WO2018121228A1 - Compound having axl inhibitory activity, preparation method therefor and use thereof - Google Patents

Compound having axl inhibitory activity, preparation method therefor and use thereof Download PDF

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WO2018121228A1
WO2018121228A1 PCT/CN2017/115380 CN2017115380W WO2018121228A1 WO 2018121228 A1 WO2018121228 A1 WO 2018121228A1 CN 2017115380 W CN2017115380 W CN 2017115380W WO 2018121228 A1 WO2018121228 A1 WO 2018121228A1
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methyl
substituted
unsubstituted
pyrrolo
group
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PCT/CN2017/115380
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段文虎
耿美玉
王蔚
丁健
艾菁
许丹丹
彭霞
曹素芬
季寅淳
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中国科学院上海药物研究所
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Priority to CN201780074009.9A priority Critical patent/CN110036014B/en
Publication of WO2018121228A1 publication Critical patent/WO2018121228A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • R 5 is selected from H, substituted or unsubstituted C1-C4 alkyl, halogen, substituted or unsubstituted C1-C4 alkoxy.
  • R 5 is selected from the group consisting of H, methyl, F, Cl, and methoxy.
  • R 6 is H.
  • R 1 is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 selected from N, O and S heteroatoms.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C4 alkyl group, a halogen, a cyano group, an amino group, a further substitution or Unsubstituted C1-C4 alkoxy group and further substituted or unsubstituted C1-C4 alkylthio group.
  • R 2 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from N, a 3-8 membered heterocycloalkyl group of O and S heteroatoms; said "substituted” means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1- a C4 alkyl group, a further substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylthio group, containing 1-3 selected from N, a 3-8 membered heterocycloalkyl group of O and S heteroatoms and -CONR 10 R 11
  • the GAS6/AXL signaling pathway abnormal expression related diseases are colon cancer, rectal cancer, skin cancer, gastric cancer, lung cancer, endometrial cancer, malignant melanoma, thyroid cancer, glioma, esophagus Tumors associated with poor prognosis such as cancer, prostate cancer, ovarian cancer, and breast cancer, and their high expression may mediate acquired resistance to EGFR.
  • the compound of the present invention is as shown in the general formula (I):
  • amine salt and other pharmaceutically acceptable amine salts (such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl) a base amine salt, an ethylenediamine salt, a glycolic acid amine salt, a dihydroxyethylamine salt, a trishydroxyethylamine salt, and an amine salt formed from morpholine, piperazine, and lysine, respectively.
  • amine salt such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl
  • base amine salt such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-buty
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • Step 1 Preparation of ethyl 3-oxo-4-phenylbutanoate
  • Step 5 Preparation of N-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-5-(4-fluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
  • Step 1 Preparation of 4-chloro-5-iodo-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine
  • Step 4 Preparation of N-(4-(4-amino-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Formamide
  • Example 38 N-(4-(4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO .38)
  • Step 3 Preparation of 5-(3,5-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- Ethyl 3-carboxylate
  • Step 2 Preparation of ethyl 4-(3-fluorophenyl)-3-oxobutanoate
  • Step 2 Preparation of ethyl 4-(4-(methylthio)phenyl)-3-oxobutanoate

Abstract

The present invention relates to a compound having AXL inhibitory activities, a preparation method therefor and use thereof. In particular, disclosed is a compound of a structure as represented by formula (I), each group and substituent thereof are as defined in the description. Further disclosed is a preparation method of the described compound and use thereof as a protein tyrosine kinase inhibitor, in particular as an AXL inhibitor, in medicaments for the treatment of cancer-related diseases.

Description

一种具有AXL抑制活性的化合物及其制备和应用Compound with AXL inhibitory activity and preparation and application thereof 技术领域Technical field
本发明属于药物领域，具体地，涉及一种具有AXL抑制活性的化合物及其制备和应用。The present invention belongs to the field of medicines, and in particular to a compound having AXL inhibitory activity and its preparation and use.
背景技术Background technique
蛋白激酶是一种通过对蛋白质上特定氨基酸的磷酸化来调节各种细胞功能的蛋白质(酶)。蛋白质通过构象的改变来调节活性以及与其化组分结合能力。蛋白质激酶的活性指的是，激酶将磷酸基团结合到底物上的速率，该速率可以通过检测一定时间内转化为产物的底物的量来进行测定。底物的磷酸化发生在蛋白质激酶的活化位点上。Protein kinases are proteins (enzymes) that regulate various cellular functions by phosphorylating specific amino acids on proteins. Proteins regulate their activity and their ability to bind to their constituents through changes in conformation. The activity of a protein kinase refers to the rate at which a kinase binds a phosphate group to a substrate, and the rate can be determined by detecting the amount of substrate converted to a product over a period of time. Phosphorylation of the substrate occurs at the activation site of the protein kinase.
酪氨酸激酶是一种可以催化将三磷酸腺苷转移到蛋白质酪氨酸残基的蛋白质酶。这些激酶在生长因子传导引发细胞增殖、分化和迁移过程中扮演着重要的角色。Tyrosine kinase is a proteinase that catalyzes the transfer of adenosine triphosphate to a protein tyrosine residue. These kinases play an important role in growth factor-mediated cell proliferation, differentiation and migration.
AXL(又名UFO，ARK或TYRO7)是编码受体酪氨酸激酶基因之一，1991年由Bryan等在人类慢性髓细胞白血病(CML)的DNA中发现，其与TYRO3及MER共同组成受体酪氨酸激酶TAM亚家族。生长停滞特异性基因6(GAS6)所编码的蛋白分子为TAM亚家族成员的共同配体之一。AXL通过与其配体GAS6的结合，导致激酶超家族活化，在调控机体炎症免疫反应、维持机体吞噬作用的稳态、调节NK细胞的分化成熟等发挥重要的调节作用。目前已在多种实体瘤中发现了AXL的高表达，包括肺癌、乳腺癌、肝癌、胰腺癌、***癌等，与肿瘤复发、不良预后密切相关。AXL异常表达激活拮抗肿瘤细胞凋亡、促进肿瘤细胞侵袭、转移，促进肿瘤血管新生，多环节推动了肿瘤的发生发展。尤其值得关注的是，近年研究显示，AXL的高表达可能介导EGFR的获得性耐药，临床研究表明高达20％的EGFR耐药病人中存在AXL的高表达；临床前研究AXL抑制剂的联合用药可以有效克服EGFR抑制剂耐药。此外，AXL过表达异常激活与其他靶向抑制剂以及化疗药物的耐药也密切相关，提示了AXL可能具有广泛的联合用药的应用空间。与其他激酶不同的是，AXL在肿瘤微环境的巨噬细胞、树突状细胞中高表达，可以通过与肿瘤细胞以及其他基质细胞交互作用，协同促进肿瘤进展。因此，近年来，靶向AXL抑制剂的研发已成为抗肿瘤药物研究的前沿和热点。针对其开发的小分子抑制剂已经在肿瘤治疗中显示效应，但大多数为多靶点激酶抑制剂。AXL (also known as UFO, ARK or TYRO7) is one of the genes encoding the receptor tyrosine kinase. It was discovered in 1991 by Bryan et al. in the DNA of human chronic myeloid leukemia (CML), which forms a receptor with TYRO3 and MER. Tyrosine kinase TAM subfamily. The protein molecule encoded by the growth arrest specific gene 6 (GAS6) is one of the common ligands of the TAM subfamily members. AXL binds to its ligand GAS6, leading to activation of the kinase superfamily, which plays an important regulatory role in regulating the body's inflammatory immune response, maintaining the homeostasis of the body's phagocytosis, and regulating the differentiation and maturation of NK cells. High expression of AXL has been found in a variety of solid tumors, including lung cancer, breast cancer, liver cancer, pancreatic cancer, prostate cancer, etc., which are closely related to tumor recurrence and poor prognosis. AXL abnormal expression activation antagonizes tumor cell apoptosis, promotes tumor cell invasion and metastasis, promotes tumor angiogenesis, and promotes tumor development through multiple links. Of particular concern is the recent study showing that high expression of AXL may mediate acquired resistance to EGFR, clinical studies indicate high expression of AXL in up to 20% of patients with EGFR resistance; preclinical studies of AXL inhibitor combinations Medication can effectively overcome EGFR inhibitor resistance. In addition, abnormal activation of AXL overexpression is also closely related to the resistance of other targeted inhibitors and chemotherapeutic drugs, suggesting that AXL may have a wide range of applications for combination therapy. Unlike other kinases, AXL is highly expressed in macrophages and dendritic cells in the tumor microenvironment, and synergistically promotes tumor progression by interacting with tumor cells and other stromal cells. Therefore, in recent years, the development of targeted AXL inhibitors has become a frontier and hot spot in anti-tumor drug research. Small molecule inhibitors developed for it have shown an effect in tumor therapy, but most are multi-target kinase inhibitors.
综上所述，本领域亟待开发新型的AXL小分子抑制剂。In summary, there is a need in the art to develop novel AXL small molecule inhibitors.
发明内容Summary of the invention
本发明的目的在于提供一种具有AXL抑制活性的新型化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物，以及上述化合物的制备方法和应用。It is an object of the present invention to provide a novel compound having AXL inhibitory activity, or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate thereof or Solvates, and preparation methods and uses of the above compounds.
本发明的第一方面提供了式(I)所示化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物，A first aspect of the invention provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate thereof or Solvate,
Figure PCTCN2017115380-appb-000001
Figure PCTCN2017115380-appb-000001
式中，In the formula,
R 1选自取代或未取代的6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂芳基；所述“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C6烷基、进一步取代或未取代的C3-C8环烷基、卤素、羟基、巯基、氰基、氨基、进一步取代或未取代的C1-C6烷氧基、进一步取代或未取代的C1-C6烷胺基和进一步取代或未取代的C1-C6烷硫基； R 1 is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 3-10 membered heteroaryl containing 1-3 selected from N, O and S heteroatoms; said "substituted" One or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C6 alkyl group, a further substituted or unsubstituted C3-C8 cycloalkyl group, a halogen, a hydroxyl group, a decyl group. a cyano group, an amino group, a further substituted or unsubstituted C1-C6 alkoxy group, a further substituted or unsubstituted C1-C6 alkylamino group, and a further substituted or unsubstituted C1-C6 alkylthio group;
R 2选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、取代或未取代的6-10元芳基和取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂芳基；所述“取代”是指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C6烷基、进一步取代或未取代的C1-C6烷氧基、进一步取代或未取代的C1-C6烷胺基、进一步取代或未取代的C1-C6烷硫基、进一步取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂环烷基和-CONR 10R 11；所述R 10、R 11独立地选自H和C1-C6烷基； R 2 is selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted, containing 1 to 3 heteroatoms selected from S, O, N and Se a 3-10 membered heterocycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group and a substituted or unsubstituted 3 to 3 membered heteroaryl group having 1 to 3 hetero atom selected from N, O and S; The "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C6 alkyl group, a further substituted or unsubstituted C1-C6 alkoxy group. a further substituted or unsubstituted C1-C6 alkylamino group, a further substituted or unsubstituted C1-C6 alkylthio group, a further substituted or unsubstituted one containing 1-3 selected from N, O and S heteroatoms a 10-membered heterocycloalkyl group and -CONR 10 R 11 ; wherein R 10 and R 11 are independently selected from H and C 1 -C 6 alkyl;
R 3选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、取代或未取代的6-10元芳基和取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂芳基；所述“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C6烷基、进一步取代或未取代的C3-C8环烷基、进一步取代或未取代的C1-C6烷氧基、进一步取代或未取代的C1-C6烷胺基、进一步取代或未取代的C1-C6烷硫基、进一步取代或未取代的含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、进一步取代或未取代的C2-C6烯基、进一步取代或未取代的C2-C6炔基、-COOR 12和-CONR 10R 11；所述R 10、R 11、R 12独立地选自H和C1-C6烷基； R 3 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, containing 1-3 heteroatoms selected from S, O, N and Se a 3-10 membered heterocycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group and a substituted or unsubstituted 3 to 3 membered heteroaryl group having 1 to 3 hetero atom selected from N, O and S; The "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C6 alkyl group, a further substituted or unsubstituted C3-C8 cycloalkyl group. Further substituted or unsubstituted C1-C6 alkoxy, further substituted or unsubstituted C1-C6 alkylamino, further substituted or unsubstituted C1-C6 alkylthio, further substituted or unsubstituted containing 1-3 a 3-10 membered heterocycloalkyl selected from the group consisting of S, O, N and Se heteroatoms, a further substituted or unsubstituted C2-C6 alkenyl group, a further substituted or unsubstituted C2-C6 alkynyl group, -COOR 12 and -CONR 10 R 11 ; the R 10 , R 11 , R 12 are independently selected from H and C1-C6 alkyl;
R 4选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、卤素、羟基、氰基、氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基和取代或未取代的C1-C6烷硫基； R 4 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C1-C6 alkylamino group and a substituted or unsubstituted C1-C6 alkylthio group;
V、W、X、Y可相同或不同，分别独立地选自N或CR 5；R 5选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、卤素、羟基、氰基、氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基和取代或未取代的C1-C6烷硫基； V, W, X, Y may be the same or different and are each independently selected from N or CR 5 ; R 5 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl , halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino and substituted or unsubstituted C1-C6 alkylthio;
M、Z可相同或不同，分别独立地选自N或CR 6；R 6选自H、取代或未取代的C1-C6 烷基、取代或未取代的C3-C8环烷基、卤素、羟基、氰基、氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基和取代或未取代的C1-C6烷硫基； M and Z may be the same or different and are each independently selected from N or CR 6 ; R 6 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, halogen, hydroxy , cyano, amino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino and substituted or unsubstituted C1-C6 alkylthio;
R 1、R 2、R 3中的“进一步取代”或R 4、R 5、R 6、V、W、X、Y、M、Z中的“取代”，是指基团上的一个或多个氢原子被选自下组的基团取代：C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷硫基、卤代的C1-C6烷硫基、C1-C6烷硅基、卤代的C1-C6烷硅基、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-(C3-C8的卤代环烷基)、-SO 2-(C1-C6烷基)、SO 2-(C3-C8环烷基)、-SO 2-(3-8元杂环烷基)、-CO-(3-8元杂环烷基)、-CO-(C1-C6烷基)、-CO-(C3-C8环烷基)、-CO 2-(3-8元杂环烷基)、-CO 2-(C1-C6烷基)、-CO 2-(C3-C8环烷基)、-CONR 8R 9、卤素、含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、氨基、被1-3个选自卤素、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、OH、氰基、硝基和氨基的基团所取代的苯基或未取代的苯基、氰基、C2-C6烯基、C2-C6炔基；其中，所述R 8、R 9独立地选自H、C1-C6烷基。 "Substitution" in R 1 , R 2 , R 3 or "substitution" in R 4 , R 5 , R 6 , V, W, X, Y, M, Z means one or more of the groups One hydrogen atom is substituted with a group selected from the group consisting of C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, hydroxy, C1-C6 Alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkylthio, C1-C6 alkyl, halogenated C1-C6 alkyl, -O -(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-(C3-C8 halocycloalkyl), -SO 2 -(C1-C6 alkyl) , SO 2 -(C3-C8 cycloalkyl), -SO 2 -(3-8 membered heterocycloalkyl), -CO-(3-8 membered heterocycloalkyl), -CO-(C1-C6 alkane) , -CO-(C3-C8 cycloalkyl), -CO 2 -(3-8 membered heterocycloalkyl), -CO 2 -(C1-C6 alkyl), -CO 2 -(C3-C8 Cycloalkyl), -CONR 8 R 9 , halogen, 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of S, O, N and Se, amino group, 1-3 selected from halogen, Phenyl or unsubstituted phenyl, cyano, C2-C6 substituted with a group of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, OH, cyano, nitro and amino Alkenyl, C2-C6 alkynyl; Wherein R 8 and R 9 are independently selected from H, C 1 -C 6 alkyl.
在另一优选例中，R 5选自H、取代或未取代的C1-C4烷基、卤素、取代或未取代的C1-C4烷氧基。 In another preferred embodiment, R 5 is selected from H, substituted or unsubstituted C1-C4 alkyl, halogen, substituted or unsubstituted C1-C4 alkoxy.
在另一优选例中，R 5选自H、甲基、F、Cl和甲氧基。 In another preferred embodiment, R 5 is selected from the group consisting of H, methyl, F, Cl, and methoxy.
在另一优选例中，R 6选自H、取代或未取代的C1-C4烷基。 In another preferred embodiment, R 6 is selected from H, substituted or unsubstituted C1-C4 alkyl.
在另一优选例中，R 6为H。 In another preferred embodiment, R 6 is H.
在另一优选例中，V、W、X、Y可相同或不同，分别独立地选自N、CH、CC1-C4烷基、CC1-C4烷氧基、CCl、CF。In another preferred embodiment, V, W, X, and Y may be the same or different and are each independently selected from the group consisting of N, CH, CC1-C4 alkyl, CC1-C4 alkoxy, CCl, CF.
在另一优选例中，M、Z可相同或不同，分别独立地选自N、CH。In another preferred embodiment, M and Z may be the same or different and are each independently selected from N, CH.
在另一优选例中，R 1选自取代或未取代的6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的5-10元杂芳基；所述“取代”是指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C4烷基、进一步取代或未取代的C3-C6环烷基、卤素、氰基、氨基、进一步取代或未取代的C1-C4烷氧基、进一步取代或未取代的C1-C4烷胺基和进一步取代或未取代的C1-C4烷硫基。 In another preferred embodiment, R 1 is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 selected from N, O and S heteroatoms. The term "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C4 alkyl group, a further substituted or unsubstituted C3-C6 ring. Alkyl, halogen, cyano, amino, further substituted or unsubstituted C1-C4 alkoxy, further substituted or unsubstituted C1-C4 alkylamino and further substituted or unsubstituted C1-C4 alkylthio.
在另一优选例中，R 1选自取代或未取代的6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的5-10元杂芳基；所述“取代”是指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C4烷基、卤素、氰基、氨基、进一步取代或未取代的C1-C4烷氧基和进一步取代或未取代的C1-C4烷硫基。 In another preferred embodiment, R 1 is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 selected from N, O and S heteroatoms. The term "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C4 alkyl group, a halogen, a cyano group, an amino group, a further substitution or Unsubstituted C1-C4 alkoxy group and further substituted or unsubstituted C1-C4 alkylthio group.
在另一优选例中，R 1选自取代或未取代的苯基、呋喃基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：甲基、F、Cl、Br、甲氧基、三氟甲氧基、三氟甲基、氰基、氨基和甲硫基。 In another preferred embodiment, R 1 is selected from substituted or unsubstituted phenyl, furanyl; said "substituted" means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: Base, F, Cl, Br, methoxy, trifluoromethoxy, trifluoromethyl, cyano, amino and methylthio.
在另一优选例中，所述取代为苯基上任意位置的取代。In another preferred embodiment, the substitution is a substitution at any position on the phenyl group.
在另一优选例中，所述取代的苯基为苯基上邻位、间位或对位上的取代。In another preferred embodiment, the substituted phenyl group is an ortho, meta or para substitution on the phenyl group.
在另一优选例中，R 2选自H、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的含有1-3个选自N、O和S杂原子的3-8元杂环烷基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C4烷基、进一步取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷胺基、取 代或未取代的C1-C4烷硫基、含有1-3个选自N、O和S杂原子的3-8元杂环烷基和-CONR 10R 11。 In another preferred embodiment, R 2 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from N, a 3-8 membered heterocycloalkyl group of O and S heteroatoms; said "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1- a C4 alkyl group, a further substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylthio group, containing 1-3 selected from N, a 3-8 membered heterocycloalkyl group of O and S heteroatoms and -CONR 10 R 11 .
在另一优选例中，R 2选自H、取代或未取代的C1-C4烷基、取代或未取代的含有1-3个选自N、O和S杂原子的3-8元杂环烷基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷胺基、含有1-3个选自N、O和S杂原子的3-8元杂环烷基和-CONR 10R 11。 In another preferred embodiment, R 2 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted, 3-8 membered heterocyclic ring containing 1-3 selected from N, O and S heteroatoms. Alkyl; said "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkane An oxy, substituted or unsubstituted C1-C4 alkylamino group, having 3 to 3 membered heterocycloalkyl groups selected from N, O and S heteroatoms and -CONR 10 R 11 .
在另一优选例中，R 2选自取代或未取代的C1-C4烷基、四氢吡喃基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：四氢吡喃基、四氢呋喃基、N-甲基哌啶基、吗啉基、C1-C4烷氧基、C1-C4烷硫基和-CON(CH 3) 2。 In another preferred embodiment, R 2 is selected from substituted or unsubstituted C1-C4 alkyl, tetrahydropyranyl; said "substituted" means that one or more hydrogen atoms on the group are selected from the group consisting of substituents: tetrahydropyranyl, tetrahydrofuranyl, N- methyl-piperidinyl, morpholinyl, C1-C4 alkoxy, C1-C4 alkylthio and -CON (CH 3) 2.
在另一优选例中，R 3选自H、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的含有1-3个选自N、O和S杂原子的3-8元杂环烷基、取代或未取代的6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的5-10元杂芳基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷胺基、取代或未取代的C1-C4烷硫基、含有1-3个选自N、O和S杂原子的3-8元杂环烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、-COOR 12和-CONR 10R 11；所述R 10、R 11、R 12独立地选自H和C1-C4烷基。 In another preferred embodiment, R 3 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from N, a 3-8 membered heterocycloalkyl group of the O and S heteroatoms, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted group containing 1-3 selected from N, O and S heteroatoms 5-10 a "heteroaryl"; said "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3- a C6 cycloalkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C1-C4 alkylthio group, containing 1-3 selected from N, 3-8 membered heterocycloalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, -COOR 12 and -CONR 10 R 11 of O and S heteroatoms; said R 10 , R 11 and R 12 are independently selected from the group consisting of H and C1-C4 alkyl.
在另一优选例中，R 3选自H、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的含有1-3个选自N、O和S杂原子的3-8元杂环烷基、取代或未取代6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的5-10元杂芳基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷胺基、取代或未取代的C1-C4烷硫基、含有1-3个选自N、O和S杂原子的3-8元杂环烷基、取代或未取代的C2-C4烯基和取代或未取代的C2-C4炔基。 In another preferred embodiment, R 3 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from N, a 3-8 membered heterocycloalkyl group of the O and S heteroatoms, a substituted or unsubstituted 6-10 membered aryl group, substituted or unsubstituted, having 1 to 3 members selected from N, O and S heteroatoms 5-10. Heteroaryl; the "substitution" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 Alkoxy, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylthio, 3 to 3 membered heterocycloalkane containing 1-3 selected from N, O and S heteroatoms A substituted or unsubstituted C2-C4 alkenyl group and a substituted or unsubstituted C2-C4 alkynyl group.
在另一优选例中，R 3选自氢、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的苯基、四氢吡喃基、氧杂环丁基、四氢呋喃基、氮杂环丁基、N-甲基氮杂环庚基、N-甲基哌啶基、取代或未取代的四氢吡咯基；所述“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C1-C4烷氧基、C1-C4烷硫基、C2-C4烯基、C1-C4烷硅基-C1-C4烷氧基、C1-C4烷胺基、四氢吡喃基、N-甲基哌啶基、-COO叔丁基、烯丙基和吗啉基。 In another preferred embodiment, R 3 is selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted phenyl, tetrahydropyranyl, Oxetanyl, tetrahydrofuranyl, azetidinyl, N-methylazetidyl, N-methylpiperidinyl, substituted or unsubstituted tetrahydropyrrole; said "substituted" group One or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C4 alkoxy, C1-C4 alkylthio, C2-C4 alkenyl, C1-C4 alkyl-C1-C4 alkane Oxyl, C1-C4 alkylamino, tetrahydropyranyl, N-methylpiperidinyl, -COO tert-butyl, allyl and morpholinyl.
在另一优选例中，R 4选自H、取代或未取代的C1-C4烷基、卤素和取代或未取代的C1-C4烷胺基。 In another preferred embodiment, R 4 is selected from H, a substituted or unsubstituted C1-C4 alkyl group, a halogen, and a substituted or unsubstituted C1-C4 alkylamino group.
在另一优选例中，R 4为H、甲基。 In another preferred embodiment, R 4 is H, methyl.
在另一优选例中，R 10、R 11、R 12各自选自C1-C4烷基。 In another preferred embodiment, each of R 10 , R 11 and R 12 is selected from a C1-C4 alkyl group.
在另一优选例中，所述化合物选自化合物NO.1、NO.2、NO.3、NO.4、NO.5、NO.6、NO.7、NO.8、NO.9、NO.10、NO.11、NO.12、NO.13、NO.14、NO.15、NO.16、NO.17、NO.18、NO.19、NO.20、NO.21、NO.22、NO.23、NO.24、NO.25、NO.26、NO.27、NO.28、NO.29、NO.30、NO.31、NO.32、NO.33、NO.34、NO.35、NO.36、NO.37、 NO.38、NO.39、NO.40、NO.41、NO.42、NO.43、NO.44、NO.45、NO.46、NO.47、NO.48、NO.49、NO.50、NO.51、NO.52、NO.53、NO.54、NO.55、NO.56、NO.57、NO.58、NO.59、NO.60、NO.61、NO.62、NO.63、NO.64、NO.65、NO.66、NO.67、NO.68、NO.69、NO.70和NO.71。In another preferred embodiment, the compound is selected from the group consisting of compounds NO. 1, NO. 2, NO. 3, NO. 4, NO. 5, NO. 6, NO. 7, NO. 8, NO. 9, NO. .10, NO.11, NO.12, NO.13, NO.14, NO.15, NO.16, NO.17, NO.18, NO.19, NO.20, NO.21, NO.22 , NO.23, NO.24, NO.25, NO.26, NO.27, NO.28, NO.29, NO.30, NO.31, NO.32, NO.33, NO.34, NO .35, NO.36, NO.37, NO.38, NO.39, NO.40, NO.41, NO.42, NO.43, NO.44, NO.45, NO.46, NO.47 , NO.48, NO.49, NO.50, NO.51, NO.52, NO.53, NO.54, NO.55, NO.56, NO.57, NO.58, NO.59, NO .60, NO.61, NO.62, NO.63, NO.64, NO.65, NO.66, NO.67, NO.68, NO.69, NO.70 and NO.71.
本发明的第二方面提供了第一方面所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物的制备方法，包括步骤：将式(II)化合物与式(III)化合物进行反应，从而形成式(I)化合物；A second aspect of the invention provides the compound of the first aspect, or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvent thereof The preparation method comprises the steps of: reacting a compound of the formula (II) with a compound of the formula (III) to form a compound of the formula (I);
Figure PCTCN2017115380-appb-000002
Figure PCTCN2017115380-appb-000002
其中，V、W、X、Y、M、Z、R 1、R 2、R 3、R 4的定义如前所述。 Wherein, the definitions of V, W, X, Y, M, Z, R 1 , R 2 , R 3 and R 4 are as defined above.
本发明的第三方面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本发明第一方面所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物的一种或多种，以及任选的药学上可接受的载体。A third aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the first aspect of the invention, or a stereoisomer, geometric isomer thereof, tautomer thereof, Or a pharmaceutically acceptable salt thereof, or one or more of its prodrugs, hydrates or solvates, and optionally a pharmaceutically acceptable carrier.
在另一优选例中，所述药物组合物用于预防和/或治疗癌症。In another preferred embodiment, the pharmaceutical composition is for preventing and/or treating cancer.
在另一优选例中，所述药物组合物用于预防和/或治疗AXL相关疾病。In another preferred embodiment, the pharmaceutical composition is for preventing and/or treating an AXL related disease.
在另一优选例中，所述药物组合物用于预防和/或治疗GAS6/AXL信号通路异常表达相关疾病。In another preferred embodiment, the pharmaceutical composition is for use in preventing and/or treating a disease associated with abnormal expression of the GAS6/AXL signaling pathway.
在另一优选例中，所述AXL相关疾病为结肠癌、直肠癌、皮肤癌、胃癌、肺癌、子宫内膜癌、恶性黑色素瘤、甲状腺癌、神经胶质瘤、食管癌、***癌、卵巢癌及乳腺癌等肿瘤发生与不良预后有关的疾病，以及其高表达可能介导的EGFR的获得性耐药。In another preferred embodiment, the AXL-related diseases are colon cancer, rectal cancer, skin cancer, gastric cancer, lung cancer, endometrial cancer, malignant melanoma, thyroid cancer, glioma, esophageal cancer, prostate cancer, ovary Tumors such as cancer and breast cancer are associated with poor prognosis, and their high expression may mediate acquired resistance to EGFR.
在另一优选例中，所述GAS6/AXL信号通路异常表达相关疾病为结肠癌、直肠癌、皮肤癌、胃癌、肺癌、子宫内膜癌、恶性黑色素瘤、甲状腺癌、神经胶质瘤、食管癌、***癌、卵巢癌及乳腺癌等肿瘤发生与不良预后有关的疾病，以及其高表达可能介导的EGFR的获得性耐药。In another preferred embodiment, the GAS6/AXL signaling pathway abnormal expression related diseases are colon cancer, rectal cancer, skin cancer, gastric cancer, lung cancer, endometrial cancer, malignant melanoma, thyroid cancer, glioma, esophagus Tumors associated with poor prognosis such as cancer, prostate cancer, ovarian cancer, and breast cancer, and their high expression may mediate acquired resistance to EGFR.
在另一优选例中，所述药物组合物的剂型选自下组：口服剂型、冻干制剂、注射剂。In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of an oral dosage form, a lyophilized preparation, and an injection.
本发明的第四方面提供了第一方面所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物或第三方面所述药物组合物的用途，用于制备用于预防和/或治疗选自下组的疾病的药物：A fourth aspect of the invention provides the compound of the first aspect, or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvent thereof Or a use of the pharmaceutical composition of the third aspect for the preparation of a medicament for preventing and/or treating a disease selected from the group consisting of:
a)肿瘤相关疾病；a) tumor-related diseases;
b)蛋白酪氨酸激酶活性相关疾病。b) Disease associated with protein tyrosine kinase activity.
在另一优选例中，所述肿瘤相关疾病选自下组：结肠癌、直肠癌、皮肤癌、胃癌、肺癌、子宫内膜癌、恶性黑色素瘤、甲状腺癌、神经胶质瘤、食管癌、***癌、卵巢癌及乳腺癌。In another preferred embodiment, the tumor-related disease is selected from the group consisting of colon cancer, rectal cancer, skin cancer, gastric cancer, lung cancer, endometrial cancer, malignant melanoma, thyroid cancer, glioma, esophageal cancer, Prostate cancer, ovarian cancer and breast cancer.
在另一优选例中，所述肺癌为非小细胞肺癌(NSCLC)。In another preferred embodiment, the lung cancer is non-small cell lung cancer (NSCLC).
在另一优选例中，所述蛋白酪氨酸激酶活性相关疾病为AXL相关疾病。In another preferred embodiment, the protein tyrosine kinase activity-related disease is an AXL-related disease.
在另一优选例中，所述蛋白酪氨酸激酶活性相关疾病为GAS6/AXL信号通路异常表达相关疾病。In another preferred embodiment, the protein tyrosine kinase activity-associated disease is a disease associated with abnormal expression of the GAS6/AXL signaling pathway.
本发明的第五方面提供了一种AXL抑制剂，所述AXL抑制剂包含抑制有效量的第一方面所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物中的一种或多种。A fifth aspect of the invention provides an AXL inhibitor comprising an inhibitory effective amount of the compound of the first aspect, or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt, or one or more of its prodrugs, hydrates or solvates.
本发明的第六方面提供了第三方面所述药物组合物的制备方法，包括步骤：将药学上可接受的载体与第一方面所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物进行混合，从而形成药物组合物。A sixth aspect of the invention provides a process for the preparation of the pharmaceutical composition of the third aspect, comprising the steps of: pharmaceutically acceptable carrier and the compound of the first aspect, or a stereoisomer, geometric isomer thereof, The isomer, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, is mixed to form a pharmaceutical composition.
本发明的第七方面提供了一种非诊断性、非治疗性抑制AXL活性的方法，所述方法包括步骤：向所需患者施用抑制有效量的第一方面所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物或第三方面所述药物组合物。A seventh aspect of the invention provides a method of non-diagnostic, non-therapeutic inhibition of AXL activity, the method comprising the step of administering to a patient in need thereof an inhibitory effective amount of the compound of the first aspect or a stereoisomer thereof a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, or a pharmaceutical composition according to the third aspect.
本发明的第八方面提供了一种肿瘤或蛋白酪氨酸激酶活性相关疾病的治疗方法，所述方法包括步骤：向所需患者施用抑制有效量的第一方面所示化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物。An eighth aspect of the invention provides a method of treating a tumor or protein tyrosine kinase activity-related disease, the method comprising the steps of: administering to a patient in need thereof an inhibitory effective amount of the compound of the first aspect or a stereoisomer thereof a body, geometric isomer, tautomer, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
附图说明DRAWINGS
图1：化合物对SNU-886细胞中AXL磷酸化的影响。Figure 1: Effect of compounds on AXL phosphorylation in SNU-886 cells.
具体实施方式detailed description
本申请的发明人经过广泛而深入的研究，研发出一种结构新颖、AXL抑制作用显著的通式(I)所示化合物。以本发明化合物制备的AXL抑制剂，可在nM水平上实现对AXL酶活性的明显抑制作用，并且所述抑制剂在细胞水平对AXL诱导的癌细胞增殖也具有显著抑制作用，这对于开发新型抗肿瘤药物具有重要意义。在此基础上，发明人完成了本发明。The inventors of the present application have conducted extensive and intensive research to develop a compound of the formula (I) which is novel in structure and has remarkable inhibition of AXL. The AXL inhibitor prepared by the compound of the present invention can achieve significant inhibition of AXL enzyme activity at the nM level, and the inhibitor also has a significant inhibitory effect on AXL-induced cancer cell proliferation at the cellular level, which is new for development. Anti-tumor drugs are of great significance. On this basis, the inventors completed the present invention.
术语the term
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷 基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷硫基、卤代的C1-C6烷硫基、C1-C6烷硅基、卤代的C1-C6烷硅基、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-(C3-C8的卤代环烷基)、-SO 2-(C1-C6烷基)、SO 2-(C3-C8环烷基)、-SO 2-(3-8元杂环烷基)、-CO-(3-8元杂环烷基)、-CO-(C1-C6烷基)、-CO-(C3-C8环烷基)、-CO 2-(3-8元杂环烷基)、-CO 2-(C1-C6烷基)、-CO 2-(C3-C8环烷基)、-CONR 8R 9、卤素、含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、氨基、苯基、氰基、C2-C6烯基、C2-C6炔基；所述R 8、R 9独立地选自H、C1-C6烷基；所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基，所述取代基选自：卤素、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、OH、氰基、硝基、氨基。 As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C6 alkyl, halo C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkane Thio group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-( a halogenated cycloalkyl group of C3-C8, -SO 2 -(C1-C6 alkyl), SO 2 -(C3-C8 cycloalkyl), -SO 2 -(3-8 membered heterocycloalkyl), -CO-(3-8 membered heterocycloalkyl), -CO-(C1-C6 alkyl), -CO-(C3-C8 cycloalkyl), -CO 2 -(3-8 membered heterocycloalkyl) ), -CO 2 -(C1-C6 alkyl), -CO 2 -(C3-C8 cycloalkyl), -CONR 8 R 9 , halogen, containing 1-3 selected from S, O, N and Se a 3-10 membered heterocycloalkyl group of an atom, an amino group, a phenyl group, a cyano group, a C2-C6 alkenyl group, a C2-C6 alkynyl group; said R 8 and R 9 are independently selected from H, C 1 -C 6 alkyl; The phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C1-C6 alkyl group, C3-C8 cycloalkyl group, C1-C6. Alkoxy, OH, cyano, nitro, amino.
除特别说明之处，本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。Unless otherwise specified, among all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
术语“3-10元杂芳基”指具有1-3个选自下组的杂原子的3-10元芳基失去一个氢原子形成的基团：N、S、O、Se，其中每个杂芳基的环状体系可以是单环或多环的；例如苯并噻吩基、苯并呋喃基、吲哚基、萘基、苯并咪唑基、苯并硒吩基、吡啶基、呋喃基、苯基、吲唑基、噻吩基、吡咯基、咪唑基、吡唑基、吡嗪基、噁唑基、噻唑基、苯并噻唑基、喹啉基或类似基团。The term "3-10 membered heteroaryl" refers to a group of 3 to 10 membered aryl groups having from 1 to 3 hetero atoms selected from the group consisting of N, S, O, Se, each of which The heteroaryl ring system may be monocyclic or polycyclic; for example, benzothienyl, benzofuranyl, fluorenyl, naphthyl, benzimidazolyl, benzoselenophene, pyridyl, furyl Phenyl, carbazolyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, oxazolyl, thiazolyl, benzothiazolyl, quinolyl or the like.
术语“6-10元芳基”指6-10元芳基失去一个氢原子形成的基团；例如苯基、萘基，或类似基团。The term "6-10 membered aryl" refers to a group formed by the loss of a hydrogen atom of a 6-10 membered aryl group; for example, a phenyl group, a naphthyl group, or the like.
术语“C1-C6烷基”指具有1-6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。The term "C1-C6 alkyl" refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.
术语“C3-C8环烷基”指具有3-8个碳原子的环烷基，例如环丙基、环丁基、环戊基、环己基，或类似基团。The term "C3-C8 cycloalkyl" refers to a cycloalkyl group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.
术语“3-10元杂环烷基”指具有1-3个选自下组的杂原子的3-10元环烷基：N、S、O、Se，其中每个环烷基的环状体系可以是单环或多环的；例如四氢呋喃基、四氢吡喃基、四氢吡咯基、四氢噻吩基、哌啶基、氮杂环丁基、氮杂环庚基、吗啉基，或类似基团。The term "3-10 membered heterocycloalkyl" refers to a 3-10 membered cycloalkyl group having 1-3 heteroatoms selected from the group consisting of N, S, O, Se, wherein each cycloalkyl ring is cyclic. The system may be monocyclic or polycyclic; for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, azetidinyl, azepanyl, morpholinyl, Or a similar group.
术语“C1-C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。The term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.
术语“C1-C6烷硫基”指具有1-6个碳原子的直链或支链烷硫基，例如甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、异丁硫基、仲丁硫基、叔丁硫基、或类似基团。术语“C1-C6烷胺基”指被具有1-6个碳原子的直链或支链烷基取代的胺基，其可以是单取代或二取代的；例如甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、仲丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二仲丁胺基、二叔丁胺基、或类似基团。The term "C1-C6 alkylthio" refers to a straight or branched alkylthio group having from 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, iso Butylthio, sec-butylthio, tert-butylthio, or the like. The term "C1-C6 alkylamino" refers to an amine group substituted by a straight or branched alkyl group having 1 to 6 carbon atoms, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diiso Butylamino, di-sec-butylamino, di-tert-butylamino, or the like.
术语“C1-C6烷硅基”指被具有1-6个碳原子的直链或支链烷基取代的硅基，其可以是单取代、二取代或三取代的；例如甲硅基、乙硅基、丙硅基、异丙硅基、丁硅基、异丁硅基、仲丁硅基、叔丁硅基、二甲硅基、二乙硅基、二丙硅基、二异丙硅基、二丁硅基、二异丁硅基、二仲丁硅基、二叔丁硅基、三甲硅基、三乙硅基、三丙硅基、三异丙硅基、三丁硅基、三异丁硅基、三仲丁硅基、三叔丁硅基、或类似基团。The term "C1-C6 alkylsilyl" refers to a silicon radical substituted by a straight or branched alkyl group having 1 to 6 carbon atoms, which may be monosubstituted, disubstituted or trisubstituted; for example, silyl, ethyl Silicon based, propyl silicon based, isopropyl silicon based, butyl silicon based, isobutyl silicon based, sec-butyl silicon based, tert-butyl silicon based, dimethicone, diethylsilyl, dipropylsilyl, diisopropylsilyl, dibutylsilyl, diisobutylsilyl , sec-butylsilyl, di-tert-butylsilyl, trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, tributylsilyl, triisobutylsilyl, tri-sec-butylsilyl, tri-tert-butylsilyl, or the like.
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基 团，所述的烯烃可以是单烯烃、二烯烃或三烯烃，例如-CH＝CH 2、-C 2H 4＝CH 2、-CH＝C 2H 4，或类似基团。 The term "C2-C6 alkenyl" means a group formed by an olefin having 2 to 6 carbon atoms which loses one or two hydrogen atoms, and the olefin may be a monoolefin, a diene or a triene, for example, -CH= CH 2 , -C 2 H 4 =CH 2 , -CH=C 2 H 4 , or the like.
术语“卤素”指F、Cl、Br和I。术语“卤代”指氟代、氯代、溴代和碘代。The term "halogen" refers to F, Cl, Br and I. The term "halo" refers to fluoro, chloro, bromo and iodo.
此外，在本发明中，术语“烷基”包括饱和或不饱和、直链、支链、环状的1-10个碳原子的全碳烷基或其中的1-3个碳原子被氧、氮、硫等杂原子取代的烷基，以及通过1个或1个以上碳原子连接的芳烷基。此外，所述的烷基是未取代的或取代的。Further, in the present invention, the term "alkyl" includes a saturated or unsaturated, linear, branched, cyclic all-carbon alkyl group of 1 to 10 carbon atoms or 1 to 3 carbon atoms thereof by oxygen, An alkyl group substituted with a hetero atom such as nitrogen or sulfur, and an aralkyl group bonded through one or more carbon atoms. Further, the alkyl group is unsubstituted or substituted.
如本文所用，术语“芳基”包括稠合或非稠合的芳基，通常含有6-30个碳原子，代表性的芳基包括苯基、萘基，或含氧、氮、硫等杂原子的芳香基团。As used herein, the term "aryl" includes fused or non-fused aryl groups, usually containing from 6 to 30 carbon atoms, and representative aryl groups include phenyl, naphthyl, or oxygen, nitrogen, sulfur, etc. Aromatic group of atoms.
化合物Compound
本发明人通过结构优化，设计合成了一系列结构新颖的在酶、细胞水平均有优异AXL抑制活性的小分子化合物，该系列化合物有望在临床上用于治疗GAS6/AXL信号通路异常表达所引起的疾病，如癌症等。The inventors designed and synthesized a series of novel small molecule compounds with excellent AXL inhibitory activity at the enzyme and cell levels through structural optimization. The compounds are expected to be used clinically to treat abnormal expression of GAS6/AXL signaling pathway. Diseases such as cancer.
本发明的化合物如通式(I)所示：The compound of the present invention is as shown in the general formula (I):
Figure PCTCN2017115380-appb-000003
Figure PCTCN2017115380-appb-000003
式中，R 1、R 2、R 3、R 4、V、W、X、Y、M、Z定义同前。 In the formula, R 1 , R 2 , R 3 , R 4 , V, W, X, Y, M, and Z are as defined above.
优选地，本发明的化合物选自下表：Preferably, the compounds of the invention are selected from the table below:
表1.Table 1.
Figure PCTCN2017115380-appb-000004
Figure PCTCN2017115380-appb-000004
Figure PCTCN2017115380-appb-000005
Figure PCTCN2017115380-appb-000005
Figure PCTCN2017115380-appb-000006
Figure PCTCN2017115380-appb-000006
Figure PCTCN2017115380-appb-000007
Figure PCTCN2017115380-appb-000007
Figure PCTCN2017115380-appb-000008
Figure PCTCN2017115380-appb-000008
Figure PCTCN2017115380-appb-000009
Figure PCTCN2017115380-appb-000009
Figure PCTCN2017115380-appb-000010
Figure PCTCN2017115380-appb-000010
Figure PCTCN2017115380-appb-000011
Figure PCTCN2017115380-appb-000011
Figure PCTCN2017115380-appb-000012
Figure PCTCN2017115380-appb-000012
Figure PCTCN2017115380-appb-000013
Figure PCTCN2017115380-appb-000013
Figure PCTCN2017115380-appb-000014
Figure PCTCN2017115380-appb-000014
Figure PCTCN2017115380-appb-000015
Figure PCTCN2017115380-appb-000015
Figure PCTCN2017115380-appb-000016
Figure PCTCN2017115380-appb-000016
Figure PCTCN2017115380-appb-000017
Figure PCTCN2017115380-appb-000017
Figure PCTCN2017115380-appb-000018
Figure PCTCN2017115380-appb-000018
Figure PCTCN2017115380-appb-000019
Figure PCTCN2017115380-appb-000019
Figure PCTCN2017115380-appb-000020
Figure PCTCN2017115380-appb-000020
Figure PCTCN2017115380-appb-000021
Figure PCTCN2017115380-appb-000021
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise stated, the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of the double bond and conformational isomers of (Z), (E). Thus a single stereochemical isomer of the compound of the invention or its enantiomer Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) are within the scope of the invention.
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。As used herein, the term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other. For example, proton tautomers (ie, proton shifts) include interconversions by proton transfer, such as 1H-carbazole with 2H-carbazole, 1H-benzo[d]imidazole, and 3H-benzo[d]imidazole. The valence tautomers include interconversion through some bonding electron recombination.
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。所述药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括且不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐，如碱金属盐(如钠盐或钾盐)、碱土金属盐(如镁盐或钙盐)、铵盐(如低级的烷醇铵盐)以及其它药学上可接受的胺盐(如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙酸胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐)。As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament. The pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for salt formation include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc.; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, rich Horse acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid An organic acid such as benzenesulfonic acid or naphthalenesulfonic acid; and an amino acid such as proline, phenylalanine, aspartic acid or glutamic acid. Another preferred class of salts are the salts of the compounds of the invention with bases, such as alkali metal salts (such as sodium or potassium salts), alkaline earth metal salts (such as magnesium or calcium salts), ammonium salts (such as lower alkanolammonium). Salt) and other pharmaceutically acceptable amine salts (such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl) a base amine salt, an ethylenediamine salt, a glycolic acid amine salt, a dihydroxyethylamine salt, a trishydroxyethylamine salt, and an amine salt formed from morpholine, piperazine, and lysine, respectively.
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。As used herein, the term "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the invention with water.
如本文所用，术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)化合物的一类化合物，或式(I)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。As used herein, the term "prodrug" includes itself which may be biologically active or inactive, which, when taken by a suitable method, is converted to a compound of formula (I) by metabolism or chemical reaction in the human body. A salt or solution of a compound or a compound of formula (I). The prodrug includes, but is not limited to, a carboxylic acid ester, a carbonate, a phosphate, a nitrate, a sulfate, a sulfone ester, a sulfoxide, an amino compound, a carbamate, an azo compound of the compound. , phosphoramide, glucoside, ether, acetal and the like.
制备方法Preparation
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发 明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。The preparation of the structural compound of the formula (I) of the present invention is more specifically described below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
具体地，本发明化合物的制备方法包括步骤：在一定温度下，将式(II)化合物与式(III)化合物进行反应一段时间，从而形成式(I)化合物；Specifically, the preparation method of the compound of the present invention comprises the steps of: reacting a compound of the formula (II) with a compound of the formula (III) at a certain temperature for a certain period of time to form a compound of the formula (I);
Figure PCTCN2017115380-appb-000022
Figure PCTCN2017115380-appb-000022
其中，V、W、X、Y、M、Z、R 1、R 2、R 3、R 4的定义同前所述。 Wherein, the definitions of V, W, X, Y, M, Z, R 1 , R 2 , R 3 and R 4 are as described above.
优选地，式(II)化合物的制备方法如下：Preferably, the preparation of the compound of formula (II) is as follows:
Figure PCTCN2017115380-appb-000023
Figure PCTCN2017115380-appb-000023
其中，R 1、R 2的定义同前所述；R 7选自C1-C6烷基，并优选自甲基和乙基；L是光延反应中的羟基或发生亲核取代时的离去基团或偶联反应的硼酸基或硼酸酯基。 Wherein R 1 and R 2 are as defined above; R 7 is selected from C1-C6 alkyl, and preferably from methyl and ethyl; and L is a hydroxyl group in a photo-delay reaction or a leaving group upon nucleophilic substitution. a boric acid group or a boronic acid ester group of a coupling reaction.
优选地，式(III)化合物的制备方法如下：Preferably, the preparation of the compound of formula (III) is as follows:
Figure PCTCN2017115380-appb-000024
Figure PCTCN2017115380-appb-000024
其中，V、W、X、Y、M、Z、R 3、R 4的定义同前所述。 Wherein, the definitions of V, W, X, Y, M, Z, R 3 and R 4 are as described above.
具体地，本发明化合物的制备方法包括如下步骤：Specifically, the preparation method of the compound of the present invention comprises the following steps:
1、化合物1可以通过本领域常见的方法制备(如利用相应的羧酸制备酰卤)，或通过市售途径获得；1. Compound 1 can be prepared by methods conventional in the art (e.g., by using the corresponding carboxylic acid to prepare an acid halide), or by commercially available routes;
2、化合物1先与米氏酸10缩合得到化合物1a，再于对应的醇中回流得到化合物2；2, the compound 1 is first condensed with the Michleric acid 10 to obtain the compound 1a, and then refluxed in the corresponding alcohol to obtain the compound 2;
Figure PCTCN2017115380-appb-000025
Figure PCTCN2017115380-appb-000025
3、化合物2与N,N-二甲基甲酰胺二甲基缩醛于适当的溶剂中加热反应得到化合物3；3, the compound 2 and N, N-dimethylformamide dimethyl acetal in a suitable solvent to obtain a compound 3;
4、化合物3与相应的胺于适当的溶剂中加热缩合得到化合物4；当然，化合物3也可与乙酸铵或甲酸铵等在适当溶剂中加热缩合得到化合物5，再利用光延反应或其它亲核取代反应甚至偶联反应得到化合物4；4. Compound 3 is heated and condensed with the corresponding amine in a suitable solvent to obtain compound 4; of course, compound 3 can also be heated and condensed with ammonium acetate or ammonium formate in a suitable solvent to obtain compound 5, which is then subjected to a light delay reaction or other nucleophilic reaction. Substitution reaction or even coupling reaction to obtain compound 4;
5、化合物4碱水解可得化合物(II)；5. Compound 4 is hydrolyzed to obtain compound (II);
6、化合物6或9均可通过本领域的常规方法制备，或通过市售途径获得，化合物6或9在N-碘代丁二酰亚胺条件下可生成相应的碘代化合物7或10；6. Compound 6 or 9 can be prepared by a conventional method in the art, or can be obtained by a commercially available route, and compound 6 or 9 can form the corresponding iodo compound 7 or 10 under N-iodosuccinimide conditions;
7、化合物10通过光延反应或者其它亲核取代反应甚至偶联反应得到化合物11；或者化合物7通过光延反应或者其它亲核取代反应甚至偶联反应得到化合物8，化合物8再于适当溶剂中与氨水封管加热或微波反应得到化合物11；7. Compound 10 obtains compound 11 by a light delay reaction or other nucleophilic substitution reaction or even a coupling reaction; or compound 7 obtains compound 8 by a photo-delay reaction or other nucleophilic substitution reaction or even a coupling reaction, and compound 8 is further mixed with ammonia water in a suitable solvent. Sealing tube heating or microwave reaction to obtain compound 11;
8、化合物12可通过市售途径获得，也可通过对应的卤代芳烃12a与联硼酸频哪醇酯偶联得到；8. Compound 12 can be obtained by a commercially available route, or can be obtained by coupling a corresponding halogenated aromatic hydrocarbon 12a with a boronic acid pinacol ester;
Figure PCTCN2017115380-appb-000026
Figure PCTCN2017115380-appb-000026
其中，A选自氯、溴及碘；Among them, A is selected from chlorine, bromine and iodine;
9、化合物11与化合物12偶联得到化合物(III)；9. Compound 11 is coupled with compound 12 to give compound (III);
10、化合物(II)和化合物(III)发生酰胺缩合得到化合物(I)，使用选自下组的合适的酰胺缩合试剂：1-羟基苯并***(HOBT)、N-羟基-7-偶氮苯并三氮唑(HOAT)、N,N’-二环己基碳二亚胺(DCC)、N-(3-二甲氨基丙基)-N’-乙基碳二亚胺或其盐酸盐(EDC或EDC·HCl)、碳酰二咪唑(CDI)、N,N’-二异丙基碳二亚胺(DIC)、O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸酯(TBTU)、O-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N’,N’-四甲基脲六氟磷酸酯(HBTU)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)和六氟磷酸苯并***-1-基-氧基三吡咯烷基(PyBOP)中的一种或几种，优选的缩合剂为O-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)等。10. Compound (II) and compound (III) are amide-condensed to give compound (I), using a suitable amide condensation reagent selected from the group consisting of 1-hydroxybenzotriazole (HOBT), N-hydroxy-7-couple Nitrobenzotriazole (HOAT), N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or a salt thereof Acid salt (EDC or EDC·HCl), carbonyl diimidazole (CDI), N,N'-diisopropylcarbodiimide (DIC), O-benzotriazole-N,N,N', N'-tetramethylurea tetrafluoroborate (TBTU), O-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate (HATU , benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate (HBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium One or more of hexafluorophosphate (BOP) and benzotriazol-1-yl-oxytripyrrolidinyl (PyBOP), the preferred condensing agent is O-(7-azobenzene) And triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and the like.
