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CN113004282A - Substituted alkynyl heterocyclic compounds - Google Patents

Substituted alkynyl heterocyclic compoundsDownload PDF

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CN113004282A
CN113004282ACN201911314609.5ACN201911314609ACN113004282ACN 113004282 ACN113004282 ACN 113004282ACN 201911314609 ACN201911314609 ACN 201911314609ACN 113004282 ACN113004282 ACN 113004282A
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pyrazolo
pyrimidin
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张晓军
闵汪洋
段小伟
陈曦
许新合
刘希杰
张凯
孙小亮
孙颖慧
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Shouyao Holdings Beijing Co Ltd
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Abstract

Translated fromChinese

本申请涉及式I所示取代的炔基杂环化合物。本发明涉及具有SHP2抑制活性的取代的炔基杂环化合物、其制备方法、其药物组合物，还涉及这类化合物及其药物组合物治疗受益于SHP2酶抑制的疾病的用途，例如治疗癌症。在制备过程中，通过碘代、胺化、上保护、偶联、脱保护、闭环反应等反应，得到式I化合物。

Figure RE-DSB0000187566330000011
The present application relates to substituted alkynyl heterocyclic compounds of formula I. The present invention relates to substituted alkynyl heterocyclic compounds with SHP2 inhibitory activity, methods for their preparation, and pharmaceutical compositions thereof, as well as the use of such compounds and pharmaceutical compositions for the treatment of diseases that benefit from SHP2 enzyme inhibition, such as the treatment of cancer. In the preparation process, the compound of formula I is obtained through reactions such as iodination, amination, upper protection, coupling, deprotection, and ring-closure reaction.
Figure RE-DSB0000187566330000011

Description

Translated fromChinese
取代的炔基杂环化合物Substituted alkynyl heterocycles

技术领域technical field

本发明一般性涉及新的具有SHP2抑制活性的取代的炔基杂环化合物、其制备方法、其药物组合物，还涉及这类化合物及其药物组合物治疗受益于SHP2酶抑制的疾病的用途，例如治疗癌症。The present invention generally relates to novel substituted alkynyl heterocyclic compounds with SHP2 inhibitory activity, methods for their preparation, and pharmaceutical compositions thereof, as well as the use of such compounds and pharmaceutical compositions for the treatment of diseases that benefit from SHP2 enzyme inhibition, such as treating cancer.

背景技术Background technique

癌症是严重威胁人类健康及生命一类疾重大疾病，尤其是癌症近几年的发病率及死亡率呈快速上升趋势，己超越心血管疾病成为人类健康的头号杀手。肿瘤的增殖、凋亡、转移等与细胞内外的一系列信号传导通路中某个环节的异常密切相关。在这些信号传导途径中，蛋白的磷酸化和去磷酸化至关重要，这个可逆的过程受到激酶和磷酸酶的共同调控。蛋白质酪氨酸激酶(PTK)的磷酸化和蛋白质酪氨酸磷酸酶(PTP)的去磷酸化即是这样一对可逆过程，它们之间保持动态平衡以维持细胞的正常生理功能。反之异常的磷酸化能导致癌症、炎症、糖尿病和其它疾病的产生。Cancer is a major disease that seriously threatens human health and life. In particular, the incidence and mortality of cancer have been rising rapidly in recent years, and it has surpassed cardiovascular disease to become the number one killer of human health. The proliferation, apoptosis and metastasis of tumors are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside the cell. In these signaling pathways, protein phosphorylation and dephosphorylation are crucial, and this reversible process is regulated by both kinases and phosphatases. Phosphorylation of protein tyrosine kinase (PTK) and dephosphorylation of protein tyrosine phosphatase (PTP) are such a pair of reversible processes, which maintain a dynamic balance between them to maintain normal physiological functions of cells. Conversely, abnormal phosphorylation can lead to cancer, inflammation, diabetes and other diseases.

SHP2蛋白是由ptpnll基因编码的一种非受体型蛋白质酪氨酸磷酸酶，广泛表达于各组织，参与胚胎发育、新陈代谢、免疫反应以及肿瘤发生等重要的生理病理过程。SHP2 protein is a non-receptor protein tyrosine phosphatase encoded by ptpnll gene. It is widely expressed in various tissues and participates in important physiological and pathological processes such as embryonic development, metabolism, immune response and tumorigenesis.

SHP2蛋白由N末端的两个串联SH2结构域(N-SH2和C-SH2)，PTP催化结构域和具有调节作用的C末端尾部组成。SH2结构域是一个构象开关，可以介导SHP2蛋白与含磷酸酪氨酸的激活剂(例如胰岛素受体底物1-IRS1和GRB2相关结合蛋白1-GAB1)的相互作用以及SH2结构域与PTP催化结构域的分子内相互作用。在未受刺激的情况下，SHP2结构域与PTP结构域结合，封闭催化活性位点，使SHP2磷酸酶活性处于自抑制状态。当SH2结构域结合激活剂，抑制性分子内相互作用解除，SHP2磷酸酶处于开放构象，允许SHP2底物定位至催化活性位点并发挥磷酸酶功能。SHP2的这种活性转换的特性，使得各种关于SHP2的突变都有可能破坏SHP2自抑制状态，导致SHP2蛋白磷酸酶活性过度激活，进而引发癌变。实验和临床数据均证实，SHP2在大多数癌症中起到了促进作用，作为第一个被发现的促进癌症发展的酪氨酸磷酸酶，其在癌症领域得到了极大地关注，它的磷酸酶活性在细胞内信号调控中起到了重要作用。The SHP2 protein consists of two tandem SH2 domains (N-SH2 and C-SH2) at the N-terminus, a PTP catalytic domain, and a regulatory C-terminal tail. The SH2 domain is a conformational switch that mediates the interaction of the SHP2 protein with phosphotyrosine-containing activators such as insulin receptor substrate 1-IRS1 and GRB2-related binding protein 1-GAB1 and the interaction of the SH2 domain with PTP Intramolecular interactions of catalytic domains. In the unstimulated condition, the SHP2 domain binds to the PTP domain, blocking the catalytically active site and making the SHP2 phosphatase activity in an autoinhibited state. When the SH2 domain binds to the activator, the inhibitory intramolecular interaction is released, and the SHP2 phosphatase is in an open conformation, allowing the SHP2 substrate to localize to the catalytically active site and function as a phosphatase. This activity-switching property of SHP2 makes it possible for various SHP2 mutations to destroy the SHP2 auto-inhibitory state, leading to excessive activation of SHP2 protein phosphatase activity, which in turn leads to carcinogenesis. Both experimental and clinical data confirm that SHP2 plays a promoting role in most cancers. As the first tyrosine phosphatase discovered to promote cancer development, it has received great attention in the field of cancer. Its phosphatase activity It plays an important role in the regulation of intracellular signaling.

SHP2参与调控由细胞因子、生长因子和激素激活的细胞信号转导途径，包括RAS/ERK，JAK/STAT，PI3K/AKT与NF-κB信号通路，进而调控细胞增殖、分化、细胞周期维持和迁移等生理功能。同时，SHP2还介导了MEK等激酶被抑制之后的代偿性激活途径，从而促进肿瘤耐药的发生。作为PD-1受体的下游分子，SHP2还参与T细胞抑制性信号的传导。已有研究表明，SHP2是PD-1信号传导的下游分子，它不仅抑制T细胞活化而且促进T细胞的失能。因此，靶向SHP2可恢复或增强T细胞介导的抗肿瘤免疫功能。另外SHP2可以通过失活信号转导及转录激活因子STAT1抑制IFN-γ介导的免疫反应。SHP2 is involved in the regulation of cell signal transduction pathways activated by cytokines, growth factors and hormones, including RAS/ERK, JAK/STAT, PI3K/AKT and NF-κB signaling pathways, thereby regulating cell proliferation, differentiation, cell cycle maintenance and migration and other physiological functions. At the same time, SHP2 also mediates the compensatory activation pathway after kinases such as MEK are inhibited, thereby promoting the occurrence of tumor resistance. As a downstream molecule of the PD-1 receptor, SHP2 is also involved in the transduction of T cell inhibitory signaling. Studies have shown that SHP2 is a downstream molecule of PD-1 signaling, which not only inhibits T cell activation but also promotes T cell inactivation. Therefore, targeting SHP2 can restore or enhance T cell-mediated antitumor immunity. In addition, SHP2 can inhibit the immune response mediated by IFN-γ by inactivating the signal transducer and transcriptional activator STAT1.

近年来，SHP2激活突变和高表达在白血病、实体瘤、黑色素瘤、恶性胶质瘤、肺癌、乳腺癌和努男综合症中陆续被发现，与肿瘤的发生、发展和预后密切相关。目前，SHP2已被研究用作临床肿瘤的靶分子。传统SHP2抑制剂(例如II-B08、PHPS1)作用机制均为与SHP2的PTP催化结构域结合，阻止酪氨酸磷酸化的底物进入催化位点，从而抑制SHP2的磷酸酶活性。然而，由于各种磷酸酶PTP催化结构域高度保守、极性和带电环境，使得SHP2传统抑制剂在特异性与生物利用度方面具有较大的缺陷，限制了其临床应用。因此，开发具有高特异性、高安全性、细胞膜渗透性强的SHP2抑制剂是决定SHP2是否可以成为新型肿瘤干预靶点的关键，SHP2蛋白变构抑制剂成为目前研究的主要方向。In recent years, activating mutations and high expression of SHP2 have been found in leukemia, solid tumors, melanoma, glioblastoma, lung cancer, breast cancer, and Numan syndrome, which are closely related to tumor occurrence, development and prognosis. Currently, SHP2 has been studied as a target molecule for clinical tumors. The mechanism of action of traditional SHP2 inhibitors (eg II-B08, PHPS1) is to bind to the PTP catalytic domain of SHP2, preventing tyrosine phosphorylated substrates from entering the catalytic site, thereby inhibiting the phosphatase activity of SHP2. However, due to the highly conserved, polar and charged environment of the PTP catalytic domains of various phosphatases, traditional SHP2 inhibitors have major defects in specificity and bioavailability, limiting their clinical applications. Therefore, the development of SHP2 inhibitors with high specificity, high safety and strong cell membrane permeability is the key to determine whether SHP2 can become a new tumor intervention target. SHP2 protein allosteric inhibitors have become the main direction of current research.

目前尚且没有SHP2抑制剂被批准上市，处于临床研究阶段的化合物有三个，其中加科思公司的JAB-3068进展最快，已被批准II期临床研究，诺华的TNO155和新锐制药公司的RMC-4630都处于临床I期研究阶段。At present, no SHP2 inhibitor has been approved for marketing, and there are three compounds in the clinical research stage. Among them, JAB-3068 of Jiakesi has the fastest progress and has been approved for phase II clinical research, Novartis' TNO155 and Xinrui Pharmaceutical's RMC- 4630 are all in phase I clinical studies.

发明内容SUMMARY OF THE INVENTION

本发明提供一种式(I)表示的化合物或其药学上可接受的盐、溶剂化物、多晶型物、互变异构体、代谢物或前药，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, metabolite or prodrug thereof,

Figure BSA0000197904800000021
Figure BSA0000197904800000021

其中，in,

A选自如下两并杂环或三并杂环；A is selected from the following di- or tri-heterocycles;

Figure BSA0000197904800000022
Figure BSA0000197904800000022

R1和R2各自独立地选自氢、卤素和C1-6烷基；R1 and R2 are each independently selected from hydrogen, halogen and C1-6 alkyl;

X选自氢、C1-6烷基、C3-8环烷基、C6-10芳基和C5-10杂芳基，所述C1-6烷基和C3-8环烷基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、或C1-6烷基取代，所述C6-10芳基和C5-10杂芳基可与不饱和的脂环、杂脂环、螺环稠合，并且可任选地被一个或多个卤素、-CF3、-OH、-CN、-O-C1-6烷基、-NR3R4、-O-C(O)NR3R4、-NH-(CO)-C1-6烷基、-S-CH2-CONH2、C1-6烷基、C3-6环烷基、C6-10芳基、或C6-10杂芳基取代；X is selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl and C5-10 heteroaryl, the C1-6 alkyl and C3-8 cycloalkane group can be optionally substituted with one or more halogen, -OH, -OC1-6 alkyl, -NH2 , or C1-6 alkyl, the C6-10 aryl and C5-10 hetero Aryl can be fused with unsaturated alicyclic, heteroalicyclic, spirocyclic, and optionally by one or more halogens,-CF3 , -OH, -CN,-OC1-6 alkyl, - NR3 R4 , -OC(O)NR3 R4 , -NH-(CO)-C1-6 alkyl, -S-CH2 -CONH2 , C1-6 alkyl, C3-6 ring Alkyl, C6-10 aryl, or C6-10 heteroaryl substitution;

R3和R4各自独立地选自氢和C1-6烷基；R3 and R4 are each independently selected from hydrogen and C1-6 alkyl;

Y选自C6-10芳基、C5-10杂芳基和C3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、C1-6烷基、或C3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C1-6烷基、或-NH2取代；Y is selected from C6-10 aryl, C5-10 heteroaryl and C3-12 heteroalicyclic groups, which aryl, heteroaryl and heteroalicyclic groups may be optionally replaced by one or more halogens , -OH, -OC1-6 alkyl, -NH2 , C1-6 alkyl, or C3-6 cycloalkyl, optionally substituted with halogen, -OH , -OC1-6 alkyl, or -NH2 substituted;

Z选自单键、-S-和-C≡C-。Z is selected from single bond, -S- and -C≡C-.

根据本发明的一些实施方式，本发明的式(I)化合物中，具有下式II～X：According to some embodiments of the present invention, the compounds of formula (I) of the present invention have the following formulas II to X:

Figure BSA0000197904800000031
Figure BSA0000197904800000031

其中，R1和R2各自独立地选自氢、卤素和C1-6烷基；wherein, R1 and R2 are each independently selected from hydrogen, halogen and C1-6 alkyl;

X选自氢、C1-6烷基、C3-8环烷基、C6-10芳基和C5-10杂芳基，所述C1-6烷基和C3-8环烷基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、或C1-6烷基取代，所述C6-10芳基和C5-10杂芳基可与不饱和的脂环、杂脂环、螺环稠合，并且可任选地被一个或多个卤素、-CF3、-OH、-CN、-O-C1-6烷基、-NR3R4、-O-C(O)NR3R4、-NH-(CO)-C1-6烷基、-S-CH2-CONH2、C1-6烷基、C3-6环烷基、C6-10芳基、或C6-10杂芳基取代；X is selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl and C5-10 heteroaryl, the C1-6 alkyl and C3-8 cycloalkane group can be optionally substituted with one or more halogen, -OH, -OC1-6 alkyl, -NH2 , or C1-6 alkyl, the C6-10 aryl and C5-10 hetero Aryl can be fused with unsaturated alicyclic, heteroalicyclic, spirocyclic, and optionally by one or more halogens,-CF3 , -OH, -CN,-OC1-6 alkyl, - NR3 R4 , -OC(O)NR3 R4 , -NH-(CO)-C1-6 alkyl, -S-CH2 -CONH2 , C1-6 alkyl, C3-6 ring Alkyl, C6-10 aryl, or C6-10 heteroaryl substitution;

R3和R4各自独立地选自氢和C1-6烷基；R3 and R4 are each independently selected from hydrogen and C1-6 alkyl;

Y选自C6-10芳基、C5-10杂芳基和C3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、C1-6烷基、或C3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C1-6烷基、或-NH2取代。Y is selected from C6-10 aryl, C5-10 heteroaryl and C3-12 heteroalicyclic groups, which aryl, heteroaryl and heteroalicyclic groups may be optionally replaced by one or more halogens , -OH, -OC1-6 alkyl, -NH2 , C1-6 alkyl, or C3-6 cycloalkyl, optionally substituted with halogen, -OH , -OC1-6 alkyl, or -NH2 substituted.

在一些实施方式中，R1和R2各自独立地选自氢和C1-6烷基；In some embodiments, R1 and R2 are each independently selected from hydrogen and C1-6 alkyl;

在一些实施方式中，X选自氢、C1-6烷基、C3-8环烷基、C6-10芳基和C5-10杂芳基，所述C1-6烷基和C3-8环烷基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、或C1-6烷基取代，所述C6-10芳基和C5-10杂芳基可任选地被一个或多个卤素、-CF3、-OH、-CN、-O-C1-6烷基、-NR3R4、-O-C(O)NR3R4、-NH-(CO)-C1-6烷基、-S-CH2-CONH2、C1-6烷基、C3-6环烷基、C6-10芳基、或C5-10杂芳基取代，In some embodiments, X is selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, and C5-10 heteroaryl, the C1-6 alkyl and C3-8 cycloalkyl can be optionally substituted with one or more halogen, -OH, -OC1-6 alkyl, -NH2 , or C1-6 alkyl, the C6-10 aryl and C5-10 heteroaryl can be optionally replaced by one or more halogen, -CF3 , -OH, -CN, -OC1-6 alkyl, -NR3 R4 , -OC(O)NR3 R4 , -NH-(CO)-C1-6 alkyl, -S-CH2 -CONH2 , C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or C5-10 heteroaryl substituted,

R3和R4各自独立地选自氢和C1-6烷基；R3 and R4 are each independently selected from hydrogen and C1-6 alkyl;

在一些实施方式中，Y选自C6-10芳基、C5-10杂芳基和C3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个-OH、-NH2、或C1-6烷基取代；In some embodiments, Y is selected from the group consisting of C6-10 aryl, C5-10 heteroaryl, and C3-12 heteroalicyclic, which may optionally be substituted with one or more -OH,-NH2 , orC1-6 alkyl;

在一些实施方式中，Y选自C3-12杂脂环基，所述杂脂环基可任选地被一个或多个-OH、-NH2、或C1-6烷基取代；In some embodiments, Y is selected from C3-12 heteroalicyclic groups, which may be optionally substituted with one or more -OH, -NH2 , or C1-6 alkyl groups;

在一些实施方式中，Y选自C3-12杂脂环基，所述杂脂环基可任选地被一个或多个-NH2或C1-6烷基取代；In some embodiments, Y is selected from C3-12 heteroalicyclic groups, which may be optionally substituted with one or more -NH2 or C1-6 alkyl groups;

根据本发明的一些实施方式，本发明提供以下化合物：According to some embodiments of the present invention, the present invention provides the following compounds:

Figure BSA0000197904800000041
Figure BSA0000197904800000041

Figure BSA0000197904800000051
Figure BSA0000197904800000051

Figure BSA0000197904800000061
Figure BSA0000197904800000061

另一方面，本发明提供一种药物组合物，其包含本发明的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体。在一些实施方案中，本发明的药物组合物还包括药学上可接受的辅料。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof. In some embodiments, the pharmaceutical compositions of the present invention further include pharmaceutically acceptable excipients.

另一方面，本发明提供治疗与SHP2相关的疾病的方法，其包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体、或其药物组合物。In another aspect, the present invention provides a method of treating a disease associated with SHP2, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polyol Crystal form, or tautomer, or pharmaceutical composition thereof.

另一方面，本发明提供本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体、或其药物组合物在制备治疗与SHP2相关的疾病的药物中的用途。In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a disease associated with SHP2 the use of.

在本发明的部分实施方式中，所述与SHP2相关的疾病为白血病、黑色素瘤、恶性胶质瘤、肺癌、乳腺癌或努男综合症。In some embodiments of the present invention, the disease associated with SHP2 is leukemia, melanoma, glioblastoma, lung cancer, breast cancer or Nuoman syndrome.

某些化学术语certain chemical terms

本发明所述的“化合物”包括所有立体异构体、几何异构体、互变异构体和同位素。"Compounds" as used herein include all stereoisomers, geometric isomers, tautomers and isotopes.

本发明化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。The compounds of the present invention may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

本发明化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

本发明还包括所有同位素的原子，无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数，但不同质量数。例如，氢的同位素包括氚和氘。The present invention also includes all isotopes of atoms, whether in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

在通式I-V化合物的上述定义中，本文中所用的术语具有如下含义：In the above definitions of compounds of general formulae I-V, the terms used herein have the following meanings:

术语“卤素”是指氟、氯、溴或碘，优选氟、氯或溴。The term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和烃基团，如C1-20烷基，优选为C1-6烷基，例如甲基、乙基、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、仲丁基或叔丁基)、戊基(例如正戊基、异戊基、新戊基)、正己基、2-甲基己基等。所述烷基可以是非取代的或是被取代的，所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基。The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, such as C1-20 alkyl, preferably C1-6 alkyl, such as methyl, ethyl, propyl butyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (eg n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, etc. The alkyl group can be unsubstituted or substituted, and the substituents include but are not limited to alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, Sulfinyl, phosphoryl and hydroxyl.

术语“C1-6烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接，其具有1-6个碳原子。所述烷基可以是非取代的或是被一个或多个选自烷基、烷氧基、氨基、卤素和羟基的取代基所取代。非取代的烷基的非限制性实例包括但不限于诸如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔-丁基、正-戊基、2-甲基丁基、新戊基、正己基、2-甲基己基等。The term "C1-6 alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the rest of the molecule by a single bond, having 1-6 carbon atoms . The alkyl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amino, halo, and hydroxy. Non-limiting examples of unsubstituted alkyl groups include, but are not limited to, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methyl butyl, neopentyl, n-hexyl, 2-methylhexyl, etc.

术语“环烷基”是指由碳原子和氢原子组成的全碳单环的饱和烃基团，如C3-20环烷基，优选为C3-6环烷基，例如环丙基、环丁基、环戊基、环己基等。所述环烷基可以是非取代的或是被取代的，所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基。The term "cycloalkyl" refers to an all-carbon monocyclic saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, such as C3-20 cycloalkyl, preferably C3-6 cycloalkyl, such as cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, etc. The cycloalkyl can be unsubstituted or substituted, and the substituents include but are not limited to alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl , sulfinyl, phosphoryl and hydroxyl.

术语“芳基”是指具有完全共轭的π电子体系的全碳单环或稠合环，其具有6-14个碳原子，优选具有6-12个碳原子，最优选具有6个碳原子。芳基可以是非取代的或被一个或多个取代基所取代，所述取代基的实例包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、磺酰基、亚磺酰基、磷酰基和杂脂环基。非取代的芳基的非限制性实例包括但不限于苯基、萘基和蒽基。The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms . Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , sulfinyl, phosphoryl and heteroalicyclic groups. Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.

术语“杂芳基”是指5-12个环原子的单环或稠合环，具有5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。杂芳基可以是非取代的或取代的，所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基。The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms are C, and have a fully conjugated π-electron system. Heteroaryl groups can be unsubstituted or substituted, including but not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and hetero Alicyclic. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, iso Quinolinyl, tetrazolyl, triazinyl.

