TW202321228A - Benzodioxane compound, preparation method therefor and application thereof - Google Patents

Benzodioxane compound, preparation method therefor and application thereof Download PDF

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TW202321228A
TW202321228A TW111129587A TW111129587A TW202321228A TW 202321228 A TW202321228 A TW 202321228A TW 111129587 A TW111129587 A TW 111129587A TW 111129587 A TW111129587 A TW 111129587A TW 202321228 A TW202321228 A TW 202321228A
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piperidinyl
piperazinyl
methyl
hydrogen
formyl
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TW111129587A
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Chinese (zh)
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鄧賢明
黃偉
吳振華
云彩紅
建明 張
黃鑫
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大陸商南京紅云生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

Provided are a benzodioxane compound, a preparation method therefor and an application thereof. Specifically, the present invention relates to a compound having EGFR inhibitory activity, a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and a use of these compounds in the preparation of a drug for preventing and/or treating EGFR kinase-mediated cancer and other diseases.

Description

苯並二噁烷類化合物、其製備方法與應用Benzodioxane compounds, their preparation method and application

本發明涉及藥物化學領域，具體地，涉及苯並二噁烷類化合物、其製備方法與應用。The invention relates to the field of medicinal chemistry, in particular to benzodioxane compounds, their preparation method and application.

近年來，癌症的發病率與死亡率呈現逐漸上升的趨勢，嚴重威脅著人類的生命健康。為了改善癌症患者的生存狀況，科研工作者對癌症的發病機制進行了廣泛而深入的研究，針對癌細胞生長、增殖過程中的關鍵蛋白，利用小分子化合物進行選擇性干預，開發出了一系列療效高、副作用小的靶向藥，造福了一大批患者。研究表明，在非小細胞肺癌患者中，至少10%存在表皮生長因數受體（EGFR）突變（Nature Reviews Cancer, 2007, 7, 169-181），其中最為常見的是19號外顯子缺失（19Del）或20號外顯子點突變（L858R）。這些突變會導致EGFR的激酶活性及下游訊號通路增強，進而導致腫瘤的發生。靶向EGFR的小分子抑制劑藉由阻礙EGFR與腺嘌呤核苷三磷酸（ATP）的結合，從而抑制EGFR的活化及下游訊號通路，引起腫瘤細胞生長、增殖與轉移停滯，進而導致細胞死亡，實現對EGFR介導的腫瘤的有效控制。 In recent years, the morbidity and mortality of cancer have shown a gradual upward trend, seriously threatening human life and health. In order to improve the living conditions of cancer patients, scientific researchers have carried out extensive and in-depth research on the pathogenesis of cancer, targeting at the key proteins in the growth and proliferation of cancer cells, using small molecule compounds for selective intervention, and developed a series of Targeted drugs with high efficacy and few side effects have benefited a large number of patients. Studies have shown that at least 10% of patients with non-small cell lung cancer have epidermal growth factor receptor (EGFR) mutations (Nature Reviews Cancer, 2007, 7, 169-181), the most common of which is exon 19 deletion (19Del) or exon 20 point mutation (L858R). These mutations lead to enhanced kinase activity and downstream signaling pathways of EGFR, leading to tumorigenesis. Small-molecule inhibitors targeting EGFR block the combination of EGFR and adenosine triphosphate (ATP), thereby inhibiting the activation of EGFR and downstream signaling pathways, causing tumor cell growth, proliferation and metastasis to stagnate, leading to cell death, Achieve effective control of EGFR-mediated tumors.

然而，臨床上使用EGFR抑制劑後很快會出現耐藥，其中主要的方式為致病性EGFR進一步發生點突變，導致小分子不能有效地與之結合，出現抑制作用下降甚至消失，如最為常見的T790M突變。針對這種情況，研究者們藉由結構最佳化，尋找到能與耐藥的EGFR有效結合的新一代抑制劑，從而克服耐藥問題。針對第一代抑制劑gefitinib或erlotinib的耐藥，第二代抑制劑afatinib藉由與EGFR的797位半胱氨酸殘基形成共價鍵，可以有效地克服T790M突變。第三代抑制劑奧希替尼同樣屬於共價抑制劑，並且由於其對野生型EGFR的活性較弱，降低了二代藥物的毒副作用。然而，奧希替尼治療後仍會出現耐藥（ Nature Medicine, 2015, 21, 560-562），其主要機制是EGFR的797位半胱氨酸殘基突變為絲氨酸殘基（C797S），導致半胱氨酸殘基的巰基與抑制劑之間的共價鍵作用消失，二者之間的相互作用大大減弱，因而出現耐藥。目前，尚無能克服C797S的藥物上市。 However, after the clinical use of EGFR inhibitors, drug resistance will soon appear, and the main way is that the pathogenic EGFR further undergoes point mutations, resulting in the inability of small molecules to effectively bind to it, and the inhibitory effect decreases or even disappears, such as the most common The T790M mutation. In response to this situation, researchers have found a new generation of inhibitors that can effectively combine with drug-resistant EGFR through structural optimization, so as to overcome the problem of drug resistance. For the resistance of the first-generation inhibitors gefitinib or erlotinib, the second-generation inhibitor afatinib can effectively overcome the T790M mutation by forming a covalent bond with the 797-position cysteine residue of EGFR. The third-generation inhibitor osimertinib is also a covalent inhibitor, and because of its weak activity against wild-type EGFR, it reduces the toxic and side effects of the second-generation drugs. However, drug resistance still occurs after osimertinib treatment ( Nature Medicine , 2015, 21 , 560-562), the main mechanism of which is the mutation of cysteine residue 797 of EGFR to serine residue (C797S), resulting in The covalent bond between the sulfhydryl group of the cysteine residue and the inhibitor disappears, and the interaction between the two is greatly weakened, resulting in drug resistance. Currently, there is no marketed drug that can overcome C797S.

因此，發展能克服C797S突變的第四代EGFR抑制劑具有重要的意義與臨床價值。Therefore, it is of great significance and clinical value to develop fourth-generation EGFR inhibitors that can overcome the C797S mutation.

本申請發明人經廣泛、深入的研究，設計並合成了一系列結構新穎的小分子化合物，對臨床常見的EGFR激酶多種突變體，包括含有C797S的突變體具有很好抑制作用。After extensive and in-depth research, the inventors of the present application have designed and synthesized a series of small molecular compounds with novel structures, which have a good inhibitory effect on various mutants of EGFR kinase commonly seen in clinical practice, including mutants containing C797S.

本發明提供如下所示化合物：

Figure 02_image001
(A) 或上述化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物。 The present invention provides compounds as shown below:
Figure 02_image001
(A) or a stereoisomer of the above compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

其中取代基和符號的定義下面詳細說明。The definitions of substituents and symbols are described in detail below.

本發明的一個目的是提供一類具有抑制EGFR激酶活性的化合物及其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物。One object of the present invention is to provide a class of compounds with the activity of inhibiting EGFR kinase, their stereoisomers, their prodrugs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates.

本發明的另一個目的是提供上述化合物的製備方法。Another object of the present invention is to provide the preparation method of the above compound.

本發明的另一個目的是提供包含上述化合物的藥物組合物。Another object of the present invention is to provide a pharmaceutical composition comprising the above compound.

本發明的另一個目的是提供上述化合物及包含上述化合物的藥物組合物在製備用於EGFR激酶介導的癌症或其他疾病的預防和/或治療的藥物中的用途。Another object of the present invention is to provide the use of the above compound and the pharmaceutical composition comprising the above compound in the preparation of medicaments for the prevention and/or treatment of EGFR kinase-mediated cancer or other diseases.

本發明的另一個目的是提供一種治療癌症的方法，該方法包括向受試者施用有效量的本發明化合物或組合物。Another object of the present invention is to provide a method of treating cancer comprising administering to a subject an effective amount of a compound or composition of the present invention.

本文描述了各種具體實施方案、方式和實施例，包括為了理解所要求保護的本發明而採用的示例性實施方式和定義。儘管以下詳細描述給出了具體的較佳實施方案，但是本領域技術人員將理解，這些實施方式僅是示例性的，並且本發明可以以其他方式實踐。為了確定侵權的目的，本發明的範圍將涉及所附申請專利範圍中的任何一個或多個，包括其等同物，以及等同於所述的那些要素或限制。Various specific embodiments, modes, and examples are described herein, including exemplary embodiments and definitions used in order to understand the invention as claimed. Although the following detailed description presents specific preferred embodiments, those skilled in the art will appreciate that these embodiments are exemplary only and that the invention may be practiced otherwise. For purposes of determining infringement, the scope of the invention shall extend to any one or more of the appended claims, including their equivalents, and elements or limitations equivalent to those described.

本發明是藉由下面的技術方案實現的。The present invention is achieved by the following technical solutions.

在本發明的第一方面，本發明提供了以下通式（A）的化合物：

Figure 02_image001
(A) 或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）2-N, N-二甲基氨基乙氧基，2-(N-甲基呱嗪基)乙氧基，2-(N-乙醯基呱嗪基)乙氧基，2-嗎啡啉基乙氧基，2-硫啡啉基乙氧基，2-呱啶基乙氧基，3-N, N-二甲基氨基丙氧基，3-N, N-二乙基氨基丙氧基，3-N, N-二異丙基氨基丙氧基，3-(N-甲基呱嗪基)丙氧基，3-(N-乙醯基呱嗪基)丙氧基，3-嗎啉基丙氧基，3-硫啡啉基丙氧基，3-呱啶基丙氧基，2-吡啶基甲氧基，3-吡啶基甲氧基，4-吡啶基甲氧基，苯基甲氧基，單鹵素取代苯基甲氧基，偕二鹵素取代苯基甲氧基，雜二鹵素取代苯基甲氧基， （4）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （5）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （6）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （7）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （8）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （9）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （10）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （11）氨基亞甲基，N, N-二甲基氨基亞甲基，N, N-二乙基氨基亞甲基，4-甲基-1-呱嗪亞甲基，4-乙基-1-呱嗪亞甲基，4-丙基-1-呱嗪亞甲基，4-異丙基-1-呱嗪亞甲基，4-(2-羥基乙基)-1-呱嗪亞甲基，4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基，呱啶-1-亞甲基，4-(N, N-二甲基氨基)-1-呱啶亞甲基，4-羥基呱啶-1-亞甲基，四氫吡咯-1-亞甲基，3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基，苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （12）氨基甲醯基，甲胺基甲醯基，N, N-二甲基氨基甲醯基，乙胺基甲醯基，環丙基胺基甲醯基，環丁基胺基甲醯基，環戊基胺基甲醯基，環己基胺基甲醯基，氨基乙醯基，甲胺基乙醯基，2-(N, N-二甲基氨基)乙醯基，乙胺基乙醯基，環丙基胺基乙醯基，環丁基胺基乙醯基，環戊基胺基乙醯基，環己基胺基乙醯基， 四氫吡咯-1-甲醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基， 嗎啡啉基-4-甲醯基，硫啡啉基-4-甲醯基，2, 6-二甲基嗎啡啉基-4-甲醯基， 呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （13）羥基甲醯基，甲氧基甲醯基，乙氧基甲醯基，丙氧基甲醯基，異丙氧基甲醯基，正丁氧基甲醯基，異丁氧基甲醯基，叔丁氧基甲醯基， （14）羥基磺醯基，氨基磺醯基，甲胺基磺醯基，乙胺基磺醯基，丙胺基磺醯基，異丙胺基磺醯基，環丙胺基磺醯基，環丁胺基磺醯基，環戊胺基磺醯基，環己胺基磺醯基， 四氫吡咯-1-磺醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基， 嗎啡啉基-4-磺醯基，硫啡啉基-4-磺醯基，2 6-二甲基嗎啡啉基-4-磺醯基， 呱啶基-1-磺醯基，4-羥基呱啶-1-磺醯基，4-(N, N-二甲基氨基)呱啶基-1-磺醯基，4-(N, N-二乙基氨基)呱啶基-1-磺醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基， N-甲基呱嗪-1-磺醯基，N-乙基呱嗪-1-磺醯基，N-異丙基呱嗪-1-磺醯基，N-(2-羥基乙基)呱嗪-1-磺醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基，4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基，4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基， （15）氨基甲醯氨基，甲氨基甲醯氨基，乙氨基甲醯氨基，丙氨基甲醯氨基，異丙氨基甲醯氨基，環丙基氨基甲醯氨基，環丁基氨基甲醯氨基，環戊基氨基甲醯氨基，呱啶基-1-甲醯氨基，4-羥基呱啶基-1-甲醯氨基，4-N, N-二甲基呱啶基-1-甲醯氨基，4-N, N-二乙基呱啶基-1-甲醯氨基，四氫吡咯基-1-甲醯氨基，3-N, N-二甲基四氫吡咯基-1-甲醯氨基，3-N, N-二乙基四氫吡咯基-1-甲醯氨基，N-甲基呱嗪基-1-甲醯氨基，N-乙基呱嗪基-1-甲醯氨基，N-乙醯基呱嗪基-1-甲醯氨基，N-叔丁氧羰基呱嗪基-1-甲醯氨基，N-(2-羥基乙基)呱嗪基-1-甲醯氨基，N-(2-氰基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基，N-(3-羥基丙基)呱嗪基-1-甲醯氨基， N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基，N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基，嗎啉基-1-甲醯氨基，3, 5-二甲基嗎啉基-1-甲醯氨基，4-(四氫吡咯基)呱啶基-1-甲醯氨基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基，N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基， （16）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 02_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 02_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； R 2選自： 1）
Figure 02_image039
，其中，Z 1、Z 2各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C6環烷基，C3-C6含氟環烷基，且Z 2不為氫； 2）
Figure 02_image041
，其中，Z 3選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C8環烷基，C1-C6含雜原子烷基，C3-C8含雜原子環烷基； 3）
Figure 02_image043
，其中，Z 4、Z 5各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C6環烷基，C3-C6含氟環烷基，或者，Z 4、Z 5與N一起形成取代或未取代的含1~2個雜原子的4-8元環，該取代基選自鹵素，C1-C6烷基，C3-C8環烷基； R 3、R 4各自獨立地選自氫，氟，氯，溴，碘，氰基，硝基，C1-C6含氧烷基，C1-C6含氟烷基（例如，三氟甲基），C1-C6烷基（例如，甲基，乙基或異丙基），C1-C6烷氧基（例如，甲氧基或乙氧基），C3-C6環烷基（例如，環丙基），C2-C6烯基； 或者，R 3、R 4和與它們相連的碳原子一起，形成含一個N、O或S原子的5元環。 In the first aspect of the present invention, the present invention provides compounds of the following general formula (A):
Figure 02_image001
(A) or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) 2-N, N-dimethylaminoethoxy, 2-(N-methylpiperazinyl) ethoxy, 2-( N-acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethyl Aminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3 -(N-acetylpiperazinyl)propoxy, 3-morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidinylpropoxy, 2-pyridylmethoxy , 3-pyridylmethoxy, 4-pyridylmethoxy, phenylmethoxy, monohalogen substituted phenylmethoxy, geminal dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy Base, (4) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propyl Piperazinyl, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deuteroisopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxy Ethyl) piperazinyl, N-(2-N, N-dimethylaminoethyl) piperazinyl, N-(2-N, N-diethylaminoethyl) piperazinyl, N-( 2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl Azinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4 -piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N- Methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azepine Cyclobutan-3-yl) piperazinyl, N-tert-butoxycarbonyl piperazinyl, N-acetyl piperazinyl, N-acryl piperazinyl, N-isobutyryl piperazinyl, N- Cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl, N-n-propylsulfonyl piperazinyl, N-isopropylsulfonyl piperazinyl Piperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (5) morpholinyl, 2, 6-dimethylmorpholinyl, thiomorpholine base, 1,1-dioxythiomorpholinyl, (6) tetrahydropyrrolyl, 3-(N, N-dimethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl Hydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazole-3 -yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propyl Pyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazole -5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, (8) piperidinyl, 4- N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- Methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N -Ethylpiperazine-1-)piperidyl, 4-(N-isopropylpiperazine-1-)piperidyl, 4-(N-acetylpiperazine-1-)piperidyl, 4 -(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperidinyl Azine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxypropyl)piperazine-1-) Piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl ) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N -Diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-dimethylaminotetrahydropyrrole-1- ) piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-) piperidinyl, (9) piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N- Methanesulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N-(3-hydroxypropyl)- 4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylaminopropyl)-4-piperidinyl Base, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (10) amino, N, N-dimethylamino, N, N -Diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N -Ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl -N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N- (2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiperazinyl)ethylamino, 3-N, N-dimethylamino Propylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylguanidine Azinyl)propylamino, N-methylpiperidine-4-amino, N-ethylpiperidine-4-amino, N-n-propylpiperidine-4-amino, N-isopropylpiperidine-4 -amino, (11) aminomethylene, N, N-dimethylaminomethylene, N, N-diethylaminomethylene, 4-methyl-1-piperazine methylene, 4- Ethyl-1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2-hydroxyethyl)-1- Piperazine methylene, 4-(2-N, N-dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4-(N, N-dimethyl Amino)-1-piperidinemethylene, 4-hydroxypiperidine-1-methylene, tetrahydropyrrole-1-methylene, 3-(N, N-dimethylamino)-1-tetrahydro Pyrromethene, Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene, (12) Aminoformyl, Methylaminoformyl, N, N-Dimethylaminoformyl, Ethylaminoformyl, Cyclopropylaminoformyl, Cyclobutylaminoformyl, Cyclopentylaminoformyl, Cyclohexylaminoformyl Formyl, aminoacetyl, methylaminoacetyl, 2-(N, N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropylaminoacetyl, cyclobutyl Aminoacetyl, Cyclopentylaminoacetyl, Cyclohexylaminoacetyl, Tetrahydropyrrole-1-formyl, 3-(N, N-Dimethylamino)tetrahydropyrrolyl -1-formyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-formyl, morpholinyl-4-formyl, thiophenanthyl-4-formyl , 2,6-dimethylmorpholinyl-4-formyl, piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethyl Amino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)guanyl Pyridyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidine Base-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N- (2-Hydroxyethyl)piperazine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N- Diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl Pyridyl) piperazin-1-formyl, (13) hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, isopropoxyformyl, normal Butoxyformyl, isobutoxyformyl, tert-butoxyformyl, (14) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, Propylaminosulfonyl, Isopropylaminosulfonyl, Cyclopropylaminosulfonyl, Cyclobutylaminosulfonyl, Cyclopentylaminosulfonyl, Cyclohexylaminosulfonyl, Tetrahydropyrrole-1- Sulfonyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-sulfonyl, Morpholinyl-4-sulfonyl, Thiophanolinyl-4-sulfonyl, 2 6-Dimethylmorpholinyl-4-sulfonyl, Piperidinyl-1-sulfonyl, 4-Hydroxy Piperidinyl-1-sulfonyl, 4-(N, N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N, N-diethylamino)piperidinyl-1-sulfonyl Acyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-sulfonyl , N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N-(2-hydroxyethyl) Piperazine-1-sulfonyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N, N-diethylaminoethyl) Piperazine-1-sulfonyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4-piperidinyl)piperazine-1 -sulfonyl, (15) carbamoylamino, carbamoylamino, carbamoylamino, carboxypropylamino, carboxypropylamino, carbamoyl isopropylamino, carbamoylcyclopropyl, carbamoylcyclobutylamino Formylamino, cyclopentylaminoformylamino, piperidinyl-1-formylamino, 4-hydroxypiperidinyl-1-formylamino, 4-N, N-dimethylpiperidinyl-1- Formylamino, 4-N, N-diethylpiperidinyl-1-formylamino, tetrahydropyrrolyl-1-formylamino, 3-N, N-dimethyltetrahydropyrrolyl-1- Formylamino, 3-N, N-diethyltetrahydropyrrolyl-1-formylamino, N-methylpiperazinyl-1-formylamino, N-ethylpiperazinyl-1-formylamino Amino, N-acetylpiperazinyl-1-formylamino, N-tert-butoxycarbonylpiperazinyl-1-formylamino, N-(2-hydroxyethyl)piperazinyl-1-formylamino Amino, N-(2-cyanoethyl)piperazinyl-1-formylamino, N-(2-N, N-dimethylaminoethyl)piperazinyl-1-formylamino, N- (2-N, N-diethylaminoethyl)piperazinyl-1-formylamino, N-(3-hydroxypropyl)piperazinyl-1-formylamino, N-(3-N, N-Dimethylpropyl)piperazinyl-1-formylamino, N-(3-N, N-diethylpropyl)piperazinyl-1-formylamino, morpholinyl-1-formylamino Amino, 3, 5-dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N-methyl-1-piperazine Base) piperidyl-1-formylamino, 4-(N-ethyl-1-piperazinyl) piperidinyl-1-formylamino, 4-(N-acetyl-1-piperazinyl ) piperidinyl-1-formylamino, N-(N-methyl-4-piperidinyl) piperazinyl-1-formylamino, (16)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 02_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 02_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; R 2 is selected from: 1)
Figure 02_image039
, wherein, Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl , C3-C6 fluorine-containing cycloalkyl, and Z 2 is not hydrogen; 2)
Figure 02_image041
, wherein, Z3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C3-C8 cycloalkyl, C1-C6 hetero Atomic alkyl, C3-C8 cycloalkyl containing heteroatoms; 3)
Figure 02_image043
, wherein, Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl , C3-C6 fluorine-containing cycloalkyl, or, Z 4 , Z 5 together with N form a substituted or unsubstituted 4-8 membered ring containing 1~2 heteroatoms, the substituent is selected from halogen, C1-C6 Alkyl, C3-C8 cycloalkyl; R 3 , R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkanes group (for example, trifluoromethyl), C1-C6 alkyl (for example, methyl, ethyl or isopropyl), C1-C6 alkoxy (for example, methoxy or ethoxy), C3-C6 Cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl; or, R 3 , R 4 and the carbon atoms connected to them together form a 5-membered ring containing one N, O or S atom.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）2-N, N-二甲基氨基乙氧基，2-(N-甲基呱嗪基)乙氧基，2-(N-乙醯基呱嗪基)乙氧基，2-嗎啡啉基乙氧基，2-硫啡啉基乙氧基，2-呱啶基乙氧基，3-N, N-二甲基氨基丙氧基，3-N, N-二乙基氨基丙氧基，3-N, N-二異丙基氨基丙氧基，3-(N-甲基呱嗪基)丙氧基，3-(N-乙醯基呱嗪基)丙氧基，3-嗎啉基丙氧基，3-硫啡啉基丙氧基，3-呱啶基丙氧基，2-吡啶基甲氧基，3-吡啶基甲氧基，4-吡啶基甲氧基，苯基甲氧基，單鹵素取代苯基甲氧基，偕二鹵素取代苯基甲氧基，雜二鹵素取代苯基甲氧基， （4）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （5）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （6）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （7）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （8）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （9）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （10）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （11）氨基亞甲基，N, N-二甲基氨基亞甲基，N, N-二乙基氨基亞甲基，4-甲基-1-呱嗪亞甲基，4-乙基-1-呱嗪亞甲基，4-丙基-1-呱嗪亞甲基，4-異丙基-1-呱嗪亞甲基，4-(2-羥基乙基)-1-呱嗪亞甲基，4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基，呱啶-1-亞甲基，4-(N, N-二甲基氨基)-1-呱啶亞甲基，4-羥基呱啶-1-亞甲基，四氫吡咯-1-亞甲基，3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基，苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （12）氨基甲醯基，甲胺基甲醯基，N, N-二甲基氨基甲醯基，乙胺基甲醯基，環丙基胺基甲醯基，環丁基胺基甲醯基，環戊基胺基甲醯基，環己基胺基甲醯基，氨基乙醯基，甲胺基乙醯基，2-(N, N-二甲基氨基)乙醯基，乙胺基乙醯基，環丙基胺基乙醯基，環丁基胺基乙醯基，環戊基胺基乙醯基，環己基胺基乙醯基， 四氫吡咯-1-甲醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基， 嗎啡啉基-4-甲醯基，硫啡啉基-4-甲醯基，2, 6-二甲基嗎啡啉基-4-甲醯基， 呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （13）羥基甲醯基，甲氧基甲醯基，乙氧基甲醯基，丙氧基甲醯基，異丙氧基甲醯基，正丁氧基甲醯基，異丁氧基甲醯基，叔丁氧基甲醯基， （14）羥基磺醯基，氨基磺醯基，甲胺基磺醯基，乙胺基磺醯基，丙胺基磺醯基，異丙胺基磺醯基，環丙胺基磺醯基，環丁胺基磺醯基，環戊胺基磺醯基，環己胺基磺醯基， 四氫吡咯-1-磺醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基， 嗎啡啉基-4-磺醯基，硫啡啉基-4-磺醯基，2 6-二甲基嗎啡啉基-4-磺醯基， 呱啶基-1-磺醯基，4-羥基呱啶-1-磺醯基，4-(N, N-二甲基氨基)呱啶基-1-磺醯基，4-(N, N-二乙基氨基)呱啶基-1-磺醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基， N-甲基呱嗪-1-磺醯基，N-乙基呱嗪-1-磺醯基，N-異丙基呱嗪-1-磺醯基，N-(2-羥基乙基)呱嗪-1-磺醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基，4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基，4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基， （15）氨基甲醯氨基，甲氨基甲醯氨基，乙氨基甲醯氨基，丙氨基甲醯氨基，異丙氨基甲醯氨基，環丙基氨基甲醯氨基，環丁基氨基甲醯氨基，環戊基氨基甲醯氨基，呱啶基-1-甲醯氨基，4-羥基呱啶基-1-甲醯氨基，4-N, N-二甲基呱啶基-1-甲醯氨基，4-N, N-二乙基呱啶基-1-甲醯氨基，四氫吡咯基-1-甲醯氨基，3-N, N-二甲基四氫吡咯基-1-甲醯氨基，3-N, N-二乙基四氫吡咯基-1-甲醯氨基，N-甲基呱嗪基-1-甲醯氨基，N-乙基呱嗪基-1-甲醯氨基，N-乙醯基呱嗪基-1-甲醯氨基，N-叔丁氧羰基呱嗪基-1-甲醯氨基，N-(2-羥基乙基)呱嗪基-1-甲醯氨基，N-(2-氰基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基，N-(3-羥基丙基)呱嗪基-1-甲醯氨基， N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基，N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基，嗎啉基-1-甲醯氨基，3, 5-二甲基嗎啉基-1-甲醯氨基，4-(四氫吡咯基)呱啶基-1-甲醯氨基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基，N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基， （16）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 02_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 02_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； R 2選自： 1）
Figure 02_image039
，其中，Z 1、Z 2各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C6環烷基，C3-C6含氟環烷基，且Z 2不為氫； 2）
Figure 02_image041
，其中，Z 3選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C8環烷基，C1-C6含雜原子烷基，C3-C8含雜原子環烷基； 3）
Figure 02_image043
，其中，Z 4、Z 5各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C6環烷基，C3-C6含氟環烷基，或者，Z 4、Z 5與N一起形成取代或未取代的含1~2個雜原子的4-8元環，該取代基選自鹵素，C1-C6烷基，C3-C8環烷基； R 3、R 4各自獨立地選自氫，氟，氯，溴，碘，氰基，硝基，C1-C6含氧烷基，C1-C6含氟烷基（例如，三氟甲基），C1-C6烷基（例如，甲基，乙基或異丙基），C1-C6烷氧基（例如，甲氧基或乙氧基），C3-C6環烷基（例如，環丙基），C2-C6烯基； 或者，R 3、R 4和與它們相連的碳原子一起，形成含一個N、O或S原子的5元環。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) 2-N, N-dimethylaminoethoxy, 2-(N-methylpiperazinyl) ethoxy, 2-( N-acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethyl Aminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3 -(N-acetylpiperazinyl)propoxy, 3-morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidinylpropoxy, 2-pyridylmethoxy , 3-pyridylmethoxy, 4-pyridylmethoxy, phenylmethoxy, monohalogen substituted phenylmethoxy, geminal dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy Base, (4) piperazinyl, N-methyl piperazinyl, N-ethyl piperazinyl, N-n-propyl piperazinyl, N-isopropyl piperazinyl, N-cyclopropyl piperazinyl Base, N-(2-hydroxyethyl) piperazinyl, N-(2-N, N-dimethylaminoethyl) piperazinyl, N-(2-N, N-diethylaminoethyl ) piperazinyl, N-(2-cyanoethyl) piperazinyl, N-cyanomethyl piperazinyl, N-(3-hydroxypropyl) piperazinyl, N-(3-N, N- Dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N -(N-ethyl-4-piperidinyl) piperazinyl, N-(N-isopropyl-4-piperidinyl) piperazinyl, 4-(azetidin-3-yl) piperazinyl Azidinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-( N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-acrylpiperazinyl, N- Isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl, N-n-propylsulfonyl piperazinyl , N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (5) morpholinyl, 2, 6-dimethyl Morpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (6) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1- Pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methyl 1-ethylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3 -yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl , 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, ( 8) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4 -Hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazine-1-) Piperidyl, 4-(N-ethylpiperazine-1-)piperidyl, 4-(N-isopropylpiperazine-1-)piperidyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonyl piperazin-1-) piperidinyl, 4-(N-methylsulfonyl piperazin-1-) piperidinyl, 4-(N- (2-Hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl Base) piperazin-1-) piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl) piperazin-1-) piperidinyl, 4-(N-(2-N , N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N, N-dimethylpropyl)piperazin-1-)piperidinyl, 4-( N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N, N-dimethyl Baseaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (9)piperidin-4-yl, N-methyl Base-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl- 4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl )-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N- (3-Hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylamino Propyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (10) amino, N, N- Dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2 -Hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylamino Ethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiperazinyl)ethylamino, 3- N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperidinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propylpiperidin-4-amino, N -Isopropylpiperidine-4-amino, (11) aminomethylene, N, N-dimethylaminomethylene, N, N-diethylaminomethylene, 4-methyl-1- Piperazine methylene, 4-ethyl-1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2 -Hydroxyethyl)-1-piperazine methylene, 4-(2-N, N-dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4- (N, N-Dimethylamino)-1-piperidine, 4-hydroxypiperidine-1-methylene, tetrahydropyrrole-1-methylene, 3-(N, N-dimethyl Amino)-1-tetrahydropyrromethene, benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, (12) carbamoyl , Methylaminoformyl, N, N-Dimethylaminoformyl, Ethylaminoformyl, Cyclopropylaminoformyl, Cyclobutylaminoformyl, Cyclopentylaminoformyl Formyl, cyclohexylaminoformyl, aminoacetyl, methylaminoacetyl, 2-(N, N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropyl Aminoacetyl, cyclobutylaminoacetyl, cyclopentylaminoacetyl, cyclohexylaminoacetyl, tetrahydropyrrole-1-formyl, 3-(N, N-di Methylamino)tetrahydropyrrolyl-1-formyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-formyl, morpholinyl-4-formyl, thiophene Linyl-4-formyl, 2, 6-dimethylmorpholinyl-4-formyl, piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4 -(N, N-dimethylamino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl -1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl- 1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine- 1-formyl, N-(2-hydroxyethyl)piperazine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-formyl, N -(2-N, N-diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-( N-ethyl-4-piperidinyl)piperazine-1-formyl, (13) hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, iso Propoxyformyl, n-butoxyformyl, isobutoxyformyl, tert-butoxyformyl, (14) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl , Ethylaminosulfonyl, Propylaminosulfonyl, Isopropylaminosulfonyl, Cyclopropylaminosulfonyl, Cyclobutylaminosulfonyl, Cyclopentylaminosulfonyl, Cyclohexylaminosulfonyl base, tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-diethylamino)tetrahydropyrrolyl Base-1-sulfonyl, morpholinyl-4-sulfonyl, thiomorpholinyl-4-sulfonyl, 2 6-dimethylmorpholinyl-4-sulfonyl, piperidinyl-1 -sulfonyl, 4-hydroxypiperidine-1-sulfonyl, 4-(N, N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N, N-diethylamino ) piperidyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl) piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl) piperidinyl Pyridyl-1-sulfonyl, N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N -(2-Hydroxyethyl)piperazine-1-sulfonyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N, N -Diethylaminoethyl)piperazine-1-sulfonyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4- Piperidinyl) piperazine-1-sulfonyl, (15) carbamoylamino, carbamoylamino, carbamoyl ethyl, carboxypropylamino, carbamoyl isopropylamino, carbamoylcyclopropylamino Formylamino, cyclobutylaminoformylamino, cyclopentylaminoformylamino, piperidinyl-1-formylamino, 4-hydroxypiperidinyl-1-formylamino, 4-N, N-di Methylpiperidinyl-1-formylamino, 4-N, N-diethylpiperidinyl-1-formylamino, tetrahydropyrrolyl-1-formylamino, 3-N, N-dimethyl Tetrahydropyrrolyl-1-formylamino, 3-N, N-diethyltetrahydropyrrolyl-1-formylamino, N-methylpiperazinyl-1-formylamino, N-ethyl Piperazinyl-1-formylamino, N-acetylpiperazinyl-1-formylamino, N-tert-butoxycarbonylpiperazinyl-1-formylamino, N-(2-hydroxyethyl) Piperazinyl-1-formylamino, N-(2-cyanoethyl)piperazinyl-1-formylamino, N-(2-N, N-dimethylaminoethyl)piperazinyl- 1-formylamino, N-(2-N, N-diethylaminoethyl)piperazinyl-1-formylamino, N-(3-hydroxypropyl)piperazinyl-1-formylamino , N-(3-N, N-Dimethylpropyl)piperazinyl-1-formylamino, N-(3-N, N-diethylpropyl)piperazinyl-1-formylamino , Morpholinyl-1-formylamino, 3, 5-dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N -Methyl-1-piperazinyl)piperidinyl-1-formylamino, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formylamino, 4-(N-ethyl Acyl-1-piperazinyl)piperidinyl-1-formylamino, N-(N-methyl-4-piperidinyl)piperazinyl-1-formylamino, (16)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 02_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 02_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; R 2 is selected from: 1)
Figure 02_image039
, wherein, Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl , C3-C6 fluorine-containing cycloalkyl, and Z 2 is not hydrogen; 2)
Figure 02_image041
, wherein, Z3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C3-C8 cycloalkyl, C1-C6 hetero Atomic alkyl, C3-C8 cycloalkyl containing heteroatoms; 3)
Figure 02_image043
, wherein, Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl , C3-C6 fluorine-containing cycloalkyl group, or, Z 4 , Z 5 together with N form a substituted or unsubstituted 4-8 membered ring containing 1~2 heteroatoms, the substituent is selected from halogen, C1-C6 Alkyl, C3-C8 cycloalkyl; R 3 , R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkanes radical (for example, trifluoromethyl), C1-C6 alkyl (for example, methyl, ethyl or isopropyl), C1-C6 alkoxy (for example, methoxy or ethoxy), C3-C6 Cycloalkyl (eg, cyclopropyl), C2-C6 alkenyl; or, R 3 , R 4 and the carbon atoms connected to them together form a 5-membered ring containing one N, O or S atom.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N- Deuterated ethyl piperazinyl, N-n-propyl piperazinyl, N-deutero-n-propyl piperazinyl, N-isopropyl piperazinyl, N-deuteroisopropyl piperazinyl, N- Cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N-(2-N, N-di Ethylaminoethyl) piperazinyl, N-(2-cyanoethyl) piperazinyl, N-cyanomethyl piperazinyl, N-(3-hydroxypropyl) piperazinyl, N-(3 -N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl) Piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidine- 3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazine Base, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-acrylpiperazinyl Azinyl, N-isobutyrylpiperazinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonyl Acyl piperazinyl, N-isopropylsulfonyl piperazinyl, N-cyclopropylsulfonyl piperazinyl, 2-oxo-piperazin-4-yl, (4) morpholinyl, 2 , 6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1- Imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4- Base, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propane Basepyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazole Azol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol- 5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylamino Piperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperidinyl Azine-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazine-1-)piperidinyl, 4-(N-ethyl Acylpiperazin-1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N- (3-Hydroxypropyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazine-1-)piperidinyl, 4-(N -(2-N, N-diethylethyl)piperazine-1-)piperidine, 4-(N-(3-N, N-dimethylpropyl)piperazine-1-)piperidine Base, 4-(N-(3-N, N-diethylpropyl) piperazin-1-) piperidinyl, 4-(tetrahydropyrrole-1-) piperidinyl, 4-(3-N , N-dimethylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (8)piperidine-4- Base, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N- tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-di Methylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl Pyridyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N -Diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (9)amino , N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl -N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N -Dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino) ) ethylamino, N-isopropyl-N-(2-N, N-dimethylamino) ethylamino, 2-morpholinyl ethylamino, 2-(N-methylpiperazinyl) ethyl 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholine Propylamino, 3-(N-methylpiperidinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propylpiperidine- 4-amino, N-isopropylpiperidine-4-amino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, ( 11) Piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethylamino)piperidinyl-1-formyl, 4-( N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl -1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1 -Formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1-formyl, N-(2-N, N-Dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N-diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazin-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazin-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N- (2-N, N-diethylaminoethyl)piperazinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl) Piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazine Base, N-propionyl piperazinyl, N-isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl Base, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (4) Morpholinyl, 2, 6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethyl ylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl , 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1 -Methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazole- 5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3- Base, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N , N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazine-1-)piperidine Base, 4-(N-acetylpiperazine-1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazine -1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl Pyridyl, 4-(N-(3-hydroxypropyl)piperazine-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazine-1-) Piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N, N-dimethylpropyl) Piperazin-1-)piperidinyl, 4-(N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrole-1-)piperidine Base, 4-(3-N, N-dimethylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl- 4-piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N- (2-N, N-dimethylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyano Ethyl)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4- Piperidinyl, (9) amino, N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxy Ethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethyl Amino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino) ethylamino, N-ethyl-N-(2- N, N-dimethylamino)ethylamino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N -methylpiperazinyl)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylamino Propylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidine-4-amino, N-ethylpiperidine-4-amino, N-n-propylpiperidin-4-amino, N-isopropylpiperidin-4-amino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene , cyclohexylmethylene, (11) piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethylamino)piperidinyl-1 -Formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl , 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)guanyl Azine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazin-1-formyl, N-(2-N, N-diethylaminoethyl)guanidine Azine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazine-1- Formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基， 3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基、N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-异丙基-N-(2-N, N-二甲基氨基)乙基氨基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, 2,6-dimethylmorpholinyl , thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethyl Amino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, Pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazole- 5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1 -n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-iso Propylpyrazol-5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N- Diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-( N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, (9) amino, N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N- (2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N,N-dimethyl Aminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethyl Amino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylamino Propylamino, 3-N, N-Diisopropylaminopropylamino, (10) Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene Base, (11) 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl Acyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine, bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-( N-isopropylpiperazine-1-)piperidinyl, (4) N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2 -N, N-dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基， 3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， （3）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazine Base, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidine-3- Base) piperazinyl, 4-(N-methyl-azetidin-3-yl) piperazinyl, 4-(N-ethyl-azetidin-3-yl) piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1- Thiomorpholinyl dioxide, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3- (N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazole- 4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazole -3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl , 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, ( 7) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4 -Hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazin-1-) Piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, (8) piperidin-4-yl, N -Methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, (9) amino, N, N-dimethylamino, N, N -Diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N -Ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl -N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N- (2-N, N-dimethylamino)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N- Diisopropylaminopropylamino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, (11) 4-(N- Methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl Base-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine, bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, (3) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl , 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-) Piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazine-1 -) piperidinyl.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基， N-三氘代甲基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基， （5）3-(N, N-二甲基氨基)四氫吡咯基， （6）1-咪唑基，1-吡唑基，1-甲基吡唑-4-基， （7）4-N, N-二甲基氨基呱啶基，4-羥基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基， （8）N-甲基-4-呱啶基， （9）2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基， 2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基， （10）苄基，環丙基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image015
，
Figure 02_image023
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）4-N, N-二甲基氨基呱啶基， 4-(N-甲基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, fluorine, ( 2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methyl piperazine Base, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4- (N-methyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, (5)3-(N,N-dimethylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl, (7) 4-N, N-dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperidinyl Perazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, (8)N-methyl-4-piperidinyl, (9)2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethyl Amino, (10) benzyl, cyclopropyl methylene, (11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image015
,
Figure 02_image023
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, (2) C1-C6 alkyl , C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl , (4) N-methyl-N-(2-N, N-dimethylamino) ethylamino.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）N-甲基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基， （5）3-(N, N-二甲基氨基)四氫吡咯基， （6）1-咪唑基，1-吡唑基，1-甲基吡唑-4-基， （7）4-N, N-二甲基氨基呱啶基，4-羥基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基， （8）N-甲基-4-呱啶基， （9）2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基， 2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基， （10）苄基，環丙基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image015
，
Figure 02_image023
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基， （3）4-N, N-二甲基氨基呱啶基， 4-(N-甲基呱嗪-1-)呱啶基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, fluorine, ( 2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) N-methyl piperazinyl, N- (N-methyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl ) piperazinyl, (4) morpholinyl, (5) 3-(N, N-dimethylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 1-pyrazolyl, 1-methyl Pyrazol-4-yl, (7) 4-N, N-dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methyl Piperazin-1-) piperidinyl, (8) N-methyl-4-piperidinyl, (9) 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino , 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, (10) benzyl, cyclopropylmethylene , (11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image015
,
Figure 02_image023
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, (2) C1-C6 alkyl , C1-C6 alkoxy, (3) 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl.

在一些實施方案中，Z 1、Z 2各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基，且Z 2不為氫。 In some embodiments, Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 2 is not for hydrogen.

在一些實施方案中，Z 1、Z 2各自獨立地選自氫，C1-C6烷基，C3-C6環烷基，且Z 2不為氫。 In some embodiments, Z 1 , Z 2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 2 is not hydrogen.

在一些實施方案中，Z 1、Z 2各自獨立地選自氫、甲基、乙基、異丙基，環丙基，且Z 2不為氫。 In some embodiments, Z 1 , Z 2 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z 2 is not hydrogen.

在一些實施方案中，Z 3選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基。 In some embodiments, Z is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl.

在一些實施方案中，Z 3選自C1-C6烷基，C3-C6環烷基。 In some embodiments, Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

在一些實施方案中，Z 3選自甲基、乙基、異丙基、環丙基。 In some embodiments, Z is selected from methyl, ethyl, isopropyl, cyclopropyl.

在一些實施方案中，Z 4、Z 5各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基，且Z 4、Z 5不同時為氫。 In some embodiments, Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 4 , Z5 is not simultaneously hydrogen.

在一些實施方案中，Z 4、Z 5各自獨立地選自氫，C1-C6烷基，C3-C6環烷基，且Z 4、Z 5不同時為氫。 In some embodiments, Z 4 and Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time.

在一些實施方案中，Z 4、Z 5各自獨立地選自氫、甲基、乙基、異丙基、環丙基，且Z 4、Z 5不同時為氫。 In some embodiments, Z 4 and Z 5 are each independently selected from hydrogen, methyl, ethyl, isopropyl and cyclopropyl, and Z 4 and Z 5 are not hydrogen at the same time.

在一些實施方案中，R 3、R 4各自獨立地選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基。 In some embodiments, R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen Alkyl, C1-C6 fluorinated alkyl, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl.

在一些實施方案中，R 3、R 4各自獨立地選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C2-C6烯基。 In some embodiments, R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing Alkyl, C2-C6 alkenyl.

在一些實施方案中，R 3、R 4各自獨立地選自氫、氟、氯、溴、甲基、乙基、異丙基、甲氧基、乙氧基、氰基、硝基、三氟甲基、乙烯基、1-甲基-乙烯基。 In some embodiments, R 3 , R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoro Methyl, vinyl, 1-methyl-vinyl.

在一些實施方案中，R 3、R 4和與它們相連的碳原子一起，形成

Figure 02_image045
，
Figure 02_image047
或
Figure 02_image049
。 In some embodiments, R 3 , R 4 , together with the carbon atoms to which they are attached, form
Figure 02_image045
,
Figure 02_image047
or
Figure 02_image049
.

在一些實施方案中，R 3、R 4和與它們相連的碳原子一起，形成

Figure 02_image045
。 In some embodiments, R 3 , R 4 , together with the carbon atoms to which they are attached, form
Figure 02_image045
.

在本發明的第二方面，本發明提供了以下式I所示的化合物：

Figure 02_image051
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）2-N, N-二甲基氨基乙氧基，2-(N-甲基呱嗪基)乙氧基，2-(N-乙醯基呱嗪基)乙氧基，2-嗎啡啉基乙氧基，2-硫啡啉基乙氧基，2-呱啶基乙氧基，3-N, N-二甲基氨基丙氧基，3-N, N-二乙基氨基丙氧基，3-N, N-二異丙基氨基丙氧基，3-(N-甲基呱嗪基)丙氧基，3-(N-乙醯基呱嗪基)丙氧基，3-嗎啉基丙氧基，3-硫啡啉基丙氧基，3-呱啶基丙氧基，2-吡啶基甲氧基，3-吡啶基甲氧基，4-吡啶基甲氧基，苯基甲氧基，單鹵素取代苯基甲氧基，偕二鹵素取代苯基甲氧基，雜二鹵素取代苯基甲氧基， （4）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （5）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （6）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （7）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （8）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （9）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （10）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （11）氨基亞甲基，N, N-二甲基氨基亞甲基，N, N-二乙基氨基亞甲基，4-甲基-1-呱嗪亞甲基，4-乙基-1-呱嗪亞甲基，4-丙基-1-呱嗪亞甲基，4-異丙基-1-呱嗪亞甲基，4-(2-羥基乙基)-1-呱嗪亞甲基，4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基，呱啶-1-亞甲基，4-(N, N-二甲基氨基)-1-呱啶亞甲基，4-羥基呱啶-1-亞甲基，四氫吡咯-1-亞甲基，3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基，苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （12）氨基甲醯基，甲胺基甲醯基，N, N-二甲基氨基甲醯基，乙胺基甲醯基，環丙基胺基甲醯基，環丁基胺基甲醯基，環戊基胺基甲醯基，環己基胺基甲醯基，氨基乙醯基，甲胺基乙醯基，2-(N, N-二甲基氨基)乙醯基，乙胺基乙醯基，環丙基胺基乙醯基，環丁基胺基乙醯基，環戊基胺基乙醯基，環己基胺基乙醯基， 四氫吡咯-1-甲醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基， 嗎啡啉基-4-甲醯基，硫啡啉基-4-甲醯基，2, 6-二甲基嗎啡啉基-4-甲醯基， 呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （13）羥基甲醯基，甲氧基甲醯基，乙氧基甲醯基，丙氧基甲醯基，異丙氧基甲醯基，正丁氧基甲醯基，異丁氧基甲醯基，叔丁氧基甲醯基， （14）羥基磺醯基，氨基磺醯基，甲胺基磺醯基，乙胺基磺醯基，丙胺基磺醯基，異丙胺基磺醯基，環丙胺基磺醯基，環丁胺基磺醯基，環戊胺基磺醯基，環己胺基磺醯基， 四氫吡咯-1-磺醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基， 嗎啡啉基-4-磺醯基，硫啡啉基-4-磺醯基，2 6-二甲基嗎啡啉基-4-磺醯基， 呱啶基-1-磺醯基，4-羥基呱啶-1-磺醯基，4-(N, N-二甲基氨基)呱啶基-1-磺醯基，4-(N, N-二乙基氨基)呱啶基-1-磺醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基， N-甲基呱嗪-1-磺醯基，N-乙基呱嗪-1-磺醯基，N-異丙基呱嗪-1-磺醯基，N-(2-羥基乙基)呱嗪-1-磺醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基，4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基，4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基， （15）氨基甲醯氨基，甲氨基甲醯氨基，乙氨基甲醯氨基，丙氨基甲醯氨基，異丙氨基甲醯氨基，環丙基氨基甲醯氨基，環丁基氨基甲醯氨基，環戊基氨基甲醯氨基，呱啶基-1-甲醯氨基，4-羥基呱啶基-1-甲醯氨基，4-N, N-二甲基呱啶基-1-甲醯氨基，4-N, N-二乙基呱啶基-1-甲醯氨基，四氫吡咯基-1-甲醯氨基，3-N, N-二甲基四氫吡咯基-1-甲醯氨基，3-N, N-二乙基四氫吡咯基-1-甲醯氨基，N-甲基呱嗪基-1-甲醯氨基，N-乙基呱嗪基-1-甲醯氨基，N-乙醯基呱嗪基-1-甲醯氨基，N-叔丁氧羰基呱嗪基-1-甲醯氨基，N-(2-羥基乙基)呱嗪基-1-甲醯氨基，N-(2-氰基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基，N-(3-羥基丙基)呱嗪基-1-甲醯氨基， N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基，N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基，嗎啉基-1-甲醯氨基，3, 5-二甲基嗎啉基-1-甲醯氨基，4-(四氫吡咯基)呱啶基-1-甲醯氨基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基，N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基， （16）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 02_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 02_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； Z 1選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； Z 2選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； R 3選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基； R 4選自氫，氟，氯，溴，碘，C1-C6烷基； 或者，R 3、R 4和與它們相連的碳原子一起，形成含一個N、O或S原子的5元環。 In a second aspect of the present invention, the present invention provides compounds represented by the following formula I:
Figure 02_image051
or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) 2-N, N-dimethylaminoethoxy, 2-(N-methylpiperazinyl) ethoxy, 2-( N-acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethyl Aminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3 -(N-acetylpiperazinyl)propoxy, 3-morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidinylpropoxy, 2-pyridylmethoxy , 3-pyridylmethoxy, 4-pyridylmethoxy, phenylmethoxy, monohalogen substituted phenylmethoxy, geminal dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy Base, (4) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propyl Piperazinyl, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deuteroisopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxy Ethyl) piperazinyl, N-(2-N, N-dimethylaminoethyl) piperazinyl, N-(2-N, N-diethylaminoethyl) piperazinyl, N-( 2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl Azinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4 -piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N- Methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azepine Cyclobutan-3-yl) piperazinyl, N-tert-butoxycarbonyl piperazinyl, N-acetyl piperazinyl, N-acryl piperazinyl, N-isobutyryl piperazinyl, N- Cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl, N-n-propylsulfonyl piperazinyl, N-isopropylsulfonyl piperazinyl Piperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (5) morpholinyl, 2, 6-dimethylmorpholinyl, thiomorpholine base, 1,1-dioxythiomorpholinyl, (6) tetrahydropyrrolyl, 3-(N, N-dimethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl Hydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazole-3 -yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propyl Pyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazole -5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, (8) piperidinyl, 4- N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- Methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N -Ethylpiperazine-1-)piperidyl, 4-(N-isopropylpiperazine-1-)piperidyl, 4-(N-acetylpiperazine-1-)piperidyl, 4 -(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperidinyl Azine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxypropyl)piperazine-1-) Piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl ) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N -Diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-dimethylaminotetrahydropyrrole-1- ) piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-) piperidinyl, (9) piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N- Methanesulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N-(3-hydroxypropyl)- 4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylaminopropyl)-4-piperidinyl Base, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (10) amino, N, N-dimethylamino, N, N -Diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N -Ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl -N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N- (2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiperazinyl)ethylamino, 3-N, N-dimethylamino Propylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylguanidine Azinyl)propylamino, N-methylpiperidine-4-amino, N-ethylpiperidine-4-amino, N-n-propylpiperidine-4-amino, N-isopropylpiperidine-4 -amino, (11) aminomethylene, N, N-dimethylaminomethylene, N, N-diethylaminomethylene, 4-methyl-1-piperazine methylene, 4- Ethyl-1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2-hydroxyethyl)-1- Piperazine methylene, 4-(2-N, N-dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4-(N, N-dimethyl Amino)-1-piperidinemethylene, 4-hydroxypiperidine-1-methylene, tetrahydropyrrole-1-methylene, 3-(N, N-dimethylamino)-1-tetrahydro Pyrromethene, Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene, (12) Aminoformyl, Methylaminoformyl, N, N-Dimethylaminoformyl, Ethylaminoformyl, Cyclopropylaminoformyl, Cyclobutylaminoformyl, Cyclopentylaminoformyl, Cyclohexylaminoformyl Formyl, aminoacetyl, methylaminoacetyl, 2-(N, N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropylaminoacetyl, cyclobutyl Aminoacetyl, Cyclopentylaminoacetyl, Cyclohexylaminoacetyl, Tetrahydropyrrole-1-formyl, 3-(N, N-Dimethylamino)tetrahydropyrrolyl -1-formyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-formyl, morpholinyl-4-formyl, thiophenanthyl-4-formyl , 2,6-dimethylmorpholinyl-4-formyl, piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethyl Amino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)guanyl Pyridyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidine Base-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N- (2-Hydroxyethyl)piperazine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N- Diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl Pyridyl) piperazin-1-formyl, (13) hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, isopropoxyformyl, normal Butoxyformyl, isobutoxyformyl, tert-butoxyformyl, (14) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, Propylaminosulfonyl, Isopropylaminosulfonyl, Cyclopropylaminosulfonyl, Cyclobutylaminosulfonyl, Cyclopentylaminosulfonyl, Cyclohexylaminosulfonyl, Tetrahydropyrrole-1- Sulfonyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-sulfonyl, Morpholinyl-4-sulfonyl, Thiophanolinyl-4-sulfonyl, 2 6-Dimethylmorpholinyl-4-sulfonyl, Piperidinyl-1-sulfonyl, 4-Hydroxy Piperidinyl-1-sulfonyl, 4-(N, N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N, N-diethylamino)piperidinyl-1-sulfonyl Acyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-sulfonyl , N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N-(2-hydroxyethyl) Piperazine-1-sulfonyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N, N-diethylaminoethyl) Piperazine-1-sulfonyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4-piperidinyl)piperazine-1 -sulfonyl, (15) carbamoylamino, carbamoylamino, carbamoylamino, carboxypropylamino, carboxypropylamino, carbamoyl isopropylamino, carbamoylcyclopropyl, carbamoylcyclobutylamino Formylamino, cyclopentylaminoformylamino, piperidinyl-1-formylamino, 4-hydroxypiperidinyl-1-formylamino, 4-N, N-dimethylpiperidinyl-1- Formylamino, 4-N, N-diethylpiperidinyl-1-formylamino, tetrahydropyrrolyl-1-formylamino, 3-N, N-dimethyltetrahydropyrrolyl-1- Formylamino, 3-N, N-diethyltetrahydropyrrolyl-1-formylamino, N-methylpiperazinyl-1-formylamino, N-ethylpiperazinyl-1-formylamino Amino, N-acetylpiperazinyl-1-formylamino, N-tert-butoxycarbonylpiperazinyl-1-formylamino, N-(2-hydroxyethyl)piperazinyl-1-formylamino Amino, N-(2-cyanoethyl)piperazinyl-1-formylamino, N-(2-N, N-dimethylaminoethyl)piperazinyl-1-formylamino, N- (2-N, N-diethylaminoethyl)piperazinyl-1-formylamino, N-(3-hydroxypropyl)piperazinyl-1-formylamino, N-(3-N, N-Dimethylpropyl)piperazinyl-1-formylamino, N-(3-N, N-diethylpropyl)piperazinyl-1-formylamino, morpholinyl-1-formylamino Amino, 3, 5-dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N-methyl-1-piperazine Base) piperidyl-1-formylamino, 4-(N-ethyl-1-piperazinyl) piperidinyl-1-formylamino, 4-(N-acetyl-1-piperazinyl ) piperidinyl-1-formylamino, N-(N-methyl-4-piperidinyl) piperazinyl-1-formylamino, (16)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 02_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 02_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; Z 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl , C1-C6 alkoxy, C3-C6 cycloalkyl; Z2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; R 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1- C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl; R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl; or, R 3 , R 4 and their The linked carbon atoms are taken together to form a 5-membered ring containing one N, O or S atom.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）2-N, N-二甲基氨基乙氧基，2-(N-甲基呱嗪基)乙氧基，2-(N-乙醯基呱嗪基)乙氧基，2-嗎啡啉基乙氧基，2-硫啡啉基乙氧基，2-呱啶基乙氧基，3-N, N-二甲基氨基丙氧基，3-N, N-二乙基氨基丙氧基，3-N, N-二異丙基氨基丙氧基，3-(N-甲基呱嗪基)丙氧基，3-(N-乙醯基呱嗪基)丙氧基，3-嗎啉基丙氧基，3-硫啡啉基丙氧基，3-呱啶基丙氧基，2-吡啶基甲氧基，3-吡啶基甲氧基，4-吡啶基甲氧基，苯基甲氧基，單鹵素取代苯基甲氧基，偕二鹵素取代苯基甲氧基，雜二鹵素取代苯基甲氧基， （4）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （5）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （6）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （7）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （8）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （9）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （10）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （11）氨基亞甲基，N, N-二甲基氨基亞甲基，N, N-二乙基氨基亞甲基，4-甲基-1-呱嗪亞甲基，4-乙基-1-呱嗪亞甲基，4-丙基-1-呱嗪亞甲基，4-異丙基-1-呱嗪亞甲基，4-(2-羥基乙基)-1-呱嗪亞甲基，4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基，呱啶-1-亞甲基，4-(N, N-二甲基氨基)-1-呱啶亞甲基，4-羥基呱啶-1-亞甲基，四氫吡咯-1-亞甲基，3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基，苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （12）氨基甲醯基，甲胺基甲醯基，N, N-二甲基氨基甲醯基，乙胺基甲醯基，環丙基胺基甲醯基，環丁基胺基甲醯基，環戊基胺基甲醯基，環己基胺基甲醯基，氨基乙醯基，甲胺基乙醯基，2-(N, N-二甲基氨基)乙醯基，乙胺基乙醯基，環丙基胺基乙醯基，環丁基胺基乙醯基，環戊基胺基乙醯基，環己基胺基乙醯基， 四氫吡咯-1-甲醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基， 嗎啡啉基-4-甲醯基，硫啡啉基-4-甲醯基，2, 6-二甲基嗎啡啉基-4-甲醯基， 呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （13）羥基甲醯基，甲氧基甲醯基，乙氧基甲醯基，丙氧基甲醯基，異丙氧基甲醯基，正丁氧基甲醯基，異丁氧基甲醯基，叔丁氧基甲醯基， （14）羥基磺醯基，氨基磺醯基，甲胺基磺醯基，乙胺基磺醯基，丙胺基磺醯基，異丙胺基磺醯基，環丙胺基磺醯基，環丁胺基磺醯基，環戊胺基磺醯基，環己胺基磺醯基， 四氫吡咯-1-磺醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基， 嗎啡啉基-4-磺醯基，硫啡啉基-4-磺醯基，2 6-二甲基嗎啡啉基-4-磺醯基， 呱啶基-1-磺醯基，4-羥基呱啶-1-磺醯基，4-(N, N-二甲基氨基)呱啶基-1-磺醯基，4-(N, N-二乙基氨基)呱啶基-1-磺醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基， N-甲基呱嗪-1-磺醯基，N-乙基呱嗪-1-磺醯基，N-異丙基呱嗪-1-磺醯基，N-(2-羥基乙基)呱嗪-1-磺醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基，4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基，4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基， （15）氨基甲醯氨基，甲氨基甲醯氨基，乙氨基甲醯氨基，丙氨基甲醯氨基，異丙氨基甲醯氨基，環丙基氨基甲醯氨基，環丁基氨基甲醯氨基，環戊基氨基甲醯氨基，呱啶基-1-甲醯氨基，4-羥基呱啶基-1-甲醯氨基，4-N, N-二甲基呱啶基-1-甲醯氨基，4-N, N-二乙基呱啶基-1-甲醯氨基，四氫吡咯基-1-甲醯氨基，3-N, N-二甲基四氫吡咯基-1-甲醯氨基，3-N, N-二乙基四氫吡咯基-1-甲醯氨基，N-甲基呱嗪基-1-甲醯氨基，N-乙基呱嗪基-1-甲醯氨基，N-乙醯基呱嗪基-1-甲醯氨基，N-叔丁氧羰基呱嗪基-1-甲醯氨基，N-(2-羥基乙基)呱嗪基-1-甲醯氨基，N-(2-氰基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基，N-(3-羥基丙基)呱嗪基-1-甲醯氨基， N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基，N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基，嗎啉基-1-甲醯氨基，3, 5-二甲基嗎啉基-1-甲醯氨基，4-(四氫吡咯基)呱啶基-1-甲醯氨基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基，N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基， （16）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 02_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 02_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； Z 1選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； Z 2選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； R 3選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基； R 4選自氫，氟，氯，溴，碘，C1-C6烷基； 或者，R 3、R 4和與它們相連的碳原子一起，形成含一個N、O或S原子的5元環。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) 2-N, N-dimethylaminoethoxy, 2-(N-methylpiperazinyl) ethoxy, 2-( N-acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethyl Aminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3 -(N-acetylpiperazinyl)propoxy, 3-morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidinylpropoxy, 2-pyridylmethoxy , 3-pyridylmethoxy, 4-pyridylmethoxy, phenylmethoxy, monohalogen substituted phenylmethoxy, geminal dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy Base, (4) piperazinyl, N-methyl piperazinyl, N-ethyl piperazinyl, N-n-propyl piperazinyl, N-isopropyl piperazinyl, N-cyclopropyl piperazinyl Base, N-(2-hydroxyethyl) piperazinyl, N-(2-N, N-dimethylaminoethyl) piperazinyl, N-(2-N, N-diethylaminoethyl ) piperazinyl, N-(2-cyanoethyl) piperazinyl, N-cyanomethyl piperazinyl, N-(3-hydroxypropyl) piperazinyl, N-(3-N, N- Dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N -(N-ethyl-4-piperidinyl) piperazinyl, N-(N-isopropyl-4-piperidinyl) piperazinyl, 4-(azetidin-3-yl) piperazinyl Azidinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-( N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-acrylpiperazinyl, N- Isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl, N-n-propylsulfonyl piperazinyl , N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (5) morpholinyl, 2, 6-dimethyl Morpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (6) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1- Pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methyl 1-ethylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3 -yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl , 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, ( 8) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4 -Hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazin-1-) Piperidyl, 4-(N-ethylpiperazine-1-)piperidyl, 4-(N-isopropylpiperazine-1-)piperidyl, 4-(N-acetylpiperazine- 1-) piperidinyl, 4-(N-tert-butoxycarbonyl piperazin-1-) piperidinyl, 4-(N-methylsulfonyl piperazin-1-) piperidinyl, 4-(N- (2-Hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N-(3-hydroxypropyl Base) piperazin-1-) piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl) piperazin-1-) piperidinyl, 4-(N-(2-N , N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N, N-dimethylpropyl)piperazin-1-)piperidinyl, 4-( N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N, N-dimethyl Baseaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (9)piperidin-4-yl, N-methyl Base-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl- 4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl )-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N- (3-Hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylamino Propyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (10) amino, N, N- Dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2 -Hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylamino Ethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiperazinyl)ethylamino, 3- N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylpiperidinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propylpiperidin-4-amino, N -Isopropylpiperidine-4-amino, (11) aminomethylene, N, N-dimethylaminomethylene, N, N-diethylaminomethylene, 4-methyl-1- Piperazine methylene, 4-ethyl-1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2 -Hydroxyethyl)-1-piperazine methylene, 4-(2-N, N-dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4- (N, N-Dimethylamino)-1-piperidine, 4-hydroxypiperidine-1-methylene, tetrahydropyrrole-1-methylene, 3-(N, N-dimethyl Amino)-1-tetrahydropyrromethene, benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, (12) carbamoyl , Methylaminoformyl, N, N-Dimethylaminoformyl, Ethylaminoformyl, Cyclopropylaminoformyl, Cyclobutylaminoformyl, Cyclopentylaminoformyl Formyl, cyclohexylaminoformyl, aminoacetyl, methylaminoacetyl, 2-(N, N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropyl Aminoacetyl, cyclobutylaminoacetyl, cyclopentylaminoacetyl, cyclohexylaminoacetyl, tetrahydropyrrole-1-formyl, 3-(N, N-di Methylamino)tetrahydropyrrolyl-1-formyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-formyl, morpholinyl-4-formyl, thiophene Linyl-4-formyl, 2, 6-dimethylmorpholinyl-4-formyl, piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4 -(N, N-dimethylamino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl -1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl- 1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine- 1-formyl, N-(2-hydroxyethyl)piperazine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-formyl, N -(2-N, N-diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-( N-ethyl-4-piperidinyl)piperazine-1-formyl, (13) hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, iso Propoxyformyl, n-butoxyformyl, isobutoxyformyl, tert-butoxyformyl, (14) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl , Ethylaminosulfonyl, Propylaminosulfonyl, Isopropylaminosulfonyl, Cyclopropylaminosulfonyl, Cyclobutylaminosulfonyl, Cyclopentylaminosulfonyl, Cyclohexylaminosulfonyl base, tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-diethylamino)tetrahydropyrrolyl Base-1-sulfonyl, morpholinyl-4-sulfonyl, thiomorpholinyl-4-sulfonyl, 2 6-dimethylmorpholinyl-4-sulfonyl, piperidinyl-1 -sulfonyl, 4-hydroxypiperidine-1-sulfonyl, 4-(N, N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N, N-diethylamino ) piperidyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl) piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl) piperidinyl Pyridyl-1-sulfonyl, N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N -(2-Hydroxyethyl)piperazine-1-sulfonyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N, N -Diethylaminoethyl)piperazine-1-sulfonyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4- Piperidinyl) piperazine-1-sulfonyl, (15) carbamoylamino, carbamoylamino, carbamoyl ethyl, carboxypropylamino, carbamoyl isopropylamino, carbamoylcyclopropylamino Formylamino, cyclobutylaminoformylamino, cyclopentylaminoformylamino, piperidinyl-1-formylamino, 4-hydroxypiperidinyl-1-formylamino, 4-N, N-di Methylpiperidinyl-1-formylamino, 4-N, N-diethylpiperidinyl-1-formylamino, tetrahydropyrrolyl-1-formylamino, 3-N, N-dimethyl Tetrahydropyrrolyl-1-formylamino, 3-N, N-diethyltetrahydropyrrolyl-1-formylamino, N-methylpiperazinyl-1-formylamino, N-ethyl Piperazinyl-1-formylamino, N-acetylpiperazinyl-1-formylamino, N-tert-butoxycarbonylpiperazinyl-1-formylamino, N-(2-hydroxyethyl) Piperazinyl-1-formylamino, N-(2-cyanoethyl)piperazinyl-1-formylamino, N-(2-N, N-dimethylaminoethyl)piperazinyl- 1-formylamino, N-(2-N, N-diethylaminoethyl)piperazinyl-1-formylamino, N-(3-hydroxypropyl)piperazinyl-1-formylamino , N-(3-N, N-Dimethylpropyl)piperazinyl-1-formylamino, N-(3-N, N-diethylpropyl)piperazinyl-1-formylamino , Morpholinyl-1-formylamino, 3, 5-dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N -Methyl-1-piperazinyl)piperidinyl-1-formylamino, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formylamino, 4-(N-ethyl Acyl-1-piperazinyl)piperidinyl-1-formylamino, N-(N-methyl-4-piperidinyl)piperazinyl-1-formylamino, (16)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 02_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 02_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; Z 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl , C1-C6 alkoxy, C3-C6 cycloalkyl; Z2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; R 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1- C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl; R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl; or, R 3 , R 4 and their The linked carbon atoms are taken together to form a 5-membered ring containing one N, O or S atom.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫。 在一些實施方案中，R 1選自 1）
Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N- Deuterated ethyl piperazinyl, N-n-propyl piperazinyl, N-deutero-n-propyl piperazinyl, N-isopropyl piperazinyl, N-deuteroisopropyl piperazinyl, N- Cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N-(2-N, N-di Ethylaminoethyl) piperazinyl, N-(2-cyanoethyl) piperazinyl, N-cyanomethyl piperazinyl, N-(3-hydroxypropyl) piperazinyl, N-(3 -N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl) Piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidine- 3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazine Base, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-acrylpiperazinyl Azinyl, N-isobutyrylpiperazinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonyl Acyl piperazinyl, N-isopropylsulfonyl piperazinyl, N-cyclopropylsulfonyl piperazinyl, 2-oxo-piperazin-4-yl, (4) morpholinyl, 2 , 6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1- Imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4- Base, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propane Basepyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazole Azol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol- 5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylamino Piperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperidinyl Azine-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazine-1-)piperidinyl, 4-(N-ethyl Acylpiperazin-1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N- (3-Hydroxypropyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazine-1-)piperidinyl, 4-(N -(2-N, N-diethylethyl)piperazine-1-)piperidine, 4-(N-(3-N, N-dimethylpropyl)piperazine-1-)piperidine Base, 4-(N-(3-N, N-diethylpropyl) piperazin-1-) piperidinyl, 4-(tetrahydropyrrole-1-) piperidinyl, 4-(3-N , N-dimethylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (8)piperidine-4- Base, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N- tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-di Methylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl Pyridyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N -Diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (9)amino , N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl -N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N -Dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino) ) ethylamino, N-isopropyl-N-(2-N, N-dimethylamino) ethylamino, 2-morpholinyl ethylamino, 2-(N-methylpiperazinyl) ethyl 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholine Propylamino, 3-(N-methylpiperidinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propylpiperidine- 4-amino, N-isopropylpiperidine-4-amino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, ( 11) Piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethylamino)piperidinyl-1-formyl, 4-( N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl -1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1 -Formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1-formyl, N-(2-N, N-Dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N-diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazin-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazin-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time. In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N- (2-N, N-diethylaminoethyl)piperazinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl) Piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazine Base, N-propionyl piperazinyl, N-isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl Base, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (4) Morpholinyl, 2, 6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethyl ylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl , 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1 -Methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazole- 5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3- Base, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N , N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazine-1-)piperidine Base, 4-(N-acetylpiperazine-1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazine-1-)piperidinyl, 4-(N-methylsulfonylpiperazine -1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl Pyridyl, 4-(N-(3-hydroxypropyl)piperazine-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazine-1-) Piperidinyl, 4-(N-(2-N, N-diethylethyl)piperazin-1-)piperidinyl, 4-(N-(3-N, N-dimethylpropyl) Piperazin-1-)piperidinyl, 4-(N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrole-1-)piperidine Base, 4-(3-N, N-dimethylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl- 4-piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N- (2-N, N-dimethylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyano Ethyl)-4-piperidinyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4- Piperidinyl, (9) amino, N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxy Ethylamino, N-methyl-N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethyl Amino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino) ethylamino, N-ethyl-N-(2- N, N-dimethylamino)ethylamino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N -methylpiperazinyl)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylamino Propylamino, 3-morpholinopropylamino, 3-(N-methylpiperazinyl)propylamino, N-methylpiperidine-4-amino, N-ethylpiperidine-4-amino, N-n-propylpiperidin-4-amino, N-isopropylpiperidin-4-amino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene , cyclohexylmethylene, (11) piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethylamino)piperidinyl-1 -Formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl , 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)guanyl Azine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazin-1-formyl, N-(2-N, N-diethylaminoethyl)guanidine Azine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazine-1- Formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-三氘代甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基， 3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-异丙基-N-(2-N, N-二甲基氨基)乙基氨基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N- Methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azepine Butan-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, 2,6-dimethylmorpholine thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-di Ethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl , pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazole -5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1- Isopropylpyrazol-5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N -Diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4- (N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, (8) piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, (9) amino, N , N-Dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N -(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-di Methylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethyl ylamino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethyl Aminopropylamino, 3-N, N-Diisopropylaminopropylamino, (10) Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene Methyl, (11) 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1- Formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine, bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-( N-isopropylpiperazine-1-)piperidinyl, (4) N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2 -N, N-dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基， 3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image009
，
Figure 02_image011
，
Figure 02_image013
，
Figure 02_image015
，
Figure 02_image017
，
Figure 02_image019
，
Figure 02_image021
，
Figure 02_image023
，
Figure 02_image025
，
Figure 02_image027
，
Figure 02_image029
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， （3）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazine Base, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidine-3- Base) piperazinyl, 4-(N-methyl-azetidin-3-yl) piperazinyl, 4-(N-ethyl-azetidin-3-yl) piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, 2,6-dimethylmorpholinyl, thiomorpholinyl, 1,1- Thiomorpholinyl dioxide, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3- (N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazole- 4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazole -3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl , 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazol-5-yl, ( 7) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4 -Hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazin-1-) Piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, (8) piperidin-4-yl, N -Methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, (9) amino, N, N-dimethylamino, N, N -Diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N -Ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl -N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N- (2-N, N-dimethylamino)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N- Diisopropylaminopropylamino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, (11) 4-(N- Methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl Base-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
,
Figure 02_image015
,
Figure 02_image017
,
Figure 02_image019
,
Figure 02_image021
,
Figure 02_image023
,
Figure 02_image025
,
Figure 02_image027
,
Figure 02_image029
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine, bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, (3) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl , 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-) Piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazine-1 -) piperidinyl.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基， N-三氘代甲基呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基， （5）3-(N, N-二甲基氨基)四氫吡咯基， （6）1-咪唑基，1-吡唑基，1-甲基吡唑-4-基， （7）4-N, N-二甲基氨基呱啶基，4-羥基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基， （8）N-甲基-4-呱啶基， （9）2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基， 2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基， （10）苄基，環丙基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image015
，
Figure 02_image023
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）4-N, N-二甲基氨基呱啶基， 4-(N-甲基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, fluorine, ( 2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methyl piperazine Base, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4- (N-methyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, (5)3-(N,N-dimethylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl, (7) 4-N, N-dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperidinyl Perazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, (8)N-methyl-4-piperidinyl, (9)2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethyl Amino, (10) benzyl, cyclopropyl methylene, (11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image015
,
Figure 02_image023
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, (2) C1-C6 alkyl , C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl , (4) N-methyl-N-(2-N, N-dimethylamino) ethylamino.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）N-甲基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基， （5）3-(N, N-二甲基氨基)四氫吡咯基， （6）1-咪唑基，1-吡唑基，1-甲基吡唑-4-基， （7）4-N, N-二甲基氨基呱啶基，4-羥基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基， （8）N-甲基-4-呱啶基， （9）2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基， 2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基， （10）苄基，環丙基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 02_image005
，
Figure 02_image007
，
Figure 02_image015
，
Figure 02_image023
； 2）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基， （3）4-N, N-二甲基氨基呱啶基， 4-(N-甲基呱嗪-1-)呱啶基。 In some embodiments, R is selected from 1 )
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, fluorine, ( 2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) N-methyl piperazinyl, N- (N-methyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl ) piperazinyl, (4) morpholinyl, (5) 3-(N, N-dimethylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 1-pyrazolyl, 1-methyl Pyrazol-4-yl, (7) 4-N, N-dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methyl Piperazin-1-) piperidinyl, (8) N-methyl-4-piperidinyl, (9) 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino , 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, (10) benzyl, cyclopropylmethylene , (11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image015
,
Figure 02_image023
; 2)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, (2) C1-C6 alkyl , C1-C6 alkoxy, (3) 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，其中： Y 1選自氫、氟、甲氧基、三氟甲氧基， Y 2選自氫、氟， Y 3選自氫、4-嗎啉基、N-甲基-N-（2-羥基）乙基氨基、2-羥基乙基氨基、2-N, N-二甲基氨基乙基氨基、N-甲基-N-(2-N, N-二甲基氨基)乙基氨基、3-(N, N-二甲基氨基)四氫吡咯基、4-羥基呱啶基、4-N, N-二甲基氨基呱啶基、4-(N-甲基呱嗪-1-)呱啶基、4-(呱嗪-1-)呱啶基、N-甲基-4-呱啶基、呱嗪基、N-甲基呱嗪基、N-三氘代甲基呱嗪基、N-(N-甲基-4-呱啶基)呱嗪基、4-(N-甲基-氮雜環丁烷-3-基)呱嗪基、4-(氮雜環丁烷-3-基)呱嗪基、4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基、
Figure 02_image005
、
Figure 02_image007
、
Figure 02_image015
、
Figure 02_image023
， Y 4選自氫、氟、甲基、乙基、異丙基、環丙基、苄基、環丙基亞甲基、乙烯基、N-甲基-4-呱啶基、N-甲基呱嗪基、4-羥基呱啶基、
Figure 02_image056
、
Figure 02_image058
、
Figure 02_image060
， Y 5為氫， 且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫； 較佳地，
Figure 02_image003
作為整體，選自：
Figure 02_image062
、
Figure 02_image064
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image148
、
Figure 02_image150
、
Figure 02_image152
、
Figure 02_image154
、
Figure 02_image156
、
Figure 02_image158
、
Figure 02_image160
、
Figure 02_image162
、
Figure 02_image164
、
Figure 02_image166
、
Figure 02_image168
、
Figure 02_image170
、
Figure 02_image172
、
Figure 02_image174
、
Figure 02_image176
、
Figure 02_image178
、
Figure 02_image180
、
Figure 02_image182
、
Figure 02_image184
、
Figure 02_image186
； 2）
Figure 02_image033
，其中： Y 1選自氫、甲氧基、
Figure 02_image188
； Y 3選自4-(N-甲基呱嗪-1-)呱啶基、4-N, N-二甲基氨基呱啶基、N-甲基-N-(2-N, N-二甲基氨基)乙基氨基； Y 4選自氫、甲基、乙基； Y 5選自氫； 較佳地，
Figure 02_image033
作為整體，選自：
Figure 02_image190
、
Figure 02_image192
、
Figure 02_image194
、
Figure 02_image196
、
Figure 02_image198
。 In some embodiments, R is selected from 1 )
Figure 02_image003
, wherein: Y 1 is selected from hydrogen, fluorine, methoxy, trifluoromethoxy, Y 2 is selected from hydrogen, fluorine, Y 3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2 -Hydroxy)ethylamino, 2-Hydroxyethylamino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino , 3-(N, N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazine-1 -)piperidinyl, 4-(piperazine-1-)piperidinyl, N-methyl-4-piperidinyl, piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperidinyl Azidinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl,
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image015
,
Figure 02_image023
, Y is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, benzyl, cyclopropyl methylene, vinyl, N-methyl-4-piperidinyl, N-methyl Piperazinyl, 4-hydroxypiperidinyl,
Figure 02_image056
,
Figure 02_image058
,
Figure 02_image060
, Y 5 is hydrogen, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time; preferably,
Figure 02_image003
As a whole, selected from:
Figure 02_image062
,
Figure 02_image064
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
,
Figure 02_image154
,
Figure 02_image156
,
Figure 02_image158
,
Figure 02_image160
,
Figure 02_image162
,
Figure 02_image164
,
Figure 02_image166
,
Figure 02_image168
,
Figure 02_image170
,
Figure 02_image172
,
Figure 02_image174
,
Figure 02_image176
,
Figure 02_image178
,
Figure 02_image180
,
Figure 02_image182
,
Figure 02_image184
,
Figure 02_image186
; 2)
Figure 02_image033
, wherein: Y 1 is selected from hydrogen, methoxy,
Figure 02_image188
; Y3 is selected from 4-(N-methylpiperazin-1-) piperidinyl, 4-N, N-dimethylaminopiperidinyl, N-methyl-N-(2-N, N- Dimethylamino) ethylamino; Y is selected from hydrogen, methyl, ethyl; Y is selected from hydrogen; preferably,
Figure 02_image033
As a whole, selected from:
Figure 02_image190
,
Figure 02_image192
,
Figure 02_image194
,
Figure 02_image196
,
Figure 02_image198
.

