WO2014194667A1

WO2014194667A1 - Alkynyl heterocyclic compound and uses thereof

Info

Publication number: WO2014194667A1
Application number: PCT/CN2014/000557
Authority: WO
Inventors: 胡有洪; 耿美玉; 刘杨; 丁健; 艾菁
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2013-06-05
Filing date: 2014-06-04
Publication date: 2014-12-11
Anticipated expiration: 2015-12-05
Also published as: CN104211639A

Abstract

The present invention relates to an alkynyl heterocyclic compound as represented by formula (I), a preparation method therefor, and uses thereof in the preparation of antitumor drugs.

Description

一类炔基杂环类化合物及其应用 A class of alkynyl heterocyclic compounds and their applications

技术领域 Technical field

本发明属于药物合成领域，具体涉及一类新型炔基杂环类化合物及其在制备抗肿瘤的药物中的用途。背景技术 The invention belongs to the field of drug synthesis, and particularly relates to a novel class of alkynyl heterocyclic compounds and their use in preparing antitumor drugs. Background technique

受体酪氨酸激酶（RTKs ) 参与调控细胞的增殖、迀移、分化、凋亡等一系列细胞生物学事件，其过表达或过度激活与肿瘤的发生发展密切相关，是肿瘤治疗的关键靶点。成纤维生长因子受体（fibroblast growth factor receptors, FGFRs )是受体酪氨酸激酶家族（RTKs ) 重要成员。 FGFR家族主要包括 FGFR1、 FGFR2、 FGFR3和 FGFR4四种亚型。（Turner N., Grose R., Fibroblast growth factor signalling: from development to cancer, Nature Reviews Cancer. (2010) 10: 116-129. Died M.V., Arnedos M., Andre F" Soria J.C., Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives, Cancer Discovery. (2013) 3:264-279. ) 在肿瘤中，由于基因扩增、突变、融合或配体诱导等原因， FGFR各成员持续激活，诱导肿瘤细胞增殖、侵袭、迀移，促进血管生成。 FGFRs在多种肿瘤中高表达或异常激活，与肿瘤病人的不良预后密切相关，如非小细胞肺癌、乳腺癌、胃癌、膀胱癌、子宫内膜癌、前列腺癌、宫颈癌、结肠癌、食管癌、角质母细胞瘤、骨髓瘤、横纹肌肉瘤等。（Died MV, Arnedos M, Andre F, Soria JC: Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer discovery, 2013, 3, 264-79; Turner N, Grose R: Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer, 2010, 10, 116-29. )研究显示， FGFRl扩增占非小细胞肺癌鳞癌的 20%, 并通过对 FGFR1 扩增的肺癌细胞株体外增殖、信号通路等研究显示 FGFR选择性抑制剂可以非常有效抑制 FGFR1信号通路的活化和细胞的增殖（Frequent and Focal FGFRl Amplification Associates with Therapeutically Tractable FGFRl Dependency in Squamous Cell Lung Cancer (vol 3, 66er5, 2011), Sci Transl Med. (2010)； Inhibitor-Sensitive FGFRl Amplification in Human Non-Small Cell Lung Cancer, PLoS ONE. (2011) 6:e20351. )。 FGFR2基因扩增或者突变导致 FGFR2信号通路的异常激活贡献于胃癌的进展过程。胃癌组织中 FGFR2的扩增率为 5%-10% (Matsumoto K, Arao T, Hamaguchi T, Shimada Y, Kato K, Oda I, Taniguchi H, Koizumi F, Yanagihara K, Sasaki H, Nishio K, Yamada Y: FGFR2 gene amplification and clinicopathological features in gastric cancer. Br. J. Cancer, 2012, 106, 727-32. ) o对 313例胃癌组织分析显示， FGFR2的扩增与肿瘤大小、局部浸润程度、淋巴结转移情况以及远端转移的发生显著相关，而且具有 FGFR2扩增的胃癌一般是进展性肿瘤，具有较差的预后，病人总体存活率相对较低（Jung EJ, Jung EJ, Min SY, Kim MA, Kim WH: Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma. Human pathology, 2012, 43, 1559-66. )。在肝癌中多种亚型的 FGFR及其配体 FGFs具有异常的表达及活化，如 FGFR2、 FGFR3、 FGFR4、 FGF19、 FGF2、 FGF5、 FGFS, FGF9等。多项临床前及临床研究均表明 FGF/FGFR轴线异常激活在肝癌中的重要性 ( Cheng AL, Shen YC, Zhu AX: Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma. Oncology-Basel, 2011, 81, 372-80. )。在非侵袭性膀胱癌中 FGFR3 突变占到 50%-60%，侵袭性膀胱癌中 FGFR3 突变占到 10%-15%。在多发性骨髓瘤中 FGFR3t(4;14)(pl6.3;q32)基因重排占到 15-20%, 这种融合基因能够导致 FGFR3的高表达和持续激活，导致克隆性浆细胞在骨骼和骨髓中的大量堆积从而影响正常的造血功能。 (Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives.)本发明针对 FGFR1 和 FGFR2 为靶点，合成了一系列具有很好的 FGFR1和 FGFR2抑制活性的新型炔基杂环类化合物，且该系列化合物对 FGFR2依赖性的胃癌细胞株 ΚΑΤΟΠΙ上显示出了很好的抑制活性。发明内容 Receptor tyrosine kinases (RTKs) are involved in the regulation of cell proliferation, migration, differentiation, apoptosis and a series of cell biological events. Overexpression or overactivation is closely related to tumor development and is a key target for tumor therapy. point. Fibroblast growth factor receptors (FGFRs) are important members of the receptor tyrosine kinase family (RTKs). The FGFR family mainly includes four subtypes of FGFR1, FGFR2, FGFR3 and FGFR4. (Turner N., Grose R., Fibroblast growth factor signalling: from development to cancer, Nature Reviews Cancer. (2010) 10: 116-129. Died MV, Arnedos M., Andre F" Soria JC, Fibroblast Growth Factor Receptor Inhibitors As a Cancer Treatment: From a Biologic Rationale to Medical Perspectives, Cancer Discovery. (2013) 3:264-279. ) In tumors, FGFR members are continuously activated due to gene amplification, mutation, fusion or ligand induction. Induces tumor cell proliferation, invasion, migration, and promotes angiogenesis. FGFRs are highly expressed or abnormally activated in various tumors, and are closely related to poor prognosis of tumor patients, such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, and uterus. Endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratinoma, myeloma, rhabdomyosarcoma, etc. (Died MV, Arnedos M, Andre F, Soria JC: Fibroblast growth factor receptor inhibitors as a cancer treatment : from a biologic rationale to medical perspectives. Cancer discovery, 2013, 3, 264-79; Turner N , Grose R: Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer, 2010, 10, 116-29. ) Studies have shown that FGFR1 amplification accounts for 20% of non-small cell lung cancer squamous cell carcinoma, and through FGFR1 In vitro proliferation and signaling pathways of expanded lung cancer cell lines have shown that FGFR selective inhibitors can effectively inhibit FGFR1 signaling pathway activation and cell proliferation (Frequent and Focal FGFRl Amplification Associates with Therapeutically Tractable FGFRl Dependency in Squamous Cell Lung Cancer (Frequent and Focal FGFRl Amplification Associates with Therapeutically Tractable FGFRl Dependency in Squamous Cell Lung Cancer Vol 3, 66er5, 2011), Sci Transl Med. (2010); Inhibitor-Sensitive FGFRl Amplification in Human Non-Small Cell Lung Cancer, PLoS ONE. (2011) 6:e20351. Amplification or mutation of the FGFR2 gene results in abnormal activation of the FGFR2 signaling pathway contributing to the progression of gastric cancer. The expansion rate of FGFR2 in gastric cancer tissues is 5%-10% (Matsumoto K, Arao T, Hamaguchi T, Shimada Y, Kato K, Oda I, Taniguchi H, Koizumi F, Yanagihara K, Sasaki H, Nishio K, Yamada Y : FGFR2 gene Amplification and clinicopathological features in gastric cancer. Br. J. Cancer, 2012, 106, 727-32. ) o Analysis of 313 cases of gastric cancer showed that FGFR2 amplification and tumor size, local infiltration, lymph node metastasis and distal The occurrence of metastasis is significantly correlated, and gastric cancer with FGFR2 expansion is generally a progressive tumor with a poor prognosis, and the overall survival rate of patients is relatively low (Jung EJ, Jung EJ, Min SY, Kim MA, Kim WH: Fibroblast growth Factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma. Human pathology, 2012, 43, 1559-66. FGFR and its ligand FGFs of various subtypes in hepatocarcinoma have abnormal expression and activation, such as FGFR2, FGFR3, FGFR4, FGF19, FGF2, FGF5, FGFS, FGF9 and so on. A number of preclinical and clinical studies have demonstrated the importance of abnormal activation of the FGF/FGFR axis in liver cancer (Chen AL, Shen YC, Zhu AX: Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma. Oncology-Basel, 2011, 81, 372 -80. ). FGFR3 mutations account for 50%-60% of non-invasive bladder cancers, and FGFR3 mutations account for 10%-15% of invasive bladder cancers. FGFR3t(4;14)(pl6.3;q32) gene rearrangement accounts for 15-20% in multiple myeloma, this fusion gene can lead to high expression and sustained activation of FGFR3, leading to clonal plasma cells in bone And a large amount of accumulation in the bone marrow affects the normal hematopoietic function. (Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives.) The present invention targets FGFR1 and FGFR2, and synthesizes a series of novel alkynyl heterocycles having excellent FGFR1 and FGFR2 inhibitory activities. Compounds, and this series of compounds showed good inhibitory activity against FGFR2-dependent gastric cancer cell lines. Summary of the invention

本发明的发明人合成了一系列新型的炔基杂环类化合物，并测定这些化合物具有良好的 FGFR1和 FGFR2的分子水平上的抑制活性，并且在 nM水平上能够有效的抑制对 FGFR2 依赖性的胃癌细胞株 ΚΑΤΟΠΙ的生长，具有显著的抗肿瘤活性。这对于开发出新的抗肿瘤药物具有重要意义。 The inventors of the present invention synthesized a series of novel alkynyl heterocyclic compounds, and determined that these compounds have good inhibitory activities at the molecular level of FGFR1 and FGFR2, and can effectively inhibit FGFR2-dependent at the nM level. The growth of gastric cancer cell lines has significant anti-tumor activity. This is important for the development of new anti-tumor drugs.

因此，本发明的一个目的是提供一类新型炔基杂环类化合物。 Accordingly, it is an object of the present invention to provide a novel class of alkynyl heterocyclic compounds.

本发明的另一目的是提供上述新型炔基杂环类化合物在制备抗肿瘤的药物中的用途。本发明的又一目的是提供一种具有抗肿瘤活性的药物组合物，其包含治疗有效量的一种或多种上述新型炔基杂环类化合物以及药学上可以接受的辅料。 Another object of the present invention is to provide the use of the above novel alkynyl heterocyclic compounds for the preparation of antitumor drugs. A further object of the present invention is to provide a pharmaceutical composition having antitumor activity comprising a therapeutically effective amount of one or more of the above novel alkynyl heterocyclic compounds and a pharmaceutically acceptable excipient.

根据本发明的第一个目的，本发明提供了一类通式 I表示的炔基杂环类化合物， According to a first object of the present invention, the present invention provides a class of alkynyl heterocyclic compounds represented by the general formula I,

其中， M和 Y各自独立地为 CH或 N;

Wherein M and Y are each independently CH or N;

W为 C或 N; 其中，当 W为 N时，不存在； W is C or N; wherein, when W is N, it does not exist;

L为 -C(0)NH-或 -NHC(O)-; L is -C(0)NH- or -NHC(O)-;

选自： From:

1 ) H、羟基； 1) H, hydroxyl;

2) Ci-Cs焼基； 2) Ci-Cs sulfhydryl;

3 ) 未取代或被选自 CrC₆垸氧基、羟基中的取代基取代的 CrC₆垸氧基； 3) unsubstituted or substituted group selected from CrC ₆ embankment, CrC ₆ substituents embankment hydroxyl group;

4) C₃-C₆环垸基； 4) C ₃ -C ₆ cyclodecyl;

5 ) 羧基、 -C(=0)0(C_rC₆垸基)、 -C(=0)NH(C_rC₆垸基)； 5) carboxyl group, -C(=0)0(C _r C ₆ fluorenyl), -C(=0)NH(C _r C ₆ fluorenyl);

6) 未取代或被 1-5个选自卤素、 C_rC₆垸基、卤素取代的 C_rC₆垸基、 C_rC₆垸氧基中的取代基取代的 C₆-C_1C1芳基； 6) C ₆ -C _1C1 aryl substituted or substituted with 1 to 5 substituents selected from halogen, C _r C ₆ fluorenyl, halogen substituted C _r C ₆ fluorenyl, C _r C ₆ fluorenyloxy base;

7 ) 未取代或被选自卤素、 d-Cs垸基、卤素取代的 d-Cs垸基、 d-Cs垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 5-8元杂芳基； 7) 1-3 selected from N, 0 and S, which are unsubstituted or substituted with a substituent selected from halogen, d-Cs fluorenyl, halogen-substituted d-Cs fluorenyl, d-Cs decyloxy 5-8 membered heteroaryl of a hetero atom;

8 ) 未取代或被选自¾素、 C_rC₆垸基、 ¾素取代的 C_rC₆垸基、 C_rC₆垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 4-7元杂环基；8) unsubstituted or substituted by selected prime ¾, substituted C _r C ₆ alkyl with, ¾ prime substituted alkyl with C _r C _6, C _r C ₆ group in the embankment containing 1-3 heteroatoms selected from N a 4-7 membered heterocyclic group of a hetero atom in 0, S;

10 ) 与 A环 Y位可以形成苯环、含有 1-2个 N原子的 5-6元杂芳环、或者含有 1-2 个 N原子的 5-6元杂环；其中，所述苯环、杂芳环或杂环可以被选自卤素、 CrC₆垸基、卤素取代的 C_rC₆垸基、 C_rC₆垸氧基、羧基、 -C(=0)0(CrC₆垸基)、 -C(=0)NH(CrC₆垸基）中的取代基取代； 10) a Y-position of the A ring may form a benzene ring, a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the benzene ring a heteroaryl ring or a heterocyclic ring may be selected from a halogen, a CrC ₆ fluorenyl group, a halogen-substituted C _r C ₆ fluorenyl group, a C _r C ₆ methoxy group, a carboxyl group, a -C(=0)0 (CrC ₆ fluorenyl group). Substituting a substituent in -C(=0)NH(CrC ₆ fluorenyl);

R₂选自： R _{2 is} selected from:

1 ) H、卤素、羟基； 1) H, halogen, hydroxyl;

2) 氧代基团； 2) an oxo group;

3 ) Ci-C₆焼基； 3) Ci-C ₆ sulfhydryl;

4) d-Cs垸氧基； 5) C₃-C₆环垸基； 4) d-Cs decyloxy; 5) C ₃ -C ₆ cyclodecyl;

7) 未取代或被选自卤素、 C_rC₆垸基、卤素取代的 C_rC₆垸基、 C_rC₆垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 5-8元杂芳基； 7) 1-3 selected from N, 0 which are unsubstituted or substituted by a substituent selected from halogen, C _r C ₆ fluorenyl, halogen substituted C _r C ₆ fluorenyl, C _r C ₆ methoxyl And a 5-8 membered heteroaryl group of a hetero atom in S;

8) 未取代或被选自¾素、 C_rC₆垸基、 ¾素取代的 C_rC₆垸基、 C_rC₆垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 4-7元杂环基；8) unsubstituted or substituted by selected prime ¾, substituted C _r C ₆ alkyl with, ¾ prime substituted alkyl with C _r C _6, C _r C ₆ group in the embankment containing 1-3 heteroatoms selected from N a 4-7 membered heterocyclic group of a hetero atom in 0, S;

10) R₂和以及相邻的原子可以形成含有 1-2个 N原子的 5-6元杂芳环、或者含有 1-2 个 N原子的 5-6元杂环；其中，所述杂芳环或杂环可以被选自卤素、氧代基团、 C_rC₆垸基、卤素取代的 C_rC₆垸基、 CrC₆垸氧基中的取代基取代； 10) R ₂ and an adjacent atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the heteroaryl The ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C _r C ₆ fluorenyl group, halogen-substituted C _r C ₆ fluorenyl group, CrC ₆ fluorenyloxy group;

11) R₂与相邻的 N原子可以形成含有 1-2个 N原子的 5-6元杂芳环、或者含有 1-2个 N原子的 5-6元杂环；其中，所述杂芳环或杂环可以被选自卤素、氧代基团、 C_rC₆垸基、卤素取代的 C_rC₆垸基、 CrC₆垸氧基中的取代基取代； 11) R ₂ and an adjacent N atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein, the heteroaryl The ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C _r C ₆ fluorenyl group, halogen-substituted C _r C ₆ fluorenyl group, CrC ₆ fluorenyloxy group;

R₃选自： R _{3 is} selected from:

1) H; 1) H;

2) 卤素； 2) halogen;

3) 未取代或卤素取代的 C_rC₆垸基； 3) unsubstituted or halogen-substituted C _r C ₆ fluorenyl;

4) C_rC₆垸氧基； 4) C _r C ₆ methoxy;

5) C₃-C₆环垸基； 5) C ₃ -C ₆ cyclodecyl;

、 R₅和 R6各自独立地选自： , R ₅ and R 6 are each independently selected from:

1) H; 1) H;

2) 未取代或¾素取代的 C_rC₆垸基； 2) unsubstituted or 3⁄4 substituted C _r C ₆ fluorenyl;

3) (CH₂)_nNR₇R_8; 3) (CH ₂ ) _n NR ₇ R _8;

其中， n为 0或 1; Where n is 0 or 1;

R₇和 R₈各自独立地为： R ₇ and R ₈ are each independently:

1) H; 1) H;

3) C₃-C₆环垸基； 3) C ₃ -C ₆ cyclodecyl;

4) R₇和 11₈与相连的 N原子可以形成环 Het¹, 其中， Het¹为含有 1-3个选自 N、 0和 S 中的杂原子的 5-8元杂芳环；含有 1-3个选自 N、 0和 S中的杂原子的 4-10元杂环；其中，所述杂芳环或杂环可以被选自卤素、氧代基团、 CrC₆垸基、卤素取代的 CrC₆垸基、 CrC₆ 垸氧基中的取代基取代； 4) R ₇ and 11 ₈ and the attached N atom may form a ring Het ¹ , wherein Het ¹ is a 5-8 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S; a 4-10 membered heterocyclic ring selected from the group consisting of hetero atoms in N, 0 and S; wherein The heteroaryl ring or heterocyclic ring may be substituted with a substituent selected from a halogen, an oxo group, a CrC ₆ fluorenyl group, a halogen-substituted CrC ₆ fluorenyl group, and a CrC ₆ fluorenyloxy group;

其中，（^和各自独立地为氢； C_rC₆垸基； C₃-C₆环垸基； C_rC₆垸酰基；未取代或被 1-5个选自 ¾素、 CrC₆垸基、 ¾素取代的 CrC₆垸基、 CrC₆垸氧基中的取代基取代的苯基； Wherein, (^ and each independently are hydrogen; C _r C ₆ fluorenyl; C ₃ -C ₆ cyclodecyl; C _r C ₆ decanoyl; unsubstituted or 1-5 selected from 3⁄4, CrC ₆垸a phenyl group substituted with a substituent in the CrC ₆ fluorenyl group and the CrC ₆ fluorenyl group;

B环为苯环；或者含有 1-3个选自 N、 0和 S中的杂原子的 5-6元杂芳环。 The B ring is a benzene ring; or a 5-6 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S.

优选地， M和 Y各自独立地为 CH或 N; Preferably, M and Y are each independently CH or N;

优选地， W为 C或 N; 其中，当 W为 N时，不存在； Preferably, W is C or N; wherein, when W is N, it does not exist;

优选地， L为 -C(0)NH-或 -NHC(O)-; Preferably, L is -C(0)NH- or -NHC(O)-;

优选地，选自： Preferably, it is selected from:

1 ) H、羟基； 1) H, hydroxyl;

2) C1-C4焼基； 2) C1-C4 sulfhydryl;

3 ) 未取代或被选自 C_rC₄垸氧基、羟基中的取代基取代的 C_rC₄垸氧基； 3) an unsubstituted substituent selected from group C _r C ₄ embankment, substituents C _r C ₄ embankment hydroxyl group;

4) C₃-C₆环垸基； 4) C ₃ -C ₆ cyclodecyl;

5 ) 羧基、 -C(=0)0(CrC₄垸基)、 -C(=0)NH(C_rC₄垸基)； 5) carboxyl group, -C(=0)0(CrC ₄ fluorenyl), -C(=0)NH(C _r C ₄ fluorenyl);

6) 未取代或被 1-5个选自卤素、 C_rC₄垸基、卤素取代的 C_rC₄垸基、 C_rC₄垸氧基中的取代基取代的苯基； 6) a phenyl group which is unsubstituted or substituted with from 1 to 5 substituents selected from halogen, C _r C ₄ fluorenyl, halogen-substituted C _r C ₄ fluorenyl, C _r C ₄ fluorenyloxy;

7 ) 未取代或被选自卤素、 C_rC₄垸基、卤素取代的 C_rC₄垸基、 C_rC₄垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 5-6元杂芳基； 7) 1-3 selected from N, 0 which are unsubstituted or substituted by a substituent selected from halogen, C _r C ₄ fluorenyl, halogen substituted C _r C ₄ fluorenyl, C _r C ₄ fluorenyloxy And a 5-6 membered heteroaryl group of a hetero atom in S;

8 ) 未取代或被选自¾素、 d-C₄垸基、 ¾素取代的 d-C₄垸基、 CrC₄垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 4-6元杂环基； 8) 1-3 selected from N, 0 and S, which are unsubstituted or substituted by a substituent selected from a dC ₄ fluorenyl group substituted by a _3⁄4 element, a dC ₄ fluorenyl group, a _3⁄4 element, or a CrC ₄ fluorenyloxy group. a 4-6 membered heterocyclic group of a hetero atom;

9) (Qi)(Q₂)N-_; 其中， (^和¾各自独立地为氢; C_rC₄垸基； C₃-C₆环垸基; C_rC₄垸酰基；未取代或被 1-5个选自卤素、 C_rC₄垸基、卤素取代的 C_rC₄垸基、 C_rC₄垸氧基中的取代基取代的苯基； 9) (Qi)(Q ₂ )N- _; wherein, (^ and 3⁄4 are each independently hydrogen; C _r C ₄ fluorenyl; C ₃ -C ₆ cyclodecyl; C _r C ₄ decanoyl; unsubstituted or a phenyl group substituted with one to five substituents selected from the group consisting of halogen, C _r C ₄ fluorenyl, halogen substituted C _r C ₄ fluorenyl, C _r C ₄ decyloxy;

10) 1¾ 与 A环 Y位可以形成苯环、含有 1-2个 N原子的 5-6元杂芳环、或者含有 1-2 个 N原子的 5-6元杂环；其中，所述苯环、杂芳环或杂环可以被选自卤素、 C_rC₄垸基、卤素取代的 C_rC₄垸基、 C_rC₄垸氧基、羧基、 -C(=0)0(CrC₄垸基)、 -C(=0)NH(C_rC₄垸基）中的取代基取代； 10) 13⁄4 and the Y ring of the A ring may form a benzene ring, a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the benzene The ring, heteroaryl ring or heterocyclic ring may be selected from halogen, C _r C ₄ fluorenyl, halogen substituted C _r C ₄ fluorenyl, C _r C ₄ decyloxy, carboxy, -C(=0)0 (CrC Substituent substitution in _4- mercapto), -C(=0)NH(C _r C ₄ fluorenyl);

优选地， R₂选自: Preferably, R _{2 is} selected from the group consisting of

1 ) H、卤素、羟基； 1) H, halogen, hydroxyl;

2) 氧代基团； 3 ) Ci-C4焼基； 2) an oxo group; 3) Ci-C4 sulfhydryl;

4) C_rC₄垸氧基； 4) C _r C ₄ methoxy;

5 ) C₃-C₆环垸基； 5) C ₃ -C ₆ cyclodecyl;

7) 未取代或被选自卤素、 C_rC₄垸基、卤素取代的 C_rC₄垸基、 C_rC₄垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 5-6元杂芳基； 7) 1-3 selected from N, 0 which are unsubstituted or substituted by a substituent selected from halogen, C _r C ₄ fluorenyl, halogen substituted C _r C ₄ fluorenyl, C _r C ₄ fluorenyloxy And a 5-6 membered heteroaryl group of a hetero atom in S;

8) 未取代或被选自¾素、 d-C₄垸基、 ¾素取代的 d-C₄垸基、 CrC₄垸氧基中的取代基取代的含有 1-3个选自 N、 0和 S中的杂原子的 4-6元杂环基； 8) 1-3 selected from N, 0 and S, which are unsubstituted or substituted with a substituent selected from the group consisting of dC ₄ fluorenyl, dC ₄ fluorenyl, and CrC ₄ fluorenyl substituted with _3⁄4 , dC ₄ fluorenyl, _3⁄4 a 4-6 membered heterocyclic group of a hetero atom;

9) (Qi)(Q₂)N-_; 其中， Q n ¾各自独立地为氢； C_rC₄垸基； C₃-C₆环垸基； C_rC₄垸酰基；未取代或被 1-5个选自卤素、 C_rC₄垸基、卤素取代的 C_rC₄垸基、 C_rC₄垸氧基中的取代基取代的苯基； 9) (Qi)(Q ₂ )N- _; wherein, Q n 3⁄4 are each independently hydrogen; C _r C ₄ fluorenyl; C ₃ -C ₆ cyclodecyl; C _r C ₄ decanoyl; unsubstituted or a phenyl group substituted with 1-5 substituents selected from the group consisting of halogen, C _r C ₄ fluorenyl, halogen-substituted C _r C ₄ fluorenyl, and C _r C ₄ fluorenyloxy;

10) R₂和以及相邻的原子可以形成含有 1-2个 N原子的 5-6元杂芳环、或者含有 1-2 个 N原子的 5-6元杂环；其中，所述杂芳环或杂环可以被选自卤素、氧代基团、 C_rC₄垸基、 ¾素取代的 C_rC₄垸基、 C_rC₄垸氧基中的取代基取代； 10) R ₂ and an adjacent atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein The ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C _r C ₄ fluorenyl group, _3⁄4 cyano substituted C _r C ₄ fluorenyl group, C _r C ₄ fluorenyloxy group;

11 ) R₂与相邻的 N原子可以形成含有 1-2个 N原子的 5-6元杂芳环、或者含有 1-2个 N原子的的 5-6元杂环；其中，所述芳杂环或杂环可以被选自卤素、氧代基团、 C_rC₄垸基、卤素取代的 d-C₄垸基、 C_rC₄垸氧基中的取代基取代； 11) R ₂ and an adjacent N atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein The heterocyclic ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C _r C ₄ fluorenyl group, halogen-substituted dC ₄ fluorenyl group, and C _r C ₄ fluorenyloxy group;

进一步优选地， R 选自： Further preferably, R is selected from the group consisting of

1 ) 氢； 1) hydrogen;

2) 甲基、乙基、异丙基、叔丁基； 2) methyl, ethyl, isopropyl, t-butyl;

3 ) 羟基、甲氧基、乙氧基、异丙氧基、叔丁氧基、甲氧基取代的乙氧基、羟基取代的乙氧基； 3) a hydroxy group, a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, a methoxy-substituted ethoxy group, a hydroxy-substituted ethoxy group;

4) 环丙基、环丁基、环戊基、环己基； 4) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

5 ) 未取代或被 1-4个选自卤素、甲基、甲氧基、三氟甲基取代的苯基； 5) unsubstituted or substituted by 1-4 phenyl groups selected from halogen, methyl, methoxy, trifluoromethyl;

6) 未取代或甲基取代的吡唑基、未取代或甲基取代的咪唑基、嘧啶基； 6) unsubstituted or methyl substituted pyrazolyl, unsubstituted or methyl substituted imidazolyl, pyrimidinyl;

7) 氮杂环丁基、吡咯垸基、哌啶基、吗啉基、未取代或甲基取代的哌嗪基； 7) azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, unsubstituted or methyl substituted piperazinyl;

8) 羧基、 -C(=0)OMe、 -C(=0)OEt、 -C(=0)NHMe、 -C(=0)NHEt; 8) carboxyl group, -C(=0)OMe, -C(=0)OEt, -C(=0)NHMe, -C(=0)NHEt;

9)氨基；甲氨基；二甲氨基；叔丁基氨基；环丙基氨基；乙酰氨基；未取代或被卤素、甲基、甲氧基、三氟甲基取代的苯基氨基； 9) amino group; methylamino; dimethylamino; tert-butylamino; cyclopropylamino; acetylamino; phenylamino group unsubstituted or substituted by halogen, methyl, methoxy, trifluoromethyl;

优选地，与 A环 Y位可以与 A环形成以下结构的骈环：

Preferably, the Y ring with the A ring may form an anthracene ring with the following structure of the A ring:

其中， R_r、 R_r,、 R₂各自独立地选自： Wherein R _r , R _r , and R ₂ are each independently selected from:

1 ) H; 1) H;

2) F、 Cl、 Br_; 2) F, Cl, Br _;

3 ) 甲基、乙基、异丙基、异丁基、三氟甲基； 3) methyl, ethyl, isopropyl, isobutyl, trifluoromethyl;

4) 环丙基； 4) cyclopropyl;

5 ) 羟基、甲氧基、乙氧基、异丙氧基、叔丁氧基； 5) hydroxy, methoxy, ethoxy, isopropoxy, tert-butoxy;

6) 羧基、 -C(=0)OMe、 -C(=0)OEt、 -C(=0)NHMe、 -C(=0)NHEt; 6) carboxyl group, -C(=0)OMe, -C(=0)OEt, -C(=0)NHMe, -C(=0)NHEt;

7) 氨基、甲氨基、二甲氨基、叔丁基氨基、环丙基氨基、乙酰氨基； 7) amino, methylamino, dimethylamino, tert-butylamino, cyclopropylamino, acetylamino;

进一步优选地， R₂选自： Further preferably, R _{2 is} selected from the group consisting of

1 ) H; 1) H;

2) F、 Cl、 Br_; 2) F, Cl, Br _;

3 ) 氧代基团； 3) an oxo group;

4) 甲基、乙基、异丙基、叔丁基； 4) methyl, ethyl, isopropyl, t-butyl;

6) 环丙基、环丁基、环戊基、环己基； 6) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

7) 未取代或被 1-4个选自卤素、甲基、甲氧基、三氟甲基取代的苯基； 7) unsubstituted or substituted by 1-4 phenyl groups selected from the group consisting of halogen, methyl, methoxy, and trifluoromethyl;

8 )氨基；甲氨基；二甲氨基；叔丁基氨基；环丙基氨基；乙酰氨基；未取代或被卤素、甲基、甲氧基、三氟甲基取代的苯基氨基； 8) amino group; methylamino; dimethylamino; tert-butylamino; cyclopropylamino; acetylamino; phenylamino group unsubstituted or substituted by halogen, methyl, methoxy, trifluoromethyl;

优选地， R₂和以及相邻的原子可以与 A环形成以下结构的骈环： Preferably, R ₂ and adjacent atoms may form an anthracene ring with the following structure of the A ring:

更优选地， R₂和以及相邻的原子可以与 A环形成以下结构的骈环:

More preferably, R ₂ and adjacent atoms may form an anthracene ring of the following structure with the A ring:

优选地， R₂与相邻的 N原子可以与 A环形成以下结构的骈环: Preferably, R ₂ and an adjacent N atom may form an anthracene ring of the following structure with the A ring:

优选地，为:

Preferably, it is:

1) H; 1) H;

2) 卤素； 2) halogen;

3) 未取代或卤素取代的 C_rC₄垸基； 3) unsubstituted or halogen-substituted C _r C ₄ fluorenyl;

4) C_rC₄垸氧基； 4) C _r C ₄ methoxy;

5) C₃-C₄环烷基; 5) C ₃ -C ₄ cycloalkyl;

进一步优选地， R₃为： Further preferably, R ₃ is:

1) H; 1) H;

2) F、 Cl、 Br_; 2) F, Cl, Br _;

3) 甲基、乙基、异丙基、叔丁基； 3) methyl, ethyl, isopropyl, t-butyl;

4) 环丙基； 4) cyclopropyl;

5) 三氟甲基； 5) trifluoromethyl;

6) 甲氧基、乙氧基、叔丁氧基； 6) methoxy, ethoxy, t-butoxy;

优选地， B环为以下结构的二价基团:

且当 B环为苯环时， 1^和1₂形成环 E，且 E环与 A环形成的骈环

以下结构:

Preferably, the B ring is a divalent group of the following structure:

And when the B ring is a benzene ring, 1^ and 1 ₂ form a ring E, and the ring of the ring formed by the ring E and the ring A

The following structure:

优选地， R₄、 R₅和 Re选自： Preferably, R ₄ , R ₅ and Re are selected from:

1) H; 2) CF₃; 1) H; 2) CF ₃ ;

3) (CH₂)_nNR₇R_8; 3) (CH ₂ ) _n NR ₇ R _8;

其中， n为 0或 1; Where n is 0 or 1;

R₇和 R₈各自独立地为： R ₇ and R ₈ are each independently:

1) H; 1) H;

2) 未取代或¾素取代的 C_rC₄垸基； 2) unsubstituted or _3⁄4 substituted C _r C ₄ fluorenyl;

3) C₃-C₆环垸基。 3) C ₃ -C ₆ cyclodecyl.

4) R₇和 Rg与相连的 N原子可以形成环 Het¹, 其中， Het¹为含有 1-3个选自 N、 0和 S 中的杂原子的 5-6元杂芳环；含有 1-3个选自 N、 0和 S中的杂原子的 4-10元杂环；其中，所述杂芳环或杂环可以被选自卤素、氧代基团、 d-C₄垸基、卤素取代的 C_rC₄垸基、 C_rC₄ 垸氧基中的取代基取代； 4) R ₇ and Rg and the attached N atom may form a ring Het ¹ , wherein Het ¹ is a 5-6 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S; 3 4-10 membered heterocyclic rings selected from heteroatoms in N, 0 and S; wherein the heteroaryl ring or heterocyclic ring may be substituted by a halogen, an oxo group, a dC ₄ fluorenyl group, a halogen Substituent substitution in C _r C ₄ fluorenyl, C _r C ₄ methoxy;

更优选地， R₄、 R₅和 Re选自： More preferably, R ₄ , R ₅ and Re are selected from:

1) H; 1) H;

2) CF₃;

2) CF ₃ ;

4) (CH₂)_n-Het； 4) (CH ₂ ) _n -Het;

其中， n为 Het¹为以下结构: Where n is Het ¹ is the following structure:

优选地， c环为以下结构：

Preferably, the c-ring is of the following structure:

ZlZl

.SS000/M0ZN3/X3d L99 6linOZ OAV

.SS000/M0ZN3/X3d L99 6linOZ OAV

.SS000/M0ZN3/X3d L99 6linOZ OAV

.SS000/M0ZN3/X3d L99 6linOZ OAV

本发明的另一目的是提供通式 I表示的炔基杂环类化合物的制备方法，上述的含炔基杂环类化合物的制备方法包括选自如下合成路线 I、 II和 III中的任意 Another object of the present invention is to provide a process for producing an alkynyl heterocyclic compound represented by the general formula I, which comprises an alkyne-containing hetero The preparation method of the cyclic compound includes any one selected from the following synthetic routes I, II and III.

合成路线 I

Synthetic route I

合成路线 I包括如下步骤： Synthetic route I includes the following steps:

步骤 1: 向圆底烧瓶中加入化合物 1-1、 NBS、 AIBN和 CC1₄，用油浴加热进行反应，反应温度为 70~120°C; 反应结束后，纯化即可得到化合物 1-2; 化合物 1-1、 NBS和 AIBN 的当量比为 1:1.1:0.2; 加热方式为油浴；温度为 100°C_; 反应时间为 36小时。 Step 1: adding the compound 1-1, NBS, AIBN and CC1 ₄ to the round bottom flask, and reacting with an oil bath, the reaction temperature is 70-120 ° C; after the reaction is completed, the compound 1-2 can be obtained by purification; The equivalent ratio of the compound 1-1, NBS and AIBN was 1:1.1:0.2; the heating method was an oil bath; the temperature was 100 ° C _{; and the} reaction time was 36 hours.

步骤 2: 向圆底烧瓶中加入化合物 1-2、 1-3、 CH₂C1₂和 Et₃N，室温下进行反应；反应结束后，纯化即可得到化合物 1-4; 化合物 1-2、化合物 1-3和 Et₃N的当量比为 1:1.1:1.2; 温度为室温；反应时间为 12小时。 Step 2: Add compound 1-2, 1-3, CH ₂ C1 ₂ and Et ₃ N to the round bottom flask, and carry out the reaction at room temperature; after the reaction is completed, the compound 1-4 can be obtained by purification; Compound 1-2, The equivalent ratio of the compound 1-3 to Et ₃ N was 1:1.1:1.2; the temperature was room temperature; and the reaction time was 12 hours.

步骤 3: 向圆底烧瓶中加入化合物 1-4、还原 Fe粉、 EtOH和 NH₄C1，用油浴加热进行反应，反应温度为 70~120°C; 反应结束后，纯化即可得到化合物 1-5; 化合物 1-4、还原 Fe粉和 NH₄C1的当量比为 1:4:2; 加热方式为油浴；温度为 100°C_; 反应时间为 10小时。步骤 4: 向圆底烧瓶中加入化合物 1-6、 S0C1₂、 DMF, 用油浴加热进行反应，反应温度为 80~ 120°C;反应结束后，纯化即可得到化合物 1-7;化合物 I-6、DMF的当量比为 1:0.05， S0C1₂为溶剂；加热方式为油浴；温度为 100°C_; 反应时间为 8小时。 Step 3: Add compound 1-4, reduced Fe powder, EtOH and NH ₄ C1 to the round bottom flask, and heat the reaction in an oil bath at a reaction temperature of 70-120 ° C. After the reaction is completed, the compound 1 can be obtained by purification. -5; The equivalent ratio of the compound 1-4, the reduced Fe powder and the NH ₄ C1 is 1:4:2; the heating method is an oil bath; the temperature is 100 ° C _{; and the} reaction time is 10 hours. Step 4: Adding compound 1-6, S0C1 ₂ and DMF to a round bottom flask, and heating the reaction in an oil bath at a reaction temperature of 80 to 120 ° C; after completion of the reaction, purification is carried out to obtain a compound 1-7; -6, DMF equivalent ratio is 1:0.05, S0C1 ₂ is solvent; heating method is oil bath; temperature is 100 ° C _; reaction time is 8 hours.

步骤 5: 向圆底烧瓶中加入化合物 1-5、 1-7、 DMF和 Et₃N，室温下进行反应；反应结束后，纯化即可得到化合物 1-8; 化合物 1-5、化合物 1-7和 Et₃N的当量比为 1:1:1.1; 温度为室温；反应时间为 4小时。 Step 5: Add the compound 1-5, 1-7, DMF and Et ₃ N to the round bottom flask, and carry out the reaction at room temperature; after the reaction is completed, the compound 1-8 can be obtained by purification; Compound 1-5, Compound 1- The equivalent ratio of 7 to Et ₃ N is 1:1:1.1; the temperature is room temperature; the reaction time is 4 hours.

步骤 6:向圆底烧瓶中加入化合物 1-8、三甲基硅基乙炔、 Pd(PPh₃)₄、CuI、DMF和 DIPEA, 用油浴加热或微波照射进行反应，反应温度为 80~ 120°C_; 反应结束后，纯化即可得到化合物 1-9；化合物 1-8、三甲基硅基乙炔、 Pd(PPh₃)₄、 Cul、和 DIPEA的当量比为 1:1.5:0.05:0.1:3；加热方式选用微波照射，功率为 150瓦，时间为 20分钟；反应温度为 80°C。 Step 6: Add compound 1-8, trimethylsilylacetylene, Pd(PPh ₃ ) ₄ , CuI, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° _C; after completion of the reaction, purification to give compound 1-9; compounds 1-8, trimethylsilyl _{_{acetylene, Pd (PPh 3) 4,}} Cul, DIPEA, and the equivalent ratio of 1: 1.5: 0.05: 0.1 :3; The heating method is microwave irradiation, the power is 150 watts, the time is 20 minutes; the reaction temperature is 80 °C.

步骤 7: 向圆底烧瓶中加入化合物 1-9、碳酸钾和甲醇，室温下进行反应；反应结束后，纯化即可得到化合物 1-10。化合物 1-9和碳酸钾的当量比为 1:10，甲醇为溶剂，室温度为室温；反应时间为 3小时。 Step 7: A compound 1-9, potassium carbonate and methanol are added to a round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound 1-10 is obtained by purification. The equivalent ratio of the compound 1-9 to potassium carbonate was 1:10, methanol was the solvent, and the chamber temperature was room temperature; the reaction time was 3 hours.

