(d，1H，J＝5.25Hz)，8.04(s，1H)，8.15(s，1H)，8.25(d，1H，J＝7.77Hz)，8.33(d，1H，J＝5.25Hz)，8.64(s，1H)，9.20(s，1H)，10.14(s，1H).Referring to the preparation method of LY-1, a yellow powdery solid was obtained by reacting 7a with imidazole-4-carbaldehyde, the yield was 65%, and mp: 210-212°C. ESI-MS: 591.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.12(s, 6H), 2.26(m, 2H), 2.72(s, 3H) , 2.99(m, 2H), 3.87(s, 3H), 3.92(s, 3H), 7.13~7.16(m, 2H), 7.20~7.25(m, 1H), 7.52(d, 1H, J=7.68Hz ), 7.96(d, 1H, J=5.25Hz), 8.04(s, 1H), 8.15(s, 1H), 8.25(d, 1H, J=7.77Hz), 8.33(d, 1H, J=5.25Hz ), 8.64(s, 1H), 9.20(s, 1H), 10.14(s, 1H).

实施例8Example 8

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-苯基丙烯酰胺(LY-8)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-phenylacrylamide (LY-8)

参照LY-1的制备方法，由7a与苯甲醛反应制得橙色粉末状固体，收率76％，mp：182～184℃。ESI-MS：601.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.11(s，6H)，2.25～2.27(m，2H)，2.75(s，3H)，2.97～3.01(m，2H)，3.89(s，3H)，3.93(s，3H)，7.15(br s，2H)，7.22(d，1H，J＝8.19Hz)，7.26(d，1H，J＝5.37Hz)，7.99(s，1H)，8.03(d，1H，J＝3.54Hz)，8.05(s，1H)，8.33(s，1H)，8.35(d，1H，J＝5.37Hz)，8.64(s，1H)，9.21(s，1H)，10.42(s，1H).Referring to the preparation method of LY-1, an orange powdery solid was obtained by reacting 7a with benzaldehyde, the yield was 76%, and mp: 182-184°C. ESI-MS: 601.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.11(s, 6H), 2.25～2.27(m, 2H), 2.75(s, 3H), 2.97～3.01(m, 2H), 3.89(s, 3H), 3.93(s, 3H), 7.15(br s, 2H), 7.22(d, 1H, J=8.19Hz), 7.26(d, 1H, J=5.37Hz), 7.99(s, 1H), 8.03(d, 1H, J=3.54Hz), 8.05(s, 1H), 8.33(s, 1H), 8.35(d, 1H, J=5.37 Hz), 8.64(s, 1H), 9.21(s, 1H), 10.42(s, 1H).

实施例9Example 9

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-环丙基丙烯酰胺(LY-9)制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-cyclopropylacrylamide (LY-9)

参照LY-1的制备方法，由7a与环丙甲醛反应制得浅白色固体，收率84％，mp：192～194℃。ESI-MS：564.3[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.13(s，6H)，2.21(m，2H)，2.70(s，3H)，2.95(m，2H)，3.87(s，3H)，3.90(s，3H)，7.09～7.16(m，3H)，7.23～7.29(m，2H)，7.53(d，1H，J＝7.38Hz)，7.96(s，1H)，8.25(d，1H，J＝7.65Hz)，8.32(d，1H，J＝4.89Hz)，8.59(d，1H，J＝7.38Hz)，9.05(s，1H)，10.02(s，1H).Referring to the preparation method of LY-1, a light white solid was obtained by reacting 7a with cyclopropanaldehyde, the yield was 84%, and mp: 192-194°C. ESI-MS: 564.3[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.13(s, 6H), 2.21(m, 2H), 2.70(s, 3H) , 2.95(m, 2H), 3.87(s, 3H), 3.90(s, 3H), 7.09~7.16(m, 3H), 7.23~7.29(m, 2H), 7.53(d, 1H, J=7.38Hz ), 7.96(s, 1H), 8.25(d, 1H, J=7.65Hz), 8.32(d, 1H, J=4.89Hz), 8.59(d, 1H, J=7.38Hz), 9.05(s, 1H ), 10.02(s, 1H).

实施例10Example 10

N-[2-[[2-(二甲胺基)乙基](甲基)胺基]-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-特戊基丙烯酰胺(LY-10)的制备N-[2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) Preparation of pyrimidin-2-yl]amino]phenyl]-2-cyano-3-pentylacrylamide (LY-10)

参照LY-1的制备方法，由7与特戊甲醛反应制得灰色固体，收率83％，mp：109～111℃。ESI-MS：581.5[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.23(s，3H)，1.30(s，3H)，2.13(s，3H)，2.22～2.27(br s，6H)，2.71(s，4H)，3.87～3.92(m，6H)，3.95(br s，3H)，7.03(d，1H，J＝2.79Hz)，7.08～7.24(m，5H)，7.55(d，1H，J＝0.72Hz)，7.57(s，1H)，7.90(d，1H，J＝0.45Hz)，7.95(s，1H)，8.22～8.27(m，2H)，8.34(d，1H，J＝4.05Hz)，8.62(s，1H)，8.67(s，1H)，9.00(s，1H)，9.13(s，1H)，10.18(s，1H)，10.30(br s，1H).Referring to the preparation method of LY-1, a gray solid was obtained by reacting 7 with pivalaldehyde, the yield was 83%, and mp: 109-111°C. ESI-MS: 581.5[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 1.23(s, 3H), 1.30(s, 3H), 2.13(s, 3H) , 2.22～2.27(br s, 6H), 2.71(s, 4H), 3.87～3.92(m, 6H), 3.95(br s, 3H), 7.03(d, 1H, J=2.79Hz), 7.08～7.24 (m, 5H), 7.55(d, 1H, J=0.72Hz), 7.57(s, 1H), 7.90(d, 1H, J=0.45Hz), 7.95(s, 1H), 8.22～8.27(m, 2H), 8.34(d, 1H, J=4.05Hz), 8.62(s, 1H), 8.67(s, 1H), 9.00(s, 1H), 9.13(s, 1H), 10.18(s, 1H), 10.30 (br s, 1H).