术语“杂脂环”是指具有3-12个环原子的单环或稠合环，具有3、4、5、6、7、8、9、10、11或12个环原子，其中1或2个环原子是选自N、O、S(O)n(其中n为0、1或2)的杂原子，其余环原子为C。这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。3元饱和杂脂环的实例包括但不限于

Figure BSA0000197904800000081
4元饱和杂脂环的实例包括但不限于
Figure BSA0000197904800000082
5元饱和杂脂环的实例包括但不限于
Figure BSA0000197904800000083
6元饱和杂脂环的实例包括但不限于
Figure BSA0000197904800000084
Figure BSA0000197904800000085
7元饱和杂脂环的实例包括但不限于
Figure BSA0000197904800000086
5元不饱和杂脂环的实例包括但不限于
Figure BSA0000197904800000087
6元不饱和杂脂环的实例包括但不限于
Figure BSA0000197904800000088
The term "heteroalicyclic" refers to a monocyclic or fused ring having 3-12 ring atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein 1 or Two ring atoms are heteroatoms selected from N, O, S(O)n (where n is 0, 1 or 2) and the remaining ring atoms are C. Such rings may be saturated or unsaturated (eg, have one or more double bonds), but do not have a fully conjugated pi-electron system. Examples of 3-membered saturated heteroalicyclic rings include, but are not limited to
Figure BSA0000197904800000081
Examples of 4-membered saturated heteroalicyclic rings include, but are not limited to
Figure BSA0000197904800000082
Examples of 5-membered saturated heteroalicyclic rings include, but are not limited to
Figure BSA0000197904800000083
Examples of 6-membered saturated heteroalicyclic rings include, but are not limited to
Figure BSA0000197904800000084
Figure BSA0000197904800000085
Examples of 7-membered saturated heteroalicyclic rings include, but are not limited to
Figure BSA0000197904800000086
Examples of 5-membered unsaturated heteroalicyclic rings include, but are not limited to
Figure BSA0000197904800000087
Examples of 6-membered unsaturated heteroalicyclic rings include, but are not limited to
Figure BSA0000197904800000088

术语“杂脂环基”是指“杂脂环”分子去掉1个氢原子后余下的基团。杂脂环基可以是非取代的或者其中的氢原子任选地被取代基取代，所述的取代基包括但不限于烷基、烷氧基、＝O、芳基、芳烷基、-COOH、-CN、氨基、卤素和羟基。The term "heteroalicyclic" refers to the group remaining after the removal of one hydrogen atom from a "heteroalicyclic" molecule. Heteroalicyclic groups may be unsubstituted or optionally substituted in hydrogen atoms by substituents including, but not limited to, alkyl, alkoxy, =O, aryl, aralkyl, -COOH, -CN, amino, halogen and hydroxyl.

本发明还提供了制备上述式化合物的方法，包括以下合成方案：The present invention also provides a method for preparing the compound of the above formula, including the following synthetic scheme:

合成方案1：Synthesis Scheme 1:

Figure BSA0000197904800000089
Figure BSA0000197904800000089

化合物式1-6可以使用合成方案1合成。4，6-二氯-1H-吡唑并[3，4-d]嘧啶与适当的保护剂反应得到中间体1-1。中间体1-1与氢氧化钠溶液反应，得到中间体1-2。中间体1-2与碘甲烷和碱反应得到中间体1-3。中间体1-3与含NH或硼酸酯的化合物反应得到中间体1-4。中间体1-4脱去保护基得到中间体1-5。中间体1-5与N-碘代丁二酰亚胺反应得到化合物1-6。Compounds of formula 1-6 can be synthesized using Synthesis Scheme 1. 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine is reacted with an appropriate protecting agent to give intermediate 1-1. Intermediate 1-1 is reacted with sodium hydroxide solution to obtain intermediate 1-2. Intermediate 1-2 is reacted with iodomethane and base to give intermediate 1-3. Reaction of intermediates 1-3 with NH or boronate containing compounds affords intermediates 1-4. Deprotection of intermediates 1-4 affords intermediates 1-5. Reaction of intermediate 1-5 with N-iodosuccinimide affords compound 1-6.

合成方案2：Synthesis Scheme 2:

Figure BSA0000197904800000091
Figure BSA0000197904800000091

化合物式2-5可以使用合成方案2合成。4，6-二氯-1H-吡唑并[3，4-d]嘧啶与N-碘代丁二酰亚胺反应得碘代中间体2-1。中间体2-1和氨水反应到中间体2-2。中间体2-2和适当的保护剂反应得到中间体2-3。中间体2-3用氯乙醛闭环得中间体2-4。中间体2-4与含NH或硼酸酯的化合物反应得到化合物2-5。Compound formula 2-5 can be synthesized using Synthesis Scheme 2. 4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine reacts with N-iodosuccinimide to give iodo intermediate 2-1. Intermediate 2-1 and ammonia water are reacted to intermediate 2-2. Reaction of intermediate 2-2 with a suitable protecting agent affords intermediate 2-3. Intermediate 2-3 is ring closed with chloroacetaldehyde to obtain intermediate 2-4. Reaction of intermediate 2-4 with an NH or boronate containing compound affords compound 2-5.

合成方案3：Synthesis Scheme 3:

Figure BSA0000197904800000092
Figure BSA0000197904800000092

化合物式3-3可以通过合成方案3合成。6-氯-1H-吡唑并[3，4-b]吡嗪与N-碘代丁二酰亚胺反应得到碘代中间体3-1。中间体3-1和适当的保护剂反应得到中间体3-2。中间体3-2与含NH或硼酸酯的化合物反应得到化合物3-3。Compound Formula 3-3 can be synthesized through Synthesis Scheme 3. Reaction of 6-chloro-1H-pyrazolo[3,4-b]pyrazine with N-iodosuccinimide affords iodo intermediate 3-1. Reaction of intermediate 3-1 with an appropriate protecting agent affords intermediate 3-2. Reaction of intermediate 3-2 with a compound containing NH or boronate ester yields compound 3-3.

合成方案4：Synthesis Scheme 4:

Figure BSA0000197904800000093
Figure BSA0000197904800000093

最终化合物4-1可以通过合成方案4合成。R1代表端基乙炔、硼酸或硼酸酯、巯基，R2代表碘或溴，两个原料在钯催化剂和碱存在下反应得到产物4-1。若4-1上的基团带有保护基则采用相应的方法脱除保护基。The final compound 4-1 can be synthesized by synthetic scheme 4. R1 represents terminal acetylene, boronic acid or boronic acid ester, mercapto group, R2 represents iodine or bromine, and the two raw materials are reacted in the presence of palladium catalyst and base to obtain product 4-1. If the group on 4-1 has a protective group, the corresponding method is used to remove the protective group.

上述合成方案只是列举了本发明中部分化合物的制备方法，按照本领域的公知技术，技术人员在上述合成方案的基础上，采用类似的方法也可合成本发明中的化合物。The above synthesis scheme only enumerates the preparation methods of some compounds in the present invention. According to the known technology in the art, the skilled person can also synthesize the compounds in the present invention by a similar method on the basis of the above synthesis scheme.

本发明的化合物或其盐可以作为活性物质单独给药，优选以其药物组合物的形式给药。The compounds of the invention or their salts can be administered alone as active substances, preferably in the form of their pharmaceutical compositions.

本发明另一方面提供一种药物组合物，其含有通式I、II、III、IV或V的化合物或其药学上可接受的盐、溶剂化物、多晶型、代谢物作为活性成份，以及一种或多种药学上可接受的载体。Another aspect of the present invention provides a pharmaceutical composition comprising a compound of general formula I, II, III, IV or V or a pharmaceutically acceptable salt, solvate, polymorph, metabolite thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.

“药物组合物”是指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给予本发明的化合物。"Pharmaceutical composition" refers to the formulation of one or more compounds of the present invention, or salts thereof, with carriers generally accepted in the art for delivering biologically active compounds to an organism (eg, a human). The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present invention to an organism.

术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于被美国食品药品管理局许可为可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。The term "pharmaceutically acceptable carrier" refers to those carriers which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carrier" means an inert substance with which the active ingredient is administered to facilitate administration of the active ingredient, including but not limited to those approved by the U.S. Food and Drug Administration as acceptable for use in humans or animals (e.g. livestock) any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier. Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

以纯的形式或以适宜的药物组合物形式的本发明化合物或其药物可接受的盐的给药可通过提供类似用途的药剂的任何可接受的给药模式来进行。本发明的药物组合物可通过将本发明的化合物与适宜的药物可接受的载剂、稀释剂或赋形剂组合而制备。本发明的药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。Administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in pure form or in a suitable pharmaceutical composition, can be effected by any acceptable mode of administration that provides a medicament for similar utility. The pharmaceutical compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.

给予本发明化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, Intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral administration.

本发明的药物组合物可以采用本领域周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present invention can be manufactured by methods known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsifying method, freeze-drying method and the like.

在优选的实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present invention to be formulated as tablets, pills, dragees, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

可以通过常规的混合、填充或压片方法来制备固体口服药物组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. It can be obtained, for example, by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable auxiliaries if desired, and processing the mixture into granules to obtain tablet or dragee core. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol Sugar alcohol or dicalcium phosphate; silicon dioxide; croscarmellose sodium, pre-interleaved starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl cellulose element, cross-linked polyvinylpyrrolidone, etc. The sugar-coated core may optionally be coated according to methods well known in ordinary pharmaceutical practice, especially using enteric coatings.

药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Appropriate excipients such as fillers, buffers or surfactants can be used.

本发明再一方面涉及通式I至通式VI的化合物或其药学上可接受的盐、溶剂化物、多晶型、代谢物等在治疗受益于SHP2抑制的疾病的药物中的用途。所述的受益于SHP2抑制的疾病选自癌症。Yet another aspect of the present invention relates to the use of compounds of formulae I to VI, or pharmaceutically acceptable salts, solvates, polymorphs, metabolites, etc. thereof, in a medicament for the treatment of diseases that benefit from SHP2 inhibition. The disease that benefits from SHP2 inhibition is selected from cancer.

本发明提供的取代的炔基杂环类化合物具有非常好的SHP2抑制活性，有望成为高效的SHP2抑制剂类药物。The substituted alkynyl heterocyclic compounds provided by the invention have very good SHP2 inhibitory activity, and are expected to become efficient SHP2 inhibitor drugs.

具体实施方式Detailed ways

下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。本领域技术人员应该理解：还有形成本发明化合物的其它合成途径，下面提供的是非限制性的实施例。The following specific examples are intended to enable those skilled in the art to more clearly understand and implement the present invention. They should not be considered as limiting the scope of the invention, but merely as illustrative and representative of the invention. It will be appreciated by those skilled in the art that there are other synthetic routes to form the compounds of the present invention, non-limiting examples are provided below.

凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是市场上直接买到未经进一步纯化直接使用的。All operations involving easily oxidizable or easily hydrolyzed raw materials are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are directly purchased from the market and used without further purification.

柱层析色谱采用青岛化工有限公司生产的硅胶(200-300目)。薄层色谱采用E.Merck公司生产的预制板(硅胶60 PF254，0.25毫米)。手性化合物分离和对映体过量值(ee)测定使用Agilent LC 1200 series(柱子：CHIRALPAK AD-H，

Figure BSA0000197904800000113
Figure BSA0000197904800000115
毫米，5微米，30℃)。核磁共振色谱(NMR)使用Varian VNMRS-400核磁共振仪测定；液质联用(LC/MS)使用FINNIGAN Thermo LCQ Advantage MAX，Agilent LC 1200 series(柱子：Waters SymmetryC18，
Figure BSA0000197904800000114
毫米，5微米，35℃)，采用ESI(+)离子模式。Column chromatography adopts silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. Thin-layer chromatography used a prefabricated plate (silica gel 60 PF254 , 0.25 mm) produced by E. Merck Company. Chiral compound separation and enantiomeric excess (ee) determination were performed using an Agilent LC 1200 series (column: CHIRALPAK AD-H,
Figure BSA0000197904800000113
Figure BSA0000197904800000115
mm, 5 microns, 30°C). Nuclear magnetic resonance chromatography (NMR) was determined using a Varian VNMRS-400 nuclear magnetic resonance instrument; liquid chromatography-mass spectrometry (LC/MS) was performed using a FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters SymmetryC18,
Figure BSA0000197904800000114
mm, 5 μm, 35°C) in ESI(+) ion mode.

实验部分Experimental part

中间体1：(3S，4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺二盐酸盐Intermediate 1:(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride

Figure BSA0000197904800000111
Figure BSA0000197904800000111

(3S，4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺二盐酸盐按照专利WO2017216706中中间体14的方法合成。(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride was synthesized according to the method of intermediate 14 in patent WO2017216706.

中间体2：6-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮Intermediate 2:6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

Figure BSA0000197904800000112
Figure BSA0000197904800000112

步骤1：4，6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶Step 1: 4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

将4，6-二氯-1H-吡唑并[3，4-d]嘧啶(2.7g)、3，4-二氢-2H-吡喃(2.4g)、对甲苯磺酸(0.25g)加入四氢呋喃(25mL)中，回流8小时，降至室温后，减压浓缩并用硅胶柱色谱分离(石油醚∶乙酸乙酯，10∶1)得4，6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶(3.0g)。MS m/z[LC-MS]：273.03[M+1]。4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (2.7g), 3,4-dihydro-2H-pyran (2.4g), p-toluenesulfonic acid (0.25g) was added to tetrahydrofuran (25 mL), refluxed for 8 hours, cooled to room temperature, concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 10:1) to obtain 4,6-dichloro-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.0 g). MS m/z [LC-MS]: 273.03 [M+1].

步骤2：6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮Step 2: 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

将4，6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶(3.0g)和20％氢氧化钠溶液(4mL)加入乙腈(40mL)中，室温搅拌过夜，减压浓缩后用硅胶柱色谱分离(石油醚∶乙酸乙酯，6∶1)得6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮(2.4g)。MS m/z[LC-MS]：255.07[M+1]。1HNMR(400MHz，DMSO-d6)：δ＝13.300(1H，brs)，8.113(1H，s)，5.693(1H，m)，3.908(1H，m)，3.645(1H，m)，2.286(1H，m)，1.967(1H，m)，1.820(1H，m)，1.708(1H，m)，1.523(2H，m)。4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.0 g) and 20% sodium hydroxide solution (4 mL ) was added to acetonitrile (40 mL), stirred at room temperature overnight, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 6:1) to obtain 6-chloro-1-(tetrahydro-2H-pyran-2). -yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (2.4 g). MS m/z [LC-MS]: 255.07 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.300 (1H, brs), 8.113 (1H, s), 5.693 (1H, m), 3.908 (1H, m), 3.645 (1H, m), 2.286 ( 1H, m), 1.967 (1H, m), 1.820 (1H, m), 1.708 (1H, m), 1.523 (2H, m).

步骤3：6-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮Step 3: 6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

将6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮(2.4g)、碳酸钾(3.8g)加入N，N-二甲基甲酰胺(40mL)中，然后滴加碘甲烷(1.0mL)，室温搅拌4小时。反应液倒入200mL水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱分离(石油醚∶乙酸乙酯，8∶1)得6-氯-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮(1.8g)。MS m/z[LC-MS]：269.08[M+1]。1HNMR(400MHz，DMSO-d6)：δ＝8.150(1H，s)，5.710(1H，m)，3.911(1H，m)，3.659(1H，m)，3.567(3H，s)，2.310(1H，m)，1.974(1H，m)，1.822(1H，m)，1.708(1H，m)，1.530(2H，m)。6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (2.4 g), potassium carbonate (3.8 g) N,N-dimethylformamide (40 mL) was added, then iodomethane (1.0 mL) was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 200 mL of water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 8:1 ) to give 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (1.8g ). MS m/z [LC-MS]: 269.08 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.150 (1H, s), 5.710 (1H, m), 3.911 (1H, m), 3.659 (1H, m), 3.567 (3H, s), 2.310 ( 1H, m), 1.974 (1H, m), 1.822 (1H, m), 1.708 (1H, m), 1.530 (2H, m).

中间体3：9-碘-5-氯-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶Intermediate 3:9-iodo-5-chloro-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine

Figure BSA0000197904800000121
Figure BSA0000197904800000121

步骤1：3-碘-4，6-二氯-1H-吡唑并[3，4-d]嘧啶Step 1: 3-Iodo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine

将4，6-二氯-1H-吡唑并[3，4-d]嘧啶(4.0g)、N-碘代丁二酰亚胺(5.72g)加入乙腈(25mL)中，加热至100℃微波反应25分钟，降至室温后，减压浓缩并用硅胶柱色谱分离(石油醚∶乙酸乙酯，8∶1)得3-碘-4，6-二氯-1H-吡唑并[3，4-d]嘧啶(5.4g)。MS m/z[LC-MS]：314.87[M+1]。4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidine (4.0 g) and N-iodosuccinimide (5.72 g) were added to acetonitrile (25 mL) and heated to 100°C The microwave reaction was carried out for 25 minutes. After cooling to room temperature, it was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 8:1) to obtain 3-iodo-4,6-dichloro-1H-pyrazolo[3, 4-d]pyrimidine (5.4g). MS m/z [LC-MS]: 314.87 [M+1].

步骤2：3-碘-6-氯-1H-吡唑并[3，4-d]嘧啶-4-胺Step 2: 3-Iodo-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine

将3-碘-4，6-二氯-1H-吡唑并[3，4-d]嘧啶(1.2g)和浓氨水(25％-28％，2mL)加入乙腈(20mL)中，室温搅拌过夜，减压浓缩后用硅胶柱色谱分离(石油醚∶乙酸乙酯，3∶1)得3-碘-6-氯-1H-吡唑并[3，4-d]嘧啶-4-胺(1.1g)。MS m/z[LC-MS]：295.92[M+1]。3-iodo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (1.2 g) and concentrated ammonia (25%-28%, 2 mL) were added to acetonitrile (20 mL), and stirred at room temperature overnight, concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 3:1) to obtain 3-iodo-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine ( 1.1g). MS m/z [LC-MS]: 295.92 [M+1].

步骤3：3-碘-6-氯-1-(4-甲氧基苄基)-1H-吡唑并[3，4-d]嘧啶-4-胺Step 3: 3-iodo-6-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

将3-碘-6-氯-1H-吡唑并[3，4-d]嘧啶-4-胺(1.1g)、碳酸钾(1.3g)加入N，N-二甲基甲酰胺(20mL)中，然后滴加4-甲氧基苄氯(0.5mL)，室温搅拌2小时。反应液倒入150mL水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱分离(石油醚∶乙酸乙酯，4∶1)得3-碘-6-氯-1-(4-甲氧基苄基)-1H-吡唑并[3，4-d]嘧啶-4-胺(0.90g)。MS m/z[LC-MS]：415.98[M+1]。3-Iodo-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.1 g), potassium carbonate (1.3 g) were added to N,N-dimethylformamide (20 mL) Then, 4-methoxybenzyl chloride (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 150 mL of water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 4:1 ) to give 3-iodo-6-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.90 g). MS m/z [LC-MS]: 415.98 [M+1].

步骤4：9-碘-5-氯-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶Step 4: 9-Iodo-5-chloro-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine

将3-碘-6-氯-1-(4-甲氧基苄基)-1H-吡唑并[3，4-d]嘧啶-4-胺(700mg)和氯乙醛(2mL)加入乙腈(20mL)中，加热至100℃封管反应5小时，倒入水中，用饱和碳酸钠水溶液调pH值到9～10，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱分离(石油醚∶乙酸乙酯，8∶1)得9-碘-5-氯-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶(460mg)。MS m/z[LC-MS]：439.98[M+1]。1HNMR(400MHz，DMSO-d6)：δ＝8.097(1H，d，J＝1.6Hz)，7.629(1H，d，J＝1.6Hz)，7.261(2H，d，J＝8.4Hz)，6.898(2H，d，J＝8.4Hz)，5.381(2H，s)，3.72(3H，s)。3-Iodo-6-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (700 mg) and chloroacetaldehyde (2 mL) were added to acetonitrile (20 mL), heated to 100°C and sealed for 5 hours, poured into water, adjusted to pH 9-10 with saturated aqueous sodium carbonate solution, extracted with dichloromethane, the extract was washed with saturated brine, anhydrous sodium sulfate Dry, filter, concentrate the filtrate under reduced pressure, and separate by silica gel column chromatography (petroleum ether:ethyl acetate, 8:1) to obtain 9-iodo-5-chloro-7-(4-methoxybenzyl)-7H-imidazole Ho[1,2-c]pyrazolo[4,3-e]pyrimidine (460 mg). MS m/z [LC-MS]: 439.98 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.097 (1H, d, J=1.6 Hz), 7.629 (1H, d, J=1.6 Hz), 7.261 (2H, d, J=8.4 Hz), 6.898 (2H, d, J=8.4 Hz), 5.381 (2H, s), 3.72 (3H, s).

中间体4：6-氯-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[4，3-b]吡嗪Intermediate 4:6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyrazine

Figure BSA0000197904800000131
Figure BSA0000197904800000131

6-氯-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[4，3-b]吡嗪按照专利WO2018057884中第83页实施例29中相同中间体的方法合成。6-Chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyrazine was the same as in Example 29 on page 83 of patent WO2018057884 Method synthesis of intermediates.

中间体5：1-(3-碘-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-4-甲基哌啶-4-基氨基甲酸叔丁酯Intermediate 5:1-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methyl tert-Butylpiperidin-4-ylcarbamate

Figure BSA0000197904800000132
Figure BSA0000197904800000132

步骤1：4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯Step 1: 4-Methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[ 3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate tert-butyl ester

将中间体2(538mg)、4-甲基哌啶-4-基氨基甲酸叔丁酯(514mg)、二异丙基乙基胺(1mL)加入四氢呋喃(20mL)中，加热至120℃搅拌2小时，减压旋蒸除去溶剂，用硅胶柱色谱分离(石油醚∶乙酸乙酯，5∶1)得4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(800mg)。MS m/z[LC-MS]：447.27[M+1]。Intermediate 2 (538 mg), tert-butyl 4-methylpiperidin-4-ylcarbamate (514 mg) and diisopropylethylamine (1 mL) were added to tetrahydrofuran (20 mL), heated to 120°C and stirred for 2 hours, the solvent was removed by rotary evaporation under reduced pressure, and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 5:1) to obtain 4-methyl-1-(5-methyl-4-oxo-1-(tetrahydro) -2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate (800mg) . MS m/z [LC-MS]: 447.27 [M+1].

步骤2：4-甲基-1-(5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯Step 2: 4-Methyl-1-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4 - tert-butyl carbamate

将4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(445mg)加入甲醇(10mL)中，再加入1M盐酸溶液(2mL)，室温搅拌过夜，用饱和碳酸氢钠水溶液调pH值到8～9，旋蒸除去有机溶剂，再用乙酸乙酯萃取，萃取液干燥浓缩后用硅胶柱色谱分离(石油醚∶乙酸乙酯，4∶1)得4-甲基-1-(5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(305mg)。MS m/z[LC-MS]：363.22[M+1]。4-methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate tert-butyl ester (445mg) was added to methanol (10mL), then 1M hydrochloric acid solution (2mL) was added, stirred at room temperature overnight, and saturated aqueous sodium bicarbonate solution was added. Adjust the pH to 8-9, remove the organic solvent by rotary evaporation, and extract with ethyl acetate. The extract is dried and concentrated, and then separated by silica gel column chromatography (petroleum ether:ethyl acetate, 4:1) to obtain 4-methyl-1 -(5-Methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate (305mg ). MS m/z [LC-MS]: 363.22 [M+1].

步骤3：1-(3-碘-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-4-甲基哌啶-4-基氨基甲酸叔丁酯Step 3: 1-(3-Iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-methyl tert-Butyl piperidin-4-ylcarbamate

将4-甲基-1-(5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯(300mg)、N-碘代丁二酰亚胺(177mg)加入乙腈(5mL)中，加热至100℃微波反应25分钟，降至室温，减压浓缩后用硅胶柱色谱分离(石油醚∶乙酸乙酯，4∶1)得1-(3-碘-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-4-甲基哌啶-4-基氨基甲酸叔丁酯(320mg)。MS m/z[LC-MS]：489.11[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.545(1H，s)，6.583(1H，s)，3.317(3H，s)，3.168(2H，m)，2.994(2H，m)，2.102(1H，m)，1.529(2H，m)，1.356(9H，s)，1.230(3H，s)。4-methyl-1-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-yl tert-Butyl carbamate (300mg) and N-iodosuccinimide (177mg) were added to acetonitrile (5mL), heated to 100°C for microwave reaction for 25 minutes, cooled to room temperature, concentrated under reduced pressure and separated by silica gel column chromatography (Petroleum ether:ethyl acetate, 4:1) to give 1-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine -6-yl)-4-methylpiperidin-4-ylcarbamate tert-butyl ester (320 mg). MS m/z [LC-MS]: 489.11 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ = 13.545 (1H, s), 6.583 (1H, s), 3.317 (3H, s), 3.168 (2H, m), 2.994 (2H, m), 2.102 (1H, m), 1.529 (2H, m), 1.356 (9H, s), 1.230 (3H, s).

