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CN103304552A - Substituted pyridine compounds and methods and uses thereof - Google Patents

Substituted pyridine compounds and methods and uses thereof Download PDF

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CN103304552A
CN103304552A CN2013100775335A CN201310077533A CN103304552A CN 103304552 A CN103304552 A CN 103304552A CN 2013100775335 A CN2013100775335 A CN 2013100775335A CN 201310077533 A CN201310077533 A CN 201310077533A CN 103304552 A CN103304552 A CN 103304552A
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alkylene
alkyl
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CN103304552B (en
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习宁
王婷瑾
易磊
王如勇
王亮
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Sunshine Lake Pharma Co Ltd
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Abstract

本发明提供了具有式（I）结构的取代吡啶类化合物，其药学上可接受的盐，及其药物制剂，用于调节蛋白激酶的活性，并调节细胞间或细胞内的信号响应。本发明同时也涉及包含本发明化合物的药物组合物，并使用该药物组合物治疗哺乳动物，特别是人类高增殖性疾病的方法。 The present invention provides a substituted pyridine compound having a structure of formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutical preparation thereof, which are used to regulate the activity of protein kinases and regulate intercellular or intracellular signal responses. The present invention also relates to a pharmaceutical composition comprising the compound of the present invention, and a method for using the pharmaceutical composition to treat mammals, especially human hyperproliferative diseases.

Description

取代的吡啶化合物及其使用方法和用途Substituted pyridine compounds and methods and uses thereof

本申请要求于2012年03月09日提交中国专利局、申请号为201210061335.5、发明名称为“取代的吡啶化合物及其使用方法和用途”的中国专利申请和于2012年03月21日提交中国专利局、申请号为201210076143.1、发明名称为“取代的螺双环和稠合双环化合物及其使用方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。  This application requires a Chinese patent application submitted to the China Patent Office on March 09, 2012, with the application number 201210061335.5, and the title of the invention is "Substituted pyridine compounds and their methods of use and uses" and the Chinese patent application filed on March 21, 2012 Office, application number 201210076143.1, invention title "Substituted spiro bicyclic and fused bicyclic compounds and their methods of use and uses", the entire content of which is incorporated by reference in this application. the

技术领域 technical field

本发明属于药物技术领域，尤其涉及一种取代的吡啶化合物及其使用方法和用途。  The invention belongs to the technical field of medicines, and in particular relates to a substituted pyridine compound and its application method and application. the

背景技术 Background technique

蛋白激酶，作为细胞功能的重要调节剂，是基因家族中数量最大、功能最广的成员之一。它们通过对底物蛋白增加磷酸基团，调节多种蛋白的活性、位置和整体功能，并参与编排许多细胞进程。激酶在信号传导和复杂功能的协作中，如：细胞周期，占有非常突出的位置。518种人类蛋白激酶中，有478种由于催化域序列相近，被归入一个超家族，根据增长序列的相似度和生化活性，它们又可以分成不同的组、家族或亚家族。  Protein kinase, as an important regulator of cell function, is one of the members with the largest number and widest functions in the gene family. By adding phosphate groups to substrate proteins, they regulate the activity, location and overall function of a variety of proteins and are involved in orchestrating many cellular processes. Kinases play a prominent role in signal transduction and the coordination of complex functions such as the cell cycle. Among the 518 human protein kinases, 478 were classified into a superfamily due to their similar catalytic domain sequences, and they could be divided into different groups, families or subfamilies according to the similarity of the growing sequence and biochemical activity. the

其中所述激酶部分列表包括abl、AATK、ALK、Akt、axl、bmx、bcr-abl、Blk、Brk、Btk、csk、c-kit、c-Met、c-src、c-fins、CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8、CDK9、CDK10、cRaf1、CSF1R、CSK、DDR1、DDR2、EPHA、EPHB、EGFR、ErbB2、ErbB3、ErbB4、Erk、Fak、fes、FER、FGFR1、FGFR2、FGFR3、FGFR4、FGFR5、Fgr、flt-1、Fps、Frk、Fyn、GSG2、GSK、Hck、ILK、INSRR、IRAK4、ITK、IGF-1R、INS-R、Jak、KSR1、KDR、LMTK2、LMTK3、LTK、Lck、Lyn、MATK、MERTK、MLTK、MST1R、MUSK、NPR1、NTRK、MEK、PLK4、PTK、p38、PDGFR、PIK、PKC、PYK2、RET、ROR1、ROR2、RYK、ros、Ron、SGK493、SRC、SRMS、STYK1、SYK、TEC、TEK、TEX14、TNK1、TNK2、TNNI3K、TXK、TYK2、TYRO3、tie、 tie2、TRK、Yes和Zap70。  Wherein the partial list of kinases includes abl, AATK, ALK, Akt, axl, bmx, bcr-abl, Blk, Brk, Btk, csk, c-kit, c-Met, c-src, c-fins, CDK1, CDK2 , CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, DDR1, DDR2, EPHA, EPHB, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FER, FGFR1, FGFR2 , FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSG2, GSK, Hck, ILK, INSRR, IRAK4, ITK, IGF-1R, INS-R, Jak, KSR1, KDR, LMTK2, LMTK3 , LTK, Lck, Lyn, MATK, MERTK, MLTK, MST1R, MUSK, NPR1, NTRK, MEK, PLK4, PTK, p38, PDGFR, PIK, PKC, PYK2, RET, ROR1, ROR2, RYK, ros, Ron, SGK493 , SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, tie, tie2, TRK, Yes, and Zap70. the

受体酪氨酸激酶(PTKs)是一种类型丰富的跨膜蛋白，可以作为细胞因子、生长因子、激素和其他信号分子的受体。受体酪氨酸激酶表达于多种类型的细胞中，在各种细胞进程中扮演重要角色，包括细胞生长、分化和血管生成。激酶的激活始于胞外区域与配体结合，继而引起构象变化，导致受体二聚化，二聚的受体之间相互磷酸化，随后自磷酸化催化区域外的酪氨酸残基。这种自磷酸化既能稳定活化受体的构象，又能在细胞内信号传导的蛋白中建立磷酸化堆积点。  Receptor tyrosine kinases (PTKs) are an abundant class of transmembrane proteins that serve as receptors for cytokines, growth factors, hormones, and other signaling molecules. Receptor tyrosine kinases are expressed in many types of cells and play important roles in a variety of cellular processes, including cell growth, differentiation, and angiogenesis. Kinase activation begins with ligand binding in the extracellular domain, which in turn causes a conformational change that leads to receptor dimerization, reciprocal phosphorylation of dimerized receptors, and subsequent autophosphorylation of tyrosine residues outside the catalytic domain. This autophosphorylation both stabilizes the conformation of activated receptors and creates phosphorylation stacking sites in intracellular signaling proteins. the

通过受体激活突变，基因放大，生长因子活化等途径，受体酪氨酸激酶在许多人类实体瘤和恶性血液病中表现为高活性。PTKs的加速激活对各种致瘤因素都有促进作用，如增生、存活、侵入、转移和血管生成，因此，抑制受体酪氨酸激酶的活性被认为是癌症治疗的有效方案(Sharma PS,et al.(2009)“Receptor tyrosine kinase inhibitors as potent weapons in war against cancers.”Curr Pharm Des.15(7):758-76.)。  Receptor tyrosine kinases are highly active in many human solid tumors and hematological malignancies through receptor activating mutations, gene amplification, and growth factor activation. Accelerated activation of PTKs contributes to various tumorigenic factors, such as proliferation, survival, invasion, metastasis, and angiogenesis, therefore, inhibition of the activity of receptor tyrosine kinases is considered an effective strategy for cancer therapy (Sharma PS, et al. (2009) "Receptor tyrosine kinase inhibitors as potent weapons in war against cancers." Curr Pharm Des.15(7):758-76.). the

受体酪氨酸激酶间变性淋巴瘤激酶(ALK)，属于胰岛素受体超家族，与多种人体肿瘤的产生有关。事实上，已初步确认ALK以组成性激活和致癌基因融合的形式存在，以存在于间变性大细胞淋巴瘤（非霍金森淋巴瘤的一种独立类型）中的(NPM)-ALK-最为常见(Morris,S.W.;et al“Fusion of a kinase gene,ALK,to a nucleolar protein gene,NPM,in non-Hodgkin's lymphoma.”Science1994,263:1281–4.)。  The receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which belongs to the insulin receptor superfamily, is involved in the development of a variety of human tumors. In fact, ALK has been tentatively identified as constitutively activated and oncogene fusions, most commonly (NPM)-ALK- in anaplastic large cell lymphoma, a separate type of non-Hodgkin's lymphoma (Morris, S.W.; et al "Fusion of a kinase gene, ALK, to a nuclear protein gene, NPM, in non-Hodgkin's lymphoma." Science 1994, 263: 1281–4.). the

此外，人们还在炎症性肌纤维母细胞瘤（IMTs）中发现了ALK融合基因，而在食管鳞状细胞癌的亚种中，也发现了ALK融合基因——TPM4-ALK。研究显示，家族型和发散性神经母细胞瘤中，都存在多种ALK基因的突变。这种存在于神经母细胞瘤细胞中的突变可引起组成型ALK磷酸化和机能衰退。相反的，使用sRNA和小分子ALK抑制剂可以抑制细胞株的快速增长(Palmer,R.H.;et al“Anaplastic lymphoma kinase:signalling in development and disease.”Biochem J.2009,420:345–61.)。  In addition, ALK fusion genes have been found in inflammatory myofibroblastic tumors (IMTs), and in a subspecies of squamous cell carcinoma of the esophagus, the TPM4-ALK fusion gene. Studies have shown that there are multiple ALK gene mutations in both familial and sporadic neuroblastoma. This mutation, present in neuroblastoma cells, causes constitutive ALK phosphorylation and functional decline. In contrast, the rapid growth of cell lines can be suppressed using sRNA and small molecule ALK inhibitors (Palmer, R.H.; et al "Anaplastic lymphoma kinase: signaling in development and disease." Biochem J. 2009, 420:345–61.). the

最近几年，人们证实在非小细胞肺癌（NSCLC）细胞中，存在由部 分棘皮动物微管相关蛋白样4（EML4）基因和ALK基因组成的融合基因的多种亚型。大约有3-7%的NSCLC患者被检出EML4-ALK融合基因转录物。体内和体外的试验证实，EML4-ALK融合基因蛋白具有致癌转化活性，对人类罹患NSCLC有重要影响(Soda,M;et al“Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.”Nature.2007,448:561–6.)。  In recent years, it has been confirmed that in non-small cell lung cancer (NSCLC) cells, there are multiple subtypes of fusion genes composed of part of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene. EML4-ALK fusion gene transcripts were detected in about 3-7% of NSCLC patients. Experiments in vivo and in vitro have confirmed that the EML4-ALK fusion gene protein has oncogenic transformation activity and has an important impact on human NSCLC (Soda, M; et al "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer .” Nature. 2007, 448:561–6.). the

ALK的融合基因显示出明显的致癌性，它异常的酪氨酸激酶活性能加强细胞增殖和存活，导致细胞骨架重排，使细胞形状发生变化。致癌的ALK信号转导过程中，ALK与下游分子相互作用，然后激活细胞内信号通路，与大多数正常和致癌的酪氨酸激酶一样，ALK融合基因可以激活多种不同的通路，这些通路紧密相连，相互重合，最后形成一个复杂的信号转导网络。据文献报道，最相关，且研究较为清楚的通路有三条：Ras-ERK（细胞外信号调节激酶）通路，JAK3（Janus激酶3）-STAT3通路和PI3K（磷脂酰肌醇3-激酶）-Akt通路。这三条通路中的许多位点可以介导ALK的活化作用。总之，JAK3-STAT3通路和PI3K-Akt通路对细胞存活和表型改变起着至关重要的作用（Nat Rev Cancer.2008,8:11–23;Barreca,A.;et al“Anaplastic lymphoma kinase(ALK)in human cancer.”JMolEndocrinol.2011,47:R11–23.）。  The fusion gene of ALK shows obvious carcinogenesis, and its abnormal tyrosine kinase activity can enhance cell proliferation and survival, lead to rearrangement of cytoskeleton, and change the shape of cells. In the process of oncogenic ALK signal transduction, ALK interacts with downstream molecules and then activates intracellular signaling pathways. Like most normal and oncogenic tyrosine kinases, ALK fusion genes can activate a variety of different pathways, which are closely related to each other. Connected, overlap each other, and finally form a complex signal transduction network. According to literature reports, there are three most relevant and well-researched pathways: Ras-ERK (extracellular signal-regulated kinase) pathway, JAK3 (Janus kinase 3)-STAT3 pathway and PI3K (phosphatidylinositol 3-kinase)-Akt path. Many sites in these three pathways can mediate the activation of ALK. In summary, the JAK3-STAT3 pathway and the PI3K-Akt pathway play a crucial role in cell survival and phenotypic changes (Nat Rev Cancer.2008,8:11–23; Barreca, A.; et al “Anaplastic lymphoma kinase( ALK) in human cancer." J Mol Endocrinol. 2011, 47: R11–23.). the

完整、正常的ALK受体与其他恶性肿瘤疾病的产生也存在关联，比如，胶质母细胞瘤、神经母细胞瘤、乳癌，等等。在一项人类癌症细胞株的收集调研中，Dirks等人证实，在神经系统细胞株和大部分外胚层实体癌症细胞株中存在ALK转录物的表达，这些细胞株包括视网膜母细胞瘤，黑素瘤和乳癌（Dirks,P.B.,Nature Medicine2008,14,373–375.）。  Intact, normal ALK receptors are also associated with the development of other malignancies, such as glioblastoma, neuroblastoma, breast cancer, and others. In a survey of a collection of human cancer cell lines, Dirks et al. demonstrated expression of ALK transcripts in nervous system cell lines and most ectodermal solid cancer cell lines, including retinoblastoma, melanoma tumor and breast cancer (Dirks, P.B., Nature Medicine 2008, 14, 373–375.). the

c-Met，即肝细胞生长因子受体(HGFR)，其主要的作用点是在内皮细胞，并已证实其在内皮细胞，肌原细胞，造血细胞和运动神经元内均有表达。c-Met天然的配体为肝细胞生长因子（HGF），其为一个多功能生长因子，即分散因子（SF）。在胎儿和成人中，激活c-Met可促进某些形态的形成，譬如，侵袭性生长将会导致细胞的快速生长，细胞间的 分裂，和细胞向其周围迁移(“From Tpr-Met to Met,tumorigenesis and tubes.”Oncogene2007,26,1276;“Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target.”Cancer Letter,2009,280,1-14)。  c-Met, namely hepatocyte growth factor receptor (HGFR), its main point of action is endothelial cells, and it has been confirmed that it is expressed in endothelial cells, myogenic cells, hematopoietic cells and motor neurons. The natural ligand of c-Met is hepatocyte growth factor (HGF), which is a multifunctional growth factor, namely scatter factor (SF). In fetuses and adults, activation of c-Met promotes the formation of certain morphological, for example, invasive growths that lead to rapid cell growth, cell-to-cell division, and cell migration to their surroundings (“From Tpr-Met to Met , tumorigenesis and tubes." Oncogene 2007, 26, 1276; "Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target." Cancer Letter, 2009, 280, 1-14). the

广泛存在的人类恶性肿瘤存在持久的c-Met刺激、过表达或变异，包括乳腺癌、肝癌、肺癌、卵巢癌、肾癌、甲状腺癌、结肠癌、恶性胶质瘤、前列腺癌等。c-Met同样牵涉动脉粥样硬化和肺纤维化。通过肿瘤间质的相互作用，包括HGF/c-Met途径，使这些癌细胞的侵袭性生长速度彻底提高了。因此，大量证据显示c-Me信号响应与一些癌症疾病的发展速度有关，并提高了其在与以c-Met为主要靶点的癌症药物开发中的角色地位(“Molecular cancer therapy:can our expectation be MET.”Euro.J.Cancer,2008,44,641-651;“Targeting the c-Met Signaling Pathway in Cancer.”Clin.Cancer Res.2006,12,3657).Agents targeting c-Met signaling pathway are now under clinical investigation.(“Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer.”Clinical Cancer Research,2009,15,2207).“Drug development of MET inhibitors:targeting oncogene addiction and expedience.”Nature Review Drug Discovery,2008,7,504)。  Persistent c-Met stimulation, overexpression or mutation exists in widespread human malignancies, including breast cancer, liver cancer, lung cancer, ovarian cancer, kidney cancer, thyroid cancer, colon cancer, malignant glioma, prostate cancer, etc. c-Met has also been implicated in atherosclerosis and pulmonary fibrosis. The aggressive growth rate of these cancer cells was radically enhanced through tumor-stroma interactions, including the HGF/c-Met pathway. Thus, substantial evidence links c-Me signaling response to the rate of progression of some cancer diseases and raises its role in the development of cancer drugs that target c-Met (“Molecular cancer therapy: can our expectation be MET."Euro.J.Cancer,2008,44,641-651;"Targeting the c-Met Signaling Pathway in Cancer."Clin.Cancer Res.2006,12,3657).Agents targeting c-Met signaling pathway are now under clinical investigation. ("Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer." Clinical Cancer Research, 2009, 15, 2207). "Drug development of MET inhibitors: targeting oncogene addiction and experience." Nature 0scovery 8 Drug Di ,7,504). the

临床上，已经有许多ALK和/或c-Met抑制剂用来治疗癌症。克卓替尼（Crizotinib）是一种小分子ATP竞争性ALK抑制剂，同时，也可作用于c-Met受体酪氨酸激酶。2008年8月26日，美国FDA批准克卓替尼（Pfizer’s Xalkori,originally known as PF-02341066）用于治疗局部晚期或转移性的，存在间变性淋巴瘤激酶（ALK）基因重排的非小细胞肺癌。ALK（EML4-ALK）基因的重排导致细胞突变，促进了肺癌细胞的恶性表型。因此，抑制突变的激酶ALK对于治疗癌症是有效的。  Clinically, many ALK and/or c-Met inhibitors have been used to treat cancer. Crizotinib is a small-molecule ATP-competitive ALK inhibitor that also acts on c-Met receptor tyrosine kinase. On August 26, 2008, the US FDA approved crizotinib (Pfizer's Xalkori, originally known as PF-02341066) for the treatment of locally advanced or metastatic non-small cells with anaplastic lymphoma kinase (ALK) gene rearrangement lung cancer. Rearrangements of the ALK (EML4-ALK) gene lead to cellular mutations that promote the malignant phenotype of lung cancer cells. Therefore, inhibition of the mutated kinase ALK would be effective in the treatment of cancer. the

发明内容 Contents of the invention

有鉴于此，本发明提供了一种新的取代的吡啶化合物，该化合物对蛋白酪氨酸激酶具有抑制作用，可以用于制备治疗细胞增殖性疾病的药物。  In view of this, the present invention provides a new substituted pyridine compound, which has inhibitory effect on protein tyrosine kinase, and can be used to prepare medicines for treating cell proliferation diseases. the

本发明的化合物对蛋白酪氨酸激酶活性有抑制作用，更让人满意的 是，本发明的化合物可以抑制像ALK（包括ALK融合基因，如：EML4-ALK，NPM-ALK等），或c-Met受体（肝细胞生长因子受体）信号响应。相应地，本发明还提供了一些新的蛋白酪氨酸激酶受体信号响应的抑制剂，如ALK受体信号响应，或c-Met受体信号响应。  The compounds of the present invention have inhibitory effect on protein tyrosine kinase activity, more satisfactory is that the compounds of the present invention can inhibit ALK (including ALK fusion genes, such as: EML4-ALK, NPM-ALK, etc.), or c -Met receptor (hepatocyte growth factor receptor) signaling response. Correspondingly, the present invention also provides some novel inhibitors of protein tyrosine kinase receptor signal response, such as ALK receptor signal response, or c-Met receptor signal response. the

特别地，本发明所涉及的化合物，及其药学上可接受的组合物，都可以有效地作为酪氨酸激酶受体，如ALK或c-Met的抑制剂。  In particular, the compounds involved in the present invention, and pharmaceutically acceptable compositions thereof, can be effectively used as inhibitors of tyrosine kinase receptors, such as ALK or c-Met. the

一方面，本发明涉及一种如式(I)所示的化合物：  On the one hand, the present invention relates to a kind of compound as shown in formula (I):

Figure BDA00002905454700051
Figure BDA00002905454700051

或其立体异构体，几何异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，其中，R1，R2，R3，R4，R5，R6和Z具有如本发明所述的含义。  Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the meanings described in the present invention.

在一些实施方案，各R1，R2，R3，R4，R5和R6独立地为H，D或F；  In some embodiments, each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H, D or F;

Z为  Z is

(1)（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代；  (1) (C 3 -C 7 ) heterocyclyl, and is independently selected from D, F, Cl, Br, I, N 3 , (C 1 -C 6 ) alkane by 1, 2, 3, 4 or 5 radical, (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene-CN, -(C 1 -C 4 ) Substituents of alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR b R c ;

当杂环基的环成员包含-N(H)-时，-N(H)-中的氢原子不能被取代；  When the ring member of the heterocyclyl group contains -N(H)-, the hydrogen atom in -N(H)- cannot be replaced;

当R1、R2、R3、R4、R5和R6为H，Z为单取代的哌啶基时，哌啶环上的4-位不能被D取代；  When R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H, and Z is a monosubstituted piperidinyl group, the 4-position on the piperidine ring cannot be substituted by D;

(2)-（C1-C4）亚烷基-（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）卤代烷基，-CN，-OH，-ORa， -NRbRc，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代；  (2)-(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, and is independently selected from D, F, Cl, Br, I by 1, 2, 3, 4 or 5 , N 3 , (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 ) Substituents of alkylene-OR a or -(C 1 -C 4 ) alkylene-NR b R c ;

-（C1-C4）亚烷基-（C3-C7）杂环基中的杂环基不能被-OH单取代；  -(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl in which the heterocyclyl cannot be monosubstituted by -OH;

(3)（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环；或  (3) (C 5 -C 12 ) fused bicyclic group, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, I, N 3 , (C 1 - C 6 )alkyl, (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene -CN, -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR b R c substituents are substituted, and the bicyclic ring system The ring in can be carbocyclic or heterocyclic; or

(4)-（C1-C4）亚烷基-（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环；  (4)-(C 1 -C 4 )alkylene-(C 5 -C 12 )fused bicyclyl, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl , Br, I, N 3 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 ) Alkylene-CN, -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR The substituent of b R c is substituted, and the ring in the bicyclic ring system can be carbocyclic or heterocyclic;

其中，Ra为（C1-C6）烷基，（C1-C6）烯基，（C1-C6）炔基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基或-（C1-C4）亚烷基-（C1-C9）杂芳基，所述各（C1-C6）烷基，（C1-C6）烯基，（C1-C6）炔基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基和-（C1-C4）亚烷基-（C1-C9）杂芳基任选地被1，2，3或4个独立选自D，F，Cl，N3，-CN，-OH，-NH2，烷氧基或烷基氨基的取代基所取代；  Among them, R a is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl, (C 3 - C 6 )heterocyclyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene -(C 3 -C 6 )cycloalkyl , -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl, each of the (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkyne radical, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aryl, (C 1 -C 9 ) heteroaryl, -(C 1 - C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene Alkyl-(C 6 -C 10 )aryl and -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl are optionally 1, 2, 3 or 4 independently selected from Substituents of D, F, Cl, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino;

Rb和Rc独立地为H，（C1-C6）烷基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基或-（C1-C4）亚烷基-（C1-C9）杂芳基；所述各（C1-C6）烷基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4） 亚烷基-（C6-C10）芳基和-（C1-C4）亚烷基-（C1-C9）杂芳基任选地被1，2，3，或4个独立选自D，F，Cl，N3，-CN，-OH，-NH2，烷氧基或烷基氨基的取代基所取代；当Rb和Rc与同一个氮原子相连时，Rb，Rc和与他们相连的氮原子一起，还可以任选地形成（C3-C6）杂环基。  R b and R c are independently H, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aromatic radical, (C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(C 1 -C 9 ) Heteroaryl; each (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aryl, ( C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 ) Heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl optionally substituted by 1, 2, 3, or 4 substituents independently selected from D, F, Cl, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino; when R When b and R c are connected to the same nitrogen atom, R b , R c and the nitrogen atom connected to them may also optionally form a (C 3 -C 6 ) heterocyclic group.

在另外一些实施方案中，R1，R2，R3，R4，R5和R6独立地为H或D。  In other embodiments, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently H or D.

在另外一些实施方案中，Z为：  In other embodiments, Z is:

(1)（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；  (1) (C 3 -C 7 ) heterocyclyl, and is independently selected from D, F, N 3 , (C 1 -C 3 ) alkyl by 1, 2, 3, 4 or 5, (C 1 - C 3 ) Haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-CN, -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c is substituted by substituents;

(2)-（C1-C4）亚烷基-（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，N3，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；  (2)-(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, and is independently selected from D, F, N 3 , (C 1 -C 3 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene- Substituents of OR a or -(C 1 -C 3 ) alkylene -NR b R c ;

(3)（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环；或  (3) (C 5 -C 12 ) fused bicyclic group, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, I, N 3 , (C 1 - C 3 )alkyl, (C 1 -C 3 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene -CN, -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c substituents, and the bicyclic ring system The ring in can be carbocyclic or heterocyclic; or

(4)-（C1-C4）亚烷基-（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环。  (4)-(C 1 -C 4 )alkylene-(C 5 -C 12 )fused bicyclyl, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl , Br, I, N 3 , (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 ) Alkylene-CN, -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b Substituents of R c are substituted, and the rings in the bicyclic ring system may be carbocyclic or heterocyclic.

在另外一些实施方案中，Ra为（C1-C3）烷基，（C1-C3）烯基，（C1-C6）炔基，（C3-C6）环烷基或-（C1-C3）亚烷基-（C3-C6）环烷基，所述各（C1-C3）烷基，（C1-C3）烯基，（C1-C6）炔基，（C3-C6）环烷基和-（C1-C3）亚烷基-（C3-C6）环烷基任选地被1，2，3或4个独立选自D或F的取 代基所取代。  In other embodiments, R a is (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl or -(C 1 -C 3 )alkylene-(C 3 -C 6 )cycloalkyl, each of the (C 1 -C 3 )alkyl, (C 1 -C 3 )alkenyl, (C 1 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl and -(C 1 -C 3 )alkylene-(C 3 -C 6 )cycloalkyl are optionally replaced by 1, 2, 3 or 4 substituents independently selected from D or F are substituted.

在另外一些实施方案中，Rb和Rc独立地为H，（C1-C3）烷基，（C3-C6）环烷基或-（C1-C4）亚烷基-（C3-C6）烷基；所述各（C1-C3）烷基，（C3-C6）环烷基和-（C1-C4）亚烷基-（C3-C6）烷基任选地被1，2，3或4个独立选自D或F的取代基所取代；当Rb和Rc与同一个氮原子相连时，Rb，Rc和与他们相连的氮原子一起，还可以任选地形成（C3-C6）杂环基。  In other embodiments, R b and R c are independently H, (C 1 -C 3 ) alkyl, (C 3 -C 6 ) cycloalkyl or -(C 1 -C 4 ) alkylene- (C 3 -C 6 )alkyl; said each (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl and -(C 1 -C 4 )alkylene-(C 3 - C 6 ) alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D or F; when R b and R c are connected to the same nitrogen atom, R b , R c and Together, their attached nitrogen atoms may also optionally form a (C 3 -C 6 )heterocyclic group.

在另外一些实施方案中，Z选自式（a）～（k）所示的子结构中的任意一种：  In some other embodiments, Z is selected from any one of the substructures shown in formulas (a) to (k):

Figure BDA00002905454700081
Figure BDA00002905454700081

或其立体异构体，其中：  or its stereoisomers, wherein:

n为0，1，2或3；  n is 0, 1, 2 or 3;

各X和X'为-O-或-N(H)-；  Each X and X' is -O- or -N(H)-;

式（a）～（k）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；  The substructures represented by formulas (a) to (k) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups independently by 1, 2, 3, 4 or 5, - OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 )alkylene Alkyl-NR b R c substituents are substituted;

当n为1，2或3时，上述各子结构或其立体异构体不能被-OH单取代；  When n is 1, 2 or 3, the above substructures or their stereoisomers cannot be monosubstituted by -OH;

当各X和X'独立地为-N(H)-时，-N(H)-中的氢原子不能被取代；  When each X and X' are independently -N(H)-, the hydrogen atom in -N(H)- cannot be replaced;

当R1,R2,R3,R4,R5和R6为H，Z为单取代的哌啶基时，哌啶环的4-位不能被D取代。  When R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H, and Z is a monosubstituted piperidinyl group, the 4-position of the piperidine ring cannot be substituted by D.

在另外一些实施方案中，Z选自式（l）～（x）所示的子结构中的任 意一种：  In some other embodiments, Z is selected from any one of the substructures shown in formulas (l) to (x):

Figure BDA00002905454700091
Figure BDA00002905454700091

或其立体异构体，其中：  or its stereoisomers, wherein:

n为0，1，2或3；  n is 0, 1, 2 or 3;

各W和W'为-O-，-N(H)-或-N(C1-C3)烷基-；  Each of W and W' is -O-, -N(H)- or -N(C 1 -C 3 )alkyl-;

式（l）～（x）所示的子结构或其立体异构体任选地被1，2，3，4或5个独立选自D，F，（C1-C3）烷基，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures represented by formulas (l) to (x) or their stereoisomers are optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, (C 1 -C 3 ) alkyl groups, (C 1 -C 3 )haloalkyl, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-ORa Or -(C 1 -C 3 )alkylene-NR b R c substituents.

在另外一些实施方案中，Z选自式（101）～（111）所示的子结构中的任意一种：  In some other embodiments, Z is selected from any one of the substructures shown in formulas (101) to (111):

Figure BDA00002905454700092
Figure BDA00002905454700092

或其立体异构体，其中：  or its stereoisomers, wherein:

式（101）～（111）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures represented by formulas (101) to (111) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups independently by 1, 2, 3, 4 or 5, - OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 )alkylene Alkyl-NR b R c substituents are substituted.

在另外一些实施方案中，Z选自式（201）～（214）所示的子结构中的任意一种：  In some other embodiments, Z is selected from any one of the substructures shown in formulas (201) to (214):

Figure BDA00002905454700101
Figure BDA00002905454700101

或其立体异构体，其中：  or its stereoisomers, wherein:

式（201）～（214）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures represented by formulas (201) to (214) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups by 1, 2, 3, 4 or 5, - OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene- NR b R c substituents are substituted.

在另外一些实施方案中，Z选自式（301）～（323）所示的子结构中的任意一种：  In some other embodiments, Z is selected from any one of the substructures shown in formulas (301) to (323):

Figure BDA00002905454700102
Figure BDA00002905454700102

或其立体异构体，其中：  or its stereoisomers, wherein:

式（301）～（323）所示的子结构或其立体异构体任选地被1，2，3，4或5个独立选自D，F，（C1-C3）烷基，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures represented by formulas (301) to (323) or their stereoisomers are optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, (C 1 -C 3 ) alkyl groups, (C 1 -C 3 )haloalkyl, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c substituents.

在另外一些实施方案中，Ra为（C1-C2）烷基，且任选地被1，2，3或4个独立选自D或F的取代基所取代。  In other embodiments, R a is (C 1 -C 2 )alkyl, optionally substituted with 1, 2, 3 or 4 substituents independently selected from D or F.

在另外一些实施方案中，Rb和Rc独立地为H或（C1-C2）烷基；所述（C1-C2）烷基和（C3-C6）杂环基任选地被1，2，3或4个独立选自D或F的取代基所取代；当Rb和Rc与同一个氮原子相连时，Rb，Rc和与他们相连的氮原子一起，还可以任选地形成（C3-C6）杂环基。  In other embodiments, R b and R c are independently H or (C 1 -C 2 ) alkyl; said (C 1 -C 2 ) alkyl and (C 3 -C 6 ) heterocyclyl are either is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D or F; when R b and R c are connected to the same nitrogen atom, R b , R c and the nitrogen atom to which they are connected , can also optionally form a (C 3 -C 6 ) heterocyclic group.

另一方面，本发明涉及一种药物组合物，其包含本发明化合物，和药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。  In another aspect, the present invention relates to a pharmaceutical composition, which comprises the compound of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. the

在一些实施方案，本发明所述的药物组合物，更进一步地包含附加治疗剂，这些附加治疗剂选自化学治疗药物，抗增殖剂，用于治疗动脉粥样硬化的药物，用于治疗肺纤维化的药物，或它们的组合。  In some embodiments, the pharmaceutical composition of the present invention further comprises additional therapeutic agents selected from chemotherapeutic drugs, antiproliferative agents, drugs for treating atherosclerosis, drugs for treating pulmonary Medications for fibrosis, or a combination of them. the

在另外一些实施方案，本发明所述的药物组合物，其中所涉及的附加治疗剂是苯丁酸氮芥(chlorambucil)，美法仑(melphalan)，环磷酰胺(cyclophosphamide)，异环磷酰胺(ifosfamide)，白消安(busulfan)，卡莫司汀(carmustine)，洛莫司汀(lomustine)，链脲佐菌素(streptozocin)，顺铂(cisplatin)，卡铂(carboplatin)，奥沙利铂(oxaliplatin)，达卡巴嗪(dacarbazine)，替莫唑胺(temozolomide)，丙卡巴肼(procarbazine)，甲氨蝶呤(methotrexate)，氟尿嘧啶(fluorouracil)，阿糖胞苷(cytarabine)，吉西他滨(gemcitabine)，巯基嘌呤(mercaptopurine)，氟达拉滨(fludarabine)，长春碱(vinblastine)，长春新碱(vincristine)，长春瑞滨(vinorelbine)，紫杉醇(paclitaxel)，多西紫杉醇(docetaxel)，拓扑替康(topotecan)，伊立替康(irinotecan)，依托泊苷(etoposide)，曲贝替定(trabectedin)，更生霉素(dactinomycin)，多柔比星(doxorubicin)，表柔比星(epirubicin)，道诺霉素(daunorubicin)，米托蒽醌(mitoxantrone)，博来霉素(bleomycin)，丝裂霉素C(mitomycin)，伊沙匹隆(ixabepilone)，他莫昔芬(tamoxifen)，氟他胺(flutamide)，戈那瑞林类似物(gonadorelinanalogues)，甲地孕酮(megestrol)，强的松(prednidone)，地塞米松(dexamethasone)，甲泼尼龙(methylprednisolone)，沙利度胺(thalidomide)，干扰素α(interferon alfa)，亚叶酸钙(leucovorin)，西罗莫司(sirolimus)，西罗莫司脂化物(temsirolimus)，依维莫司(everolimus)，阿法替尼(afatinib)，alisertib，amuvatinib，阿帕替尼(apatinib)，阿西替尼(axitinib)，硼替佐米(bortezomib)，波舒替尼(bosutinib)，brivanib，cabozantinib，西地尼布(cediranib)，crenolanib，克卓替尼(crizotinib)，dabrafenib，dacomitinib，danusertib，达沙替尼(dasatinib)，dovitinib，厄洛替尼(erlotinib)，foretinib，ganetespib，吉非替尼(gefitinib)，ibrutinib， 埃克替尼(icotinib)，伊马替尼(imatinib)，iniparib，拉帕替尼(lapatinib)，lenvatinib，linifanib，linsitinib，马赛替尼(masitinib)，momelotinib，莫替沙尼(motesanib)，来那替尼(neratinib)，尼罗替尼(nilotinib)，niraparib，oprozomib，olaparib，帕唑帕尼(pazopanib)，pictilisib，ponatinib，quizartinib，regorafenib，rigosertib，rucaparib，ruxolitinib，塞卡替尼(saracatinib)，saridegib，索拉非尼(sorafenib)，舒尼替尼(sunitinib)，tasocitinib，telatinib，tivantinib，tivozanib，tofacitinib，trametinib，凡德他尼(vandetanib)，veliparib，威罗菲尼(vemurafenib)，vismodegib，volasertib，阿仑单抗(alemtuzumab)，贝伐单抗(bevacizumab)，brentuximab vedotin，卡妥索单抗(catumaxomab)，西妥昔单抗(cetuximab)，地诺单抗(denosumab)，吉妥珠单抗(gemtuzumab)，伊匹单抗(ipilimumab)，尼妥珠单抗(nimotuzumab)，奥法木单抗(ofatumumab)，帕尼单抗(panitumumab)，利妥昔单抗(rituximab)，托西莫单抗(tositumomab)，曲妥珠单抗(trastuzumab)或它们的组合。  In other embodiments, the pharmaceutical composition of the present invention, wherein the additional therapeutic agent involved is chlorambucil, melphalan, cyclophosphamide, ifosfamide (ifosfamide), busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxage Oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine , mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan (topotecan), irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, Dow Daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, fluta Flutamide, gonadorelin analogues, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide ), interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib , alisertib, amuvatinib, apatinib, axitinib nib), bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib ( dasatinib), dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib ( lapatinib), lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, prazole Pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, card Catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab , ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, or combinations thereof. the

另一方面，可以使用本发明化合物或药物组合物来制备用于防护、处理、治疗或减轻患者增殖性疾病的药品的用途。  On the other hand, the compounds or pharmaceutical compositions of the present invention can be used to prepare medicines for preventing, treating, treating or alleviating proliferative diseases in patients. the

在一些实施方案，本发明所述的增殖性疾病是转移癌，结肠癌，胃腺癌，膀胱癌，乳腺癌，肾癌，肝癌，肺癌，甲状腺癌，头颈癌，前列腺癌，胰腺癌，CNS（中枢神经系统）的癌症，恶性胶质瘤，骨髓增生病，动脉粥样硬化或肺纤维化。  In some embodiments, the proliferative disease of the present invention is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, CNS ( central nervous system), malignant glioma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis. the

另一方面，本发明涉及使用本发明化合物或药物组合物来制备用于在生物标本内抑制或调节蛋白激酶活性的药品的用途，所述用途包含使用本发明化合物与所述的生物标本接触。  In another aspect, the present invention relates to the use of the compound or pharmaceutical composition of the present invention to prepare a drug for inhibiting or regulating protein kinase activity in a biological sample, the use comprising contacting the biological sample with the compound of the present invention. the

在其中一些实施方案，本发明所述激酶为受体酪氨酸激酶。  In some of these embodiments, the kinase described herein is a receptor tyrosine kinase. the

在另外一些实施方案，本发明所述受体酪氨酸激酶为ALK，c-Met，或它们的组合。  In other embodiments, the receptor tyrosine kinase of the present invention is ALK, c-Met, or a combination thereof. the

另一方面，本发明提供一些药物组合物，其包含本发明作为酪氨酸激酶受体抑制剂的化合物，或其立体异构体，几何异构体，互变异构体，溶剂化物，代谢产物，或其药学上可接受的盐，药学上可接受的载体、 稀释剂，辅剂，媒介物，或它们的组合。在一些实施方案中，本发明所提供药物组合物包含可作为抑制ALK受体信号响应或c-Met受体信号响应的化合物，或其立体异构体，几何异构体，互变异构体，溶剂化物，代谢产物，或其药学上可接受的盐，或药学上可接受的载体、稀释剂，辅剂，媒介物，或它们的组合。在另外一些实施方案中，本发明药物组合物更进一步地包含附加治疗剂。  In another aspect, the present invention provides pharmaceutical compositions comprising compounds of the present invention, or stereoisomers, geometric isomers, tautomers, solvates, metabolites thereof, as inhibitors of tyrosine kinase receptors product, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or a combination thereof. In some embodiments, the pharmaceutical composition provided herein comprises a compound, or a stereoisomer, geometric isomer, or tautomer thereof, that acts as an inhibitor of ALK receptor signaling response or c-Met receptor signaling response , solvate, metabolite, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or a combination thereof. In other embodiments, the pharmaceutical compositions of the present invention further comprise additional therapeutic agents. the

另一方面，本发明涉及抑制蛋白酪氨酸激酶活性的方法，该方法包含本发明化合物或其药物组合物与所述激酶接触。在一些实施方案中，本发明涉及抑制ALK受体信号响应，c-Met受体信号响应的方法，该方法包含本发明化合物或其药物组合物与所述受体接触。另外一些实施方案是，在细胞或多细胞生物体中抑制蛋白激酶受体活性，特别是抑制ALK或c-Met受体信号响应的活性。根据本发明所述的方法，该方法包含使用本发明化合物或其药物组合物对所述多细胞生物体进行给药。在一些实施方案，所述多细胞生物体是指哺乳动物。在另外一些实施方案，所述多细胞生物体是指人类。在一些实施方案，本发明所述方法更进一步地包含附加治疗剂与所述激酶接触。  In another aspect, the invention relates to a method of inhibiting the activity of a protein tyrosine kinase comprising contacting a compound of the invention, or a pharmaceutical composition thereof, with said kinase. In some embodiments, the present invention relates to a method of inhibiting ALK receptor signaling, c-Met receptor signaling, the method comprising contacting a compound of the present invention, or a pharmaceutical composition thereof, with said receptor. In other embodiments, the inhibition of protein kinase receptor activity, particularly the activity of ALK or c-Met receptor signaling in a cell or multicellular organism, is inhibited. According to the method of the present invention, the method comprises administering to said multicellular organism a compound of the present invention or a pharmaceutical composition thereof. In some embodiments, the multicellular organism is a mammal. In other embodiments, the multicellular organism is a human. In some embodiments, the methods described herein further comprise contacting the kinase with an additional therapeutic agent. the

另一方面，本发明涉及一种抑制细胞增殖活性的方法，所述方法包含使用本发明化合物或其药物组合物能抑制增殖的有效治疗量与细胞接触。在一些实施方案，本发明所述方法更进一步地包含附加治疗剂与细胞接触。  In another aspect, the present invention relates to a method of inhibiting the proliferative activity of a cell, said method comprising contacting the cell with a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof capable of inhibiting proliferation. In some embodiments, the methods described herein further comprise contacting the cell with an additional therapeutic agent. the

另一方面，本发明涉及一种治疗患者细胞增殖性疾病的方法，所述方法包含使用本发明化合物或其药物组合物的有效治疗量对患者进行给药。在一些实施方案，本发明所述方法更进一步包含附加治疗剂的给药。  In another aspect, the present invention relates to a method of treating a cell proliferative disorder in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In some embodiments, the methods described herein further comprise the administration of an additional therapeutic agent. the

另一方面，本发明涉及一种抑制患者肿瘤生长的方法，所述方法包含使用本发明化合物或其药物组合物的有效治疗量对患者进行给药。在一些实施方案，本发明所述方法更进一步地包含附加治疗剂的给药。  In another aspect, the present invention relates to a method of inhibiting tumor growth in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof. In some embodiments, the methods described herein further comprise the administration of an additional therapeutic agent. the

另一方面，本发明涉及式(I)所包含的化合物的制备、分离和纯化的方法。  In another aspect, the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I). the

实验结果表明，本发明提供的化合物表现出良好的半衰期和良好的药代动力学性质，对ALK和c-Met具有良好的抑制作用，对肿瘤的增长也具有良好的抑制作用。  Experimental results show that the compound provided by the invention exhibits good half-life and good pharmacokinetic properties, has good inhibitory effect on ALK and c-Met, and also has good inhibitory effect on tumor growth. the

前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。  The preceding description merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described in more detail and more fully below. the

具体实施方式 Detailed ways

定义和一般术语Definitions and General Terms

本发明将会把确定的具体化的内容所对应的文献详细列出，实施例都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触，其中包括但绝不限于术语的定义，术语的用法，描述的技术，或像本发明申请所控制的范围。  The present invention will list in detail the literature corresponding to the determined and embodied content, and the examples are all accompanied by illustrations of structural formulas and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The invention is in no way limited to the description of the methods and materials. There are many documents and similar materials that differ from or contradict the present application, including but in no way limited to the definitions of terms, term usage, described techniques, or the scope of control like the present application. the

除非其他方面表明，本发明将应用以下定义：  Unless otherwise indicated, the following definitions shall apply to the present invention:

根据本发明的目的，化学元素根据元素周期表，CAS版本和化学药品手册，75，thEd，1994来定义。另外，有机化学一般原理见"Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999,and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007，因此所有的内容都融合了参考文献。  For purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Edition and Handbook of Chemicals, 75, th Ed, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, so all The contents are incorporated with references.

像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。“任选地”或“任选”意思是指随后所述的事件或状况可以但未必发生，并且该描述包括其中发生该事件或状况的情况，以及其中未发生该事件或状况的情况。例如：“杂环基任选地被1或2个独立选自D，F的基团所取代”意思是指该D、F可以但未必 存在，并且该描述包括其中杂环基被1或2个独立选自D，F的基团所取代的情况，以及杂环基未被取代的情况。  As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. "Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example: "heterocyclyl is optionally substituted by 1 or 2 groups independently selected from D, F" means that D, F may but not necessarily exist, and the description includes wherein the heterocyclyl is substituted by 1 or 2 The case where two groups independently selected from D and F are substituted, and the case where the heterocyclic group is unsubstituted. the

一般而言，术语“取代的”，表示所给结构中的一个或多个氢原子可以被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，氘，氟，氯，溴，碘，氰基，硝基，叠氮基，烷基，卤代烷基，链烯基，炔基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，氰基烷基，羟基，烷氧基，巯基，烷硫基，氨基，烷氨基，氨基酰基，烷氨基酰基，氨基酰基氧基，烷氨基酰基氧基，芳基，杂芳基等等。  In general, the term "substituted" means that one or more hydrogen atoms in a given structure may be replaced by a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, azido, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl , alkoxyalkyl, aminoalkyl, alkylaminoalkyl, cyanoalkyl, hydroxyl, alkoxy, mercapto, alkylthio, amino, alkylamino, aminoacyl, alkylaminoacyl, aminoacyloxy, Alkaminoacyloxy, aryl, heteroaryl and the like. the

在本发明中所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。  As used herein, the term "unsaturated" means that a moiety contains one or more degrees of unsaturation. the

术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。  The term "comprising" is an open expression, that is, it includes the content specified in the present invention, but does not exclude other content. the

术语“H”表示单个氢原子。这样的原子团可以与其他基团连接，譬如与氧原子相连，形成羟基基团。  The term "H" denotes a single hydrogen atom. Such atomic groups can be linked to other groups, such as oxygen atoms, to form hydroxyl groups. the

术语“D”或“2H”表示单个氘原子。一个这样的原子团与一个甲基相连，形成单-氘代甲基（-CDH2），两个氘原子与一个甲基相连，形成双-氘代甲基（-CD2H），以及三个氘原子与一个甲基相连，形成三-氘代甲基（-CD3）。  The term "D" or " 2H " denotes a single deuterium atom. One such group is attached to a methyl group to form a mono-deuteromethyl group ( -CDH2 ), two deuterium atoms are attached to a methyl group to form a bis-deuteromethyl group ( -CD2H ), and three The deuterium atom is attached to a methyl group to form tri-deuteromethyl (-CD 3 ).

术语“N3”表示一个叠氮结构。这种基团可以与其他基团相连接，例如，与甲基基团相连接，可以形成叠氮甲烷(甲基叠氮，MeN3)；而与苯基基团相连接，则形成苯基叠氮(PhN3)。  The term " N3 " denotes an azide structure. This group can be linked with other groups, for example, with a methyl group, it can form azidomethane (methyl azide, MeN 3 ); and with a phenyl group, it can form a phenyl Azide (PhN 3 ).

术语“卤素”是指F，Cl，Br或I。  The term "halogen" refers to F, Cl, Br or I. the

本发明使用的术语“烷基”或“烷基基团”，表示含1-20个碳原子的饱和直链或支链一价烃基。除非另外说明，烷基基团含有1-20个碳原子；其中一些实施例是，烷基基团含有1-10个碳原子，另外一些实施例中， 烷基基团含有1-6个碳原子，又一些实施例中，烷基基团含有1-3个碳原子，还有一些实施例中，烷基基团含有1-2个碳原子。  The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1-20 carbon atoms. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms; in some embodiments, the alkyl group contains 1-10 carbon atoms, and in other embodiments, the alkyl group contains 1-6 carbon atoms Atoms, in yet other embodiments, the alkyl group contains 1-3 carbon atoms, and in still other embodiments, the alkyl group contains 1-2 carbon atoms. the

烷基基团的实例包含，但并不限于，甲基(Me，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，异丙基(i-Pr，i-propyl，-CH(CH3)2)，正丁基(n-Bu，n-butyl，-CH2CH2CH2CH3)，异丁基(i-Bu，i-butyl，-CH2CH(CH3)2)，仲丁基(s-Bu，s-butyl，-CH(CH3)CH2CH3)，叔丁基(t-Bu，t-butyl，-C(CH3)3)，正戊基(n-pentyl，-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。并且烷基可以是取代或非取代的，其中取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), n-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), isobutyl ( i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , t-butyl, -C(CH 3 ) 3 ), n-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2- Butyl (-CH(CH 3 ) CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl ( -CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3 -Methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 ) C(CH 3 ) 3 ), n-heptyl, n-octyl, etc. And the alkyl group can be substituted or unsubstituted, where the substituents can be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkoxy , amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, etc.

本发明所使用的术语“烷基”和其前缀“烷”，都包含直链和支链的饱和碳链。  As used herein, the term "alkyl" and its prefix "alk" include both straight and branched saturated carbon chains. the

本发明使用的术语“亚烷基”，表示从直链或支链饱和碳氢化合物中消去两个氢原子得到的饱和二价烃基。除非另外详细说明，亚烷基基团含有1-10个碳原子，其中一些实施例是，亚烷基基团含有1-6个碳原子，另外一些实施例是，亚烷基基团含有1-4个碳原子，还有一些实施例是，亚烷基基团含有1-3个碳原子。亚烷基基团的实例包括，但并不限于，亚甲基(-CH2-)，亚乙基(-CH2CH2-)，亚异丙基(-CH(CH3)CH2-)等等。亚烷基可被进一步取代，取代基可以是，但并不限于，氘，氟，氯，溴， 碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "alkylene" used in the present invention means a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched saturated hydrocarbon. Unless otherwise specified, the alkylene group contains 1-10 carbon atoms, in some embodiments, the alkylene group contains 1-6 carbon atoms, and in other embodiments, the alkylene group contains 1 - 4 carbon atoms, and in some embodiments, the alkylene group contains 1-3 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2 - )etc. The alkylene group can be further substituted, and the substituents can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxyl, alkoxy, amino, alkane Amino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like.

术语“烯基”表示2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp2双键，烯基基团可以有“顺”、“反”或“E”、“Z”的定位，具体的实例包括，但并不限于，乙烯基(-CH=CH2)，烯丙基(-CH2CH=CH2)，等等。本发明所述烯基可以独立任选地被进一步取代，取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "alkenyl" means a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one The position is in an unsaturated state, that is, one CC is a sp 2 double bond, and the alkenyl group can have "cis", "anti" or "E", "Z" orientations. Specific examples include, but are not limited to, ethylene radical (-CH=CH 2 ), allyl group (-CH 2 CH=CH 2 ), and so on. The alkenyl group described in the present invention can be independently and optionally further substituted, and the substituents can be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxyl, Alkoxy, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like.

术语“炔基”表示2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp三键，具体的实例包括，但并不限于，乙炔基(-C≡CH)，炔丙基(-CH2C≡CH)等等。其中烃基基团可以独立任选地被进一步取代，取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "alkynyl" means 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms linear or branched monovalent hydrocarbon groups, wherein at least one position It is an unsaturated state, that is, one CC is an sp triple bond. Specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH) and the like. Where the hydrocarbyl groups can be independently optionally further substituted, the substituents can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkoxy radical, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like.

本发明中所使用的术语“烷氧基”或“烷氧基基团”，是指烷基通过氧原子连接到主要的碳链上，其中，烷基具有如本发明所述的定义。除非另外说明，烷氧基基团含有1-20个碳原子；其中一些实施例是，烷氧基基团含有1-10个碳原子；另外一些实施例中，烷氧基基团含有1-8个碳原子；又一些实施例中，烷氧基基团含有1-6个碳原子；还有一些实施例中，烷氧基基团含有1-4个碳原子。  The term "alkoxy" or "alkoxy group" used in the present invention refers to an alkyl group connected to the main carbon chain through an oxygen atom, wherein the alkyl group has the definition as described in the present invention. Unless otherwise stated, alkoxy groups contain 1-20 carbon atoms; in some embodiments, alkoxy groups contain 1-10 carbon atoms; in other embodiments, alkoxy groups contain 1- 8 carbon atoms; in yet other embodiments, the alkoxy group contains 1-6 carbon atoms; in still other embodiments, the alkoxy group contains 1-4 carbon atoms. the

烷氧基基团的具体实例包括，但不限于：甲氧基(MeO,-OCH3)，乙氧基(EtO,-OCH2CH3)，1-丙氧基(n-PrO,n-propoxy,-OCH2CH2CH3)，2-丙氧基(i-PrO,i-propoxy,-OCH(CH3)2)，1-丁氧基(n-BuO,n-butoxy,-OCH2CH2CH2CH3)，2-甲基-l-丙氧基(i-BuO,i-butoxy,-OCH2CH(CH3)2)，2-丁氧基(s-BuO,s-butoxy,-OCH(CH3)CH2CH3)，2-甲基-2-丙氧基(t-BuO,t-butoxy,-OC(CH3)3)，1-戊氧基(n-pentoxy, -OCH2CH2CH2CH2CH3)，2-戊氧基(-OCH(CH3)CH2CH2CH3)，3-戊氧基(-OCH(CH2CH3)2)，2-甲基-2-丁氧基(-OC(CH3)2CH2CH3)，3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2)，3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2)，2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3)，等等。  Specific examples of alkoxy groups include, but are not limited to: methoxy (MeO,-OCH 3 ), ethoxy (EtO,-OCH 2 CH 3 ), 1-propoxy (n-PrO,n- propoxy,-OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO,i-propoxy,-OCH(CH 3 ) 2 ), 1-butoxy (n-BuO,n-butoxy,-OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO,i-butoxy,-OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO,s -butoxy,-OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO,t-butoxy,-OC(CH 3 ) 3 ), 1-pentyloxy (n -pentoxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentoxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentoxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-l-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ) ,etc.

术语“烷氧基烷基“表示烷基基团被一个或多个烷氧基基团所取代，其中烷基基团和烷氧基基团具有如本发明所述的含义，这样的实例包括，但并不限于甲氧基甲基，乙氧基甲基，乙氧基乙基等。  The term "alkoxyalkyl" means that an alkyl group is substituted by one or more alkoxy groups, wherein the alkyl group and the alkoxy group have the meanings described herein, examples of which include , but not limited to methoxymethyl, ethoxymethyl, ethoxyethyl, etc. the

术语“羟基烷基“包括被一个或多个羟基所取代的C1-10直链或支链烷基基团。其中一些实施例是，羟基烷基是被一个或多个羟基基团所取代的C1-6“较低级的羟基烷基”，这样的实例包括，但并不限于，羟甲基，羟乙基，羟丙基，羟丁基和羟己基。  The term "hydroxyalkyl" includes C 1-10 straight or branched chain alkyl groups substituted with one or more hydroxy groups. In some embodiments, hydroxyalkyl is C 1-6 "lower hydroxyalkyl" substituted with one or more hydroxy groups, examples of which include, but are not limited to, hydroxymethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

术语“卤代烷基”和“卤代烷氧基”表示烷基或烷氧基基团被一个或多个相同或不同的卤素原子所取代，其中烷基和烷氧基具有如本发明所述的含义，这样的实例包括，但并不限于，氯甲基，三氟甲基，三氟乙基，三氟甲氧基，等等。  The terms "haloalkyl" and "haloalkoxy" mean that an alkyl or alkoxy group is substituted by one or more identical or different halogen atoms, wherein alkyl and alkoxy have the meanings described herein, Such examples include, but are not limited to, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and the like. the

术语“烷氨基”或“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是，烷基氨基是一个或两个C1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是C1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。  The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, alkylamino is a lower alkylamino group with one or two C 1-6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino is a C 1-3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.

术语“氨基烷基”包括被一个或多个氨基所取代的C1-10直链或支链烷基基团。其中一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C1-6“较低级的氨基烷基”，这样的实例包括，但并不限于，氨甲基，氨乙基，氨丙基，氨丁基和氨己基。  The term "aminoalkyl" includes C 1-10 straight or branched chain alkyl groups substituted with one or more amino groups. In some embodiments, aminoalkyl is C 1-6 "lower aminoalkyl" substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, amino Ethyl, aminopropyl, aminobutyl and aminohexyl.

术语“氰基烷基”包括被一个或多个氰基所取代的C1-10直链或支链烷基基团。其中一些实施例是，氰基烷基是被一个或多个氰基基团所取代的C1-6“较低级的氰基烷基”，这样的实例包括，但并不限于，氰基甲 基，氰基乙基，氰基丙基，氰基丁基和氰基己基。  The term "cyanoalkyl" includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups. In some embodiments, cyanoalkyl is C 1-6 "lower cyanoalkyl" substituted with one or more cyano groups, examples of which include, but are not limited to, cyano Methyl, cyanoethyl, cyanopropyl, cyanobutyl and cyanohexyl.

术语“烷氨基烷基”包括被烷氨基取代的烷基基团。其中一些实施例是，烷氨基烷基是C1-6较低级的烷氨基烷基。另外一些实施例是，烷氨基烷基是C1-3较低级的烷氨基烷基。合适的烷氨基烷基基团可以是单烷基或二烷基取代的，这样的实施例包括，但并不限于，N-甲基氨基甲基，N,N-二甲基氨基乙基，N,N-二乙基氨基甲基等等。  The term "alkaminoalkyl" includes alkyl groups substituted with alkylamino groups. In some embodiments, the alkylaminoalkyl is a C 1-6 lower alkylaminoalkyl. In some other embodiments, the alkylaminoalkyl is C 1-3 lower alkylaminoalkyl. Suitable alkylaminoalkyl groups may be mono- or di-alkyl substituted, examples of which include, but are not limited to, N-methylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl and so on.