实施例11Example 11

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-11)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-11)

1-甲基-3-[2-[[4-(N-甲基哌嗪-1-基)-2-甲氧基-5-硝基]苯胺基]嘧啶-4-基]吲哚(5b)的制备1-methyl-3-[2-[[4-(N-methylpiperazin-1-yl)-2-methoxy-5-nitro]anilino]pyrimidin-4-yl]indole ( 5b) Preparation

参照5a的制备方法，由4与N-甲基哌嗪反应制得红色粉末状固体，收率86％。1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.25(s，3H)，3.08(s，4H)，3.87(s，3H)，4.05(s，3H)，6.84(s，1H)，7.13(t，1H，J＝7.50Hz)，7.23(d，1H，J＝5.73Hz)，7.26(d，1H，J＝8.58Hz)，7.52(d，1H，J＝7.92Hz)，8.18(s，1H)，8.32～8.37(m，3H)，8.78(s，1H)。Referring to the preparation method of 5a, a red powdery solid was prepared by reacting 4 with N-methylpiperazine with a yield of 86%. 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.25(s, 3H), 3.08(s, 4H), 3.87(s, 3H), 4.05(s, 3H), 6.84(s, 1H), 7.13(t, 1H, J=7.50Hz), 7.23(d, 1H, J=5.73Hz), 7.26(d, 1H, J=8.58Hz), 7.52(d, 1H, J=7.92Hz) , 8.18 (s, 1H), 8.32-8.37 (m, 3H), 8.78 (s, 1H).

1-甲基-3-[2-[[4-(N-甲基哌嗪-1-基)-2-甲氧基-5-氨基]苯胺基]嘧啶-4-基]吲哚(6b)的制备1-methyl-3-[2-[[4-(N-methylpiperazin-1-yl)-2-methoxy-5-amino]anilino]pyrimidin-4-yl]indole (6b ) preparation

参照6a的制备方法，由5b与H2-Pd/C反应制得白色粉末状固体，收率97％。Referring to the preparation method of 6a, a white powdery solid was prepared by reacting 5b with H 2 -Pd/C with a yield of 97%.

1-甲基-3-[2-[[4-(N-甲基哌嗪-1-基)-2-甲氧基-5-氰基乙酰胺基]苯胺基]嘧啶-4-基]吲哚(7b)的制备1-methyl-3-[2-[[4-(N-methylpiperazin-1-yl)-2-methoxy-5-cyanoacetamido]anilino]pyrimidin-4-yl] Preparation of Indole(7b)

参照7a的制备方法，由6b与氰基乙酸反应制得白色固体，收率68％，mp：230～232℃。ESI-MS：533.4[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.26(s，3H)，2.56(s，4H)，2.87(s，4H)，3.86(s，3H)，3.93(s，3H)，4.03(s，2H)，6.88(s，1H)，7.18(t，1H，J＝6.3Hz)，7.22(d，1H，J＝5.58Hz)，7.27(d，1H，J＝7.23Hz)，7.54(d，1H，J＝7.89Hz)，7.90(s，1H)，8.26(d，1H，J＝7.38Hz)，8.31(d，1H，J＝5.19Hz)，8.56(s，1H)，8.72(s，1H)，9.25(s，1H).Referring to the preparation method of 7a, a white solid was obtained by reacting 6b with cyanoacetic acid, the yield was 68%, and mp: 230-232°C. ESI-MS: 533.4[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.26(s, 3H), 2.56(s, 4H), 2.87(s, 4H) , 3.86(s, 3H), 3.93(s, 3H), 4.03(s, 2H), 6.88(s, 1H), 7.18(t, 1H, J=6.3Hz), 7.22(d, 1H, J=5.58 Hz), 7.27(d, 1H, J=7.23Hz), 7.54(d, 1H, J=7.89Hz), 7.90(s, 1H), 8.26(d, 1H, J=7.38Hz), 8.31(d, 1H, J=5.19Hz), 8.56(s, 1H), 8.72(s, 1H), 9.25(s, 1H).

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-11)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-11)

参照LY-1的制备方法，由7b与吡咯-2-甲醛反应制得黄色固体，收率73％，mp：193～195℃。ESI-MS：588.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.26(s，3H)，2.61(s，4H)，2.90(s，3H)，3.88(s，4H)，6.48(s，1H)，7.10(br，2H)，7.22(br，2H)，7.39(br，2H)，7.48～7.54(m，1H)，7.96(s，1H)，8.22～8.3(m，3H)，8.58(s，1H)，9.23(s，1H)，9.50(s，1H)，12.05(br，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7b with pyrrole-2-carbaldehyde, the yield was 73%, and mp: 193-195°C. ESI-MS: 588.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.26(s, 3H), 2.61(s, 4H), 2.90(s, 3H) , 3.88(s, 4H), 6.48(s, 1H), 7.10(br, 2H), 7.22(br, 2H), 7.39(br, 2H), 7.48～7.54(m, 1H), 7.96(s, 1H ), 8.22～8.3(m, 3H), 8.58(s, 1H), 9.23(s, 1H), 9.50(s, 1H), 12.05(br, 1H).

实施例12Example 12

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-2-基)丙烯酰胺(LY-12)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(imidazol-2-yl)acrylamide (LY-12)

参照LY-1的制备方法，由7b与咪唑-2-甲醛反应制得黄色固体，收率57％，mp：190～192℃。ESI-MS：589.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.26(s，3H)，2.62(s，4H)，2.92(s，4H)，3.88(s，3H)，3.90(s，3H)，7.11(s，1H)，7.13(t，1H，J＝7.38Hz)，7.24(m，2H)，7.52(m，3H)，8.00(s，1H)，8.07(s，1H)，8.27(d，1H，J＝7.71Hz)，8.33(d，1H，J＝4.95Hz)，8.58(s，1H)，9.23(s，1H)，9.75(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7b with imidazole-2-carbaldehyde, the yield was 57%, and mp: 190-192°C. ESI-MS: 589.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.26(s, 3H), 2.62(s, 4H), 2.92(s, 4H) , 3.88(s, 3H), 3.90(s, 3H), 7.11(s, 1H), 7.13(t, 1H, J=7.38Hz), 7.24(m, 2H), 7.52(m, 3H), 8.00( s, 1H), 8.07(s, 1H), 8.27(d, 1H, J=7.71Hz), 8.33(d, 1H, J=4.95Hz), 8.58(s, 1H), 9.23(s, 1H), 9.75(s, 1H).

