WO2023040537A1 - Aminopyrimidine derivative, preparation method therefor and use thereof - Google Patents

Aminopyrimidine derivative, preparation method therefor and use thereof Download PDF

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WO2023040537A1
WO2023040537A1 PCT/CN2022/112391 CN2022112391W WO2023040537A1 WO 2023040537 A1 WO2023040537 A1 WO 2023040537A1 CN 2022112391 W CN2022112391 W CN 2022112391W WO 2023040537 A1 WO2023040537 A1 WO 2023040537A1
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amino
chloro
fluorobenzyl
substituted
alkyl
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PCT/CN2022/112391
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French (fr)
Chinese (zh)
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赵冬梅
吴天啸
程卯生
秦桥花
张储
吕瑞成
刘念
孙逸祥
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沈阳药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • TRK Tropomyosin receptor kinase
  • RTK Receptor tyrosine kinase
  • R is selected from arylmethylamino, 2-arylpyrrolidinyl, 2-arylazetidinyl or 2-arylpiperidinyl,
  • Rb is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms,
  • aminopyrimidine derivatives or their stereoisomers pharmaceutically acceptable salts, hydrates, for solvates or prodrugs,
  • R is selected from hydrogen, halogen, nitro, cyano, methyl, trifluoromethyl, amino, methylamino or dimethylamino;
  • R is selected from hydrogen, halogen, nitro, cyano, methyl, trifluoromethyl, amino, methylamino or dimethylamino;
  • Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
  • Both X and Y are C;
  • Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
  • the present invention provides the aminopyrimidine derivatives represented by the general formula (I) or stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or The preparation method of prodrug:
  • the reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4 -Dioxane, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 30-150°C, preferably 120°C, the acid in the reaction can be saturated ethyl acetate solution of hydrogen chloride, ethanol solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, methanol solution of hydrogen chloride, aqueous solution of hydrogen chloride, p-toluenesulfonic acid, benzenesulfonic acid, etc., preferably 1,4-dioxane solution of hydrogen chloride;
  • the present invention provides the aminopyrimidine derivative represented by general formula (II) or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or The preparation method of prodrug:
  • intermediate 14 is obtained by reacting starting material 13 with different substituted benzylamines through nucleophilic substitution.
  • the reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol Alcohol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 0 ⁇ 78°C, preferably 25°C, the base in the reaction can be Triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine; intermediate 14 occurs with different aromatic amines
  • the target compound 15 can be obtained by palladium-catalyzed coupling reaction.
  • Example 17 With reference to the method for preparing Example 17, the morpholine raw material in step c was replaced with 4-methylaminopiperidine in equal proportions to obtain Example 26.
  • step c the morpholine raw material in step c was replaced by N-Boc-piperidin-4-amine in equal proportions to obtain intermediate 7.
  • Intermediate 7 (0.050 g, 0.090 mmol) was dissolved in saturated ethyl acetate solution of hydrogen chloride and stirred at room temperature (step d).
  • TLC monitored the completion of the reaction, filtered under reduced pressure, washed the filter cake three times with ethyl acetate, dissolved the filter cake in 20 mL of water, extracted with ethyl acetate (10 mL ⁇ 3), and discarded the organic layer.
  • Example 36 Referring to the method for preparing Example 34, 4-fluorobenzyl in step e was replaced with 3,4,5-trifluorobenzyl in equal proportions to obtain Example 36.
  • Example 38 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 3,4-difluorobenzyl in equal proportions to obtain Example 38.
  • Example 40 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 2,5-difluorobenzyl in equal proportions to obtain Example 40.
  • Example 44 Referring to the method for preparing Example 34, 4-fluorobenzyl in step e was replaced with 2-(4-fluorophenyl)pyrrolidine in equal proportions to obtain Example 44.
  • Example 46 Referring to the method for preparing Example 34, the 3,4,5-trifluorobenzyl in step e was replaced with 2-(3,4,5-trifluorophenyl)pyrrolidine in equal proportions to obtain Example 46.
  • Example 48 Referring to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced with 5-bromo-2,4-dichloropyrimidine in equal proportions to obtain Example 48.
  • Example 34 Referring to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced with 5-bromo-2,4-dichloropyrimidine in equal proportions to obtain Example 49. With reference to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced by 5-methyl-2,4-dichloropyrimidine in equal proportions to obtain Example 49.
  • Example 58 Referring to the preparation method of Example 56, replace 3-(3-aminobenzamide) piperidine-1-carboxamide tert-butyl ester in equal proportions with (R)-3-(3-aminobenzamide) in step q Piperidine-1-carboxamide tert-butyl ester, Example 58 was obtained.
  • Example 59 Referring to the preparation method of Example 57, replace 3-(3-aminobenzamide) piperidine-1-carboxamide tert-butyl ester in equal proportions with (R)-3-(3-aminobenzamide) in step q Piperidine-1-carboxamide tert-butyl ester, Example 59 was obtained.
  • TRKA protein concentration 0.111ng/ ⁇ l, MgCl 2 , ethylenediaminetetraacetic acid (EDTA), dithiothreitol (DL-Dithiothreitol, DTT), DMSO.
  • EDTA ethylenediaminetetraacetic acid
  • DTT dithiothreitol
  • DMSO DMSO
  • Step 2 Detection of phosphorylated products:
  • Example 54 2.80 Example 55 0.99 Example 56 0.59 Example 57 0.10 Example 58 0.53 Example 59 0.14 Example 60 0.52 Example 61 0.11

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  • Plural Heterocyclic Compounds (AREA)

Abstract

The present disclosure relates to the field of pharmaceutical chemistry, and specifically relates to an aminopyrimidine derivative having a structure represented by general formula (I) or general formula (II), a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, a preparation method therefor, and a use thereof in the preparation of a therapeutic agent, in particular an tropomyosin receptor kinase (TRK) inhibitor. Preferably, the aminopyrimidine derivative, the stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof have activity as a protein kinase inhibitor, in particular as a TRK inhibitor.

Description

一种氨基嘧啶衍生物及其制备方法和用途A kind of aminopyrimidine derivative and its preparation method and application 技术领域technical field
本发明属于药物化学领域，具体涉及一种氨基嘧啶衍生物、其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，以及其制备方法和在制备治疗剂特别是TRK抑制剂中的用途。The present invention belongs to the field of medicinal chemistry, and in particular relates to an aminopyrimidine derivative, its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug, its preparation method and the preparation of a therapeutic agent, especially TRK Use in inhibitors.
背景技术Background technique
恶性肿瘤已经成为严重危害人类健康的疾病之一。人类与癌症的抗争史已有近一个世纪之久。抗肿瘤药物的研发正在逐步由非选择性的化疗药物向具有高选择性的靶向药物转变。自伊马替尼上市以来，以激酶为靶点的抗肿瘤药物研发就步入了快车道。随着精准医疗概念的提出，针对特定生物标志物来划分肿瘤类型已经是大势所趋。而靶向特定生物标志物来医治肿瘤的疗法，已经收获了大量成功的临床经验。Malignant tumors have become one of the diseases that seriously endanger human health. Human beings have been fighting against cancer for nearly a century. The research and development of anticancer drugs is gradually changing from non-selective chemotherapy drugs to highly selective targeted drugs. Since the launch of imatinib, the development of anti-tumor drugs targeting kinases has entered the fast lane. With the introduction of the concept of precision medicine, it is a general trend to classify tumor types based on specific biomarkers. The therapy targeting specific biomarkers to treat tumors has gained a lot of successful clinical experience.
大约有17％-20％的肿瘤是由NTRK基因融合引起的，NTRK是编码TRK蛋白的DNA序列。TRK全称是原肌球蛋白受体激酶(Tropomyosin eceptor kinase)，是细胞表面受体酪氨酸激酶(Receptor tyrosine kinase，RTK)家族的一员。TRK共有三种亚型，分别是由NTRK1基因编码的TRKA，由NTRK2编码的TRKB以及由NTRK3编码的TRKC。TRK是一类跨膜受体蛋白，其包括一个与配体结合的胞外域，一个跨膜域，以及一个具有激酶活性的胞内域。受体酪氨酸激酶的胞内激酶域在结构上是相对保守的，TRK三种亚型在激酶域的同源性在71.9％至78.3％之间，而三种亚型的主要差异在于活化它们的天然配体不同。激动TRKA的天然配体主要是：神经生长因子(NGF)、神经营养蛋白-7(NT-7)和神经营养蛋白-6(NT-6)；激动TRKB的天然配体有：脑源性神经营养因子(BDNF)和神经营养蛋白4/5；而激动TRKC的天然配体则是神经营养蛋白-3(NT-3)。前期的科学研究表明，TRK作为一个神经生长因子受体，可以通过磷酸化下游蛋白来调节细胞的增殖，分化，迁移和凋亡。在人类的恶性肿瘤中，TRK可以通过多种机制被持续的活化。其中，最具代表性的机制当属NTRK的基因融合。NTRK的基因融合是指其3，末端序列在染色体内或者染色体间发生重组，然后其5，末端序列与其它基因(伴侣基因)相互链接，从而形成一个新的突变蛋白。这种蛋白会导致TRK的持续活化，并最终诱导肿瘤的形成。研究者们已经在多种肿瘤中发现了NTRK的基因融合行为，如在结肠癌(CRC)中，人们发现了存在TPM3-NTRK1的基因融合；而在分泌性中胚层先天纤维肉瘤和婴儿纤维肉瘤中，发现了ETV6-NTRK3的基因融合。除基因融合外，NTRK基因的持续活化，转录和翻译过程中产生的剪接变体以及TRK蛋白的过表达也是诱发肿瘤的关键因素。目前，人们已经在神经胶质瘤、急性髓细胞白血病(AML)、肺癌、乳腺癌等多种癌症中发现了TRK相关蛋白的异常行为，并证明了其与癌症的发生发展紧密相关。由NTRK基因融合导致的TRK蛋白异常活化，已经被证明是引起肿瘤的关键因素。而令人遗憾的是，NTRK的基因融合通常会导致TRK蛋白胞外域的遗失，这意味着，诸如单克隆抗体等靶向蛋白胞外域的抑制剂对于NTRK基因融合型癌症将不再有效。因此，小分子TRK抑制剂应是解决NTRK基因融合型癌症的唯一有效手段。About 17%-20% of tumors are caused by gene fusions of NTRK, the DNA sequence that codes for the TRK protein. The full name of TRK is Tropomyosin receptor kinase (Tropomyosin eceptor kinase), which is a member of the cell surface receptor tyrosine kinase (Receptor tyrosine kinase, RTK) family. There are three isoforms of TRK, TRKA encoded by NTRK1 gene, TRKB encoded by NTRK2 and TRKC encoded by NTRK3. TRK is a kind of transmembrane receptor protein, which includes an extracellular domain that binds to ligands, a transmembrane domain, and an intracellular domain with kinase activity. The intracellular kinase domain of receptor tyrosine kinases is relatively conserved in structure, and the homology of the three subtypes of TRK in the kinase domain is between 71.9% and 78.3%, and the main difference of the three subtypes lies in the activation Their natural ligands are different. The natural ligands that stimulate TRKA are mainly: nerve growth factor (NGF), neurotrophin-7 (NT-7) and neurotrophin-6 (NT-6); the natural ligands that stimulate TRKB are: brain-derived neurotrophin trophic factor (BDNF) and neurotrophin 4/5; and the natural ligand for agonizing TRKC is neurotrophin-3 (NT-3). Previous scientific studies have shown that TRK, as a nerve growth factor receptor, can regulate cell proliferation, differentiation, migration and apoptosis by phosphorylating downstream proteins. In human malignancies, TRK can be continuously activated through multiple mechanisms. Among them, the most representative mechanism is the gene fusion of NTRK. The gene fusion of NTRK refers to the recombination of its 3' terminal sequence within or between chromosomes, and then its 5' terminal sequence links with other genes (partner genes) to form a new mutant protein. This protein leads to the sustained activation of TRK and ultimately induces tumor formation. Researchers have discovered the gene fusion behavior of NTRK in a variety of tumors. For example, in colon cancer (CRC), people found TPM3-NTRK1 gene fusion; and in secretory mesoderm congenital fibrosarcoma and infantile fibrosarcoma In , a gene fusion of ETV6-NTRK3 was found. In addition to gene fusion, persistent activation of NTRK gene, splice variants generated during transcription and translation, and overexpression of TRK protein are also key factors in inducing tumors. At present, the abnormal behavior of TRK-related proteins has been found in glioma, acute myeloid leukemia (AML), lung cancer, breast cancer and other cancers, and it has been proved that it is closely related to the occurrence and development of cancer. Abnormal activation of TRK protein caused by NTRK gene fusion has been proved to be a key factor in causing tumors. Unfortunately, NTRK gene fusion usually results in the loss of the extracellular domain of the TRK protein, which means that inhibitors targeting the protein ectodomain, such as monoclonal antibodies, will no longer be effective against NTRK gene fusion cancers. Therefore, small-molecule TRK inhibitors should be the only effective means to solve NTRK gene fusion cancers.
本发明着眼于NTRK基因融合型肿瘤，设计具有通式(I)或通式(II)所示结构的氨基嘧啶衍生物，并发现具有此类结构的化合物表现出较好的TRK抑制活性，可以用以治疗由NTRK基因融合所引起的肿瘤或与TRK表达异常相关的其他疾病。The present invention focuses on NTRK gene fusion tumors, designs aminopyrimidine derivatives with structures shown in general formula (I) or general formula (II), and finds that compounds with such structures show better TRK inhibitory activity, which can It is used to treat tumors caused by NTRK gene fusion or other diseases related to abnormal expression of TRK.
发明内容Contents of the invention
本发明的目的在于提供一种新型氨基嘧啶衍生物、其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，以及其制备方法和在制备治疗剂特别是TRK抑制剂中的用途。The object of the present invention is to provide a novel aminopyrimidine derivative, its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug, and its preparation method and in the preparation of therapeutic agent, especially TRK inhibitor use in .
具体地，通过以下几个方面的技术方案实现了本发明：Specifically, the present invention is realized through the technical solutions of the following aspects:
在第一个方面中，本发明提供了一种氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，所述氨基嘧啶衍生物具有通式(I)或通式(II)所示结构：In a first aspect, the present invention provides an aminopyrimidine derivative having the general formula ( I) or structure shown in general formula (II):
Figure PCTCN2022112391-appb-000001
Figure PCTCN2022112391-appb-000001
其中，R 1选自氢，卤素，硝基，氰基，C1-C4烷基，C1-C4卤代烷基，N上有烷基取代或无取代的氨基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and N has alkyl substituted or unsubstituted amino;
R 2选自芳基甲基氨基，2-芳基吡咯烷基，2-芳基氮杂环丁烷基或2-芳基哌啶基， R is selected from arylmethylamino, 2-arylpyrrolidinyl, 2-arylazetidinyl or 2-arylpiperidinyl,
其中，芳基选自苯基，吡啶基或嘧啶基，并且所述芳基无取代或进一步被1-4个Ra取代；Wherein, the aryl is selected from phenyl, pyridyl or pyrimidinyl, and the aryl is unsubstituted or further substituted by 1-4 R;
Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
R 3选自氢，卤素，磺胺基，羟基，烷氧基，O上有取代或无取代的羟甲基，N上有烷基取代或无取代的氨基，N上被1-2个Rb所取代的酰胺基，含1-2个杂原子的C3-C7脂肪环， R3 is selected from hydrogen, halogen, sulfonamide, hydroxy, alkoxy, substituted or unsubstituted hydroxymethyl on O, N substituted or unsubstituted amino with alkyl, N replaced by 1-2 Rb Substituted amido, C3-C7 aliphatic ring containing 1-2 heteroatoms,
其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，或者在所述杂原子上进一步被C1-C4烷基取代；Wherein, the ring contains no more than 2 carbonyl groups, or the ring hydrogen atoms are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatoms are selected from nitrogen, oxygen or sulfur, or in the heteroatoms Atoms are further substituted by C1-C4 alkyl;
Rb选自氢，C1-C4烷基，C3-C7环烷基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms,
其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
X和Y选自C或N，且X和Y是相同的或不同的；X and Y are selected from C or N, and X and Y are the same or different;
Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a C1-C4 alkyl group.
在一个优选实施方式中，对于本发明所述的具有通式(I)或通式(II)所示结构的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药而言，In a preferred embodiment, for the aminopyrimidine derivatives or their stereoisomers, pharmaceutically acceptable salts, hydrates, For solvates or prodrugs,
其中，R 1选自氢，卤素，硝基，氰基，甲基，三氟甲基，氨基，甲氨基或二甲氨基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, methyl, trifluoromethyl, amino, methylamino or dimethylamino;
R 2选自芳基甲基氨基或2-芳基吡咯烷基， R is selected from arylmethylamino or 2-arylpyrrolidinyl,
其中，芳基选自苯基，吡啶基或嘧啶基，并且所述芳基无取代或进一步被1-4个Ra取代；Wherein, the aryl is selected from phenyl, pyridyl or pyrimidinyl, and the aryl is unsubstituted or further substituted by 1-4 R;
Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
R 3选自氢，卤素，磺胺基，羟基，烷氧基，O上有取代或无取代的羟甲基，N上有烷基取代或无取代的氨基，N上被1-2个Rb所取代的酰胺基，含1-2个杂原子的C3-C7脂肪环， R3 is selected from hydrogen, halogen, sulfonamide, hydroxy, alkoxy, substituted or unsubstituted hydroxymethyl on O, N substituted or unsubstituted amino with alkyl, N replaced by 1-2 Rb Substituted amido, C3-C7 aliphatic ring containing 1-2 heteroatoms,
其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
Rb选自氢，C1-C4烷基，C3-C7环烷基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms,
其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
X和Y均为C；Both X and Y are C;
Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被甲基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a methyl group.
在另一个优选实施方式中，对于本发明所述的具有通式(I)或通式(II)所示结构的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药而言，In another preferred embodiment, for the aminopyrimidine derivatives or their stereoisomers, pharmaceutically acceptable salts, and hydrates thereof having the structure shown in general formula (I) or general formula (II) described in the present invention , solvates or prodrugs,
其中，R 1选自氢，卤素，硝基，氰基，甲基，三氟甲基，氨基，甲氨基或二甲氨基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, methyl, trifluoromethyl, amino, methylamino or dimethylamino;
R 2选自苄胺基或2-苯基吡咯烷基，并且所述R 2无取代或进一步被1-4个Ra取代； R 2 is selected from benzylamino or 2-phenylpyrrolidinyl, and said R 2 is unsubstituted or further substituted by 1-4 Ra;
Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
R 3选自氢，卤素，磺胺基，O上有取代或无取代的羟甲基，N上有烷基取代或无取代的氨基，N上被1-2个Rb所取代的酰胺基，含1-2个杂原子的C3-C7脂肪环， R3 is selected from hydrogen, halogen, sulfonamide, substituted or unsubstituted hydroxymethyl on O, alkyl substituted or unsubstituted amino on N, amido group substituted by 1-2 Rb on N, containing C3-C7 aliphatic ring with 1-2 heteroatoms,
其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
Rb选自氢，C1-C4烷基，C3-C7环烷基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms,
其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
X和Y均为C；Both X and Y are C;
Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被甲基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a methyl group.
在又一个优选实施方式中，对于本发明所述的具有通式(I)或通式(II)所示结构的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药而言，In yet another preferred embodiment, for the aminopyrimidine derivatives or their stereoisomers, pharmaceutically acceptable salts, and hydrates thereof having the structure shown in general formula (I) or general formula (II) described in the present invention , solvates or prodrugs,
其中，R 1选自氢，卤素，硝基，氰基，甲基或三氟甲基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, methyl or trifluoromethyl;
R 2选自苄胺基或2-苯基吡咯烷基，并且所述R 2无取代或进一步被1-4个Ra取代； R 2 is selected from benzylamino or 2-phenylpyrrolidinyl, and said R 2 is unsubstituted or further substituted by 1-4 Ra;
Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
R 3选自氢，磺胺基，羟甲基，被C1-C4烷基取代的羟甲基，氨基，甲氨基，二甲氨基，吗啉基，硫代吗啉基，哌嗪基，被C1-C4烷基取代的哌嗪基，高哌嗪基，被C1-C4烷基取代的高哌嗪基，2-氧代吗啉基，2-氧代哌嗪基，3-氧代哌嗪基，哌啶基，1-氮杂环丁基，吡咯烷基或含有Rb取代的羰基； R3 is selected from hydrogen, sulfonamide, hydroxymethyl, hydroxymethyl substituted by C1-C4 alkyl, amino, methylamino, dimethylamino, morpholinyl, thiomorpholinyl, piperazinyl, substituted by C1 -C4 alkyl substituted piperazinyl, homopiperazinyl, homopiperazinyl substituted by C1-C4 alkyl, 2-oxomorpholinyl, 2-oxopiperazinyl, 3-oxopiperazinyl Base, piperidinyl, 1-azetidinyl, pyrrolidinyl or carbonyl substituted with Rb;
Rb选自氢，N上有取代或无取代的氨基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, substituted or unsubstituted amino groups on N, C3-C7 aliphatic rings containing 1-2 heteroatoms,
其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
或者，Rb选自含有Rc取代的氨基，吗啉基，硫代吗啉基，哌嗪基，被C1-C4烷基取代的哌嗪基，高哌嗪基，被C1-C4烷基取代的高哌嗪基，2-氧代吗啉基，2-氧代哌嗪基，3-氧代哌嗪基，哌啶基，1-氮杂环丁基，吡咯烷基，4-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代，3-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代；Alternatively, Rb is selected from the group consisting of Rc-substituted amino, morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl substituted by C1-C4 alkyl, homopiperazinyl, substituted by C1-C4 alkyl Homopiperazinyl, 2-oxomorpholinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, piperidinyl, 1-azetidinyl, pyrrolidinyl, 4-aminopiperidine , wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl groups, 3-aminopiperidinyl, wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl groups;
Rc选自氢，C1-C4烷基，C3-C7含1-2个杂原子的脂肪环，其中，环上可包括不多于2个羰基，环上氢原子可进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子可为氮，氧，硫，当杂原子为氮原子时，氮原子可进一步被C1-C4烷基取代；Rc is selected from hydrogen, C1-C4 alkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms, wherein, the ring may include no more than 2 carbonyl groups, and the ring hydrogen atoms may be further replaced by no more than 2 There are alkyl substituted or unsubstituted amino substituted, the heteroatom can be nitrogen, oxygen, sulfur, when the heteroatom is nitrogen atom, the nitrogen atom can be further substituted by C1-C4 alkyl;
或者，Rb选自氢，氨基，二甲氨基，哌啶-4-氨基，其中所述哌啶环上的N原子无取代或进一步被C1-C4烷基取代，哌啶-3-氨基，其中所述哌啶环上的N原子无取代或进一步被C1-C4烷基取代，四氢吡咯基-2-氨基，其中所述四氢吡唑环上的N原子无取代或进一步被C1-C4烷基取代，氮杂环丁基-2-氨基，其中所述氮杂环丁基上的N原子无取代或进一步被 C1-C4烷基取代，吗啉基，硫代吗啉基，哌嗪基，被C1-C4烷基取代的哌嗪基，高哌嗪基，被C1-C4烷基取代的高哌嗪基，2-氧代吗啉基，2-氧代哌嗪基，3-氧代哌嗪基，哌啶基，1-氮杂环丁基，吡咯烷基，4-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代，3-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代；Alternatively, Rb is selected from hydrogen, amino, dimethylamino, piperidine-4-amino, wherein the N atom on the piperidine ring is unsubstituted or further substituted by C1-C4 alkyl, piperidine-3-amino, wherein The N atom on the piperidine ring is unsubstituted or further substituted by C1-C4 alkyl, tetrahydropyrrolyl-2-amino, wherein the N atom on the tetrahydropyrazole ring is unsubstituted or further substituted by C1-C4 Alkyl substitution, azetidinyl-2-amino, wherein the N atom on the azetidinyl is unsubstituted or further substituted by C1-C4 alkyl, morpholinyl, thiomorpholinyl, piperazine Base, piperazinyl substituted by C1-C4 alkyl, homopiperazinyl, homopiperazinyl substituted by C1-C4 alkyl, 2-oxomorpholinyl, 2-oxopiperazinyl, 3- Oxopiperazinyl, piperidinyl, 1-azetidinyl, pyrrolidinyl, 4-aminopiperidinyl, wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl, 3 -aminopiperidinyl, wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl groups;
X和Y均为C；Both X and Y are C;
Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被甲基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a methyl group.
在一个更优选的实施方式中，对于本发明所述的具有通式(I)或通式(II)所示结构的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药而言，所述衍生物如下所示：In a more preferred embodiment, for the aminopyrimidine derivatives or their stereoisomers, pharmaceutically acceptable salts, hydrated For compounds, solvates or prodrugs, the derivatives are as follows:
4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基苯磺酰胺(实施例1)；4-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}aminobenzenesulfonamide (Example 1);
3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基苯磺酰胺(实施例2)；3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}aminobenzenesulfonamide (Example 2);
[3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苄基]甲醇(实施例3)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzyl]methanol (Example 3);
5-氯-N 2-[4-(二甲氨基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例4)； 5-Chloro-N 2 -[4-(dimethylamino)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 4);
5-氯-N 2-[4-(4-甲基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例5)； 5-Chloro- N2- [4-(4-methylpiperazin-1-yl)benzyl] -N4- (trifluorobenzyl)pyrimidine-2,4-diamine (Example 5);
5-氯-N 2-[3-(4-甲基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例6)； 5-Chloro- N2- [3-(4-methylpiperazin-1-yl)benzyl] -N4- (trifluorobenzyl)pyrimidine-2,4-diamine (Example 6);
5-氯-N 2-[4-(4-乙基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例7)； 5-chloro-N 2 -[4-(4-ethylpiperazin-1-yl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 7);
5-氯-N 2-[4-(4-吗啉基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例8)； 5-chloro-N 2 -[4-(4-morpholinyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 8);
5-氯-N 2-[3-(4-吗啉基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例9)； 5-chloro-N 2 -[3-(4-morpholinyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 9);
4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基苯甲酰胺(实施例10)；4-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}aminobenzamide (Example 10);
5-氯-N 2-[3-(乙氧基甲基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例11)； 5-chloro-N 2 -[3-(ethoxymethyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 11);
5-氯-N 2-[3-(异丙氧基甲基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例12)； 5-chloro-N 2 -[3-(isopropoxymethyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 12);
4-[4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苄基]吗啉-3-酮(实施例13)；4-[4-({5-Chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzyl]morpholin-3-one (Example 13);
[4-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基哌嗪-1-基)甲基酮(实施例14)；[4-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methylpiperazin-1-yl)methyl ketone (Example 14);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基哌嗪-1-基)甲基酮(实施例15)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methylpiperazin-1-yl)methylketone (Example 15);
[4-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](吗啉基)甲基酮(实施例16)；[4-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](morpholinyl)methyl ketone (Example 16);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](吗啉基)甲基酮(实施例17)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](morpholinyl)methyl ketone (Example 17);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](哌啶-1-基)甲基酮(实施例18)；[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](piperidin-1-yl)methylketone (Example 18);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-乙基哌嗪-1-基)甲基酮(实施例19)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-ethylpiperazin-1-yl)methyl ketone (Example 19);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-异丙基哌嗪-1-基)甲基酮(实施例20)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-isopropylpiperazin-1-yl)methyl ketone (implementation Example 20);
4-[3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苯甲酰基]哌嗪-2-酮(实施例21)；4-[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzoyl]piperazin-2-one (Example 21);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](哌嗪-1-基)甲基酮(实施例22)；[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](piperazin-1-yl)methylketone (Example 22);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基-1,4高哌嗪-1-基)甲基酮(实施例23)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methyl-1,4-homopiperazin-1-yl)methyl Ketone (Example 23);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](1,4高哌嗪-1-基)甲基酮(实施例24)；[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](1,4-homopiperazin-1-yl)methylketone (Example twenty four);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基][4-(二甲氨基)哌啶-1-基]甲基酮(实施例25)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl][4-(dimethylamino)piperidin-1-yl]methylketone (Example 25);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基][4-(甲氨基)哌啶-1-基]甲基酮(实施例26)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl][4-(methylamino)piperidin-1-yl]methyl ketone ( Example 26);
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-氨基哌啶-1-基)甲基酮(实施例27)；[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-aminopiperidin-1-yl)methyl ketone (Example 27 );
3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(1-甲基哌啶-4-基)苯甲酰胺(实施例28)；3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(1-methylpiperidin-4-yl)benzamide (Example 28 );
3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-4-基)苯甲酰胺(实施例29)；3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-4-yl)benzamide (Example 29);
(R)-[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](3-氨基哌啶-1-基)甲基酮(实施例 30)；(R)-[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](3-aminopiperidin-1-yl)methylketone (Example 30);
(S)-[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](3-氨基哌啶-1-基)甲基酮(实施例31)；(S)-[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](3-aminopiperidin-1-yl)methylketone (Example 31);
(S)-3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例32)；(S)-3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 32 );
(R)-3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例33)；(R)-3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 33 );
3-({5-氯-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例34)；3-({5-Chloro-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 34);
3-({5-氯-4-[(3,5-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例35)；3-({5-chloro-4-[(3,5-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 35) ;
3-({5-氯-4-[(3,4,5-三氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例36)；3-({5-chloro-4-[(3,4,5-trifluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 36);
3-({5-氯-4-[(2-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例37)；3-({5-Chloro-4-[(2-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 37);
3-({5-氯-4-[(3,4-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例38)；3-({5-chloro-4-[(3,4-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 38) ;
3-({5-氯-4-[(2,6-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例39)；3-({5-chloro-4-[(2,6-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 39) ;
3-({5-氯-4-[(2,5-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例40)；3-({5-chloro-4-[(2,5-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 40) ;
3-({5-氯-4-[(2,4-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例41)；3-({5-chloro-4-[(2,4-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 41) ;
3-({5-氯-4-[(2,3-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例42)；3-({5-chloro-4-[(2,3-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 42) ;
3-({5-氯-4-[2-(3-氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例42)；3-({5-chloro-4-[2-(3-fluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 42);
3-({5-氯-4-[2-(4-氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例44)；3-({5-chloro-4-[2-(4-fluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 44);
3-({5-氯-4-[2-(3,5-二氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例45)；3-({5-chloro-4-[2-(3,5-difluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl) Benzamide (Example 45);
3-({5-氯-4-[2-(3,4,5-三氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例46)；3-({5-chloro-4-[2-(3,4,5-trifluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidine-3- base) benzamide (Example 46);
3-({5-氟-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例47)；3-({5-fluoro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 47);
3-({5-溴-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例48)；3-({5-bromo-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 48);
3-({5-甲基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例49)；3-({5-methyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 49);
3-({5-硝基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例50)；3-({5-nitro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 50);
3-({4-[(3-氟苄基)氨基]-5H-吡咯[3,2-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例51)；3-({4-[(3-fluorobenzyl)amino]-5H-pyrrole[3,2-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (implementation Example 51);
3-({4-[(3-氟苄基)氨基]-7H-吡咯[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例52)；3-({4-[(3-fluorobenzyl)amino]-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (implementation Example 52);
3-({4-[(3-氟苄基)氨基]-7-甲基-7H-吡咯[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例53)；3-({4-[(3-fluorobenzyl)amino]-7-methyl-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl) Benzamide (Example 53);
3-({4-[(3-氟苄基)氨基]噻吩[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例54)；3-({4-[(3-fluorobenzyl)amino]thiophene[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (Example 54) ;
3-({4-[(3-氟苄基)氨基]噻吩[3,2-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例55)；3-({4-[(3-fluorobenzyl)amino]thiophene[3,2-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (Example 55) ;
3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例56)；3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 56 );
3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例57)；3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 57 );
(R)-3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例58)；(R)-3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 58);
(R)-3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例59)；(R)-3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 59);
(S)-3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例60)；或(S)-3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 60); or
(S)-3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施 例61)。(S)-3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 61).