术语“环烷基”指一价或多价的烃基，是含3-12个碳原子的单环体系。其中一些实施例是，环烷基包含3-8个碳原子，另外一些实施例是，环烷基包含3-6个碳原子。且环烷基可被进一步取代，取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "cycloalkyl" refers to a monovalent or polyvalent hydrocarbon group, which is a monocyclic ring system containing 3-12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-8 carbon atoms, and in other embodiments, the cycloalkyl group contains 3-6 carbon atoms. And the cycloalkyl group can be further substituted, the substituents can be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxyl, alkoxy, amino, Alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like. the

术语“环烷基亚烷基”表示烷基基团可以被一个或多个环烷基基团所取代，其中烷基和环烷基基团具有如本发明所述的含义。其中一些实施例是，环烷基亚烷基基团是指“较低级的环烷基亚烷基”基团，即环烷基基团连接到C1-6的烷基基团上。另外一些实施例是，环烷基基团连接到C1-4的烷基基团上。另外一些实施例是，环烷基基团连接到C1-3的烷基基团上。这样的实例包括，但并不限于，环丙基乙基，环戊基甲基，环己基甲基等等。环烷基亚烷基可被进一步取代，该取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "cycloalkylalkylene" means that an alkyl group may be substituted by one or more cycloalkyl groups, wherein alkyl and cycloalkyl groups have the meanings described herein. In some of these embodiments, a cycloalkylalkylene group refers to a "lower cycloalkylalkylene" group, ie a cycloalkyl group attached to a C 1-6 alkyl group. In some other embodiments, the cycloalkyl group is attached to a C 1-4 alkyl group. In some other embodiments, the cycloalkyl group is attached to a C 1-3 alkyl group. Such examples include, but are not limited to, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. Cycloalkylalkylene may be further substituted, the substituents may be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkoxy , amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, etc.

术语“杂原子”表示一个或多个O，S，N，P和Si，包括N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N（像3，4-二氢-2H-吡咯基中的N），NH（像吡咯烷基中的NH）或NR（像N-取代的吡咯烷基中的NR）。  The term "heteroatom" means one or more of O, S, N, P, and Si, including forms in any oxidation state of N, S, and P; forms of primary, secondary, and tertiary amines, and quaternary ammonium salts; or nitrogen in heterocycles The form in which the hydrogen on the atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidine NR in the base). the

术语“杂环”、“杂环基”或“杂环的”在此处可交换使用，都是指单环体系，其中环上一个或多个原子独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，只有一个 连接点连接到其他分子上去。一个或多个环上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，“杂环”，“杂环基”或“杂环的”基团是3-7元环的单环（2-6个碳原子和选自N，O，P，S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团，当所述的环为三元环时，其中只有一个杂原子）。  The terms "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein to refer to a monocyclic ring system in which one or more atoms of the ring are independently optionally replaced by heteroatoms, the ring Can be fully saturated or contain one or more degrees of unsaturation, but is never aromatic, having only one point of attachment to other molecules. One or more ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. In some embodiments, a "heterocycle", "heterocyclyl" or "heterocyclic" group is a 3-7 membered monocyclic ring (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 , when the ring is a three-membered ring , which has only one heteroatom).

杂环基可以是碳基或杂原子基。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基,哌啶基，吗啉基，硫代吗啉基，噻噁烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，高哌啶基，环氧丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基，咪唑啉基，咪唑烷基，杂环基团的实例还包括，环上两个碳原子被氧（=O）取代的嘧啶二酮基和1,1-二氧硫代吗啉基。并且所述杂环基独立任选地被本发明中的一个或多个取代基取代，其中取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  A heterocyclic group may be a carbon group or a heteroatom group. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Thioxanyl, Piperazinyl, Homopiperazinyl, Azetidinyl, Oxetanyl, Thietanyl, Homopiperidinyl, Glycidyl Base, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, Indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolyl, pyrazolinyl, dithianyl, dithianyl, di Hydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, examples of heterocyclic groups also include, pyrimidine diketonyl and 1,1-bis Oxythiomorpholino. And the heterocyclic group is independently and optionally substituted by one or more substituents in the present invention, wherein the substituents can be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl , haloalkyl, cyano, hydroxy, alkoxy, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkaminoalkyl, etc. the

术语“杂环基亚烷基”表示烷基基团可以被一个或多个杂环基基团所取代，其中烷基和杂环基基团具有如本发明所述的含义。其中一些实施例是，杂环基亚烷基基团是指“较低级的杂环基亚烷基”基团，即杂环基基团连接到C1-6的烷基基团上。另外一些实施例是，杂环基基团连接到C1-4的烷基基团上。这样的实例包括，但并不限于，2-吡咯烷乙基等等。杂环基亚烷基可被进一步取代，该取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "heterocyclylalkylene" means that an alkyl group may be substituted by one or more heterocyclyl groups, wherein the alkyl and heterocyclyl groups have the meanings described herein. In some of these embodiments, a heterocyclylalkylene group refers to a "lower heterocyclylalkylene" group, ie a heterocyclyl group attached to a C 1-6 alkyl group. In some other embodiments, the heterocyclyl group is attached to a C 1-4 alkyl group. Such examples include, but are not limited to, 2-pyrrolidinylethyl and the like. Heterocyclylalkylene may be further substituted, the substituents may be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkoxy , amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, etc.

术语“芳基”和“芳环”，在此处可交换使用，表示共含有6-14元环的 单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且只有一个附着点与分子的其余部分相连。芳香环可以包括苯基，萘基和蒽。并且所述芳基可以是取代或非取代的，其中取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The terms "aryl" and "aromatic ring" are used interchangeably herein to denote monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing a total of 6-14 ring members, wherein at least one ring system is aromatic , wherein each ring system contains 3-7 membered rings and only one point of attachment is attached to the rest of the molecule. Aromatic rings can include phenyl, naphthyl and anthracene. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkane Oxy, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like. the

术语“芳基亚烷基”表示烷基基团可以被一个或多个芳基基团所取代，其中烷基和芳基基团具有如本发明所述的含义，其中一些实施例是，芳基亚烷基基团是指“较低级的芳基亚烷基”基团，即芳基基团连接到C1-6的烷基基团上。另外一些实施例是，芳基亚烷基基团是指含C1-4的烷基的“苯烷撑”。其中具体实例包括苄基，二苯基甲基，苯乙基等等。芳基亚烷基可被进一步取代，该取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "arylalkylene" means that an alkyl group may be substituted by one or more aryl groups, wherein the alkyl and aryl groups have the meanings described herein, some of which are, aryl An alkylene group refers to a "lower arylalkylene" group, ie, an aryl group attached to a C 1-6 alkyl group. In some other embodiments, an arylalkylene group refers to a "phenylene alkylene" containing a C 1-4 alkyl group. Specific examples thereof include benzyl, diphenylmethyl, phenethyl and the like. Arylalkylene may be further substituted, the substituents may be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkoxy, Amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like.

术语“杂芳基”、“芳杂环”和“杂芳族化合物”，在本文中可交换使用，表示含5-14个环原子的单环，双环，和三环体系，其中至少一个环体系是芳香族的，且至少有一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7元环，且只有一个附着点与分子其余部分相连。并且所述杂芳基可以是取代或非取代的，其中取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The terms "heteroaryl", "heteroaromatic ring" and "heteroaromatic" are used interchangeably herein to denote monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring atoms, wherein at least one ring The system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains 5-7 membered rings and has only one point of attachment to the rest of the molecule. And the heteroaryl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxyl, Alkoxy, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like. the

另外一些实施例是，杂芳基包括以下的单环，但并不限于这些单环：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-异噁唑基，4-异噁唑基，5-异噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，5-嘧啶基，哒嗪基（如3-哒嗪基），2-噻唑基，4-噻唑基，5-噻唑基，四唑基（如5-四唑基），三唑基（如2-三唑基和5-三唑基）， 2-噻吩基，3-噻吩基，吡唑基（如2-吡唑基），异噻唑基，1，2，3-噁二唑基，1，2，5-噁二唑基，1，2，4-噁二唑基，1，2，3-三唑基，1，2，3-硫代二唑基，1，3，4-硫代二唑基，1，2，5-硫代二唑基，吡嗪基，1，3，5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基（如2-吲哚基），嘌呤基，喹啉基（如2-喹啉基，3-喹啉基，4-喹啉基），异喹啉基（如1-异喹啉基，3-异喹啉基或4-异喹啉基）。  In some other embodiments, heteroaryl includes, but is not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrole Base, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2 -thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3 - Thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl Azolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyr Azinyl, 1,3,5-triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indole base), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolinyl). the

术语“杂芳基亚烷基”表示烷基基团可以被一个或多个杂芳基基团所取代，其中烷基和杂芳基基团具有如本发明所述的含义，其中一些实施例是，杂芳基亚烷基基团是指“较低级的杂芳基亚烷基”基团，即杂芳基基团连接到C1-6的烷基基团上。另外一些实施例是，杂芳基基团连接到C1-4的烷基基团上。其中具体实例包括2-吡啶甲基，3-呋喃乙基等等。杂芳基亚烷基上的可进一步被取代，该取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "heteroarylalkylene" means that an alkyl group may be substituted by one or more heteroaryl groups, wherein the alkyl and heteroaryl groups have the meanings described herein, some of which Yes, a heteroarylalkylene group refers to a "lower heteroarylalkylene" group, ie a heteroaryl group attached to a C 1-6 alkyl group. In some other embodiments, the heteroaryl group is attached to a C 1-4 alkyl group. Specific examples thereof include 2-pyridylmethyl, 3-furylethyl and the like. The heteroarylalkylene can be further substituted, the substituents can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkane Oxy, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like.

术语“芳氨基”表示氨基团被一个或两个芳基基团所取代，这样的实例包括，但并不限于N-苯氨基。其中一些实施例是，芳氨基上的芳环可以进一步被取代。  The term "arylamino" means that an amino group is substituted by one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group can be further substituted. the

术语“羧基”，无论是单独使用还是和其他术语连用，如“羧烷基”，表示-CO2H；术语“羰基”，无论是单独使用还是和其他术语连用，如“氨基羰基”或“酰氧基”，表示-(C=O)-。  The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means -CO 2 H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or ""Acyloxy" means -(C=O)-.

术语“稠合双环”，“稠合环”，“稠合双环基”或“稠合环基”，如式a-c所示，表示两个五元环之间(式a)，两个六元环之间(式b)，以及一个五元环和一个六元环之间(式c)共用一个C-C键的桥环体系。体系中可以包含孤立的或共轭的不饱和键，但核心环结构中不包括芳香环或杂芳环(取代基可以是芳香性的)。稠合双环中的每个环都可以是碳环或杂环。  The term "fused bicyclic", "fused ring", "fused bicyclic group" or "fused cyclic group", as shown in formula a-c, means between two five-membered rings (formula a), two six-membered Between rings (formula b), and between a five-membered ring and a six-membered ring (formula c) share a bridged ring system with a C-C bond. The system may contain isolated or conjugated unsaturated bonds, but the core ring structure does not include aromatic or heteroaromatic rings (substituents may be aromatic). Each ring in a fused bicyclic ring can be carbocyclic or heterocyclic. the

Figure BDA00002905454700241
Figure BDA00002905454700241

稠合双环的实例包括，但不限于，六氢呋喃并[2,3-b]呋喃-3-基，六氢呋喃并[3,2-b]呋喃-3-基，八氢环戊烷并[c]吡咯-5-基，八氢并环戊二烯-2-基，八氢-1H-异吲哚-5-基，等等。稠合双环基可以是取代或非取代的，其中取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  Examples of fused bicyclic rings include, but are not limited to, hexahydrofuro[2,3-b]furan-3-yl, hexahydrofuro[3,2-b]furan-3-yl, octahydrocyclopentane a[c]pyrrol-5-yl, octahydropentalen-2-yl, octahydro-1H-isoindol-5-yl, and the like. Fused bicyclic groups can be substituted or unsubstituted, where substituents can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxy, alkoxy radical, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, and the like. the

术语“稠合双环基亚烷基”表示烷基被一个或多个稠合双环基基团所取代，其中烷基基团和稠合双环基基团具有如本发明所述的含义，这样的实例包括，但不限于六氢呋喃并[2,3-b]呋喃-3-基甲基，六氢呋喃并[2,3-b]呋喃-3-基二氘代甲基，等等。稠合双环基亚烷基可以是取代或非取代的，其中取代基可以是，但并不限于，氘，氟，氯，溴，碘，叠氮基，烷基，卤代烷基，氰基，羟基，烷氧基，氨基，烷氨基，氰基烷基，羟基烷基，烷氧基烷基，氨基烷基，烷氨基烷基，等等。  The term "fused bicyclylalkylene" means that an alkyl group is substituted by one or more fused bicyclyl groups, wherein the alkyl group and the fused bicyclyl group have the meanings described herein, such that Examples include, but are not limited to, hexahydrofuro[2,3-b]furan-3-ylmethyl, hexahydrofuro[2,3-b]furan-3-yldideuteromethyl, and the like. Fused bicycloalkylene can be substituted or unsubstituted, where substituents can be, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, azido, alkyl, haloalkyl, cyano, hydroxyl , alkoxy, amino, alkylamino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, etc. the

像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系（如下式所示）代表取代基在环上任何可取代的位置都可以取代。例如，式d代表B环上任何可能被取代的位置，如式e所示。  As described in the present invention, the substituents draw a bond to the central ring to form a ring system (as shown in the formula below) which means that any substitutable position of the substituent on the ring can be substituted. For example, formula d represents any position that may be substituted on ring B, as shown in formula e. the

Figure BDA00002905454700242
Figure BDA00002905454700242

除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式（如对映异构，非对映异构，和几何异构（或构象异构））：例如含有不对称中心的R、Ｓ构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体（或构象异构体）的混合物都属于本发明 的范围。  Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomerism (or conformational isomerism)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention. the

本发明所使用的术语“互变异构体”或“互变异构形式”表示具有不同能量的结构同分异构体可以越过低能垒，从而互相转化。譬如，质子互变异构体（即质子移变）包括通过质子迁移进行互变，如酮-烯醇式互变和亚胺-烯胺同分异构化作用。化合价互变异构体包括通过一些成键电子重组而进行互变。  The term "tautomer" or "tautomeric form" as used in the present invention means that structural isomers with different energies can cross a low energy barrier and thus interconvert. For example, proton tautomerization (ie, prototropism) includes interconversions via migration of a proton, such as keto-enol tautomerization and imine-enamine isomerization. Valence tautomers include interconversion by recombination of some of the bonding electrons. the

除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。  Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms. the

本发明所使用的术语“前药”，代表一个化合物在体内转化为式（I）所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族（C1-24）酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含OH基团，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345,每篇文献通过引用包含于此。  The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates , carbamates and amino acid esters. For example, a compound of the present invention contains an OH group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, each of which is hereby incorporated by reference.

“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包 括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。  "Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time. the

本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994．本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或（+）、（-）用来命名化合物平面偏振光旋转的符号，（-）或l是指化合物是左旋的，前缀（+）或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。  Definitions of stereochemistry in the present invention and use of conventions are generally referred to in the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the compound's plane polarized light rotation, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity. the

本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐， 环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。  The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.

本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。  A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water. the

术语“保护基团”或“PG”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC)，苄氧羰基（CBZ）和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991;and P.J.Kocienski, Protecting Groups,Thieme,Stuttgart,2005。  The term "protecting group" or "PG" refers to a substituent that reacts with another functional group, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, reference can be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

化合物compound

本发明涉及的杂环化合物，其药学上可接受的盐，及其药物制剂，对酪氨酸激酶受体，尤其是ALK和c-Met受体调节的疾病或病症的治疗有潜在的用途。特别是，本发明涉及一种如式(I)所示的化合物：  The heterocyclic compound involved in the present invention, its pharmaceutically acceptable salt, and its pharmaceutical preparation have potential application in the treatment of diseases or diseases regulated by tyrosine kinase receptors, especially ALK and c-Met receptors. In particular, the present invention relates to a compound as shown in formula (I):

Figure BDA00002905454700281
Figure BDA00002905454700281

或其立体异构体，几何异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药。  Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug. the

其中，R1，R2，R3，R4，R5，R6和Z具有如下所述的含义:  Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the following meanings:

R1，R2，R3，R4，R5和R6独立地为H，D或F，在另外一些实施方案中，可以独立地为H或D。  R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently H, D or F, and in other embodiments, may be H or D independently.

Z可以为：  Z can be:

(1)（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代；所述（C3-C7）杂环基在另外一些实施方案中，可以被1，2，3，4或5个独立选自D，F，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；  (1) (C 3 -C 7 ) heterocyclyl, and is independently selected from D, F, Cl, Br, I, N 3 , (C 1 -C 6 ) alkane by 1, 2, 3, 4 or 5 radical, (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene-CN, -(C 1 -C 4 ) Alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR b R c substituents are substituted; the (C 3 -C 7 ) Heterocyclyl In some other embodiments, it can be composed of 1, 2, 3, 4 or 5 independently selected from D, F, N 3 , (C 1 -C 3 )alkyl, (C 1 -C 3 ) Haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-CN, -(C 1 -C 3 )alkylene-OH, -( C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c substituents are substituted;

Z为（C3-C7）杂环基时，同时满足以下条件：  When Z is a (C 3 -C 7 ) heterocyclic group, the following conditions must be satisfied at the same time:

当杂环基的环成员包含-N(H)-时，-N(H)-中的氢原子不能被取代；  When the ring member of the heterocyclyl group contains -N(H)-, the hydrogen atom in -N(H)- cannot be replaced;

当R1、R2、R3、R4、R5和R6为H，Z为单取代的哌啶基时，哌啶环上的4-位不能被D取代，即当式（I）化合物为(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(哌啶-4-基)-1H-吡唑-4-基)吡啶-2-胺类化合物时，哌啶环上的4-位不能被D取代。  When R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H, and Z is a monosubstituted piperidinyl group, the 4-position on the piperidine ring cannot be replaced by D, that is, when formula (I) The compound is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazole-4 -yl) pyridin-2-amine compounds, the 4-position on the piperidine ring cannot be substituted by D.

Z也可以为：  Z can also be:

(2)-（C1-C4）亚烷基-（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代；所述-（C1-C4）亚烷基-（C3-C7）杂环基在另外一些实施方案中，可以被1，2，3，4或5个独立选自D，F，N3，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；  (2)-(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, and is independently selected from D, F, Cl, Br, I by 1, 2, 3, 4 or 5 , N 3 , (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 ) Substituents of alkylene-OR a or -(C 1 -C 4 ) alkylene -NR b R c ; the -(C 1 -C 4 ) alkylene -(C 3 -C 7 ) Heterocyclyl In some other embodiments, it can be 1, 2, 3, 4 or 5 independently selected from D, F, N 3 , (C 1 -C 3 ) haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 )alkylene Substituents of -NR b R c are substituted;

-（C1-C4）亚烷基-（C3-C7）杂环基中的杂环基不能被-OH单取代。  The heterocyclic group in the -(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclic group cannot be monosubstituted by -OH.

Z还可以为：  Z can also be:

(3)（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环；所述（C5-C12）稠合双环基在另外一些实施方案中，可以任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环。  (3) (C 5 -C 12 ) fused bicyclic group, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, I, N 3 , (C 1 - C 6 )alkyl, (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene -CN, -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR b R c substituents are substituted, and the bicyclic ring system The ring in may be carbocyclic or heterocyclic; the (C 5 -C 12 ) fused bicyclic group may optionally be selected from 1, 2, 3, 4 or 5 independently selected D , F, Cl, Br, I, N 3 , (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, -CN, -OH, -OR a , -NR b R c , -( C 1 -C 3 )alkylene-CN, -(C 1- C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene Alkyl-NR b R c is substituted with substituents, and the rings in the bicyclic ring system can be carbocyclic or heterocyclic.

Z还可以为：  Z can also be:

(4)-（C1-C4）亚烷基-（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代 基所取代，且双环体系中的环可以是碳环或杂环；所述-（C1-C4）亚烷基-（C5-C12）稠合双环基在另外一些实施方案中，可以任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环。  (4)-(C 1 -C 4 )alkylene-(C 5 -C 12 )fused bicyclyl, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl , Br, I, N 3 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 ) Alkylene-CN, -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR b R c substituents are substituted, and the ring in the bicyclic ring system can be carbocyclic or heterocyclic; the -(C 1 -C 4 )alkylene-(C 5 -C 12 )fused bicyclic group is in addition In some embodiments, 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, I, N 3 , (C 1 -C 3 )alkyl, (C 1 - C 3 ) Haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-CN, -(C 1 -C 3 )alkylene-OH, Substituents of -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c , and the ring in the bicyclic ring system can be carbocyclic or heterocyclic .

具体而言，Z可以选自以下（a）～（k）所示的子结构或其立体异构体中的任意一种：  Specifically, Z can be selected from any of the substructures shown in (a) to (k) below or their stereoisomers:

Figure BDA00002905454700301
Figure BDA00002905454700301

在所述（a）～（k）所示的子结构中：  In the substructure shown in (a)~(k):

n为0，1，2或3；  n is 0, 1, 2 or 3;

X和X'为-O-或-N(H)-；  X and X' are -O- or -N(H)-;

所述（a）～（k）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；  The substructures shown in (a) to (k) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups independently by 1, 2, 3, 4 or 5, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 ) Substituents of alkylene-NR b R c are substituted;

当n为1，2或3时，所述（a）～（k）所示的子结构或其立体异构体不能被-OH单取代；  When n is 1, 2 or 3, the substructures shown in (a) to (k) or their stereoisomers cannot be monosubstituted by -OH;

当各X和X'独立地为-N(H)-时，-N(H)-中的氢原子不能被取代；  When each X and X' are independently -N(H)-, the hydrogen atom in -N(H)- cannot be replaced;

当R1,R2,R3,R4,R5和R6为H，Z为单取代的哌啶基时，哌啶环的4-位不能被D取代。  When R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H, and Z is a monosubstituted piperidinyl group, the 4-position of the piperidine ring cannot be substituted by D.

Z也可以选自（l）～（x）所示的子结构或其立体异构体中的任意一 种：  Z can also be selected from any of the substructures shown in (l) to (x) or their stereoisomers:

Figure BDA00002905454700311
Figure BDA00002905454700311

在所述（l）～（x）所示的子结构中：  In the substructure shown in (l)~(x):

n为0，1，2或3；  n is 0, 1, 2 or 3;

W和W'为-O-，-N(H)-或-N(C1-C3)烷基-；  W and W' are -O-, -N(H)- or -N(C 1 -C 3 ) alkyl-;

所述（l）～（x）所示的子结构或其立体异构体任选地被1，2，3，4或5个独立选自D，F，（C1-C3）烷基，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures shown in (l) to (x) or their stereoisomers are optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, (C 1 -C 3 ) alkyl groups , (C 1 -C 3 )haloalkyl, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene- Substituents of ORa or -(C 1 -C 3 )alkylene-NR b R c .

Z还可以选自（101）～（111）所示的子结构或其立体异构体中的任意一种：  Z can also be selected from any of the substructures shown in (101) to (111) or their stereoisomers:

所述（101）～（111）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures represented by (101) to (111) or their stereoisomers are independently selected from 1, 2, 3, 4 or 5 independently selected from D, F, (C 1 -C 3 ) haloalkyl groups, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 ) Substituents of alkylene-NR b R c are substituted.

Z还可以选自（201）～（214）所示的子结构或其立体异构体中的任意一种：  Z can also be selected from any of the substructures shown in (201) to (214) or their stereoisomers:

Figure BDA00002905454700321
Figure BDA00002905454700321

所述（201）～（214）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures shown in (201) to (214) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups independently by 1, 2, 3, 4 or 5, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 ) Substituents of alkylene-NR b R c are substituted.

Z还可以选自（301）～（323）所示的子结构或其立体异构体中的任意一种：  Z can also be selected from any of the substructures shown in (301) to (323) or their stereoisomers:

Figure BDA00002905454700322
Figure BDA00002905454700322

Figure BDA00002905454700331
Figure BDA00002905454700331

所述（301）～（323）所示的子结构或其立体异构体任选地被1，2，3，4或5个独立选自D，F，（C1-C3）烷基，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。  The substructures shown in (301) to (323) or their stereoisomers are optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, (C 1 -C 3 ) alkyl groups , (C 1 -C 3 )haloalkyl, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene- Substituents of OR a or -(C 1 -C 3 )alkylene-NR b R c .

在Z的上述各结构中，Ra为（C1-C6）烷基，（C1-C6）烯基，（C1-C6）炔基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基或-（C1-C4）亚烷基-（C1-C9）杂芳基，所述各（C1-C6）烷基，（C1-C6）烯基，（C1-C6）炔基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基和-（C1-C4）亚烷基-（C1-C9）杂芳基任选地被1，2，3或4个独立选自-D，-F，-Cl，N3，-CN，-OH，-NH2，烷氧基或烷基氨基的取代基所取代；在另外一些实施方案中，Ra可以为（C1-C3） 烷基，（C1-C3）烯基，（C1-C6）炔基，（C3-C6）环烷基或-（C1-C3）亚烷基-（C3-C6）环烷基，所述各（C1-C3）烷基，（C1-C3）烯基，（C1-C6）炔基，（C3-C6）环烷基和-（C1-C3）亚烷基-（C3-C6）环烷基任选地被1，2，3或4个独立选自D或F的取代基所取代；，在另外一些实施方案中，Ra还可以为（C1-C2）烷基，且任选地被1，2，3或4个独立选自D或F的取代基所取代；  In each of the above structures of Z, R a is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkane radical, (C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene-(C 3 - C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl radical or -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl, each of the (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocyclyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl , -(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl are optionally replaced by 1, 2, 3 or substituted by 4 substituents independently selected from -D, -F, -Cl, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino; in other embodiments, R a Can be (C 1 -C 3 )alkyl, (C 1 -C 3 )alkenyl, (C 1 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl or -(C 1 -C 3 ) alkylene-(C 3 -C 6 )cycloalkyl, each of the (C 1 -C 3 )alkyl, (C 1 -C 3 )alkenyl, (C 1 -C 6 )alkynyl, ( C 3 -C 6 )cycloalkyl and -(C 1 -C 3 )alkylene-(C 3 -C 6 )cycloalkyl are optionally 1, 2, 3 or 4 independently selected from D or F Substituents;, in other embodiments, R a can also be (C 1 -C 2 ) alkyl, and optionally substituted by 1, 2, 3 or 4 independently selected from D or F base replaced;

Rb和Rc独立地为H，（C1-C6）烷基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基或-（C1-C4）亚烷基-（C1-C9）杂芳基；所述各（C1-C6）烷基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基和-（C1-C4）亚烷基-（C1-C9）杂芳基任选地被1，2，3，或4个独立选自D，F，Cl，N3，-CN，-OH，-NH2，烷氧基或烷基氨基的取代基所取代；在其他一些实施方案中，Rb、Rc还可以独立地为H，（C1-C3）烷基，（C3-C6）环烷基或-（C1-C4）亚烷基-（C3-C6）烷基；所述各（C1-C3）烷基，（C3-C6）环烷基和-（C1-C4）亚烷基-（C3-C6）烷基任选地被1，2，3或4个独立选自D或F的取代基所取代；在其他一些实施方案中，Rb、Rc也可以独立地为H或（C1-C2）烷基；所述（C1-C2）烷基和（C3-C6）杂环基任选地被1，2，3或4个独立选自D或F的取代基所取代；  R b and R c are independently H, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aromatic radical, (C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(C 1 -C 9 ) Heteroaryl; each (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aryl, ( C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 ) Heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl Optionally substituted by 1, 2, 3, or 4 substituents independently selected from D, F, Cl, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino; in other In some embodiments, R b and R c can also be independently H, (C 1 -C 3 ) alkyl, (C 3 -C 6 ) cycloalkyl or -(C 1 -C 4 ) alkylene- (C 3 -C 6 )alkyl; said each (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl and -(C 1 -C 4 )alkylene-(C 3 - C 6 ) alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D or F; in some other embodiments, R b , R c can also be independently H or (C 1 -C 2 ) alkyl; said (C 1 -C 2 ) alkyl and (C 3 -C 6 ) heterocyclyl are optionally substituted by 1, 2, 3 or 4 independently selected from D or F base replaced;

在本发明中，当Rb和Rc与同一个氮原子相连时，Rb，Rc和与他们相连的氮原子一起，还可以任选地形成（C3-C6）杂环基，即Rb，Rc和与他们相连的氮原子一起，可以形成（C3-C6）杂环基，也可以不形成杂环基，为本领域技术人员熟知的其他结构，如N-Ra-Rb或Ra-N-Rb等。  In the present invention, when R b and R c are connected to the same nitrogen atom, R b , R c and the nitrogen atom connected to them can also optionally form a (C 3 -C 6 ) heterocyclic group, That is, R b , R c and the nitrogen atom connected to them can form a (C 3 -C 6 ) heterocyclic group, or not form a heterocyclic group, and are other structures well known to those skilled in the art, such as NR a - R b or R a -NR b etc.

本发明所述的式（I）结构的化合物包括但不限于以下具体化合物或其氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或它的前药：  The compounds of the formula (I) structure in the present invention include but are not limited to the following specific compounds or their nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs:

Figure BDA00002905454700351
Figure BDA00002905454700351

Figure BDA00002905454700361
Figure BDA00002905454700361

Figure BDA00002905454700371
Figure BDA00002905454700371

Figure BDA00002905454700391
Figure BDA00002905454700391

Figure BDA00002905454700401
Figure BDA00002905454700401

Figure BDA00002905454700411
Figure BDA00002905454700411

Figure BDA00002905454700431
Figure BDA00002905454700431

除非其他方面表明，本发明的化合物所有的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，盐和药学上可接受的前药都属于本发明的范围。  Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are Belong to the scope of the present invention. the

具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗的哺乳动物有关。  In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically appropriate in relation to the other ingredients making up the formulation and the mammal being used for treatment. the

本发明的化合物的盐还包括用于制备或纯化式(I)所示化合物的中间体或式(I)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。  The salts of the compounds of the present invention also include the salts of the intermediates of the compounds shown in the formula (I) or the separated enantiomers used in the preparation or purification of the compounds shown in the formula (I), but not necessarily pharmaceutically acceptable Salt. the

如果本发明的化合物是碱性的，则想得到的盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸，氢溴酸，硫酸，硝酸和磷酸等等。或者使用有机酸，如乙酸，马来酸，琥珀酸，扁桃酸，富马酸，丙二酸，丙酮酸，草酸，羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸，乙磺酸，等等。  If the compound of the present invention is basic, the desired salt may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, oxalic, glycolic and salicylic acids; pyranonic acids such as glucuronic and galactose Alkyd acids; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, etc. the

如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，如，使用无机碱或有机碱，如氨（伯氨，仲氨，叔氨），碱金属氢氧化物或碱土金属氢氧化物，等等。合适的盐包括，但并不限于，从氨基酸得到的有机盐，如甘氨酸和精氨酸，氨，如伯氨、仲氨和叔氨， 和环状氨，如哌啶，吗啉和哌嗪等，和从钠，钙，钾，镁，锰，铁，铜，锌，铝和锂得到无机盐。  If the compound of the invention is acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides or alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine etc., and inorganic salts obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. the

本发明还包含本发明的化合物及其药学上可接受的盐的应用，即用于生产医药产品治疗急慢性血管发生介导的疾病，包括那些本发明所描述的在生产抗癌药物中的应用。本发明的化合物同样用于生产一种医药用品来减轻，阻止，控制或治疗由ALK或c-Met所介导的疾病。本发明包含药物组合物，该药物组合物包括式(I)所代表的化合物与至少一个药学上可接受的载体，辅剂或稀释剂的结合所需的有效治疗用量。  The present invention also includes the use of the compounds of the present invention and pharmaceutically acceptable salts thereof, that is, for the production of pharmaceutical products for the treatment of acute and chronic angiogenesis-mediated diseases, including those described in the present invention in the production of anticancer drugs . The compounds of the present invention are also useful in the manufacture of a medicinal product for alleviating, preventing, controlling or treating diseases mediated by ALK or c-Met. The present invention includes a pharmaceutical composition, which comprises a compound represented by formula (I) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent in a therapeutically effective amount. the

本发明同样包含治疗患者血管发生介导的疾病，或对此病症敏感的方法，该方法包含使用式(I)所代表化合物的治疗有效量对患者进行治疗。  The present invention also includes a method of treating an angiogenesis-mediated disease in a patient, or being susceptible to it, comprising treating the patient with a therapeutically effective amount of a compound represented by formula (I). the

组合物combination

根据另一方面，本发明还提供了一种药物组合物，包括式(I)的化合物，本发明所列出的化合物，或实施例1-24的化合物，和药学上可接受的载体，辅剂，或赋形剂。本发明的组合物中化合物的量能有效地、可探测地抑制生物标本或患者体内的蛋白激酶。  According to another aspect, the present invention also provides a pharmaceutical composition, comprising a compound of formula (I), a compound listed in the present invention, or a compound of Examples 1-24, and a pharmaceutically acceptable carrier, assisted by agents, or excipients. The amount of compound in the compositions of the invention is effective to detectably inhibit protein kinases in a biological specimen or patient. the

本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或他的残留物。  The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the present invention, their metabolites or their residues. the

像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker, New York,综合此处文献的内容，表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。  As described herein, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-19 , Marcel Dekker, New York, synthesized the contents of the literature herein, showing that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional carrier media is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable composition, they The purposes of the present invention are also considered scope. the

可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。  Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid, Potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive, corn, and soybean oils; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, sweeteners, flavors and fragrances, preservatives and antioxidants. the

本发明的组合物可以是口服给药，注射给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，含服给药，阴道给药或通过植入性药盒给药。此处所使用的术语“经注射的”包括皮下的，静脉的，肌内的，关节内的，滑膜(腔)内的，胸骨内的，膜内的，眼内的，肝内的，病灶内的，和颅内的注射或输注技术。优选的组合物为口服给药，向腹膜内给药或静脉注射。本发明的组合物无菌的注射方式可以是水的或油脂性的悬浮液。这些悬浮液可以根据公知技术采用合适的分散剂、湿润剂和悬浮剂按配方制造。无菌注射剂可以是无菌注射液或悬浮液，是注射无毒的可接受的稀释剂或溶剂，如1,3-丁二醇溶液。这些可接受的赋形剂和溶剂可以是水，林格溶液和等渗氯化钠溶液。更进一步地，无菌的非挥发性 的油按照惯例可以作为溶剂或悬浮介质。  The compositions of the present invention may be administered orally, by injection, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit . The term "injected" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial (cavity), intrasternal, intrathecal, intraocular, intrahepatic, focal Intracranial, and intracranial injection or infusion techniques. Preferred compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents and suspending agents. Sterile injections can be sterile injection solutions or suspensions, which are non-toxic acceptable diluents or solvents for injection, such as 1,3-butanediol solution. Among the acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally employed as a solvent or suspending medium. the

以此为目的，任何温和的非挥发性的油可以是合成的单或二葡基甘油二酯。脂肪酸，如油酸和它的甘油酯衍生物可用于血管注射剂的制备，作为天然的药学上可接受的油脂，如橄榄油或蓖麻油，特别是它们的聚氧乙烯衍生物。这些油溶液或悬浮液可以包含长链醇稀释剂或分散剂，如羧甲基纤维素或相似分散剂，一般用于药学上可接受剂型的药物制剂包括乳化液和悬浮液。其他常用的表面活性剂，如吐温类，司盘类和其他乳化剂或生物药效率的强化剂，一般用于药学上可接受的固体，液体，或其他剂型，并可以应用于目标药物制剂的制备。  For this purpose any bland fixed oil may be a synthetic mono- or diglyceride. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents, commonly used in pharmaceutical formulations of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or enhancers of bioavailability, are generally used in pharmaceutically acceptable solid, liquid, or other dosage forms, and can be applied to target pharmaceutical preparations preparation. the

本发明药学上可接受的组合物可以是以任何可接受的口服剂型进行口服给药，其中包括，但并不限于，胶囊，片剂，水制悬浮液或溶液。关于片剂口服使用，载体一般包括乳糖和玉米淀粉。润滑剂，如硬脂酸镁，都典型地被添加。对于胶囊口服给药，合适的稀释剂包括乳糖和干的玉米淀粉。当口服给药为水制悬浮液时，其有效成分由乳化剂和悬浮剂组成。如果想得到这些剂型，某些甜味剂、调味剂或着色剂也可以被添加。  The pharmaceutically acceptable compositions of this invention may be orally administered in any acceptable oral dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, carriers generally include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added. For oral administration in capsules, suitable diluents include lactose and dried cornstarch. When administered orally as an aqueous suspension, the active ingredient consists of emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added if desired in these dosage forms. the

另外，本发明药学上可接受的组合物可以以栓剂的形式直肠给药。这些可以通过将试剂与合适的非灌注辅药混合制备而成，这种辅药在室温下为固体但在直肠的温度下则为液体，从而在直肠中熔化并释放药物。这样的物质包括可可豆脂，蜂蜡，和聚乙二醇类。本发明药学上可接受的组合物可以是局部给药，特别是局部用药时，涉及到区域或器官的治疗目标容易达到，如眼、皮肤或下肠道的疾病。合适的局部用药制剂可以制备得到并应用于这些领域或器官。  Additionally, the pharmaceutically acceptable compositions of this invention may be administered rectally in the form of suppositories. These can be prepared by mixing the agent with a suitable non-infusing excipient which is solid at room temperature but liquid at rectal temperature, where it melts and releases the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutically acceptable compositions of the present invention may be administered topically, especially when topical administration involves areas or organs where the therapeutic target is easily accessible, such as diseases of the eyes, skin or lower intestinal tract. Suitable topical formulations can be prepared and applied to these areas or organs. the

上述直肠栓剂或合适的灌肠剂可以应用于下部肠道的局部用药。局部皮肤斑也可以这样用药。对于局部用药，药学上可接受的组合物可以按制剂方法制备成合适的软膏，该软膏包含活性成分悬浮于或溶解于一个或多个载体。本发明局部给药的载体化合物包括，但并不限于矿物油，液体石蜡，白凡士林，丙二醇，聚氧乙烯，聚氧丙烯化合物，乳化蜡和水。另外，药学上可接受的组合物可以制备成合适的洗剂或乳剂，该洗 剂或乳剂包含活性成分悬浮于或溶于一个或多个药学上可接受的载体。合适的载体包括，但并不限于，矿物油，司盘-60（脱水山梨醇单硬脂酸酯），吐温60（聚山梨酯60），十六烷基酯蜡，棕榈醇，2-辛基十二烷醇，苯甲醇和水。  The aforementioned rectal suppositories or suitable enemas may be applied topically to the lower intestinal tract. Local skin spots can also be used in this way. For topical use, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carrier compounds for topical administration of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions may be prepared in a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, Span-60 (sorbitan monostearate), Tween 60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2- Octyldodecanol, Benzyl Alcohol and Water. the

对于眼用的、药学上可接受的组合物可以制备成制剂，如等渗的微粒化悬浮液，pH调节的无菌盐水或其他水溶液，优选地，等渗溶液和pH调节的无菌盐水或其他水溶液，可以添加消毒防腐剂如苯扎氯铵。另外，对于眼用的，药学上可接受的组合物可以按制剂配方制备成软膏如凡士林油。本发明药学上可接受的组合物可以通过鼻的气溶剂或吸入剂进行给药。这样的组合物可以根据制剂配方的公知技术制备得到，或可以制备成盐溶液，使用苯甲醇或其他合适的防腐剂、吸收促进剂、碳氟化合物或其他常规增溶剂或分散剂来提高生物利用度。  For ophthalmic use, the pharmaceutically acceptable composition can be prepared as a formulation, such as isotonic micronized suspension, pH-adjusted sterile saline or other aqueous solution, preferably, isotonic solution and pH-adjusted sterile saline or For other aqueous solutions, disinfectant preservatives such as benzalkonium chloride can be added. In addition, for ophthalmic use, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to known techniques of formulation formulation, or may be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons or other conventional solubilizing or dispersing agents to enhance bioavailability Spend. the

口服给药的液体剂型包括，但并不限于，药学上可接受的乳剂，微乳剂，溶液，悬浮液，糖浆剂和酏剂。除活性化合物外，液体剂型可以包含公知的一般的惰性稀释剂，例如，水或其他溶剂，增溶剂和乳化剂，如乙醇，异丙醇，碳酸乙酯，乙酸乙酯，苯甲醇，苯甲酸苄酯，丙二醇，1,3-丁二醇，二甲基甲酰胺，油脂（特别是棉籽，落花生，玉米，微生物，橄榄，蓖麻和麻油），甘油，2-四氢呋喃甲醇，聚乙二醇，去水山梨糖醇脂肪酸酯，以及它们的混合物。除惰性的稀释剂之外，口服组合物也可以包含辅剂如湿润剂，乳化剂或悬浮剂，甜味剂，调味剂和芳香剂。  Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, generally known inert diluents, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils and fats (especially cottonseed, groundnut, corn, microbial, olive, castor and sesame oils), glycerin, 2-tetrahydrofurfurylmethanol, polyethylene glycol , sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening, flavoring, and perfuming agents. the

注射剂，如无菌注射液或油脂性的悬浮液可以根据公知技术采用合适的分散剂、湿润剂和悬浮剂按制剂配方制备得到。无菌注射剂可以是无毒的经注射地可接受的稀释剂或溶剂制成的无菌注射液、悬浮液或乳液，例如，1,3-丁二醇溶液。可接受的赋形剂和溶剂可以是水，林格(氏)溶液，U.S.P.和等渗氯化钠溶液。另外，无菌的非挥发性的油按照惯例作为溶剂或悬浮介质。以此为目的任何温和的非挥发性的油可以包括合成的单或二葡基甘油二酯。另外，脂肪酸如油酸可以应用于注射剂。  Injections, such as sterile injections or oily suspensions, can be prepared according to known techniques using suitable dispersing agents, wetting agents and suspending agents according to formulations. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions prepared with non-toxic injectable acceptable diluents or solvents, for example, 1,3-butanediol solution. Among the acceptable vehicles and solvents are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be used for this purpose including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in injectables. the

注射剂可以是无菌的，如通过细菌防卫过滤器过滤，或以无菌固体组合物的形式掺入灭菌剂，在使用前灭菌剂可以溶解于或分散于消毒水 或其他无菌注射介质中。为了延长本发明的化合物的效果，通常需要通过皮下注射或肌内注射来减缓化合物的吸收。这样可以实现利用液体悬浮液解决晶体或非晶体物质水溶性差的问题。化合物的吸收率取决于它的溶出度，依次取决于晶粒大小和晶体形状。另外，可以通过化合物在油类赋形剂中溶解或分散来完成化合物注射给药的延迟吸收。  The injection can be sterile, such as filtered through a bacteria-defense filter, or incorporated in the form of a sterile solid composition with a sterilizing agent that can be dissolved or dispersed in sterile water or other sterile injectable media before use middle. In order to prolong the effect of the compounds of the invention, it is usually necessary to slow the absorption of the compounds by subcutaneous or intramuscular injection. In this way, the liquid suspension can be used to solve the problem of poor water solubility of crystalline or amorphous substances. The rate of absorption of a compound depends upon its rate of dissolution, which in turn depends on crystal size and crystalline shape. Additionally, delayed absorption of the compound administered by injection can be accomplished by dissolving or dispersing the compound in an oil vehicle. the

注射剂储藏形式是通过可生物降解的聚合物，如多乳酸-聚乙醇酸交酯形成化合物的微胶囊基质完成的。化合物的控释比例取决于化合物形成聚合物的比例和特殊聚合物的性质。其他可生物降解聚合物包括聚（正酯类）和聚（酸酐）。注射剂储藏形式也可以通过化合物嵌入与身体组织相容的脂质体或微乳剂制备得到。  Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. The rate at which the compound is released depends on the rate at which the compound forms the polymer and the nature of the particular polymer. Other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot forms are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues. the

其中一些实施例是，直肠或阴道给药的组合物为栓剂，栓剂可以通过将本发明的化合物与合适的非灌注的辅料或载体混合来制备得到，如可可豆脂，聚乙二醇，或栓剂蜡状物，它们在室温为固体但在体温下则为液体，因此在阴道或鞘膜腔内便熔化释放活性化合物。  In some of these embodiments, the composition for rectal or vaginal administration is a suppository, which can be prepared by mixing the compound of the present invention with a suitable non-infusion adjuvant or carrier, such as cocoa butter, polyethylene glycol, or Suppositories are waxy substances that are solid at room temperature but liquid at body temperature and therefore melt in the vaginal or thecal cavity to release the active compound. the

口服给药的固体剂型包括胶囊，片剂，丸剂，粉剂和粒剂。在这些剂型中，活性化合物与至少一种药学上可接受的惰性赋形剂或载体混合，如柠檬酸钠或磷酸钙或充填剂或a)填充剂如淀粉，乳糖，蔗糖，葡萄糖，甘露醇和硅酸，b)粘合剂如羧甲基纤维素，藻酸盐，明胶，聚乙烯吡咯酮，蔗糖和阿拉伯胶，c)保湿剂如甘油，d)崩解剂如琼脂，碳酸钙，土豆淀粉或木薯淀粉，海藻酸，某些硅酸盐和碳酸钠，e)阻滞剂溶液如石蜡,f)吸收促进剂如季胺类化合物，g)湿润剂如十六醇和单硬脂酸甘油酯，h)吸收剂如白陶土和皂土，i)润滑剂如滑石粉，硬脂酸钙，硬脂酸镁，固体聚乙二醇，月桂硫酸钠，及它们的混合物。至于胶囊，片剂和丸剂，这些剂型可以包含缓冲剂。  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or fillers or a) fillers such as starch, lactose, sucrose, glucose, mannitol and Silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potatoes Starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) blocker solutions such as paraffin, f) absorption enhancers such as quaternary ammonium compounds, g) humectants such as cetyl alcohol and glycerol monostearate Esters, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. As with capsules, tablets and pills, these dosage forms may contain buffering agents. the

相似类型的固体组合物可以是填充剂充满于软的或硬的胶囊，所使用的辅料有乳糖和高分子的聚乙二醇等等。固体剂型像片剂，锭剂，胶囊，丸剂和粒剂可以通过包衣、加壳如肠溶包衣和其他药物制剂上公知的包衣方法制备得到。它们可以任选地包含遮光剂，或优选地，在肠道的某一部分，任意地，以延迟的方法释放组合物中的唯一活性成分。如 植入组合物可以包含多聚体物质和蜡状物。  A similar type of solid composition can be a soft or hard capsule filled with fillers, and the used excipients include lactose and macromolecular polyethylene glycol and the like. Solid dosage forms like tablets, lozenges, capsules, pills and granules can be prepared by coating, shelling such as enteric coating and other known coating methods for pharmaceutical preparations. They may optionally contain opacifying agents or, preferably, release the only active ingredient in the composition in a certain part of the intestinal tract, optionally in a delayed manner. For example, the implant composition may comprise polymeric substances and waxes. the

活性化合物可以与本发明所描述的一个或多个赋形剂一起形成微胶囊剂型。固体剂型像片剂、锭剂、胶囊、丸剂和粒剂可以通过包衣或加壳，如肠溶包衣、控释包衣和其他公知的药物制剂方法。在这些固体剂型中，活性化合物可以与至少一种惰性稀释剂混合，如蔗糖，乳糖或淀粉。这样的剂型作为一般的应用也可以包含除惰性稀释剂之外的添加物质，如压片润滑剂和其他压片助剂如硬脂酸镁和微晶纤维素。至于胶囊，片剂和丸剂，这些剂型可以包含缓冲剂。它们可以任选地包含镇静剂，或优选地，在肠道的某一部分，以任意延迟的方法释放组合物中的唯一活性成分。可应用的植入组合物可以包括，但并不限于，多聚体和蜡状物。  The active compounds can be in microencapsulated dosage form with one or more excipients as described herein. Solid dosage forms like tablets, lozenges, capsules, pills and granules can be coated or shelled, such as enteric coatings, release-controlling coatings and other well-known pharmaceutical formulation methods. In these solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as usual, additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. As with capsules, tablets and pills, these dosage forms may contain buffering agents. They may optionally contain a sedative or, preferably, release the only active ingredient of the composition in a certain part of the intestinal tract, with any delay. Applicable implant compositions may include, but are not limited to, polymers and waxes. the

本发明的化合物通过局部的或经皮肤给药的剂型包括软膏，糊剂，乳剂，洗剂，凝胶剂，粉剂，溶液，喷雾剂，吸入剂，贴片。活性成分在无菌的条件下与药学上可接受的载体和任何必需的防腐剂或必需的缓冲剂相混合。眼科的药物制剂，滴耳剂和滴眼剂都是本发明考虑的范围。另外，本发明还考虑透皮贴剂的应用，它在控制化合物传递到体内方面有着更多的优点，这样的剂型可以通过溶解或分散化合物到合适的介质中来制备得到。吸收促进剂可以增加化合物穿过皮肤的流量，通过速率控制薄膜或将化合物分散于聚合体基质或明胶来控制其速率。  Dosage forms for topical or dermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or necessary buffers. Ophthalmic pharmaceutical formulations, ear drops and eye drops are all contemplated by the present invention. In addition, the present invention also contemplates the application of transdermal patches, which have more advantages in controlling the delivery of the compound into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can increase the flux of the compound across the skin, controlling the rate either by rate controlling films or by dispersing the compound in a polymer matrix or gelatin. the

本发明的化合物优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而，应了解本发明的化合物或组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性，具体化合物的活性，所用的具体组合物，患者的年龄、体重、健康状况、性别和饮食习惯，给药时间，给药途径和所用具体化合物的排泄速率，治疗的持续时间，药物应用于联合用药或与有特效的化合物联用，以及其他一些药学领域公知的因素。  The compounds of the present invention are preferably formulated in dosage unit form to ease administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit of drug required to adequately treat a patient. It is to be understood, however, that the total daily usage of the compounds or compositions of the present invention will be determined by the attending physician based on sound medically sound judgment. The particular effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the activity of the particular compound, the particular composition employed, the age, weight, health, sex of the patient and dietary habits, timing of administration, route of administration and rate of excretion of the particular compound employed, duration of treatment, use of the drug in combination or with specific compounds, and other factors well known in the art of pharmacy. the

可以结合载体物质产生单个剂型组合物的本发明的化合物的用量的 改变取决于主治和特殊的给药模式。其中一些实施例是，组合物可以按制剂方法制备成剂量在0.01-200mg/kg体重/天的抑制剂，通过患者接受组合物的量来进行给药。  The amount of a compound of the invention which may be combined with carrier materials to produce a single dosage composition will vary depending upon the indication and the particular mode of administration. In some embodiments, the composition can be prepared according to the preparation method into an inhibitor with a dosage of 0.01-200 mg/kg body weight/day, and the administration is carried out according to the amount of the composition accepted by the patient. the

本发明的化合物可以以仅有的药学试剂或结合一个或多个其他附加治疗（药学的）剂来给药，其中联合用药引起可接受的不良反应，这对于高增生性疾病如癌症的治疗具有特殊的意义。在这种情况下，本发明的化合物可以结合已知的细胞毒素剂，单个转导抑制剂或其他抗癌试剂，以及它们的混合物和组合。像本发明所使用的，附加治疗剂正常给药治疗特殊的疾病，就是已知的“合适地治疗疾病”。本发明所使用的“附加治疗剂”包括化学治疗药物或其他抗增殖的药物可以结合本发明的化合物治疗增殖性疾病或癌症。  The compounds of the present invention may be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, where the combination causes acceptable adverse effects, which is of interest in the treatment of hyperproliferative diseases such as cancer special meaning. In such cases, the compounds of the invention may be combined with known cytotoxic agents, individual transduction inhibitors or other anticancer agents, as well as mixtures and combinations thereof. As used herein, an additional therapeutic agent normally administered to treat a particular disease is known as "appropriately treating a disease". "Additional therapeutic agents" as used in the present invention include chemotherapeutic drugs or other anti-proliferative drugs that can be combined with the compounds of the present invention to treat proliferative diseases or cancer. the

化学治疗药物或其他抗增殖药物包括组蛋白去乙酰化酶(HDAC)抑制剂，包括但并不限于，SAHA，MS-275，MGO103，以及那些以下专利所描述的化合物：WO2006/010264,WO03/024448,WO2004/069823,US2006/0058298,US2005/0288282,WO00/71703,WO01/38322,WO01/70675,WO03/006652,WO2004/035525,WO2005/030705,WO2005/092899,和脱甲基化试剂包括，但并不限于，5-杂氮-2′-脱氧胞苷（5-aza-dC）、阿扎胞苷（Vidaza）、地西他滨（Decitabine）和以下文献所描述的化合物：US6,268137,US5,578,716,US5,919,772,US6,054,439,US6,184,211，US6,020,318,US6,066,625,US6,506,735,US6,221,849,US6,953,783,US11/393,380。  Chemotherapeutic or other antiproliferative agents include histone deacetylase (HDAC) inhibitors, including but not limited to, SAHA, MS-275, MGO103, and those compounds described in the following patents: WO2006/010264, WO03/ 024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/09289 including and demethylating reagents But not limited to, 5-aza-2′-deoxycytidine (5-aza-dC), azacitidine (Vidaza), decitabine (Decitabine) and compounds described in the following documents: US6,268137 , US5,578,716, US5,919,772, US6,054,439, US6,184,211, US6,020,318, US6,066,625, US6,506,735, US6,221,849, US6,953,783, US11/393,380. the

另外一些实施例是，化疗试剂或其他抗增殖药物可以结合本发明的化合物治疗增殖性疾病和癌症。已知的化疗试剂包括，但并不限于，可与本发明抗癌药物联合使用的其他疗法或抗癌药物，手术，放射疗法(少许例子如γ辐射，中子束放射疗法，电子束放射疗法，质子疗法，近距离放射疗法和系统放射性同位素疗法)，内分泌疗法，紫杉烷类(紫杉醇(Taxol)，多西紫杉醇(Taxotere)等)，铂衍生物(顺铂(Cisplatin)，卡铂(Carboplatin)，奥沙利铂(oxaliplatin)，沙铂(satraplatin))，生物反应调节剂(干扰素，白细胞间素)，肿瘤坏死因子（TNF，TRAIL受体靶向物）， 过热和冷冻疗法，减轻任何不良反应的试剂（如止吐药），和其他被认可的化疗药物，包括但并不限于，烷化药物(氮芥(mechlorethamine)，苯丁酸氮芥(chlorambucil)，环磷酰胺(cyclophosphamide)，美法仑(melphalan)，异环磷酰胺(Ifosfamide))，抗代谢物(甲氨蝶呤(Methotrexate)，培美曲塞(Pemetrexed)等等)，嘌呤拮抗剂和嘧啶拮抗剂(6-巯嘌呤(6-Mercaptopurine)，5-氟尿嘧啶(5-Fluorouracil)，阿糖胞苷(Cytarabile)，吉西他滨(Gemcitabine))，纺锤体抑制剂(长春碱(Vinblastine)，长春新碱(Vincristine)，长春瑞滨(Vinorelbine))，鬼臼毒素(依托泊苷(Etoposide)，伊立替康(Irinotecan)，托泊替康(Topotecan))，抗生素(阿霉素(Doxorubicin)，博莱霉素(Bleomycin)，丝裂霉素(Mitomycin))，亚硝基脲(卡莫司汀(Carmustine)，洛莫司汀(Lomustine))，细胞分裂周期抑制剂（KSP通过有丝分裂驱动蛋白抑制剂，CENP-E和CDK抑制剂），酶(天门冬酰胺酶(Asparaginase))，激素(它莫昔芬(Tamoxifen)，亮丙瑞林(Leuprolide)，氟他胺(Flutamide)，甲地孕酮(Megestrol)，地塞米松(Dexamethasone)等等)。抗血管生成试剂（阿瓦斯丁(Avastin)等）。单抗(贝利单抗(Belimumab)，Brentuximab，西妥昔单抗(Cetuximab)，吉妥单抗(Gemtuzumab)，伊匹单抗(Ipilimumab)，Ofatumumab，帕尼单抗(Panitumumab)，雷珠单抗(Ranibizumab)，利妥昔单抗(Rituximab)，托西莫单抗(Tositumomab)，曲妥珠单抗(Trastuzumab))。激酶抑制剂(伊马替尼(Imatinib)，舒尼替尼(Sunitinib)，索拉非尼(Sorafenib)，厄洛替尼(Erlotinib)，吉非替尼(Gefitinib)，达沙替尼(Dasatinib)，尼洛替尼(Nilotinib)，拉帕替尼(Lapatinib)，克卓替尼(Crizotinib)，Ruxolitinib，Vemurafenib，Vandetanib，Pazopanib，等等)。药物抑制或激活癌症的途径如mTOR，HIF(缺氧诱导因子)途径及其他。癌症治疗较广泛的论坛见http://www.nci.nih.gov/，FAD认可的肿瘤学药物清单见http://www.fda.gov/cder/cancer/druglist-rame.htm，和默克手册，第十八版.2006，所有的内容都是结合了参考文献。  In other embodiments, chemotherapeutic agents or other anti-proliferative drugs may be combined with the compounds of the invention to treat proliferative diseases and cancers. Known chemotherapeutic agents include, but are not limited to, other therapies or anticancer drugs that may be used in combination with the anticancer agents of the present invention, surgery, radiation therapy (a few examples are gamma radiation, neutron beam radiation therapy, electron beam radiation therapy , proton therapy, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (paclitaxel (Taxol), docetaxel (Taxotere) etc.), platinum derivatives (cisplatin (Cisplatin), carboplatin ( Carboplatin), oxaliplatin, satraplatin), biological response modifiers (interferon, interleukin), tumor necrosis factor (TNF, TRAIL receptor target), hyperthermia and cryotherapy, Agents (eg, antiemetics) to mitigate any adverse effects, and other approved chemotherapeutic agents, including, but not limited to, alkylating agents (mechlorethamine, chlorambucil, cyclophosphamide ( cyclophosphamide), melphalan, ifosfamide), antimetabolites (Methotrexate, Pemetrexed, etc.), purine antagonists and pyrimidine antagonists ( 6-Mercaptopurine, 5-Fluorouracil, Cytarabine, Gemcitabine), spindle inhibitors (Vinblastine, Vincristine) , vinorelbine), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin ( Bleomycin), Mitomycin), nitrosoureas (Carmustine, Lomustine), cell division cycle inhibitors (KSP through mitotic kinesin inhibitors, CENP- E and CDK inhibitors), enzymes (Asparaginase), hormones (Tamoxifen, Leuprolide, Flutamide, Megestrol , Dexamethasone, etc.). Anti-angiogenic agents (Avastin, etc.). Monoclonal antibodies (Belimumab, Brentuximab, Cetuximab, Gemtuzumab, Ipilimumab, Ofatumumab, Panitumumab, Ranibizumab Monoclonal antibody (Ranibizumab), Rituximab (Rituximab), Tositumomab (Tositumomab), Trastuzumab (Trastuzumab)). Kinase inhibitors (Imatinib, Sunitinib, Sorafenib, Erlotinib, Gefitinib, Dasatinib ), Nilotinib, Lapatinib, Crizotinib, Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, etc.). Drugs inhibit or activate cancer pathways such as mTOR, HIF (hypoxia-inducible factor) pathway and others. See http://www.nci.nih.gov/ for a broader forum on cancer treatment, http://www.fda.gov/cder/cancer/druglist-rame.htm for a list of FAD-approved oncology drugs, and Gram Handbook, Eighteenth Edition. 2006, all contents are incorporated by reference. the