实施例13Example 13

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-苯基丙烯酰胺(LY-13)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-phenylacrylamide (LY-13)

参照LY-1的制备方法，由7b与苯甲醛反应制得黄色固体，收率66％，mp：240～241℃。ESI-MS：621.4[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.26(s，3H)，2.60(br s，4H)，2.93(br s，4H)，3.89(s，3H)，3.93(s，3H)，7.06(s，1H)，7.16(d，1H，J＝7.59Hz)，7.21～7.26(m，2H)，7.52(d，1H，J＝8.10Hz)，7.63(s，1H)，7.65～7.69(m，2H)，8.00(s，1H)，8.04(s，1H)，8.06(s，1H)，8.27(d，1H，J＝7.89Hz)，8.33(d，1H，J＝5.49Hz)，8.41(s，1H)，8.62(s，1H)，9.25(s，1H)，9.79(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7b with benzaldehyde, the yield was 66%, and mp: 240-241°C. ESI-MS: 621.4[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.26(s, 3H), 2.60(br s, 4H), 2.93(br s, 4H), 3.89(s, 3H), 3.93(s, 3H), 7.06(s, 1H), 7.16(d, 1H, J=7.59Hz), 7.21～7.26(m, 2H), 7.52(d, 1H , J=8.10Hz), 7.63(s, 1H), 7.65～7.69(m, 2H), 8.00(s, 1H), 8.04(s, 1H), 8.06(s, 1H), 8.27(d, 1H, J=7.89Hz), 8.33(d, 1H, J=5.49Hz), 8.41(s, 1H), 8.62(s, 1H), 9.25(s, 1H), 9.79(s, 1H).

实施例14Example 14

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡啶-2-基)丙烯酰胺(LY-14)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(pyridin-2-yl)acrylamide (LY-14)

参照LY-1的制备方法，由7b与苯甲醛反应制得橙色固体，收率68％，mp：220～222℃。ESI-MS：600.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.26(s，3H)，2.61(br s，4H)，2.93(br s，4H)，3.88(s，3H)，3.91(s，3H)，7.11～7.14(m，2H)，7.23～7.26(m，2H)，7.52(d，1H，J＝7.35Hz)，7.59(br s，1H)，7.91(d，1H，J＝7.65Hz)，7.99～8.03(m，2H)，8.28(d，1H，J＝9.51Hz)，8.33(d，1H，J＝4.17Hz)，8.40(s，1H)，8.59(s，1H)，8.83(d，1H，J＝7.47Hz)，9.26(s，1H)，9.92(s，1H).Referring to the preparation method of LY-1, an orange solid was obtained by reacting 7b with benzaldehyde, the yield was 68%, and mp: 220-222°C. ESI-MS: 600.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.26(s, 3H), 2.61(br s, 4H), 2.93(br s, 4H), 3.88(s, 3H), 3.91(s, 3H), 7.11～7.14(m, 2H), 7.23～7.26(m, 2H), 7.52(d, 1H, J=7.35Hz), 7.59(br s, 1H), 7.91(d, 1H, J=7.65Hz), 7.99～8.03(m, 2H), 8.28(d, 1H, J=9.51Hz), 8.33(d, 1H, J=4.17Hz), 8.40(s, 1H), 8.59(s, 1H), 8.83(d, 1H, J=7.47Hz), 9.26(s, 1H), 9.92(s, 1H).

实施例15Example 15

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(4-三氟甲基苯基)丙烯酰胺(LY-15)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(4-trifluoromethylphenyl)acrylamide (LY-15)

参照LY-1的制备方法，由7b与4-三氟甲基苯甲醛反应制橙色固体，收率67％，mp：239～240℃。ESI-MS：667.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.22(s，3H)，2.61(brs，4H)，2.93(br s，4H)，3.85(s，3H)，3.90(s，3H)，7.12(s，1H)，7.16(d，1H，J＝7.77Hz)，7.21～7.26(m，2H)，7.52(d，1H，J＝8.34Hz)，7.98(s，1H)，8.00(s，1H)，8.03(s，1H)，8.21(d，1H，J＝8.25Hz)，8.30(d，1H，J＝1.95Hz)，8.33(d，1H，J＝5.31Hz)，8.49(s，1H)，8.59(s，1H)，9.21(s，1H)，9.84(s，1H).Referring to the preparation method of LY-1, an orange solid was prepared by reacting 7b with 4-trifluoromethylbenzaldehyde, the yield was 67%, and mp: 239-240°C. ESI-MS: 667.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.22(s, 3H), 2.61(brs, 4H), 2.93(brs, 4H ), 3.85(s, 3H), 3.90(s, 3H), 7.12(s, 1H), 7.16(d, 1H, J=7.77Hz), 7.21～7.26(m, 2H), 7.52(d, 1H, J=8.34Hz), 7.98(s, 1H), 8.00(s, 1H), 8.03(s, 1H), 8.21(d, 1H, J=8.25Hz), 8.30(d, 1H, J=1.95Hz) , 8.33(d, 1H, J=5.31Hz), 8.49(s, 1H), 8.59(s, 1H), 9.21(s, 1H), 9.84(s, 1H).