在第二个方面中，本发明提供了上述第一个方面所述的通式(I)所示氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药的制备方法：In the second aspect, the present invention provides the aminopyrimidine derivatives represented by the general formula (I) or stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or The preparation method of prodrug:
Figure PCTCN2022112391-appb-000002
Figure PCTCN2022112391-appb-000002
(1)目标衍生物具有如通式3所示结构或类似结构，且R 1为卤素，硝基，氰基或其他给电子基，R 3为不含有酰胺键的取代基时，按照路线1所示方法制备，即，以多氯取代的嘧啶为起始原料1，在碱性条件下与不同取代的苄胺经过选择性取代反应得到中间体2，中间体2在酸催化的条件下，与不同取代的芳胺经过取代反应得到目标化合物3，根据路线1方法亦可制备具有与通式3类似结构的目标化合物，将条件a中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物； (1) The target derivative has a structure as shown in general formula 3 or a similar structure, and R 1 is halogen, nitro, cyano or other electron-donating groups, and R 3 is a substituent that does not contain an amide bond, according to route 1 Prepared by the method shown, that is, using polychlorinated pyrimidine as the starting material 1, undergoing selective substitution reactions with different substituted benzylamines under alkaline conditions to obtain intermediate 2, intermediate 2 is under acid-catalyzed conditions, The target compound 3 can be obtained through substitution reaction with different substituted arylamines. The target compound with a structure similar to the general formula 3 can also be prepared according to the method of route 1. The benzylamine in condition a is replaced by other amines, and the compound containing other groups can be prepared. Group substituted target compound;
进一步地，以多氯嘧啶作为起始原料1，与不同取代的苄胺经过亲核取代反应得到中间体2，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为0～78℃，优选25℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺；中间体2与不同取代的芳胺反应得到目标化合物3，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为30～150℃，优选120℃，反应中的酸可为氯化氢的乙酸乙酯饱和溶液，氯化氢的乙醇溶液，氯化氢的1,4-二氧六环溶液，氯化氢的甲醇溶液，氯化氢的水溶液，对甲苯磺酸，苯磺酸等，优选氯化氢的1,4-二氧六环溶液；Further, polychloropyrimidine is used as starting material 1, and intermediate 2 is obtained through nucleophilic substitution reaction with different substituted benzylamines. The reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec. Butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 0～78°C, preferably 25°C, the reaction The base in can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine; intermediate 2 and The target compound 3 can be obtained by reaction of different substituted aromatic amines. The reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4 -Dioxane, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 30-150°C, preferably 120°C, the acid in the reaction can be saturated ethyl acetate solution of hydrogen chloride, ethanol solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, methanol solution of hydrogen chloride, aqueous solution of hydrogen chloride, p-toluenesulfonic acid, benzenesulfonic acid, etc., preferably 1,4-dioxane solution of hydrogen chloride;
Figure PCTCN2022112391-appb-000003
Figure PCTCN2022112391-appb-000003
(2)目标衍生物具有如通式6所示结构或类似结构，且R 3为不含有酰胺键的取代基时，按照路线2所示方法制备，即，以5-三氟甲基-2,4-二氯嘧啶为起始原料4，在碱性条件下经过选择性取代反应得到中间体5，中间体5进一步在碱性条件下发生取代反应得到目标化合物6，根据路线2方法亦可制备具有与通式6类似结构的目标化合物，将条件d中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物； (2) When the target derivative has a structure as shown in general formula 6 or a similar structure, and R3 is a substituent that does not contain an amide bond, it can be prepared according to the method shown in route 2, that is, with 5-trifluoromethyl-2 , 4-dichloropyrimidine is the starting material 4, and intermediate 5 is obtained through selective substitution reaction under alkaline conditions, and intermediate 5 is further subjected to substitution reaction under alkaline conditions to obtain target compound 6, which can also be obtained according to the method of route 2 Prepare a target compound having a structure similar to that of general formula 6, and replace the benzylamine in condition d with other amines to prepare a target compound containing other group substitutions;
进一步地，以5-三氟甲基-2,4-二氯嘧啶为起始原料4，与不同取代的芳胺发生亲核取代反应得到中间体5，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选叔丁醇，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺，反应温度为0～100℃，优选70℃；中间体5与不同取代的胺发生亲核取代反应得到目标化合物6，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选N,N-二甲基甲酰胺，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺，反应温度为55～185℃，优选120℃；Further, using 5-trifluoromethyl-2,4-dichloropyrimidine as the starting material 4, nucleophilic substitution reaction with different substituted aromatic amines to obtain intermediate 5, the reaction solvent can be methanol, ethanol, isopropyl Alcohol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably tert-butanol, The base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine, and the reaction temperature is 0～100°C, preferably 70°C; intermediate 5 undergoes nucleophilic substitution reaction with different substituted amines to obtain target compound 6, the reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol , n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably N,N-dimethylformamide, the base in the reaction can be three Ethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine, the reaction temperature is 55～185℃, preferably 120 ℃;
Figure PCTCN2022112391-appb-000004
Figure PCTCN2022112391-appb-000004
(3)目标衍生物具有如通式8所示结构或类似的结构，且R 1为卤素，硝基，氰基或其他给电子基时，按照路线3所示方法制备，即，以多氯取代的嘧啶为起始原料1，在碱性条件下经过选择性取代反应得到中间体2，中间体2在酸催化条件下与间氨基苯甲酸反应得到中间体7，中间体7与不同的胺缩合得到目标化合物8，根据路线3方法亦可制备具有类似结构的目标化合物，将条件a中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物；将条件d中的反应物由间氨基苯甲酸替换为对氨基苯甲酸即可制备取代基在对位的产物；将条件e中不同的胺替换为含有Boc保护的胺，并在原有缩合反应后串联强酸性条件下的脱保护反应，即可得到通式8所示结构的其他类似物； (3) When the target derivative has a structure as shown in general formula 8 or a similar structure, and when R is halogen, nitro, cyano or other electron-donating groups, it is prepared according to the method shown in route 3, that is, with polychloro Substituted pyrimidine is the starting material 1, and intermediate 2 is obtained through selective substitution reaction under alkaline conditions, intermediate 2 is reacted with m-aminobenzoic acid under acid-catalyzed conditions to obtain intermediate 7, and intermediate 7 is combined with different amines Condensation to obtain the target compound 8, the target compound with a similar structure can also be prepared according to the method of route 3, and the benzylamine in the condition a is replaced by other amines, and the target compound containing other groups can be prepared; the reaction in the condition d The product with the substituent at the para-position can be prepared by replacing m-aminobenzoic acid with p-aminobenzoic acid; replacing the different amines in condition e with amines containing Boc protection, and connecting in series under strong acidic conditions after the original condensation reaction Deprotection reaction can obtain other analogs of the structure shown in general formula 8;
进一步地，以多氯嘧啶为起始原料1，与不同取代的苄胺经过亲核取代反应得到中间体2，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为0～78℃，优选25℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺；中间体2与间氨基苯甲酸反应中间体7，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为30～150℃，优选120℃，反应中的酸可为氯化氢的乙酸乙酯饱和溶液，氯化氢的乙醇溶液，氯化氢的1,4-二氧六环溶液，氯化氢的甲醇溶液，氯化氢的水溶液，对甲苯磺酸，苯磺酸等，优选氯化氢的1,4-二氧六环溶液。中间体7与不同的胺经过缩合反应得到目标化合物8，反应溶剂可为二氯甲烷，三氯甲烷，丙酮，N,N-二甲基甲酰胺，二甲基亚砜，四氢呋喃，1,4-二氧六环等，优选N,N-二甲基甲酰胺，反应温度为-20～40℃，优选0～20℃，反应中使用的缩合剂可为氯化亚砜，草酰氯，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，O-苯并三氮唑-四甲基脲六氟磷酸盐，二环己基碳二亚胺，1-羟基苯并三唑，(1-乙基-3(3-二甲基丙胺)碳二亚胺)等，优选1-羟基苯并三唑，及(1-乙基-3(3-二甲基丙胺)碳二亚胺)，反应中的碱可为碳酸铯，碳酸钾，碳酸钠，三乙胺，N,N-二异丙基乙胺等，优选N,N-二异丙基乙胺；强酸条件下的脱保护反应的反应溶剂可为乙酸乙酯，甲醇，乙醇，二氧六环等，优选乙酸乙酯，反应温度为-20～40℃，优选0～20℃，反应中的酸可为盐酸，三氟乙酸，苯磺酸等，优选盐酸；Further, polychloropyrimidine is used as starting material 1, and intermediate 2 is obtained through nucleophilic substitution reaction with different substituted benzylamines. The reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec. Butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 0～78°C, preferably 25°C, the reaction The base in can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine; intermediate 2 and m-aminobenzoic acid reaction intermediate 7, the reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4-di Oxycycline, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 30-150°C, preferably 120°C, the acid in the reaction can be saturated ethyl acetate solution of hydrogen chloride, ethanol solution of hydrogen chloride, hydrogen chloride 1,4-dioxane solution, methanol solution of hydrogen chloride, aqueous solution of hydrogen chloride, p-toluenesulfonic acid, benzenesulfonic acid, etc., preferably 1,4-dioxane solution of hydrogen chloride. Intermediate 7 can be condensed with different amines to obtain the target compound 8. The reaction solvent can be dichloromethane, chloroform, acetone, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4 -Dioxane, etc., preferably N,N-dimethylformamide, the reaction temperature is -20 to 40°C, preferably 0 to 20°C, the condensing agent used in the reaction can be thionyl chloride, oxalyl chloride, 2 -(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetramethyluronium hexafluorophosphate, di Cyclohexylcarbodiimide, 1-hydroxybenzotriazole, (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), etc., preferably 1-hydroxybenzotriazole, and (1- Ethyl-3 (3-dimethylpropylamine) carbodiimide), the base in the reaction can be cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine etc., preferably N,N-diisopropylethylamine; the reaction solvent for the deprotection reaction under strong acid conditions can be ethyl acetate, methanol, ethanol, dioxane, etc., preferably ethyl acetate, and the reaction temperature is -20～40℃ , preferably 0-20°C, the acid in the reaction can be hydrochloric acid, trifluoroacetic acid, benzenesulfonic acid, etc., preferably hydrochloric acid;
Figure PCTCN2022112391-appb-000005
Figure PCTCN2022112391-appb-000005
(4)目标衍生物具有如通式12所示结构或类似的结构，按照路线4所示方法制备，即，以间氨基苯甲酸为起始原料9，与不同的胺经过缩合反应得到中间体10，中间体10与5-三氟甲基-2,4-二氯嘧啶发生取代反应得到中间体11，中间体11与不同取代的苄胺经过取 代反应得到目标化合物12，根据路线4方法亦可制备具有类似结构的目标化合物，将条件e中不同的胺替换为含有Boc保护的胺，并在原有条件h后串联强酸性条件下的脱保护反应，即可得到通式12所示结构的其他类似物；将条件f中的反应物由间氨基苯甲酸替换为对氨基苯甲酸即可制备取代基在对位的产物；将条件h中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物；(4) The target derivative has a structure as shown in general formula 12 or a similar structure, and is prepared according to the method shown in route 4, that is, using m-aminobenzoic acid as the starting material 9, and reacting with different amines to obtain an intermediate 10, intermediate 10 undergoes a substitution reaction with 5-trifluoromethyl-2,4-dichloropyrimidine to obtain intermediate 11, and intermediate 11 undergoes a substitution reaction with differently substituted benzylamines to obtain target compound 12, and the method according to route 4 is also The target compound with a similar structure can be prepared by replacing the different amines in condition e with amines containing Boc protection, and deprotecting reactions under strong acidic conditions in series after the original condition h, to obtain the structure shown in general formula 12 Other analogs; the reactant in the condition f is replaced by p-aminobenzoic acid by m-aminobenzoic acid to prepare the product with the substituent at the para-position; the benzylamine in the condition h is replaced by other amines to prepare the product containing other The target compound of group substitution;
进一步地以间氨基苯甲酸为起始原料，与不同的胺发生缩合反应得到中间体10，反应溶剂可为二氯甲烷，三氯甲烷，丙酮，N,N-二甲基甲酰胺，二甲基亚砜，四氢呋喃，1,4-二氧六环等，优选N,N-二甲基甲酰胺，反应温度为-20～40℃，优选0～20℃，反应中使用的缩合剂可为氯化亚砜，草酰氯，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，O-苯并三氮唑-四甲基脲六氟磷酸盐，二环己基碳二亚胺，1-羟基苯并三唑，(1-乙基-3(3-二甲基丙胺)碳二亚胺)等，优选1-羟基苯并三唑，及(1-乙基-3(3-二甲基丙胺)碳二亚胺)，反应中的碱可为碳酸铯，碳酸钾，碳酸钠，三乙胺，N,N-二异丙基乙胺等，优选N,N-二异丙基乙胺；中间体10与5-三氟甲基-2,4-二氯嘧啶发生取代反应得到中间体11，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选叔丁醇，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺，反应温度为0～100℃，优选70℃；中间体11与不同取代的胺发生亲核取代反应得到目标化合物12，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选N,N-二甲基甲酰胺，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺，反应温度为55～185℃，优选120℃。Further, m-aminobenzoic acid is used as the starting material to undergo condensation reaction with different amines to obtain intermediate 10. The reaction solvent can be dichloromethane, chloroform, acetone, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, etc., preferably N,N-dimethylformamide, the reaction temperature is -20 to 40°C, preferably 0 to 20°C, and the condensing agent used in the reaction can be Thionyl chloride, oxalyl chloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-tetra Methylurea hexafluorophosphate, dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, (1-ethyl-3(3-dimethylpropylamine)carbodiimide), etc., preferably 1-hydroxy Benzotriazole, and (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), the base in the reaction can be cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, N,N- Diisopropylethylamine, etc., preferably N,N-diisopropylethylamine; Intermediate 10 undergoes a substitution reaction with 5-trifluoromethyl-2,4-dichloropyrimidine to obtain Intermediate 11, and the reaction solvent can be Methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide , preferably tert-butanol, the base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropyl Ethylamine, the reaction temperature is 0-100°C, preferably 70°C; intermediate 11 undergoes nucleophilic substitution reaction with different substituted amines to obtain the target compound 12, and the reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert- Butanol, sec-butanol, n-butanol, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably N,N-dimethylformamide, reaction The base in can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine, and the reaction temperature is 55 ~185°C, preferably 120°C.
在第三个方面中，本发明提供了上述第一个方面所述的通式(II)所示氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药的制备方法：In the third aspect, the present invention provides the aminopyrimidine derivative represented by general formula (II) or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or The preparation method of prodrug:
Figure PCTCN2022112391-appb-000006
Figure PCTCN2022112391-appb-000006
(1)目标衍生物具有如通式15所示结构或类似的结构，按照路线5所示方法制备，即，将起始原料13在碱性条件下与不同取代的苄胺发生取代反应得到中间体14，中间体14与不同的芳胺发生钯催化的偶联反应得到目标化合物15，其中，部分含有Boc保护的复杂芳胺需要在钯催化的偶联反应后串联强酸条件下的脱保护反应，才能得到目标化合物，根据路线5方法亦可制备具有类似结构的目标化合物，将起始原料13中的噻吩环替换为呋喃环，N上含有取代基的吡咯环或者改变杂原子的位置，即可得到不同母核的通式15所示结构的其他类似物；将条件i中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物；(1) The target derivative has a structure as shown in general formula 15 or a similar structure, and is prepared according to the method shown in route 5, that is, the starting material 13 is substituted with different substituted benzylamines under basic conditions to obtain the intermediate Compound 14, intermediate 14 undergoes palladium-catalyzed coupling reaction with different arylamines to obtain the target compound 15, among which, some of the complex arylamines containing Boc protection need to be deprotected in series under strong acid conditions after the palladium-catalyzed coupling reaction , in order to obtain the target compound, the target compound with a similar structure can also be prepared according to the method of route 5, the thiophene ring in the starting material 13 is replaced by the furan ring, the pyrrole ring with a substituent on the N or the position of the heteroatom is changed, that is Other analogs of the structure shown in the general formula 15 with different cores can be obtained; the benzylamine in the condition i is replaced by other amines, and the target compound containing other group substitutions can be prepared;
进一步地，将起始原料13与不同取代的苄胺经过亲核取代反应得到中间体14，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为0～78℃，优选25℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺；中间体14与不同的芳胺发生钯催化的偶联反应得到目标化合物15，反应温度为90～150℃，优选100～120℃，反应溶剂可为二甲基亚砜，甲苯，N,N-二甲基甲酰胺，N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃等，优选1,4-二氧六环，催化剂可为乙酸钯，Pd(dba) 2，四三苯基磷钯，PdCl 2(dppf) 2等，优选乙酸钯，配体可为三苯基磷，Xphos，Xtanphos等，优选Xtanphos，碱可为乙酸钾，碳酸钾，碳酸钠，碳酸氢钠，氢化钠，叔丁醇钾，叔丁醇 钠，碳酸铯，甲醇钠，乙醇钠等，优选碳酸铯； Further, intermediate 14 is obtained by reacting starting material 13 with different substituted benzylamines through nucleophilic substitution. The reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol Alcohol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 0～78°C, preferably 25°C, the base in the reaction can be Triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine; intermediate 14 occurs with different aromatic amines The target compound 15 can be obtained by palladium-catalyzed coupling reaction. The reaction temperature is 90-150°C, preferably 100-120°C. The reaction solvent can be dimethyl sulfoxide, toluene, N,N-dimethylformamide, N-formaldehyde Pyrrolidone, 1,4-dioxane, tetrahydrofuran, etc., preferably 1,4-dioxane, the catalyst can be palladium acetate, Pd(dba) 2 , tetrakistriphenylphosphopalladium, PdCl 2 (dppf) 2 etc., preferably palladium acetate, the ligand can be triphenylphosphine, Xphos, Xtanphos, etc., preferably Xtanphos, the base can be potassium acetate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydride, potassium tert-butoxide, tert-butanol Sodium, cesium carbonate, sodium methoxide, sodium ethoxide, etc., preferably cesium carbonate;
Figure PCTCN2022112391-appb-000007
Figure PCTCN2022112391-appb-000007
(2)目标衍生物具有如通式20所示结构或类似的结构，按照路线6所示方法制备，即，使起始原料16经过Ts保护得到中间体17，中间体17与不同取代的苄胺反应得到中间体18，中间体18经过钯催化的偶联反应得到中间体19，中间体19在碱性条件下脱除Ts保护得到目标化合物20，其中，部分含有Boc保护的复杂芳胺需要在钯催化的偶联反应后串联强酸条件下的脱保护反应，才能得到中间体19，根据路线6方法亦可制备具有类似结构的目标化合物，将条件i中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物；改变起始原料16中N原子的位置，可得到具有其他母核的目标化合物；(2) The target derivative has a structure as shown in the general formula 20 or a similar structure, and is prepared according to the method shown in Route 6, that is, the starting material 16 is protected by Ts to obtain the intermediate 17, and the intermediate 17 and different substituted benzyl Amine reaction to obtain intermediate 18, intermediate 18 undergoes a palladium-catalyzed coupling reaction to obtain intermediate 19, intermediate 19 is deprotected by Ts under basic conditions to obtain target compound 20, and some of them contain complex aromatic amines protected by Boc. Intermediate 19 can be obtained only after the palladium-catalyzed coupling reaction and deprotection reaction under strong acid conditions. The target compound with similar structure can also be prepared according to the method of route 6, and the benzylamine in the condition i is replaced by other amines, i.e. The target compound containing other group substitutions can be prepared; changing the position of the N atom in the starting material 16 can obtain the target compound with other parent nuclei;
进一步地，使起始原料16经过Ts保护得到中间体17，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，二氯甲烷，三氯甲烷，甲基叔丁基醚，乙醚等，优选四氢呋喃，反应温度可为35～125℃，优选80℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠，氢化钠，氢化钙等，优选氢化钠；中间体17与不同取代的苄胺反应得到中间体18，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为0～78℃，优选25℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺；中间体18经过钯催化的偶联反应得到中间体19，反应温度为90～150℃，优选100～120℃，反应溶剂可为二甲基亚砜，甲苯，N,N-二甲基甲酰胺，N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃等，优选1,4-二氧六环，催化剂可为乙酸钯，Pd(dba) 2，四三苯基磷钯，PdCl 2(dppf) 2等，优选乙酸钯，配体可为三苯基磷，Xphos，Xtanphos等，优选Xtanphos，碱可为乙酸钾，碳酸钾，碳酸钠，碳酸氢钠，氢化钠，叔丁醇钾，叔丁醇钠，碳酸铯，甲醇钠，乙醇钠等，优选碳酸铯；中间体19在碱性条件下脱除Ts保护得到目标化合物20，反应溶剂可为甲醇，乙醇，水，四氢呋喃，丙酮，1,4-二氧六环，N,N-二甲基甲酰胺，二甲基亚砜，N-甲基吡咯烷酮等，优选水和乙醇的混合溶液，反应温度为60～120℃，优选80～100℃，反应中的碱可为氢氧化钠，氢氧化钾，氢氧化铯等，优选氢氧化钠。 Further, the starting material 16 is protected by Ts to obtain the intermediate 17, and the reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, Tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dichloromethane, chloroform, methyl tert-butyl ether, diethyl ether, etc., preferably tetrahydrofuran, the reaction temperature can be 35～125℃ , preferably at 80°C, the base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydride, calcium hydride, etc., preferably sodium hydride; Intermediate 17 is reacted with different substituted benzylamines to obtain intermediate 18. The reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran , 1,4-dioxane, N,N-dimethylformamide, preferably ethanol, the reaction temperature is 0-78°C, preferably 25°C, the base in the reaction can be triethylamine, N,N-di Isopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably N,N-diisopropylethylamine; intermediate 18 is obtained by palladium-catalyzed coupling reaction, and the reaction temperature is 90～150℃, preferably 100～120℃, the reaction solvent can be dimethyl sulfoxide, toluene, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, etc. , preferably 1,4-dioxane, the catalyst can be palladium acetate, Pd(dba) 2 , tetrakistriphenylphosphine palladium, PdCl 2 (dppf) 2, etc., preferably palladium acetate, and the ligand can be triphenylphosphine , Xphos, Xtanphos, etc., preferably Xtanphos, the base can be potassium acetate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium methoxide, sodium ethoxide, etc., preferably carbonic acid Cesium; Intermediate 19 is deprotected by Ts under basic conditions to obtain the target compound 20, the reaction solvent can be methanol, ethanol, water, tetrahydrofuran, acetone, 1,4-dioxane, N,N-dimethylformaldehyde Amide, dimethyl sulfoxide, N-methylpyrrolidone, etc., preferably a mixed solution of water and ethanol, the reaction temperature is 60-120°C, preferably 80-100°C, the base in the reaction can be sodium hydroxide, potassium hydroxide , cesium hydroxide, etc., preferably sodium hydroxide.
在第四个方面中，本发明提供了一种药物组合物，所述药物组合物包含治疗有效量的上述第一个方面所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药以及药学上可接受的载体或赋形剂。In the fourth aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the aminopyrimidine derivative or stereoisomer thereof described in the first aspect, pharmaceutically acceptable salts, hydrates, solvates or prodrugs and pharmaceutically acceptable carriers or excipients.
在第五个方面中，本发明提供了上述第一个方面所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药或者上述第四个方面所述的药物组合物在制备TRK抑制剂中的用途。In the fifth aspect, the present invention provides the aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug described in the first aspect above or the fourth aspect Use of the pharmaceutical composition described in the aspect in the preparation of a TRK inhibitor.
在第六个方面中，本发明提供了上述第一个方面所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药或者上述第四个方面所述的药物组合物在制备预防或治疗与TRK的表达或活性相关的疾病的药物中的用途，其特征在于：优选地，所述疾病为肿瘤、癌症或由不同原因而引起的剧痛，特别是由NTRK基因融合而导致的癌症。In the sixth aspect, the present invention provides the aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug described in the first aspect above or the fourth The use of the pharmaceutical composition according to the aspect in the preparation of medicines for preventing or treating diseases related to the expression or activity of TRK, characterized in that: preferably, the diseases are tumors, cancers or severe pain caused by different reasons , especially cancers caused by NTRK gene fusions.
本发明相对于现有技术，具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
本发明着眼于NTRK基因融合型肿瘤，设计了一系列新型氨基嘧啶衍生物，并发现具有此类结构的化合物表现出较好的TRK抑制活性，可以用以治疗由NTRK基因融合所引起的肿瘤或与TRK表达异常相关的其他疾病。The present invention focuses on NTRK gene fusion tumors, designs a series of novel aminopyrimidine derivatives, and finds that compounds with such structures exhibit better TRK inhibitory activity, and can be used to treat tumors or tumors caused by NTRK gene fusion. Other diseases associated with abnormal expression of TRK.
具体实施方式Detailed ways
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。化合物的核磁共振氢谱用Bruker ARX-400测定；所用试剂均为分析纯或化学纯。The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described here are only used to explain the present invention, and are not intended to limit the scope of the present invention. The proton nuclear magnetic resonance spectrum of the compound was determined by Bruker ARX-400; the reagents used were analytically or chemically pure.
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field, or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased through regular channels.
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are commercially available products unless otherwise specified.
实施例1的制备路线如下所示：The preparation route of embodiment 1 is as follows:
Figure PCTCN2022112391-appb-000008
Figure PCTCN2022112391-appb-000008
具体合成步骤如下：Concrete synthetic steps are as follows:
2,5-二氯-N-(3-氟苄基)嘧啶-4-胺(2)的合成Synthesis of 2,5-dichloro-N-(3-fluorobenzyl)pyrimidin-4-amine (2)
将2,4,5-三氯嘧啶(1.00g,5.50mmol)溶于15mL无水乙醇，加入N,N-二异丙基乙胺(1.00mL,6.05mmol)，室温搅拌10min，向反应液内滴加3-氟苄胺(0.69mL,6.05mmol)的无水乙醇(15mL)溶液,室温反应。TLC监测原料反应完毕，旋除溶剂，柱层析纯化，得淡黄色固体，收率88％。Dissolve 2,4,5-trichloropyrimidine (1.00g, 5.50mmol) in 15mL of absolute ethanol, add N,N-diisopropylethylamine (1.00mL, 6.05mmol), stir at room temperature for 10min, and add to the reaction solution Add a solution of 3-fluorobenzylamine (0.69mL, 6.05mmol) in absolute ethanol (15mL) dropwise, and react at room temperature. The completion of the reaction of the raw materials was monitored by TLC, the solvent was removed by spin, and purified by column chromatography to obtain a light yellow solid with a yield of 88%.