中间体6：((3S，4S)-8-(3-碘-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Intermediate 6:((3S,4S)-8-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamic acid tert-butyl ester

Figure BSA0000197904800000141
Figure BSA0000197904800000141

步骤1：6-(((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Step 1: 6-(((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl-1- (Tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

参照中间体5中步骤1的方法，用中间体1替代4-甲基哌啶-4-基氨基甲酸叔丁酯，得6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮。MS m/z[LC-MS]：403.25[M+1]。Referring to the method of step 1 in intermediate 5, substituting intermediate 1 for tert-butyl 4-methylpiperidin-4-ylcarbamate to give 6-((3S,4S)-4-amino-3-methyl- 2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H - Pyrazolo[3,4-d]pyrimidin-4-one. MS m/z [LC-MS]: 403.25 [M+1].

步骤2：((3S，4S)-3-甲基-8-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 2: ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro tert-Butyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

将6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮(400mg)、三乙胺(500mg)加入二氯甲烷(10mL)中，冰水浴冷却下滴加二碳酸二叔丁酯(260mg)，滴加完后升至室温搅拌4小时，依次用水和饱和食盐水洗，有机相干燥浓缩后用硅胶柱色谱(石油醚∶乙酸乙酯，4∶1)分离得((3S，4S)-3-甲基-8-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(420mg)。MSm/z[LC-MS]：503.3[M+1]。6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl-1-(tetrahydro -2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (400mg), triethylamine (500mg) was added to dichloromethane ( 10mL), di-tert-butyl dicarbonate (260mg) was added dropwise under ice-water bath cooling, after the dropwise addition was completed, the mixture was heated to room temperature and stirred for 4 hours, washed with water and saturated brine successively, the organic phase was dried and concentrated, and then subjected to silica gel column chromatography (petroleum ether). : ethyl acetate, 4: 1) to obtain ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl) )-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-Butyl ester (420 mg). MS m/z [LC-MS]: 503.3 [M+1].

步骤3：((3S，4S)-3-甲基-8-(5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 3: ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

参照中间体5中步骤2的方法，用((3S，4S)-3-甲基-8-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯替代4-甲基-1-(5-甲基-4-氧代-1-(四氢-2H-吡喃-2-基)-4，5-二氢-1H-吡唑[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯，得((3S，4S)-3-甲基-8-(5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]：419.24[M+1]。Referring to the method of step 2 in intermediate 5, using ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl) )-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-Butyl ester instead of 4-methyl-1-(5-methyl-4-oxo-1-(tetrahydro-2H-pyran-2-yl)-4,5-dihydro-1H-pyrazole[ 3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate tert-butyl ester to give ((3S,4S)-3-methyl-8-(5-methyl-4-oxo- 4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester. MS m/z [LC-MS]: 419.24 [M+1].

步骤4：((3S，4S)-8-(3-碘-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 4: ((3S,4S)-8-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6- yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate tert-butyl ester

参照中间体5中步骤3的方法，用((3S，4S)-3-甲基-8-(5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯替代4-甲基-1-(5-甲基-4-氧代-4，5-二氢-1H-吡唑[3，4-d]嘧啶-6-基)哌啶-4-基氨基甲酸叔丁酯，得((3S，4S)-8-(3-碘-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]：545.14[M+1]。1HNMR(400MHz，DMSO-d6)：δ＝13.562(1H，s)，6.988(1H，s)，4.134(1H，m)，3.848(1H，m)，3.638(1H，d，J＝8.4Hz)，3.487(1H，d，J＝8.4Hz)，3.328(3H，s)，3.184(1H，m)，3.092(2H，m)，1.62-1.76(3H，m)，1.50-1.60(1H，m)，1.37(9H，s)，0.994(3H，d，J＝6.0Hz)。Following the procedure of step 3 in intermediate 5, using ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3 , 4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate tert-butyl ester instead of 4-methyl-1-(5-methyl) -4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-ylcarbamate tert-butyl ester to give ((3S,4S)- 8-(3-iodo-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2- tert-Butyl oxa-8-azaspiro[4.5]decan-4-yl)carbamate. MS m/z [LC-MS]: 545.14 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.562 (1H,s), 6.988 (1H,s), 4.134 (1H,m), 3.848 (1H,m), 3.638 (1H,d, J=8.4 Hz), 3.487 (1H, d, J=8.4Hz), 3.328 (3H, s), 3.184 (1H, m), 3.092 (2H, m), 1.62-1.76 (3H, m), 1.50-1.60 (1H , m), 1.37 (9H, s), 0.994 (3H, d, J=6.0 Hz).

中间体7：((3S，4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-4]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Intermediate 7:((3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-4 ]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

Figure BSA0000197904800000151
Figure BSA0000197904800000151

步骤1：(3S，4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Step 1: (3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine -5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

参照中间体5中步骤1的方法，用中间体3替代中间体2，用中间体1替代4-甲基哌啶-4基氨基甲酸叔丁酯，得(3S，4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺。MSm/z[LC-MS]：574.14[M+1]。Referring to the method of step 1 in intermediate 5, substituting intermediate 3 for intermediate 2, and substituting intermediate 1 for tert-butyl 4-methylpiperidin-4-ylcarbamate to obtain (3S,4S)-8-(9 -Iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine. MS m/z [LC-MS]: 574.14 [M+1].

步骤2：((3S，4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 2: ((3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e] pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate tert-butyl ester

参照中间体6中步骤2的方法，用(3S，4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺替代6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮，得((3S，4S)-8-(9-碘-7-(4-甲氧基苄基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]：674.2[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.707(1H，d，J＝1.2Hz)，7.437(1H，d，J＝1.2Hz)，7.251(2H，d，J＝8.4Hz)，6.850(2H，d，J＝8.4Hz)，5.391(2H，s)，4.163(1H，m)，3.913(1H，m)，3.673(3H，s)，3.35-3.55(6H，m)，1.72-1.90(3H，m)，1.60-1.72(1H，m)，1.352(9H，s)，1.007(3H，d，J＝6.4Hz)。Following the procedure of Step 2 in Intermediate 6, using (3S,4S)-8-(9-iodo-7-(4-methoxybenzyl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine instead of 6-((3S,4S)-4- Amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1 , 5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one to give ((3S,4S)-8-(9-iodo-7-(4-methoxybenzyl) -7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 4-yl) tert-butyl carbamate. MS m/z [LC-MS]: 674.2 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.707 (1H, d, J=1.2 Hz), 7.437 (1H, d, J=1.2 Hz), 7.251 (2H, d, J=8.4 Hz), 6.850 (2H, d, J=8.4Hz), 5.391 (2H, s), 4.163 (1H, m), 3.913 (1H, m), 3.673 (3H, s), 3.35-3.55 (6H, m), 1.72 -1.90 (3H, m), 1.60-1.72 (1H, m), 1.352 (9H, s), 1.007 (3H, d, J=6.4 Hz).

中间体8：((3S，4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Intermediate 8:((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6 -yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamic acid tert-butyl ester

Figure BSA0000197904800000152
Figure BSA0000197904800000152

步骤1：(3S，4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Step 1: (3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl )-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

参照中间体5中步骤1的方法，用中间体4替代中间体2，用中间体1替代4-甲基哌啶-4-基氨基甲酸叔丁酯，得(3S，4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺。MS m/z[LC-MS]：499.13[M+1]。Referring to the method of step 1 in intermediate 5, substituting intermediate 4 for intermediate 2 and intermediate 1 for tert-butyl 4-methylpiperidin-4-ylcarbamate to obtain (3S,4S)-8-( 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5]decane-4-amine. MS m/z [LC-MS]: 499.13 [M+1].

步骤2：((3S，4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 2: ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6- yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate tert-butyl ester

参照中间体6中步骤2的方法，用(3S，4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺替代6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮，得((3S，4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MSm/z[LC-MS]：599.19[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.410(1H，s)，6.988(1H，s)，5.71(1H，m)，4.14(1H，m)，3.84-3.92(2H，m)，3.65(2H，m)，3.472(1H，d，J＝8.4Hz)，3.18(1H，m)，3.09(2H，m)，2.31(1H，m)，1.98(1H，m)，1.62-1.83(5H，m)，1.49-1.60(3H，m)，1.38(9H，s)，1.004(3H，d，J＝6.0Hz)。Following the procedure of step 2 in Intermediate 6, using (3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b] Pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine instead of 6-((3S,4S)-4-amino-3- Methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-di Hydro-4H-pyrazolo[3,4-d]pyrimidin-4-one to give ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl) -1H-Pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester. MS m/z [LC-MS]: 599.19 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.410(1H,s), 6.988(1H,s), 5.71(1H,m), 4.14(1H,m), 3.84-3.92(2H,m) , 3.65 (2H, m), 3.472 (1H, d, J=8.4Hz), 3.18 (1H, m), 3.09 (2H, m), 2.31 (1H, m), 1.98 (1H, m), 1.62- 1.83 (5H, m), 1.49-1.60 (3H, m), 1.38 (9H, s), 1.004 (3H, d, J=6.0 Hz).

中间体9：((3S，4S)-8-(3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3，4-b]吡嗪-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Intermediate 9:((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine-6 -yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamic acid tert-butyl ester

Figure BSA0000197904800000161
Figure BSA0000197904800000161

步骤1：8-溴-7-氯-5-(甲硫基)咪唑并[1，2-c]嘧啶Step 1: 8-Bromo-7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine

5-溴-6-氯-2-(甲硫基)嘧啶-4-胺(1.0g)和40％氯乙醛水溶液(1.2mL)溶于二氧六环(6mL)中，氮气保护下回流14小时，冷却至室温后过滤，得8-溴-7-氯-5-(甲硫基)咪唑并[1，2-c]嘧啶(900mg)。MS m/z[LC-MS]：277.92[M+1]。5-Bromo-6-chloro-2-(methylthio)pyrimidin-4-amine (1.0 g) and 40% aqueous chloroacetaldehyde (1.2 mL) were dissolved in dioxane (6 mL) and refluxed under nitrogen After 14 hours, cooled to room temperature and filtered to give 8-bromo-7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (900 mg). MS m/z [LC-MS]: 277.92 [M+1].

步骤2：8-溴-7-氯-5-(甲基亚磺酰基)咪唑并[1，2-c]嘧啶Step 2: 8-Bromo-7-chloro-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine

8-溴-7-氯-5-(甲硫基)咪唑并[1，2-c]嘧啶(557mg)溶于二氯甲烷(20mL)中，加入间氯过氧化苯甲酸(85％，487mg)，室温搅拌6小时，反应液依次用饱和碳酸氢钠水溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋蒸浓缩，硅胶柱色谱分离纯化(石油醚∶乙酸乙酯，5∶1)得8-溴-7-氯-5-(甲基亚磺酰基)咪唑并[1，2-c]嘧啶(420mg)。MS m/z[LC-MS]：293.91[M+1]。8-Bromo-7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (557 mg) was dissolved in dichloromethane (20 mL), m-chloroperoxybenzoic acid (85%, 487 mg) was added ), stirred at room temperature for 6 hours, the reaction solution was washed successively with saturated aqueous sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate, 5:1) to give 8-bromo-7-chloro-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine (420 mg). MS m/z [LC-MS]: 293.91 [M+1].

步骤3：(3S，4S)-8-(8-溴-7-氯咪唑并[1，2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Step 3: (3S,4S)-8-(8-Bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro [4.5]Decane-4-amine

参照中间体5中步骤1的方法，用8-溴-7-氯-5-(甲基亚磺酰基)咪唑并[1，2-c]嘧啶替代中间体2，用中间体1替代4-甲基哌啶-4-基氨基甲酸叔丁酯，得(3S，4S)-8-(8-溴-7-氯咪唑并[1，2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺。MS m/z[LC-MS]：400.06[M+1]。Following the procedure of Step 1 in Intermediate 5, substituting 8-bromo-7-chloro-5-(methylsulfinyl)imidazo[1,2-c]pyrimidine for Intermediate 2 and Intermediate 1 for 4- tert-Butyl methylpiperidin-4-ylcarbamate to give (3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl yl-2-oxa-8-azaspiro[4.5]decane-4-amine. MS m/z [LC-MS]: 400.06 [M+1].

步骤4：((3S，4S)-8-(8-溴-7-氯咪唑并[1，2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 4: ((3S,4S)-8-(8-Bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-aza tert-Butyl spiro[4.5]decan-4-yl)carbamate

参照中间体6中步骤2的方法，用(3S，4S)-8-(8-溴-7-氯咪唑并[1，2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺替代6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-1-(四氢-2H-吡喃-2-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮，得((3S，4S)-8-(8-溴-7-氯咪唑并[1，2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯。MS m/z[LC-MS]：500.11[M+1]。1HNMR(400MHz，DMSO-d6)：δ＝7.79(1H，d，J＝1.6Hz)，7.62(1H，d，J＝1.6Hz)，Following the procedure of Step 2 in Intermediate 6, using (3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine instead of 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane Alk-8-yl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4 -ketone to give ((3S,4S)-8-(8-bromo-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl-2-oxa-8-nitrogen tert-Butyl heterospiro[4.5]decan-4-yl)carbamate. MS m/z [LC-MS]: 500.11 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.79 (1H, d, J=1.6 Hz), 7.62 (1H, d, J=1.6 Hz),

中间体10：2-乙炔基-1，1-二氟环丙烷Intermediate 10:2-Ethynyl-1,1-difluorocyclopropane

Figure BSA0000197904800000171
Figure BSA0000197904800000171

2-乙炔基-1，1-二氟环丙烷按照专利WO2015066413中中间体3.1.35d的方法合成。2-Ethynyl-1,1-difluorocyclopropane was synthesized according to the method of intermediate 3.1.35d in patent WO2015066413.

中间体11：1-乙炔基-1-甲基环丙烷Intermediate 11:1-Ethynyl-1-methylcyclopropane

Figure BSA0000197904800000172
Figure BSA0000197904800000172

1-乙炔基-1-甲基环丙烷按照专利WO2011059784中实施例4的方法合成。1-Ethynyl-1-methylcyclopropane was synthesized according to the method of Example 4 in patent WO2011059784.

中间体12：(2-(2-氯-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷-2-基)苯基)乙炔基)三甲基硅烷Intermediate 12:(2-(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)acetylenebase) trimethylsilane

Figure BSA0000197904800000173
Figure BSA0000197904800000173

步骤1：(2-(3-溴-2-氯苯基)乙炔基)三甲基硅烷Step 1: (2-(3-Bromo-2-chlorophenyl)ethynyl)trimethylsilane

将1-溴-2-氯-3-碘苯(560mg)、乙炔基三甲基硅烷(196mg)、碘化亚铜(34mg)、二(三苯基膦)二氯化钯(121mg)和三乙胺(533mg)加入四氢呋喃(10mL)中，用高纯氮气置换反应体系中的空气三次，回流12小时，降至室温后，减压浓缩并用硅胶柱色谱分离(以正己烷为洗脱液)得(2-(3-溴-2-氯苯基)乙炔基)三甲基硅烷(424mg)。1HNMR(400MHz，CDCl3)：δ＝7.55(1H，m)，7.43(1H，m)，7.03(1H，m)，0.25(9H，m)。1-Bromo-2-chloro-3-iodobenzene (560 mg), ethynyltrimethylsilane (196 mg), cuprous iodide (34 mg), bis(triphenylphosphine)palladium dichloride (121 mg) and Triethylamine (533 mg) was added to tetrahydrofuran (10 mL), and the air in the reaction system was replaced with high-purity nitrogen three times, refluxed for 12 hours, cooled to room temperature, concentrated under reduced pressure, and separated by silica gel column chromatography (with n-hexane as the eluent). ) to give (2-(3-bromo-2-chlorophenyl)ethynyl)trimethylsilane (424 mg).1 H NMR (400 MHz, CDCl3 ): δ=7.55 (1H,m), 7.43 (1H,m), 7.03 (1H,m), 0.25 (9H,m).

步骤2：(2-(2-氯-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷-2-基)苯基)乙炔基)三甲基硅烷Step 2: (2-(2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)ethynyl) Trimethylsilane

将(2-(3-溴-2-氯苯基)乙炔基)三甲基硅烷(232mg)、联硼酸频哪醇酯(244mg)、(1，1′-双(二苯膦基)二茂铁)二氯化钯(56mg)和无水乙酸钾(157mg)加入二氧六环(2mL)中，用高纯氮气置换反应体系中的空气三次，加热至90℃反应12小时，反应混合物不经处理可直接进行下步偶联反应。MS m/z[LC-MS]：335.14[M+1]。(2-(3-Bromo-2-chlorophenyl)ethynyl)trimethylsilane (232mg), pinacol biboronate (244mg), (1,1'-bis(diphenylphosphino)bis Ferrocene) palladium dichloride (56 mg) and anhydrous potassium acetate (157 mg) were added to dioxane (2 mL), and the air in the reaction system was replaced with high-purity nitrogen three times, heated to 90 ° C for 12 hours, and the reaction mixture was The next step coupling reaction can be carried out directly without treatment. MS m/z [LC-MS]: 335.14 [M+1].

中间体13：5-(4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷-2-基)-3H-螺[苯并呋喃-2，1′-环丙烷]-3-酮Intermediate 13:5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)-3H-spiro[benzofuran-2,1' -Cyclopropane]-3-one

Figure BSA0000197904800000174
Figure BSA0000197904800000174

原料5-溴-3H-螺[苯并呋喃-2，1′-环丙烷]-3-酮参照文献Chemical andPharmaceutical Bulletin；vol.32；nb.9；(1984)；p.3532-3550合成。The raw material 5-bromo-3H-spiro[benzofuran-2,1'-cyclopropane]-3-one was synthesized with reference to the literature Chemical and Pharmaceutical Bulletin; vol. 32; nb. 9; (1984); p.3532-3550.

将5-溴-3H-螺[苯并呋喃-2，1′-环丙烷]-3-酮按照中间体12步骤2的方法进行反应得到相应硼酸酯，反应混合物不经处理可直接进行下步偶联反应。MS m/z[LC-MS]：287.15[M+1]。The 5-bromo-3H-spiro[benzofuran-2,1'-cyclopropane]-3-one is reacted according to the method of step 2 of intermediate 12 to obtain the corresponding boronate ester, and the reaction mixture can be directly carried out without treatment. step coupling reaction. MS m/z [LC-MS]: 287.15 [M+1].

中间体14：2-(3-氯-[1，1′-联苯]-4-基)-4，4，5，5-四甲基-1，3，2-二氧杂环戊硼烷Intermediate 14:2-(3-Chloro-[1,1'-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolanealkyl

Figure BSA0000197904800000181
Figure BSA0000197904800000181

原料4-溴-3-氯-1，1′-联苯按照文献Journal of the Chemical Society；(1964)；p.3786-3790合成。The starting material, 4-bromo-3-chloro-1,1'-biphenyl, was synthesized according to the literature Journal of the Chemical Society; (1964); p.3786-3790.

将4-溴-3-氯-1，1′-联苯按照中间体12步骤2的方法进行反应得到相应硼酸酯，反应混合物不经处理可直接进行下步偶联反应。MS m/z[LC-MS]：315.13[M+1]。The 4-bromo-3-chloro-1,1'-biphenyl is reacted according to the method of step 2 of intermediate 12 to obtain the corresponding boronate ester, and the reaction mixture can be directly subjected to the next step coupling reaction without treatment. MS m/z [LC-MS]: 315.13 [M+1].

实施例1：6-(4-氨基-4-甲基哌啶-1-基)-3-(2-(2-氯苯基)乙炔基)-5-甲基-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮Example 1:6-(4-Amino-4-methylpiperidin-1-yl)-3-(2-(2-chlorophenyl)ethynyl)-5-methyl-1H-pyrazolo[ 3,4-d]pyrimidin-4(5H)-one

Figure BSA0000197904800000182
Figure BSA0000197904800000182

步骤1：1-(3-(2-((2-氯苯基)乙炔基)-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯Step 1: 1-(3-(2-((2-Chlorophenyl)ethynyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4- d] pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester

将中间体5(150mg)、1-氯-2-乙炔基苯(50mg)、碘化亚铜(12mg)、三乙胺(100mg)、二(三苯基膦)二氯化钯(21mg)和四氢呋喃(10mL)加入封管中，氮气置换，加热至80℃搅拌过夜。冷却到室温，倒入水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱分离(石油醚∶乙酸乙酯，6∶1)得1-(3-((2-(2-氯苯基)乙炔基)-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(75mg)。MS m/z[LC-MS]：498.0[M+1]。Intermediate 5 (150 mg), 1-chloro-2-ethynylbenzene (50 mg), cuprous iodide (12 mg), triethylamine (100 mg), bis(triphenylphosphine)palladium dichloride (21 mg) and tetrahydrofuran (10 mL) were added to a sealed tube, replaced with nitrogen, heated to 80°C and stirred overnight. Cooled to room temperature, poured into water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether:ethyl acetate, 6: 1) to obtain 1-(3-((2-(2-chlorophenyl)ethynyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4- d] pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester (75 mg). MS m/z [LC-MS]: 498.0 [M+1].

步骤2：6-(4-氨基-4-甲基哌啶-1-基)-3-(2-(2-氯苯基)乙炔基)-5-甲基-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮Step 2: 6-(4-Amino-4-methylpiperidin-1-yl)-3-(2-(2-chlorophenyl)ethynyl)-5-methyl-1H-pyrazolo[3 , 4-d]pyrimidin-4(5H)-one

将1-(3-(2-((2-氯苯基)乙炔基)-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(70mg)加入4M氯化氢的二氧六环溶液(3mL)中，室温搅拌1小时，旋干，加入10％碳酸钠水溶液(10mL)，用二氯甲烷萃取，萃取液用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层硅胶色谱分离(二氯甲烷∶甲醇，10∶1)得6-(4-氨基-4-甲基哌啶-1-基)-3-(2-(2-氯苯基)乙炔基)-5-甲基-1H-吡唑并[3，4-d]嘧啶-4(5H)-酮(35mg)。MS m/z[LC-MS]：397.16[M+1]。1HNMR(400MHz，DMSO-d6)：δ＝7.70-8.40(3H，brs)，7.66(1H，dd，J＝8.0Hz，1.6Hz)，7.59(1H，d，J＝8.0Hz)，7.46(1H，td，J＝8.0Hz，1.6Hz)，7.41(1H，t，J＝8.0Hz)，3.36-3.46(5H，m)，3.08-3.16(2H，m)，1.83-1.91(2H，m)，1.72-1.80(2H，m)，1.34(3H，s)。1-(3-(2-((2-chlorophenyl)ethynyl)-5-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d] Pyrimidine-6-yl)-4-methylpiperidin-4-yl)carbamate tert-butyl ester (70 mg) was added to a 4M solution of hydrogen chloride in dioxane (3 mL), stirred at room temperature for 1 hour, spin-dried, added 10 % aqueous sodium carbonate solution (10 mL), extracted with dichloromethane, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by thin-layer silica gel chromatography (dichloromethane: methanol, 10: 1) to obtain 6- (4-Amino-4-methylpiperidin-1-yl)-3-(2-(2-chlorophenyl)ethynyl)-5-methyl-1H-pyrazolo[3,4-d] Pyrimidine-4(5H)-one (35 mg). MS m/z [LC-MS]: 397.16 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.70-8.40 (3H, brs), 7.66 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.59 (1H, d, J=8.0 Hz), 7.46 (1H, td, J=8.0Hz, 1.6Hz), 7.41 (1H, t, J=8.0Hz), 3.36-3.46 (5H, m), 3.08-3.16 (2H, m), 1.83-1.91 (2H, m), 1.72-1.80 (2H, m), 1.34 (3H, s).