实施例16Example 16

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(2-甲氧基苯基)丙烯酰胺(LY-16)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(2-methoxyphenyl)acrylamide (LY-16)

参照LY-1的制备方法，由7b与2-甲氧基苯甲醛反应制得黄色固体，收率76％，mp：263～265℃。ESI-MS：629.5[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.26(s，3H)，2.62(s，4H)，2.92(s，4H)，3.88(s，3H)，3.96(s，3H)，4.02(s，3H)，7.12(s，1H)，7.15(m，1H)，7.18(m，1H)，7.21(s，1H)，7.26(s，1H)，7.28(m，1H)，7.58(d，1H，J＝8.43Hz)，7.63(d，1H，J＝8.40Hz)，7.95(s，1H)，8.18(d，1H，J＝8.22Hz)，8.24(d，1H，J＝8.25Hz)，8.37(d，1H，J＝5.07Hz)，8.71(s，1H)，8.75(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7b with 2-methoxybenzaldehyde, the yield was 76%, and mp: 263-265°C. ESI-MS: 629.5[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.26(s, 3H), 2.62(s, 4H), 2.92(s, 4H) , 3.88(s, 3H), 3.96(s, 3H), 4.02(s, 3H), 7.12(s, 1H), 7.15(m, 1H), 7.18(m, 1H), 7.21(s, 1H), 7.26(s, 1H), 7.28(m, 1H), 7.58(d, 1H, J=8.43Hz), 7.63(d, 1H, J=8.40Hz), 7.95(s, 1H), 8.18(d, 1H , J=8.22Hz), 8.24(d, 1H, J=8.25Hz), 8.37(d, 1H, J=5.07Hz), 8.71(s, 1H), 8.75(s, 1H).

实施例17Example 17

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(呋喃-2-基)丙烯酰胺(LY-17)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(furan-2-yl)acrylamide (LY-17)

参照LY-1的制备方法，由7b与呋喃甲醛反应制得黄色固体，收率74％，mp：237～239℃。ESI-MS：589.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.26(s，3H)，2.62(s，4H)，2.92(s，4H)，3.88(s，3H)，3.97(s，3H)，6.88(m，1H)，7.10(s，1H)，7.17(d，1H，J＝5.85Hz)，7.21～7.25(m，2H)，7.48(d，1H，J＝3.54Hz)，7.52(d，1H，J＝8.31Hz)，8.01(s，1H)，8.21(s，1H)，8.27(d，1H，J＝8.25Hz)，8.32(d，1H，J＝5.16Hz)，8.57(s，1H)，9.19(s，1H)，9.70(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7b with furanformaldehyde, the yield was 74%, and mp: 237-239°C. ESI-MS: 589.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.26(s, 3H), 2.62(s, 4H), 2.92(s, 4H) , 3.88(s, 3H), 3.97(s, 3H), 6.88(m, 1H), 7.10(s, 1H), 7.17(d, 1H, J=5.85Hz), 7.21～7.25(m, 2H), 7.48(d, 1H, J=3.54Hz), 7.52(d, 1H, J=8.31Hz), 8.01(s, 1H), 8.21(s, 1H), 8.27(d, 1H, J=8.25Hz), 8.32(d, 1H, J=5.16Hz), 8.57(s, 1H), 9.19(s, 1H), 9.70(s, 1H).

实施例18Example 18

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-18)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-18)

1-甲基-3-[2-[[4-(吗啉-1-基)-2-甲氧基-5-硝基]苯胺基]嘧啶-4-基]吲哚(5c)的制备Preparation of 1-methyl-3-[2-[[4-(morpholin-1-yl)-2-methoxy-5-nitro]anilino]pyrimidin-4-yl]indole (5c)

参照5a的制备方法，由4与吗啡啉反应制得红色固体，收率89％，mp：236～238℃。ESI-MS：461.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：3.08(br s，4H)，3.75(br s，4H)，3.88(s，3H)，4.00(s，3H)，6.89(s，1H)，7.10～7.15(m，1H)，7.25(d，1H，J＝7.59Hz)，7.25(t，1H，J＝6.63Hz)，7.28(d，1H，J＝7.59Hz)，8.14(s，1H)，8.34～8.41(m，3H)，8.31(d，1H，J＝3.78Hz).Referring to the preparation method of 5a, a red solid was obtained by reacting 4 with morpholine, the yield was 89%, and mp: 236-238°C. ESI-MS: 461.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 3.08(br s, 4H), 3.75(br s, 4H), 3.88(s, 3H), 4.00(s, 3H), 6.89(s, 1H), 7.10～7.15(m, 1H), 7.25(d, 1H, J=7.59Hz), 7.25(t, 1H, J=6.63Hz), 7.28(d, 1H, J=7.59Hz), 8.14(s, 1H), 8.34～8.41(m, 3H), 8.31(d, 1H, J=3.78Hz).

1-甲基-3-[2-[[4-(吗啉-1-基)-2-甲氧基-5-氨基]苯胺基]嘧啶-4-基]吲哚(6c)的制备Preparation of 1-methyl-3-[2-[[4-(morpholin-1-yl)-2-methoxy-5-amino]anilino]pyrimidin-4-yl]indole (6c)

参照6a的制备方法，由5c与H2-Pd/C反应制得白色固体，收率98％，mp：177～179℃。ESI-MS：431.3[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：1.35(s，2H)，2.49(s，1H)，2.84(s，4H)，3.59(s，1H)，3.75(br s，6H)，3.86(s，3H)，4.47(s，2H)，6.71(s，1H)，7.15(s，3H)，7.52(s，2H)，7.79(s，1H)，8.29(s，2H)，8.41(s，1H).Referring to the preparation method of 6a, a white solid was prepared by reacting 5c with H 2 -Pd/C, the yield was 98%, and mp: 177-179°C. ESI-MS: 431.3[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 1.35(s, 2H), 2.49(s, 1H), 2.84(s, 4H) , 3.59(s, 1H), 3.75(br s, 6H), 3.86(s, 3H), 4.47(s, 2H), 6.71(s, 1H), 7.15(s, 3H), 7.52(s, 2H) , 7.79(s, 1H), 8.29(s, 2H), 8.41(s, 1H).

