WO2013170774A1

WO2013170774A1 - Acetylene derivative having antineoplastic activity

Info

Publication number: WO2013170774A1
Application number: PCT/CN2013/075753
Authority: WO
Inventors: 万惠新; 李春丽; 韩雅男; 周兆丽; 马珂; 刘海燕; 张乐多
Original assignee: 上海医药集团股份有限公司
Priority date: 2012-05-16
Filing date: 2013-05-16
Publication date: 2013-11-21
Also published as: CN103421005A; CN103420977A; CN103420977B; WO2013170770A1

Abstract

The present invention relates to an aromatic ring disubstituted acetylene derivative of formula I, a pharmaceutical composition comprising the compound, and a use of the compound and of the pharmaceutical composition in the treatment and/or prevention of tumors, where A, B, T, M, Ra, Rb, Rt, m, n, and p are as defined in the present document.

Description

具有抗肿瘤活性的乙块衍生物技术领域 Ethylene block derivatives with antitumor activity

本发明涉及乙块衍生物，尤其是具有抗肿瘤活性的芳香环二取代乙块衍生物，包含该化合物的药物组合物，以及该化合物和药物组合物用于治疗和 /或预防肿瘤的用途。背景技术 The present invention relates to an ethylene block derivative, particularly an aromatic ring disubstituted ethyl block derivative having antitumor activity, a pharmaceutical composition comprising the same, and the use of the compound and the pharmaceutical composition for treating and/or preventing a tumor. Background technique

近年来，全世界肿瘤疾病的发生率呈不断上升趋势，据世界卫生组织统计数据显示， 2007年，新确诊的肿瘤病人已达 1200多万人，恶性肿瘤 (癌症)已是导致人类死亡的主要病症之一。预计到 2020年全球每年新发病例将达到 1500万。据美国 IMS Healath数据： 2007 年，全球七大医药市场的 500强药品中，靶向抗肿瘤药物市场份额已达到 200多亿美元，比上一年同期增长了 27.05%，远远高出全球抗肿瘤药物市场 19.94%的增长率。 2008年尽管受国际金融危机的影响，医药市场在刚性需求和惯性发展的推动下，抗肿瘤药物市场仍表现出强势增长，已达到了 481.89亿美元，同比增长了 15.54%。其中，靶向抗肿瘤药物市场以 290亿美元的销售额处于遥遥领先的地位，比上一年同期增长了 45%。市场分析家预测，到 2015年，抗肿瘤靶向治疗药物将超过 500亿美元，复合年增长率高达 11%，并且该领域将有 8只以上的新药成长为 "重磅炸弹"产品。 In recent years, the incidence of cancer diseases in the world is on the rise. According to statistics from the World Health Organization, in 2007, the number of newly diagnosed tumor patients has reached more than 12 million. Malignant tumors (cancers) are the main cause of human death. One of the symptoms. It is estimated that by 2020, the number of new cases worldwide will reach 15 million per year. According to the US IMS Healath data: In 2007, among the top 500 drugs in the world's seven major pharmaceutical markets, the market share of targeted anti-tumor drugs has reached more than 20 billion US dollars, an increase of 27.05% over the same period of the previous year, far higher than the global resistance. The cancer drug market has a growth rate of 19.94%. In 2008, despite the impact of the international financial crisis, the pharmaceutical market continued to show strong growth in the anti-tumor drug market, driven by rigid demand and inertia, reaching US$48.189 billion, an increase of 15.54% year-on-year. Among them, the targeted anti-cancer drug market was in a leading position with sales of US$29 billion, an increase of 45% over the same period of the previous year. Market analysts predict that by 2015, anti-tumor targeted therapies will exceed $50 billion, with compound annual growth rates of 11%, and more than eight new drugs in the field will grow into "blockbuster" products.

随着一些新型的酪氨酸蛋白激酶抑制剂类靶向抗肿瘤药的相继研发成功并上市，抗肿瘤药正从传统的非选择性单一的细胞毒性药物向针对机制的多环节作用的新型抗肿瘤药物发展，抗肿瘤药物的研究与开发已进入一个崭新的时代。肿瘤的分子靶向治疗是基于对肿瘤生长密切相关的关键蛋白分子通过化学或生物的手段选择性杀伤肿瘤细胞的一种治疗方法。其特点是特异性、针对性和有效性强，患者耐受性好，而毒副作用比传统化疗药物要低很多；联合用药时，可加强传统放化疗的疗效，减少术后复发。目前，抗肿瘤小分子靶向药物中的伊马替尼、厄洛替尼、舒尼替尼、吉非替尼、索拉非尼、达沙替尼、拉帕替尼和尼洛替尼已是临床中的主要品种。 With the successful development and market launch of some novel tyrosine protein kinase inhibitor-targeted anti-tumor drugs, anti-tumor drugs are moving from traditional non-selective single cytotoxic drugs to new mechanisms targeting multiple mechanisms The development of oncology drugs, research and development of anti-tumor drugs has entered a new era. Molecular targeted therapy of tumors is a therapeutic approach based on the selective killing of tumor cells by chemical or biological means of key protein molecules closely related to tumor growth. It is characterized by specificity, pertinence and effectiveness, and patients are well tolerated, and the side effects are much lower than traditional chemotherapy drugs; when combined, it can enhance the efficacy of traditional radiotherapy and chemotherapy, and reduce postoperative recurrence. Currently, imatinib, erlotinib, sunitinib, gefitinib, sorafenib, dasatinib, lapatinib and nilotinib in anti-tumor small molecule targeted drugs It is already the main breed in the clinic.

但是蛋白激酶抑制剂在临床使用过程中遭遇的耐药性引起高度关注。较早上市的蛋白激酶靶向药物都出现了因耐药而导致治疗失败严重后果。因此，研究耐药机制及其克服方法已成为当今靶向激酶药物研究中的重点内容之一。已阐明的蛋白激酶靶向药物的耐药机制主要有：激酶本身的二次突变；其它激酶信号通路的代偿作用；其它靶点非依赖性机制如耐药基因高表达等。 However, the resistance of protein kinase inhibitors encountered during clinical use has attracted much attention. More protein-targeted drugs in the morning have had serious consequences for treatment failure due to drug resistance. Therefore, research on drug resistance mechanisms and their overcoming methods has become one of the key points in the research of targeted kinase drugs. The drug resistance mechanisms of protein kinase-targeted drugs have been clarified: secondary mutations in the kinase itself; compensatory effects of other kinase signaling pathways; other target-independent mechanisms such as high expression of drug resistance genes.

Imatinib (商品名： Gleevec)是最早上市的小分子蛋白激酶抑制剂，用于治疗慢性粒细胞白血病，被誉为肿瘤分子靶向治疗的里程碑。随后，美国 FDA又批准了伊马替尼的第二个适用症，用于治疗胃肠道***瘤的治疗。经过全球广泛的临床使用后，获得了医学界的高度评价，于 2002年 12月 23日正式取得美国 FDA的全面认可，批准作为慢性粒细胞白血病一线治疗用药，从而被医学界誉为近年"有重大突破性"的抗肿瘤靶向小分子口服药物制剂。伊马替尼在美国、欧盟和日本等国获批作为罕见病用药后，现已在全世界 80多个国家核准用于慢性粒细胞白血病，而且在许多发达国家和发展中国家也核准用于胃肠道间质细胞瘤的治疗。 Imatinib抑制 Abl非受体酪氨酸激酶活性，是治疗费城染色体阳性 (Ph+) 的慢性髓系白血病 (Chronic Myeloid Leukemia, CML)的一线药物，但治疗后复发的患者常对其产生严重的耐药性。分子病理学研究揭示其耐药机制主要包括： 1 ) Abl激酶突变，约占总体耐药患者的 35%-45%。 2) Src 家族激酶通路的代偿作用，约占总体耐药现象的 30%-50%。晚期肿瘤患者可能激活 Src家族激酶通路，进一步促进疾病进展，使得对原有 BCR-Abl激酶通路的依赖性降低。在 Imatinib敏感的肿瘤中， Src家族成员 Src、 Lyn和 Hck 处于 BCR-Abl的下游，被 Abl激活后进而促进细胞生长、成活和分化；但在一些对 Imatinib 耐药的肿瘤中，尽管 BCR-Abl的活性处于被抑制状态，其下游 Src、 Lyn和 Hck信号通路依然处于激活状态中，显示代偿性旁路参与了 Imatinib耐药的产生。 3 )其它的耐药机制还包括 BCR-Abl本身的过度表达、耐药蛋白 BCRP/ABCG2的过度表达等。 Imatinib (trade name: Gleevec) is the first small molecule protein kinase inhibitor to be used in the treatment of chronic myeloid leukemia, and is known as a milestone in molecular targeted therapy for tumors. Subsequently, the US FDA approved the second application of imatinib for the treatment of gastrointestinal stromal tumors. After extensive clinical use worldwide, it has been highly praised by the medical community. On December 23, 2002, it was officially recognized by the US FDA. It was approved as a first-line treatment for chronic myeloid leukemia, and it has been praised by the medical community as "sometimes in recent years." A major breakthrough "anti-tumor targeted small molecule oral pharmaceutical preparation. Imatinib has been approved for use as a rare disease in countries such as the United States, the European Union, and Japan, and has been approved for use in chronic myeloid leukemia in more than 80 countries around the world, and is also approved for use in many developed and developing countries. Treatment of gastrointestinal stromal cell tumors. Imatinib inhibits Abl non-receptor tyrosine kinase activity and is a first-line treatment for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), but patients with relapse after treatment often develop severe resistance to it. Sex. Molecular pathology studies revealed that its resistance mechanisms include: 1) Abl kinase mutations, accounting for 35%-45% of patients with overall resistance. 2) The compensatory effect of the Src family kinase pathway accounts for 30%-50% of the overall drug resistance. Patients with advanced tumors may activate the Src family kinase pathway, further promoting disease progression, resulting in a reduced dependence on the original BCR-Abl kinase pathway. In Imatinib-sensitive tumors, Src family members Src, Lyn, and Hck are downstream of BCR-Abl and are activated by Abl to promote cell growth, survival, and differentiation; however, in some tumors resistant to Imatinib, despite BCR-Abl Activity is suppressed, downstream of Src, Lyn and Hck signaling pathways Still in an active state, it shows that compensatory bypass is involved in the development of Imatinib resistance. 3) Other resistance mechanisms include overexpression of BCR-Abl itself and overexpression of drug resistance protein BCRP/ABCG2.

针对 Imatinib耐药性，发展了第二代 Abl激酶靶向药物 Dasatinib (商品名： Sprycel; Bristol-Myers Squibb)。 Dasatinib是 Abl-Src双重抑制剂， FDA于 2006年 6月批准上市治疗对 Imatinib耐药或无法耐受的 CML患者。由于和 Imatinib结构完全不同， Dasatinib能与活性形式的 BCR-Abl结合；其对野生型 BCR-Abl激酶的抑制能力是 Imatinib的 325倍，并且其结合位点与 Imatinib不同，因而对 Imatinib耐药的 BCR-Abl突变型激酶，除一个位点 (T315I位点）夕卜，具有很好的抑制效果。更为突出的是， Dasatinib还能同时抑制 Src的活性，因此对由于 Src过度激活产生 Imatinib耐药的肿瘤依然有效。临床试验表明， Dasatinib 对多种不同类型的 Imatinib 耐药患者均有很好的疗效。然而， Dasatinib 仍未有效解决 BCR-Abl因 T315I位点突变产生的耐药问题，因此，开发第三代 BCR-Abl抑制剂势在必行。 In response to Imatinib resistance, the second-generation Abl kinase targeting drug Dasatinib (trade name: Sprycel; Bristol-Myers Squibb) was developed. Dasatinib is a dual inhibitor of Abl-Src, which was approved by the FDA in June 2006 for the treatment of patients with CML who are resistant or intolerant to Imatinib. Due to its completely different structure from Imatinib, Dasatinib binds to the active form of BCR-Abl; its ability to inhibit wild-type BCR-Abl kinase is 325 times that of Imatinib, and its binding site is different from Imatinib, thus it is resistant to Imatinib. The BCR-Abl mutant kinase has a good inhibitory effect except for one site (T315I site). More strikingly, Dasatinib also inhibits the activity of Src, and is therefore still effective against tumors that are imatinib-resistant due to Src overactivation. Clinical trials have shown that Dasatinib has a good effect on many different types of Imatinib-resistant patients. However, Dasatinib has not effectively solved the drug resistance caused by BCR-Abl due to the T315I site mutation. Therefore, it is imperative to develop a third-generation BCR-Abl inhibitor.

如何克服伊马替尼等现有药物引起的耐药性是当今肿瘤医学的重要课题，其中一条重要途径就是寻找新型的对以上突变体有效的酪氨酸激酶小分子抑制剂。例如小分子抑制剂 Nilotinib、 Dasatinib对部分而非全部 (除了 T315I) Bcr-Abl突变的伊马替尼耐药病例有效。因此，继续寻找有效方案寻找新型的、对各类突变体特别是 T315I和 D816V有效的小分子酪氨酸激酶抑制剂在全球肿瘤预防和治疗中显得十分必要和迫切。 How to overcome the drug resistance caused by existing drugs such as imatinib is an important topic in oncology medicine today. One of the important ways is to find a novel small molecule inhibitor of tyrosine kinase that is effective against the above mutants. For example, the small molecule inhibitors Nilotinib and Dasatinib are effective against some, but not all (except T315I) Bcr-Abl mutations in imatinib-resistant cases. Therefore, it is necessary and urgent to find effective solutions to find novel small-molecule tyrosine kinase inhibitors that are effective against various mutants, especially T315I and D816V, in global tumor prevention and treatment.

随着肺癌发病机制研究的深入，靶向治疗在 NSCLC 治疗中的地位日渐重要。其中，以厄洛替尼和吉非替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂的靶向药物取得了一定的疗效。但多数研究显示临床缓解甚至消退的 NSCLC 患者在维持治疗一段时间后出现耐药，甚至疾病进展。为此， EGFR TKI 耐药机制已成为肿瘤学界研究的热点。细胞内的 EGFR的 TK活性与包括 EGF、转化生长因子 α、双调蛋白等在内的配体结合后激活，导致 EGFRs形成同型二聚体或者与其它家族成员形成异二聚体，最常见的是 HER2。 EGFR 的 TK激活导致 EGFR细胞内区域的自身磷酸化，而这些磷酸化的残基能成为多种接合体分子的停泊位点，导致 Ras/丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK) 途径、 PI3K/Akt 途径和信号传感器和转录信号途径激活子的激活，促使细胞增殖、血管生成、转移和抑制细胞凋亡，从而增加肿瘤细胞的生存、增殖、侵犯和转移。肿瘤细胞 EGFR 的 TK激活可被多种癌基因机制扰乱，包括 EGFR基因突变导致的基因拷贝数增加和 EGFR 蛋白过表达。超过 60%的 NSCLC患者的肿瘤细胞中 EGFR过表达，这些患者预后较差。这些发现促使靶向 EGFR的抗癌药物的开发。可逆性的 EGFR TKIs (厄洛替尼和吉非替尼），对一部分 NSCLC患者具有显著的抗肿瘤功效：大约 10%的欧洲患者和 30%的东亚患者能取得临床缓解。 EGFR基因测序发现大多数对于 EGFR TKIs治疗有反应的肿瘤包含 EGFR TK区域的突变。总体上来讲， EGFR的突变频率为 5%-20%，根据研究人群不同而不同。携带 EGFR突变的肿瘤患者，对于厄洛替尼和吉非替尼的反应率大约为 75%，提示这些突变能导致细胞恶性转变。所有最初对 EGFR TKI治疗有反应的 NSCLC都会发生继发耐药。目前认为吉非替尼和厄洛替尼的功效持续时间有限，主要是因为 TK区域的第二次点突变导致的耐药。 EGFR TKI 治疗继发耐药的病人中 50%发生苏氨酸 -790 突变为蛋氨酸 (T790M 虽然 EGFR TKIs 在这些病人中也能取得显著的疗效，但是与那些未检测到 T790M 患者相比，包含 T790M 的患者无进展生存期相对较短（7.7 个月 vs 16.5 个月； P<0.001 )。临床前研究也发现 T790M为潜在耐药机制，体外试验证实这个突变能显著的抑制厄洛替尼和吉非替尼的作用，然而 TK的活性仍然存在。相似的是，将 T790M引入到吉非替尼敏感的肿瘤细胞中，激活的 EGFR突变或者是 EGFR拷贝数增加能导致吉非替尼耐药。但是 T790M导致肿瘤细胞对 EGFR TKIs耐药机制还不清楚。可能为 T790M突变导致 TK的 ATP-结合口袋的拓扑结构改变，并阻碍了 EGFR TKIs通过空间位组现象与之结合，从而继发耐药。最近的一项研究提出了另一种机制，即 T790M增加了 ATP与激酶区域的结合，继而减少了任何一种 ATP竞争剂的功效。有研究报道，其它导致耐药的点突变，如门冬氨酸 -761突变为酪氨酸（D761Y), 能减弱 EGFR TKI与它的靶点之间的相互作用。皮肤恶性黑素瘤是恶性程度较高的肿瘤之一，易于侵袭和转移.近年来发现， BRAF 基因在人黑素瘤中存在高频率的突变，临床证明，约 50%黑色素瘤存在 BRAF V600E突变。 B-raf 基因是 RAF 家族的成员之一，它编码一种丝 /苏氨酸特异性激酶，是 RAS/RAF/MEK/ERKMAPK通路的重要的转导因子，参与调控细胞内多种生物学事件，如细胞生长、分化和凋亡等。最近的研究表明， BRAF 肿瘤基因突变可见于一些人体恶性肿瘤。多数文献报道，结直肠癌中 B-raf突变率在 15%左右，且 90%以上为 V600E突变，并与 K- ras突变负相关。近年来的研究表明， BRAF基因突变因子在临床上具有重要的预测意义和预后意义，含有 B-raf突变的病人无法从针对 EGFR的靶向药物治疗中受益，且发生 B-raf突变的病人预后较差。一种口服的 BRAF激酶抑制剂 vemurafenib(PLX4032/RO5185426) 的 I和 II期临床试验已证明在 BRAF V600E突变型黑色素瘤患者中，该药的有效率 (RR; CR+PR) 大于 50%。 BRAF〜(； V600E)突变基因可以促进人黑素瘤细胞生长和增殖，可以使肿瘤细胞分泌更多的 MMPs和 VEGF, 增强肿瘤细胞侵袭和血管形成的能力，提高其转移的能力，提示 BRAF(V600E)突变在黑素瘤生长、侵袭和转移中有重要作用，而以其为靶点的基因治疗可以抑制实验性黑素瘤的生长。 With the deepening of research on the pathogenesis of lung cancer, the role of targeted therapy in the treatment of NSCLC is becoming more and more important. Among them, the targeted drugs of epidermal growth factor receptor tyrosine kinase inhibitor represented by erlotinib and gefitinib have achieved certain effects. However, most studies have shown that patients with clinical remission or even regression of NSCLC develop resistance and even disease progression after a period of maintenance therapy. To this end, the EGFR TKI resistance mechanism has become a hot topic in the field of oncology. The TK activity of EGFR in cells is activated by binding to ligands including EGF, transforming growth factor alpha, amphiregulin, etc., resulting in the formation of homodimers of EGFRs or heterodimers with other family members, the most common Is HER2. TK activation of EGFR leads to autophosphorylation of EGFR intracellular regions, and these phosphorylated residues can serve as docking sites for a variety of adaptor molecules, leading to mitogen-activated protein kinase (MAPK) Activation of the pathway, PI3K/Akt pathway, and signal transducer and transcriptional pathway activators promotes cell proliferation, angiogenesis, metastasis, and inhibition of apoptosis, thereby increasing tumor cell survival, proliferation, invasion, and metastasis. TK activation of tumor cell EGFR can be disrupted by a variety of oncogene mechanisms, including increased gene copy number and EGFR protein overexpression caused by EGFR gene mutations. More than 60% of NSCLC patients have overexpressed EGFR in their tumor cells, and these patients have a poor prognosis. These findings have led to the development of anticancer drugs that target EGFR. Reversible EGFR TKIs (erlotinib and gefitinib) have significant anti-tumor efficacy in a subset of NSCLC patients: approximately 10% of European patients and 30% of East Asian patients have clinical remission. EGFR gene sequencing revealed that most tumors that responded to EGFR TKIs treatment contained mutations in the EGFR TK region. Overall, the mutation frequency of EGFR is 5%-20%, depending on the study population. Tumor patients carrying EGFR mutations have a response rate of approximately 75% for erlotinib and gefitinib, suggesting that these mutations can cause malignant transformation of cells. All NSCLCs that initially responded to EGFR TKI treatment developed secondary resistance. The efficacy of gefitinib and erlotinib is currently considered to be limited, mainly due to resistance caused by the second point mutation in the TK region. 50% of patients with secondary drug resistance in EGFR TKI develop a threonine-790 mutation to methionine (T790M, although EGFR TKIs can also achieve significant efficacy in these patients, but T790M is included in patients who do not have T790M detected. The progression-free survival of patients was relatively short (7.7 months vs 16.5 months; P < 0.001). Preclinical studies also found that T790M is a potential resistance mechanism, and in vitro tests confirmed that this mutation significantly inhibited erlotinib and The effect of fentanyl, however, is still present in TK activity. Similarly, introduction of T790M into gefitinib-sensitive tumor cells, activated EGFR mutations or increased EGFR copy number can lead to gefitinib resistance. However, the mechanism by which T790M causes the resistance of tumor cells to EGFR TKIs remains unclear. It is likely that the T790M mutation causes a change in the topology of the ATP-binding pocket of TK and prevents EGFR TKIs from binding through the steric group phenomenon, thereby secondary resistance. A recent study suggests another mechanism by which T790M increases the binding of ATP to the kinase domain, which in turn reduces the efficacy of any ATP competitor. Study reports, other point mutations leading to drug resistance, such as The aspartate-761 mutation to tyrosine (D761Y) attenuates the interaction between the EGFR TKI and its target. Skin malignant melanoma is one of the most malignant tumors and is prone to invasion and metastasis. In recent years, BRAF gene has been found to have high frequency mutations in human melanoma. Clinically, there is a BRAF V600E mutation in about 50% of melanomas. . The B-raf gene is a member of the RAF family, which encodes a silk/threonine-specific kinase and is an important transduction factor in the RAS/RAF/MEK/ERKMAPK pathway, involved in the regulation of various biological events in cells. , such as cell growth, differentiation and apoptosis. Recent studies have shown that BRAF tumor gene mutations can be found in some human malignancies. Most literature reports that the rate of B-raf mutation in colorectal cancer is about 15%, and more than 90% are V600E mutations, and negatively correlated with K-ras mutation. Recent studies have shown that BRAF gene mutations have important predictive and prognostic significance in clinical practice. Patients with B-raf mutations cannot benefit from targeted drug therapy for EGFR, and patients with B-raf mutations have a prognosis. Poor. Phase I and phase II clinical trials of an oral BRAF kinase inhibitor vemurafenib (PLX4032/RO5185426) have demonstrated greater than 50% efficiency (RR; CR+PR) in BRAF V600E mutant melanoma patients. BRAF~(;V600E) mutant gene can promote the growth and proliferation of human melanoma cells, which can make tumor cells secrete more MMPs and VEGF, enhance the ability of tumor cells to invade and angiogenesis, and improve their ability to metastasize, suggesting BRAF ( V600E) mutations play an important role in melanoma growth, invasion and metastasis, and gene therapy targeting them can inhibit the growth of experimental melanoma.

实际上， Imatinib耐药机制及其克服途径的研究为分子靶向类药物建立了一个极好的模式。例如，靶向 EGFR的 Gefitinib或 Erlotinib的耐药肿瘤，约 50%发生了点突变（T790M ), 该突变类似于 BCR-Abl中 T315I突变，都是酶活性中心的"守护"残基 (Gatekeeper residue), 突变造成药物分子与酶活性中心结合减弱，而不影响酶对催化底物的活性。因此，可逆性抑制剂如 Gefitinib和 Erlotinib的都会受其影响；一些 EGFR不可逆抑制剂，如 Canertinib，正处于临床研究阶段，期望能够改善点突变耐药肿瘤的疗效。同样， EGFR抑制剂也可通过旁路代偿机制产生耐药，如 Met或 PDGFR基因扩增。当 EGFR被抑制剂抑制而不能与 ErbB3结合时， Met或 PDGFR能够代偿性地与 ErbB3结合，取代原有 EGFR的功能，激活下游的 PBK信号通路，使抑制剂丧失对肿瘤细胞的抑制作用。因此， EGFR抑制剂和 Met 或 PDGFR抑制剂的联用，将是临床克服 EGFR抑制剂耐药的又一可选择方案。 In fact, the study of Imatinib resistance mechanisms and their pathways of overcoming has established an excellent model for molecularly targeted drugs. For example, about 50% of Gefitinib or Erlotinib-resistant tumors targeting EGFR have a point mutation (T790M) similar to the T315I mutation in BCR-Abl, which is the "guardian" residue of the enzyme activity center (Gatekeeper residue). The mutation causes the binding of the drug molecule to the active site of the enzyme to be attenuated without affecting the activity of the enzyme on the catalytic substrate. Therefore, reversible inhibitors such as Gefitinib and Erlotinib are affected; some EGFR irreversible inhibitors, such as Canertinib, are in clinical research and are expected to improve the efficacy of point-mutant drug-resistant tumors. Similarly, EGFR inhibitors can also develop resistance through a bypass compensatory mechanism, such as Met or PDGFR gene amplification. When EGFR is inhibited by an inhibitor and cannot bind to ErbB3, Met or PDGFR can compensatoryly bind to ErbB3, replacing the function of the original EGFR, and activating the downstream PBK signaling pathway, causing the inhibitor to lose its inhibitory effect on tumor cells. Therefore, the combination of an EGFR inhibitor and a Met or PDGFR inhibitor would be an alternative to clinically overcoming EGFR inhibitor resistance.

早期上市的蛋白激酶抑制剂主要是针对单一靶点的特异性抑制剂，虽然刚上市时在肿瘤治疗中取得了令人瞩目的成就，但是随着使用时间的延长及治疗病例的增多，问题逐渐暴露出来。其中一是耐药性问题，因为靶点单一，很容易在靶点激酶突变后造成耐药；二是此类药物的使用面相当局限，必须是其靶激酶高表达或过度激活的病例才能发挥其疗效。相比较广谱性激酶抑制剂则显示出一定的优势。由于同时靶向多个激酶激酶分子和多条信号通路，不但可以避免单一靶点突变造成的耐药性，而且可以显著扩大其抗瘤谱。代表性药物除上述 Sunitinib和 Sorafenib夕卜，还包括最近上市的多靶点激酶抑制剂 Vandetanib (商品名： Zactima; AstraZeneca；)。 Vandetanib同时靶向 EGFR、 VEGFR和 RET等酪氨酸激酶，于 2005年被 FDA批准作为滤泡性、髓质性、未分化或局部晚期和转移性乳突性甲状腺癌的治疗用药。 Early marketed protein kinase inhibitors are mainly specific inhibitors for single targets. Although they have made remarkable achievements in cancer treatment at the time of market launch, with the prolongation of use time and the increase in treatment cases, the problem gradually Exposed. One of them is the problem of drug resistance. Because the target is single, it is easy to cause drug resistance after the target kinase mutation. Second, the use of such drugs is limited by the fact that it must be a case of high expression or overactivation of its target kinase. Its efficacy. Compared to broad-spectrum kinase inhibitors, it shows certain advantages. By simultaneously targeting multiple kinase kinase molecules and multiple signal pathways, not only the resistance caused by single target mutations can be avoided, but also the anti-tumor spectrum can be significantly expanded. Representative drugs include Sunitinib and Sorafenib, as well as the recently marketed multi-targeted kinase inhibitor Vandetanib (trade name: Zactima; AstraZeneca;). Vandetanib also targets tyrosine kinases such as EGFR, VEGFR and RET, and was approved by the FDA in 2005 as a therapeutic agent for follicular, medullary, undifferentiated or locally advanced and metastatic papillary thyroid cancer.

综上所述，扩大肿瘤适应症研究范围，消除或延缓耐药性的出现将是蛋白激酶抑制剂抗肿瘤药物研发的主流方向。因此，继续寻找和发现新型的蛋白激酶抑制剂作为抗肿瘤药物，特别是能抵抗现有药物引起的耐药，具有更好疗效的蛋白激酶抑制剂仍然具有非常迫切的意义。发明内容 In summary, expanding the scope of research on cancer indications, eliminating or delaying the emergence of drug resistance will be the mainstream direction of protein kinase inhibitor anti-tumor drug development. Therefore, it is still very important to continue to find and discover novel protein kinase inhibitors as anti-tumor drugs, especially resistant to drug resistance caused by existing drugs. Summary of the invention

本发明的目的是为了提供一类新的蛋白激酶抑制剂。 The object of the present invention is to provide a new class of protein kinase inhibitors.

一方面，本发明提供具有通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药， In one aspect, the invention provides a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof,

(I) (I)

其巾： Its towel:

环 A为芳基，优选为。芳基，更优选为苯基； Ring A is an aryl group, preferably . An aryl group, more preferably a phenyl group;

m为环 A上取代基 Ra的数目，且 m为 0、 1、 2、 3或 4，优选为 1或 2; m is the number of substituents Ra on ring A, and m is 0, 1, 2, 3 or 4, preferably 1 or 2;

m个 Ra各自独立地选自卤素、 -R₂、 -OH、- SH、 -OR₂、 -NH₂、 -NHR₂、 -N(R₂)₂、 -NHC(0)R₂、 -NHC(0)OR₂、 -NR₃C(0)R₂; m Ra are each independently selected from halogen, -R ₂ , -OH, -SH, -OR ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NHC (0) OR ₂ , -NR ₃ C(0)R ₂ ;

环 T为含有至少一个氮原子的杂芳基，其中 M选自 N原子、 CH和 CR，其中 R选自卤素、 -R₂、 -OR₂、 -CN、 -OH、 -SH、 -COOH、 -C(0)-R₂、 -C(0)0-R₂、 -OC(0)-R₂、 -NH₂、 -NHR₂、 -N(R₂)₂、 -NHC(0)R₂、 -NR₃C(0)R₂; Ring T is a heteroaryl group containing at least one nitrogen atom, wherein M is selected from the group consisting of N atoms, CH and CR, wherein R is selected from the group consisting of halogen, -R ₂ , -OR ₂ , -CN, -OH, -SH, -COOH, -C(0)-R ₂ , -C(0)0-R ₂ , -OC(0)-R ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NR ₃ C(0)R ₂ ;

p为环 T上取代基 Rt的数目，且 t为 0、 1、 2、 3、 4或 5，优选为 0、 1或 2; p is the number of substituents Rt on ring T, and t is 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;

p个 R1各自独立地选自卤素、 -R₂、 -CN、- COOH、 -OH、- SH、 -OR₂、 -C(0)-R₂、 -C(0)0-R₂、 -OC(0)-R₂、 -S(0)_x-R₂、 -NH₂、 -NHR₂、 -N(R₂)₂、 -NHC(0)R₂、 -NHC(0)OR₂、 -NR₃C(0)R₂，其中 x为 0、 1或 2; Each of p R1 is independently selected from the group consisting of halogen, -R ₂ , -CN, -COOH, -OH, -SH, -OR ₂ , -C(0)-R ₂ , -C(0)0-R ₂ , OC(0)-R ₂ , -S(0) _x -R ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NHC(0)OR ₂ , -NR ₃ C(0)R ₂ , wherein x is 0, 1 or 2;

环 B为芳基，优选为。芳基，更优选为苯基； Ring B is an aryl group, preferably . An aryl group, more preferably a phenyl group;

n为环 B上取代基 Rb的数目，且 n为 0、 1、 2、 3、 4或 5，优选为 1或 2，更优选为 n is the number of substituents Rb on ring B, and n is 0, 1, 2, 3, 4 or 5, preferably 1 or 2, more preferably

2； 2;

n个 Rb各自独立地选自卤素、 -R₂、 -CN、 -COOH、 -OH、 -SH、 -OR₂、 -C(0)-R₂、 -C(0)0-R₂、 -OC(0)-R₂、 -S(0)_x-R₂、 -NH₂、 -NHR₂、 -N(R₂)₂、 -NHC(0)R₂、 -NHC(0)OR₂、 -NR₃C(0)R₂，其中 x为 0、 1或 2; 或者 Each of R Rb is independently selected from the group consisting of halogen, -R ₂ , -CN, -COOH, -OH, -SH, -OR ₂ , -C(0)-R ₂ , -C(0)0-R ₂ , OC(0)-R ₂ , -S(0) _x -R ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ , -NHC(0)OR ₂ , -NR ₃ C(0)R ₂ , where x is 0, 1 or 2; or

两个相邻的 Rb与其所连接的环 B上的碳原子一起形成杂环基；所述杂环基任选地被一个或多个选自 -R₂、 -C(0)0-R₂ -C(0)-R₂的基团取代； Two adjacent Rbs together with a carbon atom on ring B to which they are attached form a heterocyclic group; said heterocyclic group optionally being selected from one or more selected from -R ₂ , -C(0)0-R ₂ a group substituted with -C(0)-R ₂ ;

L为选自 -CONR_r或者 -NR CO-的连接基团，其中选自 H原子、烷基、环烷基、羟基烷基、芳基、杂芳基或者杂环基， L is a linking group selected from -CONR _r or -NR CO-, wherein it is selected from a H atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aryl group, a heteroaryl group or a heterocyclic group,

各 R₂、 R₃独立地选自烷基、烯基、块基、环烷基、杂环基、芳基、杂芳基，且各 R₂ 和 R₃任选地被一个或多个选自卤素、 -OH、 - 、 -0 、 -C(0)-R4 -C(OP-R4、 -OC(0)-R₄、Each R ₂ , R _{3 is} independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₂ and R _{3 is} optionally selected by one or more From halogen, -OH, -, -0, -C(0)-R4 -C(OP-R4, -OC(0)-R ₄ ,

-C(0)N(R4)₂、 -S(0)_x-R4、 -NH₂、 -NH 、 -N(R₄)₂、 -NHC(0)R₄、 -爾 C(0)OR₄、 -NR₅C(0)R₄ 的基团取代，其中 x为 0、 1或 2; -C(0)N(R4) ₂ , -S(0) _x -R4, -NH ₂ , -NH , -N(R ₄ ) ₂ , -NHC(0)R ₄ , -C(0)OR ₄ , a group substituted by -NR ₅ C(0)R ₄ , wherein x is 0, 1 or 2;

各、 R₅独立地选自烷基、烯基、环烷基、杂环基、芳基、杂芳基，且各、 R₅任选地被一个或多个选自 -OH、 -CN、 -NH₂、烷基、单 (烷基)氨基、二 (浣基)氨基、环烷基、杂环基、烷基杂环基、烷氧基、羟基烷基、烷氧基烷基、羟基烷氧基烷基、烷基羰基烷基、氨基院基、二院基氨基院基、院氧基羰基氨基院基、环院基院基、杂环基院基、芳院基、烷基环烷基、环烷基羰基、烷氧基羰基、烷氧基羰基杂环基、（烷氧羰基) (烷基)氨基、（浣氧基烷基) (烷基)氨基、（烷基羰基) (烷基)氨基的基团取代。 Each R _{5 is} independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, mono(alkyl)amino, bis(indenyl)amino, cycloalkyl, heterocyclyl, alkylheterocyclyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy Alkoxyalkyl, alkylcarbonylalkyl, amino adenyl, amphoteric amide, alkoxycarbonylamino-based, ring-based base, heterocyclic-based, aromatic-based, alkyl ring Alkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (decyloxyalkyl)(alkyl)amino, (alkylcarbonyl) Substituent of the (alkyl)amino group.

本发明的另一方面涉及药物组合物，其包含本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，和药学上可接受的载体。本发明的另一方面涉及本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者本发明的药物组合物，其用于抑制蛋白激酶的活性。 Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, a polymorph, a tautomer, a metabolite or a former The drug, and a pharmaceutically acceptable carrier. Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention A composition for inhibiting the activity of a protein kinase.

本发明的另一方面涉及本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者本发明的药物组合物，其用于预防和 / 或***。 Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention A composition for preventing and/or treating a tumor.

本发明的另一方面涉及本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者本发明的药物组合物在制备用于抑制蛋白激酶活性的药物中的应用。 Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention Use of a composition for the preparation of a medicament for inhibiting protein kinase activity.

本发明的另一方面涉及本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者本发明的药物组合物在制备用于治疗和 /或预防肿瘤的药物中的应用。 Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention Use of the composition in the manufacture of a medicament for the treatment and/or prevention of a tumor.

本发明的再一方面涉及一种调节蛋白激酶活性的方法，其中包括将所述蛋白激酶与上述化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂化物、前药或代谢产物接触。所述调节蛋白激酶活性优选为抑制蛋白激酶活性。该方法可以用于体内，也可用于体外。 A further aspect of the invention relates to a method of modulating protein kinase activity, which comprises the protein kinase and the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof , solvate, prodrug or metabolite contact. Preferably, the regulatory protein kinase activity is inhibition of protein kinase activity. This method can be used in vivo as well as in vitro.

本发明的另一方面涉及抑制哺乳动物、特别是人的蛋白激酶活性的方法，所述方法包括对有需要的哺乳动物、特别是人给予治疗有效量的本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者本发明的药物组合物。 Another aspect of the invention relates to a method of inhibiting protein kinase activity in a mammal, particularly a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, which is pharmaceutically acceptable Salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention.

本发明的另一方面涉及治疗和 /或预防哺乳动物、特别是人的肿瘤的方法，所述方法包括对有需要的哺乳动物、特别是人给予治疗有效量的本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者本发明的药物组合物。根据一个实施方式，所述肿瘤是通过抑制蛋白激酶而得到抑制的。 Another aspect of the invention relates to a method of treating and/or preventing a tumor in a mammal, in particular a human, comprising administering to a mammal, in particular a human, in need thereof a therapeutically effective amount of a compound of the invention, pharmaceutically thereof Acceptable salts, stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs thereof or pharmaceutical compositions of the invention. According to one embodiment, the tumor is inhibited by inhibition of a protein kinase.

本发明的另一方面涉及本发明的化合物与一种或多种其它的本发明化合物或者一种或多种其它抗癌药物联合或组合使用，以治疗和 /或预防肿瘤的用途。具体实施方式 Another aspect of the invention relates to the use of a compound of the invention in combination or in combination with one or more other compounds of the invention or one or more other anti-cancer drugs for the treatment and/or prevention of a tumor. detailed description

除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。 Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety herein in their entirety herein

应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用 "或"、 "或者"表示 "和 /或"。此外，所用术语"包括"以及其它形式，例如 "包含"、 "含"和 "含有"并非限制性。 The above description and the following detailed description are to be considered as illustrative and not restrictive. In the present application, the use of the singular includes the plural unless otherwise specified. It must be noted that, unless the context clearly dictates otherwise, the singular forms used in the specification and the claims are in the plural. It should also be noted that "or", "or" means "and / or" unless otherwise stated. In addition, the terms "including" and "including", "including", "include", and "include" are not limiting.

可在参考文献（包括 Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4^th ED." s. A (2000) and B (2001), Plenum Press, New York) 中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、 NMR、 IR和 UV/Vis光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。 The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^th ED." s. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in relation to analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, a group and its substituents can be selected by those skilled in the art to provide a stable knot. Fractions and compounds.

当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言， -CH₂0-等同于 -OCH₂-。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH ₂ 0- is equivalent to -OCH ₂ -.

本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。 The section headings used herein are for the purpose of organizing articles only and are not to be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.

在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如， _₆烷基是指具有总共 1至 6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。 Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, _-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms. The total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.

除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。 In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specified.

在本申请中，术语"卤素"是指氟、氯、溴或碘。 In the present application, the term "halogen" means fluoro, chloro, bromo or iodo.

"羟基"是指 -OH基团。 "Hydroxy" means an -OH group.

"羟基烷基"是指被羟基 (-OH)取代的如下文所定义的烷基。 "Hydroxyalkyl" means an alkyl group as defined below which is substituted by a hydroxy group (-OH).

"羰基"是指 -C(=0)-基团。 "Carbonyl" means a -C(=0)- group.

"硝基"是指 -N0₂。 "Nitro" means -N0 ₂ .

"氰基"是指 -CN。 "Cyano" means -CN.

"氨基"是指 -NH₂。 "Amino" means -NH ₂ .

"取代的氨基"是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。 "Substituted amino" means an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.

"幾基"是指 -COOH。 "Several bases" means -COOH.

在本¹申请中，作为基团或是其它基团的一部分（例如用在卤素取代的烷基等基团中），术语"烷基"意指仅由碳原子和氢原子组成、不含不饱和键、具有例如 1至 12个（优选为 1 至 8个，更优选为 1至 6个）碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、 2-甲基丁基、 2，2-二甲基丙基、正己基、庚基、 2-甲基己基、 3-甲基己基、辛基、壬基和癸基等。 ¹ in the present application, as part of the group or other group (e.g., halogen-substituted with an alkyl group and the like), the term "alkyl" means consisting solely of carbon and hydrogen atoms, containing no A saturated bond, a linear or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and bonded to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.

在本申请中，术语 "烷氧基"是指式 -OR_a基团，其中为如上文所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。 In the present application, the term "alkoxy" refers to _a radical of the formula -OR _a where is alkyl as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

在本申请中，术语 "烷基羰基"是指 -C(0)-R_a基团，其中 R_a为如上文所定义的烷基。在本申请中，术语"烷氧基羰基"是指 -C(0)0-R_a基团，其中 R_a为如上文所定义的烷基。 In the present application, the term "alkylcarbonyl" refers to a -C(O)-R _a group, wherein R _a is alkyl as defined above. In the present application, the term "alkoxycarbonyl" refers to a -C(0)0-R _a group, wherein R _a is alkyl as defined above.

在本申请中，术语 "单烷基氨基"是指式 -NHR_a基团，其中为如上文所定义的烷基。单烷基氨基的实例包括但不限于甲氨基、乙氨基、异丙氨基等。 In the present application, the term "monoalkylamino" refers to _a radical of the formula -NHR _a where is alkyl as defined above. Examples of monoalkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, and the like.

在本申请中，术语"二烷基氨基"是指式 -NR_aR_b基团，其中和各自独立地为如上文所定义的烷基。二烷基氨基的实例包括但不限于二甲氨基、二乙氨基、二丙氨基、甲基乙基氨基等。 In the present application, the term "dialkylamino" refers to _a radical of the formula -NR _a R _b wherein each is independently alkyl as defined above. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, and the like.

在本申请中，作为基团或是其它基团的一部分，术语"烯基"意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如 2至 14个（优选为 2至 10个，更优选为 2至 6个）碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁 -1-烯基、丁 -2-烯基、戊 -1-烯基、戊 -1,4-二烯基等。 In the present application, the term "alkenyl" as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) More preferably, 2 to 6) a straight or branched hydrocarbon chain group having a carbon atom and attached to the remainder of the molecule through a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.

在本申请中，作为基团或是其它基团的一部分，术语"块基"意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如 2至 14个（优选为 2至 10个，更优选为 2至 6个）碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙块基、丙 -1-块基、丁 -1-块基、戊 -1-烯 -4-块基等。 In the present application, the term "block group" as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) a straight or branched hydrocarbon chain group having a carbon atom and attached to the remainder of the molecule by a single bond, such as, but not limited to, an ethyl group, a propan-1-yl group, But-1-blockyl, pent-1-ene-4-block, and the like.

在本申请中，作为基团或是其它基团的一部分，术语"环烷基"意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有 3至 15个碳原子，优选具有 3至 10个碳原子，更优选具有 3至 8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、 1H- 茚基、 2，3-二氢化茚基、 1，2，3，4-四氢-萘基、 5，6，7，8-四氢-萘基、 8，9-二氢 -7H-苯并环庚烯 -6- 基、 6，7，8，9-四氢 -5H-苯并环庚烯基、 5，6，7，8，9，10-六氢-苯并环辛烯基、芴基、二环 [2.2.1 ]庚基、 7，7-二甲基 -二环 [2.2.1]庚基、二环 [2.2.1]庚烯基、二环 [2.2.2]辛基、二环 [3丄 1]庚基、二环 [3.2.1]辛基、二环 [2.2.2]辛烯基、二环 [3.2.1]辛烯基、金刚烷基、八氢 -4,7-亚甲基 -1H-茚基和八氢 -2,5-亚甲基 -并环戊二烯基等。 In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing A ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed The carbon atom is connected to the rest of the molecule by a single bond. Unless otherwise specifically indicated in the specification, a carbon atom in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctene , fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] Octyl, bicyclo[3丄1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl,adamantyl, octa Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.

在本申请中，术语 "环烷基氧基"是指式基团，其中 Re为如上文所定义的环烷基。 In the present application, the term "cycloalkyloxy" refers to a radical of the formula wherein Re is cycloalkyl as defined above.

在本申请中，作为基团或是其它基团的一部分，术语 "杂环基"意指由 2至 14个碳原子以及 1至 6个选自氮、氧和硫的杂原子组成的稳定的 3元至 20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含 1至 3个选自氮、氧和硫的杂原子的稳定的 4元至 11元非芳香性单环、双环、桥环或螺环基团，更优选为包含 1至 3个选自氮、氧和硫的杂原子的稳定的 4元至 8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、 2，7-二氮杂-螺 [3.5]壬烷 -7- 基、 2-氧杂 -6-氮杂-螺 [3.3]庚烷 -6-基、 2，5-二氮杂 -双环 [2.2.1]庚烷 -2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。 In the present application, the term "heterocyclyl" as a group or part of another group means a stable consisting of 2 to 14 carbon atoms and 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur. A 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be bonded to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond. In the heterocyclic group containing a fused ring, one or more of the rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, a heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene. Alkan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.

在本申请中，术语 "杂环基氧基"是指式 -0 基团，其中为如上文所定义的杂环基。 In the present application, the term "heterocyclyloxy" refers to a radical of the formula -0, wherein is a heterocyclic radical as defined above.

在本申请中，作为基团或是其它基团的一部分，术语 "芳基"意指具有 6至 18个碳原子（优选具有 6至 10个碳原子）的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、 2，3-二氢 -1H-异吲哚基、 2-苯并噁唑啉酮、 2Η-1，4-苯并噁嗪 -3(4Η)-酮 -7-基等。 In the present application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2Η-1, 4-benzoxazine-3(4Η)-keto-7-yl and the like.

在本申请中，术语"芳基烷基"是指被上文所定义的芳基所取代的上文所定义的烷基。在本申请中，作为基团或是其它基团的一部分，术语 "杂芳基"意指环内具有 1至 15 个碳原子（优选具有 1至 10个碳原子）和 1至 6个选自氮、氧和硫的杂原子的 5元至 16 元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含 1至 5个选自氮、氧和硫的杂原子的稳定的 5元至 12元芳香性基团，更优选为包含 1至 4个选自氮、氧和硫的杂原子的稳定的 5元至 10元芳香性基团或者包含 1至 3个选自氮、氧和硫的杂原子的 5元至 6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、 ***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、 4，5，6，7-四氢苯并 [b]噻吩基、萘并吡啶基、 [1，2，4]***并 [4,3-6]哒嗪、 [1，2，4]***并 [4，3-α]吡嗪、 [1，2，4]***并 [4，3-c]嘧啶、 [1，2，4]***并 [4，3-α]吡啶、咪唑并 [1，2-α]吡啶、咪唑并 [1,2-6]哒嗪、咪唑并 [1，2-α]吡嗪等。 In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above. In the present application, the term "heteroaryl" as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the hetero The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, the heteroaryl group preferably contains from 1 to 5 selected from nitrogen, oxygen and a stable 5- to 12-membered aromatic group of a hetero atom of sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur or 1 Up to 3 5- to 6-membered aromatic groups selected from heteroatoms of nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, dinaphthyl, naphthyridyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Phenyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole, porphyrin, quinazolinyl, phenylthio, guanidinium, phenanthroline, Isoxazolyl, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 , 3-6] pyridazine, [1,2,4]triazolo[4,3-α]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-α]pyridine, imidazo[1,2-α]pyridine, imidazo[1,2-6] Pyridazine, imidazo[1,2-α]pyrazine and the like.