药物组合物及其制备方法Pharmaceutical composition and preparation method thereof
由于本发明化合物具有优异的对AXL激酶的抑制活性，因此本发明化合物及其各种晶型，及其药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与AXL活性或表达量相关的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：癌症；所述的癌症包括结肠癌、直肠癌、皮肤癌、胃癌、肺癌、子宫内膜癌、恶性黑色素瘤、甲状腺癌、神经胶质瘤、食管癌、***癌、卵巢癌及乳腺癌。Since the compound of the present invention has excellent inhibitory activity against AXL kinase, the compound of the present invention and various crystal forms thereof, and pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and the compound of the present invention are The pharmaceutical composition of the main active ingredient can be used to treat, prevent, and alleviate diseases associated with AXL activity or expression. According to the prior art, the compounds of the present invention are useful for the treatment of cancers including colon cancer, rectal cancer, skin cancer, gastric cancer, lung cancer, endometrial cancer, malignant melanoma, thyroid cancer, glioma , esophageal cancer, prostate cancer, ovarian cancer and breast cancer.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合中各组分能和本发明的化合物以及它们之间相互掺合，而不明显降低化合物的药效。药学上可接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2017115380-appb-000027
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、 抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the combination can be blended with the compounds of the invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier
Figure PCTCN2017115380-appb-000027
Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括但并不限于：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(1)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(2)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(3)保湿剂，例如，甘油；(4)崩解剂，例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸，某些复合硅酸盐和碳酸钠；(5)缓溶剂，例如石蜡；(6)吸收加速剂，例如，季胺化合物；(7)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(8)吸附剂，例如，高岭土；(9)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙醇、十二烷基硫酸钠或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (1) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (2) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (3) humectants, For example, glycerin; (4) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (5) slow solvents such as paraffin; (6) absorption acceleration Agents, for example, quaternary amine compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, for example, kaolin; (9) lubricants, for example, talc, calcium stearate , magnesium stearate, solid polyethanol, sodium lauryl sulfate or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂和香料。In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents and perfumes.
除了活性化合物外，悬浮液也可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may also contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, etc. .
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
本发明化合物可以单独给药，或者与其他治疗手段和/或其它治疗药物联用。The compounds of the invention may be administered alone or in combination with other therapeutic means and/or other therapeutic agents.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60公斤体重的人而言，日给药剂量通常为1-2000mg，优选为5-500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kilogram body weight person, The daily dose is usually from 1 to 2000 mg, preferably from 5 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
用途use
本发明还提供了本发明化合物在制备AXL激酶抑制剂或制备用于预防或治疗疾病的药物的用途。所述疾病选自下组：a)肿瘤相关疾病(例如，结肠癌、直肠癌、皮肤癌、胃癌、肺癌(如非小细胞肺癌(NSCLC))、子宫内膜癌、恶性黑色素瘤、甲状腺癌、神经胶质瘤、食管癌、***癌、卵巢癌及乳腺癌等)；b)蛋白酪氨酸激酶活性相关疾病(例如AXL相关疾病)。The invention also provides the use of a compound of the invention in the manufacture of an AXL kinase inhibitor or in the manufacture of a medicament for the prevention or treatment of a disease. The disease is selected from the group consisting of: a) tumor-related diseases (eg, colon cancer, rectal cancer, skin cancer, gastric cancer, lung cancer (eg, non-small cell lung cancer (NSCLC)), endometrial cancer, malignant melanoma, thyroid cancer) , glioma, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, etc.); b) Protein tyrosine kinase activity-related diseases (eg, AXL-related diseases).
抑制剂Inhibitor
本发明还提供了一种AXL激酶抑制剂，所述抑制剂包含抑制有效量的通式(I)化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物中的一种或多种。The invention also provides an AXL kinase inhibitor comprising an inhibitory effective amount of a compound of formula (I), or a stereoisomer, geometric isomer, tautomer thereof, or pharmaceutically acceptable thereof Accepted salt, or one or more of its prodrugs, hydrates or solvates.
治疗方法treatment method
本发明还提供了一种预防和/或治疗AXL相关疾病的方法，包括向所需患者施用抑制有效量的通式(I)化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物或本发明的药物组合物。The invention also provides a method of preventing and/or treating an AXL-related disease comprising administering to a patient in need thereof an inhibitory effective amount of a compound of formula (I) or a stereoisomer, geometric isomer, tautomer thereof Or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof or a pharmaceutical composition of the invention.
本发明还提供了一种预防和/或治疗癌症的方法，包括向所需患者施用抑制有效量的通式(I)化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物或本发明的药物组合物。The invention also provides a method of preventing and/or treating cancer comprising administering to a patient in need thereof an inhibitory effective amount of a compound of formula (I) or a stereoisomer, geometric isomer, tautomer thereof, Or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof or a pharmaceutical composition of the invention.
本发明还提供了一种预防和/或治疗GAS6/AXL信号通路异常表达相关疾病的方法，包括向所需患者施用抑制有效量的通式(I)化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物或本发明的药物组合物。The present invention also provides a method for preventing and/or treating a disease associated with abnormal expression of the GAS6/AXL signaling pathway, comprising administering to a patient in need thereof an inhibitory effective amount of a compound of the formula (I) or a stereoisomer thereof, geometric isomerism a form, a tautomer, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, or a pharmaceutical composition of the invention.
本发明上述提到的或如下实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可以任何组合形式并用，说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。The features mentioned above or mentioned in the following embodiments of the invention may be combined in any combination. All of the features disclosed in this specification can be used in any combination, and the various features disclosed in the specification can be replaced by any alternative feature that provides the same, equal or similar purpose.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人所著，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to the conditions described in conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or The conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those skilled in the art. In addition, any methods and materials similar or equivalent to those described may be employed in the methods of the invention. The preferred embodiments and materials described herein are for illustrative purposes only.
实施例1：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.1)Example 1: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.1)
Figure PCTCN2017115380-appb-000028
Figure PCTCN2017115380-appb-000028
步骤1：制备4-(4-氟苯基)-3-氧代丁酸乙酯Step 1: Preparation of ethyl 4-(4-fluorophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000029
Figure PCTCN2017115380-appb-000029
将2.1克丙二酸环(亚)异丙酯溶于30毫升干燥的二氯甲烷中，加入2.9毫升吡啶，0℃滴加2毫升4-氟苯乙酰氯，产生大量白烟，稍后回至室温搅拌4小时，加入二氯甲烷稀释，先用1N盐酸水溶液洗，再用饱和氯化钠水溶液洗，有机相用无水硫酸钠干燥，过滤浓缩后残余物溶于30毫升无水乙醇，回流4小时后浓缩反应液，残余物中压柱层析(乙酸乙酯：石油醚＝3:97)分离得无色液体2.8克为4-(4-氟苯基)-3-氧代丁酸乙酯，收率86％。 1H NMR(300MHz,DMSO)δ7.30–6.92(m,4H),4.08(q,J＝7.2Hz,2H),3.88(s,2H),3.66(s,2H),1.17(t,J＝7.2Hz,3H). 2.1 g of isopropyl (di) isopropyl ester was dissolved in 30 ml of dry dichloromethane, 2.9 ml of pyridine was added, and 2 ml of 4-fluorophenylacetyl chloride was added dropwise at 0 ° C to produce a large amount of white smoke, which was later returned. After stirring to room temperature for 4 hours, it was diluted with dichloromethane, washed with 1N aqueous hydrochloric acid, and then washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous sodium sulfate. After refluxing for 4 hours, the reaction mixture was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 3:97) to give 2.8 g of colorless liquid as 4-(4-fluorophenyl)-3-oxobutyl Ethyl acetate, yield 86%. 1 H NMR (300MHz, DMSO) δ7.30-6.92 (m, 4H), 4.08 (q, J = 7.2Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 1.17 (t, J =7.2Hz, 3H).
步骤2：制备5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 2: Preparation of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester
Figure PCTCN2017115380-appb-000030
Figure PCTCN2017115380-appb-000030
将1克4-(4-氟苯基)-3-氧代丁酸乙酯溶于10毫升干燥的甲苯，加入1.2毫升N,N-二甲基甲酰胺二甲基缩醛，100℃加热反应5小时，反应液浓缩，残余物溶于10毫升无水乙醇，加入566毫克4-氨甲基四氢吡喃，60℃加热反应9小时，反应液浓缩，残余物中压柱层析(甲醇：二氯甲烷＝1:99)分离得白色固体1.2克为5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率72％。 1H NMR(300MHz,DMSO)δ8.28(d,J＝1.8Hz,1H),7.97(d,J＝1.8Hz,1H),7.65(dd,J＝8.4,5.9Hz,2H),7.31–7.16(m,2H),4.20(q,J＝7.1Hz,2H),3.92(d,J＝7.2Hz,2H),3.85(dd,J＝11.1,2.7Hz,2H),3.31–3.20(m,2H),2.20–1.81(m,1H),1.36–1.17(m,5H). 1 g of ethyl 4-(4-fluorophenyl)-3-oxobutanoate was dissolved in 10 ml of dry toluene, and 1.2 ml of N,N-dimethylformamide dimethyl acetal was added and heated at 100 ° C. After reacting for 5 hours, the reaction liquid was concentrated, and the residue was dissolved in 10 ml of anhydrous ethanol, 566 mg of 4-aminomethyltetrahydropyran was added, and the reaction was heated at 60 ° C for 9 hours, and the reaction liquid was concentrated, and the residue was subjected to column chromatography. Methanol: dichloromethane = 1:99) 1.2 g of a white solid was obtained as 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl Ethyl 4-1,4-dihydropyridine-3-carboxylate in a yield of 72%. 1 H NMR (300 MHz, DMSO) δ 8.28 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.65 (dd, J = 8.4, 5.9 Hz, 2H), 7.31 - 7.16 (m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.92 (d, J = 7.2 Hz, 2H), 3.85 (dd, J = 11.1, 2.7 Hz, 2H), 3.31 - 3.20 (m) , 2H), 2.20–1.81 (m, 1H), 1.36–1.17 (m, 5H).
步骤3：制备5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 3: Preparation of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000031
Figure PCTCN2017115380-appb-000031
将1.2克5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯溶于16毫升甲醇，加入9.6毫升1N氢氧化钠水溶液，室温搅拌20分钟，浓缩反应液，残余物用1N盐酸水溶液调至酸性，析出固体，抽滤，滤饼水洗并刮出，干燥后得到白色固体933毫克为5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率88％。 1H NMR(300MHz,DMSO)δ8.77(s,1H),8.41(s,1H),7.74(dd,J＝8.4,5.8Hz,2H),7.47–7.15(m,2H),4.14(d,J＝7.0Hz,2H),3.85(dd,J＝11.4,2.7Hz,2H),3.25(t,J＝11.4Hz,2H),2.24–1.99(m,1H),1.52–1.23(m,4H). 1.2 g of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid The ester was dissolved in 16 ml of methanol, 9.6 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 20 minutes, and the reaction mixture was concentrated. The residue was acidified with 1N aqueous hydrochloric acid, and the solid was precipitated, filtered, filtered, washed, and dried. 933 mg of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 was obtained as a white solid. - Formic acid, yield 88%. 1 H NMR (300MHz, DMSO) δ8.77 (s, 1H), 8.41 (s, 1H), 7.74 (dd, J = 8.4,5.8Hz, 2H), 7.47-7.15 (m, 2H), 4.14 (d , J = 7.0 Hz, 2H), 3.85 (dd, J = 11.4, 2.7 Hz, 2H), 3.25 (t, J = 11.4 Hz, 2H), 2.24 - 1.99 (m, 1H), 1.52 - 1.23 (m, 4H).
步骤4：制备4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶Step 4: Preparation of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000032
Figure PCTCN2017115380-appb-000032
将3克4-氯-7H-吡咯并[2,3-d]嘧啶和4.8克N-碘代丁二酰亚胺溶于55毫升N,N-二甲基甲酰胺中，室温搅拌1小时后加入饱和硫代硫酸钠溶液，析出大量固体，抽滤，滤饼水洗并刮出，干燥后得灰白色固体5.5克为4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶，收率100％。 1H NMR(300MHz,DMSO)δ12.94(brs,1H),8.59(s,1H),7.94(s,1H). 3 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 4.8 g of N-iodosuccinimide were dissolved in 55 ml of N,N-dimethylformamide and stirred at room temperature for 1 hour. After adding saturated sodium thiosulfate solution, a large amount of solid was precipitated, suction filtration, and the filter cake was washed with water and scraped off. After drying, 5.5 g of an off-white solid was obtained as 4-chloro-5-iodo-7H-pyrrolo[2,3-d] Pyrimidine, yield 100%. 1 H NMR (300MHz, DMSO) δ12.94 (brs, 1H), 8.59 (s, 1H), 7.94 (s, 1H).
步骤5：制备4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 5: Preparation of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000033
Figure PCTCN2017115380-appb-000033
将1.5克4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶溶于25毫升干燥的N,N-二甲基甲酰胺，冰浴下分批加入430毫克氢化钠(60％，分散在矿物油中)，并于室温搅拌30分钟，再滴入402微升的碘甲烷，室温搅拌1小时后向体系中加水，析出白色固体，抽滤，滤饼水洗并刮出，干燥后得白色固体1.5克为4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率96％。 1H NMR(300MHz,DMSO)δ8.65(s,1H),7.98(s,1H),3.83(s,3H). 1.5 g of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 25 ml of dry N,N-dimethylformamide, and 430 mg of sodium hydride was added portionwise in an ice bath. 60%, dispersed in mineral oil), and stirred at room temperature for 30 minutes, then add 402 μl of methyl iodide, stirred at room temperature for 1 hour, add water to the system, precipitate a white solid, suction filtration, filter cake washed and scraped After drying, 1.5 g of a white solid was obtained as 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 96%. 1 H NMR (300 MHz, DMSO) δ 8.65 (s, 1H), 7.98 (s, 1H), 3.83 (s, 3H).
步骤6：制备4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 6: Preparation of 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000034
Figure PCTCN2017115380-appb-000034
氩气氛围下，将728毫克4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶、544毫克4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺、526毫克碳酸钠及86毫克四(三苯基膦)钯混溶于80毫升1,4-二氧六环和20毫升水中(1,4-二氧六环与水的体积比为 4:1)，90℃加热反应12小时，旋干大部分溶剂，二氯甲烷萃取，有机相用无水硫酸钠干燥后浓缩，残余物中压柱层析(乙酸乙酯：石油醚＝1:9至2:3)分离得灰白色固体570毫克为4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率89％。 1H NMR(300MHz,DMSO)δ8.61(s,1H),7.62(s,1H),7.15(d,J＝8.1Hz,2H),6.61(d,J＝8.1Hz,2H),5.15(s,2H),3.85(s,3H). Under argon, 728 mg of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, 544 mg of 4-(4,4,5,5-tetramethyl) -1,3,2-dioxaborolan-2-yl)aniline, 526 mg of sodium carbonate and 86 mg of tetrakis(triphenylphosphine)palladium are miscible in 80 ml of 1,4-dioxane And 20 ml of water (volume ratio of 1,4-dioxane to water: 4:1), heating at 90 ° C for 12 hours, spinning off most of the solvent, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate After concentration, the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:9 to 2:3) to yield 570 mg of white solid as 4-(4-chloro-7-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)aniline, yield 89%. 1 H NMR (300MHz, DMSO) δ8.61 (s, 1H), 7.62 (s, 1H), 7.15 (d, J = 8.1Hz, 2H), 6.61 (d, J = 8.1Hz, 2H), 5.15 ( s, 2H), 3.85 (s, 3H).
步骤7：制备4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 7: Preparation of 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000035
Figure PCTCN2017115380-appb-000035
将500毫克4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺溶于2毫升1,4-二氧六环和2毫升氨水的混合溶液中，封管100℃加热反应48小时，冷却后浓缩反应液，加水，用二氯甲烷萃取，有机相用无水硫酸钠干燥后浓缩，残余物中压柱层析(含有5％氨水的甲醇：二氯甲烷＝3:97至1:19)分离得灰白色固体370毫克为4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率80％。 1H NMR(300MHz,DMSO)δ8.11(s,1H),7.31–6.93(m,3H),6.65(d,J＝7.8Hz,2H),6.00(s,2H),5.21(s,2H),3.70(s,3H). 500 mg of 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline was dissolved in 2 ml of 1,4-dioxane and 2 ml of aqueous ammonia. In the mixed solution, the reaction tube was heated at 100 ° C for 48 hours. After cooling, the reaction mixture was concentrated, water was added, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was subjected to column chromatography (with 5% aqueous ammonia) Methanol: dichloromethane = 3:97 to 1:19) 370 mg of the off-white solid as 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrole[2,3- d] Pyrimidine, yield 80%. 1 H NMR (300MHz, DMSO) δ8.11 (s, 1H), 7.31-6.93 (m, 3H), 6.65 (d, J = 7.8Hz, 2H), 6.00 (s, 2H), 5.21 (s, 2H ), 3.70 (s, 3H).
步骤8：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 8: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将30毫克4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶、42毫克5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸及58毫克O-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(HATU)溶于1.5毫升N,N-二甲基甲酰胺中，加入62微升N,N-二异丙基乙胺(DIPEA)，室温搅拌2小时，体系中加水，乙酸乙酯萃取，再用饱和氯化钠水溶液洗涤有机相，无水硫酸钠干燥有机相后浓缩，残余物柱层析(甲醇：二氯甲烷＝1:10)分离得白色固体35毫克为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率51％。 1H NMR(300MHz,DMSO)δ13.01(s,1H),8.72(d,J＝1.7Hz,1H),8.22(d,J＝1.7Hz,1H),8.16(s,1H),7.81(d,J＝8.4Hz,2H),7.74(dd,J＝8.4,5.9Hz,2H),7.44(d,J＝8.4Hz,2H),7.38–7.20(m,3H),6.10(s,2H),4.11(d,J＝6.8Hz,2H),3.86(dd,J＝11.1,2.8Hz,2H),3.74(s,3H),3.35–3.17(m,2H),2.20–2.02(m,1H),1.76–0.93(m,4H). 30 mg of 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, 42 mg of 5-(4-fluorophenyl)-4-oxo Generation-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid and 58 mg O-(7-azobenzotriazole)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) was dissolved in 1.5 ml of N,N-dimethylformamide, and 62 μl of N,N-diisopropylethylamine was added. (DIPEA), stirring at room temperature for 2 hours, adding water to the system, extracting with ethyl acetate, and then washing the organic phase with saturated aqueous sodium chloride. =1:10) 35 mg of a white solid isolated as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 51% . 1 H NMR (300MHz, DMSO) δ13.01 (s, 1H), 8.72 (d, J = 1.7Hz, 1H), 8.22 (d, J = 1.7Hz, 1H), 8.16 (s, 1H), 7.81 ( d, J = 8.4 Hz, 2H), 7.74 (dd, J = 8.4, 5.9 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.38 - 7.20 (m, 3H), 6.10 (s, 2H) ), 4.11 (d, J = 6.8 Hz, 2H), 3.86 (dd, J = 11.1, 2.8 Hz, 2H), 3.74 (s, 3H), 3.35 - 3.17 (m, 2H), 2.20 - 2.02 (m, 1H), 1.76–0.93 (m, 4H).
实施例2：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺(NO.2)Example 2: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide (NO.2)
Figure PCTCN2017115380-appb-000036
Figure PCTCN2017115380-appb-000036
步骤1：制备对甲基苯乙酰氯Step 1: Preparation of p-methylphenylacetyl chloride
Figure PCTCN2017115380-appb-000037
Figure PCTCN2017115380-appb-000037
氩气氛围下，将1.2克对甲基苯乙酸溶于25毫升干燥的二氯甲烷中，加入812微升草酰氯，再于冰浴下缓缓滴入62微升干燥的N,N-二甲基甲酰胺，滴入的同时产生大量气泡，室温搅拌6小时，减压蒸馏除去溶剂，得黄色液体1.4克为对甲基苯乙酰氯，直接用于下一步。Under an argon atmosphere, 1.2 g of p-toluic acid was dissolved in 25 ml of dry dichloromethane, 812 μl of oxalyl chloride was added, and then 72 μl of dry N, N-di was slowly added dropwise in an ice bath. Methylformamide, while dropping a large amount of bubbles, was stirred at room temperature for 6 hours, and the solvent was distilled off under reduced pressure to give a pale yellow liquid (1.
步骤2：制备3-氧代-4-(对甲苯基)丁酸乙酯Step 2: Preparation of ethyl 3-oxo-4-(p-tolyl)butanoate
Figure PCTCN2017115380-appb-000038
Figure PCTCN2017115380-appb-000038
将4-氟苯乙酰氯替换成对甲基苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为3-氧代-4-(对甲苯基)丁酸乙酯，步骤1和2总收率60％。 1H NMR(300MHz,DMSO)δ7.13(d,J＝7.8Hz,2H),7.06(d,J＝7.8Hz,2H),4.07(q,J＝7.1Hz,2H),3.80(s,2H),3.62(s,2H),2.28(s,3H),1.17(t,J＝7.1Hz,3H). Replace 4-fluorophenylacetyl chloride with p-methylphenylacetyl chloride. The remaining materials, reagents and preparation methods are the same as those in Step 1 of Example 1. The colorless liquid is 3-oxo-4-(p-tolyl). Ethyl acetate, total yield of steps 1 and 2 was 60%. 1 H NMR (300MHz, DMSO) δ7.13 (d, J = 7.8Hz, 2H), 7.06 (d, J = 7.8Hz, 2H), 4.07 (q, J = 7.1Hz, 2H), 3.80 (s, 2H), 3.62 (s, 2H), 2.28 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H).
步骤3：制备4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of ethyl 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000039
Figure PCTCN2017115380-appb-000039
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成3-氧代-4-(对甲苯基)丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸乙酯，收率52％。 1H NMR(300MHz,DMSO)δ8.26(d,J＝1.8Hz,1H),7.90(d,J＝1.8Hz,1H),7.50(d,J＝7.8Hz,2H),7.19(d,J＝7.8Hz,2H),4.20(q,J＝7.5Hz,2H),3.91(d,J＝6.9Hz,2H),3.85(dd,J＝11.2,2.7Hz,2H),3.31–3.21(m,2H),2.32(s,3H),2.13–1.92(m,1H),1.50–1.06(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 3-oxo-4-(p-tolyl)butanoate, the remaining raw materials, reagents and preparation methods are the same as the examples. 1 step 2, the white solid is 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxylic acid Ethyl ester, yield 52%. 1 H NMR (300MHz, DMSO) δ8.26 (d, J = 1.8Hz, 1H), 7.90 (d, J = 1.8Hz, 1H), 7.50 (d, J = 7.8Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 4.20 (q, J = 7.5 Hz, 2H), 3.91 (d, J = 6.9 Hz, 2H), 3.85 (dd, J = 11.2, 2.7 Hz, 2H), 3.31 - 3.21 ( m, 2H), 2.32 (s, 3H), 2.13–1.92 (m, 1H), 1.50–1.06 (m, 7H).
步骤4：制备4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000040
Figure PCTCN2017115380-appb-000040
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸，收率79％。 1H NMR(300MHz,DMSO)δ8.75(d,J＝1.5Hz,1H),8.36(d,J＝1.5Hz,1H),7.59(d,J＝7.8Hz,2H),7.27(d,J＝7.8Hz,2H),4.14(d,J＝6.8Hz,2H),3.85(dd,J＝11.4,2.5Hz,2H),3.25(t,J＝11.4Hz,2H),2.35(s,3H),2.25–1.90(m,1H),1.61–1.12(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate To 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxylic acid ethyl ester, the remaining raw materials The reagent and the preparation method are the same as those in the third step of the first embodiment, and the white solid is 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4. - Dihydropyridine-3-carboxylic acid in a yield of 79%. 1 H NMR (300MHz, DMSO) δ8.75 (d, J = 1.5Hz, 1H), 8.36 (d, J = 1.5Hz, 1H), 7.59 (d, J = 7.8Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 4.14 (d, J = 6.8 Hz, 2H), 3.85 (dd, J = 11.4, 2.5 Hz, 2H), 3.25 (t, J = 11.4 Hz, 2H), 2.35 (s, 3H), 2.25–1.90 (m, 1H), 1.61–1.12 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺，收率88％。 1H NMR(300MHz,DMSO)δ13.07(s,1H),8.69(d,J＝1.1Hz,1H),8.15(brs,2H),7.80(d,J＝8.2Hz,2H),7.58(d,J＝7.8Hz,2H),7.44(d,J＝8.2Hz,2H),7.35–7.14(m,3H),6.09(s,2H),4.11(d,J＝6.8Hz,2H),3.86(dd,J＝11.2,2.4Hz,2H),3.74(s,3H),3.34–3.15(m,2H),2.36(s,3H),2.23–2.01(m,1H),1.54–1.21(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 4 -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation The same procedure as in Example 8 Step 8 gave a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4- Oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide, yield 88%. 1 H NMR (300 MHz, DMSO) δ 13.07 (s, 1H), 8.69 (d, J = 1.1 Hz, 1H), 8.15 (brs, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.58 ( d, J = 7.8 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 - 7.14 (m, 3H), 6.09 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 3.86 (dd, J = 11.2, 2.4 Hz, 2H), 3.74 (s, 3H), 3.34 - 3.15 (m, 2H), 2.36 (s, 3H), 2.23 - 2.01 (m, 1H), 1.54 - 1.21 ( m, 4H).
实施例3：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.3)Example 3: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-5-phenyl- 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.3)
Figure PCTCN2017115380-appb-000041
Figure PCTCN2017115380-appb-000041
步骤1：制备3-氧代-4-苯基丁酸乙酯Step 1: Preparation of ethyl 3-oxo-4-phenylbutanoate
Figure PCTCN2017115380-appb-000042
Figure PCTCN2017115380-appb-000042
将4-氟苯乙酰氯替换成苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为3-氧代-4-苯基丁酸乙酯，收率69％。 1H NMR(300MHz,DMSO)δ 7.47–7.22(m,3H),7.19(d,J＝7.7Hz,2H),4.09(q,J＝6.9Hz,2H),3.88(s,2H),3.66(s,2H),1.18(t,J＝6.9Hz,3H). Replace 4-fluorophenylacetyl chloride with phenylacetyl chloride, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a colorless liquid of ethyl 3-oxo-4-phenylbutyrate. 69%. 1 H NMR (300MHz, DMSO) δ 7.47-7.22 (m, 3H), 7.19 (d, J = 7.7Hz, 2H), 4.09 (q, J = 6.9Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 1.18 (t, J = 6.9 Hz, 3H).
步骤2：制备4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 2: Preparation of ethyl 4-oxo-5-phenyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000043
Figure PCTCN2017115380-appb-000043
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成3-氧代-4-苯基丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率76％。 1H NMR(300MHz,DMSO)δ8.27(d,J＝1.0Hz,1H),7.94(d,J＝1.0Hz,1H),7.59(d,J＝7.2Hz,2H),7.49–7.29(m,3H),4.20(q,J＝7.1Hz,2H),3.92(d,J＝7.0Hz,2H),3.85(dd,J＝11.1,1.2Hz,2H),3.26(t,J＝11.3Hz,2H),2.16–1.85(m,1H),1.50–1.36(m,2H),1.34–1.19(m,5H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 3-oxo-4-phenylbutanoate, and the remaining raw materials, reagents and preparation methods are the same as those in Example 1 The white solid was obtained as ethyl 4-oxo-5-phenyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate. The rate is 76%. 1 H NMR (300MHz, DMSO) δ8.27 (d, J = 1.0Hz, 1H), 7.94 (d, J = 1.0Hz, 1H), 7.59 (d, J = 7.2Hz, 2H), 7.49-7.29 ( m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 3.92 (d, J = 7.0 Hz, 2H), 3.85 (dd, J = 11.1, 1.2 Hz, 2H), 3.26 (t, J = 11.3) Hz, 2H), 2.16–1.85 (m, 1H), 1.50–1.36 (m, 2H), 1.34–1.19 (m, 5H).
步骤3：制备4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 3: Preparation of 4-oxo-5-phenyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000044
Figure PCTCN2017115380-appb-000044
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率88％。 1H NMR(300MHz,DMSO)δ8.77(d,J＝0.9Hz,1H),8.39(d,J＝0.9Hz,1H),7.68(d,J＝7.3Hz,2H),7.57–7.32(m,3H),4.15(d,J＝7.3Hz,2H),3.85(dd,J＝11.1,2.7Hz,2H),3.25(t,J＝11.1Hz,2H),2.25–1.98(m,1H),1.52–1.17(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate To 4-oxo-5-phenyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester, the remaining raw materials, The reagent and the preparation method were the same as those in the third step of Example 1, and the white solid was 4-oxo-5-phenyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Hydropyridine-3-carboxylic acid in a yield of 88%. 1 H NMR (300 MHz, DMSO) δ 8.77 (d, J = 0.9 Hz, 1H), 8.39 (d, J = 0.9 Hz, 1H), 7.68 (d, J = 7.3 Hz, 2H), 7.57 - 7.32 ( m, 3H), 4.15 (d, J = 7.3 Hz, 2H), 3.85 (dd, J = 11.1, 2.7 Hz, 2H), 3.25 (t, J = 11.1 Hz, 2H), 2.25 - 1.98 (m, 1H) ), 1.52–1.17 (m, 4H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-5-phenyl- 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-5-苯基-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率45％。 1H NMR(300MHz,DMSO)δ13.05(s,1H),8.72(s,1H),8.20(s,1H),8.15(s,1H),7.80(d,J＝8.4Hz,2H),7.67(d,J＝7.4Hz,2H),7.54–7.34(m,5H),7.30(s,1H),6.11(s,2H),4.11(d,J＝6.5Hz,2H),3.99–3.80(m,2H),3.70(s,3H),3.34–3.08(m,2H),2.23–1.96(m,1H),1.51–1.08(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 4 -oxo-5-phenyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, other required starting materials, reagents and preparation method In the same manner as in Step 8 of Example 1, a white solid was obtained as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo Generation of 5-phenyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide in 45% yield. 1 H NMR (300MHz, DMSO) δ13.05 (s, 1H), 8.72 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.67 (d, J = 7.4 Hz, 2H), 7.54 - 7.34 (m, 5H), 7.30 (s, 1H), 6.11 (s, 2H), 4.11 (d, J = 6.5 Hz, 2H), 3.99 - 3.80 (m, 2H), 3.70 (s, 3H), 3.34–3.08 (m, 2H), 2.23–1.96 (m, 1H), 1.51–1.08 (m, 4H).
实施例4：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.4)Example 4: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-chlorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.4)
Figure PCTCN2017115380-appb-000045
Figure PCTCN2017115380-appb-000045
步骤1：制备对氯苯乙酰氯Step 1: Preparation of p-chlorophenylacetyl chloride
Figure PCTCN2017115380-appb-000046
Figure PCTCN2017115380-appb-000046
将对甲基苯乙酸替换成对氯苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为对氯苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid was replaced with p-chlorophenylacetic acid, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 2, and the yellow liquid was obtained as p-chlorophenylacetyl chloride, which was directly used in the next step.
步骤2：制备4-(4-氯苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(4-chlorophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000047
Figure PCTCN2017115380-appb-000047
将4-氟苯乙酰氯替换成对氯苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为4-(4-氯苯基)-3-氧代丁酸乙酯，步骤1和2总收率60％。 1H NMR(300MHz,)δ7.37(d,J＝8.3Hz,2H),7.20(d,J＝8.3Hz,2H),4.08(q,J＝7.1Hz,2H),3.89(s,2H),3.67(s,2H),1.17(t,J＝7.1Hz,3H). Replace 4-fluorophenylacetyl chloride with p-chlorophenylacetyl chloride. The remaining raw materials, reagents and preparation methods are the same as those in step 1 of Example 1. The colorless liquid is 4-(4-chlorophenyl)-3-oxo. Ethyl butyrate, total yield of steps 1 and 2 was 60%. 1 H NMR (300 MHz,) δ 7.37 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.89 (s, 2H) ), 3.67 (s, 2H), 1.17 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(4-chlorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester
Figure PCTCN2017115380-appb-000048
Figure PCTCN2017115380-appb-000048
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(4-氯苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率74％。 1H NMR(300MHz,DMSO)δ8.29(d,J＝2.0Hz,1H),8.01(d,J＝2.0Hz,1H),7.66(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),4.20(q,J＝6.8Hz,2H),3.92(d,J＝7.2Hz,2H),3.90–3.79(m,2H),3.26(t,J＝11.2Hz,2H),2.14–1.95(m,1H),1.61–1.06(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 4-(4-chlorophenyl)-3-oxobutanoate, the remaining raw materials, reagents and preparation methods are the same Step 2 of Example 1 gave a white solid as 5-(4-chlorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Ethyl hydropyridine-3-carboxylate in a yield of 74%. 1 H NMR (300MHz, DMSO) δ8.29 (d, J = 2.0Hz, 1H), 8.01 (d, J = 2.0Hz, 1H), 7.66 (d, J = 8.5Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 4.20 (q, J = 6.8 Hz, 2H), 3.92 (d, J = 7.2 Hz, 2H), 3.90 - 3.79 (m, 2H), 3.26 (t, J = 11.2 Hz, 2H), 2.14–1.95 (m, 1H), 1.61–1.06 (m, 7H).
步骤4：制备5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(4-chlorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000049
Figure PCTCN2017115380-appb-000049
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率45％。 1H NMR(300MHz,DMSO)δ8.77(s,1H),8.44(s,1H),7.73(d,J＝8.1Hz,2H),7.54(d,J＝8.1Hz,2H),4.14(d,J＝7.0Hz,2H),4.08–3.66(m,2H),3.24(t,J＝11.4Hz,2H),2.22–2.02(m,1H),1.81–0.83(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-chlorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate, The remaining starting materials, reagents and preparation methods are the same as in the third step of Example 1, to obtain a white solid as 5-(4-chlorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl). )methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 45%. 1 H NMR (300MHz, DMSO) δ8.77 (s, 1H), 8.44 (s, 1H), 7.73 (d, J = 8.1Hz, 2H), 7.54 (d, J = 8.1Hz, 2H), 4.14 ( d, J = 7.0 Hz, 2H), 4.08 - 3.66 (m, 2H), 3.24 (t, J = 11.4 Hz, 2H), 2.22 - 2.02 (m, 1H), 1.81 - 0.83 (m, 4H).
步骤5：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-chlorophenyl)-4 -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氯苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率91％。 1H NMR(300MHz,DMSO)δ12.98(s,1H),8.72(d,J＝1.8Hz,1H),8.25(d,J＝1.8Hz,1H),8.16(s,1H),7.80(d,J＝8.4Hz,2H),7.73(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.44(d,J＝8.4Hz,2H),7.30(s,1H),6.12(s,2H),4.11(d,J＝6.8Hz,2H),3.91–3.81(m,2H),3.74(s,3H),3.35–3.18(m,2H),2.23–2.02(m,1H),1.57–1.24(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-chlorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the remaining raw materials The reagent and the preparation method are the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl. -5-(4-Chlorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, The yield was 91%. 1 H NMR (300MHz, DMSO) δ12.98 (s, 1H), 8.72 (d, J = 1.8Hz, 1H), 8.25 (d, J = 1.8Hz, 1H), 8.16 (s, 1H), 7.80 ( d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 6.12 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 3.91 - 3.81 (m, 2H), 3.74 (s, 3H), 3.35 - 3.18 (m, 2H), 2.23 - 2.02 (m, 1H), 1.57–1.24 (m, 4H).
实施例5：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.5)Example 5: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-bromophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.5)
Figure PCTCN2017115380-appb-000050
Figure PCTCN2017115380-appb-000050
步骤1：制备对溴苯乙酰氯Step 1: Preparation of p-bromophenylacetyl chloride
Figure PCTCN2017115380-appb-000051
Figure PCTCN2017115380-appb-000051
将对甲基苯乙酸替换成对溴苯乙酸，其余所需原料、试剂及制备方法同实施例2 步骤1，得黄色液体为对溴苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid was replaced with p-bromophenylacetic acid, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 2, and the yellow liquid was obtained as p-bromophenylacetyl chloride, which was directly used in the next step.
步骤2：制备4-(4-溴苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(4-bromophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000052
Figure PCTCN2017115380-appb-000052
将4-氟苯乙酰氯替换成对溴苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为4-(4-溴苯基)-3-氧代丁酸乙酯，步骤1和2总收率为47％。 1H NMR(300MHz,DMSO)δ7.51(d,J＝8.2Hz,2H),7.14(d,J＝8.2Hz,2H),4.08(q,J＝7.1Hz,2H),3.88(s,2H),3.66(s,2H),1.18(t,J＝7.1Hz,3H). Replace 4-fluorophenylacetyl chloride with p-bromophenylacetyl chloride. The remaining raw materials, reagents and preparation methods are the same as those in step 1 of Example 1. The colorless liquid is 4-(4-bromophenyl)-3-oxo. Ethyl butyrate, the total yield of steps 1 and 2 was 47%. 1 H NMR (300MHz, DMSO) δ7.51 (d, J = 8.2Hz, 2H), 7.14 (d, J = 8.2Hz, 2H), 4.08 (q, J = 7.1Hz, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 1.18 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(4-bromophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester
Figure PCTCN2017115380-appb-000053
Figure PCTCN2017115380-appb-000053
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(4-溴苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率69％。 1H NMR(300MHz,DMSO)δ8.29(d,J＝1.8Hz,1H),8.01(d,J＝1.8Hz,1H),7.59(s,4H),4.20(q,J＝6.9Hz,2H),3.92(d,J＝7.2Hz,2H),3.88–3.82(m,2H),3.25(t,J＝11.4Hz,2H),2.17–1.90(m,1H),1.52–1.04(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 4-(4-bromophenyl)-3-oxobutanoate, the remaining raw materials, reagents and preparation methods are the same Step 2 of Example 1 gave a white solid as 5-(4-bromophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Ethyl hydropyridine-3-carboxylate in a yield of 69%. 1 H NMR (300MHz, DMSO) δ8.29 (d, J = 1.8Hz, 1H), 8.01 (d, J = 1.8Hz, 1H), 7.59 (s, 4H), 4.20 (q, J = 6.9Hz, 2H), 3.92 (d, J = 7.2 Hz, 2H), 3.88 - 3.82 (m, 2H), 3.25 (t, J = 11.4 Hz, 2H), 2.17 - 1.90 (m, 1H), 1.52 - 1.04 (m , 7H).
步骤4：制备5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(4-bromophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000054
Figure PCTCN2017115380-appb-000054
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率69％。 1H NMR(300MHz,DMSO)δ8.78(s,1H),8.44(s,1H),7.67(s,4H),4.14(d,J＝6.5Hz,2H),3.88–3.81(m,2H),3.24(t,J＝11.4Hz,2H),2.32–1.87(m,1H),1.53–0.94(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-bromophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate, The remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, and the white solid is 5-(4-bromophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl). )methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 69%. 1 H NMR (300MHz, DMSO) δ8.78 (s, 1H), 8.44 (s, 1H), 7.67 (s, 4H), 4.14 (d, J = 6.5Hz, 2H), 3.88-3.81 (m, 2H ), 3.24 (t, J = 11.4 Hz, 2H), 2.32 - 1.87 (m, 1H), 1.53 - 0.94 (m, 4H).
步骤5：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-bromophenyl)-4 -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原 料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-溴苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率75％。 1H NMR(300MHz,DMSO)δ12.97(s,1H),8.72(s,1H),8.25(s,1H),8.16(s,1H),7.80(d,J＝8.4Hz,2H),7.74–7.59(m,4H),7.44(d,J＝8.4Hz,2H),7.30(s,1H),6.13(s,2H),4.11(d,J＝7.3Hz,2H),3.89–3.83(m,2H),3.74(s,3H),3.38–3.19(m,2H),2.25–2.03(m,1H),1.53–1.22(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-bromophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the remaining raw materials The reagent and the preparation method are the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl. -5-(4-bromophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, The yield was 75%. 1 H NMR (300MHz, DMSO) δ12.97 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.74–7.59 (m, 4H), 7.44 (d, J=8.4 Hz, 2H), 7.30 (s, 1H), 6.13 (s, 2H), 4.11 (d, J = 7.3 Hz, 2H), 3.89–3.83 (m, 2H), 3.74 (s, 3H), 3.38 - 3.19 (m, 2H), 2.25 - 2.03 (m, 1H), 1.53 - 1.22 (m, 4H).
实施例6：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酰胺(NO.6)Example 6: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1,4-dihydropyridine-3-carboxamide (NO.6)
Figure PCTCN2017115380-appb-000055
Figure PCTCN2017115380-appb-000055
步骤1：制备4-三氟甲氧基苯乙酰氯Step 1: Preparation of 4-trifluoromethoxyphenylacetyl chloride
Figure PCTCN2017115380-appb-000056
Figure PCTCN2017115380-appb-000056
将对甲基苯乙酸替换成4-三氟甲氧基苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为4-三氟甲氧基苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid is replaced by 4-trifluoromethoxyphenylacetic acid, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 2, and the yellow liquid is 4-trifluoromethoxyphenylacetyl chloride, directly Used in the next step.
步骤2：制备3-氧代-4-(4-三氟甲氧基苯基)丁酸乙酯Step 2: Preparation of ethyl 3-oxo-4-(4-trifluoromethoxyphenyl)butanoate
Figure PCTCN2017115380-appb-000057
Figure PCTCN2017115380-appb-000057
将4-氟苯乙酰氯替换成4-三氟甲氧基苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为3-氧代-4-(4-三氟甲氧基苯基)丁酸乙酯，步骤1和2总收率39％。 1H NMR(300MHz,DMSO)δ7.31(s,4H),4.08(q,J＝7.1Hz,2H),3.94(s,2H),3.69(s,2H),1.18(t,J＝7.1Hz,3H). 4-Fluorophenylacetyl chloride is replaced by 4-trifluoromethoxyphenylacetyl chloride, and the remaining raw materials, reagents and preparation methods are the same as in Step 1 of Example 1, and the colorless liquid is 3-oxo-4-(4). Ethyl trifluoromethoxyphenyl)butyrate, total yield of steps 1 and 2 was 39%. 1 H NMR (300 MHz, DMSO) δ 7.31 (s, 4H), 4.08 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 3.69 (s, 2H), 1.18 (t, J = 7.1 Hz, 3H).
步骤3：制备4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1,4-dihydropyridine Ethyl 3-carboxylate
Figure PCTCN2017115380-appb-000058
Figure PCTCN2017115380-appb-000058
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成3-氧代-4-(4-三氟甲氧基苯基)丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为4-氧代-1-((四氢-2H-吡 喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酸乙酯，收率68％。 1H NMR(300MHz,DMSO)δ8.30(d,J＝1.3Hz,1H),8.03(d,J＝1.3Hz,1H),7.74(d,J＝8.6Hz,2H),7.39(d,J＝8.6Hz,2H),4.21(q,J＝7.1Hz,2H),3.92(d,J＝7.2Hz,2H),3.90–3.78(m,2H),3.25(t,J＝11.5Hz,2H),2.14–1.97(m,1H),1.52–1.14(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 3-oxo-4-(4-trifluoromethoxyphenyl)butanoate, the remaining raw materials, reagents And the preparation method is the same as the second step of Example 1, to obtain a white solid as 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxybenzene Ethyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester, yield 68%. 1 H NMR (300MHz, DMSO) δ8.30 (d, J = 1.3Hz, 1H), 8.03 (d, J = 1.3Hz, 1H), 7.74 (d, J = 8.6Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.92 (d, J = 7.2 Hz, 2H), 3.90 - 3.78 (m, 2H), 3.25 (t, J = 11.5 Hz, 2H), 2.14–1.97 (m, 1H), 1.52–1.14 (m, 7H).
步骤4：制备4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1,4-dihydropyridine 3-carboxylic acid
Figure PCTCN2017115380-appb-000059
Figure PCTCN2017115380-appb-000059
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酸，收率77％。 1H NMR(300MHz,DMSO)δ8.79(s,1H),8.46(s,1H),7.82(d,J＝8.1Hz,2H),7.47(d,J＝8.1Hz,2H),4.14(d,J＝7.1Hz,2H),3.90–3.78(m,2H),3.24(t,J＝11.5Hz,2H),2.20–1.93(m,1H),1.58–1.01(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1,4-dihydropyridine-3- Ethyl formate, the remaining starting materials, reagents and preparation methods are the same as in the third step of Example 1, to obtain 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5 as a white solid. -(4-Trifluoromethoxyphenyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 77%. 1 H NMR (300MHz, DMSO) δ8.79 (s, 1H), 8.46 (s, 1H), 7.82 (d, J = 8.1Hz, 2H), 7.47 (d, J = 8.1Hz, 2H), 4.14 ( d, J = 7.1 Hz, 2H), 3.90 - 3.78 (m, 2H), 3.24 (t, J = 11.5 Hz, 2H), 2.20 - 1.93 (m, 1H), 1.58 - 1.01 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲氧基苯基)-1,4-二氢吡啶-3-甲酰胺，收率78％。 1H NMR(300MHz,DMSO)δ12.97(s,1H),8.74(d,J＝1.5Hz,1H),8.28(d,J＝1.5Hz,1H),8.16(s,1H),8.01–7.69(m,4H),7.56–7.39(m,4H),7.30(s,1H),6.12(s,2H),4.11(d,J＝7.2Hz,2H),3.90–3.83(m,2H),3.74(s,3H),3.34–3.04(m,2H),2.26–2.07(m,1H),1.52–1.24(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 4 -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1,4-dihydropyridine-3-carboxylic acid, The remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5- Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1,4-di Hydropyridine-3-carboxamide, yield 78%. 1 H NMR (300MHz, DMSO) δ12.97 (s, 1H), 8.74 (d, J = 1.5Hz, 1H), 8.28 (d, J = 1.5Hz, 1H), 8.16 (s, 1H), 8.01- 7.69 (m, 4H), 7.56–7.39 (m, 4H), 7.30 (s, 1H), 6.12 (s, 2H), 4.11 (d, J = 7.2 Hz, 2H), 3.90–3.83 (m, 2H) , 3.74 (s, 3H), 3.34–3.04 (m, 2H), 2.26–2.07 (m, 1H), 1.52–1.24 (m, 4H).
实施例7：N-(4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.7)Example 7: N-(4-(4-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.7)
Figure PCTCN2017115380-appb-000060
Figure PCTCN2017115380-appb-000060
步骤1：制备3-碘-4-氨基-1H-吡唑并[3,4-d]嘧啶Step 1: Preparation of 3-iodo-4-amino-1H-pyrazolo[3,4-d]pyrimidine
Figure PCTCN2017115380-appb-000061
Figure PCTCN2017115380-appb-000061
将2克4-氨基-1H-吡唑并[3,4-d]嘧啶和3.7克N-碘代丁二酰亚胺溶于25毫升N,N-二甲基甲酰胺，80℃加热反应6小时，加入饱和硫代硫酸钠溶液，析出大量固体，抽滤，滤饼水洗并刮出，干燥后得灰白色固体2.8克为3-碘-4-氨基-1H-吡唑并[3,4-d]嘧啶，收率72％。 1H NMR(300MHz,DMSO)δ13.79(s,1H),8.16(s,1H),7.00(s,2H). 2 g of 4-amino-1H-pyrazolo[3,4-d]pyrimidine and 3.7 g of N-iodosuccinimide were dissolved in 25 ml of N,N-dimethylformamide and heated at 80 ° C. After 6 hours, a saturated sodium thiosulfate solution was added to precipitate a large amount of solid, which was suction filtered, and the filter cake was washed with water and scraped. After drying, 2.8 g of an off-white solid was 3-iodo-4-amino-1H-pyrazole [3,4 -d] Pyrimidine in a yield of 72%. 1 H NMR (300MHz, DMSO) δ13.79 (s, 1H), 8.16 (s, 1H), 7.00 (s, 2H).
步骤2：制备1-甲基-3-碘-4-氨基-1H-吡唑并[3,4-d]嘧啶Step 2: Preparation of 1-methyl-3-iodo-4-amino-1H-pyrazolo[3,4-d]pyrimidine
Figure PCTCN2017115380-appb-000062
Figure PCTCN2017115380-appb-000062
将4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶替换成3-碘-4-氨基-1H-吡唑并[3,4-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤5，得白色固体为1-甲基-3-碘-4-氨基-1H-吡唑并[3,4-d]嘧啶，收率57％。 1H NMR(300MHz,DMSO)δ8.20(s,1H),7.05(s,2H),3.88(s,3H). Replace 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 3-iodo-4-amino-1H-pyrazolo[3,4-d]pyrimidine, the remaining starting materials, The reagent and the preparation method were the same as those in the step 5 of Example 1, to obtain a white solid as 1-methyl-3-iodo-4-amino-1H-pyrazolo[3,4-d]pyrimidine in a yield of 57%. 1 H NMR (300 MHz, DMSO) δ 8.20 (s, 1H), 7.05 (s, 2H), 3.88 (s, 3H).
步骤3：制备1-甲基-3-(4-氨基苯基)-4-氨基-1H-吡唑并[3,4-d]嘧啶Step 3: Preparation of 1-methyl-3-(4-aminophenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine
Figure PCTCN2017115380-appb-000063
Figure PCTCN2017115380-appb-000063
将4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成1-甲基-3-碘-4-氨基-1H-吡唑并[3,4-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得灰褐色固体为1-甲基-3-(4-氨基苯基)-4-氨基-1H-吡唑并[3,4-d]嘧啶，收率63％。 1H NMR(300MHz,DMSO)δ8.21(s,1H),7.31(d,J＝8.4Hz,2H),6.70(d,J＝8.4Hz,2H),6.57(s,2H),5.41(s,2H),3.90(s,3H). Replace 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 1-methyl-3-iodo-4-amino-1H-pyrazole[3,4 -d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a grayish brown solid of 1-methyl-3-(4-aminophenyl)-4-amino-1H-pyrazole. [3,4-d]pyrimidine, yield 63%. 1 H NMR (300MHz, DMSO) δ8.21 (s, 1H), 7.31 (d, J = 8.4Hz, 2H), 6.70 (d, J = 8.4Hz, 2H), 6.57 (s, 2H), 5.41 ( s, 2H), 3.90 (s, 3H).
步骤4：制备N-(4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成1-甲基-3-(4-氨基苯基)-4-氨基-1H-吡唑并[3,4-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-1-甲基-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率78％。 1H NMR(300MHz,DMSO)δ13.12(s,1H),8.73(s,1H),8.25(s,1H),8.23(s,1H),7.87(d,J＝8.4Hz,2H),7.74(dd,J＝8.3,5.8Hz,2H),7.65(d,J＝8.4Hz,2H),7.34–7.24(m,2H),6.83(s,2H),4.11(d,J＝6.9Hz,2H),3.94(s,3H),3.90–3.77(m,2H),3.39–3.05(m,2H),2.20–1.87(m,1H),1.60–1.09(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 1-methyl-3-(4-aminophenyl)-4 -amino-1H-pyrazolo[3,4-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-1-methyl) -1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran) 4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 78%. 1 H NMR (300MHz, DMSO) δ13.12 (s, 1H), 8.73 (s, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 7.87 (d, J = 8.4Hz, 2H), 7.74 (dd, J = 8.3, 5.8 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.34 - 7.24 (m, 2H), 6.83 (s, 2H), 4.11 (d, J = 6.9 Hz) , 2H), 3.94 (s, 3H), 3.90–3.77 (m, 2H), 3.39–3.05 (m, 2H), 2.20–1.87 (m, 1H), 1.60–1.09 (m, 4H).
实施例8：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酰胺(NO.8)Example 8: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(( Tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxamide (NO.8)
Figure PCTCN2017115380-appb-000064
Figure PCTCN2017115380-appb-000064
步骤1：制备4-三氟甲基苯乙酰氯Step 1: Preparation of 4-trifluoromethylphenylacetyl chloride
Figure PCTCN2017115380-appb-000065
Figure PCTCN2017115380-appb-000065
将对甲基苯乙酸替换成4-三氟甲基苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为4-三氟甲基苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid is replaced by 4-trifluoromethylphenylacetic acid, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 2, and the yellow liquid is 4-trifluoromethylphenylacetyl chloride, which is directly used for Next step.
步骤2：制备3-氧代-4-(4-三氟甲基苯基)丁酸乙酯Step 2: Preparation of ethyl 3-oxo-4-(4-trifluoromethylphenyl)butanoate
Figure PCTCN2017115380-appb-000066
Figure PCTCN2017115380-appb-000066
将4-氟苯乙酰氯替换成4-三氟甲基苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为3-氧代-4-(4-三氟甲基苯基)丁酸乙酯，步骤1和2总收率28％。 1H NMR(300MHz,DMSO)δ7.68(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),4.08(q,J＝7.1Hz,2H),4.03(s,2H),3.71(s,2H),1.18(t,J＝7.1Hz,3H). 4-Fluorophenylacetyl chloride is replaced by 4-trifluoromethylphenylacetyl chloride, and the remaining raw materials, reagents and preparation methods are the same as in Step 1 of Example 1, to obtain a colorless liquid of 3-oxo-4-(4- Ethyl trifluoromethylphenyl)butyrate, total yield of steps 1 and 2 of 28%. 1 H NMR (300MHz, DMSO) δ7.68 (d, J = 8.0Hz, 2H), 7.41 (d, J = 8.0Hz, 2H), 4.08 (q, J = 7.1Hz, 2H), 4.03 (s, 2H), 3.71 (s, 2H), 1.18 (t, J = 7.1 Hz, 3H).
步骤3：4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3 -ethyl formate
Figure PCTCN2017115380-appb-000067
Figure PCTCN2017115380-appb-000067
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成3-氧代-4-(4-三氟甲基苯基)丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酸乙酯，收率56％。 1H NMR(300MHz,DMSO)δ8.32(s,1H),8.09(s,1H),7.85(d,J＝9.0Hz,2H),7.75(d,J＝9.0Hz,2H),4.21(q,J＝7.1Hz,2H),3.93(d,J＝6.9Hz,2H),3.89–3.80(m,2H),3.25(t,J＝11.1Hz,2H),2.25–1.83(m,1H),1.61–1.06(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 3-oxo-4-(4-trifluoromethylphenyl)butanoate, the remaining raw materials, reagents and The preparation was carried out in the same manner as in the step 2 of Example 1, to give 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl) as a white solid. Ethyl 4-1,4-dihydropyridine-3-carboxylate in a yield of 56%. 1 H NMR (300MHz, DMSO) δ8.32 (s, 1H), 8.09 (s, 1H), 7.85 (d, J = 9.0Hz, 2H), 7.75 (d, J = 9.0Hz, 2H), 4.21 ( q, J = 7.1 Hz, 2H), 3.93 (d, J = 6.9 Hz, 2H), 3.89 - 3.80 (m, 2H), 3.25 (t, J = 11.1 Hz, 2H), 2.25 - 1.83 (m, 1H) ), 1.61–1.06 (m, 7H).