4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苯磺酰胺(实施例1)的制备Preparation of 4-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide (Example 1)
将中间体2(0.10g,0.37mmol)溶于3mL异丙醇，加入4-氨基苯磺酰胺(0.070g,0.41mmol)和催化量的饱和的氯化氢1,4-二氧六环溶液，在封管下加热至120℃。TLC监测原料反应完毕，冷却反应液，有白色固体析出，过滤，用少量异丙醇洗涤滤饼，甲醇重结晶，得到白色粉末状固体，收率85％。 1H NMR(600MHz,DMSO-d 6)δ10.64(s,1H),9.00(s,1H),8.27(s,1H),7.70–7.58(m,4H),7.43–7.37(m,1H),7.26(s,2H),7.17(t,J＝9.8Hz,1H),7.09(td,J＝8.7,2.2Hz,1H),4.69(d,J＝5.5Hz,2H).HRMS(ESI,m/z)理论值C 17H 15ClFN 4O 2SNa[M+Na] +,430.0517；实测值430.0521。 Intermediate 2 (0.10 g, 0.37 mmol) was dissolved in 3 mL of isopropanol, 4-aminobenzenesulfonamide (0.070 g, 0.41 mmol) and a catalytic amount of saturated hydrogen chloride 1,4-dioxane solution were added, and Heat to 120°C under sealed tube. TLC monitored the completion of the raw material reaction, cooled the reaction solution, a white solid precipitated, filtered, washed the filter cake with a small amount of isopropanol, and recrystallized methanol to obtain a white powdery solid with a yield of 85%. 1 H NMR (600MHz,DMSO-d 6 )δ10.64(s,1H),9.00(s,1H),8.27(s,1H),7.70–7.58(m,4H),7.43–7.37(m,1H ),7.26(s,2H),7.17(t,J=9.8Hz,1H),7.09(td,J=8.7,2.2Hz,1H),4.69(d,J=5.5Hz,2H).HRMS(ESI , m/z) Theoretical value for C 17 H 15 ClFN 4 O 2 SNa[M+Na] + , 430.0517; found value 430.0521.
3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苯磺酰胺(实施例2)的制备Preparation of 3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide (Example 2)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为3-胺基苯磺酰胺，即得实施例2。 1H NMR(600MHz,DMSO-d 6)δ10.23(s,1H),8.69(s,1H),8.26–8.15(m,1H),8.11(d,J＝10.7Hz,1H),7.68(s,1H),7.52–7.31(m,5H),7.14(t,J＝9.5Hz,2H),7.05(td,J＝6.8,1.7Hz,1H),4.67(d,J＝5.7Hz,2H).HRMS(ESI,m/z)理论值C 17H 15ClFN 4O 2SNa[M+Na] +,430.0517；实测值430.0518。 With reference to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 3-aminobenzenesulfonamide in equal proportions to obtain Example 2. 1 H NMR (600MHz, DMSO-d 6 ) δ10.23(s, 1H), 8.69(s, 1H), 8.26–8.15(m, 1H), 8.11(d, J=10.7Hz, 1H), 7.68( s,1H),7.52–7.31(m,5H),7.14(t,J=9.5Hz,2H),7.05(td,J=6.8,1.7Hz,1H),4.67(d,J=5.7Hz,2H ). HRMS (ESI, m/z) calcd for C 17 H 15 ClFN 4 O 2 SNa[M+Na] + , 430.0517; found 430.0518.
[3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苄基]甲醇(实施例3)的制备Preparation of [3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzyl]methanol (Example 3)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为3-氨基苄醇，即得实施例3。 1H NMR(600MHz,DMSO-d 6)δ10.44(s,1H),9.15(s,1H),8.26(s,1H),7.46(s,1H),7.36(td,J＝8.0,6.2Hz,1H),7.30(d,J＝8.1Hz,1H),7.22(t,J＝7.8Hz,1H),7.13(t,J＝7.5Hz,2H),7.10–7.02(m,3H),4.66(d,J＝6.1Hz,2H),4.42(s,2H).HRMS(ESI,m/z)理论值C 18H 17ClFN 4O[M+H] +,359.1075；实测值359.1082。 With reference to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 3-aminobenzyl alcohol in equal proportions to obtain Example 3. 1 H NMR (600MHz, DMSO-d 6 ) δ10.44(s, 1H), 9.15(s, 1H), 8.26(s, 1H), 7.46(s, 1H), 7.36(td, J=8.0, 6.2 Hz,1H),7.30(d,J=8.1Hz,1H),7.22(t,J=7.8Hz,1H),7.13(t,J=7.5Hz,2H),7.10–7.02(m,3H), 4.66 (d, J = 6.1 Hz, 2H), 4.42 (s, 2H). HRMS (ESI, m/z) calcd for C 18 H 17 ClFN 4 O [M+H] + , 359.1075; found 359.1082.
5-氯-N 2-[4-(二甲氨基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例4)的制备 Preparation of 5-chloro-N 2 -[4-(dimethylamino)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 4)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-二甲氨基苯胺，即得实施例4。 1H NMR(600MHz,DMSO-d 6)δ10.48(s,1H),9.05(s,1H),8.23(s,1H),7.55–7.35(m,5H),7.15(d,J＝7.7Hz,1H),7.09(q,J＝9.8,8.5Hz,3H),4.64(d,J＝6.0Hz,2H),3.05(s,6H).HRMS(ESI,m/z)理论值C 19H 20ClFN 5[M+H] +,372.1391；实测值372.1396。 With reference to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-dimethylaminoaniline in equal proportions to obtain Example 4. 1 H NMR (600MHz,DMSO-d 6 )δ10.48(s,1H),9.05(s,1H),8.23(s,1H),7.55–7.35(m,5H),7.15(d,J=7.7 Hz, 1H), 7.09(q, J=9.8, 8.5Hz, 3H), 4.64(d, J=6.0Hz, 2H), 3.05(s, 6H). HRMS(ESI, m/z) theoretical value C 19 H 20 ClFN 5 [M+H] + , 372.1391; found 372.1396.
5-氯-N 2-[4-(4-甲基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例5)的制备 Preparation of 5-chloro-N 2 -[4-(4-methylpiperazin-1-yl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 5)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-(4-甲基哌嗪-1-基)苯胺，即得实施例5。 1H NMR(600MHz,DMSO-d 6)δ9.12(s,1H),8.19(s,1H),7.40–7.36(m,1H),7.30(d,J＝8.9Hz,2H),7.13–7.06(m,3H),6.94(d,J＝8.9Hz,2H),4.60(d,J＝6.0Hz,2H),3.75(d,J＝12.4Hz,2H),3.48(d,J＝11.4Hz,2H),3.17–3.04(m,4H),2.80(d,J＝3.9Hz,3H).HRMS(ESI,m/z)理论值C 22H 24ClFN 6[M+H] +,427.1813；实测值427.1817。 Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-(4-methylpiperazin-1-yl)aniline in equal proportions to obtain Example 5. 1 H NMR (600MHz,DMSO-d 6 )δ9.12(s,1H),8.19(s,1H),7.40–7.36(m,1H),7.30(d,J＝8.9Hz,2H),7.13– 7.06(m,3H),6.94(d,J=8.9Hz,2H),4.60(d,J=6.0Hz,2H),3.75(d,J=12.4Hz,2H),3.48(d,J=11.4 Hz,2H),3.17–3.04(m,4H),2.80(d,J＝3.9Hz,3H).HRMS(ESI,m/z) theoretical value C 22 H 24 ClFN 6 [M+H] + ,427.1813 ; found value 427.1817.
5-氯-N 2-[3-(4-甲基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例6)的制备 Preparation of 5-chloro-N 2 -[3-(4-methylpiperazin-1-yl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 6)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为3-(4-甲基哌嗪-1-基)苯胺，即得实施例6。 1H NMR(600MHz,DMSO-d 6)δ10.82(s,1H),8.91(s,1H),8.21(s,1H),7.36(q,J＝7.1,6.5Hz,1H),7.18–7.10(m,3H),7.08(t,J＝7.6Hz,2H),7.04–6.96(m,1H),6.77(d,J＝7.2Hz,1H),4.64(d,J＝5.7Hz,2H),3.69(d,J＝11.0Hz,2H),3.42(s,2H),3.12–3.04(m,4H),2.79(s,3H).HRMS(ESI,m/z)理论值C 22H 24ClFN 6[M+H] +,427.1813；实测值427.1825。 With reference to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 3-(4-methylpiperazin-1-yl)aniline in equal proportions to obtain Example 6. 1 H NMR (600MHz,DMSO-d 6 )δ10.82(s,1H),8.91(s,1H),8.21(s,1H),7.36(q,J＝7.1,6.5Hz,1H),7.18– 7.10(m,3H),7.08(t,J=7.6Hz,2H),7.04–6.96(m,1H),6.77(d,J=7.2Hz,1H),4.64(d,J=5.7Hz,2H ), 3.69(d, J=11.0Hz, 2H), 3.42(s, 2H), 3.12–3.04(m, 4H), 2.79(s, 3H). HRMS (ESI, m/z) theoretical value C 22 H 24 ClFN 6 [M+H] + , 427.1813; found 427.1825.
5-氯-N 2-[4-(4-乙基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例7)的制备 Preparation of 5-chloro-N 2 -[4-(4-ethylpiperazin-1-yl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 7)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-(4-乙基哌嗪-1-基)苯胺，即得实施例7。 1H NMR(600MHz,DMSO-d 6)δ11.06(s,1H),10.37(s,1H),9.18(s,1H),8.21(s,1H),7.38(q,J＝7.7Hz,1H),7.29(d,J＝8.7Hz,2H),7.10(dt,J＝16.2,8.0Hz,3H),6.95(d,J＝8.6Hz,2H),4.61(d,J＝5.8Hz,2H),3.76(d,J＝12.1Hz,3H),3.54(d,J＝11.1Hz,3H),3.18–3.06(m,6H),1.29(t,J＝7.2Hz,3H).HRMS(ESI,m/z)理论值C 23H 27ClFN 6[M+H] +,441.1970；实测值441.1979。 Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-(4-ethylpiperazin-1-yl)aniline in equal proportions to obtain Example 7. 1 H NMR (600MHz, DMSO-d 6 )δ11.06(s,1H),10.37(s,1H),9.18(s,1H),8.21(s,1H),7.38(q,J=7.7Hz, 1H), 7.29(d, J=8.7Hz, 2H), 7.10(dt, J=16.2, 8.0Hz, 3H), 6.95(d, J=8.6Hz, 2H), 4.61(d, J=5.8Hz, 2H), 3.76(d, J=12.1Hz, 3H), 3.54(d, J=11.1Hz, 3H), 3.18–3.06(m, 6H), 1.29(t, J=7.2Hz, 3H).HRMS( ESI, m/z) calcd for C 23 H 27 ClFN 6 [M+H] + , 441.1970; found 441.1979.
5-氯-N 2-[4-(4-吗啉基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例8)的制备 Preparation of 5-chloro-N 2 -[4-(4-morpholinyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 8)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-吗啉基苯胺，即得实施例8。 1H NMR(600MHz,DMSO-d 6)δ10.21(s,1H),9.05(s,1H),8.17(s,1H),7.38(q,J＝7.8Hz,1H),7.31(d,J＝7.3Hz,2H),7.14–7.06(m,3H),7.02(s,2H),4.60(d,J＝5.7Hz,2H),3.79(s,4H),3.15(s,4H).HRMS(ESI,m/z)理论值C 21H 22ClFN 5O[M+H] +,414.1497；实测值414.1497。 Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-morpholinoaniline in equal proportions to obtain Example 8. 1 H NMR (600MHz,DMSO-d 6 )δ10.21(s,1H),9.05(s,1H),8.17(s,1H),7.38(q,J=7.8Hz,1H),7.31(d, J＝7.3Hz, 2H), 7.14–7.06(m, 3H), 7.02(s, 2H), 4.60(d, J＝5.7Hz, 2H), 3.79(s, 4H), 3.15(s, 4H). HRMS (ESI, m/z) calc. for C 21 H 22 ClFN 5 O [M+H] + , 414.1497; found 414.1497.
5-氯-N 2-[4-(3-吗啉基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例9)的制备 Preparation of 5-chloro-N 2 -[4-(3-morpholinyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 9)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为3-吗啉基苯胺，即得实施例9。 1H NMR(600MHz,DMSO-d 6)δ9.05(s,1H),7.98(s,1H),7.81(t,J＝6.2Hz,1H),7.39–7.34(m,1H),7.25(t,J＝2.0Hz,1H),7.17(d,J＝7.7Hz,1H),7.13(d,J＝10.1Hz,1H),7.09(d,J＝8.1Hz,1H),7.05(td,J＝8.6,2.4Hz,1H),7.01(t,J＝8.1Hz,1H),6.49(dd,J＝8.1,2.0Hz,1H),4.66(d,J＝6.2Hz,2H),3.67–3.63(m,4H),2.99–2.94(m,4H).HRMS(ESI,m/z)理论值C 21H 22ClFN 5O[M+H] +,414.1497；实测值414.1507。 With reference to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 3-morpholinoaniline in equal proportions to obtain Example 9. 1 H NMR (600MHz, DMSO-d 6 ) δ9.05(s, 1H), 7.98(s, 1H), 7.81(t, J=6.2Hz, 1H), 7.39–7.34(m, 1H), 7.25( t,J=2.0Hz,1H),7.17(d,J=7.7Hz,1H),7.13(d,J=10.1Hz,1H),7.09(d,J=8.1Hz,1H),7.05(td, J=8.6,2.4Hz,1H),7.01(t,J=8.1Hz,1H),6.49(dd,J=8.1,2.0Hz,1H),4.66(d,J=6.2Hz,2H),3.67– 3.63 (m, 4H), 2.99–2.94 (m, 4H). HRMS (ESI, m/z) calcd for C 21 H 22 ClFN 5 O [M+H] + , 414.1497; found 414.1507.
4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基苯甲酰胺(实施例10)的制备Preparation of 4-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}aminobenzamide (embodiment 10)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-氨基苯甲酰胺，即得实施例10。 1H NMR(600MHz,DMSO-d 6)δ10.55(s,1H),9.04(s,1H),8.27(s,1H),7.88(s,1H),7.79(d,J＝8.7Hz,2H),7.52(d,J＝8.7Hz,2H),7.40(td,J＝7.9,6.2Hz,1H),7.25(s,1H),7.18(d,J＝7.8Hz,1H),7.15(d,J＝10.0Hz,1H),7.09(td,J＝8.6,2.4Hz,1H),4.68(d,J＝6.1Hz,2H).HRMS(ESI,m/z)理论值C 18H 15ClFN 5ONa[M+Na] +,394.0847；实测值394.0850。 Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-aminobenzamide in equal proportions to obtain Example 10. 1 H NMR (600MHz, DMSO-d 6 )δ10.55(s,1H),9.04(s,1H),8.27(s,1H),7.88(s,1H),7.79(d,J＝8.7Hz, 2H), 7.52(d, J=8.7Hz, 2H), 7.40(td, J=7.9, 6.2Hz, 1H), 7.25(s, 1H), 7.18(d, J=7.8Hz, 1H), 7.15( d, J=10.0Hz, 1H), 7.09(td, J=8.6, 2.4Hz, 1H), 4.68(d, J=6.1Hz, 2H). HRMS (ESI, m/z) theoretical value C 18 H 15 ClFN5ONa [M+Na] + , 394.0847; found 394.0850.
5-氯-N 2-[3-(乙氧基甲基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例11)的制备 Preparation of 5-chloro-N 2 -[3-(ethoxymethyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 11)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-(乙氧基甲基)苯胺，即得实施例11。 1H NMR(600MHz,DMSO-d 6)δ9.21(s,1H),7.98(s,1H),7.86(t,J＝6.1Hz,1H),7.51(d,J＝8.4Hz,2H),7.39–7.35(m,1H),7.18(d,J＝7.7Hz,1H),7.14(d,J＝10.1Hz,1H),7.10(d,J＝8.5Hz,2H),7.05(td,J＝8.5,2.4Hz,1H),4.63(d,J＝6.1Hz,2H),4.33(s,2H),3.43(q,J＝7.0Hz,2H),1.13(t,J＝7.0Hz,3H).HRMS(ESI,m/z)理论值C 20H 21ClFN 4O[M+H] +,387.1388；实测值387.1389。 Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-(ethoxymethyl)aniline in equal proportions to obtain Example 11. 1 H NMR (600MHz,DMSO-d 6 )δ9.21(s,1H),7.98(s,1H),7.86(t,J=6.1Hz,1H),7.51(d,J=8.4Hz,2H) ,7.39–7.35(m,1H),7.18(d,J=7.7Hz,1H),7.14(d,J=10.1Hz,1H),7.10(d,J=8.5Hz,2H),7.05(td, J=8.5, 2.4Hz, 1H), 4.63(d, J=6.1Hz, 2H), 4.33(s, 2H), 3.43(q, J=7.0Hz, 2H), 1.13(t, J=7.0Hz, 3H). HRMS (ESI, m/z) calc. for C 20 H 21 ClFN 4 O [M+H] + , 387.1388; found 387.1389.
5-氯-N 2-[3-(异丙氧基甲基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺(实施例12)的制备 Preparation of 5-chloro-N 2 -[3-(isopropoxymethyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine (Example 12)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-(异丙氧基甲基)苯胺，即得实施例12。 1H NMR(600MHz,DMSO-d 6)δ9.19(s,1H),7.98(s,1H),7.85(t,J＝6.1Hz,1H),7.49(d,J＝8.4Hz,2H),7.39–7.34(m,1H),7.17(d,J＝7.8Hz,1H),7.14(d,J＝10.1Hz,1H),7.09(d,J＝8.5Hz,2H),7.05(td,J＝8.5,2.4Hz,1H),4.62(d,J＝6.4Hz,1H),4.34(s,2H),3.60(dq,J＝12.2,6.1Hz,1H),1.12(d,J＝6.1Hz,6H).HRMS(ESI,m/z)理论值C 21H 23ClFN 4O[M+H] +,401.1544；实测值401.1547。 Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-(isopropoxymethyl)aniline in equal proportions to obtain Example 12. 1 H NMR (600MHz,DMSO-d 6 )δ9.19(s,1H),7.98(s,1H),7.85(t,J=6.1Hz,1H),7.49(d,J=8.4Hz,2H) ,7.39–7.34(m,1H),7.17(d,J=7.8Hz,1H),7.14(d,J=10.1Hz,1H),7.09(d,J=8.5Hz,2H),7.05(td, J=8.5,2.4Hz,1H), 4.62(d,J=6.4Hz,1H),4.34(s,2H),3.60(dq,J=12.2,6.1Hz,1H),1.12(d,J=6.1 Hz, 6H). HRMS (ESI, m/z) Calc. C 21 H 23 ClFN 4 O [M+H] + , 401.1544; Found 401.1547.
4-[4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苄基]吗啉-3-酮(实施例13)的制备Preparation of 4-[4-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzyl]morpholin-3-one (Example 13)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为4-(4-氨基苯基)吗啉-3-酮，即得实施例13。 1H NMR(600MHz,DMSO-d 6)δ9.29(s,1H),7.99(s,1H),7.88(t,J＝6.1Hz,1H),7.56(d,J＝8.8Hz,2H),7.39–7.36(m,1H),7.18(d,J＝7.7Hz,1H),7.16–7.12(m,3H),7.05(td,J＝8.5,2.4Hz,1H),4.63(d,J＝6.1Hz,2H),4.17(s,2H),3.99–3.92(m,2H),3.68–3.61(m,2H).HRMS(ESI,m/z)理论值C 21H 20ClFN 5O 2[M+H] +,428.1290；实测值428.1301。 Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with 4-(4-aminophenyl)morpholin-3-one in equal proportions to obtain Example 13. 1 H NMR (600MHz,DMSO-d 6 )δ9.29(s,1H),7.99(s,1H),7.88(t,J=6.1Hz,1H),7.56(d,J=8.8Hz,2H) ,7.39–7.36(m,1H),7.18(d,J=7.7Hz,1H),7.16–7.12(m,3H),7.05(td,J=8.5,2.4Hz,1H),4.63(d,J =6.1Hz,2H),4.17(s,2H),3.99–3.92(m,2H),3.68–3.61(m,2H).HRMS(ESI,m/z) theoretical value C 21 H 20 ClFN 5 O 2 [M+H] + , 428.1290; found 428.1301.
实施例14的制备路线如下所示：The preparation route of embodiment 14 is as follows:
Figure PCTCN2022112391-appb-000009
Figure PCTCN2022112391-appb-000009
4-({5-氯-4-[(3-氟苄基)氨基)嘧啶-2-基)氨基苯甲酸(4)的制备Preparation of 4-({5-chloro-4-[(3-fluorobenzyl)amino)pyrimidin-2-yl)aminobenzoic acid (4)
参考制备实施例1的方法，将b步骤中4-胺基苯磺酰胺原料等比例替换为对氨基苯甲酸，即得中间体4。Referring to the method of Preparation Example 1, the 4-aminobenzenesulfonamide raw material in step b was replaced with p-aminobenzoic acid in equal proportions to obtain intermediate 4.
[4-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基哌嗪-1-基)甲基酮(实施例14)的制备[4-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methylpiperazin-1-yl)methyl ketone (Example 14) Preparation
将中间体4(0.10g,0.27mmol)，N-甲基哌嗪(0.032g,0.32mmol)，EDCI(0.061g,0.32mmol)，HOBt(0.043g,0.32mmol)和DIPEA(0.053mL,0.32mmol)溶于3mL DMF，室温反应。TLC监测原料反应完全，将反应液倾入30mL 10％的碳酸钾溶液中，有白色固体析出。减压过滤，用水洗涤滤饼三次，得到白色固体。收率75％。 1H NMR(600MHz,DMSO-d 6)δ9.45(s,1H),8.02(s,1H),7.94(t,J＝6.1Hz,1H),7.59(d,J＝8.6Hz,2H),7.37(td,J＝7.9,6.2Hz,1H),7.19(t,J＝9.1Hz,3H),7.15(d,J＝10.1Hz,2H),7.05(td,J＝8.4,2.3Hz,2H),4.64(d,J＝6.1Hz,2H),3.48(s,4H),2.36(s,4H),2.23(s,3H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1785。 Intermediate 4 (0.10g, 0.27mmol), N-methylpiperazine (0.032g, 0.32mmol), EDCI (0.061g, 0.32mmol), HOBt (0.043g, 0.32mmol) and DIPEA (0.053mL, 0.32 mmol) was dissolved in 3mL DMF and reacted at room temperature. TLC monitored the complete reaction of the raw materials, and the reaction solution was poured into 30 mL of 10% potassium carbonate solution, and a white solid was precipitated. It was filtered under reduced pressure, and the filter cake was washed with water three times to obtain a white solid. Yield 75%. 1 H NMR (600MHz,DMSO-d 6 )δ9.45(s,1H),8.02(s,1H),7.94(t,J=6.1Hz,1H),7.59(d,J=8.6Hz,2H) ,7.37(td,J=7.9,6.2Hz,1H),7.19(t,J=9.1Hz,3H),7.15(d,J=10.1Hz,2H),7.05(td,J=8.4,2.3Hz, 2H), 4.64(d, J=6.1Hz, 2H), 3.48(s, 4H), 2.36(s, 4H), 2.23(s, 3H). HRMS (ESI, m/z) theoretical value C 23 H 25 ClFN6O [M+H] + , 455.1762; found 455.1785.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基哌嗪-1-基)甲基酮(实施例15)的制备[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methylpiperazin-1-yl)methylketone (Example 15) Preparation
参考制备实施例14的方法，将b步骤中对氨基苯甲酸原料等比例替换为间氨基苯甲酸，即得实施例15。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.70(s,1H),7.64(d,J＝8.2Hz,1H),7.35(td,J＝7.9,6.3Hz,1H),7.21(t,J＝7.9Hz,1H),7.17(d,J＝7.7Hz,1H),7.13(d,J＝10.0Hz,1H),7.04(td,J＝8.7,2.6Hz,1H),6.86(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),3.58(s,2H),3.29(s,2H),2.32(s,2H),2.23(s,2H),2.18(s,3H).HRMS(ESI,m/z)理论值C 22H 25ClFN 6O[M+H] +,455.1762；实测值455.1785。 Referring to the method for preparing Example 14, the p-aminobenzoic acid raw material in step b was replaced with m-aminobenzoic acid in equal proportions to obtain Example 15. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.70(s, 1H), 7.64(d, J＝8.2Hz, 1H), 7.35(td, J＝7.9, 6.3Hz, 1H), 7.21(t, J＝7.9Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.13(d, J=10.0Hz, 1H), 7.04(td, J=8.7, 2.6Hz, 1H), 6.86(d, J=7.5Hz, 1H), 4.64(d, J=6.1Hz, 2H), 3.58(s, 2H), 3.29(s, 2H), 2.32(s, 2H), 2.23(s, 2H), 2.18(s, 3H). HRMS (ESI, m/z) theoretical value C 22 H 25 ClFN 6 O[M +H] + , 455.1762; found 455.1785.