1-甲基-3-[2-[[4-(吗啉-1-基)-2-甲氧基-5-氰基乙酰胺基]苯胺基]嘧啶-4-基]吲哚(7c)的制备1-Methyl-3-[2-[[4-(morpholin-1-yl)-2-methoxy-5-cyanoacetamido]anilino]pyrimidin-4-yl]indole (7c ) preparation

参照7a的制备方法，由6c与氰基乙酸反应制得白色固体，收率68％，mp：145～147℃。ESI-MS：498.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.88(br s，4H)，3.80(br s，4H)，3.88(s，3H)，3.93(s，3H)，4.04(s，2H)，6.92(s，1H)，7.18(d，1H，J＝6.84Hz)，7.23(d，1H，J＝5.55Hz)，7.28(d，1H，J＝7.53Hz)，7.55(d，1H，J＝7.86Hz)，7.91(s，1H)，7.26(d，1H，J＝7.68Hz)，8.32(d，1H，J＝5.34Hz)，8.58(s，1H)，8.76(s，1H)，9.34(s，1H).Referring to the preparation method of 7a, a white solid was obtained by reacting 6c with cyanoacetic acid, the yield was 68%, and mp: 145-147°C. ESI-MS: 498.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.88(br s, 4H), 3.80(br s, 4H), 3.88(s, 3H), 3.93(s, 3H), 4.04(s, 2H), 6.92(s, 1H), 7.18(d, 1H, J=6.84Hz), 7.23(d, 1H, J=5.55Hz), 7.28( d, 1H, J=7.53Hz), 7.55(d, 1H, J=7.86Hz), 7.91(s, 1H), 7.26(d, 1H, J=7.68Hz), 8.32(d, 1H, J=5.34 Hz), 8.58(s, 1H), 8.76(s, 1H), 9.34(s, 1H).

N-[2-(4-甲基哌嗪-1-基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡咯-2-基)丙烯酰胺(LY-18)的制备N-[2-(4-methylpiperazin-1-yl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino Preparation of ]phenyl]-2-cyano-3-(pyrrol-2-yl)acrylamide (LY-18)

参照LY-1的制备方法，由7c与吡咯-2-甲醛反应制得黄色固体，收率74％，mp：273～275℃。ESI-MS：575.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.91(br s，3H)，3.83(brs，4H)，3.88(s，3H)，3.91(s，3H)，6.48(br s，1H)，7.14～7.17(m，2H)，7.22～7.28(m，2H)，7.53(d，1H，J＝8.07Hz)，8.00(s，1H)，8.22(s，1H)，8.27(d，1H，J＝8.04Hz)，8.34(d，1H，J＝3.96Hz)，8.62(s，1H)，9.25(s，1H)，9.61(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7c with pyrrole-2-carbaldehyde, the yield was 74%, and mp: 273-275°C. ESI-MS: 575.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.91(brs, 3H), 3.83(brs, 4H), 3.88(s, 3H ), 3.91(s, 3H), 6.48(br s, 1H), 7.14～7.17(m, 2H), 7.22～7.28(m, 2H), 7.53(d, 1H, J=8.07Hz), 8.00(s , 1H), 8.22(s, 1H), 8.27(d, 1H, J=8.04Hz), 8.34(d, 1H, J=3.96Hz), 8.62(s, 1H), 9.25(s, 1H), 9.61 (s, 1H).

实施例19Example 19

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-2-基)丙烯酰胺(LY-19)的制备N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Preparation of cyano-3-(imidazol-2-yl)acrylamide (LY-19)

参照LY-1的制备方法，由7c与咪唑-2-甲醛反应制得黄色固体，收率64％，mp：195～196℃。ESI-MS：598.4[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.92(br s，3H)，3.84(br s，4H)，3.89(s，3H)，3.92(s，3H)，7.08(br s，1H)，7.14～7.17(m，2H)，7.24～7.26(m，2H)，7.34(s，1H)，7.47(br s，2H)，7.54(d，1H，J＝7.56Hz)，8.01(s，1H)，8.05(s，1H)，8.27(d，1H，J＝8.07Hz)，8.34(d，1H，J＝5.37Hz)，8.63(s，1H)，9.28(s，1H)，9.79(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7c with imidazole-2-carbaldehyde, the yield was 64%, and mp: 195-196°C. ESI-MS: 598.4[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.92(br s, 3H), 3.84(br s, 4H), 3.89(s, 3H), 3.92(s, 3H), 7.08(br s, 1H), 7.14～7.17(m, 2H), 7.24～7.26(m, 2H), 7.34(s, 1H), 7.47(br s, 2H) , 7.54(d, 1H, J=7.56Hz), 8.01(s, 1H), 8.05(s, 1H), 8.27(d, 1H, J=8.07Hz), 8.34(d, 1H, J=5.37Hz) , 8.63(s, 1H), 9.28(s, 1H), 9.79(s, 1H).

实施例20Example 20

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(呋喃-2-基)丙烯酰胺(LY-20)的制备N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Preparation of cyano-3-(furan-2-yl)acrylamide (LY-20)

参照LY-1的制备方法，由7c与呋喃-2-甲醛反应制得黄色固体，收率87％，mp：269～271℃。ESI-MS：598.4[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.92(s，4H)，3.88(s，4H)，3.89(s，3H)，3.90(s，3H)，6.70(s，1H)，7.06(m，2H)，7.15(m，2H)，7.47(s，1H)，7.50(s，1H)，8.03(s，1H)，8.14(d，1H，J＝3.18Hz)，8.27(s，1H)，8.30(s，1H)，8.34(s，1H)，8.40(s，1H)，8.43(s，1H)，8.58(s，1H)，9.23(s，1H)，9.76(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7c with furan-2-carbaldehyde, the yield was 87%, and mp: 269-271°C. ESI-MS: 598.4[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.92(s, 4H), 3.88(s, 4H), 3.89(s, 3H) , 3.90(s, 3H), 6.70(s, 1H), 7.06(m, 2H), 7.15(m, 2H), 7.47(s, 1H), 7.50(s, 1H), 8.03(s, 1H), 8.14(d, 1H, J=3.18Hz), 8.27(s, 1H), 8.30(s, 1H), 8.34(s, 1H), 8.40(s, 1H), 8.43(s, 1H), 8.58(s , 1H), 9.23(s, 1H), 9.76(s, 1H).