步骤 8: 向圆底烧瓶中加入化合物 1-10、化合物 1-11、 Pd(PPh₃)₄、 Cul、 DMF和 DIPEA, 用油浴加热或微波照射进行反应，反应温度为 80~ 120°C_; 反应结束后，纯化即可得到化合物 1-12。化合物 1-10、化合物 1-11、 Pd(PPh₃)₄、 Cul和 DIPEA的当量比为 1:1.5:0.05:0.1:3;Step 8: Add compound 1-10, compound 1-1-1, Pd(PPh ₃ ) ₄ , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° C. _; after the reaction, purification to give compound 1-12. The equivalent ratio of compound 1-10, compound 1-1-1, Pd(PPh ₃ ) ₄ , Cul and DIPEA is 1:1.5:0.05:0.1:3;

°C。 °C.

Π-11 Π-11

合成路线 Π 合成路线 II包括如下步骤： Synthetic routeΠ Synthetic Route II includes the following steps:

步骤 1: 向圆底烧瓶中加入化合物 11-1、 PBr₃和甲苯，室温下进行反应；反应结束后，纯化即可得到化合物 Π-2; 化合物 II-1和 PBr₃的当量比为 1:2，甲苯为溶剂；温度为室温；反应时间为 12小时。 Step 1: The compound 11-1, PBr ₃ and toluene are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound Π-2 is obtained by purification; the equivalent ratio of the compound II-1 and PBr ₃ is 1: 2, toluene is the solvent; the temperature is room temperature; the reaction time is 12 hours.

步骤 2: 向圆底烧瓶中加入化合物 11-2、 11-3、 CH₂C1₂和 Et₃N，室温下进行反应；反应结束后，纯化即可得到化合物 Π-4; 化合物 11-2、化合物 Π-3和 Et₃N的当量比为 1:1:1.1; 温度为室温；反应时间为 12小时。 Step 2: The compound 11-2, 11-3, CH ₂ C1 ₂ and Et ₃ N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound Π-4 is obtained by purification; the compound 11-2, The equivalent ratio of the compound Π-3 to Et ₃ N was 1:1:1.1; the temperature was room temperature; and the reaction time was 12 hours.

步骤 3: 向圆底烧瓶中加入化合物 11-4、还原 Fe粉、 EtOH和 NH₄C1，用油浴加热进行反应，反应温度为 70~ 120°C; 反应结束后，纯化即可得到化合物 Π-5; 化合物 11-4、还原 Fe粉和 NH₄C1的当量比为 1:4:2; 加热方式为油浴；温度为 100°C; 反应时间为 10小时。 Step 3: Adding compound 11-4, reducing Fe powder, EtOH and NH ₄ C1 to a round bottom flask, and heating the reaction in an oil bath at a reaction temperature of 70 to 120 ° C; after completion of the reaction, the compound is obtained by purification. -5; The equivalent ratio of the compound 11-4, the reduced Fe powder and the NH ₄ C1 is 1:4:2; the heating method is an oil bath; the temperature is 100 ° C; and the reaction time is 10 hours.

步骤 4: 向圆底烧瓶中加入化合物 11-6、 SOCl₂、 DMF, 用油浴加热进行反应，反应温度为 80~ 120°C; 反应结束后，纯化即可得到化合物 Π-7; 化合物 Π-6和 DMF的当量比为 1:0.05， SOCl₂为溶剂；加热方式为油浴；温度为 100°C_; 反应时间为 8小时。 Step 4: Adding compound 11-6, SOCl ₂ and DMF to a round bottom flask, and reacting with an oil bath, the reaction temperature is 80 to 120 ° C; after completion of the reaction, the compound Π-7 can be obtained by purification; The equivalent ratio of -6 to DMF is 1:0.05, SOCl ₂ is a solvent; the heating method is an oil bath; the temperature is 100 ° C _{; and the} reaction time is 8 hours.

步骤 5: 向圆底烧瓶中加入化合物 11-5、 11-7、 DMF和 Et₃N，室温下进行反应；反应结束后，纯化即可得到化合物 Π-8; 化合物 11-5、化合物 Π-7和 Et₃N的当量比为 1:1:1.1; 温度为室温；反应时间为 4小时。 Step 5: The compound 11-5, 11-7, DMF and Et ₃ N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound Π-8 is obtained by purification; the compound 11-5, the compound Π- The equivalent ratio of 7 to Et ₃ N is 1:1:1.1; the temperature is room temperature; the reaction time is 4 hours.

步骤 6: 向圆底烧瓶中加入化合物 11-8、三甲基硅基乙炔、 Pd(PPh₃)₄、 Cul、 DMF和 DIPEA, 用油浴加热或微波照射进行反应，反应温度为 80~ 120°C; 反应结束后，纯化即可得到化合物 Π-9; 化合物 11-8、三甲基硅基乙炔、 Pd(PPh₃)₄、 Cul、和 DIPEA的当量比为 1:1.5:0.05:0.1:3；加热方式选用微波照射，功率为 150瓦，时间为 20分钟；反应温度为 80 。C。 Step 6: Add compound 11-8, trimethylsilylacetylene, Pd(PPh ₃ ) ₄ , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120. After completion of the reaction, the compound Π-9 is obtained by purification; the equivalent ratio of compound 11-8, trimethylsilylacetylene, Pd(PPh ₃ ) ₄ , Cul, and DIPEA is 1:1.5:0.05:0.1 :3; The heating method is microwave irradiation, the power is 150 watts, the time is 20 minutes; the reaction temperature is 80 。. C.

步骤 7: 向圆底烧瓶中加入化合物 11-9、碳酸钾和甲醇，室温下进行反应；反应结束后，纯化即可得到化合物 11-10。化合物 Π-9和碳酸钾的当量比为 1:10，甲醇为溶剂，室温度为室温；反应时间为 3小时。 Step 7: A compound 11-9, potassium carbonate and methanol are added to a round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound 11-10 is obtained by purification. The equivalent ratio of the compound Π-9 to potassium carbonate was 1:10, methanol was the solvent, the chamber temperature was room temperature, and the reaction time was 3 hours.

步骤 8:向圆底烧瓶中加入化合物 11-10、化合物 11-11、 Pd(PPh₃)₄、 Cul、 DMF和 DIPEA, 用油浴加热或微波照射进行反应，反应温度为 80~ 120°C_; 反应结束后，纯化即可得到化合物 11-12。化合物 11-10、化合物 11-11、 Pd(PPh₃)₄、 Cul和 DIPEA的当量比为 1:1.5:0.05:0.1:3；加热方式选用微波照射，功率为 150瓦，时间为 20分钟；反应温度为 90°C。 Step 8: Add compound 11-10, compound 11-11, Pd(PPh ₃ ) ₄ , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° C. _; after the reaction, purification to give compound 11-12. The equivalent ratio of compound 11-10, compound 11-11, Pd(PPh ₃ ) ₄ , Cul and DIPEA is 1:1.5:0.05:0.1:3; the heating method is microwave irradiation, the power is 150 watts, and the time is 20 minutes; The reaction temperature was 90 °C.

III- 9 III- 9

合成路线 in Synthetic route in

合成路线 III包括如下步骤： Synthetic route III includes the following steps:

步骤 1: 向圆底烧瓶中加入化合物 111-1、 NaBr0₃、 NaHS0₃、 H₂0和 EtOAc, 室温下进行反应；反应结束后，纯化即可得到化合物 ΠΙ-2; 化合物 111-1、 NaBr0₃和 NaHS0₃的当量比为 1:3:3，溶剂 H₂0和 EtOAc的溶剂比为 1:1; 温度为室温；反应时间为 12小时。 Step 1: The compound 111-1, NaBr0 ₃ , NaHS0 ₃ , H ₂ 0 and EtOAc were added to a round bottom flask, and the reaction was carried out at room temperature; after completion of the reaction, the compound ΠΙ-2 was obtained by purification; Compound 111-1, NaBr0 The equivalent ratio of _{3 to} NaHS0 ₃ was 1:3:3, the solvent ratio of solvent H ₂ 0 to EtOAc was 1:1; the temperature was room temperature; and the reaction time was 12 hours.

步骤 2: 向圆底烧瓶中加入化合物 111-2、 111-3、 CH₂C1₂和 Et₃N，室温下进行反应；反应结束后，纯化即可得到化合物 ΙΠ-4;化合物 111-2、化合物 ΠΙ-3和 Et₃N的当量比为 1:1:1.1，温度为室温；反应时间为 12小时。 Step 2: The compound 111-2, 111-3, CH ₂ C1 ₂ and Et ₃ N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ΙΠ-4 is obtained by purification; the compound 111-2, The equivalent ratio of the compound ΠΙ-3 to Et ₃ N was 1:1:1.1, the temperature was room temperature; and the reaction time was 12 hours.

步骤 3: 向圆底烧瓶中加入化合物 111-4、 111-5、 DMF和 Et₃N，室温下进行反应；反应结束后，纯化即可得到化合物 ΠΙ-6; 化合物 111-4、化合物 ΙΠ-5和 Et₃N的当量比为 1:1:1.1，温度为室温；反应时间为 4小时。 Step 3: The compound 111-4, 111-5, DMF and Et ₃ N are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ΠΙ-6 is obtained by purification; the compound 111-4, the compound ΙΠ- The equivalent ratio of 5 to Et ₃ N is 1:1:1.1, the temperature is room temperature; and the reaction time is 4 hours.

步骤 4: 向圆底烧瓶中加入化合物 111-6、三甲基硅基乙炔、 Pd(PPh₃)₄、 Cul、 DMF和 DIPEA, 用油浴加热或微波照射进行反应，反应温度为 80~120°C; 反应结束后，纯化即可得到化合物 ΙΠ-7; 化合物 111-6、三甲基硅基乙炔、 Pd(PPh₃)₄、 Cul和 DIPEA的当量比为 1:1.5:0.05:0.1:3；加热方式选用微波照射，功率为 150瓦，时间为 20分钟；反应温度为 80 。C。步骤 5: 向圆底烧瓶中加入化合物 111-7、碳酸钾和甲醇，室温下进行反应；反应结束后，纯化即可得到化合物 ΙΠ-8; 化合物 ΙΠ-7和碳酸钾的当量比为 1:10，甲醇为溶剂，室温度为室温；反应时间为 3小时。 Step 4: Add compound 111-6, trimethylsilylacetylene, Pd(PPh ₃ ) ₄ , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120. After completion of the reaction, the compound ΙΠ-7 is obtained by purification; the equivalent ratio of the compound 111-6, trimethylsilylacetylene, Pd(PPh ₃ ) ₄ , Cul and DIPEA is 1:1.5:0.05:0.1: 3; The heating method is microwave irradiation, the power is 150 watts, the time is 20 minutes; the reaction temperature is 80 。. C. Step 5: The compound 111-7, potassium carbonate and methanol are added to the round bottom flask, and the reaction is carried out at room temperature; after completion of the reaction, the compound ΙΠ-8 is obtained by purification; the equivalent ratio of the compound ΙΠ-7 to potassium carbonate is 1: 10, methanol is the solvent, the chamber temperature is room temperature; the reaction time is 3 hours.

步骤 6: 向圆底烧瓶中加入化合物 111-8、化合物 111-9、 Pd(PPh₃)₄、 Cul、 DMF和 DIPEA, 用油浴加热或微波照射进行反应，反应温度为 80~ 120°C_; 反应结束后，纯化即可得到化合物 111-10。化合物 111-9、化合物 111-8、 Pd(PPh₃)₄、 Cul和 DIPEA的当量比为 1:1.5:0.05:0.1:3；加热方式选用微波照射，功率为 150瓦，时间为 20分钟；反应温度为 90°C。 Step 6: Add compound 111-8, compound 111-9, Pd(PPh ₃ ) ₄ , Cul, DMF and DIPEA to the round bottom flask, and react with oil bath or microwave irradiation at a reaction temperature of 80-120 ° C. _; after the reaction, purification to give compound 111-10. The equivalent ratio of compound 111-9, compound 111-8, Pd(PPh ₃ ) ₄ , Cul and DIPEA is 1:1.5:0.05:0.1:3; the heating method is microwave irradiation, the power is 150 watts, and the time is 20 minutes; The reaction temperature was 90 °C.

其中， M、 Y、 W、 Ri^ R₂、 R₃、 R₇、 Rg和 B环的定义同上。 Wherein, M, Y, W, Ri^ R ₂ , R ₃ , R ₇ , Rg and B are as defined above.

根据本发明的另一目的，本发明提供了上述通式（I) 表示的炔基杂环类化合物在制备抗肿瘤的药物中的用途。 According to another object of the present invention, the present invention provides the use of the alkynyl heterocyclic compound represented by the above formula (I) for the preparation of an antitumor drug.

根据本发明的还一目的，本发明提供了一种具有抗肿瘤活性的药物组合物，其包含治疗有效量的一种或多种上述通式（I)表示的炔基杂环类化合物及其药学上可以接受的辅料。 According to still another object of the present invention, the present invention provides a pharmaceutical composition having antitumor activity comprising a therapeutically effective amount of one or more alkynyl heterocyclic compounds represented by the above formula (I) and A pharmaceutically acceptable excipient.

所述肿瘤为非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌、胰腺癌、乳腺癌、前列腺癌、肝癌、胃癌、皮肤癌、上皮细胞癌、鼻咽癌、淋巴癌、胃肠道间质瘤、白血病等中的任一种。 The tumor is non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, gastric cancer, skin cancer, epithelial cell carcinoma, nasopharyngeal carcinoma, lymphoma, gastrointestinal Any of the stromal tumors, leukemia, and the like.

在本申请中，缩写的含义如下： In this application, the meaning of the abbreviation is as follows:

NBS: N-溴代琥珀酰亚胺； NBS: N-bromosuccinimide;

MeOH: 甲醇 MeOH: methanol

DMF: Ν,Ν-二甲基甲酰胺； DMF: hydrazine, hydrazine-dimethylformamide;

EtOH: 乙醇； EtOH: ethanol;

AIBN: 偶氮二异丁腈； AIBN: azobisisobutyronitrile;

CC1₄: 四氯化碳； CC1 ₄ : carbon tetrachloride;

CH₂C1₂: 二氯甲垸； CH ₂ C1 ₂ : dichloromethane;

Et₃N: 三乙胺； Et ₃ N: triethylamine;

NH₄C1: 氯化铵； NH ₄ C1: ammonium chloride;

Fe: 铁； Fe: iron;

S0C1₂: 二氯亚砜； S0C1 ₂ : thionyl chloride;

PBr₃: 三溴化磷 PBr ₃ : phosphorus tribromide

H₂0: 水 H ₂ 0: water

K₂C0₃: 碳酸钾 K ₂ C0 ₃ : potassium carbonate

NaBr0₃: 溴酸钠 NaHS0₃: 亚硫酸氢钠 NaBr0 ₃ : sodium bromate NaHS0 ₃ : sodium bisulfite

EtOAc: 乙酸乙酯 EtOAc: ethyl acetate

Pd(PPh₃)₄: 四三苯基磷钯； Pd(PPh ₃ ) ₄ : tetrakistriphenylphosphine palladium;

Cul: 碘化亚铜； Cul: cuprous iodide;

DIPEA: 二异丙基乙胺 DIPEA: Diisopropylethylamine

rt: 室温 Rt: room temperature

Boc: 叔丁氧羰基。具体实施方式 Boc: tert-butoxycarbonyl. detailed description

下列阐述的实施例绝非限制本发明。 The examples set forth below are in no way intended to limit the invention.

化合物制备实施例 Compound preparation example

实施例 1

Example 1

步骤一： step one:

向圆底烧瓶中加入 l g (5 mMol) 2-甲基 -5-硝基三氟甲苯、 980 mg (5.5 mMol) NBS、 164 mg (ImMol) AIBN和 20毫升的 CC1₄，用油浴加热 100°C下反应 36小时；反应结束后冷却至室温，减压蒸干溶剂，柱层析得到产物 2-三氟甲基 -4-硝基苄溴 1.04 g (产率： 71%)。 Add lg (5 mMol) 2-methyl-5-nitrobenzotrifluoride, 980 mg (5.5 mMol) NBS, 164 mg (ImMol) AIBN and 20 ml of CC1 ₄ to a round bottom flask and heat 100 with an oil bath. The reaction was carried out at ° C for 36 hours; after completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated to dryness, and the product was obtained to give the product 2-trifluoromethyl-4-nitrobenzyl bromide 1.04 g (yield: 71%).

步骤二： Step two:

向圆底烧瓶中加入 849 mg (3 mMol) 2-三氟甲基 -4-硝基苄溴、 330 mg (3.3 mMol) N- 甲基哌嗪、 364 mg (3.6 mMol) Et₃N和 10毫升 CH₂C1₂，室温下反应 12小时；反应结束后，减压蒸干溶剂，柱层析得到产物 1-甲基 -4-(4-硝基 -2- (三氟甲基)苄基)哌嗪 901 mg (产率： 99%)。 To the round bottom flask was added 849 mg (3 mMol) 2-trifluoromethyl-4-nitrobenzyl bromide, 330 mg (3.3 mMol) N-methylpiperazine, 364 mg (3.6 mMol) Et ₃ N and 10 HCl CH ₂ C1 ₂ was reacted at room temperature for 12 hours; after completion of the reaction, the solvent was evaporated to dryness vacuol, and then purified to give the product 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl Piperazine 901 mg (yield: 99%).

步骤三： Step three:

向圆底烧瓶中加入 901 mg (约 3 mMol) 1-甲基 -4-(4-硝基 -2- (三氟甲基)苄基)哌嗪、 672 mg (12 mMol)还原 Fe粉、 318 mg (6 mMol) NH₄C1和 15毫升 EtOH, 用油浴加热 100°C 下反应 10小时；反应结束后，垫硅藻土抽滤，减压蒸干滤液，柱层析得到产物 4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯胺 754 mg (产率： 92.3%)。 901 mg (about 3 mMol) of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine, 672 mg (12 mMol) of reduced Fe powder were added to the round bottom flask. 318 mg (6 mMol) NH ₄ C1 and 15 ml of EtOH were reacted in an oil bath at 100 ° C for 10 hours. After the reaction was completed, the padded diatomaceous earth was suction filtered, and the filtrate was evaporated to dryness. ((4-Methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)aniline 754 mg (yield: 92.3%).

步骤四： Step four:

向圆底烧瓶中加入 1.31 g (5 mMol) 3-碘 -4-甲基苯甲酸、 15毫升 SOCl₂和 18 mg (0.25 mMol)无水 DMF, 用油浴加热 100°C下反应 8小时；反应结束后，减压蒸干溶剂得到产物 3-碘 -4-甲基苯甲酰氯，直接用于下一步反应。步骤五: To the round bottom flask, 1.31 g (5 mMol) of 3-iodo-4-methylbenzoic acid, 15 ml of SOCl ₂ and 18 mg (0.25 mMol) of anhydrous DMF were added, and the mixture was heated at 100 ° C for 8 hours in an oil bath; After completion of the reaction, the solvent was evaporated to dryness under reduced pressure to give the product, 3-iodo-4-methylbenzoyl chloride, which was directly used for the next reaction. Step five:

向圆底烧瓶中加入 550 mg (2 mMol ) 4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯胺、 560 mg (2 mMol ) 3-碘 -4-甲基苯甲酰氯、 223 mg (2.2 mMol ) Et₃N和 15毫升 DMF, 室温下反应 4小时；反应结束后，减压蒸干溶剂，柱层析得到产物 3-碘 -4-甲基 -N-(4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯基)苯甲酰胺 786 mg (产率： 76%)。 To a round bottom flask was added 550 mg (2 mMol) 4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)aniline, 560 mg (2 mMol) 3- Iodine-4-methylbenzoyl chloride, 223 mg (2.2 mMol) Et ₃ N and 15 ml of DMF were reacted at room temperature for 4 hours; after completion of the reaction, the solvent was evaporated to dryness under reduced pressure. -methyl-N-(4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)phenyl)benzamide 786 mg (yield: 76%) .

步骤六: Step six:

向圆底烧瓶中加入 517mg ( 1 mMol ) 3-碘 -4-甲基 -N-(4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯基)苯甲酰胺、 147 mg ( 1.5 mMol )三甲基硅基乙炔、 60 mg ( 0.05 mMol ) Pd(PPh₃)₄、 20 mg (0.1 mMol ) Cul、 390 mg ( 3 mMol ) DIPEA和 1毫升 DMF, 用功率为 150瓦、温度为 90°C的微波照射 20分钟；反应结束后，减压蒸干溶剂，柱层析得到产物 4-甲基 -N-(4-((4- 甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯基) -3- ((三甲基硅基)乙炔基)苯甲酰胺 307 mg (产率： 63%)。 To a round bottom flask was added 517 mg (1 mMol) 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl) Phenyl)benzamide, 147 mg (1.5 mMol) trimethylsilylacetylene, 60 mg (0.05 mMol) Pd(PPh ₃ ) ₄ , 20 mg (0.1 mMol ) Cul, 390 mg ( 3 mMol ) DIPEA and 1 ml of DMF was irradiated with microwave at a power of 150 watts and a temperature of 90 ° C for 20 minutes; after the reaction was completed, the solvent was evaporated under reduced pressure, and the product was obtained by column chromatography to give 4-methyl-N-(4-((4- Methyl piperazin-1-yl)methylene)-3-(trifluoromethyl)phenyl)-3-((trimethylsilyl)ethynyl)benzamide 307 mg (yield: 63%) ).

步骤七: Step 7:

向圆底烧瓶中加入 307mg (0.63 mMol ) 4-甲基 -N-(4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯基) -3- ((三甲基硅基)乙炔基)苯甲酰胺、 870 mg (6.7 mMol ) 碳酸钾和 10毫升甲醇，室温下反应 3小时；反应结束后，砂芯过滤，减压蒸干滤液，柱层析得到产物 3-乙炔基 -4- 甲基 -_N-(4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯基)苯甲酰胺 252 mg (产率： 96%)。 To a round bottom flask was added 307 mg (0.63 mMol) 4-methyl-N-(4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)phenyl) -3- ((Trimethylsilyl)ethynyl)benzamide, 870 mg (6.7 mMol) potassium carbonate and 10 ml of methanol, reacted at room temperature for 3 hours; after completion of the reaction, the sand core was filtered, and the filtrate was evaporated to dryness under reduced pressure. , column chromatography gave the product 3-ethynyl-4-methyl- _N- (4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)phenyl) Benzamide 252 mg (yield: 96%).

步骤八 Step eight

向圆底烧瓶中加入 208 mg ( 0.5 mMol ) 3-乙炔基 -4-甲基 -N-(4-((4-甲基哌嗪 -1-基)亚甲基) -3- (三氟甲基)苯基)苯甲酰胺、 70 mg ( 0.33 mMol ) 4-溴异喹啉、 30 mg ( 0.025 mMol ) Pd(PPh₃)₄、 10 mg ( 0.05 mMol ) Cul、 195 mg ( 1.5 mMol ) DIPEA和 1毫升 DMF, 用功率为 150瓦、温度为 90°C的微波照射 20分钟；反应结束后，减压蒸干溶剂，柱层析得到终产物 3- (异喹啉 -4-乙炔基 )-4-甲基 -N-(4-((4-甲基哌嗪 -1-基)亚甲基) -3- (三氟甲基)苯基)苯甲酰胺 157 mg (产率： 58%) [M+1] : 543； ^XHNMR [(400MHz, c -DMS0)]:5 10.75 (1 H, s), 9.53 (1 H, s), 8.92 (1 H, s), 8.41 (1 H, d, J=8.3 Hz), 8.27-8.38 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.08 (1 H, t, J=7.3 Hz), 8.01 (1 H, d, J=8.3 Hz), 7.80-7.94 (2 H, m), 7.59 (1 H, d, J=8.3 Hz), 3.78 (2 H, s), 3.05-3.25 (4 H, m), 2.73-2.85 (4 H, m), 2.65 (3 H, s), 2.45 (3 H, s). To a round bottom flask was added 208 mg (0.5 mMol) 3-ethynyl-4-methyl-N-(4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoro) Methyl)phenyl)benzamide, 70 mg (0.33 mMol) 4-bromoisoquinoline, 30 mg (0.025 mMol) Pd(PPh ₃ ) ₄ , 10 mg ( 0.05 mMol ) Cul, 195 mg ( 1.5 mMol ) DIPEA and 1 ml of DMF were irradiated with microwaves having a power of 150 watts and a temperature of 90 ° C for 20 minutes; after the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give 3-(isoquinoline-4-ethynyl). -4-methyl-N-(4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)phenyl)benzamide 157 mg (yield: 58%) [M+1] : 543; ^X HNMR [(400MHz, c -DMS0)]: 5 10.75 (1 H, s), 9.53 (1 H, s), 8.92 (1 H, s), 8.41 ( 1 H, d, J=8.3 Hz), 8.27-8.38 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.08 (1 H, t, J=7.3 Hz), 8.01 (1 H, d, J=8.3 Hz), 7.80-7.94 (2 H, m), 7.59 (1 H, d, J=8.3 Hz), 3.78 (2 H, s), 3.05-3.25 (4 H, m) , 2.73-2.85 (4 H, m), 2.65 (3 H, s), 2.45 (3 H, s).

实施例 2

Example 2

除了用 4-溴 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 [M+l] : 532； ¾NMR [(400MHz, c -DMSO)]:5 12.39 (1 H, s), 10.73 (1 H, s), 8.80 (1 H, s), 8.47 (1 H, s), 8.22-8.27 (2 H, m), 8.08 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.94 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.77 (1 H, s), 7.71 (1 H, d, J=8.9 Hz), 7.54 (1 H, d, J=8.3 Hz), 6.69 (1 H, d, J=2.8 Hz), 3.57 (2 H, s), 2.73-3.15 (8 H, m), 2.63 (3 H, s), 2.16 (3 H, s). The synthesis was carried out as in Example 1, except that 4-bromo-1 hydrogen-pyrrole [2,3-c]pyridine was used in place of 4-bromoisoquinoline. [M+l] : 532; 3⁄4 NMR [(400MHz, c-DMSO)]: 5 12.39 (1 H, s), 10.73 (1 H, s), 8.80 (1 H, s), 8.47 (1 H, s ), 8.22-8.27 (2 H, m), 8.08 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.94 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.77 ( 1 H, s), 7.71 (1 H, d, J=8.9 Hz), 7.54 (1 H, d, J=8.3 Hz), 6.69 (1 H, d, J=2.8 Hz), 3.57 (2 H, s), 2.73-3.15 (8 H, m), 2.63 (3 H, s), 2.16 (3 H, s).

实施例 3

Example 3

除了用 4-溴 -1-甲基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 4-bromo-1-methyl-1 hydrogen-pyrrole [2,3-c]pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 546； ^XHNMR [(400MHz, c -DMSO)]:510.69 (1 H, s), 8.83 (1 H, s), 8.51 (1 H, s), 8.25-8.31 (2 H, m), 8.11 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.97 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.79 (1 H, s), 7.73 (1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.3 Hz), 6.67 (1 H, d, J=2.8 Hz), 3.59 (2 H, s), 2.71-3.11 (8 H, m), 2.67 (3 H, s), 2.56 (3 H, s), 2.18 (3 H, s). [M+1] : 546; ^X HNMR [(400MHz, c - DMSO)]: 510.69 (1 H, s), 8.83 (1 H, s), 8.51 (1 H, s), 8.25-8.31 (2 H , m), 8.11 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.97 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.79 (1 H, s), 7.73 ( 1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.3 Hz), 6.67 (1 H, d, J=2.8 Hz), 3.59 (2 H, s), 2.71-3.11 (8 H, m), 2.67 (3 H, s), 2.56 (3 H, s), 2.18 (3 H, s).

实施例 4

Example 4

除了用 4-溴 -1-甲基 -1氢-吡唑骈 [3,4-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 4-bromo-1-methyl-1,3-hydropyrazolo[3,4-c]pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 547； ^XHNMR [(400MHz, c -DMSO)]:510.60 (1 H, s), 9.24 (1 H, s), 8.49 (1 H, s), 8.37 (1 H, s), 8.28 (1 H, d, J=1.8 Hz), 8.23 (1 H, d, J=1.8 Hz), 8.10 (1 H, dd, J=1.5 Hz, J=8.5 Hz), 7.96 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.71 (1 H, d, J=8.5 Hz), 7.56 (1 H, d, J=8.2 Hz), 6.67 (1 H, d, J=2.8 Hz), 4.23 (3 H, s), 3.64 (2 H, s), 3.21-3.39 (4 H, m), 2.88-3.08 (4 H, m), 2.63 (6 H, s). [M+1] : 547; ^X HNMR [(400MHz, c - DMSO)]: 510.60 (1 H, s), 9.24 (1 H, s), 8.49 (1 H, s), 8.37 (1 H, s ), 8.28 (1 H, d, J=1.8 Hz), 8.23 (1 H, d, J=1.8 Hz), 8.10 (1 H, dd, J=1.5 Hz, J=8.5 Hz), 7.96 (1 H , dd, J=1.9 Hz, J=8.0 Hz), 7.71 (1 H, d, J=8.5 Hz), 7.56 (1 H, d, J=8.2 Hz), 6.67 (1 H, d, J=2.8 Hz), 4.23 (3 H, s), 3.64 (2 H, s), 3.21-3.39 (4 H, m), 2.88-3.08 (4 H, m), 2.63 (6 H, s).

实施例 5

Example 5

除了用 4-溴 -1-异丙基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 The synthesis method is as in the following except that 4-bromo-1-isopropyl-1 hydrogen-pyrrole [2,3-c]pyridine is used instead of 4-bromoisoquinoline.

[M+1] : 574； ¾NMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 8.81 (1 H, s), 8.47 (1 H, s), 8.26-8.33 (2 H, m), 8.12 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.97 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.77 (1 H, s), 7.71 (1 H, d, J=8.6 Hz), 7.55 (1 H, d, J=8.3 Hz), 6.69 (1 H, d, J=2.8 Hz), 5.13 (1 H, m), 3.57 (2 H, s), 3.17-3.31 (4 H, m), 2.89-3.05 (4 H, m), 2.67 (3 H, s), 2.21 (3 H, s), 1.61 (6 H, d, J=7.2 Hz). [M+1] : 574; 3⁄4 NMR [(400MHz, c-DMSO)]: 5 10.67 (1 H, s), 8.81 (1 H, s), 8.47 (1 H, s), 8.26-8.33 (2 H , m), 8.12 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.97 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.77 (1 H, s), 7.71 ( 1 H, d, J=8.6 Hz), 7.55 (1 H, d, J=8.3 Hz), 6.69 (1 H, d, J=2.8 Hz), 5.13 (1 H, m), 3.57 (2 H, s), 3.17-3.31 (4 H, m), 2.89-3.05 (4 H, m), 2.67 (3 H, s), 2.21 (3 H, s), 1.61 (6 H, d, J=7.2 Hz ).

实施例 6

Example 6

除了用 4-溴 -1-异丁基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 In addition to 4-bromo-1-isobutyl-1 hydrogen-pyrrole [2,3-c]pyridine instead of 4-bromoisoquinoline, the synthesis method is as in the examples.

[M+1] : 588； ¾NMR [(400MHz, c -DMSO)]:5 10.65 (1 H, s), 8.83 (1 H, s), 8.45 (1 H, s), 8.23-8.31 (2 H, m), 8.13 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.99 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.75 (1[M+1] : 588; 3⁄4 NMR [(400MHz, c-DMSO)]: 5 10.65 (1 H, s), 8.83 (1 H, s), 8.45 (1 H, s), 8.23-8.31 (2 H , m), 8.13 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.99 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.75 (1

H, s), 7.73 (1 H, d, J=8.6 Hz), 7.57 (1 H, d, J=8.3 Hz), 6.67 (1 H, d, J=2.8 Hz), 3.87 (1 H, m), 3.57 (2 H, s), 3.15-3.31 (4 H, m), 2.87-3.03 (4 H, m), 2.67 (3 H, s), 2.21 (3 H, s), 1.55-1.67 (5 H, m),H, s), 7.73 (1 H, d, J=8.6 Hz), 7.57 (1 H, d, J=8.3 Hz), 6.67 (1 H, d, J=2.8 Hz), 3.87 (1 H, m ), 3.57 (2 H, s), 3.15-3.31 (4 H, m), 2.87-3.03 (4 H, m), 2.67 (3 H, s), 2.21 (3 H, s), 1.55-1.67 ( 5 H, m),

I.01 (3 H, t, J=7.8 Hz).

I.01 (3 H, t, J = 7.8 Hz).

除了用 4-溴 -1-环丙基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 In addition to 4-bromo-1-cyclopropyl-1 hydrogen-pyrrole [2,3-c]pyridine instead of 4-bromoisoquinoline, the synthesis method is as in the examples.

[M+1] : 572； 'HNMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 8.81 (1 H, s), 8.43 (1 H, s), 8.21-8.31 (2 H, m), 8.12 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.95 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.71 (1 H, s), 7.72 (1 H, d, J=8.6 Hz), 7.56 (1 H, d, J=8.3 Hz), 6.66 (1 H, d, J=2.8 Hz), 3.65 (2 H, s), 3.05-3.23 (4 H, m), 2.83-3.05 (4 H, m), 2.46-2.57 (4 H, m), 2.23 (3 H, s), 0.85-1.01 (4 H, m). 实施例 8

[M+1] : 572; 'HNMR [(400MHz, c -DMSO)]: 5 10.67 (1 H, s), 8.81 (1 H, s), 8.43 (1 H, s), 8.21-8.31 (2 H, m), 8.12 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.95 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.71 (1 H, s), 7.72 (1 H, d, J=8.6 Hz), 7.56 (1 H, d, J=8.3 Hz), 6.66 (1 H, d, J=2.8 Hz), 3.65 (2 H, s), 3.05-3.23 ( 4 H, m), 2.83-3.05 (4 H, m), 2.46-2.57 (4 H, m), 2.23 (3 H, s), 0.85-1.01 (4 H, m). Example 8

除了用 4-溴 -1氢-吡咯骈 [2,3-c]吡啶 -3-羧酸代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 4-bromo-hydrogen-pyrrole [2,3-c]pyridine-3-carboxylic acid was used in place of 4-bromoisoquinoline.

[M+1] : 576； ^XHNMR [(400MHz, c -DMSO)]:5 12.37 (1 H, s), 10.71 (1 H, s), 8.83 (1 H, s), 8.41 (1 H, s), 8.22-8.27 (2 H, m), 8.03 (1 H, s), 7.77 (1 H, s), 7.71 (1 H, d, J=8.3 Hz), 7.54 (1 H, d, J=8.3 Hz), 6.68 (1 H, d, J=2.9 Hz), 3.59 (2 H, s), 2.75-3.14 (8 H, m), 2.61 (3 H, s), 2.19 (3 H, s). 实施例 9

[M+1] : 576; ^X HNMR [(400MHz, c - DMSO)]: 5 12.37 (1 H, s), 10.71 (1 H, s), 8.83 (1 H, s), 8.41 (1 H, s), 8.22-8.27 (2 H, m), 8.03 (1 H, s), 7.77 (1 H, s), 7.71 (1 H, d, J=8.3 Hz), 7.54 (1 H, d, J =8.3 Hz), 6.68 (1 H, d, J=2.9 Hz), 3.59 (2 H, s), 2.75-3.14 (8 H, m), 2.61 (3 H, s), 2.19 (3 H, s Example 9.

除了用 4-溴 -1氢-吡咯骈 [2,3-c]吡啶 -3-羧酸乙酯代替 4-溴异喹啉以外，合成方法如实施 In addition to replacing 4-bromoisoquinoline with ethyl 4-bromo-hydrogen-pyrroleium [2,3-c]pyridine-3-carboxylate, the synthesis method is carried out as

1。 1.

[M+1] : 604； ^XHNMR [(400MHz, c -DMSO)]:5 12.35 (1 H, s), 10.73 (1 H, s), 8.81 (1 H, s), 8.43 (1 H, s), 8.20-8.28 (2 H, m), 8.05 (1 H, s), 7.79 (1 H, s), 7.70 (1 H, d, J=8.5 Hz), 7.54 (1 H, d J=8.5 Hz), 6.65 (1 H, d, J=2.8 Hz), 4.23 (2 H, q, J=8.1 Hz), 3.56 (2 H, s), 2.81-3.03 (4 H, m)， 2.47-2.67 (7H, m), 2.17 (3 H, s), 1.33 (3 H, t, J=8.1 Hz). [M+1] : 604; ^X HNMR [(400MHz, c - DMSO)]: 5 12.35 (1 H, s), 10.73 (1 H, s), 8.81 (1 H, s), 8.43 (1 H, s), 8.20-8.28 (2 H, m), 8.05 (1 H, s), 7.79 (1 H, s), 7.70 (1 H, d, J=8.5 Hz), 7.54 (1 H, d J=8.5 Hz), 6.65 (1 H, d, J=2.8 Hz), 4.23 (2 H, q, J=8.1 Hz), 3.56 (2 H, s), 2.81-3.03 (4 H, m), 2.47-2.67 (7H, m), 2.17 (3 H, s), 1.33 (3 H, t, J=8.1 Hz).

实施例 10

Example 10

除了用 4-溴 -3-氟 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 4-bromo-3-fluoro-1 hydrogen-pyrrole [2,3-c]pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 550； ^XHNMR [(400MHz, c -DMSO)]:5 12.37 (1 H, s), 10.74 (1 H, s), 8.80 (1 H, s)_; 8.47 (1 H, s), 8.21-8.27 (2 H, m), 8.03 (1 H, s), 7.75 (1 H, s), 7.69 (1 H, d, J=8.3 Hz), 7.53 (1 H, d J=8.3 Hz), 6.67 (1 H, d, J=2.9 Hz), 3.59 (2 H, s), 2.72-3.11 (8 H, m), 2.65 (3 H, s), 2.15 (3 H, s). 实施例 11

[M+1] : 550; ^X HNMR [(400MHz, c - DMSO)]: 5 12.37 (1 H, s), 10.74 (1 H, s), 8.80 (1 H, s) _; 8.47 (1 H, s), 8.21-8.27 (2 H, m), 8.03 (1 H, s), 7.75 (1 H, s), 7.69 (1 H, d, J=8.3 Hz), 7.53 (1 H, d J= 8.3 Hz), 6.67 (1 H, d, J=2.9 Hz), 3.59 (2 H, s), 2.72-3.11 (8 H, m), 2.65 (3 H, s), 2.15 (3 H, s) Example 11

除了用 4-溴 -3-甲基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 4-bromo-3-methyl-1 hydrogen-pyrrole [2,3-c]pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 546； ^XHNMR [(400MHz, c -DMSO)]:5 12.39 (1 H, s), 10.71 (1 H, s), 8.83 (1 H, s), 8.46 (1 H, s), 8.22-8.29 (2 H, m), 7.89 (1 H, s), 7.73 (1 H, s), 7.67 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.5 Hz), 6.69 (1 H, d, J=2.7 Hz), 3.61 (2 H, s), 2.71-3.09 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s)， 2.09 (3 H, s). [M+1] : 546; ^X HNMR [(400MHz, c - DMSO)]: 5 12.39 (1 H, s), 10.71 (1 H, s), 8.83 (1 H, s), 8.46 (1 H, s), 8.22-8.29 (2 H, m), 7.89 (1 H, s), 7.73 (1 H, s), 7.67 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J =8.5 Hz), 6.69 (1 H, d, J=2.7 Hz), 3.61 (2 H, s), 2.71-3.09 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s ), 2.09 (3 H, s).

实施例 12

Example 12

除了用 4-溴 -7-甲氧基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 The synthesis method is as in the following except that 4-bromo-7-methoxy-1 hydrogen-pyrrole [2,3-c]pyridine is used instead of 4-bromoisoquinoline.

[M+1] : 532； ¾NMR [(400MHz, c -DMSO)]:5 12.37 (1 H, s), 10.71 (1 H, s), 8.78 (1 H, s): 8.26 (1 H, s), 8.21 (1 H, s), 8.05 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.91 (1 H, dd, J=1.9 Hz, J=8.1 Hz). 7.75 (1 H, s), 7.70 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.1 Hz), 6.67 (1 H, d, J=2.9 Hz), 3.97 (3 H, s). 3.57 (2 H, s), 2.71-3.10 (8 H, m), 2.61 (3 H, s), 2.19 (3 H, s). [M+1] : 532; 3⁄4 NMR [(400MHz, c - DMSO)]: 5 12.37 (1 H, s), 10.71 (1 H, s), 8.78 (1 H, s): 8.26 (1 H, s ), 8.21 (1 H, s), 8.05 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.91 (1 H, dd, J=1.9 Hz, J=8.1 Hz). 7.75 (1 H , s), 7.70 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.1 Hz), 6.67 (1 H, d, J=2.9 Hz), 3.97 (3 H, s) 3.57 (2 H, s), 2.71-3.10 (8 H, m), 2.61 (3 H, s), 2.19 (3 H, s).