[4-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](吗啉基)甲基酮(实施例16)的制备Preparation of [4-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](morpholinyl)methyl ketone (Example 16)
参考制备实施例14的方法，将c步骤中N-甲基哌嗪原料等比例替换为吗啉，即得实施例16。 1H NMR(600MHz,DMSO-d 6)δ9.46(s,1H),8.02(s,1H),7.95(t,J＝6.0Hz,1H),7.60(d,J＝8.5Hz,2H),7.38(q,J＝7.8Hz,1H),7.23(d,J＝8.6Hz,2H),7.19(d,J＝7.7Hz,1H),7.15(d,J＝10.0Hz,1H),7.05(td,J＝8.6,2.3Hz,0H),4.64(d,J＝6.0Hz,2H),3.60(s,4H),3.48(s,4H).HRMS(ESI,m/z)理论值C 22H 22ClFN 5O 2[M+H] +,442.1446；实测值442.1459。[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](吗啉基)甲基酮(实施例17)的制备 Referring to the method for preparing Example 14, replace the N-methylpiperazine raw material in step c with morpholine in equal proportions to obtain Example 16. 1 H NMR (600MHz,DMSO-d 6 )δ9.46(s,1H),8.02(s,1H),7.95(t,J=6.0Hz,1H),7.60(d,J=8.5Hz,2H) ,7.38(q,J=7.8Hz,1H),7.23(d,J=8.6Hz,2H),7.19(d,J=7.7Hz,1H),7.15(d,J=10.0Hz,1H),7.05 (td, J=8.6, 2.3Hz, 0H), 4.64(d, J=6.0Hz, 2H), 3.60(s, 4H), 3.48(s, 4H). HRMS (ESI, m/z) theoretical value C 22 H 22 ClFN 5 O 2 [M+H] + , 442.1446; found 442.1459. Preparation of [3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](morpholinyl)methyl ketone (Example 17)
参考制备实施例16的方法，将b步骤中对氨基苯甲酸原料等比例替换为间氨基苯甲酸，即得实施例17。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.72(s,1H),7.67–7.62(m,1H),7.39–7.31(m,1H),7.22(t,J＝7.9Hz,1H),7.17(d,J＝7.7Hz,1H),7.14(d,J＝10.1Hz,1H),7.04(td,J＝8.5,2.3Hz,1H),6.89(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),3.65–3.44(m,8H).HRMS(ESI,m/z)理论值C 22H 22ClFN 5O 2[M+H] +,442.1446；实测值442.1457。 Referring to the method for preparing Example 16, the p-aminobenzoic acid raw material in step b was replaced with m-aminobenzoic acid in equal proportions to obtain Example 17. 1 H NMR (600MHz, DMSO-d 6 ) δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.72(s, 1H), 7.67–7.62( m,1H),7.39–7.31(m,1H),7.22(t,J=7.9Hz,1H),7.17(d,J=7.7Hz,1H),7.14(d,J=10.1Hz,1H), 7.04(td, J=8.5,2.3Hz,1H),6.89(d,J=7.5Hz,1H),4.64(d,J=6.1Hz,2H),3.65–3.44(m,8H).HRMS(ESI , m/z) Theoretical for C 22 H 22 ClFN 5 O 2 [M+H] + , 442.1446; found 442.1457.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](哌啶-1-基)甲基酮(实施例18)的制备Preparation of [3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](piperidin-1-yl)methyl ketone (Example 18)
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为哌啶，即得实施例18。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.70(s,1H),7.61(d,J＝8.2Hz,1H),7.39–7.32(m,1H),7.21(t,J＝7.9Hz,1H),7.17(d,J＝7.7Hz,1H),7.14(d,J＝10.1Hz,1H),7.05(td,J＝8.5,2.4Hz,1H),6.84(d,J＝7.5Hz,1H),4.64(d,J＝6.2Hz,2H),3.54(s,2H),3.23(s,2H),1.59(q,J＝6.6,6.1Hz,2H),1.51(s,2H),1.41(s,2H).HRMS(ESI,m/z)理论值C 23H 24ClFN 5O[M+H] +,440.1653；实测值440.1660。 Referring to the method for preparing Example 17, replace the morpholine raw material in step c with piperidine in equal proportions to obtain Example 18. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.70(s, 1H), 7.61(d, J＝8.2Hz, 1H), 7.39–7.32(m, 1H), 7.21(t, J＝7.9Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.14(d, J＝10.1Hz, 1H), 7.05(td, J=8.5, 2.4Hz, 1H), 6.84(d, J=7.5Hz, 1H), 4.64(d, J=6.2Hz, 2H), 3.54(s, 2H), 3.23( s,2H),1.59(q,J=6.6,6.1Hz,2H),1.51(s,2H),1.41(s,2H).HRMS(ESI,m/z)theoretical value C 23 H 24 ClFN 5 O [M+H] + , 440.1653; found 440.1660.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-乙基哌嗪-1-基)甲基酮(实施例19)的制备[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-ethylpiperazin-1-yl)methyl ketone (Example 19) Preparation
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为N-乙基哌嗪，即得实施例19。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.70(s,1H),7.64(d,J＝9.4Hz,1H),7.39–7.31(m,1H),7.21(t,J＝7.9Hz,1H),7.17(d,J＝7.7Hz,1H),7.14(d,J＝10.0Hz,1H),7.04(td,J＝8.5,2.4Hz,1H),6.86(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),3.58(s,2H),3.30(s,2H),2.42–2.23(m,6H),0.99(t,J＝7.2Hz,3H).HRMS(ESI,m/z)理论值C 24H 27ClFN 6O[M+H] +,469.1919；实测值469.1932。 Referring to the method for preparing Example 17, the morpholine raw material in step c was replaced by N-ethylpiperazine in equal proportions, and Example 19 was obtained. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.70(s, 1H), 7.64(d, J＝9.4Hz, 1H), 7.39–7.31(m, 1H), 7.21(t, J＝7.9Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.14(d, J＝10.0Hz, 1H), 7.04(td, J=8.5, 2.4Hz, 1H), 6.86(d, J=7.5Hz, 1H), 4.64(d, J=6.1Hz, 2H), 3.58(s, 2H), 3.30( s,2H),2.42–2.23(m,6H),0.99(t,J＝7.2Hz,3H).HRMS(ESI,m/z) theoretical value C 24 H 27 ClFN 6 O[M+H] + , 469.1919; found 469.1932.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-异丙基哌嗪-1-基)甲基酮(实施例20)的制备[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-isopropylpiperazin-1-yl)methyl ketone (implementation Example 20) Preparation
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为N-异丙基哌嗪，即得实施例20。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.69(s,1H),7.64(d,J＝9.4Hz,1H),7.37–7.32(m,1H),7.21(t,J＝7.9Hz,1H),7.17(d,J＝7.7Hz,1H),7.14(d,J＝10.0Hz,1H),7.04(td,J＝8.6,2.3Hz,1H),6.86(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),3.57(s,2H),3.28(s,2H),2.66(p,J＝6.5Hz,1H),2.45(s,2H),2.36(s,2H),0.96(d,J＝6.5Hz,6H).HRMS(ESI,m/z)理论值C 25H 29ClFN 6O[M+H] +,483.2075；实测值483.2086。 Referring to the method for preparing Example 17, replace the morpholine raw material in step c with N-isopropylpiperazine in equal proportions to obtain Example 20. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.69(s, 1H), 7.64(d, J＝9.4Hz, 1H), 7.37–7.32(m, 1H), 7.21(t, J＝7.9Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.14(d, J＝10.0Hz, 1H), 7.04(td, J=8.6, 2.3Hz, 1H), 6.86(d, J=7.5Hz, 1H), 4.64(d, J=6.1Hz, 2H), 3.57(s, 2H), 3.28( s,2H),2.66(p,J=6.5Hz,1H),2.45(s,2H),2.36(s,2H),0.96(d,J=6.5Hz,6H).HRMS(ESI,m/z ) Theoretical value C 25 H 29 ClFN 6 O [M+H] + , 483.2075; found value 483.2086.
4-[3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苯甲酰基]哌嗪-2-酮(实施例21)的制备Preparation of 4-[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzoyl]piperazin-2-one (Example 21)
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为哌嗪-2-酮，即得实施例21。 1H NMR(600MHz,DMSO-d 6)δ9.41(s,1H),8.12(s,1H),8.02(s,1H),7.93(t,J＝6.2Hz,1H),7.74(s,1H),7.70–7.63(m,1H),7.38–7.31(m,1H),7.24(t,J＝7.9Hz,1H),7.15(dd,J＝18.2,8.9Hz,2H),7.04(td,J＝8.5,2.4Hz,1H),6.93(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),4.07–3.44(m,4H),3.21(s,2H).HRMS(ESI,m/z)理论值C 22H 20ClFN 6O 2Na[M+Na] +,477.1218；实测值477.1227。 Referring to the method for preparing Example 17, replace the morpholine raw material in step c with piperazin-2-one in equal proportions to obtain Example 21. 1 H NMR (600MHz, DMSO-d 6 )δ9.41(s,1H),8.12(s,1H),8.02(s,1H),7.93(t,J=6.2Hz,1H),7.74(s, 1H),7.70–7.63(m,1H),7.38–7.31(m,1H),7.24(t,J＝7.9Hz,1H),7.15(dd,J＝18.2,8.9Hz,2H),7.04(td ,J=8.5,2.4Hz,1H),6.93(d,J=7.5Hz,1H),4.64(d,J=6.1Hz,2H),4.07–3.44(m,4H),3.21(s,2H) .HRMS (ESI, m/z) Calc. C 22 H 20 ClFN 6 O 2 Na[M+Na] + , 477.1218; Found 477.1227.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](哌嗪-1-基)甲基酮(实施例22)的制备Preparation of [3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](piperazin-1-yl)methyl ketone (Example 22)
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为哌嗪，即得实施例22。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝5.9Hz,1H),7.69(s,1H),7.63(d,J＝8.1Hz,1H),7.35(q,J＝7.7Hz,1H),7.21(t,J＝7.8Hz,1H),7.17(d,J＝7.6Hz, 1H),7.14(d,J＝10.0Hz,1H),7.04(t,J＝8.4Hz,1H),6.85(d,J＝7.4Hz,1H),4.64(d,J＝5.9Hz,2H),3.51(s,2H),3.22(s,2H),2.71(s,2H),2.62(s,1H).HRMS(ESI,m/z)理论值C 22H 23ClFN 6O[M+H] +,441.1606；实测值441.1627。 Referring to the method for preparing Example 17, the morpholine raw material in step c was replaced with piperazine in equal proportions, and Example 22 was obtained. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=5.9Hz, 1H), 7.69(s, 1H), 7.63(d, J＝8.1Hz, 1H), 7.35(q, J＝7.7Hz, 1H), 7.21(t, J＝7.8Hz, 1H), 7.17(d, J＝7.6Hz, 1H), 7.14(d, J＝ 10.0Hz, 1H), 7.04(t, J=8.4Hz, 1H), 6.85(d, J=7.4Hz, 1H), 4.64(d, J=5.9Hz, 2H), 3.51(s, 2H), 3.22 (s, 2H), 2.71 (s, 2H), 2.62 (s, 1H). HRMS (ESI, m/z) calc. C 22 H 23 ClFN 6 O [M+H] + , 441.1606; found 441.1627.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基-1,4高哌嗪-1-基)甲基酮(实施例23)的制备[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methyl-1,4-homopiperazin-1-yl)methyl The preparation of base ketone (embodiment 23)
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为N-甲基高哌嗪，即得实施例23。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.90(t,J＝6.0Hz,1H),7.69(s,1H),7.61(d,J＝7.8Hz,1H),7.38–7.32(m,1H),7.20(td,J＝8.0,3.0Hz,1H),7.17(d,J＝7.7Hz,1H),7.14(d,J＝10.1Hz,1H),7.05(td,J＝8.6,2.4Hz,1H),6.84(t,J＝6.5Hz,1H),4.64(d,J＝6.1Hz,2H),3.60(s,1H),3.58–3.54(m,1H),3.37–3.30(m,4H),2.64(s,1H),2.55(s,1H),2.33–2.20(m,3H),1.82(s,1H),1.72(s,1H).HRMS(ESI,m/z)理论值C 24H 27ClFN 6O[M+H] +,469.1919；实测值469.1931。 Referring to the method for preparing Example 17, the morpholine raw material in step c was replaced by N-methylhomopiperazine in equal proportions, and Example 23 was obtained. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.90(t, J=6.0Hz, 1H), 7.69(s, 1H), 7.61(d, J＝7.8Hz, 1H), 7.38–7.32(m, 1H), 7.20(td, J＝8.0, 3.0Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.14(d, J＝10.1 Hz,1H),7.05(td,J=8.6,2.4Hz,1H),6.84(t,J=6.5Hz,1H),4.64(d,J=6.1Hz,2H),3.60(s,1H), 3.58–3.54(m,1H),3.37–3.30(m,4H),2.64(s,1H),2.55(s,1H),2.33–2.20(m,3H),1.82(s,1H),1.72( s, 1H). HRMS (ESI, m/z) calc. for C 24 H 27 ClFN 6 O [M+H] + , 469.1919; found 469.1931.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](1,4高哌嗪-1-基)甲基酮(实施例24)的制备[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](1,4-homopiperazin-1-yl)methylketone (Example 24) Preparation
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为N-甲基高哌嗪，即得实施例24。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.90(t,J＝6.0Hz,1H),7.69(s,1H),7.61(d,J＝7.8Hz,1H),7.38–7.33(m,1H),7.20(td,J＝8.0,3.0Hz,1H),7.17(d,J＝7.7Hz,1H),7.14(d,J＝10.1Hz,1H),7.05(td,J＝8.6,2.4Hz,1H),6.84(t,J＝6.5Hz,1H),4.64(d,J＝6.1Hz,2H),3.60(s,1H),3.58–3.54(m,1H),3.32(d,J＝6.2Hz,2H),2.64(s,1H),2.55(s,1H),2.30(s,1H),2.24(s,1H),1.83(s,1H),1.72(s,1H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1773。 Referring to the method for preparing Example 17, replace the morpholine raw material in step c with N-methylhomopiperazine in equal proportions to obtain Example 24. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.90(t, J=6.0Hz, 1H), 7.69(s, 1H), 7.61(d, J＝7.8Hz, 1H), 7.38–7.33(m, 1H), 7.20(td, J＝8.0, 3.0Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.14(d, J＝10.1 Hz,1H),7.05(td,J=8.6,2.4Hz,1H),6.84(t,J=6.5Hz,1H),4.64(d,J=6.1Hz,2H),3.60(s,1H), 3.58–3.54(m,1H),3.32(d,J＝6.2Hz,2H),2.64(s,1H),2.55(s,1H),2.30(s,1H),2.24(s,1H),1.83 (s, 1H), 1.72 (s, 1H). HRMS (ESI, m/z) calcd. for C 23 H 25 ClFN 6 O[M+H] + , 455.1762; found 455.1773.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基][4-(二甲氨基)哌啶-1-基]甲基酮(实施例25)的制备[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl][4-(dimethylamino)piperidin-1-yl]methylketone (Example 25) Preparation
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为4-二甲氨基哌啶，即得With reference to the method of Preparation Example 17, the morpholine raw material in step c is replaced by 4-dimethylaminopiperidine in equal proportions, to obtain
实施例25。 1H NMR(600MHz,DMSO-d 6)δ9.45–9.34(m,1H),8.00(d,J＝3.4Hz,1H),7.90(t,J＝6.3Hz,1H),7.86–7.79(m,1H),7.67(d,J＝9.4Hz,1H),7.36–7.31(m,1H),7.18(dd,J＝14.7,7.0Hz,2H),7.13(d,J＝10.2Hz,1H),7.03(td,J＝8.5,2.3Hz,1H),6.96(d,J＝7.6Hz,1H),4.65(d,J＝6.1Hz,2H),3.61(t,J＝7.0Hz,2H),3.02(p,J＝7.2Hz,2H),2.25(s,2H),2.22(s,1H),2.15–2.06(m,6H),1.66(p,J＝7.0Hz,2H).HRMS(ESI,m/z)理论值C 25H 29ClFN 6O[M+H] +,482.1997；实测值482.2072。 Example 25. 1 H NMR (600MHz, DMSO-d 6 ) δ9.45–9.34 (m, 1H), 8.00 (d, J=3.4Hz, 1H), 7.90 (t, J=6.3Hz, 1H), 7.86–7.79 ( m,1H),7.67(d,J=9.4Hz,1H),7.36–7.31(m,1H),7.18(dd,J=14.7,7.0Hz,2H),7.13(d,J=10.2Hz,1H ),7.03(td,J=8.5,2.3Hz,1H),6.96(d,J=7.6Hz,1H),4.65(d,J=6.1Hz,2H),3.61(t,J=7.0Hz,2H ),3.02(p,J=7.2Hz,2H),2.25(s,2H),2.22(s,1H),2.15–2.06(m,6H),1.66(p,J=7.0Hz,2H).HRMS (ESI, m/z) Theoretical for C 25 H 29 ClFN 6 O [M+H] + , 482.1997; Found 482.2072.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基][4-(甲氨基)哌啶-1-基]甲基酮(实施例26)的制备[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl][4-(methylamino)piperidin-1-yl]methyl ketone ( Embodiment 26) Preparation
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为4-甲氨基哌啶，即得实施例26。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.69(s,1H),7.63(d,J＝9.4Hz,1H),7.39–7.32(m,1H),7.21(t,J＝7.9Hz,1H),7.17(d,J＝7.7Hz,1H),7.14(d,J＝10.0Hz,1H),7.04(td,J＝8.6,2.3Hz,1H),6.84(d,J＝7.5Hz,1H),4.64(s,2H),4.25(s,1H),3.55(s,1H),3.17(s,1H),3.02–2.89(m,2H),2.58(s,1H),2.29(s,3H),2.03–1.94(m,1H),1.87(s,1H),1.73(s,1H).HRMS(ESI,m/z)理论值C 24H 27ClFN 6O[M+H] +,469.1919；实测值469.1933。 With reference to the method for preparing Example 17, the morpholine raw material in step c was replaced with 4-methylaminopiperidine in equal proportions to obtain Example 26. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.69(s, 1H), 7.63(d, J＝9.4Hz, 1H), 7.39–7.32(m, 1H), 7.21(t, J＝7.9Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.14(d, J＝10.0Hz, 1H), 7.04(td, J=8.6, 2.3Hz, 1H), 6.84(d, J=7.5Hz, 1H), 4.64(s, 2H), 4.25(s, 1H), 3.55(s, 1H), 3.17(s,1H),3.02–2.89(m,2H),2.58(s,1H),2.29(s,3H),2.03–1.94(m,1H),1.87(s,1H),1.73(s, 1H). HRMS (ESI, m/z) calc. for C 24 H 27 ClFN 6 O [M+H] + , 469.1919; found 469.1933.
[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-氨基哌啶-1-基)甲基酮(实施例27)的制备[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-aminopiperidin-1-yl)methyl ketone (Example 27 ) preparation
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为4-氨基哌啶，即得实施例27。 1H NMR(600MHz,DMSO-d 6)δ9.33(s,1H),8.19(d,J＝6.7Hz,1H),7.99(s,1H),7.89(s,1H),7.67(s,1H),7.34–7.29(m,2H),7.23–7.13(m,3H),7.01(t,J＝9.5Hz,1H),4.65(d,J＝6.6Hz,2H),2.93(d,J＝12.3Hz,1H),2.46(d,J＝12.1Hz,2H),2.03–1.95(m,1H),1.69(d,J＝11.9Hz,1H),1.48–1.34(m,2H),1.29(d,J＝8.0Hz,2H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1772。 Referring to the method for preparing Example 17, replace the morpholine raw material in step c with 4-aminopiperidine in equal proportions to obtain Example 27. 1 H NMR (600MHz, DMSO-d 6 )δ9.33(s, 1H), 8.19(d, J=6.7Hz, 1H), 7.99(s, 1H), 7.89(s, 1H), 7.67(s, 1H),7.34–7.29(m,2H),7.23–7.13(m,3H),7.01(t,J＝9.5Hz,1H),4.65(d,J＝6.6Hz,2H),2.93(d,J =12.3Hz,1H),2.46(d,J=12.1Hz,2H),2.03–1.95(m,1H),1.69(d,J=11.9Hz,1H),1.48–1.34(m,2H),1.29 (d, J=8.0Hz, 2H). HRMS (ESI, m/z) Theoretical value for C 23 H 25 ClFN 6 O[M+H] + , 455.1762; Found value 455.1772.
3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(1-甲基哌啶-4-基)苯甲酰胺(实施例28)的制备3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(1-methylpiperidin-4-yl)benzamide (Example 28 ) preparation
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为1-甲基哌啶-4-胺，即得With reference to the method of Preparation Example 17, the morpholine raw material in step c is replaced by 1-methylpiperidin-4-amine in equal proportions, to obtain
实施例28。 1H NMR(600MHz,DMSO-d 6)δ9.35(s,1H),8.30(d,J＝7.5Hz,1H),8.20(s,1H),7.99(s,1H),7.91(t,J＝6.2Hz,1H),7.84(d,J＝8.4Hz,1H),7.69(d,J＝7.7Hz,1H),7.55(d,J＝8.2Hz,1H),7.30–7.26(m,1H),7.23(t,J＝7.9Hz,1H),7.19–7.14(m,2H),7.02(td,J＝8.6,2.3Hz,1H),4.65(d,J＝4.9Hz,2H),3.88(s,1H),3.35–3.31(m,2H),3.12(d,J＝11.6Hz,2H),2.48(s,3H),1.87(d,J＝11.1Hz,2H),1.74(q,J＝13.8Hz,2H).HRMS(ESI,m/z)理论值C 24H 27ClFN 6O[M+H] +,469.1919；实测值469.1926。 Example 28. 1 H NMR (600MHz, DMSO-d 6 )δ9.35(s,1H),8.30(d,J＝7.5Hz,1H),8.20(s,1H),7.99(s,1H),7.91(t, J＝6.2Hz, 1H), 7.84(d, J＝8.4Hz, 1H), 7.69(d, J＝7.7Hz, 1H), 7.55(d, J＝8.2Hz, 1H), 7.30–7.26(m, 1H), 7.23(t, J=7.9Hz, 1H), 7.19–7.14(m, 2H), 7.02(td, J=8.6, 2.3Hz, 1H), 4.65(d, J=4.9Hz, 2H), 3.88(s,1H),3.35–3.31(m,2H),3.12(d,J=11.6Hz,2H),2.48(s,3H),1.87(d,J=11.1Hz,2H),1.74(q , J = 13.8 Hz, 2H). HRMS (ESI, m/z) Theoretical C 24 H 27 ClFN 6 O [M+H] + , 469.1919; Found 469.1926.
实施例29采用如下路线进行制备：Embodiment 29 adopts following route to prepare:
Figure PCTCN2022112391-appb-000010
Figure PCTCN2022112391-appb-000010
3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-4-基)苯甲酰胺(实施例29)的制备Preparation of 3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-4-yl)benzamide (Example 29)
参考制备实施例17的方法，将c步骤中吗啉原料等比例替换为N-Boc-哌啶-4-胺，即得中间体7。将中间体7(0.050g,0.090mmol)，溶于氯化氢的乙酸乙酯饱和溶液，室温搅拌(步骤d)。TLC监测反应完全，减压过滤，用乙酸乙酯洗涤滤饼三次，将滤饼溶于20mL水，乙酸乙酯萃取(10mL×3)，弃去有机层。水层在冰浴条件下用10％的氢氧化钠溶液调pH>10，乙酸乙酯萃取(10mL×3)，饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥。减压过滤除去硫酸钠，旋除乙酸乙酯，得白色固体。收率69％。 1H NMR(600MHz,DMSO-d 6)δ9.41(s,1H),8.01(s,1H),7.93(s,1H),7.69(s,1H),7.62(s,1H),7.35(q,J＝7.9Hz,1H),7.22–7.16(m,2H),7.14(d,J＝10.1Hz,1H),7.04(t,J＝8.5Hz,1H),6.83(t,J＝6.3Hz,1H),4.64(s,2H),4.25(s,1H),3.54(s,1H),3.43(s,1H),2.99–2.85(m,2H),1.78–1.36(m,4H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1772。 Referring to the method of Preparation Example 17, the morpholine raw material in step c was replaced by N-Boc-piperidin-4-amine in equal proportions to obtain intermediate 7. Intermediate 7 (0.050 g, 0.090 mmol) was dissolved in saturated ethyl acetate solution of hydrogen chloride and stirred at room temperature (step d). TLC monitored the completion of the reaction, filtered under reduced pressure, washed the filter cake three times with ethyl acetate, dissolved the filter cake in 20 mL of water, extracted with ethyl acetate (10 mL×3), and discarded the organic layer. The aqueous layer was adjusted to pH>10 with 10% sodium hydroxide solution under ice bath conditions, extracted with ethyl acetate (10 mL×3), washed with saturated brine (10 mL×3), and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration under reduced pressure, and ethyl acetate was spinned off to obtain a white solid. Yield 69%. 1 H NMR (600MHz,DMSO-d 6 )δ9.41(s,1H),8.01(s,1H),7.93(s,1H),7.69(s,1H),7.62(s,1H),7.35( q,J=7.9Hz,1H),7.22–7.16(m,2H),7.14(d,J=10.1Hz,1H),7.04(t,J=8.5Hz,1H),6.83(t,J=6.3 Hz,1H),4.64(s,2H),4.25(s,1H),3.54(s,1H),3.43(s,1H),2.99–2.85(m,2H),1.78–1.36(m,4H) .HRMS (ESI, m/z) Calc. C 23 H 25 ClFN 6 O [M+H] + , 455.1762; Found 455.1772.
(R)-[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](3-氨基哌啶-1-基)甲基酮(实施例30)的制备(R)-[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](3-aminopiperidin-1-yl)methylketone (Example 30) Preparation
参考制备实施例29的方法，将c步骤中吗啉原料等比例替换为(S)-哌啶-3-基碳酰胺叔丁酯，即得实施例30。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.69(s,1H),7.62(d,J＝9.4Hz,1H),7.36(q,J＝7.9Hz,1H),7.19(dt,J＝15.4,7.8Hz,2H),7.14(d,J＝10.0Hz,1H),7.05(td,J＝8.7,2.4Hz,1H),6.85(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),4.32–4.14(m,1H),3.51(s,1H),2.93–2.71(m,1H),2.62(s,1H),1.83(d,J＝12.8Hz,1H),1.70(s,1H),1.55(s,1H),1.35(s,1H),1.19(d,J＝12.5Hz,1H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1771。 Referring to the method for preparing Example 29, the morpholine raw material in step c was replaced by (S)-piperidin-3-ylcarboxamide tert-butyl ester in equal proportions to obtain Example 30. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.69(s, 1H), 7.62(d, J＝9.4Hz, 1H), 7.36(q, J＝7.9Hz, 1H), 7.19(dt, J＝15.4, 7.8Hz, 2H), 7.14(d, J＝10.0Hz, 1H), 7.05(td, J=8.7,2.4Hz,1H),6.85(d,J=7.5Hz,1H),4.64(d,J=6.1Hz,2H),4.32–4.14(m,1H),3.51(s,1H), 2.93–2.71(m,1H),2.62(s,1H),1.83(d,J＝12.8Hz,1H),1.70(s,1H),1.55(s,1H),1.35(s,1H),1.19 (d, J=12.5Hz, 1H). HRMS (ESI, m/z) Theoretical C 23 H 25 ClFN 6 O [M+H] + , 455.1762; Found 455.1771.
(S)-[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](3-氨基哌啶-1-基)甲基酮(实施例31)的制备(S)-[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](3-aminopiperidin-1-yl)methylketone (Example 31) Preparation
参考制备实施例29的方法，将c步骤中吗啉原料等比例替换为(R)-哌啶-3-基碳酰胺叔丁酯，即得实施例31。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.69(s,1H),7.62(d,J＝8.2Hz,1H),7.36(q,J＝7.8Hz,1H),7.19(dt,J＝15.5,7.8Hz,2H),7.14(d,J＝10.0Hz,1H),7.05(t,J＝8.6Hz,1H),6.85(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),4.35–4.08(m,1H),3.52(s,1H),2.91–2.70(m,1H),2.61(s,1H),2.47(s,1H),1.83(d,J＝10.1Hz,1H),1.73–1.53(m,2H),1.49–1.27(m,2H),1.20(d,J＝12.5Hz,1H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1769。 Referring to the method for preparing Example 29, the morpholine raw material in step c was replaced by (R)-piperidin-3-ylcarboxamide tert-butyl ester in equal proportions to obtain Example 31. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.69(s, 1H), 7.62(d, J＝8.2Hz, 1H), 7.36(q, J＝7.8Hz, 1H), 7.19(dt, J＝15.5, 7.8Hz, 2H), 7.14(d, J＝10.0Hz, 1H), 7.05(t, J＝8.6Hz, 1H), 6.85(d, J＝7.5Hz, 1H), 4.64(d, J＝6.1Hz, 2H), 4.35–4.08(m, 1H), 3.52(s, 1H), 2.91– 2.70(m,1H),2.61(s,1H),2.47(s,1H),1.83(d,J＝10.1Hz,1H),1.73–1.53(m,2H),1.49–1.27(m,2H) , 1.20 (d, J=12.5Hz, 1H). HRMS (ESI, m/z) calcd. for C 23 H 25 ClFN 6 O [M+H] + , 455.1762; found 455.1769.
(S)-3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例32)的制备(S)-3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 32 ) preparation
参考制备实施例29的方法，将c步骤中吗啉原料等比例替换为(S)-3-氨基哌啶-1-碳酰胺叔丁酯，即得实施例32。 1H NMR(600MHz,DMSO-d 6)δ9.34(s,1H),8.19(s,1H),8.03(d,J＝7.0Hz,1H),7.99(s,1H),7.89(t,J＝5.7Hz,1H),7.68(d,J＝7.4Hz,1H),7.32(t,J＝6.8Hz,2H),7.22(t,J＝7.8Hz,1H),7.17(dd,J＝15.1,9.0Hz,2H),7.02(t,J＝8.8Hz,1H),4.66(d,J＝ 5.8Hz,2H),3.77(s,1H),2.93(d,J＝10.1Hz,1H),2.77(d,J＝11.7Hz,1H),2.38(s,2H),1.81(d,J＝8.6Hz,1H),1.61(d,J＝10.9Hz,1H),1.47–1.33(m,2H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1766。 Referring to the method for preparing Example 29, the morpholine raw material in step c was replaced by (S)-3-aminopiperidine-1-carboxamide tert-butyl ester in equal proportions to obtain Example 32. 1 H NMR (600MHz, DMSO-d 6 )δ9.34(s,1H),8.19(s,1H),8.03(d,J=7.0Hz,1H),7.99(s,1H),7.89(t, J=5.7Hz, 1H), 7.68(d, J=7.4Hz, 1H), 7.32(t, J=6.8Hz, 2H), 7.22(t, J=7.8Hz, 1H), 7.17(dd, J= 15.1,9.0Hz,2H),7.02(t,J=8.8Hz,1H),4.66(d,J=5.8Hz,2H),3.77(s,1H),2.93(d,J=10.1Hz,1H) ,2.77(d,J=11.7Hz,1H),2.38(s,2H),1.81(d,J=8.6Hz,1H),1.61(d,J=10.9Hz,1H),1.47–1.33(m, 2H). HRMS (ESI, m/z) calc. for C 23 H 25 ClFN 6 O [M+H] + , 455.1762; found 455.1766.