另外一些实施例是，本发明的化合物可以结合细胞毒素抗癌剂。这 样的抗癌剂可以在第十三版默克索引（2001）里找到。这些抗癌剂包括，但绝不限于，天门冬酰胺酶，博来霉素，卡铂，卡莫司汀，苯丁酸氮芥，顺铂，L-天冬酰胺酶，环磷酰胺，阿糖胞苷，达卡巴嗪，放线菌素D，柔红霉素，阿霉素(多柔比星)，表柔比星，依托泊苷，5-氟脲嘧啶，六甲基三聚氰胺，羟基脲，异环磷酰胺，伊立替康，亚叶酸，环己亚硝脲，氮芥，6-巯基嘌呤，美司钠，甲氨蝶呤，丝裂霉素C，米托蒽醌，泼尼松龙，泼尼松，丙卡巴肼，雷洛昔芬，链唑霉素，他莫昔芬，硫鸟嘌呤，托泊替康，长春碱，长春新碱，和长春地辛。  In other embodiments, the compounds of the present invention can be combined with cytotoxic anticancer agents. Such anticancer agents can be found in the Thirteenth Edition of The Merck Index (2001). These anticancer agents include, but are by no means limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, L-asparaginase, cyclophosphamide, albino Cytosine, dacarbazine, actinomycin D, daunorubicin, doxorubicin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxy Urea, ifosfamide, irinotecan, leucovorin, cyclohexylnitrosourea, nitrogen mustard, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone Thiolone, prednisone, procarbazine, raloxifene, streptozotocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine. the

与本发明的化合物联合用药的其他合适的细胞毒类药物包括，但并不限于，这些公认地应用于肿瘤性疾病治疗的化合物，如以下文献中所描述的：Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；这些抗癌剂包括，但绝不限于，氨鲁米特（Aminoglutethimide），L-门冬酰胺酶，硫唑嘌呤，5-氮杂胞苷，克拉屈滨(Cladribine)，白消安(Busulfan)，己烯雌酚，2,2'-二氟去氧胞二磷胆碱，多西紫杉醇，赤羟基壬烷基腺嘌呤(Erythrohydroxynonyladenine)，乙炔雌二醇，5-氟尿嘧啶脱氧核苷，5-氟脱氧尿苷单磷酸，磷酸氟达拉滨（Fludarabine phosphate），氟甲睾酮（Fluoxymesterone），氟他胺（Flutamide），己酸羟孕酮，伊达比星（Idarubicin），干扰素，醋酸甲羟孕酮，醋酸甲地孕酮，美法仑（Melphalan），米托坦（Mitotane），紫杉醇，喷司他丁（Pentostatin），N-磷酸乙酰基-L-天冬氨酸（PALA），普卡霉素（Plicamycin），甲基环己亚硝脲（Semustine），替尼泊苷（Teniposide），丙酸睾丸酮，塞替派（Thiotepa），三甲基三聚氰胺，尿核苷和长春瑞滨。  Other suitable cytotoxic drugs for use in combination with the compounds of the present invention include, but are not limited to, those compounds that are recognized for use in the treatment of neoplastic diseases, as described in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill.); These anticancer agents include, but are not limited to, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, carat Cladribine, Busulfan, Diethylstilbestrol, 2,2'-difluorodeoxycytidine, Docetaxel, Erythrohydroxynonyladenine, Ethinyl estradiol, 5-fluorouridine deoxynucleoside, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin (Idarubicin), interferon, medroxyprogesterone acetate, megestrol acetate, melphalan (Melphalan), mitotane (Mitotane), paclitaxel, pentostatin (Pentostatin), N-phosphoacetyl-L -Aspartic Acid (PALA), Plicamycin (Plicamycin), Methylcyclohexylnitrosourea (Semustine), Teniposide (Teniposide), Testosterone Propionate, Thiotepa, Trimethylcyclohexyl Melamine, uridine and vinorelbine. the

其他合适的与本发明的化合物联合应用的细胞毒素类抗癌剂包括新发现的细胞毒素物质，其中包括，但并不限于，奥沙利铂（Oxaliplatin），吉西他滨（Gemcitabine），卡培他滨（Capecitabine），大环内酯类抗肿瘤药及其天然或合成的衍生物，替莫唑胺（Temozolomide）(Quinn et al.,J.Clin.Oncology,2003,21(4),646-651)，托西莫单抗(Bexxar)，Trabedectin(Vidal et al.,Proceedings of the American Society for Clinical Oncology, 2004,23,abstract3181)，和驱动蛋白纺锤体蛋白抑制剂Eg5(Wood et al.,Curr.Opin.Pharmacol.2001,1,370-377)。  Other cytotoxic anticancer agents suitable for use in combination with the compounds of the present invention include newly discovered cytotoxic substances, including, but not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), capecitabine (Capecitabine), a macrolide antineoplastic drug and its natural or synthetic derivatives, Temozolomide (Quinn et al., J. Clin. Oncology, 2003, 21 (4), 646-651), Torto Siblomab (Bexxar), Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract3181), and the kinesin spindle protein inhibitor Eg5 (Wood et al., Curr. Opin. Pharmacol. 2001, 1, 370-377). the

另外一些实施例是，本发明的化合物可以结合其他信号转导抑制剂。有趣的是信号转导抑制剂把EGFR家族作为目标，如EGFR，HER-2和HER-4(Raymond et al.,Drugs,2000,60(Suppl.l),15-23;Harari et al.,Oncogene,2000,19(53),6102-6114)和它们各自的配体。这样的试剂包括，但绝不限于，抗体疗法如曲妥珠单抗(Trastuzumab)，西妥昔单抗(Cetuximab)，伊匹单抗(Ipilimumab)和帕妥珠单抗(Pertuzumab)。这样的疗法也包括，但绝不限于，小分子激酶抑制剂如伊马替尼(Imatinib)，舒尼替尼(Sunitinib)，索拉非尼(Sorafenib)，厄洛替尼(Erlotinib)，吉非替尼(Gefitinib)，达沙替尼(Dasatinib)，尼洛替尼(Nilotinib)，拉帕替尼(Lapatinib)，克卓替尼(Crizotinib)，Ruxolitinib，Vemurafenib，Vandetanib，Pazopanib，阿法替尼(Afatinib)，amuvatinib，阿西替尼(axitinib)，波舒替尼(bosutinib)，brivanib，canertinib，cabozantinib，西地尼布(cediranib)，dabrafenib，dacomitinib，，danusertib，dovitinib，foretinib，ganetespib，ibrutinib，iniparib，lenvatinib，linifanib，linsitinib，马赛替尼（masitinib），momelotinib，莫替沙尼(motesanib)，来那替尼(neratinib)，niraparib，oprozomib，olaparib，pictilisib，ponatinib，quizartinib，regorafenib，rigosertib，rucaparib，塞卡替尼(saracatinib)，saridegib，tandutinib，tasocitinib，telatinib，tivantinib，tivozanib，tofacitinib，trametinib，vatalanib，veliparib，vismodegib，volasertib，BMS-540215，BMS777607，JNJ38877605，TKI258，GDC-0941（Folkes,et al.,J.Med.Chem.2008,51,5522），BZE235，等等。  In other embodiments, the compounds of the invention may be combined with other signal transduction inhibitors. Interestingly, signal transduction inhibitors target the EGFR family, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000, 60(Suppl.l), 15-23; Harari et al., Oncogene, 2000, 19(53), 6102-6114) and their respective ligands. Such agents include, but are by no means limited to, antibody therapies such as Trastuzumab, Cetuximab, Ipilimumab and Pertuzumab. Such therapies also include, but are by no means limited to, small molecule kinase inhibitors such as Imatinib, Sunitinib, Sorafenib, Erlotinib, Gem Gefitinib, Dasatinib, Nilotinib, Lapatinib, Crizotinib, Ruxolitinib, Vemurafenib, Vandetanib, Pazopanib, Afatinib (Afatinib), amuvatinib, axitinib, bosutinib, brivanib, canertinib, cabozantinib, cediranib, dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, ganetespib, ibrutinib , iniparib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, saracatinib, saridegib, tandutinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, volasertib, BMS-540215, BMS777607, JNJ38877605, TKI258, GDC-0941 ( et al., J.Med.Chem.2008, 51, 5522), BZE235, etc. the

另外一些实施例是，本发明的化合物可以结合组蛋白脱乙酰基酶抑制剂。这样的试剂包括，但绝不限于，辛二酰苯胺氧肟酸（SAHA），LAQ-824(Ottmann et al.,Proceedings of the American Society for Clinical Oncology,2004,23,abstract3024),LBH-589(Beck et al.,Proceedings of the American Society for Clinical Oncology,2004,23,abstract3025),MS-275(Ryan et al.,Proceedings of the American Association of Cancer  Research,2004,45,abstract2452),FR-901228(Piekarz et al.,Proceedings of the American Society for Clinical Oncology,2004,23,abstract3028)和MGCDOI03(US6,897,220)。  In other embodiments, the compounds of the invention can bind to histone deacetylase inhibitors. Such reagents include, but are by no means limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3024), LBH-589 ( Beck et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3025), MS-275 (Ryan et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 2452), FR-901228 ( Piekarz et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, abstract 3028) and MGCDOI03 (US6,897,220). the

另外一些实施例是，本发明的化合物可以结合其他抗癌剂如蛋白酶体抑制剂和m-TOR抑制剂。这些包括，但绝不限于，硼替佐米(Bortezomib)(Mackay et al.,Proceedings of the American Society for Clinical Oncology,2004,23,Abstract3109),和CCI-779(Wu et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract3849)。本发明的化合物还可以结合其他抗癌剂如拓扑异构酶抑制剂，包括但绝不限于喜树碱。  In other embodiments, the compounds of the invention may be combined with other anticancer agents such as proteasome inhibitors and m-TOR inhibitors. These include, but are by no means limited to, Bortezomib (Mackay et al., Proceedings of the American Society for Clinical Oncology, 2004, 23, Abstract 3109), and CCI-779 (Wu et al., Proceedings of the American Association of Cancer Research, 2004, 45, abstract 3849). The compounds of the invention may also be combined with other anticancer agents such as topoisomerase inhibitors, including but by no means limited to camptothecin. the

那些附加治疗剂可以与包含本发明的化合物的组合物分开给药，作为多给药方案的一部分。或者，那些治疗剂可以是单剂型的一部分，与本发明的化合物混合在一起形成单个组合物。如果给药作为多给药方案的一部分，两个活性剂可以同时连续地或在一段时间内互相传递，从而得到目标试剂活性。  Those additional therapeutic agents may be administered separately from the composition comprising the compound of the invention as part of a multiple dosing regimen. Alternatively, those therapeutic agents may be part of a single dosage form, mixed together with the compounds of this invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents may be delivered to each other simultaneously, sequentially or over a period of time, such that the desired agent activity is achieved. the

可以结合载体物质产生单剂型的化合物和附加治疗剂，其用量（那些包含一个附加治疗剂的组合物像本发明所描述的）的改变取决于主治和特殊给药模式。正常地，本发明的组合物附加治疗剂的量将不超过组合物包含治疗剂作为唯一的活性剂的正常给药的量。另一方面，现公开的组合物附加治疗剂的量的范围大约是现有组合物正常量的50%-100%，包含的试剂作为唯一活性治疗剂。在那些包含附加治疗剂的组合物中，附加治疗剂将与本发明的化合物起协同作用。  The compound and the additional therapeutic agent can be combined to produce a single dosage form, the amount used (those compositions containing an additional therapeutic agent as described herein) varying depending on the indication and the particular mode of administration. Normally, the amount of additional therapeutic agent in the compositions of the invention will not exceed the amount normally administered for a composition comprising the therapeutic agent as the only active agent. In another aspect, the disclosed compositions additional therapeutic agent in an amount ranging from about 50% to 100% of the normal amount of prior compositions, comprising the agent as the sole active therapeutic agent. In those compositions comprising an additional therapeutic agent, the additional therapeutic agent will act synergistically with the compound of the invention. the

化合物及组合物的应用Application of Compounds and Compositions

本发明提供的上述化合物和药物组合物可用于制备用于防护、处理、治疗或减轻增殖性疾病的药品，也可以用于制备用于抑制或调节蛋白激酶活性的药品。  The above-mentioned compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for preventing, treating, treating or alleviating proliferative diseases, and can also be used for preparing medicines for inhibiting or regulating protein kinase activity. the

具体而言，本发明的组合物中化合物可以有效地可探测地抑制蛋白激酶如ALK或c-Met的活性。本发明化合物可以作为抗肿瘤药物对患者进行治疗或减小ALK和c-Met信号响应的有害作用。  In particular, the compounds in the compositions of the invention are effective in detectably inhibiting the activity of protein kinases such as ALK or c-Met. The compounds of the present invention can be used as antitumor drugs to treat patients or reduce the harmful effects of ALK and c-Met signaling responses. the

本发明的化合物可以应用于，但绝不限于，使用本发明的化合物或组合物的有效量对患者给药来预防或治疗患者增殖性疾病。这样的疾病包括癌症，尤其是转移癌，动脉粥样硬化和肺纤维化等。  The compounds of the present invention may be used in, but by no means limited to, administering to a patient an effective amount of the compound or composition of the present invention to prevent or treat a proliferative disease in a patient. Such diseases include cancer, especially metastatic cancer, atherosclerosis and pulmonary fibrosis, among others. the

本发明的化合物及药物组合物可以应用于瘤的治疗，包括癌症和转移癌，进一步包括但并不限于，癌症如膀胱癌，乳腺癌，结肠癌，肾癌，肝癌，肺癌（包括小细胞肺癌），食道癌，胆囊癌，卵巢癌，胰腺癌，胃癌，宫颈癌，甲状腺癌，前列腺癌，和皮肤癌（包括鳞状细胞癌）；淋巴系统造血肿瘤（包括白血病，急性淋巴囊肿性白血病，急性成淋巴细胞性白血病，B细胞淋巴瘤，T细胞淋巴瘤，何杰金(氏)淋巴瘤，非何杰金(氏)淋巴瘤，多毛细胞白血病和伯基特淋巴瘤）；骨髓系统造血肿瘤（包括急慢性骨髓性粒细胞性白血病，骨髓增生异常综合症，和前髓细胞白血病）；间充质细胞起源的肿瘤（包括纤维肉瘤和横纹肌肉瘤，和其他肉瘤，如软组织和软骨）；中枢末梢神经系统瘤（包括星形细胞瘤，成神经细胞瘤，神经胶质瘤，和神经鞘瘤）；和其他肿瘤（包括黑素瘤，精原细胞瘤，畸胎癌，骨肉瘤，xenoderoma pigmentosum，keratoctanthoma，甲状腺滤泡瘤和卡波济(氏)肉瘤）。  The compounds and pharmaceutical compositions of the present invention can be applied to the treatment of tumors, including cancers and metastatic cancers, further including but not limited to, cancers such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including small cell lung cancer) ), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphocystic leukemia, Acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell leukemia and Burkitt's lymphoma); myeloid hematopoiesis Neoplasms (including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia); neoplasms of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and cartilage); Central peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including melanoma, seminoma, teratoma, osteosarcoma, xenorderoma pigmentosum , keratoctanthoma, thyroid follicular tumor and Kaposi's sarcoma). the

本发明的化合物及药物组合物还可用于治疗眼科病症例如角膜移植排斥，眼的新生血管形成，视网膜新生血管形成包括损伤或感染后的新生血管形成；糖尿病性视网膜病；晶状体后纤维组织增生症，和新生血管性青光眼；视网膜缺血；玻璃体出血；溃疡性疾病如胃溃疡；病理学的但非恶性状况如血管瘤，包括婴儿血管内皮细胞瘤，鼻咽和无血管性骨坏死的血管纤维瘤；雌性生殖系统紊乱如子宫内膜异位。这些化合物同样也用于治疗水肿和脉管通透性过高的状况。  The compounds and pharmaceutical compositions of the present invention are also useful in the treatment of ophthalmic conditions such as corneal transplant rejection, neovascularization of the eye, retinal neovascularization including neovascularization following injury or infection; diabetic retinopathy; retrolentic fibroplasia , and neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative diseases such as gastric ulcer; tumors; disorders of the female reproductive system such as endometriosis. These compounds are also useful in the treatment of edema and vascular hyperpermeability conditions. the

本发明的化合物及药物组合物还可以用于处理与糖尿病相关的情况如糖尿病性视网膜病和微血管病。本发明的化合物及药物组合物同样用于癌症患者血流量减少的情况。本发明的化合物及药物组合物对患者肿瘤转移减少也有有益效果。  The compounds and pharmaceutical compositions of the present invention are also useful in the management of conditions associated with diabetes such as diabetic retinopathy and microangiopathy. The compounds and pharmaceutical compositions of the present invention are also used in the condition of decreased blood flow in cancer patients. The compounds and pharmaceutical compositions of the present invention also have beneficial effects on reducing tumor metastasis in patients. the

本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物，包括哺乳动物，啮齿 类动物等等。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。  In addition to being useful in human therapy, the compounds and pharmaceutical compositions of the present invention can also be used in veterinary treatment of pets, imported animals and farm animals, including mammals, rodents and the like. Examples of additional animals include horses, dogs and cats. Here, the compounds of the present invention include their pharmaceutically acceptable derivatives. the

在将复数形式应用于化合物，盐等的情况下，其也意指单一的化合物，盐等。  Where the plural form is applied to a compound, salt, etc., it also means a single compound, salt, etc. the

本发明还提供了包含本发明的化合物或组合物给药的治疗方法，进一步包括对患者附加治疗剂（联合治疗）的给药，其中附加治疗剂选自：化学疗法、抗增殖剂或抗炎剂，其中附加治疗剂适用于所治疗的疾病，且附加治疗剂可以和本发明的化合物或组合物联合给药，本发明的化合物或组合物作为单个剂型，或分开的化合物或组合物作为多剂型的一部分。附加治疗剂可以与本发明的化合物同时给药或不同时给药。后者的情况，给药可以错开进行如6小时，12小时，1天，2天，3天，1周，2周，3周，1个月或2个月进行。  The present invention also provides a method of treatment comprising administering a compound or composition of the present invention, further comprising administering to the patient an additional therapeutic agent (combination therapy), wherein the additional therapeutic agent is selected from: chemotherapy, anti-proliferative or anti-inflammatory medicament, wherein the additional therapeutic agent is suitable for the disease being treated, and the additional therapeutic agent may be administered in combination with the compound or composition of the invention as a single dosage form, or as separate compounds or compositions as multiple dosage forms. part of the dosage form. Additional therapeutic agents may be administered at the same time or at different times as the compounds of the invention. In the latter case, the administration may be staggered for 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months. the

本发明同样包含对表达ALK或c-Met的细胞生长抑制的方法，此方法包括本发明的化合物或组合物与细胞接触，从而抑制细胞生长。能被抑制生长的细胞包括：乳腺癌细胞，结肠直肠癌细胞，肺癌细胞，乳头状癌细胞，前列腺癌细胞，淋巴瘤细胞，结肠癌细胞，胰腺癌细胞，卵巢癌细胞，子宫颈癌细胞，中枢神经系统癌细胞，成骨肉瘤细胞，肾癌细胞，肝细胞癌细胞，膀胱癌细胞，胃癌细胞，头或颈鳞癌细胞，黑色素瘤细胞和白血病细胞。  The present invention also includes a method of inhibiting the growth of cells expressing ALK or c-Met, the method comprising contacting the cell with a compound or composition of the present invention, thereby inhibiting the growth of the cell. Cells whose growth can be inhibited include: breast cancer cells, colorectal cancer cells, lung cancer cells, papillary cancer cells, prostate cancer cells, lymphoma cells, colon cancer cells, pancreatic cancer cells, ovarian cancer cells, cervical cancer cells, Central nervous system cancer cells, osteosarcoma cells, kidney cancer cells, hepatocellular carcinoma cells, bladder cancer cells, gastric cancer cells, head or neck squamous cell carcinoma cells, melanoma cells and leukemia cells. the

本发明提供了在生物标本内抑制ALK或c-Met激酶活性的方法，此方法包括将本发明的化合物或组合物与生物标本接触。本发明所使用的术语“生物标本”是指活体外部的标本，包括但绝不限于，细胞培养或细胞提取；从哺乳动物或其提取物得到的活组织检查物质；血液，唾液，尿液，粪便，精液，眼泪，或其他活组织液体物质及其提取物。抑制生物标本中激酶活性，特别是ALK或c-Met激酶活性，可用于所属领域技术人员公知的多种用途。这样的用途包括，但绝不限于，输血法，器官移植，生物标本储藏和生物鉴定。  The invention provides a method of inhibiting ALK or c-Met kinase activity in a biological sample, the method comprising contacting a compound or composition of the invention with the biological sample. The term "biological specimen" used in the present invention refers to specimens outside the living body, including but not limited to, cell culture or cell extraction; biopsy material obtained from mammals or their extracts; blood, saliva, urine, Feces, semen, tears, or other liquid substances of living tissue and their extracts. Inhibition of kinase activity, particularly ALK or c-Met kinase activity, in a biological sample can be used in a variety of ways well known to those skilled in the art. Such uses include, but are by no means limited to, blood transfusions, organ transplantation, biospecimen storage, and bioassays. the

本发明的化合物或药学上可接受的组合物的“有效量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。根据 本发明的方法，化合物和组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度，特殊的因素，给药方式，等等。化合物或组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。  An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the present invention refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the methods of the present invention, the compounds and compositions may be administered in any amount and by any route of administration effective for treating or lessening the severity of the disease. The exact amount necessary will vary from patient to patient, depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. A compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein. the

本发明的化合物或其药物组合物可以应用于可植入的内科装置的包衣，如假体，人工瓣膜，人造血管，茎和导尿管。例如，脉管茎，已经被用于克服再狭窄（损伤后血管壁的再收缩）。然而，患者使用茎或其他可植入装置将会有血块形成或血小板激活的风险。这些不利的作用可以通过使用包含本发明的化合物的药学上可接受的组合物预涂渍装置来阻止或减轻。  The compounds of the present invention or their pharmaceutical compositions can be applied to the coating of implantable medical devices, such as prostheses, artificial valves, artificial blood vessels, stems and urinary catheters. Vascular stems, for example, have been used to overcome restenosis (reconstriction of vessel walls after injury). However, patients using stems or other implantable devices will be at risk of clot formation or platelet activation. These adverse effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of the invention. the

合适的包衣和可植入装置的包衣的一般制备方法在文献US6,099,562;US5,886,026;和US5,304,121中有所描述，包衣是有代表性地生物相容的多聚体材料如水凝胶聚合体，聚甲基二硅醚，聚已酸内酯，聚乙二醇，聚乳酸，乙烯-乙酸乙烯酯，及其混合物。包衣可以任选地更进一步地被合适的包衣所覆盖，如氟代二甲硅油，多糖酶，聚乙二醇，磷脂类，或它们的组合，来表现组合物控制释放的特征。本发明的另一方面包括使用本发明的化合物涂敷的可植入装置。本发明的化合物也可以涂敷在可植入体内的医疗用具上，如珠状物，或与聚合物或其他分子混合来提供“药物储藏所”，因此与药物水溶液给药方式比较，允许药物释放有更长的时间期限。  Suitable coatings and general methods of preparation of coatings for implantable devices are described in documents US 6,099,562; US 5,886,026; and US 5,304,121, the coatings being typically biocompatible polymeric materials Such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered with a suitable coating, such as fluorosimethicone, polysaccharase, polyethylene glycol, phospholipids, or a combination thereof, to exhibit controlled-release characteristics of the composition. Another aspect of the invention includes implantable devices coated with a compound of the invention. The compounds of the present invention may also be coated on implantable medical devices, such as beads, or mixed with polymers or other molecules to provide "drug depots", thus allowing drug Release has a longer time period. the

化合物的合成方法Compound Synthesis Method

一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。  Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I). The following reaction schemes and examples serve to further illustrate the present invention. the

所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成， 如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。  Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention. the

下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，除非其他方面表明，使用时都没有经过进一步纯化。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司和青岛海洋化工厂购买得到。  In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Factory can be purchased. the

无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N，N-二甲基乙酰胺和N，N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。  Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use. the

以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管（除非其他方面表明），反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。  The following reactions are generally carried out under positive pressure of nitrogen or argon or over anhydrous solvents with a drying tube (unless otherwise indicated), the reaction vials are all stoppered with suitable rubber stoppers, and the substrate is injected by syringe. Glassware is dried. the

色谱柱是使用硅胶柱。硅胶（300-400目）购于青岛海洋化工厂。核磁共振光谱以CDC13、d6-DMSO、CD3OD或d6-丙酮为溶剂（报导以ppm为单位），用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，四重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹（Hz）表示。  The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The nuclear magnetic resonance spectrum uses CDC1 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone as the solvent (reported in ppm), and TMS (0ppm) or chloroform (7.25ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

低分辨率质谱（MS）数据的条件是：Agilent1200或Agilent6120Series LCMS(柱子型号：Zorbax SB-C18,2.1×30mm,3.5微米,6min,流速为0.6mL/min。流动相：5-95%（含0.1%甲酸的CH3CN）在（含0.1%甲酸的H2O）中的比例，在210/254nm用UV检测，用低响应电喷模式(ESI)。  The conditions for low-resolution mass spectrometry (MS) data are: Agilent1200 or Agilent6120Series LCMS (column model: Zorbax SB-C18, 2.1×30mm, 3.5 microns, 6min, flow rate 0.6mL/min. Mobile phase: 5-95% (containing 0.1% formic acid in CH 3 CN) in (0.1% formic acid in H 2 O), detected with UV at 210/254 nm, using low-response electrospray mode (ESI).

纯的化合物的表征方式为：Agilent1100Series高性能液相色谱(HPLC)，在210nm和254nm用UV检测。柱子通常在40°C下操作。  Pure compounds were characterized by Agilent 1100 Series High Performance Liquid Chromatography (HPLC) with UV detection at 210 nm and 254 nm. Columns are typically operated at 40°C. the

BBr3  三溴化硼  BBr 3 boron tribromide

BINAP  2,2'-双二苯膦基-1,1'-联萘  BINAP 2,2'-bisdiphenylphosphino-1,1'-binaphthalene

BOC，Boc  叔丁氧基羰基  BOC, Boc tert-butoxycarbonyl

BSA  牛血清白蛋白  BSA bovine serum albumin

CDC13  氘代氯仿  CDC1 3 deuterated chloroform

CHCl3  氯仿  CHCl 3 Chloroform

CH2Cl2，DCM  二氯甲烷  CH2Cl2 , DCM dichloromethane

CH3SO2Cl，MsCl  对甲苯磺酰氯  CH 3 SO 2 Cl, MsCl p-toluenesulfonyl chloride

Cs2CO3  碳酸铯  Cs 2 CO 3 cesium carbonate

Cu  铜  Cu Copper

CuI  碘化亚铜  CuI Cuprous iodide

DAST  三氟化二乙氨基硫  DAST diethylaminosulfur trifluoride

DBU  1,8-二氮杂双环[5.4.0]十一碳-7-烯  DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DEAD  偶氮二甲酸二乙酯  DEAD Diethyl Azodicarboxylate

DIAD  偶氮二甲酸二异丙酯  DIAD Diisopropyl azodicarboxylate

DIBAL  二异丁基氢化铝  DIBAL Diisobutylaluminum hydride

DIEA，DIPEA  二异丙基乙基胺  DIEA, DIPEA Diisopropylethylamine

DMAP  4-二甲氨基吡啶  DMAP 4-Dimethylaminopyridine

DMF  N，N-二甲基甲酰胺  DMF N,N-Dimethylformamide

DMSO  二甲基亚砜  DMSO Dimethyl Sulfoxide

DPPA  叠氮磷酸二苯酯  DPPA Diphenyl Phosphate Azide

EDCI  1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐  EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc，EA  乙酸乙酯  EtOAc, EA ethyl acetate

Et2O  乙醚  Et 2 O diethyl ether

Et3N，TEA  三乙胺  Et 3 N, TEA Triethylamine

FBS  胎牛血清  FBS Fetal Bovine Serum

Fe  铁  Fe iron

g  克  g grams

h  小时  h hours

HATU  O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯  HATU O-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HBr  氢溴酸  HBr hydrobromic acid

HBTU  O-苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐  HBTU O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate

HCl  盐酸  HCl hydrochloric acid

H2  氢气  H 2 hydrogen

H2O  水  H2O water

H2O2  过氧化氢  H 2 O 2 hydrogen peroxide

HOAc，AcOH  乙酸  HOAc, AcOH acetic acid

HOBt  1-羟基苯并三唑  HOBt 1-Hydroxybenzotriazole

K2CO3  碳酸钾  K2CO3potassium carbonate

KOH  氢氧化钾  KOH potassium hydroxide

LiHMDS  六甲基二硅基胺基锂  LiHMDS lithium hexamethyldisilazide

LDA  二异丙基胺基锂  LDA lithium diisopropylamide

MCPBA  间氯过氧苯甲酸  MCPBA m-chloroperoxybenzoic acid

MeCN，CH3CN  乙腈  MeCN, CH3CN acetonitrile

MeI  碘甲烷  MeI methyl iodide

MeOH，CH3OH  甲醇  MeOH, CH3OH Methanol

2-MeTHF  2-甲基四氢呋喃  2-MeTHF 2-Methyltetrahydrofuran

MgSO4硫酸镁  MgSO 4 magnesium sulfate

mL，ml  毫升  mL, ml milliliter

N2  氮气  N 2 Nitrogen

NaBH4  硼氢化钠  NaBH 4 sodium borohydride

NaBH3CN  氰基硼氢化钠  NaBH 3 CN Sodium cyanoborohydride

NaCl  氯化钠  NaCl Sodium Chloride

NaClO2  亚氯酸钠  NaClO 2 sodium chlorite

NaH  氢化钠  NaH Sodium hydride

NaHCO3  碳酸氢钠  NaHCO 3 sodium bicarbonate

NaH2PO4  磷酸二氢钠  NaH 2 PO 4 sodium dihydrogen phosphate

NaI  碘化钠  NaI Sodium iodide

NaO(t-Bu)  叔丁醇钠  NaO(t-Bu) sodium tert-butoxide

NaOH  氢氧化钠  NaOH sodium hydroxide

Na2SO4  硫酸钠  Sodium Na 2 SO 4 Sulfate

NBS  N-溴代丁二酰亚胺  NBS N-Bromosuccinimide

NH3  氨  NH 3 ammonia

NH4C1  氯化氨  NH 4 C1 ammonium chloride

NIS  N-碘代丁二酰亚胺  NIS N-iodosuccinimide

NMP  N-甲基吡咯烷酮  NMP N-Methylpyrrolidone

PBS  磷酸盐缓冲盐水  PBS Phosphate Buffered Saline

P(t-Bu)3  三(叔丁基)膦  P(t-Bu) 3 tri(tert-butyl)phosphine

Pd/C  钯/碳  Pd/C palladium/carbon

Pd2(dba)3  双(二苄亚基丙酮)钯  Pd 2 (dba) 3 Bis(dibenzylideneacetone) palladium

Pd(dppf)Cl2  1,1-双(二苯基膦基)二茂铁二氯化钯  Pd(dppf)Cl 2 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride

Pd(OAc)2  醋酸钯  Pd(OAc) 2 palladium acetate

Pd(OH)2  氢氧化钯  Pd(OH) 2 palladium hydroxide

Pd(PPh3)4  四(三苯基膦)钯  Pd(PPh 3 ) 4tetrakis (triphenylphosphine)palladium

Pd(PPh3)2Cl2  双(三苯基膦)二氯化钯  Pd(PPh 3 ) 2 Cl 2 bis(triphenylphosphine)palladium dichloride

PE  石油醚(60-90°C)  PE petroleum ether (60-90°C)

POC13  三氯氧磷  POC1 3 phosphorus oxychloride

PyBop  1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐  PyBop 1H-Benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate

RT，rt，r.t.  室温  RT, rt, r.t. room temperature

Rt  保留时间  Rt retention time

TBAB  四丁基溴化铵  TBAB Tetrabutylammonium bromide

TBAHSO4  四丁基硫酸氢铵  TBAHSO 4 Tetrabutylammonium bisulfate

TBTU  O-(1H-苯并三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸酯  TBTU O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

TFA  三氟乙酸  TFA trifluoroacetic acid

TEAC  二(四乙基铵)碳酸盐  TEAC bis(tetraethylammonium) carbonate

THF  四氢呋喃  THF Tetrahydrofuran

μL  微升  μL Microliter

下列合成方案描述了制备本发明公开化合物的步骤。除非另外说明，R1，R2，R3，R4，R5，R6和Z具有如本发明所述的定义。  The following synthetic schemes describe the steps involved in preparing the compounds disclosed in this invention. Unless otherwise stated, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the definitions as described in the present invention.

合成方法1  Synthetic method 1

式(I)所示的化合物可以通过下列过程制备得到：  The compound shown in formula (I) can be prepared through the following process:

式(1)所示的(R)-芳基醇与式(2)所示的取代的氟代吡啶在氢化钠的作用下，在非质子溶剂如四氢呋喃中反应，得到式(3)所示的偶联产物。式(3)所示的偶联产物中吡啶环上的硝基在酸性还原条件下，使用还原剂如铁粉转换成式(4)所示的氨基化合物。然后在NBS作用下，通过吡啶环上的区域选择性溴化，得到式(5)所示的化合物。最后，式(5)所示的化合物与式(6)所示的炔，如2-甲基丁-3-炔-2醇，在合适的Pd催化剂作用下，偶联生成式(I)所示的化合物，反应过程如下所示：  The (R)-aryl alcohol shown in formula ( 1 ) reacts with the substituted fluoropyridine shown in formula ( 2 ) under the action of sodium hydride in an aprotic solvent such as tetrahydrofuran to obtain the formula ( 3 ) coupling products. The nitro group on the pyridine ring in the coupling product shown in formula ( 3 ) is converted into the amino compound shown in formula ( 4 ) using a reducing agent such as iron powder under acidic reducing conditions. Then, under the action of NBS, the compound represented by formula ( 5 ) can be obtained by regioselective bromination on the pyridine ring. Finally, the compound represented by formula ( 5 ) is coupled with the alkyne represented by formula ( 6 ), such as 2-methylbut-3-yn-2 alcohol, under the action of a suitable Pd catalyst, to generate the compound represented by formula (I) For the compound shown, the reaction process is as follows:

合成方法2  Synthetic method 2

式(I)所示的化合物可以通过下列过程制备得到：  The compound shown in formula (I) can be prepared through the following process:

按照合成方法1中的方法或者其他方法制备得到式(5)所示的化合物，式(5)所示的化合物与Boc酸酐在碱如碳酸钠、碳酸氢钠或三乙胺的 存在下，生成式(8)所示的氨基保护化合物。式(8)所示氨基保护化合物与联硼酸频那醇酯在适合的Pd催化剂，如Pd(dppf)Cl2·CH2Cl2和Pd(PPh3)2Cl2作用下偶联，得到式(9)所示的硼酸化合物，该反应在非质子性溶剂（如，二甲亚砜，N,N-二甲基甲酰胺或二噁烷）中进行。之后，在碱和催化剂如Pd(dppf)Cl2·CH2Cl2的存在下，式(9)所示的硼酸化合物和式(10)所示的含氮杂环化合物发生Suzuki反应，生成式(11)所示的化合物。Suzuki反应中适合的碱包括碳酸氢钠，碳酸氢钾，碳酸钠，碳酸钾，碳酸铯，及其他。该反应最好在混合溶剂，如乙二醇二甲醚/水，二噁烷/水中进行，温度控制在70～100°C之间。最后，在酸性条件下，如三氟乙酸的二氯甲烷溶液，氯化氢的乙酸乙酯溶液，脱去Boc和其他保护基，得到式(I)所示的化合物，反应过程如下所示：  The compound shown in formula ( 5 ) is prepared according to the method in Synthesis Method 1 or other methods, and the compound shown in formula ( 5 ) and Boc anhydride are in the presence of a base such as sodium carbonate, sodium bicarbonate or triethylamine to form Amino protection compound shown in formula ( 8 ). The amino-protected compound shown in formula ( 8 ) is coupled with pinacol diboronic acid ester under the action of a suitable Pd catalyst, such as Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(PPh 3 ) 2 Cl 2 , to obtain the formula For the boronic acid compound shown in ( 9 ), the reaction is carried out in an aprotic solvent (such as dimethylsulfoxide, N,N-dimethylformamide or dioxane). Afterwards, in the presence of a base and a catalyst such as Pd(dppf)Cl 2 ·CH 2 Cl 2 , the boronic acid compound represented by formula ( 9 ) and the nitrogen-containing heterocyclic compound represented by formula ( 10 ) undergo a Suzuki reaction to generate the formula Compounds shown in ( 11 ). Suitable bases in the Suzuki reaction include sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and others. This reaction is preferably carried out in a mixed solvent, such as ethylene glycol dimethyl ether/water, dioxane/water, and the temperature is controlled between 70～100°C. Finally, under acidic conditions, such as the dichloromethane solution of trifluoroacetic acid, the ethyl acetate solution of hydrogen chloride, Boc and other protecting groups are removed to obtain the compound shown in formula (I), and the reaction process is as follows:

Figure BDA00002905454700631
Figure BDA00002905454700631

本发明采用以下方法对式（I）所示的化合物进行生物试验：  The present invention adopts the following method to carry out biological test to the compound shown in formula (I):

1、生物分析方法  1. Bioanalytical methods

采用LC/MS/MS系统进行分析，包括Agilent1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离(ESI)源的Agilent G6430三级四级杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表A所示：  LC/MS/MS system was used for analysis, including Agilent1200 series vacuum degassing furnace, binary syringe pump, orifice plate autosampler, column thermostat, and Agilent G6430 triple quadrupole mass spectrometer with electrospray ionization (ESI) source . Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:

表A MRM转换的参数  Table A Parameters of MRM conversion

多反应检测扫描 multiple reaction detection scan 490.2→383.1 490.2 → 383.1 碎裂电压 Fragmentation voltage 230V 230V 毛细管电压 capillary voltage 55V 55V 干燥器温度 Dryer temperature 350°C 350°C 雾化器 atomizer 40psi 40psi 干燥器流速 Dryer flow rate 10L/min 10L/min

分析使用Agilent XDB-C18,2.1x30mm,3.5μM柱，注入5μL样品。分析条件：流动相为0.1%的甲酸水溶液(A)和0.1%的甲酸甲醇溶液(B)。流速为0.4mL/min。流动相梯度如表B所示：  The analysis uses Agilent XDB-C18, 2.1x30mm, 3.5 μM column, injecting 5 μL of sample. Analysis conditions: mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate was 0.4 mL/min. The mobile phase gradient is shown in Table B:

表B流动相梯度  Table B mobile phase gradient

时间 time 流动相B的梯度 Gradient of mobile phase B 0.5min 0.5min 5% 5% 1.0min 1.0min 95% 95% 2.2min 2.2min 95% 95% 2.3min 2.3min 5% 5% 5.0min 5.0min Stop stop

此外，用于分析的还有Agilent6330系列LC/MS/MS光谱仪，配备有G1312A二元注射泵，G1367A自动采样器和G1314C UV检测器； LC/MS/MS光谱仪采用ESI放射源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Capcell MP-C18柱，规格为：100x4.6mm I.D.,5μM(Phenomenex,Torrance,California,USA)。流动相是5mM醋酸铵，0.1%甲醇水溶液(A)：5mM醋酸铵，0.1%甲醇乙腈溶液(B)(70:30，v/v)；流速为0.6mL/min；柱温保持在室温；注入20μL样品。  In addition, Agilent6330 series LC/MS/MS spectrometer is used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometer uses ESI radiation source. Optimum analysis is achieved using standards with appropriate cation model processing and MRM conversion for each analyte. A Capcell MP-C18 column with dimensions: 100x4.6 mm I.D., 5 μΜ (Phenomenex, Torrance, California, USA) was used during the analysis. The mobile phase is 5mM ammonium acetate, 0.1% methanol in water (A): 5mM ammonium acetate, 0.1% methanol in acetonitrile (B) (70:30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; Inject 20 μL of sample. the

2、化合物在人和大鼠肝微粒中的稳定性分析  2. Stability analysis of compounds in human and rat liver microparticles

（1）将人或大鼠肝微粒体置于聚丙烯试管中孵育，并引导其复制。典型的孵育混合液包括人或大鼠肝微粒体（0.5mg蛋白质/mL），待分析化合物（5μM）和总体积为200μL的NADPH(1.0mM)磷酸钾缓冲液(PBS，100mM，pH值为7.4)，将待分析化合物溶解在DMSO中，并使用PBS将其稀释，使其最终的DMSO溶液的浓度为0.05%。并在37°C下与空气相通的水浴中进行孵育，预孵育3分钟后向混合液中加入蛋白并开始反应。在不同的时间点(0，5，10，15，30和60min)，加入同体积冰冷乙腈终止反应。样品于-80°C下保存直到进行LC/MS/MS分析。  (1) Incubate human or rat liver microsomes in polypropylene test tubes and guide their replication. A typical incubation mixture includes human or rat liver microsomes (0.5 mg protein/mL), the compound to be analyzed (5 μM), and a total volume of 200 μL of NADPH (1.0 mM) potassium phosphate buffer (PBS, 100 mM, pH 7.4), dissolve the compound to be analyzed in DMSO, and dilute it with PBS so that the final concentration of the DMSO solution is 0.05%. And incubate at 37°C in an air-connected water bath. After pre-incubation for 3 minutes, add protein to the mixture and start the reaction. At different time points (0, 5, 10, 15, 30 and 60 min), the same volume of ice-cold acetonitrile was added to terminate the reaction. Samples were stored at -80°C until LC/MS/MS analysis. the

化合物在人或大鼠肝微粒体孵育混合物中的浓度是通过LC/MS/MS的方法来测定的。浓度范围的线性范围是通过每一个受试化合物来确定的。  Compound concentrations in human or rat liver microsome incubation mixtures were determined by LC/MS/MS. The linear range of the concentration range was determined for each compound tested. the

平行孵育试验使用变性的微粒体作为阴性对照，在37°C下孵化，反应在不同的时间点(0,15和60分钟)终止。  Parallel incubation experiments using denatured microsomes as a negative control were incubated at 37°C and the reactions were terminated at different time points (0, 15 and 60 min). the

右美沙芬(70μΜ)作为阳性对照，在37°C下孵化，反应在不同的时间点(0，5，10，15，30和60分钟)终止。每一种测定方法中都包括阳性和阴性对照样品，以保证微粒体孵化体系的完整性。  Dextromethorphan (70 μM) was used as a positive control, incubated at 37°C, and the reactions were terminated at different time points (0, 5, 10, 15, 30 and 60 minutes). Positive and negative control samples are included with each assay to ensure the integrity of the microsomal incubation system. the

（2）本发明所述化合物在人或大鼠肝微粒体中的稳定性数据也可由以下试验得到：将人或大鼠肝微粒体置于聚丙烯试管中孵育，并引导其复制。典型的孵育混合物包括人或大鼠肝微粒体(最终浓度：0.5mg蛋白/mL)，待分析化合物(最终浓度：1.5μM)和总体积为30μL的K-缓冲溶液(含1.0mM EDTA,100mM,pH7.4)。将待分析化合物溶解在DMSO中，并用K-缓冲溶液稀释，使DMSO的最终浓度为0.2%。预孵 育10分钟后，加入15μL NADPH(最终浓度：2mM)进行酶促反应，整个试验在37°C的孵育管中进行。在不同的时间点(0，15，30和60分钟)，加入135μL乙腈(含IS)终止反应。以4000rpm离心10分钟，除去蛋白，收集上层清液，用LC-MS/MS分析。  (2) The stability data of the compounds of the present invention in human or rat liver microsomes can also be obtained from the following test: human or rat liver microsomes are incubated in polypropylene test tubes and induced to replicate. A typical incubation mixture includes human or rat liver microsomes (final concentration: 0.5mg protein/mL), the compound to be analyzed (final concentration: 1.5μM) and a total volume of 30μL of K-buffer solution (containing 1.0mM EDTA, 100mM ,pH7.4). The compound to be analyzed was dissolved in DMSO and diluted with K-buffer solution so that the final concentration of DMSO was 0.2%. After pre-incubation for 10 minutes, 15 μL NADPH (final concentration: 2 mM) was added for enzymatic reaction, and the whole experiment was carried out in an incubation tube at 37°C. At various time points (0, 15, 30 and 60 minutes), the reaction was terminated by adding 135 μL of acetonitrile (with IS). Centrifuge at 4000rpm for 10 minutes to remove protein, collect supernatant and analyze by LC-MS/MS. the

在上述试验中，酮色林(1μM)被选作阳性对照，在37°C下孵化，反应在不同的时间点(0，15，30和60分钟)终止。每一种测定方法中都包括阳性对照样品，以保证微粒体孵化体系的完整性。  In the above experiments, ketanserin (1 μM) was selected as a positive control, incubated at 37°C, and the reaction was terminated at different time points (0, 15, 30 and 60 min). A positive control sample is included with each assay to ensure the integrity of the microsomal incubation system. the

本发明采用以下方法进行数据分析，以获得稳定性分析结果：  The present invention adopts following method to carry out data analysis, to obtain stability analysis result:

对于每一个反应，将化合物在人或大鼠肝微粒体孵育中的浓度(以百分比表示)按相对零时间点的百分比作图，以此来推断体内肝固有清除率CLint(ref.:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition2001,29:1316-1324.)  For each reaction, the in vivo liver intrinsic clearance CL int (ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29: 1316-1324 .)

3、本发明化合物在动物体内的药代动力学评价  3. Pharmacokinetic evaluation of the compounds of the present invention in animals

本发明采用以下方法对本发明化合物在小鼠、大鼠、犬或猴子体内的药代动力学研究进行评估：  The present invention uses the following methods to evaluate the pharmacokinetic studies of the compounds of the present invention in mice, rats, dogs or monkeys:

本发明化合物以水溶液或2%HPMC+1%土温-80的水溶液，5%DMSO+5%的盐水溶液，4%MC或胶囊形式进行给药。对于静脉注射给药，动物给予1或2mg/kg的剂量。对于口服剂量(p.o.)，大鼠和小鼠是5或10mg/kg，犬和猴子是10mg/kg。在时间点为0.25，0.5，1.0，2.0，3.0，4.0，6.0，8.0，12和24小时取血(0.3mL)，并在3,000或4,000rpm下离心10分钟。收集血浆溶液，并于-20°C或-70°C下保存直到进行上述的LC/MS/MS分析。  The compound of the present invention is administered in the form of aqueous solution or 2% HPMC + 1% Tween-80 aqueous solution, 5% DMSO + 5% saline solution, 4% MC or capsule form. For intravenous administration, animals were dosed at 1 or 2 mg/kg. Oral doses (p.o.) were 5 or 10 mg/kg for rats and mice, and 10 mg/kg for dogs and monkeys. Blood (0.3 mL) was drawn at time points 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours and centrifuged at 3,000 or 4,000 rpm for 10 minutes. Plasma solutions were collected and stored at -20°C or -70°C until LC/MS/MS analysis as described above. the

4、激酶试验  4. Kinase test

激酶试验通过检测掺入γ-33P-ATP的髓磷脂碱基蛋白（MBP）来完成的。制备20μg/ml的MBP(Sigma#M-1891)三羟甲基氨基甲烷缓冲盐溶液(TBS;50mM Tris pH8.0,138mM NaCl,2.7mM KCl)，包被高结合 性的白384孔板(Greiner)，每孔60μL。4°C，孵育24h。之后用100μL TBS洗板3次。激酶反应在总体积为34μL的激酶缓冲液(5mM Hepes pH7.6,15mM NaCl,0.01%牛血清白蛋白(Sigma#I-5506),10mM MgCl2,1mM DTT,0.02%TritonX-100)中进行。将化合物溶解在DMSO中，加入各孔中，DMSO的最终浓度为1%。每个数据测定两遍，每个化合物的测定至少进行两次试验。比如，酶的最终浓度为10nM或20nM。加入没有标记的ATP(10μM)和γ-33P标记的ATP(每孔2x106cpm，3000Ci/mmol)开始反应。反映在室温下震荡进行1个小时。384孔板用7x的PBS清洗，然后加入每孔50μL的闪烁液。用Wallac Trilux计数器检测结果。对于所属领域的技术人员来说，这仅是众多检测方法中的一种，其他的方法亦可。  Kinase assays are performed by detecting myelin basic protein (MBP) incorporated into γ- 33P -ATP. Prepare 20 μg/ml of MBP (Sigma#M-1891) tris-buffered saline solution (TBS; 50mM Tris pH8.0, 138mM NaCl, 2.7mM KCl), and coat a highly binding white 384-well plate (Greiner ), 60 μL per well. Incubate for 24 hours at 4°C. The plate was then washed 3 times with 100 μL TBS. Kinase reactions were performed in a total volume of 34 μL in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine serum albumin (Sigma #I-5506), 10 mM MgCl 2 , 1 mM DTT, 0.02% TritonX-100) . Compounds were dissolved in DMSO and added to the wells at a final concentration of 1% DMSO. Each data was determined twice, and the determination of each compound was carried out at least twice. For example, the final concentration of the enzyme is 10 nM or 20 nM. The reaction was started by adding unlabeled ATP (10 μM) and γ- 33 P-labeled ATP (2×10 6 cpm per well, 3000 Ci/mmol). The reaction was carried out with shaking at room temperature for 1 hour. The 384-well plate was washed with 7x PBS, and then 50 μL of scintillation fluid was added to each well. Results were checked with a Wallac Trilux counter. For those skilled in the art, this is only one of many detection methods, and other methods are also acceptable.

上述试验方法可以得到抑制的IC50和/或抑制常数Ki。IC50定义为在试验条件下，抑制50%酶活性时的化合物浓度。利用1/2log的稀释倍数做出包含10个浓度点的曲线，估算IC50值（例如，通过以下化合物浓度做出一条典型的曲线：10μM,3μM,1μM,0.3μM,0.1μM,0.03μM,0.01μM,0.003μM,0.001μM,0μM）。  IC 50 of inhibition and/or inhibition constant K i can be obtained by the above test method. IC50 is defined as the concentration of the compound that inhibits 50% of the enzyme activity under the test conditions. Use a 1/2 log dilution to generate a curve containing 10 concentration points to estimate the IC 50 value (for example, a typical curve is generated by the following compound concentrations: 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01μM, 0.003μM, 0.001μM, 0μM).

本发明中的激酶试验是由英国Millipore公司来完成的(Millipore UK Ltd,Dundee Technology Park,Dundee DD21SW,UK)。  The kinase test in the present invention is done by Millipore Company (Millipore UK Ltd, Dundee Technology Park, Dundee DD21SW, UK). the

4.1ALK(h)激酶测定  4.1 ALK(h) kinase assay

人ALK在8mM pH值为7.0的MOPS，0.2mM EDTA，250μM KKKSPGEYVNIEFG，10mM醋酸镁和[γ-33P-ATP](比活性约500cpm/pmol，浓度根据需求确定)存在的条件下进行孵育。加入MgATP混合物后开始反应。室温下孵育40分钟之后，向其中加入3%磷酸溶液来终止反应。将10μL的反应液呈斑点状分布于P30过滤器上，并用75mM磷酸在5分钟内清洗3次，并在干燥和闪烁计数之前立刻放入甲醇溶液中保存。  Human ALK was incubated in the presence of 8mM MOPS with a pH value of 7.0, 0.2mM EDTA, 250μM KKKSPGEYVNIEFG, 10mM magnesium acetate and [γ-33P-ATP] (specific activity about 500cpm/pmol, concentration determined according to requirements). The reaction was initiated after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to stop the reaction. 10 μL of the reaction solution was spotted onto a P30 filter, washed 3 times in 5 min with 75 mM phosphoric acid, and stored in methanol solution immediately prior to drying and scintillation counting. the

4.2c-Met(h)激酶测定  4.2 c-Met(h) kinase assay

人c-Met在8mM pH值为7.0的MOPS，0.2mM EDTA，250μMKKKSPGEYVNIEFG，10mM醋酸镁和[γ-33P-ATP](比活性约500cpm/ pmol，浓度根据需求确定)存在的条件下进行孵育。加入MgATP混合物后开始反应。室温下孵育40分钟之后，向其中加入3%磷酸溶液来终止反应。将10μL的反应液呈斑点状分布于P30过滤器上，并用75mM磷酸在5分钟内清洗3次，并在干燥和闪烁计数之前立刻放入甲醇溶液中保存。  Human c-Met was incubated in the presence of 8mM MOPS with a pH value of 7.0, 0.2mM EDTA, 250μM KKKSPGEYVNIEFG, 10mM magnesium acetate and [γ- 33 P-ATP] (specific activity about 500cpm/pmol, concentration determined according to requirements) . The reaction was initiated after the addition of the MgATP mixture. After incubation at room temperature for 40 minutes, a 3% phosphoric acid solution was added thereto to stop the reaction. 10 μL of the reaction solution was spotted onto a P30 filter, washed 3 times in 5 min with 75 mM phosphoric acid, and stored in methanol solution immediately prior to drying and scintillation counting.

5、异种移植肿瘤模型  5. Xenograft tumor model

本发明化合物的药效是通过移植肿瘤的标准鼠类模型来进行评价的，方法如下：  The drug efficacy of the compound of the present invention is evaluated by the standard mouse model of transplanted tumor, the method is as follows:

人肿瘤细胞（例如，U87MG神经母细胞瘤细胞）培养、收集后，于后腹侧皮下接种于6-7周龄的雌性裸小鼠体内(BALB/cA nu/nu，上海SLAC动物实验室)(对于溶剂组n=10，对于每一个剂量组n=8)。当肿瘤体积达到100-250mm3时，动物随机地分为溶剂对照组(2%HPMC+1%土温-80的水溶液)和化合物组。后续采用化合物对动物进行灌胃给药(3-50mpk/dose，溶解在2%HPMC+1%土温-80的水溶液中)，从肿瘤细胞接种后的0到15天中的任何地方开始，并且通常在试验中每天进行一次。  Human tumor cells (for example, U87MG neuroblastoma cells) were cultured and collected, and inoculated subcutaneously in 6-7 week old female nude mice (BALB/cA nu/nu, Shanghai SLAC Animal Laboratory) (n=10 for vehicle group, n=8 for each dose group). When the tumor volume reached 100-250 mm 3 , the animals were randomly divided into solvent control group (2% HPMC+1% Tween-80 aqueous solution) and compound group. Subsequent intragastric administration of compounds (3-50 mpk/dose, dissolved in 2% HPMC + 1% Tween-80 in water) to animals, starting anywhere from 0 to 15 days after tumor cell inoculation, And usually once a day in the trial.

5.1肿瘤生长抑制（TGI）分析  5.1 Tumor Growth Inhibition (TGI) Analysis

肿瘤的演化生长是通过肿瘤体积与时间的关系来进行评价的。皮下肿瘤的长轴（L）和短轴（W）通过测径器每周测定两次，肿瘤的体积（TV）通过公式(L×W2)/2)进行计算。TGI由溶剂组小鼠肿瘤体积的中值和药物组小鼠肿瘤体积中值的差值来进行计算，以溶剂对照组肿瘤体积中值的百分比来表示，通过下述公式进行计算：  Tumor evolutionary growth was assessed by tumor volume versus time. The long axis (L) and short axis (W) of subcutaneous tumors were measured twice a week by calipers, and the tumor volume (TV) was calculated by the formula (L×W 2 )/2). TGI is calculated from the difference between the median tumor volume of the mice in the solvent group and the median tumor volume of the mice in the drug group, expressed as a percentage of the median tumor volume of the solvent control group, and calculated by the following formula:

原始统计分析是通过重复方差测定分析(RMANOVA)来完成的。接下来通过Scheffe psot hoc试验方法进行多重比较。单独溶剂（2%HPMC+1%土温-80，等等）为阴性对照。  Raw statistical analysis was done by repeated measures of variance (RMANOVA). Next, multiple comparisons were performed by the Scheffe psot hoc test method. Solvent alone (2% HPMC + 1% Tween-80, etc.) served as a negative control. the

结果表明，本发明提供的化合物表现出良好的半衰期和良好的药代 动力学性质，对ALK和c-Met具有良好的抑制作用，对肿瘤的增长也具有良好的抑制作用。  The results show that the compound provided by the invention exhibits good half-life and good pharmacokinetic properties, has good inhibitory effect on ALK and c-Met, and also has good inhibitory effect on tumor growth. the

以下结合实施例对本发明提供的化合物、药物组合物及其应用进行进一步说明。  The compounds, pharmaceutical compositions and applications provided by the present invention will be further described below in conjunction with the examples. the

实施例13-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-氟四氢呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺Example 13-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(4-fluorotetrahydrofuran-3-yl)-1H-pyrazole -4-yl)pyridin-2-amine

Figure BDA00002905454700691
Figure BDA00002905454700691

步骤1)(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-2-硝基吡啶Step 1) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine

将(R)-1-(2,6-二氯-3-氟苯基)乙醇(10g,47.84mmol)溶解于四氢呋喃(150mL)中，冷却至0℃，在30分钟内，向其中分批加入氢化钠(2.3g,57.41mmol,60%悬浮于矿物油中)。混合物室温搅拌2小时后，再次冷却至0℃，在20分钟内，向体系中滴加3-氟-2-硝基吡啶(8.2g,57.41mmol)的四氢呋喃(80mL)溶液。反应液室温搅拌3小时。反应毕，加冰水(10mL)淬灭，并减压浓缩。将残留物分散在乙酸乙酯(150mL)和水(150mL)中，分离的水相用乙酸乙酯(150mL×2)萃取。合并的有机相依次用饱和碳酸氢钠溶液(400mL)、盐水(400mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为白色固体(13.4g,84.6%)。  Dissolve (R)-1-(2,6-dichloro-3-fluorophenyl)ethanol (10g, 47.84mmol) in tetrahydrofuran (150mL), cool to 0°C, and add to it in batches within 30 minutes Sodium hydride (2.3 g, 57.41 mmol, 60% suspension in mineral oil) was added. After the mixture was stirred at room temperature for 2 hours, it was cooled to 0°C again, and a solution of 3-fluoro-2-nitropyridine (8.2 g, 57.41 mmol) in tetrahydrofuran (80 mL) was added dropwise to the system within 20 minutes. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with ice water (10 mL), and concentrated under reduced pressure. The residue was dispersed in ethyl acetate (150 mL) and water (150 mL), and the separated aqueous phase was extracted with ethyl acetate (150 mL×2). The combined organic phases were washed successively with saturated sodium bicarbonate solution (400mL), brine (400mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/ v)=4/1) Purification afforded the title compound as a white solid (13.4 g, 84.6%). the

LC-MS(ESI,pos.ion)m/z:331[M+H]+。  LC-MS (ESI, pos.ion) m/z: 331 [M+H] + .