在一些實施方案中，R 1選自 1）

Figure 02_image003
，其中： Y 1選自氫、氟、甲氧基、三氟甲氧基， Y 2選自氫、氟， Y 3選自氫、4-嗎啉基、N-甲基-N-（2-羥基）乙基氨基、2-羥基乙基氨基、2-N, N-二甲基氨基乙基氨基、N-甲基-N-(2-N, N-二甲基氨基)乙基氨基、3-(N, N-二甲基氨基)四氫吡咯基、4-羥基呱啶基、4-N, N-二甲基氨基呱啶基、4-(N-甲基呱嗪-1-)呱啶基、4-(呱嗪-1-)呱啶基、N-甲基呱嗪基、N-(N-甲基-4-呱啶基)呱嗪基、4-(N-甲基-氮雜環丁烷-3-基)呱嗪基、4-(氮雜環丁烷-3-基)呱嗪基、4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基、
Figure 02_image005
、
Figure 02_image007
、
Figure 02_image015
、
Figure 02_image023
， Y 4選自氫、氟、甲基、乙基、異丙基、環丙基、苄基、環丙基亞甲基、乙烯基、N-甲基-4-呱啶基、N-甲基呱嗪基、4-羥基呱啶基、
Figure 02_image056
、
Figure 02_image058
、
Figure 02_image060
， Y 5為氫， 且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫； 較佳地，
Figure 02_image003
作為整體，選自：
Figure 02_image062
、
Figure 02_image064
、
Figure 02_image066
、
Figure 02_image068
、
Figure 02_image070
、
Figure 02_image072
、
Figure 02_image074
、
Figure 02_image076
、
Figure 02_image078
、
Figure 02_image080
、
Figure 02_image082
、
Figure 02_image084
、
Figure 02_image086
、
Figure 02_image088
、
Figure 02_image090
、
Figure 02_image092
、
Figure 02_image094
、
Figure 02_image096
、
Figure 02_image098
、
Figure 02_image100
、
Figure 02_image102
、
Figure 02_image104
、
Figure 02_image106
、
Figure 02_image108
、
Figure 02_image110
、
Figure 02_image112
、
Figure 02_image114
、
Figure 02_image116
、
Figure 02_image118
、
Figure 02_image120
、
Figure 02_image122
、
Figure 02_image124
、
Figure 02_image126
、
Figure 02_image128
、
Figure 02_image130
、
Figure 02_image132
、
Figure 02_image134
、
Figure 02_image136
、
Figure 02_image138
、
Figure 02_image140
、
Figure 02_image142
、
Figure 02_image144
、
Figure 02_image146
、
Figure 02_image148
、
Figure 02_image150
、
Figure 02_image152
、
Figure 02_image154
、
Figure 02_image156
、
Figure 02_image158
、
Figure 02_image160
、
Figure 02_image162
、
Figure 02_image164
、
Figure 02_image166
、
Figure 02_image168
、
Figure 02_image170
、
Figure 02_image172
、
Figure 02_image174
、
Figure 02_image176
； 2）
Figure 02_image033
，其中： Y 1選自氫、甲氧基； Y 3選自4-(N-甲基呱嗪-1-)呱啶基、4-N, N-二甲基氨基呱啶基； Y 4選自氫、甲基、乙基； Y 5選自氫； 較佳地，
Figure 02_image033
作為整體，選自：
Figure 02_image190
、
Figure 02_image192
、
Figure 02_image194
、
Figure 02_image196
。 In some embodiments, R is selected from 1 )
Figure 02_image003
, wherein: Y 1 is selected from hydrogen, fluorine, methoxy, trifluoromethoxy, Y 2 is selected from hydrogen, fluorine, Y 3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2 -Hydroxy)ethylamino, 2-Hydroxyethylamino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino , 3-(N, N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazine-1 -)piperidinyl, 4-(piperazin-1-)piperidinyl, N-methylpiperidinyl, N-(N-methyl-4-piperidinyl)piperidinyl, 4-(N- Methyl-azetidin-3-yl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-1-piperazinyl)piperidine Base-1-formyl,
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image015
,
Figure 02_image023
, Y is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, benzyl, cyclopropyl methylene, vinyl, N-methyl-4-piperidinyl, N-methyl Piperazinyl, 4-hydroxypiperidinyl,
Figure 02_image056
,
Figure 02_image058
,
Figure 02_image060
, Y 5 is hydrogen, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time; preferably,
Figure 02_image003
As a whole, selected from:
Figure 02_image062
,
Figure 02_image064
,
Figure 02_image066
,
Figure 02_image068
,
Figure 02_image070
,
Figure 02_image072
,
Figure 02_image074
,
Figure 02_image076
,
Figure 02_image078
,
Figure 02_image080
,
Figure 02_image082
,
Figure 02_image084
,
Figure 02_image086
,
Figure 02_image088
,
Figure 02_image090
,
Figure 02_image092
,
Figure 02_image094
,
Figure 02_image096
,
Figure 02_image098
,
Figure 02_image100
,
Figure 02_image102
,
Figure 02_image104
,
Figure 02_image106
,
Figure 02_image108
,
Figure 02_image110
,
Figure 02_image112
,
Figure 02_image114
,
Figure 02_image116
,
Figure 02_image118
,
Figure 02_image120
,
Figure 02_image122
,
Figure 02_image124
,
Figure 02_image126
,
Figure 02_image128
,
Figure 02_image130
,
Figure 02_image132
,
Figure 02_image134
,
Figure 02_image136
,
Figure 02_image138
,
Figure 02_image140
,
Figure 02_image142
,
Figure 02_image144
,
Figure 02_image146
,
Figure 02_image148
,
Figure 02_image150
,
Figure 02_image152
,
Figure 02_image154
,
Figure 02_image156
,
Figure 02_image158
,
Figure 02_image160
,
Figure 02_image162
,
Figure 02_image164
,
Figure 02_image166
,
Figure 02_image168
,
Figure 02_image170
,
Figure 02_image172
,
Figure 02_image174
,
Figure 02_image176
; 2)
Figure 02_image033
, wherein: Y 1 is selected from hydrogen, methoxy; Y 3 is selected from 4-(N-methylpiperazin-1-) piperidinyl, 4-N, N-dimethylaminopiperidinyl; Y 4 selected from hydrogen, methyl, ethyl; Y is selected from hydrogen; preferably,
Figure 02_image033
As a whole, selected from:
Figure 02_image190
,
Figure 02_image192
,
Figure 02_image194
,
Figure 02_image196
.

在一些實施方案中，Z 1選自氫，C1-C6烷基，C3-C6環烷基。 In some embodiments, Z is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.

在一些實施方案中，Z 1選自氫、甲基、乙基、環丙基。 In some embodiments, Z is selected from hydrogen, methyl, ethyl, cyclopropyl.

在一些實施方案中，Z 2選自C1-C6烷基，C3-C6環烷基。 In some embodiments, Z 2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

在一些實施方案中，Z 2選自甲基、乙基、異丙基、環丙基。 In some embodiments, Z is selected from methyl, ethyl, isopropyl, cyclopropyl.

在一些實施方案中，R 3選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C2-C6烯基。 In some embodiments, R is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C2-C6 Alkenyl.

在一些實施方案中，R 3選自氫、氟、氯、溴、甲基、乙基、異丙基、甲氧基、乙氧基、氰基、硝基、三氟甲基、乙烯基、1-甲基-乙烯基。 In some embodiments, R is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, methoxy, ethoxy, cyano, nitro, trifluoromethyl, vinyl, 1-Methyl-vinyl.

在一些實施方案中，R 4選自氫，C1-C6烷基。 In some embodiments, R 4 is selected from hydrogen, C1-C6 alkyl.

在一些實施方案中，R 4為氫。 In some embodiments, R4 is hydrogen.

在一些實施方案中，R 3、R 4和與它們相連的碳原子一起，形成

Figure 02_image045
，
Figure 02_image047
或
Figure 02_image049
。 In some embodiments, R 3 , R 4 , together with the carbon atoms to which they are attached, form
Figure 02_image045
,
Figure 02_image047
or
Figure 02_image049
.

在一些實施方案中，R 3、R 4和與它們相連的碳原子一起，形成

Figure 02_image045
。 In some embodiments, R 3 , R 4 , together with the carbon atoms to which they are attached, form
Figure 02_image045
.

在本發明的第三方面，本發明提供了以下式II所示的化合物：

Figure 02_image200
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （5）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基； 2）
Figure 02_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 02_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 02_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； Z 3選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； R 3選自氫，氟，氯，溴，碘，硝基，氰基，C2-C6烯基； R 4選自氫，氟，氯，溴，碘，C1-C6烷基。 In a third aspect of the present invention, the present invention provides compounds represented by the following formula II:
Figure 02_image200
or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N- (2-N, N-diethylaminoethyl)piperazinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl) Piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazine Base, N-propionyl piperazinyl, N-isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl Base, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (4) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine -1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazine-1-)piperidinyl, 4-(N -(2-Hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxy Propyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2- N, N-diethylethyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4- (N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N, N-di Methylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (5)piperidin-4-yl, N- Methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl -4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl Base)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N -(3-Hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethyl Aminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl; 2)
Figure 02_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 02_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 02_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; Z 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl , C1-C6 alkoxy, C3-C6 cycloalkyl; R 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2-C6 alkenyl; R 4 is selected from hydrogen, fluorine, chlorine , bromine, iodine, C1-C6 alkyl.

在一些實施方案中，R 1為

Figure 02_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基， （4）4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基。 In some embodiments, R is
Figure 02_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, ( 2) C1-C6 alkyl, C1-C6 alkoxy, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl -4-piperidinyl) piperidinyl, (4) 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1-)piperidinyl, 4-(N-ethyl Piperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl.

在一些實施方案中，R 1為

Figure 02_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： 氫，C1-C6烷基，C1-C6烷氧基，N-甲基呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，4-(N-甲基呱嗪-1-)呱啶基。 In some embodiments, R is
Figure 02_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen: hydrogen, C1-C6 alkane Base, C1-C6 alkoxy, N-methylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methylpiperazine-1-)piperidine base.

在一些實施方案中，R 1為

Figure 02_image003
，其中： Y 1選自氫、甲氧基， Y 2為氫， Y 3選自N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基、N-(N-甲基-4-呱啶基)呱嗪基， Y 4為乙基， Y 5為氫。 In some embodiments, R is
Figure 02_image003
, wherein: Y 1 is selected from hydrogen, methoxy, Y 2 is hydrogen, Y 3 is selected from N-methylpiperazinyl, 4-(N-methylpiperazin-1-)piperidinyl, N-( N-methyl-4-piperidinyl) piperazinyl, Y 4 is ethyl, Y 5 is hydrogen.

在一些實施方案中，R 1選自

Figure 02_image062
、
Figure 02_image096
、
Figure 02_image114
、
Figure 02_image124
。 In some embodiments, R is selected from
Figure 02_image062
,
Figure 02_image096
,
Figure 02_image114
,
Figure 02_image124
.

在一些實施方案中，Z 3選自C1-C6烷基，C3-C6環烷基。 In some embodiments, Z is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

在一些實施方案中，Z 3選自甲基、乙基、異丙基、環丙基。 In some embodiments, Z is selected from methyl, ethyl, isopropyl, cyclopropyl.

在一些實施方案中，R 3選自氟，氯，溴，碘，C2-C6烯基。 In some embodiments, R is selected from fluoro, chloro, bromo, iodo, C2-C6 alkenyl.

在一些實施方案中，R 3選自溴、乙烯基。 In some embodiments, R is selected from bromo, vinyl.

在一些實施方案中，R 4選自氫，C1-C6烷基。 In some embodiments, R 4 is selected from hydrogen, C1-C6 alkyl.

在一些實施方案中，R 4為氫。 In some embodiments, R4 is hydrogen.

在本發明的第四方面，本發明提供了以下式III所示的化合物：

Figure 02_image202
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 02_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （5）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基； 2）
Figure 02_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 02_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 02_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 02_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； Z 4、Z 5各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基，且Z 4、Z 5不同時為氫； R 3選自氫，氟，氯，溴，碘，硝基，氰基，C2-C6烯基； R 4選自氫，氟，氯，溴，碘，C1-C6烷基。 In the fourth aspect of the present invention, the present invention provides the compound shown in the following formula III:
Figure 02_image202
or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 02_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N- (2-N, N-diethylaminoethyl)piperazinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl) Piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazine Base, N-propionyl piperazinyl, N-isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl Base, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (4) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine -1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazine-1-)piperidinyl, 4-(N -(2-Hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxy Propyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2- N, N-diethylethyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4- (N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N, N-di Methylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (5)piperidin-4-yl, N- Methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl -4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl Base)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N -(3-Hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethyl Aminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl; 2)
Figure 02_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 02_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 02_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 02_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine , C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 4 , Z 5 are not hydrogen at the same time; R 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano Base, C2-C6 alkenyl; R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl.

在一些實施方案中，R 1為

Figure 02_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基。 In some embodiments, R is
Figure 02_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, ( 2) C1-C6 alkyl, C1-C6 alkoxy, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl -4-piperidinyl)piperazinyl.

在一些實施方案中，R 1為

Figure 02_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： 氫，C1-C6烷基，C1-C6烷氧基，N-甲基呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基。 In some embodiments, R is
Figure 02_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: hydrogen, C1-C6 alkane Base, C1-C6 alkoxy, N-methylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl.

在一些實施方案中，R 1為

Figure 02_image003
，其中： Y 1選自氫、甲氧基， Y 2為氫， Y 3選自N-甲基呱嗪基、N-(N-甲基-4-呱啶基)呱嗪基， Y 4為乙基， Y 5為氫。 In some embodiments, R is
Figure 02_image003
, wherein: Y 1 is selected from hydrogen, methoxy, Y 2 is hydrogen, Y 3 is selected from N-methylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl, Y 4 is ethyl, Y 5 is hydrogen.

在一些實施方案中，R 1選自

Figure 02_image062
、
Figure 02_image096
、
Figure 02_image124
。 In some embodiments, R is selected from
Figure 02_image062
,
Figure 02_image096
,
Figure 02_image124
.

在一些實施方案中，Z 4、Z 5各自獨立地選自氫，C1-C6烷基，C3-C6環烷基，且Z 4、Z 5不同時為氫。 In some embodiments, Z 4 and Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 and Z 5 are not hydrogen at the same time.

在一些實施方案中，Z 4選自氫、C1-C6烷基，較佳為氫；Z 5選自C1-C6烷基，C3-C6環烷基。 In some embodiments, Z 4 is selected from hydrogen, C1-C6 alkyl, preferably hydrogen; Z 5 is selected from C1-C6 alkyl, C3-C6 cycloalkyl.

在一些實施方案中，Z 4選自氫，Z 5選自甲基、乙基、異丙基、環丙基。 In some embodiments, Z is selected from hydrogen and Z is selected from methyl, ethyl, isopropyl, cyclopropyl.

在一些實施方案中，R 3選自氟，氯，溴，碘，C2-C6烯基。 In some embodiments, R is selected from fluoro, chloro, bromo, iodo, C2-C6 alkenyl.

在一些實施方案中，R 3選自溴、乙烯基。 In some embodiments, R is selected from bromo, vinyl.

在一些實施方案中，R 4選自氫，C1-C6烷基。 In some embodiments, R 4 is selected from hydrogen, C1-C6 alkyl.

在一些實施方案中，R 4為氫。 In some embodiments, R4 is hydrogen.

除非特殊說明，上述基團和取代基具有藥物化學領域的普通含義。Unless otherwise specified, the above-mentioned groups and substituents have ordinary meanings in the field of medicinal chemistry.

在本說明書的各部分，本發明揭露化合物的取代基按照基團種類或範圍揭露。特別指出，本發明包括這些基團種類和範圍的各個成員的每一個獨立的次級組合。例如，術語“C1-C6烷基”特別指獨立揭露的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。In each part of the specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C1-C6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

術語“C1-C6烷基”指的是任意的含有1-6個碳原子的直鏈或支鏈基團，例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。The term "C1-C6 alkyl" refers to any straight-chain or branched group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.

術語“C1-C3烷基”指的是任意的含有1-3個碳原子的直鏈或支鏈基團，例如甲基、乙基、正丙基、異丙基等。The term "C1-C3 alkyl" refers to any linear or branched chain group containing 1-3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.

術語“氘代烷基”是指任意上述烷基（例如C1-C6烷基、C1-C3烷基等）中的一個或多個氫原子被氘原子替代後形成的基團，例如，氘代烷基可以為氘代甲基、氘代乙基、氘代正丙基或氘代異丙基等等。具體例如，氘代甲基可以為單氘代甲基、二氘代甲基或三氘代甲基。The term "deuterated alkyl" refers to a group formed after one or more hydrogen atoms in any of the above-mentioned alkyl groups (such as C1-C6 alkyl, C1-C3 alkyl, etc.) are replaced by deuterium atoms, for example, deuterated The alkyl group may be deuterated methyl, deuterated ethyl, deuterated n-propyl or deuterated isopropyl and the like. Specifically, for example, the deuteromethyl group may be monodeuteromethyl group, dideuteromethyl group or trideuteromethyl group.

術語“含氧烷基”是指是指烷基骨架被一個或多個烷氧基取代所成的基團，例如，甲氧基乙基，甲氧基乙氧基甲基等。The term "oxyalkyl group" refers to a group in which the alkyl skeleton is substituted by one or more alkoxy groups, for example, methoxyethyl, methoxyethoxymethyl and the like.

例如，C1-C6含氧烷基是指是指C1-C6烷基骨架被一個或多個C1-C6烷氧基取代所成的基團，例如，甲氧基乙基，甲氧基乙氧基甲基等。類似地，C1-C3含氧烷基是指是指C1-C3烷基骨架被一個或多個C1-C6烷氧基取代所成的基團。For example, a C1-C6 oxyalkyl group refers to a group in which the C1-C6 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxy base methyl etc. Similarly, a C1-C3 oxyalkyl group refers to a group in which a C1-C3 alkyl skeleton is substituted by one or more C1-C6 alkoxy groups.

術語“C2-C6烯基”指的是任意的含有2-6個碳原子，且含有至少一個碳碳雙鍵的直鏈或支鏈基團，例如乙烯基、1-丙烯基、2-丙烯基等。The term "C2-C6 alkenyl" refers to any straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl Base etc.

術語“C3-C8環烷基”是指具有飽和環的3-8元單環系統的烴，C3-C8環烷基可以為環丙基、環丁基、環戊基、環己基等。The term "C3-C8 cycloalkyl" refers to a 3-8-membered monocyclic hydrocarbon having a saturated ring, and the C3-C8 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

術語“C3-C6環烷基”是指具有飽和環的3-6元單環系統的烴，C3-C6環烷基可以為環丙基、環丁基、環戊基、環己基等。The term "C3-C6 cycloalkyl" refers to a 3-6-membered monocyclic hydrocarbon having a saturated ring, and the C3-C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

術語“氰基”指的是-CN殘基。The term "cyano" refers to a -CN residue.

術語“硝基”指的是-NO 2基團。 The term "nitro" refers to the -NO2 group.

術語“雜原子”指的是N，O或S。The term "heteroatom" refers to N, O or S.

術語“烷氧基”、“環基氧基”及其衍生物指的是任意上述烷基（例如C1-C6烷基、C1-C3烷基等）、環烷基（例如C3-C6環烷基），其藉由氧原子(-O-)連接到分子的其餘部分。The terms "alkoxy", "cyclyloxy" and their derivatives refer to any of the above-mentioned alkyl (such as C1-C6 alkyl, C1-C3 alkyl, etc.), cycloalkyl (such as C3-C6 cycloalkane group), which is linked to the rest of the molecule by an oxygen atom (-O-).

術語“雜芳基”是指芳族的雜環，通常為具有1至3個選自N、O或S的雜原子的5-、6-、7-、8-元的雜環；雜芳基環可以任選地進一步稠合或連接於芳族和非芳族的碳環和雜環。該雜芳基的非限制性的實例為例如吡啶基、吡嗪基、嘧啶基、噠嗪基、吲哚基、咪唑基、噻唑基、異噻唑基、噻噁唑基、吡咯基、苯基-吡咯基、呋喃基、苯基-呋喃基、噁唑基、異噁唑基、吡唑基、噻吩基、苯並呋喃基、苯並噻吩基、苯並1,3-二氧戊環（苯並二噁茂）、異二氫吲哚基、苯並咪唑基、吲唑基、喹啉基、異喹啉基、1,2,3-三唑基、1-苯基-1,2,3-三唑基、2,3-二氫吲哚基、2,3-二氫苯並呋喃基、2,3-二氫苯並噻吩基、苯並吡喃基、2,3-二氫苯並噁嗪基、2,3-二氫喹喔啉基等。The term "heteroaryl" refers to an aromatic heterocycle, usually a 5-, 6-, 7-, 8-membered heterocycle having 1 to 3 heteroatoms selected from N, O or S; heteroaryl The base ring can optionally be further fused or attached to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups are e.g. pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiaxazolyl, pyrrolyl, phenyl -pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuryl, benzothienyl, benzo 1,3-dioxolane ( benzodioxol), isoindolinyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolyl, 1,2,3-triazolyl, 1-phenyl-1,2 ,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, benzopyranyl, 2,3-di Hydrobenzoxazinyl, 2,3-dihydroquinoxalinyl, etc.

術語“雜環基”(也稱作“雜環烷基”)指的是3-、4-、5-、6-和7-元飽和或部分不飽和碳環，其中一個或多個碳原子被雜原子例如氮、氧和硫替代。雜環基的非限制性實例是，例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、噻唑啉、噻唑烷、二氫呋喃、四氫呋喃、1,3-二氧戊環、呱啶、呱嗪、嗎啉、嗎啡啉基、四氫吡咯基、硫嗎啉基等。The term "heterocyclyl" (also "heterocycloalkyl") refers to 3-, 4-, 5-, 6- and 7-membered saturated or partially unsaturated carbocyclic rings in which one or more carbon atoms Replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3- Dioxolane, piperidine, piperazine, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, etc.

例如，“6元雜環基”指的是6-元飽和或部分不飽和碳環，其中一個或多個碳原子被雜原子例如氮、氧和硫替代。6元雜環基的非限制性實例是，例如吡喃、呱啶、呱嗪、嗎啉、嗎啡啉基、硫嗎啉基等。For example, "6-membered heterocyclyl" refers to a 6-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of 6-membered heterocyclic groups are, for example, pyran, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl, and the like.

“5元雜環基”指的是5-元飽和或部分不飽和碳環，其中一個或多個碳原子被雜原子例如氮、氧和硫替代。5元雜環基的非限制性實例是，例如吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、噻唑啉、噻唑烷、1,3-二氧戊環等。"5-membered heterocyclyl" refers to a 5-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples of 5-membered heterocyclic groups are, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane, and the like.

術語“任選被取代的雜環基”指的是上述“雜環基”被一個或多個“C1-C6烷基”、“C1-C3烷基”、“C3-C6環烷基”等取代。The term "optionally substituted heterocyclic group" refers to the above-mentioned "heterocyclic group" replaced by one or more "C1-C6 alkyl", "C1-C3 alkyl", "C3-C6 cycloalkyl", etc. replace.

“含氟烷基”是指上述烷基骨架（例如C1-C6烷基）被一個或多個氟基取代所成的基團，例如，單氟甲基，二氟乙基，三氟甲基等。"Fluorine-containing alkyl" refers to the above-mentioned alkyl skeleton (such as C1-C6 alkyl) is replaced by one or more fluorine groups, such as monofluoromethyl, difluoroethyl, trifluoromethyl wait.

術語“C1-C6含氟烷基”是指上述的C1-C6烷基骨架被一個或多個氟基取代所成的基團，例如，單氟甲基，二氟乙基，三氟甲基等。The term "C1-C6 fluorine-containing alkyl group" refers to a group in which the above-mentioned C1-C6 alkyl skeleton is substituted by one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl wait.

類似地，術語“C1-C3含氟烷基”是指C1-C3烷基骨架被一個或多個氟基取代所成的基團，例如，單氟甲基，二氟乙基，三氟甲基等。Similarly, the term "C1-C3 fluorine-containing alkyl group" refers to a group in which the C1-C3 alkyl skeleton is substituted by one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl Base etc.

術語“含氟烷氧基”指的是任意上述含氟烷基（例如C1-C6含氟烷基、C1-C3含氟烷基等）其藉由氧原子(-O-)連接到分子的其餘部分，如三氟甲氧基、

Figure 02_image188
等等。 The term "fluorine-containing alkoxy" refers to any of the above-mentioned fluorine-containing alkyl groups (such as C1-C6 fluorine-containing alkyl groups, C1-C3 fluorine-containing alkyl groups, etc.), which are connected to the molecule through an oxygen atom (-O-) The rest, such as trifluoromethoxy,
Figure 02_image188
etc.

術語“C1-C6含雜原子烷基”是指C1-C6烷基骨架中的一個或多個碳原子被一個或多個例如氮、氧和硫的雜原子替代所成的基團，例如，

Figure 02_image204
、
Figure 02_image206
、
Figure 02_image208
等。 The term "C1-C6 heteroatom-containing alkyl group" refers to a group in which one or more carbon atoms in the C1-C6 alkyl skeleton are replaced by one or more heteroatoms such as nitrogen, oxygen and sulfur, for example,
Figure 02_image204
,
Figure 02_image206
,
Figure 02_image208
wait.

術語“C3-C8含雜原子環烷基”是指C3-C8環烷基骨架中的一個或多個碳原子被一個或多個例如氮、氧和硫的雜原子替代所成的基團，例如吡咯烷、咪唑烷、吡唑烷、噻唑烷、呱啶、呱嗪、嗎啉、嗎啡啉基、硫嗎啉基等。The term "C3-C8 heteroatom-containing cycloalkyl" refers to a group in which one or more carbon atoms in the C3-C8 cycloalkyl skeleton are replaced by one or more heteroatoms such as nitrogen, oxygen and sulfur, For example, pyrrolidine, imidazolidine, pyrazolidine, thiazolidine, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl and the like.

術語“磺醯基”指的是和-S(=O) 2-。 The term "sulfonyl" refers to and -S(=O) 2- .

術語“C1-C6烷基磺醯基”指的是-S(=O) 2-C1-C6烷基，例如甲磺醯基、乙磺醯基、丙磺醯基、丁磺醯基等。 The term "C1-C6 alkylsulfonyl" refers to -S(=O) 2 -C1-C6 alkyl, such as methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl and the like.

從所有上述描述中，對本領域技術人員顯而易見的是，其名稱是複合名稱的任意基團，例如“含氟含氧烷基”，應該指的是常規地從其衍生的部分例如從被氟基取代的含氧烷基來建構，其中烷基如上文所定義。類似地，還有“含氟烷氧基”。又例如，“芳基氨基”，應該指的是常規地從其衍生的部分例如從被芳基取代的氨基來建構，其中芳基如上文所定義。類似地，可以理解“雜芳氨基”的含義。類似地，可以理解“羥基磺醯基”、“氨基磺醯基”等的含義。From all the foregoing descriptions, it will be apparent to those skilled in the art that any group whose name is a compound name, such as "fluorine-containing oxyalkyl", shall refer to the moiety from which it is conventionally derived, such as from a fluorinated group Substituted oxyalkyl groups wherein alkyl is as defined above. Similarly, there is also "fluorinated alkoxy". As another example, "arylamino" shall refer to the moiety derived therefrom conventionally, for example constructed from an amino group substituted by an aryl group, wherein aryl is as defined above. Similarly, the meaning of "heteroarylamino" can be understood. Similarly, "hydroxysulfonyl", "sulfamoyl" and the like are to be understood.

同樣，任意術語例如烷基氨基、二烷基氨基、烷氧基羰基、烷氧基羰基氨基、雜環基羰基、雜環基羰基氨基、環烷基氧基羰基、烷氧基甲醯基等複合基團，其中烷基、烷氧基等部分如上文所定義。Likewise, arbitrary terms such as alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, alkoxyformyl, etc. Composite groups, wherein the alkyl, alkoxy, etc. moieties are as defined above.

術語“R 3、R 4各自獨立地選自”表示R 3和R 4代表的基團可以相同，也可以不同，相互之間不受制約。例如，R 3、R 4各自獨立地選自氫或甲基，其含義為，R 3選自氫或甲基，R 4選自氫或甲基。其他類似的定義可以參照前述內容進行理解。 The term "R 3 and R 4 are each independently selected from" means that the groups represented by R 3 and R 4 may be the same or different, and there is no restriction on each other. For example, R 3 and R 4 are each independently selected from hydrogen or methyl, which means that R 3 is selected from hydrogen or methyl, and R 4 is selected from hydrogen or methyl. Other similar definitions can be understood with reference to the foregoing.

根據本發明和除非另有提供，任意上述基團可以任選地在其任意自由位置上被一個或多個基團取代，例如被1-6個基團取代，該基團獨立地選自: 鹵素原子、硝基、氧代(=O)、氰基、C1-C6 烷基、多氟化烷基、多氟化烷氧基、烯基、炔基、羥基烷基、羥基烷基氨基、羥基雜環基、芳基、芳基-烷基、雜芳基、雜芳基-烷基、雜環基、雜環基-烷基、C3-C7環烷基、環烷基-烷基、烷基-芳基、烷基-雜芳基、烷基-雜環基、烷基-環烷基、烷基-芳基-烷基、烷基-雜芳基-烷基、烷基-雜環基-烷基、烷基-環烷基-烷基、烷基-雜環基-雜環基、雜環基-雜環基、雜環基-烷基-雜環基、雜環基-烷基氨基、烷基-雜環基-烷基-氨基、羥基、烷氧基、芳氧基、雜環基氧基、烷基-雜環基氧基、亞甲二氧基、烷基羰基氧基、芳基羰基氧基、環烯基氧基、雜環基羰基氧基、亞烷基氨基氧基、羧基、烷氧基羰基、芳氧基羰基、環烷基氧基羰基、雜環基氧基羰基、氨基、脲基、烷基氨基、氨基-烷基氨基、二烷基氨基、二烷基氨基-雜環基、二烷基氨基-烷基氨基、芳基氨基、芳基烷基氨基、二芳基氨基、雜環基氨基、烷基-雜環基氨基、烷基-雜環基羰基、甲醯基氨基、烷基羰基氨基、芳基羰基氨基、雜環基羰基氨基、烷基-雜環基羰基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、雜環基氨基羰基、烷氧基羰基氨基、烷氧基羰基氨基-烷基氨基、烷氧基羰基雜環基-烷基氨基、烷氧基-芳基-烷基、羥基氨基-羰基、烷氧基亞氨基、烷基磺醯基氨基、芳基磺醯基氨基、雜環基磺醯基氨基、甲醯基、烷基羰基、芳基羰基、環烷基羰基、雜環基羰基、烷基磺醯基、芳基磺醯基、氨基磺醯基、烷基氨基磺醯基、二烷基氨基磺醯基、芳基氨基磺醯基、雜環基氨基磺醯基、芳硫基、烷硫基、膦酸酯基和烷基膦酸酯基。According to the present invention and unless otherwise provided, any of the above-mentioned groups may optionally be substituted at any free position thereof by one or more groups, for example by 1-6 groups independently selected from: Halogen atom, nitro, oxo (=O), cyano, C1-C6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkylamino, Hydroxyheterocyclyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, heterocyclyl-alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, Alkyl-aryl, Alkyl-heteroaryl, Alkyl-heterocyclyl, Alkyl-cycloalkyl, Alkyl-aryl-alkyl, Alkyl-heteroaryl-alkyl, Alkyl-hetero Cyclo-Alkyl, Alkyl-Cycloalkyl-Alkyl, Alkyl-Heterocyclyl-Heterocyclyl, Heterocyclyl-Heterocyclyl, Heterocyclyl-Alkyl-Heterocyclyl, Heterocyclyl- Alkylamino, Alkyl-Heterocyclyl-Alkyl-Amino, Hydroxy, Alkoxy, Aryloxy, Heterocyclyloxy, Alkyl-Heterocyclyloxy, Methylenedioxy, Alkylcarbonyl Oxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, alkyleneaminooxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterocyclic oxycarbonyl, amino, ureido, alkylamino, amino-alkylamino, dialkylamino, dialkylamino-heterocyclyl, dialkylamino-alkylamino, arylamino, arylalkyl Alkylamino, diarylamino, heterocyclylamino, alkyl-heterocyclylamino, alkyl-heterocyclylcarbonyl, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, Alkyl-heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, alkoxycarbonylamino-alkylamino, Alkoxycarbonylheterocyclyl-alkylamino, alkoxy-aryl-alkyl, hydroxyamino-carbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclyl Sulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl , dialkylsulfamoyl, arylsulfamoyl, heterocyclylsulfamoyl, arylthio, alkylthio, phosphonate and alkylphosphonate.

進而，如果適合，上述取代基各自可以進一步被一個或多個上述舉出的基團取代。Furthermore, each of the above-mentioned substituents may be further substituted by one or more of the above-mentioned groups, if appropriate.

術語“含氧的取代或未取代的五-七元環”或“含氮的取代或未取代的五-七元環”指的是5-、6-或7-元飽和或部分不飽和碳環，其中一個或多個碳原子被氧或氮替代。非限制性實例是，例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、二氫呋喃、四氫呋喃、1,3-二氧戊環、呱啶、呱嗪、嗎啉、四氫吡咯基、六亞甲基亞胺等。The term "oxygen-containing substituted or unsubstituted five-seven-membered ring" or "nitrogen-containing substituted or unsubstituted five-seven-membered ring" refers to 5-, 6- or 7-membered saturated or partially unsaturated carbon A ring in which one or more carbon atoms are replaced by oxygen or nitrogen. Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.

術語“取代或未取代的五-七元環”指的是5-、6-或7-元飽和或部分不飽和碳環。非限制性實例是，例如，環戊烷、環己烷、環戊烯、環戊二烯、環己烯、環己二烯（環己-1,3-二烯、環已-1,4-二烯）等。The term "substituted or unsubstituted five-seven-membered ring" refers to a 5-, 6- or 7-membered saturated or partially unsaturated carbocyclic ring. Non-limiting examples are, for example, cyclopentane, cyclohexane, cyclopentene, cyclopentadiene, cyclohexene, cyclohexadiene (cyclohexa-1,3-diene, cyclohexa-1,4 -diene), etc.

術語“取代或未取代的含1~2個雜原子的4-8元環”指的是4-、5-、6-、7-或8-元飽和或部分不飽和碳環，其中一個或2個碳原子被例如氮、氧和硫的雜原子替代。非限制性實例是，例如吡喃、吡咯烷、吡咯啉、咪唑啉、咪唑烷、吡唑烷、吡唑啉、二氫呋喃、四氫呋喃、1,3-二氧戊環、呱啶、呱嗪、嗎啉、四氫吡咯基、六亞甲基亞胺等。The term "substituted or unsubstituted 4-8 membered ring containing 1 to 2 heteroatoms" refers to a 4-, 5-, 6-, 7- or 8-membered saturated or partially unsaturated carbocyclic ring, one or 2 carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.

對於式（A）

Figure 02_image001
所示化合物，術語“R 3、R 4和與它們相連的碳原子一起，形成
Figure 02_image045
，
Figure 02_image047
或
Figure 02_image049
”，其指的是，式（A）所示的化合物的結構式為
Figure 02_image210
，
Figure 02_image212
或
Figure 02_image214
，虛線雙鍵
Figure 02_image216
表示R 3、R 4和與它們相連的碳原子一起形成的雜環與母核稠合的位置。另外，式（I）
Figure 02_image218
所示的化合物中類似的術語定義參照前述內容進行解釋和理解。 For formula (A)
Figure 02_image001
The compounds shown, the terms "R 3 , R 4 together with the carbon atoms to which they are attached, form
Figure 02_image045
,
Figure 02_image047
or
Figure 02_image049
", which means that the structural formula of the compound shown in formula (A) is
Figure 02_image210
,
Figure 02_image212
or
Figure 02_image214
, dotted double bond
Figure 02_image216
Indicates the position where the heterocyclic ring formed by R 3 , R 4 and the carbon atoms connected to them is fused with the parent nucleus. In addition, formula (I)
Figure 02_image218
Definitions of similar terms in the compounds shown are explained and understood with reference to the foregoing.

如本文所使用，除非另外說明，術語“前藥”是指可以在生物學條件（體外或體內）下水解、氧化或進行其他反應以提供本發明的化合物的衍生物。前藥僅在生物學條件下經過該反應成為活性化合物，或者它們在它們不反應的形式中不具有活性。通常可以使用公知的方法製備前藥，例如Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff編, 第5版)中描述的那些方法。As used herein, unless otherwise stated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction only under biological conditions to become active compounds, or they are inactive in their unreacted form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.).

如本文所使用，術語“式(A)、(I)、(II)或(III)的化合物的藥學上可接受的鹽”的例子是由形成藥學上可以接受的陰離子的有機酸形成的有機酸加合鹽，包括但不限於甲酸鹽、乙酸鹽、丙酸鹽、苯甲酸鹽、馬來酸鹽、富馬酸鹽、琥珀酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、α-酮戊二酸鹽、α-甘油磷酸鹽、烷基磺酸鹽或芳基磺酸鹽；較佳地，該烷基磺酸鹽為甲基磺酸鹽或乙基磺酸鹽；該芳基磺酸鹽為苯磺酸鹽或對甲苯磺酸鹽。也可形成合適的無機鹽，包括但不限於鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、碳酸氫鹽和碳酸鹽、硫酸鹽或磷酸鹽等。As used herein, examples of the term "pharmaceutically acceptable salts of compounds of formula (A), (I), (II) or (III)" are organic salts formed from organic acids that form pharmaceutically acceptable anions. Acid addition salts, including but not limited to formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, ascorbate, alpha - ketoglutarate, α-glycerophosphate, alkylsulfonate or arylsulfonate; preferably, the alkylsulfonate is methylsulfonate or ethylsulfonate; the aromatic The sulfonate is benzenesulfonate or p-toluenesulfonate. Suitable inorganic salts may also be formed including, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate, and carbonate, sulfate or phosphate salts, and the like.

藥學上可接受的鹽可使用本領域熟知的標準程式獲得，例如，藉由將足量的鹼性化合物和提供藥學上可以接受的陰離子的合適的酸反應。Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid to furnish a pharmaceutically acceptable anion.

本文使用的術語“治療”一般是指獲得需要的藥理和/或生理效應。該效應根據完全或部分地預防疾病或其症狀，可以是預防性的；和/或根據部分或完全穩定或治癒疾病和/或由於疾病產生的副作用，可以是治療性的。本文使用的“治療”涵蓋了對患者疾病的任何治療，包括：(a)預防易感染疾病或症狀但還沒診斷出患病的患者所發生的疾病或症狀；(b)抑制疾病的症狀，即阻止其發展；或(c)緩解疾病的症狀，即，導致疾病或症狀退化。The term "treating" as used herein generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) prophylaxis of a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed; (b) suppressing the symptoms of the disease, ie arresting its development; or (c) alleviating the symptoms of the disease, ie causing regression of the disease or symptoms.

按照本發明的一種具體技術方案，該化合物、其立體異構體、其前藥、 或者其藥學上可接受的鹽或藥學上可接受的溶劑合物，其中所述化合物為下面實施例中所述化合物之一。According to a specific technical scheme of the present invention, the compound, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, wherein the compound is as described in the following examples one of the above compounds.

另一方面，本發明提供了藥物組合物，其包含上述任一技術方案所述的化合物、其立體異構體、其前藥、或者其藥學上可接受的鹽或藥學上可接受的溶劑合物，和任選的藥學上可接受的載體、稀釋劑或賦形劑。In another aspect, the present invention provides a pharmaceutical composition, which comprises the compound described in any of the above technical schemes, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate material, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

在一些實施方案中，該藥物組合物進一步包含EGFR單抗。In some embodiments, the pharmaceutical composition further comprises EGFR mAb.

在一些實施方案中，該EGFR單抗為西妥昔單抗或其生物類似物。In some embodiments, the EGFR mAb is cetuximab or a biosimilar thereof.

術語“生物類似物”指的是序列與西妥昔單抗相同，理化性質以及生物活性、臨床安全性有效性也與西妥昔一致的抗體產品。The term "biological analogue" refers to an antibody product whose sequence is identical to that of cetuximab, and whose physical and chemical properties, biological activity, clinical safety and efficacy are also consistent with those of cetuximab.

製備各種含有一定量的活性成分的藥物組合物的方法是已知的，或根據本發明的揭露內容對於本領域技術人員是顯而易見的。如REMINGTON’S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed.(1995)所述，製備該藥物組合物的方法包括摻入適當的藥學賦形劑、載體、稀釋劑等。Methods for preparing various pharmaceutical compositions containing certain amounts of active ingredients are known, or will be apparent to those skilled in the art in light of the present disclosure. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, E.W., ed., Mack Publishing Company, 19th ed. (1995), the method of preparing the pharmaceutical composition includes incorporating suitable pharmaceutical excipients, carriers, diluents and the like.

以已知的方法製造本發明的藥物製劑，包括常規的混合、溶解或凍乾方法。本發明的化合物可以製成藥物組合物，並向患者以適於選定的施用方式的各種途徑施用，例如，口服或腸胃外（藉由靜脈內、肌內、局部或皮下途徑）。The pharmaceutical formulations of the present invention are manufactured in known ways, including conventional mixing, dissolving or lyophilization methods. The compounds of the present invention can be formulated into pharmaceutical compositions and administered to the patient by various routes suitable for the chosen mode of administration, for example, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).

因此，本發明的化合物結合藥學上可以接受的載體（如惰性稀釋劑或可同化的可食用的載體）可以全身施用，例如，口服。它們可以封閉在硬或軟殼的明膠膠囊中，可以壓為片劑。對於口服治療施用，活性化合物可以結合一種或多種賦形劑，並以可吞咽的片劑、頰含片劑、含片、膠囊劑、酏劑、懸浮劑、糖漿、圓片等的形式使用。這種組合物和製劑應該包含至少0.1%的活性化合物。這種組合物和製劑的比例當然可以變化，可以占給定的單位劑型重量的大約1%至大約99%。在這種治療有用的組合物中，活性化合物的量使得能夠獲得有效劑量水準。Thus, the compounds of the present invention may be administered systemically, eg, orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier. They can be enclosed in hard or soft-shell gelatin capsules, which can be compressed into tablets. For oral therapeutic administration, the active compounds can be incorporated with one or more excipients and used in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of active compound. The proportion of such compositions and preparations may of course vary and may comprise from about 1% to about 99% by weight of a given unit dosage form. In such therapeutically useful compositions, the amount of active compound is such that an effective dosage level will be obtained.

片劑、含片、丸劑、膠囊劑等也可以包含：黏合劑，如黃蓍膠、阿拉伯膠、玉米澱粉或明膠；賦形劑，如磷酸氫二鈣；崩解劑，如玉米澱粉、馬鈴薯澱粉、藻酸等；潤滑劑，如硬脂酸鎂；和甜味劑，如蔗糖、果糖、乳糖或阿斯巴甜；或調味劑，如薄荷、冬青油或櫻桃香味。當單位劑型是膠囊時，除了上面類型的材料，它還可以包含液體載體，如植物油或聚乙二醇。各種其他材料可以存在，作為包衣，或以其他方式改變固體單位劑型的物理形式。例如，片劑、丸劑或膠囊劑可以用明膠、蠟、蟲膠或糖等包衣。糖漿或酏劑可以包含活性化合物，蔗糖或果糖作為甜味劑，對羥苯甲酸甲酯或對羥苯甲酸丙酯作為防腐劑，染料和調味劑（如櫻桃香料或桔子香料）。當然，用於製備任何單位劑型的任何材料應該是藥學上可以接受的且以應用的量基本上無毒。此外，活性化合物可以摻入緩釋製劑和緩釋裝置中。Tablets, troches, pills, capsules, etc. may also contain: binders such as tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; disintegrants such as cornstarch, potato Starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavorings, such as peppermint, oil of wintergreen, or cherry flavor. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present, as coatings, or to otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar or the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl or propyl paraben as a preservative, a dye and a flavoring such as cherry flavor or orange flavor. Of course, any material used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed. Additionally, the active compounds can be incorporated into sustained release formulations and devices.

活性化合物也可以藉由輸注或注射來靜脈內或腹膜內施用。可以製備活性化合物或其鹽的水溶液，任選地混和無毒的表面活性劑。也可以製備在甘油、液體聚乙二醇、甘油三乙酸酯及其混合物以及油中的分散劑。在普通的儲存和使用條件下，這些製劑包含防腐劑以防止微生物生長。The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. Aqueous solutions of the active compound, or a salt thereof, can be prepared, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

適於注射或輸注的藥物劑型可以包括包含適於無菌的可注射或可輸注的溶液或分散劑的即時製劑的活性成分（任選封裝在脂質體中）的無菌水溶液或分散劑或無菌粉末。在所有情況下，最終的劑型在生產和儲存條件下必須是無菌的、液體的和穩定的。液體載體可以是溶劑或液體分散介質，包括，例如水、乙醇、多元醇（例如，甘油、丙二醇、液體聚乙二醇等）、植物油、無毒的甘油酯及其合適的混合物。可以維持合適的流動性，例如，藉由脂質體的形成，藉由在分散劑的情況下維持所需的粒子大小，或藉由表面活性劑的使用。可以藉由各種抗細菌劑和抗真菌劑（如對羥苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等）產生預防微生物的作用。在許多情況下，較佳包括等滲劑，如糖、緩衝劑或氯化鈉。藉由使用延緩吸收劑的組合物（例如，單硬脂酸鋁和明膠）可以產生可注射的組合物的延長吸收。Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient, optionally encapsulated in liposomes, suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oil, nontoxic glycerides, and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersions, or by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be desirable to include isotonic agents, such as sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay absorption (for example, aluminum monostearate and gelatin).

藉由將合適的溶劑中的需要量的活性化合物與需要的上面列舉的各種其他成分結合，然後進行過濾滅菌，製備無菌可注射溶液。在用於製備無菌注射溶液的無菌粉末的情況下，較佳的製備方法是真空乾燥和冷凍乾燥技術，這會產生活性成分加上任何另外需要的以前無菌過濾溶液中存在的成分的粉末。Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in an appropriate solvent with each of the other ingredients enumerated above as required, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional required ingredient which was previously present in a sterile-filtered solution.

有用的固體載體包括粉碎的固體（如滑石、黏土、微晶纖維素、二氧化矽、氧化鋁等）。有用的液體載體包括水、乙醇或乙二醇或水-乙醇/乙二醇混合物，本發明的化合物可以任選在無毒的表面活性劑的幫助下以有效含量溶解或分散在其中。可以加入佐劑（如香味）和另外的抗微生物劑來最佳化對於給定用途的性質。Useful solid carriers include comminuted solids (eg, talc, clays, microcrystalline cellulose, silica, alumina, and the like). Useful liquid carriers include water, ethanol or glycol or water-ethanol/glycol mixtures, in which the compounds of this invention can be dissolved or dispersed in effective amounts, optionally with the aid of nontoxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize properties for a given use.

增稠劑（如合成的聚合物、脂肪酸、脂肪酸鹽和酯、脂肪醇、改性纖維素或改性無機材料）也可和液體載體用於形成可塗覆的糊劑、凝膠、軟膏、肥皂等，直接用於使用者的皮膚上。Thickeners (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified inorganic materials) can also be used with liquid carriers to form spreadable pastes, gels, ointments, Soap, etc., applied directly to the user's skin.

化合物或其活性鹽或衍生物的治療需要量，不僅取決於選擇的特定的鹽，而且取決於施藥方式、待治療的疾病的本質和患者的年齡和狀態，最終取決於在場醫師或臨床醫生的決定。The therapeutically required amount of a compound or its active salt or derivative depends not only on the particular salt chosen, but also on the mode of administration, the nature of the disease to be treated and the age and condition of the patient, and ultimately on the physician or clinician present. Doctor's decision.

上述製劑可以以單位劑型存在，該單位劑型是含有單位劑量的物理分散單元，適於向人體和其它哺乳動物體給藥。單位劑型可以是膠囊或片劑，或是很多膠囊或片劑。根據所涉及的具體治療，活性成分的單位劑量的量可以在大約0.1到大約1000毫克或更多之間進行變化或調整。The formulations described above can be presented in unit dosage form, which are physically discrete units containing unit dosages, suitable for administration to the human and other mammalian bodies. The unit dosage form can be a capsule or tablet, or a plurality of capsules or tablets. The amount of a unit dose of active ingredient may be varied or adjusted from about 0.1 to about 1000 milligrams or more depending on the particular treatment involved.

此外，還包括各種藥物新劑型如乳脂質體、微球和奈米球的應用，如使用微粒分散體系包括聚合物膠束（polymeric  micelles）、奈米乳（nanoemulsion）、亞微乳（submicroemuls微囊（microcapsule）、 微球（microsphere）、脂質體（liposomes）和 類脂囊泡（niosomes）（又稱非離子表面活性劑囊泡）等製備的藥劑。In addition, it also includes the application of various new drug dosage forms such as liposomes, microspheres and nanospheres, such as the use of particle dispersion systems including polymeric micelles, nanoemulsions, submicroemulsions, and microemulsions. Drugs prepared from microcapsules, microspheres, liposomes and niosomes (also known as nonionic surfactant vesicles).

另一方面，本發明還提供了上述任一技術方案所述化合物的製備方法，包括下面步驟：

Figure 02_image220
反應條件： （a）酸性或鹼性條件下的親核取代反應； （b）金屬鈀催化的偶聯反應，或者酸性條件下的親核取代反應，或者鹼性條件下的親核取代反應； （c）金屬鈀催化的偶聯反應，或者金屬銅催化的偶聯反應； 其中： 該金屬鈀催化劑選自醋酸鈀、四(三苯基膦)鈀、雙三苯基磷二氯化鈀、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀、三(二亞苄基丙酮)二鈀； 該鹼性條件指以下任意物質存在的條件：三乙胺、二異丙基乙基胺、吡啶、碳酸氫鈉、碳酸鈉、碳酸鉀、碳酸銫、氫氧化鋰、氫氧化鈉、氫氧化鉀、氫化鈉、氫化鉀； 該酸性條件指以下任意物質存在的條件：乙酸、三氟乙酸、鹽酸、甲磺酸、對甲苯磺酸、樟腦磺酸； X代表鹵素，R 3-Y代表與R 3對應的硼酸（即
Figure 02_image222
）、硼酸酯（即
Figure 02_image224
）、錫試劑（如正三丁基錫試劑即
Figure 02_image226
）或者炔試劑（如三甲基矽基乙炔即
Figure 02_image228
）； R 1、R 2、R 3和R 4的定義詳見之前所述。 In another aspect, the present invention also provides a method for preparing the compound described in any of the above technical schemes, comprising the following steps:
Figure 02_image220
Reaction conditions: (a) Nucleophilic substitution reaction under acidic or basic conditions; (b) Coupling reaction catalyzed by metallic palladium, or nucleophilic substitution reaction under acidic conditions, or nucleophilic substitution reaction under basic conditions; (c) a coupling reaction catalyzed by metal palladium, or a coupling reaction catalyzed by metal copper; wherein: the metal palladium catalyst is selected from palladium acetate, tetrakis (triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium; the basic conditions refer to the conditions under which any of the following substances exist: triethylamine, di Isopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride; the acidic conditions refer to the conditions in which any of the following substances exist : acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid; X represents halogen, R 3 -Y represents boric acid corresponding to R 3 (ie
Figure 02_image222
), borates (ie
Figure 02_image224
), tin reagent (such as n-tributyltin reagent that is
Figure 02_image226
) or alkyne reagents (such as trimethylsilylacetylene ie
Figure 02_image228
); The definitions of R 1 , R 2 , R 3 and R 4 are detailed in the previous description.

另一方面，本發明還提供了上述任一技術方案所述化合物其立體異構體、其前藥、或者其藥學上可接受的鹽或藥學上可接受的溶劑合物及包含該化合物的藥物組合物在製備用於預防和/或治療EGFR激酶介導的癌症及其他疾病的藥物中的用途，尤其是在製備用於預防和/或治療肺癌（較佳非小細胞肺癌）的藥物中的用途，特別是在製備用於預防和/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌（較佳非小細胞肺癌）的藥物中的用途，最佳在製備用於預防和/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌（較佳非小細胞肺癌）的藥物中的用途。On the other hand, the present invention also provides stereoisomers, prodrugs, or pharmaceutically acceptable salts or pharmaceutically acceptable solvates of the compounds described in any of the above technical schemes, and medicaments containing the compounds Use of the composition in preparing medicines for preventing and/or treating EGFR kinase-mediated cancer and other diseases, especially in preparing medicines for preventing and/or treating lung cancer (preferably non-small cell lung cancer) Uses, especially in the preparation of drugs for the prevention and/or treatment of EGFR kinase 19Del, L858R, T790M, C797S or their combination mutant lung cancer (preferably non-small cell lung cancer), the best in the preparation of drugs for the prevention and treatment of / or treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer) Uses in medicine.

另一方面，本發明還提供了預防和/治療EGFR激酶介導的癌症及其他疾病的方法， 其包括給予有需要的受試者預防和/或治療有效量的上述化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物或者上述藥物組合物。On the other hand, the present invention also provides a method for preventing and/or treating EGFR kinase-mediated cancer and other diseases, which comprises administering a preventive and/or therapeutically effective amount of the above-mentioned compound or its stereoisomer to a subject in need , its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the above pharmaceutical composition.

在一些實施方案中，該方法用於預防和/或治療肺癌（較佳非小細胞肺癌）。In some embodiments, the method is used to prevent and/or treat lung cancer (preferably non-small cell lung cancer).

在一些實施方案中，該方法用於預防和/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌（較佳非小細胞肺癌）。In some embodiments, the method is used to prevent and/or treat EGFR kinase 19Del, L858R, T790M, C797S or a combination thereof mutant lung cancer (preferably non-small cell lung cancer).

在一些實施方案中，該方法用於預防和/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌（較佳非小細胞肺癌）。In some embodiments, the method is used to prevent and/or treat EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S Triple mutation lung cancer (preferably non-small cell lung cancer).

另一方面，本發明還提供了上述化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物或者上述藥物組合物，其用於預防和/或治療EGFR激酶介導的癌症及其他疾病，較佳用於預防和/或治療肺癌（較佳非小細胞肺癌），更佳用於預防和/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌（較佳非小細胞肺癌），最佳用於預防和/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌（較佳非小細胞肺癌）。On the other hand, the present invention also provides the above-mentioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the above-mentioned pharmaceutical composition, which is used for preventing and / or treatment of EGFR kinase-mediated cancer and other diseases, preferably for the prevention and / or treatment of lung cancer (preferably non-small cell lung cancer), more preferably for the prevention and / or treatment of EGFR kinase 19Del, L858R, T790M, C797S Lung cancer with mutations or its combination (preferably non-small cell lung cancer), is best used for the prevention and/or treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/ C797S triple mutation or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer).

在本發明中，“受試者”指脊椎動物。在某些實施方案中，脊椎動物指哺乳動物。哺乳動物包括，但不限於，牲畜(諸如牛)、寵物(諸如貓、犬、和馬)、靈長類動物、小鼠和大鼠。在某些實施方案中，哺乳動物指人。In the present invention, "subject" refers to a vertebrate. In certain embodiments, a vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal is a human.

在本發明中，“有效量”指在必需的劑量和時間上有效實現期望的治療或預防效果的量。本發明的物質/分子的“治療有效量”可根據諸如個體的疾病狀態、年齡、性別和體重及該物質/分子在個體中引發期望應答的能力等因素而變化。治療有效量還涵蓋該物質/分子的治療有益效果勝過任何有毒或有害後果的量。“預防有效量”指在必需的劑量和時間上有效實現期望的預防效果的量。通常而非必然，由於預防劑量是在疾病發作之前或在疾病的早期用於受試者的，因此預防有效量會低於治療有效量。在癌症的情況中，藥物的治療有效量可減少癌細胞數；縮小腫瘤體積；抑制(即一定程度的減緩，較佳停止)癌細胞浸潤到周圍器官中；抑制(即一定程度的減緩，較佳停止)腫瘤轉移；一定程度的抑制腫瘤生長；和/或一定程度的減輕與癌症有關的一種或多種症狀。 實驗部分 In the present invention, "effective amount" refers to the amount effective to achieve the desired therapeutic or preventive effect at the necessary dose and time. A "therapeutically effective amount" of a substance/molecule of the invention may vary depending on factors such as the disease state, age, sex and weight of the individual and the ability of the substance/molecule to elicit a desired response in the individual. A therapeutically effective amount also encompasses an amount in which any toxic or detrimental consequences are outweighed by the therapeutically beneficial effects of the substance/molecule. A "prophylactically effective amount" refers to an amount effective at dosages and for periods of time necessary to achieve the desired prophylactic effect. Usually, but not necessarily, the prophylactically effective amount will be lower than the therapeutically effective amount because the prophylactic dose is administered to the subject before the onset of the disease or at an early stage of the disease. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor volume; inhibit (ie, slow down to some extent, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (ie slow down to some extent, preferably stop) better stopping) tumor metastasis; some degree of inhibition of tumor growth; and/or some degree of alleviation of one or more symptoms associated with cancer. Experimental part

就如下涉及的實施例而言，使用本文所述的方法或本領域眾所周知的其他方法合成本發明的化合物。 通用純化和分析方法： For the examples referred to below, the compounds of the invention were synthesized using the methods described herein or other methods well known in the art. General purification and analysis methods:

在矽膠GF254預塗覆板（青島海洋化工廠）上進行薄層色譜。在中壓下經矽膠（300-400目，煙臺市芝罘區黃務矽膠開發試劑廠）進行柱色譜分離或藉由使用ISCO Combiflash Rf200快速純化系統，用預裝的矽膠筒（ISCO或Welch）進行柱色譜分離。成分藉由UV光（波長254 nm）和藉由碘蒸氣顯影。當必要時，將化合物通過製備型HPLC經Waters Symmetry C18 (19 x 50 mm, 5 µm)柱或經Waters X Terra RP 18 (30 x 150 mm, 5 μm)柱純化，使用裝配有996 Waters PDA檢測器的Waters製備型HPLC 600和Micromass mod. ZMD單四級質譜(電噴霧離子化，陽離子模式)檢測。方法1：相A: 0.1% TFA/MeOH 95/5；相B: MeOH/H2O 95/5。梯度：10至90% B進行8 min，保持90% B 2 min；流速20 mL/min。方法2：相A: 0.05% NH4OH/MeOH 95/5；相B: MeOH/H2O 95/5。梯度：10至100% B進行8 min，保持100% B 2 min；流速20 mL/min。Thin-layer chromatography was performed on silica gel GF254 pre-coated plates (Qingdao Ocean Chemical Factory). Column chromatography separation by silica gel (300-400 mesh, Huangwu Silica Gel Development Reagent Factory, Zhifu District, Yantai City) under medium pressure or by using ISCO Combiflash Rf200 rapid purification system with prepacked silica gel cartridges (ISCO or Welch) Column chromatography. The components are visualized by UV light (wavelength 254 nm) and by iodine vapor. When necessary, the compound was purified by preparative HPLC on a Waters Symmetry C18 (19 x 50 mm, 5 µm) column or on a Waters X Terra RP 18 (30 x 150 mm, 5 µm) column, and was equipped with a 996 Waters PDA detection Waters preparative HPLC 600 and Micromass mod. ZMD single quadruple mass spectrometer (electrospray ionization, positive ion mode) detection. Method 1: Phase A: 0.1% TFA/MeOH 95/5; Phase B: MeOH/H2O 95/5. Gradient: 10 to 90% B for 8 min, hold 90% B for 2 min; flow rate 20 mL/min. Method 2: Phase A: 0.05% NH4OH/MeOH 95/5; Phase B: MeOH/H2O 95/5. Gradient: 10 to 100% B for 8 min, hold 100% B for 2 min; flow rate 20 mL/min.

1H-NMR譜在600 MHz的Bruker Avance 600核磁共振波譜儀進行記錄。化學位移（δ）以百萬分率（ppm）進行報導且偶合常數（J）以Hz計。將四甲基矽烷訊號用作參比（δ = 0 ppm）。以下縮寫用於峰裂分: s =單；br. s. =寬訊號；d =雙；t =三；m =多重；dd =雙雙。 1 H-NMR spectra were recorded on a Bruker Avance 600 NMR spectrometer at 600 MHz. Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) in Hz. The tetramethylsilane signal was used as reference (δ = 0 ppm). The following abbreviations are used for peak splitting: s = single; br. s. = broad signal; d = double; t = triple; m = multiple; dd = double-double.

電噴霧(ESI)質譜經Finnigan LCQ離子阱獲得。Electrospray (ESI) mass spectra were acquired on a Finnigan LCQ ion trap.

除非另外說明，所有最終化合物均是均質的(純度不低於95%)，由高效液相色譜(HPLC)所確定。用於評價化合物純度的HPLC-UV-MS分析藉由組合離子阱MS設備與HPLC系統SSP4000 (Thermo Separation Products)來進行，該HPLC系統裝配有自動進樣器LC Pal (CTC Analytics)和UV6000LP二極體陣列檢測器(UV檢測215-400 nm)。用Xcalibur 1.2軟體(Finnigan)進行設備控制、資料獲取和處理。HPLC色譜法在室溫和1 mL/min流速下進行，其使用Waters X Terra RP 18柱(4.6 x 50 mm；3.5 μm)。流動相A是乙酸銨5 mM緩衝液(採用乙酸得到pH 5.5):乙腈 90:10，流動相B乙酸銨5 mM緩衝液(採用乙酸得到pH 5.5):乙腈 10:90；梯度為0至100% B進行7分鐘，然後在再平衡前保持100% B達2分鐘。Unless otherwise stated, all final compounds were homogeneous (not less than 95% pure) as determined by high performance liquid chromatography (HPLC). HPLC-UV-MS analysis for evaluating compound purity was carried out by combining ion trap MS equipment with HPLC system SSP4000 (Thermo Separation Products) equipped with autosampler LC Pal (CTC Analytics) and UV6000LP diode Volume array detector (UV detection 215-400 nm). Equipment control, data acquisition and processing were performed with Xcalibur 1.2 software (Finnigan). HPLC chromatography was performed at room temperature and a flow rate of 1 mL/min using a Waters X Terra RP 18 column (4.6 x 50 mm; 3.5 μm). Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid):acetonitrile 90:10, mobile phase B ammonium acetate 5 mM buffer (pH 5.5 with acetic acid):acetonitrile 10:90; gradient from 0 to 100 % B for 7 minutes, then hold 100% B for 2 minutes before rebalancing.

試劑純化參考Purification of Laboratory Chemicals（Perrin, D. D., Armarego, W. L. F. and Perrins Eds, D. R.; Pergamon Press: Oxford, 1980）一書進行。石油醚是60-90 ℃餾分、乙酸乙酯、甲醇、二氯甲烷均為分析純。 具體實施方式 Purification of reagents was carried out with reference to Purification of Laboratory Chemicals (Perrin, D. D., Armarego, W. L. F. and Perrins Eds, D. R.; Pergamon Press: Oxford, 1980). Petroleum ether is 60-90 ℃ distillate, ethyl acetate, methanol, dichloromethane are analytically pure. Detailed ways

化合物可分為以下三大類：

Figure 02_image051
Figure 02_image200
Figure 02_image202
合成過程中涉及的部分原料及中間體描述如下： Compounds can be divided into three main categories:
Figure 02_image051
Figure 02_image200
Figure 02_image202
Some raw materials and intermediates involved in the synthesis process are described as follows:

1.

Figure 02_image230
，由1-(2-氟-5-硝基苯基)乙酮（cas：79110-05-7，畢得，上海）與N-甲基呱嗪（cas：109-01-3，安耐吉，上海）反應到
Figure 02_image232
,再還原酮羰基與硝基而得。 1.
Figure 02_image230
, from 1-(2-fluoro-5-nitrophenyl)ethanone (cas: 79110-05-7, Bi De, Shanghai) and N-methylpiperazine (cas: 109-01-3, Anai Kat, Shanghai) reacted to
Figure 02_image232
, and then reduced ketone carbonyl and nitro derived.

以下中間體經類似的方法獲得：

Figure 02_image234
The following intermediates were obtained in a similar manner:
Figure 02_image234

所涉及的原料為： 嗎啡啉（cas：110-91-8，阿拉丁，上海），N-甲基-2-羥基乙胺（cas：109-83-1，安耐吉，上海），乙醇胺（cas：141-43-5，阿拉丁，上海）, N,N-二甲基乙二胺（cas：108-00-9，畢得，上海）, N,N,N’-三甲基乙二胺（cas：142-25-6，畢得，上海），2-氧雜-6-氮雜螺[3.3]庚烷（cas：174-78-7，畢得，上海），2-甲基-2,6-二氮雜螺[3.3]庚烷（cas：1203567-11-6，畢得，上海），1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇）, 呱嗪-1-羧酸叔丁酯（cas：57260-71-6，畢得，上海）。 The raw materials involved are: Morpholine (cas: 110-91-8, Aladdin, Shanghai), N-methyl-2-hydroxyethylamine (cas: 109-83-1, Anaiji, Shanghai), ethanolamine (cas: 141-43 -5, Aladdin, Shanghai), N,N-dimethylethylenediamine (cas: 108-00-9, Bi De, Shanghai), N,N,N'-trimethylethylenediamine (cas: 142-25-6, Biide, Shanghai), 2-oxa-6-azaspiro[3.3]heptane (cas: 174-78-7, Biide, Shanghai), 2-methyl-2,6 -Diazaspiro[3.3]heptane (cas: 1203567-11-6, Bide, Shanghai), 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu), piperazine-1-carboxylate tert-butyl ester (cas: 57260-71-6, Bi De, Shanghai).

2.

Figure 02_image236
，由3-溴-4-氟硝基苯（cas：701-45-1，畢得，上海）與N-甲基呱嗪（cas：109-01-3，安耐吉，上海）反應到
Figure 02_image238
，再與環丙基硼酸（cas：411235-57-9，畢得，上海）反應得到
Figure 02_image240
，再還原硝基而得。 2.
Figure 02_image236
, by reacting 3-bromo-4-fluoronitrobenzene (cas: 701-45-1, Bi De, Shanghai) and N-methylpiperazine (cas: 109-01-3, Anaiji, Shanghai) to
Figure 02_image238
, and then react with cyclopropylboronic acid (cas: 411235-57-9, Bi De, Shanghai) to get
Figure 02_image240
, and then obtained by reducing the nitro group.

以下中間體經類似的方法獲得：

Figure 02_image242
The following intermediates were obtained in a similar manner:
Figure 02_image242

所涉及的原料為： 2-硝基-4-溴-5-氟苯甲醚（cas：1352244-77-9，畢得，上海），嗎啡啉（cas：110-91-8，阿拉丁，上海），1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇），1-甲基-1H-吡唑-4-硼酸（cas：847818-55-7，畢得，上海），咪唑（cas：288-32-4，安耐吉，上海），吡唑（cas：288-13-1，畢得，上海）。 The raw materials involved are: 2-nitro-4-bromo-5-fluoroanisole (cas: 1352244-77-9, Bi De, Shanghai), morpholine (cas: 110-91-8, Aladdin, Shanghai), 1-methano Base-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu), 1-methyl-1H-pyrazole-4-boronic acid (cas: 847818-55-7, Biide, Shanghai), imidazole (cas: 288-32-4, Anaiji, Shanghai), pyrazole (cas: 288-13-1, Biide, Shanghai).

3.

Figure 02_image244
，由2-氟-5-硝基甲苯（cas：455-88-9，畢得，上海）與N-甲基呱嗪（cas：109-01-3，安耐吉，上海）反應得到
Figure 02_image246
，再還原硝基而得。 3.
Figure 02_image244
, obtained by reacting 2-fluoro-5-nitrotoluene (cas: 455-88-9, Biide, Shanghai) with N-methylpiperazine (cas: 109-01-3, Anaiji, Shanghai)
Figure 02_image246
, and then obtained by reducing the nitro group.

以下中間體經類似的方法獲得：

Figure 02_image248
The following intermediates were obtained in a similar manner:
Figure 02_image248

所涉及的原料為： 1-氟-5-甲氧基-2-甲基-4-硝基苯（cas：314298-13-0，畢得，上海），2,3,4-三氟硝基苯（cas：771-69-7，畢得，上海），3,4,5-三氟硝基苯（cas：66684-58-0，畢得，上海），5-氟-2-硝基苯甲醚（cas：448-19-1，畢得，上海），對氟硝基苯（cas：350-46-9，畢得，上海），2-氟-5-硝基吡啶（cas：456-24-6，畢得，上海）， 嗎啡啉（cas：110-91-8，阿拉丁，上海），3-N,N-二甲基氨基吡咯烷（cas：64021-83-6，TCI，上海），4-二甲氨基呱啶（cas：50533-97-6，韶遠，上海），1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇），4-羥基呱啶（cas：5382-16-1，安耐吉，上海）。 The raw materials involved are: 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (cas: 314298-13-0, Bi De, Shanghai), 2,3,4-trifluoronitrobenzene (cas: 771 -69-7, Bide, Shanghai), 3,4,5-trifluoronitrobenzene (cas: 66684-58-0, Bide, Shanghai), 5-fluoro-2-nitroanisole (cas : 448-19-1, Bi De, Shanghai), p-fluoronitrobenzene (cas: 350-46-9, Bi De, Shanghai), 2-fluoro-5-nitropyridine (cas: 456-24-6 , Bi De, Shanghai), Morpholine (cas: 110-91-8, Aladdin, Shanghai), 3-N,N-Dimethylaminopyrrolidine (cas: 64021-83-6, TCI, Shanghai), 4-Dimethylaminopiperidine (cas: 50533-97-6, Shaoyuan, Shanghai), 1-methyl-4-(4-piperidinyl) piperazine (cas: 53617-36-0, Aikang, Jiangsu), 4-hydroxyguanidine Pyridine (cas: 5382-16-1, Anaiji, Shanghai).

4.

Figure 02_image250
，由2-氟-4-羥基苯乙酮（cas：98619-07-9，畢得，上海）經鈀碳、氫氣還原得3-氟-4-乙基苯酚，再硝化得到3-氟-4-乙基-6-硝基苯酚，進一步與碘甲烷（cas：74-88-4，西亞試劑，山東）反應得到3-氟-4-乙基-6-硝基苯甲醚，再與N-甲基呱嗪（cas：109-01-3，安耐吉，上海）反應到
Figure 02_image252
，最後還原硝基而得。 4.
Figure 02_image250
, from 2-fluoro-4-hydroxyacetophenone (cas: 98619-07-9, Bi De, Shanghai) to 3-fluoro-4-ethylphenol by palladium carbon and hydrogen reduction, and then nitrated to obtain 3-fluoro- 4-Ethyl-6-nitrophenol was further reacted with iodomethane (cas: 74-88-4, West Asia Reagent, Shandong) to obtain 3-fluoro-4-ethyl-6-nitroanisole, and then reacted with N-methylpiperazine (cas: 109-01-3, Anaiji, Shanghai) was reacted to
Figure 02_image252
, and finally obtained by reducing the nitro group.

以下中間體經類似的方法獲得：

Figure 02_image254
The following intermediates were obtained in a similar manner:
Figure 02_image254

所涉及的原料為： 3-N,N-二甲基氨基吡咯烷（cas：64021-83-6，TCI，上海），4-二甲氨基呱啶（cas：50533-97-6，韶遠，上海），乙醇胺（cas：141-43-5，阿拉丁，上海）, N,N-二甲基乙二胺（cas：108-00-9，畢得，上海）,N,N,N’-三甲基乙二胺（cas：142-25-6，畢得，上海），4-(呱啶-4-基)呱嗪-1-甲酸叔丁酯（cas：205059-24-1，畢得，上海），1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇），1-(1-甲基呱啶-4-基)呱嗪（cas：23995-88-2，百靈威，上海），1-(1-甲基氮雜環丁烷-3-基)呱嗪（cas：864350-81-2，百靈威，上海），2-甲基-2,7-二氮雜螺[3.5]壬烷二鹽酸鹽（cas：1610028-42-6，畢得，上海），2-甲基-2,6-二氮雜螺[3.3]庚烷草酸鹽（cas：1527515-86-1，艾康，江蘇）2-氧雜-6-氮雜螺[3.3]庚烷草酸鹽（cas：1159599-99-1，畢得，上海）, 呱嗪-1-羧酸叔丁酯（cas：57260-71-6，畢得，上海）。 The raw materials involved are: 3-N,N-Dimethylaminopyrrolidine (cas: 64021-83-6, TCI, Shanghai), 4-Dimethylaminopiperidine (cas: 50533-97-6, Shaoyuan, Shanghai), ethanolamine ( cas: 141-43-5, Aladdin, Shanghai), N,N-dimethylethylenediamine (cas: 108-00-9, Bi De, Shanghai), N,N,N'-trimethylethylenediamine Diamine (cas: 142-25-6, Biide, Shanghai), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (cas: 205059-24-1, Biide, Shanghai) , 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu), 1-(1-methylpiperidin-4-yl)piperazine (cas : 23995-88-2, Bailingwei, Shanghai), 1-(1-methylazetidin-3-yl) piperazine (cas: 864350-81-2, Bailingwei, Shanghai), 2-methyl- 2,7-Diazaspiro[3.5]nonane dihydrochloride (cas: 1610028-42-6, Bide, Shanghai), 2-methyl-2,6-diazaspiro[3.3]heptane Oxalate (cas: 1527515-86-1, Aikang, Jiangsu) 2-Oxa-6-azaspiro[3.3]heptane oxalate (cas: 1159599-99-1, Bide, Shanghai), Piperazine-1-carboxylate tert-butyl ester (cas: 57260-71-6, Bi De, Shanghai).

5.

Figure 02_image256
，由2-氧代-7-氮雜螺[3.5]壬烷-7-甲酸叔丁酯（cas：203661-69-2，畢得，上海）與二甲胺（cas：124-40-3，阿拉丁，上海）反應得到
Figure 02_image258
，脫去叔丁氧羰基後與(4)中3-氟-4-乙基-6-硝基苯甲醚反應得到
Figure 02_image260
，再還原硝基而得。 5.
Figure 02_image256
, from tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (cas: 203661-69-2, Bi De, Shanghai) and dimethylamine (cas: 124-40-3 , Aladdin, Shanghai) the response gets
Figure 02_image258
, react with 3-fluoro-4-ethyl-6-nitroanisole in (4) after removing the tert-butoxycarbonyl group to obtain
Figure 02_image260
, and then obtained by reducing the nitro group.