实施例 13

Example 13

除了用 4-溴 -7-氯 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 L [M+l] : 566； ¾NMR [(400MHz, c -DMSO)] :5 12.39 (1 H, s), 10.70 (1 H, s), 8.77 (1 H, s): 8.28 (1 H, s), 8.22 (1 H, s), 8.07 (1 H, dd, J=1.8 Hz, J=8.5 Hz), 7.90 (1 H, dd, J=1.8 Hz, J=8.0 Hz). 7.73 (1 H, s), 7.69 (1 H, d, J=8.5 Hz), 7.50 (1 H, d, J=8.1 Hz), 6.69 (1 H, d, J=2.7 Hz), 3.61 (2 H, s). 2.73-3.15 (8 H, m), 2.65 (3 H, s), 2.21 (3 H, s). The synthesis method is as in Example L except that 4-bromo-7-chloro-1 hydrogen-pyrrole [2,3-c]pyridine is used instead of 4-bromoisoquinoline. [M+l] : 566; 3⁄4 NMR [(400MHz, c - DMSO)] : 5 12.39 (1 H, s), 10.70 (1 H, s), 8.77 (1 H, s): 8.28 (1 H, s ), 8.22 (1 H, s), 8.07 (1 H, dd, J=1.8 Hz, J=8.5 Hz), 7.90 (1 H, dd, J=1.8 Hz, J=8.0 Hz). 7.73 (1 H , s), 7.69 (1 H, d, J=8.5 Hz), 7.50 (1 H, d, J=8.1 Hz), 6.69 (1 H, d, J=2.7 Hz), 3.61 (2 H, s) 2.73-3.15 (8 H, m), 2.65 (3 H, s), 2.21 (3 H, s).

实施例 14

Example 14

除了用 1-氯酞嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 1-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 544； ^XHNMR [(400MHz, c -DMSO)] :5 10.75 (1 H, s), 9.43 (1 H, s), 8.43 (1 H, d, J=8.1 Hz), 8.25-8.33 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.3 Hz), 8.01 (1 H, d, J=8.1 Hz), 7.78-7.91 (2 H, m), 7.53 (1 H, d, J=8.1 Hz), 3.71 (2 H, s), 3.03-3.27 (4 H, m), 2.71 -2.89 (4 H, m), 2.61 (3 H, s), 2.35 (3 H, s). [M+1] : 544; ^X HNMR [(400MHz, c - DMSO)] : 5 10.75 (1 H, s), 9.43 (1 H, s), 8.43 (1 H, d, J = 8.1 Hz), 8.25-8.33 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.3 Hz), 8.01 (1 H, d, J=8.1 Hz), 7.78 -7.91 (2 H, m), 7.53 (1 H, d, J=8.1 Hz), 3.71 (2 H, s), 3.03-3.27 (4 H, m), 2.71 -2.89 (4 H, m), 2.61 (3 H, s), 2.35 (3 H, s).

实施例 15

Example 15

除了用 4-溴异喹啉 1 (2H)-酮代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 4-bromoisoquinoline 1 (2H)-one was used instead of 4-bromoisoquinoline.

[M+1] : 559； ^XHNMR [(400MHz, c -DMSO)] : 5 10.75 (1 H, s), 9.93 (1 H, s), 8.45 (1 H, s), 8.41 (1 H, d, J=8.1 Hz), 8.23-8.37 (3 H, m), 8.15 (1 H, d, J=7.4 Hz), 8.07 (1 H, t, J=7.1 Hz), 8.02 (1 H, d, J=8.1 Hz), 7.78-7.91 (2 H, m), 7.55 (1 H, d, J=8.2 Hz), 3.68 (2 H, s), 3.03-3.27 (4 H, m), 2.71-2.89 (4 H, m), 2.63 (3 H, s), 2.37 (3 H, s). [M+1] : 559; ^X HNMR [(400MHz, c - DMSO)] : 5 10.75 (1 H, s), 9.93 (1 H, s), 8.45 (1 H, s), 8.41 (1 H, d, J=8.1 Hz), 8.23-8.37 (3 H, m), 8.15 (1 H, d, J=7.4 Hz), 8.07 (1 H, t, J=7.1 Hz), 8.02 (1 H, d , J=8.1 Hz), 7.78-7.91 (2 H, m), 7.55 (1 H, d, J=8.2 Hz), 3.68 (2 H, s), 3.03-3.27 (4 H, m), 2.71- 2.89 (4 H, m), 2.63 (3 H, s), 2.37 (3 H, s).

实施例 16

Example 16

除了用 4-溴 -6,7-二甲氧基异喹啉 1 (2H)-酮代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 4-bromo-6,7-dimethoxyisoquinoline 1 (2H)-one was used instead of 4-bromoisoquinoline.

[M+1] : 619； ^XHNMR [(400MHz, c -DMSO)] :5 10.75 (1 H, s), 10.01 (1 H, s), 8.47 (1 H, s), 8.27 (1 H, s), 8.15 (1 H, s), 8.07 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.78-7.97 (3 H, m), 7.55 (1 H, d, J=8.1 Hz), 3.93, (6H, s), 3.63 (2 H, s), 3.01 -3.23 (4 H, m), 2.70-2.86 (4 H, m), 2.61 (3 H, s), 2.29 (3 H, s). [M+1] : 619; ^X HNMR [(400MHz, c - DMSO)] : 5 10.75 (1 H, s), 10.01 (1 H, s), 8.47 (1 H, s), 8.27 (1 H, s), 8.15 (1 H, s), 8.07 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.78-7.97 (3 H, m), 7.55 (1 H, d, J =8.1 Hz), 3.93, (6H, s), 3.63 (2 H, s), 3.01 -3.23 (4 H, m), 2.70-2.86 (4 H, m), 2.61 (3 H, s), 2.29 (3 H, s).

实施例 17

Example 17

除了用 1-氯 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 1-chloro-4-bromoisoquinoline was used instead of 4-bromoisoquinoline.

[M+1] : 577； ^XHNMR [(400MHz, c -DMSO)]:5 10.75 (1 H, s), 8.75 (1 H, s), 8.47 (1 H, d, J=8.3 Hz), 8.25-8.39 (3 H, m), 8.19 (1 H, d, J=7.6 Hz), 8.09 (1 H, t, J=7.4 Hz), 8.05 (1 H, d, J=8.3 Hz), 7.71-7.90 (2 H, m), 7.53 (1 H, d, J=8.1 Hz), 3.65 (2 H, s), 3.01-3.25 (4 H, m), 2.73-2.89 (4 H, m), 2.61 (3 H, s), 2.32 (3 H, s). [M+1] : 577; ^X HNMR [(400MHz, c - DMSO)]: 5 10.75 (1 H, s), 8.75 (1 H, s), 8.47 (1 H, d, J = 8.3 Hz), 8.25-8.39 (3 H, m), 8.19 (1 H, d, J=7.6 Hz), 8.09 (1 H, t, J=7.4 Hz), 8.05 (1 H, d, J=8.3 Hz), 7.71 -7.90 (2 H, m), 7.53 (1 H, d, J=8.1 Hz), 3.65 (2 H, s), 3.01-3.25 (4 H, m), 2.73-2.89 (4 H, m), 2.61 (3 H, s), 2.32 (3 H, s).

实施例 18

Example 18

除了用 1-氯 -4-溴 -6,7-二甲氧基异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 1-chloro-4-bromo-6,7-dimethoxyisoquinoline was used instead of 4-bromoisoquinoline.

[M+1] : 637； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.72 (1 H, s), 8.35 (1 H, s), 8.21 (1 H, s), 8.09 (1 H, s), 8.03 (1 H, d, J=8.4 Hz), 7.73-7.94 (3 H, m), 7.52 (1 H, d, J=8.4 Hz), 3.91, (6H, s), 3.61 (2 H, s), 3.03-3.25 (4 H, m), 2.71-2.85 (4 H, m), 2.59 (3 H, s), 2.19 (3 H, s). [M+1] : 637; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.72 (1 H, s), 8.35 (1 H, s), 8.21 (1 H, s), 8.09 (1 H, s), 8.03 (1 H, d, J=8.4 Hz), 7.73-7.94 (3 H, m), 7.52 (1 H, d, J=8.4 Hz), 3.91, ( 6H, s), 3.61 (2 H, s), 3.03-3.25 (4 H, m), 2.71-2.85 (4 H, m), 2.59 (3 H, s), 2.19 (3 H, s).

实施例 19

Example 19

除了用 1-溴 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 1-bromo-4-bromoisoquinoline was used in place of 4-bromoisoquinoline.

[M+1] : 622； ^XHNMR [(400MHz, c -DMSO)]:5 10.75 (1 H, s), 8.73 (1 H, s), 8.46 (1 H, d, J=8.5 Hz), 8.21-8.37 (3 H, m), 8.17 (1 H, d, J=7.4 Hz), 8.11 (1 H, t, J=7.2 Hz), 8.06 (1 H, d, J=8.5 Hz), 7.70-7.92 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 3.61 (2 H, s), 3.01-3.22 (4 H, m), 2.71-2.83 (4 H, m), 2.63 (3 H, s), 2.30 (3 H, s). [M+1] : 622; ^X HNMR [(400MHz, c - DMSO)]: 5 10.75 (1 H, s), 8.73 (1 H, s), 8.46 (1 H, d, J = 8.5 Hz), 8.21-8.37 (3 H, m), 8.17 (1 H, d, J=7.4 Hz), 8.11 (1 H, t, J=7.2 Hz), 8.06 (1 H, d, J=8.5 Hz), 7.70 -7.92 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 3.61 (2 H, s), 3.01-3.22 (4 H, m), 2.71-2.83 (4 H, m), 2.63 (3 H, s), 2.30 (3 H, s).

实施例 20

Example 20

除了用 1-甲氧基 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 1-methoxy-4-bromoisoquinoline was used instead of 4-bromoisoquinoline.

[M+1] : 573； ^XHNMR [(400MHz, c -DMSO)]:5 10.81 (1 H, s), 8.67 (1 H, s), 8.42 (1 H, d, J=8.3 Hz), 8.22-8.39 (3 H, m), 8.15 (1 H, d, J=7.2 Hz), 8.10 (1 H, t, J=7.2 Hz), 8.03 (1 H, d, J=8.3 Hz), 7.75-7.97 (2 H, m), 7.49 (1 H, d, J=8.4 Hz), 3.95 (3 H, s), 3.57 (2 H, s), 2.99-3.18 (4 H, m), 2.69-2.81 (4 H, m), 2.62 (3 H, s), 2.26 (3 H, s). [M+1] : 573; ^X HNMR [(400MHz, c - DMSO)]: 5 10.81 (1 H, s), 8.67 (1 H, s), 8.42 (1 H, d, J = 8.3 Hz), 8.22-8.39 (3 H, m), 8.15 (1 H, d, J=7.2 Hz), 8.10 (1 H, t, J=7.2 Hz), 8.03 (1 H, d, J=8.3 Hz), 7.75 -7.97 (2 H, m), 7.49 (1 H, d, J=8.4 Hz), 3.95 (3 H, s), 3.57 (2 H, s), 2.99-3.18 (4 H, m), 2.69- 2.81 (4 H, m), 2.62 (3 H, s), 2.26 (3 H, s).

实施例 21

Example 21

除了用 1-叔丁氧基 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 1-tert-butoxy-4-bromoisoquinoline was used in place of 4-bromoisoquinoline.

[M+1] : 615； ^XHNMR [(400MHz, c -DMSO)]:5 10.79 (1 H, s), 8.63 (1 H, s), 8.47 (1 H, d, J=8.1 Hz), 8.21-8.34 (3 H, m), 8.13 (1 H, d, J=7.3 Hz), 8.09 (1 H, t, J=7.3 Hz), 8.01 (1 H, d, J=8.1 Hz), 7.71-7.95 (2 H, m), 7.43 (1 H, d, J=8.3 Hz), 3.59 (2 H, s), 3.05-3.19 (4 H, m), 2.71-2.86 (4 H, m), 2.63 (3 H, s), 2.28 (3 H, s), 1.55 (9 H, s). [M+1] : 615; ^X HNMR [(400MHz, c - DMSO)]: 5 10.79 (1 H, s), 8.63 (1 H, s), 8.47 (1 H, d, J = 8.1 Hz), 8.21-8.34 (3 H, m), 8.13 (1 H, d, J=7.3 Hz), 8.09 (1 H, t, J=7.3 Hz), 8.01 (1 H, d, J=8.1 Hz), 7.71 -7.95 (2 H, m), 7.43 (1 H, d, J=8.3 Hz), 3.59 (2 H, s), 3.05-3.19 (4 H, m), 2.71-2.86 (4 H, m), 2.63 (3 H, s), 2.28 (3 H, s), 1.55 (9 H, s).

实施例 22

Example 22

除了用 1-甲基氨基 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 1-methylamino-4-bromoisoquinoline was used in place of 4-bromoisoquinoline.

[M+1] : 572； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.65 (1 H, s), 8.41 (1 H, d, J=8.1 Hz), 8.21-8.37 (3 H, m), 8.13 (1 H, d, J=7.4 Hz), 8.11 (1 H, t, J=7.4 Hz), 8.01 (1 H, d, J=8.1 Hz), 7.71-7.93 (3 H, m), 7.43 (1 H, d, J=8.2 Hz), 3.59 (2 H, s), 2.99-3.18 (4 H, m), 2.69-2.81 (7 H, m), 2.61 (3 H, s), 2.23 (3 H, s). [M+1] : 572; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1H, s), 8.65 (1 H, s), 8.41 (1 H, d, J = 8.1 Hz), 8.21-8.37 (3 H, m), 8.13 (1 H, d, J=7.4 Hz), 8.11 (1 H, t, J=7.4 Hz), 8.01 (1 H, d, J=8.1 Hz), 7.71 -7.93 (3 H, m), 7.43 (1 H, d, J=8.2 Hz), 3.59 (2 H, s), 2.99-3.18 (4 H, m), 2.69-2.81 (7 H, m), 2.61 (3 H, s), 2.23 (3 H, s).

实施例 23

Example 23

除了用 1-N,N-二甲基氨基 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 1-N,N-dimethylamino-4-bromoisoquinoline was used instead of 4-bromoisoquinoline.

[M+1] : 586； ^XHNMR [(400MHz, c -DMSO)]:5 10.77 (1 H, s), 8.69 (1 H, s), 8.43 (1 H, d, J=8.2 Hz), 8.22-8.38 (3 H, m), 8.11 (1 H, d, J=7.3 Hz), 8.07 (1 H, t, J=7.3 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.73-7.95 (2 H, m), 7.41 (1 H, d, J=8.3 Hz), 3.61 (2 H, s), 2.97-3.15 (10 H, m), 2.69-2.81 (4 H, m), 2.63 (3 H, s), 2.18 (3 H, s). [M+1] : 586; ^X HNMR [(400MHz, c - DMSO)]: 5 10.77 (1H, s), 8.69 (1 H, s), 8.43 (1 H, d, J = 8.2 Hz), 8.22-8.38 (3 H, m), 8.11 (1 H, d, J=7.3 Hz), 8.07 (1 H, t, J=7.3 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.73 -7.95 (2 H, m), 7.41 (1 H, d, J=8.3 Hz), 3.61 (2 H, s), 2.97-3.15 (10 H, m), 2.69-2.81 (4 H, m), 2.63 (3 H, s), 2.18 (3 H, s).

实施例 24

Example 24

除了用 1-叔丁基氨基 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 1-tert-butylamino-4-bromoisoquinoline was used in place of 4-bromoisoquinoline.

[M+1] : 614； ^XHNMR [(400MHz, c -DMSO)]:5 10.70 (1 H, s), 8.63 (1 H, s), 8.40 (1 H, d, J=8.3 Hz), 8.20-8.35 (3 H, m), 8.15 (1 H, d, J=7.1 Hz), 8.12 (1 H, t, J=7.1 Hz), 8.02 (1 H, d, J=8.3 Hz), 7.70-7.94 (3 H, m), 7.45 (1 H, d, J=8.4 Hz), 3.61 (2 H, s), 2.97-3.16 (4 H, m), 2.67-2.83 (4 H, m), 2.62 (3 H, s), 2.21 (3 H, s), 1.35 (9 H, s). [M+1] : 614; ^X HNMR [(400MHz, c - DMSO)]: 5 10.70 (1 H, s), 8.63 (1 H, s), 8.40 (1 H, d, J = 8.3 Hz), 8.20-8.35 (3 H, m), 8.15 (1 H, d, J=7.1 Hz), 8.12 (1 H, t, J=7.1 Hz), 8.02 (1 H, d, J=8.3 Hz), 7.70-7.94 (3 H, m), 7.45 (1 H, d, J=8.4 Hz), 3.61 (2 H, s), 2.97-3.16 (4 H, m), 2.67-2.83 (4 H, m) , 2.62 (3 H, s), 2.21 (3 H, s), 1.35 (9 H, s).

实施例 25

Example 25

除了用 1-环丙基氨基 -4-溴异喹啉代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 1-cyclopropylamino-4-bromoisoquinoline was used in place of 4-bromoisoquinoline.

[M+1] : 598； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.61 (1 H, s), 8.45 (1 H, d, J=8.5 Hz), 8.19-8.33 (3 H, m), 8.14 (1 H, d, J=7.4 Hz), 8.10 (1 H, t, J=7.4 Hz), 8.03 (1 H, d, J=8.5 Hz), 7.71-7.95 (3 H, m), 7.43 (1 H, d, J=8.2 Hz), 3.62 (2 H, s), 2.98-3.19 (4 H, m), 2.70-2.85 (4 H, m), 2.65 (3 H, s), 2.23 (3 H, s), 1.37 (1 H, m), 0.71-0.95 (4 H, m). [M+1] : 598; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.61 (1 H, s), 8.45 (1 H, d, J = 8.5 Hz), 8.19-8.33 (3 H, m), 8.14 (1 H, d, J=7.4 Hz), 8.10 (1 H, t, J=7.4 Hz), 8.03 (1 H, d, J=8.5 Hz), 7.71 -7.95 (3 H, m), 7.43 (1 H, d, J=8.2 Hz), 3.62 (2 H, s), 2.98-3.19 (4 H, m), 2.70-2.85 (4 H, m), 2.65 (3 H, s), 2.23 (3 H, s), 1.37 (1 H, m), 0.71-0.95 (4 H, m).

实施例 26

Example 26

除了用 6-氯 -1,2,4-三唑骈 [4,3-B]哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 6-chloro-1,2,4-triazolium [4,3-B]pyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 534； ^XHNMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 9.15 (1 H, s), 8.42 (1 H, d, J=7.3 Hz), 8.23 (1 H, s), 8.10 (1 H, s), 7.91 (1 H, d, J=8.3 Hz), 7.78 (1 H, d, J=7.3 Hz), 7.49-7.57 (2 H, m), 7.33 (1 H, d, J=8.3 Hz), 3.59 (2 H, s), 2.95-3.16 (4 H, m), 2.71-2.84 (4 H, m), 2.61 (3 H, s), 2.17 (3 H, s). [M+1] : 534; ^X HNMR [(400MHz, c - DMSO)]: 5 10.67 (1H, s), 9.15 (1 H, s), 8.42 (1 H, d, J = 7.3 Hz), 8.23 (1 H, s), 8.10 (1 H, s), 7.91 (1 H, d, J=8.3 Hz), 7.78 (1 H, d, J=7.3 Hz), 7.49-7.57 (2 H, m ), 7.33 (1 H, d, J=8.3 Hz), 3.59 (2 H, s), 2.95-3.16 (4 H, m), 2.71-2.84 (4 H, m), 2.61 (3 H, s) , 2.17 (3 H, s).

实施例 27

Example 27

除了用 6-氯 -3-甲基 [1,2,4]三唑骈 [4,3-B]哒嗪代替 4-溴异喹啉以夕卜，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 6-chloro-3-methyl[1,2,4]triazolium [4,3-B]pyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 548； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.45 (1 H, d, J=7.2 Hz), 8.24 (1 H, s), 8.12 (1 H, s), 7.92 (1 H, d, J=8.4 Hz), 7.75 (1 H, d, J=7.2 Hz), 7.47-7.59 (2 H, m), 7.31 (1 H, d, J=8.4 Hz), 3.63 (2 H, s), 2.91-3.12 (4 H, m), 2.70-2.85 (4 H, m), 2.63 (3 H, s), 2.49 (3 H, s), 2.19 (3 H, s). [M+1] : 548; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.45 (1 H, d, J = 7.2 Hz), 8.24 (1 H, s), 8.12 (1 H, s), 7.92 (1 H, d, J=8.4 Hz), 7.75 (1 H, d, J=7.2 Hz), 7.47-7.59 (2 H, m), 7.31 (1 H, d , J=8.4 Hz), 3.63 (2 H, s), 2.91-3.12 (4 H, m), 2.70-2.85 (4 H, m), 2.63 (3 H, s), 2.49 (3 H, s) , 2.19 (3 H, s).

实施例 28

Example 28

除了用 6-氯 -3-羟基 [1,2,4]三唑骈 [4,3-B]哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1 ₍ [M+1] : 550； 'HNMR [(400MHz, c -DMSO)]:5 10.65 (1 H, s), 8.43 (1 H, d, J=7.2 Hz), 8.21 (1 H, s), 8.13 (1 H, s), 7.92 (1 H, d, J=8.4 Hz), 7.83 (1 H, s), 7.76 (1 H, d, J=7.1 Hz), 7.47-7.55 (2 H, m), 7.31 (1 H, d, J=8.4 Hz), 3.61 (2 H, s), 2.92-3.11 (4 H, m), 2.70-2.82 (4 H, m), 2.57 (3 H, s), 2.19 (3 H, s). Except that 6-chloro-3-hydroxy [1,2,4] triazolo parallel [4,3-B] pyridazin-4-bromo-isoquinoline instead of outside, as the synthesis method of Example 1 ₍ [M+1] : 550; 'HNMR [(400MHz, c - DMSO)]: 5 10.65 (1 H, s), 8.43 (1 H, d, J = 7.2 Hz), 8.21 (1 H, s), 8.13 (1 H, s), 7.92 (1 H, d, J=8.4 Hz), 7.83 (1 H, s), 7.76 (1 H, d, J=7.1 Hz), 7.47-7.55 (2 H, m ), 7.31 (1 H, d, J=8.4 Hz), 3.61 (2 H, s), 2.92-3.11 (4 H, m), 2.70-2.82 (4 H, m), 2.57 (3 H, s) , 2.19 (3 H, s).

实施例 29

Example 29

除了用 3-氯 -7H-吡咯骈 [2,3-C]哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-chloro-7H-pyrrole [2,3-C]pyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 533； ^XHNMR [(400MHz, c -DMSO)]:5 12.39 (1 H, s), 10.73 (1 H, s), 8.43 (1 H, s), 8.21-8.25 (2 H, m), 8.07 (1 H, dd, J=1.8 Hz, J=8.4 Hz), 7.92 (1 H, dd, J=1.8 Hz, J=8.1 Hz), 7.76 (1 H, s), 7.72 (1 H, d, J=8.6 Hz), 7.51 (1 H, d, J=8.4 Hz), 6.67 (1 H, d, J=2.5 Hz), 3.61 (2 H, s), 2.71-3.13 (8 H, m), 2.61 (3 H, s), 2.19 (3 H, s). [M+1] : 533; ^X HNMR [(400MHz, c - DMSO)]: 5 12.39 (1 H, s), 10.73 (1 H, s), 8.43 (1 H, s), 8.21-8.25 (2 H, m), 8.07 (1 H, dd, J=1.8 Hz, J=8.4 Hz), 7.92 (1 H, dd, J=1.8 Hz, J=8.1 Hz), 7.76 (1 H, s), 7.72 (1 H, d, J=8.6 Hz), 7.51 (1 H, d, J=8.4 Hz), 6.67 (1 H, d, J=2.5 Hz), 3.61 (2 H, s), 2.71-3.13 ( 8 H, m), 2.61 (3 H, s), 2.19 (3 H, s).

实施例 30

Example 30

除了用 3-溴 -5-羟基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-hydroxypyridine was used in place of 4-bromoisoquinoline.

[M+1] : 509； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.67 (1 H, s), 8.35 (1 H, s), 8.31 (1 H, s), 8.24 (1 H, s), 8.01 (1 H, d, J=8.2 Hz), 7.92 (1 H, d, J=8.4 Hz), 7.85 (1 H, s), 7.73 (1 H, s), 7.68 (1 H, d, J=8.4 Hz), 7.52 (1 H, d, J=8.2 Hz), 3.63 (2 H, s), 2.70-3.14 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s). [M+1] : 509; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.67 (1 H, s), 8.35 (1 H, s), 8.31 (1 H, s), 8.24 (1 H, s), 8.01 (1 H, d, J=8.2 Hz), 7.92 (1 H, d, J=8.4 Hz), 7.85 (1 H, s), 7.73 (1 H, s), 7.68 (1 H, d, J=8.4 Hz), 7.52 (1 H, d, J=8.2 Hz), 3.63 (2 H, s), 2.70-3.14 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s).

实施例 31

Example 31

除了用 3-溴 -5-甲氧基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-methoxypyridine was used in place of 4-bromoisoquinoline.

[M+1] : 523； ^XHNMR [(400MHz, c -DMSO)]:5 10.68 (1 H, s), 8.60 (1 H, s), 8.31 (1 H, s), 8.27 (1 H, s), 8.14 (1 H, s), 7.99 (1 H, d, J=8.4 Hz), 7.90 (1 H, d, J=8.6 Hz), 7.71 (1 H, s), 7.63 (1 H, d, J=8.6 Hz), 7.55 (1 H, d, J=8.4 Hz), 3.94 (3 H, s), 3.61 (2 H, s), 2.69-3.11 (8 H, m), 2.65 (3 H, s), 2.13 (3 H, s).

除了用 3-溴 -5-甲氧基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 [M+1] : 523; ^X HNMR [(400MHz, c - DMSO)]: 5 10.68 (1 H, s), 8.60 (1 H, s), 8.31 (1 H, s), 8.27 (1 H, s), 8.14 (1 H, s), 7.99 (1 H, d, J=8.4 Hz), 7.90 (1 H, d, J=8.6 Hz), 7.71 (1 H, s), 7.63 (1 H, d, J=8.6 Hz), 7.55 (1 H, d, J=8.4 Hz), 3.94 (3 H, s), 3.61 (2 H, s), 2.69-3.11 (8 H, m), 2.65 (3 H, s), 2.13 (3 H, s).

The synthesis was carried out as in Example 1, except that 3-bromo-5-methoxypyridine was used in place of 4-bromoisoquinoline.

[M+1] : 523； ^XHNMR [(400MHz, c -DMSO)]:5 10.69 (1 H, s), 8.63 (1 H, s), 8.32 (1 H, s), 8.25 (1 H, s), 8.16 (1 H, s), 8.01 (1 H, d, J=8.3 Hz), 7.92 (1 H, d, J=8.5Hz), 7.73 (1 H, s), 7.65 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.3 Hz), 3.63 (2 H, s), 2.71-3.13 (8 H, m), 2.61 (3 H, s), 2.15 (3 H, s), 1.36 (9 H, s). [M+1] : 523; ^X HNMR [(400MHz, c - DMSO)]: 5 10.69 (1 H, s), 8.63 (1 H, s), 8.32 (1 H, s), 8.25 (1 H, s), 8.16 (1 H, s), 8.01 (1 H, d, J = 8.3 Hz), 7.92 (1 H, d, J = 8.5 Hz), 7.73 (1 H, s), 7.65 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.3 Hz), 3.63 (2 H, s), 2.71-3.13 (8 H, m), 2.61 (3 H, s), 2.15 (3 H, s), 1.36 (9 H, s).

实施例 33

Example 33

除了用 3-溴 -5-氨基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-aminopyridine was used in place of 4-bromoisoquinoline.

[M+1] : 509； ^XHNMR [(400MHz, c -DMSO)]:5 10.75 (1 H, s), 8.59 (1 H, s), 8.30 (1 H, s), 8.26 (1 H, s), 8.21 (1 H, s), 8.03 (1 H, d, J=8.3 Hz), 7.91 (1 H, d, J=8.1 Hz), 7.70 (1 H, s), 7.66 (1 H, d, J=8.1 Hz), 7.52 (3 H, m), 3.57 (2 H, s), 2.69-3.12 (8 H, m), 2.61 (3 H, s), 2.15 (3 H, s). [M+1] : 509; ^X HNMR [(400MHz, c - DMSO)]: 5 10.75 (1 H, s), 8.59 (1 H, s), 8.30 (1 H, s), 8.26 (1 H, s), 8.21 (1 H, s), 8.03 (1 H, d, J = 8.3 Hz), 7.91 (1 H, d, J = 8.1 Hz), 7.70 (1 H, s), 7.66 (1 H, d, J=8.1 Hz), 7.52 (3 H, m), 3.57 (2 H, s), 2.69-3.12 (8 H, m), 2.61 (3 H, s), 2.15 (3 H, s).

实施例 34 Example 34

除了用 3-溴 -5-甲基氨基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-methylaminopyridine was used in place of 4-bromoisoquinoline.

[M+1] : 522； ^XHNMR [(400MHz, c -DMSO)]:5 10.65 (1 H, s), 8.63 (1 H, s), 8.34 (1 H, s), 8.26 (1 H, s), 8.15 (1 H, s), 8.01 (1 H, d, J=8.3 Hz), 7.92 (1 H, d, J=8.5 Hz), 7.73 (1 H, s), 7.65 (1 H, d, J=8.5 Hz), 7.56 (2 H, m), 3.63 (2 H, s), 2.71-3.14 (8 H, m), 2.67 (3 H, s), 2.56 (3 H, s), 2.13 (3 H, s). [M+1] : 522; ^X HNMR [(400MHz, c - DMSO)]: 5 10.65 (1 H, s), 8.63 (1 H, s), 8.34 (1 H, s), 8.26 (1 H, s), 8.15 (1 H, s), 8.01 (1 H, d, J=8.3 Hz), 7.92 (1 H, d, J=8.5 Hz), 7.73 (1 H, s), 7.65 (1 H, d, J=8.5 Hz), 7.56 (2 H, m), 3.63 (2 H, s), 2.71-3.14 (8 H, m), 2.67 (3 H, s), 2.56 (3 H, s), 2.13 (3 H, s).

实施例 35

Example 35

除了用 3-溴 -5-叔丁基氨基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-tert-butylaminopyridine was used in place of 4-bromoisoquinoline.

[M+1] : 564； ^XHNMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 8.65 (1 H, s), 8.37 (1 H, s), 8.25 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.4 Hz), 7.93 (1 H, d, J=8.6 Hz), 7.75 (1 H, s), 7.63 (1 H, d, J=8.6 Hz), 7.55 (2 H, m), 3.65 (2 H, s), 2.72-3.11 (8 H, m), 2.65 (3 H, s), 2.15 (3 H, s), 1.36 (9 H, s). [M+1] : 564; ^X HNMR [(400MHz, c - DMSO)]: 5 10.67 (1 H, s), 8.65 (1 H, s), 8.37 (1 H, s), 8.25 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.4 Hz), 7.93 (1 H, d, J=8.6 Hz), 7.75 (1 H, s), 7.63 (1 H, d, J=8.6 Hz), 7.55 (2 H, m), 3.65 (2 H, s), 2.72-3.11 (8 H, m), 2.65 (3 H, s), 2.15 (3 H, s), 1.36 (9 H, s).

实施例 36

除了用 3-溴 -5-环丙基氨基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 Example 36

The synthesis was carried out as in Example 1, except that 3-bromo-5-cyclopropylaminopyridine was used in place of 4-bromoisoquinoline.

[M+1] : 564； ^XHNMR [(400MHz, c -DMSO)]:5 10.69 (1 H, s), 8.67 (1 H, s), 8.36 (1 H, s), 8.24 (1 H, s), 8.17 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.95 (1 H, d, J=8.4 Hz), 7.71 (1 H, s), 7.65 (1 H, d, J=8.4 Hz), 7.57 (1 H, d, J=8.1 Hz), 7.51 (1 H, s), 3.61 (2 H, s), 2.70-3.09 (8 H, m), 2.61 (3 H, s), 2.15 (3 H, s), 1.35 (1 H, m), 0.73-0.98 (4 H, m). [M+1] : 564; ^X HNMR [(400MHz, c - DMSO)]: 5 10.69 (1 H, s), 8.67 (1 H, s), 8.36 (1 H, s), 8.24 (1 H, s), 8.17 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.95 (1 H, d, J=8.4 Hz), 7.71 (1 H, s), 7.65 (1 H, d, J=8.4 Hz), 7.57 (1 H, d, J=8.1 Hz), 7.51 (1 H, s), 3.61 (2 H, s), 2.70-3.09 (8 H, m), 2.61 (3 H, s), 2.15 (3 H, s), 1.35 (1 H, m), 0.73-0.98 (4 H, m).

实施例 37

Example 37

除了用 3-溴 -5- (氮杂环丁 -1-基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(azetidin-1-yl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 548； ^XHNMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 8.63 (1 H, s), 8.37 (1 H, s), 8.22 (1 H, s), 8.15 (1 H, s), 8.01 (1 H, d, J=8.3 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.72 (1 H, s), 7.67 (1 H, d, J=8.5 Hz), 7.55 (1 H, d, J=8.3 Hz), 3.63 (2 H, s), 3.19-3.33 (4 H, m), 2.71-3.13 (8 H, m), 2.63 (3 H: s), 2.23-2.29 (2 H, m), 2.17 (3 H, s). [M+1] : 548; ^X HNMR [(400MHz, c - DMSO)]: 5 10.67 (1 H, s), 8.63 (1 H, s), 8.37 (1 H, s), 8.22 (1 H, s), 8.15 (1 H, s), 8.01 (1 H, d, J=8.3 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.72 (1 H, s), 7.67 (1 H, d, J=8.5 Hz), 7.55 (1 H, d, J=8.3 Hz), 3.63 (2 H, s), 3.19-3.33 (4 H, m), 2.71-3.13 (8 H, m), 2.63 (3 H: s), 2.23-2.29 (2 H, m), 2.17 (3 H, s).

实施例 38

Example 38

除了用 3-溴 -5- (氮杂环戊 -1-基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(azole-1-yl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 562； ^XHNMR [(400MHz, c -DMSO)]:5 10.65 (1 H, s), 8.65 (1 H, s), 8.36 (1 H, s), 8.23 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.4 Hz), 7.94 (1 H, d, J=8.6 Hz), 7.70 (1 H, s), 7.66 (1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.4 Hz), 3.61 (2 H, s), 3.29-3.43 (4 H, m), 2.73-3.16 (8 H, m), 2.63 (3 H: s), 1.95-2.29 (7 H, m). [M+1] : 562; ^X HNMR [(400MHz, c - DMSO)]: 5 10.65 (1 H, s), 8.65 (1 H, s), 8.36 (1 H, s), 8.23 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.4 Hz), 7.94 (1 H, d, J=8.6 Hz), 7.70 (1 H, s), 7.66 (1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.4 Hz), 3.61 (2 H, s), 3.29-3.43 (4 H, m), 2.73-3.16 (8 H, m), 2.63 (3 H: s), 1.95-2.29 (7 H, m).

实施例 39

Example 39

除了用 3-溴 -5- (氮杂环己 -1-基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 3-bromo-5-(azetidin-1-yl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 562； ^XHNMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 8.66 (1 H, s), 8.35 (1 H, s), 8.21 (1 H, s), 8.17 (1 H, s), 8.01 (1 H, d, J=8.3 Hz), 7.92 (1 H, d, J=8.4 Hz), 7.68 (1 H, s), 7.65 (1 H, d, J=8.4 Hz), 7.51 (1 H, d, J=8.3 Hz), 3.66 (2 H, s), 2.73-3.27 (12 H, m), 2.61 (3 H, s), 2.19 (3 H, s), 1.53-1.72 (6 H, m). [M+1] : 562; ^X HNMR [(400MHz, c - DMSO)]: 5 10.67 (1H, s), 8.66 (1 H, s), 8.35 (1 H, s), 8.21 (1 H, s), 8.17 (1 H, s), 8.01 (1 H, d, J=8.3 Hz), 7.92 (1 H, d, J=8.4 Hz), 7.68 (1 H, s), 7.65 (1 H, d, J=8.4 Hz), 7.51 (1 H, d, J=8.3 Hz), 3.66 (2 H, s), 2.73-3.27 (12 H, m), 2.61 (3 H, s), 2.19 (3 H, s), 1.53-1.72 (6 H, m).

实施例 40

Example 40

除了用 3-溴 -5-(4-甲基哌嗪 -1-基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(4-methylpiperazin-1-yl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 562； ^XHNMR [(400MHz, c -DMSO)]:5 10.65 (1 H, s), 8.63 (1 H, s), 8.36 (1 H, s), 8.23 (1 H, s), 8.15 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.69 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.49 (1 H, d, J=8.1 Hz), 3.67 (2 H, s), 2.75-3.23 (16 H, m), 2.64 (3 H, s), 2.61 (3 H, s), 2.15 (3 H, s). [M+1] : 562; ^X HNMR [(400MHz, c - DMSO)]: 5 10.65 (1 H, s), 8.63 (1 H, s), 8.36 (1 H, s), 8.23 (1 H, s), 8.15 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.69 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.49 (1 H, d, J=8.1 Hz), 3.67 (2 H, s), 2.75-3.23 (16 H, m), 2.64 (3 H, s), 2.61 (3 H, s), 2.15 (3 H, s).

实施例 41

Example 41

除了用 3-溴 -5-吗啉基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used in place of 4-bromoisoquinoline.

[M+1] : 562； ^XHNMR [(400MHz, CDC1₃)]: δ 8.32 (2 H, s), 8.27 (1 Η, d, J=2.8 Hz), 8.08 (1 H, d, J=1.7 Hz), 7.85-7.93 (2 H, m), 7.81 (1 H, dd, J=8.4 Hz, J=2.1 Hz), 7.74 (1 H, d, J=8.4 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.31 (1 H, s), 3.86-3.91 (4 H, m), 3.66 (2 H, s), 3.16-3.23 (4 H, m), 2.50-2.78 (8 H, m), 2.44 (3 H, s), 2.15 (3 H, s). [M+1] : 562; ^X HNMR [(400MHz, CDC1 ₃ )]: δ 8.32 (2 H, s), 8.27 (1 Η, d, J=2.8 Hz), 8.08 (1 H, d, J= 1.7 Hz), 7.85-7.93 (2 H, m), 7.81 (1 H, dd, J=8.4 Hz, J=2.1 Hz), 7.74 (1 H, d, J=8.4 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.31 (1 H, s), 3.86-3.91 (4 H, m), 3.66 (2 H, s), 3.16-3.23 (4 H, m), 2.50-2.78 (8 H , m), 2.44 (3 H, s), 2.15 (3 H, s).

实施例 42

Example 42

除了用 3-溴 -5-苯基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-phenylpyridine was used in place of 4-bromoisoquinoline.

[M+1] : 562； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.69 (1 H, s), 8.43 (1 H, s), 8.23 (1 H, s), 8.15 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.91 (1 H, d, J=8.4 Hz), 7.73 (1 H, s), 7.61 (1 H, d, J=8.4 Hz), 7.43-7.58 (6H, m), 3.61 (2 H, s), 2.75-3.14 (8 H, m), 2.61 (3 H, s), 2.13 (3 H, s). [M+1] : 562; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.69 (1 H, s), 8.43 (1 H, s), 8.23 (1 H, s), 8.15 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.91 (1 H, d, J=8.4 Hz), 7.73 (1 H, s), 7.61 (1 H, d, J=8.4 Hz), 7.43-7.58 (6H, m), 3.61 (2 H, s), 2.75-3.14 (8 H, m), 2.61 (3 H, s), 2.13 (3 H, s) .

实施例 43

Example 43

除了用 3-溴 -5-(4-三氟甲基苯基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-(4-trifluoromethylphenyl)pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 637； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.67 (1 H, s), 8.45 (1 H, s), 8.21 (1 H, s), 8.17 (1 H, s), 8.01 (1 H, d, J=8.2 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.75 (1 H, s), 7.61-7.69 (3 H, m), 7.52 (1 H, d, J=8.2 Hz), 7.41 (2 H, d, J=7.8 Hz), 3.63 (2 H, s), 2.77-3.15 (8 H, m), 2.63 (3 H, s), 2.15 (3 H, s). [M+1] : 637; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.67 (1 H, s), 8.45 (1 H, s), 8.21 (1 H, s), 8.17 (1 H, s), 8.01 (1 H, d, J=8.2 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.75 (1 H, s), 7.61-7.69 (3 H, m), 7.52 (1 H, d, J = 8.2 Hz), 7.41 (2 H, d, J = 7.8 Hz), 3.63 (2 H, s), 2.77-3.15 (8 H, m), 2.63 (3 H, s), 2.15 (3 H, s).