步骤2)(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 2) (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

将(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-2-硝基吡啶(13.4g,40.47mmol)溶解在乙醇(250mL)中，并向其中加入铁粉(11g,197mmol)。混合物在90℃搅拌20分钟后，在15分钟内，向体系中分两批加入盐酸(1M,8mL)。反应液继续在90℃搅拌2小时。反应毕，冷却至室温， 用硅藻土过滤，滤饼用乙醇(80mL×3)洗涤。将合并的滤液减压浓缩，得到标题化合物为浅棕色固体(12g,98.5%)。  Dissolve (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (13.4 g, 40.47 mmol) in ethanol (250 mL), and Iron powder (11 g, 197 mmol) was added thereto. After the mixture was stirred at 90°C for 20 minutes, hydrochloric acid (1M, 8 mL) was added to the system in two portions within 15 minutes. The reaction solution was further stirred at 90°C for 2 hours. After the reaction, cool to room temperature, filter with celite, and wash the filter cake with ethanol (80mL×3). The combined filtrates were concentrated under reduced pressure to afford the title compound as a light brown solid (12 g, 98.5%). the

LC-MS(ESI,pos.ion)m/z:301[M+H]+；  LC-MS (ESI, pos.ion) m/z: 301[M+H] + ;

1H NMR(400MHz,DMSO-d6)δ(ppm):1.75(d,J=6.6Hz,3H),5.67(brs,2H),5.97-5.92(q,J=6.6Hz,1H),6.38-6.35(dd,J=5.0Hz,7.7Hz,1H),6.61(d,J=7.1Hz,1H),7.47-7.42(m,2H),7.56-7.52(dd,J=5.0Hz,7.7Hz,1H)。  1 H NMR(400MHz,DMSO-d 6 )δ(ppm):1.75(d,J=6.6Hz,3H),5.67(brs,2H),5.97-5.92(q,J=6.6Hz,1H),6.38 -6.35(dd,J=5.0Hz,7.7Hz,1H),6.61(d,J=7.1Hz,1H),7.47-7.42(m,2H),7.56-7.52(dd,J=5.0Hz,7.7Hz ,1H).

步骤3)(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 3) (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

将(R)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(12g,39.8mmol)溶解在乙腈(250mL)中，冷却至0℃，在20分钟内，向其中分批加入NBS(9.2g,51.7mmol)。反应液在0℃搅拌1小时。反应毕，减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=3/1)纯化，得到标题化合物为浅棕色固体(10g,66%)。  Dissolve (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (12g, 39.8mmol) in acetonitrile (250mL) and cool to 0 °C, NBS (9.2 g, 51.7 mmol) was added thereto in portions within 20 minutes. The reaction was stirred at 0°C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a light brown solid (10 g, 66%). the

LC-MS(ESI,pos.ion)m/z:379[M+H]+；  LC-MS (ESI, pos.ion) m/z: 379[M+H] + ;

1H NMR(400MHz,DMSO-d6)δ(ppm):1.82(d,J=6.6Hz,3H),4.82(brs,2H),6.01-5.96(q,J=6.6Hz,1H),6.83(d,J=1.8Hz,1H),7.10-7.06(t,J=8.0Hz,1H),7.33-7.30(dd,J=4.8Hz,8.9Hz,2H),7.66(d,J=5.0Hz,1.8Hz,1H)。  1 H NMR(400MHz,DMSO-d 6 )δ(ppm):1.82(d,J=6.6Hz,3H),4.82(brs,2H),6.01-5.96(q,J=6.6Hz,1H),6.83 (d,J=1.8Hz,1H),7.10-7.06(t,J=8.0Hz,1H),7.33-7.30(dd,J=4.8Hz,8.9Hz,2H),7.66(d,J=5.0Hz ,1.8Hz,1H).

步骤4)(R)-5-溴-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 4) (R)-5-bromo-N,N-bis(tert-butoxycarbonyl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2- amine

将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(4.5g,11.8mmol)，DMAP(1.46g,11.8mmol)和Boc酸酐(7.33g,35.4mmol)溶解在四氢呋喃(100mL)中，并向其中加入三乙胺(3.65g,36mmol)。反应液在70℃搅拌过夜。反应毕，减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)=10/1)纯化，得到标题化合物为粘稠状液体(6g,87.28%)。  (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (4.5g, 11.8mmol), DMAP (1.46g, 11.8 mmol) and Boc anhydride (7.33 g, 35.4 mmol) were dissolved in tetrahydrofuran (100 mL), and triethylamine (3.65 g, 36 mmol) was added thereto. The reaction was stirred overnight at 70°C. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) to obtain the title compound as a viscous liquid (6 g, 87.28%). the

步骤5)(R)-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-2-胺Step 5) (R)-N,N-bis(tert-butoxycarbonyl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

将(R)-5-溴-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡 啶-2-胺(6g,11.8mmol)，联硼酸频钠醇酯(3.6g,14.6mmol)和乙酸钾(3.54g,35.4mmol)悬浮在二甲亚砜(150mL)中，置于氮气氛后，向体系内加入Pd(dppf)Cl2·CH2Cl2(0.48g,0.59mmol)。反应液在80°C加热5小时后，冷却至室温，加水(300mL)稀释，并用乙酸乙酯(300mL×3)萃取。将合并的有机相用盐水(200mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=6/1)纯化，得到标题化合物为无色油状物(5.8g,89.25%)。  (R)-5-bromo-N, N-bis(tert-butoxycarbonyl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine ( 6g, 11.8mmol), biboronic acid pinacol ester (3.6g, 14.6mmol) and potassium acetate (3.54g, 35.4mmol) were suspended in dimethyl sulfoxide (150mL), placed in a nitrogen atmosphere, and added to the system Pd(dppf) Cl2 - CH2Cl2 ( 0.48g , 0.59mmol). The reaction solution was heated at 80°C for 5 hours, cooled to room temperature, diluted with water (300 mL), and extracted with ethyl acetate (300 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=6/1) to obtain the title compound as a colorless oil (5.8 g, 89.25%).

LC-MS(ESI,pos.ion)m/z:627[M+H]+；  LC-MS (ESI, pos.ion) m/z: 627[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):8.37(s,1H),7.52(s,1H),7.06-7.02(m,1H),6.13-6.08(q,1H,J=6.64Hz),1.80-1.78(q,3H,J=6.68Hz),1.34-1.32(m,18H),1.26(s,12H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):8.37(s,1H),7.52(s,1H),7.06-7.02(m,1H),6.13-6.08(q,1H,J=6.64Hz) ,1.80-1.78(q,3H,J=6.68Hz),1.34-1.32(m,18H),1.26(s,12H).

步骤6)3,6-二氧杂二环[3.1.0]己烷Step 6) 3,6-dioxabicyclo[3.1.0]hexane

将2,5-二氢呋喃(5.3mL,71.3mmol)溶解在二氯甲烷(250mL)中，向其中加入m-CPBA(24.6g,142.6mmol)。反应液室温搅拌48小时。反应毕，用硅藻土过滤，滤饼用二氯甲烷(50mL)洗。将滤液用盐水(200mL)洗，无水硫酸钠干燥，并减压浓缩，得到粗产品为无色油状物(4.12g,67%)。  2,5-Dihydrofuran (5.3 mL, 71.3 mmol) was dissolved in dichloromethane (250 mL), and m-CPBA (24.6 g, 142.6 mmol) was added thereto. The reaction solution was stirred at room temperature for 48 hours. After the reaction was completed, filter with diatomaceous earth, and wash the filter cake with dichloromethane (50 mL). The filtrate was washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product as a colorless oil (4.12 g, 67%). the

GC-MS m/z:86(M)；  GC-MS m/z:86(M);

1H NMR(400MHz,CDCl3)δ(ppm):3.65-3.65(d,J=10.5Hz,2H),3.80(s,2H),4.02-4.04(d,J=10.5Hz,2H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 3.65-3.65 (d, J=10.5Hz, 2H), 3.80 (s, 2H), 4.02-4.04 (d, J=10.5Hz, 2H).

步骤7)4-(4-碘-1H-吡唑-1-基)四氢呋喃-3-醇Step 7) 4-(4-iodo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol

将4-碘-1H-吡唑(10.8g,57.6mmol)溶解在干燥的四氢呋喃(60mL)中，降温至-78℃，向其中加入LDA(31.2mL,62.4mmol)。溶液在-40℃搅拌1小时后，向体系中加入3,6-二氧杂二环[3.1.0]己烷(4.12g,48mmol)的四氢呋喃(50mL)溶液。反应液室温搅拌1小时，然后升温至80℃，继续搅拌36小时。反应毕，溶液冷却至室温，加水(50mL)稀释，并用乙酸乙酯(100mL×3)萃取。合并的有机相用盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为白色固体(5g,37%)。  4-iodo-1H-pyrazole (10.8g, 57.6mmol) was dissolved in dry tetrahydrofuran (60mL), cooled to -78°C, and LDA (31.2mL, 62.4mmol) was added thereto. After the solution was stirred at -40°C for 1 hour, a solution of 3,6-dioxabicyclo[3.1.0]hexane (4.12 g, 48 mmol) in tetrahydrofuran (50 mL) was added to the system. The reaction solution was stirred at room temperature for 1 hour, then the temperature was raised to 80° C., and stirring was continued for 36 hours. After the reaction, the solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (5 g, 37%). the

LC-MS(ESI,pos.ion)m/z:281(M+1)；  LC-MS(ESI,pos.ion)m/z:281(M+1);

1H NMR(400MHz,CDCl3)δ(ppm):3.44(s,1H),3.79-3.82(dd,J=2.8,10.0Hz,1H),4.15-4.22(m,2H),4.29-4.33(m,1H),4.55(s,1H),4.75-4.78(m,1H),7.53(s,1H),7.55(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 3.44 (s, 1H), 3.79-3.82 (dd, J=2.8, 10.0Hz, 1H), 4.15-4.22 (m, 2H), 4.29-4.33 ( m, 1H), 4.55(s, 1H), 4.75-4.78(m, 1H), 7.53(s, 1H), 7.55(s, 1H).

步骤8)1-(4-氟代四氢呋喃-3-基)-4-碘-1H-吡唑Step 8) 1-(4-fluorotetrahydrofuran-3-yl)-4-iodo-1H-pyrazole

将4-(4-碘-1H-吡唑-1-基)四氢呋喃-3-醇(1.5g,5.4mmol)溶解在二氯甲烷(15mL)中，冷却至-78℃后，向其中缓慢加入DAST(1.53mL,10.8mmol,95%)。反应液在-78℃搅拌2小时后，恢复至室温，继续搅拌40小时。反应毕，混合液加水(30mL)淬灭，并用二氯甲烷(80mL×3)萃取。将合并的有机相用盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)，得到标题化合物为黄色油状物(1.1g,72%)。  Dissolve 4-(4-iodo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (1.5g, 5.4mmol) in dichloromethane (15mL), cool to -78°C, and slowly add DAST (1.53 mL, 10.8 mmol, 95%). The reaction solution was stirred at -78°C for 2 hours, then returned to room temperature, and stirred for 40 hours. After the reaction was complete, the mixture was quenched with water (30 mL), and extracted with dichloromethane (80 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a yellow oil (1.1 g, 72%). the

LC-MS(ESI,pos.ion)m/z:283(M+1)；  LC-MS(ESI,pos.ion)m/z:283(M+1);

1H NMR(400MHz,CDCl3)δ(ppm):4.07-4.25(m,3H),4.33-4.37(m,1H),4.95-5.02(m,1H),5.26-5.27(d,J=3.6Hz,0.5H),5.39-5.40(d,J=3.8Hz,0.5H),7.52(s,1H),7.58(s,1H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):4.07-4.25(m,3H),4.33-4.37(m,1H),4.95-5.02(m,1H),5.26-5.27(d,J=3.6 Hz,0.5H), 5.39-5.40(d,J=3.8Hz,0.5H),7.52(s,1H),7.58(s,1H).

步骤9)N,N-双(叔丁氧羰基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-氟四氢呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺Step 9) N,N-bis(tert-butoxycarbonyl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(4 -Fluorotetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-amine

将(R)-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-2-胺(266mg,0.43mmol)，1-(4-氟四氢呋喃-3-基)-4-碘-1H-吡唑(0.1g,0.35mmol)和碳酸钠(150mg,1.42mmol)溶解在乙二醇二甲醚/水(3mL/0.7mL)混合液中，置于氮气氛后，向体系内加入Pd(PPh3)2Cl2(25mg,0.035mmol)。反应液在90°C搅拌16小时。反应毕，冷却至室温，加乙酸乙酯(60mL)稀释，并用硅藻土过滤。滤液经盐水(20mL×2)洗，真空干燥后，用经硅胶柱层析纯化(石油醚/乙酸乙酯(v/v)=2/1)，得到标题化合物为黄色固体(136mg,59%)。  (R)-N,N-bis(tert-butoxycarbonyl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (266mg, 0.43mmol), 1-(4-fluorotetrahydrofuran-3-yl)-4 -Iodine-1H-pyrazole (0.1g, 0.35mmol) and sodium carbonate (150mg, 1.42mmol) were dissolved in ethylene glycol dimethyl ether/water (3mL/0.7mL) mixture, placed in a nitrogen atmosphere, and Pd(PPh 3 ) 2 Cl 2 (25 mg, 0.035 mmol) was added to the system. The reaction was stirred at 90°C for 16 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (60 mL), and filtered through celite. The filtrate was washed with brine (20mL×2), dried in vacuo, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a yellow solid (136mg, 59% ).

LC-MS(ESI,pos.ion)m/z:655(M+1)；  LC-MS(ESI,pos.ion)m/z:655(M+1);

1H NMR(400MHz,CDCl3)δ(ppm):1.30-1.53(m,18H),1.82-1.84(d, J=6.7Hz,3H),4.11-4.29(m,3H),4.78-4.42(m,1H),4.98-5.05(m,1H),5.30-5.46(m,1H),6.02-6.07(q,J=6.6Hz,1H),7.05-7.09(t,J=8.6Hz,1H),7.15-7.16(t,J=1.8Hz,1H),7.70-7.73(m,3H),8.17(d,J=1.8Hz,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.30-1.53 (m, 18H), 1.82-1.84 (d, J=6.7Hz, 3H), 4.11-4.29 (m, 3H), 4.78-4.42 ( m,1H),4.98-5.05(m,1H),5.30-5.46(m,1H),6.02-6.07(q,J=6.6Hz,1H),7.05-7.09(t,J=8.6Hz,1H) , 7.15-7.16 (t, J=1.8Hz, 1H), 7.70-7.73 (m, 3H), 8.17 (d, J=1.8Hz, 1H).

步骤10)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-氟四氢呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺Step 10) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(4-fluorotetrahydrofuran-3-yl)-1H-pyridine Azol-4-yl)pyridin-2-amine

将N,N-双(叔丁氧羰基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-氟四氢呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺(136mg,0.2mmol)溶解在二氯甲烷(5mL)中，冷却至0°C，向其中缓慢加入氯化氢的乙酸乙酯溶液(3M,1.5mL)。反应液室温搅拌过夜。反应毕，减压浓缩。将残留物溶解在水(10mL)中，用饱和碳酸钠溶液调节pH值为10，并用二氯甲烷(50mL×3)萃取。合并的有机相经无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(PE/EtOAc(v/v)=1/1)纯化，得到标题化合物为白色固体(90mg,95%)。  N,N-bis(tert-butoxycarbonyl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(4-fluoro Tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-amine (136mg, 0.2mmol) was dissolved in dichloromethane (5mL), cooled to 0°C, and hydrogen chloride in acetic acid was slowly added thereto Ethyl ester solution (3M, 1.5 mL). The reaction solution was stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure. The residue was dissolved in water (10 mL), adjusted to pH 10 with saturated sodium carbonate solution, and extracted with dichloromethane (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a white solid (90 mg, 95%). the

LC-MS(ESI,pos.ion)m/z:455(M+1)；  LC-MS (ESI, pos.ion) m/z: 455 (M+1);

1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.87(d,J=6.6Hz,3H),4.09-4.27(m,3H),4.36-4.40(m,1H),4.83(s,2H),4.95-5.00(m,1H),5.30-5.43(m,1H),6.04-6.09(q,J=6.4Hz,1H),6.84(s,1H),7.03-7.07(m,1H),7.29-7.32(m,1H),7.54(s,1H),7.60(s,1H),7.75(s,1H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm): 1.85-1.87(d, J=6.6Hz, 3H), 4.09-4.27(m, 3H), 4.36-4.40(m, 1H), 4.83(s, 2H),4.95-5.00(m,1H),5.30-5.43(m,1H),6.04-6.09(q,J=6.4Hz,1H),6.84(s,1H),7.03-7.07(m,1H) ,7.29-7.32(m,1H),7.54(s,1H),7.60(s,1H),7.75(s,1H).

实施例24-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)四氢呋喃-3-醇Example 24-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole -1-yl)tetrahydrofuran-3-ol

Figure BDA00002905454700731
Figure BDA00002905454700731

步骤1)4-碘-1-(4-(四氢-2H-吡喃-2-基氧基)四氢呋喃-3-基)-1H-吡唑Step 1) 4-iodo-1-(4-(tetrahydro-2H-pyran-2-yloxy)tetrahydrofuran-3-yl)-1H-pyrazole

将4-(4-碘-1H-吡唑-1-基)四氢呋喃-3-醇(1g,3.57mmol)，PPTS(113mg,0.43mmol)悬浮在二氯甲烷(46mL)中，向其中加入DHP(788mg,9.4mmol)。反应液室温搅拌48小时。反应毕，减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为无色油状物(1.3g,100%)。  4-(4-Iodo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (1 g, 3.57 mmol), PPTS (113 mg, 0.43 mmol) were suspended in dichloromethane (46 mL), to which was added DHP (788 mg, 9.4 mmol). The reaction solution was stirred at room temperature for 48 hours. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a colorless oil (1.3 g, 100%). the

LC-MS(ESI,pos.ion)m/z:365(M+1)；  LC-MS(ESI,pos.ion)m/z:365(M+1);

1H NMR(400MHz,CDCl3)δ(ppm):1.50-1.65(m,4H),1.71-1.80(m,2H),1.80-1.84(m,2H),3.47-3.51(m,1H),3.77-3.89(m,2H),4.11-4.27(m,3H),4.47-4.58(m,1H),4.59-4.75(m,1H),4.79-5.04(m,1H),7.53(s,1H),7.54(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.50-1.65 (m, 4H), 1.71-1.80 (m, 2H), 1.80-1.84 (m, 2H), 3.47-3.51 (m, 1H), 3.77-3.89(m,2H),4.11-4.27(m,3H),4.47-4.58(m,1H),4.59-4.75(m,1H),4.79-5.04(m,1H),7.53(s,1H ), 7.54(s,1H).

步骤2)N,N-双(叔丁氧羰基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-((四氢-2H-吡喃-2-基)氧基)四氢呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺Step 2) N,N-bis(tert-butoxycarbonyl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(4 -((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-amine

标题化合物通过实施例1步骤9所描述的方法制备得到，即将(R)-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-2-胺(224mg,0.357mmol)，4-碘-1-(4-(四氢-2H-吡喃-2-基氧基)四氢呋喃-3-基)-1H-吡唑(100mg,0.275mmol)，碳酸钠(117mg,1.1mmol)和Pd(PPh3)2Cl2(21.6mg,0.031mmol)悬浮在乙二醇二甲醚/水(2.5mL/0.6mL)的混合液中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为白色固体(87mg,44%)。  The title compound was prepared by the method described in step 9 of Example 1, that is, (R)-N,N-bis(tert-butoxycarbonyl)-3-(1-(2,6-dichloro-3-fluorophenyl )ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (224mg, 0.357mmol) , 4-iodo-1-(4-(tetrahydro-2H-pyran-2-yloxy)tetrahydrofuran-3-yl)-1H-pyrazole (100mg, 0.275mmol), sodium carbonate (117mg, 1.1mmol ) and Pd(PPh 3 ) 2 Cl 2 (21.6mg, 0.031mmol) were suspended in a mixture of ethylene glycol dimethyl ether/water (2.5mL/0.6mL). The crude product was subjected to silica gel column chromatography (PE/ Purification with EtOAc (v/v)=2/1) afforded the title compound as a white solid (87 mg, 44%).

LC-MS(ESI,pos.ion)m/z:737(M+1)；  LC-MS (ESI, pos.ion) m/z: 737 (M+1);

1H NMR(400MHz,CDCl3)δ(ppm):1.35-1.50(m,18H),1.50-1.60(m,4H),1.71-1.85(m,5H),3.45-3.54(m,1H),3.77-3.93(m,2H),4.17-4.33(m,3H),4.52-4.79(m,2H),4.82-5.06(m,1H),6.02-6.07(q,J=6.6Hz,1H),7.04-7.08(t,J=8.2Hz,1H),7.15(s,1H),7.29-7.33(m,1H),7.69-7.73(m,2H),8.17(d,J=1.5Hz,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.35-1.50 (m, 18H), 1.50-1.60 (m, 4H), 1.71-1.85 (m, 5H), 3.45-3.54 (m, 1H), 3.77-3.93(m,2H),4.17-4.33(m,3H),4.52-4.79(m,2H),4.82-5.06(m,1H),6.02-6.07(q,J=6.6Hz,1H), 7.04-7.08(t,J=8.2Hz,1H),7.15(s,1H),7.29-7.33(m,1H),7.69-7.73(m,2H),8.17(d,J=1.5Hz,1H) .

步骤3)4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)四氢呋喃-3-醇Step 3) 4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyridine Azol-1-yl)tetrahydrofuran-3-ol

标题化合物通过实施例1步骤10所描述的方法制备得到，即使用N,N-双(叔丁氧羰基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-((四氢-2H-吡喃-2-基)氧基)四氢呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺(264mg,0.36mmol)的二氯甲烷(12mL)溶液和氯化氢乙酸乙酯溶液(3.5mL,3M)制备，粗产品经硅胶柱层析(100%乙酸乙酯)纯化，得到标题化合物为黄色固体(131mg,80%)。  The title compound was prepared by the method described in step 10 of Example 1, using N,N-bis(tert-butoxycarbonyl)-3-((R)-1-(2,6-dichloro-3-fluorobenzene Base) ethoxy) -5-(1-(4-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridine- 2-Amine (264mg, 0.36mmol) was prepared in dichloromethane (12mL) and hydrogen chloride in ethyl acetate (3.5mL, 3M). The crude product was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound As a yellow solid (131 mg, 80%). the

LC-MS(ESI,pos.ion)m/z:453(M+1)；  LC-MS (ESI, pos.ion) m/z: 453 (M+1);

1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.86(d,J=6.6Hz,3H),3.83-3.86(m,1H),4.18-4.26(m,2H),4.32-4.38(m,1H),4.58-4.61(m,1H),4.71-4.79(m,1H),4.85(s,2H),6.01-6.09(m,1H),6.83(s,1H),6.98-7.07(m,1H),7.29-7.33(m,1H),7.49-7.51(d,J=8.6Hz,1H),7.57(s,1H),7.67(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.85-1.86 (d, J=6.6Hz, 3H), 3.83-3.86 (m, 1H), 4.18-4.26 (m, 2H), 4.32-4.38 ( m,1H),4.58-4.61(m,1H),4.71-4.79(m,1H),4.85(s,2H),6.01-6.09(m,1H),6.83(s,1H),6.98-7.07( m, 1H), 7.29-7.33(m, 1H), 7.49-7.51(d, J=8.6Hz, 1H), 7.57(s, 1H), 7.67(s, 1H).

实施例33-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-氟吡咯烷-3-基)-1H-吡唑-4-基)吡啶-2-胺Example 33-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(4-fluoropyrrolidin-3-yl)-1H-pyridine Azol-4-yl)pyridin-2-amine

Figure BDA00002905454700751
Figure BDA00002905454700751

步骤1)氨基甲酸叔丁酯Step 1) tert-butyl carbamate

将二碳酸二叔丁酯(10g,45.8mmol)溶解在甲醇(200mL)中，冷却至0°C，通入NH3。反应液于0°C搅拌2小时后，升至室温，继续搅拌5小时。反应毕，将混合物减压浓缩，残留物用正己烷稀释，并加热至65°C，保温30分钟。冷却至室温，过滤，滤饼用正己烷淋洗，得到标题化合物为白色固体(5g,94%)。  Di-tert-butyl dicarbonate (10 g, 45.8 mmol) was dissolved in methanol (200 mL), cooled to 0° C., and NH 3 was passed through. After the reaction solution was stirred at 0° C. for 2 hours, it was warmed up to room temperature, and stirring was continued for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was diluted with n-hexane, and heated to 65° C. for 30 minutes. Cool to room temperature, filter, and rinse the filter cake with n-hexane to obtain the title compound as a white solid (5 g, 94%).

1H NMR(400MHz,CDCl3)δ(ppm):4.48(brs,2H,),1.46(s,9H)。  1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.48 (brs, 2H,), 1.46 (s, 9H).

步骤2)1-(叔丁氧羰基)-2,5-二氢-1H-吡咯Step 2) 1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole

将氨基甲酸叔丁酯(5g,42.5mmol)溶解在N,N-二甲基甲酰胺(50 mL)中，冷却至0°C，在15分钟内，向其中分批加入氢化钠(3.1g,106mmol)。混合物在0°C搅拌1小时后，继续向体系内滴加顺-1,4-二氯-2-丁烯(8mL)。反应液在80°C搅拌5小时，冷却至室温，加水(150mL)淬灭，并用乙酸乙酯(150mL×3)萃取。合并的有机相用盐水(400mL)洗，无水硫酸钠干燥，并减压浓缩，得到粗产品为黄色油状物(6.5g)，该产品不经纯化，直接用于下一步反应。  Dissolve tert-butyl carbamate (5 g, 42.5 mmol) in N,N-dimethylformamide (50 mL), cool to 0° C., add sodium hydride (3.1 g ,106mmol). After the mixture was stirred at 0°C for 1 hour, cis-1,4-dichloro-2-butene (8 mL) was continuously added dropwise into the system. The reaction solution was stirred at 80°C for 5 hours, cooled to room temperature, quenched with water (150 mL), and extracted with ethyl acetate (150 mL×3). The combined organic phases were washed with brine (400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product as a yellow oil (6.5 g), which was directly used in the next reaction without purification. the

步骤3)4-溴-1-(叔丁氧羰基)吡咯烷-3-醇Step 3) 4-bromo-1-(tert-butoxycarbonyl)pyrrolidin-3-ol

将1-(叔丁氧羰基)-2,5-二氢-1H-吡咯(6.4g,37.8mmol)溶解于二甲亚砜/水(30mL/3mL)的混合液中，冷却至0°C，向其中分批加入NBS(8g,45.4mmol)。反应液室温搅拌2小时。反应毕，加水(100mL)淬灭，并用乙酸乙酯(100mL×3)萃取。合并的有机相用盐水(300mL)洗，无水硫酸钠干燥，并减压浓缩，所的残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=3/1)纯化，得到标题化合物为白色固体(5g,60%)。  Dissolve 1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole (6.4g, 37.8mmol) in a mixture of dimethylsulfoxide/water (30mL/3mL) and cool to 0°C , to which NBS (8 g, 45.4 mmol) was added in portions. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to quench, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1), The title compound was obtained as a white solid (5 g, 60%). the

1H NMR(400MHz,CDCl3)δ(ppm):4.47-4.46(t,J=1.94Hz,1H),4.18-4.16(t,J=2.36Hz,1H),4.05-4.01(dd,J=4.86Hz,1H),3.88-3.70(m,2H),3.40(t,J=13.2Hz,1H),3.03(brs,1H),1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm): 4.47-4.46(t, J=1.94Hz, 1H), 4.18-4.16(t, J=2.36Hz, 1H), 4.05-4.01(dd, J= 4.86Hz, 1H), 3.88-3.70(m, 2H), 3.40(t, J=13.2Hz, 1H), 3.03(brs, 1H), 1.47(s, 9H).

步骤4)3-(叔丁氧羰基)-6-氧杂-3-氮杂双环[3.1.0]己烷Step 4) 3-(tert-butoxycarbonyl)-6-oxa-3-azabicyclo[3.1.0]hexane

将4-溴-1-(叔丁氧羰基)吡咯烷-3-醇(2.5g,9.4mmol)溶解在2M氢氧化钠/四氢呋喃(20mL/10mL)的混合液中。反应液室温搅拌2小时。反应毕，加水(40mL)稀释，并用二氯甲烷(50mL×3)萃取。合并的有机相用盐水(50mL)洗，无水硫酸钠干燥，并减压浓缩，得到标题化合物为黄色油状物(1.6g,98%)。  4-Bromo-1-(tert-butoxycarbonyl)pyrrolidin-3-ol (2.5 g, 9.4 mmol) was dissolved in a mixture of 2M sodium hydroxide/tetrahydrofuran (20 mL/10 mL). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it was diluted with water (40 mL), and extracted with dichloromethane (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (1.6 g, 98%). the

1H NMR(400MHz,CDCl3)δ(ppm):3.83-3.72(dd,J=12.8Hz,2H),3.67-3.66(m,2H),3.34-3.30(dd,J=5.1Hz,12.8Hz,2H),1.45(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 3.83-3.72 (dd, J=12.8Hz, 2H), 3.67-3.66 (m, 2H), 3.34-3.30 (dd, J=5.1Hz, 12.8Hz ,2H), 1.45(s,9H).

步骤5)1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)吡咯烷-3-醇Step 5) 1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)pyrrolidin-3-ol

标题化合物通过实施例1步骤7所描述的方法制备得到，即将4-碘-1H-吡唑(1.8g,9.7mmol)，3-(叔丁氧羰基)-6-氧杂-3-氮杂双环[3.1.0]己烷(1.5g,8mmol)，LDA(5.2mL,1M in THF)溶解在四氢呋喃(20mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得 到目标产物为白色固体(2g,67%)。  The title compound was prepared by the method described in step 7 of Example 1, that is, 4-iodo-1H-pyrazole (1.8g, 9.7mmol), 3-(tert-butoxycarbonyl)-6-oxa-3-aza Bicyclo[3.1.0]hexane (1.5g, 8mmol), LDA (5.2mL, 1M in THF) was prepared by dissolving in tetrahydrofuran (20mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/ v)=2/1) Purification, the target product was obtained as a white solid (2g, 67%). the

1H NMR(400MHz,CDCl3)δ(ppm):7.54(s,1H),7.48(s,1H),4.64-4.60(m,2H),3.99-3.97(m,1H),3.80-3.72(m,2H),3.40-3.35(m,2H),1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.54 (s, 1H), 7.48 (s, 1H), 4.64-4.60 (m, 2H), 3.99-3.97 (m, 1H), 3.80-3.72 ( m,2H), 3.40-3.35(m,2H), 1.47(s,9H).

步骤6)1-(1-(叔丁氧羰基)-4-氟吡咯烷-3-基)-4-碘-1H-吡唑Step 6) 1-(1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-iodo-1H-pyrazole

将1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)吡咯烷-3-醇(1g,2.5mmol)溶解在二氯甲烷(20mL)中，冷却至-78°C，向其中滴加DAST(1.5mL)的二氯甲烷(2mL)溶液。混合液在-78°C搅拌1小时后，恢复至室温，搅拌过夜。反应毕，将混合液减压浓缩，残留物用1M碳酸氢钠(30mL)稀释，并用乙酸乙酯(30mL×3)萃取，合并的有机相用盐水(70mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=5/1)纯化，得到标题化合物为黄色油状物(0.5g,50%)。  Dissolve 1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)pyrrolidin-3-ol (1 g, 2.5 mmol) in dichloromethane (20 mL) and cool to -78°C, a solution of DAST (1.5 mL) in dichloromethane (2 mL) was added dropwise thereto. The mixture was stirred at -78°C for 1 hour, then returned to room temperature and stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was diluted with 1M sodium bicarbonate (30 mL), and extracted with ethyl acetate (30 mL×3), the combined organic phases were washed with brine (70 mL), dried over anhydrous sodium sulfate, And concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound as a yellow oil (0.5 g, 50%). the

1H NMR(400MHz,CDCl3)δ(ppm):7.54(s,1H),7.48(s,1H),5.34-5.21(m,1H),4.93-4.91(m,1H),3.96-3.68(m,4H),1.47(s,9H).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.54 (s, 1H), 7.48 (s, 1H), 5.34-5.21 (m, 1H), 4.93-4.91 (m, 1H), 3.96-3.68 ( m,4H), 1.47(s,9H).

步骤7)1-(1-(叔丁氧羰基)-4-氟吡咯烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑Step 7) 1-(1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-1H-pyrazole

氮气保护下，将1-(1-(叔丁氧羰基)-4-氟吡咯烷-3-基)-4-碘-1H-吡唑(0.5g,1.3mmol)，联硼酸频那醇酯(0.4g,1.5mmol)，Pd(dppf)Cl2(60mg,0.13mmol)和乙酸钾(0.38g,3.9mmol)的二甲亚砜(10mL)悬浮液在75°C搅拌2小时。反应毕，冷却至室温，加水(30mL)淬灭，并用乙酸乙酯(30mL×3)萃取。合并的有机相用盐水(70mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为黄色油状物(0.4g,80%)。  Under nitrogen protection, 1-(1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-iodo-1H-pyrazole (0.5g, 1.3mmol), diboronic acid pinacol ester (0.4g, 1.5mmol), a suspension of Pd(dppf) Cl2 (60mg, 0.13mmol) and potassium acetate (0.38g, 3.9mmol) in dimethylsulfoxide (10mL) was stirred at 75°C for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (70 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain The title compound was a yellow oil (0.4 g, 80%).

LC-MS(ESI,pos.ion)m/z:382[M+1]。  LC-MS (ESI, pos. ion) m/z: 382 [M+1]. the

步骤8)5-(1-(1-(叔丁氧羰基)-4-氟吡咯烷-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 8) 5-(1-(1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2 ,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

氮气保护下，将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.48g,1.26mmol)，1-(1-(叔丁氧羰基)-4-氟吡咯烷-3-基)-4-(4,4,5,5-四甲 基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(0.4g,1.05mmol)，Pd(OAc)2(84mg,0.37mmol)，Cs2CO3(0.86g,2.63mmol)和(t-Bu)3P(0.925mmol,1M的甲苯溶液)的乙二醇二甲醚(20mL)悬浮液在87°C搅拌36小时。反应毕，加水(50mL)淬灭，并用乙酸乙酯(50mL×3)萃取，合并的有机相用盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/1)纯化，得到标题化合物为黄色固体(0.16g,32%)。  Under nitrogen protection, (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.48g, 1.26mmol), 1 -(1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-pyrazole (0.4g, 1.05mmol), Pd(OAc) 2 (84mg, 0.37mmol), Cs 2 CO 3 (0.86g, 2.63mmol) and (t-Bu) 3 P( 0.925 mmol, 1 M solution in toluene) in ethylene glycol dimethyl ether (20 mL) was stirred at 87°C for 36 hours. After the reaction was completed, add water (50mL) to quench, and extract with ethyl acetate (50mL×3), the combined organic phase was washed with brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting residue was subjected to silica gel column layer Purification by analysis (petroleum ether/ethyl acetate (v/v)=1/1) gave the title compound as a yellow solid (0.16 g, 32%).

1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.59(s,1H),7.48(s,1H),7.33-7.30(m,1H),7.07-7.04(m,1H),6.84(s,1H),6.09-6.04(t,J=6.64Hz,1H),5.37-5.24(m,1H),4.94-4.85(m,3H),3.92-3.72(m,4H),2.18-2.15(d,J=6.64Hz,3H),1.49(s,9H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.74(s,1H),7.59(s,1H),7.48(s,1H),7.33-7.30(m,1H),7.07-7.04(m, 1H),6.84(s,1H),6.09-6.04(t,J=6.64Hz,1H),5.37-5.24(m,1H),4.94-4.85(m,3H),3.92-3.72(m,4H) ,2.18-2.15(d,J=6.64Hz,3H),1.49(s,9H).

步骤9)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(4-氟吡咯烷-3-基)-1H-吡唑-4-基)吡啶-2-胺Step 9) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(4-fluoropyrrolidin-3-yl)-1H- Pyrazol-4-yl)pyridin-2-amine

将5-(1-(1-(叔丁氧羰基)-4-氟吡咯烷-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.16g,0.29mmol)溶解在乙酸乙酯(5mL)中，并向其中加入HCl(5mL,1M的乙酸乙酯溶液)。反应液在40°C搅拌1小时。反应毕，依次用2M碳酸钠溶液(5mL)、水(20mL)处理，并用乙酸乙酯萃取(20mL×3)。合并的有机相用饱和食盐水(60mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(二氯甲烷/甲醇(v/v)=10/1)纯化，得到标题化合物为黄色固体(0.1g,78%)。  5-(1-(1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6 -Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.16g, 0.29mmol) was dissolved in ethyl acetate (5mL), and to it was added HCl (5mL, 1M in ethyl acetate ). The reaction was stirred at 40°C for 1 hour. After the reaction was completed, it was successively treated with 2M sodium carbonate solution (5 mL), water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10/1), The title compound was obtained as a yellow solid (0.1 g, 78%). the

LC-MS(ESI,pos.ion)m/z:227.6[M+2]/2；  LC-MS(ESI,pos.ion)m/z:227.6[M+2]/2;

1H NMR(400MHz,CDCl3)δ(ppm):7.56(s,1H),7.53-7.31(m,2H),7.30-7.26(s,1H),7.08-7.04(m,1H),6.85(s,1H),6.09-6.04(t,J=6.64Hz,1H),5.38-5.22(m,1H),4.85-4.74(m,3H),3.58-3.21(m,4H),1.87-1.85(d,J=6.64Hz,3H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.56 (s, 1H), 7.53-7.31 (m, 2H), 7.30-7.26 (s, 1H), 7.08-7.04 (m, 1H), 6.85 ( s,1H),6.09-6.04(t,J=6.64Hz,1H),5.38-5.22(m,1H),4.85-4.74(m,3H),3.58-3.21(m,4H),1.87-1.85( d, J=6.64Hz, 3H).

实施例44-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)吡咯烷-3-醇Example 44-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole -1-yl)pyrrolidin-3-ol

步骤1)1-(1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-3-基)-4-碘-1H-吡唑Step 1) 1-(1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-3-yl)-4-iodo-1H-pyrazole

将1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)吡咯烷-3-醇(1g,2.6mmol)溶解在二氯甲烷(20mL)中，向其中加入DHP(1mL)和PPTS(0.065g,0.26mmol)。反应液室温搅拌12小时。反应毕，减压浓缩。残留物经硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为白色固体(1.1g,92%)。  1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)pyrrolidin-3-ol (1 g, 2.6 mmol) was dissolved in dichloromethane (20 mL), and DHP (1 mL) and PPTS (0.065 g, 0.26 mmol) were added. The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a white solid (1.1 g, 92%). the

LC-MS(ESI,pos.ion)m/z:464(M+1)；  LC-MS (ESI, pos.ion) m/z: 464 (M+1);

1H NMR(400MHz,CDCl3)δ(ppm):7.54(s,1H),7.48(s,1H),4.70-4.50(m,3H),3.94-3.73(m,3H),3.66-3.40(m,3H),1.77-1.60(m,3H),1.62-1.51(m,3H),1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.54 (s, 1H), 7.48 (s, 1H), 4.70-4.50 (m, 3H), 3.94-3.73 (m, 3H), 3.66-3.40 ( m,3H), 1.77-1.60(m,3H), 1.62-1.51(m,3H), 1.47(s,9H).

步骤2)N,N-双(叔丁氧羰基)-5-(1-(1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 2) N,N-bis(tert-butoxycarbonyl)-5-(1-(1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrole Alk-3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

将(R)-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-2-胺(0.6g,1.1mmol)，1-(1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-3-基)-4-碘-1H-吡唑(0.5g,1.05mmol)和碳酸钠(0.22g,2.1mmol)溶解在乙二醇二甲醚/水(30mL/2mL)的混合液中，溶液置于氮气氛中，向体系内加入Pd(dppf)Cl2·CH2Cl2(0.075g,0.01mmol)。反应液在87°C搅拌12小时，反应毕，减压浓缩。残留物经硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为浅黄色固体(250mg,92%)。  (R)-N,N-bis(tert-butoxycarbonyl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.6g, 1.1mmol), 1-(1-(tert-butoxycarbonyl)-4 -((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-3-yl)-4-iodo-1H-pyrazole (0.5g, 1.05mmol) and sodium carbonate (0.22g, 2.1mmol ) was dissolved in a mixture of ethylene glycol dimethyl ether/water (30mL/2mL), the solution was placed in a nitrogen atmosphere, and Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.075g, 0.01mmol) was added to the system . The reaction solution was stirred at 87° C. for 12 hours, and after completion of the reaction, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a pale yellow solid (250 mg, 92%).

LC-MS(ESI,pos.ion)m/z:836(M+1)；  LC-MS (ESI, pos.ion) m/z: 836 (M+1);

1H NMR(400MHz,CDCl3)δ(ppm):8.16(s,1H),7.32-7.12(m,1H),7.65(s,1H),7.33-7.30(m,1H),7.16(m,1H),7.09-7.04(m,1H),6.07-6.02(t,J=6.64Hz,1H),3.99-3.61(m,3H),3.58-3.41(m,3H),1.83-1.81(d,J=6.64Hz,1H),1.52-1.48(2H,m),1.48-1.44(m,13H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):8.16(s,1H),7.32-7.12(m,1H),7.65(s,1H),7.33-7.30(m,1H),7.16(m, 1H),7.09-7.04(m,1H),6.07-6.02(t,J=6.64Hz,1H),3.99-3.61(m,3H),3.58-3.41(m,3H),1.83-1.81(d, J=6.64Hz, 1H), 1.52-1.48(2H, m), 1.48-1.44(m, 13H).

步骤3)4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)吡咯烷-3-醇Step 3) 4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyridine Azol-1-yl)pyrrolidin-3-ol

将N,N-双(叔丁氧羰基)-5-(1-(1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.23g,0.275mmol)溶解在乙酸乙酯(10mL)中，向其中加入HCl(10mL,1M的乙酸乙酯溶液)。反应液在40°C搅拌3小时，反应毕，冷却至室温，并加水(20mL)稀释。分离的水相用乙酸乙酯(20mL×2)洗后，加2M碳酸钠溶液(10mL)处理，所得混合物用乙酸乙酯(20mL×3)萃取。将合并的有机相用盐水(60mL)洗，无水硫酸钠干燥，并减压浓缩，得到标题化合物为白色固体(70mg,62%)。  N,N-bis(tert-butoxycarbonyl)-5-(1-(1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine- 3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.23g , 0.275 mmol) was dissolved in ethyl acetate (10 mL), and HCl (10 mL, 1M in ethyl acetate) was added thereto. The reaction solution was stirred at 40° C. for 3 hours. After the reaction was completed, it was cooled to room temperature and diluted with water (20 mL). The separated aqueous phase was washed with ethyl acetate (20 mL×2), treated with 2M sodium carbonate solution (10 mL), and the resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the title compound as a white solid (70 mg, 62%). the

LC-MS(ESI,pos.ion)m/z:452(M+1);  LC-MS(ESI,pos.ion)m/z:452(M+1);

1H NMR(400MHz,CDCl3)δ(ppm):7.50(s,1H),7.47(s,1H),7.30-7.29(m,1H),7.29-7.28(m,1H),7.03-6.99(m,1H),6.85-6.84(m,1H),6.09-6.04(t,J=6.64Hz,1H),4.87(s,2H),4.56-4.54(m,2H),3.56-3.52(m,1H),3.46-3.41(dd,J=5.5Hz,1H),3.34-3.31(dd,J=4.2Hz,1H),3.01-2.97(m,1H),1.87-1.86(d,J=6.64Hz,1H).  1 H NMR (400MHz, CDCl 3 )δ(ppm): 7.50(s,1H),7.47(s,1H),7.30-7.29(m,1H),7.29-7.28(m,1H),7.03-6.99( m,1H),6.85-6.84(m,1H),6.09-6.04(t,J=6.64Hz,1H),4.87(s,2H),4.56-4.54(m,2H),3.56-3.52(m, 1H),3.46-3.41(dd,J=5.5Hz,1H),3.34-3.31(dd,J=4.2Hz,1H),3.01-2.97(m,1H),1.87-1.86(d,J=6.64Hz ,1H).

实施例5((2S)-4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)吡咯烷-2-基)甲醇Example 5 ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)pyrrolidin-2-yl)methanol

步骤1)(3R,5S)-1-(叔丁氧羰基)-5-(甲氧羰基)吡咯烷-3-基甲磺酸酯Step 1) (3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl methanesulfonate

将(3R,5S)-1-(叔丁氧羰基)-5-(甲氧羰基)吡咯烷-3-醇(0.50g,2.04mmol)溶解在二氯甲烷(20mL)中，向其中加入DMAP(3mg,0.02mmol)和三乙胺(0.28mL,2.04mmol)，混合液冷却至0°C后，继续向体系内滴加甲磺酰氯(0.16mL,2.04mmol)。反应液在0°C搅拌1小时，恢复至室温，继续搅拌24小时。反应毕，将混合物减压浓缩，得到粗产品为黄色粘稠状液体(0.64g,100%)，该产品不经纯化，直接用于下一步反应。  (3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-ol (0.50 g, 2.04 mmol) was dissolved in dichloromethane (20 mL), to which was added DMAP (3mg, 0.02mmol) and triethylamine (0.28mL, 2.04mmol), after the mixture was cooled to 0°C, methanesulfonyl chloride (0.16mL, 2.04mmol) was added dropwise to the system. The reaction solution was stirred at 0° C. for 1 hour, returned to room temperature, and stirred for 24 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product as a yellow viscous liquid (0.64 g, 100%), which was directly used in the next reaction without purification. the

LC-MS(ESI,pos.ion)m/z:224.0[M-Boc+H].  LC-MS(ESI,pos.ion)m/z:224.0[M-Boc+H]. 

步骤2)1-((5S)-1-(叔丁氧羰基)-5-(甲氧羰基)吡咯烷-3-基)-4-碘-1H-吡唑Step 2) 1-((5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl)-4-iodo-1H-pyrazole

将4-碘-1H-吡唑(0.35g,1.80mmol)溶解在干燥的N,N-二甲基甲酰胺(6mL)中，冷却至0°C，向其中加入氢化钠(0.15g,3.75mmol,60%分散在矿物油中)。混合物在0°C搅拌1小时后，向体系内加入(3R,5S)-1-(叔丁氧羰基)-5-(甲氧羰基)吡咯烷-3-基甲磺酸酯(0.64g,1.98mmol)的干燥N,N-二甲基甲酰胺(4mL)溶液。反应液在100°C搅拌12小时，反应毕，冷却至室温，加水(40mL)淬灭，并用二氯甲烷(30mL×4)萃取。将合并的有机相依次用5%氯化锂溶液(100mL×2)、盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为黄色固体(0.58g,76%)。  4-iodo-1H-pyrazole (0.35g, 1.80mmol) was dissolved in dry N,N-dimethylformamide (6mL), cooled to 0°C, and sodium hydride (0.15g, 3.75 mmol, 60% dispersed in mineral oil). After the mixture was stirred at 0°C for 1 hour, (3R,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.64g, 1.98 mmol) in dry N,N-dimethylformamide (4 mL). The reaction solution was stirred at 100° C. for 12 hours. After the reaction was completed, it was cooled to room temperature, quenched with water (40 mL), and extracted with dichloromethane (30 mL×4). The combined organic phases were successively washed with 5% lithium chloride solution (100 mL×2), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a yellow solid (0.58 g, 76%). the

LC-MS(ESI,pos.ion)m/z:365.9[M-56+H]。  LC-MS (ESI, pos. ion) m/z: 365.9 [M-56+H]. the

步骤3)((2S)-1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)吡咯烷-2-基)甲醇Step 3) ((2S)-1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)pyrrolidin-2-yl)methanol

将1-((5S)-1-(叔丁氧羰基)-5-(甲氧羰基)吡咯烷-3-基)-4-碘-1H-吡唑(0.46g,1.09mol)溶解在四氢呋喃(10mL)中，冷却至0°C，向其中分批加入硼氢化锂(0.12g,5.46mmol)。混合物在0°C搅拌30分钟后，恢复至室温，搅拌过夜。反应毕，加水(10mL)淬灭，并用乙酸乙酯(30mL×4)萃取。将合并的有机相用盐水(30mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物将硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为粘稠状液体(0.21g,28%)。  1-((5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl)-4-iodo-1H-pyrazole (0.46 g, 1.09 mol) was dissolved in tetrahydrofuran (10mL), cooled to 0°C, and lithium borohydride (0.12g, 5.46mmol) was added in portions. After the mixture was stirred at 0°C for 30 minutes, it was allowed to warm to room temperature and stirred overnight. After the reaction was completed, water (10 mL) was added to quench, and extracted with ethyl acetate (30 mL×4). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a viscous liquid (0.21 g, 28%). the

LC-MS(ESI,pos.ion)m/z:338.0[M-56+H]；  LC-MS(ESI,pos.ion)m/z:338.0[M-56+H];

1H NMR(400MHz,CDCl3)δ(ppm):7.53(s,1H),7.49(s,1H),4.68-4.82(m,1H),4.00-4.18(m,2H),3.52-3.82(m,3H),2.50-2.68(m,1H),2.11-2.38(m,1H),1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.53 (s, 1H), 7.49 (s, 1H), 4.68-4.82 (m, 1H), 4.00-4.18 (m, 2H), 3.52-3.82 ( m, 3H), 2.50-2.68(m, 1H), 2.11-2.38(m, 1H), 1.47(s, 9H).

步骤4)((2S)-1-(叔丁氧羰基)-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)吡咯烷-2-基)甲醇Step 4) ((2S)-1-(tert-butoxycarbonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazol-1-yl)pyrrolidin-2-yl)methanol

将((2S)-1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)吡咯烷-2-基)甲醇(0.50g,1.27mmol)溶解在二甲亚砜(12mL)中，向其中加入联硼酸频钠醇酯(0.48g,1.91mmol)后，置于氮气氛中，继续向其中加入Pd(dppf)2Cl2·CH2Cl2(0.10g,0.13mmol)和乙酸钾(0.50g,5.09mmol)。反应液在90°C搅拌过夜，反应毕，冷却至室温，加水(40mL)稀释，并用乙酸乙酯(50mL×3)萃取。将合并的有机相用盐水(50mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为粘稠状黄色液体(0.38g,76%)。  Dissolve ((2S)-1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)pyrrolidin-2-yl)methanol (0.50 g, 1.27 mmol) in dimethyl Sulfoxide (12mL), after adding pinazolate (0.48g, 1.91mmol) to it, placed in nitrogen atmosphere, continue to add Pd(dppf) 2 Cl 2 ·CH 2 Cl 2 (0.10g , 0.13mmol) and potassium acetate (0.50g, 5.09mmol). The reaction solution was stirred at 90°C overnight, after the reaction was completed, it was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a viscous yellow liquid (0.38 g, 76%).

LC-MS(ESI,pos.ion)m/z:394.2[M+H]；  LC-MS(ESI,pos.ion)m/z:394.2[M+H];

1H NMR(400MHz,CDCl3)δ(ppm):7.79(s,1H),7.74(s,1H),4.70-4.82(m,1H),4.04-4.18(m,2H),3.55-3.85(m,3H),2.52-2.66(m,1H),2.12-2.30(m,1H),1.46(s,9H),1.30(s,12H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.79 (s, 1H), 7.74 (s, 1H), 4.70-4.82 (m, 1H), 4.04-4.18 (m, 2H), 3.55-3.85 ( m,3H), 2.52-2.66(m,1H), 2.12-2.30(m,1H), 1.46(s,9H), 1.30(s,12H).

步骤5)((2S)-4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)-1-(叔丁氧羰基)吡咯烷-2-基)甲醇Step 5) ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol

将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.30g,0.79mmol)和((2S)-1-(叔丁氧羰基)-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)吡咯烷-2-基)甲醇(0.46g,1.18mmol)溶解在乙二醇二甲醚(10mL)中，置于氮气氛后，向其中加入碳酸铯(0.77g,2.37mmol)，Pd(dppf)Cl2·CH2Cl2(64mg,0.08mmol)和水(2mL)。反应液回流过夜。反应毕，冷却至室温，加水(30mL)稀释，并用二氯甲烷(40mL×3)萃取。将合并的有机相用盐水(50mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为黄色固体(0.26g,58%)。  (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.30g, 0.79mmol) and ((2S)- 1-(tert-butoxycarbonyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole -1-yl)pyrrolidin-2-yl)methanol (0.46g, 1.18mmol) was dissolved in ethylene glycol dimethyl ether (10mL), and after being placed in a nitrogen atmosphere, cesium carbonate (0.77g, 2.37mmol) was added thereto ), Pd(dppf)Cl 2 ·CH 2 Cl 2 (64 mg, 0.08 mmol) and water (2 mL). The reaction solution was refluxed overnight. After the reaction was completed, it was cooled to room temperature, diluted with water (30 mL), and extracted with dichloromethane (40 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (0.26 g, 58%).

LC-MS(ESI,pos.ion)m/z:566.2[M+H]；  LC-MS(ESI,pos.ion)m/z:566.2[M+H];

1H NMR(400MHz,CDCl3)δ(ppm):7.71(d,J=1.7Hz,1H),7.56(s,1H),7.49(s,1H),7.28-7.34(dd,J=8.8Hz,4.8Hz,1H),7.01-7.08(t,J=8.0Hz,1H),6.84(d,J=1.6Hz,1H),6.02-6.10(q,J=6.7Hz,1H),4.91(s,2H),4.69-4.82(m,1H),4.04-4.18(m,2H),3.60-3.80(m,2H),2.52-2.79(m,2H),2.12-2.30(m,1H),1.84(d,J=6.7Hz,3H),1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ(ppm): 7.71(d, J=1.7Hz, 1H), 7.56(s, 1H), 7.49(s, 1H), 7.28-7.34(dd, J=8.8Hz ,4.8Hz,1H),7.01-7.08(t,J=8.0Hz,1H),6.84(d,J=1.6Hz,1H),6.02-6.10(q,J=6.7Hz,1H),4.91(s ,2H),4.69-4.82(m,1H),4.04-4.18(m,2H),3.60-3.80(m,2H),2.52-2.79(m,2H),2.12-2.30(m,1H),1.84 (d, J=6.7Hz, 3H), 1.47(s, 9H).

步骤6)((2S)-4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)吡咯烷-2-基)甲醇Step 6) ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)pyrrolidin-2-yl)methanol

将((2S)-4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)-1-(叔丁氧羰基)吡咯烷-2-基)甲醇(0.26g,0.46mmol)溶解在二氯甲烷(10mL)中，向其中加入HCl(3mL,3M的乙酸乙酯溶液)。反应液室温搅拌过夜。反应毕，减压浓缩。将残留物用饱和碳酸钠溶液(10mL)和乙酸乙酯(10mL)稀释，搅拌10分钟后，分离的水相用乙酸乙酯/甲醇(v/v,10/1)的混合液(30mL×3)萃取。合并有机相，用盐水(40mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(DCM/MeOH(v/v)=8/1)纯化，得到标题化合物为黄色固体(84mg,39%)。  ((2S)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- 1H-pyrazol-1-yl)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol (0.26g, 0.46mmol) was dissolved in dichloromethane (10mL), and HCl (3mL, 3M ethyl acetate solution). The reaction solution was stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure. The residue was diluted with saturated sodium carbonate solution (10 mL) and ethyl acetate (10 mL), and after stirring for 10 minutes, the separated aqueous phase was washed with a mixture of ethyl acetate/methanol (v/v, 10/1) (30 mL× 3) Extraction. The organic phases were combined, washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=8/1) to obtain the title compound as a yellow solid (84 mg, 39%). the

LC-MS(ESI,pos.ion)m/z:466.2[M+H]；  LC-MS (ESI, pos.ion) m/z: 466.2[M+H];

1H NMR(400MHz,CDCl3)δ(ppm):7.71(d,J=1.4Hz,1H),7.56(s,1H),7.51(s,1H),7.27-7.32(dd,J=8.8Hz,4.8Hz,1H),6.99-7.07(t,J=8.5Hz,1H),6.83(d,J=1.4Hz,1H),6.01-6.09(q,J=6.7Hz,1H),4.90(br,2H),4.77-4.85(m,1H),3.81-3.87(m,1H),3.74(m,1H),3.64(m,1H),3.44-3.53(m,1H),3.27(m,2H),2.42-2.53(m,1H),2.08-2.19(m,1H),1.82(d,J=6.7Hz,3H)。  1 H NMR (400MHz, CDCl 3 ) δ(ppm): 7.71(d, J=1.4Hz, 1H), 7.56(s, 1H), 7.51(s, 1H), 7.27-7.32(dd, J=8.8Hz ,4.8Hz,1H),6.99-7.07(t,J=8.5Hz,1H),6.83(d,J=1.4Hz,1H),6.01-6.09(q,J=6.7Hz,1H),4.90(br ,2H),4.77-4.85(m,1H),3.81-3.87(m,1H),3.74(m,1H),3.64(m,1H),3.44-3.53(m,1H),3.27(m,2H ), 2.42-2.53(m,1H), 2.08-2.19(m,1H), 1.82(d,J=6.7Hz,3H).