(R)-3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例33)的制备(R)-3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 33 ) preparation
参考制备实施例29的方法，将c步骤中吗啉原料等比例替换为(R)-3-氨基哌啶-1-碳酰胺叔丁酯，即得实施例33。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.01(s,1H),7.91(t,J＝6.2Hz,1H),7.69(s,1H),7.62(d,J＝9.4Hz,1H),7.36(q,J＝7.9Hz,1H),7.19(dt,J＝15.4,7.8Hz,2H),7.14(d,J＝10.0Hz,1H),7.05(td,J＝8.7,2.4Hz,1H),6.85(d,J＝7.5Hz,1H),4.64(d,J＝6.1Hz,2H),4.32–4.14(m,1H),3.51(s,1H),2.93–2.71(m,1H),2.62(s,1H),1.83(d,J＝12.8Hz,1H),1.70(s,1H),1.55(s,1H),1.35(s,1H),1.19(d,J＝12.5Hz,1H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1774。 Referring to the method for preparing Example 29, the morpholine raw material in step c was replaced by (R)-3-aminopiperidine-1-carboxamide tert-butyl ester in equal proportions to obtain Example 33. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.01(s, 1H), 7.91(t, J=6.2Hz, 1H), 7.69(s, 1H), 7.62(d, J＝9.4Hz, 1H), 7.36(q, J＝7.9Hz, 1H), 7.19(dt, J＝15.4, 7.8Hz, 2H), 7.14(d, J＝10.0Hz, 1H), 7.05(td, J=8.7,2.4Hz,1H),6.85(d,J=7.5Hz,1H),4.64(d,J=6.1Hz,2H),4.32–4.14(m,1H),3.51(s,1H), 2.93–2.71(m,1H),2.62(s,1H),1.83(d,J＝12.8Hz,1H),1.70(s,1H),1.55(s,1H),1.35(s,1H),1.19 (d, J=12.5Hz, 1H). HRMS (ESI, m/z) calc. C 23 H 25 ClFN 6 O [M+H] + , 455.1762; found 455.1774.
实施例34按照如下路线进行制备：Embodiment 34 is prepared according to the following route:
Figure PCTCN2022112391-appb-000011
Figure PCTCN2022112391-appb-000011
2,5-二氯-N-(4-氟苄基)嘧啶-4-胺的制备(9)Preparation of 2,5-dichloro-N-(4-fluorobenzyl)pyrimidin-4-amine (9)
参考2,5-二氯-N-(3-氟苄基)嘧啶-4-胺(2)的制备方法，将反应中的3-氟苄胺等比例替换为4-氟苄胺即可制得中间体9。Referring to the preparation method of 2,5-dichloro-N-(3-fluorobenzyl)pyrimidin-4-amine (2), the 3-fluorobenzylamine in the reaction is replaced by 4-fluorobenzylamine in equal proportions to prepare Intermediate 9 was obtained.
3-({5-氯-4-[(4-氟苄基)氨基)嘧啶-2-基)氨基苯甲酸(10)的制备Preparation of 3-({5-chloro-4-[(4-fluorobenzyl)amino)pyrimidin-2-yl)aminobenzoic acid (10)
将中间体4(0.10g,0.37mmol)溶于3mL异丙醇，加入间氨基苯甲酸(0.056g,0.41mmol)和催化量的饱和的氯化氢1,4-二氧六环溶液，在封管下加热至120℃。TLC监测原料反应完毕，冷却反应液，有白色固体析出，过滤，用少量异丙醇洗涤滤饼，甲醇重结晶，得到白色粉末状固体，收率88％。Intermediate 4 (0.10g, 0.37mmol) was dissolved in 3mL of isopropanol, m-aminobenzoic acid (0.056g, 0.41mmol) and a catalytic amount of saturated hydrogen chloride 1,4-dioxane solution were added, Heating to 120°C. The completion of the raw material reaction was monitored by TLC, the reaction solution was cooled, a white solid precipitated out, filtered, the filter cake was washed with a small amount of isopropanol, and recrystallized from methanol to obtain a white powdery solid with a yield of 88%.
3-({5-氯-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例34)的制备Preparation of 3-({5-chloro-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 34)
参考制备实施例29的方法，将c步骤中的中间体6等比例替换为中间体10，吗啉等比例替换为哌啶-3-基碳酰胺叔丁酯，即得实施例34。 1H NMR(600MHz,DMSO-d 6)δ9.32(s,1H),8.18(s,1H),8.03(d,J＝8.0Hz,1H),7.98(s,1H),7.85(t,J＝6.2Hz,1H),7.70(d,J＝7.7Hz,1H),7.38(dd,J＝8.4,5.7Hz,2H),7.33(d,J＝7.7Hz,1H),7.24(t,J＝7.9Hz,1H),7.09(t,J＝8.9Hz,2H),4.62(d,J＝6.1Hz,3H),3.79(d,J＝8.2Hz,1H),2.99–2.89(m,1H),2.79(d,J＝12.4Hz,1H),2.43–2.35(m,2H),1.81(d,J＝11.6Hz,1H),1.61(d,J＝12.5Hz,1H),1.47–1.36(m,2H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1769。3-({5-氯-4-[(3,5-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例35)的制备 Referring to the method for preparing Example 29, intermediate 6 in step c was replaced with intermediate 10 in equal proportions, and morpholine was replaced with piperidin-3-ylcarboxamide tert-butyl ester in equal proportions to obtain Example 34. 1 H NMR (600MHz, DMSO-d 6 )δ9.32(s,1H),8.18(s,1H),8.03(d,J=8.0Hz,1H),7.98(s,1H),7.85(t, J＝6.2Hz, 1H), 7.70(d, J＝7.7Hz, 1H), 7.38(dd, J＝8.4, 5.7Hz, 2H), 7.33(d, J＝7.7Hz, 1H), 7.24(t, J＝7.9Hz, 1H), 7.09(t, J＝8.9Hz, 2H), 4.62(d, J＝6.1Hz, 3H), 3.79(d, J＝8.2Hz, 1H), 2.99–2.89(m, 1H), 2.79(d, J=12.4Hz, 1H), 2.43–2.35(m, 2H), 1.81(d, J=11.6Hz, 1H), 1.61(d, J=12.5Hz, 1H), 1.47– 1.36 (m, 2H). HRMS (ESI, m/z) Theoretical C 23 H 25 ClFN 6 O [M+H] + , 455.1762; Found 455.1769. 3-({5-Chloro-4-[(3 , Preparation of 5-difluorobenzyl) amino] pyrimidin-2-yl} amino)-N-(piperidin-3-yl) benzamide (embodiment 35)
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为3,5-二氟苄基，即得实施例35。 1H NMR(600MHz,DMSO-d 6)δ9.39(s,1H),8.24(s,1H),8.05(d,J＝7.5Hz,1H),8.01(s,1H),7.92(t,J＝5.5Hz,1H),7.66(d,J＝7.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.22(t,J＝7.7Hz,1H),7.08–7.02(m,3H),4.65(d,J＝5.4Hz,2H),3.78(s,1H),2.94(d,J＝10.6Hz,1H),2.77(d,J＝11.7Hz,1H),2.38(t,J＝10.4Hz,2H),1.86–1.78(m,1H),1.61(d,J＝11.4Hz,1H),1.49–1.33(m,2H).HRMS(ESI,m/z)理论值C 23H 24ClF 2N 6O[M+H] +,473.1668；实测值473.1679。 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 3,5-difluorobenzyl in equal proportions to obtain Example 35. 1 H NMR (600MHz, DMSO-d 6 )δ9.39(s,1H),8.24(s,1H),8.05(d,J=7.5Hz,1H),8.01(s,1H),7.92(t, J＝5.5Hz, 1H), 7.66(d, J＝7.1Hz, 1H), 7.35(d, J＝7.5Hz, 1H), 7.22(t, J＝7.7Hz, 1H), 7.08–7.02(m, 3H), 4.65(d, J=5.4Hz, 2H), 3.78(s, 1H), 2.94(d, J=10.6Hz, 1H), 2.77(d, J=11.7Hz, 1H), 2.38(t, J＝10.4Hz, 2H), 1.86–1.78(m, 1H), 1.61(d, J＝11.4Hz, 1H), 1.49–1.33(m, 2H). HRMS (ESI, m/z) theoretical value C 23 H 24 ClF 2 N 6 O [M+H] + , 473.1668; found 473.1679.
3-({5-氯-4-[(3,4,5-三氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例36)的制备3-({5-chloro-4-[(3,4,5-trifluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 36) Preparation
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为3,4,5-三氟苄基，即得实施例36。 1H NMR(600MHz,DMSO-d 6)δ9.41(s,1H),8.28(s,1H),8.08(d,J＝7.1Hz,1H),8.00(s,1H),7.92(t,J＝5.7Hz,1H),7.66(d,J＝7.0Hz,1H),7.37(d,J＝7.6Hz,1H),7.32–7.27(m,2H),7.25(t,J＝7.9Hz,1H),4.61(d,J＝5.6Hz,2H),3.78(s,1H),2.94(d,J＝11.2Hz,1H),2.77(d,J＝12.1Hz,1H),2.39(t,J＝10.5Hz,2H),1.81(d,J＝9.3Hz,1H),1.61(d,J＝12.4Hz,1H),1.53–1.36(m,2H).HRMS(ESI,m/z)理论值C 23H 23ClF 3N 6O[M+H] +,491.1574；实测值473.1589。 Referring to the method for preparing Example 34, 4-fluorobenzyl in step e was replaced with 3,4,5-trifluorobenzyl in equal proportions to obtain Example 36. 1 H NMR (600MHz, DMSO-d 6 )δ9.41(s,1H),8.28(s,1H),8.08(d,J=7.1Hz,1H),8.00(s,1H),7.92(t, J＝5.7Hz, 1H), 7.66(d, J＝7.0Hz, 1H), 7.37(d, J＝7.6Hz, 1H), 7.32–7.27(m, 2H), 7.25(t, J＝7.9Hz, 1H), 4.61(d, J=5.6Hz, 2H), 3.78(s, 1H), 2.94(d, J=11.2Hz, 1H), 2.77(d, J=12.1Hz, 1H), 2.39(t, J＝10.5Hz, 2H), 1.81(d, J＝9.3Hz, 1H), 1.61(d, J＝12.4Hz, 1H), 1.53–1.36(m, 2H). HRMS (ESI, m/z) theory Value for C 23 H 23 ClF 3 N 6 O [M+H] + , 491.1574; found 473.1589.
3-({5-氯-4-[(2-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例37)的制备Preparation of 3-({5-chloro-4-[(2-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 37)
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为2-氟苄基，即得实施例37。 1H NMR(600MHz,DMSO-d 6)δ9.33(s,1H),8.41(d,J＝7.7Hz,1H),8.04(s,1H),8.01(s,1H),7.78(t,J＝6.0Hz,1H),7.74(d,J＝9.3Hz,1H),7.39(d,J＝7.7Hz,1H),7.29(q,J＝8.1Hz,2H),7.19(q,J＝7.5Hz,2H),7.12(t,J＝7.4Hz,1H),4.70(d,J＝5.9Hz,2H),4.12(d,J＝7.7Hz,1H),3.20(dd,J＝12.1,3.8Hz,1H),3.09(d,J＝12.4Hz,1H),2.76(t,J＝10.9Hz,2H),1.84(s,2H),1.66(d,J＝10.6Hz,1H),1.58–1.53(m,1H).HRMS(ESI,m/z)理论值C 23H 25ClFN 6O[M+H] +,455.1762；实测值455.1787。 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 2-fluorobenzyl in equal proportions to obtain Example 37. 1 H NMR (600MHz, DMSO-d 6 )δ9.33(s, 1H), 8.41(d, J=7.7Hz, 1H), 8.04(s, 1H), 8.01(s, 1H), 7.78(t, J=6.0Hz, 1H), 7.74(d, J=9.3Hz, 1H), 7.39(d, J=7.7Hz, 1H), 7.29(q, J=8.1Hz, 2H), 7.19(q, J= 7.5Hz, 2H), 7.12(t, J=7.4Hz, 1H), 4.70(d, J=5.9Hz, 2H), 4.12(d, J=7.7Hz, 1H), 3.20(dd, J=12.1, 3.8Hz, 1H), 3.09(d, J=12.4Hz, 1H), 2.76(t, J=10.9Hz, 2H), 1.84(s, 2H), 1.66(d, J=10.6Hz, 1H), 1.58 - 1.53 (m, 1H). HRMS (ESI, m/z) calcd. for C 23 H 25 ClFN 6 O [M+H] + , 455.1762; found 455.1787.
3-({5-氯-4-[(3,4-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例38)的制备3-({5-chloro-4-[(3,4-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 38) preparation of
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为3,4-二氟苄基，即得实施例38。 1H NMR(600MHz,DMSO-d 6)δ9.35(s,1H),8.22(s,1H),8.03(d,J＝7.8Hz,1H),7.99(s,1H),7.89(t,J＝5.8Hz,1H),7.68(d,J＝7.5Hz,1H),7.43–7.37(m,1H),7.36–7.28(m,2H),7.24(t,J＝7.8Hz,1H),7.19(s,1H),4.62(d,J＝5.8Hz,2H),3.78(d,J＝8.0Hz,1H),2.93(d,J＝9.8Hz,1H),2.77(d,J＝12.1Hz,1H),2.38(t,J＝10.1Hz,2H),2.18(s,1H),1.81(d,J＝9.0Hz,1H),1.61(d,J＝12.2Hz,1H),1.50–1.34(m,2H).HRMS(ESI,m/z)理论值C 23H 24ClF 2N 6O[M+H] +,473.1668；实测值473.1686。 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 3,4-difluorobenzyl in equal proportions to obtain Example 38. 1 H NMR (600MHz, DMSO-d 6 )δ9.35(s,1H),8.22(s,1H),8.03(d,J=7.8Hz,1H),7.99(s,1H),7.89(t, J＝5.8Hz, 1H), 7.68(d, J＝7.5Hz, 1H), 7.43–7.37(m, 1H), 7.36–7.28(m, 2H), 7.24(t, J＝7.8Hz, 1H), 7.19(s, 1H), 4.62(d, J=5.8Hz, 2H), 3.78(d, J=8.0Hz, 1H), 2.93(d, J=9.8Hz, 1H), 2.77(d, J=12.1 Hz, 1H), 2.38(t, J=10.1Hz, 2H), 2.18(s, 1H), 1.81(d, J=9.0Hz, 1H), 1.61(d, J=12.2Hz, 1H), 1.50– 1.34 (m, 2H). HRMS (ESI, m/z) calcd. for C 23 H 24 ClF 2 N 6 O [M+H] + , 473.1668; found 473.1686.
3-({5-氯-4-[(2,6-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例39)的制备3-({5-chloro-4-[(2,6-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 39) preparation of
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为2,6-二氟苄基，即得实施例39。 1H NMR(600MHz,DMSO-d 6)δ9.36(s,1H),8.23(s,1H),8.02–7.98(m,2H),7.77(d,J＝8.1Hz,1H),7.47(t,J＝5.2Hz,1H),7.43–7.35(m,1H),7.34–7.26(m,2H),7.08(t,J＝8.0Hz,2H),4.75(d,J＝5.4Hz,2H),3.73(d,J＝8.1Hz,1H),2.92–2.85(m,1H),2.75(d,J＝12.4Hz,1H),2.35–2.28(m,2H),1.75(d,J＝9.3Hz,1H),1.55(dd,J＝8.8,3.6Hz,1H),1.43–1.31(m,2H).HRMS(ESI,m/z)理论值C 23H 24ClF 2N 6O[M+H] +,473.1668；实测值473.1681。3-({5-氯-4-[(2,5-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例40)的制备 Referring to the method for preparing Example 34, 4-fluorobenzyl in step e was replaced with 2,6-difluorobenzyl in equal proportions to obtain Example 39. 1 H NMR (600MHz, DMSO-d 6 ) δ9.36(s, 1H), 8.23(s, 1H), 8.02–7.98(m, 2H), 7.77(d, J=8.1Hz, 1H), 7.47( t,J=5.2Hz,1H),7.43–7.35(m,1H),7.34–7.26(m,2H),7.08(t,J=8.0Hz,2H),4.75(d,J=5.4Hz,2H ), 3.73(d, J＝8.1Hz, 1H), 2.92–2.85(m, 1H), 2.75(d, J＝12.4Hz, 1H), 2.35–2.28(m, 2H), 1.75(d, J＝ 9.3Hz, 1H), 1.55(dd, J＝8.8, 3.6Hz, 1H), 1.43–1.31(m, 2H). HRMS(ESI, m/z) theoretical value C 23 H 24 ClF 2 N 6 O[M +H] + , 473.1668; found 473.1681. 3-({5-chloro-4-[(2,5-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidine-3 -base) preparation of benzamide (embodiment 40)
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为2,5-二氟苄基，即得实施例40。 1H NMR(600MHz,DMSO-d 6)δ9.35(s,1H),8.03(s,1H),8.01(t,J＝1.8Hz,1H),7.98(d,J＝8.0Hz,1H),7.79(t,J＝6.0Hz,1H),7.73(d,J＝8.1Hz,1H),7.31(d,J＝7.8Hz,1H),7.26(td,J＝9.2,4.4Hz,1H),7.19(t,J＝7.9Hz,1H),7.14–7.07(m,2H),4.67(d,J＝5.9Hz,2H),3.75(d,J＝8.3Hz,1H),2.92(dd,J＝11.8,3.3Hz,1H),2.76(d,J＝12.4Hz,1H),2.36(q,J＝9.7Hz,2H),1.82–1.75(m,1H),1.59(d,J＝12.6Hz,1H),1.47–1.33(m,2H).HRMS(ESI,m/z)理论值C 23H 24ClF 2N 6O[M+H] +,473.1668；实测值473.1686。 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 2,5-difluorobenzyl in equal proportions to obtain Example 40. 1 H NMR (600MHz,DMSO-d 6 )δ9.35(s,1H),8.03(s,1H),8.01(t,J=1.8Hz,1H),7.98(d,J=8.0Hz,1H) ,7.79(t,J=6.0Hz,1H),7.73(d,J=8.1Hz,1H),7.31(d,J=7.8Hz,1H),7.26(td,J=9.2,4.4Hz,1H) ,7.19(t,J=7.9Hz,1H),7.14–7.07(m,2H),4.67(d,J=5.9Hz,2H),3.75(d,J=8.3Hz,1H),2.92(dd, J=11.8,3.3Hz,1H), 2.76(d,J=12.4Hz,1H),2.36(q,J=9.7Hz,2H),1.82–1.75(m,1H),1.59(d,J=12.6 Hz, 1H), 1.47–1.33 (m, 2H). HRMS (ESI, m/z) Theoretical C 23 H 24 ClF 2 N 6 O[M+H] + , 473.1668; Found 473.1686.
3-({5-氯-4-[(2,4-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例41)的制备3-({5-chloro-4-[(2,4-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 41) preparation of
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为2,4-二氟苄基，即得实施例41。 1H NMR(600MHz,DMSO-d 6)δ9.32(s,1H),8.03–8.00(m,2H),7.98(d,J＝8.0Hz,1H),7.76(t,J＝5.9Hz,1H),7.73(d,J＝8.0Hz,1H),7.35(q,J＝8.5Hz,1H),7.31(d,J＝7.7Hz,1H),7.26–7.17(m,2H),7.00(td,J＝8.5,2.2Hz,1H),4.65(d,J＝5.8Hz,2H),3.79– 3.70(m,1H),2.91(dd,J＝11.7,3.1Hz,2H),2.76(d,J＝12.5Hz,1H),2.42–2.30(m,2H),2.18(s,1H),1.83–1.72(m,1H),1.59(dd,J＝8.8,3.8Hz,1H),1.47–1.34(m,2H).HRMS(ESI,m/z)理论值C 23H 24ClF 2N 6O[M+H] +,473.1668；实测值473.1679。 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 2,4-difluorobenzyl in equal proportions to obtain Example 41. 1 H NMR (600MHz,DMSO-d 6 )δ9.32(s,1H),8.03–8.00(m,2H),7.98(d,J=8.0Hz,1H),7.76(t,J=5.9Hz, 1H), 7.73(d, J=8.0Hz, 1H), 7.35(q, J=8.5Hz, 1H), 7.31(d, J=7.7Hz, 1H), 7.26–7.17(m, 2H), 7.00( td, J＝8.5, 2.2Hz, 1H), 4.65(d, J＝5.8Hz, 2H), 3.79– 3.70(m, 1H), 2.91(dd, J＝11.7, 3.1Hz, 2H), 2.76(d ,J=12.5Hz,1H),2.42–2.30(m,2H),2.18(s,1H),1.83–1.72(m,1H),1.59(dd,J=8.8,3.8Hz,1H),1.47– 1.34 (m, 2H). HRMS (ESI, m/z) calc. for C 23 H 24 ClF 2 N 6 O [M+H] + , 473.1668; found 473.1679.
3-({5-氯-4-[(2,3-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例42)的制备3-({5-chloro-4-[(2,3-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 42) preparation of
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为2,3-二氟苄基，即得实施例42。 1H NMR(600MHz,DMSO-d 6)δ9.33(s,1H),8.02(s,1H),8.00(s,1H),7.97(d,J＝8.0Hz,1H),7.83(t,J＝5.9Hz,1H),7.71(d,J＝8.0Hz,1H),7.32–7.26(m,2H),7.17(t,J＝7.9Hz,1H),7.14–7.09(m,2H),4.72(d,J＝5.9Hz,2H),3.77–3.70(m,1H),2.91(dd,J＝11.6,3.1Hz,1H),2.76(d,J＝12.4Hz,1H),2.36(q,J＝9.9Hz,2H),2.14(s,1H),1.79(d,J＝13.9Hz,1H),1.59(dd,J＝8.8,3.8Hz,1H),1.46–1.34(m,2H).HRMS(ESI,m/z)理论值C 23H 24ClF 2N 6O[M+H] +,473.1668；实测值473.1678。 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 2,3-difluorobenzyl in equal proportions to obtain Example 42. 1 H NMR (600MHz,DMSO-d 6 )δ9.33(s,1H),8.02(s,1H),8.00(s,1H),7.97(d,J=8.0Hz,1H),7.83(t, J＝5.9Hz, 1H), 7.71(d, J＝8.0Hz, 1H), 7.32–7.26(m, 2H), 7.17(t, J＝7.9Hz, 1H), 7.14–7.09(m, 2H), 4.72(d, J=5.9Hz, 2H), 3.77–3.70(m, 1H), 2.91(dd, J=11.6, 3.1Hz, 1H), 2.76(d, J=12.4Hz, 1H), 2.36(q ,J=9.9Hz,2H),2.14(s,1H),1.79(d,J=13.9Hz,1H),1.59(dd,J=8.8,3.8Hz,1H),1.46–1.34(m,2H) .HRMS (ESI, m/z) Calc. C 23 H 24 ClF 2 N 6 O [M+H] + , 473.1668; Found 473.1678.
3-({5-氯-4-[2-(3-氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例43)的制备3-({5-chloro-4-[2-(3-fluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 43) Preparation
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为2-(3-氟苯基)吡咯烷，即得实施例43。 1H NMR(600MHz,DMSO-d 6)δ9.36(s,1H),8.47(d,J＝7.7Hz,1H),8.13(s,1H),7.98(s,1H),7.59(d,J＝7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.30(q,J＝6.9Hz,1H),7.24(t,J＝7.9Hz,1H),7.03(d,J＝7.8Hz,2H),6.98(t,J＝8.8Hz,1H),5.64(s,1H),4.21(s,2H),3.97–3.86(m,1H),3.28(d,J＝12.1Hz,1H),3.16(d,J＝12.5Hz,1H),2.82(t,J＝12.5Hz,2H),2.42–2.34(m,1H),2.03–1.83(m,5H),1.80(dt,J＝11.6,5.5Hz,1H),1.71(d,J＝11.3Hz,1H),1.65–1.57(m,1H).HRMS(ESI,m/z)理论值C 26H 29ClFN 6O[M+H] +,495.2075；实测值495.2084。 Referring to the method for preparing Example 34, the 4-fluorobenzyl in step e was replaced with 2-(3-fluorophenyl)pyrrolidine in equal proportions to obtain Example 43. 1 H NMR (600MHz, DMSO-d 6 )δ9.36(s, 1H), 8.47(d, J=7.7Hz, 1H), 8.13(s, 1H), 7.98(s, 1H), 7.59(d, J=7.6Hz, 1H), 7.42(d, J=7.6Hz, 1H), 7.30(q, J=6.9Hz, 1H), 7.24(t, J=7.9Hz, 1H), 7.03(d, J= 7.8Hz, 2H), 6.98(t, J=8.8Hz, 1H), 5.64(s, 1H), 4.21(s, 2H), 3.97–3.86(m, 1H), 3.28(d, J=12.1Hz, 1H), 3.16(d, J＝12.5Hz, 1H), 2.82(t, J＝12.5Hz, 2H), 2.42–2.34(m, 1H), 2.03–1.83(m, 5H), 1.80(dt,J =11.6,5.5Hz,1H),1.71(d,J=11.3Hz,1H),1.65–1.57(m,1H).HRMS(ESI,m/z) theoretical value C 26 H 29 ClFN 6 O[M+ H] + , 495.2075; found 495.2084.
3-({5-氯-4-[2-(4-氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例44)的制备3-({5-chloro-4-[2-(4-fluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 44) Preparation
参考制备实施例34的方法，将e步骤中的4-氟苄基等比例替换为2-(4-氟苯基)吡咯烷，即得实施例44。 1H NMR(600MHz,DMSO-d 6)δ9.32(s,1H),8.15(d,J＝7.9Hz,1H),8.10(s,1H),7.95(s,1H),7.57(d,J＝7.3Hz,1H),7.34(d,J＝7.6Hz,1H),7.26–7.19(m,3H),7.07(t,J＝8.8Hz,2H),5.63(s,1H),4.19(dt,J＝12.4,6.9Hz,1H),3.90(dt,J＝10.8,7.1Hz,2H),3.38(q,J＝7.0Hz,1H),3.06(d,J＝11.7Hz,1H),2.90(d,J＝11.9Hz,1H),2.41–2.33(m,1H),2.03–1.81(m,4H),1.78(dt,J＝11.5,5.6Hz,1H),1.70(d,J＝9.9Hz,1H),1.50(q,J＝9.8Hz,2H).HRMS(ESI,m/z)理论值C 26H 29ClFN 6O[M+H] +,495.2075；实测值495.2084。 Referring to the method for preparing Example 34, 4-fluorobenzyl in step e was replaced with 2-(4-fluorophenyl)pyrrolidine in equal proportions to obtain Example 44. 1 H NMR (600MHz, DMSO-d 6 )δ9.32(s, 1H), 8.15(d, J=7.9Hz, 1H), 8.10(s, 1H), 7.95(s, 1H), 7.57(d, J＝7.3Hz, 1H), 7.34(d, J＝7.6Hz, 1H), 7.26–7.19(m, 3H), 7.07(t, J＝8.8Hz, 2H), 5.63(s, 1H), 4.19( dt,J=12.4,6.9Hz,1H),3.90(dt,J=10.8,7.1Hz,2H),3.38(q,J=7.0Hz,1H),3.06(d,J=11.7Hz,1H), 2.90(d,J=11.9Hz,1H),2.41–2.33(m,1H),2.03–1.81(m,4H),1.78(dt,J=11.5,5.6Hz,1H),1.70(d,J= 9.9Hz, 1H), 1.50 (q, J=9.8Hz, 2H). HRMS (ESI, m/z) Theoretical C 26 H 29 ClFN 6 O[M+H] + , 495.2075; Found 495.2084.
3-({5-氯-4-[2-(3,5-二氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例45)的制备3-({5-chloro-4-[2-(3,5-difluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl) Preparation of Benzamide (Example 45)
参考制备实施例34的方法，将e步骤中的3,5-二氟苄基等比例替换为2-(4-氟苯基)吡咯烷，即得实施例45。 1H NMR(600MHz,DMSO-d 6)δ9.35(s,1H),8.13(s,1H),8.09(d,J＝7.8Hz,1H),8.00(s,1H),7.56(d,J＝7.6Hz,1H),7.36(d,J＝7.1Hz,1H),7.22(t,J＝7.9Hz,1H),6.99(t,J＝9.1Hz,1H),6.94(d,J＝8.1Hz,2H),5.62(s,1H),4.26–4.19(m,1H),3.94–3.84(m,2H),3.38(q,J＝7.0Hz,1H),3.00(d,J＝11.8Hz,1H),2.83(d,J＝12.5Hz,1H),2.48–2.42(m,2H),2.40–2.35(m,1H),1.94–1.77(m,4H),1.65(d,J＝11.2Hz,1H),1.54–1.41(m,2H).HRMS(ESI,m/z)理论值C 26H 28ClF 2N 6O[M+H] +,513.1981；实测值513.1990。 Referring to the method for preparing Example 34, the 3,5-difluorobenzyl in step e was replaced with 2-(4-fluorophenyl)pyrrolidine in equal proportions to obtain Example 45. 1 H NMR (600MHz, DMSO-d 6 )δ9.35(s, 1H), 8.13(s, 1H), 8.09(d, J=7.8Hz, 1H), 8.00(s, 1H), 7.56(d, J=7.6Hz, 1H), 7.36(d, J=7.1Hz, 1H), 7.22(t, J=7.9Hz, 1H), 6.99(t, J=9.1Hz, 1H), 6.94(d, J= 8.1Hz, 2H), 5.62(s, 1H), 4.26–4.19(m, 1H), 3.94–3.84(m, 2H), 3.38(q, J=7.0Hz, 1H), 3.00(d, J=11.8 Hz,1H),2.83(d,J＝12.5Hz,1H),2.48–2.42(m,2H),2.40–2.35(m,1H),1.94–1.77(m,4H),1.65(d,J＝ 11.2Hz, 1H), 1.54–1.41 (m, 2H). HRMS (ESI, m/z) Theoretical C 26 H 28 ClF 2 N 6 O[M+H] + , 513.1981; Found 513.1990.