实施例2：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2，4-二氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 2:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2,4 -Difluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000191
Figure BSA0000197904800000191

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：455.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.2-13.9(1H，brs)，7.69(1H，td，J＝8.4Hz，6.4Hz)，7.45(1H，td，J＝9.6Hz，2.8Hz)，7.19(1H，td，J＝8.4Hz，2.8Hz)，6.71-6.84(2H，brs)，4.13-4.17(1H，m)，3.79(1H，d，J＝8.8Hz)，3.59(1H，d，J＝8.8Hz)，3.34-3.48(6H，m)，2.85-2.96(2H，m)，1.82-1.91(2H，m)，1.66-1.73(1H，m)，1.56-1.62(1H，m)，1.17(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 455.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.2-13.9 (1H, brs), 7.69 (1H, td, J=8.4Hz, 6.4Hz), 7.45 (1H, td, J=9.6Hz, 2.8 Hz), 7.19 (1H, td, J=8.4Hz, 2.8Hz), 6.71-6.84 (2H, brs), 4.13-4.17 (1H, m), 3.79 (1H, d, J=8.8Hz), 3.59 ( 1H, d, J=8.8Hz), 3.34-3.48 (6H, m), 2.85-2.96 (2H, m), 1.82-1.91 (2H, m), 1.66-1.73 (1H, m), 1.56-1.62 ( 1H, m), 1.17 (3H, d, J=6.4 Hz).

实施例3：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氯苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 3:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2-chloro Phenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000192
Figure BSA0000197904800000192

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：453.18[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.66(1H，dd，J＝7.6Hz，2.0Hz)，7.59(1H，dd，J＝8.0Hz，1.6Hz)，7.46(1H，td，J＝7.6Hz，1.6Hz)，7.41(1H，td，J＝7.6Hz，1.6Hz)，6.71-6.84(3H，brs)，4.01-4.08(1H，m)，3.64(1H，d，J＝8.8Hz)，3.47(1H，d，J＝8.8Hz)，3.39(3H，s)，3.22-3.34(2H，m)，2.90-3.07(3H，m)，1.79-1.87(1H，m)，1.69-1.78(1H，m)，1.50-1.63(2H，m)，1.06(3H，d，J＝6.0Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 453.18 [M+1].1 H NMR (400MHz, DMSO-d6 ): δ=7.66 (1H, dd, J=7.6Hz, 2.0Hz), 7.59 (1H, dd, J=8.0Hz, 1.6Hz), 7.46 (1H, td, J=7.6Hz, 1.6Hz), 7.41 (1H, td, J=7.6Hz, 1.6Hz), 6.71-6.84 (3H, brs), 4.01-4.08 (1H, m), 3.64 (1H, d, J= 8.8Hz), 3.47 (1H, d, J=8.8Hz), 3.39 (3H, s), 3.22-3.34 (2H, m), 2.90-3.07 (3H, m), 1.79-1.87 (1H, m), 1.69-1.78 (1H, m), 1.50-1.63 (2H, m), 1.06 (3H, d, J=6.0 Hz).

实施例4：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3-氮苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 4:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((3-nitrogen Phenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000193
Figure BSA0000197904800000193

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：453.18[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.60(1H，t，J＝2.0Hz)，7.45-7.54(3H，m)，4.01-4.06(1H，m)，3.63(1H，d，J＝8.4Hz)，3.46(1H，d，J＝8.4Hz)，3.39(3H，s)，3.26-3.34(2H，m)，2.89-3.07(3H，m)，1.80-1.86(1H，m)，1.69-1.77(1H，m)，1.51-1.61(2H，m)，1.06(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 453.18 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.60 (1H, t, J=2.0 Hz), 7.45-7.54 (3H, m), 4.01-4.06 (1H, m), 3.63 (1H, d, J=8.4Hz), 3.46 (1H, d, J=8.4Hz), 3.39 (3H, s), 3.26-3.34 (2H, m), 2.89-3.07 (3H, m), 1.80-1.86 (1H, m) ), 1.69-1.77 (1H, m), 1.51-1.61 (2H, m), 1.06 (3H, d, J=6.4 Hz).

实施例5：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-甲氧基苯基)乙炔基)-5-甲基-1，5-二氧-4H-吡唑并[3，4-d]嘧啶-4-酮Example 5:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2-methyl oxyphenyl)ethynyl)-5-methyl-1,5-dioxo-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000201
Figure BSA0000197904800000201

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：449.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝12.80-13.80(1H，brs)，7.46(1H，dd，J＝7.6Hz，1.6Hz)，7.41(1H，td，J＝7.6Hz，1.6Hz)，7.09(1H，d，J＝8.4Hz)，6.98(1H，t，J＝7.6Hz)，4.01-4.08(1H，m)，3.84(3H，s)，3.64(1H，d，J＝8.8Hz)，3.47(1H，d，J＝8.8Hz)，3.38(3H，s)，3.26-3.34(2H，m)，2.88-3.05(3H，m)，1.79-1.88(1H，m)，1.69-1.76(1H，m)，1.50-1.62(2H，m)，1.07(3H，d，J＝6.0Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 449.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=12.80-13.80 (1H, brs), 7.46 (1H, dd, J=7.6Hz, 1.6Hz), 7.41 (1H, td, J=7.6Hz, 1.6 Hz), 7.09 (1H, d, J=8.4Hz), 6.98 (1H, t, J=7.6Hz), 4.01-4.08 (1H, m), 3.84 (3H, s), 3.64 (1H, d, J =8.8Hz), 3.47(1H,d,J=8.8Hz), 3.38(3H,s), 3.26-3.34(2H,m), 2.88-3.05(3H,m), 1.79-1.88(1H,m) , 1.69-1.76 (1H, m), 1.50-1.62 (2H, m), 1.07 (3H, d, J=6.0 Hz).

实施例6：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(苯基乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 6:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-(Phenylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000202
Figure BSA0000197904800000202

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：419.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.54-7.57(2H，m)，7.42-7.47(3H，m)，4.03-4.09(1H，m)，3.66(1H，d，J＝8.4Hz)，3.49(1H，d，J＝8.4Hz)，3.39(3H，s)，3.26-3.35(2H，m)，2.90-3.04(3H，m)，1.82-1.88(1H，m)，1.72-1.78(1H，m)，1.52-1.64(2H，m)，1.08(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 419.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.54-7.57 (2H,m), 7.42-7.47 (3H,m), 4.03-4.09 (1H,m), 3.66 (1H,d, J=8.4 Hz), 3.49 (1H, d, J=8.4Hz), 3.39 (3H, s), 3.26-3.35 (2H, m), 2.90-3.04 (3H, m), 1.82-1.88 (1H, m), 1.72 -1.78 (1H, m), 1.52-1.64 (2H, m), 1.08 (3H, d, J=6.8 Hz).

实施例7：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(((2-氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 7:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(((2- Fluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000203
Figure BSA0000197904800000203

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：437.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.62(1H，td，J＝7.6Hz，1.6Hz)，7.47-7.53(1H，m)，7.35(1H，t，J＝8.8Hz)，7.28(1H，t，J＝8.0Hz)，4.01-4.07(1H，m)，3.63(1H，d，J＝8.4Hz)，3.46(1H，d，J＝8.4Hz)，3.39(3H，s)，3.25-3.34(2H，m)，2.88-3.07(3H，m)，1.80-1.87(1H，m)，1.68-1.76(1H，m)，1.50-1.62(2H，m)，1.06(3H，d，J＝6.0Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 437.21 [M+1].1 H NMR (400MHz, DMSO-d6 ): δ=7.62 (1H, td, J=7.6Hz, 1.6Hz), 7.47-7.53 (1H, m), 7.35 (1H, t, J=8.8Hz), 7.28 (1H, t, J=8.0Hz), 4.01-4.07 (1H, m), 3.63 (1H, d, J=8.4Hz), 3.46 (1H, d, J=8.4Hz), 3.39 (3H, s) ), 3.25-3.34 (2H, m), 2.88-3.07 (3H, m), 1.80-1.87 (1H, m), 1.68-1.76 (1H, m), 1.50-1.62 (2H, m), 1.06 (3H , d, J=6.0 Hz).

实施例8：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3-氨基苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 8:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((3-amino Phenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000211
Figure BSA0000197904800000211

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：434.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.3-13.8(1H，brs)，7.05(1H，t，J＝8.0Hz)，6.73(1H，s)，6.65(1H，d，J＝7.6Hz)，6.61(1H，d，J＝7.6Hz)，5.30(2H，s)，4.08-4.16(1H，m)，3.75(1H，d，J＝8.8Hz)，3.54(1H，d，J＝8.8Hz)，3.39(3H，s)，3.26-3.37(3H，m)，2.88-2.98(2H，m)，1.80-1.90(2H，m)，1.56-1.70(2H，m)，1.14(3H，5.6Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 434.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.3-13.8 (1H, brs), 7.05 (1H, t, J=8.0 Hz), 6.73 (1H, s), 6.65 (1H, d, J=8.0 Hz) 7.6Hz), 6.61 (1H, d, J=7.6Hz), 5.30 (2H, s), 4.08-4.16 (1H, m), 3.75 (1H, d, J=8.8Hz), 3.54 (1H, d, J=8.8Hz), 3.39(3H,s), 3.26-3.37(3H,m), 2.88-2.98(2H,m), 1.80-1.90(2H,m), 1.56-1.70(2H,m), 1.14 (3H, 5.6Hz).

实施例9：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(吡啶-3-基乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 9:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-(Pyridin-3-ylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000212
Figure BSA0000197904800000212

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：420.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.71(1H，s)，8.74(1H，s)，8.62(1H，d，J＝4.8Hz)，7.96-8.04(3H，m)，7.49(1H，dd，J＝8.0hz，4.8Hz)，4.16-4.22(1H，m)，3.83(1H，d，J＝9.2Hz)，3.64(1H，d，J＝9.2Hz)，3.40-3.50(3H，m)，3.39(3H，s)，2.84-2.94(2H，m)，1.82-1.92(2H，m)，1.70-1.76(1H，m)，1.58-1.64(1H，m)，1.20(3H，d，J＝6.0Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 420.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.71 (1H,s), 8.74 (1H,s), 8.62 (1H,d, J=4.8Hz), 7.96-8.04 (3H,m), 7.49 (1H, dd, J=8.0hz, 4.8Hz), 4.16-4.22 (1H, m), 3.83 (1H, d, J=9.2Hz), 3.64 (1H, d, J=9.2Hz), 3.40-3.50 (3H, m), 3.39 (3H, s), 2.84-2.94 (2H, m), 1.82-1.92 (2H, m), 1.70-1.76 (1H, m), 1.58-1.64 (1H, m), 1.20 (3H, d, J=6.0 Hz).

实施例10：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(吡啶-4-基乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 10:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-(Pyridin-4-ylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000213
Figure BSA0000197904800000213

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：420.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.65(2H，d，J＝5.6Hz)，7.51(2H，d，J＝5.6Hz)，4.10-4.16(1H，m)，3.77(1H，d，J＝8.8Hz)，3.56(1H，d，J＝8.8Hz)，3.40(3H，s)，3.22-3.32(3H，m)，2.87-2.99(2H，m)，1.80-1.90(2H，m)，1.65-1.70(1H，m)，1.55-1.61(1H，m)，1.15(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 420.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.65 (2H, d, J=5.6 Hz), 7.51 (2H, d, J=5.6 Hz), 4.10-4.16 (1H, m), 3.77 (1H , d, J=8.8Hz), 3.56 (1H, d, J=8.8Hz), 3.40 (3H, s), 3.22-3.32 (3H, m), 2.87-2.99 (2H, m), 1.80-1.90 ( 2H, m), 1.65-1.70 (1H, m), 1.55-1.61 (1H, m), 1.15 (3H, d, J=6.4 Hz).

实施例11：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3，5-二甲氧基苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 11:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((3,5 -Dimethoxyphenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000221
Figure BSA0000197904800000221

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：479.24[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.48-13.80(1H，brs)，6.68(2H，s)，6.58(1H，s)，4.08-4.16(1H，m)，3.76(6H，s)，3.74(1H，d，J＝8.8Hz)，3.56(1H，d，J＝8.8Hz)，3.35-3.43(5H，m)，3.16-3.22(1H，m)，2.86-2.99(2H，m)，1.78-1.88(2H，m)，1.64-1.69(1H，m)，1.54-1.61(1H，m)，1.14(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 479.24 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.48-13.80 (1H, brs), 6.68 (2H, s), 6.58 (1H, s), 4.08-4.16 (1H, m), 3.76 (6H, s), 3.74 (1H, d, J=8.8Hz), 3.56 (1H, d, J=8.8Hz), 3.35-3.43 (5H, m), 3.16-3.22 (1H, m), 2.86-2.99 (2H) , m), 1.78-1.88 (2H, m), 1.64-1.69 (1H, m), 1.54-1.61 (1H, m), 1.14 (3H, d, J=6.4 Hz).

实施例12：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(3-羟基-3-甲基丁-1-炔-1-基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 12:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(3-hydroxy- 3-Methylbut-1-yn-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000222
Figure BSA0000197904800000222

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：401.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.36-13.48(1H，brs)，5.52(1H，s)，4.08-4.14(1H，m)，3.73(1H，d，J＝8.8Hz)，3.55(1H，d，J＝8.8Hz)，3.37(3H，s)，3.11-3.21(2H，m)，2.84-2.96(3H，m)，1.77-1.86(2H，m)，1.63-1.67(1H，m)，1.54-1.58(1H，m)，1.45(6H，s)，1.13(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 401.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.36-13.48 (1H, brs), 5.52 (1H, s), 4.08-4.14 (1H, m), 3.73 (1H, d, J=8.8 Hz) , 3.55 (1H, d, J=8.8Hz), 3.37 (3H, s), 3.11-3.21 (2H, m), 2.84-2.96 (3H, m), 1.77-1.86 (2H, m), 1.63-1.67 (1H,m), 1.54-1.58 (1H,m), 1.45 (6H,s), 1.13 (3H,d, J=6.4Hz).

实施例13：4-((6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-3-基)乙炔基)苯甲腈Example 13:4-((6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl yl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)benzonitrile

Figure BSA0000197904800000223
Figure BSA0000197904800000223

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：444.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.91(2H，d，J＝8.0Hz)，7.73(2H，d，J＝8.0Hz)，4.06-4.13(1H，m)，3.72(1H，d，J＝8.8Hz)，3.53(1H，d，J＝8.8Hz)，3.40(3H，s)，3.34-3.38(2H，m)，3.09-3.13(1H，m)，2.89-3.01(2H，m)，1.77-1.88(2H，m)，1.62-1.66(1H，m)，1.54-1.58(1H，m)，1.12(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 444.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.91 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.0 Hz), 4.06-4.13 (1H, m), 3.72 (1H , d, J=8.8Hz), 3.53 (1H, d, J=8.8Hz), 3.40 (3H, s), 3.34-3.38 (2H, m), 3.09-3.13 (1H, m), 2.89-3.01 ( 2H,m), 1.77-1.88 (2H,m), 1.62-1.66 (1H,m), 1.54-1.58 (1H,m), 1.12 (3H,d, J=6.8Hz).

实施例14：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((4-氯苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 14:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((4-chloro Phenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000231
Figure BSA0000197904800000231

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：453.18[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.57(2H，d，J＝8.0Hz)，7.51(2H，d，J＝8.0Hz)，4.08-4.14(1H，m)，3.74(1H，d，J＝8.8Hz)，3.54(1H，d，J＝8.8Hz)，3.39(3H，s)，3.34-3.38(2H，m)，3.15-3.18(1H，m)，2.87-2.99(2H，m)，1.79-1.89(2H，m)，1.63-1.67(1H，m)，1.55-1.59(1H，m)，1.14(3H，d，J＝6.0Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 453.18 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.57 (2H, d, J=8.0 Hz), 7.51 (2H, d, J=8.0 Hz), 4.08-4.14 (1H, m), 3.74 (1H , d, J=8.8Hz), 3.54 (1H, d, J=8.8Hz), 3.39 (3H, s), 3.34-3.38 (2H, m), 3.15-3.18 (1H, m), 2.87-2.99 ( 2H,m), 1.79-1.89 (2H,m), 1.63-1.67 (1H,m), 1.55-1.59 (1H,m), 1.14 (3H,d, J=6.0Hz).

实施例15：(3S，4S)-8-(3-((2-氯苯基)乙炔基)-1H-吡唑并[4，3-b]吡嗪-6基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 15:(3S,4S)-8-(3-((2-Chlorophenyl)ethynyl)-1H-pyrazolo[4,3-b]pyrazin-6yl)-3-methyl -2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000232
Figure BSA0000197904800000232

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：423.17[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.30(1H，s)，7.68(1H，dd，J＝7.2Hz，2.0Hz)，7.43(1H，d，J＝8.0Hz)，7.23-7.32(2H，m)，4.17-4.22(1H，m)，3.96-4.06(2H，m)，3.82(1H，d，J＝8.4Hz)，3.70(1H，d，J＝8.4Hz)，3.52-3.59(1H，m)，3.42-3.49(1H，m)，3.01(1H，d，J＝4.0Hz)，1.88-2.03(2H，m)，1.67-1.79(2H，m)，1.24(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 423.17 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.30 (1H, s), 7.68 (1H, dd, J=7.2Hz, 2.0Hz), 7.43 (1H, d, J=8.0Hz), 7.23- 7.32 (2H, m), 4.17-4.22 (1H, m), 3.96-4.06 (2H, m), 3.82 (1H, d, J=8.4Hz), 3.70 (1H, d, J=8.4Hz), 3.52 -3.59(1H,m), 3.42-3.49(1H,m), 3.01(1H,d, J=4.0Hz), 1.88-2.03(2H,m), 1.67-1.79(2H,m), 1.24(3H) , d, J=6.8 Hz).

实施例16：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(3-氨基-3-甲基丁-1-炔-1-基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 16:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(3-amino- 3-Methylbut-1-yn-1-yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000233
Figure BSA0000197904800000233

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：400.25[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.33-13.46(1H，brs)，4.08-4.14(1H，m)，3.73(1H，d，J＝8.8Hz)，3.55(1H，d，J＝8.8Hz)，3.37(3H，s)，3.11-3.21(2H，m)，2.85-2.96(3H，m)，1.76-1.86(2H，m)，1.63-1.67(1H，m)，1.54-1.59(1H，m)，1.43(6H，s)，1.14(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 400.25 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.33-13.46 (1H, brs), 4.08-4.14 (1H, m), 3.73 (1H, d, J=8.8 Hz), 3.55 (1H, d, J=8.8Hz), 3.37(3H,s), 3.11-3.21(2H,m), 2.85-2.96(3H,m), 1.76-1.86(2H,m), 1.63-1.67(1H,m), 1.54 -1.59 (1H, m), 1.43 (6H, s), 1.14 (3H, d, J=6.4 Hz).

实施例17：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-((噻吩-2-基)乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 17:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-((Thien-2-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000241
Figure BSA0000197904800000241

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：425.18[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.71(1H，dd，J＝5.2Hz，0.8Hz)，7.45(1H，dd，J＝3.6Hz，0.8Hz)，7.14(1H，dd，J＝5.2Hz，3.6Hz)，4.07-4.13(1H，m)，3.72(1H，d，J＝8.8Hz)，3.53(1H，d，J＝8.8Hz)，3.39(3H，s)，3.32-3.38(2H，m)，3.11(1H，d，J＝5.2Hz)，2.88-2.99(2H，m)，1.77-1.88(2H，m)，1.61-1.66(1H，m)，1.53-1.58(1H，m)，1.12(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 425.18 [M+1].1 H NMR (400MHz, DMSO-d6 ): δ=7.71 (1H, dd, J=5.2Hz, 0.8Hz), 7.45 (1H, dd, J=3.6Hz, 0.8Hz), 7.14 (1H, dd, J=5.2Hz, 3.6Hz), 4.07-4.13 (1H, m), 3.72 (1H, d, J=8.8Hz), 3.53 (1H, d, J=8.8Hz), 3.39 (3H, s), 3.32 -3.38(2H,m), 3.11(1H,d, J=5.2Hz), 2.88-2.99(2H,m), 1.77-1.88(2H,m), 1.61-1.66(1H,m), 1.53-1.58 (1H, m), 1.12 (3H, d, J=6.8 Hz).

实施例18：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氨基苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 18:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2-amino Phenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000242
Figure BSA0000197904800000242

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：434.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.21(1H，d，J＝8.0Hz)，7.09(1H，t，J＝8.0Hz)，6.71(1H，d，J＝8.4Hz)，6.51(1H，t，J＝7.2Hz)，6.01(2H，s)，4.41-4.46(1H，m)，4.12-4.20(1H，m)，3.82(1H，d，J＝8.4Hz)，3.58(1H，d，J＝8.4Hz)，3.45-3.49(1H，m)，3.42(3H，s)，3.13-3.15(1H，m)，2.85-2.95(2H，m)，1.84-1.98(2H，m)，1.66-1.72(2H，m)，1.58-1.63(2H，m)，1.19(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 434.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.21 (1H, d, J=8.0 Hz), 7.09 (1H, t, J=8.0 Hz), 6.71 (1H, d, J=8.4 Hz), 6.51 (1H, t, J=7.2Hz), 6.01 (2H, s), 4.41-4.46 (1H, m), 4.12-4.20 (1H, m), 3.82 (1H, d, J=8.4Hz), 3.58 (1H, d, J=8.4Hz), 3.45-3.49 (1H, m), 3.42 (3H, s), 3.13-3.15 (1H, m), 2.85-2.95 (2H, m), 1.84-1.98 (2H , m), 1.66-1.72 (2H, m), 1.58-1.63 (2H, m), 1.19 (3H, d, J=6.4 Hz).

实施例19：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(环丙基乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 19:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(cyclopropylacetylene yl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000243
Figure BSA0000197904800000243

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：383.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.20-13.58(1H，brs)，4.02-4.08(1H，m)，3.90-4.00(1H，m)，3.65(1H，d，J＝8.4Hz)，3.47(1H，d，J＝8.4Hz)，3.35(3H，s)，3.24-3.30(1H，m)，3.11-3.15(1H，m)，2.86-2.99(3H，m)，1.70-1.85(2H，m)，1.50-1.62(2H，m)，1.08(3H，d，J＝6.4Hz)，0.91-0.94(2H，m)，0.75-0.83(2H，m)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 383.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.20-13.58 (1H, brs), 4.02-4.08 (1H, m), 3.90-4.00 (1H, m), 3.65 (1H, d, J=8.4 Hz), 3.47 (1H, d, J=8.4Hz), 3.35 (3H, s), 3.24-3.30 (1H, m), 3.11-3.15 (1H, m), 2.86-2.99 (3H, m), 1.70 -1.85 (2H, m), 1.50-1.62 (2H, m), 1.08 (3H, d, J=6.4 Hz), 0.91-0.94 (2H, m), 0.75-0.83 (2H, m).