实施例63-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((S)-吡咯烷-3-基)-1H-吡唑-4-基)吡啶-2-胺Example 63-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((S)-pyrrolidin-3-yl)-1H- Pyrazol-4-yl)pyridin-2-amine

步骤1)(R)-1-(叔丁氧羰基)吡咯烷-3-基甲磺酸酯Step 1) (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate

将(R)-1-(叔丁氧羰基)吡咯烷-3-醇(1g,5.3mmol)，三乙胺(1.2mL)溶解在二氯甲烷(15mL)中，降温至0°C，向其中滴加甲磺酰氯(0.62mL)。反应液室温搅拌2小时，反应毕，减压浓缩。残留物用水(35mL)稀释，并用乙酸乙酯(25mL×3)萃取。合并有机相，依次用1M硫酸氢钾溶液(20mL)、水(20mL)洗，经无水硫酸钠干燥，并减压浓缩后，得到粗产品为黄色油状物(1.4g)，该化合物不经纯化，直接用于下一步。  Dissolve (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ol (1g, 5.3mmol) and triethylamine (1.2mL) in dichloromethane (15mL), cool to 0°C, and To this was added dropwise methanesulfonyl chloride (0.62 mL). The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, it was concentrated under reduced pressure. The residue was diluted with water (35 mL), and extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed successively with 1M potassium bisulfate solution (20 mL), water (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product as a yellow oil (1.4 g). Purified and used directly in the next step. the

步骤2)(S)-1-(1-(叔丁氧羰基)吡咯烷-3-基)-4-碘-1H-吡唑Step 2) (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-iodo-1H-pyrazole

将4-碘-1H-吡唑(840mg,7.4mmol)溶解在在N,N-二甲基甲酰胺(15mL)中，降温至0°C，向其中加入氢化钠(320mg,12mmol,90%分散在矿物油中)。混合物在0°C搅拌1小时后，向体系内加入(R)-1-(叔丁氧羰基)吡咯烷-3-基甲磺酸酯(1.4g)的N,N-二甲基甲酰胺(5mL)溶液。反应液在70°C搅拌6小时，冷却至室温，加水(50mL)淬灭，并用乙酸乙酯(30mL×3)萃取。合并的有机相用盐水(20mL)洗，无水 硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(PE/EtOAc(v/v)=5/1)纯化，得到标题化合物为无色油状物(1.6g,80%)。  Dissolve 4-iodo-1H-pyrazole (840mg, 7.4mmol) in N,N-dimethylformamide (15mL), cool to 0°C, add sodium hydride (320mg, 12mmol, 90% dispersed in mineral oil). After the mixture was stirred at 0°C for 1 hour, (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (1.4 g) in N,N-dimethylformamide was added to the system (5 mL) solution. The reaction solution was stirred at 70°C for 6 hours, cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=5/1) to obtain the title compound as Colorless oil (1.6g, 80%). the

LC-MS(ESI,pos.ion)m/z:308[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 308[M+H-56] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.52(s,1H),7.47(s,1H),4.89-4.85(m,1H),3.84-3.51(m,4H),2.36-2.32(m,2H).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.52 (s, 1H), 7.47 (s, 1H), 4.89-4.85 (m, 1H), 3.84-3.51 (m, 4H), 2.36-2.32 ( m,2H).

步骤3)(S)-1-(1-(叔丁氧羰基)吡咯烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑Step 3) (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Cyclopentaboran-2-yl)-1H-pyrazole

氮气保护下，将(S)-1-(1-(叔丁氧羰基)吡咯烷-3-基)-4-碘-1H-吡唑(1g,2.75mmol)，联硼酸频钠醇酯(0.8g,3.32mmol)，Pd(dppf)Cl2·CH2Cl2(0.22g,0.275mmol)和乙酸钾(0.53g,5.3mmol)的二甲亚砜(15mL)悬浮液在80°C搅拌2小时。反应毕，冷却至室温，加水(30mL)稀释，并用乙酸乙酯(25mL×3)萃取。合并的有机相用盐水(75mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到目标化合物为白色固体(800mg,80%)。  Under nitrogen protection, (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-iodo-1H-pyrazole (1g, 2.75mmol), pinazolate diboronate ( 0.8g, 3.32mmol), a suspension of Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.22g, 0.275mmol) and potassium acetate (0.53g, 5.3mmol) in dimethylsulfoxide (15mL) was stirred at 80°C 2 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (25 mL×3). The combined organic phases were washed with brine (75 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the target compound as a white solid (800 mg, 80%).

LC-MS(ESI,pos.ion)m/z:364[M+H]+。  LC-MS (ESI, pos. ion) m/z: 364 [M+H] + .

步骤4)5-(1-((S)-1-(叔丁氧羰基)吡咯烷-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 4) 5-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2 ,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

氮气保护下，将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(500mg,1.32mmol)，(S)-1-(1-(叔丁氧羰基)吡咯烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(500mg,1.32mmol)，Pd(PPh3)2Cl2(108mg,0.15mmol)和碳酸钠(2.64mmol,280mg)的乙二醇二甲醚/水(15mL/1.5mL)悬浮液在87°C搅拌16小时。反应毕，减压浓缩，所得残留物经硅胶柱层析(PE/EtOAc(v/v)=1/1)纯化，得到目标化合物为棕色固体(300mg,42.4%)。  Under nitrogen protection, (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (500mg, 1.32mmol), (S )-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-pyrazole (500mg, 1.32mmol), Pd(PPh 3 ) 2 Cl 2 (108mg, 0.15mmol) and sodium carbonate (2.64mmol, 280mg) in ethylene glycol dimethyl ether/water (15mL /1.5mL) suspension was stirred at 87°C for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the target compound as a brown solid (300 mg, 42.4%).

LC-MS(ESI,pos.ion)m/z:536[M+H]+；  LC-MS (ESI, pos.ion) m/z: 536[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H,),7.59-7.57(m,1H),7.52-7.48(m,1H),7.47-7.29(m,2H),7.07-7.03(t,J=8.4Hz,1H),6.85(s,1H),6.09-6.04(q,J=6.64Hz,1H),4.88-4.83(m,3H),3.85-3.54(m,3H),2.39-2.37(m,2H),1.86(d,J=6.64Hz,3H),1.66(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.74 (s, 1H,), 7.59-7.57 (m, 1H), 7.52-7.48 (m, 1H), 7.47-7.29 (m, 2H), 7.07 -7.03(t,J=8.4Hz,1H),6.85(s,1H),6.09-6.04(q,J=6.64Hz,1H),4.88-4.83(m,3H),3.85-3.54(m,3H ), 2.39-2.37(m, 2H), 1.86(d, J=6.64Hz, 3H), 1.66(s, 9H).

步骤5)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((S)-吡咯烷-3-基)-1H-吡唑-4-基)吡啶-2-胺Step 5) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((S)-pyrrolidin-3-yl)-1H -pyrazol-4-yl)pyridin-2-amine

将5-(1-((S)-1-(叔丁氧羰基)吡咯烷-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(280mg,0.523mmol)溶解在乙酸乙酯(5mL)中，向其中加入HCl(5mL,1M的乙酸乙酯溶液)。反应液在40°C搅拌1小时。反应毕，冷却至室温，加水(35mL)稀释，并用乙酸乙酯(20mL)洗。将混合液用2M碳酸钠溶液(3mL)处理后，用乙酸乙酯(含1%甲醇,15mL×3)萃取。合并的有机相经盐水(40mL)洗，无水硫酸钠干燥，并减压浓缩，得到标题化合物为黄色固体(180mg,80%)。  5-(1-((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6 -Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (280 mg, 0.523 mmol) was dissolved in ethyl acetate (5 mL), to which was added HCl (5 mL, 1 M in ethyl acetate). The reaction was stirred at 40°C for 1 hour. After the reaction was completed, it was cooled to room temperature, diluted with water (35 mL), and washed with ethyl acetate (20 mL). The mixture was treated with 2M sodium carbonate solution (3 mL), and extracted with ethyl acetate (containing 1% methanol, 15 mL×3). The combined organic phases were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (180 mg, 80%). the

LC-MS(ESI,pos.ion)m/z:436[M+H]+；  LC-MS (ESI, pos.ion) m/z: 436[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.75(s,1H),7.54-7.51(m,2H),7.31-7.28(m,1H),7.07-7.03(t,J=8.4Hz,1H),6.09-6.04(q,J=6.64Hz,1H),4.80-4.73(m,3H),3.33-3.24(m,3H),3.19-3.15(m,1H),2.33-2.09(m,2H),1.87(d,J=6.64Hz,3H).  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.75(s,1H),7.54-7.51(m,2H),7.31-7.28(m,1H),7.07-7.03(t,J=8.4Hz, 1H),6.09-6.04(q,J=6.64Hz,1H),4.80-4.73(m,3H),3.33-3.24(m,3H),3.19-3.15(m,1H),2.33-2.09(m, 2H),1.87(d,J=6.64Hz,3H).

实施例73-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((4,4-二甲基氧杂环丁-2-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Example 73-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((4,4-dimethyloxetane-2 -yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454700861
Figure BDA00002905454700861

步骤1)2-甲基戊-4-烯-2-醇Step 1) 2-Methylpent-4-en-2-ol

氩气保护下，将烯丙基溴化镁(20mL,0.02mol,2M的乙醚溶液)置于双颈瓶中，并用冰浴冷却至0℃，在10分钟内向其中滴加丙酮(1.7mL,0.02mol)。反应液回流搅拌2小时后，边降温边用水(10mL)淬灭。 降温至0℃，向混合物中滴加盐酸(3mL,6M)调节pH值为2，分离的水相用乙醚(50mL×2)萃取。.合并有机相，用盐水(50mL)洗，无水硫酸镁干燥，并减压浓缩，得到粗产品为无色油状物(1g,50%)。  Under the protection of argon, place allylmagnesium bromide (20mL, 0.02mol, 2M ether solution) in a double-necked flask, and cool it to 0°C with an ice bath, and add acetone (1.7mL, 0.02mol). After the reaction solution was stirred at reflux for 2 hours, it was quenched with water (10 mL) while cooling down. The temperature was lowered to 0°C, hydrochloric acid (3 mL, 6M) was added dropwise to the mixture to adjust the pH to 2, and the separated aqueous phase was extracted with diethyl ether (50 mL×2). . The organic phases were combined, washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product as a colorless oil (1 g, 50%). the

LC-MS(ESI,pos.ion)m/z:101[M+H]+；  LC-MS (ESI, pos.ion) m/z: 101 [M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.20(s,6H),2.21-2.23(d,J=7.5Hz,2H),5.07-5.04(m,2H),5.81-5.93(m,1H).  1 H NMR(400MHz, CDCl 3 )δ(ppm):1.20(s,6H),2.21-2.23(d,J=7.5Hz,2H),5.07-5.04(m,2H),5.81-5.93(m, 1H).

步骤2)4-(碘甲基)-2,2-二甲基氧杂环丁烷Step 2) 4-(iodomethyl)-2,2-dimethyloxetane

Figure BDA00002905454700871
Figure BDA00002905454700871

将2-甲基戊-4-烯-2-醇(510mg,5.1mmol)，碘(1.81g,7.14mmol)悬浮在二氯甲烷(43mL)中，置于氮气氛后，向其中加入双(2,4,6-三甲基吡啶)高氯酸银(3.5g,7.14mmol)。反应液室温搅拌24小时。反应毕，用硅藻土过滤，滤饼用乙酸乙酯(50mL)洗。滤液依次经10%硫代硫酸钠(10mL×2)、10%盐酸(50mL×2)洗后，减压浓缩。所得残留物用硅胶柱层析(石油醚/二氯甲烷(v/v)=1/2)纯化，得到标题化合物为无色油状物(629mg,55%)。  2-Methylpent-4-en-2-ol (510mg, 5.1mmol), iodine (1.81g, 7.14mmol) were suspended in dichloromethane (43mL), placed in a nitrogen atmosphere, and bis( 2,4,6-collidine) silver perchlorate (3.5 g, 7.14 mmol). The reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, it was filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed successively with 10% sodium thiosulfate (10mL×2) and 10% hydrochloric acid (50mL×2), and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/dichloromethane (v/v)=1/2) to obtain the title compound as a colorless oil (629 mg, 55%). the

LC-MS(ESI,pos.ion)m/z:226[M+H]+；  LC-MS (ESI, pos.ion) m/z: 226[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.41(s,3H),1.45(s,3H),2.05-2.09(m,1H),2.44-2.49(m,1H),3.22-3.27(m,1H),3.34-3.38(m,1H),4.57-4.64(m,1H).  1 H NMR (400MHz, CDCl 3 )δ(ppm): 1.41(s,3H), 1.45(s,3H), 2.05-2.09(m,1H), 2.44-2.49(m,1H), 3.22-3.27( m,1H),3.34-3.38(m,1H),4.57-4.64(m,1H).

步骤3)1-((4,4-二甲基氧杂环丁-2-基)甲基)-4-碘-1H-吡唑Step 3) 1-((4,4-Dimethyloxetan-2-yl)methyl)-4-iodo-1H-pyrazole

将4-碘-1H-吡唑(1.13g,5.85mmol)溶解在干燥的N,N-二甲基甲酰胺(32mL)中，降温至0°C，向其中分批加入氢化钠(296mg,11.7mmol,95%)。混合物室温搅拌1.5小时后，向体系内加入4-(碘甲基)-2,2-二甲基氧杂环丁烷(1.32g,5.85mmol)。反应液在90°C搅拌19小时。反应毕，冷却至室温，加饱和氯化铵溶液(20mL)淬灭，并用乙酸乙酯(80mL×2)萃取。合并的有机相经无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为无色油 状物(890mg,53%)。  4-iodo-1H-pyrazole (1.13g, 5.85mmol) was dissolved in dry N,N-dimethylformamide (32mL), cooled to 0°C, and sodium hydride (296mg, 11.7 mmol, 95%). After the mixture was stirred at room temperature for 1.5 hours, 4-(iodomethyl)-2,2-dimethyloxetane (1.32 g, 5.85 mmol) was added to the system. The reaction was stirred at 90°C for 19 hours. After the reaction was completed, it was cooled to room temperature, quenched with saturated ammonium chloride solution (20 mL), and extracted with ethyl acetate (80 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a colorless oil ( 890mg, 53%). the

1H NMR(400MHz,CDCl3)δ(ppm):1.19(s,3H),1.45(s,3H),2.17-2.22(m,1H),2.36-2.41(m,1H),4.30(d,J=4.5Hz,2H),4.84-4.90(m,1H),7.52(s,1H),7.58(s,1H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):1.19(s,3H),1.45(s,3H),2.17-2.22(m,1H),2.36-2.41(m,1H),4.30(d, J=4.5Hz, 2H), 4.84-4.90(m, 1H), 7.52(s, 1H), 7.58(s, 1H).

步骤4)1-((4,4-二甲基氧杂环丁-2-基)甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑Step 4) 1-((4,4-Dimethyloxetan-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Borolan-2-yl)-1H-pyrazole

将联硼酸频钠醇酯(995mg,3.9mmol)溶解在二甲亚砜(22mL)中，向其中加入1-((4,4-二甲基氧杂环丁-2-基)甲基)-4-碘-1H-吡唑(880mg,3.0mmol)和乙酸钾(1.22g,12mmol)，氮气保护后，继续向体系内加入Pd(PPh3)2Cl2(218mg,0.3mmol)。反应液在80°C搅拌3小时。反应毕，冷却至室温，并用硅藻土过滤，滤渣用乙酸乙酯(100mL)洗。将滤液用盐水(50mL×2)洗，无水硫酸钠干燥，并减压浓缩。残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为无色油状物(650mg,74%)。  Diboronic acid pinadol ester (995mg, 3.9mmol) was dissolved in dimethyl sulfoxide (22mL), to which was added 1-((4,4-dimethyloxetan-2-yl)methyl) -4-iodo-1H-pyrazole (880mg, 3.0mmol) and potassium acetate (1.22g, 12mmol), after nitrogen protection, continue to add Pd(PPh 3 ) 2 Cl 2 (218mg, 0.3mmol) into the system. The reaction was stirred at 80°C for 3 hours. After the reaction, it was cooled to room temperature and filtered through celite, and the filter residue was washed with ethyl acetate (100 mL). The filtrate was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a colorless oil (650 mg, 74%).

LC-MS(ESI,pos.ion)m/z:293[M+H]+；  LC-MS (ESI, pos.ion) m/z: 293[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.21(s,3H),1.31(s,12H),1.45(s,3H),2.21-2.26(m,1H),2.37-2.42(m,1H),4.32(d,J=4.9Hz,2H),4.87-4.92(m,1H),7.79(s,1H),7.81(s,1H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):1.21(s,3H),1.31(s,12H),1.45(s,3H),2.21-2.26(m,1H),2.37-2.42(m, 1H), 4.32(d, J=4.9Hz, 2H), 4.87-4.92(m, 1H), 7.79(s, 1H), 7.81(s, 1H).

步骤5)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((4,4-二甲基氧杂环丁-2-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Step 5) 3-((R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-(1-((4,4-Dimethyloxetane- 2-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine

将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(1.27g,3.3mmol)，1-((4,4-二甲基氧杂环丁-2-基)甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(650mg,2.2mmol)，Pd(OAc)2(50mg,0.22mmol)悬浮在乙二醇二甲醚(20mL)中，向其中加入碳酸钠(707mg,6.7mmol)的水(3.25mL)溶液，氮气保护后，继续向体系内加入(t-Bu)3P(0.7mL,1M的甲苯溶液)。反应液在90°C搅拌16小时。反应毕，冷却至室温，加乙酸乙酯(30mL)稀释，并用硅藻土过滤，滤渣用乙酸乙酯(50mL)洗。将滤液用盐水(20mL×2)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/1) 纯化，得到标题化合物为黄色固体(370mg,36%)。  (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (1.27g, 3.3mmol), 1-((4 ,4-Dimethyloxetan-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base)-1H-pyrazole (650mg, 2.2mmol), Pd(OAc) 2 (50mg, 0.22mmol) was suspended in ethylene glycol dimethyl ether (20mL), and sodium carbonate (707mg, 6.7mmol) was added thereto Water (3.25 mL) solution, after nitrogen protection, continued to add (t-Bu) 3 P (0.7 mL, 1M solution in toluene) to the system. The reaction was stirred at 90°C for 16 hours. After completion of the reaction, cool to room temperature, add ethyl acetate (30 mL) to dilute, and filter with diatomaceous earth, and the filter residue is washed with ethyl acetate (50 mL). The filtrate was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (370 mg, 36%).

LC-MS(ESI,pos.ion)m/z:465[M+H]+；  LC-MS (ESI, pos.ion) m/z: 465[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.37(s,3H),1.40(s,3H),1.84-1.86(d,J=6.7Hz,3H),2.18-2.29(m,2H),2.17(d,J=4.5Hz,2H),4.80(s,2H),4.87-4.93(m,1H),6.05-6.10(q,J=6.5Hz,1H),6.88(d,J=1.3Hz,2H),7.02-7.07(m,1H),7.29-7.32(m,1H),7.57-7.60(m,2H),7.77(s,1H)。  1 H NMR(400MHz,CDCl 3 )δ(ppm):1.37(s,3H),1.40(s,3H),1.84-1.86(d,J=6.7Hz,3H),2.18-2.29(m,2H) ,2.17(d,J=4.5Hz,2H),4.80(s,2H),4.87-4.93(m,1H),6.05-6.10(q,J=6.5Hz,1H),6.88(d,J=1.3 Hz, 2H), 7.02-7.07(m, 1H), 7.29-7.32(m, 1H), 7.57-7.60(m, 2H), 7.77(s, 1H).

实施例83-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3-氟吡咯烷-3-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Example 83-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3-fluoropyrrolidin-3-yl)methyl) -1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454700891
Figure BDA00002905454700891

步骤1)5-(叔丁氧羰基)-1-氧杂-5-氮杂螺[2.4]庚烷Step 1) 5-(tert-butoxycarbonyl)-1-oxa-5-azaspiro[2.4]heptane

将三甲基碘化亚砜(2.57g,11.7mmol)溶解在二甲亚砜(8.8mL)中，降温至10℃，向其中加入氢化钠(351mg,80%分散在矿物油中)。混合物室温搅拌2小时后，向体系内加入1-(叔丁氧羰基)吡咯烷-3-酮(2.00g,10.8mmol)的二甲亚砜(3.0mL)溶液。反应液继续搅拌3小时。反应毕，依次加冰水(50mL)、盐水(50mL)淬灭，并用二氯甲烷(100mL×3)萃取。将合并的有机相用盐水(50mL)洗，无水硫酸钠干燥，并减压浓缩，得到粘稠状液体，该液体不经纯化，直接用于下一步反应。  Trimethylsulfoxide iodide (2.57g, 11.7mmol) was dissolved in dimethylsulfoxide (8.8mL), cooled to 10°C, and sodium hydride (351mg, 80% dispersed in mineral oil) was added thereto. After the mixture was stirred at room temperature for 2 hours, a solution of 1-(tert-butoxycarbonyl)pyrrolidin-3-one (2.00 g, 10.8 mmol) in dimethyl sulfoxide (3.0 mL) was added to the system. The reaction was stirred for an additional 3 hours. After the reaction was completed, it was quenched with ice water (50 mL) and brine (50 mL) successively, and extracted with dichloromethane (100 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a viscous liquid, which was directly used in the next reaction without purification. the

步骤2)1-(叔丁氧羰基)-3-((4-碘-1H-吡唑-1-基)甲基)吡咯烷-3-醇Step 2) 1-(tert-butoxycarbonyl)-3-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidin-3-ol

将4-碘-1H-吡唑(2.1g,10.8mmol)溶解在N,N-二甲基甲酰胺(20mL)中，冷却至0°C，向其中加入氢化钠(390mg,80%分散在矿物油中)，混合物在0°C搅拌1小时后，向体系内加入5-(叔丁氧羰基)-1-氧杂 -5-氮杂螺[2.4]庚烷(2.1g,10.8mmol)的N,N-二甲基甲酰胺(10ml)溶液。反应液在70°C加热搅拌36小时。反应毕，冷却至室温，加水(10mL)淬灭，并减压浓缩。将残留物分散在二氯甲烷(100mL)和水(100mL)中，分离的有机相用盐水(50mL)洗，无水硫酸钠干燥，并减压浓缩。残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=3/1)纯化，得到标题化合物为无色油状物(1.15g,27%,两步收率)。  4-iodo-1H-pyrazole (2.1g, 10.8mmol) was dissolved in N,N-dimethylformamide (20mL), cooled to 0°C, and sodium hydride (390mg, 80% dispersed in mineral oil), the mixture was stirred at 0°C for 1 hour, and 5-(tert-butoxycarbonyl)-1-oxa-5-azaspiro[2.4]heptane (2.1g, 10.8mmol) was added to the system N,N-dimethylformamide (10ml) solution. The reaction solution was heated and stirred at 70° C. for 36 hours. After the reaction was completed, it was cooled to room temperature, quenched with water (10 mL), and concentrated under reduced pressure. The residue was dispersed in dichloromethane (100 mL) and water (100 mL), and the separated organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a colorless oil (1.15 g, 27%, two-step yield). the

LC-MS(ESI,pos.ion)m/z:338[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 338[M+H-56] + ;

1H NMR(400MHz,DMSO-d6)δ(ppm):1.38(s,9H),1.57-1.73(m,1H),1.74-1.90(m,1H),3.05-3.13(m,1H),3.21-3.32(m,3H),4.23(d,J=3.6Hz,2H),5.16(d,J=1.6Hz,2H),7.54(s,1H),7.82(d,J=2.9Hz,2H)。  1 H NMR(400MHz,DMSO-d 6 )δ(ppm):1.38(s,9H),1.57-1.73(m,1H),1.74-1.90(m,1H),3.05-3.13(m,1H), 3.21-3.32(m,3H),4.23(d,J=3.6Hz,2H),5.16(d,J=1.6Hz,2H),7.54(s,1H),7.82(d,J=2.9Hz,2H ).

步骤3)1-((1-(叔丁氧羰基)-3-氟吡咯烷-3-基)甲基)-4-碘-1H-吡唑Step 3) 1-((1-(tert-butoxycarbonyl)-3-fluoropyrrolidin-3-yl)methyl)-4-iodo-1H-pyrazole

将DAST(0.5mL,4mmol)溶解在二氯甲烷(30mL)中，降温至-78°C，向其中滴加1-(叔丁氧羰基)-3-((4-碘-1H-吡唑-1-基)甲基)吡咯烷-3-醇(786mg,2.0mmol)的二氯甲烷(10mL)溶液。反应液室温搅拌6小时。反应毕，加二氯甲烷稀释(50mL)，并依次用水(20mL)和盐水(20mL)洗。将溶液用无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为无色油状物(600mg,76%)。  DAST (0.5mL, 4mmol) was dissolved in dichloromethane (30mL), cooled to -78°C, and 1-(tert-butoxycarbonyl)-3-((4-iodo-1H-pyrazole) was added dropwise thereto -1-yl)methyl)pyrrolidin-3-ol (786 mg, 2.0 mmol) in dichloromethane (10 mL). The reaction solution was stirred at room temperature for 6 hours. After the reaction was completed, it was diluted with dichloromethane (50 mL), and washed with water (20 mL) and brine (20 mL) successively. The solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a colorless oil (600 mg, 76%). the

LC-MS(ESI,pos.ion)m/z:340[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 340[M+H-56] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.45(s,9H),1.96-2.03(m,2H),3.40-3.70(m,4H),3.97-4.20(m,1H),4.38-4.55(m,2H),7.45-7.60(m,2H).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.45 (s, 9H), 1.96-2.03 (m, 2H), 3.40-3.70 (m, 4H), 3.97-4.20 (m, 1H), 4.38- 4.55(m,2H),7.45-7.60(m,2H).

步骤4)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3-氟吡咯烷-3-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Step 4) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3-fluoropyrrolidin-3-yl)methyl )-1H-pyrazol-4-yl)pyridin-2-amine

将1-((1-(叔丁氧羰基)-3-氟吡咯烷-3-基)甲基)-4-碘-1H-吡唑(215mg,0.54mmol)和(R)-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-2-胺(284mg,0.45mmol)溶解在乙二醇二甲醚(40mL)中，向其中依次加入碳酸钠(148mg,1.4mmol)的水(10mL)溶液，氮气保护后，继续向体系内加入Pd(dppf)Cl2·CH2Cl2(35mg,0.05mmol)。反应液在88°C加热搅拌 16小时。反应毕，减压浓缩，将残留物分散在二氯甲烷(60mL)和水(60mL)中，分离的有机相用盐水(30mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)=1/1)纯化，得到粗产品。将该产品溶解在二氯甲烷(40mL)中，降温至0°C后，向其中加入HCl(8mL,1M的乙酸乙酯溶液)。反应液搅拌12小时。反应毕，减压浓缩。将残留物用水(100mL)再次溶解，加饱和碳酸钠溶液调节pH值为10，并用二氯甲烷/甲醇混合液(8/1,50mL×3)萃取。合并的有机相经无水硫酸钠干燥，并减压浓缩后，用残留物经硅胶柱层析(DCM/MeOH(v/v)=7/1)纯化，得到标题化合物为黄色固体(75mg,31%)。  1-((1-(tert-butoxycarbonyl)-3-fluoropyrrolidin-3-yl)methyl)-4-iodo-1H-pyrazole (215mg, 0.54mmol) and (R)-N,N -Bis(tert-butoxycarbonyl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridin-2-amine (284mg, 0.45mmol) was dissolved in ethylene glycol dimethyl ether (40mL), and sodium carbonate (148mg, 1.4 mmol) in water (10 mL), under nitrogen protection, Pd(dppf)Cl 2 ·CH 2 Cl 2 (35 mg, 0.05 mmol) was continuously added to the system. The reaction solution was heated and stirred at 88° C. for 16 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was dispersed in dichloromethane (60 mL) and water (60 mL), and the separated organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain a crude product. The product was dissolved in dichloromethane (40 mL), and after cooling to 0° C., HCl (8 mL, 1M in ethyl acetate) was added thereto. The reaction was stirred for 12 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was redissolved in water (100 mL), adjusted to pH 10 by adding saturated sodium carbonate solution, and extracted with dichloromethane/methanol mixture (8/1, 50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=7/1) to obtain the title compound as a yellow solid (75 mg, 31%).

LC-MS(ESI,pos.ion)m/z:234.5(M+2)/2；  LC-MS(ESI,pos.ion)m/z:234.5(M+2)/2;

1H NMR(400MHz,DMSO-d6)δ(ppm):1.79(d,J=6.6Hz,3H),1.80-2.05(m,3H),2.82-3.13(m,4H),4.47(s,1H),4.52(s,1H),5.67(s,2H),6.09(q,J=6.6Hz,1H),6.88(d,J=1.5Hz,1H),7.40-7.47(m,1H),7.52-7.58(m,1H),7.59(s,1H),7.75(d,J=1.7Hz,1H),7.84(s,1H)。  1 H NMR(400MHz,DMSO-d 6 )δ(ppm):1.79(d,J=6.6Hz,3H),1.80-2.05(m,3H),2.82-3.13(m,4H),4.47(s, 1H),4.52(s,1H),5.67(s,2H),6.09(q,J=6.6Hz,1H),6.88(d,J=1.5Hz,1H),7.40-7.47(m,1H), 7.52-7.58 (m, 1H), 7.59 (s, 1H), 7.75 (d, J=1.7Hz, 1H), 7.84 (s, 1H).

实施例93-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((S)-吡咯烷-2-基甲基)-1H-吡唑-4-基)吡啶-2-胺Example 93-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((S)-pyrrolidin-2-ylmethyl)- 1H-pyrazol-4-yl)pyridin-2-amine

步骤1)(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲基甲磺酸酯Step 1) (S)-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl methanesulfonate

标题化合物通过实施例6步骤1所描述的方法制备得到，即将(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲醇(1g,4.9mmol)，甲磺酰氯(0.6mL)和三乙胺(1.1mL)溶解在二氯甲烷(15mL)中制备，得到粗产品为黄色油状物(1.4g)，该产品不经纯化，直接用于下一步。  The title compound was prepared by the method described in step 1 of Example 6, namely (S)-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methanol (1 g, 4.9 mmol), methanesulfonyl chloride (0.6 mL ) and triethylamine (1.1 mL) were dissolved in dichloromethane (15 mL) to give the crude product as a yellow oil (1.4 g), which was used directly in the next step without purification. the

步骤2)(S)-1-((1-(叔丁氧羰基)吡咯烷-2-基)甲基)-4-碘-1H-吡唑Step 2) (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-iodo-1H-pyrazole

标题化合物通过实施例6步骤2所描述的方法制备得到，即将4-碘-1H-吡唑(840mg,7.4mmol)，(S)-(1-(叔丁氧羰基)吡咯烷-2-基)甲基甲磺酸酯(1.4g)和氢化钠(320mg,12mmol,90%分散在矿物油中)溶解在N,N-二甲基甲酰胺(20mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=5/1)纯化，得到目标产物为无色油状物(1.6g,89%)。  The title compound was prepared by the method described in step 2 of Example 6, namely 4-iodo-1H-pyrazole (840 mg, 7.4 mmol), (S)-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl ) methyl mesylate (1.4g) and sodium hydride (320mg, 12mmol, 90% dispersed in mineral oil) were prepared by dissolving N,N-dimethylformamide (20mL), and the crude product was passed through a silica gel column Purification by analysis (PE/EtOAc (v/v)=5/1) gave the target product as a colorless oil (1.6 g, 89%). the

LC-MS(ESI,pos.ion)m/z:378.1[M+H]+；  LC-MS (ESI, pos.ion) m/z: 378.1[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.40(1H,s),7.31(1H,s),4.26-3.96(3H,m),3.30-3.06(2H,m),2.80-1.64(4H,m),1.42(9H,s)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.40 (1H, s), 7.31 (1H, s), 4.26-3.96 (3H, m), 3.30-3.06 (2H, m), 2.80-1.64 ( 4H,m), 1.42(9H,s).

步骤3)(S)-1-((1-(叔丁氧羰基)吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑Step 3) (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-1H-pyrazole

标题化合物通过实施例6步骤3所描述的方法制备得到，即将(S)-1-((1-(叔丁氧羰基)吡咯烷-2-基)甲基)-4-碘-1H-吡唑(1g,2.65mmol)，联硼酸频钠醇酯(3.9mmol,1g)，Pd(dppf)Cl2·CH2Cl2(0.2g,0.265mmol)和乙酸钾(0.53g,5.3mmol)悬浮在二甲亚砜(15mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到目标产物为白色固体(800mg,80%)。  The title compound was prepared by the method described in step 3 of Example 6, that is, (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-iodo-1H-pyrrolidinyl Azole (1g, 2.65mmol), pinoborate (3.9mmol, 1g), Pd(dppf)Cl 2 ·CH 2 Cl 2 (0.2g, 0.265mmol) and potassium acetate (0.53g, 5.3mmol) suspension Prepared in dimethyl sulfoxide (15 mL), the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the desired product as a white solid (800 mg, 80%).

LC-MS(ESI,pos.ion)m/z:378.1[M+H]+；  LC-MS (ESI, pos.ion) m/z: 378.1[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.69(1H,s),7.58(1H,s),4.29-4.07(3H,m),3.31-3.07(2H,m),2.00-1.66(4H,m),1.43(9H,s),1.18(12H,s).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.69 (1H, s), 7.58 (1H, s), 4.29-4.07 (3H, m), 3.31-3.07 (2H, m), 2.00-1.66 ( 4H,m),1.43(9H,s),1.18(12H,s).

步骤4)5-(1-(((S)-1-(叔丁氧羰基)吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 4) 5-(1-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)-3-((R)- 1-(2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

标题化合物通过实施例6步骤4所描述的方法制备得到，即将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(500mg,1.32mmol)，(S)-1-((1-(叔丁氧羰基)吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(500mg,1.32mmol)，Pd(PPh3)2Cl2(108mg,15.3mmol)和碳酸钠(2.64mmol,280mg)悬浮在乙二醇二甲醚/水(15mL/1.5mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=1/1)纯 化，得到目标化合物为棕色固体(200mg,27%)。  The title compound was prepared by the method described in step 4 of Example 6, that is, (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2 -Amine (500mg, 1.32mmol), (S)-1-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500mg, 1.32mmol), Pd(PPh 3 ) 2 Cl 2 (108mg, 15.3mmol) and sodium carbonate (2.64 mmol, 280mg) was suspended in ethylene glycol dimethyl ether/water (15mL/1.5mL), and the crude product was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/1) to obtain the target compound as Brown solid (200mg, 27%).

LC-MS(ESI,pos.ion)m/z:550[M+H]+。  LC-MS (ESI, pos.ion) m/z: 550 [M+H] + .

步骤5)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((S)-吡咯烷-2-基甲基)-1H-吡唑-4-基)吡啶-2-胺Step 5) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((S)-pyrrolidin-2-ylmethyl) -1H-pyrazol-4-yl)pyridin-2-amine

标题化合物通过实施例6步骤5所描述的方法制备得到，即将5-(1-(((S)-1-(叔丁氧羰基)吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(160mg,0.29mmol)和HCl(5mL,1M的乙酸乙酯溶液)溶解在乙酸乙酯(5mL)中制备，得到标题化合物为黄色固体(60mg,46%)。  The title compound was prepared by the method described in step 5 of Example 6, that is, 5-(1-(((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)-1H-pyrazole -4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (160mg, 0.29mmol) and HCl (5mL, 1M solution in ethyl acetate) was dissolved in ethyl acetate (5 mL) to give the title compound as a yellow solid (60 mg, 46%). the

LC-MS(ESI,pos.ion)m/z:225.7(M+2)/2；  LC-MS(ESI,pos.ion)m/z:225.7(M+2)/2;

1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.55-7.52(m,2H),7.32-7.30(m,2H),7.07-6.86(m,1H),6.07(q,J=6.64Hz,1H),4.85(s,2H),4.28-4.23(dd,J=4.4Hz,1H),4.13-4.08(dd,J=7.4Hz,1H),3.73-3.68(m,1H),3.04-3.02(m,2H),1.86-1.84(m,2H),1.81(d,J=6.64Hz,3H),1.49-1.47(m,2H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.74 (s, 1H), 7.55-7.52 (m, 2H), 7.32-7.30 (m, 2H), 7.07-6.86 (m, 1H), 6.07 ( q,J=6.64Hz,1H),4.85(s,2H),4.28-4.23(dd,J=4.4Hz,1H),4.13-4.08(dd,J=7.4Hz,1H),3.73-3.68(m ,1H), 3.04-3.02(m,2H), 1.86-1.84(m,2H), 1.81(d,J=6.64Hz,3H), 1.49-1.47(m,2H).

实施例103-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(((2S)-4-氟吡咯烷-2-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Example 103-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(((2S)-4-fluoropyrrolidin-2-yl )methyl)-1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454700931
Figure BDA00002905454700931

步骤1)(2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-甲酸甲酯Step 1) (2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid methyl ester

标题化合物通过实施例1步骤8所描述的方法制备得到，即将(2S)-1-(叔丁氧羰基)-4-羟基吡咯烷-2-甲酸甲酯(1g,4.1mmol)和DAST(1.1mL,8.2mmol)溶解在二氯甲烷(5mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=5/1)纯化，得到目标产物为黄色油状物 (0.93g,93%)。  The title compound was prepared by the method described in step 8 of Example 1, namely (2S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (1 g, 4.1 mmol) and DAST (1.1 mL, 8.2mmol) was prepared by dissolving in dichloromethane (5mL), and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain the target product as a yellow oil ( 0.93g, 93%). the

LC-MS(ESI,pos.ion)m/z:248[M+H]+。  LC-MS (ESI, pos.ion) m/z: 248 [M+H] + .

步骤2)((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲醇Step 2) ((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methanol

将(2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-甲酸甲酯(0.95g,3.85mmol)溶解四氢呋喃(18mL)中，冷却至0°C，向其中缓慢加入硼氢化锂(0.13g,5.78mmol)。将反应液升至室温，搅拌过夜。反应毕，加稀乙酸(0.5mL溶解于60mL水)淬灭，并用乙酸乙酯(20mL×3)萃取。合并的有机相依次用1M碳酸氢钠溶液(50mL)、盐水(50mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为黄色油状物(0.82g,97%)。  (2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid methyl ester (0.95g, 3.85mmol) was dissolved in tetrahydrofuran (18mL), cooled to 0°C, and boron was slowly added thereto Lithium hydride (0.13 g, 5.78 mmol). The reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, dilute acetic acid (0.5 mL dissolved in 60 mL water) was added to quench, and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed successively with 1M sodium bicarbonate solution (50mL), brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/ v)=4/1) Purification afforded the title compound as a yellow oil (0.82 g, 97%). the

LC-MS(ESI,pos.ion)m/z:242[M+Na]+。  LC-MS (ESI, pos.ion) m/z: 242 [M+Na] + .

步骤3)((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基甲磺酸酯Step 3) ((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl mesylate

将((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲醇(0.41g,1.87mmol)和DMAP(22.8mg,0.1mmol)溶解在二氯甲烷(6mL)中，冷却至0°C，依次向其中加入三乙胺(0.52mL,3.74mmol)和甲磺酰氯(0.23mL,2.81mmol)。反应液室温搅拌2.5小时。反应毕，加1M碳酸氢钠溶液(25mL)淬灭，并用二氯甲烷(30mL×3)萃取，合并的有机相用盐水(25mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物不经纯化，直接用于下一步反应。  Dissolve ((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methanol (0.41 g, 1.87 mmol) and DMAP (22.8 mg, 0.1 mmol) in dichloromethane (6 mL) , cooled to 0°C, and triethylamine (0.52mL, 3.74mmol) and methanesulfonyl chloride (0.23mL, 2.81mmol) were sequentially added thereto. The reaction solution was stirred at room temperature for 2.5 hours. After the reaction was completed, it was quenched by adding 1M sodium bicarbonate solution (25mL), and extracted with dichloromethane (30mL×3), the combined organic phase was washed with brine (25mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue The product was directly used in the next reaction without purification. the

步骤4)1-(((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基)-4-碘-1H-吡唑Step 4) 1-(((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-iodo-1H-pyrazole

将4-碘-1H-吡唑(0.51g,2.64mmol)溶解在干燥的N,N-二甲基甲酰胺(45mL)中，冷却至0°C，向其中分批加入氢化钠(0.17g,7.0mmol)，混合物在0°C搅拌8小时后，升至室温，并向其中加入((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基甲磺酸酯。将反应液加热至100°C，搅拌反应8小时。反应毕，加入NH4Cl水溶液(50mL)，并用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(25mL)洗，无水Na2SO4干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=6/1)纯化，得到标题化合物为无色油状物(700mg,95%)。  4-iodo-1H-pyrazole (0.51g, 2.64mmol) was dissolved in dry N,N-dimethylformamide (45mL), cooled to 0°C, and sodium hydride (0.17g , 7.0mmol), the mixture was stirred at 0°C for 8 hours, then raised to room temperature, and ((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methylformazol was added thereto Sulfonate. The reaction solution was heated to 100° C. and stirred for 8 hours. After the reaction was complete, aqueous NH 4 Cl solution (50 mL) was added, and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=6/1 ) to obtain the title compound as a colorless oil (700 mg, 95%).

LC-MS(ESI,pos.ion)m/z:396[M+H]+；  LC-MS (ESI, pos.ion) m/z: 396[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),1.56-2.39(m,2H),3.49-3.75(m,2H),4.14-4.58(m,3H),5.18-5.32(m,1H),7.42(s,1H),7.53(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.46 (s, 9H), 1.56-2.39 (m, 2H), 3.49-3.75 (m, 2H), 4.14-4.58 (m, 3H), 5.18- 5.32 (m, 1H), 7.42 (s, 1H), 7.53 (s, 1H).

步骤5)1-(((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3-二氧杂环戊硼烷-2-基)-1H-吡唑Step 5) 1-(((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1 ,3-dioxaborolan-2-yl)-1H-pyrazole

标题化合物通过实施例7步骤4所描述的方法制备得到，即将1-(((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基)-4-碘-1H-吡唑(0.7g,1.77mmol)，联硼酸频那醇酯(0.68g,2.66mmol)，KOAc(0.38g,3.9mmol)和Pd(PPh3)2Cl2(62mg,0.09mmol)悬浮在二甲亚砜(10mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到目标产物为黄色油状物(0.66g,94%)。  The title compound was prepared by the method described in step 4 of Example 7, that is, 1-(((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-iodo - 1H-pyrazole (0.7g, 1.77mmol), pinacol diboronate (0.68g, 2.66mmol), KOAc (0.38g, 3.9mmol) and Pd(PPh 3 ) 2 Cl 2 (62mg, 0.09mmol) Suspended in dimethyl sulfoxide (10mL), the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the target product as a yellow oil (0.66g, 94 %).

LC-MS(ESI,pos.ion)m/z:398[M+H]+；  LC-MS (ESI, pos.ion) m/z: 398[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.30(s,12H),1.46(s,9H),2.01-2.31(m,2H),3.52-3.79(m,2H),4.09-4.15(m,1H),4.32-4.37(m,1H),4.45-4.60(m,1H),5.16-5.29(m,1H),7.67(s,1H),7.79(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.30 (s, 12H), 1.46 (s, 9H), 2.01-2.31 (m, 2H), 3.52-3.79 (m, 2H), 4.09-4.15 ( m, 1H), 4.32-4.37(m, 1H), 4.45-4.60(m, 1H), 5.16-5.29(m, 1H), 7.67(s, 1H), 7.79(s, 1H).

步骤6)5-(1-(((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 6) 5-(1-(((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)-3-( (R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

标题化合物通过实施例7步骤5所描述的方法制备得到，即将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.54g,1.44mmol)，1-(((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3-二氧杂环戊硼烷-2-基)-1H-吡唑(0.38g,0.96mmol)，Pd(OAc)2(22mg,0.096mmol)，Na2CO3(0.3g,2.87mmol)和(t-Bu)3P(49mg,0.24mmol)悬浮在乙二醇二甲醚/水(6mL/1.5mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/2)纯化，得到目标产物为黄色固体(0.5g,55%)。  The title compound was prepared by the method described in step 5 of Example 7, namely (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2 -amine (0.54g, 1.44mmol), 1-(((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-4-(4,4,5, 5-Tetramethyl-1,3-dioxaborolan-2-yl)-1H-pyrazole (0.38g, 0.96mmol), Pd(OAc) 2 (22mg, 0.096mmol), Na2CO 3 (0.3g, 2.87mmol) and (t-Bu) 3 P (49mg, 0.24mmol) were prepared by suspending in ethylene glycol dimethyl ether/water (6mL/1.5mL), and the crude product was subjected to silica gel column chromatography (petroleum Ether/ethyl acetate (v/v)=1/2) to obtain the target product as a yellow solid (0.5 g, 55%).

LC-MS(ESI,pos.ion)m/z:569[M+H]+；  LC-MS (ESI, pos.ion) m/z: 569[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),1.84-1.86(d,J=6.6Hz,3H),2.04-2.45(m,2H),3.49-3.76(m,2H),4.09-4.14(m,1H),4.30-4.36 (m,1H),4.43-4.59(m,1H),4.77(s,2H),5.16-5.32(m,1H),6.04-6.09(q,J=6.6Hz,1H),6.85(s,1H),7.03-7.07(m,1H),7.28-7.32(m,1H),7.41(s,1H),7.54-7.58(m,1H),7.75-7.76(d,J=1.6Hz,1H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):1.46(s,9H),1.84-1.86(d,J=6.6Hz,3H),2.04-2.45(m,2H),3.49-3.76(m, 2H),4.09-4.14(m,1H),4.30-4.36(m,1H),4.43-4.59(m,1H),4.77(s,2H),5.16-5.32(m,1H),6.04-6.09( q,J=6.6Hz,1H),6.85(s,1H),7.03-7.07(m,1H),7.28-7.32(m,1H),7.41(s,1H),7.54-7.58(m,1H) , 7.75-7.76 (d, J=1.6Hz, 1H).

步骤7)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(((2S)-4-氟吡咯烷-2-基-)甲基)-1H-吡唑-4-基)吡啶-2-胺Step 7) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(((2S)-4-fluoropyrrolidine-2- Base-)methyl)-1H-pyrazol-4-yl)pyridin-2-amine

标题化合物通过实施例1步骤10描述的方法制备得到，即将5-(1-(((2S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.4g,0.52mmol)和HCl(5mL,3M的乙酸乙酯溶液)溶解在二氯甲烷(15mL)中制备，粗产品经硅胶柱层析(二氯甲烷/甲醇/三乙胺(v/v/v)=200/20/1)纯化，得到标题化合物为黄色固体(0.29g,90%)。  The title compound was prepared by the method described in step 10 of Example 1, that is, 5-(1-(((2S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)methyl)-1H -pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.4g, 0.52mmol) and HCl (5mL, 3M ethyl acetate solution) was prepared by dissolving in dichloromethane (15mL), and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol/triethylamine (v/v/v)=200/20/ 1) Purification to obtain the title compound as a yellow solid (0.29g, 90%). the

LC-MS(ESI,pos.ion)m/z:468[M+H]+；  LC-MS (ESI, pos.ion) m/z: 468[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.80-2.05(m,1H),1.84(d,J=6.0Hz,3H),2.05-2.24(m,1H),2.95-3.08(m,1H),3.30-3.39(m,1H),3.64-3.68(m,1H),4.12-4.18(m,1H),4.21-4.26(m,1H),4.78(s,2H),5.14-5.30(m,1H),6.05-6.10(q,J=6.7Hz,1H),6.86-6.87(d,J=1.5Hz,1H),7.03-7.07(t,J=1.7Hz,1H),7.29-7.32(m,1H),7.54(s,1H),7.58(s,1H),7.76-7.77(d,J=1.7Hz,1H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):1.80-2.05(m,1H),1.84(d,J=6.0Hz,3H),2.05-2.24(m,1H),2.95-3.08(m, 1H),3.30-3.39(m,1H),3.64-3.68(m,1H),4.12-4.18(m,1H),4.21-4.26(m,1H),4.78(s,2H),5.14-5.30( m,1H),6.05-6.10(q,J=6.7Hz,1H),6.86-6.87(d,J=1.5Hz,1H),7.03-7.07(t,J=1.7Hz,1H),7.29-7.32 (m,1H),7.54(s,1H),7.58(s,1H),7.76-7.77(d,J=1.7Hz,1H).

实施例113-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(((S)-4,4-二氟吡咯烷-2-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Example 113-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(((S)-4,4-difluoropyrrolidine- 2-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454700961
Figure BDA00002905454700961

步骤1)(2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-甲酸甲酯Step 1) Methyl (2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxylate

将(2S)-1-(叔丁氧羰基)-4-羟基吡咯烷-2-甲酸甲酯(2.0g,8.15mmol)悬浮在二氯甲烷(100mL)，并向其中加入DHP(1.71g,20.4mmol)和PPTS(246mg,0.978mmol)。反应液在35°C加热搅拌36小时。反应毕，减压浓缩，并用硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为无色油状物(2.65g,99%)。  Methyl (2S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylate (2.0 g, 8.15 mmol) was suspended in dichloromethane (100 mL), and DHP (1.71 g, 20.4mmol) and PPTS (246mg, 0.978mmol). The reaction solution was heated and stirred at 35° C. for 36 hours. After completion of the reaction, it was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a colorless oil (2.65 g, 99%). the

1H NMR(400MHz,CDCl3)δ(ppm):1.41-1.46(d,9H),1.50-1.63(m,5H),1.64-1.75(m,1H),1.75-1.86(m,1H),2.01-2.18(m,2H),2.23-2.51(m,1H),3.39-3.72(m,3H),3.73(s,3H),3.78-3.90(m,1H),4.28-4.46(m,2H),4.61-4.69(m,1H).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.41-1.46 (d, 9H), 1.50-1.63 (m, 5H), 1.64-1.75 (m, 1H), 1.75-1.86 (m, 1H), 2.01-2.18(m,2H),2.23-2.51(m,1H),3.39-3.72(m,3H),3.73(s,3H),3.78-3.90(m,1H),4.28-4.46(m,2H ),4.61-4.69(m,1H).

步骤2)((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲醇Step 2) ((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methanol

将(2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-甲酸甲酯(1.0g,3.0mmol)溶解在四氢呋喃(15mL)中，用冰浴冷却后，向其中加入硼氢化锂(94.5mg,4.5mmol)。反应液在35°C搅拌过夜。反应毕，用冰浴冷却，缓慢加入饱和氯化铵溶液(20mL)淬灭，并用乙酸乙酯(60mL×3)萃取。合并的有机相，用无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为无色油状物(850mg,94%)。  Dissolve (2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine-2-carboxylic acid methyl ester (1.0 g, 3.0 mmol) in Tetrahydrofuran (15 mL) was cooled with an ice bath, and lithium borohydride (94.5 mg, 4.5 mmol) was added thereto. The reaction was stirred overnight at 35°C. After the reaction was completed, it was cooled with an ice bath, quenched by adding saturated ammonium chloride solution (20 mL) slowly, and extracted with ethyl acetate (60 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a colorless oil (850 mg, 94%). the

LC-MS(ESI,pos.ion)m/z:324[M+Na]+；  LC-MS (ESI, pos.ion) m/z: 324[M+Na] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.47(s,9H),1.49-1.75(m,6H),1.75-1.87(m,1H),1.87-2.02(m,1H),2.05-2.24(m,1H),3.25-3.79(m,5H),3.79-3.86(m,1H),3.78-3.90(m,1H),4.22-4.39(m,1H),4.61-4.69(m,1H),4.82-5.02(m,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.47 (s, 9H), 1.49-1.75 (m, 6H), 1.75-1.87 (m, 1H), 1.87-2.02 (m, 1H), 2.05- 2.24(m,1H),3.25-3.79(m,5H),3.79-3.86(m,1H),3.78-3.90(m,1H),4.22-4.39(m,1H),4.61-4.69(m,1H ), 4.82-5.02(m,1H).

步骤3)((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基甲磺酸酯Step 3) ((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl mesylate

标题化合物通过实施例10步骤3描述的方法制备得到，即将((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲醇(1.0g,3.3mmol)，甲磺酰氯(0.38mL,4.95mmol)，DMAP(40mg,0.33mmol)和三乙胺(0.92mL,6.6mmol)溶解在二氯甲烷(10mL)中制备 得到粗产品(1.25g,100%)，该产品不经纯化，直接用于下一步反应。  The title compound was prepared by the method described in step 3 of Example 10, that is, ((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidine -2-yl)methanol (1.0g, 3.3mmol), methanesulfonyl chloride (0.38mL, 4.95mmol), DMAP (40mg, 0.33mmol) and triethylamine (0.92mL, 6.6mmol) were dissolved in dichloromethane (10mL ) to obtain a crude product (1.25 g, 100%), which was directly used in the next step without purification. the

步骤4)1-(((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基)-4-碘-1H-吡唑Step 4) 1-(((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl)- 4-iodo-1H-pyrazole

将4-碘-1H-吡唑(704.2mg,3.63mmol)溶解在干燥的N,N-二甲基甲酰胺(15mL)中，冷却至0℃后，向其中分批加入氢化钠(7.6mmol,192mg,95%)。悬浮液在0℃搅拌8小时后，恢复至室温搅拌1.5小时，并继续向体系内加入((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基甲磺酸酯(1.25g,3.3mmol)的N,N-二甲基甲酰胺(3mL)溶液。反应液在100℃搅拌13小时。反应毕，冷却至室温，加饱和氯化铵溶液(30mL)淬灭，并用乙酸乙酯(50mL×2)萃取。合并的有机相用盐水(25mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为白色固体(1.3g,83%)。  Dissolve 4-iodo-1H-pyrazole (704.2mg, 3.63mmol) in dry N,N-dimethylformamide (15mL), cool to 0°C, add sodium hydride (7.6mmol , 192mg, 95%). After the suspension was stirred at 0°C for 8 hours, it was returned to room temperature and stirred for 1.5 hours, and ((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2 -yl)oxy)pyrrolidin-2-yl)methyl methanesulfonate (1.25 g, 3.3 mmol) in N,N-dimethylformamide (3 mL). The reaction solution was stirred at 100°C for 13 hours. After the reaction was completed, it was cooled to room temperature, quenched with saturated ammonium chloride solution (30 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (1.3 g, 83%). the

LC-MS(ESI,pos.ion)m/z:478[M+H]+；  LC-MS (ESI, pos.ion) m/z: 478[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.40-1.59(m,13H),1.60-1.70(m,1H),1.70-1.95(m,2H),1.95-2.05(m,1H),2.05-2.20(m,1H),3.02-3.72(m,3H),3.73-3.86(m,1H),3.80-4.02(m,1H),4.05-4.39(m,3H),4.45-4.69(m,2H),7.35-7.40(m,1H),7.48(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.40-1.59 (m, 13H), 1.60-1.70 (m, 1H), 1.70-1.95 (m, 2H), 1.95-2.05 (m, 1H), 2.05-2.20(m,1H),3.02-3.72(m,3H),3.73-3.86(m,1H),3.80-4.02(m,1H),4.05-4.39(m,3H),4.45-4.69(m ,2H),7.35-7.40(m,1H),7.48(s,1H).

步骤5)(5S)-1-(叔丁氧羰基)-5-((4-碘-1H-吡唑-1-基)甲基)吡咯烷-3-醇Step 5) (5S)-1-(tert-butoxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidin-3-ol

将1-(((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基)-4-碘-1H-吡唑(200mg,0.42mmol)悬浮在四氢呋喃/水(5mL/5mL)的混合液中，向其中加入乙酸(1mL,16.8mmol)。反应液在70℃搅拌16小时。反应毕，冷却至室温。混合物用饱和碳酸钠溶液调节pH值为10，并用乙酸乙酯(50mL×3)萃取。将合并的有机相用无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/1)纯化，得到标题化合物为无色油状物(157mg,95%)。  1-(((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl)-4- Iodine-1H-pyrazole (200 mg, 0.42 mmol) was suspended in a mixture of tetrahydrofuran/water (5 mL/5 mL), and acetic acid (1 mL, 16.8 mmol) was added thereto. The reaction solution was stirred at 70°C for 16 hours. After the reaction was completed, it was cooled to room temperature. The mixture was adjusted to pH 10 with saturated sodium carbonate solution, and extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a colorless oil ( 157mg, 95%). the

LC-MS(ESI,pos.ion)m/z:394[M+H]+。  LC-MS (ESI, pos.ion) m/z: 394 [M+H] + .

步骤6)(S)-1-(叔丁氧羰基)-5-((4-碘-1H-吡唑-1-基)甲基)吡咯烷-3-酮Step 6) (S)-1-(tert-butoxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidin-3-one

将(5S)-1-(叔丁氧羰基)-5-((4-碘-1H-吡唑-1-基)甲基)吡咯烷-3-醇(1.39g,3.54mmol)悬浮在二氯甲烷(44mL)中，向其中加入Dess-Martin氧化剂(3g,7.07mmol)。反应液室温搅拌16小时，过滤。将滤液减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为白色固体(1.2g,87%)。  (5S)-1-(tert-butoxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidin-3-ol (1.39 g, 3.54 mmol) was suspended in Methyl chloride (44 mL), to which Dess-Martin oxidant (3 g, 7.07 mmol) was added. The reaction solution was stirred at room temperature for 16 hours and filtered. After the filtrate was concentrated under reduced pressure, it was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (1.2 g, 87%). the

1H NMR(400MHz,CDCl3)δ(ppm):1.49(s,9H),2.60-2.90(m,2H),2.90-3.29(m,1H),3.50-3.98(m,1H),4.20-4.27(m,1H),4.61(s,2H),7.34(s,1H),7.49(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.49 (s, 9H), 2.60-2.90 (m, 2H), 2.90-3.29 (m, 1H), 3.50-3.98 (m, 1H), 4.20- 4.27 (m, 1H), 4.61 (s, 2H), 7.34 (s, 1H), 7.49 (s, 1H).

步骤7)(S)-1-((1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-基)甲基)-4-碘-1H-吡唑Step 7) (S)-1-((1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl)-4-iodo-1H-pyrazole

将(S)-1-(叔丁氧羰基)-5-((4-碘-1H-吡唑-1-基)甲基)吡咯烷-3-酮(100mg,0.26mmol)溶解在二氯甲烷(3mL)中，降温至-78℃，向其中加入DAST(95%,0.15mL,1.04mmol)。反应液在-40°C搅拌2小时后，恢复至室温，继续搅拌21小时。反应毕，减压浓缩，将残留物用水(30mL)稀释，并用二氯甲烷(30mL×3)萃取。合并的有机相用盐水(30mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到目标产物为黄色油状物(100mg,93%)。  Dissolve (S)-1-(tert-butoxycarbonyl)-5-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidin-3-one (100mg, 0.26mmol) in dichloro In methane (3 mL), the temperature was lowered to -78°C, and DAST (95%, 0.15 mL, 1.04 mmol) was added thereto. The reaction solution was stirred at -40°C for 2 hours, then returned to room temperature, and stirred for 21 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was diluted with water (30 mL), and extracted with dichloromethane (30 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the target product as a yellow oil (100 mg, 93%). the

LC-MS(ESI,pos.ion)m/z:414[M+H]+；  LC-MS (ESI, pos.ion) m/z: 414[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.49(s,9H),2.29-2.70(m,2H),3.25-3.60(m,1H),3.60-3.98(m,1H),4.12-4.55(m,3H),7.44(s,1H),7.51(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.49 (s, 9H), 2.29-2.70 (m, 2H), 3.25-3.60 (m, 1H), 3.60-3.98 (m, 1H), 4.12- 4.55 (m, 3H), 7.44 (s, 1H), 7.51 (s, 1H).