3-({5-氯-4-[2-(3,4,5-三氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例46)的制备3-({5-chloro-4-[2-(3,4,5-trifluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidine-3- base) preparation of benzamide (embodiment 46)
参考制备实施例34的方法，将e步骤中的3,4,5-三氟苄基等比例替换为2-(3,4,5-三氟苯基)吡咯烷，即得实施例46。 1H NMR(600MHz,DMSO-d 6)δ9.37(s,1H),8.48(d,J＝7.4Hz,1H),8.13(s,1H),8.00(s,1H),7.59(s,1H),7.46(d,J＝7.0Hz,1H),7.24(t,J＝7.4Hz,1H),6.97(d,J＝8.7Hz,2H),5.55(s,1H),4.22(s,2H),4.05(d,J＝6.8Hz,2H),3.89(d,J＝9.0Hz,1H),3.26(d,J＝11.6Hz,1H),3.13(d,J＝11.8Hz,1H),2.95(q,J＝6.5Hz,1H),2.81(s,2H), 2.34(s,1H),1.89(s,4H),1.84–1.76(m,1H),1.71(d,J＝10.5Hz,1H),1.65–1.58(m,1H).HRMS(ESI,m/z)理论值C 26H 26ClF 3N 6ONa[M+Na] +,553.1706；实测值553.1722。 Referring to the method for preparing Example 34, the 3,4,5-trifluorobenzyl in step e was replaced with 2-(3,4,5-trifluorophenyl)pyrrolidine in equal proportions to obtain Example 46. 1 H NMR (600MHz, DMSO-d 6 )δ9.37(s, 1H), 8.48(d, J=7.4Hz, 1H), 8.13(s, 1H), 8.00(s, 1H), 7.59(s, 1H), 7.46(d, J=7.0Hz, 1H), 7.24(t, J=7.4Hz, 1H), 6.97(d, J=8.7Hz, 2H), 5.55(s, 1H), 4.22(s, 2H), 4.05(d, J=6.8Hz, 2H), 3.89(d, J=9.0Hz, 1H), 3.26(d, J=11.6Hz, 1H), 3.13(d, J=11.8Hz, 1H) ,2.95(q,J=6.5Hz,1H),2.81(s,2H), 2.34(s,1H),1.89(s,4H),1.84–1.76(m,1H),1.71(d,J=10.5 Hz, 1H), 1.65–1.58 (m, 1H). HRMS (ESI, m/z) calcd for C 26 H 26 ClF 3 N 6 ONa[M+Na] + , 553.1706; found 553.1722.
3-({5-氟-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例47)的制备Preparation of 3-({5-fluoro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 47)
参考制备实施例34的方法，将e步骤中的2,4,5-三氯嘧啶等比例替换为5-氟-2,4-二氯嘧啶，即得实施例47。 1H NMR(600MHz,DMSO-d 6)δ9.21(s,1H),8.11–8.05(m,2H),8.00(d,J＝7.5Hz,1H),7.95(d,J＝3.5Hz,1H),7.75(d,J＝7.8Hz,1H),7.35–7.27(m,2H),7.22–7.10(m,3H),4.70(d,J＝5.8Hz,2H),3.75(s,1H),3.38(q,J＝7.0Hz,1H),2.91(d,J＝10.5Hz,1H),2.76(d,J＝11.4Hz,1H),2.36(s,2H),1.79(s,1H),1.58(s,1H),1.47–1.35(m,2H).HRMS(ESI,m/z)理论值C 23H 24F 2N 6ONa[M+Na] +,461.1877；实测值461.1874。 Referring to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced with 5-fluoro-2,4-dichloropyrimidine in equal proportions to obtain Example 47. 1 H NMR (600MHz, DMSO-d 6 )δ9.21(s, 1H), 8.11–8.05(m, 2H), 8.00(d, J=7.5Hz, 1H), 7.95(d, J=3.5Hz, 1H), 7.75(d, J＝7.8Hz, 1H), 7.35–7.27(m, 2H), 7.22–7.10(m, 3H), 4.70(d, J＝5.8Hz, 2H), 3.75(s, 1H) ), 3.38(q, J=7.0Hz, 1H), 2.91(d, J=10.5Hz, 1H), 2.76(d, J=11.4Hz, 1H), 2.36(s, 2H), 1.79(s, 1H ), 1.58 (s, 1H), 1.47–1.35 (m, 2H). HRMS (ESI, m/z) Theoretical C 23 H 24 F 2 N 6 ONa[M+Na] + , 461.1877; Found 461.1874.
3-({5-溴-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例48)的制备Preparation of 3-({5-bromo-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 48)
参考制备实施例34的方法，将e步骤中的2,4,5-三氯嘧啶等比例替换为5-溴-2,4-二氯嘧啶，即得实施例48。 1H NMR(600MHz,DMSO-d 6)δ9.35(s,1H),8.18(s,1H),8.07(s,1H),8.03(d,J＝7.8Hz,1H),7.71(t,J＝6.2Hz,1H),7.67(d,J＝7.8Hz,1H),7.34–7.28(m,2H),7.22(t,J＝7.9Hz,1H),7.17(d,J＝7.7Hz,1H),7.15(d,J＝10.1Hz,1H),7.01(td,J＝8.5,2.3Hz,1H),4.65(d,J＝6.2Hz,2H),3.78(d,J＝8.3Hz,1H),3.44(q,J＝7.0Hz,1H),2.93(d,J＝9.6Hz,1H),2.77(d,J＝12.2Hz,1H),2.38(t,J＝10.1Hz,3H),1.81(d,J＝9.4Hz,1H),1.60(dd,J＝8.7,3.9Hz,1H),1.49–1.33(m,2H).HRMS(ESI,m/z)理论值C 23H 25BrFN 6O[M+H] +,501.1237；实测值501.1255。 Referring to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced with 5-bromo-2,4-dichloropyrimidine in equal proportions to obtain Example 48. 1 H NMR (600MHz, DMSO-d 6 )δ9.35(s,1H),8.18(s,1H),8.07(s,1H),8.03(d,J=7.8Hz,1H),7.71(t, J＝6.2Hz, 1H), 7.67(d, J＝7.8Hz, 1H), 7.34–7.28(m, 2H), 7.22(t, J＝7.9Hz, 1H), 7.17(d, J＝7.7Hz, 1H), 7.15(d, J=10.1Hz, 1H), 7.01(td, J=8.5, 2.3Hz, 1H), 4.65(d, J=6.2Hz, 2H), 3.78(d, J=8.3Hz, 1H), 3.44(q, J=7.0Hz, 1H), 2.93(d, J=9.6Hz, 1H), 2.77(d, J=12.2Hz, 1H), 2.38(t, J=10.1Hz, 3H) , 1.81(d, J＝9.4Hz, 1H), 1.60(dd, J＝8.7, 3.9Hz, 1H), 1.49–1.33(m, 2H). HRMS (ESI, m/z) theoretical value C 23 H 25 BrFN 6 O[M+H] + , 501.1237; found 501.1255.
3-({5-甲基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例49)的制备Preparation of 3-({5-methyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 49)
参考制备实施例34的方法，将e步骤中的2,4,5-三氯嘧啶等比例替换为5-溴-2,4-二氯嘧啶，即得实施例49。参考制备实施例34的方法，将e步骤中的2,4,5-三氯嘧啶等比例替换为5-甲基-2,4-二氯嘧啶，即得实施例49. 1H NMR(600MHz,DMSO-d 6)δ8.95(s,1H),8.20(s,1H),7.99(d,J＝7.8Hz,1H),7.72(d,J＝8.8Hz,2H),7.35–7.28(m,2H),7.25(d,J＝7.5Hz,1H),7.21–7.14(m,3H),7.00(t,J＝7.5Hz,1H),4.66(d,J＝5.8Hz,2H),3.79(s,1H),2.95(d,J＝10.8Hz,1H),2.79(d,J＝12.1Hz,1H),2.40(s,2H),1.99(s,3H),1.81(d,J＝9.5Hz,1H),1.62(d,J＝12.2Hz,1H),1.50–1.34(m,2H).HRMS(ESI,m/z)理论值C 24H 28FN 6O[M+H] +,435.2309；实测值435.2317。 Referring to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced with 5-bromo-2,4-dichloropyrimidine in equal proportions to obtain Example 49. With reference to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced by 5-methyl-2,4-dichloropyrimidine in equal proportions to obtain Example 49. 1 H NMR (600MHz ,DMSO-d 6 )δ8.95(s,1H),8.20(s,1H),7.99(d,J=7.8Hz,1H),7.72(d,J=8.8Hz,2H),7.35–7.28( m,2H),7.25(d,J=7.5Hz,1H),7.21–7.14(m,3H),7.00(t,J=7.5Hz,1H),4.66(d,J=5.8Hz,2H), 3.79(s,1H),2.95(d,J=10.8Hz,1H),2.79(d,J=12.1Hz,1H),2.40(s,2H),1.99(s,3H),1.81(d,J ＝9.5Hz, 1H), 1.62(d, J＝12.2Hz, 1H), 1.50–1.34(m, 2H). HRMS(ESI, m/z) theoretical value C 24 H 28 FN 6 O[M+H] + ,435.2309; found 435.2317.
3-({5-硝基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例50)的制备Preparation of 3-({5-nitro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 50)
参考制备实施例34的方法，将e步骤中的2,4,5-三氯嘧啶等比例替换为5-硝基-2,4-二氯嘧啶，即得实施例50。 1H NMR(600MHz,DMSO-d 6)δ10.41(s,1H),9.46(s,1H),9.02(s,1H),8.29(s,1H),8.12(d,J＝7.4Hz,1H),7.65(s,1H),7.51(d,J＝7.4Hz,1H),7.34–7.12(m,4H),7.02(s,1H),4.82(d,J＝5.6Hz,2H),3.79(s,1H),2.95(d,J＝10.6Hz,1H),2.78(d,J＝11.9Hz,1H),2.38(t,J＝10.3Hz,2H),1.82(d,J＝8.6Hz,1H),1.61(d,J＝10.9Hz,1H),1.49–1.33(m,2H).HRMS(ESI,m/z)理论值C 24H 28FN 6O[M+H] +,466.2003；实测值435.2012。 Referring to the method for preparing Example 34, the 2,4,5-trichloropyrimidine in step e was replaced with 5-nitro-2,4-dichloropyrimidine in equal proportions to obtain Example 50. 1 H NMR (600MHz, DMSO-d 6 )δ10.41(s,1H),9.46(s,1H),9.02(s,1H),8.29(s,1H),8.12(d,J＝7.4Hz, 1H),7.65(s,1H),7.51(d,J=7.4Hz,1H),7.34–7.12(m,4H),7.02(s,1H),4.82(d,J=5.6Hz,2H), 3.79(s, 1H), 2.95(d, J=10.6Hz, 1H), 2.78(d, J=11.9Hz, 1H), 2.38(t, J=10.3Hz, 2H), 1.82(d, J=8.6 Hz,1H),1.61(d,J＝10.9Hz,1H),1.49–1.33(m,2H).HRMS(ESI,m/z) theoretical value C 24 H 28 FN 6 O[M+H] + , 466.2003; found 435.2012.
实施例51按照如下路线进行制备：Example 51 was prepared according to the following route:
Figure PCTCN2022112391-appb-000012
Figure PCTCN2022112391-appb-000012
2,4-二氯-5-对甲苯磺酰基-5H-吡咯[3,2-d]嘧啶(14)的制备Preparation of 2,4-dichloro-5-p-toluenesulfonyl-5H-pyrrolo[3,2-d]pyrimidine (14)
将原料13(0.30g,1.60mmol)和DMAP(0.098g,0.80mmol)溶于5mL无水二氯甲烷，缓慢滴加对甲苯磺酰氯(0.46g,2.40mmol)的无水二氯甲烷溶液，滴毕，加入三乙胺(0.33mL,2.40mmol)，室温下搅拌。TLC监测反应完全，有机层用饱和氯化铵溶液洗涤(5mL×3)，饱和食盐水洗涤(5mL×3)，无水硫酸钠干燥。减压过滤，旋除二氯甲烷，得到淡黄色固体，收率99％。The raw material 13 (0.30g, 1.60mmol) and DMAP (0.098g, 0.80mmol) were dissolved in 5mL of anhydrous dichloromethane, and a solution of p-toluenesulfonyl chloride (0.46g, 2.40mmol) in anhydrous dichloromethane was slowly added dropwise, After dropping, triethylamine (0.33 mL, 2.40 mmol) was added and stirred at room temperature. The completion of the reaction was monitored by TLC, and the organic layer was washed with saturated ammonium chloride solution (5 mL×3), saturated brine (5 mL×3), and dried over anhydrous sodium sulfate. Filtrate under reduced pressure and spin off dichloromethane to obtain a light yellow solid with a yield of 99%.
2-氯-N-(3-氟苄基)-5-对甲苯磺酰基-5H-吡咯[3,2-d]嘧啶-4-胺(15)的制备Preparation of 2-chloro-N-(3-fluorobenzyl)-5-p-toluenesulfonyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (15)
将中间体14(0.50g,1.46mmol)，3-氟苄胺(0.18mL,1.60mmol)和DIPEA(0.26mL,1.60mmol)溶于5mL无水乙醇，封管中加热至100℃。TLC监测，原料反应完全，旋除溶剂，柱层析纯化。展开剂极性：二氯甲烷。收率85％。Intermediate 14 (0.50g, 1.46mmol), 3-fluorobenzylamine (0.18mL, 1.60mmol) and DIPEA (0.26mL, 1.60mmol) were dissolved in 5mL of absolute ethanol, and heated to 100°C in a sealed tube. TLC monitoring showed that the reaction of raw materials was complete, the solvent was removed by spin, and purified by column chromatography. Developing agent polarity: dichloromethane. Yield 85%.
3-[3-({4-[(3-氟苄基)氨基]-5-对甲苯磺酰基-5H-吡咯[3,2-d]嘧啶-2-基}氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯(16)的制备3-[3-({4-[(3-fluorobenzyl)amino]-5-p-toluenesulfonyl-5H-pyrrole[3,2-d]pyrimidin-2-yl}aminobenzamide)piperidine - Preparation of 1-carbamide tert-butyl ester (16)
将中间体15(0.030g,0.07mmol)，3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯(0.022g,0.07mmol)和碳酸铯(0.046g,0.14mmol)溶于3mL无水1,4-二氧六环，加入催化量的醋酸钯和Xphos，惰性气体置换，回流反应。TLC监测，原料反应完全，旋除溶剂。乙酸乙酯复溶，减压过滤，浓缩滤液至临界状态，加入1.5mL无水甲醇，搅拌2h，减压过滤，得白色固体。收率75％。Intermediate 15 (0.030 g, 0.07 mmol), 3-(3-aminobenzamide)piperidine-1-carboxamide tert-butyl ester (0.022 g, 0.07 mmol) and cesium carbonate (0.046 g, 0.14 mmol) were dissolved Add catalytic amount of palladium acetate and Xphos to 3 mL of anhydrous 1,4-dioxane, replace with inert gas, and reflux for reaction. TLC monitoring showed that the reaction of raw materials was complete, and the solvent was removed by spin. Redissolve in ethyl acetate, filter under reduced pressure, concentrate the filtrate to a critical state, add 1.5 mL of anhydrous methanol, stir for 2 hours, and filter under reduced pressure to obtain a white solid. Yield 75%.
3-[3-({4-[(3-氟苄基)氨基]-5H-吡咯[3,2-d]嘧啶-2-基}氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯(17)的制备3-[3-({4-[(3-fluorobenzyl)amino]-5H-pyrrole[3,2-d]pyrimidin-2-yl}aminobenzamide)piperidine-1-carboxamide tert-butyl Preparation of ester (17)
将中间体16(0.037g,0.05mmol)溶于1mL无水乙醇，加入3mL 2mol/L的氢氧化钠溶液，50℃反应1h。浓缩反应液，用饱和氯化铵溶液调pH＝7，二氯甲烷萃取(5mL×3)，饱和食盐水洗涤(5mL×3)，无水硫酸钠干燥。减压过滤，旋除二氯甲烷，得到淡黄色固体，收率99％。Intermediate 16 (0.037g, 0.05mmol) was dissolved in 1mL of absolute ethanol, 3mL of 2mol/L sodium hydroxide solution was added, and reacted at 50°C for 1h. The reaction solution was concentrated, adjusted to pH=7 with saturated ammonium chloride solution, extracted with dichloromethane (5 mL×3), washed with saturated brine (5 mL×3), and dried over anhydrous sodium sulfate. Filtrate under reduced pressure and spin off dichloromethane to obtain a light yellow solid with a yield of 99%.
3-({4-[(3-氟苄基)氨基]-5H-吡咯[3,2-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例51)的制备3-({4-[(3-fluorobenzyl)amino]-5H-pyrrole[3,2-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (implementation Example 51) Preparation
将中间体17(0.028g,0.05mmol)溶于氯化氢的饱和乙酸乙酯溶液，室温搅拌。TLC监测反应完全。减压过滤，滤饼用5mL水溶解，乙酸乙酯洗涤(5mL×3)，弃去有机层。水层用10％的氢氧化钠调pH>11，乙酸乙酯萃取(5mL×3)，饱和食盐水洗涤(5mL×3)，无水硫酸钠干燥。减压过滤，旋除乙酸乙酯，得到白色固体，收率99％。 1H NMR(600MHz,DMSO-d 6)δ11.13(s,1H),8.69(s,1H),8.30(s,1H),7.94(d,J＝7.7Hz,1H),7.90(d,J＝6.9Hz,1H),7.87(s,1H),7.39–7.31(m,2H),7.27(t,J＝8.4Hz,2H),7.23–7.17(m,2H),7.06(t,J＝7.7Hz,1H),6.14(s,1H),4.78(d,J＝5.5Hz,2H),3.78(s,1H),2.94(d,J＝10.0Hz,1H),2.76(d, J＝10.5Hz,1H),2.39(s,2H),1.81(s,1H),1.59(s,1H),1.49–1.31(m,2H).HRMS(ESI,m/z)理论值C 25H 27FN 7O[M+H] +,460.2261；实测值460.2282。 Intermediate 17 (0.028g, 0.05mmol) was dissolved in saturated ethyl acetate solution of hydrogen chloride and stirred at room temperature. TLC monitored the complete reaction. Filter under reduced pressure, dissolve the filter cake with 5 mL of water, wash with ethyl acetate (5 mL×3), and discard the organic layer. The aqueous layer was adjusted to pH>11 with 10% sodium hydroxide, extracted with ethyl acetate (5 mL×3), washed with saturated brine (5 mL×3), and dried over anhydrous sodium sulfate. Filtrate under reduced pressure and spin off ethyl acetate to obtain a white solid with a yield of 99%. 1 H NMR (600MHz,DMSO-d 6 )δ11.13(s,1H),8.69(s,1H),8.30(s,1H),7.94(d,J=7.7Hz,1H),7.90(d, J=6.9Hz,1H),7.87(s,1H),7.39–7.31(m,2H),7.27(t,J=8.4Hz,2H),7.23–7.17(m,2H),7.06(t,J =7.7Hz,1H),6.14(s,1H),4.78(d,J=5.5Hz,2H),3.78(s,1H),2.94(d,J=10.0Hz,1H),2.76(d,J =10.5Hz, 1H), 2.39(s, 2H), 1.81(s, 1H), 1.59(s, 1H), 1.49–1.31(m, 2H). HRMS (ESI, m/z) theoretical value C 25 H 27 FN 7 O[M+H] + , 460.2261; found 460.2282.
3-({4-[(3-氟苄基)氨基]-7H-吡咯[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例52)的制备3-({4-[(3-fluorobenzyl)amino]-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (implementation Example 52) Preparation
参考制备实施例51的方法，将i步骤中13等比例替换为2,4-二氯-7H-吡咯[2,3-d]嘧啶，即得实施例52。 1H NMR(600MHz,DMSO-d 6)δ11.05(s,1H),8.78(s,1H),8.20(s,1H),7.96(d,J＝7.6Hz,1H),7.90(d,J＝11.7Hz,1H),7.34(d,J＝6.7Hz,1H),7.26–7.15(m,4H),7.03(t,J＝7.8Hz,1H),6.81(s,1H),6.46(s,1H),4.75(d,J＝5.6Hz,2H),3.79(s,1H),2.94(d,J＝10.2Hz,1H),2.77(d,J＝11.7Hz,1H),2.38(t,J＝9.9Hz,2H),1.80(s,1H),1.60(d,J＝11.4Hz,1H),1.49–1.35(m,2H).HRMS(ESI,m/z)理论值C 25H 27FN 7O[M+H] +,460.2261；实测值460.2278。 Referring to the method for preparing Example 51, replace 13 in step i with 2,4-dichloro-7H-pyrrole[2,3-d]pyrimidine in equal proportions to obtain Example 52. 1 H NMR (600MHz,DMSO-d 6 )δ11.05(s,1H),8.78(s,1H),8.20(s,1H),7.96(d,J=7.6Hz,1H),7.90(d, J＝11.7Hz, 1H), 7.34(d, J＝6.7Hz, 1H), 7.26–7.15(m, 4H), 7.03(t, J＝7.8Hz, 1H), 6.81(s, 1H), 6.46( s,1H),4.75(d,J=5.6Hz,2H),3.79(s,1H),2.94(d,J=10.2Hz,1H),2.77(d,J=11.7Hz,1H),2.38( t, J=9.9Hz, 2H), 1.80(s, 1H), 1.60(d, J=11.4Hz, 1H), 1.49–1.35(m, 2H). HRMS (ESI, m/z) theoretical value C 25 H 27 FN 7 O [M+H] + , 460.2261; found 460.2278.
实施例53的制备路线如下所示：The preparation route of embodiment 53 is as follows:
Figure PCTCN2022112391-appb-000013
Figure PCTCN2022112391-appb-000013
2-氯-N-(3-氟苄基)-7-甲基-7H-吡咯[2,3-d]嘧啶-4-胺(20)的制备Preparation of 2-chloro-N-(3-fluorobenzyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (20)
参考制备中间体15的方法，将j步骤中14等比例替换19，即得中间体20。Refer to the method for preparing intermediate 15, and replace 19 in equal proportions with 14 in step j to obtain intermediate 20.
3-[3-({4-[(3-氟苄基)氨基]-7-甲基-7H-吡咯[2,3-d]嘧啶-2-基}氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯(21)的制备3-[3-({4-[(3-fluorobenzyl)amino]-7-methyl-7H-pyrrole[2,3-d]pyrimidin-2-yl}aminobenzamide)piperidine-1 -Preparation of carboxamide tert-butyl ester (21)
参考制备中间体16的方法，将k步骤中15等比例替换20，即得中间体21。Referring to the method for preparing intermediate 16, replace 15 in equal proportions with 20 in step k to obtain intermediate 21.
3-({4-[(3-氟苄基)氨基]-7-甲基-7H-吡咯[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例53)的制备3-({4-[(3-fluorobenzyl)amino]-7-methyl-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl) Preparation of Benzamide (Example 53)
参考制备实施例51的方法，将m步骤中17等比例替换为21，即得实施例53。 1H NMR(600MHz,DMSO-d 6)δ8.92(s,1H),8.52(s,1H),7.96(d,J＝8.0Hz,1H),7.92(s,1H),7.80(d,J＝7.6Hz,1H),7.34(q,J＝7.8Hz,1H),7.25–7.15(m,4H),7.03(td,J＝8.7,2.1Hz,1H),6.87(d,J＝3.4Hz,1H),6.48(d,J＝3.2Hz,1H),4.76(d,J＝6.1Hz,2H),3.79(d,J＝8.3Hz,1H),3.65(s,3H),2.93(d,J＝9.9Hz,1H),2.77(d,J＝12.1Hz,1H),2.39(t,J＝10.4Hz,2H),1.81(d,J＝8.5Hz,1H),1.60(d,J＝12.2Hz,1H),1.50–1.33(m,2H).HRMS(ESI,m/z)理论值C 26H 29FN 7O[M+H] +,474.2418；实测值474.2413。 Referring to the method for preparing Example 51, replace 17 with 21 in equal proportions in step m to obtain Example 53. 1 H NMR (600MHz, DMSO-d 6 )δ8.92(s, 1H), 8.52(s, 1H), 7.96(d, J=8.0Hz, 1H), 7.92(s, 1H), 7.80(d, J＝7.6Hz, 1H), 7.34(q, J＝7.8Hz, 1H), 7.25–7.15(m, 4H), 7.03(td, J＝8.7, 2.1Hz, 1H), 6.87(d, J＝3.4 Hz,1H),6.48(d,J=3.2Hz,1H),4.76(d,J=6.1Hz,2H),3.79(d,J=8.3Hz,1H),3.65(s,3H),2.93( d, J=9.9Hz, 1H), 2.77(d, J=12.1Hz, 1H), 2.39(t, J=10.4Hz, 2H), 1.81(d, J=8.5Hz, 1H), 1.60(d, J=12.2Hz, 1H), 1.50-1.33 (m, 2H). HRMS (ESI, m/z) Theoretical C 26 H 29 FN 7 O [M+H] + , 474.2418; Found 474.2413.
3-({4-[(3-氟苄基)氨基]噻吩[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例54)的制备3-({4-[(3-fluorobenzyl)amino]thiophene[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (Example 54) preparation of
参考制备实施例53的方法，将n步骤中19等比例替换为2,4-二氯噻吩[2,3-d]嘧啶，即得实施例54。 1H NMR(600MHz,DMSO-d 6)δ9.31(s,1H),8.47(s,1H),8.30(s,1H),8.03(d,J＝7.1Hz,1H),7.79(d,J＝7.0Hz,1H),7.51(d,J＝5.4Hz,1H),7.36–7.29(m,2H),7.26–7.20(m,3H),7.16(d,J＝5.4Hz,1H),7.04(t,J＝7.2Hz,1H),4.78(d,J＝4.6Hz,2H),3.78(s,1H),2.94(d,J＝10.7Hz,1H),2.77(d,J＝11.2Hz,1H),2.39(t,J＝9.6Hz,3H),2.24(s,1H),1.85–1.76(m,1H),1.60(d,J＝9.4Hz,1H),1.51–1.33(m,2H).HRMS(ESI,m/z)理论值C 25H 26FN 6OS[M+H] +,477.1873；实测值477.1883。 Referring to the method for preparing Example 53, replace 19 in step n with 2,4-dichlorothieno[2,3-d]pyrimidine in equal proportions to obtain Example 54. 1 H NMR (600MHz, DMSO-d 6 )δ9.31(s, 1H), 8.47(s, 1H), 8.30(s, 1H), 8.03(d, J=7.1Hz, 1H), 7.79(d, J=7.0Hz,1H),7.51(d,J=5.4Hz,1H),7.36–7.29(m,2H),7.26–7.20(m,3H),7.16(d,J=5.4Hz,1H), 7.04(t, J=7.2Hz, 1H), 4.78(d, J=4.6Hz, 2H), 3.78(s, 1H), 2.94(d, J=10.7Hz, 1H), 2.77(d, J=11.2 Hz, 1H), 2.39(t, J=9.6Hz, 3H), 2.24(s, 1H), 1.85–1.76(m, 1H), 1.60(d, J=9.4Hz, 1H), 1.51–1.33(m , 2H). HRMS (ESI, m/z) calcd. for C 25 H 26 FN 6 OS [M+H] + , 477.1873; found 477.1883.