实施例20：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((3-氨基-4-氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 20:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((3-amino -4-Fluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000251
Figure BSA0000197904800000251

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：452.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.07(1H，d，J＝8.0Hz)，6.94-6.99(1H，m)，6.87-6.91(1H，m)，4.26-4.32(1H，m)，3.93(1H，d，J＝8.0Hz)，3.82(1H，d，J＝8.4Hz)，3.47-3.58(5H，m)，3.39-3.42(1H，m)，2.96-3.08(2H，m)，1.86-2.02(3H，m)，1.71-1.75(1H，m)，1.30(3H，d，J＝7.2Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 452.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.07 (1H, d, J=8.0 Hz), 6.94-6.99 (1H, m), 6.87-6.91 (1H, m), 4.26-4.32 (1H, m), 3.93 (1H, d, J=8.0Hz), 3.82 (1H, d, J=8.4Hz), 3.47-3.58 (5H, m), 3.39-3.42 (1H, m), 2.96-3.08 (2H) , m), 1.86-2.02 (3H, m), 1.71-1.75 (1H, m), 1.30 (3H, d, J=7.2 Hz).

实施例21：2-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氰基苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 21:2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2-cyano ylphenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000252
Figure BSA0000197904800000252

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：444.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.75(1H，d，J＝8.0Hz)，7.63-7.68(1H，m)，7.51-7.58(1H，m)，7.45(1H，m)，4.14-4.20(1H，m)，3.81(1H，d，J＝8.8Hz)，3.68(1H，d，J＝8.8Hz)，3.53(3H，s)，3.30-3.43(2H，m)，2.94-3.16(3H，m)，1.52-1.86(4H，m)，0.86(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 444.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.75 (1H, d, J=8.0 Hz), 7.63-7.68 (1H, m), 7.51-7.58 (1H, m), 7.45 (1H, m) , 4.14-4.20 (1H, m), 3.81 (1H, d, J=8.8Hz), 3.68 (1H, d, J=8.8Hz), 3.53 (3H, s), 3.30-3.43 (2H, m), 2.94-3.16 (3H, m), 1.52-1.86 (4H, m), 0.86 (3H, d, J=6.4 Hz).

实施例22：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-((2-(三氟甲基)苯基)乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 22:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-((2-(trifluoromethyl)phenyl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000253
Figure BSA0000197904800000253

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：487.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.82(1H，d，J＝7.6Hz)，7.68(1H，d，J＝8.4Hz)，7.52(1H，m)，7.44(1H，m)，4.13-4.19(1H，m)，3.79(1H，d，J＝8.8Hz)，3.67(1H，d，J＝8.8Hz)，3.53(3H，s)，3.31-3.41(2H，m)，2.98-3.16(3H，m)，1.46-1.90(4H，m)，0.95(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 487.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.82 (1H, d, J=7.6 Hz), 7.68 (1H, d, J=8.4 Hz), 7.52 (1H, m), 7.44 (1H, m ), 4.13-4.19 (1H, m), 3.79 (1H, d, J=8.8Hz), 3.67 (1H, d, J=8.8Hz), 3.53 (3H, s), 3.31-3.41 (2H, m) , 2.98-3.16 (3H, m), 1.46-1.90 (4H, m), 0.95 (3H, d, J=6.8 Hz).

实施例23：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2，6-二氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 23:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2,6 -Difluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000261
Figure BSA0000197904800000261

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：455.2[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.51-7.59(1H，m)，7.22-7.27(2H，m)，4.04-4.11(1H，m)，3.69(1H，d，J＝8.4Hz)，3.51(1H，d，J＝8.8Hz)，3.38(3H，s)，3.32-3.6(1H，m)，3.11-3.15(1H，m)，3.05-3.08(1H，m)，2.88-3.01(2H，m)，1.73-1.86(2H，m)，1.60-1.66(1H，m)，1.52-1.58(1H，m)，1.10(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 455.2 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.51-7.59 (1H, m), 7.22-7.27 (2H, m), 4.04-4.11 (1H, m), 3.69 (1H, d, J=8.4 Hz), 3.51 (1H, d, J=8.8Hz), 3.38 (3H, s), 3.32-3.6 (1H, m), 3.11-3.15 (1H, m), 3.05-3.08 (1H, m), 2.88 -3.01(2H,m), 1.73-1.86(2H,m), 1.60-1.66(1H,m), 1.52-1.58(1H,m), 1.10(3H,d, J=6.4Hz).

实施例24：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(丙-1-炔-1-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 24:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-(Prop-1-yn-1-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000262
Figure BSA0000197904800000262

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：357.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.12-13.58(1H，brs)，4.02-4.08(1H，m)，3.65(1H，d，J＝8.4Hz)，3.47(1H，d，J＝8.4Hz)，3.35(3H，s)，3.24-3.30(1H，m)，3.11-3.15(1H，m)，2.86-2.99(3H，m)，2.05(3H，s)，1.70-1.85(2H，m)，1.50-1.62(2H，m)，1.07(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 357.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.12-13.58 (1H, brs), 4.02-4.08 (1H, m), 3.65 (1H, d, J=8.4 Hz), 3.47 (1H, d, J=8.4Hz), 3.35(3H,s), 3.24-3.30(1H,m), 3.11-3.15(1H,m), 2.86-2.99(3H,m), 2.05(3H,s), 1.70-1.85 (2H, m), 1.50-1.62 (2H, m), 1.07 (3H, d, J=6.4 Hz).

实施例25：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(咪唑并[1，2-b]哒嗪-3-基乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 25:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(imidazo[1 , 2-b]pyridazin-3-ylethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000263
Figure BSA0000197904800000263

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：460.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.66-1.84(1H，brs)，8.67(1H，dd，J＝4.8Hz，2.4Hz)，8.24(1H，dd，J＝8.8Hz，1.6Hz)，8.19(1H，s)，7.37(1H，dd，J＝8.8Hz，4.8Hz)，4.40-4.43(1H，m)，4.16-4.20(1H，m)，3.83(1H，d，J＝8.8Hz)，3.62(1H，d，J＝8.8Hz)，3.43-3.50(1H，m)，3.39(3H，s)，3.34-3.36(1H，m)，2.85-2.94(2H，m)，1.85-1.94(2H，m)，1.70-1.73(1H，m)，1.58-1.62(1H，m)，1.19(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 460.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.66-1.84 (1H, brs), 8.67 (1H, dd, J=4.8Hz, 2.4Hz), 8.24 (1H, dd, J=8.8Hz, 1.6 Hz), 8.19 (1H, s), 7.37 (1H, dd, J=8.8Hz, 4.8Hz), 4.40-4.43 (1H, m), 4.16-4.20 (1H, m), 3.83 (1H, d, J) =8.8Hz), 3.62(1H,d,J=8.8Hz), 3.43-3.50(1H,m), 3.39(3H,s), 3.34-3.36(1H,m), 2.85-2.94(2H,m) , 1.85-1.94 (2H, m), 1.70-1.73 (1H, m), 1.58-1.62 (1H, m), 1.19 (3H, d, J=6.4 Hz).

实施例26：(3S，4S)-8-(9-((2-氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 26:(3S,4S)-8-(9-((2-Fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine- 5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000271
Figure BSA0000197904800000271

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：446.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.71(1H，m)，7.68(1H，t，J＝8.0Hz)，7.50-7.55(2H，m)，7.37(1H，t，J＝8.0Hz)，7.31(1H，t，J＝8.0Hz)，4.11-4.16(1H，m)，3.76(1H，d，J＝8.0Hz)，3.58-3.64(2H，m)，3.14-3.32(4H，m)，1.89-1.99(2H，m)，1.72-1.77(1H，m)，1.62-1.68(1H，m)，1.14(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 446.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.71 (1H, m), 7.68 (1H, t, J=8.0 Hz), 7.50-7.55 (2H, m), 7.37 (1H, t, J=8.0 Hz) 8.0Hz), 7.31 (1H, t, J=8.0Hz), 4.11-4.16 (1H, m), 3.76 (1H, d, J=8.0Hz), 3.58-3.64 (2H, m), 3.14-3.32 ( 4H, m), 1.89-1.99 (2H, m), 1.72-1.77 (1H, m), 1.62-1.68 (1H, m), 1.14 (3H, d, J=6.8 Hz).

实施例27：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-乙炔基-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 27:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-ethynyl -5-Methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000272
Figure BSA0000197904800000272

步骤1：((3S，4S)-3-甲基-8-(5-甲基-4-氧代-3-((三甲基硅基)乙炔基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 1: ((3S,4S)-3-methyl-8-(5-methyl-4-oxo-3-((trimethylsilyl)ethynyl)-4,5-dihydro-1H -pyrazolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate tert-butyl ester

参照实施例1中步骤1的方法，用中间体6代替中间体5，三甲基硅基乙炔代替1-氯-2-乙炔基苯，得到目标化合物。MS m/z[LC-MS]：515.28[M+1]。Referring to the method of step 1 in Example 1, using intermediate 6 instead of intermediate 5 and trimethylsilylacetylene instead of 1-chloro-2-ethynylbenzene, the target compound was obtained. MS m/z [LC-MS]: 515.28 [M+1].

步骤2：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-乙炔基-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Step 2: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-ethynyl-5-methyl yl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

将((3S，4S)-3-甲基-8-(5-甲基-4-氧代-3-((三甲基硅基)乙炔基)-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(40mg)溶于二氯甲烷(1mL)，加入1M四丁基氟化铵的四氢呋喃溶液(0.5mL)，室温搅拌0.5小时。再加入4M氯化氢的二氧六环溶液(3mL)，室温搅拌1小时，旋干，加入10％碳酸钠水溶液(10mL)，用二氯甲烷萃取，萃取液用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层硅胶色谱分离得，得到目标化合物(15mg)。MS m/z[LC-MS]：343.19[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.29-13.74(1H，brs)，4.35(1H，s)，4.05-4.12(1H，m)，3.70(1H，d，J＝8.8Hz)，3.52(1H，d，J＝8.8Hz)，3.36(3H，s)，3.22-3.35(2H，m)，3.08-3.12(1H，m)，2.86-2.98(2H，m)，1.74-1.88(2H，m)，1.60-1.64(1H，m)，1.52-1.56(1H，m)，1.11(3H，d，J＝6.0Hz)。((3S,4S)-3-methyl-8-(5-methyl-4-oxo-3-((trimethylsilyl)ethynyl)-4,5-dihydro-1H-pyridine tert-butyl azolo[3,4-d]pyrimidin-6-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (40 mg) was dissolved in dichloromethane ( 1 mL), a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.5 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. Then add 4M hydrogen chloride solution in dioxane (3 mL), stir at room temperature for 1 hour, spin dry, add 10% sodium carbonate aqueous solution (10 mL), extract with dichloromethane, the extract is dried with anhydrous sodium sulfate, filtered, and the filtrate It was concentrated under reduced pressure and separated by thin-layer silica gel chromatography to obtain the title compound (15 mg). MS m/z [LC-MS]: 343.19 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.29-13.74 (1H, brs), 4.35 (1H, s), 4.05-4.12 (1H, m), 3.70 (1H, d, J=8.8 Hz) , 3.52 (1H, d, J=8.8Hz), 3.36 (3H, s), 3.22-3.35 (2H, m), 3.08-3.12 (1H, m), 2.86-2.98 (2H, m), 1.74-1.88 (2H,m), 1.60-1.64 (1H,m), 1.52-1.56 (1H,m), 1.11 (3H,d, J=6.0Hz).

实施例28：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(3，3，3-三氟丙-1-炔-1-基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 28:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-(3,3,3-Trifluoroprop-1-yn-1-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000273
Figure BSA0000197904800000273

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：452.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝4.06-4.12(1H，m)，3.71(1H，d，J＝8.8Hz)，3.52(1H，d，J＝8.8Hz)，3.38(3H，s)，3.24-3.36(2H，m)，3.10-3.14(1H，m)，2.89-3.01(2H，m)，1.76-1.86(2H，m)，1.61-1.65(1H，m)，1.53-1.57(1H，m)，1.11(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 452.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=4.06-4.12 (1H, m), 3.71 (1H, d, J=8.8Hz), 3.52 (1H, d, J=8.8Hz), 3.38 (3H) , s), 3.24-3.36 (2H, m), 3.10-3.14 (1H, m), 2.89-3.01 (2H, m), 1.76-1.86 (2H, m), 1.61-1.65 (1H, m), 1.53 -1.57 (1H, m), 1.11 (3H, d, J=6.4 Hz).

实施例29：(3S，4S)-8-(8-((3-氨基苯基)乙炔基)-7-氯咪唑并[1，2-c]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 29:(3S,4S)-8-(8-((3-aminophenyl)ethynyl)-7-chloroimidazo[1,2-c]pyrimidin-5-yl)-3-methyl -2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000281
Figure BSA0000197904800000281

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：437.19[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.75(1H，d，J＝1.6Hz)，7.59(1H，d，J＝1.6Hz)，7.10(1H，t，J＝8.0Hz)，6.98(1H，t，J＝1.6Hz)，6.95(1H，d，J＝7.6Hz)，6.73(1H，dd，J＝8.0Hz，1.6Hz)，4.56(1H，s)，4.23-4.29(1H，m)，3.84-3.93(3H，m)，3.79(1H，d，J＝9.2Hz)，3.35-3.39(1H，m)，3.23(1H，d，J＝4.8Hz)，1.94-2.05(2H，m)，1.83-1.87(1H，m)，1.74-1.78(1H，m)，1.26(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 437.19 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.75 (1H, d, J=1.6 Hz), 7.59 (1H, d, J=1.6 Hz), 7.10 (1H, t, J=8.0 Hz), 6.98 (1H, t, J=1.6Hz), 6.95 (1H, d, J=7.6Hz), 6.73 (1H, dd, J=8.0Hz, 1.6Hz), 4.56 (1H, s), 4.23-4.29 ( 1H, m), 3.84-3.93 (3H, m), 3.79 (1H, d, J=9.2Hz), 3.35-3.39 (1H, m), 3.23 (1H, d, J=4.8Hz), 1.94-2.05 (2H, m), 1.83-1.87 (1H, m), 1.74-1.78 (1H, m), 1.26 (3H, d, J=6.4 Hz).

实施例30：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氨基吡啶-3-基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 30:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2-amino Pyridin-3-yl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000282
Figure BSA0000197904800000282

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：435.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.97(1H，d，J＝5.2Hz)，7.60(1H，dd，J＝7.6Hz，2.0Hz)，6.73(2H，s)，6.55(1H，dd，J＝7.6Hz，5.2Hz)，4.09-4.16(1H，m)，3.77(1H，d，J＝8.8Hz)，3.55(1H，d，J＝8.8Hz)，3.41(3H，s)，3.22-3.39(2H，m)，2.86-2.97(3H，m)，1.82-1.92(2H，m)，1.65-1.68(1H，m)，1.56-1.61(1H，m)，1.15(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 435.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.97 (1H, d, J=5.2 Hz), 7.60 (1H, dd, J=7.6 Hz, 2.0 Hz), 6.73 (2H, s), 6.55 ( 1H, dd, J=7.6Hz, 5.2Hz), 4.09-4.16 (1H, m), 3.77 (1H, d, J=8.8Hz), 3.55 (1H, d, J=8.8Hz), 3.41 (3H, s), 3.22-3.39 (2H, m), 2.86-2.97 (3H, m), 1.82-1.92 (2H, m), 1.65-1.68 (1H, m), 1.56-1.61 (1H, m), 1.15 ( 3H, d, J = 6.8 Hz).

实施例31：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((1-羟基环丙基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 31:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((1-hydroxy Cyclopropyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000283
Figure BSA0000197904800000283

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：399.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.38-13.54(1H，brs)，6.35(1H，s)，4.05-4.11(1H，m)，3.68(1H，d，J＝9.2Hz)，3.51(1H，d，J＝8.4Hz)，3.35(3H，s)，3.17-3.32(2H，m)，3.02-3.08(1H，m)，2.84-2.98(2H，m)，1.72-1.84(2H，m)，1.59-1.64(1H，m)，1.51-1.56(1H，m)，1.09(3H，d，J＝6.0Hz)，0.97-0.99(2H，m)，0.85-0.93(2H，m)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 399.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.38-13.54 (1H, brs), 6.35 (1H, s), 4.05-4.11 (1H, m), 3.68 (1H, d, J=9.2 Hz) , 3.51 (1H, d, J=8.4Hz), 3.35 (3H, s), 3.17-3.32 (2H, m), 3.02-3.08 (1H, m), 2.84-2.98 (2H, m), 1.72-1.84 (2H, m), 1.59-1.64 (1H, m), 1.51-1.56 (1H, m), 1.09 (3H, d, J=6.0Hz), 0.97-0.99 (2H, m), 0.85-0.93 (2H , m).

实施例32：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-((1-甲基-1H-咪唑-4-基)乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 32:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-((1-Methyl-1H-imidazol-4-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000291
Figure BSA0000197904800000291

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：423.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.54(1H，s)，7.69(1H，s)，7.58(1H，s)，4.15-4.20(1H，m)，3.82(1H，d，J＝8.8Hz)，3.66(3H，s)，3.63(1H，d，J＝8.8Hz)，3.36-3.47(5H，m)，2.82-2.93(3H，m)，1.82-1.92(2H，m)，1.70-1.74(1H，m)，1.57-1.60(1H，m)，1.19(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 423.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.54 (1H,s), 7.69 (1H,s), 7.58 (1H,s), 4.15-4.20 (1H,m), 3.82 (1H,d, J=8.8Hz), 3.66 (3H, s), 3.63 (1H, d, J=8.8Hz), 3.36-3.47 (5H, m), 2.82-2.93 (3H, m), 1.82-1.92 (2H, m) ), 1.70-1.74 (1H, m), 1.57-1.60 (1H, m), 1.19 (3H, d, J=6.8 Hz).

实施例33：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-(吡啶-2-基乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 33:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-(Pyridin-2-ylethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000292
Figure BSA0000197904800000292

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物.MS m/z[LC-MS]：420.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝12.92-13.88(1H，brs)，8.61(1H，d，J＝5.2Hz)，7.86(1H，td，J＝8.0Hz，1.6Hz)，7.62(1H，d，J＝7.6Hz)，7.43(1H，dd，J＝7.6Hz，5.2Hz)，4.04-4.10(1H，m)，3.68(1H，d，J＝8.8Hz)，3.51(1H，d，J＝8.8Hz)，3.36-3.42(5H，m)，2.89-3.06(3H，m)，1.72-1.84(2H，m)，1.60-1.64(1H，m)，1.52-1.56(1H，m)，1.09(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 420.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=12.92-13.88 (1H, brs), 8.61 (1H, d, J=5.2Hz), 7.86 (1H, td, J=8.0Hz, 1.6Hz), 7.62 (1H, d, J=7.6Hz), 7.43 (1H, dd, J=7.6Hz, 5.2Hz), 4.04-4.10 (1H, m), 3.68 (1H, d, J=8.8Hz), 3.51 ( 1H, d, J=8.8Hz), 3.36-3.42 (5H, m), 2.89-3.06 (3H, m), 1.72-1.84 (2H, m), 1.60-1.64 (1H, m), 1.52-1.56 ( 1H, m), 1.09 (3H, d, J=6.4 Hz).

实施例34：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-((1-甲基-1H-吡唑-4-基)乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 34:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-((1-Methyl-1H-pyrazol-4-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000293
Figure BSA0000197904800000293

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：423.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.22-1.82(1H，brs)，7.85(1H，s)，7.70(1H，s)，4.04-4.10(1H，m)，3.85(3H，s)，3.68(1H，d，J＝8.8Hz)，3.51(1H，d，J＝8.8Hz)，3.32-3.42(5H，m)，2.88-3.04(3H，m)，1.72-1.86(2H，m)，1.60-1.64(1H，m)，1.52-1.56(1H，m)，1.09(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 423.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.22-1.82 (1H, brs), 7.85 (1H, s), 7.70 (1H, s), 4.04-4.10 (1H, m), 3.85 (3H, s), 3.68 (1H, d, J=8.8Hz), 3.51 (1H, d, J=8.8Hz), 3.32-3.42 (5H, m), 2.88-3.04 (3H, m), 1.72-1.86 (2H) , m), 1.60-1.64 (1H, m), 1.52-1.56 (1H, m), 1.09 (3H, d, J=6.4 Hz).

实施例35：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-5-甲基-3-((1-甲基-1H-吡唑-3-基)乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 35:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methyl- 3-((1-Methyl-1H-pyrazol-3-yl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000301
Figure BSA0000197904800000301

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：423.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.22-1.82(1H，brs)，7.78(1H，d，J＝2.4Hz)，6.52(1H，d，J＝2.4Hz)，4.04-4.10(1H，m)，3.85(3H，s)，3.68(1H，d，J＝8.8Hz)，3.51(1H，d，J＝8.8Hz)，3.32-3.42(5H，m)，2.88-3.04(3H，m)，1.72-1.86(2H，m)，1.60-1.64(1H，m)，1.52-1.56(1H，m)，1.09(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 423.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.22-1.82 (1H, brs), 7.78 (1H, d, J=2.4Hz), 6.52 (1H, d, J=2.4Hz), 4.04-4.10 (1H, m), 3.85 (3H, s), 3.68 (1H, d, J=8.8Hz), 3.51 (1H, d, J=8.8Hz), 3.32-3.42 (5H, m), 2.88-3.04 ( 3H,m), 1.72-1.86 (2H,m), 1.60-1.64 (1H,m), 1.52-1.56 (1H,m), 1.09 (3H,d, J=6.4Hz).

实施例36：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2-氯-3-乙炔基苯基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 36:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(2-chloro- 3-Ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000302
Figure BSA0000197904800000302

步骤1：((3S，4S)-8-(3-(2-氯-3-((三甲基硅基)乙炔基)苯基)-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯Step 1: ((3S,4S)-8-(3-(2-chloro-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-4-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

将中间体6(160mg)、含中间体12的反应液(0.8mL)、四(三苯基膦)钯(18mg)、磷酸钾(185mg)加入二氧六环和水的混合溶剂(10∶1，5mL)中，用氮气置换反应体系中的空气三次，加热至80℃搅拌过夜。冷却到室温，倒入水中，用二氯甲烷萃取，萃取液用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱分离(石油醚∶乙酸乙酯，3∶1)得((3S，4S)-8-(3-(2-氯-3-((三甲基硅基)乙炔基)苯基)-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(80mg)。MS m/z[LC-MS]：625.27[M+1]。Intermediate 6 (160 mg), the reaction solution containing intermediate 12 (0.8 mL), tetrakis(triphenylphosphine)palladium (18 mg), and potassium phosphate (185 mg) were added to a mixed solvent of dioxane and water (10: 1, 5 mL), replaced the air in the reaction system with nitrogen three times, heated to 80 °C and stirred overnight. Cooled to room temperature, poured into water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate, 3: 1) get ((3S,4S)-8-(3-(2-chloro-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-4-oxo-4,5 -Dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-Butyl ester (80 mg). MS m/z [LC-MS]: 625.27 [M+1].