步骤4：制备4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl)-1,4-dihydropyridine- 3-formic acid
Figure PCTCN2017115380-appb-000068
Figure PCTCN2017115380-appb-000068
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得黄色固体为4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酸，收率77％。 1H NMR(300MHz,DMSO)δ8.81(s,1H),8.50(s,1H),7.92(d,J＝8.1Hz,2H),7.83(d,J＝8.1Hz,2H),4.15(d,J＝7.0Hz,2H),3.92–3.76(m,2H),3.25(t,J＝11.5Hz,2H),2.19–2.01(m,1H),1.53–1.13(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester, the remaining starting materials, reagents and preparation methods are the same as in the third step of Example 1, to obtain a yellow solid as 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5- (4-Trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 77%. 1 H NMR (300MHz, DMSO) δ8.81 (s, 1H), 8.50 (s, 1H), 7.92 (d, J = 8.1Hz, 2H), 7.83 (d, J = 8.1Hz, 2H), 4.15 ( d, J = 7.0 Hz, 2H), 3.92 - 3.76 (m, 2H), 3.25 (t, J = 11.5 Hz, 2H), 2.19 - 2.01 (m, 1H), 1.53 - 1.13 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-(4-三氟甲基苯基)-1,4-二氢吡啶-3-甲酰胺，收率63％。 1H NMR(300MHz,DMSO)δ12.92(s,1H),8.75(s,1H),8.32(s,1H),8.15(s,1H),7.92(d,J＝8.1Hz,2H),7.85–7.73(m,4H),7.44(d,J＝8.1Hz,2H),7.29(s,1H),6.08(s,2H),4.12(d,J＝7.5Hz,2H),3.91–3.81(m,2H),3.74(s,3H),3.32–3.21(m,2H),2.21–2.01(m,1H),1.56–1.19(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 4 -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylic acid, the rest The desired starting materials, reagents and preparation methods were the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl. Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(4-trifluoromethylphenyl)-1,4-dihydropyridine -3-carboxamide, yield 63%. 1 H NMR (300MHz, DMSO) δ12.92 (s, 1H), 8.75 (s, 1H), 8.32 (s, 1H), 8.15 (s, 1H), 7.92 (d, J = 8.1Hz, 2H), 7.85–7.73 (m, 4H), 7.44 (d, J=8.1 Hz, 2H), 7.29 (s, 1H), 6.08 (s, 2H), 4.12 (d, J = 7.5 Hz, 2H), 3.91–3.81 (m, 2H), 3.74 (s, 3H), 3.32–3.21 (m, 2H), 2.21–2.01 (m, 1H), 1.56–1.19 (m, 4H).
实施例9：N-(4-(4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.9)Example 9: N-(4-(4-Amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.9)
Figure PCTCN2017115380-appb-000069
Figure PCTCN2017115380-appb-000069
步骤1：制备4-氯-7-乙基-5-碘-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-7-ethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000070
Figure PCTCN2017115380-appb-000070
将碘甲烷替换成碘乙烷，其余所需原料、试剂及制备方法同实施例1步骤5，得白色固体为4-氯-7-乙基-5-碘-7H-吡咯并[2,3-d]嘧啶，收率89％。 1H NMR(300MHz,DMSO)δ8.64(s,1H),8.07(s,1H),4.29(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H). The methyl iodide was replaced with ethyl iodide, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 1. The white solid was 4-chloro-7-ethyl-5-iodo-7H-pyrrole[2,3 -d] Pyrimidine in a yield of 89%. 1 H NMR (300 MHz, DMSO) δ 8.64 (s, 1H), 8.07 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).
步骤2：制备4-(4-氯-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000071
Figure PCTCN2017115380-appb-000071
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-7-乙基-5-碘-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率93％。 1H NMR(300MHz,DMSO)δ8.60(s,1H),7.70(s,1H),7.16(d,J＝8.2Hz,2H),6.61(d,J＝8.2Hz,2H),5.14(s,2H),4.32(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-7-ethyl-5-iodo-7H-pyrrolo[2,3- d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine-5 -Base) Aniline, yield 93%. 1 H NMR (300MHz, DMSO) δ8.60 (s, 1H), 7.70 (s, 1H), 7.16 (d, J = 8.2Hz, 2H), 6.61 (d, J = 8.2Hz, 2H), 5.14 ( s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-乙基-7H-吡咯并[2，3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-ethyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000072
Figure PCTCN2017115380-appb-000072
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-乙基-7H-吡咯并[2,3-d]嘧啶，收率48％。Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-ethyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid 4-amino-5-(4-aminophenyl)-7- Ethyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 48%.
步骤4：制备N-(4-(4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯 基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-乙基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率37％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(s,1H),8.23(s,1H),8.15(s,1H),7.81(d,J＝8.1Hz,2H),7.73(dd,J＝8.4,5.8Hz,2H),7.45(d,J＝8.1Hz,2H),7.38(s,1H),7.29(t,J＝8.4Hz,2H),6.12(s,2H),4.20(q,J＝7.0Hz,2H),4.11(d,J＝7.2Hz,2H),3.95–3.68(m,2H),3.37–3.16(m,2H),2.24–2.00(m,1H),1.58–1.03(m,7H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Ethyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 8 of Example 1, to obtain a white solid as N-(4-(4-amino-7-ethyl) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4) -yl)methyl)-1,4-dihydropyridine-3-carboxamide in a yield of 37%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.81 (d, J = 8.1Hz, 2H), 7.73 (dd, J = 8.4, 5.8 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.38 (s, 1H), 7.29 (t, J = 8.4 Hz, 2H), 6.12 (s, 2H) ), 4.20 (q, J = 7.0 Hz, 2H), 4.11 (d, J = 7.2 Hz, 2H), 3.95 - 3.68 (m, 2H), 3.37 - 3.16 (m, 2H), 2.24 - 2.00 (m, 1H), 1.58–1.03 (m, 7H).
实施例10：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.10)Example 10: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-((1-Methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.10)
Figure PCTCN2017115380-appb-000073
Figure PCTCN2017115380-appb-000073
步骤1：制备5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of 5-(4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ester
Figure PCTCN2017115380-appb-000074
Figure PCTCN2017115380-appb-000074
将4-氨甲基四氢吡喃替换成(1-甲基哌啶-4-基)甲胺，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率64％。 1H NMR(300MHz,DMSO)δ8.27(d,J＝1.5Hz,1H),7.97(d,J＝1.5Hz,1H),7.65(dd,J＝8.4,5.7Hz,2H),7.22(t,J＝8.4Hz,2H),4.20(q,J＝7.0Hz,2H),3.90(d,J＝7.2Hz,2H),2.75(d,J＝11.4Hz,2H),2.12(s,3H),1.95–1.64(m,3H),1.48(d,J＝11.4Hz,2H),1.37–1.04(m,5H). The 4-aminomethyltetrahydropyran is replaced by (1-methylpiperidin-4-yl)methylamine, and the remaining starting materials, reagents and preparation methods are the same as those in the second step of Example 1, to obtain a white solid of 5- ( Ethyl 4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, yield 64%. 1 H NMR (300MHz, DMSO) δ8.27 (d, J = 1.5Hz, 1H), 7.97 (d, J = 1.5Hz, 1H), 7.65 (dd, J = 8.4,5.7Hz, 2H), 7.22 ( t, J = 8.4 Hz, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.90 (d, J = 7.2 Hz, 2H), 2.75 (d, J = 11.4 Hz, 2H), 2.12 (s, 3H), 1.95–1.64 (m, 3H), 1.48 (d, J = 11.4 Hz, 2H), 1.37–1.04 (m, 5H).
步骤2：制备5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000075
Figure PCTCN2017115380-appb-000075
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为制备5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酸，收率61％。 1H NMR(300MHz,DMSO)δ8.80(s,1H),8.49(s,1H),7.75(dd,J＝8.1,5.7Hz,2H),7.53–6.99(m,2H),4.20(d,J＝6.7Hz,2H),3.15(d,J＝11.1Hz,2H),2.65–2.44(m,5H),2.14–1.91(m,1H),1.82–1.40(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate To 5-(4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester, the rest The desired starting materials, reagents and preparation methods were the same as those in the third step of Example 1, to obtain 5-(4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-4 as a white solid. - Oxo-1,4-dihydropyridine-3-carboxylic acid in a yield of 61%. 1 H NMR (300 MHz, DMSO) δ 8.80 (s, 1H), 8.49 (s, 1H), 7.75 (dd, J = 8.1, 5.7 Hz, 2H), 7.53 - 6.99 (m, 2H), 4.20 (d) , J = 6.7 Hz, 2H), 3.15 (d, J = 11.1 Hz, 2H), 2.65 - 2.44 (m, 5H), 2.14 - 1.91 (m, 1H), 1.82 - 1.40 (m, 4H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-((1-甲基哌啶-4-基)甲基)-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率29％。 1H NMR(300MHz,DMSO)δ13.01(s,1H),8.77(s,1H),8.26(s,1H),8.16(s,1H),7.81(d,J＝8.1Hz,2H),7.73(dd,J＝8.4,5.6Hz,2H),7.44(d,J＝8.1Hz,2H),7.34–7.21(m,3H),6.15(s,2H),4.16(d,J＝6.5Hz,2H),3.74(s,3H),3.49–3.36(m,2H),2.99–2.79(m,2H),2.72(s,3H),2.16–2.02(m,1H),1.79(d,J＝11.3Hz,2H),1.63–1.42(m,2H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the remaining starting materials, The reagent and the preparation method were the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) 5-(4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-4-oxo-1,4-dihydropyridine-3-carboxamide, yield 29%. 1 H NMR (300MHz, DMSO) δ13.01 (s, 1H), 8.77 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.81 (d, J = 8.1Hz, 2H), 7.73 (dd, J = 8.4, 5.6 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.34 - 7.21 (m, 3H), 6.15 (s, 2H), 4.16 (d, J = 6.5 Hz) , 2H), 3.74 (s, 3H), 3.49 - 3.36 (m, 2H), 2.99 - 2.79 (m, 2H), 2.72 (s, 3H), 2.16 - 2.02 (m, 1H), 1.79 (d, J = 11.3 Hz, 2H), 1.63 - 1.42 (m, 2H).
实施例11：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酰胺(NO.11)Example 11: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxamide (NO.11)
Figure PCTCN2017115380-appb-000076
Figure PCTCN2017115380-appb-000076
步骤1：制备5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000077
Figure PCTCN2017115380-appb-000077
将4-氨甲基四氢吡喃替换成4-氨基四氢吡喃，其余所需原料、试剂及制备方法同实施例1步骤2，得白色固体为5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酸乙酯，收率72％。 1H NMR(300MHz,DMSO)δ8.33(d,J＝2.1Hz,1H),8.04(d,J＝2.1Hz,1H),7.68(dd,J＝8.6,5.9Hz,2H),7.40–6.89(m,2H),4.42–4.26(m,1H),4.20(q,J＝7.0Hz,2H),4.04–3.95(m,2H),3.40(t,J＝11.3Hz,2H),2.16–1.81(m,4H),1.27(t,J＝7.0Hz,3H). 4-Aminomethyltetrahydropyran is replaced by 4-aminotetrahydropyran, the remaining starting materials, reagents and preparation methods are the same as in Step 2 of Example 1, to obtain a white solid of 5-(4-fluorophenyl)- Ethyl 4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxylate, yield 72%. 1 H NMR (300 MHz, DMSO) δ 8.33 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.68 (dd, J = 8.6, 5.9 Hz, 2H), 7.40– 6.89 (m, 2H), 4.42 - 4.26 (m, 1H), 4.20 (q, J = 7.0 Hz, 2H), 4.04 - 3.95 (m, 2H), 3.40 (t, J = 11.3 Hz, 2H), 2.16 –1.81 (m, 4H), 1.27 (t, J = 7.0 Hz, 3H).
步骤2：制备5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000078
Figure PCTCN2017115380-appb-000078
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酸，收率79％。 1H NMR(300MHz,DMSO)δ8.78(s,1H),8.47(s,1H),7.76(dd,J＝8.4,6.1Hz,2H),7.53–6.91(m,2H),4.89–4.38(m,1H),4.09–3.91(m,2H),3.59–3.27(m,2H),2.23–1.94(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate To 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester, the remaining raw materials The reagent and the preparation method are the same as those in the third step of the first embodiment, and the white solid is 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4. - Dihydropyridine-3-carboxylic acid in a yield of 79%. 1 H NMR (300MHz, DMSO) δ8.78 (s, 1H), 8.47 (s, 1H), 7.76 (dd, J = 8.4,6.1Hz, 2H), 7.53-6.91 (m, 2H), 4.89-4.38 (m, 1H), 4.09–3.91 (m, 2H), 3.59–3.27 (m, 2H), 2.23–1.94 (m, 4H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-(四氢-2H-吡喃-4-基)-1,4-二氢吡啶-3-甲酰胺，收率74％。 1H NMR(300MHz,DMSO)δ12.99(s,1H),8.76(s,1H),8.28(s,1H),8.15(s,1H),7.81(d,J＝8.1Hz,2H),7.78–7.72(m,2H),7.43(d,J＝8.1Hz,2H),7.36–7.23(m,3H),6.11(s,2H),4.70–4.32(m,1H),4.08–3.97(m,2H),3.74(s,3H),3.44(t,J＝11.3Hz,2H),2.29–1.88(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation The same procedure as in Example 8 Step 8 gave a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (4-Fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxamide, yield 74%. 1 H NMR (300MHz, DMSO) δ12.99 (s, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.81 (d, J = 8.1Hz, 2H), 7.78–7.72 (m, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.36–7.23 (m, 3H), 6.11 (s, 2H), 4.70–4.32 (m, 1H), 4.08–3.97 ( m, 2H), 3.74 (s, 3H), 3.44 (t, J = 11.3 Hz, 2H), 2.29 - 1.88 (m, 4H).
实施例12：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.12)Example 12: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.12)
Figure PCTCN2017115380-appb-000079
Figure PCTCN2017115380-appb-000079
步骤1：制备5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000080
Figure PCTCN2017115380-appb-000080
将1克4-(4-氟苯基)-3-氧代丁酸乙酯溶于10毫升干燥的甲苯，加入1.2毫升N,N-二甲基甲酰胺二甲基缩醛，100℃加热反应5小时，反应液浓缩，残余物溶于10毫升无水乙醇，加入1.7克乙酸铵，60℃加热反应5小时，过滤，滤饼用甲醇洗涤后刮出，得白色固体506毫克为5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率43％。 1H NMR(300MHz,DMSO)δ11.87(s,1H),8.18(s,1H),7.84(s,1H),7.62(dd,J＝8.6,6.1Hz,2H),7.32–7.03(m,2H),4.18(q,J＝6.8Hz,2H),1.24(t,J＝6.8Hz,3H). 1 g of ethyl 4-(4-fluorophenyl)-3-oxobutanoate was dissolved in 10 ml of dry toluene, and 1.2 ml of N,N-dimethylformamide dimethyl acetal was added and heated at 100 ° C. The reaction mixture was concentrated for 5 hours, and the residue was dissolved in 10 ml of anhydrous ethanol. 1.7 g of ammonium acetate was added, and the mixture was heated at 60 ° C for 5 hours, filtered, and the filter cake was washed with methanol and then scraped off to obtain a white solid 506 mg of 5- Ethyl (4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, yield 43%. 1 H NMR (300MHz, DMSO) δ11.87 (s, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 7.62 (dd, J = 8.6,6.1Hz, 2H), 7.32-7.03 (m , 2H), 4.18 (q, J = 6.8 Hz, 2H), 1.24 (t, J = 6.8 Hz, 3H).
步骤2：制备5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 2: Preparation of ethyl 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000081
Figure PCTCN2017115380-appb-000081
将120毫克5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯、190毫克无水碳酸钾及48微升2-溴乙基甲基醚混溶于2毫升N,N-二甲基甲酰胺，80℃加热反应2小时，冷却至室温，乙酸乙酯稀释反应液，再用饱和氯化钠溶液分液洗涤，无水硫酸钠干燥有机相并浓缩，残余物中压柱层析(甲醇：二氯甲烷＝1:99至1:24)分离得透明液体181毫克为5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率100％。 1H NMR(300MHz,DMSO)δ8.26(s,1H),7.94(s,1H),7.65(dd,J＝7.8,6.6Hz,2H),7.38–6.93(m,2H),4.36–4.14(m,4H),3.84–3.59(m,2H),3.27(s,3H),1.26(t,J＝7.1Hz,3H). 120 mg of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, 190 mg of anhydrous potassium carbonate and 48 μl of 2-bromoethyl methyl ether Soluble in 2 ml of N,N-dimethylformamide, heat at 80 °C for 2 hours, cool to room temperature, dilute the reaction mixture with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate The phases were concentrated, and the residue was purified by column chromatography (methanol: methylene chloride = 1:99 to 1:24) to obtain a transparent liquid 181 mg of 5-(4-fluorophenyl)-1-(2-methoxy Ethyl ethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester, yield 100%. 1 H NMR (300 MHz, DMSO) δ 8.26 (s, 1H), 7.94 (s, 1H), 7.65 (dd, J = 7.8, 6.6 Hz, 2H), 7.38 - 6.93 (m, 2H), 4.36 - 4.14 (m, 4H), 3.84–3.59 (m, 2H), 3.27 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 3: Preparation of 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000082
Figure PCTCN2017115380-appb-000082
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧 代-1,4-二氢吡啶-3-甲酸，收率63％。 1H NMR(300MHz,DMSO)δ8.73(s,1H),8.37(s,1H),7.74(dd,J＝8.1,6.0Hz,2H),7.50–6.85(m,2H),4.63–4.11(m,2H),4.07–3.64(m,2H),3.27(s,3H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, the remaining starting materials, reagents and preparation The procedure was the same as in the step 3 of Example 1 to give 5-(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid as a white solid. The yield was 63%. 1 H NMR (300MHz, DMSO) δ8.73 (s, 1H), 8.37 (s, 1H), 7.74 (dd, J = 8.1,6.0Hz, 2H), 7.50-6.85 (m, 2H), 4.63-4.11 (m, 2H), 4.07–3.64 (m, 2H), 3.27 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-甲氧基乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率67％。 1H NMR(300MHz,DMSO)δ13.00(s,1H),8.70(s,1H),8.18(s,1H),8.15(s,1H),7.81(d,J＝8.4Hz,2H),7.73(dd,J＝8.3,5.9Hz,2H),7.44(d,J＝8.4Hz,2H),7.37–7.23(m,3H),6.09(s,2H),4.59–4.23(m,2H),3.84–3.64(m,5H),3.29(s,3H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the same required starting materials, reagents and preparation methods are the same as the examples 1 step 8, the white solid is N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluoro Phenyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide, yield 67%. 1 H NMR (300MHz, DMSO) δ13.00 (s, 1H), 8.70 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 7.81 (d, J = 8.4Hz, 2H), 7.73 (dd, J = 8.3, 5.9 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.37 - 7.23 (m, 3H), 6.09 (s, 2H), 4.59 - 4.23 (m, 2H) , 3.84–3.64 (m, 5H), 3.29 (s, 3H).
实施例13；N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.13)Example 13; N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1-(2-dimethylamino)- 2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.13)
Figure PCTCN2017115380-appb-000083
Figure PCTCN2017115380-appb-000083
步骤1：制备1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 1-(2-dimethylamino-2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000084
Figure PCTCN2017115380-appb-000084
将2-溴乙基甲基醚替换成2-溴-N,N-二甲基乙酰胺，其余所需原料、试剂及制备方法同实施例12步骤2，得白色固体为1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率44％。 1H NMR(300MHz,DMSO)δ8.19(d,J＝1.8Hz,1H),7.82(d,J＝1.8Hz,1H),7.61(dd,J＝8.5,5.9Hz,2H),7.31–6.89(m,2H),5.04(s,2H),4.20(q,J＝7.2Hz,2H),2.98(s,3H),2.87(s,3H),1.26(t,J＝7.2Hz,3H). The 2-bromoethyl methyl ether is replaced by 2-bromo-N,N-dimethylacetamide, and the remaining raw materials, reagents and preparation methods are the same as those in the second step of Example 12, and the white solid is 1-(2- Ethyl dimethylamino-2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, yield 44%. 1 H NMR (300 MHz, DMSO) δ 8.19 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 8.5, 5.9 Hz, 2H), 7.31 - 6.89 (m, 2H), 5.04 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.98 (s, 3H), 2.87 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ).
步骤2：制备1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 1-(2-dimethylamino-2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000085
Figure PCTCN2017115380-appb-000085
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸，收率74％。 1H NMR(300MHz,DMSO)δ8.81(d,J＝1.2Hz,1H),8.41(d,J＝1.2Hz,1H),7.84–7.65(m,2H),7.41–7.11(m,2H),5.09(s,2H),3.00(s,3H),2.89(s,3H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 1-(2-dimethylamino-2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, the rest The starting materials, reagents and preparation methods are the same as those in the third step of Example 1, and the white solid is 1-(2-dimethylamino-2-oxoethyl)-5-(4-fluorophenyl)-4-oxo. -1,4-dihydropyridine-3-carboxylic acid in a yield of 74%. 1 H NMR (300MHz, DMSO) δ8.81 (d, J = 1.2Hz, 1H), 8.41 (d, J = 1.2Hz, 1H), 7.84-7.65 (m, 2H), 7.41-7.11 (m, 2H ), 5.09 (s, 2H), 3.00 (s, 3H), 2.89 (s, 3H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1-(2-dimethylamino)- 2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1-(2-二甲胺基-2-氧代乙基)-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率83％。 1H NMR(300MHz,DMSO)δ12.98(s,1H),8.64(s,1H),8.15(s,1H),8.07(s,1H),7.81(d,J＝8.3Hz,2H),7.70(dd,J＝8.4,5.5Hz,2H),7.44(d,J＝8.3Hz,2H),7.39–7.17(m,3H),6.12(s,2H),5.25(s,2H),3.74(s,3H),3.02(s,3H),2.90(s,3H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 1 -(2-dimethylamino-2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the remaining raw materials, reagents And the preparation method is the same as in the step 8 of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 1-(2-Dimethylamino-2-oxoethyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide, yield 83% . 1 H NMR (300MHz, DMSO) δ12.98 (s, 1H), 8.64 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.81 (d, J = 8.3Hz, 2H), 7.70 (dd, J = 8.4, 5.5 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.39 - 7.17 (m, 3H), 6.12 (s, 2H), 5.25 (s, 2H), 3.74 (s, 3H), 3.02 (s, 3H), 2.90 (s, 3H).
实施例14：N-(4-(4-氨基-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.14)Example 14: N-(4-(4-Amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO. 14)
Figure PCTCN2017115380-appb-000086
Figure PCTCN2017115380-appb-000086
步骤1：制备4-氯-5-碘-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]吡啶Step 1: Preparation of 4-chloro-5-iodo-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyridine
Figure PCTCN2017115380-appb-000087
Figure PCTCN2017115380-appb-000087
将600毫克4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶、1.1克三苯基膦及757微升1-甲基-4-哌啶醇混溶于30毫升干燥的四氢呋喃，冰浴条件下滴加846微升偶氮二甲酸二异丙酯 (DIAD)，稍后回至室温搅拌4小时，反应液浓缩，残余物中压柱层析(甲醇：二氯甲烷＝1:99)分离得淡黄色固体327毫克为4-氯-5-碘-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]吡啶，收率25％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.46(s,1H),4.99–4.61(m,1H),3.03(d,J＝11.6Hz,2H),2.37(s,3H),2.31–1.93(m,6H). 600 mg of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, 1.1 g of triphenylphosphine and 757 μl of 1-methyl-4-piperidinol were dissolved in 30 ml of dryness. Tetrahydrofuran, 846 μl of diisopropyl azodicarboxylate (DIAD) was added dropwise under ice bath, and then stirred back to room temperature for 4 hours, the reaction mixture was concentrated, and the residue was purified by column chromatography (methanol: dichloromethane =1:99) 327 mg of 4-chloro-5-iodo-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyridine was isolated as a pale yellow solid. The rate is 25%. 1 H NMR (300MHz, CDCl 3 ) δ8.61 (s, 1H), 7.46 (s, 1H), 4.99-4.61 (m, 1H), 3.03 (d, J = 11.6Hz, 2H), 2.37 (s, 3H), 2.31–1.93 (m, 6H).
步骤2：制备4-(4-氯-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000088
Figure PCTCN2017115380-appb-000088
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]吡啶，其余所需原料、试剂及制备方法同实施例1步骤6，得褐色固体为4-(4-氯-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率78％。 1H NMR(300MHz,DMSO)δ8.59(s,1H),7.78(s,1H),7.16(d,J＝8.1Hz,2H),6.61(d,J＝8.1Hz,2H),5.14(s,2H),4.82–4.46(m,1H),2.92(d,J＝8.5Hz,2H),2.24(s,3H),2.20–1.84(m,6H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-(1-methylpiperidin-4-yl) -7H-pyrrolo[2,3-d]pyridine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a brown solid as 4-(4-chloro-7-(1-methylpiperidine). 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 78%. 1 H NMR (300MHz, DMSO) δ8.59 (s, 1H), 7.78 (s, 1H), 7.16 (d, J = 8.1Hz, 2H), 6.61 (d, J = 8.1Hz, 2H), 5.14 ( s, 2H), 4.82 - 4.46 (m, 1H), 2.92 (d, J = 8.5 Hz, 2H), 2.24 (s, 3H), 2.20 - 1.84 (m, 6H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000089
Figure PCTCN2017115380-appb-000089
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶，收率55％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.18(s,1H),7.11(d,J＝6.4Hz,2H),6.66(d,J＝6.4Hz,2H),6.02(s,2H),5.20(s,2H),4.89–4.31(m,1H),3.23–2.82(m,2H),2.41(s,3H),2.28–1.80(m,6H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(1-methylpiperidine- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid as 4-amino-5- (4-Aminophenyl)-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 55%. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.18 (s, 1H), 7.11 (d, J = 6.4Hz, 2H), 6.66 (d, J = 6.4Hz, 2H), 6.02 ( s, 2H), 5.20 (s, 2H), 4.89 - 4.31 (m, 1H), 3.23 - 2.82 (m, 2H), 2.41 (s, 3H), 2.28 - 1.80 (m, 6H).
步骤4：制备N-(4-(4-氨基-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺， 收率56％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝1.7Hz,1H),8.23(d,J＝1.7Hz,1H),8.15(s,1H),7.81(d,J＝8.4Hz,2H),7.73(dd,J＝8.5,5.6Hz,2H),7.46(d,J＝8.4Hz,2H),7.40(s,1H),7.35–7.20(m,2H),6.12(s,2H),4.89–4.39(m,1H),4.11(d,J＝6.8Hz,2H),3.90–3.80(m,2H),3.37–3.13(m,2H),2.76–2.63(m,2H),2.50(s,3H),2.37–1.85(m,7H),1.65–1.02(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4 -(4-Amino-7-(1-methylpiperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 56%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 1.7Hz, 1H), 8.23 (d, J = 1.7Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.4 Hz, 2H), 7.73 (dd, J = 8.5, 5.6 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.40 (s, 1H), 7.35 - 7.20 (m, 2H) ), 6.12 (s, 2H), 4.89 - 4.39 (m, 1H), 4.11 (d, J = 6.8 Hz, 2H), 3.90 - 3.80 (m, 2H), 3.37 - 3.13 (m, 2H), 2.76 - 2.63 (m, 2H), 2.50 (s, 3H), 2.37 - 1.85 (m, 7H), 1.65 - 1.02 (m, 4H).
实施例15：N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.15)Example 15: N-(4-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.15)
Figure PCTCN2017115380-appb-000090
Figure PCTCN2017115380-appb-000090
步骤1：制备4-氯-5-碘-7-异丙基-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000091
Figure PCTCN2017115380-appb-000091
将碘甲烷替换成2-碘代丙烷，其余所需原料、试剂及制备方法同实施例1步骤5，得白色固体为4-氯-5-碘-7-异丙基-7H-吡咯并[2,3-d]嘧啶，收率83％。The methyl iodide is replaced by 2-iodopropane, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain 4-chloro-5-iodo-7-isopropyl-7H-pyrrole [ 2,3-d]pyrimidine, yield 83%.
步骤2：制备4-(4-氯-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000092
Figure PCTCN2017115380-appb-000092
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-异丙基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色液体为4-(4-氯-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率70％。 1H NMR(300MHz,DMSO)δ8.59(s,1H),7.79(s,1H),7.17(d,J＝8.0Hz,2H),6.61(d,J＝8.0Hz,2H),5.15(s,2H),5.12–5.03(m,1H),1.50(d,J＝6.7Hz,6H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3 -d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow liquid which is 4-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine. -5-yl) aniline, yield 70%. 1 H NMR (300MHz, DMSO) δ8.59 (s, 1H), 7.79 (s, 1H), 7.17 (d, J = 8.0Hz, 2H), 6.61 (d, J = 8.0Hz, 2H), 5.15 ( s, 2H), 5.12–5.03 (m, 1H), 1.50 (d, J = 6.7 Hz, 6H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-异丙基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000093
Figure PCTCN2017115380-appb-000093
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-异丙基-7H-吡咯并[2,3-d]嘧啶，收率62％。 1H NMR(300MHz,DMSO)δ8.09(s,1H),7.23(s,1H),7.11(d,J＝8.2Hz,2H),6.65(d,J＝8.2Hz,2H),6.02(s,2H),5.16(s,2H),5.00–4.88(m,1H),1.44(d,J＝6.7Hz,6H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-isopropyl-7H-pyrrole [2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid 4-amino-5-(4-aminophenyl)-7 -Isopropyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 62%. 1 H NMR (300MHz, DMSO) δ8.09 (s, 1H), 7.23 (s, 1H), 7.11 (d, J = 8.2Hz, 2H), 6.65 (d, J = 8.2Hz, 2H), 6.02 ( s, 2H), 5.16 (s, 2H), 5.00 - 4.88 (m, 1H), 1.44 (d, J = 6.7 Hz, 6H).
步骤4：制备N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-异丙基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率64％。 1HNMR(300MHz,DMSO)δ13.01(s,1H),8.72(s,1H),8.22(s,1H),8.13(s,1H),7.80(d,J＝8.4Hz,2H),7.74(dd,J＝8.4,5.7Hz,2H),7.47(s,1H),7.45(d,J＝8.4Hz,2H),7.34–7.24(m,2H),6.08(s,2H),5.14–4.81(m,1H),4.11(d,J＝6.9Hz,2H),3.90–3.83(m,2H),3.42–3.04(m,2H),2.20–2.02(m,1H),1.46(d,J＝6.8Hz,6H),1.41–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Isopropyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-7-iso) Propyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran) 4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 64%. 1 H NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 8.72 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.74 (dd, J = 8.4, 5.7 Hz, 2H), 7.47 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.34 - 7.24 (m, 2H), 6.08 (s, 2H), 5.14 - 4.81 (m, 1H), 4.11 (d, J = 6.9 Hz, 2H), 3.90 - 3.83 (m, 2H), 3.42 - 3.04 (m, 2H), 2.20 - 2.02 (m, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.41 - 1.22 (m, 4H).
实施例16：N-(4-(4-氨基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.16)Example 16: N-(4-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.16)
Figure PCTCN2017115380-appb-000094
Figure PCTCN2017115380-appb-000094
步骤1：制备4-氯-7-环戊基-5-碘-7H-吡咯并[2，3-d]嘧啶Step 1: Preparation of 4-chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000095
Figure PCTCN2017115380-appb-000095
将碘甲烷替换成溴代环戊烷，其余所需原料、试剂及制备方法同实施例1步骤5， 得白色固体为4-氯-7-环戊基-5-碘-7H-吡咯并[2,3-d]嘧啶，收率64％。 1H NMR(300MHz,DMSO)δ8.63(s,1H),8.10(s,1H),5.31–5.03(m,1H),2.19–1.63(m,8H). The methyl iodide is replaced with bromocyclopentane, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain 4-chloro-7-cyclopentyl-5-iodo-7H-pyrrole [ 2,3-d]pyrimidine, yield 64%. 1 H NMR (300MHz, DMSO) δ8.63 (s, 1H), 8.10 (s, 1H), 5.31-5.03 (m, 1H), 2.19-1.63 (m, 8H).
步骤2：制备4-(4-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000096
Figure PCTCN2017115380-appb-000096
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-7-环戊基-5-碘-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色液体为4-(4-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率89％。 1H NMR(300MHz,DMSO)δ8.59(s,1H),7.72(s,1H),7.17(d,J＝8.2Hz,2H),6.61(d,J＝8.2Hz,2H),5.26–5.10(m,3H),2.25–1.55(m,8H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-7-cyclopentyl-5-iodo-7H-pyrrolo[2,3 -d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow liquid which is 4-(4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine. -5-yl) aniline, yield 89%. 1 H NMR (300MHz, DMSO) δ8.59 (s, 1H), 7.72 (s, 1H), 7.17 (d, J = 8.2Hz, 2H), 6.61 (d, J = 8.2Hz, 2H), 5.26- 5.10 (m, 3H), 2.25–1.55 (m, 8H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-环戊基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000097
Figure PCTCN2017115380-appb-000097
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-环戊基-7H-吡咯并[2,3-d]嘧啶，收率79％。 1H NMR(300MHz,DMSO)δ8.09(s,1H),7.18(s,1H),7.11(d,J＝8.0Hz,2H),6.65(d,J＝8.0Hz,2H),6.02(s,2H),5.18(s,2H),5.12–4.97(m,1H),2.29–1.58(m,8H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-cyclopentyl-7H-pyrrole [2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid 4-amino-5-(4-aminophenyl)-7 - cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 79%. 1 H NMR (300MHz, DMSO) δ8.09 (s, 1H), 7.18 (s, 1H), 7.11 (d, J = 8.0Hz, 2H), 6.65 (d, J = 8.0Hz, 2H), 6.02 ( s, 2H), 5.18 (s, 2H), 5.12 - 4.97 (m, 1H), 2.29 - 1.58 (m, 8H).
步骤4：制备N-(4-(4-氨基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-环戊基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率92％。 1H NMR(300MHz,DMSO)δ13.01(s,1H),8.72(d,J＝1.3Hz,1H),8.22(d,J＝1.3Hz,1H),8.14(s,1H),7.80(d,J＝8.3Hz,2H),7.74(dd,J＝8.4,5.7Hz,2H),7.46(d,J＝8.3Hz,2H),7.41(s,1H),7.33–7.25(m,2H),6.11(s,2H),5.18–4.99(m,1H),4.11(d,J＝7.2Hz,2H),3.94–3.80(m,2H),3.38–3.21(m,2H),2.20–1.64(m,9H),1.57–1.23(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-7-cyclo). Amyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran) 4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 92%. 1 H NMR (300 MHz, DMSO) δ 13.01 (s, 1H), 8.72 (d, J = 1.3 Hz, 1H), 8.22 (d, J = 1.3 Hz, 1H), 8.14 (s, 1H), 7.80 ( d, J = 8.3 Hz, 2H), 7.74 (dd, J = 8.4, 5.7 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.41 (s, 1H), 7.33 - 7.25 (m, 2H) ), 6.11 (s, 2H), 5.18 - 4.99 (m, 1H), 4.11 (d, J = 7.2 Hz, 2H), 3.94 - 3.80 (m, 2H), 3.38 - 3.21 (m, 2H), 2.20 - 1.64 (m, 9H), 1.57–1.23 (m, 4H).
实施例17：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺(NO.17)Example 17: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-4-oxo-1 -((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide (NO.17)
Figure PCTCN2017115380-appb-000098
Figure PCTCN2017115380-appb-000098
步骤1：制备2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺Step 1: Preparation of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2017115380-appb-000099
Figure PCTCN2017115380-appb-000099
氩气氛围下，将1克2-氟-4-碘苯胺、1.3克联硼酸频那醇酯、1.2克乙酸钾及309毫克[1,1’-双(二苯基膦基)二茂铁]二氯化钯混溶于8毫升N,N-二甲基甲酰胺，90℃加热反应12小时后冷却至室温，过滤，乙酸乙酯稀释反应液，用饱和氯化钠水溶液分液洗涤，无水硫酸钠干燥有机相并浓缩，残余物中压柱层析(乙酸乙酯：石油醚＝3:97)分离得白色固体376毫克为2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，收率38％。 1H NMR(300MHz,DMSO)δ7.18(d,J＝8.4Hz,1H),7.13(d,J＝12.5Hz,1H),6.72(t,J＝8.4Hz,1H),5.56(s,2H),1.24(s,12H). Under argon atmosphere, 1 g of 2-fluoro-4-iodoaniline, 1.3 g of pinacol borate, 1.2 g of potassium acetate and 309 mg of [1,1'-bis(diphenylphosphino)ferrocene The palladium dichloride was dissolved in 8 ml of N,N-dimethylformamide, and the reaction was heated at 90 ° C for 12 hours, then cooled to room temperature, filtered, and the mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate and evaporated. EtOAcjjjjjjjjj -Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in a yield of 38%. 1 H NMR (300MHz, DMSO) δ7.18 (d, J = 8.4Hz, 1H), 7.13 (d, J = 12.5Hz, 1H), 6.72 (t, J = 8.4Hz, 1H), 5.56 (s, 2H), 1.24 (s, 12H).
步骤2：制备4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯胺Step 2: Preparation of 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoroaniline
Figure PCTCN2017115380-appb-000100
Figure PCTCN2017115380-appb-000100
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤6，得白色固体为4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯胺，收率93％。 1H NMR(300MHz,DMSO)δ8.63(s,1H),7.70(s,1H),7.12(d,J＝13.6Hz,1H),7.02(d,J＝8.4Hz,1H),6.93–6.60(m,1H),5.22(s,2H),3.86(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 2-fluoro-4-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the remaining raw materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid 4- (4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoroaniline, yield 93%. 1 H NMR (300MHz, DMSO) δ8.63 (s, 1H), 7.70 (s, 1H), 7.12 (d, J = 13.6Hz, 1H), 7.02 (d, J = 8.4Hz, 1H), 6.93- 6.60 (m, 1H), 5.22 (s, 2H), 3.86 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-amino-3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000101
Figure PCTCN2017115380-appb-000101
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得类白色固体为4-氨基-5-(4-氨基-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率89％。 1H NMR(300MHz,DMSO)δ8.12(s,1H),7.17(s,1H),7.05(d,J＝12.4Hz,1H),6.96(d,J＝8.1Hz,1H),6.88–6.80(m,1H),6.04(s,2H),5.22(s,2H),3.70(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)-2-fluoroaniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a white solid as 4-amino-5-(4-amino- 3-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, yield 89%. 1 H NMR (300MHz, DMSO) δ8.12 (s, 1H), 7.17 (s, 1H), 7.05 (d, J = 12.4Hz, 1H), 6.96 (d, J = 8.1Hz, 1H), 6.88- 6.80 (m, 1H), 6.04 (s, 2H), 5.22 (s, 2H), 3.70 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-4-oxo-1 -((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺，收率71％。 1H NMR(300MHz,DMSO)δ13.30(s,1H),8.72(s,1H),8.57(t,J＝8.1Hz,1H),8.16(s,2H),7.57(d,J＝7.9Hz,2H),7.40–7.20(m,5H),6.21(s,2H),4.11(d,J＝5.7Hz,2H),3.93–3.79(m,2H),3.74(s,3H),3.40–3.17(m,2H),2.36(s,3H),2.18–2.04(m,1H),1.56–1.21(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-3-fluorophenyl )-7-Methyl-7H-pyrrolo[2,3-d]pyrimidine, 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl) Replacement of methyl)-1,4-dihydropyridine-3-carboxylic acid with 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1 , 4-dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrole). [2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-toluene Base-1,4-dihydropyridine-3-carboxamide, 71% yield. 1 H NMR (300MHz, DMSO) δ13.30 (s, 1H), 8.72 (s, 1H), 8.57 (t, J = 8.1Hz, 1H), 8.16 (s, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.40–7.20 (m, 5H), 6.21 (s, 2H), 4.11 (d, J = 5.7 Hz, 2H), 3.93–3.79 (m, 2H), 3.74 (s, 3H), 3.40 –3.17(m,2H), 2.36(s,3H), 2.18–2.04(m,1H),1.56–1.21(m,4H).
实施例18：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺(NO.18)Example 18: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-oxo-1 -((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide (NO.18)
Figure PCTCN2017115380-appb-000102
Figure PCTCN2017115380-appb-000102
步骤1：制备3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺Step 1: Preparation of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2017115380-appb-000103
Figure PCTCN2017115380-appb-000103
将2-氟-4-碘苯胺替换成3-氟-4-碘苯胺，其余所需原料、试剂及制备方法同实施例17步骤1，得白色固体为3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，收率77％。 1H NMR(300MHz,DMSO)δ7.32–7.19(m,1H),6.33(d,J＝8.2Hz,1H),6.19(d,J＝12.9Hz,1H),5.81(s,2H),1.23(s,12H). 2-Fluoro-4-iodoaniline was replaced with 3-fluoro-4-iodoaniline, and the remaining starting materials, reagents and preparation methods were the same as those in Example 17 Step 1. The white solid was 3-fluoro-4-(4,4). , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine, yield 77%. 1 H NMR (300MHz, DMSO) δ7.32-7.19 (m, 1H), 6.33 (d, J = 8.2Hz, 1H), 6.19 (d, J = 12.9Hz, 1H), 5.81 (s, 2H), 1.23(s,12H).
步骤2：制备4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺Step 2: Preparation of 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline
Figure PCTCN2017115380-appb-000104
Figure PCTCN2017115380-appb-000104
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺，收率73％。 1H NMR(300MHz,DMSO)δ8.63(s,1H),7.66(s,1H),7.04(t,J＝8.6Hz,1H),6.64–6.23(m,2H),5.50(s,2H),3.87(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 3-fluoro-4-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid of 4- (4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline, yield 73%. 1 H NMR (300MHz, DMSO) δ8.63 (s, 1H), 7.66 (s, 1H), 7.04 (t, J = 8.6Hz, 1H), 6.64-6.23 (m, 2H), 5.50 (s, 2H ), 3.87 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基-2-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-amino-2-fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000105
Figure PCTCN2017115380-appb-000105
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基-2-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率96％。 1H NMR(300MHz,DMSO)δ8.11(s,1H),7.12(s,1H),7.02(t,J＝9.0Hz,1H),6.60–6.36(m,2H),5.88(s,2H),5.52(s,2H),3.71(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)-3-fluoroaniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid 4-amino-5-(4-amino-2 -Fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in 96% yield. 1 H NMR (300 MHz, DMSO) δ 8.11 (s, 1 H), 7.12 (s, 1H), 7.02 (t, J = 9.0 Hz, 1H), 6.60 - 6.36 (m, 2H), 5.88 (s, 2H) ), 5.52 (s, 2H), 3.71 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-oxo-1 -((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-2-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺，收率67％。 1H NMR(300MHz,DMSO)δ13.23(s,1H),8.71(d,J＝1.8Hz,1H),8.17(d,J＝1.8Hz,1H),8.15(s,1H),7.92(d,J＝12.7Hz,1H),7.58(d,J＝8.0Hz,2H),7.48–7.33(m,2H),7.31(s,1H),7.26(d,J＝8.0Hz,2H),6.06(s,2H),4.11(d,J＝7.2Hz,2H),3.90–3.81(m,2H),3.75(s,3H),3.36–3.21(m,2H),2.36(s,3H),2.19–2.04(m,1H),1.53–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-2-fluorophenyl )-7-Methyl-7H-pyrrolo[2,3-d]pyrimidine, 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl) Replacement of methyl)-1,4-dihydropyridine-3-carboxylic acid with 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1 , 4-dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrole). [2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-toluene Base-1,4-dihydropyridine-3-carboxamide, yield 67%. 1 H NMR (300MHz, DMSO) δ13.23 (s, 1H), 8.71 (d, J = 1.8Hz, 1H), 8.17 (d, J = 1.8Hz, 1H), 8.15 (s, 1H), 7.92 ( d, J = 12.7 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.48 - 7.33 (m, 2H), 7.31 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 6.06(s,2H), 4.11(d,J=7.2Hz,2H), 3.90–3.81(m,2H),3.75(s,3H),3.36–3.21(m,2H),2.36(s,3H) , 2.19–2.04 (m, 1H), 1.53–1.22 (m, 4H).
实施例19：N-(4-(4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺(NO.19)Example 19: N-(4-(4-Amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide (NO.19)
Figure PCTCN2017115380-appb-000106
Figure PCTCN2017115380-appb-000106
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-乙基-7H-吡咯并[2,3-d]嘧啶，5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺，收率66％。 1H NMR(300MHz,DMSO)δ13.08(s,1H),8.70(s,1H),8.16(s,1H),8.14(s,1H),7.80(d,J＝8.1Hz,2H),7.58(d,J＝8.1Hz,2H),7.45(d,J＝8.1Hz,2H),7.37(s,1H),7.26(d,J＝8.1Hz,2H),6.10(s,2H),4.20(q,J＝7.5Hz,2H),4.11(d,J＝6.3Hz,2H),3.89–3.83(m,2H),3.36–3.15(m,2H),2.36(s,3H),2.19–2.04(m,1H),1.55–1.21(m,7H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Ethyl-7H-pyrrolo[2,3-d]pyrimidine, 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl) -1,4-dihydropyridine-3-carboxylic acid replaced with 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-di Hydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-ethyl-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydrol Pyridine-3-carboxamide, yield 66%. 1 H NMR (300MHz, DMSO) δ13.08 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.80 (d, J = 8.1Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.37 (s, 1H), 7.26 (d, J = 8.1 Hz, 2H), 6.10 (s, 2H), 4.20 (q, J = 7.5 Hz, 2H), 4.11 (d, J = 6.3 Hz, 2H), 3.89 - 3.83 (m, 2H), 3.36 - 3.15 (m, 2H), 2.36 (s, 3H), 2.19 –2.04 (m, 1H), 1.55–1.21 (m, 7H).
实施例20：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5基)-2-甲基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.20)Example 20: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)-2-methylphenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.20)
Figure PCTCN2017115380-appb-000107
Figure PCTCN2017115380-appb-000107
步骤1：制备2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺Step 1: Preparation of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2017115380-appb-000108
Figure PCTCN2017115380-appb-000108
将2-氟-4-碘苯胺替换成4-碘-2-甲基苯胺，其余所需原料、试剂及制备方法同实施例17步骤1，得黑色固体为2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，收率40％。 1H NMR(300MHz,DMSO)δ7.23(s,1H),7.22(d,J＝7.8Hz,1H),6.54(d,J＝7.8Hz,1H),5.23(s,2H),2.02(s,3H),1.23(s,12H). The 2-fluoro-4-iodoaniline was replaced by 4-iodo-2-methylaniline, and the remaining materials, reagents and preparation methods were the same as those in the first step of Example 17, and the black solid was 2-methyl-4-(4). , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, yield 40%. 1 H NMR (300MHz, DMSO) δ7.23 (s, 1H), 7.22 (d, J = 7.8Hz, 1H), 6.54 (d, J = 7.8Hz, 1H), 5.23 (s, 2H), 2.02 ( s, 3H), 1.23 (s, 12H).
步骤2：制备4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲基苯胺Step 2: Preparation of 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylaniline
Figure PCTCN2017115380-appb-000109
Figure PCTCN2017115380-appb-000109
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲基苯胺，收率77％。 1H NMR(300MHz,DMSO)δ8.61(s,1H),7.61(s,1H),7.06(s,1H),7.04(d,J＝7.9Hz,1H),6.65(d,J＝7.9Hz,1H),4.92(s,2H),3.85(s,3H),2.10(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 2-methyl-4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid of 4 -(4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylaniline, yield 77%. 1 H NMR (300MHz, DMSO) δ8.61 (s, 1H), 7.61 (s, 1H), 7.06 (s, 1H), 7.04 (d, J = 7.9Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.92 (s, 2H), 3.85 (s, 3H), 2.10 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基-3-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-amino-3-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000110
Figure PCTCN2017115380-appb-000110
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲基苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基-3-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率66％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.07(s,1H),7.01(s,1H),6.97(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),5.98(s,2H),4.94(s,2H),3.70(s,3H),2.10(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)-2-methylaniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid as 4-amino-5-(4-amino- 3-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in 66% yield. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.07 (s, 1H), 7.01 (s, 1H), 6.97 (d, J = 8.0Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H), 4.94 (s, 2H), 3.70 (s, 3H), 2.10 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5基)-2-甲基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)-2-methylphenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-3-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5基)-2-甲基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率88％。 1H NMR(300MHz,DMSO)δ12.83(s,1H),8.74(s,1H),8.45(d,J＝7.9Hz,1H),8.22(s,1H),8.15(s,1H),7.73(dd,J＝8.5,5.7Hz,2H),7.40–7.23(m,5H),6.09(s,2H),4.11(d,J＝7.5Hz,2H),3.91–3.78(m,2H),3.74(s,3H),3.47–3.08(m,2H),2.39(s,3H),2.24–2.04(m,1H),1.56–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-3-methylbenzene Base 7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino) -7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)-2-methylphenyl)-5-(4-fluorophenyl)-4-oxo-1-(( Tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 88%. 1 H NMR (300MHz, DMSO) δ12.83 (s, 1H), 8.74 (s, 1H), 8.45 (d, J = 7.9Hz, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.73 (dd, J = 8.5, 5.7 Hz, 2H), 7.40 - 7.23 (m, 5H), 6.09 (s, 2H), 4.11 (d, J = 7.5 Hz, 2H), 3.91 - 3.78 (m, 2H) , 3.74 (s, 3H), 3.47 - 3.08 (m, 2H), 2.39 (s, 3H), 2.24 - 2.04 (m, 1H), 1.56 - 1.22 (m, 4H).
实施例21：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5基)-3-甲基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.21)Example 21: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)-3-methylphenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.21)
Figure PCTCN2017115380-appb-000111
Figure PCTCN2017115380-appb-000111
步骤1：制备3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺Step 1: Preparation of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2017115380-appb-000112
Figure PCTCN2017115380-appb-000112
将2-氟-4-碘苯胺替换成4-溴-3-甲基苯胺，其余所需原料、试剂及制备方法同实施例17步骤1，得黄色液体为3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，收率90％。 1H NMR(300MHz,DMSO)δ7.31(d,J＝8.4Hz,1H),6.36–6.28(m,2H),5.34(s,2H),2.29(s,3H),1.24(s,12H). The 2-fluoro-4-iodoaniline was replaced with 4-bromo-3-methylaniline, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 17, and the yellow liquid was 3-methyl-4-(4). , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, yield 90%. 1 H NMR (300 MHz, DMSO) δ 7.31 (d, J = 8.4 Hz, 1H), 6.36 - 6.28 (m, 2H), 5.34 (s, 2H), 2.29 (s, 3H), 1.24 (s, 12H) ).
步骤2：制备4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-甲基苯胺Step 2: Preparation of 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylaniline
Figure PCTCN2017115380-appb-000113
Figure PCTCN2017115380-appb-000113
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤6，得棕色固体为4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-甲基苯胺，收率66％。 1H NMR(300MHz,DMSO)δ8.60(s,1H),7.53(s,1H),6.86(d,J＝8.1Hz,1H),6.49(d,J＝1.6Hz,1H),6.41(dd,J＝8.1,1.6Hz,1H),5.05(s,2H),3.86(s,3H),1.98(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 3-methyl-4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a brown solid of 4 -(4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-methylaniline, yield 66%. 1 H NMR (300MHz, DMSO) δ8.60 (s, 1H), 7.53 (s, 1H), 6.86 (d, J = 8.1Hz, 1H), 6.49 (d, J = 1.6Hz, 1H), 6.41 ( Dd, J = 8.1, 1.6 Hz, 1H), 5.05 (s, 2H), 3.86 (s, 3H), 1.98 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基-2-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-amino-2-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000114
Figure PCTCN2017115380-appb-000114
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-甲基-7H-吡咯 并[2,3-d]嘧啶-5-基)-3-甲基苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色液体为4-氨基-5-(4-氨基-2-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率26％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.01(s,1H),6.88(d,J＝8.0Hz,1H),6.53(s,1H),6.46(d,J＝8.0Hz,1H),5.76(s,2H),5.14(s,2H),3.71(s,3H),2.03(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)-3-methylaniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of the first embodiment, the yellow liquid is 4-amino-5-(4-amino- 2-methylphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in 26% yield. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.01 (s, 1H), 6.88 (d, J = 8.0Hz, 1H), 6.53 (s, 1H), 6.46 (d, J = 8.0 Hz, 1H), 5.76 (s, 2H), 5.14 (s, 2H), 3.71 (s, 3H), 2.03 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5基)-3-甲基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)-3-methylphenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-2-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5基)-3-甲基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率29％。 1H NMR(300MHz,DMSO)δ12.98(s,1H),8.70(s,1H),8.22(s,1H),8.13(s,1H),7.79–7.65(m,3H),7.58(s,1H),7.38–7.12(m,4H),5.74(s,2H),4.11(d,J＝6.7Hz,2H),3.95–3.82(m,2H),3.74(s,3H),3.46–3.14(m,2H),2.20(s,3H),2.20–2.02(m,1H),1.57–1.09(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-2-methylbenzene Base 7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino) -7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)-3-methylphenyl)-5-(4-fluorophenyl)-4-oxo-1-(( Tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 29%. 1 H NMR (300MHz, DMSO) δ12.98 (s, 1H), 8.70 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.79-7.65 (m, 3H), 7.58 (s , 1H), 7.38–7.12 (m, 4H), 5.74 (s, 2H), 4.11 (d, J = 6.7 Hz, 2H), 3.95–3.82 (m, 2H), 3.74 (s, 3H), 3.46– 3.14 (m, 2H), 2.20 (s, 3H), 2.20–2.02 (m, 1H), 1.57–1.09 (m, 4H).