3-({4-[(3-氟苄基)氨基]噻吩[3,2-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺(实施例55)的制备3-({4-[(3-fluorobenzyl)amino]thiophene[3,2-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide (Example 55) preparation of
参考制备实施例53的方法，将n步骤中19等比例替换为2,4-二氯噻吩[3,2-d]嘧啶，即得实施例55。 1H NMR(600MHz,DMSO-d 6)δ9.15(s,1H),8.30(dd,J＝12.4,6.2Hz,2H),8.00(d,J＝5.3Hz,2H),7.85(d,J＝7.5Hz,1H),7.34(q,J＝7.6Hz,1H),7.29(d,J＝7.5Hz,1H),7.26–7.20(m,3H),7.16(d,J＝5.3Hz,1H),7.04(t,J＝8.3Hz,1H),4.77(d,J＝5.8Hz,2H),3.79(d,J＝8.2Hz,1H),2.94(d,J＝9.7Hz,1H),2.77(d,J＝12.2Hz,1H),2.39(t,J＝10.4Hz,2H),1.81(d,J＝8.8Hz,1H),1.61(d,J＝12.2Hz,1H),1.50–1.36(m,2H).HRMS(ESI,m/z)理论值C 25H 26FN 6OS[M+H] +,477.1873；实测值477.1891。 Referring to the method for preparing Example 53, replace 19 in step n with 2,4-dichlorothieno[3,2-d]pyrimidine in equal proportions to obtain Example 55. 1 H NMR (600MHz, DMSO-d 6 )δ9.15(s, 1H), 8.30(dd, J=12.4, 6.2Hz, 2H), 8.00(d, J=5.3Hz, 2H), 7.85(d, J＝7.5Hz, 1H), 7.34(q, J＝7.6Hz, 1H), 7.29(d, J＝7.5Hz, 1H), 7.26–7.20(m, 3H), 7.16(d, J＝5.3Hz, 1H), 7.04(t, J=8.3Hz, 1H), 4.77(d, J=5.8Hz, 2H), 3.79(d, J=8.2Hz, 1H), 2.94(d, J=9.7Hz, 1H) ,2.77(d,J=12.2Hz,1H),2.39(t,J=10.4Hz,2H),1.81(d,J=8.8Hz,1H),1.61(d,J=12.2Hz,1H),1.50 - 1.36 (m, 2H). HRMS (ESI, m/z) calcd for C 25 H 26 FN 6 OS [M+H] + , 477.1873; found 477.1891.
实施例56按照如下路线进行制备：Embodiment 56 is prepared according to the following route:
Figure PCTCN2022112391-appb-000014
Figure PCTCN2022112391-appb-000014
3-(3-{[4-氯-5-(三氟甲基)嘧啶-2-基]氨基}苯甲酰胺)哌啶-1-碳酰胺叔丁酯(24)的制备Preparation of tert-butyl 3-(3-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzamide)piperidine-1-carboxamide (24)
将23(1.05g,4.82mmol)，3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯(1.40g,4.38mmol)和DIPEA(1.81mL,10.94mmol)溶于20mL叔丁醇，70℃反应。TLC监测，原料反应完全，旋除叔丁醇，柱层析纯化。展开剂极性：二氯甲烷:甲醇＝200:1。得白色固体，收率77％。23 (1.05g, 4.82mmol), 3-(3-aminobenzamide) piperidine-1-carboxamide tert-butyl ester (1.40g, 4.38mmol) and DIPEA (1.81mL, 10.94mmol) were dissolved in 20mL tert Butanol, react at 70°C. TLC monitoring showed that the reaction of raw materials was complete, tert-butanol was removed by spin, and purified by column chromatography. Developing agent polarity: dichloromethane:methanol=200:1. A white solid was obtained with a yield of 77%.
3-[3-({4-[(3-氟苄基)氨基]-5-(三氟甲基)嘧啶-2-基}氨基)苯甲酰基]哌啶-1-碳酰胺叔丁酯(25)的制备3-[3-({4-[(3-fluorobenzyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoyl]piperidine-1-carboxamide tert-butyl ester Preparation of (25)
将24(0.25g,0.50mmol)，4-氟苄胺(0.069mL,0.60mmol)和DIPEA(0.25mL,1.5mmol)溶于5mL DMF，140℃反应7h。将反应液倾入50mL冰水中，乙酸乙酯萃取(25mL×3)，饱和食盐水洗涤(25mL×3)，无水硫酸钠干燥。减压过滤，除去硫酸钠，旋除溶剂。将剩余物用2mL二氯甲烷复溶，室温搅拌2h。有白色固体析出，减压过滤，用0.5mL二氯甲烷洗涤滤饼，得白色固体。收率45％。24 (0.25g, 0.50mmol), 4-fluorobenzylamine (0.069mL, 0.60mmol) and DIPEA (0.25mL, 1.5mmol) were dissolved in 5mL DMF and reacted at 140°C for 7h. The reaction solution was poured into 50 mL of ice water, extracted with ethyl acetate (25 mL×3), washed with saturated brine (25 mL×3), and dried over anhydrous sodium sulfate. Filter under reduced pressure to remove sodium sulfate and spin off the solvent. The residue was redissolved with 2 mL of dichloromethane and stirred at room temperature for 2 h. A white solid was precipitated, filtered under reduced pressure, and the filter cake was washed with 0.5 mL of dichloromethane to obtain a white solid. Yield 45%.
3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例56)的制备3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 56 ) preparation
参考实施例29的制备方法，将d步骤中7等比例替换为25，即得实施例56。 1H NMR(600MHz,DMSO-d 6)δ9.71(s,1H),8.23(s,1H),8.19(s,1H),8.15–8.10(m,1H),7.81(s,1H),7.68(s,1H),7.40(d,J＝7.0Hz,1H),7.33(s,2H),7.27(t,J＝7.3Hz,1H),7.08(t,J＝8.1Hz,2H),4.69–4.58(m,2H),3.83(s,1H),2.98(d,J＝9.3Hz,1H),2.82(d,J＝10.2Hz,1H),2.45(s,2H),1.82(s,1H),1.64(s,1H),1.51–1.37(m,2H).HRMS(ESI,m/z)理论值C 24H 25F 4N 6O[M+H] +,489.2026；实测值489.2052。 Referring to the preparation method of Example 29, replace 7 with 25 in equal proportions in step d to obtain Example 56. 1 H NMR (600MHz,DMSO-d 6 )δ9.71(s,1H),8.23(s,1H),8.19(s,1H),8.15–8.10(m,1H),7.81(s,1H), 7.68(s,1H),7.40(d,J=7.0Hz,1H),7.33(s,2H),7.27(t,J=7.3Hz,1H),7.08(t,J=8.1Hz,2H), 4.69–4.58(m,2H),3.83(s,1H),2.98(d,J=9.3Hz,1H),2.82(d,J=10.2Hz,1H),2.45(s,2H),1.82(s ,1H),1.64(s,1H),1.51–1.37(m,2H).HRMS(ESI,m/z)theoretical value C 24 H 25 F 4 N 6 O[M+H] + ,489.2026; measured value 489.2052.
3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例57)的制备3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 57 ) preparation
参考实施例56的制备方法，将r步骤中3-氟苄胺等比例替换为4-氟苄胺，即得实施例57。 1H NMR(600MHz,DMSO-d 6)δ9.72(s,1H),8.24(s,1H),8.20(s,1H),8.09(d,J＝8.0Hz,1H),7.85(s,1H),7.65(s,1H),7.41(d,J＝7.7Hz,1H),7.30(q,J＝7.7Hz,1H),7.25(t,J＝7.9Hz,1H),7.14(d,J＝7.6Hz,1H),7.10(d,J＝10.0Hz,1H),7.00(t,J＝9.4Hz,1H),4.69(d,J＝6.0Hz,2H),3.84–3.75(m,1H),2.95(dd,J＝11.7,3.1Hz,1H),2.79(d,J＝12.3Hz,1H),2.44–2.36(m,2H),1.82(d,J＝14.7Hz,1H),1.62(d,J＝9.0Hz,1H),1.51–1.36(m,2H).HRMS(ESI,m/z)理论值C 24H 25F 4N 6O[M+H] +,489.2026；实测值489.2051。 Referring to the preparation method of Example 56, in step r, 3-fluorobenzylamine was replaced by 4-fluorobenzylamine in equal proportions to obtain Example 57. 1 H NMR (600MHz,DMSO-d 6 )δ9.72(s,1H),8.24(s,1H),8.20(s,1H),8.09(d,J=8.0Hz,1H),7.85(s, 1H), 7.65(s, 1H), 7.41(d, J=7.7Hz, 1H), 7.30(q, J=7.7Hz, 1H), 7.25(t, J=7.9Hz, 1H), 7.14(d, J＝7.6Hz, 1H), 7.10(d, J＝10.0Hz, 1H), 7.00(t, J＝9.4Hz, 1H), 4.69(d, J＝6.0Hz, 2H), 3.84–3.75(m, 1H), 2.95(dd, J=11.7, 3.1Hz, 1H), 2.79(d, J=12.3Hz, 1H), 2.44–2.36(m, 2H), 1.82(d, J=14.7Hz, 1H), 1.62(d,J＝9.0Hz,1H),1.51–1.36(m,2H).HRMS(ESI,m/z) theoretical value C 24 H 25 F 4 N 6 O[M+H] + ,489.2026; actual measurement Value 489.2051.
(R)-3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例58)的制备(R)-3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 58) Preparation
参考实施例56的制备方法，将q步骤中3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯等比例替换为(R)-3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯，即得实施例58。 1H NMR(600MHz,DMSO-d 6)δ9.72(s,1H),8.31–8.16(m,2H),8.07(d,J＝8.1Hz,1H),7.85(s,1H),7.65(s,1H),7.41(d,J＝7.8Hz,1H),7.32–7.21(m,2H),7.17–7.07(m,2H),7.01(d,J＝8.9Hz,1H),4.69(d,J＝6.1Hz,2H),3.80(s,1H),2.95(d,J＝11.6Hz,1H),2.80–2.70(m,1H),2.40(s,2H),1.89–1.74(m,1H),1.62(s,1H),1.53–1.34(m,2H).HRMS(ESI,m/z)理论值C 24H 25F 4N 6O[M+H] +,489.2026；实测值489.2042。 Referring to the preparation method of Example 56, replace 3-(3-aminobenzamide) piperidine-1-carboxamide tert-butyl ester in equal proportions with (R)-3-(3-aminobenzamide) in step q Piperidine-1-carboxamide tert-butyl ester, Example 58 was obtained. 1 H NMR (600MHz, DMSO-d 6 ) δ9.72(s, 1H), 8.31–8.16(m, 2H), 8.07(d, J=8.1Hz, 1H), 7.85(s, 1H), 7.65( s,1H),7.41(d,J=7.8Hz,1H),7.32–7.21(m,2H),7.17–7.07(m,2H),7.01(d,J=8.9Hz,1H),4.69(d ,J=6.1Hz,2H),3.80(s,1H),2.95(d,J=11.6Hz,1H),2.80–2.70(m,1H),2.40(s,2H),1.89–1.74(m, 1H),1.62(s,1H),1.53–1.34(m,2H).HRMS(ESI,m/z) Theoretical C 24 H 25 F 4 N 6 O[M+H] + ,489.2026; Found 489.2042 .
(R)-3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例59)的制备(R)-3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 59) Preparation
参考实施例57的制备方法，将q步骤中3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯等比例替换为(R)-3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯，即得实施例59。 1H NMR(600MHz,DMSO-d 6)δ9.41(s,1H),9.11(s,1H),8.67(d,J＝7.6Hz,1H),8.39(s,1H),8.16(s,1H),7.65(t,J＝8.5Hz,2H),7.37(t,J＝7.9Hz,1H),7.28(s,2H),7.09(t,J＝8.8Hz,2H),4.66(d,J＝5.9Hz,2H),4.23(td,J＝13.4,6.7Hz,1H),3.27(d,J＝9.9Hz,1H),3.15(d,J＝12.4Hz,1H),2.86(p,J＝11.8,10.7Hz,2H),1.93–1.85(m,2H),1.73(qd,J＝12.2,10.9,3.8Hz,1H),1.66–1.57(m,1H).HRMS(ESI,m/z)理论值C 24H 25F 4N 6O[M+H] +,489.2026；实测值489.2044。 Referring to the preparation method of Example 57, replace 3-(3-aminobenzamide) piperidine-1-carboxamide tert-butyl ester in equal proportions with (R)-3-(3-aminobenzamide) in step q Piperidine-1-carboxamide tert-butyl ester, Example 59 was obtained. 1 H NMR (600MHz, DMSO-d 6 )δ9.41(s, 1H), 9.11(s, 1H), 8.67(d, J=7.6Hz, 1H), 8.39(s, 1H), 8.16(s, 1H), 7.65(t, J=8.5Hz, 2H), 7.37(t, J=7.9Hz, 1H), 7.28(s, 2H), 7.09(t, J=8.8Hz, 2H), 4.66(d, J=5.9Hz, 2H), 4.23(td, J=13.4, 6.7Hz, 1H), 3.27(d, J=9.9Hz, 1H), 3.15(d, J=12.4Hz, 1H), 2.86(p, J=11.8,10.7Hz,2H), 1.93–1.85(m,2H),1.73(qd,J=12.2,10.9,3.8Hz,1H),1.66–1.57(m,1H).HRMS(ESI,m/ z) Theoretical value C 24 H 25 F 4 N 6 O [M+H] + , 489.2026; found value 489.2044.
(S)-3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例60)的制备(S)-3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 60) Preparation
参考实施例56的制备方法，将q步骤中3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯等比例替换为(S)-3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯，即得实施例60。 1H NMR(600MHz,DMSO-d 6)δ9.46(d,J＝8.5Hz,1H),9.16(d,J＝8.5Hz,1H),8.68(d,J＝7.7Hz,1H),8.42(s,1H),8.17(s,1H),7.67(d,J＝7.7Hz,1H),7.62(d,J＝6.5Hz,1H),7.36–7.29(m,2H),7.08(dd,J＝15.7,8.6Hz,2H),7.05–7.00(m,1H),4.70(d,J＝6.0Hz,2H),4.24(d,J＝7.9Hz,1H),3.27(d,J＝10.1Hz,1H),3.15(d,J＝12.3Hz,1H),2.89(dd,J＝13.0,8.4Hz,1H),1.89(d,J＝6.4Hz,1H),1.73(dd,J＝10.8,3.9Hz,1H),1.62(q,J＝9.9Hz,1H).HRMS(ESI,m/z)理论值C 24H 25F 4N 6O[M+H] +,489.2026；实测值489.2044。 Referring to the preparation method of Example 56, replace 3-(3-aminobenzamide) piperidine-1-carboxamide tert-butyl ester in equal proportions with (S)-3-(3-aminobenzamide) in step q Piperidine-1-carboxamide tert-butyl ester, Example 60 was obtained. 1 H NMR (600MHz, DMSO-d 6 )δ9.46(d, J=8.5Hz, 1H), 9.16(d, J=8.5Hz, 1H), 8.68(d, J=7.7Hz, 1H), 8.42 (s,1H),8.17(s,1H),7.67(d,J=7.7Hz,1H),7.62(d,J=6.5Hz,1H),7.36–7.29(m,2H),7.08(dd, J=15.7,8.6Hz,2H),7.05–7.00(m,1H),4.70(d,J=6.0Hz,2H),4.24(d,J=7.9Hz,1H),3.27(d,J=10.1 Hz, 1H), 3.15(d, J=12.3Hz, 1H), 2.89(dd, J=13.0, 8.4Hz, 1H), 1.89(d, J=6.4Hz, 1H), 1.73(dd, J=10.8 ,3.9Hz,1H),1.62(q,J＝9.9Hz,1H).HRMS(ESI,m/z) theoretical value C 24 H 25 F 4 N 6 O[M+H] + ,489.2026; measured value 489.2044 .
(S)-3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(实施例61)的制备(S)-3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide (Example 61) Preparation
参考实施例57的制备方法，将q步骤中3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯等比例替换为(R)-3-(3-氨基苯甲酰胺)哌啶-1-碳酰胺叔丁酯，即得实施例61。 1H NMR(600MHz,DMSO-d 6)δ9.45(d,J＝7.8Hz,1H),9.15(d,J＝8.9Hz,1H),8.69(d,J＝7.7Hz,1H),8.40(s,1H),8.16(s,1H),7.67(d,J＝7.7Hz,1H),7.64(d,J＝7.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.28(s,2H),7.09(t,J＝8.8Hz,2H),4.66(d,J＝5.9Hz,2H),4.23(d,J＝7.9Hz,1H),3.27(d,J＝9.9Hz,1H),3.15(d,J＝12.5Hz,1H),2.87(q,J＝10.2,9.3Hz,2H),1.88(d,J＝6.3Hz,2H),1.73(dd,J＝10.7,3.9Hz,1H),1.61(q,J＝13.5,11.5Hz,1H).HRMS(ESI,m/z)理论值C 24H 25F 4N 6O[M+H] +,489.2026；实测值489.2043。 Referring to the preparation method of Example 57, replace 3-(3-aminobenzamide) piperidine-1-carboxamide tert-butyl ester in equal proportions with (R)-3-(3-aminobenzamide) in step q Piperidine-1-carboxamide tert-butyl ester, Example 61 was obtained. 1 H NMR (600MHz, DMSO-d 6 ) δ9.45(d, J=7.8Hz, 1H), 9.15(d, J=8.9Hz, 1H), 8.69(d, J=7.7Hz, 1H), 8.40 (s,1H),8.16(s,1H),7.67(d,J=7.7Hz,1H),7.64(d,J=7.2Hz,1H),7.38(t,J=7.9Hz,1H),7.28 (s,2H),7.09(t,J=8.8Hz,2H),4.66(d,J=5.9Hz,2H),4.23(d,J=7.9Hz,1H),3.27(d,J=9.9Hz ,1H),3.15(d,J=12.5Hz,1H),2.87(q,J=10.2,9.3Hz,2H),1.88(d,J=6.3Hz,2H),1.73(dd,J=10.7, 3.9Hz, 1H), 1.61(q, J＝13.5, 11.5Hz, 1H). HRMS (ESI, m/z) theoretical value C 24 H 25 F 4 N 6 O[M+H] + , 489.2026; measured value 489.2043.
实施例62：本发明部分氨基嘧啶衍生物的体外酶抑制活性研究Example 62: Study on in vitro enzyme inhibitory activity of some aminopyrimidine derivatives of the present invention
实验材料：Experimental Materials:
Tecan
Figure PCTCN2022112391-appb-000015
F500酶标仪。 Tecan
Figure PCTCN2022112391-appb-000015
F500 microplate reader.
Figure PCTCN2022112391-appb-000016
KinEASETM-STK试剂盒(包含生物素化的多肽底物S2，Eu 3+标记的只针对特异性磷酸化位点的单抗，Sa-XL665标记的链霉亲和素，激酶反应缓冲溶液(KinEASE酶反应缓冲液)，384浅孔板，TRKA全长蛋白。
Figure PCTCN2022112391-appb-000016
KinEASETM-STK kit (contains biotinylated polypeptide substrate S2, Eu 3+ labeled monoclonal antibody against specific phosphorylation sites, Sa-XL665-labeled streptavidin, kinase reaction buffer solution (KinEASE Enzyme reaction buffer), 384 shallow well plate, TRKA full-length protein.
TRKA蛋白浓度0.111ng/μl，MgCl 2，乙二胺四乙酸(EDTA)，二硫苏糖醇(DL-Dithiothreitol，DTT)，DMSO。 TRKA protein concentration 0.111ng/μl, MgCl 2 , ethylenediaminetetraacetic acid (EDTA), dithiothreitol (DL-Dithiothreitol, DTT), DMSO.
实验方法：experimental method:
第一步：激酶反应：Step 1: Kinase Reaction:
首先将上述实施例制备化合物样品用DMSO配成20mM的溶液，之后根据测试需要， 再用激酶反应缓冲溶液稀释成100μM、10μM、1μM等浓度。然后将TRKA激酶(浓度为0.111ng/μL)、ATP(4μM)、生物素标记的多肽底物TK(1μM)和化合物样品(4μL)加入到10μL激酶反应缓冲溶液(含有MgCl 2 5mM和DTT 1mM)中，在室温下孵育40分钟，激酶将底物TK磷酸化。之后加入10μL的含有EDTA的检测试剂(试剂盒自带)，来检测磷酸化产物。 First, the compound samples prepared in the above examples were prepared into a 20 mM solution with DMSO, and then diluted with a kinase reaction buffer solution to a concentration of 100 μM, 10 μM, 1 μM, etc. according to the test requirements. Then TRKA kinase (0.111 ng/μL concentration), ATP (4 μM), biotinylated polypeptide substrate TK (1 μM) and compound sample (4 μL) were added to 10 μL kinase reaction buffer solution (containing MgCl 2 5 mM and DTT 1 mM ), incubated at room temperature for 40 minutes, the kinase phosphorylates the substrate TK. Then add 10 μL of EDTA-containing detection reagent (included in the kit) to detect phosphorylated products.
第二步：检测磷酸化产物：Step 2: Detection of phosphorylated products:
稀土元素铕(Eu 3+)标记的抗体识别磷酸化底物，XL665标记的链霉亲和素与底物上的生物素结合。Eu3 +是荧光供体，XL665是荧光受体，当Eu 3+与XL665接近，Eu 3+能量转移给XL665，产生HTRF信号。 The rare earth element europium (Eu 3+ )-labeled antibody recognizes the phosphorylated substrate, and XL665-labeled streptavidin binds to the biotin on the substrate. Eu3 + is a fluorescence donor, and XL665 is a fluorescence acceptor. When Eu3 + is close to XL665, the energy of Eu3 + is transferred to XL665, generating HTRF signal.
结果评定方法：荧光信号是由Eu 3+的620nm和XL665的665nm荧光吸收信号产生的。所以每一个孔板反应的HTRF信号(665/620)比值被计算。结果被表征为Delta F(DF％)： Result evaluation method: The fluorescence signal is generated by the 620nm fluorescence absorption signal of Eu 3+ and the 665nm fluorescence absorption signal of XL665. So the ratio of HTRF signal (665/620) for each plate reaction was calculated. The result is characterized as Delta F (DF%):
Figure PCTCN2022112391-appb-000017
Figure PCTCN2022112391-appb-000017
计算抑制率(活性％)：在不加化合物样品的情况下，激酶活性的DF％被定义为100％。当加入化合物样品后，激酶活性率：Calculation of inhibition rate (activity %): DF% of kinase activity was defined as 100% in the absence of compound samples. When the compound sample is added, the kinase activity rate:
Figure PCTCN2022112391-appb-000018
Figure PCTCN2022112391-appb-000018
计算IC 50：在加入化合物的情况下，激酶活性的DF％被绘制成Y-轴，化合物的浓度对数值被绘制成X-轴。IC 50值是通过数据拟合成S-型计量反应曲线获得。 Calculation of IC50 : % DF of kinase activity with added compound is plotted on the Y-axis and log concentration of the compound is plotted on the X-axis. IC50 values were obtained by fitting the data to a sigmoidal stoichiometric response curve.
表1：本发明部分氨基嘧啶衍生物的IC 50值 Table 1: IC50 values of some aminopyrimidine derivatives of the present invention
实施例Example IC 50(μM) IC50 (μM) 实施例Example IC 50(μM) IC50 (μM)
实施例1Example 1 1.601.60 实施例2Example 2 0.140.14
实施例3Example 3 0.250.25 实施例4Example 4 7.647.64
实施例5Example 5 0.130.13 实施例6Example 6 0.060.06
实施例7Example 7 0.120.12 实施例8Example 8 0.800.80
实施例9Example 9 0.100.10 实施例10Example 10 0.090.09
实施例11Example 11 0.520.52 实施例12Example 12 1.631.63
实施例13Example 13 0.860.86 实施例14Example 14 0.100.10
实施例15Example 15 0.0740.074 实施例16Example 16 0.390.39
实施例17Example 17 0.270.27 实施例18Example 18 1.161.16
实施例19Example 19 0.450.45 实施例20Example 20 0.660.66
实施例21Example 21 0.200.20 实施例23Example 23 0.140.14
实施例24Example 24 0.360.36 实施例25Example 25 0.220.22
实施例26Example 26 0.0530.053 实施例27Example 27 0.0600.060
实施例28Example 28 0.0640.064 实施例29Example 29 0.0850.085
实施例30Example 30 0.140.14 实施例31Example 31 0.140.14
实施例32Example 32 0.0230.023 实施例33Example 33 0.0370.037
实施例34Example 34 1.171.17 实施例35Example 35 0.130.13
实施例36Example 36 3.153.15 实施例37Example 37 0.880.88
实施例38Example 38 2.472.47 实施例39Example 39 1.411.41
实施例40Example 40 0.150.15 实施例41Example 41 2.582.58
实施例42Example 42 0.300.30 实施例43Example 43 0.0410.041
实施例44Example 44 3.973.97 实施例45Example 45 2.672.67
实施例47Example 47 0.210.21 实施例48Example 48 0.0780.078
实施例49Example 49 0.120.12 实施例50Example 50 4.254.25
实施例52Example 52 3.013.01 实施例53Example 53 5.645.64
实施例54Example 54 2.802.80 实施例55Example 55 0.990.99
实施例56Example 56 0.590.59 实施例57Example 57 0.100.10
实施例58Example 58 0.530.53 实施例59Example 59 0.140.14
实施例60Example 60 0.520.52 实施例61Example 61 0.110.11
以上测试结果表明，上述实施例均对于TRKA激酶具有较好的抑制作用，大部分实施例的IC 50值在nM范围内。 The above test results show that the above-mentioned examples all have good inhibitory effects on TRKA kinase, and the IC 50 values of most of the examples are in the nM range.
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and equivalent technologies thereof, the present invention also intends to include these modifications and variations.

Claims (10)

  1. 一种氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：所述氨基嘧啶衍生物具有通式(I)或通式(II)所示结构：An aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug, characterized in that: the aminopyrimidine derivative has general formula (I) or general formula (II ) shows the structure:
    Figure PCTCN2022112391-appb-100001
    Figure PCTCN2022112391-appb-100001
    其中，R 1选自氢，卤素，硝基，氰基，C1-C4烷基，C1-C4卤代烷基，N上有烷基取代或无取代的氨基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, and N has alkyl substituted or unsubstituted amino;
    R 2选自芳基甲基氨基，2-芳基吡咯烷基，2-芳基氮杂环丁烷基或2-芳基哌啶基， R is selected from arylmethylamino, 2-arylpyrrolidinyl, 2-arylazetidinyl or 2-arylpiperidinyl,
    其中，芳基选自苯基，吡啶基或嘧啶基，并且所述芳基无取代或进一步被1-4个Ra取代；Wherein, the aryl is selected from phenyl, pyridyl or pyrimidinyl, and the aryl is unsubstituted or further substituted by 1-4 R;
    Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
    R 3选自氢，卤素，磺胺基，羟基，烷氧基，O上有取代或无取代的羟甲基，N上有烷基取代或无取代的氨基，N上被1-2个Rb所取代的酰胺基，含1-2个杂原子的C3-C7脂肪环， R3 is selected from hydrogen, halogen, sulfonamide, hydroxy, alkoxy, substituted or unsubstituted hydroxymethyl on O, N substituted or unsubstituted amino with alkyl, N replaced by 1-2 Rb Substituted amido, C3-C7 aliphatic ring containing 1-2 heteroatoms,
    其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，或者在所述杂原子上进一步被C1-C4烷基取代；Wherein, the ring contains no more than 2 carbonyl groups, or the ring hydrogen atoms are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatoms are selected from nitrogen, oxygen or sulfur, or in the heteroatoms Atoms are further substituted by C1-C4 alkyl;
    Rb选自氢，C1-C4烷基，C3-C7环烷基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms,
    其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
    X和Y选自C或N，且X和Y是相同的或不同的；X and Y are selected from C or N, and X and Y are the same or different;
    Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
    其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a C1-C4 alkyl group.
  2. 根据权利要求1所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：The aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that:
    其中，R 1选自氢，卤素，硝基，氰基，甲基，三氟甲基，氨基，甲氨基或二甲氨基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, methyl, trifluoromethyl, amino, methylamino or dimethylamino;
    R 2选自芳基甲基氨基或2-芳基吡咯烷基， R is selected from arylmethylamino or 2-arylpyrrolidinyl,
    其中，芳基选自苯基，吡啶基或嘧啶基，并且所述芳基无取代或进一步被1-4个Ra取代；Wherein, the aryl is selected from phenyl, pyridyl or pyrimidinyl, and the aryl is unsubstituted or further substituted by 1-4 R;
    Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
    R 3选自氢，卤素，磺胺基，羟基，烷氧基，O上有取代或无取代的羟甲基，N上有烷基取代或无取代的氨基，N上被1-2个Rb所取代的酰胺基，含1-2个杂原子的C3-C7脂肪环， R3 is selected from hydrogen, halogen, sulfonamide, hydroxy, alkoxy, substituted or unsubstituted hydroxymethyl on O, N substituted or unsubstituted amino with alkyl, N replaced by 1-2 Rb Substituted amido, C3-C7 aliphatic ring containing 1-2 heteroatoms,
    其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
    Rb选自氢，C1-C4烷基，C3-C7环烷基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms,
    其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
    X和Y均为C；Both X and Y are C;
    Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
    其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被甲基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a methyl group.
  3. 根据权利要求1或权利要求2所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：The aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1 or claim 2, is characterized in that:
    其中，R 1选自氢，卤素，硝基，氰基，甲基，三氟甲基，氨基，甲氨基或二甲氨基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, methyl, trifluoromethyl, amino, methylamino or dimethylamino;
    R 2选自苄胺基或2-苯基吡咯烷基，并且所述R 2无取代或进一步被1-4个Ra取代； R 2 is selected from benzylamino or 2-phenylpyrrolidinyl, and said R 2 is unsubstituted or further substituted by 1-4 Ra;
    Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
    R 3选自氢，卤素，磺胺基，O上有取代或无取代的羟甲基，N上有烷基取代或无取代的氨基，N上被1-2个Rb所取代的酰胺基，含1-2个杂原子的C3-C7脂肪环， R3 is selected from hydrogen, halogen, sulfonamide, substituted or unsubstituted hydroxymethyl on O, alkyl substituted or unsubstituted amino on N, amido group substituted by 1-2 Rb on N, containing C3-C7 aliphatic ring with 1-2 heteroatoms,
    其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
    Rb选自氢，C1-C4烷基，C3-C7环烷基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms,
    其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
    X和Y均为C；Both X and Y are C;
    Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
    其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被甲基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a methyl group.