实施例 44

Example 44

除了用 3-溴 -5-(4-甲氧基苯基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(4-methoxyphenyl)pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 599； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.65 (1 H, s), 8.43 (1 H, s), 8.23 (1 H, s), 8.15 (1 H, s), 8.03 (1 H, d, J=8.3 Hz), 7.91 (1 H, d, J=8.5 Hz), 7.73 (1 H, s), 7.62 (1 H, d, J=8.3 Hz), 7.49-7.56 (3 H, m), 7.08 (2 H, d, J=7.9 Hz), 3.93 (3 H, s), 3.61 (2 H, s), 2.76-3.13 (8 H: m), 2.61 (3 H, s), 2.19 (3 H, s). [M+1] : 599; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.65 (1 H, s), 8.43 (1 H, s), 8.23 (1 H, s), 8.15 (1 H, s), 8.03 (1 H, d, J = 8.3 Hz), 7.91 (1 H, d, J = 8.5 Hz), 7.73 (1 H, s), 7.62 (1 H, d, J=8.3 Hz), 7.49-7.56 (3 H, m), 7.08 (2 H, d, J=7.9 Hz), 3.93 (3 H, s), 3.61 (2 H, s), 2.76-3.13 (8 H: m), 2.61 (3 H, s), 2.19 (3 H, s).

实施例 45

Example 45

除了用 3-溴 -5-(3,4,5-三甲氧基苯基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(3,4,5-trimethoxyphenyl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 659； ^XHNMR [(400MHz, c -DMSO)]:5 10.69 (1 H, s), 8.61 (1 H, s), 8.39 (1 H, s), 8.21 (1 H, s), 8.13 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.92 (1 H, d, J=8.4 Hz), 7.71 (1 H, s), 7.61 (1 H, d, J=8.4 Hz), 7.53 (1 H, d, J=8.1 Hz), 6.67 (2 H, s), 3.89 (9 H, s), 3.59 (2 H, s), 2.73-3.10 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s). [M+1] : 659; ^X HNMR [(400MHz, c - DMSO)]: 5 10.69 (1 H, s), 8.61 (1 H, s), 8.39 (1 H, s), 8.21 (1 H, s), 8.13 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.92 (1 H, d, J=8.4 Hz), 7.71 (1 H, s), 7.61 (1 H, d, J=8.4 Hz), 7.53 (1 H, d, J=8.1 Hz), 6.67 (2 H, s), 3.89 (9 H, s), 3.59 (2 H, s), 2.73-3.10 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s).

实施例 46

Example 46

除了用 3-溴 -5-(2,6-二氯 -3,5-二甲氧基苯基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 3-bromo-5-(2,6-dichloro-3,5-dimethoxyphenyl)pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 697； ^XHNMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 8.63 (1 H, s), 8.41 (1 H, s), 8.20 (1 H, s), 8.15 (1 H, s), 8.04 (1 H, d, J=8.2 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.70 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.2 Hz), 6.61 (1 H, s), 3.90 (6 H, s), 3.62 (2 H, s), 2.75-3.11 (8 H, m), 2.62 (3 H, s), 2.19 (3 H, s). [M+1] : 697; ^X HNMR [(400MHz, c - DMSO)]: 5 10.67 (1 H, s), 8.63 (1 H, s), 8.41 (1 H, s), 8.20 (1 H, s), 8.15 (1 H, s), 8.04 (1 H, d, J = 8.2 Hz), 7.93 (1 H, d, J = 8.5 Hz), 7.70 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.2 Hz), 6.61 (1 H, s), 3.90 (6 H, s), 3.62 (2 H, s), 2.75-3.11 (8 H, m), 2.62 (3 H, s), 2.19 (3 H, s).

实施例 47

Example 47

除了用 3-溴 -5-(l-甲基 -1H-吡唑 -4-基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 573； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.65 (1 H, s), 8.43 (1 H, s), 8.23 (1 H, s), 8.17 (1 H, s), 8.05 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.96 (1 H, s), 7.91 (1 H, d, J=8.6 Hz), 7.76 (1 H, s), 7.60 (1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.1 Hz), 3.87 (3 H, s), 3.61 (2 H, s), 2.76-3.13 (8 H, m), 2.57 (3 H, s), 2.17 (3 H, s). [M+1] : 573; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.65 (1 H, s), 8.43 (1 H, s), 8.23 (1 H, s), 8.17 (1 H, s), 8.05 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.96 (1 H, s), 7.91 (1 H, d , J=8.6 Hz), 7.76 (1 H, s), 7.60 (1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.1 Hz), 3.87 (3 H, s), 3.61 (2 H, s), 2.76-3.13 (8 H, m), 2.57 (3 H, s), 2.17 (3 H, s).

实施例 48

Example 48

除了用 3-溴 -5- (嘧啶 -5-基)吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(pyrimidin-5-yl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 571； ^XHNMR [(400MHz, c -DMSO)]:5 10.69 (1 H, s), 8.67 (1 H, s), 8.61 (1 H, s), 8.42 (1 H, s), 8.33 (2 H, s), 8.21 (1 H, s), 8.12 (1 H, s), 8.02 (1 H, d, J=8.3 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.75 (1 H, s), 7.67 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.3 Hz), 3.65 (2 H, s), 2.72-3.11 (8 H, m), 2.62 (3 H, s), 2.16 (3 H, s). [M+1] : 571; ^X HNMR [(400MHz, c - DMSO)]: 5 10.69 (1 H, s), 8.67 (1 H, s), 8.61 (1 H, s), 8.42 (1 H, s), 8.33 (2 H, s), 8.21 (1 H, s), 8.12 (1 H, s), 8.02 (1 H, d, J=8.3 Hz), 7.93 (1 H, d, J=8.5 Hz), 7.75 (1 H, s), 7.67 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.3 Hz), 3.65 (2 H, s), 2.72-3.11 (8 H, m), 2.62 (3 H, s), 2.16 (3 H, s).

实施例 49

Example 49

除了用 3-溴 -5-(1Η-咪唑 -1-基)吡啶代替 4-溴异喹啉以夕卜，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 3-bromo-5-(1Η-imidazol-1-yl)pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 559； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.63 (1 H, s), 8.41 (1 H, s), 8.25 (1 H, s), 8.13 (1 H, s), 8.01 (1 H, d, J=8.2 Hz), 7.92 (1 H, d, J=8.5 Hz), 7.73 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.2 Hz), 7.44 (1 H, dd, J=l. l Hz, J=7.4 Hz), 7.15-7.17 (2 H, m), 3.64 (2 H, s), 2.78-3.13 (8 H, m), 2.61 (3 H, s), 2.19 (3 H, s). [M+1] : 559; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.63 (1 H, s), 8.41 (1 H, s), 8.25 (1 H, s), 8.13 (1 H, s), 8.01 (1 H, d, J = 8.2 Hz), 7.92 (1 H, d, J = 8.5 Hz), 7.73 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.2 Hz), 7.44 (1 H, dd, J=l. l Hz, J=7.4 Hz), 7.15-7.17 (2 H, m) , 3.64 (2 H, s), 2.78-3.13 (8 H, m), 2.61 (3 H, s), 2.19 (3 H, s).

实施例 50

Example 50

除了用 3-溴 -5-(4-甲基 -1H-咪唑 -1-基)吡啶代替 4-溴异喹啉以夕卜，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-(4-methyl-1H-imidazol-1-yl)pyridine was used in place of 4-bromoisoquinoline.

[M+1] : 573； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.63 (1 H, s), 8.41 (1 H, s), 8.25 (1 H, s), 8.13 (1 H, s), 8.01 (1 H, d, J=8.2 Hz), 7.92 (1 H, d, J=8.5 Hz), 7.73 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.2 Hz), 7.43 (1 H, s), 7.19 (1 H, s), 3.63 (2 H, s), 2.77-3.11 (8 H, m), 2.63 (3 H, s), 2.29 (3 H, s), 2.18 (3 H, s). [M+1] : 573; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.63 (1 H, s), 8.41 (1 H, s), 8.25 (1 H, s), 8.13 (1 H, s), 8.01 (1 H, d, J = 8.2 Hz), 7.92 (1 H, d, J = 8.5 Hz), 7.73 (1 H, s), 7.63 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.2 Hz), 7.43 (1 H, s), 7.19 (1 H, s), 3.63 (2 H, s), 2.77-3.11 (8 H, m), 2.63 (3 H, s), 2.29 (3 H, s), 2.18 (3 H, s).

实施例 51

Example 51

除了用 3-溴 -5-乙氧羰基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 [M+1] : 565； ¾NMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.67 (1 H, s), 8.34 (1 H, s), 8.29 (1 H, s), 8.15 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.93 (1 H, d, J=8.4 Hz), 7.73 (1 H, s), 7.67 (1 H, d, J=8.4 Hz), 7.51 (1 H, d, J=8.1 Hz), 4.21 (2 H, q, J=8.1 Hz), 3.63 (2 H, s), 2.71-3.13 (8 H, m), 2.63 (3 H, s), 2.15 (3 H, s), 1.32 (3 H, t, J=8.1 Hz). The synthesis was carried out as in Example 1, except that 3-bromo-5-ethoxycarbonylpyridine was used in place of 4-bromoisoquinoline. [M+1] : 565; 3⁄4 NMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.67 (1 H, s), 8.34 (1 H, s), 8.29 (1 H, s ), 8.15 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.93 (1 H, d, J=8.4 Hz), 7.73 (1 H, s), 7.67 (1 H, d , J=8.4 Hz), 7.51 (1 H, d, J=8.1 Hz), 4.21 (2 H, q, J=8.1 Hz), 3.63 (2 H, s), 2.71-3.13 (8 H, m) , 2.63 (3 H, s), 2.15 (3 H, s), 1.32 (3 H, t, J=8.1 Hz).

实施例 52

Example 52

除了用 3-溴 -5-羧基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-carboxypyridine was used in place of 4-bromoisoquinoline.

[M+1] : 537； ^XHNMR [(400MHz, c -DMSO)]:5 10.68 (1 H, s), 8.65 (1 H, s), 8.32 (1 H, s), 8.27 (1 H, s), 8.11 (1 H, s), 8.02 (1 H, d, J=8.2 Hz), 7.95 (1 H, d, J=8.6 Hz), 7.71 (1 H, s), 7.69 (1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.2 Hz), 3.65 (2 H, s), 2.76-3.15 (8 H, m), 2.65 (3 H, s), 2.19 (3 H, s). 实施例 53

[M+1] : 537; ^X HNMR [(400MHz, c - DMSO)]: 5 10.68 (1 H, s), 8.65 (1 H, s), 8.32 (1 H, s), 8.27 (1 H, s), 8.11 (1 H, s), 8.02 (1 H, d, J = 8.2 Hz), 7.95 (1 H, d, J = 8.6 Hz), 7.71 (1 H, s), 7.69 (1 H, d, J=8.6 Hz), 7.53 (1 H, d, J=8.2 Hz), 3.65 (2 H, s), 2.76-3.15 (8 H, m), 2.65 (3 H, s), 2.19 (3 H, s). Example 53

除了用 3-溴 -5-乙基氨基羰基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-ethylaminocarbonylpyridine was used in place of 4-bromoisoquinoline.

[M+1] : 564； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 9.62 (1 H, s), 8.63 (1 H, s), 8.31 (1 H, s), 8.27 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.2 Hz), 7.91 (1 H, d, J=8.5 Hz), 7.75 (1 H, s), 7.68 (1 H, d, J=8.5 Hz), 7.53 (1 H, d, J=8.2 Hz), 3.65 (2 H, s), 2.71-3.17 (10 H, m), 2.61 (3 H, s), 2.17 (3 H, s), 1.05 (3 H, t, J=8.0 Hz). [M+1] : 564; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 9.62 (1 H, s), 8.63 (1 H, s), 8.31 (1 H, s), 8.27 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.2 Hz), 7.91 (1 H, d, J=8.5 Hz), 7.75 (1 H, s), 7.68 (1 H, d, J=8.5 Hz), 7.53 (1 H, d, J=8.2 Hz), 3.65 (2 H, s), 2.71-3.17 (10 H, m), 2.61 (3 H, s), 2.17 (3 H, s), 1.05 (3 H, t, J=8.0 Hz).

实施例 54

Example 54

除了用二氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that dichloropyridazine was used in place of 4-bromoisoquinoline.

[M+1] : 528； ^XHNMR [(400MHz, c -DMSO)]:5 10.75 (1 H, s), 8.32 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.2 Hz), 7.86 (1 H, d, J=8.4 Hz), 7.75 (1 H, d, J=7.4 Hz), 7.58 (1 H, d, J=8.4 Hz), 7.39 (1 H, d, J=7.4 Hz), 7.19 (1 H, d, J=8.2 Hz), 3.61 (2 H, s), 2.70-3.09 (8 H, m), 2.63 (3 H, s), 2.14 (3 H, s). [M+1] : 528; ^X HNMR [(400MHz, c - DMSO)]: 5 10.75 (1 H, s), 8.32 (1 H, s), 8.16 (1 H, s), 8.03 (1 H, d, J=8.2 Hz), 7.86 (1 H, d, J=8.4 Hz), 7.75 (1 H, d, J=7.4 Hz), 7.58 (1 H, d, J=8.4 Hz), 7.39 (1 H, d, J=7.4 Hz), 7.19 (1 H, d, J=8.2 Hz), 3.61 (2 H, s), 2.70-3.09 (8 H, m), 2.63 (3 H, s), 2.14 (3 H, s).

实施例 55

除了用 3-羟基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 Example 55

The synthesis method was as in Example 1, except that 3-hydroxy-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 510； ^XHNMR [(400MHz, c -DMSO)]:5 10.76 (1 H, s), 8.33 (1 H, s), 8.17 (1 H, s), 8.11 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.5 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.57 (1 H, d, J=8.4 Hz), 7.36 (1 H, d, J=7.3 Hz), 7.18 (1 H, d, J=8.1 Hz), 3.62 (2 H, s), 2.73-3.11 (8 H, m), 2.65 (3 H, s), 2.16 (3 H, s). [M+1] : 510; ^X HNMR [(400MHz, c - DMSO)]: 5 10.76 (1 H, s), 8.33 (1 H, s), 8.17 (1 H, s), 8.11 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.5 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.57 (1 H, d, J =8.4 Hz), 7.36 (1 H, d, J=7.3 Hz), 7.18 (1 H, d, J=8.1 Hz), 3.62 (2 H, s), 2.73-3.11 (8 H, m), 2.65 (3 H, s), 2.16 (3 H, s).

实施例 56 Example 56

除了用 3-甲氧基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-methoxy-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 524； ^XHNMR [(400MHz, c -DMSO)]:5 10.77 (1 H, s), 8.31 (1 H, s), 8.13 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.5 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.38 (1 H, d, J=7.3 Hz), 7.17 (1 H, d, J=8.1 Hz), 3.95 (3 H, s), 3.63 (2 H, s), 2.72-3.12 (8 H, m), 2.61 (3 H, s), 2.13 (3 H, s). [M+1] : 524; ^X HNMR [(400MHz, c - DMSO)]: 5 10.77 (1 H, s), 8.31 (1 H, s), 8.13 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.5 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.38 (1 H, d, J=7.3 Hz), 7.17 (1 H, d, J=8.1 Hz), 3.95 (3 H, s), 3.63 (2 H, s), 2.72-3.12 (8 H, m), 2.61 (3 H, s), 2.13 (3 H, s).

实施例 57 Example 57

除了用 3-叔丁氧基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-tert-butoxy-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 566； ^XHNMR [(400MHz, c -DMSO)]:5 10.78 (1 H, s), 8.32 (1 H, s), 8.12 (1 H, s), 8.00 (1 H, d, J=8.0 Hz), 7.84 (1 H, d, J=8.4 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.55 (1 H, d, J=8.4 Hz), 7.36 (1 H, d, J=7.2 Hz), 7.15 (1 H, d, J=8.0 Hz), 3.65 (2 H, s), 2.73-3.15 (8 H, m), 2.64 (3 H, s), 2.16 (3 H, s), 1.51 (9 H, s). [M+1] : 566; ^X HNMR [(400MHz, c - DMSO)]: 5 10.78 (1 H, s), 8.32 (1 H, s), 8.12 (1 H, s), 8.00 (1 H, d, J=8.0 Hz), 7.84 (1 H, d, J=8.4 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.55 (1 H, d, J=8.4 Hz), 7.36 (1 H, d, J=7.2 Hz), 7.15 (1 H, d, J=8.0 Hz), 3.65 (2 H, s), 2.73-3.15 (8 H, m), 2.64 (3 H, s), 2.16 (3 H, s), 1.51 (9 H, s).

实施例 58 Example 58

除了用 3-氨基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-amino-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 509； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.35 (1 H, s), 8.13 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.4 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.65 (2 H, s), 7.57 (1 H, d, J=8.4 Hz), 7.36 (1 H, d, J=7.3 Hz), 7.18 (1 H, d, J=8.1 Hz), 3.62 (2 H, s), 2.73-3.11 (8 H, m), 2.65 (3 H, s), 2.16 (3 H, s). [M+1] : 509; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.35 (1 H, s), 8.13 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.4 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.65 (2 H, s), 7.57 (1 H, d, J =8.4 Hz), 7.36 (1 H, d, J=7.3 Hz), 7.18 (1 H, d, J=8.1 Hz), 3.62 (2 H, s), 2.73-3.11 (8 H, m), 2.65 (3 H, s), 2.16 (3 H, s).

实施例 59

Example 59

除了用 3-甲基氨基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-methylamino-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 523； ^XHNMR [(400MHz, c -DMSO)]:5 10.76 (1 H, s), 8.32 (1 H, s), 8.12 (1 H, s), 8.02 (1 H, d, J=8.2 Hz), 7.85 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.43 (1 H, s), 7.38 (1 H, d, J=7.2 Hz), 7.17 (1 H, d, J=8.2 Hz), 3.63 (2 H, s), 2.71-3.10 (8 H, m), 2.61 (3 H, s), 2.55 (3 H, s), 2.12 (3 H, s). [M+1] : 523; ^X HNMR [(400MHz, c - DMSO)]: 5 10.76 (1 H, s), 8.32 (1 H, s), 8.12 (1 H, s), 8.02 (1 H, d, J=8.2 Hz), 7.85 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.43 (1 H, s), 7.38 (1 H, d, J = 7.2 Hz), 7.17 (1 H, d, J = 8.2 Hz), 3.63 (2 H, s), 2.71-3.10 (8 H, m), 2.61 (3 H, s), 2.55 (3 H, s), 2.12 (3 H, s).

实施例 60

Example 60

除了用 3-环丙基氨基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-cyclopropylamino-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 549； ^XHNMR [(400MHz, c -DMSO)]:5 10.75 (1 H, s), 8.31 (1 H, s), 8.13 (1 H, s), 8.03[M+1] : 549; ^X HNMR [(400MHz, c - DMSO)]: 5 10.75 (1 H, s), 8.31 (1 H, s), 8.13 (1 H, s), 8.03

(1 H, d, J=8.1 Hz), 7.86 (1 H, d, J=8.4 Hz), 7.72 (1 H, d, J=7.3 Hz), 7.55 (1 H, d, J=8.4 Hz), 7.41 (1 H, s), 7.38 (1 H, d, J=7.3 Hz), 7.17 (1 H, d, J=8.1 Hz), 3.61 (2 H, s), 2.69-3.08 (8 H, m), 2.62 (3 H, s), 2.12 (3 H, s), 1.33 (1 H, m), 0.72-0.95 (4 H, m). (1 H, d, J=8.1 Hz), 7.86 (1 H, d, J=8.4 Hz), 7.72 (1 H, d, J=7.3 Hz), 7.55 (1 H, d, J=8.4 Hz) , 7.41 (1 H, s), 7.38 (1 H, d, J = 7.3 Hz), 7.17 (1 H, d, J = 8.1 Hz), 3.61 (2 H, s), 2.69-3.08 (8 H, m), 2.62 (3 H, s), 2.12 (3 H, s), 1.33 (1 H, m), 0.72-0.95 (4 H, m).

实施例 61

Example 61

除了用 3-叔丁基氨基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-tert-butylamino-6-chloropyridazine was used in place of 4-bromoisoquinoline.

[M+1] : 565； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.30 (1 H, s), 8.11 (1 H, s), 8.01 (1 H, d, J=8.0 Hz), 7.83 (1 H, d, J=8.3 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.56 (1 H, d, J=8.3 Hz), 7.43 (1 H, s), 7.37 (1 H, d, J=7.2 Hz), 7.18 (1 H, d, J=8.0 Hz), 3.63 (2 H, s), 2.72-3.09 (8 H, m), 2.61 (3 H, s), 2.13 (3 H, s), 1.33 (9 H, s). [M+1] : 565; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.30 (1 H, s), 8.11 (1 H, s), 8.01 (1 H, d, J=8.0 Hz), 7.83 (1 H, d, J=8.3 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.56 (1 H, d, J=8.3 Hz), 7.43 (1 H, s), 7.37 (1 H, d, J=7.2 Hz), 7.18 (1 H, d, J=8.0 Hz), 3.63 (2 H, s), 2.72-3.09 (8 H, m), 2.61 (3 H, s), 2.13 (3 H, s), 1.33 (9 H, s).

实施例 62

Example 62

除了用 3-苯胺基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-anilino-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 585； ^XHNMR [(400MHz, c -DMSO)]:5 10.67 (1 H, s), 8.31 (1 H, s), 8.13 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.4 Hz), 7.70 (1 H, d, J=7.1 Hz), 7.55-7.67 (3 H, m), 7.41-7.49 (3 H, m), 7.36 (1 H, d, J=7.1 Hz), 7.18 (1 H, d, J=8.1 Hz), 6.88 (1 H, t, J=7.8 Hz), 3.61 (2 H, s), 2.73-3.11 (8 H, m), 2.62 (3 H, s), 2.18 (3 H, s). [M+1] : 585; ^X HNMR [(400MHz, c - DMSO)]: 5 10.67 (1 H, s), 8.31 (1 H, s), 8.13 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.4 Hz), 7.70 (1 H, d, J=7.1 Hz), 7.55-7.67 (3 H, m), 7.41- 7.49 (3 H, m), 7.36 (1 H, d, J=7.1 Hz), 7.18 (1 H, d, J=8.1 Hz), 6.88 (1 H, t, J=7.8 Hz), 3.61 (2 H, s), 2.73-3.11 (8 H, m), 2.62 (3 H, s), 2.18 (3 H, s).

实施例 63

Example 63

除了用 3-(2,6-二氯 -3,5二甲氧基苯胺基) -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-(2,6-dichloro-3,5-dimethoxyanilino)-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 713； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.33 (1 H, s), 8.14 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.4 Hz), 7.73 (1 H, d, J=7.1 Hz), 7.58 (1 H, d, J=8.4 Hz), 7.45 (1 H, s), 7.33 (1 H, d, J=7.1 Hz), 7.19 (1 H, d, J=8.1 Hz), 6.12 (1 H, s), 3.89 (6 H, s), 3.65 (2 H, s), 2.73-3.11 (8 H, m), 2.62 (3 H, s), 2.19 (3 H, s). [M+1] : 713; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.33 (1 H, s), 8.14 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.85 (1 H, d, J=8.4 Hz), 7.73 (1 H, d, J=7.1 Hz), 7.58 (1 H, d, J=8.4 Hz), 7.45 (1 H, s), 7.33 (1 H, d, J=7.1 Hz), 7.19 (1 H, d, J=8.1 Hz), 6.12 (1 H, s), 3.89 (6 H, s), 3.65 (2 H, s), 2.73-3.11 (8 H, m), 2.62 (3 H, s), 2.19 (3 H, s).

实施例 64

Example 64

除了用 3-(4-三氟甲基苯胺基) -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-(4-trifluoromethylanilino)-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 653； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.35 (1 H, s), 8.12 (1 H, s), 8.04 (1 H, d, J=8.2 Hz), 7.83 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.55 (1 H, d, J=8.5 Hz), 7.35-7.45 (5 H, m), 7.31 (1 H, d, J=7.2 Hz), 7.17 (1 H, d, J=8.2 Hz), 3.63 (2 H, s), 2.71-3.09 (8 H, m), 2.60 (3 H, s), 2.17 (3 H, s). [M+1] : 653; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.35 (1 H, s), 8.12 (1 H, s), 8.04 (1 H, d, J=8.2 Hz), 7.83 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.55 (1 H, d, J=8.5 Hz), 7.35-7.45 (5 H, m), 7.31 (1 H, d, J=7.2 Hz), 7.17 (1 H, d, J=8.2 Hz), 3.63 (2 H, s), 2.71-3.09 (8 H, m) , 2.60 (3 H, s), 2.17 (3 H, s).

实施例 65

Example 65

除了用 3-乙酰氨基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-acetamido-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 551； ^XHNMR [(400MHz, c -DMSO)]:5 10.77 (1 H, s), 9.63 (1 H, s), 8.33 (1 H, s), 8.13 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.83 (1 H, d, J=8.6 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.55 (1 H, d, J=8.6 Hz), 7.37 (1 H, d, J=7.3 Hz), 7.15 (1 H, d, J=8.1 Hz), 3.61 (2 H, s), 2.75-3.13 (8 H, m), 2.62 (3 H, s), 2.12 (3 H, s), 2.05 (3 H, s). [M+1] : 551; ^X HNMR [(400MHz, c - DMSO)]: 5 10.77 (1 H, s), 9.63 (1 H, s), 8.33 (1 H, s), 8.13 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.83 (1 H, d, J=8.6 Hz), 7.73 (1 H, d, J=7.3 Hz), 7.55 (1 H, d, J =8.6 Hz), 7.37 (1 H, d, J=7.3 Hz), 7.15 (1 H, d, J=8.1 Hz), 3.61 (2 H, s), 2.75-3.13 (8 H, m), 2.62 (3 H, s), 2.12 (3 H, s), 2.05 (3 H, s).

实施例 66

Example 66

除了用 3-苯基 -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-phenyl-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 570； ^XHNMR [(400MHz, c -DMSO)]:5 10.65 (1 H, s), 8.31 (1 H, s), 8.12 (1 H, s), 8.06 (2 H, t, J=7.8 Hz), 8.01 (1 H, d, J=8.2 Hz), 7.81 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.53 (1 H, d, J=8.5 Hz), 7.42-7.51 (3 H, m), 7.36 (1 H, d, J=7.2 Hz), 7.18 (1 H, d, J=8.2 Hz), 3.62 (2 H, s), 2.71-3.10 (8 H, m), 2.63 (3 H, s), 2.15 (3 H, s). [M+1] : 570; ^X HNMR [(400MHz, c - DMSO)]: 5 10.65 (1 H, s), 8.31 (1 H, s), 8.12 (1 H, s), 8.06 (2 H, t, J=7.8 Hz), 8.01 (1 H, d, J=8.2 Hz), 7.81 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.53 (1 H, d, J=8.5 Hz), 7.42-7.51 (3 H, m), 7.36 (1 H, d, J=7.2 Hz), 7.18 (1 H, d, J=8.2 Hz), 3.62 (2 H , s), 2.71-3.10 (8 H, m), 2.63 (3 H, s), 2.15 (3 H, s).

实施例 67

Example 67

除了用 3-(4-甲氧基苯基) -6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-(4-methoxyphenyl)-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 600； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.37 (1 H, s), 8.15 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.82 (1 H, d, J=8.6 Hz), 7.73 (1 H, d, J=7.2 Hz), 7.51-7.56 (3 H, m), 7.31 (1 H, d J=7.2 Hz), 7.22 (2 H, d, J=7.9 Hz), 7.13 (1 H, d, J=8.2 Hz), 3.88 (3 H, s), 3.65 (2 H, s), 2.70-3.07 (8 H, m), 2.58 (3 H, s), 2.13 (3 H, s). [M+1] : 600; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.37 (1 H, s), 8.15 (1 H, s), 8.03 (1 H, d, J=8.1 Hz), 7.82 (1 H, d, J=8.6 Hz), 7.73 (1 H, d, J=7.2 Hz), 7.51-7.56 (3 H, m), 7.31 (1 H, d J=7.2 Hz), 7.22 (2 H, d, J=7.9 Hz), 7.13 (1 H, d, J=8.2 Hz), 3.88 (3 H, s), 3.65 (2 H, s), 2.70- 3.07 (8 H, m), 2.58 (3 H, s), 2.13 (3 H, s).

实施例 68

Example 68

除了用 3-(4-三氟甲基苯基 )-6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-(4-trifluoromethylphenyl)-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 638； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.35 (1 H, s), 8.12 (1 H, s), 8.04 (1 H, d, J=8.2 Hz), 7.83 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.61-7.35 (4 H, m), 7.53 (1 H, d J=8.5 Hz), 7.33 (1 H, d, J=7.2 Hz), 7.15 (1 H, d, J=8.2 Hz), 3.61 (2 H, s), 2.70-3.09 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s). [M+1] : 638; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.35 (1 H, s), 8.12 (1 H, s), 8.04 (1 H, d, J=8.2 Hz), 7.83 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=7.2 Hz), 7.61-7.35 (4 H, m), 7.53 (1 H, d J=8.5 Hz), 7.33 (1 H, d, J=7.2 Hz), 7.15 (1 H, d, J=8.2 Hz), 3.61 (2 H, s), 2.70-3.09 (8 H, m), 2.63 (3 H, s), 2.17 (3 H, s).

实施例 69

Example 69

除了用 3-(3-三氟甲基 -4-氯苯基 )-6-氯哒嗪代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-(3-trifluoromethyl-4-chlorophenyl)-6-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 672； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 8.33 (1 H, s), 8.18 (1 H, s), 8.13 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.99 (1 H, d, J=7.9 Hz), 7.82 (1 H, d, J=8.6 Hz), 7.71 (1 H, d J=7.1 Hz), 7.49-7.53 (2 H, m), 7.33 (1 H, d, J=7.1 Hz), 7.16 (1 H, d, J=8.1 Hz), 3.63 (2 H, s)_: 2.75-3.11 (8 H, m), 2.61 (3 H, s), 2.18 (3 H, s). [M+1] : 672; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 8.33 (1 H, s), 8.18 (1 H, s), 8.13 (1 H, s), 8.02 (1 H, d, J=8.1 Hz), 7.99 (1 H, d, J=7.9 Hz), 7.82 (1 H, d, J=8.6 Hz), 7.71 (1 H , d J=7.1 Hz), 7.49-7.53 (2 H, m), 7.33 (1 H, d, J=7.1 Hz), 7.16 (1 H, d, J=8.1 Hz), 3.63 (2 H, s ) _: 2.75-3.11 (8 H, m), 2.61 (3 H, s), 2.18 (3 H, s).

实施例 70

Example 70

除了用 3-碘苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-iodobenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 529； ^XHNMR [(400MHz, c -DMSO)]:5 10.83 (1 H, s), 9.50 (1 H, s), 8.87 (1 H, s), 8.45 (1 H, d, J=8.2 Hz), 8.38 (1 H, s), 8.29-8.36 (2 H, m), 8.17 (1 H, d, J=8.2 Hz), 8.03-8.12 (2 H, m), 8.00 (1 H, d, J=7.9 Hz), 7.89 (2 H, d, J=8.2 Hz), 7.70 (1 H, d, J=7.8 Hz), 3.34-3.57 (6 H, m), 3.00-3.24 (4 H, m), 2.78 (3 H, s). [M+1] : 529; ^X HNMR [(400MHz, c - DMSO)]: 5 10.83 (1 H, s), 9.50 (1 H, s), 8.87 (1 H, s), 8.45 (1 H, d, J=8.2 Hz), 8.38 (1 H, s), 8.29-8.36 (2 H, m), 8.17 (1 H, d, J=8.2 Hz), 8.03-8.12 (2 H, m), 8.00 (1 H, d, J=7.9 Hz), 7.89 (2 H, d, J=8.2 Hz), 7.70 (1 H, d, J=7.8 Hz), 3.34-3.57 (6 H, m), 3.00- 3.24 (4 H, m), 2.78 (3 H, s).

实施例 71

Example 71

除了用 3-碘 -4-乙基苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-iodo-4-ethylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 557； ^XHNMR [(400MHz, c -DMSO)]:5 10.81 (1 H, s), 9.51 (1 H, s), 8.93 (1 H, s), 8.42 (1 H, d, J=8.2 Hz), 8.25-8.35 (3 H, m), 8.16 (1 H, d, J=7.9 Hz), 8.07 (1 H, t, J=7.5 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.79-7.93 (2 H, m), 7.57 (1 H, d, J=8.3 Hz), 3.71 (2 H, s), 3.03-3.22 (4 H, m), 2.71-2.83 (4 H, m), 2.62 (3 H, s), 2.57 (2 H, q, J=7.5 Hz), 1.23 (3 H, t, J=7.5 Hz). [M+1] : 557; ^X HNMR [(400MHz, c - DMSO)]: 5 10.81 (1 H, s), 9.51 (1 H, s), 8.93 (1 H, s), 8.42 (1 H, d, J=8.2 Hz), 8.25-8.35 (3 H, m), 8.16 (1 H, d, J=7.9 Hz), 8.07 (1 H, t, J=7.5 Hz), 8.02 (1 H, d , J=8.2 Hz), 7.79-7.93 (2 H, m), 7.57 (1 H, d, J=8.3 Hz), 3.71 (2 H, s), 3.03-3.22 (4 H, m), 2.71- 2.83 (4 H, m), 2.62 (3 H, s), 2.57 (2 H, q, J=7.5 Hz), 1.23 (3 H, t, J=7.5 Hz).

实施例 72

Example 72

除了用 3-碘 -4-异丙基苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 3-iodo-4-isopropylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 557； ^XHNMR [(400MHz, c -DMSO)]:5 10.85 (1 H, s), 9.52 (1 H, s), 8.91 (1 H, s), 8.43 (1 H, d, J=8.1 Hz), 8.26-8.37 (3 H, m), 8.15 (1 H, d, J=7.8 Hz), 8.06 (1 H, t, J=7.6 Hz), 8.01 (1 H, d, J=8.1 Hz), 7.78-7.91 (2 H, m), 7.55 (1 H, d, J=8.2 Hz), 3.72 (2 H, s), 3.01-3.20 (4 H, m), 2.73-2.87 (4 H, m), 2.61-2.63 (4 H, m), 1.27 (6 H, d, J=6.9 Hz). [M+1] : 557; ^X HNMR [(400MHz, c - DMSO)]: 5 10.85 (1 H, s), 9.52 (1 H, s), 8.91 (1 H, s), 8.43 (1 H, d, J=8.1 Hz), 8.26-8.37 (3 H, m), 8.15 (1 H, d, J=7.8 Hz), 8.06 (1 H, t, J=7.6 Hz), 8.01 (1 H, d , J=8.1 Hz), 7.78-7.91 (2 H, m), 7.55 (1 H, d, J=8.2 Hz), 3.72 (2 H, s), 3.01-3.20 (4 H, m), 2.73- 2.87 (4 H, m), 2.61-2.63 (4 H, m), 1.27 (6 H, d, J=6.9 Hz).

实施例 73

除了用 3-碘 -4-环丙基苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 Example 73

The synthesis method was as in Example 1, except that 3-iodo-4-cyclopropylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 569； ^XHNMR [(400MHz, c -DMSO)]:5 10.82 (1 H, s), 9.55 (1 H, s), 8.92 (1 H, s), 8.41 (1 H, d, J=8.2 Hz), 8.23-8.34 (3 H, m), 8.12 (1 H, d, J=7.7 Hz), 8.05 (1 H, t, J=7.7 Hz), 8.03 (1 H, d, J=8.2 Hz), 7.77-7.90 (2 H, m), 7.54 (1 H, d, J=8.3 Hz), 3.69 (2 H, s), 3.00-3.18 (4 H, m), 2.75-2.89 (4 H, m), 2.65 (3 H, s), 1.61 (1 H, m), 1.01-1.25 (4 H, m). [M+1] : 569; ^X HNMR [(400MHz, c - DMSO)]: 5 10.82 (1 H, s), 9.55 (1 H, s), 8.92 (1 H, s), 8.41 (1 H, d, J=8.2 Hz), 8.23-8.34 (3 H, m), 8.12 (1 H, d, J=7.7 Hz), 8.05 (1 H, t, J=7.7 Hz), 8.03 (1 H, d , J=8.2 Hz), 7.77-7.90 (2 H, m), 7.54 (1 H, d, J=8.3 Hz), 3.69 (2 H, s), 3.00-3.18 (4 H, m), 2.75- 2.89 (4 H, m), 2.65 (3 H, s), 1.61 (1 H, m), 1.01-1.25 (4 H, m).

实施例 74

Example 74

除了用 3-碘 -4-叔丁基苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 3-iodo-4-tert-butylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 585； ^XHNMR [(400MHz, c -DMSO)]:5 10.87 (1 H, s), 9.51 (1 H, s), 8.93 (1 H, s), 8.45 (1 H, d, J=8.1 Hz), 8.21-8.33 (3 H, m), 8.09 (1 H, d, J=7.8 Hz), 8.01 (1 H, t, J=7.8 Hz), 7.99 (1 H, d, J=8.1 Hz), 7.79-7.92 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 3.67 (2 H, s), 3.03-3.17 (4 H, m), 2.73-2.87 (4 H, m), 2.62 (3 H, s), 1.37 (9 H, s). [M+1] : 585; ^X HNMR [(400MHz, c - DMSO)]: 5 10.87 (1 H, s), 9.51 (1 H, s), 8.93 (1 H, s), 8.45 (1 H, d, J=8.1 Hz), 8.21-8.33 (3 H, m), 8.09 (1 H, d, J=7.8 Hz), 8.01 (1 H, t, J=7.8 Hz), 7.99 (1 H, d , J=8.1 Hz), 7.79-7.92 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 3.67 (2 H, s), 3.03-3.17 (4 H, m), 2.73- 2.87 (4 H, m), 2.62 (3 H, s), 1.37 (9 H, s).

实施例 75

Example 75

除了用 3-碘 -4-氟苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-iodo-4-fluorobenzoic acid was used instead of 3-iodo-4-methylbenzoic acid.

[M+1] : 547； ^XHNMR [(400MHz, c -DMSO)]:5 10.79 (1 H, s), 9.42 (1 H, s), 8.83 (1 H, s), 8.49 (1 H, dd, J=2.3 Hz , J=6.6 Hz), 8.34 (1 H, d, J=8.2 Hz), 8.23-8.30 (2 H, m), 8.13-8.19 (1 H, m), 8.11 (1 H, dd, J=1.6 Hz , J=8.2 Hz), 8.00 (1 H, td, J=0.8 Hz, J=6.6 Hz), 7.83 (1 H, td, J=1.2 Hz, J=8.2 Hz), 7.72 (1 H, d, J=8.2 Hz), 7.61 (1 H, t, J=9.0 Hz), 3.63 (2 H, s), 2.72-2.95 (4 H, m), 2.49-2.66 (7 H, m). [M+1] : 547; ^X HNMR [(400MHz, c - DMSO)]: 5 10.79 (1 H, s), 9.42 (1 H, s), 8.83 (1 H, s), 8.49 (1 H, Dd, J=2.3 Hz , J=6.6 Hz), 8.34 (1 H, d, J=8.2 Hz), 8.23-8.30 (2 H, m), 8.13-8.19 (1 H, m), 8.11 (1 H , dd, J=1.6 Hz , J=8.2 Hz), 8.00 (1 H, td, J=0.8 Hz, J=6.6 Hz), 7.83 (1 H, td, J=1.2 Hz, J=8.2 Hz), 7.72 (1 H, d, J=8.2 Hz), 7.61 (1 H, t, J=9.0 Hz), 3.63 (2 H, s), 2.72-2.95 (4 H, m), 2.49-2.66 (7 H , m).