步骤8)(S)-1-((1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3-二氧环戊烷-2-基)-1H-吡唑Step 8) (S)-1-((1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl Base-1,3-dioxolan-2-yl)-1H-pyrazole

将联硼酸频钠醇酯(128mg,0.504mmol)溶解在二甲亚砜(3mL)中，向其中加入(S)-1-((1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-基)甲基)-4-碘-1H-吡唑(80mg,0.194mmol)和乙酸钾(76mg,0.776mol)，将体系置于氮气氛中，继续向其中加入Pd(PPh3)2Cl2(16.3mg,0.023mmol)。反应液在80°C搅拌3小时后，冷却至室温，加水(30mL)稀释，并用乙酸 乙酯(30mL×3)萃取。合并的有机相经无水硫酸钠干燥，并减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=5/1)纯化，得到标题化合物为黄色油状物(30mg,37.5%)。  Diboronic acid pinadol ester (128 mg, 0.504 mmol) was dissolved in dimethyl sulfoxide (3 mL), and (S)-1-((1-(tert-butoxycarbonyl)-4,4-difluoro Pyrrolidin-2-yl)methyl)-4-iodo-1H-pyrazole (80mg, 0.194mmol) and potassium acetate (76mg, 0.776mol), the system was placed in a nitrogen atmosphere, and Pd(PPh 3 ) 2 Cl 2 (16.3 mg, 0.023 mmol). The reaction solution was stirred at 80° C. for 3 hours, cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound as a yellow oil (30mg ,37.5%).

LC-MS(ESI,pos.ion)m/z:414[M+H]+。  LC-MS (ESI, pos.ion) m/z: 414 [M+H] + .

步骤9)5-(1-(((S)-1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 9) 5-(1-(((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)- 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(195mg,0.51mmol)，(S)-1-((1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3-二氧环戊烷-2-基)-1H-吡唑(141mg,0.34mmol)和Pd(OAc)2(7.7mg,0.034mmol)悬浮在乙二醇二甲醚/水(3mL/0.5mL)中，向其中加入碳酸钠(145mg,1.37mmol)的水(0.5mL)溶液，氮气保护后，继续向体系内加入(t-Bu)3P(0.15mL,1M的甲苯溶液)。反应液在90°C搅拌13小时后，降至室温，加乙酸乙酯(40mL)稀释，并用硅藻土过滤，滤渣用乙酸乙酯(40mL)洗。收集滤液，经盐水(30mL×2)洗，减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/2)纯化，得到目标产物为黄色固体(80mg,44%)。  (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (195mg, 0.51mmol), (S)-1- ((1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3-dioxane Pentan-2-yl)-1H-pyrazole (141 mg, 0.34 mmol) and Pd(OAc) 2 (7.7 mg, 0.034 mmol) were suspended in ethylene glycol dimethyl ether/water (3 mL/0.5 mL) and added to A solution of sodium carbonate (145 mg, 1.37 mmol) in water (0.5 mL) was added thereto, and (t-Bu) 3 P (0.15 mL, 1M solution in toluene) was added to the system after nitrogen protection. After the reaction solution was stirred at 90°C for 13 hours, it was cooled to room temperature, diluted with ethyl acetate (40 mL), filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate (40 mL). The filtrate was collected, washed with brine (30mL×2), concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain the target product as a yellow solid (80mg, 44%).

LC-MS(ESI,pos.ion)m/z:586[M+H]+。  LC-MS (ESI, pos.ion) m/z: 586 [M+H] + .

步骤10)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(((S)-4,4-二氟吡咯烷-2-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Step 10) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(((S)-4,4-difluoropyrrolidine -2-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine

目标化合物通过实施例1步骤10所描述的方法制备得到，即将5-(1-(((S)-1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(140mg,0.24mmol)和HCl(2mL,3M的乙酸乙酯溶液)溶解在二氯甲烷(6mL)中制备，粗产品经硅胶柱层析(乙酸乙酯/甲醇(v/v)=20/1)纯化，得到标题化合物为黄色固体(80mg,69%)。  The target compound was prepared by the method described in step 10 of Example 1, that is, 5-(1-(((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl Base)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (140mg, 0.24mmol ) and HCl (2mL, 3M in ethyl acetate) were prepared by dissolving in dichloromethane (6mL), and the crude product was purified by silica gel column chromatography (ethyl acetate/methanol (v/v)=20/1) to obtain The title compound was a yellow solid (80 mg, 69%). the

LC-MS(ESI,pos.ion)m/z:243(M+1/2)；  LC-MS(ESI,pos.ion)m/z:243(M+1/2);

1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.87(d,J=6.5Hz,3H),1.95-2.10(m,1H),2.32-2.45(m,1H),3.12-3.35(m,2H),3.75-3.86(m,1H),4.06-4.18(m,1H),4.19-4.29(m,1H),4.84(s,2H),6.05-6.10(q,J=6.3Hz, 1H),6.86(s,1H),7.03-7.08(t,J=8.4Hz,1H),7.28-7.33(m,1H),7.51(s,1H),7.57(s,1H),7.75(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.85-1.87 (d, J=6.5Hz, 3H), 1.95-2.10 (m, 1H), 2.32-2.45 (m, 1H), 3.12-3.35 ( m,2H),3.75-3.86(m,1H),4.06-4.18(m,1H),4.19-4.29(m,1H),4.84(s,2H),6.05-6.10(q,J=6.3Hz, 1H),6.86(s,1H),7.03-7.08(t,J=8.4Hz,1H),7.28-7.33(m,1H),7.51(s,1H),7.57(s,1H),7.75(s ,1H).

实施例12(5S)-5-((4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)甲基)吡咯烷-3-醇Example 12 (5S)-5-((4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)methyl)pyrrolidin-3-ol

Figure BDA00002905454701011
Figure BDA00002905454701011

步骤1)1-(((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3-二氧杂环戊硼烷-2-基)-1H-吡唑Step 1) 1-(((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methyl)- 4-(4,4,5,5-Tetramethyl-1,3-dioxaborolan-2-yl)-1H-pyrazole

标题化合物通过实施例11步骤8所描述的方案制备得到，即将1-(((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基)-4-碘-1H-吡唑(100mg,0.21mmol)，联硼酸频钠醇酯(140mg,0.54mmol)，Pd(PPh3)2Cl2(16mg,0.23mmol)和乙酸钾(82mg,0.84mol)悬浮在二甲亚砜(3mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/4)纯化，得到目标化合物为白色固体(80mg,80%)。  The title compound was prepared by the scheme described in step 8 of Example 11, that is, 1-(((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy base) pyrrolidin-2-yl) methyl) -4-iodo-1H-pyrazole (100mg, 0.21mmol), pinazolate diboronate (140mg, 0.54mmol), Pd(PPh 3 ) 2 Cl 2 ( 16mg, 0.23mmol) and potassium acetate (82mg, 0.84mol) were suspended in dimethyl sulfoxide (3mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/4) Purification afforded the title compound as a white solid (80 mg, 80%).

LC-MS(ESI,pos.ion)m/z:477[M+H]+；  LC-MS (ESI, pos.ion) m/z: 477[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.25-1.27(m,12H),1.40-1.59(m,13H),1.60-1.85(m,3H),1.95-2.05(m,1H),2.05-2.22(m,1H),2.98-3.72(m,3H),3.73-3.86(m,1H),3.80-4.02(m,1H),4.05-4.30(m,2H),4.31-4.42(m,1H),4.43-4.62(m,2H),7.62-7.70(s,1H),7.75-7.76(m,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.25-1.27 (m, 12H), 1.40-1.59 (m, 13H), 1.60-1.85 (m, 3H), 1.95-2.05 (m, 1H), 2.05-2.22(m,1H),2.98-3.72(m,3H),3.73-3.86(m,1H),3.80-4.02(m,1H),4.05-4.30(m,2H),4.31-4.42(m ,1H), 4.43-4.62(m,2H), 7.62-7.70(s,1H), 7.75-7.76(m,1H).

步骤2)5-(1-(((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 2) 5-(1-(((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl)methanol Base)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

标题化合物通过实施例11步骤9描述的方案制备得到，即将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(96mg,0.25mmol)， 1-(((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基)-4-(4,4,5,5-四甲基-1,3-二氧杂环戊硼烷-2-基)-1H-吡唑(100mg,0.21mmol)，Pd(OAc)2(4.7mg,0.021mmol)，碳酸钠(89mg,0.84mmol)和(t-Bu)3P(0.06mL,1M的甲苯溶液)悬浮在乙二醇二甲醚/水(3mL/0.5mL)的混合液中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/1)纯化，得到标题化合物为黄色固体(60mg,44%)。  The title compound was prepared by the scheme described in step 9 of Example 11, namely (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2- Amine (96mg, 0.25mmol), 1-(((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)pyrrolidin-2-yl )methyl)-4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)-1H-pyrazole (100mg, 0.21mmol), Pd( OAc) 2 (4.7mg, 0.021mmol), sodium carbonate (89mg, 0.84mmol) and (t-Bu) 3 P (0.06mL, 1M solution in toluene) were suspended in ethylene glycol dimethyl ether/water (3mL/0.5 mL), the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain the title compound as a yellow solid (60 mg, 44%).

LC-MS(ESI,pos.ion)m/z:650[M+H]+；  LC-MS (ESI, pos.ion) m/z: 650[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.45-1.59(m,13H),1.60-1.70(m,2H),1.70-1.95(m,1H),1.95-2.20(m,2H),3.02-3.25(m,1H),3.25-3.52(m,2H),3.52-4.02(m,2H),4.15-4.39(m,3H),4.45-4.69(m,2H),4.79(s,2H),6.05-6.10(q,J=6.6Hz,1H),6.84-6.87(m,1H),7.03-7.07(t,J=8.7Hz,1H),7.29-7.33(m,1H),7.35-7.45(m,1H),7.52-7.60(m,1H),7.74(d,J=1.5Hz,1H).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.45-1.59 (m, 13H), 1.60-1.70 (m, 2H), 1.70-1.95 (m, 1H), 1.95-2.20 (m, 2H), 3.02-3.25(m,1H),3.25-3.52(m,2H),3.52-4.02(m,2H),4.15-4.39(m,3H),4.45-4.69(m,2H),4.79(s,2H ),6.05-6.10(q,J=6.6Hz,1H),6.84-6.87(m,1H),7.03-7.07(t,J=8.7Hz,1H),7.29-7.33(m,1H),7.35- 7.45(m,1H),7.52-7.60(m,1H),7.74(d,J=1.5Hz,1H).

步骤3)(5S)-5-((4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)甲基)吡咯烷-3-醇Step 3) (5S)-5-((4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl )-1H-pyrazol-1-yl)methyl)pyrrolidin-3-ol

目标化合物通过实施例1步骤10所描述的方法制备得到，即将5-(1-(((2S)-1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)吡咯烷-2-基)甲基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(250mg,0.385mmol)和HCl(3.5mL,3M的乙酸乙酯溶液)溶解在二氯甲烷(12mL)中制备，粗产品经硅胶柱层析(乙酸乙酯/甲醇(v/v)=5/1)纯化，得到标题化合物为黄色固体(120mg,67%)。  The target compound was prepared by the method described in step 10 of Example 1, that is, 5-(1-(((2S)-1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2- Base)oxy)pyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethyl Oxy)pyridin-2-amine (250mg, 0.385mmol) and HCl (3.5mL, 3M solution in ethyl acetate) were prepared by dissolving in dichloromethane (12mL), and the crude product was subjected to silica gel column chromatography (ethyl acetate/ Purification with methanol (v/v)=5/1) gave the title compound as a yellow solid (120 mg, 67%). the

LC-MS(ESI,pos.ion)m/z:233(M+1/2)；  LC-MS(ESI,pos.ion)m/z:233(M+1/2);

1H NMR(400MHz,CDCl3)δ(ppm):1.41-1.50(m,1H),1.59-1.65(m,1H),1.80(d,J=6.6Hz,3H),1.89(s,1H),2.62-2.65(m,1H),2.84-2.89(m,1H),3.55-3.62(m,1H),3.96-3.96(d,J=6.2Hz,2H),4.11-4.18(m,1H),4.57(s,1H),5.65(s,2H),6.06-6.11(q,J=6.6Hz,1H),6.87-6.88(d,J=1.6Hz,1H),7.42-7.47(t,J=8.8Hz,1H),7.51(s,1H),7.55-7.59(m,1H),7.73-7.74(d,J=1.7Hz,1H),7.87(s,1H)。  1 H NMR(400MHz,CDCl 3 )δ(ppm):1.41-1.50(m,1H),1.59-1.65(m,1H),1.80(d,J=6.6Hz,3H),1.89(s,1H) ,2.62-2.65(m,1H),2.84-2.89(m,1H),3.55-3.62(m,1H),3.96-3.96(d,J=6.2Hz,2H),4.11-4.18(m,1H) ,4.57(s,1H),5.65(s,2H),6.06-6.11(q,J=6.6Hz,1H),6.87-6.88(d,J=1.6Hz,1H),7.42-7.47(t,J =8.8Hz, 1H), 7.51(s, 1H), 7.55-7.59(m, 1H), 7.73-7.74(d, J=1.7Hz, 1H), 7.87(s, 1H).

实施例13Example 13

4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)四氢-2H-吡喃-3-醇(13a)4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole-1 -yl)tetrahydro-2H-pyran-3-ol (13a)

3-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)四氢-2H-吡喃-4-醇(13b)3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole-1 -yl)tetrahydro-2H-pyran-4-ol (13b)

步骤1)3,6-二氢-2H-吡喃Step 1) 3,6-Dihydro-2H-pyran

将四氢-2H-吡喃-4-醇(20.4g,0.2mol)和三乙胺(36.2mL,0.26mol)溶解在二氯甲烷(200mL)中，降温至0°C，向其中加入甲磺酰氯(17mL,0.22mol)。反应液室温搅拌3小时后，倒入水(100mL)中。分离的有机相经盐水(100mL×2)洗，无水硫酸钠干燥，并减压浓缩得到橙色油状物。将该油状物加热至50°C，然后向其中滴加DBU(40mL)。混合物在100°C搅拌2小时。残留物经减压蒸馏(92-93°C)纯化，得到标题化合物为无色液体(10.0g,60%)。  Dissolve tetrahydro-2H-pyran-4-ol (20.4g, 0.2mol) and triethylamine (36.2mL, 0.26mol) in dichloromethane (200mL), cool down to 0°C, add formaldehyde Sulfonyl chloride (17 mL, 0.22 mol). After stirring the reaction solution at room temperature for 3 hours, it was poured into water (100 mL). The separated organic phase was washed with brine (100 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an orange oil. The oil was heated to 50° C., then DBU (40 mL) was added dropwise thereto. The mixture was stirred at 100°C for 2 hours. The residue was purified by distillation under reduced pressure (92-93°C) to give the title compound as a colorless liquid (10.0 g, 60%). the

GC-MS m/z:84(M)。  GC-MS m/z: 84(M). the

步骤2)3,7-二氧杂双环[4.1.0]庚烷Step 2) 3,7-dioxabicyclo[4.1.0]heptane

将m-CPBA(25.6g,296mmol)悬浮在二氯甲烷(200mL)中，降温至0°C，向其中滴加3,6-二氢-2H-吡喃(8.3g,98.7mmol)。反应液室温搅拌过夜。反应毕，减压浓缩，残留物用二氯甲烷(30mL)稀释。将混合物冷却至0°C，过滤，滤液经减压浓缩得到标题化合物为无色油状物(7.5g,76%)。  m-CPBA (25.6g, 296mmol) was suspended in dichloromethane (200mL), cooled to 0°C, and 3,6-dihydro-2H-pyran (8.3g, 98.7mmol) was added dropwise thereto. The reaction solution was stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, and the residue was diluted with dichloromethane (30 mL). The mixture was cooled to 0°C, filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (7.5 g, 76%). the

GC-MS m/z:100(M)。  GC-MS m/z: 100(M). the

步骤3)step 3)

3-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-pyran-4-ol(13.3a)3-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-pyran-4-ol (13.3a)

4-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-pyran-3-ol(13.3b)4-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-pyran-3-ol(13.3b)

将氢化钠(1.6g,40.0mmol,60%分散在矿物油中)悬浮在N,N-二甲基甲酰胺(30mL)中，降温至0°C，向其中加入4-碘-1H-吡唑(5.8g,30.0mmol)。混合物在0°C搅拌2.5小时后，继续向其中加入3,7-二氧杂双环[4.1.0]庚烷(2.0g,20.0mmol)的N,N-二甲基甲酰胺(5mL)溶液。反应液在100°C搅拌18小时后，减压浓缩。将残留物分散在乙酸乙酯(300mL)和水(150mL)中，分离水相，并用乙酸乙酯(300mL)萃取。合并的有机相经无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=3/1)纯化，得到(13.3a)和(13.3b)的混合物为黄色油状物(4.2g,36%)。  Sodium hydride (1.6g, 40.0mmol, 60% dispersed in mineral oil) was suspended in N,N-dimethylformamide (30mL), cooled to 0°C, and 4-iodo-1H-pyridine was added Azole (5.8 g, 30.0 mmol). After the mixture was stirred at 0°C for 2.5 hours, a solution of 3,7-dioxabicyclo[4.1.0]heptane (2.0 g, 20.0 mmol) in N,N-dimethylformamide (5 mL) was further added thereto . The reaction solution was stirred at 100°C for 18 hours, then concentrated under reduced pressure. The residue was dispersed in ethyl acetate (300 mL) and water (150 mL), the aqueous phase was separated and extracted with ethyl acetate (300 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain (13.3a) and (13.3b) The mixture was a yellow oil (4.2 g, 36%). the

LC-MS(ESI,pos.ion)m/z:295[M+H]+。  LC-MS (ESI, pos.ion) m/z: 295 [M+H] + .

步骤4step 4

4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)四氢-2H-吡喃-3-醇(13a)4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole-1 -yl)tetrahydro-2H-pyran-3-ol (13a)

3-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)四氢-2H-吡喃-4-醇(13b)3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole-1 -yl)tetrahydro-2H-pyran-4-ol (13b)

将(13.3a)和(13.3b)的混合物(530mg,1.8mmol)溶解在乙二醇 二甲醚(25mL)中，向其中加入(R)-N,N-双(叔丁氧羰基)-3-(1-(2,6-二氯-3-氟苯基)乙氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶-2-胺(941mg,1.5mmol)和碳酸铯(1467mg,4.5mmol)的水(5mL)溶液，氮气保护后，继续向体系内加入Pd(dppf)Cl2·CH2Cl2(122mg,0.15mmol)。反应液在90°C搅拌18小时。反应毕，倒入盐水(50mL)中，并用乙酸乙酯(100mL×3)萃取。合并的有机相经无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为类白色固体。将该固体溶解在二氯甲烷(20mL)中，降温至0°C，向其中加入HCl(3mL,3M的乙酸乙酯溶液)。反应液室温搅拌过夜，减压浓缩。残留物用水(15mL)稀释，加饱和碳酸钠溶液调节pH10，并用乙酸乙酯(100mL×3)萃取混合液。合并的有机相经无水硫酸钠干燥，减压浓缩后，用乙醚(5mL)洗，得到(13a)和(13b)的混合物为褐色固体(55mg,7%)。  The mixture (530 mg, 1.8 mmol) of (13.3a) and (13.3b) was dissolved in ethylene glycol dimethyl ether (25 mL), and (R)-N,N-bis(tert-butoxycarbonyl)- 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane Borane-2-yl)pyridin-2-amine (941mg, 1.5mmol) and cesium carbonate (1467mg, 4.5mmol) in water (5mL) solution, after nitrogen protection, continue to add Pd(dppf)Cl 2 in the system. CH2Cl2 ( 122 mg, 0.15 mmol). The reaction was stirred at 90°C for 18 hours. After the reaction was completed, it was poured into brine (50 mL), and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as an off-white solid. The solid was dissolved in dichloromethane (20 mL), cooled to 0° C., and HCl (3 mL, 3M in ethyl acetate) was added thereto. The reaction solution was stirred overnight at room temperature and concentrated under reduced pressure. The residue was diluted with water (15 mL), adjusted to pH 10 by adding saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and washed with diethyl ether (5 mL) to give a mixture of (13a) and (13b) as a brown solid (55 mg, 7%).

LC-MS(ESI,pos.ion)m/z:467[M+H]+。  LC-MS (ESI, pos.ion) m/z: 467 [M+H] + .

实施例143-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(5-氟哌啶-3-基)-1H-吡唑-4-基)吡啶-2-胺Example 143-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(5-fluoropiperidin-3-yl)-1H-pyridine Azol-4-yl)pyridin-2-amine

Figure BDA00002905454701051
Figure BDA00002905454701051

步骤1)1-(叔丁氧羰基)哌啶-4-基甲磺酸酯Step 1) 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate

将1-(叔丁氧羰基)哌啶-4-醇(10g,49.3mmol)和三乙胺(10g,74mmol)溶解在二氯甲烷(150mL)中，降温至0℃后，向其中滴加甲磺酰氯(8.6g,59mmol)。反应液在室温搅拌2小时。反应毕，将混合液用二氯甲烷(100mL)稀释，依次用饱和碳酸钠溶液(250mL)、盐水(250 mL)洗。有机相经无水硫酸钠干燥，并减压浓缩，得到粗产品为黄色油状物(14g,97%)，该化合物不经纯化，直接用于下一步反应。  Dissolve 1-(tert-butoxycarbonyl)piperidin-4-ol (10g, 49.3mmol) and triethylamine (10g, 74mmol) in dichloromethane (150mL), cool to 0°C, add dropwise Methanesulfonyl chloride (8.6 g, 59 mmol). The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with dichloromethane (100 mL), and washed successively with saturated sodium carbonate solution (250 mL) and brine (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a yellow oil (14 g, 97%), which was directly used in the next reaction without further purification. the

步骤2)1-(叔丁氧羰基)-1,2,3,6-四氢吡啶Step 2) 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine

将1-(叔丁氧羰基)哌啶-4-基甲磺酸酯(14g,48mmol)的DBU(80mL)溶液加热到80℃，搅拌16小时。反应毕，冷却至室温，加水(200mL)稀释，并用乙酸乙酯(150mL x3)萃取，合并的有机相依次用1M盐酸(450mL×3)、饱和碳酸钠溶液(450mL×2)洗。所得溶液经无水硫酸钠干燥，并减压浓缩得到标题化合物为棕色油状物(8g,100%)，该化合物不经纯化，直接用于下一步。  A solution of 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate (14 g, 48 mmol) in DBU (80 mL) was heated to 80° C. and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (200mL), and extracted with ethyl acetate (150mL x 3). The combined organic phase was washed with 1M hydrochloric acid (450mL x 3) and saturated sodium carbonate solution (450mL x 2). The resulting solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a brown oil (8 g, 100%), which was directly used in the next step without purification. the

LC-MS(ESI,pos.ion)m/z:128[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 128[M+H-56] + ;

1H NMR(400MHz,CDCl3)δ(ppm):5.83-5.80(m,1H),5.66(m,1H),3.87(m,2H),3.49-3.47(t,J=5.2Hz,2H),2.13(m,2H),1.47(s,9H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):5.83-5.80(m,1H),5.66(m,1H),3.87(m,2H),3.49-3.47(t,J=5.2Hz,2H) ,2.13(m,2H),1.47(s,9H).

步骤3)3-(叔丁氧羰基)-7-氧杂-3-氮杂双环[4.1.0]庚烷Step 3) 3-(tert-butoxycarbonyl)-7-oxa-3-azabicyclo[4.1.0]heptane

将m-CPBA(20g,87.4mmol)溶解在二氯甲烷(150mL)中，降温至0℃，向其中滴加1-(叔丁氧羰基)-1,2,3,6-四氢吡啶(8g,43.7mmol)。反应液室温搅拌14小时。反应毕，过滤。滤饼用二氯甲烷(50mL×2)洗，合并的滤液用饱和碳酸钠溶液(300mL×2)洗。所得溶液经无水硫酸钠干燥，并减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为无色油状物(8g,93%)。  Dissolve m-CPBA (20g, 87.4mmol) in dichloromethane (150mL), cool down to 0°C, and dropwise add 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine ( 8g, 43.7mmol). The reaction solution was stirred at room temperature for 14 hours. After the reaction, filter. The filter cake was washed with dichloromethane (50 mL×2), and the combined filtrate was washed with saturated sodium carbonate solution (300 mL×2). The resulting solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a colorless oil (8g, 93%). the

1H NMR(400MHz,CDCl3)δ(ppm):3.92-3.82(m,1H),3.71(m,1H),3.44(m,1H),3.29-3.28(m,1H),3.21-3.10(m,2H),2.04(m,1H),1.95-1.88(m,1H),1.45(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 3.92-3.82 (m, 1H), 3.71 (m, 1H), 3.44 (m, 1H), 3.29-3.28 (m, 1H), 3.21-3.10 ( m, 2H), 2.04(m, 1H), 1.95-1.88(m, 1H), 1.45(s, 9H).

步骤4)1-(叔丁氧羰基)-4-碘哌啶-3-醇Step 4) 1-(tert-butoxycarbonyl)-4-iodopiperidin-3-ol

将3-(叔丁氧羰基)-7-氧杂-3-氮杂双环[4.1.0]庚烷(100mg,0.5mmol)溶解在N,N-二甲基甲酰胺(5mL)，冰浴冷却后，向其中ISiMe3(0.078mL,0.55mmol)。反应液室温搅拌过夜。反应毕，加乙酸乙酯(50mL)稀释，依次用1M盐酸(25mL×2)、饱和碳酸钠溶液(20mL×2)洗。混合液经无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为黄色油状物(60mg,37%)。  Dissolve 3-(tert-butoxycarbonyl)-7-oxa-3-azabicyclo[4.1.0]heptane (100mg, 0.5mmol) in N,N-dimethylformamide (5mL), ice bath After cooling, SiMe 3 (0.078 mL, 0.55 mmol) was added to it. The reaction solution was stirred overnight at room temperature. After the reaction was completed, dilute with ethyl acetate (50 mL), and wash with 1M hydrochloric acid (25 mL×2) and saturated sodium carbonate solution (20 mL×2) successively. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a yellow oil (60 mg, 37%).

LC-MS(ESI,pos.ion)m/z:350[M+Na]+,254[M+H-56-18]+；  LC-MS (ESI, pos.ion) m/z: 350[M+Na] + ,254[M+H-56-18] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),2.05-2.16(m,1H),2.33-2.39(m,1H),2.59-3.00(m,3H),3.65-3.87(m,2H),4.05-4.11(m,1H),4.17-4.21(m,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.46 (s, 9H), 2.05-2.16 (m, 1H), 2.33-2.39 (m, 1H), 2.59-3.00 (m, 3H), 3.65- 3.87 (m, 2H), 4.05-4.11 (m, 1H), 4.17-4.21 (m, 1H).

步骤5)1-(叔丁氧羰基)-4-碘-3-((四氢-2H-吡喃-2-基)氧基)哌啶Step 5) 1-(tert-butoxycarbonyl)-4-iodo-3-((tetrahydro-2H-pyran-2-yl)oxy)piperidine

将1-(叔丁氧羰基)-4-碘哌啶-3-醇(1g,3.1mmol)，PPTS(77mg,0.31mmol)悬浮在二氯甲烷(20mL)中，向其中加入DHP(0.56mL,9.4mmol)。反应液室温搅拌过夜。反应毕，减压浓缩，所得残留物用硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为无色油状物(1.0g,80%)。  1-(tert-butoxycarbonyl)-4-iodopiperidin-3-ol (1 g, 3.1 mmol), PPTS (77 mg, 0.31 mmol) were suspended in dichloromethane (20 mL), and DHP (0.56 mL ,9.4mmol). The reaction solution was stirred overnight at room temperature. After the reaction was complete, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a colorless oil (1.0 g, 80%). the

LC-MS(ESI,pos.ion)m/z:434[M+Na]+；  LC-MS (ESI, pos.ion) m/z: 434[M+Na] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.45(s,9H),1.54-1.82(m,4H),1.82-2.14(m,2H),2.27-2.41(m,1H),2.80-3.05(m,1H),3.30-3.59(m,3H),3.59-3.78(m,1H),3.79-3.95(m,2H),3.98-4.15(m,1H),4.15-4.39(m,1H),4.81-4.96(m,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.45 (s, 9H), 1.54-1.82 (m, 4H), 1.82-2.14 (m, 2H), 2.27-2.41 (m, 1H), 2.80- 3.05(m,1H),3.30-3.59(m,3H),3.59-3.78(m,1H),3.79-3.95(m,2H),3.98-4.15(m,1H),4.15-4.39(m,1H ), 4.81-4.96 (m, 1H).

步骤6)1-(叔丁氧羰基)-3-((四氢-2H-吡喃-2-基)氧基)-1,2,3,6-四氢吡啶Step 6) 1-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,6-tetrahydropyridine

向1-(叔丁氧羰基)-4-碘-3-((四氢-2H-吡喃-2-基)氧基)哌啶(7.7g,18.7mmol)中加入DBU(50mL)。反应液在80°C搅拌27小时。反应毕，冷却至室温，加乙酸乙酯(50mL)稀释。混合液依次用1M盐酸(50mL×3)、饱和碳酸钠溶液(50mL×2)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=15/1)纯化，得到标题化合物为无色油状物(4.2g,72%)。  To 1-(tert-butoxycarbonyl)-4-iodo-3-((tetrahydro-2H-pyran-2-yl)oxy)piperidine (7.7 g, 18.7 mmol) was added DBU (50 mL). The reaction was stirred at 80°C for 27 hours. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed successively with 1M hydrochloric acid (50 mL×3), saturated sodium carbonate solution (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=15/1) to obtain the title compound as a colorless oil (4.2 g, 72%). the

LC-MS(ESI,pos.ion)m/z:306[M+Na]+；  LC-MS (ESI, pos.ion) m/z: 306[M+Na] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.47(s,9H),1.50-1.68(m,4H),1.69-1.79(m,1H),1.79-1.90(m,1H),3.30-4.15(m,6H),4.15-4.32(m,1H),4.70-4.85(m,1H),5.82-5.93(m,2H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.47 (s, 9H), 1.50-1.68 (m, 4H), 1.69-1.79 (m, 1H), 1.79-1.90 (m, 1H), 3.30- 4.15 (m, 6H), 4.15-4.32 (m, 1H), 4.70-4.85 (m, 1H), 5.82-5.93 (m, 2H).

步骤7)1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-3-醇Step 7) 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-3-ol

将1-(叔丁氧羰基)-3-((四氢-2H-吡喃-2-基)氧基)-1,2,3,6-四氢吡啶 (500mg,1.64mmol)溶解在二氯甲烷/甲醇(25mL/5mL)混合液中，冷却至0°C，向其中缓慢加入HCl(11mL,3M的乙酸乙酯溶液)。反应液室温搅拌过夜后，减压浓缩得到粗产品，并将该产品直接溶解在四氢呋喃/水(76mL/60mL)的混合液中。将溶液用饱和碳酸钠溶液调节pH10，向其中加入Boc酸酐(1.5mL)。反应液室温搅拌过夜。反应毕，加乙酸乙酯/水(30mL/30mL)稀释，分离的水相用乙酸乙酯(80mL×2)萃取。合并的有机相经无水硫酸钠干燥，并减压浓缩后，用硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为无色油状物(0.30g,92%)。  Dissolve 1-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,6-tetrahydropyridine (500 mg, 1.64 mmol) in Methyl chloride/methanol (25mL/5mL) mixture was cooled to 0°C, and HCl (11mL, 3M solution in ethyl acetate) was slowly added thereto. After the reaction solution was stirred overnight at room temperature, it was concentrated under reduced pressure to obtain a crude product, which was directly dissolved in a mixture of tetrahydrofuran/water (76 mL/60 mL). The solution was adjusted to pH 10 with saturated sodium carbonate solution, and Boc anhydride (1.5 mL) was added thereto. The reaction solution was stirred overnight at room temperature. After the reaction was completed, it was diluted with ethyl acetate/water (30 mL/30 mL), and the separated aqueous phase was extracted with ethyl acetate (80 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a colorless oil (0.30 g, 92%). the

MS(ESI,pos.ion)m/z:126[M+H-56-18]+。  MS (ESI, pos.ion) m/z: 126 [M+H-56-18] + .

步骤8)1-(叔丁氧羰基)-1,6-二氢吡啶-3(2H)-酮Step 8) 1-(tert-butoxycarbonyl)-1,6-dihydropyridin-3(2H)-one

将1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-3-醇(350mg,1.76mmol)溶解在二氯甲烷(12mL)中，向其中加入Dess-Martin氧化剂(1.5g,3.52mmol)。反应液室温搅拌2小时后，过滤。滤液用饱和碳酸钠溶液(50mL)洗，并减压浓缩，所得残留物经硅胶层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为无色油状物(340mg,98%)。  1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-3-ol (350 mg, 1.76 mmol) was dissolved in dichloromethane (12 mL), and Dess-Martin oxidant (1.5 g, 3.52 mmol). After the reaction solution was stirred at room temperature for 2 hours, it was filtered. The filtrate was washed with saturated sodium carbonate solution (50 mL), and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a colorless oil (340 mg, 98%). the

LC-MS(ESI,pos.ion)m/z:142[M+H-56]+,220[M+Na]+；  LC-MS (ESI, pos.ion) m/z: 142[M+H-56] + ,220[M+Na] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.48(s,9H),4.11(s,2H),4.24(s,2H),6.16-6.20(m,1H),7.04(s,1H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm): 1.48(s,9H),4.11(s,2H),4.24(s,2H),6.16-6.20(m,1H),7.04(s,1H) .

步骤9)1-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)哌啶-3-酮Step 9) 1-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)piperidin-3-one

将4-碘-1H-吡唑(389.9mg,2.01mmol)溶解在乙腈(6mL)中，向其中加入1-(叔丁氧羰基)-1,6-二氢吡啶-3(2H)-酮(260mg,1.34mmol)。反应液在80°C搅拌过夜。反应毕，冷却至室温，加水(20mL)稀释，并用乙酸乙酯(30mL×2)萃取。合并的有机相经无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为白色固体(110mg,21%)。  4-iodo-1H-pyrazole (389.9 mg, 2.01 mmol) was dissolved in acetonitrile (6 mL), and 1-(tert-butoxycarbonyl)-1,6-dihydropyridin-3(2H)-one was added thereto (260 mg, 1.34 mmol). The reaction was stirred overnight at 80°C. After the reaction was completed, it was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a white solid (110 mg, 21%). the

LC-MS(ESI,pos.ion)m/z:336[M+H-56]+,414[M+Na]+；  LC-MS (ESI, pos.ion) m/z: 336[M+H-56] + , 414[M+Na] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.39(s,9H),2.86-2.92(m,1H),2.80-3.05(m,1H),3.09-3.15(m,1H),3.50-4.42(m,4H),4.78-4.82(m,1H), 7.49(s,1H),7.51(s,1H).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.39 (s, 9H), 2.86-2.92 (m, 1H), 2.80-3.05 (m, 1H), 3.09-3.15 (m, 1H), 3.50- 4.42(m,4H),4.78-4.82(m,1H), 7.49(s,1H),7.51(s,1H).

步骤10)1-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)哌啶-3-醇Step 10) 1-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)piperidin-3-ol

将1-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)哌啶-3-酮(3.45g,8.82mmol)溶解在甲醇(50mL)中，冷却至0℃，向其中加入硼氢化钠(670mg,17.64mmol)。反应液室温搅拌1小时。反应毕，加饱和氯化铵溶液(50mL)淬灭，并用乙酸乙酯(100mL×2)萃取。合并的有机相经无水硫酸钠干燥，并减压浓缩后，用硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为白色固体(2.1g,60.7%)。  Dissolve 1-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)piperidin-3-one (3.45g, 8.82mmol) in methanol (50mL) and cool to 0 °C, sodium borohydride (670 mg, 17.64 mmol) was added thereto. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, it was quenched by adding saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a white solid (2.1 g, 60.7% ). the

LC-MS(ESI,pos.ion)m/z:394[M+H]+。  LC-MS (ESI, pos.ion) m/z: 394 [M+H] + .

步骤11)1-(叔丁氧羰基)-3-氟-5-(4-碘-1H-吡唑-1-基)哌啶Step 11) 1-(tert-butoxycarbonyl)-3-fluoro-5-(4-iodo-1H-pyrazol-1-yl)piperidine

标题化合物可以通过实施例11步骤7所描述的方法制备得到，即将1-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)哌啶-3-醇(240mg,0.61mmol)，DAST(95%,0.15mL,1.04mmol)溶解在二氯甲烷(5mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到目标产物为黄色固体(900mg,45%)。  The title compound can be prepared by the method described in step 7 of Example 11, that is, 1-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)piperidin-3-ol (240mg , 0.61mmol), DAST (95%, 0.15mL, 1.04mmol) was prepared by dissolving in dichloromethane (5mL), and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1), The target product was obtained as a yellow solid (900 mg, 45%). the

MS(ESI,pos.ion)m/z:340[M+H-56]+。  MS (ESI, pos.ion) m/z: 340 [M+H-56] + .

步骤12)1-(叔丁氧羰基)-3-氟-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶Step 12) 1-(tert-butoxycarbonyl)-3-fluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Base)-1H-pyrazol-1-yl)piperidine

目标化合物通过实施例11步骤8所描述的步骤制备得到，即将1-(叔丁氧羰基)-3-氟-5-(4-碘-1H-吡唑-1-基)哌啶(900mg,2.07mmol)，联硼酸频钠醇酯(1.04g,4.14mmol)，Pd(PPh3)2Cl2(174.6mg,0.12mmol)和乙酸钾(608mg,6.21mol)悬浮在二甲亚砜(50mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=5/1)纯化，得到目标产物为黄色油状物(650mg,72%)。  The target compound was prepared by the steps described in step 8 of Example 11, that is, 1-(tert-butoxycarbonyl)-3-fluoro-5-(4-iodo-1H-pyrazol-1-yl)piperidine (900mg, 2.07mmol), pinazolate diboronate (1.04g, 4.14mmol), Pd(PPh 3 ) 2 Cl 2 (174.6mg, 0.12mmol) and potassium acetate (608mg, 6.21mol) were suspended in dimethyl sulfoxide (50mL ), the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1), and the target product was obtained as a yellow oil (650 mg, 72%).

LC-MS(ESI,pos.ion)m/z:396[M+H]+。  LC-MS (ESI, pos. ion) m/z: 396 [M+H] + .

步骤13)5-(1-(1-(叔丁氧羰基)-5-氟哌啶-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 13) 5-(1-(1-(tert-butoxycarbonyl)-5-fluoropiperidin-3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2 ,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

目标化合物通过实施例11步骤9所描述的步骤制备得到，即将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(195mg,0.5139mmol)， 1-(叔丁氧羰基)-3-氟-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶(521.5mg,1.32mmol)，Pd(OAc)2(35.5mg,mmol)，碳酸钠(560mg,5.28mmol)和(t-Bu)3P(0.15mL,1M的甲苯溶液)悬浮在乙二醇二甲醚/水(15mL/4mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/1)纯化，得到标题化合物为黄色固体(350mg,47%)。  The target compound was prepared by the steps described in step 9 of Example 11, that is, (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2 -amine (195mg, 0.5139mmol), 1-(tert-butoxycarbonyl)-3-fluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxane Pentaboran-2-yl)-1H-pyrazol-1-yl)piperidine (521.5mg, 1.32mmol), Pd(OAc) 2 (35.5mg, mmol), sodium carbonate (560mg, 5.28mmol) and ( t-Bu) 3 P (0.15mL, 1M solution in toluene) was suspended in ethylene glycol dimethyl ether/water (15mL/4mL), and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/ v)=1/1) Purification afforded the title compound as a yellow solid (350 mg, 47%).

MS(ESI,pos.ion)m/z:568[M+H]+。  MS (ESI, pos.ion) m/z: 568 [M+H] + .

步骤14)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(5-氟哌啶-3-基)-1H-吡唑-4-基)吡啶-2-胺Step 14) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(5-fluoropiperidin-3-yl)-1H- Pyrazol-4-yl)pyridin-2-amine

目标化合物通过实施例1步骤10所描述的方法制备得到，即将5-(1-(1-(叔丁氧羰基)-5-氟哌啶-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(350mg,0.62mmol)和HCl(4mL,3M的乙酸乙酯溶液)溶解在二氯甲烷(6mL)中制备，粗产品经硅胶柱层析(乙酸乙酯/甲醇(v/v)=6/1)纯化，得到标题化合物为黄色固体(235mg,81%)。  The target compound was prepared by the method described in step 10 of Example 1, that is, 5-(1-(1-(tert-butoxycarbonyl)-5-fluoropiperidin-3-yl)-1H-pyrazol-4-yl )-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (350mg, 0.62mmol) and HCl (4mL, 3M in ethyl acetate solution) was prepared by dissolving in dichloromethane (6mL), and the crude product was purified by silica gel column chromatography (ethyl acetate/methanol (v/v)=6/1) to obtain the title compound as a yellow solid (235mg, 81%) . the

LC-MS(ESI,pos.ion)m/z:234.5(M+1/2)；  LC-MS(ESI,pos.ion)m/z:234.5(M+1/2);

1H NMR(400MHz,CDCl3)δ(ppm):1.86-1.88(d,J=6.6Hz,3H),2.16-2.24(m,1H),2.59-2.75(m,1H),2.90-3.00(m,1H),3.25-339(m,2H),4.20-4.32(m,1H),4.53-4.75(m,1H),4.83(s,2H),6.06-6.11(q,J=6.5Hz,1H),6.88(s,1H),7.04-7.08(t,J=8.4Hz,1H),7.28-7.33(m,1H),7.54(s,1H),7.58(s,1H),7.77(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.86-1.88 (d, J=6.6Hz, 3H), 2.16-2.24 (m, 1H), 2.59-2.75 (m, 1H), 2.90-3.00 ( m,1H),3.25-339(m,2H),4.20-4.32(m,1H),4.53-4.75(m,1H),4.83(s,2H),6.06-6.11(q,J=6.5Hz, 1H),6.88(s,1H),7.04-7.08(t,J=8.4Hz,1H),7.28-7.33(m,1H),7.54(s,1H),7.58(s,1H),7.77(s ,1H).

实施例155-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-3-醇Example 15 5-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazole -1-yl)piperidin-3-ol

Figure BDA00002905454701111
Figure BDA00002905454701111

步骤1)1-(叔丁氧羰基)-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-3-醇Step 1) 1-(tert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrazol-1-yl)piperidin-3-ol

将1-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)哌啶-3-醇(1.5g,3.81mmol)和联硼酸频钠醇酯(1.94g,7.62mmol)溶解在二甲亚砜(20mL)中，向其中加入乙酸钾(1.5g,15.24mmol)，氮气保护下，继续向体系中加入Pd(dppf)Cl2·CH2Cl2(310mg,0.38mmol)。反应液在90°C搅拌12小时后，冷却至室温，并倒入水/乙酸乙酯(100mL/300mL)混合液中。将分离的有机相用盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为棕色固体(720mg,48%)。  1-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)piperidin-3-ol (1.5g, 3.81mmol) and pinadol diboronate (1.94g, 7.62mmol) was dissolved in dimethyl sulfoxide (20mL), potassium acetate (1.5g, 15.24mmol) was added thereto, under nitrogen protection, Pd(dppf)Cl 2 ·CH 2 Cl 2 (310mg, 0.38 mmol). The reaction solution was stirred at 90° C. for 12 hours, cooled to room temperature, and poured into a water/ethyl acetate (100 mL/300 mL) mixture. The separated organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a brown solid (720 mg, 48%).

LC-MS(ESI,pos.ion)m/z:394.20[M+H]+。  LC-MS (ESI, pos.ion) m/z: 394.20 [M+H] + .

步骤2)5-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)-1-(叔丁氧羰基)哌啶-3-醇Step 2) 5-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyridine Azol-1-yl)-1-(tert-butoxycarbonyl)piperidin-3-ol

将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(515mg,1.36mmol)和1-(叔丁氧羰基)-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-3-醇(800mg,2.03mmol)溶解在乙二醇二甲醚(25mL)中，向其中加入碳酸铯(1.33g,4.08mmol)的水(5mL)溶液后，在氮气保护下，继续向体系中加入Pd(dppf)Cl2·CH2Cl2(114mg,0.14mmol)。反应液在90°C搅拌12小时，冷却至室温，加水(20mL)稀释，并用二氯甲烷(3×50mL)萃取。将合并的有机相用盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(二氯甲烷/甲醇(v/v)=60/1)纯化，得到标题化合物为黄色油状物(400mg,52%)。  (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (515mg, 1.36mmol) and 1-(tert-butoxy Carbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piper Pyridine-3-ol (800mg, 2.03mmol) was dissolved in ethylene glycol dimethyl ether (25mL), after adding cesium carbonate (1.33g, 4.08mmol) in water (5mL) solution, under nitrogen protection, continue Pd(dppf)Cl 2 ·CH 2 Cl 2 (114 mg, 0.14 mmol) was added to the system. The reaction was stirred at 90° C. for 12 hours, cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1) to obtain the title compound as a yellow oil (400 mg, 52%).

LC-MS(ESI,pos.ion)m/z:566.20[M+H]+；  LC-MS (ESI, pos.ion) m/z: 566.20[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.72(s,1H),7.50-7.54(m,2H),7.28-7.32(m,1H),7.02-7.07(m,1H),6.85(s,1H),6.02-6.10(m,1H),4.96(s,2H),4.31-4.34(m,1H),3.86(s,1H),3.76-3.80(m,1H),3.64-3.67(m,1H),3.52-3.60(m,1H),3.42-3.47(m,1H),2.38-2.41(m,1H),2.15-2.21(m,1H),1.84-1.86(d,J=6.6Hz,3H),1.36(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.72 (s, 1H), 7.50-7.54 (m, 2H), 7.28-7.32 (m, 1H), 7.02-7.07 (m, 1H), 6.85 ( s,1H),6.02-6.10(m,1H),4.96(s,2H),4.31-4.34(m,1H),3.86(s,1H),3.76-3.80(m,1H),3.64-3.67( m,1H),3.52-3.60(m,1H),3.42-3.47(m,1H),2.38-2.41(m,1H),2.15-2.21(m,1H),1.84-1.86(d,J=6.6 Hz, 3H), 1.36(s, 9H).

步骤3)5-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-3-醇Step 3) 5-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyridine Azol-1-yl)piperidin-3-ol

目标化合物通过实施例1步骤10所描述的方法制备得到，即将5-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)-1-(叔丁氧羰基)哌啶-3-醇(350mg,0.62mmol)和HCl(4mL,3M的乙酸乙酯溶液)溶解在二氯甲烷(5mL)中制备，粗产品经硅胶柱层析(二氯甲烷/甲醇(v/v)=40/1)纯化，得到标题化合物为棕黄色固体(60mg,21%)。  The target compound was prepared by the method described in step 10 of Example 1, that is, 5-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethyl Oxy)pyridin-3-yl)-1H-pyrazol-1-yl)-1-(tert-butoxycarbonyl)piperidin-3-ol (350mg, 0.62mmol) and HCl (4mL, 3M in ethyl acetate solution) was prepared by dissolving in dichloromethane (5mL), and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain the title compound as a tan solid (60mg, 21% ). the

LC-MS(ESI,pos.ion)m/z:466.20[M+H]+；  LC-MS (ESI, pos.ion) m/z: 466.20[M+H] + ;

1H NMR(400MHz,DMSO-d6)δ(ppm):7.92(s,1H),7.75(s,1H),7.54-7.58(m,1H),7.52(s,1H),7.41-7.45(m,1H),6.89(s,1H),6.04-6.10(m,1H),5.63(s,2H),4.87(s,1H),4.07-4.16(m,1H),3.46-3.58(m,4H),3.05-3.10(m,1H),2.96-3.01(m,1H),2.26-2.31(m,1H),2.13-2.19(m,1H),1.78-1.81(d,J=6.6Hz,3H)。  1 H NMR (400MHz,DMSO-d 6 )δ(ppm):7.92(s,1H),7.75(s,1H),7.54-7.58(m,1H),7.52(s,1H),7.41-7.45( m,1H),6.89(s,1H),6.04-6.10(m,1H),5.63(s,2H),4.87(s,1H),4.07-4.16(m,1H),3.46-3.58(m, 4H),3.05-3.10(m,1H),2.96-3.01(m,1H),2.26-2.31(m,1H),2.13-2.19(m,1H),1.78-1.81(d,J=6.6Hz, 3H).

实施例165-(1-(2,2-二氘代-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Example 16 5-(1-(2,2-Dideutero-4-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3- Fluorophenyl)ethoxy)pyridin-2-amine

Figure BDA00002905454701121
Figure BDA00002905454701121

步骤1)4-羟基哌啶-2-酮Step 1) 4-Hydroxypiperidin-2-one

将哌啶-2,4-二酮(1g,8.8mmol)溶解在甲醇(25mL)中，降温至0℃，向其中加入硼氢化钠(1g,26.55mmol)。反应液室温搅拌过夜。反应毕，减压浓缩。所得残留物经硅胶柱层析(二氯甲烷/甲醇(v/v)=5/1)纯化，得到标题化合物为黄色固体(960mg,87%)。  Piperidine-2,4-dione (1 g, 8.8 mmol) was dissolved in methanol (25 mL), cooled to 0° C., and sodium borohydride (1 g, 26.55 mmol) was added thereto. The reaction solution was stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=5/1) to obtain the title compound as a yellow solid (960 mg, 87%). the

LC-MS(ESI,pos.ion)m/z:138[M+Na]+。  LC-MS (ESI, pos.ion) m/z: 138 [M+Na] + .

步骤2)4-((四氢-2H-吡喃-2-基)氧基)哌啶-2-酮Step 2) 4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-2-one

将4-羟基哌啶-2-酮(1.4g,12.18mmol)，PPTS(367mg,1.462mmol)悬浮在二氯甲烷(200mL)中，向其中加入DHP(4.1g,48.72mmol)。反应液在35°C搅拌48小时后，减压浓缩。所得残留物经硅胶柱层析(二氯甲烷/甲醇(v/v)=10/1)纯化，得到标题化合物为白色固体(2.16g,89%)。  4-Hydroxypiperidin-2-one (1.4 g, 12.18 mmol), PPTS (367 mg, 1.462 mmol) were suspended in dichloromethane (200 mL), and DHP (4.1 g, 48.72 mmol) was added thereto. The reaction solution was stirred at 35°C for 48 hours, then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain the title compound as a white solid (2.16 g, 89%). the

LC-MS(ESI,pos.ion)m/z:200[M+H]+。  LC-MS (ESI, pos.ion) m/z: 200 [M+H] + .

1H NMR(400MHz,CDCl3)δ(ppm):1.50-1.70(m,4H),1.71-1.80(m,1H),1.80-2.10(m,4H),2.40-2.71(m,3H),3.21-3.35(m,1H),3.36-3.62(m,2H),3.80-3.95(m,1H),4.11-4.20(m,1H),4.65-4.79(m,1H),6.50(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.50-1.70 (m, 4H), 1.71-1.80 (m, 1H), 1.80-2.10 (m, 4H), 2.40-2.71 (m, 3H), 3.21-3.35(m,1H),3.36-3.62(m,2H),3.80-3.95(m,1H),4.11-4.20(m,1H),4.65-4.79(m,1H),6.50(s,1H) ).

步骤3)1-(叔丁氧羰基)-2,2-二氘代哌啶-4-醇Step 3) 1-(tert-butoxycarbonyl)-2,2-dideuteriopiperidin-4-ol

将4-((四氢-2H-吡喃-2-基)氧基)哌啶-2-酮(1.17g,5.88mmol)溶解在四氢呋喃(33.3mL)中，用冰浴冷却，并向其中加入LiAlD4(272mg,6.47mmol)。反应液在70°C搅拌过夜。反应毕，再次用冰浴冷却，缓慢加入饱和氯化铵溶液(50mL)淬灭。将混合物用乙酸乙酯(50mL×2)萃取，合并的有机相经无水硫酸钠干燥，并减压浓缩，得到粗产品，该产品立即被使用。  4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-2-one (1.17g, 5.88mmol) was dissolved in tetrahydrofuran (33.3mL), cooled in an ice bath, and poured into LiAlD4 (272mg, 6.47mmol) was added. The reaction was stirred overnight at 70°C. After the reaction was completed, it was cooled in an ice bath again, and saturated ammonium chloride solution (50 mL) was slowly added to quench. The mixture was extracted with ethyl acetate (50 mL x 2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product which was used immediately.

MS(ESI,pos.ion)m/z:188[M+H]+。  MS (ESI, pos.ion) m/z: 188 [M+H] + .

将2,2-二氘代-4-((四氢-2H-吡喃-2-基)氧基)哌啶溶解在二氯甲烷/甲醇(45mL/9mL)中，降温至0°C，向其中加入HCl(26mL,3M的乙酸乙酯溶液)。反应液室温搅拌过夜后，减压浓缩。  Dissolve 2,2-dideutero-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine in dichloromethane/methanol (45mL/9mL), cool to 0°C, To this was added HCl (26 mL, 3M in ethyl acetate). The reaction solution was stirred at room temperature overnight, then concentrated under reduced pressure. the

将所得残留物和碳酸钠(16.80g,158.5mmol)溶解在四氢呋喃/水(76mL/60mL)的混合液中，向其中加入Boc酸酐(5mL)。反应液室温 搅拌过夜。反应毕，分散在乙酸乙酯(50mL)和水(50mL)中，分离的水相用乙酸乙酯(50mL×2)萃取。合并的有机相经无水硫酸钠干燥，减压浓缩后，用硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为白色固体(0.52g,17%)。  The obtained residue and sodium carbonate (16.80 g, 158.5 mmol) were dissolved in a mixture of tetrahydrofuran/water (76 mL/60 mL), and Boc anhydride (5 mL) was added thereto. The reaction solution was stirred overnight at room temperature. After the reaction, it was dispersed in ethyl acetate (50 mL) and water (50 mL), and the separated aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a white solid (0.52 g, 17%). the

LC-MS(ESI,pos.ion)m/z:149[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 149[M+H-56] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.46(s,9H),1.73(s,2H),1.82-1.86(m,2H),2.99-3.06(m,1H),3.81-3.87(m,2H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.46 (s, 9H), 1.73 (s, 2H), 1.82-1.86 (m, 2H), 2.99-3.06 (m, 1H), 3.81-3.87 ( m,2H).

步骤4)1-(叔丁氧羰基)-2,2-二氘代-4-(4-碘-1H-吡唑-1-基)哌啶Step 4) 1-(tert-butoxycarbonyl)-2,2-dideutero-4-(4-iodo-1H-pyrazol-1-yl)piperidine

将1-(叔丁氧羰基)-2,2-二氘代哌啶-4-醇(490mg,2.41mmol)和DMAP(29.4mg,0.241mmol)溶解在二氯甲烷(15mL)中，冷却至0℃，向其中加入三乙胺(0.67mL,4.82mmol)后，继续滴加甲磺酰氯(0.223mL,2.897mmol)。反应液室温搅拌5小时。反应毕，加1M碳酸氢钠溶液(25mL)淬灭，并用二氯甲烷(50mL×2)萃取。合并的有机相经盐水(25mL)洗，无水硫酸钠干燥，并减压浓缩，得到残留物，该残留物立即被使用。  Dissolve 1-(tert-butoxycarbonyl)-2,2-dideuteriopiperidin-4-ol (490mg, 2.41mmol) and DMAP (29.4mg, 0.241mmol) in dichloromethane (15mL) and cool to After adding triethylamine (0.67mL, 4.82mmol) at 0°C, methanesulfonyl chloride (0.223mL, 2.897mmol) was added dropwise. The reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, it was quenched by adding 1M sodium bicarbonate solution (25 mL), and extracted with dichloromethane (50 mL×2). The combined organic phases were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue which was used immediately. the

将4-碘-1H-吡唑(467.5mg,2.41mmol)溶解在干燥的N,N-二甲基甲酰胺(8mL)中，冷却至0℃，向其中分批加入氢化钠(193mg,4.82mmol,60%分散在矿物油中)。混合物室温搅拌2小时后，继续向体系中加入上述残留物的N,N-二甲基甲酰胺(4mL)溶液。反应液在100℃搅拌12小时。反应毕，冷却至室温，加饱和氯化铵溶液(50mL)淬灭，并用乙酸乙酯(50mL×2)萃取。合并的有机相用盐水(25mL)洗，无水硫酸钠干燥，并减压浓缩。残留物经硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为黄色固体(620mg,68%)。  4-iodo-1H-pyrazole (467.5mg, 2.41mmol) was dissolved in dry N,N-dimethylformamide (8mL), cooled to 0°C, and sodium hydride (193mg, 4.82 mmol, 60% dispersed in mineral oil). After the mixture was stirred at room temperature for 2 hours, a solution of the above residue in N,N-dimethylformamide (4 mL) was further added to the system. The reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, it was cooled to room temperature, quenched with saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a yellow solid (620 mg, 68%). the

LC-MS(ESI,pos.ion)m/z:324[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 324[M+H-56] + ;

1H NMR(400MHz,CDCl3)δ(ppm):1.47(s,9H),1.83-1.89(m,2H),2.07-2.11(m,2H),2.85-2.90(m,1H),4.23-4.30(m,2H),7.46(s,1H),7.51(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.47 (s, 9H), 1.83-1.89 (m, 2H), 2.07-2.11 (m, 2H), 2.85-2.90 (m, 1H), 4.23- 4.30 (m, 2H), 7.46 (s, 1H), 7.51 (s, 1H).

步骤5)1-(叔丁氧羰基)-2,2-二氘代-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶Step 5) 1-(tert-butoxycarbonyl)-2,2-dideutero-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol Alkyl-2-yl)-1H-pyrazol-1-yl)piperidine

标题化合物通过实施例11步骤8所描述的方法制备得到，即将1-(叔丁氧羰基)-2,2-二氘代-4-(4-碘-1H-吡唑-1-基)哌啶(300mg,0.792mmol)，联硼酸频钠醇酯(281.6mg,1.11mmol)，醋酸钾(310.5mg,3.17mol)和Pd(PPh3)2Cl2(33.36mg,0.0475mmol)悬浮在二甲亚砜(6mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为白色固体(250mg,83%)。  The title compound was prepared by the method described in step 8 of Example 11, that is, 1-(tert-butoxycarbonyl)-2,2-dideutero-4-(4-iodo-1H-pyrazol-1-yl)piper Pyridine (300mg, 0.792mmol), pinazolate (281.6mg, 1.11mmol), potassium acetate (310.5mg, 3.17mol) and Pd(PPh 3 ) 2 Cl 2 (33.36mg, 0.0475mmol) were suspended in di Methyl sulfoxide (6 mL), the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a white solid (250 mg, 83%).

LC-MS(ESI,pos.ion)m/z:380[M+H]+。  LC-MS (ESI, pos.ion) m/z: 380 [M+H] + .