在本申请中，术语 "杂芳基烷基"是指被上文所定义的杂芳基所取代的上文所定义的焼基。 In the present application, the term "heteroarylalkyl" refers to a fluorenyl group as defined above which is substituted by a heteroaryl group as defined above.

在本申请中， "任选的" 或 "任选地"表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如， "任选地被取代的芳基" 表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。 In the present application, "optional" or "optionally" means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.

在本申请中，当某一基团被描述为 "任选地取代" 时，该基团可任选地在一个或多个适当的位置被下列基团取代：烷基、烯基、块基、卤素、卤代烷基、卤代烯基、氰基、硝基、环烷基、杂环基、芳基、杂芳基、三甲基甲硅烷基、 -OR_1Q、 -C(O)-R₁₀ -C(O)O-R₁₀ -OC(O)-R₁₀、 -N(R₁₀)₂、 -C(O)N(R₁₀)₂、 -N(R₁₀)C(O)R_u、 -N(R₁₀)C(O)OR_n -N(R₁₀)S(O)_tR_u (其中 t为 1或 S X -S O ORu (其中 t为 1或 S X - S O Ru (其中 t为 0、 1或 2)、- S(O)_tN(R₁₀)₂ In the present application, when a group is described as "optionally substituted", the group may be optionally substituted at one or more suitable positions with the following groups: alkyl, alkenyl, block , halogen, haloalkyl, haloalkenyl, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, trimethylsilyl, -OR _1Q , -C(O)-R ₁₀ -C(O)OR ₁₀ -OC(O)-R ₁₀ , -N(R ₁₀ ) ₂ , -C(O)N(R ₁₀ ) ₂ , -N(R ₁₀ )C(O)R _u , -N(R ₁₀ )C(O)OR _n -N(R ₁₀ )S(O) _t R _u (where t is 1 or SX -SO ORu (where t is 1 or SX - SO Ru (where t is 0 , 1 or 2), - S(O) _t N(R ₁₀ ) ₂

(其中 t为 1或 2)，其中各 R_1Q独立地为氢、烷基、卤代烷基、环烷基、环烷基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基；且各 Ru独立地为烷基、 ¾代烷基、环烷基、环烷基烷基、芳基、芳烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基。 (wherein t is 1 or 2), wherein each R _{1Q is} independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl , heteroaryl or heteroarylalkyl; and each Ru is independently alkyl, 3⁄4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl A heteroaryl or heteroarylalkyl group.

本文所用术语 "部分"、 "结构部分"、 "化学部分"、 "基团"、 "化学基团"是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。 The terms "part", "structural moiety", "chemical moiety", "group", and "chemical group" as used herein mean a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.

"立体异构体 "是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。 "Stereoisomer" means a compound composed of the same atom, bonded by the same bond, but having a different three-dimensional structure. The invention will cover various stereoisomers and mixtures thereof.

当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含 Ε- 和 Ζ-几何异构体。 When the compound of the present invention contains an olefinic double bond, the compound of the present invention is intended to contain Ε- and Ζ-geometric isomers unless otherwise stated.

"互变异构体"是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。 "Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.

本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为 (R)-或 (S) -。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。 The compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof. The preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.

制备 /分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体（或盐或衍生物的外消旋体），例如可参见 Gerald Giibitz and M artin G. Schmid (Eds.), Chiral Se arations, M ethods and Protocols, Methods in Molecular Biology, No\. 243, 2004； A.M . Stalcup , Chiral Separations, Annu. Rev. Anal Chem. 3 :341-63, 2010； Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.si¾) .TH ED., Longman Scientific and Technical Ltd., Essex, 1991， 809-816； Heller, Acc. Chem. Res. 1990, 23, 128。在本申请中，术语 "药学上可接受的盐"包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。 Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemic form of a salt or derivative) using, for example, chiral high performance liquid chromatography. For example, see Gerald Giibitz and M artin G. Schmid (Eds.), Chiral Se arations, M ethods and Protocols, Methods in Molecular Biology, No. 243, 2004; AM . Stalcup , Chiral Separations, Annu. Rev. Anal Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.si3⁄4) .TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128. In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"药学上可接受的酸加成盐"是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、 2，2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、 4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。 "Pharmaceutically acceptable acid addition salt" means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. These salts can be prepared by methods known in the art.

"药学上可接受的碱加成盐"是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、 2-二甲氨基乙醇、 2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、 N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。 "Pharmaceutically acceptable base addition salt" means a salt formed with an inorganic base or an organic base capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

"多晶型物 "是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。 "Polymorph" means a different solid crystalline phase of certain compounds of the present invention which are produced in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.

通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语 "溶剂化物" 是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。 Generally, crystallization will result in a solvate of the compound of the invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules. The solvent may be water, and the solvate in this case is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention form true solvates, but in some cases, it is also possible to retain only a variable amount of water or a mixture of water and a portion of the indefinite solvent. The compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

本申请中， "代谢产物" 是指药物被机体吸收后，在酶的作用下经过体内的官能团化反应（I相生物转化反应，包括氧化、还原、水解等）和结合反应（Π相生物转化反应）等生物转化而产生的化合物。 In the present application, "metabolite" refers to a functional group reaction (I phase biotransformation reaction, including oxidation, reduction, hydrolysis, etc.) and binding reaction (phase biotransformation) of a drug after being absorbed by the body and under the action of an enzyme. Reaction) A compound produced by biological transformation.

本发明还包括上述化合物的前药。在本申请中，术语 "前药"表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语 "前药" 是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照 Saulnier, M . G.， et al.， Bioorg. Med. Chem. Lett. 1994， 4， 1985-1990； Greenwald, R. B.， et al.， J. Med. Chem. 2000, 43, 475。 The invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood. Prodrug compounds generally provide the advantage of solubility, histocompatibility or sustained release in mammalian organisms. Prodrugs include known amino protecting groups and carboxy protecting groups. For specific preparation methods of prodrugs, see Saulnier, M. G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, RB, et al., J. Med. Chem. 2000 , 43, 475.

在本申请中， "药物组合物"是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物（例如人）的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。本文所用术语 "药学上可接受的"是指不影响本发明化合物的生物活性或性质的物质 (如载体或稀释剂），并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。 In the present application, "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. The medium includes a pharmaceutically acceptable carrier. Drug The purpose of the composition is to promote the administration of the organism, to facilitate the absorption of the active ingredient and to exert biological activity. The term "pharmaceutically acceptable" as used herein, refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.

在本申请中， "药学上可接受的载体"包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料 /着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化齐 U。 In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvants, carriers, excipients, glidants, sweeteners approved by the relevant government authorities for acceptable use by humans or domestic animals. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsions.

本文所用的有关术语 "受试者"、 "患者"或 "个体"是指患有疾病或病症等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物（例如黑猩猩和其它猿类和猴）；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。 The term "subject", "patient" or "individual" as used herein refers to an individual having a disease or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals For example, rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

本文所用术语 "预防的"、 "预防"和 "防止"包括使病患减少疾病或病症的发生或恶化的可能性。 The terms "preventing", "preventing" and "preventing" as used herein include the possibility of reducing the occurrence or deterioration of a disease or condition by a patient.

本文所用的术语 "治疗"和其它类似的同义词包括以下含义： The term "treatment" and other similar synonyms as used herein includes the following meanings:

( 预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时； (Prevention of a disease or condition in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;

(ii) 抑制疾病或病症，即遏制其发展； (ii) inhibiting a disease or condition, ie curbing its development;

(iii) 缓解疾病或病症，即，使该疾病或病症的状态消退；或者 (iii) alleviating the disease or condition, ie, causing the condition of the disease or condition to subside; or

(iv) 减轻该疾病或病症所造成的症状。 (iv) alleviate the symptoms caused by the disease or condition.

本文所使用术语 "有效量"、 "治疗有效量"或 "药学有效量"是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和 /或缓解，或生物***的任何其它所需变化。例如，用于治疗的 "有效量"是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。 The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be the reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system. For example, an "effective amount" for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.

本文所用术语 "服用"、 "施用"、 "给药"等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射（包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在 Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Perg^mon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。 The terms "administering," "administering," "administering," and the like, as used herein, refer to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. The techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Perg^mon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co ., Easton, those discussed in Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

本文所使用术语 "药物组合"、 "药物联用"、 "联合用药"、 "施用其它治疗"、 "施用其它治疗剂"等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语 "固定组合"是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语 "不固定组合"是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。 The terms "pharmaceutical combination", "drug combination", "combination", "administering other treatments", "administering other therapeutic agents" and the like as used herein mean a medical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one of the compounds described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "unfixed combination" refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.

其巾：

Its towel:

2； 2;

L为选自 -CONRi -或者 -NR O-的连接基团，其中选自 H原子、烷基、环烷基、羟基烷基、芳基、杂芳基或者杂环基， L is a linking group selected from -CONRi - or -NR O-, wherein is selected from the group consisting of H atom, alkyl group, cycloalkyl group, hydroxyalkyl group, aryl group, heteroaryl group or heterocyclic group,

各 R₂、 R₃独立地选自烷基、烯基、块基、环烷基、杂环基、芳基、杂芳基，且各 R₂ 和 R₃任选地被一个或多个选自卤素、 -OH、 - 、 -0 、 -C(0)-R4 -C(OP-R4、 -OC(0)-R₄、 -C(0)N(R4)₂、 -S(0)_x-R4、 -NH₂、 -ΝΗ 、 -N(R₄)₂、 -NHC(0)R₄、 -爾 C(0)OR₄、 -NR₅C(0)R₄ 的基团取代，其中 x为 0、 1或 2; Each R ₂ , R _{3 is} independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₂ and R _{3 is} optionally selected by one or more From halogen, -OH, -, -0, -C(0)-R4 -C(OP-R4, -OC(0)-R ₄ , -C(0)N(R4) ₂ , -S(0) _a group substitution of _x -R4, -NH ₂ , -ΝΗ , -N(R ₄ ) ₂ , -NHC(0)R ₄ , -C(0)OR ₄ , -NR ₅ C(0)R ₄ , Where x is 0, 1 or 2;

各、 R₅独立地选自烷基、烯基、环烷基、杂环基、芳基、杂芳基，且各、 R₅任选地被一个或多个选自 -OH、 -CN、 -NH₂、烷基、单 (烷基)氨基、二 (浣基)氨基、环烷基、杂环基、烷基杂环基、烷氧基、羟基烷基、烷氧基烷基、羟基烷氧基烷基、烷基羰基烷基、氨基院基、二院基氨基院基、院氧基羰基氨基院基、环院基院基、杂环基院基、芳院基、烷基环烷基、环烷基羰基、烷氧基羰基、烷氧基羰基杂环基、（烷氧羰基) (烷基)氨基、（浣氧基烷基 X烷基)氨基、（浣基羰基 X烷基)氨基的基团取代。 Each R _{5 is} independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, mono(alkyl)amino, bis(indenyl)amino, cycloalkyl, heterocyclyl, alkylheterocyclyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy Alkoxyalkyl, alkylcarbonylalkyl, amino adenyl, amphoteric amide, alkoxycarbonylamino-based, ring-based base, heterocyclic-based, aromatic-based, alkyl ring Alkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (decyloxyalkyl X alkyl)amino, (decylcarbonyl X-alkyl) Substituted by a group of amino groups.

在一个实施方式中，本发明还涉及通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： In one embodiment, the invention also relates to a compound of formula I, a pharmaceutically acceptable salt thereof, A conformation, solvate, polymorph, tautomer, metabolite or prodrug, wherein:

m个 Ra各自独立地选自卤素、烷基、环烷基、杂环基、 -OH、烷氧基、 -NH_2; 且该烷基、环烷基、杂环基、烷氧基任选地被一个或多个选自卤素、 -OH、烷氧基、环烷基氧基、杂环基氧基、 -NH₂、 -NH 、 -N(R₄)₂的基团取代；且该烷氧基、环烷基氧基和杂环基氧基任选地被一个或多个选自 -OH、 -CN、 -NH₂、烷基的基团取代。 m Ra are each independently selected from halogen, alkyl, cycloalkyl, heterocyclic, -OH, alkoxy, -NH _{2 ;} and the alkyl, cycloalkyl, heterocyclyl, alkoxy optionally Substituted with one or more groups selected from the group consisting of halogen, -OH, alkoxy, cycloalkyloxy, heterocyclyloxy, -NH ₂ , -NH , -N(R ₄ ) ₂ ; alkoxyalkyl, cycloalkyl group and heterocyclyl group optionally substituted with one or more groups selected from -OH, -CN, -NH _2, substituted alkyl groups.

在另一个实施方式中，本发明还涉及通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： In another embodiment, the present invention is also directed to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof , among them:

m个 Ra各自独立地选自卤素、烷基，且该烷基任选地被一个或多个选自卤素、 -OH、烷氧基、环烷基氧基、杂环基氧基的基团取代。 m Ra are each independently selected from halogen, alkyl, and the alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, -OH, alkoxy, cycloalkyloxy, heterocyclyloxy Replace.

m个 Ra各自独立地选自卤素、 d_₆烷基，且该烷基任选地被一个或多个选自卤素、 -OH、 C^烷氧基、 C₃_₈环烷基氧基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基氧基的基团取代。 m Ra are each independently selected from halogen, d- ₆ alkyl, and the alkyl is optionally selected from one or more selected from the group consisting of halogen, -OH, C alkoxy, C ₃ _-8 cycloalkyloxy, Substituent substitution of a 4- to 8-membered heterocyclic oxy group containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur.

在一个实施方式中，本发明还涉及通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： In one embodiment, the invention further relates to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, among them:

在通式 I中，乙块基部分与 L部分在环 A上呈间位取代，且至少一个 Ra位于环 A上 L部分的对位。 In Formula I, the E-block moiety and the L moiety are meta-substituted on Ring A, and at least one Ra is located in the para position of the L moiety on Ring A.

M为 CH; M is CH;

环 T选自包含 1至 5个选自氮、氧和硫的杂原子的 5元至 12元单环或稠合杂芳基，其中至少一个杂原子为氮原子； Ring T is selected from a 5- to 12-membered monocyclic or fused heteroaryl group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein at least one hetero atom is a nitrogen atom;

p个 Rt各自独立地为烷基，优选为 d_₆烷基； Each of p Rt is independently an alkyl group, preferably a d ₆ alkyl group;

两个相邻的 Rb与其所连接的环 B上的碳原子一起形成包含 1至 3个选自氮、氧和硫的杂原子的 4元至 11 元杂环基；所述杂环基任选地被一个或多个选自烷氧基羰基、烷基羰基、杂环基羰基、杂芳基羰基、环烷基烷基、杂环基烷基、芳烷基的基团取代；且烷基羰基中的烷基任选地被烷氧基酰氨基取代，杂环基烷基中的杂环基任选地被烷氧基羰基取代，杂环基羰基中的杂环基任选地被一个或多个选自烷基、烷基羰基、烷氧基羰基、羟基烷基的基团取代。 Two adjacent Rbs together with the carbon atom on the ring B to which they are attached form a 4- to 11-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; Substituted with one or more groups selected from the group consisting of alkoxycarbonyl, alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl; The alkyl group in the carbonyl group is optionally substituted by an alkoxyamido group, the heterocyclic group in the heterocyclylalkyl group is optionally substituted by an alkoxycarbonyl group, and the heterocyclic group in the heterocyclic carbonyl group is optionally a Or a plurality of groups selected from the group consisting of an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, and a hydroxyalkyl group.

在一个优选的实施方式中，本发明还涉及通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： In a preferred embodiment, the invention also relates to compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers, solvates, polymorphs, tautomers, metabolites thereof or Medicine, where:

环 T选自以下结构：

Ring T is selected from the following structures:

两个相邻的 Rb与其一起形成选自以下的结构: Two adjacent Rbs together with them form a structure selected from the following:

且该结构任选地被一个或多个选自烷氧基羰基、 d_₆烷基羰基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基羰基、包含 1至 3个选自氮、氧和硫的杂原子的 5元至 6元杂芳基羰基、 C₃_₈环烷基 -d_₆烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基 -d_₆烷基、 Q^。芳基 -d_₆烷基的基团取代；且烷基羰基中的烷基任选地被 Ci_₆烷氧基酰氨基取代，杂环基烷基中的杂环基任选地被烷氧基羰基取代，杂环基羰基中的杂环基任选地被一个或多个选自烷基、 d_₆烷基羰基、 d_₆烷氧基羰基、羟基 -Ci_₆烷基的基团取代。 And the structure is optionally one or more selected from the group consisting of an alkoxycarbonyl group, a d- ₆ alkylcarbonyl group, a 4- to 8-membered heterocyclic carbonyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, Containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur 5- to 6-membered heteroarylcarbonyl, C ₃ _-8 cycloalkyl-d- ₆ alkyl, 4- to 8-membered heterocyclic-d_ containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur ₆ alkyl, Q^. a group substituted with an aryl-d- ₆ alkyl group; and the alkyl group in the alkylcarbonyl group is optionally substituted with a Ci- ₆ alkoxyamido group, and the heterocyclic group in the heterocyclylalkyl group is optionally alkoxy The carbonyl group is substituted, and the heterocyclic group in the heterocyclic carbonyl group is optionally substituted by one or more groups selected from the group consisting of an alkyl group, a d- ₆ alkylcarbonyl group, a d- ₆ alkoxycarbonyl group, and a hydroxy-Ci- ₆ alkyl group.

M为 N原子； M is a N atom;

环 T选自包含 2至 5个选自氮、氧和硫的杂原子的 5元至 12元杂芳基，其中至少两个杂原子为氮原子； Ring T is selected from a 5- to 12-membered heteroaryl group containing 2 to 5 hetero atoms selected from nitrogen, oxygen and sulfur, wherein at least two of the heteroatoms are nitrogen atoms;

p个 R1各自独立地选自卤素； -OH; -NH₂; 烷基；烯基；任选地被烷氧基烷基取代的芳基；任选地被烷基、羟基烷基、 ¾素、烷氧基取代的杂环基；任选地被 -ΝΗ₂、烷基取代的杂芳基，其中该烷基任选地进一步被选自 -CN、烷氧基、环烷基、杂环基、单烷基氨基、二烷基氨基的基团取代；任选地被二烷基氨基、环烷基取代的烷氧基；任选地被烷基取代的杂环基氧基；环烷基氨基；单烷基氨基；二烷基氨基；该单烷基氨基和二烷基氨基中的烷基任选地进一步被烷氧基、二烷基氨基、烷基 S0₂ -、二烷基氨基羰基取代； Each of p R1 is independently selected from halogen; -OH; -NH ₂ ; alkyl; alkenyl; aryl optionally substituted by alkoxyalkyl; optionally alkyl, hydroxyalkyl, 3⁄4 An alkoxy-substituted heterocyclic group; a heteroaryl group optionally substituted by -ΝΗ ₂ , alkyl, wherein the alkyl group is optionally further selected from -CN, alkoxy, cycloalkyl, heterocyclic Substituted by a group of a monoalkylamino group, a dialkylamino group; an alkoxy group optionally substituted by a dialkylamino group, a cycloalkyl group; a heterocyclic oxy group optionally substituted by an alkyl group; a cycloalkane Alkylamino; a monoalkylamino group; a dialkylamino group; the alkyl group in the monoalkylamino group and the dialkylamino group optionally further substituted with an alkoxy group, a dialkylamino group, an alkyl S0 ₂ -, a dialkyl group Aminocarbonyl substitution;

n个 Rb各自独立地选自 ¾代烷基；环烷基；任选地被烷基取代的杂环基；杂环基烷基，其中该杂环基烷基中的杂环基任选地被一个或多个选自 -ΟΗ、烷基、羟基烷基、氨基烷基、杂环基、烷氧基烷基、羟基烷氧基烷基、烷基羰基烷基、杂环基烷基、环烷基烷基、芳基院基、单院基氨基院基、二院基氨基院基、院氧基羰基氨基院基、院氧基羰基、环院基羰基、单院基氨基、二院基氨基、 (院氧基羰基 )(院基)氨基、 (院氧基院基 )(院基)氨基、 (院基羰基) (浣基)氨基的基团取代。 Each of R Rb is independently selected from a 3⁄4 alkyl group; a cycloalkyl group; a heterocyclic group optionally substituted by an alkyl group; a heterocyclylalkyl group, wherein the heterocyclic group in the heterocyclylalkyl group is optionally One or more selected from the group consisting of -indole, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkylcarbonylalkyl, heterocyclylalkyl, Cycloalkylalkyl, aryl-based, single-yard amino-based, secondary-base amino-based, oxycarbonylamino-based, oxycarbonyl, ring-based carbonyl, single-hospital amino, second Substituted by a group of a base amino group, a (homoyloxycarbonyl) (homo-based) amino group, a (homo-oxyl group) (homo-based) amino group, a (homo-based carbonyl group) (fluorenyl) amino group.

环构 Structure

ρ个 R1各自独立地选自卤素； -OH; -NH₂; d— ₆烷基； C₂— ₆烯基；任选地被 C^烷氧基 C^烷基取代的。芳基；任选地被 d_₆烷基、羟基 -d_₆烷基、卤素、 d_₆烷氧基取代的包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基；任选地被 -NH₂、 d_₆烷基取代的包含 1至 4个选自氮、氧和硫的杂原子的 5元至 10元杂芳基，其中该烷基任选地进一步被选自 -CN、 d_₆烷氧基、 C₃_₈环烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基、单 ^_₆烷基)氨基、二 (^_₆烷基)氨基的基团取代；任选地被二 (^_₆烷基)氨基、 C₃_₈环烷基取代的 d_₆烷氧基；任选地被 d_₆烷基取代的包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基氧基； C₃_₈环烷基氨基；单 (d_₆烷基)氨基；二 (d_₆烷基)氨基；该单烷基氨基和二烷基氨基中的烷基任选地进一步被烷氧基、二 (C^烷基)氨基、 d_₆烷基 -S0₂-、二 (d_₆烷基)氨基羰基取代； ρ a R1 are each independently selected from halogen; -OH; -NH _2; d- ₆ alkyl; C ₂ - ₆ alkenyl; optionally substituted C ^ alkoxy-C ^ alkyl. An aryl group; a 4- to 8-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur, optionally substituted by d- ₆ alkyl, hydroxy-d- ₆ alkyl, halogen, d- ₆ alkoxy a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by -NH ₂ , d ₆ alkyl, wherein the alkyl group optionally further 4- to 8-membered heterocyclic group, mono- ₆ -alkane selected from -CN, d- ₆ alkoxy, C ₃ _-8 cycloalkyl, heteroatoms containing from 1 to 3 selected from nitrogen, oxygen and sulfur yl) amino, di (^ _ ₆ alkyl) amino groups; ₆ alkoxy optionally substituted with bis (^ _ ₆ alkyl) amino, C ₃ _ ₈ cycloalkyl substituted D_; optionally a 4- to 8-membered heterocyclic oxy group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, substituted by d ₆ alkyl; C ₃ _-8 cycloalkylamino; mono(d- ₆ alkyl) An amino group; a di(d- ₆ alkyl)amino group; the alkyl group in the monoalkylamino group and the dialkylamino group optionally further alkoxy group, di(C^alkyl)amino group, d- ₆ alkyl-S0 ₂ -, di(d- ₆ alkyl)aminocarbonyl substitution;

n个 Rb各自独立地选自卤代 -d_₆烷基； C₃_₈环烷基；任选地被 C_w烷基取代的包含 1 至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基；包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基 -d_₆烷基，其中该杂环基烷基中的杂环基任选地被一个或多个选自 -OH、 d_₆烷基、羟基 -^_₆烷基、氨基 -C_w烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基、 d_₆烷氧基 -d_₆烷基、羟基 -d_₆烷氧基 -d_₆烷基、 d_₆烷基羰基 -d_₆ 烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基 -^_₆烷基、 C₃_₈环烷基 -d_₆ 院基、 C₆_10芳基 -Ci— 6院基、单 (Ci— 6院基)氨基 -Ci— 6院基、二 (Ci— 6院基)氨基 -Ci— 6院基、 Ci_₆ 烷氧基羰基氨基 -c^烷基、 d_₆烷氧基羰基、 C₃_₈环烷基羰基、单 (d_₆烷基)氨基、二 (d_₆ 院基)氨基、 (Ci— 6院氧基羰基) (Ci— 6院基)氨基、 (Ci— ₆院氧基院基) (C 院基)氨基、 (Ci— 6院基羰基 XCw烷基)氨基的基团取代。 Each of R Rb is independently selected from halo-d- ₆ alkyl; C ₃ _-8 cycloalkyl; optionally substituted by C _w alkyl a 4- to 8-membered heterocyclic group to 3 hetero atoms selected from nitrogen, oxygen and sulfur; a 4- to 8-membered heterocyclic group-d_ ₆ containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur An alkyl group, wherein the heterocyclic group in the heterocyclylalkyl group is optionally one or more selected from the group consisting of -OH, d- ₆ alkyl, hydroxy-^- ₆ alkyl, amino- _Cw alkyl, including 1 to 3 heteroatoms selected from nitrogen, 4-8 yuan heterocyclic groups, oxygen and sulfur, d_ ₆ alkoxy -d_ ₆ alkyl, hydroxy -d_ ₆ -d_ ₆ alkoxy group, d_ ₆ alkoxy ylcarbonyl -d_ ₆ alkyl group, containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur heteroatoms 4- to 8-membered heterocyclic group - ^ _ ₆ alkyl, C ₃ _ ₈ cycloalkyl -d_ ₆ homes Base, C ₆ _10 aryl-Ci-6 yard base, single (Ci-6 yard base) amino-Ci-6 yard base, two (Ci-6 yard base) amino-Ci-6 yard base, Ci- ₆ alkoxy Alkylcarbonylamino-c^alkyl, d- ₆ alkoxycarbonyl, C ₃ _-8 cycloalkylcarbonyl, mono(d- ₆ alkyl)amino, bis(d- ₆ )amino, (Ci-6)oxy A group of a carbonyl group (Ci-6)-amino group, a (Ci- _6- yard oxy-based group) (C-institutional) amino group, (Ci-6-yard carbonyl XCw alkyl)amino group.

Μ为 CR，其中 R选自卤素、烷基、环烷基，且该烷基、环烷基任选地被一个或多个卤素取代；优选地， R选自 Ci_₆烷基或 C₃_₈环烷基，且该烷基或环烷基任选地被一个或多个卤素取代； Μ is CR, wherein R is selected from halogen, alkyl, cycloalkyl and the alkyl group, cycloalkyl group optionally substituted with one or more halogen; preferably, R is selected from Ci_ ₆ alkyl or C ₃ _ ₈ -cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halogens;

环 T选自包含 1至 5个选自氮、氧和硫的杂原子的 9元至 12元稠合杂芳基，其中至少一^ ^杂原子为氮原子； The ring T is selected from a 9- to 12-membered fused heteroaryl group containing 1 to 5 hetero atoms selected from nitrogen, oxygen and sulfur, wherein at least one of the hetero atoms is a nitrogen atom;

p个 R1各自独立地为卤素、杂环基、芳基、杂芳基；优选为卤素、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基、 C 芳基、包含 1至 3个选自氮、氧和硫的杂原子的 5元至 6元杂芳基；且该杂环基、芳基或杂芳基任选地被一个或多个烷基取代； Each of p R1 is independently halogen, heterocyclic, aryl, heteroaryl; preferably halogen, 4 to 8 membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, C An aryl group, a 5- to 6-membered heteroaryl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur; and the heterocyclic group, aryl or heteroaryl group is optionally substituted by one or more alkyl groups Replace

n个 Rb各自独立地为烷基或烷基取代的杂芳基，优选为 d_₆烷基或 d_₆烷基取代的包含 1至 3个选自氮、氧和硫的杂原子的 5元至 6元杂芳基，且各烷基任选地被一个或多个选自卤素、 -OH、单 (d_₆烷基)氨基、二 (Ci_₆烷基)氨基、包含 1至 3个选自氮、氧和硫的杂原子的 4 元至 8 元杂环基的基团取代；且该杂环基任选地被一个或多个选自 ΌΗ、 C_1-6 烷基、单 (Ci_₆烷基)氨基、二 (Ci_₆烷基)氨基、包含 1 至 3个选自氮、氧和硫的杂原子的 4 元至 8元杂环基、 d_₆烷基取代的包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基、轻基 -Ci— ₆院基、 Ci— ₆院氧基 -Ci— ₆院基、 C₃— ₈环院基 -Ci— ₆院基、 C ₆院氧基羰基、 (Ci_₆ 烷氧羰基) (d_₆烷基)氨基的基团取代。 Each of R Rb is independently an alkyl or alkyl-substituted heteroaryl group, preferably a d- ₆ alkyl group or a d- ₆ alkyl group substituted with 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur to 5 a 6-membered heteroaryl group, and each alkyl group is optionally selected from one or more selected from the group consisting of halogen, -OH, mono(d- ₆ alkyl)amino, di(Ci- ₆ alkyl)amino, and 1 to 3 selected from Substituted by a 4- to 8-membered heterocyclic group of a hetero atom of nitrogen, oxygen and sulfur; and the heterocyclic group is optionally selected from one or more selected from the group consisting of fluorene, C _1-6 alkyl, and mono (Ci_ ₆ Alkylamino, bis(Ci- ₆ alkyl)amino, 4 to 8 membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, and 1 to 3 substituted by d- ₆ alkyl heteroatom selected from nitrogen, oxygen and sulfur 4- to 8-membered heterocyclic group, hospital light -Ci- _6-yl group, Ci- ₆ alkoxy hospital hospital -Ci- _6-yl, C ₃ - ₈ cycloalkyl group homes - Ci- _{6 is} substituted with a group of a C _6- yard oxycarbonyl group or a (Ci- ₆ alkoxycarbonyl) (d- ₆ alkyl)amino group.

环 T选自以

Ring T is selected from

在另一个实施方式中，本发明还涉及通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体或前药，其中： In another embodiment, the present invention is also directed to a compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:

选自 H原子、烷基、环烷基和羟基烷基，优选为 H原子、 d_₆烷基、 ¾₈环烷基和基國。1— 6焼基； Is selected from H, alkyl, cycloalkyl and hydroxyalkyl, preferably H atom, d_ ₆ alkyl, ¾ ₈ cycloalkyl group and country. 1-6 焼 base;

优选地，选自 H原子或 ₆烷基； Preferably, it is selected from a H atom or a ₆ alkyl group;

更优选地，为11原子。 More preferably, it is 11 atoms.

在一个优选的实施方式中，本发明还涉及通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中所述化合物选自：

In a preferred embodiment, the invention also relates to compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers, solvates, polymorphs, tautomers, metabolites thereof or a drug, wherein the compound is selected from the group consisting of

CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV

CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV

20

本发明的另一方面涉及药物组合物，其包含本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药以及药学上可接受的载体。本发明的药物组合物可以被配制为固态、半固态、液态或气态制剂，如片剂、胶囊、粉剂、颗粒剂、膏剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶。 20

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate, a polymorph, a tautomer, a metabolite or a former A drug and a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and Aerosol.

本发明的药物组合物可以通过制药领域中公知的方法制备。例如，旨在注射给药的药物组合物可以通过将本发明的化合物或其药学上可接受的盐或前药与灭菌的蒸馏水组合来制备，从而形成溶液剂。可添加表面活性剂以促进形成均匀溶液或混悬液。制备药物组合物的实际方法为本领域技术人员所已知，例如可参见 The Science and Practice of Pharmacy (制药科学与实践）， 20^th Edition (Philadel hia Colle^ of Pharmacy and Science, 2000)。 The pharmaceutical compositions of the present invention can be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof with sterilized distilled water to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension. Actual methods of preparing pharmaceutical compositions are known to those skilled in the art, for example see The Science and Practice of Pharmacy (Pharmaceutical Science and ^{Practice), 20 th Edition (Philadel hia} Colle ^ of Pharmacy and Science, 2000).

本发明的药物组合物的给药途径包括但不限于口服、局部、经皮、肌肉、静脉、吸入、肠胃外、舌下、直肠、 ***及鼻内。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括但不限于水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。具体的给药方式和剂型取决于化合物本身的理化性质以及所应用疾病的严重程度等。本领域技术人员能够根据上述因素并结合其自身具有的知识来确定具体的给药途径。例如可参见：李俊，《临床药理学》，人民卫生出版社， 2008.06; 丁玉峰，论临床剂型因素与合理用药，医药导报, 26(5), 2007； Howard C. Ansel, Loyd V Allen, Jr., Nicholas G. Po ovich著，江志强主译，《药物剂型与给药体系》，中国医药科技出版社， 2003.05。 Routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, topical, transdermal, intramuscular, intravenous, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like. The compound of the present invention contained in these preparations may be a solid powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; a water-in-oil or oil-in-water emulsion or the like. The above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid formulations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compound can form a solution or suspension with the above carriers. The specific mode of administration and dosage form will depend on the physical and chemical properties of the compound itself, as well as the severity of the disease being applied. Those skilled in the art will be able to determine the specific route of administration based on the above factors in combination with their own knowledge. For example, see: Li Jun, Clinical Pharmacology, People's Medical Publishing House, 2008.06; Ding Yufeng, On Clinical Formulation Factors and Rational Use of Medicine, Medical Herald, 26(5), 2007; Howard C. Ansel, Loyd V Allen, Jr Nicholas G. Po ovich, Jiang Zhiqiang, “Pharmaceutical Formulation and Drug Delivery System”, China Medical Science and Technology Press, 2003.05.

本发明的另一方面涉及本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者本发明的药物组合物，其用于抑制蛋白激酶的活性。 Another aspect of the invention relates to a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or a medicament of the invention A composition for inhibiting the activity of a protein kinase.

本发明的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药可以有效抑制多种肿瘤细胞的生长，并对 Bcr-Abl、 c-KIT、 PDGFR、 c-Src、 KDR、 RET、 FYN、 FES、 AXL、 RSK、 FER、 SYK、 HER2、 LTK、 ZAP70、 ARG、 LYN、 LCK、 BRAF、 BRAFV600E、 AblT315I、 FGR、 HCK、 HER4、 p 38、 MINK、 MAPK、 EphB、 YES、 BRK、 TIE、 C SK、 MUSK、 FGFR、 JAK、 EphA、 KKB、 P70S6K、 FLT、 EGFR、 BTK、 ITK、 PDGFR等激酶产生抑制作用，特别是对突变体 AblT315I、 BRAFV600E 等有效，可用于制备抗肿瘤药物。 The compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a prodrug thereof can effectively inhibit the growth of various tumor cells, and Bcr-Abl, c-KIT, PDGFR, c-Src, KDR, RET, FYN, FES, AXL, RSK, FER, SYK, HER2, LTK, ZAP70, ARG, LYN, LCK, BRAF, BRAFV600E, AblT315I, FGR, Inhibition of kinases such as HCK, HER4, p38, MINK, MAPK, EphB, YES, BRK, TIE, C SK, MUSK, FGFR, JAK, EphA, KKB, P70S6K, FLT, EGFR, BTK, ITK, PDGFR, etc. It is effective against mutants AblT315I, BRAFV600E, etc., and can be used to prepare antitumor drugs.

在本申请中，术语"肿瘤"包括但不限于：白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、 ***癌、肝癌、皮肤癌、上皮细胞癌、 ***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。 In the present application, the term "tumor" includes but is not limited to: leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer , prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer and other diseases.

本发明的再一方面涉及一种调节蛋白激酶活性的方法，其中包括将所述蛋白激酶与本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂化物、前药或代谢产物或者本发明的药物组合物接触。所述调节蛋白激酶活性优选为抑制蛋白激酶活性。该方法可以用于体内，也可用于体外。 A further aspect of the invention relates to a method of modulating protein kinase activity, which comprises combining said protein kinase with a compound of the invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polycrystal thereof Shape, solvate, The prodrug or metabolite or the pharmaceutical composition of the invention is contacted. Preferably, the regulatory protein kinase activity is inhibition of protein kinase activity. This method can be used in vivo as well as in vitro.

通常，治疗有效的日剂量为约 0.001 mg/kg至约 lOO mg kg; 优选的治疗有效剂量为约 0.01 mg/kg至约 50 mg/kg; 更优选的治疗有效剂量为约 1 mg^kg至约 25 mg/kg。 Generally, a therapeutically effective daily dose is from about 0.001 mg/kg to about 100 mg kg; a preferred therapeutically effective dose is from about 0.01 mg/kg to about 50 mg/kg; a more preferred therapeutically effective dose is from about 1 mg^kg to About 25 mg/kg.

本文中所提供的有效剂量的范围并非意图限制本发明的范围，而是代表优选的剂量范围。但是，最优选的剂量可针对个别个体而进行调整，这是本领域技术人员所了解且可决定的（例如参阅 Berkow等人编著， Merck手册，第 16版， Merck公司， Rahway, N.J., 1992)。 The range of effective dosages provided herein is not intended to limit the scope of the invention, but rather to the preferred dosage range. However, the most preferred dosages can be adjusted for individual individuals, as will be appreciated and determined by those skilled in the art (see, for example, Berkow et al., Merck Handbook, 16th Edition, Merck, Rahway, NJ, 1992). .

本发明化合物可以与一种或多种其它的本发明化合物或者一种或多种其它抗癌药物联合或组合使用，以治疗和 /或预防肿瘤。可以与本发明化合物联用的药物包括但不限于多西他赛、吉西他滨、顺铂、卡铂、格列卫、替莫唑胺、阿霉素、达卡巴嗪、特罗凯、依托泊苷、柔红霉素以及阿糖胞苷等。本发明化合物的制备 The compounds of the invention may be used in combination or in combination with one or more other compounds of the invention or one or more other anti-cancer drugs to treat and/or prevent tumors. Drugs that can be used in combination with the compounds of the invention include, but are not limited to, docetaxel, gemcitabine, cisplatin, carboplatin, Gleevec, temozolomide, doxorubicin, dacarbazine, tro***e, etoposide, soft red And cytarabine and the like. Preparation of the compounds of the invention

以下反应方案示例性地说明本发明化合物的制备方法。 The following reaction scheme exemplifies the preparation method of the compound of the present invention.

本领域技术人员应当理解，在以下描述中，只有当取代基的组合可以得到稳定的化合物时，这类取代基的组合才是允许的。 Those skilled in the art will appreciate that in the following description, combinations of such substituents are permissible only if a combination of substituents results in a stable compound.

本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基（例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基）、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括 -C(0)-R" (其中 R"为烷基、芳基或芳烷基）、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。 It will also be understood by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by a suitable protecting group. Such functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include -C(0)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.

保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。 Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein.

保护基的使用详述于 Greene, T. W.与 P. G. M . Wuts, Protective Groins in Organi Synthesis, (1999), 4^th Ed., Wiley中。保护基还可为聚合物树脂。 Use of protecting groups are detailed in Greene, TW and PG M. Wuts, Protective Groins in Organi Synthesis, (1999), 4 th Ed., Wiley medium. The protecting group can also be a polymeric resin.

本发明通式 I所示化合物可通过方法 A-E来制备。 The compounds of the formula I according to the invention can be prepared by the method AE.

方法 A

Method A

方法 A包括以下步骤：（1 ) 使肼基化合物 A-1 (其是可商购的或通过本领域技术人员已知的方法制备的）在通常的缩合条件下（如缩合剂法、混合酸酐法、活化法等）与 A-2 缩合得到酰肼 A-3; (2)使酰肼 A-3缩合关环得到中间体 A-4,关环可以采用在适当溶剂（如水，甲醇，乙醇，异丙醇，甲苯，二甲苯，冰醋酸， DMF， THF等）中通过酸催化（如冰醋酸，盐酸，氯化亚砜，三氯氧磷，五氯化磷等）或者碱催化（如碳酸钾，氢氧化钾，氢氧化钠，碳酸钠等）反应；（3 ) 使中间体 A-4脱除保护基得到 A-5，脱保护可以采用稀盐酸，碳酸钾或者 TBAF等试剂；（4) 使中间体 A-5与 A-6在过渡金属催化下进行偶联反应得到通式 1(A)所示化合物，偶联反应采用钯催化剂（如 Pd(PPh₃)₄、 PdAc₂、 Pd₂(Dba)₃、 PdPPh₃Cl₂等）、铜盐（如氯化亚铜、溴化亚铜、碘化亚铜等），和各种有机碱或者无机碱（如三乙胺、 DIPEA、碳酸钾、碳酸钠、碳酸氢钠等）在适当溶剂（如 THF、甲苯、 DMF等）和温度（如 20-150度）下反应得到。在方法 A中， M l、 M2、 M3和 M4为 C原子或杂原子，当为 C Process A comprises the steps of: (1) subjecting mercapto compound A-1 (which is commercially available or prepared by methods known to those skilled in the art) under typical condensation conditions (e.g., condensing agent method, mixed anhydride) Method, activation method, etc.) is condensed with A-2 to give hydrazide A-3; (2) hydrazide hydrazide A-3 is condensed to give intermediate A-4, and the ring can be used in a suitable solvent (such as water, methanol, ethanol). , isopropanol, toluene, xylene, glacial acetic acid, DMF, THF, etc.) by acid catalysis (such as glacial acetic acid, hydrochloric acid, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc.) or base catalysis (such as Potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, etc.); (3) removing the protecting group from the intermediate A-4 to obtain A-5, and deprotecting using a reagent such as dilute hydrochloric acid, potassium carbonate or TBAF; 4) The intermediate A-5 and A-6 are subjected to a coupling reaction under transition metal catalysis to obtain a compound of the formula 1 (A), and the coupling reaction is carried out by using a palladium catalyst (such as Pd(PPh ₃ ) ₄ , PdAc ₂ , _{_{Pd 2 (Dba) 3, PdPPh}} 3 Cl 2 , etc.), copper salt (e.g. cuprous chloride, cuprous bromide, cuprous iodide, etc.) And various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees) get. In Method A, M l, M2, M3 and M4 are C atoms or heteroatoms, when C

方法 B Method B

方法 B包括以下步骤：（1 ) 使肼基化合物 B-1 (其是可商购的或通过本领域技术人员已知的方法制备的）与甲酸或甲酸酯或原甲酸酯等经过加热关环得到中间体 B-2; (2 ) 使中间体 B-2在各种卤代试剂（如 Cl₂、 Br₂、 I₂、 NIS、 NBS、 NCS、 IC1、 IBr等）作用下进行卤代反应得到中间体 B-3; (3 )使中间体 B-3与 TMS保护的乙块在过渡金属催化下进行偶联反应得到中间体 B-4，偶联反应采用钯催化剂（如 Pd(PPh₃)₄、 PdAc₂、 Pd₂(Dba)₃ Pd(PPh)₃Cl₂等）、铜盐（如氯化亚铜、溴化亚铜、碘化亚铜等）和各种有机碱或者无机碱（如三乙胺、 DIPEA、碳酸钾、碳酸钠、碳酸氢钠等）在适当溶剂（如 THF、甲苯、 DMF等）和温度（如 20-150度）下反应得到；（4 ) 使中间体 B-4脱除保护基得到 B-5，脱保护可以采用稀盐酸、碳酸钾或者 TBAF等试剂； ( 5 ) 使中间体 B-5与 B-6在过渡金属催化下进行偶联反应得到通式 1(B)所示化合物，偶联反应采用钯催化剂（如 Pd(PPh₃)₄、PdAc₂、Pd₂(Dba)₃、 PdPPh₃Cl₂等）、铜盐如（氯化亚铜、溴化亚铜、碘化亚铜等）和各种有机碱或者无机碱（如三乙胺、 DIPEA、碳酸钾、碳酸钠、碳酸氢钠等）在适当溶剂（如 THF、甲苯、 DMF等）和温度（如 20-150度）下反应得到。在方法 B中， M l、 M2、 M 3和 M4为 C原子或 N原子，当为 Process B comprises the steps of: (1) heating a mercapto compound B-1 (which is commercially available or prepared by methods known to those skilled in the art) with formic acid or formate or orthoformate Guanhuan gives intermediate B-2; (2) intermediate B-2 is halogenated under various halogenating reagents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) Substituting to give intermediate B-3; (3) coupling intermediate B-3 with TMS protected block B under transition metal catalysis to obtain intermediate B-4, the coupling reaction using palladium catalyst (such as Pd ( PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ Pd(PPh) ₃ Cl _{2 ,} etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic bases or Inorganic base (such as Triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) are obtained by reaction in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees); (4) intermediate B- 4 Removal of the protecting group to obtain B-5, deprotection can be carried out using reagents such as dilute hydrochloric acid, potassium carbonate or TBAF; (5) coupling intermediates B-5 and B-6 under transition metal catalysis to obtain formula 1 The compound shown in (B) is a palladium catalyst (such as Pd(PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ , PdPPh ₃ Cl _{2 ,} etc.), a copper salt such as (copper chloride, brominated). Cuprous, cuprous iodide, etc.) and various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in suitable solvents (such as THF, toluene, DMF, etc.) and temperature (eg 20-150 degrees) the reaction is obtained. In method B, M l, M 2 , M 3 and M 4 are C atoms or N atoms, when

方法 C Method C

方法 C包括以下步骤：（1 ) 使肼基化合物 C-1 (其是可商购的或通过本领域技术人员已知的方法制备的）与甲酸或甲酸酯或原甲酸酯等经过加热关环得到中间体 C-2; ( 2 ) 使中间体 C-2在各种卤代试剂（如 Cl₂、 Br₂、 I₂、 NIS、 NBS、 NCS、 IC1、 IBr等）作用下进行卤代反应得到中间体 C-3； ( 3 )使中间体 C-4与 TM S保护的乙块在过渡金属催化下进行偶联反应得到中间体 C-5，偶联反应采用钯催化剂（如 Pd(PPh₃)₄、 PdAc₂、 Pd₂(Dba)₃ Pd(PPh)₃Cl₂等）、铜盐（如氯化亚铜、溴化亚铜、碘化亚铜等）和各种有机碱或者无机碱（如三乙胺、 DIPEA、碳酸钾、碳酸钠、碳酸氢钠等）在适当溶剂（如 THF、甲苯、 DMF等）和温度（如 20-150度）下反应得到；（4 ) 使中间体 C-5脱除保护基得到 C-6，脱保护可以采用稀盐酸、碳酸钾或者 TBAF等试剂；（5 ) 使中间体 C-3与 C-6在过渡金属催化下进行偶联反应得到 1(C), 偶联反应采用钯催化剂（如 Pd(PPh₃)₄、 PdAc₂、 Pd₂(Dba)₃、 Pd(PPh)₃Cl₂ 等）、铜盐（如氯化亚铜、溴化亚铜、碘化亚铜等）和各种有机碱或者无机碱（如三乙胺、 DIPEA、碳酸钾、碳酸钠、碳酸氢钠等）在适当溶剂（如 THF、甲苯、 DMF等）和温度（如 20-150度）下反应得到。在方法 C中， M l、 M2、 M 3和 M4为 C原子或 N原子，当为 C 原子时 Process C comprises the steps of: (1) heating a mercapto compound C-1 (which is commercially available or prepared by methods known to those skilled in the art) with formic acid or formate or orthoformate Guanhuan gives intermediate C-2; (2) intermediate C-2 is halogenated under various halogenating reagents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) Substituting to obtain intermediate C-3; (3) coupling intermediate C-4 with TM S protected block B under transition metal catalysis to obtain intermediate C-5, coupling reaction using palladium catalyst (such as Pd) (PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ Pd(PPh) ₃ Cl _{2 ,} etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic bases Or an inorganic base (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) is obtained by reacting in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (such as 20-150 degrees); (4) The intermediate C-5 is deprotected to obtain a C-6, and the deprotection may be carried out using a reagent such as dilute hydrochloric acid, potassium carbonate or TBAF; (5) intermediates C-3 and C-6 in a transition metal The coupling reaction of the resulting 1 (C), the coupling reaction using a palladium catalyst (e.g. _{_{Pd (PPh 3) 4, PdAc}} 2, Pd 2 (Dba) 3, Pd (PPh) 3 Cl 2 , etc.), copper ( Such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic or inorganic bases (such as triethylamine, DIPEA, potassium carbonate, sodium carbonate, sodium bicarbonate, etc.) in a suitable solvent (such as THF) , toluene, DMF, etc.) and temperature (such as 20-150 degrees) reaction. In Method C, M l, M2, M 3 and M4 are C atoms or N atoms, when C atoms

方法 D Method D

方法 D包括以下步骤：（1 ) 使芳香基胺 D-1 (其是可商购的或通过本领域技术人员已知的方法制备的）与各种卤代的醛、酮或者相应的缩醛、缩酮（如 2-氯乙醛、 2-溴乙醛、 2-氯乙醛缩醛、 2-溴丙酮、 1 -溴 -2-丁酮、 2-溴 -1 -环丙基乙酮、 3-溴 -1 -三氟甲基 -2-丙酮或溴代丙酮酸甲酯等）在酸（浓盐酸、氢溴酸等）或者碱（TEA、碳酸钠等）催化下环合得到中间体 D-2; (2)使中间体 D-2在各种卤代试剂（如 Cl₂、 Br₂、 I₂、 NIS、 NBS、 NCS、 IC1、 IBr等）作用下进行卤代反应得到中间体 D-3; (3 ) 使中间体 D-3与 D-4在过渡金属催化下进行偶联反应得到 1(D) , 偶联反应采用钯催化剂（如 Pd(PPh₃)₄、 PdAc₂、 Pd₂(Dba)₃ Pd(PPh)₃Cl₂等）、铜盐（如氯化亚铜、溴化亚铜、碘化亚铜等）和各种有机碱或者无机碱（如三乙胺、 DIPEA、碳酸钾、碳酸钠、碳酸氢钠等）在适当溶剂（如 THF、甲苯、 DMF等）和温度（如 20-150度）下反应得到。在方法 D中， M l、 M2、 M3和 M4为 C原子或 N原子，当为 C原； X为卤素 Process D comprises the steps of: (1) rendering an aromatic amine D-1 (which is commercially available or prepared by methods known to those skilled in the art) with various halogenated aldehydes, ketones or corresponding acetals , ketal (such as 2-chloroacetaldehyde, 2-bromoacetaldehyde, 2-chloroacetaldehyde acetal, 2-bromoacetone, 1-bromo-2-butanone, 2-bromo-1 -cyclopropylethanone , 3-bromo-1-trifluoromethyl-2-propanone or methyl bromopyruvate, etc.) cyclized under the catalysis of acid (concentrated hydrochloric acid, hydrobromic acid, etc.) or alkali (TEA, sodium carbonate, etc.) Intermediate D-2; (2) Intermediate D-2 is subjected to halogenation reaction under various halogen reagents (such as Cl ₂ , Br ₂ , I ₂ , NIS, NBS, NCS, IC1, IBr, etc.) Intermediate D-3; (3) coupling intermediate D-3 with D-4 under transition metal catalysis to obtain 1(D), the coupling reaction using palladium catalyst (such as Pd(PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (Dba) ₃ Pd (PPh) ₃ Cl _2, etc.), copper salts (such as cuprous chloride, cuprous bromide, cuprous iodide, etc.) and various organic or inorganic bases (such as three B Amine, DIPEA, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.) are obtained by reaction in a suitable solvent (such as THF, toluene, DMF, etc.) and temperature (e.g., 20-150 degrees). In Method D, M l, M2, M3 and M4 are C atoms or N atoms, as C original; X is halogen

方法 E Method E

方法 E包括以下步骤：（1 )采用方法 A-D的合成方法或者其它文献方法得到芳基乙块中间体 E-1和中间体 E-2，其中 La和 Lb分别为酰基和氨基或者氨基和酰基；（2) 采用传统的酰胺键缩合方法，合成得到目标化合物 1(E)。 The method E comprises the following steps: (1) obtaining an aryl b-block intermediate E-1 and an intermediate E-2 by a method of the method AD or other literature methods, wherein La and Lb are an acyl group and an amino group or an amino group and an acyl group, respectively; (2) The target compound 1 (E) is synthesized by a conventional amide bond condensation method.