实施例 76

Example 76

除了用 3-碘 -4-氯苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-iodo-4-chlorobenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 563； ^XHNMR [(400MHz, c -DMSO)]:5 10.77 (1 H, s), 9.41 (1 H, s), 8.82 (1 H, s), 8.45 (1 H, d, J=8.1 Hz), 8.33 (1 H, d, J=8.3 Hz), 8.16-8.29 (3 H, m), 8.11 (1 H, d, J=8.3 Hz), 8.00 (1 H, t, J=8.1 Hz), 7.81 (1 H, t, J=8.2 Hz), 7.73 (1 H, d, J=8.2 Hz), 7.60 (1 H, t, J=8.8 Hz), 3.65 (2 H, s), 2.76-2.98 (4 H, m), 2.51-2.69 (7 H, m). 实施例 77

[M+1] : 563; ^X HNMR [(400MHz, c - DMSO)]: 5 10.77 (1 H, s), 9.41 (1 H, s), 8.82 (1 H, s), 8.45 (1 H, d, J=8.1 Hz), 8.33 (1 H, d, J=8.3 Hz), 8.16-8.29 (3 H, m), 8.11 (1 H, d, J=8.3 Hz), 8.00 (1 H, t , J=8.1 Hz), 7.81 (1 H, t, J=8.2 Hz), 7.73 (1 H, d, J=8.2 Hz), 7.60 (1 H, t, J=8.8 Hz), 3.65 (2 H , s), 2.76-2.98 (4 H, m), 2.51-2.69 (7 H, m). Example 77

除了用 3-碘 -4-溴苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-iodo-4-bromobenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 607； ^XHNMR [(400MHz, c -DMSO)]:5 10.75 (1 H, s), 9.45 (1 H, s), 8.81 (1 H, s), 8.49 (1 H, d, J=8.0 Hz), 8.32 (1 H, d, J=8.2 Hz), 8.15-8.27 (3 H, m), 8.12 (1 H, d, J=8.2 Hz), 8.01 (1 H, t, J=8.0 Hz), 7.80 (1 H, t, J=8.2 Hz), 7.75 (1 H, d, J=8.2 Hz), 7.61 (1 H, t, J=8.5 Hz), 3.63 (2 H, s), 2.73-2.95 (4 H, m), 2.50-2.70 (7 H, m). [M+1] : 607; ^X HNMR [(400MHz, c - DMSO)]: 5 10.75 (1 H, s), 9.45 (1 H, s), 8.81 (1 H, s), 8.49 (1 H, d, J=8.0 Hz), 8.32 (1 H, d, J=8.2 Hz), 8.15-8.27 (3 H, m), 8.12 (1 H, d, J=8.2 Hz), 8.01 (1 H, t , J=8.0 Hz), 7.80 (1 H, t, J=8.2 Hz), 7.75 (1 H, d, J=8.2 Hz), 7.61 (1 H, t, J=8.5 Hz), 3.63 (2 H , s), 2.73-2.95 (4 H, m), 2.50-2.70 (7 H, m).

实施例 78

Example 78

除了用 3-碘 -4-甲氧基苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-iodo-4-methoxybenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 607； ^XHNMR [(400MHz, c -DMSO)]:5 10.57 (1 H, s), 9.37 (1 H, s), 8.77 (1 H, s), 8.40 (1 H, d, J=8.3 Hz), 8.34 (1 H, d, J=2.3 Hz), 8.22-8.28 (2 H, m), 8.12 (1 H, td, J=2.3 Hz, J=8.6 Hz), 8.00 (1 H, td, J=1.2 Hz, J=7.0 Hz), 7.82 (1 H, td, J=l. l Hz, J=7.0 Hz), 7.70 (1 H, d, J=8.6 Hz), 7.34 (1 H, d, J=8.6 Hz), 4.05 (3 H, s), 3.62 (2 H, s), 2.71-2.92 (4 H, m), 2.38-2.63 (7 H, m). [M+1] : 607; ^X HNMR [(400MHz, c - DMSO)]: 5 10.57 (1H, s), 9.37 (1 H, s), 8.77 (1 H, s), 8.40 (1 H, d, J=8.3 Hz), 8.34 (1 H, d, J=2.3 Hz), 8.22-8.28 (2 H, m), 8.12 (1 H, td, J=2.3 Hz, J=8.6 Hz), 8.00 (1 H, td, J=1.2 Hz, J=7.0 Hz), 7.82 (1 H, td, J=l. l Hz, J=7.0 Hz), 7.70 (1 H, d, J=8.6 Hz), 7.34 (1 H, d, J=8.6 Hz), 4.05 (3 H, s), 3.62 (2 H, s), 2.71-2.92 (4 H, m), 2.38-2.63 (7 H, m).

实施例 79

Example 79

除了用 3-碘 -4-三氟甲基苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-iodo-4-trifluoromethylbenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 597； ^XHNMR [(400MHz, c -DMSO)]:5 10.81 (1 H, s), 9.43 (1 H, s), 8.82 (1 H, s), 8.43 (1 H, dd, J=2.1 Hz , J=6.8 Hz), 8.35 (1 H, d, J=8.3 Hz), 8.21-8.28 (2 H, m), 8.11-8.18 (1 H, m), 8.13 (1 H, dd, J=1.7 Hz , J=8.3 Hz), 8.01 (1 H, td, J=0.9 Hz, J=6.8 Hz), 7.82 (1 H, td, J=l. l Hz, J=8.1 Hz), 7.71 (1 H, d, J=8.1 Hz), 7.63 (1 H, t, J=8.8 Hz), 3.65 (2 H, s), 2.73-2.98 (4 H, m), 2.51-2.68 (7 H, m). [M+1] : 597; ^X HNMR [(400MHz, c - DMSO)]: 5 10.81 (1 H, s), 9.43 (1 H, s), 8.82 (1 H, s), 8.43 (1 H, Dd, J=2.1 Hz , J=6.8 Hz), 8.35 (1 H, d, J=8.3 Hz), 8.21-8.28 (2 H, m), 8.11-8.18 (1 H, m), 8.13 (1 H , dd, J=1.7 Hz , J=8.3 Hz), 8.01 (1 H, td, J=0.9 Hz, J=6.8 Hz), 7.82 (1 H, td, J=l. l Hz, J=8.1 Hz ), 7.71 (1 H, d, J=8.1 Hz), 7.63 (1 H, t, J=8.8 Hz), 3.65 (2 H, s), 2.73-2.98 (4 H, m), 2.51-2.68 ( 7 H, m).

实施例 80

Example 80

除了用 4-溴吡啶 -2-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 4-bromopyridine-2-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 530； ^XHNMR [(400MHz, CDC1₃)]:5 9.73 (1 H, s), 9.23 (1 H, s), 8.83 (1 H, s), 8.77 (1 H: s), 8.33 (1 H, d, J=8.3 Hz), 8.21 (1 H, s), 8.13 (1 H, d, J=1.9 Hz), 8.03 (1 H, dd, J=1.5 Hz, J=8.4 Hz),7.99 (1 H, d, J=8.3 Hz), 7.91 (1 H, dd, J=1.5 Hz, J=5.3 Hz), 7.79 (1 H, td, J=1.6 Hz, J=7.1 Hz), 7.62-7.73 (2 H, m), 3.63 (2 H, s), 2.73-2.95 (4 H, m), 2.59-2.73 (4 H, m), 2.53 (3 H, s). [M+1] : 530; ^X HNMR [(400MHz, CDC1 ₃ )]: 5 9.73 (1 H, s), 9.23 (1 H, s), 8.83 (1 H, s), 8.77 (1 H: s ), 8.33 (1 H, d, J=8.3 Hz), 8.21 (1 H, s), 8.13 (1 H, d, J=1.9 Hz), 8.03 (1 H, dd, J=1.5 Hz, J= 8.4 Hz), 7.99 (1 H, d, J=8.3 Hz), 7.91 (1 H, dd, J=1.5 Hz, J=5.3 Hz), 7.79 (1 H, td, J=1.6 Hz, J=7.1 Hz ), 7.62-7.73 (2 H, m), 3.63 (2 H, s), 2.73-2.95 (4 H, m), 2.59-2.73 (4 H, m), 2.53 (3 H, s).

实施例 81

Example 81

除了用 6-氯吡啶 -2-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 6-chloropyridine-2-carboxylic acid was used instead of 3-iodo-4-methylbenzoic acid.

[M+1] : 530； ^XHNMR [(300MHz, CDC1₃)] : 5 10.06 (1 H, s), 9.29 (1 H, s), 8.90 (1 H, s), 8.38 (1 H, d, J=8.4 Hz), 8.32 (1 H, d, J=6.7 Hz), 8.08 (1 H, s), 7.96-8.06 (3 H, m), 7.82-7.92 (2 H, m), 7.78 (1 H, d, J=8.4 Hz), 7.73 (1 H, t, J=7.0 Hz), 3.66 (2 H, s), 2.43-2.67 (8 H, m), 2.34 (3 H, s). 实施例 82

[M+1] : 530; ^X HNMR [(300MHz, CDC1 ₃ )] : 5 10.06 (1 H, s), 9.29 (1 H, s), 8.90 (1 H, s), 8.38 (1 H, d , J=8.4 Hz), 8.32 (1 H, d, J=6.7 Hz), 8.08 (1 H, s), 7.96-8.06 (3 H, m), 7.82-7.92 (2 H, m), 7.78 ( 1 H, d, J=8.4 Hz), 7.73 (1 H, t, J=7.0 Hz), 3.66 (2 H, s), 2.43-2.67 (8 H, m), 2.34 (3 H, s). Example 82

除了用 5-溴烟酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 5-bromonicotinic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+l] : 530; ^XHNMR [(300MHz, CDC1₃)] :5 9.36 (1 H, s), 9.29 (1 H, s), 9.03 (1 H, s), 8.81 (1 H: s), 8.45-8.55 (2 H, m), 8.31 (1 H, d, J=8.4 Hz), 8.05 (1 H, d, J=8.7 Hz), 7.95-8.05 (2 H, m), 7.86 (1 H, t, J=8.4 Hz), 7.65-7.76 (2 H, m), 3.72 (2 H, s), 2.68-2.96 (8 H, m), 2.58 (3 H, s). [M+l] : 530; ^X HNMR [(300MHz, CDC1 ₃ )] : 5 9.36 (1 H, s), 9.29 (1 H, s), 9.03 (1 H, s), 8.81 (1 H: s ), 8.45-8.55 (2 H, m), 8.31 (1 H, d, J=8.4 Hz), 8.05 (1 H, d, J=8.7 Hz), 7.95-8.05 (2 H, m), 7.86 ( 1 H, t, J=8.4 Hz), 7.65-7.76 (2 H, m), 3.72 (2 H, s), 2.68-2.96 (8 H, m), 2.58 (3 H, s).

实施例 83

Example 83

除了用 2-溴异烟酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 2-bromoisonicotinic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+l] : 530; ^XHNMR [(400MHz, CDC1₃)] :5 9.75 (1 H, s), 9.21 (1 H, s), 8.81 (1 H, s), 8.78 (1 H: s), 8.31 (1 H, d, J=8.4 Hz), 8.24 (1 H, s), 8.11 (1 H, d, J=2.0 Hz), 8.06 (1 H, dd, J=1.7 Hz, J=8.6 Hz), 8.00 (1 H, d, J=8.4 Hz), 7.91 (1 H, dd, J=1.5 Hz, J=5.1 Hz), 7.79 (1 H, td, J=1.4 Hz, J=7.0 Hz), 7.61-7.71 (2 H, m), 3.65 (2 H, s), 2.75-2.96 (4 H, m), 2.60-2.75 (4 H, m), 2.55 (3 H, s). [M+l] : 530; ^X HNMR [(400MHz, CDC1 ₃ )] : 5 9.75 (1 H, s), 9.21 (1 H, s), 8.81 (1 H, s), 8.78 (1 H: s ), 8.31 (1 H, d, J=8.4 Hz), 8.24 (1 H, s), 8.11 (1 H, d, J=2.0 Hz), 8.06 (1 H, dd, J=1.7 Hz, J= 8.6 Hz), 8.00 (1 H, d, J=8.4 Hz), 7.91 (1 H, dd, J=1.5 Hz, J=5.1 Hz), 7.79 (1 H, td, J=1.4 Hz, J=7.0 Hz), 7.61-7.71 (2 H, m), 3.65 (2 H, s), 2.75-2.96 (4 H, m), 2.60-2.75 (4 H, m), 2.55 (3 H, s).

实施例 84

Example 84

除了用 6-溴烟酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 6-bromonicotinic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 530； ^XHNMR [(400MHz, CDC1₃)] :5 9.25 (1 H, s), 9.19 (1 H, d, J=2.4 Hz), 8.80 (1 H: s), 8.65 (1 H, s), 8.28-8.38 (2 H, m), 8.03 (1 H, d, J=8.0 Hz), 7.88-7.97 (2 H, m), 7.73-7.87 (3 H: m), 7.70 (1 H, t, J=7.0 Hz), 3.64 (2 H, s), 2.38-2.63 (8 H, m), 2.34 (3 H, s). 实施例 85

[M+1] : 530; ^X HNMR [(400MHz, CDC1 ₃ )] : 5 9.25 (1 H, s), 9.19 (1 H, d, J = 2.4 Hz), 8.80 (1 H: s), 8.65 (1 H, s), 8.28-8.38 (2 H, m), 8.03 (1 H, d, J=8.0 Hz), 7.88-7.97 (2 H, m), 7.73-7.87 (3 H: m), 7.70 (1 H, t, J=7.0 Hz), 3.64 (2 H, s), 2.38-2.63 (8 H, m), 2.34 (3 H, s). Example 85

除了用 2-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 2-chloropyrimidine-4-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 531； ^XHNMR [(400MHz, c -DMSO)]:5 11.15 (1 H, s), 10.41 (1 H, s), 9.56 (1 H, s), 9.21 (1 H, d, J=5.0 Hz), 8.25-8.41 (3 H, m), 8.20 (1 H, d, J=8.8 Hz), 8.13 (1 H, d, J=5.0 Hz), 8.03 (1 H, t, J=8.0 Hz), 7.85 (1 H, t, J=7.3 Hz), 7.74 (1 H, d, J=8.5 Hz), 3.64 (2 H, s), 3.15-3.49 (8 H, m), 2.61 (3 H, s). [M+1] : 531; ^X HNMR [(400MHz, c - DMSO)]: 5 11.15 (1 H, s), 10.41 (1 H, s), 9.56 (1 H, s), 9.21 (1 H, d, J=5.0 Hz), 8.25-8.41 (3 H, m), 8.20 (1 H, d, J=8.8 Hz), 8.13 (1 H, d, J=5.0 Hz), 8.03 (1 H, t , J=8.0 Hz), 7.85 (1 H, t, J=7.3 Hz), 7.74 (1 H, d, J=8.5 Hz), 3.64 (2 H, s), 3.15-3.49 (8 H, m) , 2.61 (3 H, s).

实施例 86

Example 86

除了用 4-氯嘧啶 -2-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 4-chloropyrimidine-2-carboxylic acid was used instead of 3-iodo-4-methylbenzoic acid.

[M+1] : 531； ^XHNMR [(400MHz, c -DMSO)]:5 11.11 (1 H, s), 10.39 (1 H, s), 9.53 (1 H, s), 9.18 (1 H, d, J=5.1 Hz), 8.23-8.40 (3 H, m), 8.18 (1 H, d, J=8.6 Hz), 8.11 (1 H, d, J=5.1 Hz), 8.02 (1 H, t, J=7.8 Hz), 7.84 (1 H, t, J=7.2 Hz), 7.73 (1 H, d, J=8.4 Hz), 3.62 (2 H, s), 3.12-3.45 (8 H, m), 2.63 (3 H, s). [M+1] : 531; ^X HNMR [(400MHz, c - DMSO)]: 5 11.11 (1 H, s), 10.39 (1 H, s), 9.53 (1 H, s), 9.18 (1 H, d, J=5.1 Hz), 8.23-8.40 (3 H, m), 8.18 (1 H, d, J=8.6 Hz), 8.11 (1 H, d, J=5.1 Hz), 8.02 (1 H, t , J=7.8 Hz), 7.84 (1 H, t, J=7.2 Hz), 7.73 (1 H, d, J=8.4 Hz), 3.62 (2 H, s), 3.12-3.45 (8 H, m) , 2.63 (3 H, s).

实施例 87

Example 87

除了用 6-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 6-chloropyrimidine-4-carboxylic acid was used instead of 3-iodo-4-methylbenzoic acid.

[M+1] : 531； ^XHNMR [(400MHz, c -DMSO)]:5 11.07 (1 H, s), 10.32 (1 H, s), 9.51 (1 H, s). 9.43 (1 H, s), 8.61 (1 H, s), 8.21-8.42 (3 H, m), 8.15 (1 H, d, J=8.4 Hz), 8.01 (1 H, t, J=7.8 Hz) 7.83 (1 H, t, J=7.5 Hz), 7.71 (1 H, d, J=8.4 Hz), 3.65 (2 H, s), 3.11-3.43 (8 H, m), 2.65 (3 H, s). 实施例 88

[M+1] : 531; ^X HNMR [(400MHz, c - DMSO)]: 5 11.07 (1 H, s), 10.32 (1 H, s), 9.51 (1 H, s). 9.43 (1 H, s), 8.61 (1 H, s), 8.21-8.42 (3 H, m), 8.15 (1 H, d, J=8.4 Hz), 8.01 (1 H, t, J=7.8 Hz) 7.83 (1 H , t, J=7.5 Hz), 7.71 (1 H, d, J=8.4 Hz), 3.65 (2 H, s), 3.11-3.43 (8 H, m), 2.65 (3 H, s). 88

除了用 6-氯咪唑骈 [1,2-A]嘧啶代替 4-溴异喹啉，用 2-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 In addition to using 6-chloroimidazolium [1,2-A]pyrimidine instead of 4-bromoisoquinoline and 2-chloropyrimidine-4-carboxylic acid instead of 3-iodo-4-methylbenzoic acid, the synthesis method is carried out as example 1.

[M+1] : 521； ^XHNMR [(400MHz, c -DMSO)]:5 11.03 (1 H, s), 9.21 (1 H, d, J=5.2 Hz), 9.08 (2 H, s), 8.42 (1 H, d, J=5.2 Hz), 8.17 (1 H, s), 7.73 (1 H, d, J=8.1 Hz), 7.13-7.25 (2 H, m), 7.05 (1 H, d, J=7.2 Hz), 3.67 (2 H, s), 3.07-3.41 (8 H, m), 2.62 (3 H, s). 实施例 89

[M+1] : 521; ^X HNMR [(400MHz, c - DMSO)]: 5 11.03 (1 H, s), 9.21 (1 H, d, J = 5.2 Hz), 9.08 (2 H, s), 8.42 (1 H, d, J=5.2 Hz), 8.17 (1 H, s), 7.73 (1 H, d, J=8.1 Hz), 7.13-7.25 (2 H, m), 7.05 (1 H, d , J=7.2 Hz), 3.67 (2 H, s), 3.07-3.41 (8 H, m), 2.62 (3 H, s). Example 89

除了用 6-溴 -4-氢-咪唑骈 [4,5-B]吡啶代替 4-溴异喹啉，用 2-氯嘧啶 -4-羧酸代替 3-碘 -4- 甲基苯甲酸以外，合成方法如实施例 1。 In addition to using 4-bromo-4-hydro-imidazolium [4,5-B]pyridine instead of 4-bromoisoquinoline, 2-chloropyrimidine-4-carboxylic acid instead of 3-iodo-4-methylbenzoic acid The synthesis method is as in Example 1.

[M+1] : 521； ^XHNMR [(400MHz, c -DMSO)]:511.33 (1 H, s), 10.97 (1 H, s), 9.23 (1 H, d, J=5.2 Hz), 9.01 (1 H, s), 8.55 (1 H, s), 8.41 (1 H, d, J=5.2 Hz), 8.16 (1 H, s), 8.06 (1 H, s), 7.75 (1 H_: d, J=8.1 Hz), 7.15 (1 H, d, J=8.1 Hz), 3.65 (2 H, s), 3.02-3.39 (8 H, m), 2.65 (3 H, s). [M+1] : 521; ^X H NMR [(400MHz, c - DMSO)]: 511.33 (1 H, s), 10.97 (1 H, s), 9.23 (1 H, d, J = 5.2 Hz), 9.01 (1 H, s), 8.55 (1 H, s), 8.41 (1 H, d, J=5.2 Hz), 8.16 (1 H, s), 8.06 (1 H, s), 7.75 (1 H _: d , J=8.1 Hz), 7.15 (1 H, d, J=8.1 Hz), 3.65 (2 H, s), 3.02-3.39 (8 H, m), 2.65 (3 H, s).

实施例 90

Example 90

除了用 6-溴 [1,2,4]三氮唑骈 [1,5-A]嘧啶代替 4-溴异喹啉，用 2-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 In addition to 6-bromo[1,2,4]triazolium [1,5-A]pyrimidine instead of 4-bromoisoquinoline, 2-chloropyrimidine-4-carboxylic acid instead of 3-iodo-4-methyl In addition to the benzoic acid, the synthesis method is as in Example 1.

[M+1] : 522； ^XHNMR [(400MHz, c -DMSO)]:5 11.07 (1 H, s), 9.31 (1 H, d, J=5.1 Hz), 9.07 (2 H, s), 8.87 (1 H, s), 8.42 (1 H, d, J=5.2 Hz), 8.17 (1 H, s), 7.73 (1 H, d, J=8.1 Hz), 7.18 (1 H, d, J=8.2 Hz), 3.67 (2 H, s), 3.07-3.41 (8 H, m), 2.62 (3 H, s). [M+1] : 522; ^X HNMR [(400MHz, c - DMSO)]: 5 11.07 (1 H, s), 9.31 (1 H, d, J = 5.1 Hz), 9.07 (2 H, s), 8.87 (1 H, s), 8.42 (1 H, d, J=5.2 Hz), 8.17 (1 H, s), 7.73 (1 H, d, J=8.1 Hz), 7.18 (1 H, d, J =8.2 Hz), 3.67 (2 H, s), 3.07-3.41 (8 H, m), 2.62 (3 H, s).

实施例 91

Example 91

除了用 6-溴吡唑骈 [1,5-A]嘧啶代替 4-溴异喹啉，用 2-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 In addition to using 6-bromopyrazolium [1,5-A]pyrimidine instead of 4-bromoisoquinoline, 2-chloropyrimidine-4-carboxylic acid instead of 3-iodo-4-methylbenzoic acid, the synthesis method is as follows Example 1.

[M+1] : 521； ^XHNMR [(400MHz, c -DMSO)]:5 11.03 (1 H, s), 9.33 (1 H, d, J=5.1 Hz), 9.09 (2 H, s), 8.45 (1 H, d, J=5.2 Hz), 8.15 (1 H, s), 7.71 (1 H, d, J=8.2 Hz), 7.62 (1 H, d, J=7.8 Hz), 7.19 (1 H, d, J=8.2 Hz), 6.69 (1 H, d, J=7.8 Hz), 3.67 (2 H, s), 3.05-3.39 (8 H, m), 2.65 (3 H, s). [M+1] : 521; ^X HNMR [(400MHz, c - DMSO)]: 5 11.03 (1 H, s), 9.33 (1 H, d, J = 5.1 Hz), 9.09 (2 H, s), 8.45 (1 H, d, J=5.2 Hz), 8.15 (1 H, s), 7.71 (1 H, d, J=8.2 Hz), 7.62 (1 H, d, J=7.8 Hz), 7.19 (1 H, d, J = 8.2 Hz), 6.69 (1 H, d, J = 7.8 Hz), 3.67 (2 H, s), 3.05-3.39 (8 H, m), 2.65 (3 H, s).

实施例 92

Example 92

除了用 5-溴 -7-氮杂吲哚代替 4-溴异喹啉，用 2-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 [M+1] : 520； ¾NMR [(400MHz, c -DMSO)] :51 1.31 (1 H, s), 10.96 (1 H, s), 9.23 (1 H, d, J=5.2 Hz), 8.89 (1 H, s), 8.41 (1 H, d, J=5.2 Hz), 8.16 (1 H, s), 8.06 (1 H, s), 7.75 (1 H, d, J=8.1 Hz) 7.55 (1 H, d, J=3.1 Hz), 7.15 (1 H, d, J=8.1 Hz), 6.63 (1 H, d, J=3.1 Hz), 3.62 (2 H, s), 3.03-3.37 (8 H, m), 2.63 (3 H, s). The synthesis was carried out in the same manner as in Example 1, except that 5-bromo-7-azaindole was used in place of 4-bromoisoquinoline, and 2-chloropyrimidine-4-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid. [M+1] : 520; 3⁄4 NMR [(400MHz, c-DMSO)]: 51 1.31 (1 H, s), 10.96 (1 H, s), 9.23 (1 H, d, J = 5.2 Hz), 8.89 (1 H, s), 8.41 (1 H, d, J=5.2 Hz), 8.16 (1 H, s), 8.06 (1 H, s), 7.75 (1 H, d, J=8.1 Hz) 7.55 ( 1 H, d, J=3.1 Hz), 7.15 (1 H, d, J=8.1 Hz), 6.63 (1 H, d, J=3.1 Hz), 3.62 (2 H, s), 3.03-3.37 (8 H, m), 2.63 (3 H, s).

实施例 93 Example 93

除了用 5-溴 -7-氮杂氧化吲哚代替 4-溴异喹啉，用 2-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method is as in Example 1, except that 5-bromo-7-azaphosphorium is used instead of 4-bromoisoquinoline, and 2-chloropyrimidine-4-carboxylic acid is used instead of 3-iodo-4-methylbenzoic acid. .

[M+1] : 536； ^XHNMR [(400MHz, c -DMSO)] :51 1.37 (1 H, s), 10.97 (1 H, s), 9.27 (1 H, d, J=5.2 Hz), 8.87 (1 H, s), 8.43 (1 H, d, J=5.2 Hz), 8.16 (1 H, s), 7.86 (1 H, s), 7.73 (1 H, d, J=8.3 Hz) 7.19 (1 H, d, J=8.3 Hz), 3.72 (2 H, s), 3.62 (2 H, s), 3.01 -3.35 (8 H, m), 2.65 (3 H, s). [M+1] : 536; ^X HNMR [(400MHz, c - DMSO)]: 51 1.37 (1H, s), 10.97 (1 H, s), 9.27 (1 H, d, J = 5.2 Hz), 8.87 (1 H, s), 8.43 (1 H, d, J=5.2 Hz), 8.16 (1 H, s), 7.86 (1 H, s), 7.73 (1 H, d, J=8.3 Hz) 7.19 (1 H, d, J=8.3 Hz), 3.72 (2 H, s), 3.62 (2 H, s), 3.01 -3.35 (8 H, m), 2.65 (3 H, s).

实施例 94 Example 94

除了用 5-溴 -2,3-二氢 -1H-吡咯骈 [2,3-B]吡啶代替 4-溴异喹啉，用 2-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 In place of 5-bromo-2,3-dihydro-1H-pyrrole[2,3-B]pyridine instead of 4-bromoisoquinoline, 2-chloropyrimidine-4-carboxylic acid was used instead of 3-iodo-4- In addition to methylbenzoic acid, the synthesis method is as in Example 1.

[M+1] : 522； ^XHNMR [(400MHz, c -DMSO)] :51 1.39 (1 H, s), 10.91 (1 H, s), 9.29 (1 H, d, J=5.2 Hz), 8.43 (1 H, d, J=5.2 Hz), 8.33 (1 H, s), 8.12 (1 H, s), 7.71 (1 H, d, J=8.2 Hz), 7.43 (1 H, s)_: 7.18 (1 H, d, J=8.2 Hz), 3.62 (2 H, s), 3.58 (2 H, m), 3.01-3.35 (10 H, m), 2.61 (3 H, s). [M+1] : 522; ^X HNMR [(400MHz, c - DMSO)]: 51 1.39 (1H, s), 10.91 (1 H, s), 9.29 (1 H, d, J = 5.2 Hz), 8.43 (1 H, d, J=5.2 Hz), 8.33 (1 H, s), 8.12 (1 H, s), 7.71 (1 H, d, J=8.2 Hz), 7.43 (1 H, s) _: 7.18 (1 H, d, J = 8.2 Hz), 3.62 (2 H, s), 3.58 (2 H, m), 3.01-3.35 (10 H, m), 2.61 (3 H, s).

除了用 2-溴呋喃 -5-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 2-bromofuran-5-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+l] : 519; ^XHNMR [(400MHz, CD₃OD)] :5 9.24 (1 H, s), 8.66 (1 H, s), 8.28 (1 H, J=9.1 Hz), 8.10-8.19 (2 H, m), 7.93 (1 H, t, J=7.1 Hz), 7.83 (1 H, t, J=7.5 Hz), 7.79 (1 H, d, J=8.0 Hz), 7.73 (1 H, d, J=9.0 Hz), 7.35 (1 H, d, J=3.6 Hz), 7.05 (1 H, d, J=3.6 Hz), 3.63 (2 H, s), 2.37-2.67 (8 H, m), 2.29 (3 H, s). [M+l] : 519; ^X HNMR [(400MHz, CD ₃ OD)] : 5 9.24 (1 H, s), 8.66 (1 H, s), 8.28 (1 H, J = 9.1 Hz), 8.10- 8.19 (2 H, m), 7.93 (1 H, t, J=7.1 Hz), 7.83 (1 H, t, J=7.5 Hz), 7.79 (1 H, d, J=8.0 Hz), 7.73 (1 H, d, J=9.0 Hz), 7.35 (1 H, d, J=3.6 Hz), 7.05 (1 H, d, J=3.6 Hz), 3.63 (2 H, s), 2.37-2.67 (8 H , m), 2.29 (3 H, s).

实施例 96

Example 96

除了用 2-溴噻唑 -5-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 2-bromothiazole-5-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 536； ^XHNMR [(400MHz, c -DMSO)]:5 10.93 (1 H, s), 9.27 (1 H, s), 8.71 (1 H, s), 8.43 (1 H, s), 8.31 (1 H, d, J=8.9 Hz), 8.12-8.21 (2 H, m), 7.91 (1 H, t, J=7.4 Hz), 7.82 (1 H, t, J=7.5 Hz), 7.76 (1 H, d, J=8.2 Hz), 7.71 (1 H, d, J=8.8 Hz), 3.65 (2 H, s), 2.71-3.01 (8 H, m), 2.26 (3 H, s). [M+1] : 536; ^X HNMR [(400MHz, c - DMSO)]: 5 10.93 (1 H, s), 9.27 (1 H, s), 8.71 (1 H, s), 8.43 (1 H, s), 8.31 (1 H, d, J=8.9 Hz), 8.12-8.21 (2 H, m), 7.91 (1 H, t, J=7.4 Hz), 7.82 (1 H, t, J=7.5 Hz) ), 7.76 (1 H, d, J=8.2 Hz), 7.71 (1 H, d, J=8.8 Hz), 3.65 (2 H, s), 2.71-3.01 (8 H, m), 2.26 (3 H , s).

实施例 97

Example 97

除了用 2-溴噁唑 -5-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis was carried out in the same manner as in Example 1 except that 2-bromooxazolyl-5-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 520； ^XHNMR [(400MHz, c -DMSO)]:5 10.99 (1 H, s), 9.33 (1 H, s), 8.81 (1 H, s), 8.49 (1 H, s), 8.33 (1 H, d, J=8.7 Hz), 8.13-8.25 (2 H, m), 7.97 (1 H, t, J=7.6 Hz), 7.85 (1 H, t, J=7.6 Hz), 7.71 (1 H, d, J=8.1 Hz), 7.70 (1 H, d, J=8.7 Hz), 3.67 (2 H, s), 2.75-3.06 (8 H, m), 2.21 (3 H, s). [M+1] : 520; ^X HNMR [(400MHz, c - DMSO)]: 5 10.99 (1 H, s), 9.33 (1 H, s), 8.81 (1 H, s), 8.49 (1 H, s), 8.33 (1 H, d, J=8.7 Hz), 8.13-8.25 (2 H, m), 7.97 (1 H, t, J=7.6 Hz), 7.85 (1 H, t, J=7.6 Hz) ), 7.71 (1 H, d, J=8.1 Hz), 7.70 (1 H, d, J=8.7 Hz), 3.67 (2 H, s), 2.75-3.06 (8 H, m), 2.21 (3 H , s).

实施例 98

Example 98

除了用 3-碘苯甲酸代替 3-碘 -4-甲基苯甲酸，用 4-溴 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method is as follows except that 3-iodobenzoic acid is used instead of 3-iodo-4-methylbenzoic acid, and 4-bromo-1 hydrogen-pyrrole [2,3-c]pyridine is used instead of 4-bromoisoquinoline. example 1.

[M+1] : 518； ^XHNMR [(400MHz, c -DMSO)]:5 12.38 (1 H, s), 10.71 (1 H, s), 8.82 (1 H, s), 8.49 (1 H, s), 8.21-8.26 (2 H, m), 8.07 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.93 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.76 (1 H, s), 7.65-7.71 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 6.68 (1 H, d, J=2.8 Hz), 3.57 (2 H, s), 2.73-3.15 (8 H, m), 2.63 (3 H, s). [M+1] : 518; ^X HNMR [(400MHz, c - DMSO)]: 5 12.38 (1 H, s), 10.71 (1 H, s), 8.82 (1 H, s), 8.49 (1 H, s), 8.21-8.26 (2 H, m), 8.07 (1 H, dd, J=1.9 Hz, J=8.6 Hz), 7.93 (1 H, dd, J=1.9 Hz, J=8.0 Hz), 7.76 (1 H, s), 7.65-7.71 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 6.68 (1 H, d, J=2.8 Hz), 3.57 (2 H, s) , 2.73-3.15 (8 H, m), 2.63 (3 H, s).

实施例 99

Example 99

除了用吗啉代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that morpholine was used instead of N-methylpiperazine.

[M+1] : 530； ^XHNMR [(400MHz, c -DMSO)]:5 10.77 (1 H, s), 9.51 (1 H, s), 8.95 (1 H, s), 8.43 (1 H, d, J=8.1 Hz), 8.23-8.34 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.3 Hz), 8.02 (1 H, d, J=8.1 Hz), 7.81-7.96 (2 H, m), 7.58 (1 H, d, J=8.2 Hz), 3.78 (2 H, s), 3.62-3.72 (4 H, m), 2.63-2.75 (4 H, m), 2.35 (3 H, s). [M+1] : 530; ^X HNMR [(400MHz, c - DMSO)]: 5 10.77 (1 H, s), 9.51 (1 H, s), 8.95 (1 H, s), 8.43 (1 H, d, J=8.1 Hz), 8.23-8.34 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.3 Hz), 8.02 ( 1 H, d, J=8.1 Hz), 7.81-7.96 (2 H, m), 7.58 (1 H, d, J=8.2 Hz), 3.78 (2 H, s), 3.62-3.72 (4 H, m ), 2.63-2.75 (4 H, m), 2.35 (3 H, s).

实施例 100

Example 100

除了用六氢吡啶代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that hexahydropyridine was used in place of N-methylpiperazine.

[M+l] : 528 ; ^XHNMR [(400MHz, c -DMSO)] : δ 10.73 (1 H, s), 9.49 (1 H, s), 8.89 (1 H, s), 8.41 (1 H, d, J=8.2 Hz), 8.22-8.31 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.02 (1 H, t, J=7.5 Hz), 8.01 (1 H, d, J=8.2 Hz), 7.80-7.95 (2 H, m), 7.55 (1 H, d, J=8.1 Hz), 3.77 (2 H, s), 2.62-2.72 (4 H, m), 2.31 (3 H_: s), 1.63-1.75 (6 H, m). [M+l] : 528 ; ^X H NMR [(400MHz, c - DMSO)] : δ 10.73 (1 H, s), 9.49 (1 H, s), 8.89 (1 H, s), 8.41 (1 H, d, J=8.2 Hz), 8.22-8.31 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.02 (1 H, t, J=7.5 Hz), 8.01 (1 H, d , J=8.2 Hz), 7.80-7.95 (2 H, m), 7.55 (1 H, d, J=8.1 Hz), 3.77 (2 H, s), 2.62-2.72 (4 H, m), 2.31 ( 3 H _: s), 1.63-1.75 (6 H, m).

实施例 101

Example 101

除了用 1-Boc-哌嗪代替 N-甲基哌嗪以外，合成方法如实施例 1，得到的产物以二氯甲垸为溶剂，加入 0.3当量的三氟醋酸，室温搅拌 3小时脱除 Boc保护基，得到最终产物。 In addition to 1-Boc-piperazine instead of N-methylpiperazine, the synthesis method was as in Example 1, and the obtained product was added with 0.3 equivalent of trifluoroacetic acid as a solvent, and stirred at room temperature for 3 hours to remove Boc. Protect the group to give the final product.

[M+l] : 529; ^XHNMR [(400MHz, c -DMSO)] : δ 10.75 (1 H, s), 9.47 (1 H, s), 8.83 (1 H, s), 8.43 (1 H, d, J=8.2 Hz), 8.22-8.33 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.02 (1 H, t, J=7.5 Hz), 8.01 (1 H, d, J=8.2 Hz), 7.80-7.95 (3 H, m), 7.55 (1 H, d, J=8.1 Hz), 3.77 (2 H, s), 2.81-2.93 (4 H, m), 2.61-2.70 (4 H, m)2.31 (3 H, s). [M+l] : 529; ^X HNMR [(400MHz, c - DMSO)] : δ 10.75 (1 H, s), 9.47 (1 H, s), 8.83 (1 H, s), 8.43 (1 H, d, J=8.2 Hz), 8.22-8.33 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.02 (1 H, t, J=7.5 Hz), 8.01 (1 H, d , J=8.2 Hz), 7.80-7.95 (3 H, m), 7.55 (1 H, d, J=8.1 Hz), 3.77 (2 H, s), 2.81-2.93 (4 H, m), 2.61- 2.70 (4 H, m) 2.31 (3 H, s).

实施例 102

Example 102

除了用 1H-1,2,3-三氮唑代替 N-甲基哌嗪以夕卜，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 1H-1,2,3-triazole was used in place of N-methylpiperazine.

[M+l] : 512; ^XHNMR [(400MHz, c -DMSO)] : δ 10.73 (1 H, s), 9.43 (1 H, s), 8.81 (1 H, s), 8.45 (1 H, d, J=8.1 Hz), 8.21-8.30 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.02 (1 H, t, J=7.6 Hz), 8.01 (1 H, d, J=8.2 Hz), 7.80-7.95 (2 H, m), 7.75 (1 H, d, J=7.4 Hz), 7.65 (1 H, d, J=7.4 Hz), 7.55 (1 H, d, J=8.1 Hz), 5.57 (2 H, s), 2.28 (3 H, s). [M+l] : 512; ^X H NMR [(400MHz, c - DMSO)] : δ 10.73 (1 H, s), 9.43 (1 H, s), 8.81 (1 H, s), 8.45 (1 H, d, J=8.1 Hz), 8.21-8.30 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.02 (1 H, t, J=7.6 Hz), 8.01 (1 H, d , J=8.2 Hz), 7.80-7.95 (2 H, m), 7.75 (1 H, d, J=7.4 Hz), 7.65 (1 H, d, J=7.4 Hz), 7.55 (1 H, d, J=8.1 Hz), 5.57 (2 H, s), 2.28 (3 H, s).

实施例 103

除了用四氢吡咯代替 N-甲基哌嗪以外，合成方法如实施例 1。 Example 103

The synthesis method was as in Example 1, except that tetrahydropyrrole was used in place of N-methylpiperazine.

[M+l] : 514; ^XHNMR [(400MHz, c -DMSO)]: δ 10.75 (1 H, s), 9.42 (1 H, s), 8.80 (1 H, s), 8.47 (1 H, d, J=8.2 Hz), 8.22-8.32 (3 H, m), 8.15 (1 H, d, J=7.4 Hz), 8.01 (1 H, t, J=7.4 Hz), 7.99 (1 H, d, J=8.2 Hz), 7.81-7.93 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 3.77 (2 H, s), 2.62-2.76 (4 H, m), 2.28 (3 H_: s), 1.71-1.86 (4 H, m). [M+l] : 514; ^X HNMR [(400MHz, c - DMSO)]: δ 10.75 (1 H, s), 9.42 (1 H, s), 8.80 (1 H, s), 8.47 (1 H, d, J=8.2 Hz), 8.22-8.32 (3 H, m), 8.15 (1 H, d, J=7.4 Hz), 8.01 (1 H, t, J=7.4 Hz), 7.99 (1 H, d , J=8.2 Hz), 7.81-7.93 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 3.77 (2 H, s), 2.62-2.76 (4 H, m), 2.28 ( 3 H _: s), 1.71-1.86 (4 H, m).

实施例 104

Example 104

除了用吡咯代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that pyrrole was used instead of N-methylpiperazine.

[M+l] : 510; ^XHNMR [(400MHz, c -DMSO)]: δ 10.77 (1 H, s), 9.45 (1 H, s), 8.80 (1 H, s), 8.41 (1 H, d, J=8.3 Hz), 8.23-8.35 (3 H, m), 8.15 (1 H, d, J=7.7 Hz), 8.07 (1 H, t, J=7.5 Hz), 8.03 (1 H, d, J=8.4 Hz), 7.83-7.97 (2 H, m), 7.55 (1 H, d, J=8.1 Hz), 7.43 (2 H, d, J=7.3 Hz), 6.55 (2 H, d, J=7.3 Hz), 5.51 (2 H, s), 2.23 (3 H, s). [M+l] : 510; ^X H NMR [(400MHz, c - DMSO)]: δ 10.77 (1 H, s), 9.45 (1 H, s), 8.80 (1 H, s), 8.41 (1 H, d, J=8.3 Hz), 8.23-8.35 (3 H, m), 8.15 (1 H, d, J=7.7 Hz), 8.07 (1 H, t, J=7.5 Hz), 8.03 (1 H, d , J=8.4 Hz), 7.83-7.97 (2 H, m), 7.55 (1 H, d, J=8.1 Hz), 7.43 (2 H, d, J=7.3 Hz), 6.55 (2 H, d, J=7.3 Hz), 5.51 (2 H, s), 2.23 (3 H, s).