步骤2：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2-氯-3-乙炔基苯基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Step 2: 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(2-chloro-3 -Ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

将((3S，4S)-8-(3-(2-氯-3-((三甲基硅基)乙炔基)苯基)-5-甲基-4-氧代-4，5-二氢-1H-吡唑并[3，4-d]嘧啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-基)氨基甲酸叔丁酯(80mg)加入4M氯化氢的二氧六环溶液(3mL)中，室温搅拌1小时，旋干，加入10％碳酸钠水溶液(10mL)，用二氯甲烷萃取，萃取液用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层硅胶色谱分离(二氯甲烷∶甲醇，10∶1)得6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2-氯-3-乙炔基苯基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮(38mg)。MS m/z[LC-MS]：453.18[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.70(1H，d，J＝8.0Hz)，7.49(1H，d，J＝7.6Hz)，7.34-7.40(1H，m)，4.25-4.32(1H，m)，3.94(1H，d，J＝10.4Hz)，3.83(1H，d，J＝10.4Hz)，3.71-3.73(1H，m)，3.46-3.68(6H，m)，2.94-3.09(2H，m)，1.87-2.05(2H，m)，1.70-1.77(1H，m)，1.56-1.62(1H，m)，1.29(3H，d，J＝7.6Hz)。((3S,4S)-8-(3-(2-chloro-3-((trimethylsilyl)ethynyl)phenyl)-5-methyl-4-oxo-4,5-di Hydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl The ester (80 mg) was added to a 4M solution of hydrogen chloride in dioxane (3 mL), stirred at room temperature for 1 hour, spin-dried, added with 10% aqueous sodium carbonate solution (10 mL), extracted with dichloromethane, and the extract was dried with anhydrous sodium sulfate , filtered, the filtrate was concentrated under reduced pressure, and separated by thin-layer silica gel chromatography (dichloromethane: methanol, 10:1) to obtain 6-((3S,4S)-4-amino-3-methyl-2-oxa-8 -Azaspiro[4.5]decan-8-yl)-3-(2-chloro-3-ethynylphenyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one (38 mg). MS m/z [LC-MS]: 453.18 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.70 (1H, d, J=8.0 Hz), 7.49 (1H, d, J=7.6 Hz), 7.34-7.40 (1H, m), 4.25-4.32 ( 1H, m), 3.94 (1H, d, J=10.4Hz), 3.83 (1H, d, J=10.4Hz), 3.71-3.73 (1H, m), 3.46-3.68 (6H, m), 2.94-3.09 (2H,m), 1.87-2.05 (2H,m), 1.70-1.77 (1H,m), 1.56-1.62 (1H,m), 1.29 (3H,d, J=7.6Hz).

实施例37：6-(4-氨基-4-甲基哌啶-1-基)-3-((2-氟-3，5-二甲氧基苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 37:6-(4-Amino-4-methylpiperidin-1-yl)-3-((2-fluoro-3,5-dimethoxyphenyl)ethynyl)-5-methyl -1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000311
Figure BSA0000197904800000311

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：441.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.21-13.90(1H，brs)，8.22(2H，s)，6.81(1H，dd，J＝7.2Hz，2.8Hz)，6.60(1H，dd，J＝4.4Hz，2.8Hz)，3.84(3H，s)，3.76(3H，s)，3.38-3.46(2H，m)，3.37(3H，s)，3.07-3.14(2H，m)，1.86-1.95(2H，m)，1.73-1.82(2H，m)，1.35(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 441.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.21-13.90 (1H, brs), 8.22 (2H, s), 6.81 (1H, dd, J=7.2 Hz, 2.8 Hz), 6.60 (1H, dd , J=4.4Hz, 2.8Hz), 3.84 (3H, s), 3.76 (3H, s), 3.38-3.46 (2H, m), 3.37 (3H, s), 3.07-3.14 (2H, m), 1.86 -1.95 (2H, m), 1.73-1.82 (2H, m), 1.35 (3H, s).

实施例38：6-(4-氨基-4-甲基哌啶-1-基)-3-((2，5-二氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 38:6-(4-Amino-4-methylpiperidin-1-yl)-3-((2,5-difluorophenyl)ethynyl)-5-methyl-1,5-di Hydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000312
Figure BSA0000197904800000312

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：399.18[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.63-13.90(1H，brs)，8.13(2H，s)，7.47-7.51(1H，m)，7.34-7.44(2H，m)，3.41-3.44(2H，m)，3.37(3H，s)，3.08-3.14(2H，m)，1.85-1.92(2H，m)，1.73-1.79(2H，m)，1.35(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 399.18 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.63-13.90 (1H, brs), 8.13 (2H, s), 7.47-7.51 (1H, m), 7.34-7.44 (2H, m), 3.41- 3.44 (2H, m), 3.37 (3H, s), 3.08-3.14 (2H, m), 1.85-1.92 (2H, m), 1.73-1.79 (2H, m), 1.35 (3H, s).

实施例39：(S)-1-(4-(9-(2，3-二氯苯基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-1H-吡唑-1-基)丙烷-2-胺Example 39:(S)-1-(4-(9-(2,3-dichlorophenyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine-5-yl)-1H-pyrazol-1-yl)propan-2-amine

Figure BSA0000197904800000313
Figure BSA0000197904800000313

参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：427.10[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.78-8.92(1H，brs)，8.28-8.42(1H，brs)，8.24(1H，s)，7.77(1H，dd，J＝8.0Hz，1.6Hz)，7.69(1H，dd，J＝7.6Hz，1.6Hz)，7.48-7.51(2H，m)，4.22-4.54(2H，m)，3.50-3.85(1H，m)，1.02-1.32(3H，m)。Referring to the method in Example 36, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 427.10 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.78-8.92 (1H, brs), 8.28-8.42 (1H, brs), 8.24 (1H, s), 7.77 (1H, dd, J=8.0 Hz, 1.6Hz), 7.69 (1H, dd, J=7.6Hz, 1.6Hz), 7.48-7.51 (2H, m), 4.22-4.54 (2H, m), 3.50-3.85 (1H, m), 1.02-1.32 ( 3H, m).

实施例40：3-((1H-吡唑-4-基)乙炔基)-6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 40:3-((1H-pyrazol-4-yl)ethynyl)-6-(4-amino-4-methylpiperidin-1-yl)-5-methyl-1,5-di Hydro-4H-pyrazolo[3,4-d ]pyrimidin-4-one

Figure BSA0000197904800000321
Figure BSA0000197904800000321

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：353.19[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.19-13.86(1H，brs)，8.23(2H，s)，7.94(2H，s)，3.37-3.44(2H，m)，3.35(3H，s)，3.05-3.13(2H，m)，1.86-1.94(2H，m)，1.72-7.8(2H，m)，1.34(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 353.19 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.19-13.86 (1H, brs), 8.23 (2H, s), 7.94 (2H, s), 3.37-3.44 (2H, m), 3.35 (3H, s), 3.05-3.13 (2H, m), 1.86-1.94 (2H, m), 1.72-7.8 (2H, m), 1.34 (3H, s).

实施例41：6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-3-(嘧啶-5-基乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 41:6-(4-Amino-4-methylpiperidin-1-yl)-5-methyl-3-(pyrimidin-5-ylethynyl)-1,5-dihydro- 4H-pyridineazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000322
Figure BSA0000197904800000322

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：365.18[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.61-13.94(1H，brs)，9.22(1H，s)，8.99(2H，s)，7.78-8.22(2H，brs)，3.39-3.46(2H，m)，3.38(3H，s)，3.08-3.15(2H，m)，1.83-1.91(2H，m)，1.72-1.79(2H，m)，1.34(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 365.18 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.61-13.94 (1H, brs), 9.22 (1H, s), 8.99 (2H, s), 7.78-8.22 (2H, brs), 3.39-3.46 ( 2H, m), 3.38 (3H, s), 3.08-3.15 (2H, m), 1.83-1.91 (2H, m), 1.72-1.79 (2H, m), 1.34 (3H, s).

实施例42：6-(4-氨基-4-甲基哌啶-1-基)-3-((3，5-二(三氟甲基)苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 42:6-(4-Amino-4-methylpiperidin-1-yl)-3-((3,5-bis(trifluoromethyl)phenyl)ethynyl)-5-methyl- 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000323
Figure BSA0000197904800000323

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：499.17[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.17-8.21(3H，m)，3.37(3H，s)，3.12-3.28(4H，m)，1.54-1.61(2H，m)，1.46-1.52(2H，m)，1.10(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 499.17 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.17-8.21 (3H, m), 3.37 (3H, s), 3.12-3.28 (4H, m), 1.54-1.61 (2H, m), 1.46- 1.52 (2H, m), 1.10 (3H, s).

实施例43：6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-3-((3-(三氟甲基)苯基)乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 43:6-(4-Amino-4-methylpiperidin-1-yl)-5-methyl-3-((3-(trifluoromethyl)phenyl)ethynyl)-1,5 -Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000324
Figure BSA0000197904800000324

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：431.18[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.58-13.86(1H，brs)，8.08-8.18(2H，brs)，7.85-7.87(2H，m)，7.81(1H，d，J＝7.6Hz)，7.69(1H，t，J＝7.6Hz)，3.40-3.46(2H，m)，3.38(3H，s)，3.08-3.14(2H，m)，1.86-1.93(2H，m)，1.73-1.80(2H，m)，1.35(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 431.18 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.58-13.86 (1H, brs), 8.08-8.18 (2H, brs), 7.85-7.87 (2H, m), 7.81 (1H, d, J=7.6 Hz), 7.69 (1H, t, J=7.6Hz), 3.40-3.46 (2H, m), 3.38 (3H, s), 3.08-3.14 (2H, m), 1.86-1.93 (2H, m), 1.73 -1.80 (2H, m), 1.35 (3H, s).

实施例44：6-(4-氨基-4-甲基哌啶-1-基)-5-甲基-3-(噻吩-3-基乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 44:6-(4-Amino-4-methylpiperidin-1-yl)-5-methyl-3-(thiophen-3-ylethynyl)-1,5-dihydro- 4H-pyridineazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000331
Figure BSA0000197904800000331

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：369.14[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.21(2H，s)，7.95(1H，d，J＝1.6Hz)，7.69(1H，dd，J＝4.8Hz，2.8Hz)，7.27(1H，d，J＝4.8Hz)，3.65-3.73(2H，m)，3.39(3H，s)，3.01-3.06(2H，m)，1.89-1.97(2H，m)，1.76-1.84(2H，m)，1.38(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 369.14 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.21 (2H, s), 7.95 (1H, d, J=1.6 Hz), 7.69 (1H, dd, J=4.8 Hz, 2.8 Hz), 7.27 ( 1H, d, J=4.8Hz), 3.65-3.73 (2H, m), 3.39 (3H, s), 3.01-3.06 (2H, m), 1.89-1.97 (2H, m), 1.76-1.84 (2H, m), 1.38 (3H, s).

实施例45：6-(4-氨基-4-甲基哌啶-1-基)-3-((3-氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 45:6-(4-Amino-4-methylpiperidin-1-yl)-3-((3-fluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H -Pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000332
Figure BSA0000197904800000332

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：381.19[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝12.74-13.90(1H，brs)，7.70-8.90(2H，brs)，7.46-7.51(1H，m)，7.36-7.40(2H，m)，7.28-7.33(1H，m)，3.38-3.46(2H，m)，3.37(3H，s)，3.07-3.14(2H，m)，1.91-1.98(2H，m)，1.75-1.80(2H，m)，1.35(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 381.19 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=12.74-13.90 (1H, brs), 7.70-8.90 (2H, brs), 7.46-7.51 (1H, m), 7.36-7.40 (2H, m), 7.28-7.33(1H,m), 3.38-3.46(2H,m), 3.37(3H,s), 3.07-3.14(2H,m), 1.91-1.98(2H,m), 1.75-1.80(2H,m) ), 1.35 (3H, s).

实施例46：6-(4-氨基-4-甲基哌啶-1-基)-3-((2，3-二氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 46:6-(4-Amino-4-methylpiperidin-1-yl)-3-((2,3-difluorophenyl)ethynyl)-5-methyl-1,5-di Hydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000333
Figure BSA0000197904800000333

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：399.18[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.43-7.47(1H，m)，7.30-7.37(1H，m)，7.17-7.23(1H，m)，3.51-3.59(5H，m)，3.21-3.29(2H，m)，1.99-2.06(2H，m)，1.88-1.94(2H，m)，1.48(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 399.18 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.43-7.47(1H,m), 7.30-7.37(1H,m), 7.17-7.23(1H,m), 3.51-3.59(5H,m), 3.21 -3.29 (2H, m), 1.99-2.06 (2H, m), 1.88-1.94 (2H, m), 1.48 (3H, s).

实施例47：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2，3-二氟苯基)乙炔基)-5-甲基-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 47:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2,3 -Difluorophenyl)ethynyl)-5-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000334
Figure BSA0000197904800000334

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：455.20[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.43-7.47(1H，m)，7.30-7.37(1H，m)，7.17-7.22(1H，m)，4.22-4.28(1H，m)，3.89(1H，d，J＝8.8Hz)，3.76(1H，d，J＝8.8Hz)，3.46-3.54(5H，m)，3.24-3.29(1H，m)，3.97-3.12(2H，m)，1.91-2.02(2H，m)，1.80-1.86(1H，m)，1.68-1.74(1H，m)，1.40(3H，s)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 455.20 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.43-7.47(1H,m), 7.30-7.37(1H,m), 7.17-7.22(1H,m), 4.22-4.28(1H,m), 3.89 (1H, d, J=8.8Hz), 3.76 (1H, d, J=8.8Hz), 3.46-3.54 (5H, m), 3.24-3.29 (1H, m), 3.97-3.12 (2H, m), 1.91-2.02 (2H, m), 1.80-1.86 (1H, m), 1.68-1.74 (1H, m), 1.40 (3H, s).

实施例48：6-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-((2-氟苯基)乙炔基)-1，5-二氢-4H-吡唑并[3，4-d]嘧啶-4-酮Example 48:6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-((2-fluoro Phenyl)ethynyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Figure BSA0000197904800000341
Figure BSA0000197904800000341

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：423.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.19-13.37(1H，brs)，7.61(1H，td，J＝7.2Hz，1.6Hz)，7.46-7.52(1H，m)，7.34(1H，t，J＝8.4Hz)，7.27(1H，td，J＝8.4Hz，0.8Hz)，3.96-4.19(3H，m)，3.77(1H，d，J＝8.8Hz)，3.54(1H，d，J＝8.8Hz)，3.13-3.25(m，3H)，1.64-1.75(2H，m)，1.53-1.62(1H，m)，1.43-1.50(1H，m)，1.14(3H，d，J＝6.0Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 423.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.19-13.37 (1H, brs), 7.61 (1H, td, J=7.2Hz, 1.6Hz), 7.46-7.52 (1H, m), 7.34 (1H) , t, J=8.4Hz), 7.27 (1H, td, J=8.4Hz, 0.8Hz), 3.96-4.19 (3H, m), 3.77 (1H, d, J=8.8Hz), 3.54 (1H, d , J=8.8Hz), 3.13-3.25 (m, 3H), 1.64-1.75 (2H, m), 1.53-1.62 (1H, m), 1.43-1.50 (1H, m), 1.14 (3H, d, J) = 6.0 Hz).

实施例49：(3S，4S)-8-(9-((2，3-二氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 49:(3S,4S)-8-(9-((2,3-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e ]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000342
Figure BSA0000197904800000342

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：464.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.70(1H，m)，7.48-7.59(3H，m)，7.28-7.33(1H，m)，4.13-4.21(1H，m)，3.81(1H，d，J＝8.4Hz)，3.60-3.72(3H，m)，3.13-3.25(3H，m)，1.90-2.01(2H，m)，1.62-1.80(2H，m)，1.17(3H，d，J＝5.6Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 464.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.70(1H,m), 7.48-7.59(3H,m), 7.28-7.33(1H,m), 4.13-4.21(1H,m), 3.81( 1H, d, J=8.4Hz), 3.60-3.72 (3H, m), 3.13-3.25 (3H, m), 1.90-2.01 (2H, m), 1.62-1.80 (2H, m), 1.17 (3H, d, J=5.6 Hz).

实施例50：(3S，4S)-8-(9-((3-氯-2-氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 50:(3S,4S)-8-(9-((3-Chloro-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3- e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000343
Figure BSA0000197904800000343

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：480.17[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.62-7.72(3H，m)，7.52(1H，d，J＝1.6Hz)，7.33(1H，t，J＝7.6Hz)，4.14-4.20(1H，m)，3.82(1H，d，J＝8.8Hz)，3.62-3.72(3H，m)，3.12-3.24(3H，m)，1.91-1.99(2H，m)，1.74-1.81(1H，m)，1.64-1.71(1H，m)，1.17(3H，d，J＝6.0Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 480.17 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.62-7.72 (3H, m), 7.52 (1H, d, J=1.6 Hz), 7.33 (1H, t, J=7.6 Hz), 4.14-4.20 (1H, m), 3.82 (1H, d, J=8.8Hz), 3.62-3.72 (3H, m), 3.12-3.24 (3H, m), 1.91-1.99 (2H, m), 1.74-1.81 (1H , m), 1.64-1.71 (1H, m), 1.17 (3H, d, J=6.0 Hz).

实施例51：(3S，4S)-8-(9-((2-氟-3，5-二甲氧基苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 51:(3S,4S)-8-(9-((2-Fluoro-3,5-dimethoxyphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000351
Figure BSA0000197904800000351

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：506.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.69(1H，s)，7.50(1H，s)，6.84(1H，dd，J＝6.8Hz，2.8Hz)，6.70-6.69(1H，m)，4.14-4.19(1H，m)，3.85(3H，s)，3.77-3.81(4H，m)，3.60-3.69(3H，m)，3.12-3.22(4H，m)，1.89-1.99(2H，m)，1.63-1.68(1H，m)，1.64-1.68(1H，m)，1.16(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 506.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.69 (1H,s), 7.50 (1H,s), 6.84 (1H, dd, J=6.8Hz, 2.8Hz), 6.70-6.69 (1H,m ), 4.14-4.19 (1H, m), 3.85 (3H, s), 3.77-3.81 (4H, m), 3.60-3.69 (3H, m), 3.12-3.22 (4H, m), 1.89-1.99 (2H , m), 1.63-1.68 (1H, m), 1.64-1.68 (1H, m), 1.16 (3H, d, J=6.8 Hz).

实施例52：(3S，4S)-8-(9-((2-氟-5-(三氟甲基)苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 52:(3S,4S)-8-(9-((2-Fluoro-5-(trifluoromethyl)phenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000352
Figure BSA0000197904800000352

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：514.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝8.04-8.07(1H，m)，7.89-7.94(1H，m)，7.70(1H，s)，7.64(1H，t，J＝8.8Hz)，7.52(1H，s)，4.15-4.21(1H，m)，3.81(1H，d，J＝8.0Hz)，3.61-3.70(3H，m)，3.13-3.23(3H，m)，1.90-2.01(2H，m)，1.73-1.80(1H，m)，1.62-1.70(1H，m)，1.17(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 514.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=8.04-8.07 (1H, m), 7.89-7.94 (1H, m), 7.70 (1H, s), 7.64 (1H, t, J=8.8 Hz) , 7.52 (1H, s), 4.15-4.21 (1H, m), 3.81 (1H, d, J=8.0Hz), 3.61-3.70 (3H, m), 3.13-3.23 (3H, m), 1.90-2.01 (2H,m), 1.73-1.80 (1H,m), 1.62-1.70 (1H,m), 1.17 (3H,d, J=6.4Hz).

实施例53：(3S，4S)-3-甲基-8-(9-((3-(三氟甲基)苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 53:(3S,4S)-3-methyl-8-(9-((3-(trifluoromethyl)phenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole [4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000353
Figure BSA0000197904800000353

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：496.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.90-7.93(2H，m)，7.83(1H，d，J＝7.6Hz)，7.69-7.74(2H，m)，7.53(1H，s)，4.15-4.21(1H，m)，3.83(1H，d，J＝9.2Hz)，3.63-3.71(3H，m)，3.34(1H，d，J＝5.2Hz)，3.10-3.19(2H，m)，1.92-2.01(2H，m)，1.75-1.79(1H，m)，1.65-1.70(1H，m)，1.18(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 496.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.90-7.93 (2H, m), 7.83 (1H, d, J=7.6 Hz), 7.69-7.74 (2H, m), 7.53 (1H, s) , 4.15-4.21 (1H, m), 3.83 (1H, d, J=9.2Hz), 3.63-3.71 (3H, m), 3.34 (1H, d, J=5.2Hz), 3.10-3.19 (2H, m ), 1.92-2.01 (2H, m), 1.75-1.79 (1H, m), 1.65-1.70 (1H, m), 1.18 (3H, d, J=6.4 Hz).

实施例54：(3S，4S)-8-(9-((2，5-二氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 54:(3S,4S)-8-(9-((2,5-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e ]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000361
Figure BSA0000197904800000361

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：464.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.70(1H，m)，7.48-7.59(2H，m)，7.35-7.44(2H，m)，4.13-4.21(1H，m)，3.82(1H，d，J＝8.4Hz)，3.61-3.72(3H，m)，3.13-3.25(3H，m)，1.91-2.01(2H，m)，1.62-1.81(2H，m)，1.17(3H，d，J＝5.6Hz)。。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 464.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.70 (1H, m), 7.48-7.59 (2H, m), 7.35-7.44 (2H, m), 4.13-4.21 (1H, m), 3.82 ( 1H, d, J=8.4Hz), 3.61-3.72 (3H, m), 3.13-3.25 (3H, m), 1.91-2.01 (2H, m), 1.62-1.81 (2H, m), 1.17 (3H, d, J=5.6 Hz). .

实施例55：(3S，4S)-8-(9-((2-氟-3-(三氟甲基)苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 55:(3S,4S)-8-(9-((2-Fluoro-3-(trifluoromethyl)phenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000362
Figure BSA0000197904800000362

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：514.20[M+1]。1H NMR(400MHz，CD3OD)：δ＝8.11(1H，t，J＝6.8Hz)，7.72-7.77(2H，m)，7.52(1H，d，J＝1.2Hz)，7.42(1H，t，J＝8.0Hz)，4.27-4.32(1H，m)，3.96(1H，d，J＝8.8Hz)，3.79-3.89(3H，m)，3.41(1H，d，J＝4.0Hz)，3.17-3.28(2H，m)，1.95-2.09(3H，m)，1.78-1.82(1H，m)，1.30(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 514.20 [M+1].1 H NMR (400 MHz, CD3 OD): δ=8.11 (1H, t, J=6.8 Hz), 7.72-7.77 (2H, m), 7.52 (1H, d, J=1.2 Hz), 7.42 (1H, t, J=8.0Hz), 4.27-4.32 (1H, m), 3.96 (1H, d, J=8.8Hz), 3.79-3.89 (3H, m), 3.41 (1H, d, J=4.0Hz), 3.17-3.28 (2H, m), 1.95-2.09 (3H, m), 1.78-1.82 (1H, m), 1.30 (3H, d, J=6.8 Hz).

实施例56：3-(5-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-9-基)-2-氯苯基二甲基氨基甲酸酯Example 56:3-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-7H-imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-2-chlorophenyldimethylcarbamate

Figure BSA0000197904800000363
Figure BSA0000197904800000363

参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：525.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.85(1H，s)，7.64(1H，d，J＝1.6Hz)，7.60(1H，dd，J＝7.2Hz，1.6Hz)，7.45(1H，t，J＝7.6Hz)，7.36-7.39(2H，m)，4.15-4.21(1H，m)，3.84(1H，d，J＝9.2Hz)，3.60-3.72(3H，m)，3.06-3.20(6H，m)，2.91(3H，s)，1.90-1.99(2H，m)，1.74-1.81(1H，m)，1.64-1.70(1H，m)，1.19(3H，d，J＝6.4Hz)。Referring to the method in Example 36, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 525.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.85 (1H, s), 7.64 (1H, d, J=1.6 Hz), 7.60 (1H, dd, J=7.2 Hz, 1.6 Hz), 7.45 ( 1H, t, J=7.6Hz), 7.36-7.39 (2H, m), 4.15-4.21 (1H, m), 3.84 (1H, d, J=9.2Hz), 3.60-3.72 (3H, m), 3.06 -3.20(6H,m), 2.91(3H,s), 1.90-1.99(2H,m), 1.74-1.81(1H,m), 1.64-1.70(1H,m), 1.19(3H,d, J= 6.4Hz).