实施例22：N-(4-(4-氨基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.22)Example 22: N-(4-(4-Amino-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5- Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 -formamide (NO.22)
Figure PCTCN2017115380-appb-000115
Figure PCTCN2017115380-appb-000115
步骤1：制备4-氯-5-碘-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000116
Figure PCTCN2017115380-appb-000116
将碘甲烷替换成2-(三甲基硅烷基)乙氧甲基氯，其余所需原料、试剂及制备方法同实施例1步骤5，得白色固体为4-氯-5-碘-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率84％。 1H NMR(300MHz,DMSO)δ8.69(s,1H),8.14(s,1H),5.60(s,2H),3.52(t,J＝7.9Hz,2H),0.82(t,J＝7.9Hz,2H),-0.09(s,9H). The methyl iodide is replaced by 2-(trimethylsilyl)ethoxymethyl chloride, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain 4-chloro-5-iodo-7- as a white solid. ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield 84%. 1 H NMR (300MHz, DMSO) δ8.69 (s, 1H), 8.14 (s, 1H), 5.60 (s, 2H), 3.52 (t, J = 7.9Hz, 2H), 0.82 (t, J = 7.9 Hz, 2H), -0.09 (s, 9H).
步骤2：制备4-(4-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000117
Figure PCTCN2017115380-appb-000117
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率78％。 1H NMR(300MHz,DMSO)δ8.66(s,1H),7.75(s,1H),7.16(d,J＝8.1Hz,2H),6.62(d,J＝8.1Hz,2H),5.66(s,2H),5.18(s,2H),3.56(t,J＝7.9Hz,2H),0.84(t,J＝7.9Hz,2H),-0.09(s,9H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-((2-(trimethylsilyl)) Oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a yellow solid of 4-(4-chloro-7-( (2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 78%. 1 H NMR (300MHz, DMSO) δ8.66 (s, 1H), 7.75 (s, 1H), 7.16 (d, J = 8.1Hz, 2H), 6.62 (d, J = 8.1Hz, 2H), 5.66 ( s, 2H), 5.18 (s, 2H), 3.56 (t, J = 7.9 Hz, 2H), 0.84 (t, J = 7.9 Hz, 2H), -0.09 (s, 9H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Pyrimidine
Figure PCTCN2017115380-appb-000118
Figure PCTCN2017115380-appb-000118
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率85％。 1H NMR(300MHz,DMSO)δ8.13(s,1H),7.19(s,1H),7.10(d,J＝7.7Hz,2H),6.66(d,J＝7.7Hz,2H),6.06(s,2H),5.50(s,2H),5.21(s,2H),3.53(t,J＝7.9Hz,2H),0.83(t,J＝7.9Hz,2H),-0.08(s,9H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-((2-(trimethyl)) Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in step 7 of Example 1, to obtain a yellow solid 4-amino-5-(4-aminophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield 85%. 1 H NMR (300MHz, DMSO) δ8.13 (s, 1H), 7.19 (s, 1H), 7.10 (d, J = 7.7Hz, 2H), 6.66 (d, J = 7.7Hz, 2H), 6.06 ( s, 2H), 5.50 (s, 2H), 5.21 (s, 2H), 3.53 (t, J = 7.9 Hz, 2H), 0.83 (t, J = 7.9 Hz, 2H), -0.08 (s, 9H) .
步骤4：制备N-(4-(4-氨基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5- Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3 -formamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率87％。 1H NMR(300MHz,DMSO)δ13.03(s,1H),8.72(s,1H),8.22(s,1H),8.17(s,1H),7.82(d,J＝8.7Hz,2H),7.74(dd,J＝8.6,5.7Hz, 2H),7.45(d,J＝8.7Hz,2H),7.41(s,1H),7.35–7.23(m,2H),6.15(s,2H),5.53(s,2H),4.11(d,J＝7.5Hz,2H),3.96–3.72(m,2H),3.56(t,J＝7.6Hz,2H),3.38–3.14(m,2H),2.22–2.03(m,1H),1.55–1.15(m,4H),0.84(t,J＝7.6Hz,2H),-0.10(s,9H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining raw materials, reagents and preparation methods are the same as in the first step of Example 1, and obtained white The solid is N-(4-(4-amino-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-methyl Amide, yield 87%. 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 8.72 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.74 (dd, J = 8.6, 5.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.41 (s, 1H), 7.35 - 7.23 (m, 2H), 6.15 (s, 2H), 5.53 (s, 2H), 4.11 (d, J = 7.5 Hz, 2H), 3.96 - 3.72 (m, 2H), 3.56 (t, J = 7.6 Hz, 2H), 3.38 - 3.14 (m, 2H), 2.22 - 2.03 (m, 1H), 1.55–1.15 (m, 4H), 0.84 (t, J = 7.6 Hz, 2H), -0.10 (s, 9H).
实施例23：N-(4-(4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.23)Example 23: N-(4-(4-Amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo- 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.23)
Figure PCTCN2017115380-appb-000119
Figure PCTCN2017115380-appb-000119
将30毫克N-(4-(4-氨基-7-((2-(三甲基硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺溶于0.5毫升三氟乙酸，室温搅拌1小时，反应液浓缩，加入1毫升乙腈和1毫升氨水，室温搅拌半小时，体系用乙酸乙酯稀释，饱和氯化钠溶液分液洗涤，无水硫酸钠干燥后浓缩，残余物柱层析(甲醇：二氯甲烷＝1:10)分离得白色固体18毫克为N-(4-(4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率75％。 1H NMR(300MHz,DMSO)δ13.00(s,1H),11.79(s,1H),8.73(s,1H),8.22(s,1H),8.11(s,1H),7.80(d,J＝8.4Hz,2H),7.74(dd,J＝8.4,5.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.40–7.17(m,3H),6.05(s,2H),4.11(d,J＝6.8Hz,2H),3.94–3.68(m,2H),3.43–3.19(m,2H),2.26–2.00(m,1H),1.62–1.17(m,4H). 30 mg of N-(4-(4-amino-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- The formamide was dissolved in 0.5 ml of trifluoroacetic acid, stirred at room temperature for 1 hour, and the reaction mixture was concentrated. 1 ml of acetonitrile and 1 ml of aqueous ammonia were added and stirred at room temperature for half an hour. The system was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated, and the residue was applied to EtOAc (methanol: m. Pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxamide, 75% yield. 1 H NMR (300MHz, DMSO) δ13.00 (s, 1H), 11.79 (s, 1H), 8.73 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.74 (dd, J = 8.4, 5.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.40 - 7.17 (m, 3H), 6.05 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 3.94 - 3.68 (m, 2H), 3.43 - 3.19 (m, 2H), 2.26 - 2.00 (m, 1H), 1.62 - 1.17 (m, 4H).
实施例24：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.24)Example 24: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.24)
Figure PCTCN2017115380-appb-000120
Figure PCTCN2017115380-appb-000120
步骤1：制备5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000121
Figure PCTCN2017115380-appb-000121
将2-溴乙基甲基醚替换成溴甲基甲基醚，其余所需原料、试剂及制备方法同实施 例12步骤2，得透明液体为5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率71％。 1H NMR(300MHz,DMSO)δ8.26(d,J＝2.1Hz,1H),7.91(d,J＝2.1Hz,1H),7.65(dd,J＝8.4,6.0Hz,2H),7.41–7.01(m,2H),4.19(q,J＝7.1Hz,2H),3.75(s,3H),1.26(t,J＝7.1Hz,3H). Replace 2-bromoethyl methyl ether with bromomethyl methyl ether, and the remaining materials, reagents and preparation methods are the same as those in step 12 of Example 12. The transparent liquid is 5-(4-fluorophenyl)-1- Ethyl methyl-4-oxo-1,4-dihydropyridine-3-carboxylate in a yield of 71%. 1 H NMR (300MHz, DMSO) δ8.26 (d, J = 2.1Hz, 1H), 7.91 (d, J = 2.1Hz, 1H), 7.65 (dd, J = 8.4,6.0Hz, 2H), 7.41- 7.01 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
步骤2：制备5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000122
Figure PCTCN2017115380-appb-000122
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酸，收率50％。 1H NMR(300MHz,DMSO)δ8.73(d,J＝1.2Hz,1H),8.34(d,J＝1.2Hz,1H),7.74(dd,J＝8.3,5.7Hz,2H),7.55–6.77(m,2H),3.95(s,3H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate To 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester, the remaining required raw materials, reagents and preparation methods are the same as in the first embodiment step 3. The white solid was obtained as 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid in a yield of 50%. 1 H NMR (300 MHz, DMSO) δ 8.73 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 1.2 Hz, 1H), 7.74 (dd, J = 8.3, 5.7 Hz, 2H), 7.55 - 6.77 (m, 2H), 3.95 (s, 3H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-甲基-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率44％。 1H NMR(300MHz,DMSO)δ13.05(s,1H),8.69(d,J＝1.7Hz,1H),8.15(s,2H),7.80(d,J＝8.5Hz,2H),7.73(dd,J＝8.5,5.7Hz,2H),7.43(d,J＝8.5Hz,2H),7.37–7.21(m,3H),6.10(s,2H),3.93(s,3H),3.74(s,3H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-Fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid Is N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-1-methyl 4-Oxo-1,4-dihydropyridine-3-carboxamide, yield 44%. 1 H NMR (300 MHz, DMSO) δ 13.05 (s, 1H), 8.69 (d, J = 1.7 Hz, 1H), 8.15 (s, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.73 ( Dd, J = 8.5, 5.7 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.37 - 7.21 (m, 3H), 6.10 (s, 2H), 3.93 (s, 3H), 3.74 (s , 3H).
实施例25：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.25)Example 25: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.25)
Figure PCTCN2017115380-appb-000123
Figure PCTCN2017115380-appb-000123
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率90％。 1H NMR(300MHz,DMSO)δ13.23(s,1H),8.74(s,1H),8.57(t,J＝8.4Hz,1H),8.23(s,1H), 8.16(s,1H),7.80–7.64(m,2H),7.41–7.21(m,5H),6.21(s,2H),4.11(d,J＝6.6Hz,2H),3.92–3.80(m,2H),3.74(s,3H),3.40–3.14(m,2H),2.23–2.03(m,1H),1.56–1.23(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-3-fluorophenyl - 7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-) 7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide in a yield of 90%. 1 H NMR (300MHz, DMSO) δ13.23 (s, 1H), 8.74 (s, 1H), 8.57 (t, J = 8.4Hz, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.80–7.64 (m, 2H), 7.41–7.21 (m, 5H), 6.21 (s, 2H), 4.11 (d, J = 6.6 Hz, 2H), 3.92–3.80 (m, 2H), 3.74 (s, 3H), 3.40–3.14 (m, 2H), 2.23–2.03 (m, 1H), 1.56–1.23 (m, 4H).
实施例26：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.26)Example 26: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.26)
Figure PCTCN2017115380-appb-000124
Figure PCTCN2017115380-appb-000124
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-2-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率81％。 1H NMR(300MHz,DMSO)δ13.17(s,1H),8.74(d,J＝1.8Hz,1H),8.23(d,J＝1.8Hz,1H),8.16(s,1H),7.93(d,J＝12.5Hz,1H),7.73(dd,J＝8.6,5.7Hz,2H),7.53–7.23(m,5H),6.11(s,2H),4.11(d,J＝7.3Hz,2H),3.93–3.81(m,2H),3.75(s,3H),3.40–3.23(m,2H),2.23–2.05(m,1H),1.61–1.21(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-2-fluorophenyl - 7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-) 7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 81%. 1 H NMR (300MHz, DMSO) δ13.17 (s, 1H), 8.74 (d, J = 1.8Hz, 1H), 8.23 (d, J = 1.8Hz, 1H), 8.16 (s, 1H), 7.93 ( d, J = 12.5 Hz, 1H), 7.73 (dd, J = 8.6, 5.7 Hz, 2H), 7.53 - 7.23 (m, 5H), 6.11 (s, 2H), 4.11 (d, J = 7.3 Hz, 2H) ), 3.93–3.81 (m, 2H), 3.75 (s, 3H), 3.40–3.23 (m, 2H), 2.23–2.05 (m, 1H), 1.61–1.21 (m, 4H).
实施例27：N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺(NO.27)Example 27: N-(4-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(( Tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide (NO.27)
Figure PCTCN2017115380-appb-000125
Figure PCTCN2017115380-appb-000125
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-异丙基-7H-吡咯并[2,3-d]嘧啶，5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺，收率72％。 1H NMR(300MHz,DMSO)δ 13.08(s,1H),8.69(d,J＝1.2Hz,1H),8.16(d,J＝1.2Hz,1H),8.14(s,1H),7.80(d,J＝8.2Hz,2H),7.58(d,J＝8.2Hz,2H),7.49–7.39(m,3H),7.26(d,J＝8.2Hz,2H),6.10(s,2H),5.11–4.79(m,1H),4.10(d,J＝7.4Hz,2H),3.91–3.82(m,2H),3.32–3.18(m,2H),2.36(s,3H),2.20–2.02(m,1H),1.46(d,J＝6.8Hz,6H),1.42–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Isopropyl-7H-pyrrolo[2,3-d]pyrimidine, 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl )-1,4-dihydropyridine-3-carboxylic acid replaced with 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4- Dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-isopropyl-7H-pyrrolo[2 ,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4- Dihydropyridine-3-carboxamide, yield 72%. 1 H NMR (300 MHz, DMSO) δ 13.08 (s, 1H), 8.69 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 1.2 Hz, 1H), 8.14 (s, 1H), 7.80 (d) , J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.49 - 7.39 (m, 3H), 7.26 (d, J = 8.2 Hz, 2H), 6.10 (s, 2H), 5.11 –4.79(m,1H), 4.10(d,J=7.4Hz, 2H), 3.91–3.82(m,2H), 3.32–3.18(m,2H), 2.36(s,3H), 2.20–2.02(m , 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.42 - 1.22 (m, 4H).
实施例28：N-(4-(4-氨基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺(NO.28)Example 28: N-(4-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-(( Tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4-dihydropyridine-3-carboxamide (NO.28)
Figure PCTCN2017115380-appb-000126
Figure PCTCN2017115380-appb-000126
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-环戊基-7H-吡咯并[2,3-d]嘧啶，5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-5-对甲苯基-1,4-二氢吡啶-3-甲酰胺，收率82％。 1H NMR(300MHz,DMSO)δ13.07(s,1H),8.69(d,J＝1.6Hz,1H),8.16(d,J＝1.6Hz,1H),8.14(s,1H),7.80(d,J＝8.4Hz,2H),7.58(d,J＝8.1Hz,2H),7.46(d,J＝8.4Hz,2H),7.41(s,1H),7.26(d,J＝8.1Hz,2H),6.11(s,2H),5.32–4.70(m,1H),4.10(d,J＝6.7Hz,2H),3.90–3.72(m,2H),3.33–3.13(m,2H),2.36(s,3H),2.18–1.63(m,9H),1.57–1.20(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine, 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl )-1,4-dihydropyridine-3-carboxylic acid replaced with 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4- Dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-cyclopentyl-7H-pyrrolo[2 ,3-d]pyrimidin-5-yl)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-p-tolyl-1,4- Dihydropyridine-3-carboxamide, yield 82%. 1 H NMR (300 MHz, DMSO) δ 13.07 (s, 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.14 (s, 1H), 7.80 ( d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.26 (d, J = 8.1 Hz, 2H), 6.11 (s, 2H), 5.32 - 4.70 (m, 1H), 4.10 (d, J = 6.7 Hz, 2H), 3.90 - 3.72 (m, 2H), 3.33 - 3.13 (m, 2H), 2.36 (s, 3H), 2.18–1.63 (m, 9H), 1.57–1.20 (m, 4H).
实施例29：3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯(NO.29)Example 29: 3-(4-Amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl) )-1,4-Dihydropyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (NO.29) )
Figure PCTCN2017115380-appb-000127
Figure PCTCN2017115380-appb-000127
步骤1：制备3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯Step 1: Preparation of tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate
Figure PCTCN2017115380-appb-000128
Figure PCTCN2017115380-appb-000128
将1-甲基-4-哌啶醇替换成3-羟基吡咯烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯，收率53％。 1H NMR(300MHz,CDCl 3)δ8.62(s,1H),7.39(s,1H),5.60–5.28(m,1H),4.04–3.42(m,4H),2.60–2.38(m,1H),2.32–2.08(m,1H),1.50(s,9H). Replace 1-methyl-4-piperidinol with 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. The remaining starting materials, reagents and preparation methods are the same as those in step 14 of Example 14. The white solid is 3-(4). -Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, yield 53%. 1 H NMR (300MHz, CDCl 3 ) δ 8.62 (s, 1H), 7.39 (s, 1H), 5.60 - 5.28 (m, 1H), 4.04 - 3.42 (m, 4H), 2.60 - 2.38 (m, 1H) ), 2.32–2.08 (m, 1H), 1.50 (s, 9H).
步骤2：制备3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯Step 2: Preparation of tert-butyl 3-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate
Figure PCTCN2017115380-appb-000129
Figure PCTCN2017115380-appb-000129
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯，收率86％。 1H NMR(300MHz,DMSO)δ8.63(s,1H),7.68(s,1H),7.17(d,J＝8.2Hz,2H),6.61(d,J＝8.2Hz,2H),5.65–5.31(m,1H),3.88–3.78(m,1H),3.67–3.49(m,2H),3.49–3.37(m,1H),2.47–2.22(m,2H),1.42(s,3H),1.39(s,6H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d] Pyrimidine-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid of 3-(5-(4-aminophenyl)-4. -Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, yield 86%. 1 H NMR (300MHz, DMSO) δ8.63 (s, 1H), 7.68 (s, 1H), 7.17 (d, J = 8.2Hz, 2H), 6.61 (d, J = 8.2Hz, 2H), 5.65- 5.31 (m, 1H), 3.88–3.78 (m, 1H), 3.67–3.49 (m, 2H), 3.49–3.37 (m, 1H), 2.47–2.22 (m, 2H), 1.42 (s, 3H), 1.39(s,6H).
步骤3：制备3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯Step 3: Preparation of tert-butyl 3-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate
Figure PCTCN2017115380-appb-000130
Figure PCTCN2017115380-appb-000130
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例1步骤7，得灰色固体为3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯，收率75％。 1H NMR(300MHz,DMSO)δ8.09(s,1H),7.16(s,1H),7.11(d,J＝8.1Hz,2H),6.66(d,J＝8.1Hz,2H),6.09(s,2H),5.27–5.23(m,3H),3.81–3.70(m,1H),3.56–3.49(m,3H),2.36–2.30(m,2H),1.41(s,6H),1.39(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 3-(5-(4-aminophenyl)-4-chloro- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a gray solid of 3-( 4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, yield 75%. 1 H NMR (300MHz, DMSO) δ8.09 (s, 1H), 7.16 (s, 1H), 7.11 (d, J = 8.1Hz, 2H), 6.66 (d, J = 8.1Hz, 2H), 6.09 ( s, 2H), 5.27–5.23 (m, 3H), 3.81–3.70 (m, 1H), 3.56–3.49 (m, 3H), 2.36–2.30 (m, 2H), 1.41 (s, 6H), 1.39 ( s, 3H).
步骤4：制备3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯Step 4: Preparation of 3-(4-amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl) )-1,4-Dihydropyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯，收率81％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝1.5Hz,1H),8.23(d,J＝1.5Hz,1H),8.16(s,1H),7.81(d,J＝8.2Hz,2H),7.74(dd,J＝8.6,5.6Hz,2H),7.46(d,J＝8.2Hz,2H),7.39(s,1H),7.33–7.18(m,2H),6.17(s,2H),5.43–5.18(m,1H),4.11(d,J＝7.2Hz,2H),3.94–3.83(m,2H),3.82–3.72(m,1H),3.63–3.49(m,2H),3.49–3.38(m,1H),3.32–3.15(m,2H),2.45–2.30(m,2H),2.19–2.04(m,1H),1.65–1.26(m,13H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 3-(4-amino-5-(4-aminophenyl) -7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a white solid of 3 -(4-Amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4 -Dihydropyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, yield 81%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 1.5Hz, 1H), 8.23 (d, J = 1.5Hz, 1H), 8.16 (s, 1H), 7.81 ( d, J = 8.2 Hz, 2H), 7.74 (dd, J = 8.6, 5.6 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.39 (s, 1H), 7.33 - 7.18 (m, 2H) ), 6.17 (s, 2H), 5.43 - 5.18 (m, 1H), 4.11 (d, J = 7.2 Hz, 2H), 3.94 - 3.83 (m, 2H), 3.82 - 3.72 (m, 1H), 3.63 - 3.49 (m, 2H), 3.49–3.38 (m, 1H), 3.32–3.15 (m, 2H), 2.45–2.30 (m, 2H), 2.19–2.04 (m, 1H), 1.65–1.26 (m, 13H) ).
实施例30：N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.30)Example 30: N-(4-(4-Amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4- Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.30)
Figure PCTCN2017115380-appb-000131
Figure PCTCN2017115380-appb-000131
步骤1：制备4-氯-5-碘-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000132
Figure PCTCN2017115380-appb-000132
将1-甲基-4-哌啶醇替换成四氢呋喃-3-醇，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-氯-5-碘-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶，收率44％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.56(s,1H),5.85–5.38(m,1H),4.36–4.14(m,1H),4.14–3.74(m,3H),2.82–2.44(m,1H),2.39–1.84(m,1H). Replacing 1-methyl-4-piperidinol with tetrahydrofuran-3-ol, the remaining starting materials, reagents and preparation methods are the same as in Step 1 of Example 14 to give 4-chloro-5-iodo-7- (white solid). Tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine, yield 44%. 1 H NMR (300MHz, CDCl 3 ) δ 8.61 (s, 1H), 7.56 (s, 1H), 5.85 - 5.38 (m, 1H), 4.36 - 4.14 (m, 1H), 4.14 - 3.74 (m, 3H) ), 2.82–2.44 (m, 1H), 2.39–1.84 (m, 1H).
步骤2：制备4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-苯胺Step 2: Preparation of 4-(4-chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-aniline
Figure PCTCN2017115380-appb-000133
Figure PCTCN2017115380-appb-000133
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-苯胺，收率85％。 1H NMR(300MHz,DMSO)δ8.62(s,1H),7.61(s,1H),7.18(d,J＝8.3Hz,2H),6.61(d,J＝8.3Hz,2H),5.65–5.34(m,1H),5.16(s,2H),4.26–4.05(m,1H),4.04–3.92(m,2H),3.92–3.77(m,1H),2.65–2.40(m,1H),2.31–2.11(m,1H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-(tetrahydrofuran-3-yl)-7H-pyrrole [2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrole [2,3-d]pyrimidin-5-yl)-aniline, yield 85%. 1 H NMR (300MHz, DMSO) δ8.62 (s, 1H), 7.61 (s, 1H), 7.18 (d, J = 8.3Hz, 2H), 6.61 (d, J = 8.3Hz, 2H), 5.65- 5.34 (m, 1H), 5.16 (s, 2H), 4.26 - 4.05 (m, 1H), 4.04 - 3.92 (m, 2H), 3.92 - 3.77 (m, 1H), 2.65 - 2.40 (m, 1H), 2.31–2.11 (m, 1H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000134
Figure PCTCN2017115380-appb-000134
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得类白色固体为4-氨基-5-(4-氨基苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶，收率90％。 1H NMR(300MHz,DMSO)δ8.28–7.90(m,1H),7.29–7.00(m,3H),6.65(d,J＝8.3Hz,2H),6.06(s,2H),5.49–5.24(m,3H),4.27–4.02(m,1H),3.99–3.91(m,1H),3.91–3.67(m,2H),2.55–2.38(m,1H),2.29–2.05(m,1H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(tetrahydrofuran-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenylamine, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a white solid as 4-amino-5-(4- Aminophenyl)-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 90%. 1 H NMR (300 MHz, DMSO) δ 8.28 - 7.90 (m, 1H), 7.29 - 7.00 (m, 3H), 6.65 (d, J = 8.3 Hz, 2H), 6.06 (s, 2H), 5.49 - 5.24 (m, 3H), 4.27–4.02 (m, 1H), 3.99–3.91 (m, 1H), 3.91–3.67 (m, 2H), 2.55–2.38 (m, 1H), 2.29–2.05 (m, 1H) .
步骤4：制备N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4- Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-(四氢呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率66％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝1.5Hz,1H),8.23(d,J＝1.5Hz,1H),8.16(s,1H),7.81(d,J＝8.3Hz,2H),7.74(dd,J＝8.4,5.8Hz,2H),7.47(d,J＝8.3Hz,2H),7.38–7.17(m,3H),6.16(s,2H),5.47–5.29(m,1H),4.21–4.05(m,3H),4.03–3.94(m,1H),3.94–3.75(m,4H),3.39–3.20(m,2H),2.51–2.41(m,1H),2.32–2.07(m,2H),1.52–1.21(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4- Amino-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1- ((Tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 66%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 1.5Hz, 1H), 8.23 (d, J = 1.5Hz, 1H), 8.16 (s, 1H), 7.81 ( d, J = 8.3 Hz, 2H), 7.74 (dd, J = 8.4, 5.8 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.38 - 7.17 (m, 3H), 6.16 (s, 2H) ), 5.47–5.29 (m, 1H), 4.21–4.05 (m, 3H), 4.03–3.94 (m, 1H), 3.94–3.75 (m, 4H), 3.39–3.20 (m, 2H), 2.51–2.41 (m, 1H), 2.32–2.07 (m, 2H), 1.52–1.21 (m, 4H).
实施例31：N-(4-(4-氨基-7-(吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.31)Example 31: N-(4-(4-Amino-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4 -fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.31)
Figure PCTCN2017115380-appb-000135
Figure PCTCN2017115380-appb-000135
将50毫克3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯溶于1毫升三氟乙酸，室温搅拌1小时，反应液倾入冰水中，用6N氢氧化钠溶液调至碱性，二氯甲烷分液萃取，有机相用无水硫酸钠干燥后浓缩，残余物中压柱层析(甲醇：二氯甲烷＝1:10)分离得白色固体32毫克为N-(4-(4-氨基-7-(吡咯烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率75％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),9.41(s,1H),8.70(d,J＝1.8Hz,1H),8.22(d,J＝1.8Hz,1H),8.15(s,1H),7.81(d,J＝8.4Hz,2H),7.72(dd,J＝8.3,6.0Hz,2H),7.55(s,1H),7.45(d,J＝8.4Hz,2H),7.36–7.20(m,2H),6.21(s,2H),5.57–5.06(m,1H),4.10(d,J＝6.8Hz,2H),3.95–3.75(m,2H),3.74–3.60(m,1H),3.59–3.44(m,2H),3.41–3.14(m,3H),2.54–2.40(m,1H),2.37–2.20(m,1H),2.17–1.97(m,1H),1.60–1.02(m,4H). 50 mg of 3-(4-amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)) -1,4-dihydropyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester dissolved in 1 ml of three Fluorine acetic acid, stirring at room temperature for 1 hour, the reaction solution was poured into ice water, adjusted to basic with 6N sodium hydroxide solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. Resolution (methanol: dichloromethane = 1:10) gave a white solid (yield: 32 mg) of N-(4-(4-amino-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d Pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxamide, 75% yield. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 9.41 (s, 1H), 8.70 (d, J = 1.8Hz, 1H), 8.22 (d, J = 1.8Hz, 1H), 8.15 ( s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 8.3, 6.0 Hz, 2H), 7.55 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.36–7.20 (m, 2H), 6.21 (s, 2H), 5.57–5.06 (m, 1H), 4.10 (d, J = 6.8 Hz, 2H), 3.95–3.75 (m, 2H), 3.74–3.60 ( m, 1H), 3.59–3.44 (m, 2H), 3.41–3.14 (m, 3H), 2.54–2.40 (m, 1H), 2.37–2.20 (m, 1H), 2.17–1.97 (m, 1H), 1.60–1.02 (m, 4H).
实施例32：N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.32)Example 32: N-(4-(4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.32 )
Figure PCTCN2017115380-appb-000136
Figure PCTCN2017115380-appb-000136
步骤1：制备4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000137
Figure PCTCN2017115380-appb-000137
将1-甲基-4-哌啶醇替换成氧杂环丁-3-醇，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶，收率45％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.86(s,1H),6.10–5.91(m,1H),5.25–5.13(m,2H),5.02–4.89(m,2H). Replace 1-methyl-4-piperidinol with oxetan-3-ol, the remaining starting materials, reagents and preparation methods are the same as in Step 1 of Example 14, to obtain 4-chloro-5-iodine as a white solid. 7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 45%. 1 H NMR (300MHz, CDCl 3 ) δ 8.61 (s, 1H), 7.86 (s, 1H), 6.10 - 5.91 (m, 1H), 5.25 - 5.13 (m, 2H), 5.02 - 4.89 (m, 2H) ).
步骤2：制备4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000138
Figure PCTCN2017115380-appb-000138
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率100％。 1H NMR(300MHz,DMSO)δ8.62(s,1H),8.04(s,1H),7.22(d,J＝8.0Hz,2H),6.64(d,J＝8.0Hz,2H),6.15–5.89(m,1H),5.26(s,2H),5.09–4.98(m,4H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-(oxetan-3-yl)- 7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-(oxetane-3) -yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline in a yield of 100%. 1 H NMR (300MHz, DMSO) δ8.62 (s, 1H), 8.04 (s, 1H), 7.22 (d, J = 8.0Hz, 2H), 6.64 (d, J = 8.0Hz, 2H), 6.15- 5.89 (m, 1H), 5.26 (s, 2H), 5.09–4.98 (m, 4H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000139
Figure PCTCN2017115380-appb-000139
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得类白色固体为4-氨基-5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶，收率39％。 1H NMR(300MHz,DMSO)δ8.11(s,1H),7.52(s,1H),7.15(d,J＝8.1Hz,2H),6.67(d,J＝8.1Hz,2H),6.08(s,2H),5.94–5.79(m,1H),5.27(s,2H),5.02–4.93(m,4H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(oxetane-3) -yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a white solid as 4-amino-5- (4-Aminophenyl)-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine, yield 39%. 1 H NMR (300MHz, DMSO) δ8.11 (s, 1H), 7.52 (s, 1H), 7.15 (d, J = 8.1Hz, 2H), 6.67 (d, J = 8.1Hz, 2H), 6.08 ( s, 2H), 5.94–5.79 (m, 1H), 5.27 (s, 2H), 5.02–4.93 (m, 4H).
步骤4：制备N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-(氧杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率81％。 1H NMR(300MHz,DMSO)δ13.03(s,1H),8.72(d,J＝1.8Hz,1H),8.23(d,J＝1.8Hz,1H),8.15(s,1H),7.83(d,J＝8.4Hz,2H),7.78–7.70(m,3H),7.50(d,J＝8.4Hz,2H),7.38–7.20(m,2H),6.19(s,2H),5.99–5.83(m,1H),5.18–4.71(m,4H),4.11(d,J＝7.4Hz,2H),3.91–3.77(m,2H),3.36–3.23(m,2H),2.17–2.03(m,1H),1.63–1.21(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (oxetane-3-yl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4- (4-Amino-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 81%. 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.15 (s, 1H), 7.83 ( d, J = 8.4 Hz, 2H), 7.78 - 7.70 (m, 3H), 7.50 (d, J = 8.4 Hz, 2H), 7.38 - 7.20 (m, 2H), 6.19 (s, 2H), 5.99 - 5.83 (m,1H), 5.18–4.71 (m, 4H), 4.11 (d, J=7.4 Hz, 2H), 3.91–3.77 (m, 2H), 3.36–3.23 (m, 2H), 2.17–2.03 (m) , 1H), 1.63–1.21 (m, 4H).
实施例33：N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.33)Example 33: N-(4-(4-Amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.33)
Figure PCTCN2017115380-appb-000140
Figure PCTCN2017115380-appb-000140
步骤1：制备4-氯-5-碘-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000141
Figure PCTCN2017115380-appb-000141
将500毫克4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶、742毫克无水碳酸钾及185微升2-溴乙基甲基醚混溶于9毫升N,N-二甲基甲酰胺，80℃加热反应2小时，冷却至室温，乙酸乙酯稀释反应液，再用饱和氯化钠溶液分液洗涤，无水硫酸钠干燥有机相并浓缩，残余物中压柱层析(乙酸乙酯；石油醚＝1:19至1:9)分离得黄色固体644毫克为4-氯-5-碘-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶，收率86％。 1H NMR(300MHz,CDCl 3)δ8.60(s,1H),7.51(s,1H),5.24–3.96(m,2H),3.90–3.51(m,2H),3.34(s,3H). 500 mg of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, 742 mg of anhydrous potassium carbonate and 185 μl of 2-bromoethyl methyl ether were dissolved in 9 ml of N,N. - dimethylformamide, heating at 80 ° C for 2 hours, cooling to room temperature, diluting the reaction mixture with ethyl acetate, washing with a saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate and concentrating, residue pressure Column chromatography (ethyl acetate; petroleum ether = 1:19 to 1:9) gave 644 mg ofyield as 4-chloro-5-iodo-7-(2-methoxyethyl)-7H-pyrrole. [2,3-d]pyrimidine, yield 86%. 1 H NMR (300MHz, CDCl 3 ) δ8.60 (s, 1H), 7.51 (s, 1H), 5.24-3.96 (m, 2H), 3.90-3.51 (m, 2H), 3.34 (s, 3H).
步骤2：制备4-(4-氯-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000142
Figure PCTCN2017115380-appb-000142
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率100％。 1H NMR(300MHz,DMSO)δ8.61(s,1H),7.64(s,1H),7.16(d,J＝8.4Hz,2H),6.61(d,J＝8.4Hz,2H),5.16(s,2H),4.66–4.31(m,2H),3.84–3.68(m,2H),3.24(s,3H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-(2-methoxyethyl)-7H- Pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a yellow solid as 4-(4-chloro-7-(2-methoxyethyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 100%. 1 H NMR (300MHz, DMSO) δ8.61 (s, 1H), 7.64 (s, 1H), 7.16 (d, J = 8.4Hz, 2H), 6.61 (d, J = 8.4Hz, 2H), 5.16 ( s, 2H), 4.66–4.31 (m, 2H), 3.84–3.68 (m, 2H), 3.24 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000143
Figure PCTCN2017115380-appb-000143
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得类白色固体为4-氨基-5-(4-氨基苯基)-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶，收率60％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.11(s,1H),7.10(d,J＝8.2Hz,2H),6.65(d,J＝8.2Hz,2H),5.99(s,2H),5.19(s,2H),4.33–4.22(m,2H),3.74–3.51(m,2H),3.24(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(2-methoxyethyl) - 7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a white solid as 4-amino-5-(4) -Aminophenyl)-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 60%. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.11 (s, 1H), 7.10 (d, J = 8.2Hz, 2H), 6.65 (d, J = 8.2Hz, 2H), 5.99 ( s, 2H), 5.19 (s, 2H), 4.33–4.22 (m, 2H), 3.74–3.51 (m, 2H), 3.24 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率78％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(s,1H),8.22(s,1H),8.14(s,1H),7.81(d,J＝8.1Hz,2H),7.73(dd,J＝8.3,5.7Hz,2H),7.44(d,J＝8.1Hz,2H),7.34–7.23(m,3H),6.09(s,2H),4.56–4.23(m,2H),4.11(d,J＝7.9Hz,2H),3.91–3.78(m,2H),3.77–3.66(m,2H),3.30–3.19(m,5H),2.18–1.96(m,1H),1.54–1.20(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-( 4-amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo Generation-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 78%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.81 (d, J = 8.1Hz, 2H), 7.73 (dd, J = 8.3, 5.7 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.34 - 7.23 (m, 3H), 6.09 (s, 2H), 4.56 - 4.23 (m, 2H) , 4.11 (d, J = 7.9 Hz, 2H), 3.91 - 3.78 (m, 2H), 3.77 - 3.66 (m, 2H), 3.30 - 3.19 (m, 5H), 2.18 - 1.96 (m, 1H), 1.54 –1.20(m,4H).
实施例34：N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.34)Example 34: N-(5-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-5-(4-fluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.34)
Figure PCTCN2017115380-appb-000144
Figure PCTCN2017115380-appb-000144
步骤1：制备2-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶Step 1: Preparation of 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Figure PCTCN2017115380-appb-000145
Figure PCTCN2017115380-appb-000145
将2-氟-4-碘苯胺替换成5-溴-2-硝基吡啶，其余所需原料、试剂及制备方法同实施例17步骤1，得白色固体为2-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶，收率67％。 1H NMR(300MHz,DMSO)δ8.81(s,1H),8.42(d,J＝8.1Hz,1H),8.29(d,J＝8.1Hz,1H),1.34(s,12H). The 2-fluoro-4-iodoaniline was replaced with 5-bromo-2-nitropyridine, and the remaining starting materials, reagents and preparation methods were the same as those in the first step of Example 17, to obtain a 2-nitro-5-(4) white solid. 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, yield 67%. 1 H NMR (300 MHz, DMSO) δ 8.81 (s, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 1.34 (s, 12H).
步骤2：制备4-氨基-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 2: Preparation of 4-amino-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000146
Figure PCTCN2017115380-appb-000146
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率88％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.42(s,1H),6.59(s,2H),3.67(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-chloro-5-iodo-7-methyl-7H-pyrrole [2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, and the yellow solid is 4-amino-5-iodo-7-methyl-7H-pyrrolo[2,3 -d] Pyrimidine in a yield of 88%. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.42 (s, 1H), 6.59 (s, 2H), 3.67 (s, 3H).
步骤3：制备4-氨基-5-(6-硝基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(6-nitropyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000147
Figure PCTCN2017115380-appb-000147
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成2-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶，4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-氨基-5-(6-硝基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率36％。 1H NMR(300MHz,DMSO)δ8.71(s,1H),8.39(d,J＝8.2Hz,1H),8.22(s,1H),8.17(d,J＝8.2Hz,1H),7.69(s,1H),6.50(s,2H),3.78(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 2-nitro-5-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3 -d]pyrimidine is replaced by 4-amino-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, and the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain yellow The solid was 4-amino-5-(6-nitropyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in 36% yield. 1 H NMR (300MHz, DMSO) δ8.71 (s, 1H), 8.39 (d, J = 8.2Hz, 1H), 8.22 (s, 1H), 8.17 (d, J = 8.2Hz, 1H), 7.69 ( s, 1H), 6.50 (s, 2H), 3.78 (s, 3H).
步骤4：制备4-氨基-5-(6-氨基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 4: Preparation of 4-amino-5-(6-aminopyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000148
Figure PCTCN2017115380-appb-000148
氩气氛围下，将100毫克4-氨基-5-(6-硝基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶溶于7.5毫升乙醇及5毫升水组成的混合溶剂，加入124毫克还原铁粉及127毫克氯化铵，50℃加热反应1小时后冷却至室温，过滤，硅藻土助滤，滤液浓缩后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后浓缩，残余物柱层析(甲醇：二氯甲烷＝1:15)分离得黄色固体63毫克为4-氨基-5-(6-氨基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率71％。 1H NMR(300MHz,DMSO)δ8.12(s,1H),7.98(s,1H),7.44(d,J＝8.4Hz,1H),7.17(s,1H),6.53(d,J＝8.4Hz,1H),5.99(s,4H),3.71(s,3H). 100 mg of 4-amino-5-(6-nitropyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 7.5 ml of ethanol and 5 under an argon atmosphere. a mixed solvent consisting of ml of water, adding 124 mg of reduced iron powder and 127 mg of ammonium chloride, heating at 50 ° C for 1 hour, cooling to room temperature, filtering, diatomaceous earth filtration, concentration of the filtrate, extraction with ethyl acetate, organic phase After drying over anhydrous sodium sulfate and concentrating, the residue was purified (jjjjjjjjj -Methyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 71%. 1 H NMR (300 MHz, DMSO) δ 8.12 (s, 1H), 7.98 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.53 (d, J = 8.4) Hz, 1H), 5.99 (s, 4H), 3.71 (s, 3H).
步骤5：制备N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-5-(4-fluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(6-氨基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率66％。 1H  NMR(300MHz,DMSO)δ13.28(s,1H),8.75(d,J＝1.6Hz,1H),8.41(d,J＝1.6Hz,1H),8.36(d,J＝8.5Hz,1H),8.23(d,J＝2.2Hz,1H),8.17(s,1H),7.88(dd,J＝8.5,2.2Hz,1H),7.75(dd,J＝8.6,5.6Hz,2H),7.39(s,1H),7.34–7.16(m,2H),6.20(s,2H),4.11(d,J＝6.8Hz,2H),3.94–3.80(m,2H),3.75(s,3H),3.38–3.16(m,2H),2.21–2.03(m,1H),1.55–1.21(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(6-aminopyridin-3-yl) -7-Methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(5-(4-amino-) 7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-2-yl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro) -2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 66%. 1 H NMR (300MHz, DMSO) δ13.28 (s, 1H), 8.75 (d, J = 1.6Hz, 1H), 8.41 (d, J = 1.6Hz, 1H), 8.36 (d, J = 8.5Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 7.88 (dd, J = 8.5, 2.2 Hz, 1H), 7.75 (dd, J = 8.6, 5.6 Hz, 2H), 7.39(s,1H), 7.34–7.16(m,2H), 6.20(s,2H), 4.11(d,J=6.8Hz,2H),3.94–3.80(m,2H),3.75(s,3H) , 3.38–3.16 (m, 2H), 2.21–2.03 (m, 1H), 1.55–1.21 (m, 4H).
实施例35：N-(4-(4-氨基-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.35)Example 35: N-(4-(4-Amino-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-methyl Amide (NO.35)
Figure PCTCN2017115380-appb-000149
Figure PCTCN2017115380-appb-000149
步骤1：制备4-氯-5-碘-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000150
Figure PCTCN2017115380-appb-000150
将1-甲基-4-哌啶醇替换成(1-甲基哌啶-4-基)甲醇，其余所需原料、试剂及制备方法同实施例14步骤1，得黄色液体为4-氯-5-碘-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率52％。 1H NMR(300MHz,DMSO)δ8.65(s,1H),8.05(s,1H),4.19(d,J＝7.2Hz,2H),3.23–2.93(m,2H),2.54(s,3H),2.13–1.98(m,3H),1.68–1.29(m,4H). Replace 1-methyl-4-piperidinol with (1-methylpiperidin-4-yl)methanol, the remaining starting materials, reagents and preparation methods are the same as in step 14 of Example 14, to obtain a yellow liquid of 4-chloro 5-5-iodo-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine in 52% yield. 1 H NMR (300 MHz, DMSO) δ 8.65 (s, 1H), 8.05 (s, 1H), 4.19 (d, J = 7.2 Hz, 2H), 3.23 - 2.93 (m, 2H), 2.54 (s, 3H) ), 2.13–1.98 (m, 3H), 1.68–1.29 (m, 4H).
步骤2：制备4-(4-氯-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000151
Figure PCTCN2017115380-appb-000151
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率为45％。 1H NMR(300MHz,DMSO)δ8.59(s,1H),7.66(s,1H),7.15(d,J＝8.1Hz,2H),6.61(d,J＝8.1Hz,2H),5.16(s,2H),4.18(d,J＝6.1Hz,2H),2.83–2.68(m,2H),2.18(s,3H),2.05–1.81(m,3H),1.63–1.20(m,4H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-((1-methylpiperidin-4-yl) )methyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a yellow solid as 4-(4-chloro-7-((1) -Methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 45%. 1 H NMR (300MHz, DMSO) δ8.59 (s, 1H), 7.66 (s, 1H), 7.15 (d, J = 8.1Hz, 2H), 6.61 (d, J = 8.1Hz, 2H), 5.16 ( s, 2H), 4.18 (d, J = 6.1 Hz, 2H), 2.83 - 2.68 (m, 2H), 2.18 (s, 3H), 2.05 - 1.81 (m, 3H), 1.63 - 1.20 (m, 4H) .
步骤3：制备4-氨基-5-(4-氨基苯基)-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d] 嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000152
Figure PCTCN2017115380-appb-000152
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得棕色固体为4-氨基-5-(4-氨基苯基)-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率39％。 1H NMR(300MHz,DMSO)δ8.09(s,1H),7.26–7.04(m,3H),6.65(d,J＝8.1Hz,2H),6.00(s,2H),5.20(s,2H),4.03(d,J＝7.3Hz,2H),3.03–2.87(m,2H),2.33(s,3H),2.30–2.12(m,2H),2.08–1.85(m,1H),1.60–1.31(m,4H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-((1-methylpiperidine) 4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in step 7 of Example 1, to obtain a brown solid of 4- Amino-5-(4-aminophenyl)-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield 39%. 1 H NMR (300 MHz, DMSO) δ 8.09 (s, 1H), 7.26 - 7.04 (m, 3H), 6.65 (d, J = 8.1 Hz, 2H), 6.00 (s, 2H), 5.20 (s, 2H) ), 4.03 (d, J = 7.3 Hz, 2H), 3.03 - 2.87 (m, 2H), 2.33 (s, 3H), 2.30 - 2.12 (m, 2H), 2.08 - 1.85 (m, 1H), 1.60 - 1.31 (m, 4H).
步骤4：制备N-(4-(4-氨基-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-methyl Amide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-((1-甲基哌啶-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率53％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(s,1H),8.24(s,1H),8.13(s,1H),7.80(d,J＝8.4Hz,2H),7.74(dd,J＝8.0,5.5Hz,2H),7.44(d,J＝8.4Hz,2H),7.36–7.21(m,3H),6.10(s,2H),4.12(d,J＝7.5Hz,2H),4.04(d,J＝7.1Hz,2H),3.93–3.73(m,2H),3.38–3.13(m,2H),2.78–2.63(m,2H),2.21–2.02(m,4H),1.92–1.67(m,3H),1.51–1.16(m,8H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- ((1-Methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 8 of Example 1, to obtain a white solid N-(4-(4-Amino-7-((1-methylpiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 53%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.74 (dd, J = 8.0, 5.5 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.36 - 7.21 (m, 3H), 6.10 (s, 2H), 4.12 (d, J = 7.5 Hz) , 2H), 4.04 (d, J = 7.1 Hz, 2H), 3.93 - 3.73 (m, 2H), 3.38 - 3.13 (m, 2H), 2.78 - 2.63 (m, 2H), 2.21 - 2.02 (m, 4H) ), 1.92–1.67 (m, 3H), 1.51–1.16 (m, 8H).
实施例36：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.36)Example 36: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(2,4-difluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.36)
Figure PCTCN2017115380-appb-000153
Figure PCTCN2017115380-appb-000153
步骤1：制备2,4-二氟苯乙酰氯Step 1: Preparation of 2,4-difluorophenylacetyl chloride
Figure PCTCN2017115380-appb-000154
Figure PCTCN2017115380-appb-000154
将对甲基苯乙酸替换成2,4-二氟苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为2,4-二氟苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid is replaced with 2,4-difluorophenylacetic acid, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 2, and the yellow liquid is 2,4-difluorophenylacetyl chloride, which is directly used for Next step.
步骤2：制备4-(2,4-二氟苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(2,4-difluorophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000155
Figure PCTCN2017115380-appb-000155
将4-氟苯乙酰氯替换成2,4-二氟苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为4-(2,4-二氟苯基)-3-氧代丁酸乙酯，步骤1和2总收率47％。 1H NMR(300MHz,DMSO)δ7.30(q,J＝8.2Hz,1H),7.25–7.14(m,1H),7.09–6.96(m,1H),4.09(q,J＝7.2Hz,2H),3.95(s,2H),3.71(s,2H),1.18(t,J＝7.2Hz,3H). Replace 4-fluorophenylacetyl chloride with 2,4-difluorophenylacetyl chloride. The remaining raw materials, reagents and preparation methods are the same as those in step 1 of Example 1. The colorless liquid is 4-(2,4-difluorobenzene). Ethyl 3-oxobutanoate, the total yield of steps 1 and 2 was 47%. 1 H NMR (300 MHz, DMSO) δ 7.30 (q, J = 8.2 Hz, 1H), 7.25 - 7.14 (m, 1H), 7.09 - 6.96 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H) ), 3.95 (s, 2H), 3.71 (s, 2H), 1.18 (t, J = 7.2 Hz, 3H).
步骤3：制备5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(2,4-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- Ethyl 3-carboxylate
Figure PCTCN2017115380-appb-000156
Figure PCTCN2017115380-appb-000156
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(2,4-二氟苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色固体为5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率50％。 1H NMR(300MHz,DMSO)δ8.34(s,1H),7.92(s,1H),7.44(q,J＝8.3Hz,1H),7.34–7.21(m,1H),7.21–7.05(m,1H),4.20(q,J＝7.1Hz,2H),3.94–3.78(m,4H),3.42–3.11(m,2H),2.11–1.86(m,1H),1.54–1.08(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 4-(2,4-difluorophenyl)-3-oxobutanoate, the remaining raw materials, reagents and The preparation method was the same as in the step 2 of Example 1, to obtain a yellow solid as 5-(2,4-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl) Ethyl 4-1,4-dihydropyridine-3-carboxylate in a yield of 50%. 1 H NMR (300MHz, DMSO) δ8.34 (s, 1H), 7.92 (s, 1H), 7.44 (q, J = 8.3Hz, 1H), 7.34-7.21 (m, 1H), 7.21-7.05 (m , 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.94 - 3.78 (m, 4H), 3.42 - 3.11 (m, 2H), 2.11 - 1.86 (m, 1H), 1.54 - 1.08 (m, 7H) ).
步骤4：制备5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(2,4-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- 3-formic acid
Figure PCTCN2017115380-appb-000157
Figure PCTCN2017115380-appb-000157
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得黄色固体为5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率97％。 1H NMR(300MHz,DMSO)δ8.82(s,1H),8.37(s,1H),7.55(q,J＝7.9Hz,1H),7.43–7.32(m,1H),7.29– 7.03(m,1H),4.12(d,J＝7.1Hz,2H),4.01–3.55(m,2H),3.47–2.99(m,2H),2.19–1.90(m,1H),1.51–1.17(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate 5-(2,4-Difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester, the remaining starting materials, reagents and preparation methods are the same as in the third step of Example 1, to obtain a yellow solid of 5-(2,4-difluorophenyl)-4-oxo-1-((tetrahydro-2H-) Pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 97%. 1 H NMR (300 MHz, DMSO) δ 8.82 (s, 1H), 8.37 (s, 1H), 7.55 (q, J = 7.9 Hz, 1H), 7.43 - 7.32 (m, 1H), 7.29 - 7.03 (m) , 1H), 4.12 (d, J = 7.1 Hz, 2H), 4.01 - 3.55 (m, 2H), 3.47 - 2.99 (m, 2H), 2.19 - 1.90 (m, 1H), 1.51 - 1.17 (m, 4H) ).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(2,4-difluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(2,4-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率37％。 1H NMR(300MHz,DMSO)δ12.96(s,1H),8.77(s,1H),8.25(s,1H),8.20(s,1H),7.86(d,J＝8.6Hz,2H),7.64(d,J＝8.6Hz,2H),7.62–7.46(m,1H),7.48–7.32(m,1H),7.30–7.05(m,1H),6.86(s,2H),4.10(d,J＝6.7Hz,2H),3.94(s,3H),3.90–3.68(m,2H),3.35–3.07(m,2H),2.26–2.02(m,1H),1.53–1.22(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(2,4-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the rest The desired starting materials, reagents and preparation methods were the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl. Phenyl)-5-(2,4-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine -3-carboxamide, yield 37%. 1 H NMR (300MHz, DMSO) δ12.96 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.86 (d, J = 8.6Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.62 - 7.46 (m, 1H), 7.48 - 7.32 (m, 1H), 7.30 - 7.05 (m, 1H), 6.86 (s, 2H), 4.10 (d, J=6.7 Hz, 2H), 3.94 (s, 3H), 3.90–3.68 (m, 2H), 3.35–3.07 (m, 2H), 2.26–2.02 (m, 1H), 1.53–1.22 (m, 4H) .
实施例37：N-(4-(4-氨基-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.37)Example 37: N-(4-(4-Amino-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Formamide (NO.37)
Figure PCTCN2017115380-appb-000158
Figure PCTCN2017115380-appb-000158
步骤1：制备4-氯-5-碘-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000159
Figure PCTCN2017115380-appb-000159
将1-甲基-4-哌啶醇替换成(四氢-2H-吡喃-4-基)甲醇，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-氯-5-碘-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率100％。 1H NMR(300MHz,CDCl 3)δ8.60(s,1H),7.35(s,1H),4.14(d,J＝7.2Hz,2H),4.03–3.87(m,2H),3.32(t,J＝11.4Hz,2H),2.25–2.04(m,1H),1.53–1.33(m,4H). Replacing 1-methyl-4-piperidinol with (tetrahydro-2H-pyran-4-yl)methanol, the remaining starting materials, reagents and preparation methods are the same as in step 14 of Example 14, to obtain a white solid of 4- Chloro-5-iodo-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine in 100% yield. 1 H NMR (300MHz, CDCl 3 ) δ 8.60 (s, 1H), 7.35 (s, 1H), 4.14 (d, J = 7.2 Hz, 2H), 4.03 - 3.87 (m, 2H), 3.32 (t, J=11.4Hz, 2H), 2.25–2.04 (m, 1H), 1.53–1.33 (m, 4H).
步骤2：制备4-(4-氯-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000160
Figure PCTCN2017115380-appb-000160
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率72％。 1H NMR(300MHz,DMSO)δ8.60(s,1H),7.66(s,1H),7.16(d,J＝8.1Hz,2H),6.61(d,J＝8.1Hz,2H),5.16(s,2H),4.19(d,J＝7.1Hz,2H),3.88–3.72(m,2H),3.22(t,J＝11.1Hz,2H),2.26–2.06(m,1H),1.46–1.22(m,4H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-((tetrahydro-2H-pyran-4- Methyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid of 4-(4-chloro-7-(( Tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 72%. 1 H NMR (300MHz, DMSO) δ8.60 (s, 1H), 7.66 (s, 1H), 7.16 (d, J = 8.1Hz, 2H), 6.61 (d, J = 8.1Hz, 2H), 5.16 ( s, 2H), 4.19 (d, J = 7.1 Hz, 2H), 3.88 - 3.72 (m, 2H), 3.22 (t, J = 11.1 Hz, 2H), 2.26 - 2.06 (m, 1H), 1.46 - 1.22 (m, 4H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000161
Figure PCTCN2017115380-appb-000161
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色液体为4-氨基-5-(4-氨基苯基)-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率59％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.12(s,1H),7.10(d,J＝8.4Hz,2H),6.65(d,J＝8.4Hz,2H),5.99(s,2H),5.21(s,2H),4.03(d,J＝7.1Hz,2H),3.87–3.73(m,2H),3.28–3.14(m,2H),2.19–1.93(m,1H),1.47–1.17(m,4H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-((tetrahydro-2H-pyridyl)喃-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in step 7 of Example 1, to obtain a yellow liquid of 4 -amino-5-(4-aminophenyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield 59% . 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.12 (s, 1H), 7.10 (d, J = 8.4Hz, 2H), 6.65 (d, J = 8.4Hz, 2H), 5.99 ( s, 2H), 5.21 (s, 2H), 4.03 (d, J = 7.1 Hz, 2H), 3.87 - 3.73 (m, 2H), 3.28 - 3.14 (m, 2H), 2.19 - 1.93 (m, 1H) , 1.47–1.17(m,4H).