实施例 105

Example 105

除了用咪唑代替 N-甲基哌嗪以夕卜，合成方法如实施例 1。 The synthesis method was as in Example 1, except that imidazole was used instead of N-methylpiperazine.

[M+1] : 511； ^XHNMR [(400MHz, c -DMSO)]: δ 10.79 (1 Η, s), 9.43 (1 Η, s), 8.79 (1 Η, s), 8.43 (1 Η, d, J=8.4 Hz), 8.19-8.32 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.8 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.81-7.95 (2 H, m), 7.71 (1 H, s), 7.52 (1 H, d, J=8.3 Hz), 7.11 (1 H, d, J=7.6 Hz), 6.95 (1 H, d, J=7.7 Hz), 5.53 (2 H, s), 2.19 (3 H, s). [M+1] : 511; ^X HNMR [(400MHz, c -DMSO)]: δ 10.79 (1 Η, s), 9.43 (1 Η, s), 8.79 (1 Η, s), 8.43 (1 Η, d, J=8.4 Hz), 8.19-8.32 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.8 Hz), 8.02 (1 H, d , J=8.2 Hz), 7.81-7.95 (2 H, m), 7.71 (1 H, s), 7.52 (1 H, d, J=8.3 Hz), 7.11 (1 H, d, J=7.6 Hz) , 6.95 (1 H, d, J=7.7 Hz), 5.53 (2 H, s), 2.19 (3 H, s).

实施例 106

Example 106

除了用吡唑代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that pyrazole was used instead of N-methylpiperazine.

[M+1] : 511； ^XHNMR [(400MHz, c -DMSO)]: δ 10.81 (1 Η, s), 9.45 (1 Η, s), 8.81 (1 Η, s), 8.45 (1 Η, d, J=8.3 Hz), 8.21-8.33 (3 H, m), 8.17 (1 H, d, J=7.5 Hz), 8.07 (1 H, t, J=7.6 Hz), 8.01 (1 H, d, J=8.3 Hz), 7.81-7.95 (3 H, m), 7.52 (1 H, d, J=8.3 Hz), 7.33 (1 H, d, J=7.5 Hz), 6.35 (1 H, m), 5.53 (2 H, s), 2.29 (3 H, s). [M+1] : 511; ^X HNMR [(400MHz, c -DMSO)]: δ 10.81 (1 Η, s), 9.45 (1 Η, s), 8.81 (1 Η, s), 8.45 (1 Η, d, J=8.3 Hz), 8.21-8.33 (3 H, m), 8.17 (1 H, d, J=7.5 Hz), 8.07 (1 H, t, J=7.6 Hz), 8.01 (1 H, d , J=8.3 Hz), 7.81-7.95 (3 H, m), 7.52 (1 H, d, J=8.3 Hz), 7.33 (1 H, d, J=7.5 Hz), 6.35 (1 H, m) , 5.53 (2 H, s), 2.29 (3 H, s).

实施例 107

Example 107

除了用 4-甲基吡唑代替 N-甲基哌嗪以夕卜，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 4-methylpyrazole was used in place of N-methylpiperazine.

[M+l] : 525 ; ^XHNMR [(400MHz, c -DMSO)]: δ 10.83 (1 H, s), 9.43 (1 H, s), 8.80 (1 H, s), 8.43 (1 H, d, J=8.4 Hz), 8.22-8.35 (3 H, m), 8.16 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.6 Hz), 8.02 (1 H, d, J=8.4 Hz), 7.79-7.93 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 7.45 (1 H, s), 7.27 (1 H, s), 5.49 (2 H, s), 2.27 (3 H, s), 2.07 (3 H, s). [M+l] : 525 ; ^X H NMR [(400MHz, c - DMSO)]: δ 10.83 (1 H, s), 9.43 (1 H, s), 8.80 (1 H, s), 8.43 (1 H, d, J=8.4 Hz), 8.22-8.35 (3 H, m), 8.16 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.6 Hz), 8.02 (1 H, d , J=8.4 Hz), 7.79-7.93 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 7.45 (1 H, s), 7.27 (1 H, s), 5.49 (2 H , s), 2.27 (3 H, s), 2.07 (3 H, s).

实施例 108

Example 108

除了用高哌啶代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that high piperidine was used in place of N-methylpiperazine.

[M+l] : 542; ^XHNMR [(400MHz, c -DMSO)]: δ 10.75 (1 H, s), 9.45 (1 H, s), 8.87 (1 H, s), 8.45 (1 H, d, J=8.3 Hz), 8.23-8.32 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.6 Hz), 8.02 (1 H, d, J=8.4 Hz), 7.81-7.93 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 3.78 (2 H, s), 2.92-3.01 (4 H, m), 2.27 (3 H: s), 1.67-1.85 (8 H, m). [M+l] : 542; ^X HNMR [(400MHz, c - DMSO)]: δ 10.75 (1 H, s), 9.45 (1 H, s), 8.87 (1 H, s), 8.45 (1 H, d, J=8.3 Hz), 8.23-8.32 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.05 (1 H, t, J=7.6 Hz), 8.02 (1 H, d , J=8.4 Hz), 7.81-7.93 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 3.78 (2 H, s), 2.92-3.01 (4 H, m), 2.27 ( 3 H: s), 1.67-1.85 (8 H, m).

实施例 109

Example 109

除了用 1-Boc-高哌嗪代替 N-甲基哌嗪以外，合成方法如实施例 1，得到的产物以二氯甲垸为溶剂，加入 0.3当量的三氟醋酸，室温搅拌 3小时脱除 Boc保护基，得到最终产物。 In addition to using 1-Boc-homopiperazine instead of N-methylpiperazine, the synthesis method was as in Example 1, and the obtained product was added with 0.3 equivalent of trifluoroacetic acid as a solvent, and stirred at room temperature for 3 hours. The Boc protecting group gives the final product.

[M+l] : 543 ; ^XHNMR [(400MHz, c -DMSO)]: δ 10.77 (1 H, s), 9.43 (1 H, s), 8.83 (1 H, s), 8.41 (1 H, d, J=8.2 Hz), 8.20-8.33 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.06 (1 H, t, J=7.8 Hz), 8.01 (1 H, d, J=8.3 Hz), 7.80-7.91 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 7.37 (1 H, s), 3.75 (2 H, s), 3.11 (2 H, t, J=7.4 Hz), 2.42-2.71 (6 H, m), 2.20 (3 H, s), 1.60-1.72 (2 H, m). [M+l] : 543 ; ^X H NMR [(400MHz, c - DMSO)]: δ 10.77 (1 H, s), 9.43 (1 H, s), 8.83 (1 H, s), 8.41 (1 H, d, J=8.2 Hz), 8.20-8.33 (3 H, m), 8.13 (1 H, d, J=7.5 Hz), 8.06 (1 H, t, J=7.8 Hz), 8.01 (1 H, d , J=8.3 Hz), 7.80-7.91 (2 H, m), 7.53 (1 H, d, J=8.3 Hz), 7.37 (1 H, s), 3.75 (2 H, s), 3.11 (2 H , t, J=7.4 Hz), 2.42-2.71 (6 H, m), 2.20 (3 H, s), 1.60-1.72 (2 H, m).

实施例 110

Example 110

除了用氮杂环丁垸代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that azetidinium was used in place of N-methylpiperazine.

[M+1] : 542； 1HNMR [(400MHz, d-DMSO)]: δ 10.71 (1 H, s), 9.43 (1 Η, s), 8.85 (1 Η, s), 8.42 (1 Η, d, J=8.2 Hz), 8.25-8.37 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.8 Hz), 8.03 (1 H, d, J=8.3 Hz), 7.73-7.85 (2 H, m), 7.55 (1 H, d, J=8.2 Hz), 3.73 (2 H, s), 3.31 (4 H, t, J=7.0 Hz), 2.23 (5 H, m). [M+1] : 542; 1HNMR [(400MHz, d-DMSO)]: δ 10.71 (1 H, s), 9.43 (1 Η, s), 8.85 (1 Η, s), 8.42 (1 Η, d , J=8.2 Hz), 8.25-8.37 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.8 Hz), 8.03 (1 H, d, J=8.3 Hz), 7.73-7.85 (2 H, m), 7.55 (1 H, d, J=8.2 Hz), 3.73 (2 H, s), 3.31 (4 H, t, J=7.0 Hz), 2.23 (5 H, m).

实施例 111

Example 111

除了用硫代吗啉代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that thiomorpholine was used in place of N-methylpiperazine.

[M+1] : 546； ^XHNMR [(400MHz, c -DMSO)]:5 10.79 (1 H, s), 9.52 (1 H, s), 8.93 (1 H, s), 8.45 (1 H, d, J=8.2 Hz), 8.24-8.37 (3 H, m), 8.17 (1 H, d, J=7.4 Hz), 8.07 (1 H, t, J=7.4 Hz), 8.01 (1 H, d, J=8.3 Hz), 7.83-7.97 (2 H, m), 7.59 (1 H, d, J=8.4 Hz), 3.73 (2 H, s), 2.63-2.75 (4 H, m), 2.42-2.55 (4 H, m), 2.32 (3 H, s). [M+1] : 546; ^X HNMR [(400MHz, c - DMSO)]: 5 10.79 (1 H, s), 9.52 (1 H, s), 8.93 (1 H, s), 8.45 (1 H, d, J=8.2 Hz), 8.24-8.37 (3 H, m), 8.17 (1 H, d, J=7.4 Hz), 8.07 (1 H, t, J=7.4 Hz), 8.01 (1 H, d , J=8.3 Hz), 7.83-7.97 (2 H, m), 7.59 (1 H, d, J=8.4 Hz), 3.73 (2 H, s), 2.63-2.75 (4 H, m), 2.42- 2.55 (4 H, m), 2.32 (3 H, s).

实施例 112

Example 112

除了用硫代吗啉 -U-二氧化物代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that thiomorpholine-U-dioxide was used in place of N-methylpiperazine.

[M+1] : 578； ^XHNMR [(400MHz, c -DMSO)]:5 10.77 (1 H, s), 9.53 (1 H, s), 8.91 (1 H, s), 8.43 (1 H, d, J=8.3 Hz), 8.25-8.36 (3 H, m), 8.18 (1 H, d, J=7.5 Hz), 8.08 (1 H, t, J=7.6 Hz), 8.03 (1 H, d, J=8.4 Hz), 7.80-7.93 (2 H, m), 7.55 (1 H, d, J=8.3 Hz), 3.71 (2 H, s), 3.53-3.67 (4 H, m), 2.92-3.05 (4 H, m), 2.28 (3 H, s). [M+1] : 578; ^X H NMR [(400MHz, c - DMSO)]: 5 10.77 (1 H, s), 9.53 (1 H, s), 8.91 (1 H, s), 8.43 (1 H, d, J=8.3 Hz), 8.25-8.36 (3 H, m), 8.18 (1 H, d, J=7.5 Hz), 8.08 (1 H, t, J=7.6 Hz), 8.03 (1 H, d , J=8.4 Hz), 7.80-7.93 (2 H, m), 7.55 (1 H, d, J=8.3 Hz), 3.71 (2 H, s), 3.53-3.67 (4 H, m), 2.92- 3.05 (4 H, m), 2.28 (3 H, s).

实施例 113 Example 113

除了用异噻唑垸 1,1-二氧化物代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that isothiazolium ruthenium 1,1-dioxide was used instead of N-methylpiperazine.

[M+1] : 564； ^XHNMR [(400MHz, c -DMSO)]:5 10.78 (1 H, s), 9.52 (1 H, s), 8.92 (1 H, s), 8.41 (1 H, d, J=8.4 Hz), 8.23-8.35 (3 H, m), 8.17 (1 H, d, J=7.7 Hz), 8.09 (1 H, t, J=7.8 Hz), 8.05 (1 H, d, J=8.3 Hz), 7.81-7.94 (2 H, m), 7.53 (1 H, d, J=8.4 Hz), 3.71 (2 H, s), 3.51 (2 H, t, J=7.0 Hz), 2.62 (2 H, t, J=7.1 Hz), 2.28 (3 H, s), 2.01 (2 H, m). [M+1] : 564; ^X HNMR [(400MHz, c - DMSO)]: 5 10.78 (1 H, s), 9.52 (1 H, s), 8.92 (1 H, s), 8.41 (1 H, d, J=8.4 Hz), 8.23-8.35 (3 H, m), 8.17 (1 H, d, J=7.7 Hz), 8.09 (1 H, t, J=7.8 Hz), 8.05 (1 H, d , J=8.3 Hz), 7.81-7.94 (2 H, m), 7.53 (1 H, d, J=8.4 Hz), 3.71 (2 H, s), 3.51 (2 H, t, J=7.0 Hz) , 2.62 (2 H, t, J=7.1 Hz), 2.28 (3 H, s), 2.01 (2 H, m).

实施例 114

Example 114

除了用四氢异喹啉代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that tetrahydroisoquinoline was used in place of N-methylpiperazine.

[M+1] : 576； ^XHNMR [(400MHz, c -DMSO)]:5 10.75 (1 H, s), 9.53 (1 H, s), 8.91 (1 H, s), 8.43 (1 H, d, J=8.3 Hz), 8.21-8.33 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.08 (1 H, t, J=7.5 Hz), 8.03 (1 H, d, J=8.0 Hz), 7.77-7.90 (2 H, m), 7.42-7.55 (5 H, m), 3.79 (2 H, s), 3.67 (2 H, s), 2.82-2.95 (4 H, m)_: 2.23 (3 H, s). [M+1] : 576; ^X HNMR [(400MHz, c - DMSO)]: 5 10.75 (1 H, s), 9.53 (1 H, s), 8.91 (1 H, s), 8.43 (1 H, d, J=8.3 Hz), 8.21-8.33 (3 H, m), 8.15 (1 H, d, J=7.6 Hz), 8.08 (1 H, t, J=7.5 Hz), 8.03 (1 H, d , J=8.0 Hz), 7.77-7.90 (2 H, m), 7.42-7.55 (5 H, m), 3.79 (2 H, s), 3.67 (2 H, s), 2.82-2.95 (4 H, m ) _: 2.23 (3 H, s).

实施例 115

Example 115

除了用异吲哚啉代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that iso-porphyrin was used in place of N-methylpiperazine.

[M+1] : 562； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 9.57 (1 H, s), 8.93 (1 H, s), 8.45 (1 H, d, J=8.4 Hz), 8.22-8.35 (3 H, m), 8.16 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.8 Hz), 8.02 (1 H, d, J=8.1 Hz), 7.75-7.92 (2 H, m), 7.41-7.53 (5 H, m), 3.79 (2 H, s), 3.67 (4 H, s), 2.26 (3 H, s). [M+1] : 562; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 9.57 (1 H, s), 8.93 (1 H, s), 8.45 (1 H, d, J=8.4 Hz), 8.22-8.35 (3 H, m), 8.16 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.8 Hz), 8.02 (1 H, d , J=8.1 Hz), 7.75-7.92 (2 H, m), 7.41-7.53 (5 H, m), 3.79 (2 H, s), 3.67 (4 H, s), 2.26 (3 H, s) .

实施例 116

Example 116

除了用 4-甲基咪唑代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 4-methylimidazole was used instead of N-methylpiperazine.

[M+l] : 525 ; ^XHNMR [(400MHz, c -DMSO)] : δ 10.85 (1 H, s), 9.40 (1 H, s), 8.81 (1 H, s), 8.41 (1 H, d, J=8.5 Hz), 8.23-8.37 (3 H, m), 8.18 (1 H, d, J=7.8 Hz), 8.09 (1 H, t, J=7.7 Hz), 8.05 (1 H, d, J=8.2 Hz), 7.97 (1 H, s), 7.77-7.91 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 7.07 (1 H, s), 5.45 (2 H, s), 2.31 (3 H, s), 2.23 (3 H, s). [M+l] : 525 ; ^X H NMR [(400MHz, c - DMSO)] : δ 10.85 (1 H, s), 9.40 (1 H, s), 8.81 (1 H, s), 8.41 (1 H, d, J=8.5 Hz), 8.23-8.37 (3 H, m), 8.18 (1 H, d, J=7.8 Hz), 8.09 (1 H, t, J=7.7 Hz), 8.05 (1 H, d , J=8.2 Hz), 7.97 (1 H, s), 7.77-7.91 (2 H, m), 7.51 (1 H, d, J=8.2 Hz), 7.07 (1 H, s), 5.45 (2 H , s), 2.31 (3 H, s), 2.23 (3 H, s).

实施例 117

Example 117

除了用 N-甲基高哌嗪代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that N-methylhomopiperazine was used in place of N-methylpiperazine.

[M+l] : 557 ; ^XHNMR [(400MHz, c -DMSO)] : δ 10.87 (1 H, s), 9.45 (1 H, s), 8.83 (1 H, s), 8.49 (1 H, d, J=8.4 Hz), 8.22-8.35 (3 H, m), 8.19 (1 H, d, J=7.7 Hz), 8.08 (1 H, t, J=7.6 Hz), 8.06 (1 H, d, J=8.3 Hz), 7.76-7.93 (2 H, m), 7.53 (1 H, d, J=8.4 Hz), 3.77 (2 H, s), 3.08-3.13 (4 H, m), 2.45-2.51 (4 H, m), 2.37 (3 H, s), 2.17 (3 H, s), 1.55 (2 H, m). [M+l] : 557 ; ^X H NMR [(400MHz, c - DMSO)] : δ 10.87 (1 H, s), 9.45 (1 H, s), 8.83 (1 H, s), 8.49 (1 H, d, J=8.4 Hz), 8.22-8.35 (3 H, m), 8.19 (1 H, d, J=7.7 Hz), 8.08 (1 H, t, J=7.6 Hz), 8.06 (1 H, d , J=8.3 Hz), 7.76-7.93 (2 H, m), 7.53 (1 H, d, J=8.4 Hz), 3.77 (2 H, s), 3.08-3.13 (4 H, m), 2.45- 2.51 (4 H, m), 2.37 (3 H, s), 2.17 (3 H, s), 1.55 (2 H, m).

实施例 118

Example 118

步骤一： step one:

向圆底烧瓶中加入 l g ( 5 mMol ) 3-硝基 -5-三氟甲基苄醇、 2.7 g ( lO mMol) PBr₃和 20 毫升的甲苯，室温下反应 12 小时；反应结束后减压蒸干溶剂，柱层析得到产物 3-硝基 -5- 三氟甲基苄溴 966 mg (产率： 68%)。 LF (5 mMol) 3-nitro-5-trifluoromethylbenzyl alcohol, 2.7 g (10 mMol) PBr ₃ and 20 ml of toluene were added to the round bottom flask, and reacted at room temperature for 12 hours; Evaporate the solvent and chromatography to give the product 3-nitro-5- Trifluoromethylbenzyl bromide 966 mg (yield: 68%).

步骤二至八同实施例 1 Steps 2 to 8 with the same embodiment 1

[M+1] : 543； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 9.52 (1 H, s), 8.91 (1 H, s), 8.45 (1 H, d, J=8.4 Hz), 8.26-8.37 (3 H, m), 8.17 (1 H, d, J=7.6 Hz), 8.09 (1 H, t, J=7.3 Hz), 8.01 (1 H, s): 7.95 (1 H, t, J=7.4 Hz), 7.77 (1 H, s), 7.52 (1 H, s), 3.77 (2 H, s), 3.03-3.21 (4 H, m), 2.71-2.84 (4 H_: m), 2.66 (3 H, s), 2.43 (3 H, s). [M+1] : 543; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 9.52 (1 H, s), 8.91 (1 H, s), 8.45 (1 H, d, J=8.4 Hz), 8.26-8.37 (3 H, m), 8.17 (1 H, d, J=7.6 Hz), 8.09 (1 H, t, J=7.3 Hz), 8.01 (1 H, s ): 7.95 (1 H, t, J = 7.4 Hz), 7.77 (1 H, s), 7.52 (1 H, s), 3.77 (2 H, s), 3.03-3.21 (4 H, m), 2.71 -2.84 (4 H _: m), 2.66 (3 H, s), 2.43 (3 H, s).

实施例 119

Example 119

除了用 3-碘 -4-氟苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 3-iodo-4-fluorobenzoic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 547； ^XHNMR [(400MHz, c -DMSO)]:5 10.78 (1 H, s), 9.43 (1 H, s), 8.81 (1 H, s), 8.47 (1 H, dd, J=2.2 Hz , J=6.5 Hz), 8.34 (1 H, d, J=8.1 Hz), 8.21-8.29 (2 H, m), 8.15 (1 H, m), 8.10 (1 H, dd, J=1.6 Hz , J=8.2 Hz), 8.02 (1 H, td, J=0.8 Hz, J=6.6 Hz), 7.82 (1 H, s), 7.61 (1 H, t, J=9.0 Hz), 7.50 (1 H, s), 3.65 (2 H, s), 2.71-2.93 (4 H, m), 2.45-2.63 (7 H, m). [M+1] : 547; ^X HNMR [(400MHz, c - DMSO)]: 5 10.78 (1 H, s), 9.43 (1 H, s), 8.81 (1 H, s), 8.47 (1 H, Dd, J=2.2 Hz , J=6.5 Hz), 8.34 (1 H, d, J=8.1 Hz), 8.21-8.29 (2 H, m), 8.15 (1 H, m), 8.10 (1 H, dd , J=1.6 Hz , J=8.2 Hz), 8.02 (1 H, td, J=0.8 Hz, J=6.6 Hz), 7.82 (1 H, s), 7.61 (1 H, t, J=9.0 Hz) , 7.50 (1 H, s), 3.65 (2 H, s), 2.71-2.93 (4 H, m), 2.45-2.63 (7 H, m).

实施例 120

Example 120

除了用 4-溴 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 4-bromo-hydrogen-pyrrole [2,3-c]pyridine was used instead of 4-bromoisoquinoline.

[M+1] : 532； ^XHNMR [(400MHz, c -DMSO)]:5 12.37 (1 H, s), 10.72 (1 H, s), 8.81 (1 H, s), 8.43 (1 H, s), 8.23-8.29 (2 H, m), 8.09 (1 H, dd, J=1.8 Hz, J=8.8 Hz), 7.96 (1 H, dd, J=1.7 Hz, J=8.0 Hz), 7.93 (1 H, s), 7.77 (1 H, s), 7.52 (1 H, s), 6.69 (1 H, d, J=2.8 Hz), 3.59 (2 H, s), 2.71-3.13 (8 H, m), 2.62 (3 H, s), 2.19 (3 H, s). [M+1] : 532; ^X HNMR [(400MHz, c - DMSO)]: 5 12.37 (1 H, s), 10.72 (1 H, s), 8.81 (1 H, s), 8.43 (1 H, s), 8.23-8.29 (2 H, m), 8.09 (1 H, dd, J=1.8 Hz, J=8.8 Hz), 7.96 (1 H, dd, J=1.7 Hz, J=8.0 Hz), 7.93 (1 H, s), 7.77 (1 H, s), 7.52 (1 H, s), 6.69 (1 H, d, J=2.8 Hz), 3.59 (2 H, s), 2.71-3.13 (8 H , m), 2.62 (3 H, s), 2.19 (3 H, s).

实施例 121

Example 121

除了用 4-溴 -1-甲基 -1 氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 In addition to 4-bromo-1-methyl-1 hydro-pyrrole [2,3-c]pyridine instead of 4-bromoisoquinoline, the synthesis method is as in the examples

118。 118.

[M+1] : 546； ^XHNMR [(400MHz, c -DMSO)]:510.70 (1 H, s), 8.85 (1 H, s), 8.52 (1 H, s), 8.26-8.32 (2 H, m), 8.12 (1 H, dd, J=1.8 Hz, J=8.6 Hz), 7.99 (1 H, dd, J=1.8 Hz, J=8.3 Hz), 7.91 (1 H, s), 7.79 (1 H, s), 7.53 (1 H, s), 6.65 (1 H, d, J=2.3 Hz), 3.63 (2 H, s), 2.73-3.16 (8 H, m), 2.69 (3 H, s), 2.58 (3 H, s), 2.19 (3 H, s). 实施例 122

[M+1] : 546; ^X HNMR [(400MHz, c - DMSO)]: 510.70 (1 H, s), 8.85 (1 H, s), 8.52 (1 H, s), 8.26-8.32 (2 H , m), 8.12 (1 H, dd, J=1.8 Hz, J=8.6 Hz), 7.99 (1 H, dd, J=1.8 Hz, J=8.3 Hz), 7.91 (1 H, s), 7.79 ( 1 H, s), 7.53 (1 H, s), 6.65 (1 H, d, J = 2.3 Hz), 3.63 (2 H, s), 2.73-3.16 (8 H, m), 2.69 (3 H, s), 2.58 (3 H, s), 2.19 (3 H, s). Example 122

除了用 4-溴 -1-甲基 -1 氢-吡唑骈 [3,4-c]吡啶代替 4-溴异喹啉以外，合成方法如实施例 In addition to 4-bromo-1-methyl-1 hydro-pyrazol[3,4-c]pyridine instead of 4-bromoisoquinoline, the synthesis method is as in the examples.

118。 118.

[M+1] : 547； ^XHNMR [(400MHz, c -DMSO)]:510.67 (1 H, s), 9.26 (1 H, s), 8.45 (1 H, s), 8.39 (1 H, s), 8.27 (1 H, d, J=1.7 Hz), 8.23 (1 H, d, J=1.7 Hz), 8.12 (1 H, dd, J=1.7 Hz, J=8.5 Hz), 7.96 (1 H, dd, J=1.6 Hz, J=8.3 Hz), 7.87 (1 H, s), 7.55 (1 H, s), 6.61 (1 H, d, J=2.8 Hz), 4.22 (3 H, s), 3.67 (2 H, s), 3.23-3.39 (4 H, m), 2.85-3.05 (4 H, m), 2.67 (6 H, s). [M+1] : 547; ^X HNMR [(400MHz, c - DMSO)]: 510.67 (1 H, s), 9.26 (1 H, s), 8.45 (1 H, s), 8.39 (1 H, s ), 8.27 (1 H, d, J=1.7 Hz), 8.23 (1 H, d, J=1.7 Hz), 8.12 (1 H, dd, J=1.7 Hz, J=8.5 Hz), 7.96 (1 H , dd, J=1.6 Hz, J=8.3 Hz), 7.87 (1 H, s), 7.55 (1 H, s), 6.61 (1 H, d, J=2.8 Hz), 4.22 (3 H, s) , 3.67 (2 H, s), 3.23-3.39 (4 H, m), 2.85-3.05 (4 H, m), 2.67 (6 H, s).

实施例 123

Example 123

用 1-氯酞嗪代替 4-溴异喹啉以外，合成方法如实施例 118。 The synthesis was carried out in the same manner as in Example 118 except that 1-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 544； ^XHNMR [(400MHz, c -DMSO)]:5 10.79 (1 H, s), 9.45 (1 H, s), 8.41 (1 H, d, J=8.2 Hz), 8.23-8.32 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.06 (1 H, t, J=7.6 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.93 (1 H, d, J=8.3 Hz), 7.88 (1 H, s), 7.50 (1 H, s), 3.71 (2 H, s), 3.03-3.27 (4 H, m), 2.71-2.89 (4 H, m), 2.61 (3 H, s), 2.35 (3 H, s). [M+1] : 544; ^X HNMR [(400MHz, c - DMSO)]: 5 10.79 (1 H, s), 9.45 (1 H, s), 8.41 (1 H, d, J = 8.2 Hz), 8.23-8.32 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.06 (1 H, t, J=7.6 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.93 (1 H, d, J=8.3 Hz), 7.88 (1 H, s), 7.50 (1 H, s), 3.71 (2 H, s), 3.03-3.27 (4 H, m), 2.71-2.89 ( 4 H, m), 2.61 (3 H, s), 2.35 (3 H, s).

实施例 124

Example 124

除了用 5-溴烟酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 5-bromonicotinic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+l] : 530; ^XHNMR [(400MHz, CDC1₃)]:5 9.39 (1 H, s), 9.27 (1 H, s), 9.09 (1 H, s), 8.88 (1 H: s), 8.42-8.57 (2 H, m), 8.33 (1 H, d, J=8.4 Hz), 8.03 (1 H, d, J=8.5 Hz), 7.99 (1 H, d, J=8.5 Hz), 7.91 (1 H, s), 7.85 (1 H, t, J=8.4 Hz), 7.66-7.75 (2 H, m), 3.73 (2 H, s), 2.67-2.93 (8 H, m), 2.61 (3 H, s). [M+l] : 530; ^X HNMR [(400MHz, CDC1 ₃ )]: 5 9.39 (1 H, s), 9.27 (1 H, s), 9.09 (1 H, s), 8.88 (1 H: s ), 8.42-8.57 (2 H, m), 8.33 (1 H, d, J=8.4 Hz), 8.03 (1 H, d, J=8.5 Hz), 7.99 (1 H, d, J=8.5 Hz) , 7.91 (1 H, s), 7.85 (1 H, t, J=8.4 Hz), 7.66-7.75 (2 H, m), 3.73 (2 H, s), 2.67-2.93 (8 H, m), 2.61 (3 H, s).

实施例 125

Example 125

除了用 4-溴吡啶 -2-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 4-bromopyridine-2-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 530； ^XHNMR [(400MHz, CDC1₃)]:5 9.77 (1 H, s), 9.26 (1 H, s), 8.85 (1 H, s), 8.78 (1 H: s), 8.32 (1 H, d, J=8.4 Hz), 8.20 (1 H, s), 8.11 (1 H, d, J=1.7 Hz), 8.01 (1 H, dd, J=1.6 Hz, J=8.5 Hz), 7.97 (1 H, s), 7.91 (1 H, dd, J=1.5 Hz, J=5.5 Hz), 7.79 (1 H, td, J=1.6 Hz, J=7.1 Hz), 7.61-7.70 (2 H, m), 3.62 (2 H, s), 2.75-2.93 (4 H, m), 2.62-2.72 (4 H, m), 2.59 (3 H, s). [M+1] : 530; ^X HNMR [(400MHz, CDC1 ₃ )]: 5 9.77 (1 H, s), 9.26 (1 H, s), 8.85 (1 H, s), 8.78 (1 H: s ), 8.32 (1 H, d, J=8.4 Hz), 8.20 (1 H, s), 8.11 (1 H, d, J=1.7 Hz), 8.01 (1 H, dd, J=1.6 Hz, J= 8.5 Hz), 7.97 (1 H, s), 7.91 (1 H, dd, J=1.5 Hz, J=5.5 Hz), 7.79 (1 H, td, J=1.6 Hz, J=7.1 Hz), 7.61-7.70 (2 H, m), 3.62 (2 H, s), 2.75-2.93 (4 H, m), 2.62-2.72 (4 H, m), 2.59 (3 H, s).

实施例 126

Example 126

除了用 4-氯嘧啶 -2-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 4-chloropyrimidine-2-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 531； ^XHNMR [(400MHz, c -DMSO)]:5 11.13 (1 H, s), 10.37 (1 H, s), 9.55 (1 H, s), 9.19 (1 H, d, J=5.2 Hz), 8.21-8.37 (3 H, m), 8.16 (1 H, d, J=8.4 Hz), 8.07 (1 H, d, J=5.2 Hz), 8.03 (1 H, s), 7.89 (1 H, t, J=7.2 Hz), 7.73 (1 H, s), 3.62 (2 H, s), 3.12-3.45 (8 H, m), 2.63 (3 H, s). [M+1] : 531; ^X HNMR [(400MHz, c - DMSO)]: 5 11.13 (1 H, s), 10.37 (1 H, s), 9.55 (1 H, s), 9.19 (1 H, d, J=5.2 Hz), 8.21-8.37 (3 H, m), 8.16 (1 H, d, J=8.4 Hz), 8.07 (1 H, d, J=5.2 Hz), 8.03 (1 H, s ), 7.89 (1 H, t, J = 7.2 Hz), 7.73 (1 H, s), 3.62 (2 H, s), 3.12-3.45 (8 H, m), 2.63 (3 H, s).

实施例 127

Example 127

除了用 2-氯嘧啶 -3-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 2-chloropyrimidine-3-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 531； ^XHNMR [(400MHz, c -DMSO)]:5 11.18 (1 H, s), 10.43 (1 H, s), 9.58 (1 H, s), 9.22 (1 H, d, J=5.3 Hz), 8.22-8.39 (3 H, m), 8.17 (1 H, d, J=8.8 Hz), 8.11 (1 H, d, J=5.0 Hz), 8.00 (1 H, s), 7.85 (1 H, t, J=7.3 Hz), 7.71 (1 H, s), 3.63 (2 H, s), 3.17-3.51 (8 H, m), 2.67 (3 H, s). [M+1] : 531; ^X HNMR [(400MHz, c - DMSO)]: 5 11.18 (1 H, s), 10.43 (1 H, s), 9.58 (1 H, s), 9.22 (1 H, d, J=5.3 Hz), 8.22-8.39 (3 H, m), 8.17 (1 H, d, J=8.8 Hz), 8.11 (1 H, d, J=5.0 Hz), 8.00 (1 H, s ), 7.85 (1 H, t, J = 7.3 Hz), 7.71 (1 H, s), 3.63 (2 H, s), 3.17-3.51 (8 H, m), 2.67 (3 H, s).

实施例 128

Example 128

除了用 6-氯嘧啶 -4-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 6-chloropyrimidine-4-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 531； ^XHNMR [(400MHz, c -DMSO)]:5 11.09 (1 H, s), 10.35 (1 H, s), 9.55 (1 H, s),[M+1] : 531; ^X HNMR [(400MHz, c - DMSO)]: 5 11.09 (1 H, s), 10.35 (1 H, s), 9.55 (1 H, s),

9.42 (1 H, s), 8.63 (1 H, s), 8.23-8.47 (3 H, m), 8.15 (1 H, s), 8.02 (1 H, t, J=7.7 Hz), 7.87 (1 H, t,9.42 (1 H, s), 8.63 (1 H, s), 8.23-8.47 (3 H, m), 8.15 (1 H, s), 8.02 (1 H, t, J=7.7 Hz), 7.87 (1 H, t,

J=7.5 Hz), 7.73 (1 H, s), 3.67 (2 H, s), 3.12-3.45 (8 H, m), 2.67 (3 H, s). J=7.5 Hz), 7.73 (1 H, s), 3.67 (2 H, s), 3.12-3.45 (8 H, m), 2.67 (3 H, s).

实施例 129

Example 129

除了用 2-溴噻唑 -5-羧酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 118。 The synthesis was carried out as in Example 118 except that 2-bromothiazole-5-carboxylic acid was used in place of 3-iodo-4-methylbenzoic acid.

[M+1] : 536； ^XHNMR [(400MHz, c -DMSO)]:5 10.97 (1 H, s), 9.23 (1 H, s), 8.73 (1 H, s), 8.45 (1 H, s), 8.33 (1 H, d, J=8.9 Hz), 8.11-8.17 (2 H, m), 7.91 (1 H, t, J=7.4 Hz), 7.82 (1 H, t, J=7.5 Hz), 7.79 (1 H, s), 7.71 (1 H, s), 3.67 (2 H, s), 2.72-3.03 (8 H, m), 2.29 (3 H, s). [M+1] : 536; ^X HNMR [(400MHz, c - DMSO)]: 5 10.97 (1 H, s), 9.23 (1 H, s), 8.73 (1 H, s), 8.45 (1 H, s), 8.33 (1 H, d, J=8.9 Hz), 8.11-8.17 (2 H, m), 7.91 (1 H, t, J=7.4 Hz), 7.82 (1 H, t, J=7.5 Hz) ), 7.79 (1 H, s), 7.71 (1 H, s), 3.67 (2 H, s), 2.72-3.03 (8 H, m), 2.29 (3 H, s).

实施例 130

Example 130

步骤一： step one:

向圆底烧瓶中加入 820 mg (5 mMol) 3-三氟甲基 -4-甲基苯甲酸、 2.25 g (15 mMol) NaBr0₃、 1.56 g (15 mMol) NaHS0₃和 40毫升的体积比 1:1的 H₂0和 EtOAc混合溶液，室温下反应 12小时；反应结束后乙酸乙酯萃取，减压蒸干溶剂，柱层析得到产物 2-三氟甲基 -4-羧基苄溴 920 mg (产率： 65%)。 To a round bottom flask was added 820 mg (5 mMol) 3-trifluoromethyl-4-methylbenzoic acid, 2.25 g (15 mMol) NaBr0 ₃ , 1.56 g (15 mMol) NaHS0 ₃ and 40 ml volume ratio 1 A mixed solution of H ₂ 0 and EtOAc was reacted at room temperature for 12 hours; after completion of the reaction, ethyl acetate was extracted, and the solvent was evaporated to dryness under vacuo to yield product 2-trifluoromethyl-4-carboxybenzyl bromide 920 mg (Yield: 65%).

步骤二： Step two:

向圆底烧瓶中加入 849mg (3 mMol) 2-三氟甲基 -4-羧基苄溴、 330 mg (3.3 mMol) N- 甲基哌嗪、 364 mg (3.6 mMol) Et₃N和 10毫升 CH₂C1₂，室温下反应 12小时；反应结束后，减压蒸干溶剂，柱层析得到产物 1-甲基 -4-(4-羧基 -2- (三氟甲基)苄基)哌嗪 901 mg (产率： 99%)。 To the round bottom flask was added 849 mg (3 mMol) 2-trifluoromethyl-4-carboxybenzyl bromide, 330 mg (3.3 mMol) N-methylpiperazine, 364 mg (3.6 mMol) Et ₃ N and 10 ml CH ₂ C1 ₂ , react at room temperature for 12 hours; after completion of the reaction, the solvent is evaporated to dryness under reduced pressure, and then purified to give 1-methyl-4-(4-carboxy-2-(trifluoromethyl)benzyl)piperazine. 901 mg (yield: 99%).

步骤三： Step three:

向圆底烧瓶中加入 901 mg (3 mMol) 1-甲基 -4-(4-羧基 -2- (三氟甲基)苄基)哌嗪、 15毫升 S0C1₂和 18 mg (0.25 mMol)无水 DMF, 用油浴加热 100°C下反应 8小时；反应结束后，减压蒸干溶剂得到产物 4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯甲酰氯，直接用于下一步反应。 901 mg (3 mMol) 1-methyl-4-(4-carboxy-2-(trifluoromethyl)benzyl)piperazine, 15 ml of S0C1 ₂ and 18 mg (0.25 mMol) were added to the round bottom flask. Water DMF, heated in an oil bath at 100 ° C for 8 hours; after completion of the reaction, the solvent was evaporated under reduced pressure to give the product 4-((4-methylpiperazin-1-yl)methylene)-3- Fluoromethyl)benzoyl chloride is used directly in the next step.

步骤四： Step four:

向圆底烧瓶中加入 640 mg (2 mMol) 4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯甲酰氯、 466 mg (2 mMol) 3-碘 -4-甲基苯胺、 223 mg (2.2 mMol) Et₃N和 15毫升 DMF, 室温下反应 4小时；反应结束后，减压蒸干溶剂，柱层析得到产物 N-(3-碘 -4-甲基苯基； )-4-((4- 甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯甲酰胺 706 mg (产率： 69%)。 To a round bottom flask was added 640 mg (2 mMol) 4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)benzoyl chloride, 466 mg (2 mMol) 3-iodo-4-methylaniline, 223 mg (2.2 mMol) Et ₃ N and 15 ml of DMF, and reacted at room temperature for 4 hours; after completion of the reaction, the solvent was evaporated to dryness under reduced pressure and then purified to afford product N-(3- Iodo-4-methylphenyl; )-4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)benzamide 706 mg (yield: 69%) ).

步骤五： Step five:

向圆底烧瓶中加入 517mg (1 mMol) N-(3-碘 -4-甲基苯基) -4-((4-甲基哌嗪 -1-基)亚甲基) -3- (三氟甲基)苯甲酰胺、 147 mg (1.5 mMol) 三甲基硅基乙炔、 60 mg (0.05 mMol) Pd(PPh₃)₄、 20 mg (0.1 mMol) Cul、 390 mg (3 mMol) DIPEA和 1毫升 DMF, 用功率为 150瓦、温度为 90°C的微波照射 20分钟；反应结束后，减压蒸干溶剂，柱层析得到产物 N-(3- ((三甲基硅基)乙炔基 -4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯基) -3- ((三甲基硅基) 乙炔基)苯甲酰胺 285 mg (产率： 59%)。 To the round bottom flask was added 517 mg (1 mMol) of N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methylene)-3- (three Fluoromethyl)benzamide, 147 mg (1.5 mMol) trimethylsilylacetylene, 60 mg (0.05 mMol) Pd(PPh ₃ ) ₄ , 20 mg (0.1 mMol) Cul, 390 mg (3 mMol) DIPEA and 1 ml of DMF was irradiated with microwaves having a power of 150 watts and a temperature of 90 ° C for 20 minutes; after the reaction, the solvent was evaporated under reduced pressure, and the product was obtained by column chromatography to give the product N-(3-((trimethylsilyl) acetylene. 4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)phenyl)-3-((trimethylsilyl)ethynyl)benzamide 285 mg (yield: 59%).