6.

Figure 02_image262
，由1-溴-2-甲基-4-甲氧基-5-硝基苯（cas：89978-56-3，九鼎化學，上海）經氧化為2-溴-4-硝基-5-甲氧基苯甲酸，再與1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇）縮合得到
Figure 02_image264
，進一步與乙烯三氟硼酸鉀（cas：13682-77-4，畢得，上海）偶聯得到
Figure 02_image266
，再經還原而得。 6.
Figure 02_image262
, from 1-bromo-2-methyl-4-methoxy-5-nitrobenzene (cas: 89978-56-3, Jiuding Chemical, Shanghai) to 2-bromo-4-nitro-5- Methoxybenzoic acid, then condensed with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu)
Figure 02_image264
, further coupled with potassium ethylene trifluoroborate (cas: 13682-77-4, Bi De, Shanghai) to get
Figure 02_image266
, and then obtained by restoration.

7.

Figure 02_image268
，由1-溴-2-氟-4-甲氧基-5-硝基苯（cas：1352244-77-9，畢得，上海）與1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇）反應得到
Figure 02_image270
，再與異丙烯基硼酸頻哪醇酯（cas：126726-62-3，畢得，上海）偶聯得到
Figure 02_image272
，進一步還原而得。 7.
Figure 02_image268
, from 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (cas: 1352244-77-9, Bi De, Shanghai) and 1-methyl-4-(4-piperidinyl) Guazine (cas: 53617-36-0, Aikang, Jiangsu) was reacted to get
Figure 02_image270
, and then coupled with isopropenylboronic acid pinacol ester (cas: 126726-62-3, Bi De, Shanghai) to obtain
Figure 02_image272
, obtained by further reduction.

8.

Figure 02_image274
，由2-氟-4-甲氧基苯甲醛（cas：331-64-6）硝化得到2-氟-4-甲氧基-5-硝基苯甲醛，再還原得2-氟-4-甲氧基-5-硝基苯甲醇，進一步溴代為2-氟-4-甲氧基-5-硝基苄溴，再與環丙基硼酸（cas：411235-57-9，畢得，上海）反應得
Figure 02_image276
，再與1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇）反應得到
Figure 02_image278
，最後還原硝基而得。 8.
Figure 02_image274
, by nitration of 2-fluoro-4-methoxybenzaldehyde (cas: 331-64-6) to obtain 2-fluoro-4-methoxy-5-nitrobenzaldehyde, and then reduction to 2-fluoro-4- Methoxy-5-nitrobenzyl alcohol, further brominated to 2-fluoro-4-methoxy-5-nitrobenzyl bromide, and then combined with cyclopropylboronic acid (cas: 411235-57-9, Bi De, Shanghai ) respond to
Figure 02_image276
, and then react with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to obtain
Figure 02_image278
, and finally obtained by reducing the nitro group.

將環丙基硼酸換為苯硼酸（cas：98-80-6，安耐吉，上海），經類似的方法可得

Figure 02_image280
。 Replace cyclopropylboronic acid with phenylboronic acid (cas: 98-80-6, Anaiji, Shanghai), and obtain
Figure 02_image280
.

9.

Figure 02_image282
，由1-溴-2-氟-4-三氟甲氧基苯（cas：168971-68-4，畢得，上海）硝化得到2-三氟甲氧基-4-氟-5溴硝基苯，再與1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇）反應得
Figure 02_image284
，再脫溴並還原硝基而得； 以上溴代物進一步與乙烯基頻哪醇硼酸酯（cas：75927-49-0，畢得，上海）反應可得
Figure 02_image286
，再還原硝基可得
Figure 02_image288
； 同時還原硝基與雙鍵可得
Figure 02_image290
。 9.
Figure 02_image282
, from nitration of 1-bromo-2-fluoro-4-trifluoromethoxybenzene (cas: 168971-68-4, Bi De, Shanghai) to obtain 2-trifluoromethoxy-4-fluoro-5-bromonitro Benzene, then react with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to get
Figure 02_image284
, obtained by debromination and reduction of nitro group; the above bromide can be further reacted with vinyl pinacol borate (cas: 75927-49-0, Bide, Shanghai) to obtain
Figure 02_image286
, and then reduce the nitro group to get
Figure 02_image288
; Simultaneous reduction of nitro group and double bond available
Figure 02_image290
.

10.

Figure 02_image292
，由2,6-二氯-3-硝基吡啶與甲醇鈉（cas：124-41-4，安耐吉，上海）反應得2-甲氧基-3-硝基-6-氯吡啶，再與1-甲基-4-(4-呱啶基)呱嗪（cas：53617-36-0，艾康，江蘇）反應得
Figure 02_image294
，再還原氨基而得。 10.
Figure 02_image292
, 2-methoxy-3-nitro-6-chloropyridine was obtained by reacting 2,6-dichloro-3-nitropyridine with sodium methoxide (cas: 124-41-4, Anaiji, Shanghai), Then react with 1-methyl-4-(4-piperidinyl)piperazine (cas: 53617-36-0, Aikang, Jiangsu) to get
Figure 02_image294
, and then obtained by reducing the amino group.

Figure 02_image296
由2,6-二氯-3-硝基-5-甲基吡啶經相似的方法獲得。
Figure 02_image296
From 2,6-dichloro-3-nitro-5-picoline obtained by a similar method.

Figure 02_image294
與液溴（cas：7726-95-6，國藥集團，上海）反應可得
Figure 02_image298
，再與乙烯基頻哪醇硼酸酯（cas：75927-49-0，畢得，上海）反應得
Figure 02_image300
，再還原硝基與雙鍵可得
Figure 02_image302
。
Figure 02_image294
It can be obtained by reacting with liquid bromine (cas: 7726-95-6, Sinopharm Group, Shanghai)
Figure 02_image298
, and then react with vinyl pinacol borate (cas: 75927-49-0, Bi De, Shanghai) to get
Figure 02_image300
, and then reduce the nitro group and the double bond to obtain
Figure 02_image302
.

11.

Figure 02_image304
，由間溴硝基苯（cas：585-79-5，阿拉丁，上海）與4-吡啶硼酸（cas：1692-15-5，書亞，上海）反應得到
Figure 02_image306
，進一步與碘甲烷（ cas：74-88-4，西亞試劑，山東）反應得到
Figure 02_image308
，最後還原硝基與吡啶環而得。 11.
Figure 02_image304
, obtained by reacting m-bromonitrobenzene (cas: 585-79-5, Aladdin, Shanghai) with 4-pyridineboronic acid (cas: 1692-15-5, Shuya, Shanghai)
Figure 02_image306
, and further reacted with methyl iodide (cas: 74-88-4, West Asia reagent, Shandong) to get
Figure 02_image308
, and finally obtained by reducing the nitro group and the pyridine ring.

Figure 02_image310
，由4-溴-2-硝基苯甲醚（cas：33696-00-3，畢得，上海）經相似的方法獲得。
Figure 02_image310
, obtained from 4-bromo-2-nitroanisole (cas: 33696-00-3, Bi De, Shanghai) by a similar method.

12.

Figure 02_image312
，由間溴硝基苯（cas：585-79-5，安耐吉，上海）與4-羥基呱啶（cas：5382-16-1，安耐吉，上海）反應得到
Figure 02_image314
，再還原硝基而得； 12.
Figure 02_image312
, obtained by reacting m-bromonitrobenzene (cas: 585-79-5, Anaiji, Shanghai) with 4-hydroxypiperidine (cas: 5382-16-1, Anaiji, Shanghai)
Figure 02_image314
, and then obtained by reducing the nitro group;

以下中間體經類似方法獲得：

Figure 02_image316
The following intermediates were obtained in a similar manner:
Figure 02_image316

所涉及的原料為： N-甲基呱嗪（cas：109-01-3，安耐吉，上海），4-溴-2-硝基苯甲醚（cas：33696-00-3，書亞，上海）。 The raw materials involved are: N-methylpiperazine (cas: 109-01-3, Anaiji, Shanghai), 4-bromo-2-nitroanisole (cas: 33696-00-3, Shuya, Shanghai).

13. 2,4-二氯-5-溴嘧啶（cas：36082-50-5，畢得，上海）。13. 2,4-dichloro-5-bromopyrimidine (cas: 36082-50-5, Bide, Shanghai).

14. 2,4,5-三氯嘧啶（cas：5750-76-5，安耐吉，上海）。14. 2,4,5-Trichloropyrimidine (cas: 5750-76-5, Anaiji, Shanghai).

15. 2,4-二氯-5-甲基嘧啶（cas：1780-31-0，畢得，上海）。15. 2,4-dichloro-5-methylpyrimidine (cas: 1780-31-0, Bi De, Shanghai).

16. 2,4-二氯嘧啶（cas：3934-20-1，畢得，上海）16. 2,4-Dichloropyrimidine (cas: 3934-20-1, Bide, Shanghai)

17. 2,4-二氯-5-氟嘧啶（cas：2927-71-7，畢得，上海）。17. 2,4-dichloro-5-fluoropyrimidine (cas: 2927-71-7, Bi De, Shanghai).

18. 2,4-二氯-5-三氟甲基嘧啶（cas：3932-97-6，畢得，上海）。18. 2,4-Dichloro-5-trifluoromethylpyrimidine (cas: 3932-97-6, Bide, Shanghai).

19. 2,4-二氯-5-乙基嘧啶（cas：34171-40-9，畢得，上海）19. 2,4-Dichloro-5-ethylpyrimidine (cas: 34171-40-9, Biide, Shanghai)

20. 2,4-二氯-5-異丙基嘧啶（cas：514843-12-0，畢得，上海）20. 2,4-Dichloro-5-isopropylpyrimidine (cas: 514843-12-0, Biide, Shanghai)

21. 2,4-二氯-5-甲氧基嘧啶（cas：19646-07-2，畢得，上海）。21. 2,4-dichloro-5-methoxypyrimidine (cas: 19646-07-2, Bi De, Shanghai).

22. 2,4-二氯-5-乙基嘧啶（cas：34171-40-9，畢得，上海）22. 2,4-Dichloro-5-ethylpyrimidine (cas: 34171-40-9, Biide, Shanghai)

23. 2,4-二氯-5-氰基嘧啶（cas：3177-24-0，畢得，上海）。23. 2,4-Dichloro-5-cyanopyrimidine (cas: 3177-24-0, Biide, Shanghai).

24. 2,4-二氯-5-硝基嘧啶（cas：49845-33-2，艾康，上海）。24. 2,4-dichloro-5-nitropyrimidine (cas: 49845-33-2, Ai Kang, Shanghai).

25. 2,4-二氯-7-(2-三甲基矽乙氧基甲基)-7H-吡咯並[2,3-d]嘧啶，由2,4-二氯-7H-吡咯並[2,3-d]嘧啶（cas：90213-66-4，書亞，上海）與2-（三甲基矽基）乙氧甲基氯（CAS:76513-69-4，一飛，上海）反應而得。25. 2,4-dichloro-7-(2-trimethylsilethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, derived from 2,4-dichloro-7H-pyrrolo [2,3-d]pyrimidine (cas: 90213-66-4, Shuya, Shanghai) and 2-(trimethylsilyl)ethoxymethyl chloride (CAS: 76513-69-4, Yifei, Shanghai) ) is derived from the reaction.

26.

Figure 02_image318
，由2-甲氧基-5-硝基苯酚（cas：636-93-1，畢得，上海）與1,3-二氯-5,5-二甲基海因（cas：118-52-5，畢得，上海）反應得到2-氯-6-甲氧基-3-硝基苯酚，脫去甲基得3-氯-4-硝基-1,2-苯二酚，再與甲磺醯乙胺（由甲基磺醯氯（cas：124-63-0，西亞試劑，山東）與乙胺（cas：75-04-7，阿拉丁，上海）反應而得）反應得到
Figure 02_image320
，再與1,2-二溴乙烷（cas：106-93-4，阿拉丁，上海）反應得
Figure 02_image322
，再還原硝基而得。 26.
Figure 02_image318
, composed of 2-methoxy-5-nitrophenol (cas: 636-93-1, Bi De, Shanghai) and 1,3-dichloro-5,5-dimethylhydantoin (cas: 118-52 -5, Bi De, Shanghai) reaction to get 2-chloro-6-methoxy-3-nitrophenol, demethylated to get 3-chloro-4-nitro-1,2-benzenediol, and then with Methylsulfonyl ethylamine (obtained from the reaction of methylsulfonyl chloride (cas: 124-63-0, West Asia Reagent, Shandong) and ethylamine (cas: 75-04-7, Aladdin, Shanghai))
Figure 02_image320
, and then react with 1,2-dibromoethane (cas: 106-93-4, Aladdin, Shanghai) to get
Figure 02_image322
, and then obtained by reducing the nitro group.

以下中間體經類似方法獲得：

Figure 02_image324
The following intermediates were obtained in a similar manner:
Figure 02_image324

所涉及的原料為： 環丙基胺（cas：765-30-0，安耐吉，上海），甲磺醯甲基胺（cas：1184-85-6，畢得，上海），甲基磺醯胺（cas：3144-09-0，畢得，上海），甲胺（cas：74-89-5，安耐吉，上海），乙基磺醯氯（cas：594-44-5，安耐吉，上海），異丙基磺醯氯（cas：10147-37-2，TCI，上海），環丙基磺醯氯（cas：139631-62-2，安耐吉，上海）。 The raw materials involved are: Cyclopropylamine (cas: 765-30-0, Anaiji, Shanghai), Methylsulfonamide (cas: 1184-85-6, Bide, Shanghai), Methylsulfonamide (cas: 3144 -09-0, Bide, Shanghai), methylamine (cas: 74-89-5, Anaiji, Shanghai), ethylsulfonyl chloride (cas: 594-44-5, Anaiji, Shanghai), Isopropylsulfonyl chloride (cas: 10147-37-2, TCI, Shanghai), cyclopropylsulfonyl chloride (cas: 139631-62-2, Anaiji, Shanghai).

27.

Figure 02_image326
，由2-甲氧基-5-硝基苯酚（cas：636-93-1，畢得，上海）與N-溴代丁二醯亞胺（cas：128-08-5，畢得，上海）反應得2-溴-6-甲氧基-3-硝基苯酚，脫去甲基得3-溴-4-硝基-1,2-苯二酚，再與1,2-二溴乙烷（cas：106-93-4，阿拉丁，上海）反應得
Figure 02_image328
，進一步與甲基亞磺酸鈉（cas：20277-69-4，畢得，上海）反應得
Figure 02_image330
，再還原硝基而得。 27.
Figure 02_image326
, from 2-methoxy-5-nitrophenol (cas: 636-93-1, Bi De, Shanghai) and N-bromosuccinimide (cas: 128-08-5, Bi De, Shanghai ) reaction to get 2-bromo-6-methoxy-3-nitrophenol, demethylated to get 3-bromo-4-nitro-1,2-benzenediol, and then with 1,2-dibromoethyl Alkane (cas: 106-93-4, Aladdin, Shanghai) reacts to give
Figure 02_image328
, further reacted with sodium methanesulfinate (cas: 20277-69-4, Bi De, Shanghai) to get
Figure 02_image330
, and then obtained by reducing the nitro group.

以下中間體經類似方法獲得：

Figure 02_image332
The following intermediates were obtained in a similar manner:
Figure 02_image332

所涉及的原料為： 乙基亞磺酸鈉（cas：20035-08-9，阿拉丁，上海），異丙基亞磺酸鈉（cas：4160-19-4，畢得，上海），環丙基亞磺酸鈉（cas：910209-21-1，畢得，上海）。 The raw materials involved are: Sodium ethyl sulfinate (cas: 20035-08-9, Aladdin, Shanghai), sodium isopropyl sulfinate (cas: 4160-19-4, Bi De, Shanghai), sodium cyclopropyl sulfinate (cas: 910209-21-1, Bi De, Shanghai).

28.

Figure 02_image334
，由（27）中
Figure 02_image328
與苄硫醇（cas：100-53-8，阿拉丁，上海）反應得到
Figure 02_image336
，再氧化得到
Figure 02_image338
，再與甲胺（cas：74-89-5，安耐吉，上海）反應轉化為
Figure 02_image340
，最後還原硝基而得。 28.
Figure 02_image334
, by (27)
Figure 02_image328
Reaction with benzylthiol (cas: 100-53-8, Aladdin, Shanghai) to give
Figure 02_image336
, and then oxidized to get
Figure 02_image338
, and then reacted with methylamine (cas: 74-89-5, Anaiji, Shanghai) to convert to
Figure 02_image340
, and finally obtained by reducing the nitro group.

以下中間體經類似方法獲得：

Figure 02_image342
The following intermediates were obtained in a similar manner:
Figure 02_image342

所涉及的原料為： 乙胺（cas：75-04-7，阿拉丁，上海），異丙基胺（cas：75-31-0，安耐吉，上海），環丙基胺（cas：765-30-0，安耐吉，上海）。 The raw materials involved are: Ethylamine (cas: 75-04-7, Aladdin, Shanghai), Isopropylamine (cas: 75-31-0, Anaiji, Shanghai), Cyclopropylamine (cas: 765-30-0, Anaji, Shanghai).

29. 乙烯基硼酸頻哪醇酯（cas：75927-49-0，畢得，上海）。29. Vinyl boronic acid pinacol ester (cas: 75927-49-0, Bi De, Shanghai).

30. 異丙烯基硼酸頻哪醇酯（cas：126726-62-3，畢得，上海）。30. Isopropenylboronic acid pinacol ester (cas: 126726-62-3, Bide, Shanghai).

31.

Figure 02_image344
，由（4）中3-氟-4-乙基-6-硝基苯甲醚與呱嗪-1-羧酸叔丁酯（cas：57260-71-6，畢得，上海）反應得到
Figure 02_image346
，再脫去叔丁氧羰基，進一步與氘代碘甲烷（cas：865-50-9，阿拉丁，上海）反應得到
Figure 02_image348
，最後還原硝基而得。 31.
Figure 02_image344
, obtained by the reaction of 3-fluoro-4-ethyl-6-nitroanisole in (4) with tert-butyl piperazine-1-carboxylate (cas: 57260-71-6, Bide, Shanghai)
Figure 02_image346
, and then remove the tert-butoxycarbonyl group, and further react with deuterated methyl iodide (cas: 865-50-9, Aladdin, Shanghai) to obtain
Figure 02_image348
, and finally obtained by reducing the nitro group.

32.

Figure 02_image350
，由1-(2-氟-5-硝基苯基)乙酮（cas：79110-05-7，畢得，上海）與呱嗪-1-羧酸叔丁酯（cas：57260-71-6，畢得，上海）反應得到
Figure 02_image352
，再脫去叔丁氧羰基，進一步與氘代碘甲烷（cas：865-50-9，阿拉丁，上海）反應得到
Figure 02_image354
，再還原硝基與羰基而得。 32.
Figure 02_image350
, from 1-(2-fluoro-5-nitrophenyl)ethanone (cas: 79110-05-7, Bi De, Shanghai) and piperazine-1-carboxylate tert-butyl ester (cas: 57260-71- 6, Bi De, Shanghai) Response to get
Figure 02_image352
, and then remove the tert-butoxycarbonyl group, and further react with deuterated methyl iodide (cas: 865-50-9, Aladdin, Shanghai) to obtain
Figure 02_image354
, and then reduced nitro and carbonyl derived.

33.

Figure 02_image356
，由2-硝基-4-甲基-5-氯苯酚（cas：100278-74-8，畢得，上海）與碘甲烷（ cas：74-88-4，西亞試劑，山東）反應得到2-硝基-4-甲基-5-氯苯甲醚，再與4-吡啶硼酸（cas：1692-15-5，書亞，上海）反應得到
Figure 02_image358
，進一步與碘甲烷（ cas：74-88-4，西亞試劑，山東）反應得到
Figure 02_image360
，最後還原硝基與吡啶環而得。 33.
Figure 02_image356
, from 2-nitro-4-methyl-5-chlorophenol (cas: 100278-74-8, Bi De, Shanghai) and iodomethane (cas: 74-88-4, West Asia reagent, Shandong) to get 2 -Nitro-4-methyl-5-chloroanisole, then reacted with 4-pyridineboronic acid (cas: 1692-15-5, Shuya, Shanghai) to get
Figure 02_image358
, and further reacted with methyl iodide (cas: 74-88-4, West Asia reagent, Shandong) to get
Figure 02_image360
, and finally obtained by reducing the nitro group and the pyridine ring.

34．

Figure 02_image362
,由2,6-二氯-3-硝基吡啶（cas：16013-85-7，畢得，上海）與三氟乙醇（cas：75-89-8，阿拉丁，上海）反應得到
Figure 02_image364
，進一步與N,N,N’-三甲基乙二胺（cas：142-25-6，畢得，上海）反應得到
Figure 02_image366
，再與液溴（cas：7726-95-6，國藥集團，上海）反應得
Figure 02_image368
，進而與乙烯基頻哪醇硼酸酯（cas：75927-49-0，畢得，上海）反應得
Figure 02_image370
，最後還原雙鍵與硝基而得。 34．
Figure 02_image362
, obtained by reacting 2,6-dichloro-3-nitropyridine (cas: 16013-85-7, Bi De, Shanghai) with trifluoroethanol (cas: 75-89-8, Aladdin, Shanghai)
Figure 02_image364
, and further reacted with N,N,N'-trimethylethylenediamine (cas: 142-25-6, Bi De, Shanghai) to obtain
Figure 02_image366
, and then react with liquid bromine (cas: 7726-95-6, Sinopharm Group, Shanghai) to get
Figure 02_image368
, and then react with vinyl pinacol borate (cas: 75927-49-0, Bi De, Shanghai) to get
Figure 02_image370
, and finally obtained by reduction of double bond and nitro group.

下面藉由具體實施例詳細描述本發明的實施方式，但是無論如何它們不能解釋為對本發明的限制。The implementation of the present invention will be described in detail below by means of specific examples, but they should not be construed as limiting the present invention in any case.

化合物I-1、I-79的合成：

Figure 02_image372
Synthesis of compounds I-1 and I-79:
Figure 02_image372

第一步：將化合物1（200 mg，0.77 mmol）溶於DMF（2 mL）中，0 ℃下分批次加入NaH（60%含量，分散於液體石蠟，62 mg，1.54 mmol），5分鐘後加入2,4-二氯-5-溴嘧啶（194 mg，0.85 mmol），自熱升溫反應1小時，TLC及LCMS檢測反應完畢。加水100 mL，有固體析出，過濾，抽乾，得化合物2（281 mg），直接用於下一步。Step 1: Dissolve compound 1 (200 mg, 0.77 mmol) in DMF (2 mL), add NaH (60% content, dispersed in liquid paraffin, 62 mg, 1.54 mmol) in batches at 0 °C for 5 minutes Then, 2,4-dichloro-5-bromopyrimidine (194 mg, 0.85 mmol) was added, and the reaction was carried out by heating up for 1 hour. TLC and LCMS detected that the reaction was complete. After adding 100 mL of water, solids were precipitated, filtered, and drained to obtain compound 2 (281 mg), which was directly used in the next step.

第二步：化合物2（45 mg，0.1 mmol）、化合物3（22 mg，0.1 mmol）及甲磺酸（19 µL，0.3 mmol）於t-BuOH（2 mL）中100 ℃加熱4 h，TLC及LCMS檢測反應完畢。冷卻後將反應混合物濃縮，經矽膠柱純化（以二氯甲烷/甲醇洗脫），再經製備型HPLC（以含0.35%三氟乙酸的水和甲醇為流動相）純化得化合物I-1（51 mg）。Step 2: Heat compound 2 (45 mg, 0.1 mmol), compound 3 (22 mg, 0.1 mmol) and methanesulfonic acid (19 µL, 0.3 mmol) in t-BuOH (2 mL) at 100 °C for 4 h, TLC And LCMS detects that the reaction is complete. After cooling, the reaction mixture was concentrated, purified by silica gel column (eluted with dichloromethane/methanol), and then purified by preparative HPLC (with water and methanol containing 0.35% trifluoroacetic acid as mobile phase) to obtain compound I-1 ( 51 mg).

第三步：化合物I-1（0.051 mmol, 32 mg）、乙烯基硼酸頻哪醇酯（0.102 mmol, 17 µL）、PdCl 2(dppf)•CH 2Cl 2（0.0051 mmol, 4.1 mg）、Na 2CO 3（0.20 mmol, 22 mg）分散於1,4-dioxane（1 mL）和水（0.5 mL）中，置換氮氣後反應體系在100 ℃下加熱4 h。TLC和LC-MS檢測反應完畢，反應體系用50 mL水稀釋後使用DCM萃取，有機相濃縮後矽膠柱純化（以二氯甲烷/甲醇洗脫），再經製備型HPLC（以含0.35%三氟乙酸的水和甲醇為流動相）純化得化合物I-79（15.7 mg）。 Step 3: Compound I-1 (0.051 mmol, 32 mg), vinylboronic acid pinacol ester (0.102 mmol, 17 µL), PdCl 2 (dppf)•CH 2 Cl 2 (0.0051 mmol, 4.1 mg), Na 2 CO 3 (0.20 mmol, 22 mg) was dispersed in 1,4-dioxane (1 mL) and water (0.5 mL), and the reaction system was heated at 100 °C for 4 h after replacing nitrogen. The completion of the reaction was detected by TLC and LC-MS. The reaction system was diluted with 50 mL of water and extracted with DCM. The organic phase was concentrated and purified on a silica gel column (eluted with dichloromethane/methanol), and then subjected to preparative HPLC (with 0.35% Tris Fluoroacetic acid (water and methanol as mobile phase) was purified to obtain compound I-79 (15.7 mg).

化合物I-220的合成：

Figure 02_image374
Synthesis of Compound I-220:
Figure 02_image374

第一步：化合物4由化合物1與2,4-二氯-7-(2-三甲基矽乙氧基甲基)-7H-吡咯並[2,3-d]嘧啶經過製備化合物2相同的方法而得。The first step: compound 4 is the same as compound 2 prepared from compound 1 and 2,4-dichloro-7-(2-trimethylsilethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine obtained by the method.

第二步：化合物4（54.1 mg，0.1 mmol）、化合物5（23.5 mg，0.1 mmol）、2-二環己基磷-2,4,6-三異丙基聯苯（7.2 mg，0.015 mmol），三(二亞苄基丙酮)二鈀（9.2 mg，0.01 mmol）及碳酸鉀（41.4 mg，0.3 mmol）分散於 t-BuOH（2 mL）中，置換氮氣後將反應體系置於預熱至100℃的油浴中加熱攪拌，6小時後TLC及LCMS檢測反應完畢。冷卻後加入水（50 mL）稀釋，DCM（50 mL）萃取，有機相濃縮，經矽膠柱純化（以二氯甲烷/甲醇洗脫）得化合物6（55.7 mg）。 The second step: compound 4 (54.1 mg, 0.1 mmol), compound 5 (23.5 mg, 0.1 mmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (7.2 mg, 0.015 mmol) , tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.01 mmol) and potassium carbonate (41.4 mg, 0.3 mmol) were dispersed in t -BuOH (2 mL), and the reaction system was preheated to Heat and stir in an oil bath at 100° C. After 6 hours, TLC and LCMS detect that the reaction is complete. After cooling, it was diluted with water (50 mL), extracted with DCM (50 mL), the organic phase was concentrated, and purified by silica gel column (eluted with dichloromethane/methanol) to obtain compound 6 (55.7 mg).

第三步：化合物6（35 mg，0.047 mmol）於TFA/DCM（1/2 mL）中室溫下攪拌2小時後TLC及LCMS檢測反應完畢，濃縮，殘留物溶於甲醇（2 mL），加入25%氨水（1 mL），室溫反應4小時後LCMS檢測反應完全。以二氯甲烷（50 mL）稀釋，飽和食鹽水（30 mL）洗滌1次，分液，有機相經無水Na 2SO 4乾燥，過濾，濃縮後經矽膠柱純化（以二氯甲烷/甲醇洗脫），再經製備型HPLC（以含0.35%三氟乙酸的水和甲醇為流動相）純化得化合物1-220（13.5 mg）。 Step 3: Compound 6 (35 mg, 0.047 mmol) was stirred in TFA/DCM (1/2 mL) at room temperature for 2 hours, then TLC and LCMS detected that the reaction was complete, concentrated, and the residue was dissolved in methanol (2 mL), Add 25% ammonia water (1 mL), react at room temperature for 4 hours, and LCMS detects that the reaction is complete. Dilute with dichloromethane (50 mL), wash once with saturated saline (30 mL), separate the layers, dry the organic phase over anhydrous Na 2 SO 4 , filter, concentrate and purify by silica gel column (wash with dichloromethane/methanol detachment), and then purified by preparative HPLC (water and methanol containing 0.35% trifluoroacetic acid as mobile phase) to obtain compound 1-220 (13.5 mg).

其餘化合物經相似的方法獲得。The rest of the compounds were obtained by similar methods.