中间体制备 Intermediate preparation

中间体 1 : 3-乙块基 - 1，2，4]*** [4，3-a]吡啶

Intermediate 1: 3-Ethyl- 1,2,4]triazole [4,3-a]pyridine

第一步：三甲基硅基 -丙酸 -Ν'-吡啶 -2-基 -酰肼 First step: Trimethylsilyl-propionic acid -Ν'-pyridine-2-yl-hydrazide

将 Ν-甲基吗啉 (0.27 mL, 2.5 mmol)缓慢加入至三甲基硅基丙块酸 (0.39 g, 2.75 mmol)的乙酸乙酯 (20 mL)溶液，冰浴冷却，再向上述溶液中缓慢滴加氯甲酸异丙酯 (2.0 M甲苯溶液， 1.25 mL, 2.5 mmol), 滴加完毕后继续搅拌 2小时。反应完毕，向反应液中加入冰水 (20 mL) 淬灭反应，分出有机相。有机相分别用饱和碳酸氢钠溶液、水和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩得到黄色油状物 (混酐)。将此油状物溶于无水四氢呋喃 (30 mL) 中，搅拌下加入 2-肼基吡啶 (0.24 _& 2.25 mmol), 继续搅拌 1小时。减压浓缩除去溶剂，剩余物直接用硅胶柱层析分离纯化得到三甲基硅基丙块酰基 -Ν'-吡啶基 -2-酰肼 (黄色固体， 0.5 g)，收率 88%。 1H-NMR (300MHz, CDC1₃): δ 8.15(s, 1H), 7.53-7.57(m, 1H), 6.80-6.83(m, 1H)， 6.74(s, lH), 0.21(s, 9H)。 MSm/z (ESI): 234.1[M+H]。 Ν-Methylmorpholine (0.27 mL, 2.5 mmol) was slowly added to a solution of trimethylsilylpropanoic acid (0.39 g, 2.75 mmol) in ethyl acetate (20 mL). Isopropyl chloroformate (2.0 M toluene solution, 1.25 mL, 2.5 mmol) was slowly added dropwise, and stirring was continued for 2 hours after the completion of the dropwise addition. After completion of the reaction, ice water (20 mL) was added to the reaction mixture to quench the reaction, and the organic phase was separated. The organic layer was washed with aq. EtOAc (EtOAc m. This oil was dissolved in anhydrous tetrahydrofuran (30 mL). <EMI ID=9.1 > The solvent was concentrated under reduced pressure and the residue was crystallijjjjjlililililililililililili 1H-NMR (300MHz, CDC1 ₃ ): δ 8.15 (s, 1H), 7.53-7.57 (m, 1H), 6.80-6.83 (m, 1H), 6.74 (s, lH), 0.21 (s, 9H). MS m / z (ESI): 234.1 [M+H].

第二步： 3-三甲基硅基乙块基 -[1，2，4]三氮唑 [4，3-a]吡啶 Step 2: 3-Trimethylsilylethane-yl-[1,2,4]triazole [4,3-a]pyridine

将三甲基硅基 -丙酸 -Ν'-吡啶 -2-基 -酰肼 (0.5 _& 2.1 mmol)溶于三氯氧磷 (5 mL)中。将混合物在 60°C下加热搅拌 18小时。反应完毕，将反应液冷却至室温，减压浓缩除去过量三氯氧磷，剩余物用二氯甲烷 (50 mL)溶解，用饱和碳酸氢钠溶液中和至碱性，分出有机相。有机相分别用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩物直接用于下一步反应。 Trimethylsilyl-propionic acid-Ν'-pyridin-2-yl-hydrazide (0.5 _& 2.1 mmol) was dissolved in phosphorus oxychloride (5 mL). The mixture was stirred with heating at 60 ° C for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure to remove excess phosphorus oxychloride. The residue was dissolved in dichloromethane (50 mL) and neutralized with saturated sodium hydrogen carbonate solution to give an organic phase. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated.

第三步： 3-乙块基 -[1，2，4]三氮唑 [4，3-a]吡啶 Step 3: 3-Ethyl-[1,2,4]triazole [4,3-a]pyridine

将上述浓缩物溶解于四氢呋喃 (8 mL)中，然后滴加四丁基氟化铵水溶液 (809 mg四丁基氟化铵溶于 0.5 mL水配成的溶液)，室温搅拌 2小时。反应液减压浓缩，加入水 (2 mL)和二氯甲烷 (15 mL)萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，浓缩物用硅胶柱层析分离纯化得到中间体 3-乙块基 -[1，2，4]*** [4，3-a]吡啶 (黄色固体， 242 mg)，收率 85%。 1H-NMR (300MHz, DMSO-d6): δ 8.48 (d， J=6.6Hz, IH), 7.91(d, J=9.3Hz, IH) 7.51(t,J=8.1Hz, 1H)， 7.15(t,J=6.6Hz, 1H)， 5.34(s, 1H)。 MSm/z (ESI): 144.1[M+H]。 The concentrate was dissolved in tetrahydrofuran (8 mL), and then a tetrabutylammonium fluoride aqueous solution (809 mg of tetrabutylammonium fluoride dissolved in 0.5 mL of water) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Purification of the intermediate 3-ethylidene-[1,2,4]triazolo[4,3-a]pyridine (yellow solid, 242 Mg), yield 85%. 1H-NMR (300MHz, DMSO-d6): δ 8.48 (d, J = 6.6 Hz, IH), 7.91 (d, J = 9.3 Hz, IH) 7.51 (t, J = 8.1 Hz, 1H), 7.15 (t , J = 6.6 Hz, 1H), 5.34 (s, 1H). MS m / z (ESI): 144.1 [M+H].

以不同的肼基吡啶、肼基嘧啶和肼基吡嗪等为原料，采用与中间体 1 类似的合成方法 Using different pyridyl pyridine, mercaptopyrimidine and decylpyrazine as raw materials, a synthesis method similar to that of intermediate 1 is employed.

中间 11 : 3-乙块基 -6-***啉 -4-基 -[1，2，4]三氮唑 [4，3-a]嘧啶

Intermediate 11: 3-Ethyl-6-morpholine-4-yl-[1,2,4]triazole [4,3-a]pyrimidine

第一步： 2-苄氧基 -5-溴代 -嘧啶 First step: 2-benzyloxy-5-bromo-pyrimidine

将 5-溴 -2-氯 -嘧啶 ( 10 g， 51.7 mmol)及苄醇 (6.4 ml, 62 mmol)溶于 N，N-二甲基甲酰胺（140 mL) 中，向其中加入叔丁醇钾（6.96 g， 62 mmol) ，室温反应 2 h。反应结束后，向反应液中加入水，析出固体。减压过滤收集固体，滤饼用少量甲醇洗涤，干燥，得到 2- 苄氧基 -5-溴代 -嘧啶（白色固体， 10.2 g -NMR (400MHz, CD₃OD): 8.65(2Η, d, J=0.8Hz) 7.44-7.47(2Η, m)， 7.31-7.44(3Η, m)， 5.42(2Η, s)。 MSm/z (ESI): 265.80[M+H]。 5-Bromo-2-chloro-pyrimidine (10 g, 51.7 mmol) and benzyl alcohol (6.4 ml, 62 mmol) were dissolved in N,N-dimethylformamide (140 mL), and t-butanol was added thereto. Potassium (6.96 g, 62 mmol) was reacted at room temperature for 2 h. After the reaction, Water was added to the reaction liquid to precipitate a solid. The solid was collected by filtration under reduced pressure, the filter cake was washed with small amount of methanol, and dried to give 2-benzyloxy-5-bromo - pyrimidine (white solid, 10.2 g -NMR (400MHz, CD 3 OD): 8.65 (2Η, d, J=0.8 Hz) 7.44-7.47 (2Η, m), 7.31-7.44 (3Η, m), 5.42 (2Η, s) MSm/z (ESI): 265.80 [M+H].

第二步： 4-(2-苄氧基 -嘧啶 -5-基) -***啉 Step 2: 4-(2-Benzyloxy-pyrimidin-5-yl)-morpholine

将 2-苄氧基 -5-溴 -嘧啶（5.3 g， 20 mmol) 及吗啉（2.1 mL， 24 mmol) 溶于 1,4-二氧六环（60 mL) 中，氩气保护下向其中加入 Pd₂ dba)₃ (920 mg， 1 mmol) 、 2- (；二叔丁基膦基) - 联苯（1.2 g， 4 mmol)及叔丁醇钠（2.3 g， 24 mmol) ，混合物加热至 50^QC反应 2h。反应结束后，冷却至室温，向反应液中加入水，用乙酸乙酯萃取，无水硫酸钠干燥有机相，过滤，蒸干溶剂，硅胶柱层析纯化得到 4-(2-苄氧基 -嘧啶 -5-基) -***啉（黄色固体， 4.75 g)。 1H-NMR (400MHz, CD₃OD): 8.29(2H, s), 7.43-7.45(2Η, m)， 7.27-7.37(3Η, m)， 5.38(2Η, s), 3.83(4H, t, J=4.8Hz), 3.11(4H, t,J=4.8Hz MSm/z (ESI): 271.90[M+H]。 2-Benzyloxy-5-bromo-pyrimidine (5.3 g, 20 mmol) and morpholine (2.1 mL, 24 mmol) were dissolved in 1,4-dioxane (60 mL) under argon Pd ₂ dba) ₃ (920 mg, 1 mmol), 2- (; di-tert-butylphosphino)-biphenyl (1.2 g, 4 mmol) and sodium tert-butoxide (2.3 g, 24 mmol), mixture Heat to 50 ^Q C for 2 h. After the completion of the reaction, the mixture was cooled to room temperature, and water was added to the mixture, and the mixture was evaporated. Pyrimidin-5-yl)-morpholine (yellow solid, 4.75 g). 1H-NMR (400MHz, CD ₃ OD): 8.29(2H, s), 7.43-7.45(2Η, m), 7.27-7.37(3Η, m), 5.38(2Η, s), 3.83(4H, t, J = 4.8 Hz), 3.11 (4H, t, J = 4.8 Hz MS m/z (ESI): 271.90 [M+H].

第三步： 5-***啉 -4-基 -嘧啶 -2-醇 Step 3: 5-morpholine-4-yl-pyrimidine-2-ol

将 4-0 (；苄氧基)嘧啶 -5-基)吗啉（4.75 g， 17.489 mmol) 溶于 4N 氯化氢的二氧六环溶液（57 mL) 中，加热至 50^QC反应 lh。反应结束后，反应液冷却至室温，析出的固体过滤收集，用石油醚洗涤，干燥，得到 5-***啉 -4-基 -嘧啶 -2-醇（黄色固体， 3.81 g)。 1H-NMR (400MHz DMSO-d6): 8.56(2Η, s), 3.71(4H, t,J=4.8Hz), 3.02(4Η, t，J=2.0Hz)。 MSm/z (ESI): 4-0 (; Benzyloxy)pyrimidin-5-yl)morpholine (4.75 g, 17.489 mmol) was dissolved in 4N hydrogen chloride in dioxane (57 mL) and heated to 50 ^Q C for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration, washed with petroleum ether and dried to give 5- morpholine-4-yl-pyrimidine-2-ol (yellow solid, 3.81 g). 1H-NMR (400 MHz DMSO-d6): 8.56 (2 s, s), 3.71 (4H, t, J = 4.8 Hz), 3.02 (4 Η, t, J = 2.0 Hz). MSm/z (ESI):

181.95[M+H 181.95[M+H

第四步： 4-(2-氯 -嘧啶 -5-基) -***啉 Step 4: 4-(2-Chloro-pyrimidin-5-yl)-morpholine

5-吗啉 -2-羟基嘧啶盐酸盐（3.76 _& 17.3 mmol) 及二乙基苯胺（5.54 ml, 34.64 mmol) 溶于乙腈（75 ml) ，向其中加入三氯氧磷（8 mL，86.6 mmol) ，然后加热回流 3.5 h。反应结束后，冷却至室温，向反应液中加入饱和碳酸氢钠溶液中和，二氯甲烷萃取，无水硫酸钠干燥有机相，过滤，蒸干溶剂，硅胶柱层析纯化得到 4-(2-氯 -嘧啶 -5-基) -***啉（黄色固体， 2.26 g) ^-NMRi^OMMz^DCls): 8.22(2H, s), 3.87(4Η, t,J=4.8Hz), 3.20(4Η, t, J=4.8Hz)。 MSm/z (ESI): 199.90[M+H]。 5-morpholine-2-hydroxypyrimidine hydrochloride (3.76 _& 17.3 mmol) and diethyl aniline (5.54 ml, 34.64 mmol) dissolved in acetonitrile (75 ml), and phosphorus oxychloride (8 mL, 86.6) Methyl), then heated to reflux for 3.5 h. After the reaction is completed, it is cooled to room temperature, and the mixture is neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to dryness. -Chloro-pyrimidin-5-yl)-morpholine (yellow solid, 2.26 g) ^-NMRi^OMMz^DCls): 8.22 (2H, s), 3.87 (4 Η, t, J = 4.8 Hz), 3.20 (4 Η , t, J = 4.8 Hz). MS m/z (ESI): 195.90 [M+H].

第五步：（5-***啉 -4-基 -嘧啶 -2-基) -肼 Step 5: (5-morpholine-4-yl-pyrimidin-2-yl)-oxime

将 4-(2-氯嘧啶 -5-基)吗啉（2.06 g， 10.34 mmol) 溶于乙醇（6 mL) ，向其中加入 64% 水合肼（4.05 g， 51.71 mmol) ，反应液加热回流 3h。 TLC检测反应结束后，冷却至室温，析出固体，减压过滤，滤饼用冷水洗涤，干燥得到 (5-***啉 -4-基 -嘧啶 -2-基) -肼（黄色固体， 1.57 g) 。 1H-NMR (400MHz, CD₃OD): 8.18(2Η, s), 3.83(4Η, t,J=4.8Hz), 3.04(4Η, t, J=4.8Hz)。 MSm/z (ESI): 196.00[M+H]。 4-(2-Chloropyrimidin-5-yl)morpholine (2.06 g, 10.34 mmol) was dissolved in ethanol (6 mL), then EtOAc (EtOAc, EtOAc (EtOAc) . After the completion of the TLC reaction, the mixture was cooled to room temperature, and a solid was precipitated, which was filtered under reduced pressure. The filter cake was washed with cold water and dried to give (5-morpholine-4-yl-pyrimidin-2-yl)-indole (yellow solid, 1.57 g) . 1H-NMR (400 MHz, CD ₃ OD): 8.18 (2 Η, s), 3.83 (4 Η, t, J = 4.8 Hz), 3.04 (4 Η, t, J = 4.8 Hz). MS m/z (ESI): 196.00 [M+H].

第六步：三甲基硅基 -丙酸 N'-(5-***啉 -4-基 -嘧啶 -2-基) -酰肼 Step 6: Trimethylsilyl-propionic acid N'-(5-morpholine-4-yl-pyrimidin-2-yl)-hydrazide

将 3-甲基硅基丙块酸 (1.49 g， 14.478 mmol)和 4-甲基吗啉 (0.97 mL， 8.86 mmol)溶于无水乙酸乙酯（30 mL) ，向其中加入氯甲酸异丙酯（2M溶液， 4.43 mL， 8.86 mmol) ，室温搅拌 3h后，有机相分别用水，饱和 NaHC0₃溶液及饱和 NaCl溶液洗涤，蒸干有机相，残余物溶于无水四氢呋喃（20 mL) ，向其中缓慢加入 (5-吗啉嘧啶 -2-基)肼（1.57 g， 8.06 mmol)，室温搅拌 0.5h， TLC检测反应结束后，向其中加入水，用二氯甲烷萃取，无水硫酸钠干燥有机相，过滤，蒸干溶剂，硅胶柱层析纯化得到三甲基硅基 -丙酸 N'-(5-***啉 -4-基 -嘧啶 -2- 基) -酰肼（黄色固体， 1.98 g 1H-NMR (400MHz, CDC1₃): δ 8.15(2H, s), 3.84(4H, t, J=4.8Hz), 3.05(4H，t，J=4.8Hz)，0.18(9H， s)。 MSm/z (ESI): 319.90[M+H]。 3-Methylsilylpropanoic acid (1.49 g, 14.478 mmol) and 4-methylmorpholine (0.97 mL, 8.86 mmol) were dissolved in anhydrous ethyl acetate (30 mL), and isopropyl chloroformate was added thereto. ester (2M solution, 4.43 mL, 8.86 mmol), stirred at room temperature after 3h, the organic phase washed with water, saturated NaHC0 ₃ solution and saturated NaCl solution, the organic phase was evaporated to dryness, the residue was dissolved in anhydrous tetrahydrofuran (20 mL), the (5-Morpholin-2-yl)indole (1.57 g, 8.06 mmol) was added slowly, and stirred at room temperature for 0.5 h. After the TLC reaction was completed, water was added thereto, extracted with dichloromethane, dried over anhydrous sodium sulfate. The organic phase was filtered, evaporated to dryness eluting with silicagel g 1H-NMR (400MHz, CDC1 ₃ ): δ 8.15 (2H, s), 3.84 (4H, t, J = 4.8 Hz), 3.05 (4H, t, J = 4.8 Hz), 0.18 (9H, s). MS m / z (ESI): 319.90 [M+H].

第七步： 6-***啉 -4-基 -3-三甲基硅基乙块基 -[1，2，4]三氮唑 [4，3-a]嘧啶 Step 7: 6-morpholine-4-yl-3-trimethylsilylethidyl-[1,2,4]triazole [4,3-a]pyrimidine

将三甲基硅基 -丙酸 N'-(5-***啉 -4-基 -嘧啶 -2-基) -酰肼（1.98 g， 6.23 mmol)溶于四氢呋喃（40 mL) ，氮气保护下向其中加入三苯基膦（1.96 g， 7.47 mmol) 、叠氮三甲基硅烷 ( 1.07mL, 8.10 mmol) 及二异丙基偶氮二羧酸酯（1.35 mL， 6.85 mmol) 。此混合物在室温搅拌 3h。 TLC检测反应结束后，向其中加入水，二氯甲烷萃取，无水硫酸钠干燥有机相，过滤，蒸干溶剂，硅胶柱层析纯化得到 6-***啉 -4-基 -3-三甲基硅基乙块基 -[1，2，4]三氮唑 [4，3-a]嘧啶（987 mg，黄色固体）。 1H-NMR (400MHz， CDC1₃): δ 8.63(1H, d, J=2.8Hz), 7.56(1H， d, J=2.8Hz), 3.92(4H, t,J=4.8Hz), 3.18(4H, t,J=4.8Hz), 0.32(9H, s)。 MSm/z (ESI): N-methylsilyl-propionic acid N'-(5-morpholine-4-yl-pyrimidin-2-yl)-hydrazide (1.98 g, 6.23 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen Triphenylphosphine (1.96 g, 7.47 mmol), azide trimethylsilane (1.07 mL, 8.10 mmol) and diisopropylazodicarboxylate (1.35 mL, 6.85 mmol) were added. This mixture was stirred at room temperature for 3 h. After the TLC reaction was completed, water was added thereto, and dichloromethane was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, and evaporated to silica gel column chromatography to afford 6-morpholine-4-yl-3-trimethyl Silyl-branched-[1,2,4]triazole [4,3-a]pyrimidine (987 mg, yellow solid). 1H-NMR (400MHz, CDC1 ₃ ): δ 8.63 (1H, d, J = 2.8 Hz), 7.56 (1H, d, J = 2.8 Hz), 3.92 (4H, t, J = 4.8 Hz), 3.18 (4H , t, J = 4.8 Hz), 0.32 (9H, s). MSm/z (ESI):

301.90[M+H] o 301.90[M+H] o

第八步： 3-乙块基 -6-***啉 -4-基 -[1，2，4]三氮唑 [4，3-a]嘧啶 Step 8: 3-Ethyl -6-morpholine-4-yl-[1,2,4]triazole [4,3-a]pyrimidine

采用中间体 1第三步相同的方法合成得到中间体 3-乙块基 -6-***啉 -4-基 -[1，2，4]三氮唑 [4，3-a]嘧啶（黄色固体， 228mg) o 1H-NMR (400MHz, CDC1₃): δ 8.68(1H， d, J=2.8Hz), 7.64(1H, d， J=2.8Hz), 3.93(4H, t， J=4.8Hz), 3.83(1H, s)， 3.20(4H, t， J=4.8Hz)。 MS m/z (ESI): 229.95[M+H] oThe intermediate 3-ethylidene-6-morphinolin-4-yl-[1,2,4]triazole [4,3-a]pyrimidine (yellow solid) was synthesized in the same manner as in the third step of Intermediate 1. , 228mg) o 1H-NMR (400MHz, CDC1 ₃ ): δ 8.68(1H, d, J=2.8Hz), 7.64(1H, d, J=2.8Hz), 3.93(4H, t, J=4.8Hz) , 3.83 (1H, s), 3.20 (4H, t, J = 4.8 Hz). MS m/z (ESI): 229.95 [M+H] o

第一步： 5-环丙基 -2-氟 -吡啶 First step: 5-cyclopropyl -2-fluoro-pyridine

将 5-溴 -2-氟 -吡啶（1.41 g， 8 mmol )及环丙基硼酸（1.37 g， 16 mmol)混于甲苯 /水 (26 mL/1.3 mL) 中，向其中加入磷酸钾（7.46 g， 28 mmol) ，氩气保护下向其中加入 Pd(OAc)₂ (90 mg, 0.4 mmol) 及三环己基膦（224 mg， 0.8 mmol) ，混合物加热至 80^QC反应 16 h。 TLC检测反应结束后，冷却至室温，向其中加入水，乙酸乙酯萃取，无水硫酸钠干燥有机相，过滤，蒸干溶剂，硅胶柱层析纯化得到 5-环丙基 -2-氟 -吡啶（黄色油状物， 647 mg) 。 1H-NMR (400MHz, CD₃OD): δ 7.99(1H, s)， 7.59(1Η, td， J=10.0, 2.0Hz), 6.95(1H， d，J=8.4Hz)， 1.95-1.99(lH, m), 1.01-1.05(2H， m)， 0.69-0.73(2H， m)。 MS m/z (ESI): 138.00[M+H]。 5-Bromo-2-fluoro-pyridine (1.41 g, 8 mmol) and cyclopropylboronic acid (1.37 g, 16 mmol) were mixed in toluene/water (26 mL / 1.3 mL), and potassium phosphate (7.46) was added thereto. g, 28 mmol), Pd(OAc) ₂ (90 mg, 0.4 mmol) and tricyclohexylphosphine (224 mg, 0.8 mmol) were added thereto under argon atmosphere, and the mixture was heated to 80 ^Q C for 16 h. After the completion of the TLC reaction, the mixture was cooled to room temperature, water was added thereto, ethyl acetate was evaporated, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Pyridine (yellow oil, 647 mg). 1H-NMR (400MHz, CD ₃ OD): δ 7.99(1H, s), 7.59 (1Η, td, J=10.0, 2.0Hz), 6.95(1H, d, J=8.4Hz), 1.95-1.99 (lH , m), 1.01-1.05 (2H, m), 0.69-0.73 (2H, m). MS m/z (ESI): 138.00 [M+H].

第二步：（5-环丙基 -吡啶 -2-基) -肼 Second step: (5-cyclopropyl-pyridin-2-yl)-oxime

将 5-环丙基 -2-氟 -吡啶（0.32 g， 2.34 mmol)溶于乙醇（2 mL) ，向其中加入 64% 水合肼（2.27 mL， 46.7mmol) ，反应液加热回流过夜。 TLC检测反应结束后，冷却至室温，蒸干溶剂，残余物溶于二氯甲烷，用水洗涤，无水硫酸钠干燥有机相，过滤，蒸干溶剂，得到褐色油状液体（0.35 g) ，未经纯化，直接投入下一反应。 MS m/z (ESI) : 150.00[M+H]。第三步：三甲基硅基 -丙酸 N'-(5-环丙基 -吡啶 -2-基) -酰肼 5-Cyclopropyl-2-fluoro-pyridine (0.32 g, 2.34 mmol) was dissolved in ethanol (2 mL). EtOAc (EtOAc:EtOAc: After the completion of the TLC reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification, direct injection into the next reaction. MS m/z (ESI): 150.00 [M+H]. The third step: trimethylsilyl-propionic acid N'-(5-cyclopropyl-pyridin-2-yl)-hydrazide

将 3-甲基硅基丙块酸 (0.41 g， 2.86 mmol), 4-甲基吗啉 (0.29 mL， 2.6 mmol)溶于乙酸乙酯 ( lO mL) ，向其中加入氯甲酸异丙酯（2M， 1.3 mL, 2.6 mmol) ，室温搅拌 3h后，反应液分别用水，饱和 NaHC0₃溶液及饱和 NaCl溶液洗涤，蒸干有机相，残余物溶于四氢呋喃 ( lO mL) ，后向其中缓慢加入 (5-环丙基 -2-基)肼（0.35 g， 2.34 mmol) ，室温搅拌 0.5h， TLC检测反应结束后，向其中加入水，二氯甲烷萃取，无水硫酸钠干燥有机相，过滤，蒸干溶剂，硅胶柱层析纯化得到三甲基硅基 -丙酸 N'-(5-环丙基 -吡啶 -2-基) -酰肼（黄色固体， 0.11 g)。 1H-NMR (400MHz, CDC1₃): δ 7.90(1H, d, J=1.6Hz), 7.26-7.29(lH,m), 6.69(lH，d， J=8.4Hz)， 1.77-1.83(1H, m)， 0.90-0.95(2H, m)， 0.58-0.62(2H, m)， 0.22(9H, s)。 MSm/z (ESI): 273.95 [M+H]。 3-Methylsilylpropanoic acid (0.41 g, 2.86 mmol), 4-methylmorpholine (0.29 mL, 2.6 mmol) was dissolved in ethyl acetate (10 mL), and isopropyl chloroformate was added thereto. 2M, 1.3 mL, 2.6 mmol), after stirring at room temperature for 3 h, the reaction solution was washed with water, saturated NaHC0 ₃ solution and saturated NaCl solution, evaporated to dryness, and the residue was dissolved in tetrahydrofuran (10 mL) and then slowly added thereto ( 5-cyclopropyl-2-yl)indole (0.35 g, 2.34 mmol), stirred at room temperature for 0.5 h. After TLC was applied, water was added and dichloromethane was evaporated. The solvent was evaporated to dryness crystalljjjjlilililililililililililili 1H-NMR (400MHz, CDC1 ₃ ): δ 7.90 (1H, d, J = 1.6 Hz), 7.26-7.29 (lH, m), 6.69 (lH, d, J = 8.4 Hz), 1.77-1.83 (1H, m), 0.90-0.95 (2H, m), 0.58-0.62 (2H, m), 0.22 (9H, s). MS m/z (ESI): 273.95 [M+H].

第四步： 6-环丙基 -3-三甲基硅基乙块基 -[1，2，4]三氮唑 [4，3-a]吡啶 Fourth step: 6-cyclopropyl-3-trimethylsilylethyl bromide-[1,2,4]triazole [4,3-a]pyridine

将三甲基硅基 -丙酸 N'-(5-环丙基 -吡啶 -2-基) -酰肼（0.1 g， 0.366 mmol) 溶于四氢呋喃 (2 mL)， N₂保护下向其中加入三苯基膦（0.115 g， 0.439 mmol)、叠氮三甲基硅烷（0.063 ml, 0.476 mmol)及二异丙基偶氮二羧酸酯（0.079 mL， 0.403 mmol) 。此混合物于室温搅拌 2h， TLC检测反应结束后，向其中加入水，二氯甲烷萃取，无水硫酸钠干燥有机相，过滤，蒸干溶剂，硅胶柱层析纯化得到 6-环丙基 -3-三甲基硅基乙块基 -[1，2，4]三氮唑 [4，3-a]吡啶 (黄色油状物， 44 mg) 1H-NMR(400MHz, CDCl₃): δ 7.91(1H, s), 7.73(1Η, d, J=9.2Hz), 7.07(1H, dd， J=9.2, 1.2Hz), 1.95-1.99(1H, m)， 1.03-1.08(2H, m)， 0.74-0.78(2H, m)， 0.34(9H, s)。 OP N-methylsilyl-propionic acid N'-(5-cyclopropyl-pyridin-2-yl)-hydrazide (0.1 g, 0.366 mmol) was dissolved in tetrahydrofuran (2 mL) and added under N ₂ Triphenylphosphine (0.115 g, 0.439 mmol), azide trimethylsilane (0.063 ml, 0.476 mmol) and diisopropylazodicarboxylate (0.079 mL, 0.403 mmol). The mixture was stirred at room temperature for 2 h. After TLC was applied, water was added, dichloromethane was evaporated, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. -trimethylsilylethylidene-[1,2,4]triazole [4,3-a]pyridine (yellow oil, 44 mg) 1H-NMR (400 MHz, CDCl ₃ ): δ 7.91 (1H , s), 7.73 (1Η, d, J=9.2Hz), 7.07(1H, dd, J=9.2, 1.2Hz), 1.95-1.99(1H, m), 1.03-1.08(2H, m), 0.74- 0.78 (2H, m), 0.34 (9H, s). OP

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第一步： 3-碘 -咪唑 [l，2-a]吡啶 First step: 3-iodo-imidazole [l,2-a]pyridine

将咪唑 [l，2-a]吡啶 (1.18 g, 0.1 mol)溶于 N，N-二甲基甲酰胺（10 mL)中，冰浴冷却下分批加入N-碘代丁二酰亚胺(2.7 _& 0.12 m_Ol)，加完继续在室温搅拌过夜。反应完毕，向反应液中加入饱和碳酸氢钠溶液 (20 mL)淬灭反应，继续搅拌 1小时，析出黄色固体，减压过滤收集固体，固体用蒸馏水洗涤，干燥，得到中间体 3-碘 -咪唑 [l，2-a]吡啶 (黄色固体， 1.85 g)，收率 76%。1H-爾 R (300MHz，DMSO-d6): δ 8.35(d, J=5.4Hz, IH), 7.75(s, 1H)， 7.62(d, J=6.9Hz IH), 7.36(t,J=5.4Hz, 1H)， 7.09(d, J=5.4Hz, 1H)。 MSm/z (ESI): 244.9[M+H]。 Imidazole [l,2-a]pyridine (1.18 g, 0.1 mol) was dissolved in N,N-dimethylformamide (10 mL), and N-iodosuccinimide was added portionwise in an ice bath. (2.7 _& 0.12 m _O l), continue to stir at room temperature overnight. After the reaction was completed, a saturated sodium hydrogencarbonate solution (20 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour, and then the mixture was stirred for 1 hour to precipitate a yellow solid. The solid was collected by filtration under reduced pressure. Imidazole [l,2-a]pyridine (yellow solid, 1.85 g), yield 76%. 1H-r R (300MHz, DMSO-d6): δ 8.35 (d, J=5.4Hz, IH), 7.75(s, 1H), 7.62(d, J=6.9Hz IH), 7.36(t, J=5.4 Hz, 1H), 7.09 (d, J = 5.4 Hz, 1H). MS m / z (ESI): 244.9 [M+H].

第二步： 3-三甲基硅基乙块基 -咪唑 [l，2-a]吡啶 Step 2: 3-Trimethylsilylethylidene-imidazole [l,2-a]pyridine

将 3-碘咪唑并 [l，2-a]吡啶 (3.6 g， 15 mmol)溶于 N，N-二甲基甲酰胺 (30 mL)中，向其中加入乙块基三甲基硅烷 (2.16 mL， 19.5 mmol)和二异丙基乙胺 (3.72 mL， 22.5 mmol), 上述混合物用氮气鼓泡 5分钟置于封管中，继续加入四三苯基膦钯 (867 mg， 0.75 mmol)和碘化亚铜 (214 mg， 1.125 mmol), 氮气保护下加热至 60^QC反应过夜。反应结束后，冷却至室温，加水淬灭反应，乙酸乙酯萃取 (50mLx3)，合并有机相。有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到棕色油状物，未经纯化直接投入下一反应。 3-Isoimidazo[l,2-a]pyridine (3.6 g, 15 mmol) was dissolved in N,N-dimethylformamide (30 mL), and ethyltrimethylsilane (2.16) was added thereto. mL, 19.5 mmol) and diisopropylethylamine (3.72 mL, 22.5 mmol), and the mixture was bubbled with nitrogen for 5 min and placed in a sealed tube, and then was added tetratriphenylphosphine palladium (867 mg, 0.75 mmol) and Cuprous iodide (214 mg, 1.125 mmol) was heated to 60 ^Q C under nitrogen for overnight reaction. After completion of the reaction, the mixture was cooled to room temperature, and then the mixture was evaporated to ethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate

第三步： 3-乙块基 -咪唑 [l，2-a]吡啶 Step 3: 3-Ethyl-imidazole [l,2-a]pyridine

将上述油状物溶解于四氢呋喃 (20 mL)中，然后滴加四丁基氟化铵水溶液 (809 mg四丁基氟化铵溶于 0.5 mL水配成的溶液)，室温搅拌 2小时。反应液减压浓缩，加入水 (2 mL) 和二氯甲烷 (15 mL)萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩物用硅胶柱层析分离纯化得到中间体 3-乙块基 -[1，2，4]*** [4，3-a]吡啶 (黄色固体， 242 mg), 收率 85% o 1H-NMR (300MHz, CDC1₃): δ 8.29( d， J=5.4Hz, 1H)， 7.87(s, 1H)， 7.67(d, J=6.9Hz, 1H)， 7.28(m, 1H)， 6.94(d, J=5.4Hz, 1H)， 3.81(s, 1H)。 MS m/z (ESI): 143.1 [M+H] o The above oil was dissolved in tetrahydrofuran (20 mL), and then a solution of tetrabutylammonium fluoride (809 mg of tetrabutylammonium fluoride in 0.5 mL of water) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The intermediate 3-ethylidene-[1,2,4]triazolo[4,3-a]pyridine (yellow solid, 242 mg) was obtained, eluted, yield, yield: 85% o 1H-NMR (300 MHz, CDC1 ₃ ): δ 8.29 ( d, J = 5.4 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.28 (m, 1H), 6.94 (d, J = 5.4 Hz, 1H), 3.81 (s, 1H). MS m/z (ESI): 143.1 [M+H] o

以 6-氯 -咪唑 [l，2-a]吡啶， 6-氯 -咪唑 [l，2-b]哒嗪，咪唑 [l，2-b]哒嗪， 1-甲基 -1H-咪唑， 1H- 吲唑和 1H-吡唑 [3，4-b]吡啶为原料，采用中间体 14类似的方法合成得到以下中间体 15〜中间体 20。 . Taking 6-chloro-imidazole [l,2-a]pyridine, 6-chloro-imidazole [l,2-b]pyridazine, imidazo[l,2-b]pyridazine, 1-methyl-1H-imidazole, The following intermediates 15 to 20 were synthesized by a similar method to Intermediate 14 using 1H-carbazole and 1H-pyrazole [3,4-b]pyridine as starting materials. .

(300MHz, DMSO-d6): δ 13.4(s, IH), 7.69(d, J=8.4Hz, 1H)， 7.58(d,

(300MHz, DMSO-d6): δ 13.4(s, IH), 7.69(d, J=8.4Hz, 1H), 7.58(d,

19 143.1 19 143.1

J=8.4Hz， IH), 7.40(t,J=7.5Hz, IH), 7.21(t,J=7.5Hz, IH), 4.47(s, IH) J=8.4Hz, IH), 7.40(t, J=7.5Hz, IH), 7.21(t, J=7.5Hz, IH), 4.47(s, IH)

(300MHz, DMSO-d6): δ 14.0(s, IH), 8.59(dd， J=1.8， 4.8Hz, 1H)， (300MHz, DMSO-d6): δ 14.0(s, IH), 8.59 (dd, J=1.8, 4.8Hz, 1H),

20 144.2 20 144.2

2.21(d, J=4.8Hz, IH), 7.30(dd, J=4.8, 7.8Hz, lH)，4.56(s， IH) 2.21 (d, J = 4.8 Hz, IH), 7.30 (dd, J = 4.8, 7.8 Hz, lH), 4.56 (s, IH)

(400MHz, CDC1₃): 5 9.14 (s， 1H)， 8.23 (d, J=4.4Hz, IH) ， 8.04(d， (400MHz, CDC1 ₃ ): 5 9.14 (s, 1H), 8.23 (d, J=4.4Hz, IH) , 8.04(d,

21 144.1 21 144.1

J=4.4Hz, lH)，8.00(s， lH), 3.85(s, IH). 中间体 22: 3- J=4.4Hz, lH), 8.00(s, lH), 3.85(s, IH). Intermediate 22: 3-

第一步：咪唑 [l，2-a]吡啶 -2-甲酸乙酯 First step: Imidazole [l,2-a]pyridine 2-carboxylic acid ethyl ester

将 2-氨基吡啶 (3 g, 32 mmol)溶于无水乙醇 (15 mL)中，冰浴冷却下向上述溶液中缓慢滴加 3-溴丙酮酸乙酯 (6.4 _& 38 mmol)，滴加完毕，反应液加热至 80°C搅拌 2小时。薄层色谱监测反应结束，减压蒸去大部分溶剂，剩余物用乙酸乙酯溶解，有机相分别用饱和碳酸氢钠溶液，水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。浓缩物用硅胶柱层析分离纯化得到中间体咪唑 [l，2-a]吡啶 -2-甲酸乙酉旨 (黄色固体， 3.3 g)。 1H-NMR (300MHz, CDCI3): δ 8.17(s, 1H)， 8.12(d, J=6.0Hz, 1H)， 7.67(d, J=6.0Hz, IH), 7.22-7.24(m, IH), 6.86(t， J=6.0Hz， IH), 4.42-4.48(q, J=6.0Hz, 2H), 1.41-1.45(t, J=6.0Hz, 3H)。 MS m/z (ESI): 190.2[M+H 2-Aminopyridine (3 g, 32 mmol) was dissolved in absolute ethanol (15 mL), and ethyl 3-bromopyruvate (6.4 _& 38 mmol) was slowly added dropwise to the above solution under ice-cooling, and added dropwise. After completion, the reaction solution was heated to 80 ° C and stirred for 2 hours. The reaction was monitored by thin-layer chromatography. The solvent was evaporated to dryness, and the residue was evaporated, evaporated, evaporated, evaporated, concentrate. The concentrate was separated and purified by silica gel column chromatography toield of Intermediate <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt; 1H-NMR (300MHz, CDCI3): δ 8.17(s, 1H), 8.12 (d, J=6.0Hz, 1H), 7.67 (d, J=6.0Hz, IH), 7.22-7.24(m, IH), 6.86 (t, J = 6.0 Hz, IH), 4.42-4.48 (q, J = 6.0 Hz, 2H), 1.41-1.45 (t, J = 6.0 Hz, 3H). MS m/z (ESI): 190.2 [M+H

第二步：咪唑 [l，2-a]吡啶 -2-基 -甲醇 Step 2: Imidazole [l,2-a]pyridine-2-yl-methanol

将咪唑 [l，2-a]吡啶 -2-甲酸乙酯2 g, 10.5 mmol)溶解在无水四氢呋喃 (10 mL)中的溶液，缓慢滴加到冰浴冷却下的四氢铝鋰 (1.2 _& 31.5 mmol)的四氢呋喃 (5 mL)溶液中。滴加完毕，反应液缓慢升温至室温继续反应 2h至反应结束。反应液再次用冰浴冷却，慢慢用 15%的氢氧化钠水溶液淬灭反应，继续搅拌 1小时。减压过滤，滤液浓缩后直接用硅胶柱层析分离纯化得到中间体咪唑 [l，2-a]吡啶 -2-基 -甲醇 (黄色固体， 1.4 g)。 1H-NMR (300MHz， CDC1₃): δ 7.98(d, J=3.0Hz, IH), 7.43(d, J=9.0Hz, 2H), 7.05-7.10(m, IH), 6.89(s， 2H), 6.66-6.89(m, 1H)， 4.73(s, 2H MSm/z (ESI): 148.2 [M+H]。 A solution of 2 μm of imidazo [l,2-a]pyridine-2-carboxylate (10.5 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to lithium tetrahydrogenate (1.2) cooled in ice bath. _& 31.5 mmol) in tetrahydrofuran (5 mL). After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature and the reaction was continued for 2 hours until the end of the reaction. The reaction solution was again cooled with an ice bath, and the mixture was slowly quenched with 15% aqueous sodium hydroxide and stirring was continued for one hour. Filtration under reduced pressure, and the filtrate was concentrated and purified using silica gel column chromatography to afford intermediate <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt; 1H-NMR (300MHz, CDC1 ₃ ): δ 7.98 (d, J = 3.0 Hz, IH), 7.43 (d, J = 9.0 Hz, 2H), 7.05-7.10 (m, IH), 6.89 (s, 2H) , 6.66-6.89 (m, 1H), 4.73 (s, 2H MS m/z (ESI): 148.2 [M+H].

第三步： 2-氟甲基 -咪唑 [l，2-a]吡啶 Step 3: 2-fluoromethyl-imidazole [l,2-a]pyridine

将咪唑 [l，2-a]吡啶 -2-基 -甲醇 (0.5 g, 3.38 mmol)溶解在二氯甲烷 (8 mL)中，冰浴冷却下向上述溶液缓慢滴加二乙胺基三氟化硫试剂 (0.5 mL, 4.10 mmol 滴加完毕，继续在室温下反应过夜。反应完毕，反应液降温至 0 °C，用饱和氯化铵溶液淬灭反应，二氯甲烷萃取，有机相分别用饱和碳酸氢钠溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。浓缩物直接用硅胶柱层析分离纯化得到中间体 2-氟甲基 -咪唑 [l，2-a]吡啶 (黄色固体， 0.4 g), 收率 79% 1H-NMR (300MHz, CDC1₃): δ 8.10(d， J=6.0Hz, IH), 7.65(s, IH), 7.58(d, J=9.0Hz, IH), 7.17-7.2 l(m, 1H)， 6.78-6.81(m, 1H)， 5.61(s， 1H)， 5.49(s， 1H)。 MS m/z (ESI): 150.2[M+H]。第四步： 2-氟甲基 -3-碘 -咪唑 [l，2-a]吡啶 The imidazole [l,2-a]pyridin-2-yl-methanol (0.5 g, 3.38 mmol) was dissolved in dichloromethane (8 mL), and diethylamine trifluorotide was slowly added dropwise to the above solution under ice cooling. Sulfur reagent (0.5 mL, 4.10 mmol), continue to react at room temperature overnight. After the reaction is completed, the reaction solution is cooled to 0 ° C, quenched with saturated ammonium chloride solution, extracted with dichloromethane, and organic phase is used separately. The mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. a]pyridine (yellow solid, 0.4 g), yield 79% 1H-NMR (300MHz, CDC1 ₃ ): δ 8.10 (d, J = 6.0 Hz, IH), 7.65 (s, IH), 7.58 (d, J = 9.0Hz, IH), 7.17-7.2 l(m, 1H), 6.78-6.81(m, 1H), 5.61(s, 1H), 5.49(s, 1H) MS m/z (ESI): 150.2[ M+H]. Step 4: 2-fluoromethyl-3-iodo-imidazole [l,2-a]pyridine

采用中间体 14第一步类似的方法合成得到中间体 2-氟甲基 -3-碘 -咪唑 [l，2-a]吡啶 (黄色固体， 260 mg)。 1H-NMR (300MHz, CDC1₃): δ 8.13(d, J=7.2Hz, IH), 7.60(d, J=7.2Hz, 1H)， 7.26-7.30(m, IH), 6.94-6.97 (m， IH), 5.55(d， J=66.9Hz， 2H)。 MSm/z (ESI): 276.1[M+H]。第五步： 2-氟甲基 -3-三甲基硅基乙块 -咪唑 [l，2-a]吡啶 The intermediate 2-fluoromethyl-3-iodo-imidazole [l,2-a]pyridine (yellow solid, 260 mg) was obtained by the analogous procedure of Intermediate 14 . 1H-NMR (300MHz, CDC1 ₃ ): δ 8.13 (d, J = 7.2 Hz, IH), 7.60 (d, J = 7.2 Hz, 1H), 7.26-7.30 (m, IH), 6.94-6.97 (m, IH), 5.55 (d, J = 66.9 Hz, 2H). MS m / z (ESI): 276.1 [M+H]. Step 5: 2-fluoromethyl-3-trimethylsilyl b-imidazole [l,2-a]pyridine

采用中间体 14 第二步类似的方法合成得到中间体 2-氟甲基 -3-三甲基硅基乙块 -咪唑 [l，2-a]吡啶 (黄色固体， 300 mg)。 1H-NMR (300MHz, CDC1₃): δ 8.23(d, J=5.4Hz, IH), 7.64(d, J=6.6Hz， IH), 7.28-7.32(m, IH), 6.97(d, J=5.4Hz, IH), 5.58(d, J=36.0Hz, 2H)。 The intermediate 2-fluoromethyl-3-trimethylsilylethyl bromide-imidazole [l,2-a]pyridine (yellow solid, 300 mg) was obtained. 1H-NMR (300MHz, CDC1 ₃ ): δ 8.23 (d, J = 5.4 Hz, IH), 7.64 (d, J = 6.6 Hz, IH), 7.28-7.32 (m, IH), 6.97 (d, J = 5.4 Hz, IH), 5.58 (d, J = 36.0 Hz, 2H).