步骤6)5-(1-(1-(叔丁氧羰基)-2,2-二氘代哌啶-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 6) 5-(1-(1-(tert-butoxycarbonyl)-2,2-dideuteriopiperidin-4-yl)-1H-pyrazol-4-yl)-3-((R)- 1-(2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(300.8mg,0.792mmol)，1-(叔丁氧羰基)-2,2-二氘代-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶(250mg,0.66mmol)和碳酸钠(245mg,2.31mmol)悬浮在乙二醇二甲醚/水(6mL/1mL)的混合液中，氮气保护下，向其中加入Pd(PPh3)2Cl2(37mg,0.053mmol)。反应液在90°C搅拌14小时。反应毕，冷却至室温，加乙酸乙酯(150mL)稀释，并用硅藻土过滤，滤饼用乙酸乙酯(50mL)洗。合并的滤液经盐水(50mL×2)洗，并减压浓缩后，用硅胶柱层析(PE/EtOAc(v/v)=1/1)纯化，得到标题化合物为黄色固体(180mg,50%)。  (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (300.8mg, 0.792mmol), 1-(tert-butyl Oxycarbonyl)-2,2-dideutero-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -Pyrazol-1-yl)piperidine (250mg, 0.66mmol) and sodium carbonate (245mg, 2.31mmol) were suspended in a mixture of ethylene glycol dimethyl ether/water (6mL/1mL), under nitrogen protection, to To this was added Pd(PPh 3 ) 2 Cl 2 (37 mg, 0.053 mmol). The reaction was stirred at 90°C for 14 hours. After completion of the reaction, cool to room temperature, add ethyl acetate (150 mL) to dilute, and filter with diatomaceous earth, and the filter cake is washed with ethyl acetate (50 mL). The combined filtrate was washed with brine (50mL×2), concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a yellow solid (180mg, 50% ).

LC-MS(ESI,pos.ion)m/z:552[M+H]+。  LC-MS (ESI, pos.ion) m/z: 552 [M+H] + .

步骤7)5-(1-(2,2-二氘代-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 7) 5-(1-(2,2-Dideutero-4-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3 -fluorophenyl)ethoxy)pyridin-2-amine

目标化合物通过实施例1步骤10所描述的方法制备得到，即将5-(1-(1-(叔丁氧羰基)-2,2-二氘代哌啶-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(440mg,0.80mmol)和HCl(5mL,3M的乙酸乙酯溶液)溶解在二氯甲烷(20mL)中制备，粗产品经硅胶柱层析(DCM/MeOH/Et3N(v/v/v)=100/20/1)纯化，得到标题化合物为白色固体(180mg,50%)。  The target compound was prepared by the method described in step 10 of Example 1, that is, 5-(1-(1-(tert-butoxycarbonyl)-2,2-dideuteriopiperidin-4-yl)-1H-pyrazole -4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (440mg, 0.80mmol) and HCl (5mL, 3M ethyl acetate solution) was dissolved in dichloromethane (20 mL), and the crude product was purified by silica gel column chromatography (DCM/MeOH/Et 3 N (v/v/v)=100/20/1) to obtain the title Compound was a white solid (180 mg, 50%).

LC-MS(ESI)m/z:226.6(M+2/2)；  LC-MS(ESI)m/z:226.6(M+2/2);

1H NMR(400MHz,CDCl3)δ(ppm):1.85-1.86(d,J=6.7Hz,3H),1.86-1.95(m,2H),2.13-2.18(m,2H),2.76-2.81(t,J=10.6Hz,1H),3.24-3.28(m,1H),4.18-4.24(m,1H),4.78(s,2H),6.05-6.10(q,J=6.6Hz,1H),6.87(s,1H),7.03-7.07(t,J=8.5Hz,1H),7.27-7.32(m,1H),7.50(s,1H),7.56(s,1H),7.76(s,1H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.85-1.86 (d, J=6.7Hz, 3H), 1.86-1.95 (m, 2H), 2.13-2.18 (m, 2H), 2.76-2.81 ( t,J=10.6Hz,1H),3.24-3.28(m,1H),4.18-4.24(m,1H),4.78(s,2H),6.05-6.10(q,J=6.6Hz,1H),6.87 (s,1H),7.03-7.07(t,J=8.5Hz,1H),7.27-7.32(m,1H),7.50(s,1H),7.56(s,1H),7.76(s,1H).

实施例17Example 17

3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3S,4R)-3-氟哌啶-4-基)-1H-吡唑-4-基)吡啶-2-胺(17a)3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3S,4R)-3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl)pyridin-2-amine (17a)

3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3R,4S)-3-氟哌啶-4-基)-1H-吡唑-4-基)吡啶-2-胺(17b)3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3R,4S)-3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl)pyridin-2-amine (17b)

Figure BDA00002905454701161
Figure BDA00002905454701161

步骤1)step 1)

1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)哌啶-3-醇(17.1a)1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)piperidin-3-ol (17.1a)

1-(叔丁氧羰基)-3-(4-碘-1H-吡唑-1-基)哌啶-4-醇(17.1b)1-(tert-butoxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl)piperidin-4-ol (17.1b)

Figure BDA00002905454701162
Figure BDA00002905454701162

将4-碘-1H-吡唑(3g,16mmol)溶解在四氢呋喃(20mL)中，降温至-78°C，在30分钟内向其中滴加LDA(10mL,2M in THF)。混合物搅拌3小时后，在20分钟内向其中滴加3-(叔丁氧羰基)-7-氧杂-3-氮杂双环[4.1.0]庚烷(3g,14mmol)的四氢呋喃(20mL)溶液。反应液室温搅 拌1小时，然后加热至70°C，继续搅拌12小时。反应毕，冷却至室温，加水(4mL)淬灭，减压浓缩后，经硅胶柱层析(PE/EtOAc(v/v)=4:1)纯化，得到(17.1a)(2.5g,41%)和1-(叔丁氧羰基)-3-(4-碘-1H-吡唑-1-基)哌啶-4-醇(17.1b)为白色固体。  4-iodo-1H-pyrazole (3g, 16mmol) was dissolved in tetrahydrofuran (20mL), cooled to -78°C, and LDA (10mL, 2M in THF) was added dropwise thereto within 30 minutes. After the mixture was stirred for 3 hours, a solution of 3-(tert-butoxycarbonyl)-7-oxa-3-azabicyclo[4.1.0]heptane (3 g, 14 mmol) in tetrahydrofuran (20 mL) was added dropwise thereto within 20 minutes . The reaction solution was stirred at room temperature for 1 hour, then heated to 70° C., and continued to stir for 12 hours. After the reaction was completed, it was cooled to room temperature, quenched by adding water (4 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EtOAc (v/v)=4:1) to obtain (17.1a) (2.5 g, 41 %) and 1-(tert-butoxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl)piperidin-4-ol (17.1b) as white solids. the

(17.1a):  (17.1a):

LC-MS(ESI,pos.ion)m/z:394[M+H]+；  LC-MS (ESI, pos.ion) m/z: 394[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.56(s,1H),7.24(s,1H),4.39-4.04(m,2H),4.02-3.99(m,1H),3.87(m,1H),2.82-2.70(m,2H),2.12-2.04(m,1H),2.00-1.95(m,1H),1.46(s,9H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.56(s,1H),7.24(s,1H),4.39-4.04(m,2H),4.02-3.99(m,1H),3.87(m, 1H), 2.82-2.70(m, 2H), 2.12-2.04(m, 1H), 2.00-1.95(m, 1H), 1.46(s, 9H).

(17.1b):  (17.1b):

LC-MS(ESI,pos.ion)m/z:394[M+H]+；  LC-MS (ESI, pos.ion) m/z: 394[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.55(s,2H),4.34-4.16(m,3H),3.95-3.89(m,1H),3.08(m,2H),2.88-2.82(t,J=12Hz,1H),2.07-2.03(m,1H),1.65-1.56(m,1H),1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.55 (s, 2H), 4.34-4.16 (m, 3H), 3.95-3.89 (m, 1H), 3.08 (m, 2H), 2.88-2.82 ( t, J=12Hz, 1H), 2.07-2.03(m, 1H), 1.65-1.56(m, 1H), 1.47(s, 9H).

步骤2)1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)-3-((四氢-2H-吡喃-2-基)氧基)哌啶Step 2) 1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)piperidine

将1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)哌啶-3-醇(0.5g,1.27mmol)和PPTS(0.032g,0.127mmol)溶解在二氯甲烷(20mL)中，向其中加入DHP(0.5mL)。反应液室温搅拌3小时后，减压浓缩。所得残留物用硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为浅黄色油状物(0.5g,84%)。  1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)piperidin-3-ol (0.5 g, 1.27 mmol) and PPTS (0.032 g, 0.127 mmol) were dissolved in In dichloromethane (20 mL), DHP (0.5 mL) was added thereto. After stirring the reaction solution at room temperature for 3 hours, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as a pale yellow oil (0.5 g, 84%). the

LC-MS(ESI,pos.ion)m/z:478[M+H]+。  LC-MS (ESI, pos.ion) m/z: 478 [M+H] + .

步骤3)1-(叔丁氧羰基)-3-((四氢-2H-吡喃-2-基)氧基)-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶Step 3) 1-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine

氮气保护下，将1-(叔丁氧羰基)-4-(4-碘-1H-吡唑-1-基)-3-((四氢-2H-吡喃-2-基)氧基)哌啶(0.5g,1mmol)，联硼酸频钠醇酯(0.8g,3mmol)，乙酸钾(0.2g,2mmol)和Pd(dppf)Cl2·CH2Cl2(0.08g,0.1mmol)的二甲亚砜(15mL)悬浮液在50°C搅拌4小时。反应毕，冷却至室温，加水(40mL)稀释，并用乙酸乙酯(30mL×3)萃取。合并的有机相用盐 水(80mL x2)洗，无水硫酸钠干燥，并减压浓缩。残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=3/1)纯化，得到标题化合为白色固体(0.45g,90%)。  Under nitrogen protection, 1-(tert-butoxycarbonyl)-4-(4-iodo-1H-pyrazol-1-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy) Piperidine (0.5g, 1mmol), pinadium borate (0.8g, 3mmol), potassium acetate (0.2g, 2mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (0.08g, 0.1mmol) The dimethyl sulfoxide (15 mL) suspension was stirred at 50°C for 4 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a white solid (0.45 g, 90%).

LC-MS(ESI,pos.ion)m/z:478[M+H]+。  LC-MS (ESI, pos.ion) m/z: 478 [M+H] + .

步骤4)5-(1-(1-(叔丁氧羰基)-3-((四氢-2H-吡喃-2-基)氧基)哌啶-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 4) 5-(1-(1-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-4-yl)-1H-pyrazole- 4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

将1-(叔丁氧羰基)-3-((四氢-2H-吡喃-2-基)氧基)-4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶(0.45g,0.94mmol)，(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.4g,1mmol)，Pd(OAc)2(22mg,0.1mmol)和碳酸钠(0.22g,2mmol)悬浮在乙二醇二甲醚/水(20mL/1mL)的混合液中，氮气保护下，向其中加入(t-Bu)3P(0.25mL,1M的甲苯溶液)。反应液在100°C搅拌36小时后，减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/2)纯化，得到标题化合物为浅棕色固体(0.38g,61%)。  1-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (0.45g, 0.94mmol), (R)-5-bromo-3-(1-( 2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.4g, 1mmol), Pd(OAc) 2 (22mg, 0.1mmol) and sodium carbonate (0.22g, 2mmol) were suspended In a mixture of ethylene glycol dimethyl ether/water (20 mL/1 mL) under nitrogen protection, (t-Bu) 3 P (0.25 mL, 1M solution in toluene) was added thereto. The reaction solution was stirred at 100°C for 36 hours, then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain the title compound as a light brown solid (0.38 g, 61%).

LC-MS(ESI,pos.ion)m/z:650[M+H]+；  LC-MS (ESI, pos.ion) m/z: 650[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.75-7.73(m,1H),7.67(s,1H),7.61-7.50(m,1H),7.31-7.29(m,1H),7.07-7.02(m,1H),6.88-6.86(m,1H),6.10-6.05(t,J=6.64Hz,1H),4.80(s,2H),4.70-4.18(m,2H),4.12-3.65(m,4H),3.57-2.98(m,1H),2.91-2.45(m,2H),2.40-1.92(4H,m),1.86-1.84(d,J=6.64Hz,3H),1.78-1.45(m,13H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.75-7.73(m,1H),7.67(s,1H),7.61-7.50(m,1H),7.31-7.29(m,1H),7.07- 7.02(m,1H),6.88-6.86(m,1H),6.10-6.05(t,J=6.64Hz,1H),4.80(s,2H),4.70-4.18(m,2H),4.12-3.65( m,4H),3.57-2.98(m,1H),2.91-2.45(m,2H),2.40-1.92(4H,m),1.86-1.84(d,J=6.64Hz,3H),1.78-1.45( m,13H).

步骤5)Step 5)

(3R,4R)-4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)-1-(叔丁氧羰基)哌啶-3-醇(17.5a)(3R,4R)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- 1H-pyrazol-1-yl)-1-(tert-butoxycarbonyl)piperidin-3-ol (17.5a)

(3S,4S)-4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)-1-(叔丁氧羰基)哌啶-3-醇(17.5b)(3S,4S)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- 1H-pyrazol-1-yl)-1-(tert-butoxycarbonyl)piperidin-3-ol (17.5b)

Figure BDA00002905454701191
Figure BDA00002905454701191

将5-(1-(1-(叔丁氧羰基)-3-((四氢-2H-吡喃-2-基)氧基)哌啶-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(1g,1.54mmol)和PPTS(0.12g,0.46mmol)的甲醇(30mL)溶液在75°C搅拌30小时。反应毕，减压浓缩，加水(40mL)稀释，并用二氯甲烷(30mL×3)萃取。合并的有机相用水(90mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(DCM/MeOH(v/v)=40/1)纯化，得到(17.5a)和(17.5b)的混合物为棕色固体(0.6g,71%).  5-(1-(1-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-4-yl)-1H-pyrazole-4- yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (1g, 1.54mmol) and PPTS (0.12g, 0.46mmol) A solution of methanol (30 mL) was stirred at 75°C for 30 hours. After the reaction was completed, it was concentrated under reduced pressure, diluted with water (40 mL), and extracted with dichloromethane (30 mL×3). The combined organic phases were washed with water (90 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) to obtain a mixture of (17.5a) and (17.5b) as a brown solid (0.6 g, 71%).

LC-MS(ESI,pos.ion)m/z:565[M+H]+。  LC-MS (ESI, pos.ion) m/z: 565 [M+H] + .

步骤6)Step 6)

5-(1-((3S,4R)-1-(叔丁氧羰基)-3-氟哌啶-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(17.6a)5-(1-((3S,4R)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-3-((R)-1 -(2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (17.6a)

5-(1-((3R,4S)-1-(叔丁氧羰基)-3-氟哌啶-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(17.6b)5-(1-((3R,4S)-1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-4-yl)-3-((R)-1 -(2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (17.6b)

Figure BDA00002905454701192
Figure BDA00002905454701192

将(17.5a)和(17.5b)的混合物(0.6g,1mmol)溶解在二氯甲烷 (15mL)中，冷却至-78°C，向其中滴加DAST(0.34g,2mmol)的二氯甲烷(5mL)溶液。反应液搅拌在-78°C搅拌30分钟后，升温至-40°C，继续搅拌4小时。反应毕，加1M碳酸氢钠溶液(30mL)淬灭，并用二氯甲烷(30mL×3)萃取。合并的有机相依次用水(90mL)、盐水(90mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(二氯甲烷/甲醇(v/v)=40/1)纯化，得到(17.6a)和(17.6b)的混合物为棕色固体(0.28g,47%)。  A mixture (0.6 g, 1 mmol) of (17.5a) and (17.5b) was dissolved in dichloromethane (15 mL), cooled to -78° C., to which DAST (0.34 g, 2 mmol) was added dropwise in dichloromethane (5 mL) solution. After the reaction solution was stirred at -78°C for 30 minutes, the temperature was raised to -40°C, and stirring was continued for 4 hours. After the reaction was completed, it was quenched by adding 1M sodium bicarbonate solution (30 mL), and extracted with dichloromethane (30 mL×3). The combined organic phases were washed successively with water (90 mL), brine (90 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to obtain a mixture of (17.6a) and (17.6b) as a brown solid (0.28 g, 47%). the

LC-MS(ESI,pos.ion)m/z:568[M+H]+。  LC-MS (ESI, pos.ion) m/z: 568 [M+H] + .

步骤7)Step 7)

3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3S,4R)-3-氟哌啶-4-基)-1H-吡唑-4-基)吡啶-2-胺(17a)3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3S,4R)-3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl)pyridin-2-amine (17a)

3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3R,4S)-3-氟哌啶-4-基)-1H-吡唑-4-基)吡啶-2-胺(17b)3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3R,4S)-3-fluoropiperidin-4-yl) -1H-pyrazol-4-yl)pyridin-2-amine (17b)

将HCl(10mL,1M的乙酸乙酯溶液)滴加到(17.6a)和(17.6b)的混合物(0.28g,0.49mmol)中。反应液室温搅拌2小时。反应毕，减压浓缩。残留物用2M碳酸钠溶液(20mL)处理后，用二氯甲烷(20mL x3)萃取。合并的有机相用盐水(60mL)洗，无水硫酸钠干燥，并减压浓缩。残留物经硅胶柱层析(DCM/MeOH/NH4OH(v/v/v)=50/1/1)纯化，得到(17a)和(17b)的混合物为浅黄色固体(0.15g,75%)。  HCl (10 mL, 1 M in ethyl acetate) was added dropwise to a mixture of (17.6a) and (17.6b) (0.28 g, 0.49 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was treated with 2M sodium carbonate solution (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH/NH 4 OH (v/v/v)=50/1/1) to obtain a mixture of (17a) and (17b) as a pale yellow solid (0.15g, 75 %).

LC-MS(ESI,pos.ion)m/z:234.7(M+2)/2；  LC-MS(ESI,pos.ion)m/z:234.7(M+2)/2;

1H NMR(400MHz,CDCl3)δ(ppm):7.77(s,1H),7.62(s,1H),7.58-7.52(m,1H),7.32-7.29(dd,J=4.80Hz,1H),7.07-7.03(t,J=8.60Hz,1H),6.88(s,1H),6.10-6.05(t,J=6.68Hz,1H),4.80(s,2H),4.69-4.60(m,1H),4.23-4.13(m,1H),3.52-3.47(m,1H),3.19-3.15(m,1H),2.74-2.70(m,2H),2.20-2.16(m,2H),1.86-1.84(d,J=6.68Hz,3H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):7.77(s,1H),7.62(s,1H),7.58-7.52(m,1H),7.32-7.29(dd,J=4.80Hz,1H) ,7.07-7.03(t,J=8.60Hz,1H),6.88(s,1H),6.10-6.05(t,J=6.68Hz,1H),4.80(s,2H),4.69-4.60(m,1H ),4.23-4.13(m,1H),3.52-3.47(m,1H),3.19-3.15(m,1H),2.74-2.70(m,2H),2.20-2.16(m,2H),1.86-1.84 (d, J=6.68Hz, 3H).

实施例18Example 18

(3R,4R)-4-(4-(6-胺基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-3-醇(18a)(3R,4R)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl) -1H-pyrazol-1-yl)piperidin-3-ol (18a)

(3S,4S)-4-(4-(6-胺基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-3-醇(18b)(3S,4S)-4-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl) -1H-pyrazol-1-yl)piperidin-3-ol (18b)

将HCl(5mL,1M的乙酸乙酯溶液)滴加到5-(1-(1-(叔丁氧羰基)-3-((四氢-2H-吡喃-2-基)氧基)哌啶-4-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.25g,0.38mmol)中。反应液室温搅拌2小时。反应毕，加水(20mL)稀释，并用乙酸乙酯(20mL×2)洗。将混合液用2M碳酸钠溶液(10mL)处理后，加乙酸乙酯(20mL×3)萃取。合并的有机相经盐水(60mL)洗，无水硫酸钠干燥，并减压浓缩，得到标题化合物为白色固体(0.12g,70%)。  HCl (5 mL, 1M in ethyl acetate) was added dropwise to 5-(1-(1-(tert-butoxycarbonyl)-3-((tetrahydro-2H-pyran-2-yl)oxy)piper Pyridin-4-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine ( 0.25g, 0.38mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, it was diluted with water (20 mL), and washed with ethyl acetate (20 mL×2). The mixture was treated with 2M sodium carbonate solution (10 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a white solid (0.12 g, 70%). the

LC-MS(ESI,pos.ion)m/z:233.7(M+2)/2；  LC-MS(ESI,pos.ion)m/z:233.7(M+2)/2;

1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=1.68Hz,1H),7.60(s,1H),7.54(s,1H),7.33-7.29(m,1H),7.07-7.04(t,J=7.92Hz,1H),6.86(s,1H),6.10-6.05(t,J=6.64Hz,1H),4.78(s,2H),3.99-3.95(m,2H),3.41-3.19(m,2H),2.78-2.59(m,2H),2.19-1.97(m,2H),1.86-1.84(d,J=6.64Hz,3H).  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.75 (d, J=1.68Hz, 1H), 7.60 (s, 1H), 7.54 (s, 1H), 7.33-7.29 (m, 1H), 7.07 -7.04(t,J=7.92Hz,1H),6.86(s,1H),6.10-6.05(t,J=6.64Hz,1H),4.78(s,2H),3.99-3.95(m,2H), 3.41-3.19(m,2H),2.78-2.59(m,2H),2.19-1.97(m,2H),1.86-1.84(d,J=6.64Hz,3H).

实施例19Example 19

(3R,4R)-3-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-4-醇(19a)(3R,4R)-3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- 1H-pyrazol-1-yl)piperidin-4-ol (19a)

(3S,4S)-3-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-4-醇(19b)(3S,4S)-3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- 1H-pyrazol-1-yl)piperidin-4-ol (19b)

Figure BDA00002905454701221
Figure BDA00002905454701221

步骤1)1-(叔丁氧羰基)-3-(4-碘-1H-吡唑-1-基)-4-((四氢-2H-吡喃-2-基)氧基)哌啶Step 1) 1-(tert-butoxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine

标题化合物通过实施例17步骤2描述的方法制备得到，即将1-(叔丁氧羰基)-3-(4-碘-1H-吡唑-1-基)哌啶-4-醇(1g,2.6mmol)，PPTS(0.064g,0.26mmol)和DHP(1mL)悬浮在二氯甲烷(30mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=6/1)纯化，得到标题化合物为浅黄色油状物(0.5g,84%)。  The title compound was prepared by the method described in step 2 of Example 17, that is, 1-(tert-butoxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl)piperidin-4-ol (1g, 2.6 mmol), PPTS (0.064 g, 0.26 mmol) and DHP (1 mL) were suspended in dichloromethane (30 mL), and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v)=6/1), The title compound was obtained as a pale yellow oil (0.5 g, 84%). the

LC-MS(ESI,pos.ion)m/z:478[M+H]+。  LC-MS (ESI, pos.ion) m/z: 478 [M+H] + .

步骤2)1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶Step 2) 1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine

标题化合物通过实施例17步骤3所描述的方法制备得到，即将1-(叔丁氧羰基)-3-(4-碘-1H-吡唑-1-基)-4-((四氢-2H-吡喃-2-基)氧基)哌啶(0.6g,1.25mmol),联硼酸频钠醇酯(0.9g,3.8mmol)，乙酸钾(0.25g,2.5mmol)和Pd(dppf)Cl2·CH2Cl2(0.1g,0.125mmol)悬浮在二甲亚砜(20mL)中制备。粗产品经硅胶柱层析(PE/EtOAc(v/v)=2/1)纯化，得到标题化合物为黄色固体(0.58g,94%)。  The title compound was prepared by the method described in step 3 of Example 17, that is, 1-(tert-butoxycarbonyl)-3-(4-iodo-1H-pyrazol-1-yl)-4-((tetrahydro-2H -pyran-2-yl)oxy)piperidine (0.6g, 1.25mmol), pinazolate diboronate (0.9g, 3.8mmol), potassium acetate (0.25g, 2.5mmol) and Pd(dppf)Cl 2 · CH 2 Cl 2 (0.1 g, 0.125 mmol) was prepared by suspending in dimethyl sulfoxide (20 mL). The crude product was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to obtain the title compound as a yellow solid (0.58 g, 94%).

LC-MS(ESI,pos.ion)m/z:478[M+H]+。  LC-MS (ESI, pos.ion) m/z: 478 [M+H] + .

步骤3)5-(1-(1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)哌啶-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 3) 5-(1-(1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidin-3-yl)-1H-pyrazole- 4-yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

标题化合物通过实施例17步骤4所描述的方法制备得到，即将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.6g,1.58mmol)，1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)-3-(4-(4,4,5,5-四甲基-1,3,2- 二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶(0.58g,1.2mmol)，Pd(OAc)2(34mg,0.15mmol)，碳酸钠(0.26g,2.5mmol)和(t-Bu)3P(0.38mL,1M的甲苯溶液)悬浮在乙二醇二甲醚/水(30mL/1mL)的悬浮液中制备。粗产品经硅胶柱层析(PE/EtOAc(v/v)=1/1)纯化，得到标题化合物为浅棕色固体(0.5g,60%)。  The title compound was prepared by the method described in step 4 of Example 17, that is, (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2 -Amine (0.6g, 1.58mmol), 1-(tert-butoxycarbonyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (0.58g, 1.2mmol), Pd(OAc) 2 (34mg, 0.15mmol), sodium carbonate (0.26g, 2.5mmol) and (t-Bu) 3 P (0.38mL, 1M solution in toluene) were suspended in ethylene glycol dimethyl ether/water (30mL/1mL) prepared in liquid. The crude product was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to obtain the title compound as a light brown solid (0.5 g, 60%).

LC-MS(ESI,pos.ion)m/z:650[M+H]+；  LC-MS (ESI, pos.ion) m/z: 650[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.75-7.40(m,1H),7.62-7.60(m,1H),7.53-7.51(m,1H),7.34-7.28(m,1H),7.08-7.02(dd,J=8.02Hz,1H),6.87-6.86(m,1H),6.10-6.05(t,J=6.64Hz,1H),4.48-4.01(m,3H),3.95-3.80(m,3H),3.41-3.37(m,1H),3.01-2.78(m,1H),2.15-2.12(m,1H),1.86-1.84(d,J=6.64Hz,3H),1.66-1.62(m,3H),1.58-1.36(m,13H).  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.75-7.40(m,1H),7.62-7.60(m,1H),7.53-7.51(m,1H),7.34-7.28(m,1H), 7.08-7.02(dd,J=8.02Hz,1H),6.87-6.86(m,1H),6.10-6.05(t,J=6.64Hz,1H),4.48-4.01(m,3H),3.95-3.80( m,3H),3.41-3.37(m,1H),3.01-2.78(m,1H),2.15-2.12(m,1H),1.86-1.84(d,J=6.64Hz,3H),1.66-1.62( m,3H),1.58-1.36(m,13H).

步骤4)Step 4)

(3R,4R)-3-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-4-醇(19a)(3R,4R)-3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- 1H-pyrazol-1-yl)piperidin-4-ol (19a)

(3S,4S)-3-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-4-醇(19b)(3S,4S)-3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)- 1H-pyrazol-1-yl)piperidin-4-ol (19b)

Figure BDA00002905454701231
Figure BDA00002905454701231

标题化合物通过实施例18所描述的方法制备得到，即使用HCl(5mL,1M的乙酸乙酯溶液)和5-(1-(1-(叔丁氧羰基)-4-((四氢-2H-吡喃-2-基)氧基)哌啶-3-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.25g,0.38mmol)来制备，所得目标产物为白色固体(0.09g,50%).  The title compound was prepared as described in Example 18 using HCl (5 mL, 1 M in ethyl acetate) and 5-(1-(1-(tert-butoxycarbonyl)-4-((tetrahydro-2H -pyran-2-yl)oxy)piperidin-3-yl)-1H-pyrazol-4-yl)-3-((R)-1-(2,6-dichloro-3-fluorobenzene base) ethoxy) pyridin-2-amine (0.25g, 0.38mmol) to prepare, the resulting target product is a white solid (0.09g, 50%). 

LC-MS(ESI,pos.ion)m/z:233.7(M+2)/2；  LC-MS(ESI,pos.ion)m/z:233.7(M+2)/2;

1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.60(s,1H),7.50-7.49(d,J=3.2Hz,1H),7.32-7.28(m,1H),7.07-7.03(m,1H),6.85(s,1H),6.09-6.04(t,J=6.64Hz,1H),4.78(s,2H),4.15-4.08(m,1H),3.96-3.90(m,1H),3.42-3.38(m,1H),3.18-3.15(m,1H),3.00-2.93(m,1H),2.77-2.70(m,1H),2.17-2.13(m,1H),1.86-1.84(d,J=6.64Hz,3H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):7.74(s,1H),7.60(s,1H),7.50-7.49(d,J=3.2Hz,1H),7.32-7.28(m,1H) ,7.07-7.03(m,1H),6.85(s,1H),6.09-6.04(t,J=6.64Hz,1H),4.78(s,2H),4.15-4.08(m,1H),3.96-3.90 (m,1H),3.42-3.38(m,1H),3.18-3.15(m,1H),3.00-2.93(m,1H),2.77-2.70(m,1H),2.17-2.13(m,1H) , 1.86-1.84 (d, J=6.64Hz, 3H).

实施例203-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((六氢呋喃并[2,3-b]呋喃-3-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Example 203-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((hexahydrofuro[2,3-b]furan- 3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454701241
Figure BDA00002905454701241

步骤1)(2R,3S)-2-(烯丙氧基)-3-碘四氢呋喃Step 1) (2R,3S)-2-(allyloxy)-3-iodotetrahydrofuran

将NIS(15.1g,66.6mmol)悬浮在二氯甲烷(150mL)中，降温至0°C，30分钟内，向其中加入二氢呋喃(5.1mL,66.6mmol)和烯丙醇(6.8mL,100mmol)的二氯甲烷(50mL)溶液。反应液在0°C下搅拌3小时。反应毕，恢复至室温，并加水(200mL)稀释。所得混合物于室温继续搅拌1小时后，用二氯甲烷(200mL)萃取。有机相用食盐水(400mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=9/1)纯化，得到标题化合物为黄色油状物(15.53g,91.8%)。  NIS (15.1g, 66.6mmol) was suspended in dichloromethane (150mL), cooled to 0°C, and dihydrofuran (5.1mL, 66.6mmol) and allyl alcohol (6.8mL, 100mmol) in dichloromethane (50mL). The reaction was stirred at 0°C for 3 hours. After the reaction, return to room temperature and add water (200 mL) to dilute. After stirring the resulting mixture at room temperature for 1 hour, it was extracted with dichloromethane (200 mL). The organic phase was washed with brine (400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=9/1) to obtain the title The compound was a yellow oil (15.53 g, 91.8%). the

1H NMR(400MHz,CDCl3)δ(ppm):5.88(m,1H),5.39(s,1H),5.29(m,1H),5.23(m,1H),4.20-3.95(m,5H),2.63(m,1H),2.21(m,1H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):5.88(m,1H),5.39(s,1H),5.29(m,1H),5.23(m,1H),4.20-3.95(m,5H) ,2.63(m,1H),2.21(m,1H).

步骤2)3-(碘甲基)六氢呋喃并[2,3-b]呋喃Step 2) 3-(iodomethyl)hexahydrofuro[2,3-b]furan

将(2R,3S)-2-(烯丙氧基)-3-碘四氢呋喃(2g,7.87mmol)悬浮于水(100mL)中，氮气保护下，向其中加入三乙基硼(0.7mL,1M的四氢呋喃溶液)。反应液室温搅拌3小时。反应毕，用乙酸乙酯(100mL×3)萃 取。合并的有机相用盐水(300mL)洗，无水硫酸钠干燥，并减压浓缩，得到标题化合物为黄色油状物(1.6g,80%)，该产品不经纯化，直接用于下一步反应。  Suspend (2R,3S)-2-(allyloxy)-3-iodotetrahydrofuran (2g, 7.87mmol) in water (100mL), and add triethylboron (0.7mL, 1M solution in tetrahydrofuran). The reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, it was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (1.6 g, 80%), which was directly used in the next reaction without purification. the

MS(ESI,pos.ion)m/z254[M+H]+；  MS(ESI,pos.ion)m/z254[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):5.78(d,J=4.92Hz,1H),4.05-4.02(m,1H),3.92-3.88(m,2H),3.48-3.43(dd,J=8.6Hz,1H),3.19-3.15(dd,J=7.68Hz,1H),3.10-3.05(dd,J=8.46Hz,1H),2.93-2.76(m,2H),1.94-1.80(m,2H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 5.78 (d, J=4.92Hz, 1H), 4.05-4.02 (m, 1H), 3.92-3.88 (m, 2H), 3.48-3.43 (dd, J=8.6Hz,1H),3.19-3.15(dd,J=7.68Hz,1H),3.10-3.05(dd,J=8.46Hz,1H),2.93-2.76(m,2H),1.94-1.80(m ,2H).

步骤3)1-((六氢呋喃并[2,3-b]呋喃-3-基)甲基)-4-碘-1H-吡唑Step 3) 1-((Hexahydrofuro[2,3-b]furan-3-yl)methyl)-4-iodo-1H-pyrazole

将4-碘-1H-吡唑(2g,9.48mmol)溶解在无水N,N-二甲基甲酰胺(30mL)中，降温至0°C，向其中分批加入氢化钠(0.7g,23.7mmol,80%分散在矿物油中)后，继续加入3-(碘甲基)六氢呋喃并[2,3-b]呋喃(1.6g,7.9mmol)的N,N-二甲基甲酰胺(10mL)溶液。反应液在80°C搅拌10小时，反应毕，冷却至室温，加水(80mL)淬灭，并用乙酸乙酯(100mL×3)萃取。合并的有机相用盐水(300mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=3/1)纯化，得到标题化合物为黄色油状物(1.5g,60%)。  4-iodo-1H-pyrazole (2g, 9.48mmol) was dissolved in anhydrous N,N-dimethylformamide (30mL), cooled to 0°C, and sodium hydride (0.7g, 23.7mmol, 80% dispersed in mineral oil), continue to add 3-(iodomethyl)hexahydrofuro[2,3-b]furan (1.6g, 7.9mmol) of N,N-dimethyl Amide (10 mL) solution. The reaction solution was stirred at 80° C. for 10 hours. After the reaction was completed, it was cooled to room temperature, quenched by adding water (80 mL), and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain The title compound was a yellow oil (1.5 g, 60%). the

LC-MS(ESI,pos.ion)m/z:321[M+H]+；  LC-MS (ESI, pos.ion) m/z: 321[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.47(s,1H),7.40(s,1H),5.70(d,J=4.8Hz,1H),4.28-4.23(dd,J=7.32Hz,1H),4.16-4.11(dd,J=7.7Hz,1H),3.95-3.85(m,3H),3.63-3.58(dd,J=8.64Hz,1H),2.91-2.79(m,2H),1.93-1.88(m,2H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):7.47(s,1H),7.40(s,1H),5.70(d,J=4.8Hz,1H),4.28-4.23(dd,J=7.32Hz ,1H),4.16-4.11(dd,J=7.7Hz,1H),3.95-3.85(m,3H),3.63-3.58(dd,J=8.64Hz,1H),2.91-2.79(m,2H), 1.93-1.88 (m, 2H).

步骤4)1-((六氢呋喃并[2,3-b]呋喃-3-基)甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑Step 4) 1-((Hexahydrofuro[2,3-b]furan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1H-pyrazole

将1-((六氢呋喃并[2,3-b]呋喃-3-基)甲基)-4-碘-1H-吡唑(1.2g,3.75mmol)，联硼酸频那醇酯(1.14g,4.5mmol)和乙酸钾(1.1g,11.25mmol)溶解在二甲亚砜(25mL)中，氮气保护下，向其中加入Pd(dppf)Cl2·CH2Cl2(153mg,0.19mmol)。反应液在80°C搅拌3小时，反应毕，冷却至室温，加水(60mL)稀释，并用乙酸乙酯(50mL×3)萃 取。合并的有机相用盐水(120mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为黄色油状物(0.6g,50%)。  1-((Hexahydrofuro[2,3-b]furan-3-yl)methyl)-4-iodo-1H-pyrazole (1.2g, 3.75mmol), pinacol diboronate (1.14 g, 4.5mmol) and potassium acetate (1.1g, 11.25mmol) were dissolved in dimethylsulfoxide (25mL), and Pd(dppf)Cl 2 ·CH 2 Cl 2 (153mg, 0.19mmol) was added thereto under nitrogen protection . The reaction solution was stirred at 80° C. for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (120 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain The title compound was a yellow oil (0.6 g, 50%).

1H NMR(400MHz,CDCl3)δ(ppm):7.78(s,1H),7.67(s,1H),5.73(d,J=4.3Hz,2H),4.29-4.26(m,1H),4.20-4.14(m,1H),3.98-3.88(m,3H),3.67-3.65(m,1H),1.97-1.93(m,2H),1.32(s,6H),1.25(m,6H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.78(s,1H),7.67(s,1H),5.73(d,J=4.3Hz,2H),4.29-4.26(m,1H),4.20 -4.14 (m, 1H), 3.98-3.88 (m, 3H), 3.67-3.65 (m, 1H), 1.97-1.93 (m, 2H), 1.32 (s, 6H), 1.25 (m, 6H).

步骤5)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((六氢呋喃并[2,3-b]呋喃-3-基)甲基)-1H-吡唑-4-基)吡啶-2-胺Step 5) 3-((R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-(1-((Hexahydrofuro[2,3-b]furan -3-yl)methyl)-1H-pyrazol-4-yl)pyridin-2-amine

将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.8g,1.8mmol)，1-((六氢呋喃并[2,3-b]呋喃-3-基)甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(0.8g,2mmol)和碳酸钠(0.4g,3.6mmol)溶解在乙二醇二甲醚/水(20mL/0.2mL)的混合液中，氮气保护下，向其中依次加入Pd(OAc)2(40mg,0.18mmol)和(t-Bu)3P(0.6mL,1M的甲苯溶液)。反应液在100°C搅拌16小时。反应毕，冷却至室温，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯/甲醇(v/v/v)=10/10/1)纯化，得到标题化合物为白色固体(0.3g,25%)。  (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.8g, 1.8mmol), 1-((hexa Hydrofuro[2,3-b]furan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazole (0.8g, 2mmol) and sodium carbonate (0.4g, 3.6mmol) were dissolved in a mixture of ethylene glycol dimethyl ether/water (20mL/0.2mL), under nitrogen protection, to Pd(OAc) 2 (40 mg, 0.18 mmol) and (t-Bu) 3 P (0.6 mL, 1M in toluene) were added sequentially. The reaction was stirred at 100°C for 16 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/methanol (v/v/v)=10/10/1) to obtain the title compound as a white solid (0.3 g, 25%).

LC-MS(ESI,pos.ion)m/z:493[M+H]+；  LC-MS (ESI, p os.ion) m/z: 493[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.74(d,J=1.76Hz,1H),7.56(s,1H),7.42(s,1H),7.30-7.28(m,1H),7.08-7.05(m,1H),6.85(dd,J=1.52Hz,1H),6.10-6.05(q,J=2.66Hz,1H),5.76(d,J=4.84Hz,1H),4.85(s,2H),4.13-4.11(m,1H),4.01-3.88(m,3H),3.70-3.65(m,1H),2.96-2.84(m,2H),1.99-1.95(m,2H),1.86(d,J=2.66Hz,3H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.74 (d, J=1.76Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.30-7.28 (m, 1H), 7.08 -7.05(m,1H),6.85(dd,J=1.52Hz,1H),6.10-6.05(q,J=2.66Hz,1H),5.76(d,J=4.84Hz,1H),4.85(s, 2H),4.13-4.11(m,1H),4.01-3.88(m,3H),3.70-3.65(m,1H),2.96-2.84(m,2H),1.99-1.95(m,2H),1.86( d, J=2.66Hz, 3H).

实施例21(3S,3aS,6aS)-6-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)甲基)-1H-吡唑-1-基)六氢呋喃并[3,2-b]呋喃-3-醇Example 21 (3S, 3aS, 6aS)-6-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine- 3-yl)methyl)-1H-pyrazol-1-yl)hexahydrofuro[3,2-b]furan-3-ol

Figure BDA00002905454701271
Figure BDA00002905454701271

步骤1)step 1)

(3R,3aR,6S,6aS)-6-羟基六氢呋喃并[3,2-b]呋喃-3-对甲苯磺酸酯(21.1a)(3R,3aR,6S,6aS)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-p-toluenesulfonate (21.1a)

(3S,3aR,6R,6aS)-6-羟基六氢呋喃并[3,2-b]呋喃-3-对甲苯磺酸酯(21.1b)(3S,3aR,6R,6aS)-6-Hydroxyhexahydrofuro[3,2-b]furan-3-p-toluenesulfonate (21.1b)

(3R,3aR,6S,6aR)-六氢呋喃并[3,2-b]呋喃-3,6-双(对甲苯磺酸酯)(21.1c)(3R,3aR,6S,6aR)-Hexahydrofuro[3,2-b]furan-3,6-bis(p-toluenesulfonate) (21.1c)

Figure BDA00002905454701272
Figure BDA00002905454701272

将异山梨醇(5g,34.2mmol)溶解在水(20mL)中，降温至0°C，向其中依次加入对甲苯磺酰氯(7.34g,38.5mmol)的甲苯(25mL)溶液和氢氧化钾(2.5g,44.6mmol)的水(9mL)溶液。反应液于5°C搅拌4小时后，恢复至室温，继续搅拌过夜。反应毕，混合物加水(100mL)淬灭，并用乙酸乙酯(100mL×3)萃取。合并的有机相用盐水(120mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到(21.1a)和(21.1b)(2.8g,28%)，以及(21.1c)(0.6g,5%)均为白色固体。  Isosorbide (5g, 34.2mmol) was dissolved in water (20mL), cooled to 0°C, and toluene (25mL) solution of p-toluenesulfonyl chloride (7.34g, 38.5mmol) and potassium hydroxide ( 2.5g, 44.6mmol) in water (9mL). The reaction solution was stirred at 5° C. for 4 hours, then returned to room temperature, and stirred overnight. After the reaction was complete, the mixture was quenched with water (100 mL), and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine (120 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain (21.1a) and (21.1b) (2.8g, 28%), and (21.1c) (0.6g, 5%) were all white solids. the

LC-MS(ESI,pos.ion)m/z:301[M+H]+。  LC-MS (ESI, pos.ion) m/z: 301 [M+H] + .

步骤2)(3R,3aR,6S,6aS)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-对甲苯磺酸酯Step 2) (3R,3aR,6S,6aS)-6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-p-toluenesulfonate Ester

将DHP溶解在二氯甲烷(20mL)中，冰盐浴冷却，向其中加入PPTS(0.2g,0.9mmol)，氮气保护下，继续向体系内加入(21.1a)和(21.1b)(2.7g,9mmol)的二氯甲烷(20mL)溶液。反应液在0°C搅拌30分钟后，恢复至室温，继续搅拌过夜。反应毕，将混合物减压浓缩，残留物加水(50mL)稀释，并用乙酸乙酯(50mL×3)萃取。合并的有机相用盐水(150mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=3/1)纯化，得到标题化合物为无色油状物(3.1g,88.5%)。  Dissolve DHP in dichloromethane (20mL), cool in an ice-salt bath, add PPTS (0.2g, 0.9mmol) to it, and continue to add (21.1a) and (21.1b) (2.7g , 9mmol) in dichloromethane (20mL) solution. The reaction solution was stirred at 0° C. for 30 minutes, then returned to room temperature, and stirred overnight. After the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain The title compound was a colorless oil (3.1 g, 88.5%). the

LC-MS(ESI,pos.ion)m/z:407[M+H]+；  LC-MS (ESI, pos.ion) m/z: 407[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.84(d,J=1.36Hz,2H),7.82(d,J=1.44Hz,2H),4.67-4.64(m,1H),4.53-4.51(m,2H),4.44-4.39(dd,J=4.28Hz,2H),4.22-4.2(m,1H),3.88-3.73(m,4H),3.52-3.33(m,2H),2.43(s,3H),1.72-1.43(m,6H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.84 (d, J=1.36Hz, 2H), 7.82 (d, J=1.44Hz, 2H), 4.67-4.64 (m, 1H), 4.53-4.51 (m,2H),4.44-4.39(dd,J=4.28Hz,2H),4.22-4.2(m,1H),3.88-3.73(m,4H),3.52-3.33(m,2H),2.43(s ,3H), 1.72-1.43(m,6H).

步骤3)4-碘-1-((3aS,6S,6aR)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-基)-1H-吡唑Step 3) 4-iodo-1-((3aS,6S,6aR)-6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan- 3-yl)-1H-pyrazole

将4-碘-1H-吡唑(0.89g,4.5mmol)溶解在无水N,N-二甲基甲酰胺(15mL)中，降温至0°C，向其中分批加入氢化钠(0.3g,9mmol,80%分散在矿物油中)。混合物在0°C搅拌1小时后，向体系内加入(3R,3aR,6S,6aS)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-对甲苯磺酸酯(1.6g,5.2mmol)的N,N-二甲基甲酰胺(10mL)溶液。反应液在0°C搅拌30分钟，然后加热至80°C，继续搅拌10小时。反应毕，加水(70mL)淬灭，并用乙酸乙酯(70mL×3)萃取。合并的有机相用盐水(180mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=4/1)纯化，得到标题化合物为黄色固体(0.9g,50%)。  Dissolve 4-iodo-1H-pyrazole (0.89g, 4.5mmol) in anhydrous N,N-dimethylformamide (15mL), cool to 0°C, add sodium hydride (0.3g , 9mmol, 80% dispersed in mineral oil). After the mixture was stirred at 0°C for 1 hour, (3R,3aR,6S,6aS)-6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3, 2-b] Furan-3-p-toluenesulfonate (1.6 g, 5.2 mmol) in N,N-dimethylformamide (10 mL). The reaction solution was stirred at 0° C. for 30 minutes, then heated to 80° C., and stirred for 10 hours. After the reaction was completed, water (70 mL) was added to quench, and extracted with ethyl acetate (70 mL×3). The combined organic phases were washed with brine (180 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain The title compound was a yellow solid (0.9 g, 50%). the

LC-MS(ESI,pos.ion)m/z:429[M+Na]+。  LC-MS (ESI, pos.ion) m/z: 429 [M+Na] + .

步骤4)1-((3aS,6S,6aR)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑Step 4) 1-((3aS,6S,6aR)-6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-yl) -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

将4-碘-1-((3aS,6S,6aR)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-基)-1H-吡唑(0.9g,2.2mmol)，联硼酸频那醇酯(1.5g,6.6mmol)和醋酸钾(646mg,6.6mmol)溶解在二甲亚砜(20mL)中，氮气保护下，向其中加入Pd(dppf)Cl2(179mg,0.22mmol)。反应液在60°C搅拌2小时。反应毕，冷却至室温，加水(50mL)稀释，并用乙酸乙酯(40mL×3)萃取。合并的有机相用盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/1)纯化，得到标题化合物为黄色固体(0.6g,67%)。  4-iodo-1-((3aS,6S,6aR)-6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3- base)-1H-pyrazole (0.9g, 2.2mmol), diboronic acid pinacol ester (1.5g, 6.6mmol) and potassium acetate (646mg, 6.6mmol) were dissolved in dimethyl sulfoxide (20mL), nitrogen protection , Pd(dppf)Cl 2 (179 mg, 0.22 mmol) was added thereto. The reaction was stirred at 60°C for 2 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain The title compound was a yellow solid (0.6 g, 67%).

LC-MS(ESI,pos.ion)m/z:407[M+H]+；  LC-MS (ESI, pos.ion) m/z: 407[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.93(s,1H),7.80(s,1H),5.12-4.92(m,1H),4.81-4.68(m,3H),4.44-4.41(m,2H),4.36-3.73(m,4H),3.54-3.53(m,1H),2.05-1.50(m,6H),1.25(s,12H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.93 (s, 1H), 7.80 (s, 1H), 5.12-4.92 (m, 1H), 4.81-4.68 (m, 3H), 4.44-4.41 ( m, 2H), 4.36-3.73 (m, 4H), 3.54-3.53 (m, 1H), 2.05-1.50 (m, 6H), 1.25 (s, 12H).

步骤5)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3aS,6S,6aR)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺Step 5) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3aS,6S,6aR)-6-(( Hydrogen-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-yl)-1H-pyrazol-4-yl)pyridin-2-amine

将1-((3aS,6S,6aR)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(857mg,2.3mmol),(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.77g,1.89mmol)和碳酸钠(0.4g,3.78mmol)溶解在乙二醇二甲醚/水(25mL/2mL)的混合液中，氮气保护下，依次加入Pd(OAc)2(43mg,0.19mmol)和(t-Bu)3P(0.57mL,2N的甲苯溶液)。混合物在87°C搅拌18小时。反应毕，冷却至室温，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯/甲醇(v/v/v)=10/10/1)纯化，得到标题化合物为黄色固体(0.7g,54%)。  1-((3aS,6S,6aR)-6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-yl)-4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (857mg, 2.3mmol), (R)-5- Bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.77g, 1.89mmol) and sodium carbonate (0.4g, 3.78mmol) were dissolved in ethanol In the mixed solution of glycol dimethyl ether/water (25mL/2mL), under nitrogen protection, add Pd(OAc) 2 (43mg, 0.19mmol) and (t-Bu) 3 P (0.57mL, 2N toluene solution ). The mixture was stirred at 87°C for 18 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/methanol (v/v/v)=10/10/1) to obtain the title compound as a yellow solid (0.7 g, 54%).

LC-MS(ESI,pos.ion)m/z:579[M+H]+；  LC-MS (ESI, pos.ion) m/z: 579[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.75(s,1H),7.69(d,J=6.04Hz,1H),7.58(s,1H),7.29-7.27(m,1H),7.05-7.01(m,1H),6.08-6.03(q,J=6.64Hz,1H),4.97-4.91(m,1H),4.85(m,2H),4.82-4.69(m,3H),4.46-4.33(m,2H),4.18-3.98(m,3H),3.86-3.78(m,1H),3.56-3.52(m,1H),1.84(d,J=6.64 Hz,3H),1.58-1.23(m,6H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.75(s,1H),7.69(d,J=6.04Hz,1H),7.58(s,1H),7.29-7.27(m,1H),7.05 -7.01(m,1H),6.08-6.03(q,J=6.64Hz,1H),4.97-4.91(m,1H),4.85(m,2H),4.82-4.69(m,3H),4.46-4.33 (m,2H),4.18-3.98(m,3H),3.86-3.78(m,1H),3.56-3.52(m,1H),1.84(d,J=6.64 Hz,3H),1.58-1.23(m ,6H).

步骤6)(3S,3aS,6aS)-6-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)六氢呋喃并[3,2-b]呋喃-3-醇Step 6) (3S,3aS,6aS)-6-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine- 3-yl)-1H-pyrazol-1-yl)hexahydrofuro[3,2-b]furan-3-ol

将3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3aS,6S,6aR)-6-((四氢-2H-吡喃-2-基)氧基)六氢呋喃并[3,2-b]呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺(0.5g,0.86mmol)溶解于甲醇(25mL)中，向其中加入2M盐酸(2mL)。反应液在45°C搅拌1小时，反应毕，减压浓缩。将残留物用二氯甲烷(30mL)，水(30mL)和2M碳酸钠溶液(5mL)稀释，所得混合物用二氯甲烷(30mL×2)萃取。合并的有机相用盐水(100mL)洗，无水硫酸钠干燥，并减压浓缩，残留物经硅胶柱层析(石油醚/乙酸乙酯/甲醇(v/v/v)=10/10/1)纯化，得到标题化合物为黄色固体(0.3g,70%)。  3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3aS,6S,6aR)-6-((tetrahydro- 2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-yl)-1H-pyrazol-4-yl)pyridin-2-amine (0.5g, 0.86mmol ) was dissolved in methanol (25 mL), and 2M hydrochloric acid (2 mL) was added thereto. The reaction solution was stirred at 45° C. for 1 hour, and after completion of the reaction, it was concentrated under reduced pressure. The residue was diluted with dichloromethane (30 mL), water (30 mL) and 2M sodium carbonate solution (5 mL), and the resulting mixture was extracted with dichloromethane (30 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate/methanol (v/v/v)=10/10/ 1) Purification to obtain the title compound as a yellow solid (0.3g, 70%). the

LC-MS(ESI,pos.ion)m/z:495[M+H]+；  LC-MS (ESI, pos.ion) m/z: 495[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.77(d,J=1.4Hz,1H),7.69(d,J=6.04Hz,1H),7.59(s,1H),7.31(s,1H),7.07-7.03(m,1H),6.86(d,J=1.4Hz,1H),6.08-6.03(q,J=6.68Hz,1H),4.99-4.95(m,1H),4.81(s,2H),4.73-4.71(m,2H),4.44-4.40(m,2H),4.19-4.14(t,J=8.84Hz,2H),3.98-3.95(dd,J=5.76Hz,1H),3.80-3.77(dd,J=5.76Hz,1H),1.85(d,J=6.68Hz,3H)。  1 H NMR(400MHz,CDCl 3 )δ(ppm):7.77(d,J=1.4Hz,1H),7.69(d,J=6.04Hz,1H),7.59(s,1H),7.31(s,1H ),7.07-7.03(m,1H),6.86(d,J=1.4Hz,1H),6.08-6.03(q,J=6.68Hz,1H),4.99-4.95(m,1H),4.81(s, 2H),4.73-4.71(m,2H),4.44-4.40(m,2H),4.19-4.14(t,J=8.84Hz,2H),3.98-3.95(dd,J=5.76Hz,1H),3.80 -3.77(dd, J=5.76Hz, 1H), 1.85(d, J=6.68Hz, 3H).

实施例22((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-((3aS,6R,6aR)-6-氟六氢呋喃并[3,2-b]呋喃-3-基)-1H-吡唑-4-基)吡啶-2-胺Example 22 ((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-((3aS,6R,6aR)-6-fluorohexahydrofuro [3,2-b]furan-3-yl)-1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454701301
Figure BDA00002905454701301

将(3S,3aS,6aS)-6-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡 啶-3-基)-1H-吡唑-1-基)六氢呋喃并[3,2-b]呋喃-3-醇(0.14g,0.28mmol)溶解在二氯甲烷(4mL)中，降温至-78°C，向体系内滴加DAST(70mg,0.43mmol)的二氯甲烷(1mL)溶液。反应液在-78°C搅拌1小时后，恢复至室温，并搅拌过夜。反应毕，减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯/甲醇(v/v/v)=20/20/1)纯化，得到标题化合物为黄色固体(40mg,28.5%)。  (3S,3aS,6aS)-6-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-3- Base)-1H-pyrazol-1-yl)hexahydrofuro[3,2-b]furan-3-ol (0.14g, 0.28mmol) was dissolved in dichloromethane (4mL), cooled to -78 ° C. A solution of DAST (70 mg, 0.43 mmol) in dichloromethane (1 mL) was added dropwise to the system. The reaction solution was stirred at -78°C for 1 hour, then returned to room temperature, and stirred overnight. After the reaction was completed, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate/methanol (v/v/v)=20/20/1) to obtain the title compound as a yellow solid (40 mg , 28.5%).

LC-MS(ESI,pos.ion)m/z:497[M+H]+；  LC-MS (ESI, pos.ion) m/z: 497[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=1.68Hz,1H),7.69(s,1H),7.59(s,1H),7.33-7.28(s,1H),7.08-7.03(m,1H),6.86(d,J=1.48Hz,1H),6.09-6.04(q,J=6.68Hz,1H),5.24-5.10(dd,J=2.8Hz,1H),4.98-4.93(m,4H),4.84-4.82(m,1H),4.34-4.32(m,1H),4.26-3.97(m,3H),1.87-1.85(d,J=6.68Hz,3H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.75 (d, J=1.68Hz, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.33-7.28 (s, 1H), 7.08 -7.03(m,1H),6.86(d,J=1.48Hz,1H),6.09-6.04(q,J=6.68Hz,1H),5.24-5.10(dd,J=2.8Hz,1H),4.98- 4.93 (m, 4H), 4.84-4.82 (m, 1H), 4.34-4.32 (m, 1H), 4.26-3.97 (m, 3H), 1.87-1.85 (d, J=6.68Hz, 3H).

实施例234-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(八氢环戊烷并[c]吡咯5-基)-1H-吡唑-4-基)吡啶-2-胺Example 234-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(octahydrocyclopenta[c]pyrrol 5-yl) -1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454701311
Figure BDA00002905454701311

步骤1)2-(叔丁氧羰基)-2,3,3a,4,7,7a-六氢-1H-异吲哚Step 1) 2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole

将氢化锂铝(3.04g,80mmol)溶解在四氢呋喃(80mL)中，向其中分批加入3a,4,7,7a-四氢-1H-异吲哚-1,3(2H)-二酮(5.26g,34.8mmol)。反应液在60°C搅拌21小时。反应毕，冷却至室温，加入乙酸乙酯(25mL)稀释后，依次用水(3mL)和15%氢氧化钾溶液（3mL）淬灭。所得混合物继续在室温下搅拌1小时，然后用硅藻土过滤，滤饼用二氯甲烷(40mL)洗。将滤液减压浓缩，得到2,3,3a,4,7,7a-六氢-1H-异吲哚为黄色油状物。  Lithium aluminum hydride (3.04 g, 80 mmol) was dissolved in tetrahydrofuran (80 mL), and 3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione ( 5.26 g, 34.8 mmol). The reaction was stirred at 60°C for 21 hours. After completion of the reaction, cool to room temperature, add ethyl acetate (25 mL) to dilute, and then quench with water (3 mL) and 15% potassium hydroxide solution (3 mL) successively. The resulting mixture was stirred at room temperature for an additional 1 hour, then filtered through celite, and the filter cake was washed with dichloromethane (40 mL). The filtrate was concentrated under reduced pressure to obtain 2,3,3a,4,7,7a-hexahydro-1H-isoindole as a yellow oil. the

将2,3,3a,4,7,7a-六氢-1H-异吲哚(3.89g,31.3mmol)溶解在二氯甲烷(40mL)中，降温至0°C，向其中加入Boc酸酐(10.3g,47mmol)。反应液在0°C搅拌0.5小时后，恢复至室温，继续搅拌21小时。反应毕，将混合物减压浓缩，残留物用乙酸乙酯(80mL)稀释。所得溶液依次用1M柠檬酸(17mL×2)、水(17mL×2)、饱和碳酸氢钠溶液(17mL×2)和盐水(17mL)洗。有机溶液经无水硫酸钠干燥，并减压浓缩后，用硅胶柱层析(正己烷/乙酸乙酯(v/v)=85/15)纯化，得到标题化合物为橙红色油状物(4.7g,54.5%)。  2,3,3a,4,7,7a-hexahydro-1H-isoindole (3.89g, 31.3mmol) was dissolved in dichloromethane (40mL), cooled to 0°C, and Boc anhydride ( 10.3g, 47mmol). After the reaction solution was stirred at 0° C. for 0.5 hour, it was returned to room temperature, and stirring was continued for 21 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (80 mL). The resulting solution was washed sequentially with 1M citric acid (17 mL×2), water (17 mL×2), saturated sodium bicarbonate solution (17 mL×2) and brine (17 mL). The organic solution was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane/ethyl acetate (v/v)=85/15) to obtain the title compound as an orange-red oil (4.7 g ,54.5%). the

MS(ESI,pos.ion)m/z168.2[(M+H)+-C4H8]；  MS(ESI,pos.ion)m/z168.2[(M+H) + - C4H8 ];

1H NMR(400MHz,CDCl3)δ(ppm):5.64(s,2H),3.40(m,2H),3.16(m,1H),3.07(m,1H),2.25(m,4H),1.90(m,2H),1.46(s,9H)。  1 H NMR (400MHz, CDCl 3 )δ( pp m):5.64(s,2H),3.40(m,2H),3.16(m,1H),3.07(m,1H),2.25(m,4H), 1.90(m,2H),1.46(s,9H).