下表列出具體化合物及結構鑒定資料： 序號 結構 核磁共振氫譜和（或）質譜數據 I-1

Figure 02_image376
1H NMR (600 MHz, DMSO- d 6) δ 9.89 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.57 – 7.49 (m, 1H), 7.44 (d, J= 2.6 Hz, 1H), 7.36 (d, J= 8.5 Hz, 1H), 6.99 (d, J= 8.6 Hz, 1H), 6.92 (d, J= 9.0 Hz, 1H), 4.38 – 4.24 (m, 4H), 3.53 – 3.44 (m, 2H), 3.25 – 3.14 (m, 2H), 3.10 (s, 3H), 3.08 (s, 3H), 3.07 – 3.02 (m, 2H), 2.99 – 2.91 (m, 2H), 2.88 (s, 3H), 2.59 – 2.55 (m, 2H), 1.07 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 632 [M+H] +. I-2
Figure 02_image378
 1H NMR (600 MHz, DMSO- d 6) δ 9.84 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 7.47 – 7.40 (m, 1H), 7.39 – 7.35 (m, 1H), 7.28 (d, J= 8.7 Hz, 1H), 7.02 (d, J= 8.6 Hz, 1H), 6.92 (d, J= 8.9 Hz, 1H), 4.45 – 4.24 (m, 4H), 3.74 (t, J= 4.5 Hz, 4H), 3.09 (s, 3H), 3.07 (s, 3H), 2.80 (t, J= 4.6 Hz, 4H), 2.57 (q, J= 7.5 Hz, 2H), 1.14 – 1.01 (m, 3H). MS (ESI) m/z: 619 [M+H] +. I-3
Figure 02_image380
 1H NMR (600 MHz, DMSO- d 6) δ 9.79 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.64 (s, 1H), 7.62 – 7.57 (m, 2H), 7.51 (d, J= 8.9 Hz, 1H), 6.98 (d, J= 8.9 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.62 (s, 2H), 3.40 (s, 2H), 3.15 (s, 3H), 3.12 (s, 3H), 3.08 (s, 3H), 2.68 (d, J= 7.5 Hz, 2H), 1.09 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 607 [M+H] +. I-4
Figure 02_image382
 1H NMR (600 MHz, DMSO- d 6) δ 9.86 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 7.50 – 7.43 (m, 2H), 7.40 (d, J= 9.0 Hz, 1H), 7.04 (d, J= 8.7 Hz, 1H), 6.94 (d, J= 9.0 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.65 (t, J= 5.4 Hz, 2H), 3.24 (t, J= 5.4 Hz, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.54 (t, J= 7.5 Hz, 2H), 1.09 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 593 [M+H] +. I-5
Figure 02_image384
 H NMR (600 MHz, DMSO- d 6) δ 9.32 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.60 (s, 1H), 7.21 (s, 1H), 7.19 – 7.14 (m, 1H), 6.87 (d, J= 9.0 Hz, 1H), 6.56 (d, J= 8.6 Hz, 1H), 4.47 – 4.22 (m, 4H), 3.42 (t, J= 6.3 Hz, 2H), 3.29 (t, J= 6.2 Hz, 2H), 3.12 (s, 3H), 3.08 (s, 3H), 2.86 (s, 6H), 2.42 (t, J= 7.5 Hz, 2H), 1.08 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 620 [M+H] +. I-6
Figure 02_image386
 1H NMR (600 MHz, DMSO- d 6) δ 9.67 – 9.64 (m, 1H), 9.51 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.45 – 7.41 (m, 1H), 7.38 – 7.34 (m, 1H), 7.08 (d, J= 8.6 Hz, 1H), 6.92 (d, J= 8.9 Hz, 1H), 4.44 – 4.22 (m, 4H), 3.20 (d, J= 6.4 Hz, 2H), 3.18 – 3.13 (m, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 2.80 (s, 6H), 2.61 – 2.57 (m, 2H), 2.56 (s, 3H), 1.06 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 634 [M+H] +. I-7
Figure 02_image388
 MS (ESI) m/z: 631 [M+H] +. I-8
Figure 02_image390
 MS (ESI) m/z: 644 [M+H] +. I-9
Figure 02_image392
 1H NMR (600 MHz, DMSO- d 6) δ 10.02 (s, 1H), 9.47 (s, 1H), 8.25 (s, 2H), 7.55 (s, 1H), 7.40 (s, 1H), 6.99 – 6.85 (m, 2H), 4.47 – 4.21 (m, 4H), 3.53 (d, J= 11.7 Hz, 2H), 3.33 – 3.21 (m, 4H), 3.12 (s, 3H), 3.08 (s, 3H), 3.01 – 2.84 (m, 5H), 1.04 (d, J= 6.1 Hz, 1H), 0.93 (d, J= 8.6 Hz, 2H), 0.57 – 0.47 (m, 2H). MS (ESI) m/z: 644 [M+H] +. I-10
Figure 02_image394
 1H NMR (600 MHz, DMSO- d 6) δ 8.52 (s, 1H), 8.29 (s, 1H), 7.52 – 7.42 (m, 2H), 7.35 – 7.25 (m, 1H), 6.94 (d, J= 8.7 Hz, 1H), 6.90 (d, J= 9.0 Hz, 1H), 6.87 – 6.82 (m, 1H), 4.47 – 4.21 (m, 4H), 3.77 (t, J= 4.4 Hz, 4H), 3.11 (s, 3H), 3.10 – 3.05 (m, 4H), 2.92 (t, J= 4.5 Hz, 3H), 1.04 (d, J= 6.1 Hz, 1H), 0.92 (d, J= 8.6 Hz, 2H), 0.57 – 0.43 (m, 2H). MS (ESI) m/z: 631 [M+H] +. I-11
Figure 02_image396
 1H NMR (600 MHz, DMSO- d 6) δ 9.95 (s, 1H), 9.58 – 9.46 (m, 1H), 8.28 – 8.19 (m, 2H), 7.47 – 7.42 (m, 1H), 7.32 – 7.25 (m, 1H), 6.96 – 6.90 (m, 2H), 4.46 – 4.19 (m, 4H), 3.50 (d, J= 11.8 Hz, 2H), 3.24 – 3.18 (m, 2H), 3.13 (d, J= 12.8 Hz, 2H), 3.10 (s, 2H), 3.08 (s, 3H), 2.92 (t, J= 11.3 Hz, 2H), 2.88 (s, 3H), 2.17 (s, 3H). MS (ESI) m/z: 618 [M+H] +. I-12
Figure 02_image398
 1H NMR (600 MHz, DMSO- d 6) δ 9.63 (s, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.52 – 7.44 (m, 1H), 7.37 (d, J= 2.6 Hz, 1H), 7.24 (d, J= 8.7 Hz, 1H), 6.96 (d, J= 8.7 Hz, 1H), 6.93 (d, J= 8.9 Hz, 1H), 4.43 – 4.25 (m, 4H), 3.78 – 3.70 (m, 4H), 3.09 (s, 3H), 3.07 (s, 3H), 2.86 – 2.76 (m, 4H), 2.17 (s, 3H). MS (ESI) m/z: 605 [M+H] +. I-13
Figure 02_image400
 1H NMR (600 MHz, Methanol- d 4) δ 8.13 (s, 1H), 7.46 – 7.11 (m, 2H), 6.90 (d, J= 8.9 Hz, 1H), 6.71 (s, 1H), 4.44 – 4.27 (m, 4H), 4.05 – 3.99 (m, 1H), 3.85 (s, 3H), 3.54 – 3.47 (m, 1H), 3.47 – 3.37 (m, 2H), 3.23 – 3.12 (m, 4H), 3.03 (s, 3H), 2.97 (s, 6H), 2.54 – 2.43 (m, 1H), 2.26 – 2.19 (m, 1H), 2.16 (s, 3H). MS (ESI) m/z: 662 [M+H] +. I-14
Figure 02_image402
 1H NMR (600 MHz, Methanol- d 4) δ 8.14 (s, 1H), 7.41 – 7.18 (m, 2H), 6.90 (d, J= 8.9 Hz, 1H), 6.77 (s, 1H), 4.45 – 4.28 (m, 4H), 3.84 (s, 3H), 3.37 – 3.34 (m, 1H), 3.30 – 3.25 (m, 2H), 3.18 (s, 3H), 3.03 (s, 3H), 2.93 (s, 6H), 2.86 – 2.73 (m, 2H), 2.25 – 2.17 (m, 2H), 2.14 (s, 3H), 1.99 – 1.88 (m, 2H). MS (ESI) m/z: 676 [M+H] +. I-15
Figure 02_image404
 1H NMR (600 MHz, Methanol- d 4) δ 8.16 (s, 1H), 7.43 – 7.18 (m, 2H), 6.91 (d, J= 8.9 Hz, 1H), 6.78 (s, 1H), 4.43 – 4.27 (m, 4H), 3.86 (s, 3H), 3.67 – 3.56 (m, 2H), 3.36 – 3.33 (m, 2H), 3.29 – 3.24 (m, 2H), 3.18 (s, 3H), 3.15 – 3.07 (m, 2H), 3.03 (s, 3H), 2.99 (s, 3H), 2.15 (s, 3H). MS (ESI) m/z: 648 [M+H] +. I-16
Figure 02_image406
 1H NMR (600 MHz, Methanol- d 4) δ 8.15 (s, 1H), 7.49 – 7.15 (m, 2H), 6.88 (s, 1H), 6.80 (d, J= 2.4 Hz, 1H), 4.45 – 4.27 (m, 4H), 4.06 – 3.98 (m, 1H), 3.85 (s, 3H), 3.48 – 3.39 (m, 2H), 3.36 – 3.33 (m, 1H), 3.20 (s, 3H), 3.17 – 3.11 (m, 1H), 3.03 (s, 3H), 2.97 (s, 6H), 2.63 – 2.44 (m, 3H), 2.28 – 2.16 (m, 1H), 1.07 (s, 3H). MS (ESI) m/z: 676 [M+H] +. I-17
Figure 02_image408
 1H NMR (600 MHz, Methanol- d 4) δ 8.15 (s, 1H), 7.51 – 7.16 (m, 2H), 6.93 – 6.84 (m, 1H), 6.82 (s, 1H), 4.46 – 4.28 (m, 4H), 3.84 (s, 3H), 3.34 (d, J= 5.2 Hz, 1H), 3.24 – 3.10 (m, 5H), 3.03 (s, 3H), 2.93 (s, 6H), 2.89 – 2.77 (m, 2H), 2.64 – 2.48 (m, 2H), 2.27 – 2.13 (m, 2H), 1.99 – 1.82 (m, 2H), 1.06 (s, 3H). MS (ESI) m/z: 690 [M+H] +. I-18
Figure 02_image410
 1H NMR (600 MHz, Methanol- d 4) δ 8.25 – 8.07 (m, 1H), 7.46 (s, 1H), 7.36 – 7.18 (m, 1H), 6.89 (d, J= 9.0 Hz, 1H), 6.85 (s, 1H), 4.44 – 4.26 (m, 4H), 3.86 (s, 3H), 3.63 – 3.54 (m, 2H), 3.35 – 3.32 (m, 2H), 3.22 – 3.12 (m, 7H), 3.03 (s, 3H), 2.99 (s, 3H), 2.66 – 2.44 (m, 2H), 1.06 (s, 3H). MS (ESI) m/z: 662 [M+H] +. I-19
Figure 02_image412
 1H NMR (600 MHz, DMSO- d 6) δ 9.27 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.16 (t, J= 5.7 Hz, 3H), 7.29 (s, 1H), 6.88 – 6.79 (m, 1H), 6.74 (s, 1H), 4.43 – 4.23 (m, 4H), 4.21 (t, J= 5.2 Hz, 2H), 3.80 (s, 3H), 3.30 – 3.24 (m, 2H), 3.10 (s, 3H), 3.06 (s, 3H), 2.54 – 2.39 (m, 2H), 1.01 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 623 [M+H] +. I-20
Figure 02_image414
 1H NMR (600 MHz, DMSO- d 6) δ 10.18 – 9.87 (m, 1H), 9.66 – 9.35 (m, 1H), 8.92 (s, 1H), 8.47 – 8.15 (m, 1H), 7.42 – 7.25 (m, 1H), 7.10 – 6.93 (m, 1H), 6.88 – 6.70 (m, 1H), 6.33 (s, 1H), 4.45 – 4.21 (m, 4H), 3.78 (s, 3H), 3.54 (t, J= 6.4 Hz, 2H), 3.31 (t, J= 6.4 Hz, 2H), 3.11 (s, 3H), 3.06 (s, 3H), 2.87 (s, 6H), 2.43 – 2.27 (m, 2H), 1.07 – 0.98 (m, 3H). MS (ESI) m/z: 650 [M+H] +. I-21
Figure 02_image416
 1H NMR (600 MHz, DMSO- d 6) δ 9.22 (s, 1H), 8.82 (s, 1H), 8.37 (s, 1H), 7.43 (s, 1H), 7.30 (d, J= 8.9 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J= 8.9 Hz, 1H), 4.46 – 4.22 (m, 4H), 3.81 (s, 3H), 3.26 – 3.21 (m, 4H), 3.10 (s, 3H), 3.06 (s, 3H), 2.82 (s, 6H), 2.53 – 2.43 (m, 5H), 0.98 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 664 [M+H] +. I-22
Figure 02_image418
 MS (ESI) m/z: 714 [M+H] +. I-23
Figure 02_image420
 MS (ESI) m/z: 700 [M+H] +. I-24
Figure 02_image422
 MS (ESI) m/z: 700 [M+H] +. I-25
Figure 02_image424
 1H NMR (600 MHz, Methanol- d 4) δ 8.12 (s, 1H), 7.55 – 7.45 (m, 1H), 7.36 (d, J= 9.0 Hz, 1H), 6.95 – 6.88 (m, 2H), 6.76 – 6.64 (m, 1H), 4.44 – 4.26 (m, 4H), 3.90 – 3.81 (m, 5H), 3.66 – 3.32 (m, 8H), 3.25 – 3.20 (m, 1H), 3.19 (s, 3H), 3.12 (t, J= 12.2 Hz, 2H), 3.03 (s, 3H), 2.94 (s, 3H), 2.25 – 2.18 (m, 2H), 2.01 – 1.89 (m, 2H). MS (ESI) m/z: 717 [M+H] +. I-26
Figure 02_image426
 1H NMR (600 MHz, Methanol- d 4) δ 8.15 (s, 1H), 7.44 – 7.17 (m, 2H), 6.91 (d, J= 8.9 Hz, 1H), 6.80 (s, 1H), 4.45 – 4.24 (m, 4H), 3.84 (s, 3H), 3.78 – 3.50 (m, 8H), 3.45 – 3.37 (m, 1H), 3.35 – 3.31 (m, 2H), 3.17 (s, 3H), 3.02 (s, 3H), 3.00 (s, 3H), 2.88 (q, J= 11.4 Hz, 2H), 2.29 – 2.22 (m, 2H), 2.14 (s, 3H), 2.06 – 1.94 (m, 2H). MS (ESI) m/z: 731 [M+H] +. I-27
Figure 02_image428
 1H NMR (600 MHz, Methanol- d 4) δ 8.16 (s, 1H), 7.51 – 7.16 (m, 2H), 6.88 (d, J= 8.9 Hz, 1H), 6.84 (s, 1H), 4.43 – 4.27 (m, 4H), 3.84 (s, 3H), 3.80 – 3.51 (m, 8H), 3.47 – 3.39 (m, 1H), 3.27 – 3.21 (m, 2H), 3.18 (s, 3H), 3.02 (s, 3H), 3.00 (s, 3H), 2.90 (t, J= 11.7 Hz, 2H), 2.62 – 2.43 (m, 2H), 2.31 – 2.18 (m, 2H), 2.06 – 1.93 (m, 2H), 1.05 (s, 3H). MS (ESI) m/z: 745 [M+H] +. I-28
Figure 02_image430
 1H NMR (600 MHz, DMSO- d 6) δ 9.43 (s, 1H), 8.83 (s, 1H), 8.33 (s, 1H), 7.32 (s, 1H), 7.30 – 7.23 (m, 1H), 6.81 (s, 1H), 6.79 – 6.74 (m, 1H), 4.48 – 4.19 (m, 4H), 3.76 (s, 3H), 3.68 – 3.31 (m, 11H), 3.24 (q, J= 6.9 Hz, 1H), 3.09 (s, 3H), 3.06 (s, 3H), 2.92 (s, 3H), 2.81 (d, J= 9.2 Hz, 2H), 2.22 – 2.09 (m, 2H), 1.90 – 1.75 (m, 2H), 1.08 – 0.87 (m, 6H). MS (ESI) m/z: 759 [M+H] +. I-29
Figure 02_image432
 MS (ESI) m/z: 757 [M+H] +. I-30
Figure 02_image434
 1H NMR (600 MHz, DMSO- d 6) δ 10.02 (s, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.42 (s, 1H), 7.40 – 7.36 (m, 1H), 7.32 – 7.25 (m, 1H), 7.02 (d, J= 8.7 Hz, 1H), 6.92 (d, J= 8.9 Hz, 1H), 4.48 – 4.23 (m, 4H), 3.86 – 3.27 (m, 8H), 3.14 (d, J= 8.0 Hz, 1H), 3.10 (s, 3H), 3.07 (s, 3H), 2.92 (s, 3H), 2.73 (t, J= 12.0 Hz, 2H), 2.58 – 2.54 (m, 4H), 2.20 – 2.11 (m, 2H), 1.91 – 1.75 (m, 2H), 1.07 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 715 [M+H] +. I-31
Figure 02_image436
 1H NMR (600 MHz, DMSO- d 6) δ 9.49 – 9.33 (m, 2H), 8.67 (s, 1H), 8.30 (s, 1H), 7.41 (s, 1H), 7.37 – 7.28 (m, 1H), 6.82 (d, J= 9.0 Hz, 1H), 6.76 (s, 1H), 4.44 – 4.17 (m, 4H), 3.78 (s, 3H), 3.62 – 3.33 (m, 12H), 3.12 – 3.08 (m, 3H), 3.06 (s, 3H), 2.76 (t, J= 11.7 Hz, 2H), 2.49 – 2.43 (m, 1H), 2.20 – 2.10 (m, 2H), 1.82 (dd, J= 12.0, 3.9 Hz, 2H), 1.01 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 731 [M+H] +. I-32
Figure 02_image438
 1H NMR (600 MHz, DMSO- d 6) δ 8.95 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 7.49 (s, 1H), 7.38 – 7.29 (m, 1H), 6.88 – 6.79 (m, 1H), 6.74 (s, 1H), 4.46 – 4.16 (m, 5H), 3.80 (s, 3H), 3.69 – 3.58 (m, 4H), 3.56 – 3.49 (m, 1H), 3.46 – 3.12 (m, 9H), 3.10 (s, 3H), 3.07 (s, 3H), 2.81 (s, 3H), 2.44 – 2.34 (m, 2H), 2.06 – 1.86 (m, 2H), 1.01 (t, J= 7.6 Hz, 3H). MS (ESI) m/z: 745 [M+H] +. I-33
Figure 02_image440
 MS (ESI) m/z: 717 [M+H] +. I-34
Figure 02_image442
 1H NMR (600 MHz, DMSO- d 6) δ 9.35 – 9.25 (m, 1H), 9.21 – 9.12 (m, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 7.46 (s, 1H), 7.33 (d, J= 8.8 Hz, 1H), 6.83 (d, J= 9.0 Hz, 1H), 6.76 (s, 1H), 4.43 – 4.23 (m, 6H), 4.15 (s, 3H), 3.79 (s, 3H), 3.24 – 3.11 (m, 4H), 3.09 (s, 3H), 3.06 (s, 3H), 3.03 (d, J= 4.6 Hz, 5H), 2.49 – 2.45 (m, 1H), 1.00 (t, J= 7.6 Hz, 3H). MS (ESI) m/z: 703 [M+H] +. I-35
Figure 02_image444
 1H NMR (600 MHz, DMSO- d 6) δ 10.44 – 10.04 (m, 1H), 9.20 (s, 1H), 8.81 (s, 1H), 8.34 (s, 1H), 7.40 (s, 1H), 7.36 – 7.17 (m, 1H), 6.81 (s, 1H), 4.49 – 4.23 (m, 4H), 3.79 (s, 3H), 3.75 – 3.69 (m, 1H), 3.12 – 3.07 (m, 4H), 3.06 (s, 3H), 2.91 – 2.76 (m, 4H), 2.70 (d, J= 4.5 Hz, 6H), 2.49 – 2.43 (m, 1H), 2.28 – 2.19 (m, 2H), 2.07 – 1.97 (m, 2H), 1.79 – 1.66 (m, 4H), 1.04 – 0.95 (m, 3H). MS (ESI) m/z: 730 [M+H] +. I-36
Figure 02_image446
 1H NMR (600 MHz, DMSO- d 6) δ 9.02 (s, 1H), 8.74 (s, 1H), 8.31 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.86 – 6.80 (m, 1H), 6.77 (s, 1H), 4.44 – 4.21 (m, 4H), 4.08 – 3.99 (m, 2H), 3.87 – 3.78 (m, 2H), 3.77 (s, 3H), 3.08 (s, 3H), 3.06 (s, 3H), 2.87 (d, J= 5.0 Hz, 3H), 2.84 – 2.78 (m, 2H), 2.73 – 2.65 (m, 2H), 2.49 – 2.40 (m, 2H), 2.00 – 1.88 (m, 4H), 1.09 – 0.93 (m, 3H). MS (ESI) m/z: 702 [M+H] +. I-37
Figure 02_image448
 MS (ESI) m/z: 674 [M+H] +. I-38
Figure 02_image450
 MS (ESI) m/z: 661 [M+H] +. I-39
Figure 02_image452
 1H NMR (600 MHz, DMSO- d 6) δ 9.01 (s, 1H), 8.24 – 8.12 (m, 1H), 8.08 – 7.98 (m, 1H), 7.56 (s, 1H), 7.13 (s, 1H), 6.86 – 6.74 (m, 1H), 6.75 – 6.66 (m, 1H), 4.46 – 4.19 (m, 4H), 3.65 – 3.20 (m, 9H), 3.19 – 3.03 (m, 6H), 2.76 – 2.65 (m, 2H), 2.39 – 2.28 (m, 2H), 2.19 (s, 3H), 1.94 – 1.79 (m, 2H), 1.68 – 1.50 (m, 2H). MS (ESI) m/z: 723 [M+H] +. I-40
Figure 02_image454
 1H NMR (600 MHz, DMSO- d 6) δ 9.60 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.33 – 7.19 (m, 1H), 6.97 – 6.88 (m, 1H), 6.16 – 6.05 (m, 1H), 5.41 (s, 1H), 4.46 – 4.24 (m, 4H), 3.81 – 3.73 (m, 1H), 3.48 – 3.27 (m, 5H), 3.11 – 3.03 (m, 6H), 3.00 – 2.89 (m, 4H), 2.40 – 2.20 (m, 1H), 2.16 – 2.12 (m, 4H), 1.81 – 1.69 (m, 3H), 1.55 – 1.43 (m, 2H). MS (ESI) m/z: 723 [M+H] +. I-41
Figure 02_image456
 1H NMR (600 MHz, DMSO- d 6) δ 8.89 (s, 1H), 8.71 – 8.61 (m, 1H), 8.38 (s, 1H), 7.64 (s, 1H), 7.29 (s, 1H), 6.91 – 6.86 (m, 1H), 6.86 – 6.83 (m, 1H), 4.73 – 4.61 (m, 1H), 4.47 – 4.19 (m, 4H), 3.81 (s, 3H), 3.76 – 3.55 (m, 7H), 3.55 – 3.37 (m, 2H), 3.11 (s, 1H), 3.09 (s, 3H), 3.06 (s, 3H), 3.00 (t, J= 13.8 Hz, 0H), 2.88 (s, 3H), 2.78 (t, J= 12.6 Hz, 1H), 2.45 – 1.89 (m, 4H), 1.75 – 1.29 (m, 3H), 1.01 – 0.88 (m, 3H). MS (ESI) m/z: 773 [M+H] +. I-42
Figure 02_image458
 1H NMR (600 MHz, DMSO- d 6) δ 8.94 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 7.47 (s, 1H), 7.35 – 7.32 (m, 1H), 7.23 – 7.18 (m, 2H), 7.16 – 7.11 (m, 1H), 7.11 – 7.07 (m, 2H), 6.84 (s, 1H), 6.81 – 6.77 (m, 1H), 4.35 – 4.05 (m, 4H), 3.97 (s, 2H), 3.85 – 3.75 (m, 2H), 3.78 (s, 3H), 3.72 – 3.37 (m, 5H), 3.34 – 3.31 (m, 2H), 3.10 (s, 3H), 3.06 (s, 3H), 2.97 – 2.85 (m, 5H), 2.76 – 2.69 (m, 2H), 2.09 – 2.06 (m, 2H), 1.83 – 1.73 (m, 2H). MS (ESI) m/z: 807 [M+H] +. I-43
Figure 02_image460
 1H NMR (600 MHz, DMSO- d 6) δ 9.32 (s, 1H), 8.82 (s, 1H), 8.34 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 6.79 (s, 1H), 4.47 – 4.21 (m, 4H), 3.78 (s, 3H), 3.72 – 3.44 (m, 8H), 3.44 – 3.33 (m, 2H), 3.13 – 3.07 (m, 4H), 3.06 (s, 3H), 2.91 (s, 3H), 2.76 (q, J= 10.6 Hz, 2H), 2.36 (d, J= 6.7 Hz, 2H), 2.20 – 2.12 (m, 2H), 1.79 (dd, J= 11.8, 4.0 Hz, 2H), 0.77 (s, 1H), 0.38 (d, J= 8.0 Hz, 2H), 0.16 – -0.08 (m, 2H). MS (ESI) m/z: 771 [M+H] +. I-44
Figure 02_image462
 1H NMR (600 MHz, DMSO- d 6) δ 9.26 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.48 (d, J= 9.0 Hz, 1H), 7.38 (d, J= 8.9 Hz, 1H), 7.02 – 6.99 (m, 1H), 6.97 (s, 1H), 6.81 – 6.77 (m, 1H), 4.45 – 4.16 (m, 4H), 3.97 (s, 3H), 3.96 – 3.88 (m, 2H), 3.83 – 3.21 (m, 6H), 3.11 (s, 3H), 3.07 (s, 3H), 2.89 (s, 3H), 2.83 – 2.72 (m, 2H), 2.19 – 2.04 (m, 2H), 1.74 – 1.62 (m, 2H). MS (ESI) m/z: 771 [M+H] +. I-45
Figure 02_image464
 1H NMR (600 MHz, DMSO- d 6) δ 9.07 (s, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.45 (s, 1H), 7.44 – 7.39 (m, 1H), 7.03 (s, 1H), 6.80 – 6.68 (m, 1H), 4.48 – 4.19 (m, 4H), 3.89 – 3.23 (m, 9H), 3.15 – 3.09 (m, 5H), 3.07 (s, 3H), 2.89 (s, 3H), 2.70 (t, J= 11.6 Hz, 2H), 2.57 (q, J= 7.6 Hz, 2H), 2.21 – 2.07 (m, 2H), 1.87 – 1.71 (m, 2H), 1.09 (t, J= 7.4 Hz, 3H). MS (ESI) m/z: 799 [M+H] +. I-46
Figure 02_image466
 1H NMR (600 MHz, DMSO- d 6) δ 9.28 (s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.72 (s, 1H), 7.42 (d, J= 9.0 Hz, 1H), 7.01 (s, 1H), 6.87 (dd, J= 17.7, 11.1 Hz, 1H), 6.67 (d, J= 9.0 Hz, 1H), 5.68 (d, J= 17.7 Hz, 1H), 5.32 (d, J= 11.2 Hz, 1H), 4.43 – 4.19 (m, 4H), 3.85 – 3.30 (m, 9H), 3.23 (d, J= 11.5 Hz, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.90 (s, 3H), 2.72 (d, J= 11.2 Hz, 2H), 2.20 – 2.09 (m, 2H), 1.84 (dd, J= 11.7, 3.8 Hz, 2H). MS (ESI) m/z: 797 [M+H] +. I-47
Figure 02_image468
 1H NMR (600 MHz, DMSO- d 6) δ 9.26 – 9.10 (m, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 4.44 – 4.21 (m, 4H), 3.88 (s, 3H), 3.81 – 3.71 (m, 2H), 3.67 – 3.19 (m, 9H), 3.09 (s, 3H), 3.06 (s, 3H), 2.87 (s, 3H), 2.84 – 2.71 (m, 2H), 2.06 – 1.96 (m, 5H), 1.71 – 1.54 (m, 2H). MS (ESI) m/z: 732 [M+H] +. I-48
Figure 02_image470
 1H NMR (600 MHz, DMSO- d 6) δ 9.12 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 6.82 (d, J= 8.9 Hz, 1H), 4.45 – 4.22 (m, 4H), 3.84 (s, 3H), 3.78 – 3.19 (m, 11H), 3.10 (s, 3H), 3.06 (s, 3H), 2.91 (s, 3H), 2.88 – 2.79 (m, 2H), 2.44 (t, J= 7.1 Hz, 2H), 2.19 – 2.08 (m, 2H), 1.87 – 1.74 (m, 2H), 1.05 – 1.00 (m, 3H). MS (ESI) m/z: 746 [M+H] +. I-49
Figure 02_image472
 1H NMR (600 MHz, DMSO- d 6) δ 9.35 (s, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.42 (s, 1H), 6.85 (s, 1H), 6.43 (d, J= 8.5 Hz, 1H), 4.47 – 4.42 (m, 2H), 4.41 – 4.22 (m, 4H), 3.81 (s, 3H), 3.73 – 3.24 (m, 9H), 3.12 (s, 3H), 3.07 (s, 3H), 2.89 (s, 3H), 2.84 (t, J= 12.7 Hz, 2H), 2.17 – 2.09 (m, 2H), 1.62 – 1.54 (m, 2H). MS (ESI) m/z: 718 [M+H] +. I-50
Figure 02_image474
 1H NMR (600 MHz, DMSO- d 6) δ 10.11 (s, 1H), 9.75 (s, 1H), 8.39 – 8.25 (m, 2H), 8.03 (s, 1H), 7.55 (s, 1H), 7.27 (s, 1H), 6.98 – 6.91 (m, 1H), 4.50 – 4.20 (m, 6H), 3.47 (dt, J= 8.8, 4.5 Hz, 1H), 3.13 (s, 3H), 3.08 (s, 3H), 3.07 – 3.02 (m, 2H), 2.79 (d, J= 4.2 Hz, 6H), 2.17 – 2.07 (m, 2H), 1.73 – 1.60 (m, 2H). MS (ESI) m/z: 633 [M+H] +. I-51
Figure 02_image476
 1H NMR (600 MHz, DMSO- d 6) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.33 (s, 1H), 7.50 – 7.44 (m, 1H), 7.37 (d, J= 9.0 Hz, 1H), 7.09 – 7.00 (m, 2H), 6.88 (d, J= 8.9 Hz, 1H), 4.42 – 4.24 (m, 4H), 3.77 (s, 3H), 3.52 (d, J= 12.0 Hz, 2H), 3.07 (d, J= 7.1 Hz, 6H), 3.05 – 3.00 (m, 2H), 2.82 (d, J= 4.1 Hz, 3H), 2.66 – 2.58 (m, 1H), 1.97 – 1.74 (m, 4H). MS (ESI) m/z: 633 [M+H] +. I-52
Figure 02_image478
 1H NMR (600 MHz, DMSO- d 6) δ 9.81 (s, 2H), 8.39 (s, 1H), 8.31 (s, 1H), 7.58 – 7.48 (m, 1H), 7.35 (s, 1H), 7.19 (t, J= 7.9 Hz, 1H), 6.97 (d, J= 9.0 Hz, 1H), 6.87 (d, J= 7.6 Hz, 1H), 4.51 – 4.20 (m, 4H), 3.53 (d, J= 12.0 Hz, 2H), 3.10 (s, 3H), 3.08 (s, 3H), 3.07 – 3.01 (m, 2H), 2.82 (d, J= 4.3 Hz, 3H), 2.73 – 2.65 (m, 1H), 2.00 – 1.90 (m, 2H), 1.89 – 1.76 (m, 2H). MS (ESI) m/z: 603 [M+H] +. I-53
Figure 02_image480
 1H NMR (600 MHz, DMSO- d 6) δ 8.86 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.45 (d, J= 9.1 Hz, 1H), 7.33 (s, 1H), 6.99 (d, J= 8.8 Hz, 1H), 6.87 – 6.75 (m, 2H), 4.42 – 4.24 (m, 4H), 3.74 (s, 3H), 3.55 (t, J= 13.8 Hz, 2H), 3.47 (d, J= 9.9 Hz, 2H), 3.18 – 3.13 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.90 – 2.79 (m, 5H). MS (ESI) m/z: 634 [M+H] +. I-54
Figure 02_image482
 1H NMR (600 MHz, DMSO- d 6) δ 10.15 (s, 1H), 9.75 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 7.54 (d, J= 9.0 Hz, 1H), 7.23 – 7.02 (m, 2H), 6.93 (d, J= 8.9 Hz, 1H), 6.74 – 6.66 (m, 1H), 4.44 – 4.25 (m, 4H), 3.70 (t, J= 11.9 Hz, 2H), 3.54 – 3.47 (m, 2H), 3.19 – 3.12 (m, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 2.95 (t, J= 12.5 Hz, 2H), 2.87 (s, 3H). MS (ESI) m/z: 604 [M+H] +. I-55
Figure 02_image484
 MS (ESI) m/z: 635 [M+H] +. I-56
Figure 02_image486
 1H NMR (600 MHz, DMSO- d 6) δ 9.79 (s, 1H), 8.31 (s, 1H), 7.68 (s, 1H), 7.54 (d, J= 8.9 Hz, 1H), 7.48 (s, 1H), 7.29 (t, J= 8.1 Hz, 1H), 7.13 – 7.03 (m, 1H), 6.94 (d, J= 9.0 Hz, 1H), 4.50 – 4.19 (m, 4H), 3.80 (s, 1H), 3.52 (t, J= 6.2 Hz, 2H), 3.29 – 3.17 (m, 2H), 3.12 (s, 3H), 3.08 (s, 3H), 2.01 – 1.92 (m, 2H), 1.75 – 1.67 (m, 2H). MS (ESI) m/z: 605 [M+H] +. I-57
Figure 02_image488
 1H NMR (600 MHz, DMSO- d 6) δ 10.11 (s, 1H), 9.22 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 7.47 (s, 1H), 7.44 – 7.39 (m, 1H), 7.38 – 7.32 (m, 1H), 6.99 (d, J= 8.6 Hz, 1H), 6.89 (d, J= 9.0 Hz, 1H), 4.41 – 4.26 (m, 4H), 3.56 – 3.48 (m, 2H), 3.26 – 3.17 (m, 2H), 3.08 – 3.04 (m, 2H), 3.03 (s, 3H), 2.97 (t, J= 12.2 Hz, 2H), 2.89 (s, 3H), 2.62 – 2.54 (m, 2H), 1.08 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 618 [M+H] +. I-58
Figure 02_image490
 MS (ESI) m/z: 646 [M+H] +. I-59
Figure 02_image492
 MS (ESI) m/z: 658 [M+H] +. I-60
Figure 02_image494
 MS (ESI) m/z: 646 [M+H] +. I-61
Figure 02_image496
 MS (ESI) m/z: 658 [M+H] +. I-62
Figure 02_image498
 MS (ESI) m/z: 660 [M+H] +. I-63
Figure 02_image500
 1H NMR (600 MHz, DMSO- d 6) δ 10.20 (s, 1H), 9.26 (s, 1H), 8.91 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 7.50 (s, 1H), 7.39 – 7.30 (m, 1H), 6.78 (s, 1H), 4.38 – 4.26 (m, 4H), 3.81 (s, 3H), 3.53 (d, J= 11.8 Hz, 2H), 3.22 (d, J= 13.2 Hz, 2H), 3.12 (d, J= 12.8 Hz, 2H), 3.09 – 3.00 (m, 5H), 2.90 (s, 3H), 2.54 – 2.46 (m, 2H), 1.01 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 648 [M+H] +. I-64
Figure 02_image502
 MS (ESI) m/z: 676 [M+H] +. I-65
Figure 02_image504
 MS (ESI) m/z: 688 [M+H] +. I-66
Figure 02_image506
 MS (ESI) m/z: 676 [M+H] +. I-67
Figure 02_image508
 MS (ESI) m/z: 688 [M+H] +. I-68
Figure 02_image510
 MS (ESI) m/z: 690 [M+H] +. I-69
Figure 02_image512
 1H NMR (600 MHz, DMSO- d 6) δ 9.28 (s, 1H), 9.17 (s, 1H), 8.86 (s, 1H), 8.36 (s, 1H), 7.43 (s, 1H), 7.37 – 7.27 (m, 1H), 6.83 – 6.73 (m, 2H), 4.40 – 4.25 (m, 4H), 3.80 (s, 3H), 3.72 – 3.31 (m, 9H), 3.11 (d, J= 11.2 Hz, 2H), 3.03 (s, 3H), 2.91 (s, 3H), 2.78 (t, J= 11.7 Hz, 2H), 2.55 – 2.45 (m, 2H), 2.21 – 2.12 (m, 2H), 1.83 (dt, J= 11.9, 6.0 Hz, 2H), 1.02 (t, J= 7.4 Hz, 3H). MS (ESI) m/z: 731 [M+H] +. I-70
Figure 02_image514
 MS (ESI) m/z: 759 [M+H] +. I-71
Figure 02_image516
 MS (ESI) m/z: 771 [M+H] +. I-72
Figure 02_image518
 MS (ESI) m/z: 759 [M+H] +. I-73
Figure 02_image520
 MS (ESI) m/z: 771 [M+H] +. I-74
Figure 02_image522
 MS (ESI) m/z: 773 [M+H] +. I-75
Figure 02_image524
 1H NMR (600 MHz, Methanol- d 4) δ 8.07 (s, 1H), 7.37 (s, 1H), 7.32 – 7.20 (m, 1H), 6.92 (d, J= 9.0 Hz, 1H), 6.70 (s, 1H), 6.54 (d, J= 8.7 Hz, 1H), 4.45 – 4.28 (m, 4H), 3.86 (t, J= 4.8 Hz, 4H), 3.84 (s, 3H), 3.22 (t, J= 4.8 Hz, 4H), 3.20 (s, 3H), 3.03 (s, 3H). MS (ESI) m/z: 621 [M+H] +. I-76
Figure 02_image526
 1H NMR (600 MHz, Methanol- d 4) δ 8.09 (s, 1H), 7.44 – 7.31 (m, 2H), 6.91 (d, J= 9.1 Hz, 1H), 6.74 (d, J= 2.5 Hz, 1H), 6.55 (d, J= 8.7 Hz, 1H), 4.43 – 4.28 (m, 4H), 3.96 – 3.86 (m, 2H), 3.85 (s, 3H), 3.72 – 3.60 (m, 2H), 3.33 – 3.24 (m, 2H), 3.20 (s, 3H), 3.13 – 3.05 (m, 2H), 3.04 (s, 3H), 2.98 (s, 3H). MS (ESI) m/z: 634 [M+H] +. I-77
Figure 02_image528
 1H NMR (600 MHz, Methanol- d 4) δ 8.10 (s, 1H), 7.41 (d, J= 9.0 Hz, 1H), 7.32 (d, J= 8.9 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.90 (d, J= 9.0 Hz, 1H), 4.45 – 4.27 (m, 4H), 3.86 – 3.74 (m, 2H), 3.68 – 3.57 (m, 2H), 3.30 – 3.23 (m, 2H), 3.17 (s, 3H), 3.13 – 3.00 (m, 5H), 2.97 (s, 3H). MS (ESI) m/z: 604 [M+H] +. I-78
Figure 02_image530
 1H NMR (600 MHz, Methanol- d 4) δ 8.20 (s, 1H), 7.86 (d, J= 8.7 Hz, 1H), 7.34 (d, J= 8.9 Hz, 1H), 7.18 (d, J= 2.5 Hz, 1H), 6.99 (d, J= 8.9 Hz, 1H), 6.94 (dd, J= 8.9, 2.6 Hz, 1H), 4.48 – 4.24 (m, 4H), 4.07 – 3.99 (m, 1H), 3.94 (s, 3H), 3.78 (t, J= 10.2 Hz, 2H), 3.47 (t, J= 8.6 Hz, 2H), 3.19 (s, 3H), 3.03 (s, 3H), 2.30 – 2.10 (m, 2H), 2.05 – 1.84 (m, 2H). MS (ESI) m/z: 635 [M+H] +. I-79
Figure 02_image532
 1H NMR (600 MHz, DMSO- d 6) δ 10.20 (s, 1H), 9.52 (s, 1H), 8.26 (s, 1H), 7.34 (d, J= 2.5 Hz, 1H), 7.12 (dd, J= 8.6, 2.5 Hz, 1H), 7.05 (d, J= 8.8 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.95 (d, J= 8.5 Hz, 1H), 6.79 (dd, J= 17.2, 11.1 Hz, 1H), 5.86 (d, J= 17.2 Hz, 1H), 5.45 (d, J= 11.1 Hz, 1H), 4.46 – 4.22 (m, 4H), 3.53 – 3.47 (m, 2H), 3.26 – 3.14 (m, 2H), 3.09 – 3.02 (m, 2H), 2.99 (s, 3H), 2.97 – 2.92 (m, 5H), 2.88 (s, 3H), 2.47 – 2.37 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 580 [M+H] +. I-80
Figure 02_image534
 1H NMR (600 MHz, DMSO- d 6) δ 10.51 (s, 1H), 9.57 (s, 1H), 8.17 (s, 1H), 7.32 – 7.20 (m, 1H), 7.09 – 7.06 (m, 1H), 7.03 – 7.00 (m, 1H), 6.98 – 6.95 (m, 2H), 6.79 (dd, J= 17.2, 11.1 Hz, 1H), 5.85 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.1 Hz, 1H), 4.43 – 4.24 (m, 4H), 3.77 – 3.69 (m, 4H), 2.98 (s, 3H), 2.95 (s, 3H), 2.77 (t, J= 4.5 Hz, 4H), 2.63 – 2.53 (m, 1H), 2.48 – 2.37 (m, 1H), 1.07 – 0.99 (m, 3H). MS (ESI) m/z: 567 [M+H] +. I-81
Figure 02_image536
 1H NMR (600 MHz, DMSO- d 6) δ 10.75 (s, 1H), 9.36 (s, 1H), 8.29 (s, 1H), 7.49 (d, J= 2.7 Hz, 1H), 7.36 – 7.28 (m, 1H), 7.09 (d, J= 8.8 Hz, 1H), 6.99 (d, J= 8.8 Hz, 1H), 6.79 (dd, J= 17.3, 11.1 Hz, 1H), 5.85 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 11.2 Hz, 1H), 4.42 – 4.26 (m, 4H), 3.47 (d, J= 5.4 Hz, 2H), 3.41 (s, 2H), 3.04 (s, 3H), 2.99 (d, J= 2.6 Hz, 6H), 2.73 – 2.59 (m, 2H), 1.01 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 555 [M+H] +. I-82
Figure 02_image538
 1H NMR (600 MHz, DMSO- d 6) δ 10.26 (s, 1H), 9.40 (s, 1H), 8.16 – 8.03 (m, 1H), 7.09 (s, 1H), 7.06 (d, J= 8.8 Hz, 1H), 7.04 – 7.02 (m, 1H), 6.94 (d, J= 8.8 Hz, 1H), 6.76 (dd, J= 17.2, 11.1 Hz, 1H), 6.65 (d, J= 8.7 Hz, 1H), 5.82 (d, J= 17.3 Hz, 1H), 5.44 (d, J= 11.2 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.65 – 3.55 (m, 3H), 3.17 (s, 2H), 2.99 (s, 6H), 2.47 – 2.33 (m, 2H), 1.13 – 0.98 (m, 3H). MS (ESI) m/z: 541 [M+H] +. I-83
Figure 02_image540
 1H NMR (600 MHz, Methanol- d 4) δ 7.88 – 7.65 (m, 1H), 7.25 (s, 1H), 7.09 (s, 1H), 7.06 – 7.02 (m, 1H), 6.89 (s, 1H), 6.71 – 6.62 (m, 2H), 5.79 (d, J= 17.3 Hz, 1H), 5.56 (d, J= 11.1 Hz, 1H), 4.45 – 4.25 (m, 4H), 3.60 (t, J= 6.1 Hz, 2H), 3.41 (t, J= 6.1 Hz, 2H), 3.18 – 3.11 (m, 3H), 3.01 (s, 3H), 2.96 (s, 6H), 2.57 – 2.42 (m, 2H), 1.21 – 1.11 (m, 3H). MS (ESI) m/z: 568 [M+H] +. I-84
Figure 02_image542
 1H NMR (600 MHz, Methanol- d 4) δ 7.78 (s, 1H), 7.25 (d, J= 2.4 Hz, 1H), 7.11 – 7.04 (m, 3H), 6.81 (d, J= 8.9 Hz, 1H), 6.59 (dd, J= 17.3, 11.0 Hz, 1H), 5.73 (d, J= 17.3 Hz, 1H), 5.48 (d, J= 11.0 Hz, 1H), 4.32 – 4.20 (m, 4H), 3.23 – 3.19 (m, 7H), 3.04 (s, 3H), 2.91 (s, 3H), 2.82 (s, 6H), 2.57 – 2.54 (m, 2H), 1.01 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 582 [M+H] +. I-85
Figure 02_image544
 MS (ESI) m/z: 579 [M+H] +. I-86
Figure 02_image546
 MS (ESI) m/z: 592 [M+H] +. I-87
Figure 02_image548
 1H NMR (600 MHz, DMSO- d 6) δ 10.14 (s, 1H), 9.25 (s, 1H), 8.19 (s, 1H), 7.15 (d, J= 8.9 Hz, 1H), 7.10 (d, J= 8.9 Hz, 1H), 6.94 (d, J= 8.8 Hz, 1H), 6.87 (d, J= 8.6 Hz, 1H), 6.82 (d, J= 2.5 Hz, 1H), 6.76 (dd, J= 17.2, 11.2 Hz, 1H), 5.82 (d, J= 17.3 Hz, 1H), 5.42 (d, J= 11.1 Hz, 1H), 4.46 – 4.20 (m, 4H), 3.58 – 3.49 (m, 3H), 3.38 – 3.20 (m, 5H), 3.00 (s, 3H), 2.97 (s, 3H), 2.91 – 2.86 (m, 3H), 1.04 (d, J= 6.1 Hz, 1H), 0.94 – 0.88 (m, 2H), 0.45 (d, J= 25.3 Hz, 2H). MS (ESI) m/z: 592 [M+H] +. I-88
Figure 02_image550
 1H NMR (600 MHz, DMSO- d 6) δ 10.41 (s, 1H), 9.43 (s, 1H), 8.14 (s, 1H), 7.09 – 7.06 (m, 1H), 7.04 (d, J= 8.9 Hz, 1H), 6.94 (d, J= 8.8 Hz, 1H), 6.89 – 6.85 (m, 1H), 6.77 (dd, J= 17.3, 11.3 Hz, 1H), 6.73 (d, J= 2.5 Hz, 1H), 5.83 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 11.1 Hz, 1H), 4.48 – 4.19 (m, 4H), 3.81 – 3.70 (m, 4H), 2.99 (s, 3H), 2.98 – 2.93 (m, 3H), 2.93 – 2.86 (m, 4H), 1.06 – 1.02 (m, 1H), 0.93 – 0.85 (m, 2H), 0.55 – 0.35 (m, 2H). MS (ESI) m/z: 579 [M+H] +. I-89
Figure 02_image552
 1H NMR (600 MHz, Methanol- d 4) δ 7.86 (s, 1H), 7.34 – 7.29 (m, 1H), 7.20 (d, J= 8.9 Hz, 1H), 7.16 – 7.09 (m, 1H), 7.04 (d, J= 8.5 Hz, 1H), 6.93 (d, J= 8.9 Hz, 1H), 6.69 (dd, J= 17.2, 11.0 Hz, 1H), 5.81 (d, J= 17.3 Hz, 1H), 5.56 (d, J= 11.1 Hz, 1H), 4.45 – 4.25 (m, 4H), 3.60 (d, J= 12.1 Hz, 2H), 3.34 (d, J= 11.7 Hz, 2H), 3.25 (d, J= 13.5 Hz, 2H), 3.12 (s, 3H), 3.09 – 3.02 (m, 2H), 3.00 (s, 3H), 2.99 (s, 3H), 2.23 (s, 3H). MS (ESI) m/z: 566 [M+H] +. I-90
Figure 02_image554
 1H NMR (600 MHz, DMSO- d 6) δ 10.54 (s, 1H), 9.59 (s, 1H), 8.19 (s, 1H), 7.24 (d, J= 2.6 Hz, 1H), 7.05 (dd, J= 8.6, 2.6 Hz, 1H), 7.02 (d, J= 8.8 Hz, 1H), 6.98 (d, J= 8.8 Hz, 1H), 6.90 (d, J= 8.6 Hz, 1H), 6.79 (dd, J= 17.2, 11.1 Hz, 1H), 5.85 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 11.2 Hz, 1H), 4.42 – 4.23 (m, 4H), 3.78 – 3.64 (m, 4H), 2.99 (s, 3H), 2.95 (s, 3H), 2.83 – 2.73 (m, 4H), 2.10 (s, 3H). MS (ESI) m/z: 553 [M+H] +. I-91
Figure 02_image556
 1H NMR (600 MHz, Methanol- d 4) δ 7.87 (s, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 6.92 (d, J= 8.9 Hz, 1H), 6.71 (s, 1H), 6.69 – 6.62 (m, 1H), 5.80 (d, J= 17.2 Hz, 1H), 5.55 (d, J= 11.0 Hz, 1H), 4.43 – 4.28 (m, 4H), 4.03 – 3.98 (m, 1H), 3.85 (s, 3H), 3.54 – 3.44 (m, 1H), 3.44 – 3.36 (m, 2H), 3.22 – 3.04 (m, 4H), 3.00 (s, 3H), 2.97 (s, 6H), 2.55 – 2.40 (m, 1H), 2.27 – 2.19 (m, 1H), 2.12 (s, 3H). MS (ESI) m/z: 610 [M+H] +. I-92
Figure 02_image558
 1H NMR (600 MHz, Methanol- d 4) δ 7.88 (s, 1H), 7.45 – 7.25 (m, 1H), 7.16 (s, 1H), 6.92 (d, J= 8.9 Hz, 1H), 6.76 (s, 1H), 6.68 (dd, J= 17.2, 11.0 Hz, 1H), 5.80 (d, J= 17.3 Hz, 1H), 5.55 (d, J= 11.0 Hz, 1H), 4.48 – 4.23 (m, 4H), 3.84 (s, 3H), 3.37 – 3.32 (m, 1H), 3.28 – 3.22 (m, 2H), 3.12 (s, 3H), 3.00 (s, 3H), 2.93 (s, 6H), 2.84 – 2.73 (m, 2H), 2.26 – 2.15 (m, 2H), 2.10 (s, 3H), 1.97 – 1.87 (m, 2H). MS (ESI) m/z: 624 [M+H] +. I-93
Figure 02_image560
 1H NMR (600 MHz, Methanol- d 4) δ 7.90 (s, 1H), 7.42 (s, 1H), 7.22 – 7.08 (m, 1H), 6.93 (d, J= 8.9 Hz, 1H), 6.78 (s, 1H), 6.69 (dd, J= 17.2, 11.0 Hz, 1H), 5.81 (d, J= 17.3 Hz, 1H), 5.55 (d, J= 11.1 Hz, 1H), 4.45 – 4.26 (m, 4H), 3.86 (s, 3H), 3.63 – 3.56 (m, 2H), 3.36 – 3.31 (m, 2H), 3.28 – 3.22 (m, 2H), 3.12 (s, 3H), 3.12 – 3.06 (m, 2H), 3.00 (s, 3H), 2.99 (s, 3H), 2.11 (s, 3H). MS (ESI) m/z: 596 [M+H] +. I-94
Figure 02_image562
 1H NMR (600 MHz, Methanol- d 4) δ 7.88 (s, 1H), 7.51 – 7.30 (m, 1H), 7.17 (d, J= 19.2 Hz, 1H), 6.90 (d, J= 8.9 Hz, 1H), 6.79 (d, J= 3.3 Hz, 1H), 6.68 (dd, J= 17.2, 10.9 Hz, 1H), 5.81 (d, J= 17.3 Hz, 1H), 5.55 (d, J= 11.0 Hz, 1H), 4.43 – 4.28 (m, 4H), 4.04 – 3.96 (m, 1H), 3.86 (d, J= 1.8 Hz, 3H), 3.47 – 3.37 (m, 2H), 3.36 – 3.30 (m, 2H), 3.20 – 3.11 (m, 3H), 3.00 (s, 3H), 2.96 (s, 6H), 2.60 – 2.39 (m, 3H), 2.28 – 2.17 (m, 1H), 1.04 (s, 3H). MS (ESI) m/z: 624 [M+H] +. I-95
Figure 02_image564
 1H NMR (600 MHz, Methanol- d 4) δ 7.89 (s, 1H), 7.56 – 7.24 (m, 1H), 7.15 (s, 1H), 6.90 (d, J= 9.0 Hz, 1H), 6.81 (s, 1H), 6.68 (dd, J= 17.2, 11.0 Hz, 1H), 5.81 (d, J= 17.2 Hz, 1H), 5.55 (d, J= 11.0 Hz, 1H), 4.43 – 4.27 (m, 4H), 3.84 (s, 3H), 3.37 – 3.32 (m, 1H), 3.22 – 3.16 (m, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 2.93 (s, 6H), 2.84 (t, J= 11.7 Hz, 2H), 2.63 – 2.36 (m, 2H), 2.22 – 2.13 (m, 2H), 2.01 – 1.86 (m, 2H), 1.04 (s, 3H). MS (ESI) m/z: 638 [M+H] +. I-96
Figure 02_image566
 1H NMR (600 MHz, Methanol- d 4) δ 7.91 (s, 1H), 7.55 – 7.39 (m, 1H), 7.14 (s, 1H), 6.91 (d, J= 8.9 Hz, 1H), 6.84 (s, 1H), 6.68 (dd, J= 17.3, 11.0 Hz, 1H), 5.81 (d, J= 17.3 Hz, 1H), 5.56 (d, J= 11.1 Hz, 1H), 4.42 – 4.30 (m, 4H), 3.87 (s, 3H), 3.65 – 3.55 (m, 2H), 3.35 – 3.33 (m, 2H), 3.20 – 3.08 (m, 7H), 3.00 (s, 3H), 2.98 (s, 3H), 2.64 – 2.37 (m, 2H), 1.04 (s, 3H). MS (ESI) m/z: 610 [M+H] +. I-97
Figure 02_image568
 1H NMR (600 MHz, DMSO- d 6) δ 9.53 (s, 1H), 8.18 (s, 4H), 7.39 – 7.17 (m, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.91 (d, J= 8.7 Hz, 1H), 6.77 (dd, J= 17.2, 11.1 Hz, 1H), 6.72 (s, 1H), 5.83 (d, J= 17.2 Hz, 1H), 5.46 (d, J= 11.1 Hz, 1H), 4.42 – 4.22 (m, 4H), 4.23 – 4.16 (m, 2H), 3.81 (s, 3H), 3.30 – 3.20 (m, 2H), 3.03 – 2.91 (m, 6H), 2.40 – 2.05 (m, 2H), 0.95 (s, 3H). MS (ESI) m/z: 571 [M+H] +. I-98
Figure 02_image570
 1H NMR (600 MHz, DMSO- d 6) δ 10.01 (s, 2H), 9.42 (s, 1H), 8.23 (s, 1H), 7.04 (s, 1H), 6.89 (s, 2H), 6.75 (dd, J= 17.2, 11.1 Hz, 1H), 6.31 (s, 1H), 5.80 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 11.1 Hz, 1H), 4.42 – 4.22 (m, 4H), 3.78 (s, 3H), 3.52 (s, 2H), 3.32 – 3.25 (m, 2H), 2.99 (s, 3H), 2.87 (s, 9H), 2.34 (s, 2H), 1.25 – 0.69 (m, 3H). MS (ESI) m/z: 598 [M+H] +. I-99
Figure 02_image572
 1H NMR (600 MHz, Chloroform- d) δ 9.72 – 9.57 (m, 1H), 9.52 (s, 1H), 8.28 – 8.15 (m, 1H), 7.41 – 7.34 (m, 1H), 7.00 (d, J= 8.9 Hz, 1H), 6.90 (d, J= 8.9 Hz, 1H), 6.87 (s, 1H), 6.78 (dd, J= 17.2, 11.1 Hz, 1H), 5.83 (d, J= 17.2 Hz, 1H), 5.47 (d, J= 11.2 Hz, 1H), 4.42 – 4.19 (m, 4H), 3.80 (s, 3H), 3.25 – 3.18 (m, 4H), 2.98 (d, J= 6.3 Hz, 6H), 2.80 (s, 9H), 2.61 – 2.56 (m, 2H), 0.91 (s, 3H). MS (ESI) m/z: 612 [M+H] +. I-100
Figure 02_image574
 1H NMR (600 MHz, Methanol- d 4) δ 7.96 – 7.85 (m, 2H), 7.70 – 7.51 (m, 2H), 7.16 – 7.04 (m, 1H), 6.84 (s, 1H), 6.67 (dd, J= 17.2, 11.0 Hz, 1H), 6.60 – 6.37 (m, 1H), 5.81 (d, J= 17.3 Hz, 1H), 5.56 (d, J= 11.0 Hz, 1H), 4.39 – 4.18 (m, 4H), 3.97 (s, 3H), 3.91 (s, 3H), 3.90 – 3.78 (m, 1H), 3.60 – 3.50 (m, 2H), 3.28 – 3.21 (m, 2H), 3.17 – 3.03 (m, 4H), 3.03 – 2.89 (m, 8H). MS (ESI) m/z: 662 [M+H] +. I-101
Figure 02_image576
 MS (ESI) m/z: 648 [M+H] +. I-102
Figure 02_image578
 MS (ESI) m/z: 648 [M+H] +. I-103
Figure 02_image580
 1H NMR (600 MHz, Methanol- d 4) δ 7.85 (s, 1H), 7.41 (s, 1H), 7.20 (d, J= 9.0 Hz, 1H), 6.95 (d, J= 8.9 Hz, 1H), 6.89 (d, J= 2.6 Hz, 1H), 6.72 – 6.62 (m, 2H), 5.81 (d, J= 17.3 Hz, 1H), 5.56 (d, J= 11.1 Hz, 1H), 4.41 – 4.30 (m, 4H), 3.92 – 3.83 (m, 5H), 3.63 – 3.33 (m, 8H), 3.26 – 3.20 (m, 1H), 3.14 (s, 3H), 3.12 – 3.05 (m, 2H), 3.00 (s, 3H), 2.94 (s, 3H), 2.29 – 2.17 (m, 2H), 2.01 – 1.88 (m, 2H). MS (ESI) m/z: 665 [M+H] +. I-104
Figure 02_image582
 1H NMR (600 MHz, Methanol- d 4) δ 7.88 (s, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 6.93 (d, J= 8.9 Hz, 1H), 6.78 (s, 1H), 6.68 (dd, J= 17.2, 11.0 Hz, 1H), 5.80 (d, J= 17.2 Hz, 1H), 5.55 (d, J= 11.0 Hz, 1H), 4.40 – 4.30 (m, 4H), 3.85 (s, 3H), 3.65 – 3.46 (m, 8H), 3.29 – 3.21 (m, 3H), 3.12 (s, 3H), 3.00 (s, 3H), 2.95 (s, 3H), 2.89 – 2.79 (m, 2H), 2.26 – 2.17 (m, 2H), 2.10 (s, 3H), 1.99 – 1.90 (m, 2H). MS (ESI) m/z: 679 [M+H] +. I-105
Figure 02_image584
 1H NMR (600 MHz, Methanol- d 4) δ 7.89 (s, 1H), 7.55 – 7.33 (m, 1H), 7.13 (s, 1H), 6.91 (d, J= 9.0 Hz, 1H), 6.83 (s, 1H), 6.68 (dd, J= 17.2, 11.0 Hz, 1H), 5.81 (d, J= 17.2 Hz, 1H), 5.55 (d, J= 11.1 Hz, 1H), 4.44 – 4.28 (m, 4H), 3.85 (s, 3H), 3.73 – 3.50 (m, 8H), 3.42 – 3.33 (m, 1H), 3.25 – 3.18 (m, 2H), 3.13 (s, 3H), 2.99 (d, J= 7.1 Hz, 6H), 2.92 – 2.82 (m, 2H), 2.61 – 2.40 (m, 2H), 2.29 – 2.16 (m, 2H), 2.04 – 1.90 (m, 2H), 1.04 (s, 3H). MS (ESI) m/z: 693 [M+H] +. I-106
Figure 02_image586
 1H NMR (600 MHz, DMSO- d 6) δ 9.87 – 9.56 (m, 1H), 9.45 (s, 1H), 8.27 – 7.97 (m, 1H), 7.26 (s, 1H), 6.97 (s, 1H), 6.85 (s, 1H), 6.80 – 6.70 (m, 2H), 5.82 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.43 – 4.08 (m, 4H), 3.75 (s, 3H), 3.66 – 3.13 (m, 10H), 3.12 – 3.00 (m, 2H), 2.97 (s, 3H), 2.90 (s, 3H), 2.77 (q, J= 11.2 Hz, 2H), 2.55 (s, 3H), 2.23 – 2.05 (m, 2H), 1.87 – 1.69 (m, 2H), 0.96 (d, J= 25.2 Hz, 6H). MS (ESI) m/z: 707 [M+H] +. I-107
Figure 02_image588
 MS (ESI) m/z: 705 [M+H] +. I-108
Figure 02_image590
 1H NMR (600 MHz, DMSO- d 6) δ 10.51 (s, 1H), 9.46 (s, 1H), 8.20 (s, 1H), 7.69 – 7.44 (m, 1H), 7.34 – 7.26 (m, 1H), 7.13 – 7.01 (m, 2H), 7.00 – 6.92 (m, 1H), 6.78 (dd, J= 17.2, 11.1 Hz, 1H), 5.84 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 11.1 Hz, 1H), 4.43 – 4.23 (m, 4H), 3.57 – 3.09 (m, 9H), 3.08 – 3.01 (m, 3H), 2.99 (s, 3H), 2.96 (s, 3H), 2.88 (s, 3H), 2.72 – 2.59 (m, 2H), 2.45 – 2.35 (m, 1H), 2.16 – 2.06 (m, 2H), 1.83 – 1.68 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 663 [M+H] +. I-109
Figure 02_image592
 1H NMR (600 MHz, DMSO- d 6) δ 9.53 (s, 1H), 9.39 – 9.28 (m, 3H), 7.34 (s, 1H), 6.99 (d, J= 8.7 Hz, 1H), 6.91 (d, J= 8.8 Hz, 1H), 6.82 – 6.72 (m, 2H), 5.82 (d, J= 17.3 Hz, 1H), 5.47 (d, J= 11.1 Hz, 1H), 4.47 – 4.22 (m, 4H), 3.98 – 3.92 (m, 1H), 3.79 (s, 3H), 3.61 – 3.27 (m, 9H), 3.14 – 2.89 (m, 6H), 2.79 – 2.67 (m, 2H), 2.33 – 2.22 (m, 1H), 2.17 – 2.06 (m, 3H), 1.79 (dd, J= 11.7, 3.9 Hz, 2H), 1.24 (s, 1H), 1.01 – 0.90 (m, 3H). MS (ESI) m/z: 679 [M+H] +. I-110
Figure 02_image594
 1H NMR (600 MHz, DMSO- d 6) δ 9.01 – 8.98 (m, 1H), 8.96 – 8.93 (m, 1H), 8.82 (s, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 8.20 (d, J= 9.2 Hz, 1H), 7.99 (d, J= 9.3 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J= 8.9 Hz, 1H), 6.66 – 6.61 (m, 1H), 3.75 (s, 3H), 3.44 (d, J= 7.4 Hz, 2H), 3.38 (s, 3H), 3.25 – 3.21 (m, 3H), 3.16 (t, J= 7.2 Hz, 2H), 2.80 (s, 6H), 2.66 (s, 3H). MS (ESI) m/z: 693 [M+H] +. I-111
Figure 02_image596
 MS (ESI) m/z: 665 [M+H] +. I-112
Figure 02_image598
 1H NMR (600 MHz, DMSO- d 6) δ 9.51 (s, 1H), 9.07 – 8.86 (m, 3H), 8.16 (s, 1H), 6.99 (d, J= 8.8 Hz, 1H), 6.90 (d, J= 8.8 Hz, 1H), 6.81 – 6.74 (m, 2H), 5.82 (d, J= 17.3 Hz, 1H), 5.47 (d, J= 11.1 Hz, 1H), 4.51 – 4.20 (m, 4H), 4.12 – 4.03 (m, 7H), 3.81 – 3.77 (m, 3H), 2.98 (s, 3H), 2.96 – 2.91 (m, 4H), 2.85 (s, 5H), 2.37 – 2.17 (m, 1H), 1.24 (s, 1H), 0.94 (s, 3H). MS (ESI) m/z: 651 [M+H] +. I-113
Figure 02_image600
 1H NMR (600 MHz, DMSO- d 6) δ 10.04 (s, 1H), 9.51 (s, 1H), 8.16 (s, 1H), 7.41 – 7.26 (m, 1H), 6.98 (d, J= 8.8 Hz, 1H), 6.90 (d, J= 8.8 Hz, 1H), 6.81 – 6.72 (m, 2H), 5.81 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.44 – 4.21 (m, 4H), 3.78 (s, 3H), 3.73 – 3.64 (m, 2H), 2.98 (s, 3H), 2.75 (s, 3H), 2.73 – 2.66 (m, 9H), 2.22 (t, J= 10.1 Hz, 2H), 1.97 (dd, J= 12.2, 8.5 Hz, 3H), 1.68 (dt, J= 15.8, 5.1 Hz, 5H), 0.94 (s, 3H). MS (ESI) m/z: 678 [M+H] +. I-114
Figure 02_image602
 1H NMR (600 MHz, DMSO- d 6) δ 10.16 (s, 1H), 9.45 (s, 1H), 8.44 – 8.00 (m, 1H), 7.42 – 7.28 (m, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.90 (d, J= 8.7 Hz, 1H), 6.81 – 6.73 (m, 2H), 5.81 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 11.2 Hz, 1H), 4.45 – 4.21 (m, 4H), 4.02 (dd, J= 10.4, 6.5 Hz, 3H), 3.84 – 3.79 (m, 2H), 3.78 (s, 3H), 2.98 (s, 3H), 2.90 – 2.84 (m, 6H), 2.77 (s, 2H), 2.66 (s, 2H), 2.03 – 1.80 (m, 5H), 0.94 (s, 3H). MS (ESI) m/z: 650 [M+H] +. I-115
Figure 02_image604
 MS (ESI) m/z: 622 [M+H] +. I-116
Figure 02_image606
 MS (ESI) m/z: 609 [M+H] +. I-117
Figure 02_image608
 1H NMR (600 MHz, DMSO- d 6) δ 8.82 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.52 – 7.44 (m, 1H), 7.16 (s, 1H), 6.77 – 6.69 (m, 2H), 6.66 (dd, J= 17.6, 11.4 Hz, 1H), 5.66 (d, J= 17.5 Hz, 1H), 5.26 (d, J= 11.2 Hz, 1H), 4.44 – 4.20 (m, 4H), 3.38 (s, 6H), 3.06 (s, 3H), 3.05 (s, 3H), 2.68 (t, J= 11.7 Hz, 2H), 2.39 – 2.26 (m, 5H), 2.17 (s, 3H), 1.86 (d, J= 12.2 Hz, 2H), 1.63 – 1.52 (m, 2H). MS (ESI) m/z: 671 [M+H] +. I-118
Figure 02_image610
 1H NMR (600 MHz, DMSO- d 6) δ 10.35 (s, 1H), 8.99 (s, 1H), 8.30 (s, 1H), 7.17 – 7.11 (m, 2H), 7.09 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 8.8 Hz, 1H), 6.79 (dd, J= 17.3, 11.1 Hz, 1H), 5.80 (d, J= 17.2 Hz, 1H), 5.37 (d, J= 11.3 Hz, 1H), 4.43 – 4.22 (m, 4H), 3.84 – 3.22 (m, 9H), 3.21 – 3.13 (m, 2H), 3.03 (d, J= 12.4 Hz, 2H), 3.00 (s, 3H), 2.98 (s, 3H), 2.87 (s, 3H), 2.13 – 2.00 (m, 2H), 1.75 – 1.64 (m, 2H). MS (ESI) m/z: 671 [M+H] +. I-119
Figure 02_image612
 1H NMR (600 MHz, DMSO- d 6) δ 9.73 – 9.52 (m, 2H), 8.29 (s, 1H), 7.54 (s, 1H), 6.98 (d, J= 8.9 Hz, 1H), 6.93 (d, J= 8.3 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.80 (dd, J= 17.2, 11.2 Hz, 1H), 5.85 (d, J= 17.2 Hz, 1H), 5.49 (d, J= 11.1 Hz, 1H), 4.74 – 4.60 (m, 1H), 4.30 – 4.25 (m, 4H), 3.88 – 3.75 (m, 3H), 3.62 – 3.23 (m, 9H), 3.03 (s, 1H), 3.01 – 2.94 (m, 4H), 2.87 (s, 3H), 2.77 (t, J= 12.0 Hz, 1H), 2.55 (d, J= 1.1 Hz, 3H), 2.46 – 1.84 (m, 4H), 1.75 – 1.20 (m, 2H), 0.94 – 0.83 (m, 3H). MS (ESI) m/z: 721 [M+H] +. I-120
Figure 02_image614
 1H NMR (600 MHz, Methanol- d 4) δ 7.94 – 7.91 (m, 1H), 7.22 (t, J= 7.3 Hz, 3H), 7.14 (t, J= 7.2 Hz, 2H), 7.07 (s, 3H), 6.90 – 6.85 (m, 1H), 6.70 (dd, J= 17.2, 11.0 Hz, 1H), 5.83 (d, J= 17.2 Hz, 1H), 5.58 (d, J= 11.0 Hz, 1H), 4.32 – 4.14 (m, 4H), 4.12 – 4.09 (m, 1H), 3.89 (s, 3H), 3.53 – 3.36 (m, 7H), 3.16 (s, 3H), 2.99 (s, 3H), 2.89 (s, 4H), 2.79 – 2.72 (m, 2H), 2.02 (d, J= 11.8 Hz, 3H), 1.78 – 1.71 (m, 3H), 1.31 (s, 2H). MS (ESI) m/z: 755 [M+H] +. I-121
Figure 02_image616
 1H NMR (600 MHz, DMSO- d 6) δ 9.60 (s, 0H), 9.48 (s, 1H), 8.16 – 8.13 (m, 1H), 7.42 (s, 1H), 7.01 (d, J= 8.8 Hz, 1H), 6.88 (d, J= 8.7 Hz, 1H), 6.78 (s, 1H), 6.76 (dd, J= 17.2, 11.1 Hz, 1H), 5.82 (d, J= 17.3 Hz, 1H), 5.47 (d, J= 11.2 Hz, 1H), 4.46 – 4.21 (m, 4H), 3.78 (s, 3H), 3.26 (d, J= 14.4 Hz, 13H), 3.09 – 3.02 (m, 2H), 2.98 (s, 3H), 2.88 (s, 3H), 2.79 – 2.68 (m, 2H), 2.45 – 2.38 (m, 1H), 2.14 – 2.09 (m, 3H), 1.77 – 1.71 (m, 1H), 0.74 (s, 1H), 0.37 (d, J= 7.4 Hz, 2H), 0.05 (s, 2H). MS (ESI) m/z: 719 [M+H] +. I-122
Figure 02_image618
 1H NMR (600 MHz, DMSO- d 6) δ 10.12 (s, 1H), 9.48 (s, 1H), 8.08 (s, 1H), 7.33 (d, J= 8.9 Hz, 1H), 7.02 (d, J= 8.9 Hz, 1H), 6.97 (s, 1H), 6.93 – 6.89 (m, 1H), 6.75 (dd, J= 17.3, 11.1 Hz, 1H), 5.84 (d, J= 17.3 Hz, 1H), 5.48 (d, J= 11.2 Hz, 1H), 4.45 – 4.20 (m, 4H), 3.92 (d, J= 12.7 Hz, 2H), 3.77 – 3.21 (m, 9H), 2.99 (s, 3H), 2.97 (s, 2H), 2.88 (s, 3H), 2.77 (t, J= 12.4 Hz, 2H), 2.15 – 2.10 (m, 3H), 1.69 – 1.60 (m, 2H). MS (ESI) m/z: 719 [M+H] +. I-123
Figure 02_image620
 1H NMR (600 MHz, DMSO- d 6) δ 10.10 (s, 1H), 9.53 (s, 1H), 8.19 (s, 1H), 7.46 (s, 1H), 7.03 (s, 1H), 6.94 (d, J= 8.8 Hz, 1H), 6.85 (d, J= 8.8 Hz, 1H), 6.77 (dd, J= 17.2, 11.1 Hz, 1H), 5.85 (d, J= 17.3 Hz, 1H), 5.48 (d, J= 11.1 Hz, 1H), 4.40 – 4.19 (m, 4H), 4.09 – 3.39 (m, 8H), 3.34 (s, 1H), 3.12 – 3.05 (m, 2H), 2.97 (s, 3H), 2.93 (s, 3H), 2.89 (s, 3H), 2.76 – 2.64 (m, 2H), 2.60 – 2.53 (m, 1H), 2.37 (s, 1H), 2.14 (d, J= 11.6 Hz, 2H), 1.86 – 1.73 (m, 2H), 1.00 (d, J= 7.6 Hz, 3H). MS (ESI) m/z: 747 [M+H] +. I-124
Figure 02_image622
 1H NMR (600 MHz, CDCl 3) δ 9.38 (s, 1H), 8.16 (s, 1H), 7.69 (s, 1H), 6.99 (s, 1H), 6.96 (d, J= 8.8 Hz, 1H), 6.83 – 6.68 (m, 3H), 5.83 (d, J= 17.3 Hz, 1H), 5.56 – 5.48 (m, 1H), 5.46 (d, J= 11.2 Hz, 1H), 5.28 (d, J= 11.1 Hz, 1H), 4.44 – 4.13 (m, 4H), 3.86 – 3.34 (m, 9H), 3.22 – 3.17 (m, 3H), 2.96 (s, 3H), 2.95 – 2.89 (m, 2H), 2.86 (s, 3H), 2.69 (t, J= 11.9 Hz, 2H), 2.14 – 2.04 (m, 2H), 1.85 – 1.73 (m, 2H). MS (ESI) m/z: 745 [M+H] +. I-125
Figure 02_image624
 1H NMR (600 MHz, DMSO- d 6) δ 9.95 – 9.60 (m, 1H), 9.53 (s, 1H), 8.42 – 8.06 (m, 1H), 7.38 (s, 1H), 7.04 – 6.94 (m, 1H), 6.89 (s, 1H), 6.77 (dd, J= 17.2, 11.1 Hz, 1H), 5.83 (d, J= 17.2 Hz, 1H), 5.46 (d, J= 11.0 Hz, 1H), 4.44 – 4.18 (m, 4H), 3.86 (s, 3H), 3.60 (s, 9H), 3.33 (s, 2H), 2.98 (s, 3H), 2.92 – 2.77 (m, 6H), 2.71 (s, 2H), 2.01 – 1.96 (m, 2H), 1.94 (s, 3H), 1.66 – 1.46 (m, 2H). MS (ESI) m/z: 680 [M+H] +. I-126
Figure 02_image626
 1H NMR (600 MHz, Chloroform- d) δ 9.70 (s, 1H), 9.56 (s, 1H), 8.36 – 8.11 (m, 1H), 7.61 (s, 1H), 7.01 – 6.92 (m, 1H), 6.92 – 6.85 (m, 1H), 6.77 (dd, J= 17.3, 11.1 Hz, 1H), 5.83 (d, J= 17.2 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.50 – 4.16 (m, 4H), 3.83 (s, 3H), 3.74 – 3.07 (m, 11H), 3.02 – 2.91 (m, 6H), 2.88 (s, 3H), 2.81 (q, J= 12.8 Hz, 2H), 2.44 – 2.19 (m, 2H), 2.11 (d, J= 11.5 Hz, 2H), 1.83 – 1.71 (m, 2H), 0.96 (s, 3H). MS (ESI) m/z: 694 [M+H] +. I-127
Figure 02_image628
 1H NMR (600 MHz, Chloroform- d) δ 9.75 – 9.63 (m, 1H), 9.42 (s, 1H), 8.32 – 8.04 (m, 1H), 7.44 (s, 1H), 7.05 (d, J= 8.8 Hz, 1H), 6.92 (s, 1H), 6.73 (dd, J= 17.2, 11.1 Hz, 1H), 6.57 – 6.09 (m, 1H), 5.81 (d, J= 17.4 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.46 – 4.24 (m, 8H), 3.80 (s, 3H), 3.65 – 3.16 (m, 9H), 2.99 (s, 3H), 2.87 – 2.79 (m, 6H), 2.11 – 2.03 (m, 2H), 1.58 – 1.46 (m, 2H). MS (ESI) m/z: 666 [M+H] +. I-128
Figure 02_image630
 1H NMR (600 MHz, DMSO- d 6) δ 10.80 – 10.38 (m, 1H), 10.02 (s, 1H), 9.35 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.64 – 7.57 (m, 1H), 7.10 (d, J= 8.9 Hz, 1H), 6.95 (d, J= 8.9 Hz, 1H), 6.76 (dd, J= 17.3, 11.1 Hz, 1H), 5.84 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.44 – 4.22 (m, 6H), 3.44 (td, J= 12.1, 6.0 Hz, 1H), 3.04 – 2.95 (m, 6H), 2.89 (t, J= 12.9 Hz, 2H), 2.78 (d, J= 4.4 Hz, 6H), 2.09 (d, J= 11.9 Hz, 2H), 1.58 (td, J= 12.5, 8.8 Hz, 2H). MS (ESI) m/z: 581 [M+H] +. I-129
Figure 02_image632
 1H NMR (600 MHz, DMSO- d 6) δ 10.05 (s, 1H), 9.76 (s, 1H), 9.45 (s, 1H), 8.18 (s, 1H), 7.30 (s, 1H), 7.05 (s, 1H), 7.03 (d, J= 9.1 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.77 (dd, J= 17.2, 11.1 Hz, 1H), 5.83 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.39 – 4.20 (m, 4H), 3.75 (s, 3H), 3.51 (t, J= 11.3 Hz, 2H), 3.10 – 2.97 (m, 2H), 2.97 (s, 3H), 2.94 – 2.88 (m, 3H), 2.88 – 2.85 (m, 1H), 2.83 (d, J= 3.2 Hz, 3H), 1.87 – 1.65 (m, 4H). MS (ESI) m/z: 581 [M+H] +. I-130
Figure 02_image634
 1H NMR (600 MHz, DMSO- d 6) δ 9.84 (s, 1H), 9.51 (s, 1H), 8.28 (s, 1H), 7.33 – 7.27 (m, 1H), 7.16 (s, 1H), 7.13 (t, J= 7.9 Hz, 1H), 7.07 (d, J= 8.8 Hz, 1H), 7.03 (d, J= 8.8 Hz, 1H), 6.96 (d, J= 7.7 Hz, 1H), 6.79 (dd, J= 17.2, 11.1 Hz, 1H), 5.86 (d, J= 17.3 Hz, 1H), 5.45 (d, J= 11.1 Hz, 1H), 4.41 – 4.24 (m, 4H), 3.55 – 3.49 (m, 2H), 3.09 – 3.00 (m, 2H), 2.98 (s, 3H), 2.91 (s, 3H), 2.82 (d, J= 4.0 Hz, 3H), 2.63 (tt, J= 12.3, 3.8 Hz, 1H), 1.94 – 1.72 (m, 4H). MS (ESI) m/z: 551 [M+H] +. I-131
Figure 02_image636
 1H NMR (600 MHz, DMSO- d 6) δ 9.83 (s, 1H), 9.46 (s, 1H), 8.11 (s, 1H), 7.07 (d, J= 2.9 Hz, 1H), 7.02 (d, J= 3.5 Hz, 1H), 7.01 (d, J= 3.7 Hz, 1H), 6.95 – 6.85 (m, 2H), 6.75 (dd, J= 17.2, 11.1 Hz, 1H), 5.83 (d, J= 17.3 Hz, 1H), 5.47 (d, J= 11.2 Hz, 1H), 4.41 – 4.23 (m, 4H), 3.73 (s, 3H), 3.49 (d, J= 13.2 Hz, 4H), 3.14 – 3.01 (m, 3H), 2.97 (s, 3H), 2.95 (d, J= 6.3 Hz, 2H), 2.88 (s, 2H), 2.86 (s, 3H). MS (ESI) m/z: 582 [M+H] +. I-132
Figure 02_image638
 1H NMR (600 MHz, DMSO- d 6) δ 10.72 (s, 1H), 9.51 (s, 1H), 8.24 (s, 1H), 7.09 – 7.05 (m, 2H), 6.98 (d, J= 8.8 Hz, 1H), 6.93 – 6.88 (m, 2H), 6.82 – 6.76 (m, 2H), 5.86 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.41 – 4.24 (m, 4H), 3.64 (s, 2H), 3.50 (s, 2H), 3.16 – 3.06 (m, 2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.92 – 2.88 (m, 2H), 2.86 (s, 3H). MS (ESI) m/z: 552 [M+H] +. I-133
Figure 02_image640
 1H NMR (600 MHz, Methanol- d 4) δ 7.99 (s, 1H), 7.84 (d, J= 2.9 Hz, 1H), 7.43 (dd, J= 9.0, 2.9 Hz, 1H), 7.24 (d, J= 9.1 Hz, 1H), 7.11 (d, J= 8.9 Hz, 1H), 6.89 (d, J= 8.9 Hz, 1H), 6.69 (dd, J= 17.2, 11.0 Hz, 1H), 5.84 (d, J= 17.2 Hz, 1H), 5.58 (d, J= 11.1 Hz, 1H), 4.44 – 4.27 (m, 4H), 3.99 – 3.95 (m, 1H), 3.93 (s, 3H), 3.54 – 3.46 (m, 2H), 3.29 – 3.24 (m, 1H), 3.20 – 3.16 (m, 1H), 3.12 (s, 3H), 3.01 (s, 3H), 2.20 – 2.10 (m, 2H), 2.02 – 1.86 (m, 2H). MS (ESI) m/z: 583 [M+H] +. I-134
Figure 02_image642
 1H NMR (600 MHz, DMSO- d 6) δ 10.64 (s, 1H), 9.46 (s, 1H), 8.23 (s, 1H), 7.18 (s, 1H), 7.14 (t, J= 8.2 Hz, 1H), 7.07 (d, J= 8.9 Hz, 1H), 7.04 – 6.98 (m, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.78 (dd, J= 17.2, 11.1 Hz, 1H), 5.85 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 4.41 – 4.24 (m, 5H), 3.74 – 3.67 (m, 1H), 3.46 – 3.38 (m, 2H), 2.98 (s, 3H), 2.97 – 2.86 (m, 5H), 1.91 – 1.84 (m, 2H), 1.61 – 1.51 (m, 2H). MS (ESI) m/z: 553 [M+H] +. I-135
Figure 02_image644
 1H NMR (600 MHz, DMSO- d 6) δ 10.18 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H), 8.27 (s, 1H), 7.33 (d, J= 2.5 Hz, 1H), 7.21 (d, J= 8.7 Hz, 1H), 7.16 (d, J= 8.9 Hz, 1H), 6.96 (d, J= 8.7 Hz, 1H), 6.90 (d, J= 8.8 Hz, 1H), 6.73 (dd, J= 17.3, 11.1 Hz, 1H), 5.85 (d, J= 17.2 Hz, 1H), 5.44 (d, J= 11.0 Hz, 1H), 4.39 – 4.27 (m, 4H), 3.54 – 3.47 (m, 2H), 3.22 (d, J= 12.9 Hz, 2H), 3.08 – 3.03 (m, 2H), 3.02 – 2.92 (m, 5H), 2.89 (s, 3H), 2.57 – 2.51 (m, 2H), 1.05 (t, J= 7.4 Hz, 3H). MS (ESI) m/z: 566 [M+H] +. I-136
Figure 02_image646
 MS (ESI) m/z: 594 [M+H] +. I-137
Figure 02_image648
 MS (ESI) m/z: 606 [M+H] +. I-138
Figure 02_image650
 MS (ESI) m/z: 594 [M+H] +. I-139
Figure 02_image652
 MS (ESI) m/z: 606 [M+H] +. I-140
Figure 02_image654
 MS (ESI) m/z: 608 [M+H] +. I-141
Figure 02_image656
 1H NMR (600 MHz, DMSO- d 6) δ 9.56 (s, 1H), 9.27 (s, 1H), 9.11 – 9.05 (m, 1H), 8.23 (s, 1H), 7.47 (s, 1H), 7.14 (s, 1H), 6.87 – 6.76 (m, 2H), 6.71 (dd, J= 17.2, 11.1 Hz, 1H), 5.84 (d, J= 17.2 Hz, 1H), 5.48 (d, J= 11.0 Hz, 1H), 4.40 – 4.24 (m, 4H), 3.83 (d, J= 5.6 Hz, 3H), 3.58 – 3.47 (m, 2H), 3.23 (d, J= 11.4 Hz, 2H), 3.14 – 3.02 (m, 4H), 3.00 (s, 3H), 2.90 (d, J= 5.6 Hz, 3H), 2.44 (q, J= 7.4 Hz, 2H), 1.03 – 0.87 (m, 3H). MS (ESI) m/z: 596 [M+H] +. I-142
Figure 02_image658
 MS (ESI) m/z: 624 [M+H] +. I-143
Figure 02_image660
 MS (ESI) m/z: 636 [M+H] +. I-144
Figure 02_image662
 MS (ESI) m/z: 624 [M+H] +. I-145
Figure 02_image664
 MS (ESI) m/z: 636 [M+H] +. I-146
Figure 02_image666
 MS (ESI) m/z: 638 [M+H] +. I-147
Figure 02_image668
 1H NMR (600 MHz, DMSO- d 6) δ 9.60 (s, 1H), 9.29 (s, 1H), 9.08 (s, 1H), 8.21 (s, 1H), 7.40 (s, 1H), 7.14 (s, 1H), 6.85 – 6.74 (m, 2H), 6.71 (dd, J= 17.2, 11.1 Hz, 1H), 5.84 (d, J= 17.2 Hz, 1H), 5.49 (d, J= 11.1 Hz, 1H), 4.37 – 4.25 (m, 4H), 3.81 (s, 3H), 3.72 – 3.20 (m, 9H), 3.08 (d, J= 11.6 Hz, 2H), 3.00 (s, 3H), 2.87 (s, 3H), 2.74 (t, J= 11.7 Hz, 2H), 2.46 – 2.36 (m, 2H), 2.12 (d, J= 11.5 Hz, 2H), 1.78 (dq, J= 16.7, 5.9, 3.5 Hz, 2H), 1.01 – 0.89 (m, 3H). MS (ESI) m/z: 679 [M+H] +. I-148
Figure 02_image670
 MS (ESI) m/z: 707 [M+H] +. I-149
Figure 02_image672
 MS (ESI) m/z: 719 [M+H] +. I-150
Figure 02_image674
 MS (ESI) m/z: 707 [M+H] +. I-151
Figure 02_image676
 MS (ESI) m/z: 719 [M+H] +. I-152
Figure 02_image678
 MS (ESI) m/z: 721 [M+H] +. I-153
Figure 02_image680
 1H NMR (600 MHz, Methanol- d 4) δ 7.84 (s, 1H), 7.28 (d, J= 8.9 Hz, 2H), 7.23 (d, J= 9.0 Hz, 1H), 7.03 – 6.95 (m, 2H), 6.93 (d, J= 8.9 Hz, 1H), 6.67 (dd, J= 17.3, 11.0 Hz, 1H), 5.81 (d, J= 17.3 Hz, 1H), 5.56 (d, J= 11.0 Hz, 1H), 4.44 – 4.26 (m, 4H), 3.91 – 3.76 (m, 2H), 3.71 – 3.57 (m, 2H), 3.30 – 3.25 (m, 2H), 3.15 – 3.03 (m, 5H), 3.00 (s, 3H), 2.97 (s, 3H). MS (ESI) m/z: 552 [M+H] +. I-154
Figure 02_image682
 MS (ESI) m/z: 583 [M+H] +. I-155
Figure 02_image684
 1H NMR (600 MHz, Methanol- d 4) δ 7.79 (s, 1H), 7.38 – 7.09 (m, 2H), 6.93 (d, J= 8.9 Hz, 1H), 6.71 (d, J= 2.5 Hz, 1H), 6.66 (dd, J= 17.2, 11.0 Hz, 1H), 6.51 (s, 1H), 5.79 (d, J= 17.3 Hz, 1H), 5.55 (d, J= 11.0 Hz, 1H), 4.42 – 4.28 (m, 4H), 3.88 – 3.82 (m, 7H), 3.24 – 3.19 (m, 4H), 3.14 (s, 3H), 3.00 (s, 3H). MS (ESI) m/z: 569 [M+H] +. I-156
Figure 02_image686
 1H NMR (600 MHz, Methanol- d 4) δ 7.81 (s, 1H), 7.37 – 7.16 (m, 2H), 6.92 (d, J= 8.9 Hz, 1H), 6.76 – 6.70 (m, 1H), 6.67 (dd, J= 17.3, 11.1 Hz, 1H), 6.51 (s, 1H), 5.80 (d, J= 17.3 Hz, 1H), 5.55 (d, J= 11.0 Hz, 1H), 4.41 – 4.28 (m, 4H), 3.95 – 3.85 (m, 2H), 3.85 (s, 3H), 3.68 – 3.60 (m, 2H), 3.30 – 3.22 (m, 2H), 3.20 – 3.06 (m, 5H), 3.00 (s, 3H), 2.98 (s, 3H).MS (ESI) m/z: 582 [M+H] +. I-157
Figure 02_image688
 1H NMR (600 MHz, DMSO- d 6) δ 10.82 (s, 1H), 8.99 (s, 1H), 8.01 (s, 1H), 7.38 – 7.34 (m, 1H), 7.29 (d, J= 8.9 Hz, 1H), 7.22 – 7.16 (m, 1H), 7.07 – 7.01 (m, 1H), 6.91 (d, J= 8.9 Hz, 1H), 5.49 (s, 1H), 5.36 (s, 1H), 4.48 – 4.20 (m, 4H), 3.52 (d, J= 11.7 Hz, 2H), 3.24 (q, J= 11.8, 9.0 Hz, 2H), 3.12 – 3.06 (m, 2H), 3.05 (s, 3H), 3.04 (s, 3H), 3.03 – 2.95 (m, 2H), 2.90 (s, 3H), 2.63 – 2.51 (m, 2H), 2.09 (s, 3H), 1.06 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 594 [M+H] +. I-158
Figure 02_image690
 1H NMR (600 MHz, DMSO- d 6) δ 10.20 (s, 1H), 9.83 – 9.66 (m, 1H), 8.99 (s, 1H), 8.08 – 7.84 (m, 1H), 7.46 – 7.32 (m, 1H), 7.30 – 7.15 (m, 1H), 6.80 (s, 1H), 5.48 (s, 1H), 5.35 (s, 1H), 4.43 – 4.22 (m, 4H), 3.81 (s, 3H), 3.53 (d, J= 11.7 Hz, 2H), 3.24 (t, J= 11.6 Hz, 2H), 3.14 (d, J= 12.7 Hz, 2H), 3.07 (s, 3H), 3.03 (s, 3H), 3.02 – 2.97 (m, 2H), 2.90 (s, 3H), 2.44 (s, 2H), 2.08 (s, 3H), 1.00 (s, 3H). MS (ESI) m/z: 624 [M+H] +. I-159
Figure 02_image692
 1H NMR (600 MHz, DMSO- d 6) δ 9.92 – 9.66 (m, 1H), 8.99 (s, 1H), 8.09 – 7.79 (m, 1H), 7.31 (d, J= 25.4 Hz, 1H), 7.21 (s, 1H), 6.80 (s, 1H), 5.49 (s, 1H), 5.35 (s, 1H), 4.44 – 4.20 (m, 4H), 3.79 (s, 3H), 3.40 (s, 9H), 3.12 (d, J= 11.2 Hz, 2H), 3.09 – 3.03 (m, 3H), 3.03 (s, 3H), 2.91 (s, 3H), 2.77 (t, J= 11.8 Hz, 2H), 2.47 – 2.35 (m, 2H), 2.22 – 2.12 (m, 2H), 2.08 (s, 3H), 1.81 (dt, J= 12.3, 6.2 Hz, 2H), 1.01 (s, 3H). MS (ESI) m/z: 707 [M+H] +. I-160
Figure 02_image694
 1H NMR (600 MHz, DMSO- d 6) δ 10.12 (s, 1H), 9.92 – 9.78 (m, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.48 – 7.40 (m, 1H), 7.33 (d, J= 8.5 Hz, 1H), 6.99 (d, J= 8.7 Hz, 1H), 6.96 – 6.91 (m, 1H), 4.44 – 4.24 (m, 4H), 3.50 (d, J= 11.7 Hz, 2H), 3.25 – 3.16 (m, 2H), 3.09 (s, 3H), 3.07 (s, 3H), 3.04 (s, 2H), 2.98 (qd, J= 11.8, 9.8, 5.1 Hz, 2H), 2.89 (s, 3H), 2.59 – 2.53 (m, 2H), 1.07 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 588 [M+H] +. I-161
Figure 02_image696
 1H NMR (600 MHz, DMSO- d 6) δ 10.01 – 9.89 (m, 1H), 8.80 (s, 1H), 8.26 (s, 1H), 7.41 – 7.35 (m, 1H), 7.27 (d, J= 8.6 Hz, 1H), 7.02 (d, J= 8.6 Hz, 1H), 6.96 – 6.90 (m, 1H), 4.43 – 4.23 (m, 4H), 3.74 (t, J= 4.4 Hz, 4H), 3.08 (s, 3H), 3.06 (s, 3H), 2.80 (t, J= 4.6 Hz, 4H), 2.63 – 2.52 (m, 2H), 1.07 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 575 [M+H] +. I-162
Figure 02_image698
 1H NMR (600 MHz, DMSO- d 6) δ 9.81 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.69 – 7.64 (m, 1H), 7.64 – 7.56 (m, 2H), 7.49 (d, J= 8.6 Hz, 1H), 7.00 (d, J= 8.9 Hz, 1H), 4.45 – 4.24 (m, 4H), 3.61 (d, J= 5.5 Hz, 2H), 3.42 (s, 2H), 3.18 (s, 1H), 3.15 (s, 3H), 3.12 (s, 3H), 3.08 (s, 3H), 2.73 – 2.64 (m, 2H), 1.10 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 563 [M+H] +. I-163
Figure 02_image700
 1H NMR (600 MHz, DMSO- d 6) δ 9.86 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 7.46 (s, 1H), 7.45 – 7.35 (m, 2H), 7.03 (d, J= 8.7 Hz, 1H), 6.95 (d, J= 8.9 Hz, 1H), 4.45 – 4.25 (m, 4H), 3.65 (t, J= 5.4 Hz, 2H), 3.25 (t, J= 5.4 Hz, 2H), 3.18 (s, 1H), 3.09 (s, 3H), 3.07 (s, 3H), 2.58 – 2.51 (m, 2H), 1.09 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 549 [M+H] +. I-164
Figure 02_image702
 1H NMR (600 MHz, DMSO- d 6) δ 10.17 – 9.87 (m, 2H), 8.83 (s, 1H), 8.25 (d, J= 6.7 Hz, 1H), 7.42 (s, 1H), 7.20 – 7.09 (m, 2H), 6.91 (d, J= 8.9 Hz, 1H), 6.58 (d, J= 8.5 Hz, 1H), 4.45 – 4.23 (m, 4H), 3.45 (t, J= 6.3 Hz, 2H), 3.30 (t, J= 6.3 Hz, 2H), 3.09 (s, 3H), 3.06 (s, 3H), 2.86 (s, 6H), 2.47 – 2.34 (m, 2H), 1.06 (t, J= 7.7 Hz, 3H). MS (ESI) m/z: 576 [M+H] +. I-165
Figure 02_image704
 1H NMR (600 MHz, DMSO- d 6) δ 9.95 – 9.79 (m, 1H), 9.73 – 9.60 (m, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 7.48 – 7.37 (m, 1H), 7.33 (d, J= 8.5 Hz, 1H), 7.09 (d, J= 8.7 Hz, 1H), 6.94 (d, J= 8.9 Hz, 1H), 4.46 – 4.22 (m, 4H), 3.23 – 3.19 (m, 2H), 3.19 – 3.15 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.80 (s, 6H), 2.61 – 2.55 (m, 5H), 1.05 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 590 [M+H] +. I-166
Figure 02_image706
 1H NMR (600 MHz, DMSO- d 6) δ 9.05 (s, 1H), 8.11 – 8.07 (m, 1H), 8.05 (s, 1H), 7.64 – 7.53 (m, 1H), 7.29 – 7.21 (m, 1H), 6.88 (d, J= 8.9 Hz, 1H), 6.35 (d, J= 8.1 Hz, 1H), 4.71 (s, 4H), 4.43 – 4.21 (m, 4H), 3.92 (s, 4H), 3.10 (s, 3H), 3.08 (s, 3H), 2.44 – 2.35 (m, 2H), 1.06 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 587 [M+H] +. I-167
Figure 02_image708
 1H NMR (600 MHz, Methanol- d 4) δ 7.94 (s, 1H), 7.61 – 7.51 (m, 1H), 7.20 – 7.13 (m, 2H), 6.85 (d, J= 9.0 Hz, 1H), 6.44 (d, J= 8.5 Hz, 1H), 4.46 – 4.20 (m, 4H), 3.88 (s, 4H), 3.44 (s, 3H), 3.17 (s, 3H), 3.03 (s, 3H), 2.48 (q, J= 7.5 Hz, 2H), 2.34 (s, 4H), 1.12 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 600 [M+H] +. I-168
Figure 02_image710
 1H NMR (600 MHz, DMSO- d 6) δ 9.94 (s, 1H), 8.41 – 8.34 (m, 1H), 8.23 – 8.17 (m, 1H), 7.59 – 7.46 (m, 1H), 7.39 (d, J= 8.8 Hz, 1H), 6.95 (d, J= 8.7 Hz, 1H), 6.94 – 6.90 (m, 2H), 4.45 – 4.20 (m, 4H), 3.53 (d, J= 11.0 Hz, 2H), 3.32 – 3.12 (m, 4H), 3.10 (d, J= 6.4 Hz, 3H), 3.07 (s, 3H), 2.95 (dt, J= 23.4, 12.3 Hz, 2H), 2.88 (d, J= 3.6 Hz, 3H), 1.87 (d, J= 6.5 Hz, 1H), 0.98 – 0.86 (m, 2H), 0.58 – 0.44 (m, 2H). MS (ESI) m/z: 600 [M+H] +. I-169
Figure 02_image712
 1H NMR (600 MHz, DMSO- d 6) δ 9.68 (s, 1H), 8.64 (s, 1H), 8.22 (s, 1H), 7.52 – 7.39 (m, 1H), 7.31 (d, J= 8.5 Hz, 1H), 6.95 – 6.90 (m, 2H), 6.85 (s, 1H), 4.43 – 4.23 (m, 4H), 3.80 – 3.72 (m, 4H), 3.09 (s, 3H), 3.07 (s, 4H), 2.92 (d, J= 4.4 Hz, 3H), 2.27 – 2.19 (m, 1H), 0.92 (d, J= 8.5 Hz, 2H), 0.61 – 0.35 (m, 2H). MS (ESI) m/z: 587 [M+H] +. I-170
Figure 02_image714
 1H NMR (600 MHz, DMSO- d 6) δ 10.16 (s, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 7.50 – 7.36 (m, 2H), 7.26 (d, J= 8.6 Hz, 1H), 6.95 (t, J= 8.4 Hz, 2H), 4.45 – 4.23 (m, 4H), 3.52 (d, J= 11.7 Hz, 2H), 3.22 (d, J= 12.1 Hz, 2H), 3.17 – 3.10 (m, 2H), 3.09 (s, 3H), 3.07 (s, 3H), 2.95 (t, J= 13.0 Hz, 2H), 2.89 (s, 3H), 2.17 (s, 3H). MS (ESI) m/z: 574 [M+H] +. I-171
Figure 02_image716
 1H NMR (600 MHz, DMSO- d 6) δ 9.99 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 7.42 – 7.32 (m, 2H), 7.26 – 7.18 (m, 1H), 6.96 (t, J= 9.3 Hz, 2H), 4.44 – 4.24 (m, 4H), 3.75 (t, J= 4.3 Hz, 4H), 3.07 (s, 3H), 3.06 (s, 3H), 2.87 – 2.79 (m, 4H), 2.17 (s, 3H). MS (ESI) m/z: 561 [M+H] +. I-172
Figure 02_image718
 1H NMR (600 MHz, DMSO- d 6) δ 10.09 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.78 (s, 1H), 7.69 – 7.61 (m, 1H), 7.42 (s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.04 (d, J= 8.6 Hz, 1H), 6.56 (s, 1H), 4.43 – 4.21 (m, 4H), 3.92 (s, 3H), 3.48 (t, J= 11.0 Hz, 2H), 3.28 (d, J= 13.8 Hz, 2H), 3.19 – 3.09 (m, 5H), 3.07 (s, 3H), 2.96 – 2.82 (m, 5H). MS (ESI) m/z: 640 [M+H] +. I-173
Figure 02_image720
 1H NMR (600 MHz, DMSO- d 6) δ 9.94 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 7.63 – 7.56 (m, 1H), 7.39 (s, 1H), 7.25 (d, J= 8.4 Hz, 1H), 7.03 (d, J= 8.6 Hz, 1H), 6.65 – 6.51 (m, 1H), 4.41 – 4.21 (m, 4H), 3.90 (s, 3H), 3.75 – 3.69 (m, 4H), 3.10 (s, 3H), 3.06 (s, 3H), 2.79 – 2.72 (m, 4H). MS (ESI) m/z: 627 [M+H] +. I-174
Figure 02_image722
 1H NMR (600 MHz, Methanol- d 4) δ 8.09 (s, 1H), 7.39 (s, 1H), 7.22 (s, 1H), 6.90 (d, J= 8.9 Hz, 1H), 6.84 (s, 1H), 4.47 – 4.19 (m, 4H), 3.84 (s, 3H), 3.78 – 3.47 (m, 8H), 3.47 – 3.35 (m, 1H), 3.26 – 3.20 (m, 2H), 3.17 (s, 3H), 3.02 (s, 3H), 3.00 (s, 3H), 2.90 (t, J= 11.7 Hz, 2H), 2.63 – 2.40 (m, 2H), 2.35 – 2.17 (m, 2H), 2.07 – 1.86 (m, 2H), 1.05 (s, 3H). MS (ESI) m/z: 701 [M+H] +. I-175
Figure 02_image724
 MS (ESI) m/z: 713 [M+H] +. I-176
Figure 02_image726
 MS (ESI) m/z: 671 [M+H] +. I-177
Figure 02_image728
 MS (ESI) m/z: 630 [M+H] +. I-178
Figure 02_image730
 1H NMR (600 MHz, DMSO- d 6) δ 8.02 (d, J= 19.6 Hz, 2H), 7.88 (s, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.74 (d, J= 9.0 Hz, 1H), 6.12 (s, 1H), 4.73 (s, 4H), 4.42 – 4.19 (m, 4H), 4.00 (s, 4H), 3.74 (s, 3H), 3.10 (s, 3H), 3.07 (s, 3H), 2.35 (t, J= 7.5 Hz, 2H), 1.01 (t, J= 7.4 Hz, 3H). MS (ESI) m/z: 617 [M+H] +. I-179
Figure 02_image732
 1H NMR (600 MHz, Methanol- d 4) δ 8.08 (s, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 6.92 (d, J= 8.9 Hz, 1H), 6.79 (s, 1H), 4.46 – 4.23 (m, 4H), 3.84 (s, 3H), 3.67 (s, 8H), 3.44 – 3.35 (m, 1H), 3.34 – 3.31 (m, 2H), 3.16 (s, 3H), 3.02 (s, 3H), 2.99 (s, 3H), 2.88 (q, J= 12.0 Hz, 2H), 2.29 – 2.21 (m, 2H), 2.13 (s, 3H), 2.06 – 1.94 (m, 2H). MS (ESI) m/z: 687 [M+H] +. I-180
Figure 02_image734
 1H NMR (600 MHz, Methanol- d 4) δ 8.04 (s, 1H), 7.36 (d, J= 9.0 Hz, 1H), 7.31 (d, J= 9.0 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.91 (d, J= 8.9 Hz, 1H), 4.42 – 4.28 (m, 4H), 3.88 – 3.76 (m, 2H), 3.67 – 3.56 (m, 2H), 3.29 – 3.21 (m, 2H), 3.16 (s, 3H), 3.11 – 3.04 (m, 2H), 3.02 (s, 3H), 2.97 (s, 3H). MS (ESI) m/z: 560 [M+H] +. I-181