步骤4：制备N-(4-(4-氨基-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl Phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Formamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-((四氢-2H-吡喃-4-基)甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率65％。 1H NMR(300MHz,DMSO)δ13.01(s,1H),8.72(s,1H),8.22(s,1H),8.14(s,1H),7.81(d,J＝8.1Hz,2H),7.74(dd,J＝8.2,6.0Hz,2H),7.45(d,J＝8.1Hz,2H),7.35–7.21(m,3H),6.09(s,2H),4.11(d,J＝7.4Hz,2H),4.07(d,J＝7.5Hz,2H),3.94–3.67(m,4H),3.30–3.03(m,4H),2.23–2.02(m,2H),1.64–1.22(m,8H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- ((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid Is N-(4-(4-Amino-7-((tetrahydro-2H-pyran-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl -5-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, The yield was 65%. 1 H NMR (300MHz, DMSO) δ13.01 (s, 1H), 8.72 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.81 (d, J = 8.1Hz, 2H), 7.74 (dd, J = 8.2, 6.0 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.35 - 7.21 (m, 3H), 6.09 (s, 2H), 4.11 (d, J = 7.4 Hz) , 2H), 4.07 (d, J = 7.5 Hz, 2H), 3.94 - 3.67 (m, 4H), 3.30 - 3.03 (m, 4H), 2.23 - 2.02 (m, 2H), 1.64 - 1.22 (m, 8H) ).
实施例38：N-(4-(4-氨基-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.38)Example 38: N-(4-(4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO .38)
Figure PCTCN2017115380-appb-000162
Figure PCTCN2017115380-appb-000162
步骤1：制备4-氯-5-碘-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000163
Figure PCTCN2017115380-appb-000163
将1-甲基-4-哌啶醇替换成四氢吡喃-4-醇，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-氯-5-碘-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶，收率84％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.46(s,1H),5.39–4.71(m,1H),4.21–4.09(m,2H),3.70–3.55(m,2H),2.27–1.80(m,4H). Replacing 1-methyl-4-piperidinol with tetrahydropyran-4-ol, the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 14, to obtain 4-chloro-5-iodine as a white solid. 7-(Tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, yield 84%. 1 H NMR (300MHz, CDCl 3 ) δ 8.61 (s, 1H), 7.46 (s, 1H), 5.39 - 4.71 (m, 1H), 4.21 - 4.09 (m, 2H), 3.70 - 3.55 (m, 2H) ), 2.27–1.80 (m, 4H).
步骤2：制备4-(4-氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000164
Figure PCTCN2017115380-appb-000164
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率100％。 1H NMR(300MHz,DMSO)δ8.61(s,1H),7.83(s,1H),7.17(d,J＝8.4Hz,2H),6.61(d,J＝8.4Hz,2H),5.09–4.87(m,1H),4.01(dd,J＝11.5,4.1Hz,2H),3.55(t,J＝11.5Hz,2H),2.29–2.08(m,2H),1.93–1.85(m,2H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-(tetrahydro-2H-pyran-4-yl -7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-(tetrahydro-2H- Pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 100%. 1 H NMR (300MHz, DMSO) δ8.61 (s, 1H), 7.83 (s, 1H), 7.17 (d, J = 8.4Hz, 2H), 6.61 (d, J = 8.4Hz, 2H), 5.09- 4.87 (m, 1H), 4.01 (dd, J = 11.5, 4.1 Hz, 2H), 3.55 (t, J = 11.5 Hz, 2H), 2.29 - 2.08 (m, 2H), 1.93 - 1.85 (m, 2H) .
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000165
Figure PCTCN2017115380-appb-000165
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶，收率72％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.26(s,1H),7.11(d,J＝8.1Hz,2H),6.65(d,J＝8.1Hz,2H),6.00(s,2H),5.18(s,2H),4.87–4.58(m,1H),3.99(dd,J＝11.4,3.0Hz,2H),3.51(t,J＝11.4Hz,2H),2.18–2.00(m,2H),1.92–1.70(m,2H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(tetrahydro-2H-pyran) 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid as 4-amino-5. -(4-Aminophenyl)-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 72%. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.26 (s, 1H), 7.11 (d, J = 8.1Hz, 2H), 6.65 (d, J = 8.1Hz, 2H), 6.00 ( s, 2H), 5.18 (s, 2H), 4.87 - 4.58 (m, 1H), 3.99 (dd, J = 11.4, 3.0 Hz, 2H), 3.51 (t, J = 11.4 Hz, 2H), 2.18 - 2.00 (m, 2H), 1.92–1.70 (m, 2H).
步骤4：制备N-(4-(4-氨基-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) -5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-(四氢-2H-吡喃-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率69％。 1H NMR(300MHz,DMSO)δ13.01(s,1H),8.72(s,1H),8.22(s,1H),8.14(s,1H),7.81(d,J＝8.2Hz,2H),7.74(dd,J＝8.2,5.8Hz,2H),7.48(s,1H),7.46(d,J＝8.2Hz,2H),7.37–7.17(m,2H),6.10(s,2H),5.03–4.63(m,1H),4.11(d,J＝7.0Hz,2H),4.05–3.93(m,2H),3.92–3.81(m,2H),3.53(t,J＝11.7Hz,2H),3.41–3.18(m,2H),2.24–2.01(m,2H),1.93–1.79(m,2H),1.53–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-( 4-(4-Amino-7-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 69%. 1 H NMR (300MHz, DMSO) δ13.01 (s, 1H), 8.72 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.81 (d, J = 8.2Hz, 2H), 7.74 (dd, J = 8.2, 5.8 Hz, 2H), 7.48 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.37 - 7.17 (m, 2H), 6.10 (s, 2H), 5.03 –4.63 (m, 1H), 4.11 (d, J = 7.0 Hz, 2H), 4.05–3.93 (m, 2H), 3.92–3.81 (m, 2H), 3.53 (t, J = 11.7 Hz, 2H), 3.41–3.18 (m, 2H), 2.24–2.01 (m, 2H), 1.93–1.79 (m, 2H), 1.53–1.22 (m, 4H).
实施例39：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.39)Example 39: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(3,5-difluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.39)
Figure PCTCN2017115380-appb-000166
Figure PCTCN2017115380-appb-000166
步骤1：制备3,5-二氟苯乙酰氯Step 1: Preparation of 3,5-difluorophenylacetyl chloride
Figure PCTCN2017115380-appb-000167
Figure PCTCN2017115380-appb-000167
将对甲基苯乙酸替换成3,5-二氟苯乙酸，其余所需原料、试剂及制备方法同实施 例2步骤1，得黄色液体为3,5-二氟苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid is replaced by 3,5-difluorophenylacetic acid, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of the second embodiment, and the yellow liquid is 3,5-difluorophenylacetyl chloride, which is directly used for Next step.
步骤2：制备4-(3,5-二氟苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(3,5-difluorophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000168
Figure PCTCN2017115380-appb-000168
将4-氟苯乙酰氯替换成3,5-二氟苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为4-(3,5-二氟苯基)-3-氧代丁酸乙酯，步骤1和2总收率36％。 1H NMR(300MHz,DMSO)δ7.18–7.08(m,1H),6.94(dd,J＝7.3,1.0Hz,2H),4.09(q,J＝7.1Hz,2H),3.95(s,2H),3.69(s,2H),1.18(t,J＝7.1Hz,3H). Replace 4-fluorophenylacetyl chloride with 3,5-difluorophenylacetyl chloride. The remaining raw materials, reagents and preparation methods are the same as those in step 1 of Example 1. The colorless liquid is 4-(3,5-difluorobenzene). Ethyl 3-oxobutanoate, total yield of steps 1 and 2 was 36%. 1 H NMR (300 MHz, DMSO) δ 7.18 - 7.08 (m, 1H), 6.94 (dd, J = 7.3, 1.0 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H) ), 3.69 (s, 2H), 1.18 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(3,5-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- Ethyl 3-carboxylate
Figure PCTCN2017115380-appb-000169
Figure PCTCN2017115380-appb-000169
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(3,5-二氟苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色固体为5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率59％。 1H NMR(300MHz,DMSO)δ8.31(d,J＝1.8Hz,1H),8.16(d,J＝1.8Hz,1H),7.61–7.11(m,2H),7.31–6.98(m,1H),4.21(q,J＝7.2Hz,2H),3.92(d,J＝7.1Hz,2H),3.88–3.81(m,2H),3.25(t,J＝11.4Hz,2H),2.16–1.99(m,1H),1.47–1.13(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 4-(3,5-difluorophenyl)-3-oxobutanoate, the remaining raw materials, reagents and The preparation method was the same as that in the second step of Example 1, to obtain a yellow solid as 5-(3,5-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl) Ethyl 4-1,4-dihydropyridine-3-carboxylate in a yield of 59%. 1 H NMR (300MHz, DMSO) δ8.31 (d, J = 1.8Hz, 1H), 8.16 (d, J = 1.8Hz, 1H), 7.61-7.11 (m, 2H), 7.31-6.98 (m, 1H ), 4.21 (q, J = 7.2 Hz, 2H), 3.92 (d, J = 7.1 Hz, 2H), 3.88 - 3.81 (m, 2H), 3.25 (t, J = 11.4 Hz, 2H), 2.16 - 1.99 (m, 1H), 1.47–1.13 (m, 7H).
步骤4：制备5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(3,5-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- 3-formic acid
Figure PCTCN2017115380-appb-000170
Figure PCTCN2017115380-appb-000170
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得黄色固体为5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率82％。 1H NMR(300MHz,DMSO)δ8.81(s,1H),8.55(s,1H),7.57–7.44(m,2H),7.43–7.15(m,1H),4.14(d,J＝7.2Hz,2H),3.97–3.72(m,2H),3.25(t,J＝11.4Hz,2H),2.19–2.08(m,1H),1.53–1.15(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate 5-(3,5-Difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester, the remaining starting materials, reagents and preparation methods are the same as in the third step of Example 1, to obtain a yellow solid of 5-(3,5-difluorophenyl)-4-oxo-1-((tetrahydro-2H-) Pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 82%. 1 H NMR (300 MHz, DMSO) δ 8.81 (s, 1H), 8.55 (s, 1H), 7.57 - 7.44 (m, 2H), 7.43 - 7.15 (m, 1H), 4.14 (d, J = 7.2 Hz) , 2H), 3.97–3.72 (m, 2H), 3.25 (t, J = 11.4 Hz, 2H), 2.19–2.08 (m, 1H), 1.53–1.15 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(3,5-difluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3,5-二氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率77％。 1H NMR(300MHz,DMSO)δ12.88(s,1H),8.74(s,1H),8.37(s,1H),8.15(s,1H),7.82(d,J＝8.4Hz,2H),7.57–7.48(m,2H),7.44(d,J＝8.4Hz,2H),7.34–7.21(m,2H),6.12(s,2H),4.11(d,J＝7.1Hz,2H),3.96–3.74(m,2H),3.74(s,3H),3.38–3.14(m,2H),2.22–2.03(m,1H),1.54–1.24(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(3,5-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the rest The desired starting materials, reagents and preparation methods were the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl. Phenyl)-5-(3,5-difluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine -3-carboxamide, yield 77%. 1 H NMR (300MHz, DMSO) δ12.88 (s, 1H), 8.74 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.57–7.48 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.34–7.21 (m, 2H), 6.12 (s, 2H), 4.11 (d, J = 7.1 Hz, 2H), 3.96 – 3.74 (m, 2H), 3.74 (s, 3H), 3.38–3.14 (m, 2H), 2.22–2.03 (m, 1H), 1.54–1.24 (m, 4H).
实施例40：N-(4-(4-氨基-7-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.40)Example 40: N-(4-(4-Amino-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.40)
Figure PCTCN2017115380-appb-000171
Figure PCTCN2017115380-appb-000171
步骤1：制备4-氯-7-苯基-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000172
Figure PCTCN2017115380-appb-000172
空气氛围下(反应瓶加空心塞)，将800毫克4-氯-7H-吡咯并[2,3-d]嘧啶、1.9克醋酸铜及2.9毫升三乙胺混溶于50毫升二氯甲烷中，室温搅拌半小时后加入953毫克苯硼酸，室温搅拌14小时后过滤，滤液浓缩，残余物中压柱层析(乙酸乙酯：石油醚＝1:19至1:9)分离得白色固体400毫克为4-氯-7-苯基-7H-吡咯并[2,3-d]嘧啶，收率33％。 1H NMR(300MHz,DMSO)δ8.71(s,1H),8.16(d,J＝3.7Hz,1H),7.84(d,J＝7.8Hz,2H),7.60(t,J＝7.8Hz,2H),7.46(t,J＝7.8Hz,1H),6.90(d,J＝3.7Hz,1H). Under air atmosphere (reaction flask with hollow plug), 800 mg of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 1.9 g of copper acetate and 2.9 ml of triethylamine were dissolved in 50 ml of dichloromethane. After stirring at room temperature for half an hour, 953 mg of phenylboric acid was added, and the mixture was stirred at room temperature for 14 hours, then filtered, and the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:19 to 1:9) The mg was 4-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 33%. 1 H NMR (300MHz, DMSO) δ8.71 (s, 1H), 8.16 (d, J = 3.7Hz, 1H), 7.84 (d, J = 7.8Hz, 2H), 7.60 (t, J = 7.8Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 3.7 Hz, 1H).
步骤2：制备4-氯-5-碘-7-苯基-7H-吡咯并[2,3-d]嘧啶Step 2: Preparation of 4-chloro-5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000173
Figure PCTCN2017115380-appb-000173
将350毫克4-氯-7-苯基-7H-吡咯并[2,3-d]嘧啶及412毫克N-碘代丁二酰亚胺溶于5毫升N,N-二甲基甲酰胺中，60℃加热反应3小时，冷却至室温，加入饱和硫代硫酸钠 溶液，析出固体，抽滤，滤饼水洗并刮出，干燥后得白色固体325毫克为4-氯-5-碘-7-苯基-7H-吡咯并[2,3-d]嘧啶，收率64％。 1H NMR(300MHz,DMSO)δ8.69(s,1H),8.38(s,1H),7.79(d,J＝7.8Hz,2H),7.58(t,J＝7.8Hz,2H),7.46(t,J＝7.8Hz,1H). 350 mg of 4-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine and 412 mg of N-iodosuccinimide were dissolved in 5 ml of N,N-dimethylformamide. The reaction was heated at 60 ° C for 3 hours, cooled to room temperature, a saturated sodium thiosulfate solution was added, and the solid was precipitated, suction filtered, and the filter cake was washed with water and scraped. After drying, 325 mg of white solid was 4-chloro-5-iodo-7. -Phenyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 64%. 1 H NMR (300MHz, DMSO) δ8.69 (s, 1H), 8.38 (s, 1H), 7.79 (d, J = 7.8Hz, 2H), 7.58 (t, J = 7.8Hz, 2H), 7.46 ( t, J = 7.8 Hz, 1H).
步骤3：制备4-(4-氯-7-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 3: Preparation of 4-(4-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000174
Figure PCTCN2017115380-appb-000174
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-苯基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率85％。 1H NMR(300MHz,DMSO)δ8.68(s,1H),8.03(s,1H),7.88(d,J＝7.5Hz,2H),7.59(t,J＝7.5Hz,2H),7.45(t,J＝7.5Hz,1H),7.26(d,J＝8.4Hz,2H),6.64(d,J＝8.4Hz,2H),5.22(s,2H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-phenyl-7H-pyrrolo[2,3- d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-5. - phenylamine, yield 85%. 1 H NMR (300MHz, DMSO) δ8.68 (s, 1H), 8.03 (s, 1H), 7.88 (d, J = 7.5Hz, 2H), 7.59 (t, J = 7.5Hz, 2H), 7.45 ( t, J = 7.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H).
步骤4：制备4-氨基-5-(4-氨基苯基)-7-苯基-7H-吡咯并[2,3-d]嘧啶Step 4: Preparation of 4-amino-5-(4-aminophenyl)-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000175
Figure PCTCN2017115380-appb-000175
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-苯基-7H-吡咯并[2,3-d]嘧啶，收率60％。 1H NMR(300MHz,DMSO)δ8.18(s,1H),7.88(d,J＝7.5Hz,2H),7.60–7.47(m,3H),7.35(t,J＝7.5Hz,1H),7.21(d,J＝8.4Hz,2H),6.69(d,J＝8.4Hz,2H),6.15(s,2H),5.29(s,2H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-phenyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid 4-amino-5-(4-aminophenyl)-7- Phenyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 60%. 1 H NMR (300MHz, DMSO) δ8.18 (s, 1H), 7.88 (d, J = 7.5Hz, 2H), 7.60-7.47 (m, 3H), 7.35 (t, J = 7.5Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 6.15 (s, 2H), 5.29 (s, 2H).
步骤5：制备N-(4-(4-氨基-7-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-苯基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-苯基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率88％。 1H NMR(300MHz,DMSO)δ13.06(s,1H),8.73(d,J＝1.9Hz,1H),8.23(d,J＝1.9Hz,1H),8.21(s,1H),7.89(d,J＝7.8Hz,2H),7.85(d,J＝8.5Hz,2H),7.80–7.68(m,3H),7.61–7.49(m,4H),7.37(t,J＝7.8Hz,1H),7.30(t,J＝9.0Hz,2H),6.27(s,2H),4.11(d,J＝7.9Hz,2H),3.93–3.60(m,2H),3.37–3.22(m,2H),2.20–2.02(m,1H),1.53–1.23(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Phenyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-phenyl) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4) -yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 88%. 1 H NMR (300MHz, DMSO) δ13.06 (s, 1H), 8.73 (d, J = 1.9Hz, 1H), 8.23 (d, J = 1.9Hz, 1H), 8.21 (s, 1H), 7.89 ( d, J = 7.8 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.80 - 7.68 (m, 3H), 7.61 - 7.49 (m, 4H), 7.37 (t, J = 7.8 Hz, 1H) ), 7.30 (t, J = 9.0 Hz, 2H), 6.27 (s, 2H), 4.11 (d, J = 7.9 Hz, 2H), 3.93 - 3.60 (m, 2H), 3.37 - 3.22 (m, 2H) , 2.20–2.02 (m, 1H), 1.53–1.23 (m, 4H).
实施例41：N-(4-(4-氨基-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯 基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.41)Example 41: N-(4-(4-Amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.41)
Figure PCTCN2017115380-appb-000176
Figure PCTCN2017115380-appb-000176
步骤1：制备4-氯-5-碘-2-甲基-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000177
Figure PCTCN2017115380-appb-000177
将4-氯-7H-吡咯并[2,3-d]嘧啶替换成4-氯-2-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤4，得白色固体为4-氯-5-碘-2-甲基-7H-吡咯并[2,3-d]嘧啶，收率100％。 1H NMR(300MHz,DMSO)δ12.69(s,1H),7.81(s,1H),2.60(s,3H). Substituting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine to 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine, remaining materials, reagents and preparation methods In the same manner as in Step 4 of Example 1, a white solid was obtained as 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 100%. 1 H NMR (300MHz, DMSO) δ12.69 (s, 1H), 7.81 (s, 1H), 2.60 (s, 3H).
步骤2：制备4-氯5-碘-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶Step 2: Preparation of 4-chloro-5-iodo-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000178
Figure PCTCN2017115380-appb-000178
将4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-2-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤5，得白色固体为4-氯5-碘-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶，收率90％。 1H NMR(300MHz,DMSO)δ7.85(s,1H),3.77(s,3H),2.64(s,3H). Replace 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine, the rest The desired starting materials, reagents and preparation methods were the same as those in the step 5 of Example 1. The white solid was 4-chloro 5-iodo-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine, yield 90 %. 1 H NMR (300MHz, DMSO) δ7.85 (s, 1H), 3.77 (s, 3H), 2.64 (s, 3H).
步骤3：制备4-(4-氯-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 3: Preparation of 4-(4-chloro-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000179
Figure PCTCN2017115380-appb-000179
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯5-碘-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得类白色固体为4-(4-氯-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率91％。 1H NMR(300MHz,DMSO)δ7.49(s,1H),7.14(d,J＝8.3Hz,2H),6.60(d,J＝8.3Hz,2H),5.13(s,2H),3.80(s,3H),2.64(s,3H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-2,7-dimethyl-7H-pyrrolo[2, 3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid which is 4-(4-chloro-2,7-dimethyl-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)aniline in a yield of 91%. 1 H NMR (300MHz, DMSO) δ7.49 (s, 1H), 7.14 (d, J = 8.3Hz, 2H), 6.60 (d, J = 8.3Hz, 2H), 5.13 (s, 2H), 3.80 ( s, 3H), 2.64 (s, 3H).
步骤4：制备4-氨基-5-(4-氨基苯基)-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶Step 4: Preparation of 4-amino-5-(4-aminophenyl)-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000180
Figure PCTCN2017115380-appb-000180
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得白色固体为4-氨基-5-(4-氨基苯基)-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶，收率55％。 1H NMR(300MHz,DMSO)δ7.08(d,J＝8.4Hz,2H),7.02(s,1H),6.65(d,J＝8.4Hz,2H),6.02(s,2H),5.50(s,2H),3.67(s,3H),2.38(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-2,7-dimethyl-7H- Pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain 4-amino-5-(4-aminophenyl) as a white solid. -2,7-Dimethyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 55%. 1 H NMR (300MHz, DMSO) δ7.08 (d, J = 8.4Hz, 2H), 7.02 (s, 1H), 6.65 (d, J = 8.4Hz, 2H), 6.02 (s, 2H), 5.50 ( s, 2H), 3.67 (s, 3H), 2.38 (s, 3H).
步骤5：制备N-(4-(4-氨基-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-2,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorobenzene 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-2,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率73％。 1H NMR(300MHz,DMSO)δ13.01(s,1H),8.72(d,J＝1.8Hz,1H),8.22(d,J＝1.8Hz,1H),7.80(d,J＝8.4Hz,2H),7.73(dd,J＝8.7,5.7Hz,2H),7.42(d,J＝8.4Hz,2H),7.29(t,J＝8.7Hz,2H),7.23(s,1H),6.13(s,2H),4.11(d,J＝7.2Hz,2H),3.91–3.80(m,2H),3.70(s,3H),3.27(t,J＝11.4Hz,2H),2.43(s,3H),2.20–2.04(m,1H),1.51–1.20(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-2, 7-Dimethyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-2) ,7-Dimethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-) 2H-Pyr-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 73%. 1 H NMR (300MHz, DMSO) δ13.01 (s, 1H), 8.72 (d, J = 1.8Hz, 1H), 8.22 (d, J = 1.8Hz, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.73 (dd, J = 8.7, 5.7 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 8.7 Hz, 2H), 7.23 (s, 1H), 6.13 ( s, 2H), 4.11 (d, J = 7.2 Hz, 2H), 3.91 - 3.80 (m, 2H), 3.70 (s, 3H), 3.27 (t, J = 11.4 Hz, 2H), 2.43 (s, 3H) ), 2.20–2.04 (m, 1H), 1.51–1.20 (m, 4H).
实施例42：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.42)Example 42: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(3-fluoro-4-methyl Oxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.42)
Figure PCTCN2017115380-appb-000181
Figure PCTCN2017115380-appb-000181
步骤1：制备3-氟-4-甲氧基苯乙酰氯Step 1: Preparation of 3-fluoro-4-methoxyphenylacetyl chloride
Figure PCTCN2017115380-appb-000182
Figure PCTCN2017115380-appb-000182
将对甲基苯乙酸替换成3-氟-4-甲氧基苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为3-氟-4-甲氧基苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid was replaced by 3-fluoro-4-methoxyphenylacetic acid, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 2, and the yellow liquid was obtained as 3-fluoro-4-methoxybenzene. Acetyl chloride is used directly in the next step.
步骤2：制备4-(3-氟-4-甲氧基苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(3-fluoro-4-methoxyphenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000183
Figure PCTCN2017115380-appb-000183
将4-氟苯乙酰氯替换成3-氟-4-甲氧基苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得无色液体为4-(3-氟-4-甲氧基苯基)-3-氧代丁酸乙酯，步骤1和2总收率51％。 1H NMR(300MHz,DMSO)δ7.26–6.65(m,3H),4.07(q,J＝7.1Hz,2H),3.81(s,5H),3.64(s,2H),1.17(t,J＝7.1Hz,3H). Replacing 4-fluorophenylacetyl chloride with 3-fluoro-4-methoxyphenylacetyl chloride, the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a colorless liquid of 4-(3-fluoro- Ethyl 4-methoxyphenyl)-3-oxobutanoate, the overall yield of steps 1 and 2 was 51%. 1 H NMR (300MHz, DMSO) δ7.26-6.65 (m, 3H), 4.07 (q, J = 7.1Hz, 2H), 3.81 (s, 5H), 3.64 (s, 2H), 1.17 (t, J =7.1Hz, 3H).
步骤3：制备5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(3-fluoro-4-methoxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Ethyl hydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000184
Figure PCTCN2017115380-appb-000184
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(3-氟-4-甲氧基苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色固体为5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率75％。 1H NMR(300MHz,DMSO)δ8.27(d,J＝2.3Hz,1H),8.00(d,J＝2.3Hz,1H),7.57(dd,J＝13.4,2.1Hz,1H),7.50–7.42(m,1H),7.18(t,J＝9.0Hz,1H),4.20(q,J＝7.1Hz,2H),3.91(d,J＝7.3Hz,2H),3.89–3.75(m,5H),3.25(t,J＝10.8Hz,2H),2.11–1.98(m,1H),1.51–1.20(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate was replaced with ethyl 4-(3-fluoro-4-methoxyphenyl)-3-oxobutanoate, the remaining raw materials The reagent and the preparation method were the same as those in the second step of Example 1, to obtain a yellow solid as 5-(3-fluoro-4-methoxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4). -Methyl)methyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester in a yield of 75%. 1 H NMR (300MHz, DMSO) δ8.27 (d, J = 2.3Hz, 1H), 8.00 (d, J = 2.3Hz, 1H), 7.57 (dd, J = 13.4,2.1Hz, 1H), 7.50- 7.42 (m, 1H), 7.18 (t, J = 9.0 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.91 (d, J = 7.3 Hz, 2H), 3.89 - 3.75 (m, 5H) ), 3.25 (t, J = 10.8 Hz, 2H), 2.11 - 1.98 (m, 1H), 1.51 - 1.20 (m, 7H).
步骤4：制备5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(3-fluoro-4-methoxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Hydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000185
Figure PCTCN2017115380-appb-000185
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得黄色固体为5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率90％。 1H NMR(300MHz,DMSO)δ8.75(d,J＝1.8Hz,1H),8.43(d,J＝1.8Hz,1H),7.63(dd,J＝13.2,2.0Hz,1H),7.58–7.52(m,1H),7.26(t,J＝8.9Hz,1H),4.13(d,J＝7.4Hz,2H),3.97–3.63(m,5H),3.30–3.09(m,2H),2.20–2.01(m,1H),1.55–1.17(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate 5-(3-Fluoro-4-methoxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine- Ethyl 3-carboxylate, the remaining starting materials, reagents and preparation methods are the same as in the third step of Example 1, to obtain a yellow solid as 5-(3-fluoro-4-methoxyphenyl)-4-oxo-1-( (Tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 90%. 1 H NMR (300MHz, DMSO) δ8.75 (d, J = 1.8Hz, 1H), 8.43 (d, J = 1.8Hz, 1H), 7.63 (dd, J = 13.2,2.0Hz, 1H), 7.58- 7.52 (m, 1H), 7.26 (t, J = 8.9 Hz, 1H), 4.13 (d, J = 7.4 Hz, 2H), 3.97 - 3.63 (m, 5H), 3.30 - 3.09 (m, 2H), 2.20 –2.01 (m, 1H), 1.55–1.17 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(3-fluoro-4-methyl Oxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3-氟-4-甲氧基苯基)-4-氧代-1-((四氢-2H-吡喃-4- 基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率71％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.70(d,J＝2.1Hz,1H),8.24(d,J＝2.1Hz,1H),8.15(s,1H),7.81(d,J＝8.5Hz,2H),7.64(dd,J＝13.2,2.0Hz,1H),7.58–7.49(m,1H),7.44(d,J＝8.5Hz,2H),7.30(s,1H),7.24(t,J＝8.9Hz,1H),6.10(s,2H),4.11(d,J＝7.0Hz,2H),3.92–3.82(m,5H),3.74(s,3H),3.32–3.22(m,2H),2.27–2.04(m,1H),1.58–1.10(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(3-fluoro-4-methoxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Formic acid, the remaining starting materials, reagents and preparation methods are the same as in Step 8 of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine. -5-yl)phenyl)-5-(3-fluoro-4-methoxyphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)- 1,4-Dihydropyridine-3-carboxamide, 71% yield. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.70 (d, J = 2.1Hz, 1H), 8.24 (d, J = 2.1Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.5 Hz, 2H), 7.64 (dd, J = 13.2, 2.0 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H) ), 7.24 (t, J = 8.9 Hz, 1H), 6.10 (s, 2H), 4.11 (d, J = 7.0 Hz, 2H), 3.92 - 3.82 (m, 5H), 3.74 (s, 3H), 3.32 –3.22 (m, 2H), 2.27–2.04 (m, 1H), 1.58–1.10 (m, 4H).
实施例43：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.43)Example 43: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(furan-2-yl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.43)
Figure PCTCN2017115380-appb-000186
Figure PCTCN2017115380-appb-000186
步骤1：制备2-呋喃乙酰氯Step 1: Preparation of 2-furanacetyl chloride
Figure PCTCN2017115380-appb-000187
Figure PCTCN2017115380-appb-000187
将对甲基苯乙酸替换成2-呋喃乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为2-呋喃乙酰氯，直接用于下一步。The p-methylphenylacetic acid was replaced by 2-furanacetic acid, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 2 to obtain a yellow liquid which was 2-furanacetyl chloride, which was directly used in the next step.
步骤2：制备4-(呋喃-2-基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(furan-2-yl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000188
Figure PCTCN2017115380-appb-000188
将4-氟苯乙酰氯替换成2-呋喃乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得黄色液体为4-(呋喃-2-基)-3-氧代丁酸乙酯，步骤1和2总收率11％。 1H NMR(300MHz,DMSO)δ7.58(dd,J＝1.8,0.8Hz,1H),6.41(dd,J＝3.1,1.8Hz,1H),6.26(dd,J＝3.1,0.8Hz,1H),4.08(q,J＝7.1Hz,2H),3.94(s,2H),3.63(s,2H),1.18(t,J＝7.1Hz,3H). Replacing 4-fluorophenylacetyl chloride with 2-furanacetyl chloride, the remaining starting materials, reagents and preparation methods are the same as in step 1 of Example 1, to obtain a yellow liquid of 4-(furan-2-yl)-3-oxobutyl Ethyl acetate, total yield of steps 1 and 2 was 11%. 1 H NMR (300MHz, DMSO) δ7.58 (dd, J = 1.8,0.8Hz, 1H), 6.41 (dd, J = 3.1,1.8Hz, 1H), 6.26 (dd, J = 3.1,0.8Hz, 1H ), 4.08 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 3.63 (s, 2H), 1.18 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(furan-2-yl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester
Figure PCTCN2017115380-appb-000189
Figure PCTCN2017115380-appb-000189
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(呋喃-2-基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色液体为5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率69％。 1H NMR(300MHz,DMSO) δ8.29(d,J＝2.3Hz,1H),8.21(d,J＝2.3Hz,1H),7.71(dd,J＝1.8,0.7Hz,1H),7.33(dd,J＝3.3,0.7Hz,1H),6.57(dd,J＝3.3,1.8Hz,1H),4.21(q,J＝7.1Hz,2H),3.99(d,J＝7.5Hz,2H),3.91–3.73(m,2H),3.31–3.20(m,2H),2.14–1.92(m,1H),1.52–1.18(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 4-(furan-2-yl)-3-oxobutanoate, the remaining raw materials, reagents and preparation methods are the same In step 2 of Example 1, the yellow liquid was obtained as 5-(furan-2-yl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Ethyl hydropyridine-3-carboxylate in a yield of 69%. 1 H NMR (300MHz, DMSO) δ8.29 (d, J = 2.3Hz, 1H), 8.21 (d, J = 2.3Hz, 1H), 7.71 (dd, J = 1.8,0.7Hz, 1H), 7.33 ( Dd, J = 3.3, 0.7 Hz, 1H), 6.57 (dd, J = 3.3, 1.8 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.99 (d, J = 7.5 Hz, 2H), 3.91–3.73 (m, 2H), 3.31–3.20 (m, 2H), 2.14–1.92 (m, 1H), 1.52–1.18 (m, 7H).
步骤4：制备5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(furan-2-yl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000190
Figure PCTCN2017115380-appb-000190
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得类白色固体为5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率76％。 1H NMR(300MHz,DMSO)δ8.73(s,1H),8.59(s,1H),7.84(s,1H),7.35(d,J＝3.1Hz,1H),6.89–6.59(m,1H),4.20(d,J＝7.4Hz,2H),3.95–3.68(m,2H),3.24(t,J＝11.1Hz,2H),2.20–1.95(m,1H),1.49–1.19(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(furan-2-yl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate, The remaining starting materials, reagents and preparation methods are the same as those in the third step of Example 1, to obtain a white solid as 5-(furan-2-yl)-4-oxo-1-((tetrahydro-2H-pyran-4-) Methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 76%. 1 H NMR (300MHz, DMSO) δ8.73 (s, 1H), 8.59 (s, 1H), 7.84 (s, 1H), 7.35 (d, J = 3.1Hz, 1H), 6.89-6.59 (m, 1H ), 4.20 (d, J = 7.4 Hz, 2H), 3.95 - 3.68 (m, 2H), 3.24 (t, J = 11.1 Hz, 2H), 2.20 - 1.95 (m, 1H), 1.49 - 1.19 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(furan-2-yl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(呋喃-2-基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率64％。 1H NMR(300MHz,DMSO)δ12.92(s,1H),8.69(d,J＝2.1Hz,1H),8.45(d,J＝2.1Hz,1H),8.16(s,1H),7.83(d,J＝8.6Hz,2H),7.79(dd,J＝1.7,0.7Hz,1H),7.48–7.41(m,3H),7.31(s,1H),6.65(dd,J＝3.3,1.8Hz,1H),6.11(s,2H),4.18(d,J＝7.0Hz,2H),3.93–3.81(m,2H),3.74(s,3H),3.26(t,J＝11.3Hz,2H),2.14–2.01(m,1H),1.52–1.19(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(furan-2-yl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the remaining raw materials The reagent and the preparation method are the same as those in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl. -5-(furan-2-yl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, The yield was 64%. 1 H NMR (300 MHz, DMSO) δ 12.92 (s, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.16 (s, 1H), 7.83 ( d, J = 8.6 Hz, 2H), 7.79 (dd, J = 1.7, 0.7 Hz, 1H), 7.48 - 7.41 (m, 3H), 7.31 (s, 1H), 6.65 (dd, J = 3.3, 1.8 Hz) , 1H), 6.11 (s, 2H), 4.18 (d, J = 7.0 Hz, 2H), 3.93 - 3.81 (m, 2H), 3.74 (s, 3H), 3.26 (t, J = 11.3 Hz, 2H) , 2.14–2.01 (m, 1H), 1.52–1.19 (m, 4H).
实施例44：N-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.44)Example 44: N-(4-(4-Amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.44)
Figure PCTCN2017115380-appb-000191
Figure PCTCN2017115380-appb-000191
步骤1：制备4-氯-7-环丙基-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000192
Figure PCTCN2017115380-appb-000192
将苯硼酸替换成环丙基硼酸，其余所需原料、试剂及制备方法同实施例40步骤1，得黄色固体为4-氯-7-环丙基-7H-吡咯并[2,3-d]嘧啶，收率17％。 1H NMR(300MHz,DMSO)δ8.65(s,1H),7.70(d,J＝3.4Hz,1H),6.59(d,J＝3.4Hz,1H),3.83–3.48(m,1H),1.12–1.03(m,4H). The phenylboronic acid was replaced with cyclopropylboronic acid, and the remaining starting materials, reagents and preparation methods were the same as those in the first step of Example 40 to obtain 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d. Pyrimidine, yield 17%. 1 H NMR (300MHz, DMSO) δ8.65 (s, 1H), 7.70 (d, J = 3.4Hz, 1H), 6.59 (d, J = 3.4Hz, 1H), 3.83-3.48 (m, 1H), 1.12–1.03 (m, 4H).
步骤2：制备4-氯-7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶Step 2: Preparation of 4-chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000193
Figure PCTCN2017115380-appb-000193
将4-氯-7H-吡咯并[2,3-d]嘧啶替换成4-氯-7-环丙基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤4，得类白色固体为4-氯-7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶，收率49％。 1H NMR(300MHz,DMSO)δ8.66(s,1H),7.95(s,1H),3.72–3.54(m,1H),1.20–0.98(m,4H). Replace 4-chloro-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation The same procedure as in Example 4, Step 4 gave a white solid as 4-chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine in a yield of 49%. 1 H NMR (300 MHz, DMSO) δ 8.66 (s, 1H), 7.95 (s, 1H), 3.72 - 3.54 (m, 1H), 1.20 - 0.98 (m, 4H).
步骤3：制备4-(4-氯-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 3: Preparation of 4-(4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000194
Figure PCTCN2017115380-appb-000194
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率58％。 1H NMR(300MHz,DMSO)δ8.62(s,1H),7.57(s,1H),7.16(d,J＝7.8Hz,2H),6.61(d,J＝7.8Hz,2H),5.20(s,2H),3.79–3.54(m,1H),1.17–1.05(m,4H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-7-cyclopropyl-5-iodo-7H-pyrrolo[2,3 -d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine. -5-yl) aniline, yield 58%. 1 H NMR (300MHz, DMSO) δ8.62 (s, 1H), 7.57 (s, 1H), 7.16 (d, J = 7.8Hz, 2H), 6.61 (d, J = 7.8Hz, 2H), 5.20 ( s, 2H), 3.79–3.54 (m, 1H), 1.17–1.05 (m, 4H).
步骤4：制备4-氨基-5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶Step 4: Preparation of 4-amino-5-(4-aminophenyl)-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000195
Figure PCTCN2017115380-appb-000195
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-环丙基-7H-吡 咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得白色固体为4-氨基-5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶，收率60％。 1H NMR(300MHz,DMSO)δ8.11(s,1H),7.09(d,J＝8.1Hz,2H),7.02(s,1H),6.64(d,J＝8.1Hz,2H),5.98(s,2H),5.19(s,2H),3.60–3.43(m,1H),1.08–0.94(m,4H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-cyclopropyl-7H-pyrrole [2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to give 4-amino-5-(4-aminophenyl)-7 as a white solid. - cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 60%. 1 H NMR (300MHz, DMSO) δ8.11 (s, 1H), 7.09 (d, J = 8.1Hz, 2H), 7.02 (s, 1H), 6.64 (d, J = 8.1Hz, 2H), 5.98 ( s, 2H), 5.19 (s, 2H), 3.60–3.43 (m, 1H), 1.08–0.94 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率48％。 1H NMR(300MHz,DMSO)δ13.01(s,1H),8.72(d,J＝1.7Hz,1H),8.22(d,J＝1.7Hz,1H),8.16(s,1H),7.80(d,J＝8.2Hz,2H),7.73(dd,J＝8.1,5.3Hz,2H),7.44(d,J＝8.2Hz,2H),7.34–7.26(m,2H),7.25(s,1H),6.12(s,2H),4.11(d,J＝7.0Hz,2H),3.93–3.79(m,2H),3.68–3.52(m,1H),3.33–3.15(m,2H),2.18–2.03(m,1H),1.54–1.22(m,4H),1.09–0.98(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-7-cyclo). Propyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran) 4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 48%. 1 H NMR (300MHz, DMSO) δ13.01 (s, 1H), 8.72 (d, J = 1.7Hz, 1H), 8.22 (d, J = 1.7Hz, 1H), 8.16 (s, 1H), 7.80 ( d, J = 8.2 Hz, 2H), 7.73 (dd, J = 8.1, 5.3 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.34 - 7.26 (m, 2H), 7.25 (s, 1H) ), 6.12 (s, 2H), 4.11 (d, J = 7.0 Hz, 2H), 3.93 - 3.79 (m, 2H), 3.68 - 3.52 (m, 1H), 3.33 - 3.15 (m, 2H), 2.18 - 2.03 (m, 1H), 1.54–1.22 (m, 4H), 1.09–0.98 (m, 4H).
实施例45：N-(4-(4-氨基-7-(2-(二甲氨基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.45)Example 45: N-(4-(4-Amino-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.45 )
Figure PCTCN2017115380-appb-000196
Figure PCTCN2017115380-appb-000196
步骤1：制备4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-N,N-二甲基乙胺Step 1: Preparation of 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N,N-dimethylethylamine
Figure PCTCN2017115380-appb-000197
Figure PCTCN2017115380-appb-000197
将1-甲基-4-哌啶醇替换成N,N-二甲基乙醇胺，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-N,N-二甲基乙胺，收率96％。 1H NMR(300MHz,DMSO)δ8.64(s,1H),8.03(s,1H),4.44–4.27(m,2H),2.85–2.54(m,2H),2.19(s,6H). Replacing 1-methyl-4-piperidinol with N,N-dimethylethanolamine, the remaining starting materials, reagents and preparation methods are the same as in Step 1 of Example 14, to obtain 4-(4-chloro-5) as a white solid. - Iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N,N-dimethylethylamine, yield 96%. 1 H NMR (300MHz, DMSO) δ8.64 (s, 1H), 8.03 (s, 1H), 4.44-4.27 (m, 2H), 2.85-2.54 (m, 2H), 2.19 (s, 6H).
步骤2：制备4-(4-氯-7-(2-(二甲氨基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000198
Figure PCTCN2017115380-appb-000198
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)-N,N-二甲基乙胺，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色液体为4-(4-氯-7-(2-(二甲氨基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率27％。 1H NMR(300MHz,DMSO)δ8.60(s,1H),7.68(s,1H),7.16(d,J＝7.9Hz,2H),6.61(d,J＝7.9Hz,2H),5.16(s,2H),4.54–4.23(m,2H),2.84–2.61(m,2H),2.19(s,6H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d] Pyrimidine-7-yl)-N,N-dimethylethylamine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow liquid of 4-(4-chloro-7-(2-( Dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 27%. 1 H NMR (300MHz, DMSO) δ8.60 (s, 1H), 7.68 (s, 1H), 7.16 (d, J = 7.9Hz, 2H), 6.61 (d, J = 7.9Hz, 2H), 5.16 ( s, 2H), 4.54–4.23 (m, 2H), 2.84–2.61 (m, 2H), 2.19 (s, 6H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(2-(二甲胺基)乙基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000199
Figure PCTCN2017115380-appb-000199
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(2-(二甲氨基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得白色固体为4-氨基-5-(4-氨基苯基)-7-(2-(二甲胺基)乙基)-7H-吡咯并[2,3-d]嘧啶，收率71％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.15(s,1H),7.10(d,J＝8.3Hz,2H),6.66(d,J＝8.3Hz,2H),5.99(s,2H),5.18(s,2H),4.34–4.13(m,2H),2.80–2.58(m,2H),2.21(s,6H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(2-(dimethylamino)) Ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a white solid 4-amino-5-( 4-aminophenyl)-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidine, yield 71%. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.15 (s, 1H), 7.10 (d, J = 8.3Hz, 2H), 6.66 (d, J = 8.3Hz, 2H), 5.99 ( s, 2H), 5.18 (s, 2H), 4.34 - 4.13 (m, 2H), 2.80 - 2.58 (m, 2H), 2.21 (s, 6H).
步骤4：制备N-(4-(4-氨基-7-(2-(二甲氨基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(2-(二甲胺基)乙基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-(2-(二甲氨基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率79％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝2.2Hz,1H),8.26(d,J＝2.2Hz,1H),8.14(s,1H),7.81(d,J＝8.2Hz,2H),7.74(dd,J＝8.9,5.9Hz,2H),7.44(d,J＝8.2Hz,2H),7.37(s,1H),7.34–7.21(m,2H),6.10(s,2H),4.35–4.22(m,2H),4.13(d,J＝6.5Hz,2H),3.92–3.78(m,2H),3.26(t,J＝11.6Hz,2H),2.76–2.59(m,2H),2.20(s,6H),2.16–2.04(m,1H),1.54–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (2-(Dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4 -(4-Amino-7-(2-(dimethylamino)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 79%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.26 (d, J = 2.2Hz, 1H), 8.14 (s, 1H), 7.81 ( d, J = 8.2 Hz, 2H), 7.74 (dd, J = 8.9, 5.9 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.37 (s, 1H), 7.34 - 7.21 (m, 2H) ), 6.10 (s, 2H), 4.35 - 4.22 (m, 2H), 4.13 (d, J = 6.5 Hz, 2H), 3.92 - 3.78 (m, 2H), 3.26 (t, J = 11.6 Hz, 2H) , 2.76–2.59 (m, 2H), 2.20 (s, 6H), 2.16–2.04 (m, 1H), 1.54–1.22 (m, 4H).
实施例46：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.46)Example 46: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(3-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.46)
Figure PCTCN2017115380-appb-000200
Figure PCTCN2017115380-appb-000200
步骤1：制备3-氟苯乙酰氯Step 1: Preparation of 3-fluorophenylacetyl chloride
Figure PCTCN2017115380-appb-000201
Figure PCTCN2017115380-appb-000201
将对甲基苯乙酸替换成3-氟苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为3-氟苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid was replaced with 3-fluorophenylacetic acid, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 2, and the yellow liquid was 3-fluorophenylacetyl chloride, which was directly used in the next step.
步骤2：制备4-(3-氟苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(3-fluorophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000202
Figure PCTCN2017115380-appb-000202
将4-氟苯乙酰氯替换成3-氟苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得黄色液体为4-(3-氟苯基)-3-氧代丁酸乙酯，步骤1和2总收率29％。 1H NMR(300MHz,DMSO)δ7.43–7.30(m,1H),7.16–6.97(m,3H),4.11(q,J＝7.1Hz,2H),3.92(s,2H),3.67(s,2H),1.19(t,J＝7.1Hz,3H). 4-Fluorophenylacetyl chloride is replaced by 3-fluorophenylacetyl chloride, and the remaining raw materials, reagents and preparation methods are the same as in Step 1 of Example 1, and the yellow liquid is 4-(3-fluorophenyl)-3-oxo. Ethyl butyrate, total yield of steps 1 and 2 was 29%. 1 H NMR (300MHz, DMSO) δ7.43-7.30 (m, 1H), 7.16-6.97 (m, 3H), 4.11 (q, J = 7.1Hz, 2H), 3.92 (s, 2H), 3.67 (s , 2H), 1.19 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(3-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid Ethyl ester
Figure PCTCN2017115380-appb-000203
Figure PCTCN2017115380-appb-000203
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(3-氟苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色液体为5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率19％。 1H NMR(300MHz,DMSO)δ8.30(d,J＝1.2Hz,1H),8.06(d,J＝1.2Hz,1H),7.69–7.29(m,3H),7.29–6.97(m,1H),4.21(q,J＝7.3Hz,2H),3.92(d,J＝7.7Hz,2H),3.89–3.77(m,2H),3.34–3.16(m,2H),2.13–1.87(m,1H),1.52–1.10(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 4-(3-fluorophenyl)-3-oxobutanoate, the remaining raw materials, reagents and preparation methods are the same In step 2 of Example 1, the yellow liquid was obtained as 5-(3-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-di Ethyl hydropyridine-3-carboxylate in a yield of 19%. 1 H NMR (300MHz, DMSO) δ8.30 (d, J = 1.2Hz, 1H), 8.06 (d, J = 1.2Hz, 1H), 7.69-7.29 (m, 3H), 7.29-6.97 (m, 1H ), 4.21 (q, J = 7.3 Hz, 2H), 3.92 (d, J = 7.7 Hz, 2H), 3.89 - 3.77 (m, 2H), 3.34 - 3.16 (m, 2H), 2.13 - 1.87 (m, 1H), 1.52–1.10 (m, 7H).
步骤4：制备5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(3-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000204
Figure PCTCN2017115380-appb-000204
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得黄色固体为5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率65％。 1H NMR(300MHz,DMSO)δ8.79(s,1H),8.48(s,1H),7.81–7.27(m,3H),7.39–6.79(m,1H),4.14(d,J＝7.2Hz,2H),3.90–3.76(m,2H),3.24(t,J＝11.6Hz,2H),2.23–1.96(m,1H),1.52–1.15(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(3-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate, The remaining starting materials, reagents and preparation methods are the same as those in the third step of Example 1, to obtain a yellow solid as 5-(3-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl). )methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 65%. 1 H NMR (300MHz, DMSO) δ8.79 (s, 1H), 8.48 (s, 1H), 7.81-7.27 (m, 3H), 7.39-6.79 (m, 1H), 4.14 (d, J = 7.2Hz , 2H), 3.90–3.76 (m, 2H), 3.24 (t, J = 11.6 Hz, 2H), 2.23–1.96 (m, 1H), 1.52–1.15 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(3-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(3-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率96％。 1H NMR(300MHz,DMSO)δ12.96(s,1H),8.73(d,J＝2.1Hz,1H),8.30(d,J＝2.1Hz,1H),8.14(s,1H),7.81(d,J＝8.5Hz,2H),7.64–7.47(m,3H),7.43(d,J＝8.5Hz,2H),7.30(s,1H),7.28–7.16(m,1H),6.09(s,2H),4.12(d,J＝7.0Hz,2H),3.92–3.76(m,2H),3.73(s,3H),3.34–3.20(m,2H),2.20–1.92(m,1H),1.60–0.99(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(3-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the remaining raw materials The reagent and the preparation method are the same as those in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl. -5-(3-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, The yield was 96%. 1 H NMR (300MHz, DMSO) δ12.96 (s, 1H), 8.73 (d, J = 2.1Hz, 1H), 8.30 (d, J = 2.1Hz, 1H), 8.14 (s, 1H), 7.81 ( d, J = 8.5 Hz, 2H), 7.64 - 7.47 (m, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H), 7.28 - 7.16 (m, 1H), 6.09 (s , 2H), 4.12 (d, J = 7.0 Hz, 2H), 3.92 - 3.76 (m, 2H), 3.73 (s, 3H), 3.34 - 3.20 (m, 2H), 2.20 - 1.92 (m, 1H), 1.60–0.99 (m, 4H).
实施例47：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.47)Example 47: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-cyanophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.47)
Figure PCTCN2017115380-appb-000205
Figure PCTCN2017115380-appb-000205
步骤1：制备4-氰基苯乙酰氯Step 1: Preparation of 4-cyanophenylacetyl chloride
Figure PCTCN2017115380-appb-000206
Figure PCTCN2017115380-appb-000206
将对甲基苯乙酸替换成4-氰基苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得红色液体为4-氰基苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid was replaced with 4-cyanophenylacetic acid, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 2 to obtain a red liquid of 4-cyanophenylacetyl chloride, which was directly used in the next step.
步骤2：制备4-(4-氰基苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(4-cyanophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000207
Figure PCTCN2017115380-appb-000207
将4-氟苯乙酰氯替换成4-氰基苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得红色液体为4-(4-氰基苯基)-3-氧代丁酸乙酯，步骤1和2总收率18％。 1H NMR(300MHz,DMSO)δ7.79(d,J＝8.3Hz,2H),7.39(d,J＝8.3Hz,2H),4.09(q,J＝7.1Hz,2H),4.03(s,2H),3.71(s,2H),1.18(t,J＝7.1Hz,3H). Replacing 4-fluorophenylacetyl chloride with 4-cyanophenylacetyl chloride, the remaining starting materials, reagents and preparation methods are the same as in step 1 of Example 1, and the red liquid is 4-(4-cyanophenyl)-3- Ethyl oxobutyrate, total yield of steps 1 and 2 was 18%. 1 H NMR (300MHz, DMSO) δ7.79 (d, J = 8.3Hz, 2H), 7.39 (d, J = 8.3Hz, 2H), 4.09 (q, J = 7.1Hz, 2H), 4.03 (s, 2H), 3.71 (s, 2H), 1.18 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(4-cyanophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Ethyl formate
Figure PCTCN2017115380-appb-000208
Figure PCTCN2017115380-appb-000208
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(4-氰基苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色液体为5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率64％。 1H NMR(300MHz,DMSO)δ8.32(d,J＝2.2Hz,1H),8.13(d,J＝2.2Hz,1H),7.86(s,4H),4.21(q,J＝7.1Hz,2H),3.93(d,J＝7.5Hz,2H),3.88–3.82(m,2H),3.31–3.14(m,2H),2.26–1.80(m,1H),1.52–1.03(m,7H). Replacement of ethyl 4-(4-fluorophenyl)-3-oxobutanoate with ethyl 4-(4-cyanophenyl)-3-oxobutanoate, remaining materials, reagents and preparation methods In the same manner as in Step 2 of Example 1, the yellow liquid was obtained as 5-(4-cyanophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4. - Dihydropyridine-3-carboxylic acid ethyl ester in a yield of 64%. 1 H NMR (300MHz, DMSO) δ8.32 (d, J = 2.2Hz, 1H), 8.13 (d, J = 2.2Hz, 1H), 7.86 (s, 4H), 4.21 (q, J = 7.1Hz, 2H), 3.93 (d, J = 7.5 Hz, 2H), 3.88 - 3.82 (m, 2H), 3.31 - 3.14 (m, 2H), 2.26 - 1.80 (m, 1H), 1.52 - 1.03 (m, 7H) .