第六步： 3-乙块基 -2-氟甲基 -咪唑 [l，2-a]吡啶 Step 6: 3-Ethyl-2-fluoromethyl-imidazole [l,2-a]pyridine

采用中间体 14第三步类似的方法合成得到中间体 3-乙块基 -2-氟甲基 -咪唑 [l，2-a]吡啶 (黄色固体， 106 mg)。 1H-爾 R (300MHz, CDC1₃): δ 8.28(d, J=6.3Hz, IH), 7.66(d, J=9.3Hz, 1H)， 7.33(t, J=6.9Hz, IH), 6.97(t, J=6.9Hz， IH), 5.60(d, J=48.0Hz, 2H), 3.93(s, 1H)。 MS m/z (ESI): 174.1[M+H] o The intermediate 3-ethylidene-2-fluoromethyl-imidazole [l,2-a]pyridine (yellow solid, 106 mg) was obtained by the procedure of the intermediate step. 1H-r R (300MHz, CDC1 ₃ ): δ 8.28(d, J=6.3Hz, IH), 7.66(d, J=9.3Hz, 1H), 7.33(t, J=6.9Hz, IH), 6.97( t, J = 6.9 Hz, IH), 5.60 (d, J = 48.0 Hz, 2H), 3.93 (s, 1H). MS m/z (ESI): 174.1 [M+H] o

采用氨基吡啶，氨基哒嗪，氨基嘧啶和 1-溴-丁 -2-酮， 1-溴-丙 -2-酮， 2-溴 -1-环丙基-乙酮为原料，采用中间体 22类似的方法合成得到以下中间体 23〜中间体 28。 Using aminopyridine, aminopyridazine, aminopyrimidine and 1-bromo-butan-2-one, 1-bromo-propan-2-one, 2-bromo-1-cyclopropyl-ethanone as raw materials, using intermediate 22 A similar method was synthesized to give the following intermediate 23 to intermediate 28.

中间体 29: 2-二氟甲基 -3-乙块基 -咪唑 l，2-a]吡啶

Intermediate 29: 2-Difluoromethyl-3-ethylidene-imidazole l,2-a]pyridine

第一步：咪唑 [l，2-a]吡啶 -2-甲醛 First step: Imidazole [l,2-a]pyridine-2-carbaldehyde

将咪唑 [l，2-a]吡啶 -2-基 -甲醇 500 mg, 3.38 mmol)溶解在二氯甲烷 (8 mL)中，冰浴冷却下向其中缓慢加入戴斯-马丁试剂 (1.7 _& 4.05 mmol)。加完，继续在室温反应 2h， TLC监测反应完毕，用饱和碳酸氢钠溶液和饱和硫代硫酸钠淬灭反应，二氯甲烷萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。浓缩物用硅胶柱层析分离纯化得到中间体咪唑 [l，2-a]吡啶 -2-甲醛 (黄色固体， 420 mg)，收率 85%。1H-NMR (300MHz, CDC1₃) δ 10.157(s, IH), 8.15-8.17(m, 2H), 7.67-7.70(dd, J=6.9, 0.6Hz， IH), 7.26-7.31(m, 1H)， 6.91-6.92(d, J=0.6Hz, lH)o MS m/z (ESI): 146.1 [M+H] o 第二步： 2-二氟甲基 -咪唑 [l，2-a]吡啶 Imidazole [l,2-a]pyridin-2-yl-methanol 500 mg, 3.38 mmol) was dissolved in dichloromethane (8 mL) and slowly added to the Dess-Martin reagent (1.7 _& 4.05) under ice cooling. Mm). After the completion of the reaction, the reaction was continued at room temperature for 2 h, and the reaction was completed by TLC. EtOAc (EtOAc m.). , filtered, concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography toield of intermediate <RTI ID=0.0>#</RTI><RTIgt;</RTI><RTIgt; 1H-NMR (300MHz, CDC1 ₃ ) δ 10.157(s, IH), 8.15-8.17(m, 2H), 7.67-7.70 (dd, J=6.9, 0.6Hz, IH), 7.26-7.31(m, 1H) , 6.91-6.92(d, J=0.6Hz, lH)o MS m/z (ESI): 146.1 [M+H] o Second step: 2-difluoromethyl-imidazole [l,2-a]pyridine

采用中间体 22第三步类似的方法合成得到中间体 2-二氟甲基 -咪唑 [1， 2-a]吡啶 (黄色固体， 200 mg)。 H-NMR (300MHz, CDC1₃) δ 8.12-8.14(m, IH), 7.79(s, 1H)， 7.62(dd, J=6.9, 0.6Hz， IH), 7.22-7.26(m, IH), 6.85(t，J=51.4Hz， IH), 6.87(m, 1H)。 MSm/z (ESI): 168.1[M+H]。 The intermediate 2-difluoromethyl-imidazo[1,2-a]pyridine (yellow solid, 200 mg) was obtained in a similar manner to the intermediate step. H-NMR (300MHz, CDC1 ₃ ) δ 8.12-8.14(m, IH), 7.79(s, 1H), 7.62 (dd, J=6.9, 0.6Hz, IH), 7.22-7.26(m, IH), 6.85 (t, J = 51.4 Hz, IH), 6.87 (m, 1H). MS m/z (ESI): 168.1 [M+H].

第三步： 2-二氟甲基 -3-碘 -咪唑 [l，2-a]吡啶 Step 3: 2-Difluoromethyl-3-iodo-imidazole [l,2-a]pyridine

采用中间体 14第一步类似的方法合成得到中间体 2-二氟甲基 -3-碘 -咪唑 [l，2-a]吡啶 (黄色固体， 270 mg) o 1H-NMR (300MHz, CDC1₃) δ 8.18-8.21(m, IH), 7.65(td, J=6.9, 0.9Hz， 1H)， 7.31-7.35(m, IH), 6.99-7.03 (m， IH), 6.79(d, J=40.5Hz, 1H)。 MSm/z (ESI): 294.1[M+H]。 The intermediate 2-difluoromethyl-3-iodo-imidazole [l,2-a]pyridine (yellow solid, 270 mg) was synthesized using a similar method in the first step of Intermediate 14. o 1H-NMR (300 MHz, CDC1 ₃ δ 8.18-8.21(m, IH), 7.65(td, J=6.9, 0.9Hz, 1H), 7.31-7.35(m, IH), 6.99-7.03 (m, IH), 6.79(d, J=40.5 Hz, 1H). MS m / z (ESI): 294.1 [M+H].

第四步： 2-二氟甲基 -3-三甲基硅基乙块基 -咪唑 [l，2-a]吡啶 Step 4: 2-Difluoromethyl-3-trimethylsilylethylidene-imidazole [l,2-a]pyridine

采用中间体 14第二步类似的方法合成得到中间体 2-二氟甲基 -3-三甲基硅基乙块基 -咪唑 [l，2-a]吡啶 (黄色固体， 170 mg)。 1H-NMR (300MHz, CDC1₃) δ 8.25-8.28(m, IH), 7.66-7.69(m, IH), 7.32-7.38(m, IH), 6.98-7.03(m, 1 H)， 6.90(t,J=54.3Hz, 1H)。 The intermediate 2-difluoromethyl-3-trimethylsilylethylidene-imidazole [l,2-a]pyridine (yellow solid, 170 mg) was obtained in a similar manner to the intermediate step. 1H-NMR (300MHz, CDC1 ₃ ) δ 8.25-8.28 (m, IH), 7.66-7.69 (m, IH), 7.32-7.38 (m, IH), 6.98-7.03 (m, 1 H), 6.90 (t , J = 54.3 Hz, 1H).

第五步： 2-二氟甲基 -3-乙块基 -咪唑 [1， 2-a]吡啶 Step 5: 2-Difluoromethyl-3-ethylidene-imidazole [1, 2-a]pyridine

采用中间体 14 第三步类似的方法合成得到中间体 2-二氟甲基 -3-乙块基 -咪唑 [1， 2-a] 吡啶 (黄色固体， 76 mg)。 1H-NMR (300MHz， CDC1₃) δ 8.32(d, J=3.0Hz, IH), 7.68-7.70(m, 1H)， 7.35-7.39(m, IH), 7.02-7.04 (m, IH), 6.91(t，J=40.8Hz， 1H)。 MSm/z (ESI): 192.2[M+H]。中间体 30: 2-二氟甲基 -3-乙块基 -咪唑 [l，2-b]哒嗪 The intermediate 2-difluoromethyl-3-ethlyl-imidazo[1,2-a]pyridine (yellow solid, 76 mg 1H-NMR (300MHz, CDC1 ₃ ) δ 8.32 (d, J = 3.0Hz, IH), 7.68-7.70 (m, 1H), 7.35-7.39 (m, IH), 7.02-7.04 (m, IH), 6.91 (t, J = 40.8 Hz, 1H). MS m / z (ESI): 192.2 [M+H]. Intermediate 30: 2-Difluoromethyl-3-ethylidene-imidazole [l,2-b]pyridazine

第一步： 6-氯 -咪唑 [l，2-b]哒嗪 -2-甲酸乙酯 First step: 6-chloro-imidazole [l,2-b]pyridazine-2-carboxylic acid ethyl ester

将 6-氯 -3-氨基哒嗪 (10 _& 77.2 mmol)溶于无水乙醇 (120 mL)中，然后向其中缓慢加入溴丙酮酸乙酯 (11.70 mL， 92.6 mmol), 加完将反应液加热回流过夜。 TLC检测反应完毕后，反应液冷却至室温，减压除去大部分溶剂，残余物溶于饱和碳酸氢钠溶液，二氯甲烷萃取 (50mLx3), 有机相分别用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析纯化得中间体氯 -咪唑 [l，2-b]哒嗪 -2-甲酸乙酯 (浅黄色固体， 8.2 g)。 1H-NMR (300MHz, CDC1₃): δ 8.44(d, J=0.6Hz， 1H)， 7.96(dd, J=6.9, 0.6Hz， 1H)， 7.14(d, J=7.2Hz, 1H)， 4.46(q，J=5.4Hz，2H)， 1.43(t， J=5.4Hz， 3H)。 MSm/z (ESI): 226.0[M+H]。 6-Chloro-3-aminopyridazine (10 _& 77.2 mmol) was dissolved in absolute ethanol (120 mL), then ethyl bromopyruvate (11.70 mL, 92.6 mmol) was slowly added thereto, and the reaction mixture was added. Heat to reflux overnight. After the TLC reaction was completed, the reaction solution was cooled to room temperature, and most of the solvent was removed under reduced pressure. The residue was dissolved in saturated sodium bicarbonate and extracted with dichloromethane (50mL×3), and the organic phase was washed with water, saturated brine, anhydrous sulfuric acid The mixture was dried with EtOAc EtOAc EtOAc m. 1H-NMR (300MHz, CDC1 ₃ ): δ 8.44 (d, J = 0.6 Hz, 1H), 7.96 (dd, J = 6.9, 0.6 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 4.46 (q, J = 5.4 Hz, 2H), 1.43 (t, J = 5.4 Hz, 3H). MS m / z (ESI): 226.0 [M+H].

第二步：咪唑 [l，2-b]哒嗪 -2-甲酸乙酯 Step 2: Imidazole [l,2-b]pyridazine-2-carboxylic acid ethyl ester

将 6-氯 -咪唑 [l，2-b]哒嗪 -2-甲酸乙酯 (8.2 g， 36 mmol)溶于甲醇 (250 mL)中，氮气保护下向其中加入 10% Pd/C(l g), 然后体系用氢气置换三次，继续在室温下反应 2h。 TLC检测反应完毕后，过滤除去催化剂，滤饼用甲醇洗涤。滤液减压浓缩，未经进一步纯化即得中间体咪唑 [l，2-b]哒嗪 -2-甲酸乙酉旨 (黄色固体， 6.4 g)，收率 93%。 1H-NMR (300MHz, CDC1₃): δ 8.64-8.67(m, 2H), 8.54(s， IH), 7.54(d, J=4.5Hz, IH), 4.5 l(q, J=6.9Hz, 2H), 1.47(t, J=6.9Hz, 3H) o MSm/z (ESI): 192.1[M+H]。 Ethyl 6-chloro-imidazole [l,2-b]pyridazine-2-carboxylate (8.2 g, 36 mmol) was dissolved in methanol (250 mL), and 10% Pd/C (lg) Then, the system was replaced with hydrogen three times and continued to react at room temperature for 2 h. After completion of the TLC reaction, the catalyst was removed by filtration, and the cake was washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (1,2-b]pyridazine-2-carboxylic acid ethyl ester (yellow solid, 6.4 g). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.64-8.67(m, 2H), 8.54(s, IH), 7.54(d, J=4.5Hz, IH), 4.5 l(q, J=6.9Hz, 2H ), 1.47 (t, J = 6.9 Hz, 3H) o MS m/z (ESI): 192.1 [M+H].

第三步：咪唑 [l，2-b]哒嗪 -2-基 -甲醇 Step 3: Imidazole [l,2-b]pyridazine-2-yl-methanol

将四氢锂铝 (3.8 g， 100 mmol)置于氮气保护的 250 mL三颈瓶中，冰浴冷却下向其中缓慢注入无水四氢呋喃 (100 mL), 待无气泡产生后，向其中缓慢加入咪唑并 [l，2-b]哒嗪 -2-甲酸乙酯 (6.4 _& 33.5 mmol), 室温反应 4h。薄层层析检测反应完毕后，将反应液用冰浴冷却至 0^QC，向其中缓慢滴加水 (3.8 mL)以及 10%的氢氧化钠溶液 (3.8 mL)，搅拌半小时。减压过滤，滤饼用乙酸乙酯洗涤多次，滤液减压浓缩，残余物硅胶柱层析分离纯化得中间体咪唑 [l，2-b]哒嗪 -2-基 -甲醇 (黄色固体， 2.7 g) o 1H-NMR (300MHz, CDC1₃): δ 8.28(d, J=3.3Hz, 1H), 7.88-7.94(m, 2H), 7.03(dd, J=9.0, 4.5Hz, 1H)， 4.88(s， 2H)。 MS m/z (ESI): 150.1[M+H]。第四步：咪唑并 [l，2-b]哒嗪 -2-甲醛 Lithium tetrahydrogen aluminum (3.8 g, 100 mmol) was placed in a nitrogen-protected 250 mL three-necked flask, and anhydrous tetrahydrofuran (100 mL) was slowly poured into it under ice cooling, and slowly added to the bubble-free gas. Ethyl imidazo[l,2-b]pyridazine-2-carboxylate (6.4 _& 33.5 mmol) was reacted at room temperature for 4 h. After the reaction was completed by thin layer chromatography, the reaction solution was cooled to 0 ^Q C in an ice bath, and water (3.8 mL) and a 10% sodium hydroxide solution (3.8 mL) were slowly added dropwise thereto, and stirred for half an hour. Filtration under reduced pressure, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford intermediate imid[l,2-b]pyridazin-2-yl-methanol (yellow solid, 2.7 g) o 1H-NMR (300MHz, CDC1 ₃ ): δ 8.28 (d, J=3.3Hz, 1H), 7.88-7.94 (m, 2H), 7.03 (dd, J = 9.0, 4.5 Hz, 1H), 4.88 (s, 2H). MS m/z (ESI): 150.1 [M+H]. Step 4: Imidazo[l,2-b]pyridazine-2-carboxaldehyde

将咪唑并 [l，2-b]哒嗪 -2-基甲醇 (270 mg, 1.8 mmol)溶于二氯甲烷 (20 mL)中，冰浴冷却下向其中加入戴斯 -马丁氧化剂 (1.2 g， 2.7 mmol)及碳酸氢钠粉末 (457 mg， 5.4 mmol) , 加完继续室温反应 2h。 TLC检测反应完毕后，反应液中加入饱和硫代硫酸钠溶液 (20 mL), 搅拌 10分钟后，分出有机相，水相用二氯甲烷萃取 (10 mLx3)，合并有机相，有机相分别用水，饱和食盐水洗涤，无水硫酸纳干燥，过滤，减压浓缩，残余物硅胶柱层析分离纯化得中间体咪唑并 [l，2-b]哒嗪 -2-甲醛（白色固体， 240 mg)，收率 90.0%。 1H-NMR (300MHz， DMSO-d6): Imidazo[l,2-b]pyridazin-2-ylmethanol (270 mg, 1.8 mmol) was dissolved in dichloromethane (20 mL). , 2.7 mmol) and sodium bicarbonate powder (457 mg, 5.4 mmol), continue to react at room temperature for 2 h. After the TLC detection reaction was completed, a saturated sodium thiosulfate solution (20 mL) was added to the reaction mixture, and after stirring for 10 minutes, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL×3), and the organic phase was combined. Washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated. Mg), yield 90.0%. 1H-NMR (300MHz, DMSO-d6):

10.05(s, 1H), 8.98(s， 1H), 8.65(d， J=4.5Hz， 1H), 8.24(d, J=9.6Hz, 1H)， 7.36(dd, J= 9.6， 4.2Hz, 1H)。 MSm/z (ESI): 148.1[M+H]。 10.05(s, 1H), 8.98(s, 1H), 8.65(d, J=4.5Hz, 1H), 8.24(d, J=9.6Hz, 1H), 7.36(dd, J= 9.6, 4.2Hz, 1H ). MS m/z (ESI): 148.1 [M+H].

第五步： 2-二氟甲基 -咪唑 [l，2-b]哒嗪 Step 5: 2-Difluoromethyl-imidazole [l,2-b]pyridazine

将咪唑并 [l，2-b]哒嗪 -2-甲醛（350 mg 2.38 mmol)溶于二氯甲烷 (10 mL)中，冰浴冷却至 0°C,氮气保护下向其中缓慢滴加二乙胺基三氟化硫试剂 (0.58 ml, 4.76 mmol) 滴加完毕后，撤去冰浴，室温反应过夜。 TLC检测反应完毕后，将反应液用冰浴冷却至 0^QC，向其中缓慢加入饱和碳酸氢钠溶液调 pH至 6-7，水相用二氯甲烷萃取 (20 mLx3), 合并有机相，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化得中间体 2-二氟甲基 -咪唑 [l，2-b]哒嗪（白色固体， 204 mg)。 1H-NMR (300MHz, CDC1₃): 8.38(dd, J=4.2, 1.2Hz, 1H), 8.19(s, 1H), 7.98(dd, J=10.2, 1.2Hz, 1H)， 7.13(dd, J=9.6, 4.2Hz， 1H)， 6.88(t，J=55.2Hz， 1H)。 MSm/z (ESI): 170.1[M+H] Imidazo[l,2-b]pyridazine-2-carboxaldehyde (350 mg 2.38 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ° C under ice-cooling, and slowly added dropwise thereto under nitrogen. After the dropwise addition of the ethylamine trifluoride reagent (0.58 ml, 4.76 mmol), the ice bath was removed and allowed to react at room temperature overnight. After the TLC detection reaction was completed, the reaction solution was cooled to 0 ^Q C in an ice bath, and a saturated sodium hydrogen carbonate solution was slowly added thereto to adjust the pH to 6-7, and the aqueous phase was extracted with dichloromethane (20 mL×3), and the organic phase was combined. The organic layer was washed with water and aq. The residue was purified by silica gel column chromatography eluting elute 1H-NMR (300MHz, CDC1 ₃ ): 8.38 (dd, J = 4.2, 1.2 Hz, 1H), 8.19 (s, 1H), 7.98 (dd, J = 10.2, 1.2 Hz, 1H), 7.13 (dd, J = 9.6, 4.2 Hz, 1H), 6.88 (t, J = 55.2 Hz, 1H). MSm/z (ESI): 170.1 [M+H]

第六步： 2-二氟甲基 -3-碘 -咪唑 [l，2-b]哒嗪 Step 6: 2-Difluoromethyl-3-iodo-imidazole [l,2-b]pyridazine

采用中间体 14第一步类似的方法合成得到中间体 2-二氟甲基 -3-碘 -咪唑 [l，2-b]哒嗪 (白色固体， 285 mg 1H-NMR (300MHz, CDC1₃): 8.52(dd, J=3.3, 1.2Hz, 1H), 7.97(dd, J=7.2, 1.2Hz, 1H), 7.19(dd, J=7.2, 3.3Hz, 1H)， 6.88(t， J=40.2Hz， 1H)。 MSm/z (ESI): 295.9 [M+H]。第七步： 2-二氟甲基 -3-乙块基 -咪唑 [l，2-b]哒嗪 The intermediate 2-difluoromethyl-3-iodo-imidazole [l,2-b]pyridazine (white solid, 285 mg 1H-NMR (300MHz, CDC1 ₃ ) : 8.52 (dd, J=3.3, 1.2 Hz, 1H), 7.97 (dd, J=7.2, 1.2 Hz, 1H), 7.19 (dd, J=7.2, 3.3 Hz, 1H), 6.88 (t, J=40.2) Hz, 1H) MSm/z (ESI): 295.9 [M+H]. Step 7: 2-Difluoromethyl-3-ethylidene-imidazole [l,2-b]pyridazine

采用中间体 14 第二，第三步类似的方法合成得到中间体 2-二氟甲基 -3-乙块基 -咪唑 Intermediate 14 was synthesized in a similar manner to the second step. 2-Difluoromethyl-3-ethylidene-imidazole

[l，2-b]哒嗪（白色固体， 64 mg)。 1H-NMR (300MHz, CDC1₃): 8.52-8.53(m, 1H), 8.03(dd, J=6.3, 1.5Hz, 1H), 7.02-7.25(m, 1H), 6.93(t, J=40.5Hz, 1H), 3.93(s, 1H)。 MS m/z (ESI): 194.1 [M+H 中间体 3 -乙块基小甲基 -IH-吲唑和 3-乙块基 -2-甲基 -2H-吲唑 [l,2-b]pyridazine (white solid, 64 mg). 1H-NMR (300MHz, CDC1 ₃ ): 8.52-8.53(m, 1H), 8.03 (dd, J=6.3, 1.5Hz, 1H), 7.02-7.25(m, 1H), 6.93(t, J=40.5Hz , 1H), 3.93(s, 1H). MS m/z (ESI): 194.1 [M+H Intermediate 3 -ethyl-bromomethyl-IH-carbazole and 3-ethyl-bromo-2-methyl-2H-carbazole

以 1H-吲唑为原料，采用文献（Journal of Organometallic Chemistry, 2000, 604, 2 , 157-169)方法合成得到中间体 a-1 ( 1.7 g,黄色固体）和 a- 2 (0.6 &黄色固体）。 a-1 : 1H-NMR (300MHz, CDC13): δ 7.79 (d, J=8.1Hz, 1 H)， 7.39-7.4 l(m, 2H), 7.24(m, IH), 4,07(s, 3H)。 M S m/z (ESI): 259.1 [M+H]。 a-2: IH- NMR (300MHz, CDC13): δ 7.67-7.7 l(m, 2H), 7.30- 7.32(m, IH), 7.12-7.17(t, J=7.8Hz, lH), 4.23(s, 3H)。 Using a 1H-carbazole as a starting material, an intermediate a-1 (1.7 g, yellow solid) and a-2 (0.6 & yellow solid) were synthesized by the method of Journal of Organometallic Chemistry, 2000, 604, 2, 157-169. ). A-1 : 1H-NMR (300MHz, CDC13): δ 7.79 (d, J=8.1Hz, 1 H), 7.39-7.4 l(m, 2H), 7.24(m, IH), 4,07(s, 3H). M S m/z (ESI): 259.1 [M+H]. A-2: IH-NMR (300MHz, CDC13): δ 7.67-7.7 l(m, 2H), 7.30- 7.32(m, IH), 7.12-7.17(t, J=7.8Hz, lH), 4.23(s , 3H).

以 a- 1和 a-2为原料，采用中间体 13相同的方法合成得到中间体 3-乙块基 -1-甲基 -1Η- 吲唑和 3-乙块基 -2-甲基 -2H-吲唑。 3-乙块基 -1-甲基 -1H-吲唑： 1H- NMR (300MHz, CDC1₃): δ 7.79(d, J:::6 0Hz, IH), 7.4 -7.43(m, 2H), 7.22-7.24(m, I H), 4 08(s, 3H), 3.38(s, 1H)。 M S m/z (ESI): 157.2[M十 H]。 3-乙块基 -2-甲基 -2H-吲唑： ^-NMR (300MHz， CDC1₃): 7.67-7.73(m, 2H), 7.31(td, J=4.8, 0.9Hz, 1H)， 7.15-7.19(m, 1H)， 4.26(s, 3H), 3.90(s, 1H)。 MS m/z (ESI): 157.1[M+H 中间体 32: -碘 -4-甲基 -N-(4-吗啉 -4-甲基 -3-三氟甲基苯基) -苯甲酰胺 Using a-1 and a-2 as starting materials, the intermediate 3-ester-1-1-methyl-1Η-carbazole and 3-ethylidene-2-methyl-2H were synthesized by the same method as Intermediate 13. - carbazole. 3-ethylidene-1-methyl-1H-carbazole: 1H-NMR (300MHz, CDC1 ₃ ): δ 7.79 (d, J:::60 Hz, IH), 7.4 -7.43 (m, 2H), 7.22-7.24(m, IH), 4 08(s, 3H), 3.38(s, 1H). MS m/z (ESI): 157.2 [M 十 H]. 3-Ethyl-2-methyl-2H-carbazole: ^-NMR (300MHz, CDC1 ₃ ): 7.67-7.73 (m, 2H), 7.31 (td, J = 4.8, 0.9 Hz, 1H), 7.15 -7.19 (m, 1H), 4.26 (s, 3H), 3.90 (s, 1H). MS m/z (ESI): 157.1 [M+H Intermediate 32:: <RTI ID=0.0> Amide

第一步： 1-溴甲基 -4-硝基 -2-三氟甲基-苯 First step: 1-bromomethyl-4-nitro-2-trifluoromethyl-benzene

将 1-甲基 -4-硝基 -2- (三氟甲基)苯 (0.5 g, 2.5 mmol)溶于冰醋酸 (15 mL), 然后依次向上述溶液中加入 N-溴代丁二酰亚胺 (0.7 _& 3.7 mmol)和苯甲酰过氧（6 m_& 0.024 mmol), 反应液加热回流过夜。将反应液冷却至室温，减压除去大部分溶剂，再加入乙酸乙酯和饱和碳酸氢钠溶液稀释，有机相用水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，直接用于下一步反应。 1-Methyl-4-nitro-2-(trifluoromethyl)benzene (0.5 g, 2.5 mmol) was dissolved in glacial acetic acid (15 mL), then N-bromosuccinyl was added to the above solution. The imine (0.7 _& 3.7 mmol) and benzoyl peroxy (6 m _& 0.024 mmol) were heated to reflux overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. One step reaction.

第二步： 4-(4-硝基 -2-三氟甲基-苄基)-***啉 Step 2: 4-(4-Nitro-2-trifluoromethyl-benzyl)-morpholine

将上述浓缩物溶于二氯甲烷 (10 mL) , 然后加入三乙胺 (0.17 mL)和***啉（0.11 mL, 0.12 mmol), 反应液室温搅拌 2小时。反应结束后，向反应液中加入饱和碳酸氢钠溶液，分出有机层，有机相用水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，浓缩物硅胶柱层析分离得到 4-(4-硝基 -2- (三氟甲基)苄基)***啉 (黄色固体， 2.8 g)，收率 100%。 1H-NMR (300MHz, DMSO-d6): 8.50(d, J=8.4Hz, IH), 8.40(s, IH), 8.10(d， J=8.7Hz, IH), 3.72(s, 2H), 3.58-3.61(m, 4H)， 2.35-2.45(m, 4H)。 MSm/z (ESI): 291.1[M+H]。 The above concentrate was dissolved in dichloromethane (10 mL), then triethylamine (0.17 mL) and morpholine (0.11 mL, 0.12 mmol). After the completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the organic layer was separated, and the organic layer was evaporated. 4-Nitro-2-(trifluoromethyl)benzyl)morpholine (yellow solid, 2.8 g), yield 100%. 1H-NMR (300MHz, DMSO-d6): 8.50 (d, J = 8.4 Hz, IH), 8.40 (s, IH), 8.10 (d, J = 8.7 Hz, IH), 3.72 (s, 2H), 3.58 -3.61 (m, 4H), 2.35-2.45 (m, 4H). MS m / z (ESI): 291.1 [M+H].

第三步： 4-***啉 -4-基甲基 -3-三氟甲基 -苯胺 Step 3: 4-morpholine-4-ylmethyl-3-trifluoromethyl-aniline

将 4-(4-硝基 -2- (三氟甲基)苄基)***啉 (276 mg 0.95 mmol)溶于甲醇 (20 mL), 氮气置换体系，再加入 10%钯碳催化剂 (100 mL)，反应液在氢气氛下室温搅拌 2小时，反应完全。反应液减压过滤，浓缩得到 4-***啉 -4-甲基 -3-三氟甲基 -苯胺 (黄色油状物， 222 mg), 收率 90%。 1H-丽 R (300MHz，DMSO-d6): 7.28(d, J=8.4Hz, 1H)， 6.84(s， IH), 6.73(d, J=8.4Hz, 1H)， 5.44(s, 2H), 3.52-3.55(m, 4H), 3.37(s, 2H), 2.29(s, 4H MS m/z (ESI): 261.1[M+H]。 Dissolve 4-(4-nitro-2-(trifluoromethyl)benzyl)morphinphyrin (276 mg 0.95 mmol) in methanol (20 mL), replace the system with nitrogen, then add 10% palladium on carbon catalyst (100 mL) The reaction solution was stirred at room temperature for 2 hours under a hydrogen atmosphere, and the reaction was completed. The reaction mixture was filtered under reduced pressure and evaporated to ethylamine. 1H-丽R (300MHz, DMSO-d6): 7.28 (d, J=8.4Hz, 1H), 6.84(s, IH), 6.73(d, J=8.4Hz, 1H), 5.44(s, 2H), 3.52-3.55 (m, 4H), 3.37 (s, 2H), 2.29 (s, 4H MS m/z (ESI): 261.1 [M+H].

第四步： 3-碘 -4-甲基 -N-(4-***啉 -4-基甲基 -3-三氟甲基-苯基) -苯甲酰胺 Step 4: 3-iodo-4-methyl-N-(4-morpholine-4-ylmethyl-3-trifluoromethyl-phenyl)-benzamide

将 3-碘 -4-甲基苯甲酸 (0.25 g, 0.93 mmol)和 4-***啉 -4-甲基 -3-三氟甲基 -苯胺 (0.22 g, 0.85 mmol)溶于 N，N-二甲基甲酰胺（10 mL) , 冰浴冷却下分别加入 2-(7-氮杂苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯（0.39 _& 1.02 mmol)和二异丙基乙胺 (0.20 mL, 1.27 mmol), 继续搅拌过夜。将反应液倒入水中，乙酸乙酯萃取，有机相分别用 10%的稀盐酸、饱和碳酸氢钠溶液、水和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，硅胶柱层析分离得到 3-碘 -4-甲基 -N-(4-***啉 -4-甲基 -3-三氟甲基-苯基) -苯甲酰胺 (黄色油状物， 0.23 g)，收率 53%。 1H-NMR (300MHz, CDC1₃): 8.29(d, J=0.9Hz, IH), 7.85-7.90(m, 3H), 7.74-7.80(m, 2H)， 7.34(d, J= 6.0Hz, IH), 3.72(m, 4H)， 2.48-2.50(m, 7H)。 MSm/z (ESI): 505.1[M+H]。 3-iodo-4-methylbenzoic acid (0.25 g, 0.93 mmol) and 4-morpholine-4-methyl-3-trifluoromethyl-phenylamine (0.22 g, 0.85 mmol) were dissolved in N,N- Dimethylformamide (10 mL) was added to 2-(7-azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate (0.39) under ice cooling. _& 1.02 mmol) and diisopropylethylamine (0.20 mL, 1.27 mmol). The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc EtOAc. 3-iodo-4-methyl-N-(4-morpholine-4-methyl-3-trifluoromethyl-phenyl)-benzamide (yellow oil, 0.23 g), yield 53% . 1H-NMR (300MHz, CDC1 ₃ ): 8.29 (d, J = 0.9Hz, IH), 7.85-7.90 (m, 3H), 7.74-7.80 (m, 2H), 7.34 (d, J = 6.0Hz, IH ), 3.72 (m, 4H), 2.48-2.50 (m, 7H). MS m/z (ESI): 505.1 [M+H].

以 3-碘 -4-甲基-苯甲酸和 3-氟 -5-碘 -4-甲基-苯甲酸为原料，用不同的哌嗪及其衍生物，哌啶及其衍生物和高哌嗪及其衍生物等环状胺替换***啉，采用中间体 32相同的方法合成得到以下中间体 33〜中间体 51。

Using 3-iodo-4-methyl-benzoic acid and 3-fluoro-5-iodo-4-methyl-benzoic acid as starting materials, using different piperazine and its derivatives, piperidine and its derivatives and high piperazine The following intermediate 33 to intermediate 51 were synthesized by the same method as Intermediate 32 by substituting a cyclic amine such as a azine or a derivative thereof for morpholine.

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CS.S.0/CT0ZN3/X3d 中间体 52: N-(3-碘 -4-甲基-苯基) -4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯甲酰胺 CS.S.0/CT0ZN3/X3d Intermediate 52: N-(3-iodo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

第一步： 4-甲基 -3-三氟甲基 -苯甲酸乙酯 First step: 4-methyl-3-trifluoromethyl-benzoic acid ethyl ester

将 4-甲基 -3-三氟甲基苯甲酸 (2.0 g 9.80 mmol) 和浓硫酸（0.5 mL)溶于无水乙醇（30 mL)中，氮气保护下加热至 85°C反应过夜。反应完毕后，减压除去大部分溶剂，剩余物用乙酸乙酯溶解，有机相依次用饱和碳酸氢钠水溶液，水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得中间体 4-甲基 -3-三氟甲基 -苯甲酸乙酯 (淡黄色油状物， 2.2 g 1H-NMR (300MHz, DMSO-d₆): δ 8.26(s, IH), 8.08 (dd，J=6.0， 0.9 Hz, IH), 7.35(d, J=6.0Hz, IH), 4.39(q, J=5.4Hz, 2H), 2.52(s, 3H), 1.39(t，J=5.4Hz， 3H)。 MSm/z (ESI): 233.1 [M+H]。 4-Methyl-3-trifluoromethylbenzoic acid (2.0 g 9.80 mmol) and concentrated sulfuric acid (0.5 mL) were dissolved in anhydrous ethanol (30 mL) and heated to 85 ° C under N2 overnight. After the completion of the reaction, the solvent was evaporated to dryness crystals crystals crystals crystals crystals 4-methyl-3-trifluoromethyl-benzoic acid ethyl ester (light yellow oil, 2.2 g 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.26 (s, IH), 8.08 (dd, J = 6.0, 0.9 Hz, IH), 7.35 (d, J = 6.0 Hz, IH), 4.39 (q, J = 5.4 Hz, 2H), 2.52 (s, 3H), 1.39 (t, J = 5.4 Hz, 3H) MSm/z (ESI): 233.1 [M+H].

第二步： 4-溴甲基 -3-三氟甲基 -苯甲酸乙酯 Second step: 4-bromomethyl-3-trifluoromethyl-benzoic acid ethyl ester

将 4-甲基 -3-三氟甲基苯甲酸乙酯 (2.2 g, 9.6 mmol) 禾卩苯甲酰过氧（0.02_& 0.1 mmol) 溶于无水四氯化碳 (100 mL)中，氮气保护下向上述反应液中加入 N-溴代丁二酰亚胺（1.9 _& 10.6 mmol 加完，反应液加热至 85°C搅拌过夜。反应完毕后，减压除去大部分溶剂，剩余物用二氯甲烷溶解，有机相依次用饱和碳酸氢钠溶液，水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到中间体 4-溴甲基 -3-三氟甲基 -苯甲酸乙酉旨 (淡黄色固体， 1.4 g)。 1H-NMR (300MHz, DMSO-d₆): δ 8.25(d, J=6.0Hz, 1H)， 8.21(s, 1H)， 7.80(d, J=6.0Hz, 1H)， 4.72(s, 2H), 4.42(q, J=5.4Hz, 2H), 1.41(t, J=5.4Hz, 3H)。 MS m/z (ESI): 311.0 [M+H]。 Ethyl 4-methyl-3-trifluoromethylbenzoate (2.2 g, 9.6 mmol) and benzoyl peroxide (0.02 _& 0.1 mmol) were dissolved in anhydrous carbon tetrachloride (100 mL). N-bromosuccinimide was added to the above reaction solution under nitrogen (1.9 _& 10.6 mmol), and the reaction mixture was heated to 85 ° C and stirred overnight. After the reaction was completed, most of the solvent was removed under reduced pressure. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. Benzyl-3-trifluoromethyl-benzoic acid ethyl ester (light yellow solid, 1.4 g). 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.25 (d, J = 6.0 Hz, 1H), 8.21 (s , 1H), 7.80(d, J=6.0Hz, 1H), 4.72(s, 2H), 4.42(q, J=5.4Hz, 2H), 1.41(t, J=5.4Hz, 3H) MS m/ z (ESI): 311.0 [M+H].

第三步： 4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基 -苯甲酸乙酯 Step 3: 4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid ethyl ester

将 4-溴甲基 -3-三氟甲基 -苯甲酸乙酯 (1.3 _& 4.4 mmol)溶于无水 N，N-二甲基甲酰胺Ethyl 4-bromomethyl-3-trifluoromethyl-benzoate (1.3 _& 4.4 mmol) was dissolved in anhydrous N,N-dimethylformamide

(10mL)中，冰浴冷却下向其中滴加 N-甲基哌嗪（657 m_& 6.6 mmol), 滴加完毕，室温反应过夜。反应结束后，反应液用乙酸乙酯和水稀释，分出有机相，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。浓缩液用硅胶柱层析分离纯化得到中间体 4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基 -苯甲酸乙酯 (淡黄色油状物， 1.44 g)。 1H-NMR (300MHz, DMSO-d₆): δ 8.20-8.24(m, 2Η), 7.97(d, J=7.2Hz, 1H)， 4.39(q, J=5.4Hz, 2H), 3.72(s, 2H), 2.85(m, 4H), 3.72(m, 4H), 2.29(s, 3H), 1.41(t,J=5.4Hz, 3H) 。 MS m/z (ESI): 331.2 [M+H] (10 mL), N-methylpiperazine (657 m _& 6.6 mmol) was added dropwise thereto under ice cooling, and the mixture was added dropwise, and the mixture was allowed to react at room temperature overnight. After the reaction, the reaction mixture was diluted with EtOAc EtOAc. The concentrate was purified by silica gel column chromatography eluting eluting elut elut eluting eluting . 1H-NMR (300MHz, DMSO-d ₆ ): δ 8.20-8.24 (m, 2 Η), 7.97 (d, J = 7.2 Hz, 1H), 4.39 (q, J = 5.4 Hz, 2H), 3.72 (s, 2H), 2.85 (m, 4H), 3.72 (m, 4H), 2.29 (s, 3H), 1.41 (t, J = 5.4 Hz, 3H). MS m/z (ESI): 331.2 [M+H]

第四步： 4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯甲酸 Step 4: 4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid

将 4-((4-甲基哌嗪基)甲基) -3-三氟甲基苯甲酸甲酯（1.35 _& 4.1 mmol)溶于甲醇（15 mL) 中，冰浴冷却下向其中滴加氢氧化钠水溶液 (0.82 g氢氧化钠溶于 3.5 mL水中配成的溶液)，滴加完毕室温搅拌过夜。反应完毕，用稀盐酸调 pH至 6.0左右，减压浓缩。浓缩液用四氢呋喃稀释，过滤除去固体，滤液浓缩得到中间体 4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基 -苯甲酸（白色固体， 1.2 g -NMR (300MHz, DMSO-d₆): δ 8.48(s， IH), 8.27(s, 1H)， 8.15(d， J=6.0Hz， IH), 7.82(d, J=6.0Hz, IH), 3.78(s, 2H), 3.20(m, 4H)， 2.78(s, 3H), 2.7 l(m, 4H)。 MS m/z (ESI): 303.1[M+H Methyl 4-((4-methylpiperazinyl)methyl)-3-trifluoromethylbenzoate (1.35 _& 4.1 mmol) was dissolved in methanol (15 mL). Aqueous sodium hydroxide solution (0.82 g of sodium hydroxide dissolved in 3.5 mL of water) was added and stirred at room temperature overnight. After the reaction was completed, the pH was adjusted to about 6.0 with dilute hydrochloric acid and concentrated under reduced pressure. The concentrate was diluted with tetrahydrofuran, the solid was filtered, and the filtrate was concentrated to give 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid as a white solid. (300MHz, DMSO-d ₆ ): δ 8.48(s, IH), 8.27(s, 1H), 8.15(d, J=6.0Hz, IH), 7.82(d, J=6.0Hz, IH), 3.78( s, 2H), 3.20(m, 4H), 2.78(s, 3H), 2.7 l(m, 4H) MS m/z (ESI): 303.1 [M+H

第五步： N-(3-碘 -4-甲基-苯基) -4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯甲酰胺 Step 5: N-(3-Iodo-4-methyl-phenyl)-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

采用中间体 32第四步类似的缩合方法合成得到中间体 N-(3-碘 -4-甲基-苯基) -4-(4-甲基- 哌嗪小基甲基 )—3-三氟甲基-苯甲酰胺 (淡黄色固体， 908 mg)。 1H-NMR (300MHz, DM SO-d₆): δ 8.24(s, IH), 8.23(s, IH), 8.09(d， J=6.0Hz, 1H)， 7.92(d, J=6.0Hz, IH), 7.58(dd, J=6.0, 1.5Hz, IH), 7.2 l(d, J=6.0Hz, 1H)， 3.70(s, 2H), 2.23-2.55(m, 8H)， 2.36(s, 3H), 2.27(s, 3H)。 MS m/z S-i-¾½o -¾ - -¾i 5-¾i ii-s ot7The intermediate N-(3-iodo-4-methyl-phenyl)-4-(4-methyl-piperazine small group methyl)-3-three was synthesized by the similar condensation method of Intermediate 32. Fluoromethyl-benzamide (light yellow solid, 908 mg). 1H-NMR (300MHz, DM SO-d ₆ ): δ 8.24(s, IH), 8.23(s, IH), 8.09(d, J=6.0Hz, 1H), 7.92(d, J=6.0Hz, IH ), 7.58 (dd, J=6.0, 1.5Hz, IH), 7.2 l(d, J=6.0Hz, 1H), 3.70(s, 2H), 2.23-2.55(m, 8H), 2.36(s, 3H) ), 2.27(s, 3H). MS m/z Si-3⁄41⁄2o -3⁄4 - -3⁄4i 5-3⁄4i ii-s ot7

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CS.S.0/CT0ZN3/X3d LLOL iOZ OAV 将 2-溴甲基 -4-硝基 -苯甲酸甲酯 (2 g， 10.9 mmol)溶于四氢呋喃 (6 mL)中，冰浴冷却下向其中滴加环丙甲基胺 (1 & 14.1 mmol), 加完反应液加热回流 8小时。反应液冷却至室温，析出白色固体，过滤，滤饼用少量乙醇洗涤，干燥即得 2-环丙甲基 -5-硝基 -2,3-二氢-异吲哚 -1-酮 (黄色固体， 1 g)。 ifi-NMR (300MHz, DMSO-d₆): δ 8.5 l(m, IH), 8.33(m, IH), 7.9 l(m, 1H)， 4.69(s， 2H), 3.43(m, 2H), 1.06(m, IH), 0.53(m, 2H)， 0.343(m, 2H)。MS m/z (ESI): 233.1[M+H]。第三步： 5-氨基 -2-环丙甲基 -2，3-二氢-异吲哚 -1-酮 CS.S.0/CT0ZN3/X3d LLOL iOZ OAV 2-Bromomethyl-4-nitro-benzoic acid methyl ester (2 g, 10.9 mmol) was dissolved in tetrahydrofuran (6 mL). EtOAc (1 & 14.1 mmol) ), the reaction solution was heated and refluxed for 8 hours. The reaction solution was cooled to room temperature, a white solid was precipitated, filtered, and the filter cake was washed with a small amount of ethanol and dried to give 2-cyclopropylmethyl-5-nitro-2,3-dihydro-isoindole-1-one (yellow Solid, 1 g). Ifi-NMR (300MHz, DMSO-d ₆ ): δ 8.5 l (m, IH), 8.33 (m, IH), 7.9 l (m, 1H), 4.69 (s, 2H), 3.43 (m, 2H), 1.06 (m, IH), 0.53 (m, 2H), 0.343 (m, 2H). MS m/z (ESI): 233.1 [M+H]. The third step: 5-amino-2-cyclopropylmethyl-2,3-dihydro-isoindole-1-one

采用中间体 32第三步类似的方法合成得到中间体 5-氨基 -2-环丙甲基 -2,3-二氢-异吲哚 -1-酮 (黄色固体， 502 mg)。 1H-NMR (300MHz, DM SO-d₆): S 7.29(m， IH), 6.59(m, 2H), 5.71(s, 2H), 4.34(s, 2H), 3.26(m, 2H), 0.98(m， 1H)， 0.48(m， 2H), 0.24(m, 2H)。 MS m/z (ESI): 203.1[M+H The intermediate 5-amino-2-cyclopropanyl-2,3-dihydro-isoindole-1-one (yellow solid, 502 mg) was obtained using a similar procedure from Intermediate 32. 1H-NMR (300MHz, DM SO-d ₆ ): S 7.29 (m, IH), 6.59 (m, 2H), 5.71 (s, 2H), 4.34 (s, 2H), 3.26 (m, 2H), 0.98 (m, 1H), 0.48 (m, 2H), 0.24 (m, 2H). MS m/z (ESI): 203.1 [M+H

第四步： N-(2-环丙甲基 -1-氧代 -2，3-二氢 -IH-异吲哚 -5-基 3-碘 -4-甲基苯甲酰胺 Step 4: N-(2-Cyclopropylmethyl-1-oxo-2,3-dihydro-IH-isoindole-5-yl 3-iodo-4-methylbenzamide

采用中间体 31第四步类似的缩合方法合成得到中间体 Ν-(2-环丙甲基 -1-氧代 -2,3-二氢 -1Η-异吲哚 -5-基) -3-碘 -4-甲基苯甲酰胺 (黄色固体， 463 mg)。 1H-NMR (300MHz, CDC1₃): δ 8.42(s, IH), 8.32(m, IH), 8.21 (s, IH), 7.77(m, 2H), 7.42(m, IH), 7.33(m, IH), 4.49(s， 2H), 3.45(m, 2H), 2.48(s, 3H), 1.03(m, IH), 0.57(m, 2H), 0.3 l(m, 2H)。 MS m/z (ESI): 447.1[M+H]。中间 55: N-(2-环丙甲基 -3-氧代 -2，3-二氢 -IH-异吲哚 -5-基 3-碘 -4-甲基-苯甲酰胺

The intermediate Ν-(2-cyclopropylmethyl-1-oxo-2,3-dihydro-1Η-isoindol-5-yl)-3- is synthesized by a similar condensation method in the fourth step of intermediate 31. Iodo-4-methylbenzamide (yellow solid, 463 mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.42 (s, IH), 8.32 (m, IH), 8.21 (s, IH), 7.77 (m, 2H), 7.42 (m, IH), 7.33 (m, IH), 4.49 (s, 2H), 3.45 (m, 2H), 2.48 (s, 3H), 1.03 (m, IH), 0.57 (m, 2H), 0.3 l (m, 2H). MS m/z (ESI): 447.1 [M+H]. Intermediate 55: N-(2-cyclopropylmethyl-3-oxo-2,3-dihydro-IH-isoindole-5-yl 3-iodo-4-methyl-benzamide

采用中间体 54同样的方法合成，得到中间体 N-(2-环丙甲基 -3-氧代 -2,3-二氢 -1H-异吲哚 -5-基) -3-碘 -4-甲基-苯甲酰胺 (橙色固体， 490 mg)。 The same procedure as Intermediate 54 was carried out to give the intermediate N-(2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindole-5-yl)-3-iodo-4. -Methyl-benzamide (orange solid, 490 mg).