Figure 02_image736
 1H NMR (600 MHz, Methanol- d 4) δ 8.01 (s, 1H), 7.35 (d, J= 10.2 Hz, 2H), 6.92 (d, J= 9.0 Hz, 1H), 6.73 (d, J= 2.6 Hz, 1H), 6.54 (d, J= 8.7 Hz, 1H), 4.43 – 4.26 (m, 4H), 3.96 – 3.85 (m, 2H), 3.85 (s, 3H), 3.69 – 3.55 (m, 2H), 3.30 – 3.23 (m, 2H), 3.19 (s, 3H), 3.14 – 3.05 (m, 2H), 3.03 (s, 3H), 2.98 (s, 3H). MS (ESI) m/z: 590 [M+H] +. I-182
Figure 02_image738
 1H NMR (600 MHz, Methanol- d 4) δ 8.24 (d, J= 2.9 Hz, 1H), 8.17 (s, 1H), 7.38 – 7.28 (m, 2H), 7.18 (d, J= 8.9 Hz, 1H), 6.91 (d, J= 8.9 Hz, 1H), 4.47 – 4.21 (m, 4H), 4.01 – 3.96 (m, 2H), 3.94 (s, 3H), 3.60 (q, J= 12.1, 10.2 Hz, 2H), 3.40 – 3.35 (m, 1H), 3.20 (s, 3H), 3.04 (s, 3H), 2.26 – 2.09 (m, 2H), 2.02 – 1.83 (m, 2H). MS (ESI) m/z: 591 [M+H] +. I-183
Figure 02_image740
 1H NMR (600 MHz, Methanol- d 4) δ 8.08 (s, 1H), 7.40 (s, 1H), 7.26 (d, J= 8.9 Hz, 1H), 6.92 (d, J= 8.9 Hz, 1H), 6.78 (s, 1H), 4.42 – 4.28 (m, 4H), 3.86 (s, 3H), 3.61 (d, J= 11.9 Hz, 2H), 3.35 – 3.33 (m, 2H), 3.29 – 3.24 (m, 2H), 3.17 (s, 3H), 3.14 – 3.07 (m, 2H), 3.02 (s, 3H), 2.99 (s, 3H), 2.14 (s, 3H). MS (ESI) m/z: 604 [M+H] +. I-184
Figure 02_image742
 1H NMR (600 MHz, Methanol- d 4) δ 8.10 (s, 1H), 7.45 (s, 1H), 7.23 (s, 1H), 6.90 (d, J= 8.9 Hz, 1H), 6.84 (s, 1H), 4.44 – 4.24 (m, 4H), 3.86 (s, 3H), 3.64 – 3.55 (m, 2H), 3.36 – 3.32 (m, 2H), 3.23 – 3.11 (m, 7H), 3.02 (s, 3H), 2.99 (s, 3H), 2.62 – 2.44 (m, 2H), 1.05 (s, 3H). MS (ESI) m/z: 618 [M+H] +. I-185
Figure 02_image744
 1H NMR (600 MHz, Methanol- d 4) δ 8.07 (s, 1H), 7.41 – 7.18 (m, 2H), 6.91 (d, J= 9.0 Hz, 1H), 6.77 (s, 1H), 4.42 – 4.26 (m, 4H), 3.84 (s, 3H), 3.41 – 3.32 (m, 1H), 3.30 – 3.24 (m, 2H), 3.17 (s, 3H), 3.02 (s, 3H), 2.93 (s, 6H), 2.86 – 2.78 (m, 2H), 2.24 – 2.17 (m, 2H), 2.13 (s, 3H), 2.01 – 1.87 (m, 2H). MS (ESI) m/z: 632 [M+H] +. I-186
Figure 02_image746
 1H NMR (600 MHz, Methanol- d 4) δ 8.08 (s, 1H), 7.37 (s, 1H), 7.23 (s, 1H), 6.89 (d, J= 9.0 Hz, 1H), 6.82 (s, 1H), 4.45 – 4.24 (m, 4H), 3.84 (s, 3H), 3.35 – 3.33 (m, 1H), 3.25 – 3.14 (m, 5H), 3.02 (s, 3H), 2.93 (s, 6H), 2.89 – 2.79 (m, 2H), 2.61 – 2.45 (m, 2H), 2.19 (q, J= 12.7, 3.1 Hz, 2H), 2.00 – 1.84 (m, 2H), 1.06 (s, 3H). MS (ESI) m/z: 646 [M+H] +. I-187
Figure 02_image748
 1H NMR (600 MHz, Methanol- d 4) δ 8.06 (s, 1H), 7.37 – 7.18 (m, 2H), 6.92 (d, J= 9.0 Hz, 1H), 6.71 (s, 1H), 4.43 – 4.26 (m, 4H), 4.05 – 3.98 (m, 1H), 3.85 (s, 3H), 3.53 – 3.46 (m, 1H), 3.45 – 3.36 (m, 2H), 3.21 – 3.12 (m, 4H), 3.02 (s, 3H), 2.97 (s, 6H), 2.53 – 2.43 (m, 1H), 2.26 – 2.19 (m, 1H), 2.15 (s, 3H). MS (ESI) m/z: 618 [M+H] +. I-188
Figure 02_image750
 1H NMR (600 MHz, Methanol- d 4) δ 8.07 (s, 1H), 7.44 – 7.15 (m, 2H), 6.89 (d, J= 9.0 Hz, 1H), 6.79 (d, J= 2.6 Hz, 1H), 4.44 – 4.26 (m, 4H), 4.07 – 3.94 (m, 1H), 3.85 (s, 3H), 3.46 – 3.40 (m, 2H), 3.35 – 3.32 (m, 1H), 3.19 (s, 3H), 3.17 – 3.12 (m, 1H), 3.02 (s, 3H), 2.97 (s, 6H), 2.61 – 2.43 (m, 3H), 2.30 – 2.07 (m, 1H), 1.06 (s, 3H). MS (ESI) m/z: 632 [M+H] +. I-189
Figure 02_image752
 1H NMR (600 MHz, Methanol- d 4) δ 8.01 (s, 1H), 7.32 (d, J= 8.9 Hz, 2H), 6.93 (d, J= 9.0 Hz, 1H), 6.75 (d, J= 2.6 Hz, 1H), 6.58 (dd, J= 8.8, 2.5 Hz, 1H), 4.43 – 4.28 (m, 4H), 3.87 (t, J= 4.8 Hz, 4H), 3.84 (s, 3H), 3.26 (t, J= 4.8 Hz, 4H), 3.19 (s, 3H), 3.02 (s, 3H). MS (ESI) m/z: 577 [M+H] +. I-190
Figure 02_image754
 1H NMR (600 MHz, DMSO- d 6) δ 10.62 (s, 1H), 10.20 (s, 1H), 10.02 (s, 1H), 7.97 – 7.89 (m, 1H), 7.37 – 7.33 (m, 1H), 7.06 – 7.01 (m, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.95 (d, J= 8.8 Hz, 1H), 6.71 – 6.27 (m, 1H), 4.42 – 4.23 (m, 4H), 3.50 (d, J= 11.9 Hz, 2H), 3.21 (s, 2H), 3.06 (d, J= 11.4 Hz, 2H), 3.04 – 2.99 (m, 6H), 2.96 (t, J= 12.4 Hz, 2H), 2.88 (s, 3H), 2.58 – 2.54 (m, 2H), 1.03 (s, 3H). MS (ESI) m/z: 554 [M+H] +. I-191
Figure 02_image756
 1H NMR (600 MHz, DMSO- d 6) δ 10.28 (s, 1H), 10.15 (s, 1H), 9.44 (s, 1H), 8.28 (d, J= 4.5 Hz, 1H), 7.43 (d, J= 2.6 Hz, 1H), 7.26 – 7.18 (m, 2H), 6.99 (d, J= 8.6 Hz, 1H), 6.96 (d, J= 8.9 Hz, 1H), 4.43 – 4.26 (m, 4H), 3.51 (d, J= 11.7 Hz, 2H), 3.22 (d, J= 10.5 Hz, 2H), 3.18 (s, 2H), 3.06 (s, 3H), 3.04 – 3.03 (m, 2H), 3.02 (s, 3H), 3.01 – 2.94 (m, 2H), 2.60 – 2.42 (m, 2H), 1.04 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 572 [M+H] +. I-192
Figure 02_image758
 1H NMR (600 MHz, DMSO- d 6) δ 10.37 (s, 1H), 9.21 (s, 1H), 7.89 (s, 1H), 7.31 (d, J= 2.6 Hz, 1H), 7.13 – 7.06 (m, 2H), 6.99 (d, J= 8.6 Hz, 1H), 6.96 (d, J= 8.8 Hz, 1H), 4.44 – 4.21 (m, 4H), 3.50 (d, J= 12.0 Hz, 2H), 3.15 – 3.09 (m, 2H), 3.09 – 3.03 (m, 2H), 3.01 (s, 3H), 2.99 (s, 3H), 2.97 – 2.91 (m, 2H), 2.88 (s, 3H), 2.61 – 2.52 (m, 2H), 2.13 (s, 3H), 1.03 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 568 [M+H] +. I-193
Figure 02_image760
 1H NMR (600 MHz, Methanol- d 4) δ 8.32 (s, 1H), 7.37 – 7.33 (m, 1H), 7.24 – 7.13 (m, 2H), 7.09 – 7.03 (m, 1H), 6.90 (d, J= 8.9 Hz, 1H), 4.44 – 4.25 (m, 4H), 3.59 (d, J= 12.2 Hz, 2H), 3.36 – 3.32 (m, 2H), 3.17 (d, J= 13.5 Hz, 2H), 3.14 (s, 3H), 3.09 (t, J= 12.5 Hz, 2H), 3.00 (s, 3H), 2.98 (s, 3H), 2.63 (s, 2H), 1.12 (s, 3H). MS (ESI) m/z: 622 [M+H] +. I-194
Figure 02_image762
 1H NMR (600 MHz, DMSO- d 6) δ 10.35 (s, 1H), 9.92 – 9.77 (m, 1H), 7.83 (s, 1H), 7.30 (d, J= 2.6 Hz, 1H), 7.12 – 7.09 (m, 1H), 7.06 (d, J= 8.9 Hz, 1H), 6.99 – 6.95 (m, 2H), 4.45 – 4.22 (m, 4H), 3.54 – 3.46 (m, 2H), 3.26 – 3.17 (m, 2H), 3.08 – 3.02 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 2.97 – 2.90 (m, 2H), 2.88 (s, 3H), 2.59 – 2.52 (m, 2H), 2.44 (h, J= 7.8 Hz, 2H), 1.21 (t, J= 7.4 Hz, 3H), 1.03 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 582 [M+H] +. I-195
Figure 02_image764
 1H NMR (600 MHz, DMSO- d 6) δ 10.62 (s, 1H), 9.39 (s, 1H), 7.85 (s, 1H), 7.29 (d, J= 2.6 Hz, 1H), 7.08 (dd, J= 8.7, 2.5 Hz, 1H), 7.03 (d, J= 8.8 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 8.5 Hz, 1H), 4.43 – 4.23 (m, 4H), 3.50 (d, J= 11.9 Hz, 2H), 3.26 – 3.18 (m, 2H), 3.09 – 3.02 (m, 2H), 3.00 (s, 3H), 2.99 – 2.91 (m, 6H), 2.88 (s, 3H), 2.60 – 2.53 (m, 2H), 1.26 (dd, J= 6.8, 3.1 Hz, 6H), 1.02 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 596 [M+H] +. I-196
Figure 02_image766
 1H NMR (600 MHz, DMSO- d 6) δ 10.54 (s, 1H), 9.40 (s, 1H), 7.81 (s, 1H), 7.37 – 7.35 (m, 1H), 7.27 (d, J= 8.9 Hz, 1H), 7.18 – 7.11 (m, 1H), 7.08 – 7.02 (m, 1H), 6.93 (d, J= 8.9 Hz, 1H), 4.43 – 4.21 (m, 4H), 3.90 (s, 3H), 3.51 (d, J= 11.8 Hz, 2H), 3.26 – 3.16 (m, 2H), 3.09 – 3.05 (m, 5H), 3.03 (s, 3H), 3.01 – 2.93 (m, 2H), 2.89 (s, 3H), 2.62 – 2.51 (m, 2H), 1.04 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 584 [M+H] +. I-197
Figure 02_image768
 1H NMR (600 MHz, DMSO- d 6) δ 10.37 (s, 1H), 9.10 (s, 1H), 7.83 (s, 1H), 7.52 (d, J= 9.0 Hz, 1H), 7.38 (d, J= 2.6 Hz, 1H), 7.24 (dd, J= 8.5, 2.6 Hz, 1H), 7.08 (d, J= 8.6 Hz, 1H), 6.90 (d, J= 8.9 Hz, 1H), 4.44 – 4.23 (m, 4H), 4.13 (qd, J= 7.0, 3.8 Hz, 2H), 3.51 (d, J= 11.8 Hz, 2H), 3.21 (d, J= 13.4 Hz, 2H), 3.10 (s, 3H), 3.10 – 3.04 (m, 5H), 3.02 – 2.93 (m, 2H), 2.89 (s, 3H), 2.65 – 2.53 (m, 2H), 1.39 (t, J= 7.0 Hz, 3H), 1.09 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 598 [M+H] +. I-198
Figure 02_image770
 1H NMR (600 MHz, Methanol- d 4) δ 8.39 (s, 1H), 7.43 (d, J= 2.6 Hz, 1H), 7.30 – 7.16 (m, 3H), 7.04 (s, 1H), 6.91 (d, J= 8.9 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.58 (d, J= 12.0 Hz, 2H), 3.31 (dd, J= 23.9, 3.2 Hz, 2H), 3.18 – 3.12 (m, 5H), 3.11 – 3.04 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 2.62 (s, 2H), 1.11 (s, 3H). MS (ESI) m/z: 579 [M+H] +. I-199
Figure 02_image772
 1H NMR (600 MHz, Methanol- d 4) δ 9.04 (s, 1H), 7.47 – 7.45 (m, 1H), 7.44 – 7.37 (m, 1H), 7.36 – 7.28 (m, 1H), 7.04 – 6.98 (m, 1H), 6.91 – 6.80 (m, 1H), 4.46 – 4.26 (m, 4H), 3.58 (d, J= 12.0 Hz, 2H), 3.35 – 3.32 (m, 2H), 3.20 – 3.14 (m, 5H), 3.12 – 3.06 (m, 2H), 3.04 (s, 3H), 2.99 (s, 3H), 2.62 (s, 2H), 1.10 (s, 3H). MS (ESI) m/z: 599 [M+H] +. I-200
Figure 02_image774
 1H NMR (600 MHz, DMSO- d 6) δ 10.26 – 10.14 (m, 1H), 9.76 – 9.48 (m, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 6.77 (s, 1H), 6.52 (s, 1H), 4.42 – 4.21 (m, 4H), 3.81 (s, 3H), 3.51 (d, J= 11.7 Hz, 2H), 3.27 – 3.18 (m, 2H), 3.15 – 3.07 (m, 2H), 3.07 – 3.01 (m, 5H), 2.99 (s, 3H), 2.89 (s, 3H), 2.40 – 2.26 (m, 2H), 0.97 (s, 3H). MS (ESI) m/z: 584 [M+H] +. I-201
Figure 02_image776
 1H NMR (600 MHz, DMSO- d 6) δ 9.78 (s, 1H), 9.19 (s, 1H), 8.27 (d, J= 4.9 Hz, 1H), 7.46 (s, 1H), 7.07 (d, J= 8.9 Hz, 1H), 6.91 (d, J= 8.9 Hz, 1H), 6.76 (s, 1H), 4.43 – 4.21 (m, 4H), 3.79 (s, 3H), 3.52 (d, J= 11.7 Hz, 2H), 3.22 (t, J= 11.5 Hz, 2H), 3.19 – 3.16 (m, 2H), 3.13 – 3.04 (m, 2H), 3.04 (s, 3H), 3.00 (s, 3H), 2.90 (s, 3H), 2.44 – 2.32 (m, 2H), 0.98 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 602 [M+H] +. I-202
Figure 02_image778
 1H NMR (600 MHz, DMSO- d 6) δ 9.89 (s, 1H), 9.22 (s, 1H), 7.84 (s, 1H), 7.42 – 7.30 (m, 1H), 7.03 (d, J= 8.9 Hz, 1H), 6.92 (d, J= 8.8 Hz, 1H), 6.76 (s, 1H), 4.45 – 4.21 (m, 4H), 3.80 (s, 3H), 3.67 – 3.39 (m, 2H), 3.21 (s, 2H), 3.15 – 3.06 (m, 2H), 3.00 (q, J= 11.4, 8.8 Hz, 8H), 2.89 (s, 3H), 2.41 – 2.25 (m, 2H), 2.12 (s, 3H), 0.98 (s, 3H). MS (ESI) m/z: 598 [M+H] +. I-203
Figure 02_image780
 1H NMR (600 MHz, DMSO- d 6) δ 10.01 (s, 1H), 8.77 – 8.66 (m, 1H), 8.43 – 8.31 (m, 1H), 8.20 – 8.09 (m, 1H), 7.53 – 7.40 (m, 1H), 7.41 – 7.23 (m, 1H), 6.87 – 6.60 (m, 1H), 4.44 – 4.20 (m, 4H), 3.79 (s, 3H), 3.52 (d, J= 11.8 Hz, 2H), 3.30 – 3.19 (m, 2H), 3.16 – 3.10 (m, 2H), 3.07 (s, 3H), 3.05 (s, 3H), 3.03 – 2.98 (m, 2H), 2.90 (s, 3H), 2.50 – 2.37 (m, 2H), 1.01 (s, 3H). MS (ESI) m/z: 652 [M+H] +. I-204
Figure 02_image782
 1H NMR (600 MHz, DMSO- d 6) δ 9.99 (s, 1H), 9.29 (s, 1H), 7.81 (s, 1H), 7.37 (s, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.91 (d, J= 8.7 Hz, 1H), 6.76 (s, 1H), 4.43 – 4.21 (m, 4H), 3.80 (s, 3H), 3.51 (d, J= 11.9 Hz, 2H), 3.21 (s, 2H), 3.12 – 3.06 (m, 2H), 3.05 – 2.94 (m, 8H), 2.89 (s, 3H), 2.59 – 2.52 (m, 2H), 2.41 – 2.22 (m, 2H), 1.21 (t, J= 7.4 Hz, 3H), 1.01 – 0.90 (m, 3H). MS (ESI) m/z: 612 [M+H] +. I-205
Figure 02_image784
 1H NMR (600 MHz, DMSO- d 6) δ 10.13 (s, 1H), 9.33 (s, 1H), 7.89 – 7.72 (m, 1H), 7.38 (s, 1H), 6.99 (d, J= 8.9 Hz, 1H), 6.91 (d, J= 8.8 Hz, 1H), 6.75 (s, 1H), 4.41 – 4.23 (m, 4H), 3.80 (s, 3H), 3.51 (d, J= 11.8 Hz, 2H), 3.21 (s, 2H), 3.12 – 2.93 (m, 11H), 2.89 (s, 3H), 2.33 – 2.20 (m, 2H), 1.25 (dd, J= 6.8, 1.8 Hz, 6H), 0.94 (s, 3H). MS (ESI) m/z: 626 [M+H] +. I-206
Figure 02_image786
 1H NMR (600 MHz, DMSO- d 6) δ 10.07 (s, 1H), 9.43 (s, 1H), 7.73 (s, 1H), 7.42 (s, 1H), 7.20 (d, J= 8.4 Hz, 1H), 6.87 (d, J= 8.9 Hz, 1H), 6.78 (s, 1H), 4.43 – 4.20 (m, 4H), 3.90 (s, 3H), 3.81 (s, 3H), 3.51 (d, J= 11.8 Hz, 2H), 3.21 (d, J= 12.6 Hz, 2H), 3.15 – 3.09 (m, 2H), 3.07 (s, 3H), 3.02 (s, 5H), 2.89 (s, 3H), 2.41 (dd, J= 14.4, 7.3 Hz, 2H), 0.98 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 614 [M+H] +. I-207
Figure 02_image788
 1H NMR (600 MHz, DMSO- d 6) δ 9.66 (s, 1H), 9.23 (s, 1H), 7.76 (s, 1H), 7.44 – 7.36 (m, 2H), 6.86 – 6.82 (m, 1H), 6.81 (s, 1H), 4.46 – 4.23 (m, 4H), 4.13 (qt, J= 6.7, 3.3 Hz, 2H), 3.81 (s, 3H), 3.53 (d, J= 11.8 Hz, 2H), 3.24 (t, J= 11.9 Hz, 2H), 3.17 – 3.12 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 3.06 – 3.01 (m, 2H), 2.91 (s, 3H), 2.57 – 2.52 (m, 2H), 1.39 (t, J= 6.9 Hz, 3H), 1.04 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 628 [M+H] +. I-208
Figure 02_image790
 1H NMR (600 MHz, DMSO- d 6) δ 10.09 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.78 (s, 1H), 7.69 – 7.61 (m, 1H), 7.42 (s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.04 (d, J= 8.6 Hz, 1H), 6.56 (s, 1H), 4.43 – 4.21 (m, 4H), 3.92 (s, 3H), 3.48 (t, J= 11.0 Hz, 2H), 3.28 (d, J= 13.8 Hz, 2H), 3.19 – 3.09 (m, 5H), 3.07 (s, 3H), 2.96 – 2.82 (m, 5H). MS (ESI) m/z: 609 [M+H] +. I-209
Figure 02_image792
 1H NMR (600 MHz, Methanol- d 4) δ 9.01 (s, 1H), 7.76 (s, 1H), 7.37 – 7.28 (m, 1H), 6.88 – 6.80 (m, 1H), 6.78 (s, 1H), 4.46 – 4.25 (m, 4H), 3.86 (s, 3H), 3.59 (d, J= 12.0 Hz, 2H), 3.36 – 3.31 (m, 2H), 3.22 – 3.07 (m, 7H), 3.03 (s, 3H), 2.99 (s, 3H), 2.48 (s, 2H), 0.96 (s, 3H). MS (ESI) m/z: 629 [M+H] +. I-210
Figure 02_image794
 1H NMR (600 MHz, DMSO- d 6) δ 10.18 (s, 1H), 9.60 (s, 1H), 7.89 (s, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 4.41 – 4.23 (m, 4H), 3.79 (d, J= 3.1 Hz, 3H), 3.69 – 3.20 (m, 9H), 3.18 – 2.90 (m, 8H), 2.88 (s, 3H), 2.73 (s, 2H), 2.47 – 2.22 (m, 2H), 2.11 (d, J= 11.0 Hz, 2H), 1.77 (d, J= 12.6 Hz, 2H), 0.97 (s, 3H). MS (ESI) m/z: 667 [M+H] +. I-211
Figure 02_image796
 1H NMR (600 MHz, DMSO- d 6) δ 9.90 (s, 1H), 9.30 (s, 1H), 8.30 – 8.24 (m, 1H), 7.37 (s, 1H), 7.04 (d, J= 8.8 Hz, 1H), 6.91 (d, J= 8.9 Hz, 1H), 6.75 (s, 1H), 4.42 – 4.21 (m, 4H), 3.77 (s, 3H), 3.73 – 3.22 (m, 9H), 3.08 (d, J= 11.2 Hz, 2H), 3.02 (s, 3H), 3.00 (s, 3H), 2.89 (s, 3H), 2.74 (t, J= 12.0 Hz, 2H), 2.35 (d, J= 7.1 Hz, 2H), 2.16 – 2.09 (m, 2H), 1.85 – 1.72 (m, 2H), 0.97 (t, J= 7.6 Hz, 3H). MS (ESI) m/z: 685 [M+H] +. I-212
Figure 02_image798
 1H NMR (600 MHz, DMSO- d 6) δ 9.55 – 9.41 (m, 1H), 9.22 (s, 1H), 7.83 (s, 1H), 7.34 – 7.22 (m, 1H), 7.03 (d, J= 8.8 Hz, 1H), 6.91 (d, J= 8.8 Hz, 1H), 6.75 (s, 1H), 4.42 – 4.21 (m, 4H), 3.77 (s, 3H), 3.72 – 3.14 (m, 9H), 3.07 (d, J= 11.5 Hz, 2H), 3.04 – 2.95 (m, 6H), 2.86 (s, 3H), 2.72 (t, J= 12.1 Hz, 2H), 2.36 (d, J= 30.0 Hz, 2H), 2.15 – 2.02 (m, 5H), 1.82 – 1.70 (m, 2H), 0.98 (s, 3H). MS (ESI) m/z: 681 [M+H] +. I-213
Figure 02_image800
 1H NMR (600 MHz, DMSO- d 6) δ 9.55 – 9.34 (m, 1H), 9.27 (s, 1H), 7.84 – 7.72 (m, 1H), 7.30 (s, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.91 (d, J= 8.8 Hz, 1H), 6.75 (s, 1H), 4.43 – 4.21 (m, 4H), 3.77 (s, 3H), 3.68 – 3.11 (m, 9H), 3.10 – 3.02 (m, 2H), 3.00 (s, 3H), 2.84 (s, 3H), 2.76 – 2.68 (m, 2H), 2.54 (s, 3H), 2.41 – 2.23 (m, 2H), 2.07 (d, J= 11.0 Hz, 2H), 1.74 (s, 2H), 0.96 (s, 3H). MS (ESI) m/z: 735 [M+H] +. I-214
Figure 02_image802
 1H NMR (600 MHz, DMSO- d 6) δ 8.75 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 6.76 (s, 1H), 4.42 – 4.21 (m, 4H), 3.77 (s, 3H), 3.67 – 3.18 (m, 9H), 3.13 – 3.08 (m, 2H), 3.06 (s, 3H), 3.04 (s, 3H), 2.89 (s, 3H), 2.77 (t, J= 10.5 Hz, 2H), 2.48 – 2.42 (m, 4H), 2.17 – 2.09 (m, 2H), 1.79 (d, J= 11.7 Hz, 2H), 1.07 – 0.94 (m, 6H). MS (ESI) m/z: 695 [M+H] +. I-215
Figure 02_image804
 1H NMR (600 MHz, DMSO- d 6) δ 9.49 – 9.35 (m, 1H), 9.32 (s, 1H), 7.88 – 7.64 (m, 1H), 7.31 (s, 1H), 6.98 (d, J= 8.9 Hz, 1H), 6.90 (d, J= 8.8 Hz, 1H), 6.74 (s, 1H), 4.42 – 4.21 (m, 4H), 3.78 (s, 3H), 3.72 – 3.12 (m, 9H), 3.05 (dt, J= 12.2, 6.3 Hz, 6H), 2.99 (s, 3H), 2.84 (s, 3H), 2.76 – 2.66 (m, 2H), 2.39 – 2.17 (m, 2H), 2.07 (d, J= 11.2 Hz, 2H), 1.73 (d, J= 12.0 Hz, 2H), 1.24 (dd, J= 6.7, 2.5 Hz, 6H), 0.94 (s, 3H). MS (ESI) m/z: 709 [M+H] +. I-216
Figure 02_image806
 1H NMR (600 MHz, DMSO- d 6) δ 9.51 (s, 1H), 9.41 (s, 1H), 7.72 (s, 1H), 7.35 (s, 1H), 7.21 (d, J= 8.6 Hz, 1H), 6.86 (d, J= 8.9 Hz, 1H), 6.78 (s, 1H), 4.42 – 4.21 (m, 4H), 3.90 (s, 3H), 3.79 (s, 3H), 3.73 – 3.17 (m, 9H), 3.10 (d, J= 11.6 Hz, 2H), 3.07 (s, 3H), 3.03 (s, 3H), 2.90 (s, 3H), 2.75 (t, J= 11.7 Hz, 2H), 2.49 – 2.36 (m, 2H), 2.19 – 2.09 (m, 2H), 1.80 (dt, J= 13.0, 6.5 Hz, 2H), 0.99 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 697 [M+H] +. I-217
Figure 02_image808
 1H NMR (600 MHz, DMSO- d 6) δ 9.64 (s, 1H), 9.21 (s, 1H), 7.73 (s, 1H), 7.43 – 7.38 (m, 1H), 7.34 (s, 1H), 6.86 – 6.80 (m, 1H), 6.80 (s, 1H), 4.42 – 4.22 (m, 4H), 4.12 (tt, J= 7.0, 3.5 Hz, 2H), 3.79 (s, 3H), 3.32 (s, 9H), 3.15 – 3.11 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.89 (s, 3H), 2.76 (t, J= 11.7 Hz, 2H), 2.50 – 2.44 (m, 2H), 2.18 – 2.10 (m, 2H), 1.80 (td, J= 13.3, 9.3 Hz, 2H), 1.39 (t, J= 6.9 Hz, 3H), 1.04 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 711 [M+H] +. I-218
Figure 02_image810
 1H NMR (600 MHz, DMSO- d 6) δ 8.71 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 7.37 (s, 1H), 7.25 – 7.09 (m, 1H), 6.86 – 6.77 (m, 1H), 6.75 (s, 1H), 4.44 – 4.18 (m, 4H), 3.76 (s, 3H), 3.66 – 3.24 (m, 9H), 3.09 (d, J= 11.9 Hz, 2H), 3.06 – 2.97 (m, 6H), 2.90 (s, 3H), 2.75 (t, J= 11.7 Hz, 2H), 2.49 – 2.32 (m, 2H), 2.15 (d, J= 11.3 Hz, 2H), 1.80 (dt, J= 12.3, 6.2 Hz, 2H), 0.99 (s, 3H). MS (ESI) m/z: 692 [M+H] +. I-219
Figure 02_image812
 1H NMR (600 MHz, Methanol- d 4) δ 9.04 (s, 1H), 7.75 (s, 1H), 7.36 – 7.24 (m, 1H), 6.86 (s, 1H), 6.85 – 6.79 (m, 1H), 4.45 – 4.26 (m, 4H), 3.86 (s, 3H), 3.76 – 3.41 (m, 9H), 3.30 – 3.27 (m, 2H), 3.17 (s, 3H), 3.06 – 2.99 (m, 5H), 2.98 (s, 3H), 2.49 (s, 2H), 2.23 (d, J= 12.2 Hz, 2H), 2.01 (d, J= 12.3 Hz, 2H), 0.96 (s, 3H). MS (ESI) m/z: 712 [M+H] +. I-220
Figure 02_image814
 1H NMR (600 MHz, Methanol- d 4) δ 7.98 (s, 1H), 7.12 – 6.95 (m, 3H), 6.77 (s, 1H), 6.50 (d, J= 28.7 Hz, 1H), 4.44 – 4.32 (m, 4H), 3.88 (s, 3H), 3.64 – 3.54 (m, 2H), 3.35 – 3.31 (m, 2H), 3.27 – 3.22 (m, 2H), 3.17 (s, 3H), 3.14 – 3.06 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 2.21 (s, 3H). MS (ESI) m/z: 609 [M+H] +. I-221
Figure 02_image816
 1H NMR (600 MHz, Methanol- d 4) δ 8.20 – 7.69 (m, 1H), 7.18 – 6.94 (m, 3H), 6.75 (s, 1H), 6.64 – 6.37 (m, 1H), 4.45 – 4.29 (m, 4H), 3.86 (s, 3H), 3.37 – 3.32 (m, 1H), 3.29 – 3.22 (m, 2H), 3.16 (s, 3H), 3.01 (s, 3H), 2.93 (s, 6H), 2.84 – 2.76 (m, 2H), 2.25 – 2.12 (m, 5H), 2.00 – 1.86 (m, 2H). MS (ESI) m/z: 637 [M+H] +. I-222
Figure 02_image818
 1H NMR (600 MHz, Methanol- d 4) δ 8.29 – 7.80 (m, 1H), 7.12 – 6.99 (m, 3H), 6.83 (s, 1H), 6.67 – 6.35 (m, 1H), 4.46 – 4.32 (m, 4H), 3.89 (s, 3H), 3.64 – 3.54 (m, 2H), 3.36 – 3.31 (m, 2H), 3.21 – 3.11 (m, 7H), 3.01 (s, 3H), 2.98 (s, 3H), 2.77 – 2.50 (m, 2H), 1.17 (s, 3H). MS (ESI) m/z: 623 [M+H] +. I-223
Figure 02_image820
 1H NMR (600 MHz, Methanol- d 4) δ 8.15 – 7.81 (m, 1H), 7.11 – 6.96 (m, 3H), 6.81 (s, 1H), 6.66 – 6.39 (m, 1H), 4.45 – 4.31 (m, 4H), 3.86 (s, 3H), 3.39 – 3.32 (m, 1H), 3.24 – 3.12 (m, 5H), 3.01 (s, 3H), 2.93 (s, 6H), 2.90 – 2.81 (m, 2H), 2.71 – 2.47 (m, 2H), 2.23 – 2.11 (m, 2H), 2.03 – 1.81 (m, 2H), 1.15 (s, 3H). MS (ESI) m/z: 651 [M+H] +. I-224
Figure 02_image822
 1H NMR (600 MHz, Methanol- d 4) δ 7.99 (s, 1H), 7.17 – 6.97 (m, 3H), 6.85 (s, 1H), 6.53 (s, 1H), 4.46 – 4.31 (m, 4H), 3.88 (s, 3H), 3.58 – 3.40 (m, 8H), 3.39 – 3.33 (m, 2H), 3.24 – 3.19 (m, 1H), 3.16 (s, 3H), 3.04 – 2.96 (m, 5H), 2.94 (s, 3H), 2.29 – 2.14 (m, 5H), 2.04 – 1.94 (m, 2H). MS (ESI) m/z: 692 [M+H] +. I-225
Figure 02_image824
 1H NMR (600 MHz, Methanol- d 4) δ 8.04 (br s, 1H), 7.11 – 7.05 (m, 1H), 7.05 – 6.98 (m, 2H), 6.87 (s, 1H), 6.65 – 6.38 (m, 1H), 4.43 – 4.33 (m, 4H), 3.88 (s, 3H), 3.61 – 3.38 (m, 8H), 3.29 – 3.23 (m, 2H), 3.22 – 3.19 (m, 1H), 3.17 (s, 3H), 3.01 (s, 3H), 2.99 – 2.94 (m, 2H), 2.93 (s, 3H), 2.77 – 2.49 (m, 2H), 2.25 – 2.11 (m, 2H), 2.03 – 1.88 (m, 2H), 1.17 (s, 3H). MS (ESI) m/z: 706 [M+H] +. I-226
Figure 02_image826
 1H NMR (600 MHz, Methanol- d 4) δ 8.39 – 8.08 (m, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.14 – 6.97 (m, 2H), 6.98 – 6.86 (m, 1H), 6.83 (s, 1H), 6.62 – 6.33 (m, 1H), 4.46 – 4.23 (m, 4H), 3.96 (s, 3H), 3.93 (s, 3H), 3.60 – 3.49 (m, 2H), 3.30 – 3.23 (m, 4H), 3.17 (s, 3H), 3.08 – 2.99 (m, 5H), 2.97 (s, 3H). MS (ESI) m/z: 675 [M+H] +. I-227
Figure 02_image828
 1H NMR (600 MHz, Methanol- d 4) δ 8.92 (s, 1H), 7.29 (dd, J= 8.8, 2.9 Hz, 1H), 7.17 (d, J= 8.8 Hz, 1H), 7.14 – 7.01 (m, 3H), 6.52 (s, 1H), 4.47 – 4.35 (m, 4H), 4.19 – 4.03 (m, 1H), 3.96 (s, 3H), 3.84 – 3.69 (m, 2H), 3.62 – 3.48 (m, 2H), 3.20 (s, 3H), 3.03 (s, 3H), 2.36 – 2.18 (m, 2H), 2.11 – 1.97 (m, 2H). MS (ESI) m/z: 596 [M+H] +. I-228
Figure 02_image830
 1H NMR (600 MHz, Methanol- d 4) δ 8.06 (s, 1H), 7.46 (d, J= 8.6 Hz, 1H), 7.31 (d, J= 9.1 Hz, 1H), 6.94 (d, J= 8.9 Hz, 1H), 6.91 (d, J= 2.6 Hz, 1H), 6.71 (dd, J= 8.8, 2.6 Hz, 1H), 4.43 – 4.26 (m, 4H), 3.91 – 3.82 (m, 5H), 3.66 – 3.38 (m, 8H), 3.30 – 3.24 (m, 1H), 3.18 (s, 3H), 3.13 (t, J= 12.4 Hz, 2H), 3.02 (s, 3H), 2.96 (s, 3H), 2.33 – 2.19 (m, 2H), 1.97 (qd, J= 12.3, 4.0 Hz, 2H). MS (ESI) m/z: 673 [M+H] +. I-229
Figure 02_image832
 1H NMR (600 MHz, DMSO- d 6) δ 9.92 (s, 1H), 9.75 – 9.60 (m, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.79 (s, 1H), 7.70 – 7.59 (m, 1H), 7.53 – 7.47 (m, 1H), 7.34 (s, 1H), 7.04 – 6.98 (m, 1H), 4.44 – 4.20 (m, 4H), 3.91 (s, 3H), 3.47 (t, J= 10.8 Hz, 2H), 3.26 (t, J= 11.6 Hz, 2H), 3.14 – 3.10 (m, 5H), 3.08 (s, 3H), 2.92 – 2.81 (m, 5H). MS (ESI) m/z: 684 [M+H] +. I-230
Figure 02_image834
 1H NMR (600 MHz, DMSO- d 6) δ 9.79 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.76 (s, 1H), 7.63 – 7.57 (m, 1H), 7.47 (s, 1H), 7.32 – 7.24 (m, 1H), 7.08 – 6.97 (m, 1H), 6.56 (s, 1H), 4.42 – 4.22 (m, 4H), 3.89 (s, 3H), 3.72 (t, J= 4.6 Hz, 4H), 3.12 (s, 3H), 3.07 (s, 3H), 2.80 – 2.72 (m, 4H). MS (ESI) m/z: 671 [M+H] +. I-231
Figure 02_image836
 1H NMR (600 MHz, DMSO- d 6) δ 10.71 (s, 1H), 10.03 (s, 1H), 9.42 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.74 (s, 1H), 7.50 (d, J= 2.6 Hz, 1H), 7.14 – 7.09 (m, 1H), 7.04 (d, J= 8.9 Hz, 1H), 6.99 (d, J= 8.6 Hz, 1H), 6.77 (dd, J= 17.2, 11.1 Hz, 1H), 5.86 (d, J= 17.3 Hz, 1H), 5.47 (d, J= 11.2 Hz, 1H), 4.43 – 4.10 (m, 4H), 3.92 (s, 3H), 3.48 (t, J= 12.0 Hz, 2H), 3.28 (s, 2H), 3.12 (t, J= 10.4 Hz, 2H), 2.99 (s, 3H), 2.93 – 2.78 (m, 8H). MS (ESI) m/z: 632 [M+H] +. I-232
Figure 02_image838
 1H NMR (600 MHz, DMSO- d 6) δ 10.56 (s, 1H), 9.41 (s, 1H), 8.18 – 8.15 (m, 1H), 8.13 (s, 1H), 7.72 (s, 1H), 7.49 – 7.43 (m, 1H), 7.12 – 7.08 (m, 1H), 7.05 (d, J= 8.8 Hz, 1H), 6.99 (d, J= 8.6 Hz, 1H), 6.77 (dd, J= 17.3, 11.1 Hz, 1H), 6.65 (s, 1H), 5.85 (d, J= 17.2 Hz, 1H), 5.47 (d, J= 11.1 Hz, 1H), 4.41 – 4.14 (m, 4H), 3.90 (s, 3H), 3.76 – 3.71 (m, 4H), 2.99 (s, 6H), 2.76 (t, J= 4.5 Hz, 4H). MS (ESI) m/z: 619 [M+H] +. I-233
Figure 02_image840
 1H NMR (600 MHz, Methanol- d 4) δ 7.91 (s, 1H), 7.48 (s, 1H), 7.16 – 7.12 (m, 2H), 6.92 (d, J= 8.8 Hz, 1H), 6.83 (s, 1H), 6.69 (dd, J= 17.2, 11.0 Hz, 1H), 5.81 (d, J= 17.3 Hz, 1H), 5.56 (d, J= 11.0 Hz, 1H), 4.42 – 4.28 (m, 4H), 3.87 (s, 3H), 3.38 (t, J= 4.9 Hz, 4H), 3.13 (dd, J= 10.1, 4.9 Hz, 7H), 3.00 (s, 3H), 2.61 – 2.38 (m, 2H), 1.06 – 1.02 (m, 3H). MS (ESI) m/z: 596 [M+H] +. I-234
Figure 02_image842
 1H NMR (600 MHz, DMSO- d 6) δ 9.35 (s, 1H), 8.98 – 8.89 (m, 2H), 8.25 (s, 1H), 7.40 – 7.31 (m, 1H), 7.15 (d, J= 8.6 Hz, 1H), 7.09 (d, J= 8.8 Hz, 1H), 6.98 – 6.92 (m, 2H), 6.78 (dd, J= 17.2, 11.1 Hz, 1H), 5.84 (d, J= 17.3 Hz, 1H), 5.43 (d, J= 11.0 Hz, 1H), 4.52 – 4.19 (m, 4H), 3.29 – 3.19 (m, 4H), 3.00 (s, 3H), 2.97 (s, 3H), 2.96 – 2.91 (m, 4H), 2.47 – 2.38 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 566 [M+H] +. I-235
Figure 02_image844
 1H NMR (600 MHz, DMSO- d 6) δ 9.04 (s, 2H), 8.94 (s, 1H), 8.28 (s, 1H), 7.47 (s, 1H), 7.27 (d, J= 8.9 Hz, 1H), 6.86 (d, J= 8.9 Hz, 1H), 6.75 (s, 1H), 4.43 – 4.24 (m, 4H), 3.80 (s, 3H), 3.32 – 3.22 (m, 4H), 3.08 (s, 3H), 3.05 (s, 3H), 3.04 – 2.99 (m, 4H), 2.50 – 2.40 (m, 2H), 1.00 (t, J= 7.6 Hz, 3H). MS (ESI) m/z: 604 [M+H] +. I-236
Figure 02_image846
 1H NMR (600 MHz, DMSO- d 6) δ 8.96 (s, 2H), 8.61 (s, 1H), 8.25 (s, 1H), 7.43 (d, J= 2.4 Hz, 2H), 7.34 (d, J= 8.5 Hz, 1H), 6.99 (d, J= 8.6 Hz, 1H), 6.94 (d, J= 8.8 Hz, 1H), 4.45 – 4.24 (m, 4H), 3.29 – 3.21 (m, 4H), 3.09 (s, 3H), 3.07 (s, 3H), 3.00 – 2.94 (m, 4H), 2.61 – 2.56 (m, 2H), 1.07 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 574 [M+H] +. I-237
Figure 02_image848
 1H NMR (600 MHz, DMSO- d 6) δ 10.28 (s, 1H), 8.99 (s, 1H), 8.89 (s, 1H), 8.28 (s, 1H), 7.48 (s, 1H), 6.90 – 6.82 (m, 1H), 6.77 (s, 1H), 4.44 – 4.24 (m, 4H), 3.80 (s, 3H), 3.53 (d, J= 11.7 Hz, 2H), 3.22 (d, J= 11.8 Hz, 2H), 3.15 – 3.09 (m, 2H), 3.08 (s, 3H), 3.07 – 3.01 (m, 5H), 2.52 – 2.40 (m, 2H), 1.01 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 621 [M+H] +. I-238
Figure 02_image850
 1H NMR (600 MHz, DMSO- d 6) δ 10.24 (s, 1H), 9.48 (s, 1H), 8.19 (d, J= 14.4 Hz, 1H), 7.41 (s, 1H), 7.01 (d, J= 8.8 Hz, 1H), 6.91 (d, J= 8.8 Hz, 1H), 6.81 – 6.75 (m, 2H), 5.82 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.4 Hz, 1H), 4.42 – 4.20 (m, 4H), 3.80 (s, 3H), 3.51 (d, J= 11.8 Hz, 2H), 3.21 (d, J= 12.2 Hz, 2H), 3.13 – 3.06 (m, 2H), 3.05 – 3.01 (m, 2H), 2.98 (s, 6H), 2.42 – 2.23 (m, 2H), 0.95 (s, 3H). MS (ESI) m/z: 613 [M+H] +. I-239
Figure 02_image852
 1H NMR (600 MHz, DMSO- d 6) δ 9.94 (s, 1H), 9.01 (s, 1H), 8.29 (s, 1H), 7.44 (s, 1H), 7.29 (d, J= 8.9 Hz, 1H), 6.89 (d, J= 8.8 Hz, 1H), 6.79 (s, 1H), 4.43 – 4.22 (m, 4H), 3.80 (s, 3H), 3.52 (d, J= 11.9 Hz, 2H), 3.16 – 3.10 (m, 2H), 3.08 – 3.06 (m, 4H), 3.05 (s, 3H), 2.83 (d, J= 4.3 Hz, 3H), 2.11 (s, 3H), 1.98 – 1.91 (m, 2H), 1.90 – 1.83 (m, 2H). MS (ESI) m/z: 603 [M+H] +. I-240
Figure 02_image854
 1H NMR (600 MHz, DMSO- d 6) δ 10.11 (s, 1H), 10.01 (s, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.46 – 7.39 (m, 1H), 7.34 – 7.27 (m, 1H), 7.00 (d, J= 8.6 Hz, 1H), 6.95 (d, J= 8.9 Hz, 1H), 4.48 – 4.24 (m, 4H), 3.51 (d, J= 11.8 Hz, 2H), 3.20 (d, J= 17.0 Hz, 2H), 3.09 (s, 3H), 3.07 (s, 3H), 3.06 – 3.03 (m, 2H), 2.98 (tt, J= 11.4, 5.1 Hz, 2H), 2.62 – 2.52 (m, 2H), 1.07 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 591 [M+H] +. I-241
Figure 02_image856
 1H NMR (600 MHz, DMSO- d 6) δ 9.71 (s, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 7.75 (s, 1H), 7.31 (d, J= 9.2 Hz, 1H), 6.80 (d, J= 9.0 Hz, 1H), 4.92 (q, J= 9.0 Hz, 2H), 4.43 – 4.21 (m, 4H), 3.46 (t, J= 6.8 Hz, 2H), 3.26 (t, J= 6.0 Hz, 2H), 3.09 (s, 3H), 3.05 (s, 3H), 2.82 (d, J= 4.0 Hz, 6H), 2.75 (s, 3H), 2.58 – 2.44 (m, 2H), 1.04 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 689 [M+H] +. I-242
Figure 02_image858
 1H NMR (600 MHz, DMSO- d 6) δ 9.94 (s, 1H), 9.61 (s, 1H), 8.24 (s, 1H), 7.39 (s, 1H), 7.00 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 8.8 Hz, 1H), 6.83 – 6.77 (m, 2H), 5.83 (d, J= 17.3 Hz, 1H), 5.47 (d, J= 11.2 Hz, 1H), 4.41 – 4.23 (m, 4H), 3.81 (s, 3H), 3.55 – 3.47 (m, 2H), 3.16 – 3.06 (m, 2H), 3.05 – 2.91 (m, 8H), 2.82 (d, J= 4.2 Hz, 3H), 2.02 (s, 3H), 1.98 – 1.88 (m, 1H), 1.84 (d, J= 13.4 Hz, 2H). MS (ESI) m/z: 595 [M+H] +. I-243
Figure 02_image860
 1H NMR (600 MHz, DMSO- d 6) δ 10.09 (s, 1H), 9.52 – 9.41 (m, 1H), 8.25 (s, 1H), 7.40 – 7.29 (m, 1H), 7.17 – 7.08 (m, 1H), 7.08 – 7.02 (m, 1H), 6.99 – 6.93 (m, 2H), 6.79 (dd, J= 17.2, 11.1 Hz, 1H), 5.85 (d, J= 17.3 Hz, 1H), 5.44 (d, J= 11.1 Hz, 1H), 4.43 – 4.21 (m, 4H), 3.53 – 3.47 (m, 2H), 3.20 (s, 2H), 3.08 – 3.01 (m, 2H), 2.99 (s, 3H), 2.98 – 2.91 (m, 5H), 2.60 – 2.39 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 583 [M+H] +. I-244
Figure 02_image862
 1H NMR (600 MHz, DMSO- d 6) δ 9.86 (s, 1H), 9.44 (s, 1H), 8.14 (s, 1H), 7.67 (s, 1H), 6.97 (d, J= 8.9 Hz, 1H), 6.88 (d, J= 8.9 Hz, 1H), 6.77 (dd, J= 17.2, 11.1 Hz, 1H), 5.82 (d, J= 17.3 Hz, 1H), 5.46 (d, J= 11.2 Hz, 1H), 5.03 – 4.75 (m, 2H), 4.50 – 4.16 (m, 4H), 3.49 (t, J= 6.9 Hz, 2H), 3.27 (q, J= 6.2 Hz, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 2.81 (d, J= 3.7 Hz, 6H), 2.78 (s, 3H), 2.39 (s, 2H), 1.00 (s, 3H). MS (ESI) m/z: 681 [M+H] +. I-245
Figure 02_image864
 1H NMR (600 MHz, DMSO- d 6) δ 10.30 – 10.17 (m, 1H), 9.19 (s, 1H), 8.31 (s, 1H), 7.40 (s, 1H), 7.20 (d, J= 9.0 Hz, 1H), 6.87 (d, J= 8.9 Hz, 1H), 6.82 (s, 1H), 4.44 – 4.20 (m, 4H), 3.79 (s, 3H), 3.71 (q, J= 8.4 Hz, 1H), 3.06 (s, 3H), 3.04 (s, 3H), 2.92 – 2.76 (m, 4H), 2.70 (d, J= 4.5 Hz, 6H), 2.45 – 2.36 (m, 2H), 2.25 (t, J= 10.1 Hz, 2H), 2.01 (dd, J= 12.1, 8.4 Hz, 2H), 1.81 – 1.68 (m, 4H), 0.99 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 686 [M+H] +. The following table lists specific compounds and structural identification information: serial number structure H NMR and/or MS data I-1
Figure 02_image376
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.89 (s, 1H), 8.29 (s, 1H), 8.27 (s, 1H), 7.57 – 7.49 (m, 1H), 7.44 (d, J = 2.6 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 4.38 – 4.24 (m, 4H), 3.53 – 3.44 (m, 2H), 3.25 – 3.14 (m, 2H), 3.10 (s, 3H), 3.08 (s, 3H), 3.07 – 3.02 (m, 2H), 2.99 – 2.91 (m, 2H), 2.88 (s, 3H), 2.59 – 2.55 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 632 [M+H] + . I-2
Figure 02_image378
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.84 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 7.47 – 7.40 (m, 1H), 7.39 – 7.35 (m, 1H ), 7.28 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 4.45 – 4.24 (m, 4H), 3.74 (t , J = 4.5 Hz, 4H), 3.09 (s, 3H), 3.07 (s, 3H), 2.80 (t, J = 4.6 Hz, 4H), 2.57 (q, J = 7.5 Hz, 2H), 1.14 – 1.01 (m, 3H). MS (ESI) m/z : 619 [M+H] + . I-3
Figure 02_image380
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.79 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.64 (s, 1H), 7.62 – 7.57 (m, 2H), 7.51 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.62 (s, 2H), 3.40 (s, 2H), 3.15 (s , 3H), 3.12 (s, 3H), 3.08 (s, 3H), 2.68 (d, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 607 [M+H] + . I-4
Figure 02_image382
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.86 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 7.50 – 7.43 (m, 2H), 7.40 (d, J = 9.0 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.65 (t, J = 5.4 Hz, 2H), 3.24 (t, J = 5.4 Hz, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.54 (t, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 593 [M+H] + . I-5
Figure 02_image384
 H NMR (600 MHz, DMSO- d 6 ) δ 9.32 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.60 (s, 1H), 7.21 (s , 1H), 7.19 – 7.14 (m, 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 8.6 Hz, 1H), 4.47 – 4.22 (m, 4H), 3.42 (t, J = 6.3 Hz, 2H), 3.29 (t, J = 6.2 Hz, 2H), 3.12 (s, 3H), 3.08 (s, 3H), 2.86 (s, 6H), 2.42 (t, J = 7.5 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 620 [M+H] + . I-6
Figure 02_image386
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.67 – 9.64 (m, 1H), 9.51 (s, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.45 – 7.41 (m, 1H ), 7.38 – 7.34 (m, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 4.44 – 4.22 (m, 4H), 3.20 (d, J = 6.4 Hz, 2H), 3.18 – 3.13 (m, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 2.80 (s, 6H), 2.61 – 2.57 (m, 2H), 2.56 (s, 3H ), 1.06 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 634 [M+H] + . I-7
Figure 02_image388
 MS (ESI) m/z : 631 [M+H] + . I-8
Figure 02_image390
 MS (ESI) m/z : 644 [M+H] + . I-9
Figure 02_image392
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.02 (s, 1H), 9.47 (s, 1H), 8.25 (s, 2H), 7.55 (s, 1H), 7.40 (s, 1H), 6.99 – 6.85 (m, 2H), 4.47 – 4.21 (m, 4H), 3.53 (d, J = 11.7 Hz, 2H), 3.33 – 3.21 (m, 4H), 3.12 (s, 3H), 3.08 (s, 3H) , 3.01 – 2.84 (m, 5H), 1.04 (d, J = 6.1 Hz, 1H), 0.93 (d, J = 8.6 Hz, 2H), 0.57 – 0.47 (m, 2H). MS (ESI) m/z : 644 [M+H] + . I-10
Figure 02_image394
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.52 (s, 1H), 8.29 (s, 1H), 7.52 – 7.42 (m, 2H), 7.35 – 7.25 (m, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.87 – 6.82 (m, 1H), 4.47 – 4.21 (m, 4H), 3.77 (t, J = 4.4 Hz, 4H), 3.11 (s, 3H), 3.10 – 3.05 (m, 4H), 2.92 (t, J = 4.5 Hz, 3H), 1.04 (d, J = 6.1 Hz, 1H), 0.92 (d, J = 8.6 Hz, 2H) , 0.57 – 0.43 (m, 2H). MS (ESI) m/z : 631 [M+H] + . I-11
Figure 02_image396
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.95 (s, 1H), 9.58 – 9.46 (m, 1H), 8.28 – 8.19 (m, 2H), 7.47 – 7.42 (m, 1H), 7.32 – 7.25 (m, 1H), 6.96 – 6.90 (m, 2H), 4.46 – 4.19 (m, 4H), 3.50 (d, J = 11.8 Hz, 2H), 3.24 – 3.18 (m, 2H), 3.13 (d, J = 12.8 Hz, 2H), 3.10 (s, 2H), 3.08 (s, 3H), 2.92 (t, J = 11.3 Hz, 2H), 2.88 (s, 3H), 2.17 (s, 3H). MS (ESI ) m/z : 618 [M+H] + . I-12
Figure 02_image398
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.63 (s, 1H), 8.43 (s, 1H), 8.26 (s, 1H), 7.52 – 7.44 (m, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 4.43 – 4.25 (m, 4H), 3.78 – 3.70 (m, 4H), 3.09 (s, 3H), 3.07 (s, 3H), 2.86 – 2.76 (m, 4H), 2.17 (s, 3H). MS (ESI) m/z : 605 [M +H] + . I-13
Figure 02_image400
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.13 (s, 1H), 7.46 – 7.11 (m, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.71 (s, 1H), 4.44 – 4.27 (m, 4H), 4.05 – 3.99 (m, 1H), 3.85 (s, 3H), 3.54 – 3.47 (m, 1H), 3.47 – 3.37 (m, 2H), 3.23 – 3.12 (m, 4H), 3.03 (s, 3H), 2.97 (s, 6H), 2.54 – 2.43 (m, 1H), 2.26 – 2.19 (m, 1H), 2.16 (s, 3H). MS (ESI) m/z : 662 [M +H] + . I-14
Figure 02_image402
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.14 (s, 1H), 7.41 – 7.18 (m, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.77 (s, 1H), 4.45 – 4.28 (m, 4H), 3.84 (s, 3H), 3.37 – 3.34 (m, 1H), 3.30 – 3.25 (m, 2H), 3.18 (s, 3H), 3.03 (s, 3H), 2.93 (s, 6H), 2.86 – 2.73 (m, 2H), 2.25 – 2.17 (m, 2H), 2.14 (s, 3H), 1.99 – 1.88 (m, 2H). MS (ESI) m/z : 676 [M+H ] + . I-15
Figure 02_image404
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.16 (s, 1H), 7.43 – 7.18 (m, 2H), 6.91 (d, J = 8.9 Hz, 1H), 6.78 (s, 1H), 4.43 – 4.27 (m, 4H), 3.86 (s, 3H), 3.67 – 3.56 (m, 2H), 3.36 – 3.33 (m, 2H), 3.29 – 3.24 (m, 2H), 3.18 (s, 3H), 3.15 – 3.07 (m, 2H), 3.03 (s, 3H), 2.99 (s, 3H), 2.15 (s, 3H). MS (ESI) m/z : 648 [M+H] + . I-16
Figure 02_image406
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.15 (s, 1H), 7.49 – 7.15 (m, 2H), 6.88 (s, 1H), 6.80 (d, J = 2.4 Hz, 1H), 4.45 – 4.27 (m, 4H), 4.06 – 3.98 (m, 1H), 3.85 (s, 3H), 3.48 – 3.39 (m, 2H), 3.36 – 3.33 (m, 1H), 3.20 (s, 3H), 3.17 – 3.11 (m, 1H), 3.03 (s, 3H), 2.97 (s, 6H), 2.63 – 2.44 (m, 3H), 2.28 – 2.16 (m, 1H), 1.07 (s, 3H). MS (ESI) m/z : 676 [M+H] + . I-17
Figure 02_image408
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.15 (s, 1H), 7.51 – 7.16 (m, 2H), 6.93 – 6.84 (m, 1H), 6.82 (s, 1H), 4.46 – 4.28 (m , 4H), 3.84 (s, 3H), 3.34 (d, J = 5.2 Hz, 1H), 3.24 – 3.10 (m, 5H), 3.03 (s, 3H), 2.93 (s, 6H), 2.89 – 2.77 ( m, 2H), 2.64 – 2.48 (m, 2H), 2.27 – 2.13 (m, 2H), 1.99 – 1.82 (m, 2H), 1.06 (s, 3H). MS (ESI) m/z : 690 [M +H] + . I-18
Figure 02_image410
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.25 – 8.07 (m, 1H), 7.46 (s, 1H), 7.36 – 7.18 (m, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.85 (s, 1H), 4.44 – 4.26 (m, 4H), 3.86 (s, 3H), 3.63 – 3.54 (m, 2H), 3.35 – 3.32 (m, 2H), 3.22 – 3.12 (m, 7H), 3.03 (s, 3H), 2.99 (s, 3H), 2.66 – 2.44 (m, 2H), 1.06 (s, 3H). MS (ESI) m/z : 662 [M+H] + . I-19
Figure 02_image412
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.27 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 8.16 (t, J = 5.7 Hz, 3H), 7.29 (s, 1H), 6.88 – 6.79 (m, 1H), 6.74 (s, 1H), 4.43 – 4.23 (m, 4H), 4.21 (t, J = 5.2 Hz, 2H), 3.80 (s, 3H), 3.30 – 3.24 (m, 2H), 3.10 (s, 3H), 3.06 (s, 3H), 2.54 – 2.39 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 623 [M+H] + . I-20
Figure 02_image414
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.18 – 9.87 (m, 1H), 9.66 – 9.35 (m, 1H), 8.92 (s, 1H), 8.47 – 8.15 (m, 1H), 7.42 – 7.25 (m, 1H), 7.10 – 6.93 (m, 1H), 6.88 – 6.70 (m, 1H), 6.33 (s, 1H), 4.45 – 4.21 (m, 4H), 3.78 (s, 3H), 3.54 (t , J = 6.4 Hz, 2H), 3.31 (t, J = 6.4 Hz, 2H), 3.11 (s, 3H), 3.06 (s, 3H), 2.87 (s, 6H), 2.43 – 2.27 (m, 2H) , 1.07 – 0.98 (m, 3H). MS (ESI) m/z : 650 [M+H] + . I-21
Figure 02_image416
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.22 (s, 1H), 8.82 (s, 1H), 8.37 (s, 1H), 7.43 (s, 1H), 7.30 (d, J = 8.9 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J = 8.9 Hz, 1H), 4.46 – 4.22 (m, 4H), 3.81 (s, 3H), 3.26 – 3.21 (m, 4H), 3.10 (s , 3H), 3.06 (s, 3H), 2.82 (s, 6H), 2.53 – 2.43 (m, 5H), 0.98 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 664 [M +H] + . I-22
Figure 02_image418
 MS (ESI) m/z : 714 [M+H] + . I-23
Figure 02_image420
 MS (ESI) m/z : 700 [M+H] + . I-24
Figure 02_image422
 MS (ESI) m/z : 700 [M+H] + . I-25
Figure 02_image424
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.12 (s, 1H), 7.55 – 7.45 (m, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.95 – 6.88 (m, 2H), 6.76 – 6.64 (m, 1H), 4.44 – 4.26 (m, 4H), 3.90 – 3.81 (m, 5H), 3.66 – 3.32 (m, 8H), 3.25 – 3.20 (m, 1H), 3.19 (s, 3H) ), 3.12 (t, J = 12.2 Hz, 2H), 3.03 (s, 3H), 2.94 (s, 3H), 2.25 – 2.18 (m, 2H), 2.01 – 1.89 (m, 2H). MS (ESI) m/z : 717 [M+H] + . I-26
Figure 02_image426
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.15 (s, 1H), 7.44 – 7.17 (m, 2H), 6.91 (d, J = 8.9 Hz, 1H), 6.80 (s, 1H), 4.45 – 4.24 (m, 4H), 3.84 (s, 3H), 3.78 – 3.50 (m, 8H), 3.45 – 3.37 (m, 1H), 3.35 – 3.31 (m, 2H), 3.17 (s, 3H), 3.02 ( s, 3H), 3.00 (s, 3H), 2.88 (q, J = 11.4 Hz, 2H), 2.29 – 2.22 (m, 2H), 2.14 (s, 3H), 2.06 – 1.94 (m, 2H). (ESI) m/z : 731 [M+H] + . I-27
Figure 02_image428
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.16 (s, 1H), 7.51 – 7.16 (m, 2H), 6.88 (d, J = 8.9 Hz, 1H), 6.84 (s, 1H), 4.43 – 4.27 (m, 4H), 3.84 (s, 3H), 3.80 – 3.51 (m, 8H), 3.47 – 3.39 (m, 1H), 3.27 – 3.21 (m, 2H), 3.18 (s, 3H), 3.02 ( s, 3H), 3.00 (s, 3H), 2.90 (t, J = 11.7 Hz, 2H), 2.62 – 2.43 (m, 2H), 2.31 – 2.18 (m, 2H), 2.06 – 1.93 (m, 2H) , 1.05 (s, 3H). MS (ESI) m/z : 745 [M+H] + . I-28
Figure 02_image430
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.43 (s, 1H), 8.83 (s, 1H), 8.33 (s, 1H), 7.32 (s, 1H), 7.30 – 7.23 (m, 1H), 6.81 (s, 1H), 6.79 – 6.74 (m, 1H), 4.48 – 4.19 (m, 4H), 3.76 (s, 3H), 3.68 – 3.31 (m, 11H), 3.24 (q, J = 6.9 Hz, 1H), 3.09 (s, 3H), 3.06 (s, 3H), 2.92 (s, 3H), 2.81 (d, J = 9.2 Hz, 2H), 2.22 – 2.09 (m, 2H), 1.90 – 1.75 (m , 2H), 1.08 – 0.87 (m, 6H). MS (ESI) m/z : 759 [M+H] + . I-29
Figure 02_image432
 MS (ESI) m/z : 757 [M+H] + . I-30
Figure 02_image434
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.02 (s, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.42 (s, 1H), 7.40 – 7.36 (m, 1H), 7.32 – 7.25 (m, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 4.48 – 4.23 (m, 4H), 3.86 – 3.27 (m, 8H) , 3.14 (d, J = 8.0 Hz, 1H), 3.10 (s, 3H), 3.07 (s, 3H), 2.92 (s, 3H), 2.73 (t, J = 12.0 Hz, 2H), 2.58 – 2.54 ( m, 4H), 2.20 – 2.11 (m, 2H), 1.91 – 1.75 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 715 [M+H] + . I-31
Figure 02_image436
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.49 – 9.33 (m, 2H), 8.67 (s, 1H), 8.30 (s, 1H), 7.41 (s, 1H), 7.37 – 7.28 (m, 1H ), 6.82 (d, J = 9.0 Hz, 1H), 6.76 (s, 1H), 4.44 – 4.17 (m, 4H), 3.78 (s, 3H), 3.62 – 3.33 (m, 12H), 3.12 – 3.08 ( m, 3H), 3.06 (s, 3H), 2.76 (t, J = 11.7 Hz, 2H), 2.49 – 2.43 (m, 1H), 2.20 – 2.10 (m, 2H), 1.82 (dd, J = 12.0, 3.9 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 731 [M+H] + . I-32
Figure 02_image438
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.95 (s, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 7.49 (s, 1H), 7.38 – 7.29 (m, 1H), 6.88 – 6.79 (m, 1H), 6.74 (s, 1H), 4.46 – 4.16 (m, 5H), 3.80 (s, 3H), 3.69 – 3.58 (m, 4H), 3.56 – 3.49 (m, 1H), 3.46 – 3.12 (m, 9H), 3.10 (s, 3H), 3.07 (s, 3H), 2.81 (s, 3H), 2.44 – 2.34 (m, 2H), 2.06 – 1.86 (m, 2H), 1.01 ( t, J = 7.6 Hz, 3H). MS (ESI) m/z : 745 [M+H] + . I-33
Figure 02_image440
 MS (ESI) m/z : 717 [M+H] + . I-34
Figure 02_image442
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.35 – 9.25 (m, 1H), 9.21 – 9.12 (m, 1H), 8.65 (s, 1H), 8.31 (s, 1H), 7.46 (s, 1H) ), 7.33 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.76 (s, 1H), 4.43 – 4.23 (m, 6H), 4.15 (s, 3H), 3.79 (s, 3H), 3.24 – 3.11 (m, 4H), 3.09 (s, 3H), 3.06 (s, 3H), 3.03 (d, J = 4.6 Hz, 5H), 2.49 – 2.45 (m, 1H), 1.00 (t, J = 7.6 Hz, 3H). MS (ESI) m/z : 703 [M+H] + . I-35
Figure 02_image444
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.44 – 10.04 (m, 1H), 9.20 (s, 1H), 8.81 (s, 1H), 8.34 (s, 1H), 7.40 (s, 1H), 7.36 – 7.17 (m, 1H), 6.81 (s, 1H), 4.49 – 4.23 (m, 4H), 3.79 (s, 3H), 3.75 – 3.69 (m, 1H), 3.12 – 3.07 (m, 4H), 3.06 (s, 3H), 2.91 – 2.76 (m, 4H), 2.70 (d, J = 4.5 Hz, 6H), 2.49 – 2.43 (m, 1H), 2.28 – 2.19 (m, 2H), 2.07 – 1.97 ( m, 2H), 1.79 – 1.66 (m, 4H), 1.04 – 0.95 (m, 3H). MS (ESI) m/z : 730 [M+H] + . I-36
Figure 02_image446
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.02 (s, 1H), 8.74 (s, 1H), 8.31 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.86 – 6.80 (m, 1H), 6.77 (s, 1H), 4.44 – 4.21 (m, 4H), 4.08 – 3.99 (m, 2H), 3.87 – 3.78 (m, 2H), 3.77 (s, 3H), 3.08 ( s, 3H), 3.06 (s, 3H), 2.87 (d, J = 5.0 Hz, 3H), 2.84 – 2.78 (m, 2H), 2.73 – 2.65 (m, 2H), 2.49 – 2.40 (m, 2H) , 2.00 – 1.88 (m, 4H), 1.09 – 0.93 (m, 3H). MS (ESI) m/z : 702 [M+H] + . I-37
Figure 02_image448
 MS (ESI) m/z : 674 [M+H] + . I-38
Figure 02_image450
 MS (ESI) m/z : 661 [M+H] + . I-39
Figure 02_image452
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01 (s, 1H), 8.24 – 8.12 (m, 1H), 8.08 – 7.98 (m, 1H), 7.56 (s, 1H), 7.13 (s, 1H) ), 6.86 – 6.74 (m, 1H), 6.75 – 6.66 (m, 1H), 4.46 – 4.19 (m, 4H), 3.65 – 3.20 (m, 9H), 3.19 – 3.03 (m, 6H), 2.76 – 2.65 (m, 2H), 2.39 – 2.28 (m, 2H), 2.19 (s, 3H), 1.94 – 1.79 (m, 2H), 1.68 – 1.50 (m, 2H). MS (ESI) m/z : 723 [ M+H] + . I-40
Figure 02_image454
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.60 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.33 – 7.19 (m, 1H), 6.97 – 6.88 (m, 1H ), 6.16 – 6.05 (m, 1H), 5.41 (s, 1H), 4.46 – 4.24 (m, 4H), 3.81 – 3.73 (m, 1H), 3.48 – 3.27 (m, 5H), 3.11 – 3.03 (m , 6H), 3.00 – 2.89 (m, 4H), 2.40 – 2.20 (m, 1H), 2.16 – 2.12 (m, 4H), 1.81 – 1.69 (m, 3H), 1.55 – 1.43 (m, 2H). MS (ESI) m/z : 723 [M+H] + . I-41
Figure 02_image456
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.89 (s, 1H), 8.71 – 8.61 (m, 1H), 8.38 (s, 1H), 7.64 (s, 1H), 7.29 (s, 1H), 6.91 – 6.86 (m, 1H), 6.86 – 6.83 (m, 1H), 4.73 – 4.61 (m, 1H), 4.47 – 4.19 (m, 4H), 3.81 (s, 3H), 3.76 – 3.55 (m, 7H ), 3.55 – 3.37 (m, 2H), 3.11 (s, 1H), 3.09 (s, 3H), 3.06 (s, 3H), 3.00 (t, J = 13.8 Hz, 0H), 2.88 (s, 3H) , 2.78 (t, J = 12.6 Hz, 1H), 2.45 – 1.89 (m, 4H), 1.75 – 1.29 (m, 3H), 1.01 – 0.88 (m, 3H). MS (ESI) m/z : 773 [ M+H] + . I-42
Figure 02_image458
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.94 (s, 1H), 8.61 (s, 1H), 8.30 (s, 1H), 7.47 (s, 1H), 7.35 – 7.32 (m, 1H), 7.23 – 7.18 (m, 2H), 7.16 – 7.11 (m, 1H), 7.11 – 7.07 (m, 2H), 6.84 (s, 1H), 6.81 – 6.77 (m, 1H), 4.35 – 4.05 (m, 4H ), 3.97 (s, 2H), 3.85 – 3.75 (m, 2H), 3.78 (s, 3H), 3.72 – 3.37 (m, 5H), 3.34 – 3.31 (m, 2H), 3.10 (s, 3H), 3.06 (s, 3H), 2.97 – 2.85 (m, 5H), 2.76 – 2.69 (m, 2H), 2.09 – 2.06 (m, 2H), 1.83 – 1.73 (m, 2H). MS (ESI) m/z : 807 [M+H] + . I-43
Figure 02_image460
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.32 (s, 1H), 8.82 (s, 1H), 8.34 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 6.79 ( s, 1H), 4.47 – 4.21 (m, 4H), 3.78 (s, 3H), 3.72 – 3.44 (m, 8H), 3.44 – 3.33 (m, 2H), 3.13 – 3.07 (m, 4H), 3.06 ( s, 3H), 2.91 (s, 3H), 2.76 (q, J = 10.6 Hz, 2H), 2.36 (d, J = 6.7 Hz, 2H), 2.20 – 2.12 (m, 2H), 1.79 (dd, J = 11.8, 4.0 Hz, 2H), 0.77 (s, 1H), 0.38 (d, J = 8.0 Hz, 2H), 0.16 – -0.08 (m, 2H). MS (ESI) m/z : 771 [M+ H] + . I-44
Figure 02_image462
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.26 (s, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.02 – 6.99 (m, 1H), 6.97 (s, 1H), 6.81 – 6.77 (m, 1H), 4.45 – 4.16 (m, 4H), 3.97 (s, 3H), 3.96 – 3.88 (m, 2H), 3.83 – 3.21 (m, 6H), 3.11 (s, 3H), 3.07 (s, 3H), 2.89 (s, 3H), 2.83 – 2.72 (m, 2H), 2.19 – 2.04 (m, 2H), 1.74 – 1.62 (m, 2H). MS (ESI) m/z : 771 [M+H] + . I-45
Figure 02_image464
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.45 (s, 1H), 7.44 – 7.39 (m, 1H), 7.03 (s, 1H), 6.80 – 6.68 (m, 1H), 4.48 – 4.19 (m, 4H), 3.89 – 3.23 (m, 9H), 3.15 – 3.09 (m, 5H), 3.07 (s, 3H), 2.89 (s, 3H), 2.70 (t, J = 11.6 Hz, 2H), 2.57 (q, J = 7.6 Hz, 2H), 2.21 – 2.07 (m, 2H), 1.87 – 1.71 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H). MS (ESI) m/z : 799 [M+H] + . I-46
Figure 02_image466
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.28 (s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.72 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.01 (s, 1H), 6.87 (dd, J = 17.7, 11.1 Hz, 1H), 6.67 (d, J = 9.0 Hz, 1H), 5.68 (d, J = 17.7 Hz, 1H), 5.32 ( d, J = 11.2 Hz, 1H), 4.43 – 4.19 (m, 4H), 3.85 – 3.30 (m, 9H), 3.23 (d, J = 11.5 Hz, 2H), 3.10 (s, 3H), 3.07 (s , 3H), 2.90 (s, 3H), 2.72 (d, J = 11.2 Hz, 2H), 2.20 – 2.09 (m, 2H), 1.84 (dd, J = 11.7, 3.8 Hz, 2H). MS (ESI) m/z : 797 [M+H] + . I-47
Figure 02_image468
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.26 – 9.10 (m, 1H), 8.65 (s, 1H), 8.28 (s, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 4.44 – 4.21 (m, 4H), 3.88 (s, 3H), 3.81 – 3.71 (m, 2H), 3.67 – 3.19 (m, 9H), 3.09 (s, 3H), 3.06 ( s, 3H), 2.87 (s, 3H), 2.84 – 2.71 (m, 2H), 2.06 – 1.96 (m, 5H), 1.71 – 1.54 (m, 2H). MS (ESI) m/z : 732 [M +H] + . I-48
Figure 02_image470
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.12 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 6.82 ( d, J = 8.9 Hz, 1H), 4.45 – 4.22 (m, 4H), 3.84 (s, 3H), 3.78 – 3.19 (m, 11H), 3.10 (s, 3H), 3.06 (s, 3H), 2.91 (s, 3H), 2.88 – 2.79 (m, 2H), 2.44 (t, J = 7.1 Hz, 2H), 2.19 – 2.08 (m, 2H), 1.87 – 1.74 (m, 2H), 1.05 – 1.00 (m , 3H). MS (ESI) m/z : 746 [M+H] + . I-49
Figure 02_image472
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.35 (s, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 6.85 (s, 1H), 6.43 (d, J = 8.5 Hz, 1H), 4.47 – 4.42 (m, 2H), 4.41 – 4.22 (m, 4H), 3.81 (s, 3H), 3.73 – 3.24 (m, 9H), 3.12 (s, 3H), 3.07 (s, 3H), 2.89 (s, 3H), 2.84 (t, J = 12.7 Hz, 2H), 2.17 – 2.09 (m, 2H), 1.62 – 1.54 (m, 2H). MS (ESI) m/z : 718 [M+H] + . I-50
Figure 02_image474
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.11 (s, 1H), 9.75 (s, 1H), 8.39 – 8.25 (m, 2H), 8.03 (s, 1H), 7.55 (s, 1H), 7.27 (s, 1H), 6.98 – 6.91 (m, 1H), 4.50 – 4.20 (m, 6H), 3.47 (dt, J = 8.8, 4.5 Hz, 1H), 3.13 (s, 3H), 3.08 (s, 3H), 3.07 – 3.02 (m, 2H), 2.79 (d, J = 4.2 Hz, 6H), 2.17 – 2.07 (m, 2H), 1.73 – 1.60 (m, 2H). MS (ESI) m/z : 633 [M+H] + . I-51
Figure 02_image476
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.14 (s, 1H), 8.68 (s, 1H), 8.33 (s, 1H), 7.50 – 7.44 (m, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.09 – 7.00 (m, 2H), 6.88 (d, J = 8.9 Hz, 1H), 4.42 – 4.24 (m, 4H), 3.77 (s, 3H), 3.52 (d, J = 12.0 Hz , 2H), 3.07 (d, J = 7.1 Hz, 6H), 3.05 – 3.00 (m, 2H), 2.82 (d, J = 4.1 Hz, 3H), 2.66 – 2.58 (m, 1H), 1.97 – 1.74 ( m, 4H). MS (ESI) m/z : 633 [M+H] + . I-52
Figure 02_image478
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.81 (s, 2H), 8.39 (s, 1H), 8.31 (s, 1H), 7.58 – 7.48 (m, 1H), 7.35 (s, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 4.51 – 4.20 (m, 4H), 3.53 (d, J = 12.0 Hz, 2H), 3.10 (s, 3H), 3.08 (s, 3H), 3.07 – 3.01 (m, 2H), 2.82 (d, J = 4.3 Hz, 3H), 2.73 – 2.65 (m, 1H) , 2.00 – 1.90 (m, 2H), 1.89 – 1.76 (m, 2H). MS (ESI) m/z : 603 [M+H] + . I-53
Figure 02_image480
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.86 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.33 (s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.87 – 6.75 (m, 2H), 4.42 – 4.24 (m, 4H), 3.74 (s, 3H), 3.55 (t, J = 13.8 Hz, 2H ), 3.47 (d, J = 9.9 Hz, 2H), 3.18 – 3.13 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.90 – 2.79 (m, 5H). MS (ESI) m/z : 634 [M+H] + . I-54
Figure 02_image482
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.15 (s, 1H), 9.75 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.23 – 7.02 (m, 2H), 6.93 (d, J = 8.9 Hz, 1H), 6.74 – 6.66 (m, 1H), 4.44 – 4.25 (m, 4H), 3.70 (t, J = 11.9 Hz , 2H), 3.54 – 3.47 (m, 2H), 3.19 – 3.12 (m, 2H), 3.11 (s, 3H), 3.08 (s, 3H), 2.95 (t, J = 12.5 Hz, 2H), 2.87 ( s, 3H). MS (ESI) m/z : 604 [M+H] + . I-55
Figure 02_image484
 MS (ESI) m/z : 635 [M+H] + . I-56
Figure 02_image486
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.79 (s, 1H), 8.31 (s, 1H), 7.68 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.48 (s, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.13 – 7.03 (m, 1H), 6.94 (d, J = 9.0 Hz, 1H), 4.50 – 4.19 (m, 4H), 3.80 (s, 1H ), 3.52 (t, J = 6.2 Hz, 2H), 3.29 – 3.17 (m, 2H), 3.12 (s, 3H), 3.08 (s, 3H), 2.01 – 1.92 (m, 2H), 1.75 – 1.67 ( m, 2H). MS (ESI) m/z : 605 [M+H] + . I-57
Figure 02_image488
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.11 (s, 1H), 9.22 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 7.47 (s, 1H), 7.44 – 7.39 (m, 1H), 7.38 – 7.32 (m, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.41 – 4.26 (m, 4H), 3.56 – 3.48 (m, 2H), 3.26 – 3.17 (m, 2H), 3.08 – 3.04 (m, 2H), 3.03 (s, 3H), 2.97 (t, J = 12.2 Hz, 2H), 2.89 (s, 3H) ), 2.62 – 2.54 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 618 [M+H] + . I-58
Figure 02_image490
 MS (ESI) m/z : 646 [M+H] + . I-59
Figure 02_image492
 MS (ESI) m/z : 658 [M+H] + . I-60
Figure 02_image494
 MS (ESI) m/z : 646 [M+H] + . I-61
Figure 02_image496
 MS (ESI) m/z : 658 [M+H] + . I-62
Figure 02_image498
 MS (ESI) m/z : 660 [M+H] + . I-63
Figure 02_image500
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.20 (s, 1H), 9.26 (s, 1H), 8.91 (s, 1H), 8.76 (s, 1H), 8.33 (s, 1H), 7.50 ( s, 1H), 7.39 – 7.30 (m, 1H), 6.78 (s, 1H), 4.38 – 4.26 (m, 4H), 3.81 (s, 3H), 3.53 (d, J = 11.8 Hz, 2H), 3.22 (d, J = 13.2 Hz, 2H), 3.12 (d, J = 12.8 Hz, 2H), 3.09 – 3.00 (m, 5H), 2.90 (s, 3H), 2.54 – 2.46 (m, 2H), 1.01 ( t, J = 7.5 Hz, 3H). MS (ESI) m/z : 648 [M+H] + . I-64
Figure 02_image502
 MS (ESI) m/z : 676 [M+H] + . I-65
Figure 02_image504
 MS (ESI) m/z : 688 [M+H] + . I-66
Figure 02_image506
 MS (ESI) m/z : 676 [M+H] + . I-67
Figure 02_image508
 MS (ESI) m/z : 688 [M+H] + . I-68
Figure 02_image510
 MS (ESI) m/z : 690 [M+H] + . I-69
Figure 02_image512
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.28 (s, 1H), 9.17 (s, 1H), 8.86 (s, 1H), 8.36 (s, 1H), 7.43 (s, 1H), 7.37 – 7.27 (m, 1H), 6.83 – 6.73 (m, 2H), 4.40 – 4.25 (m, 4H), 3.80 (s, 3H), 3.72 – 3.31 (m, 9H), 3.11 (d, J = 11.2 Hz, 2H), 3.03 (s, 3H), 2.91 (s, 3H), 2.78 (t, J = 11.7 Hz, 2H), 2.55 – 2.45 (m, 2H), 2.21 – 2.12 (m, 2H), 1.83 (dt , J = 11.9, 6.0 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). MS (ESI) m/z : 731 [M+H] + . I-70
Figure 02_image514
 MS (ESI) m/z : 759 [M+H] + . I-71
Figure 02_image516
 MS (ESI) m/z : 771 [M+H] + . I-72
Figure 02_image518
 MS (ESI) m/z : 759 [M+H] + . I-73
Figure 02_image520
 MS (ESI) m/z : 771 [M+H] + . I-74
Figure 02_image522
 MS (ESI) m/z : 773 [M+H] + . I-75
Figure 02_image524
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.07 (s, 1H), 7.37 (s, 1H), 7.32 – 7.20 (m, 1H), 6.92 (d, J = 9.0 Hz, 1H), 6.70 ( s, 1H), 6.54 (d, J = 8.7 Hz, 1H), 4.45 – 4.28 (m, 4H), 3.86 (t, J = 4.8 Hz, 4H), 3.84 (s, 3H), 3.22 (t, J = 4.8 Hz, 4H), 3.20 (s, 3H), 3.03 (s, 3H). MS (ESI) m/z : 621 [M+H] + . I-76
Figure 02_image526
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.09 (s, 1H), 7.44 – 7.31 (m, 2H), 6.91 (d, J = 9.1 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 4.43 – 4.28 (m, 4H), 3.96 – 3.86 (m, 2H), 3.85 (s, 3H), 3.72 – 3.60 (m, 2H), 3.33 – 3.24 (m, 2H), 3.20 (s, 3H), 3.13 – 3.05 (m, 2H), 3.04 (s, 3H), 2.98 (s, 3H). MS (ESI) m/z : 634 [M+ H] + . I-77
Figure 02_image528
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.10 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 9.0 Hz, 1H), 4.45 – 4.27 (m, 4H), 3.86 – 3.74 (m, 2H), 3.68 – 3.57 (m, 2H), 3.30 – 3.23 (m , 2H), 3.17 (s, 3H), 3.13 – 3.00 (m, 5H), 2.97 (s, 3H). MS (ESI) m/z : 604 [M+H] + . I-78
Figure 02_image530
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.20 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.6 Hz, 1H), 4.48 – 4.24 (m, 4H), 4.07 – 3.99 (m, 1H), 3.94 (s, 3H), 3.78 (t, J = 10.2 Hz, 2H), 3.47 (t, J = 8.6 Hz, 2H), 3.19 (s, 3H), 3.03 (s, 3H), 2.30 – 2.10 (m , 2H), 2.05 – 1.84 (m, 2H). MS (ESI) m/z : 635 [M+H] + . I-79
Figure 02_image532
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.20 (s, 1H), 9.52 (s, 1H), 8.26 (s, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.6, 2.5 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.79 (dd, J = 17.2, 11.1 Hz, 1H), 5.86 (d, J = 17.2 Hz, 1H), 5.45 (d, J = 11.1 Hz, 1H), 4.46 – 4.22 (m, 4H), 3.53 – 3.47 (m, 2H ), 3.26 – 3.14 (m, 2H), 3.09 – 3.02 (m, 2H), 2.99 (s, 3H), 2.97 – 2.92 (m, 5H), 2.88 (s, 3H), 2.47 – 2.37 (m, 2H ), 1.02 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 580 [M+H] + . I-80
Figure 02_image534
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.51 (s, 1H), 9.57 (s, 1H), 8.17 (s, 1H), 7.32 – 7.20 (m, 1H), 7.09 – 7.06 (m, 1H ), 7.03 – 7.00 (m, 1H), 6.98 – 6.95 (m, 2H), 6.79 (dd, J = 17.2, 11.1 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.1 Hz, 1H), 4.43 – 4.24 (m, 4H), 3.77 – 3.69 (m, 4H), 2.98 (s, 3H), 2.95 (s, 3H), 2.77 (t, J = 4.5 Hz, 4H ), 2.63 – 2.53 (m, 1H), 2.48 – 2.37 (m, 1H), 1.07 – 0.99 (m, 3H). MS (ESI) m/z : 567 [M+H] + . I-81
Figure 02_image536
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.75 (s, 1H), 9.36 (s, 1H), 8.29 (s, 1H), 7.49 (d, J = 2.7 Hz, 1H), 7.36 – 7.28 ( m, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 17.3, 11.1 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 11.2 Hz, 1H), 4.42 – 4.26 (m, 4H), 3.47 (d, J = 5.4 Hz, 2H), 3.41 (s, 2H), 3.04 (s, 3H ), 2.99 (d, J = 2.6 Hz, 6H), 2.73 – 2.59 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 555 [M+H] + . I-82
Figure 02_image538
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.26 (s, 1H), 9.40 (s, 1H), 8.16 – 8.03 (m, 1H), 7.09 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.04 – 7.02 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.76 (dd, J = 17.2, 11.1 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H ), 5.82 (d, J = 17.3 Hz, 1H), 5.44 (d, J = 11.2 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.65 – 3.55 (m, 3H), 3.17 (s, 2H) , 2.99 (s, 6H), 2.47 – 2.33 (m, 2H), 1.13 – 0.98 (m, 3H). MS (ESI) m/z : 541 [M+H] + . I-83
Figure 02_image540
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.88 – 7.65 (m, 1H), 7.25 (s, 1H), 7.09 (s, 1H), 7.06 – 7.02 (m, 1H), 6.89 (s, 1H) ), 6.71 – 6.62 (m, 2H), 5.79 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 11.1 Hz, 1H), 4.45 – 4.25 (m, 4H), 3.60 (t, J = 6.1 Hz, 2H), 3.41 (t, J = 6.1 Hz, 2H), 3.18 – 3.11 (m, 3H), 3.01 (s, 3H), 2.96 (s, 6H), 2.57 – 2.42 (m, 2H), 1.21 – 1.11 (m, 3H). MS (ESI) m/z : 568 [M+H] + . I-84
Figure 02_image542
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.78 (s, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.11 – 7.04 (m, 3H), 6.81 (d, J = 8.9 Hz, 1H), 6.59 (dd, J = 17.3, 11.0 Hz, 1H), 5.73 (d, J = 17.3 Hz, 1H), 5.48 (d, J = 11.0 Hz, 1H), 4.32 – 4.20 (m, 4H), 3.23 – 3.19 (m, 7H), 3.04 (s, 3H), 2.91 (s, 3H), 2.82 (s, 6H), 2.57 – 2.54 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H) . MS (ESI) m/z : 582 [M+H] + . I-85
Figure 02_image544
 MS (ESI) m/z : 579 [M+H] + . I-86
Figure 02_image546
 MS (ESI) m/z : 592 [M+H] + . I-87
Figure 02_image548
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.14 (s, 1H), 9.25 (s, 1H), 8.19 (s, 1H), 7.15 (d, J = 8.9 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.76 (dd, J = 17.2, 11.2 Hz, 1H), 5.82 (d, J = 17.3 Hz, 1H), 5.42 (d, J = 11.1 Hz, 1H), 4.46 – 4.20 (m, 4H), 3.58 – 3.49 (m, 3H), 3.38 – 3.20 (m, 5H), 3.00 (s, 3H), 2.97 (s, 3H), 2.91 – 2.86 (m, 3H), 1.04 (d, J = 6.1 Hz, 1H), 0.94 – 0.88 (m, 2H), 0.45 (d, J = 25.3 Hz, 2H). MS (ESI) m/z : 592 [M+H] + . I-88
Figure 02_image550
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.41 (s, 1H), 9.43 (s, 1H), 8.14 (s, 1H), 7.09 – 7.06 (m, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.89 – 6.85 (m, 1H), 6.77 (dd, J = 17.3, 11.3 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H ), 5.83 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 11.1 Hz, 1H), 4.48 – 4.19 (m, 4H), 3.81 – 3.70 (m, 4H), 2.99 (s, 3H) , 2.98 – 2.93 (m, 3H), 2.93 – 2.86 (m, 4H), 1.06 – 1.02 (m, 1H), 0.93 – 0.85 (m, 2H), 0.55 – 0.35 (m, 2H). m/z : 579 [M+H] + . I-89
Figure 02_image552
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.86 (s, 1H), 7.34 – 7.29 (m, 1H), 7.20 (d, J = 8.9 Hz, 1H), 7.16 – 7.09 (m, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.69 (dd, J = 17.2, 11.0 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 11.1 Hz, 1H), 4.45 – 4.25 (m, 4H), 3.60 (d, J = 12.1 Hz, 2H), 3.34 (d, J = 11.7 Hz, 2H), 3.25 (d, J = 13.5 Hz, 2H), 3.12 (s, 3H), 3.09 – 3.02 (m, 2H), 3.00 (s, 3H), 2.99 (s, 3H), 2.23 (s, 3H). MS (ESI) m/ z : 566 [M+H] + . I-90
Figure 02_image554
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.54 (s, 1H), 9.59 (s, 1H), 8.19 (s, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.05 (dd, J = 8.6, 2.6 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.79 (dd, J = 17.2, 11.1 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 11.2 Hz, 1H), 4.42 – 4.23 (m, 4H), 3.78 – 3.64 (m, 4H ), 2.99 (s, 3H), 2.95 (s, 3H), 2.83 – 2.73 (m, 4H), 2.10 (s, 3H). MS (ESI) m/z : 553 [M+H] + . I-91
Figure 02_image556
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.87 (s, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.71 (s, 1H), 6.69 – 6.62 (m, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.43 – 4.28 (m, 4H), 4.03 – 3.98 (m , 1H), 3.85 (s, 3H), 3.54 – 3.44 (m, 1H), 3.44 – 3.36 (m, 2H), 3.22 – 3.04 (m, 4H), 3.00 (s, 3H), 2.97 (s, 6H ), 2.55 – 2.40 (m, 1H), 2.27 – 2.19 (m, 1H), 2.12 (s, 3H). MS (ESI) m/z : 610 [M+H] + . I-92
Figure 02_image558
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.88 (s, 1H), 7.45 – 7.25 (m, 1H), 7.16 (s, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.76 ( s, 1H), 6.68 (dd, J = 17.2, 11.0 Hz, 1H), 5.80 (d, J = 17.3 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.48 – 4.23 (m, 4H ), 3.84 (s, 3H), 3.37 – 3.32 (m, 1H), 3.28 – 3.22 (m, 2H), 3.12 (s, 3H), 3.00 (s, 3H), 2.93 (s, 6H), 2.84 – 2.73 (m, 2H), 2.26 – 2.15 (m, 2H), 2.10 (s, 3H), 1.97 – 1.87 (m, 2H). MS (ESI) m/z : 624 [M+H] + . I-93
Figure 02_image560
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.90 (s, 1H), 7.42 (s, 1H), 7.22 – 7.08 (m, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.78 ( s, 1H), 6.69 (dd, J = 17.2, 11.0 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.55 (d, J = 11.1 Hz, 1H), 4.45 – 4.26 (m, 4H ), 3.86 (s, 3H), 3.63 – 3.56 (m, 2H), 3.36 – 3.31 (m, 2H), 3.28 – 3.22 (m, 2H), 3.12 (s, 3H), 3.12 – 3.06 (m, 2H ), 3.00 (s, 3H), 2.99 (s, 3H), 2.11 (s, 3H). MS (ESI) m/z : 596 [M+H] + . I-94
Figure 02_image562
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.88 (s, 1H), 7.51 – 7.30 (m, 1H), 7.17 (d, J = 19.2 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 3.3 Hz, 1H), 6.68 (dd, J = 17.2, 10.9 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.43 – 4.28 (m, 4H), 4.04 – 3.96 (m, 1H), 3.86 (d, J = 1.8 Hz, 3H), 3.47 – 3.37 (m, 2H), 3.36 – 3.30 (m, 2H) , 3.20 – 3.11 (m, 3H), 3.00 (s, 3H), 2.96 (s, 6H), 2.60 – 2.39 (m, 3H), 2.28 – 2.17 (m, 1H), 1.04 (s, 3H). MS (ESI) m/z : 624 [M+H] + . I-95
Figure 02_image564
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.89 (s, 1H), 7.56 – 7.24 (m, 1H), 7.15 (s, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.81 ( s, 1H), 6.68 (dd, J = 17.2, 11.0 Hz, 1H), 5.81 (d, J = 17.2 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.43 – 4.27 (m, 4H ), 3.84 (s, 3H), 3.37 – 3.32 (m, 1H), 3.22 – 3.16 (m, 2H), 3.13 (s, 3H), 2.99 (s, 3H), 2.93 (s, 6H), 2.84 ( t, J = 11.7 Hz, 2H), 2.63 – 2.36 (m, 2H), 2.22 – 2.13 (m, 2H), 2.01 – 1.86 (m, 2H), 1.04 (s, 3H). MS (ESI) m/ z : 638 [M+H] + . I-96