步骤4：制备5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(4-cyanophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Formic acid
Figure PCTCN2017115380-appb-000209
Figure PCTCN2017115380-appb-000209
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得类白色固体为5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率48％。 1H NMR(300MHz,DMSO)δ8.81(s,1H),8.54(s,1H),8.10–7.64(m,4H),4.15(d,J＝7.1Hz,2H),3.97–3.57(m,2H),3.24(t,J＝11.2Hz,2H),2.21–1.98(m,1H),1.53–1.19(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-cyanophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate The remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, and the white solid is 5-(4-cyanophenyl)-4-oxo-1-((tetrahydro-2H-pyran)- 4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 48%. 1 H NMR (300 MHz, DMSO) δ 8.81 (s, 1H), 8.54 (s, 1H), 8.10 - 7.64 (m, 4H), 4.15 (d, J = 7.1 Hz, 2H), 3.97 - 3.57 (m) , 2H), 3.24 (t, J = 11.2 Hz, 2H), 2.21 - 1.98 (m, 1H), 1.53 - 1.19 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-cyanophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氰基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二 氢吡啶-3-甲酰胺，收率79％。 1H NMR(300MHz,DMSO)δ12.90(s,1H),8.76(s,1H),8.36(s,1H),8.15(s,1H),7.93(s,4H),7.81(d,J＝8.2Hz,2H),7.44(d,J＝8.2Hz,2H),7.30(s,1H),6.10(s,2H),4.13(d,J＝6.9Hz,2H),3.93–3.80(m,2H),3.74(s,3H),3.27(t,J＝11.8Hz,2H),2.24–2.03(m,1H),1.52–1.18(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-cyanophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the rest required The starting materials, reagents and preparation methods were the same as those in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene. 5-(4-cyanophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-methyl Amide, yield 79%. 1 H NMR (300MHz, DMSO) δ12.90 (s, 1H), 8.76 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.93 (s, 4H), 7.81 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 6.10 (s, 2H), 4.13 (d, J = 6.9 Hz, 2H), 3.93 - 3.80 (m) , 2H), 3.74 (s, 3H), 3.27 (t, J = 11.8 Hz, 2H), 2.24 - 2.03 (m, 1H), 1.52 - 1.18 (m, 4H).
实施例48：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.48)Example 48: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-(methylthio) Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.48)
Figure PCTCN2017115380-appb-000210
Figure PCTCN2017115380-appb-000210
步骤1：制备4-甲硫基苯乙酰氯Step 1: Preparation of 4-methylthiophenylacetyl chloride
Figure PCTCN2017115380-appb-000211
Figure PCTCN2017115380-appb-000211
将对甲基苯乙酸替换成4-甲硫基苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为4-甲硫基苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid is replaced by 4-methylthiophenylacetic acid, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 2, and the yellow liquid is 4-methylthiophenylacetyl chloride, which is directly used in the next step. .
步骤2：制备4-(4-(甲硫基)苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(4-(methylthio)phenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000212
Figure PCTCN2017115380-appb-000212
将4-氟苯乙酰氯替换成4-甲硫基苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得黄色液体为4-(4-(甲硫基)苯基)-3-氧代丁酸乙酯，步骤1和2总收率23％。 1H NMR(300MHz,DMSO)δ7.21(d,J＝8.2Hz,2H),7.12(d,J＝8.2Hz,2H),4.07(q,J＝7.1Hz,2H),3.83(s,2H),3.64(s,2H),2.45(s,3H),1.17(t,J＝7.1Hz,3H). Replace 4-fluorophenylacetyl chloride with 4-methylthiophenylacetyl chloride. The remaining raw materials, reagents and preparation methods are the same as those in step 1 of Example 1. The yellow liquid is 4-(4-(methylthio)phenyl. Ethyl 3-oxobutanoate, total yield of steps 1 and 2 of 23%. 1 H NMR (300MHz, DMSO) δ7.21 (d, J = 8.2Hz, 2H), 7.12 (d, J = 8.2Hz, 2H), 4.07 (q, J = 7.1Hz, 2H), 3.83 (s, 2H), 3.64 (s, 2H), 2.45 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H).
步骤3：制备5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(4-(methylthio)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine Ethyl 3-carboxylate
Figure PCTCN2017115380-appb-000213
Figure PCTCN2017115380-appb-000213
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(4-(甲硫基)苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色液体为5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率21％。 1H NMR(300MHz,DMSO)δ8.27(d,J＝2.1Hz,1H),7.95(d,J＝2.1Hz,1H),7.58(d,J＝8.3Hz,2H),7.27(d,J＝8.3Hz,2H),4.20(q,J＝7.2Hz,2H),3.91(d,J＝7.5Hz,2H),3.89– 3.80(m,2H),3.25(t,J＝10.9Hz,2H),2.49(s,3H),2.17–1.87(m,1H),1.50–1.08(m,7H). Ethyl 4-(4-fluorophenyl)-3-oxobutanoate is replaced by ethyl 4-(4-(methylthio)phenyl)-3-oxobutanoate, the remaining raw materials, reagents And the preparation method is the same as the second step of the first embodiment, the yellow liquid is 5-(4-(methylthio)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)- Ethyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester, yield 21%. 1 H NMR (300MHz, DMSO) δ8.27 (d, J = 2.1Hz, 1H), 7.95 (d, J = 2.1Hz, 1H), 7.58 (d, J = 8.3Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.91 (d, J = 7.5 Hz, 2H), 3.89 - 3.80 (m, 2H), 3.25 (t, J = 10.9 Hz, 2H), 2.49 (s, 3H), 2.17–1.87 (m, 1H), 1.50–1.08 (m, 7H).
步骤4：制备5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(4-(methylthio)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine 3-carboxylic acid
Figure PCTCN2017115380-appb-000214
Figure PCTCN2017115380-appb-000214
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得类白色固体为5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率30％。 1H NMR(300MHz,DMSO)δ8.76(d,J＝1.8Hz,1H),8.40(d,J＝1.8Hz,1H),7.66(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),4.14(d,J＝7.3Hz,2H),3.90–3.73(m,2H),3.24(t,J＝11.0Hz,2H),2.52(s,3H),2.21–2.02(m,1H),1.51–1.23(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate 5-(4-(Methylthio)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Ethyl formate, the remaining starting materials, reagents and preparation methods are the same as in the third step of Example 1, to obtain a white solid as 5-(4-(methylthio)phenyl)-4-oxo-1-((tetrahydro) -2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 30%. 1 H NMR (300MHz, DMSO) δ8.76 (d, J = 1.8Hz, 1H), 8.40 (d, J = 1.8Hz, 1H), 7.66 (d, J = 8.4Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 4.14 (d, J = 7.3 Hz, 2H), 3.90 - 3.73 (m, 2H), 3.24 (t, J = 11.0 Hz, 2H), 2.52 (s, 3H), 2.21 - 2.02 (m, 1H), 1.51–1.23 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-(methylthio) Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-(甲硫基)苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率58％。 1H NMR(300MHz,DMSO)δ13.05(s,1H),8.70(d,J＝1.7Hz,1H),8.20(d,J＝1.7Hz,1H),8.15(s,1H),7.80(d,J＝8.4Hz,2H),7.66(d,J＝8.4Hz,2H),7.44(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,2H),7.30(s,1H),6.11(s,2H),4.11(d,J＝7.4Hz,2H),3.91–3.80(m,2H),3.74(s,3H),3.27(t,J＝11.5Hz,2H),2.52(s,3H),2.21–2.01(m,1H),1.60–1.21(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-(methylthio)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, The remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5. -yl)phenyl)-5-(4-(methylthio)phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxamide, yield 58%. 1 H NMR (300MHz, DMSO) δ13.05 (s, 1H), 8.70 (d, J = 1.7Hz, 1H), 8.20 (d, J = 1.7Hz, 1H), 8.15 (s, 1H), 7.80 ( d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 6.11 (s, 2H), 4.11 (d, J = 7.4 Hz, 2H), 3.91 - 3.80 (m, 2H), 3.74 (s, 3H), 3.27 (t, J = 11.5 Hz, 2H), 2.52 (s, 3H), 2.21–2.01 (m, 1H), 1.60–1.21 (m, 4H).
实施例49：N-(4-(4-氨基-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.49)Example 49: N-(4-(4-Amino-7-(2-(methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.49 )
Figure PCTCN2017115380-appb-000215
Figure PCTCN2017115380-appb-000215
步骤1：制备4-氯-5-碘-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-(2-(methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000216
Figure PCTCN2017115380-appb-000216
将1-甲基-4-哌啶醇替换成2-甲硫基乙醇，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-氯-5-碘-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶，收率95.4％。 1H NMR(300MHz,DMSO)δ8.64(s,1H),8.06(s,1H),4.46(t,J＝6.7Hz,2H),2.94(t,J＝6.7Hz,2H),2.06(s,3H). Replace 1-methyl-4-piperidinol with 2-methylthioethanol. The remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 14. The white solid is 4-chloro-5-iodo-7- (2-(Methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidine, yield 95.4%. 1 H NMR (300MHz, DMSO) δ8.64 (s, 1H), 8.06 (s, 1H), 4.46 (t, J = 6.7Hz, 2H), 2.94 (t, J = 6.7Hz, 2H), 2.06 ( s, 3H).
步骤2：制备4-(4-氯-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(2-(methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000217
Figure PCTCN2017115380-appb-000217
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率75％。 1H NMR(300MHz,DMSO)δ8.61(s,1H),7.72(s,1H),7.16(d,J＝7.9Hz,2H),6.62(d,J＝7.9Hz,2H),5.17(s,2H),4.49(t,J＝6.5Hz,2H),2.98(t,J＝6.5Hz,2H),2.07(s,3H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-(2-(methylthio)ethyl)- 7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-(2-(methylthio)). Ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline in a yield of 75%. 1 H NMR (300MHz, DMSO) δ8.61 (s, 1H), 7.72 (s, 1H), 7.16 (d, J = 7.9Hz, 2H), 6.62 (d, J = 7.9Hz, 2H), 5.17 ( s, 2H), 4.49 (t, J = 6.5 Hz, 2H), 2.98 (t, J = 6.5 Hz, 2H), 2.07 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(2-(甲硫基)乙基)-7H-吡咯并[2，3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(2-(methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000218
Figure PCTCN2017115380-appb-000218
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得褐色固体为4-氨基-5-(4-氨基苯基)-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶，收率69％。 1H NMR(300MHz,DMSO)δ8.11(s,1H),7.19(s,1H),7.10(d,J＝7.6Hz,2H),6.66(d,J＝7.6Hz,2H),6.03(s,2H),5.23(s,2H),4.40–4.22(m,2H),2.98–2.81(m,2H),2.07(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(2-(methylthio)) Ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a brown solid of 4-amino-5-( 4-aminophenyl)-7-(2-(methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidine, yield 69%. 1 H NMR (300MHz, DMSO) δ8.11 (s, 1H), 7.19 (s, 1H), 7.10 (d, J = 7.6Hz, 2H), 6.66 (d, J = 7.6Hz, 2H), 6.03 ( s, 2H), 5.23 (s, 2H), 4.40–4.22 (m, 2H), 2.98–2.81 (m, 2H), 2.07 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(2-(methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实 施例1步骤8，得黄色固体为N-(4-(4-氨基-7-(2-(甲硫基)乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率84％。 1H NMR(300MHz,DMSO)δ13.03(s,1H),8.72(d,J＝2.1Hz,1H),8.23(d,J＝2.1Hz,1H),8.15(s,1H),7.81(d,J＝8.6Hz,2H),7.74(dd,J＝8.7,5.6Hz,2H),7.44(d,J＝8.6Hz,2H),7.39(s,1H),7.36–7.23(m,2H),6.12(s,2H),4.36(t,J＝6.8Hz,2H),4.11(d,J＝7.3Hz,2H),3.91–3.82(m,2H),3.32–3.21(m,2H),2.93(t,J＝6.8Hz,2H),2.16–2.03(m,4H),1.56–1.21(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (2-(Methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4- (4-Amino-7-(2-(methylthio)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 84%. 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.6 Hz, 2H), 7.74 (dd, J = 8.7, 5.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.39 (s, 1H), 7.36 - 7.23 (m, 2H) ), 6.12 (s, 2H), 4.36 (t, J = 6.8 Hz, 2H), 4.11 (d, J = 7.3 Hz, 2H), 3.91 - 3.82 (m, 2H), 3.32 - 3.21 (m, 2H) , 2.93 (t, J = 6.8 Hz, 2H), 2.16 - 2.03 (m, 4H), 1.56 - 1.21 (m, 4H).
实施例50：N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.50)Example 50: N-(4-(4-Amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.50 )
Figure PCTCN2017115380-appb-000219
Figure PCTCN2017115380-appb-000219
步骤1：制备3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 1: Preparation of tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylate
Figure PCTCN2017115380-appb-000220
Figure PCTCN2017115380-appb-000220
将1-甲基-4-哌啶醇替换成3-羟基氮杂叔丁烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为3-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，收率51％。 1H NMR(300MHz,DMSO)δ8.64(s,1H),8.33(s,1H),5.62–5.43(m,1H),4.47–4.12(m,4H),1.42(s,9H). Replace 1-methyl-4-piperidinol with 3-hydroxyaza-tert-butane-l-carboxylic acid tert-butyl ester. The remaining materials, reagents and preparation methods are the same as those in the first step of Example 14. -(4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylic acid tert-butyl ester, yield 51%. 1 H NMR (300MHz, DMSO) δ8.64 (s, 1H), 8.33 (s, 1H), 5.62-5.43 (m, 1H), 4.47-4.12 (m, 4H), 1.42 (s, 9H).
步骤2：制备3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 2: Preparation of tert-butyl 3-(5-(4-aminophenyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylate
Figure PCTCN2017115380-appb-000221
Figure PCTCN2017115380-appb-000221
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成3-(4-氯-5-碘-7H-吡咯并[2,3-d] 嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例1步骤6，得褐色固体为3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，收率93％。 1H NMR(300MHz,DMSO)δ8.62(s,1H),7.97(s,1H),7.21(d,J＝8.4Hz,2H),6.61(d,J＝8.4Hz,2H),5.79–5.38(m,1H),5.18(s,2H),4.35(d,J＝7.6Hz,4H),1.42(s,9H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d] Tert-butyl pyridin-7-yl)azetidin-1-carboxylate, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a brown solid as 3-(5-(4-aminophenyl) -4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylic acid tert-butyl ester, yield 93%. 1 H NMR (300 MHz, DMSO) δ 8.62 (s, 1H), 7.97 (s, 1H), 7.21. (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 5.79 - 5.38 (m, 1H), 5.18 (s, 2H), 4.35 (d, J = 7.6 Hz, 4H), 1.42 (s, 9H).
步骤3：制备3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 3: Preparation of tert-butyl 3-(4-amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylate
Figure PCTCN2017115380-appb-000222
Figure PCTCN2017115380-appb-000222
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成3-(5-(4-氨基苯基)-4-氯-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例1步骤7，得灰白色固体为3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，收率72％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.42(s,1H),7.14(d,J＝7.2Hz,2H),6.66(d,J＝7.2Hz,2H),6.06(s,2H),5.63–5.34(m,1H),5.24(s,2H),4.31(d,J＝7.4Hz,4H),1.42(s,9H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 3-(5-(4-aminophenyl)-4-chloro- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylic acid tert-butyl ester, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain an off-white solid 3-(4-Amino-5-(4-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylic acid tert-butyl ester, yield 72 %. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.42 (s, 1H), 7.14 (d, J = 7.2Hz, 2H), 6.66 (d, J = 7.2Hz, 2H), 6.06 ( s, 2H), 5.63–5.34 (m, 1H), 5.24 (s, 2H), 4.31 (d, J = 7.4 Hz, 4H), 1.42 (s, 9H).
步骤4：制备3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯Step 4: Preparation of 3-(4-amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl) )-1,4-dihydropyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylic acid tert-butyl ester
Figure PCTCN2017115380-appb-000223
Figure PCTCN2017115380-appb-000223
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成3-(4-氨基-5-(4-氨基苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，收率55％。 1H NMR(300MHz,DMSO)δ13.03(s,1H),8.72(d,J＝2.1Hz,1H),8.23(d,J＝2.1Hz,1H),8.14(s,1H),7.82(d,J＝8.7Hz,2H),7.74(dd,J＝8.8,5.7Hz,2H),7.65(s,1H),7.50(d,J＝8.7Hz,2H),7.36–7.16(m,2H),6.18 (s,2H),5.66–5.08(m,1H),4.46–4.19(m,4H),4.11(d,J＝7.5Hz,2H),3.93–3.76(m,2H),3.32–3.18(m,2H),2.23–1.99(m,1H),1.53–1.20(m,13H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 3-(4-amino-5-(4-aminophenyl) -7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylic acid tert-butyl ester, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid 3-(4-Amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1) , 4-dihydropyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylic acid tert-butyl ester, yield 55 %. 1 H NMR (300 MHz, DMSO) δ 13.03 (s, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.82 ( d, J = 8.7 Hz, 2H), 7.74 (dd, J = 8.8, 5.7 Hz, 2H), 7.65 (s, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.36 - 7.16 (m, 2H) ), 6.18 (s, 2H), 5.66 - 5.08 (m, 1H), 4.46 - 4.19 (m, 4H), 4.11 (d, J = 7.5 Hz, 2H), 3.93 - 3.76 (m, 2H), 3.32 - 3.18 (m, 2H), 2.23–1.99 (m, 1H), 1.53–1.20 (m, 13H).
步骤5：制备N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)吡咯烷-1-甲酸叔丁酯替换成3-(4-氨基-5-(4-(5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)氮杂环丁烷-1-甲酸叔丁酯，得白色固体为N-(4-(4-氨基-7-(氮杂环丁烷-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率31％。 1H NMR(300MHz,DMSO)δ13.04(s,1H),8.72(d,J＝1.8Hz,1H),8.23(d,J＝1.8Hz,1H),8.18(s,1H),7.84(d,J＝8.4Hz,2H),7.74(dd,J＝8.4,5.8Hz,2H),7.70(s,1H),7.48(d,J＝8.4Hz,2H),7.29(t,J＝8.4Hz,2H),6.22(s,2H),5.73–5.42(m,1H),4.59–4.45(m,2H),4.40–4.27(m,2H),4.12(d,J＝7.0Hz,2H),3.92–3.77(m,2H),3.45–3.05(m,2H),2.21–2.05(m,1H),1.56–1.22(m,4H). 3-(4-Amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1) , 4-dihydropyridine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester was replaced by 3-(4- Amino-5-(4-(5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine tert-Butyl -3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)azetidin-1-carboxylate gave N-(4- (4-Amino-7-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 31%. 1 H NMR (300MHz, DMSO) δ13.04 (s, 1H), 8.72 (d, J = 1.8Hz, 1H), 8.23 (d, J = 1.8Hz, 1H), 8.18 (s, 1H), 7.84 ( d, J = 8.4 Hz, 2H), 7.74 (dd, J = 8.4, 5.8 Hz, 2H), 7.70 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 8.4) Hz, 2H), 6.22 (s, 2H), 5.73 - 5.42 (m, 1H), 4.59 - 4.45 (m, 2H), 4.40 - 4.27 (m, 2H), 4.12 (d, J = 7.0 Hz, 2H) , 3.92–3.77 (m, 2H), 3.45–3.05 (m, 2H), 2.21–2.05 (m, 1H), 1.56–1.22 (m, 4H).
实施例51：N-(4-(7-烯丙基-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.51)Example 51: N-(4-(7-allyl-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.51)
Figure PCTCN2017115380-appb-000224
Figure PCTCN2017115380-appb-000224
步骤1：制备7-烯丙基-4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 7-allyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000225
Figure PCTCN2017115380-appb-000225
将碘甲烷替换成3-溴丙烯，其余所需原料、试剂及制备方法同实施例1步骤5，得白色固体为7-烯丙基-4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶，收率92％。 1H NMR(300MHz,DMSO)δ8.64(s,1H),7.98(s,1H),6.24–5.66(m,1H),5.29–5.12(m,1H),5.10–4.96(m,1H),4.95–4.80(m,2H). The methyl iodide is replaced by 3-bromopropene, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, and the white solid is 7-allyl-4-chloro-5-iodo-7H-pyrrole[2 , 3-d] pyrimidine, yield 92%. 1 H NMR (300 MHz, DMSO) δ 8.64 (s, 1H), 7.98 (s, 1H), 6.24 - 5.66 (m, 1H), 5.29 - 5.12 (m, 1H), 5.10 - 4.96 (m, 1H) , 4.95–4.80 (m, 2H).
步骤2：制备4-(7-烯丙基-4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(7-allyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000226
Figure PCTCN2017115380-appb-000226
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成7-烯丙基-4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(7-烯丙基-4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率30％。 1H NMR(300MHz,DMSO)δ8.61(s,1H),7.61(s,1H),7.15(d,J＝8.4Hz,2H),6.60(d,J＝8.4Hz,2H),6.34–5.88(m,1H),5.25–5.12(m,3H),5.07(dd,J＝17.1,1.3Hz,1H),4.92(d,J＝5.4Hz,2H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 7-allyl-4-chloro-5-iodo-7H-pyrrolo[2,3 -d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow solid which is 4-(7-allyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine. -5-yl) aniline, yield 30%. 1 H NMR (300MHz, DMSO) δ8.61 (s, 1H), 7.61 (s, 1H), 7.15 (d, J = 8.4Hz, 2H), 6.60 (d, J = 8.4Hz, 2H), 6.34- 5.88 (m, 1H), 5.25 - 5.12 (m, 3H), 5.07 (dd, J = 17.1, 1.3 Hz, 1H), 4.92 (d, J = 5.4 Hz, 2H).
步骤3：制备7-烯丙基-5-(4-氨基苯基)-4-氨基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 7-allyl-5-(4-aminophenyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000227
Figure PCTCN2017115380-appb-000227
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(7-烯丙基-4-氯-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为7-烯丙基-5-(4-氨基苯基)-4-氨基-7H-吡咯并[2,3-d]嘧啶，收率77％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.10(d,J＝8.3Hz,2H),7.07(s,1H),6.65(d,J＝8.3Hz,2H),6.30–5.67(m,3H),5.22(s,2H),5.15(dd,J＝10.4,1.2Hz,1H),5.05(dd,J＝17.1,1.2Hz,1H),4.76(d,J＝5.2Hz,2H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(7-allyl-4-chloro-7H-pyrrole [2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid as 7-allyl-5-(4-aminophenyl). 4-amino-7H-pyrrolo[2,3-d]pyrimidine, yield 77%. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.10 (d, J = 8.3Hz, 2H), 7.07 (s, 1H), 6.65 (d, J = 8.3Hz, 2H), 6.30- 5.67 (m, 3H), 5.22 (s, 2H), 5.15 (dd, J = 10.4, 1.2 Hz, 1H), 5.05 (dd, J = 17.1, 1.2 Hz, 1H), 4.76 (d, J = 5.2 Hz) , 2H).
步骤4：制备N-(4-(7-烯丙基-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(7-allyl-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成7-烯丙基-5-(4-氨基苯基)-4-氨基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(7-烯丙基-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率49％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝1.6Hz,1H),8.22(d,J＝1.6Hz,1H),8.15(s,1H),7.81(d,J＝8.3Hz,2H),7.73(dd,J＝8.7,5.6Hz,2H),7.45(d,J＝8.3Hz,2H),7.38–7.20(m,3H),6.57–5.79(m,3H),5.17(dd,J＝10.3,1.1Hz,1H),5.07(dd,J＝17.3,1.1Hz,1H),4.80(d,J＝5.3Hz,2H),4.11(d,J＝7.1Hz,2H),3.95–3.74(m,2H),3.35–3.08(m,2H),2.20–1.83(m,1H),1.62–1.13(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 7-allyl-5-(4-aminophenyl)- 4-amino-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(7-allyl-4) -amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran) 4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 49%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 1.6Hz, 1H), 8.22 (d, J = 1.6Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.3 Hz, 2H), 7.73 (dd, J = 8.7, 5.6 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.38 - 7.20 (m, 3H), 6.57 - 5.79 (m , 3H), 5.17 (dd, J = 10.3, 1.1 Hz, 1H), 5.07 (dd, J = 17.3, 1.1 Hz, 1H), 4.80 (d, J = 5.3 Hz, 2H), 4.11 (d, J = 7.1 Hz, 2H), 3.95–3.74 (m, 2H), 3.35–3.08 (m, 2H), 2.20–1.83 (m, 1H), 1.62–1.13 (m, 4H).
实施例52：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氨基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.52)Example 52: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-aminophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.52)
Figure PCTCN2017115380-appb-000228
Figure PCTCN2017115380-appb-000228
步骤1：制备对硝基苯乙酰氯Step 1: Preparation of p-nitrophenylacetyl chloride
Figure PCTCN2017115380-appb-000229
Figure PCTCN2017115380-appb-000229
将对甲基苯乙酸替换成对硝基苯乙酸，其余所需原料、试剂及制备方法同实施例2步骤1，得黄色液体为对硝基苯乙酰氯，直接用于下一步。The p-methylphenylacetic acid was replaced with p-nitrophenylacetic acid, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 2, and the yellow liquid was obtained as p-nitrophenylacetyl chloride, which was directly used in the next step.
步骤2：制备4-(4-硝基苯基)-3-氧代丁酸乙酯Step 2: Preparation of ethyl 4-(4-nitrophenyl)-3-oxobutanoate
Figure PCTCN2017115380-appb-000230
Figure PCTCN2017115380-appb-000230
将4-氟苯乙酰氯替换成对硝基苯乙酰氯，其余所需原料、试剂及制备方法同实施例1步骤1，得黄色液体为4-(4-硝基苯基)-3-氧代丁酸乙酯，步骤1和2总收率43％。 1H NMR(300MHz,CDCl 3)δ8.21(d,J＝8.4Hz,2H),7.38(d,J＝8.4Hz,2H),4.21(q,J＝7.2Hz,2H),4.00(s,2H),3.52(s,2H),1.29(t,J＝7.2Hz,3H). Replace 4-fluorophenylacetyl chloride with p-nitrophenylacetyl chloride. The remaining raw materials, reagents and preparation methods are the same as those in step 1 of Example 1. The yellow liquid is 4-(4-nitrophenyl)-3-oxo. Ethyl butyrate, the total yield of steps 1 and 2 was 43%. 1 H NMR (300MHz, CDCl 3 ) δ8.21 (d, J = 8.4Hz, 2H), 7.38 (d, J = 8.4Hz, 2H), 4.21 (q, J = 7.2Hz, 2H), 4.00 (s , 2H), 3.52 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H).
步骤3：制备5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 3: Preparation of 5-(4-nitrophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Ethyl formate
Figure PCTCN2017115380-appb-000231
Figure PCTCN2017115380-appb-000231
将4-(4-氟苯基)-3-氧代丁酸乙酯替换成4-(4-硝基苯基)-3-氧代丁酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色液体为5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率30％。 1H NMR(300MHz,DMSO)δ8.35(s,1H),8.29–8.21(m,3H),7.95(d,J＝8.6Hz,2H),4.22(q,J＝7.2Hz,2H),3.96(d,J＝7.6Hz,2H),3.92–3.72(m,2H),3.32–3.14(m,2H),2.23–1.83(m,1H),1.48–1.09(m,7H). Replacement of ethyl 4-(4-fluorophenyl)-3-oxobutanoate with ethyl 4-(4-nitrophenyl)-3-oxobutanoate, remaining materials, reagents and preparation methods In the same manner as in Step 2 of Example 1, the yellow liquid was obtained as 5-(4-nitrophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4. - Dihydropyridine-3-carboxylic acid ethyl ester in a yield of 30%. 1 H NMR (300MHz, DMSO) δ8.35 (s, 1H), 8.29-8.21 (m, 3H), 7.95 (d, J = 8.6Hz, 2H), 4.22 (q, J = 7.2Hz, 2H), 3.96 (d, J = 7.6 Hz, 2H), 3.92 - 3.72 (m, 2H), 3.32 - 3.14 (m, 2H), 2.23 - 1.83 (m, 1H), 1.48 - 1.09 (m, 7H).
步骤4：制备5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸Step 4: Preparation of 5-(4-nitrophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3- Formic acid
Figure PCTCN2017115380-appb-000232
Figure PCTCN2017115380-appb-000232
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得黄色固体为5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，收率64％。 1H NMR(300MHz,DMSO)δ8.83(s,1H),8.58(s,1H),8.33(d,J＝8.6Hz,2H),8.00(d,J＝8.6Hz,2H),4.16(d,J＝8.3Hz,2H),3.95–3.76(m,2H),3.25(t,J＝11.3Hz,2H),2.21–2.02(m,1H),1.52–1.20(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-nitrophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate The remaining starting materials, reagents and preparation methods are the same as those in the third step of Example 1, to obtain a yellow solid which is 5-(4-nitrophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4) -yl)methyl)-1,4-dihydropyridine-3-carboxylic acid in a yield of 64%. 1 H NMR (300MHz, DMSO) δ8.83 (s, 1H), 8.58 (s, 1H), 8.33 (d, J = 8.6Hz, 2H), 8.00 (d, J = 8.6Hz, 2H), 4.16 ( d, J = 8.3 Hz, 2H), 3.95 - 3.76 (m, 2H), 3.25 (t, J = 11.3 Hz, 2H), 2.21 - 2.02 (m, 1H), 1.52 - 1.20 (m, 4H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-nitrophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
Figure PCTCN2017115380-appb-000233
Figure PCTCN2017115380-appb-000233
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率57％。 1H NMR(300MHz,DMSO)δ12.88(s,1H),8.76(s,1H),8.40(s,1H),8.32(d,J＝8.2Hz,2H),8.15(s,1H),8.01(d,J＝8.2Hz,2H),7.81(d,J＝8.0Hz,2H),7.44(d,J＝8.0Hz,2H),7.30(s,1H),6.08(s,2H),4.14(d,J＝6.6Hz,2H),3.92–3.80(m,2H),3.74(s,3H),3.32–3.21(m,2H),2.30–1.97(m,1H),1.65–1.24(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-nitrophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the rest required The starting materials, reagents and preparation methods were the same as those in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene. 5-(4-nitrophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-methyl Amide, yield 57%. 1 H NMR (300MHz, DMSO) δ12.88 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 8.32 (d, J = 8.2Hz, 2H), 8.15 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.30 (s, 1H), 6.08 (s, 2H), 4.14 (d, J = 6.6 Hz, 2H), 3.92 - 3.80 (m, 2H), 3.74 (s, 3H), 3.32 - 3.21 (m, 2H), 2.30 - 1.97 (m, 1H), 1.65 - 1.24 ( m, 4H).
步骤6：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氨基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 6: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-aminophenyl)- 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
氩气氛围下，将46毫克N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-硝基苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺溶于2毫升乙醇及1.3毫升水组成的混合溶剂，加入27毫克还原铁粉及27毫克氯化铵，50℃加热反应1小时后冷却至室温，过滤，硅藻土助滤，滤液浓缩后用乙酸乙酯萃取，有机相用无水硫酸钠干燥后浓缩，残余物柱层析(甲醇：二氯甲烷＝1:10)分离得白色固体20毫克为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氨基苯基)-4-氧 代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率87％。 1H NMR(300MHz,DMSO)δ13.20(s,1H),8.62(d,J＝2.2Hz,1H),8.15(s,1H),8.05(d,J＝2.2Hz,1H),7.80(d,J＝8.4Hz,2H),7.48–7.38(m,4H),7.30(s,1H),6.61(d,J＝8.4Hz,2H),6.10(s,2H),5.30(s,2H),4.09(d,J＝7.2Hz,2H),3.90–3.80(m,2H),3.73(s,3H),3.26(t,J＝11.1Hz,2H),2.18–2.00(m,1H),1.53–1.14(m,4H). Under an argon atmosphere, 46 mg of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-nitrogen Phenylphenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide dissolved in 2 ml of ethanol and 1.3 ml A mixed solvent of water, adding 27 mg of reduced iron powder and 27 mg of ammonium chloride, heating at 50 ° C for 1 hour, cooling to room temperature, filtering, diatomaceous earth filtration, concentration of the filtrate, extraction with ethyl acetate, organic phase After drying over anhydrous sodium sulfate and concentrating, the residue was purified (jjjjjjjjjjjj [2,3-d]pyrimidin-5-yl)phenyl)-5-(4-aminophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl )-1,4-dihydropyridine-3-carboxamide, yield 87%. 1 H NMR (300MHz, DMSO) δ13.20 (s, 1H), 8.62 (d, J = 2.2Hz, 1H), 8.15 (s, 1H), 8.05 (d, J = 2.2Hz, 1H), 7.80 ( d, J = 8.4 Hz, 2H), 7.48 - 7.38 (m, 4H), 7.30 (s, 1H), 6.61 (d, J = 8.4 Hz, 2H), 6.10 (s, 2H), 5.30 (s, 2H) ), 4.09 (d, J = 7.2 Hz, 2H), 3.90 - 3.80 (m, 2H), 3.73 (s, 3H), 3.26 (t, J = 11.1 Hz, 2H), 2.18 - 2.00 (m, 1H) , 1.53–1.14 (m, 4H).
实施例53：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.53)Example 53: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)-5-(4 -fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.53)
Figure PCTCN2017115380-appb-000234
Figure PCTCN2017115380-appb-000234
步骤1：制备(4-溴-2-甲氧基苯基)氨基甲酸叔丁酯Step 1: Preparation of (4-bromo-2-methoxyphenyl)carbamic acid tert-butyl ester
Figure PCTCN2017115380-appb-000235
Figure PCTCN2017115380-appb-000235
将500毫克4-溴-2-甲氧基苯胺溶于10毫升干燥的二氯甲烷，依次加入680微升二碳酸二叔丁酯和450毫克4-二甲氨基吡啶，室温反应5小时后浓缩反应液，残余物柱层析(乙酸乙酯：石油醚＝3:97)分离得透明液体510毫克为(4-溴-2-甲氧基苯基)氨基甲酸叔丁酯，收率68％。 1H NMR(300MHz,DMSO)δ8.04(s,1H),7.62(d,J＝8.4Hz,1H),7.17(s,1H),7.07(d,J＝8.4Hz,1H),3.81(s,3H),1.44(s,9H). 500 mg of 4-bromo-2-methoxyaniline was dissolved in 10 ml of dry dichloromethane, and 680 μl of di-tert-butyl dicarbonate and 450 mg of 4-dimethylaminopyridine were successively added, and reacted at room temperature for 5 hours to concentrate. The reaction mixture was purified by column chromatography (ethyl acetate: petroleum ether=3:97) to afford 510 mg of (yield of 4-bromo-2-methoxyphenyl)carbamate as a clear liquid, yield 68%. . 1 H NMR (300MHz, DMSO) δ8.04 (s, 1H), 7.62 (d, J = 8.4Hz, 1H), 7.17 (s, 1H), 7.07 (d, J = 8.4Hz, 1H), 3.81 ( s, 3H), 1.44 (s, 9H).
步骤2：制备(2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯Step 2: Preparation of (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamic acid Tert-butyl ester
Figure PCTCN2017115380-appb-000236
Figure PCTCN2017115380-appb-000236
将2-氟-4-碘苯胺替换成(4-溴-2-甲氧基苯基)氨基甲酸叔丁酯，其余所需原料、试剂及制备方法同实施例17步骤1，得透明液体为(2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯，收率76％。 1H NMR(300MHz,DMSO)δ7.96(s,1H),7.82(d,J＝7.8Hz,1H),7.24(d,J＝7.8Hz,1H),7.15(s,1H),3.82(s,3H),1.46(s,9H),1.28(s,12H). The 2-fluoro-4-iodoaniline was replaced with (4-bromo-2-methoxyphenyl)carbamic acid tert-butyl ester, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 17, to obtain a transparent liquid. (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamic acid tert-butyl ester, The yield was 76%. 1 H NMR (300MHz, DMSO) δ7.96 (s, 1H), 7.82 (d, J = 7.8Hz, 1H), 7.24 (d, J = 7.8Hz, 1H), 7.15 (s, 1H), 3.82 ( s, 3H), 1.46 (s, 9H), 1.28 (s, 12H).
步骤3：制备(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基苯基)氨基甲酸叔丁酯Step 3: Preparation of tert-butyl (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate
Figure PCTCN2017115380-appb-000237
Figure PCTCN2017115380-appb-000237
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成(2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁酯，4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基苯基)氨基甲酸叔丁酯，收率66％。 1H NMR(300MHz,DMSO)δ8.16(s,1H),7.98(s,1H),7.77(d,J＝8.2Hz,1H),7.32(s,1H),7.05(d,J＝1.5Hz,1H),6.98(dd,J＝8.2,1.5Hz,1H),6.18(s,2H),3.85(s,3H),3.74(s,3H),1.47(s,9H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with (2-methoxy-4-(4, Tert-butyl 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate, 4-chloro-7-methyl-5-iodo Substituting -7H-pyrrolo[2,3-d]pyrimidine to 4-amino-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, remaining raw materials, reagents and preparation method In the same manner as in the step 6 of Example 1, the yellow solid was (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl) Tert-butyl carbamate, yield 66%. 1 H NMR (300 MHz, DMSO) δ 8.16 (s, 1H), 7.98 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.05 (d, J = 1.5) Hz, 1H), 6.98 (dd, J = 8.2, 1.5 Hz, 1H), 6.18 (s, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 1.47 (s, 9H).
步骤4：制备4-氨基-5-(4-氨基-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 4: Preparation of 4-amino-5-(4-amino-3-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000238
Figure PCTCN2017115380-appb-000238
将20毫克(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基苯基)氨基甲酸叔丁酯溶于1毫升干燥的二氯甲烷，加入1毫升三氟乙酸，室温搅拌1小时后浓缩，氨水调至碱性，固体析出，过滤，滤饼水洗刮出，干燥后得类白色固体11毫克为4-氨基-5-(4-氨基-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率75％。 1H NMR(300MHz,DMSO)δ8.12(s,1H),7.14(s,1H),6.86(s,1H),6.77(d,J＝7.6Hz,1H),6.72(d,J＝7.6Hz,1H),6.03(s,2H),4.80(s,2H),3.80(s,3H),3.71(s,3H). 20 mg of (4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamic acid tert-butyl ester was dissolved in 1 ML dry dichloromethane, add 1 ml of trifluoroacetic acid, stir at room temperature for 1 hour, concentrate, ammonia to make alkaline, solid precipitated, filtered, filter cake washed with water, dried to give a white solid 11 mg of 4-amino 5-(4-Amino-3-methoxyphenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 75%. 1 H NMR (300MHz, DMSO) δ8.12 (s, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 6.77 (d, J = 7.6Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.03 (s, 2H), 4.80 (s, 2H), 3.80 (s, 3H), 3.71 (s, 3H).
步骤5：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)-5-(4 -fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率86％。 1H NMR(300MHz,DMSO)δ12.87(s,1H),8.69(d,J＝2.1Hz,1H),8.57(d,J＝8.3Hz,1H),8.17(d,J＝2.1Hz,1H),8.15(s,1H),7.71(dd,J＝8.7,5.7Hz,2H),7.34(s,1H),7.30(t,J＝8.7Hz,2H),7.12(s,1H),7.03(d,J＝8.3Hz,1H),6.15(s,2H),4.09(d,J＝8.1Hz,2H),3.91(s,3H),3.90–3.81(m,2H),3.74(s,3H),3.33–3.19(m,2H),2.20 –2.04(m,1H),1.55–1.20(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-3-methoxy Phenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(4- Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)-5-(4-fluorophenyl)-4-oxo-1 -((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 86%. 1 H NMR (300MHz, DMSO) δ12.87 (s, 1H), 8.69 (d, J = 2.1Hz, 1H), 8.57 (d, J = 8.3Hz, 1H), 8.17 (d, J = 2.1Hz, 1H), 8.15 (s, 1H), 7.71 (dd, J = 8.7, 5.7 Hz, 2H), 7.34 (s, 1H), 7.30 (t, J = 8.7 Hz, 2H), 7.12 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.15 (s, 2H), 4.09 (d, J = 8.1 Hz, 2H), 3.91 (s, 3H), 3.90 - 3.81 (m, 2H), 3.74 (s) , 3H), 3.33–3.19 (m, 2H), 2.20 – 2.04 (m, 1H), 1.55–1.20 (m, 4H).
实施例54：N-(4-(4-氨基-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.54)Example 54: N-(4-(4-Amino-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO. 54)
Figure PCTCN2017115380-appb-000239
Figure PCTCN2017115380-appb-000239
步骤1：制备4-氯-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000240
Figure PCTCN2017115380-appb-000240
将苯硼酸替换成3,4-二甲氧基苯硼酸，其余所需原料、试剂及制备方法同实施例40步骤1，得类白色固体为4-氯-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶，收率45％。 1H NMR(300MHz,DMSO)δ8.69(s,1H),8.10(d,J＝3.7Hz,1H),7.38(d,J＝2.4Hz,1H),7.32(dd,J＝8.6,2.4Hz,1H),7.13(d,J＝8.6Hz,1H),6.86(d,J＝3.7Hz,1H),3.83(s,6H). The phenylboronic acid is replaced with 3,4-dimethoxybenzeneboronic acid, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 40, and the white solid is 4-chloro-7-(3,4-dimethyl Oxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine in 45% yield. 1 H NMR (300MHz, DMSO) δ8.69 (s, 1H), 8.10 (d, J = 3.7Hz, 1H), 7.38 (d, J = 2.4Hz, 1H), 7.32 (dd, J = 8.6,2.4 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 3.7 Hz, 1H), 3.83 (s, 6H).
步骤2：制备4-氯-7-(3,4-二甲氧基苯基)-5-碘-7H-吡咯并[2,3-d]嘧啶Step 2: Preparation of 4-chloro-7-(3,4-dimethoxyphenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000241
Figure PCTCN2017115380-appb-000241
将4-氯-7-苯基-7H-吡咯并[2,3-d]嘧啶替换成4-氯-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例40步骤2，得紫色固体为4-氯-7-(3,4-二甲氧基苯基)-5-碘-7H-吡咯并[2,3-d]嘧啶，收率97％。 1H NMR(300MHz,DMSO)δ8.67(s,1H),8.32(s,1H),7.33(d,J＝2.1Hz,1H),7.30(dd,J＝8.7,2.1Hz,1H),7.12(d,J＝8.7Hz,1H),3.83(s,3H),3.82(s,3H). Replace 4-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2, 3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the step 2 of Example 40, and the purple solid is 4-chloro-7-(3,4-dimethoxyphenyl)-5-iodo-7H. Pyrrodo[2,3-d]pyrimidine in a yield of 97%. 1 H NMR (300MHz, DMSO) δ8.67 (s, 1H), 8.32 (s, 1H), 7.33 (d, J = 2.1Hz, 1H), 7.30 (dd, J = 8.7,2.1Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H).
步骤3：制备4-(4-氯-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 3: Preparation of 4-(4-chloro-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000242
Figure PCTCN2017115380-appb-000242
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成制备4-氯-7-(3,4-二甲氧基苯基)-5-碘-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得类白色固体为4-(4-氯-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率53％。 1H NMR(300MHz,DMSO)δ8.66(s,1H),7.98(s,1H),7.41(s,1H),7.39(d,J＝8.1Hz,1H),7.25(d,J＝8.4Hz,2H),7.13(d,J＝8.1Hz,1H),6.64(d,J＝8.4Hz,2H),5.19(s,2H),3.83(s,6H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine to 4-chloro-7-(3,4-dimethoxyphenyl)-5- Iodine-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, and the white solid is 4-(4-chloro-7-(3,4- Dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 53%. 1 H NMR (300MHz, DMSO) δ8.66 (s, 1H), 7.98 (s, 1H), 7.41 (s, 1H), 7.39 (d, J = 8.1Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 8.4 Hz, 2H), 5.19 (s, 2H), 3.83 (s, 6H).
步骤4：制备4-氨基-5-(4-氨基苯基)-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶Step 4: Preparation of 4-amino-5-(4-aminophenyl)-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000243
Figure PCTCN2017115380-appb-000243
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基苯基)-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶，收率72％。 1H NMR(300MHz,DMSO)δ8.16(s,1H),7.49(s,1H),7.46–7.31(m,2H),7.20(d,J＝8.4Hz,2H),7.08(d,J＝8.7Hz,1H),6.69(d,J＝8.4Hz,2H),6.12(s,2H),5.29(s,2H),3.82(s,3H),3.81(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(3,4-dimethoxy) Phenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid as 4-amino-5- (4-Aminophenyl)-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine in a yield of 72%. 1 H NMR (300MHz, DMSO) δ8.16 (s, 1H), 7.49 (s, 1H), 7.46-7.31 (m, 2H), 7.20 (d, J = 8.4Hz, 2H), 7.08 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 6.12 (s, 2H), 5.29 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H).
步骤5：制备N-(4-(4-氨基-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 5: Preparation of N-(4-(4-amino-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 5-(4-Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-(3,4-二甲氧基苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率77％。 1H NMR(300MHz,DMSO)δ13.05(s,1H),8.73(d,J＝2.1Hz,1H),8.23(d,J＝2.1Hz,1H),8.19(s,1H),7.85(d,J＝8.6Hz,2H),7.79–7.71(m,2H),7.68(s,1H),7.55(d,J＝8.6Hz,2H),7.44–7.36(m,2H),7.35–7.24(m,2H),7.10(d,J＝8.6Hz,1H),6.23(s,2H),4.11(d,J＝7.2Hz,2H),3.96–3.78(m,8H),3.34–3.18(m,2H), 2.22–2.03(m,1H),1.57–1.43(m,2H),1.42–1.21(m,2H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (3,4-Dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4 -(4-Amino-7-(3,4-dimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 77%. 1 H NMR (300 MHz, DMSO) δ 13.05 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 7.85 ( d, J = 8.6 Hz, 2H), 7.79 - 7.71 (m, 2H), 7.68 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.44 - 7.36 (m, 2H), 7.35 - 7.24 (m, 2H), 7.10 (d, J = 8.6 Hz, 1H), 6.23 (s, 2H), 4.11 (d, J = 7.2 Hz, 2H), 3.96 - 3.78 (m, 8H), 3.34 - 3.18 ( m, 2H), 2.22–2.03 (m, 1H), 1.57–1.43 (m, 2H), 1.42–1.21 (m, 2H).
实施例55：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氯苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.55)Example 55: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-chlorophenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.55)
Figure PCTCN2017115380-appb-000244
Figure PCTCN2017115380-appb-000244
步骤1：制备2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺Step 1: Preparation of 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2017115380-appb-000245
Figure PCTCN2017115380-appb-000245
将2-氟-4-碘苯胺替换成2-氯-4-碘苯胺，其余所需原料、试剂及制备方法同实施例17步骤1，得白色固体为2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，收率74％。 1H NMR(300MHz,DMSO)δ7.39(d,J＝1.2Hz,1H),7.29(dd,J＝8.0,1.2Hz,1H),6.74(d,J＝8.0Hz,1H),5.78(s,2H),1.25(s,12H). 2-Fluoro-4-iodoaniline was replaced by 2-chloro-4-iodoaniline, and the remaining raw materials, reagents and preparation methods were the same as those in Example 17 Step 1. The white solid was 2-chloro-4-(4,4). , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, yield 74%. 1 H NMR (300MHz, DMSO) δ7.39 (d, J = 1.2Hz, 1H), 7.29 (dd, J = 8.0,1.2Hz, 1H), 6.74 (d, J = 8.0Hz, 1H), 5.78 ( s, 2H), 1.25 (s, 12H).
步骤2：制备2-氯-4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 2-chloro-4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000246
Figure PCTCN2017115380-appb-000246
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成2-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为2-氯-4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率97％。 1H NMR(300MHz,DMSO)δ8.64(s,1H),7.73(s,1H),7.32(d,J＝2.0Hz,1H),7.17(dd,J＝8.2,2.0Hz,1H),6.84(d,J＝8.2Hz,1H),5.45(s,2H),3.86(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 2-chloro-4-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid of 2- Chloro-4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 97%. 1 H NMR (300MHz, DMSO) δ8.64 (s, 1H), 7.73 (s, 1H), 7.32 (d, J = 2.0Hz, 1H), 7.17 (dd, J = 8.2,2.0Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.45 (s, 2H), 3.86 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基-3-氯苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-amino-3-chlorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000247
Figure PCTCN2017115380-appb-000247
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成2-氯-4-(4-氯-7-甲基 -7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得黄色固体为4-氨基-5-(4-氨基-3-氯苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率54％。 1H NMR(300MHz,DMSO)δ8.12(s,1H),7.24(d,J＝1.9Hz,1H),7.18(s,1H),7.10(dd,J＝8.2,1.9Hz,1H),6.88(d,J＝8.2Hz,1H),6.03(s,2H),5.44(s,2H),3.70(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 2-chloro-4-(4-chloro-7-methyl-7H -pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a yellow solid as 4-amino-5-(4-amino-3) -Chlorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 54%. 1 H NMR (300MHz, DMSO) δ8.12 (s, 1H), 7.24 (d, J = 1.9Hz, 1H), 7.18 (s, 1H), 7.10 (dd, J = 8.2,1.9Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.03 (s, 2H), 5.44 (s, 2H), 3.70 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氯苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-chlorophenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-3-氯苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得黄色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氯苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率54％。 1H NMR(300MHz,DMSO)δ13.26(s,1H),8.74(d,J＝2.1Hz,1H),8.65(d,J＝8.6Hz,1H),8.21(d,J＝2.1Hz,1H),8.16(s,1H),7.72(dd,J＝8.8,5.7Hz,2H),7.57(d,J＝1.9Hz,1H),7.43(dd,J＝8.6,1.9Hz,1H),7.39(s,1H),7.30(t,J＝8.8Hz,2H),6.19(s,2H),4.11(d,J＝7.5Hz,2H),3.86(d,J＝10.6Hz,2H),3.74(s,3H),3.40–3.20(m,2H),2.20–2.03(m,1H),1.53–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-3-chlorophenyl -7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a yellow solid as N-(4-(4-amino-) 7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-chlorophenyl)-5-(4-fluorophenyl)-4-oxo-1-(4 Hydrogen-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 54%. 1 H NMR (300MHz, DMSO) δ13.26 (s, 1H), 8.74 (d, J = 2.1Hz, 1H), 8.65 (d, J = 8.6Hz, 1H), 8.21 (d, J = 2.1Hz, 1H), 8.16 (s, 1H), 7.72 (dd, J = 8.8, 5.7 Hz, 2H), 7.57 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 8.6, 1.9 Hz, 1H), 7.39 (s, 1H), 7.30 (t, J = 8.8 Hz, 2H), 6.19 (s, 2H), 4.11 (d, J = 7.5 Hz, 2H), 3.86 (d, J = 10.6 Hz, 2H), 3.74 (s, 3H), 3.40–3.20 (m, 2H), 2.20–2.03 (m, 1H), 1.53–1.22 (m, 4H).
实施例56：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,6-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.56)Example 56: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,6-difluorophenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.56)
Figure PCTCN2017115380-appb-000248
Figure PCTCN2017115380-appb-000248
步骤1：制备2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺Step 1: Preparation of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2017115380-appb-000249
Figure PCTCN2017115380-appb-000249
将2-氟-4-碘苯胺替换成2,6-二氟-4-碘苯胺，其余所需原料、试剂及制备方法同实施例17步骤1，得白色固体为2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，收率43％。 1H NMR(300MHz,DMSO)δ7.12–6.78(m,2H),5.68(s,2H),1.25(s,12H). The 2-fluoro-4-iodoaniline was replaced with 2,6-difluoro-4-iodoaniline, and the remaining raw materials, reagents and preparation methods were the same as those in the first step of Example 17, to obtain a white solid as 2,6-difluoro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, yield 43%. 1 H NMR (300 MHz, DMSO) δ 7.12 - 6.78 (m, 2H), 5.68 (s, 2H), 1.25 (s, 12H).
步骤2：制备4-氨基-5-(4-氨基-3,5-二氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 2: Preparation of 4-amino-5-(4-amino-3,5-difluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000250
Figure PCTCN2017115380-appb-000250
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成2,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得褐色固体为4-氨基-5-(4-氨基-3,5-二氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率90％。 1H NMR(300MHz,DMSO)δ8.13(s,1H),7.24(s,1H),7.02–6.90(m,2H),6.15(s,2H),5.26(s,2H),3.70(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 2,6-difluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2 , 3-d] pyrimidine is replaced by 4-amino-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, and the remaining materials, reagents and preparation methods are the same as in step 6 of Example 1, The obtained brown solid was 4-amino-5-(4-amino-3,5-difluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 90%. 1 H NMR (300MHz, DMSO) δ8.13 (s, 1H), 7.24 (s, 1H), 7.02-6.90 (m, 2H), 6.15 (s, 2H), 5.26 (s, 2H), 3.70 (s , 3H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,6-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,6-difluorophenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-3,5-二氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,6-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率26％。 1H NMR(300MHz,DMSO)δ12.39(s,1H),8.72(d,J＝1.6Hz,1H),8.24(d,J＝1.6Hz,1H),8.17(s,1H),7.73(dd,J＝8.4,5.5Hz,2H),7.50(s,1H),7.36–7.15(m,4H),6.34(s,2H),4.11(d,J＝7.0Hz,2H),3.92–3.79(m,2H),3.74(s,3H),3.32–3.16(m,2H),2.25–2.02(m,1H),1.58–1.40(m,2H),1.38–1.21(m,2H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-3,5-di Fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-( 4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,6-difluorophenyl)-5-(4-fluorophenyl)-4-oxo Generation-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 26%. 1 H NMR (300MHz, DMSO) δ12.39 (s, 1H), 8.72 (d, J = 1.6Hz, 1H), 8.24 (d, J = 1.6Hz, 1H), 8.17 (s, 1H), 7.73 ( Dd, J = 8.4, 5.5 Hz, 2H), 7.50 (s, 1H), 7.36 - 7.15 (m, 4H), 6.34 (s, 2H), 4.11 (d, J = 7.0 Hz, 2H), 3.92 - 3.79 (m, 2H), 3.74 (s, 3H), 3.32–3.16 (m, 2H), 2.25–2.02 (m, 1H), 1.58–1.40 (m, 2H), 1.38–1.21 (m, 2H).