第一步： 2-溴甲基 -5-硝基 -苯甲酸甲酯 First step: 2-bromomethyl-5-nitro-benzoic acid methyl ester

1H-NMR (300MHz, DM SO-d₆): δ 8.57(d, J=6.0Hz, IH), 8.43(dd, J=1.5, 6.0Hz, IH), 7.90(d, J=6.0Hz, IH), 5.07(s, 2H), 3.91(s, 3H)。 MSm/z (ESI): 274.0[M+H]。 1H-NMR (300MHz, DM SO-d ₆ ): δ 8.57 (d, J = 6.0 Hz, IH), 8.43 (dd, J = 1.5, 6.0 Hz, IH), 7.90 (d, J = 6.0 Hz, IH) ), 5.07(s, 2H), 3.91(s, 3H). MS m / z (ESI): 274.0 [M+H].

第二步： 2-环丙甲基 -6-硝基 -2，3-二氢-异吲哚 -1-酮 Step 2: 2-Cyclopropylmethyl-6-nitro-2,3-dihydro-isoindole-1-one

1H-NMR (300MHz, DM SO-d₆): δ 8.47(dd, J=1.5, 6.0Hz, IH), 8.33(d, J=1.5Hz, 1H)， 7.91(d,1H-NMR (300MHz, DM SO-d ₆ ): δ 8.47 (dd, J = 1.5, 6.0 Hz, IH), 8.33 (d, J = 1.5 Hz, 1H), 7.91 (d,

J=6.0Hz, 1H)， 4.73(s, 2H), 3.42(d, J=5.4Hz, 2H), 1.06(m， 1H)， 0.53(m, 2H), 0.32(m, 2H)。 MS m/z (ESI): 233.1[M+H J = 6.0 Hz, 1H), 4.73 (s, 2H), 3.42 (d, J = 5.4 Hz, 2H), 1.06 (m, 1H), 0.53 (m, 2H), 0.32 (m, 2H). MS m/z (ESI): 233.1 [M+H

第三步： 6-氨基 -2-环丙甲基 -2，3-二氢-异吲哚 -1-酮 The third step: 6-amino-2-cyclopropylmethyl-2,3-dihydro-isoindole-1-one

1H-NMR (300MHz, DMSO-d₆): δ 7.20(d, J=6.0Hz, IH), 6.82(s, IH), 6.78(d, J=6.0Hz, IH), 5.28(s, 2H), 4.34(d, J=5.4Hz, 2H), 0.99(m， 1H)， 0.49(m， 2H), 0.27(m, 2H)。 MS m/z (ESI) : 203.1[M+H 1H-NMR (300MHz, DMSO-d ₆ ): δ 7.20 (d, J = 6.0 Hz, IH), 6.82 (s, IH), 6.78 (d, J = 6.0 Hz, IH), 5.28 (s, 2H) , 4.34 (d, J = 5.4 Hz, 2H), 0.99 (m, 1H), 0.49 (m, 2H), 0.27 (m, 2H). MS m/z (ESI): 203.1 [M+H

第四步： N-(2-环丙甲基 -3-氧代 -2，3-二氢 -IH-异吲哚 -5-基) -3-碘 -4-甲基-苯甲酰胺 Fourth step: N-(2-cyclopropanyl-3-oxo-2,3-dihydro-IH-isoindole-5-yl)-3-iodo-4-methyl-benzamide

1H-NMR (300MHz, DMSO-d₆): δ 10.44(s, 1H)， 8.43(s, 1H)， 8.16(s， 1H)， 7.95(d, J=6.0Hz, IH), 7.93(d, J=6.0Hz, IH), 7.59(d, J=6.0Hz, IH), 7.51(d, J=6.0Hz, IH), 4.53(s, IH), 2.88(s, 3H), 2.72(s, 2H), 2.44(s, 3H), 1.05(m, IH), 0.52(m, 2H), 0.3 l(m, 2H)。 MSm/z (ESI): 447.1[M+H]。中间体 56: 3-碘 -4-甲基 -N-[3-(4-甲基 -咪唑 -1-基) -5-三氟甲基-苯基] -苯甲酰胺 1H-NMR (300MHz, DMSO-d ₆ ): δ 10.44 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 6.0 Hz, IH), 7.93 (d, J=6.0Hz, IH), 7.59(d, J=6.0Hz, IH), 7.51(d, J=6.0Hz, IH), 4.53(s, IH), 2.88(s, 3H), 2.72(s, 2H), 2.44 (s, 3H), 1.05 (m, IH), 0.52 (m, 2H), 0.3 l (m, 2H). MS m / z (ESI): 447.1 [M+H]. Intermediate 56: 3-iodo-4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-benzamide

第一步： 3-(4-甲基 -咪唑 -1-基) -5-三氟甲基 -苯胺

First step: 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-aniline

将 3-溴 -5- (三氟甲基)苯胺 (500 mg, 2.1 mmol)、 4-甲基 -1H-咪唑 (205 mg,2.5 mmol)和碳酸钾 (345 mg 2.5 mmol)和碘化亚铜 (60 m_&0.3 mmol)和 8-羟基喹啉 (44 mg, 0.3 mmol)溶解在二甲亚砜 (3 mL)中，氩气鼓泡 5分钟，反应混合物在氩气保护下加热至 120oC搅拌过夜。反应完毕，加水稀释，二氯甲烷萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到中间体 3-(4-甲基 -咪唑 -1-基) -5-三氟甲基 -苯胺 (黄色固体， 400 mg -NMR (300MHz,CDCl₃): δ 7.74(s, IH), 6.99(s, 1H)， 6.92(s, 1H)， 6.83(s, lH), 6.77(s, 1H)， 4.13(s，2H)， 2.27(s， 3H)。 MSm/z (ESI): 242.1[M+H]。 3-bromo-5-(trifluoromethyl)aniline (500 mg, 2.1 mmol), 4-methyl-1H-imidazole (205 mg, 2.5 mmol) and potassium carbonate (345 mg 2.5 mmol) and iodide Copper (60 m _& 0.3 mmol) and 8-hydroxyquinoline (44 mg, 0.3 mmol) were dissolved in dimethyl sulfoxide (3 mL), argon was bubbled for 5 minutes, and the reaction mixture was heated to 120 ° C under argon atmosphere. Stir overnight. After completion of the reaction, the mixture was diluted with EtOAc EtOAc. The residue was separated and purified by silica gel column chromatography to give Intermediate 3- (4-methyl - imidazol-1-yl) -5-trifluoromethyl - phenylamine (yellow solid, 400 mg -NMR (300MHz, CDCl 3): δ 7.74(s, IH), 6.99(s, 1H), 6.92(s, 1H), 6.83(s, lH), 6.77(s, 1H), 4.13(s, 2H), 2.27(s, 3H). MS m / z (ESI): 242.1 [M+H].

第二步： 3-碘 -4-甲基 -N-[3-(4-甲基 -咪唑 -1-基) -5-三氟甲基-苯基] -苯甲酰胺 Step 2: 3-iodo-4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-benzamide

采用中间体 32第四步类似的缩合方法合成得到中间体 3-碘 -4-甲基 -N-[3-(4-甲基 -咪唑 Intermediate 3-iodo-4-methyl-N-[3-(4-methyl-imidazole) was synthesized by the similar condensation method of Intermediate 32.

-1-基) -5-三氟甲基-苯基] -苯甲酰胺 (黄色固体， 355 mg)。 1H-NMR (300MHz，CDCl₃): δ 8.32(s, IH), 8.18(m， 2H), 7.79(m, 3H), 7.38(m, 2H), 7.09(s, 1H)， 2.51(s, 3H), 2.30(s, 3H)。 MS m/z (ESI): 485.1[M+H 中间体 57: 3-碘 -4- -苯甲酰胺

-1-yl)-5-trifluoromethyl-phenyl]-benzamide (yellow solid, 355 mg). 1H-NMR (300MHz, CDCl ₃ ): δ 8.32 (s, IH), 8.18 (m, 2H), 7.79 (m, 3H), 7.38 (m, 2H), 7.09 (s, 1H), 2.51 (s, 3H), 2.30(s, 3H). MS m/z (ESI): 485.1 [M+H Intermediate 57: 3-iodo-4-benzamide

第一步： 3-(1-甲基 -1H-吡唑 -4-基) -5-三氟甲基 -苯胺 First step: 3-(1-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl-aniline

将 3-溴 -5- (三氟甲基)苯胺 (500 mg, 2.1mmol), 1-甲基 -4-(4，4，5，5-四甲基 -1，3，2-二氧杂戊硼烷 -2-基) -1H-吡唑 (655 mg,3.1 mmol)和四三苯基磷钯 (121 mg, 0.1 mmol)和碳酸钠 (668 mg, 6.3 mmol)溶解在水 (3 mL)和二氧六环 (6 mL)的混合溶剂中，氩气鼓泡 5分钟，加热至 80°C 搅拌过夜。反应完毕，用二氯甲烷萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到 3-G-甲基 -1H-吡唑 -4-基) -5-三氟甲基 -苯胺 (黄色固体， 480 mg)。 iH-NMR (300MHz,CDCl₃): δ 7.73(s, IH), 7.60(s, IH), 7.06(s, IH), 6.91(s, IH), 6.75(s, lH), 3.94(s, 3H)。 MSm/z (ESI): 242.1[M+H]。 3-Bromo-5-(trifluoromethyl)aniline (500 mg, 2.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Heteroborolan-2-yl)-1H-pyrazole (655 mg, 3.1 mmol) and tetratriphenylphosphine palladium (121 mg, 0.1 mmol) and sodium carbonate (668 mg, 6.3 mmol) dissolved in water (3 In a mixed solvent of mL) and dioxane (6 mL), argon was bubbled for 5 minutes, heated to 80 ° C and stirred overnight. After completion of the reaction, the mixture was extracted with methylene chloride. The residue was purified by silica gel column chromatography eluting eluting eluting eluting _{iH-NMR (300MHz, CDCl 3} ): δ 7.73 (s, IH), 7.60 (s, IH), 7.06 (s, IH), 6.91 (s, IH), 6.75 (s, lH), 3.94 (s, 3H). MS m / z (ESI): 242.1 [M+H].

第二步： 3-碘 -4-甲基 -N-[3-(l-甲基 -IH-吡唑 -4-基) -5-三氟甲基-苯基] -苯甲酰胺 Step 2: 3-iodo-4-methyl-N-[3-(l-methyl-IH-pyrazol-4-yl)-5-trifluoromethyl-phenyl]-benzamide

采用中间体 32第四步类似的缩合方法合成得到中间体 3-碘 -4-甲基 -N-[3-(l-甲基 -1H-吡唑 -4-基) -5-三氟甲基-苯基] -苯甲酰胺 (黄色固体， 420 mg)。 1H-NMR (300MHz,CDCl₃): δ 8.32(s, IH), 8.05(m， 2H), 7.80(s, 1H)， 7.77(m, 1H)， 7.70(m, 2H), 7.47(s, IH), 7.34(m, IH), 3.95(s, 3H), 2.50(s, 3H)。 MSm/z (ESI): 486.1 [M+H]。中间体 58: N-(3-咪唑 -

The intermediate 3-iodo-4-methyl-N-[3-(l-methyl-1H-pyrazol-4-yl)-5-trifluoromethyl was synthesized by the similar condensation method of Intermediate 32. Base-phenyl]-benzamide (yellow solid, 420 mg). 1H-NMR (300MHz, CDCl ₃ ): δ 8.32 (s, IH), 8.05 (m, 2H), 7.80 (s, 1H), 7.77 (m, 1H), 7.70 (m, 2H), 7.47 (s, IH), 7.34 (m, IH), 3.95 (s, 3H), 2.50 (s, 3H). MS m/z (ESI): 486.1 [M+H]. Intermediate 58: N-(3-imidazole-

采用中间体 57相同的方法合成得到中间体 N-(3-咪唑 -1-基 -5-三氟甲基-苯基) -3-碘 -4-甲基-苯甲酰胺（黄色固体， 235 mg)。 1H-NMR (300MHz, CDC1₃): δ 8.32(s, IH), 8.18(m， 2H), 7.79(m, 3H), 7.38(m, 2H), 7.09(s, lH), 2.51(s, 3H)。 MSm/z (ESI): 472.1[M+H]。中间体 59 : N-(3-碘 -4-甲基-苯基) -4-(4-甲基 -咪唑 - 1 -基) -3-三氟甲基-苯甲酰胺

The intermediate N-(3-imidazol-1-yl-5-trifluoromethyl-phenyl)-3-iodo-4-methyl-benzamide (yellow solid, 235) Mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.32(s, IH), 8.18(m, 2H), 7.79(m, 3H), 7.38(m, 2H), 7.09(s, lH), 2.51(s, 3H). MS m/z (ESI): 4721. [M+H]. Intermediate 59: N-(3-Iodo-4-methyl-phenyl)-4-(4-methyl-imidazolium-1-yl)-3-trifluoromethyl-benzamide

以 3—碘 -4—甲基苯胺 _& 5.2 mmol)和 4-(4-甲基 -1H-咪唑小基) -3- (三氟甲基)苯甲酸 [采用文献 WO2004/29038A1的方法合成得到] ( 1.5 _& 7.1 mmol)为原料，采用中间体 32第四步类似的方法合成得到中间体 N-(3-碘 -4-甲基-苯基) -4-(4-甲基 -咪唑 -1-基) -3-三氟甲基-苯甲酰胺（淡黄色固体， 1.4 g, 收率 56.3%)。 1H-NMR (300MHz, CD₃OD): δ 9.48s, IH)， 8.54(s, 1H)， 8.49(s， IH), 8.32-8.34(m, 4H)， 7.96(s, 1H)， 7.66(dd, J=8.0, 2.0Hz, 1H)， 7.32(d, J=8.0Hz, 1H)， 2.49(s, 3H), 2.44(s, 3H)。 MSm/z (ESI):486.2[M+H]。中间体 60: N-[4-(4-环丙甲基 -[1，4]二氮杂环庚烷 -1-基甲基 )-3-三氟甲基-苯基] -3-碘 -4-甲基- 苯甲酰胺

3-Iodo-4-methylaniline _& 5.2 mmol) and 4-(4-methyl-1H-imidazolyl)-3-(trifluoromethyl)benzoic acid [synthesized by the method of WO2004/29038A1] (1.5 _& 7.1 mmol) was used as the starting material, and the intermediate N-(3-iodo-4-methyl-phenyl)-4-(4-methyl-imidazole- 1-yl)-3-trifluoromethyl-benzamide (light yellow solid, 1.4 g, yield 56.3%). 1H-NMR (300MHz, CD ₃ OD): δ 9.48s, IH), 8.54 (s, 1H), 8.49 (s, IH), 8.32-8.34 (m, 4H), 7.96 (s, 1H), 7.66 ( Dd, J = 8.0, 2.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H), 2.44 (s, 3H). MS m / z (ESI): 486.2 [M+H]. Intermediate 60: N-[4-(4-Cyclopropylmethyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-iodo -4-methyl-benzamide

将 4-[4-(3-碘 -4-甲基 -苯甲酰胺) -2-三氟甲基-节基] -[1，4]二氮杂环庚烷 -1-甲酸叔丁酯 (450 mg, 0.73 mmol)溶于二氯甲烷 (10 mL)中，冰浴冷却下向其中滴加 4N的氯化氢的 1， 4-二氧六环溶液 (2 mL)，滴加完毕，室温反应 2小时。减压除去过量溶剂和氯化氢，析出白色固体 (480 mg)，直接用于下步反应。 4-[4-(3-Iodo-4-methyl-benzamide)-2-trifluoromethyl-]]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (450 mg, 0.73 mmol) was dissolved in dichloromethane (10 mL), and 4N hydrogen chloride in 1,4-dioxane solution (2 mL) was added dropwise under ice-cooling. 2 hours. Excess solvent and hydrogen chloride were removed under reduced pressure to precipitate a white solid (480 mg) which was used directly for the next step.

将上述白色固体 (150 mg,0.29 mmol)和环丙基甲醛 (61 mg, 0.87 mmol)溶解在甲醇 (5 mL) 中，加入冰醋酸 (10 uL)后在室温搅拌 1小时。冰浴冷却下向其中加入硼氢化钠固体 (29 mg)，加完后室温搅拌过夜，薄层色谱监测显示反应结束后，向反应液中加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取 (10mLx3)，合并有机相，有机相分别用饱和碳酸氢钠，水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到中间体 N-[4-(4-环丙甲基 -[1，4]二氮杂环庚烷 -1-基甲基 )-3-三氟甲基-苯基] -3-碘 -4-甲基-苯甲酰胺 (黄色固体， 120 mg)。1H-NMR (300MHz, CDCl₃) S 9.18(s， IH), 8.37(d, J=1.2Hz, IH), 7.95-7.97(m, 2H), 7.82-7.85(dd, J=7.8, 1.2Hz, IH), 7.62-7.64(d, J=8.1Hz, IH), 7.28-7.3 l(d, J=7.8Hz, 1H)， 3.72(s, 2H), 3.18(t, J=2.1Hz, 2H), 3.05-3.07(m, 2H), 2.77-2.82(m, 2H), 2.69-2.70(m, 4H)， 2.46(s, 3H), 0.84-0.87(m, IH), 0.62-0.67(m, 2H), 0.59-0.61(m, 2H), 0.21-0.23(m, 2H)。 MS m/z (ESI): 572.1[M+H The above white solid (150 mg, 0.29 mmol) and cyclopropylcarbaldehyde (61 mg, 0.87 mmol) were dissolved in methanol (5 mL). Sodium borohydride solid (29 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight, and the mixture was monitored by thin-layer chromatography. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was combined and washed with EtOAc EtOAc. The residue was purified by silica gel column chromatography toield toield of N-[4-(4-cyclopropylmethyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethyl -Phenyl]-3-iodo-4-methyl-benzamide (yellow solid, 120 mg). 1H-NMR (300MHz, CDCl ₃ ) S 9.18(s, IH), 8.37 (d, J=1.2Hz, IH), 7.95-7.97(m, 2H), 7.82-7.85 (dd, J=7.8, 1.2Hz , IH), 7.62-7.64 (d, J=8.1Hz, IH), 7.28-7.3 l(d, J=7.8Hz, 1H), 3.72(s, 2H), 3.18(t, J=2.1Hz, 2H ), 3.05-3.07(m, 2H), 2.77-2.82(m, 2H), 2.69-2.70(m, 4H), 2.46(s, 3H), 0.84-0.87(m, IH), 0.62-0.67(m , 2H), 0.59-0.61 (m, 2H), 0.21-0.23 (m, 2H). MS m/z (ESI): 572.1 [M+H

以 N-(4-[l，4]二氮杂 -1-基甲基 -3-三氟甲基-苯基) -3-碘 -4-甲基 -苯甲酰胺和丙酮、乙醛为 N-(4-[l,4]diazepin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-iodo-4-methyl-benzamide and acetone, acetaldehyde

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CS.S.0/CT0ZN3/X3d LLOL iOZ OAV 第四步： 3—碘—4- (四氢 -2H-吡喃 -2-氧甲基)苯胺 CS.S.0/CT0ZN3/X3d LLOL iOZ OAV Step 4: 3-Iodo-4-(tetrahydro-2H-pyran-2-oxomethyl)aniline

将 1- (四氢 -2H-吡喃 -2-氧甲基 )-3-碘 -4-硝基苯（400 mg， 1.1 mmol) 铁粉（368 mg， 6.6 mmol) 和氯化铵（528 mg， 9.9 mmol) 溶于乙醇（5 mL) 和水（5 mL)， 80 °C搅拌反应 3 ho 反应结束后，过滤，蒸除溶剂，残留物加入水，乙酸乙酯萃取，合并有机层，洗涤、干燥，蒸除溶剂得到白色固体（360 mg， 98%)。 1H-NMR(CDC1₃, 400ΜΗζ): δ 1.60_1.92(m， 6Η)， 3.57-3.59(m, 1Η), 3.95_3.97(m， 1H), 4.41_4.44(m， 1H), 4.69_4.77(m， 2H), 6.67_6.70(m， 1H), 7.20-7.28(m, 1H), 8.68(m， 1H). MSm/z (ESI): 333.8[M+H]。 1-(Tetrahydro-2H-pyran-2-oxomethyl)-3-iodo-4-nitrobenzene (400 mg, 1.1 mmol) iron powder (368 mg, 6.6 mmol) and ammonium chloride (528) Mg, 9.9 mmol) Dissolved in ethanol (5 mL) and water (5 mL). The reaction mixture was stirred at 80 ° C. After the reaction was completed, the mixture was filtered and evaporated to dryness. Washing, drying and evaporation of solvent gave a white solid (360 mg, 98%). 1H-NMR (CDC1 ₃ , 400ΜΗζ): δ 1.60_1.92 (m, 6Η), 3.57-3.59 (m, 1Η), 3.95_3.97 (m, 1H), 4.41_4.44 (m, 1H), 4.69_4.77(m, 2H), 6.67_6.70 (m, 1H), 7.20-7.28 (m, 1H), 8.68 (m, 1H). MS m/z (ESI): 333.8 [M+H].

第五步： N-[3-碘 -4- (四氢 -2H-B比喃 -2-氧甲基)苯基] -3-三氟甲基 -4-(4-甲基哌嗪基小甲基)苯甲酰胺 Step 5: N-[3-Iodo-4-(tetrahydro-2H-Bpyran-2-oxomethyl)phenyl]-3-trifluoromethyl-4-(4-methylpiperazinyl) Small methyl)benzamide

将 3-三氟甲基 -4-(4-甲基哌嗪基小甲基)苯甲酸（88 mg， 0.29 mmol) 溶于 N，N-二甲基甲酰胺（10 mL), 加入 N，N-二异丙基乙胺（66 L, 0.39 mmol) 禾 B 2-(7-偶氮苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯（ 120 g， 0.31 mmol),搅拌 5min后加入 3-碘 -4- (四氢 -2H- 吡喃 -2-氧甲基)苯胺（89 mg， 0.27 mmol), 室温搅拌反应 26 h。反应结束后体系加入水，乙酸乙酯萃取两次。合并有机层，柱层析纯化得到白色固体（60 mg， 36% ) o 1H-NMR(CD₃OD, 400MHz): δ 1.70-1.92(m, 6Η), 2.67(br, 8H)， 3.01(s, 4H)， 3.58— 3.61(m， 1H)， 3.87(s, 2H), 3.95-3.97(m, 1H), 4.48-4.5 l(m, 1H), 4.74_4.90(m， 2H), 7.46_7.48(m， 1H), 7.73-7.75(m, 1H), 8.01— 8.02(m， 1H), 8.19— 8.21(m， 1H), 8.30— 8.36(m， 2H). MS m/z(ESI): 617.7[M+H]。中 -氟甲基 -3-碘 -N-[4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -苯甲酰胺

3-Trifluoromethyl-4-(4-methylpiperazinylmethyl)benzoic acid (88 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (10 mL). N-diisopropylethylamine (66 L, 0.39 mmol) and B 2-(7-azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate ( 120 g, 0.31 mmol), after stirring for 5 min, 3-iodo-4-(tetrahydro-2H-pyran-2-oxomethyl)aniline (89 mg, 0.27 mmol). After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to give a white solid (60 mg, 36%) o 1H-NMR (CD 3 OD, 400MHz): δ 1.70-1.92 (m, 6Η), 2.67 (br, 8H), 3.01 (s , 4H), 3.58— 3.61(m, 1H), 3.87(s, 2H), 3.95-3.97(m, 1H), 4.48-4.5 l(m, 1H), 4.74_4.90(m, 2H), 7.46 _7.48(m, 1H), 7.73-7.75(m, 1H), 8.01— 8.02(m, 1H), 8.19— 8.21(m, 1H), 8.30— 8.36(m, 2H). MS m/z( ESI): 617.7 [M+H]. Medium-fluoromethyl-3-iodo-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

第一步： 3-碘 -4-溴甲基苯甲酸甲酯 First step: 3-iodo-4-methylbromomethylbenzoate

将 3-碘 -4-甲基苯甲酸甲酯（200 mg， 0.7 mmol) 溶于四氯化碳（5 mL)，依次加入 N- 溴代丁二酰亚胺（180 mg， 1.0 mmol) 和过氧化苯甲酰（17.5 mg， 0.07 mmol), 100 °C搅拌反应 24 h。反应结束后蒸除溶剂，残留物用饱和碳酸氢钠溶液调至 pH为 9，乙酸乙酯萃取两次，合并有机层，水洗、饱和食盐水洗、干燥，减压浓缩得到红棕色油状物粗品，未经进一步纯化直接用于下一步反应。 Methyl 3-iodo-4-methylbenzoate (200 mg, 0.7 mmol) was dissolved in carbon tetrachloride (5 mL). N-bromosuccinimide (180 mg, 1.0 mmol) Benzoyl peroxide (17.5 mg, 0.07 mmol) was stirred at 100 °C for 24 h. After the reaction was completed, the solvent was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj It was used in the next reaction without further purification.

第二步： 3-碘 -4-羟甲基苯甲酸甲酯 Step 2: Methyl 3-iodo-4-hydroxymethylbenzoate

将上述 3-碘 -4-溴甲基苯甲酸甲酯粗品（300 mg)溶于乙醇（14 mL)和水（3.6 mL ) 的混合溶剂，加入甲酸钠固体（220 mg， 2.1 mmol), 90 °C搅拌反应 5 h。反应结束后蒸除大部分溶剂，用乙酸乙酯萃取，柱层析纯化得到 3-碘 -4-羟甲基苯甲酸甲酯（白色固体， 130 mg)。 The above crude methyl 3-iodo-4-bromomethylbenzoate (300 mg) was dissolved in a mixed solvent of ethanol (14 mL) and water (3.6 mL), and sodium formate solid (220 mg, 2.1 mmol), 90 ° The reaction was stirred for 5 h. After completion of the reaction, most of the solvent was evaporated.

1H-NMR (CDC1₃, 400MHz): δ 3.94(s, 3H), 4.73(s, 2H), 7.58— 7.60(m， 1H), 8.05_8.07(m， 1H),1H-NMR (CDC1 ₃ , 400MHz): δ 3.94 (s, 3H), 4.73 (s, 2H), 7.58 - 7.60 (m, 1H), 8.05_8.07 (m, 1H),

8.49-8.50(m, 1H)。 MSm/z (ESI): 292.7[M+H]。 8.49-8.50 (m, 1H). MS m / z (ESI): 292.7 [M+H].

第三步： 3-碘 -4-氟甲基苯甲酸甲酯 Step 3: Methyl 3-iodo-4-fluoromethylbenzoate

将 3-碘 -4-羟甲基苯甲酸甲酯（300 mg， 1.0 mmol) 溶于二氯甲烷（10 mL)，冰浴冷却，氩气保护下缓慢加入二乙胺基三氟化硫（0.25 mL, 2.0 mmol), 滴完撤去冰浴室温搅拌反应 24 h。反应结束后蒸除溶剂，残留物加入水，乙酸乙酯萃取，柱层析纯化得到 3-碘 -4-氟甲基苯甲酸甲酯（白色固体， 197 mg)。 1H-NMR (CDC1₃， 400MHz): S 3.95(s，3H)，5.37(s， 1H),Methyl 3-iodo-4-hydroxymethylbenzoate (300 mg, 1.0 mmol) was dissolved in dichloromethane (10 mL), cooled in ice-cooling, and diethylamine trifluorosulfide was slowly added under argon ( 0.25 mL, 2.0 mmol), the ice bath was removed and the reaction was stirred for 24 h. After completion of the reaction, the solvent was evaporated. mjjjjjjjjjjjjj 1H-NMR (CDC1 ₃ , 400MHz): S 3.95 (s, 3H), 5.37 (s, 1H),

5.48(s， lH), 7.52-7.54(m, 1H), 8.07_8.09(m， 1H), 8.51(s, 1H)。 MSm/z (ESI): 294.7[M+H]。第四步： 3-碘 -4-氟甲基苯甲酸 5.48(s, lH), 7.52-7.54(m, 1H), 8.07_8.09(m, 1H), 8.51(s, 1H). MS m / z (ESI): 294.7 [M+H]. Step 4: 3-iodo-4-fluoromethylbenzoic acid

将 3-碘 -4-氟甲基苯甲酸甲酯（280 mg， 0.95 mmol) 溶于甲醇（10 mL)，加入 4N氢氧化钠溶液（0.88 mL, 3.5 mmol), 75 °C搅拌反应 2.5 h。反应结束后蒸除溶剂，残留物用 Methyl 3-iodo-4-fluoromethylbenzoate (280 mg, 0.95 mmol) was dissolved in methanol (10 mL), 4N sodium hydroxide solution (0.88 mL, 3.5 mmol), and stirred at 75 ° C for 2.5 h . After the reaction is completed, the solvent is distilled off, and the residue is used.

2N盐酸调至 pH为 3，乙酸乙酯萃取两次。合并有机层，蒸除溶剂得到 3-碘 -4-氟甲基苯甲酸（白色固体， 245 mg )。

400ΜΗζ): 5.42(s, 1H), 5.54(s， 1H)， 7.58— 7.60(m， 1H), 8.00— 8.02(m， 1H), 8.37(s, 1H)。 MSm/z (ESI): 280.7[M+Na]。 2N Hydrochloric acid was adjusted to pH 3 and extracted with ethyl acetate twice. The organic layers were combined and evaporated to give 3-iodo-4-fluoromethylbenzene. Acid (white solid, 245 mg).

400ΜΗζ): 5.42(s, 1H), 5.54(s, 1H), 7.58— 7.60(m, 1H), 8.00— 8.02(m, 1H), 8.37(s, 1H). MS m / z (ESI): 280.7 [M+Na].

第五步： 4-氟甲基 -3-碘 -N-[4-(4-甲基-哌嗪小基甲基 )-3-三氟甲基-苯基] -苯甲酰胺 Step 5: 4-Fluoromethyl-3-iodo-N-[4-(4-methyl-piperazinylmethyl)-3-trifluoromethyl-phenyl]-benzamide

将 3-碘 -4-氟甲基苯甲酸（225 mg， 0.8 mmol) 溶于 N，N-二甲基甲酰胺（5 mL), 加入 N，N-二异丙基乙胺（180 L， 1.09 mmol)禾卩 2-(7-偶氮苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯（610 mg， 1.6 mmol), 搅拌 5min后加入 3-三氟甲基 -4-(4-甲基哌嗪基小甲基)苯胺（198 mg， 0.72 mmol), 室温搅拌反应 26h。反应结束后体系加入水，乙酸乙酯萃取两次。合并有机层，柱层析纯化得到 4-氟甲基 -3-碘 -N-[4-(4-甲基 -哌嗪 -1 -基甲基 )-3-三氟甲基-苯基] -苯甲酰胺（白色固体， 420 mg 1H-NMR (CD₃OD, 400ΜΗζ): 2.49(s, 4Η), 2.92(s, 3H), 3.01(s, 4H)， 3.79(s, 2H), 5.43(s, 1H)， 5.54(s， 1H)， 7.61— 7.63(m， 1H)， 7.78— 7.80(m， 1H)， 8.01— 8.05(m， 1H), 8.15(s， 1H), 8.48(s， 1H)。 MSm/z (ESI): 535.7[M+H]。中间体 66: 3-碘 -N-[4-(4-甲基-哌嗪小基甲基 )-3-三氟甲基-苯基] -4- (四氢 -B比喃 -2-基氧基甲基) -苯

3-Iodo-4-fluoromethylbenzoic acid (225 mg, 0.8 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (180 L, 1.09 mmol), 2-(7-azobenzotriazole) - hydrazine, hydrazine, hydrazine, Ν'-tetramethyluron hexafluorophosphate (610 mg, 1.6 mmol), stirred for 5 min, then added 3 -Trifluoromethyl-4-(4-methylpiperazinylmethyl)aniline (198 mg, 0.72 mmol). After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to give 4-fluoromethyl-3-iodo-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl] -benzamide (white solid, 420 mg 1H-NMR (CD ₃ OD, 400 ΜΗζ): 2.49 (s, 4 Η), 2.92 (s, 3H), 3.01 (s, 4H), 3.79 (s, 2H), 5.43 (s, 1H), 5.54(s, 1H), 7.61— 7.63(m, 1H), 7.78— 7.80(m, 1H), 8.01— 8.05(m, 1H), 8.15(s, 1H), 8.48(s , 1H) MSm/z (ESI): 535.7 [M+H] Intermediate 66: 3-iodo-N-[4-(4-methyl-piperazinylmethyl)-3-trifluoromethyl Phenyl-phenyl]-4-(tetrahydro-B-pyran-2-yloxymethyl)-benzene

第一步： 3-碘 -4- (四氢 -2H-吡喃 -2-氧基)甲基 First step: 3-iodo-4-(tetrahydro-2H-pyran-2-yloxy)methyl

将 3-碘 -4-羟甲基苯甲酸甲酯（300 mg， 1.0 mmol)和 3， 4-二氢吡喃（0.47 mL， 5.1 mmol) 溶于二氯甲烷（10 mL)，加入对甲苯磺酸一水合物（19.5 mg， 0.1 mmol), 室温搅拌反应反应结束后蒸除溶剂，残留物加入水，乙酸乙酯萃取，柱层析纯化得到碘 (四氢 -2H-吡喃 -2-氧基）甲基苯甲酸甲酯（无色油状物， 303 mg)。 1H-NMR (CDC1₃, 400 MHz): 1.60—1.82(m， 6Η)， 3.58— 3.61(m， 1Η), 3.90—3.92 (m， 1H)， 3.94(s, 3H), 4.52(d, 1H, J=14.4Hz), 4.80(d, lH, J=17.2Hz), 7.58— 7.60(m， 1H), 8.02_8.05(m， 1H), 8.49_8.50(m， 1H)。 MS m/z (ESI): 376.90[M+H] Methyl 3-iodo-4-hydroxymethylbenzoate (300 mg, 1.0 mmol) and 3,4-dihydropyran (0.47 mL, 5.1 mmol) were dissolved in dichloromethane (10 mL). The sulfonic acid monohydrate (19.5 mg, 0.1 mmol) was stirred at room temperature and the solvent was evaporated. The residue was evaporated,jjjjjjjjjjjj Methyl oxy)methylbenzoate (colorless oil, 303 mg). 1H-NMR (CDC1 ₃ , 400 MHz): 1.60—1.82 (m, 6Η), 3.58— 3.61 (m, 1Η), 3.90—3.92 (m, 1H), 3.94(s, 3H), 4.52(d, 1H) , J = 14.4 Hz), 4.80 (d, lH, J = 17.2 Hz), 7.58 - 7.60 (m, 1H), 8.02_8.05 (m, 1H), 8.49_8.50 (m, 1H). MS m/z (ESI): 376.90 [M+H]

第二步： 3-碘 -4- (四氢 -2H-吡喃 -2-氧基)甲基苯甲酸 Step 2: 3-iodo-4-(tetrahydro-2H-pyran-2-yloxy)methylbenzoic acid

将 3-碘 -4- (四氢 -2H-吡喃 -2-氧基)甲基苯甲酸甲酯（300 mg， 0.79 mmol) 溶于甲醇（10 mL), 加入 4N氢氧化钠溶液（0.7 mL， 2.9 mmol), 75 °C搅拌反应 3 h。反应结束后蒸除溶剂，残留物用 1N盐酸调至为 3，乙酸乙酯萃取两次，合并有机层，蒸除溶剂得到 3- 碘 -4- (四氢 -2H-吡喃 -2-氧基）甲基苯甲酸（白色固体， 305 mg)。 1H-NMR(DMSO-d6, 400MHz): Methyl 3-iodo-4-(tetrahydro-2H-pyran-2-oxy)methylbenzoate (300 mg, 0.79 mmol) was dissolved in methanol (10 mL). mL, 2.9 mmol), stir at 75 °C for 3 h. After completion of the reaction, the solvent was evaporated, and the residue was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methyl benzoic acid (white solid, 305 mg). 1H-NMR (DMSO-d6, 400MHz):

1.50— 1.78(m， 6Η)， 3.50— 3.52(m， 1Η)， 3.77-3.82(m, 1Η)， 3.94(s, 3Η), 4.46(d， 1H, J=13.8Hz), 4.67(d, 1 H， J=13.8Hz), 4.79(s, 1H)， 7.57— 7.59(m， 1H)， 7.96— 7.98(m， 1H)， 8.33(s, 1H). MS m/z (ESI): 384.7[M+Na] 1.50— 1.78(m, 6Η), 3.50—3.52(m, 1Η), 3.77-3.82(m, 1Η), 3.94(s, 3Η), 4.46(d, 1H, J=13.8Hz), 4.67(d, 1 H, J = 13.8 Hz), 4.79 (s, 1H), 7.57 - 7.59 (m, 1H), 7.96 - 7.98 (m, 1H), 8.33 (s, 1H). MS m/z (ESI): 384.7 [M+Na]

第三步： N-(4-(4-甲基哌嗪基 -1-甲基) -3-三氟甲基苯基 )-3-碘 -4- (四氢 -2H-吡喃 -2-氧甲基)苯甲酰胺 Step 3: N-(4-(4-Methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-(tetrahydro-2H-pyran-2 -oxymethyl)benzamide

将 3-碘 -4-氟甲基苯甲酸（1.08 g， 2.98 mmol) 溶于 N，N-二甲基甲酰胺（40 mL) 中，加入 N，N-二异丙基乙胺（672 L, 4.07 mmol) 禾卩 2-(7-偶氮苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯（1.23 g， 3.23 mmol), 搅拌 5 min后加入再 3-三氟甲基 -4-(4-甲基哌嗪基 -1- 甲基)苯胺（742 mg， 2.72 mmol), 室温搅拌反应 26 h。反应结束后体系加入水，乙酸乙酯萃取两次。合并有机层，柱层析纯化得到 N-(4-(4-甲基哌嗪基 -1-甲基) -3-三氟甲基苯基 )-3- 碘 -4- (四氢 -2H-吡喃 -2-氧甲基)苯甲酰胺（白色固体， 1.1 g)。 1H-NMR (CD₃OD， 400 MHz): 1.60— 1.92(m， 6Η)， 2.67(s, 7Η), 3.01(s, 4H)， 3.59— 3.61(m， 1H), 3.73(s, 2H), 3.91— 3.96(m， 1H)， 4.53— 4.57(m， 1H), 4.78— 4.84(m， 2H), 7.63-7.65(m, 1H), 7.77-7.79(m, 1H), 7.96—8.00 (m， 2H), 8.15(s, 1H), 8.44(s, 1H)。 MSm/z (ESI): 617.70[M+H]。中间体 67: 4-二氟甲基 -3-碘 -N-[4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -苯甲酰胺 3-iodo-4-fluoromethylbenzoic acid (1.08 g, 2.98 mmol) was dissolved in N,N-dimethylformamide (40 mL). N,N-diisopropylethylamine (672 L) , 4.07 mmol) 卩 2-(7-azobenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (1.23 g, 3.23 mmol), after stirring for 5 min Further, 3-trifluoromethyl-4-(4-methylpiperazinyl-1-methyl)aniline (742 mg, 2.72 mmol) was added, and the mixture was stirred at room temperature for 26 h. After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to afford N-(4-(4-methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4- (tetrahydro-2H) - pyran-2-oxomethyl)benzamide (white solid, 1.1 g). 1H-NMR (CD ₃ OD, 400 MHz): 1.60 - 1.92 (m, 6 Η), 2.67 (s, 7 Η), 3.01 (s, 4H), 3.59 - 3.61 (m, 1H), 3.73 (s, 2H) , 3.91— 3.96(m, 1H), 4.53—4.57(m, 1H), 4.78— 4.84(m, 2H), 7.63-7.65(m, 1H), 7.77-7.79(m, 1H), 7.96-8.00 ( m, 2H), 8.15 (s, 1H), 8.44 (s, 1H). MS m/z (ESI): 617.70 [M+H]. Intermediate 67: 4-Difluoromethyl-3-iodo-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

第一步： 4-甲酰基 -3-碘-苯甲酸酯 ³ First step: 4-formyl-3-iodo-benzoate ³

将 3-碘 -4-羟甲基苯甲酸甲酯（1 g， 3.4 mmol)溶于二氯甲烷（20 mL)，加入 Dess-Martin 试剂（2.18 g， 5.1 mmol) 和固体碳酸氢钠粉末（863 mg， 10.3 mmol), 室温搅拌反应 5 h。反应结束后过滤，蒸除溶剂，残留物用饱和碳酸氢钠洗涤，乙酸乙酯萃取两次。合并有机层，干燥浓缩得到 4-甲酰基 -3-碘 -苯甲酸甲酯（黄色油状物， 920 mg)。 1H-NMR (CDC1₃, 400 MHz): δ 3.98(s, 3 Η)， 5.54(s， 1 Η)， 7.93- 7.95(m， 1 Η)， 8.11— 8.12(m， 1 Η)， 8.63(s, 1 Η)， 10.14(s， 1 Η)。 MSm/z (ESI): 291.8[M+H]。 Methyl 3-iodo-4-hydroxymethylbenzoate (1 g, 3.4 mmol) was dissolved in dichloromethane (20 mL) EtOAc (EtOAc:EtOAc: 863 mg, 10.3 mmol), stir the reaction for 5 h at room temperature. After the reaction was completed, the mixture was evaporated. The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAc 1H-NMR (CDC1 ₃ , 400 MHz): δ 3.98 (s, 3 Η), 5.54 (s, 1 Η), 7.93- 7.95 (m, 1 Η), 8.11— 8.12 (m, 1 Η), 8.63 ( s, 1 Η), 10.14(s, 1 Η). MS m / z (ESI): 291.8 [M+H].

第二步： 3-碘 -4-二氟甲基苯甲酸甲酯 Step 2: Methyl 3-iodo-4-difluoromethylbenzoate

将 3-碘 -4-氧代苯甲酸甲酯（920 mg， 3.1 mmol) 溶于二氯甲烷（10 mL)，冰浴冷却，氩气保护下缓慢加入二乙胺基三氟化硫试剂（777 L， 6.3 mmol), 滴加完毕撤去冰浴，室温搅拌反应 24 h。反应结束后蒸除溶剂，残留物加入水，乙酸乙酯萃取，柱层析纯化得到 3-碘 -4-二氟甲基苯甲酸甲酉旨（白色固体， 900 mg)。1H-NMR(CDCl₃， 400 MHz): δ 3.97(s, 3 H), 6.80(t， 1H, J=56Hz), 7.70-7.72(m, 1H), 8.12_8.14(m， 1H), 8.56(s， 1H)。 MS m/z (ESI) : 312.7[M+H] o Methyl 3-iodo-4-oxobenzoate (920 mg, 3.1 mmol) was dissolved in dichloromethane (10 mL), cooled in ice-cooled, and then diethylamine trifluorosulfide reagent was slowly added under argon ( 777 L, 6.3 mmol), after the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the solvent was evaporated. EtOAcjjjjjjjjjj 1H-NMR (CDCl ₃ , 400 MHz): δ 3.97 (s, 3 H), 6.80 (t, 1H, J = 56 Hz), 7.70-7.72 (m, 1H), 8.12_8.14 (m, 1H), 8.56 (s, 1H). MS m/z (ESI): 312.7 [M+H] o

第三步： 3-碘 -4-二氟甲基苯甲酸 The third step: 3-iodo-4-difluoromethylbenzoic acid

将 3-碘 -4-二氟甲基苯甲酸甲酯（900 mg， 2.88 mmol) 溶于甲醇（10 mL)，加入 4N氢氧化钠水溶液（2.6 mL， 10.4mmol) , 在 75 °C下搅拌反应 2.5 h。反应结束后蒸除溶剂，残留物用 2N盐酸调至 pH约为 3，乙酸乙酯萃取两次。合并有机层，蒸除溶剂得到 3-碘 -4- 二氟甲基苯甲酸（白色固体， 860 mg)。 1H-NMR (CDC1₃, 400 MHz): δ 6.82(t， 1H， J=56Hz)， 7.74-7.76(m, 1H), 8.18— 8.21(m， 1H), 8.63(s, 1H)。 MSm/z (ESI): 298.7[M+H]。 Methyl 3-iodo-4-difluoromethylbenzoate (900 mg, 2.88 mmol) was dissolved in methanol (10 mL). 4N aqueous sodium hydroxide (2.6 mL, 10.4 mmol) The reaction was 2.5 h. After the end of the reaction, the solvent was evaporated, and the residue was evaporated to m. The organic layers were combined and evaporated to dryness crystals crystals 1H-NMR (CDC1 ₃ , 400 MHz): δ 6.82 (t, 1H, J = 56 Hz), 7.74-7.76 (m, 1H), 8.18 - 8.21 (m, 1H), 8.63 (s, 1H). MS m / z (ESI): 298.7 [M+H].

第四步： N-(4-(4-甲基哌嗪基 -1-甲基) -3-三氟甲基苯基 )-3-碘 -4-二氟甲基苯甲酰胺 Step 4: N-(4-(4-Methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-difluoromethylbenzamide

将 3-碘 -4-二氟甲基苯甲酸（860 mg， 2.88 mmol) 溶于 N，N-二甲基甲酰胺（5 mL)，加入 N，N-二异丙基乙胺（668 L, 4.04 mmol) 禾卩 2-(7-偶氮苯并三氮唑) -N，N，N，，N，-四甲基脲六氟磷酸酯（1.2 g， 3.2 mmol), 搅拌 5min后加入 3-三氟甲基 -4-(4-甲基哌嗪基 -1-甲基）苯胺（737 mg， 2.69 mmol), 室温搅拌反应 26 h。反应结束后体系加入水，乙酸乙酯萃取两次。合并有机层，柱层析纯化得到 N-(4-(4-甲基哌嗪基 -1-甲基) -3-三氟甲基苯基 )-3-碘 -4- 二氟甲基苯甲酰胺（白色固体， 1.5 g)。 1H-NMR (CD₃0D， 400MHz): δ 2.76(br, 4 Η), 2.90(s, 3 Η)， 3.29(br, 4 Η)， 3.78(s, 2 Η)， 6.94(t， 1 Η， J=56Hz), 5.54(s， 1 H)， 7.75- 7.82(m， 2 H)， 7.99-8.16(m, 3 H)， 8.53(s, 1 H).MSm/z (ESI): 554.7[M+H]。中间体 68: 胺 3-iodo-4-difluoromethylbenzoic acid (860 mg, 2.88 mmol) was dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (668 L) , 4.04 mmol) 2-(7-azobenzotriazole)-N,N,N,,N,-tetramethylurea hexafluorophosphate (1.2 g, 3.2 mmol), stirred for 5 min, then added 3-Trifluoromethyl-4-(4-methylpiperazinyl-1-methyl)phenylamine (737 mg, 2.69 mmol). After the reaction, the system was added with water and extracted with ethyl acetate twice. The organic layers were combined and purified by column chromatography to afford N-(4-(4-methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-iodo-4-difluoromethylbenzene Formamide (white solid, 1.5 g). 1H-NMR (CD ₃ 0D, 400MHz): δ 2.76(br, 4 Η), 2.90(s, 3 Η), 3.29(br, 4 Η), 3.78(s, 2 Η), 6.94(t, 1 Η , J=56Hz), 5.54(s, 1 H), 7.75- 7.82(m, 2 H), 7.99-8.16(m, 3 H), 8.53(s, 1 H).MSm/z (ESI): 554.7 [M+H]. Intermediate 68: Amine

第一步：溴甲基 -₂-碘 -4-硝基-苯 First step: bromomethyl- ₂ -iodo-4-nitro-benzene

将 3-碘 -4-甲基硝基苯（263 mg， 1.0 mmol) 溶于四氯化碳（5 mL)，依次加入 N-溴代丁二酰亚胺（180 mg， 1.0 mmol) 和过氧化苯甲酰（ 17.5 mg， 0.07 mmol), 100 °C搅拌反应 24 h。反应结束后蒸除溶剂，残留物用饱和碳酸氢钠溶液调至 pH为 9，乙酸乙酯萃取两次，合并有机层，水洗、饱和食盐水洗、干燥，减压浓缩得到红棕色油状物粗品，未经进一步纯化直接用于下一步反应。 3-iodo-4-methylnitrobenzene (263 mg, 1.0 mmol) was dissolved in carbon tetrachloride (5 mL), then N-bromosuccinimide (180 mg, 1.0 mmol) was added and Benzoyl peroxide (17.5 mg, 0.07 mmol) was stirred at 100 °C for 24 h. After the reaction was completed, the solvent was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Not entering One-step purification was used directly for the next reaction.