Figure 02_image566
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.91 (s, 1H), 7.55 – 7.39 (m, 1H), 7.14 (s, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.84 ( s, 1H), 6.68 (dd, J = 17.3, 11.0 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 11.1 Hz, 1H), 4.42 – 4.30 (m, 4H ), 3.87 (s, 3H), 3.65 – 3.55 (m, 2H), 3.35 – 3.33 (m, 2H), 3.20 – 3.08 (m, 7H), 3.00 (s, 3H), 2.98 (s, 3H), 2.64 – 2.37 (m, 2H), 1.04 (s, 3H). MS (ESI) m/z : 610 [M+H] + . I-97
Figure 02_image568
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.53 (s, 1H), 8.18 (s, 4H), 7.39 – 7.17 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.91 ( d, J = 8.7 Hz, 1H), 6.77 (dd, J = 17.2, 11.1 Hz, 1H), 6.72 (s, 1H), 5.83 (d, J = 17.2 Hz, 1H), 5.46 (d, J = 11.1 Hz, 1H), 4.42 – 4.22 (m, 4H), 4.23 – 4.16 (m, 2H), 3.81 (s, 3H), 3.30 – 3.20 (m, 2H), 3.03 – 2.91 (m, 6H), 2.40 – 2.05 (m, 2H), 0.95 (s, 3H). MS (ESI) m/z : 571 [M+H] + . I-98
Figure 02_image570
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.01 (s, 2H), 9.42 (s, 1H), 8.23 (s, 1H), 7.04 (s, 1H), 6.89 (s, 2H), 6.75 ( dd, J = 17.2, 11.1 Hz, 1H), 6.31 (s, 1H), 5.80 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 11.1 Hz, 1H), 4.42 – 4.22 (m, 4H ), 3.78 (s, 3H), 3.52 (s, 2H), 3.32 – 3.25 (m, 2H), 2.99 (s, 3H), 2.87 (s, 9H), 2.34 (s, 2H), 1.25 – 0.69 ( m, 3H). MS (ESI) m/z : 598 [M+H] + . I-99
Figure 02_image572
 1 H NMR (600 MHz, Chloroform- d ) δ 9.72 – 9.57 (m, 1H), 9.52 (s, 1H), 8.28 – 8.15 (m, 1H), 7.41 – 7.34 (m, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.87 (s, 1H), 6.78 (dd, J = 17.2, 11.1 Hz, 1H), 5.83 (d, J = 17.2 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 4.42 – 4.19 (m, 4H), 3.80 (s, 3H), 3.25 – 3.18 (m, 4H), 2.98 (d, J = 6.3 Hz, 6H ), 2.80 (s, 9H), 2.61 – 2.56 (m, 2H), 0.91 (s, 3H). MS (ESI) m/z : 612 [M+H] + . I-100
Figure 02_image574
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.96 – 7.85 (m, 2H), 7.70 – 7.51 (m, 2H), 7.16 – 7.04 (m, 1H), 6.84 (s, 1H), 6.67 (dd , J = 17.2, 11.0 Hz, 1H), 6.60 – 6.37 (m, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 11.0 Hz, 1H), 4.39 – 4.18 (m, 4H), 3.97 (s, 3H), 3.91 (s, 3H), 3.90 – 3.78 (m, 1H), 3.60 – 3.50 (m, 2H), 3.28 – 3.21 (m, 2H), 3.17 – 3.03 (m, 4H), 3.03 – 2.89 (m, 8H). MS (ESI) m/z : 662 [M+H] + . I-101
Figure 02_image576
 MS (ESI) m/z : 648 [M+H] + . I-102
Figure 02_image578
 MS (ESI) m/z : 648 [M+H] + . I-103
Figure 02_image580
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.85 (s, 1H), 7.41 (s, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H) , 6.89 (d, J = 2.6 Hz, 1H), 6.72 – 6.62 (m, 2H), 5.81 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 11.1 Hz, 1H), 4.41 – 4.30 ( m, 4H), 3.92 – 3.83 (m, 5H), 3.63 – 3.33 (m, 8H), 3.26 – 3.20 (m, 1H), 3.14 (s, 3H), 3.12 – 3.05 (m, 2H), 3.00 ( s, 3H), 2.94 (s, 3H), 2.29 – 2.17 (m, 2H), 2.01 – 1.88 (m, 2H). MS (ESI) m/z : 665 [M+H] + . I-104
Figure 02_image582
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.88 (s, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.78 (s, 1H), 6.68 (dd, J = 17.2, 11.0 Hz, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.40 – 4.30 (m, 4H), 3.85 (s, 3H), 3.65 – 3.46 (m, 8H), 3.29 – 3.21 (m, 3H), 3.12 (s, 3H), 3.00 (s, 3H), 2.95 (s, 3H), 2.89 – 2.79 ( m, 2H), 2.26 – 2.17 (m, 2H), 2.10 (s, 3H), 1.99 – 1.90 (m, 2H). MS (ESI) m/z : 679 [M+H] + . I-105
Figure 02_image584
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.89 (s, 1H), 7.55 – 7.33 (m, 1H), 7.13 (s, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.83 ( s, 1H), 6.68 (dd, J = 17.2, 11.0 Hz, 1H), 5.81 (d, J = 17.2 Hz, 1H), 5.55 (d, J = 11.1 Hz, 1H), 4.44 – 4.28 (m, 4H ), 3.85 (s, 3H), 3.73 – 3.50 (m, 8H), 3.42 – 3.33 (m, 1H), 3.25 – 3.18 (m, 2H), 3.13 (s, 3H), 2.99 (d, J = 7.1 Hz, 6H), 2.92 – 2.82 (m, 2H), 2.61 – 2.40 (m, 2H), 2.29 – 2.16 (m, 2H), 2.04 – 1.90 (m, 2H), 1.04 (s, 3H). MS ( ESI) m/z : 693 [M+H] + . I-106
Figure 02_image586
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.87 – 9.56 (m, 1H), 9.45 (s, 1H), 8.27 – 7.97 (m, 1H), 7.26 (s, 1H), 6.97 (s, 1H) ), 6.85 (s, 1H), 6.80 – 6.70 (m, 2H), 5.82 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 4.43 – 4.08 (m, 4H) , 3.75 (s, 3H), 3.66 – 3.13 (m, 10H), 3.12 – 3.00 (m, 2H), 2.97 (s, 3H), 2.90 (s, 3H), 2.77 (q, J = 11.2 Hz, 2H ), 2.55 (s, 3H), 2.23 – 2.05 (m, 2H), 1.87 – 1.69 (m, 2H), 0.96 (d, J = 25.2 Hz, 6H). MS (ESI) m/z : 707 [M +H] + . I-107
Figure 02_image588
 MS (ESI) m/z : 705 [M+H] + . I-108
Figure 02_image590
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.51 (s, 1H), 9.46 (s, 1H), 8.20 (s, 1H), 7.69 – 7.44 (m, 1H), 7.34 – 7.26 (m, 1H ), 7.13 – 7.01 (m, 2H), 7.00 – 6.92 (m, 1H), 6.78 (dd, J = 17.2, 11.1 Hz, 1H), 5.84 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 11.1 Hz, 1H), 4.43 – 4.23 (m, 4H), 3.57 – 3.09 (m, 9H), 3.08 – 3.01 (m, 3H), 2.99 (s, 3H), 2.96 (s, 3H), 2.88 (s, 3H), 2.72 – 2.59 (m, 2H), 2.45 – 2.35 (m, 1H), 2.16 – 2.06 (m, 2H), 1.83 – 1.68 (m, 2H), 1.02 (t, J = 7.5 Hz , 3H). MS (ESI) m/z : 663 [M+H] + . I-109
Figure 02_image592
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.53 (s, 1H), 9.39 – 9.28 (m, 3H), 7.34 (s, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.91 ( d, J = 8.8 Hz, 1H), 6.82 – 6.72 (m, 2H), 5.82 (d, J = 17.3 Hz, 1H), 5.47 (d, J = 11.1 Hz, 1H), 4.47 – 4.22 (m, 4H ), 3.98 – 3.92 (m, 1H), 3.79 (s, 3H), 3.61 – 3.27 (m, 9H), 3.14 – 2.89 (m, 6H), 2.79 – 2.67 (m, 2H), 2.33 – 2.22 (m , 1H), 2.17 – 2.06 (m, 3H), 1.79 (dd, J = 11.7, 3.9 Hz, 2H), 1.24 (s, 1H), 1.01 – 0.90 (m, 3H). MS (ESI) m/z : 679 [M+H] + . I-110
Figure 02_image594
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.01 – 8.98 (m, 1H), 8.96 – 8.93 (m, 1H), 8.82 (s, 1H), 8.68 (s, 1H), 8.32 (s, 1H) ), 8.20 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 9.3 Hz, 1H), 7.24 (s, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.66 – 6.61 (m , 1H), 3.75 (s, 3H), 3.44 (d, J = 7.4 Hz, 2H), 3.38 (s, 3H), 3.25 – 3.21 (m, 3H), 3.16 (t, J = 7.2 Hz, 2H) , 2.80 (s, 6H), 2.66 (s, 3H). MS (ESI) m/z : 693 [M+H] + . I-111
Figure 02_image596
 MS (ESI) m/z : 665 [M+H] + . I-112
Figure 02_image598
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.51 (s, 1H), 9.07 – 8.86 (m, 3H), 8.16 (s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.90 ( d, J = 8.8 Hz, 1H), 6.81 – 6.74 (m, 2H), 5.82 (d, J = 17.3 Hz, 1H), 5.47 (d, J = 11.1 Hz, 1H), 4.51 – 4.20 (m, 4H ), 4.12 – 4.03 (m, 7H), 3.81 – 3.77 (m, 3H), 2.98 (s, 3H), 2.96 – 2.91 (m, 4H), 2.85 (s, 5H), 2.37 – 2.17 (m, 1H ), 1.24 (s, 1H), 0.94 (s, 3H). MS (ESI) m/z : 651 [M+H] + . I-113
Figure 02_image600
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.04 (s, 1H), 9.51 (s, 1H), 8.16 (s, 1H), 7.41 – 7.26 (m, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.81 – 6.72 (m, 2H), 5.81 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 4.44 – 4.21 (m, 4H), 3.78 (s, 3H), 3.73 – 3.64 (m, 2H), 2.98 (s, 3H), 2.75 (s, 3H), 2.73 – 2.66 (m, 9H), 2.22 ( t, J = 10.1 Hz, 2H), 1.97 (dd, J = 12.2, 8.5 Hz, 3H), 1.68 (dt, J = 15.8, 5.1 Hz, 5H), 0.94 (s, 3H). MS (ESI) m /z : 678 [M+H] + . I-114
Figure 02_image602
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.16 (s, 1H), 9.45 (s, 1H), 8.44 – 8.00 (m, 1H), 7.42 – 7.28 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.81 – 6.73 (m, 2H), 5.81 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 11.2 Hz, 1H ), 4.45 – 4.21 (m, 4H), 4.02 (dd, J = 10.4, 6.5 Hz, 3H), 3.84 – 3.79 (m, 2H), 3.78 (s, 3H), 2.98 (s, 3H), 2.90 – 2.84 (m, 6H), 2.77 (s, 2H), 2.66 (s, 2H), 2.03 – 1.80 (m, 5H), 0.94 (s, 3H). MS (ESI) m/z : 650 [M+H ] + . I-115
Figure 02_image604
 MS (ESI) m/z : 622 [M+H] + . I-116
Figure 02_image606
 MS (ESI) m/z : 609 [M+H] + . I-117
Figure 02_image608
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.82 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.52 – 7.44 (m, 1H), 7.16 (s, 1H), 6.77 – 6.69 (m, 2H), 6.66 (dd, J = 17.6, 11.4 Hz, 1H), 5.66 (d, J = 17.5 Hz, 1H), 5.26 (d, J = 11.2 Hz, 1H), 4.44 – 4.20 (m, 4H), 3.38 (s, 6H), 3.06 (s, 3H), 3.05 (s, 3H), 2.68 (t, J = 11.7 Hz, 2H), 2.39 – 2.26 (m, 5H), 2.17 ( s, 3H), 1.86 (d, J = 12.2 Hz, 2H), 1.63 – 1.52 (m, 2H). MS (ESI) m/z : 671 [M+H] + . I-118
Figure 02_image610
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.35 (s, 1H), 8.99 (s, 1H), 8.30 (s, 1H), 7.17 – 7.11 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 17.3, 11.1 Hz, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.37 (d, J = 11.3 Hz, 1H), 4.43 – 4.22 (m, 4H), 3.84 – 3.22 (m, 9H), 3.21 – 3.13 (m, 2H), 3.03 (d, J = 12.4 Hz, 2H), 3.00 (s, 3H) , 2.98 (s, 3H), 2.87 (s, 3H), 2.13 – 2.00 (m, 2H), 1.75 – 1.64 (m, 2H). MS (ESI) m/z : 671 [M+H] + . I-119
Figure 02_image612
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.73 – 9.52 (m, 2H), 8.29 (s, 1H), 7.54 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 6.93 ( d, J = 8.3 Hz, 1H), 6.90 – 6.84 (m, 1H), 6.80 (dd, J = 17.2, 11.2 Hz, 1H), 5.85 (d, J = 17.2 Hz, 1H), 5.49 (d, J = 11.1 Hz, 1H), 4.74 – 4.60 (m, 1H), 4.30 – 4.25 (m, 4H), 3.88 – 3.75 (m, 3H), 3.62 – 3.23 (m, 9H), 3.03 (s, 1H), 3.01 – 2.94 (m, 4H), 2.87 (s, 3H), 2.77 (t, J = 12.0 Hz, 1H), 2.55 (d, J = 1.1 Hz, 3H), 2.46 – 1.84 (m, 4H), 1.75 – 1.20 (m, 2H), 0.94 – 0.83 (m, 3H). MS (ESI) m/z : 721 [M+H] + . I-120
Figure 02_image614
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.94 – 7.91 (m, 1H), 7.22 (t, J = 7.3 Hz, 3H), 7.14 (t, J = 7.2 Hz, 2H), 7.07 (s, 3H), 6.90 – 6.85 (m, 1H), 6.70 (dd, J = 17.2, 11.0 Hz, 1H), 5.83 (d, J = 17.2 Hz, 1H), 5.58 (d, J = 11.0 Hz, 1H), 4.32 – 4.14 (m, 4H), 4.12 – 4.09 (m, 1H), 3.89 (s, 3H), 3.53 – 3.36 (m, 7H), 3.16 (s, 3H), 2.99 (s, 3H), 2.89 ( s, 4H), 2.79 – 2.72 (m, 2H), 2.02 (d, J = 11.8 Hz, 3H), 1.78 – 1.71 (m, 3H), 1.31 (s, 2H). MS (ESI) m/z : 755 [M+H] + . I-121
Figure 02_image616
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.60 (s, 0H), 9.48 (s, 1H), 8.16 – 8.13 (m, 1H), 7.42 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 6.78 (s, 1H), 6.76 (dd, J = 17.2, 11.1 Hz, 1H), 5.82 (d, J = 17.3 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 4.46 – 4.21 (m, 4H), 3.78 (s, 3H), 3.26 (d, J = 14.4 Hz, 13H), 3.09 – 3.02 (m, 2H), 2.98 (s, 3H), 2.88 (s, 3H), 2.79 – 2.68 (m, 2H), 2.45 – 2.38 (m, 1H), 2.14 – 2.09 (m, 3H), 1.77 – 1.71 (m, 1H), 0.74 (s, 1H), 0.37 (d, J = 7.4 Hz, 2H), 0.05 (s, 2H). MS (ESI) m/z : 719 [M+H] + . I-122
Figure 02_image618
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.12 (s, 1H), 9.48 (s, 1H), 8.08 (s, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.97 (s, 1H), 6.93 – 6.89 (m, 1H), 6.75 (dd, J = 17.3, 11.1 Hz, 1H), 5.84 (d, J = 17.3 Hz, 1H), 5.48 (d, J = 11.2 Hz, 1H), 4.45 – 4.20 (m, 4H), 3.92 (d, J = 12.7 Hz, 2H), 3.77 – 3.21 (m, 9H), 2.99 (s, 3H), 2.97 (s, 2H), 2.88 (s, 3H), 2.77 (t, J = 12.4 Hz, 2H), 2.15 – 2.10 (m, 3H), 1.69 – 1.60 (m, 2H). MS (ESI) m/z : 719 [M+H] + . I-123
Figure 02_image620
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.10 (s, 1H), 9.53 (s, 1H), 8.19 (s, 1H), 7.46 (s, 1H), 7.03 (s, 1H), 6.94 ( d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 17.2, 11.1 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.48 ( d, J = 11.1 Hz, 1H), 4.40 – 4.19 (m, 4H), 4.09 – 3.39 (m, 8H), 3.34 (s, 1H), 3.12 – 3.05 (m, 2H), 2.97 (s, 3H) , 2.93 (s, 3H), 2.89 (s, 3H), 2.76 – 2.64 (m, 2H), 2.60 – 2.53 (m, 1H), 2.37 (s, 1H), 2.14 (d, J = 11.6 Hz, 2H ), 1.86 – 1.73 (m, 2H), 1.00 (d, J = 7.6 Hz, 3H). MS (ESI) m/z : 747 [M+H] + . I-124
Figure 02_image622
 1 H NMR (600 MHz, CDCl 3 ) δ 9.38 (s, 1H), 8.16 (s, 1H), 7.69 (s, 1H), 6.99 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H) , 6.83 – 6.68 (m, 3H), 5.83 (d, J = 17.3 Hz, 1H), 5.56 – 5.48 (m, 1H), 5.46 (d, J = 11.2 Hz, 1H), 5.28 (d, J = 11.1 Hz, 1H), 4.44 – 4.13 (m, 4H), 3.86 – 3.34 (m, 9H), 3.22 – 3.17 (m, 3H), 2.96 (s, 3H), 2.95 – 2.89 (m, 2H), 2.86 ( s, 3H), 2.69 (t, J = 11.9 Hz, 2H), 2.14 – 2.04 (m, 2H), 1.85 – 1.73 (m, 2H). MS (ESI) m/z : 745 [M+H] + . I-125
Figure 02_image624
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.95 – 9.60 (m, 1H), 9.53 (s, 1H), 8.42 – 8.06 (m, 1H), 7.38 (s, 1H), 7.04 – 6.94 (m , 1H), 6.89 (s, 1H), 6.77 (dd, J = 17.2, 11.1 Hz, 1H), 5.83 (d, J = 17.2 Hz, 1H), 5.46 (d, J = 11.0 Hz, 1H), 4.44 – 4.18 (m, 4H), 3.86 (s, 3H), 3.60 (s, 9H), 3.33 (s, 2H), 2.98 (s, 3H), 2.92 – 2.77 (m, 6H), 2.71 (s, 2H ), 2.01 – 1.96 (m, 2H), 1.94 (s, 3H), 1.66 – 1.46 (m, 2H). MS (ESI) m/z : 680 [M+H] + . I-126
Figure 02_image626
 1 H NMR (600 MHz, Chloroform- d ) δ 9.70 (s, 1H), 9.56 (s, 1H), 8.36 – 8.11 (m, 1H), 7.61 (s, 1H), 7.01 – 6.92 (m, 1H) , 6.92 – 6.85 (m, 1H), 6.77 (dd, J = 17.3, 11.1 Hz, 1H), 5.83 (d, J = 17.2 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 4.50 – 4.16 (m, 4H), 3.83 (s, 3H), 3.74 – 3.07 (m, 11H), 3.02 – 2.91 (m, 6H), 2.88 (s, 3H), 2.81 (q, J = 12.8 Hz, 2H) , 2.44 – 2.19 (m, 2H), 2.11 (d, J = 11.5 Hz, 2H), 1.83 – 1.71 (m, 2H), 0.96 (s, 3H). MS (ESI) m/z : 694 [M+ H] + . I-127
Figure 02_image628
 1 H NMR (600 MHz, Chloroform- d ) δ 9.75 – 9.63 (m, 1H), 9.42 (s, 1H), 8.32 – 8.04 (m, 1H), 7.44 (s, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.92 (s, 1H), 6.73 (dd, J =17.2, 11.1 Hz, 1H), 6.57 – 6.09 (m, 1H), 5.81 (d, J =17.4 Hz, 1H), 5.46 ( d, J = 11.2 Hz, 1H), 4.46 – 4.24 (m, 8H), 3.80 (s, 3H), 3.65 – 3.16 (m, 9H), 2.99 (s, 3H), 2.87 – 2.79 (m, 6H) , 2.11 – 2.03 (m, 2H), 1.58 – 1.46 (m, 2H). MS (ESI) m/z : 666 [M+H] + . I-128
Figure 02_image630
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.80 – 10.38 (m, 1H), 10.02 (s, 1H), 9.35 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.64 – 7.57 (m, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.76 (dd, J = 17.3, 11.1 Hz, 1H), 5.84 (d , J = 17.3 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 4.44 – 4.22 (m, 6H), 3.44 (td, J = 12.1, 6.0 Hz, 1H), 3.04 – 2.95 (m, 6H), 2.89 (t, J = 12.9 Hz, 2H), 2.78 (d, J = 4.4 Hz, 6H), 2.09 (d, J = 11.9 Hz, 2H), 1.58 (td, J = 12.5, 8.8 Hz, 2H). MS (ESI) m/z : 581 [M+H] + . I-129
Figure 02_image632
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.05 (s, 1H), 9.76 (s, 1H), 9.45 (s, 1H), 8.18 (s, 1H), 7.30 (s, 1H), 7.05 ( s, 1H), 7.03 (d, J = 9.1 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 17.2, 11.1 Hz, 1H), 5.83 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 4.39 – 4.20 (m, 4H), 3.75 (s, 3H), 3.51 (t, J = 11.3 Hz, 2H), 3.10 – 2.97 (m , 2H), 2.97 (s, 3H), 2.94 – 2.88 (m, 3H), 2.88 – 2.85 (m, 1H), 2.83 (d, J = 3.2 Hz, 3H), 1.87 – 1.65 (m, 4H). MS (ESI) m/z : 581 [M+H] + . I-130
Figure 02_image634
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.84 (s, 1H), 9.51 (s, 1H), 8.28 (s, 1H), 7.33 – 7.27 (m, 1H), 7.16 (s, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.79 ( dd, J = 17.2, 11.1 Hz, 1H), 5.86 (d, J = 17.3 Hz, 1H), 5.45 (d, J = 11.1 Hz, 1H), 4.41 – 4.24 (m, 4H), 3.55 – 3.49 (m , 2H), 3.09 – 3.00 (m, 2H), 2.98 (s, 3H), 2.91 (s, 3H), 2.82 (d, J = 4.0 Hz, 3H), 2.63 (tt, J = 12.3, 3.8 Hz, 1H), 1.94 – 1.72 (m, 4H). MS (ESI) m/z : 551 [M+H] + . I-131
Figure 02_image636
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.83 (s, 1H), 9.46 (s, 1H), 8.11 (s, 1H), 7.07 (d, J = 2.9 Hz, 1H), 7.02 (d, J = 3.5 Hz, 1H), 7.01 (d, J = 3.7 Hz, 1H), 6.95 – 6.85 (m, 2H), 6.75 (dd, J = 17.2, 11.1 Hz, 1H), 5.83 (d, J = 17.3 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 4.41 – 4.23 (m, 4H), 3.73 (s, 3H), 3.49 (d, J = 13.2 Hz, 4H), 3.14 – 3.01 (m , 3H), 2.97 (s, 3H), 2.95 (d, J = 6.3 Hz, 2H), 2.88 (s, 2H), 2.86 (s, 3H). MS (ESI) m/z : 582 [M+H ] + . I-132
Figure 02_image638
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.72 (s, 1H), 9.51 (s, 1H), 8.24 (s, 1H), 7.09 – 7.05 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 6.93 – 6.88 (m, 2H), 6.82 – 6.76 (m, 2H), 5.86 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 4.41 – 4.24 (m, 4H), 3.64 (s, 2H), 3.50 (s, 2H), 3.16 – 3.06 (m, 2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.92 – 2.88 (m, 2H ), 2.86 (s, 3H). MS (ESI) m/z : 552 [M+H] + . I-133
Figure 02_image640
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.99 (s, 1H), 7.84 (d, J = 2.9 Hz, 1H), 7.43 (dd, J = 9.0, 2.9 Hz, 1H), 7.24 (d, J = 9.1 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.69 (dd, J = 17.2, 11.0 Hz, 1H), 5.84 (d, J = 17.2 Hz, 1H), 5.58 (d, J = 11.1 Hz, 1H), 4.44 – 4.27 (m, 4H), 3.99 – 3.95 (m, 1H), 3.93 (s, 3H), 3.54 – 3.46 (m , 2H), 3.29 – 3.24 (m, 1H), 3.20 – 3.16 (m, 1H), 3.12 (s, 3H), 3.01 (s, 3H), 2.20 – 2.10 (m, 2H), 2.02 – 1.86 (m , 2H). MS (ESI) m/z : 583 [M+H] + . I-134
Figure 02_image642
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.64 (s, 1H), 9.46 (s, 1H), 8.23 (s, 1H), 7.18 (s, 1H), 7.14 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 7.04 – 6.98 (m, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.78 (dd, J = 17.2, 11.1 Hz, 1H ), 5.85 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 4.41 – 4.24 (m, 5H), 3.74 – 3.67 (m, 1H), 3.46 – 3.38 (m, 2H), 2.98 (s, 3H), 2.97 – 2.86 (m, 5H), 1.91 – 1.84 (m, 2H), 1.61 – 1.51 (m, 2H). MS (ESI) m/z : 553 [M+H ] + . I-135
Figure 02_image644
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.18 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H), 8.27 (s, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.16 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H) , 6.73 (dd, J = 17.3, 11.1 Hz, 1H), 5.85 (d, J = 17.2 Hz, 1H), 5.44 (d, J = 11.0 Hz, 1H), 4.39 – 4.27 (m, 4H), 3.54 – 3.47 (m, 2H), 3.22 (d, J = 12.9 Hz, 2H), 3.08 – 3.03 (m, 2H), 3.02 – 2.92 (m, 5H), 2.89 (s, 3H), 2.57 – 2.51 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H). MS (ESI) m/z : 566 [M+H] + . I-136
Figure 02_image646
 MS (ESI) m/z : 594 [M+H] + . I-137
Figure 02_image648
 MS (ESI) m/z : 606 [M+H] + . I-138
Figure 02_image650
 MS (ESI) m/z : 594 [M+H] + . I-139
Figure 02_image652
 MS (ESI) m/z : 606 [M+H] + . I-140
Figure 02_image654
 MS (ESI) m/z : 608 [M+H] + . I-141
Figure 02_image656
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.56 (s, 1H), 9.27 (s, 1H), 9.11 – 9.05 (m, 1H), 8.23 (s, 1H), 7.47 (s, 1H), 7.14 (s, 1H), 6.87 – 6.76 (m, 2H), 6.71 (dd, J = 17.2, 11.1 Hz, 1H), 5.84 (d, J = 17.2 Hz, 1H), 5.48 (d, J = 11.0 Hz , 1H), 4.40 – 4.24 (m, 4H), 3.83 (d, J = 5.6 Hz, 3H), 3.58 – 3.47 (m, 2H), 3.23 (d, J = 11.4 Hz, 2H), 3.14 – 3.02 ( m, 4H), 3.00 (s, 3H), 2.90 (d, J = 5.6 Hz, 3H), 2.44 (q, J = 7.4 Hz, 2H), 1.03 – 0.87 (m, 3H). MS (ESI) m /z : 596 [M+H] + . I-142
Figure 02_image658
 MS (ESI) m/z : 624 [M+H] + . I-143
Figure 02_image660
 MS (ESI) m/z : 636 [M+H] + . I-144
Figure 02_image662
 MS (ESI) m/z : 624 [M+H] + . I-145
Figure 02_image664
 MS (ESI) m/z : 636 [M+H] + . I-146
Figure 02_image666
 MS (ESI) m/z : 638 [M+H] + . I-147
Figure 02_image668
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.60 (s, 1H), 9.29 (s, 1H), 9.08 (s, 1H), 8.21 (s, 1H), 7.40 (s, 1H), 7.14 ( s, 1H), 6.85 – 6.74 (m, 2H), 6.71 (dd, J = 17.2, 11.1 Hz, 1H), 5.84 (d, J = 17.2 Hz, 1H), 5.49 (d, J = 11.1 Hz, 1H ), 4.37 – 4.25 (m, 4H), 3.81 (s, 3H), 3.72 – 3.20 (m, 9H), 3.08 (d, J = 11.6 Hz, 2H), 3.00 (s, 3H), 2.87 (s, 3H), 2.74 (t, J = 11.7 Hz, 2H), 2.46 – 2.36 (m, 2H), 2.12 (d, J = 11.5 Hz, 2H), 1.78 (dq, J = 16.7, 5.9, 3.5 Hz, 2H ), 1.01 – 0.89 (m, 3H). MS (ESI) m/z : 679 [M+H] + . I-148
Figure 02_image670
 MS (ESI) m/z : 707 [M+H] + . I-149
Figure 02_image672
 MS (ESI) m/z : 719 [M+H] + . I-150
Figure 02_image674
 MS (ESI) m/z : 707 [M+H] + . I-151
Figure 02_image676
 MS (ESI) m/z : 719 [M+H] + . I-152
Figure 02_image678
 MS (ESI) m/z : 721 [M+H] + . I-153
Figure 02_image680
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.84 (s, 1H), 7.28 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 9.0 Hz, 1H), 7.03 – 6.95 (m, 2H), 6.93 (d, J = 8.9 Hz, 1H), 6.67 (dd, J = 17.3, 11.0 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 11.0 Hz, 1H), 4.44 – 4.26 (m, 4H), 3.91 – 3.76 (m, 2H), 3.71 – 3.57 (m, 2H), 3.30 – 3.25 (m, 2H), 3.15 – 3.03 (m, 5H), 3.00 ( s, 3H), 2.97 (s, 3H). MS (ESI) m/z : 552 [M+H] + . I-154
Figure 02_image682
 MS (ESI) m/z : 583 [M+H] + . I-155
Figure 02_image684
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.79 (s, 1H), 7.38 – 7.09 (m, 2H), 6.93 (d, J = 8.9 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 17.2, 11.0 Hz, 1H), 6.51 (s, 1H), 5.79 (d, J = 17.3 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.42 – 4.28 (m, 4H), 3.88 – 3.82 (m, 7H), 3.24 – 3.19 (m, 4H), 3.14 (s, 3H), 3.00 (s, 3H). MS (ESI) m/z : 569 [M +H] + . I-156
Figure 02_image686
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.81 (s, 1H), 7.37 – 7.16 (m, 2H), 6.92 (d, J = 8.9 Hz, 1H), 6.76 – 6.70 (m, 1H), 6.67 (dd, J = 17.3, 11.1 Hz, 1H), 6.51 (s, 1H), 5.80 (d, J = 17.3 Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.41 – 4.28 (m , 4H), 3.95 – 3.85 (m, 2H), 3.85 (s, 3H), 3.68 – 3.60 (m, 2H), 3.30 – 3.22 (m, 2H), 3.20 – 3.06 (m, 5H), 3.00 (s , 3H), 2.98 (s, 3H).MS (ESI) m/z : 582 [M+H] + . I-157
Figure 02_image688
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.82 (s, 1H), 8.99 (s, 1H), 8.01 (s, 1H), 7.38 – 7.34 (m, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.22 – 7.16 (m, 1H), 7.07 – 7.01 (m, 1H), 6.91 (d, J = 8.9 Hz, 1H), 5.49 (s, 1H), 5.36 (s, 1H), 4.48 – 4.20 (m, 4H), 3.52 (d, J = 11.7 Hz, 2H), 3.24 (q, J = 11.8, 9.0 Hz, 2H), 3.12 – 3.06 (m, 2H), 3.05 (s, 3H), 3.04 (s, 3H), 3.03 – 2.95 (m, 2H), 2.90 (s, 3H), 2.63 – 2.51 (m, 2H), 2.09 (s, 3H), 1.06 (t, J = 7.5 Hz, 3H) . MS (ESI) m/z : 594 [M+H] + . I-158
Figure 02_image690
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.20 (s, 1H), 9.83 – 9.66 (m, 1H), 8.99 (s, 1H), 8.08 – 7.84 (m, 1H), 7.46 – 7.32 (m , 1H), 7.30 – 7.15 (m, 1H), 6.80 (s, 1H), 5.48 (s, 1H), 5.35 (s, 1H), 4.43 – 4.22 (m, 4H), 3.81 (s, 3H), 3.53 (d, J = 11.7 Hz, 2H), 3.24 (t, J = 11.6 Hz, 2H), 3.14 (d, J = 12.7 Hz, 2H), 3.07 (s, 3H), 3.03 (s, 3H), 3.02 – 2.97 (m, 2H), 2.90 (s, 3H), 2.44 (s, 2H), 2.08 (s, 3H), 1.00 (s, 3H). MS (ESI) m/z : 624 [M+H ] + . I-159
Figure 02_image692
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.92 – 9.66 (m, 1H), 8.99 (s, 1H), 8.09 – 7.79 (m, 1H), 7.31 (d, J = 25.4 Hz, 1H), 7.21 (s, 1H), 6.80 (s, 1H), 5.49 (s, 1H), 5.35 (s, 1H), 4.44 – 4.20 (m, 4H), 3.79 (s, 3H), 3.40 (s, 9H) , 3.12 (d, J = 11.2 Hz, 2H), 3.09 – 3.03 (m, 3H), 3.03 (s, 3H), 2.91 (s, 3H), 2.77 (t, J = 11.8 Hz, 2H), 2.47 – 2.35 (m, 2H), 2.22 – 2.12 (m, 2H), 2.08 (s, 3H), 1.81 (dt, J = 12.3, 6.2 Hz, 2H), 1.01 (s, 3H). MS (ESI) m/ z : 707 [M+H] + . I-160
Figure 02_image694
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.12 (s, 1H), 9.92 – 9.78 (m, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.48 – 7.40 (m, 1H ), 7.33 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.96 – 6.91 (m, 1H), 4.44 – 4.24 (m, 4H), 3.50 (d, J = 11.7 Hz, 2H), 3.25 – 3.16 (m, 2H), 3.09 (s, 3H), 3.07 (s, 3H), 3.04 (s, 2H), 2.98 (qd, J = 11.8, 9.8, 5.1 Hz, 2H ), 2.89 (s, 3H), 2.59 – 2.53 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 588 [M+H] + . I-161
Figure 02_image696
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.01 – 9.89 (m, 1H), 8.80 (s, 1H), 8.26 (s, 1H), 7.41 – 7.35 (m, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.96 – 6.90 (m, 1H), 4.43 – 4.23 (m, 4H), 3.74 (t, J = 4.4 Hz, 4H), 3.08 (s, 3H), 3.06 (s, 3H), 2.80 (t, J = 4.6 Hz, 4H), 2.63 – 2.52 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). m/z : 575 [M+H] + . I-162
Figure 02_image698
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.81 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.69 – 7.64 (m, 1H), 7.64 – 7.56 (m, 2H ), 7.49 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 4.45 – 4.24 (m, 4H), 3.61 (d, J = 5.5 Hz, 2H), 3.42 (s , 2H), 3.18 (s, 1H), 3.15 (s, 3H), 3.12 (s, 3H), 3.08 (s, 3H), 2.73 – 2.64 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 563 [M+H] + . I-163
Figure 02_image700
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.86 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 7.46 (s, 1H), 7.45 – 7.35 (m, 2H), 7.03 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 4.45 – 4.25 (m, 4H), 3.65 (t, J = 5.4 Hz, 2H), 3.25 (t, J = 5.4 Hz, 2H), 3.18 (s, 1H), 3.09 (s, 3H), 3.07 (s, 3H), 2.58 – 2.51 (m, 2H), 1.09 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 549 [M+H] + . I-164
Figure 02_image702
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.17 – 9.87 (m, 2H), 8.83 (s, 1H), 8.25 (d, J = 6.7 Hz, 1H), 7.42 (s, 1H), 7.20 – 7.09 (m, 2H), 6.91 (d, J = 8.9 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 4.45 – 4.23 (m, 4H), 3.45 (t, J = 6.3 Hz, 2H ), 3.30 (t, J = 6.3 Hz, 2H), 3.09 (s, 3H), 3.06 (s, 3H), 2.86 (s, 6H), 2.47 – 2.34 (m, 2H), 1.06 (t, J = 7.7 Hz, 3H). MS (ESI) m/z : 576 [M+H] + . I-165
Figure 02_image704
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.95 – 9.79 (m, 1H), 9.73 – 9.60 (m, 1H), 8.63 (s, 1H), 8.26 (s, 1H), 7.48 – 7.37 (m , 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H), 4.46 – 4.22 (m, 4H), 3.23 – 3.19 (m, 2H), 3.19 – 3.15 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.80 (s, 6H), 2.61 – 2.55 (m, 5H), 1.05 (t , J = 7.5 Hz, 3H). MS (ESI) m/z : 590 [M+H] + . I-166
Figure 02_image706
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.05 (s, 1H), 8.11 – 8.07 (m, 1H), 8.05 (s, 1H), 7.64 – 7.53 (m, 1H), 7.29 – 7.21 (m , 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 4.71 (s, 4H), 4.43 – 4.21 (m, 4H), 3.92 (s, 4H) , 3.10 (s, 3H), 3.08 (s, 3H), 2.44 – 2.35 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 587 [M+H] + . I-167
Figure 02_image708
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.94 (s, 1H), 7.61 – 7.51 (m, 1H), 7.20 – 7.13 (m, 2H), 6.85 (d, J = 9.0 Hz, 1H), 6.44 (d, J = 8.5 Hz, 1H), 4.46 – 4.20 (m, 4H), 3.88 (s, 4H), 3.44 (s, 3H), 3.17 (s, 3H), 3.03 (s, 3H), 2.48 (q, J = 7.5 Hz, 2H), 2.34 (s, 4H), 1.12 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 600 [M+H] + . I-168
Figure 02_image710
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.94 (s, 1H), 8.41 – 8.34 (m, 1H), 8.23 – 8.17 (m, 1H), 7.59 – 7.46 (m, 1H), 7.39 (d , J = 8.8 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.94 – 6.90 (m, 2H), 4.45 – 4.20 (m, 4H), 3.53 (d, J = 11.0 Hz, 2H) , 3.32 – 3.12 (m, 4H), 3.10 (d, J = 6.4 Hz, 3H), 3.07 (s, 3H), 2.95 (dt, J = 23.4, 12.3 Hz, 2H), 2.88 (d, J = 3.6 Hz, 3H), 1.87 (d, J = 6.5 Hz, 1H), 0.98 – 0.86 (m, 2H), 0.58 – 0.44 (m, 2H). MS (ESI) m/z : 600 [M+H] + . I-169
Figure 02_image712
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.68 (s, 1H), 8.64 (s, 1H), 8.22 (s, 1H), 7.52 – 7.39 (m, 1H), 7.31 (d, J = 8.5 Hz, 1H), 6.95 – 6.90 (m, 2H), 6.85 (s, 1H), 4.43 – 4.23 (m, 4H), 3.80 – 3.72 (m, 4H), 3.09 (s, 3H), 3.07 (s, 4H), 2.92 (d, J = 4.4 Hz, 3H), 2.27 – 2.19 (m, 1H), 0.92 (d, J = 8.5 Hz, 2H), 0.61 – 0.35 (m, 2H) . /z : 587 [M+H] + . I-170
Figure 02_image714
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.16 (s, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 7.50 – 7.36 (m, 2H), 7.26 (d, J = 8.6 Hz, 1H), 6.95 (t, J = 8.4 Hz, 2H), 4.45 – 4.23 (m, 4H), 3.52 (d, J = 11.7 Hz, 2H), 3.22 (d, J = 12.1 Hz, 2H), 3.17 – 3.10 (m, 2H), 3.09 (s, 3H), 3.07 (s, 3H), 2.95 (t, J = 13.0 Hz, 2H), 2.89 (s, 3H), 2.17 (s, 3H). MS (ESI) m/z : 574 [M+H] + . I-171
Figure 02_image716
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.99 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 7.42 – 7.32 (m, 2H), 7.26 – 7.18 (m, 1H ), 6.96 (t, J = 9.3 Hz, 2H), 4.44 – 4.24 (m, 4H), 3.75 (t, J = 4.3 Hz, 4H), 3.07 (s, 3H), 3.06 (s, 3H), 2.87 – 2.79 (m, 4H), 2.17 (s, 3H). MS (ESI) m/z : 561 [M+H] + . I-172
Figure 02_image718
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.09 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.78 (s, 1H), 7.69 – 7.61 (m, 1H), 7.42 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.56 (s, 1H), 4.43 – 4.21 (m , 4H), 3.92 (s, 3H), 3.48 (t, J = 11.0 Hz, 2H), 3.28 (d, J = 13.8 Hz, 2H), 3.19 – 3.09 (m, 5H), 3.07 (s, 3H) , 2.96 – 2.82 (m, 5H). MS (ESI) m/z : 640 [M+H] + . I-173
Figure 02_image720
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.94 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 7.63 – 7.56 (m, 1H), 7.39 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.65 – 6.51 (m, 1H), 4.41 – 4.21 (m, 4H), 3.90 (s, 3H), 3.75 – 3.69 (m, 4H), 3.10 (s, 3H), 3.06 (s, 3H), 2.79 – 2.72 (m, 4H) . /z : 627 [M+H] + . I-174
Figure 02_image722
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.09 (s, 1H), 7.39 (s, 1H), 7.22 (s, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.84 (s, 1H), 4.47 – 4.19 (m, 4H), 3.84 (s, 3H), 3.78 – 3.47 (m, 8H), 3.47 – 3.35 (m, 1H), 3.26 – 3.20 (m, 2H), 3.17 (s, 3H), 3.02 (s, 3H), 3.00 (s, 3H), 2.90 (t, J = 11.7 Hz, 2H), 2.63 – 2.40 (m, 2H), 2.35 – 2.17 (m, 2H), 2.07 – 1.86 (m, 2H), 1.05 (s, 3H). MS (ESI) m/z : 701 [M+H] + . I-175
Figure 02_image724
 MS (ESI) m/z : 713 [M+H] + . I-176
Figure 02_image726
 MS (ESI) m/z : 671 [M+H] + . I-177
Figure 02_image728
 MS (ESI) m/z : 630 [M+H] + . I-178
Figure 02_image730
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.02 (d, J = 19.6 Hz, 2H), 7.88 (s, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.74 (d, J = 9.0 Hz, 1H), 6.12 (s, 1H), 4.73 (s, 4H), 4.42 – 4.19 (m, 4H), 4.00 (s, 4H), 3.74 (s, 3H), 3.10 (s, 3H ), 3.07 (s, 3H), 2.35 (t, J = 7.5 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). MS (ESI) m/z : 617 [M+H] + . I-179
Figure 02_image732
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.08 (s, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.79 (s, 1H), 4.46 – 4.23 (m, 4H), 3.84 (s, 3H), 3.67 (s, 8H), 3.44 – 3.35 (m, 1H), 3.34 – 3.31 (m, 2H), 3.16 (s, 3H) , 3.02 (s, 3H), 2.99 (s, 3H), 2.88 (q, J = 12.0 Hz, 2H), 2.29 – 2.21 (m, 2H), 2.13 (s, 3H), 2.06 – 1.94 (m, 2H ). MS (ESI) m/z : 687 [M+H] + . I-180
Figure 02_image734
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.04 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.9 Hz, 1H), 4.42 – 4.28 (m, 4H), 3.88 – 3.76 (m, 2H), 3.67 – 3.56 (m, 2H), 3.29 – 3.21 (m , 2H), 3.16 (s, 3H), 3.11 – 3.04 (m, 2H), 3.02 (s, 3H), 2.97 (s, 3H). MS (ESI) m/z : 560 [M+H] + . I-181
Figure 02_image736
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.01 (s, 1H), 7.35 (d, J = 10.2 Hz, 2H), 6.92 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 4.43 – 4.26 (m, 4H), 3.96 – 3.85 (m, 2H), 3.85 (s, 3H), 3.69 – 3.55 (m, 2H ), 3.30 – 3.23 (m, 2H), 3.19 (s, 3H), 3.14 – 3.05 (m, 2H), 3.03 (s, 3H), 2.98 (s, 3H). MS (ESI) m/z : 590 [M+H] + . I-182
Figure 02_image738
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.24 (d, J = 2.9 Hz, 1H), 8.17 (s, 1H), 7.38 – 7.28 (m, 2H), 7.18 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 4.47 – 4.21 (m, 4H), 4.01 – 3.96 (m, 2H), 3.94 (s, 3H), 3.60 (q, J = 12.1, 10.2 Hz , 2H), 3.40 – 3.35 (m, 1H), 3.20 (s, 3H), 3.04 (s, 3H), 2.26 – 2.09 (m, 2H), 2.02 – 1.83 (m, 2H). MS (ESI) m /z : 591 [M+H] + . I-183
Figure 02_image740
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.08 (s, 1H), 7.40 (s, 1H), 7.26 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H) , 6.78 (s, 1H), 4.42 – 4.28 (m, 4H), 3.86 (s, 3H), 3.61 (d, J = 11.9 Hz, 2H), 3.35 – 3.33 (m, 2H), 3.29 – 3.24 (m , 2H), 3.17 (s, 3H), 3.14 – 3.07 (m, 2H), 3.02 (s, 3H), 2.99 (s, 3H), 2.14 (s, 3H). MS (ESI) m/z : 604 [M+H] + . I-184
Figure 02_image742
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.10 (s, 1H), 7.45 (s, 1H), 7.23 (s, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.84 (s, 1H), 4.44 – 4.24 (m, 4H), 3.86 (s, 3H), 3.64 – 3.55 (m, 2H), 3.36 – 3.32 (m, 2H), 3.23 – 3.11 (m, 7H), 3.02 (s, 3H), 2.99 (s, 3H), 2.62 – 2.44 (m, 2H), 1.05 (s, 3H). MS (ESI) m/z : 618 [M+H] + . I-185
Figure 02_image744
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.07 (s, 1H), 7.41 – 7.18 (m, 2H), 6.91 (d, J = 9.0 Hz, 1H), 6.77 (s, 1H), 4.42 – 4.26 (m, 4H), 3.84 (s, 3H), 3.41 – 3.32 (m, 1H), 3.30 – 3.24 (m, 2H), 3.17 (s, 3H), 3.02 (s, 3H), 2.93 (s, 6H), 2.86 – 2.78 (m, 2H), 2.24 – 2.17 (m, 2H), 2.13 (s, 3H), 2.01 – 1.87 (m, 2H). MS (ESI) m/z : 632 [M+H ] + . I-186
Figure 02_image746
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.08 (s, 1H), 7.37 (s, 1H), 7.23 (s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.82 (s, 1H), 4.45 – 4.24 (m, 4H), 3.84 (s, 3H), 3.35 – 3.33 (m, 1H), 3.25 – 3.14 (m, 5H), 3.02 (s, 3H), 2.93 (s, 6H) , 2.89 – 2.79 (m, 2H), 2.61 – 2.45 (m, 2H), 2.19 (q, J = 12.7, 3.1 Hz, 2H), 2.00 – 1.84 (m, 2H), 1.06 (s, 3H). MS (ESI) m/z : 646 [M+H] + . I-187
Figure 02_image748
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.06 (s, 1H), 7.37 – 7.18 (m, 2H), 6.92 (d, J = 9.0 Hz, 1H), 6.71 (s, 1H), 4.43 – 4.26 (m, 4H), 4.05 – 3.98 (m, 1H), 3.85 (s, 3H), 3.53 – 3.46 (m, 1H), 3.45 – 3.36 (m, 2H), 3.21 – 3.12 (m, 4H), 3.02 (s, 3H), 2.97 (s, 6H), 2.53 – 2.43 (m, 1H), 2.26 – 2.19 (m, 1H), 2.15 (s, 3H). MS (ESI) m/z : 618 [M +H] + . I-188
Figure 02_image750
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.07 (s, 1H), 7.44 – 7.15 (m, 2H), 6.89 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 4.44 – 4.26 (m, 4H), 4.07 – 3.94 (m, 1H), 3.85 (s, 3H), 3.46 – 3.40 (m, 2H), 3.35 – 3.32 (m, 1H), 3.19 (s, 3H), 3.17 – 3.12 (m, 1H), 3.02 (s, 3H), 2.97 (s, 6H), 2.61 – 2.43 (m, 3H), 2.30 – 2.07 (m, 1H), 1.06 (s, 3H) . MS (ESI) m/z : 632 [M+H] + . I-189
Figure 02_image752
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.01 (s, 1H), 7.32 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 6.58 (dd, J = 8.8, 2.5 Hz, 1H), 4.43 – 4.28 (m, 4H), 3.87 (t, J = 4.8 Hz, 4H), 3.84 (s, 3H), 3.26 ( t, J = 4.8 Hz, 4H), 3.19 (s, 3H), 3.02 (s, 3H). MS (ESI) m/z : 577 [M+H] + . I-190
Figure 02_image754
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.62 (s, 1H), 10.20 (s, 1H), 10.02 (s, 1H), 7.97 – 7.89 (m, 1H), 7.37 – 7.33 (m, 1H ), 7.06 – 7.01 (m, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.71 – 6.27 (m, 1H), 4.42 – 4.23 (m, 4H), 3.50 (d, J = 11.9 Hz, 2H), 3.21 (s, 2H), 3.06 (d, J = 11.4 Hz, 2H), 3.04 – 2.99 (m, 6H), 2.96 (t, J = 12.4 Hz, 2H), 2.88 (s, 3H), 2.58 – 2.54 (m, 2H), 1.03 (s, 3H). MS (ESI) m/z : 554 [M+H] + . I-191
Figure 02_image756
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.28 (s, 1H), 10.15 (s, 1H), 9.44 (s, 1H), 8.28 (d, J = 4.5 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.26 – 7.18 (m, 2H), 6.99 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 4.43 – 4.26 (m, 4H), 3.51 (d, J = 11.7 Hz, 2H), 3.22 (d, J = 10.5 Hz, 2H), 3.18 (s, 2H), 3.06 (s, 3H), 3.04 – 3.03 (m, 2H), 3.02 (s , 3H), 3.01 – 2.94 (m, 2H), 2.60 – 2.42 (m, 2H), 1.04 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 572 [M+H] + . I-192
Figure 02_image758
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.37 (s, 1H), 9.21 (s, 1H), 7.89 (s, 1H), 7.31 (d, J = 2.6 Hz, 1H), 7.13 – 7.06 ( m, 2H), 6.99 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.44 – 4.21 (m, 4H), 3.50 (d, J = 12.0 Hz, 2H), 3.15 – 3.09 (m, 2H), 3.09 – 3.03 (m, 2H), 3.01 (s, 3H), 2.99 (s, 3H), 2.97 – 2.91 (m, 2H), 2.88 (s, 3H), 2.61 – 2.52 (m, 2H), 2.13 (s, 3H), 1.03 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 568 [M+H] + . I-193
Figure 02_image760
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.32 (s, 1H), 7.37 – 7.33 (m, 1H), 7.24 – 7.13 (m, 2H), 7.09 – 7.03 (m, 1H), 6.90 (d , J = 8.9 Hz, 1H), 4.44 – 4.25 (m, 4H), 3.59 (d, J = 12.2 Hz, 2H), 3.36 – 3.32 (m, 2H), 3.17 (d, J = 13.5 Hz, 2H) , 3.14 (s, 3H), 3.09 (t, J = 12.5 Hz, 2H), 3.00 (s, 3H), 2.98 (s, 3H), 2.63 (s, 2H), 1.12 (s, 3H). MS ( ESI) m/z : 622 [M+H] + . I-194
Figure 02_image762
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.35 (s, 1H), 9.92 – 9.77 (m, 1H), 7.83 (s, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.12 – 7.09 (m, 1H), 7.06 (d, J = 8.9 Hz, 1H), 6.99 – 6.95 (m, 2H), 4.45 – 4.22 (m, 4H), 3.54 – 3.46 (m, 2H), 3.26 – 3.17 ( m, 2H), 3.08 – 3.02 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 2.97 – 2.90 (m, 2H), 2.88 (s, 3H), 2.59 – 2.52 (m, 2H), 2.44 (h, J = 7.8 Hz, 2H), 1.21 (t, J = 7.4 Hz, 3H), 1.03 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 582 [M +H] + . I-195
Figure 02_image764
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.62 (s, 1H), 9.39 (s, 1H), 7.85 (s, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.7, 2.5 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.43 – 4.23 ( m, 4H), 3.50 (d, J = 11.9 Hz, 2H), 3.26 – 3.18 (m, 2H), 3.09 – 3.02 (m, 2H), 3.00 (s, 3H), 2.99 – 2.91 (m, 6H) , 2.88 (s, 3H), 2.60 – 2.53 (m, 2H), 1.26 (dd, J = 6.8, 3.1 Hz, 6H), 1.02 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 596 [M+H] + . I-196
Figure 02_image766
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.54 (s, 1H), 9.40 (s, 1H), 7.81 (s, 1H), 7.37 – 7.35 (m, 1H), 7.27 (d, J = 8.9 Hz, 1H), 7.18 – 7.11 (m, 1H), 7.08 – 7.02 (m, 1H), 6.93 (d, J = 8.9 Hz, 1H), 4.43 – 4.21 (m, 4H), 3.90 (s, 3H) , 3.51 (d, J = 11.8 Hz, 2H), 3.26 – 3.16 (m, 2H), 3.09 – 3.05 (m, 5H), 3.03 (s, 3H), 3.01 – 2.93 (m, 2H), 2.89 (s , 3H), 2.62 – 2.51 (m, 2H), 1.04 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 584 [M+H] + . I-197
Figure 02_image768
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.37 (s, 1H), 9.10 (s, 1H), 7.83 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 8.5, 2.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 4.44 – 4.23 ( m, 4H), 4.13 (qd, J = 7.0, 3.8 Hz, 2H), 3.51 (d, J = 11.8 Hz, 2H), 3.21 (d, J = 13.4 Hz, 2H), 3.10 (s, 3H), 3.10 – 3.04 (m, 5H), 3.02 – 2.93 (m, 2H), 2.89 (s, 3H), 2.65 – 2.53 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 598 [M+H] + . I-198
Figure 02_image770
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.39 (s, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.30 – 7.16 (m, 3H), 7.04 (s, 1H), 6.91 ( d, J = 8.9 Hz, 1H), 4.46 – 4.24 (m, 4H), 3.58 (d, J = 12.0 Hz, 2H), 3.31 (dd, J = 23.9, 3.2 Hz, 2H), 3.18 – 3.12 (m , 5H), 3.11 – 3.04 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 2.62 (s, 2H), 1.11 (s, 3H). MS (ESI) m/z : 579 [M+H] + . I-199
Figure 02_image772
 1 H NMR (600 MHz, Methanol- d 4 ) δ 9.04 (s, 1H), 7.47 – 7.45 (m, 1H), 7.44 – 7.37 (m, 1H), 7.36 – 7.28 (m, 1H), 7.04 – 6.98 (m, 1H), 6.91 – 6.80 (m, 1H), 4.46 – 4.26 (m, 4H), 3.58 (d, J = 12.0 Hz, 2H), 3.35 – 3.32 (m, 2H), 3.20 – 3.14 (m , 5H), 3.12 – 3.06 (m, 2H), 3.04 (s, 3H), 2.99 (s, 3H), 2.62 (s, 2H), 1.10 (s, 3H). MS (ESI) m/z : 599 [M+H] + . I-200
Figure 02_image774
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.26 – 10.14 (m, 1H), 9.76 – 9.48 (m, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.96 (s, 1H) ), 6.91 (s, 1H), 6.77 (s, 1H), 6.52 (s, 1H), 4.42 – 4.21 (m, 4H), 3.81 (s, 3H), 3.51 (d, J = 11.7 Hz, 2H) , 3.27 – 3.18 (m, 2H), 3.15 – 3.07 (m, 2H), 3.07 – 3.01 (m, 5H), 2.99 (s, 3H), 2.89 (s, 3H), 2.40 – 2.26 (m, 2H) , 0.97 (s, 3H). MS (ESI) m/z : 584 [M+H] + . I-201
Figure 02_image776
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.78 (s, 1H), 9.19 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 7.46 (s, 1H), 7.07 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.76 (s, 1H), 4.43 – 4.21 (m, 4H), 3.79 (s, 3H), 3.52 (d, J = 11.7 Hz, 2H), 3.22 (t, J = 11.5 Hz, 2H), 3.19 – 3.16 (m, 2H), 3.13 – 3.04 (m, 2H), 3.04 (s, 3H), 3.00 (s, 3H), 2.90 (s, 3H), 2.44 – 2.32 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 602 [M+H] + . I-202
Figure 02_image778
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.89 (s, 1H), 9.22 (s, 1H), 7.84 (s, 1H), 7.42 – 7.30 (m, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H), 4.45 – 4.21 (m, 4H), 3.80 (s, 3H), 3.67 – 3.39 (m, 2H), 3.21 (s, 2H), 3.15 – 3.06 (m, 2H), 3.00 (q, J = 11.4, 8.8 Hz, 8H), 2.89 (s, 3H), 2.41 – 2.25 (m, 2H), 2.12 (s, 3H ), 0.98 (s, 3H). MS (ESI) m/z : 598 [M+H] + . I-203
Figure 02_image780
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.01 (s, 1H), 8.77 – 8.66 (m, 1H), 8.43 – 8.31 (m, 1H), 8.20 – 8.09 (m, 1H), 7.53 – 7.40 (m, 1H), 7.41 – 7.23 (m, 1H), 6.87 – 6.60 (m, 1H), 4.44 – 4.20 (m, 4H), 3.79 (s, 3H), 3.52 (d, J = 11.8 Hz, 2H ), 3.30 – 3.19 (m, 2H), 3.16 – 3.10 (m, 2H), 3.07 (s, 3H), 3.05 (s, 3H), 3.03 – 2.98 (m, 2H), 2.90 (s, 3H), 2.50 – 2.37 (m, 2H), 1.01 (s, 3H). MS (ESI) m/z : 652 [M+H] + . I-204
Figure 02_image782
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.99 (s, 1H), 9.29 (s, 1H), 7.81 (s, 1H), 7.37 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 6.76 (s, 1H), 4.43 – 4.21 (m, 4H), 3.80 (s, 3H), 3.51 (d, J = 11.9 Hz, 2H), 3.21 (s, 2H), 3.12 – 3.06 (m, 2H), 3.05 – 2.94 (m, 8H), 2.89 (s, 3H), 2.59 – 2.52 (m, 2H), 2.41 – 2.22 (m, 2H), 1.21 (t, J = 7.4 Hz, 3H), 1.01 – 0.90 (m, 3H). MS (ESI) m/z : 612 [M+H] + . I-205
Figure 02_image784
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.13 (s, 1H), 9.33 (s, 1H), 7.89 – 7.72 (m, 1H), 7.38 (s, 1H), 6.99 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.75 (s, 1H), 4.41 – 4.23 (m, 4H), 3.80 (s, 3H), 3.51 (d, J = 11.8 Hz, 2H ), 3.21 (s, 2H), 3.12 – 2.93 (m, 11H), 2.89 (s, 3H), 2.33 – 2.20 (m, 2H), 1.25 (dd, J = 6.8, 1.8 Hz, 6H), 0.94 ( s, 3H). MS (ESI) m/z : 626 [M+H] + . I-206
Figure 02_image786
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.07 (s, 1H), 9.43 (s, 1H), 7.73 (s, 1H), 7.42 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.78 (s, 1H), 4.43 – 4.20 (m, 4H), 3.90 (s, 3H), 3.81 (s, 3H), 3.51 (d, J = 11.8 Hz, 2H), 3.21 (d, J = 12.6 Hz, 2H), 3.15 – 3.09 (m, 2H), 3.07 (s, 3H), 3.02 (s, 5H), 2.89 (s, 3H), 2.41 (dd, J = 14.4, 7.3 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 614 [M+H] + . I-207
Figure 02_image788
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.66 (s, 1H), 9.23 (s, 1H), 7.76 (s, 1H), 7.44 – 7.36 (m, 2H), 6.86 – 6.82 (m, 1H ), 6.81 (s, 1H), 4.46 – 4.23 (m, 4H), 4.13 (qt, J = 6.7, 3.3 Hz, 2H), 3.81 (s, 3H), 3.53 (d, J = 11.8 Hz, 2H) , 3.24 (t, J = 11.9 Hz, 2H), 3.17 – 3.12 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 3.06 – 3.01 (m, 2H), 2.91 (s, 3H ), 2.57 – 2.52 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 628 [M+H] + . I-208
Figure 02_image790
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.09 (s, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 7.78 (s, 1H), 7.69 – 7.61 (m, 1H), 7.42 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.56 (s, 1H), 4.43 – 4.21 (m , 4H), 3.92 (s, 3H), 3.48 (t, J = 11.0 Hz, 2H), 3.28 (d, J = 13.8 Hz, 2H), 3.19 – 3.09 (m, 5H), 3.07 (s, 3H) , 2.96 – 2.82 (m, 5H). MS (ESI) m/z : 609 [M+H] + . I-209
Figure 02_image792
 1 H NMR (600 MHz, Methanol- d 4 ) δ 9.01 (s, 1H), 7.76 (s, 1H), 7.37 – 7.28 (m, 1H), 6.88 – 6.80 (m, 1H), 6.78 (s, 1H) ), 4.46 – 4.25 (m, 4H), 3.86 (s, 3H), 3.59 (d, J = 12.0 Hz, 2H), 3.36 – 3.31 (m, 2H), 3.22 – 3.07 (m, 7H), 3.03 ( s, 3H), 2.99 (s, 3H), 2.48 (s, 2H), 0.96 (s, 3H). MS (ESI) m/z : 629 [M+H] + . I-210
Figure 02_image794
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.18 (s, 1H), 9.60 (s, 1H), 7.89 (s, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 6.89 ( s, 1H), 6.76 (s, 1H), 6.51 (s, 1H), 4.41 – 4.23 (m, 4H), 3.79 (d, J = 3.1 Hz, 3H), 3.69 – 3.20 (m, 9H), 3.18 – 2.90 (m, 8H), 2.88 (s, 3H), 2.73 (s, 2H), 2.47 – 2.22 (m, 2H), 2.11 (d, J = 11.0 Hz, 2H), 1.77 (d, J = 12.6 Hz, 2H), 0.97 (s, 3H). MS (ESI) m/z : 667 [M+H] + . I-211
Figure 02_image796
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.90 (s, 1H), 9.30 (s, 1H), 8.30 – 8.24 (m, 1H), 7.37 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.75 (s, 1H), 4.42 – 4.21 (m, 4H), 3.77 (s, 3H), 3.73 – 3.22 (m, 9H), 3.08 (d, J = 11.2 Hz, 2H), 3.02 (s, 3H), 3.00 (s, 3H), 2.89 (s, 3H), 2.74 (t, J = 12.0 Hz, 2H), 2.35 (d, J = 7.1 Hz, 2H), 2.16 – 2.09 (m, 2H), 1.85 – 1.72 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H). MS (ESI) m/z : 685 [M+H] + . I-212
Figure 02_image798
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.55 – 9.41 (m, 1H), 9.22 (s, 1H), 7.83 (s, 1H), 7.34 – 7.22 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.75 (s, 1H), 4.42 – 4.21 (m, 4H), 3.77 (s, 3H), 3.72 – 3.14 (m, 9H) , 3.07 (d, J = 11.5 Hz, 2H), 3.04 – 2.95 (m, 6H), 2.86 (s, 3H), 2.72 (t, J = 12.1 Hz, 2H), 2.36 (d, J = 30.0 Hz, 2H), 2.15 – 2.02 (m, 5H), 1.82 – 1.70 (m, 2H), 0.98 (s, 3H). MS (ESI) m/z : 681 [M+H] + . I-213
Figure 02_image800
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.55 – 9.34 (m, 1H), 9.27 (s, 1H), 7.84 – 7.72 (m, 1H), 7.30 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.75 (s, 1H), 4.43 – 4.21 (m, 4H), 3.77 (s, 3H), 3.68 – 3.11 (m, 9H) , 3.10 – 3.02 (m, 2H), 3.00 (s, 3H), 2.84 (s, 3H), 2.76 – 2.68 (m, 2H), 2.54 (s, 3H), 2.41 – 2.23 (m, 2H), 2.07 (d, J = 11.0 Hz, 2H), 1.74 (s, 2H), 0.96 (s, 3H). MS (ESI) m/z : 735 [M+H] + . I-214
Figure 02_image802
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.75 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 6.76 ( s, 1H), 4.42 – 4.21 (m, 4H), 3.77 (s, 3H), 3.67 – 3.18 (m, 9H), 3.13 – 3.08 (m, 2H), 3.06 (s, 3H), 3.04 (s, 3H), 2.89 (s, 3H), 2.77 (t, J = 10.5 Hz, 2H), 2.48 – 2.42 (m, 4H), 2.17 – 2.09 (m, 2H), 1.79 (d, J = 11.7 Hz, 2H ), 1.07 – 0.94 (m, 6H). MS (ESI) m/z : 695 [M+H] + . I-215
Figure 02_image804
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.49 – 9.35 (m, 1H), 9.32 (s, 1H), 7.88 – 7.64 (m, 1H), 7.31 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.74 (s, 1H), 4.42 – 4.21 (m, 4H), 3.78 (s, 3H), 3.72 – 3.12 (m, 9H) , 3.05 (dt, J = 12.2, 6.3 Hz, 6H), 2.99 (s, 3H), 2.84 (s, 3H), 2.76 – 2.66 (m, 2H), 2.39 – 2.17 (m, 2H), 2.07 (d , J = 11.2 Hz, 2H), 1.73 (d, J = 12.0 Hz, 2H), 1.24 (dd, J = 6.7, 2.5 Hz, 6H), 0.94 (s, 3H). MS (ESI) m/z : 709 [M+H] + . I-216
Figure 02_image806
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.51 (s, 1H), 9.41 (s, 1H), 7.72 (s, 1H), 7.35 (s, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.78 (s, 1H), 4.42 – 4.21 (m, 4H), 3.90 (s, 3H), 3.79 (s, 3H), 3.73 – 3.17 (m , 9H), 3.10 (d, J = 11.6 Hz, 2H), 3.07 (s, 3H), 3.03 (s, 3H), 2.90 (s, 3H), 2.75 (t, J = 11.7 Hz, 2H), 2.49 – 2.36 (m, 2H), 2.19 – 2.09 (m, 2H), 1.80 (dt, J = 13.0, 6.5 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 697 [M+H] + . I-217
Figure 02_image808
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.64 (s, 1H), 9.21 (s, 1H), 7.73 (s, 1H), 7.43 – 7.38 (m, 1H), 7.34 (s, 1H), 6.86 – 6.80 (m, 1H), 6.80 (s, 1H), 4.42 – 4.22 (m, 4H), 4.12 (tt, J = 7.0, 3.5 Hz, 2H), 3.79 (s, 3H), 3.32 (s, 9H), 3.15 – 3.11 (m, 2H), 3.10 (s, 3H), 3.07 (s, 3H), 2.89 (s, 3H), 2.76 (t, J = 11.7 Hz, 2H), 2.50 – 2.44 (m , 2H), 2.18 – 2.10 (m, 2H), 1.80 (td, J = 13.3, 9.3 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H) . MS (ESI) m/z : 711 [M+H] + . I-218
Figure 02_image810
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.71 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 7.37 (s, 1H), 7.25 – 7.09 (m, 1H), 6.86 – 6.77 (m, 1H), 6.75 (s, 1H), 4.44 – 4.18 (m, 4H), 3.76 (s, 3H), 3.66 – 3.24 (m, 9H), 3.09 (d, J = 11.9 Hz, 2H), 3.06 – 2.97 (m, 6H), 2.90 (s, 3H), 2.75 (t, J = 11.7 Hz, 2H), 2.49 – 2.32 (m, 2H), 2.15 (d, J = 11.3 Hz, 2H ), 1.80 (dt, J = 12.3, 6.2 Hz, 2H), 0.99 (s, 3H). MS (ESI) m/z : 692 [M+H] + . I-219
Figure 02_image812
 1 H NMR (600 MHz, Methanol- d 4 ) δ 9.04 (s, 1H), 7.75 (s, 1H), 7.36 – 7.24 (m, 1H), 6.86 (s, 1H), 6.85 – 6.79 (m, 1H ), 4.45 – 4.26 (m, 4H), 3.86 (s, 3H), 3.76 – 3.41 (m, 9H), 3.30 – 3.27 (m, 2H), 3.17 (s, 3H), 3.06 – 2.99 (m, 5H ), 2.98 (s, 3H), 2.49 (s, 2H), 2.23 (d, J = 12.2 Hz, 2H), 2.01 (d, J = 12.3 Hz, 2H), 0.96 (s, 3H). MS (ESI ) m/z : 712 [M+H] + . I-220
Figure 02_image814
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.98 (s, 1H), 7.12 – 6.95 (m, 3H), 6.77 (s, 1H), 6.50 (d, J = 28.7 Hz, 1H), 4.44 – 4.32 (m, 4H), 3.88 (s, 3H), 3.64 – 3.54 (m, 2H), 3.35 – 3.31 (m, 2H), 3.27 – 3.22 (m, 2H), 3.17 (s, 3H), 3.14 – 3.06 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 2.21 (s, 3H). MS (ESI) m/z : 609 [M+H] + . I-221
Figure 02_image816
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.20 – 7.69 (m, 1H), 7.18 – 6.94 (m, 3H), 6.75 (s, 1H), 6.64 – 6.37 (m, 1H), 4.45 – 4.29 (m, 4H), 3.86 (s, 3H), 3.37 – 3.32 (m, 1H), 3.29 – 3.22 (m, 2H), 3.16 (s, 3H), 3.01 (s, 3H), 2.93 (s, 6H) ), 2.84 – 2.76 (m, 2H), 2.25 – 2.12 (m, 5H), 2.00 – 1.86 (m, 2H). MS (ESI) m/z : 637 [M+H] + . I-222
Figure 02_image818
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.29 – 7.80 (m, 1H), 7.12 – 6.99 (m, 3H), 6.83 (s, 1H), 6.67 – 6.35 (m, 1H), 4.46 – 4.32 (m, 4H), 3.89 (s, 3H), 3.64 – 3.54 (m, 2H), 3.36 – 3.31 (m, 2H), 3.21 – 3.11 (m, 7H), 3.01 (s, 3H), 2.98 (s , 3H), 2.77 – 2.50 (m, 2H), 1.17 (s, 3H). MS (ESI) m/z : 623 [M+H] + . I-223
Figure 02_image820
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.15 – 7.81 (m, 1H), 7.11 – 6.96 (m, 3H), 6.81 (s, 1H), 6.66 – 6.39 (m, 1H), 4.45 – 4.31 (m, 4H), 3.86 (s, 3H), 3.39 – 3.32 (m, 1H), 3.24 – 3.12 (m, 5H), 3.01 (s, 3H), 2.93 (s, 6H), 2.90 – 2.81 (m , 2H), 2.71 – 2.47 (m, 2H), 2.23 – 2.11 (m, 2H), 2.03 – 1.81 (m, 2H), 1.15 (s, 3H). MS (ESI) m/z : 651 [M+ H] + . I-224
Figure 02_image822
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.99 (s, 1H), 7.17 – 6.97 (m, 3H), 6.85 (s, 1H), 6.53 (s, 1H), 4.46 – 4.31 (m, 4H ), 3.88 (s, 3H), 3.58 – 3.40 (m, 8H), 3.39 – 3.33 (m, 2H), 3.24 – 3.19 (m, 1H), 3.16 (s, 3H), 3.04 – 2.96 (m, 5H ), 2.94 (s, 3H), 2.29 – 2.14 (m, 5H), 2.04 – 1.94 (m, 2H). MS (ESI) m/z : 692 [M+H] + . I-225
Figure 02_image824
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.04 (br s, 1H), 7.11 – 7.05 (m, 1H), 7.05 – 6.98 (m, 2H), 6.87 (s, 1H), 6.65 – 6.38 ( m, 1H), 4.43 – 4.33 (m, 4H), 3.88 (s, 3H), 3.61 – 3.38 (m, 8H), 3.29 – 3.23 (m, 2H), 3.22 – 3.19 (m, 1H), 3.17 ( ( m, 2H), 1.17 (s, 3H). MS (ESI) m/z : 706 [M+H] + . I-226
Figure 02_image826
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.39 – 8.08 (m, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.14 – 6.97 (m, 2H), 6.98 – 6.86 (m , 1H), 6.83 (s, 1H), 6.62 – 6.33 (m, 1H), 4.46 – 4.23 (m, 4H), 3.96 (s, 3H), 3.93 (s, 3H), 3.60 – 3.49 (m, 2H ), 3.30 – 3.23 (m, 4H), 3.17 (s, 3H), 3.08 – 2.99 (m, 5H), 2.97 (s, 3H). MS (ESI) m/z : 675 [M+H] + . I-227
Figure 02_image828
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.92 (s, 1H), 7.29 (dd, J = 8.8, 2.9 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.14 – 7.01 ( m, 3H), 6.52 (s, 1H), 4.47 – 4.35 (m, 4H), 4.19 – 4.03 (m, 1H), 3.96 (s, 3H), 3.84 – 3.69 (m, 2H), 3.62 – 3.48 ( m, 2H), 3.20 (s, 3H), 3.03 (s, 3H), 2.36 – 2.18 (m, 2H), 2.11 – 1.97 (m, 2H). MS (ESI) m/z : 596 [M+H ] + . I-228
Figure 02_image830
 1 H NMR (600 MHz, Methanol- d 4 ) δ 8.06 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 9.1 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 2.6 Hz, 1H), 6.71 (dd, J = 8.8, 2.6 Hz, 1H), 4.43 – 4.26 (m, 4H), 3.91 – 3.82 (m, 5H), 3.66 – 3.38 (m, 8H), 3.30 – 3.24 (m, 1H), 3.18 (s, 3H), 3.13 (t, J = 12.4 Hz, 2H), 3.02 (s, 3H), 2.96 (s, 3H) , 2.33 – 2.19 (m, 2H), 1.97 (qd, J = 12.3, 4.0 Hz, 2H). MS (ESI) m/z : 673 [M+H] + . I-229
Figure 02_image832
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.92 (s, 1H), 9.75 – 9.60 (m, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 7.79 (s, 1H), 7.70 – 7.59 (m, 1H), 7.53 – 7.47 (m, 1H), 7.34 (s, 1H), 7.04 – 6.98 (m, 1H), 4.44 – 4.20 (m, 4H), 3.91 (s, 3H), 3.47 (t, J = 10.8 Hz, 2H), 3.26 (t, J = 11.6 Hz, 2H), 3.14 – 3.10 (m, 5H), 3.08 (s, 3H), 2.92 – 2.81 (m, 5H). MS (ESI) m/z : 684 [M+H] + . I-230
Figure 02_image834
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.79 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.76 (s, 1H), 7.63 – 7.57 (m, 1H), 7.47 (s, 1H), 7.32 – 7.24 (m, 1H), 7.08 – 6.97 (m, 1H), 6.56 (s, 1H), 4.42 – 4.22 (m, 4H), 3.89 ( s, 3H), 3.72 (t, J = 4.6 Hz, 4H), 3.12 (s, 3H), 3.07 (s, 3H), 2.80 – 2.72 (m, 4H). MS (ESI) m/z : 671 [ M+H] + . I-231
Figure 02_image836
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.71 (s, 1H), 10.03 (s, 1H), 9.42 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.74 ( s, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.14 – 7.09 (m, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 17.2, 11.1 Hz, 1H), 5.86 (d, J = 17.3 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 4.43 – 4.10 (m, 4H), 3.92 (s , 3H), 3.48 (t, J = 12.0 Hz, 2H), 3.28 (s, 2H), 3.12 (t, J = 10.4 Hz, 2H), 2.99 (s, 3H), 2.93 – 2.78 (m, 8H) . MS (ESI) m/z : 632 [M+H] + . I-232
Figure 02_image838
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.56 (s, 1H), 9.41 (s, 1H), 8.18 – 8.15 (m, 1H), 8.13 (s, 1H), 7.72 (s, 1H), 7.49 – 7.43 (m, 1H), 7.12 – 7.08 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 17.3, 11.1 Hz, 1H), 6.65 (s, 1H), 5.85 (d, J = 17.2 Hz, 1H), 5.47 (d, J = 11.1 Hz, 1H), 4.41 – 4.14 (m, 4H), 3.90 (s, 3H), 3.76 – 3.71 (m, 4H), 2.99 (s, 6H), 2.76 (t, J = 4.5 Hz, 4H). MS (ESI) m/z : 619 [M+H] + . I-233
Figure 02_image840
 1 H NMR (600 MHz, Methanol- d 4 ) δ 7.91 (s, 1H), 7.48 (s, 1H), 7.16 – 7.12 (m, 2H), 6.92 (d, J = 8.8 Hz, 1H), 6.83 ( s, 1H), 6.69 (dd, J = 17.2, 11.0 Hz, 1H), 5.81 (d, J = 17.3 Hz, 1H), 5.56 (d, J = 11.0 Hz, 1H), 4.42 – 4.28 (m, 4H ), 3.87 (s, 3H), 3.38 (t, J = 4.9 Hz, 4H), 3.13 (dd, J = 10.1, 4.9 Hz, 7H), 3.00 (s, 3H), 2.61 – 2.38 (m, 2H) , 1.06 – 1.02 (m, 3H). MS (ESI) m/z : 596 [M+H] + . I-234
Figure 02_image842
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.35 (s, 1H), 8.98 – 8.89 (m, 2H), 8.25 (s, 1H), 7.40 – 7.31 (m, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.98 – 6.92 (m, 2H), 6.78 (dd, J = 17.2, 11.1 Hz, 1H), 5.84 (d, J = 17.3 Hz , 1H), 5.43 (d, J = 11.0 Hz, 1H), 4.52 – 4.19 (m, 4H), 3.29 – 3.19 (m, 4H), 3.00 (s, 3H), 2.97 (s, 3H), 2.96 – 2.91 (m, 4H), 2.47 – 2.38 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 566 [M+H] + . I-235
Figure 02_image844
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.04 (s, 2H), 8.94 (s, 1H), 8.28 (s, 1H), 7.47 (s, 1H), 7.27 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.75 (s, 1H), 4.43 – 4.24 (m, 4H), 3.80 (s, 3H), 3.32 – 3.22 (m, 4H), 3.08 (s , 3H), 3.05 (s, 3H), 3.04 – 2.99 (m, 4H), 2.50 – 2.40 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H). MS (ESI) m/z : 604 [M+H] + . I-236
Figure 02_image846
 1 H NMR (600 MHz, DMSO- d 6 ) δ 8.96 (s, 2H), 8.61 (s, 1H), 8.25 (s, 1H), 7.43 (d, J = 2.4 Hz, 2H), 7.34 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.45 – 4.24 (m, 4H), 3.29 – 3.21 (m, 4H), 3.09 (s, 3H), 3.07 (s, 3H), 3.00 – 2.94 (m, 4H), 2.61 – 2.56 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). MS (ESI) m/ z : 574 [M+H] + . I-237
Figure 02_image848
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.28 (s, 1H), 8.99 (s, 1H), 8.89 (s, 1H), 8.28 (s, 1H), 7.48 (s, 1H), 6.90 – 6.82 (m, 1H), 6.77 (s, 1H), 4.44 – 4.24 (m, 4H), 3.80 (s, 3H), 3.53 (d, J = 11.7 Hz, 2H), 3.22 (d, J = 11.8 Hz , 2H), 3.15 – 3.09 (m, 2H), 3.08 (s, 3H), 3.07 – 3.01 (m, 5H), 2.52 – 2.40 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 621 [M+H] + . I-238
Figure 02_image850
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.24 (s, 1H), 9.48 (s, 1H), 8.19 (d, J = 14.4 Hz, 1H), 7.41 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.81 – 6.75 (m, 2H), 5.82 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.4 Hz, 1H), 4.42 – 4.20 (m, 4H), 3.80 (s, 3H), 3.51 (d, J = 11.8 Hz, 2H), 3.21 (d, J = 12.2 Hz, 2H), 3.13 – 3.06 (m, 2H ), 3.05 – 3.01 (m, 2H), 2.98 (s, 6H), 2.42 – 2.23 (m, 2H), 0.95 (s, 3H). MS (ESI) m/z : 613 [M+H] + . I-239
Figure 02_image852
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.94 (s, 1H), 9.01 (s, 1H), 8.29 (s, 1H), 7.44 (s, 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.79 (s, 1H), 4.43 – 4.22 (m, 4H), 3.80 (s, 3H), 3.52 (d, J = 11.9 Hz, 2H), 3.16 – 3.10 (m, 2H), 3.08 – 3.06 (m, 4H), 3.05 (s, 3H), 2.83 (d, J = 4.3 Hz, 3H), 2.11 (s, 3H), 1.98 – 1.91 (m, 2H), 1.90 – 1.83 (m, 2H). MS (ESI) m/z : 603 [M+H] + . I-240
Figure 02_image854
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.11 (s, 1H), 10.01 (s, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.46 – 7.39 (m, 1H), 7.34 – 7.27 (m, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 4.48 – 4.24 (m, 4H), 3.51 (d, J = 11.8 Hz , 2H), 3.20 (d, J = 17.0 Hz, 2H), 3.09 (s, 3H), 3.07 (s, 3H), 3.06 – 3.03 (m, 2H), 2.98 (tt, J = 11.4, 5.1 Hz, 2H), 2.62 – 2.52 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 591 [M+H] + . I-241
Figure 02_image856
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.71 (s, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 7.75 (s, 1H), 7.31 (d, J = 9.2 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 4.92 (q, J = 9.0 Hz, 2H), 4.43 – 4.21 (m, 4H), 3.46 (t, J = 6.8 Hz, 2H), 3.26 ( t, J = 6.0 Hz, 2H), 3.09 (s, 3H), 3.05 (s, 3H), 2.82 (d, J = 4.0 Hz, 6H), 2.75 (s, 3H), 2.58 – 2.44 (m, 2H ), 1.04 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 689 [M+H] + . I-242
Figure 02_image858
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.94 (s, 1H), 9.61 (s, 1H), 8.24 (s, 1H), 7.39 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.83 – 6.77 (m, 2H), 5.83 (d, J = 17.3 Hz, 1H), 5.47 (d, J = 11.2 Hz, 1H), 4.41 – 4.23 (m, 4H), 3.81 (s, 3H), 3.55 – 3.47 (m, 2H), 3.16 – 3.06 (m, 2H), 3.05 – 2.91 (m, 8H), 2.82 (d, J = 4.2 Hz, 3H), 2.02 (s, 3H), 1.98 – 1.88 (m, 1H), 1.84 (d, J = 13.4 Hz, 2H). MS (ESI) m/z : 595 [M+H] + . I-243
Figure 02_image860
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.09 (s, 1H), 9.52 – 9.41 (m, 1H), 8.25 (s, 1H), 7.40 – 7.29 (m, 1H), 7.17 – 7.08 (m , 1H), 7.08 – 7.02 (m, 1H), 6.99 – 6.93 (m, 2H), 6.79 (dd, J = 17.2, 11.1 Hz, 1H), 5.85 (d, J = 17.3 Hz, 1H), 5.44 ( d, J = 11.1 Hz, 1H), 4.43 – 4.21 (m, 4H), 3.53 – 3.47 (m, 2H), 3.20 (s, 2H), 3.08 – 3.01 (m, 2H), 2.99 (s, 3H) , 2.98 – 2.91 (m, 5H), 2.60 – 2.39 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 583 [M+H] + . I-244
Figure 02_image862
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.86 (s, 1H), 9.44 (s, 1H), 8.14 (s, 1H), 7.67 (s, 1H), 6.97 (d, J = 8.9 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.77 (dd, J = 17.2, 11.1 Hz, 1H), 5.82 (d, J = 17.3 Hz, 1H), 5.46 (d, J = 11.2 Hz, 1H), 5.03 – 4.75 (m, 2H), 4.50 – 4.16 (m, 4H), 3.49 (t, J = 6.9 Hz, 2H), 3.27 (q, J = 6.2 Hz, 2H), 3.01 (s, 3H ), 2.98 (s, 3H), 2.81 (d, J = 3.7 Hz, 6H), 2.78 (s, 3H), 2.39 (s, 2H), 1.00 (s, 3H). MS (ESI) m/z : 681 [M+H] + . I-245
Figure 02_image864
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.30 – 10.17 (m, 1H), 9.19 (s, 1H), 8.31 (s, 1H), 7.40 (s, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.82 (s, 1H), 4.44 – 4.20 (m, 4H), 3.79 (s, 3H), 3.71 (q, J = 8.4 Hz, 1H ), 3.06 (s, 3H), 3.04 (s, 3H), 2.92 – 2.76 (m, 4H), 2.70 (d, J = 4.5 Hz, 6H), 2.45 – 2.36 (m, 2H), 2.25 (t, J = 10.1 Hz, 2H), 2.01 (dd, J = 12.1, 8.4 Hz, 2H), 1.81 – 1.68 (m, 4H), 0.99 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 686 [M+H] + .