实施例21Example 21

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(2-甲氧基苯基)丙烯酰胺(LY-21)的制备N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Preparation of cyano-3-(2-methoxyphenyl)acrylamide (LY-21)

参照LY-1的制备方法，由7c与2-甲氧基苯甲醛反应制得黄色固体，收率72％，mp：264～266℃。ESI-MS：638.3[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.92(br s，4H)，3.86(br s，4H)，3.91(s，3H)，3.94(s，3H)，3.97(s，3H)，7.16～7.22(m，2H)，7.23～7.27(m，2H)，7.57～7.66(m，2H)，7.94(s，1H)，8.16(d，1H，J＝9.78Hz)，8.23(d，1H，J＝6.96Hz)，8.34(s，1H)，8.72(d，1H，J＝8.61Hz)，8.77(d，1H，J＝8.22Hz)，9.39(s，1H)，9.91(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7c with 2-methoxybenzaldehyde, the yield was 72%, and mp: 264-266°C. ESI-MS: 638.3[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.92(br s, 4H), 3.86(br s, 4H), 3.91(s, 3H), 3.94(s, 3H), 3.97(s, 3H), 7.16～7.22(m, 2H), 7.23～7.27(m, 2H), 7.57～7.66(m, 2H), 7.94(s, 1H) , 8.16(d, 1H, J=9.78Hz), 8.23(d, 1H, J=6.96Hz), 8.34(s, 1H), 8.72(d, 1H, J=8.61Hz), 8.77(d, 1H, J=8.22Hz), 9.39(s, 1H), 9.91(s, 1H).

实施例22Example 22

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡啶-2-基)丙烯酰胺(LY-22)的制备N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Preparation of cyano-3-(pyridin-2-yl)acrylamide (LY-22)

参照LY-1的制备方法，由7c与吡啶-2-甲醛反应制得橙色固体，收率66％，mp：264～266℃。ESI-MS：609.4[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.10(s，8H)，2.23(s，3H)，2.73(s，5H)，2.99(s，4H)，3.92(s，13H)，6.91(m，8H)，7.57(s，2H)，7.92(m，2H)，8.11(m，2H)，8.23(s，1H)，8.32(s，1H)，8.60(s，1H)，8.73(s，1H)，9.28(s，1H)，10.42(s，1H).Referring to the preparation method of LY-1, an orange solid was obtained by reacting 7c with pyridine-2-carbaldehyde, the yield was 66%, and mp: 264-266°C. ESI-MS: 609.4[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ (ppm): 2.10(s, 8H), 2.23(s, 3H), 2.73(s, 5H) , 2.99(s, 4H), 3.92(s, 13H), 6.91(m, 8H), 7.57(s, 2H), 7.92(m, 2H), 8.11(m, 2H), 8.23(s, 1H), 8.32(s, 1H), 8.60(s, 1H), 8.73(s, 1H), 9.28(s, 1H), 10.42(s, 1H).

实施例23Example 23

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(吡唑-3-基)丙烯酰胺(LY-23)的制备N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Preparation of cyano-3-(pyrazol-3-yl)acrylamide (LY-23)

参照LY-1的制备方法，由7c与吡唑-3-甲醛反应制得黄色固体，收率67％，mp：259～261℃。ESI-MS：598.4[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.93(br s，4H)，3.87(br s，4H)，3.89(s，3H)，3.93(s，3H)，7.10～7.29(m，6H)，7.54(d，1H，J＝7.71Hz)，8.01(s，1H)，8.28(d，1H，J＝10.32Hz)，8.34(d，1H，J＝5.55Hz)，8.76(s，1H)，9.26(s，1H)，9.82(brs，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7c with pyrazole-3-carbaldehyde, the yield was 67%, and mp: 259-261°C. ESI-MS: 598.4[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.93(br s, 4H), 3.87(br s, 4H), 3.89(s, 3H), 3.93(s, 3H), 7.10～7.29(m, 6H), 7.54(d, 1H, J=7.71Hz), 8.01(s, 1H), 8.28(d, 1H, J=10.32Hz), 8.34(d, 1H, J=5.55Hz), 8.76(s, 1H), 9.26(s, 1H), 9.82(brs, 1H).

实施例24Example 24

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-(咪唑-4-基)丙烯酰胺(LY-24)的制备N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Preparation of cyano-3-(imidazol-4-yl)acrylamide (LY-24)

参照LY-1的制备方法，由7c与咪唑-4-甲醛反应制得黄色固体，收率57％，mp：289～291℃。ESI-MS：598.4[M+Na]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.91(br s，4H)，3.88(br s，4H)，3.92(s，3H)，4.00(s，3H)，7.13～7.19(m，2H)，7.21～7.26(m，2H)，7.53(d，1H，J＝8.43Hz)，7.93(s，1H)，8.00(s，1H)，8.03(s，1H)，8.21(s，1H)，8.26(d，1H，J＝7.89Hz)，8.34(d，1H，J＝5.40Hz)，8.64(s，1H)，9.29(s，1H)，9.70(s，1H).Referring to the preparation method of LY-1, a yellow solid was obtained by reacting 7c with imidazole-4-carbaldehyde, the yield was 57%, and mp: 289-291°C. ESI-MS: 598.4[M+Na] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.91(br s, 4H), 3.88(br s, 4H), 3.92(s, 3H), 4.00(s, 3H), 7.13~7.19(m, 2H), 7.21~7.26(m, 2H), 7.53(d, 1H, J=8.43Hz), 7.93(s, 1H), 8.00(s , 1H), 8.03(s, 1H), 8.21(s, 1H), 8.26(d, 1H, J=7.89Hz), 8.34(d, 1H, J=5.40Hz), 8.64(s, 1H), 9.29 (s, 1H), 9.70 (s, 1H).