第二步：碘 -4-硝基-苄基) -4-甲基 -哌嗪 Step 2: Iodine-4-nitro-benzyl)-4-methyl-piperazine

将 1-溴甲基 -2-碘 -4-硝基-苯村品溶于二氯甲烷（10 mL) 中，室温搅拌下一次加入 4-甲基哌嗪（120 m_& 1.2 mmol)，继续搅拌过夜。反应结束，加入水和二氯甲烷稀释，分出有机相，有机相分别用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到 1 -(2-碘 -4-硝基 -苄基 )-4-甲基 -哌嗪（黄色固体， 250 mg)。 ESI-M S m/z 362 (M + H)⁺ 第三步： 1-(2-环丙基 -4-硝基-苄基) -4-甲基 -哌嗪 Dissolve 1-bromomethyl-2-iodo-4-nitro-benzene in dichloromethane (10 mL) and add 4-methylpiperazine (120 m _& 1.2 mmol) once at room temperature with stirring. Stir overnight. After completion of the reaction, the mixture was diluted with water and dichloromethane, and the organic layer was evaporated. EtOAcjjjjjjjjjjj -Nitro-benzyl)-4-methyl-piperazine (yellow solid, 250 mg). ESI-M S m/z 362 (M + H) ⁺ third step: 1-(2-cyclopropyl-4-nitro-benzyl)-4-methyl-piperazine

将 1—(2-碘 -4-硝基-苄基) -4-甲基 -哌嗪（250 mg, 0.95 mmol), 环丙基硼酸（163 mg, 1.9 mmol), 磷酸钾粉末（700 m_& 3.3 mmol) 与 N，N-二甲基甲酰胺（10 mL) 混匀置于反应瓶中，氮气鼓泡 10分钟后，快速加入催化剂醋酸钯（22 m_& 0.095 mmol) 和三环己基膦配体 ( 53 mg, 0.19 mmol) , 混合物在氮气保护下室温反应过夜 24小时。反应完毕，加入二氯甲烷萃取，有机相分别用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，浓缩物用硅胶柱层析分离纯化得到 1-(2-环丙基 -4-硝基-节基) -4-甲基 -哌嗪（黄色固体， 160 mg)。

1-(2-Iodo-4-nitro-benzyl)-4-methyl-piperazine (250 mg, 0.95 mmol), cyclopropylboronic acid (163 mg, 1.9 mmol), potassium phosphate powder (700 m _& 3.3 mmol) was mixed with N,N-dimethylformamide (10 mL) in a reaction flask. After bubbling nitrogen for 10 minutes, the catalyst palladium acetate (22 m _& 0.095 mmol) and tricyclohexylphosphine were quickly added. Ligand (53 mg, 0.19 mmol), the mixture was reacted at room temperature under nitrogen for 24 hours. After completion of the reaction, the mixture was extracted with methylene chloride. The organic layer was washed with EtOAc EtOAc. 4-Nitro-pyrimidinyl)-4-methyl-piperazine (yellow solid, 160 mg).

第四步： 3-环丙基 -4-(4-甲基 -哌嗪 -1-基甲基) -苯胺 Step 4: 3-Cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-aniline

将还原铁粉（ 637 m_& 11.37 mmol) 投入 25 mL反应瓶中，加入 5 mL水和 0.5 mL冰醋酸，加热至回流，搅拌 20分钟。将 l-O环丙基 -4-硝基-苄基) -4-甲基 -哌嗪（626 m_& 2.27 mmol) 的乙醇（l mL)溶液加入反应体系，回流反应 15分钟后，停止加热。趁热用饱和碳酸钠溶液调节体系 pH值至 8〜9，待体系冷却至室温后，减压旋去溶剂。用硅胶柱层析分离纯化得到 3-环丙基-4-(4-甲基-哌嗪小基甲基)-苯胺（黄色油状物，230 mg)。¹l·^-MR (400MHz， CDC1₃) δ 7.04 (d, J=8.0Hz, 1H), 6.46(dd， J=8.0, 2.4Hz, 1H), 6.30(d, J=2.4Hz, 1H)， 3.59(m, 4H)， 3.50(s, 2H), 2.43(m, 4H)， 2.27(s, 3H), 2.13(m, 1H), 0.89(m， 2H), 0.59(m， 2H)。 ESI-M S m/z 246 (M + H) 第五步： N-[3-环丙基 -4-(4-甲基 -哌嗪 -1-基甲基) -苯基 ]-6-二氟甲基 -5-碘-苯甲酰胺 The reduced iron powder (637 m _& 11.37 mmol) was placed in a 25 mL reaction flask, 5 mL of water and 0.5 mL of glacial acetic acid were added, heated to reflux and stirred for 20 minutes. A solution of lO cyclopropyl-4-nitro-benzyl)-4-methyl-piperazine (626 m _& 2.27 mmol) in ethanol (1 mL) was added to the reaction mixture. The pH of the system was adjusted to 8 to 9 with a saturated sodium carbonate solution while hot. After the system was cooled to room temperature, the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography gave 3-cyclopropyl-4-(4-methyl-piperazinylmethyl)-phenylamine (yield: ¹ l·^-MR (400MHz, CDC1 ₃ ) δ 7.04 (d, J=8.0Hz, 1H), 6.46 (dd, J=8.0, 2.4Hz, 1H), 6.30(d, J=2.4Hz, 1H) , 3.59 (m, 4H), 3.50 (s, 2H), 2.43 (m, 4H), 2.27 (s, 3H), 2.13 (m, 1H), 0.89 (m, 2H), 0.59 (m, 2H). ESI-M S m/z 246 (M + H) Step 5: N-[3-Cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-6- Difluoromethyl-5-iodo-benzamide

将 6-二氟甲基 -5-碘-苯甲酸（74 mg, 0.245 mmol), 3-环丙基 -4-(4-甲基-哌嗪小基甲基) - 苯胺（40 mg, 0.163 mmol )和 2-(7-氮杂苯并三氮唑) -Ν,Ν,Ν',Ν'-四甲基脲六氟磷酸酯（94 mg, 0.245 mmol)溶于 N， N-二甲基甲酰胺（ 3 mL )中，将 N，N-二甲基甲酰胺（ 42 m_& 0.326 mmol) 缓慢加入体系中，室温搅拌过夜。反应完毕后，减压旋去溶剂，用硅胶柱层析分离，得到 N-[3-环丙基 -4-(4-甲基 -哌嗪 -1-基甲基) -苯基 ]-6-二氟甲基 -5-碘-苯甲酰胺（黄色油状物， 72 mg)。 ESI-M S m/z 526 (M + H)+ 6-Difluoromethyl-5-iodo-benzoic acid (74 mg, 0.245 mmol), 3-cyclopropyl-4-(4-methyl-piperazinemethylidenemethyl)-aniline (40 mg, 0.163 Ment) and 2-(7-azabenzotriazole)-Ν,Ν,Ν',Ν'-tetramethylurea hexafluorophosphate (94 mg, 0.245 mmol) dissolved in N, N-dimethyl N,N-dimethylformamide (42 m _& 0.326 mmol) was slowly added to the carbamide (3 mL) and stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and purified to silicagel eluting -Difluoromethyl-5-iodo-benzamide (yellow oil, 72 mg). ESI-M S m/z 526 (M + H)+

分别以 3-环丙基 -4-(4-甲基 -哌嗪 -1-基甲基)-苯胺和 5-碘 -6-甲基-苯甲酸， 6-氟甲基 -5-碘- 苯甲酸为原料，采用中间体 68相同的方法合成得到以下中间体 69 N-[3-环丙基 -4-(4-甲基- 哌嗪 -1—基甲基)—苯基]—5-碘 -6-甲基 -苯甲酰胺， ESI-M S m/z 491 (M+H)和中间体 70 N-[3-环丙基 -4-(4-甲基 -哌嗪 -1 /z 509 (M+H)。

3-cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 5-iodo-6-methyl-benzoic acid, 6-fluoromethyl-5-iodine- Benzoic acid was used as the starting material, and the following intermediate 69 N-[3-cyclopropyl-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-5 was synthesized by the same procedure as Intermediate 68. -iodo-6-methyl-benzamide, ESI-M S m/z 491 (M+H) and intermediate 70 N-[3-cyclopropyl-4-(4-methyl-piperazine-1 /z 509 (M+H).

中间体 69 中间体 70 制备实施例 Intermediate 69 Intermediate 70 Preparation Examples

通用方法一：将芳基乙块中间体 (1.1 eq)、溴代或碘代-苯甲酰胺中间体 (1 eq.)、 N，N-二异丙基乙胺 (2 eq.)溶解在无水 N，N-二甲基甲酰胺中，氮气鼓泡 10分钟后，向上述溶液中快速加入四三苯基膦钯 (5 mol %)以及碘化亚铜 (7.5 mmol %)。反应液在 60<€加热搅拌 18小时，反应结束后，加入饱和碳酸氢钠溶液淬灭反应，用乙酸乙酯等有机溶剂萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。浓缩液用硅胶柱层析分离纯化得到目标化合物。实施例 1 : 4-甲基 -N-(4-吗啉 -4-甲基 -3-三氟甲基-苯基) -3-[1，2，4]*** [4，3-a]吡啶 -3-乙块基-苯甲酰胺

General Procedure One: Dissolve the aryl b-block intermediate (1.1 eq), the bromo or iodo-benzamide intermediate (1 eq.), N,N-diisopropylethylamine (2 eq.) in In anhydrous N,N-dimethylformamide, after bubbling nitrogen for 10 minutes, tetrakistriphenylphosphine palladium (5 mol%) and cuprous iodide (7.5 mmol%) were quickly added to the above solution. The reaction mixture was heated and stirred at 60 °C for 18 hours. After the reaction was completed, the reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate and ethyl acetate. Filter and concentrate under reduced pressure. The concentrate is separated and purified by silica gel column chromatography. Target compound. Example 1: 4-Methyl-N-(4-morpholin-4-methyl-3-trifluoromethyl-phenyl)-3-[1,2,4]triazole [4,3-a Pyridine-3-ethylidene-benzamide

将 3-乙块基 -[1，2，4]三氮唑 [4，3-a]吡啶 (24 mg, 0.168 mmol)、 3-碘 -4-甲基 -N-(4-***啉 -4- 基甲基 -3-三氟甲基-苯基) -苯甲酰胺 (74 mg 0.146 mmol) N，N-二异丙基乙胺 (42 L, 0.25 mmol)溶解在无水 N，N-二甲基甲酰胺（1 mL)中，氮气鼓泡 10分钟后，同四三苯基膦钯 (10 m_& 5 mol %)以及碘化亚铜 (3 m_& 7.5 mmol %)置于 10 mL封管中。反应液在 60°C加热搅拌 18小时，反应结束后，加入饱和碳酸氢钠溶液淬灭反应，乙酸乙酯萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。浓缩液用硅胶柱层析分离纯化得到目标化合物 4-甲基 -N-(4-吗啉 -4-甲基 -3-三氟甲基-苯基) -3-[1，2，4]*** [4，3-a]吡啶 -3-乙块基-苯甲酰胺 (黄色固体， 27 mg -NMR (300MHz, CDC1₃): δ 8.3 l(m, 2Η), 8.12(s, 1H)， 7.07-7.02(m, IH), 3.74-3.71(m, 4H)， 3.64(s, 2H), 2.50(s, 3H), 2.49(m, 4H)。 MSm/z (ESI): 521.1[M+H]。 3-Ethyl-[1,2,4]triazole [4,3-a]pyridine (24 mg, 0.168 mmol), 3-iodo-4-methyl-N-(4-morpholine- 4-Methyl-3-trifluoromethyl-phenyl)-benzamide (74 mg 0.146 mmol) N,N-diisopropylethylamine (42 L, 0.25 mmol) dissolved in anhydrous N, N In dimethylformamide (1 mL), after bubbling nitrogen for 10 minutes, the same tetrakistriphenylphosphine palladium (10 m _& 5 mol %) and cuprous iodide (3 m _& 7.5 mmol %) were placed in 10 The mL is sealed in the tube. The reaction mixture was heated and stirred at 60 ° C for 18 hours. After the reaction was completed, the mixture was stirred and evaporated, evaporated, evaporated, evaporated. concentrate. The concentrate was separated and purified by silica gel column chromatography to give the title compound 4-methyl-N-(4-morpholin-4-methyl-3-trifluoromethyl-phenyl)-3-[1,2,4] Triazole [4,3-a]pyridine-3-ethylidene-benzamide (yellow solid, 27 mg - NMR (300MHz, CDC1 ₃ ): δ 8.3 l (m, 2 Η), 8.12 (s, 1H) , 7.07-7.02(m, IH), 3.74-3.71(m, 4H), 3.64(s, 2H), 2.50(s, 3H), 2.49(m, 4H) MSm/z (ESI): 521.1[M +H].

以不同的芳基乙块和卤代物为原料，采用通用方法一和实施例 1相同的合成方法得到实施例化合物 2〜实施例化合物 97。 The compound of Example 2 to Example 97 was obtained by the same general procedure as in Example 1 using different aryl b-blocks and halogens as starting materials.

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CS.S.0/CT0ZN3/X3d CS.S.0/CT0ZN3/X3d

通用方法二：将带有 Boc保护基的原料（1 eq.) 溶解在二氯甲烷中，冰浴冷却下向其中滴加 4N的氯化氢的二氧六环溶液（4 eq.)。滴加完毕，室温搅拌至反应完全，减压浓缩除去过量溶剂，得到目标产物，未经纯化直接用于下步反应。实施例 98: 4-甲基 -N-(4-哌嗪 -1-甲基 -3-三氟甲基苯基 )-3-[1，2，4]*** [4，3-a]吡啶 -3-乙块基-苯

General Method 2: A material with a Boc protecting group (1 eq.) was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in dioxane (4 eq.) was added dropwise thereto under ice cooling. After completion of the dropwise addition, the mixture was stirred at room temperature until the reaction was completed, and the solvent was concentrated under reduced pressure to give the desired product, which was used for the next step without purification. Example 98: 4-Methyl-N-(4-piperazin-1-methyl-3-trifluoromethylphenyl)-3-[1,2,4]triazole [4,3-a] Pyridine-3-ethylidene-benzene

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CSLSLO/CWZ D/lDd LLOL iOZ OAV

实施例 106: 4-甲基 -N-[4-(4-甲基哌嗪 -1-甲基) -3- [4，3-b]哒嗪 -3-乙 CSLSLO/CWZ D/lDd LLOL iOZ OAV

Example 106: 4-Methyl-N-[4-(4-methylpiperazin-1-methyl)-3-[4,3-b]pyridazine-3-ethyl

将 3-(6-氯 -[1，2，4]*** [4，3-b]哒嗪 -3-乙块基 )-4-甲基 -N-[4-(4-甲基哌嗪 -1-甲基) -3-三氟甲基苯基] -苯甲酰胺 (30 m_& 0.05 mmol)溶解在***啉 (2 mL)中，加热到 100 反应过夜。反应液冷却至室温，加入二氯甲烷稀释，有机相分别用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析 (淋洗液用二氯甲烷：甲醇体积比为 10: 1 的溶液) 分离纯化得到目标化合物 4-甲基 -N-[4-(4-甲基哌嗪小甲基) -3-三氟甲基苯基 ]-3-(6-吗啉 -4-基 -[1，2，4]*** [4，3-b]哒嗪 -3-乙块基) -苯甲酰胺 (黄色固体， 12 mg)。 1H-NMR (300MHz， CD₃OD): δ 8.15-8.20(m, 2H), 7.93-8.03(m, 3H), 7.77(d, J=9.0Hz, IH), 7.50(d, J=8.1Hz, IH), 7.40-7.43(m, IH), 3.81-3.86(m, 4H)， 3.72(s, 2H), 3.65-3.68(m, 4H)， 3.00(s, 4H)， 3.66-3.67(m, 10H)。 MS m/z (ESI): 619.3[M+H] 3-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene)-4-methyl-N-[4-(4-methylpiperidin Pyrazin-1-methyl)-3-trifluoromethylphenyl]-benzamide (30 m _& 0.05 mmol) was dissolved in morpholine (2 mL) and heated to 100 overnight. The reaction mixture was cooled to room temperature, diluted with methylene chloride. The residue was purified by silica gel column chromatography (eluent eluting with dichloromethane: methanol: 10:1) to give the title compound 4-methyl-N-[4-(4-methylpiperazine) -3-trifluoromethylphenyl]-3-(6-morpholin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-3-ethylidene) -benzamide (yellow solid, 12 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.15-8.20 (m, 2H), 7.93-8.03 (m, 3H), 7.77 (d, J = 9.0 Hz, IH), 7.50 (d, J = 8.1 Hz) , IH), 7.40-7.43 (m, IH), 3.81-3.86 (m, 4H), 3.72 (s, 2H), 3.65-3.68 (m, 4H), 3.00 (s, 4H), 3.66-3.67 (m , 10H). MS m/z (ESI): 619.3 [M+H]

以 3-(6-氯 -[1，2，4]*** [4，3-b]哒嗪 -3-乙块基 )-4-甲基 -N-[4-(4-甲基哌嗪 -1-甲基) -3-三氟甲基苯基] -苯甲酰胺和哌嗪及其衍生物，吡咯，哌啶及其衍生物为原料，采用实施例 106的方法合成得到以下实施例 107-实施例 111。 3-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene)-4-methyl-N-[4-(4-methylpiperidin The following implementation was carried out by the method of Example 106 using azine-1-methyl)-3-trifluoromethylphenyl]-benzamide and piperazine and its derivatives, pyrrole, piperidine and its derivatives as raw materials. Example 107 - Example 111.

通用方法三：将芳基卤化物原料 (1 eq.)溶于干燥的溶剂如 1，4-二氧六环， N，N-二甲基甲酰胺等中，氮气保护下快速向其中加入有机胺 (2 eq.)如***啉、哌嗪、吡咯烷及其衍生物、氨基酸及其衍生物和链状胺等，钯催化剂（0.1 eq. )如 Pd₂ (dba)₃、醋酸钯、氯化钯等，膦配体 (0.2 eq.) 如 BINAP、 X-Phous和 XantPhous等及无机碱（2 eq. ) 如叔丁醇钠、叔丁醇钾、碳酸铯和碳酸钾等，加热至 ioo°c反应。反应结束后，冷却至室温，加入水淬灭反应，乙酸乙酯萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化得到目标化合物。实施例 112: 4-甲基 -N-[4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -3-(6-***啉 -4-基 -[1，2，4] 三氮唑 [4，3-a]吡啶 -3-

General Method 3: The aryl halide starting material (1 eq.) is dissolved in a dry solvent such as 1,4-dioxane, N,N-dimethylformamide, etc., and organic is quickly added thereto under the protection of nitrogen. Amine (2 eq.) such as morpholine, piperazine, pyrrolidine and its derivatives, amino acids and derivatives thereof, and chain amines, etc., palladium catalyst (0.1 eq.) such as Pd ₂ (dba) ₃ , palladium acetate, chlorine Palladium, etc., phosphine ligand (0.2 eq.) such as BINAT, X-Phous and XantPhous, and inorganic bases (2 eq.) such as sodium t-butoxide, potassium t-butoxide, cesium carbonate and potassium carbonate, etc., heated to ioo °c reaction. After completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated. The residue was purified by silica gel column chromatography to give the title compound. Example 112: 4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-(6-morpholine-4 -yl-[1,2,4] triazole [4,3-a]pyridine-3-

将 3-( 6-氯 -[ 1，2，4]***并 [4，3-a]吡啶 -3-基）乙块基 )-4-甲基 -Ν-(4-( Φ甲基哌嗪 - 1 -基）甲基) -3- (三氟甲基)苯基)苯甲酰胺 (57 mg， 0.1 mmol)溶于干燥的 1，4-二氧六环 (2 mL)中，氮气保护下快速向其中加入***啉 (17 mg， 0.2 mmol) Pd₂ (dba)₃ (9 mg， 0.01 mmol)、 BINAP (12 mg， 0.02 mmol)及叔丁醇钠 (19 mg， 0.2 mmol), 加热至反应过夜。反应结束后，冷却至室温，加入水淬灭反应，乙酸乙酯萃取 (15 mL 3), 有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化 (淋洗液用二氯甲烷: 甲醇体积比为 90:10的溶液)得到目标化合物 4-甲基 -N-[4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -3-(6-***啉 -4-基 -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基) -苯甲酰胺 (黄色固体， 15 mg)。 iH-NMR (300MHz, CD₃OD): δ 8.14(d， J=1.8Hz, 1H)， 8.06(d， J=1.5Hz, 1H)， 7.96(d, J=8.4Hz, 1H)， 7.72-7.84 (m， 4H)， 7.40(d, J=8.4Hz, 1H)， 7.20(d, J=9.6Hz, 1H)， 3.81(t, J=4.2Hz, 4H)， 3.73(s, 2H), 3.57(t, J=4.8Hz, 4H)， 3.18(m, 4H)， 2.60-2.79(m, 10H)。 MS m/z (ESI): 618.3[M+H

3-( 6-Chloro-[ 1,2,4]triazolo[4,3-a]pyridin-3-yl)ethylidene)-4-methyl-indole-(4-( Φmethyl) Piperazine-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (57 mg, 0.1 mmol) was dissolved in dry 1,4-dioxane (2 mL). Rapidly added morpholine (17 mg, 0.2 mmol) Pd ₂ (dba) ₃ (9 mg, 0.01 mmol), BINAP (12 mg, 0.02 mmol) and sodium tert-butoxide (19 mg, 0.2 mmol) under nitrogen. , heat to the reaction overnight. After the reaction was completed, the mixture was cooled to room temperature, EtOAc EtOAc m. The residue was separated and purified by silica gel column chromatography (eluent eluting with methylene chloride: methanol: 90:10) to give the title compound 4-methyl-N-[4-(4-methyl-piperazine- 1-ylmethyl)-3-trifluoromethyl-phenyl]-3-(6-morpholine-4-yl-[1,2,4]triazole[4,3-a]pyridine-3 -benyl block) -benzamide (yellow solid, 15 mg). iH-NMR (300MHz, CD ₃ OD): δ 8.14 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.72- 7.84 (m, 4H), 7.40 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 9.6 Hz, 1H), 3.81 (t, J = 4.2 Hz, 4H), 3.73 (s, 2H), 3.57 (t, J = 4.8 Hz, 4H), 3.18 (m, 4H), 2.60-2.79 (m, 10H). MS m/z (ESI): 618.3 [M+H

以各种芳基卤化物为起始原料，用吗啉及其衍生物，哌嗪及其衍生物，哌啶及其衍生物，哌啶醇，四氢呋喃醇，取代乙胺及其衍生物和取代氨基乙醇衍生物为另一原料，采用通用方法三相同的合成方法得到实施例化合物 113〜实施例化合物 139。 Starting from various aryl halides, using morpholine and its derivatives, piperazine and its derivatives, piperidine and its derivatives, piperidinol, tetrahydrofuranol, substituted ethylamine and its derivatives and substitutions The aminoethanol derivative was used as another starting material, and Example Compound 113 to Example Compound 139 were obtained by the same synthetic method as in General Method 3.

CS.S.0/CT0ZN3/X3d LLOLllZIOZ OAV CS.S.0/CT0ZN3/X3d LLOLllZIOZ OAV

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CS.S.0/CT0ZN3/X3d LLOL iOZ OAV

CS.S.0/CT0ZN3/X3d LLOL iOZ OAV

将 3-(6-氯 -[1，2，4]*** [4，3-b]哒嗪 -3-乙块基 )-4-甲基 -N-[4-(4-甲基哌嗪 -1-甲基) -3-三氟甲基苯基] -苯甲酰胺 (30 mg, 0.05 mmol)、 1-甲基 -4-(4，4，5，5-四甲基 -[1，3，2]二氧硼烷 -2-基) -1H- 吡唑 (21 mg, 0.10 mmol)和碳酸钾 (21 m_& 0.15 mmol)溶于 N，N-二甲基甲酰胺 (2 mL)和水 (0.5 mL)的混合溶剂中，置于 lO mL封管中。体系用氮气鼓泡 10分钟，快速加入四三苯基膦钯 (6 mg, 0.005 mmol), 加热到 90°C反应过夜。反应液冷却到室温，加入二氯甲烷稀释，分出有机相，有机相分别用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到目标化合物 4-甲基 -Ν-[4-(Φ甲基哌嗪 -1-甲基) -3-三氟甲基苯 —3-[6-(1-甲基 -1Η-吡唑 -4-基 )-[1，2，4]*** [4，3-b]哒嗪 -3-乙块基] -苯甲酰胺 (黄色固体， 16mg)。 1H-NMR (300MHz, CD₃OD): δ 8.35(s, 1Η), 8.11-8.22(m, 4H)， 7.92-7.97(m, 2H), 7.71-7.76(m, 2H), 7.47(d, J=7.8Hz, 1H), 7.90(s, 1H), 3.95(s, 3H), 3.70(s, 2H), 2.95(m, 4H)， 2.54-2.70(m, 10H)o MSm/z (ESI): 614.2 [M+H]。 3-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene)-4-methyl-N-[4-(4-methylpiperidin Pyrazin-1-methyl)-3-trifluoromethylphenyl]-benzamide (30 mg, 0.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21 mg, 0.10 mmol) and potassium carbonate (21 m _& 0.15 mmol) dissolved in N,N-dimethylformamide (2 In a mixed solvent of mL) and water (0.5 mL), place in a 10 mL sealed tube. The system was sparged with nitrogen for 10 minutes, and tetratriphenylphosphine palladium (6 mg, 0.005 mmol) was quickly added and heated to 90 ° C overnight. The reaction mixture was cooled to room temperature, diluted with methylene chloride, and the organic layer was evaporated. The residue was purified by silica gel column chromatography to give the title compound 4-methyl-indole-[4-(p-methylpiperazin-1-methyl)-3-trifluoromethylbenzene-3-[6-(1 Methyl-1 -pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ethylidene]-benzamide (yellow solid, 16 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.35(s, 1Η), 8.11-8.22(m, 4H), 7.92-7.97(m, 2H), 7.71-7.76(m, 2H), 7.47(d, J=7.8Hz, 1H), 7.90(s, 1H), 3.95(s, 3H), 3.70(s, 2H), 2.95(m, 4H), 2.54-2.70(m, 10H)o MSm/z (ESI ): 614.2 [M+H].

以各类芳基卤化物和芳基硼酸或者硼酸酯为起始原料，采用通用方法四合成得到实施例化合物 142〜实施例 171。 Starting from various types of aryl halides and arylboronic acids or boric acid esters, the compounds of Examples 142 to 171 were obtained by the general method.

编 ESI+ 结构 1H-NMR ESI+ structure 1H-NMR

号 [M+H] No. [M+H]

(300MHz, CDC1₃): δ 8.52-8.58(m, 1H)， _{(300MHz, CDC1 3): δ} 8.52-8.58 (m, 1H),

8.16-8.22(m, 2H), 7.90-8.02(m, 5H)， 7.73(d, 8.16-8.22(m, 2H), 7.90-8.02(m, 5H), 7.73(d,

142 J=8.4Hz, 1H), 7.65(d, J=9.9Hz, 1H), 7.50-7.56(m, 610.2 142 J=8.4Hz, 1H), 7.65(d, J=9.9Hz, 1H), 7.50-7.56(m, 610.2

3H), 7.41(d, J=8.1Hz， 1H)， 3.66(s, 2H), 2.61-2.68 3H), 7.41 (d, J=8.1Hz, 1H), 3.66(s, 2H), 2.61-2.68

(m， HH), 2.42(s, 3H) (m, HH), 2.42(s, 3H)

(300MHz, CD3OD): δ 8.26-8.2 l(m, 1H)， (300MHz, CD3OD): δ 8.26-8.2 l(m, 1H),

8.17-8.1 l(m, 2H), 8.08-8.05(m, 1H), 7.98-7.92(m, 8.17-8.1 l(m, 2H), 8.08-8.05(m, 1H), 7.98-7.92(m,

143 1H), 7.89-7.83(m, 2H), 7.79-7.73 (m， 1H)， 7.54(d, 627.3 143 1H), 7.89-7.83 (m, 2H), 7.79-7.73 (m, 1H), 7.54 (d, 627.3

J=9.3Hz, 1H)， 7.48-7.42(m, 1H)， 3.95(s, 3H), J=9.3Hz, 1H), 7.48-7.42(m, 1H), 3.95(s, 3H),

3.68(s, 2H), 2.81-2.52(m, 14H), 2.47(s, 3H) 3.68(s, 2H), 2.81-2.52(m, 14H), 2.47(s, 3H)

(300MHz, CD3OD): δ 8.12(d, J=2.1Hz, 1H)， (300MHz, CD3OD): δ 8.12 (d, J=2.1Hz, 1H),

8.10-8.04(m, 3H), 7.96-7.90 (m， 2H), 7.82(dd, 8.10-8.04(m, 3H), 7.96-7.90 (m, 2H), 7.82 (dd,

144 J=8.1, 2.1Hz, 1H), 7.74(m, 2H), 7.48 (dd， J=5.1, 551.1 144 J=8.1, 2.1Hz, 1H), 7.74(m, 2H), 7.48 (dd, J=5.1, 551.1

1.8Hz, 3H), 7.40(d, J=8.1Hz, 1H)， 3.67(s, 2H), 1.8Hz, 3H), 7.40 (d, J=8.1Hz, 1H), 3.67(s, 2H),

2.75-2.50(m, 14H), 2.43(s, 3H) 2.75-2.50(m, 14H), 2.43(s, 3H)

(300MHz, CDCI3): δ 8.54(s， 1H), 8.07(d, J=1.2Hz, (300MHz, CDCI3): δ 8.54(s, 1H), 8.07(d, J=1.2Hz,

1H), 8.01(s， 1H), 8.00(s， 1H), 7.94-7.96(m, 3H), 1H), 8.01(s, 1H), 8.00(s, 1H), 7.94-7.96(m, 3H),

7.85(d, J=6.9Hz, 1H)， 7.81 (dd, J=6.3, 1.5Hz， 1H)， 7.85 (d, J = 6.9 Hz, 1H), 7.81 (dd, J = 6.3, 1.5 Hz, 1H),

145 613.3 145 613.3

7.74(d, J=6.6Hz, 1H), 7.39(d, J=6.0Hz, 1H), 7.74 (d, J = 6.6 Hz, 1H), 7.39 (d, J = 6.0 Hz, 1H),

7.27(d, J=6.3Hz, 1H)， 3.98(s, 3H), 3.66(s, 2H), 7.27 (d, J = 6.3 Hz, 1H), 3.98 (s, 3H), 3.66 (s, 2H),

2.70(s, 3H), 2.57(m, 8H), 2.37(s, 3H) 2.70(s, 3H), 2.57(m, 8H), 2.37(s, 3H)

(300MHz, CDCI3): δ 8.74(s, 1H)， 8.06(s， 1H)， (300MHz, CDCI3): δ 8.74(s, 1H), 8.06(s, 1H),

8.03(d, J=1.5Hz, 1H)， 7.92-8.01(m, 5H)， 7.82(dd, 8.03 (d, J = 1.5 Hz, 1H), 7.92-8.01 (m, 5H), 7.82 (dd,

146 J=6.0, 1.5Hz, 1H), 7.67(d, J=6.3 Hz, 1H), 7.53(d, 610.3 146 J=6.0, 1.5Hz, 1H), 7.67(d, J=6.3 Hz, 1H), 7.53(d, 610.3

J=7.2Hz, 1H), 7.47-7.50(m, 3H), 7.36(d, J=6.3 Hz, J=7.2Hz, 1H), 7.47-7.50(m, 3H), 7.36(d, J=6.3 Hz,

1H), 3.67(s, 2H), 2.70-2.72(m, 11H), 2.47(s, 3H) 1H), 3.67(s, 2H), 2.70-2.72(m, 11H), 2.47(s, 3H)

CS.S.0/CT0ZN3/X3d LLOL iOZ OAV CS.S.0/CT0ZN3/X3d LLOL iOZ OAV

CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV

CS.S.0/CTOZN3/X3d

实施例 172 : 3-[6-(l-丁基 -IH-吡唑 -4-基) -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基] -4-甲基 -_N-[4-(4-甲 CS.S.0/CTOZN3/X3d

Example 172: 3-[6-(l-Butyl-IH-pyrazol-4-yl)-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene ]-4-Methyl- _N- [4-(4-A

第一步： 1-丁基 -4-(4，4，5，5-四甲基 -[1，3，2]二氧硼烷 -2-基) -1Η-吡唑 First step: 1-butyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)-1pyridazole

将 4-(4，4，5，5-四甲基 -1，3，2-二噁硼戊环 -2-基) -1Η-吡唑 (194 mg， 1 mmol)溶于 N，N-二甲基甲酰胺 5 mL)中，向其中加入 1-碘-正丁烷0.13 mL， 1.1 mmol)及无水碳酸铯 (489 mg， 1.5 mmol), 加热至 100°C反应过夜。反应结束后，冷却至室温，加入水淬灭反应，乙酸乙酯萃取，有机相分别用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化 (淋洗液用石油醚：乙酸乙酯体积比为 80:20 的溶液)得到中间体 1-丁基 -4-(4，4，5，5-四甲基 -[1，3，2]二氧硼烷 -2-基) -1H-吡唑 (无色油状物， 180 mg)。 i i-NMR (300MHz, CDCI3): δ 7.77(s, 1Η)， 7.67(s, 1Η)， 4.1 l(t, J=5.4Hz, 2Η), 1.79-1.87(m, 2H), 1.27-1.35(m, 14H), 0.91 (t,J=5.4Hz, 3H M Sm/z (ESI): 251.2 [M+H]。 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-l-pyrazole (194 mg, 1 mmol) was dissolved in N,N- To dimethylformamide (5 mL), 0.13 mL of 1-iodo-n-butane, 1.1 mmol) and anhydrous cesium carbonate ( 489 mg, 1.5 mmol) were added thereto, and the mixture was heated to 100 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature. EtOAc was evaporated. The residue was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc Base-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (colorless oil, 180 mg). i i-NMR (300MHz, CDCI3): δ 7.77(s, 1Η), 7.67(s, 1Η), 4.1 l(t, J=5.4Hz, 2Η), 1.79-1.87(m, 2H), 1.27-1.35 (m, 14H), 0.91 (t, J = 5.4 Hz, 3H M Sm/z (ESI): 251.2 [M+H].

第二步： 3-[6-(l-丁基 -IH-吡唑 -4-基) -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基] -4-甲基 -N-[4-(4- 甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -苯甲酰胺 Second step: 3-[6-(l-butyl-IH-pyrazol-4-yl)-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene -4-Methyl-N-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide

将 3-( 6-氯 -[ 1，2,4]***并 [4，3-a]吡啶 -3-基）乙块基 )-4-甲基 -Ν-(4-( Φ甲基哌嗪 - 1 -基）甲基) -3- (三氟甲基)苯基)苯甲酰胺 (57 mg， 0.1 mmol)溶于 N，N-二甲基甲酰胺（2 mL)及水 (0.5 mL)的混合溶液中，搅拌下依次加入 1-丁基 -4-(4，4，5，5 -四甲基 -1，3，2-二噁硼戊环 -2-基) -1H- 吡唑50 mg， 0.2 mmol)及无水碳酸钾 41 mg， 0.3 mmol), 体系用氮气鼓泡 15分钟后快速向其中加入催化剂 PdCl₂ (dppf)CH₂Cl₂ (8 mg， 0.01 mmol), 加完后，反应液加热至 100 反应过夜。反应结束后，冷却至室温，加入乙酸乙酯萃取，分出有机相，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化 (淋洗液用二氯甲烷：甲醇体积比为 90: 10的溶液)得到目标化合物 3-[6-(1-丁基 -1H-吡唑 -4-基 )-[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基] -4-甲基 -N-[4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -苯甲酰胺 (黄色固体， 30 mg)。1H-NMR (300MHz, CD₃OD): δ 8.26(d, J=3.0 Hz, IH), 8.15(d, J=1.5Hz, 1H)_: 8.06(m， 2H), 7.90-7.96(m, 2H), 7.80-7.87 (m, 2H), 7.73(d, J=8.4Hz, IH), 7.53-7.57(m, 1H)， 7.35-7.39(m, IH), 4.16(t, J=6.9Hz, 2H), 3.73(s, 2H), 3.17(m, 4H)， 2.62-2.79(m, 10H), 1.79-1.89(m, 2H), 1.26-1.35(m, 2H), 0.93(t，J=7.2Hz， 3H)。 MSm/z (ESI): 655.3 [M+H]。 3-( 6-Chloro-[ 1,2,4]triazolo[4,3-a]pyridin-3-yl)ethylidene)-4-methyl-indole-(4-( Φmethyl) Piperazine-1 -yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (57 mg, 0.1 mmol) dissolved in N,N-dimethylformamide (2 mL) In a mixed solution of 0.5 mL), 1-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H was added in sequence with stirring. - pyrazole 50 mg, 0.2 mmol) and anhydrous potassium carbonate 41 mg, 0.3 mmol). The system was bubbled with nitrogen for 15 minutes and then rapidly added to the catalyst PdCl ₂ (dppf) CH ₂ Cl ₂ (8 mg, 0.01 mmol) , after the addition, the reaction solution is heated to 100 reaction Overnight. After completion of the reaction, the mixture was cooled to room temperature, EtOAc was evaporated, evaporated, evaporated. The residue was purified by column chromatography on silica gel eluting eluting eluting eluting eluting eluting eluting with )-[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene]-4-methyl-N-[4-(4-methyl-piperazin-1- Methyl)-3-trifluoromethyl-phenyl]-benzamide (yellow solid, 30 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.26 (d, J = 3.0 Hz, IH), 8.15 (d, J = 1.5 Hz, 1H) _: 8.06 (m, 2H), 7.90-7.96 (m, 2H) ), 7.80-7.87 (m, 2H), 7.73 (d, J = 8.4 Hz, IH), 7.53-7.57 (m, 1H), 7.35-7.39 (m, IH), 4.16 (t, J = 6.9 Hz, 2H), 3.73(s, 2H), 3.17(m, 4H), 2.62-2.79(m, 10H), 1.79-1.89(m, 2H), 1.26-1.35(m, 2H), 0.93(t,J= 7.2 Hz, 3H). MS m/z (ESI): 655.3 [M+H].

分别以异丙基溴， 3—溴丙腈， 4-(2-氯-乙基) -***啉盐酸盐，（2-氯-乙基) -二甲基胺盐酸盐和 1-氯 -2-甲氧基-乙烷等卤化物为原料合成取代吡唑硼酸酯，采用实施例 172相同的方法合成得到实施例化合物 173〜实施例 181。 By isopropyl bromide, 3-bromopropionitrile, 4-(2-chloro-ethyl)-morpholine hydrochloride, (2-chloro-ethyl)-dimethylamine hydrochloride and 1-chloro The compound of Example 173 to Example 181 was synthesized in the same manner as in Example 172 by substituting a substituted pyrazole boronic acid ester with a halide such as 2-methoxy-ethane.

通用方法五：将游离碱（l eq. ) 溶解在干燥的溶剂中，如无水 N，N-二甲基甲酰胺，二氯甲烷等，加入有机碱（2 eq. ) 如三乙胺、二异丙基乙胺和 DMAP等，冰浴冷却下缓慢滴加酰氯，氯甲酸酯或者酸酐（1.5 eq. )等，滴加完毕室温反应至原料消失。加入二氯甲烷等有机溶剂萃取，有机相用饱和碳酸氢钠溶液、水、饱和食盐水洗涤，干燥，过滤，减压浓缩，硅胶柱层析分离纯化得到目标化合物。实施例 182: N-(2-乙酰基 -2,3-二氢 -1H-异吲哚啉 -5-基) -3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基- 苯甲酰胺

General Method 5: Dissolve the free base (l eq.) in a dry solvent such as anhydrous N,N-dimethylformamide, dichloromethane, etc., and add an organic base (2 eq.) such as triethylamine. Diisopropylethylamine, DMAP, etc., slowly add an acid chloride, a chloroformate or an acid anhydride (1.5 eq.), etc. under ice cooling, and react at room temperature until the starting material disappears. The organic phase is extracted with an organic solvent such as dichloromethane, and the organic phase is washed with saturated aqueous sodium hydrogen carbonate, water, and brine, dried, filtered, and evaporated. Example 182: N-(2-acetyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridine-3-ethylidene-4 -methyl-benzamide

将 N-(2，3-二氢 -1H-异吲哚 -5-基) -3-咪唑 [l，2-a]吡啶 -3-基乙块基 -4-甲基-苯甲酰胺 (40 m_& 0.1 mmol)和 N，N-二异丙基乙胺 (52 mg, 0.4 mmol)溶于无水 N，N-二甲基甲酰胺（3 mL)中，冰浴冷却下向其中缓慢滴加乙酰氯 (16 m_& 0.2 mmol), 滴加完毕，室温继续反应 2小时。反应完毕，加入二氯甲烷和饱和碳酸氢钠溶液淬灭反应，分出有机相，有机相依次用稀盐酸、水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到目标化合物 N-(2-乙酰基 -2,3-二氢 -1H-异吲哚啉 -5-基) -3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基-苯甲酰胺 (黄色固体， 16 mg)。 iH-NMR (300MHz, CDC1₃): δ 8.61(s, IH), 8.33(m, IH), 8.07(s 1H), 7.96(s, 1H), 7.72-7.92(m, 2H), 7.59-7.65(m, 2H), 7.38-7.42(m, 2H), 7.29-7.3 l(m, 1H)， 6.97-7.00(m, 1H)， 4.79(m, 4H)， 2.60(s, 3H), 2.16(s, 3H)。 MSm/z (ESI): 435.2 [M+H]。实施例 183: N-O环丙甲基 -2，3-二氢 -1H-异吲哚啉 -5-基) -3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基 -苯甲酰胺 N-(2,3-Dihydro-1H-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide ( 40 m _& 0.1 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). Acetyl chloride (16 m _& 0.2 mmol) was added dropwise, and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction mixture was combined with methylene chloride and aq. The residue was purified by silica gel column chromatography to give the title compound N-(2-acetyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridine 3-Ethyl 4-methyl-benzamide (yellow solid, 16 mg). iH-NMR (300MHz, CDC1 ₃ ): δ 8.61(s, IH), 8.33(m, IH), 8.07(s 1H), 7.96(s, 1H), 7.72-7.92(m, 2H), 7.59-7.65(m, 2H), 7.38-7.42(m, 2H), 7.29-7.3 l(m, 1H), 6.97-7.00 (m, 1H), 4.79 (m, 4H), 2.60 (s, 3H), 2.16 (s, 3H). MS m/z (ESI): 435.2 [M+H]. Example 183: NOcyclopropylmethyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridin-3-ethlyl-4-yl Base-benzamide

将 N-(2，3-二氢 -1H-异吲哚 -5-基) -3-咪唑 [l，2-a]吡啶 -3-基乙块基 -4-甲基-苯甲酰胺 (40 m_& 0.1 mmol)和 N，N-二异丙基乙胺 (52 mg, 0.4 mmol)溶于无水 N，N-二甲基甲酰胺（3 mL)中，冰浴冷却下向其中缓慢滴加环丙基甲基溴 (27 m_& 0.2 mmol), 滴加完毕，加热至 50<€继续反应过夜。反应完毕，加入二氯甲烷和饱和碳酸氢钠溶液淬灭反应，分出有机相，有机相依次用稀盐酸，水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩.剩余物用硅胶柱层析分离纯化得到目标化合物 N-(2-环丙甲基 -2,3-二氢 -1H-异吲哚啉 -5-基) -3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基-苯甲酰胺 (黄色固体， 14 mg)。 1H-NMR (300MHz, CDC1₃): δ 8.74(s, 1Η)， 8.43(d, J=4.8Hz, 1H), 8.18(s， 1H)， 7.94(s, 1H), 7.87(m, 1H), 7.79(s, 1H), 7.65(m, 1H), 7.54(m, 1H), 7.37(s, 1H), 7.26-7.32(m, 1H), 7.14(s, 1H), 6.97-7.00(m, 1H), 4.29(m, 4H)， 2.88(m, 2H), 2.59(s, 3H), 0.86(m, lH)，0.65(m， 2H), 0.32(m, 2H)。 MSm/z (ESI): 447.2 [M+H]。 N-(2,3-Dihydro-1H-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide ( 40 m _& 0.1 mmol) and N,N-diisopropylethylamine (52 mg, 0.4 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). Cyclopropylmethyl bromide (27 m _& 0.2 mmol) was added dropwise, and the addition was completed, and the reaction was continued until 50 < €. After completion of the reaction, the reaction mixture was quenched with methylene chloride and saturated aqueous sodium hydrogen carbonate, and the organic phase was separated. The organic phase was washed with dilute hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The title compound N-(2-cyclopropylmethyl-2,3-dihydro-1H-isoindoline-5-yl)-3-imidazo[l,2-a]pyridine was isolated and purified by silica gel column chromatography. 3-Ethyl 4-methyl-benzamide (yellow solid, 14 mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.74(s, 1Η), 8.43(d, J=4.8Hz, 1H), 8.18(s, 1H), 7.94(s, 1H), 7.87(m, 1H) , 7.79(s, 1H), 7.65(m, 1H), 7.54(m, 1H), 7.37(s, 1H), 7.26-7.32(m, 1H), 7.14(s, 1H), 6.97-7.00(m , 1H), 4.29 (m, 4H), 2.88 (m, 2H), 2.59 (s, 3H), 0.86 (m, lH), 0.65 (m, 2H), 0.32 (m, 2H). MS m/z (ESI): 447.2 [M+H].

以 Ν-(2，3-二氢 -1Η-异吲哚 -5-基) -3-咪唑 [l，2-a]吡啶 -3-基乙块基 -4-甲基-苯甲酰胺为原料，分别用苄溴和 4-溴甲基 -哌啶 -1-甲酸叔丁酯替换环丙甲基溴，采用实施例 183相同的方 Ν-(2,3-Dihydro-1 Η-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide The starting materials were replaced with benzyl bromide and 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester, respectively, using the same formula as in Example 183.