化合物II-1、II-13的合成：

Figure 02_image866
Synthesis of compounds II-1, II-13:
Figure 02_image866

第一步：由化合物7（250 mg, 1.09 mmol）與2,4-二氯-5-溴嘧啶（274 mg, 1.2 mmol）經合成化合物2相同的方法可得化合物8（334 mg）。Step 1: Compound 8 (334 mg) was obtained from compound 7 (250 mg, 1.09 mmol) and 2,4-dichloro-5-bromopyrimidine (274 mg, 1.2 mmol) by the same method as compound 2.

化合物II-1的合成：由化合物8（42 mg，0.1 mmol）與化合物3（22 mg，0.1 mmol）經合成化合物I-1相同的方法而得（43 mg）。Synthesis of compound II-1: obtained from compound 8 (42 mg, 0.1 mmol) and compound 3 (22 mg, 0.1 mmol) by the same method as compound I-1 (43 mg).

化合物II-13的合成：由化合物II-1（0.05 mmol, 30 mg）與乙烯基硼酸頻哪醇酯（0.1 mmol, 17 µL）經製備化合物I-79同的方法而得（12.8 mg）。Synthesis of compound II-13: It was obtained from compound II-1 (0.05 mmol, 30 mg) and vinylboronic acid pinacol ester (0.1 mmol, 17 µL) by the same method as compound I-79 (12.8 mg).

下表列出具體化合物及結構鑒定資料： 序號 結構 核磁共振氫譜和（或）質譜數據 II-1

Figure 02_image868
1H NMR (600 MHz, DMSO- d 6) δ 9.81 (s, 1H), 9.64 (s, 1H), 9.49 (s, 1H), 8.26 (s, 1H), 7.43 – 7.34 (m, 2H), 7.17 (d, J= 9.1 Hz, 1H), 6.97 (d, J= 8.5 Hz, 1H), 4.48 – 4.32 (m, 4H), 3.49 (d, J= 11.9 Hz, 2H), 3.36 (s, 3H), 3.24 – 3.15 (m, 2H), 3.05 (d, J= 12.7 Hz, 2H), 2.94 (t, J= 12.2 Hz, 2H), 2.88 (d, J= 3.2 Hz, 3H), 2.60 – 2.53 (m, 2H), 1.08 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 603 [M+H] +. II-2
Figure 02_image870
 MS (ESI) m/z: 617 [M+H] +. II-3
Figure 02_image872
 MS (ESI) m/z: 631 [M+H] +. II-4
Figure 02_image874
 MS (ESI) m/z: 629 [M+H] +. II-5
Figure 02_image876
 1H NMR (600 MHz, DMSO- d 6) δ 9.81 (s, 1H), 9.64 (s, 1H), 9.49 (s, 1H), 8.26 (s, 1H), 7.43 – 7.34 (m, 2H), 7.17 (d, J= 9.1 Hz, 1H), 6.97 (d, J= 8.5 Hz, 1H), 4.48 – 4.32 (m, 4H), 3.49 (d, J= 11.9 Hz, 2H), 3.36 (s, 3H), 3.24 – 3.15 (m, 2H), 3.05 (d, J= 12.7 Hz, 2H), 2.94 (t, J= 12.2 Hz, 2H), 2.88 (d, J= 3.2 Hz, 3H), 2.60 – 2.53 (m, 2H), 1.08 (t, J= 7.5 Hz, 3H). MS (ESI) m/z: 633 [M+H] +. II-6
Figure 02_image878
 MS (ESI) m/z: 647 [M+H] +. II-7
Figure 02_image880
 MS (ESI) m/z: 661 [M+H] +. II-8
Figure 02_image882
 MS (ESI) m/z: 659 [M+H] +. II-9
Figure 02_image884
 1H NMR (600 MHz, DMSO- d 6) δ 9.93 (s, 1H), 8.96 (s, 1H), 8.30 (s, 1H), 7.51 – 7.40 (m, 1H), 7.34 (s, 1H), 7.12 – 7.04 (m, 1H), 6.77 (s, 1H), 4.46 – 4.30 (m, 4H), 3.78 (s, 3H), 3.71 – 3.34 (m, 9H), 3.31 (s, 3H), 3.09 (d, J= 11.2 Hz, 2H), 2.90 (s, 3H), 2.76 (t, J= 11.7 Hz, 2H), 2.44 (q, J= 7.7 Hz, 2H), 2.18 – 2.09 (m, 2H), 1.80 (qd, J= 12.2, 3.9 Hz, 2H), 1.01 (t, J= 7.6 Hz, 3H). MS (ESI) m/z: 716 [M+H] +. II-10
Figure 02_image886
 MS (ESI) m/z: 730 [M+H] +. II-11
Figure 02_image888
 MS (ESI) m/z: 744 [M+H] +. II-12
Figure 02_image890
 MS (ESI) m/z: 742 [M+H] +. II-13
Figure 02_image892
 1H NMR (600 MHz, DMSO- d 6) δ 10.42 (s, 1H), 10.00 – 9.89 (m, 1H), 8.24 (s, 1H), 7.32 – 7.22 (m, 2H), 7.17 (d, J= 8.2 Hz, 1H), 6.94 (d, J= 8.7 Hz, 1H), 6.75 (dd, J= 17.2, 11.0 Hz, 1H), 5.83 (d, J= 17.2 Hz, 1H), 5.41 (d, J= 11.0 Hz, 1H), 4.49 – 4.34 (m, 4H), 3.50 (d, J= 11.7 Hz, 2H), 3.26 – 3.14 (m, 5H), 3.05 (d, J= 12.7 Hz, 2H), 2.94 (t, J= 12.1 Hz, 2H), 2.88 (s, 3H), 1.04 (q, J= 7.8 Hz, 3H). MS (ESI) m/z: 551 [M+H] +. II-14
Figure 02_image894
 MS (ESI) m/z: 565 [M+H] +. II-15
Figure 02_image896
 MS (ESI) m/z: 579 [M+H] +. II-16
Figure 02_image898
 MS (ESI) m/z: 577 [M+H] +. II-17
Figure 02_image900
 1H NMR (600 MHz, DMSO- d 6) δ 10.30 (s, 1H), 10.04 (s, 1H), 8.29 – 8.13 (m, 1H), 7.35 (s, 1H), 7.19 (d, J= 8.7 Hz, 1H), 7.14 (d, J= 9.0 Hz, 1H), 6.82 – 6.72 (m, 2H), 5.83 (d, J= 17.2 Hz, 1H), 5.45 (d, J= 11.0 Hz, 1H), 4.48 – 4.32 (m, 4H), 3.81 (s, 3H), 3.52 (d, J= 11.7 Hz, 2H), 3.30 – 3.13 (m, 5H), 3.09 (d, J= 12.4 Hz, 2H), 3.02 (t, J= 12.2 Hz, 2H), 2.90 (s, 3H), 2.39 (s, 2H), 0.96 (d, J= 8.2 Hz, 3H). MS (ESI) m/z: 581 [M+H] +. II-18
Figure 02_image902
 MS (ESI) m/z: 595 [M+H] +. II-19
Figure 02_image904
 MS (ESI) m/z: 609 [M+H] +. II-20
Figure 02_image906
 MS (ESI) m/z: 607 [M+H] +. II-21
Figure 02_image908
 1H NMR (600 MHz, DMSO- d 6) δ 10.07 (s, 1H), 9.66 (s, 1H), 8.21 (d, J= 32.8 Hz, 1H), 7.28 (s, 1H), 7.18 (d, J= 8.7 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 6.81 – 6.72 (m, 2H), 5.84 (d, J= 17.2 Hz, 1H), 5.45 (d, J= 11.0 Hz, 1H), 4.47 – 4.33 (m, 4H), 3.78 (s, 3H), 3.71 – 3.27 (m, 9H), 3.18 (d, J= 1.3 Hz, 3H), 3.07 (d, J= 11.5 Hz, 2H), 2.89 (s, 3H), 2.74 (t, J= 11.7 Hz, 2H), 2.38 (s, 2H), 2.17 – 2.08 (m, 2H), 1.84 – 1.74 (m, 2H), 0.97 (s, 3H). MS (ESI) m/z: 664 [M+H] +. II-22
Figure 02_image910
 MS (ESI) m/z: 678 [M+H] +. II-23
Figure 02_image912
 MS (ESI) m/z: 692 [M+H] +. II-24
Figure 02_image914
 MS (ESI) m/z: 690 [M+H] +. The following table lists specific compounds and structural identification information: serial number structure H NMR and/or MS data II-1
Figure 02_image868
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.81 (s, 1H), 9.64 (s, 1H), 9.49 (s, 1H), 8.26 (s, 1H), 7.43 – 7.34 (m, 2H), 7.17 (d, J = 9.1 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.48 – 4.32 (m, 4H), 3.49 (d, J = 11.9 Hz, 2H), 3.36 (s, 3H ), 3.24 – 3.15 (m, 2H), 3.05 (d, J = 12.7 Hz, 2H), 2.94 (t, J = 12.2 Hz, 2H), 2.88 (d, J = 3.2 Hz, 3H), 2.60 – 2.53 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 603 [M+H] + . II-2
Figure 02_image870
 MS (ESI) m/z : 617 [M+H] + . II-3
Figure 02_image872
 MS (ESI) m/z : 631 [M+H] + . II-4
Figure 02_image874
 MS (ESI) m/z : 629 [M+H] + . II-5
Figure 02_image876
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.81 (s, 1H), 9.64 (s, 1H), 9.49 (s, 1H), 8.26 (s, 1H), 7.43 – 7.34 (m, 2H), 7.17 (d, J = 9.1 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 4.48 – 4.32 (m, 4H), 3.49 (d, J = 11.9 Hz, 2H), 3.36 (s, 3H ), 3.24 – 3.15 (m, 2H), 3.05 (d, J = 12.7 Hz, 2H), 2.94 (t, J = 12.2 Hz, 2H), 2.88 (d, J = 3.2 Hz, 3H), 2.60 – 2.53 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H). MS (ESI) m/z : 633 [M+H] + . II-6
Figure 02_image878
 MS (ESI) m/z : 647 [M+H] + . II-7
Figure 02_image880
 MS (ESI) m/z : 661 [M+H] + . II-8
Figure 02_image882
 MS (ESI) m/z : 659 [M+H] + . II-9
Figure 02_image884
 1 H NMR (600 MHz, DMSO- d 6 ) δ 9.93 (s, 1H), 8.96 (s, 1H), 8.30 (s, 1H), 7.51 – 7.40 (m, 1H), 7.34 (s, 1H), 7.12 – 7.04 (m, 1H), 6.77 (s, 1H), 4.46 – 4.30 (m, 4H), 3.78 (s, 3H), 3.71 – 3.34 (m, 9H), 3.31 (s, 3H), 3.09 ( d, J = 11.2 Hz, 2H), 2.90 (s, 3H), 2.76 (t, J = 11.7 Hz, 2H), 2.44 (q, J = 7.7 Hz, 2H), 2.18 – 2.09 (m, 2H), 1.80 (qd, J = 12.2, 3.9 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H). MS (ESI) m/z : 716 [M+H] + . II-10
Figure 02_image886
 MS (ESI) m/z : 730 [M+H] + . II-11
Figure 02_image888
 MS (ESI) m/z : 744 [M+H] + . II-12
Figure 02_image890
 MS (ESI) m/z : 742 [M+H] + . II-13
Figure 02_image892
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.42 (s, 1H), 10.00 – 9.89 (m, 1H), 8.24 (s, 1H), 7.32 – 7.22 (m, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.75 (dd, J = 17.2, 11.0 Hz, 1H), 5.83 (d, J = 17.2 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 4.49 – 4.34 (m, 4H), 3.50 (d, J = 11.7 Hz, 2H), 3.26 – 3.14 (m, 5H), 3.05 (d, J = 12.7 Hz, 2H), 2.94 (t, J = 12.1 Hz, 2H), 2.88 (s, 3H), 1.04 (q, J = 7.8 Hz, 3H). MS (ESI) m/z : 551 [M+H] + . II-14
Figure 02_image894
 MS (ESI) m/z : 565 [M+H] + . II-15
Figure 02_image896
 MS (ESI) m/z : 579 [M+H] + . II-16
Figure 02_image898
 MS (ESI) m/z : 577 [M+H] + . II-17
Figure 02_image900
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.30 (s, 1H), 10.04 (s, 1H), 8.29 – 8.13 (m, 1H), 7.35 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H), 6.82 – 6.72 (m, 2H), 5.83 (d, J = 17.2 Hz, 1H), 5.45 (d, J = 11.0 Hz, 1H), 4.48 – 4.32 (m, 4H), 3.81 (s, 3H), 3.52 (d, J = 11.7 Hz, 2H), 3.30 – 3.13 (m, 5H), 3.09 (d, J = 12.4 Hz, 2H), 3.02 (t, J = 12.2 Hz, 2H), 2.90 (s, 3H), 2.39 (s, 2H), 0.96 (d, J = 8.2 Hz, 3H). MS (ESI) m/z : 581 [M+H ] + . II-18
Figure 02_image902
 MS (ESI) m/z : 595 [M+H] + . II-19
Figure 02_image904
 MS (ESI) m/z : 609 [M+H] + . II-20
Figure 02_image906
 MS (ESI) m/z : 607 [M+H] + . II-21
Figure 02_image908
 1 H NMR (600 MHz, DMSO- d 6 ) δ 10.07 (s, 1H), 9.66 (s, 1H), 8.21 (d, J = 32.8 Hz, 1H), 7.28 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.81 – 6.72 (m, 2H), 5.84 (d, J = 17.2 Hz, 1H), 5.45 (d, J = 11.0 Hz, 1H), 4.47 – 4.33 (m, 4H), 3.78 (s, 3H), 3.71 – 3.27 (m, 9H), 3.18 (d, J = 1.3 Hz, 3H), 3.07 (d, J = 11.5 Hz, 2H ), 2.89 (s, 3H), 2.74 (t, J = 11.7 Hz, 2H), 2.38 (s, 2H), 2.17 – 2.08 (m, 2H), 1.84 – 1.74 (m, 2H), 0.97 (s, 3H). MS (ESI) m/z : 664 [M+H] + . II-22
Figure 02_image910
 MS (ESI) m/z : 678 [M+H] + . II-23
Figure 02_image912
 MS (ESI) m/z : 692 [M+H] + . II-24
Figure 02_image914
 MS (ESI) m/z : 690 [M+H] + .

III-1、III-13的合成：

Figure 02_image916
Synthesis of III-1 and III-13:
Figure 02_image916

第一步：將化合物9（300 mg, 1.23 mmol）、氟化銫（19 mg, 0.12 mmol）、碳酸銫（802 mg, 2.46 mmol）溶於DMF（3 mL）中，0 ℃下加入2,4-二氯-5-溴嘧啶（308 mg，1.35 mmol），自熱升溫反應5小時，TLC及LCMS檢測反應完畢。加水100 mL，有固體析出，過濾，抽乾，得化合物10（418 mg），直接用於下一步。Step 1: Dissolve compound 9 (300 mg, 1.23 mmol), cesium fluoride (19 mg, 0.12 mmol), cesium carbonate (802 mg, 2.46 mmol) in DMF (3 mL), add 2, 4-Dichloro-5-bromopyrimidine (308 mg, 1.35 mmol) was reacted for 5 hours by autothermal heating, and the reaction was completed as detected by TLC and LCMS. After adding 100 mL of water, a solid precipitated out, filtered and dried to obtain compound 10 (418 mg), which was directly used in the next step.

化合物III-1的合成：由化合物10（44 mg，0.1 mmol）與化合物3（22 mg，0.1 mmol）經合成化合物I-1相同的方法而得（51 mg）。Synthesis of compound III-1: obtained from compound 10 (44 mg, 0.1 mmol) and compound 3 (22 mg, 0.1 mmol) by the same method as compound I-1 (51 mg).

化合物III-13的合成：由化合物III-1（0.05 mmol, 31 mg）與乙烯基硼酸頻哪醇酯（0.1 mmol, 17 µL）經製備化合物I-79相同的方法而得（12.8 mg）。Synthesis of compound III-13: It was obtained from compound III-1 (0.05 mmol, 31 mg) and vinylboronic acid pinacol ester (0.1 mmol, 17 µL) by the same method as compound I-79 (12.8 mg).

下表列出具體化合物及結構鑒定資料： 序號 結構 核磁共振氫譜和（或）質譜數據 III-1

Figure 02_image918
MS (ESI) m/z: 618 [M+H] +. III-2
Figure 02_image920
 MS (ESI) m/z: 632 [M+H] +. III-3
Figure 02_image922
 MS (ESI) m/z: 646 [M+H] +. III-4
Figure 02_image924
 MS (ESI) m/z: 644 [M+H] +. III-5
Figure 02_image926
 MS (ESI) m/z: 648 [M+H] +. III-6
Figure 02_image928
 MS (ESI) m/z: 662 [M+H] +. III-7
Figure 02_image930
 MS (ESI) m/z: 676 [M+H] +. III-8
Figure 02_image932
 MS (ESI) m/z: 674 [M+H] +. III-9
Figure 02_image934
 MS (ESI) m/z: 731 [M+H] +. III-10
Figure 02_image936
 MS (ESI) m/z: 745 [M+H] +. III-11
Figure 02_image938
 MS (ESI) m/z: 759 [M+H] +. III-12
Figure 02_image940
 MS (ESI) m/z: 757 [M+H] +. III-13
Figure 02_image942
 MS (ESI) m/z: 566 [M+H] +. III-14
Figure 02_image944
 MS (ESI) m/z: 580 [M+H] +. III-15
Figure 02_image946
 MS (ESI) m/z: 594 [M+H] +. III-16
Figure 02_image948
 MS (ESI) m/z: 592 [M+H] +. III-17
Figure 02_image950
 MS (ESI) m/z: 596 [M+H] +. III-18
Figure 02_image952
 MS (ESI) m/z: 610 [M+H] +. III-19
Figure 02_image954
 MS (ESI) m/z: 624 [M+H] +. III-20
Figure 02_image956
 MS (ESI) m/z: 622 [M+H] +. III-21
Figure 02_image958
 MS (ESI) m/z: 679 [M+H] +. III-22
Figure 02_image960
 MS (ESI) m/z: 693 [M+H] +. III-23
Figure 02_image962
 MS (ESI) m/z: 707 [M+H] +. III-24
Figure 02_image964
 MS (ESI) m/z: 705 [M+H] +. 生物活性測試 The following table lists specific compounds and structural identification information: serial number structure H NMR and/or MS data III-1
Figure 02_image918
 MS (ESI) m/z : 618 [M+H] + . III-2
Figure 02_image920
 MS (ESI) m/z : 632 [M+H] + . III-3
Figure 02_image922
 MS (ESI) m/z : 646 [M+H] + . III-4
Figure 02_image924
 MS (ESI) m/z : 644 [M+H] + . III-5
Figure 02_image926
 MS (ESI) m/z : 648 [M+H] + . III-6
Figure 02_image928
 MS (ESI) m/z : 662 [M+H] + . III-7
Figure 02_image930
 MS (ESI) m/z : 676 [M+H] + . III-8
Figure 02_image932
 MS (ESI) m/z : 674 [M+H] + . III-9
Figure 02_image934
 MS (ESI) m/z : 731 [M+H] + . III-10
Figure 02_image936
 MS (ESI) m/z : 745 [M+H] + . III-11
Figure 02_image938
 MS (ESI) m/z : 759 [M+H] + . III-12
Figure 02_image940
 MS (ESI) m/z : 757 [M+H] + . III-13
Figure 02_image942
 MS (ESI) m/z : 566 [M+H] + . III-14
Figure 02_image944
 MS (ESI) m/z : 580 [M+H] + . III-15
Figure 02_image946
 MS (ESI) m/z : 594 [M+H] + . III-16
Figure 02_image948
 MS (ESI) m/z : 592 [M+H] + . III-17
Figure 02_image950
 MS (ESI) m/z : 596 [M+H] + . III-18
Figure 02_image952
 MS (ESI) m/z : 610 [M+H] + . III-19
Figure 02_image954
 MS (ESI) m/z : 624 [M+H] + . III-20
Figure 02_image956
 MS (ESI) m/z : 622 [M+H] + . III-21
Figure 02_image958
 MS (ESI) m/z : 679 [M+H] + . III-22
Figure 02_image960
 MS (ESI) m/z : 693 [M+H] + . III-23
Figure 02_image962
 MS (ESI) m/z : 707 [M+H] + . III-24
Figure 02_image964
 MS (ESI) m/z : 705 [M+H] + . Biological activity test

化合物對激酶穩轉細胞系的生長抑制活性。 化合物對激酶EGFR各種突變體的活性藉由其抑制激酶穩轉的BaF 3細胞系的生長進行評價。具體試驗方法如下： Growth inhibitory activity of compounds against kinase-stabilized cell lines. The activity of compounds against various mutants of the kinase EGFR was assessed by their inhibition of the growth of the kinase-stabilized BaF 3 cell line. The specific test method is as follows:

1）培養基：DMEM (Dulbecco's modified eagle medium) 或RPMI1640 (含10% 胎牛血清，100 μg/mL氨苄青黴素，100 μg/mL鏈黴素)。1) Medium: DMEM (Dulbecco's modified eagle medium) or RPMI1640 (containing 10% fetal bovine serum, 100 μg/mL ampicillin, 100 μg/mL streptomycin).

2）試劑：MTS反應液 (含2 mg/mL的MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt); 100 μg/mL的PES (phenazine methosulfate)。2) Reagent: MTS reaction solution (containing 2 mg/mL of MTS (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt); 100 μg/mL of PES (phenazine methosulfate).

3）化合物測試：將細胞接入96-孔培養板，細胞液體積為90 μL，然後加入各梯度濃度化合物10 μL，最高濃度為10 μM，依次按1/3逐級稀釋，共設置8個濃度點，體系中含0.1% DMSO（二甲基亞碸）。混勻化合物的細胞板置於細胞培養箱中（37 ℃；5% CO 2）培養48 h，再加入20 μL的MTS反應液，混勻後置於細胞培養箱中（37 ℃；5% CO 2）孵育1-4 h；採用酶標儀（VARIOSKAN FLASH, Thermo）測量490 nm波長下的OD值。每組實驗設置兩個平行，以終濃度為0.1% DMSO為陰性對照，以不含細胞及化合物的培養基為空白對照。細胞生長抑制率由如下公式計算： 抑制率%=1-（OD實驗組-OD空白組）/（OD陰性組-OD空白組）*100% 3) Compound test: insert the cells into a 96-well culture plate, the volume of the cell solution is 90 μL, and then add 10 μL of each gradient concentration of the compound, the highest concentration is 10 μM, successively dilute by 1/3, a total of 8 sets Concentration point, the system contains 0.1% DMSO (dimethyl sulfide). The mixed compound cell plate was placed in a cell culture incubator (37 °C; 5% CO 2 ) for 48 h, and then 20 μL of MTS reaction solution was added, mixed and placed in a cell culture incubator (37 °C; 5% CO 2 ). 2 ) Incubate for 1-4 h; use a microplate reader (VARIOSKAN FLASH, Thermo) to measure the OD value at a wavelength of 490 nm. Two parallel experiments were set up in each group, with the final concentration of 0.1% DMSO as the negative control, and the culture medium without cells and compounds as the blank control. The cell growth inhibition rate is calculated by the following formula: Inhibition rate%=1-(OD experimental group-OD blank group)/(OD negative group-OD blank group)*100%

4）IC 50值計算：根據測量的細胞抑制率利用GradPad Prism 5軟體計算化合物作用於細胞的半抑制濃度。 4) Calculation of IC 50 value: According to the measured cell inhibition rate, the half-inhibitory concentration of the compound acting on the cells was calculated using GradPad Prism 5 software.

下表列出化合物對激酶穩轉細胞系的生長抑制活性： 序號 Del L858R Del/ T790M L858R /T790M Del/ T790M/C797S L858R/ T790M/C797S I-1 ++++ ++++ ++++ ++++ ++++ ++++ I-2 +++ +++ +++ +++ +++ ++++ I-3 +++ +++ +++ +++ +++ ++++ I-4 +++ +++ +++ +++ +++ ++++ I-5 +++ +++ +++ +++ +++ ++++ I-6 +++ +++ +++ ++++ ++++ ++++ I-9 ++++ +++ +++ ++++ +++ ++++ I-10 +++ +++ ++ +++ ++ ++++ I-11 ++++ ++++ ++++ ++++ ++++ ++++ I-12 +++ +++ +++ +++ ++++ ++++ I-13 +++ +++ +++ +++ ++++ ++++ I-14 ++++ ++++ +++ ++++ ++++ ++++ I-15 +++ +++ +++ +++ ++++ ++++ I-16 +++ +++ ++++ ++++ ++++ ++++ I-17 ++++ ++++ ++++ ++++ ++++ ++++ I-18 +++ +++ +++ ++++ ++++ ++++ I-19 +++ ++ ++ +++ +++ +++ I-20 +++ ++ +++ +++ +++ +++ I-21 +++ +++ +++ +++ +++ ++++ I-25 +++ +++ +++ +++ +++ ++++ I-26 ++++ ++++ ++++ ++++ ++++ ++++ I-27 ++++ ++++ ++++ ++++ ++++ ++++ I-28 +++ ++ ++ +++ ++++ ++++ I-30 ++++ ++++ ++++ ++++ ++++ ++++ I-31 +++ ++++ +++ ++++ ++++ ++++ I-32 +++ +++ +++ +++ ++++ ++++ I-34 +++ +++ +++ +++ ++++ ++++ I-35 +++ +++ +++ +++ ++++ ++++ I-36 +++ +++ +++ ++++ ++++ ++++ I-39 +++ ++++ +++ +++ ++++ ++++ I-40 +++ +++ +++ +++ ++++ ++++ I-41 ++ ++ ++ ++ ++ +++ I-43 +++ +++ +++ ++++ +++ ++++ I-44 ++ ++ ++ +++ ++ +++ I-45 +++ +++ +++ +++ +++ ++++ I-46 +++ +++ +++ ++++ ++++ ++++ I-48 +++ +++ +++ ++++ ++++ ++++ I-49 +++ ++ ++ +++ +++ +++ I-50 +++ +++ +++ ++++ +++ ++++ I-51 ++ ++ ++ +++ +++ ++++ I-52 +++ +++ +++ ++++ +++ ++++ I-53 +++ ++ ++ +++ ++ +++ I-54 +++ +++ +++ +++ +++ ++++ I-55 ++++ ++++ +++ ++++ ++++ ++++ I-56 ++++ +++ +++ ++++ +++ ++++ I-57 ++++ ++++ ++++ ++++ ++++ ++++ I-63 ++++ +++ +++ ++++ +++ ++++ I-69 ++++ ++++ ++++ ++++ ++++ ++++ I-75 ++ ++ ++ +++ +++ +++ I-76 +++ +++ +++ +++ ++++ +++ I-77 ++++ ++++ ++++ ++++ ++++ ++++ I-78 +++ +++ ++ +++ +++ +++ I-79 ++++ ++++ +++ +++ ++++ ++++ I-80 +++ +++ ++ +++ +++ ++++ I-81 +++ +++ ++ +++ +++ ++++ I-82 +++ +++ ++ ++ ++ +++ I-83 +++ +++ ++ +++ +++ +++ I-84 +++ +++ +++ +++ +++ ++++ I-87 +++ +++ +++ ++++ +++ ++++ I-88 +++ +++ ++ ++ ++ +++ I-89 ++++ ++++ +++ ++++ +++ ++++ I-90 +++ +++ ++ ++ +++ ++++ I-91 +++ +++ ++ ++ ++++ +++ I-92 +++ ++++ +++ +++ ++++ +++ I-93 +++ +++ ++ +++ ++++ +++ I-94 +++ +++ +++ +++ ++++ +++ I-95 ++++ ++++ +++ +++ ++++ ++++ I-96 +++ +++ +++ +++ ++++ ++++ I-97 +++ ++ ++ ++ ++ +++ I-98 +++ +++ ++ ++ ++ +++ I-99 +++ +++ ++ +++ +++ ++++ I-100 ++++ ++++ ++++ ++++ ++++ ++++ I-103 +++ +++ ++ ++ ++ +++ I-104 ++++ ++++ +++ +++ ++++ ++++ I-105 ++++ ++++ ++++ ++++ ++++ ++++ I-106 ++ +++ ++ ++ +++ +++ I-108 ++++ ++++ +++ +++ ++++ ++++ I-109 +++ ++++ +++ +++ ++++ ++++ I-110 +++ +++ +++ +++ ++++ ++++ I-112 +++ +++ ++ +++ +++ ++++ I-113 +++ +++ ++ +++ ++++ ++++ I-114 +++ +++ +++ +++ ++++ ++++ I-117 +++ +++ +++ +++ +++ ++++ I-118 +++ +++ +++ +++ +++ ++++ I-121 +++ +++ +++ +++ +++ ++++ I-122 ++ ++ ++ ++ ++ +++ I-123 +++ +++ +++ +++ +++ ++++ I-124 ++++ +++ +++ +++ +++ ++++ I-126 ++++ +++ +++ +++ +++ ++++ I-127 ++ ++ ++ ++ ++ +++ I-128 +++ +++ +++ +++ +++ +++ I-129 ++ ++ ++ ++ ++ +++ I-130 +++ +++ +++ +++ +++ ++++ I-131 ++ ++ ++ ++ ++ +++ I-132 +++ +++ +++ +++ +++ +++ I-133 ++++ ++++ +++ +++ ++++ ++++ I-153 +++ ++++ +++ ++++ ++++ ++++ I-134 +++ +++ ++ +++ +++ ++++ I-135 ++++ ++++ +++ ++++ ++++ ++++ I-141 +++ +++ +++ +++ ++++ ++++ I-147 ++++ ++++ +++ ++++ ++++ ++++ I-155 ++ ++ ++ ++ +++ +++ I-156 +++ +++ ++ ++ +++ +++ I-157 ++++ ++++ ++++ ++++ ++++ ++++ I-158 ++++ ++++ +++ +++ +++ ++++ I-159 ++++ ++++ +++ ++++ ++++ ++++ I-160 ++++ ++++ +++ ++++ ++++ ++++ I-161 +++ +++ +++ +++ +++ ++++ I-162 +++ +++ +++ +++ +++ ++++ I-163 +++ +++ +++ +++ +++ ++++ I-164 +++ +++ +++ +++ +++ ++++ I-165 +++ +++ +++ ++++ +++ ++++ I-166 ++++ ++++ +++ ++++ ++++ ++++ I-167 ++++ ++++ ++++ ++++ ++++ ++++ I-168 +++ +++ +++ ++++ +++ ++++ I-169 +++ +++ ++ +++ ++ +++ I-170 ++++ ++++ +++ ++++ ++++ ++++ I-171 +++ +++ +++ +++ +++ ++++ I-172 ++++ ++++ +++ ++++ ++++ ++++ I-173 ++++ ++++ +++ ++++ +++ ++++ I-174 ++++ ++++ ++++ ++++ ++++ ++++ I-178 +++ +++ +++ ++++ ++++ ++++ I-179 ++++ ++++ +++ ++++ ++++ ++++ I-180 ++++ ++++ +++ ++++ ++++ ++++ I-181 +++ +++ ++ +++ +++ ++++ I-182 +++ +++ +++ ++++ ++++ ++++ I-183 +++ +++ +++ +++ +++ ++++ I-184 ++++ ++++ +++ ++++ ++++ ++++ I-185 ++++ ++++ +++ +++ ++++ ++++ I-186 ++++ ++++ +++ ++++ ++++ ++++ I-187 ++++ +++ ++ +++ +++ ++++ I-188 ++++ ++++ +++ +++ ++++ ++++ I-189 +++ +++ ++ ++ ++ +++ I-190 +++ +++ ++ +++ +++ ++++ I-191 ++++ ++++ +++ ++++ ++++ ++++ I-192 +++ ++++ +++ ++++ ++++ ++++ I-193 ++++ ++++ ++++ ++++ ++++ ++++ I-194 ++++ ++++ ++++ ++++ ++++ ++++ I-195 +++ +++ ++++ ++++ ++++ +++ I-196 +++ +++ +++ ++++ ++++ ++++ I-197 +++ +++ +++ +++ +++ +++ I-198 ++++ ++++ ++++ ++++ ++++ ++++ I-199 +++ ++++ ++++ ++++ ++++ ++++ I-200 +++ +++ ++ +++ +++ +++ I-201 +++ +++ +++ +++ +++ +++ I-202 +++ +++ +++ +++ ++++ ++++ I-203 +++ +++ ++++ ++++ ++++ ++++ I-204 +++ ++++ ++++ +++ ++++ ++++ I-205 +++ +++ +++ +++ +++ +++ I-206 +++ +++ +++ +++ +++ ++++ I-207 +++ +++ +++ +++ +++ +++ I-208 ++++ ++++ +++ ++++ ++++ ++++ I-209 +++ +++ +++ +++ ++++ ++++ I-210 +++ +++ +++ +++ +++ ++++ I-211 +++ ++++ ++++ ++++ ++++ ++++ I-212 ++++ ++++ ++++ ++++ ++++ ++++ I-213 ++++ ++++ ++++ ++++ ++++ ++++ I-214 ++++ ++++ ++++ ++++ ++++ ++++ I-215 +++ ++++ ++++ ++++ ++++ ++++ I-216 +++ ++++ ++++ ++++ ++++ ++++ I-217 +++ ++++ +++ +++ +++ +++ I-218 ++++ ++++ ++++ ++++ ++++ ++++ I-219 ++++ ++++ ++++ ++++ ++++ ++++ I-220 ++ ++ ++ ++ +++ ++++ I-221 ++ ++ ++ +++ ++++ ++++ I-222 ++ ++ ++ +++ ++++ ++++ I-223 +++ +++ +++ +++ ++++ ++++ I-224 ++ +++ +++ +++ ++++ ++++ I-225 +++ +++ +++ ++++ ++++ ++++ I-226 +++ +++ +++ +++ ++++ ++++ I-227 ++ ++ ++ +++ ++++ ++++ I-228 +++ +++ ++ +++ ++ ++++ I-229 ++++ ++++ ++++ ++++ ++++ ++++ I-230 ++++ ++++ +++ ++++ ++++ ++++ I-231 ++++ +++ +++ +++ +++ ++++ I-232 ++++ ++++ +++ +++ +++ ++++ I-233 +++ +++ +++ +++ +++ ++++ I-234 +++ +++ +++ +++ +++ ++++ I-235 +++ +++ +++ +++ +++ ++++ I-236 +++ +++ +++ +++ ++++ ++++ I-237 +++ +++ +++ ++++ ++++ ++++ I-238 ++++ ++++ +++ ++++ ++++ ++++ I-239 +++ +++ +++ +++ ++++ +++ I-240 ++++ ++++ ++++ ++++ ++++ ++++ I-241 +++ +++ +++ +++ ++++ ++++ I-242 +++ +++ +++ +++ +++ +++ I-243 ++++ ++++ ++++ ++++ ++++ ++++ I-244 +++ +++ ++++ +++ ++++ ++++ I-245 ND ND ND ND ND ++++ II-1 ++++ ++++ +++ ++++ ++++ ++++ II-5 ++ ++ +++ +++ +++ ++++ II-9 +++ +++ +++ ++++ ++++ ++++ II-13 +++ +++ +++ +++ +++ +++ II-17 ++ ++ ++ +++ +++ +++ II-21 +++ +++ +++ +++ +++ +++ The following table lists the growth inhibitory activity of compounds against kinase-stabilized cell lines: serial number Del L858R Del/T790M L858R/T790M Del/ T790M/C797S L858R/ T790M/C797S I-1 ++++ ++++ ++++ ++++ ++++ ++++ I-2 +++ +++ +++ +++ +++ ++++ I-3 +++ +++ +++ +++ +++ ++++ I-4 +++ +++ +++ +++ +++ ++++ I-5 +++ +++ +++ +++ +++ ++++ I-6 +++ +++ +++ ++++ ++++ ++++ I-9 ++++ +++ +++ ++++ +++ ++++ I-10 +++ +++ ++ +++ ++ ++++ I-11 ++++ ++++ ++++ ++++ ++++ ++++ I-12 +++ +++ +++ +++ ++++ ++++ I-13 +++ +++ +++ +++ ++++ ++++ I-14 ++++ ++++ +++ ++++ ++++ ++++ I-15 +++ +++ +++ +++ ++++ ++++ I-16 +++ +++ ++++ ++++ ++++ ++++ I-17 ++++ ++++ ++++ ++++ ++++ ++++ I-18 +++ +++ +++ ++++ ++++ ++++ I-19 +++ ++ ++ +++ +++ +++ I-20 +++ ++ +++ +++ +++ +++ I-21 +++ +++ +++ +++ +++ ++++ I-25 +++ +++ +++ +++ +++ ++++ I-26 ++++ ++++ ++++ ++++ ++++ ++++ I-27 ++++ ++++ ++++ ++++ ++++ ++++ I-28 +++ ++ ++ +++ ++++ ++++ I-30 ++++ ++++ ++++ ++++ ++++ ++++ I-31 +++ ++++ +++ ++++ ++++ ++++ I-32 +++ +++ +++ +++ ++++ ++++ I-34 +++ +++ +++ +++ ++++ ++++ I-35 +++ +++ +++ +++ ++++ ++++ I-36 +++ +++ +++ ++++ ++++ ++++ I-39 +++ ++++ +++ +++ ++++ ++++ I-40 +++ +++ +++ +++ ++++ ++++ I-41 ++ ++ ++ ++ ++ +++ I-43 +++ +++ +++ ++++ +++ ++++ I-44 ++ ++ ++ +++ ++ +++ I-45 +++ +++ +++ +++ +++ ++++ I-46 +++ +++ +++ ++++ ++++ ++++ I-48 +++ +++ +++ ++++ ++++ ++++ I-49 +++ ++ ++ +++ +++ +++ I-50 +++ +++ +++ ++++ +++ ++++ I-51 ++ ++ ++ +++ +++ ++++ I-52 +++ +++ +++ ++++ +++ ++++ I-53 +++ ++ ++ +++ ++ +++ I-54 +++ +++ +++ +++ +++ ++++ I-55 ++++ ++++ +++ ++++ ++++ ++++ I-56 ++++ +++ +++ ++++ +++ ++++ I-57 ++++ ++++ ++++ ++++ ++++ ++++ I-63 ++++ +++ +++ ++++ +++ ++++ I-69 ++++ ++++ ++++ ++++ ++++ ++++ I-75 ++ ++ ++ +++ +++ +++ I-76 +++ +++ +++ +++ ++++ +++ I-77 ++++ ++++ ++++ ++++ ++++ ++++ I-78 +++ +++ ++ +++ +++ +++ I-79 ++++ ++++ +++ +++ ++++ ++++ I-80 +++ +++ ++ +++ +++ ++++ I-81 +++ +++ ++ +++ +++ ++++ I-82 +++ +++ ++ ++ ++ +++ I-83 +++ +++ ++ +++ +++ +++ I-84 +++ +++ +++ +++ +++ ++++ I-87 +++ +++ +++ ++++ +++ ++++ I-88 +++ +++ ++ ++ ++ +++ I-89 ++++ ++++ +++ ++++ +++ ++++ I-90 +++ +++ ++ ++ +++ ++++ I-91 +++ +++ ++ ++ ++++ +++ I-92 +++ ++++ +++ +++ ++++ +++ I-93 +++ +++ ++ +++ ++++ +++ I-94 +++ +++ +++ +++ ++++ +++ I-95 ++++ ++++ +++ +++ ++++ ++++ I-96 +++ +++ +++ +++ ++++ ++++ I-97 +++ ++ ++ ++ ++ +++ I-98 +++ +++ ++ ++ ++ +++ I-99 +++ +++ ++ +++ +++ ++++ I-100 ++++ ++++ ++++ ++++ ++++ ++++ I-103 +++ +++ ++ ++ ++ +++ I-104 ++++ ++++ +++ +++ ++++ ++++ I-105 ++++ ++++ ++++ ++++ ++++ ++++ I-106 ++ +++ ++ ++ +++ +++ I-108 ++++ ++++ +++ +++ ++++ ++++ I-109 +++ ++++ +++ +++ ++++ ++++ I-110 +++ +++ +++ +++ ++++ ++++ I-112 +++ +++ ++ +++ +++ ++++ I-113 +++ +++ ++ +++ ++++ ++++ I-114 +++ +++ +++ +++ ++++ ++++ I-117 +++ +++ +++ +++ +++ ++++ I-118 +++ +++ +++ +++ +++ ++++ I-121 +++ +++ +++ +++ +++ ++++ I-122 ++ ++ ++ ++ ++ +++ I-123 +++ +++ +++ +++ +++ ++++ I-124 ++++ +++ +++ +++ +++ ++++ I-126 ++++ +++ +++ +++ +++ ++++ I-127 ++ ++ ++ ++ ++ +++ I-128 +++ +++ +++ +++ +++ +++ I-129 ++ ++ ++ ++ ++ +++ I-130 +++ +++ +++ +++ +++ ++++ I-131 ++ ++ ++ ++ ++ +++ I-132 +++ +++ +++ +++ +++ +++ I-133 ++++ ++++ +++ +++ ++++ ++++ I-153 +++ ++++ +++ ++++ ++++ ++++ I-134 +++ +++ ++ +++ +++ ++++ I-135 ++++ ++++ +++ ++++ ++++ ++++ I-141 +++ +++ +++ +++ ++++ ++++ I-147 ++++ ++++ +++ ++++ ++++ ++++ I-155 ++ ++ ++ ++ +++ +++ I-156 +++ +++ ++ ++ +++ +++ I-157 ++++ ++++ ++++ ++++ ++++ ++++ I-158 ++++ ++++ +++ +++ +++ ++++ I-159 ++++ ++++ +++ ++++ ++++ ++++ I-160 ++++ ++++ +++ ++++ ++++ ++++ I-161 +++ +++ +++ +++ +++ ++++ I-162 +++ +++ +++ +++ +++ ++++ I-163 +++ +++ +++ +++ +++ ++++ I-164 +++ +++ +++ +++ +++ ++++ I-165 +++ +++ +++ ++++ +++ ++++ I-166 ++++ ++++ +++ ++++ ++++ ++++ I-167 ++++ ++++ ++++ ++++ ++++ ++++ I-168 +++ +++ +++ ++++ +++ ++++ I-169 +++ +++ ++ +++ ++ +++ I-170 ++++ ++++ +++ ++++ ++++ ++++ I-171 +++ +++ +++ +++ +++ ++++ I-172 ++++ ++++ +++ ++++ ++++ ++++ I-173 ++++ ++++ +++ ++++ +++ ++++ I-174 ++++ ++++ ++++ ++++ ++++ ++++ I-178 +++ +++ +++ ++++ ++++ ++++ I-179 ++++ ++++ +++ ++++ ++++ ++++ I-180 ++++ ++++ +++ ++++ ++++ ++++ I-181 +++ +++ ++ +++ +++ ++++ I-182 +++ +++ +++ ++++ ++++ ++++ I-183 +++ +++ +++ +++ +++ ++++ I-184 ++++ ++++ +++ ++++ ++++ ++++ I-185 ++++ ++++ +++ +++ ++++ ++++ I-186 ++++ ++++ +++ ++++ ++++ ++++ I-187 ++++ +++ ++ +++ +++ ++++ I-188 ++++ ++++ +++ +++ ++++ ++++ I-189 +++ +++ ++ ++ ++ +++ I-190 +++ +++ ++ +++ +++ ++++ I-191 ++++ ++++ +++ ++++ ++++ ++++ I-192 +++ ++++ +++ ++++ ++++ ++++ I-193 ++++ ++++ ++++ ++++ ++++ ++++ I-194 ++++ ++++ ++++ ++++ ++++ ++++ I-195 +++ +++ ++++ ++++ ++++ +++ I-196 +++ +++ +++ ++++ ++++ ++++ I-197 +++ +++ +++ +++ +++ +++ I-198 ++++ ++++ ++++ ++++ ++++ ++++ I-199 +++ ++++ ++++ ++++ ++++ ++++ I-200 +++ +++ ++ +++ +++ +++ I-201 +++ +++ +++ +++ +++ +++ I-202 +++ +++ +++ +++ ++++ ++++ I-203 +++ +++ ++++ ++++ ++++ ++++ I-204 +++ ++++ ++++ +++ ++++ ++++ I-205 +++ +++ +++ +++ +++ +++ I-206 +++ +++ +++ +++ +++ ++++ I-207 +++ +++ +++ +++ +++ +++ I-208 ++++ ++++ +++ ++++ ++++ ++++ I-209 +++ +++ +++ +++ ++++ ++++ I-210 +++ +++ +++ +++ +++ ++++ I-211 +++ ++++ ++++ ++++ ++++ ++++ I-212 ++++ ++++ ++++ ++++ ++++ ++++ I-213 ++++ ++++ ++++ ++++ ++++ ++++ I-214 ++++ ++++ ++++ ++++ ++++ ++++ I-215 +++ ++++ ++++ ++++ ++++ ++++ I-216 +++ ++++ ++++ ++++ ++++ ++++ I-217 +++ ++++ +++ +++ +++ +++ I-218 ++++ ++++ ++++ ++++ ++++ ++++ I-219 ++++ ++++ ++++ ++++ ++++ ++++ I-220 ++ ++ ++ ++ +++ ++++ I-221 ++ ++ ++ +++ ++++ ++++ I-222 ++ ++ ++ +++ ++++ ++++ I-223 +++ +++ +++ +++ ++++ ++++ I-224 ++ +++ +++ +++ ++++ ++++ I-225 +++ +++ +++ ++++ ++++ ++++ I-226 +++ +++ +++ +++ ++++ ++++ I-227 ++ ++ ++ +++ ++++ ++++ I-228 +++ +++ ++ +++ ++ ++++ I-229 ++++ ++++ ++++ ++++ ++++ ++++ I-230 ++++ ++++ +++ ++++ ++++ ++++ I-231 ++++ +++ +++ +++ +++ ++++ I-232 ++++ ++++ +++ +++ +++ ++++ I-233 +++ +++ +++ +++ +++ ++++ I-234 +++ +++ +++ +++ +++ ++++ I-235 +++ +++ +++ +++ +++ ++++ I-236 +++ +++ +++ +++ ++++ ++++ I-237 +++ +++ +++ ++++ ++++ ++++ I-238 ++++ ++++ +++ ++++ ++++ ++++ I-239 +++ +++ +++ +++ ++++ +++ I-240 ++++ ++++ ++++ ++++ ++++ ++++ I-241 +++ +++ +++ +++ ++++ ++++ I-242 +++ +++ +++ +++ +++ +++ I-243 ++++ ++++ ++++ ++++ ++++ ++++ I-244 +++ +++ ++++ +++ ++++ ++++ I-245 ND ND ND ND ND ++++ II-1 ++++ ++++ +++ ++++ ++++ ++++ II-5 ++ ++ +++ +++ +++ ++++ II-9 +++ +++ +++ ++++ ++++ ++++ II-13 +++ +++ +++ +++ +++ +++ II-17 ++ ++ ++ +++ +++ +++ II-21 +++ +++ +++ +++ +++ +++

注：++++代表IC 50≤ 50 nM；+++代表50 nM ＜ IC 50≤ 500 nM；++代表500 nM ＜ IC 50≤ 2500 nM；ND代表未測定。 Note: ++++ means IC 50 ≤ 50 nM; +++ means 50 nM < IC 50 ≤ 500 nM; ++ means 500 nM < IC 50 ≤ 2500 nM; ND means not determined.

其餘化合物同樣對上述激酶穩轉細胞系的生長具有優良的抑制活性。The rest of the compounds also have excellent inhibitory activity on the growth of the above-mentioned kinase stably transfected cell lines.

Figure 111129587-A0101-11-0001-2
Figure 111129587-A0101-11-0001-2

Claims (10)