步骤六： Step six:

向圆底烧瓶中加入 285 mg (0.59 mMol) N-(3- ((三甲基硅基)乙炔基 -4-((4-甲基哌嗪 -1- 基)亚甲基 )-3- (三氟甲基)苯基) -3- ((三甲基硅基)乙炔基)苯甲酰胺、 814 mg (5.9 mMol) 碳酸钾和 10毫升甲醇，室温下反应 3小时；反应结束后，砂芯过滤，减压蒸干滤液，柱层析得到产物 N-(3-乙炔基 -4-甲基苯基) -4-((4-甲基哌嗪 -1-基)亚甲基 )-3- (三氟甲基)苯基)苯甲酰胺 220 mg (产率： 90%)。 To a round bottom flask was added 285 mg (0.59 mMol) N-(3-((trimethylsilyl)ethynyl-4-((4-methylpiperazin-1-) Methyl)-3-(trifluoromethyl)phenyl)-3-((trimethylsilyl)ethynyl)benzamide, 814 mg (5.9 mMol) potassium carbonate and 10 ml of methanol, room temperature The reaction was carried out for 3 hours; after the reaction was completed, the sand core was filtered, and the filtrate was evaporated to dryness under reduced pressure to give the product N-(3-ethynyl-4-methylphenyl)-4-((4-methylpiperazine). -1-yl)methylene)-3-(trifluoromethyl)phenyl)benzamide 220 mg (yield: 90%).

步骤七 Step seven

向圆底烧瓶中加入 208 mg (0.5 mMol) N-(3-乙炔基 -4-甲基苯基) -4-((4-甲基哌嗪 -1-基) 亚甲基 )-3- (三氟甲基)苯基)苯甲酰胺、 70 mg (0.33 mMol) 4-溴异喹啉、 30 mg (0.025 mMol) Pd(PPh₃)₄、 10 mg (0.05 mMol) Cul、 195 mg ( 1.5 mMol) DIPEA和 1毫升 DMF，用功率为 150瓦、温度为 90°C的微波照射 20分钟；反应结束后，减压蒸干溶剂，柱层析得到终产物 N-(3- (异喹啉 -4-乙炔基 )-4-甲基苯基 )-4-((4-甲基哌嗪 -1-基)亚甲基) -3- (三氟甲基)苯基)苯甲酰胺 122 mg (产率： 45%) [M+1] : 543； ^XHNMR [(400MHz, c -DMSO)]:5 10.79 (1 H, s), 9.56 (1 H, s), 8.93 (1 H, s), 8.42 (1 H, d, J=8.5 Hz), 8.23-8.37 (3 H, m), 8.16 (1 H, d, J=7.9 Hz), 8.09 (1 H: t, J=7.5 Hz), 8.03 (1 H, d, J=8.4 Hz), 7.83-7.96 (2 H, m), 7.53 (1 H, d, J=8.4 Hz), 3.72 (2 H, s), 3.06-3.27 (4 H, m), 2.76-2.87 (4 H, m), 2.68 (3 H, s), 2.43 (3 H, s). To a round bottom flask was added 208 mg (0.5 mMol) N-(3-ethynyl-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methylene)-3- (trifluoromethyl)phenyl)benzamide, 70 mg (0.33 mMol) 4-bromoisoquinoline, 30 mg (0.025 mMol) Pd(PPh ₃ ) ₄ , 10 mg (0.05 mMol) Cul, 195 mg ( 1.5 mMol) DIPEA and 1 ml of DMF were irradiated with microwaves at a power of 150 watts and a temperature of 90 ° C for 20 minutes. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to give N-(3-( Phenyl-4-ethynyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methylene)-3-(trifluoromethyl)phenyl)benzamide ^{</ RTI} ><RTIgt; , s), 8.42 (1 H, d, J=8.5 Hz), 8.23-8.37 (3 H, m), 8.16 (1 H, d, J=7.9 Hz), 8.09 (1 H: t, J=7.5 Hz), 8.03 (1 H, d, J=8.4 Hz), 7.83-7.96 (2 H, m), 7.53 (1 H, d, J=8.4 Hz), 3.72 (2 H, s), 3.06-3.27 (4 H, m), 2.76-2.87 (4 H, m), 2.68 (3 H, s), 2.43 (3 H, s).

实施例 131

Example 131

除了用 1-氯酞嗪代替 4-溴异喹啉以外，合成方法如实施例 130。 The synthesis was carried out as in Example 130 except that 1-chloropyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 544； ^XHNMR [(400MHz, c -DMSO)]:5 10.73 (1 H, s), 9.45 (1 H, s), 8.42 (1 H, d, J=8.2 Hz), 8.23-8.32 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.4 Hz), 8.03 (1 H, d, J=8.2 Hz), 7.75-7.89 (2 H, m), 7.51 (1 H, d, J=8.3 Hz), 3.73 (2 H, s), 3.02-3.25 (4 H, m), 2.70-2.87 (4 H, m), 2.63 (3 H, s), 2.37 (3 H, s). [M+1] : 544; ^X HNMR [(400MHz, c - DMSO)]: 5 10.73 (1 H, s), 9.45 (1 H, s), 8.42 (1 H, d, J = 8.2 Hz), 8.23-8.32 (3 H, m), 8.17 (1 H, d, J=7.8 Hz), 8.07 (1 H, t, J=7.4 Hz), 8.03 (1 H, d, J=8.2 Hz), 7.75 -7.89 (2 H, m), 7.51 (1 H, d, J=8.3 Hz), 3.73 (2 H, s), 3.02-3.25 (4 H, m), 2.70-2.87 (4 H, m), 2.63 (3 H, s), 2.37 (3 H, s).

实施例 132

Example 132

[M+1] : 547； ¾NMR [(400MHz, c -DMSO)]:510.63 (1 H, s), 9.27 (1 H, s), 8.45 (1 H, s), 8.33 (1 H, s), 8.25 (1 H, d, J=1.7 Hz), 8.21 (1 H, d, J=1.6 Hz), 8.07 (1 H, dd, J=1.6 Hz, J=8.4 Hz), 7.93 (1 H, dd, J=1.5 Hz, J=8.3 Hz), 7.75 (1 H, d, J=8.3 Hz), 7.57 (1 H, d, J=8.5 Hz), 6.63 (1 H, d, J=2.3 Hz), 4.21 (3 H, s), 3.63 (2 H, s), 3.23-3.37 (4 H, m), 2.86-3.05 (4 H, m), 2.66 (6 H, s). 实施例 133

[M+1] : 547; 3⁄4 NMR [(400MHz, c - DMSO)]: 510.63 (1 H, s), 9.27 (1 H, s), 8.45 (1 H, s), 8.33 (1 H, s) , 8.25 (1 H, d, J=1.7 Hz), 8.21 (1 H, d, J=1.6 Hz), 8.07 (1 H, dd, J=1.6 Hz, J=8.4 Hz), 7.93 (1 H, Dd, J=1.5 Hz, J=8.3 Hz), 7.75 (1 H, d, J=8.3 Hz), 7.57 (1 H, d, J=8.5 Hz), 6.63 (1 H, d, J=2.3 Hz ), 4.21 (3 H, s), 3.63 (2 H, s), 3.23-3.37 (4 H, m), 2.86-3.05 (4 H, m), 2.66 (6 H, s). Example 133

130。 130.

[M+1] : 546； ^XHNMR [(400MHz, c -DMSO)]:510.68 (1 H, s), 8.85 (1 H, s), 8.53 (1 H, s), 8.23-8.30 (2 H, m), 8.13 (1 H, dd, J=1.5 Hz, J=8.2 Hz), 7.93 (1 H, dd, J=1.5 Hz, J=8.1 Hz), 7.77 (1 H, s), 7.71 (1 H, d, J=8.5 Hz), 7.52 (1 H, d, J=8.3 Hz), 6.66 (1 H, d, J=2.9 Hz), 3.62 (2 H, s), 2.73-3.10 (8 H, m), 2.65 (3 H, s), 2.59 (3 H, s), 2.15 (3 H, s). [M+1] : 546; ^X H NMR [(400MHz, c - DMSO)]: 510.68 (1 H, s), 8.85 (1 H, s), 8.53 (1 H, s), 8.23-8.30 (2 H , m), 8.13 (1 H, dd, J=1.5 Hz, J=8.2 Hz), 7.93 (1 H, dd, J=1.5 Hz, J=8.1 Hz), 7.77 (1 H, s), 7.71 ( 1 H, d, J=8.5 Hz), 7.52 (1 H, d, J=8.3 Hz), 6.66 (1 H, d, J=2.9 Hz), 3.62 (2 H, s), 2.73-3.10 (8 H, m), 2.65 (3 H, s), 2.59 (3 H, s), 2.15 (3 H, s).

实施例 134

Example 134

除了用 6-氯 -1,2,4-三唑骈 [4,3-B]哒嗪代替 4-溴异喹啉以外，合成方法如实施例 130。 The synthesis was carried out as in Example 130 except that 6-chloro-1,2,4-triazolium [4,3-B]pyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 534； ^XHNMR [(400MHz, c -DMSO)]:5 10.69 (1 H, s), 9.17 (1 H, s), 8.41 (1 H, d, J=7.5 Hz), 8.25 (1 H, s), 8.12 (1 H, s), 7.93 (1 H, d, J=8.4 Hz), 7.79 (1 H, d, J=7.4 Hz), 7.45-7.53 (2 H, m), 7.32 (1 H, d, J=8.4 Hz), 3.62 (2 H, s), 2.97-3.18 (4 H, m), 2.75-2.83 (4 H, m), 2.63 (3 H, s), 2.19 (3 H, s). [M+1] : 534; ^X HNMR [(400MHz, c - DMSO)]: 5 10.69 (1H, s), 9.17 (1 H, s), 8.41 (1 H, d, J = 7.5 Hz), 8.25 (1 H, s), 8.12 (1 H, s), 7.93 (1 H, d, J=8.4 Hz), 7.79 (1 H, d, J=7.4 Hz), 7.45-7.53 (2 H, m ), 7.32 (1 H, d, J=8.4 Hz), 3.62 (2 H, s), 2.97-3.18 (4 H, m), 2.75-2.83 (4 H, m), 2.63 (3 H, s) , 2.19 (3 H, s).

实施例 135

Example 135

除了用 3-氯 -7H-吡咯骈 [2,3-C]哒嗪代替 4-溴异喹啉以外，合成方法如实施例 130。 The synthesis was carried out as in Example 130 except that 3-chloro-7H-pyrrole [2,3-C]pyridazine was used instead of 4-bromoisoquinoline.

[M+1] : 533； ^XHNMR [(400MHz, c -DMSO)]:5 12.31 (1 H, s), 10.75 (1 H, s), 8.47 (1 H, s), 8.22-8.27 (2 H, m), 8.05 (1 H, dd, J=1.5 Hz, J=8.3 Hz), 7.93 (1 H, dd, J=1.5 Hz, J=8.2 Hz), 7.73 (1 H, s), 7.71 (1 H, d, J=8.3 Hz), 7.50(1 H, d, J=8.5 Hz), 6.63 (1 H, d, J=2.2 Hz), 3.64 (2 H, s), 2.75-3.10 (8 H, m), 2.65 (3 H, s), 2.21 (3 H, s). [M+1] : 533; ^X HNMR [(400MHz, c - DMSO)]: 5 12.31 (1 H, s), 10.75 (1 H, s), 8.47 (1 H, s), 8.22-8.27 (2 H, m), 8.05 (1 H, dd, J=1.5 Hz, J=8.3 Hz), 7.93 (1 H, dd, J=1.5 Hz, J=8.2 Hz), 7.73 (1 H, s), 7.71 (1 H, d, J=8.3 Hz), 7.50 (1 H, d, J=8.5 Hz), 6.63 (1 H, d, J=2.2 Hz), 3.64 (2 H, s), 2.75-3.10 ( 8 H, m), 2.65 (3 H, s), 2.21 (3 H, s).

实施例 136

Example 136

除了用 2-溴 4-胺基吡啶代替 3-碘 -4-甲基苯胺以外，合成方法如实施例 130。 The synthesis was carried out as in Example 130 except that 2-bromo-4-aminopyridine was used in place of 3-iodo-4-methylaniline.

[M+l] : 530; ^XHNMR [(400MHz, CDC1₃)]:5 9.73 (1 H, s), 9.20 (1 H, s), 8.85 (1 H, s), 8.77 (1 H: s), 8.33 (1 H, d, J=8.3 Hz), 8.21 (1 H, s), 8.15 (1 H, d, J=2.2 Hz), 8.07 (1 H, dd, J=1.5 Hz, J=8.4 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.93 (1 H, dd, J=1.3 Hz, J=5.0 Hz), 7.79 (1 H, td, J=1.4 Hz, J=7.2 Hz), 7.63-7.70 (2 H, m), 3.61 (2 H, s), 2.72-2.93 (4 H, m), 2.61-2.72 (4 H, m), 2.57 (3 H, s). [M+l] : 530; ^X HNMR [(400MHz, CDC1 ₃ )]: 5 9.73 (1 H, s), 9.20 (1 H, s), 8.85 (1 H, s), 8.77 (1 H: s), 8.33 (1 H, d, J=8.3 Hz), 8.21 (1 H, s), 8.15 (1 H, d, J=2.2 Hz), 8.07 (1 H, dd, J=1.5 Hz, J =8.4 Hz), 8.02 (1 H, d, J=8.2 Hz), 7.93 (1 H, dd, J=1.3 Hz, J=5.0 Hz), 7.79 (1 H, td, J=1.4 Hz, J= 7.2 Hz), 7.63-7.70 (2 H, m), 3.61 (2 H, s), 2.72-2.93 (4 H, m), 2.61-2.72 (4 H, m), 2.57 (3 H, s).

实施例 137

Example 137

除了用 3-溴 -5-胺基吡啶代替 3-碘 -4-甲基苯胺以外，合成方法如实施例 130。 The synthesis was carried out as in Example 130 except that 3-bromo-5-aminopyridine was used in place of 3-iodo-4-methylaniline.

[M+l] : 530; ^XHNMR [(400MHz, CDC1₃)]:5 9.42 (1 H, s), 9.27 (1 H, s), 9.09 (1 H, s), 8.85 (1 H: s), 8.43-8.51 (2 H, m), 8.35 (1 H, d, J=8.2 Hz), 8.08 (1 H, d, J=8.6 Hz), 7.93-8.01 (2 H, m), 7.87 (1 H, t, J=8.5 Hz), 7.62-7.70 (2 H, m), 3.73 (2 H, s), 2.65-2.93 (8 H, m), 2.59 (3 H, s). [M+l] : 530; ^X HNMR [(400MHz, CDC1 ₃ )]: 5 9.42 (1 H, s), 9.27 (1 H, s), 9.09 (1 H, s), 8.85 (1 H: s ), 8.43-8.51 (2 H, m), 8.35 (1 H, d, J=8.2 Hz), 8.08 (1 H, d, J=8.6 Hz), 7.93-8.01 (2 H, m), 7.87 ( 1 H, t, J=8.5 Hz), 7.62-7.70 (2 H, m), 3.73 (2 H, s), 2.65-2.93 (8 H, m), 2.59 (3 H, s).

实施例 138

Example 138

除了用 2-氯 -4-胺基嘧啶代替 3-碘 -4-甲基苯胺以外，合成方法如实施例 130。 The synthesis was carried out as in Example 130 except that 2-chloro-4-aminopyrimidine was used in place of 3-iodo-4-methylaniline.

^XHNMR [(400MHz, d-DMSO)] :5 9.27 (1 H, s), 9.21 (1 H, s), 8.93 (1 H, s), 8.15 (1 H, d, J=4.2 ^X H NMR [(400MHz, d-DMSO)]: 5 9.27 (1 H, s), 9.21 (1 H, s), 8.93 (1 H, s), 8.15 (1 H, d, J=4.2

Hz), 8.07 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.45-7.93 (4 H, m), 7.35 (1 H, d, J=7.6 Hz), 6.87 (1 H, d,Hz), 8.07 (1 H, s), 8.01 (1 H, d, J=8.1 Hz), 7.45-7.93 (4 H, m), 7.35 (1 H, d, J=7.6 Hz), 6.87 (1 H, d,

J=4.2 Hz), 3.59 (2 H, s), 2.62-3.09 (8 H, m), 2.57 (3 H, s). J=4.2 Hz), 3.59 (2 H, s), 2.62-3.09 (8 H, m), 2.57 (3 H, s).

实施例 139

Example 139

除了用 6-氯咪唑骈 [1,2-A]嘧啶代替 4-溴异喹啉，用 2-氯 -4-胺基嘧啶代替 3-碘 -4-甲基苯胺以外，合成方法如实施例 130。 In addition to using 6-chloroimidazolium [1,2-A]pyrimidine instead of 4-bromoisoquinoline and 2-chloro-4-aminopyrimidine instead of 3-iodo-4-methylaniline, the synthesis method is as in the examples. 130.

^XHNMR [(400MHz, d-DMSO)] :5 9.18 (1 H, s), 8.97 (1 H, s), 8.89 (1 H, s), 8.43 (1 H, d, J=5.4 Hz), 8.11 (1 H, s), 7.89 (1 H, d, J=7.8 Hz), 7.35 (1 H, d, J=7.8 Hz), 7.19 (1 H, d, J=3.4 Hz), 7.05 (1 H, d, J=3.4 Hz), 6.63 (1 H, d, J=5.4 Hz), 3.67 (2 H, s), 2.56-3.01 (8 H, m), 2.60 (3 H, s). ^X H NMR [(400MHz, d-DMSO)]: 5 9.18 (1 H, s), 8.97 (1 H, s), 8.89 (1 H, s), 8.43 (1 H, d, J = 5.4 Hz), 8.11 (1 H, s), 7.89 (1 H, d, J=7.8 Hz), 7.35 (1 H, d, J=7.8 Hz), 7.19 (1 H, d, J=3.4 Hz), 7.05 (1 H, d, J = 3.4 Hz), 6.63 (1 H, d, J = 5.4 Hz), 3.67 (2 H, s), 2.56-3.01 (8 H, m), 2.60 (3 H, s).

实施例 140

Example 140

除了用 6-溴 [1,2,4]三氮唑骈 [1,5-A]嘧啶代替 4-溴异喹啉，用 2-氯 -4-胺基嘧啶代替 3-碘 In addition to using 4-bromo[1,2,4]triazolium [1,5-A]pyrimidine instead of 4-bromoisoquinoline, 2-chloro-4-aminopyrimidine was substituted for 3-iodo

-4-甲基苯胺以外，合成方法如实施例 130。 'HNMR [(400MHz, d-DMSO)] :5 9.21 (1 H, s), 8.95 (1 H, s), 8.87 (1 H, s), 8.71 (1 H, s), 8.43 (1 H, d, J=5.4 Hz), 8.11 (1 H, s), 7.89 (1 H, d, J=7.8 Hz), 7.35 (1 H, d, J=7.8 Hz), 6.67 (1 H, d, J=5.4 Hz), 3.61 (2 H, s), 2.6-3.11 (8 H, m), 2.61 (3 H, s). In addition to -4-methylaniline, the synthesis method is as in Example 130. 'HNMR [(400MHz, d-DMSO)] : 5 9.21 (1 H, s), 8.95 (1 H, s), 8.87 (1 H, s), 8.71 (1 H, s), 8.43 (1 H, d, J=5.4 Hz), 8.11 (1 H, s), 7.89 (1 H, d, J=7.8 Hz), 7.35 (1 H, d, J=7.8 Hz), 6.67 (1 H, d, J =5.4 Hz), 3.61 (2 H, s), 2.6-3.11 (8 H, m), 2.61 (3 H, s).

实施例 141

Example 141

除了用 4-氯 -6-氨基嘧啶代替 3-碘 -4-甲基苯胺以外，合成方法如实施例 130。 The synthesis was carried out as in Example 130 except that 4-chloro-6-aminopyrimidine was used in place of 3-iodo-4-methylaniline.

^XHNMR [(400MHz, d-DMSO)] :5 9.71 (1 H, s), 9.31 (1 H, s), 8.98 (1 H, s), 8.47 (1 H, s), 8.21 ^X H NMR [(400MHz, d-DMSO)]: 5 9.71 (1 H, s), 9.31 (1 H, s), 8.98 (1 H, s), 8.47 (1 H, s), 8.21

(1 H, d, J=8.4 Hz), 7.45-8.03 (5 H, m), 7.55 (1 H, d, J=7.5 Hz), 6.87 (1 H, s), 3.65 (2 H, s), 2.6-3.08(1 H, d, J=8.4 Hz), 7.45-8.03 (5 H, m), 7.55 (1 H, d, J=7.5 Hz), 6.87 (1 H, s), 3.65 (2 H, s) , 2.6-3.08

(8 H, m), 2.59 (3 H, s). (8 H, m), 2.59 (3 H, s).

实施例 142

Example 142

除了用 2-氨基 -5-溴噻唑代替 3-碘 -4-甲基苯胺以外，合成方法如实施例 130。 The synthesis method was as in Example 130 except that 2-amino-5-bromothiazole was used instead of 3-iodo-4-methylaniline.

^XHNMR [(400MHz, d-DMSO)] :5 9.36 (1 H, s), 8.81 (1 H, s), 8.45 (1 H, s), 8.21 (1 H, s), 8.15 (1 ^X H NMR [(400MHz, d-DMSO)] : 5 9.36 (1 H, s), 8.81 (1 H, s), 8.45 (1 H, s), 8.21 (1 H, s), 8.15 (1

H, d, J=8.2 Hz), 7.50-7.95 (4 H, m), 7.78 (1 H, s), 7.55 (1 H, d, J=7.5 Hz), 3.69 (2 H, s), 2.6-2.98 (8H, d, J=8.2 Hz), 7.50-7.95 (4 H, m), 7.78 (1 H, s), 7.55 (1 H, d, J=7.5 Hz), 3.69 (2 H, s), 2.6 -2.98 (8

H, m), 2.55 (3 H, s). H, m), 2.55 (3 H, s).

实施例 143

Example 143

除了用 3-溴 -5-甲基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-methylpyridine was used in place of 4-bromoisoquinoline.

[M+1] : 507； ^XHNMR [(400MHz, c -DMSO)]:5 10.71 (1 H, s), 8.56 (1 H, s), 8.31 (1 H, s), 8.22 (1 H, s), 8.17 (1 H, s), 8.02 (1 H, d, J=8.2 Hz), 7.88 (1 H, d, J=8.0 Hz), 7.79 (1 H, s), 7.69 (1 H, d, J=8.1 Hz), 7.51 (1 H, s), 3.55 (2 H, s), 2.69-3.12 (8 H, m), 2.61 (3 H, s), 2.42 (3 H, s), 2.15 (3 H, s). [M+1] : 507; ^X HNMR [(400MHz, c - DMSO)]: 5 10.71 (1 H, s), 8.56 (1 H, s), 8.31 (1 H, s), 8.22 (1 H, s), 8.17 (1 H, s), 8.02 (1 H, d, J = 8.2 Hz), 7.88 (1 H, d, J = 8.0 Hz), 7.79 (1 H, s), 7.69 (1 H, d, J=8.1 Hz), 7.51 (1 H, s), 3.55 (2 H, s), 2.69-3.12 (8 H, m), 2.61 (3 H, s), 2.42 (3 H, s), 2.15 (3 H, s).

实施例 144

Example 144

除了用 3-溴 -5-异丙基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-isopropylpyridine was used instead of 4-bromoisoquinoline.

[M+1] : 535； ^XHNMR [(400MHz, c -DMSO)]:5 10.77 (1 H, s), 8.59 (1 H, s), 8.33 (1 H, s), 8.21 (1 H, s), 8.18 (1 H, s), 8.05 (1 H, d, J=8.2 Hz), 7.89 (1 H, d, J=8.0 Hz), 7.78 (1 H, s), 7.67 (1 H, d, J=8.1 Hz), 7.53 (1 H, s), 3.53 (2 H, s), 2.66-3.10 (9 H, m), 2.59 (3 H, s), 2.13 (3 H, s), 1.23 (6 H, d, J=6.8 Hz). [M+1] : 535; ^X HNMR [(400MHz, c - DMSO)]: 5 10.77 (1 H, s), 8.59 (1 H, s), 8.33 (1 H, s), 8.21 (1 H, s), 8.18 (1 H, s), 8.05 (1 H, d, J = 8.2 Hz), 7.89 (1 H, d, J = 8.0 Hz), 7.78 (1 H, s), 7.67 (1 H, d, J=8.1 Hz), 7.53 (1 H, s), 3.53 (2 H, s), 2.66-3.10 (9 H, m), 2.59 (3 H, s), 2.13 (3 H, s), 1.23 (6 H, d, J=6.8 Hz).

实施例 145

Example 145

除了用 3-溴 -5-环丙基吡啶代替 4-溴异喹啉以外，合成方法如实施例 1。 The synthesis was carried out as in Example 1, except that 3-bromo-5-cyclopropylpyridine was used in place of 4-bromoisoquinoline.

[M+1] : 533； ^XHNMR [(400MHz, c -DMSO)]:5 10.76 (1 H, s), 8.53 (1 H, s), 8.35 (1 H, s), 8.23 (1[M+1] : 533; ^X HNMR [(400MHz, c - DMSO)]: 5 10.76 (1 H, s), 8.53 (1 H, s), 8.35 (1 H, s), 8.23 (1

H, s), 8.19 (1 H, s), 8.06 (1 H, d, J=8.0 Hz), 7.87 (1 H, d, J=8.1 Hz), 7.77 (1 H, s), 7.68 (1 H, d, J=8.0 Hz), 7.52 (1 H, s), 3.53 (2 H, s), 2.73-3.15 (8 H, m), 2.65 (3 H, s), 2.18 (3 H, s)， 1.60 (1 H, m),H, s), 8.19 (1 H, s), 8.06 (1 H, d, J=8.0 Hz), 7.87 (1 H, d, J=8.1 Hz), 7.77 (1 H, s), 7.68 (1 H, d, J=8.0 Hz), 7.52 (1 H, s), 3.53 (2 H, s), 2.73-3.15 (8 H, m), 2.65 (3 H, s), 2.18 (3 H, s ), 1.60 (1 H, m),

I.02-1.28 (4 H, m). I.02-1.28 (4 H, m).

实施例 146

Example 146

除了用二甲胺代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that dimethylamine was used in place of N-methylpiperazine.

[M+l] : 488; ^XHNMR [(400MHz, c -DMSO)]: δ 10.73 (1 H, s), 9.45 (1 H, s), 8.87 (1 H, s), 8.43 (1 H, d, J=8.1 Hz), 8.21-8.33 (3 H, m), 8.15 (1 H, d, J=7.3 Hz), 8.03 (1 H, t, J=7.2 Hz), 8.01 (1 H, d, J=8.2 Hz), 7.81-7.93 (2 H, m), 7.53 (1 H, d, J=8.1 Hz), 3.76 (2 H, s), 2.31 (3 H, s), 2.16 (6 H, s). 实施例 147

[M+l] : 488; ^X HNMR [(400MHz, c - DMSO)]: δ 10.73 (1 H, s), 9.45 (1 H, s), 8.87 (1 H, s), 8.43 (1 H, d, J=8.1 Hz), 8.21-8.33 (3 H, m), 8.15 (1 H, d, J=7.3 Hz), 8.03 (1 H, t, J=7.2 Hz), 8.01 (1 H, d , J=8.2 Hz), 7.81-7.93 (2 H, m), 7.53 (1 H, d, J=8.1 Hz), 3.76 (2 H, s), 2.31 (3 H, s), 2.16 (6 H , s). Example 147

除了用异丙胺代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that isopropylamine was used in place of N-methylpiperazine.

[M+l] : 502; ^XHNMR [(400MHz, c -DMSO)]: δ 10.71 (1 H, s), 9.43 (1 H, s), 8.88 (1 H, s), 8.42 (1 H, d, J=8.0 Hz), 8.23-8.30 (3 H, m), 8.12 (1 H, d, J=7.3 Hz), 8.05 (1 H, t, J=7.1 Hz), 8.03 (1 H, d, J=8.1 Hz), 7.80-7.93 (3 H, m), 7.54 (1 H, d, J=8.0 Hz), 3.71 (2 H, s), 2.95 (1 H, m), 2.37 (3 H, s), 1.13 (6 H, d, J=6.3 Hz). [M+l] : 502; ^X HNMR [(400MHz, c - DMSO)]: δ 10.71 (1 H, s), 9.43 (1 H, s), 8.88 (1 H, s), 8.42 (1 H, d, J=8.0 Hz), 8.23-8.30 (3 H, m), 8.12 (1 H, d, J=7.3 Hz), 8.05 (1 H, t, J=7.1 Hz), 8.03 (1 H, d , J=8.1 Hz), 7.80-7.93 (3 H, m), 7.54 (1 H, d, J=8.0 Hz), 3.71 (2 H, s), 2.95 (1 H, m), 2.37 (3 H , s), 1.13 (6 H, d, J = 6.3 Hz).

实施例 148

Example 148

除了用环戊胺代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that cyclopentylamine was used in place of N-methylpiperazine.

[M+l] : 528; ^XHNMR [(400MHz, c -DMSO)]: δ 10.72 (1 H, s), 9.42 (1 H, s), 8.85 (1 H, s), 8.43 (1 H, d, J=7.9 Hz), 8.21-8.30 (3 H, m), 8.11 (1 H, d, J=7.6 Hz), 8.03 (1 H, t, J=7.7 Hz), 8.00 (1 H, d, J=8.0 Hz), 7.81-7.93 (3 H, m), 7.53 (1 H, d, J=8.0 Hz), 3.73 (2 H, s), 2.92 (1 H, m), 2.33 (3 H, s), 1.62-1.73 (4 H, m), 1.33-1.45 (4 H, m). [M+l] : 528; ^X HNMR [(400MHz, c - DMSO)]: δ 10.72 (1 H, s), 9.42 (1 H, s), 8.85 (1 H, s), 8.43 (1 H, d, J=7.9 Hz), 8.21-8.30 (3 H, m), 8.11 (1 H, d, J=7.6 Hz), 8.03 (1 H, t, J=7.7 Hz), 8.00 (1 H, d , J=8.0 Hz), 7.81-7.93 (3 H, m), 7.53 (1 H, d, J=8.0 Hz), 3.73 (2 H, s), 2.92 (1 H, m), 2.33 (3 H , s), 1.62-1.73 (4 H, m), 1.33-1.45 (4 H, m).

实施例 149

Example 149

除了用环丙胺代替 N-甲基哌嗪以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that cyclopropylamine was used in place of N-methylpiperazine.

[M+1] : 500； ^XHNMR [(400MHz, c -DMSO)] : δ 10.75 (1 Η, s), 9.41 (1 Η, s), 8.83 (1 Η, s), 8.41 (1 Η, d, J=8.0 Hz), 8.20-8.31 (3 H, m), 8.11 (1 H, d, J=7.6 Hz), 8.04 (1 H, t, J=7.5 Hz), 8.02 (1 H, d, J=8.1 Hz), 7.79-7.92 (2 H, m), 7.53 (1 H, d, J=8.0 Hz), 3.73 (2 H, s), 2.35 (3 H, s), 1.58-1.61 (1 H, m), 1.03-1.07 (4 H, m). [M+1] : 500; ^X HNMR [(400MHz, c -DMSO)] : δ 10.75 (1 Η, s), 9.41 (1 Η, s), 8.83 (1 Η, s), 8.41 (1 Η, d, J=8.0 Hz), 8.20-8.31 (3 H, m), 8.11 (1 H, d, J=7.6 Hz), 8.04 (1 H, t, J=7.5 Hz), 8.02 (1 H, d , J=8.1 Hz), 7.79-7.92 (2 H, m), 7.53 (1 H, d, J=8.0 Hz), 3.73 (2 H, s), 2.35 (3 H, s), 1.58-1.61 ( 1 H, m), 1.03-1.07 (4 H, m).

实施例 150

Example 150

除了用 4-溴 -1-甲基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉、 3-碘 -4-氯苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 In addition to 4-bromo-1-methyl-1 hydrogen-pyrrole [2,3-c] pyridine instead of 4-bromoisoquinoline, 3-iodo-4-chlorobenzoic acid instead of 3-iodo-4-methyl In addition to benzoic acid, the synthesis method is as in Example 1.

[M+1] : 566； 1HNMR [(400MHz, d-DMSO)] :510.67 (1 H, s), 8.81 (1 H, s), 8.53 (1 H, s), 8.22-8.30 (2 H, m), 8.12 (1 H, dd, J=1.8 Hz, J=8.4 Hz), 7.95 (1 H, dd, J=1.8 Hz, J=8.1 Hz), 7.79 (1 H, s), 7.73 (1 H, d, J=8.4 Hz), 7.53 (1 H, d, J=8.2 Hz), 6.65 (1 H, d, J=2.5 Hz), 3.57 (2 H, s), 2.72-3.13 (8 H, m), 2.63 (3 H, s), 2.51 (3 H, s). [M+1] : 566; 1H NMR [(400MHz, d-DMSO)]: 510.67 (1H, s), 8.81 (1 H, s), 8.53 (1 H, s), 8.22-8.30 (2 H, m), 8.12 (1 H, dd, J=1.8 Hz, J=8.4 Hz), 7.95 (1 H, dd, J=1.8 Hz, J=8.1 Hz), 7.79 (1 H, s), 7.73 (1 H, d, J=8.4 Hz), 7.53 (1 H, d, J=8.2 Hz), 6.65 (1 H, d, J=2.5 Hz), 3.57 (2 H, s), 2.72-3.13 (8 H , m), 2.63 (3 H, s), 2.51 (3 H, s).

实施例 151

Example 151

除了用 4-溴 -1-甲基 -1氢-吡咯骈 [2,3-c]吡啶代替 4-溴异喹啉、 3-碘 -4-氯苯胺代替 3-碘 -4- 甲基苯胺以外，合成方法如如实施例 130。 In addition to 4-bromo-1-methyl-1 hydrogen-pyrrole [2,3-c] pyridine instead of 4-bromoisoquinoline, 3-iodo-4-chloroaniline instead of 3-iodo-4-methylaniline The synthesis method was as in Example 130.

[M+1] : 566； 1HNMR [(400MHz, d-DMSO)] :510.65 (1 H, s), 8.83 (1 H, s), 8.55 (1 H, s), 8.23-8.32 (2 H, m), 8.13 (1 H, dd, J=1.7 Hz, J=8.5 Hz), 7.95 (1 H, dd, J=1.7 Hz, J=8.2 Hz), 7.78 (1 H, s), 7.72 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.1 Hz), 6.67 (1 H, d, J=2.8 Hz), 3.57 (2 H, s), 2.71-3.10 (8 H, m), 2.61 (3 H, s), 2.55 (3 H, s). [M+1] : 566; 1H NMR [(400MHz, d-DMSO)]: 510.65 (1 H, s), 8.83 (1 H, s), 8.55 (1 H, s), 8.23-8.32 (2 H, m), 8.13 (1 H, dd, J=1.7 Hz, J=8.5 Hz), 7.95 (1 H, dd, J=1.7 Hz, J=8.2 Hz), 7.78 (1 H, s), 7.72 (1 H, d, J=8.5 Hz), 7.51 (1 H, d, J=8.1 Hz), 6.67 (1 H, d, J=2.8 Hz), 3.57 (2 H, s), 2.71-3.10 (8 H , m), 2.61 (3 H, s), 2.55 (3 H, s).

实施例 152

Example 152

除了用 3-溴 -5-吗啉基吡啶代替 4-溴异喹啉、 3-碘 -4-氯苯胺代替 3-碘 -4-甲基苯胺以外，合成方法如如实施例 130。 In addition to 3-bromo-5-morpholinylpyridine instead of 4-bromoisoquinoline, 3-iodo-4-chloroaniline instead of 3-iodo-4-methylaniline, The synthesis method is as in Example 130.

[M+1] : 598； IHNMR [(400MHz, CDC13)]: δ 8.33 (2 H, s), 8.27 (1 H, d, J=2.8 Hz), 8.08 (1 H: d, J=1.7 Hz), 7.85-7.93 (2 H, m), 7.82 (1 H, dd, J=8.4 Hz, J=2.3 Hz), 7.74 (1 H, d, J=8.6 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.31 (1 H, s), 3.83-3.89 (4 H, m), 3.66 (2 H, s), 3.17-3.23 (4 H, m), 2.50-2.78 (8 H, m), 2.43 (3 H, s). [M+1] : 598; IHNMR [(400MHz, CDC13)]: δ 8.33 (2 H, s), 8.27 (1 H, d, J = 2.8 Hz), 8.08 (1 H: d, J = 1.7 Hz ), 7.85-7.93 (2 H, m), 7.82 (1 H, dd, J=8.4 Hz, J=2.3 Hz), 7.74 (1 H, d, J=8.6 Hz), 7.56 (1 H, d, J=8.5 Hz), 7.31 (1 H, s), 3.83-3.89 (4 H, m), 3.66 (2 H, s), 3.17-3.23 (4 H, m), 2.50-2.78 (8 H, m ), 2.43 (3 H, s).

实施例 153

Example 153

除了用 3-溴 -5-吗啉基吡啶代替 4-溴异喹啉、 3-碘 -4-氯苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodo-4-chlorobenzoic acid instead of 3-iodo-4-methylbenzoic acid.

[M+l] : 598; IHNMR [(400MHz, CDC13)]: δ 8.31 (2 Η, s), 8.26 (1 Η, d,】=2.7 Hz), 8.07 (1 Η, d, J=1.8 Hz), 7.86-7.94 (2 H, m), 7.83 (1 H, dd, J=8.3 Hz, J=2.2 Hz), 7.73 (1 H, d, J=8.5 Hz), 7.57 (1 H, d, J=8.6 Hz), 7.30 (1 H, s), 3.85-3.90 (4 H, m), 3.67 (2 H, s), 3.18-3.24 (4 H, m), 2.51-2.79 (8 H, m), 2.44 (3 H, s). [M+l] : 598; IHNMR [(400MHz, CDC13)]: δ 8.31 (2 Η, s), 8.26 (1 Η, d, ==2.7 Hz), 8.07 (1 Η, d, J=1.8 Hz ), 7.86-7.94 (2 H, m), 7.83 (1 H, dd, J=8.3 Hz, J=2.2 Hz), 7.73 (1 H, d, J=8.5 Hz), 7.57 (1 H, d, J=8.6 Hz), 7.30 (1 H, s), 3.85-3.90 (4 H, m), 3.67 (2 H, s), 3.18-3.24 (4 H, m), 2.51-2.79 (8 H, m ), 2.44 (3 H, s).

实施例 154

Example 154

除了用 3-溴 -5-吗啉基吡啶代替 4-溴异喹啉、 3-碘 -4-氟苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodo-4-fluorobenzoic acid instead of 3-iodo-4-methylbenzoic acid.

[M+1] : 582； IHNMR [(400MHz, CDC13)]: δ 8.32 (2 H, s), 8.27 (1 H, d, J=2.5 Hz), 8.09 (1 H, d, J=1.7 Hz), 7.85-7.93 (2 H, m), 7.82 (1 H, dd, J=8.2 Hz, J=2.3 Hz), 7.74 (1 H, d, J=8.4 Hz), 7.55 (1 H, d, J=8.5 Hz), 7.31 (1 H, s), 3.83-3.89 (4 H, m), 3.66 (2 H, s), 3.17-3.23 (4 H, m), 2.52-2.79 (8 H, m), 2.42 (3 H, s). [M+1] : 582; IHNMR [(400MHz, CDC13)]: δ 8.32 (2H, s), 8.27 (1 H, d, J=2.5 Hz), 8.09 (1 H, d, J=1.7 Hz ), 7.85-7.93 (2 H, m), 7.82 (1 H, dd, J=8.2 Hz, J=2.3 Hz), 7.74 (1 H, d, J=8.4 Hz), 7.55 (1 H, d, J=8.5 Hz), 7.31 (1 H, s), 3.83-3.89 (4 H, m), 3.66 (2 H, s), 3.17-3.23 (4 H, m), 2.52-2.79 (8 H, m ), 2.42 (3 H, s).

实施例 155

Example 155

除了用 3-溴 -5-吗啉基吡啶代替 4-溴异喹啉、 3-碘苯甲酸代替 3-碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 The synthesis method was as in Example 1, except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodobenzoic acid instead of 3-iodo-4-methylbenzoic acid.