实施例57：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.57)Example 57: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.57)
Figure PCTCN2017115380-appb-000251
Figure PCTCN2017115380-appb-000251
步骤1：制备2,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺Step 1: Preparation of 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
Figure PCTCN2017115380-appb-000252
Figure PCTCN2017115380-appb-000252
将2-氟-4-碘苯胺替换成4-溴-2,5-二氟苯胺，其余所需原料、试剂及制备方法同实施例17步骤1，得白色固体为2,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，收率72％。 1H NMR(300MHz,DMSO)δ7.04(dd,J＝11.6,5.4Hz,1H),6.40(dd, J＝10.8,7.0Hz,1H),5.94(s,2H),1.24(s,12H). 2-Fluoro-4-iodoaniline was replaced by 4-bromo-2,5-difluoroaniline, and the remaining materials, reagents and preparation methods were the same as those in Example 17, Step 1, to obtain a white solid as 2,5-difluoro- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, yield 72%. 1 H NMR (300MHz, DMSO) δ7.04 (dd, J = 11.6,5.4Hz, 1H), 6.40 (dd, J = 10.8,7.0Hz, 1H), 5.94 (s, 2H), 1.24 (s, 12H ).
步骤2：制备4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯胺Step 2: Preparation of 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluoroaniline
Figure PCTCN2017115380-appb-000253
Figure PCTCN2017115380-appb-000253
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺替换成2,5-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤6，得类白色固体为4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯胺，收率55％。 1H NMR(300MHz,DMSO)δ8.65(s,1H),7.74(s,1H),7.07(dd,J＝11.6,6.8Hz,1H),6.62(dd,J＝11.3,7.7Hz,1H),5.59(s,2H),3.87(s,3H). Replace 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline with 2,5-difluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 1, obtaining white The solid was 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluoroaniline in a yield of 55%. 1 H NMR (300MHz, DMSO) δ8.65 (s, 1H), 7.74 (s, 1H), 7.07 (dd, J = 11.6,6.8Hz, 1H), 6.62 (dd, J = 11.3,7.7Hz, 1H ), 5.59 (s, 2H), 3.87 (s, 3H).
步骤3：制备4-氨基-5-(4-氨基-2,5-二氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-amino-2,5-difluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000254
Figure PCTCN2017115380-appb-000254
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得类白色固体为4-氨基-5-(4-氨基-2,5-二氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，收率51％。 1H NMR(300MHz,DMSO)δ8.12(s,1H),7.18(s,1H),6.99(dd,J＝11.7,7.1Hz,1H),6.64(dd,J＝11.4,7.7Hz,1H),5.99(s,2H),5.55(s,2H),3.71(s,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-methyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)-2,5-difluoroaniline, the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, and the white solid is 4-amino-5-(4) -Amino-2,5-difluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 51%. 1 H NMR (300MHz, DMSO) δ8.12 (s, 1H), 7.18 (s, 1H), 6.99 (dd, J = 11.7,7.1Hz, 1H), 6.64 (dd, J = 11.4,7.7Hz, 1H ), 5.99 (s, 2H), 5.55 (s, 2H), 3.71 (s, 3H).
步骤4：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-2,5-二氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率53％。 1H NMR(300MHz,DMSO)δ13.44(s,1H),8.76(d,J＝2.0Hz,1H),8.46(dd,J＝11.6,6.7Hz,1H),8.25(d,J＝2.0Hz,1H),8.15(s,1H),7.80–7.67(m,2H),7.40–7.25(m,4H),6.22(s,2H),4.12(d,J＝7.4Hz,2H),4.00–3.81(m,2H),3.74(s,3H),3.32–3.16(m,2H),2.22–2.00(m,1H),1.52–1.21(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-2,5-di Fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4) -amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-(4-fluorophenyl)-4-oxo 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 53%. 1 H NMR (300MHz, DMSO) δ13.44 (s, 1H), 8.76 (d, J = 2.0Hz, 1H), 8.46 (dd, J = 11.6,6.7Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 7.80 - 7.67 (m, 2H), 7.40 - 7.25 (m, 4H), 6.22 (s, 2H), 4.12 (d, J = 7.4 Hz, 2H), 4.00 –3.81 (m, 2H), 3.74 (s, 3H), 3.32–3.16 (m, 2H), 2.22–2.00 (m, 1H), 1.52–1.21 (m, 4H).
实施例58：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-(甲硫基)乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.58)Example 58: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-(2-(methylthio)ethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.58)
Figure PCTCN2017115380-appb-000255
Figure PCTCN2017115380-appb-000255
步骤1：制备5-(4-氟苯基)-1-(2-甲硫基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-1-(2-methylthioethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000256
Figure PCTCN2017115380-appb-000256
将400毫克5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和803毫克三苯基膦混溶于15毫升干燥的四氢呋喃，0℃下加入200微升2-甲硫基乙醇,然后逐滴加入600微升偶氮二甲酸二异丙酯(DIAD)，稍后回至室温搅拌2小时，反应液浓缩，残余物中压柱层析(乙酸乙酯：石油醚＝5:95)分离得透明液体513毫克为5-(4-氟苯基)-1-(2-甲硫基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率100％。 1H NMR(300MHz,DMSO)δ8.79(s,1H),8.64(s,1H),7.68–7.58(m,2H),7.40–7.29(m,2H),4.36(q,J＝7.1Hz,2H),3.84(t,J＝6.8Hz,2H),2.56(t,J＝6.8Hz,2H),1.88(s,3H),1.34(t,J＝7.1Hz,3H). 400 mg of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate and 803 mg of triphenylphosphine were dissolved in 15 ml of dry tetrahydrofuran at 0 ° C. Add 200 μl of 2-methylthioethanol, then add 600 μl of diisopropyl azodicarboxylate (DIAD) dropwise, then return to room temperature for 2 hours, concentrate the reaction, and compress the column by column chromatography. (ethyl acetate: petroleum ether = 5:95) 513 mg of a clear liquid was isolated as 5-(4-fluorophenyl)-1-(2-methylthioethyl)-4-oxo-1,4- Dihydropyridine-3-carboxylate ethyl ester, yield 100%. 1 H NMR (300 MHz, DMSO) δ 8.79 (s, 1H), 8.64 (s, 1H), 7.68 - 7.58 (m, 2H), 7.40 - 7.29 (m, 2H), 4.36 (q, J = 7.1 Hz) , 2H), 3.84 (t, J = 6.8 Hz, 2H), 2.56 (t, J = 6.8 Hz, 2H), 1.88 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
步骤2：制备5-(4-氟苯基)-1-(2-甲硫基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-1-(2-methylthioethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000257
Figure PCTCN2017115380-appb-000257
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-1-(2-甲硫基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氟苯基)-1-(2-甲硫基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸，收率46％。 1H NMR(300MHz,DMSO)δ8.47(s,1H),8.31(s,1H),7.56(dd,J＝8.8,5.6Hz,2H),7.28(t,J＝8.8Hz,2H),4.13(t,J＝6.8Hz,2H),2.58(t,J＝6.8Hz,2H),1.90(s,3H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-fluorophenyl)-1-(2-methylthioethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, the remaining starting materials, reagents and preparation The same procedure as in Example 3, Step 3 gave 5-(4-fluorophenyl)-1-(2-methylthioethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid as a white solid. The yield was 46%. 1 H NMR (300MHz, DMSO) δ8.47 (s, 1H), 8.31 (s, 1H), 7.56 (dd, J = 8.8,5.6Hz, 2H), 7.28 (t, J = 8.8Hz, 2H), 4.13 (t, J = 6.8 Hz, 2H), 2.58 (t, J = 6.8 Hz, 2H), 1.90 (s, 3H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-(甲硫基)乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-(2-(methylthio)ethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成 5-(4-氟苯基)-1-(2-甲硫基乙基)-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(2-(甲硫基)乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率25％。 1H NMR(300MHz,DMSO)δ10.72(s,1H),8.66(s,1H),8.60(s,1H),8.16(s,1H),7.83(d,J＝8.6Hz,2H),7.67(dd,J＝8.8,5.5Hz,2H),7.46(d,J＝8.6Hz,2H),7.36(t,J＝8.8Hz,2H),7.31(s,1H),6.12(s,2H),3.98(t,J＝6.7Hz,2H),3.75(s,3H),2.59(t,J＝6.7Hz,2H),1.84(s,3H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-1-(2-methylthioethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the same required starting materials, reagents and preparation methods are the same as the examples 1 step 8, the white solid is N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4- Fluorophenyl)-1-(2-(methylthio)ethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide, yield 25%. 1 H NMR (300MHz, DMSO) δ10.72 (s, 1H), 8.66 (s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 7.83 (d, J = 8.6Hz, 2H), 7.67 (dd, J = 8.8, 5.5 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 8.8 Hz, 2H), 7.31 (s, 1H), 6.12 (s, 2H) ), 3.98 (t, J = 6.7 Hz, 2H), 3.75 (s, 3H), 2.59 (t, J = 6.7 Hz, 2H), 1.84 (s, 3H).
实施例59：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.59)Example 59: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.59)
Figure PCTCN2017115380-appb-000258
Figure PCTCN2017115380-appb-000258
步骤1：制备5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000259
Figure PCTCN2017115380-appb-000259
将4-氨甲基四氢吡喃替换成(四氢呋喃-3-基)甲胺，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色液体为5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率80％。 1H NMR(300MHz,DMSO)δ8.35(d,J＝2.3Hz,1H),8.04(d,J＝2.3Hz,1H),7.73–7.56(m,2H),7.30–7.16(m,2H),4.20(q,J＝7.1Hz,2H),4.07–4.00(m,2H),3.87–3.75(m,1H),3.75–3.58(m,2H),3.50–3.37(m,1H),2.81–2.67(m,1H),1.98–1.79(m,1H),1.71–1.51(m,1H),1.26(t,J＝7.1Hz,3H). Replacing 4-aminomethyltetrahydropyran with (tetrahydrofuran-3-yl)methylamine, the remaining starting materials, reagents and preparation methods are the same as in Step 2 of Example 1, to obtain a yellow liquid of 5-(4-fluorophenyl). Ethyl 4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxylate, yield 80%. 1 H NMR (300MHz, DMSO) δ8.35 (d, J = 2.3Hz, 1H), 8.04 (d, J = 2.3Hz, 1H), 7.73-7.56 (m, 2H), 7.30-7.16 (m, 2H ), 4.20 (q, J = 7.1 Hz, 2H), 4.07 - 4.00 (m, 2H), 3.87 - 3.75 (m, 1H), 3.75 - 3.58 (m, 2H), 3.50 - 3.37 (m, 1H), 2.81–2.67 (m, 1H), 1.98–1.79 (m, 1H), 1.71–1.51 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H).
步骤2：制备5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000260
Figure PCTCN2017115380-appb-000260
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酸，收率76％。 1H NMR(300MHz,DMSO)δ8.84(d,J＝1.9Hz,1H),8.47(d,J＝1.9Hz,1H),7.75(dd,J＝8.7,5.6Hz,2H),7.31(t,J＝8.7Hz,2H),4.36–4.10(m,2H),3.90–3.76(m,1H),3.76–3.59(m,2H),3.51–3.40(m,1H),2.91–2.69(m,1H),2.04–1.85(m,1H),1.72–1.55(m,1H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate To 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester, the remaining raw materials, reagents And the preparation method is the same as in the step 3 of Example 1, to obtain a white solid as 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine. 3-carboxylic acid in a yield of 76%. 1 H NMR (300 MHz, DMSO) δ 8.84 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 8.7, 5.6 Hz, 2H), 7.31 ( t, J=8.7 Hz, 2H), 4.36–4.10 (m, 2H), 3.90–3.76 (m, 1H), 3.76–3.59 (m, 2H), 3.51–3.40 (m, 1H), 2.91–2.69 ( m, 1H), 2.04–1.85 (m, 1H), 1.72–1.55 (m, 1H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率62％。 1H NMR(300MHz,DMSO)δ13.00(s,1H),8.78(d,J＝2.1Hz,1H),8.28(d,J＝2.1Hz,1H),8.15(s,1H),7.81(d,J＝8.6Hz,2H),7.74(dd,J＝8.8,5.7Hz,2H),7.44(d,J＝8.6Hz,2H),7.36–7.20(m,3H),6.10(s,2H),4.33–4.01(m,2H),3.90–3.79(m,1H),3.77–3.58(m,5H),3.55–3.41(m,1H),2.95–2.65(m,1H),2.13–1.81(m,1H),1.80–1.43(m,1H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the same required raw materials, reagents and preparation methods are the same Step 8 of Example 1 gave the white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 62%. 1 H NMR (300MHz, DMSO) δ13.00 (s, 1H), 8.78 (d, J = 2.1Hz, 1H), 8.28 (d, J = 2.1Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.6 Hz, 2H), 7.74 (dd, J = 8.8, 5.7 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.36 - 7.20 (m, 3H), 6.10 (s, 2H) ), 4.33–4.01 (m, 2H), 3.90–3.79 (m, 1H), 3.77–3.58 (m, 5H), 3.55–3.41 (m, 1H), 2.95–2.65 (m, 1H), 2.13–1.81 (m, 1H), 1.80–1.43 (m, 1H).
实施例60：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.60)Example 60: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.60)
Figure PCTCN2017115380-appb-000261
Figure PCTCN2017115380-appb-000261
步骤1：制备5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000262
Figure PCTCN2017115380-appb-000262
将4-氨甲基四氢吡喃替换成(四氢呋喃-2-基)甲胺，其余所需原料、试剂及制备方法同实施例1步骤2，得黄色液体为5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，收率69％。 1H NMR(300MHz,DMSO)δ8.27(d,J＝2.2Hz,1H),7.95(d,J＝2.2Hz,1H),7.74–7.34(m,2H),7.23(t,J＝9.0Hz,2H),4.27–4.08(m,4H),4.07–3.90(m,1H),3.86–3.72(m,1H),3.72–3.60(m,1H),2.07–1.89(m,1H),1.89–1.74(m,2H),1.63–1.43(m,1H),1.26(t,J＝7.1Hz,3H). Replacing 4-aminomethyltetrahydropyran with (tetrahydrofuran-2-yl)methylamine, the remaining starting materials, reagents and preparation methods are the same as in Step 2 of Example 1, to obtain a yellow liquid of 5-(4-fluorophenyl). Ethyl 4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxylate, yield 69%. 1 H NMR (300MHz, DMSO) δ8.27 (d, J = 2.2Hz, 1H), 7.95 (d, J = 2.2Hz, 1H), 7.74-7.34 (m, 2H), 7.23 (t, J = 9.0 Hz, 2H), 4.27–4.08 (m, 4H), 4.07–3.90 (m, 1H), 3.86–3.72 (m, 1H), 3.72–3.60 (m, 1H), 2.07–1.89 (m, 1H), 1.89–1.74 (m, 2H), 1.63–1.43 (m, 1H), 1.26 (t, J=7.1 Hz, 3H).
步骤2：制备5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000263
Figure PCTCN2017115380-appb-000263
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酸，收率90％。 1H NMR(300MHz,DMSO)δ8.74(d,J＝2.1Hz,1H),8.37(d,J＝2.1Hz,1H),7.73(dd,J＝8.9,5.6Hz,2H),7.31(t,J＝8.9Hz,2H),4.49–4.26(m,1H),4.26–4.14(m,2H),3.86–3.75(m,1H),3.73–3.59(m,1H),2.12–1.93(m,1H),1.91–1.75(m,2H),1.65–1.46(m,1H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate To 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester, the remaining raw materials, reagents And the preparation method is the same as in the step 3 of Example 1, to obtain a white solid as 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine. 3-carboxylic acid, yield 90%. 1 H NMR (300MHz, DMSO) δ8.74 (d, J = 2.1Hz, 1H), 8.37 (d, J = 2.1Hz, 1H), 7.73 (dd, J = 8.9,5.6Hz, 2H), 7.31 ( t, J=8.9 Hz, 2H), 4.49–4.26 (m, 1H), 4.26–4.14 (m, 2H), 3.86–3.75 (m, 1H), 3.73–3.59 (m, 1H), 2.12–1.93 ( m, 1H), 1.91–1.75 (m, 2H), 1.65–1.46 (m, 1H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-2-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率67％。 1H NMR(300MHz,DMSO)δ13.00(s,1H),8.72(d,J＝2.1Hz,1H),8.19(d,J＝2.1Hz,1H),8.15(s,1H),7.81(d,J＝8.4Hz,2H),7.72(dd,J＝8.4,6.1Hz,2H),7.44(d,J＝8.4Hz,2H),7.37–7.24(m,3H),6.09(s,2H),4.43–4.06(m,3H),3.88–3.56(m,5H),2.15–1.92(m,1H),1.93–1.74(m,2H),1.67–1.35(m,1H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid, the same required raw materials, reagents and preparation methods are the same Step 8 of Example 1 gave the white solid as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-2-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 67%. 1 H NMR (300MHz, DMSO) δ13.00 (s, 1H), 8.72 (d, J = 2.1Hz, 1H), 8.19 (d, J = 2.1Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.4 Hz, 2H), 7.72 (dd, J = 8.4, 6.1 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.37 - 7.24 (m, 3H), 6.09 (s, 2H) ), 4.43–4.06 (m, 3H), 3.88–3.56 (m, 5H), 2.15–1.92 (m, 1H), 1.93–1.74 (m, 2H), 1.67–1.35 (m, 1H).
实施例61：N-(4-(4-氨基-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.61)Example 61: N-(4-(4-Amino-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.61)
Figure PCTCN2017115380-appb-000264
Figure PCTCN2017115380-appb-000264
步骤1：制备4-氯-5-碘-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000265
Figure PCTCN2017115380-appb-000265
将1-甲基-4-哌啶醇替换成4-羟基-1-甲基六氢氮杂卓，其余所需原料、试剂及制备方法同实施例14步骤1，得无色液体为4-氯-5-碘-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶，收率33％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.41(s,1H),3.29–2.99(m,1H),2.30(s,3H),2.27–1.64(m,9H),1.63–1.34(m,1H). Replacing 1-methyl-4-piperidinol with 4-hydroxy-1-methylhexahydroazepine, the remaining starting materials, reagents and preparation methods are the same as in step 14 of Example 14, to obtain a colorless liquid of 4- Chloro-5-iodo-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, yield 33%. 1 H NMR (300MHz, CDCl 3 ) δ 8.61 (s, 1H), 7.41 (s, 1H), 3.29 - 2.99 (m, 1H), 2.30 (s, 3H), 2.27 - 1.64 (m, 9H), 1.63–1.34(m,1H).
步骤2：制备4-(4-氯-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000266
Figure PCTCN2017115380-appb-000266
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得无色胶状物为4-(4-氯-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率72％。 1H NMR(300MHz,CDCl 3)δ8.61(s,1H),7.29(d,J＝8.4Hz,2H),7.23(s,1H),6.74(d,J＝8.4Hz,2H),4.56–4.19(m,2H),3.77(s,2H),3.48(s,3H),2.68–1.62(m,9H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-(1-methylhexahydroazepine-4 -yl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a colorless gum of 4-(4-chloro-7-( 1-methylhexahydroazepine-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, yield 72%. 1 H NMR (300MHz, CDCl 3 ) δ8.61 (s, 1H), 7.29 (d, J = 8.4Hz, 2H), 7.23 (s, 1H), 6.74 (d, J = 8.4Hz, 2H), 4.56 – 4.19 (m, 2H), 3.77 (s, 2H), 3.48 (s, 3H), 2.68–1.62 (m, 9H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000267
Figure PCTCN2017115380-appb-000267
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得无色胶状物为4-氨基-5-(4-氨基苯基)-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶，收率73％。 1H NMR(300MHz,CDCl 3)δ8.28(s,1H),7.25(d,J＝8.4Hz,2H),6.92(s,1H),6.77(d,J＝8.4Hz,2H),5.16(s,2H),4.59–4.05(m,2H),3.78(s,2H),3.49(s,3H),2.89–1.53(m,9H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(1-methylhexahydronitrogen) Benzene-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a colorless gel. 4-amino-5-(4-aminophenyl)-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, yield 73%. 1 H NMR (300MHz, CDCl 3 ) δ8.28 (s, 1H), 7.25 (d, J = 8.4Hz, 2H), 6.92 (s, 1H), 6.77 (d, J = 8.4Hz, 2H), 5.16 (s, 2H), 4.59–4.05 (m, 2H), 3.78 (s, 2H), 3.49 (s, 3H), 2.89–1.53 (m, 9H).
步骤4：制备N-(4-(4-氨基-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzene 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-(1-甲基六氢氮杂卓-4-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率40％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝1.4Hz,1H),8.25(d,J＝1.4Hz,1H),8.15(s,1H),7.81(d,J＝8.4Hz,2H),7.74(dd,J＝8.9,5.9Hz,2H),7.49–7.38(m,3H),7.29(t,J＝8.9Hz,2H),6.12(s,2H),4.31–4.16(m,2H),4.12(d,J＝6.6Hz,2H),3.94–3.71(m,2H),3.35(s,3H),3.26(t,J＝11.2Hz,2H),3.20–3.00(m,2H),2.45–1.62(m,8H),1.62–1.16(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (1-methylhexahydroazepine-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid N -(4-(4-Amino-7-(1-methylhexahydroazepin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5- (4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 40% . 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 1.4Hz, 1H), 8.25 (d, J = 1.4Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.4 Hz, 2H), 7.74 (dd, J = 8.9, 5.9 Hz, 2H), 7.49 - 7.38 (m, 3H), 7.29 (t, J = 8.9 Hz, 2H), 6.12 (s, 2H) ), 4.31 - 4.16 (m, 2H), 4.12 (d, J = 6.6 Hz, 2H), 3.94 - 3.71 (m, 2H), 3.35 (s, 3H), 3.26 (t, J = 11.2 Hz, 2H) , 3.20–3.00 (m, 2H), 2.45–1.62 (m, 8H), 1.62–1.16 (m, 4H).
实施例62：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-(2-吗啉基乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.62)Example 62: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-(2-morpholinylethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.62)
Figure PCTCN2017115380-appb-000268
Figure PCTCN2017115380-appb-000268
步骤1：制备5-(4-氟苯基)-1-(2-吗啉乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-1-(2-morpholinethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000269
Figure PCTCN2017115380-appb-000269
将2-甲硫基乙醇替换成2-吗啉乙醇，其余所需原料、试剂及制备方法同实施例58步骤1，得无色胶状物为5-(4-氟苯基)-1-(2-吗啉乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率97％。 1H NMR(300MHz,DMSO)δ8.77(s,1H),8.62(s,1H),7.79–7.48(m,2H),7.38–7.28(m,2H),4.35(q,J＝7.1Hz,2H),3.83(t,J＝5.4Hz,2H),3.45–3.37(m,4H),2.40(t,J＝5.4Hz,2H),2.24–2.10(m,4H),1.34(t,J＝7.1Hz,3H). The 2-methylthioethanol is replaced by 2-morpholinoethanol, and the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 58 to obtain a colorless gum of 5-(4-fluorophenyl)-1- (2-morpholineethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid ethyl ester, yield 97%. 1 H NMR (300 MHz, DMSO) δ 8.77 (s, 1H), 8.62 (s, 1H), 7.79 - 7.48 (m, 2H), 7.38 - 7.28 (m, 2H), 4.35 (q, J = 7.1 Hz) , 2H), 3.83 (t, J = 5.4 Hz, 2H), 3.45 - 3.37 (m, 4H), 2.40 (t, J = 5.4 Hz, 2H), 2.24 - 2.10 (m, 4H), 1.34 (t, J=7.1Hz, 3H).
步骤2：制备5-(4-氟苯基)-1-(2-吗啉乙基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-1-(2-morpholinethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000270
Figure PCTCN2017115380-appb-000270
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-1-(2-吗啉乙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为5-(4-氟苯基)-1-(2-吗啉乙基)-4-氧代-1,4-二氢吡啶-3-甲酸，收率56％。 1H NMR(300MHz,DMSO)δ8.53(s,1H),8.37(s,1H),7.69–7.53(m,2H),7.37–7.21(m,2H),3.99(t,J＝5.4Hz,2H),3.63–3.46(m,4H),2.57(t,J＝5.4Hz,2H),2.45–2.31(m,4H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-fluorophenyl)-1-(2-morpholinoethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, the remaining raw materials, reagents and preparation method In the same manner as in Step 3 of Example 1, a white solid was obtained as 5-(4-fluorophenyl)-1-(2-morpholinethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid. The rate is 56%. 1 H NMR (300MHz, DMSO) δ8.53 (s, 1H), 8.37 (s, 1H), 7.69-7.53 (m, 2H), 7.37-7.21 (m, 2H), 3.99 (t, J = 5.4Hz , 2H), 3.63–3.46 (m, 4H), 2.57 (t, J = 5.4 Hz, 2H), 2.45–2.31 (m, 4H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-(2-吗啉基乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-(2-morpholinylethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-1-(2-吗啉乙基)-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-(2-吗啉基乙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率34％。 1H NMR(300MHz,DMSO)δ10.70(s,1H),8.67(s,1H),8.59(s,1H),8.16(s,1H),7.83(d,J＝8.6Hz,2H),7.73–7.65(m,2H),7.46(d,J＝8.6Hz,2H),7.41–7.31(m,2H),7.30(s,1H),6.08(s,2H),3.95(t,J＝5.3Hz,2H),3.75(s,3H),3.40–3.27(m,4H),2.42(t,J＝5.3Hz,2H),2.22–2.12(m,4H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-1-(2-morpholinethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the remaining raw materials, reagents and preparation methods are the same as in the first embodiment Step 8. The white solid is obtained as N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluoro Phenyl)-4-oxo-1-(2-morpholinylethyl)-4-oxo-1,4-dihydropyridine-3-carboxamide, yield 34%. 1 H NMR (300MHz, DMSO) δ10.70 (s, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.83 (d, J = 8.6Hz, 2H), 7.73–7.65(m,2H), 7.46(d,J=8.6Hz,2H), 7.41–7.31(m,2H), 7.30(s,1H),6.08(s,2H),3.95(t,J= 5.3 Hz, 2H), 3.75 (s, 3H), 3.40–3.27 (m, 4H), 2.42 (t, J = 5.3 Hz, 2H), 2.22–2.12 (m, 4H).
实施例63：N-(4-(4-氨基-7-(2-吗啉基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.63)Example 63: N-(4-(4-Amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.63)
Figure PCTCN2017115380-appb-000271
Figure PCTCN2017115380-appb-000271
步骤1：制备4-(2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙基)吗啉Step 1: Preparation of 4-(2-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)morpholine
Figure PCTCN2017115380-appb-000272
Figure PCTCN2017115380-appb-000272
将1-甲基-4-哌啶醇替换成2-吗啉乙醇，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-(2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙基)吗啉，收率40％。 1H NMR(300MHz,DMSO)δ8.63(s,1H),8.04(s,1H),4.38(t,J＝6.2Hz,2H),3.67–3.42(m,4H),2.69(t,J＝6.2Hz,2H),2.46–2.23(m,4H). Replacing 1-methyl-4-piperidinol with 2-morpholinoethanol, the remaining starting materials, reagents and preparation methods are the same as in Step 1 of Example 14, to give 4-(2-(4-chloro-5) as a white solid. - Iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl)morpholine, yield 40%. 1 H NMR (300MHz, DMSO) δ8.63 (s, 1H), 8.04 (s, 1H), 4.38 (t, J = 6.2Hz, 2H), 3.67-3.42 (m, 4H), 2.69 (t, J =6.2 Hz, 2H), 2.46–2.23 (m, 4H).
步骤2：制备4-(4-氯-7-(2-吗啉乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-(2-morpholinethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000273
Figure PCTCN2017115380-appb-000273
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-(2-(4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)乙基)吗啉，其余所需原料、试剂及制备方法同实施例1步骤6，得白色固体为4-(4-氯-7-(2-吗啉乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率61％。 1H NMR(300MHz,DMSO)δ8.60(s,1H),7.69(s,1H),7.16(d,J＝8.4Hz,2H),6.61(d,J＝8.4Hz,2H),5.17(s,2H),4.41(t,J＝6.2Hz,2H),3.54–3.38(m,4H),2.73(t,J＝6.2Hz,2H),2.47–2.37(m,4H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-(2-(4-chloro-5-iodo-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)ethyl)morpholine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain 4-(4-chloro-7-(2-morpholine B) as a white solid. Base)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline in a yield of 61%. 1 H NMR (300MHz, DMSO) δ8.60 (s, 1H), 7.69 (s, 1H), 7.16 (d, J = 8.4Hz, 2H), 6.61 (d, J = 8.4Hz, 2H), 5.17 ( s, 2H), 4.41 (t, J = 6.2 Hz, 2H), 3.54 - 3.38 (m, 4H), 2.73 (t, J = 6.2 Hz, 2H), 2.47 - 2.37 (m, 4H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-(2-吗啉乙基)-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-(2-morpholinethyl)-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000274
Figure PCTCN2017115380-appb-000274
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-(2-吗啉乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得类白色固体为4-氨基-5-(4-氨基苯基)-7-(2-吗啉乙基)-7H-吡咯并[2,3-d]嘧啶，收率100％。 1H NMR(300MHz,DMSO)δ8.10(s,1H),7.17(s,1H),7.10(d,J＝8.4Hz,2H),6.66(d,J＝8.4Hz,2H),6.00(s,2H),5.29(s,2H),4.26(t,J＝6.7Hz,2H),3.58–3.52(m,4H),2.72(t,J＝6.7Hz,2H),2.56–2.45(m,4H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-(2-morpholinylethyl) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a white solid as 4-amino-5-(4- Aminophenyl)-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidine in 100% yield. 1 H NMR (300MHz, DMSO) δ8.10 (s, 1H), 7.17 (s, 1H), 7.10 (d, J = 8.4Hz, 2H), 6.66 (d, J = 8.4Hz, 2H), 6.00 ( s, 2H), 5.29 (s, 2H), 4.26 (t, J = 6.7 Hz, 2H), 3.58 - 3.52 (m, 4H), 2.72 (t, J = 6.7 Hz, 2H), 2.56 - 2.45 (m , 4H).
步骤4：制备N-(4-(4-氨基-7-(2-吗啉基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-(2-吗啉乙基)-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得类白色固体为N-(4-(4-氨基-7-(2-吗啉基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率67％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝1.7Hz,1H),8.22(d,J＝1.7Hz,1H),8.14(s,1H),7.81(d,J＝8.4Hz,2H),7.74(dd,J＝8.9,6.1Hz,2H),7.44(d,J＝8.4Hz,2H),7.37(s,1H),7.29(t,J＝8.9Hz,2H),6.09(s,2H),4.29(t,J＝6.4Hz,2H),4.11(d,J＝7.1Hz,2H),3.94–3.75(m,2H),3.62–3.46(m,4H),3.31–3.19(m,2H),2.71(t,J＝6.4Hz,2H),2.48–2.37(m,4H),2.19–2.03(m,1H),1.52–1.22(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- (2-morpholineethyl)-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as those in the first step of Example 1, to obtain a white solid N-(4-(4) -amino-7-(2-morpholinoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 67%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 1.7Hz, 1H), 8.22 (d, J = 1.7Hz, 1H), 8.14 (s, 1H), 7.81 ( d, J = 8.4 Hz, 2H), 7.74 (dd, J = 8.9, 6.1 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 7.29 (t, J = 8.9) Hz, 2H), 6.09 (s, 2H), 4.29 (t, J = 6.4 Hz, 2H), 4.11 (d, J = 7.1 Hz, 2H), 3.94 - 3.75 (m, 2H), 3.62 - 3.46 (m , 4H), 3.31–3.19 (m, 2H), 2.71 (t, J = 6.4 Hz, 2H), 2.48–2.37 (m, 4H), 2.19–2.03 (m, 1H), 1.52–1.22 (m, 4H) ).
实施例64：N-(4-(4-氨基-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.64)Example 64: N-(4-(4-Amino-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl) -5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO .64)
Figure PCTCN2017115380-appb-000275
Figure PCTCN2017115380-appb-000275
步骤1：制备3-碘-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺Step 1: Preparation of 3-iodo-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Figure PCTCN2017115380-appb-000276
Figure PCTCN2017115380-appb-000276
将4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶替换成3-碘-1H-吡唑并[3,4-d]嘧啶-4-胺，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为3-碘-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺，收率24％。 1H NMR(300MHz,DMSO)δ8.18(s,1H),6.99(s,2H),4.73–4.29(m,1H),2.92–2.82(m,2H),2.21(s,3H),2.14–1.97(m,4H),1.91–1.73(m,2H). Replace 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine, the remaining starting materials, The reagent and the preparation method were the same as those in the first step of Example 14 to give 3-iodo-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-. Amine, yield 24%. 1 H NMR (300MHz, DMSO) δ8.18 (s, 1H), 6.99 (s, 2H), 4.73-4.29 (m, 1H), 2.92-2.82 (m, 2H), 2.21 (s, 3H), 2.14 –1.97 (m, 4H), 1.91–1.73 (m, 2H).
步骤2：制备3-(4-氨基苯基)-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺Step 2: Preparation of 3-(4-aminophenyl)-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Figure PCTCN2017115380-appb-000277
Figure PCTCN2017115380-appb-000277
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成3-碘-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺，其余所需原料、试剂及制备方法同实施例1步骤6，得白色固体为3-(4-氨基苯基)-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺，收率100％。 1H NMR(300MHz,DMSO)δ8.19(s,1H),7.31(d,J＝8.4Hz,2H),6.70(d,J＝8.4Hz,2H),6.60(s,2H),5.44(s,2H),4.83–4.56(m,1H),3.24–3.05(m,2H),2.40(s,3H),2.38–2.19(m,4H),1.96–1.85(m,2H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 3-iodo-1-(1-methylpiperidin-4-yl)-1H-pyridyl Zoxao[3,4-d]pyrimidin-4-amine, the remaining starting materials, reagents and preparation methods are the same as in the step 6 of Example 1, to obtain a white solid as 3-(4-aminophenyl)-1-(1- Methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, yield 100%. 1 H NMR (300MHz, DMSO) δ8.19 (s, 1H), 7.31 (d, J = 8.4Hz, 2H), 6.70 (d, J = 8.4Hz, 2H), 6.60 (s, 2H), 5.44 ( s, 2H), 4.83–4.56 (m, 1H), 3.24–3.05 (m, 2H), 2.40 (s, 3H), 2.38–2.19 (m, 4H), 1.96–1.85 (m, 2H).
步骤3：制备N-(4-(4-氨基-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl) -5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成3-(4-氨基苯基)-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-1-(1-甲基哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率68％。 1H NMR(300MHz,DMSO)δ13.13(s,1H),8.73(d,J＝2.0Hz,1H),8.32–8.15(m,2H),7.88(d,J＝8.6Hz,2H),7.74(dd,J＝8.9,5.7Hz,2H),7.65(d,J＝8.6Hz,2H),7.29(t,J＝8.9Hz,2H),6.88(s,2H),4.86–4.57(m,1H),4.12(d,J＝6.4Hz,2H),3.96–3.52(m,2H),3.32–3.21(m,2H),3.19–3.02(m,2H),2.44–2.23(m,7H),2.19–2.03(m,1H),2.03–1.91(m,2H),1.55–1.19(m,4H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 3-(4-aminophenyl)-1-(1-methyl Isopiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-( 4-(4-Amino-1-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-5-(4-fluoro Phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 68%. 1 H NMR (300MHz, DMSO) δ13.13 (s, 1H), 8.73 (d, J = 2.0Hz, 1H), 8.32-8.15 (m, 2H), 7.88 (d, J = 8.6Hz, 2H), 7.74 (dd, J = 8.9, 5.7 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.29 (t, J = 8.9 Hz, 2H), 6.88 (s, 2H), 4.86 - 4.57 (m) , 1H), 4.12 (d, J = 6.4 Hz, 2H), 3.96 - 3.52 (m, 2H), 3.32 - 3.21 (m, 2H), 3.19 - 3.02 (m, 2H), 2.44 - 2.23 (m, 7H) ), 2.19–2.03 (m, 1H), 2.03–1.91 (m, 2H), 1.55–1.19 (m, 4H).
实施例65：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.65)Example 65: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.65)
Figure PCTCN2017115380-appb-000278
Figure PCTCN2017115380-appb-000278
步骤1：制备5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 5-(4-fluorophenyl)-1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000279
Figure PCTCN2017115380-appb-000279
将2-甲硫基乙醇替换成1-溴-3-甲氧基丙烷，其余所需原料、试剂及制备方法同实施例58步骤1，得无色液体为5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率82％。 1H NMR(300MHz,DMSO)δ8.26(d,J＝2.1Hz,1H),7.96(d,J＝2.1Hz,1H),7.66(dd,J＝8.9,5.7Hz,2H),7.22(t,J＝8.9Hz,2H),4.19(q,J＝7.0Hz,2H),4.10–4.02(m,2H),3.37–3.29(m,2H),3.22(s,3H),2.09–1.92(m,2H),1.26(t,J＝7.0Hz,3H). The 2-methylthioethanol is replaced by 1-bromo-3-methoxypropane, and the remaining raw materials, reagents and preparation methods are the same as those in the first step of Example 58 to obtain a colorless liquid of 5-(4-fluorophenyl). Ethyl 1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, yield 82%. 1 H NMR (300MHz, DMSO) δ8.26 (d, J = 2.1Hz, 1H), 7.96 (d, J = 2.1Hz, 1H), 7.66 (dd, J = 8.9,5.7Hz, 2H), 7.22 ( t, J = 8.9 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 4.10 - 4.02 (m, 2H), 3.37 - 3.29 (m, 2H), 3.22 (s, 3H), 2.09 - 1.92 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H).
步骤2：制备5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 5-(4-fluorophenyl)-1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000280
Figure PCTCN2017115380-appb-000280
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得无色液体为5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酸，收率75％。 1H NMR(300MHz,DMSO)δ8.74(d,J＝2.2Hz,1H),8.40(d,J＝2.2Hz,1H),7.97–7.56(m,2H),7.37–6.99(m,2H),4.28(t,J＝7.0Hz,2H),3.45–3.27(m,2H),3.20(s,3H),2.20–2.00(m,2H). Replacement of ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate Ethyl 5-(4-fluorophenyl)-1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, the remaining starting materials, reagents and preparation The method was the same as in the step 3 of Example 1, to obtain a colorless liquid of 5-(4-fluorophenyl)-1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3- Formic acid, yield 75%. 1 H NMR (300MHz, DMSO) δ8.74 (d, J = 2.2Hz, 1H), 8.40 (d, J = 2.2Hz, 1H), 7.97-7.56 (m, 2H), 7.37-6.99 (m, 2H ), 4.28 (t, J = 7.0 Hz, 2H), 3.45 - 3.27 (m, 2H), 3.20 (s, 3H), 2.20 - 2.00 (m, 2H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成 5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-1-(3-甲氧基丙基)-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率42％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.69(d,J＝2.2Hz,1H),8.20(d,J＝2.2Hz,1H),8.15(s,1H),7.81(d,J＝8.5Hz,2H),7.78–7.69(m,2H),7.44(d,J＝8.5Hz,2H),7.36–7.21(m,3H),6.08(s,2H),4.24(t,J＝6.9Hz,2H),3.74(s,3H),3.36(t,J＝6.3Hz,2H),3.24(s,3H),2.19–1.90(m,2H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 5 -(4-fluorophenyl)-1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the same required starting materials, reagents and preparation methods are the same as the examples 1 step 8, the white solid is N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluoro Phenyl)-1-(3-methoxypropyl)-4-oxo-1,4-dihydropyridine-3-carboxamide in a yield of 42%. 1 H NMR (300 MHz, DMSO) δ 13.02 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.81 ( d, J = 8.5 Hz, 2H), 7.78 - 7.69 (m, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.36 - 7.21 (m, 3H), 6.08 (s, 2H), 4.24 (t , J = 6.9 Hz, 2H), 3.74 (s, 3H), 3.36 (t, J = 6.3 Hz, 2H), 3.24 (s, 3H), 2.19 - 1.90 (m, 2H).
实施例66：N-(4-(4-氨基-7-正丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.66)Example 66: N-(4-(4-Amino-7-n-propyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.66)
Figure PCTCN2017115380-appb-000281
Figure PCTCN2017115380-appb-000281
步骤1：制备4-氯-5-碘-7-丙基-7H-吡咯并[2,3-d]嘧啶Step 1: Preparation of 4-chloro-5-iodo-7-propyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000282
Figure PCTCN2017115380-appb-000282
将1-甲基-4-哌啶醇替换成正丙醇，其余所需原料、试剂及制备方法同实施例14步骤1，得白色固体为4-氯-5-碘-7-丙基-7H-吡咯并[2,3-d]嘧啶，收率98％。 1H NMR(300MHz,DMSO)δ8.62(s,1H),8.05(s,1H),4.21(t,J＝7.1Hz,2H),1.89–1.68(m,2H),0.80(t,J＝7.1Hz,3H). Replacing 1-methyl-4-piperidinol with n-propanol, the remaining starting materials, reagents and preparation methods are the same as in Step 1 of Example 14, to give 4-chloro-5-iodo-7-propyl-7H as a white solid. - Pyrrolo[2,3-d]pyrimidine in a yield of 98%. 1 H NMR (300 MHz, DMSO) δ 8.62 (s, 1H), 8.05 (s, 1H), 4.21. (t, J = 7.1 Hz, 2H), 1.89 - 1.68 (m, 2H), 0.80 (t, J) =7.1Hz, 3H).
步骤2：制备4-(4-氯-7-丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺Step 2: Preparation of 4-(4-chloro-7-propyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
Figure PCTCN2017115380-appb-000283
Figure PCTCN2017115380-appb-000283
将4-氯-7-甲基-5-碘-7H-吡咯并[2,3-d]嘧啶替换成4-氯-5-碘-7-丙基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤6，得黄色固体为4-(4-氯-7-丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，收率96％。 1H NMR(300MHz,DMSO)δ8.60(s,1H),7.69(s,1H),7.16(d,J＝8.4Hz,2H),6.61(d,J＝8.4Hz,2H),5.15(s,2H),4.25(t,J＝7.1Hz,2H),1.94–1.77(m,2H),0.85(t,J＝7.1Hz,3H). Replace 4-chloro-7-methyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine with 4-chloro-5-iodo-7-propyl-7H-pyrrolo[2,3- d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in step 6 of Example 1, to obtain a yellow solid which is 4-(4-chloro-7-propyl-7H-pyrrolo[2,3-d]pyrimidine-5. -Base) Aniline, yield 96%. 1 H NMR (300MHz, DMSO) δ8.60 (s, 1H), 7.69 (s, 1H), 7.16 (d, J = 8.4Hz, 2H), 6.61 (d, J = 8.4Hz, 2H), 5.15 ( s, 2H), 4.25 (t, J = 7.1 Hz, 2H), 1.94 - 1.77 (m, 2H), 0.85 (t, J = 7.1 Hz, 3H).
步骤3：制备4-氨基-5-(4-氨基苯基)-7-丙基-7H-吡咯并[2,3-d]嘧啶Step 3: Preparation of 4-amino-5-(4-aminophenyl)-7-propyl-7H-pyrrolo[2,3-d]pyrimidine
Figure PCTCN2017115380-appb-000284
Figure PCTCN2017115380-appb-000284
将4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺替换成4-(4-氯-7-丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺，其余所需原料、试剂及制备方法同实施例1步骤7，得类白色固体为4-氨基-5-(4-氨基苯基)-7-丙基-7H-吡咯并[2,3-d]嘧啶，收率74％。 1H NMR(300MHz,DMSO)δ8.09(s,1H),7.14(s,1H),7.10(d,J＝8.4Hz,2H),6.65(d,J＝8.4Hz,2H),5.98(s,2H),5.20(s,2H),4.08(t,J＝7.2Hz,2H),1.90–1.67(m,2H),0.85(t,J＝7.2Hz,3H). Replace 4-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline with 4-(4-chloro-7-propyl-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)aniline, the remaining starting materials, reagents and preparation methods are the same as in the step 7 of Example 1, to obtain a white solid as 4-amino-5-(4-aminophenyl)-7. -propyl-7H-pyrrolo[2,3-d]pyrimidine in a yield of 74%. 1 H NMR (300MHz, DMSO) δ8.09 (s, 1H), 7.14 (s, 1H), 7.10 (d, J = 8.4Hz, 2H), 6.65 (d, J = 8.4Hz, 2H), 5.98 ( s, 2H), 5.20 (s, 2H), 4.08 (t, J = 7.2 Hz, 2H), 1.90 - 1.67 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).
步骤4：制备N-(4-(4-氨基-7-正丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺Step 4: Preparation of N-(4-(4-amino-7-n-propyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl) 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基苯基)-7-丙基-7H-吡咯并[2,3-d]嘧啶，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-正丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率73％。 1H NMR(300MHz,DMSO)δ13.02(s,1H),8.72(d,J＝2.1Hz,1H),8.22(d,J＝2.1Hz,1H),8.13(s,1H),7.80(d,J＝8.5Hz,2H),7.73(dd,J＝8.9,5.6Hz,2H),7.45(d,J＝8.5Hz,2H),7.35(s,1H),7.29(t,J＝8.9Hz,2H),6.08(s,2H),4.22–3.98(m,4H),3.94–3.74(m,2H),3.30–3.16(m,2H),2.24–2.02(m,1H),1.93–1.71(m,2H),1.52–1.21(m,4H),0.86(t,J＝7.4Hz,3H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-aminophenyl)-7- propyl-7H-pyrrolo[2,3-d]pyrimidine, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7----- -7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran)- 4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, yield 73%. 1 H NMR (300MHz, DMSO) δ13.02 (s, 1H), 8.72 (d, J = 2.1Hz, 1H), 8.22 (d, J = 2.1Hz, 1H), 8.13 (s, 1H), 7.80 ( d, J = 8.5 Hz, 2H), 7.73 (dd, J = 8.9, 5.6 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.35 (s, 1H), 7.29 (t, J = 8.9) Hz, 2H), 6.08 (s, 2H), 4.22–3.98 (m, 4H), 3.94–3.74 (m, 2H), 3.30–3.16 (m, 2H), 2.24–2.02 (m, 1H), 1.93– 1.71 (m, 2H), 1.52–1.21 (m, 4H), 0.86 (t, J = 7.4 Hz, 3H).
实施例67：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酰胺(NO.67)Example 67: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1-cyclopropyl-5-(4 -fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (NO.67)
Figure PCTCN2017115380-appb-000285
Figure PCTCN2017115380-appb-000285
步骤1：制备1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯Step 1: Preparation of ethyl 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate
Figure PCTCN2017115380-appb-000286
Figure PCTCN2017115380-appb-000286
将4-氨甲基四氢吡喃替换环丙胺，其余所需原料、试剂及制备方法同实施例1步骤2，得类白色固体为1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，收率57％。 1H NMR(300MHz,CDCl 3)δ8.27(d,J＝2.2Hz,1H),7.83–7.39(m,3H),7.07(t,J＝8.8Hz,2H),4.37(q,J＝7.1Hz,2H),3.88–3.26(m,1H),1.38(t,J＝7.1Hz,3H),1.20–1.04(m,4H). 4-Aminomethyltetrahydropyran is replaced by cyclopropylamine, and the remaining raw materials, reagents and preparation methods are the same as those in the second step of Example 1, to obtain a white solid as 1-cyclopropyl-5-(4-fluorophenyl). Ethyl 4-oxo-1,4-dihydropyridine-3-carboxylate, yield 57%. 1 H NMR (300MHz, CDCl 3 ) δ 8.27 (d, J = 2.2 Hz, 1H), 7.83 - 7.39 (m, 3H), 7.07 (t, J = 8.8 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.88–3.26 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.20–1.04 (m, 4H).
步骤2：制备1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸Step 2: Preparation of 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid
Figure PCTCN2017115380-appb-000287
Figure PCTCN2017115380-appb-000287
5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸乙酯替换成1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯，其余所需原料、试剂及制备方法同实施例1步骤3，得白色固体为1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸，收率88％。 1H NMR(300MHz,CDCl 3)δ8.64(s,1H),7.79(s,1H),7.69–7.39(m,2H),7.14(t,J＝8.4Hz,2H),3.84–3.41(m,1H),1.35–1.08(m,4H). Ethyl 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylate was replaced with Ethyl 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate, the remaining raw materials, reagents and preparation methods are the same as those in the first embodiment. The white solid was 1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid in a yield of 88%. 1 H NMR (300MHz, CDCl 3 ) δ 8.64 (s, 1H), 7.79 (s, 1H), 7.69 - 7.39 (m, 2H), 7.14 (t, J = 8.4 Hz, 2H), 3.84 - 3.41 ( m, 1H), 1.35–1.08 (m, 4H).
步骤3：制备N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酰胺Step 3: Preparation of N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1-cyclopropyl-5-(4 -fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide
将5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1-环丙基-5-(4-氟苯基)-4-氧代-1,4-二氢吡啶-3-甲酰胺，收率为77％。 1H NMR(300MHz,DMSO)δ12.92(s,1H),8.63(d,J＝2.3Hz,1H),8.15(s,1H),8.13(d,J＝2.3Hz,1H),7.80(d,J＝8.4Hz,2H),7.73(dd,J＝8.8,5.7Hz,2H),7.44(d,J＝8.4Hz,2H),7.36–7.19(m,3H),6.09(s,2H),3.94–3.81(m,1H),3.74(s,3H),1.29–1.21(m,2H),1.12–1.02(m,2H). Replace 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid with 1 -cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, obtaining white The solid is N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1-cyclopropyl-5-(4-fluoro Phenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide in a yield of 77%. 1 H NMR (300MHz, DMSO) δ12.92 (s, 1H), 8.63 (d, J = 2.3Hz, 1H), 8.15 (s, 1H), 8.13 (d, J = 2.3Hz, 1H), 7.80 ( d, J = 8.4 Hz, 2H), 7.73 (dd, J = 8.8, 5.7 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.36 - 7.19 (m, 3H), 6.09 (s, 2H) ), 3.94–3.81 (m, 1H), 3.74 (s, 3H), 1.29–1.21 (m, 2H), 1.12–1.02 (m, 2H).
实施例68：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺(NO.68)Example 68: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxamide (NO.68)
Figure PCTCN2017115380-appb-000288
Figure PCTCN2017115380-appb-000288
将4-氨基-5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶替换成4-氨基-5-(4-氨基-2,5-二氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶，5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酸替换成5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲 基)-1,4-二氢吡啶-3-甲酸，其余所需原料、试剂及制备方法同实施例1步骤8，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺，收率12％。 1H NMR(300MHz,DMSO)δ13.42(s,1H),8.82(d,J＝1.9Hz,1H),8.46(dd,J＝11.7,6.6Hz,1H),8.30(d,J＝1.9Hz,1H),8.15(s,1H),7.73(dd,J＝8.6,5.7Hz,2H),7.58–6.99(m,4H),6.20(s,2H),4.35–4.08(m,2H),3.92–3.61(m,6H),3.56–3.40(m,1H),2.96–2.64(m,1H),2.02–1.88(m,1H),1.74–1.57(m,1H). Replace 4-amino-5-(4-aminophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine with 4-amino-5-(4-amino-2,5-di Fluorophenyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran)- 4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid was replaced by 5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl)methyl)- 1,4-Dihydropyridine-3-carboxylic acid, the remaining starting materials, reagents and preparation methods are the same as in the first step of Example 1, to obtain a white solid as N-(4-(4-amino-7-methyl-7H-pyrrole) And [2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl) Methyl)-1,4-dihydropyridine-3-carboxamide, yield 12%. 1 H NMR (300MHz, DMSO) δ13.42 (s, 1H), 8.82 (d, J = 1.9Hz, 1H), 8.46 (dd, J = 11.7,6.6Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.15(s, 1H), 7.73 (dd, J=8.6, 5.7 Hz, 2H), 7.58–6.99 (m, 4H), 6.20 (s, 2H), 4.35–4.08 (m, 2H) , 3.92–3.61 (m, 6H), 3.56–3.40 (m, 1H), 2.96–2.64 (m, 1H), 2.02–1.88 (m, 1H), 1.74–1.57 (m, 1H).
实施例69：N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺甲磺酸盐(NO.69)Example 69: N-(4-(4-Amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide methanesulfonate (NO .69)
Figure PCTCN2017115380-appb-000289
Figure PCTCN2017115380-appb-000289
将60毫克N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺溶于5毫升氯仿，加入102微升1N甲磺酸乙醇溶液，室温搅拌30分钟后浓缩，向残余物中加入二异丙基醚，沉淀的固体通过过滤收集，滤饼用二异丙基醚洗后刮出，干燥后得白色固体56毫克为N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺甲磺酸盐，收率81％。 1H NMR(300MHz,DMSO)δ13.08(s,1H),8.72(d,J＝2.1Hz,1H),8.43(s,1H),8.24(d,J＝2.1Hz,1H),7.85(d,J＝8.6Hz,2H),7.81–7.68(m,4H),7.64(s,1H),7.47(d,J＝8.6Hz,2H),7.30(t,J＝8.9Hz,2H),4.43(t,J＝5.0Hz,2H),4.11(d,J＝7.0Hz,2H),3.94–3.82(m,2H),3.75(t,J＝5.0Hz,2H),3.33–3.17(m,5H),2.32(s,3H),2.18–2.04(m,1H),1.55–1.41(m,2H),1.39–1.25(m,2H). 60 mg of N-(4-(4-amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4 -fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide dissolved in 5 ml of chloroform, added 102 μl of 1N methanesulfonic acid in ethanol, stirred at room temperature for 30 minutes, concentrated, diisopropyl ether was added to the residue, and the precipitated solid was collected by filtration. The filter cake was washed with diisopropyl ether and then dried. Obtained 56 mg of white solid as N-(4-(4-amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5 -(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide methanesulfonate The yield was 81%. 1 H NMR (300MHz, DMSO) δ13.08 (s, 1H), 8.72 (d, J = 2.1Hz, 1H), 8.43 (s, 1H), 8.24 (d, J = 2.1Hz, 1H), 7.85 ( d, J = 8.6 Hz, 2H), 7.81 - 7.68 (m, 4H), 7.64 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 8.9 Hz, 2H), 4.43 (t, J = 5.0 Hz, 2H), 4.11 (d, J = 7.0 Hz, 2H), 3.94 - 3.82 (m, 2H), 3.75 (t, J = 5.0 Hz, 2H), 3.33 - 3.17 (m , 5H), 2.32 (s, 3H), 2.18–2.04 (m, 1H), 1.55–1.41 (m, 2H), 1.39–1.25 (m, 2H).