  4. 根据权利要求1-3中任一项所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：The aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 1-3, characterized in that:
    其中，R 1选自氢，卤素，硝基，氰基，甲基或三氟甲基； Wherein, R is selected from hydrogen, halogen, nitro, cyano, methyl or trifluoromethyl;
    R 2选自苄胺基或2-苯基吡咯烷基，并且所述R 2无取代或进一步被1-4个Ra取代； R 2 is selected from benzylamino or 2-phenylpyrrolidinyl, and said R 2 is unsubstituted or further substituted by 1-4 Ra;
    Ra选自氢，卤素，C1-C4烷基或C1-C4卤代烷基；Ra is selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 haloalkyl;
    R 3选自氢，磺胺基，羟甲基，被C1-C4烷基取代的羟甲基，氨基，甲氨基，二甲氨基，吗啉基，硫代吗啉基，哌嗪基，被C1-C4烷基取代的哌嗪基，高哌嗪基，被C1-C4烷基取代的高哌嗪基，2-氧代吗啉基，2-氧代哌嗪基，3-氧代哌嗪基，哌啶基，1-氮杂环丁基，吡咯烷基或含有Rb取代的羰基； R3 is selected from hydrogen, sulfonamide, hydroxymethyl, hydroxymethyl substituted by C1-C4 alkyl, amino, methylamino, dimethylamino, morpholinyl, thiomorpholinyl, piperazinyl, substituted by C1 -C4 alkyl substituted piperazinyl, homopiperazinyl, homopiperazinyl substituted by C1-C4 alkyl, 2-oxomorpholinyl, 2-oxopiperazinyl, 3-oxopiperazinyl Base, piperidinyl, 1-azetidinyl, pyrrolidinyl or carbonyl substituted with Rb;
    Rb选自氢，N上有取代或无取代的氨基，含1-2个杂原子的C3-C7脂肪环，Rb is selected from hydrogen, substituted or unsubstituted amino groups on N, C3-C7 aliphatic rings containing 1-2 heteroatoms,
    其中，环上包含不多于2个羰基，或者环上氢原子进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被C1-C4烷基取代；Among them, the ring contains no more than 2 carbonyl groups, or the hydrogen atoms on the ring are further substituted by no more than 2 alkyl-substituted or unsubstituted amino groups, and the heteroatom is selected from nitrogen, oxygen or sulfur, when the heteroatom is nitrogen When atom, the nitrogen atom is unsubstituted or further substituted by C1-C4 alkyl;
    或者，Rb选自含有Rc取代的氨基，吗啉基，硫代吗啉基，哌嗪基，被C1-C4烷基取代的哌嗪基，高哌嗪基，被C1-C4烷基取代的高哌嗪基，2-氧代吗啉基，2-氧代哌嗪基，3-氧代哌嗪基，哌啶基，1-氮杂环丁基，吡咯烷基，4-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代，3-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代；Alternatively, Rb is selected from the group consisting of Rc-substituted amino, morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl substituted by C1-C4 alkyl, homopiperazinyl, substituted by C1-C4 alkyl Homopiperazinyl, 2-oxomorpholinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, piperidinyl, 1-azetidinyl, pyrrolidinyl, 4-aminopiperidine , wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl groups, 3-aminopiperidinyl, wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl groups;
    Rc选自氢，C1-C4烷基，C3-C7含1-2个杂原子的脂肪环，其中，环上可包括不多于2个羰基，环上氢原子可进一步被不多于2个有烷基取代或无取代的氨基取代，杂原子可为氮，氧，硫，当杂原子为氮原子时，氮原子可进一步被C1-C4烷基取代；Rc is selected from hydrogen, C1-C4 alkyl, C3-C7 aliphatic ring containing 1-2 heteroatoms, wherein, the ring may include no more than 2 carbonyl groups, and the ring hydrogen atoms may be further replaced by no more than 2 There are alkyl substituted or unsubstituted amino substituted, the heteroatom can be nitrogen, oxygen, sulfur, when the heteroatom is nitrogen atom, the nitrogen atom can be further substituted by C1-C4 alkyl;
    或者，Rb选自氢，氨基，二甲氨基，哌啶-4-氨基，其中所述哌啶环上的N原子无取代或进一步被C1-C4烷基取代，哌啶-3-氨基，其中所述哌啶环上的N原子无取代或进一步被C1-C4烷基取代，四氢吡咯基-2-氨基，其中所述四氢吡唑环上的N原子无取代或进一步被C1-C4烷基取代，氮杂环丁基-2-氨基，其中所述氮杂环丁基上的N原子无取代或进一步被C1-C4烷基取代，吗啉基，硫代吗啉基，哌嗪基，被C1-C4烷基取代的哌嗪基，高哌嗪基，被C1-C4烷基取代的高哌嗪基，2-氧代吗啉基，2-氧代哌嗪基，3-氧代哌嗪基，哌啶基，1-氮杂环丁基，吡咯烷基，4-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代，3-氨基哌啶基，其中所述氨基无取代或进一步被1-2个C1-C4烷基取代；Alternatively, Rb is selected from hydrogen, amino, dimethylamino, piperidine-4-amino, wherein the N atom on the piperidine ring is unsubstituted or further substituted by C1-C4 alkyl, piperidine-3-amino, wherein The N atom on the piperidine ring is unsubstituted or further substituted by C1-C4 alkyl, tetrahydropyrrolyl-2-amino, wherein the N atom on the tetrahydropyrazole ring is unsubstituted or further substituted by C1-C4 Alkyl substitution, azetidinyl-2-amino, wherein the N atom on the azetidinyl is unsubstituted or further substituted by C1-C4 alkyl, morpholinyl, thiomorpholinyl, piperazine Base, piperazinyl substituted by C1-C4 alkyl, homopiperazinyl, homopiperazinyl substituted by C1-C4 alkyl, 2-oxomorpholinyl, 2-oxopiperazinyl, 3- Oxopiperazinyl, piperidinyl, 1-azetidinyl, pyrrolidinyl, 4-aminopiperidinyl, wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl, 3 -aminopiperidinyl, wherein the amino group is unsubstituted or further substituted by 1-2 C1-C4 alkyl groups;
    X和Y均为C；Both X and Y are C;
    Z 1和Z 2选自C或杂原子，且Z 1和Z 2是相同的或不同的， Z1 and Z2 are selected from C or heteroatoms, and Z1 and Z2 are the same or different,
    其中，杂原子选自氮，氧或硫，当杂原子为氮原子时，氮原子无取代或进一步被甲基取代。Wherein, the heteroatom is selected from nitrogen, oxygen or sulfur, and when the heteroatom is a nitrogen atom, the nitrogen atom is unsubstituted or further substituted by a methyl group.
  5. 根据权利要求1所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，其特征在于：所述衍生物为；The aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to claim 1, characterized in that: the derivative is;
    4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基苯磺酰胺4-({5-Chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}aminobenzenesulfonamide
    Figure PCTCN2022112391-appb-100002
    Figure PCTCN2022112391-appb-100002
    3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基苯磺酰胺3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}aminobenzenesulfonamide
    Figure PCTCN2022112391-appb-100003
    Figure PCTCN2022112391-appb-100003
    [3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苄基]甲醇[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzyl]methanol
    Figure PCTCN2022112391-appb-100004
    Figure PCTCN2022112391-appb-100004
    5-氯-N 2-[4-(二甲氨基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[4-(dimethylamino)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100005
    Figure PCTCN2022112391-appb-100005
    5-氯-N 2-[4-(4-甲基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[4-(4-methylpiperazin-1-yl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100006
    Figure PCTCN2022112391-appb-100006
    5-氯-N 2-[3-(4-甲基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[3-(4-methylpiperazin-1-yl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100007
    Figure PCTCN2022112391-appb-100007
    5-氯-N 2-[4-(4-乙基哌嗪-1-基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[4-(4-ethylpiperazin-1-yl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100008
    Figure PCTCN2022112391-appb-100008
    5-氯-N 2-[4-(4-吗啉基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[4-(4-morpholinyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100009
    Figure PCTCN2022112391-appb-100009
    5-氯-N 2-[3-(4-吗啉基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[3-(4-morpholinyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100010
    Figure PCTCN2022112391-appb-100010
    4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基苯甲酰胺4-({5-Chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}aminobenzamide
    Figure PCTCN2022112391-appb-100011
    Figure PCTCN2022112391-appb-100011
    5-氯-N 2-[3-(乙氧基甲基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[3-(ethoxymethyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100012
    Figure PCTCN2022112391-appb-100012
    5-氯-N 2-[3-(异丙氧基甲基)苄基]-N 4-(三氟苄基)嘧啶-2,4-二胺 5-Chloro-N 2 -[3-(isopropoxymethyl)benzyl]-N 4 -(trifluorobenzyl)pyrimidine-2,4-diamine
    Figure PCTCN2022112391-appb-100013
    Figure PCTCN2022112391-appb-100013
    4-[4-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苄基]吗啉-3-酮4-[4-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzyl]morpholin-3-one
    Figure PCTCN2022112391-appb-100014
    Figure PCTCN2022112391-appb-100014
    [4-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基哌嗪-1-基)甲基酮[4-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methylpiperazin-1-yl)methyl ketone
    Figure PCTCN2022112391-appb-100015
    Figure PCTCN2022112391-appb-100015
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基哌嗪-1-基)甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methylpiperazin-1-yl)methyl ketone
    Figure PCTCN2022112391-appb-100016
    Figure PCTCN2022112391-appb-100016
    [4-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](吗啉基)甲基酮[4-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](morpholinyl)methyl ketone
    Figure PCTCN2022112391-appb-100017
    Figure PCTCN2022112391-appb-100017
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](吗啉基)甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](morpholinyl)methyl ketone
    Figure PCTCN2022112391-appb-100018
    Figure PCTCN2022112391-appb-100018
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](哌啶-1-基)甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](piperidin-1-yl)methyl ketone
    Figure PCTCN2022112391-appb-100019
    Figure PCTCN2022112391-appb-100019
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-乙基哌嗪-1-基)甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-ethylpiperazin-1-yl)methylketone
    Figure PCTCN2022112391-appb-100020
    Figure PCTCN2022112391-appb-100020
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-异丙基哌嗪-1-基)甲基酮[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-isopropylpiperazin-1-yl)methylketone
    Figure PCTCN2022112391-appb-100021
    Figure PCTCN2022112391-appb-100021
    4-[3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)苯甲酰基]哌嗪-2-酮4-[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)benzoyl]piperazin-2-one
    Figure PCTCN2022112391-appb-100022
    Figure PCTCN2022112391-appb-100022
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](哌嗪-1-基)甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](piperazin-1-yl)methyl ketone
    Figure PCTCN2022112391-appb-100023
    Figure PCTCN2022112391-appb-100023
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-甲基-1,4高哌嗪-1-基)甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-methyl-1,4-homopiperazin-1-yl)methyl base ketone
    Figure PCTCN2022112391-appb-100024
    Figure PCTCN2022112391-appb-100024
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](1,4高哌嗪-1-基)甲基酮[3-({5-Chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](1,4-homopiperazin-1-yl)methylketone
    Figure PCTCN2022112391-appb-100025
    Figure PCTCN2022112391-appb-100025
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基][4-(二甲氨基)哌啶-1-基]甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl][4-(dimethylamino)piperidin-1-yl]methylketone
    Figure PCTCN2022112391-appb-100026
    Figure PCTCN2022112391-appb-100026
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基][4-(甲氨基)哌啶-1-基]甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl][4-(methylamino)piperidin-1-yl]methylketone
    Figure PCTCN2022112391-appb-100027
    Figure PCTCN2022112391-appb-100027
    [3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](4-氨基哌啶-1-基)甲基酮[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](4-aminopiperidin-1-yl)methyl ketone
    Figure PCTCN2022112391-appb-100028
    Figure PCTCN2022112391-appb-100028
    3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(1-甲基哌啶-4-基)苯甲酰胺3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(1-methylpiperidin-4-yl)benzamide
    Figure PCTCN2022112391-appb-100029
    Figure PCTCN2022112391-appb-100029
    3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-4-基)苯甲酰胺3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-4-yl)benzamide
    Figure PCTCN2022112391-appb-100030
    Figure PCTCN2022112391-appb-100030
    (R)-[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](3-氨基哌啶-1-基)甲基酮(R)-[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](3-aminopiperidin-1-yl)methylketone
    Figure PCTCN2022112391-appb-100031
    Figure PCTCN2022112391-appb-100031
    (S)-[3-({5-氯-4-[(3-氟苄基)氨基]吡啶-2-基}氨基)苯基](3-氨基哌啶-1-基)甲基酮(S)-[3-({5-chloro-4-[(3-fluorobenzyl)amino]pyridin-2-yl}amino)phenyl](3-aminopiperidin-1-yl)methylketone
    Figure PCTCN2022112391-appb-100032
    Figure PCTCN2022112391-appb-100032
    (S)-3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(S)-3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100033
    Figure PCTCN2022112391-appb-100033
    (R)-3-({5-氯-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(R)-3-({5-chloro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100034
    Figure PCTCN2022112391-appb-100034
    3-({5-氯-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100035
    Figure PCTCN2022112391-appb-100035
    3-({5-氯-4-[(3,5-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(3,5-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100036
    Figure PCTCN2022112391-appb-100036
    3-({5-氯-4-[(3,4,5-三氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-Chloro-4-[(3,4,5-trifluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100037
    Figure PCTCN2022112391-appb-100037
    3-({5-氯-4-[(2-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(2-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100038
    Figure PCTCN2022112391-appb-100038
    3-({5-氯-4-[(3,4-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(3,4-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100039
    Figure PCTCN2022112391-appb-100039
    3-({5-氯-4-[(2,6-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(2,6-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100040
    Figure PCTCN2022112391-appb-100040
    3-({5-氯-4-[(2,5-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(2,5-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100041
    Figure PCTCN2022112391-appb-100041
    3-({5-氯-4-[(2,4-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(2,4-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100042
    Figure PCTCN2022112391-appb-100042
    3-({5-氯-4-[(2,3-二氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[(2,3-difluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100043
    Figure PCTCN2022112391-appb-100043
    3-({5-氯-4-[2-(3-氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[2-(3-fluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100044
    Figure PCTCN2022112391-appb-100044
    3-({5-氯-4-[2-(4-氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[2-(4-fluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100045
    Figure PCTCN2022112391-appb-100045
    3-({5-氯-4-[2-(3,5-二氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[2-(3,5-difluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidin-3-yl) benzamide
    Figure PCTCN2022112391-appb-100046
    Figure PCTCN2022112391-appb-100046
    3-({5-氯-4-[2-(3,4,5-三氟苯基)四氢吡咯-1-基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-chloro-4-[2-(3,4,5-trifluorophenyl)tetrahydropyrrol-1-yl]pyrimidin-2-yl}amino)-N-(piperidine-3- base) benzamide
    Figure PCTCN2022112391-appb-100047
    Figure PCTCN2022112391-appb-100047
    3-({5-氟-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-fluoro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100048
    Figure PCTCN2022112391-appb-100048
    3-({5-溴-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-bromo-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100049
    Figure PCTCN2022112391-appb-100049
    3-({5-甲基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-methyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100050
    Figure PCTCN2022112391-appb-100050
    3-({5-硝基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-nitro-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100051
    Figure PCTCN2022112391-appb-100051
    3-({4-[(3-氟苄基)氨基]-5H-吡咯[3,2-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺3-({4-[(3-fluorobenzyl)amino]-5H-pyrrole[3,2-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100052
    Figure PCTCN2022112391-appb-100052
    3-({4-[(3-氟苄基)氨基]-7H-吡咯[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺3-({4-[(3-fluorobenzyl)amino]-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100053
    Figure PCTCN2022112391-appb-100053
    3-({4-[(3-氟苄基)氨基]-7-甲基-7H-吡咯[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺3-({4-[(3-fluorobenzyl)amino]-7-methyl-7H-pyrrole[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl) benzamide
    Figure PCTCN2022112391-appb-100054
    Figure PCTCN2022112391-appb-100054
    3-({4-[(3-氟苄基)氨基]噻吩[2,3-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺3-({4-[(3-fluorobenzyl)amino]thiophene[2,3-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100055
    Figure PCTCN2022112391-appb-100055
    3-({4-[(3-氟苄基)氨基]噻吩[3,2-d]嘧啶-2-基)氨基-N-(哌啶-3-基)苯甲酰胺3-({4-[(3-fluorobenzyl)amino]thiophene[3,2-d]pyrimidin-2-yl)amino-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100056
    Figure PCTCN2022112391-appb-100056
    3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100057
    Figure PCTCN2022112391-appb-100057
    3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100058
    Figure PCTCN2022112391-appb-100058
    (R)-3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(R)-3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100059
    Figure PCTCN2022112391-appb-100059
    (R)-3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(R)-3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100060
    Figure PCTCN2022112391-appb-100060
    (S)-3-({5-三氟甲基基-4-[(3-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(S)-3-({5-trifluoromethyl-4-[(3-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100061
    Figure PCTCN2022112391-appb-100061
    (S)-3-({5-三氟甲基基-4-[(4-氟苄基)氨基]嘧啶-2-基}氨基)-N-(哌啶-3-基)苯甲酰胺(S)-3-({5-trifluoromethyl-4-[(4-fluorobenzyl)amino]pyrimidin-2-yl}amino)-N-(piperidin-3-yl)benzamide
    Figure PCTCN2022112391-appb-100062
    Figure PCTCN2022112391-appb-100062
  6. 权利要求1-5中任一项所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药的制备方法，其特征在于：所述通式(I)所示衍生物的制备反应如下所示：The preparation method of the aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 1-5, characterized in that: the general formula The preparation reaction of derivative shown in (1) is as follows:
    Figure PCTCN2022112391-appb-100063
    Figure PCTCN2022112391-appb-100063
    (1)目标衍生物具有如通式3所示结构或类似结构，且R 1为卤素，硝基，氰基或其他给电子基，R 3为不含有酰胺键的取代基时，按照路线1所示方法制备，即，以多氯取代的嘧啶为起始原料1，在碱性条件下与不同取代的苄胺经过选择性取代反应得到中间体2，中间体2在酸催化的条件下，与不同取代的芳胺经过取代反应得到目标化合物3，根据路线1方法亦可制备具有与通式3类似结构的目标化合物，将条件a中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物； (1) The target derivative has a structure as shown in general formula 3 or a similar structure, and R 1 is halogen, nitro, cyano or other electron-donating groups, and R 3 is a substituent that does not contain an amide bond, according to route 1 Prepared by the method shown, that is, using polychlorinated pyrimidine as the starting material 1, undergoing selective substitution reactions with different substituted benzylamines under alkaline conditions to obtain intermediate 2, intermediate 2 is under acid-catalyzed conditions, The target compound 3 can be obtained through substitution reaction with different substituted arylamines. The target compound with a structure similar to the general formula 3 can also be prepared according to the method of route 1. The benzylamine in condition a is replaced by other amines, and the compound containing other groups can be prepared. Group substituted target compound;
    Figure PCTCN2022112391-appb-100064
    Figure PCTCN2022112391-appb-100064
    (2)目标衍生物具有如通式6所示结构或类似结构，且R 3为不含有酰胺键的取代基时，按照路线2所示方法制备，即，以5-三氟甲基-2,4-二氯嘧啶为起始原料4，在碱性条件下经过选择性取代反应得到中间体5，中间体5进一步在碱性条件下发生取代反应得到目标化合物6，根据路线2方法亦可制备具有与通式6类似结构的目标化合物，将条件d中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物； (2) When the target derivative has a structure as shown in general formula 6 or a similar structure, and R3 is a substituent that does not contain an amide bond, it can be prepared according to the method shown in route 2, that is, with 5-trifluoromethyl-2 , 4-dichloropyrimidine is the starting material 4, and intermediate 5 is obtained through selective substitution reaction under alkaline conditions, and intermediate 5 is further subjected to substitution reaction under alkaline conditions to obtain target compound 6, which can also be obtained according to the method of route 2 Prepare a target compound having a structure similar to that of general formula 6, and replace the benzylamine in condition d with other amines to prepare a target compound containing other group substitutions;
    Figure PCTCN2022112391-appb-100065
    Figure PCTCN2022112391-appb-100065
    (3)目标衍生物具有如通式8所示结构或类似的结构，且R 1为卤素，硝基，氰基或其他给电子基时，按照路线3所示方法制备，即，以多氯取代的嘧啶为起始原料1，在碱性条件下经过选择性取代反应得到中间体2，中间体2在酸催化条件下与间氨基苯甲酸反应得到中间体7，中间体7与不同的胺缩合得到目标化合物8，根据路线3方法亦可制备具有类似结构的目标化合物，将条件a中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物；将条件d中的反应物由间氨基苯甲酸替换为对氨基苯甲酸即可制备取代基在对位的产物；将条件e中不同的胺替换为含有Boc保护的胺，并在原有缩合反应后串联强酸性条件下的脱保护反应，即可得到通式8所示结构的其他类似物； (3) When the target derivative has a structure as shown in general formula 8 or a similar structure, and when R is halogen, nitro, cyano or other electron-donating groups, it is prepared according to the method shown in route 3, that is, with polychloro Substituted pyrimidine is the starting material 1, and intermediate 2 is obtained through selective substitution reaction under alkaline conditions, intermediate 2 is reacted with m-aminobenzoic acid under acid-catalyzed conditions to obtain intermediate 7, and intermediate 7 is combined with different amines Condensation to obtain the target compound 8, the target compound with a similar structure can also be prepared according to the method of route 3, and the benzylamine in the condition a is replaced by other amines, and the target compound containing other groups can be prepared; the reaction in the condition d The product with the substituent at the para-position can be prepared by replacing m-aminobenzoic acid with p-aminobenzoic acid; replacing the different amines in condition e with amines containing Boc protection, and connecting in series under strong acidic conditions after the original condensation reaction Deprotection reaction can obtain other analogs of the structure shown in general formula 8;
    Figure PCTCN2022112391-appb-100066
    Figure PCTCN2022112391-appb-100066
    (4)目标衍生物具有如通式12所示结构或类似的结构，按照路线4所示方法制备，即，以间氨基苯甲酸为起始原料9，与不同的胺经过缩合反应得到中间体10，中间体10与5-三氟甲基-2,4-二氯嘧啶发生取代反应得到中间体11，中间体11与不同取代的苄胺经过取代反应得到目标化合物12，根据路线4方法亦可制备具有类似结构的目标化合物，将条件e中不同的胺替换为含有Boc保护的胺，并在原有条 件h后串联强酸性条件下的脱保护反应，即可得到通式12所示结构的其他类似物；将条件f中的反应物由间氨基苯甲酸替换为对氨基苯甲酸即可制备取代基在对位的产物；将条件h中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物。(4) The target derivative has a structure as shown in general formula 12 or a similar structure, and is prepared according to the method shown in route 4, that is, using m-aminobenzoic acid as the starting material 9, and reacting with different amines to obtain an intermediate 10, intermediate 10 undergoes a substitution reaction with 5-trifluoromethyl-2,4-dichloropyrimidine to obtain intermediate 11, and intermediate 11 undergoes a substitution reaction with differently substituted benzylamines to obtain target compound 12, and the method according to route 4 is also The target compound with a similar structure can be prepared by replacing the different amines in condition e with amines containing Boc protection, and deprotecting reactions under strong acidic conditions in series after the original condition h, to obtain the structure shown in general formula 12 Other analogs; the reactant in the condition f is replaced by p-aminobenzoic acid by m-aminobenzoic acid to prepare the product with the substituent at the para-position; the benzylamine in the condition h is replaced by other amines to prepare the product containing other The target compound for group substitution.
  7. 权利要求1-5中任一项所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药的制备方法，其特征在于：所述通式(II)所示衍生物的制备反应如下所示：The preparation method of the aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug according to any one of claims 1-5, characterized in that: the general formula The preparation reaction of derivative shown in (II) is as follows:
    Figure PCTCN2022112391-appb-100067
    Figure PCTCN2022112391-appb-100067
    (1)目标衍生物具有如通式15所示结构或类似的结构，按照路线5所示方法制备，即，将起始原料13在碱性条件下与不同取代的苄胺发生取代反应得到中间体14，中间体14与不同的芳胺发生钯催化的偶联反应得到目标化合物15，其中，部分含有Boc保护的复杂芳胺需要在钯催化的偶联反应后串联强酸条件下的脱保护反应，才能得到目标化合物，根据路线5方法亦可制备具有类似结构的目标化合物，将起始原料13中的噻吩环替换为呋喃环，N上含有取代基的吡咯环或者改变杂原子的位置，即可得到不同母核的通式15所示结构的其他类似物；将条件i中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物；(1) The target derivative has a structure as shown in general formula 15 or a similar structure, and is prepared according to the method shown in route 5, that is, the starting material 13 is substituted with different substituted benzylamines under basic conditions to obtain the intermediate Compound 14, intermediate 14 undergoes palladium-catalyzed coupling reaction with different arylamines to obtain the target compound 15, among which, some of the complex arylamines containing Boc protection need to be deprotected in series under strong acid conditions after the palladium-catalyzed coupling reaction , in order to obtain the target compound, the target compound with a similar structure can also be prepared according to the method of route 5, the thiophene ring in the starting material 13 is replaced by the furan ring, the pyrrole ring with a substituent on the N or the position of the heteroatom is changed, that is Other analogs of the structure shown in the general formula 15 with different cores can be obtained; the benzylamine in the condition i is replaced by other amines, and the target compound containing other group substitutions can be prepared;
    Figure PCTCN2022112391-appb-100068
    Figure PCTCN2022112391-appb-100068
    (2)目标衍生物具有如通式20所示结构或类似的结构，按照路线6所示方法制备，即，使起始原料16经过Ts保护得到中间体17，中间体17与不同取代的苄胺反应得到中间体18，中间体18经过钯催化的偶联反应得到中间体19，中间体19在碱性条件下脱除Ts保护得到目标化合物20，其中，部分含有Boc保护的复杂芳胺需要在钯催化的偶联反应后串联强酸条件下的脱保护反应，才能得到中间体19，根据路线6方法亦可制备具有类似结构的目标化合物，将条件i中的苄胺替换为其他胺，即可制备含有其他基团取代的目标化合物；改变起始原料16中N原子的位置，可得到具有其他母核的目标化合物。(2) The target derivative has a structure as shown in the general formula 20 or a similar structure, and is prepared according to the method shown in Route 6, that is, the starting material 16 is protected by Ts to obtain the intermediate 17, and the intermediate 17 and different substituted benzyl Amine reaction to obtain intermediate 18, intermediate 18 undergoes a palladium-catalyzed coupling reaction to obtain intermediate 19, intermediate 19 is deprotected by Ts under basic conditions to obtain target compound 20, and some of them contain complex aromatic amines protected by Boc. Intermediate 19 can be obtained only after the palladium-catalyzed coupling reaction and deprotection reaction under strong acid conditions. The target compound with similar structure can also be prepared according to the method of route 6, and the benzylamine in the condition i is replaced by other amines, i.e. The target compound containing other group substitutions can be prepared; changing the position of the N atom in the starting material 16 can obtain the target compound with other parent nuclei.
  8. 一种药物组合物，其特征在于：所述药物组合物包含治疗有效量的权利要求1-5中任一项所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药以及药学上可接受的载体或赋形剂。A pharmaceutical composition, characterized in that: the pharmaceutical composition comprises a therapeutically effective amount of the aminopyrimidine derivative or its stereoisomers, pharmaceutically acceptable salts, Hydrate, solvate or prodrug and pharmaceutically acceptable carrier or excipient.
  9. 权利要求1-5中任一项所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药或者权利要求8所述的药物组合物在制备TRK抑制剂中的用途。The aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug described in any one of claims 1-5 or the pharmaceutical composition described in claim 8 are prepared Use in TRK inhibitors.
  10. 权利要求1-5中任一项所述的氨基嘧啶衍生物或其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药或者权利要求8所述的药物组合物在制备预防或治疗与TRK的表达或活性相关的疾病的药物中的用途，其特征在于：优选地，所述疾病为肿瘤、癌症或由不同原因而引起的剧痛。The aminopyrimidine derivative or its stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or prodrug described in any one of claims 1-5 or the pharmaceutical composition described in claim 8 are prepared The use in medicine for preventing or treating diseases related to the expression or activity of TRK is characterized in that: preferably, the diseases are tumors, cancers or severe pain caused by different reasons.
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