实施例57：3-((5-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-9-基)乙炔基)-2-氟苯腈Example 57:3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-7H-imidazole Do[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)ethynyl)-2-fluorobenzonitrile

Figure BSA0000197904800000371
Figure BSA0000197904800000371

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：471.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.99-8.06(2H，m)，7.72(1H，s)，7.48-7.52(2H，m)，4.09-4.15(1H，m)，3.46(1H，d，J＝8.4Hz)，3.55-3.66(3H，m)，3.12-3.25(3H，m)，1.87-1.99(2H，m)，1.62-1.74(2H，m)，1.13(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 471.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.99-8.06(2H,m), 7.72(1H,s), 7.48-7.52(2H,m), 4.09-4.15(1H,m), 3.46( 1H, d, J=8.4Hz), 3.55-3.66 (3H, m), 3.12-3.25 (3H, m), 1.87-1.99 (2H, m), 1.62-1.74 (2H, m), 1.13 (3H, d, J=6.4 Hz).

实施例58：(3S，4S)-8-(9-(环丙基乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 58:(3S,4S)-8-(9-(cyclopropylethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin -5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000372
Figure BSA0000197904800000372

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：392.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.56-13.84(1H，brs)，7.65(1H，d，J＝0.8Hz)，7.45(1H，d，J＝0.8Hz)，4.05-4.13(1H，m)，3.94-4.02(1H，m)，3.71(1H，d，J＝8.4Hz)，3.46-3.60(3H，m)，3.02-3.23(3H，m)，1.80-1.99(3H，m)，1.64-1.74(1H，m)，1.10(3H，d，J＝6.4Hz)，0.90-0.94(2H，m)，0.75-0.82(2H，m)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 392.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.56-13.84 (1H, brs), 7.65 (1H, d, J=0.8Hz), 7.45 (1H, d, J=0.8Hz), 4.05-4.13 (1H, m), 3.94-4.02 (1H, m), 3.71 (1H, d, J=8.4Hz), 3.46-3.60 (3H, m), 3.02-3.23 (3H, m), 1.80-1.99 (3H , m), 1.64-1.74 (1H, m), 1.10 (3H, d, J=6.4 Hz), 0.90-0.94 (2H, m), 0.75-0.82 (2H, m).

实施例59：N-(3-((5-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-9-基)乙炔基)-2-氟苯基)乙酰胺Example 59:N-(3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)- 7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)ethynyl)-2-fluorophenyl)acetamide

Figure BSA0000197904800000373
Figure BSA0000197904800000373

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：503.23[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.98(1H，t，J＝7.6Hz)，7.75(1H，d，J＝1.6Hz)，7.59(1H，t，J＝7.2Hz)，7.50(1H，d，J＝1.6Hz)，7.19(1H，t，J＝8.0Hz)，4.26-4.32(1H，m)，3.95(1H，d，J＝9.2Hz)，3.77-3.85(3H，m)，3.33-3.36(1H，m)，3.14-3.24(2H，m)，2.18(3H，s)，1.99-2.10(2H，m)，1.89-1.95(1H，m)，1.76-1.83(1H，m)，1.29(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 503.23 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.98 (1H, t, J=7.6 Hz), 7.75 (1H, d, J=1.6 Hz), 7.59 (1H, t, J=7.2 Hz), 7.50 (1H, d, J=1.6Hz), 7.19 (1H, t, J=8.0Hz), 4.26-4.32 (1H, m), 3.95 (1H, d, J=9.2Hz), 3.77-3.85 (3H, m), 3.33-3.36 (1H, m), 3.14-3.24 (2H, m), 2.18 (3H, s), 1.99-2.10 (2H, m), 1.89-1.95 (1H, m), 1.76-1.83 ( 1H, m), 1.29 (3H, d, J=6.4 Hz).

实施例60：(3S，4S)-8-(9-((3-氨基-2-氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 60:(3S,4S)-8-(9-((3-amino-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3- e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000381
Figure BSA0000197904800000381

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：461.22[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.73(1H，d，J＝2.0Hz)，7.49(1H，d，J＝2.0Hz)，7.03-7.07(1H，m)，6.93(1H，t，J＝7.6Hz)，6.88(1H，td，J＝8.0Hz，2.0Hz)，4.26-4.32(1H，m)，3.95(1H，d，J＝9.2Hz)，3.76-3.85(3H，m)，3.35(1H，d，J＝4.4Hz)，3.17-3.25(2H，m)，1.99-2.10(2H，m)，1.88-1.96(1H，m)，1.76-1.83(1H，m)，1.29(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 461.22 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.73 (1H, d, J=2.0 Hz), 7.49 (1H, d, J=2.0 Hz), 7.03-7.07 (1H, m), 6.93 (1H, t, J=7.6Hz), 6.88 (1H, td, J=8.0Hz, 2.0Hz), 4.26-4.32 (1H, m), 3.95 (1H, d, J=9.2Hz), 3.76-3.85 (3H, m), 3.35 (1H, d, J=4.4Hz), 3.17-3.25 (2H, m), 1.99-2.10 (2H, m), 1.88-1.96 (1H, m), 1.76-1.83 (1H, m) , 1.29 (3H, d, J=6.4Hz).

实施例61：5-(5-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-9-基)-3H-螺[苯并呋喃-2，1′-环丙烷]-3-酮Example 61:5-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-7H-imidazo [1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)-3H-spiro[benzofuran-2,1'-cyclopropan]-3-one

Figure BSA0000197904800000382
Figure BSA0000197904800000382

参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：486.23[M+1]。1H NMR(400MHz，CD3OD)：δ＝8.93(1H，s)，7.87(1H，d，J＝8.8Hz)，7.73(1H，s)，7.49(1H，s)，7.38(1H，d，J＝8.4Hz)，4.25-4.32(1H，m)，3.98(1H，d，J＝9.2Hz)，3.76-3.88(3H，m)，3.44(1H，d，J＝4.4Hz)，3.11-3.29(2H，m)，2.04-2.11(2H，m)，1.93-1.98(1H，m)，1.74-1.84(3H，m)，1.55-1.58(2H，m)，1.31(3H，d，J＝6.4Hz)。Referring to the method in Example 36, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 486.23 [M+1].1 H NMR (400 MHz, CD3 OD): δ=8.93 (1H,s), 7.87 (1H,d, J=8.8Hz), 7.73 (1H,s), 7.49 (1H,s), 7.38 (1H, d, J=8.4Hz), 4.25-4.32 (1H, m), 3.98 (1H, d, J=9.2Hz), 3.76-3.88 (3H, m), 3.44 (1H, d, J=4.4Hz), 3.11-3.29(2H,m), 2.04-2.11(2H,m), 1.93-1.98(1H,m), 1.74-1.84(3H,m), 1.55-1.58(2H,m), 1.31(3H,d) , J=6.4Hz).

实施例62：(3S，4S)-8-(9-((2，3-二氯苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 62:(3S,4S)-8-(9-((2,3-dichlorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3-e ]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000383
Figure BSA0000197904800000383

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：496.14[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.61-7.74(3H，m)，7.51(1H，d，J＝1.6Hz)，7.31(1H，t，J＝7.6Hz)，4.11-4.20(1H，m)，3.78(1H，d，J＝8.4Hz)，3.61-3.74(3H，m)，3.10-3.24(3H，m)，1.89-1.99(2H，m)，1.73-1.85(1H，m)，1.64-1.72(1H，m)，1.16(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 496.14 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.61-7.74 (3H, m), 7.51 (1H, d, J=1.6 Hz), 7.31 (1H, t, J=7.6 Hz), 4.11-4.20 (1H, m), 3.78 (1H, d, J=8.4Hz), 3.61-3.74 (3H, m), 3.10-3.24 (3H, m), 1.89-1.99 (2H, m), 1.73-1.85 (1H , m), 1.64-1.72 (1H, m), 1.16 (3H, d, J=6.4 Hz).

实施例63：(3S，4S)-8-(9-((2-氟-3-甲氧基苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 63:(3S,4S)-8-(9-((2-Fluoro-3-methoxyphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4, 3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000391
Figure BSA0000197904800000391

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：476.22[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.70(1H，m)，7.50(1H，m)，7.16-7.32(3H，m)，4.10-4.22(1H，m)，3.87(3H，s)，3.78(1H，d，J＝8.4Hz)，3.57-3.69(3H，m)，3.12-3.26(3H，m)，1.87-2.01(2H，m)，1.71-1.79(1H，m)，1.62-1.69(1H，m)，1.15(3H，d，J＝5.6Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 476.22 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.70(1H,m), 7.50(1H,m), 7.16-7.32(3H,m), 4.10-4.22(1H,m), 3.87(3H,m) s), 3.78 (1H, d, J=8.4Hz), 3.57-3.69 (3H, m), 3.12-3.26 (3H, m), 1.87-2.01 (2H, m), 1.71-1.79 (1H, m) , 1.62-1.69 (1H, m), 1.15 (3H, d, J=5.6Hz).

实施例64：(3S，4S)-8-(9-(3-氯-[1，1′-联苯基]-4-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 64: (3S,4S)-8-(9-(3-Chloro-[1,1'-biphenyl]-4-yl)-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000392
Figure BSA0000197904800000392

参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：514.21[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.84(1H，s)，7.70-7.72(5H，m)，7.49(2H，t，J＝7.6Hz)，7.38-7.42(1H，m)，7.35(1H，d，J＝1.6Hz)，4.26-4.32(1H，m)，3.97(1H，d，J＝8.8Hz)，3.78-3.87(3H，m)，3.39(1H，d，J＝3.6Hz)，3.17-3.27(2H，m)，1.99-2.12(2H，m)，1.91-1.98(1H，m)，1.78-1.84(1H，m)，1.30(3H，d，J＝6.8Hz)。Referring to the method in Example 36, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 514.21 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.84 (1H, s), 7.70-7.72 (5H, m), 7.49 (2H, t, J=7.6 Hz), 7.38-7.42 (1H, m), 7.35 (1H, d, J=1.6Hz), 4.26-4.32 (1H, m), 3.97 (1H, d, J=8.8Hz), 3.78-3.87 (3H, m), 3.39 (1H, d, J= 3.6Hz), 3.17-3.27(2H,m), 1.99-2.12(2H,m), 1.91-1.98(1H,m), 1.78-1.84(1H,m), 1.30(3H,d, J=6.8Hz ).

实施例65：2-((3-(5-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑并[1，2-c]吡唑并[43-e]嘧啶-9-基)-2-氯苯基)硫基)乙酰胺Example 65:2-((3-(5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)- 7H-imidazo[1,2-c]pyrazolo[43-e]pyrimidin-9-yl)-2-chlorophenyl)sulfanyl)acetamide

Figure BSA0000197904800000393
Figure BSA0000197904800000393

参照实施例36中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：527.18[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.71-7.77(1H，m)，7.53(1H，d，J＝6.8Hz)，7.36-7.46(3H，m)，4.29-4.35(1H，m)，4.01(1H，d，J＝10.0Hz)，3.81-3.91(3H，m)，3.76(2H，s)，3.52-3.54(1H，m)，3.17-3.24(2H，m)，2.03-2.22(2H，m)，1.95-2.04(1H，m)，1.80-1.86(1H，m)，1.33(3H，d，J＝6.4Hz)。Referring to the method in Example 36, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 527.18 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.71-7.77 (1H, m), 7.53 (1H, d, J=6.8 Hz), 7.36-7.46 (3H, m), 4.29-4.35 (1H, m) ), 4.01 (1H, d, J=10.0Hz), 3.81-3.91 (3H, m), 3.76 (2H, s), 3.52-3.54 (1H, m), 3.17-3.24 (2H, m), 2.03- 2.22 (2H, m), 1.95-2.04 (1H, m), 1.80-1.86 (1H, m), 1.33 (3H, d, J=6.4 Hz).

实施例66：3-((5-((3S，4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-9-基)乙炔基)-2-氟苯酚Example 66:3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-7H-imidazole Do[1,2-c]pyrazolo[4,3-e]pyrimidin-9-yl)ethynyl)-2-fluorophenol

Figure BSA0000197904800000401
Figure BSA0000197904800000401

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：462.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝10.14-10.29(1H，brs)，7.68(1H，d，J＝1.2Hz)，7.50(1H，d，J＝1.2Hz)，7.01-7.08(3H，m)，4.16-4.23(1H，m)，3.84(1H，d，J＝9.2Hz)，3.63-3.73(3H，m)，3.40(1H，d，J＝4.4Hz)，3.08-3.19(2H，m)，1.89-2.01(2H，m)，1.76-1.82(1H，m)，1.64-1.72(1H，m)，1.19(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 462.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=10.14-10.29 (1H, brs), 7.68 (1H, d, J=1.2 Hz), 7.50 (1H, d, J=1.2 Hz), 7.01-7.08 (3H, m), 4.16-4.23 (1H, m), 3.84 (1H, d, J=9.2Hz), 3.63-3.73 (3H, m), 3.40 (1H, d, J=4.4Hz), 3.08- 3.19(2H,m), 1.89-2.01(2H,m), 1.76-1.82(1H,m), 1.64-1.72(1H,m), 1.19(3H,d, J=6.8Hz).

实施例67：(3S，4S)-8-(9-((2，2-二氟苯并[d][1，3]二氧杂环戊烯-4-基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 67:(3S,4S)-8-(9-((2,2-Difluorobenzo[d][1,3]dioxol-4-yl)ethynyl)-7H- Imidazo[1,2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000402
Figure BSA0000197904800000402

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：508.19[M+1]。1H NMR(400MHz，CD3OD)：δ＝7.74(1H，d，J＝1.6Hz)，7.55(1H，d，J＝8.0Hz)，7.51(1H，d，J＝1.6Hz)，7.26(1H，d，J＝8.0Hz)，7.20(1H，t，J＝8.0Hz)，4.26-4.32(1H，m)，3.95(1H，d，J＝8.8Hz)，3.77-3.88(3H，m)，3.39(1H，d，J＝4.4Hz)，3.16-3.25(2H，m)，2.01-2.02(2H，m)，1.89-1.96(1H，m)，1.76-1.83(1H，m)，1.29(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 508.19 [M+1].1 H NMR (400 MHz, CD3 OD): δ=7.74 (1H, d, J=1.6 Hz), 7.55 (1H, d, J=8.0 Hz), 7.51 (1H, d, J=1.6 Hz), 7.26 (1H, d, J=8.0Hz), 7.20 (1H, t, J=8.0Hz), 4.26-4.32 (1H, m), 3.95 (1H, d, J=8.8Hz), 3.77-3.88 (3H, m), 3.39 (1H, d, J=4.4Hz), 3.16-3.25 (2H, m), 2.01-2.02 (2H, m), 1.89-1.96 (1H, m), 1.76-1.83 (1H, m) , 1.29 (3H, d, J=6.4Hz).

实施例68：(3S，4S)-8-(9-((2-氟-3-甲基苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 68:(3S,4S)-8-(9-((2-Fluoro-3-methylphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3 -e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000403
Figure BSA0000197904800000403

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：460.23[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.80(1H，m)，7.62-7.70(2H，m)，7.52(1H，d，J＝1.6Hz)，7.41-7.20(1H，m)，4.13-4.20(1H，m)，3.81(1H，d，J＝8.8Hz)，3.60-3.72(3H，m)，3.27-3.29(1H，m)，3.12-3.21(2H，m)，2.35(3H，s)，1.89-1.97(2H，m)，1.61-1.79(2H，m)，1.18(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 460.23 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.80 (1H, m), 7.62-7.70 (2H, m), 7.52 (1H, d, J=1.6 Hz), 7.41-7.20 (1H, m) , 4.13-4.20 (1H, m), 3.81 (1H, d, J=8.8Hz), 3.60-3.72 (3H, m), 3.27-3.29 (1H, m), 3.12-3.21 (2H, m), 2.35 (3H, s), 1.89-1.97 (2H, m), 1.61-1.79 (2H, m), 1.18 (3H, d, J=6.4 Hz).

实施例69：(3S，4S)-8-(9-((2-氟-3-异丙基苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 69:(3S,4S)-8-(9-((2-Fluoro-3-isopropylphenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4, 3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000411
Figure BSA0000197904800000411

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：504.25[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.70(1H，d，J＝1.4Hz)，7.51(1H，d，J＝1.4Hz)，7.18-7.32(3H，m)，4.55(1H，m)，4.10-4.21(1H，m)，3.77(1H，d，J＝8.4Hz)，3.57-3.68(3H，m)，3.10-3.25(3H，m)，1.87-2.02(2H，m)，1.70-1.79(1H，m)，1.60-1.70(1H，m)，1.32(6H，d，J＝6.8Hz)，1.16(3H，d，J＝5.6Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 504.25 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.70 (1H, d, J=1.4Hz), 7.51 (1H, d, J=1.4Hz), 7.18-7.32 (3H, m), 4.55 (1H) , m), 4.10-4.21 (1H, m), 3.77 (1H, d, J=8.4Hz), 3.57-3.68 (3H, m), 3.10-3.25 (3H, m), 1.87-2.02 (2H, m) ), 1.70-1.79 (1H, m), 1.60-1.70 (1H, m), 1.32 (6H, d, J=6.8 Hz), 1.16 (3H, d, J=5.6 Hz).

实施例70：(3S，4S)-8-(9-((3-(二氟甲氧基)-2-氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 70:(3S,4S)-8-(9-((3-(difluoromethoxy)-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000412
Figure BSA0000197904800000412

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：512.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.76(1H，d，J＝1.6Hz)，7.51(1H，d，J＝1.6Hz)，7.38(1H，t，J＝56.0Hz)，7.21-7.35(3H，m)，4.12-4.22(1H，m)，3.79(1H，d，J＝8.4Hz)，3.58-3.68(3H，m)，3.12-3.26(3H，m)，1.88-2.01(2H，m)，1.70-1.80(1H，m)，1.61-1.70(1H，m)，1.18(3H，d，J＝5.6Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 512.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.76 (1H, d, J=1.6 Hz), 7.51 (1H, d, J=1.6 Hz), 7.38 (1H, t, J=56.0 Hz), 7.21-7.35(3H,m), 4.12-4.22(1H,m), 3.79(1H,d, J=8.4Hz), 3.58-3.68(3H,m), 3.12-3.26(3H,m), 1.88- 2.01 (2H, m), 1.70-1.80 (1H, m), 1.61-1.70 (1H, m), 1.18 (3H, d, J=5.6 Hz).

实施例71：(3S，4S)-8-(9-((3-(二氟甲基)-2-氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 71:(3S,4S)-8-(9-((3-(difluoromethyl)-2-fluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000413
Figure BSA0000197904800000413

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：496.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.84-7.88(1H，m)，7.70-7.74(2H，m)，7.51(1H，d，J＝1.6Hz)，7.41-7.18(1H，m)，7.28(1H，t，J＝54.0Hz)，4.13-4.19(1H，m)，3.80(1H，d，J＝8.8Hz)，3.60-3.71(3H，m)，3.27-3.28(1H，m)，3.12-3.21(2H，m)，1.90-1.99(2H，m)，1.61-1.78(2H，m)，1.17(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 496.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.84-7.88 (1H, m), 7.70-7.74 (2H, m), 7.51 (1H, d, J=1.6 Hz), 7.41-7.18 (1H, m), 7.28 (1H, t, J=54.0Hz), 4.13-4.19 (1H, m), 3.80 (1H, d, J=8.8Hz), 3.60-3.71 (3H, m), 3.27-3.28 (1H , m), 3.12-3.21 (2H, m), 1.90-1.99 (2H, m), 1.61-1.78 (2H, m), 1.17 (3H, d, J=6.8 Hz).

实施例72：(3S，4S)-3-甲基-8-(9-((2，3，4-三氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 72:(3S,4S)-3-methyl-8-(9-((2,3,4-trifluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazole [4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000421
Figure BSA0000197904800000421

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：482.19[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.70(1H，d，J＝1.2Hz)，7.52-7.59(1H，m)，7.51(1H，d，J＝1.2Hz)，7.40-7.47(1H，m)，4.13-4.19(1H，m)，3.80(1H，d，J＝8.8Hz)，3.60-3.71(3H，m)，3.28-3.29(1H，m)，3.12-3.21(2H，m)，1.90-1.99(2H，m)，1.72-1.79(1H，m)，1.64-1.70(1H，m)，1.16(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 482.19 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.70 (1H, d, J=1.2 Hz), 7.52-7.59 (1H, m), 7.51 (1H, d, J=1.2 Hz), 7.40-7.47 (1H, m), 4.13-4.19 (1H, m), 3.80 (1H, d, J=8.8Hz), 3.60-3.71 (3H, m), 3.28-3.29 (1H, m), 3.12-3.21 (2H , m), 1.90-1.99 (2H, m), 1.72-1.79 (1H, m), 1.64-1.70 (1H, m), 1.16 (3H, d, J=6.8 Hz).

实施例73：(3S，4S)-8-(9-((3-氯-2，5-二氟苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 73:(3S,4S)-8-(9-((3-Chloro-2,5-difluorophenyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4 , 3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000422
Figure BSA0000197904800000422

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：498.16[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.85-8.11(1H，brs)，7.77-7.83(1H，m)，7.74(0.5H，d，J＝1.6Hz)，7.70(0.5H，d，J＝1.6Hz)，7.59-7.63(1H，m)，7.52(0.5H，d，J＝1.6Hz)，7.49(0.5H，d，J＝1.6Hz)，4.18-4.28(1H，m)，3.66-3.88(4H，m)，3.43(1H，d，J＝4.4Hz)，3.11-3.21(2H，m)，1.91-2.02(2H，m)，1.66-1.86(2H，m)，1.14-1.28(3H，m)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 498.16 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.85-8.11 (1H, brs), 7.77-7.83 (1H, m), 7.74 (0.5H, d, J=1.6Hz), 7.70 (0.5H, d, J=1.6Hz), 7.59-7.63 (1H, m), 7.52 (0.5H, d, J=1.6Hz), 7.49 (0.5H, d, J=1.6Hz), 4.18-4.28 (1H, m ), 3.66-3.88 (4H, m), 3.43 (1H, d, J=4.4Hz), 3.11-3.21 (2H, m), 1.91-2.02 (2H, m), 1.66-1.86 (2H, m), 1.14-1.28 (3H, m).

实施例74：(3S，4S)-8-(9-((2-氟-3-(2，2，2-三氟乙氧基)苯基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 74:(3S,4S)-8-(9-((2-fluoro-3-(2,2,2-trifluoroethoxy)phenyl)ethynyl)-7H-imidazo[1, 2-c]pyrazolo[4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000423
Figure BSA0000197904800000423

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：544.21[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.73(1H，d，J＝1.6Hz)，7.50(1H，d，J＝1.6Hz)，7.20-7.34(3H，m)，4.46(2H，m)，4.10-4.22(1H，m)，3.78(1H，d，J＝8.4Hz)，3.57-3.68(3H，m)，3.12-3.25(3H，m)，1.87-2.01(2H，m)，1.70-1.79(1H，m)，1.62-1.70(1H，m)，1.17(3H，d，J＝5.6Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 544.21 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.73 (1H, d, J=1.6 Hz), 7.50 (1H, d, J=1.6 Hz), 7.20-7.34 (3H, m), 4.46 (2H) , m), 4.10-4.22 (1H, m), 3.78 (1H, d, J=8.4Hz), 3.57-3.68 (3H, m), 3.12-3.25 (3H, m), 1.87-2.01 (2H, m) ), 1.70-1.79 (1H, m), 1.62-1.70 (1H, m), 1.17 (3H, d, J=5.6 Hz).