步骤2)2,2'-(1-(叔丁氧羰基)吡咯烷-3,4-二基)二乙酸Step 2) 2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid

将2-(叔丁氧羰基)-2,3,3a,4,7,7a-六氢-1H-异吲哚(4.7g,21mmol)溶解在CCl4(50mL)，MeCN(50mL)和水(75mL)的混合液中，并向其中依次加入NaIO4(18g,84.2mmol)和RuO2(0.16g,1.2mmol)。反应液在室温搅拌24小时后，用DCM(60mL)稀释，并用硅藻土过滤，水相用DCM(50mL)萃取。将合并的有机相用盐水(60mL)洗，Na2SO4干燥，并减压浓缩，残留物经硅胶柱层析(100%DCM)纯化，得到标题化合物为黄色油状物(3g,49.6%)。  2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole (4.7 g, 21 mmol) was dissolved in CCl4 (50 mL), MeCN (50 mL) and water (75 mL), and NaIO 4 (18 g, 84.2 mmol) and RuO 2 (0.16 g, 1.2 mmol) were sequentially added thereto. After the reaction solution was stirred at room temperature for 24 hours, it was diluted with DCM (60 mL), filtered through celite, and the aqueous phase was extracted with DCM (50 mL). The combined organic phases were washed with brine (60 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by silica gel column chromatography ( 100 % DCM) to give the title compound as a yellow oil (3 g, 49.6%) .

MS(ESI,pos.ion)m/z232.2[(M+H)+-C4H8]；  MS(ESI,pos.ion)m/z232.2[(M+H) + - C4H8 ];

1H NMR(400MHz,CDCl3)δ(ppm):3.53(m,2H),3.04(m,2H),2.80(m,2H),2.44(m,4H),1.43(s,9H)。  1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 3.53 (m, 2H), 3.04 (m, 2H), 2.80 (m, 2H), 2.44 (m, 4H), 1.43 (s, 9H).

步骤3)2-(叔丁氧羰基)六氢环戊烷并[c]吡咯-5(1H)-酮Step 3) 2-(tert-butoxycarbonyl)hexahydrocyclopenta[c]pyrrol-5(1H)-one

将2,2'-(1-(叔丁氧羰基)吡咯烷-3,4-二基)二乙酸(3g,10.4mmol)溶解在乙酸酐(30mL)中，向其中加入乙酸钠(0.79g,9.6mmol)。反应液在120°C搅拌3小时后，冷却到室温，并过滤。滤饼用乙酸乙酯(20mLx2)洗，滤液减压浓缩。所得残留物经硅胶柱层析(正己烷/乙酸乙酯(v/v)=1/1)纯化，得到标题化合物为橙黄色油状物(0.55g,23.4%)。  2,2'-(1-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (3 g, 10.4 mmol) was dissolved in acetic anhydride (30 mL), and sodium acetate (0.79 g ,9.6mmol). The reaction solution was stirred at 120° C. for 3 hours, cooled to room temperature, and filtered. The filter cake was washed with ethyl acetate (20 mLx2), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate (v/v)=1/1) to obtain the title compound as an orange-yellow oil (0.55 g, 23.4%). the

1H NMR(400MHz,CDCl3)δ(ppm):3.69(m,2H),3.00(m,4H),2.61(dd,J =8.2,18.4Hz,2H),2.29(dd,J=5.8,18.4Hz,2H),1.43(s,9H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):3.69(m,2H),3.00(m,4H),2.61(dd,J=8.2,18.4Hz,2H),2.29(dd,J=5.8, 18.4Hz, 2H), 1.43(s, 9H).

步骤4)2-(叔丁氧羰基)八氢环戊烷并[c]吡咯-5-醇Step 4) 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-ol

将2-(叔丁氧羰基)八氢环戊烷并[c]吡咯-5-醇(0.9g,4mmol)溶解在乙醇(20mL)中，向其中分批加入硼氢化钠(0.82g,21.7mmol)。反应液室温搅拌4.5小时。反应毕，减压浓缩。将残留物用乙酸乙酯(50mL)稀释，并依次用水(50mL)、盐水(50mL)洗。所得溶液经无水硫酸钠干燥，减压浓缩，得到标题化合物为黄色油状物(0.99g,100%)。该化合物不需纯化，直接用于下一步。  2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-ol (0.9g, 4mmol) was dissolved in ethanol (20mL), and sodium borohydride (0.82g, 21.7 mmol). The reaction solution was stirred at room temperature for 4.5 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), and washed successively with water (50 mL), brine (50 mL). The resulting solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a yellow oil (0.99 g, 100%). The compound was used directly in the next step without purification. the

步骤5)2-(叔丁氧羰基)八氢环戊烷并[c]吡咯-5-基甲磺酸酯Step 5) 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl mesylate

将2-(叔丁氧羰基)八氢环戊烷并[c]吡咯-5-醇(0.91g,3.56mmol)溶解在二氯甲烷(8mL)中，冷却至0°C，向其中依次加入三乙胺(0.8mL,5.74mmol)，甲磺酰氯(0.35mL,4.52mmol)和DMAP(5mg,0.04mmol)的二氯甲烷(2mL)悬浮液。反应液室温搅拌16小时，反应毕，依次用水(15mL)、食盐水(15mL)洗。所得溶液经无水硫酸钠干燥，并减压浓缩，得到标题化合物为黄色油状物(1.3g,100%)。该产物不经纯化，直接用于下一步。  Dissolve 2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-ol (0.91g, 3.56mmol) in dichloromethane (8mL), cool to 0°C, and add Suspension of triethylamine (0.8 mL, 5.74 mmol), methanesulfonyl chloride (0.35 mL, 4.52 mmol) and DMAP (5 mg, 0.04 mmol) in dichloromethane (2 mL). The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with water (15 mL) and brine (15 mL) successively. The resulting solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (1.3 g, 100%). The product was used directly in the next step without purification. the

步骤6)2-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)八氢环戊烷并[c]吡咯Step 6) 2-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)octahydrocyclopenta[c]pyrrole

将4-碘-1H-吡唑(1.16g,6mmol)溶解在无水N,N-二甲基甲酰胺(10mL)中，降温至0°C，向其中分批加入氢化钠(538mg,17.9mmol,80%分散在矿物油中)。混合物在0°C搅拌1小时后，向体系内加入2-(叔丁氧羰基)八氢环戊烷并[c]吡咯-5-基甲磺酸酯(1.22g,4mmol)的N,N-二甲基甲酰胺(5mL)溶液。反应液在100°C搅拌21小时。反应毕，冷却至室温，加乙酸乙酯(30mL)稀释。混合物依次用水(20mL×3)、盐水(20mL)洗，无水硫酸钠干燥，并减压浓缩，所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=5/1)纯化，得到标题化合物浅黄色固体(1.37g,85.1%)。  4-iodo-1H-pyrazole (1.16g, 6mmol) was dissolved in anhydrous N,N-dimethylformamide (10mL), cooled to 0°C, and sodium hydride (538mg, 17.9 mmol, 80% dispersed in mineral oil). After the mixture was stirred at 0°C for 1 hour, N,N - Dimethylformamide (5 mL) solution. The reaction was stirred at 100°C for 21 hours. After the reaction was completed, it was cooled to room temperature and diluted with ethyl acetate (30 mL). The mixture was washed with water (20mL×3) and brine (20mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5/1 ) to obtain the title compound as a pale yellow solid (1.37 g, 85.1%). the

MS(ESI,pos.ion)m/z348.0[(M+H)+-C4H8]；  MS(ESI, pos.ion )m/z348.0[(M+H) + - C4H8 ];

1H NMR(400MHz,CDCl3)δ(ppm):7.50(s,1H),7.45(s,1H),4.82(m,1H),3.55(brs,2H),3.23(brs,2H),2.92(m,2H),2.33(m,2H),2.05(brs,2H), 1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.50 (s, 1H), 7.45 (s, 1H), 4.82 (m, 1H), 3.55 (brs, 2H), 3.23 (brs, 2H), 2.92 (m,2H), 2.33(m,2H), 2.05(brs,2H), 1.47(s,9H).

步骤7)2-(叔丁氧羰基)-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)八氢环戊烷并[c]吡咯Step 7) 2-(tert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrazol-1-yl)octahydrocyclopenta[c]pyrrole

将2-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)八氢环戊烷并[c]吡咯(0.48g,1.2mmol)和联硼酸频那醇酯(0.36g,1.44mmol)溶解在二甲亚砜(8mL)中，向其中加入醋酸钾(0.35g,3.6mmol)，氮气保护后，继续向体系内加入Pd(dppf)Cl2(98mg,0.12mmol)。反应液在80°C搅拌1小时。反应毕，加水(10mL)淬灭，并用乙酸乙酯(20mL×3)萃取。合并的有机相用盐水(30mL)洗，无水硫酸钠干燥，并减压浓缩。所得残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=2/1)纯化，得到标题化合物为黄色油状物(256mg,53.3%)。  2-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)octahydrocyclopenta[c]pyrrole (0.48g, 1.2mmol) and diboronic acid pinacol ester (0.36g, 1.44mmol) was dissolved in dimethyl sulfoxide (8mL), and potassium acetate (0.35g, 3.6mmol) was added thereto. After nitrogen protection, Pd(dppf)Cl 2 (98mg, 0.12 mmol). The reaction was stirred at 80°C for 1 hour. After the reaction was completed, water (10 mL) was added to quench, and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain the title compound as a yellow oil (256 mg, 53.3%).

MS(ESI,pos.ion)m/z404.3[M+H]+；  MS(ESI,pos.ion)m/z404.3[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.79(s,1H),7.71(s,1H),4.84(m,1H),3.56(brs,2H),3.23(brs,2H),2.93(brs,2H),2.34(m,2H),2.08(brs,2H),1.47(s,9H),1.27(s,12H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.79(s,1H),7.71(s,1H),4.84(m,1H),3.56(brs,2H),3.23(brs,2H),2.93 (brs, 2H), 2.34 (m, 2H), 2.08 (brs, 2H), 1.47 (s, 9H), 1.27 (s, 12H).

步骤8)5-(1-(2-(叔丁氧羰基)八氢环戊烷并[c]吡咯-5-基)-1H-吡唑-4-基)-4-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 8) 5-(1-(2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-4-((R)- 1-(2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

将2-(叔丁氧羰基)-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)八氢环戊烷并[c]吡咯(256mg,0.64mmol)和(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(326mg,0.95mmol)溶解于乙二醇二甲醚(8mL)中，向其中加入1.2M碳酸钠溶液(2mL,1.91mmol)，氮气保护后，继续向体系内加入Pd(dppf)Cl2(104mg,0.13mmol)。反应液在100°C搅拌8小时，反应毕，冷却至室温，加水(20mL)稀释，并用乙酸乙酯(20mL×3)萃取。合并的有机相用盐水(30mL)洗，无水硫酸钠干燥，并减压浓缩，残留物经硅胶柱层析(石油醚/乙酸乙酯(v/v)=1/2)纯化，得到标题化合物为黄色固体(157mg,42.9%)。  2-(tert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridine Azol-1-yl)octahydrocyclopenta[c]pyrrole (256mg, 0.64mmol) and (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl) Ethoxy)pyridin-2-amine (326mg, 0.95mmol) was dissolved in ethylene glycol dimethyl ether (8mL), 1.2M sodium carbonate solution (2mL, 1.91mmol) was added thereto, and after nitrogen protection, the system was continued to Pd(dppf) Cl2 (104 mg, 0.13 mmol) was added internally. The reaction solution was stirred at 100° C. for 8 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain the title Compound was a yellow solid (157mg, 42.9%).

LC-MS(ESI,pos.ion)m/z:576.2[M+H]+；  LC-MS (ESI, pos.ion) m/z: 576.2[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.74(d,J=1.6Hz,1H),7.56(s,1H),7.46(s,1H),7.30(m,1H),7.05(t,J=8.0Hz,1H),6.85(d,J=1.4Hz,1H), 6.07(m,1H),4.82(m,3H),3.57(brs,2H),3.25(brs,2H),2.95(brs,2H),2.35(m,2H),2.05(brs,2H),1.85(d,J=6.7Hz,1H),1.47(s,9H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm): 7.74(d, J=1.6Hz, 1H), 7.56(s, 1H), 7.46(s, 1H), 7.30(m, 1H), 7.05(t ,J=8.0Hz,1H),6.85(d,J=1.4Hz,1H), 6.07(m,1H),4.82(m,3H),3.57(brs,2H),3.25(brs,2H),2.95 (brs, 2H), 2.35 (m, 2H), 2.05 (brs, 2H), 1.85 (d, J=6.7Hz, 1H), 1.47 (s, 9H).

步骤9)4-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(八氢环戊烷并[c]吡咯5-基)-1H-吡唑-4-基)吡啶-2-胺Step 9) 4-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(octahydrocyclopenta[c]pyrrol 5-yl )-1H-pyrazol-4-yl)pyridin-2-amine

将5-(1-(2-(叔丁氧羰基)八氢环戊烷并[c]吡咯-5-基)-1H-吡唑-4-基)-4-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(157mg,0.27mmol)溶解在二氯甲烷(10mL)中，向其中缓慢加入HCl(4mL,3M的乙酸乙酯溶液)。反应液室温搅拌2小时后，减压浓缩。将残留物用水(30mL)和二氯甲烷(50mL)稀释，然后用饱和碳酸钠溶液调节pH10，并用二氯甲烷(50mL×3)萃取。合并的有机相用盐水(80mL)洗，无水硫酸钠干燥，并减压浓缩，残留物经硅胶柱层析(二氯甲烷/甲醇/三乙胺(v/v/v)=500/50/1)纯化，得到标题化合物为黄色固体(0.1g,76.9%)。  5-(1-(2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)-1H-pyrazol-4-yl)-4-((R)-1- (2,6-Dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (157mg, 0.27mmol) was dissolved in dichloromethane (10mL), and HCl (4mL, 3M acetic acid ethyl ester solution). After stirring the reaction solution at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was diluted with water (30 mL) and dichloromethane (50 mL), then adjusted to pH 10 with saturated sodium carbonate solution, and extracted with dichloromethane (50 mL×3). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol/triethylamine (v/v/v)=500/50 /1) Purification afforded the title compound as a yellow solid (0.1 g, 76.9%). the

LC-MS(ESI,pos.ion)m/z:476.1[M+H]；  LC-MS (ESI, pos.ion) m/z: 476.1 [M+H];

1H NMR(400MHz,CDCl3)δ(ppm):7.72(d,J=1.6Hz,1H),7.54(s,1H),7.48(s,1H),7.30(m,1H),7.05(t,J=8.2Hz,1H),6.85(d,J=1.4Hz,1H),6.07(m,1H),4.91(s,2H),4.88(m,1H),3.66(s,1H),3.29(m,2H),3.03(m,2H),2.43(m,2H),2.11(m,2H),2.07(d,J=17.2Hz,2H),1.85(d,J=6.7Hz,1H)。  1 H NMR(400MHz, CDCl 3 )δ(ppm):7.72(d,J=1.6Hz,1H),7.54(s,1H),7.48(s,1H),7.30(m,1H),7.05(t ,J=8.2Hz,1H),6.85(d,J=1.4Hz,1H),6.07(m,1H),4.91(s,2H),4.88(m,1H),3.66(s,1H),3.29 (m,2H),3.03(m,2H),2.43(m,2H),2.11(m,2H),2.07(d,J=17.2Hz,2H),1.85(d,J=6.7Hz,1H) .

实施例243-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(八氢-1H-异吲哚-5-基)-1H-吡唑-4-基)吡啶-2-胺Example 243-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(octahydro-1H-isoindol-5-yl)- 1H-pyrazol-4-yl)pyridin-2-amine

Figure BDA00002905454701351
Figure BDA00002905454701351

步骤1)2-(叔丁氧羰基)八氢-1H-异吲哚-5-醇Step 1) 2-(tert-butoxycarbonyl)octahydro-1H-isoindol-5-ol

将2-(叔丁氧羰基)-2,3,3a,4,7,7a-六氢-1H-异吲哚(3.16g,14.2mmol)溶解在无水四氢呋喃(35mL)中，氮气保护后，降温至0℃，向其中滴加BH3-DMS(1.5mL,15.0mmol,10M的四氢呋喃溶液)。反应液室温搅拌过夜，反应毕，降温至0℃。反应液依次用甲醇(8mL)、3M氢氧化钠(5mL)和30%双氧水(5mL)混合液淬灭。所得悬浮液在60℃搅拌1.5小时后，降至室温，加乙醚/水(30mL/30mL)稀释，并用乙酸乙酯(30mL×3)萃取。合并的有机相用盐水(30mL×3)洗，无水硫酸钠干燥，并减压浓缩，得到橙色油状物(2.46g,71.7%)，该产品不经纯化，直接用于下一步。  Dissolve 2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole (3.16g, 14.2mmol) in anhydrous tetrahydrofuran (35mL), and protect it under nitrogen , cooled to 0° C., and BH 3 -DMS (1.5 mL, 15.0 mmol, 10 M solution in tetrahydrofuran) was added dropwise thereto. The reaction solution was stirred at room temperature overnight, and after the reaction was completed, the temperature was lowered to 0°C. The reaction solution was sequentially quenched with a mixture of methanol (8 mL), 3M sodium hydroxide (5 mL) and 30% hydrogen peroxide (5 mL). The resulting suspension was stirred at 60°C for 1.5 hours, cooled to room temperature, diluted with ether/water (30 mL/30 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an orange oil (2.46 g, 71.7%), which was directly used in the next step without purification.

LC-MS(ESI,pos.ion)m/z:186.2[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 186.2 [M+H-56] + ;

1H NMR(400MHz,CDCl3)δ(ppm):3.89(m,1H),3.35(m,2H),3.22(m,2H),2.47(m,1H),2.10(m,1H),1.82(m,4H),1.62(m,1H),1.54(m2H),1.46(s,9H)。  1 H NMR (400MHz, CDCl 3 ) δ (ppm): 3.89 (m, 1H), 3.35 (m, 2H), 3.22 (m, 2H), 2.47 (m, 1H), 2.10 (m, 1H), 1.82 (m,4H), 1.62(m,1H), 1.54(m2H), 1.46(s,9H).

步骤2)2-(叔丁氧羰基)八氢-1H-异吲哚-5-基甲磺酸酯Step 2) 2-(tert-butoxycarbonyl) octahydro-1H-isoindol-5-yl methanesulfonate

标题化合物通过实施例23步骤5所描述的方法制备得到，即将2-(叔丁氧羰基)八氢-1H-异吲哚-5-醇(4.51g,18.69mmol)，三乙胺(4mL,28.70mmol)，甲磺酰氯(2.2mL,28.41mmol)和DMAP(34.3mg,0.28mmol)悬浮在二氯甲烷(50mL)中制备，得到粗产品为棕色油状物(5.30g,88.8%)，该产品不经纯化，直接用于下一步。  The title compound was prepared by the method described in step 5 of Example 23, that is, 2-(tert-butoxycarbonyl)octahydro-1H-isoindol-5-ol (4.51g, 18.69mmol), triethylamine (4mL, 28.70mmol), methanesulfonyl chloride (2.2mL, 28.41mmol) and DMAP (34.3mg, 0.28mmol) were suspended in dichloromethane (50mL), and the crude product was obtained as a brown oil (5.30g, 88.8%). The product was used directly in the next step without purification. the

LC-MS(ESI,pos.ion)m/z:264.0[M+H-56]+。  LC-MS (ESI, pos. ion) m/z: 264.0 [M+H-56] + .

步骤3)2-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)八氢-1H-异吲哚Step 3) 2-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)octahydro-1H-isoindole

标题化合物通过实施例23步骤6所描述的方法制备得到，即将2-(叔丁氧羰基)八氢-1H-异吲哚-5-基甲磺酸酯(5.30g,16.6mmol)，4-碘-1H-吡唑(4.83g,24.9mmol)和氢化钠(2.26g,56.4mmol,60%分散在矿物油中)悬浮在无水N,N-二甲基甲酰胺(60mL)中制备，粗产品经硅胶柱层析(石油醚/乙酸乙酯(v/v)=6/1)纯化，得到标题化合物为白色固体(2.67g,38.6%)。  The title compound was prepared by the method described in step 6 of Example 23, that is, 2-(tert-butoxycarbonyl)octahydro-1H-isoindol-5-yl methanesulfonate (5.30g, 16.6mmol), 4- Iodo-1H-pyrazole (4.83 g, 24.9 mmol) and sodium hydride (2.26 g, 56.4 mmol, 60% dispersed in mineral oil) were suspended in anhydrous N,N-dimethylformamide (60 mL), The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=6/1) to obtain the title compound as a white solid (2.67 g, 38.6%). the

LC-MS(ESI,pos.ion)m/z:362.2[M+H-56]+；  LC-MS (ESI, pos.ion) m/z: 362.2 [M+H-56] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.50(d,J=4.1Hz,1H),7.46(s,1H),3.32(m,4H),2.30(brs,1H),2.28(m,1H),2.02(m,2H),1.73(m,5H),1.46(d,J=6.8Hz,9H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm): 7.50(d, J=4.1Hz, 1H), 7.46(s, 1H), 3.32(m, 4H), 2.30(brs, 1H), 2.28(m ,1H), 2.02(m,2H), 1.73(m,5H), 1.46(d,J=6.8Hz,9H).

步骤4)2-(叔丁氧羰基)-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)八氢-1H-异吲哚Step 4) 2-(tert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -pyrazol-1-yl)octahydro-1H-isoindole

标题化合物通过实施例23步骤7所描述的方法制备得到，即将2-(叔丁氧羰基)-5-(4-碘-1H-吡唑-1-基)八氢-1H-异吲哚(2.67g,6.40mmol),联硼酸频那醇酯(1.95g,7.68mmol)，乙酸钾(1.88g,19.20mmol)和Pd(dppf)Cl2(523mg,0.64mmol)悬浮在二甲亚砜(50mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=4/1)纯化，得到标题化合物为橙色油状物(1.34g,50.2%)。  The title compound was prepared by the method described in step 7 of Example 23, that is, 2-(tert-butoxycarbonyl)-5-(4-iodo-1H-pyrazol-1-yl)octahydro-1H-isoindole ( 2.67g, 6.40mmol), biboronic acid pinacol ester (1.95g, 7.68mmol), potassium acetate (1.88g, 19.20mmol) and Pd (dppf) Cl 2 (523mg, 0.64mmol) suspended in dimethyl sulfoxide ( 50 mL), the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to obtain the title compound as an orange oil (1.34 g, 50.2%).

LC-MS(ESI,pos.ion)m/z:418.1[M+H]+；  LC-MS (ESI, pos.ion) m/z: 418.1[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.78(d,J=2.3Hz,1H),7.74(s,1H),3.36(m,4H),2.42(br.s,1H),2.28(m,1H),2.05(m,2H),1.84(m,5H),1.46(d,J=8.0Hz,9H),1.32(d,J=5.4Hz,12H)。  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.78(d,J=2.3Hz,1H),7.74(s,1H),3.36(m,4H),2.42(br.s,1H),2.28 (m,1H),2.05(m,2H),1.84(m,5H),1.46(d,J=8.0Hz,9H),1.32(d,J=5.4Hz,12H).

步骤5)5-(1-(2-(叔丁氧羰基)八氢-1H-异吲哚-5-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺Step 5) 5-(1-(2-(tert-butoxycarbonyl)octahydro-1H-isoindol-5-yl)-1H-pyrazol-4-yl)-3-((R)-1- (2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine

标题化合物通过实施例23步骤8所描述的方法制备得到，即将(R)-5-溴-3-(1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(1.83g,4.82mmol)，2-(叔丁氧羰基)-5-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)八氢-1H-异吲哚(1.34g,3.21mmol)，Pd(dppf)Cl2(524mg,0.642mmol)和1.2M碳酸钠溶液(8mL,9.63mmol)悬浮在乙二醇二甲醚(40mL)中制备，粗产品经硅胶柱层析(PE/EtOAc(v/v)=1/2)纯化，得到标题化合物为橙色固体(230mg,12.1%)。  The title compound was prepared by the method described in step 8 of Example 23, namely (R)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine-2 -Amine (1.83g, 4.82mmol), 2-(tert-butoxycarbonyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-pyrazol-1-yl)octahydro-1H-isoindole (1.34g, 3.21mmol), Pd(dppf)Cl 2 (524mg, 0.642mmol) and 1.2M sodium carbonate solution ( 8mL, 9.63mmol) was suspended in ethylene glycol dimethyl ether (40mL), and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) to obtain the title compound as an orange solid (230mg ,12.1%).

LC-MS(ESI,pos.ion)m/z:590.0[M+H]+;  LC-MS (ESI, pos.ion) m/z:590.0[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.74(s,1H),7.55(d,J=4.2Hz,1H),7.48(s,1H),7.30(m,1H),7.05(t,J=8.1Hz,1H),6.88(s,1H),6.07(m,1H),4.90(s,2H),3.41(m,2H),3.33(m,2H),2.44(br.s,1H),2.31(m,1H),2.04(m,2H),1.86(d,J=6.7Hz,3H),1.71(br.s,5H),1.46(d,J=7.6 Hz,9H).  1 H NMR (400MHz, CDCl 3 )δ(ppm):7.74(s,1H),7.55(d,J=4.2Hz,1H),7.48(s,1H),7.30(m,1H),7.05(t ,J=8.1Hz,1H),6.88(s,1H),6.07(m,1H),4.90(s,2H),3.41(m,2H),3.33(m,2H),2.44(br.s, 1H),2.31(m,1H),2.04(m,2H),1.86(d,J=6.7Hz,3H),1.71(br.s,5H),1.46(d,J=7.6Hz,9H).

步骤6)3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-5-(1-(八氢-1H-异吲哚-5-基)-1H-吡唑-4-基)吡啶-2-胺Step 6) 3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(octahydro-1H-isoindol-5-yl) -1H-pyrazol-4-yl)pyridin-2-amine

标题化合物通过实施例23步骤9所描述的方法制备得到，即将5-(1-(2-(叔丁氧羰基)八氢-1H-异吲哚-5-基)-1H-吡唑-4-基)-3-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-2-胺(0.23g,0.39mmol)和HCl(4mL,3M的乙酸乙酯溶液)溶解在二氯甲烷(10mL)中制备。粗产品经硅胶柱层析(二氯甲烷/甲醇/三乙胺(v/v/v)=250/50/1)纯化，得到标题化合物为黄色固体(100mg,52.4%)。  The title compound was prepared by the method described in step 9 of Example 23, that is, 5-(1-(2-(tert-butoxycarbonyl)octahydro-1H-isoindol-5-yl)-1H-pyrazole-4 -yl)-3-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine (0.23g, 0.39mmol) and HCl (4mL, 3M ethyl acetate solution) was prepared by dissolving in dichloromethane (10 mL). The crude product was purified by silica gel column chromatography (dichloromethane/methanol/triethylamine (v/v/v)=250/50/1) to obtain the title compound as a yellow solid (100 mg, 52.4%). the

LC-MS(ESI,pos.ion)m/z:489.9[M+H]+；  LC-MS (ESI, pos.ion) m/z: 489.9[M+H] + ;

1H NMR(400MHz,CDCl3)δ(ppm):7.75(d,J=1.7Hz,1H),7.53(d,J=8.4Hz,2H),7.30(m,1H),7.05(t,J=8.4Hz,1H),6.87(d,J=1.6Hz,1H),6.07(m,1H),4.78(s,2H),4.10(m,1H),3.66(m,2H),3.18(m,1H),3.07(m,2H),2.88(d,J=11.0Hz,1H),2.37(br.s,1H),2.30(m,1H),2.04(m,2H),1.95(br.s,5H),1.85(d,J=6.7Hz,3H)。  1 H NMR(400MHz,CDCl 3 )δ(ppm):7.75(d,J=1.7Hz,1H),7.53(d,J=8.4Hz,2H),7.30(m,1H),7.05(t,J =8.4Hz,1H),6.87(d,J=1.6Hz,1H),6.07(m,1H),4.78(s,2H),4.10(m,1H),3.66(m,2H),3.18(m ,1H),3.07(m,2H),2.88(d,J=11.0Hz,1H),2.37(br.s,1H),2.30(m,1H),2.04(m,2H),1.95(br. s,5H), 1.85(d,J=6.7Hz,3H).

生物试验  biological test

采用上文所述的方法及设备对本发明实施例制备的化合物进行生物分析。  The compounds prepared in the examples of the present invention were subjected to biological analysis using the methods and equipment described above. the

实施例A在人和大鼠肝微粒体中的稳定性  The stability of embodiment A in people and rat liver microsome

将人或大鼠肝微粒体置于聚丙烯试管中孵育，并引导其复制。典型的孵育混合液包括人或大鼠肝微粒体（0.5mg蛋白质/mL），目标化合物（5μM）和总体积为200μL的NADPH(1.0mM)磷酸钾缓冲液(PBS，100mM，pH值为7.4)，将化合物溶解在DMSO中，并使用PBS将其稀释，使其最终的DMSO溶液的浓度为0.05%。并在37°C下与空气相通的水浴中进行孵育，预孵育3分钟后向混合液中加入蛋白并开始反应。在不同的时间点(0，5，10，15，30和60min)，加入同体积冰冷乙腈终止反应。样品于-80°C下保存直到进行LC/MS/MS分析。  Human or rat liver microsomes are incubated in polypropylene tubes and primed for replication. A typical incubation mixture consists of human or rat liver microsomes (0.5 mg protein/mL), target compound (5 μM), and NADPH (1.0 mM) potassium phosphate buffer (PBS, 100 mM, pH 7.4) in a total volume of 200 μL ), the compounds were dissolved in DMSO and diluted with PBS so that the final concentration of the DMSO solution was 0.05%. And incubate at 37°C in an air-connected water bath. After pre-incubation for 3 minutes, add protein to the mixture and start the reaction. At different time points (0, 5, 10, 15, 30 and 60 min), the same volume of ice-cold acetonitrile was added to terminate the reaction. Samples were stored at -80°C until LC/MS/MS analysis. the

化合物在人或大鼠肝微粒体孵育混合物中的浓度是通过LC/MS/MS的方法来测定的。浓度范围的线性范围是通过每一个受试化合物来确定 的。  Compound concentrations in human or rat liver microsome incubation mixtures were determined by LC/MS/MS. The linear range of the concentration range was determined for each test compound. the

平行孵育试验使用变性的微粒体作为阴性对照，在37°C下孵化，反应在不同的时间点(0,15和60分钟)终止。  Parallel incubation experiments using denatured microsomes as a negative control were incubated at 37°C and the reactions were terminated at different time points (0, 15 and 60 min). the

右美沙芬(70μΜ)作为阳性对照，在37°C下孵化，反应在不同的时间点(0，5，10，15，30和60分钟)终止。每一种测定方法中都包括阳性和阴性对照样品，以保证微粒体孵化体系的完整性。  Dextromethorphan (70 μM) was used as a positive control, incubated at 37°C, and the reactions were terminated at different time points (0, 5, 10, 15, 30 and 60 minutes). Positive and negative control samples are included with each assay to ensure the integrity of the microsomal incubation system. the

对于每一个反应，将化合物在人或大鼠肝微粒体孵育中的浓度(以百分比表示)按相对零时间点的百分比作图，以此来推断体内肝固有清除率CLint(ref.:Naritomi Y,Terashita S,Kimura S,Suzuki A,Kagayama A,Sugiyama Y.Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition2001,29:1316-1324.)，结果参见表1，表1为本发明实施例提供的化合物在人和大鼠肝微粒中稳定性的实验结果。  For each reaction, the in vivo liver intrinsic clearance CL int (ref.:Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metabolism and Disposition 2001, 29: 1316-1324 .), the results are shown in Table 1, Table 1 is the experimental results of the stability of the compounds provided in the examples of the present invention in human and rat liver microparticles.

表1本发明实施例提供的化合物在人和大鼠肝微粒中稳定性的实验结果  Table 1 The experimental results of the stability of the compounds provided by the embodiments of the present invention in human and rat liver microparticles

Figure BDA00002905454701391
Figure BDA00002905454701391

由表1可知，将本发明提供的化合物孵育在人和大鼠肝微粒体中时，本发明所述化合物表现出良好的半衰期(T1/2)。  It can be seen from Table 1 that when the compounds provided by the present invention are incubated in human and rat liver microsomes, the compounds of the present invention exhibit good half-life (T 1/2 ).

实施例B本发明化合物在动物体内的药代动力学评价  Embodiment B The pharmacokinetic evaluation of compound of the present invention in animal body

本发明对本发明化合物在小鼠、大鼠、犬或猴子体内的药代动力学研究进行了评估。  The present invention evaluates the pharmacokinetic studies of the compounds of the present invention in mice, rats, dogs or monkeys. the

本发明化合物以水溶液形式进行给药。对于口服剂量(p.o.)，大鼠和小鼠是5或10mg/kg，犬和猴子是10mg/kg。在时间点为0.25，0.5，1.0，2.0，3.0，4.0，6.0，8.0，12和24小时取血(0.3mL)，并在3,000或4,000rpm下离心10分钟。收集血浆溶液，并于-20°C或-70°C下保存直到进行上述的LC/MS/MS分析。结果表明，将本发明提供的化合物口服给药时，其表现出良好的药代动力学性质，包括理想的清除率(Cl)，半衰期(T1/2)和好的口服生物利用度。  The compounds of the invention are administered in aqueous solution. Oral doses (po) were 5 or 10 mg/kg for rats and mice, and 10 mg/kg for dogs and monkeys. Blood (0.3 mL) was drawn at time points 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours and centrifuged at 3,000 or 4,000 rpm for 10 minutes. Plasma solutions were collected and stored at -20°C or -70°C until LC/MS/MS analysis as described above. The results show that when the compound provided by the invention is administered orally, it exhibits good pharmacokinetic properties, including ideal clearance rate (Cl), half-life (T 1/2 ) and good oral bioavailability.

本发明化合物以水溶液形式进行给药。对于静脉注射给药，动物给予1或2mg/kg的剂量。在时间点为0.25，0.5，1.0，2.0，3.0，4.0，6.0，8.0，12和24小时取血(0.3mL)，并在3,000或4,000rpm下离心10分钟。收集血浆溶液，并于-20°C或-70°C下保存直到进行上述的LC/MS/MS分析。结果表明，将本发明提供的化合物静注给药时，其表现出良好的药代动力学性质，包括理想的清除率(Cl)，半衰期(T1/2)和好的口服生物利用度。  The compounds of the invention are administered in aqueous solution. For intravenous administration, animals were dosed at 1 or 2 mg/kg. Blood (0.3 mL) was drawn at time points 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours and centrifuged at 3,000 or 4,000 rpm for 10 minutes. Plasma solutions were collected and stored at -20°C or -70°C until LC/MS/MS analysis as described above. The results show that when the compound provided by the invention is administered intravenously, it exhibits good pharmacokinetic properties, including ideal clearance rate (Cl), half-life (T 1/2 ) and good oral bioavailability.

实施例C激酶试验  Example C Kinase Assay

按照上文所述的方法对本发明实施例提供的化合物进行ALK(h)激酶测定和c-Met(h)激酶测定，结果参见表2，表2为本发明实施例提供的激酶试验结果。  ALK(h) kinase assay and c-Met(h) kinase assay were performed on the compounds provided in the examples of the present invention according to the method described above, and the results are shown in Table 2, which is the results of the kinase assays provided in the examples of the present invention. the

表2本发明实施例提供的激酶试验结果  The kinase assay result that table 2 the embodiment of the present invention provides

Figure BDA00002905454701401
Figure BDA00002905454701401

Figure BDA00002905454701411
Figure BDA00002905454701411

由表2可知，本发明所述化合物在ALK和c-Met(h)的试验中普遍显示出很高的活性。  It can be seen from Table 2 that the compounds of the present invention generally show very high activity in the tests of ALK and c-Met(h). the

实施例D异种移植肿瘤模型  Example D xenograft tumor model

采用上文所述的方法建立U87MG移植瘤模型，并采用上文所述的方法进行分析。在U87MG移植瘤模型中，将实施例化合物每天（QD）口服给药（p.o.），并持续13-21天，结果参见表3，表3为本发明实施例提供的移植瘤研究结果。  The U87MG transplanted tumor model was established by the method described above, and analyzed by the method described above. In the U87MG xenograft tumor model, the compounds of the examples were administered orally (p.o.) daily (QD) for 13-21 days, and the results are shown in Table 3, which is the xenograft tumor research results provided in the examples of the present invention. the

表3本发明实施例提供的移植瘤研究结果  Table 3 The transplanted tumor research result that the embodiment of the present invention provides

Figure BDA00002905454701412
Figure BDA00002905454701412

由表3可知，在60mg/kg剂量下，实施例化合物都具有统计学上的意义，可抑制裸鼠皮下肿瘤的生长。  It can be seen from Table 3 that at a dose of 60 mg/kg, all the compounds of the examples have statistical significance and can inhibit the growth of subcutaneous tumors in nude mice. the

最后，需要注意的是，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。  Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention will be described as illustrations, but are not limited to the content described in the present invention, and may be modified within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention shall be regarded as reference documents of the present invention. the

Claims (21)

1.一种如式（I）所示的化合物：1. A compound as shown in formula (I):
Figure FDA00002905454600011
Figure FDA00002905454600011
 或其立体异构体，几何异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐或它的前药，其中：Or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, wherein: 各R1，R2，R3，R4，R5和R6独立地为H，D或F；each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently H, D or F; Z为Z is (1)（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代；(1) (C 3 -C 7 ) heterocyclyl, and is independently selected from D, F, Cl, Br, I, N 3 , (C 1 -C 6 ) alkane by 1, 2, 3, 4 or 5 radical, (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene-CN, -(C 1 -C 4 ) Substituents of alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR b R c ; 当杂环基的环成员包含-N(H)-时，-N(H)-中的氢原子不能被取代；When the ring member of the heterocyclyl group contains -N(H)-, the hydrogen atom in -N(H)- cannot be substituted; 当R1、R2、R3、R4、R5和R6为H，Z为单取代的哌啶基时，哌啶环上的4-位不能被D取代；When R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H, and Z is a monosubstituted piperidinyl group, the 4-position on the piperidine ring cannot be substituted by D; (2)-（C1-C4）亚烷基-（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代；(2)-(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, and is independently selected from D, F, Cl, Br, I by 1, 2, 3, 4 or 5 , N 3 , (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 ) Substituents of alkylene-OR a or -(C 1 -C 4 ) alkylene-NR b R c ; -（C1-C4）亚烷基-（C3-C7）杂环基中的杂环基不能被-OH单取代；-(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl in which the heterocyclyl cannot be monosubstituted by -OH; (3)（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环；或(3) (C 5 -C 12 ) fused bicyclic group, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, I, N 3 , (C 1 - C 6 )alkyl, (C 1 -C 6 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 )alkylene -CN, -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR b R c substituents are substituted, and the bicyclic ring system The ring in can be carbocyclic or heterocyclic; or (4)-（C1-C4）亚烷基-（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C6）烷基，（C1-C6）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C4）亚烷基-CN，-（C1-C4）亚烷基-OH，-（C1-C4）亚烷基-ORa或-（C1-C4）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环；(4)-(C 1 -C 4 )alkylene-(C 5 -C 12 )fused bicyclyl, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl , Br, I, N 3 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 4 ) Alkylene-CN, -(C 1 -C 4 )alkylene-OH, -(C 1 -C 4 )alkylene-OR a or -(C 1 -C 4 )alkylene-NR The substituent of b R c is substituted, and the ring in the bicyclic ring system can be carbocyclic or heterocyclic; 其中，Ra为（C1-C6）烷基，（C1-C6）烯基，（C1-C6）炔基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基或-（C1-C4）亚烷基-（C1-C9）杂芳基，所述各（C1-C6）烷基，（C1-C6）烯基，（C1-C6）炔基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基和-（C1-C4）亚烷基-（C1-C9）杂芳基任选地被1，2，3或4个独立选自D，F，Cl，N3，-CN，-OH，-NH2，烷氧基或烷基氨基的取代基所取代；Among them, R a is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl, (C 3 - C 6 )heterocyclyl, (C 6 -C 10 )aryl, (C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene -(C 3 -C 6 )cycloalkyl , -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl, each of the (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkyne radical, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aryl, (C 1 -C 9 ) heteroaryl, -(C 1 - C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene Alkyl-(C 6 -C 10 )aryl and -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl are optionally 1, 2, 3 or 4 independently selected from Substituents of D, F, Cl, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino; Rb和Rc独立地为H，（C1-C6）烷基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基或-（C1-C4）亚烷基-（C1-C9）杂芳基；所述各（C1-C6）烷基，（C3-C6）环烷基，（C3-C6）杂环基，（C6-C10）芳基，（C1-C9）杂芳基，-（C1-C4）亚烷基-（C3-C6）环烷基，-（C1-C4）亚烷基-（C3-C6）杂环基，-（C1-C4）亚烷基-（C6-C10）芳基和-（C1-C4）亚烷基-（C1-C9）杂芳基任选地被1，2，3，或4个独立选自D，F，Cl，N3，-CN，-OH，-NH2，烷氧基或烷基氨基的取代基所取代；当Rb和Rc与同一个氮原子相连时，Rb，Rc和与他们相连的氮原子一起，还可以任选地形成（C3-C6）杂环基。R b and R c are independently H, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aromatic radical, (C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl or -(C 1 -C 4 )alkylene-(C 1 -C 9 ) Heteroaryl; each (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocyclyl, (C 6 -C 10 ) aryl, ( C 1 -C 9 )heteroaryl, -(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, -(C 1 -C 4 )alkylene-(C 3 -C 6 ) Heterocyclyl, -(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl and -(C 1 -C 4 )alkylene-(C 1 -C 9 )heteroaryl optionally substituted by 1, 2, 3, or 4 substituents independently selected from D, F, Cl, N 3 , -CN, -OH, -NH 2 , alkoxy or alkylamino; when R When b and R c are connected to the same nitrogen atom, R b , R c and the nitrogen atom connected to them may also optionally form a (C 3 -C 6 ) heterocyclic group. 2.根据权利要求1所述的化合物，其特征在于，其中，R1，R2，R3，R4，R5和R6独立地为H或D。2. The compound according to claim 1, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently H or D. 3.根据权利要求1所述的化合物，其特征在于，其中，Z为：3. The compound according to claim 1, wherein Z is: (1)（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；(1) (C 3 -C 7 ) heterocyclyl, and is independently selected from D, F, N 3 , (C 1 -C 3 ) alkyl by 1, 2, 3, 4 or 5, (C 1 - C 3 ) Haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-CN, -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c is substituted by substituents; (2)-（C1-C4）亚烷基-（C3-C7）杂环基，且被1，2，3，4或5个独立选自D，F，N3，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；(2)-(C 1 -C 4 )alkylene-(C 3 -C 7 )heterocyclyl, and is independently selected from D, F, N 3 , (C 1 -C 3 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene- Substituents of OR a or -(C 1 -C 3 ) alkylene -NR b R c ; (3)（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环；或(3) (C 5 -C 12 ) fused bicyclic group, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl, Br, I, N 3 , (C 1 - C 3 )alkyl, (C 1 -C 3 )haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene -CN, -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c substituents are substituted, and the bicyclic ring system The ring in can be carbocyclic or heterocyclic; or (4)-（C1-C4）亚烷基-（C5-C12）稠合双环基，且任选地被1，2，3，4或5个独立选自D，F，Cl，Br，I，N3，（C1-C3）烷基，（C1-C3）卤代烷基，-CN，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-CN，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代，且双环体系中的环可以是碳环或杂环。(4)-(C 1 -C 4 )alkylene-(C 5 -C 12 )fused bicyclyl, and optionally 1, 2, 3, 4 or 5 independently selected from D, F, Cl , Br, I, N 3 , (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, -CN, -OH, -OR a , -NR b R c , -(C 1 -C 3 ) Alkylene-CN, -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b Substituents of R c are substituted, and the rings in the bicyclic ring system may be carbocyclic or heterocyclic. 4.根据权利要求1所述的化合物，其中，Ra为（C1-C3）烷基，（C1-C3）烯基，（C1-C6）炔基，（C3-C6）环烷基或-（C1-C3）亚烷基-（C3-C6）环烷基，所述各（C1-C3）烷基，（C1-C3）烯基，（C1-C6）炔基，（C3-C6）环烷基和-（C1-C3）亚烷基-（C3-C6）环烷基任选地被1，2，3或4个独立选自D或F的取代基所取代。4. The compound according to claim 1, wherein R a is (C 1 -C 3 ) alkyl, (C 1 -C 3 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 3 - C 6 )cycloalkyl or -(C 1 -C 3 )alkylene-(C 3 -C 6 )cycloalkyl, each of the (C 1 -C 3 )alkyl, (C 1 -C 3 ) Alkenyl, (C 1 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl and -(C 1 -C 3 )alkylene-(C 3 -C 6 )cycloalkyl are optionally 1, 2, 3 or 4 substituents independently selected from D or F are substituted. 5.根据权利要求1所述的化合物，其特征在于，其中，Rb和Rc独立地为H，（C1-C3）烷基，（C3-C6）环烷基或-（C1-C4）亚烷基-（C3-C6）烷基；所述各（C1-C3）烷基，（C3-C6）环烷基和-（C1-C4）亚烷基-（C3-C6）烷基任选地被1，2，3或4个独立选自D或F的取代基所取代；当Rb和Rc与同一个氮原子相连时，Rb，Rc和与他们相连的氮原子一起，还可以任选地形成（C3-C6）杂环基。5. The compound according to claim 1, wherein, R b and R c are independently H, (C 1 -C 3 ) alkyl, (C 3 -C 6 ) cycloalkyl or -( C 1 -C 4 )alkylene-(C 3 -C 6 )alkyl; said each (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl and -(C 1 -C 4 ) Alkylene-(C 3 -C 6 )alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D or F; when R b and R c are with the same nitrogen atom When linked, R b , R c together with the nitrogen atom to which they are linked, may also optionally form a (C 3 -C 6 )heterocyclic group. 6.根据权利要求1所述的化合物，其特征在于，其中，Z选自式（a）～（k）所示的子结构中的任意一种：6. The compound according to claim 1, wherein Z is selected from any one of the substructures shown in formulas (a) to (k): 或其立体异构体，其中：or its stereoisomers, wherein: n为0，1，2或3；n is 0, 1, 2 or 3; 各X和X'为-O-或-N(H)-；each of X and X' is -O- or -N(H)-; 式（a）～（k）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代；The substructures represented by formulas (a) to (k) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups independently by 1, 2, 3, 4 or 5, - OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 )alkylene Alkyl-NR b R c substituents are substituted; 当n为1，2或3时，上述各子结构或其立体异构体不能被-OH单取代；When n is 1, 2 or 3, the above substructures or their stereoisomers cannot be monosubstituted by -OH; 当各X和X'独立地为-N(H)-时，-N(H)-中的氢原子不能被取代；When each X and X' is independently -N(H)-, the hydrogen atom in -N(H)- cannot be substituted; 当R1,R2,R3,R4,R5和R6为H，Z为单取代的哌啶基时，哌啶环的4-位不能被D取代。When R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are H, and Z is a monosubstituted piperidinyl group, the 4-position of the piperidine ring cannot be substituted by D. 7.根据权利要求1所述的化合物，其特征在于，其中，Z选自式（l）～（x）所示的子结构中的任意一种：7. The compound according to claim 1, wherein Z is selected from any one of the substructures shown in formulas (l) to (x):
Figure FDA00002905454600042
Figure FDA00002905454600042
Figure FDA00002905454600051
Figure FDA00002905454600051
 或其立体异构体，其中：or its stereoisomers, wherein: n为0，1，2或3；n is 0, 1, 2 or 3; 各W和W'为-O-，-N(H)-或-N(C1-C3)烷基-；Each of W and W' is -O-, -N(H)- or -N(C 1 -C 3 )alkyl-; 式（l）～（x）所示的子结构或其立体异构体任选地被1，2，3，4或5个独立选自D，F，（C1-C3）烷基，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。The substructures represented by formulas (l) to (x) or their stereoisomers are optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, (C 1 -C 3 ) alkyl groups, (C 1 -C 3 )haloalkyl, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-ORa Or -(C 1 -C 3 )alkylene-NR b R c substituents. 8.根据权利要求6所述的化合物，其特征在于，其中，Z选自式（101）～（111）所示的子结构中的任意一种：8. The compound according to claim 6, wherein Z is selected from any one of the substructures shown in formulas (101) to (111):
Figure FDA00002905454600052
Figure FDA00002905454600052
 或其立体异构体，其中：or its stereoisomers, wherein: 式（101）～（111）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。The substructures represented by formulas (101) to (111) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups independently by 1, 2, 3, 4 or 5, - OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene -OR a or -(C 1 -C 3 )alkylene Alkyl-NR b R c substituents are substituted. 9.根据权利要求6所述的化合物，其特征在于，其中，Z选自式（201）～（214）所示的子结构中的任意一种：9. The compound according to claim 6, wherein Z is selected from any one of the substructures shown in formulas (201) to (214):
Figure FDA00002905454600061
Figure FDA00002905454600061
 或其立体异构体，其中：or its stereoisomers, wherein: 式（201）～（214）所示的子结构或其立体异构体独立地被1，2，3，4或5个独立选自D，F，（C1-C3）卤代烷基，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。The substructures represented by formulas (201) to (214) or their stereoisomers are independently selected from D, F, (C 1 -C 3 ) haloalkyl groups by 1, 2, 3, 4 or 5, - OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene- NR b R c substituents are substituted. 10.根据权利要求7所述的化合物，其特征在于，其中，Z选自式（301）～（323）所示的子结构中的任意一种：10. The compound according to claim 7, wherein Z is selected from any one of the substructures shown in formulas (301) to (323):
Figure FDA00002905454600071
Figure FDA00002905454600071
 或其立体异构体，其中：or its stereoisomers, wherein: 式（301）～（323）所示的子结构或其立体异构体任选地被1，2，3，4或5个独立选自D，F，（C1-C3）烷基，（C1-C3）卤代烷基，-OH，-ORa，-NRbRc，-（C1-C3）亚烷基-OH，-（C1-C3）亚烷基-ORa或-（C1-C3）亚烷基-NRbRc的取代基所取代。The substructures represented by formulas (301) to (323) or their stereoisomers are optionally replaced by 1, 2, 3, 4 or 5 independently selected from D, F, (C 1 -C 3 ) alkyl groups, (C 1 -C 3 )haloalkyl, -OH, -OR a , -NR b R c , -(C 1 -C 3 )alkylene-OH, -(C 1 -C 3 )alkylene-OR a or -(C 1 -C 3 )alkylene-NR b R c substituents. 11.根据权利要求1所述的化合物，其特征在于，其中，Ra为（C1-C2）烷基，且任选地被1，2，3或4个独立选自D或F的取代基所取代。11. The compound according to claim 1, wherein, R a is (C 1 -C 2 ) alkyl, and is optionally replaced by 1, 2, 3 or 4 independently selected from D or F Substituents are substituted. 12.根据权利要求1所述的化合物，其特征在于，其中，Rb和Rc独立地为H或（C1-C2）烷基；所述（C1-C2）烷基和（C3-C6）杂环基任选地被1，2，3或4个独立选自D或F的取代基所取代；当Rb和Rc与同一个氮原子相连时，Rb，Rc和与他们相连的氮原子一起，还可以任选地形成（C3-C6）杂环基。12. The compound according to claim 1, wherein, R b and R c are independently H or (C 1 -C 2 ) alkyl; said (C 1 -C 2 ) alkyl and ( C 3 -C 6 ) The heterocyclic group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from D or F; when R b and R c are connected to the same nitrogen atom, R b , Rc , together with the nitrogen atom to which they are attached, may also optionally form a (C 3 -C 6 )heterocyclyl. 13.根据权利要求1所述的化合物，其特征在于，具有以下其中之一的结构：13. The compound according to claim 1, characterized in that it has one of the following structures:
Figure FDA00002905454600081
Figure FDA00002905454600081
Figure FDA00002905454600091
Figure FDA00002905454600091
Figure FDA00002905454600101
Figure FDA00002905454600101
Figure FDA00002905454600121
Figure FDA00002905454600121
Figure FDA00002905454600131
Figure FDA00002905454600131
Figure FDA00002905454600141
Figure FDA00002905454600141
Figure FDA00002905454600151
Figure FDA00002905454600151
 14.一种药物组合物，包含权利要求1～13任意一项所述的化合物或药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。14. A pharmaceutical composition, comprising the compound according to any one of claims 1-13 or a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. 15.根据权利要求14所述的药物组合物，其特征在于，还包含附加治疗剂，这些附加治疗剂选自化学治疗药物，抗增殖剂，用于治疗动脉粥样硬化的药物，用于治疗肺纤维化的药物或它们的组合。15. The pharmaceutical composition according to claim 14, characterized in that, it also comprises additional therapeutic agents selected from chemotherapeutic drugs, antiproliferative agents, drugs for the treatment of atherosclerosis, drugs for the treatment of Medicines for pulmonary fibrosis or their combination. 16.根据权利要求15所述的药物组合物，其特征在于，其中所述的附加治疗剂是苯丁酸氮芥，美法仑，环磷酰胺，异环磷酰胺，白消安，卡莫司汀，洛莫司汀，链脲佐菌素，顺铂，卡铂，奥沙利铂，达卡巴嗪，替莫唑胺，丙卡巴肼，甲氨蝶呤，氟尿嘧啶，阿糖胞苷，吉西他滨，巯基嘌呤，氟达拉滨，长春碱，长春新碱，长春瑞滨，紫杉醇，多西紫杉醇，拓扑替康，伊立替康，依托泊苷，曲贝替定，更生霉素，多柔比星，表柔比星，道诺霉素，米托蒽醌，博来霉素，丝裂霉素C，伊沙匹隆，他莫昔芬，氟他胺，戈那瑞林类似物，甲地孕酮，强的松，地塞米松，甲泼尼龙，沙利度胺，干扰素α，亚叶酸钙，西罗莫司，西罗莫司脂化物，依维莫司，阿法替尼，alisertib，amuvatinib，阿帕替尼，阿西替尼，硼替佐米，波舒替尼，brivanib，cabozantinib，西地尼布，crenolanib，克卓替尼，dabrafenib，dacomitinib，danusertib，达沙替尼，dovitinib，厄洛替尼，foretinib，ganetespib，吉非替尼，ibrutinib，埃克替尼，伊马替尼，iniparib，拉帕替尼，lenvatinib，linifanib，linsitinib，马赛替尼，momelotinib，莫替沙尼，来那替尼，尼罗替尼，niraparib，oprozomib，olaparib，帕唑帕尼，pictilisib，ponatinib，quizartinib，regorafenib，rigosertib，rucaparib，ruxolitinib，塞卡替尼，saridegib，索拉非尼，舒尼替尼，tasocitinib，telatinib，tivantinib，tivozanib，tofacitinib，trametinib，凡德他尼，veliparib，威罗菲尼，vismodegib，volasertib，阿仑单抗，贝伐单抗，brentuximab vedotin，卡妥索单抗，西妥昔单抗，地诺单抗，吉妥珠单抗，伊匹单抗，尼妥珠单抗，奥法木单抗，帕尼单抗，利妥昔单抗，托西莫单抗，曲妥珠单抗或它们的组合。16. The pharmaceutical composition according to claim 15, wherein said additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmel Stine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercapto Purine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, Epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, medigestrel Ketone, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, sirolimus, everolimus, afatinib, alisertib , amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, Erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib Ni, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, west Touximab, Denosumab, Gemtuzumab, Ipilimumab, Nimotuzumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab or a combination thereof. 17.一种使用权利要求1～13任意一项所述化合物或权利要求14～16任意一项所述的药物组合物来制备用于防护、处理、治疗或减轻患者增殖性疾病的药品的用途。17. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to any one of claims 14 to 16 to prepare medicines for preventing, treating, treating or alleviating proliferative diseases in patients . 18.根据权利要求17所述化合物或药物组合物的用途，其特征在于，其中所述的增殖性疾病是转移癌，结肠癌，胃腺癌，膀胱癌，乳腺癌，肾癌，肝癌，肺癌，甲状腺癌，头颈癌，前列腺癌，胰腺癌，中枢神经系统的癌症，恶性胶质瘤，骨髓增生病，动脉粥样硬化或肺纤维化。18. The use of the compound or pharmaceutical composition according to claim 17, wherein the proliferative disease is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, Thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the central nervous system, malignant glioma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis. 19.一种使用权利要求1～13任意一项所述的化合物或权利要求14～16任意一项所述的药物组合物来制备用于在生物标本内抑制或调节蛋白激酶活性的药品的用途，所述用途包含使用权利要求1～13任意一项所述化合物或使用权利要求14～16任意一项所述的药物组合物与所述的生物标本接触。19. Use of the compound according to any one of claims 1-13 or the pharmaceutical composition according to any one of claims 14-16 to prepare medicines for inhibiting or regulating protein kinase activity in biological samples , the use comprises using the compound described in any one of claims 1-13 or using the pharmaceutical composition described in any one of claims 14-16 to contact the biological specimen. 20.根据权利要求19所述的用途，其特征在于，其中所述蛋白激酶为受体酪氨酸激酶受体。20. The use according to claim 19, wherein the protein kinase is a receptor tyrosine kinase receptor. 21.根据权利要求20所述的用途，其特征在于，其中所述受体酪氨酸激酶受体为ALK、c-Met或它们的组合。21. The use according to claim 20, wherein the receptor tyrosine kinase receptor is ALK, c-Met or a combination thereof.
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