一種以下通式（A）的化合物：
Figure 03_image001
(A) 或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）2-N, N-二甲基氨基乙氧基，2-(N-甲基呱嗪基)乙氧基，2-(N-乙醯基呱嗪基)乙氧基，2-嗎啡啉基乙氧基，2-硫啡啉基乙氧基，2-呱啶基乙氧基，3-N, N-二甲基氨基丙氧基，3-N, N-二乙基氨基丙氧基，3-N, N-二異丙基氨基丙氧基，3-(N-甲基呱嗪基)丙氧基，3-(N-乙醯基呱嗪基)丙氧基，3-嗎啉基丙氧基，3-硫啡啉基丙氧基，3-呱啶基丙氧基，2-吡啶基甲氧基，3-吡啶基甲氧基，4-吡啶基甲氧基，苯基甲氧基，單鹵素取代苯基甲氧基，偕二鹵素取代苯基甲氧基，雜二鹵素取代苯基甲氧基， （4）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （5）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （6）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （7）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （8）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （9）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （10）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （11）氨基亞甲基，N, N-二甲基氨基亞甲基，N, N-二乙基氨基亞甲基，4-甲基-1-呱嗪亞甲基，4-乙基-1-呱嗪亞甲基，4-丙基-1-呱嗪亞甲基，4-異丙基-1-呱嗪亞甲基，4-(2-羥基乙基)-1-呱嗪亞甲基，4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基，呱啶-1-亞甲基，4-(N, N-二甲基氨基)-1-呱啶亞甲基，4-羥基呱啶-1-亞甲基，四氫吡咯-1-亞甲基，3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基，苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （12）氨基甲醯基，甲胺基甲醯基，N, N-二甲基氨基甲醯基，乙胺基甲醯基，環丙基胺基甲醯基，環丁基胺基甲醯基，環戊基胺基甲醯基，環己基胺基甲醯基，氨基乙醯基，甲胺基乙醯基，2-(N, N-二甲基氨基)乙醯基，乙胺基乙醯基，環丙基胺基乙醯基，環丁基胺基乙醯基，環戊基胺基乙醯基，環己基胺基乙醯基， 四氫吡咯-1-甲醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基， 嗎啡啉基-4-甲醯基，硫啡啉基-4-甲醯基，2, 6-二甲基嗎啡啉基-4-甲醯基， 呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （13）羥基甲醯基，甲氧基甲醯基，乙氧基甲醯基，丙氧基甲醯基，異丙氧基甲醯基，正丁氧基甲醯基，異丁氧基甲醯基，叔丁氧基甲醯基， （14）羥基磺醯基，氨基磺醯基，甲胺基磺醯基，乙胺基磺醯基，丙胺基磺醯基，異丙胺基磺醯基，環丙胺基磺醯基，環丁胺基磺醯基，環戊胺基磺醯基，環己胺基磺醯基， 四氫吡咯-1-磺醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基， 嗎啡啉基-4-磺醯基，硫啡啉基-4-磺醯基，2 6-二甲基嗎啡啉基-4-磺醯基， 呱啶基-1-磺醯基，4-羥基呱啶-1-磺醯基，4-(N, N-二甲基氨基)呱啶基-1-磺醯基，4-(N, N-二乙基氨基)呱啶基-1-磺醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基， N-甲基呱嗪-1-磺醯基，N-乙基呱嗪-1-磺醯基，N-異丙基呱嗪-1-磺醯基，N-(2-羥基乙基)呱嗪-1-磺醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基，4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基，4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基， （15）氨基甲醯氨基，甲氨基甲醯氨基，乙氨基甲醯氨基，丙氨基甲醯氨基，異丙氨基甲醯氨基，環丙基氨基甲醯氨基，環丁基氨基甲醯氨基，環戊基氨基甲醯氨基，呱啶基-1-甲醯氨基，4-羥基呱啶基-1-甲醯氨基，4-N, N-二甲基呱啶基-1-甲醯氨基，4-N, N-二乙基呱啶基-1-甲醯氨基，四氫吡咯基-1-甲醯氨基，3-N, N-二甲基四氫吡咯基-1-甲醯氨基，3-N, N-二乙基四氫吡咯基-1-甲醯氨基，N-甲基呱嗪基-1-甲醯氨基，N-乙基呱嗪基-1-甲醯氨基，N-乙醯基呱嗪基-1-甲醯氨基，N-叔丁氧羰基呱嗪基-1-甲醯氨基，N-(2-羥基乙基)呱嗪基-1-甲醯氨基，N-(2-氰基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基，N-(3-羥基丙基)呱嗪基-1-甲醯氨基， N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基，N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基，嗎啉基-1-甲醯氨基，3, 5-二甲基嗎啉基-1-甲醯氨基，4-(四氫吡咯基)呱啶基-1-甲醯氨基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基，N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基， （16）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image009
，
Figure 03_image011
，
Figure 03_image013
，
Figure 03_image015
，
Figure 03_image017
，
Figure 03_image019
，
Figure 03_image021
，
Figure 03_image023
，
Figure 03_image025
，
Figure 03_image027
，
Figure 03_image029
； 2）
Figure 03_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 03_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 03_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； 較佳地，R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （12）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image009
，
Figure 03_image011
，
Figure 03_image013
，
Figure 03_image015
，
Figure 03_image017
，
Figure 03_image019
，
Figure 03_image021
，
Figure 03_image023
，
Figure 03_image025
，
Figure 03_image027
，
Figure 03_image029
； 2）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 更佳地，R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基， 3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image009
，
Figure 03_image011
，
Figure 03_image013
，
Figure 03_image015
，
Figure 03_image017
，
Figure 03_image019
，
Figure 03_image021
，
Figure 03_image023
，
Figure 03_image025
，
Figure 03_image027
，
Figure 03_image029
； 2）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基、N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-异丙基-N-(2-N, N-二甲基氨基)乙基氨基； 最佳地，R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基， N-三氘代甲基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基， （5）3-(N, N-二甲基氨基)四氫吡咯基， （6）1-咪唑基，1-吡唑基，1-甲基吡唑-4-基， （7）4-N, N-二甲基氨基呱啶基，4-羥基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基， （8）N-甲基-4-呱啶基， （9）2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基， 2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基， （10）苄基，環丙基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image015
，
Figure 03_image023
； 2）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）4-N, N-二甲基氨基呱啶基， 4-(N-甲基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基； R 2選自： 1）
Figure 03_image039
，其中，Z 1、Z 2各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C6環烷基，C3-C6含氟環烷基，且Z 2不為氫； 較佳地，Z 1、Z 2各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基，且Z 2不為氫； 更佳地，Z 1、Z 2各自獨立地選自氫，C1-C6烷基，C3-C6環烷基，且Z 2不為氫； 最佳地，Z 1、Z 2各自獨立地選自氫、甲基、乙基、異丙基，環丙基，且Z 2不為氫； 2）
Figure 03_image041
，其中，Z 3選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C8環烷基，C1-C6含雜原子烷基，C3-C8含雜原子環烷基； 較佳地，Z 3選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； 更佳地，Z 3選自C1-C6烷基，C3-C6環烷基； 最佳地，Z 3選自甲基、乙基、異丙基、環丙基； 3）
Figure 03_image043
，其中，Z 4、Z 5各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C3-C6環烷基，C3-C6含氟環烷基，或者，Z 4、Z 5與N一起形成取代或未取代的含1~2個雜原子的4-8元環，該取代基選自鹵素，C1-C6烷基，C3-C8環烷基； 較佳地，Z 4、Z 5各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基，且Z 4、Z 5不同時為氫； 更佳地，Z 4、Z 5各自獨立地選自氫，C1-C6烷基，C3-C6環烷基，且Z 4、Z 5不同時為氫； 最佳地，Z 4、Z 5各自獨立地選自氫、甲基、乙基、異丙基、環丙基，且Z 4、Z 5不同時為氫； R 3、R 4各自獨立地選自氫，氟，氯，溴，碘，氰基，硝基，C1-C6含氧烷基，C1-C6含氟烷基（例如，三氟甲基），C1-C6烷基（例如，甲基，乙基或異丙基），C1-C6烷氧基（例如，甲氧基或乙氧基），C3-C6環烷基（例如，環丙基），C2-C6烯基； 或者，R 3、R 4和與它們相連的碳原子一起，形成含一個N、O或S原子的5元環； 較佳地，R 3、R 4各自獨立地選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基； 更佳地，R 3、R 4各自獨立地選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C2-C6烯基； 最佳地，R 3、R 4各自獨立地選自氫、氟、氯、溴、甲基、乙基、異丙基、甲氧基、乙氧基、氰基、硝基、三氟甲基、乙烯基、1-甲基-乙烯基; 或者較佳地，R 3、R 4和與它們相連的碳原子一起，形成
Figure 03_image045
，
Figure 03_image047
或
Figure 03_image049
； 或者更佳地，R 3、R 4和與它們相連的碳原子一起，形成
Figure 03_image045
。 A compound of the general formula (A):
Figure 03_image001
(A) or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) 2-N, N-dimethylaminoethoxy, 2-(N-methylpiperazinyl) ethoxy, 2-( N-acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethyl Aminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3 -(N-acetylpiperazinyl)propoxy, 3-morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidinylpropoxy, 2-pyridylmethoxy , 3-pyridylmethoxy, 4-pyridylmethoxy, phenylmethoxy, monohalogen substituted phenylmethoxy, geminal dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy Base, (4) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propyl Piperazinyl, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deuteroisopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxy Ethyl) piperazinyl, N-(2-N, N-dimethylaminoethyl) piperazinyl, N-(2-N, N-diethylaminoethyl) piperazinyl, N-( 2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl Azinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4 -piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N- Methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azepine Cyclobutan-3-yl) piperazinyl, N-tert-butoxycarbonyl piperazinyl, N-acetyl piperazinyl, N-acryl piperazinyl, N-isobutyryl piperazinyl, N- Cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl, N-n-propylsulfonyl piperazinyl, N-isopropylsulfonyl piperazinyl Piperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (5) morpholinyl, 2, 6-dimethylmorpholinyl, thiomorpholine base, 1,1-dioxythiomorpholinyl, (6) tetrahydropyrrolyl, 3-(N, N-dimethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl Hydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazole-3 -yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propyl Pyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazole -5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, (8) piperidinyl, 4- N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- Methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N -Ethylpiperazine-1-)piperidyl, 4-(N-isopropylpiperazine-1-)piperidyl, 4-(N-acetylpiperazine-1-)piperidyl, 4 -(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperidinyl Azine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxypropyl)piperazine-1-) Piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl ) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N -Diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-dimethylaminotetrahydropyrrole-1- ) piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-) piperidinyl, (9) piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N- Methanesulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N-(3-hydroxypropyl)- 4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylaminopropyl)-4-piperidinyl Base, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (10) amino, N, N-dimethylamino, N, N -Diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N -Ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl -N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N- (2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiperazinyl)ethylamino, 3-N, N-dimethylamino Propylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylguanidine Azinyl)propylamino, N-methylpiperidine-4-amino, N-ethylpiperidine-4-amino, N-n-propylpiperidine-4-amino, N-isopropylpiperidine-4 -amino, (11) aminomethylene, N, N-dimethylaminomethylene, N, N-diethylaminomethylene, 4-methyl-1-piperazine methylene, 4- Ethyl-1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2-hydroxyethyl)-1- Piperazine methylene, 4-(2-N, N-dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4-(N, N-dimethyl Amino)-1-piperidinemethylene, 4-hydroxypiperidine-1-methylene, tetrahydropyrrole-1-methylene, 3-(N, N-dimethylamino)-1-tetrahydro Pyrromethene, Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene, (12) Aminoformyl, Methylaminoformyl, N, N-Dimethylaminoformyl, Ethylaminoformyl, Cyclopropylaminoformyl, Cyclobutylaminoformyl, Cyclopentylaminoformyl, Cyclohexylaminoformyl Formyl, aminoacetyl, methylaminoacetyl, 2-(N, N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropylaminoacetyl, cyclobutyl Aminoacetyl, Cyclopentylaminoacetyl, Cyclohexylaminoacetyl, Tetrahydropyrrole-1-formyl, 3-(N, N-Dimethylamino)tetrahydropyrrolyl -1-formyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-formyl, morpholinyl-4-formyl, thiophenanthyl-4-formyl , 2,6-dimethylmorpholinyl-4-formyl, piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethyl Amino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)guanyl Pyridyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidine Base-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N- (2-Hydroxyethyl)piperazine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N- Diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl Pyridyl) piperazin-1-formyl, (13) hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, isopropoxyformyl, normal Butoxyformyl, isobutoxyformyl, tert-butoxyformyl, (14) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, Propylaminosulfonyl, Isopropylaminosulfonyl, Cyclopropylaminosulfonyl, Cyclobutylaminosulfonyl, Cyclopentylaminosulfonyl, Cyclohexylaminosulfonyl, Tetrahydropyrrole-1- Sulfonyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-sulfonyl, Morpholinyl-4-sulfonyl, Thiophanolinyl-4-sulfonyl, 2 6-Dimethylmorpholinyl-4-sulfonyl, Piperidinyl-1-sulfonyl, 4-Hydroxy Piperidinyl-1-sulfonyl, 4-(N, N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N, N-diethylamino)piperidinyl-1-sulfonyl Acyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-sulfonyl , N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N-(2-hydroxyethyl) Piperazine-1-sulfonyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N, N-diethylaminoethyl) Piperazine-1-sulfonyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4-piperidinyl)piperazine-1 -sulfonyl, (15) carbamoylamino, carbamoylamino, carbamoylamino, carboxypropylamino, carboxypropylamino, carbamoyl isopropylamino, carbamoylcyclopropyl, carbamoylcyclobutylamino Formylamino, cyclopentylaminoformylamino, piperidinyl-1-formylamino, 4-hydroxypiperidinyl-1-formylamino, 4-N, N-dimethylpiperidinyl-1- Formylamino, 4-N, N-diethylpiperidinyl-1-formylamino, tetrahydropyrrolyl-1-formylamino, 3-N, N-dimethyltetrahydropyrrolyl-1- Formylamino, 3-N, N-diethyltetrahydropyrrolyl-1-formylamino, N-methylpiperazinyl-1-formylamino, N-ethylpiperazinyl-1-formylamino Amino, N-acetylpiperazinyl-1-formylamino, N-tert-butoxycarbonylpiperazinyl-1-formylamino, N-(2-hydroxyethyl)piperazinyl-1-formylamino Amino, N-(2-cyanoethyl)piperazinyl-1-formylamino, N-(2-N, N-dimethylaminoethyl)piperazinyl-1-formylamino, N- (2-N, N-diethylaminoethyl)piperazinyl-1-formylamino, N-(3-hydroxypropyl)piperazinyl-1-formylamino, N-(3-N, N-Dimethylpropyl)piperazinyl-1-formylamino, N-(3-N, N-diethylpropyl)piperazinyl-1-formylamino, morpholinyl-1-formylamino Amino, 3, 5-dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N-methyl-1-piperazine Base) piperidyl-1-formylamino, 4-(N-ethyl-1-piperazinyl) piperidinyl-1-formylamino, 4-(N-acetyl-1-piperazinyl ) piperidinyl-1-formylamino, N-(N-methyl-4-piperidinyl) piperazinyl-1-formylamino, (16)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
; 2)
Figure 03_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 03_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 03_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; preferably, R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N- Deuterated ethyl piperazinyl, N-n-propyl piperazinyl, N-deutero-n-propyl piperazinyl, N-isopropyl piperazinyl, N-deuteroisopropyl piperazinyl, N- Cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N-(2-N, N-di Ethylaminoethyl) piperazinyl, N-(2-cyanoethyl) piperazinyl, N-cyanomethyl piperazinyl, N-(3-hydroxypropyl) piperazinyl, N-(3 -N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl) Piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidine- 3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazine Base, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-acrylpiperazinyl Azinyl, N-isobutyrylpiperazinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonyl Acyl piperazinyl, N-isopropylsulfonyl piperazinyl, N-cyclopropylsulfonyl piperazinyl, 2-oxo-piperazin-4-yl, (4) morpholinyl, 2 , 6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1- Imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4- Base, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propane Basepyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazole Azol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol- 5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylamino Piperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperidinyl Azine-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazine-1-)piperidinyl, 4-(N-ethyl Acylpiperazin-1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N- (3-Hydroxypropyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazine-1-)piperidinyl, 4-(N -(2-N, N-diethylethyl)piperazine-1-)piperidine, 4-(N-(3-N, N-dimethylpropyl)piperazine-1-)piperidine Base, 4-(N-(3-N, N-diethylpropyl) piperazin-1-) piperidinyl, 4-(tetrahydropyrrole-1-) piperidinyl, 4-(3-N , N-dimethylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (8)piperidine-4- Base, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N- tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-di Methylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl Pyridyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N -Diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (9)amino , N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl -N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N -Dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino) ) ethylamino, N-isopropyl-N-(2-N, N-dimethylamino) ethylamino, 2-morpholinyl ethylamino, 2-(N-methylpiperazinyl) ethyl 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholine Propylamino, 3-(N-methylpiperidinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propylpiperidine- 4-amino, N-isopropylpiperidine-4-amino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, ( 11) Piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethylamino)piperidinyl-1-formyl, 4-( N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl -1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1 -Formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1-formyl, N-(2-N, N-Dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N-diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazin-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazin-1-formyl, (12)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
; 2)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; more preferably, R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, 2,6-dimethylmorpholinyl , thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethyl Amino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, Pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazole- 5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1 -n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-iso Propylpyrazol-5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N- Diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-( N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 8) Piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, (9) amino, N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N- (2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N,N-dimethyl Aminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethyl Amino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethylamino Propylamino, 3-N, N-Diisopropylaminopropylamino, (10) Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene Base, (11) 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl Acyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, (12)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
; 2)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine, bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-( N-isopropylpiperazine-1-)piperidinyl, (4) N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2 -N,N-dimethylamino)ethylamino, N-isopropyl-N-(2-N,N-dimethylamino)ethylamino; optimally, R1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, fluorine, ( 2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methyl piperazine Base, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4- (N-methyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, (5)3-(N,N-dimethylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl, (7) 4-N, N-dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperidinyl Perazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, (8)N-methyl-4-piperidinyl, (9)2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethyl Amino, (10) benzyl, cyclopropyl methylene, (11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image015
,
Figure 03_image023
; 2)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, (2) C1-C6 alkyl , C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl , (4) N-methyl-N-(2-N, N-dimethylamino) ethylamino; R 2 is selected from: 1)
Figure 03_image039
, wherein, Z 1 and Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl , C3-C6 fluorine-containing cycloalkyl, and Z 2 is not hydrogen; preferably, Z 1 , Z 2 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 Alkoxy, C3-C6 cycloalkyl, and Z 2 is not hydrogen; more preferably, Z 1 , Z 2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 2 is not hydrogen; optimally, Z 1 and Z 2 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z 2 is not hydrogen; 2)
Figure 03_image041
, wherein, Z3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C3-C8 cycloalkyl, C1-C6 hetero Atomic alkyl, C3-C8 cycloalkyl containing heteroatoms; Preferably, Z3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkane Base; More preferably, Z 3 is selected from C1-C6 alkyl, C3-C6 cycloalkyl; Most preferably, Z 3 is selected from methyl, ethyl, isopropyl, cyclopropyl; 3)
Figure 03_image043
, wherein, Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C3-C6 cycloalkyl , C3-C6 fluorine-containing cycloalkyl group, or, Z 4 , Z 5 together with N form a substituted or unsubstituted 4-8 membered ring containing 1~2 heteroatoms, the substituent is selected from halogen, C1-C6 Alkyl, C3-C8 cycloalkyl; Preferably, Z 4 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 Cycloalkyl, and Z 4 , Z 5 are not hydrogen at the same time; more preferably, Z 4 , Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 , Z 5 are not hydrogen at the same time; optimally, Z 4 and Z 5 are each independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, and Z 4 and Z 5 are not hydrogen at the same time; R 3 , R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl (for example, trifluoromethyl), C1-C6 alkane radical (for example, methyl, ethyl or isopropyl), C1-C6 alkoxy (for example, methoxy or ethoxy), C3-C6 cycloalkyl (for example, cyclopropyl), C2-C6 Alkenyl; or, R 3 , R 4 and the carbon atoms connected to them form a 5-membered ring containing one N, O or S atom; preferably, R 3 , R 4 are each independently selected from hydrogen, fluorine , chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy , C3-C6 cycloalkyl, C2-C6 alkenyl; more preferably, R 3 , R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C2-C6 alkenyl; optimally, R 3 , R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, iso Propyl, methoxy, ethoxy, cyano, nitro, trifluoromethyl, vinyl, 1-methyl-vinyl; or preferably, R 3 , R 4 and the carbon atoms attached to them together to form
Figure 03_image045
,
Figure 03_image047
or
Figure 03_image049
; Or more preferably, R 3 , R 4 and the carbon atoms connected to them together form
Figure 03_image045
. 如請求項1所述的化合物，其為以下：
Figure 03_image051
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）2-N, N-二甲基氨基乙氧基，2-(N-甲基呱嗪基)乙氧基，2-(N-乙醯基呱嗪基)乙氧基，2-嗎啡啉基乙氧基，2-硫啡啉基乙氧基，2-呱啶基乙氧基，3-N, N-二甲基氨基丙氧基，3-N, N-二乙基氨基丙氧基，3-N, N-二異丙基氨基丙氧基，3-(N-甲基呱嗪基)丙氧基，3-(N-乙醯基呱嗪基)丙氧基，3-嗎啉基丙氧基，3-硫啡啉基丙氧基，3-呱啶基丙氧基，2-吡啶基甲氧基，3-吡啶基甲氧基，4-吡啶基甲氧基，苯基甲氧基，單鹵素取代苯基甲氧基，偕二鹵素取代苯基甲氧基，雜二鹵素取代苯基甲氧基， （4）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （5）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （6）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （7）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （8）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （9）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （10）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （11）氨基亞甲基，N, N-二甲基氨基亞甲基，N, N-二乙基氨基亞甲基，4-甲基-1-呱嗪亞甲基，4-乙基-1-呱嗪亞甲基，4-丙基-1-呱嗪亞甲基，4-異丙基-1-呱嗪亞甲基，4-(2-羥基乙基)-1-呱嗪亞甲基，4-(2- N, N-二甲基氨基乙基)-1-呱嗪亞甲基，呱啶-1-亞甲基，4-(N, N-二甲基氨基)-1-呱啶亞甲基，4-羥基呱啶-1-亞甲基，四氫吡咯-1-亞甲基，3-(N, N-二甲基氨基)-1-四氫吡咯亞甲基，苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （12）氨基甲醯基，甲胺基甲醯基，N, N-二甲基氨基甲醯基，乙胺基甲醯基，環丙基胺基甲醯基，環丁基胺基甲醯基，環戊基胺基甲醯基，環己基胺基甲醯基，氨基乙醯基，甲胺基乙醯基，2-(N, N-二甲基氨基)乙醯基，乙胺基乙醯基，環丙基胺基乙醯基，環丁基胺基乙醯基，環戊基胺基乙醯基，環己基胺基乙醯基， 四氫吡咯-1-甲醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-甲醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-甲醯基， 嗎啡啉基-4-甲醯基，硫啡啉基-4-甲醯基，2, 6-二甲基嗎啡啉基-4-甲醯基， 呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （13）羥基甲醯基，甲氧基甲醯基，乙氧基甲醯基，丙氧基甲醯基，異丙氧基甲醯基，正丁氧基甲醯基，異丁氧基甲醯基，叔丁氧基甲醯基， （14）羥基磺醯基，氨基磺醯基，甲胺基磺醯基，乙胺基磺醯基，丙胺基磺醯基，異丙胺基磺醯基，環丙胺基磺醯基，環丁胺基磺醯基，環戊胺基磺醯基，環己胺基磺醯基， 四氫吡咯-1-磺醯基，3-(N, N-二甲基氨基)四氫吡咯基-1-磺醯基，3-(N, N-二乙基氨基)四氫吡咯基-1-磺醯基， 嗎啡啉基-4-磺醯基，硫啡啉基-4-磺醯基，2 6-二甲基嗎啡啉基-4-磺醯基， 呱啶基-1-磺醯基，4-羥基呱啶-1-磺醯基，4-(N, N-二甲基氨基)呱啶基-1-磺醯基，4-(N, N-二乙基氨基)呱啶基-1-磺醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-磺醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-磺醯基， N-甲基呱嗪-1-磺醯基，N-乙基呱嗪-1-磺醯基，N-異丙基呱嗪-1-磺醯基，N-(2-羥基乙基)呱嗪-1-磺醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-磺醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-磺醯基，4-(N-甲基-4-呱啶基)呱嗪-1-磺醯基，4-(N-乙基-4-呱啶基)呱嗪-1-磺醯基， （15）氨基甲醯氨基，甲氨基甲醯氨基，乙氨基甲醯氨基，丙氨基甲醯氨基，異丙氨基甲醯氨基，環丙基氨基甲醯氨基，環丁基氨基甲醯氨基，環戊基氨基甲醯氨基，呱啶基-1-甲醯氨基，4-羥基呱啶基-1-甲醯氨基，4-N, N-二甲基呱啶基-1-甲醯氨基，4-N, N-二乙基呱啶基-1-甲醯氨基，四氫吡咯基-1-甲醯氨基，3-N, N-二甲基四氫吡咯基-1-甲醯氨基，3-N, N-二乙基四氫吡咯基-1-甲醯氨基，N-甲基呱嗪基-1-甲醯氨基，N-乙基呱嗪基-1-甲醯氨基，N-乙醯基呱嗪基-1-甲醯氨基，N-叔丁氧羰基呱嗪基-1-甲醯氨基，N-(2-羥基乙基)呱嗪基-1-甲醯氨基，N-(2-氰基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二甲基氨基乙基)呱嗪基-1-甲醯氨基，N-(2-N, N-二乙基氨基乙基)呱嗪基-1-甲醯氨基，N-(3-羥基丙基)呱嗪基-1-甲醯氨基， N-(3-N, N-二甲基丙基)呱嗪基-1-甲醯氨基，N-(3-N, N-二乙基丙基)呱嗪基-1-甲醯氨基，嗎啉基-1-甲醯氨基，3, 5-二甲基嗎啉基-1-甲醯氨基，4-(四氫吡咯基)呱啶基-1-甲醯氨基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯氨基，4-(N-乙醯基-1-呱嗪基)呱啶基-1-甲醯氨基，N-(N-甲基-4-呱啶基)呱嗪基-1-甲醯氨基， （16）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image009
，
Figure 03_image011
，
Figure 03_image013
，
Figure 03_image015
，
Figure 03_image017
，
Figure 03_image019
，
Figure 03_image021
，
Figure 03_image023
，
Figure 03_image025
，
Figure 03_image027
，
Figure 03_image029
； 2）
Figure 03_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 03_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 03_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； 較佳地，R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-氘代甲基呱嗪基，N-乙基呱嗪基，N-氘代乙基呱嗪基，N-正丙基呱嗪基，N-氘代正丙基呱嗪基，N-異丙基呱嗪基，N-氘代異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基，1-環丙基吡唑-3-基，1-環丙基吡唑-4-基，1-環丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基，2-嗎啡啉基乙基氨基，2-(N-甲基呱嗪基)乙基氨基，3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基，3-嗎啉基丙基氨基，3-(N-甲基呱嗪基)丙基氨基，N-甲基呱啶-4-氨基，N-乙基呱啶-4-氨基，N-正丙基呱啶-4-氨基，N-異丙基呱啶-4-氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）呱啶基-1-甲醯基，4-羥基呱啶基-1-甲醯基，4-(N, N-二甲基氨基)呱啶基-1-甲醯基，4-(N, N-二乙基氨基)呱啶基-1-甲醯基，4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， N-甲基呱嗪-1-甲醯基，N-乙基呱嗪-1-甲醯基，N-異丙基呱嗪-1-甲醯基，N-(2-羥基乙基)呱嗪-1-甲醯基，N-(2-N, N-二甲基氨基乙基)呱嗪-1-甲醯基，N-(2-N, N-二乙基氨基乙基)呱嗪-1-甲醯基，4-(N-甲基-4-呱啶基)呱嗪-1-甲醯基，4-(N-乙基-4-呱啶基)呱嗪-1-甲醯基， （12）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image009
，
Figure 03_image011
，
Figure 03_image013
，
Figure 03_image015
，
Figure 03_image017
，
Figure 03_image019
，
Figure 03_image021
，
Figure 03_image023
，
Figure 03_image025
，
Figure 03_image027
，
Figure 03_image029
； 2）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 更佳地，R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-三氘代甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基，2, 6-二甲基嗎啡啉基，硫啡啉基，1,1-二氧化硫代嗎啉基， （5）四氫吡咯基，3-(N, N-二甲基氨基)四氫吡咯基，3-(N, N-二乙基氨基)四氫吡咯基，3-(N, N-二異丙基氨基)四氫吡咯基， （6）1-咪唑基，4-甲基-1-咪唑基，1-吡唑基，吡唑-3-基，吡唑-4-基，吡唑-5-基，1-甲基吡唑-3-基，1-甲基吡唑-4-基，1-甲基吡唑-5-基，1-乙基吡唑-3-基，1-乙基吡唑-4-基，1-乙基吡唑-5-基，1-正丙基吡唑-3-基，1-正丙基吡唑-4-基，1-正丙基吡唑-5-基，1-異丙基吡唑-3-基，1-異丙基吡唑-4-基，1-異丙基吡唑-5-基， （7）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （8）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基， （9）氨基，N, N-二甲基氨基，N, N-二乙基氨基，N, N-二正丙基氨基，N, N-二異丙基氨基，2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基，N-乙基-N-（2-羥基）乙基氨基，N-異丙基-N-（2-羥基）乙基氨基，2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-異丙基-N-(2-N, N-二甲基氨基)乙基氨基， 3-N, N-二甲基氨基丙基氨基，3-N, N-二乙基氨基丙基氨基，3-N, N-二異丙基氨基丙基氨基， （10）苄基，環丙基亞甲基，環丁基亞甲基，環戊基亞甲基，環己基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-乙基-1-呱嗪基)呱啶基-1-甲醯基，4-(N-異丙基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image009
，
Figure 03_image011
，
Figure 03_image013
，
Figure 03_image015
，
Figure 03_image017
，
Figure 03_image019
，
Figure 03_image021
，
Figure 03_image023
，
Figure 03_image025
，
Figure 03_image027
，
Figure 03_image029
； 2）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基，N-乙基-N-(2-N, N-二甲基氨基)乙基氨基，N-异丙基-N-(2-N, N-二甲基氨基)乙基氨基； 進一步較佳地，R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟， （2）C1-C6烷基，C1-C6烷氧基， C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-三氘代甲基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基， （4）嗎啉基， （5）3-(N, N-二甲基氨基)四氫吡咯基， （6）1-咪唑基，1-吡唑基，1-甲基吡唑-4-基， （7）4-N, N-二甲基氨基呱啶基，4-羥基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基， （8）N-甲基-4-呱啶基， （9）2-羥基乙基氨基，N-甲基-N-（2-羥基）乙基氨基， 2-N, N-二甲基氨基乙基氨基，N-甲基-N-(2-N, N-二甲基氨基)乙基氨基， （10）苄基，環丙基亞甲基， （11）4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基， （12）
Figure 03_image005
，
Figure 03_image007
，
Figure 03_image015
，
Figure 03_image023
； 2）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷氧基， （3）4-N, N-二甲基氨基呱啶基， 4-(N-甲基呱嗪-1-)呱啶基， （4）N-甲基-N-(2-N, N-二甲基氨基)乙基氨基； 最佳地，R 1選自 1）
Figure 03_image003
，其中： Y 1選自氫、氟、甲氧基、三氟甲氧基， Y 2選自氫、氟， Y 3選自氫、4-嗎啉基、N-甲基-N-（2-羥基）乙基氨基、2-羥基乙基氨基、2-N, N-二甲基氨基乙基氨基、N-甲基-N-(2-N, N-二甲基氨基)乙基氨基、3-(N, N-二甲基氨基)四氫吡咯基、4-羥基呱啶基、4-N, N-二甲基氨基呱啶基、4-(N-甲基呱嗪-1-)呱啶基、4-(呱嗪-1-)呱啶基、N-甲基-4-呱啶基、呱嗪基、N-甲基呱嗪基、N-三氘代甲基呱嗪基、N-(N-甲基-4-呱啶基)呱嗪基、4-(N-甲基-氮雜環丁烷-3-基)呱嗪基、4-(氮雜環丁烷-3-基)呱嗪基、4-(N-甲基-1-呱嗪基)呱啶基-1-甲醯基、
Figure 03_image005
、
Figure 03_image007
、
Figure 03_image015
、
Figure 03_image023
， Y 4選自氫、氟、甲基、乙基、異丙基、環丙基、苄基、環丙基亞甲基、乙烯基、N-甲基-4-呱啶基、N-甲基呱嗪基、4-羥基呱啶基、
Figure 03_image056
、
Figure 03_image058
、
Figure 03_image060
， Y 5為氫， 且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫； 較佳地，
Figure 03_image003
作為整體，選自：
Figure 03_image062
、
Figure 03_image064
、
Figure 03_image066
、
Figure 03_image068
、
Figure 03_image070
、
Figure 03_image072
、
Figure 03_image074
、
Figure 03_image076
、
Figure 03_image078
、
Figure 03_image080
、
Figure 03_image082
、
Figure 03_image084
、
Figure 03_image086
、
Figure 03_image088
、
Figure 03_image090
、
Figure 03_image092
、
Figure 03_image094
、
Figure 03_image096
、
Figure 03_image098
、
Figure 03_image100
、
Figure 03_image102
、
Figure 03_image104
、
Figure 03_image106
、
Figure 03_image108
、
Figure 03_image110
、
Figure 03_image112
、
Figure 03_image114
、
Figure 03_image116
、
Figure 03_image118
、
Figure 03_image120
、
Figure 03_image122
、
Figure 03_image124
、
Figure 03_image126
、
Figure 03_image128
、
Figure 03_image130
、
Figure 03_image132
、
Figure 03_image134
、
Figure 03_image136
、
Figure 03_image138
、
Figure 03_image140
、
Figure 03_image142
、
Figure 03_image144
、
Figure 03_image146
、
Figure 03_image148
、
Figure 03_image150
、
Figure 03_image152
、
Figure 03_image154
、
Figure 03_image156
、
Figure 03_image158
、
Figure 03_image160
、
Figure 03_image162
、
Figure 03_image164
、
Figure 03_image166
、
Figure 03_image168
、
Figure 03_image170
、
Figure 03_image172
、
Figure 03_image174
、
Figure 03_image176
、
Figure 03_image178
、
Figure 03_image180
、
Figure 03_image182
、
Figure 03_image184
、
Figure 03_image186
； 2）
Figure 03_image033
，其中： Y 1選自氫、甲氧基、
Figure 03_image188
； Y 3選自4-(N-甲基呱嗪-1-)呱啶基、4-N, N-二甲基氨基呱啶基、N-甲基-N-(2-N, N-二甲基氨基)乙基氨基； Y 4選自氫、甲基、乙基； Y 5選自氫； 較佳地，
Figure 03_image033
作為整體，選自：
Figure 03_image190
、
Figure 03_image192
、
Figure 03_image194
、
Figure 03_image196
、
Figure 03_image198
； Z 1選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； 較佳地，Z 1選自氫，C1-C6烷基，C3-C6環烷基； 更佳地，Z 1選自氫、甲基、乙基、環丙基； Z 2選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； 較佳地，Z 2選自C1-C6烷基，C3-C6環烷基； 更佳地，Z 2選自甲基、乙基、異丙基、環丙基； R 3選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基； 較佳地，R 3選自氫，氟，氯，溴，碘，硝基，氰基，C1-C6烷基，C1-C6烷氧基，C1-C6含氟烷基，C2-C6烯基； 更佳地，R 3選自氫、氟、氯、溴、甲基、乙基、異丙基、甲氧基、乙氧基、氰基、硝基、三氟甲基、乙烯基、1-甲基-乙烯基； R 4選自氫，氟，氯，溴，碘，C1-C6烷基； 較佳地，R 4選自氫，C1-C6烷基； 更佳地，R 4為氫； 或者，R 3、R 4和與它們相連的碳原子一起，形成含一個N、O或S原子的5元環； 較佳地，R 3、R 4和與它們相連的碳原子一起，形成
Figure 03_image045
，
Figure 03_image047
或
Figure 03_image049
； 更佳地，R 3、R 4和與它們相連的碳原子一起，形成
Figure 03_image045
。 The compound as described in Claim 1, which is as follows:
Figure 03_image051
or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) 2-N, N-dimethylaminoethoxy, 2-(N-methylpiperazinyl) ethoxy, 2-( N-acetylpiperazinyl)ethoxy, 2-morpholinylethoxy, 2-thiomorpholinylethoxy, 2-piperidinylethoxy, 3-N, N-dimethyl Aminopropoxy, 3-N, N-diethylaminopropoxy, 3-N, N-diisopropylaminopropoxy, 3-(N-methylpiperazinyl)propoxy, 3 -(N-acetylpiperazinyl)propoxy, 3-morpholinylpropoxy, 3-thiophenanthylpropoxy, 3-piperidinylpropoxy, 2-pyridylmethoxy , 3-pyridylmethoxy, 4-pyridylmethoxy, phenylmethoxy, monohalogen substituted phenylmethoxy, geminal dihalogen substituted phenylmethoxy, heterodihalogen substituted phenylmethoxy Base, (4) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N-deuteroethylpiperazinyl, N-n-propyl Piperazinyl, N-deutero-n-propylpiperazinyl, N-isopropylpiperazinyl, N-deuteroisopropylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxy Ethyl) piperazinyl, N-(2-N, N-dimethylaminoethyl) piperazinyl, N-(2-N, N-diethylaminoethyl) piperazinyl, N-( 2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl)piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl Azinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4 -piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N- Methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazinyl, 4-(N-isopropyl-azepine Cyclobutan-3-yl) piperazinyl, N-tert-butoxycarbonyl piperazinyl, N-acetyl piperazinyl, N-acryl piperazinyl, N-isobutyryl piperazinyl, N- Cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl, N-n-propylsulfonyl piperazinyl, N-isopropylsulfonyl piperazinyl Piperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (5) morpholinyl, 2, 6-dimethylmorpholinyl, thiomorpholine base, 1,1-dioxythiomorpholinyl, (6) tetrahydropyrrolyl, 3-(N, N-dimethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl, 3-(N, N-diethylamino) tetrahydropyrrolyl Hydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (7) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl, pyrazole-3 -yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propyl Pyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1-isopropylpyrazole -5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol-5-yl, (8) piperidinyl, 4- N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4- Methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N -Ethylpiperazine-1-)piperidyl, 4-(N-isopropylpiperazine-1-)piperidyl, 4-(N-acetylpiperazine-1-)piperidyl, 4 -(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperidinyl Azine-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxypropyl)piperazine-1-) Piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-diethylethyl ) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N -Diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-dimethylaminotetrahydropyrrole-1- ) piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-) piperidinyl, (9) piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl-4-piperidinyl, N- Methanesulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N-(3-hydroxypropyl)- 4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethylaminopropyl)-4-piperidinyl Base, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (10) amino, N, N-dimethylamino, N, N -Diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, N -Ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl -N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethylamino, N-isopropyl-N- (2-N, N-dimethylamino)ethylamino, 2-morpholinylethylamino, 2-(N-methylpiperazinyl)ethylamino, 3-N, N-dimethylamino Propylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholinopropylamino, 3-(N-methylguanidine Azinyl)propylamino, N-methylpiperidine-4-amino, N-ethylpiperidine-4-amino, N-n-propylpiperidine-4-amino, N-isopropylpiperidine-4 -amino, (11) aminomethylene, N, N-dimethylaminomethylene, N, N-diethylaminomethylene, 4-methyl-1-piperazine methylene, 4- Ethyl-1-piperazine methylene, 4-propyl-1-piperazine methylene, 4-isopropyl-1-piperazine methylene, 4-(2-hydroxyethyl)-1- Piperazine methylene, 4-(2-N, N-dimethylaminoethyl)-1-piperazine methylene, piperidine-1-methylene, 4-(N, N-dimethyl Amino)-1-piperidinemethylene, 4-hydroxypiperidine-1-methylene, tetrahydropyrrole-1-methylene, 3-(N, N-dimethylamino)-1-tetrahydro Pyrromethene, Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene, (12) Aminoformyl, Methylaminoformyl, N, N-Dimethylaminoformyl, Ethylaminoformyl, Cyclopropylaminoformyl, Cyclobutylaminoformyl, Cyclopentylaminoformyl, Cyclohexylaminoformyl Formyl, aminoacetyl, methylaminoacetyl, 2-(N, N-dimethylamino)acetyl, ethylaminoacetyl, cyclopropylaminoacetyl, cyclobutyl Aminoacetyl, Cyclopentylaminoacetyl, Cyclohexylaminoacetyl, Tetrahydropyrrole-1-formyl, 3-(N, N-Dimethylamino)tetrahydropyrrolyl -1-formyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-formyl, morpholinyl-4-formyl, thiophenanthyl-4-formyl , 2,6-dimethylmorpholinyl-4-formyl, piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethyl Amino)piperidinyl-1-formyl, 4-(N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)guanyl Pyridyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidine Base-1-formyl, N-methylpiperazine-1-formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N- (2-Hydroxyethyl)piperazine-1-formyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N- Diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazine-1-formyl, 4-(N-ethyl-4-piperidinyl Pyridyl) piperazin-1-formyl, (13) hydroxyformyl, methoxyformyl, ethoxyformyl, propoxyformyl, isopropoxyformyl, normal Butoxyformyl, isobutoxyformyl, tert-butoxyformyl, (14) hydroxysulfonyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, Propylaminosulfonyl, Isopropylaminosulfonyl, Cyclopropylaminosulfonyl, Cyclobutylaminosulfonyl, Cyclopentylaminosulfonyl, Cyclohexylaminosulfonyl, Tetrahydropyrrole-1- Sulfonyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N, N-diethylamino)tetrahydropyrrolyl-1-sulfonyl, Morpholinyl-4-sulfonyl, Thiophanolinyl-4-sulfonyl, 2 6-Dimethylmorpholinyl-4-sulfonyl, Piperidinyl-1-sulfonyl, 4-Hydroxy Piperidinyl-1-sulfonyl, 4-(N, N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N, N-diethylamino)piperidinyl-1-sulfonyl Acyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1-sulfonyl , N-methylpiperazine-1-sulfonyl, N-ethylpiperazine-1-sulfonyl, N-isopropylpiperazine-1-sulfonyl, N-(2-hydroxyethyl) Piperazine-1-sulfonyl, N-(2-N, N-dimethylaminoethyl)piperazine-1-sulfonyl, N-(2-N, N-diethylaminoethyl) Piperazine-1-sulfonyl, 4-(N-methyl-4-piperidinyl)piperazine-1-sulfonyl, 4-(N-ethyl-4-piperidinyl)piperazine-1 -sulfonyl, (15) carbamoylamino, carbamoylamino, carbamoylamino, carboxypropylamino, carboxypropylamino, carbamoyl isopropylamino, carbamoylcyclopropyl, carbamoylcyclobutylamino Formylamino, cyclopentylaminoformylamino, piperidinyl-1-formylamino, 4-hydroxypiperidinyl-1-formylamino, 4-N, N-dimethylpiperidinyl-1- Formylamino, 4-N, N-diethylpiperidinyl-1-formylamino, tetrahydropyrrolyl-1-formylamino, 3-N, N-dimethyltetrahydropyrrolyl-1- Formylamino, 3-N, N-diethyltetrahydropyrrolyl-1-formylamino, N-methylpiperazinyl-1-formylamino, N-ethylpiperazinyl-1-formylamino Amino, N-acetylpiperazinyl-1-formylamino, N-tert-butoxycarbonylpiperazinyl-1-formylamino, N-(2-hydroxyethyl)piperazinyl-1-formylamino Amino, N-(2-cyanoethyl)piperazinyl-1-formylamino, N-(2-N, N-dimethylaminoethyl)piperazinyl-1-formylamino, N- (2-N, N-diethylaminoethyl)piperazinyl-1-formylamino, N-(3-hydroxypropyl)piperazinyl-1-formylamino, N-(3-N, N-Dimethylpropyl)piperazinyl-1-formylamino, N-(3-N, N-diethylpropyl)piperazinyl-1-formylamino, morpholinyl-1-formylamino Amino, 3, 5-dimethylmorpholinyl-1-formylamino, 4-(tetrahydropyrrolyl)piperidinyl-1-formylamino, 4-(N-methyl-1-piperazine Base) piperidyl-1-formylamino, 4-(N-ethyl-1-piperazinyl) piperidinyl-1-formylamino, 4-(N-acetyl-1-piperazinyl ) piperidinyl-1-formylamino, N-(N-methyl-4-piperidinyl) piperazinyl-1-formylamino, (16)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
; 2)
Figure 03_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 03_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 03_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; preferably, R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-deuteromethylpiperazinyl, N-ethylpiperazinyl, N- Deuterated ethyl piperazinyl, N-n-propyl piperazinyl, N-deutero-n-propyl piperazinyl, N-isopropyl piperazinyl, N-deuteroisopropyl piperazinyl, N- Cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N-(2-N, N-di Ethylaminoethyl) piperazinyl, N-(2-cyanoethyl) piperazinyl, N-cyanomethyl piperazinyl, N-(3-hydroxypropyl) piperazinyl, N-(3 -N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl-4-piperidinyl) Piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidine- 3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidin-3-yl)piperazine Base, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazinyl, N-acrylpiperazinyl Azinyl, N-isobutyrylpiperazinyl, N-cyclopropylformylpiperazinyl, N-methylsulfonylpiperazinyl, N-ethylsulfonylpiperazinyl, N-n-propylsulfonyl Acyl piperazinyl, N-isopropylsulfonyl piperazinyl, N-cyclopropylsulfonyl piperazinyl, 2-oxo-piperazin-4-yl, (4) morpholinyl, 2 , 6-dimethylmorpholinyl, thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-diethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1- Imidazolyl, 1-pyrazolyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4- Base, 1-methylpyrazol-5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propane Basepyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazole Azol-4-yl, 1-isopropylpyrazol-5-yl, 1-cyclopropylpyrazol-3-yl, 1-cyclopropylpyrazol-4-yl, 1-cyclopropylpyrazol- 5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylamino Piperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperidinyl Azine-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazine-1-)piperidinyl, 4-(N-ethyl Acylpiperazin-1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazin-1-)piperidinyl, 4-(N-(2-hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazin-1-)piperidinyl, 4-(N- (3-Hydroxypropyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazine-1-)piperidinyl, 4-(N -(2-N, N-diethylethyl)piperazine-1-)piperidine, 4-(N-(3-N, N-dimethylpropyl)piperazine-1-)piperidine Base, 4-(N-(3-N, N-diethylpropyl) piperazin-1-) piperidinyl, 4-(tetrahydropyrrole-1-) piperidinyl, 4-(3-N , N-dimethylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (8)piperidine-4- Base, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N- tert-butoxycarbonyl-4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-di Methylaminoethyl)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl Pyridyl, N-(3-hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N -Diethylaminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl, (9)amino , N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl -N-(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N -Dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino) ) ethylamino, N-isopropyl-N-(2-N, N-dimethylamino) ethylamino, 2-morpholinyl ethylamino, 2-(N-methylpiperazinyl) ethyl 3-N, N-dimethylaminopropylamino, 3-N, N-diethylaminopropylamino, 3-N, N-diisopropylaminopropylamino, 3-morpholine Propylamino, 3-(N-methylpiperidinyl)propylamino, N-methylpiperidin-4-amino, N-ethylpiperidin-4-amino, N-n-propylpiperidine- 4-amino, N-isopropylpiperidine-4-amino, (10) benzyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, ( 11) Piperidinyl-1-formyl, 4-hydroxypiperidinyl-1-formyl, 4-(N, N-dimethylamino)piperidinyl-1-formyl, 4-( N, N-diethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl -1-piperazinyl)piperidinyl-1-formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, N-methylpiperazine-1 -Formyl, N-ethylpiperazine-1-formyl, N-isopropylpiperazine-1-formyl, N-(2-hydroxyethyl)piperazine-1-formyl, N-(2-N, N-Dimethylaminoethyl)piperazine-1-formyl, N-(2-N, N-diethylaminoethyl)piperazine-1-formyl, 4-(N-methyl-4-piperidinyl)piperazin-1-formyl, 4-(N-ethyl-4-piperidinyl)piperazin-1-formyl, (12)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
; 2)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are as defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; more preferably, R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-isopropylpiperazinyl, N-(N- Methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azepine Butan-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, 2,6-dimethylmorpholine thiomorpholinyl, 1,1-dioxythiomorpholinyl, (5) tetrahydropyrrolyl, 3-(N, N-dimethylamino)tetrahydropyrrolyl, 3-(N, N-di Ethylamino)tetrahydropyrrolyl, 3-(N, N-diisopropylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 4-methyl-1-imidazolyl, 1-pyrazolyl , pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-methylpyrazole -5-yl, 1-ethylpyrazol-3-yl, 1-ethylpyrazol-4-yl, 1-ethylpyrazol-5-yl, 1-n-propylpyrazol-3-yl, 1-n-propylpyrazol-4-yl, 1-n-propylpyrazol-5-yl, 1-isopropylpyrazol-3-yl, 1-isopropylpyrazol-4-yl, 1- Isopropylpyrazol-5-yl, (7) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N -Diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4- (N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazin-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, (8) piperidin-4-yl, N-methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, (9) amino, N , N-Dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, 2-hydroxyethylamino, N-methyl-N -(2-hydroxy)ethylamino, N-ethyl-N-(2-hydroxy)ethylamino, N-isopropyl-N-(2-hydroxy)ethylamino, 2-N, N-di Methylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2-N, N-dimethylamino)ethyl ylamino, N-isopropyl-N-(2-N, N-dimethylamino)ethylamino, 3-N, N-dimethylaminopropylamino, 3-N, N-diethyl Aminopropylamino, 3-N, N-Diisopropylaminopropylamino, (10) Benzyl, Cyclopropylmethylene, Cyclobutylmethylene, Cyclopentylmethylene, Cyclohexylmethylene Methyl, (11) 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl)piperidinyl-1- Formyl, 4-(N-isopropyl-1-piperazinyl)piperidinyl-1-formyl, (12)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
,
Figure 03_image015
,
Figure 03_image017
,
Figure 03_image019
,
Figure 03_image021
,
Figure 03_image023
,
Figure 03_image025
,
Figure 03_image027
,
Figure 03_image029
; 2)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine, bromine, iodine, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-( N-isopropylpiperazine-1-)piperidinyl, (4) N-methyl-N-(2-N, N-dimethylamino)ethylamino, N-ethyl-N-(2 -N, N-dimethylamino) ethylamino, N-isopropyl-N-(2-N, N-dimethylamino) ethylamino; further preferably, R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, fluorine, ( 2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorinated alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methyl piperazine Base, N-trideuteromethylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(azetidin-3-yl)piperazinyl, 4- (N-methyl-azetidin-3-yl)piperazinyl, (4)morpholinyl, (5)3-(N,N-dimethylamino)tetrahydropyrrolyl, (6) 1-imidazolyl, 1-pyrazolyl, 1-methylpyrazol-4-yl, (7) 4-N, N-dimethylaminopiperidinyl, 4-hydroxypiperidinyl, 4-(piperidinyl Perazine-1-)piperidinyl, 4-(N-methylpiperazin-1-)piperidinyl, (8)N-methyl-4-piperidinyl, (9)2-hydroxyethylamino, N-methyl-N-(2-hydroxy)ethylamino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethyl Amino, (10) benzyl, cyclopropyl methylene, (11) 4-(N-methyl-1-piperazinyl) piperidinyl-1-formyl, (12)
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image015
,
Figure 03_image023
; 2)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time: (1) hydrogen, (2) C1-C6 alkyl , C1-C6 alkoxy, C1-C6 fluorinated alkoxy, (3) 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazin-1-)piperidinyl , (4) N-methyl-N-(2-N, N-dimethylamino)ethylamino; optimally, R 1 is selected from 1)
Figure 03_image003
, wherein: Y 1 is selected from hydrogen, fluorine, methoxy, trifluoromethoxy, Y 2 is selected from hydrogen, fluorine, Y 3 is selected from hydrogen, 4-morpholinyl, N-methyl-N-(2 -Hydroxy)ethylamino, 2-Hydroxyethylamino, 2-N, N-dimethylaminoethylamino, N-methyl-N-(2-N, N-dimethylamino)ethylamino , 3-(N, N-dimethylamino)tetrahydropyrrolyl, 4-hydroxypiperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-(N-methylpiperazine-1 -)piperidinyl, 4-(piperazine-1-)piperidinyl, N-methyl-4-piperidinyl, piperazinyl, N-methylpiperazinyl, N-trideuteromethylpiperidinyl Azidinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl,
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image015
,
Figure 03_image023
, Y is selected from hydrogen, fluorine, methyl, ethyl, isopropyl, cyclopropyl, benzyl, cyclopropyl methylene, vinyl, N-methyl-4-piperidinyl, N-methyl Piperazinyl, 4-hydroxypiperidinyl,
Figure 03_image056
,
Figure 03_image058
,
Figure 03_image060
, Y 5 is hydrogen, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not hydrogen at the same time; preferably,
Figure 03_image003
As a whole, selected from:
Figure 03_image062
,
Figure 03_image064
,
Figure 03_image066
,
Figure 03_image068
,
Figure 03_image070
,
Figure 03_image072
,
Figure 03_image074
,
Figure 03_image076
,
Figure 03_image078
,
Figure 03_image080
,
Figure 03_image082
,
Figure 03_image084
,
Figure 03_image086
,
Figure 03_image088
,
Figure 03_image090
,
Figure 03_image092
,
Figure 03_image094
,
Figure 03_image096
,
Figure 03_image098
,
Figure 03_image100
,
Figure 03_image102
,
Figure 03_image104
,
Figure 03_image106
,
Figure 03_image108
,
Figure 03_image110
,
Figure 03_image112
,
Figure 03_image114
,
Figure 03_image116
,
Figure 03_image118
,
Figure 03_image120
,
Figure 03_image122
,
Figure 03_image124
,
Figure 03_image126
,
Figure 03_image128
,
Figure 03_image130
,
Figure 03_image132
,
Figure 03_image134
,
Figure 03_image136
,
Figure 03_image138
,
Figure 03_image140
,
Figure 03_image142
,
Figure 03_image144
,
Figure 03_image146
,
Figure 03_image148
,
Figure 03_image150
,
Figure 03_image152
,
Figure 03_image154
,
Figure 03_image156
,
Figure 03_image158
,
Figure 03_image160
,
Figure 03_image162
,
Figure 03_image164
,
Figure 03_image166
,
Figure 03_image168
,
Figure 03_image170
,
Figure 03_image172
,
Figure 03_image174
,
Figure 03_image176
,
Figure 03_image178
,
Figure 03_image180
,
Figure 03_image182
,
Figure 03_image184
,
Figure 03_image186
; 2)
Figure 03_image033
, wherein: Y 1 is selected from hydrogen, methoxy,
Figure 03_image188
; Y3 is selected from 4-(N-methylpiperazin-1-) piperidinyl, 4-N, N-dimethylaminopiperidinyl, N-methyl-N-(2-N, N- Dimethylamino) ethylamino; Y is selected from hydrogen, methyl, ethyl; Y is selected from hydrogen; preferably,
Figure 03_image033
As a whole, selected from:
Figure 03_image190
,
Figure 03_image192
,
Figure 03_image194
,
Figure 03_image196
,
Figure 03_image198
; Z 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; Preferably, Z 1 is selected from hydrogen, C1-C6 alkyl , C3-C6 cycloalkyl; More preferably, Z 1 is selected from hydrogen, methyl, ethyl, cyclopropyl; Z 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1- C6 alkoxy, C3-C6 cycloalkyl; Preferably, Z2 is selected from C1-C6 alkyl, C3-C6 cycloalkyl; More preferably, Z2 is selected from methyl, ethyl, isopropyl , cyclopropyl; R 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 containing Fluoroalkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl; Preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluorine-containing alkyl, C2-C6 alkenyl; more preferably, R3 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, iso Propyl, methoxy, ethoxy, cyano, nitro, trifluoromethyl, vinyl, 1-methyl-vinyl; R4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 Alkyl; Preferably, R 4 is selected from hydrogen, C1-C6 alkyl; More preferably, R 4 is hydrogen; Or, R 3 , R 4 and the carbon atoms connected to them together form a or a 5-membered ring of S atoms; preferably, R 3 , R 4 and the carbon atoms connected to them together form
Figure 03_image045
,
Figure 03_image047
or
Figure 03_image049
; More preferably, R 3 , R 4 and the carbon atoms connected to them together form
Figure 03_image045
. 如請求項1所述的化合物，其為以下：
Figure 03_image200
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （5）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基； 2）
Figure 03_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 03_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 03_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； 較佳地，R 1為
Figure 03_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基， （4）4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基； 更佳地，R 1為
Figure 03_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： 氫，C1-C6烷基，C1-C6烷氧基，N-甲基呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，4-(N-甲基呱嗪-1-)呱啶基； 進一步較佳地，R 1為
Figure 03_image003
，其中： Y 1選自氫、甲氧基， Y 2為氫， Y 3選自N-甲基呱嗪基、4-(N-甲基呱嗪-1-)呱啶基、N-(N-甲基-4-呱啶基)呱嗪基， Y 4為乙基， Y 5為氫； 最佳地，R 1選自
Figure 03_image062
、
Figure 03_image096
、
Figure 03_image114
、
Figure 03_image124
； Z 3選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基； 較佳地，Z 3選自C1-C6烷基，C3-C6環烷基； 更佳地，Z 3選自甲基、乙基、異丙基、環丙基； R 3選自氫，氟，氯，溴，碘，硝基，氰基，C2-C6烯基； 較佳地，R 3選自氟，氯，溴，碘，C2-C6烯基； 更佳地，R 3選自溴、乙烯基； R 4選自氫，氟，氯，溴，碘，C1-C6烷基； 較佳地，R 4選自氫，C1-C6烷基； 更佳地，R 4為氫。 The compound as described in Claim 1, which is as follows:
Figure 03_image200
or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N- (2-N, N-diethylaminoethyl)piperazinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl) Piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazine Base, N-propionyl piperazinyl, N-isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl Base, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (4) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine -1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazine-1-)piperidinyl, 4-(N -(2-Hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxy Propyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2- N, N-diethylethyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4- (N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N, N-di Methylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (5)piperidin-4-yl, N- Methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl -4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl Base)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N -(3-Hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethyl Aminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl; 2)
Figure 03_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 03_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 03_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; preferably, R 1 is
Figure 03_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, ( 2) C1-C6 alkyl, C1-C6 alkoxy, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl -4-piperidinyl) piperidinyl, (4) 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1-)piperidinyl, 4-(N-ethyl Base piperazin-1-) piperidinyl, 4-(N-isopropyl piperazin-1-) piperidinyl; more preferably, R is
Figure 03_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen: hydrogen, C1-C6 alkane Base, C1-C6 alkoxy, N-methylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, 4-(N-methylpiperazine-1-)piperidine Base; Further preferably, R 1 is
Figure 03_image003
, wherein: Y 1 is selected from hydrogen, methoxy, Y 2 is hydrogen, Y 3 is selected from N-methylpiperazinyl, 4-(N-methylpiperazin-1-)piperidinyl, N-( N-methyl-4-piperidinyl) piperazinyl, Y 4 is ethyl, Y 5 is hydrogen; optimally, R 1 is selected from
Figure 03_image062
,
Figure 03_image096
,
Figure 03_image114
,
Figure 03_image124
; Z 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl; Preferably, Z 3 is selected from C1-C6 alkyl, C3 -C6 cycloalkyl; More preferably, Z 3 is selected from methyl, ethyl, isopropyl, cyclopropyl; R 3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2- C6 alkenyl; Preferably, R 3 is selected from fluorine, chlorine, bromine, iodine, C2-C6 alkenyl; More preferably, R 3 is selected from bromine, vinyl; R 4 is selected from hydrogen, fluorine, chlorine, bromine , iodine, C1-C6 alkyl; Preferably, R 4 is selected from hydrogen, C1-C6 alkyl; More preferably, R 4 is hydrogen. 如請求項1所述的化合物，其為以下：
Figure 03_image202
或該化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物， 其中： R 1選自 1）
Figure 03_image003
，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫，氟，氯，溴，碘，硝基，氰基， （2）C1-C6烷基，C1-C6烷氧基，C1-C6含氧烷基，C1-C6含氟烷基，C1-C6含氟烷氧基，C3-C6環烷基，C2-C6烯基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基，N-環丙基呱嗪基，N-(2-羥基乙基)呱嗪基，N-(2-N, N-二甲基氨基乙基)呱嗪基，N-(2-N, N-二乙基氨基乙基)呱嗪基，N-(2-氰基乙基)呱嗪基，N-氰甲基呱嗪基，N-(3-羥基丙基)呱嗪基，N-(3-N, N-二甲基氨基丙基)呱嗪基，N-(3-N, N-二乙基氨基丙基)呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基，4-(氮雜環丁烷-3-基)呱嗪基，4-(N-甲基-氮雜環丁烷-3-基)呱嗪基，4-(N-乙基-氮雜環丁烷-3-基)呱嗪基，4-(N-異丙基-氮雜環丁烷-3-基)呱嗪基，N-叔丁氧羰基呱嗪基，N-乙醯基呱嗪基，N-丙醯基呱嗪基，N-異丁醯基呱嗪基，N-環丙基甲醯基呱嗪基，N-甲磺醯基呱嗪基，N-乙基磺醯基呱嗪基，N-正丙基磺醯基呱嗪基，N-異丙基磺醯基呱嗪基，N-環丙基磺醯基呱嗪基，2-氧代-呱嗪-4-基， （4）呱啶基，4-N, N-二甲基氨基呱啶基，4-N, N-二乙基氨基呱啶基，4-N, N-二異丙基氨基呱啶基，4-羥基呱啶基，4-甲氧基呱啶基，4-乙氧基呱啶基，4-(呱嗪-1-)呱啶基，4-(N-甲基呱嗪-1-)呱啶基，4-(N-乙基呱嗪-1-)呱啶基，4-(N-異丙基呱嗪-1-)呱啶基，4-(N-乙醯基呱嗪-1-)呱啶基，4-(N-叔丁氧羰基呱嗪-1-)呱啶基，4-(N-甲磺醯基呱嗪-1-)呱啶基，4-(N-(2-羥基乙基)呱嗪-1-)呱啶基，4-(N-(2-氰基乙基)呱嗪-1-)呱啶基，4-(N-(3-羥基丙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二甲基氨基乙基)呱嗪-1-)呱啶基，4-(N-(2-N, N-二乙基乙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二甲基丙基)呱嗪-1-)呱啶基，4-(N-(3-N, N-二乙基丙基)呱嗪-1-)呱啶基，4-(四氫吡咯-1-)呱啶基，4-(3-N, N-二甲基氨基四氫吡咯-1-)呱啶基，4-(3-N, N-二乙基氨基四氫吡咯-1-)呱啶基， （5）呱啶-4-基，N-甲基-4-呱啶基，N-乙基-4-呱啶基，N-異丙基-4-呱啶基，N-乙醯基-4-呱啶基，N-叔丁氧羰基-4-呱啶基，N-甲磺醯基-4-呱啶基，N-(2-羥基乙基)-4-呱啶基，N-(2-N, N-二甲基氨基乙基)-4-呱啶基，N-(2-N, N-二乙基氨基乙基)-4-呱啶基，N-(2-氰基乙基)-4-呱啶基，N-(3-羥基丙基)-4-呱啶基，N-(3-N, N-二甲基氨基丙基)-4-呱啶基，N-(3-N, N-二乙基氨基丙基)-4-呱啶基，N-(3-氰基丙基)-4-呱啶基，N-氰基亞甲基-4-呱啶基； 2）
Figure 03_image031
，其中Y 2，Y 3，Y 4，Y 5與1）中定義相同，且Y 2，Y 3，Y 4，Y 5不同時為氫； 3）
Figure 03_image033
，其中Y 1，Y 3，Y 4，Y 5與1）中定義相同，且Y 1，Y 3，Y 4，Y 5不同時為氫； 4）
Figure 03_image035
，其中Y 1，Y 2，Y 4，Y 5與1）中定義相同，且Y 1，Y 2，Y 4，Y 5不同時為氫； 5）
Figure 03_image037
，其中Y 1，Y 3，Y 5與1）中定義相同，且Y 1，Y 3，Y 5不同時為氫； 較佳地，R 1為
Figure 03_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： （1）氫， （2）C1-C6烷基，C1-C6烷氧基， （3）呱嗪基，N-甲基呱嗪基，N-乙基呱嗪基，N-正丙基呱嗪基，N-異丙基呱嗪基， N-(N-甲基-4-呱啶基)呱嗪基，N-(N-乙基-4-呱啶基)呱嗪基，N-(N-異丙基-4-呱啶基)呱嗪基； 更佳地，R 1為
Figure 03_image003
，其中，Y 1，Y 2，Y 3，Y 4，Y 5各自獨立地選自以下，且Y 1，Y 2，Y 3，Y 4，Y 5不同時為氫： 氫，C1-C6烷基，C1-C6烷氧基，N-甲基呱嗪基，N-(N-甲基-4-呱啶基)呱嗪基； 進一步較佳地，R 1為
Figure 03_image003
，其中： Y 1選自氫、甲氧基， Y 2為氫， Y 3選自N-甲基呱嗪基、N-(N-甲基-4-呱啶基)呱嗪基， Y 4為乙基， Y 5為氫； 最佳地，R 1選自
Figure 03_image062
、
Figure 03_image096
、
Figure 03_image124
； Z 4、Z 5各自獨立地選自氫，氟，氯，溴，碘，C1-C6烷基，C1-C6烷氧基，C3-C6環烷基，且Z 4、Z 5不同時為氫； 較佳地，Z 4、Z 5各自獨立地選自氫，C1-C6烷基，C3-C6環烷基，且Z 4、Z 5不同時為氫； 更佳地，Z 4選自氫、C1-C6烷基，較佳為氫；Z 5選自C1-C6烷基，C3-C6環烷基； 最佳地，Z 4選自氫，Z 5選自甲基、乙基、異丙基、環丙基； R 3選自氫，氟，氯，溴，碘，硝基，氰基，C2-C6烯基； 較佳地，R 3選自氟，氯，溴，碘，C2-C6烯基； 更佳地，R 3選自溴、乙烯基； R 4選自氫，氟，氯，溴，碘，C1-C6烷基； 較佳地，R 4選自氫，C1-C6烷基； 更佳地，R 4為氫。 The compound as described in Claim 1, which is as follows:
Figure 03_image202
or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: R 1 is selected from 1)
Figure 03_image003
, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time: (1) hydrogen, fluorine, chlorine , bromine, iodine, nitro, cyano, (2) C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy Base, C3-C6 cycloalkyl, C2-C6 alkenyl, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-cyclopropylpiperazinyl, N-(2-hydroxyethyl)piperazinyl, N-(2-N, N-dimethylaminoethyl)piperazinyl, N- (2-N, N-diethylaminoethyl)piperazinyl, N-(2-cyanoethyl)piperazinyl, N-cyanomethylpiperazinyl, N-(3-hydroxypropyl) Piperazinyl, N-(3-N, N-dimethylaminopropyl)piperazinyl, N-(3-N, N-diethylaminopropyl)piperazinyl, N-(N-methyl Base-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl-4-piperidinyl)piperazinyl, 4 -(azetidin-3-yl)piperazinyl, 4-(N-methyl-azetidin-3-yl)piperazinyl, 4-(N-ethyl-azetidinyl Alkyl-3-yl)piperazinyl, 4-(N-isopropyl-azetidin-3-yl)piperazinyl, N-tert-butoxycarbonylpiperazinyl, N-acetylpiperazine Base, N-propionyl piperazinyl, N-isobutyryl piperazinyl, N-cyclopropylformyl piperazinyl, N-methylsulfonyl piperazinyl, N-ethylsulfonyl piperazinyl Base, N-n-propylsulfonylpiperazinyl, N-isopropylsulfonylpiperazinyl, N-cyclopropylsulfonylpiperazinyl, 2-oxo-piperazin-4-yl, (4) Piperidinyl, 4-N, N-dimethylaminopiperidinyl, 4-N, N-diethylaminopiperidinyl, 4-N, N-diisopropylaminopiperidinyl, 4-hydroxypiperidinyl, 4-methoxypiperidinyl, 4-ethoxypiperidinyl, 4-(piperazin-1-)piperidinyl, 4-(N-methylpiperazine-1- ) piperidinyl, 4-(N-ethylpiperazine-1-)piperidinyl, 4-(N-isopropylpiperazin-1-)piperidinyl, 4-(N-acetylpiperazine -1-)piperidinyl, 4-(N-tert-butoxycarbonylpiperazin-1-)piperidinyl, 4-(N-methylsulfonylpiperazine-1-)piperidinyl, 4-(N -(2-Hydroxyethyl)piperazin-1-)piperidinyl, 4-(N-(2-cyanoethyl)piperazine-1-)piperidinyl, 4-(N-(3-hydroxy Propyl)piperazin-1-)piperidinyl, 4-(N-(2-N, N-dimethylaminoethyl)piperazin-1-)piperidinyl, 4-(N-(2- N, N-diethylethyl) piperazin-1-) piperidinyl, 4-(N-(3-N, N-dimethylpropyl) piperazin-1-) piperidinyl, 4- (N-(3-N, N-diethylpropyl)piperazin-1-)piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(3-N, N-di Methylaminotetrahydropyrrole-1-)piperidinyl, 4-(3-N, N-diethylaminotetrahydropyrrole-1-)piperidinyl, (5)piperidin-4-yl, N- Methyl-4-piperidinyl, N-ethyl-4-piperidinyl, N-isopropyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-tert-butoxycarbonyl -4-piperidinyl, N-methylsulfonyl-4-piperidinyl, N-(2-hydroxyethyl)-4-piperidinyl, N-(2-N, N-dimethylaminoethyl Base)-4-piperidinyl, N-(2-N, N-diethylaminoethyl)-4-piperidinyl, N-(2-cyanoethyl)-4-piperidinyl, N -(3-Hydroxypropyl)-4-piperidinyl, N-(3-N, N-dimethylaminopropyl)-4-piperidinyl, N-(3-N, N-diethyl Aminopropyl)-4-piperidinyl, N-(3-cyanopropyl)-4-piperidinyl, N-cyanomethylene-4-piperidinyl; 2)
Figure 03_image031
, where Y 2 , Y 3 , Y 4 , Y 5 are defined the same as in 1), and Y 2 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 3)
Figure 03_image033
, wherein Y 1 , Y 3 , Y 4 , Y 5 are the same as those defined in 1), and Y 1 , Y 3 , Y 4 , Y 5 are not hydrogen at the same time; 4)
Figure 03_image035
, where Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 1), and Y 1 , Y 2 , Y 4 , Y 5 are not hydrogen at the same time; 5)
Figure 03_image037
, wherein Y 1 , Y 3 , Y 5 are the same as defined in 1), and Y 1 , Y 3 , Y 5 are not hydrogen at the same time; preferably, R 1 is
Figure 03_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are not simultaneously hydrogen: (1) hydrogen, ( 2) C1-C6 alkyl, C1-C6 alkoxy, (3) piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, N-n-propylpiperazinyl, N-iso Propylpiperazinyl, N-(N-methyl-4-piperidinyl)piperazinyl, N-(N-ethyl-4-piperidinyl)piperazinyl, N-(N-isopropyl -4-piperidinyl) piperazinyl; more preferably, R 1 is
Figure 03_image003
, wherein, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from the following, and Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are not simultaneously hydrogen: hydrogen, C1-C6 alkane Base, C1-C6 alkoxy group, N-methyl piperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl; Further preferably, R is
Figure 03_image003
, wherein: Y 1 is selected from hydrogen, methoxy, Y 2 is hydrogen, Y 3 is selected from N-methylpiperazinyl, N-(N-methyl-4-piperidinyl) piperazinyl, Y 4 is ethyl, Y 5 is hydrogen; optimally, R 1 is selected from
Figure 03_image062
,
Figure 03_image096
,
Figure 03_image124
Z 4 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and Z 4 and Z 5 are not simultaneously Hydrogen; Preferably, Z 4 , Z 5 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and Z 4 , Z 5 are not hydrogen at the same time; more preferably, Z 4 is selected from Hydrogen, C1-C6 alkyl, preferably hydrogen; Z5 is selected from C1-C6 alkyl, C3-C6 cycloalkyl; most preferably, Z4 is selected from hydrogen, Z5 is selected from methyl, ethyl, Isopropyl, cyclopropyl; R3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C2-C6 alkenyl; preferably, R3 is selected from fluorine, chlorine, bromine, iodine, C2-C6 alkenyl; More preferably, R 3 is selected from bromine, vinyl; R 4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C6 alkyl; Preferably, R 4 is selected from hydrogen, C1 -C6 alkyl; More preferably, R 4 is hydrogen. 如請求項1至請求項4中任一項所述的化合物，選自以下： 序列號 結構 序列號 結構 I-1
Figure 03_image376
 I-135
Figure 03_image644
 I-2
Figure 03_image378
 I-136
Figure 03_image646
 I-3
Figure 03_image380
 I-137
Figure 03_image648
 I-4
Figure 03_image382
 I-138
Figure 03_image650
 I-5
Figure 03_image384
 I-139
Figure 03_image652
 I-6
Figure 03_image386
 I-140
Figure 03_image654
 I-7
Figure 03_image388
 I-141
Figure 03_image656
 I-8
Figure 03_image390
 I-142
Figure 03_image658
 I-9
Figure 03_image392
 I-143
Figure 03_image660
 I-10
Figure 03_image394
 I-144
Figure 03_image662
 I-11
Figure 03_image396
 I-145
Figure 03_image664
 I-12
Figure 03_image398
 I-146
Figure 03_image666
 I-13
Figure 03_image400
 I-147
Figure 03_image668
 I-14
Figure 03_image402
 I-148
Figure 03_image670
 I-15
Figure 03_image404
 I-149
Figure 03_image672
 I-16
Figure 03_image406
 I-150
Figure 03_image674
 I-17
Figure 03_image408
 I-151
Figure 03_image676
 I-18
Figure 03_image410
 I-152
Figure 03_image678
 I-19
Figure 03_image412
 I-153
Figure 03_image680
 I-20
Figure 03_image414
 I-154
Figure 03_image682
 I-21
Figure 03_image416
 I-155
Figure 03_image684
 I-22
Figure 03_image418
 I-156
Figure 03_image686
 I-23
Figure 03_image420
 I-157
Figure 03_image688
 I-24
Figure 03_image422
 I-158
Figure 03_image690
 I-25
Figure 03_image424
 I-159
Figure 03_image692
 I-26
Figure 03_image426
 I-160
Figure 03_image694
 I-27
Figure 03_image428
 I-161
Figure 03_image696
 I-28
Figure 03_image430
 I-162
Figure 03_image698
 I-29
Figure 03_image432
 I-163
Figure 03_image700
 I-30
Figure 03_image434
 I-164
Figure 03_image702
 I-31
Figure 03_image436
 I-165
Figure 03_image704
 I-32
Figure 03_image438
 I-166
Figure 03_image706
 I-33
Figure 03_image440
 I-167
Figure 03_image708
 I-34
Figure 03_image442
 I-168
Figure 03_image710
 I-35
Figure 03_image444
 I-169
Figure 03_image712
 I-36
Figure 03_image446
 I-170
Figure 03_image714
 I-37
Figure 03_image448
 I-171
Figure 03_image716
 I-38
Figure 03_image450
 I-172
Figure 03_image718
 I-39
Figure 03_image452
 I-173
Figure 03_image720
 I-40
Figure 03_image454
 I-174
Figure 03_image722
 I-41
Figure 03_image456
 I-175
Figure 03_image724
 I-42
Figure 03_image458
 I-176
Figure 03_image726
 I-43
Figure 03_image460
 I-177
Figure 03_image728
 I-44
Figure 03_image462
 I-178
Figure 03_image730
 I-45
Figure 03_image464
 I-179
Figure 03_image732
 I-46
Figure 03_image466
 I-180
Figure 03_image734
 I-47
Figure 03_image468
 I-181
Figure 03_image736
 I-48
Figure 03_image470
 I-182
Figure 03_image967
 I-49
Figure 03_image472
 I-183
Figure 03_image740
 I-50
Figure 03_image474
 I-184
Figure 03_image742
 I-51
Figure 03_image476
 I-185
Figure 03_image744
 I-52
Figure 03_image478
 I-186
Figure 03_image746
 I-53
Figure 03_image480
 I-187
Figure 03_image748
 I-54
Figure 03_image482
 I-188
Figure 03_image750
 I-55
Figure 03_image484
 I-189
Figure 03_image752
 I-56
Figure 03_image486
 I-190
Figure 03_image754
 I-57
Figure 03_image488
 I-191
Figure 03_image756
 I-58
Figure 03_image490
 I-192
Figure 03_image758
 I-59
Figure 03_image492
 I-193
Figure 03_image760
 I-60
Figure 03_image494
 I-194
Figure 03_image762
 I-61
Figure 03_image496
 I-195
Figure 03_image764
 I-62
Figure 03_image498
 I-196
Figure 03_image766
 I-63
Figure 03_image500
 I-197
Figure 03_image768
 I-64
Figure 03_image502
 I-198
Figure 03_image770
 I-65
Figure 03_image504
 I-199
Figure 03_image772
 I-66
Figure 03_image506
 I-200
Figure 03_image774
 I-67
Figure 03_image508
 I-201
Figure 03_image776
 I-68
Figure 03_image510
 I-202
Figure 03_image778
 I-69
Figure 03_image512
 I-203
Figure 03_image780
 I-70
Figure 03_image514
 I-204
Figure 03_image782
 I-71
Figure 03_image516
 I-205
Figure 03_image784
 I-72
Figure 03_image518
 I-206
Figure 03_image786
 I-73
Figure 03_image520
 I-207
Figure 03_image788
 I-74
Figure 03_image522
 I-208
Figure 03_image790
 I-75
Figure 03_image524
 I-209
Figure 03_image792
 I-76
Figure 03_image526
 I-210
Figure 03_image794
 I-77
Figure 03_image528
 I-211
Figure 03_image796
 I-78
Figure 03_image530
 I-212
Figure 03_image798
 I-79
Figure 03_image532
 I-213
Figure 03_image800
 I-80
Figure 03_image534
 I-214
Figure 03_image802
 I-81
Figure 03_image536
 I-215
Figure 03_image804
 I-82
Figure 03_image538
 I-216
Figure 03_image806
 I-83
Figure 03_image540
 I-217
Figure 03_image808
 I-84
Figure 03_image542
 I-218
Figure 03_image810
 I-85
Figure 03_image544
 I-219
Figure 03_image812
 I-86
Figure 03_image546
 II-1
Figure 03_image868
 I-87
Figure 03_image548
 II-2
Figure 03_image870
 I-88
Figure 03_image550
 II-3
Figure 03_image872
 I-89
Figure 03_image552
 II-4
Figure 03_image874
 I-90
Figure 03_image554
 II-5
Figure 03_image876
 I-91
Figure 03_image556
 II-6
Figure 03_image878
 I-92
Figure 03_image558
 II-7
Figure 03_image880
 I-93
Figure 03_image560
 II-8
Figure 03_image882
 I-94
Figure 03_image562
 II-9
Figure 03_image884
 I-95
Figure 03_image564
 II-10
Figure 03_image886
 I-96
Figure 03_image566
 II-11
Figure 03_image888
 I-97
Figure 03_image568
 II-12
Figure 03_image890
 I-98
Figure 03_image570
 II-13
Figure 03_image892
 I-99
Figure 03_image572
 II-14
Figure 03_image894
 I-100
Figure 03_image574
 II-15
Figure 03_image896
 I-101
Figure 03_image576
 II-16
Figure 03_image898
 I-102
Figure 03_image578
 II-17
Figure 03_image900
 I-103
Figure 03_image580
 II-18
Figure 03_image902
 I-104
Figure 03_image582
 II-19
Figure 03_image904
 I-105
Figure 03_image584
 II-20
Figure 03_image906
 I-106
Figure 03_image586
 II-21
Figure 03_image908
 I-107
Figure 03_image588
 II-22
Figure 03_image910
 I-108
Figure 03_image590
 II-23
Figure 03_image912
 I-109
Figure 03_image592
 II-24
Figure 03_image914
 I-110
Figure 03_image594
 III-1
Figure 03_image918
 I-111
Figure 03_image596
 III-2
Figure 03_image920
 I-112
Figure 03_image598
 III-3
Figure 03_image922
 I-113
Figure 03_image600
 III-4
Figure 03_image924
 I-114
Figure 03_image602
 III-5
Figure 03_image926
 I-115
Figure 03_image604
 III-6
Figure 03_image928
 I-116
Figure 03_image606
 III-7
Figure 03_image930
 I-117
Figure 03_image608
 III-8
Figure 03_image932
 I-118
Figure 03_image610
 III-9
Figure 03_image934
 I-119
Figure 03_image612
 III-10
Figure 03_image936
 I-120
Figure 03_image614
 III-11
Figure 03_image938
 I-121
Figure 03_image616
 III-12
Figure 03_image940
 I-122
Figure 03_image618
 III-13
Figure 03_image942
 I-123
Figure 03_image620
 III-14
Figure 03_image944
 I-124
Figure 03_image622
 III-15
Figure 03_image946
 I-125
Figure 03_image624
 III-16
Figure 03_image948
 I-126
Figure 03_image626
 III-17
Figure 03_image950
 I-127
Figure 03_image628
 III-18
Figure 03_image952
 I-128
Figure 03_image630
 III-19
Figure 03_image954
 I-129
Figure 03_image632
 III-20
Figure 03_image956
 I-130
Figure 03_image634
 III-21
Figure 03_image958
 I-131
Figure 03_image636
 III-22
Figure 03_image960
 I-132
Figure 03_image638
 III-23
Figure 03_image962
 I-133
Figure 03_image640
 III-24
Figure 03_image964
 I-134
Figure 03_image642
 I-220
Figure 03_image814
 I-221
Figure 03_image816
 I-225
Figure 03_image824
 I-222
Figure 03_image818
 I-226
Figure 03_image826
 I-223
Figure 03_image820
 I-227
Figure 03_image828
 I-224
Figure 03_image822
 I-228
Figure 03_image830
 I-229
Figure 03_image832
 I-238
Figure 03_image850
 I-230
Figure 03_image834
 I-239
Figure 03_image852
 I-231
Figure 03_image836
 I-240
Figure 03_image854
 I-232
Figure 03_image838
 I-241
Figure 03_image856
 I-233
Figure 03_image840
 I-242
Figure 03_image858
 I-234
Figure 03_image842
 I-243
Figure 03_image860
 I-235
Figure 03_image844
 I-244
Figure 03_image862
 I-236
Figure 03_image846
 I-245
Figure 03_image864
 I-237
Figure 03_image848
      
或上述化合物的立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物。 The compound as described in any one of claim 1 to claim 4, selected from the following: serial number structure serial number structure I-1
Figure 03_image376
 I-135
Figure 03_image644
 I-2
Figure 03_image378
 I-136
Figure 03_image646
 I-3
Figure 03_image380
 I-137
Figure 03_image648
 I-4
Figure 03_image382
 I-138
Figure 03_image650
 I-5
Figure 03_image384
 I-139
Figure 03_image652
 I-6
Figure 03_image386
 I-140
Figure 03_image654
 I-7
Figure 03_image388
 I-141
Figure 03_image656
 I-8
Figure 03_image390
 I-142
Figure 03_image658
 I-9
Figure 03_image392
 I-143
Figure 03_image660
 I-10
Figure 03_image394
 I-144
Figure 03_image662
 I-11
Figure 03_image396
 I-145
Figure 03_image664
 I-12
Figure 03_image398
 I-146
Figure 03_image666
 I-13
Figure 03_image400
 I-147
Figure 03_image668
 I-14
Figure 03_image402
 I-148
Figure 03_image670
 I-15
Figure 03_image404
 I-149
Figure 03_image672
 I-16
Figure 03_image406
 I-150
Figure 03_image674
 I-17
Figure 03_image408
 I-151
Figure 03_image676
 I-18
Figure 03_image410
 I-152
Figure 03_image678
 I-19
Figure 03_image412
 I-153
Figure 03_image680
 I-20
Figure 03_image414
 I-154
Figure 03_image682
 I-21
Figure 03_image416
 I-155
Figure 03_image684
 I-22
Figure 03_image418
 I-156
Figure 03_image686
 I-23
Figure 03_image420
 I-157
Figure 03_image688
 I-24
Figure 03_image422
 I-158
Figure 03_image690
 I-25
Figure 03_image424
 I-159
Figure 03_image692
 I-26
Figure 03_image426
 I-160
Figure 03_image694
 I-27
Figure 03_image428
 I-161
Figure 03_image696
 I-28
Figure 03_image430
 I-162
Figure 03_image698
 I-29
Figure 03_image432
 I-163
Figure 03_image700
 I-30
Figure 03_image434
 I-164
Figure 03_image702
 I-31
Figure 03_image436
 I-165
Figure 03_image704
 I-32
Figure 03_image438
 I-166
Figure 03_image706
 I-33
Figure 03_image440
 I-167
Figure 03_image708
 I-34
Figure 03_image442
 I-168
Figure 03_image710
 I-35
Figure 03_image444
 I-169
Figure 03_image712
 I-36
Figure 03_image446
 I-170
Figure 03_image714
 I-37
Figure 03_image448
 I-171
Figure 03_image716
 I-38
Figure 03_image450
 I-172
Figure 03_image718
 I-39
Figure 03_image452
 I-173
Figure 03_image720
 I-40
Figure 03_image454
 I-174
Figure 03_image722
 I-41
Figure 03_image456
 I-175
Figure 03_image724
 I-42
Figure 03_image458
 I-176
Figure 03_image726
 I-43
Figure 03_image460
 I-177
Figure 03_image728
 I-44
Figure 03_image462
 I-178
Figure 03_image730
 I-45
Figure 03_image464
 I-179
Figure 03_image732
 I-46
Figure 03_image466
 I-180
Figure 03_image734
 I-47
Figure 03_image468
 I-181
Figure 03_image736
 I-48
Figure 03_image470
 I-182
Figure 03_image967
 I-49
Figure 03_image472
 I-183
Figure 03_image740
 I-50
Figure 03_image474
 I-184
Figure 03_image742
 I-51
Figure 03_image476
 I-185
Figure 03_image744
 I-52
Figure 03_image478
 I-186
Figure 03_image746
 I-53
Figure 03_image480
 I-187
Figure 03_image748
 I-54
Figure 03_image482
 I-188
Figure 03_image750
 I-55
Figure 03_image484
 I-189
Figure 03_image752
 I-56
Figure 03_image486
 I-190
Figure 03_image754
 I-57
Figure 03_image488
 I-191
Figure 03_image756
 I-58
Figure 03_image490
 I-192
Figure 03_image758
 I-59
Figure 03_image492
 I-193
Figure 03_image760
 I-60
Figure 03_image494
 I-194
Figure 03_image762
 I-61
Figure 03_image496
 I-195
Figure 03_image764
 I-62
Figure 03_image498
 I-196
Figure 03_image766
 I-63
Figure 03_image500
 I-197
Figure 03_image768
 I-64
Figure 03_image502
 I-198
Figure 03_image770
 I-65
Figure 03_image504
 I-199
Figure 03_image772
 I-66
Figure 03_image506
 I-200
Figure 03_image774
 I-67
Figure 03_image508
 I-201
Figure 03_image776
 I-68
Figure 03_image510
 I-202
Figure 03_image778
 I-69
Figure 03_image512
 I-203
Figure 03_image780
 I-70
Figure 03_image514
 I-204
Figure 03_image782
 I-71
Figure 03_image516
 I-205
Figure 03_image784
 I-72
Figure 03_image518
 I-206
Figure 03_image786
 I-73
Figure 03_image520
 I-207
Figure 03_image788
 I-74
Figure 03_image522
 I-208
Figure 03_image790
 I-75
Figure 03_image524
 I-209
Figure 03_image792
 I-76
Figure 03_image526
 I-210
Figure 03_image794
 I-77
Figure 03_image528
 I-211
Figure 03_image796
 I-78
Figure 03_image530
 I-212
Figure 03_image798
 I-79
Figure 03_image532
 I-213
Figure 03_image800
 I-80
Figure 03_image534
 I-214
Figure 03_image802
 I-81
Figure 03_image536
 I-215
Figure 03_image804
 I-82
Figure 03_image538
 I-216
Figure 03_image806
 I-83
Figure 03_image540
 I-217
Figure 03_image808
 I-84
Figure 03_image542
 I-218
Figure 03_image810
 I-85
Figure 03_image544
 I-219
Figure 03_image812
 I-86
Figure 03_image546
 II-1
Figure 03_image868
 I-87
Figure 03_image548
 II-2
Figure 03_image870
 I-88
Figure 03_image550
 II-3
Figure 03_image872
 I-89
Figure 03_image552
 II-4
Figure 03_image874
 I-90
Figure 03_image554
 II-5
Figure 03_image876
 I-91
Figure 03_image556
 II-6
Figure 03_image878
 I-92
Figure 03_image558
 II-7
Figure 03_image880
 I-93
Figure 03_image560
 II-8
Figure 03_image882
 I-94
Figure 03_image562
 II-9
Figure 03_image884
 I-95
Figure 03_image564
 II-10
Figure 03_image886
 I-96
Figure 03_image566
 II-11
Figure 03_image888
 I-97
Figure 03_image568
 II-12
Figure 03_image890
 I-98
Figure 03_image570
 II-13
Figure 03_image892
 I-99
Figure 03_image572
 II-14
Figure 03_image894
 I-100
Figure 03_image574
 II-15
Figure 03_image896
 I-101
Figure 03_image576
 II-16
Figure 03_image898
 I-102
Figure 03_image578
 II-17
Figure 03_image900
 I-103
Figure 03_image580
 II-18
Figure 03_image902
 I-104
Figure 03_image582
 II-19
Figure 03_image904
 I-105
Figure 03_image584
 II-20
Figure 03_image906
 I-106
Figure 03_image586
 II-21
Figure 03_image908
 I-107
Figure 03_image588
 II-22
Figure 03_image910
 I-108
Figure 03_image590
 II-23
Figure 03_image912
 I-109
Figure 03_image592
 II-24
Figure 03_image914
 I-110
Figure 03_image594
 III-1
Figure 03_image918
 I-111
Figure 03_image596
 III-2
Figure 03_image920
 I-112
Figure 03_image598
 III-3
Figure 03_image922
 I-113
Figure 03_image600
 III-4
Figure 03_image924
 I-114
Figure 03_image602
 III-5
Figure 03_image926
 I-115
Figure 03_image604
 III-6
Figure 03_image928
 I-116
Figure 03_image606
 III-7
Figure 03_image930
 I-117
Figure 03_image608
 III-8
Figure 03_image932
 I-118
Figure 03_image610
 III-9
Figure 03_image934
 I-119
Figure 03_image612
 III-10
Figure 03_image936
 I-120
Figure 03_image614
 III-11
Figure 03_image938
 I-121
Figure 03_image616
 III-12
Figure 03_image940
 I-122
Figure 03_image618
 III-13
Figure 03_image942
 I-123
Figure 03_image620
 III-14
Figure 03_image944
 I-124
Figure 03_image622
 III-15
Figure 03_image946
 I-125
Figure 03_image624
 III-16
Figure 03_image948
 I-126
Figure 03_image626
 III-17
Figure 03_image950
 I-127
Figure 03_image628
 III-18
Figure 03_image952
 I-128
Figure 03_image630
 III-19
Figure 03_image954
 I-129
Figure 03_image632
 III-20
Figure 03_image956
 I-130
Figure 03_image634
 III-21
Figure 03_image958
 I-131
Figure 03_image636
 III-22
Figure 03_image960
 I-132
Figure 03_image638
 III-23
Figure 03_image962
 I-133
Figure 03_image640
 III-24
Figure 03_image964
 I-134
Figure 03_image642
 I-220
Figure 03_image814
 I-221
Figure 03_image816
 I-225
Figure 03_image824
 I-222
Figure 03_image818
 I-226
Figure 03_image826
 I-223
Figure 03_image820
 I-227
Figure 03_image828
 I-224
Figure 03_image822
 I-228
Figure 03_image830
 I-229
Figure 03_image832
 I-238
Figure 03_image850
 I-230
Figure 03_image834
 I-239
Figure 03_image852
 I-231
Figure 03_image836
 I-240
Figure 03_image854
 I-232
Figure 03_image838
 I-241
Figure 03_image856
 I-233
Figure 03_image840
 I-242
Figure 03_image858
 I-234
Figure 03_image842
 I-243
Figure 03_image860
 I-235
Figure 03_image844
 I-244
Figure 03_image862
 I-236
Figure 03_image846
 I-245
Figure 03_image864
 I-237
Figure 03_image848
Or a stereoisomer of the above compound, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate. 一種製備請求項1至請求項5中任一項所述的化合物的方法，包括下面步驟：
Figure 03_image220
反應條件： （a）酸性或鹼性條件下的親核取代反應； （b）金屬鈀催化的偶聯反應，或者酸性條件下的親核取代反應，或者鹼性條件下的親核取代反應； （c）金屬鈀催化的偶聯反應，或者金屬銅催化的偶聯反應； 其中： 該金屬鈀催化劑選自醋酸鈀、四(三苯基膦)鈀、雙三苯基磷二氯化鈀、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀、三(二亞苄基丙酮)二鈀； 該鹼性條件指以下任意物質存在的條件：三乙胺、二異丙基乙基胺、吡啶、碳酸氫鈉、碳酸鈉、碳酸鉀、碳酸銫、氫氧化鋰、氫氧化鈉、氫氧化鉀、氫化鈉、氫化鉀； 該酸性條件指以下任意物質存在的條件：乙酸、三氟乙酸、鹽酸、甲磺酸、對甲苯磺酸、樟腦磺酸； X代表鹵素，R 3-Y代表與R 3對應的硼酸（即
Figure 03_image222
）、硼酸酯（即
Figure 03_image224
）、錫試劑（如正三丁基錫試劑即
Figure 03_image226
）或者炔試劑（如三甲基矽基乙炔即
Figure 03_image228
）； R 1、R 2、R 3和R 4如請求項1至請求項4中任一項所限定。 A method for preparing the compound described in any one of Claim 1 to Claim 5, comprising the following steps:
Figure 03_image220
Reaction conditions: (a) Nucleophilic substitution reaction under acidic or basic conditions; (b) Coupling reaction catalyzed by metal palladium, or nucleophilic substitution reaction under acidic conditions, or nucleophilic substitution reaction under basic conditions; (c) a coupling reaction catalyzed by metal palladium, or a coupling reaction catalyzed by metal copper; wherein: the metal palladium catalyst is selected from palladium acetate, tetrakis (triphenylphosphine) palladium, bistriphenylphosphine palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium; the basic conditions refer to the conditions under which any of the following substances exist: triethylamine, di Isopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride; the acidic conditions refer to the conditions in which any of the following substances exist : acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid; X represents halogen, R 3 -Y represents boric acid corresponding to R 3 (ie
Figure 03_image222
), borates (ie
Figure 03_image224
), tin reagent (such as n-tributyltin reagent that is
Figure 03_image226
) or alkyne reagents (such as trimethylsilylacetylene ie
Figure 03_image228
); R 1 , R 2 , R 3 and R 4 are as defined in any one of claim 1 to claim 4. 一種藥物組合物，其包含請求項1至請求項5中任一項所述的化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物以及任選的藥學上可以接受的賦形劑； 較佳地，該藥物組合物進一步包含EGFR單抗； 較佳地，該EGFR單抗為西妥昔單抗或其生物類似物。 A pharmaceutical composition comprising the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate according to any one of Claim 1 to Claim 5 and optional pharmaceutically acceptable excipients; Preferably, the pharmaceutical composition further comprises EGFR monoclonal antibody; Preferably, the EGFR monoclonal antibody is cetuximab or its biosimilar. 如請求項1至請求項5中任一項所述的化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物或者請求項7所述的藥物組合物在製備用於預防和/或治療EGFR激酶介導的癌症及其他疾病的藥物中的用途，尤其是在製備用於預防和/或治療肺癌（較佳非小細胞肺癌）的藥物中的用途，特別是在製備用於預防和/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌（較佳非小細胞肺癌）的藥物中的用途，最佳在製備用於預防和/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌（較佳非小細胞肺癌）的藥物中的用途。The compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or claim item 7 described in any one of Claim 1 to Claim 5 Use of the pharmaceutical composition in the preparation of medicines for preventing and/or treating EGFR kinase-mediated cancer and other diseases, especially in the preparation of medicines for preventing and/or treating lung cancer (preferably non-small cell lung cancer) The purposes in, especially in the preparation of the medicine for the prevention and/or treatment of EGFR kinase 19Del, L858R, T790M, C797S or its combination mutation type lung cancer (preferably non-small cell lung cancer), the best in the preparation of Prevention and/or treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer ) for use in medicine. 一種預防和/治療EGFR激酶介導的癌症及其他疾病的方法，其包括給予有需要的受試者預防和/或治療有效量的請求項1至請求項5中任一項的化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物或者請求項7所述的藥物組合物； 較佳地，該方法用於預防和/或治療肺癌（較佳非小細胞肺癌）； 更佳地，該方法用於預防和/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌（較佳非小細胞肺癌）； 最佳地，該方法用於預防和/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌（較佳非小細胞肺癌）。 A method for preventing and/treating EGFR kinase-mediated cancer and other diseases, comprising administering to a subject in need a preventive and/or therapeutically effective amount of the compound of any one of claims 1 to 5 or its stereo The isomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or the pharmaceutical composition described in Claim 7; Preferably, the method is used to prevent and/or treat lung cancer (preferably non-small cell lung cancer); More preferably, the method is used to prevent and/or treat EGFR kinase 19Del, L858R, T790M, C797S or their combination mutant lung cancer (preferably non-small cell lung cancer); Optimally, the method is used to prevent and/or treat EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S triple mutation Lung cancer (preferably non-small cell lung cancer). 如請求項1至請求項5中任一項的化合物或其立體異構體、其前藥、其藥學上可接受的鹽或其藥學上可接受的溶劑合物或者請求項7所述的藥物組合物，其用於預防和/或治療EGFR激酶介導的癌症及其他疾病，較佳用於預防和/或治療肺癌（較佳非小細胞肺癌），更佳用於預防和/或治療EGFR激酶19Del、L858R、T790M、C797S或其組合突變型肺癌（較佳非小細胞肺癌），最佳用於預防和/或治療EGFR激酶19Del單突變、L858R單突變、19Del/T790M雙突變、L858R/T790M雙突變、19Del/T790M/C797S三突變或L858R/T790M/C797S三突變肺癌（較佳非小細胞肺癌）。The compound according to any one of claims 1 to 5 or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, or the drug described in claim 7 Composition for preventing and/or treating cancer and other diseases mediated by EGFR kinase, preferably for preventing and/or treating lung cancer (preferably non-small cell lung cancer), more preferably for preventing and/or treating EGFR Kinase 19Del, L858R, T790M, C797S or their combination mutation lung cancer (preferably non-small cell lung cancer), best used for the prevention and/or treatment of EGFR kinase 19Del single mutation, L858R single mutation, 19Del/T790M double mutation, L858R/ T790M double mutation, 19Del/T790M/C797S triple mutation or L858R/T790M/C797S triple mutation lung cancer (preferably non-small cell lung cancer).
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