[M+1] : 564； IHNMR [(400MHz, CDC13)]:5 8.32 (2 H, s), 8.27 (1 H, d, J=2.5 Hz), 8.17 (1 H: d, J=8.2 Hz), 8.03-8.12 (2 H, m), 8.00 (1 H, d, J=7.9 Hz), 7.89 (2 H, d, J=8.2 Hz), 7.70 (1 H, d, J=7.8 Hz), 7.31 (1 H, s), 3.83-3.89 (4 H, m), 3.66 (2 H, s), 3.17-3.23 (4 H, m), 2.52-2.79 (8 H, m), 2.42 (3 H, s). [M+1] : 564; IHNMR [(400MHz, CDC13)]: 5 8.32 (2 H, s), 8.27 (1 H, d, J=2.5 Hz), 8.17 (1 H: d, J=8.2 Hz ), 8.03-8.12 (2 H, m), 8.00 (1 H, d, J=7.9 Hz), 7.89 (2 H, d, J=8.2 Hz), 7.70 (1 H, d, J=7.8 Hz) , 7.31 (1 H, s), 3.83-3.89 (4 H, m), 3.66 (2 H, s), 3.17-3.23 (4 H, m), 2.52-2.79 (8 H, m), 2.42 (3 H, s).

实施例 156

Example 156

除了用 3-溴 -5-吗啉基吡啶代替 4-溴异喹啉、 3-碘 -4-氟苯胺代替 3-碘 -4-甲基苯胺以外，合成方法如如实施例 130。 The synthesis was carried out as in Example 130 except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodo-4-fluoroaniline instead of 3-iodo-4-methylaniline.

[M+l] : 582; 1HNMR [(400MHz, CDC13)]: δ 8.31 (2 H, s), 8.26 (1 Η, d, J=2.6 Hz), 8.08 (1 H: d, J=1.8 Hz), 7.84-7.91 (2 H, m), 7.80 (1 H, dd, J=8.3 Hz, J=2.4 Hz), 7.73 (1 H, d, J=8.5 Hz), 7.55 (1 H, d, J=8.6 Hz), 7.32 (1 H, s), 3.81-3.87 (4 H, m), 3.67 (2 H, s), 3.18-3.24 (4 H, m), 2.53-2.79 (8 H, m), 2.43 (3 H, s). [M+l] : 582; 1HNMR [(400MHz, CDC13)]: δ 8.31 (2 H, s), 8.26 (1 Η, d, J=2.6 Hz), 8.08 (1 H: d, J=1.8 Hz ), 7.84-7.91 (2 H, m), 7.80 (1 H, dd, J=8.3 Hz, J=2.4 Hz), 7.73 (1 H, d, J=8.5 Hz), 7.55 (1 H, d, J=8.6 Hz), 7.32 (1 H, s), 3.81-3.87 (4 H, m), 3.67 (2 H, s), 3.18-3.24 (4 H, m), 2.53-2.79 (8 H, m ), 2.43 (3 H, s).

实施例 157

Example 157

除了用 3-溴 -5-吗啉基吡啶代替 4-溴异喹啉、 3-碘苯胺代替 3-碘 -4-甲基苯胺以外，合成方法如如实施例 130。 The synthesis was carried out as in Example 130 except that 3-bromo-5-morpholinylpyridine was used instead of 4-bromoisoquinoline or 3-iodoaniline instead of 3-iodo-4-methylaniline.

[M+1] : 564； 1HNMR [(400MHz, CDC13)] :5 8.31 (2 H, s), 8.28 (1 H, d, J=2.3 Hz), 8.16 (1 H, d, J=8.3 Hz), 8.04-8.13 (2 H, m), 8.01 (1 H, d, J=7.8 Hz), 7.88 (2 H, d, J=8.3 Hz), 7.71 (1 H, d, J=7.9 Hz), 7.32 (1 H, s), 3.81-3.88 (4 H, m), 3.67 (2 H, s), 3.16-3.24 (4 H, m), 2.51-2.79 (8 H, m), 2.43 (3 H, s). [M+1] : 564; 1HNMR [(400MHz, CDC13)] :5 8.31 (2H, s), 8.28 (1 H, d, J=2.3 Hz), 8.16 (1 H, d, J=8.3 Hz ), 8.04-8.13 (2 H, m), 8.01 (1 H, d, J=7.8 Hz), 7.88 (2 H, d, J=8.3 Hz), 7.71 (1 H, d, J=7.9 Hz) , 7.32 (1 H, s), 3.81-3.88 (4 H, m), 3.67 (2 H, s), 3.16-3.24 (4 H, m), 2.51-2.79 (8 H, m), 2.43 (3 H, s).

实施例 158

Example 158

除了用 3-溴 -5- (2-甲氧基乙氧基） -吡啶代替 4-溴异喹啉、 3-碘 -4-氯苯甲酸代替 3-碘 -4- 甲基苯甲酸以外，合成方法如实施例 1。 In addition to 3-bromo-5-(2-methoxyethoxy)-pyridine instead of 4-bromoisoquinoline, 3-iodo-4-chlorobenzoic acid instead of 3-iodo-4-methylbenzoic acid, The synthesis method was as in Example 1.

[M+1] : 587； 1HNMR [(400MHz, d-DMSO)] : δ 10.67 (1 H, s), 8.40 (1 Η, d, J=1.7 Hz), 8.38 (1 H, d, J=2.7 Hz), 8.33 (1 H, d, J=2.2 Hz), 8.19 (1 H, d, J=2.2 Hz), 8.00-8.08 (2 H, m), 7.82 (1 H, d, J=8.6 Hz), 7.72 (1 H, d, J=8.5 Hz), 7.62-7.64 (1 H, m), 4.22-4.26 (2 H, m), 3.66-3.71 (2 H, m), 3.58 (2 H, s), 3.29-3.38 (5 H, m), 2.33-2.56 (6 H, m), 2.26 (3 H, s). [M+1] : 587; 1H NMR [(400MHz, d-DMSO)] : δ 10.67 (1H, s), 8.40 (1 Η, d, J = 1.7 Hz), 8.38 (1 H, d, J= 2.7 Hz), 8.33 (1 H, d, J=2.2 Hz), 8.19 (1 H, d, J=2.2 Hz), 8.00-8.08 (2 H, m), 7.82 (1 H, d, J=8.6 Hz), 7.72 (1 H, d, J=8.5 Hz), 7.62-7.64 (1 H, m), 4.22-4.26 (2 H, m), 3.66-3.71 (2 H, m), 3.58 (2 H , s), 3.29-3.38 (5 H, m), 2.33-2.56 (6 H, m), 2.26 (3 H, s).

实施例 159

Example 159

除了用 3-溴 -5- (2-羟基乙氧基） -吡啶代替 4-溴异喹啉、 3-碘 -4-氯苯甲酸代替 3-碘 -4- 甲基苯甲酸以外，合成方法如实施例 1。 Synthesis method other than 3-bromo-5-(2-hydroxyethoxy)-pyridine instead of 4-bromoisoquinoline or 3-iodo-4-chlorobenzoic acid instead of 3-iodo-4-methylbenzoic acid As in Example 1.

[M+1] : 573； 1HNMR [(400MHz, d-DMSO)] : δ 10.67 (1 H, s), 8.41 (1 Η, d, J=1.8 Hz), 8.37 (1 H, d, J=2.6 Hz), 8.32 (1 H, d, J=2.3 Hz), 8.18 (1 H, d, J=2.3 Hz), 8.01-8.09 (2 H, m), 7.83 (1 H, d, J=8.7 Hz), 7.71 (1 H, d, J=8.4 Hz), 7.61-7.63 (1 H, m), 4.21-4.25 (2 H, m), 3.64-3.70 (2 H, m), 3.59 (2 H, s), 3.27-3.35 (3 H, m), 2.32-2.55 (6 H, m), 2.29 (3 H, s). [M+1] : 573; 1H NMR [(400MHz, d-DMSO)] : δ 10.67 (1H, s), 8.41 (1 Η, d, J = 1.8 Hz), 8.37 (1 H, d, J= 2.6 Hz), 8.32 (1 H, d, J=2.3 Hz), 8.18 (1 H, d, J=2.3 Hz), 8.01-8.09 (2 H, m), 7.83 (1 H, d, J=8.7 Hz), 7.71 (1 H, d, J=8.4 Hz), 7.61-7.63 (1 H, m), 4.21-4.25 (2 H, m), 3.64-3.70 (2 H, m), 3.59 (2 H , s), 3.27-3.35 (3 H, m), 2.32-2.55 (6 H, m), 2.29 (3 H, s).

实施例 160

Example 160

除了用 3-溴 -5- ( 1-甲氧 -1H-吡唑 -4-基） -吡啶代替 4-溴异喹啉、 3-碘 -4-氯苯甲酸代替 3- 碘 -4-甲基苯甲酸以外，合成方法如实施例 1。 In addition to 3-bromo-5-(1-methoxy-1H-pyrazol-4-yl)-pyridine instead of 4-bromoisoquinoline, 3-iodo-4-chlorobenzoic acid instead of 3-iodo-4-methyl In addition to the benzoic acid, the synthesis method is as in Example 1.

[M+1] : 593； 1HNMR [(400MHz, d-DMSO)] : δ 10.66 (1 H, s), 8.89 (1 Η, d, J=2.2 Hz), 8.59 (1 H, d, J=2.0 Hz), 8.36 (1 H, s), 8.32 (1 H, d, J=2.2 Hz), 8.16-8.24 (2 H, m), 8.07 (1 H, s), 8.03 (2 H, td, J=8.6 Hz, J=2.2 Hz), 7.81 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=8.6 Hz), 3.87 (3 H, s), 3.55 (2 H, s), 3.28-3.39 (2 H, m), 2.22-2.49 (8 H, m), 2.16 (1H, s). 生物活性检测实施例 [M+1] : 593; 1H NMR [(400MHz, d-DMSO)] : δ 10.66 (1H, s), 8.89 (1 Η, d, J = 2.2 Hz), 8.59 (1 H, d, J= 2.0 Hz), 8.36 (1 H, s), 8.32 (1 H, d, J=2.2 Hz), 8.16-8.24 (2 H, m), 8.07 (1 H, s), 8.03 (2 H, td, J=8.6 Hz, J=2.2 Hz), 7.81 (1 H, d, J=8.5 Hz), 7.71 (1 H, d, J=8.6 Hz), 3.87 (3 H, s), 3.55 (2 H, s), 3.28-3.39 (2 H, m), 2.22-2.49 (8 H, m), 2.16 (1H, s). Biological Activity Detection Example

试验实施例一：分子水平受体酪氨酸激酶 FGFR活性抑制实验 Test Example 1: Molecular level receptor tyrosine kinase FGFR activity inhibition experiment

1、受体酪氨酸激酶 FGFR分子水平酶活抑制初步评价实验 1. Receptor tyrosine kinase FGFR molecular level enzyme activity inhibition preliminary evaluation experiment

(1)酶反应底物 Poly(Glu,Tyr)4: l用无钾离子的 PBS( 10mM磷酸钠缓冲液， 150mM NaCl, pH7.2-7.4)稀释成 2(^g/ml， 125μ1/孔包被酶标板，置 37°C反应 12-16小时。弃去孔中液体。洗板，用 200μ1/孔的 T-PBS (含 0.1% Tween-20的无钾离子的 PBS )洗板三次，每次 5分钟。于 37 °C烘箱中干燥酶标板 1-2小时。 (1) Enzyme reaction substrate Poly(Glu, Tyr) 4: 1 diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 2 (^g/ml, 125μ1/well) The plate was coated with an enzyme and reacted at 37 ° C for 12-16 hours. The liquid in the well was discarded. The plate was washed and washed three times with 200 μl/well of T-PBS (PBS containing 0.1% Tween-20 in potassium free). 5 minutes each time. The enzyme plate was dried in an oven at 37 °C for 1-2 hours.

(2)每孔加入用反应缓冲液 (50 mM HEPES pH 7.4, 50 mM MgCl₂, 0.5 mM MnCl₂, 0.2 mM Na₃V0₄, 1 mM DTT)稀释的 ATP溶液 50μί，终浓度 5μΜ。每孔中加入 1 μΐ化合物（ 1% DMSO溶解），再加入 50μ1用反应缓冲液稀释的 FGFR酪氨酸激酶蛋白。置 37 °C摇床 (lOOrpm) 反应 1小时。每次实验需设无 ATP对照孔两孔及相应 DMSO溶剂对照孔（阴性对照孔)。弃去孔中液体， T-PBS洗板三次。 (3)加入抗体 PY99 ΙΟΟμΙ/孔（抗体用含 BSA 5mg/ml 的 T-PBS稀释，浓度为 0.4 g/ml)， 37。C摇床反应 0.5小时。弃去孔中液体， T-PBS洗板三次。 (2) 50 μί of ATP solution diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl ₂ , 0.5 mM MnCl ₂ , 0.2 mM Na ₃ V0 ₄ , 1 mM DTT) was added to each well to a final concentration of 5 μM. 1 μM compound (1% DMSO dissolved) was added to each well, and 50 μl of FGFR tyrosine kinase protein diluted in reaction buffer was added. The reaction was carried out for 1 hour at 37 ° C in a shaker (100 rpm). For each experiment, two wells without ATP control wells and corresponding DMSO solvent control wells (negative control wells) were required. The liquid in the well was discarded and the plate was washed three times with T-PBS. (3) The antibody PY99 ΙΟΟμΙ/well was added (the antibody was diluted with BSA 5 mg/ml in T-PBS at a concentration of 0.4 g/ml), 37. C shaker reaction for 0.5 hours. The liquid in the well was discarded and the plate was washed three times with T-PBS.

(4)加入辣根过氧化物酶标记的羊抗鼠二抗 ΙΟΟμΙ/孔（抗体用含 BSA 5mg/ml 的 T-PBS 稀释，浓度为 0.5 g/ml)， 37°C摇床反应 0.5小时。弃去孔中液体， T-PBS洗板三次。 (4) Horseradish peroxidase-labeled goat anti-mouse secondary antibody ΙΟΟμΙ/well (antibody diluted with BSA 5 mg/ml T-PBS at a concentration of 0.5 g/ml) and shaken at 37 ° C for 0.5 hour . The liquid in the well was discarded and the plate was washed three times with T-PBS.

(5)加入 2mg/ml的 OPD显色液 ΙΟΟμΙ/孔（用含有 0.03%Η₂Ο₂的 0.1M柠檬酸—柠檬酸钠缓冲液（ρΗ=5.4)稀释）， 25 °C避光反应 1-10分钟。（OPD溶解时需用超声，显色液需现配现用）。 (5) Add 2 mg/ml of OPD chromogenic solution ΙΟΟμΙ/well (diluted with 0.1M citric acid-sodium citrate buffer (ρΗ=5.4) containing 0.03% Η ₂ Ο ₂ ), 25 °C protected from light 1 -10 minutes. (Ultrasound is required for the dissolution of OPD, and the coloring solution needs to be used now).

(6)加入 2M H₂S0₄ 50μ1/孔中止反应，用可调波长式微孔板酶标仪 VERSAmax读数，波长为 490nm。 (6) The reaction was stopped by adding 2 M H ₂ S0 ₄ 50 μl/well, and read at VERSAmax using a tunable wavelength microplate reader with a wavelength of 490 nm.

(7)样品的抑制率通过下列公式求得： (7) The inhibition rate of the sample is obtained by the following formula:

样品隱摔 ( o/o ) = (i - 。維―删照孔喊 ₀₀ Sample drop (o/o) = (i - . dimension - deleted photo shout ₀₀

阴性对照孔 0D值 -无酶对照孔 0D值 Negative control well 0D value - no enzyme control well 0D value

药理实验例二：细胞水平受体酪氨酸激酶 FGFR酶活抑制试验 Pharmacological Experiment 2: Cell Level Receptor Tyrosine Kinase FGFR Enzyme Activity Inhibition Test

免疫印迹杂交（Western Blot)检测化合物对 ΚΑΤΟΠΙ细胞中 FGFR2磷酸化的影响将 ΚΑΤΟΠΙ细胞接种于 12孔板中（25万 /?L)，培养 18-24小时后加入各化合物作用 2 小时后，收集细胞。先用冷的 PBS (含 ImM钒酸钠）洗一次；然后加入 l xSDS凝胶加样缓冲液（50mM Tris-HCl (pH6.8)， lOOmM DTT, 2% SDS , 10%甘油， ImM钒酸钠， 0.1%溴酚蓝）裂解细胞。细胞裂解物在沸水浴中加热 10分钟后，于 4°C 12000 rpm离心 10分钟。取上清液进行 SDS-PAGE电泳（Mini-PROTEAN 3 Cell, Bio-Rad, Hercules, CA， USA) , 电泳结束后，用半干电转移系统将蛋白转移至硝酸纤维素膜 (Amersham Life Sciences, Arlington Heights, IL, USA), 将硝酸纤维素膜置于封闭液（5%脱脂奶粉稀释于含 ImM钒酸钠的 TBS )中室温封闭 2小时，然后将膜置于抗 p-FGFR(Cell Sinaling Technology )(1 : 1000) 或抗 GAPDH(Kangcheng Bio) (1 :6000)的抗体中 4°C过夜。用含 ImM钒酸钠的 TBS洗涤三次，每次 15 mm。将膜置于二抗溶液中室温反应 1-2小时；同上洗膜 3次后，用 ECL (Picece, Rockford, IL) 试剂发色，显影。 Western Blot was used to detect the effect of compounds on FGFR2 phosphorylation in sputum cells. The sputum cells were seeded in 12-well plates (250,000/?L), and after 18-24 hours of culture, the compounds were added for 2 hours and collected. cell. Wash once with cold PBS (containing 1 mM sodium vanadate); then add l xSDS gel loading buffer (50 mM Tris-HCl (pH 6.8), 100 mM DTT, 2% SDS, 10% glycerol, 1 mM vanadic acid Sodium, 0.1% bromophenol blue) lysed cells. The cell lysate was heated in a boiling water bath for 10 minutes and then centrifuged at 12,000 rpm for 10 minutes at 4 °C. The supernatant was taken for SDS-PAGE electrophoresis (Mini-PROTEAN 3 Cell, Bio-Rad, Hercules, CA, USA), and after electrophoresis, the protein was transferred to a nitrocellulose membrane using a semi-dry electrotransfer system (Amersham Life Sciences, Arlington Heights, IL, USA), the nitrocellulose membrane was placed in a blocking solution (5% skimmed milk powder diluted in TBS containing 1 mM sodium vanadate) for 2 hours at room temperature, and then the membrane was placed in anti-p-FGFR (Cell Sinaling) Technology ) (1 : 1000) or anti-GAPDH (Kangcheng Bio) (1:6000) antibody at 4 ° C overnight. Wash three times with TBS containing 1 mM sodium vanadate for 15 mm each time. The membrane was placed in a secondary antibody solution for 1-2 hours at room temperature; after washing the membrane three times as above, it was developed with ECL (Picece, Rockford, IL) reagent and developed.

药理实验例三：细胞水平受体酪氨酸激酶 FGFR酶活抑制试验 Pharmacological Experiment 3: Cell Level Receptor Tyrosine Kinase FGFR Enzyme Activity Inhibition Test

检测化合物对 ΚΑΤΟΠΙ细胞增殖能力的影响 The effect of detecting compounds on the proliferation of sputum cells

肿瘤细胞的生长抑制检测采用 CCK8细胞活力检测法。具体步骤如下：处于对数生长期的 ΚΑΤΟΠΙ (3000/?L) 细胞按合适密度接种至 96孔微培养板，每孔 100 μί，培养过夜后，加入不同浓度 (1、 0.2、 0.04、 0.008μΜ) 的化合物作用 72 hr，每个浓度设三复孔，并设相应浓度的生理盐水溶媒对照及无细胞调零孔。作用结束后，每孔加入 CCK8 ΙΟμί按以下列公式计算药物对肿瘤细胞生长的抑制率：抑制率(％) = (00对照孔 -OD给药孔） I OD对照孔 χ100%。实验重复两次取均值。 The growth inhibition assay of tumor cells was performed using the CCK8 cell viability assay. The specific steps are as follows: ΚΑΤΟΠΙ (3000/?L) cells in logarithmic growth phase are inoculated to a 96-well microplate at a suitable density of 100 μί per well. After overnight incubation, different concentrations (1, 0.2, 0.04, 0.008 μΜ) are added. The compounds were treated for 72 hr, three wells per concentration, and the corresponding concentrations of saline control and cell-free zeros were set. After the end of the action, add CCK8 to each hole and press the following The inhibition rate of the drug on tumor cell growth was calculated: inhibition rate (%) = (00 control well-OD administration well) I OD control well 100%. The experiment was repeated twice to take the mean.

综合生物数据见表 1和表 2。 The comprehensive biological data are shown in Tables 1 and 2.

表 1 Table 1

FGFR1 FGFR2 KATOIII (cell) 编号 M+1峰合成路线 FGFR1 FGFR2 KATOIII (cell) No. M+1 Peak Synthetic route

IC₅₀ (nM) IC ₅₀ (nM)

A1 543 路线 I <50 <50 < 100 A1 543 Route I <50 <50 < 100

Α2 532 路线 I <50 <50 < 100Α2 532 Route I <50 <50 < 100

A3 546 路线 I <50 <50 < 100A3 546 Route I <50 <50 < 100

Α4 547 路线 I <50 <50 < 100Α4 547 Route I <50 <50 < 100

Α5 574 路线 I <50 <50 < 100Α5 574 Route I <50 <50 < 100

Α6 588 路线 I <50 <50 < 100Α6 588 Route I <50 <50 < 100

Α7 572 路线 I <50 <50 < 100Α7 572 Route I <50 <50 < 100

Α8 576 路线 I 50-100 50-100 100-200Α8 576 Route I 50-100 50-100 100-200

Α9 604 路线 I 50-100 50-100 200-500Α9 604 Route I 50-100 50-100 200-500

A10 550 路线 I <50 <50 < 100A10 550 Route I <50 <50 < 100

All 546 路线 I <50 <50 < 100All 546 Route I <50 <50 < 100

A12 562 路线 I <50 <50 < 100A12 562 Route I <50 <50 < 100

A13 566 路线 I <50 <50 < 100A13 566 Route I <50 <50 < 100

A14 544 路线 I <50 <50 < 100A14 544 Route I <50 <50 < 100

A15 559 路线 I <50 <50 < 100A15 559 Route I <50 <50 < 100

A16 619 路线 I <50 <50 < 100A16 619 Route I <50 <50 < 100

A17 577 路线 I <50 <50 < 100A17 577 Route I <50 <50 < 100

A18 637 路线 I <50 <50 < 100A18 637 Route I <50 <50 < 100

A19 622 路线 I 50-100 50-100 100-200A19 622 Route I 50-100 50-100 100-200

A20 573 路线 I <50 <50 < 100A20 573 Route I <50 <50 < 100

A21 615 路线 I 100-200 100-200 500-1000A21 615 Route I 100-200 100-200 500-1000

A22 572 路线 I <50 <50 < 100A22 572 Route I <50 <50 < 100

A23 586 路线 I <50 <50 100-200A23 586 Route I <50 <50 100-200

A24 614 路线 I 200-500 200-500 500-1000 A24 614 Route I 200-500 200-500 500-1000

001 > 001 -os ooi-os 01 s ssv 001 > 001 -os ooi-os 01 s ssv

OLOL

.SS000/M0ZN3/X3d L99 6linOZ OAV

.SS000/M0ZN3/X3d L99 6linOZ OAV

A115 562 路线 I 50-100 50-100 500-1000A115 562 Route I 50-100 50-100 500-1000

A116 525 路线 I <50 <50 < 100A116 525 Route I <50 <50 < 100

A117 557 路线 I <50 <50 100- 200A117 557 Route I <50 <50 100- 200

A118 543 路线 π <50 <50 < 100A118 543 route π <50 <50 < 100

A119 543 路线 π <50 <50 < 100A119 543 route π <50 <50 < 100

A120 532 路线 π <50 <50 < 100A120 532 route π <50 <50 < 100

A121 546 路线 π <50 <50 < 100A121 546 route π <50 <50 < 100

A122 547 路线 π <50 <50 < 100A122 547 route π <50 <50 < 100

A123 544 路线 π <50 <50 < 100A123 544 route π <50 <50 < 100

A124 530 路线 π <50 <50 < 100A124 530 route π <50 <50 < 100

A125 530 路线 π <50 <50 < 100A125 530 route π <50 <50 < 100

A126 531 路线 π <50 <50 < 100A126 531 route π <50 <50 < 100

A127 531 路线 π <50 50-100 < 100A127 531 Route π <50 50-100 < 100

A128 531 路线 π <50 50-100 < 100A128 531 Route π <50 50-100 < 100

A129 536 路线 π <50 <50 < 100A129 536 route π <50 <50 < 100

A130 543 路线 III <50 50-100 100 -200A130 543 Route III <50 50-100 100 -200

A131 544 路线 III <50 50-100 100 -200A131 544 Route III <50 50-100 100 -200

A132 547 路线 III <50 50-100 100 -200A132 547 Route III <50 50-100 100 -200

A133 546 路线 in <50 50-100 100 -200A133 546 Route in <50 50-100 100 -200

A134 534 路线 in <50 50-100 100 -200A134 534 Route in <50 50-100 100 -200

A135 533 路线 III <50 50-100 100 -200A135 533 Route III <50 50-100 100 -200

A136 530 路线 in <50 50-100 50-100A136 530 Route in <50 50-100 50-100

A137 530 路线 in <50 50-100 50-100A137 530 Route in <50 50-100 50-100

A138 531 路线 in <50 50-100 50-100A138 531 Route in <50 50-100 50-100

A139 521 路线 III <50 50-100 50-100A139 521 Route III <50 50-100 50-100

A140 522 路线 III <50 50-100 50-100A140 522 Route III <50 50-100 50-100

A141 531 路线 in <50 50-100 50-100A141 531 Route in <50 50-100 50-100

A142 536 路线 III <50 50-100 50-100A142 536 Route III <50 50-100 50-100

A143 507 路线 I <50 50-100 50-100A143 507 Route I <50 50-100 50-100

A144 535 路线 I <50 100 -200 100 -200 A144 535 Route I <50 100 -200 100 -200

001 > os> os> £6S 09TV001 > os> os> £6S 09TV

001 > os> os> £LS 6STV001 > os> os> £LS 6STV

001 > os> os> LSS 8STV001 > os> os> LSS 8STV

001 > os> os> P9S Lsi001 > os> os> P9S Lsi

001 > os> os> zss 9STV001 > os> os> zss 9STV

001 > os> os> SSTV001 > os> os> SSTV

001 > os> os> zss I^STV001 > os> os> zss I^STV

001 > os> os> S6S £STV001 > os> os> S6S £STV

001 > os> os> S6S zsiy001 > os> os> S6S zsiy

001 > os> os> 99S TSTV001 > os> os> 99S TSTV

001 > os> os> 99S OSTV οοοτ-oos oos -ooz OOZ- 001 I窮¾ oos 6HV οοοτ-oos oos -ooz OOZ- 001 8HV001 > os> os> 99S OSTV οοοτ-oos oos -ooz OOZ- 001 I poor 3⁄4 oos 6HV οοοτ-oos oos -ooz OOZ- 001 8HV

OOOT-OOS oos -ooz OOZ- 001 1窮¾ z s LPiOOOT-OOS oos -ooz OOZ- 001 1 poor 3⁄4 z s LPi

OOOT-OOS oos -ooz OOZ- 001 881^ 9HVOOOT-OOS oos -ooz OOZ- 001 881^ 9HV

OOZ- 001 OOZ- 001 os> ££S SHV tLOOZ- 001 OOZ- 001 os> ££S SHV tL

.SS000/M0ZN3/X3d L99 6linOZ OAV /S/uu O z-sioHOSld /-9H0iAV .SS000/M0ZN3/X3d L99 6linOZ OAV /S/uu O z-sioHOSld /-9H0iAV

¾¾¾¾¾麵凝腺 3⁄43⁄43⁄43⁄43⁄4 face condensate

/S/uu O z-sioHOSld /-9H0iAV /S/uu O z-sioHOSld /-9H0iAV

oooi-oos os> oooi-oos os> OOi-OOI OOi-OOI os> os> I魏 C6S 09IV oooi-oos os> oooi-oos os> OOi-OOI OOi-OOI os> os> t^9S Z.SIV oooi-oos os> oooi-oos os> ooi-ooi ooi-ooi os> os> J8S 9SIV Oooi-oos os> oooi-oos os> OOi-OOI OOi-OOI os> os> I Wei C6S 09IV oooi-oos os> oooi-oos os> OOi-OOI OOi-OOI os> os> t^9S Z.SIV Oooi-oos os> oooi-oos os> ooi-ooi ooi-ooi os> os> J8S 9SIV

Claims

Rights request

1 - an alkynyl group represented by the following formula α)

Wherein, Μ and Υ are each independently CH or Ν;

W is C or Ν; where, when W is Ν, it does not exist;

L is -C(0)NH- or -NHC(O)-;

From:

1) H, hydroxyl;

2) Ci-Cs sulfhydryl;

3) unsubstituted or substituted group selected from CrC ₆ embankment, CrC ₆ substituents embankment hydroxyl group;

4) C ₃ -C ₆ cyclodecyl;

5) carboxyl group, -C(=0)0(C _r C ₆ fluorenyl), -C(=0)NH(C _r C ₆ fluorenyl);

6) C ₆ -C _1C1 aryl substituted or substituted with 1 to 5 substituents selected from halogen, C _r C ₆ fluorenyl, halogen substituted C _r C ₆ fluorenyl, C _r C ₆ fluorenyloxy base;

7) 1-3 selected from N, 0 which are unsubstituted or substituted by a substituent selected from halogen, C _r C ₆ fluorenyl, halogen-substituted C _r C ₆ fluorenyl, C _r C ₆ methoxyl And a 5-8 membered heteroaryl group of a hetero atom in S;

8) unsubstituted or substituted by selected prime ¾, substituted C _r C ₆ alkyl with, ¾ prime substituted alkyl with C _r C _6, C _r C ₆ group in the embankment containing 1-3 heteroatoms selected from N a 4-7 membered heterocyclic group of a hetero atom in 0, S;

10) a Y-position of the A ring may form a benzene ring, a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the benzene ring , a heteroaromatic ring or a heterocyclic ring may be selected from a halogen, C _r C ₆ fluorenyl group, a halogen-substituted C _r C ₆ fluorenyl group, a C _r C ₆ decyloxy group, a carboxyl group, -C(=0)0 (CrC ₆ Substituent substitution in fluorenyl), -C(=0)NH(CrC ₆ fluorenyl);

R _{2 is} selected from:

1) H, halogen, hydroxyl; 2) an oxo group;

3) Ci-C ₆ sulfhydryl;

4) C _r C ₆ methoxy;

5) C ₃ -C ₆ cyclodecyl;

7) 1-3 selected from N, 0 and S which are unsubstituted or substituted by a substituent selected from a halogen, d-Cs fluorenyl group, a halogen-substituted d-Cs fluorenyl group, and a d-Cs decyloxy group. 5-8 membered heteroaryl of a hetero atom;

10) R ₂ and an adjacent atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein The ring or heterocyclic ring may be substituted with a substituent selected from a halogen, an oxo group, a CrC ₆ fluorenyl group, a halogen-substituted C _r C ₆ fluorenyl group, and a CrC ₆ fluorenyloxy group;

11) R ₂ and an adjacent N atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or 1 to 2

a 5-6 membered heterocyclic ring of a N atom; wherein the heteroaryl ring or heterocyclic ring may be selected from a halogen, an oxo group, a C _r C ₆ fluorenyl group, a halogen-substituted C _r C ₆ fluorenyl group, CrC ₆ Substituted in a decyloxy group;

From:

1) H;

2) halogen;

3) unsubstituted or halogen-substituted d-Cs fluorenyl;

4) C _r C ₆ methoxy;

5) C ₃ -C ₆ cyclodecyl;

, R ₅ and Re are each independently selected from:

1) H;

2) unsubstituted or 3⁄4 substituted C _r C ₆ fluorenyl;

3 ) (CH ₂ ) _n NR ₇ R _{8 ;}

Where n is 0 or 1;

R ₇ and R ₈ are each independently:

1) H;

2) unsubstituted or 3⁄4 substituted C _r C ₆ fluorenyl; 3) C ₃ -C ₆ cyclodecyl;

4) R ₇ and 1 ₈ and a bonded N atom may form a ring Het ¹ , wherein Het ¹ is a 5-8 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S; a 4-10 membered heterocyclic ring selected from the group consisting of a hetero atom in N, 0 and S; wherein the heteroaryl ring or heterocyclic ring may be substituted by a halogen, an oxo group, a CrC ₆ fluorenyl group, a halogen Substituted in a CrC ₆ fluorenyl group, a CrC ₆ methoxy group;

Wherein, (^ and each independently are hydrogen; C _r C ₆ fluorenyl; C ₃ -C ₆ cyclodecyl; C _r C ₆ decanoyl; unsubstituted or 1-5 selected from 3⁄4, d-Cs a phenyl group substituted with a substituent in the fluorenyl group, a 3⁄4-substituted d-Cs fluorenyl group, and a d-Cs methoxy group;

The B ring is a benzene ring; or a 5-6 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S.

2. The alkynyl heterocyclic compound according to claim 1,

Where R is selected from:

1) H, hydroxyl;

2) C1-C4 sulfhydryl;

3) an unsubstituted substituent selected from group C _r C ₄ embankment, substituents C _r C ₄ embankment hydroxyl group;

4) C ₃ -C ₆ cyclodecyl;

5) carboxyl group, -C(=0)0(CrC ₄ fluorenyl), -C(=0)NH(C _r C ₄ fluorenyl);

6) a phenyl group which is unsubstituted or substituted with from 1 to 5 substituents selected from halogen, C _r C ₄ fluorenyl, halogen-substituted C _r C ₄ fluorenyl, C _r C ₄ fluorenyloxy;

7) 1-3 selected from N, 0 which are unsubstituted or substituted by a substituent selected from halogen, C _r C ₄ fluorenyl, halogen substituted C _r C ₄ fluorenyl, C _r C ₄ fluorenyloxy And a 5-6 membered heteroaryl group of a hetero atom in S;

8) 1-3 selected from N, 0 and S, which are unsubstituted or substituted with a substituent selected from the group consisting of dC ₄ fluorenyl, dC ₄ fluorenyl, and CrC ₄ fluorenyl substituted with _3⁄4 , dC ₄ fluorenyl, _3⁄4 a 4-6 membered heterocyclic group of a hetero atom;

10) 13⁄4 and the Y ring of the A ring may form a benzene ring, a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the benzene The ring, heteroaryl ring or heterocyclic ring may be selected from halogen, C _r C ₄ fluorenyl, halogen substituted C _r C ₄ fluorenyl, C _r C ₄ decyloxy, carboxy, -C(=0)0 (CrC Substituent substitution in _4- mercapto), -C(=0)NH(C _r C ₄ fluorenyl);

R _{2 is} selected from:

1) H, halogen, hydroxyl;

2) an oxo group;

3) Ci-C4 sulfhydryl; 4) C _r C ₄ methoxy;

5) C ₃ -C ₆ cyclodecyl;

8) 1-3 selected from N, 0 and S, which are unsubstituted or substituted by a substituent selected from a dC ₄ fluorenyl group substituted by a _3⁄4 element, a dC ₄ fluorenyl group, a _3⁄4 element, or a CrC ₄ fluorenyloxy group. a 4-6 membered heterocyclic group of a hetero atom;

10) R ₂ and an adjacent atom may form a 5-6 membered heteroaryl ring containing 1-2 N atoms, or a 5-6 membered heterocyclic ring containing 1-2 N atoms; wherein the heteroaryl The ring or heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C _r C ₄ fluorenyl group, halogen-substituted dC ₄ fluorenyl group, and C _r C ₄ fluorenyloxy group;

11) a 5-6 membered heteroaryl ring containing 1-2 N atoms or a 5-6 membered heterocyclic ring containing 1-2 N atoms may be formed with an adjacent N atom; wherein the aromatic heterocyclic ring Or a heterocyclic ring may be substituted with a substituent selected from the group consisting of halogen, oxo group, C _r C ₄ fluorenyl group, _3⁄4 cyano substituted C _r C ₄ fluorenyl group, C _r C ₄ fluorenyloxy group;

Wherein, (^ and 3⁄4 are each independently hydrogen; C _r C ₄ fluorenyl; C ₃ -C ₆ cyclodecyl; C _r C ₄ decanoyl; unsubstituted or 1-5 selected from 3⁄4, C _r alkyl with C _4, ¾ prime substituted alkyl with C _r C _4, C _r C ₄ alkoxy substituents embankment substituted phenyl;

For:

1) H;

2) halogen;

3) unsubstituted or halogen-substituted C _r C ₄ fluorenyl;

4) C _r C ₄ methoxy;

5) C ₃ -C ₄ cyclodecyl;

, R ₅ and Re are selected from:

1) H;

2) CF ₃ ;

3 ) (CH ₂ ) _n NR ₇ R _{8 ;}

Where n is 0 or 1;

R ₇ and R ₈ are each independently:

1) H; 2) unsubstituted or _3⁄4 substituted C _r C ₄ fluorenyl;

3) C ₃ -C ₆ cyclodecyl;

4) R ₇ and ₁₈ and the attached N atom may form a ring Het ¹ , wherein Het ¹ is a 5-6 membered heteroaryl ring containing 1-3 hetero atoms selected from N, 0 and S; a 4-10 membered heterocyclic ring selected from the group consisting of a hetero atom in N, 0 and S; wherein the heteroaryl ring or heterocyclic ring may be selected from the group consisting of halogen, oxo group, C _r C ₄ fluorenyl group, Substituted by a halogen-substituted C _r C ₄ fluorenyl group or a C _r C ₄ methoxy group.

3. The alkynyl heterocyclic compound according to claim 2,

Where R is selected from:

1) hydrogen;

2) methyl, ethyl, isopropyl, t-butyl;

3) a hydroxy group, a methoxy group, an ethoxy group, an isopropoxy group, a t-butoxy group, a methoxy-substituted ethoxy group, a hydroxy-substituted ethoxy group;

4) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

5) unsubstituted or substituted by 1-4 phenyl groups selected from halogen, methyl, methoxy, trifluoromethyl;

6) unsubstituted or methyl substituted pyrazolyl, unsubstituted or methyl substituted imidazolyl, pyrimidinyl;

7) azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, unsubstituted or methyl substituted piperazinyl;

8) carboxyl group, -C(=0)OMe, -C(=0)OEt, -C(=0)NHMe, -C(=0)NHEt;

9) amino group; methylamino; dimethylamino; tert-butylamino; cyclopropylamino; acetylamino; phenylamino group unsubstituted or substituted by halogen, methyl, methoxy, trifluoromethyl;

R _{2 is} selected from:

1) H;

2) F, Cl, Br _;

3) an oxo group;

4) methyl, ethyl, isopropyl, t-butyl;

5) hydroxy, methoxy, ethoxy, isopropoxy, tert-butoxy;

6) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

7) unsubstituted or substituted by 1-4 phenyl groups selected from halogen, methyl, methoxy, trifluoromethyl;

8) amino group; methylamino; dimethylamino; tert-butylamino; cyclopropylamino; acetylamino; phenylamino group unsubstituted or substituted by halogen, methyl, methoxy, trifluoromethyl;

R ₃ is:

1) H; 2) F, Cl, Br _;

3) methyl, ethyl, isopropyl, t-butyl;

4) cyclopropyl;

5) trifluoromethyl;

6) methoxy, ethoxy, t-butoxy;

, R ₅ and Re are selected from:

1) H;

2) CF ₃ ;

Where n is 1; Het ¹ is the following structure:

The alkynyl heterocyclic compound according to any one of claims 1 to 3, wherein an anthracene ring having the following structure with the ring A of the ring A with the ring A of the ring A:

Wherein R _r , Rr and R are each independently selected from:

1) H;

2) F, Cl, Br _;

3) methyl, ethyl, isopropyl, isobutyl, trifluoromethyl;

4) cyclopropyl;

5) hydroxy, methoxy, ethoxy, isopropoxy, tert-butoxy; 6) carboxyl group, -C(=0)OMe, -C(=0)OEt, -C(=0)NHMe, -C(=0)NHEt;

7) an amino group, a methylamino group, a dimethylamino group, a tert-butylamino group, a cyclopropylamino group, an acetylamino group; or, R ₂ and an adjacent atom may form an anthracene ring having the following structure with the A ring:

Alternatively, R ₂ and an adjacent N atom may be linked to an A structure:

The alkynyl heterocyclic compound according to any one of claims 1 to 3,

Wherein, the anthracene ring is a divalent group of the following structure:

The alkynyl heterocyclic compound according to any one of claims 1 to 3,

Among them, the C ring is the following structure:

Among them, Het ¹ is the following structure:

s/uϋ-siosld-99ί

.8

.SS000/M0ZN3/X3d L99 6linOZ OAV

The use of the alkynyl heterocyclic compound according to any one of claims 1 to 7 for the preparation of an antitumor drug.

9. The use according to claim 8, wherein the tumor is non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, gastric cancer, skin cancer, epithelial cells. Any of cancer, nasopharyngeal carcinoma, lymphoma, gastrointestinal stromal tumor, and leukemia.

A pharmaceutical composition having antitumor activity, comprising a therapeutically effective amount of one or more selected from the alkynyl heterocyclic compounds according to any one of claims 1 to 7 and pharmaceutically Acceptable excipients.