实施例 186: 2-[5-(3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基 -苯甲酰胺) -1，3-二氢-异吲哚啉 -2-酰基吡咯啉 -1-甲酸叔丁酯

Example 186: 2-[5-(3-Imidazo[l,2-a]pyridine-3-ethylidene-4-methyl-benzamide)-1,3-dihydro-isoindoline- 2-Acylpyrroline-1-carboxylic acid tert-butyl ester

将 N-(2，3-二氢 - 1H-异吲哚 -5-基) -3 -咪唑 [1，2-a]吡啶 -3 -基乙块基 -4 -甲基-苯甲酰胺 (200 mg, 0.47 mmol)及 2-(7-氮杂苯并三氮唑)- ^-四甲基脲六氟磷酸酯(213 mg, 0.56mmol) 溶于无水 N，N-二甲基甲酰胺（10 mL)中，冰浴冷却下依次向其中加入 (S)-l- (叔丁氧羰基)口比咯烷 -2-甲酸 (121 mg， 0.56 mmol)及 N，N-二异丙基乙胺 (0.12 mL， 0.70 mmol), 室温反应过夜。反应结束后，加水淬灭反应，乙酸乙酯萃取 (25 mL X 3), 有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化得到目标化合物 2-[5-(3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基 -苯甲酰胺) -1,3-二氢-异吲哚啉 -2-酰基] -吡咯啉 -1-甲酸叔丁酉旨 (黄色固体， 116 mg)。 1H-NMR (300MHz, CDC1₃): δ 8.45(s, 1Η), 7.94-8.13(m, 2H), 7.82-7.86(m, 2H), 7.73-7.78(m, 2H), 7.35-7.44(m, 3H), 7.05-7.15(m, 2H), 4.45-5.07(m, 5H)， 3.41-3.65(m, 2H), 2.60(s, 3H), 2.09-2.29(m, 2H), 1.44-2.00(m, 2H), 1.43(s, 9H)。 MS m/z (ESI) : 590.3 [M+H] N-(2,3-Dihydro-1H-isoindol-5-yl)-3-imidazo[1,2-a]pyridin-3-ylethylidene-4-methyl-benzamide ( 200 mg, 0.47 mmol) and 2-(7-azabenzotriazole)-^-tetramethylurea hexafluorophosphate (213 mg, 0.56 mmol) dissolved in anhydrous N,N-dimethyl In the amide (10 mL), the (S)-l-(tert-butoxycarbonyl) port ratio was sequentially added thereto under ice cooling. R.sub.2-carboxylic acid (121 mg, 0.56 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.70 mmol). After the reaction was completed, the mixture was evaporated. The residue was purified by silica gel column chromatography to give the title compound 2-[5-(3-imidazo[l,2-a]pyridin-3-ethylidyl-4-methyl-benzamide)-1,3- Dihydro-isoindoline-2-yl]-pyrroline-1-carboxylic acid tert-butylate (yellow solid, 116 mg). 1H-NMR (300MHz, CDC1 ₃ ): δ 8.45(s, 1Η), 7.94-8.13(m, 2H), 7.82-7.86(m, 2H), 7.73-7.78(m, 2H), 7.35-7.44(m , 3H), 7.05-7.15(m, 2H), 4.45-5.07(m, 5H), 3.41-3.65(m, 2H), 2.60(s, 3H), 2.09-2.29(m, 2H), 1.44-2.00 (m, 2H), 1.43 (s, 9H). MS m/z (ESI): 590.3 [M+H]

以 N-(2，3-二氢 -1H-异吲哚 -5-基) -3-咪唑 [l，2-a]吡啶 -3-基乙块基 -4-甲基-苯甲酰胺为原料，用各种氨基酸衍生物和烟酸替换脯氨酸叔丁酯，采用实施例 186相同的方法合成得到实施例化合物 187〜实施例 191。 N-(2,3-dihydro-1H-isoindol-5-yl)-3-imidazo[l,2-a]pyridin-3-ylethylidene-4-methyl-benzamide The starting material, the valine tert-butyl ester was replaced with various amino acid derivatives and nicotinic acid, and Example Compound 187 to Example 191 were synthesized in the same manner as in Example 186.

实施例 192: 4-{4-[4-(4-甲基 -3-[l，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基-苯甲酰胺 )-2-三氟甲基- 苄基] -哌嗪 -1—基哌啶 -1—甲酸叔丁酯

Example 192: 4-{4-[4-(4-methyl-3-[l,2,4]triazolo[4,3-a]pyridin-3-ylethylidene-benzamide) -2-trifluoromethyl-benzyl]-piperazine-1-piperidine-1-carboxylic acid tert-butyl ester

将 4-甲基 -N-(4-哌嗪 -1-基甲基 -3-三氟甲基-苯基) -3-[l，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基 -苯甲酰胺 (160 mg, 0.31 mmol)溶于甲醇 (5 ml), 然后向其中加入 4-氧代 -哌啶 -1-甲酸叔丁酯 (309 m_& 1.55 mmol)及冰醋酸 (19 m_& 0.31 mmol)，加热回流 24 h后，冷却至室温，继续向其中缓慢加入硼氢化钠 (329 m_& 1.55 mmol), 室温反应 2 h后继续加热回流 24 h。反应结束后，冷却至室温，加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取，有机相分别用饱和碳酸氢钠溶液、水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化得到目标化合物 (黄色固体， 27 mg)。 1H-NMR (300MHz, CD₃OD): δ 8.56(d， J=6.0Hz, IH), 8.29(s, 1H)， 8.13(s, IH), 7.95(m, 2H), 7.87(d, J=9.6Hz, 1H)， 7.75(d, J=8.7Hz, 1H)_: 7.59 (t, J=6.9Hz, 1H)， 7.51(dd, J=8.1,3.6Hz, 1H)， 7.23(t, J=7.2Hz, 1H)， 4.12(m, 2H), 3.64(s, 2H),4-Methyl-N-(4-piperazin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-[l,2,4]triazole [4,3-a] Pyridin-3-ylethylidene-benzamide (160 mg, 0.31 mmol) was dissolved in methanol (5 ml), then 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (309 m _& 1.55) Ethyl acetate and glacial acetic acid (19 m _& 0.31 mmol), heated to reflux for 24 h, then cooled to room temperature and then slowly added sodium borohydride (329 m _& 1.55 mmol), and allowed to react at room temperature for 2 h and then heated to reflux for 24 h. After completion of the reaction, the mixture was cooled to room temperature, and then the mixture was evaporated to dryness. concentrate. The residue was purified by silica gel column chromatography eluting 1H-NMR (300MHz, CD ₃ OD): δ 8.56 (d, J = 6.0Hz, IH), 8.29(s, 1H), 8.13(s, IH), 7.95(m, 2H), 7.87(d, J = 9.6 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H) _: 7.59 (t, J = 6.9 Hz, 1H), 7.51 (dd, J = 8.1, 3.6 Hz, 1H), 7.23 (t, J =7.2Hz, 1H), 4.12(m, 2H), 3.64(s, 2H),

2.40-2.73(m, 14H), 1.91(m, 2H), 1.44(s, 9H)， 1.33-1.38(m, 2H)。 MSm/z (ESI): 604.3 [M+H]。 2.40-2.73 (m, 14H), 1.91 (m, 2H), 1.44 (s, 9H), 1.33-1.38 (m, 2H). MS m/z (ESI): 604.3 [M+H].

以实施例化合物 185， 191， 192为原料，采用通用方法二合成得到实施例 193〜实施例 Using Example Compounds 185, 191, and 192 as raw materials, the general method 2 was used to obtain Examples 193 to #Examples.

195。 195.

实施例 196: 3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基 -N-[2-(l-甲基 -B比咯烷 -2-酰基) -2，3-二氢 -1H- 异吲哚啉 -5-基] -苯甲酰胺

Example 196: 3-imidazo[1,2-a]pyridin-3-ethenyl-4-methyl-N-[2-(l-methyl-B-pyrrol-2-yl)-2, 3-dihydro-1H-isoindoline-5-yl]-benzamide

以 3-咪唑 [1，2-a]吡啶 -3-基乙块基 -4-甲基 -N-[2-(B比咯烷 -2-酰基) -2，3 -二氢 -1H-异吲哚 -5- 基] -苯甲酰胺为原料，采用实施例 184类似的方法合成，用碘甲烷替换环丙甲基溴，得到目标化合物 3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基 -N-[2-(l-甲基 -B比咯啉 -2-酰基) -2,3-二氢 -1H-异吲哚啉 -5-基] -苯甲酰胺 (浅黄色固体， 31 mg -NMR (300MHz, CDC1₃): δ 8.79(1Η, s), 8.32(d J=8.1Hz, IH), 8.08(s， IH), 7.95(s, IH), 7.75-7.89(m, 2H), 7.59-7.62(m, 2H), 7.30-7.45(m, 2H), 7.20-7.26(m, IH), 6.94-6.99(m, IH), 4.74-4.97(m, 5H)， 3.48-3.53(s, IH), 3.30(s, IH), 2.58(s, 3H)_: 2.5 l(m, IH), 2.18-2.32(m, 2H), 1.94-2.06(m, 4H)。 MSm/z (ESI): 504.2 [M+H]。实施例 197: N-[2-(l-乙酰基 -哌啶 -4-酰基) -2，3-二氢 -IH-异吲哚啉 -5-基] -3-咪唑 [l，2-a]吡啶 -3- 乙块基—4-甲基-苯甲酰胺

3-Imidazo[1,2-a]pyridin-3-ylethylidene-4-methyl-N-[2-(B-pyrrolidino-2-yl)-2,3-dihydro-1H- Isoindole-5-yl]-benzamide was used as a starting material, which was synthesized by a similar method as in Example 184, and Cyclomethicone was replaced with methyl iodide to obtain Standard compound 3-imidazole [l,2-a]pyridine-3-ethylidene-4-methyl-N-[2-(l-methyl-B-pyroline-2-yl)-2,3- Dihydro-1H-isoindoline-5-yl]-benzamide (light yellow solid, 31 mg - NMR (300MHz, CDC1 ₃ ): δ 8.79 (1 Η, s), 8.32 (d J = 8.1 Hz, IH), 8.08(s, IH), 7.95(s, IH), 7.75-7.89(m, 2H), 7.59-7.62(m, 2H), 7.30-7.45(m, 2H), 7.20-7.26(m, IH), 6.94-6.99(m, IH), 4.74-4.97(m, 5H), 3.48-3.53(s, IH), 3.30(s, IH), 2.58(s, 3H) _: 2.5 l(m, IH ), 2.18-2.32 (m, 2H), 1.94-2.06 (m, 4H) MS m/z (ESI): 504.2 [M+H]. Pyridin-4-yl)-2,3-dihydro-IH-isoindoline-5-yl]-3-imidazo[l,2-a]pyridine-3-ethylidene-4-methyl-benzene Formamide

以 3-咪唑 [l，2-a]吡啶 -3-基乙块基 ylethynyl-4-甲基 methyl-N-[2- (哌啶 piperidine-4-酰基 carbonyl)-2，3-二氢 di ydro-lH-异吲哚 -5-基 yl]-苯甲酰胺 benzamide为原料，采用通用方法五合成得到目标化合物 N-[2-(l-乙酰基 -哌啶 -4-酰基) -2,3-二氢 -1H-异吲哚啉 -5-基] -3-咪唑 [l，2-a 吡啶 -3-乙块基 -4-甲基-苯甲酰胺 (黄色固体， 30 mg)。 1H-NMR(300MHz，CD₃OD): S 8.55(s， IH), 8.14(s, IH), 7.94(s, lH), 7.83(m, 2H), 7.42-7.70(m, 5H), 7.29(m, 2H), 7.20(m, lH)，4.96(m， 2H), 4.69(m， 2H), 4.56(m， IH), 3.99(m, IH), 3.23(m, IH), 2.89-2.96(m, IH), 2.75(m, IH), 2.61(s, 3H), 2.11(s, 3H), 1.55-1.90(m，4H)。 MSm/z (ESI): 546.2 [M+H]。实施例 198: 4-甲基 -N-[4-(4-正丙基 -哌嗪 -1-甲基) -3-三氟甲基苯基 ]-3-[l，2，4]*** [4，3-a]吡啶 -3-乙块基-苯甲酰胺 3-Imidazo[l,2-a]pyridin-3-ylethyl ylethynyl-4-methylmethyl-N-[2-(piperidinylpiperidine-4-ylcarbonyl)-2,3-dihydrodi ydro-lH-isoindole-5-yl-yl]-benzamide benzamide is used as a raw material, and the target compound N-[2-(l-acetyl-piperidin-4-yl)-2 is obtained by the general method. 3-Dihydro-1H-isoindoline-5-yl]-3-imidazole [l,2-a pyridine-3-ethylidene-4-methyl-benzamide (yellow solid, 30 mg). 1H-NMR (300MHz, CD ₃ OD): S 8.55 (s, IH), 8.14 (s, IH), 7.94 (s, lH), 7.83 (m, 2H), 7.42-7.70 (m, 5H), 7.29 (m, 2H), 7.20(m, lH), 4.96(m, 2H), 4.69(m, 2H), 4.56(m, IH), 3.99(m, IH), 3.23(m, IH), 2.89- 2.96 (m, IH), 2.75 (m, IH), 2.61 (s, 3H), 2.11 (s, 3H), 1.55-1.90 (m, 4H). MS m / z (ESI): 546.2 [M+H]. Example 198: 4-Methyl-N-[4-(4-n-propyl-piperazine-1-methyl)-3-trifluoromethylphenyl]-3-[l,2,4] Azole [4,3-a]pyridine-3-ethylidene-benzamide

将 4-甲基 -N-(4-哌嗪 -1-基甲基 -3-三氟甲基-苯基) -3-[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基 -苯甲酰胺 (52 mg, 0.1 mmol), 正丙醛 (29 mg, 0.5 mmol)和冰醋酸 (0.1 mL)溶于甲醇 (3 mL)中，室温搅拌 2小时后，冰浴冷却下，继续向上述反应液中缓慢加入硼氢化钠 (20 mg, 0.5 mmol), 加完后，继续在室温搅拌过夜。反应结束后，加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到目标化合物 4-甲基 -N-[4-(4-正丙基 -哌嗪 -1-甲基) -3-三氟甲基苯基] -3-[1，2，4]*** [4，3-a]吡啶 -3-乙块基-苯甲酰胺 (黄色固体， 26 mg)。 1H-NMR (300MHz, CD₃OD): δ 8.57(s, 1H)， 8.31(s, 1H)， 8.15(s, 1H)， 7.96-8.01(m, 2H), 7.98(d, J=9.3Hz, 1H)， 7.76(d J =8.7Hz, 1H)， 7.58-7.64(m, 1H)， 7.53(d, J=8.1Hz, 1H)， 7.25(t, J=7.2Hz, 1H)， 4.58(m， 1H)， 3.76(s, 2H), 3.13-3.31(m, 4H)， 2.95-3.05(m, 2H), 2.55-2.88(m, 7H), 1.69-1.80(m, 2H), 1.01(t, J=7.5Hz, 3H MSm/z (ESI): 561.3[M+H]。分别以 4-甲基 -N-(4-哌嗪 -1-基甲基 -3-三氟甲基-苯基) -3-[l，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基 -苯甲酰胺， 4-甲基 -N-[4-(3-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -3-[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基 -苯甲酰胺， 3-咪唑 [l，2-a]吡啶 -3-乙块基 -4-甲基 -N-[2- (哌啶 -4-酰基) -2,3-二氢 -1H-异吲哚 -5-基] -苯甲酰胺和 4-甲基 -3-(2-甲基 -咪唑 [l，2-a]吡啶 -3-基乙块基) -_N-(4-哌嗪 -1-基甲基 -3-三氟甲基-苯基)-苯甲酰胺等为原料，采用 2-溴乙醇， 3-溴丙醇， 1-溴 -3-甲氧基-丙烷， 2-(2-溴 -乙氧基)-乙醇， 1-溴 -2-甲氧基-乙烷， 1-溴代丙酮， 4-(2-氯-乙基) -***啉，环丙甲基溴，苄溴，（2-溴乙基) -氨基甲酸酯和 (3-溴丙基) -氨基甲酸叔丁酯等为 4-Methyl-N-(4-piperazin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-[1,2,4]triazole [4,3-a] Pyridin-3-ylethylidene-benzamide (52 mg, 0.1 mmol), n-propanal (29 mg, 0.5 mmol) and glacial acetic acid (0.1 mL) dissolved in methanol (3 mL) Thereafter, under ice cooling, sodium borohydride (20 mg, 0.5 mmol) was slowly added to the above reaction mixture, and after the addition was completed, stirring was continued at room temperature overnight. After the reaction was completed, the mixture was evaporated. The residue was purified by silica gel column chromatography toield toield of 4-methyl-N-[4-(4-n-propyl-piperazine-1-methyl)-3-trifluoromethylphenyl]-3- [1,2,4]triazolo[4,3-a]pyridin-3-ethlyl-benzamide (yellow solid, 26 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.57(s, 1H), 8.31(s, 1H), 8.15(s, 1H), 7.96-8.01(m, 2H), 7.98(d, J=9.3Hz , 1H), 7.76(d J =8.7Hz, 1H), 7.58-7.64(m, 1H), 7.53(d, J=8.1Hz, 1H), 7.25(t, J=7.2Hz, 1H), 4.58( m, 1H), 3.76(s, 2H), 3.13-3.31(m, 4H), 2.95-3.05(m, 2H), 2.55-2.88(m, 7H), 1.69-1.80(m, 2H), 1.01( t, J=7.5 Hz, 3H MSm/z (ESI): 561.3 [M+H]. 4-methyl-N-(4-piperazin-1-ylmethyl-3-trifluoromethyl- Phenyl)-3-[l,2,4]triazole[4,3-a]pyridin-3-ylethylidene-benzamide, 4-methyl-N-[4-(3-A Benzyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene -benzamide, 3-imidazo[l,2-a]pyridin-3-ethenyl-4-methyl-N-[2-(piperidin-4-yl)-2,3-dihydro-1H - isoindol-5-yl] - benzamide and 4-methyl-3- (2-methyl - imidazo [l, 2-a] pyridin-3-yl acetylene-yl) - _N - (4- Piperazine-1-ylmethyl-3-trifluoromethyl-phenyl)-benzamide or the like as a starting material, using 2-bromoethanol, 3-bromopropanol, 1-bromo-3-methoxy-propane , 2-(2-bromo-ethoxy)-ethanol, 1-bromo-2-methoxy-B Alkanes, 1-bromoacetone, 4-(2-chloro-ethyl)-morpholine, cyclopropylmethyl bromide, benzyl bromide, (2-bromoethyl)-carbamate and (3-bromopropyl) ) - tert-butyl carbamate, etc.

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CS.S.0/CT0ZN3/X3d LLOLllZIOZ OAV 以实施例化合物 98， 191， 193为原料，采用通用方法五合成得到以下实施例 216〜实施例 220。CS.S.0/CT0ZN3/X3d LLOLllZIOZ OAV Using the example compounds 98, 191, and 193 as raw materials, the following Examples 216 to 220 were obtained by the general method.

实施例 221 : N-{4-[4-(3-羟基 -2-甲基-丙基) -哌嗪 -1-基甲基 ]-3- 三氮唑 [4，3-a]吡啶 -3-基乙块基-苯甲酰胺

Example 221: N-{4-[4-(3-Hydroxy-2-methyl-propyl)-piperazin-1-ylmethyl]-3-triazole [4,3-a]pyridine- 3-ylethylidene-benzamide

= =

^rS ^o丫' ^rS ^o丫'

第一步：甲苯 -4-磺酸 3-羟基 -2-甲基 -丙酯将 2-甲基 -1,3-丙二醇 (0.9 g， 10 mmol)溶于吡啶 (10 mL)，冰浴冷却至 0°C，向其中分批加入 4-甲基苯磺酰氯 (2.0 g, 11 mmol), 加完后，撤去冰浴，继续室温搅拌过夜。反应结束后，蒸干溶剂，残余物溶于水，用乙酸乙酯萃取，分出有机相，分别用稀盐酸、水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化得到中间体甲苯 -4-磺酸 3-羟基 -2-甲基 -丙酯 (；无色油状液体， 1.3 g 1H-NMR (300MHz, CDC1₃): δ 7.79(m, 2Η), 7.35(m, 2H), 3.98-4.05(m, 2H), 3.49-3.60(m, 2H), 2.45(s, 3H), 1.96-2.04(m, 1H)， 0.92(d, J=5.4Hz, 3H MSm/z (ESI): 267.1 [M+H]。 First step: 3-hydroxy-2-methyl-propyl toluene-4-sulfonate 2-Methyl-1,3-propanediol (0.9 g, 10 mmol) was dissolved in pyridine (10 mL), cooled to 0 ° C in an ice bath, and 4-methylbenzenesulfonyl chloride (2.0 g, 11 mmol), after the addition was completed, the ice bath was removed and stirring was continued at room temperature overnight. After the reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The residue obtained intermediate toluene-4-sulfonic acid 3-hydroxy-2-methyl purified by silica gel column chromatography separation - ester (; colorless oil, 1.3 g 1H-NMR (300MHz , CDC1 3): δ 7.79 (m, 2Η), 7.35(m, 2H), 3.98-4.05(m, 2H), 3.49-3.60(m, 2H), 2.45(s, 3H), 1.96-2.04(m, 1H), 0.92(d , J = 5.4 Hz, 3H MSm/z (ESI): 267.1 [M+H].

第二步： _N-{4-[4-(3-羟基 -2-甲基-丙基) -哌嗪 -1-基甲基 ]-3-三氟甲基-苯基 4-甲基 -3-[l，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基-苯甲酰胺 Second step: _N- {4-[4-(3-hydroxy-2-methyl-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl-phenyl 4-methyl- 3-[l,2,4]triazole[4,3-a]pyridin-3-ylethylidene-benzamide

将 3-([1，2，4]***并 [4，3-a]吡啶 -3-基乙块基) -Ν-(4-((4-(3-氨基丙基)哌嗪 -1-基)甲基 H三氟甲基)苯基) -4-甲基苯酰胺 (52 mg 0.10 mmol)溶于 Ν，Ν-二甲基甲酰胺（2 mL)，向其中加入甲苯 -4-磺酸 3-羟基 -2-甲基 -丙酯 (49 mg, 0.20 mmol)及 N，N-二异丙基乙胺 (0.033 mL, 0.20 mmol), 反应液加热至 80°C搅拌过夜。反应结束后，冷却至室温，向其中加入水淬灭反应，乙酸乙酯萃取，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化得到目标化合物 N-{4-[4-(3-羟基 -2-甲基-丙基) -哌嗪 -1-基甲基] -3-三氟甲基 -苯基 }-4-甲基 -3-[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基-苯甲酰胺 (黄色固体， 10 mg)。 1H-NMR (300MHz, CD₃OD): δ 8.58(d， J=5.1Hz， 1H)， 8.32(d, J=1.5Hz， 1H)， 8.15(d， J=1.5Hz, IH), 7.95-8.00(m, 2H), 7.88(d, J=7.2Hz, IH), 7.77(d, J=6.6Hz, IH), 7.59-7.63(m, 1H)， 7.54(d, J=6.0Hz， IH), 7.25(t, J=5.1Hz, 1H)， 3.69(m, 2H), 3.47-3.56(m, 2H), 2.49-2.98(m, 13H), 2.00-2.1 l(m, IH), 0.87-0.92(m, 3H)。 MSm/z (ESI): 591.2 [M+H]。实施例 222: N-{4-[4-(3-二甲胺基-丙基) -哌嗪 -1-基甲基 ]-3-三氟甲基-苯基}-4-甲基 -3-[l，2，4] 三氮唑 [4，3-a]吡啶 -3-基乙块基-苯

3-([1,2,4]Triazolo[4,3-a]pyridin-3-ylethylidene)-indole-(4-((4-(3-aminopropyl)piperazine)- 1-yl)methylH-trifluoromethyl)phenyl)-4-methylbenzamide (52 mg 0.10 mmol) was dissolved in hydrazine, dimethyl-dimethylformamide (2 mL), toluene-4 3-Hydroxy-2-methyl-propyl sulfonate (49 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.033 mL, 0.20 mmol). After the completion of the reaction, the mixture was cooled to room temperature, and then the mixture was evaporated, evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography toield of the title compound N-{4-[4-(3-hydroxy-2-methyl-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl -Phenyl}-4-methyl-3-[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene-benzamide (yellow solid, 10 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.58 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 1.5 Hz, IH), 7.95- 8.00(m, 2H), 7.88(d, J=7.2Hz, IH), 7.77(d, J=6.6Hz, IH), 7.59-7.63(m, 1H), 7.54(d, J=6.0Hz, IH ), 7.25(t, J=5.1Hz, 1H), 3.69(m, 2H), 3.47-3.56(m, 2H), 2.49-2.98(m, 13H), 2.00-2.1 l(m, IH), 0.87 -0.92 (m, 3H). MS m/z (ESI): 591.2 [M+H]. Example 222: N-{4-[4-(3-Dimethylamino-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl-phenyl}-4-methyl- 3-[l,2,4] Triazole [4,3-a]pyridin-3-ylethylidene-benzene

将 N-{4-[4-(3-氨基-丙基) -哌嗪 -1-甲基] -3-三氟甲基-苯基}-4-甲基 -3-[1，2，4]*** [4，3-a]吡啶 -3-乙块基-苯甲酰胺46 mg, 0.08 mmol)溶于甲醇 (；2 mL), 向其中加入 37%甲醛水溶液 (；65 mg, 0.80 mmol)及冰醋酸 (0.1 mL), 室温反应 2 h后，冰浴冷却向其中缓慢加入硼氢化钠 (15 mg, 0.4 mmol), 加完后室温反应过夜。反应结束后，加入饱和氯化铵溶液淬灭反应，用二氯甲烷 (25 mL 3)萃取，合并有机相，有机相分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物用硅胶柱层析分离纯化得到目标化合物 N-{4-[4-(3-二甲胺基- 丙基) -哌嗪 -1-基甲基 ]-3-三氟甲基 -苯基 }-4-甲基 -3-[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基-苯甲酰胺 (黄色固体， 13 mg)。 1H-NMR (300MHz, CD₃OD): δ 8.56(d， J=6.9Hz, IH), 8.28(d, J=1.8Hz, IH), 8.15(d, J=2.4Hz, IH), 7.93-7.96(m, 2H), 7.85(d, J=9.6Hz, IH), 7.74(d, J=8.7Hz, IH), 7.59-7.62(m, IH), 7.48(d, J=8.1Hz, IH), 7.24(t, J=6.6Hz, IH), 3.69(s, 2H), 3.17(t, J=7.2Hz, 2H), 2.64-2.86(m, 19H), 1.99(t,J=6.9 Hz，2H)。 MSm/z (ESI): 604.3 [M+H]。实施例 223: 3-(6-烯丙基 -[1，2，4]三氮唑 [4，3-b]哒嗪 -3-基乙块基) -4-甲基 -N-[4-(4-甲基 -哌嗪 -1- 基甲基) -3-三氟甲基-苯基] -苯甲酰

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誓由卞 (誓^ 7誓 -ε-翁？ ¾[q- ¾¾≡[Wi]-¾¾iMii-9H; 呦目 Γιί ^¾ N-{4-[4-(3-Amino-propyl)-piperazin-1-methyl]-3-trifluoromethyl-phenyl}-4-methyl-3-[1,2, 4] Triazole [4,3-a]pyridine-3-ethylidene-benzamide 46 mg, 0.08 mmol) was dissolved in methanol (2 mL), and 37% aqueous formaldehyde solution (65 mg, 0.80) was added thereto. Ethyl acetate and glacial acetic acid (0.1 mL) were reacted at room temperature for 2 h, then sodium borohydride (15 mg, 0.4 mmol) was slowly added to the mixture and cooled overnight. After completion of the reaction, the reaction was quenched with EtOAc EtOAc (EtOAc m. . The residue was purified by silica gel column chromatography to afford the title compound N-{4-[4-(3-dimethylamino-propyl)-piperazin-1-ylmethyl]-3-trifluoromethyl-benzene 4-methyl-3-[1,2,4]triazole[4,3-a]pyridin-3-ylethylidene-benzamide (yellow solid, 13 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.56 (d, J = 6.9 Hz, IH), 8.28 (d, J = 1.8 Hz, IH), 8.15 (d, J = 2.4 Hz, IH), 7.93- 7.96(m, 2H), 7.85(d, J=9.6Hz, IH), 7.74(d, J=8.7Hz, IH), 7.59-7.62(m, IH), 7.48(d, J=8.1Hz, IH ), 7.24(t, J=6.6Hz, IH), 3.69(s, 2H), 3.17(t, J=7.2Hz, 2H), 2.64-2.86(m, 19H), 1.99(t,J=6.9 Hz , 2H). MS m/z (ESI): 604.3 [M+H]. Example 223: 3-(6-allyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylethylidene)-4-methyl-N-[4 -(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzoyl

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CS.S.0/CT0ZN3/X3d LLOLllZIOZ OAV 2.87(m, 4H)， 2.56-2.80(m, 10H), 0.88-0.91(m, IH), 0.66-0.69 (m, 2H), 0.42-0.46(m, 2H)。 MS m/z (ESI): 604.3 [M+H 实施例 226 : N-[4-(3，4-二甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -4-甲基 -3-[l，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基-苯甲酰胺 CS.S.0/CT0ZN3/X3d LLOLllZIOZ OAV 2.87 (m, 4H), 2.56-2.80 (m, 10H), 0.88-0.91 (m, IH), 0.66-0.69 (m, 2H), 0.42-0.46 (m, 2H). MS m/z (ESI): 604.3 [M+H </RTI><RTIgt;</RTI><RTIgt;</RTI></RTI> N-[4-(3,4-dimethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl ]-4-methyl-3-[l,2,4]triazole[4,3-a]pyridin-3-ylethylidene-benzamide

将 3-([1，2，4]***并 [4，3-a]吡啶 -3-基乙块基) -N-(4-((3，4-二甲基哌嗪 -1-基）甲基) -3- (三氟甲基)苯基) -4-甲基苯酰胺 C37 mg， 0.07 mmol)溶于 N，N-二甲基甲酰胺 (2 mL)中，向其中加入无水碳酸钾粉末（），室温反应 10分钟后，向其中缓慢加入碘甲烷 ()，加完后在室温继续反应过夜。反应结束后，加入饱和氯化铵溶液淬灭反应，二氯甲烷萃取 (20 mL X 3), 合并有机相，有机相分别用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。剩余物用硅胶柱层析分离纯化得到目标化合物 N-[4-(3，4-二甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -4- 甲基 -3-[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基-苯甲酰胺（白色固体， 34mg)。 1H-NMR (300MHz, CD₃OD): δ 8.58(d， J=5.1Hz, IH), 8.31(s, IH), 8.15(m, IH), 7.97-8.00(m, 2H), 7.88(d, J=7.2Hz, IH), 7.76(d, J =6.6Hz, IH), 7.52-7.63(m, 2H), 7.25(t, J=5.1Hz, IH), 3.73(m, 2H), 3.35-3.38(m, IH), 3.18(m, IH), 3.07-3.12 (m， IH), 2.94-2.96(m, 2H), 2.80(s, 3H), 2.68(s, 3H), 2.5 l(m, 1H)， 3-([1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-N-(4-((3,4-dimethylpiperazin-1-) Methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide C37 mg, 0.07 mmol) dissolved in N,N-dimethylformamide (2 mL) After the anhydrous potassium carbonate powder () was reacted at room temperature for 10 minutes, methyl iodide () was slowly added thereto, and the reaction was continued at room temperature overnight after the addition. After the reaction was completed, the reaction was quenched with EtOAc EtOAc (EtOAc m. . The residue was purified by silica gel column chromatography to give the title compound N-[4-(3,4-dimethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4- 3-[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene-benzamide (white solid, 34 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.58 (d, J = 5.1 Hz, IH), 8.31 (s, IH), 8.15 (m, IH), 7.97-8.00 (m, 2H), 7.88 (d) , J=7.2Hz, IH), 7.76(d, J =6.6Hz, IH), 7.52-7.63(m, 2H), 7.25(t, J=5.1Hz, IH), 3.73(m, 2H), 3.35 -3.38(m, IH), 3.18(m, IH), 3.07-3.12 (m, IH), 2.94-2.96(m, 2H), 2.80(s, 3H), 2.68(s, 3H), 2.5 l ( m, 1H),

以实施例，等化合物为原料，采用通用方法二合成得到以下实施例〜实施例

In the examples, the compounds are used as raw materials, and the following examples are used to obtain the following examples to the examples.

实施例 232: N-[4-(4-环丙甲基 -哌嗪 -1-基甲基 )-3- -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块 -苯甲酰胺

Example 232: N-[4-(4-Cyclopropylmethyl-piperazin-1-ylmethyl)-3-[1,2,4]triazole [4,3-a]pyridine-3 - base block - benzamide

将 4-甲基 -3-((6 -吗啉代 -[ 1，2,4]***并 [4，3-a]吡啶 -3 -基）乙块基 )-N-(4-(哌嗪 - 1 -基甲基) -3- (三氟甲基)苯基)苯甲酰胺（81 mg， 0.12 mmol) 溶于 N，N-二甲基甲酰胺（2 mL)，向其中加入 (溴甲基)环丙烷（64 mg， 0.5 mmol) 及无水碳酸钾粉末（66 mg， 0.48 mmol), 加热回流过夜。反应结束后，冷却至室温，向反应液中加入水烊灭反应，后用乙酸乙酯萃取三次，无水硫酸钠干燥有机相，过滤，滤液蒸干，残余物硅胶柱层析纯化得到目标化合物 N-[4-(4-环丙甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -4-甲基 -3-(6-***啉 -4-基 -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基) -苯甲酰胺（黄色固体， 14 mg)。 1H-NMR (300MHz， CD₃OD): δ 8.14(1H, d, J=1.8Hz), 8.06(1Η， d, J=1.5Hz), 7.95(1Η, d, J=8.7Hz), 7.73-7.84(4Η, m), 7.41(1Η, d_: J=8.4Hz), 7.21(1H, d， J=9.6Hz), 3.80-3.83(4H, m)， 3.72(2H, s)， 3.56-3.59(4H, m)， 3.16(4H, s)， 2.83(2H, d， J=7.5Hz), 2.72(4H, s), 2.60(3H, s), 1.00-1.09(1H, m)， 0.67-0.73(2H, m)， 0.33-0.38(2H，m)。 MSm/z (ESI): 329.4[M+2H]。 4-methyl-3-((6-morpholino-[ 1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-N-(4-( Piperazine-1- 1 -methyl)-3-(trifluoromethyl)phenyl)benzamide (81 mg, 0.12 mmol) dissolved in N,N-dimethylformamide (2 mL) (Bromomethyl)cyclopropane (64 mg, 0.5 mmol) and anhydrous potassium carbonate powder (66 mg, 0.48 mmol). After the completion of the reaction, the mixture was cooled to room temperature, and the mixture was evaporated to dryness. N-[4-(4-Cyclopropylmethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-4-methyl-3-(6-morpholine-4-yl -[1,2,4]triazo[4,3-a]pyridin-3-ylethylidene)-benzamide (yellow solid, 14 mg). 1H-NMR (300MHz, CD ₃ OD): δ 8.14 (1H, d, J = 1.8Hz), 8.06 (1Η, d, J=1.5Hz), 7.95(1Η, d, J=8.7Hz), 7.73- 7.84(4Η, m), 7.41(1Η, d _: J=8.4Hz), 7.21(1H, d, J=9.6Hz), 3.80-3.83(4H, m), 3.72(2H, s), 3.56-3.59 (4H, m), 3.16(4H, s), 2.83(2H, d, J=7.5Hz), 2.72(4H, s), 2.60(3H, s), 1.00-1.09(1H, m), 0.67- 0.73 (2H, m), 0.33-0.38 (2H, m). MS m/z (ESI): 329.4 [M+2].

以 4-甲基 -3-((6-吗啉代 -[ 1 ,2,4]***并 [4,3-a]吡啶 -3-基）乙块基 )-N-(4-(哌嗪 - 1 -基甲基) -3- (三氟甲基)苯基)苯甲酰胺为原料，分别用 3-溴-丙 -1-醇和 1-溴 -3-甲氧基-丙烷替换环丙甲基溴，采用实施例 232相同的方法合成得到实施例 233-实施例 235。 4-methyl-3-((6-morpholino-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-N-(4-( Piperazine-1 -ylmethyl)-3-(trifluoromethyl)phenyl)benzamide as starting material, replaced with 3-bromo-propan-1-ol and 1-bromo-3-methoxy-propane, respectively Example 233 to Example 235 were synthesized in the same manner as in Example 232.

以 4-甲基 -3-[6-(l-甲基 -1H-吡唑 -4-基 )-[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基] -N-(4-哌嗪

4-methyl-3-[6-(l-methyl-1H-pyrazol-4-yl)-[1,2,4]triazole[4,3-a]pyridin-3-yl-ethyl Block base] -N-(4-piperazine

-1-基甲基 -3-三氟甲基-苯基) -苯甲酰胺为原料，分别用 1-溴 -2-甲氧基-乙烷和溴乙烷替换环 -1-ylmethyl-3-trifluoromethyl-phenyl)-benzamide as a starting material, replacing the ring with 1-bromo-2-methoxy-ethane and ethyl bromide, respectively

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以 3-((8-溴 -[ 1 ,2,4]***并 [4，3-a]吡啶 -3-基）乙块基 )-4-甲基 -Ν-(4-((Φ甲基哌嗪 - 1-基）甲基) -3- (三氟甲基)苯基)苯甲酰胺为原料，用各种胺替换***啉，采用实施例 240相同的方法合成得到实施例 241_实施例 244。 3-((8-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethlyl)-4-methyl-indole-(4-((Φ) Example 241 was synthesized in the same manner as in Example 240, using methyl piperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide as a starting material. Example 244.

实施例 245： 4-{4-[3-(8-甲氧基 -[1，2，4]三氮唑 [4，3-a]B比嗪 -3-基乙块基) -4-甲基-苯甲酰胺 ]-2- 三氟甲基-苄基 U-二甲基 -哌嗪 -1 Example 245: 4-{4-[3-(8-Methoxy-[1,2,4]triazolo[4,3-a]B-pyrazin-3-ylethylidene)-4- Methyl-benzamide]-2-trifluoromethyl-benzyl U-dimethyl-piperazine-1

将 3-[2-(8-羟基 -[1，2，4]***并 [4，3-a]吡嗪 -3-基）乙块基 ]-4-甲基 -N-[4-[(4-甲基哌嗪 -1-基) 甲基] -3- (三氟甲基)苯基]苯酰胺（50 mg 0.091 mmol) 及无水碳酸钾粉末（19 mg, 0.137 mmol)溶于干燥的 N，N-二甲基甲酰胺 (2 mL) 中，然后向其中加入碘甲烷 (0.06 mL， 0.11 mmol), 反应液室温搅拌 2 h。 TLC检测，反应结束后，向反应液中加入水，用乙酸乙酯萃取三次，无水硫酸钠干燥有机相，过滤，蒸干溶剂，残余物硅胶柱层析纯化得到化合物 4-{4-[3-(8-甲氧基 -[1，2，4]三氮唑 [4，3-a]吡嗪 -3 -基乙块基) -4-甲基 -苯甲酰胺] -2-三氟甲基-苄基}-1，1-二甲基 -哌嗪 -1-碘鑰盐（12 mg，黄色固体）。 1H-NMR (400MHz, CD₃OD): δ 8.30(1Η, d， J=1.6Hz), 8.15(1H， d， J=2.0Hz), 7.99-8.02(2H, m)， 7.77(1H, d， J=8.8Hz), 7.53-7.58(2H, m)， 7.24(1H, d， J=6.0Hz), 3.85(2H, s)， 3.59(3H, s)， 3.51(4H, t， J=4.8Hz), 3.21(6H, s)， 2.87(4H, t， J=4.4Hz), 2.67(3H, s).MSm/z (ESI):578.8[M+H]。实施例 246: 3-(6-氯 -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基) -4-羟甲基 -N-[4-(4-甲基 -哌嗪 -1-基甲基) -3-三氟甲基-苯基] -苯甲酰 3-[2-(8-Hydroxy-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)ethidyl]-4-methyl-N-[4- [(4-Methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide (50 mg 0.091 mmol) and anhydrous potassium carbonate powder (19 mg, 0.137 mmol) Methyl iodide (0.06 mL, 0.11 mmol) was added to dry EtOAc (2 mL). After the completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with EtOAc EtOAc. 4-{4-[3-(8-methoxy-[1,2,4]triazolo[4,3-a]pyrazine-3-ylethylidene)-4-methyl-phenyl Amido]-2-trifluoromethyl-benzyl}-1,1-dimethyl-piperazine-1-iodonium salt (12 mg, yellow solid). 1H-NMR (400MHz, CD ₃ OD): δ 8.30 (1Η, d, J=1.6Hz), 8.15(1H, d, J=2.0Hz), 7.99-8.02(2H, m), 7.77(1H, d , J=8.8Hz), 7.53-7.58(2H, m), 7.24(1H, d, J=6.0Hz), 3.85(2H, s), 3.59(3H, s), 3.51(4H, t, J= 4.8 Hz), 3.21 (6H, s), 2.87 (4H, t, J = 4.4 Hz), 2.67 (3H, s). MSm/z (ESI): 578.8 [M+H]. Example 246: 3-(6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl-N-[4-( 4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzoyl

将 N-(4-(4-甲基哌嗪基 -1-甲基) -3-三氟甲基苯基 )-3-(6-氯 -1，2，4-三氮唑并 [4，3-a]吡啶 -3-乙块基) - 4- (四氢 -2H-吡喃 -2-氧甲基)苯甲酰胺（200 mg， 0.3 mmol) 溶于甲醇（5 mL)，加入甲苯磺酸一水合物（66 mg， 0.34 mmol), 室温搅拌反应 3 h。反应结束后蒸除溶剂，残留物加入饱和碳酸氢钠溶液，乙酸乙酯萃取两次。合并有机层，柱层析纯化得到目标化合物 3-(6-氯 -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基) -4-羟甲基 -N-[4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基-苯基] -苯甲酰胺（黄色固体， 94 mg)。 1H-NMR (CD30D, 400ΜΗζ): δ 2.3 l(s, 3H), 2.54(s, 8H)， 3.67(s, 2H), 5.02(s, 2H), 7.41— 7.44(m， 1H), 7.77-7.79(m, 2H), 7.94-8.18(m, 6H). MS m/z (ESI):292.9[M+2H]。实施例 247: N-[3-(6-氯 -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基) -4-羟甲基 -苯基 ]-4-(4-甲基-哌嗪 -1-基甲基 )-3-三氟甲基-苯甲酰胺 N-(4-(4-Methylpiperazinyl-1-methyl)-3-trifluoromethylphenyl)-3-(6-chloro-1,2,4-triazolo[4 ,3-a]pyridine-3-ethylidene)-4- 4-(tetrahydro-2H-pyran-2-oxomethyl)benzamide (200 mg, 0.3 mmol) dissolved in methanol (5 mL) Toluenesulfonic acid monohydrate (66 mg, 0.34 mmol) was stirred at room temperature for 3 h. After the reaction was completed, the solvent was evaporated, and the residue was evaporated. The organic layer was combined and purified by column chromatography to give the title compound 3-(6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl -N-[4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-benzamide (yellow solid, 94 mg). 1H-NMR (CD30D, 400 ΜΗζ): δ 2.3 l (s, 3H), 2.54 (s, 8H), 3.67 (s, 2H), 5.02 (s, 2H), 7.41 - 7.44 (m, 1H), 7.77- 7.79 (m, 2H), 7.94 - 8.18 (m, 6H). MS m/z (ESI) Example 247: N-[3-(6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl-phenyl] -4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide

以 N-[3-(6-氯 -[ 1 ,2,4]三氮唑 [4，3-a]吡啶 -3-基乙块基) -4-(四氢吡喃 -2 -基氧甲基) -苯基] -4-(4-甲基 -哌嗪 -1-基甲基 )-3-三氟甲基 -苯甲酰胺为原料，采用实施例 246相同的方法合成得到目标化合物 N-[3-(6-氯 -[1，2，4]三氮唑 [4，3-a]吡啶 -3-基乙块基) -4-羟甲基 -苯基 ]-4-(4-甲基 -哌嗪—1-基甲基 )—3-三氟甲基 -苯甲酰胺。 1H-NMR (CD₃OD, 400ΜΗζ): δ 2.38(s, 3 H), 2.61(br, 8 H)， 3.79(s, 2 H)， 4.95(s， 2 H)， 7.42_7.45(m， 1 H)， 7.60_7.62(m， 1 H)， 7.80- 7.82(m， 1 H)， 8.01-8.14(m, 4 H)， 8.20— 8.22(m， 1 H)， 8.30(s, 1 H). LC-MS m/z 291.9 [M+2H]。 N-[3-(6-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-(tetrahydropyran-2-yloxy) Methyl)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzamide was used as a starting material, and the title compound was obtained by the same procedure as in Example 246. N-[3-(6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-ylethylidene)-4-hydroxymethyl-phenyl]-4-( 4-Methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-benzamide. 1H-NMR (CD ₃ OD, 400 ΜΗζ): δ 2.38 (s, 3 H), 2.61 (br, 8 H), 3.79 (s, 2 H), 4.95 (s, 2 H), 7.42_7.45 (m) , 1 H), 7.60_7.62(m, 1 H), 7.80- 7.82(m, 1 H), 8.01-8.14(m, 4 H), 8.20— 8.22(m, 1 H), 8.30(s, 1 H). LC-MS m/z 291.9 [M+2H].

实施例 250: 3-(2-二氟甲基 -咪唑 [l，2-a]吡啶 -3-基乙块基) -4-甲基 -N-(4-***啉 -4-基甲基 -3- 氟甲基-苯基) -苯甲酰胺

Example 250: 3-(2-Difluoromethyl-imidazo[l,2-a]pyridin-3-ylethylidene)-4-methyl-N-(4-morphinolin-4-ylmethyl -3-fluoromethyl-phenyl)-benzamide

将 N-(4-羟甲基 -3-三氟甲基-苯基) -3-碘 -4-甲基-苯甲酰胺 (20 mg)溶解在无水 N，N-二甲基甲酰胺 (5 mL)和二氯甲烷 (5 mL)的混合溶剂中，加入 N，N-二异丙基乙胺 (1 mL)后体系用冰浴冷却，滴加甲磺酰氯（200 uL )并搅拌两小时， TLC监测反应结束。随后加入***啉（500 uL)，室温搅拌过夜。反应液用乙酸乙酯和水稀释后分层，有机相用水洗，饱和食盐水洗涤，干燥、过滤后浓缩得到粗产品。粗品经过制备分离纯化得到目标化合物 3-(2-二氟甲基 -咪唑 [l，2-a]吡啶 -3-基乙块基) -4-甲基 -N-(4-***啉 -4-基甲基 -3-三氟甲基-苯基) -苯甲酰胺 (20 mg，淡黄色固体丽 R(400MHz， DMSO-d6): δ 10.60(s, 1H)， 8.73-8.71(m, 1H)， 8.29-8.22(m, 2H), 8.08-7.94(m, 2H)， 7.82-7.73(m, 2H), 7.58-7.46(m, 2H), 7.28(m, 1H), 3.62 (m， 6H)， 2.88(s, 3H), 2.49(m, 4H). MSm/z (ESI):569.5[M+H]。 Dissolving N-(4-hydroxymethyl-3-trifluoromethyl-phenyl)-3-iodo-4-methyl-benzamide (20 mg) in anhydrous N,N-dimethylformamide (5 mL) and dichloromethane (5 mL) were mixed with N,N-diisopropylethylamine (1 mL), the system was cooled in an ice bath, and methanesulfonyl chloride (200 uL) was added dropwise and stirred. Two hours, TLC monitored the end of the reaction. Then morpholine (500 uL) was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water and then evaporated and evaporated. The crude product was isolated and purified to give the title compound 3-(2-difluoromethyl-imidazo[l,2-a]pyridin-3-ylethylidene)-4-methyl-N-(4-morpholine-4 -ylmethyl-3-trifluoromethyl-phenyl)-benzamide (20 mg, pale yellow solid R (400MHz, DMSO-d6): δ 10.60 (s, 1H), 8.73-8.71 (m, 1H), 8.29-8.22(m, 2H), 8.08-7.94(m, 2H), 7.82-7.73(m, 2H), 7.58-7.46(m, 2H), 7.28(m, 1H), 3.62 (m, 6H), 2.88 (s, 3H), 2.49 (m, 4H). MS m/z (ESI): 569.5 [M+H].