实施例70：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺甲磺酸盐(NO.70)Example 70: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)- 4-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,4-dihydropyridine-3-carboxamide methanesulfonate (NO.70)
Figure PCTCN2017115380-appb-000290
Figure PCTCN2017115380-appb-000290
将N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺替换成N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺，其余所需原料、试剂及制备方法同实施例69，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢呋喃-3-基)甲基)-1,4-二氢吡啶-3-甲酰胺甲磺酸盐，收率94％。 1H NMR(300MHz,DMSO)δ13.06(s,1H),8.78(d,J＝2.1Hz,1H),8.43(s,1H),8.29(d,J＝2.1Hz,1H),7.85(d,J＝8.4Hz,2H),7.79–7.51(m,5H),7.45(d,J＝8.4Hz,2H),7.30(t,J＝8.9Hz,2H),4.34–4.11(m,2H),3.90–3.77(m,4H),3.77–3.59(m,2H),3.51–3.43(m,1H),2.89–2.72(m,1H),2.33(s,3H),2.02–1.87(m,1H),1.75–1.55(m,1H). N-(4-(4-Amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluoro Replacement of phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide to N-(4-(4) -amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran- 3-yl)methyl)-1,4-dihydropyridine-3-carboxamide, the remaining starting materials, reagents and preparation methods are the same as in Example 69 to give a white solid as N-(4-(4-amino-7) -methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1-((tetrahydrofuran-3-yl) Methyl)-1,4-dihydropyridine-3-carboxamide methanesulfonate, yield 94%. 1 H NMR (300MHz, DMSO) δ13.06 (s, 1H), 8.78 (d, J = 2.1Hz, 1H), 8.43 (s, 1H), 8.29 (d, J = 2.1Hz, 1H), 7.85 ( d, J = 8.4 Hz, 2H), 7.79 - 7.51 (m, 5H), 7.45 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 8.9 Hz, 2H), 4.34 - 4.11 (m, 2H) ), 3.90–3.77 (m, 4H), 3.77–3.59 (m, 2H), 3.51–3.43 (m, 1H), 2.89–2.72 (m, 1H), 2.33 (s, 3H), 2.02–1.87 (m) , 1H), 1.75–1.55 (m, 1H).
实施例71：N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺甲磺酸盐(NO.71)Example 71: N-(4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-( 4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide methanesulfonate (NO .71)
Figure PCTCN2017115380-appb-000291
Figure PCTCN2017115380-appb-000291
将N-(4-(4-氨基-7-(2-甲氧基乙基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺替换成N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺，其余所需原料、试剂及制备方法同实施例69，得白色固体为N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,5-二氟苯基)-5-(4-氟苯基)-4-氧代-1-((四氢-2H-吡喃-4-基)甲基)-1,4-二氢吡啶-3-甲酰胺甲磺酸盐，收率57％。 1H NMR(300MHz,DMSO)δ13.52(s,1H),8.76(d,J＝2.0Hz,1H),8.59–8.36(m,2H),8.26(d,J＝2.0Hz,1H),8.02(s,2H),7.81–7.67(m,3H),7.43(dd,J＝11.2,6.9Hz,1H),7.30(t,J＝9.0Hz,2H),4.13(d,J＝7.3Hz,2H),3.97–3.75(m,5H),3.34–3.18(m,2H),2.33(s,3H),2.22–2.00(m,1H),1.54–1.40(m,2H),1.41–1.19(m,2H). N-(4-(4-Amino-7-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-5-(4-fluoro Replacement of phenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide to N-(4-(4) -amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-(4-fluorophenyl)-4-oxo 1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide, the remaining raw materials, reagents and preparation methods are the same as in Example 69, white The solid is N-(4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2,5-difluorophenyl)-5-(4- Fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxamide methanesulfonate, yield 57 %. 1 H NMR (300MHz, DMSO) δ13.52 (s, 1H), 8.76 (d, J = 2.0Hz, 1H), 8.59-8.36 (m, 2H), 8.26 (d, J = 2.0Hz, 1H), 8.02 (s, 2H), 7.81 - 7.67 (m, 3H), 7.43 (dd, J = 11.2, 6.9 Hz, 1H), 7.30 (t, J = 9.0 Hz, 2H), 4.13 (d, J = 7.3 Hz) , 2H), 3.97–3.75 (m, 5H), 3.34–3.18 (m, 2H), 2.33 (s, 3H), 2.22–2.00 (m, 1H), 1.54–1.40 (m, 2H), 1.41–1.19 (m, 2H).
对照化合物Control compound
1、BGB324(R428)1, BGB324 (R428)
Figure PCTCN2017115380-appb-000292
Figure PCTCN2017115380-appb-000292
化合物研发代码为BGB324或R428，CAS号为1037624-75-1，是Rigel公司开发的AXL选择性小分子抑制剂，2011年此化合物被授权给BerGenBio公司开发，目前处于临床一/二期，适应症为非小细胞肺癌和急性骨髓性白血病。本发明采用市售的对照化合物。The compound development code is BGB324 or R428, and the CAS number is 1037624-75-1. It is an AXL selective small molecule inhibitor developed by Rigel. In 2011, this compound was authorized to be developed by BerGenBio, and is currently in clinical phase I/II. The disease is non-small cell lung cancer and acute myeloid leukemia. Commercially available control compounds are employed in the present invention.
2、Cabozantinib S-malate(卡博替尼苹果酸盐)2, Cabozantinib S-malate (cabotinib malate)
Figure PCTCN2017115380-appb-000293
Figure PCTCN2017115380-appb-000293
化合物研发代码为XL-184或BMS-907351，CAS号为1140909-48-3，是Exelixis公司开发的目前已经上市的酪氨酸激酶多靶点小分子抑制剂，适应症为肾细胞癌、晚期肾细胞癌和甲状腺髓样癌。本发明采用市售的对照化合物。The compound development code is XL-184 or BMS-907351, and the CAS number is 1140909-48-3. It is a multi-target small molecule inhibitor of tyrosine kinase developed by Exelixis. The indication is renal cell carcinoma and advanced stage. Renal cell carcinoma and medullary thyroid carcinoma. Commercially available control compounds are employed in the present invention.
3、Gilteritinib3, Gilteritinib
Figure PCTCN2017115380-appb-000294
Figure PCTCN2017115380-appb-000294
化合物研发代码为ASP-2215、ASP2215 hemifumarate或66D92MGC8M(UN Ⅱ code)，CAS号为1254053-43-4，是安斯泰来公司开发的AXL/FLT3小分子抑制剂，目前用于治疗复发性和难治性急性髓细胞白血病的研究已进入临床三期，用于冶疗非小细胞肺癌的研临床二期。本发明采用市售的对照化合物。The compound development code is ASP-2215, ASP2215 hemifumarate or 66D92MGC8M (UN II code), CAS number is 1254053-43-4, which is an AXL/FLT3 small molecule inhibitor developed by Astellas. It is currently used to treat recurrence and The study of refractory acute myeloid leukemia has entered the clinical phase III, and is used in the second phase of research for the treatment of non-small cell lung cancer. Commercially available control compounds are employed in the present invention.
4、Crizotinib4, Crizotinib
Figure PCTCN2017115380-appb-000295
Figure PCTCN2017115380-appb-000295
化合物研发代码为PF-02341066、PF-2341066、PF-002341066或PF-1066，CAS号为877399-52-5，是辉瑞公司开发的目前已经上市的酪氨酸激酶多靶点小分子抑制剂，适应症为非小细胞肺癌和ROS1阳性非小细胞肺癌。本发明采用市售的对照化合物。The compound development code is PF-02341066, PF-2341066, PF-002341066 or PF-1066, CAS No. 877399-52-5, which is a multi-target small molecule inhibitor of tyrosine kinase currently developed by Pfizer. The indications are non-small cell lung cancer and ROS1-positive non-small cell lung cancer. Commercially available control compounds are employed in the present invention.
5、Capmatinib5, Capmatinib
Figure PCTCN2017115380-appb-000296
Figure PCTCN2017115380-appb-000296
化合物研发代码为INC-280、INCB-028060、INCB-28060、NVP-INC280-NX、C2A374O70X，CAS号为1029712-80-8，是诺华和Incyte公司开发的目前处于临床二期的c-MET选择性小分子抑制剂，适应症为多形性成胶质细胞瘤、非小细胞肺癌、肝细胞癌和黑色素瘤。本发明采用市售的对照化合物。The compound development code is INC-280, INCB-028060, INCB-28060, NVP-INC280-NX, C2A374O70X, CAS No. 1029712-80-8, which is the current clinical phase II c-MET selection developed by Novartis and Incyte. Small molecule inhibitors, indications for pleomorphic glioblastoma, non-small cell lung cancer, hepatocellular carcinoma and melanoma. Commercially available control compounds are employed in the present invention.
实验例1：化合物对受体酪氨酸激酶AXL、c-MET酶活的影响Experimental Example 1: Effect of Compounds on Receptor Tyrosine Kinase AXL, c-MET Enzyme Activity
1、试验方法：1. Test method:
(1)酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl，pH7.2-7.4)稀释成20μg/mL，125μL/孔包被酶标板，置37℃反应12-16小时。弃去孔中液体。洗板，用T-PBS(含0.1％Tween-20的无钾离子的PBS，200μL/孔)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时。(1) Enzyme reaction substrate Poly(Glu, Tyr) 4:1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 μg/mL, 125 μL/well coated enzyme The target plate was reacted at 37 ° C for 12-16 hours. Discard the liquid in the well. The plate was washed, and the plate was washed three times with T-PBS (0.1% Tween-20 in potassium-free PBS, 200 μL/well) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
(2)每孔加入以反应缓冲液(50mM HEPES pH 7.4,50mM MgCl 2,0.5mM MnCl 2,0.2mM Na 3VO 4,1mM DTT)稀释的ATP溶液49μL，每孔中加入1μL待测试化合物，再加入50μL以反应缓冲液稀释的AXL、c-MET激酶域重组蛋白启动反应，每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。弃去孔中液体，T-PBS洗板三次。 (2) 49 μL of ATP solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT) was added to each well, and 1 μL of the compound to be tested was added to each well. 50 μL of AXL and c-MET kinase domain recombinant protein diluted in reaction buffer were added to initiate the reaction. Two wells without ATP control wells were required for each experiment. The reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). The liquid in the well was discarded and the plate was washed three times with T-PBS.
(3)加入抗体PY99稀释液(抗体用含BSA 5mg/mL的T-PBS 1:500稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。(3) The antibody PY99 dilution (antibody diluted 1:500 with BSA 5 mg/mL T-PBS) was added, 100 μL/well, and shaken at 37 ° C for 0.5 hour. The liquid in the well was discarded and the plate was washed three times with T-PBS.
(4)加入辣根过氧化物酶标记的羊抗鼠二抗稀释液(抗体用含BSA 5mg/ml的T-PBS 1:2000稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。(4) Horseradish peroxidase-labeled goat anti-mouse secondary antibody dilution (antibody diluted 1:2000 with BSA 5 mg/ml T-PBS) was added, 100 μL/well, and shaken at 37 ° C for 0.5 hour. The liquid in the well was discarded and the plate was washed three times with T-PBS.
(5)加入2mg/ml的OPD显色液100μL/孔【用含有0.03％H 2O 2的0.1M柠檬酸－柠檬酸钠缓冲液(pH＝5.4)稀释】，25℃避光反应1-10分钟。 (5) Add 2 mg/ml OPD coloring solution 100 μL/well [diluted with 0.1 M citric acid-sodium citrate buffer (pH=5.4) containing 0.03% H 2 O 2 ), protected from light at 25 ° C 10 minutes.
(6)加入2M H 2SO 4 50μL/孔中止反应，用可调波长式微孔板酶标仪VERSAmax读数，波长为490nm。 (6) Add 2M H 2 SO 4 50 μL/well to stop the reaction, and read with a VERSAmax tunable wavelength microplate reader with a wavelength of 490 nm.
(7)结果分析(7) Analysis of results
Figure PCTCN2017115380-appb-000297
Figure PCTCN2017115380-appb-000297
IC 50值采用酶标仪随机附带软件以四参数法回归求得。 IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
2、实验结果：2. Experimental results:
表2：化合物对AXL酶活抑制活性Table 2: Compound inhibition activity of AXL enzyme activity
实施例中的化合物Compound in the examples AXL酶抑制活性AXL enzyme inhibitory activity c-MET酶抑制活性c-METase inhibitory activity
NO.1NO.1 AA BB
NO.2NO.2 AA BB
NO.3NO.3 BB //
NO.4NO.4 AA AA
NO.5NO.5 BB //
NO.6NO.6 BB //
NO.7NO.7 BB //
NO.8NO.8 AA BB
NO.9NO.9 AA //
NO.10NO.10 CC //
NO.11NO.11 BB //
NO.12NO.12 AA BB
NO.13NO.13 BB //
NO.14NO.14 AA BB
NO.15NO.15 AA BB
NO.16NO.16 AA BB
NO.17NO.17 AA //
NO.18NO.18 AA //
NO.19NO.19 AA BB
NO.20NO.20 BB //
NO.21NO.21 AA //
NO.22NO.22 CC //
NO.23NO.23 AA //
NO.24NO.24 CC //
NO.25NO.25 AA //
NO.26NO.26 BB //
NO.27NO.27 BB //
NO.28NO.28 BB //
NO.29NO.29 BB BB
NO.30NO.30 AA //
NO.31NO.31 BB //
NO.32NO.32 AA //
NO.33NO.33 AA AA
NO.34NO.34 AA //
NO.35NO.35 AA //
NO.36NO.36 CC //
NO.37NO.37 BB //
NO.38NO.38 BB //
NO.39NO.39 CC //
NO.40NO.40 BB //
NO.41NO.41 CC //
NO.42NO.42 CC //
NO.43NO.43 CC //
NO.44NO.44 BB //
NO.45NO.45 CC //
NO.46NO.46 CC //
NO.47NO.47 CC //
NO.48NO.48 BB CC
NO.49NO.49 BB //
NO.50NO.50 CC //
NO.51NO.51 BB //
NO.52NO.52 DD //
NO.53NO.53 CC //
NO.54NO.54 BB //
NO.55NO.55 CC //
NO.56NO.56 BB AA
NO.57NO.57 AA AA
NO.58NO.58 CC //
NO.59NO.59 BB AA
NO.60NO.60 BB //
NO.61NO.61 BB //
NO.62NO.62 DD //
NO.63NO.63 BB //
NO.64NO.64 CC //
NO.65NO.65 CC //
NO.66NO.66 BB //
NO.67NO.67 BB //
NO.68NO.68 AA //
R428R428 BB //
XL-184XL-184 BB //
PF-2341066PF-2341066 // AA
INCB-28060INCB-28060 // AA
其中，A表示IC 50小于(≤)1nM Where A indicates that the IC 50 is less than (≤) 1nM
B表示IC 50小于(≤)10nM且大于(＞)1nM B indicates that the IC 50 is less than (≤) 10 nM and greater than (>) 1 nM
C表示IC 50小于(≤)100nM且大于(＞)10nM C indicates that the IC 50 is less than (≤) 100 nM and greater than (>) 10 nM
D表示IC 50大于(＞)100nM D indicates that the IC 50 is greater than (>) 100nM
/表示未测试/ indicates no test
从表2可以看出，本发明化合物对AXL酶在浓度为nM水平具有明显的抑制作用，部分化合物对AXL的半数抑制浓度低于1nM，是一类强效的AXL酪氨酸激酶抑制剂，在浓度为nM水平具有明显的抑制作用；另外抽选部分化合物测试了对c-MET的酶抑制活性，发现该系列化合物对c-MET在浓度为nM水平也具有明显的抑制作用。基于本发明前期酶谱测试结果，有望开发AXL/c-MET双靶抑制剂。注：阳性化合物活性与文献报道相近。It can be seen from Table 2 that the compound of the present invention has a significant inhibitory effect on the AXL enzyme at a concentration of nM, and a partial compound has a half inhibitory concentration to AXL of less than 1 nM, which is a potent AXL tyrosine kinase inhibitor. It has obvious inhibitory effect at the concentration of nM; another part of the compound was tested for the enzyme inhibitory activity against c-MET, and it was found that the series of compounds also had a significant inhibitory effect on c-MET at a concentration of nM. Based on the results of the preliminary zymography test of the present invention, it is expected to develop an AXL/c-MET dual target inhibitor. Note: The activity of positive compounds is similar to that reported in the literature.
实验例2：化合物对SNU-886细胞中AXL磷酸化的影响Experimental Example 2: Effect of Compounds on AXL Phosphorylation in SNU-886 Cells
1、试验方法：1. Test method:
将SNU-886细胞(购自南京科佰生物科技有限公司)接种于12孔板中(30万/孔)，培养过夜后换为无血清培液培养24小时，加入各化合物作用2小时后，再加入GAS6(250ng/mL)刺激15分钟收集细胞。先用冷的PBS(含1mM钒酸钠)洗一次；然后加入1×SDS凝胶加样缓冲液(50mM Tris-HCl(pH6.8)，100mM DTT，2％SDS，10％甘油，1mM钒酸钠，0.1％溴酚蓝)裂解细胞。细胞裂解物在沸水浴中加热10分钟后，于4℃ 12000rpm离心10分钟。SNU-886 cells (purchased from Nanjing Kezhen Biotechnology Co., Ltd.) were inoculated into a 12-well plate (300,000/well), cultured overnight, and then cultured in serum-free medium for 24 hours. After each compound was added for 2 hours, Cells were harvested by adding GAS6 (250 ng/mL) for 15 minutes. Wash once with cold PBS (containing 1 mM sodium vanadate); then add 1 x SDS gel loading buffer (50 mM Tris-HCl (pH 6.8), 100 mM DTT, 2% SDS, 10% glycerol, 1 mM vanadium Sodium, 0.1% bromophenol blue) lysed cells. After the cell lysate was heated in a boiling water bath for 10 minutes, it was centrifuged at 12,000 rpm for 10 minutes at 4 °C.
取上清液进行SDS-PAGE电泳(Mini-PROTEAN 3 Cell，Bio-Rad，Hercules,CA，USA)，电泳结束后，用半干电转移***将蛋白转移至硝酸纤维素膜(Amersham Life Sciences,阿灵顿高地,IL，USA)，将硝酸纤维素膜置于封闭液(5％脱脂奶粉稀释于含1mM钒酸钠的TBS)中室温封闭2小时，然后将膜置于抗p-AXL、AXL、p-AKT、AKT(1:1000)或抗GAPDH(1:10000)的抗体中4℃过夜。用含1mM钒酸钠的TBS洗涤三 次，每次15分钟。将膜置于二抗溶液中室温反应1-2小时；同上洗膜3次后，用ECL(Picece,罗克福德,IL，USA)试剂发色，显影。The supernatant was taken for SDS-PAGE electrophoresis (Mini-PROTEAN 3 Cell, Bio-Rad, Hercules, CA, USA), and after electrophoresis, the protein was transferred to a nitrocellulose membrane (Amersham Life Sciences, using a semi-dry electrotransfer system). Arlington Heights, IL, USA), the nitrocellulose membrane was placed in a blocking solution (5% skim milk powder diluted in TBS containing 1 mM sodium vanadate) for 2 hours at room temperature, then the membrane was placed in anti-p-AXL, AXL, p-AKT, AKT (1:1000) or anti-GAPDH (1:10000) antibodies were incubated overnight at 4 °C. Wash three times with TBS containing 1 mM sodium vanadate for 15 minutes each time. The membrane was placed in a secondary antibody solution for 1-2 hours at room temperature; after washing the membrane three times as above, it was developed with ECL (Picece, Rockford, IL, USA) reagent and developed.
2、实验结果：2. Experimental results:
作用2小时后，化合物NO.1对SNU-886细胞中由GAS6刺激引起的AXL磷酸化有较强的抑制作用，在20nM浓度下活性就非常显著。如图1所示。After 2 hours of action, compound NO.1 had a strong inhibitory effect on AXL phosphorylation induced by GAS6 stimulation in SNU-886 cells, and the activity was very significant at 20 nM concentration. As shown in Figure 1.
实验例3：化合物对BaF3/TEL-AXL细胞增殖效应的影响Experimental Example 3: Effect of Compounds on Proliferation of BaF3/TEL-AXL Cells
1、试验方法：1. Test method:
测试细胞株为BaF3/TEL-AXL细胞株(细胞中TEL-AXL融合蛋白表达在胞浆中，为AXL依赖性敏感细胞株)，化合物对BaF3-TEL-AXL细胞的增殖抑制作用以CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下：处于对数生长期的BaF3-TEL-AXL细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。The test cell line was a BaF3/TEL-AXL cell line (the TEL-AXL fusion protein was expressed in the cytoplasm and was an AXL-dependent sensitive cell line), and the compound inhibited the proliferation of BaF3-TEL-AXL cells by CCK-8. Detection by the Cell Counting Kit (Dojindo). The specific steps are as follows: BaF3-TEL-AXL cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 μL per well, and cultured overnight, different concentrations of compounds were added for 72 hr, and the solvent control group was set ( Negative control). After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo). Add 10 μL of CCK-8 reagent to each well and place in a 37 ° C incubator for 2-4 hours. The full-wavelength microplate reader SpectraMax 190 reads at a wavelength of 450 nm.
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：The inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula:
抑制率(％)＝(OD对照孔-OD给药孔)/OD对照孔×100％Inhibition rate (%) = (OD control well-OD administration well) / OD control well × 100%
IC 50值采用酶标仪随机附带软件以四参数法回归求得。 IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
2、实验结果：2. Experimental results:
表3：化合物对BaF3-TEL-AXL细胞的增殖抑制活性Table 3: Proliferation inhibitory activity of compounds on BaF3-TEL-AXL cells
实施例中的化合物Compound in the examples 对BaF3-TEL-AXL细胞的增殖抑制活性Proliferative inhibitory activity against BaF3-TEL-AXL cells
NO.1NO.1 AA
NO.2NO.2 AA
NO.4NO.4 AA
NO.8NO.8 AA
NO.12NO.12 AA
NO.14NO.14 AA
NO.15NO.15 AA
NO.16NO.16 AA
NO.19NO.19 AA
NO.33NO.33 AA
NO.48NO.48 AA
NO.56NO.56 AA
NO.57NO.57 AA
NO.59NO.59 AA
NO.61NO.61 AA
NO.67NO.67 AA
NO.68NO.68 AA
R428R428 BB
XL-184XL-184 AA
GilteritinibGilteritinib AA
其中，A表示IC 50小于(≤)10nM Where A indicates that the IC 50 is less than (≤) 10nM
B表示IC 50小于(≤)100nM且大于(＞)10nM B indicates that the IC 50 is less than (≤) 100 nM and greater than (>) 10 nM
C表示IC 50大于(＞)100nM C means IC 50 is greater than (>) 100nM
从表3可以看出，本发明化合物对BaF3-TEL-AXL细胞在浓度为nM水平具有明显的抑制增殖作用，且抽选试验的化合物对BaF3-TEL-AXL细胞增殖的半数抑制浓度全部低于10nM，有待进一步的降浓度试验。注：阳性化合物活性与文献报道相近。As can be seen from Table 3, the compound of the present invention has a significant inhibitory effect on the proliferation of BaF3-TEL-AXL cells at a concentration of nM, and the half-inhibitory concentration of the compound of the selection test on the proliferation of BaF3-TEL-AXL cells is all lower than that. 10nM, to be further tested for concentration reduction. Note: The activity of positive compounds is similar to that reported in the literature.
实验例4：化合物对MKN45细胞增殖效应的影响Experimental Example 4: Effect of Compounds on Proliferation of MKN45 Cells
1、试验方法：1. Test method:
测试细胞株为MKN45(胃癌细胞株，MET基因扩增导致MET持续活化细胞株，为MET依赖性肿瘤细胞株)，化合物对MKN45细胞的增殖抑制作用采用磺酰罗丹明B(sulforhodamine B,SRB)蛋白染色法检测。具体步骤如下：处于对数生长期的MKN45细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物(DMSO浓度低于0.5％)作用72hr，每个浓度设三复孔，并设定溶剂对照组(阴性对照)。作用结束后，弃去培养液，加入10％(w/v)三氯乙酸(100μL/孔)于4℃固定1hr，随后用蒸馏水冲洗五次，待在室温下干燥后，每孔加入SRB溶液(4mg/mL，溶于1％冰乙酸)100μL，室温下孵育染色15min后，用1％冰乙酸冲洗五次洗去未结合的SRB，室温下干燥后，每孔加入10mM Tris溶液100μL，全波长式微孔板酶标仪SpectraMax 190 515nm波长下测定OD值。The test cell strain was MKN45 (a gastric cancer cell line, MET gene amplification resulted in a MET-sustained cell line, which is a MET-dependent tumor cell line), and the compound inhibited the proliferation of MKN45 cells by using sulforhodamine B (SRB). Protein staining assay. The specific steps are as follows: MKN45 cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 μL per well, and after incubation overnight, different concentrations of compounds (DMSO concentration less than 0.5%) were added for 72 hr, each concentration. Three replicate wells were set and the solvent control group (negative control) was set. After the end of the action, discard the culture solution, add 10% (w / v) trichloroacetic acid (100 μL / well) and fix at 4 ° C for 1 hr, then rinse with distilled water five times. After drying at room temperature, add SRB solution to each well. (4mg/mL, dissolved in 1% glacial acetic acid) 100μL, incubate for 15min at room temperature, rinse with unwashed SRB five times with 1% glacial acetic acid, dry at room temperature, add 100μL of 10mM Tris solution to each well. The OD value was measured at a wavelength of 515 nm by a wavelength microplate reader SpectraMax 190.
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：The inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula:
抑制率(％)＝(OD对照孔-OD给药孔)/OD对照孔×100％Inhibition rate (%) = (OD control well-OD administration well) / OD control well × 100%
IC 50值采用酶标仪随机附带软件以四参数法回归求得。 IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
表4：化合物对MKN45细胞增殖抑制的IC 50值 Table 4: IC 50 values of the compounds on cell proliferation inhibition MKN45
实施例中的化合物Compound in the examples 对MKN45细胞增殖抑制的IC 50值(nM) IC 50 value (nM) for inhibition of MKN45 cell proliferation
NO.1NO.1 226.6±39.2226.6±39.2
NO.2NO.2 246.8±21.0246.8±21.0
NO.4NO.4 >333>333
NO.12NO.12 144.2±21.2144.2±21.2
NO.14NO.14 169.9169.9
NO.15NO.15 87.4±16.887.4±16.8
NO.16NO.16 118.2±26.7118.2±26.7
NO.33NO.33 39.1±7.439.1 ± 7.4
NO.57NO.57 21.4±4.821.4±4.8
NO.59NO.59 129.3±40.9129.3±40.9
PF-2341066PF-2341066 21.4±2.121.4±2.1
从表4可以看出，本发明化合物对MKN45细胞具有增殖抑制活性，且部分化合物与阳性化合物PF-2341066活性相当。注：阳性化合物活性与文献报道相近。As can be seen from Table 4, the compound of the present invention has proliferation inhibitory activity against MKN45 cells, and some of the compounds are equivalent to the positive compound PF-2341066. Note: The activity of positive compounds is similar to that reported in the literature.
实验例5：化合物对EBC-1细胞增殖效应的影响Experimental Example 5: Effect of Compounds on Proliferation of EBC-1 Cells
1、试验方法：1. Test method:
测试细胞株为EBC-1细胞株(非小细胞肺癌细胞株，MET基因扩增导致MET持续活化细胞株，为MET依赖性细胞株)。化合物对EBC-1细胞的增殖抑制作用采用磺酰罗丹明B(sulforhodamine B,SRB)蛋白染色法检测。具体步骤如下：处于对数生长 期的EBC-1细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物(DMSO浓度低于0.5％)作用72hr，每个浓度设三复孔，并设定溶剂对照组(阴性对照)。作用结束后，弃去培养液，加入10％(w/v)三氯乙酸(100μL/孔)于4℃固定1hr，随后用蒸馏水冲洗五次，待在室温下干燥后，每孔加入SRB溶液(4mg/mL，溶于1％冰乙酸)100μL，室温下孵育染色15min后，用1％冰乙酸冲洗五次洗去未结合的SRB，室温下干燥后，每孔加入10mM Tris溶液100μL，全波长式微孔板酶标仪SpectraMax 190 515nm波长下测定OD值。The test cell strain was an EBC-1 cell line (a non-small cell lung cancer cell line, and the MET gene amplification resulted in a MET-sustained cell line, which is a MET-dependent cell line). The inhibitory effect of the compound on the proliferation of EBC-1 cells was detected by sulforhodamine B (SRB) protein staining. The specific steps are as follows: EBC-1 cells in logarithmic growth phase are inoculated into 96-well culture plates at a suitable density, 90 μL per well, and after incubation overnight, different concentrations of compounds (DMSO concentration less than 0.5%) are added for 72 hr, each time. Three replicate wells were set at each concentration, and a solvent control group (negative control) was set. After the end of the action, discard the culture solution, add 10% (w / v) trichloroacetic acid (100 μL / well) and fix at 4 ° C for 1 hr, then rinse with distilled water five times. After drying at room temperature, add SRB solution to each well. (4mg/mL, dissolved in 1% glacial acetic acid) 100μL, incubate for 15min at room temperature, rinse with unwashed SRB five times with 1% glacial acetic acid, dry at room temperature, add 100μL of 10mM Tris solution to each well. The OD value was measured at a wavelength of 515 nm by a wavelength microplate reader SpectraMax 190.
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：The inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula:
抑制率(％)＝(OD对照孔-OD给药孔)/OD对照孔×100％Inhibition rate (%) = (OD control well-OD administration well) / OD control well × 100%
IC 50值采用酶标仪随机附带软件以四参数法回归求得。 IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
表5：化合物对EBC-1细胞增殖抑制的IC 50值 Table 5: Proliferation Compound IC 50 values for inhibition of EBC-1 cells
实施例中的化合物Compound in the examples 对EBC-1细胞增殖抑制的IC 50值(nM) IC 50 value (nM) for inhibition of EBC-1 cell proliferation
NO.1NO.1 120.3±19.4120.3±19.4
NO.2NO.2 208.2±19.0208.2±19.0
NO.4NO.4 140.4±38.9140.4±38.9
NO.12NO.12 368.9±145.9368.9±145.9
NO.14NO.14 410.9±42.2410.9±42.2
NO.15NO.15 49.1±6.449.1 ± 6.4
NO.16NO.16 72.9±3.872.9±3.8
NO.33NO.33 105.7±17.7105.7±17.7
NO.57NO.57 59.3±22.459.3±22.4
NO.59NO.59 100.1±26.7100.1±26.7
PF-2341066PF-2341066 21.4±6.021.4±6.0
从表5可以看出，本发明化合物对EBC-1细胞具有增殖抑制活性，趋势与对MKN45细胞的增殖抑制活性总体一致。As can be seen from Table 5, the compound of the present invention has proliferation inhibitory activity against EBC-1 cells, and the trend is generally consistent with the proliferation inhibitory activity against MKN45 cells.
总的来说，实验例1证明了分子水平上，本发明化合物对AXL及c-MET均有较强的抑制作用，很多化合物对AXL的半数抑制浓度低于1nM；实验例2证明了本发明化合物对于GAS6刺激引起的AXL磷酸化有较强的抑制作用，且化合物可通过细胞膜；实验例3证明了本发明化合物对BaF3/TEL-AXL细胞株十分敏感，对BaF3/TEL-AXL细胞增殖的半数抑制浓度均低于10nM，后期的降浓度试验表明部分化合物IC 50甚至低于1nM；实验例4和实验例5表明了本发明化合物对于MET依赖性细胞株的增殖也具有一定的抑制活性。 In general, Experimental Example 1 demonstrates that at the molecular level, the compounds of the present invention have a strong inhibitory effect on AXL and c-MET, and the half inhibitory concentration of many compounds to AXL is less than 1 nM; Experimental Example 2 demonstrates the present invention. The compound has a strong inhibitory effect on AXL phosphorylation induced by GAS6 stimulation, and the compound can pass through the cell membrane; Experimental Example 3 demonstrates that the compound of the present invention is very sensitive to BaF3/TEL-AXL cell line and proliferates BaF3/TEL-AXL cells. The half-inhibitory concentration was lower than 10 nM, and the late concentration-reducing test showed that the IC 50 of some compounds was even lower than 1 nM; Experimental Example 4 and Experimental Example 5 showed that the compound of the present invention also had certain inhibitory activity against the proliferation of MET-dependent cell lines.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (12)

  1. 一种式(I)所示化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物，A compound of the formula (I): or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof,
    Figure PCTCN2017115380-appb-100001
    Figure PCTCN2017115380-appb-100001
    式中，In the formula,
    R 1选自取代或未取代的6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂芳基；所述“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C6烷基、进一步取代或未取代的C3-C8环烷基、卤素、羟基、巯基、氰基、氨基、进一步取代或未取代的C1-C6烷氧基、进一步取代或未取代的C1-C6烷胺基和进一步取代或未取代的C1-C6烷硫基； R 1 is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 3-10 membered heteroaryl containing 1-3 selected from N, O and S heteroatoms; said "substituted" One or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C6 alkyl group, a further substituted or unsubstituted C3-C8 cycloalkyl group, a halogen, a hydroxyl group, a decyl group. a cyano group, an amino group, a further substituted or unsubstituted C1-C6 alkoxy group, a further substituted or unsubstituted C1-C6 alkylamino group, and a further substituted or unsubstituted C1-C6 alkylthio group;
    R 2选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、取代或未取代的6-10元芳基和取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂芳基；所述“取代”是指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C6烷基、进一步取代或未取代的C1-C6烷氧基、进一步取代或未取代的C1-C6烷胺基、进一步取代或未取代的C1-C6烷硫基、进一步取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂环烷基和-CONR 10R 11；所述R 10、R 11独立地选自H和C1-C6烷基； R 2 is selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted, containing 1 to 3 heteroatoms selected from S, O, N and Se a 3-10 membered heterocycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group and a substituted or unsubstituted 3 to 3 membered heteroaryl group having 1 to 3 hetero atom selected from N, O and S; The "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C6 alkyl group, a further substituted or unsubstituted C1-C6 alkoxy group. a further substituted or unsubstituted C1-C6 alkylamino group, a further substituted or unsubstituted C1-C6 alkylthio group, a further substituted or unsubstituted one containing 1-3 selected from N, O and S heteroatoms a 10-membered heterocycloalkyl group and -CONR 10 R 11 ; wherein R 10 and R 11 are independently selected from H and C 1 -C 6 alkyl;
    R 3选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、取代或未取代的6-10元芳基和取代或未取代的含有1-3个选自N、O和S杂原子的3-10元杂芳基；所述“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C6烷基、进一步取代或未取代的C3-C8环烷基、进一步取代或未取代的C1-C6烷氧基、进一步取代或未取代的C1-C6烷胺基、进一步取代或未取代的C1-C6烷硫基、进一步取代或未取代的含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、进一步取代或未取代的C2-C6烯基、进一步取代或未取代的C2-C6炔基、-COOR 12和-CONR 10R 11；所述R 10、R 11、R 12独立地选自H和C1-C6烷基； R 3 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted, containing 1-3 heteroatoms selected from S, O, N and Se a 3-10 membered heterocycloalkyl group, a substituted or unsubstituted 6-10 membered aryl group and a substituted or unsubstituted 3 to 3 membered heteroaryl group having 1 to 3 hetero atom selected from N, O and S; The "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C6 alkyl group, a further substituted or unsubstituted C3-C8 cycloalkyl group. Further substituted or unsubstituted C1-C6 alkoxy, further substituted or unsubstituted C1-C6 alkylamino, further substituted or unsubstituted C1-C6 alkylthio, further substituted or unsubstituted containing 1-3 a 3-10 membered heterocycloalkyl selected from the group consisting of S, O, N and Se heteroatoms, a further substituted or unsubstituted C2-C6 alkenyl group, a further substituted or unsubstituted C2-C6 alkynyl group, -COOR 12 and -CONR 10 R 11 ; the R 10 , R 11 , R 12 are independently selected from H and C1-C6 alkyl;
    R 4选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、卤素、羟基、氰基、氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基和取代或未取代的C1-C6烷硫基； R 4 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C1-C6 alkylamino group and a substituted or unsubstituted C1-C6 alkylthio group;
    V、W、X、Y可相同或不同，分别独立地选自N或CR 5；R 5选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、卤素、羟基、氰基、氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基和取代或未取代的C1-C6烷硫基； V, W, X, Y may be the same or different and are each independently selected from N or CR 5 ; R 5 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl , halogen, hydroxy, cyano, amino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino and substituted or unsubstituted C1-C6 alkylthio;
    M、Z可相同或不同，分别独立地选自N或CR 6；R 6选自H、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、卤素、羟基、氰基、氨基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基和取代或未取代的C1-C6烷硫基； M and Z may be the same or different and are each independently selected from N or CR 6 ; R 6 is selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, halogen, hydroxy , cyano, amino, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino and substituted or unsubstituted C1-C6 alkylthio;
    R 1、R 2、R 3中的“进一步取代”或R 4、R 5、R 6、V、W、X、Y、M、Z中的“取代”，是指基团上的一个或多个氢原子被选自下组的基团取代：C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、羟基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷硫基、卤代的C1-C6烷硫基、C1-C6烷硅基、卤代的C1-C6烷硅基、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-(C3-C8的卤代环烷基)、-SO 2-(C1-C6烷基)、SO 2-(C3-C8环烷基)、-SO 2-(3-8元杂环烷基)、-CO-(3-8元杂环烷基)、-CO-(C1-C6烷基)、-CO-(C3-C8环烷基)、-CO 2-(3-8元杂环烷基)、-CO 2-(C1-C6烷基)、-CO 2-(C3-C8环烷基)、-CONR 8R 9、卤素、含有1-3个选自S、O、N和Se杂原子的3-10元杂环烷基、氨基、被1-3个选自卤素、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基、OH、氰基、硝基和氨基的基团所取代的苯基或未取代的苯基、氰基、C2-C6烯基、C2-C6炔基；其中，所述R 8、R 9独立地选自H、C1-C6烷基。 "Substitution" in R 1 , R 2 , R 3 or "substitution" in R 4 , R 5 , R 6 , V, W, X, Y, M, Z means one or more of the groups One hydrogen atom is substituted with a group selected from the group consisting of C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, hydroxy, C1-C6 Alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkylthio, C1-C6 alkyl, halogenated C1-C6 alkyl, -O -(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-(C3-C8 halocycloalkyl), -SO 2 -(C1-C6 alkyl) , SO 2 -(C3-C8 cycloalkyl), -SO 2 -(3-8 membered heterocycloalkyl), -CO-(3-8 membered heterocycloalkyl), -CO-(C1-C6 alkane) , -CO-(C3-C8 cycloalkyl), -CO 2 -(3-8 membered heterocycloalkyl), -CO 2 -(C1-C6 alkyl), -CO 2 -(C3-C8 Cycloalkyl), -CONR 8 R 9 , halogen, 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of S, O, N and Se, amino group, 1-3 selected from halogen, Phenyl or unsubstituted phenyl, cyano, C2-C6 substituted with a group of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, OH, cyano, nitro and amino Alkenyl, C2-C6 alkynyl; Wherein R 8 and R 9 are independently selected from H, C 1 -C 6 alkyl.
  2. 如权利要求1所述的化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物，其特征在于，R 1选自取代或未取代的6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的5-10元杂芳基；所述“取代”是指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C4烷基、进一步取代或未取代的C3-C6环烷基、卤素、氰基、氨基、进一步取代或未取代的C1-C4烷氧基、进一步取代或未取代的C1-C4烷胺基和进一步取代或未取代的C1-C4烷硫基。 A compound according to claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, characterized in that R 1 is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 selected from N, O and S heteroatoms; said "substituted" It is meant that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C4 alkyl group, a further substituted or unsubstituted C3-C6 cycloalkyl group, a halogen, a cyanogen a base, an amino group, a further substituted or unsubstituted C1-C4 alkoxy group, a further substituted or unsubstituted C1-C4 alkylamino group, and a further substituted or unsubstituted C1-C4 alkylthio group.
  3. 如权利要求1所述的化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物，其特征在于，R 2选自H、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的含有1-3个选自N、O和S杂原子的3-8元杂环烷基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：进一步取代或未取代的C1-C4烷基、进一步取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷胺基、取代或未取代的C1-C4烷硫基、含有1-3个选自N、O和S杂原子的3-8元杂环烷基和-CONR 10R 11。 A compound according to claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, characterized in that R 2 is selected from H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted, containing 1-3 selected from N, O and S heteroatoms a 3-8 membered heterocycloalkyl group; said "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of a further substituted or unsubstituted C1-C4 alkyl group, further substituted Or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylthio, containing 1-3 selected from N, O and S heteroatoms 3-8 membered heterocycloalkyl and -CONR 10 R 11 .
  4. 如权利要求1所述的化合物或其立体异构体、几何异构体、互变异构体，或其 药学上可接受的盐，或其前药、水合物或溶剂合物，其特征在于，R 3选自H、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的含有1-3个选自N、O和S杂原子的3-8元杂环烷基、取代或未取代的6-10元芳基、取代或未取代的含有1-3个选自N、O和S杂原子的5-10元杂芳基；所述“取代“是指基团上的一个或多个氢原子被选自下组的取代基取代：取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C1-C4烷胺基、取代或未取代的C1-C4烷硫基、含有1-3个选自N、O和S杂原子的3-8元杂环烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、-COOR 12和-CONR 10R 11；所述R 10、R 11、R 12独立地选自H和C1-C4烷基。 A compound according to claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, characterized in that , R 3 is selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted, containing 1-3 selected from N, O and S heteroatoms a 3-8 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted, 5 to 3 membered heteroaryl containing 1-3 selected from N, O and S heteroatoms; The term "substituted" means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted Or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylthio, containing 1-3 selected from N, O and S heteroatoms 3-8 membered heterocycloalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, -COOR 12 and -CONR 10 R 11 ; said R 10 , R 11 , R 12 is independently selected from the group consisting of H and C1-C4 alkyl.
  5. 如权利要求1所述的化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物，其特征在于，R 4选自H、取代或未取代的C1-C4烷基、卤素和取代或未取代的C1-C4烷胺基。 A compound according to claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, characterized in that R 4 is selected from H, a substituted or unsubstituted C1-C4 alkyl group, a halogen, and a substituted or unsubstituted C1-C4 alkylamino group.
  6. 如权利要求1所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物，其特征在于，所述化合物选自化合物NO.1、NO.2、NO.3、NO.4、NO.5、NO.6、NO.7、NO.8、NO.9、NO.10、NO.11、NO.12、NO.13、NO.14、NO.15、NO.16、NO.17、NO.18、NO.19、NO.20、NO.21、NO.22、NO.23、NO.24、NO.25、NO.26、NO.27、NO.28、NO.29、NO.30、NO.31、NO.32、NO.33、NO.34、NO.35、NO.36、NO.37、NO.38、NO.39、NO.40、NO.41、NO.42、NO.43、NO.44、NO.45、NO.46、NO.47、NO.48、NO.49、NO.50、NO.51、NO.52、NO.53、NO.54、NO.55、NO.56、NO.57、NO.58、NO.59、NO.60、NO.61、NO.62、NO.63、NO.64、NO.65、NO.66、NO.67、NO.68、NO.69、NO.70和NO.71。A compound according to claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, wherein The compound is selected from the group consisting of compounds NO.1, NO.2, NO.3, NO.4, NO.5, NO.6, NO.7, NO.8, NO.9, NO.10, NO.11, NO.12, NO.13, NO.14, NO.15, NO.16, NO.17, NO.18, NO.19, NO.20, NO.21, NO.22, NO.23, NO. 24. NO.25, NO.26, NO.27, NO.28, NO.29, NO.30, NO.31, NO.32, NO.33, NO.34, NO.35, NO.36, NO.37, NO.38, NO.39, NO.40, NO.41, NO.42, NO.43, NO.44, NO.45, NO.46, NO.47, NO.48, NO. 49, NO.50, NO.51, NO.52, NO.53, NO.54, NO.55, NO.56, NO.57, NO.58, NO.59, NO.60, NO.61, NO.62, NO.63, NO.64, NO.65, NO.66, NO.67, NO.68, NO.69, NO.70 and NO.71.
  7. 一种权利要求1所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物的制备方法，其特征在于，包括步骤：将式(II)化合物与式(III)化合物进行反应，从而形成式(I)化合物；A method of preparing a compound of claim 1, or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, The method comprises the steps of: reacting a compound of the formula (II) with a compound of the formula (III) to form a compound of the formula (I);
    Figure PCTCN2017115380-appb-100002
    Figure PCTCN2017115380-appb-100002
    其中，V、W、X、Y、M、Z、R 1、R 2、R 3、R 4的定义如权利要求1所述。 Wherein, V, W, X, Y, M, Z, R 1 , R 2 , R 3 , and R 4 are as defined in claim 1.
  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所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物的一种或多种，以及任选的药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or pharmaceutically acceptable thereof a salt, or one or more of its prodrugs, hydrates or solvates, and optionally a pharmaceutically acceptable carrier.
  9. 一种权利要求1所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物或权利要求8所述药物组合物的用途，其特征在于，用于制备用于预防和/或治疗选自下组的疾病的药物：A compound of claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, or claim 8 Use of the pharmaceutical composition, characterized in that it is used for the preparation of a medicament for preventing and/or treating a disease selected from the group consisting of:
    a)肿瘤相关疾病；a) tumor-related diseases;
    b)蛋白酪氨酸激酶活性相关疾病。b) Disease associated with protein tyrosine kinase activity.
  10. 一种AXL抑制剂，其特征在于，所述AXL抑制剂包含抑制有效量的权利要求1所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物中的一种或多种。An AXL inhibitor, characterized in that the AXL inhibitor comprises an inhibitory effective amount of a compound of claim 1 or a stereoisomer, geometric isomer, tautomer thereof, or pharmaceutically acceptable thereof a salt, or one or more of its prodrugs, hydrates or solvates.
  11. 一种权利要求8所述药物组合物的制备方法，其特征在于，包括步骤：将药学上可接受的载体与权利要求1所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物进行混合，从而形成药物组合物。A process for the preparation of a pharmaceutical composition according to Claim 8 which comprises the steps of: pharmaceutically acceptable carrier and the compound of claim 1 or a stereoisomer, geometric isomer thereof, tautomer The construct, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, is mixed to form a pharmaceutical composition.
  12. 一种非诊断性、非治疗性抑制AXL活性的方法，其特征在于，所述方法包括步骤：向所需患者施用抑制有效量的权利要求1所述化合物或其立体异构体、几何异构体、互变异构体，或其药学上可接受的盐，或其前药、水合物或溶剂合物或权利要求8所述药物组合物。A method for non-diagnostic, non-therapeutic inhibition of AXL activity, the method comprising the steps of: administering to a patient in need thereof an inhibitory effective amount of a compound of claim 1 or a stereoisomer thereof, geometrically isomerized a steroid, a tautomer, or a pharmaceutically acceptable salt thereof, or a prodrug, hydrate or solvate thereof, or a pharmaceutical composition according to claim 8.
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
WO2021155004A1 (en) * 2020-01-30 2021-08-05 The Regents Of The University Of California Strad-binding agents and uses thereof
US11104676B2 (en) 2018-08-30 2021-08-31 Array Biopharma Inc. Pyrazolo[3,4-b]pyridine compounds as inhibitors of TAM and MET kinases
CN113683629A (en) * 2020-05-18 2021-11-23 北京范恩柯尔生物科技有限公司 Substituted heteroaryl compounds, compositions and uses thereof
WO2021252488A1 (en) 2020-06-08 2021-12-16 Halia Therapeutics, Inc. Inhibitors of nek7 kinase
WO2022007921A1 (en) * 2020-07-10 2022-01-13 北京范恩柯尔生物科技有限公司 Triazine compound and composition and use thereof
WO2022242752A1 (en) * 2021-05-21 2022-11-24 江苏恒瑞医药股份有限公司 Method for preparing btk inhibitor intermediate
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019141202A1 (en) * 2018-01-17 2019-07-25 南京药捷安康生物科技有限公司 Tam family kinase /and csf1r kinase inhibitor and use thereof
CN110627796B (en) * 2018-06-21 2022-07-12 北京越之康泰生物医药科技有限公司 Nitrogenous heterocyclic derivative and application thereof in medicine
WO2020182188A1 (en) * 2019-03-13 2020-09-17 习峰 Substituted heteroaryl compound, composition of same, and uses thereof
CN111689991B (en) * 2019-03-13 2023-06-09 习峰 Substituted heteroaryl compounds, compositions and uses thereof
WO2021088787A1 (en) * 2019-11-07 2021-05-14 南京正大天晴制药有限公司 Quinazoline compound used as axl inhibitor
CN116583287A (en) * 2021-02-05 2023-08-11 四川科伦博泰生物医药股份有限公司 Pyridazinone heterocyclic compound, preparation method and application thereof
WO2023016296A1 (en) * 2021-08-12 2023-02-16 四川科伦博泰生物医药股份有限公司 Heterocyclic compound and preparation method therefor and use thereof
WO2023155886A1 (en) * 2022-02-17 2023-08-24 Shanghai Antengene Corporation Limited Pyrazolopyridine compounds as tam inhibitors
CN115340557A (en) * 2022-09-19 2022-11-15 安徽大学 Synthesis method of 4-chloro-5-iodo-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine
CN115745993B (en) * 2022-11-08 2024-03-12 上海皓元生物医药科技有限公司 Preparation method of MPO inhibitor

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101296928A (en) * 2005-10-28 2008-10-29 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN102131783A (en) * 2008-04-16 2011-07-20 马克斯普朗克科学发展组织 Quinoline derivatives as axl kinase inhibitors
CN102216300A (en) * 2009-09-30 2011-10-12 浙江贝达药业有限公司 Compounds and compositions as protein kinase inhibitors
CN103958497A (en) * 2011-11-14 2014-07-30 赛福伦公司 Uracil derivatives as AXL and c-MET kinase inhibitors
CN104185627A (en) * 2012-01-31 2014-12-03 第一三共株式会社 Pyridone derivative
WO2016006706A1 (en) * 2014-07-07 2016-01-14 第一三共株式会社 Pyridone derivative having tetrahydropyranyl methyl group
CN105408312A (en) * 2013-07-24 2016-03-16 小野药品工业株式会社 Quinoline derivative
EP3067356A1 (en) * 2013-11-08 2016-09-14 ONO Pharmaceutical Co., Ltd. Pyrrolo pyrimidine derivative

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101296928A (en) * 2005-10-28 2008-10-29 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
CN102131783A (en) * 2008-04-16 2011-07-20 马克斯普朗克科学发展组织 Quinoline derivatives as axl kinase inhibitors
CN102216300A (en) * 2009-09-30 2011-10-12 浙江贝达药业有限公司 Compounds and compositions as protein kinase inhibitors
CN103958497A (en) * 2011-11-14 2014-07-30 赛福伦公司 Uracil derivatives as AXL and c-MET kinase inhibitors
CN104185627A (en) * 2012-01-31 2014-12-03 第一三共株式会社 Pyridone derivative
CN105408312A (en) * 2013-07-24 2016-03-16 小野药品工业株式会社 Quinoline derivative
EP3067356A1 (en) * 2013-11-08 2016-09-14 ONO Pharmaceutical Co., Ltd. Pyrrolo pyrimidine derivative
WO2016006706A1 (en) * 2014-07-07 2016-01-14 第一三共株式会社 Pyridone derivative having tetrahydropyranyl methyl group

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11104676B2 (en) 2018-08-30 2021-08-31 Array Biopharma Inc. Pyrazolo[3,4-b]pyridine compounds as inhibitors of TAM and MET kinases
US11780835B2 (en) 2018-08-30 2023-10-10 Array Biopharma Inc. Pyrazolo[3,4-b]pyridine compounds as inhibitors of TAM and MET kinases
WO2020188015A1 (en) 2019-03-21 2020-09-24 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
WO2021155004A1 (en) * 2020-01-30 2021-08-05 The Regents Of The University Of California Strad-binding agents and uses thereof
CN113683629A (en) * 2020-05-18 2021-11-23 北京范恩柯尔生物科技有限公司 Substituted heteroaryl compounds, compositions and uses thereof
WO2021233236A1 (en) * 2020-05-18 2021-11-25 北京范恩柯尔生物科技有限公司 Substituted heteroaryl compound, and composition and use thereof
WO2021252488A1 (en) 2020-06-08 2021-12-16 Halia Therapeutics, Inc. Inhibitors of nek7 kinase
WO2022007921A1 (en) * 2020-07-10 2022-01-13 北京范恩柯尔生物科技有限公司 Triazine compound and composition and use thereof
WO2022242752A1 (en) * 2021-05-21 2022-11-24 江苏恒瑞医药股份有限公司 Method for preparing btk inhibitor intermediate
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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