实施例75：(3S，4S)-8-(9-(33-二甲基丁-1-炔-1-基)-7H-咪唑并[1，2-c]吡唑并[4.3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 75:(3S,4S)-8-(9-(33-Dimethylbut-1-yn-1-yl)-7H-imidazo[1,2-c]pyrazolo[4.3-e ]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000431
Figure BSA0000197904800000431

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：408.25[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.65(1H，d，J＝1.2Hz)，7.45(1H，d，J＝1.2Hz)，4.04-4.16(1H，m)，3.70(1H，d，J＝8.6Hz)，3.40-3.60(3H，m)，3.00-3.24(3H，m)，1.81-1.99(3H，m)，1.64-1.75(1H，d，J＝6.8Hz)，1.27(9H，s)，1.08(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 408.25 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.65 (1H, d, J=1.2 Hz), 7.45 (1H, d, J=1.2 Hz), 4.04-4.16 (1H, m), 3.70 (1H , d, J=8.6Hz), 3.40-3.60 (3H, m), 3.00-3.24 (3H, m), 1.81-1.99 (3H, m), 1.64-1.75 (1H, d, J=6.8Hz), 1.27 (9H, s), 1.08 (3H, d, J=6.4 Hz).

实施例76：(3S，4S)-8-(9-(3-氯-3-甲基丁-1-炔-1-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 76:(3S,4S)-8-(9-(3-Chloro-3-methylbut-1-yn-1-yl)-7H-imidazo[1,2-c]pyrazolo[ 4,3-e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000432
Figure BSA0000197904800000432

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：428.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.46-13.81(1H，brs)，7.68(1H，d，J＝1.2Hz)，7.50(1H，d，J＝1.2Hz)，4.02-4.17(1H，m)，3.71(1H，m)，3.42-3.61(3H，m)，2.99-3.25(3H，m)，1.80-2.00(9H，m)，1.64-1.79(1H，d，J＝6.8Hz)，1.10(3H，d，J＝6.8Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 428.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.46-13.81 (1H, brs), 7.68 (1H, d, J=1.2Hz), 7.50 (1H, d, J=1.2Hz), 4.02-4.17 (1H, m), 3.71 (1H, m), 3.42-3.61 (3H, m), 2.99-3.25 (3H, m), 1.80-2.00 (9H, m), 1.64-1.79 (1H, d, J= 6.8 Hz), 1.10 (3H, d, J=6.8 Hz).

实施例77：(3S，4S)-3-甲基-8-(9-(3-甲基丁-1-炔-1-基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 77:(3S,4S)-3-Methyl-8-(9-(3-methylbut-1-yn-1-yl)-7H-imidazo[1,2-c]pyrazolo [4,3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000433
Figure BSA0000197904800000433

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：394.24[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.65(1H，d，J＝1.2Hz)，7.45(1H，d，J＝1.2Hz)，4.04-4.16(1H，m)，3.70(1H，d，J＝8.6Hz)，3.40-3.60(3H，m)，2.98-3.24(4H，m)，1.81-1.99(3H，m)，1.64-1.75(1H，m)，1.28(6H，d，J＝6.8Hz)，1.07(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 394.24 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.65 (1H, d, J=1.2 Hz), 7.45 (1H, d, J=1.2 Hz), 4.04-4.16 (1H, m), 3.70 (1H , d, J=8.6Hz), 3.40-3.60 (3H, m), 2.98-3.24 (4H, m), 1.81-1.99 (3H, m), 1.64-1.75 (1H, m), 1.28 (6H, d) , J=6.8 Hz), 1.07 (3H, d, J=6.4 Hz).

实施例78：(3S，4S)-3-甲基-8-(9-((1-甲基环丙基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 78:(3S,4S)-3-Methyl-8-(9-((1-methylcyclopropyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4 , 3-e]pyrimidin-5-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000441
Figure BSA0000197904800000441

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：406.24[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝13.58-13.84(1H，brs)，7.63(1H，d，J＝0.8Hz)，7.43(1H，d，J＝0.8Hz)，4.05-4.14(1H，m)，3.72(1H，d，J＝8.6Hz)，3.46-3.60(3H，m)，3.02-3.23(3H，m)，1.80-1.99(3H，m)，1.64-1.74(1H，m)，1.26(3H，s)，1.10(3H，d，J＝6.4Hz)，0.92-0.95(2H，m)，0.72-0.80(2H，m)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 406.24 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=13.58-13.84 (1H, brs), 7.63 (1H, d, J=0.8Hz), 7.43 (1H, d, J=0.8Hz), 4.05-4.14 (1H, m), 3.72 (1H, d, J=8.6Hz), 3.46-3.60 (3H, m), 3.02-3.23 (3H, m), 1.80-1.99 (3H, m), 1.64-1.74 (1H , m), 1.26 (3H, s), 1.10 (3H, d, J=6.4 Hz), 0.92-0.95 (2H, m), 0.72-0.80 (2H, m).

实施例79：(3S，4S)-8-(9-((2，2-二氟环丙基)乙炔基)-7H-咪唑并[1，2-c]吡唑并[4，3-e]嘧啶-5-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺Example 79:(3S,4S)-8-(9-((2,2-difluorocyclopropyl)ethynyl)-7H-imidazo[1,2-c]pyrazolo[4,3- e]pyrimidin-5-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

Figure BSA0000197904800000442
Figure BSA0000197904800000442

参照实施例1中的方法，采用合适的起始原料和中间体可以合成得到目标化合物。MS m/z[LC-MS]：428.20[M+1]。1H NMR(400MHz，DMSO-d6)：δ＝7.68(1H，d，J＝1.2Hz)，7.48(1H，d，J＝1.2Hz)，4.05-4.17(2H，m)，3.71(1H，d，J＝8.6Hz)，3.46-3.60(3H，m)，3.02-3.23(3H，m)，1.80-1.99(3H，m)，1.64-1.78(2H，m)，1.52(1H，m)，1.12(3H，d，J＝6.4Hz)。Referring to the method in Example 1, the target compound can be synthesized by using suitable starting materials and intermediates. MS m/z [LC-MS]: 428.20 [M+1].1 H NMR (400 MHz, DMSO-d6 ): δ=7.68 (1H, d, J=1.2 Hz), 7.48 (1H, d, J=1.2 Hz), 4.05-4.17 (2H, m), 3.71 (1H , d, J=8.6Hz), 3.46-3.60 (3H, m), 3.02-3.23 (3H, m), 1.80-1.99 (3H, m), 1.64-1.78 (2H, m), 1.52 (1H, m) ), 1.12 (3H, d, J=6.4 Hz).

化合物对SHP2的体外酶学活性抑制作用的测定Determination of Inhibitory Effects of Compounds on Enzymatic Activity of SHP2 in Vitro

本专利中SHP2的酶学活性检测采用快速荧光法进行，使用DiFMUP作为替代底物进行反应并且优化建立了高通量的筛选平台。化合物对SHP2的抑制活性的检测在此平台进行操作。具体方法如下：将终浓度1nM的SHP2与2.5μM的二磷酸化的IRS1肽段(序列：H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide)混合物在23℃预孵育30分钟。将化合物从0.2mM开始用100％DMSO进行5倍的梯度稀释(共7个浓度)，每个浓度取2μL的化合物加入48μL的反应缓冲液(60mM HEPES，pH 7.2，75mM NaCl，75mM KCl，1mM EDTA，0.05％Tween 20，5mM DTT)中进行稀释混匀。取5μL稀释后的化合物加入黑色384孔板中(OptiPlate-384，货号6007270，购买于PerkinElmer)，然后加入10μL的预孵育的SHP2和IRS1肽段混合液，离心混匀，23℃孵育30分钟。加入5μL替代底物DiFMUP(终浓度50μM，货号D6567，购买于Invitrogen)加入反应中并在23℃下孵育60分钟。然后通过加入5μL 160μMbpV(Phen)溶液(SC-22137，购买于Santa)终止反应。反应终止后立即使用酶标仪(Perkin-Elmer)分别在340nm和450nm的激发和发射波长检测测荧光信号，数据使用GraphPad Prism软件计算得到该化合物的IC50值。The enzymatic activity detection of SHP2 in this patent is carried out by a fast fluorescence method, using DiFMUP as an alternative substrate for the reaction and optimized to establish a high-throughput screening platform. Detection of the inhibitory activity of compounds against SHP2 is performed on this platform. The specific method is as follows: a mixture of SHP2 at a final concentration of 1 nM and 2.5 μM of diphosphorylated IRS1 peptide (sequence: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) was pre-incubated at 23°C for 30 minutes . Compounds were diluted 5-fold in 100% DMSO starting at 0.2 mM (7 concentrations in total), and 2 μL of each concentration was added to 48 μL of reaction buffer (60 mM HEPES, pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM). EDTA, 0.05% Tween 20, 5 mM DTT) for dilution and mixing. Add 5 μL of the diluted compound to a black 384-well plate (OptiPlate-384, Cat. No. 6007270, purchased from PerkinElmer), then add 10 μL of pre-incubated SHP2 and IRS1 peptide mixture, centrifuge to mix well, and incubate at 23°C for 30 minutes. 5 μL of the surrogate substrate DiFMUP (50 μM final concentration, Cat. No. D6567, purchased from Invitrogen) was added to the reaction and incubated at 23° C. for 60 minutes. The reaction was then stopped by adding 5 μL of 160 μM bpV(Phen) solution (SC-22137, purchased from Santa). Immediately after the reaction was terminated, a microplate reader (Perkin-Elmer) was used to detect the fluorescence signals at excitation and emission wavelengths of 340 nm and 450 nm, respectively. The data were calculated using GraphPad Prism software to obtain the IC50 value of the compound.

化合物对SHP2阳性细胞增殖抑制作用的测定Determination of Inhibitory Effect of Compounds on SHP2 Positive Cell Proliferation

人非小细胞肺癌细胞系NCI-H358细胞使用RPMI-1640培养基(货号C11875500BT，购买于Biological Industries)加10％的胎牛血清(FBS，货号04-001-1ACS，购买于Biological Industries，BI)和1％青霉素/链霉素双抗(P/S，货号15070-063，购买于Cibco)进行培养，培养条件为37℃，5％CO2。进行化合物检测的前一天，将NCI-H358细胞以2000个细胞/195μL/孔的浓度铺于196孔板(货号3917，购买于Corning)中。24小时后将化合物从10mM开始用100％DMSO进行3倍的梯度稀释(共10个浓度)，然后每个浓度取2μL的化合物加入48μL的不合血清和双抗的培养基中进行稀释。稀释后的化合物每个浓度取5μL加入铺好的细胞悬液中，将化合物与细胞在细胞培养箱中共孵育72小时(3天)，吸尽培养基后加入25μL的Cell-Titer Glo(G7570，购买于Promega)试剂再次孵育5-10分钟。之后在Envision上读取荧光值，数据使用GraphPad Prism软件计算得到该化合物对细胞增殖的抑制的IC50值。Human non-small cell lung cancer cell line NCI-H358 cells were used RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) plus 10% fetal bovine serum (FBS, Item No. 04-001-1ACS, purchased from Biological Industries, BI) and 1% penicillin/streptomycin double antibody (P/S, product number 15070-063, purchased from Cibco) for cultivation under 37°C, 5% CO2. One day before compound assays, NCI-H358 cells were plated in 196-well plates (Cat. No. 3917, purchased from Corning) at a concentration of 2000 cells/195 μL/well. Twenty-four hours later, compounds were serially diluted 3-fold with 100% DMSO starting from 10 mM (10 concentrations in total), and then 2 μL of each concentration was added to 48 μL of serum- and double-antibody-free medium for dilution. Add 5 μL of each concentration of diluted compounds to the plated cell suspension, incubate the compounds and cells in a cell incubator for 72 hours (3 days), and add 25 μL of Cell-Titer Glo (G7570, Reagents purchased from Promega) were incubated for 5-10 minutes. After that, the fluorescence value was read on the Envision, and the data was calculated using GraphPad Prism software to obtain theIC50 value of the compound's inhibition of cell proliferation.

人急性成髓细胞白血病细胞系Kasumi-1细胞使用RPMI-1640培养基(货号C11875500BT，购买于Biological Industries)加20％的胎牛血清(FBS，货号04-001-1ACS，购买于Biological Industries，BI)和1％青霉素/链霉素双抗(P/S，货号15070-063，购买于Gibco)进行培养，培养条件为37℃，5％CO2。进行化合物检测的前一天，将Kasumi-1细胞细胞以3000个细胞/195μL/孔的浓度铺于196孔板(货号3599，购买于Corning)中。24小时后将化合物从10mM开始用100％DMSO进行3倍的梯度稀释(共10个浓度)，然后每个浓度取2μL的化合物加入48μL的不含血清和双抗的培养基中进行稀释。稀释后的化合物每个浓度取5μL加入铺好的细胞悬液中，将化合物与细胞在细胞培养箱中共孵育72小时(3天)，加入35μL的Cell-Titer Blue(G8082，购买于Promega)试剂再次孵育4小时。之后在Flexstation III上读取荧光值(560nm激发，590nm检测)，数据使用GraphPad Prism软件计算得到该化合物对细胞增殖的抑制的IC50值。Human acute myeloid leukemia cell line Kasumi-1 cells were used RPMI-1640 medium (Cat. No. C11875500BT, purchased from Biological Industries) plus 20% fetal bovine serum (FBS, Cat. No. 04-001-1ACS, purchased from Biological Industries, BI ) and 1% penicillin/streptomycin double antibody (P/S, product number 15070-063, purchased from Gibco) for culture at 37°C, 5% CO2. The day before compound assays, Kasumi-1 cells were plated in 196-well plates (Cat. No. 3599, purchased from Corning) at a concentration of 3000 cells/195 μL/well. After 24 hours, compounds were serially diluted 3-fold with 100% DMSO starting from 10 mM (10 concentrations in total), and then 2 μL of each concentration was added to 48 μL of serum- and double-antibody-free medium for dilution. Add 5 μL of each concentration of diluted compounds to the plated cell suspension, incubate the compounds and cells in a cell incubator for 72 hours (3 days), and add 35 μL of Cell-Titer Blue (G8082, purchased from Promega) reagent Incubate again for 4 hours. Fluorescence values were then read on a Flexstation III (excitation at 560 nm, detection at 590 nm), and the data were calculated using GraphPad Prism software to obtain theIC50 value of the compound's inhibition of cell proliferation.

表1实施例化合物对SHP2酶及细胞增殖抑制活性Table 1 Example compounds on SHP2 enzyme and cell proliferation inhibitory activity

Figure BSA0000197904800000451
Figure BSA0000197904800000451

表1的试验数据表明，本发明提供的化合物具有很好的SHP2激酶抑制活性，同时对SHP2阳性表达细胞的增殖也有很好的抑制活性。The test data in Table 1 shows that the compounds provided by the present invention have good SHP2 kinase inhibitory activity, and also have good inhibitory activity on the proliferation of SHP2-positive cells.

Claims (10)

Translated fromChinese
1.式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof,
Figure FSA0000197904790000011
Figure FSA0000197904790000011
其中，in,A选自如下两并杂环或三并杂环；A is selected from the following di- or tri-heterocycles;
Figure FSA0000197904790000012
Figure FSA0000197904790000012
R1和R2各自独立地选自氢、卤素和C1-6烷基；R1 and R2 are each independently selected from hydrogen, halogen and C1-6 alkyl;X选自氢、C1-6烷基、C3-8环烷基、C6-10芳基和C5-10杂芳基，所述C1-6烷基和C3-8环烷基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、或C1-6烷基取代，所述C6-10芳基和C5-10杂芳基可与不饱和的脂环、杂脂环、螺环稠合，并且可任选地被一个或多个卤素、-CF3、-OH、-CN、-O-C1-6烷基、-NR3R4、-O-C(O)NR3R4、-NH-(CO)-C1-6烷基、-S-CH2-CONH2、C1-6烷基、C3-6环烷基、C6-10芳基、或C6-10杂芳基取代；X is selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl and C5-10 heteroaryl, the C1-6 alkyl and C3-8 cycloalkane group can be optionally substituted with one or more halogen, -OH, -OC1-6 alkyl, -NH2 , or C1-6 alkyl, the C6-10 aryl and C5-10 hetero Aryl can be fused with unsaturated alicyclic, heteroalicyclic, spirocyclic, and optionally by one or more halogens,-CF3 , -OH, -CN,-OC1-6 alkyl, - NR3 R4 , -OC(O)NR3 R4 , -NH-(CO)-C1-6 alkyl, -S-CH2 -CONH2 , C1-6 alkyl, C3-6 ring Alkyl, C6-10 aryl, or C6-10 heteroaryl substitution;R3和R4各自独立地选自氢和C1-6烷基；R3 and R4 are each independently selected from hydrogen and C1-6 alkyl;Y选自C6-10芳基、C5-10杂芳基和C3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、C1-6烷基、或C3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C1-6烷基、或-NH2取代；Y is selected from C6-10 aryl, C5-10 heteroaryl and C3-12 heteroalicyclic groups, which aryl, heteroaryl and heteroalicyclic groups may be optionally replaced by one or more halogens , -OH, -OC1-6 alkyl, -NH2 , C1-6 alkyl, or C3-6 cycloalkyl, optionally substituted with halogen, -OH , -OC1-6 alkyl, or -NH2 substituted;Z选自单键、-S-和-C≡C-。Z is selected from single bond, -S- and -C≡C-.2.根据权利要求1所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其具有下式II～X：2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, having the following formulas II-X:
Figure FSA0000197904790000013
Figure FSA0000197904790000021
Figure FSA0000197904790000013
Figure FSA0000197904790000021
其中，R1和R2各自独立地选自氢、卤素和C1-6烷基；wherein, R1 and R2 are each independently selected from hydrogen, halogen and C1-6 alkyl;X选自氢、C1-6烷基、C3-8环烷基、C6-10芳基和C5-10杂芳基，所述C1-6烷基和C3-8环烷基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、或C1-6烷基取代，所述C6-10芳基和C5-10杂芳基可与不饱和的脂环、杂脂环、螺环稠合，并且可任选地被一个或多个卤素、-CF3、-OH、-CN、-O-C1-6烷基、-NR3R4、-O-C(O)NR3R4、-NH-(CO)-C1-6烷基、-S-CH2-CONH2、C1-6烷基、C3-6环烷基、C6-10芳基、或C6-10杂芳基取代；X is selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl and C5-10 heteroaryl, the C1-6 alkyl and C3-8 cycloalkane group can be optionally substituted with one or more halogen, -OH, -OC1-6 alkyl, -NH2 , or C1-6 alkyl, the C6-10 aryl and C5-10 hetero Aryl can be fused with unsaturated alicyclic, heteroalicyclic, spirocyclic, and optionally by one or more halogens,-CF3 , -OH, -CN,-OC1-6 alkyl, - NR3 R4 , -OC(O)NR3 R4 , -NH-(CO)-C1-6 alkyl, -S-CH2 -CONH2 , C1-6 alkyl, C3-6 ring Alkyl, C6-10 aryl, or C6-10 heteroaryl substitution;R3和R4各自独立地选自氢和C1-6烷基；R3 and R4 are each independently selected from hydrogen and C1-6 alkyl;Y选自C6-10芳基、C5-10杂芳基和C3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、C1-6烷基、或C3-6环烷基取代，所述烷基或环烷基可任选地被卤素、-OH、-O-C1-6烷基、或-NH2取代。Y is selected from C6-10 aryl, C5-10 heteroaryl and C3-12 heteroalicyclic groups, which aryl, heteroaryl and heteroalicyclic groups may be optionally replaced by one or more halogens , -OH, -OC1-6 alkyl, -NH2 , C1-6 alkyl, or C3-6 cycloalkyl, optionally substituted with halogen, -OH , -OC1-6 alkyl, or -NH2 substituted.3.根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其中R1和R2各自独立地选自氢和C1-6烷基。3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein R1 and R2 are each independently selected from hydrogen and C1-6 alkyl.4.根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其中X选自氢、C1-6烷基、C3-8环烷基、C6-10芳基和C5-10杂芳基，所述C1-6烷基和C3-8环烷基可任选地被一个或多个卤素、-OH、-O-C1-6烷基、-NH2、或C1-6烷基取代，所述C6-10芳基和C5-10杂芳基可任选地被一个或多个卤素、-CF3、-OH、-CN、-O-C1-6烷基、-NR3R4、-O-C(O)NR3R4、-NH-(CO)-C1-6烷基、-S-CH2-CONH2、C1-6烷基、C3-6环烷基、C6-10芳基、或C5-10杂芳基取代，4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein X is selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl and C5-10 heteroaryl, the C1-6 alkyl and C3-8 cycloalkyl may be optionally replaced by one or more halogens, - OH, -OC1-6 alkyl, -NH2 , or C1-6 alkyl substituted, the C6-10 aryl and C5-10 heteroaryl may be optionally substituted with one or more halogens, -CF3 , -OH, -CN, -OC1-6 alkyl, -NR3 R4 , -OC(O)NR3 R4 , -NH-(CO)-C1-6 alkyl, -S -CH2 -CONH2 , C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or C5-10 heteroaryl substituted,R3和R4各自独立地选自氢和C1-6烷基。R3 and R4 are each independently selected from hydrogen and C1-6 alkyl.5.根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其中Y选自C6-10芳基、C5-10杂芳基和C3-12杂脂环基，所述芳基、杂芳基和杂脂环基可任选地被一个或多个-OH、-NH2、或C1-6烷基取代。5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, wherein Y is selected from C6-10 aryl, C5- 10 Heteroaryl and C3-12 Heteroalicyclic, which may be optionally replaced by one or more -OH, -NH2 , or C1-6 alkyl replace.6.根据权利要求1或2所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，其中Y选自C3-12杂脂环基，所述杂脂环基可任选地被一个或多个-OH、-NH2、或C1-6烷基取代。6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, solvate, polymorph or tautomer thereof, wherein Y is selected from C3-12 heteroalicyclic groups, and the The heteroalicyclic group may be optionally substituted with one or more -OH,-NH2 , orC1-6 alkyl.7.以下化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体：7. The following compounds or pharmaceutically acceptable salts, solvates, polymorphs, or tautomers thereof:
Figure FSA0000197904790000031
Figure FSA0000197904790000031
Figure FSA0000197904790000041
Figure FSA0000197904790000041
Figure FSA0000197904790000051
Figure FSA0000197904790000051
8.一种药物组合物，其包含根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体，并任选地包含药学上可接受的辅料。8. A pharmaceutical composition comprising a compound according to any one of claims 1-7 or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, and any Optionally include pharmaceutically acceptable excipients.9.权利要求1-7中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或互变异构体、或者根据权利要求8所述的药物组合物在制备治疗与SHP2相关的疾病的药物中的用途。9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, or a pharmaceutical composition according to claim 8 Use in the preparation of a medicament for treating diseases related to SHP2.10.根据权利要求9所述的用途，其中所述与SHP2相关的疾病为白血病、黑色素瘤、恶性胶质瘤、肺癌、乳腺癌或努男综合症。10. The use according to claim 9, wherein the disease associated with SHP2 is leukemia, melanoma, glioblastoma, lung cancer, breast cancer or Numan syndrome.
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