以 N-(4-羟甲基 -3-三氟甲基-苯基) -3-碘 -4-甲基-苯甲酰胺为起始原料，分别用哌嗪及其衍生物，哌啶及其衍生物，吡咯烷及其衍生物，甲胺及其衍生物替换***啉，采用实施例 Starting from N-(4-hydroxymethyl-3-trifluoromethyl-phenyl)-3-iodo-4-methyl-benzamide, piperazine and its derivatives, piperidine and Its derivatives, pyrrolidine and its derivatives, methylamine and its derivatives are substituted for morpholine, using examples

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1H), 8.13(dd, J=2.0, 8.0Hz, 1H)， 7.92(dd, J=2.0, 8.0Hz, 1H), 8.13 (dd, J=2.0, 8.0Hz, 1H), 7.92 (dd, J=2.0, 8.0Hz,

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263 7.59(dd, J=1.2， 6.8Hz， 1H)， 7.56(d, J=6.4Hz, 1H)， 640.2 263 7.59 (dd, J=1.2, 6.8 Hz, 1H), 7.56 (d, J=6.4 Hz, 1H), 640.2

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测试例一：激酶抑制测试 Test Example 1: Kinase inhibition test

本测试例所描述的激酶抑制活性测定试验，是用来测定本发明化合物对 c-Src、 Bcr-Abk EGFR等激酶的体外抑制活性的，受试化合物对激酶酶活力的抑制活性用半抑制浓度： IC₅。值来表示。该类试验采用均相时间分辨荧光 (HTRF)技术进行测定，方法如下：将一系列浓度梯度的受试化合物，在室温条件下与特定浓度的酶溶液共同孵育 5分钟；之后加入适量的酶反应底物： ATP, 启动酶反应过程； 30分钟后，向酶反应体系中加入适量的反应终止液和检测液；孵育 1小时后，在 Molecular device公司的 Flexstation III多功能酶标仪上，测定特定化合物浓度下的酶活力，并计算不同浓度的化合物对酶活力的抑制活性；之后根据四参数方程，对不同浓度化合物下酶活力的抑制活性进行拟合，计算出 IC₅。值。本测试例所采用的激酶： c-Src、Bcr-Abl购自 Cama Biosciences, Inc，检测试剂盒 HTRF KinEASE-TK购自 Cisbio Bioassays公司， ATP购自 Sigma Aldrich公司。 The kinase inhibitory activity assay described in the test examples is for determining the in vitro inhibitory activity of the compound of the present invention against kinases such as c-Src and Bcr-Abk EGFR, and the test compound inhibits kinase activity by a semi-inhibitory concentration. : IC ₅ . The value is expressed. This type of test is performed by homogeneous time-resolved fluorescence (HTRF) technique as follows: A series of concentration gradient test compounds are incubated with a specific concentration of enzyme solution for 5 minutes at room temperature; then an appropriate amount of enzyme reaction is added. Substrate: ATP, start the enzyme reaction process; 30 minutes later, add appropriate amount of reaction stop solution and detection solution to the enzyme reaction system; after 1 hour of incubation, determine the specificity on the Molecular device Flexstation III multi-function microplate reader The enzyme activity at the concentration of the compound, and the inhibitory activity of the compound at different concentrations on the enzyme activity were calculated. Then, according to the four-parameter equation, the inhibitory activity of the enzyme activity under different concentrations of the compound was fitted to calculate IC ₅ . value. The kinases used in this test example: c-Src, Bcr-Abl were purchased from Cama Biosciences, Inc, the test kit HTRF KinEASE-TK was purchased from Cisbio Bioassays, and ATP was purchased from Sigma Aldrich.

1、本发明化合物对激酶的抑制活性用 IC₅。值表 ^。部分实施例化合物的激酶抑制活性结果如下表所示（其中 IC_5Q < 100 nM用符号 ++++表示； 100 nM < IC₅₀ < 500 nM用符号 +++ 1. The inhibitory activity of the compound of the present invention against kinase is IC ₅ . Value table ^. The results of the kinase inhibitory activity of some of the compounds of the Examples are shown in the following table (wherein IC _5Q < 100 nM is represented by the symbol ++++; 100 nM < IC ₅₀ < 500 nM by the symbol +++)

实施例 Bcr-Abl c-Src 实施例 Bcr-Abl c-Src 实施例 Bcr-Abl c-Src

Example Bcr-Abl c-Src Example Bcr-Abl c-Src Example Bcr-Abl c-Src

27 ++ + 116 ++ +++ 202 ++++ +27 ++ + 116 ++ +++ 202 ++++ +

28 ++++ + 117 ++++ ++++ 203 ++++ +28 ++++ + 117 ++++ ++++ 203 ++++ +

30 +++ + 118 ++++ ++++ 204 ++++ +30 +++ + 118 ++++ ++++ 204 ++++ +

31 + + 119 ++++ ++++ 205 +++ +31 + + 119 ++++ ++++ 205 +++ +

32 ++++ + 120 ++++ ++++ 206 +++ +32 ++++ + 120 ++++ ++++ 206 +++ +

33 ++++ + 121 +++ +++ 207 ++++ +33 ++++ + 121 +++ +++ 207 ++++ +

34 +++ + 122 ++++ ++++ 208 +++ +34 +++ + 122 ++++ ++++ 208 +++ +

35 ++ + 123 +++ +++ 210 ++++ +35 ++ + 123 +++ +++ 210 ++++ +

36 +++ + 124 ++++ ++++ 211 ++++ +36 +++ + 124 ++++ ++++ 211 ++++ +

37 +++ + 125 ++++ ++++ 212 +++ +37 +++ + 125 ++++ ++++ 212 +++ +

38 ++ + 126 +++ +++ 213 ++ +38 ++ + 126 +++ +++ 213 ++ +

39 ++ + 127 ++++ ++++ 214 +++ +39 ++ + 127 ++++ ++++ 214 +++ +

40 ++++ ++ 128 ++++ ++++ 215 +++ +40 ++++ ++ 128 ++++ ++++ 215 +++ +

41 ++++ + 129 ++++ +++ 216 ++++ +41 ++++ + 129 ++++ +++ 216 ++++ +

42 ++++ + 130 +++ +++ 217 ++++ +42 ++++ + 130 +++ +++ 217 ++++ +

43 ++++ + 131 ++++ ++++ 218 ++++ +43 ++++ + 131 ++++ ++++ 218 ++++ +

44 ++++ + 132 +++ +++ 219 +++ +44 ++++ + 132 +++ +++ 219 +++ +

45 ++++ + 133 ++++ ++++ 220 ++++ +45 ++++ + 133 ++++ ++++ 220 ++++ +

46 ++++ +++ 134 +++ ++ 221 ++++ +46 ++++ +++ 134 +++ ++ 221 ++++ +

47 ++ + 135 ++ ++ 222 +++ +47 ++ + 135 ++ ++ 222 +++ +

48 ++++ +++ 136 +++ +++ 223 ++++ +48 ++++ +++ 136 +++ +++ 223 ++++ +

49 ++++ + 137 ++++ ++++ 224 +++ ++49 ++++ + 137 ++++ ++++ 224 +++ ++

50 ++ + 138 +++ +++ 225 +++ ++50 ++ + 138 +++ +++ 225 +++ ++

51 +++ +++ 139 ++++ +++ 226 +++ +51 +++ +++ 139 ++++ +++ 226 +++ +

52 +++ + 140 ++++ + 227 ++++ +52 +++ + 140 ++++ + 227 ++++ +

53 ++ + 141 ++++ ++ 228 ++++ +53 ++ + 141 ++++ ++ 228 ++++ +

54 ++ + 142 ++++ ++ 229 ++++ +54 ++ + 142 ++++ ++ 229 ++++ +

55 ++ + 143 ++ ++ 230 ++++ ++++55 ++ + 143 ++ ++ 230 ++++ ++++

58 ++ + 144 +++ ++ 231 ++++ +58 ++ + 144 +++ ++ 231 ++++ +

59 ++++ + 145 ++ ++ 232 ++++ ++++59 ++++ + 145 ++ ++ 232 ++++ ++++

60 ++ + 146 ++++ ++++ 233 ++++ ++++60 ++ + 146 ++++ ++++ 233 ++++ ++++

61 ++ + 147 +++ +++ 234 +++ ++++61 ++ + 147 +++ +++ 234 +++ ++++

62 +++ + 148 ++++ ++++ 235 +++ ++++62 +++ + 148 ++++ ++++ 235 +++ ++++

63 +++ + 149 ++++ ++++ 236 +++ +++63 +++ + 149 ++++ ++++ 236 +++ +++

64 ++++ + 150 ++++ ++++ 237 ++++ ++++64 ++++ + 150 ++++ ++++ 237 ++++ ++++

65 ++++ +++ 151 ++++ ++++ 238 ++++ ++++65 ++++ +++ 151 ++++ ++++ 238 ++++ ++++

66 ++ +++ 152 ++++ ++++ 239 ++++ ++++66 ++ +++ 152 ++++ ++++ 239 ++++ ++++

67 ++ + 153 +++ ++ 240 ++++ ++++67 ++ + 153 +++ ++ 240 ++++ ++++

68 + + 154 ++++ ++++ 241 +++ ++68 + + 154 ++++ ++++ 241 +++ ++

69 + + 156 ++++ ++++ 242 ++++ ++69 + + 156 ++++ ++++ 242 ++++ ++

70 ++++ +++ 157 ++++ ++++ 243 +++ ++70 ++++ +++ 157 ++++ ++++ 243 +++ ++

71 + + 159 ++++ ++++ 244 +++ ++71 + + 159 ++++ ++++ 244 +++ ++

72 ++++ + 160 +++ +++ 245 +++ ++ 实施例 Bcr-Abl c-Src 实施例 Bcr-Abl c-Src 实施例 Bcr-Abl c-Src72 ++++ + 160 +++ +++ 245 +++ ++ Example Bcr-Abl c-Src Example Bcr-Abl c-Src Example Bcr-Abl c-Src

73 ++ + 161 +++ +++ 246 +++ ++73 ++ + 161 +++ +++ 246 +++ ++

74 ++++ ++++ 162 ++++ ++++ 247 ++++ ++++74 ++++ ++++ 162 ++++ ++++ 247 ++++ ++++

77 ++++ ++++ 163 +++ +++ 248 ++++ ++++77 ++++ ++++ 163 +++ +++ 248 ++++ ++++

78 +++ +++ 164 +++ +++ 249 + +78 +++ +++ 164 +++ +++ 249 + +

79 +++ + 165 +++ +++ 250 + +79 +++ + 165 +++ +++ 250 + +

80 ++++ ++ 166 +++ +++ 251 + +80 ++++ ++ 166 +++ +++ 251 + +

81 + + 167 ++++ ++++ 252 +++ +81 + + 167 ++++ ++++ 252 +++ +

82 ++++ ++++ 168 +++ +++ 253 +++ ++82 ++++ ++++ 168 +++ +++ 253 +++ ++

83 +++ +++ 169 +++ +++ 254 ++++ +++83 +++ +++ 169 +++ +++ 254 ++++ +++

84 +++ +++ 170 ++++ ++++ 255 ++++ +84 +++ +++ 170 ++++ ++++ 255 ++++ +

85 ++++ +++ 171 ++++ ++++ 256 +++ +85 ++++ +++ 171 ++++ ++++ 256 +++ +

86 +++ +++ 172 ++++ ++++ 257 + +86 +++ +++ 172 ++++ ++++ 257 + +

87 +++ + 173 +++ +++ 258 ++ +87 +++ + 173 +++ +++ 258 ++ +

88 + + 174 +++ +++ 259 + +88 + + 174 +++ +++ 259 + +

89 ++ + 175 ++++ ++++ 260 +++ +89 ++ + 175 ++++ ++++ 260 +++ +

90 ++ + 176 ++++ ++++ 261 +++ ++90 ++ + 176 ++++ ++++ 261 +++ ++

92 ++ + 177 ++++ ++++ 262 ++ +92 ++ + 177 ++++ ++++ 262 ++ +

94 + + 178 ++++ ++++ 263 ++ +94 + + 178 ++++ ++++ 263 ++ +

95 ++ ++ 179 +++ +++ 264 ++ + 95 ++ ++ 179 +++ +++ 264 ++ +

2、本发明实施例化合物对如 Abl， EGFR, VEGFR, JAK, PDGFR, BRAF, RET , KIT , LYN, LCK, FGFR， EphB, Src等数十种激酶及其突变体均具有较好的抑制活性，如实施例化合物 10， 112， 146， 201等在 luM浓度下对不同激酶的抑制率大于 90%，显示了较好的激酶抑制活性。 2. The compounds of the present invention have good inhibitory activities against dozens of kinases such as Abl, EGFR, VEGFR, JAK, PDGFR, BRAF, RET, KIT, LYN, LCK, FGFR, EphB, Src and the like. As shown in the example compounds 10, 112, 146, 201, etc., the inhibition rate of different kinases at luM concentration was greater than 90%, indicating better kinase inhibitory activity.

3、本发明化合物对不同激酶突变体如 AblT315I、 BrafV600E等具有较好的抑制活性。部分实施例化合物对 AWT315I激酶的抑制活性如下表所示（其中 IC₅。 < 100 nM用符号 ++++ 表示； 100 nM < IC₅₀ < 500 nM用符号 +++表示； 500 nM < IC₅₀ < 1000 nM用符号 ++表示； IC₅₀ > ΙΟΟΟ ηΜ用符号 +表示）。 3. The compound of the present invention has good inhibitory activity against different kinase mutants such as AblT315I, BrafV600E and the like. The inhibitory activity of some of the compounds of the compounds against AWT315I kinase is shown in the following table (where IC ₅ < 100 nM is represented by the symbol ++++; 100 nM < IC ₅₀ < 500 nM is represented by the symbol +++; 500 nM < IC ₅₀ < 1000 nM is represented by the symbol ++; IC ₅₀ > ΙΟΟΟ ηΜ is represented by the symbol +).

实施例 IC₅₀(AblT315I) 实施例 IC₅₀(AblT315I) 实施例 IC₅₀(AblT315I)EXAMPLE IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I)

4 + 85 ++++ 154 ++++4 + 85 ++++ 154 ++++

5 +++ 87 +++ 156 ++++5 +++ 87 +++ 156 ++++

7 ++++ 98 ++++ 159 ++++7 ++++ 98 ++++ 159 ++++

8 +++ 99 ++ 160 +++8 +++ 99 ++ 160 +++

9 +++ 101 +++ 161 +++9 +++ 101 +++ 161 +++

10 +++ 103 ++++ 162 +++10 +++ 103 ++++ 162 +++

11 ++++ 106 ++++ 176 ++++11 ++++ 106 ++++ 176 ++++

12 +++ 108 +++ 177 ++++12 +++ 108 +++ 177 ++++

16 ++++ 110 ++++ 181 ++++16 ++++ 110 ++++ 181 ++++

22 +++ 112 ++++ 199 +++22 +++ 112 ++++ 199 +++

25 ++++ 113 +++ 200 ++++25 ++++ 113 +++ 200 ++++

26 ++ 114 ++ 201 +++26 ++ 114 ++ 201 +++

32 ++++ 115 ++++ 203 +++ 实施例 IC₅₀(AblT315I) 实施例 IC₅₀(AblT315I) 实施例 IC₅₀(AblT315I)32 ++++ 115 ++++ 203 +++ EXAMPLE IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I) Example IC ₅₀ (AblT315I)

33 ++++ 117 +++ 204 +++33 ++++ 117 +++ 204 +++

40 ++ 118 +++ 207 ++++40 ++ 118 +++ 207 ++++

41 +++ 120 ++++ 208 +41 +++ 120 ++++ 208 +

42 +++ 122 ++++ 210 ++++42 +++ 122 ++++ 210 ++++

43 +++ 123 +++ 214 +++43 +++ 123 +++ 214 +++

44 ++ 125 ++++ 215 ++++44 ++ 125 ++++ 215 ++++

46 ++++ 129 ++++ 216 ++++46 ++++ 129 ++++ 216 ++++

51 +++ 136 ++++ 222 +++51 +++ 136 ++++ 222 +++

64 +++ 140 + 224 +++64 +++ 140 + 224 +++

65 +++ 141 +++ 225 +++65 +++ 141 +++ 225 +++

72 ++++ 142 ++++ 228 +++72 ++++ 142 ++++ 228 +++

78 ++++ 143 +++ 229 +++78 ++++ 143 +++ 229 +++

79 +++ 144 +++ 236 ++++79 +++ 144 +++ 236 ++++

80 +++ 146 ++++ 237 ++++80 +++ 146 ++++ 237 ++++

82 ++++ 149 ++++ 238 ++++82 ++++ 149 ++++ 238 ++++

83 ++++ 151 ++++ 239 ++++83 ++++ 151 ++++ 239 ++++

84 +++ 152 ++++ 242 ++++ 测试例二：细胞增殖抑制测试 84 +++ 152 ++++ 242 ++++ Test Example 2: Cell proliferation inhibition test

本测试例所描述的细胞增殖抑制活性实验，是用来测定本发明化合物对于如 EGFR、 Bcr-Abl等高表达的细胞株的增殖抑制活性，受试化合物对细胞增殖的抑制活性用半数抑制浓度： IC₅。来表示。该类试验的试验方案如下：选择不同细胞，如 K-562细胞、 A431细胞等（细胞购于中国科学院典型培养物保藏委员会细胞库 /中国科学院上海生命科学研究院细胞资源中心），以适宜的细胞浓度（例如， 25000个细胞 /mL培养基）将细胞接种于白色不透明的 384孔培养板上；之后将细胞放置于 37°C， 5% C0₂的环境中进行培养； 24小时后，向培养的细胞培养基中加入一系列浓度梯度的药物，一般选择 10个浓度；之后将细胞放回原培养环境中继续培养 48小时，之后按照 CellTiter-Glo Luminescent Cell Viability Assay的方法，测定受试化合物对不同细胞增殖的影响，并计算不同浓度的化合物对细胞增殖的抑制活性（CellTiter-Glo Luminescent Cell Viability Assay检测试剂购自 Promega)；之后对不同浓度的化合物下细胞增殖抑制活性进行四参数拟合，计算出 IC₅。数据。 The cell proliferation inhibitory activity test described in the test example is for measuring the proliferation inhibitory activity of the compound of the present invention against a cell line highly expressed such as EGFR, Bcr-Abl, etc., and the test compound inhibits cell proliferation by a half inhibitory concentration. : IC ₅ . To represent. The experimental protocol for this type of test is as follows: Select different cells, such as K-562 cells, A431 cells, etc. (The cells are purchased from the Cell Culture Bank of the Chinese Academy of Sciences, The Culture Collection Committee of the Chinese Academy of Sciences/The Shanghai Institute of Life Sciences, Chinese Academy of Sciences) Cell concentration (for example, 25,000 cells/mL medium) The cells were seeded on a white opaque 384-well culture plate; the cells were then cultured at 37 ° C in a 5% CO ₂ atmosphere; after 24 hours, A series of concentration gradients are added to the cultured cell culture medium, generally 10 concentrations are selected; the cells are then returned to the original culture environment for further 48 hours, and then the test compound is determined according to the CellTiter-Glo Luminescent Cell Viability Assay method. Effects on different cell proliferation, and calculation of inhibitory activities of different concentrations of compounds on cell proliferation (CellTiter-Glo Luminescent Cell Viability Assay was purchased from Promega); four-parameter fit was then performed on cell proliferation inhibitory activity at different concentrations of compounds. , calculate IC ₅ . data.

本发明化合物具有抑制 K-562细胞增殖的活性，部分实施例化合物的细胞增殖抑制活性结果如下所示（抑制活性用 IC₅。值表示，其中 IC₅。< ΙΟΟ ηΜ用符号 +表示； 100 nM < IC < 500 nM用符号 ++表示； IC₅。 > 500 nM用符号 +表示） The compound of the present invention has an activity of inhibiting proliferation of K-562 cells, and the results of cell proliferation inhibitory activity of some of the compounds of the examples are shown below (inhibition activity is represented by an IC ₅ value, wherein IC ₅ . < ΙΟΟ η 表示 is represented by a symbol +; 100 nM < IC < 500 nM is represented by the symbol ++; IC ₅ > 500 nM is represented by the symbol +)

实施例 IC₅₀(nM) 实施例 IC₅₀(nM) 实施例 IC₅₀(nM) 实施例 IC₅₀(nM)

EXAMPLE IC ₅₀ (nM) Example IC ₅₀ (nM) Example IC ₅₀ (nM) Example IC ₅₀ (nM)

24 +++ 96 +++ 163 ++++ 216 ++++24 +++ 96 +++ 163 ++++ 216 ++++

25 ++++ 97 +++ 164 ++++ 217 +++25 ++++ 97 +++ 164 ++++ 217 +++

26 ++++ 106 ++++ 165 ++++ 219 ++26 ++++ 106 ++++ 165 ++++ 219 ++

27 ++++ 110 ++++ 166 ++++ 220 ++++27 ++++ 110 ++++ 166 ++++ 220 ++++

28 +++ 111 ++++ 167 ++++ 225 ++++28 +++ 111 ++++ 167 ++++ 225 ++++

30 +++ 113 ++++ 168 ++++ 227 ++++30 +++ 113 ++++ 168 ++++ 227 ++++

32 ++++ 114 ++++ 169 ++++ 228 ++++32 ++++ 114 ++++ 169 ++++ 228 ++++

33 ++++ 115 ++++ 170 ++++ 229 ++++33 ++++ 115 ++++ 170 ++++ 229 ++++

34 +++ 116 ++++ 171 ++++ 233 ++++34 +++ 116 ++++ 171 ++++ 233 ++++

40 ++++ 120 ++++ 172 ++++ 234 ++++40 ++++ 120 ++++ 172 ++++ 234 ++++

41 ++++ 121 ++++ 173 ++++ 235 ++++41 ++++ 121 ++++ 173 ++++ 235 ++++

43 ++++ 122 ++++ 174 ++++ 242 ++++43 ++++ 122 ++++ 174 ++++ 242 ++++

44 ++++ 123 ++++ 176 ++++ 243 +++44 ++++ 123 ++++ 176 ++++ 243 +++

48 ++++ 125 ++++ 177 ++++ 244 ++++48 ++++ 125 ++++ 177 ++++ 244 ++++

54 +++ 126 ++++ 178 ++++ 247 ++++54 +++ 126 ++++ 178 ++++ 247 ++++

55 +++ 127 ++++ 179 ++++ 248 ++++55 +++ 127 ++++ 179 ++++ 248 ++++

59 ++++ 128 ++++ 180 ++++ 249 ++++59 ++++ 128 ++++ 180 ++++ 249 ++++

61 +++ 131 ++++ 181 ++++ 250 ++++61 +++ 131 ++++ 181 ++++ 250 ++++

65 +++ 132 ++++ 182 ++++ 252 +++65 +++ 132 ++++ 182 ++++ 252 +++

66 ++++ 133 ++++ 187 +++ 260 +++66 ++++ 133 ++++ 187 +++ 260 +++

72 ++++ 136 ++++ 190 +++ 261 +++72 ++++ 136 ++++ 190 +++ 261 +++

73 ++++ 137 ++++ 199 ++++ 263 +++73 ++++ 137 ++++ 199 ++++ 263 +++

74 ++++ 140 ++++ 200 ++++ 264 +++74 ++++ 140 ++++ 200 ++++ 264 +++

77 ++++ 测试例三：药代动力学评价 77 ++++ Test Example 3: Pharmacokinetic Evaluation

本发明化合物的药代动力学测试：以大鼠或小鼠为受试动物，应用 LC/M S/M S法测定了大鼠或小鼠分别灌胃和静注给予实施例化合物后不同时刻血浆中的药物浓度，研究本发明化合物在大鼠或小鼠体内的药代动力学行为，评价其药动学特征。 Pharmacokinetic test of the compound of the present invention: Rat or mouse is used as a test animal, and the plasma or the mouse is administered by the LC/MS/MS method at different times after intragastric administration and intravenous administration of the compound of the example. Drug concentration, the pharmacokinetic behavior of the compounds of the invention in rats or mice was investigated and their pharmacokinetic characteristics were evaluated.

实验方案：试验动物为健康成年雄性 SD大鼠或小鼠，由上海西普尔必凯实验动物有限公司提供；给药方式及样品采集：分别给于 SD大鼠或小鼠静脉注射（3 mg/kg， l mg/mL受试化合物的混悬液）和灌胃给药（lO mg/kg, l mg/mL受试化合物的混悬液），分别于给药前和给药后 2、 5、 15、 30、 60、 90、 120、 240、 360、 480、 1440 min于大鼠或小鼠眼底静脉丛取血 0.4 mL; 取血浆样品 50 分别加入 200 含内标的乙腈溶液沉淀蛋白，涡旋 10 min, 6000 g离心 10 min; 取 200 上清液 6000 g再次离心 10 min; 再取 75 上清液，加梯度初始流动相稀释， 6000 g离心 10 min ; 最终取上清液 70 于 96孔板中进样，进样量 5 进行 LC-M S-M S分析。 Experimental protocol: The test animals were healthy adult male SD rats or mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: intravenous injection into SD rats or mice (3 mg/ Kg, l mg/mL suspension of test compound) and intragastric administration (10 mg/kg, l mg/mL suspension of test compound), before and after administration 2, 5 , 15, 30, 60, 90, 120, 240, 360, 480, 1440 min. Take 0.4 mL of blood from the fundus venous plexus of rats or mice; take plasma sample 50 and add 200 acetonitrile solution containing internal standard to precipitate protein, vortex 10 min, centrifuged at 6000 g for 10 min; centrifuge 200 g of 6000 g for another 10 min; then take 75 supernatant, add gradient initial mobile phase to dilute, centrifuge at 6000 g for 10 min; finally take supernatant 70 at 96 wells. In-plate injection, injection volume 5 for LC-M SM S analysis.

实施例化合物 8， 10， 11， 28， 41， 44， 49， 70， 74， 77, 112, 134, 146， 207等在大小鼠血浆中稳定性良好，半衰期分别为 196min， 600min, 1194min, 702 min, 398min, 396min, 150 min, 1061min, 210min, 655 min, 873min, 178min, 428min, 284min_; 静脉给药后血药浓度-时间曲线下面积 AUC分别为 92uM .min， lOOuM .min , 210uM .min , 68uM .min , 202uM .min, 216uM .min, 230uM .min, 73uM .min, 193uM .min, 174uM .min, 68uM .min, 120uM .min, 165uM .min, 最高血药浓度在 0.37〜1.75uM，相对生物利用度在 20%〜80%。因此，结果表明本发明化合物在大鼠或小鼠体内具有较好的药代动力学性质。测试例四：裸小鼠体内药效学测试 The compounds of the examples 8, 10, 11, 28, 41, 44, 49, 70, 74, 77, 112, 134, 146, 207, etc. have good stability in the plasma of large mice, and the half-lives are 196 min, 600 min, 1194 min, 702, respectively. Min, 398min, 396min, 150 min, 1061min, 210min, 655min, 873min, 178min, 428min, 284min _{; the} area under the plasma concentration-time curve after intravenous administration was 92uM.min, lOOuM.min, 210uM.min , 68uM .min , 202uM .min, 216uM .min, 230uM .min, 73uM .min, 193uM .min, 174uM .min, 68uM .min, 120uM .min, 165uM .min, the highest blood concentration is 0.37~1.75uM The relative bioavailability is between 20% and 80%. Cause Thus, the results indicate that the compounds of the present invention have better pharmacokinetic properties in rats or mice. Test Example 4: Pharmacodynamic test in nude mice

实验材料及方法：采用 BALB/c裸小鼠（上海西普尔-必凯实验动物公司），体重 16-18g，雌性。 BD基质胶， K562细胞或 32DT315I细胞。收集对数生长期细胞，培养基与基质胶 1 :1，调节细胞浓度为 5.0X10⁷/ml，放入冰盒内，以 0.2ml/只接种于小鼠腋窝下侧，选择肿瘤在 100mm3以上的荷瘤鼠进行给药测试。每天灌胃给药一次，给药 5天，停药 2天，共给药 9天。每天测量肿瘤体积和体重，测量肿瘤体积时用游标卡尺分别测量肿瘤的长径和宽径，然后按照公式计算肿瘤的体积和相对体积：肿瘤体积（Tumor \Wume， TV)，计算公式为： TV=l/2XaXb²，其中 a、b分别表示长宽；相对肿瘤体积（Relative Tumor \¾lume, RTV), 计算公式为： RTV=TV_t/TV。，其中 TV。为分笼时（即 d。）肿瘤体积， TV_t为每次测量时的肿瘤体积；相对肿瘤增殖率 T/C (%)，计算公式为： T/C (%) = T_RTV/ C_RTVx l00, 其中 T_RTV：治疗组 RTV， C_RTV为阴性对照组 RTV。试验结果以相对肿瘤增殖率 T/C (%) 作为抗肿瘤活性 ^评价指标。 Experimental materials and methods: BALB/c nude mice (Shanghai Xipuer-Beikai Experimental Animals Co., Ltd.) were used, weighing 16-18 g, female. BD Matrigel, K562 cells or 32DT315I cells. Collect logarithmic growth phase cells, medium and matrigel 1:1, adjust the cell concentration to 5.0× ^{10 7} /ml, place in ice box, inoculate 0.2ml/only in the lower side of mouse armpit, and select tumor above 100mm3 The tumor-bearing mice were tested for drug administration. The drug was administered once a day for 5 days, and the drug was stopped for 2 days for a total of 9 days. The tumor volume and body weight were measured daily. The tumor diameter was measured with a vernier caliper to measure the long diameter and the broad diameter of the tumor. Then, the volume and relative volume of the tumor were calculated according to the formula: Tumor volume (Tumor \Wume, TV), and the calculation formula is: TV= l/2XaXb ² , where a and b represent the length and width, respectively; relative tumor volume (Relative Tumor \3⁄4lume, RTV), the formula is: RTV=TV _t /TV. , where TV. For the case of cage (ie d.) tumor volume, TV _t is the tumor volume at each measurement; relative tumor growth rate T/C (%), calculated as: T/C (%) = T _RTV / C _RTV x l00, where T _RTV : treatment group RTV, C _RTV was negative control group RTV. The test results were based on the relative tumor growth rate T/C (%) as an evaluation index for anti-tumor activity.

采用上述方法测试，实施例化合物 11， 74， 77, 112， 134， 247等在 2.5mg/kg〜10mg kg 剂量下对 K562移植瘤模型裸小鼠肿瘤具有显著的抑制生长直至消退的作用，给药第 9天 T/C 比小于 10%，并且试验动物能较好耐受，体重变化幅度小于 20%; 同时实施例化合物 11， 74， 77, 112， 134， 247等在 15mg/kg剂量下对 32DT315I细胞移植瘤模型裸小鼠肿瘤也具有显著的抑制生长直至消退的作用，给药第 9天 T/C比小于 50%，并且能明显延长实验动物的生存期，中位生存时间从 11-13天提高到 15-18天。 Using the above method, the compound of the example, 11, 74, 77, 112, 134, 247, etc., at a dose of 2.5 mg/kg to 10 mg kg, significantly inhibited the growth of the K562 xenograft model nude mice until the regression, giving On the 9th day, the T/C ratio of the drug was less than 10%, and the test animals were better tolerated, and the body weight change range was less than 20%; and the example compounds 11, 74, 77, 112, 134, 247, etc. were at the dose of 15 mg/kg. The nude mice with 32DT315I cell xenograft model also had significant inhibition of growth until regression. The T/C ratio was less than 50% on the 9th day of administration, and the survival time of the experimental animals was significantly prolonged. The median survival time was 11 - 13 days to 15-18 days.

因此，本发明部分实施例经灌胃给药后，具有较好的抑制裸小鼠移植瘤生长的药效，并且能显著延长实验荷瘤裸小鼠的生存期。 Therefore, some embodiments of the present invention have a good effect of inhibiting the growth of xenografted tumors in nude mice after intragastric administration, and can significantly prolong the survival of the experimental tumor-bearing nude mice.

Claims

权利要求书 Claim

1、具有通式 I的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前 A compound of the formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a former

(I) (I)

其巾： Its towel:

m个 Ra各自独立地选自卤素、 -R₂、 -OH、- SH、 -OR₂、 -NH₂、 -NHR₂、 -N(R₂)₂、 -NHC(0)R₂、m Ra are each independently selected from the group consisting of halogen, -R ₂ , -OH, -SH, -OR ₂ , -NH ₂ , -NHR ₂ , -N(R ₂ ) ₂ , -NHC(0)R ₂ ,

-NHC(0)OR₂、 -NR₃C(0)R₂; -NHC(0)OR ₂ , -NR ₃ C(0)R ₂ ;

2； 2;

各 R₂、 R₃独立地选自烷基、烯基、块基、环烷基、杂环基、芳基、杂芳基，且各 R₂ 和 R₃任选地被一个或多个选自卤素、 -OH、 - 、 -0 、 -C(0)-R4、 -C(OP-R4、 -OC(0)-R₄、 -C(0)N(R4)₂、 -S(0)_x-R4、 -NH₂、 -NH 、 -N(R₄)₂、 -NHC(0)R₄、 -爾 C(0)OR₄、 -NR₅C(0)R₄ 的基团取代，其中 x为 0、 1或 2; Each R ₂ , R _{3 is} independently selected from the group consisting of alkyl, alkenyl, blocked, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R ₂ and R _{3 is} optionally selected by one or more From halogen, -OH, -, -0, -C(0)-R4, -C(OP-R4, -OC(0)-R ₄ , -C(0)N(R4) ₂ , -S(0 a group substitution of _x -R4, -NH ₂ , -NH , -N(R ₄ ) ₂ , -NHC(0)R ₄ , -C(0)OR ₄ , -NR ₅ C(0)R ₄ Where x is 0, 1 or 2;

各、 R₅独立地选自烷基、烯基、环烷基、杂环基、芳基、杂芳基，且各、 R₅任选地被一个或多个选自 -OH、 -CN、 -NH₂、烷基、单 (烷基)氨基、二 (浣基)氨基、环烷基、杂环基、烷基杂环基、烷氧基、羟基烷基、烷氧基烷基、羟基烷氧基烷基、烷基羰基烷基、氨基院基、二院基氨基院基、院氧基羰基氨基院基、环院基院基、杂环基院基、芳院基、烷基环烷基、环烷基羰基、烷氧基羰基、烷氧基羰基杂环基、（烷氧羰基) (烷基)氨基、（浣氧基烷基) (烷基)氨基、（烷基羰基) (烷基)氨基的基团取代。 Each R _{5 is} independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and each R _{5 is} optionally selected from one or more selected from the group consisting of -OH, -CN, -NH ₂ , alkyl, mono(alkyl)amino, bis(indenyl)amino, cycloalkyl, heterocyclyl, alkylheterocyclyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy Alkoxyalkyl, alkylcarbonylalkyl, amino-based, alkoxy, alkoxy, alkoxy, alkoxy, alkoxy, amphoteric, amphoteric, a heterocyclic, a Alkylcycloalkyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylheterocyclyl, (alkoxycarbonyl)(alkyl)amino, (decyloxyalkyl)(alkyl)amino, (alkane) Substituted by a group of (carbonyl)amino groups.

2、如权利要求 1所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： 2. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof according to claim 1, wherein:

m个 Ra各自独立地选自卤素、烷基、环烷基、杂环基、 -OH、烷氧基、 -NH_2; 且该烷基、环烷基、杂环基、烷氧基任选地被一个或多个选自卤素、 -OH、烷氧基、环烷基氧基、杂环基氧基、 -NH₂、 -NH 、 -N(R₄)₂的基团取代；且该烷氧基、环烷基氧基和杂环基氧基任选地被一个或多个选自 -OH、 -CN、 -NH₂、烷基的基团取代； m Ra are each independently selected from halogen, alkyl, cycloalkyl, heterocyclic, -OH, alkoxy, -NH _{2 ;} and the alkyl, cycloalkyl, heterocyclyl, alkoxy optionally Substituted with one or more groups selected from the group consisting of halogen, -OH, alkoxy, cycloalkyloxy, heterocyclyloxy, -NH ₂ , -NH , -N(R ₄ ) ₂ ; alkoxyalkyl, cycloalkyl group and heterocyclyl group optionally substituted with one or more groups selected from -OH, -CN, -NH _2, a substituted alkyl group;

优选地， m个 Ra各自独立地选自卤素、烷基，且该烷基任选地被一个或多个选自卤素、 Preferably, m Ra are each independently selected from halogen, alkyl, and the alkyl is optionally selected from one or more selected from halogen,

-OH、烷氧基、环烷基氧基、杂环基氧基的基团取代； Substituent substitution of -OH, alkoxy, cycloalkyloxy, heterocyclyloxy;

更优选地， m个 Ra各自独立地选自卤素、 d_₆烷基，且该烷基任选地被一个或多个选自卤素、 -OH、 d_₆烷氧基、 C₃_₈环烷基氧基、包含 1至 3个选自氮、氧和硫的杂原子的 4 元至 8元杂环基氧基的基团取代。 More preferably, m of Ra is independently selected from halogen, d_ ₆ alkyl group, and the alkyl is optionally substituted with one or more groups selected from halo, -OH, d_ ₆ alkoxy, C ₃ _ ₈ cycloalkyl The group is substituted with a group of 4 to 8 membered heterocyclic oxy groups containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur.

3、如权利要求 1或 2所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： 3. A compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein:

4、如前述任一权利要求所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： 4. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a prodrug thereof, according to any of the preceding claims, wherein:

M为 CH; M is CH;

两个相邻的 Rb与其所连接的环 B上的碳原子一起形成包含 1至 3个选自氮、氧和硫的杂原子的 4元至 11 元杂环基；所述杂环基任选地被一个或多个选自烷氧基羰基、烷基羰基、杂环基羰基、杂芳基羰基、环烷基烷基、杂环基烷基、芳烷基的基团取代；且烷基羰基中的烷基任选地被烷氧基酰氨基取代，杂环基烷基中的杂环基任选地被烷氧基羰基取代，杂环基羰基中的杂环基任选地被一个或多个选自烷基、烷基羰基、烷氧基羰基、羟基烷基的基团取代。构体、溶剂化物、多 Two adjacent Rbs together with the carbon atom on the ring B to which they are attached form a 4- to 11-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; Substituted with one or more groups selected from the group consisting of alkoxycarbonyl, alkylcarbonyl, heterocyclylcarbonyl, heteroarylcarbonyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl; The alkyl group in the carbonyl group is optionally substituted by an alkoxyamido group, the heterocyclic group in the heterocyclylalkyl group is optionally substituted by an alkoxycarbonyl group, and the heterocyclic group in the heterocyclic carbonyl group is optionally a Or a plurality of groups selected from the group consisting of an alkyl group, an alkylcarbonyl group, an alkoxycarbonyl group, and a hydroxyalkyl group. Structure, solvate, more

两个相邻的 Rb与其所连接的环 B上的碳原子一起形成选自以下的结构:

Two adjacent Rbs together with the carbon atoms on the ring B to which they are attached form a structure selected from the group consisting of:

且该结构任选地被一个或多个选自烷氧基羰基、 d_₆烷基羰基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基羰基、包含 1至 3个选自氮、氧和硫的杂原子的 5元至 6元杂芳基羰基、 C₃_₈环烷基 -d_₆烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基 -d_₆烷基、 Q^。芳基 -d_₆烷基的基团取代；且烷基羰基中的烷基任选地被烷氧基酰氨基取代，杂环基烷基中的杂环基任选地被烷氧基羰基取代，杂环基羰基中的杂环基任选地被一个或多个选自烷基、 d_₆烷基羰基、 d_₆烷氧基羰基、羟基 -C^烷基的基团取代。 And the structure is optionally one or more selected from the group consisting of an alkoxycarbonyl group, a d- ₆ alkylcarbonyl group, a 4- to 8-membered heterocyclic carbonyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, a 5- to 6-membered heteroarylcarbonyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, C ₃ _-8 cycloalkyl-d- ₆ alkyl group, containing 1 to 3 selected from nitrogen, oxygen and 4-8 yuan heterocyclyl -d_ sulfur heteroatoms ₆ alkyl, Q ^. a group substituted with an aryl-d- ₆ alkyl group; and the alkyl group in the alkylcarbonyl group is optionally substituted with an alkoxyamido group, and the heterocyclic group in the heterocyclylalkyl group is optionally substituted with an alkoxycarbonyl group The heterocyclic group in the heterocyclic carbonyl group is optionally substituted by one or more groups selected from the group consisting of an alkyl group, a d- ₆ alkylcarbonyl group, a d- ₆ alkoxycarbonyl group, a hydroxy-C^alkyl group.

6、如权利要求 1至 3中任一项所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： 6. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof , among them:

M为 N原子； M is a N atom;

n个 Rb各自独立地选自 ¾代烷基；环烷基；任选地被烷基取代的杂环基；杂环基烷基，其中该杂环基烷基中的杂环基任选地被一个或多个选自 -ΟΗ、烷基、羟基烷基、氨基烷基、杂环基、烷氧基烷基、羟基烷氧基烷基、烷基羰基烷基、杂环基烷基、环烷基烷基、芳基院基、单院基氨基院基、二院基氨基院基、院氧基羰基氨基院基、院氧基羰基、环院基羰基、单院基氨基、二院基氨基、 (院氧基羰基 )(院基)氨基、 (院氧基院基 )(院基)氨基、 (院基羰基) (烷基)氨基的基团取代。 Each of R Rb is independently selected from a 3⁄4 alkyl group; a cycloalkyl group; a heterocyclic group optionally substituted by an alkyl group; a heterocyclylalkyl group, wherein the heterocyclic group in the heterocyclylalkyl group is optionally One or more selected from the group consisting of -indole, alkyl, hydroxyalkyl, aminoalkyl, heterocyclyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkylcarbonylalkyl, heterocyclylalkyl, Cycloalkylalkyl, aryl-based, single-yard amino-based, secondary-base amino-based, oxycarbonylamino-based, oxycarbonyl, ring-based carbonyl, single-hospital amino, second Substituted by a group of a base amino group, a (homoyloxycarbonyl) (hospital) amino group, an (homo-oxyl group) (homo-based) amino group, a (homo-based carbonyl) (alkyl)amino group.

7、如权利要求 6所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： 7. A compound according to claim 6, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein:

环 Ring

ρ个 R1各自独立地选自卤素； -OH; -NH₂; d_₆烷基； C₂_₆烯基；任选地被 d_₆烷氧基 C^烷基取代的。芳基；任选地被 C^烷基、羟基 -C^烷基、卤素、 Cw烷氧基取代的包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基；任选地被 -NH₂、 d_₆烷基取代的包含 1至 4个选自氮、氧和硫的杂原子的 5元至 10元杂芳基，其中该烷基任选地进一步被选自 -CN、 Ci_₆烷氧基、 C₃_₈环烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基、单 (d_₆烷基)氨基、二 (d_₆烷基)氨基的基团取代；任选地被二 (d_₆烷基)氨基、 C₃_₈环烷基取代的烷氧基；任选地被 Ci_₆烷基取代的包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基氧基； C₃_₈环烷基氨基；单 (d_₆烷基)氨基；二 (d_₆烷基)氨基；该单烷基氨基和二烷基氨基中的烷基任选地进一步被 Ci_₆烷氧基、二 (d_₆烷基)氨基、 d_₆烷基 -S0₂-、二 (C^烷基)氨基羰基取代； ρ R1 are each independently selected from halogen; -OH; -NH ₂ ; d- ₆ alkyl; C ₂ _-6 alkenyl; optionally substituted by d- ₆ alkoxy C^alkyl. Aryl; optionally substituted by C^alkyl, hydroxy-C^alkyl, halogen, Cw alkoxy a 4- to 8-membered heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur; optionally substituted by -NH ₂ , d ₆ alkyl, 1 to 4 selected from nitrogen, oxygen and a 5- to 10-membered heteroaryl group of a sulfur hetero atom, wherein the alkyl group is optionally further selected from the group consisting of -CN, Ci- ₆ alkoxy, C ₃ _-8 cycloalkyl, and 1 to 3 selected from nitrogen Substituted by a 4- to 8-membered heterocyclic group of a hetero atom of oxygen and sulfur, a mono(d- ₆ alkyl)amino group, a bis(d- ₆ alkyl)amino group; optionally a di(d- ₆ alkyl) group Amino, C ₃ _-8 cycloalkyl substituted alkoxy; 4 to 8 membered heterocyclooxy containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by Ci- ₆ alkyl group; C ₃ _ ₈ cycloalkyl group; mono (d_ ₆ alkyl) amino; two (d_ ₆ alkyl) amino; the monoalkylamino and dialkylamino groups are optionally further substituted Ci_ ₆ Alkoxy, bis(d- ₆ alkyl)amino, d- ₆ alkyl-S0 ₂ -, di(C^alkyl)aminocarbonyl;

n个 Rb各自独立地选自卤代 -d_₆烷基； C₃_₈环烷基；任选地被 d_₆烷基取代的包含 1 至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基；包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基 -d_₆烷基，其中该杂环基烷基中的杂环基任选地被一个或多个选自 -OH、 d_₆烷基、羟基 -d_₆烷基、氨基 -d_₆烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基、 ₆烷氧基 -d— ₆烷基、羟基 - — ₆烷氧基 -d— ₆烷基、 ₆烷基羰基 -d— ₆ 烷基、包含 1至 3个选自氮、氧和硫的杂原子的 4元至 8元杂环基 -d_₆烷基、 C₃_₈环烷基 -d_₆ 院基、 C₆— ₁₀芳基 -Ci— 6院基、单 (Ci— 6院基)氨基 -Ci— 6院基、二 (Ci— 6院基)氨基 -Ci— 6院基、 C ₆ 烷氧基羰基氨基 -Cw烷基、 d_₆烷氧基羰基、 C₃_₈环烷基羰基、单 (d_₆烷基)氨基、二 (d_₆ 院基)氨基、 (Ci_₆院氧基羰基) (Ci— 6院基)氨基、 (Ci_₆院氧基院基) (Cw院基)氨基、 (Ci_₆院基羰基 )( ₆烷基)氨基的基团取代。 Each of R Rb is independently selected from halo-d- ₆ alkyl; C ₃ _-8 cycloalkyl; optionally substituted by d- ₆ alkyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur a 4- to 8-membered heterocyclic group; a 4- to 8-membered heterocyclic-d- ₆ alkyl group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the heterocyclic ring in the heterocyclic alkyl group The base is optionally one or more selected from the group consisting of -OH, d- ₆ alkyl, hydroxy-d- ₆ alkyl, amino-d- ₆ alkyl, heteroatoms containing from 1 to 3 selected from nitrogen, oxygen and sulfur. a meta- to 8-membered heterocyclic group, a ₆ -alkoxy-d- ₆ alkyl group, a hydroxy- ₆ -alkoxy-d- ₆ alkyl group, a ₆ -alkylcarbonyl-d- ₆ alkyl group, and contains 1 to 3 selected 4 yuan heteroatom from nitrogen, oxygen and sulfur to 8-membered heterocyclyl -d_ ₆ alkyl, C ₃ _ ₈ cycloalkyl group hospital -d_ _6, C ₆ - ₁₀ aryl group -Ci- 6 hospital, Mono (Ci-6 yard base) amino-Ci-6 yard base, bis(Ci-6 yard base) amino-Ci-6 yard base, C ₆ alkoxycarbonylamino-Cw alkyl group, d- ₆ alkoxycarbonyl group , C ₃ _ ₈ cycloalkyl-carbonyl group, mono (d_ ₆ alkyl) amino, di (d_ ₆ hospital yl) amino, (Ci_ ₆ hospital butoxycarbonyl) (Ci- 6 hospital yl) amino, (Ci_ ₆ hospital oxygen base Yl) (Cw of hospital-yl) amino, (Ci_ ₆ hospital-ylcarbonyl) ₍₆ alkyl) amino groups.

8、如权利要求 1至 3中任一项所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof , among them:

M为 CR，其中 R选自卤素、烷基、环烷基，且该烷基、环烷基任选地被一个或多个卤素取代；优选地， R选自 Ci_₆烷基或 C₃_₈环烷基，且该烷基或环烷基任选地被一个或多个卤素取代； M is CR, wherein R is selected from halogen, alkyl, cycloalkyl and the alkyl group, cycloalkyl group optionally substituted with one or more halo; Preferably, R is selected from Ci_ ₆ alkyl or C ₃ _ ₈ -cycloalkyl, and the alkyl or cycloalkyl is optionally substituted with one or more halogens;

9、如权利要求 8所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： 9. A compound according to claim 8, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein:

环 T选自以下结构：

Ring T is selected from the following structures:

10、如前述任一权利要求所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中： A compound, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph, a tautomer, a metabolite or a prodrug thereof according to any of the preceding claims, wherein:

更优选地，为11原子。 More preferably, it is 11 atoms.

11、如权利要求 1所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药，其中所述化合物选自： The compound according to claim 1, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof, wherein the compound is selected From:

ŉll

ʼnll

HI

CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV CS.S.0/CT0ZN3/X3d tLLOLl/£lOZ OAV

CS.S.0/CT0ZN3/X3d LLOL iOZ OAV CS.S.0/CT0ZN3/X3d LLOL iOZ OAV

116

116

12、药物组合物，其包含权利要求 1-11中任一项所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药以及药学上可接受的载体。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer, a solvate, a polymorph thereof, a tautomer, Metabolite or prodrug and a pharmaceutically acceptable carrier.

13、权利要求 1-11中任一项所述的化合物、其药学上可接受的盐、其立体异构体、溶剂化物、多晶型物、互变异构体、代谢产物或前药或者权利要求 12所述的药物组合物，其用于预防和 /或***。 13. A compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a stereoisomer, solvate, polymorph, tautomer, metabolite or prodrug thereof or The pharmaceutical composition according to claim 12 for use in the prevention and/or treatment of a tumor.