实施例25Example 25

N-[2-(吗啉基)-4-甲氧基-5-[[4-(1-甲基吲哚-3-基)嘧啶-2-基]胺基]苯基]-2-氰基-3-环丙基丙烯酰胺(LY-25)的制备N-[2-(morpholinyl)-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]-2- Preparation of cyano-3-cyclopropylacrylamide (LY-25)

参照LY-1的制备方法，由7c与环丙甲醛反应制得浅黄色固体，收率86％，mp：257～259℃。ESI-MS：550.4[M+H]+；1H-NMR(300MHz，DMSO-d6)，δ(ppm)：2.90(br s，4H)，3.84(brs，4H)，3.92(s，4H)，7.06(s，1H)，7.11(s，1H)，7.17(s，1H)，7.24(s，1H)，7.27(s，1H)，7.53(d，1H，J＝7.71Hz)，7.98(s，1H)，8.30(s，1H)，8.36(s，1H)，8.59(s，1H)，9.18(s，1H)，9.53(s，1H).Referring to the preparation method of LY-1, a light yellow solid was obtained by reacting 7c with cyclopropanaldehyde, the yield was 86%, and mp: 257-259°C. ESI-MS: 550.4[M+H] + ; 1 H-NMR (300MHz, DMSO-d 6 ), δ(ppm): 2.90(br s, 4H), 3.84(brs, 4H), 3.92(s, 4H ), 7.06(s, 1H), 7.11(s, 1H), 7.17(s, 1H), 7.24(s, 1H), 7.27(s, 1H), 7.53(d, 1H, J=7.71Hz), 7.98 (s, 1H), 8.30(s, 1H), 8.36(s, 1H), 8.59(s, 1H), 9.18(s, 1H), 9.53(s, 1H).

实施例39Example 39

本发明化合物的EGFR激酶抑制活性测试EGFR kinase inhibitory activity test of the compounds of the present invention

采用Z’-LyteTM激酶测试盒(invitrogenTM，Z’-LyteTM Kinase assay kit-Tyr6peptide)进行测试。先把酶和化合物分别按照一定的配比加于384孔板，混匀，放置30min；然后加入ATP，混匀，放置2h；加5μL Development Regent，混匀，于室温下放置15min，30min，1h后，用酶标仪进行检测；1h后加入5μL的Stop regent，混匀后用酶标仪进行检测。计算相应的磷酸化比例，根据化合物的浓度与对应的激酶抑制率作图，得到剂量反应曲线，据此求得药物的半数抑制浓度(IC50)。结果如表1所示。The Z'-Lyte TM Kinase assay kit (invitrogen TM , Z'-Lyte TM Kinase assay kit-Tyr6peptide) was used for testing. First add the enzyme and the compound to the 384-well plate according to a certain ratio, mix well, and let stand for 30 minutes; then add ATP, mix well, let stand for 2 hours; add 5 μL Development Regent, mix well, let stand at room temperature for 15 minutes, 30 minutes, 1 hour After that, detect with a microplate reader; add 5 μL of Stop regent after 1 h, mix well and detect with a microplate reader. The corresponding phosphorylation ratio was calculated, and the concentration of the compound was plotted against the corresponding kinase inhibition rate to obtain a dose-response curve, based on which the half inhibitory concentration (IC 50 ) of the drug was obtained. The results are shown in Table 1.

抑制率(％)＝[1-(A样品组-A样品空白组)/(A对照组-A空白组)]×100％Inhibition rate (%)=[1-(A sample group -A sample blank group )/(A control group -A blank group )]×100%

表1 本发明化合物的EGFR激酶抑制活性(IC50：nM)Table 1 EGFR kinase inhibitory activity of the compounds of the present invention (IC 50 : nM)

EGFR激酶抑制活性测试结果显示，本发明化合物对EGFR(WT)、EGF(T790M)、EGFR(L861Q)、EGFR(L858R)具有良好的抑制活性，其中，LY-2、LY-5、LY-12和LY-13与阳性药WZ4002和AZD9291活性相当。EGFR kinase inhibitory activity test results show that the compound of the present invention has good inhibitory activity to EGFR (WT), EGF (T790M), EGFR (L861Q), EGFR (L858R), wherein, LY-2, LY-5, LY-12 And LY-13 have the same activity as positive drugs WZ4002 and AZD9291.

实施例40Example 40

本发明化合物细胞增殖抑制活性测试Cell Proliferation Inhibitory Activity Test of Compounds of the Invention

采用四甲基氮唑蓝比色法(MTT)评价本发明部分化合物对8种人非小细胞肺癌、乳腺癌、胃癌和结肠癌细胞株增殖的抑制活性。MTT法已广泛用于大规模的抗肿瘤药物筛选、细胞毒性试验以及肿瘤放射敏感测定等。The inhibitory activity of some compounds of the present invention on the proliferation of 8 kinds of human non-small cell lung cancer, breast cancer, gastric cancer and colon cancer cell lines was evaluated by tetramethylazolium blue colorimetric method (MTT). MTT method has been widely used in large-scale antitumor drug screening, cytotoxicity test and tumor radiosensitivity determination.

肿瘤细胞株：A549肺癌细胞(WT EGFR)；HCC827肺癌细胞(EGFR del E746-A750)；A431上皮细胞(过度表达的EGFR)；H1975肺癌细胞(EGFR L858R/T790M)；MCF-7乳腺癌细胞(不表达EGFR和HER-2)；SK-Br-3乳腺癌细胞(HER-2过度表达)；N87胃癌细胞(过度表达的EGFR)；LoVo结肠癌细胞(过度表达的EGFR)。Tumor cell lines: A549 lung cancer cells (WT EGFR); HCC827 lung cancer cells (EGFR del E746-A750); A431 epithelial cells (overexpressed EGFR); H1975 lung cancer cells (EGFR L858R/T790M); MCF-7 breast cancer cells ( EGFR and HER-2 not expressed); SK-Br-3 breast cancer cells (HER-2 overexpression); N87 gastric cancer cells (EGFR overexpression); LoVo colon carcinoma cells (EGFR overexpression).

实验方法：取对数生长期的细胞配成4.5×105/mL细胞悬液，接种至96孔培养板中，每孔180μL，每组设5个平行孔，分别加入不同浓度受试物各20μL。置于恒温CO2培养箱中培养48小时，将四甲基氮唑蓝加入96孔板中，每孔20μL，继续培养4小时。吸去上清液，加入DMSO，每孔150μL，平板摇床上振摇5分钟。用酶联免疫检测仪在波长为570nm处测定每孔的吸收度，以上实验各重复3次。计算细胞增殖抑制率(抑制率％＝(阴性对照组OD值-受试组OD值)/阴性对照组OD值×100％)，根据抑制率建立直线回归方程求得半数抑制浓度IC50值。结果见表2。Experimental method: Take the cells in the logarithmic growth phase to make a 4.5×105/mL cell suspension, inoculate into a 96-well culture plate, 180 μL per well, set 5 parallel wells in each group, add 20 μL of each test substance at different concentrations . Place in a constant temperature CO2 incubator and cultivate for 48 hours, add tetramethylazolium blue into the 96-well plate, 20 μL per well, and continue to cultivate for 4 hours. Aspirate the supernatant, add DMSO, 150 μL per well, and shake on a plate shaker for 5 minutes. The absorbance of each well was measured at a wavelength of 570nm by an enzyme-linked immunosorbent detector, and each of the above experiments was repeated 3 times. Calculate the inhibition rate of cell proliferation (inhibition rate%=(OD value of negative control group-OD value of test group)/OD value of negative control group×100%), and establish a linear regression equation according to the inhibition rate to obtain the IC50 value of the half inhibitory concentration. The results are shown in Table 2.

表2 本发明部分化合物抗肿瘤细胞增殖活性(IC50：μM)Table 2 Anti-tumor cell proliferation activity of some compounds of the present invention (IC 50 : μM)

细胞活性测试显示本发明化合物对A549、HCC827、A431、H1975、MCF-7、SK-Br-3、N87和LoVo具有良好的增殖抑制活性。其中，LY-5、LY-6、LY-7、LY-8和LY-9对A549、A431、H1975、MCF-7、SK-Br-3、N87和LoVo增殖抑制活性优于或与阳性药AZD9291相当。The cell activity test shows that the compound of the present invention has good growth inhibitory activity on A549, HCC827, A431, H1975, MCF-7, SK-Br-3, N87 and LoVo. Among them, LY-5, LY-6, LY-7, LY-8 and LY-9 have better antiproliferative activity on A549, A431, H1975, MCF-7, SK-Br-3, N87 and LoVo than or with positive drugs AZD9291 is comparable.

Claims (7)

1. pyrimidines, its stereoisomer or its pharmaceutically acceptable salt shown in logical formula (I)：
Wherein：
R1Represent C1-C8Alkyl, C3-C6Cycloalkyl, C5-C10Aryl or C5-C10Aromatic heterocyclic, described alkyl, cycloalkyl, aryl Or aromatic heterocyclic is optionally monosubstituted to five substitutions by substituent that is following identical or differing, described substituent is selected from： Trifluoromethyl or methoxyl group；
R2Represent N, N, N- trimethyl ethylenediamines base, N methyl piperazine base or morpholinyl.
2. pyrimidines according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, its feature It is：
R1Represent tertiary amyl, cyclopropyl, phenyl, 2- methoxyphenyls, 4- trifluoromethyls, pyrazolyl, pyrrole radicals, imidazole radicals, Furyl or pyridine radicals；
R2Represent N, N, N- trimethyl ethylenediamines base, N methyl piperazine base or morpholinyl.
3. pyrimidines according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, its feature It is, the compound is selected from：
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (imidazoles -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (furans -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (2- methoxyphenyls) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (pyridine -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (pyrazole-3-yl) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (imidazol-4 yl) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- Phenyl Acrylamides；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- cyclopropyl acrylamides；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- tertiary amyl acrylamides；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (pyrroles -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (imidazoles -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- Phenyl Acrylamides；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (pyridine -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (4- trifluoromethyls) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (2- methoxyphenyls) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (furans -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (pyrroles -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (imidazoles -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (furans -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (2- methoxyphenyls) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (pyridine -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (pyrazole-3-yl) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (imidazol-4 yl) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- cyclopropyl acrylamides.
4. the preparation method of the pyrimidines described in claim 1, it is characterised in that：2- nitro -5- fluoroanisoles are through also The obtained 2- methoxyl group -4- fluoroanilines 1,1 of original through nitrification obtain the fluoro- dichloro pyrimidines of 5- nitroanilines 2,2,4- of 2- methoxyl groups -4- with The coupling under alchlor effect of N- methyl indols obtains the reaction of 1- methyl -3- (2- chlorine pyrimidine-4-yl) indoles 3,3 and 2 and is made 1- methyl -3- [[2- (the fluoro- 5- nitros of 2- methoxyl groups -4-) anilino-] pyrimidine-4-yl] indoles 4,4 is condensed with aminated compounds and made Intermediate 5,5 through reduction be made intermediate 6,6 and cyanoacetic acid be condensed to yield intermediate 7,7 under the catalysis of Piperidineacetic acid with Aldehyde compound is condensed to yield LY-1~LY-25；Synthetic route is as follows：
Wherein, R1And R2Definition it is as claimed in claim 1.
5. a kind of pharmaceutical composition, different by any one of the claim 1-3 of the upper effective dose for the treatment of pyrimidines, its solid Structure body or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or auxiliary material composition.
6. any one of claim 1-3 pyrimidines, its stereoisomer or its pharmaceutically acceptable salt and right It is required that application of the pharmaceutical composition described in 5 in antineoplastic is prepared.
7. purposes according to claim 6, described tumor disease is non-small cell lung cancer, breast cancer, stomach cancer, the carcinoma of the rectum, liver Cancer, prostate cancer, carcinoma of urinary bladder and oophoroma, head and neck neoplasm or glioblastoma.
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